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Geriatric Neurology edited by

anil k. nair | marwan n. sabbagh

Geriatric Neurology

I dedicate this book to my patients and mentors. This book would not be possible without my grandfather who carried me on his shoulders daily to an elementary school miles away and my very supportive family. AKN I dedicate this work to my mother and father, who nurtured my unquenchable thirst for knowledge. MNS

Geriatric Neurology EDI T ED BY

ANIL K. NA IR

MD

Director, Clinic for Cognitive Disorders and Alzheimer’s Disease Center Chief of Neurology, Quincy Medical Center Quincy, MA, USA

MARWAN N. SABBAGH Director, Banner Sun Health Research Institute Research Professor of Neurology University of Arizona College of Medicine – Phoenix Sun City, AZ, USA

MD, FAAN

This edition first published 2014 © 2014 by John Wiley & Sons, Ltd Registered office: John Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www .wiley.com/wiley-blackwell The right of the author to be identified as the author of this work has been asserted in accordance with the UK Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by health science practitioners for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Geriatric neurology (Nair) Geriatric neurology/edited by Anil K. Nair and Marwan N. Sabbagh. 1 online resource. Includes bibliographical references and index. Description based on print version record and CIP data provided by publisher; resource not viewed. ISBN 978-1-118-73064-5 (ePub) – ISBN 978-1-118-73065-2 (Adobe PDF) – ISBN 978-1-118-73068-3 (cloth) I. Nair, Anil (Anil Kadoor), 1970- editor of compilation. II. Sabbagh, Marwan Noel, editor of compilation. III. Title. [DNLM: 1. Nervous System Diseases. 2. Aged. 3. Aging–physiology. 4. Nervous System Physiological Phenomena. WL 140] RC451.4.A5 618.97’68–dc23 2013038615 A catalogue record for this book is available from the British Library. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Cover images: top row - copyright Wiley; bottom - courtesy of Anil K. Nair Cover design by Andy Meaden Set in 9.25/12 pt Palatino by Aptara Inc., New Delhi, India

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2014

Contents

About the Editors, vii List of Contributors, viii Preface, xii Acknowledgments, xiii

Part 1 The Aging Brain in Neurology, 1 1 The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century, 3 Douglas F. Watt 2 Functional Changes Associated with the Aging Nervous System, 38 Julie A. Schneider and Chunhui Yang

Part 2 Assessment of the Geriatric Neurology Patient, 69 3 Approach to the Geriatric Neurology Patient: The Neurologic Examination, 71 Marwan N. Sabbagh and Anil K. Nair 4 Assessment of Cognitive Status in Geriatric Neurology, 85 4.1 Mental Status Examination in the Geriatric Neurology Patient, 87 Papan Thaipisuttikul and James E. Galvin 4.2 Neuropsychology in Geriatric Neurology, 98 Donald J. Connor and Marc A. Norman 5 Cognitive Reserve and the Aging Brain, 118 Adrienne M. Tucker and Yaakov Stern 6 Gait Disorders in the Graying Population, 126 Joe Verghese and Jessica Zwerling 7 Imaging of the Geriatric Brain, 136 7.1 Structural Neuroimaging in Degenerative Dementias, 138 Liana G. Apostolova

7.2 Functional Imaging in Dementia, 146 Adam S. Fleisher and Alexander Drzezga 7.3 Amyloid Imaging, 162 Anil K. Nair and Marwan N. Sabbagh 8 Clinical Laboratory Investigations in Geriatric Neurology, 170 Geoffrey S. Baird and Thomas J. Montine

Part 3 Neurologic Conditions in the Elderly, 181 9 Cognitive Impairment and the Dementias, 183 9.1 Mild Cognitive Impairment, 187 Ranjan Duara, Miriam Jocelyn Rodriguez, and David A. Loewenstein 9.2 Alzheimer’s Disease, 200 Martin R. Farlow 9.3 Dementia with Lewy Bodies, 208 Clive Ballard 9.4 Vascular Cognitive Impairment, 224 Helena C. Chui and Freddi Segal-Gidan 9.5 Frontotemporal Dementia, 239 David Perry and Howard Rosen 9.6 Primary Progressive Aphasia, 251 Maya L. Henry, Stephen M. Wilson, and Steven Z. Rapcsak 9.7 Prion Diseases, 267 Michael D. Geschwind and Katherine Wong 9.8 Normal Pressure Hydrocephalus, 281 Norman R. Relkin 10 Depression in the Elderly: Interactions with Aging, Stress, Chronic Pain, Inflammation, and Neurodegenerative Disorders, 287 Douglas F. Watt 11 Cerebrovascular Diseases in Geriatrics, 302 Patrick Lyden, Khalil Amir and Ilana Tidus

v

vi

Contents

12 Movement Disorders, 313 12.1 Parkinson’s Disease, 315 Robert Fekete and Joseph Jankovic 12.2 Essential Tremor and Other Tremor Disorders, 325 Holly Shill 12.3 Progressive Supranuclear Palsy, 333 Virgilio Gerald H. Evidente 12.4 Corticobasal Degeneration, 344 Katrina Gwinn 13 Sleep Disorders, 347 Sanford Auerbach 14 Autonomic Dysfunction and Syncope, 358 Rohit R. Das 15 Geriatric Epilepsy, 370 David V. Lardizabal 16 Vertigo and Dizziness in the Elderly, 379 Terry D. Fife and Salih Demirhan 17 Disorders of the Special Senses in the Elderly, 396 Douglas J. Lanska 18 Nervous System Infections, 460 Ronald Ellis, David Croteau, and Suzi Hong

23.1 Evidence-Based Pharmacologic Treatment of Dementia, 557 Jasmeet Singh, Marwan N. Sabbagh, and Anil K. Nair 23.2 Immunotherapy for Alzheimer’s Disease, 574 Michael Grundman, Gene G. Kinney, Eric Yuen, and Ronald Black 24 Geriatric Psychopharmacology, 586 Sandra A. Jacobson 25 Nonpharmacologic Treatment of Behavioral Problems in Persons with Dementia, 615 Gary A. Martin and John Ranseen 26 Expressive Art Therapies in Geriatric Neurology, 630 Daniel C. Potts, Bruce L. Miller, Carol A. Prickett, Andrea M. Cevasco, and Angel C. Duncan

Part 5 Important Management Issues Beyond Therapeutics in the Geriatric Neurology Patient, 645 27 Dietary Factors in Geriatric Neurology, 647 Yian Gu and Nikolaos Scarmeas

20 Headache in the Elderly, 486 Brian McGeeney

28 Exercising the Brain: Nonpharmacologic Interventions for Cognitive Decline Associated with Aging and Dementia, 669 Brenna A. Cholerton, Jeannine Skinner, and Laura D. Baker

21 Neuromuscular Disorders, 494 Heber Varela and Clifton Gooch

29 Driving Impairment in Older Adults, 682 Anne D. Halli-Tierney and Brian R. Ott

19 Delirium, 478 Alan Lerner, Stefani Parrisbalogun, and Joseph Locala

Part 4 Therapeutics for the Geriatric Neurology Patient, 519

30 Elder Abuse and Mistreatment, 699 Elliott Schulman, Ashley Roque, and Anna Hohler 31 Advocacy in Geriatric Neurology, 707 Glenn Finney and Anil K. Nair

22 Neurosurgical Care of the Geriatric Patient, 521 David Fusco, Rasha Germain, and Peter Nakaji 23 Treatment of Dementia, 556

Color plate section appears between pages 50 and 51

Index, 713

About the Editors

Anil K. Nair, MD, is the director of TheAlzCenter.org and chief of neurology at Quincy Medical Center. He is also the site director for clinical trials in neurology. He completed his fellowship from Mayo Clinic, Rochester, MN, and his neurology residency at the Cleveland Clinic and Temple University after graduation from JIPMER, Pondicherry, India. His interest area is early and preclinical detection, prevention, and treatment of Alzheimer’s dementia, and other neurocognitive disorders and dementias. Dr. Nair oversees the clinical and research facility called TheAlzCenter.org (The Alzheimer’s Center) serving the south shore of Boston. The center aims to advance the field of geriatric neurology and reduce the costs of debilitating diseases such as Alzheimer’s disease and other related dementias. In addition to providing preventive, diagnostic, and therapeutic services to patients with neurodegenerative and related diseases, Dr. Nair runs clinical trials in multiple indications, primarily in Alzheimer’s disease. He is dedicated to providing healthcare and referral services of the highest quality and is committed to building partnerships that increase the independence and quality of life for patients with dementia. Dr. Nair is also an investigator for the stroke and memory project at the Framingham Heart Study, which aims to identify the risk factors involved in such diseases as Alzheimer’s disease and related dementias.

Marwan N. Sabbagh, MD, FAAN, is a board-certified neurologist and geriatric neurologist. As the director of the Banner Sun Health Research Institute, Dr. Sabbagh has dedicated his entire career to finding a cure for Alzheimer’s and other age-related neurodegenerative diseases. Dr. Sabbagh is a leading investigator for many prominent national Alzheimer’s prevention and treatment trials. He is senior editor for Journal of Alzheimer’s Disease, BMC Neurology, and Clinical Neurology News, and has authored and coauthored more than 200 medical and scientific chapters, reviews, original research articles, and abstracts on Alzheimer’s research. Dr. Sabbagh has also authored The Alzheimer’s Answer—the book’s foreword was written by Justice Sandra Day O’Connor—and edited Palliative Care for Advanced Alzheimer’s and Dementia: Guidelines and Standards for Evidence Based Care and coauthored The Alzheimer's Prevention Cookbook: Recipes to Boost Brain Health (RandomHouse/TenSpeed, 2012). Dr. Sabbagh is research professor in the Department of Neurology, University of Arizona College of Medicine– Phoenix. He is also an adjunct professor at Midwestern University and Arizona State University. He earned his undergraduate degree from the University of California Berkeley and his medical degree from the University of Arizona in Tucson. He received his internship at the Banner Good Samaritan Regional Medical Center in Phoenix, AZ, and his residency training in neurology at Baylor College of Medicine in Houston, TX. He completed his fellowship in geriatric neurology and dementia at the UCSD School of Medicine.

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List of Contributors

Khalil Amir

Helena C. Chui

MD

Department of Neurology Cedars-Sinai Medical Centre Los Angeles, CA, USA

MD

Department of Neurology Keck School of Medicine University of Southern California Los Angeles, CA, USA

Liana G. Apostolova

MD, MS

Department of Neurology David Geffen School of Medicine University of California Los Angeles, CA, USA

Donald J. Connor

Sanford Auerbach

David Croteau

MD

PhD, PhD

Independent Practice Consultant in Clinical Trials San Diego, CA, USA MD

Departments of Neurology Psychiatry and Behavioral Neurosciences Boston University School of Medicine Boston, MA, USA

Department of Neurosciences and HIV Neurobehavioral Research Center University of California San Diego, CA, USA

Geoffrey S. Baird

Rohit R. Das

MD

Departments of Laboratory Medicine and Pathology University of Washington Seattle, WA, USA

MD, MPH

Indiana University School of Medicine Indianapolis, IN, USA

Salih Demirhan Laura D. Baker

PhD

Department of Medicine - Geriatrics Wake Forest School of Medicine Winston-Salem, NC, USA

Clive Ballard

MBChB MMedSci MRCPsych MD

Wolfson Centre for Age-Related Diseases King’s College London London, UK

Ronald Black

MD

Chief Medical Officer Probiodrug AG Halle, Germany

Andrea M. Cevasco

PhD, MT-BC

School of Music College of Arts and Sciences University of Alabama Tuscaloosa, AL, USA

Brenna A. Cholerton

Alexander Drzezga

PhD

MD

Department of Nuclear Medicine University Hospital of Cologne Cologne, Germany

Ranjan Duara

MD, FAAN

Wien Center for Alzheimer's Disease and Memory Disorders Mount Sinai Medical Center Miami Beach; Department of Neurology Herbert Wertheim College of Medicine Florida International University, Miami and University of Florida College of Medicine University of Florida Gainesville, FL, USA

Angel C. Duncan

Department of Psychiatry and Behavioral Science University of Washington School of Medicine and Geriatric Research, Education, and Clinical Center Veterans Affairs Puget Sound Health Care System Seattle, WA, USA

viii

MD

Marmara University School of Medicine Istanbul, Turkey

MA-MFT, ATR

Cognitive Dynamics Foundation Neuropsychiatric Research Center of Southwest Florida Albertus Magnus College American Art Therapy Association Fort Myers, FL, USA

List of Contributors

Ronald Ellis

Clifton Gooch

MD, PhD

Department of Neurosciences and HIV Neurobehavioral Research Center University of California San Diego, CA, USA

MD, FAAN

Department of Neurology University of South Florida College of Medicine Tampa, FL, USA

Michael Grundman Virgilio Gerald H. Evidente

MD

Movement Disorders Center of Arizona Ironwood Square Drive Scottsdale, AZ, USA

Martin R. Farlow

Yian Gu

PhD

Taub Institute for Research on Alzheimer’s Disease and the Aging Brain Columbia University Medical Center New York, NY, USA

MD

Department of Neurology Indiana University Indianapolis, IN, USA

Katrina Gwinn Robert Fekete

MD, MPH

President, Global R&D Partners, LLC San Diego, CA, USA

MD

National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda, MD, USA

MD

Department of Neurology New York Medical College Valhalla, NY, USA

Anne D. Halli-Tierney Terry D. Fife

MD, FAAN

Barrow Neurological Institute and Department of Neurology University of Arizona College of Medicine Phoenix, AZ, USA

Glenn Finney

Maya L. Henry

PhD

Department of Communication Sciences and Disorders University of Texas at Austin and Memory and Aging Center Department of Neurology University of California San Francisco, CA, USA

MD

Department of Neurology McKnight Brain Institute Gainesville, FL, USA

Adam S. Fleisher

MD

Warren Alpert Medical School of Brown University Rhode Island Hospital Providence, RI, USA

MD, MAS

Banner Alzheimer's Institute Department of Neurosciences University of California San Diego, CA, USA

Anna Hohler

David Fusco

Suzi Hong

MD

Department of Neurology Boston University School of Medicine Boston, MA, USA

MD

PhD

Division of Neurological Surgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, AZ, USA

Department of Psychiatry School of Medicine University of California San Diego, CA, USA

James E. Galvin

Sandra A. Jacobson

MD, MPH

MD

Department of Neurology and Department of Psychiatry New York University Langone Medical Center New York, NY, USA

University of Arizona College of Medicine-Phoenix Banner Sun Health Research Institute and Cleo Roberts Center for Clinical Research Sun City, AZ, USA

Rasha Germain

Joseph Jankovic

MD

Division of Neurological Surgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, AZ, USA

Michael D. Geschwind Memory and Aging Center Department of Neurology University of California San Francisco, CA, USA

MD

Parkinson’s Disease Center and Movement Disorders Clinic Department of Neurology Baylor College of Medicine Houston, TX, USA

MD, PhD

Gene G. Kinney

PhD

Chief Scientific Officer Prothena Biosciences, Inc. South San Francisco, CA, USA

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x

List of Contributors

Douglas J. Lanska

MD, MS, MSPH, FAAN

Neurology Service Veterans Affairs Medical Center Great Lakes Health Care System Tomah, WI, USA

Marc A. Norman

Brian R. Ott David V. Lardizabal

PhD, ABPP

Department of Psychiatry University of California San Diego, CA, USA MD

Epilepsy Program and Intraoperative Monitoring University of Missouri Columbia, MO, USA

Warren Alpert Medical School of Brown University and The Alzheimer’s Disease and Memory Disorders Center Rhode Island Hospital Providence, RI, USA

Alan Lerner

Stefani Parrisbalogun

MD

MD

Department of Neurology Case Western Reserve University School of Medicine Cleveland, OH, USA

David Perry Joseph Locala

MD

Department of Psychiatry Case Western Reserve University School of Medicine Cleveland, OH, USA

David A. Loewenstein

Gary A. Martin

MD

Cognitive Dynamics Foundation Veterans Affairs Medical Center The University of Alabama Tuscaloosa, AL, USA

Carol A. Prickett

PhD

Brian McGeeney

MD

Department of Neurology Boston University School of Medicine Boston, MA, USA

Bruce L. Miller

John Ranseen

PhD

Department of Psychiatry University of Kentucky College of Medicine Lexington, KY, USA

Steven Z. Rapcsak

MD

Department of Neurology University of Arizona Neurology Section Southern Arizona VA Health Care System Tucson, AZ, USA

MD

Memory and Aging Center University of California San Francisco, CA, USA

Thomas J. Montine

PhD, MT-BC

School of Music College of Arts and Sciences University of Alabama Tuscaloosa, AL, USA

Integrated Geriatric Behavioral Health Associates Scottsdale, AZ, USA

MD

Departments of Pathology and Neurological Surgery University of Washington Seattle, WA, USA MD

Clinic for Cognitive Disorders and Alzheimer’s Disease Center Quincy Medical Center Quincy, MA, USA

Peter Nakaji

Daniel C. Potts

MD

Department of Neurology Cedars-Sinai Medical Center Los Angeles, CA, USA

Anil K. Nair

MD

Memory and Aging Center Department of Neurology School of Medicine University of California San Francisco, USA

PhD, ABPP

Department of Psychiatry and Behavioral Sciences Miller School of Medicine University of Miami Miami, FL, USA

Patrick Lyden

MD

Rawson-Neal Psychiatric Hospital Las Vegas, NV, USA

MD

Division of Neurological Surgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, AZ, USA

Norman R. Relkin

MD, PhD

Memory Disorders Program Department of Neurology and Brain Mind Research Institute Weill Cornell Medical College New York, NY, USA

Miriam Joscelyn Rodriguez

PhD

Wien Center for Alzheimer's Disease and Memory Disorders Mount Sinai Medical Center Miami Beach, FL, USA

Ashley Roque

MD

Boston University School of Medicine Boston, MA, USA

List of Contributors

Howard Rosen

Papan Thaipisuttikul

MD

Memory and Aging Center Department of Neurology School of Medicine University of California San Francisco, CA, USA

Ilana Tidus

BSc

Banner Sun Health Research Institute Sun City, AZ, USA

Department of Neurology Cedars-Sinai Medical Centre Los Angeles, CA, USA

Nikolaos Scarmeas

Adrienne M. Tucker

Marwan N. Sabbagh

MD, FAAN

MD, MSc

Taub Institute, Sergievsky Center Department of Neurology Columbia University New York, NY, USA and Department of Social Medicine, Psychiatry and Neurology National and Kapodistrian University of Athens Athens, Greece

Julie A. Schneider

MD, MS

Rush Alzheimer’s Disease Center Department of Pathology and Department of Neurological Sciences Rush University Medical Center Chicago, IL, USA

Elliott Schulman

MD

Lankenau Institute for Medical Research Lankenau Medical Center Wynnewood, PA, USA PA, PhD

Department of Neurology Keck School of Medicine University of Southern California Los Angeles, CA, USA

Heber Varela

MD

Department of Neurology University of South Florida College of Medicine Tampa, FL, USA

Joe Verghese

MD

Department of Neurology and Medicine Albert Einstein College of Medicine Bronx, NY, USA

Douglas F. Watt

PhD

Department of Neuropsychology Cambridge City Hospital, Harvard Medical School and Alzheimer’s Disease Center/Clinic for Cognitive Disorders Quincy Medical Center Quincy, MA, USA

Banner Sun Health Research Institute Sun City, AZ, USA

Jasmeet Singh

MD, MPHA

Alzheimer’s Disease Center Quincy Medical Center Quincy, MA, USA

Jeannine Skinner

PhD

Department of Neurology Vanderbilt School of Medicine Nashville, TN

Yaakov Stern

PhD

Cognitive Neuroscience Division Department of Neurology Columbia University Medical Center New York, NY, USA

PhD

Department of Speech Language and Hearing Sciences University of Arizona Tucson, AZ, USA

Katherine Wong MD

PhD

Cognitive Science Center Amsterdam University of Amsterdam Amsterdam, The Netherlands

Stephen M. Wilson Freddi Segal-Gidan

Holly Shill

MD

Department of Neurology and Department of Psychiatry New York University Langone Medical Center New York, NY, USA

BA

Memory and Aging Center Department of Neurology University of California San Francisco, CA, USA

Chunhui Yang

MD, PhD

Rush Alzheimer’s Disease Center and Department of Pathology Rush University Medical Center Chicago, IL, USA

Eric Yuen

MD

Clinical Development Janssen Alzheimer Immunotherapy Research & Development South San Francisco, CA, USA

Jessica Zwerling

MD

Department of Neurology Albert Einstein College of Medicine Bronx, NY, USA

xi

Preface

As scientific knowledge about the nervous system and neurological diseases explodes at an exponential rate, the ability to master all aspects of neurology becomes increasingly difficult. Because of this, neurology as a profession is fragmenting much the same way that internal medicine has, with many subspecialties of neurology emerging and establishing themselves as board-recognized subspecialties by the American Academy of Neurology and the United Council of Neurological Subspecialties (UCNS). Currently recognized subspecialties of the UCNS include autonomic disorders, behavioral neurology and neuropsychiatry, clinical neuromuscular disease, headache medicine, neural repair and rehabilitation, neurocritical care, neuroimaging, and neuro-oncology. Other recognized subspecialties include epilepsy, stroke, and movement disorders. For the past several years, the American Academy of Neurology’s Geriatric Neurology section has been advocating strongly for the creation of a boarded, recognized subspecialty in geriatric neurology. This recommendation was approved by the AAN and adopted by the UCNS. Subsequently, the UCNS drafted a course outline for examination purposes, convened an examining committee that drafted the exam questions, and has since proctored three exam sessions. This book mirrors the new board subspecialty of geriatric neurology within the larger field of neurology. This project is written as a textbook for an emerging field of neurology and provides evidencebased scientific review of the current thinking in the field. The content will be clearly articulated and summarized. Geriatric neurology is the field of neurology dedicated to age-related neurological diseases, including

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degenerative diseases (Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis), gait and balance disorders, neuropathies, stroke, and sleep disturbances. Geriatric neurology is emerging as a subspecialty of neurology. This emergence reflects the growing understanding that geriatric patients have different neurological conditions that require different diagnostic evaluations and ultimately different features. Geriatric neurology is not adult neurology redux. The field has similarities to geriatrics and the approach to the geriatric patient is, by definition, different. As such, clinical syndromes can have features in common with younger patients but the etiologies are frequently different. Additionally, many neurodegenerative diseases are prevalent in the aged but less so in general neurology. This handbook is the summation of the field at present. It follows the UCNS examination outline to an extent in terms of topics covered. It covers all topics germane to geriatric neurology from disease-specific, neuroanatomical, diagnostic, and therapeutic perspectives. The good news is that we have made tremendous strides in understanding and managing the complications and challenges of diseases that are encompassed within geriatric neurology. We now understand the neurological changes that occur with age and the mechanisms that contribute to changes. We hope it will enhance practice skills and knowledge base for practitioners, residents, and students.

Anil K. Nair Marwan N. Sabbagh

Acknowledgments

This work would not exist without the exhaustive efforts of our contributors, who are the venerable authorities in their respective fields. We would also like to thank our assistants who were tireless and patient throughout— Bonnie Tigner, Myste Havens, Deborah Nadler, Nicole Chan, Roshni Patel, Sheela Chandrashekar, Ardriane Hancock, Krystal Kan, and Vishakadutta Kumaraswamy. We would like to thank the publishing team at

Wiley for their feedback, responsiveness, patience, and support. Finally, we would like to thank our spouses and children who endured our many late nights staying up writing and editing. Anil K. Nair Marwan N. Sabbagh

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Part 1 The Aging Brain in Neurology

Chapter 1 The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century Douglas F. Watt Department of Neuropsychology Cambridge City Hospital, Harvard Medical School, and Alzheimer’s Center/Clinic for Cognitive Disorders, Quincy Medical Center, Quincy, MA, USA

Summary • Aging demographics, increasing penetration of diseases of aging, and the heightening expense of high technology health-care interventions are creating exploding costs that are becoming economically unsustainable. • Evolutionary theory suggests that aging is the fading out of adaptation once reproductive competence is achieved, and reflects the lack of selection for a sustained post-reproductive adaptation. • If extrinsic mortality is high in the natural environment, selection effects are less likely to promote organism maintenance for extended periods. Alternatively, aging is simply change of the organism over time, and is primarily under the control of the hypothalamic pituitary gonadotropin axis. Although traditionally viewed as opposing theories, these may be simply different perspectives on the same process. • Cellular and molecular theories attribute aging to a genetically modulated process, a consequence of “wear-and-tear”, or a combination of both types of processes. • Aging is probably a complex and recursive network of many changes. • Molecular and cellular models of aging include: nuclear and mitochondrial and even ribosomal DNA damage, including genomic instability, loss of epigenetic regulation, and mitochrondrial DNA deletion. • Oxidative stress (OS) and associated mitochondrial dysfunction and decline • Inflammation which is progressively disinhibited (‘inflammaging’) • Glycation • Declining autophagy • Dysregulation of apoptosis • Sarcopenia • Cellular senescence • Calorie or dietary restriction (CR/DR) has been shown to have positive effects in most but not all species on longevity and aging. • A network of interacting molecular pathways has been implicated in CR physiology. Sirtuins, a class of transcription factors, are thought to play an important role in cell signaling and aging, in concert with mTOR, AMPK, PGC-1a, and insulin signaling pathways. • The target of rapamycin (TOR) signaling network influences growth, proliferation, and lifespan. Rapamycin, an immunosuppressive macrolide, inhibits mammalian target of rapamycin (mTOR) and has been shown to increase lifespan. • CR mimetics are substances that potentially mimic the molecular effects and physiology of CR. Resveratrol is the most well known CR mimetic but only extends lifespan in obese animals. • Genetic manipulation of growth hormone, IGF-1, and insulin signaling pathways may mimic CR effects. • Lifestyle factors such as sleep, diet, exercise, and social support may affect a shared set of cellular and molecular pathways. • Exercise: elicits an acute anti-inflammatory response and inhibits production of proinflammatory cytokines. Protective against disease associated with low grade systemic inflammation. • Obesity: abdominal fat may contribute to the disinhibition of inflammation. • Polyphenols, often regarded as antioxidants, affect cell physiology and cell signaling in a wide variety of ways that are probably far more critical to their effects in mammalian physiology beyond any putative free radical scavenging. • Healthy lifestyle practices match those of ancestral hunter gatherers (HGs), suggesting that diseases of aging may be potentated by a mismatch between our genes and the modern environment.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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4

The Aging Brain in Neurology

Do not go gentle into that good night, Old age should burn and rave at close of day; Rage, rage against the dying of the light. Dylan Thomas Aging is arguably the most familiar yet least-well understood aspect of human biology. Murgatroyd, Wu, Bockmuhl, and Spengler (2009) Old age is no place for sissies. Bette Davis

Dedication: To my Dad, Richard F. Watt, who believed that the best scholarship and the best social values would eventually reveal each other.

Introduction Aging, now the focus of a rapidly expanding, if still immature, biological science, remains one of the most fundamental yet mysterious aspects of biology. The science of aging has explored the cellular and molecular basis of aging largely in three target organisms with fully sequenced genomes and short lifespans (yeast, roundworms, and fruit flies), as well as an increasing number of in vivo studies in mammalian animal models. Evidence argues that multiple pathways modulating aging in these three target organisms are well conserved in mammals, primates, and humans, although perhaps with additional modifications. The science of aging has made progress in describing and analyzing several critical phenotypes or components of aging, including sarcopenia, glycation, inflammation and oxidative stress (OS), endocrine dyscrasia, apoptosis, telomere loss and cellular senescence, genomic damage and instability, mitochondrial dysfunction and decline, and increasing junk protein and declining autophagy (removal of damaged or “junk” proteins). Although the relationships among these various aspects of aging remain incompletely mapped, evidence increasingly indicates that they are deeply interactive, perhaps reflecting the many linked “faces” or facets of aging. Increasing evidence links most, if not all, of these processes to the major diseases of aging and most neurodegenerative disorders. Evolutionary perspectives argue that aging must be a process against which natural selection operates minimally, in a postreproductive animal. In other words, basic selection processes ensure that enough members of the species (absent predation or other accidental death) survive to a period of maximum reproductive competence (otherwise, a species would not exist), but selection does not and indeed cannot ensure longevity much past a peak reproductive period. Aging is the result of this relative absence of selection for an extended postreproductive adaptation. In this sense, evolution “does not care too much about aging”, although partial exceptions to this principle in humans

may exist due to the likely contribution of tribal elders to an extended “group fitness,” possibly helping to explain why humans are longer lived than almost all other mammals. Such evolutionary perspectives also suggest that aging (and its deceleration) is likely to be highly polygenetic and not easily radically modified, arguing strongly against any wild optimism about improvements to maximum human lifespan beyond its documented maxima (about 120 years). Current thinking also suggests that aging clearly reflects an “antagonistic pleiotropy”—genes beneficial to and even critically necessary for growth and reproduction “backfire” in older animals and contribute to aging, in part through “unexpected” interactions. However, aging research has extensively probed highly conserved protective effects associated with dietary or calorie restriction (DR/CR), the gold standard in terms of a basic environmental manipulation that slows aging in virtually every species in which it has been closely studied, from yeast to mammals. CR/DR functions as a global metabolic “reprogramming” for most organisms, reflecting a shift of biological priorities from growth and reproduction toward stasis and conservation. CR physiology was presumably selected by allowing organisms to survive in times of nutrient shortage and then resume the critical business of growth and procreation when again in environments more supportive of fecundity. CR extends lifespan and reduces penetration of the diseases of aging significantly, if not dramatically, in almost every species in which it has been studied, but does not appear to be a viable health-care strategy for the vast majority of individuals (due to the intrinsic stresses of chronic hunger). CR mimetics (substances offering at least some of the physiology of CR without the stress of chronic hunger) may offer some or many of the benefits of CR, protective effects of enormous relevance to Western societies as they undergo progressive demographic shifts in the direction of a larger percentage of elderly citizens than at any point in human history, with an impending tsunami of diseases of aging. However, clinical and long-term data on CR mimetics is badly lacking beyond animal models, where they show

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

impressive protective effects. CR mimetics are currently being studied in multiple diseases of aging, including cancer, heart disease, Alzheimer’s disease (AD), diabetes, and several others. Last but not least, accumulating evidence also indicates that Western lifestyles and an associated pandemic of obesity, reflecting a radical departure from our evolutionary environment, will expose us to increased penetration by the diseases of aging, despite (or perhaps because of) increasing life expectancy. These multifactorial lifestyle changes (poorer sleep, little exercise, complex dietary shifts, increased social isolation) may increase many of the phenotypes or components of aging, including OS, inflammation, glycation, insulin resistance, telomere loss, disordered cell cycling and aberrant growth signals, increased junk proteins, and DNA damage. Fundamental shifts in health-care strategy and priorities will be needed in the coming decades, away from high-technology interventions aimed at an advanced disease of aging (often one at which little real prevention was ever aimed) and toward a reprioritizing of meaningful prevention via substantive lifestyle modifications. Such a shift in healthcare priorities is likely to be politically contentious, but the current (and unsustainable) escalation of health-care spending will eventually force basic changes in both health-care policy and clinical practice. The science of aging may eventually heuristically integrate much of our currently fragmented approach to the diseases of aging and thus merits much more attention and review not only in medical school curriculums, but also in basic biomedical research initiatives.

Aging and mortality All complex organisms age and eventually die1, with highly variable limits to their typical lifespans, a variability still poorly understood. The outer biological limit to the human lifespan is generally thought to be approximately 120 years. The oldest carefully verified human known was Jeanne Calment of France (1875–1997), who died at age 122 years, 164 days (Robine and Allard, 1995). As far as we know, we are the only species with a vivid awareness of and preoccupation with our own mortality (and perhaps, at other times, an equally great denial). Cultures from the earliest recorded history have been preoccupied with themes of dying and immortality, along with whether it would be possible to escape death or find a true “fountain of youth.” Wishes for and even expectations of immortality are a powerful driver in many

1

Only in organisms in which there is no real distinction between soma and germ line (such as hydra and most bacteria) is aging absent.

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organized religions and spiritual traditions. Yet despite such perennial and fundamental human wishes, no way of truly preventing aging or achieving any version of biological immortality has ever been achieved in human history. Aging and our eventual demise from it both seem as unavoidable as the next sunrise. Benjamin Franklin is credited with the famous quote, “The only thing certain in life are death and taxes.” More humorous perspectives on these existential challenges include George Bernard Shaw’s lament that youth was a wonderful thing and a shame that it had to be wasted on the young. When I was too young to fully appreciate the humor, my own father, who passed away during the writing of this chapter at the age of 93, offered, “Aging is vastly overrated, but most of the time, it beats the alternative.” But ultimately, aging is no joking matter, exposing humans to slow and inevitable degradation of virtually every organ system, progressive disability, and eventual outright physiological failure of one sort or another, with inevitably fatal consequences. Yet if we did not age and die, humans and their progeny would quickly overrun the planet and totally exhaust its ecology and resources, causing mass extinctions not only for many other species, but potentially for our own as well. Thus, any true “fountain of youth” for humans might prove to be a seductive but ultimately deadly Faustian bargain. Yet who does not want more life, particularly if in decent health and with preserved functional capacities? Such primordial motivation and longing was surely captured in Dylan Thomas’s haunting poem “Do Not Go Gentle into That Good Night,” tapping universal sentiments in the face of aging and mortality. In this context, one might ask why a chapter on the biology of aging appears in a textbook of geriatric neurology. Trivially, the obvious answer is that aging has everything to do with all things geriatric. However, less trivially and less obviously, one might argue that an understanding of the basic biology of aging could function as a “touchstone” or integrative “hub” around which much of the science of geriatric neurology might eventually be organized. Central questions here could include: What is aging? What drives the progressive deterioration of the human organism over time? Why does it lead to what have been called the “diseases of aging?” These diseases would include not just classic neurodegenerative disorders (most paradigmatically, AD, but also Parkinson’s disease (PD), frontotemporal dementias, and motor neuron diseases—all core clinical concerns for geriatric neurologists, neuropsychologists, and psychiatrists), but also coronary artery and cerebrovascular disease, other forms of age-related vascular disease, diabetes, cancers, macular degeneration and glaucoma, arthritis, failing immunocompetence, and perhaps many, if not most, forms of end-stage organ disease. Additional central questions potentially addressed by the science of aging include the following: what can we

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The Aging Brain in Neurology

do about slowing aging and extending the lifespan or, for that matter, protecting ourselves from the diseases of aging? Exactly how does aging lead to the various diseases of aging, and what determines which disease of aging an individual gets? Does someone truly die just from “old age,” or do we die of a disease of aging? What are the core biological processes responsible for aging? Are these a few biological processes or many dozens? What are the potential relationships (interactions) among various core processes implicated in aging? What is the relationship between aging in the brain and aging of the body in general? Can the brain be differentially protected from aging and age-related diseases? Would a slowing of aging itself potentially delimit the penetration by the diseases of aging in some or even all individuals? How radically? Is it possible to substantially slow aging, or perhaps even to arrest it? Even more radically, could aging ever be substantially reversed? Many of these questions do not have well-validated scientific answers yet. Most of these questions could be considered central biological questions for all the health-care disciplines and also questions around which there is now a rich and emerging, if still fundamentally young and incomplete, science of aging.

Implications of an aging demographic in Western societies for priorities in health care: prevention versus hightechnology medicine Unfortunately, very little of an emerging science of aging has trickled down into the health-care system and into the awareness of most health-care professionals, where a largely fragmented approach to the diseases of aging predominates theory, clinical research, and treatment. In addition, almost none of it seems to inform the way our health-care system currently works. Substantive prevention in relationship to the diseases of aging (let alone any concerted focus on potentially slowing aging) garners little substantive attention or meaningful share of fiscal resources; instead high-technology intervention, often aimed at an advanced disease of aging (at which little, if any, prevention was typically ever aimed), consumes an enormous fraction of medical resources and costs (Conrad, 2009). Recent estimates are that no more than 5% of health care is spent on prevention, broadly defined, whereas 75–85% is spent on an established illness, typically a disease of aging (Centers for Disease Control and Prevention (CDC), 2010). In 2010, at least $55 billion was spent on the last 2 months of life, and an enormous fraction of total medical costs was spent on end-of-life care (Social Security Advisory Board (SSAB), 2009), often with little evidence that this considerable expenditure improves the quality of life (and may even cause it to deteriorate, in some instances). If one were to extrapolate our current (average)

end-of-life care costs to the baby boomers (a demographic of roughly 60 million people), this could potentially yield a total price tag of about $6 trillion for end-of-life care for the baby boomer generation. Obviously, these trends are unsustainable, but there is little evidence of progress toward addressing, let alone reversing, them. The emerging and expanding science of the biology of aging, as a vigorous area of scientific inquiry, takes place at a time when the demographics of Western societies are tilting toward an increasingly high percentage of elderly citizens. At the beginning of the twentieth century, when life expectancy was about 47 years in the United States, until today, there has been a roughly 30-year increase in life expectation at birth (Minino et al., 2002). Roughly 25 years of this 30-year gain in lifespan can be attributed to one primary factor: lessening the impact from early mortality due to infectious diseases in children and young adults, in the context of better hygiene and the creation of effective antibiotics and vaccines (CDC, 1999). This has yielded a situation in which many Western societies are now for the first time in human history facing the prospect of having more people over the age of 60 than under the age of 15. Although currently roughly 13% of the United States is over the age of 65, within the next 20 years, this percentage is expected to increase by more than half again, to roughly 20%. By the end of the century, a whole one-third of the world’s population will be over the age of 60 (Lutz et al., 2008). These demographic shifts will centrally include a huge increase in the very old in the coming four decades. In 2010, more than an estimated 5.5 million Americans were 85 years or older; by the year 2050, that number is expected to almost quadruple to 19 million. Currently, the number of centenarians in this country (Americans 100 years and older) is estimated at roughly 80,000, but by 2050, there will be more than 500,000 Americans aged 100 years or older. This is unprecedented in human history. However, these significant increases in lifespan have not been accompanied by concomitant increases in “healthspan,” or in our ability to substantially prevent (or successfully treat and delimit) the disabling illnesses of later life, the major diseases of aging (centrally including diabetes, cardiovascular disease, stroke, AD, and cancers), which remain largely refractory to amelioration. Some evidence (summarized later in this chapter) argues that these diseases may be largely of Western civilization (primarily due to modern lifestyles) and relatively rare in elders from hunter gatherer (HG) societies, compared to Western societies, even when the younger mortality of HGs is taken into account (Eaton et al., 1988 a,b). The impact of these large demographic shifts and the associated increased penetration of diseases of aging on health-care economics, combined with the increasing costs of technology-driven health-care interventions, is quietly anticipated to be fiscally catastrophic, involving a steady annual escalation of health-care costs to unsustainable levels (US Government Accountability Office, 2007; Conrad, 2009). The impact on health-care economics of an

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

aging demographic, combined with an increasing emphasis on high technology, is increasingly penetrant and, frankly, worrisome, particularly in terms of its impact on health-care economics in this country. In 2010, health-care expenditures in the United States were approximately 18% of the gross domestic product (GDP), almost twice as much, in terms of percentage of GDP, as in any other Western society. Even just within the next several years, at a current rate of increase of between 4% and 8% a year (rates of increase moderated more by the recent recession than by changing practice), by 2018–2019, roughly 20% ($1 in every $5) of the US GDP could be spent on healthcare expenses, an unprecedented fraction of our national wealth and resources. The health-care expense as a proportion of GDP is projected (without substantive changes in practice trends or chronic illnesses) to rise to 28% in 2030 (more than $1 in every $4) and to 34% by 2040 (more than $1 in every $3; Council of Economic Advisers (CEA), 2009). These are frightening statistics, suggesting that the current rate of escalation in health-care expenditures is totally unsustainable. However, the demographic shifts toward an aging population are only one contributing factor in these accelerating expenditures and are paired with the escalating cost of first-line drugs and high-technology interventions and the high overhead associated with the burgeoning health-care and health-insurance bureaucracy itself (CEA, 2009). Evidence suggests that as much as threequarters of the increasing costs are due to factors other than an aging demographic (CEA, 2009). Despite these enormous and escalating financial outlays in health care, the overall health may be actually declining in the United States, as measured by several indices. Currently, the United States rank around 50th in life expectancy, while other indices, such as infant mortality, are also worrisome and rank 46th, behind all of Western Europe and Canada (CIA Factbook). Reflecting the major disease of aging with special relevance for this textbook, costs for AD in 2010 were roughly $170 billion in the United States alone (not counting an additional roughly $140 billion in unpaid caretaker costs, suggesting a real cost of over $300 billion in 2010 alone) (Alzheimer’s Association, 2010). These total costs of AD (assuming that current costs continue and no cure or highly effective treatment is found) are expected to potentially reach $2 trillion per year in the United States alone by 2050, with 65 million expected to suffer from the disease in 20 years worldwide, at a cost of many trillions of dollars (Olshansky et al., 2006). As the baby boomers enter the decades of greatest risk for cancers, heart disease, stroke, arthritis, AD, macular degeneration, and other diseases of aging, evidence indicates that the health-care system (as it is currently structured) will eventually undergo a slowly progressive but fundamental collapse in the context of these unsustainable cost escalations. Meaningful strategic options to prevent this fiscal implosion have not yet been developed.

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In addition to its financial impact on health-care economics, aging in the Western societies is anticipated to have a more generalized and severely deleterious impact on Western economies, as an increasing percentage of retired elderly severely strain basic social safety net and entitlement programs such as Medicare and Social Security, deteriorate tax and revenue margins, and stretch virtually every societal resource (McKinsey Global Institute, 2008). In this context, scientific work on the biology of aging, particularly if it might reduce or substantially delay penetration by the diseases of aging into an aging population and extend “healthspan” (as distinct from lifespan), appears vitally relevant, if not badly needed. Despite these considerations, the funding of research into all aspects of aging and age-related disease garners only 11% of the $31 billion NIH budget (Freudenheim 2010), and research into CR, our only well-replicated lifestyle intervention to slow aging and reduce diseases of aging, garners less than 1/100th of 1% of all biomedical research monies (Guarente, 2003).

Historical and basic evolutionary perspectives on aging Aging appears somehow woven into the very fabric of life itself; a still controversial question is whether this is accidental (in a sense, evolution did not worry much about aging, as postreproductive deterioration in a complex biological system is inevitable) or whether aging is selected (as nearly immortal organisms would destroy their environment and thus render themselves extinct). These may not be mutually exclusive perspectives. Aging is difficult to define and has no single pathognomonic biomarker, but to paraphrase a famous quote about obscenity, “You’ll know it when you see it.” Aging can be defined operationally as a progressive and time-dependent “loss of fitness” that begins to manifest itself after the organism attains its maximum reproductive competence (Vijg, 2009) but aging could also be seen as simply the change of the organism over time (Bowen and Atwood, 2004). Although this seems to conflate development with aging, it has other theoretical advantages (see discussion of endocrine dyscrasia). Aging consists of a composite of characteristic and often readily recognizable phenotypic changes and can be defined statistically as a point at which normal or expectable development shows an increasing probability of death from all-cause mortality (excepting traumatic injury, starvation, poisoning, or other accidental death) with increasing chronological age of the organism. Intrinsic to aging is that its characteristic phenotypic changes are progressive and affect virtually every aspect of physiology and every organ of the body, from the skin, to cardiac and muscle tissues, to the brain. Ontologically, aging may reflect “entropy’s revenge,” as fundamental aspects of life organization become increasingly disorganized,

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The Aging Brain in Neurology

presumably due to a complex composite of processes (Hayflick, 2007). Modern biological thought holds it axiomatic that purposeful genetic programs drive all biological processes occurring from the beginning of life to reproductive maturity. However, after reproductive competence is attained, current thinking is still divided on the question of whether aging is a continuation of some collection of genetic programs or whether it is the result of the accumulation of random, irreparable losses in cellular organization. Again, these may not be mutually exclusive. References to aging abound in the earliest human cultures’ writings and records, suggesting that humans have been keenly aware of aging for millennia. The Bible refers to aging and death as “the wages of sin,” at best, a colorful metaphor and, of course, totally scientifically inadequate. However, a modern biology of aging suggests that the metaphor of aging as a “wage” is both appropriate and heuristic: aging may readily reflect the “wages” of growth, metabolism, and reproduction (excess junk proteins, OS, glycation of proteins, and damage to both mitochondrial and nuclear DNA) and also to the “wages” of organism defense and repair (also known as inflammation). Additionally, one must accept evolutionary principles as fundamental here and grounding any discussion of biological phenomenon, suggesting that aging must, in a direct sense, reflect a relative absence of selection against aging itself. However, what this might mean is not clear. Initial evolutionary theories of aging hypothesized that aging was “programmed” to limit the population size (immortal organisms would destroy their environment and render themselves quickly extinct) and/or to accelerate an adaptive turnover of generations, thereby possibly enhancing adaptation to shifting environments. However, this argument has modest evidence for it, at best, as senescence typically contributes minimally to mortality in the wild (Kirkwood and Austad, 2000). Instead, mortality in wild populations (as opposed to that seen in protected populations) is mostly due to extrinsic factors, such as infection, predation, and starvation, and occurs mainly in younger animals (Charlesworth, 1994). As a general rule, many, if not most, wild animals simply do not live long enough to grow old, again due to these extrinsic factors and not to aging. In this sense, natural selection has a limited opportunity to exert any direct influence over the processes of aging. Even in species in which aging and senescence do make some contribution to mortality in the wild (for example, in larger mammals and some birds), any hypothetical “aging gene” would be clearly deleterious; thus, it is highly unlikely that it would be selected (Kirkwood and Austad, 2000). Indeed, the relative rarity of aged animals in the wild is an important clue about how fundamental evolutionary processes relate to aging. With extrinsic factors being the primary causes of mortality, there is invariably a progressive weakening in the force of selection with increasing age (Kirkwood and Austad, 2000). By the time an animal

in the wild reaches an age at which the percentage of a given population surviving has declined to very low levels, the force of selection is likely far too weakened (if not almost nonexistent, given the low probability of reproductive success in an aged animal) to effectively weed out the accumulation of genes with “late-acting” deleterious (in other words, pro-aging) effects. This constitutes a “selection gap” that allows any alleles with late deleterious (proaging) effects to accumulate over many generations, with little or no intrinsic “countermechanism” (referred to as the mutation accumulation theory of aging). A prediction emerging from this theory is that because the negative alleles are basically unselected mutations, there might be considerable heterogeneity in their distribution within a population of individuals. There is some evidence both for and against this (Kirkwood and Austad, 2000). A substantial modification of this basic idea is found in the notion of aging as “antagonistic pleiotropy” (Williams, 1957), that evolution would favor genes that have good effects early in development (for example, genes promoting growth and fecundity) even if these genes had clearly bad effects at later stages of life. A critical and heuristic modification of this basic idea has been provided by Bowen and Atwood (2004), who suggest that alterations in the hypothalamic–pituitary–gonadal (HPG) axis, characterized by increasing gonadotropins and declining sex steroids create aging and by implication its diseases, a process which is “paradoxically” under the control of the very same hormonal systems that regulate growth and reproduction (see Section “Endocrine Dyscrasia”). In this sense, a small but reproductively significant benefit early in life derived from particular genes or alleles would easily outweigh (in terms of selection effect) later deleterious effects, even if those later effects guaranteed eventual senescence and death, especially if those genes promote growth and reproduction. Aging is thus not the “wages of sin” but the wages of growth, reproduction, and metabolism. Of course, this suggests that aging expresses intrinsic trade-offs, a theme also echoed in the widely quoted “disposable soma” theory of aging (Kirkwood, 1977) which suggests a balance of allocation of metabolic resources between somatic maintenance and reproduction. Effective maintenance of the organism is required only for as long as it might typically survive in the wild. For example, because roughly 90% of wild mice die in their first year of life, biological programming for metabolically expensive body maintenance programs beyond this age benefits only 10% of the total population, at most (Phelan and Austad, 1989). Given that a primary cause for early mortality in wild mice is excessive cold (Berry and Bronson, 1992), the disposable soma theory suggests that mice would not benefit from developing body maintenance and repair programs that would slow aging nearly as much as investing metabolic resources into thermogenesis and thermoregulatory mechanisms.

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

Thus, longevity may be determined in large part by the level of “extrinsic” mortality in the natural environmental niche (Kirkwood and Austad, 2000). If this level is high (life expectancy thus is quite short), there is little chance that the force of selection would create a high level of protracted and successful somatic maintenance; the more critical issue is making sure that organisms either reproduce quickly before extrinsic mortality takes its toll or have high fecundity and reproduction rates to ensure that early mortality for many members of a species does not eliminate reproduction for all members of a species (rendering them extinct). On the other hand, if “extrinsic” mortality is relatively low over long periods of time, selection effects might well direct greater resources toward building and maintaining a more durable organism, by modulating genes that might otherwise contribute to rapid aging. If this set of assumptions is correct, one would predict that, in organisms in relatively safe environments (those with low extrinsic mortality), aging will evolve to be more retarded, while it would be predicted to be more rapid in hazardous environments (slowed aging in these environments would make little difference to procreative success and species survival)—and these predictions are generally well supported (Kirkwood and Austad, 2000). Additionally, evolutionary developments that reduce extrinsic mortality (for example, wings or other adaptations to reduce vulnerability to predation, highly protective armor (such as shells), or large brains (enabling transition from prey species to top predator status) are linked to increased longevity (as seen in birds, turtles, and humans), although mechanisms for this increased longevity are still debated and remain to be conclusively outlined (see Bowen and Atwood, 2004). However, disposable soma theory has been criticized (Blagosklonny, 2010b) as failing to account for many aspects of aging, most particularly the greater longevity of women and the role of specific genetic pathways (such as mammalian target of rapamycin (mTOR),–see later sections on mTOR) that may heavily modulate aging. Aging is increasingly thought to be not preprogrammed, but more likely the result of a relative absence of selection for “perfect” maintenance of the organism, past the period of reproductive competence. Another way of putting this is that aging is simply the “fading out of adaptation,” after achieving the age of reproductive success and moving into the postreproductive age (Rose, 2009). In other words, there is no basis for evolution to have selected against aging and for much better body maintenance, as these issues would escape selection, unless there was a specific selection pressure toward this. An example of a basic selection pressure that could reduce aging significantly might be progressively delayed reproduction (procreating at slightly later and later ages), which has been shown in animal models to result in significant enhancement of longevity, in complete concert with basic evolutionary principles

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(Teotônio et al., 2009). In animal models of aging, this is referred to as “experimental evolution” (Bennett, 2003). Intriguingly, experimental work with delayed reproduction has successfully developed longer lived species (for example, long-lived Drosophila, or fruit flies), but with the cost of depression of early life fecundity, suggesting again intrinsic trade-offs between slowed aging and growth and reproduction (Sgrò and Partridge, 1999). However, there is expert opinion (Johnson, Sinclair, and Guarente, 1999) that there could well be selection to slow the pace of aging, as such organisms could potentially have a more protracted period of reproductive fitness, conferring an adaptive advantage. Slower aging also appears intrinsically related to later age of reproductive fitness (Bowen and Atwood, 2004). Additionally, in hominid lines, evolutionary perspectives indicate that the existence of tribal elders, with greater accumulated wisdom and experience, would have improved evolutionary fitness for their tribal groups, despite being largely past a reproductive age, suggesting another potential selection mechanism driving “antiaging” (“group fitness” or “inclusive fitness” in highly social species such as hominids; Carey, 2003). Basic cellular and molecular theories of aging probably come in two fundamental forms: (1) aging as a genetically modulated process (under the control of discrete genes and molecular pathways—but not “preprogrammed”); (2) aging as an “error” or stochastic or “wear-and-tear” process (the best known of these being the oxidative damage/ stress theory). Neither “pure” type of theory is fully able to explain all aspects of aging, suggesting that aging is “quasiprogrammed” (Blagosklonny, 2009) and perhaps related to both growth programs (which are continued past the period of peak reproductive competence, as an example of antagonistic pleiotropy) and stochastic cellular damage/wear and tear aspects (such as emerging from disinhibited inflammation). CR, as the only conserved antiaging physiology yet discovered (see the later sections on CR and CR mimetics) may impact both of these (reducing growth programs and also attenuating factors such as OS and inflammation that may drive stochastic damage). Again, one has to assume that these issues do not contradict or replace a basic evolutionary perspective (in which aging reflects a relative absence of selection against wear and tear, stochastic damage, or failure of inhibition of many genes/pathways that might accelerate or drive agerelated decline). Kirkwood and Austad (2000) summarize these considerations for an evolutionary genetics of aging as three basic predictions (p. 236). 1 Specific genes selected to promote ageing are unlikely to exist. 2 Aging is not programmed but results largely from accumulation of somatic damage, owing to limited investments in maintenance and repair. Longevity is thus regulated by genes controlling levels of activities such as DNA repair and antioxidant defense.

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3 In addition, there may be adverse gene actions at older ages arising either from purely deleterious genes that escape the force of natural selection or from pleiotropic genes that trade benefit at an early age against harm at older ages. Thus, aging could reflect the species-variable interactions and intrinsic “tug-of-war” between deleterious and degrading changes (and the declining influence of selection/adaptation in a postreproductive animal), with many of these pro-aging factors intrinsic to growth, reproduction, metabolism, inflammation, and other aspects of physiology (“antagonistic pleiotropy”), versus various (and presumably selected) counterbalanced repair, protection, and maintenance programs. Of course, if aging itself potentially deteriorates those counterbalanced cellular repair and maintenance programs, this suggests that aging is a losing tugof-war between forces of cellular protection and forces of cellular degradation, and that (as the tug-of-war metaphor suggests), as one side loses, it may lose at an accelerating rate. There is indeed some evidence, although it is hardly conclusive, that aging may actually accelerate (Guarente, 2003). Few elderly would find this possibility surprising. Cellular and molecular aspects of aging that might map onto these various considerations about the evolutionary basis for aging suggest a dizzying composite of phenotypic changes, including changes in mitochondrial, nuclear, and ribosomal DNA; subsequent genomic and chromatin changes and instability; increasing levels of OS (including pleiotropic and differential expression of OS on membranes and lipids, proteins, and nucleic acids, particularly mitochondrial); increasing systemic inflammation (“inflammaging”), paradoxically concomitant with declining immunocompetence; increasing glycation of proteins (and increasing amounts of advanced glycation end products (AGEs), which potentiate inflammation); increasing cellular senescence and loss of telomeres; dysregulation of apoptosis (programmed cell death is over- or under-recruited); and increasing junk proteins, combined with impaired protein turnover and declining removal of damaged (and glycated) proteins (declining “autophagy”). Last but certainly not least, even our stem cells age and reach senescence, preventing rejuvenation of many organ systems and structures. A clear sense of what are leading versus trailing edges in this process (in other words, clearly distinguished “causes” vs “effects”) are still unclear and biology is clearly a place where causes become effects and effects become causes. However, there is evidence for each of these various aspects of cellular change as direct contributors to all the manifestations of aging, including evidence linking virtually all of these processes (“phenotypes of aging”) to all the diseases of aging. Like many aspects of biological regulation, and indeed life itself, recursive interactions among these various processes may be essential; in other words, the many mechanisms of aging may be highly interactive, suggesting that there cannot be a single pathway into aging (see the discussion of the network of molecular pathways in CR effects), and that instead aging probably reflects a

complex and recursive network of (still incompletely understood) changes. This is consistent with the severe limitations of all “linear causality” models in biological systems, where causality is intrinsically more recursive, circular, and multifactorial (Freeman, 2000). As critical examples of this principle of reciprocal interaction, inflammation and OS are increasingly linked and seen as mutually reinforcing (Jesmin et al., 2010), OS is thought to drive DNA damage (both mitochondrial and nuclear), glycation promotes inflammation, and declining removal of junk (including glycated) proteins may be related to increased OS (Kurz, Terman, and Brunk, 2007) and mitochondrial decline, while senescence promotes inflammation, as does endocrine decline, as does increasing junk protein while chronic inflammation and OS contribute to senescence. All of these phenotypes may thus be interlinked aspects of declining biological organization and increasing entropy, as basic phenotypes of aging with positive feedback loops between these phenotypes; new interactions seem to be emerging regularly in research into aging and its diseases. Such interaction may explain how processes involved in a modest departure from an ideal youthful physiology gives rise to a process that, over time, deterministically kills the organism without exception. Aging in other words may emerge from a deadly ‘recursion matrix’ of these interactive phenotypes. This is consistent with overwhelming evidence that nothing in biology truly emerges from single factors, but from the concerted crosstalk and feedback between multiple partners. At the same time, several molecular pathways (such as mTOR, and many molecular and cell-signaling pathways with which mTOR interacts) may be particularly critical to aging and the modulation of age-related change. At the end of this chapter, we also summarize evidence that lifestyle factors modulate risk for diseases of aging (and perhaps aging itself), possibly accelerating or retarding it at least to some degree. We also examine the difference between the current Western technological environment and our original evolutionary environment, in terms of the impact that multiple lifestyle variables may have on the cellular mechanisms and the physiology of aging and the diseases of aging.

Basic molecular and cellular perspectives on aging: phenotypes of aging Although popular conceptions of the molecular basis of aging center around reactive oxygen species (ROS), hard evidence for this as the prime driver of aging is actually very mixed, and increasing evidence argues against it, as least as the central process driving aging. However, OS may interact with many of the other phenotypes of aging, particularly inflammation, as well as disinhibited growth factors/programs, suggesting that a softer form of OS theory (that ROS may contribute to aging) may still be valid.

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

Oxidative stress and associated mitochondrial perspectives A basic assumption about aging is that it must have a fundamental cellular basis, and cellular and molecular perspectives on aging have dominated the scientific landscape of aging research and theory. The oldest and most widely quoted molecular theory about aging was provided by Harman, 1956, who postulated that oxidizing “free radicals” damaged and degraded cells over time, causing aging. Harman’s early work on radiation with experimental animals demonstrated that aging had important similarities to the aftereffects of massive exposure to radiation, particularly cancer, inflammation, apoptosis, and other tissue changes not dissimilar to classic phenotypes of aging in older animals and humans. Harman’s hypothesis emerged from his familiarity with work on radiation exposure and early findings that large doses of ionizing radiation generated enormous quantities of free radicals. Harman subsequently published what may be the first dietary antioxidant study (1957), studying the effects of dietary 2-mercaptoethylamine, the most potent radioprotective compound known at the time, and demonstrating a modest 20% increase in average lifespan, although the mechanism of action of this compound is still debated. In 1972, Harman published an important extension to the free radical theory, suggesting that the mitochondria were the primary source for OS, as well as the primary site for oxidative damage, and that the mitochondria therefore represented a kind of “biological clock” that he argued determined maximum lifespan. He concluded that his inability to extend maximum lifespan with dietary supplements must derive from the fact that most exogenous antioxidants do not get into the mitochondria. He hypothesized that OS in the mitochondria (vs its endogenous antioxidant defenses) set an outer limit on a given species longevity. Some work has suggested that OS is mostly generated by mitochondrial complex 1 (Mozaffari et al., 2011). This led to a second “vicious circle hypothesis” about OS in relation to the mitochondria: that OS caused deterioration in mitochondrial antioxidant defense systems and mitochondrial function in general, leading to more OS and, in turn, driving more damage and increasing age-related deterioration. Although this is clearly the most widely quoted and accepted molecular theory of aging, particularly in the popular media and product advertising, the most comprehensive and wide-ranging review of this theory to date (Van Remmen, Lustgarten, and Muller, 2011) concludes that hard support for it is actually quite mixed. Therefore, the authors conclude that this theory remains unproven (but also not clearly falsified either), at least in the original “hard” form of the hypothesis (that OS in the mitochondria was the driver of aging. It has also been known for some time that OS markers increase with aging, although debate still rages about how much of this is cause or effect of aging (Sohal and Weindruch, 1996). There are many data points both for and against the oxidative-stress-in-the-mitochondria theory

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of aging, which might readily lead even the advanced student of aging to a sense of confusion and frustration. On the other hand, a softer form of the hypothesis—that OS in the mitochondria may significantly contribute to aging—may be better supported, particularly in view of the interaction between ROS and other molecular pathways that clearly have been shown to contribute to aging, and to the diseases of aging, such as inflammatory signaling, and growth signaling (see Blagosklonny, 2008) (see Section “Mammalian target of rapamycin”). Much experimental work to test the basic hypothesis has focused on genetic manipulations of antioxidant enzyme systems in short-lived species. Support for the hypothesis can be drawn from the results of knockouts of superoxide dismutase (SOD) 2 (Perez et al., 2009) and glutathione peroxidase 4 (Ran et al., 2007), both of which show lethal effects. Other primary data points in favor of the hypothesis emerge from work correlating species longevity with lowered rates of mitochondrial DNA mutation (Sanz et al., 2006) and with other experimental manipulations of OS and mitochondrial function (Hagen et al., 1999). Additionally, longer lived rodents (white-footed mouse (Peromyscus leucopus)) exhibit lower levels of ROS (superoxide and hydrogen peroxide), compared to the shorter lived house mouse (Mus musculus), and show higher cellular concentrations of some antioxidant enzymes (catalase and glutathione peroxidase) and lowered markers for protein oxidative damage (Sohal et al., 1993). Schriner et al. (2005) generated transgenic mice that overexpressed human catalase localized to peroxisome, nucleus, or mitochondria (MCAT). Median and maximum lifespans were maximally increased (averages of 5 months and 5.5 months, respectively) in the MCAT group. Cardiac pathology and cataract development were both delayed, markers for oxidative damage were reduced, peroxide production was attenuated, and mitochondrial DNA deletions (perhaps the most serious form of mitochondrial damage) were also reduced. These results offer strong support for the free radical theory of aging and also argue that the mitochondria are indeed the most biologically relevant source of these free radicals. In general, there is also broad, although occasionally inconsistent, correlation among OS in the mitochondria, rates of mitochondrial DNA damage, and longevity (Sanz et al., 2006;Barja and Herrero, 2000). However, there is equally compelling data against this classic hypothesis. The naked mole rat (NMR) demonstrates an unusual phenotype of significantly delayed aging and the longest lifespan of any rodent (about 30 years), five times the expected lifespan based on body size, and exceptional cancer resistance, despite elevated markers for OS and short telomeres (Buffenstein et al., 2011). Additionally, the lack of a significant lifespan decrease or accelerated aging phenotypes in SOD 2−/+ mice (missing one copy of the gene), despite evidence for increased OS (Mansouri et al., 2006), and increased mitochondrial DNA damage (Osterod et al., 2001) are data points against this classic theory. Further complicating the picture is the evidence that although oxidation

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The Aging Brain in Neurology

of mitochondrial DNA is elevated in SOD 2−/+ mice, mitochondrial DNA deletions (thought to reflect the most serious form of mitochondrial DNA damage) are not increased (Lin et al., 2001). This suggests that this particular partial knockout model may not adequately probe the question of the relationship between mitochondrial OS and longevity. Other animal models demonstrate that increased expression of the major antioxidant enzymes involved in protection from mitochondrial OS, including upregulation of the two isoforms of SOD (MnSOD and Cu/ZnSOD) and catalase, individually or in various combinations, does not extend maximum lifespan in mouse models (see Van Remmen, Lustgarten, and Muller, 2011 for detailed review). Mice with genetically reduced individual components of the antioxidant defense system have also been extensively studied, including knockouts of two isoforms of SOD (MnSOD and Cu/ZnSOD), glutathione peroxidases (Gpx-1, Gpx-2, and Gpx-4), catalase, thioredoxin, and peroxiredoxin. Complete ablation of individual components of antioxidant defense can often be embryonically lethal (specifically, homozygous knockout of thioredoxin 2, glutathione peroxidase 4, or MnSOD), but simply a loss of one allele (generating about 50% loss in activity) in heterozygous knockout mouse models (SOD1+/−, SOD2+/−, and Gpx4+/−) does not result in reduced lifespan (Van Remmen, Lustgarten, and Muller, 2011). Lastly, recent work shows that combining a heterozygous knockout of MnSOD and homozygous glutathione peroxidase 1 knockout clearly results in increased OS, indexed through several classic markers (both protein carbonyls and oxidized nucleic acids), but not in a decrease in lifespan (Zhang et al., 2009). At face value, such negative results might suggest that the “hard” form of the mitochondrial OS hypothesis (OS is the primary driver of aging and mortality) is not well supported. However, some very recent work argues that antioxidant defense in the mitochondria involves factors beyond these classic antioxidant enzyme systems and requires activation of one of the seven sirtuins (SIRT3), which promotes acetylation of antioxidant enzymes, significantly enhancing their effectiveness. Hafner et al. (2010) show that SIRT3-/- knockout mice show accelerated aging phenotypes, including classical mitochondrial swelling. Although earlier work on OS and CR emphasized the role of SIRT1 and its homologs (Sinclair, 2005), recent work has demonstrated that SIRT3 appears essential for CRmediated reduction in OS (Qiu et al., 2010), as homonymous knockout of SIRT3 prevents the expected reduction of OS during CR. SIRT3 reduces OS by increasing activity of SOD2 through deacetylation (Tao et al., 2010; Qiu et al., 2010). In addition to regulating SOD2, SIRT3 reduces OS by modulating the activity of isocitrate dehydrogenase 2 (IDH2), a mitochondrial enzyme generating nicotinamide adenine dinucleotide phosphate (part of antioxidant defense in the MITO; Someya et al., 2010). Thus, there may be many players in the defense against OS in the MITO,

arguing that a comprehensive test of the OS hypothesis of aging may be challenging to design and that single or even combined manipulations of antioxidant enzyme systems may be insufficient to fully probe Harman’s original and provocative idea. In general, however, there is increasing skepticism that the OS emerging from mitochondrial respiration is the driver of aging or any version of a sole “prime mover” in aging organisms. Additionally, many of the data points supporting a classic OS hypothesis can potentially be reinterpreted in light of evidence that ROS are a secondary driver for mTOR (Blagosklonny, 2008) (see Section “Mammalian target of rapamycin”); antioxidant interventions may therefore reduce overall drive or activation of mTOR (which may slow aging). Additionally, cellular senescence, another fundamental phenotype of aging, may be hinged to DNA damage detection (Chen et al., 2007), damage caused by ROS, suggesting that ROS concepts have to be seen not as operating in etiological isolation, but more as interactive with other phenotypes of aging. A major practical challenge to test the basic hypotheses of OS perspectives on aging and also explore therapeutic implications of this idea has been the question of how to deliver antioxidants into the mitochondria (as the primary cellular nexus for OS vs antioxidant protection). Most organic compounds conventionally regarded as antioxidants (particularly the so-called “antioxidant” vitamins A, E, and C) do not get into the mitochondria in meaningful quantities, nor do others common in the diet, such as many polyphenols. Work by Skulachev et al. (2009) however, suggests that one can design molecules that do materially affect OS (SkQs, in this case, comprising plastoquinone, an antioxidant moiety, and a penetrating cation and a decane/pentane link). In vitro work indeed confirms that SkQ1 accumulates almost exclusively in mitochondria. In several species of varying phylogenetic complexity (the fungus Podospora anserina, the crustacean Ceriodaphnia affinis, Drosophila, and mice), SkQ1 prolonged lifespan, especially at the early and middle stages of aging. In mammals, SkQs inhibited development of age-related diseases and involutional markers (cataracts, retinopathy, glaucoma, balding, canities, osteoporosis, involution of the thymus, hypothermia, torpor, peroxidation of lipids and proteins). SkQ1 manifested “a strong therapeutic action on some already pronounced retinopathies, in particular, congenital retinal dysplasia.” With eye drops containing 250 nM SkQ1, vision was restored to 67 of 89 animals (dogs, cats, and horses) that became blind because of a retinopathy. Moreover, SkQ1 pretreatment of rats significantly decreased hydrogen peroxide or ischemia-induced arrhythmia of the heart, reducing the damaged area in myocardial infarction or stroke and preventing the death of animals from kidney ischemia. In p53 (−/−) knockout mice, 5 nmol/kg/day of SkQ1 decreased ROS levels in spleen and inhibited lymphomas. Thus, such “designer antioxidants” show promise

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

in slowing aging and in both preventing and potentially treating diseases of aging. Intriguingly, of the many common dietary supplements regarded as “antioxidant” (see Section “Polyphenols”), only melatonin has evidence for consistent mitochondrial localization (Srinivasan et al., 2011), with some evidence suggesting that it may function as a significant mitochondrial protectant and regulator of MITO bioenergetic function. Intriguingly, and underlining the intrinsic connections among the many biological phenotypes of aging, in recent years, the OS theory of aging has forged increasing connections to disinhibited inflammation and inflammatory signaling, with many positive feedback loops between the two processes, such that neatly separating these two processes is difficult (see Section “Inflammation”). Recent work on gene interactions (Jesmin et al., 2010) suggests that OS is perhaps the critical common denominator underpinning the intimate associations between obesity, type II diabetes, and hypertension, and that obesity itself may increase OS (Fernàndez-Sànchez et al., 2011). Evidence also indicates that cancers and AD are hinged to OS, suggesting that the long-term reduction of OS in aging may have significant health benefits and may offer protection against many diseases of aging, even if the hard form of the OS hypothesis (that ROS are the driver of aging) is unsupported. Further evidence for critical interactions among these various phenotypes of aging is suggested in the landmark study by Sahin et al. (2011) which shows that telomere dysfunction causes repression of mitochondrial biogenesis regulatory enzymes (PGC-1α/PGC-1β) through activation of p53, leading to increased OS and impaired mitochondrial biogenesis and bioenergetic function. Suggesting another dimension to these dynamic relationships among phenotypes of aging, recent work has suggested that telomere loss may be directly related to lifetime inflammation and OS burden, and that rate of telomere loss in leukocytes predicts cardiovascular mortality in men (Epel et al., 2009).

Inflammation Increasing evidence argues that aging centrally involves changes in both innate and adaptive immunity (in the direction of declining adaptive immunity and compensatory upregulation of innate immunity), combined with increasing systemic inflammation, recently dubbed “inflammaging” (Franceschi et al., 2007), even in the absence of obvious pathological consequences or lesions. While traditional perspectives on inflammation emphasize acute and local inflammatory processes and the classic cardinal signs of localized inflammation (rubor et tumor cum calore et dolore—redness and swelling with heat and pain) involving many “acute phase” proteins, recent work on “inflammaging” emphasizes a different side of inflammation that is more systemic, chronic, and often (at least initially, if not over the long term) asymptomatic.

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Of course, inflammation is also a highly adaptive and selected process, central to both organism defense and tissue repair; without it, we could not survive long at all, and it operates at virtually all levels of biological organization, from the small molecular level all the way to the level of behavioral organization (see Chapter 21, “Depression in the Elderly: Interactions with Aging, Stress, Chronic Pain, Inflammation, and Neurodegenerative Disorders”). Yet it is centrally implicated in many, if not virtually all, of the major diseases of aging, particularly atherosclerosis (see Section “Diseases of Aging with Relevance to Neurology”), AD, PD, most cancers, arthritis, and type II diabetes (see Finch, 2011 for a detailed review). This profoundly Janus-faced nature of inflammation may be one of the most striking examples of “antagonistic pleiotropy,” suggesting that aging and its acceleration may be at least partially one of the “wages” of successful organism defense and tissue repair. From the perspective of aging and its diseases, the immune system may be simultaneously a best friend and a worst enemy. Blood levels of proinflammatory cytokines (such as C-reactive protein and interleukin-6) are now widely understood to be primary risk factors for vascular disease and predictors of mortality/morbidity in cardiovascular events. Underlining intimate relationships between proinflammatory and anti-inflammatory signaling, the adaptive up-regulation of IL-6 due to exercise appears critical to the anti-inflammatory production of IL-10 (Walsh et al., 2011) and IL-1ra while inhibiting production of a cardinal proinflammatory cytokine, TNF- . IL-6 was suggested to be a “myokine,” defined as a cytokine that is produced and released by contracting skeletal muscle fibers; it is responsible for the anti-inflammatory effects of exercise, part of increasing evidence that systemic inflammatory signaling and “tone” are highly plastic and perhaps highly responsive to diet and lifestyle issues (see the last sections on lifestyle and dietary factors.). Indeed, many if not most important lifestyle variables appear to modulate systemic inflammatory tone directly, including classic dietary factors such as fiber consumption (Galland, 2010), omega-3 intake (Mittal et al., 2010), and polyphenol intake (Zhou et al., 2011); sleep quality versus sleep deprivation (Motivala, 2011); aerobic exercise (Walsh et al., 2011); and even social stress (social isolation vs social comfort; Slavich et al., 2010). This suggests that Western lifestyles (sedentary and with typical Western diet patterns) may be, in toto, seriously proinflammatory and may significantly increase the risk of the diseases of aging most related to chronic and systemic inflammation (many cancers, cardiovascular disease, AD and PD, diabetes, and arthritis).

Glycation, advanced glycation end products, and AGE receptors Glycation of proteins is a fundamental mechanism in aging and in the deterioration of both organ structure

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and function, and is probably neglected in many treatments of aging relative to its importance (Semba et al., 2010; Bengmark, 2007). Glycation appears implicated in almost every disease of aging, and not simply diabetes, with glycation as a primary contributing cause and not simply as a secondary effect. Additionally, AGEs interact with receptors (rAGE) to upregulate inflammation, another primary factor in the biology of aging (see Section “Inflammation”), potentially contributing to another critical dimension of aging. The creation of AGEs involves bonding two or more proteins, a process known as “cross-linking,” typically by the creation of sugar–protein bonds. While some AGEs are relatively short lived and fluctuate in response to diet and metabolic state, other AGEs are long lived and virtually impossible for the body to break down. The creation and accumulation of these AGEs, particularly in essential tissues such as coronary arteries and the brain, can have serious effects on function and constitute a major risk factor for a disease of aging in those organs (Semba et al., 2010). For example, areas of arterial glycation are much more likely to eventually become regions of atherosclerosis and plaque accumulation, while glycation of CNS tissue is associated with increasing inflammation and the classic plaque and tangle pathology of AD (Srikanth et al., 2011; Lue et al., 2010), with AGEs a major facilitating cofactor in the creation of both amyloid oligomers and tangles (Gella and Durany, 2009). On the other hand, rAGE activation may also increase autophagy as a protective response, and may reduce apoptosis after oxidative injury (Kang et al., 2011), suggesting yet another layer of interactions between these phenotypes of aging (see Sections “Autophagy” and “Apoptosis”). Glycation of tendons and other connective tissue may form important foundations for loss of flexibility in aging. Obviously, diabetes provides a classic model for the acceleration of glycation and generates a more rapid accumulation of AGEs, with hemoglobin A1C a direct measure of glycation of hemoglobin molecules (an example of a relatively short-lived form of glycation). rAGE receptors are also implicated in AD as a channel for amyloid oligomers to enter cells where the oligomers potentially wreak havoc with multiple cellular compartments, particularly mitochondria and lysosomes (LeFerla, 2008). Glycation can be inhibited by AGE breakers, which includes the amino acid l-carnosine, and also blocked by multiple polyphenols particularly ellagic acid. Green tea extract (Babu et al., 2008), curcumin (Pari and Murugan, 2007), and many flavonoids (Urios et al., 2007) have shown at least some antiglycation functionality, along with alpha lipoic acid (Thirunavukkarasu et al., 2005). This suggests that a diet high in polyphenols and relatively low in free sugars might prevent or reduce long-term glycation of tissues (although this is never been proven in a human clinical assay to our knowledge).

Autophagy Autophagy is an essential catabolic process through which existing proteins and other cellular components are degraded and recycled, supporting the adaptive function of removal and potential repair of damaged, dysfunctional, or even toxic proteins and cellular organelles. This function is dependent on “autophagosomes” (an intracytoplasmic vacuole containing elements of a cell’s own cytoplasm), typically fused with lysosomes to facilitate the digestion of target proteins by lysosomal proteases. Autophagy, like glycation, is perhaps one of the more neglected critical storylines in aging in many popular treatments of the subject, and its importance in aging appears central. Indeed, it appears that aging can be slowed significantly by simply improving this critical process—or, alternatively, perhaps aging itself causes degradation of this process (Madeo et al., 2010). Antiaging effects from improved autophagy are robust (Petrovski and Das, 2010) and include lifespan extension. Severe dysfunction in the various autophagy pathways (typically caused by mutations) can correspondingly generate severe progeroid pathology, affecting multiple organ systems, including muscle, the liver, the immune system, and the brain. Defects in autophagy have shown accelerated aging phenotypes in classic yeast, worm, and fruit fly model organisms (primary models for aging in terms of unraveling its basic cellular and molecular mechanisms). In mammals, autophagy appears essential to life and survival, as genetic knock-out of proteins required for the process is lethal, suggesting a basic role in homeostasis and development. More limited knock-out of genes involved in autophagy in mice results in accelerated aging phenotypes. While the precise underlying mechanisms driving autophagy-related pathology remain obscure, the study of Finkel and colleagues (Wu et al., 2009) suggests that mitochondrial dysfunction is likely a critical factor. Underscoring important reciprocal relationships among the many phenotypes of aging, recent work suggests that disruption of autophagy may manifest itself physiologically in terms of mitochondrial dysfunction and increased OS (Wu et al., 2009). Growing evidence links declining autophagy to all the neurodegenerative disorders, with their characteristic protein aggregations (often ubiquitinated, suggesting that they are being tagged for removal), although pathological changes can result from excessive or disinhibited as well as deficient autophagy (Cherra and Chu, 2008). Experimental animals genetically defective in autophagy develop neurodegeneration accompanied by ubiquitinated protein aggregates, demonstrating that basic autophagy function is essential for long-term neuronal health. Additionally, both age- and disease-associated (with AD) reductions in the autophagy regulatory protein beclin 1 have been found in patient brain samples (Cherra and Chu, 2008), while treatments that promote autophagy

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

have been shown to reduce levels of pathological proteins in several in vivo and in vitro models of neurodegeneration. Rapamycin, lithium, and several polyphenols have been shown to enhance degradation and also possibly reduce synthesis of proteins that may contribute to toxic oligomer formation, as well as larger extracellular aggregates of toxic protein seen in several neurodegenerative diseases. Quercetin, several other polyphenols, and vitamin D all appear to increase autophagy, suggesting important but incompletely mapped roles for diet and lifestyle in modulating this critical aging-related process (Wang et al., 2010b; Wu et al., 2011). These considerations suggest that many neurodegenerative disorders (which are all primary proteinopathies) may have future effective treatments based at least in part on the improvement of autophagy function.

Apoptosis Apoptosis, originally thought to be a deleterious and primarily negative process, now is appreciated to have a critical role in adaptation and longevity. Apoptosis must balance regulation of the potential benefits of eliminating damaged cells against the pathogenic impact of more maladaptive forms of cell death (such as progressive cell loss in postmitotic tissues, a major mechanism driving atrophy in neurodegenerative disorders and contributing to endstage organ disease in postmitotic tissues.). Thus, a delicate balance must be struck, and dysfunction in the regulation of programmed cell death can mean that, on one hand, apoptosis potentially contributes to atrophy and a senescent cell phenotype, while, on the other, its failure potentially leads to neoplastic cell proliferation. Apoptosis is thus an important cellular defense for maintaining both genetic stability and physiological function. An intriguing question is whether centenarians may be more or less prone to apoptosis and whether longevity may slightly favor an excessive trimming of still possibly viable cells over allowing an increased percentage of potentially rogue cells to survive–or the reverse (Monti et al., 2000). Additional data points underscoring the importance of a finely tuned apoptosis equation include that cells that avoid apoptosis, particularly proliferating vascular smooth muscle cells, participate centrally in atherosclerosis. Cancer could be thought of as the paradigmatic failure of apoptosis, and several lines of evidence suggest that cellular senescence and apoptosis (both of which contribute to aging) are primary defenses against cancer (Chen et al., 2007). On the other hand, accelerated apoptosis in postmitotic tissues such as the brain clearly contributes to virtually all neurodegenerative disorders. This suggests that adaptive regulation of apoptosis and its tuning and modulation may be highly protective in relation to the diseases of aging and, conversely, that disregulated apoptosis may contribute to both aging and the diseases of aging. Just as future modulators of autophagy may be treatments for

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neurodegenerative diseases, similar prospects may apply for regulators of apoptosis, although promotion of cancers and perhaps obesity also would be potential concerns. However, promoting apoptosis in senescent cells could be highly desirable and might slow aging significantly (see discussion in later section on Cellular Senescence).

Sarcopenia Sarcopenia, the loss of both muscle mass and function, is a universal feature of aging that has a major impact on individual health and quality of life, predisposing people to falls and eventual frailty, also often neglected in treatments of aging and its phenotypes. Although the term sarcopenia was first coined in 1989, its etiology is still incompletely understood and its precise definition is still debated. It centrally includes losses in muscle fiber quantity and quality, alpha-motor neurons, protein synthesis, and several anabolic and sex hormones (Waters et al., 2010). Other factors may include altered basal metabolic rate, increased protein requirement, and chronic inflammation and OS. These changes lead to decreased overall physical functioning, increased frailty, falls risk, and, ultimately, the loss of independent living. Sarcopenia is a critical aging phenotype. All elderly show evidence of it, particularly after the seventh decade, with a roughly 40% decline in muscle mass by the age of 80 (Evans, 1995). Mechanisms leading to this are multifactorial and include mitochondrial dysfunction and decline, altered apoptotic and autophagic processes, and even altered trace metal homeostasis (Marzetti et al., 2009). Like virtually every other aspect of aging, CR mitigates this process in a variety of species studied, again via pleiotropic effects of CR, including mitochondrial biogenesis, reduction of OS, and improved apoptotic regulation and autophagic processing. To our knowledge, reduction of sarcopenia has not been demonstrated in humans with CR mimetics. Cellular senescence No discussion of aging would be complete and without at least a basic review of cellular senescence, first discovered by Hayflick in vitro (Hayflick, 1965). Evidence argues that cellular senescence probably evolved as a defense against cancer and as a response to DNA damage and genomic instability (Chen et al., 2007), and has to be seen as sitting, like apoptosis, as a critical adaptive checkpoint on all cell cycling. In this important sense, the cell cycle, apoptosis, senescence and carcinogenesis have to be all seen as intimately related biological processes. Although cellular senescence is popularly understood mechanistically as driven by a simple loss of telomeres, evidence argues that like all other phenotypes of aging, its true derivation is complex and highly multifactorial, and additionally, that loss of telomeres is not simply due to the total number of replication events, as originally assumed by

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Hayflick. Instead, evidence suggest many factors, particularly those related to chronic OS, chronic inflammation and even chronic emotional stress (perhaps as proxy for inflammation but perhaps reflecting other effects in addition to this) determine the rate of telomere loss, suggesting a critical role for lifestyle in protecting against loss of telomeres (Falus et al., 2010). Specifically, recent work has shown that cumulative inflammatory load, as indexed by the combination of high levels of IL-6 and TNF-α, is associated with increased odds for short telomere length in leukocytes (O’Donovan et. al., 2011). Emotional regulation may play an underappreciated role in protection of telomeres, and consistent with this, lifestyle interventions that reduce stress, such as mindfulness meditation, have even been shown to enhance both telomerase (Jacobs et al., 2011) and preserve telomeres (Epel et al., 2009). Additionally, recent work makes a principled distinction between cellular quiescence (cell cycle arrest) and cellular senescence (Blagosklonny, 2011), with the former reversible, and paradoxically, with activation of the progrowth mTOR pathways increasing the likelihood of senescence, while inhibition of TOR saves cells from this biological “dead-end” and shifts them into quiescence. Thus, cell signaling pathways involved in aging also have a critical role as well, suggesting that conjoined activation of DNA-damage sensing systems such as p53 and p21 (which orchestrate blocks on cell cycling) and growth pathways simultaneously helps to select senescence. Additionally, and perhaps critically important in many clinical situations, senescent cells develop a large cell morphology and become hypersecretory in a proinflammatory direction. This is part of the evidence that aging is a kind of a dysregulated “hyper-functional” state, driven in part by disinhibited growth signals (mTOR acting as a central integrator of those signals). As Blagosklonny states, “cellular functions are tissue-specific: contraction for smooth muscle cells, secretion of lipoproteins for hepatocytes, aggregation for platelets, oxidative burst for neutrophils, bone resorption for osteoclasts and so on. These hyperfunctions lead to age-related diseases, such as atherosclerosis, hypertension, macular degeneration, increasing the probability of organismal death” (Blagosklonny, 2011. p 95). Thus, as Blagosklonny notes, senescence reflects a biological version of cells responding simultaneously to “pressing the gas pedal” (growth drive) and “getting on the brakes” at the same time (cell cycle blocks driven by DNA-damage sensing systems). Additionally, senescence both promotes inflammation and is promoted by it, further underscoring recursive relationships between these phenotypes of aging, and offering further evidence of the Janus-faced nature of inflammation, as an example of antagonistic pleiotropy (Blagosklonny, 2011; Figure 1.1).That removing senescent cells slows aging in a progeroid mouse model demonstrates that senescence is not simply an aging phenotype

(an effect or component of aging), but a driver of aging itself (Baker et al., 2011). This is consistent with much other evidence that most if not all the phenotypes of aging reciprocally reinforce one another, consistent with a circular/ recursive causality model of biological causation.

Endocrine dyscrasia It has been only in the last 10 years or so (since the seminal paper of Bowen and Atwood, 2004) that evidence has accumulated for a primary role in aging for changes in the hormonal-reproductive (HPG) axis potentially characterized as an “endocrine dyscrasia”. Although many are aware of the more famous components of this dyscrasia (age-related declines in classic sex steroids with the decline in male testosterone more gradual but starting earlier than the steep menopausal decline of estrogen and progesterone in females), Bowen and Atwood have argued persuasively that the less appreciated upregulation of luteinizing hormone and follicle stimulating hormone from the pituitary and the associated increase in gonadotropin-releasing hormone (GnRH) from the hypothalamus to the pituitary (along with associated down regulation of inhibins and upregulation of activins—as peripheral modulators of HPG axis function) may play a central role in aging and its phenotypes. As Atwood and Bowen (2011) summarize, this theory is a clear extension of basic antagonistic pleiotropy concepts of aging: “hormones that regulate reproduction act in an antagonistic pleiotropic manner to control aging via cell cycle signaling—promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence. Since reproduction is the most important function of an organism from the perspective of the survival of the species, if reproductive-cell cycle signaling factors determine the rate of growth, determine the rate of development, determine the rate of reproduction, and determine the rate of senescence, then by definition they determine the rate of aging and thus lifespan.” (p.100). As support for the theory, HPG axis dysregulation may be a primary factor in AD, with elevation of luteinizing hormone and FSH, and decline of sex steroids as etiological, and as contributing to an exaggerated mitogenic signal that promotes beta-amyloid pathways, hyperphosphorylation of tau, synaptic retraction, and drives dysfunctional neurons into the cell cycle and from there into programmed cell death (Atwood et al., 2005; Casadesus et al., 2006). Challenges to this novel and heuristic theory of aging include relatively its undeveloped linkages to classic mTOR and insulin signaling pathways, as well as links to other classic aging phenotypes, such as mitochondrial decline, OS, and “inflammaging”. However, recent updates (Atwood and Bowen, 2011) summarize data linking evidence for endocrine dyscrasia with multiple diseases of aging, suggesting that an endocrine dyscrasia

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

(a)

(b)

UPS dysfunction

Normal DA content (%)

Unknown factors

Compensatory mechanisms

Stochastic interaction between multiple factors

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Normal aging

DA metabolism

DA neuron dysfunction and death Oxidative and nitrative stress

Inflammation PD (accelerated DA loss) Mitochondrial damage Threshold for PD

Time (yrs)

Accelerants • Genetic predispositions • Environmental toxins • Cellular predispositions • Prenatal infections • Unknown factors

Figure 1.1 Cell cycle factors related to aging based on the stochastic acceleration hypothesis of Collier, Kanaan & Kordower (2011). A revised

hypothesis of the relationship between aging and Parkinson’s disease (PD) as they affect the biology of midbrain dopamine (DA) neurons. The hypothesis incorporates evidence that supports the involvement of common cellular mechanisms in dopamine neuron dysfunction in ageing and degeneration in Parkinson’s disease. (a) The effects of these altered cellular mechanisms as they accumulate during normal ageing result in Parkinsonian dopamine neuron dysfunction, either very late in life or not at all (shown by the light gray line). However, when these same cellular mechanisms are accelerated by specific, individually determined factors, Parkinsonism emerges earlier in the lifespan (shown by the dark gray line). (b) The hypothesis contends that the cellular mechanisms that threaten dopamine neuron function are identical, but are not linked in an orderly cascade of cause and effect; instead, they can contribute to varying degrees and combine in patient-specific patterns, thus fulfilling the definition of a stochastic interaction: incorporating elements of randomness with directionality toward dopamine neuron dysfunction. Light gray double-ended arrows show cellular events in normal ageing. Thicker, dark gray doubleended arrows show accelerated cellular events in PD. UPS, ubiquitin-proteasome system. Similar mechanisms are implicated in cancer pathogenesis also. Source: Blagosklonny (2011). Reproduced with permission from US Administration on Aging.

may interdigitate with and generate reciprocal synergies with many other core phenotypes of aging mentioned in this chapter, particularly disinhibited particularly inflammation via promotion of TNF-α (Clark and Atwood, 2011). Novel approaches to antiaging therapies from this theory would centrally include efforts to normalize HPG axis function, not just through classic supplementation of sex steroids, but also intercepting other aspects of altered cell signaling, particularly overactivation of activins and an undersupply of inhibins, although these two latter manipulations are currently unavailable and represent highly appealing targets for future technologies.

The slowing of aging: dietary or calorie restriction and lifestyle interventions Calorie restriction: evolutionary and animal models Although the effects of CR on longevity were described more than 115 years ago (Jones, 1884), and its protection against the diseases of aging has been appreciated for

almost a century (Rous, 1914), only more recently have we begin to unravel the molecular mechanisms by which CR extends lifespan and protects the organism from agerelated change. CR functions as a kind of global metabolic reprogramming for virtually all organisms, extends lifespan, and reduces penetration of the diseases of aging significantly, if not dramatically, in most species in which it has been studied. Although the precise molecular pathways and cellular effects of CR are still being studied and debated, in general, it is viewed as a selected and phylogenetically conserved trade-off between reproductive fecundity and physiological conservation/preservation, and consistent with ideas in the previous section, results in a downregulation of the gonadotropic axis (Bowen and Atwood, 2004). A basic speculation has been that some version of a basic CR mechanism arose relatively early in evolution, during common periods of nutrient shortfalls, to allow organisms to trade off reproduction for conservation (when major energy shortages would have made reproductive efforts too metabolically costly), allowing an adaptive shift back to growth and reproduction at a time when nutritional supplies were more abundant.

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Recent work has confirmed that CR effects are conserved virtually throughout the entire animal kingdom, starting with organisms as primitive as yeast and extending into insects and other invertebrates, lower vertebrates such as fish, mammals (Fernandes et al., 1976), primates (Lane et al., 2001; Roth et al., 2001), and even humans (Rochon et al., 2011), although long-term studies on CR effects in humans are still lacking. (Short-term studies clearly demonstrate that the basic physiology of CR is well conserved in humans, but life extension—confirming that aging is indeed slowed—has not yet been empirically confirmed. Most researchers, however, anticipate that this will be eventually demonstrated.) CR/DR lacks a precise quantitative definition but might be considered to reflect a roughly 30% reduction in calories from eating freely until satiation (Richardson, 1985). CR effects for many species might begin at around a 25% to 30% reduction and extend to a 50% to 65% reduction, at which point CR transitions into starvation, a process that does not demonstrate any of the protective effects of CR and actively destroys global health. CR also requires that basic macro- and micronutrients be obtained (vitamins, minerals, fatty acids, and at least some protein). CR/DR is probably not a simple “homogeneous” issue, and can include differential restriction of proteins, carbohydrates, and fats, with these different forms of DR probably activating different cellular pathways involved in nutrient sensing and, therefore, having somewhat different physiological effects. However, protein and amino acid restriction clearly appears to be the more critical component, as protein restriction without CR elicits a significantly more robust profile of CR effects (Simpson and Raubenheimer, 2009) than the reverse (CR but without protein restriction; Kim et al., 2010a). Reasons for this may hinge on the importance of protein restriction for downregulation of mTOR, which is required for maximal CR benefits (see Section “Mammalian target of rapamycin”). Protein restriction may cause downregulation of growth factors and growth hormones (particularly GH, but also IGF), as well as provide downstream inhibition of TOR pathways (Figures 1.2, 1.3 and 1.4), improving autophagy and decreasing protein synthesis, among other effects, and may be particularly protective in relation to carcinogenesis (Anisimov et al., 2010); CR without protein restriction may not be nearly as protective in relation to cancers (Baur et al., 2006). Carbohydrate and glucose restriction, on the other hand, may more directly modulate insulin pathways and their several downstream targets. Intriguingly, evidence indicates that single amino acid restriction (specifically limiting dietary methionine or tryptophan) can yield CR effects (Caro et al., 2009), with subsequent reduced ROS in the mitochondria, lowered insulin and blood sugar levels, improved insulin sensitivity, and more (in other words, a CR physiology). This suggests an intriguing and perhaps less burdensome

Glucose Testosterone

Amino acids

Insulin

Fatty acids

IGF-1

TOR

Growth Hyperfunction

Aging Diseases of aging Life time

Figure 1.2 A simple schematic for the molecular pathway of mTOR

as “antagonistic pleiotropy”–that, in some sense, aging is simply the flip side of a protracted growth process that is not sufficiently turned off after a peak reproductive period. Source: Blagosklonny (2009). Reproduced with permission from US Administration on Aging.

option to classic CR approaches, without at least some of the aversive effects of classic CR diets (foods high in methionine include eggs, fish, soy, and many seeds, especially sesame seeds). CR without protein restriction, on the other hand, may not produce lifespan extension, probably because of a blunting of the CR protective effects against carcinogenesis, as well as perhaps a more limited downregulation of IGF (and other growth factors) and lessened overall inhibition of mTOR (Anisimov et al., 2010; see the next sections on mTOR).

Calorie restriction

Insulin IR S1/2

GF

PI-3K

LKB1 AMPK

Metformin

TOR S6K

Environmental factors

Aging Age-related diseases

RAPA Other genetic factors

Figure 1.3 A simple schematic of some of the cellular pathways

implicated in calorie restriction, aging, and the slowing of aging. Nutrients, growth factors (GF), and insulin activate the TOR pathway, which is involved in aging and age-related diseases. Other genetic factors and environmental factors (such as smoking, sedentary lifestyles, and obesity) contribute to age-related diseases. Several potential antiaging modalities (metformin, calorie restriction, and rapamycin and several polyphenols particularly resveratrol) all directly or indirectly (via impact on AMP kinase) inhibit the TOR pathway. Source: Blagosklonny (2009, 2010a). Reproduced with permission from US Administration on Aging.

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

Low P:C diet

Levels of glucose

AMPK activity

Levels of glucose

TOR activity

Levels of amino acids

High P:C diet

Levels of amino acids

Leptin; insulin/IGF; etc.

Stress factors; sirtuins; etc

High aa:glu

Insulin resistance; autophagy and repair inhibited

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Nutrients

TOR

Low aa:glu

AMPK Eat less

Insulin sensitivity; autophagy and repair promoted

Eat more

Anabolic responses

Catabolic responses

Protein synthesis, lipogenesis, cell proliferation, growth, reproduction

Cell cycle arrest, inhibition of growth and reproduction, lipolysis, proteolysis

Vicious cycle to obesity Overeat on low %P diets Live longer Obesity and insulin resistance Die early Lipolysis, elevated FA, lean muscle breakdown, enhanced hepatic gluconeogenesis Figure 1.4 A schematic summarizing the hypothesis

for how diet balance might affect lifespan via the TOR and AMPK signaling pathways. Source: Simpson and Raubenheimer (2009). Reproduced with permission from US Administration on Aging.

Calorie restriction: genes and pathways Many genes and molecular pathways are implicated in CR effects, consistent with the previous discussion. Indeed, many researchers and theorists at this point believe that CR involves a whole family or network of interacting molecular pathways. These would include insulin signaling 1/2, IGF and other growth factors, PI3 kinase, AKT (protein kinase B), forkhead transcription factors, PGC1- , AMP kinase, sirtuins, and mTOR (Figures 1.3 and 1.4). This network of pathways argues against any version of a single primary pathway being responsible for CR effects, and suggests a highly pleiotropic phenotype, consistent with other evidence that adaptive growth processes must be, by necessity, sensitive to a host of signals (see Section Mammalian Target of Rapamycin). Thus CR as a protective and antiaging intervention, probably operates through a network of linked molecular pathways, where recursive interactions and relationships may be incompletely understood at present. Although a class of transcription factors called sirtuins, particularly SIRT1, were initially conceptualized as the critical regulators of CR effects (Sinclair, 2005),

Depleted muscle mass and aa pool; reduced lean signal (IL15?); low aa:glu; high AMPK

recent work suggests that SIRT1 may operate on and influence some, but not all, of the CR network, while SIRT3 may also be critical as well. However, research suggests that CR (if it includes significant protein restriction) downregulates mTOR while also upregulating AMPK (Baur, 2006), up-regulates several sirtuins (Sinclair 2005), promotes mitochondrial biogenesis, and significantly reduces inflammation (Figures 1.3 and 1.4). Effects from inhibition of TOR are increasingly thought to be critical to mediating lifespan extension and slowing the aging process with DR. As a result, this TOR pathway has supplanted the sirtuins as the most studied and most intriguing cell-signaling group of pathways in aging (and antiaging) science. As such, it merits a detailed overview.

Mammalian Target of Rapamycin Target of rapamycin (TOR) belongs to a highly conserved group of kinases from the PIKK (phosphatidylinositol) family, increasingly conceptualized as core and essential integrators of growth signaling. Knockout of mTOR is consistently embryonically lethal across several species,

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The Aging Brain in Neurology

suggesting a strong antagonistic pleiotropy affect for this particular gene (Blagosklonny, 2010a). Rapamycin, an immunosuppressive macrolide, was first discovered as the product of a soil bacteria from Easter Island. It directly and potently inhibits the activity of TOR (TOR complex 1 (TORC1), but not until recently did we understand that it also impacts TOR complex 2 (TORC2)). TOR was first identified in yeast but subsequently has been found to exist in all eukaryotic organisms. TORC1 (rapamycin sensitive) is thought to be the central element of the TOR signaling network, monitoring and integrating a large set of intra- and extracellular processes and controlling growth, proliferation, and lifespan with a host of complex downstream effects (Kapahi et al., 2010). TORC2 is also rapamycin sensitive, but contributes to the full activation of AKT, an upstream and critical signaler of TORC1; it also mediates spatial control of cell growth by regulating the actin cytoskeleton (Hall, 2008) and disruption of TORC2 by rapalogs appears to drive the “paradoxical” insulin resistance seen in chronic administration (Lamming et al., 2012). TOR plays a highly conserved and central role in coupling nutrient sensing to growth signals, integrating signals from wnt-β-catenin signaling pathway (growth factors involved in stem cell differentiation and regulation), glucose and lipid availability (signaled by AMP kinase), protein and amino acids deficiency or availability (growth resources), signals from multiple other growth factors and hormones, and even oxygen availability and hypoxia signals to dynamically determine the envelope of growth versus conservation signaling in the cell. TORC1 is thus thought to act as a growth “checkpoint” and signal integrator, determining whether the extra- and intra cellular milieu is favorable to growth and, if not, producing effects consistent with a CR phenotype. TORC1 has many output targets, altered in either CR or CR mimetic effects from rapamycin, including messenger RNA translation (inhibited in CR), autophagy (increased in CR), transcription and ribosome biogenesis (inhibited in CR), proliferation and growth (inhibited in CR), and several other key cellular processes, including stress resistance (increased by CR); for a fine technical review of TOR research, see Kapahi et al. (2010). Inhibition of mTOR by rapamycin has been shown experimentally to increase lifespan, even when given to mice in late middle age (Harrison et al., 2009). This finding suggests that rapamycin is a more powerful CR mimetic than resveratrol, which has failed to extend lifespan outside of obese animals (Baur et al., 2006; Miller et al., 2011). On the basis of age at 90% mortality, rapamycin led to increased lifespan of 14% for females and 9% for males. Intriguingly, patterns of mortality and disease in rapamycin-treated mice did not differ from those of control mice, suggesting that treatment with rapamycin globally delays aging and age-related disease in a nonspecific and fairly “even” fashion (Harrison et al., 2009),

arguing for at least some involvement of mTOR in virtually all age-related disease that might cause or contribute to mortality (at least in mice). Inhibition of TOR’s major downstream targets, such as S6K, a kinase involved in ribosome biogenesis, appears to be important to the protective (antiaging) effects of TOR inhibition, and a knockout of this gene (S6K) also increases lifespan in mice and, intriguingly, generates activation of AMP kinase; this suggests dynamic relationships between mTOR and AMP kinase (Selman et al., 2009) that are probably incompletely mapped at this time (as two core primary mediators of CR/DR effects). Figure 1.4 (from Simpson and Raubenheimer, 2009) schematically summarizes relationships between AMP kinase and mTOR. These two kinases are increasingly viewed as possibly integrating much of CR physiology, with an upregulation of AMP kinase and a downregulation of mTOR potentially orchestrating the entire range of CR effects through their conjoint activity. These two kinases are differentially involved in nutrient sensing, with TOR activated by high amino acid/glucose ratios (in other words, plenty of amino acids and proteins to build new tissue, thus releasing a “go” signal to anabolic processes and growth) and AMP kinase activated by low amino acid/glucose ratios. Thus, protein/carbohydrate dietary ratio may influence differential activation/inhibition of TOR and of AMP kinase (and these two integrators of CR physiology are also interactive, with AMP kinase inhibiting mTOR). These differential nutrient-sensing systems may help explain why CR without at least some protein restriction may not be as effective as a general antiaging strategy (Blagosklonny, 2010a, 2010b), particularly in relation to the prevention of cancers, because such a diet does not maximally downregulate mTOR. Additionally, Figure 1.4 may help explain why resveratrol by itself (a primary activator of AMP kinase, but not a primary or direct inhibitor of mTOR) does not produce a lifespan extension in animal models (outside of obesity) because it does not inhibit mTOR sufficiently.

Calorie-restriction mimetics Given the intrinsically stressful and unpleasant nature of basic CR approaches (for example, CR animals typically cannot be housed together because they are too irritable and will fight), most believe that CR is simply not a viable health-maintenance strategy for most people. If anything, the recent pandemic of obesity has underlined that most individuals, when given ready access to tasty and addicting high-calorie-density foods, are simply not going to restrict their calorie intake voluntarily, regardless of the well-known and widely appreciated negative consequences. This has led to increasing interest in CR mimetics, defined as any substance that potentially mimics the molecular effects and physiology of CR (without the stress of making a person hungry much of the time). There are probably many substances that cause

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

mild nausea, visceral upset, or other GI distress and that subsequently inhibit food intake, but although these can show CR effects in sustained administration in animal models, they cannot be considered CR mimetics. Additionally, drugs that may directly modulate appetite (such as Rimonabant, an endocannabinoid-1 receptor blocker) might also show CR effects in sustained administration by modulating consumption and hunger drive at central levels, but they also cannot be considered true CR mimetics. One emerging prediction might be that CR mimetics will occupy an increasingly central role in primary prevention in relation to the diseases of aging in the coming decades, but an enormous amount of basic research remains to be done before widespread implementation of CR mimetics would be advisable or feasible; long-term data in both preclinical and clinical populations also is lacking (although data collection and trials of CR mimetics are underway in relation to many diseases of aging). There are actually a number of CR mimetics with accumulating research supporting CR effects, but the most famous of these is clearly resveratrol, a molecule that has received enormous research attention in the last 15 years. In addition, metformin is a true CR mimetic (a drug commonly used to treat type II diabetes and rarely categorized in conventional medical literature as a CR mimetic) and 2-deoxyglucose are CR mimetics (2-deoxyglucose was actually the first described CR mimetic and interferes with glycolysis, preventing glucose utilization by cells even when abundant glucose is available, but it is cardiotoxic in chronic administration). Fisetin, derived from Fustet shrubs, is a flavonoid polyphenol that has also demonstrated CR mimetic effects. Rapamycin (as a primary inhibitor of TOR) is also a potent CR mimetic; to date, only rapamycin has demonstrated lifespan extension when given to older mammals (many CR mimetics have demonstrated lifespan extension in other target species, such as yeast, fruit flies, fish, and worms). Other polyphenols (a very large group of compounds found in fruits and vegetables, totaling perhaps as many as 6000 substances) may have mild CR effects, particularly quercetin, resveratrol, and its first cousin, pterostilbene (Belinha et al., 2007). However, single-polyphenol regimens, particularly resveratrol, have not shown lifespan extension (Pearson et al., 2008)2, except in obese animals (protecting mice from premature mortality and the undesirable physiology of obesity (Baur et al., 2006) or cases in which resveratrol was combined with every-other-day dieting (EOD) as a

2

Given that AMP kinase inhibits mTOR, resveratrol might have some modest indirect effects on this critical pathway. Studies on resveratrol reviewed in later sections (see the section on CR mimetics) suggest that mTOR inhibition is likely to be modest, given the absence of lifespan extension in mammalian animal models, outside of obese animals, where its AMPK promotion may be protective and promote similar aging trajectories to non-obese animals.

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mild CR alternative (also demonstrated in a mouse model in Pearson et al., 2008). Although resveratrol was initially assumed to have its protective effects through SIRT1 activation, recent work has clarified that AMP kinase is probably the necessary and sufficient target for the protective effects of resveratrol (Um et al., 2010). Recent work has suggested that pterostilbene may be a more effective CR mimetic, with better bioavailability than resveratrol, and also a better activator of PPAR-α (Rimando et al., 2005), with more beneficial effects on lipid profiles, while still showing extraordinarily low toxicity (Ruiz et al., 2009). Evidence suggest that resveratrol and its analogs, like pterostilbene (along with metformin and quercetin, two other CR mimetics), are probably only partial CR mimetics; even moderately high-dose resveratrol (20–30 mg per kilogram) does not appear to protect mice against latelife cancers (particularly a form of virally induced lymphoma, a very common cause of death in aged laboratory mice; Pearson et al., 2008) and does not extend lifespan outside of obese animals. Intriguingly, a nutraceutical combination of resveratrol and quercetin appeared to provide better mimicking of CR physiology than resveratrol alone (Barger et al., 2008; although longevity was not indexed specifically). This suggests that combinations of partial CR agents may get us closer to mimicking a full CR physiology than a single compound particularly a combination of rapamycin and an AMPK modulator such as resveratrol or metformin -- a logical combination that has yet to be tested, and where AMPK modulation might help reduce the insulin resistance seen on chronic administration of rapalogs (associated with its TORC2 disruption). These considerations (Figure 1.4, by Simpson and Raubenheimer 2009) suggest that a complete or ideal CR mimetic might both activate AMP kinase and directly inhibit mTOR (not simply indirectly through increased AMPK activity), without toxicities or major side effects, a design target that no single known compound at this time yet achieves. Inhibition of mTOR (via rapamycin) has shown promising protection against diseases of aging in mammalian animal models (Stanfel et al., 2009). Perhaps a combination of low-dose rapamycin and resveratrol or pterostilbene might achieve the desirable targets of mTOR inhibition and AMPK activation, and thus function as a full CR/DR mimetic. To prove this in a mouse model, one would have to show further protective benefits from those achieved with rapamycin alone if resveratrol or pterostilbene were added in late middle age. This intriguing hypothesis has never been probed or tested even in a mammalian animal model. Full testing of these ideas in humans appears even further away, underlining an enormous gap between research promise and clinical reality in this vital area of biological science. Given the potential impact that a full, robust, and safe CR mimetic could have on aging and the diseases of aging (particularly the potential extension of “healthspan”), there is remarkably little

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research into this area, relative to its potential biological promise. Indeed, conventional medicine still sees CR/DR and CR mimetics largely as biological “fringe” subjects, instead of appreciating their potentially enormous protective functions and central and paradigmatic insights. Large pharmaceutical firms have just recently begun to pay more attention to this area of CR and its mimetics (see the recent GSK acquisition of Sirtris, www.gsk.com/ media/pressreleases/2008/2008_us_pressrelease_10038 .htm).

Calorie-restriction variants and mutants There are many ways to generate CR effects, beyond classic CR approaches. One of the most basic of these is simply intermittent fasting (which may not result in nearly as much weight loss as full CR but still activates a CR physiology), along with methionine restriction (as noted earlier). In addition, there is manipulation of growth hormone (such as growth hormone knockout) and IGF-1 and insulin signaling manipulations (consistent with overwhelming evidence that insulin-signaling pathways are primary targets for CR effects; Figures 1.3 and 1.4). A dwarf mouse implementing a growth hormone knockout shows a roughly 60% life extension (and won a recent Methuselah prize; Bartke and Brown-Borg, 2004). This animal showed reduced hepatic synthesis of IGF-1, reduced secretion of insulin, increased sensitivity to insulin actions, reduced plasma glucose, reduced generation of ROS markers, upregulated antioxidant defenses, increased resistance to OS, and reduced oxidative damage, all quite consistent with CR physiology. Probably many dozens of genes can be modified to yield some variation of a CR physiology and at least some increase in longevity (and therefore slowing of aging), consistent with the evidence that CR/DR activates a complex and highly interactive network of cell signaling and regulatory pathways (Yuan et al., 2011; Lorenz et al., 2009).

Lifestyle and dietary factors There is increasing, if not collectively convincing, evidence that core lifestyle factors such as exercise and diet (as well as sleep quality and social stress vs social comfort) potentially influence many aspects of aging, thus constituting a complex collection of negative and positive risk factors for all the diseases of aging. This collection of lifestyle variables are also presumably interactive with a small group of known polymorphisms and a likely much larger group of unmapped polymorphisms that collectively may have a large effect on longevity (Yashin et al., 2010) and risk for specific diseases of aging. Future mapping of those polymorphisms (and their likely complex interactions with lifestyle variables) may allow much better prediction of risk, and eventually allow for more effective and tailored early interventions, to reduce specific

risk for a particular disease of aging. As but a small example of these issues, IL-10 endowment may affect risk for AD. Although a good night’s sleep, a healthy and more balanced diet, regular aerobic exercise, and social support are generally regarded as having nothing to do with each other biologically, recent work in relationship to all of these lifestyle factors suggests that they impact a broad but fundamentally shared set of cellular and molecular pathways. These shared effect pathways include multiple if not most aspects of cell signaling (internal cellular regulation): regulation of cell cycling, regulation of inflammatory, stress, defense and growth pathways, including mTOR. Although our understanding of diet, exercise versus sedentary lifestyle, sleep, and stress versus social comfort is still evolving, evidence suggests that basic lifestyle factors either promote or inhibit inflammation, protect insulin sensitivity versus generating insulin resistance, and create more OS versus protect against it, while promoting (or inhibiting) autophagy, cellular senescence, and apoptosis in aging, thus modulating virtually every known phenotype of aging. Additionally and rarely appreciated within traditional medicine, all the individual components of so-called healthy lifestyle practices appear to be part of our ancient evolutionary environment and reflect HG lifestyle characteristics. This suggests the possibility of a version of a “unified field theory” in relationship to long-term health versus chronic disease, and that healthy living may reduce complex and still poorly understood “mismatches” between our genome and our current biological environment in Western societies. In general, such ideas have little current visibility within conventional medical circles (although a reprioritizing of prevention is now being widely emphasized), but a nascent awareness of these more global biological perspectives on health versus chronic disease is slowly emerging, energized by increasing research into lifestyle and its complex biological impact.

Exercise Regular aerobic exercise is widely recognized as an essential component of a healthy lifestyle, yet fewer than 15% of individuals living in the United States engage in adequate amounts of aerobic exercise; a majority of people in the United States are almost completely sedentary (Roberts and Barnard, 2005). Sedentary lifestyles are thought to contribute to risk for all diseases of aging, particularly cardiovascular disease, metabolic syndrome, and type II diabetes, especially when combined with a Western diet. Exercise has an extremely complex biological footprint, but among its many effects, exercise offers protection against all-cause mortality, particularly against atherosclerosis, DMII, and several but perhaps not all cancers, notably colon and breast cancer. It also significantly reduces frailty and sarcopenia. Regular exercise appears specifically protective against diseases associated

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

with chronic low-grade systemic inflammation (Peterson and Peterson, 2005), perhaps due the anti-inflammatory response elicited by an acute bout of exercise, largely mediated by muscle-derived IL-6. IL-6 stimulates production of anti-inflammatory cytokines (such as IL-1ra and IL-10) and inhibits subsequent (postexercise) production of the key proinflammatory cytokine TNF-α. In addition, IL-6 stimulates lipolysis and fat oxidation and metabolism (see Peterson and Peterson, 2005 for a detailed review). These anti-inflammatory effects also inhibit insulin resistance, which is partly modulated by TNF-α and by NFκ-B/AP-1, transcription factors centrally involved in inflammatory signaling. Exercise may also upregulate antioxidant defenses (Kaliman et al., 2011), while OS actually initially increases during a bout of exercise, with subsequent upregulation of endogenous defenses (referred to as mitochondrial hormesis or “mitohormesis”). Some work on the effects of exercise calls into question the conventional wisdom of blocking OS, as evidence suggests that this actually impairs exercise benefit and even may prevent beneficial effects of CR (Ristow and Schmeisser, 2011). Exercise may also increase neurotrophins, improve stress resistance, improve mood, increase emotional and stress resilience, and enhance cognitive function and learning (Ratey, 2009), and consistent with these effects, at least some preventative/protective effects against most neurodegenerative disorders, particularly AD, have also been demonstrated.

Obesity One of the most worrisome public health trends over the last 20 years has been a steady and dramatic increase in the prevalence of overweight and obese individuals. Current statistics suggest that roughly one-third of the United States is obese (with a body mass index (BMI), greater than 30), with another one-third of the population overweight (BMI over 25 but less than 30; Wang et al., 2007). Additionally some evidence suggests that the rate of obesity is still increasing despite much attention to this public health issue, and may reach 50% penetration in the United States by 2025. Equally worrisome is the emerging evidence that the rates of obesity in the United States are actually higher in children than in adults, perhaps due to a highly undesirable combination of increasingly sedentary gameplay (in which video games have largely supplanted more physical activity), increasing fast food consumption, and overconsumption of sugary beverages. Obesity is increasingly appreciated as a risk factor for virtually every disease of aging, beyond its popular link to risk for cardiovascular disease. Obesity contributes significantly to risk for hypertension, dyslipidemia, insulin resistance and type II diabetes, multiple cancers, and even AD. Evidence suggests that increased abdominal fat (vs subcutaneous fat) is a more significant risk factor than generalized obesity, and this relationship is potentiated,

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curiously enough, in otherwise leaner subjects (Pischon et al., 2008), as abdominal fat may have a particularly potent effect on dysregulation of inflammation (Fontana et al., 2007) via promotion of proinflammatory cytokines. Aging itself decreases subcutaneous fat while increasing abdominal fat, and simply reducing abdominal fat surgically has a prolongevity effect in animal models. Increased visceral fat is independently associated with all-cause mortality, insulin resistance and diabetes, cardiovascular disease, cerebrovascular disease, AD, and disability in the elderly (Florido et al., 2011). Additionally, there is evidence for intrinsic relationships between obesity and upregulated inflammation (in part as compensatory and a way of using more energy) and, on the other hand, CR and reduced inflammation (Ye and Keller, 2010).

Polyphenols Although conventionally regarded as “antioxidants”, polyphenols are an enormous class of substances (constituting perhaps as many as 6000 distinct compounds) found in plants, principally fruits and vegetables, that have enormously pleiotropic effects on human and mammalian physiology. Some of these effects may be more biologically significant than any direct “free radical scavenging” done by any polyphenol; they include many effects on cell signaling, the regulation of growth factors and apoptosis, the regulation of cell cycling, the regulation of inflammation, the modulation of many (if not most) cellular stress pathways, an impact on multiple transcription factors (including those involved in energy homeostasis), and (consistent with their conventional designation) the management of OS (Virgili and Marino, 2008). Many of these effects on aspects of cell signaling require much lower levels of polyphenol than any direct free radical scavenging in serum or tissues. Indeed, from this perspective, polyphenols look less like “antioxidants” and more like complex cell physiology and cell signaling modulators. However, it seems unlikely that such a designation will replace the catchy title of “antioxidant,” even in the context of increasing evidence that such a title may be fundamentally if not profoundly misleading. Many, if not most, of the phenotypes of aging (OS, mitochondrial dysfunction, inflammation, and declining autophagy, among others) appear to be partially modulated by various polyphenols. From this perspective, if our ancestors consumed more plants than we do and did so over tens of thousands of years (if not much longer), the relative removal of polyphenols from the human diet (in those eating minimal fruits and vegetables) would be predicted to have complex but potentially profound effects on physiology and on the biological trajectories of aging. Conversely, those eating a rich variety of plants may be more protected against accelerated aging and the diseases

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of aging. Of these two predictions, the second has been better studied, and is generally supported, while the first has some evidence for it as well, but is not well elucidated. Polyphenols consist of several classes of chemical substances, including nonflavonoid compounds (such as resveratrol, other stilbenes, and curcuminoids), and classic flavonoids (consisting of two large classes, anthocyanins, which are colorful and pigmented, and anthoxanthins, which are colorless). Resveratrol and its first cousin, pterostilbene, are both naturally occurring phytoalexins produced by plants in response to fungal infection (phytoalexins are all “plant defense” compounds). Of the anthoxanthin family, quercetin is one of the best-known and best-studied members, along with EGCG (a member of the catechins family, with catechins constituting a large group of polyphenols in tea and wine). Dietary sources for polyphenols include many foods that have been ancient components of the human diet for many hundreds and even thousands of years: fruits and their juices (typically containing both anthocyanins and anthoxanthins), tea (catechins), coffee (chlorogenic, caffeic and ferulic acids), red wine (anthocyanins, resveratrol, and quercetin), vegetables (many anthoxanthins and anthocyanins), some cereals, chocolate (multiple flavonoids, including catechins and proanthocyanidins), and various legumes, particularly soy (isoflavones) and peanuts. In this context, there are multiple challenges to any emerging science that might explain the roles polyphenols could play in health maintenance and the slowing of at least some aspects of aging and/or age-related disease. First, there are many thousands of different bioflavonoids in toto, but only a handful with much in vivo research (resveratrol, curcumin, green tea extract, and quercetin are perhaps best studied). Most of the studies of polyphenols use in vitro approaches; although there are increasing numbers of in vivo studies in animal models, very few clinical studies have taken place in humans. As an additional major challenge to potential therapeutic use, virtually all bioflavonoids have relatively poor bioavailability, which may be part of their extraordinarily nontoxic biological footprint. Most polyphenols are rapidly conjugated (typically sulfated and glucuronided), and variably metabolized, often with an uncertain biological status of their multiple metabolites. The proper study of any polyphenol in potentially slowing or preventing any disease of aging is methodologically challenging and also expensive (long time frames are needed and it is difficult to control for many other positive and negative lifestyle risk factors). With all these scientific and methodological challenges, there is little financial incentive to study polyphenols in humans in relation to the diseases of aging or aging itself, given the poor return on investment with inexpensive agents that cannot be patented. This collection of factors has generated the current situation, where one finds much promising animal-model data for

multiple polyphenols in relation to a disease of aging, but a dearth of good human clinical studies. This is changing slowly, and several polyphenols are in clinical trails related to several diseases of aging. One of the few completed studies of a polyphenol in a human clinical population demonstrated that resveratrol is effective at higher doses in treating diabetes (Patel et al., 2011). Clinical studies are underway related to cancer, AD, and heart disease. Curcumin is also being increasingly studied for its anti-inflammatory, antiproliferative, and antiaging effects. Curcuminoids are thought to affect many dozens of cellular pathways and, like many polyphenols, block NF kappa-B, a transcription factor involved in the regulation and activation of inflammatory responses (Aggarwal, 2010). Curcumin is also one of several polyphenolic inhibitors of mTOR, a critical nutrient-sensing and growth factor integrative pathway that is increasingly implicated as a molecular target of CR; if inhibited, it may slow aging and also inhibit or delay diseases of aging (Beevers et al., 2009), but curcumin has notoriously poor bioavailability and rapid metabolism (Bengmark, 2006).

Diseases of aging (with particular relevance to neurology) This list of diseases is truncated due to space considerations, and does not include many important illnesses, including motor neuron diseases, frontotemporal lobar degenerative disorders, and various brain cancers. Cardiovascular disease Although “cardiovascular disease” technically refers to any disease that affects the heart or blood vessels, the term has become increasingly synonymous over the last 20 years with atherosclerosis. This disease of aging is directly responsible for more deaths than any other in Western societies, killing twice as many individuals as all cancers combined and probably more than all the other diseases of aging put together (Minino et al., 2006). Thus, it clearly merits a summary review. Evidence argues that lifestyle and cultural factors have to be considered as primary etiological issues here. As Kones pointedly states “Americans are under assault by a fierce epidemic of obesity, diabetes, and cardiovascular disease, of their own doing. Latest data indicate that 32% of children are overweight or obese, and fewer than 17% exercise sufficiently. Over 68% of adults are overweight, 35% are obese, nearly 40% fulfill criteria for metabolic syndrome, 8–13% have diabetes, 34% have hypertension, 36% have prehypertension, 29% have prediabetes, 15% of the population with either diabetes, hypertension, or dyslipidemia are undiagnosed, 59% engage in no vigorous activity, and fewer than 5% of the US population qualifies for the American Heart Association (AHA) definition of ideal cardiovascular health. Health, nutrition, and exercise illiteracy is prevalent, while misinformation and unrealistic expectations are the norm. Half of American

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

adults have at least one cardiovascular risk factor. Up to 65% do not have their conventional risk biomarkers under control. Of those patients with multiple risk factors, fewer than 10% have all of them adequately controlled. Even when patients are treated according to evidence-based protocols, about 70% of cardiac events remain unaddressed. Undertreatment is also common. Poor patient adherence, probably well below 50%, adds further difficulty in reducing cardiovascular risk. Available data indicate that only a modest fraction of the total cardiovascular risk burden in the population is actually now being eliminated. A fresh view of these issues, a change in current philosophy, leading to new and different, multimechanistic methods of prevention may be needed. Adherence to published guidelines will improve substantially outcomes in both primary and secondary prevention. Primordial prevention, which does not allow risk values to appear in a population, affords more complete protection than subsequent partial reversal of elevated risk factors or biomarkers” (Kones, 2011, p. 61). Consistent with these statements, recent research demonstrates that the underlying process of atherogenesis is a complex and long-term process involving many players, including endothelial cells, cytokines and immunoglobulins, immune cells, growth factors, extracellular matrix molecules, and lipids, but with a primary role for OS and inflammation. Atherogenesis requires a cascade of processes, starting with a maladaptive, sustained proinflammatory reaction to oxidized lipid deposition in the arterial wall. The initiating event appears to be the deposition of apoB-containing lipids, typically oxidized low-density lipoproteins. Oxidation of these lipids dramatically increases the likelihood that the deposition process will irritate the vessel, promoting increased proinflammatory cytokine release; this suggests that plasma redox balance may be a critical variable (Maharjan et al., 2008). Hyperlipidemia is also associated with declining endothelial nitric oxide synthase (eNOS) and increasing nitroxidative stress in the endothelium (Heeba et al., 2009). These inflammatory cascades lead to accumulation and swelling in arterial structures, mostly from macrophage cells combined with lipids (principally, oxidized low-density lipoprotein (LDL), VLDL, and other fatty acids), calcium (particularly in advanced lesions), and a certain amount of fibrous connective tissue. Glycation of proteins (an intrinsic component or phenotype of aging), as well as foreign antigens, can also promote these fundamental inflammatory changes (Milioti et al., 2008), with regions of more glycated tissue and AGEs promoting and accelerating the formation of these plaque structures (Kim et al., 2010b). These slowly developing structures (atheromatous plaques) are found at least to some degree in most individuals in Western societies, and early asymptomatic stages of this process are found in many young adults; however, they are rare in HGs (Eaton et al., 1988 a,b). LDL is the most common ApoB plasma lipoprotein, but ApoB-containing VLDL,

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remnant VLDL (depleted of triglycerides), intermediatedensity lipoprotein (IDL), and LP(a) have also been shown to be atherogenic, along with ApoB from chylomicron remnants; this suggests that many forms of lipid contribute to risk. These lesions actually begin in childhood and develop slowly over many, many decades. The early stages of deposition are called “fatty streaks,” but they are not composed of adipose cells; instead, they consist of white cells, especially macrophages, that have taken up oxidized LDL. After these cells accumulate large amounts of cytoplasmic membranes (and high cholesterol content), they become “foam cells.” When foam cells undergo apoptosis, the contents are deposited into the surrounding tissue, attracting more macrophages and inflammation, and causing a positive and self-sustaining feedback loop. Upon activation by proinflammatory stimuli, macrophages and lymphocytes release proinflammatory cytokines that stimulate the migration of smooth muscle cells (SMCs) from the medium of the vessel wall. SMCs then contribute to more foam cell and fibrous cap formation, also under the influence of proinflammatory cytokines (for example, IFN-γ and TNF-α secreted by T helper cells, and IL-12 secreted by macrophages and foam cells; Milioti et al., 2008). Eventually, foam cells die via apoptosis, dumping nondegradable cholesterol crystals that form the lipid core of the plaque structure. Plaque structures can be either stable or unstable, with vulnerable plaque tending to be faster growing and with higher macrophage content, suggesting that autoinflammatory processes not only contribute to the early, more silent stage of the process, but also drive the deadly late stages of the process well. Recent work by Wang et al., 2011 suggests a potentially pivotal role by immunoglobulins (IgE) as a critical player in the activation of macrophages, and with high correlations between IgE levels and degree of plaque instability. Although popularly viewed as a disease of cholesterol (a perspective that dominated the earlier conceptualizations of vascular disease in the 1960s and 1970s), increasing scientific opinion favors atherosclerotic vascular disease as a disease of inflammation and OS. Consistent with this, increasing evidence shows that statins actually impact both inflammatory and OS issues (Heeba et al., 2009), while promoting upregulation of heme oxygenase (an important antioxidant defense enzyme). Statins appear to inhibit vascular disease through pleiotropic mechanisms, including decreased synthesis of LDL, increased removal of LDL (through hepatic LDL receptors), upregulation of eNOS, increased tissue-type plasminogen activator, and also inhibited endothelin 1, a potent vasoconstrictor and mitogen. All of these promote improved endothelial function. Statins also reduce free radical release, thus inhibiting LDL-C oxidation (Liao and Laufs, 2005), while increasing endothelial progenitor cells and reducing both the number and activity of inflammatory cells and cytokines. They also may help stabilize atherosclerotic plaques, reduce production of

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metalloproteinases, and inhibit platelet adhesion/aggregation (Liao and Laufs, 2005). Although it is extremely common in Western societies (at least in some stage, even if clinically silent), extensive vascular disease is virtually nonexistent in HG groups (Eaton and Eaton, 2002). This suggests a primary role for etiology in the Western lifestyle and diet (see later sections on diet and lifestyle variables), in which multiple, if not virtually all, components of the Western diet and lifestyle appear proinflammatory relative to HG lifestyles (sedentary vs highly aerobically active, altered omega-6/ omega-3 ratios, poorer sleep, greater social isolation, lower consumption of fiber, lower consumption of protective polyphenol phytochemicals, and high BMI vs low BMI in HG groups). In addition to atherosclerosis (which is clearly the largest problem in pathological vascular aging in Western cultures), there is also vascular aging independent of atherogenesis. Increasing evidence implicates angiotensin II (Ang II) signaling as central to this process (Wang, Khazan, and Lakatta 2010). Arterial remodeling and decline in aging (even without atherosclerosis) is increasingly thought to be linked to Ang II signaling (Wang, Khazan, and Lakatta, 2010a). Components of Ang II signaling (including several reactive oxygen species, multiple growth factors, matrix metalloproteinases, chemokines, and nicotinamide adenine dinucleotide phosphate-oxidase) are upregulated within arterial walls in many species including humans, during aging. In vivo studies suggest that elevation of Ang II signaling drives accumulation of AGE (advanced glycated end products, which are themselves proinflammatory), increased collagen, disruption of elastin, and invasive hypertrophy of both smooth muscle and endothelial cells (Wang, Khazan, and Lakatta 2010a). Obvious clinical implications are that attenuating Ang II signaling may significantly retard this age-associated arterial remodeling, suggesting important protective effects for ACE inhibitors and ARB compounds. Intriguingly, multiple polyphenols, including those in pomegranate juice (rich in tannins and anthocyanins), appear to inhibit angiotensin signaling (perhaps in part from nonspecific antioxidant effects, but also from inhibition of angiotensin-converting enzyme activity) and may also reduce blood pressure (Stowe, 2011). Ang II also enhances ROS production by activating NAD(P)H oxidase and uncoupling eNOS. Systemic inhibition of Ang II thus may potentially have CR mimetic (antiaging) effects, due to its central role in coordination of vascular aging, OS, and impact on the mitochondria (de Cavanagh, et al., 2011). These processes driving vascular aging and disease are of obvious primary relevance to vascular dementias, as well as to common findings of white matter erosion (typically referred to as white matter hyperintensities or white matter ischemic change on MRI and CT scans), sometimes appearing as a highly comorbid pathology with AD (Brickman et al., 2009). Indeed, separating amyloid

angiopathy (a frequent vascular concomitant to AD) from other forms of atherosclerosis is almost impossible within clinical settings.

Alzheimer’s disease As the disease of aging with perhaps the greatest relevance to this textbook, there has been a paradigm shift over the last 20 years away from the original assumption that AD has nothing to do with aging. Of course, this could not possibly have been true, given the simple fact that AD roughly doubles in incidence every 5 years after the age of 60–65 and that aging remains the greatest risk factor for nonfamilial sporadic AD. Recent research suggests that markers for OS and mitochondrial decline (Pratico, 2010; Aliev et al., 2010; Mancuso et al., 2007) are elevated even prior to the appearance of extracellular amyloid deposition, which takes place in the preclinical stages of the disease. Indeed, multiple lines of evidence link AD to many, if not virtually all, of the phenotypes of aging, including inflammation (Masters and O’Neill, 2011), OS, accumulation and/or clearance failure of characteristic pathogenic proteins (Barnett and Brewer, 2011), and increasing deleterious synaptic effects from those proteins and from associated inflammation (De Strooper, 2010; Mondragon-Rodriguez et al., 2010; Palop and Mucke, 2010). Recent work has suggested that pathogenic proteins (such as oligomeric amyloid) are not being cleared out (Mawuenyega et al., 2010), underlining an important role for declining autophagy in the etiology. These considerations suggest that AD is indeed a highly pleiotropic and complex disease with several stages in which we may still not understand fully all the critical factors, or exactly how they interact to create a cascade with distinct stages, and with different processes and interactions presumably critical at different stages. What were originally adaptive mechanisms (such as inflammation, recruitment of amyloid pathways by various stresses and neuroplasticity challenge, phosphorylation, apoptosis, cell cycling, and so on) may become pathogenic in the context of chronic synergistic recruitment, biological stress, and neuroplasticity challenge. This suggests an image of AD in which a host of individually adaptive and compensatory mechanisms jointly “conspire” to drive the brain into a neurodegenerative process (MondragonRodriguez et al., 2010). Given that these interactions among a host of individually adaptive processes occur well past a reproductive period, they would escape virtually any conceivable selection pressure or modification. In this sense, the vulnerability to AD may reflect a “fault line” in the human genome consistent with the evolutionary perspectives outlined earlier. Thus, AD itself may be an expression of antagonistic pleiotropy in which genes and molecular pathways that were adaptive during periods of youth and fecundity potentially backfire in aging, particularly when synergistically recruited. Table 1.1 summarizes some, but not all, of the complex interactions

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

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Table 1.1 Factors contributing to a neurodegenerative mratrix in AD Biomarker

Produced by

Producing

Clinical/Other correlates

Beta amyloid plaque (extracellular Aβ)

Inflammation (glial activation), oxidative stress, more oligomers?

Subtle regional atrophic changes. Second biomarker appearing after OS/MITO decline

Synaptic loss and dysfunction, OS, inflammation

Synaptic loss (NMDA, AMPA), loss of LTP, increased LTD

Inflammation (INFLAM) (↑ innate immunity)

Aging, ↓ clearance, oxidative stress/ inflammation APOE4, altered BBB function? ↑ gonadotropins (LH/FSH) and declining sex steroids? β/γ secretases, inflammation, oxidative stress, ↓ clearance, endocrine dyscrasia? Plaque? Amyloid fibrils and oligomers, ↓ ACh, ↑ rAGE signaling, aging, OS, endocrine dyscrasia?

Contributes directly to cognitive dysfunction via multiple effects

Central insulin resistance (in CNS)

Inflammation (↑ NFk-b, AP-1, TNF-α, other proinflammatory cytokines), chronic stress?

Oxidative stress (OS), MITO decline

Declining control over OS in aging, Aβ oligomers in MITO, metal ions, INFLAM, advanced glycation end products, junk protein

Synaptic dysfunction, apoptosis, declining neurotrophins, OS, ↑Aβ? ↓ Energy, HC damage, ↑ kinases (→ neurofibrillary tangles?), declining autophagy? Synaptic and neural loss, INFLAM, Aβ, increased tangling? aberrant cell cycling → apoptosis

Excitotoxicity and Ca++ dysfunction

Oligomers (Aβ) in MITO, and at Ca++ channels, ↑ kynurenine (from increased cytokines) Oligomers (Aβ) → receptor internalization, tau pathology → microtubule dysfunction, inflammation Oxidative stress (OS) → ↑ kinases (w/ ↓ phosphatases), insulin resistance? Downstream effect of Aβ oligomers? Aberrant cell cycling? Multifactorial, with many factors listed contributing to synaptic loss and apoptosis

Proceeds functional declines (slightly)

Tracks atrophic change (SL/NL) and declining cognitive function closely. Precursors (PHF) appear long before beta amyloid deposition Major biomarker for degenerative changes in clinical stages of AD

Synaptic loss early, SL plus NL later (apoptosis)

Declining fxn, compensatory neuroplasticity effort?

Primary functional measure, necessary for diagnosis

Small aggregate amyloid (oligomeric Aβ)

Neurotrophin and neurotransmitter depletion Neurofibrillary tangling and tau aggregates

Atrophy HC/EC → lateral temporal → frontal/ parietal Cognitive loss, especially STM, then language and executive function

Synaptic dysfunction, apoptosis, esp. in HC/EC regions ACh loss → ↑ Aβ, BDNF/ NGF declines, aberrant cell cycling and apoptosis Basal forebrain (ACh) loss, SL, apoptosis

Promotes synaptic dysfunction and loss; promotes amyloidosis Appears before plaques/tangling; membrane OS increases with disease, but DNA OS markers do not Synaptic dysfunction, eventually SL/NL Synaptic dysfunction, promotion of both SL and apoptosis

Source: Adapted from Watt et al. (2012) with permission from Springer. SL: synaptic loss, NL: neural loss (neuronal cell death), Aβ: beta-amyloid, BBB fx: Blood Brain Barrier Function, MITO: mitochondria, ACh: acetylcholine, NGF: nerve growth factor, BDNF: Brain Derived Neurotrophic Factor, rAGE: receptors for advanced glycation end products (which promote inflammation), HC: hippocampus, EC: entorhinal cortex, apoptosis: programmed cell death, NFk-b: Nuclear Factor Kappa B (transcription factor involved in inflammatory signaling), AP-1: activator protein 1 (transcription factor involved in inflammatory signaling), Oligomers: several molecules of beta amyloid stuck together, Kinases: enzymes promoting phosphorylation and tangling, NMDA/AMPA: subtypes of glutamate receptor, LTP: long-term potentiation, LTD: long-term depression, lateral temporal: lateral temporal lobe, frontal/parietal: frontal and parietal convexity.

between putative etiological factors in AD, emphasizing an image of the disease as highly multifactorial, but one in which many primary phenotypes of aging (OS, disordered cell cycling, inflammation, glycation, apoptosis, mitochondrial decline, accumulation of junk proteins, and declining autophagy) appear not only contributory, but also highly interactive, arguing against any version of a single factor etiology.

Parkinson’s disease PD and its more aggressive and malignant close relative, diffuse Lewy body disease (DLBD), are idiopathic neurodegenerative diseases characterized by intraneuronal accumulation of Lewy bodies (aggregates of alpha-synuclein), particularly in substantia nigra (midbrain dopamine-producing

regions) in classical PD (and much more widely in DLBD). It is marked by progressive loss of DA cell bodies, deafferentation of basal ganglia, and dysfunction in direct and indirect corticostriatal pathways. Subsequent primary symptoms include resting tremor, slowing of movement, rigidity and gait difficulties, and eventual postural instability. There is evidence of differential vulnerability to degeneration in nigral regions, with “ventral tier” neurons more vulnerable than “dorsal tier,” and with VTA neurons least effected (Collier et al., 2011), despite the fact that these fields form a continuous sheet of DA neurons. This differential vulnerability is viewed in recent work as multifactorial. In animal models, it appears linked to several markers, including the appearance of alpha-synuclein, ubiquitin (as a marker of proteasome activation), lipofuscin (as a marker of lysosome

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activation), 3-nitrotyrosine (as a marker for nitroxidative stress), dopamine transporter activation, and markers of astrocyte and microglial activation (inflammation markers). Dysfunctional mitochondria and activated microglial cells are thought to be the primary intracellular source of reactive oxygen species, and lysosome-mediated autophagy is the primary cellular mechanism for removing defective mitochondria. The progressive accumulation of lipofuscin (conventionally regarded as “age pigment”) is thought to reflect an index of mitochondrial damage and subsequent lysosomal degradation of defective mitochondria (Terman et al., 2006). Collier et al. (2011) argue that the etiology of PD, while still uncertain, may reflect stochastic interactions among inflammation, OS, declining autophagy, and accumulations of pathogenic junk proteins, producing a “stochastic acceleration hypothesis”. These kinds of basic models (although omitting inclusion of many other aging phenotypes such as glycation, endocrine change, and telomere loss) (Figure 1.1) may provide a template for unraveling the etiology of other neurodegenerative disorders, particularly AD, but also the FTD family and some types of cancer, where the connections to aging and aging phenotypes are less clearly established. The high percentage of AD pathology in patients with DLBD argues also for a fundamental relationship between AD and PD that is still incompletely mapped.

Aging processes and the brain: cognitive changes in aging Although enormous evidence suggests that aging in the brain cannot be neatly separated from aging of the whole organism, at the same time, one has to consider that aging may be differentially expressed across different organ systems, and that the brain might be exposed differentially to aging processes (and perhaps differentially protected as well), including effects on the brain of pathological forms of aging, as described in the discussions of AD and PD. Much work suggests that a variety of neurocognitive functions decline with aging, even in those without demonstrable neurological disease (although the enormous difficulty in removing preclinical AD completely from one’s aging cohort/control group, plus the ubiquitous penetration of vascular disease in Western societies raises serious questions about how many studies purporting to show age-related cognitive change may be measuring at least in part prodromal stages of neurological decline from a major disease of aging). In any case, robust evidence suggests that a host of neurocognitive processes decline in aging, including episodic memory, working memory, spatial memory, processing speed, and even implicit (skill) learning, along with various motor functions, particularly motor speed and fine motor control (see Yeoman et al., 2012 for overview). The precise neural bases for these declines are still open to debate, and although initial

assumptions heavily emphasized age-related neuronal loss, increasing evidence argues that these neurocognitive declines are probably pleiotropic in origin, with synaptic loss possibly more important than actual neuronal loss. This itself also appears multifactorial, with roles for aminergic and neurotrophin decline, and where increased CNS inflammation might also play a role, but this has until recently been minimally probed, both in clinical and preclinical approaches (Cribbs et al., 2012). Loss of the smaller and highly plastic thin dendritic spines (more than the “fat” mushroom spines which appear more resistant to aging) appears to be one of the best candidates for an ultrastructural basis to age-related cognitive change, at least in relevant animal models (and thin spines which are more NMDA receptor-dense also appear more sensitive to deprivation of classic sex steroid hormones) (Dumitriu et al., 2010). A physiological correlate to cognitive declines in aging related to declarative (episodic) memory appears to be the phenomenon of prolonged hyperpolarization in aged hippocampal neurons, associated with changes in NMDA, AMPA, calcium channels, and other ion channels (Yeoman et al., 2012).

Departure from ancient evolutionary environment: impact on aging processes and promotion of diseases of aging Enormous evidence indicates that Western societies involve diets and lifestyles that are radically different from HG lifestyles and diets and, indeed, radically different from the original evolutionary environment in which the entire hominid line evolved. This may produce an “evolutionary discordance” (Konner, 2001) that may have profound effects on human health and a major influence on the biological trajectories of human aging. This notion of a radical departure from an evolutionary environment and a subsequent mismatch between our genes and our environment may provide a unifying context for connecting all increased risk factors for all the diseases of aging: Humans in modern technological societies are now living much longer (primarily due to our successful control over predation, starvation, and infection as primary causes of early mortality for children and younger adults). Put differently, all of the so-called healthy lifestyle practices that have been discovered piecemeal through many empirical studies (such as a diet high in fruits and vegetables, healthy omega-3/omega-6 ratios, high intake of fiber, and regular exercise) all have as a unifying context that they are components of our original long-term biological environment as HGs (Eaton and Eaton, 2002). This suggests that healthy lifestyle practices reduce or perhaps even virtually eliminate chronic mismatches between a genome carved in a more ancient HG environment and our current technological environment. Unfortunately, adoption of these healthy lifestyle practices is far from widespread in the United States or in other Western societies, and it may be relatively restricted

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

to those better educated and those belonging to more fortunate socioeconomic groups (Johannson et al., 1999). The fundamental hominid diet for probably more than two million years (preagriculture) was lean protein sources (game and fish), supplemented by significant quantities of fruits and vegetables (Cordain et al., 2005). Modern technological diets are higher in fat (particularly omega-6 fats) and carbohydrates (largely from grains and other agricultural products) and now contain significant transfats (which did not exist in our original biological environment); they also are frequently deficient in fiber and multiple protective phytochemicals (polyphenols) and possibly low in other several critical micronutrients, including choline and phospolipids, multiple B vitamins, and several minerals (Eaton et al., 2007). In addition, vitamin D deficiency is now quite common (Holick, 2007), while this was probably very rare, if not nonexistent, in ancient HG societies, in which skin color seems to have evolved to match latitudes and to balance vitamin D production with skin protection, given that both modern sunscreens and indoor living were nonexistent. The following tables summarize some of these fundamental differences between an ancient biological environment for humans and the current environment, including

Original Evolutionary Environment 1 2 3 4 5 6 7 8 9 10 11 12

Regular aerobic exercise (2-3+ hours per day) 9+ hours sleep (see #1) Calorie limitations (intermittent CR) High-phytochemical/polyphenol diets Omega-6/omega-3 ratio 1:1 to 3:1 with modest intake of overall fats High intake of fiber (about 50-100 g per day) Low sugar/carbs, except fruits/veggies Intake of K+ > Na+ (K+ > 4 gm/d) Pro-alkaline diet Minimal to no glycated proteins Intimate social groups/tribes Early mortality: infection, starvation, predation, and intraspecies violence: life expectancy 35-45 years

work on biomarkers from studies of HG societies (Eaton and Eaton, 1999; Eaton et al., 2007; Eaton et al., 1998a,b; Cordain et al., 2005). This evidence for huge biological environment shifts during a period of minimal genetic change for humans (the last 10,000 years) suggests a potential “unified field theory” for the diseases of aging (and that diseases of aging are largely “diseases of civilization”; Melnik et al., 2011). Ironically, humans have never lived longer than they are living in modern technological societies: The average life expectancy at birth within preindustrial HG societies was probably roughly 30–35 years (Konner and Eaton, 2010). However, this significantly extended lifespan in technological cultures is one in which penetration by a major disease of aging (excepting osteoarthritis, which is common in HG groups) appears more likely, relative to the few elders who existed in HG societies (Dunn, 1968; Konner and Eaton, 2010). Conclusive data on this question is lacking, however, and reconstruction of more ancient (Paleolithic) HG lifestyles and biological state involves extrapolating from the relatively few HG societies that survived into the twentieth century (columns adapted from Eaton and Eaton, 1999; Eaton et al., 2007; Eaton et al., 1998a,b; Cordain et al., 2005).

Modern Technological Environment 1 2 3 4 5 6 7 8 9 10 11 12

Minimal to no aerobic exercise (< 15 min/d) 7 hours or less of sleep (see #1) Unlimited calories Low phytochemical/polyphenol diets Omega-6/Omega-3 ratio 10:1 to 20:1 with typically higher intake of fats Low intake of fiber (≤ 15 gm/d) High sugar/carbs, not from fruits/veggies Intake of Na+ > K+ (Na+ > 4 gm/d) Pro-acidic diet Common glycated protein (especially milk products) Social isolation common Death from an advanced disease of aging: life expectancy 75-85 years

Biomarkers Hunter Gatherers 1 2 3 4 5 6 7 8 9 10 11

BMI 21–24 Total cholesterol under 125 Blood pressure 100–110/70–75 VO2 max good to superior Homocysteine low Vitamin D about 50–100 ng/mL Higher B vitamin/folate levels High insulin sensitivity Fasting plasma leptin 2–4ng/mL Waist/height ratio 1000 kcal/d

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Current Technological Societies 1 2 3 4 5 6 7 8 9 10 11

About 30% BMI >30, about 30% BMI 25–30 Total cholesterol about 200 or higher 120/80 (normative), with hypertension common VO2 max fair to poor (sedentary lifestyles) Homocysteine significantly higher Vitamin D deficiency common (10–30 ng/mL) Common B12 and folate deficiencies Variable degrees of insulin resistance Fasting plasma leptin 4–8ng/mL Waist/height ratio 52–56 Physical activity about 150–490 kcal/d for most

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Although conclusive data is still lacking, preliminary evidence suggests that HG societies did not appear to have nearly the incidence of cancer and heart disease (Eaton and Eaton, 2002), diabetes (Eaton et al., 2002), or AD (Eaton and Eaton, 1999) suffered by modern societies, even when the relative rarity of elder members is taken into account (Konner and Eaton, 2010). Consistent with these findings and hypotheses, a paleolithic diet improved diabetic biomarkers more than the highly touted Mediterranean diet (Lindeberg et al., 2007) and improved BP and glucose tolerance, decreased insulin secretion, increased insulin sensitivity, and improved lipid profiles, all without weight loss in healthy sedentary humans (Frassetto et al., 2009). Additional evidence (summarized in Spreadbury, 2012) suggests the provocative hypothesis that virtually all processed or “acellular” carbohydrates—which tend to be high-density carbohydrate foods—(ancient sources of carbohydrates in fruits and vegetables were low density) contribute directly to an inflammatory gastrointestinal microbiota which leads directly to leptin resistance, disordering of fundamental energy homeostasis through effects on multiple satiety peptides, and promotion of obesity. Spreadbury further argues that modern diets are truly distinct from ancient diets not in relationship to either nutrient density or glycemic index but only around carbohydrate density (Spreadbury, 2012) due to acellular grain-based foods. It is difficult to know precisely what the sum total or composite effect of such global and pervasive shifts in our basic biological environment might be, or what each factor may contribute to the overall increasing burden of diseases of aging in Western societies. However, the evidence favors the hypothesis that these shifts are first of all individually deleterious. Therefore, collectively, they are likely to be highly undesirable and potentially profound. Indeed, there may be poorly mapped synergisms among these various factors in promoting diseases of aging, as virtually every one of these factors—the complex multifactorial dietary shifts, sedentary versus aerobic lifestyles, common obesity generated by these two factors, vitamin D deficiency, low-grade sleep deprivation, and increased social isolation and stress (vs the intimate social groups of our ancestors)—all impact the regulation and management of inflammation (as even psychosocial isolation and social stress is a proinflammatory event). This suggests that, collectively, Western lifestyles (when compared to the lifestyles of our HG ancestors) may be hugely proinflammatory. There is evidence that autoinflammation involves increased OS (Finch, 2011), drives insulin resistance, and is potentiated by glycation (Semba et al., 2010), and increases cellular senescence. Such a global view of the biological environment also suggests strongly that singlecomponent “fad diet” approaches, such as the elimination of all fructose, sugar, or carbohydrates, are not likely to be successful unless combined with a larger group of dietary and lifestyle changes (although refined carbohydrate reduction as noted may help with reducing obesity, inflammation,

and pulsatile insulin over-production all of which may be critical in the Western society burden of diseases of aging). In any case, this analysis, which suggests a complex and highly interactive composite of environmental shifts relative to ancient HG environments that collectively are probably biologically profound. Many, if not most, of these lifestyle and dietary factors may also deteriorate the endogenous management of OS (Kaliman et al., 2011). Given that autoinflammation creates OS for “bystander” tissues (Finch, 2011), these lifestyle variables may impose a double burden: increasing OS while depriving us of several protective factors (found in our ancient evolutionary diet and lifestyle) that might ameliorate or protect against OS. OS, modulated by both diet and exercise, is also believed to be a primary factor in genetic damage and genomic instability (Prado et al., 2010), leading potentially into cancers and the acceleration of cellular senescence, as a primary defense against cancer (Ogrunc and Fagagna 2011). Cellular senescence in turn appears to be proinflammatory, creating a so-called “senescence-associated secretory phenotype” (SASP) (Blagosklonny, 2011). Many of these dietary and lifestyle factors also modulate the glycation of proteins and the formation of AGEs (particularly diets low in fiber and polyphenols and high in refined sugars/carbs), with AGE products a primary regulator and inducer of inflammation. Inflammation itself may promote insulin resistance and, thus, glycation, suggesting many positive feedback loops between these classic metabolic and age-related processes. Common vitamin D, B12 and folate deficiencies may contribute to declining autophagy, and also increasing inflammation (Holick, 2007), promoting cognitive decline in aging, increased homocysteine (as a marker and proxy for OS and inflammation), and possibly increased AD (Tangney et al., 2011). Many lifestyle factors also impinge on the cell signaling related to endogenous defenses against OS, particularly exercise, polyphenol intake, inflammatory state, obesity and excessive energy, and insulin resistance. Indeed, the typical alterations in energy homeostasis in Western diets and lifestyles, leading to an excess of energy (in turn, leading to obesity), are a primary activator of mTOR (mTOR, as a pathway that integrates nutrient signaling and growth factors), increasingly implicated as a central factor in the regulation and induction of aging (Blagosklonny, 2009, 2010a). In addition, multiple polyphenols (modestly) and DR, particularly protein restriction, inhibit mTOR. Collectively, these considerations suggest that Western lifestyles may directly impact the biology of the diseases of aging (and aging itself) directly and powerfully in a multitude of undesirable ways. Thus, although the central prolongevity triumph of Western civilization and medicine, the prevention and treatment of bacterial infection, has had a very positive impact on median survival to old age, Western lifestyles may accelerate aging and the diseases of aging in a multitude of other ways. Preventing the diseases of aging therefore has to begin with an appreciation for the central importance of lifestyle change,

The Biology of Aging: Implications for Diseases of Aging and Health Care in the Twenty-First Century

back toward at least some approximation of our evolutionary environment.

What constitutes optimal prevention of the diseases of aging? In sum, this large constellation of globally altered lifestyle variables impacts the fundamental biology of aging and also modulates the underlying mechanisms directly driving all the diseases of aging. Jointly, these lifestyle factors, interacting with our genome (containing many currently unmapped polymorphisms that presumably directly modulate aging processes and the vulnerability to diseases of aging variably across individuals), in concert with multiple lifestyle behaviors, determine what aging trajectories our systems enter as we get older. These basic interactions between lifestyle (which we can map out) and many polymorphisms in our genetic endowment (which we can now map only minimally) determine how much our fundamental cellular repair mechanisms and defenses against cellular damage and aging are supported and enhanced as much as possible, versus overtaxed and overwhelmed. The primary and multifactorial mechanisms of aging reviewed in this chapter appear to lead invariably into the diseases of aging, if given enough time and enough room to work. Indeed, the sum total of presence or absence of all the diseases of aging in an individual may be one of the best ways to globally index aging itself (Blagosklonny, 2009). Challenges remain in operationalizing such a definition, of course, given that practical, cost-effective (and nonintrusive) metrics in relation to many of the diseases of aging are not yet clinically available. Unfortunately, the conventional medical perspective on diseases of aging in this country is still largely unaware of evidence that they may reflect common mechanisms operating in different tissues and systems; instead, conventional medicine mostly approaches each major disease of aging in a piecemeal and fragmented fashion. This chapter argues strongly against that traditional approach. Western lifestyles (consisting of a typical Western diet pattern and a sedentary lifestyle with poor sleep and increased social isolation) appear quite undesirable in terms of aging of the brain and body, deteriorate capacities to deal with various biological and social stresses, and remove us from our proper and ancient evolutionary environment. We have changed remarkably little genetically since our days as HGs, but our lifestyles have changed dramatically. This suggests that much of our current difficulties with health are not due to some exotic collection of esoteric biological derailments that can only be interpreted and treated by a “medical–industrial complex” and understood by someone with a doctoral degree; instead, they are due to a fundamental, if not profound, mismatch between our genes and our environment (Stipp, 2011). This suggests that basic health considerations should focus on approximating that ancient

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biological environment as much as possible: regular aerobic exercise, large amounts of fruits and vegetables, not too many calories, minimal processed food and other products of “food technology” (particularly our highly addicting fast food), a better omega-6/omega-3 ratio (typically very high in most Western diets with significant omega-3 deficiency), reduced social isolation, and improved sleep quality and quantity. As noted earlier, all these common recommendations place us closer to our ancient evolutionary environment and reduce this fundamental and destructive discordance between genes and environment in Western lifestyles. At this point, there is no cure for virtually any disease of aging (perhaps excepting some cancers), so meaningful prevention needs to a genuine priority instead of an afterthought in our health-care system. We must be willing to spend money on prevention and to make lifestyle changes a genuine cultural priority. It is also quite sobering to realize that, even in the context of the best possible preventative efforts, all one can do is delay the onset of a major disease of aging: Eventually, we will all succumb to one of these manifestations of aging. However, such delay in onset of a major disease of aging can potentially increase healthspan (even if major lifespan extension remains elusive) and substantially decrease the burden of diseases of aging in old age, along with their often punitive impact on quality of life and personal and societal economics (see Chapter 21). Prevention, in this context of the many considerations reviewed in this chapter, thus has to mean much more than “statins and beta-blockers” (controlling multiple conventional risk biomarkers that clearly have some prognostic value but may only minimally index our deceptive yet radical physiological departure from our ancestors). Instead, real prevention must mean, for the large majority of individuals in a culture and not simply for a fortunate few, reapproaching our original evolutionary environment. In simplest terms, as a culture, these major lifestyle changes must mean that we exercise and sleep significantly more, eat significantly less, and eat more wisely (consuming more of the “paleolithic” foods of our ancestors and less the questionable and addictive products of food technology). In addition, we need to aim more for quality of social connection than quantity of material consumption, as quality and depth of social attachment is emerging as one of the better predictors of long-term health (Seeman and Crimmins, 2001; see Chapter 10). Making these critical changes in priorities and approach, both individually and in terms of the embedded high-tech priorities of our health-care systems, is likely to be painful in many ways, as well as profoundly politically contentious. However, one cannot envision any viable long-term prescription or big-picture view of biological health that does not place these simple principles first. Additionally, this view of health (that it emerges from the basic fit between genes and environment) places health back into a proper evolutionary perspective that is badly lacking in many treatments of diseases of aging. There seems to be little

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sense in the current health-care environment that Darwin’s central insights (about the match between genetic endowment and environment determining adaptive success) has any relevance to discussions of basic health or illness. Has modern medicine abandoned Darwin? A central implicit myth of the “medical–industrial complex” (implicit in the sense that it is largely embedded in relentless advertising and is never explicitly stated) may be that high-tech medicine and first-line drugs are our best defense against the chronic diseases of aging, a supposition for which there is very little substantive evidence, and much counterevidence. An additional option for the future may be the possibility of a highly effective CR mimetic: perhaps a future version of resveratrol or rapamycin, some combination of our current (partial) CR mimetics, or perhaps even a completely new and different compound yet to be discovered. It seems an easy prediction that a truly safe and effective CR mimetic (which, by definition, would give the physiology of CR without the pain of chronic hunger) that could both slow aging and substantively delay onset of all the diseases of aging would be a compound that almost everyone would readily consider taking and many if not virtually everyone would find highly attractive. Indeed, if a patentable agent were proven highly effective and safe, one could easily predict that it would eventually become the best-selling prescription medicine of all time. However, such considerations (potential widespread use of CR mimetics) embed a major conundrum, similar to that posed by the potential creation of an “exercise pill.” Would individuals with the option to take a safe and effective CR mimetic still be adequately motivated to modify problematic lifestyle habits and move closer toward the original evolutionary environment of humans, which we believe promotes long-term health and healthy (or at least healthier) aging? One can readily appreciate the temptation to continue eating problematic but tasty foods and remaining overweight and sedentary, if one’s anxiety about any potential disease of aging could be significantly ameliorated by simply taking a pill. Such a dilemma in many ways goes to the heart of difficult choices confronting modern technological Homo sapiens in relation to both health care and, more fundamentally, long-term health. Do we trust in our high technology first and foremost? Do we place exclusive faith in our technological competencies, to the exclusion of trusting in biological relationships that are (at least, in some sense) pretechnological? Or must we place equal or even greater trust in our basic evolutionary heritage and our embeddedness in a complex biological matrix and ecology, the environment that carved our genome? Put in simplest terms, do we think that health promotion is primarily a technological or a lifestyle matter? Answers to these questions may determine a great many things about our long-term health in the coming century and our health-care system. Additionally, these choices mirror much larger and even more difficult choices about our basic relationship to a complex biological matrix (the extended environment), which is clearly showing

the negative impact of human technologies. A tempting hypothesis is that our disregard of the environment may be intrinsically hinged to the overvaluation of technology and the undervaluation of our biological “embeddedness” and our fundamental evolutionary context; these considerations were summarized in the previous sections regarding the basic notion of an evolutionary discordance between our genes and our current technological environment, diet, and lifestyles. In simplest terms, overvaluing high-tech medicine over “low-tech” lifestyle change may be a mistake we are culturally primed to make in how we view health and how we construct and finance our health-care systems. Whatever answers we might construct to such questions, there seems little question that Western societies face enormous challenges in a tsunami of age-related disease, in an aging population, at a time when fundamentally unhealthy lifestyles promoting those very same diseases of aging are widespread within the United States and in other Western societies. Health-care professionals of virtually all disciplinary persuasions need to take responsibility for educating both patients and the general public about these issues, as a critical part of reprioritizing genuinely proactive and early prevention efforts and health maintenance via lifestyle change over much later high-technology interventions that are proving to be prohibitively costly while at the same time yielding very uncertain if not minimal benefits in relation to quality of life.

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Chapter 2 Functional Changes Associated with the Aging Nervous System Julie A. Schneider1,2,3 and Chunhui Yang1,2 1

Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA Department of Pathology, Rush University Medical Center, Chicago, IL, USA 3 Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA 2

Summary • The aging brain undergoes complex changes with an increased vulnerability to distinct pathologies, particularly degenerative and vascular. • Age-related brain changes may include changes in volume, neuron size and number, white matter integrity, and synapse/dendrites; however, may be difficult to distinguish effects of normal aging vs. disease. • Amyloid plaques one of the hallmarks of Alzheimer’s disease (AD) are common in aging and may represent early AD. • Neurofibrillary tangles (NFT) another hallmark of AD are seen in other conditions, and in the hippocampus in the aging brain, where they may be related to memory loss separate from AD. • Vascular diseases including atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy, and infarcts are exceedingly common in the brains of older persons. • The most common causes of dementia in aging are AD, vascular, and Lewy body pathology. These pathologies are often mixed in the brains of older persons. • AD is characterized by the wide-spread accumulation of amyloid, neocortical neuritic plaques and extensive limbic NFT (often extending to neocortex). A pathologic diagnosis of AD is found in some “normal” elders suggesting subclinical disease. • Dementia with Lewy bodies (DLB) is characterized by Lewy bodies in the substantia nigra, limbic structures and neocortex. AD changes often coexist • Vascular dementia is characterized by diffuse or strategically located infarcts or other vascular lesions (eg. hemorrhages). Microinfarcts are also related to dementia. • Frontotemporal Lobar degeneration (FTLD) with tau or ubiquitin (TDP) inclusions is increasingly recognized; FTLD is the underlying pathology of Frontotemporal dementia but may also underlie dementias with more typical presentations. • Less common causes of dementia include Corticobasal degeneration (CBD), Progressive Supranuclear Palsy (PSP), Creutzfeld-Jacob disease, Wernicke-Korsakoff syndrome (WKS) and other structural, metabolic, or infectious conditions. • Mild cognitive impairment (MCI) is characterized by the same common age-related pathologies, but often the pathology is intermediate in severity. In some cases there is sufficient pathology for a pathologic diagnosis of AD. • The presence of significant brain pathology in persons with MCI and dementia suggests that there are structural and cognitive reserve mechanisms in aging. • Movement disorders, particularly parkinsonism are very common in aging. Mild changes often don’t fit into a specific disease category. • Idiopathic Parkinson’s disease (bradykinesia, rigidity, tremor, and gait impairment) is characterized by loss of dopaminergic neurons in the substantia nigra and Lewy bodies. Co-existing dementia is common and may be related to concomitant AD changes or neocortical Lewy bodies (DLB) • Multisystem atrophy, CBD and PSP are less common causes of parkinsonism. • Amyotrophic Lateral Sclerosis is characterized by loss of upper and lower motor neurons and leads to progressive weakness and may have accompanying dementia. • Brain tumors, notably metastases, glioblastomas (malignant glial tumor), and meningiomas (benign growths attached to the dura) are common in aging. • Toxic metabolic encephalopathies may include changes related to systemic diseases such as liver or kidney disease, in which astrocytes undergo Alzheimer type II changes. Excessive alcohol use may lead to thiamine deficiency and WKS.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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• Older persons are more susceptible to infectious diseases including bacterial, viral and fungal meningitis, cerebritis and encephalitis. • Recent and past head trauma may cause problems in aging. • Subdural hematomas are most commonly related to tearing of bridging veins from relatively minor head trauma and falls. • Chronic traumatic encephalopathy is related to repeated clinical or subclinical concussions and may be associated with a degenerative dementia characterized by changes in memory, personality and behavior.

Introduction It is widely recognized that the brain and other parts of the nervous system undergo complex changes with age. For example, loss of brain weight and volume, changes in neurons and synapses, and oxidative, inflammatory, and biochemical changes have all been described in the aging brain. Moreover, the aging brain and nervous system show an increased vulnerability to a variety of distinct pathologies, particularly degenerative and vascular. The relationship between what may be considered “normal” age-related brain changes and disease has been debated. This chapter provides an overview of the neuropathology of the aging brain, including “normal” aging, the pathology of cognitive impairment and dementia, vascular disease, motor impairments, and other common geriatric brain conditions, such as toxic metabolic conditions, neoplasms, infections, and traumatic injury that may affect the elderly.

The aging brain The differentiation between “normal” aging and disease in the brain is complicated by multiple factors, including changing historical perspectives on what constitutes normal cognition and motor function in aging, the presence of slowly accumulating pathologies, and the concept of neural reserve (that is, normal cognitive or motor function in spite of significant amounts of pathology). This is to be considered on a background of changing techniques, more sophisticated studies, and semantic arguments about common changes versus disease. Although concepts regarding normal versus disease will likely continue to change, it remains valuable to discuss some of the currently considered age-related neuropathologic changes.

Brain size and neuronal loss Numerous studies have investigated age-related changes in brain weight, size, and neuron number. Although studies have been conflicting, it remains widely accepted that most of these brain parameters

decrease with advancing age. Most of the data from the early part of the twentieth century were based on studies with variable clinical information, making conclusions uncertain (Duckett, 2001). In general, studies of normal aging have been hindered by the intrusion of early disease states and the absence of detailed cognitive testing proximate to death (Peters et al., 1998). Recent pathologic studies using carefully selected controls and/or sophisticated stereologic techniques have shown that, on average, normal older subjects show only slight changes in the overall weight (Tomlinson and Blessed, 1968), cortical thickness (Mouton et al., 1998), and neuronal number in the absence of diseases (Tomlinson and Blessed, 1968; Terry and DeTeresa, 1987; Hof and Glannakopoulos, 1996; Mouton et al., 1998; Peters et al., 1998; Duckett, 2001). Inherent intersubject premorbid variability, especially for neuron number, remains a concern in evaluating the results of pathologic studies. Neuroimaging studies can provide expanded data on size and also evaluate longitudinal change. These studies suggest that ventricular rather than cortical volume shows the largest annual change (Resenick et al., 2000). Effects may also be regional; neuroimaging studies show agerelated thinning of the prefrontal cortex (Fjell et al., 2009), with lesser (Sullivan et al., 1995) or more variable (Fjell et al., 2009) involvement of the entorhinal and hippocampus in normal aging. Overall, neuronal loss is probably small, estimated at likely no more than 10% (Peters et al., 1998). Importantly, although morphologic changes may be slight, animal (Stemmelin and Cassel, 2003) and neuroimaging (Resenick et al., 2000) studies suggest that even small changes in the structure may have functional consequences. Studies on aging are now increasingly focused on cell-specific and lamina-specific vulnerabilities (Peters et al., 1998), regional modifications in synaptic remodeling (Terry et al., 1991; Masliah et al., 2006) and dendritic complexity (Scheibel, 1988; Richard and Taylor, 2010), white matter changes (Moody et al., 1995; Fernando et al., 2006; Gunning-Dixon et al., 2009; Simpson et al., 2009; Murray et al., 2010), and other downstream or compensatory changes, such as neurogenesis (Willott, 1999; Lowe et al., 2008; Pannese, 2011).

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White matter changes Neuroimaging studies have shown that there is a greater loss of volume in the cerebrum from white matter compared to gray matter in aging (Resenick et al., 2000). Moreover, these changes appear to preferentially affect the prefrontal white matter (Gunning-Dixon et al., 2009). This partly explains the increase in ventricular size often seen in aging (Tomlinson and Blessed, 1968; Duckett, 2001). Neuropathologic studies also show age-related white matter changes (Moody et al., 1995; Fernando et al., 2006; Simpson et al., 2009), with changes in multiple functional pathways (Simpson et al., 2009) and a possible relationship with chronic hypoperfusion (Fernando et al., 2006). White matter changes may result in cortical “disconnection” (Gunning-Dixon et al., 2009), and executive function appears to be specifically vulnerable to these age-related white matter changes (Murray et al., 2010). Synaptic and dendritic changes in aging Synapses are among the most important structures for neuronal communication. Synaptic loss during normal aging has been studied extensively in the last couple of decades. Quantitative studies using electron microscopy have revealed significant losses of synapses with age in laboratory animals and humans and have been estimated at about 10% (Terry et al., 1991; Duckett, 2001; Masliah et al., 2006; Pannese, 2011). However, neurons in older brains appear to retain some capacity for synaptic and dendritic plasticity and ability to form new synapses in response to injury or environmental manipulations (Pannese, 2011). These data are supported by studies suggesting that cognitive activities and training may improve function (Wilson and Mendes de Leon, 2002; Treiber et al., 2011). Dendrites (see Figure 2.1) account for 90% of the total surface area of a neuron’s receptive area, with more than 90% of excitatory synapses connected by dendritic spines (see Figure 2.2) and complexity that may vary by region (Scheibel, 1988). Studies have reported a significant

Figure 2.1 Apical dendrite (arrow head) and cell body (arrow) of pyramidal neuron, hippocampus CA1, mouse brain (Golgi stain). (For a color version, see the color plate section.)

Figure 2.2 Dendritic spines, mouse brain, hippocampus CA1 (Golgi stain). (For a color version, see the color plate section.)

age-related loss of dendrites, both shortening and fewer dendritic branches, in the cerebral cortex (Masliah et al., 2006). Large projection neurons have been shown to have simplification (pruning) of the neuronal dendritic tree; because these dendrites are located in layer I of the cerebral cortex, this loss may result in layer I cortical atrophy (Lowe et al., 2008).

Alzheimer’s disease changes in “normal aging” Neurofibrillary tangles (NFTs) and amyloid beta (Aβ) plaques are the pathologic hallmarks of Alzheimer’s disease (AD; Section “Alzheimer’s disease”) and accumulate in large number in persons with AD dementia. Yet it is not uncommon to see NFT and plaques in small numbers in the aging brain of persons without cognitive impairment (Bennett et al., 2006). In some instances, this may represent the earliest pathologic stage of AD. Indeed, with notable exceptions such as chronic traumatic encephalopathy, Aβ plaques appear to be relatively specific to the AD pathophysiologic process. In contrast, NFTs are observed in a variety of other diseases and are extremely common in the limbic regions of almost all older persons. It has been suggested that NFT in the mesial temporal lobe may be related to the memory loss in AD and separately underlie age-related memory loss (Jack et al., 2010). Microscopic vascular pathology in the aged brain Vascular changes are extraordinarily common, with the majority of older persons having some degree of atherosclerosis, arteriosclerosis, or cerebral amyloid angiopathy (CAA) (Section “Cerebrovascular disease in the elderly”). Atherosclerotic plaques commonly occur in the intra and extracranial vessels of the Circle of Willis. Arteriolosclerosis (hyaline thickening of small vessels) is particularly common in the white matter, basal

Functional Changes Associated with the Aging Nervous System

ganglia, and thalamus. More severe forms are associated with hypertension and diabetes and are thought to underlie the development of infarcts. Mild dilation of perivascular Virchow–Robin spaces may occur with or without small vessel disease. Small venules in the periventricular white matter tend to show increased deposition of collagen in the adventitia (Moody et al., 1995), referred to as periventricular venous collagenosis. Mild forms of amyloid angiopathy are also common even in the absence of AD (Arvanitakis et al., 2011a). The role of each of these vascular changes, particularly when mild or in the absence of infarction, is not clear, although data suggest that severe vessel disease in the absence of frank infarction is related to damage to the brain and functional impairment (Arvanitakis et al., 2011a; Buchman et al., 2011). Vascular disease is discussed in detail in Section “Cerebrovascular disease in the elderly.”

Other changes Age-associated macroscopic changes also include thickening of the arachnoid and prominence of arachnoid granulations. Microscopically, aged brains often show an accumulation of lipofuscin in specific neuronal populations and regional prominence of corpora amylacea. Although not related to a specific disease state, and often considered benign, the significance of these changes has been debated. In addition, although more numerous in disease, older brains may show granulovacuolar degeneration and Hirano bodies primarily in the hippocampal region. Other biochemical and cellular changes, such as inflammatory shifts, oxidative stresses, and glial pathology, may also be important in normal aging and/or disease. For instance, microglia are normally inconspicuous in the young brain, but with aging, microglia may show signs of activation (Jurgens and Johnson, 2012), even in older persons with normal cognition. This is particularly the case with expression of class II major histocompatibility antigen (MHCII; see Figure 2.3).

Neuropathology of mild cognitive impairment and dementia Mild cognitive impairment (MCI) and dementia are clinical diagnoses based on history, cognitive testing, neurologic examination, and supportive studies. It is currently believed that there is a continuum of normal cognitive aging, MCI, and dementia, and although each has a characteristic clinical phenotype, it can be difficult to distinguish normal aging from MCI and to distinguish MCI from dementia, especially at their intersections. The brain pathologies underlying normal cognitive aging, MCI, and dementia also lie on a continuum

41

Figure 2.3 Activated cortical microglia in older person without cognitive impairment; antibody to class II major histocompatibility antigen (MHCII). (For a color version, see the color plate section.)

from no pathology to mild pathology and from mild pathology to abundant pathology. The most common pathologies associated with MCI and dementia are AD, infarcts (with or without associated clinical stroke), and Lewy body (LB) pathology. Although it has long been recognized that AD pathology is the most common pathology underlying dementia, we now know that older persons with dementia most often have mixed brain pathologies, most commonly AD pathology and infarcts, followed by AD and LBs (MRC CFAS, 2001; White et al., 2005; Schneider et al., 2007a; Sonnen et al., 2007; O’Brien et al., 2009; Nelson and Abner, 2010). Furthermore, it is recognized that older persons without cognitive impairment may have many of the same types and burdens of pathologies as in persons with dementia, suggesting neural or cognitive reserve and subclinical disease (Elkins et al., 2006; Rentz et al., 2010; Tucker and Stern, 2011). This section focuses on the neuropathology of AD, MCI, mixed dementias, vascular dementia (also known as vascular cognitive impairment), and dementia with Lewy bodies (DLB). This section also covers the expanding spectrum of the less common frontotemporal lobar degenerations (FTLD) and briefly reviews less common conditions associated with age-related cognitive impairment, such as Wernicke–Korsakoff syndrome (WKS) and Creutzfeldt– Jakob disease (CJD). Cognitive impairment may also occur as a result of other changes in the brain, including infections, trauma, and neoplasms, which other sections discuss.

Alzheimer’s disease There are both macroscopic and microscopic changes that occur in AD. These changes are evident prior to the clinical diagnosis in majority of the patients.

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The Aging Brain in Neurology

(a)

(b)

Figure 2.4 Alzheimer’s disease brain showing

(a) narrowing of gyri and widened sulci, and hippocampal atrophy with enlargement of lateral ventricles, especially temporal horn (b). (For a color version, see the color plate section.)

Macroscopic appearance of AD A decrease in brain weight is a usual but inconstant finding. Cortical atrophy is typical but also variable and has been shown to correlate with the level of cognition (Mouton et al., 1998). The mesial temporal lobe structures, including the temporal cortex, amygdala, entorhinal cortex, and hippocampus, are most affected, with the temporal horns of the lateral ventricles often being enlarged (see Figure 2.4); frontal and parietal regions are also commonly affected. The occipital lobe and the motor cortex are relatively spared (see Figure  2.4). The gross appearance of the basal ganglia, thalamus, and hypothalamus is usually unremarkable. The midbrain exhibits pallor of the substantia nigra (SN) in about one-quarter to one-third of AD cases. Pallor of the locus coeruleus in the rostral pons is common in AD.

(a)

Microscopic findings of Alzheimer’s disease: neurofibrillary tangles and amyloid beta plaques The two histologic hallmarks defining the pathology of AD since the original description by Alois Alzheimer in 1906 are NFTs and the extracellular amyloid beta (Aβ) deposits of senile plaques. NFTs are intraneuronal inclusions that consist of abnormally phosphorylated tau protein aggregate as paired helical filaments. NFTs occupy the cell body and extend into the apical dendrite. They are not easily discerned on hematoxylin–eosin (H&E) staining but are agyrophilic (that is, visualized by silver impregnation methods, such as modified Bielschowsky (see Figure  2.5), Gallyas, Campbell–Switzer, and Bodian stains. In addition, specific immunohistochemical staining with antibodies to the abnormal tau protein sensitively demonstrates NFT (see Figure 2.5). The morphology

(b)

Figure 2.5 Neurofibrillary tangles:

(a) hippocampus CA1 (modified Bielschowsky stain); (b) frontal cortex (immunohistochemistry with antibodies to paired helical filament). (For a color version, see the color plate section.)

Functional Changes Associated with the Aging Nervous System

Figure 2.6 Ghost tangles, hippocampus CA1 (modified

Bielschowsky silver stain). (For a color version, see the color plate section.)

of NFTs varies with the nature of the neurons in which they reside. Those in the cortex are usually flame shaped or triangular, and those in the subcortical or brainstem nuclei are typically globose. NFTs that survive after the neurons have died are visualized as “extracellular ghost tangles” and tend to be slightly larger and less densely stained than typical NFT (see Figure 2.6). Braak and Braak observed that the progression of NFT changes in older persons follow a predictable pattern (Braak and Braak, 1991). They found a characteristic distribution and progression of NFTs in older persons, which comprised of six stages, starting in the transentorhinal and entorhinal layers and progressing to the neocortex. The first two stages involve NFTs in the entorhinal, transentorhinal, CA1, and subiculum. In stages III and IV, increasing numbers of NFTs accumulate in the limbic system, and in stages V and VI, NFTs become abundant in neocortical areas. NFTs generally occur in a predictable laminar distribution; in the entorhinal cortex, NFTs are almost always present in large projection neurons of layers II and IV, whereas layers III, V, and VI have relatively few tangles.

(a)

Figure 2.7 Neuritic plaque

pathology in AD. (a) Three NPs in the neocortex on H&E stain are difficult to see. (b) The same NPs are easily visualized on modified Bielschowsky silver stain. (For a color version, see the color plate section.)

43

Senile plaques are the other hallmark of AD pathology and consist of fibrillar amyloid material, composed of Aβ, which shows a characteristic red–green birefringence in Congo red-stained sections. Aβ is produced by the abnormal proteolytic cleavage of amyloid precursor protein (APP), a membrane protein that, when normally cleaved by alpha secretase, secretes nonamyloidogenic fragments. Abnormal cleavage with beta secretase and gamma secretase results in the production of Aβ peptide that is 39–43 amino acids in length; the insoluble form is deposited as Aβ40 or Aβ42. Other proteins, such as interleukins, apoE, and components of the complement system, also deposit in plaques (Thal et al., 2006). AD is pathologically characterized by at least two plaque types, neuritic plaques (NP) and diffuse plaques (DP). NP is the type of plaque critical for neuropathologic diagnosis of AD (Mirra et al., 1991) and is characterized by thickened neurites; these plaques often have a dense central core of amyloid surrounded by a less compact peripheral halo of amyloid. Plaques may be difficult to visualize on routine H&E stains but are easily seen on silver stain (see Figure 2.7) or with antibodies to the Aβ protein (see Figure 2.8). The dense core and peripheral halo are often separated by a clear zone that contains glial cells and dystrophic neuronal processes that often show abnormally phosphorylated tau protein (Thal et al., 2000). NP may be associated with reactive astrocytes, and microglial cells may be seen within the dense central core (Thal et al., 2000). Immunostaining with antibodies to specific forms of Aβ typically shows that the dense center core is enriched in Aβ40, while the periphery has predominantly Aβ42 (Thal et al., 2000). NPs are prominent in the amygdala and hippocampal subicular complex and are present in association cortices in AD; similar to NFTs; however, they are less common in primary motor and visual cortices. DPs are also common in AD and consist of deposits of amyloid without thickened or PHF-containing neurites. Some plaques, especially DPs, have a perivascular orientation, usually in association with amyloid angiopathy (see Figure 2.8). Morphologic characteristics and protein and cellular components of senile plaques permit differentiation of plaque types (Thal et al., 2000).

(b)

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The Aging Brain in Neurology

(a)

(b)

(c)

(d)

Figure 2.8 Amyloid pathology

in AD. (a) Numerous amyloid immunostained plaques in the cortex at low power. (b) Leptomeningeal arterioles also may show amyloid deposition. (c, d) Higher power of plaque pathology using amyloid immunostain. (For a color version, see the color plate section.)

Similar to the stages of NFT as described by Braak, the progression of senile plaque pathology has also been described (Thal et al., 2000; Thal et al., 2006). In the first phase, DPs deposit in the neocortex. In the second phase, Aβ plaques deposit in allocortical areas, such as the entorhinal region, and in the subiculum/CA1 region of hippocampus. In the third phase, the basal ganglia, the thalamus, and the hypothalamus become involved, followed in the fourth phase with the involvement of the midbrain and the medulla oblongata. Finally, in the fifth phase, senile plaques develop in the pons and the cerebellum. Deposition of Aβ amyloid in the leptomeningeal and cortical small arteries and arterioles occurs in most individuals with AD, but it also occurs in “normal” aging (Arvanitakis et al., 2011a). When severe, CAA is associated with lobar hemorrhages, perivascular scarring, and less commonly infarcts. CAA is preferentially deposited in the small vessels of the occipital cortex and meninges; thus, CAA should be considered in the presence of posterior lobar hemorrhages (see Figure 2.8).

Criteria for the pathologic diagnosis of AD Significant progress has been made in identifying clinical biomarkers for the diagnosis of AD, yet a definitive diagnosis of AD still requires pathologic examination of the brain. Pathologic criteria for the diagnosis of AD were initially established to confirm the clinical diagnosis in persons with dementia. These criteria have changed three times over the past four decades and have been strongly influenced by the contemporaneous views of dementia and the normal aging brain. The

first set of criteria developed in 1985, termed Khachaturian criteria, used an age-dependent specific density of senile plaques (Zhachaturian, 1985). More plaques were required in older persons than younger patients to confirm a diagnosis of AD, apparently to allow for sparse plaques in older individuals without dementia. Plaque type was not specified. The Consortium to Establish a Registry for Alzheimer’s disease (CERAD) criteria for a pathologic diagnosis of AD, developed in 1991, proposed semiquantitative measures of neocortical NP to establish a probability statement on the diagnosis of AD (possible, probably, definite) after considering age and clinical diagnosis (Mirra et al., 1991). Probable or definite AD required a larger number of plaques in older persons and a premorbid diagnosis of dementia. NIA–Reagan criteria (The National Institute on Aging, 1997), proposed in 1997, made a couple of important changes, including incorporation of NFT—using Braak score (Braak and Braak, 1991), and included plaque estimates without regard to age, to allow for probability statements of the likelihood that dementia occurs as a result of AD (high, intermediate, low). These criteria were formulated for pathologic examination of brains with dementia but do not take into account AD neuropathologic changes in MCI (Section “Mild cognitive impairment”) and in persons with no cognitive impairment. Criteria are currently being revised to allow for the description of AD neuropathologic changes in persons with MCI and no cognitive impairment. The presence of significant AD pathology in normal older persons suggests the presence of preclinical disease and neural reserve.

Functional Changes Associated with the Aging Nervous System

Mild cognitive impairment MCI is a clinical diagnosis and represents an intermediate stage between normal aging and dementia (Bennett et al., 2002). Persons with MCI have cognitive impairment, memory, or nonmemory, but do not fulfill the criteria for dementia. In the past decade, there has been expanding data on the pathologic basis of MCI (Morris et al., 2001; Markesbery et al., 2006; Petersen et al., 2006). As with dementia (Section “Mixed pathology (AD, infarct, and LB Pathology) in dementia”), the underlying pathology is heterogeneous, with AD being the most common underlying pathology, followed by infarcts and then LBs, supporting that MCI represents a transition between normal aging and dementia (Bennett et al., 2006). While the pathology is often intermediate, it is interesting to note that more than half of persons with MCI have sufficient pathology to render a pathologic diagnosis of AD (Schneider et al., 2009). This has implications for preventions and treatments targeting early disease. Infarcts are also common, especially in persons with nonamnestic MCI and mixed with AD pathology in persons with amnestic MCI. LB disease is the third most common pathology in MCI and is most commonly mixed with AD pathology. FTLD and related dementias also likely pass through an intermediate clinical stage, but a little is known regarding the pathologic phenotype. Vascular cognitive impairment and dementia Early in the twentieth century, vascular disease was believed to be the primary pathologic cause of cognitive decline in older persons, often called senility. Recognition that AD pathology was the most common pathology underlying late-life dementia and the lack of definitive criteria for a pathologic diagnosis of vascular dementia resulted in a lesser emphasis on vascular dementia as a pathologic substrate for age-related dementia. More recently, there has been a resurgence of interest in vascular disease as a pathologic substrate for age-related dementia, especially as a mixed disorder (Schneider and Bennett, 2010). Community-based and population-based prospective epidemiologic studies have shown that infarcts and other vascular pathologies are very common in the brains of older persons, from one-third to one-quarter of older persons with some vascular brain pathology (MRC CFAS, 2001; White et al., 2005; Schneider et al., 2007a; Sonnen et al., 2007). Initial studies suggested that infarcts must be in a certain volume, such as 100 mL (Lowe et al., 2008) order to result in dementia, but it was later recognized that multiple infarcts were also an important factor, so the term multi-infarct dementia (MID) was coined (Hachinski et al., 1974). Because myriad vascular lesions, including smaller strategically located infarcts, can also result in dementia, the terminology was subsequently changed to vascular dementia. The alternative nomenclature vascular cognitive impairment is based on the recognition that

45

vascular lesions may not result in the pattern of cognitive impairment required for the clinical diagnosis of dementia, which is typically geared toward the diagnosis of AD, emphasizing episodic memory impairment (Hachinski et al., 2006). Indeed, though vascular and AD pathology may have overlapping phenotypes, studies show that cerebral infarcts do not affect all cognitive systems equally, showing the strongest association with perceptual speed and the weakest with episodic memory (Schneider et al., 2003). While AD is still considered the most common pathology underlying dementia, vascular disease is considered the second leading cause of dementia, representing about 10% of the cases (Roman, 2003). This number is most certainly greater if one considers microscopic infarcts, mixed pathologies, and the role of additional vascular lesions, such as amyloid angiopathy. No generally accepted pathologic criteria apply for a diagnosis of VCI or vascular dementia. Vascular substrates for dementia are heterogeneous and include single strategic infarcts, multiple infarcts, cortical infarcts, subcortical infarcts, and microscopic infarcts. Other vascular pathology, including global ischemia, white matter degeneration, and small vessel disease (arteriolosclerosis and amyloid angiopathy) may also play a role. Finally, there has been increasing interest in the hippocampal sclerosis, which is at least partly related to global ischemia and selective vulnerability. There are numerous classification schemes used to differentiate vascular lesions that may contribute to vascular dementia, including divisions into large and small vessel diseases, ischemic and hemorrhagic infarcts, and focal versus multifocal disease (Hachinski et al., 1974; Romàn et al., 2002; Roman, 2003; Hachinski et al., 2006; Chui, 2007; Jellinger, 2008; Schneider and Bennett, 2010). Focal disease includes single infarcts and hippocampal sclerosis, whereas multifocal disease includes multiple infarcts, as well as global ischemia and ischemic white matter disease.

Infarct size, number, and location It has long been recognized that large infarcts can be related to dementia, especially in the form of post-stroke dementia. Data from longitudinal clinical pathologic studies of aging and AD (Schneider et al., 2003) have also shown that the odds of dementia are higher in persons with large or clinically evident infarctions. With large infarcts, the underlying disorder is atherosclerosis affecting large intracranial or extracranial blood vessels, giving rise to local thromboses or emboli. In addition, cardiac disorders, such as atrial fibrillation and myocardial infarction, can be the source of cerebral emboli. The number of lesions also contributes to the development of dementia (Hachinski et al., 1974). Dementia associated with MID has been reported to account for a substantial proportion of vascular dementia and to more frequently involve the dominant hemisphere (Jellinger, 2008). Indeed, location of lesions may be more

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(a)

The Aging Brain in Neurology

(b)

Figure 2.9 An old lacunar infarct in the

anterior thalamic nucleus: (a) gross coronal brain slab; (b) histologic appearance of old infarct with few macrophages and cavitation. (For a color version, see the color plate section.)

critical than total volume. In some cases, a single relatively small infarct (strategic infarct) can damage the brain enough to cause dementia (Chui, 2007). Infarcts in the left hemisphere disproportionately increase the risk of dementia (Roman, 2003; Kuller et al., 2005) as do infarcts in the hippocampus, anterior thalamus, genu of internal capsule, and anterior caudate (Chui, 2007; see Figure 2.9).

Subcortical ischemic vascular dementia Subcortical ischemic vascular dementia (SIVD) is a subtype of vascular dementia defined by the presence of lacunar infarcts and deep white matter changes (Romàn et al., 2002; Chui, 2007). The syndrome conceptually includes at least two previously defined pathologies: lacunar states (état lacunaire), with multiple lacunes in the subcortical nuclei and softening of the white matter; and Binswanger’s disease, with white matter degeneration and secondary dilatation of ventricles (subcortical arteriosclerotic/ leukoencephalopathy (SAE) and leukoaraiosis (Romàn et al., 2002; Roman, 2003; Chui, 2007). État crible, which describes the appearance of multiple enlarged perivascular spaces in deep gray and white structures, may also be present (see Figure 2.10). The microangiopathy underlying these changes is thought to be the result of arteriolosclerosis (often erroneously referred to has lipohyalinosis (LH)) and is related to aging, hypertension, diabetes mellitus, and possibly other conditions, such as hyperhomocysteinemia (Esiri et al., 1997; Chui, 2007; Jellinger, 2008; Schwartz et al., 2010). Lacunar infarcts, generally about 1 cm or less in diameter, are cavitating lesions in the gray and white matter (see Figure 2.9). Lacunar infarcts occur predominantly in subcortical gray matter, predominantly basal ganglia and thalamus, internal capsule, and brainstem. Subcortical infarcts may not be clinically recognized and may be

discovered incidentally on neuroimaging (Chui, 2007) or at autopsy (Schneider et al., 2007b). Lacunar infarcts are frequently multiple and bilateral and often coexist with other vascular lesions. These lesions appear as foci of ischemic necrosis and result from narrowing or occlusion (arteriolosclerosis) of penetrating (striate) arteries branching directly from larger cerebral arteries. White matter degeneration (subcortical arteriolar encephalopathy and leukoaraiosis) is associated with small vessel disease with vascular hyalinization (arteriolosclerosis), expansion of the perivascular space, pallor of perivascular myelin, and astrocytic gliosis (see Figure 2.10). Pathologically, ischemic white matter lesions appear as foci of confluent white matter softening, with pale staining of myelin, often sparing subcortical U-fibers. Radiographic studies have proposed that 25–38% of the cerebral white matter needs to be affected to allow for a diagnosis of subcortical vascular dementia (Price et al., 2005). Clinical signs may be the result of disruption of pathways from the prefrontal cortex to the basal ganglia and of thalamocortical pathways. Although executive function is often considered the most commonly affected cognitive system, subcortical infarcts can also be related to memory loss (Schneider et al., 2007b) and parkinsonism (Buchman et al., 2011) (see Figure 2.10).

Microscopic infarcts Microscopic infarcts are most commonly defined as the infarcts visualized by light microscopy in the absence of the infarcts seen on gross examination. Microscopic infarcts are found in about 50% of older persons with macroscopic infarcts but also may be seen in the absence of macroscopic infarcts (Arvanitakis et al., 2011b ). When cortical and multiple, these tiny infarcts have been shown to be a strong correlate and add to the

Functional Changes Associated with the Aging Nervous System

(a)

47

(b)

Figure 2.10 Subcortical ischemic vascular

disease. Both (a) gross and (b) histologic brain sections show lacunar infarcts and enlarged perivascular spaces predominantly in the caudate in a person with vascular parkinsonism. (For a color version, see the color plate section.)

likelihood of dementia even after controlling for macroscopic infarcts and AD (White et al., 2005; Sonnen et al., 2007; Arvanitakis et al., 2011b). These infarcts are not yet identifiable on neuroimaging, although they have been found to correlate with measures of white matter pathology, including macroinfarcts, hemorrhages, and leukoencephalopathy (Longstreth and Sonnen, 2009). The mechanism by which these tiny infarcts result in dementia is not known. Because only a very small amount of tissue is sampled in most brains, several microinfarcts may represent a far greater number of occult infarctions and a large loss of tissue. Alternatively or in addition, microinfarcts may be a surrogate for the presence of other vascular damage.

Dementia with Lewy body disease Lewy bodies are the pathognomonic inclusion found in the SN in Parkinson’s disease (PD). Almost five decades ago, cortical LBs were found in an atypical dementia syndrome (Kosaka et al., 1984), variably called diffuse LB disease (Dickson et al., 1987), DLB (Sima et al., 1986), and LB variant of AD (Samuel and Galasko, 1996). Most recent criteria use the term dementia with LBs (DLB; McKeith et al., 1996). DLB manifests with a decline in cognition with associated fluctuations, hallucinations, and parkinsonism. While pure DLB (without concomitant AD pathology) is a relatively uncommon cause of dementia (Schneider et al., 2007a), probably representing only about 5% of all dementia cases, DLB with concomitant AD pathology is more common, including about 10–20% of dementia cases, depending on the cohort. Because of associated neurobehavioral difficulties, DLB may be more common in clinic cohorts, compared to the community (Wakisaka et al., 2003). Overall, DLB is currently considered as the second most common neurodegenerative cause of dementia. Similar to AD, diagnosis requires pathologic confirmation.

Macroscopic and microscopic appearances of DLB The macroscopic appearance of the brain in DLB is usually similar to that in PD, including mild cortical atrophy of the frontal lobe, with variable pallor of the SN and locus coeruleus. Pallor of the locus coeruleus also occurs in AD without LB. In DLB with significant AD changes, there may be more severe atrophy of the hippocampus and temporal and parietal lobes. LBs and Lewy neurites (LN) are present in multiple selective brain regions, including the brainstem, limbic, and neocortical regions. The olfactory bulb and spinal cord are also commonly involved in LB disease and may be related to olfactory and autonomic disturbances. LBs are believed to progress in a caudal to rostral distribution; however, amygdala LBs may occur in the absence of brainstem involvement and may represent a distinct form of LB disease (Uchikado et al., 2006). The pathology of DLB overlaps with the pathology of idiopathic PD and PD dementia. The neuronal loss from the SN and locus coeruleus is more variable than in typical PD but may also be severe. Nigral and other brainstem neurons often contain classic LBs (see Figure 2.11), and LBs may also lie free in the neuropil. The cortical LBs (see Figure 2.12) that are predominant in the lower layers of cortex, particularly in the small-size to medium-size pyramidal neurons, are smaller and less well-defined and lack halos (see Figure  2.12). LB can be seen in the sections stained with H&E and ubiquitin immunohistochemistry, but α-synuclein is the most sensitive and most specific stain. LN can be seen in all regions with LBs but can also be seen separately in CA2-3 region of the hippocampus. In DLB, cortical LB density has been associated with severity of cognitive impairment (Samuel and Galasko, 1996). In addition to LB and LN, DLB cases commonly have transmural spongiform change in the entorhinal cortex and other temporal regions. Coexisting AD pathology is very common in DLB; conversely, LBs

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The Aging Brain in Neurology

(a)

(b)

Figure 2.11 Substantia nigra

neurons with multiple LBs: (a) classic dense concentric appearance with peripheral halo on H&E; (b) LB halo stains darker using antibodies to α-synuclein. (For a color version, see the color plate section.)

are common in AD, described in more than 50% of cases (Hamilton, 2000), depending on the cohort and regions (for example, the amygdala). The presence of significant AD pathology may modify and obscure the typical DLB clinical presentation (McKeith et al., 2005).

pathologic diagnosis of AD or mixed with sufficient AD pathology to render an additional pathologic diagnosis of AD. It has been suggested that there is an interaction of β-amyloid and α-synuclein, accounting for the common co-occurrence of these two types of pathologies (Pletnikova et al., 2005).

Diagnostic criteria for DLB Current criteria for the neuropathologic diagnosis of DLB require the histologic observation of LB and divide the disease into three types: brainstem-predominant, limbic type, and neocortical type (McKeith et al., 1996; McKeith et al., 2005). Evaluation of LBs in the brainstem is recommended and includes SN, locus coeruleus, and dorsal nucleus of the vagus. Basal forebrain/limbic system evaluation includes the basal nucleus of meynert, amygdala, anterior cingulate cortex, and entorhinal cortex. Neocortical regions include the middle temporal gyrus, middle frontal gyrus, and inferior parietal lobule. DLB may be “pure” without sufficient AD to render an additional (a)

Mixed pathology (AD, infarct, and Lewy bodies pathology) in dementia Both infarcts and LBs more commonly coexist with AD pathology than as an isolated pathology in older persons with dementia (MRC CFAS, 2001; White et al., 2005; Schneider et al., 2007a; Sonnen et al., 2007; O’Brien et al., 2009; Nelson and Abner, 2010). Indeed, mixed brain pathologies are very common in the brains of community-dwelling older persons and are more common than any single pathology in older persons with dementia (Schneider et al., 2007a). AD pathology mixed with infarcts is the most common mixed pathology, followed by AD mixed with LBs.

(b)

(c)

Figure 2.12 Cortical LBs in the superior

temporal cortex. (a) H&E stain shows an eosinophilic cytoplasmic inclusion without a clearly defined halo. (b) Low-magnification view showing numerous α-synucleinimmunostained cortical LBs. (c) Cortical LBs may stain uniformly or show a peripheral halo with α-synuclein immunostain. (For a color version, see the color plate section.)

Functional Changes Associated with the Aging Nervous System

The addition of each pathology is not benign but rather further adds to the likelihood of dementia and the severity of cognitive impairment (Schneider et al., 2003; Schneider et al., 2007b; Schneider et al., 2009). Mixed pathologies are also common in clinically diagnosed probable AD and may be seen in MCI, particularly amnestic MCI (Schneider et al., 2009). Clinicians should recognize mixed pathologies (particularly AD mixed with infarcts and/or LBs) as an important etiology of dementia in older persons.

Frontotemporal lobar degeneration FTLD is the designation for a heterogeneous group of non-AD neurodegenerative disorders typically associated with frontotemporal dementias (FTD). In contrast to AD, FTD typically presents with behavioral (behavioral variant) or language (including primary progressive aphasia or semantic dementia) disturbances rather than episodic memory, which is preserved until later in the disease. As its name implies, FTLD is associated with selective degeneration of the frontal and/or temporal lobes and also variable involvement of subcortical gray matter. Atrophy may be asymmetric, with corresponding underlying neuronal loss and gliosis. Layer 2 spongy change of the cortical regions is often noteworthy. Clinical phenotypes in FTLD may reflect the abnormalities associated with these anatomic regions. The increased application of immunohistochemistry for tau, ubiquitin, and the recent recognition of TAR DNAbinding protein 43 (TDP-43) and FUS protein inclusions has led to increased recognition of FTLD and has enhanced the two main classification groups: FTLD-tau (tau-associated disorder) and FTLD-ubiquitin (FTLD-TDP-43 and FTLDFUS; Mackenzie et al., 2009). These pathologies (especially FTLD-TDP-43) are now more easily and commonly recognized, which will allow for increased detection and a recalculation of the frequency of the different subgroups of disease (Cairns et al., 2007; Mackenzie et al., 2009). When no inclusions are identified (FTLD-NI), this is often referred to as dementia lacking distinctive histology (DLDH). Clinical phenotypes of dementias are currently being investigated in relation to the broadening spectrum of inclusions that are now recognized in the FTLD spectrum.

FTLD-tau and other tauopathies The non-Alzheimer tauopathies are characterized by the accumulation of abnormal tau protein in neurons or glial cells or both. The major tauopathies associated with dementia under the rubric of FTLD-tau include Pick’s disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and multisystem tauopathy with dementia. Most of these disorders can be distinguished by characteristic patterns of pathologies, inclusions, and predominant tau isoforms. FTD with parkinsonism linked to chromosome 17 (FTLD17) is also a FTLD-tau that is linked to MAPT mutations and typically has three and four repeat isoforms of tau-tangles, but it does not

49

have a characteristic pattern of pathology (Mackenzie et al., 2009). Other disorders more variably linked to the typical FTD syndrome that have characteristic tau pathology include agyrophilic grain disease, chronic traumatic encephalopathy, and tangle-predominant dementia.

Pick’s disease Pick’s disease was first described in 1892 by Albert Pick. The histopathology was detailed by Alzheimer and Altman two decades later (Lowe et al., 2008). In the past, the designation of Pick’s disease was synonymous with FTLD; we now recognize that Pick’s disease is one of the multiple pathologic subtypes of FTLD, specifically one of the subtypes of FTLD-tau (Mackenzie et al., 2009). Gross pathology includes frontotemporal atrophy, usually superior temporal gyrus, with relative sparing of the posterior twothirds of cortex. With severe atrophy, the involved cortical gyri have a so-called knife blade appearance. There is variable atrophy of the caudate and SN. Microscopically, in addition to severe neuronal loss and gliosis in the described regions, the pathognomonic finding is the Pick body, which is the cytoplasmic inclusion found in neurons in the frontal and temporal cortices, as well as in the limbic and paralimbic cortices and temporal lobe, especially the granule cell layer of the hippocampus. Pick bodies are commonly found in layers II and IV, are argyrophilic, and stain with antibodies to abnormally phosphorylated tau protein. Pick bodies consist of mostly straight but also twisted filaments, compared to the paired helical filaments of AD (Lowe et al., 2008). Biochemically, Pick bodies consist primarily of the three repeat-tau isoform. In addition to Pick bodies, cases often show ballooned neurons, called Pick cells, in the involved regions of cortex. These can be highlighted using antibodies to neurofilament.

Corticobasal degeneration CBD was first described in 1967 as “corticodentatonigral degeneration with neuronal achromasia” (Gibb et al., 1988). The patients with classic CBD develop an atypical parkinsonian disorder, asymmetrical clumsiness, and stiffness or jerking of a limb, commonly an arm. Dystonic rigidity, akinesia, and myoclonus develop after 2–3 years. Many patients develop the “alien limb” phenomenon (Gibb et al., 1988; Paulus and Selim, 2005; Lowe et al., 2008). It has been increasingly recognized that CBD may also be associated with focal cortical syndromes, such as frontal lobe dementia or progressive aphasia, with the clinical phenotype of CBD corresponding to the specifically affected cortical regions of damage (Dickson, 1999). For example, in cases with language abnormalities, the brunt of the pathology may be in the peri-Sylvian region. Macroscopically, typically there is asymmetrical cortical atrophy of the posterior frontal, parietal, and perirolandic cortex. The superior frontal and parietal gyri are usually more involved than the middle and inferior frontal gyri

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The Aging Brain in Neurology

and the temporal or occipital lobes. There is usually pallor of the SN. Histologically, there is neuronal loss with astrocytosis, which is often most severe in the superficial cortical laminae and associated with superficial spongiosis similar to that seen in FTLD. Ballooned neurons (see Figure 2.13) are seen usually in layers III, V, and VI (Lowe et al., 2008). The ballooned neurons are enlarged eosinophilic and are weakly argyrophilic, lack Nissl substance, and are occasionally vacuolated; and this is referred to as neuronal achromasia (Dickson, 1999). The presence of these ballooned neurons in the cortical areas of the cerebral convexities is important for the diagnosis of CBD. These ballooned neurons are immunoreactive for phosphorylated neurofilaments and αβ-crystallin and are variably reactive for tau protein and ubiquitin (Dickson, 1999). The SN typically usually shows moderate-tosevere neuronal loss with gliosis. The remaining neurons may contain ill-defined neurofibrillary inclusions or corticobasal bodies (Riley et al., 1990; Schneider et al., 1997). Immunohistochemistry shows widespread tau-positive inclusions within glial processes in the involved regions and abundantly in white matter. These can be a helpful diagnostic feature. Tau-positive, argyrophilic granular, and coiled bodies (oligodendroglial filamentous inclusions) are also widespread in the cortex and white matter. Another helpful diagnostic feature is astrocytic plaques (see Figure  2.14), which consist of a collection of tauimmunoreactive processes of astrocytes that surround unstained neuropil and are frequent in premotor, prefrontal, and orbital regions, as well as the striatum, caudate, and putamen. There is regional and immunohistochemical heterogeneity of CBD pathology; and the distinction between CBD and PSP can be difficult in some cases (Bergeron et al., 1997; Schneider et al., 1997). Extensive neuropil tau-positive threads, ballooned neurons, and astrocytic plaques are of significant value in the diagnosis of CBD (Bergeron et al., 1997; Dickson, 1999).

Figure 2.13 Corticobasal degeneration: ballooned neuron (neuronal achromasia) on H&E stain. (For a color version, see the color plate section.)

Figure 2.14 Tau-immunopositive astrocytic plaques are characteristic of CBD (AT8 immunohistochemistry). (For a color version, see the color plate section.)

Progressive supranuclear palsy PSP is typically described as sporadic movement disorder; but as with CBD, it can also be associated with dementia. While the initial clinical description of PSP by Steele et al. (1964) (Lowe et al., 2008) emphasized a unique constellation of clinical findings (parkinsonism, supranuclear gaze palsy, and falls), other presentations may suggest typical PD, multiple system atrophy (MSA), CBD, or another degenerative disease (Collins et al., 1995; Bergeron et al., 1997; Schneider et al., 1997; Dickson, 1999). Macroscopically, in PSP, the cerebral cortex is usually unremarkable, but there may be atrophy and discoloration, especially of the subthalamic nucleus, but also involving globus pallidus, dentate nucleus of cerebellum, midbrain, and pontine tegmentum; there may also be tectal and tegmental atrophy with dilatation of the cerebral aqueduct. Decreased pigmentation of the SN and locus coeruleus is also typical but variable (Gibb et al., 1988; Schneider et al., 1997). Histologically, there is neuronal loss and gliosis predominant in the subcortical nuclei, particularly in the globus pallidus, subthalamic nucleus, red nucleus, and SN. The subthalamic nucleus is typically severely involved; the SN shows diffuse involvement but is most severe in the ventrolateral tier, as in PD and CBD (Dickson, 1999). Cortical pathology is less severe and may be noted in the precentral cortex (Dickson, 1999); specific pathology is also typical in the dentate granule cells (Gibb et al., 1988; Dickson, 1999). The hallmark of PSP is the presence of NFTs and tau-positive threads in subcortical gray matter, including subthalamic nucleus, globus pallidus, and striatum (see  Figure 2.15). Tau pathology including tangles and threads is detected using antibodies specific for 4-repeat forms of tau, but it is negative for 3-repeat forms of tau, consistent with a

Functional Changes Associated with the Aging Nervous System

51

(a)

(b)

(c)

Figure 2.15 Progressive supranuclear

palsy: neurofibrillary tangle (NFT) pathology. (a) Globose NFT with basophilic filamentous appearance (H&E). (b) NFT in SN highlighted with tau immunohistochemistry. (c) Antibody to 4-repeat tau isoforms labels two NFT. (For a color version, see the color plate section.)

4-repeat tauopathy (Collins et al., 1995; Katsuse et al., 2003). A distinctive form of astrocytic pathology in gray matter is designated tufted astrocytes (see Figure 2.16), which are stellate with fine radiating processes surrounding the nucleus and contrast with the “astrocytic plaques” of CBD (Matsusaka et al., 1998; Dickson, 1999). Another distinctive form of inclusions is coiled bodies (see Figure 2.16), which are tau-immunopositive and silver-positive oligodendroglial inclusions presenting in the white and gray matter; however, these are identical to those seen in CBD (Collins et al., 1995; Bergeron et al., 1997; Dickson, 1999). PSP pathology may also be found in the superior colliculus, tegmentum, periaqueductal gray matter, red nucleus, oculomotor complex, trochlear nucleus, pontine nuclei, inferior olives, and cerebellar dentate (Gibb et al., 1988; Riley et al., 1990; Daniel et al., 1995; Schneider et al., 1997; Dickson, 1999; Paulus and Selim, 2005). (a)

Figure 2.16 PSP: astrocytic pathology. (a)

Tau-immunoreactive tufted astrocyte in the subthalamic nucleus (AT8 antibody). (b) Coiled bodies that immunolabel with antibodies specific to 4-repeat tau. (For a color version, see the color plate section.)

FTLD-ubiquitin FTLD-U was originally named for cases in which the characteristic inclusions were visible only with ubiquitin immunohistochemistry. TDP-43, a nuclear protein implicated in exon skipping and transcription regulation, was recently identified as the major ubiquinated component of the pathologic inclusions of most sporadic and familial cases of FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease, and sporadic amyotrophic lateral sclerosis (ALS) (Mackenzie et al., 2009). Thus, most, but not all, cases that were previously designated as FTLD-U have been renamed as FTLDTDP (Cairns et al., 2007; Mackenzie et al., 2009). This pathology is associated with several genes, including progranulin, and, much less commonly, mutations associated with valosin-containing protein (VCP), TDP, and cases linked to chromosome 9. About 10% of cases that were (b)

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ubiquitin-positive but not related to TDP-43 have been subsequently found to consist of FUS (fused in sarcoma), a protein previously implicated in ALS. The designation of FTLD-UPS (ubiquitin–proteasome syndrome) now refers to cases with ubiquitin positivity that have not been linked to a specific protein (such as familial syndrome of FTD3 as a result of CHMP2B mutations; Mackenzie et al., 2009). In FTLD-TDP, brain atrophy is variable but may be severe, especially in frontotemporal distribution and the hippocampus, and there is associated dilation of the lateral ventricles. There may also be pallor of the SN, atrophy, and discoloration of the head of the caudate nucleus and cerebral white matter. Histologically, there is variable neuronal loss in the affected regions, and there may be hippocampal sclerosis. Cases may be screened using ubiquitin immunohistochemistry but must be confirmed by immunohistochemical assessment for TDP-43 protein, which is translocated from the nucleus to the cytoplasm, ubiquinated, and phosphorylated (see Figure 2.17). Ubiquitin and TDP-43-positive neuronal cytoplasmic inclusions (NCIs), neuronal intranuclear (NIIs), dystrophic neuritis (DNs), and glial cytoplasmic inclusions (GCIs) are most often seen in neurons in outer cortical layers of the frontal and temporal lobes, in the dentate layer of the hippocampus, and in the basal ganglia (Cairns et al., 2007).

ALS-dementia Dementia is now recognized as a common co-occurrence in ALS, and the neuropathology associated with ALS-dementia shares many of the characteristics of FTLD-TDP, which is also the major disease protein implicated in the anterior horn neurons in ALS. TDP-43 pathology is found in multiple brain areas and in a spectrum of diseases as both a primary and a secondary pathology, suggesting that ALS is a disease that not only affects the pyramidal motor system, but instead it is a multisystem neurodegenerative TDP-43 proteinopathy (Geser et al., 2008). In ALS-dementia cases, TDP-43 positive inclusions are most predominantly found in neurons in outer cortical layers of the frontal and temporal cortices and in the dentate layer of the hippocampus, as well as in the basal ganglia (Geser et al., 2008).

Creutzfeldt–Jakob disease CJD is a spongiform encephalopathy associated with a rare form of dementia that may be sporadic (sCJD), iatrogenic, or familial (Mahadevan et al., 2002; Gambetti et al., 2003). sCJD is the most frequently occurring human prion disease. Prions are infectious proteineous agents that lack DNA or RNA structure and are normally produced by cells in a nonpathogenic form. Brains of CJD patients may be grossly normal or exhibit mild, diffuse atrophy and are distinguished from other causes of dementia by histologic examination characterized by variable distribution and severity of spongiform change, neuronal loss, and reactive astrocytosis in the frontal, temporal, and occipital lobes; basal ganglia; and cerebellum. Ten percent of cases of sCJD show amyloid plaques composed of prion protein (kuru plaques; Mahadevan et al., 2002; Gambetti et al., 2003). Prion protein (PrP) immunohistochemistry is used routinely to aid diagnosis (Mahadevan et al., 2002; Gambetti et al., 2003). Variant CJD (vCJD), first reported in the United Kingdom, is believed to occur as a result of the transmission of an animal prion disease, bovine spongiform encephalopathy, to humans. vCJD is characterized by severe neuronal loss and severe astrocytosis in the posterior thalamic nuclei, particularly the pulvinar, with spongiform change most severe in the basal ganglia, particularly the putamen and caudate nucleus (Ironside et al., 2002). Florid plaques encircled by a rim of microvacuolar spongiform change are immunopositive for PrP and are especially prominent in the occipital and cerebellar cortices (Ironside et al., 2002). Wernicke–Korsakoff syndrome Two overlapping clinical pathologic entities exist within the WKS spectrum: Wernicke’s encephalopathy (WE) and Korsakoff’s psychosis (KP). Wernicke’s and Korsakoff’s are generally considered to be different stages of the same disorder, WKS, caused by the deficiency of thiamine (Vitamin B1). It is most commonly seen in persons with alcohol abuse, dietary deficiencies, prolonged vomiting, eating disorders, or the effects of chemotherapy. Clinical

(a)

Figure 2.17 FTLD-TDP: TDP-43 immunoreactive

(b)

inclusions in the neurons of the dentate layer of hippocampus. (a) Low magnification shows diffuse nuclear staining and numerous TDP-43 positive inclusions (arrows). (b) High magnification shows cytoplasm inclusions with nuclear clearing in affected neurons. (For a color version, see the color plate section.)

Functional Changes Associated with the Aging Nervous System

features of WE include mental confusion, visual impairment, and ataxia and hypotension/hypothermia. Patients with KP have a memory disorder with amnesia, confabulation, attentional deficits, disorientation, and vision impairment. KP may be the end result of the repeated episodes of WE, but it has also been described without a known episode of WE. The characteristic lesions of WKS, particularly WE, are surrounding the third and fourth ventricles and include the mamillary bodies, which show atrophy and brown discoloration from old hemorrhage. Other regions of similar involvement include the hypothalamus, thalamus, periaqueductal gray matter, colliculi, and floor of the fourth ventricle (oculomotor nuclei, dorsal motor nuclei of vagus, vestibular nuclei). Lesions of the medial dorsal nuclei or, alternatively, the anterior nucleus of thalamus (Harper, 2009) showing neuronal loss and gliosis, with or without hemorrhages, have been postulated to be responsible for the memory defect of KP. More recently, it has been postulated that an interruption of complex diencephalic-hippocampal circuitry including thalamic nuclei and mamillary bodies rather than a single lesion in the thalamus is responsible for KS (Harper, 2009). In about 27% of cases, there is degeneration of the anterior superior aspect of the cerebellar vermis (Harper, 2009). Other changes may be seen specifically as a toxic effect of alcohol, including neuronal loss and white matter degeneration; some changes may be temporary, with others permanent (Harper, 2009).

53

pathology in dementia, some of these conditions have already been reviewed in Section “Neuropathology of other dementias.”

Atherosclerosis Atherosclerosis of the cerebral vasculature is common in older persons and represents the most common underlying pathology for large territory and embolic cortical infarcts. As might be expected, the risk factors for atherosclerosis are similar as those for stroke and include hypertension, diabetes, dyslipidemia, and cigarette smoking. White people have been described to more often harbor atherosclerotic lesions in extracranial vessels, whereas Afro-Caribbean populations are more likely to have intracranial atherosclerosis (Moossy, 1993). Atherosclerosis affects medium and large arteries, particularly in the major branches of the Circle of Willis and occurs when fat, cholesterol, and other substances build up in the walls and form plaques (see Figure 2.18). Sufficient blood flow is often maintained in spite of significant narrowing and rigidity from plaques. Complicated plaques with damage to the endothelium are the key triggers for the development of thrombus, occlusion, and emboli (Ferrer et al., 2008). Emboli cause abrupt occlusion of distal downstream arteries, whereas local thrombotic processes are typically slower, allowing time for collateral channels to develop. Clots can also form around tears (fissures) in the plaques. In some cases, the atherosclerotic plaque is associated with a weak-

Neuropathology of other dementias Numerous other rare forms of dementia exist, including neurodegeneration with brain iron accumulation, adultonset polyglucosan disease, adult-onset leukodystrophy, adult neuronal ceroid lipofuscinosis, and some of the spinocerebellar atrophies. In addition, nondegenerative dementias may result from inflammatory, neoplastic, and demyelinating conditions. The following sections discuss some of these more common conditions.

Cerebrovascular disease in the elderly Vascular disease is common with aging, and the pathologic classification of cerebrovascular disease is similar to other age groups; it includes large vessel disease, small vessel disease, ischemic parenchymal injury, and hemorrhagic parenchymal injury. Older persons are particularly prone to large vessel disease in the form of atherosclerosis, small vessel diseases including arteriolosclerosis and CAA, and ischemic and hemorrhagic parenchymal injury. In addition, older persons are more likely to experience global hypoxic events from cardiac disease resulting in global/hypoxic ischemic encephalopathy and are more prone to subdural hematomas (SDH) from falls. Because cerebrovascular disease is a common underlying

Figure 2.18 Atherosclerosis, the Circle of Willis. Note the asymmetric involvement of vertebral arteries, extension into basilar artery, and posterior cerebral arteries. (For a color version, see the color plate section.)

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The Aging Brain in Neurology

ening of the wall of an artery, leading to an aneurysm. Severe atheroma, especially in the basilar artery, may cause fusiform enlargement (see Figure 2.19), or fusiform aneurysm, and result in mechanical compression, clinical cranial nerve palsies, excitation, and hydrocephalus. While hemorrhage is rare, ischemia and infarction may result from thrombi or fragments of plaques that embolize (Ferrer et al., 2008).

Small vessel disease Small cerebral vessels include perforating arteries with diameters of 40—900  μm (Ferrer et al., 2008). Diseases of small vessels have been associated with lacunar infarcts (Sections “Vascular cognitive impairment and dementia” and “Infarction”), subacute ischemic vascular dementia, and primary intraparenchymal hemorrhages (Section “Intraparenchymal hemorrhages”). The most common small vessel disease in aging is arteriosclerosis/ arteriolosclerosis (AS; see Figure 2.20). Arteriolosclerosis affects arteries 40–150 μm in diameter (Ferrer et al., 2008). Microscopic features of AS include hyaline thickening, intimal fibromuscular hyperplasia, luminal narrowing, thinning of the media, and concentric onion-skintype smooth muscle cell proliferation, with or without the presence of foamy macrophages in the arterial wall (Vinters, 2001; Yahnis, 2005; Ferrer et al., 2008). Although the term lipohyalinosis (LH) is often used synonymously with AS, LH was initially used to describe small blood vessels that first underwent fibrinoid change and then subsequent hyalinization, especially in association with

Figure 2.19 Fusiform aneurysm of the basilar artery. Artery is

dilated and tortuous and may compress and distort the brain stem. (For a color version, see the color plate section.)

Figure 2.20 Arteriolosclerosis: hyaline thickening of two small vessels in the deep white matter. Note that the upper vessel appears occluded. (For a color version, see the color plate section.)

hypertension. The uniform eosinophilia on H&E-stained sections may result from either fibrinoid change (necrosis) or collagenous fibrosis (hyalinosis). Special stains may be needed to distinguish the two changes. Traditionally, hypertension, age, and diabetes mellitus are the main risk factors for small vessel disease (Yahnis, 2005).

Cerebral amyloid angiopathy Cerebral amyloid angiopathy affects capillaries, arterioles, and small-size and medium-size arteries of the cerebral and cerebellar cortex and leptomeninges (see Figures 2.8 and 2.21), with the subcortical regions and brain stem relatively spared (Mandybur, 1986; Vonsattel et al., 1991; Ellis et al., 1996; Vinters, 1998). The distribution is very patchy, and heavily involved vessel segments alternate with amyloid-free regions (Mandybur, 1986). The most common form of CAA is sporadic and associated with deposition of Aβ, the same protein implicated in AD (Vinters, 1998). Indeed, most AD cases have concomitant CAA (Ellis et al., 1996; Arvanitakis et al., 2011a), but CAA also increases in extent and severity with age and is common in older persons without a pathologic diagnosis of AD. When CAA appears to be “leaking” from the capillary wall into the adjacent brain, the latter is described as dysphoric angiopathy (Attems and Jellinger, 2004). The affected blood vessels in Aβ-CAA may show segmental dilations, micro-aneurysms, fibrinoid necrosis (Ellis et al., 1996), and inflammation (Vonsattel et al., 1991). In general, the extent of amyloid deposition within vessel walls correlates with the increasing risk of cerebral lobar hemorrhage (Ellis et al., 1996). CAA has also been associated with microbleeds and cognitive impairment (Arvanitakis et al., 2011a). Hereditary forms of CAA may be associated with Aβ or other amyloid-forming proteins (Yahnis, 2005).

Functional Changes Associated with the Aging Nervous System

(a)

(b)

(c)

(d)

55

Figure 2.21 Cerebral amyloid

angiopathy. (a) Cortex involves small-size and medium-size arteries, arterioles, and capillaries (arrows; small arrow also shows dysphoric change). (b) Leptomeninges vessels. (c) Amyloid alternating with amyloid-free regions. (d) “Double-barrel” appearance from separation of endothelium from the affected muscularis. (a–c, Aβ immunostain.) (For a color version, see the color plate section.)

Vasculitis Vasculitis refers to a heterogeneous group of disorders that are characterized by inflammatory destruction of blood vessels. Vasculitis is classified according to vessel size, systemic versus primary CNS localization, and the presence or absence of giant cells. Vasculitis may also be secondary to infections such as syphilis, tuberculosis, or fungal infections. Giant cell arteritis (GCA, temporal arteritis) is particularly important in the aging brain. Giant cell arteritis occurs in adults older than 50 years and has a peak incidence between 75 and 85 years of age. Women are affected twice as often as men. The classic symptoms are headache, scalp tenderness, jaw claudication, and blindness. The blindness occurs usually as a result of the extension of the disease into the ocular (most commonly, the ophthalmic) arteries and/or their branches (Weyand et al., 2004; Yahnis, 2005; Ferrer et al., 2008). Extracranial branches of the aorta are also typically involved, especially the external and internal carotid arteries and vertebral arteries, which may lead to brain infarct in a small percentage of cases (Yahnis, 2005). The affected vessel becomes tortuously thickened and tender, with diminished pulsations. Microscopically, there is intimal proliferation with a transmural infiltration by lymphocytes, including CD4+ T-lymphocytes, and lesser numbers of CD8+ T-lymphocytes, monocytes/macrophages, and giant cells. A definitive diagnosis can be made only by temporal artery biopsy. The changes are most often focal and patchy rather than generalized, thus a negative biopsy cannot completely rule out GCA (Yahnis, 2005). Multiple other pathologies can affect large and small cerebral vessels, including other types of emboli (septic,

fat, tumor), vasculitis (infectious, systemic), hereditary angiopathies (CADASIL), arterial dissection, and vascular malformations. Saccular aneurysms are discussed later in this section. In spite of a multitude of vessel pathologies, the final common pathway of most, if not all, of the vessel pathologies is cerebral ischemia, infarction, and/or hemorrhage.

Infarction Brain infarction accounts for the majority of strokes and has been related to both cognitive and motor changes in aging (Schneider et al., 2003; Buchman et al., 2011). However, it is very common to find brain infarcts in older persons without a history of clinical stroke (Schneider et al., 2003). Pathologically, gross (macroscopic) infarcts are the infarcts that can be visualized by the naked eye. Similar to neuroimaging studies, about one-third of the older persons have evidence of chronic gross infarcts at the time of autopsy (Schneider et al., 2003). Gross infarcts can be described as acute, subacute, or chronic. At around 8–12 hours, there is blurring of the cortical white matter junction and, microscopically, red or ischemic neurons appear. Cytotoxic edema reaches a maximum at 48–96 hours, during which time there is a higher risk of herniation. If reperfusion occurs, as is typical for most embolic infarcts, the area of ischemia may become hemorrhagic. At the same time, macrophages infiltrate, and by 10 days, there is a reactive gliosis. At 3 weeks, the infarct begins to cavitate (liquefaction necrosis) and there are abundant macrophages by microscopy. Eventually, the infarct is filled with fluid and traversed by a network of small vessels. The subpial cortex, which has a separate

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blood supply, is typically preserved in cortical infarcts. Lacunar infarcts refer to small (10 or 15  mm maximal dimension) regions of cystic cavitation most often seen within basal ganglia, thalamus, pons, internal capsule, and deep subcortical white matter. Microscopic infarcts are lesions that are not visible on macroscopic inspection but are observed during the examination of the histologic sections (Arvanitakis et al., 2011b).

Anoxic/hypoxic encephalopathy In older persons, this is most often the result of cardiac arrest with low blood flow and oxygenation and tissue anoxia. The brain shows selective regional and cell type vulnerability, with the neurons of the CA1 sector of the hippocampus, Purkinje cells of the cerebellum, and layers III and V of the cortex preferentially damaged. There is variable damage of the basal ganglia. If the person survives, these regions acutely show red neurons, followed by infiltration of macrophages and liquefaction necrosis, typically in a linear pattern called laminar necrosis. Carbon monoxide results in an acute pink discoloration of the brain, followed by bilateral necrosis of the globus pallidus. Intraparenchymal hemorrhages Intraparenchymal hemorrhage most often occurs from the rupture of small blood vessels, such as lenticulostriate or pial perforating artery, in association with hypertension, CAA, or other predisposing factors. Hypertensive hemorrhage typically occurs from rupture of the lenticulostriate branches of the middle cerebral artery or pontine perforators of the basilar artery, accounting for the common subcortical distribution of hypertensive hemorrhage in the deep cerebral nuclei (putamen, thalamus) and pons/

cerebellum (Ferrer et al., 2008). Massive hemorrhages are manifested as foci of acutely clotted blood that displace and disrupt, resulting in mass effect and possible herniation. Although Charcot–Bouchard microaneurysms (see Figure 2.22) formed by focal weakening and aneurysmal dilatation of small vessels are often reported as the classic underlying pathology of hypertensive hemorrhage, these are rarely found on pathologic examination and rupture of nonaneurysmal, but damaged vessel walls have been argued as the more common pathophysiology (Yahnis, 2005; Ferrer et al., 2008). Sporadic CAA accounts for about 10% of primary nontraumatic intraparenchymal hemorrhage and is the most common cause of lobar intracerebral hemorrhage in normotensive older persons (Vonsattel et al., 1991; Ferrer et al., 2008). CAA hemorrhages tend to superficial and may also cause subarachnoid hemorrhage (SAH). Microhemorrhages from arteriolosclerosis and CAA are probably even more frequent (see Figure 2.22) and can be detected using special neuroimaging techniques.

Subarachnoid hemorrhage By definition, a SAH is located between the meninges and the pial surface of the brain. SAH is most commonly caused by the rupture of a cerebral artery aneurysm or trauma. The annual incidence of aneurysmal SAH increases with age, with a median age of onset in the fifth or sixth decade (Fogelholm et al., 1993; Yahnis, 2005). Saccular aneurysms (berry aneurysms) typically arise at the points of bifurcation of intracranial arteries, within the Circle of Willis. Aneurysms increase in size with time, and size is closely associated with rupture (Yahnis, 2005). Pathologically, aneurysms have a narrow neck and thin walls and show attenuation and disruption of

Figure 2.22 Charcot–Bouchard aneurysm; note the markedly thinned region of the vessel wall. (For a color version, see the color plate section.)

Functional Changes Associated with the Aging Nervous System

the internal elastic lamina and fibrosis of the vessel wall. Although rupture typically causes SAH, blood may also penetrate into brain tissue (intracerebral hemorrhage). Rebleeding may rise during the first 24 hours and at 1–4 weeks after the initial hemorrhage (Inagawa et al., 1987). One of the complications of SAH is arterial vasospasm and associated delayed cerebral ischemia and infarction about 4–7 days post-hemorrhage. SAH is also a common consequence of trauma. Older persons at risk of falling are particularly prone to focal SAH, along with contusions of the frontal orbital and anterior temporal superficial cortex.

Movements disorders The most commonly diagnosed movement disorder associated with aging is PD. Parkinsonism also occurs with other neurodegenerative diseases, including CBD, PSP, and MSA. In addition, older persons often show mild motor problems, including problems with gait and slowing that does not easily fit into a specific disease category. Other subclinical degenerative and vascular diseases (Buchman et al., 2011) in the aging brain likely can disturb the nigrostriatal and frontostriatal pathways.

Parkinson’s disease Idiopathic PD describes the common idiopathic disorder that shows a slowly progressive course and is characterized by bradykinesia, rigidity, gait disorder, and tremor. Gross pathologic features include pallor of the SN and locus coeruleus, with severe loss of the melanin-containing dopaminergic neurons with melanin-containing macrophages and free melanin pigment in the SN pars compacta, most prominently in the ventrolateral portion of SN. It has been estimated that symptoms of PD occur when more than 50% of nigra neurons have been lost, but recent data challenge this notion (Ince et al., 2008). LBs, the pathologic hallmark of PD (see Figures 2.11 and 2.12), not only occur in the SN in PD but also are found in the dorsal motor nucleus of the vagus, substantia innominata, other brainstem nuclei, the intermedolateral cell columns of the spinal cord, and sympathetic ganglia (Braak et al., 2003). More caudal structures, including brainstem, olfactory bulbs, spinal cord, and peripheral nervous system, are believed to be involved prior to the SN (Braak et al., 2003; Beach et al., 2009), and the development of LB probably follows a caudal-to-rostral progression in most cases of PD. Extension into cortical regions is common and associated with DLB as well as PD dementia. PD dementia is clinically separated from DLB by the temporal sequence of motor signs being established before the onset of dementia (McKeith et al., 2005). LBs and LN are the central pathology of DLB and PD, and there is significant overlap between the pathologic features. Synuclein

57

has been reported in the olfactory bulbs of subjects with PD and DLB, suggesting that olfactory bulb involvement is common to all LB disorders and occurs at an early stage of the disease (Beach et al., 2009). Pathologic staging of PD has been suggested based on anatomic distribution and severity of LB and LN (Braak et al., 2003). In stages 1 and 2, the pathology is restricted to the brainstem and olfactory bulb. Involvement of the pars compacta of the substantia nigra (SNc) occurs in stage 3, without degeneration until stage 4. In stages 5 and 6, the α-synuclein pathology involves the neocortex (Braak et al., 2003; Ince et al., 2008; Beach et al., 2009; Jellinger, 2009). Motor and cognitive manifestations have been proposed to depend on the anatomic distribution and load of α-synuclein pathology (Braak et al., 2005; Beach et al., 2009). Dementia is seen in a large number of PD patients (Braak et al., 2005; Ince et al., 2008; Beach et al., 2009), and although the pathologic correlates of dementia have been debated, cortical LBs are believed to play a role (Braak et al., 2005; Beach et al., 2009). In PD dementia, the amount of concomitant AD pathology is typically less than that in classic DLB (Cummings, 2004), but cortical LBs are said to be present in small numbers in virtually all cases of idiopathic PD, with or without a history of dementia (Ince et al., 2008). Incidental LB disease is the term used when LBs are pathologically found in the nervous system in subjects without clinically documented parkinsonism or cognitive impairment. Epidemiologic studies indicate that autonomic symptoms, REM sleep behavioral disorder, and olfactory dysfunction may precede the presentation of parkinsonian motor signs and symptoms by years and may be related to LBs and LNs in these more caudal structures (Jellinger, 2009).

Multiple System atrophy MSA is a sporadic neurodegenerative disease that presents with the cardinal features of orthostatic hypotension, parkinsonism, and cerebellar signs and symptoms (Gilman et al., 1998; Gilman et al., 2008); it encompasses the previous nomenclature of olivopontocerebellar atrophy, Shy–Drager syndrome, and striatonigral degeneration. Diagnostic criteria for MSA proposed by a Consensus Conference in 1998 (Gilman et al., 1998) recommended MSA to encompass two groups, including MSA-P (parkinsonian-predominant) and MSA-C (cerebellar-predominant). α-synuclein immunoreactive glial cytoplasmic oligodendroglial inclusions in areas of degeneration are a required feature for a definite diagnosis of both MSA-P and MSA-C (Gilman et al., 1998; Gilman et al., 2008). MSA-P accounts for the majority of the cases of MSA. Pathologically, there is atrophy and grayish discoloration of the putamen, pallor of the SN, and slight cortical

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atrophy. Neuronal loss and gliosis are most severe in the dorsolateral zone of the caudal putamen and lateral portion of the SN. MSA-C shows grayish discoloration of the cerebellum, middle cerebellar peduncle, and the pons. There is Purkinje cell loss and proliferation of Bergmann glia, especially in the vermis. In addition, neuronal loss and gliosis are prominent in the basis pontis and accessory and inferior olivary nuclei, and the cerebellopontine fibers are degenerated. Both MSA-P and MSA-C may have degeneration of the SN, intermediolateral cell column, and locus coeruleus (Watanabe et al., 2002).

Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the degeneration of upper (UMN) and lower motor neurons (LMN). There is progressive and often asymmetric weakness and wasting, with involvement of the bulbar/respirator muscles, but sparing of ocular, urinary, and anal sphincter muscles. Fasiculations are a prominent feature, reflecting LMN involvement. Pseudo-bulbar palsy, progressive atrophy, and corticospinal signs may be present. Sensory nerves and the autonomic nervous system are generally unaffected but may be involved for some patients. Patients with familial ALS associated with an SOD1 mutation frequently have degeneration of the posterior columns, Clarke’s column, and spinocerebellar tracts (Ince et al., 2008). At autopsy the cervical and lumbosacral enlargements of the spinal cord may be atrophic, and anterior motor roots shrunken and gray. The brain may show frontal or temporal lobe when there is coexisting dementia. The key histology is loss of motor neurons, with associated astrocytosis, in anterior horns of the spinal cord. In the medulla, the hypoglossal nucleus is most obviously degenerated, and the nucleus ambiguous, motor nuclei of the trigeminal and facial nerves, and motor cortex may be affected. The nuclei of cranial nerves III, IV, and VI and Onufrowicz nuclei are preserved, consistent with the preservation of (a)

(b)

eye movements and sphincter control. Axonal spheroids are frequently seen in the anterior horns but are not specific for ALS. The spinal cord typically shows myelin pallor in the anterior and lateral corticospinal tracts, which can be demonstrated using immunohistochemistry for microglial markers (see Figure 2.23). Myelin loss is most evident in lower cord segments. Muscle morphology at biopsy or autopsy shows neurogenic atrophy, including grouped atrophy and fiber-type grouping affecting type 1 and type 2 fibers. A variety of inclusion bodies are seen in surviving motor neurons (Ince et al., 2008). Bunina bodies (see Figure 2.24) are thought to be a specific feature of ALS and are small intracellular eosinophilic inclusions, often arranged in small beaded chains. Ubiquitin-immunostained inclusions (see Figure 2.25) are typically seen in both UMN and LMN and include skein inclusions or threadlike structures, and hyaline-like or Lewy-like inclusions. It is now recognized that the underlying ubiquinated protein in these inclusions is TDP-43 (see Figure 2.24), the same protein of FTLD. Indeed, in some cases of ALS, TDP-43 positive inclusions are also seen in the neurons of dentate nucleus of hippocampus, basal ganglia, and cortex. Accordingly, ALS may affect cognition and is associated with FTLD. Patients with ALS may have subtle executive deficits, and a small number will have a clinical subtype of FTLD (Geser et al., 2008). Indeed, cognitive and behavioral symptoms in association with ALS and an association between ALS and FTD were considered in the earlier part of the twentieth century. Indeed, it now appears that ALS and FTLD may represent a multiple-system TDP-43 proteinopathy, with ALS and FTLD at two ends of the disease spectrum (Geser et al., 2008; Traub et al., 2011).

Huntington’s disease Huntington’s disease (HD) is an autosomal dominant disorder caused by a mutation in the HD gene on (c)

Figure 2.23 Amyotrophic

lateral sclerosis. (a) Pallor of the lateral corticospinal tracts of spinal cord on myelin stain. (b) Low and (c) high magnification show CD8 immunostained macrophages indicative of degeneration. (For a color version, see the color plate section.)

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Brain tumors The overall incidence of brain tumors appears to be increasing, with the highest increase noted in patients older than 60 years of age (Flowers, 2000). The average annual percentage increases in primary brain tumor incidence for ages 75–79, 80–84, and 85 and older are 7, 20.4, and 23.4%, respectively (Flowers, 2000). These tumors include astrocytoma, glioblastoma multiforme (GBM), meningioma, schwannomas, primary malignant lymphomas of the brain, and metastatic brain tumors. Figure 2.24 Amyotrophic lateral sclerosis anterior horn cell with a

Bunina body. (For a color version, see the color plate section.)

chromosome 4p16.3 that typically manifests as chorea and psychiatric symptoms and progresses to dementia (Yahnis,  2005; Ince et al., 2008). HD results from an expansion of the trinucleotide repeat CAG to over 36 repeats, compared to normal repeats of 26. Onset is usually in midlife, with a mean survival of 17 years. The first clinical manifestation of the hyperkinetic form is chorea, but neuropsychological problems such as personality change, depression, and psychosis can antedate the onset of the movement disorder (Yahnis, 2005). Neuropathologically, the brain is atrophic, with specific atrophy of the caudate and putamen and compensatory enlargement of the lateral ventricles. Histologically, there is neuronal loss, especially of the GABAergic medium spiny neurons (Joel, 2001) of the striatum. Ubiquitin-positive intranuclear inclusions and abnormal neurites are present in degenerated regions (Yahnis, 2005; Ince et al., 2008; Cochran, 2005).

(a)

(c)

Figure 2.25 Amyotrophic lateral sclerosis.

Hyaline inclusions in an anterior horn motor neuron on H&E (a) and ubiquitin (b). (c) Skein-like inclusions in the anterior horn cells in ALS also stain with antibodies to ubiquitin. (For a color version, see the color plate section.)

Glial neoplasms Glial neoplasms include astrocytomas, GBMs, oligodendrogliomas, and other glial neoplasms. These tumors develop in all ages but are particularly challenging in geriatric patients.

Astrocytomas Diffuse astrocytomas (WHO grade II) including fibroblastic, protoplasmic, and gemistocytic variants, occur at any age but most frequently in the sixth decade of life (Perry, 2005). Like most tumors, they may present with headache, seizures, or focal signs, depending on the location. Astrocytomas are most frequent in the cerebral white matter, where they appear as ill-defined, slightly firm, yellow-white, homogeneous tumors that enlarge and distort the hemisphere. Tumor cells individually and diffusely infiltrate surrounding normal tissue without obvious borders between normal and diseased tissue (Louis et al., 2008). There is increased cellularity with mild pleomorphism; mitoses, vascular proliferation, and necrosis are absent, and the proliferative index (MIB1/Ki67) tends

(b)

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to be low (less than 5%). Tumor cells are confirmed as astrocytes using antibodies against glial fibrillary acidic protein (GFAP). Diffuse astrocytomas frequently undergo malignant transition to anaplastic astrocytoma and GBM multiforme.

Anaplastic astrocytoma Anaplastic astrocytomas (WHO grade III) may arise from diffuse astrocytoma, WHO grade II or de novo, without the evidence of a less malignant precursor. They tend to occur in slightly older individuals, compared to diffuse astrocytomas, and are located in the hemispheres, leading to enlargement of invaded structures and a more discernible mass, compared to diffuse astrocytomas (Louis et al., 2008). There may be edema, mass effect, and increased intracranial pressure. Anaplastic astrocytomas show histologic features of malignancy, including cellular and nuclear pleomorphism, increased cellularity and mitotic activity, and Ki-67/MIB-1, usually in the range of 5–10%.

Glioblastoma Glioblastomas are malignant (WHO grade IV) glial neoplasms that manifest at any age but preferentially affect older adults (Ohgaki et al., 2004; Louis et al., 2007). Primary GBMs develop in older patients (mean age about 62 years), whereas secondary GBMs derived from lowergrade astrocytomas usually occur in younger patients (mean age about 45 years). Clinical presentations depend on the region involved; with frontal lobe tumors, extensive growth may already be evident at the time of presentation. GBMs occur most often in the subcortical white matter and may spread along myelinated tracks across corpus callosum, giving rise to a characteristic butterfly pattern. Although they may appear discrete, distant cellular spread is extensive, making complete surgical resection impossible in most cases (Louis et al., 2008). Pathologically, GBM shows variable colors with grayish tumor masses and central areas of yellowish necrosis and hemorrhages (see Figure 2.26). Histologically, there is high cellularity, pleomorphism, mitoses, and microvascular proliferation and/or necrosis. Necrosis characteristically has a pseudopalisading pattern (see Figure 2.27) of large necrotic areas surrounded by viable tumor cells at the periphery. Recent data show that the cellular pseudopalisades are hypoxic, thereby overexpressing hypoxiainducible factor (HIF-1), and secrete proangiogenic factors such as VEGF and IL-8 (Rong et al., 2006). Proliferative activity is usually prominent, and the proliferative index determined using Ki-67/MIB-1 may reach very high percentages. GFAP immunopositivity is variable but, if positive, may be helpful in the diagnosis.

Other glial neoplasms Oligodendrogliomas can develop at any age, but the majority of tumors arise in adults with an incidence peak

Figure 2.26 Glioblastoma multiforme: gross appearance with

variegated necrotic-appearing mass without definite borders. (For a color version, see the color plate section.)

between 40 and 45 years of age (Ohgaki and Kleihues, 2005). Oligodendrogliomas are diffusely infiltrating lowgrade (WHO grade II) gliomas and often harbor deletions of chromosomal arms 1p and 19q (Louis et al., 2007; Louis et al., 2008). These tumors account for approximately 2.5% of all primary brain tumor and 5–6% of all gliomas (Louis et al., 2007; Louis et al., 2008). They develop in the cortex and white matter of the cerebral hemispheres, and calcifications are frequent. Histologically, they are diffusely infiltrating gliomas composed of uniform round nuclei with perinuclear halos, resulting in the characteristic

Figure 2.27 Glioblastoma: histologic appearance of pseudopalisading necrosis. (For a color version, see the color plate section.)

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“fried-egg” appearance on paraffin sections. Extracellular mucin and microcysts are frequent, and a dense network of branching capillaries resembles the pattern of chicken wire (Herpers and Budka, 1984; Louis et al., 2007; Louis et al., 2008). Ependymomas are slowly growing gliomas, originating from the cells of the ventricular walls or spinal canal, and are composed of neoplastic ependymal cells. Ependymomas correspond histologically to WHO grade II. These tumors develop in all age groups ranging from 1 month to 81 years (Louis et al., 2007), but most commonly in the fourth ventricle in children and in the spinal cord in adults. A specific variant, called myxopapillary ependymoma, is found at the filum terminale in adults. The key histologic features are perivascular pseudorosettes and ependymal rosettes. Subependymomas of the fourth ventricle are typically an incidental finding in older adults and uncommonly are symptomatic.

Metastatic lesions Metastatic tumors originate outside the CNS and spread secondarily to the CNS via blood or by direct invasion. Metastatic tumors to the brain are approximately 10 times more common than primary intracranial neoplasms (Ellison et al., 2008) and are arguably the most common CNS neoplasm in older persons. About 25% of patients who die from cancer have CNS metastases detected at autopsy (Gavrilovic and Posner, 2005). Lung (especially small cell and adenocarcinoma), breast, and skin (melanoma) are the most common sources (Soffietti et al., 2002). More than 80% of brain metastases are located in the cerebral hemispheres, 10–15% in the cerebellum, and 2–3% in the brain stem. Because they are typically of hematogenous origin, their distribution is generally in arterial border zones and at the junction of cerebral cortex and white matter (Louis et al., 2007; Ellison et al., 2008). Melanoma and lung carcinoma more often cause multiple lesions, whereas breast carcinoma frequently is single (Delattre et al., 1988; Ellison et al., 2008). Pathologically, they are usually well-demarcated, rounded masses that displace the surrounding brain parenchyma (see Figure 2.28). Malignant melanoma, lung carcinoma, renal cell carcinoma, and choriocarcinoma tend to be hemorrhagic and may present as intracranial hemorrhages (Nutt and Patchell, 1992; Louis et al., 2007). Histopathologic features of metastatic tumors are usually similar to those of their primary lesions, but there may be less differentiation. For example, metastatic melanomas may be amelanotic. Primary CNS lymphoma Primary CNS lymphomas (PCNSL) are malignant lymphomas that occur in the CNS without evidence of a coexisting systemic lymphoma. The incidence of PCNSL has markedly increased, at least partly because HIV-positive patients develop CNS lymphomas. PCNSL affect all ages,

Figure 2.28 Metastatic adenocarcinoma: cortical lesion appears well demarcated and necrotic. (For a color version, see the color plate section.)

with a peak incidence in immunocompetent subjects during the sixth and seventh decades of life (Koeller et al., 1997; Louis et al., 2007). More than half of PCNSLs involve the supratentorial space, most commonly frontal, temporal, or parietal cortex, and they are occasionally multiple (Louis et al., 2007). PCNSLs also have a propensity to involve periventricular regions. The tumors are often centrally necrotic or focally hemorrhagic, and visible demarcation from surrounding parenchyma is variable (Koeller et al., 1997). Tumor cells typically form concentric collars of perivascular cuffs, packing the perivascular spaces and creating a concentric pattern of reticulin-positive material around vessels. Tumor cells also invade the surrounding parenchyma and may form tumor masses. The vast majority of CNS lymphomas are classified as diffuse large B-cell lymphoma (Koeller et al., 1997; Louis et al., 2007; Ellison et al., 2008). Reactive small T-lymphocytes are identified among the tumor cells, usually in moderate numbers. Most B-cell PCNSLs have a very high Ki-67 labeling index (Koeller et al., 1997; Louis et al., 2007; Ellison et al., 2008). Because individual tumor cells extensively invade the surrounding parenchyma, similar to most glial tumors and unlike metastases, complete resections are typically not feasible. PCNL are, at least initially, steroid responsive and also responsive to radiation and chemotherapy; however, long-term prognosis remains poor.

Meningiomas Meningiomas are derived from meningothelial (arachnoid) cells and are typically attached to the dural inner

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surface. Most meningiomas are benign and correspond to WHO grade I. Meningiomas account for about 24–30% of primary intracranial tumors occurring in the United States (Louis et al., 2007) and can occur at any age but most commonly are seen in middle-aged and elderly patients, with a peak during the sixth and seventh decades (Louis et al., 2007; Ellison et al., 2008). They are significantly more common in women than in men, with a female:male ratio of nearly 2:1 (Louis et al., 2007). Meningiomas are wellcircumscribed spherical growths that are firmly attached to the dura. Dural and bone invasion are common and do not indicate malignancy; brain invasion is relatively rare. Meningiomas present a wide range of histologic patterns, and mixed patterns are frequent. Characteristic histologic features include whorls and psammoma bodies. The atypical designation is largely based on histologic features, especially mitoses, and specific morphologic patterns rather than brain invasion, although the latter is also associated with higher recurrence (Louis et al., 2007). Anaplasia (malignancy) is also based on histology/morphology and is associated with aggressive behavior, but metastases are rare.

Schwannomas Schwannomas are benign nerve sheath tumors (WHO grade I) and represent about 8% of intracranial tumors, 85% of cerebellopontine angle tumors (acoustic neuromas), and 29% of spinal nerve root tumors (Louis et al., 2007). Approximately 90% of the cases are solitary and sporadic. All ages are affected, with the peak incidence from the fourth to sixth decade. Schwannomas are generally well-encapsulated globoid tumors and may have cysts, lipid accumulation, and hemorrhage. The histology shows a spindle cell neoplasm with dense (Antoni A) and loose (Antoni B) areas and characteristic nuclear palisades (Verocay bodies). Schwannomas are adjacent to the involved nerve and, therefore, can be surgically removed with preservation of some, if not all, nerve function in many cases (Ellison et al., 2008). Neurofibromas Neurofibromas consist of a mixture of cell types, including Schwann cells, perineurial-like cells, and fibroblasts. Solitary neurofibromas are the most common tumor of peripheral nerves. They may be well-demarcated intraneural lesions or diffusely infiltrative extraneural tumors. Multiple and particularly plexiform neurofibromas are associated with neurofibromatosis type I (Louis et al., 2007; Ellison et al., 2008). Unlike schwannomas, neurofibromas are extremely rare within the cranium; in addition, they show a tendency to undergo malignant transformation, which occurs in about 5–10% of plexiform neurofibromas (Ellison et al., 2008). Complete resection of neurofibromas is difficult, because tumor cells are intermixed within the nerve.

Toxic metabolic encephalopathy Primary metabolic encephalopathies are those resulting from inherited metabolic abnormalities. Secondary or acquired metabolic encephalopathies describe the abnormalities of the water, electrolytes, malnutrition, alcohol, blood sugar, and other chemicals that adversely affect brain function.

Hepatic encephalopathy Hepatic encephalopathy occurs in patients with significant liver disease and conditions in which blood circulation bypasses the liver. Neuropathologically, astrocytes, particularly in the basal ganglia, undergo Alzheimer type II change, which includes enlarged, pale nuclei, with a rim of chromatin and prominent nucleoli. These astrocytes lose GFAP immunoreactivity and contain increased numbers of mitochondria; in severe cases, the nuclei may be lobulated and contain glycogen granules (Norenberg, 1994). It is hypothesized that elevated ammonia levels impair postsynaptic inhibitory neurotransmission, eventually resulting in impaired uptake of synaptic glutamate, increased extracellular glutamate, and the downregulation of glutamate receptors (Norenberg, 1994; Harris et al., 2008). Alcohol Alcohol may be related to a host of acute and chronic brain impairments. WKS, related to thiamine deficiency, was described with pathologies of cognitive impairment (Section “Wernicke-Korsakoff syndrome”). Atrophy of the cerebellum may occur separate from WKS and is less clearly linked to thiamine deficiency. In addition, long-term alcohol use has been related to atrophy involving both gray and white matter, which may be reversible with cessation of drinking. Neuronal loss appears to be specific to the superior frontal cortex (Smith et al., 1992). Central pontine myelinolysis Central pontine myelinolysis (CPM) is a relatively uncommon disorder with a very high mortality, usually occurring in alcoholics with WKS, severe liver disease, severe burns, malnutrition, anorexia, and severe electrolyte disorders (Harris et al., 2008). Too-rapid correction of a profound hyponatremia gives rise to the absolute change in serum sodium and appears to be an important contributing factor. Macroscopically, the area of demyelination is often triangular- or butterfly-shaped and symmetrical in transverse sections. Histopathologically, myelin-stained sections show a relatively sharply demarcated area of pallor within the basis pontis, with a relative preservation of axons. Extrapontine regions of demyelination have been reported to occur in over half the cases (Harris et al., 2008).

Functional Changes Associated with the Aging Nervous System

Infections and inflammation of the CNS Older persons are more susceptible to specific infections, probably reflecting an age-associated decline in cell-mediated immunity and antibody responses (Smith et al., 1992; Kipnis et al., 2008). In aging, immune competence declines with an alteration of T-cell populations and monocytes/macrophage cell efficiency. This may also make older persons more susceptible to certain inflammatory conditions.

Bacterial meningitis More than half of deaths from meningitis occur in persons over the age of 60 and are most commonly the result of Streptococcus pneumoniae, Neisseria meningitidis, Listeria monocytogenes, Haemophilus influenzae, and Staphylococcus aureus (Chimella, 2001). Bacterial meningitis may result from hematogenous spread or from local extension. Signs and symptoms may progress rapidly and include headache, fever, lethargy, and confusion. The brain is swollen and congested and is surrounded by creamy yellow or green pus. On microscopic exam, neutrophils fill the subarachnoid space and the perivascular spaces within the brain parenchyma. Unless there was treatment prior to death, Gram stain often demonstrates bacteria. Complications include cerebral ischemia, infarction, hydrocephalus, subdural effusion, sagittal sinus, or cortical vein thrombosis (Chimella, 2001; Gyure, 2005). Viral infections Viral infections of the CNS may result in aseptic meningitis or meningoencephalitis. Viral meningitis is typically less severe than bacterial, and most patients recover without complications. This disorder is usually caused by enterovirus and is uncommon in older adults (Chimella, 2001). The meninges may be slightly opaque, and inflammatory infiltrate is composed almost exclusively of lymphocytes.

Herpes simplex encephalitis Herpes simplex virus (HSV) encephalitis, the most common sporadic, nonseasonal encephalitis, occurs at all ages, and about half are in patients older than 50. Indeed, in older age groups, HSV (typically, HSV-1) is the most prevalent cause of encephalitis (Chimella, 2001). Clinically, patients present with a subacute onset of fever, headache, and confusion. Grossly, HSV encephalitis typically shows bilateral, asymmetric, hemorrhagic necrosis affecting the temporal lobes, the insula, the cingulate gyri, and the posterior orbitofrontal cortices (Chimella, 2001; Gyure, 2005). Histology shows hemorrhagic necrosis with perivascular and parenchymal chronic inflammation, macrophages, and microglial nodules. Cowdry A intranuclear inclusions are a characteristic feature of HSV encephalitis. Immunohistochemistry and electron microscopy may be helpful in identifying the organisms.

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Progressive multifocal leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is an infectious demyelinating disease of the CNS that results from the infection of oligodendroglial cells by JC virus, a papovavirus. It occurs most commonly in immunocompromised patients and has been described as a complication of specific drugs, cancers, and aging; it is commonly associated with HIV infection (Gyure, 2005). Clinical presentations include focal signs/symptoms and cognitive impairment. Grossly, the white matter shows small foci of gray discoloration, often forming large confluent areas of abnormal parenchyma. Lesions are typically subcortical in the cerebral hemispheres and have a predilection for the parieto-occipital regions (Chimella, 2001; Gyure, 2005). Microscopic examination shows foci of demyelination with surrounding infected enlarged and hyperchromatic oligodendroglial nuclei. Astrocytes in PML often appear “neoplastic” and show lobulated, hyperchromatic nuclei (Gyure, 2005).

Cryptococcosis Cryptococcosis infections are caused by the fungus Cryptococcus neoformans, a common environmental fungus that infects mostly immunocompromised humans via the lungs. It is associated with lymphoproliferative disorders, alcoholism, advanced age, generalized malnutrition, corticosteroid therapy, organ transplantation, and HIV (Chimella, 2001). It signifies transition into AIDS in patients with HIV who present as subacute meningitis. In patients without HIV, it is usually diagnosed postmortem, as these patients rarely present with the clinical signs and symptoms of subacute or chronic meningitis. Grossly, the leptomeninges are thickened and opaque, and there might be associated hydrocephalus. There might be a Swiss cheese-like appearance, especially in the basal ganglia. The fungi are budding oval yeasts and typically have an empty-looking appearance. They can be highlighted with PAS stain and may be found around blood vessels. Toxoplasmosis Toxoplasmosis is caused by the intracellular protozoan toxoplasma gondii. The definitive hosts for this parasite are domestic cats and other feline species. It is most commonly associated with HIV, but other causes of immunosuppression can also underlie reactivation (Chimelli et al., 1992; Chimella, 2001). Brain lesions may produce focal signs and symptoms. The brain lesions are typically necrotic, with focal hemorrhage, acute and chronic inflammation with neutrophils, mononuclear cells, newly formed capillaries, astrocytes, and microglial cells. The organisms are characteristically located at the periphery of the necrotic areas, either free in the parenchyma or within cysts.

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Other infectious and inflammatory diseases of the brain Over the past decades, there has been a growing list of inflammatory conditions of the nervous system (Rosenbloom and Smith, 2009). These diseases typically have a subacute presentation with the evidence of pathologic antibodies and/or extensive inflammation. Signs and symptoms vary but, in older age groups, commonly include a subacute onset of cognitive and behavioral changes, as seen in limbic encephalitis. These conditions may or may not be associated with specific antibodies, and those associated with antibodies may or may not be paraneoplastic. Small-cell lung carcinomas are one of the more common underlying tumors of the paraneoplastic syndromes, so determining whether there is a history of smoking is important. Some diseases have been associated with specific pathologies, such as limbic encephalitis and systemic lupus erythematosus, whereas the underlying pathology of some of the other conditions (such as Hashimoto’s encephalitis) is less clear. There is also a group of inflammatory diseases without specific antigen or antibodies, such as sarcoidosis and primary CNS vasculitis. Overall, these diseases are uncommon, and late presentations in the geriatric population are relatively rare. Pathology may show a fulminant encephalitis, with inflammation, neuronophagia, and microglial nodules (as seen in limbic encephalitis), or inflammation and necrosis focused primarily at the blood vessels (vasculitis). Some of these pathologies have been described in the previous sections, and a complete review of these neuropathologies is out of the scope of this chapter. Finally, markedly improved treatments have significantly increased longevity in persons with HIV, and some studies suggest that aging HIV patients may be at higher risk for specific age-related conditions, such as AD; interestingly, IV drug abusers without HIV may also be at higher risk (Anthony et al., 2010).

Trauma Acute hemorrhages and chronic traumatic encephalopathy are significant in the geriatric population. Both conditions can significantly increase the morbidity and decrease the functional ability.

Subdural hematomas Subdural hematomas (SDHs) may be acute or chronic. Acute traumatic SDHs may be associated with diffuse cerebral contusions and lacerations and adjacent intracerebral hematoma. These patients are typically unconscious from the time of injury (Blumbergs et al., 2008). More commonly, there is a less severe type of acute SDHs that may not be associated with obvious trauma and that is the result of rupture of bridging veins, with little or no associated brain damage (Blumbergs et al., 2008).

Pathologically, SDHs are considered chronic when at approximately 3 weeks of age or status post injury. Chronic SDHs may or may not be associated with recognized trauma and are usually the result of rupture of bridging dural arachnoid veins. Chronic SDHs occur most commonly in patients over the age of 50 years and are most common in those from 70 to 80 years old (Blumbergs et al., 2008). Cerebral atrophy seems to be an important predisposing factor, supposedly secondary to tension on bridging veins. This atrophy may allow hemorrhage without a significant mass effect. The age of the SDH may be approximated by the microscopic examination of the clot and subdural membranes. In the first few days, the outer dural membrane shows a few layers of fibroblastic membrane; this progresses to equal the dura thickness after 4–6 weeks (Blumbergs et al., 2008). The membrane is highly vascular, which predisposes to rebleeding; thus, an SDH may show hemorrhage and membranes of varying age.

Chronic traumatic encephalopathy It has long been recognized that boxers with repeated head injury and concussions are predisposed to an earlyonset dementia syndrome often referred to as dementia pugilistica. The pathology underlying this syndrome has been shown to have similarities but also distinctions compared to AD. This relationship is intriguing, given that repeated head trauma has been shown to be a risk factor for sporadic late-onset clinical AD. More recent studies have provided a more in-depth description of this disorder. Clinical symptoms include changes in memory, personality, and behavior with parkinsonism. The syndrome is not only in boxers, but also in those involved in other competitive sports, such as football (McKee et al., 2009). The pathology shows what appears to be a separate degenerative tauopathy with tangles and threads in a patchy but unique distribution, with a predilection for superficial cortex, sulcal depths, and perivascular regions in the frontal and temporal cortices. Diffuse amyloid is a common but variable feature (McKee et al., 2009). Further work is needed to determine the relationship between chronic traumatic encephalopathy and AD.

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Functional Changes Associated with the Aging Nervous System

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Part 2 Assessment of the Geriatric Neurology Patient

Chapter 3 Approach to the Geriatric Neurology Patient: The Neurologic Examination Marwan N. Sabbagh1 and Anil K. Nair2 1 2

Banner Sun Health Research Institute, Sun City, AZ, USA Clinic for Cognitive Alzheimer’s Disease Center, Quincy Medical Center, Quincy, MA, USA

Summary • Neurologic examinations of geriatric patients must focus on the patient’s overall functional ability according to his or her physical, neurologic, behavioral, and cognitive changes that occur with aging. • A review of medications and physical, head and neck, and cardiovascular examinations are essential. • Neurologic examinations include/assess: • Mental status testing using a cognitive screen such as the MOCA. • Speech articulation, loudness, and phonation. • Language comprehension, repetition, naming, ability to follow commands, fluency, and prosody. • Cranial nerves. • Muscle bulk, tone, and strength as well as pronator drift and other abnormal movements. • Sensory perception, loss, neglect, pain, and proprioception. • Deep tendon and primitive reflexes, as well as clonus. • Coordination/Cerebellar function. • Gait and posture. • Careful investigation of the nervous system can reveal underlying causes of various symptoms and prompt further investigation and treatment. Examinations can also provide information that helps to improve care.

Introduction As the population ages, the number of patients over age 65 is expected to grow almost exponentially. In fact, the geriatric population is the fastest-growing segment of the population. The geriatric population has unique medical challenges. Their physical and neurologic findings have different root etiologies from their younger counterparts. Thus, there is a consideration for reviewing the neurologic examination for the geriatric patient. Like geriatrics and geriatric psychiatry, which are wellestablished subspecialties of primary care and psychiatry, respectively, geriatric neurology is emerging as a subspecialty of neurology. This emergence reflects the growing understanding that geriatric patients have different neurologic conditions that require different diagnostic evaluations and, ultimately, different features. As such, clinical syndromes can have features common to younger patients, but the etiologies are frequently different. Careful attention to features of the physical and neurologic examination as findings, as with the younger patient, frequently points to root causes, prompting

further investigation. In this chapter, we review the neurologic examination of the geriatric patient and briefly review key elements of the physical examination. Physical and neurologic findings are also detailed throughout the textbook and are cross-referenced accordingly.

The geriatric neurologic examination with a focus on function The focus of the geriatric neurologic examination is different from an examination for a typical patient seen at a neurology service or in an office setting. For the latter, the primary purpose of the examination is to localize the site of the lesion and guide the appropriate workup to determine the diagnosis and most appropriate treatment for the condition (Bickley, Szilagyi, and Bates, 2007). In contrast, the focus of the geriatric neurology examination is determining the physical, neurologic, cognitive, and behavioral deficits that will impair a patient’s functional ability, as well as identifying his or her ability to carry out specific tasks. The geriatric neurologist must go beyond

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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neurologic impairment and assess the impact that other diseases, such as arthritis, chronic obstructive pulmonary disease, and cardiovascular disease, may have on the patient’s function, in a way a primary care physician would not be able to do. For example, muscle rigidity may affect a person’s ability to transfer, dress, or walk independently. Spasticity might impede nursing care by causing difficulty in catheterization or by causing problems with positioning in a wheelchair or bed. Identifying these deficits and determining their effect on function allows the care team to set appropriate goals and develop specific treatment strategies to address a patient’s needs. This also allows the team to plan for a patient’s continued functioning at home and within the community. Serial examinations in a patient may also provide useful information regarding prognosis for functional recovery. The initial evaluation of a patient in the geriatric setting should include a detailed history, including the history of psychiatric disorders. Because many patients with cognitive and language impairments have difficulty communicating, obtaining the history from family and medical records may be necessary. Additional information about the inciting event should be sought. In patients with mild cognitive impairment (MCI), the presence and duration of amnesia is important. Concurrent medical problems, such as strokes, brain hemorrhage, hypoxia, hypotension, and seizures; systemic injuries, including skeletal fractures and peripheral nerve injuries; and the presence of intoxicant drugs and alcohol may help in establishing a cognitive prognosis. Knowledge of premorbid cognitive and functional status is important. An education and employment history is essential. A general physical examination is to be performed on all patients. This examination should include the assessment of the level of consciousness, as detailed in Chapter 4.1, “Mental Status Examination in the Geriatric Neurology Patient.” The skin should be examined for evidence of skin breakdown (decubitus ulcers). A thorough musculoskeletal examination should be performed, focusing on joint range of motion, skeletal deformities, and abnormal postures of limbs. Finally, a detailed neurologic examination should be performed, including an assessment of mental status, cranial nerves, motor and sensory systems, reflexes, coordination, and gait.

Physical examination The physical examination of the geriatric patient is quite important and might be considered part of the neurologic examination.

Biometrics Gathering vital signs and body weight is seemingly obvious and is routine. Nevertheless, complaints of

syncope and dizziness might prompt checking orthostatic blood pressures, as orthostatic hypotension is common in the elderly (see Chapter 14, “Autonomic Dysfunction and Syncope,” and Chapter 16, “Vertigo and Dizziness in the Elderly”). Additionally, hypotension can be caused by neurologic conditions (see Chapter 12.1, “Parkinson’s Disease”). Similarly, checking pulse is important, as bradycardia can be symptomatic as syncope and dizziness. Tachyarrhythmias can also present as dizziness and syncope. Serial weight measurements over time might be important. For example, weight loss is common in the elderly. It is particularly common in degenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) and can portend a negative prognosis. Alternately, weight loss might be related to medication consumption, as many medications can cause anorexia. Taking the temperature of the geriatric patient is also important. Geriatric patients do mount fever, but in many cases, the hyperthermia can be mild, even in the setting of significant infections. Conversely, hypothermia could indicate sepsis.

Medications The assessment of the geriatric patient, including the neurologic patient, should start with a review of the medications. Patients are unaware of their medications, in many cases. Redundancy is common, and medication errors are frequent. Another confounding feature in the elderly is polypharmacy. The elderly tend to consume more medications and more classes of medications than other groups of patients. Thus, drug–drug interactions emerge, which can contribute to symptoms. Medications frequently have neurologic side effects (dizziness, lightheadedness, confusion, tremor, somnolence). Thus, a common therapeutic approach might be to reduce medication or reduce the doses of medication rather than add medication to treat specific symptoms. Head and neck examination The assessment of the head and neck is important as well, primarily with vision and hearing. Vision and hearing loss are ubiquitous among the elderly and can cause significant challenges in assessing the patient in other areas, such as mentation, and so should be accounted for. Patients with severe hearing loss can present as cognitively impaired. Examination of the neck for bruit, carotid hypersensitivity, and thyromegaly should be routine. The presence of a unilateral bruit can be an indication of vascular stenosis in the carotids but is unreliable as a marker of vascular disease (see Chapter 11, “Cerebrovascular Diseases in Geriatrics”), whereas bilateral bruit can be referred from the chest from aortic stenosis.

Approach to the Geriatric Neurology Patient: The Neurologic Examination

Cardiovascular Though neurologists are unlikely to suddenly become cardiologists, they should have a solid grasp of common cardiac findings, as these findings can manifest as neurologic conditions. For example, bradycardia can be symptomatic as syncope and dizziness. Tachyarrhythmias can also present as dizziness and syncope. Atrial fibrillation is very common in the elderly and can manifest as tachy- or bradyarrhythmias. A right apical crescendo decrescendo murmur might indicate aortic stenosis, which is often referred to the neck as bilateral bruit.

Neurologic examination Changes in the nervous system that occur with aging (see Table 3.1) are to be considered when a geriatric patient is examined (Rathe, 1996).

Mental status testing Mental status testing, including the assessment of cognition, alertness, concentration, praxis, speech, and language, is covered in detail in Chapter 4.1, “Mental Status Examination in the Geriatric Neurology Patient.” A cognitive screen such as www.mocatest.org is typically used (Figure 3.1). As mentioned earlier, this can be confounded by hearing and vision loss, so patients should be screened for impairments of vision and acusis in the context of the mental status examination. In many cases, their cognitive assessment might appear artificially worse because of visual or auditory impairment. Speech Several elements of speech need to be evaluated, including articulation, loudness, and phonation. When listening to your patient, pay attention to the articulation. Are the words spoken clearly? Disturbances in articulation of speech are called dysarthria. Dysarthria refers to defective Table 3.1 Changes in the neurologic examination with age Localization

Diminished modality

CN I

Diminished smell

CN 2

Diminished pupil size Abnormal pupillary reaction time Diminished accommodation Abnormal upward gaze

CN 8

High-tone hearing loss

Motor system

Diminished bulk and power Prolonged reaction time Diminished coordination

Sensory

Diminished vibration

Reflexes

Diminished ankle jerk

Gait

Diminished fluidity of movement Diminished coordination

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articulation without ascribing etiology. It could be from mechanical issues (such as dentures) but also can reflect neurologic conditions, such as cerebrovascular accidents (CVAs), amyotrophic lateral sclerosis (ALS), Parkinson’s disease, and progressive supranuclear palsy. Loudness also needs to be assessed. Loudness is compromised in PD and progressive supranuclear palsy (PSP) but can be seen in depression. Phonation refers to the utterance of vocal sounds. It also refers to the production of voiced sound by means of vocal cord vibrations. Phonation can be impaired in cranial neuropathies and in bulbar conditions such as ALS.

Language Language evaluation includes the assessment of comprehension, repetition, naming, ability to follow commands, fluency, and prosody. Prosody is the rhythm, stress, and intonation of speech. Aprosodia is the impairment in comprehending or generating the emotion conveyed in spoken language. Producing these nonverbal elements requires intact motor areas of the face, mouth, tongue, and throat. Damage to areas 44/45 produces motor aprosodia, with the nonverbal elements of speech being disturbed (facial expression, tone, rhythm of voice). Right-hemispheric area 22 aids in the interpretation of prosody, and damage causes sensory aprosodia, with the patient unable to comprehend changes in voice and body language. Prosody is dealt with by a right-hemisphere network that is largely a mirror image of the left perisylvian zone. Damage to the right inferior frontal gyrus causes a diminished ability to convey emotion or emphasis by voice or gesture, and damage to right superior temporal gyrus causes problems comprehending emotion or emphasis in the voice or gestures of others. Disorders of comprehension, repetition, naming, and fluency are broadly subsumed under the category of the aphasias. Aphasia refers to impairment of language ability (Aphasia Symptoms, Causes, Treatment–-How Is Aphasia Diagnosed? 2011). Aphasia disorders have multiple etiologies in the elderly. Among the more common considerations in the geriatric population are head injury, stroke, brain tumor, infection, and dementia. Degenerative forms of aphasias are referred to as the progressive aphasias. (See Chapter 9.6, “Primary Progressive Aphasias,” for more details.) The area and extent of brain damage determine the type of aphasia and its symptoms. Aphasia types include Broca’s aphasia, nonfluent aphasia, motor aphasia, receptive aphasia, global aphasia, and many others. Broca’s aphasia (also termed expressive aphasia) is caused by lesions to the medial insular cortex. In contrast to Broca’s aphasia, damage to the temporal lobe may result in a fluent aphasia that is called Wernicke’s aphasia (also termed sensory aphasia). The other types of aphasia in the localizationist model include pure word deafness, conduction aphasia,

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Assessment of the Geriatric Neurology Patient

Image not available in this digital edition.

Figure 3.1 Montreal cognitive assessment (MOCA)—http://www.mocatest.org (accessed on April 8, 2013).

global aphasia, transcortical motor aphasia, transcortical sensory aphasia, and anomic aphasia. In most cases in the geriatric population, cerebrovascular disease is the leading cause, followed by progressive aphasias. However, anomic aphasia is commonly seen in AD.

Cranial nerves The cranial nerve examination is routinely performed, but findings from the examination may have different etiologies than similar findings from younger individuals. Start with observation of the individual. Consider these

Approach to the Geriatric Neurology Patient: The Neurologic Examination

possibilities when examining a patient for ptosis (III), facial droop or asymmetry (VII), hoarse voice (X), articulation of words (V, VII, X, XII), abnormal eye position (III, IV, VI), and abnormal or asymmetrical pupils (II, III).

Cranial nerve I Olfaction is frequently impaired in the elderly. It is not routinely assessed. This is manifested as anosmia, ageusia, or dysgeusia. Etiologies of olfactory dysfunction include sinus disease, medication, and degenerative neurologic disorders such as AD and PD. Though olfaction is not routinely assessed in neurologic practice, smell testing is available and can be a sensitive detection method for neurodegenerative disease; however, the specificity is somewhat lacking. Although uncommon except following stroke, anosmia (olfactory dysfunction) occurs in 13–50% of patients with AD, most commonly because of malfunction to olfactory pathways. Anosmia also develops in 18% of patients following ruptured cerebral aneurysms, correlating to the presence of intraventricular hemorrhage. Anosmia can cause decreased life satisfaction and lead to safety concerns, as with, for example, the inability to smell smoke, gas, or spoiled food. Standardized, commercially available “scratch-and-sniff” tests may be used for formal testing.

Cranial nerve II The optic nerve and anterior visual pathways are affected in many patients with dementia and other geriatric illnesses, resulting in impaired visual acuity, visual field defects, or blindness. Stroke can affect the visual pathways anywhere along their course, with monocular blindness from optic nerve injury or retinal lesions, bitemporal hemianopsia from the optic chiasm, homonymous hemianopsia from injury to the optic radiations, and cortical blindness from an insult to the calcarine cortex in the occipital lobes. Visual acuity may be affected by direct injury to the optic nerve or by diffuse occipital lobe injury. Loss of vision can significantly impair function by affecting the ability to read, navigate safely, and perform activities of daily living (ADLs), and is important to document at each visit. Vision and fundoscopy are very important. Presbyopia is expected. Diminished vision comes from many causes, including cataracts, glaucoma, and macular degeneration. Age-related macular degeneration is a medical condition that usually affects older adults, resulting in a loss of vision in the macular (central) region of the retina. It occurs in “dry” and “wet” forms. It is a major cause of visual impairment in adults older than 50 years (de Jong, 2006). Macular degeneration can make it difficult or impossible to read or recognize faces, although enough peripheral vision remains to allow other activities of daily life. Other forms of macular degeneration include dry central geographic atrophy, the “dry” form

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of advanced age-related macular degeneration (AMD). It results from atrophy to the retinal pigment epithelial layer below the retina, which causes vision loss through loss of photoreceptors (rods and cones) in the central part of the eye. Neovascular or exudative AMD, the “wet” form of advanced AMD, causes vision loss due to abnormal blood vessel growth (choroidal neovascularization) in the choriocapillaris, ultimately leading to blood and protein leakage below the macula. Bleeding, leaking, and scarring from these blood vessels eventually cause irreversible damage to the photoreceptors and rapid vision loss if left untreated (Horton, 2005). Glaucoma is an ocular disorder that is common in the elderly. With glaucoma, the optic nerve is damaged, permanently damaging vision in the affected eye(s) and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the aqueous humor (Rhee, 2008). The two subtypes of glaucoma are termed open-angle and closed-angle glaucoma. Closed-angle glaucoma can appear suddenly and is often painful; visual loss can progress quickly, but the discomfort often leads patients to seek medical attention before permanent damage occurs. Open-angle, chronic glaucoma tends to progress at a slower rate, and patients may not notice that they have lost vision until the disease has progressed significantly. Cataracts are among the most common age-related ocular changes. Cataracts affect the anterior chamber of the eye, where clouding develops in the crystalline lens. Cataracts vary in degree from slight to complete opacity and obstruct the passage of light. Cataracts typically progress slowly to cause vision loss and are potentially blinding if untreated. The condition usually affects both eyes, but almost always one eye is affected earlier than the other (Pavan-Langston, 2007). The senile cataract is characterized by an initial opacity in the lens, subsequent swelling of the lens, and final shrinkage with complete loss of transparency (Quillen, 1999).

Testing cranial nerve II • Test visual acuity: 1 Allow the patient to use his or her glasses or contact lens, if available. You are interested in the patient’s best corrected vision. 2 Position the patient 20 feet in front of the Snellen eye chart (or hold a Rosenbaum pocket card at a 14 in “reading” distance). 3 Have the patient cover one eye at a time with a card. 4 Ask the patient to read progressively smaller letters until he or she can go no further. 5 Record the smallest line the patient can read successfully (such as 20/20 or 20/30). Visual acuity is reported as a pair of numbers (20/20); the first number is how far the patient is from the chart, and the second number is the distance from which the “normal” eye can read a

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Assessment of the Geriatric Neurology Patient

line of letters. For example, 20/40 means that, at 20 feet, the patient can read only letters a “normal” person can read from twice that distance. 6 Repeat with the other eye. • Screen visual fields by confrontation: 1 Stand 2 feet in front of the patient and have him or her look into your eyes. 2 Hold your hands about 1 foot away from the patient’s ears, and wiggle a finger on one hand. 3 Ask the patient to indicate on which side he or she sees the finger move. 4 Repeat two or three times, to test both temporal fields. 5 If an abnormality is suspected, test the four quadrants of each eye while asking the patient to cover the opposite eye with a card (optional). • Test pupillary reactions to light: 1 Dim the room lights as necessary. 2 Ask the patient to look into the distance. 3 Shine a bright light obliquely into each pupil, in turn. 4 Look for both the direct (same eye) and consensual (other eye) reactions. 5 Record pupil size in millimeters and any asymmetry or irregularity. 6 If abnormal, proceed with the test for accommodation. • Test pupillary reactions to accommodation (optional): 1 Hold your finger about 10 cm from the patient’s nose. 2 Ask the patient to alternate looking into the distance and at your finger. 3 Observe the pupillary response in each eye. Pupillary abnormalities need to be assessed in the elderly but are confounded by the frequent use of ophthalmic treatments for glaucoma and macular degeneration. Considerations include anisocoria, posterior communicating artery aneurysm, diabetes, Adie’s tonic pupil, and surgical coloboma following cataract surgery. Evaluation of papillary abnormalities is done in conjunction with the ophthalmologist.

Cranial nerves III, IV, and VI Injury to the oculomotor, trochlear, or abducens nerves can occur following a brainstem stroke or contusion, orbital wall fracture, or basilar skull fracture resulting in cavernous sinus injury. Patients may complain of double vision and dizziness, and findings on examination may include eye deviation, dysconjugate gaze, abnormal head postures, and problems with balance and coordination. Alternate eye patching may be beneficial, especially during therapy sessions. Evaluation of the extraocular movements can be revealing of specific pathologies. Eye movement abnormalities are referable to nuclear lesions in the form of cranial neuropathies (III, IV, and VI) or in the form of supranuclear impairment. Cranial neuropathies affecting eye

movement most commonly present as diplopia. Cranial neuropathies affecting ocular movements have many causes, including sarcoid, DM, cavernous sinus thrombosis, aneurysms, and CVAs. Supranuclear oculomotor impairments are common in the elderly also. These types of impairments affect vertical gaze, smooth pursuit, and saccades. Saccades are the very quick, simultaneous movements made by the eye to receive visual information and shift the line of vision from one position to another (Iwamoto and Yoshida, 2002). The area of the brain that controls saccades is the superior colliculus, specifically the fastigial oculomotor region (FOR) (Iwamoto et al., 2002). The information is received from the retina, translated into spatial information, and then transferred to motor centers for motor response. A person with saccadic dysmetria constantly produces abnormal eye movements, including microsaccades, ocular flutter, and square wave jerks, even when the eye is at rest (Schmahmann, 2004). During eye movements, hypometric and hypermetric saccades occur, and interruption and slowing of normal saccadic movement is common (Schmahmann, 2004). Ocular dysmetria makes it difficult to focus vision on one object. Impairments in vertical gaze are typical of progressive supranuclear palsy. Impairments of smooth pursuit gaze reflect abnormal function of the frontal eye fields and can be seen in neurodegenerative diseases such as PD and AD.

Testing cranial nerves III, IV, and VI • Observe for ptosis. • Test extraocular movements: 1 Stand or sit 3–6 feet in front of the patient. 2 Ask the patient to follow your finger with the eyes without moving the head. 3 Check gaze in the six cardinal directions using a cross or “H” pattern. 4 Pause during upward and lateral gaze to check for nystagmus. 5 Check convergence by moving your finger toward the bridge of the patient’s nose. • Test pupillary reactions to light.

Cranial nerve V Trigeminal nerve injuries occur in patients with head injuries, most commonly because of facial bone fractures. These injuries can also occur following brainstem stroke or contusion. Complete trigeminal nerve injury causes hemianesthesia of the face, whereas partial injuries generally result in facial pain. Motor branch involvement can lead to chewing problems, and loss of sensation inside the mouth may cause pocketing of food and increase the risk of aspiration. Facial sensation reflects the trigeminal nerve dermatomes (cranial nerve V). The three divisions of the trigeminal nerve include ophthalmic, maxillary, and mandibular.

Approach to the Geriatric Neurology Patient: The Neurologic Examination

The ophthalmic region includes the forehead, eyebrow, eyelid, and cornea. The maxillary region includes the zygomatic arch to the mouth. The mandibular region covers the mouth to the jaw. The subdivisions overlap. Hypoesthesia involving the trigeminal nerve dermatomes can be caused by either a cranial neuropathy or a CVA in the elderly. Hyperesthesia/dysesthesia involving the trigeminal nerve is referred to as trigeminal neuralgia. The pain of trigeminal neuralgia originates on the trigeminal nerve. This nerve carries pain, feeling, and other sensations from the brain to the skin of the face. It can involve all divisions. The condition usually affects older adults, but it may affect anyone at any age. Trigeminal neuralgia may be part of the normal aging process. Alternatively, trigeminal neuralgia may be caused by pressure on the trigeminal nerve from a swollen blood vessel or tumor. Often no specific cause is found. Symptoms are unilateral and intermittent and can be triggered by touch or sounds (such as brushing teeth, chewing, drinking, eating, light touching, or shaving). The neurologic examination is usually normal. For additional details, see Chapter 17, “Disorders of the Special Senses in the Elderly.”

Testing cranial nerve V • Test temporal and masseter muscle strength: 1 Ask the patient to both open the mouth and clench the teeth. 2 Palpate the temporal and masseter muscles as the patient does this. • Test the three divisions for pain sensation: 1 Explain what you intend to do. 2 Use a suitable sharp object to test the forehead, cheeks, and jaw on both sides. 3 Substitute a blunt object occasionally and ask the patient to report “sharp” or “dull.” • If you find an abnormality: 1 Test the three divisions for temperature sensation with a tuning fork heated or cooled by water (optional). 2 Test the three divisions for sensation to light touch using a wisp of cotton (optional). • Test the corneal reflex (optional): 1 Ask the patient to look up and away. 2 From the other side, touch the cornea lightly with a fine wisp of cotton. 3 Look for the normal blink reaction of both eyes. 4 Repeat on the other side.

Cranial nerve VII Facial movement (Bell’s, CVA, hypomimia) involves the facial nerve (cranial nerve VII). The examination involves having the patient show the teeth or raise eyebrows. When the frontalis muscle is spared in an asymmetric presentation of facial droop, consider a central nervous system (CNS) event such as a CVA. If the frontalis muscle is involved, consider Bell’s palsy.

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Facial muscle weakness is common in patients who have experienced a stroke or traumatic brain injury (TBI) and can affect articulation and swallowing. Injury to the upper motor (corticobulbar) pathways in the frontal lobe, internal capsule, and upper brainstem causes contralateral facial weakness, usually sparing the forehead. Lower motor neuron injury in the pons (brainstem stroke or trauma) results in ipsilateral facial weakness, including the forehead.

Testing cranial nerve VII • Observe for any facial droop or asymmetry. • Ask the patient to do the following, and note any lag, weakness, or asymmetry: 1 Raise the eyebrows. 2 Close both eyes to resistance. 3 Smile. 4 Frown. 5 Show the teeth. 6 Puff out the cheeks.

Cranial nerve VIII Hearing loss occurs in the majority of patients with geriatric neurologic conditions. High-frequency hearing loss from cochlear insensitivity and dislocation and disruption of the ossicles may be associated with vertigo and disequilibrium due to injury to the acoustic nerve, cochlea, and/or labyrinths. Brainstem contusion or stroke, damaging the acoustic or cochlear nuclei, can result in similar symptoms. Vestibular dysfunction can lead to problems with balance and coordination. The presence of horizontal nystagmus is suggestive of unilateral vestibular nerve injury. Vertical nystagmus may be seen following brainstem or cerebellar injuries. Certain medications, including anticonvulsants, can also cause nystagmus.

Testing cranial nerve VIII • Screen for hearing loss: 1 Face the patient and hold out your arms, with your fingers near each ear. 2 Rub your fingers together on one side while moving the fingers noiselessly on the other. 3 Ask the patient to tell you when and on which side he or she hears the rubbing. 4 Increase intensity as needed and note any asymmetry. 5 If abnormal, proceed with the Weber and Rinne tests. • Test for lateralization (Weber) (optional): 1 Use a 512 Hz or 1024 Hz tuning fork. 2 Start vibrating the fork by tapping it on your opposite hand. 3 Place the base of the tuning fork firmly on top of the patient’s head. 4 Ask the patient from where the sound appears to be coming from (normally in the midline).

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Assessment of the Geriatric Neurology Patient

• Compare air and bone conduction (Rinne) (optional): 1 Use a 512 Hz or 1024 Hz tuning fork. 2 Start vibrating the fork by tapping it on your opposite hand. 3 Place the base of the tuning fork against the mastoid bone behind the ear. 4 When the patient no longer hears the sound, hold the end of the fork near the patient’s ear (air conduction is normally greater than bone conduction). • Vestibular function is not normally tested routinely.

Cranial nerves IX and X The glossopharyngeal and vagus nerves are often affected in patients with medullary strokes. Injury results in impaired phonation and swallowing. The gag reflex is diminished or absent on the side of nerve injury. The palate and uvula may also be deviated to the opposite side. The gag reflex may be hyperactive in patients with injuries to the corticobulbar tracts bilaterally, bilateral strokes, or injuries to the deep white matter. This is often accompanied by spastic quadriparesis and emotional lability. The oropharynx, soft and hard palates, and tongue need to be assessed for asymmetry. These are innervated by cranial nerves IX–XII. Asymmetry of responsiveness to gag or palatal elevation might represent cranial neuropathies, which, in turn, could reflect brainstem lesions. These abnormalities would manifest as dysphonia, dysarthria, or hypophonia. Ungual paresis could reflect a brainstem abnormality as well, but fasciculation or atrophy of the tongue might represent denervation, which is seen in ALS. This would also manifest as dysarthria.

• Ask the patient to shrug the shoulders against resistance. • Ask the patient to turn the head against resistance. Watch and palpate the sternomastoid muscle on the opposite side.

Cranial nerve XII The hypoglossal nerve, which provides motor function to the ipsilateral tongue, is rarely affected as a consequence of geriatric neurologic diseases but can be involved in fracture or medullary stroke. Swallowing difficulties in dementia and parkinsonism can arise because patients may have difficulty manipulating a food bolus in the mouth.

Testing cranial nerve XII • Listen to the articulation of the patient’s words. • Observe the tongue as it lies in the mouth. • Ask patient to: 1 Protrude tongue. 2 Move tongue from side to side.

Motor examination As with the neurologic examination of the younger patient, the neurologic examination of the geriatric patient includes the motor exam. Elements of the motor examination include tone, bulk, and strength. Other considerations beyond the motor examination include the assessment of kinesis and for tremor. These extrapyramidal elements are addressed in Chapter 12.1, “Parkinson’s Disease,” and Chapter 12.2, “Essential Tremor and Other Tremor Disorders,” respectively. Additional considerations include kinesis.

Testing cranial nerves IX and X • Listen to the patient’s voice—is it hoarse or nasal? • Ask the patient to swallow. • Ask the patient to say “Ah.” • Watch the movements of the soft palate and the pharynx. • Test the gag reflex (unconscious/uncooperative patient) (optional). 1 Stimulate the back of the throat on each side. 2 It is normal to gag after each stimulus.

Muscle bulk Generalized muscle atrophy can occur because of prolonged immobility and poor intake in dementia. Damage to the lower motor neuron causes focal muscle atrophy. This can occur as a result of direct trauma to the peripheral nerve, plexus, nerve root, or anterior horn cells in the spinal cord. Focal nerve injuries can also occur because of limb ischemia following trauma or from improper positioning or casting (for example, peroneal neuropathy with a foot drop from an excessively tight leg restraint).

Cranial nerve XI The spinal accessory nerve, innervating the ipsilateral stemocleidomastoid and trapezius muscles, is only rarely injured. Spinal accessory nerve injuries can cause limited neck rotation and shoulder abduction, affecting the ability to do activities above the head, such as reach for objects in a high cabinet.

Testing cranial nerve XI • From behind, look for atrophy or asymmetry of the trapezius muscles.

Muscle tone Spasticity is the most common abnormality of tone seen in patients with stroke, TBI, and spinal cord injury. Spasticity predominantly affects the flexor muscles of the arms and extensor muscles of the legs, while in spinal cord injuries, it predominates in the flexor muscles of both the arms and legs. Tone may also be increased in trunk muscles. Spasticity is caused by injury to the corticospinal tracts and is often accompanied by muscle weakness, hyperreflexia, and an extensor plantar reflex response.

Approach to the Geriatric Neurology Patient: The Neurologic Examination

Hypotonia may be seen in association with cerebellar lesions and also often occurs early following stroke and spinal cord injuries (spinal shock). In the latter, spasticity may develop later, after a period of days to weeks. A long period of hypotonia in this setting usually suggests a poorer likelihood of functional motor recovery. Rigidity generally results from injury to the basal ganglia. Common in Parkinson’s disease, rigidity also occurs in patients who have had subcortical strokes, trauma involving the basal ganglia, and anoxic brain injury. Paratonia is a consequence of bilateral frontal lobe injury or dementia. Spasticity and rigidity may be painful, can be accompanied by muscle spasms, and may affect nursing care by interfering with positioning, bracing, transfer, nursing care, and ADLs. Neck and head control can be affected, hampering feeding and grooming. Spasticity of laryngeal and pharyngeal muscles can affect breathing, articulation, phonation, and swallowing. Truncal spasticity can affect wheelchair positioning, standing, and ambulation. If spasticity is severe and prolonged, fixed joint contractures can develop, further impeding the care progress.

Testing muscle tone • Ask the patient to relax. • Flex and extend the patient’s fingers, wrist, and elbow. • Flex and extend the patient’s ankle and knee. • There is normally a small, continuous resistance to passive movement. • Observe for decreased (flaccid) or increased (rigid/ spastic) tone. The tone can be graded as normal, hypertonic, or hypotonic. Also indicate the type of hypertonia, include spastic, rigid, or gegenhalten. Spastic hypertonia, defined as velocity-dependent resistance to stretch, is referable to upper motor neuron lesions and occurs because of a lack of inhibition from the CNS, which results in excessive contraction of the muscles. Common considerations include residua from CVAs or spinal cord injury. Rigid hypertonia is seen in extrapyramidal disorders (such as PD; see Chapter 12.1). Rigidity, also called increased muscle tone, means stiffness or inflexibility of the muscles. Gegenhalten (also known as paratonia) refers to an involuntary resistance to passive movement as may occur in cerebral cortical disorders. It may occur as a symptom of catatonia, in which there is passive resistance to stretching movements, even when the patient attempts to cooperate. The effect may be psychogenic in origin or may be a sign of dementia or cerebral deterioration. Hypotonia is reduced muscle tone (the amount of tension or resistance to movement in a muscle, also known as flaccidity), and is usually associated with weakness (reduced muscle strength). Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve

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control by the brain or muscle strength. Diminished deep tendon reflexes also may be noted. Causes of hypotonia in the elderly include acute changes related to CVAs and spinal cord injury.

Muscle strength Assessing the muscle bulk is part of the motor exam. Atrophy of muscle groups is, by definition, decreased bulk. Atrophy can occur from myopathies, neuropathies, or radiculopathies and reflects lower motor neuron lesions. The most common patterns of weakness are hemiparesis or tetraparesis because of injury to the corticospinal tracts in the cerebral hemispheres or brainstem. Strokes typically result in hemiparesis, with the arm affected to a greater extent than the leg in middle cerebral artery distribution infarcts affecting cortical structures. In patients with anterior cerebral artery (ACA) distribution infarcts, the leg is predominantly affected. Subcortical strokes generally affect the arm and leg equally. Any deviation from an expected pattern should trigger a search for additional spinal cord or peripheral nerve injuries. Cervical spinal cord injuries often result in tetraparesis, while thoracic and lumbar spine injuries lead to paraparesis. The level of spinal cord injury is defined as the most rostral cord level innervating muscles with at least grade 3 strength.

Testing muscle strength • Test strength by having the patient move against your resistance. • Always compare one side to the other. • Grade strength on a scale from 0 to 5 out of 5 (see Table 3.2). • Test the following movements: 1 Flexion at the elbow (C5, C6, biceps). 2 Extension at the elbow (C6, C7, C8, triceps). 3 Extension at the wrist (C6, C7, C8, radial nerve). 4 Ability to squeeze two of your fingers as hard as possible (“grip,” C7, C8, T1). 5 Finger abduction (C8, T1, ulnar nerve). 6 Opposition of the thumb (C8, T1, median nerve). 7 Flexion at the hip (L2, L3, L4, iliopsoas). 8 Adduction at the hips (L2, L3, L4, adductors). 9 Abduction at the hips (L4, L5, S1, gluteus medius and minimus). Table 3.2 Grading motor strength Grade

Description

0/5 1/5 2/5 3/5 4/5 5/5

No muscle movement Visible muscle movement, but no movement at the joint Movement at the joint but not against gravity Movement against gravity but not against added resistance Movement against resistance, but less than normal Normal strength

Assessment of the Geriatric Neurology Patient

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10 11 12 13 14

Extension at the hips (S1, gluteus maximus). Extension at the knee (L2, L3, L4, quadriceps). Flexion at the knee (L4, L5, S1, S2, hamstrings). Dorsiflexion at the ankle (L4, L5). Plantar flexion (S1).

Testing pronator drift • Ask the patient to stand for 20–30 seconds with both arms straight forward, palms up, and eyes closed. • Instruct the patient to keep the arms still while you tap them briskly downward. • The patient will not be able to maintain extension and supination. Assessing the strength of all muscle groups in the upper and lower extremities is also part of the motor exam. Similar to younger patients, the motor examination should be assessed in detail. Focal weakness of a limb could reflect CVA (ACA infarct leads to monoparesis of the lower extremity), polyradiculopathy, or plexopathy. Weakness in a group of muscles could reflect radiculopathy or neuropathy.

Abnormal movements Abnormal motor movements or postures may result from dementia or brain injuries. Dystonia can occur because of basal ganglia injury (trauma or stroke) or may be seen as an adverse effect of neuroleptic medications and metoclopramide. Dyskinesias of the limbs or orofacial muscles and choreoathetosis may also result from basal ganglia injury or adverse effects of anticonvulsants, oral contraceptives, or antipsychotic medications. Ballismus may occur as a result of trauma or hemorrhage involving the subthalamic region. Tremor of the head or limbs may also result from brain injuries. Myoclonus can be focal, segmental, or generalized, and can occur as a direct consequence of brain injury, including anoxic encephalopathy. Myoclonus is also a common sequela of metabolic abnormalities, including hepatic and renal failure. Asterixis most commonly manifests as a wrist flap when holding the arms outstretched. This can occur in patients with injury to the thalamus, internal capsule, parietal cortex, and midbrain, but is often associated with liver failure. Post-traumatic parkinsonism can result from TBI or anoxic brain injury. Abnormal movements or postures interfere with normal coordinated movements, hampering a patient’s ability to perform ADLs, such as feeding and grooming, or to carry out mobility skills, including wheelchair positioning, sitting balance, standing, or ambulation.

Sensory examination The sensory examination encompasses assessing peripheral and central sensory elements. The primary peripheral sensory modalities include light touch, pinprick, vibration, and proprioception. Central sensory elements

include face–hand test for asimultagnosia, assessment of agraphesthesia, stereognosis, and assessment for neglect. (Also see Chapters 12.2 and 17.)

Sensory perception Sensory perception is commonly affected in patients with geriatric neurology, although sensory deficits are generally overshadowed by motor and cognitive deficits. Thalamic injuries result in loss of sensation on the contralateral side of the body. Parietal lobe injuries cause loss of ability to localize the site of sensory stimulation, with impaired joint position sense, stereognosis, and graphesthesia. Sensory neglect, including visual neglect, hemi-inattention, tactile extinction, and anosognosia, may also be present and is more common following nondominant parietal lobe involvement. Spinal cord injuries result in impaired sensation below the level of the injury, and even in the absence of weakness, bilateral lower extremity proprioceptive loss can significantly impair gait. Sensory deficits can lead to functional impairments. The inability of a patient to detect or localize pain or the presence of sensory neglect can result in injury, as patients may be unable to protect their affected limbs. The inability to control limb position in space because of impaired proprioception can cause problems with feeding and grooming. Lack of feeling in the hands can lead to difficulty with fine motor tasks such as buttoning or fastening snaps or zippers. Lower extremity sensory deficits can lead to problems with transfers and walking because of impairment in foot placement and balance. Patients with impaired sensation of the buttocks and lower extremities are at increased risk of developing decubitus ulcers, especially if spasticity, impaired mobility, and bowel and/ or bladder incontinence are present.

Testing sensory loss General • Explain each test before you do it. • Unless otherwise specified, the patient’s eyes should be closed during the actual testing. • Compare symmetrical areas on the two sides of the body. • Also compare distal and proximal areas of the extremities. • When you detect an area of sensory loss, map out its boundaries in detail. Vibration • Use a low-pitched tuning fork (128 Hz). 1 Test with a nonvibrating tuning fork first to ensure that the patient is responding to the correct stimulus. 2 Place the stem of the fork over the distal interphalangeal joint of the patient’s index fingers and big toes. 3 Ask the patient to tell you if he or she feel the vibration.

Approach to the Geriatric Neurology Patient: The Neurologic Examination

• If vibration sense is impaired, proceed proximally (optional): 1 Wrists. 2 Elbows. 3 Medial malleoli. 4 Patellas. 5 Anterior and superior iliac spines. 6 Spinous processes. 7 Clavicles.

Subjective light touch • Use your fingers to touch the skin lightly on both sides simultaneously. • Test several areas on both the upper and lower extremities. • Ask the patient to tell you if there is difference from side to side or if other “strange” sensations are experienced. Position sense 1 Grasp the patient’s big toe and hold it away from the other toes to avoid friction (optional). 2 Show the patient “up” and “down.” 3 With the patient’s eyes closed, ask the patient to identify the direction you move the toe. 4 If position sense is impaired, move proximally to test the ankle joint (optional). 5 Test the fingers in a similar fashion. 6 If indicated, move proximally to the metacarpophalangeal joints, wrists, and elbows (optional). Dermatomal testing If vibration, position sense, and subjective light touch are normal in the fingers and toes, you may assume the rest of this examination will be normal (optional). Pain • Use a suitable sharp object to test “sharp” or “dull” sensation. • Test the following areas: 1 Shoulders (C4). 2 Inner and outer aspects of the forearms (C6 and T1). 3 Thumbs and little fingers (C6 and C8). 4 Front of both thighs (L2). 5 Medial and lateral aspects of both calves (L4 and L5). 6 Little toes (S1). Temperature • Examination in this category is often omitted if pain sensation is normal (optional). • Use a tuning fork heated or cooled by water and ask the patient to identify “hot” or “cold.” • Test the following areas: 1 Shoulders (C4). 2 Inner and outer aspects of the forearms (C6 and T1). 3 Thumbs and little fingers (C6 and C8).

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4 Front of both thighs (L2). 5 Medial and lateral aspects of both calves (L4 and L5). 6 Little toes (S1).

Light touch • Use a fine wisp of cotton or your fingers to touch the skin lightly. • Ask the patient to respond whenever a touch is felt. • Test the following areas: 1 Shoulders (C4). 2 Inner and outer aspects of the forearms (C6 and T1). 3 Thumbs and little fingers (C6 and C8). 4 Front of both thighs (L2). 5 Medial and lateral aspects of both calves (L4 and L5). 6 Little toes (S1). Discrimination Because these tests are dependent on touch and position sense, they cannot be performed when the previous tests are clearly abnormal (optional). • Graphesthesia: 1 With the blunt end of a pen or pencil, draw a large number on the patient’s palm. 2 Ask the patient to identify the number. • Stereognosis: 1 Use this as an alternative to graphesthesia (optional). 2 Place a familiar object in the patient’s hand (coin, paper clip, pencil, etc.). 3 Ask the patient to tell you what it is. • Two-point discrimination: 1 Use this when more quantitative data are needed, such as following the progression of a cortical lesion (optional). 2 Use an opened paper clip to touch the patient’s finger pads in two places simultaneously. 3 Alternate irregularly with one-point touch. 4 Ask the patient to identify “one” or “two.” 5 Find the minimal distance at which the patient can discriminate. Reflexes Evaluation of muscle stretch reflexes helps localize the site of neurologic injury. Hyperreflexia suggests injury to corticospinal tracts in either the brain or the spinal cord and is often associated with spasticity and muscle weakness. Hyporeflexia is associated with lower motor neuron injuries and also occurs in the period of acute spinal shock below the level of injury. Hyporeflexia may also be seen in association with peripheral neuropathies and, at times, with cerebellar disease.

Deep tendon reflexes Reflexes are frequently diminished in the elderly. A global diminution might be associated with myopathy or neuropathy (see Chapter 21, “Neuromuscular Disorders”)

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Table 3.3 Tendon reflex grading scale Grade

Description

• Note contraction of the quadriceps and extension of the knee.

0 1+ or + 2+ or ++ 3+ or +++ 4+ or ++++

Absent Hypoactive Normal Hyperactive without clonus Hyperactive with clonus

Ankle (S1, S2) • Dorsiflex the foot at the ankle. • Strike the Achilles tendon. • Watch and feel for plantar flexion at the ankle.

Testing for clonus but might also be a reflection of aging. Focal loss of DTRs is indicative of radiculopathy (cervical or lumbar) or focal neuropathy (see Chapter 21).

Testing reflexes • The patient must be relaxed and positioned properly before starting. • Reflex response depends on the force of your stimulus. Use no more force than you need to provoke a definite response. • Reflexes can be reinforced by having the patient perform isometric contraction of other muscles (clenched teeth). • Reflexes should be graded on a 0–4 “plus” scale (see Table 3.3):

Biceps (C5, C6) • The patient’s arm should be partially flexed at the elbow with the palm down. • Place your thumb or finger firmly on the biceps tendon. • Strike your finger with the reflex hammer. • You should feel the response even if you cannot see it. Triceps (C6, C7) • Support the upper arm and let the patient’s forearm hang free. • Strike the triceps tendon above the elbow with the broad side of the hammer. • If the patient is sitting or lying down, flex the patient’s arm at the elbow and hold it close to the chest. Brachioradialis (C5, C6) • Have the patient rest the forearm on the abdomen or lap. • Strike the radius about 1–2 in above the wrist. • Watch for flexion and supination of the forearm. Abdominal (T8, T9, T10, T11, T12) • Use a blunt object such as a key or tongue blade. • Stroke the abdomen lightly on each side in an inward and downward direction above (T8, T9, T10) and below the umbilicus (T10, T11, T12). • Note the contraction of the abdominal muscles and deviation of the umbilicus toward the stimulus. Knee (L2, L3, L4) • Have the patient sit or lie down with the knee flexed. • Strike the patellar tendon just below the patella.

• If the reflexes seem hyperactive, test for ankle clonus (optional). 1 Support the knee in a partly flexed position. 2 With the patient relaxed, quickly dorsiflex the foot. 3 Observe for rhythmic oscillations. • Plantar response (Babinski) 1 Stroke the lateral aspect of the sole of each foot with the end of a reflex hammer or key. 2 Note movement of the toes, normally flexion (withdrawal). 3 Extension of the big toe with fanning of the other toes is abnormal. This is referred to as a positive Babinski.

Primitive reflexes Snout, root, grasp, palmomental, and glabellar can be examined. Primitive reflexes originate in the CNS and are exhibited by normal infants but not neurologically intact adults, in response to tactile stimuli. As the brain develops, these reflexes disappear or are inhibited by the frontal lobes (Primitive and Postural Reflexes, 2008). Primitive reflexes may reappear in adults because of certain neurologic conditions, including but not limited to degenerative neurologic conditions such as dementia, traumatic brain injuries, and cerebrovascular lesions (Schott et al., 2003; Rauch, 2006).

Coordination and cerebellar examination Coordination is modulated by a number of peripheral and central nervous system structures and can be affected by brain and spinal cord injuries. Injury to the corticospinal tracts results in muscle weakness with slowing of gross and fine motor tasks. Basal ganglia insults result in slowed initiation of movements. Cerebellar injuries can lead to truncal and limb ataxia, dysmetria, dysdiadochokinesia, dyssynergia, and intention tremor. Sensory ataxia can result from impaired proprioception due to either peripheral neuropathy or spinal cord injury involving the posterior columns. Truncal ataxia can affect sitting and standing balance, impairing the ability to sit upright in a wheelchair or to walk. Limb ataxia can make ADLs difficult. The assessment of coordination and cerebellar function is part of the geriatric neurologic examination. Impairment is referred to as dysmetria. Dysmetria refers to a lack of coordination of movement typified by the undershoot or overshoot (hypometria and hypermetria,

Approach to the Geriatric Neurology Patient: The Neurologic Examination

respectively) of intended position with the hand, arm, leg, or eye. It is sometimes described as an inability to judge distance or scale. Dysmetria occurs because of disorders of the cerebellum. Dysmetria of the extremities caused by hemispheric syndromes is manifested in two ways: dysrhythmic tapping of hands and feet and dysdiadochokinesis, which is the impairment of alternating movements (Schmahmann, 2004). The actual cause of dysmetria is thought to be caused by lesions in the cerebellum or lesions in the proprioceptive nerves that lead to the cerebellum that coordinate visual, spatial, and other sensory information with motor control (Townsend et al., 1999). Two types of cerebellar disorders produce dysmetria, specifically midline cerebellar syndromes and hemispheric cerebellar syndromes (Hain, 2002). Midline cerebellar syndromes can cause ocular dysmetria, a condition in which the pupils of the eye overshoot (Hain, 2002). Hemispheric cerebellar syndromes cause dysmetria in the typical motor sense that many think of when hearing the term dysmetria (Hain, 2002). A common motor syndrome that causes dysmetria is cerebellar motor syndrome, which is also marked by impairments in gait (also known as ataxia), disordered eye movements, tremor, difficulty swallowing, and poor articulation (Schmahmann, 2004). As stated earlier, cerebellar cognitive affective syndrome (CCAS) also causes dysmetria. Dysmetria is often found in individuals with ALS and persons who have suffered from tumors or strokes. Persons who have been diagnosed with autosomal dominant spinocerebellar ataxia (SCAs) also exhibit dysmetria. SCAs are rarely seen in the elderly. Dysmetria from sporadic causes should be considered first (Dysmetria, 2007).

Testing coordination Rapid alternating movements • Ask the patient to strike one hand on the thigh, raise the hand, turn it over, and then strike it back down as fast as possible. • Ask the patient to tap the distal thumb with the tip of the index finger as fast as possible. • Ask the patient to tap your hand with the ball of each foot as fast as possible. Point-to-point movements • Ask the patient to touch your index finger and his or her nose alternately several times. Move your finger about as the patient performs this task. • Hold your finger still so that the patient can touch it with one arm and finger outstretched. Ask the patient to move the arm and return to your finger with the eyes closed. • Ask the patient to place one heel on the opposite knee and run it down the shin to the big toe. Repeat with the patient’s eyes closed.

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Romberg • Be prepared to catch the patient if he or she is unstable. • Ask the patient to stand with the feet together and eyes closed for 5–10 seconds without support. • The test is said to be positive if the patient becomes unstable (indicating a vestibular or proprioceptive problem). Gait and posture Brain and spinal cord lesions in geriatric neurology often affect posture and gait because of injury to the sensory and motor pathways that affect ambulation. Patients with spastic hemiparesis due to stroke or other brain injuries often have weakness and spasticity of the chest and abdominal musculature, leading to trunk instability and difficulty with weight shifting. Gait deviation may be observed. Weakness of hip flexors and ankle dorsiflexors results in an impaired swing-through of the limb and inadequate toe clearance during the swing phase of gait, resulting in hiking of the hip and circumduction of the leg. Decreased arm swing on the paretic side may also occur. Spasticity may limit the range of motion of the hip, knee, and ankle. Patients with basal ganglia disorders often have a shuffling-type gait. Cerebellar disorders may result in gait ataxia. Patients with proprioceptive deficits may have problems with foot placement and balance. Spinal cord injuries typically result in spastic paraparesis or quadriparesis, with difficulty walking as a result. Patients with cervical spinal cord injuries may have weakness of chest and abdominal muscles, affecting their ability to sit upright and transfer without support, as well as compromising respiratory reserve. The evaluation of gait and the features of gait abnormalities of neurologic diseases are covered in detail in Chapter 6, “Gait Disorders in the Elderly.” Features to evaluate include base, stance, posture, turning, rising from a chair, arm swing, stride, toe, heel, and tandem. Disorders of gait are common in the elderly and falls are a huge risk. Identifying the different gait types helps identify the underlying etiology. For magnetic gaits, consider normal pressure hydrocephalus. For shuffling, festinating gaits, consider parkinsonism, dementia with lewy bodies (DLB), or idiopathic PD. For ataxic gaits, consider peripheral neuropathies or cerebellar disorders. For spastic or paraparetic gaits, consider spinal cord injuries, or spinal stenosis. For hemiparesis, consider focal CNS lesions such as CVAs or mass lesions. Peripheral pathology can affect gait. Antalgic gaits are attributable to orthopedic or arthritic changes of the hip, knee, and ankle. Foot drop from L5 radiculopathy or peroneal neuropathy can affect the gait also.

Testing posture and gait Ask the patient to perform the following activities. • Walk across the room, turn, and come back. • Walk heel-to-toe in a straight line.

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Assessment of the Geriatric Neurology Patient

Walk on the toes in a straight line. Walk on the heels in a straight line. Hop in place on each foot. Do a shallow knee bend. Rise from a sitting position.

Conclusion Careful attention to features of the physical and neurologic examination is essential in a geriatric patient. Careful examination can frequently point to root causes, prompting further investigation. A good geriatric neurologic examination with a focus on functional ability can allow for improving the quality of care in geriatric neurology.

References “Aphasia Symptoms, Causes, Treatment—How Is Aphasia Diagnosed?” Medicinenet.com, May 2011. http://www.medicinenet .com/ aphasia/page3.htm (accessed on August 26, 2011). Bickley, L.S., Szilagyi, P.G., and Bates, B. (2007) Bates’ Guide to Physical Examination and History Taking. Philadelphia: Lippincott Williams & Wilkins. de Jong, P.T. (2006) Age-related macular degeneration. N Engl J Med, 355 (14): 1474–1485. “Dysmetria.” Multiple Sclerosis Encyclopaedia, October 2007. http://www.mult-sclerosis.org/dysmetria.html (accessed on August 26, 2011). Hain, T.C. (2002) “Cerebellar Disorders.” http://www.dizzinessand-balance.com/disorders/central/cerebellar/cerebellar.htm (accessed on August 26, 2011).

Horton, J.C. (2005) Disorders of the eye. In: D.L. Kasper, E. Braunwald, S. Hauser, D. Longo, J.L. Jameson, and A.S. Fauci (eds), Harrison’s Principles of Internal Medicine, 16th edn. New York: McGraw-Hill. Iwamoto, Y. and Yoshida, K. (2002) Saccadic dysmetria following inactivation of the primate fastigial oculomotor region. Neurosci Lett, 325 (3): 211–215. Pavan-Langston, D. (2007) Manual of Ocular Diagnosis and Therapy. Philadelphia: Lippincott, Williams & Wilkins. “Primitive and Postural Reflexes.” The Institute for NeuroPhysiological Psychology, October 2008. http://www.inpp.org.uk/ intervention-adults-children/more-information/reflexes/ primitive-postural-reflex (accessed on August 26, 2011). Quillen, D.A. (1999) Common causes of vision loss in elderly patients. Am Fam Physician, 60 (1): 99–108. Rathe, R. (1996) “Neurologic Examination.” University of Florida. http://medinfo.ufl.edu/year1/bcs/clist/neuro.html (accessed on August 26, 2011). Rauch, D. (2006) “Infantile Reflexes on MedLine Plus.” MedlinePlus. www.nlm.nih.gov/medlineplus/ency/article/003292.htm (accessed on August 26, 2011). Rhee, D.J. (2008) “Glaucoma: Eye Disorders: Merck Manual Home Edition.” The Merck Manuals. www.merck.com/mmhe/sec20/ ch233/ch233a.html (accessed on August 26, 2011). Schmahmann, J.D. (2004) Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. J Neuropsychiatry Clin Neurosci, 16 (3): 367–378. Schott, J.M. and Rossor, M.N. (2003) The grasp and other primitive reflexes. J Neurol Neurosurg Psychiatr, 74 (5): 558–560. Townsend, J., Courchesne, E., Covington, J., et al. (1999) Spatial attention deficits in patients with acquired or developmental cerebellar abnormality. J Neurosci, 19 (13): 5632–5643.

Chapter 4 Assessment of Cognitive Status in Geriatric Neurology 4.1 Mental Status Examination in the Geriatric Neurology Patient

Papan Thaipisuttikul1,2 and James E. Galvin1,2 4.2 Neuropsychology in Geriatric Neurology

Donald J. Connor3 and Marc A. Norman4 1

Department of Neurology, New York University Langone Medical Center, New York, NY, USA Department of Psychiatry, New York University Langone Medical Center, New York, NY, USA 3 Independent Practice, Consultant Clinical Trials, San Diego, CA, USA 4 Department of Psychiatry University of California, San Diego, CA, USA 2

Summary Mental Status Examination in the Geriatric Neurology Patient • Level of consciousness, general appearance, mood and affect, behavior, movement, speech and communication, thought form and content, perception, and insight should be observed during an assessment of cognitive status. • Performance testing provides an objective measure of cognitive performance and the ability to compare with previous and subsequent tests. • Individual cognitive domains can be tested including attention, working memory and concentration, orientation, memory, language, abstract thinking, judgment and problem-solving, visuospatial and construction skills, calculation, executive function, and world list generation. • Several brief scales used to detect depression in the elderly include the Geriatric Depression Scale (GDS), the Patient Health Questionnaire (PHQ-9), and the Hospital Anxiety and Depression Scale (HADS). • Performance-based cognitive evaluation tools include the mini-mental state examination (MMSE), Mini-Cog, short blessed test (SBT), and Saint Louis University Mental Status (SLUMS). • Informant-based tools provide assessments of changes in cognition and its impact on daily function. Questionnaires for informants include the AD8 and the IQCODE. Neuropsychology in Geriatric Neurology • Patient scores collected from standardized instruments are quantified using normative data in order to assess the individual’s performance relative to a demographically similar cohort. • Test results are integrated with observation and noncognitive factors that may influence the performance. • The relative performance on several tests is compared to create a profile of relative strengths and weaknesses. • Neuropsychological assessments play a role in differential diagnosis, assessment of function, and treatment. • Five domains of cognition are commonly tested. • Attention/Orientation: separated into selective, sustained, and divided attention for both verbal and spatial stimuli, awareness of the self and the environment. • Language and communication: assessment of aphasia in expression, comprehension, and repetition (e.g., Broca’s, Wernicke’s, or conduction aphasia). • Memory: several models exist for the concept of memory including temporal, characteristic, modality, and stage models. Within each model are unique terms classifying different types of memory. Neuropsychological tests rely heavily on verbal episodic memory, and visual episodic memory tasks to assess cognitive function. (Continued)

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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• Executive abilities: the abilities for initiation, organization, abstract thinking, and inhibition of impulsive behavior in order to complete a goal-oriented task. • Visuospatial abilities: visual information is separated into two pathways wherein the ventral pathway is involved with symbolic representation and the dorsal pathway is involved with spatial awareness. • Neuropsychological profiles of common disorders. • Mild cognitive impairment (MCI): impaired episodic memory and/or other cognitive functions insufficient to meet criteria for dementia. • Alzheimer’s disease (AD): pattern of impaired episodic memory (learning and free recall). As the disease progresses, impairments in executive functions and recognition memory are noted. • Frontotemporal dementia (FTD): executive dysfunction (e.g., primary progressive aphasia, semantic dementia). • Parkinson’s disease dementia (PDD): alterations or fluctuations in arousal and complex attention, impaired executive dysfunction, impaired memory retrieval. • Dementia with Lewy bodies (DLB): in mild stages, attentional, visuospatial, constructional, and executive dysfunction is greater than impairments in memory and naming compared to AD. • Progressive supranuclear palsy (PSP): characterized by a subcortical profile that includes deficits in attention, executive function, and visuospatial abilities. • Corticobasal ganglionic degneration (CBD): characterized by a subcortical profile. • Vascular dementia (VaD): clinical presentations and neuropsychological profiles vary widely due to the heterogeneity of the anatomical areas damaged. • Delirium: deficits in attention, orientation, and fluctuating levels of arousal caused by an underlying medical condition. • Depression: a risk factor for dementia but the diseases can be separate or comorbid. • Preclinical states of dementia are currently being studied in hopes of developing methods of slowing or temporarily halting the disease (disease modification).

Chapter 4.1 Mental Status Examination in the Geriatric Neurology Patient Papan Thaipisuttikul and James E. Galvin

The elements of a comprehensive mental status examination include observational, cognitive, and neuropsychiatric assessments. Although each of these elements is presented separately, they are inter-related and collectively characterize the neurobehavioral function of the patient. The initial contact with the patient affords the opportunity to assess whether a cognitive, attention, or language disorder is present. Questioning of an informant may bring to light changes in cognition, function, and behavior that the patient either is not aware of or denies. Because the frequency of cognitive disorders increases dramatically with advancing age, examination of mental status is one of the most important components of the neurologic examination. Unfortunately, it is often one of the parts of the examination most likely to be ignored and amongst the most difficult parts of the examination to be interpreted. In general, our fund of knowledge continues to expand throughout life and learning ability does not appreciably decline. Cognitive changes associated with normal aging include decrease in processing speed, cognitive flexibility, visuospatial perception (often in conjunction with decreased visual acuity), working memory, and sustained attention (Tarawneh and Galvin, 2010). Other cognitive abilities such as access to remotely learned information and retention of encoded new information appear to be relatively spared in aging; allowing their use as sensitive indicators for onset of cognitive impairment (Smith, 2003).

Observational and neuropsychiatric assessment In addition to detailed history taking and the more common components of the neurologic examination (motor and sensory function, gait, balance, etc.), careful and thoughtful observation of the patients’ appearance, behavior, and demeanor can provide insight into the nature of the cognitive status. Observation of the patient’s level of consciousness, general appearance, affect, movements, and speech provide important initial evaluation of the patient’s mental status, followed by asking probing questions to sample mood, thought, perception, and insight.

Level of consciousness An accurate assessment of a patient’s mental status and neurologic function must first document the patient’s alertness or level of arousal. Abnormal patterns of arousal include hypo-aroused or hyper-aroused states. Decreasing levels of arousal include lethargy, obtundation, stupor, and coma (Strub and Black, 2000). The lethargic patient is drowsy or fatigued and falls asleep if not stimulated; however, while being interviewed the patient will usually be able to attend to questioning. Obtundation refers to a state of moderately reduced alertness with diminished ability to consistently engage in the environment. Even in the presence of the examiner, if not stimulated, the obtunded patient will drift off. The stuporous patient requires vigorous stimulation to be aroused. Responses are usually limited to simple “yes/no” responses or may consist of groans and grimaces. Coma, which represents the end of the continuum of hypo-arousal states, is a state of unresponsiveness to the external environment. In the elderly, hypo-arousal states can be associated with systemic infection, cardiac or pulmonary insufficiencies, meningoencephalitis, increased intracranial pressure, toxic–metabolic insults, traumatic brain injury, seizures, or cerebrovascular disease. Coma requires either bilateral hemispheric dysfunction or brainstem dysfunction. Another important consideration is the role of polypharmacy (Samaras et al., 2010). Drug interactions are more common in older adults and can significantly impair consciousness (Samaras et al., 2010). Hyper-arousal states on the other hand, are characterized by anxiety, autonomic hyperactivity (tachycardia, tachypnea, hyperthermia), agitation or aggression, tremor, seizures, or exaggerated startle response (Strub and Black, 2000). In the elderly, hyper-arousal states are most often encountered in toxic–metabolic disorders including withdrawal from alcohol, opiates, or sedative– hypnotic agents. Other causes include tumors (both primary and metastatic), viral encephalitis (particularly herpes simplex), cerebrovascular, and hypoxemia (Caplan, 2010). Some patients, for instance, a patient with herpes simplex encephalitis may experience fluctuating periods of both hypo- and hyper-arousal (Ramrez-Bermdez et al., 2005).

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General appearance Assessment of a patient’s physical appearance should acknowledge body size and type, apparent age, posture, facial expressions, eye contact, hygiene, dress, and general activity level. A disheveled appearance may indicate dementia, delirium, frontal lobe dysfunction, or schizophrenia (Strub and Black, 2000). Wearing excessive makeup or flamboyant grooming or attire in an old individual should raise the suspicion of a manic episode or frontal lobe dysfunction (Sadock and Sadock, 2007). Patients with unilateral neglect due to dementia, stroke, or head injury may fail to dress, groom, or bathe one side of their body (Strub and Black, 2000). Patients with Parkinson’s disease (PD) may display a flexed posture, whereas patients with progressive supranuclear palsy (PSP) have an extended, rigid posture. The overall appearance of an individual should also provide information regarding their general health status. The cachectic patient may harbor a systemic illness (e.g., cancer), or have anorexia or depression (Sadock and Sadock, 2007). Mood and affect While mood is a subjective report of the patient’s emotional status that is sustained over time, affect is the patient’s present emotional response that can be inferred from facial expressions, vocal tone, and body movements (Sadock and Sadock, 2007). Affect can change during the interview, while mood usually remains stable during the office visit (Sadock and Sadock, 2007). Constriction or flatness is observed in apathetic states; for example, in the context of negative symptoms of schizophrenia, severe melancholic depression, or in demented patients with apathy (Sadock and Sadock, 2007). Increased intensity, on the other hand, is seen in mood disorders such as bipolar illness, and in personality disorders such as borderline personality (Sadock and Sadock, 2007). Lability is a disorder of emotional regulation. Patients with marked lability are irritable and shift rapidly among anger, depression, and euphoria commonly referred to a pseudobulbar affect (Schiffer and Pope, 2005). The emotional outbursts are usually shortlived. Labile mood is seen in mood disorders such as bipolar illness, and in certain personality disorders such as borderline personality. It also may occur in frontotemporal dementia (FTD), amyotrophic lateral sclerosis, cerebrovascular disease, multiple sclerosis, and head injury (Schiffer and Pope, 2005). In its full form as pseudobulbar palsy, it is commonly seen with lower cranial nerve (CN IX-XII) deficits and hyperactive reflexes (Gillig and Sanders, 2010). Depression is a common mood disorder in older adults and can occur in a variety of neurologic disorders, for example, cerebrovascular disease, Alzheimer’s disease (AD) and other types of dementia, PD, and epilepsy

(Lyness et al., 2006). Euphoria or full-blown mania occurs less often than depression in the course of neurologic illness. Euphoria is most common with frontal lobe dysfunction (trauma, frontotemporal degenerations, infections) and with secondary mania (Woolley et al., 2007). Even though geriatric-onset anxiety disorder is not common in older adults, anxiety symptoms occur in a variety of neuropsychiatric conditions, for example, depression, AD, PD, metabolic encephalopathies (hyperthyroid, anoxia), and toxic disorders (lidocaine toxicity) (Flint, 2005). Objective and subjective emotional components may be incongruent in certain psychiatric disorders (e.g., schizophrenia and schizotypal personality disorder), and in neurologic conditions such as pseudobulbar palsy due to a variety of underlying illnesses.

Behavior A variety of personality alterations can be encountered with focal brain lesions. Orbitofrontal dysfunction may be characterized by impulsiveness or undue familiarity with the examiner, lack of judgment or lack of social anxiety, and antisocial behavior (Newcombe et al., 2011). Individuals with dorsolateral frontal lobe dysfunction may be inattentive and distractible (Brooks et al., 2010). Apathy (lack of motivation, energy, emotional reciprocity, social isolation) may be caused by medial frontal dysfunction and injury to the anterior cingulate (Roth et al., 2007). The various dementias are associated with increased rigidity of thought, egocentricity, diminished emotional responsiveness, and impaired emotional control (Pulsford and Duxbury, 2006). Passivity, social withdrawal and apathy can be seen in Lewy body disorders (Galvin et al., 2007a). Movement Observation of patient’s movements may provide evidence of parkinsonism, chorea, myoclonus, or tics. Psychomotor retardation (i.e., slowed central processing and movement) may be indicative of vascular dementia (VaD), subcortical neurologic disorders, parkinsonism, medial frontal syndromes, or depression (Sadock and Sadock, 2007). Psychomotor agitation may be indicative of a metabolic disorder, choreoathetosis, seizure disorder, mania, or anxiety (Sadock and Sadock, 2007). Speech and communication Observation of spontaneous speech is the first step in formal language testing and can be assessed during history taking as well as in the course of the mental status examination. Mutism may be encountered in several neurologic conditions such as akinetic mutism, vegetative state, locked-in syndrome, catatonic unresponsiveness, or large left hemispheric lesions (Altshuler et al., 1986). Spontaneous speech is characterized by its rate, rhythm, volume, response latency, and inflection (Strub and Black, 2000). Accelerated speech may be encountered in mania,

Mental Status Examination in the Geriatric Neurology Patient

disinhibited orbitofrontal syndromes, or festinating parkinsonian conditions, whereas a reduced rate of speech output can occur as a component of psychomotor retardation (Sadock and Sadock, 2007). Response latencies may be prolonged or the patient may impulsively interrupt the examiner, anticipating the question. Perturbed speech prosody (loss of melody or inflection) can be encountered in brain disorders affecting the right hemisphere or the basal ganglia (Sidtis and Van Lancker Sidtis, 2003). Empty speech with hesitations or circumlocutions can be exhibited in patients with word-finding difficulties (Rohrer et al., 2008). Word-finding impairment may occur in dementia, aphasia, metabolic encephalopathies, physical exhaustion, sleep deprivation, anxiety, depression, or dorsolateral frontal lobe damage even in the absence of an anomia (Rohrer et al., 2008). Aphasia is characterized by impairment in oral and/ or written communication. Deficits will vary depending on the location and extent of anatomic involvement. Aphasias are generally characterized as nonfluent or fluent. Nonfluent aphasias are characterized by a paucity of speech, often with a hesitant quality (Strub and Black, 2000). In contrary, fluent aphasias are characterized by normal word production or may be increased, but there is a lack of comprehension about what words mean, often associated with impairment in reading ability (Strub and Black, 2000).

Thought form and thought content Thought form or thought process refers to the way of thinking, where a person puts ideas and associate them together. Examples of thought form disorders are circumstantial, tangential, derailment, flight of idea, thought blocking, loosening of association or incoherence. Perseveration (Sadock and Sadock, 2007) and incoherence are disorders of the form of thought that are common in neuropsychiatric conditions. Perseveration refers to the inappropriate continuation of an act or thought after conclusion of its proper context. Intrusions are a special case of perseveration with late recurrences of words or thoughts from an earlier context. Perseverations and intrusions can be seen in aphasias and dementing illnesses. Incoherence refers to the absence of logical association between words or ideas. It is observed in delirium, advanced dementias, and as part of the output of fluent aphasia. Thought content refers to what a person is actually thinking about, such as ideas, beliefs, preoccupations, and obsessions. Delusions are the most common manifestation of psychosis in neuropsychiatric disorders and are characterized by false beliefs based on incorrect inference about external reality. Common types of delusions encountered involve being followed or spied on, theft of personal property, spousal infidelity, or the presence of unwelcome strangers in one’s home. Theme-specific delusions such as

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the Capgras syndrome (the belief that someone has been replaced by an identical-appearing impostor) (Josephs, 2007) may also be observed in neurologic illnesses. Delusions are common in a number of dementia etiologies including AD and dementia with Lewy bodies (DLB), and may occur in VaD, FTD, and Huntington’s disease.

Perception Perceptual disturbances can be classified as hallucination or illusion/misperception. Hallucination is a false sensory perception that occurs without stimulation of the relevant sensory organ, while, illusion is a misperception or misinterpretation of real external sensory stimuli. Hallucinations and delusions frequently occur together in psychosis; hallucinations are nondelusional when the patient recognizes the sensory experience to be unreal. Hallucinations may involve any sensory modality (visual, auditory, tactile, gustatory, olfactory) and may be formed (e.g., people or things) or unformed (flashing lights or colors). Hallucinations occur with ocular and structural brain disorders as well as Charles Bonnet syndrome, epilepsy, narcolepsy, and migraine (Pelak and Liu, 2004). Well-formed visual hallucinations (children, furry animals) are a prominent early sign in DLB (Hanson and Lippa, 2009). Less well-formed visual hallucinations occur in the moderate-to-severe stages of AD with the patient typically not well able to describe what they saw. Gustatory or olfactory hallucinations are most common in seizure disorders, bipolar and schizophrenia, and with tumors located in the medial temporal lobe (Capampangan et al., 2010). Tactile hallucinations are most commonly associated with schizophrenia, affective disorders or drug intoxication, or withdrawal (Sadock and Sadock, 2007). Insight Insight is the patient’s ability to understand the true cause and meaning of his/her condition, as well as the implication of diagnosis and its prognosis. Patients with neuropsychiatric disease may display limited insight and be unaware of their medical conditions or limitations in function, thus assessment of a patient’s insight into the severity of their illness can yield useful diagnostic information and assist in developing a therapeutic plan. For example, AD patients have impaired insight into their memory and cognitive difficulties, whereas patients with VaD and DLB often exhibit more appropriate concern regarding their cognitive dysfunction (Del Ser et al., 2001). However, it should not be assumed that the patient is unaware of problems. Instead, they may be unable to attribute causality and are usually unable to rate the frequency and severity of their problems. Lesions of the right parietal lobe are associated with unawareness, neglect, or denial of the abnormalities of the contralateral side (anosagnosia) (Pia et al., 2004).

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Cognitive assessment Following observation, the clinician should begin a formal assessment of cognitive abilities. The assessment of cognitive function should be conducted methodically and should assess comprehensively the major domains of neuropsychological function (attention, memory, language, visuospatial skills, executive ability). The patient’s age, handedness, educational level, and sociocultural backgrounds may all influence the cognitive function and should be determined prior to initiating or interpreting the evaluation. In general there are two ways to assess the patient—informant assessments and performance testing. Using performance testing, the clinician may gain a sense of the objective performance of the patient in relation to published normative values, usually corrected for age and education. If the patient was previously assessed, comparison to previous tests offers the potential to measure change. Brief performance tests while providing a “snap shot” of abilities at the time of examination, are themselves unable to provide information regarding the change from previous abilities or how the scores on the tests interfere with the patients social and occupational functioning (i.e., their activities of daily living). Formal neuropsychological testing provides a more comprehensive assessment of cognitive abilities with estimates of premorbid intelligence (Section 4.2). However, neuropsychological testing is not practical in the office setting and may not be readily available outside major metropolitan areas. In this section, we take two approaches— (1) individual cognitive domains to create a brief 20–30 minute (depending on the level of dementia severity and language ability) battery of tests that could be done in the office setting (Table 4.1), and (2) brief global measures. Table 4.1 Example of a brief neurobehavioral status examination Verbal memory

Animal naming 15-item Boston naming

Working memory

Digit span forward Digit span backward

Episodic memory

Word list recall (Hopkins, California, CERAD) Paragraph recall

Visual construction

Clock drawing

Psychomotor speed

Trailmaking A

Executive function

Trailmaking B Digit symbol substitution

Abstraction

Similarities and differences Proverb interpretation

Concentration

Months in reverse order Counting backward from 20

Global measurement (Choose one)

Mini-mental status examination Short blessed test

Mood (Choose one)

Geriatric depression scale PHQ-9 Hospital anxiety and depression scale

Attention, working memory, and concentration Attention is very important in order to process other cognitive abilities. Two tests are useful in assessing attention: digit span and continuous performance tests. In the digit span forward (Strub and Black, 2000) test, the patient is asked to repeat increasingly long series of numbers (e.g., 1, 3-7, 4-6-3, 5-1-9-2, etc.). A normal forward digit span is seven digits; fewer than five is abnormal. Digit span backward (Strub and Black, 2000) is a test of mental control, and complex attention, as well as executive dysfunction. It entails saying increasingly long series of numbers and asking the patient to say them backward (give 2-5-8, response should be 8-5-2). A normal digit span in reverse is five digits; fewer than three is abnormal. Concentration is an ability to maintain attention. Concentration is evaluated by a continuous performance test, for example, ask the patient to count backward from 20, say months of the year backward, and serial subtraction (100−7 or 20−3). However, serial subtraction should be used with caution, because of its dependence on education and mathematical ability (Karzmark, 2000). Orientation Orientation to time is tested by asking the patient to identify the correct day of the week, date, month, and year. This could be followed by asking the patient to state the correct time of the day without looking at a watch or clock. The patient should be within 1 hour of the correct time. Orientation to place is assessed by asking about city, county, state, and current location. Orientation to situation can be assessed by asking the patient why they are in the clinic/hospital on the particular day. Memory Learning, recall, recognition, and memory for remote information are assessed in the course of mental status examination. Asking the patient to remember three words and then asking him or her to recall the words 3 minutes later can help assess learning, recall, and recognition. In general, the shorter the list, the easier it is to remember, particularly in high-functioning individuals. When told to remember items, patients will often remember the first two items heard (known as “primacy”) and the last two items heard (known as “recency”), therefore longer lists of 10 words may be preferable (Morris et al., 1989). After a delay, recall of less than five words is considered abnormal. Patients having difficulty with recall may be given clues (e.g., the category of items to which the word belongs or a list of words containing the target) to distinguish between storage and retrieval deficits. For example, giving clue to patient with AD will generally not help a patient to remember because of his/her primary storage disorder, while giv-

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Table 4.2 Useful screening tests for office setting Screening test

Numbers of items

Scoring system

Validity

Limitations

MMSE

30 items

Cutoff 23–24

Sensitivity 85–100% Specificity 66–100%

Mini-Cog

3 recall with clock drawing

SBT

6 items of orientation, memory and concentration

Recall 2/3 use clock to determine the problem 5–9/28 questionable 10 or over/28 dementia

SLUMS

11 items

MoCA

12 items,10 minutes administered, multicognitive domain assessing

Less than 26 detect MCI or dementia

Sensitivity of 90 for MCI and 100 for dementia

AD8

8 items

More than 2

Sensitivity 90% Specificity 68%

IQCODE

16 items

More than 3.44

Sensitivity 76–100% Specificity 65–86%

Score influenced by education, ethnicity, social class. Not ideal to identify mild impairment. Test focus on recall, visuospatial ability and construction. Test focus on orientation, memory and concentration. May not detect nonamnestic dementias. Limited validation on different groups of patients from original study. Tests are complicated and take time to use in an office setting. Takes 10 minutes or more for patients with more severe impairment. Not as extensively studied as MMSE. Depends on observant informant. In the absence of informant, the AD8 can be administered to the patient. Depends on observant informant.

Sensitivity and specificity comparable to MMSE High correlation of 0.52 between score and autopsy Cutoff of 21–26: mild cognitive Sensitivity 96–98% impairment (MCI), 20 and Specificity 61–100% below: dementia for high school education

ing clue to a patient with DLB may help the patient to recall since his/her primary deficit might be retrieval (Hamilton et al., 2004). To evaluate remote memory, information needs to be gathered on the patient’s life events and important historic events (marriage, birth of children). An informant may be helpful to verify the accuracy of the information. The pattern of memory loss in most forms of dementia usually starts with short-term (learning, recall, recognition) memory first, then gradually involving in long-term memory in the later stages of disease. However, psychogenic amnesia memory-loss patterns can be variable and typically involve both long and short memory (HennigFast et al., 2008).

Language Language assessment entails the evaluation of all aspects of communication including spontaneous speech, comprehension, repetition, naming, reading, and writing. Language comprehension is tested by asking the patient to follow increasingly complex verbal instructions. The easiest commands are one-step orders such as “close your eyes,” or “stick out your tongue” to multistep commands “take the piece of paper, fold it in half and place on the floor” to more complex questions, such as “If a lion is killed by a tiger, which animal is dead?” Impaired comprehension usually implies dysfunction of parietotemporal regions of the left hemisphere. In the elderly, it is important to establish that hearing is intact before testing

verbal comprehension. Failure to comprehend commands may reflect the inability to hear as opposed to impaired comprehension. Repetition is assessed by asking the patient to repeat increasingly long phrases or sentences. Repetition is impaired in Wernicke, Broca, conductive, and global aphasia but is generally preserved in transcortical aphasias. Naming tests involve asking the patient to name objects, parts of objects, and colors. Aphasic patients may use descriptive terms rather than give the proper name. Anomia, loss of naming ability, occurs in aphasia, dementia, delirium, and can sometimes be seen as a consequence of head trauma. Adequate vision and object recognition must be ensured before errors are ascribed to naming deficits. The 15-item Boston Naming Test (Mack et al., 1992) is an example of a brief measure of confrontational naming. When assessing reading, the patient’s ability to read aloud and to comprehend what is read should both be tested. Adequate vision must be ensured before failures are ascribed to an alexia. Many aphasias have concomitant alexias; however, the converse may not be true. In alexia with agraphia and alexia without agraphia, reading abnormalities may occur in the absence of other signs of aphasia (Maeshima et al., 2011). Patients with agraphia lose their ability to write/ draw things when asked by the examiner. Micrographia (Gangadhar et al., 2008) is a characteristic aspect of parkinsonism in which the script becomes progressively smaller as the patient writes a sentence or extended series

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of numbers or letters, and mechanical agraphias occur in patients with limb paresis, limb apraxia, or movement disorders such as tremor and chorea (Ferguson and Boller, 1977). Agraphias may accompany aphasic syndromes and errors found in written language are often similar to those noted in verbal output. In Gerstmann syndrome (agraphia, acalculia, right–left disorientation, finger agnosia), alexia with agraphia, and disconnection agraphia (occurring with injury of the corpus callosum), agraphia occurs without aphasia (Rusconi et al., 2010).

Calculation Patients are asked to add or multiply one or two digits mentally or to execute more demanding problems with pencil and paper. Calculation abilities are related to education and occupation. Acalculias may occur in association with a number of aphasic syndromes while visuospatial disorders lead to incorrect alignment of columns of numbers (Ardila and Rosselli, 1994). Primary anarithmetias (inability to do math) are produced by damage to the posterior left hemisphere (Grafman et al., 1982).

Abstract thinking Abstract thinking is the ability to deal with concepts. Similarities, differences, idioms, and proverb interpretation can all be used to assess abstracting capacity. These tests are influenced by culture and educational level. Abstraction abnormalities are a nonspecific indicator of cerebral dysfunction. Patients with neurodegenerative dementias typically offer concrete answers to abstract questions, thus comprehension should always be assessed before asking the patient to provide interpretations.

Executive function Executive function, or higher cortical function, has been mediated by frontal-subcortical system, complex neural circuits that include the dorsolateral prefrontal cortex, striatum, globus pallidus/substantia nigra, thalamic nuclei, and connecting white matter tracts. Patients with executive dysfunction manifest perseveration, motor programming abnormalities, reduced word list generation (left dorsolateral dysfunction), reduced nonverbal fluency (right dorsolateral dysfunction), poor set-shifting, abnormal recall with intact recognition memory, loss of abstraction abilities, poor judgment, and impaired mental control (Bullock and Lane, 2007). Simple executive function tests that are useful in clinical settings include Trail making A test that requires the patient to draw lines sequentially connecting 25 encircled numbers distributed on a paper. Trail making A (Corrigan and Hinkeldey, 1987) measures psychomotor speed with minimal executive function and if completed allows further testing with Trail making B (Corrigan and Hinkeldey, 1987) that requires alternating between numbers and letters (1-A-2-B…etc.).

Judgment and problem-solving abilities Assessing judgment assists in exploring the patient’s interpersonal and social insight. Damage to orbitofrontal subcortical circuit (e.g., in FTD, trauma, or focal syndromes) produces marked alterations in social judgment (Gleichgerrcht et al., 2010). Problem solving can be assessed by giving a scenario “If traveling in a strange town, how would a person locate a friend they wished to see?” Correct answers might include use of phone book, the internet, or city directory. Visuospatial and construction skills In the clinic, simple tests that are usually used to evaluate the patient’s visuospatial abilities are clock-drawing test and copying intersecting pentagons or cubes. The clock-drawing test (Libon et al., 1993) assesses the ability to plan and arrange the numbers on the clock face and to place the hands at the correct time. The hands should be of different lengths. Patients with executive dysfunction may draw a clock face that is too small to contain the required numbers (poor planning), whereas patients with unilateral neglect will ignore half of the clock face. There are a number of different scoring paradigms for the clock, although the simplest might simply be scoring the clock as normal or abnormal. Abnormalities of other copy tests (pentagons, cubes) include failures to reproduce the shapes accurately, perseveration on individual elements, drawing over the stimulus figure, or unilateral neglect. Drawing disturbances are common with many types of neurologic conditions including focal brain damage, degenerative disorders, and toxic and metabolic encephalopathies (Mechtcheriakov et  al., 2005).

Word list generation Ask the patient to think of as many members of a specific category (most commonly animals or vegetables) as possible within 1 minute. Typically, older adults can name approximately 18 animals within 1 minute; less than 14 is considered abnormal. Word lists can also be generated using the first letter (for example S and F (Brandt and Manning, 2009)). Word list generation deficits occur with anomia, frontal-subcortical systems dysfunction, and psychomotor retardation. It is a highly sensitive test for impairment but lacks specificity (Brandt and Manning, 2009).

Effects of mood and affect disorder on cognition Depression is common in older adults. Memory complaints are likely to be the chief complaints in this group of patients, as known as “pseudodementia” in the past. When depression improves, the cognitive impairment often improves as well. However, comorbid depression and cognitive impairment are a risk for the later emergence of AD (Alexopoulos et al., 1993). Therefore, early depressive symptoms with mild cognitive impairment

Mental Status Examination in the Geriatric Neurology Patient

(MCI) may represent a preclinical sign and should be considered a risk for impending dementia (Li et al., 2001). Concept of vascular depression or depression-executive dysfunction syndrome is also famous in older adults (Alexopoulos et al., 1997). The clinical presentations are psychomotor retardation, apathy, and severe disability related to impaired executive function. Depression in the elderly is not a unitary construct. There is a wide range of variations in etiologies and manifestations; therefore, early detection and appropriate management are important. Some brief scales that are usually used for detecting depression in the elderly are (1)  Geriatric Depression Scale (GDS), the 15-items and 30-items self-administered questionnaire that usually takes only 5–10 minutes, was first developed by Yeasavage in 1983 (Yesavage et al., 1983). GDS has shown a good sensitivity of 80% and specificity of 100% at the cutoff of 14/30 (Brink et al., 1982). (2) Patient Health Questionnaire (PHQ-9), the 9-item self-administered questionnaire that has been studied widely in primary care populations (Spitzer et al., 1999) was found to have overall 85% accuracy, 75% sensitivity, and 90% specificity for depression diagnosis. (3) Hospital Anxiety and Depression Scale (HADS), the 7-items depression combine with 7-items of anxiety self-administered questionnaire was first developed in the United Kingdom to use in general medical outpatient clinic settings (Snaith, 2003). HADS-D at cutoff of eight or over had 80% sensitivity and 88% specificity, while HADS-A at cutoff of eight or over had 89% sensitivity and 75% specificity from previous study (Olssn et al., 2005). Anxiety symptoms are common in the elderly, especially as a comorbid with late-life depression. In the past, experts believed that anxiety disorder usually have an onset in childhood or early adulthood; however, some researchers also found clinical samples with late-onset anxiety disorders (Blazer and Steffens, 2009). A preliminary study comparing generalized anxiety disorder (GAD) patients, major depressive disorder (MDD) patients, and healthy elderly individuals found that GAD patients had impaired short-term and delayed memory, but no executive deficits as seen in MDD patients (Mantella et al., 2007). Apathy, withdrawal or indifference is one of the most common behavioral symptoms in AD. Apathy defines as a reduction in a voluntary goal-directed behavior. Studies found that Alzheimer’s patients with apathy (lacks initiative) also have problem with multitasking (executive function) which can be an underlying factor of goaldirected behaviors (Esposito et al., 2010).

Performance-based tools for cognitive evaluation Though creating a unique, brief psychometric battery might seem appealing, administration of even a brief battery can take 20–30 minutes. Alternatively, there are

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a variety of brief, cognitive tests that were developed to help assess the general cognitive functions. Each has limitations, but in the setting of a busy office, practice may provide the quickest way to get a global assessment of the patients’ cognitive abilities (Table 4.2). The following are examples of general cognitive tests that are practical to use in geriatric patients in clinical setting.

Mini-Mental Status Examination The 30-item mini-mental state examination (MMSE) test, which takes around 10 minutes to complete, has been frequently used for initial assessment of memory problem, and its sensitivity increases if a decline of the score over time is taken into account (Folstein et al., 1975). The MMSE covers six areas: (1) orientation, (2) registration, (3) attention and calculation, (4) recall, (5) language, and (6) ability to copy a figure. However, although the MMSE is quick and easy to administer and can track the overall progression of cognitive decline, it is not considered to be a good test for definitive AD diagnosis (deSouza et al., 2009), particularly because of its greater emphasis on orientation (10 of 30 points) that is typically not impaired at the earliest stages of dementia. In addition, there are several issues associated with the MMSE, including bias according to age, race, education, and socioeconomic status (Caplan, 2010). There are also copyright issues that may limit its use. Several diagnostic tests are now available for use in primary care as alternatives to the MMSE; these are continually being updated and simplified in order to provide brief, easy to administer, and effective diagnostic tools.

Mini-Cog The Mini Cognitive Assessment Instrument (Mini-Cog) combines an un-cued 3-item recall test with a clockdrawing test that serves as a recall distractor; it can be administered in about 3 minutes and requires no special equipment. (Borson et al., 2005) The Mini-Cog, and the MMSE have similar sensitivity (76% vs. 79%) and specificity (89% vs. 88%) for dementia, correlating with findings achieved using a conventional neuropsychological battery. The Mini-Cog’s brevity is a distinct advantage when the goal is to improve recognition of cognitive impairment in primary care, particularly in milder stages of impairment. (Borson et al., 2005) It has also been suggested that cognitive impairment assessed by the Mini-Cog is a more powerful predictor of impaired activities of daily living than the disease burden in older adults. In addition, the Mini-Cog also has proven good performance in ethnically diverse populations of the United States, where widely used cognitive screens often fail, and is easier to administer to non-English populations.

Short Blessed Test Short blessed test (SBT), consisting of the items in the Blessed orientation–memory–concentration test, includes

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three orientation questions (month, year, and time of day), counting from 20 to 1, saying the months backward, and recalling a 5-item name and address memory phase (Katzman et al., 1983). This test was developed using scores from a validated 26-item mental status questionnaire of two patient groups in a skilled nursing home, patients in a health-related facility, and in a senior citizens’ center. There was a positive correlation between scores on the 6-item test and plaque counts obtained from the cerebral cortex of 38 subjects at autopsy. This test, which is easily administered by a nonphysician, has been shown to discriminate among mild, moderate, and severe cognitive deficits (Katzman et al., 1983). The SBT is quite sensitive to early cognitive changes due to AD. Based on clinical research findings from the Memory and Aging Project at Washington University in Saint Louis, the proposal of new cut-points, after adding weighting factors (total score of Katzman et al., 1983) were suggested: 0–4 normal cognition, 5–9 questionable impairment, and 10 or more impairments consistent with dementia (Morris et al., 1989).

The Saint Louis University Mental Status The Saint Louis University Mental Status (SLUMS) is a 30-point, 11-item, clinician-administered screening questionnaire that tests for orientation, memory, attention, and executive functions. The SLUMS is similar in the format of MMSE; however, it supplements the MMSE with enhanced tasks corresponding to attention, numeric calculation, immediate and delayed recall, animal naming, digit span, clock drawing, figure recognition/size differentiation, and immediate recall of facts from a paragraph. In particular, the clock-drawing test is designed to assess impairment in executive function (Schiffer and Pope, 2005). At a cut-off score of 27–30 normal, 21–26 mild neurocognitive disorder, and 1–20 dementia for high school education have 0.98 sensitivity and 0.61 specificity for MNCD and 0.96 sensitivity and 1.0 specificity for dementia diagnosis (Tariq et al., 2006). Therefore, the developer team suggests benefit of SLUMS over MMSE in order to identify minor neurocognitive disorders early. Due to copyright issues the Veterans Administration has stopped using the MMSE and now many use SLUMS. However, to date the SLUMS has not been validated outside of the original research sample.

The Montreal Cognitive Assessment The Montreal Cognitive Assessment (MoCA) is a 10-minute cognitive screening tool developed to assist physicians in the detection of MCI (Gillig and Sanders, 2010). MoCA is gaining credibility due to improvements in sensitivity, addressing frontal/executive functioning, and decreasing susceptibility to cultural and educational biases. It has high sensitivity and specificity for

detecting MCI in those patients who perform within the normal range of the MMSE. Compared with the MMSE, which had a sensitivity of 18% to detect MCI, the MoCA detected 90% of MCI subjects and, in patients with mild AD the MMSE had a sensitivity of 78%, whereas the MoCA detected 100% (Nasreddine et al., 2005). MoCA is also well-suited as a screening test for cognitive impairment in PD (Dalrymple-Alford et al., 2010), in which memory impairment may be involved later in the stage of disease compared to executive function. The limitation of the MoCA may be in its more complex interpretation.

Informant-based tools for cognitive evaluation The diagnosis of dementia is a clinical one, based on the principles of intraindividual decline in cognitive function that interferes with social and occupational functioning. The limitations to all brief performance measures is that they (1) fail to capture the “change” and “interference” when used as a dementia screen and (2) may be biased by age, gender, race, education, and culture. Informant-based instruments on the other hand rely on an observant collateral source to assess whether there have been changes in cognition and if said changes interferes with function. A particular strength compared to other cognitive screening tests is that informant assessments are relatively unaffected by education and premorbid ability or by proficiency in the culture’s dominant language. Because each person serves as their own control, there is little bias due to age, education, gender or race (Morales et al., 1997). The disadvantages of informant assessments are the reliability of the informant and the quality of the relationship between the informant and the patient. Because the informant assessments provide information complementary to cognitive tests, harnessing them together may improve screening accuracy. A gold standard in informant assessment is the Clinical Dementia Rating (CDR) used in many clinical trials and research projects. However, the length of the interview makes it impractical for use in the busy office setting. The value of including a reliable informant (spouse, adult child, caregiver) in the evaluation of cognitive and affective disorders in older adults has been incorporated into the following questionnaires.

AD8 AD8 screening interview is a brief, sensitive measure that reliably differentiates between individuals with and without dementia by querying memory, orientation, judgment, and function (Galvin et al., 2006). The AD8 comprises eight yes/no questions asked to an informant to rate changes, and takes approximately 2–3 minutes for the informant to complete (Table 4.3). In the absence of an informant, the AD8 can be directly administered to the patient as a self-rating tool (Galvin et al., 2007b) with

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Table 4.3 The AD8 Remember, “Yes, a change” indicates that there has been a change in the last several years caused by cognitive (thinking and memory) problems.

YES, A change

NO, No change

N/A, Do not know

1. Problems with judgment (e.g., problems making decisions, bad financial decisions, problems with thinking) 2. Less interest in hobbies/activities 3. Repeats the same things over and over (questions, stories, or statements) 4. Trouble learning how to use a tool, appliance, or gadget (e.g., VCR, computer, microwave, remote control) 5. Forgets correct month or year 6. Trouble handling complicated financial affairs (e.g., balancing checkbook, income taxes, paying bills) 7. Trouble remembering appointments 8. Daily problems with thinking and/or memory TOTAL AD8 SCORE Source: Adapted from Galvin, J.E. et al. (2005) The AD8, a brief informant interview to detect dementia. Neurology, 65: 559–564. Reproduced with permission of Washington University, St. Louis, MO.

similar large-effect sizes (Cohen’s d for informant = 1.66; for patient = 0.98 (Galvin et al., 2007b). Use of the AD8 in conjunction with a brief assessment of the participant, such as a word list, could improve detection of dementia in the primary setting to 97% and 91% for MCI (Galvin et al., 2006). The AD8 has a sensitivity of 84%, and specificity of 80% with excellent ability to discriminate between nondemented older adults and those with mild dementia (92%) regardless of the cause of impairment (Galvin et al., 2006). The AD8 is highly correlated with the CDR and neuropsychological testing. More recently the AD8 has been biologically validated against amyloid PET imaging and cerebrospinal fluid biomarkers of AD (Galvin et al., 2010). The AD8 has been translated into Spanish (Muoz et al., 2010), Korean (Ryu et al., 2009), and Chinese (Yang et al., 2011) with similar psychometric properties.

The Informant Questionnaire on Cognitive Decline in the Elderly The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) was developed as a way of measuring cognitive decline from a premorbid level using informant reports. Subsequently, the short version of 16-item correlated 0.98 with the full version and had comparable validity when judged against clinical diagnosis. Each item is rated on a 5-point scale from 1-“much better” to 5-“much worse” and the ratings are averaged over the 16 items to give a 1–5 score, with three representing no change on any item. In clinical situations, a screening cutoff of 3.44+ on the short IQCODE is a reasonable compromise for balancing sensitivity and specificity. The rating scale was deliberately designed to reflect cognitive improvement as well as cognitive decline, to allow for the questionnaire to be used in treatment trials and following acute illnesses (Form, 2004).

Summary Cognitive disorders are common in older adults; however, cognitive complaints may not be readily offered by patients due to denial, lack of insight, fear of stigma and/ or a general lack of knowledge about what is “normal” for an age. The elements of a comprehensive mental status examination include observational, cognitive, and neuropsychiatric assessments. In the absence of a comprehensive approach to evaluate cognitive abilities, it is unlikely that a clinician will detect impairment at the mildest stages when intervention may offer the greatest potential for benefit. In addition, the presence of cognitive impairment leads to poorer adherence, higher costs, and worse outcomes for other medical conditions compared with age-matched older adults without cognitive impairment. Whether the clinician designs their own unique assessments or utilizes one of the many standardized instruments available, failure to include a mental status examination in the assessment of older adults represents a missed opportunity.

Acknowledgments This work was supported by P30 AG008051 from the National Institute on Aging, National Institutes of Health.

References Alexopoulos, G.S., Meyers, B.S., Young, R.C., et al. (1993) The course of geriatric depression with “reversible dementia”: a controlled study. Am J Psychiatry, 150: 1693–1699. Alexopoulos, G.S., Meyers, B.S., Young, R.C. (1997) ‘Vascular Depression’ hypothesis. Arch Gen Psychiatry, 54: 915–922. Altshuler, L.L., Cummings, J.L., and Mills, M.J. (1986) Mutism: review, differential diagnosis, and report of 22 cases. Am J Psychiatry, 143 (11): 1409–1414.

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Ardila, A. and Rosselli, M. (1994) Spatial acalculia. Int J Neurosci, 78 (3–4): 177–184. Blazer, D.G. and Steffens, D.C. (2009) The American Psychiatry Publishing Textbook of Geriatric Psychiatry, 4th edn, Washington, DC: American Psychiatric Publishing Inc. Borson, S., Scanlan, J.M., Watanabe, J., et al. (2005) Simplifying detection of cognitive impairment: comparison of the Mini-Cog and Mini-Mental State Examination in a multiethnic sample. J Am Geriatr Soc, 53: 871–874. Brandt, J. and Manning, K.J. (2009) Patterns of world list generation in Mild Cognitive Impairment and Alzheimer disease. Clin Neuropsychol, 23 (5): 870–879. Brink, T., Yesavage, J., Lum, O. et al. (1982) Screening tests for geriatric depression. Clin Gerontologist, 1: 37–43. Brooks, J.O. 3rd, Bearden, C.E., Hoblyn, J.C., et al. (2010) Prefrontal and paralimbic metabolic dysregulation related to sustained attention in euthymic older adults with bipolar disorder. Bipolar Disord, 12 (8): 866–874. Bullock, R. and Lane, R. (2007) Executive dyscontrol in dementia, with emphasis on subcortical pathology and the role of butyrylcholinesterase. Curr Alzheimer Res, 4 (3): 277–293. Capampangan, D.J., Hoerth, M.T., Drazkowski, J.F., and Lipinski,  C.A. (2010) Olfactory and gustatory hallucination presenting as partial status epilepticus because of glioblastoma multiforme. Ann Emerg Med, 56 (4): 374–377. Caplan, L.R. (2010) Delirium: a neurologist’s view-the neurology of agitation and overactivity. Rev Neurol Dis, 7 (4): 111–118. Corrigan, J.D. and Hinkeldey, M.S. (1987) Relationships between part A and part B of the Trail Making Test. J Clin Psychol, 43 (4): 402–409. Dalrymple-Alford, J.C., MacAskill, M.R., Nakas, C.T., et al. (2010) The MoCA: well-suited screen for cognitive impairment in Parkinson disease. Neurology, 75 (19): 1717–1725. Del Ser, T., Hachinski, V., Merskey, S., and Munosk, D.G. (2001) Clinical and pathological features of two groups of patients with dementia with Lewy bodies: effect of coexisting Alzheimer type lesion load. Alzheimer Dis Assoc Disord, 15 (1): 31–44. deSouza, L., Sarazin, M., Goetz, C., and Dubois, B. (2009) Clinical investigations in primary care. Front Neurol Neurosci, 24,: 1–11. Esposito, F., Rochat, L., Van der Linden, A.C., et al. (2010) Apathy and executive dysfunction in Alzheimer disease. Alzheimer Dis Assoc Disord, 24 (2): 131–137. Ferguson, J.H. and Boller F. (1977) A different form of “pure agraphia”: syntactic writing errors in a patients with motor speech and movement disorders. Neurol Neurocir Psiquitr, 18 (Suppl. 2–3): 79–86. Flint, A.J. (2005) Anxiety and its disorders in late life: moving the field forward. Am J Geriatr Psychiatry, 13 (1): 3–6. Folstein, M.F., Folstein, S.E., and McHugh, P.R. (1975) Mini-mental State: a practical method for grading the cognitive status of patients for the clinicians. J Psychiatr Res, 12: 189–198. Form, A.J. (2004) The Informant Questionnaire on cognitive decline in the elderly (IQCODE): a review. Int Psychogeriatr, 16 (3): 275–193. Galvin, J.E., Roe, C.M., Xiong, C., and Morris, J.C. (2006) The validity and reliability of the AD8 informant interview for dementia. Neurology, 67: 1942–1948. Galvin, J.E., Malcom, H., Johnson, D., and Morris, J.C. (2007a) Personality traits distinguishing dementia with Lewy bodies from Alzheimer’s disease. Neurology, 68 (22): 1895–1901.

Galvin, J.E., Roe, C.M., Coats, M.A., and Morris, J.C. (2007b) Patient’s rating of cognitive ability: using the AD8, a brief informant interview, as a self-rating tool to detect dementia. Arch Neurol, 64 (5): 725–730. Galvin, J.E., Fagan, A.M., Holtzman, D.M., et al. (2010) Relationship of dementia screening tests with biomarkers of Alzheimer’s Disease. Brain, 133 (11): 3290–3300. Gangadhar, G., Joseph, D., and Chakravarthy, V.S. (2008) Understanding Parkinsonian handwriting through a computational model of basal ganglia. Neural Comput, 20 (10): 2491–2525. Gillig, P.M. and Sanders, R.D. (2010) Cranial Nerves IX, X, XI and XII. Psychiatry(Edgmont), 7 (5): 37–41. Gleichgerrcht, E., Torralva, T., Roca, M., et al. (2010) The role of social cognition in moral judgment in frontotemporal dementia. Soc Neurosci, 12: 1–10. Grafman, J., Passafiume, D., Faglioni, P., and Boller, F. (1982) Calculation disturbances in adults with focal hemispheric damage. Cortex, 18 (1): 38–49. Hamilton, J.M., Salmon, D.P., Galasko, D., et al. (2004) A comparison of episodic memory deficits in neuropathologically-confirmed Dementia with Lewy bodies and Alzheimer’s disease. J Int Neuropsychol Soc, 10 (5): 689–697. Hanson, J.C. and Lippa, C.F. (2009) Lewy body dementia. Int Rev Neurobiol, 84: 215–228. Hennig-Fast, K., Meister, F., Frodl, T., et al. (2008) A case of persistent retrograde amnesia following a dissociative fugue: neuropsychological and neurofunctional underpinnings of loss of autobiography memory and self-awareness. Neuropsychologia, 46 (12): 2993–3005. Josephs, K.A. (2007) Capgras syndrome and its relationship to neurodegenerative disease. Arch Neurol, 64 (12), 1762–1766. Karantzoulis, S. and Galvin, J.E. (2011) Distinguishing Alzheimer’s disease from other major forms of dementia. Expert Rev Neurother, 11 (11): 1579–1591. Karzmark, P. (2000) Validity of serial seven procedure. Int J Geriatr Psychiatry, 15 (8): 677–679. Katzman, R., Brown, T., Fuld, P., et al. (1983) Validation of a short orientation-memory concentration test of cognitive impairment. Am J Psyhciatry, 140: 734–739. Li, Y.S., Meyer, J.S. and Thornby, J. (2001) Longitudinal follow up of depressive symptoms among normal versus cognitive impaired elderly. Int J Geriatr Psychiatry 16: 718–727. Libon, D.J., Swenson, R.A., Barnoski, E.J., and Sands, L.P. (1993) Clock drawing as an assessment tool for dementia. Arch Clin Neurolpsychol, 8 (5): 405–415. Lyness, J.M., Niculescu, A., Tu, X., et al. (2006) The relationship of medical comorbidity and depression in older, primary care patients. Psychosomatics, 47 (5): 435–439. Mack, W.J., Freed, D.M., Williams, B.W., and Henderson, V.W. (1992) Boston Naming test: shortened versions for use in Alzheimer’s disease. J Gerontol, 47 (3): 154–158. Maeshima, S., Osawa, A., Sujino, K., et al. (2011) Pure alexia caused by separate lesions of the splenium and optic radiation. J Neurol, 258 (2): 223–226. Mantella, R.C., Butters, M.A., Dew, M.A., et al. (2007) Cognitive impairment in late-life generalized anxiety disorder. Am J Geriatr Psychiatry, 15: 673–679. Mechtcheriakov, S., Graziadei, I.W., Rettenbacher, M., et al. (2005) Diagnostic value of fine motor deficits in patient with low-grade hepatic encephalopathy. World J Gastroenterol, 11 (18): 2777–2780.

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Morales, J.M., Bermejo, F., Romero, M., and Del-Ser, T. (1997) Screening of dementia in community dwelling elderly through informant report. Int J Geriatr Psychiatry, 12 (8): 808–816. Morris, J.C., Heyman, A., Mohs, R.C., et al. (1989) The consortium to establish a Registry for Alzheimer’s disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology, 39 (9): 1159–1165. Muñoz, C., Núñez, J., Flores, P., et al. (2010) Usefulness of brief informant interview to detect dementia, translated into Spanish (AD8-Ch). Rev Med Chil, 138 (8): 1063–1065. Nasreddine, Z.S., Phillips, N.A., Bedirian, V., et al. (2005) The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc, 53: 695–699. Newcombe, V.F., Outtrim, J.G., Chatfield, D.A., et al. (2011) Parcellating the neuroanatomical basis of impaired decision making in traumatic brain injury. Brain, 134 (Pt3): 759–768. Olssøn, I., Mykletun, A., Dahl, A.A. (2005) The Hospital Anxiety and Depression Rating Scale: a cross sectional study of psychometrics and case-finding abilities in general practice. BMC Psychiatry, 5: 46. Pelak, V.S. and Liu, G.T. (2004) Visual hallucinations. Curr Treat Options Neurol, 6 (1): 75–83. Pia, L., Neppi-Modona, M., Ricci, R., Berti, A. (2004) The anatomy for anosognosia for hemiplegia: a meta-analysis. Cortex, 40 (2): 367–377. Pulsford, D. and Duxbury, J. (2006) Aggressive behaviour in residential care settings: a review. J Psychiatr Ment Health Nurs, 13 (5): 611–618. Ramírez-Bermúdez, J., Soto-Hernández, J.L., López-Gómez, M., et al. (2005) Frequency of neuropsychiatric signs and symptoms in patients with viral encephalitis. Rev Neurol, 41 (3): 140–144. Rohrer, J.D., Knight, W.D., Warren, J.E., et al. (2008) Word-finding difficulty: a clinical analysis of the progressive aphasias. Brain, 131 (Pt1): 8–38. Roth, R.M., Flashman, L.A., and McAllister, T.W. (2007) Apathy and its treatment. Curr Treat Options Neurol, 9 (5): 36–70. Rusconi, E., Pinel, P., Dehaene, S., and Kleinschmidt, A. (2010) The enigma of Gerstmann’s syndrome revisited: a telling tale of the vicissitudes of neuropsychology. Brain, 133 (Pt2): 320–332.

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Chapter 4.2 Neuropsychology in Geriatric Neurology Donald J. Connor and Marc A. Norman Basis of neuropsychological assessment Psychometric testing is based on the administration of standardized instruments, quantified using appropriate normative data, to produce a measurement of an individual’s relative cognitive strengths and weaknesses. Ideally, the normative transformation of the raw data will include factors that may influence test performance such as age, gender, education, premorbid intelligence, socioeconomic status, culture, and race (Mitrushina, 1999, pp. 24–27). This allows the examiner to estimate the relative probability that the test score is abnormal, and estimate the degree of impairment. Neuropsychological assessment involves the integration of the psychometric test results along with medical history, psychological/ psychiatric status, and subjective symptom report by the patient and family. This integration is done based on an intimate knowledge of brain–behavior–disease relationships that are the core of a neuropsychologist’s training. Neuropsychological testing is similar to a clinician’s mental status testing but differs quantitatively in the amount of testing and qualitatively in the integration of differential profiles and use of demographic-based normative data.

Normative data The issue of appropriate normative data is critical to the interpretation of the test profile. If the normative dataset is not appropriate to the individual patient’s demographic factors then the validity of the transformed data must be brought into question. Single cut points as commonly seen in mental status examinations are useful in clinical practice but can be misleading. Since the final interpretation of the data is a synthesis of all information available to the neuropsychologist, a valid and clinically useful conclusion may be reached despite the norms not accounting for all variables, but the decrease in the strength of the conclusions should be recognized (American Psychological Association Ethics standard 9.02, 2010). The subject’s performance is most commonly expressed as standard deviations (Z-scores), T-scores, standard scores, scaled scores, or percentiles. The differences between these transformations and their implications for interpretation are beyond the scope of this chapter. However, as a guideline, except for percentiles, these transformations of the raw scores assume a normal distribution of the data (e.g., standard

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bell curve). Z-scores have a mean of 0 with a standard deviation of 1; T-scores have a mean of 50 with a standard deviation of 10; standard scores such as those used in IQ tests have a mean of 100 and a standard deviation of 15; scaled scores have a mean of 10 with a standard deviation of 3. Percentiles are expressed somewhat differently as they are nonlinear and reflect the percentage of scores in a sample that fall at or below a given raw score. Because of this, conversion of percentiles into standardized scores (Z-scores, T-scores, etc.) assumes that the percentile distribution can reflect the normative curve which may not be the case in tests with a skewed distribution. However, assuming a normal distribution of the normative data, a Z-score = −1.0 (one standard deviation below the mean) would reflect a percentile score of sixteenth percentile, a Z-score of −1.5 would be in the seventh percentile and a Z-score of −2.0 would be in the second percentile. In general, cut scores of approximately −1 standard deviation may be taken as low average; scores of approximately −1.5 standard deviations may be taken as borderline or questionable; and scores of −2 standard deviations may be taken as impaired (Lezak et al., 2004; pp. 145–149) although there is significant variability in this and deficits of −1.0–1.5 have been used in the diagnosis of mild cognitive impairment (MCI) (Albert et al., 2011). The level of score that is indicative of a clinically relevant pathologic state is based on multiple factors (premorbid abilities, profile against other abilities, etc.) and is interpreted both as a probability that there is an impairment as well as the degree of impairment. The level of performance the practitioner uses to determine the clinical impairment may be greater or less than what may be considered statistically different depending on the factors mentioned above (premorbid abilities, demographics, sensory/motor deficits, distribution of the normative data, etc.) and the consequences of a false negative versus false positive result (Lezak et al., 2004; p. 148; Busch et al., 2006).

Standardized assessment In addition to limitations imposed by appropriateness of the normative data, other factors that may influence test performance must be taken into account. As detailed in a previous section on mental status testing, all psychometric testing should begin with at least a cursory examination of sensory and motor function. For example, if a subject demonstrates impaired performance on visual memory tasks but has significant uncorrected visual deficits, then

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the results of the testing must be carefully interpreted or discounted. The breadth of neuropsychological tests available allows the clinician some ability to measure cognitive function even in the presence of significant sensory or motor deficits, but ultimately the impact of the deficits on test performance, the effect on the cognitive profile and the validity of the results is determined by the clinical interpretation of the neuropsychologist. The basis of neuropsychological assessment is that test instruments are administered in a standardized manner so that appropriate normative data can be applied for a valid reflection of the patient’s abilities. Thus, neuropsychological tests tend to have detailed administration manuals and highly structured administration procedures. This quantitative approach emphasizes the final performance score as indicative of the patient’s abilities. However, observations made during the test session (apparent effort, level of consciousness, acute confusion, etc.) that may influence the validity of the results are also included in the interpretation. In some cases, a “process approach” may be used that emphasizes the method the patient uses to complete the task (Milberg, 1986). This approach involves a more sophisticated and complex analysis of the qualitative aspects of the test behavior and is integrated with the quantitative test scores. Some neuropsychological instruments have attempted to standardize the qualitative methodology as is reflected in tests such as the Wechsler Adult Intelligence Scale revised as a neuropsychological Instrument (Kaplan et al., 1991). However, the process approach method is seen as an adjunct to the quantitative method of analysis rather than a replacement for it.

Interpretation It is the integration of the test results into a cognitive profile that is the core feature of a neuropsychological assessment. This integration involves both the awareness of noncognitive factors that may influence the test results (mood, effort, sensory/motor, etc.) as well as the intertest patterns. Since no single test is a pure measure of any cognitive construct, using the relative performance of several tests compared to each other is necessary to define the impaired areas of function. One example of this is the Trail Making Test A/B (Reitan, 1958). This is a sequencing test consisting of two conditions. The first condition (Trails A) is a simple sequencing task where the patient is presented with a paper with numbers scattered over the page. The patient then draws a line from one number to the next—in order—with the time to completion and any errors recorded. The second condition (Trails B) is similar but involves alternating between numbers and letters (e.g., 1-A-2-B-3- etc.). Poor performance on Trails B can be due to visual–motor impairment or difficulties in maintaining the sequence set (executive dysfunction). By comparing the performance on Trials B to the performance on

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Trails A, the visual–motor component can be accounted for and a more accurate measure of executive function (EF) can be obtained. As mentioned in chapter 4.1, proficiency in mental status testing is a necessity in geriatric neurology. However, the abbreviated nature of the mental status tests tends to limit its sensitivity and specificity in very mild dementia (Tombaugh and McIntyre, 1992; Tariq et al., 2006) and the ability to detect relative levels of deficit in different cognitive domains (e.g., cognitive profiles). Many of the standard screening instruments (MMSE, MOCA, SLUMS) are useful for initial detection of clinical dementia based on their total score (Nasreddine et al., 2005; Ismail et al., 2010), but their reliability tends to decrease when individual items are interpreted. While these tests can be influenced by age, education, etc., this is often not taken into account when “cut” or threshold scores are used. In the MMSE manual (Folstein et al., 2001), a reference to an extensive normative study is given (Crum et al., 1993) as a way to take demographics into account. In particular, this study demonstrates the significant effect that age and education can have on what is considered a “normal” performance on the test. However, it should be noted that the administration procedures in the normative study are different from those described in the test manual, making use of the normative data questionable for the copyrighted version of the MMSE. Therefore, even when using abbreviated instruments it is necessary to ensure that the administration methods are appropriate to the normative data and that the normative data are appropriate for the individual patient. As mentioned previously, neuropsychological testing can be seen as a more extensive and expansive—albeit more time consuming—extension of mental status testing. Similarly to mental status testing, neuropsychological assessment can be done using a series of individual instruments chosen for the specific referral question or for appropriateness to the patient. Alternatively, a “comprehensive instrument” (Neurological Assessment Battery, Halstead–Reitan Neuropsychological Battery, Wechlser Adult Intelligence Scale, etc.) can be used in which the subtests are all designed to work together (e.g., minimize interference effects) and are co-normed which facilitates profile interpretation. A survey of the most common neuropsychological instruments can be found in Rabin et al. (2005).

Utility of neuropsychological assessment Neuropsychological assessment in a geriatric population can be used for many purposes, but the major applications fall into three broad categories: diagnosis, effect on function, and treatment.

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Diagnosis Incorrect diagnosis of an incurable degenerative disease (false positive) can cause unnecessary stress, pain and inappropriate choices (financial and social) to the patient and their family. Conversely, early detection of dementing disorders can have a significant positive effect on the patient and their family. It has been suggested that starting treatment early in the course of a dementia optimizes the treatment effects of medications and allows positive lifestyle changes that may slow the decline, although results of early treatment have been variable (Holt et al., 2009; Assal and van der Meulen, 2009). Accurate early detection also has the practical benefit of allowing the patient and their family to make future plans while the patient is still cognitively intact. Reaching early agreements on when to restrict driving, developing safe habits and routines that may carry forward into the moderate stages of dementia, and other social and treatment interventions can enhance the long-term quality of life of the patient and caregiver (Gessert et al., 2000; Papastavrou et al., 2007). Along with early and increased accuracy of detection of suspected dementia, neuropsychology can contribute to differential diagnosis of the underlying processes. While AD is the most common cause of dementia in the elderly, there are many other disease states that can cause dementia with significant implications for treatment and outcome. One of the most apparent differentials is when cognitive decline is caused by a delirium rather than a dementia. Delirium is often the result of an underlying medical condition that is often treatable (unlike most progressive dementias); however, if left undetected it may progress and be life-threatening. Differentiating between degenerative dementias can also have significant clinical utility. Perhaps the second most common cause of degenerative dementia is Lewy body disease (LBD). While it may often be found to have comorbidity underlying AD pathology, there are differences in presentation and cognitive profiles that can be used to increase the diagnostic certainty (McKeith et al., 2005). The clinical treatment implications are significant in those patients with LBD who show increased sensitivity to neuroleptics and, when used for treatment of agitation, can result in permanent rigidity (Weisman and McKeith, 2007). Treatment implications of differential diagnosis are of course not limited to medications, but include social interventions, rehabilitation, and family planning. For example, AD and FTD have different presentations, progressions, and treatments (Salmon and Bondi, 2009). Issues on what the family can expect through different stages, prediction of possible dangerous situations and behaviors, and coping programs can be quite different. Assessment of functional limitations The impact of the cognitive deficits on a patient’s ability to function and related safety issues can also be informed by neuropsychological assessment. While the structure of

most psychometric tests are geared toward measurement of cognitive abilities, some test batteries have attempted to include items that are ecologically valid measures of day-to-day functioning (Farias et al., 2003). However, while neuropsychological assessment can inform the level of function and track changes over time, it is not a replacement for direct evaluation (e.g., on road driving tests (Brown et al., 2005)). This in part may be due to the structured nature of the assessment instruments and the controlled environment in which the testing is administered. While this is necessary for accurate measurement of function, it does not reflect the complex and multimodal environment patients may find themselves functioning in. For example, in driving aspects of attention, reaction time, processing speed (monitoring the environment, observing traffic signals, traffic conditions), memory and orientation (getting lost), visual–spatial skills, and executive abilities (EA) (decision making with regard to other drivers and road conditions) are all involved in effective performance. Many patients with early Alzheimer’s disease (AD) may be able to drive safely in well-known areas as long as no confusing or conflicting elements occur in their environment since much of driving skill involves procedural memory that tends to be spared in the early stages of this disease. However, if the patient suddenly comes upon extensive road work with multiple lane restrictions or finds themselves in an unfamiliar area, other cognitive abilities that are affected by the disease (e.g., frontal executive) are necessary, and a dangerous situation could occur. Neuropsychological test results can be a useful adjunct to determination of functional problems, but are insufficient in and of themselves (Iverson et al., 2010). Competency is a legal term but is usually based on clinical information. In essence, it reflects the patient’s ability to make a decision, have a rationale for the decision and appreciate the consequences of that decision (Marson et  al., 2001; Moye and Marson, 2007). Competency itself can have multiple areas—such as the ability to make financial decisions, medical decisions and self-care—and a patient may be competent in one area and incompetent in another. As in other aspects of determination of function, neuropsychological assessment can aid in the determination of competency by providing information on deficits in various cognitive domains, but is not in and of itself sufficient.

Treatment The importance of neuropsychological testing for treatment extends beyond differential diagnosis or the detection of comorbid processes. While it is certainly important to determine the presence of a disorder before treating it (e.g., MCI), and it is important to make sure the correct disease is being treated (e.g., AD vs. LBD), the pattern of strengths and weaknesses a patient presents is important

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in any cognitive remediation or social intervention strategies. For example, if memory is a central issue, then electronic reminders to take medications along with written notes can prove helpful. Determination of the memory system affected can further guide intervention as the type of difficulty (encoding information vs. storage vs. retrieval) can have significant effects on the type of intervention that will prove most effective (Bayles and Kim, 2003). For example, written notes—while very useful in patients with AD—lose their impact if the patient develops an undetected Alexia. Most interventions in degenerative dementias concentrate on compensation and coping strategies, which will be under constant modification as the course of the disease progresses (Ptak et al., 2010). Patients who have had a stroke, traumatic brain injury (e.g., auto accident, falls), or who are post CNS surgery can benefit from more traditional rehabilitation treatments that seek to augment the normal recovery process. A critical step in this treatment is the identification of specific cognitive areas of impairment and remaining areas of strength (Yamaguchi et al., 2010).

Cognitive domains in neuropsychology Multiple approaches, models, and theories have been created to organize and explain mental processes. In clinical practice, five general cognitive domains that are widely recognized include: attention, language, memory, executive abilities, and visuospatial abilities.

Attention, orientation, concentration Assessment of attention varies from clinic screening to longer duration and precision computerized testing to inferential imaging (i.e., ERP, PET, fMRI, and SPECT). Attention is a primary component of multifactorial cognitive processing; however, there is no pure test for attention and there is no test that assesses all components of attention. Like other cognitive domains, attention is not a unitary construct and while some measures are very sensitive, attentional profiles lacks specificity; however, before interpreting attentional problems arousal and orientation must be adequate (see also previous section on mental status testing). Orientation in clinical use can range from a basic awareness of self, body, and immediate environment to understanding of time, place, and purpose. At its most basic, the construct of orientation overlaps with that of alertness and vigilance. Clinical assessment usually involves basic questions of person, place, and time (oriented × 3). Attention requires that sensory events must first be detected and oriented to, although at the most basic level this may

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be involuntary. This requires the individual to be sufficiently aroused and have sensory awareness. Those who are sedated or obtunded will have problems with the first step of attention. Attention is a complex construct and there exist many cognitive models dividing attention into subtypes (i.e., selective attention, sustained attention, and divided attention) and may overlap with the concept of alertness/vigilance on one end and working memory on the other. Selective attention is the process by which individuals preferentially select relevant, salient stimuli over less germane ones. Humans are remarkably facile in filtering irrelevant stimuli, but this may become compromised with normal aging, cerebral insults, or degenerative processes. After a stimulus is selected, sustained attention allows for the maintenance of vigilance, focused attention, and response persistence. In sustained attention, tasks measure the ability to hold information, concentrate, ignore other stimuli, and perform mental operations (see also working memory). In mental status testing, the “A” letter test can be used to test sustained attention where a list of random letters is read to the patient and is asked to tap the table every time they hear the letter “A”. Neuropsychologists use tests that may last from 5 (i.e., digit vigilance test) to 30 minutes (i.e., computerized continuous performance tests). These tests allow the patient to focus their attention on one task, but there are other measures that assess the ability to divide attention across two or more tasks, divided attention. Divided attention is not often challenged within the clinical setting, but some neuropsychological paradigms assess this (i.e., paced addition serial attention test, and consonant trigrams) (Gronwall, 1977; Morris, 1986). Intact attention is a prerequisite for cognitive function in any of the other domains. Clinically, impairment in attention may be reported by the patient or family as memory disturbance (encoding) or lack of effort. Patients with poor attention may complain that they are unable to remember information, but formal testing may reveal that they are unable to attend to verbal or visual information. For example, they may notice that after reading a page they are unable to “remember” what they have read; however, attentional impairment may render them unable to direct their attention to the information to be encoded, thus, it is not a true memory deficit. This level of differentiation (i.e., attention versus memory) may only be evident with detailed neuropsychological measures. Even within healthy aging, attentional resources lessen. This is typically noted in the diminished ability to attend to multiple stimuli at the same time (i.e., divided attention). Patients may complain of the inability to carry out conversations, because they are unable to focus or are easily distracted, but this may be a “normal” finding of healthy aging until it begins to affect function.

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Within a clinical population, attention can be used to distinguish general disorders within the elderly. For example, in AD, attention tends to be relatively better preserved than many other cognitive domains (i.e., memory and EF), but attention is more impaired than in healthy individuals (Rizzo et al., 2000a, 2000b; Peretti et al., 2008; Duchek et al., 2009). In contrast, attention is proportionately more impaired in Lewy body dementia (DLB) than in AD and significant fluctuation in attention are core characteristics of delirium (Ballard et al., 2001). Significant impairments of attention up to and including an acute confusional state, can be seen in metabolic disorders, intoxication, mania, fatigue, psychosis (distracted from internal stimuli), chronic sleep disorders (i.e., sleep apnea) and multifocal disorders (i.e., meningitis, encephalitis, acute traumatic brain injury). Because there are several components to attention, and models involve multiple neurosubstrates, lesions or neuropathology to almost any area of the brain may produce a disorder of attention (or a component of attention). Although most clinic attention assessment is within the verbal domain, spatial inattention may be evident in office screening. An example of verbal attention is a Digit Span task. Reciting a progressively longer sequence of digits (digits forward) is seen as a test of simple attention, and reciting the digit sequence in reverse order (digit backward) as a test of more complex attention, which overlaps with the construct of working memory. WORLD backwards and serial sevens in the mini-mental state examination (MMSE) are other examples of brief measures of attention. Information may be briefly held within working memory, but this is not necessarily stored for later memory retrieval. A simple spatial task that can be done within a few seconds is the line bisection test. The patient is asked to draw a perpendicular line in the center of the lines drawn on the paper. Figure 4.1 demonstrates left hemispatial inattention. Not only did the patient omit drawing the bisecting line in the page’s left hemispace, the lines they bisected in right hemispace were inaccurately bisected.

Figure 4.1 Line bisection test.

Language and communication Human expression and communication occurs through a variety of modalities including speech, writing, reading, drawing, and gestures. Three features can be used to generally classify broad aphasia subtypes: expression, reception, and repetition. Although the term aphasia (absence of speech) is commonly used and will be used in this section, in most cases dysphasia (impaired speech) is more accurate. Informal language assessment begins during the initial interaction and interview; however, subtle deficits may only be identified with further screening or a comprehensive, systematic approach. Practitioners should observe the quantity and quality of speech fluency, prosody, articulation, and grammar. As with any other part of the neurologic/neuropsychological examination, aberrant findings should be viewed in the context of other findings. For example, what may appear to be comprehension problems may be secondary to psychiatric or other factors (i.e., poor output secondary to depression, minimal motivation, negative attitude, poor hearing, etc.). Normal expressive speech should include fluent, spontaneous discourse. Expressive changes may range from mild to profound. Mild paraphasias may be subtle, but at the other end of the spectrum a patient may be completely unable to produce verbal language. Most language screening includes asking the patient to name items. Spontaneously naming items on confrontation requires aspects of object recognition, item identification, retrieval, and expression. It is also important to note that although a patient is unable to name an object, this may be due to a retrieval deficit, rather than anomia. In the case of a retrieval deficit, although the person is unable to spontaneously name the item, he/she would be able to do so with a phonemic cue (i.e., cuing them with “com…” for “computer”). In the latter case, anomia, they would be unable to generate the word even with a cue. Most clinical screening measures include some aspect of naming (i.e., MMSE, SLUMS, etc.). Neuropsychological assessments commonly include the Boston Naming Test (60 items) or other standardized naming tools. An often-overlooked aspect of language is automatic speech that includes overlearned sequences and phrases. Even when patients may have profound expressive language loss, automatic phrases like “hi”, or sequences like counting or singing the alphabet may be less impaired. Also, the automatic nature of overlearned songs (like “Happy Birthday”) can be performed when other speech is absent. Even when a patient is able to sing the alphabet, they may be unable to speak it without the prosodic tune. Comprehension deficits may be more difficult to identify than expressive ones. Patients display nonverbal communication (e.g., head nodding) that may mislead others to

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believe they understand what is being said when such is not the case. Practitioners may contribute to the problem in using their own gestures when asking a question (e.g., nodding affirmatively when asking if the person is having a good day or marriage). Comprehension can be assessed in several ways including, yes–no responses, responsive answers, pointing to responses, and simple commands; however, errors may not be apparent unless complex questions are asked. Simple yes–no questions may be needed for those with significant receptive aphasia (i.e., “Is your name Jane?”). Increasing complexity includes “Are the lights on in the room?” With greater complexity, responsive answers require greater understanding and expression (i.e., “the colors of the flag are red, white, and  _____”). However, when expression is impaired, patients may be unable to verbally respond to questions, so asking them to point toward objects and follow commands can be done. When asking a patient to point or follow commands, however, it is important to rule out pointing errors related to apraxia or agnosia. The third essential language area is repetition. Repetition of sounds, words, phrases, and sentences should be assessed. Like expression and reception, patients may display deficits with only complex items. On the simple end, noncomplex words can be repeated (i.e., car, house, etc.). Phrases and sentences offer a greater range of complexity (i.e., “Methodist Episcopal… The door to the office is closed… No ifs, ands or buts… The phantom soared across the foggy heath”). Because of the proximity of other cerebral structures to eloquent cortices, association cortices or fasciculi make it possible that other communication deficits may be present. Although not core pieces of subtyping aphasia, the neurologic examination may or may not include academic tasks of reading, writing, and arithmetic (functions associated with association areas around the supramarginal gyrus). Because of frontal and parietal proximity to language eloquent cortices, motor and sensory dysfunction is common. Reading, writing, and arithmetic may produce functional limitations, but are often not fully assessed, but changes may occur due to their proximity to association cortices. Alexia, apraxia, and agnosia are associated findings that are typically assessed in a neuropsychologist’s comprehensive aphasia battery. Also, neuropathologic correlates may be associated with alexia with (central) or without (posterior) agraphia. Many of the language tasks mentioned in the mental status examination section are used in neuropsychological screening (i.e., the Reitan–Indiana Aphasia Screening Test), but the neuropsychologist’s assessment armamentarium also includes comprehensive batteries including the Boston Diagnostic Aphasia Examination, Multilingual Aphasia Examination, Western Aphasia Battery, and a variety of other measures. Each tool assesses

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expression, reception, and repetition, but vary in their measures of apraxia, reading, writing, and agnosia. Also, some tasks are specific to one modality (i.e., comprehension). Neuropsychologists may use a tool like the Token Test to measure aspects of receptive dysfunction. For the Token Test, an array of various colored and sized shapes is presented, and the patient is asked to follow commands such as “touch the small red square with the large blue circle.” Once assessment of the disruption and/or preservation of language components is completed, an aphasia syndrome may be evident. Acute expressive and receptive changes are most commonly associated with vascular events; however, progressive changes can occur with degenerative disorders. There are many models and nosologies applied to language syndromes, and although described as discrete syndromes within the literature, they rarely occur in their purest forms. Generally, acquired language disorders can be separated into expressive, receptive, and mixed aphasias (Table 4.1). There are myriad models of language and aphasia with most language researchers identifying at least five types of aphasia. The distinctions vary in the presence or absence of deficits in expression, reception, and/or repetition. The most common term associated with expressive aphasia is Broca’s aphasia, a nonfluent aphasia. Because the underlying problem is language based, it differs from the articulation or motor aspects of speech, as in dysarthria or verbal apraxia. Agrammatism is the primary feature of Broca’s aphasia, where speech is labored and disjointed. Anatomically, Broca’s aphasia involves damage to Broca’s area (Broadmann area 44 and 45), which is within the dominant, posterior inferior frontal gyrus. In Broca’s Aphasia connector words are often omitted, making speech telegraphic. For example, a patient may describe their appointment as, “Hospital… two o’clock… Dr.  Smith.” Verbs and prepositions are omitted in this example. In Broca’s, comprehension is relatively preserved, but repetition is impaired. The latter point is the differential characteristic from Transcortical Motor Aphasia. Transcortical Motor Aphasia is a nonfluent aphasia, similar to Broca’s, but repetition is not impaired.

Table 4.1 Aphasias Expression Reception Expressive aphasias Broca’s or nonfluent aphasia Transcortical motor aphasia Receptive aphasias Wernicke’s or fluent aphasia Transcortical sensory aphasia Conduction aphasia Global aphasia + = intact; − = impaired.

Repetition

− −

+ +

− +

+ + + −

− − + −

− + − −

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Wernicke’s aphasia (a receptive aphasia) is a fluent aphasia, involving impairment of receptive language and repetition, but sparing in expressive speech. Anatomically, it is thought to involve Wernicke’s area (Broadmann area 22), an area in the posterior part of the superior temporal gyrus in the dominant hemisphere. Because the patient is unable to understand oral language, they fail to appreciate their own spoken language errors, tending to use real words, but their speech may be incomprehensible or frequent errors are evident. Their mixture of errors may produce a “word salad”. Similar to Wernicke’s aphasia, transcortical sensory aphasia produces fluent speech and impaired comprehension; however, repetition is not impaired. Conduction aphasia occurs when a patient has spared expression and reception, but repetition is impaired. This suggests a disconnection of primary expressive and receptive cortices and involvement of the arcuate fasciculus, although this has recently been brought into question (Bernal and Ardila, 2009). In these acquired aphasia syndromes, the most common etiologies of aphasia syndromes in the elderly are cerebrovascular accidents, and the most common vascular territory associated with aphasia is the middle cerebral artery. While cortical lesions are most commonly associated with aphasia, subcortical lesions may also produce aphasia. Aphasia can also occur as a primary or secondary feature of dementia. For example, primary progressive aphasia and semantic dementia may be categorized as subsets of FTD, and their primary presentation is that of language dysfunction.

Verbal and episodic memory Memory is a complex construct that has many different but overlapping conceptual models. Terminology varies widely depending on the orientation of the model and some are listed in Table 4.2. The major approaches to classifying memory and the associated terminology are discussed below.

Table 4.2 Examples of terminology used in conceptual models of memory Declarative Nondeclarative Episodic Semantic Procedural Skill learning Immediate Secondary Primary Working

Explicit Implicit Representational Dispositional Familiarity Reference Short-term Long-term Conditioning Priming

Temporal model One approach for classifying memory is to conceptualize it as an organization of systems for progressively longer periods of storage. In this approach, after attending to a stimuli (see attention, orientation, concentration section above) a representation of the material is kept in an immediate memory store. In immediate memory the information is stored for only moments. This memory store is limited not only in time but also can only hold a limited amount of information. This construct significantly overlaps with that of attention and working memory. For example, recalling a sequence of numbers immediately after presentation (e.g., digits forward) is  seen as a test of attention (“digit span” is sometimes used synonymously with attention span), but also meets the definition of immediate memory. Working memory is also seen as a very short-term store of information where bits of information are held while they undergo mental manipulation. Working memory can also overlap with concepts of attention and other constructs (e.g., some definitions of short-term memory). In a test sometimes used to measure “complex” attention, the patient is asked to repeat a sequence of numbers in reverse order (digit backward) that requires them to briefly hold the numbers in memory while manipulating their order. More complex versions of this (ordering sequences of numbers and letters, paced serial addition tasks) can detect subtle cognitive deficits, but tend to be nonspecific because of the overlapping constructs (sustained attention, immediate memory, working memory). Regardless, immediate memory can be conceptualized as a momentary memory that will be quickly degraded unless it is immediately refreshed (e.g., rehearsal) or transferred into a longterm memory store. A second temporal stage is short-term memory. This term is sometimes used synonymously with immediate memory in that it is the acquisition and retention of a memory trace for a measureable but brief period of time. The exact time period this term refers to is highly variable and some authors argue that it is not a meaningful construct as it may use the same neuroanatomic system as long-term memory, and therefore simply be a different stage of the same process (Brewer and Gabrieli, 2007). However, for clinical purposes short-term memory is usually defined as the retention of the material for a period of seconds to a few minutes. Thus, in a task requiring the patient to learn a list of words over a series of trials, the increase in the number of words recalled after each presentation (e.g., learning) is an aspect of short-term memory. The recall of the words after a delay of a few minutes—whether or not an interference list is given—has also been termed shortterm recall. The next temporal stage is long-term memory. As it implies, this term refers to the semipermanent to

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permanent storage of information over long periods of time. Again, there is no absolute minimum or maximum time frame that this term refers to. In clinical practice, retention of material after 20–30 minutes is said to enter long-term memory, although degeneration of the memory trace certainly continues after that point. Notably, significant disruption of long-term memory for hours or days prior to head injury (e.g., retrograde amnesia) indicating that the laying down of long-term memories (consolidation) is a continuing process. Remote memory is usually taken as a period of autobiographic memory (in geriatrics where the patient grew up, worked, was married, etc.), although this may also vary considerably between authors and often is simply considered an extension of long-term memory.

Characteristic model Another theoretical model has shown some success in parceling long-term memory into divisions based on the characteristics of the memory and the way they are expressed (Tulving, 1972; Schacter and Tulving, 1994; Squire and Knowlton, 1994). In this context, long-term memory is taken as the memory that has been consolidated and exists in a more stable form than immediate or short-term memory. The basic structure of this model is as follows. Declarative (explicit) memory: This type of memory involves the conscious recall of previous experiences. Two main divisions of this type of memory are episodic memory and semantic memory. • Episodic memory refers to the conscious recall of information linked to specific events (or episodes) that occurred in a specific context (time and place). Memories of specific instances from where someone grew up, went to school, a conversation with one’s spouse a week ago, what they had for breakfast today, or of a list of words they have read several minutes ago are examples of episodic memory. • Semantic memory refers to general knowledge about the world such as vocabulary, facts and concepts that are not contextually dependent. How we organize the world and its inter-relationships is an important aspect of this type of memory. For example, chairs may have very different forms, but we are able to associate them under the concept “chair.” Memories that have become generalized out of specific context (such as where one lived, who one’s relatives are) are also classified in this system (Warrington and McCarthy, 1988). Nondeclarative (implicit) memory: This type of memory is defined by a memory trace that is not consciously recalled and manifests in behavioral changes such as abilities (skill learning or procedural memory), habit formation, or priming effects. The ability of amnesic patients to alter behavior based on past

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events without conscious recall of those events has led to distinguishing this system from the episodic memory system (Mosccovitch, 2004). Several systems classified under implicit memory are clinically relevant, with procedural memory being perhaps the most important for patient functioning (Squire and Knowlton, 2000). • Procedural memory is based on learned abilities that we perform without conscious recall. Riding a bicycle, reading, writing, etc., are activities that we perform without conscious remembrance of the event or sequence. These abilities are often intact in dementia and other amnesic syndromes. • Priming phenomena can be seen as a nonconscious activation of memory traces that influence responses in ambiguous situations. The classic experimental demonstration of this is when subjects are asked to generate whole words from word fragments. Subjects tend to generate more words that they had been recently exposed to (primed) than other words that may be of higher frequency. • Classical conditioning is one of the earliest theories of learning in experimental psychology. It is based on the linking of a stimulus to an associated stimulus such that the presence of the associated stimulus alone will produce a similar response to that seen with the original stimulus. Animal studies and work with brain-damaged patients have indicated that different neural systems and structures underlie the different memory types above, supporting the validity of the model (Squire and Zola, 1996; Squire, 2009).

Modality model The nature of the stimulus can also be used to define memory systems. There is some evidence from imaging studies as well as patients with brain injury that different sensory systems use different storage networks in the brain (Wheeler et al., 2000). Clinically, verbal memory and visual memory are the modalities most often assessed. However, it should be noted that obtaining a “pure” measure of either is difficult as patients may verbalize the visual stimuli (e.g., describing drawings) and some may visualize the verbal material (e.g., visually linking items from a list). Other modalities have been assessed in the research literature, but are not commonly assessed separately in clinical practice. Stage model Clinically, a useful way of thinking of the memory process is by organizing it into a series of stages. Encoding (acquiring the memory), storage/consolidation (transferring into long-term stores) and retrieval (accessing the memory either into consciousness or as evidenced by

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behavior) is often used as a general guideline when conducting an assessment. Encoding: Seen as the initial stage in memory formation, encoding includes several processes. The patient must first attend to the particular stimuli to be encoded; this information is processed by the appropriate modality systems (e.g., verbal, visual, etc.) and linked with associated stimuli (context). This is usually seen as an active process as opposed to a passive reflection of sensory information (Blumenfeld and Ranganath, 2007). Storage: Consolidation is the transfer of the processed memory into a form that can be maintained over time without conscious rehearsal. Rather than a unitary process, consolidation appears to take place by multiple functional systems, molecular mechanisms, and structural changes. Further processing of the memory may occur at this stage and some authors have suggested that the postencoding process may continue to operate for years as new information is acquired and linked to previous memories (Brewer and Gabrieli, 2007). Delayed proactive interference and retroactive interference effects seen in normal individuals and retrograde amnesia that may occur for hours or days prior to brain injury appear to support this. Retrieval: Retrieval of an encoded and stored memory may take several forms in clinical assessment. Free recall is the ability to bring to consciousness a memory without any external or related associated stimulus (reminders). Cued recall involves the presentation of an associated stimulus to aid in recalling. Many mnemonic techniques will involve associating an external stimulus with an item to be remembered to both enhance encoding and recall (e.g., a person’s facial feature with their name). Clinically, cued recall may be done by providing semantic cues (the word was a type of fruit), phonemic cues (it began with the sound a…), or others (there were two figures on the page). Recognition is a third clinically useful construct where the patient is presented with the actual target item and several distracters and asked to identify the original item. Differences in the relative performance on free recall versus recognition tasks have been suggested to be useful in differentiating between some progressive dementias (see preclinical diagnosis of dementia section below). Familiarity is a related but slightly different construct. In familiarity the patient is aware of having encountered the stimulus before, but is not able to attach any context to the memory (e.g., source memory). Other terms and models exist for memory but they are less often used in clinical practice and some suggest the integration of several domains and complex neural circuits. Metamemory is a complex construct that includes judgment of learning, feeling of knowing, and other

memory self-monitoring-related phenomena (Pannu and Kaszniak, 2005). Prospective memory is the ability to remember to do something in the future (either time or event based), and involves not only declarative/episodic memory but also frontal EFs such as self-monitoring (Fish et al., 2010). While the above terms may be derived from different models of memory, they are complimentary and can be used together. In clinical practice, measurement of memory weighs heavily on verbal episodic memory tasks with visual episodic memory also assessed, but often to a lesser degree. Semantic memory can be assessed, but it is often done as part of the language examination (e.g., category fluency). In geriatric neuropsychology the most common tests of memory include learning lists of words (Rey Auditory Verbal Learning Test, California Verbal Learning Test, Hopkins Verbal Learning Test-Revised) or short stories (WMS logical memory), although there are multiple variations on administration (e.g., repeating the entire word list versus selective reminding—repeating only the words not recalled on the last trial) and the nature of the stimulus (unrelated word lists, semantically related word lists, etc.). Most of these tests follow the initial learning stage with a free recall after a few minutes delay (shortterm delay) and after a longer delay of 20–40  minutes (long-term delay). Multiple variations in delayed recall conditions are also present including cueing trials, recognition trials and/or forced choice trials (e.g., choose between the target word and one distractor word). In addition to individual instruments, most comprehensive memory batteries will contain these elements (Repeatable Battery for the Assessment of Neuropsychological Status; Wechsler Memory Scale; Wide Range Assessment of Memory and Learning, etc.).

Executive abilities/function The frontal lobes comprise about 30% of the cortical surface, and EAs/EFs are an important component of frontal lobe functioning. Many structures (i.e., temporal lobe, basal ganglia, cerebellum, etc.) have reciprocal projections to the frontal lobes, so damage or disconnection to or from these areas may result in executive dysfunction (Ravizza and Ciranni, 2002). There is no uniformity in the way EFs  are defined, conceptualized, or measured; however, EAs are broadly related to the higher-order functions that co-ordinate and manage other cognitive processes and allow individuals to engage in goal-oriented behavior. EF is measured by behavioral outflow, but involves the steps from ideation to behavioral execution. EF cannot be simply measured by asking patients what they would do in a certain circumstance, since ideation may be disconnected from the actual behavior. Patients may be able to verbalize what they should do, but they are unable to carry it

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out. Efficient EAs allow interaction with the environment by developing and implementing effective strategies while inhibiting impulsive, ineffective strategies. Behavior must be analyzed and modified according to internal and external feedback. There are discrete components to EF and as with other models of cognitive functioning there are multiple theoretical models of EF (Norman and Shallice, 2000; Miller and Cohen, 2001). Although separate from other cognitive domains, EAs are both independent and interdependent from other domains. Aspects of EF are included in Table 4.3. Neuropsychologists use different measures and techniques in attempting to isolate these features; however, task demands make this difficult or impossible. Most cognitive measures are multifactorial and require several aspects of EF in addition to other domains. Behavioral disturbance can be manifested in components of inhibition, problems stopping a behavior, difficulty in making mental or behavioral shifts, concrete thinking, and deficits in self-awareness assessment. Initiation involves spontaneously starting ideation and behavior. When there is severe impairment in ideation, patients fail to start thinking or acting. Family members describe that they have stopped doing activities that they once enjoyed (i.e., hobbies, reading, etc.), and they may sit for extended periods of time without doing anything. Within the clinical setting, they lack spontaneous speech and may appear lethargic and apathetic. Fluency is a common metric for assessing initiation within the clinic, but a poor score may be related to other factors (i.e., retrieval, aphasia, semantic loss, etc.). As it relates to initiation, verbal or design fluency may be diminished because of the lack of spontaneous creativity, and patients have slow, minimal output. Once a behavior is started, EAs then must stop the ongoing behavior. The established response tendency must be inhibited and unwanted responses resisted. Problems in suppressing activity can result from impulsivity, disinhibition, or over-reactivity. A simple clinical technique for assessing behavioral disinhibition is a go/no go paradigm. In screening, a patient can be told to tap his/her leg once when the examiner touches their leg twice and vice versa. The task requires the suppression of copying the examiner’s behavior as well as maintaining the alternate pattern. Several neuropsychological tests may pull for inhibition, including proximity errors on Trail Making B and commission errors on computerized continuous performance tests. Table 4.3 Functions subsumed under executive functioning (EF) Organization

Abstract thinking

Inhibition

Planning

Cognitive flexibility

Selecting relevant stimuli

Problem solving

Initiation

Strategizing

Managing time and space

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Individuals with executive dysfunction may also have a deficit in mental or behavioral shifting. Inflexibility, cognitive rigidity, being “stuck” in a response set, and perseveration are hallmarks. Asking patients to do a task and then having them shift their thinking can elicit evidence of inflexibility. Most neuropsychological tests of EF (i.e., Halstead Category Test, Wisconsin Card Sorting, etc.) do not tell patients what the rules are, and do not tell them when the rules have changed. Thus, the patient is not only required to solve the problem to find the correct response set, but they must then alter their thinking and behavior in response to negative feedback. When one examines the quality of error responses, a pattern of concrete thinking may be apparent. Concrete thinking may appear as literal explanations and interpretations. As opposed to “being stuck” in a response set, patient responses lack a deep understanding of concepts, and stimuli are taken at their obvious face value. Common clinical assessment involves asking the patient similarities, such as “In what way are an apple and orange alike”. Concrete answers involve obvious physical characteristics, like the fact that they are round or “can be different colors”. At times, patients will respond with how they are different (i.e., “one is red and one is orange”) or they may personalize the response (i.e., “I like apples, but I don’t like oranges”). A more integrated response will be the identification that they are edible and an abstract understanding will be that they are both fruits. Longer forms of the similarities task are found in neuropsychological testing, in addition to other tests such as the 20-questions and proverbs subtests of the Delis–Kaplan Executive Functions System (Delis et al., 2001). Self-monitoring and self-assessment are critical components for effectively appraising oneself and using the information to effectively alter behavior. In executive dysfunction, patients may be unable to perceive their performance errors, their impact on others, and lack social awareness. They make errors, but are unable to accurately recognize their poor performance. There is no formal test to measure this ability, but asking patients to evaluate their clearly poor performances is one way to assess this. For example in Figure 4.2, the patient was asked to draw a clock. After doing so, the patient spontaneously offered, “I’m sure you can’t tell what it is, but it looks right to me.” In this case, the patient appreciated that something seemed wrong, but perceived the drawing as correct. This lack of awareness of his impairment is anosognosia, and can create problems when a patient wants to continue activities in which they can no longer do well (driving, cooking, finances, etc.). Because patients may lack self-awareness or may inaccurately assess personality changes, collateral interviews may prove useful. Family members often raise this issue as the most disconcerting change in dementia and frontal cerebrovascular accidents. Social interactions may be

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Figure 4.2 Clock-drawing test.

marked with disinhibited, inappropriate responses, which are changes from the patient’s premorbid status, but the patient is unable to appreciate this. Also, sexual talk and sexual behaviors (including public masturbation) may occur. Rating scales, such as the Frontal Systems Behavior Scale (FrSBE; Grace and Mallow, 2001) can help to detect and group these behaviors, and provide some measure of the patient’s insight into them. The patient completes an FrSBE self-rating that can be compared to the ratings from an informant who is in regular contact with the patient. There is considerable variability to the behavioral manifestations of EAs. Not all facets of EF can be measured through psychometric testing, and there is considerable variability among patients. Different conceptualizations may have overlapping neuropathologic correlates and interconnections. Common frontal subcortical pathways mediate executive activities, speed of information processing and working memory where executive control is needed; however, these “frontal systems” may have subsystems. Miller and Cummings (1999) described three circuits within the frontal lobe—orbitofrontal, dorsolateral, and anterior cingulate. Persons with orbitofrontal injuries may not demonstrate impairment on neuropsychological testing, but they may display neurobehavioral manifestations of irritability, impulsivity, disinhibition, and they may show an inappropriate response to social cues, lack of empathy, and over-familiarity. Dorsolateral lesions have been associated with poor organizational strategies, poor memory search strategies, stimulus boundedness, and impaired set shifting and maintenance. Anterior cingulate lesions may manifest in apathy, poor response inhibition,

and poverty of speech (Miller and Cummings, 1999). These theoretical distinctions are infrequently seen in pure forms because injuries and degenerative processes involve multiple frontal areas, and damage to other connected areas may produce behavioral changes. Executive dysfunction can interfere with the functioning of other cognitive (particularly memory) domains. For example poor organization may be reflected in relatively poor learning on a memory test that benefits from the ability to organize a word list into semantic categories (e.g., California Verbal Learning Test-II and Hopkins Verbal Learning Test) (Delis et al., 2000; Brandt and Benedict, 2001). Thus, poor semantic organization (an EF) may be related to a poor learning score on the CVLT-II. In contrast, the same patient’s memory score may not be impaired on a test that does not benefit from this organizational strategy (i.e., Rey Auditory Verbal Learning Test, etc.) (Rey, 1964). Similarly, a patient’s visual drawing memory score for simple figures (i.e., Wechsler Memory Scale-III) (Wechsler, 1997b) may not be impaired, but their figure memory score may be impaired on a task with high organizational demand (i.e., Rey–Osterrieth Complex Figure) (Rey, 1941). Functionally, expression of executive dysfunction may be dependent on environmental demands. Older individuals who are still working may demonstrate changes in organizing time, space, and multitasking beyond what would be expected with normal aging. Colleagues, friends, and family may notice these changes before the person is aware of them. For those no longer working, subtle changes may only be noticed by those living with the patient, but subtle changes may affect self-care and safety awareness to the point of the person needing a higher level of care. Executive dysfunction may predict loss of autonomy independent of—or more than—memory loss (Royall et al., 2005; Tomaszewski et al., 2009).

Visuospatial abilities As with other domains, visual processing and construction dysfunction can occur due to complex and multifactorial reasons, including perceptual, spatial, or processing errors. For example, impairment in clock drawings may be secondary to conception, perception, spatial analysis, or construction. Efficient visuoconstruction relies on cerebral integration within the temporal–parietal–occipital association areas. Thus, lesions or dysfunction in any of these areas or within their interconnections by-produce visual misperceptions, such as agnosias (color, familiar or unfamiliar faces, and objects). In these instances, a patient may incorrectly name an item they see. It is not uncommon for misperceptions to be misconstrued as naming deficits. Visuoperception involves the detection, visual analysis, and synthesis. Ware (2004) offers a three-step model of

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visual perception based on detection, pattern analysis, and integration of attention and memory. In the first stage objects undergo detection for color, texture, shape, and spatial detection. In the second stage regional and simple pattern analysis occurs, and in the third stage objects are held in working memory by attention (Ware, 2004). Mishkin and Ungerleider 1982 theorized two pathways of visual analysis—the ventral stream and the dorsal stream. After visual information leaves the occipital lobe the ventral stream projects to the temporal lobe and is involved with object identification (the “what pathway”). Symbolic representation takes place within the ventral system, drawing from limbic and medial temporal memory areas. The dorsal stream projects from the occipital lobe to the parietal lobe where this “where pathway” processes spatial location. Spatial awareness from the dorsal stream then guides meaningful actions (Mishkin and Ungerleider, 1982). The ventral and dorsal streams are theorized to be interconnected, thus integrating visual information in meaning and space; however, this theory is controversial because of the complexity of the visuoperception. The complexity of this system necessarily means that it does not localize or lateralize. Both hemispheres are involved with aspects of visual synthesis. Visual images are processed as wholes and as parts. Delis et al., 1992 and others describe that in analyzing complex visual stimuli, the nondominant hemisphere analyzes configural (or global) features. In contrast, the dominant hemisphere processes visual stimulus details (or local features) (Delis et al., 1992). Differences in global–local errors were used to identify asymmetric profiles in AD and other cerebral changes, and this emphasizes the importance of qualitative visual analysis. Spatial cognition can be measured by many techniques (i.e., discrimination, recognition, drawing, 2D and 3D construction). Clock drawing and the MMSE figure are common clinical office drawing tasks. Errors on these relatively simple tasks can reveal qualitative subtleties, and these qualitative features may illuminate underlying conceptualization impairment or spatial inattention. For example, in Figure 4.3, the patient was unable to conceptualize the clock. This type of error is qualitatively different from errors in which all the numbers are present but misplaced (i.e., planning error). Also, perseveration is evident with three numbers being repeated, and the patient failed to appreciate how poor this drawing was. Expanded neuropsychological visuospatial testing may include noncomplex drawings (i.e., Benton Visual Recognition Test, WMS-III Visual Reproduction Copy) (Benton et al., 1983; Wechsler, 1997b) and complex drawings (i.e.,  Rey–Osterrieth Complex Figure, Taylor Complex Figure) (Rey, 1941; Taylor, 1969). Block construction (i.e., WAIS-III Block Construction) and other measures are commonly used for spatial cognition; however, the timed nature of these tasks may affect the score (Wechsler, 1997a).

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Figure 4.3 Clock-drawing test.

In Figure 4.4, the patient was not only unable to correctly draw the house and cube in three dimensions, they demonstrated left hemispatial inattention, although they had full visual fields. The left side of the house was missing, and the patient was unable to effectively scan to the left hemi space. This case highlights the difference between a field cut (i.e., homonymous hemianopsia) and hemi-inattention (also called visual inattention, visual neglect or visual extinction); however, the presence of the former increases the possibility of coexisting hemiinattention (De Renzi, 1978; Diller and Weinberg, 1977). Greater hemi-inattention deficits are generally more common in acute stages of traumatic event (i.e., CVA) than degenerative disorders.

Figure 4.4 House-drawing test.

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Clock, house, and cube examples of 2D and 3D constructional drawing are often used, but because they involve motor skills, clinicians may not be able to rule out a perceptual or motor deficit. Perception must be intact for accurate drawings. Neuropsychologists may use visual discrimination (Visual Form Discrimination Test) and line orientation (Judgment of Line Orientation) to assess nonmotor perception (Benton et al., 1983). Facial recognition is a complex process, although it is not typically assessed as part of the neurologic examination. Healthy adults can discriminate very subtle aspects of facial features and expressions. Prosopagnosia is the inability to recognize familiar faces, but impaired facial recognition can also occur in discriminating unfamiliar faces. Neuropsychological assessment can measure facial recognition through a Famous Faces Test, facial discrimination with the Benton Facial Recognition Test (Benton et al., 1983), and facial recognition with the Warrington Recognition Memory Test (Benton et al., 1983). Higher-level visual integration can be measured with the Hooper Visual Organization Test (Hooper, 1958), where pictures have been cut into pieces and must be mentally rotated and spatially integrated before being recognized.

Neuropsychological profiles of disorders in geriatric neuropsychology The basis of using cognitive profiles to diagnose disease, predict behaviors and guide treatment is the principle that the cognitive deficits accurately reflect a characteristic dysfunction or degeneration of the underlying neural network. For example, if the disease primarily affects the hippocampal system then the cognitive profile should reflect a primary episodic memory deficit. If the dorsolateral prefrontal regions are affected then an executive dysfunction should predominate (Cummings, 1993). A caveat to this concept is that if a morphologically defined disease such as AD (presence of neuritic plaques and neurofibrillary tangles) damages the brain in a distribution other than what is prototypical for that disease (e.g., as in a frontal variant of AD, with significant early neurodegeneration in the frontal lobes), then the cognitive profile can be expected to reflect the neural degeneration pattern rather than the disease etiology that underlies it. The following sections provide a brief neuropsychological overview of some common disorders that can affect cognitive function in the elderly. The reader is referred to individual chapters in this text for more details on each disease.

Mild cognitive impairment MCI is an attempt to detect dementia at an early stage, prior to the impairments becoming clinically significant. The basis for the diagnosis is performance in one or more cognitive domains that are lower than expected for an

individual, but do not yet indicate a significant decline in the ability to function. In the most widely utilized diagnostic guidelines (Petersen and Smith, 1999), four criteria are set out for the diagnosis of MCI. Two of these are based on interview (subjective memory complaint, no significant decline in daily function), one is based on cognitive assessment (objective impairment in one or more cognitive domains) and one synthesizes these elements (does not meet criteria for dementia). These elements have been retained and further refined in a recent set of diagnostic criteria from a joint effort of the National Institute on Aging and the Alzheimer’s Association (Albert et al., 2011). Sources of variability in standardization of this diagnosis include determining if a “significant decline in daily function” exists (e.g., in the case of a retired senior with multiple medical issues living in an assisted living environment) and in the criteria for detecting an objective impairment in cognition. Because of this, diagnosis of MCI has ranged from 10% to 74% depending on the criteria used (Portet et al., 2006; Jak et al., 2009). While the minimum level of objective cognitive impairment varies in different studies, cut points of 1.0 or 1.5 standard deviations below the mean are the most commonly used (Albert et al., 2011). MCI is not a unitary construct and various “MCI subtypes” exist. The classic MCI profile is characterized by impaired performance on standardized episodic memory tasks (word lists, paragraph recall, selective reminding test) and is denoted as amnesic MCI (aMCI). This profile is believed to lead to the most common form of dementia in the elderly, AD. MCI profiles that indicate nonmemory systems primarily affected are designated as non-aMCI and it has been suggested that the cognitive areas affected have some predictive value for the type of dementia that will develop (Petersen and Morris, 2005; Petersen, 2003). For example, if the frontal executive domain is the most severely impaired, then an FTD might be predicted. Often, more than one area may show impairment and when multiple cognitive areas are impaired, this is termed multidomain MCI. Multidomain MCI is sometimes further broken down into a multidomain aMCI (characterized by impairments in memory and at least one other domain) and multidomain non-aMCI (characterized by relatively intact memory performance, but impaired performance in two nonmemory domains) (Petersen, 2003). Since this diagnosis requires detection of deficits at an early stage, tests that are prone to ceiling effects (e.g., MMSE, Mini-Cog) are often insufficient. Since the predominant form of MCI is the amnesic type (single or multidomain), verbal delayed free recall tasks with greater sensitivity at the higher levels of function (e.g., Rey Auditory Learning Test, California Verbal Learning Test, Selective Reminding Test, WMS-R logical memory) tend to be most sensitive to the early deficits (Jak et al., 2009; Albert et al., 2011).

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While there is some probabilistic validity of using MCI as a predictor of incipient dementia, it is not entirely accurate. Studies have shown wide ranges of sensitivity (46–88%) and specificity (37–90%) in predicting conversion to AD (Visser et al., 2005; Rasquin et al., 2005). Identification of the underlying etiology by MCI subtype has also been shown to be questionable (Jicha et al., 2006). Longitudinal assessment showing further decline in cognitive function may add to the diagnostic certainty; advanced imaging techniques and biomarkers may further support the diagnosis, but are not yet suggested for clinical use (Albert et al., 2011).

Alzheimer’s disease AD is the most prevalent cause of dementia in the elderly. It frequently is the primary etiology of the cognitive decline, but also has a high co-occurrence with pathology seen in other diseases such as LBD and vascular ischemia. Its clinical diagnosis has traditionally been designated as either “possible AD” or “probable AD”, with a diagnosis of “definite” AD reserved for autopsy confirmation of the presence of the defining neuritic plaques and neurofibrillary tangles (McKhann et al., 1984; Storey et al., 2002; Hort et al., 2010; McKhann et al., 2011). Revision of the original NINCDS–ADRDA criteria (McKhann et al., 1984) by a joint work group of the National Institute on Aging and the Alzheimer’s Association kept the basic structure of the probable and possible definitions for their clinical criteria, while adding an additional division of research criteria that incorporates imaging and other biomarkers (McKhann et al., 2011). Cognitive testing with evidence of impairment in two or more areas is required, with neuropsychological testing recommended when bedside mental status testing is not sufficient for a “confident” diagnosis. AD has been called the prototypical “cortical” dementia because of the typical clinical presentation of impaired episodic memory as the first clinical sign. The overall cognitive decline is characterized by gradual onset and a progressive course. Neuropsychological tests sensitive to the typical AD presentation include learning and recall of word lists or paragraph-length stories, with impairments noted in learning, free recall, cued recall and recognition of the material. In the early stages free recall may be the most notably impaired, as recognition tasks often have low sensitivity due to ceiling effects. As the pathology spreads through the frontal lobes, executive dysfunction is typically noted on such tests as category fluency and Trails B. In the mild-to-moderate stages, performance on category fluency (e.g., animals) is typically seen to be more impaired than letter fluency, reflecting the early involvement of the frontal systems and the later spread to the language areas. Impairment in confrontation naming can be clinically observed in the moderate stages, but can be detected in earlier stages by instruments such as the Boston Naming Test.

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Frontotemporal dementia FTD encompasses several conditions that are characterized by degeneration of the frontal and/or temporal lobes (Pick’s disease, semantic dementia, primary progressive aphasia, dementia lacking distinctive histopathology). The most common presentation of FTD begins with personality and behavioral changes preceding or concurrent with the cognitive decline. The nature of the personality change varies, but may present as apathy (medial frontal/ anterior cingulated syndrome), disinhibition and inappropriate social interactions (orbitofrontal syndrome), loss of insight, or perseverative behaviors. The behavioral changes can sometimes be striking, and they represent an important factor in the diagnosis of the disease and as a target of treatment (Cummings, 1993; Kertesz, 2006). As would be expected, the profile of cognitive deficits reflects the distribution of the neuronal damage. FTD may present with executive dysfunction (dorsolateral prefrontal syndrome), a progressive decrease in speech output (primary progressive aphasia), or an impairment in understanding word meaning (semantic dementia) that is relatively more severe than the deficits in episodic memory—a profile opposite to that seen in AD (Cummings and Trimble, 2002). At the earliest stages of the dysexecutive syndrome a formal assessment of cognitive flexibility, multitasking, set switching, and higher-order conceptualization can detect deficits in the presence of only minor memory impairment. Performance on verbal fluency tasks may also show a pattern opposite to that seen in AD, with letter fluency being relatively more impaired than category fluency in FTD. The meaning of visuospatial deficits in FTD is somewhat ambiguous, as some tasks that involve complex stimuli (e.g., Rey–Osterrieth Complex Figure task) can show proportionate deficits, while others with a lower degree of complexity appear relatively spared (e.g., Block Design) (Salmon and Bondi, 2009). At the later stages of the disease, most cognitive functions can become affected and differentiation from other dementia types becomes dependent on an accurate history of the course of the disease. Primary progressive aphasia is a gradually progressing nonfluent expressive aphasia that initially presents with minimal impairment in memory or other cognitive functions, although most patients will progress to dementia with time (Mesulam, 1982; Rogalski and Mesulam, 2009). Clinically it is primarily characterized by a nonfluent expressive aphasia with phonemic paraphasias, anomia, and deficits in repetition (Neary et al., 1998). Comprehension and other cognitive areas are relatively intact in the initial stages, although the expressive impairments can make testing of verbal episodic memory difficult. Semantic dementia is a relatively rare condition that initially presents as a progressive fluent expressive aphasia. In this condition the patient begins to lose the meaning of words and concepts despite intact grammar and

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syntax (Snowden et al., 1996). Patients demonstrate fluent but empty spontaneous speech, semantic paraphasias, impaired naming, and comprehension due to loss of word meaning, while reading, writing, and repetition are typically intact (Neary et al., 1998).

Parkinson’s disease dementia Parkinson’s disease is initially a predominately motor disorder characterized by rigidity, bradykinesia, and tremor. The morphologic characteristics are defined by neuronal death and presence of Lewy bodies in brainstem nuclei (particularly the substantia nigra), and loss of dopaminergic inputs into the neostriatum and neocortex (Levy and Cummings, 2000). As the disease progresses, cognitive impairment becomes more prevalent, and estimates of dementia range from 25% to 40% prior to death (Hughes et al., 1993). Autopsy studies show that comorbid AD pathology occurs not infrequently, but the development of dementia is more strongly correlated to the presence of Lewy bodies in the cortex than AD pathology (Hurtig et al., 2000). Cognitive characteristics of PDD can include alterations/fluctuations in arousal and complex attention, impairment in EFs and memory retrieval deficits. Visuospatial deficits are also reported (Emre et al., 2007) but there is some controversy in the literature as to whether these are primary deficits or a consequence of other deficits (e.g., executive dysfunction) (Grossman et al., 1993). The pattern has been classified as a typical “subcortical” dementia because of the early prevalence of the attentional, visuospatial, and executive deficits combined with the type of memory impairment observed (Albert et al., 1974; Bondi et al., 1996). This memory deficit differs from the characteristic “cortical” amnesia (e.g., as in AD) in that the performance on recognition memory tasks appears relatively better than free recall, suggesting a problem with the retrieval mechanism rather than storage (as in AD). The executive dysfunction can be seen in tasks that involve set shifting (e.g., Wisconsin card sort, Trails B) and concept formation (Category test) (Duke and Kaszniak, 2000). Attempts to diagnose PDD at a MCItype stage have indicated significant early heterogeneity (Caviness et al., 2007; Adler, 2009). Notable AD pathology can occur in PDD and may result in a “mixed” cortical/ subcortical profile (Levy and Cummings, 2000).

Dementia with Lewy bodies The morphologic basis of DLB overlaps with that of Parkinson’s disease and the diseases can be difficult to distinguish at autopsy. Clinically, the disorders are distinguished by the relative appearance of significant motor signs sufficient for the diagnosis of Parkinson’s disease (PD) at least 1 year before the dementia (PDD), or the cognitive impairment is observed in the early stages of the extrapyramidal motor symptom onset (DLB). In DLB

eosinophilic intracytoplasmic neuronal inclusion bodies are present in both cortical and subcortical areas. Like PD, the Lewy bodies are prevalent in substantia nigra and locus coeruleus; however, the distribution tends to be more widespread across the cortical and limbic areas (McKeith, 2000). Clinical presentation includes mild parkinsonism (rigidity, bradykinesia, and masked facies), recurrent and well-formed hallucinations, and fluctuating cognition (McKeith et al., 2005; Weisman and McKeith, 2007). However, these clinical signs are not present in all patients with autopsy-confirmed DLB (Tiraboschi et al., 2006), and differential diagnosis with other conditions continues to be a challenge. Comorbid AD pathology is common, and can make the cognitive profiles difficult to be distinguished in individual patients (Hohl et al., 2000). However, at the mild stage, DLB may manifest greater attentional, visuospatial, constructional, and executive deficits relative to the memory and naming impairments than is typical for AD, and the pattern of impairments between category and letter fluency tend to be the reverse of that seen in AD (e.g., in DLB, letter fluency is as impaired or more than category fluency) (Metzler-Baddeley, 2007). Profiles on the subtests of the Mattis Dementia Rating Scale (Connor et al., 1998) and on the California Verbal Learning Test (Hamilton et  al., 2004) have been moderately successful in distinguishing the two diseases in autopsy-verified cases. Distinguishing LBD from other neurodegenerative disorders such as PDD, PSP, and corticobasal degeneration (CBD) is often based on the characteristic motor findings and clinical progression of each disease.

Progressive supranuclear palsy PSP is a tauopathy that is clinically diagnosed by the presence of a supranuclear gaze palsy, axial rigidity, pseudobulbar palsy, and falls. Tremor is not usually present. Autopsy results show neurofibrillary tangles, granulovacuolar degeneration, and cell loss in the midbrain, globus pallidus, and thalamus. Dementia is characterized by a subcortical profile including deficits in attention, EF, and visuospatial abilities early in the course of cognitive decline (Albert et al., 1974). While neuropsychological testing is useful for early detection of the cognitive deficit, differential diagnosis from other parkinsonian-like dementias (corticobasal ganglionic degeneration, multiple system atrophy, etc.) is usually based on the neurologic signs.

Corticobasal ganglionic degeneration Corticobasal ganglionic degeneration (CBGD) is a relatively rare disease with notable asymmetrical degeneration of the frontal–parietal cortex and substantia nigra degeneration. Clinically, it often presents with an asymmetrical, focal motor apraxia, and asymmetrical dystonia, rigidity, bradykinesia, and tremor. In a subset of patients,

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the cognitive changes may be evident prior to the motor signs (Murray et al., 2007). As mentioned for PSP, it presents with a subcortical profile and the cognitive profile is difficult to distinguish from other Parkinson-plus syndromes (Wadia and Lang, 2007).

Vascular dementia VaD is a heterogeneous dementia that can result from a single large stroke, multiple smaller infarctions (multiinfarct dementia), or small vessel diseases that cause ischemic damage to multiple areas of the brain. As such the clinical presentation and neuropsychological profile varies widely. A detailed history (step-wise pattern of deterioration), neurologic examination, and imaging combined with the psychometric testing can both solidify the diagnosis and provide valuable information regarding the nature of the cognitive deficits for treatment planning. Some forms of VaD may not show the step-wise decline and the results of imaging may be unclear (e.g., diffuse white matter pathology). In these cases a “subcortical” pattern of deficits on formal testing may help differentiate the etiology of the dementia. As such, impairments of EF that equal or exceed those of memory function are more indicative of a subcortical process than a cortical dementia (e.g., AD) (Reed et al., 2007). However, a broadbased neuropsychological battery that encompasses all cognitive domains (attention, language, visuospatial, memory, EF) is usually necessary to identify and characterize the impairments.

Delirium Delirium is an acute confusional state characterized by fast onset, deficits in attention, orientation, and fluctuating levels of arousal. It may present as a sudden change in a cognitively intact adult, or as a sudden decline in a cognitively impaired patient. It is important to diagnose this condition early and run a full medical work-up as a serious and life-threatening medical condition may underlay the delirium. Brief cognitive assessment is sufficient to detect most cases. Neuropsychological assessment may be of use in differentiating mild cases (medication interactions, low-grade infections, etc.) from the normal progression in a patient who already has dementia.

Depression There is a complex relationship between depression and dementia as each can be a risk factor for the other and they often co-occur (Wright and Persad, 2007). In the elderly, depressive symptoms often include memory complaints and the cognitive inefficiencies of depression can be difficult to distinguish from early dementia. However, quantitative and qualitative assessment can aid in the diagnosis and treatment of each as individual or comorbid diseases (Kaszniak and DiTraglia-Christenson, 1994; Potter and Steffens, 2007).

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Preclinical diagnosis of dementia Despite the advances in neurosciences of the last few decades, no treatment or intervention has been shown to halt or reverse the course of most progressive dementias. It has been suggested that if treatments are instituted before extensive damage has been done to the neural network, then disease progression is more likely to be slowed (disease modification) or even temporarily halted (DeKosky, 2003). In an elderly population, even a delay in onset of 5 years has been suggested to reduce the occurrence of the disease by half. The concept of diagnosing a disease before the clinical symptoms become apparent is not new and is used in many branches of medicine (e.g., cardiovascular, hepatic, etc.). In most of these conditions, a laboratory test indicates an abnormal value either in the presence of only minimal (or no) clinical complaints. As discussed in a previous section on MCI, a cluster of symptoms (MCI) have been suggested to be predictive of progression to a clinical dementia. However, most definitions of MCI require some clinical signs/impairments that, while not reaching the full criteria for dementia, may only be apparent after there has been significant damage to the underlying neural network. In the diagnosis of dementia, research into a preclinical diagnosis has several significant challenges including lack of a definition of “preclinical”, inability to sample brain tissue while the patient is alive, questionable specificity and sensitivity of noninvasive biomarkers in the general population, and poor prediction of progression to MCI or dementia in patients who may be positive for the biomarker (Backman et al., 2005). The accepted definitions of preclinical dementia vary widely and may overlap with those of MCI or similar classifications (e.g., cognitive impairment not demented) or may be seen as the stages preceding any abnormal cognitive measures (Backman, 2008; Guarch et al., 2008). This range of definitions has led to significant confusion in the literature and in estimates of prediction of progression to dementia. Recently a definition of preclinical dementia for AD has been published offered by a joint NIA–Alzheimer’s Association workgroup for Preclinical dementia (Sperling et al., 2011). As emphasized several times in their publication, this definition is for research purposes only and should not be used in clinical practice. In their conceptualization of preclinical dementia there are no notable declines in the patient’s ability to function and no evidence of significantly impaired cognitive function, thus it prestages MCI. The three-stage categorical model suggested by the workgroup reflects the current beliefs in the development of the pathology underlying AD. Briefly, the first stage reflects detection of amyloidosis in the brain (by CSF- or PET-amyloid imaging), in the second stage there is additional evidence of neuronal degeneration (by FDG-PET, volumetric MRI, etc.) and the third evolutionary stage

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includes the presence of the previously mentioned markers along with “subtle cognitive decline”. As the authors point out, this third stage approaches the border of the definition of MCI, the main differential being that the subtle cognitive decline here may only be evident as a change from the individual patient’s previous level of functioning and not be abnormally below the performance of an age and education-matched cohort. This general approach of identifying changes in the basic elements that define the disease (amyloid for AD, Lewy bodies for LBD, etc.) followed by the physical/physiologic consequences of those elements (disruption of neural transmission, neuronal cell death, etc.) and finally by subtle clinical signs (decline in function from previous abilities) appear a reasonable approach toward guiding the investigation into the “preclinical” evolution of various dementias. It should be emphasized that the preclinical diagnosis of any of the dementing disorders (AD, vascular, Lewy body, FTD, etc.) is a vital and important research area. However, until appropriate definitions can be agreed on, clarification of concepts provided (e.g., determining if a marker is a risk factor or an early stage of the disease) and predictive values assessed for the individual patient, it appears far too early to utilize the research results in clinical guidelines.

Conclusion Neuropsychological assessment utilizing well-established techniques can be a useful addition to the physician’s resources in geriatric neurology. Assistance in early diagnosis, differential diagnosis, assessment of the patient’s deficits and remaining strengths as well as information to help guide the treatment may be obtained from a proper assessment. While there are many theories and models in cognitive psychology, several that address five major domains of cognition (attention, language, memory, EF, visuospatial skills) have shown to be useful in modeling the functions affected in dementia and brain dysfunction. As technology advances and biomarkers (e.g., biochemical and imaging) of the central nervous system disorders become a more important part of the clinician’s resources, careful direct assessment of cognitive functions will continue to offer complementary information for the best treatment of the patient.

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Chapter 5 Cognitive Reserve and the Aging Brain Adrienne M. Tucker1 and Yaakov Stern2 1

Cognitive Science Center Amsterdam, University of Amsterdam, Amsterdam, The Netherlands Cognitive Neuroscience Division, Department of Neurology, Columbia University Medical Center, New York, NY, USA (Financial support provided by National Institute of Aging (NIA)—grants T32 AG00261 and R01 AG026158) 2

Summary • Cognitive reserve, which is often estimated with education and IQ, is the ability to make flexible and efficient use of available brain reserve during tasks. It has been found to be protective against the cognitive outcomes of brain injury. • Cognitive reserve is reflected in neural reserve and neural compensation. • Neural reserve allows healthy individuals more efficient processing (processing which requires less neural activity) as well as higher processing capacity (the ability to recruit more neural activity when task demands are high). • Neural compensation is the activation of alternate brain regions to compensate for deficiencies in individuals with brain impairments. • Young adults with high cognitive reserve display greater neural efficiency. This may be a result of better or more efficient use of strategies. • Neural markers for cognitive reserve may differ between younger and older adults. This may be an indication of compensatory reorganization during aging. • Activation patterns related to cognitive reserve are reversed between healthy older adults and individuals with Alzheimer’s. • Individuals with high cognitive reserve may present with pathology without functional deficits. Thus, accounting for cognitive reserve in addition to the underlying pathology may aid clinical judgment.

Introduction The theory of reserve against brain insult arose to explain individuals who continue to function clinically despite brain pathology (Gertz et al., 1996; Davis et al., 1999; Gold et al., 2000; Jellinger, 2000; Riley et al., 2002). In an early example, the brains of 10 cognitively normal elderly women were found to have Alzheimer’s plaques at autopsy (Katzman et al., 1988). These women’s brains were heavier and contained more neurons, which were thought to provide “reserve,” to help the women function despite their pathology. Indeed, later studies found that 25–67% of subjects characterized as cognitively normal throughout longitudinal assessments meet pathologic criteria for dementia at autopsy (Crystal et al., 1988; Morris et al., 1996; Price and Morris, 1999; Ince, 2001; Mortimer et al., 2003). Two types of reserve contribute to maintaining functioning after brain insult: brain reserve and cognitive reserve. Standard proxies for brain reserve include brain size (Katzman, 1993) and/or neuronal count (Mortimer et al., 1981). For any level of pathology, more brain reserve is associated with better functional outcomes (Satz, 1993; Graves et al., 1996; Jenkins et al., 2000). The brain reserve model posits a threshold at which functional deficits

manifest and suggests that individuals with more brain reserve will accumulate more pathology before reaching that threshold. For example, in the case of Alzheimer’s, the disease will advance longer and additional pathology will be acquired before deficits are seen in individuals who start with more neurons and/or a bigger brain. The initial brain reserve model was entirely quantitative: a given brain injury affects each individual in the same manner, and brain injuries throughout the lifespan sum together. Evidence indicates that some brain deficits do sum across the lifespan. For example, the risk for Alzheimer’s rises with each psychiatric episode (Kessing and Andersen, 2004) and/ or concussion (Guskiewicz et al., 2005). A limitation of this model, however, is that brain reserve is thought to constitute the only meaningful difference between individuals, with the idea that accumulated damage either does or does not reach the threshold necessary for functional deficits. Although the brain reserve model explains some observations, the generalization that more is better may be too simple. As one example, autism is associated with a brain that is bigger than normal, perhaps reflecting a failure of pruning mechanisms that eliminate unused or faulty neural connections, or a larger glia/neuron ratio (Redcay and Courchesne, 2005). Furthermore it has been

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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found that in healthy children, young adults, and elderly samples, more gray matter is associated with worse memory performance (Salat et al., 2002; Van Petten, 2004). This strongly suggests that those with the biggest brains are not always at the biggest advantage. Another limitation of brain reserve theory is that it does not explain the counterintuitive finding that, once Alzheimer’s is diagnosed, higher IQ and more education are associated with faster deterioration and more rapid death (Stern et al., 1994; Stern et al., 1995; Teri et al., 1995; Stern et al., 1999; Scarmeas et al., 2006; Hall et al., 2007; Helzner et al., 2007). By contrast, cognitive reserve refers to the ability to make flexible and efficient use of available brain reserve when performing tasks (Stern, 2002). Cognitive reserve has been most often estimated using education (Stern et al., 1992) and IQ (Alexander et al., 1997), although other variables have also been used, including literacy (Manly et al., 2003; Manly et al., 2005), occupational complexity (Stern et al., 1994; Richards and Sacker, 2003; Staff et al., 2004), participation in leisure activities (Scarmeas et al., 2001; Wilson et al., 2002; Scarmeas et al., 2003a), and the cohesion of social networks (Fratiglioni et al., 2000; Bennett et al., 2006). Recently, personality variables have also been incorporated (Wilson et al., 2006; Wilson et al., 2007). Those with higher cognitive reserve tend to have better clinical outcomes for any level of pathology and brain reserve. As one example, Mortimer et al. (2003) found that those with smaller brain reserve, operationalized with head circumference, were at increased risk of Alzheimer’s. Yet this relationship was moderated by cognitive reserve such that those with smaller heads and more education were not at increased risk. This suggests that cognitive reserve allowed individuals to compensate for any pathology present in their smaller brains by making more optimal use of that brain reserve present. It further suggests that the threshold of brain reserve necessary to maintain functioning is not fixed, but instead varies among people such that those higher in cognitive reserve can maintain functioning at lower levels of brain reserve. Although cognitive reserve is discussed most often in the context of Alzheimer’s disease and normal aging, it has also been demonstrated to provide benefit in vascular injury (Dufouil et al., 2003; Elkins et al., 2006), Parkinson’s disease (Glatt et al., 1996), traumatic brain injury (Kesler et al., 2003), HIV (Farinpour et al., 2003), and multiple sclerosis (Sumowski et al., 2009). While it has been established in these diverse conditions that cognitive reserve is protective against brain injury for cognitive outcomes, it remains to be determined whether cognitive reserve is similarly protective for affective or psychiatric outcomes. One report found that higher cognitive reserve is not protective against the depressive symptoms that arise with the early stages of Alzheimer’s (Geerlings et al., 2000); however, other reports of healthy individuals have found

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that higher cognitive reserve does protect against psychiatric diseases such as depression (Barnett et al., 2006; Koenen et al., 2009). Many aspects of cognitive reserve are intercorrelated. For example, people with higher IQs obtain more education, which, in turn, increases IQ (Ceci, 1991). Yet, although they are intercorrelated, these aspects of cognitive reserve impart both independent and interactive effects that accrue over the lifespan. Richards and Sacker (2003) examined how cognitive reserve variables collected at different points in the lifespan affected cognitive function at midlife. The authors found that the earliest point, childhood IQ, had the strongest effect; a later point, educational attainment by early adulthood, less effect; and the latest point, occupation in middle age, the least strong effect. These results suggest that while early childhood factors are crucial for the buildup of cognitive reserve, cognitive reserve continues to be influenced by circumstances throughout the lifespan. It has been pointed out that many of the variables used to measure cognitive reserve, such as education, are conflated with socioeconomic status (SES). However, Karp et al. (2004) found that while less education and lower SES are independently associated with higher risk for Alzheimer’s disease, with both in the model simultaneously, only education is significant. Thus, the lower risk for Alzheimer’s in those more highly educated is not mediated by SES. Furthermore, Turrell et al. (2002) found that a relationship between more years of education and better cognitive outcomes in middle age was independent of both childhood and current SES. Thus, the benefits arising from cognitive reserve are not reducible to SES. Another potential limitation is that individuals with more education and higher IQ display superior performance on the tests used to measure cognitive decline and diagnose dementia; this has been called the ascertainment bias (Tuokko et al., 2003). In other words, although an individual high in cognitive reserve might slip from the previous high level of performance as a result of pathology or aging, this deterioration might go unnoticed in testing, because performance may still be average. Yet cognitive reserve still provides benefit even when dementia is diagnosed with measures of daily functioning instead of neuropsychological tests (Liao et al., 2005). Further, cognitive reserve has been demonstrated even in longitudinal studies with a clear baseline for each subject from which to assess performance (Scarmeas and Stern, 2004). Unlike brain reserve, cognitive reserve makes clear why those with higher IQ, more education, and/or more participation in leisure activities have poorer outcomes, in that they deteriorate more quickly and proceed to death soon after Alzheimer’s is diagnosed (Stern et al., 1994; Stern et al., 1995; Teri et al., 1995; Stern et al., 1999; Scarmeas et al., 2006; Hall et al., 2007; Helzner et al., 2007). The cognitive reserve model posits that those with higher

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reserve are able to compensate for pathology early on in the course of Alzheimer’s disease. Not until the pathology is more advanced and the patient is nearer to death are deficits observable in an individual with high cognitive reserve. This also implies that, for any given functional level, those higher in reserve will have more pathology (Bennett et al., 2003; Bennett et al., 2005; Serra et al., 2011). Although the initial conception of brain reserve was entirely quantitative, recent evidence suggests that this concept is more nuanced. First, brain and cognitive reserve share some overlap. For example, IQ and brain volume show a small but significant correlation (McDaniel, 2005). More importantly, stimulating environments–-a component of cognitive reserve measured in humans by variables such as engagement in leisure activities and occupational attainment–-foster the growth of new neurons (Churchill et al., 2002) and upregulate brain-derived neurotrophic factor (BDNF), which fosters neural plasticity. Furthermore, animal studies suggest that enriching environments may reduce Alzheimer’s pathology directly (Costa et al., 2007). In humans, it has been demonstrated that higher IQ reflects higher metabolic efficiency in the brain, which may slow the development of neuropathology (Yeo et al., 2011). Nonetheless, although they are in some ways interdependent, brain reserve and cognitive reserve make independent yet synergistic contributions to understanding individual differences in clinical resilience to brain pathology. In terms of cognitive performance, cognitive reserve may help by enabling more flexible strategy usage, a skill tapped by executive function tasks. In support of this, structural equation modeling performed in nondemented older adults aged 53–97 revealed that cognitive reserve–-as measured using years of education, Wide Range Achievement Test (WRAT) score or, for Spanish speakers the Word Accentuation Test (WAT) score, and picture vocabulary from the Peabody Picture Vocabulary Test, 3rd edition (PPVT-III)–-overlapped greatly with executive functioning measured using the letter-number (LN) sequencing subtest of the third version of the Wechsler Adult Inventory Scale (WAIS-III), the odd-manout task, and the difference score from the Color Trails Test (Siedlecki et al., 2009). In healthy adults aged 20–81, cognitive reserve measured as mentioned previously (education, WRAT, and picture vocabulary) was found to entirely overlap with executive functioning as measured using the same LN sequencing subtest and also the Wisconsin Card Sorting Task and the Matrix Reasoning Test. These results suggest that cognitive reserve could involve fluid executive abilities. In terms of neuroimaging, cognitive reserve is thought to be reflected in neural reserve and neural compensation. Neural reserve provides young, healthy individuals the ability to process tasks with more efficiency and greater capacity. For tasks of low-to-moderate difficulty,

those higher in cognitive reserve may display less neural activation, because they are able to process the task with greater neural efficiency. Opposingly, when tasks involve high levels of difficulty, those higher in cognitive reserve may display more neural activation, because they have a greater neural capacity to use when performing the task. Attending to difficulty is thus vital for understanding the meaning of differences in neural activation between groups. Neural reserve operates similarly to mitigate the effects of aging and brain pathology. Those higher in neural reserve are expected to perform better than or equivalently to those with lower neural reserve. Neural compensation is defined as the activation of alternate brain regions not often used by healthy young adults, to compensate for deficiencies in primary routes to effectual task performance. As defined, then, neural compensation occurs not in healthy young adults, but only in those with brain deficits. As for neural reserve, attending to difficulty is vital for accurately identifying neural compensation. For example, neural compensation may be suspected if a region is activated in older adults and not in younger adults. Yet in a more difficult version of the task, this region might also be activated by the young adults. Sometimes, it is even the case that young adults are using the brain area, but this is missed because of the statistical threshold chosen to define brain activation. Neural compensation can sometimes be accompanied by worse performance, although this is not always the case. In some instances, neural compensation could act like a cane, which enables individuals to walk but will not return the ability to sprint. As this metaphor suggests, neural compensation is sometimes associated with slower performance (Zarahn et al., 2007; Steffener et al., 2009). Some think that this happens because, with neural compensation, processing travels across more brain regions, each of which may take some additional amount of time. An alternate idea is that, with neural compensation, processing shifts from a primary network to a slower secondary network. It should be remembered that neural compensation has been found to correlate with better performance in terms of accurately remembering more words (Stern et al., 2000). To sum, neural compensation can accompany performance that is either enhanced or degraded. A further consideration is that when additional brain areas are activated in the presence of pathology, this does not always indicate compensation. The activation of additional regions can be malfunctional when it arises from detrimental processes such as dedifferentiation (blurring) of sensory maps (Park et al., 2004), deficits in handling competition between brain regions (Logan et al., 2002), or a deficit in the ability to inhibit the default network (Lustig et al., 2003). Thus when performance is worse, it is necessary to rule out these detrimental processes before labeling the activation of neural compensation.

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An implicit assumption is that neural compensation differs from task to task (that is, it is an emergent property of the task at hand). Yet, as cognitive reserve protects functioning on a wide variety of tasks, it is possible that one generic cognitive reserve network subserves one general cognitive function. Some evidence in support of this idea (Stern et al., 2008) is reviewed in the next section. If this is true, activation of this network would likely indicate a positive, helpful form of neural compensation.

Neural markers of cognitive reserve in young, healthy adults Stern et al. (2003) conducted an event-related fMRI analysis of young adults performing a nonverbal serial recognition task, looking for regions whose activation changed with difficulty. Low-difficulty trials involved one shape to remember, while the number of shapes to remember for high-difficulty trials was customized for each subject to achieve 75% accuracy. Univariate analyses were performed to find regions where the change in activation with difficulty was associated with cognitive reserve, here measured using the National Adult Reading Test (NART) IQ score. Such regions were found for both study and test task phases. These results indicate that cognitive reserve is linked to differential task-related activation (neural reserve) even in healthy young adults. These differences in task-related processing may provide benefits to those higher in cognitive reserve when they become challenged by age-related brain changes or pathology. The previous data were re-examined using multivariate analyses (Habeck et al., 2003). For this study, first a network of regions was sought that changed activation with difficulty. Next, it was investigated whether this network showed differential expression as a function of cognitive reserve. First, a difficulty-related network was found in the study phase. As hypothesized, individuals higher in cognitive reserve expressed this network less (r2 = 0.24), demonstrating higher neural efficiency. Then forward application of this network to the test phase similarly found that those higher in cognitive reserve had lower network activation (r2 = 0.23). Thus, even with this more conservative method, young adults higher in cognitive reserve displayed evidence for greater neural efficiency. Habeck et al. (2005) explored the same question on another task: delayed letter recognition. In this task, memory set sizes of one, three, and six letters constituted the manipulation of difficulty. At the study phase, the difficulty-related network was not associated with cognitive reserve as measured by NART IQ. At the retention phase, or 7-second delay over which items had to be actively held in mind, a difficulty-related network was found that was expressed less by those higher in cognitive reserve (r2 = 0.15). In a second task, then, neural efficiency

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was again detected in young adults higher in cognitive reserve, here during retention. To some extent, individuals higher in cognitive reserve may have higher neural efficiency as a result of employing better performance strategies. This idea is supported by a study that failed to find the usual neural efficiency advantage with intelligence after controlling for strategy usage (Toffanin et al., 2007). Further support comes from a study that found that more activation was associated with trying out more strategies. The idea is that those with higher intelligence are able to decide on a good strategy more quickly and, as a result, show less activation (Jaeggi et al., 2007). Gray et al. (2003) examined healthy young adults performing a three-back working memory task. In this study, event-related activation differed as a function of fluid intelligence, as measured with the Raven’s Advanced Progressive Matrices, for trials at various levels of difficulty, here manipulated through high-interference as opposed to low-interference items. Although this was not explicitly a study of cognitive reserve, fluid intelligence would be expected to be a good proxy for cognitive reserve (Siedlecki et al., 2009). The authors found that activation on the most difficult trials was greater for those higher in fluid intelligence. Higher fluid intelligence was also associated with improved accuracy for lure trials. Interestingly, the increase in activation from nonlure to lure trials mediated the intelligence–accuracy relationship on lure trials by 99%. These results provide support for the idea that those higher in cognitive reserve have greater neural capacity to use, which provides an advantage when tasks are highly difficult. One limitation of these studies is that the tasks used did not have the range of difficulty needed to see neural efficiency and neural capacity operating in the same individuals. There is thus an outstanding research need to find neural efficiency and neural capacity operating with higher cognitive reserve in the same task in young people. Our group has one such report (Stern et al., 2012).

Neural markers of cognitive reserve in healthy young and older adults In older as compared to younger adults, the neural activation associated with cognitive reserve is sometimes the same but can be altered as well. Scarmeas et al. (2003b) examined PET activation in healthy younger and older adults on a nonverbal serial recognition task; cognitive reserve was measured by a factor score extracted from years of education, NART, and age-scaled vocabulary scores from the revised version of the Wechsler Adult Intelligence Scale (WAIS-R). The low-difficulty condition was a single shape, while the high-difficulty condition was adjusted to each subject so that they achieved 75%

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accuracy. Univariate analyses were used to find regions associated with cognitive reserve for each group separately and next to find regions differentially associated with cognitive reserve between the young and the old. The first analyses found some regions associated with cognitive reserve only for the young and other regions associated with cognitive reserve only for the old. The second analyses found three types of differential expression between the two groups: some regions were positively expressed with higher cognitive reserve in the young and negatively expressed with higher cognitive reserve in the old; some regions showed the opposite pattern; and some regions were positively expressed with cognitive reserve in the young and positively, albeit more faintly expressed with cognitive reserve for the old. The authors posit that these differences between young and old in cognitive reserve expression indicate that compensatory reorganization happens with aging. Stern et al. (2005) re-examined the data with multivariate analyses to find regions that were differentially activated with difficulty and age. The authors found a network of brain regions that were activated differently between young and older individuals. Expression of this network was positively associated with cognitive reserve in the young (r = 0.45), indicating higher neural efficiency, and negatively associated with cognitive reserve in older individuals (r = −0.50), indicating higher neural capacity. To sum, young and older individuals expressed the cognitive reserve pattern in opposite ways. The authors posit that this difference reflects helpful reorganization of brain networks in aging, or neural compensation. Stern et al. (2008) next examined in young and older adults whether cognitive reserve might operate similarly in different tasks. Event-related fMRI was used to probe for a cognitive-reserve-related network shared by two different tasks: delayed letter and shape Sternberg. Cognitive reserve was measured with the NART and the vocabulary subtest of the WAIS-R. The letter task contained difficulty levels of one, three, and six letters, while the shape task contained difficulty levels of one, two, and three shapes. On the whole, the shape task was considerably more challenging than the letter task. Two networks were found for the study phase. While the first network was used only during the letter task, the second network was used during both the letter and shape tasks. For young subjects, network activation in both tasks was negatively associated with cognitive reserve, indicating higher neural efficiency in those with greater cognitive reserve. For older subjects, network expression was negatively associated with cognitive reserve only for the less challenging letter task. These results suggest a generic “cognitive reserve network” that can be utilized for performing many tasks. This is concordant with the observation that cognitive reserve provides benefits against brain pathology for many different tasks and real-world functions.

Steffener et al. (2009) examined event-related fMRI activation between young and older subjects performing a delayed letter recognition task. Memory set sizes of one, three, and six letters comprised three levels of difficulty; networks were found that changed expression with increasing difficulty during retention. While young adults utilized a single network, older adults utilized this network along with an additional network. The authors demonstrated that greater pathology in the primary network, operationalized here as more atrophy in the precentral gyrus, was associated with greater utilization of the secondary network in the elders. Because the young subjects did not use the secondary network, it can be presumed to reflect neural compensation in the older subjects. Importantly, older individuals with more cognitive reserve were able to tolerate greater pathology before having to employ the secondary network.

Neural markers of cognitive reserve in healthy elderly and Alzheimer’s patients Scarmeas et al. (2004) examined PET activation in healthy older and Alzheimer’s patients performing a nonverbal serial recognition task. The low-difficulty condition involved a single shape, while the high-difficulty condition was adjusted so that each subject achieved 75% accuracy; cognitive reserve was measured using a factor score extracted from years of education, NART IQ, and the vocabulary subtest of the WAIS-R. Activation patterns differed between healthy older and Alzheimer’s patients. In some regions, Alzheimer’s patients with higher cognitive reserve displayed greater activation, while healthy older individuals with higher cognitive reserve displayed less activation, while in other regions, the relationships were reversed. These region-specific differences were posited to reflect compensatory reorganization of brain networks in Alzheimer’s patients. Solé-Padullés et al. (2009) compared cognitive-reserverelated fMRI activation on a recognition task between healthy old, mild cognitive impairment patients and Alzheimer’s patients. Stimuli were images of landscapes and people engaging in outdoor activities; cognitive reserve was measured with a composite score of the vocabulary subtest of the WAIS-III, an education–occupation scale, and a scale of participation in leisure activities. Univariate analyses were performed after adjusting for the differential performance between the groups. In healthy older individuals, more cognitive reserve was associated with less activation, indicating higher neural efficiency. Conversely, in mild cognitive impairment and Alzheimer’s disease, those with more cognitive reserve displayed greater activation, thought to indicate greater neural capacity. Taken together with the previous study, reverse cognitive-reserve-related brain activation is seen between healthy and diseased older individuals.

Cognitive Reserve and the Aging Brain

Implications of cognitive reserve for diagnosis and prevention Individuals with greater cognitive reserve create a diagnostic challenge, as pathology may be present without functional consequences. Furthermore, for patients with dementia at any stage of clinical severity, individuals with greater cognitive reserve will have more advanced pathology. Neuroimaging biomarkers are currently being developed to assist in early detection of Alzheimer’s pathology, even prior to clinical consequences. Complicating this endeavor, individuals with greater cognitive reserve can tolerate more decreases in cortical thickness (Querbes et al., 2009), levels of amyloid peptides in cerebrospinal fluid (Shaw et al., 2009) and plasma (Yaffe et al., 2011), and more regional atrophy (Hua et al., 2008) before clinical consequences emerge. For these reasons, the predictive accuracy of biomarkers is improved when adding cognitive reserve variables to the model (Roe et al., 2011). More generally, clinical status can best be understood when both underlying pathology and cognitive reserve are taken into account. With the future growth of the aging US population, the number of dementia cases will triple by 2050 if interventions are not applied (Hebert et al., 2003). Katzman (1993) reasoned that as higher education staves off Alzheimer’s for 5 years, it may considerably lessen its prevalence. Thus, cognitive reserve interventions may constitute a chief nonpharmacologic approach for preventing this disease (Stern, 2006). Although Alzheimer’s has a large genetic component (Gatz et al., 2006), behavioral and environmental factors still exert considerable influence over its expression and timing of onset. Even in early-life onset Alzheimer’s, which has a stronger genetic component than does late-life onset Alzheimer’s, cognitive reserve has recently been demonstrated to play a protective role (Fairjones et al., 2011). Future studies might elucidate optimal strategies for augmenting cognitive reserve in order to delay or prevent Alzheimer’s disease and other age-related afflictions.

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Chapter 6 Gait Disorders in the Graying Population Joe Verghese and Jessica Zwerling Department of Neurology and Medicine, Albert Einstein College of Medicine, Bronx, NY, USA

Summary • Gait disorders can increase the risk of falls, disability, and mortality in the elderly. Gait dysfunction is also common in individuals with cognitive impairment. • Gait disorders can be classified as neurologic or non-neurologic. Within these classifications, the disorder can also fall under different subtypes. Gait is assessed by standard neurologic examinations, visual screens, and the Romberg test for balance. • Neurologic gait disorders can have several underlying etiologies including myelopathy, Parkinson’s disease (PD), vascular or other structural causes, normal pressure hydrocephalus (NPH), strokes, disorders of the cerebellum, and subacute or chronic sensorimotor axonal neuropathy. • Prevention strategies and treatment should be tailored to each individual according to their underlying etiology.

Introduction: a historical perspective

Epidemiology

What has four legs in the morning, two legs in the afternoon, and three legs at nighttime? Man. This riddle illustrates three phases of life. The first phase represents an infant crawling. In the second phase, the child progresses to walking. The third stage then describes a phase in which man requires assistance for walking. In this latter stage, identifying gait disorders is crucial to prevent morbidity and mortality in the elderly. The locomotor system of the animal is based on a spinal neural network (Grillner, 1975; Mor and Lev-Tov, 2007). From the four-legged animal in early evolutionary stages to modern upright man, the advantage of bipedalism has enabled humans to have a unique interaction with the environment. The upright structure has both advantages and disadvantages. The “three legs at nighttime” represents the downside of bipedalism. This locomotor strategy can be fraught with “slipped disks, dislocated hips, wrenched knees, fallen arches, and a whole catalog of associated woes” (Tattersall, 1998). Identifying gait disturbances is crucial. It enables efficient diagnosis of neurologic illnesses in clinical settings as well as facilitates the identification of high-risk older individuals to institute interventions to prevent outcomes such as falls that are associated with high personal and societal costs.

In older adults, gait disturbance is common and can be associated with pain, functional impairment, and falls. The ability to ambulate independently is a major contributor to overall well-being and autonomy in elderly individuals. In the “oldest-old” (over age 85) living in the community, the prevalence of walking limitations approaches more than 50% (Ostchega et al., 2000). In an urban community-based study, abnormal gaits were reported in one-third of older persons and accounted for 58% of the overall number of deaths and institutionalizations over 5 years in this sample (Verghese et al., 2006). The prevalence of clinically diagnosed gait abnormalities was 35% in this sample (Verghese et al., 2006). Incidence of abnormal gait was 168.6 per 1000 person years, and increased with age (Verghese et al., 2006).

Gait and adverse outcomes Falls Falls are a significant health concern because they cause significant morbidity and mortality in the elderly and result in a significant burden on a socioeconomic level. Over age 65, falls are the leading cause of fatal injuries (Stevens et al., 2008). About one-third of the community population over age 65 falls each year (Gillespie et  al.,

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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2009). Emergency departments are frequently overwhelmed with older adults who have unintentional falls. In 2005, 1.8 million elderly people were admitted in emergency rooms across the country (Stevens et al., 2006). Falls are predictors of future falls; in other words, patients who have fallen are more likely to fall again, especially if there are detected abnormalities of gait (Ganz et al., 2007). The latter fact underscores the importance of identifying patients who fall with simple screening questions. In addition, falling occurs in the setting of “fear of falling”; therefore identification of patients with this particular “fear” is also essential. Fear of falling is a well-known independent risk factor for falls (Delbaere et al., 2010). Race has no preference when it comes to falls; African Americans and White elderly individuals fall at the same rate. However, African Americans are more likely to have a traumatic brain injury, and women are more likely to experience a fracture (Ganz et al., 2007; Delbaere et al., 2010). Clinical gait abnormalities predict future risk of falls (Tinetti et al., 1994, 1995; Verghese et al., 2006; DeMott et al., 2007; Ganz et al., 2007). In a prospective study of community-residing elderly, the presence of neurologic gaits was a strong risk factor for falls and was associated with a 49% increased risk of falls over a 20-month period (Verghese et al., 2010). Unsteady and neuropathic gait were the two gait subtypes among the six studied that predicted risk of falls (risk ratio: 1.52, and 1.94, respectively) (Verghese et al., 2010). This study showed that classifying gait disorders is crucial to identifying individuals at risk for falls, as well as to identifying gait problems to institute preventative measures. Gait should be treated as a potential modifiable risk factor for falls (Tinetti et al., 1994, 1995; Mor and Lev-Tov, 2007; Delbaere et al., 2010; Verghese et al., 2010).

Gait and disability The risk of developing disability can be predicted in community elders by lower-extremity performance tests, of which gait speed is the main factor in community-based cohort studies (Verghese et al., 2010). Gait speed is a key component of the clinical definition of frailty (Gill et al., 2010), which is conceptualized as a state of heightened vulnerability to stressors and increases the risk of disability in older adults. Gait speed is a potentially modifiable risk factor to prevent disability and related outcomes. Gait and survival Gait speed and survival are associated (Markides et  al., 2001; Boyle et al., 2005; Louis et al., 2005; Stevens et  al., 2006; Ganz et al., 2007; Cesari et al., 2009; Gillespie et al., 2009; Delbaere et al., 2010). In a pooled analysis, Studenski et al. found that slower gait speed is an absolute risk for shorter survival in older adults (Studenski et al., 2011). Improvement in gait speed by 0.1 m/s over 1 year has been termed as a meaningful clinical difference, and

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this change has been associated with reduced mortality in prospective cohort studies (Perera et al., 2006; Hardy et al., 2007). Variability in gait is an important predictor of mobility difficulty in older adults. In a small sample of subjects in the Einstein Aging cohort, meaningful changes in various quantitative indices of gait were determined (Brach et al., 2010). Preliminary criteria for meaningful change are 0.01 seconds for stance time and swing time variability, and 0.25 cm for step length variability (Perera et al., 2006).

Cognition and gait Gait disorders are common in the elderly, particularly in patients with cognitive impairment (Verghese et al., 2008). Studies have shown that there is likely a link between the cognitive and motor systems (Verghese et al., 2008). Furthermore, Verghese et al. underscored that clinical and quantitative gait dysfunction is common in mild cognitive impairment (MCI) and is associated with poorer status (Verghese et al., 2007). In this same elderly cohort, subjects with amnestic-MCI (a-MCI) had worse swing time and stride length variability than those with nonamnestic-MCI (na-MCI) (Verghese et al., 2008). Subjects with a-MCI had worse performance on rhythm and variability gait domains than age-matched and sex-matched controls and those with na-MCI (Verghese et al., 2008). Neurologic gaits were more common in subjects with a-MCI (Verghese et al., 2008). Parkinsonian signs in MCI were related to the severity and type of cognitive impairment in another elderly cohort (Boyle et al., 2005) Another community-based study reported that mild parkinsonian signs were associated with a-MCI but not na-MCI (Louis et al., 2005; Verghese et al., 2008).Motor decline as indexed by gait speed declined up to 12 before other cognitive domains in patients with MCI (Buracchio et al., 2010).

The “aging” of walking Changes that are seen with aging include shorter and broad-based strides, as well as a reduction in pelvic rotation and joint excursion (Sudarsky, 1990, 2001). In the Einstein Aging Study cohort, gait velocity and stride length decreased with advancing age (Oh-Park et al., 2010). However, the aging effect on walking was less pronounced when clinical and subclinical disease influence on gait was taken into account. These results suggest that gait changes with aging are better explained by age-related diseases than they are age-associated. Hence, underlying causes for gait changes need to be investigated regardless of the age of the patient. In a study of community elders, the most important factors associated with walking speed were leg extensor power, standing balance, and physical activity, regardless of body mass index or gender (Sallinen et al., 2011). These

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are all potentially modifiable risk factors that interventions aimed at improving lower extremity impairments can improve (Sallinen et al., 2011). Cross-sectional conventional norms may underestimate gait performance in aging (Oh-Park et al., 2010). Longitudinal robust norms provide more accurate estimates of normal gait performance and thus may improve early detection of gait disorders in older adults (Oh-Park et al., 2010). Robust norms consider subjects with prevalent or “in transition” gait abnormalities to develop clinical gait abnormalities and exclude them (Oh-Park et al., 2010). This allows for a gait to reflect more of the “normal” elderly population, so that targeted interventions can be more accurately guided (Oh-Park et al., 2010). The following sections contain a discussion of clinical gait evaluation and classification, quantitative indices of gait, and performance-based measures.

Clinical gait classification Several different clinical classification systems exist for gait and have been described. All these clinical gait classifications rely on the clinician’s observation of walking patterns. Nutt and colleagues proposed a system that classifies clinical gait abnormalities based on abnormal sensorimotor levels as low, middle, and high (Nutt et al., 1993). Higher-level gait disorders are thought to stem from pathology in the frontal lobes and their connections with parietal lobes, subcortical structures (cerebellum and basal ganglia), and the upper brainstem (Nutt et al., 1993). Lower-level gait disorders can be divided into motor and sensory systems. Lower-level gait disorders are thought to arrive from perturbation of the muscle or peripheral nerve. An example of lower-level gait disorder is neuropathic gait secondary to neuropathy (see the description in the Section Case Discussions, later in this chapter). Lower-level gait dysfunction is also classified secondary to disorders of vision, vestibular sensation, and proprioception (Nutt et al., 1993). The middle-level gait disorder is thought to originate from “motor” dysfunction. This level includes causes such as spasticity due to spinal cord pathology, cerebellar ataxia, and dystonia. Patients with Parkinson’s disease (PD) have dysfunction at the high or cortical level of processing and the middle level (subcortical structures), as they may have rigidity and bradykinesia. The higher-level disorders primarily involve problems integrating information in the environment (Nutt et al., 1993). For example, the execution of locomotion is the main higher-level disturbance in the “freezing” phenomenon during walking seen in patients with PD. Gait is evaluated as part of the standard neurologic examination to test cranial nerves, strength, sensation, and deep tendon reflexes. Visual screening should be

included, along with evaluation for range of motion. The Romberg test is used to assess standing balance with visual cues removed or eyes closed. A positive test refers to a patient’s inability to maintain balance when standing erect with feet together and eyes closed. Cognitive screening is also important to include, given the correlation between the motor and cognitive functions (Verghese et al., 2008). We have been using a clinical gait classification during our clinical evaluation at the Einstein Aging Study for the past two decades. In the Bronx Aging Study (now known as the Einstein Aging Study), clinicians blinded to the gait evaluation of the subjects showed 89% agreement (κ = 0.6) on gait classification, specifically whether the gait was neurologic or non-neurologic (Verghese et al., 2002b). Inter-rater reliability (normal vs any abnormal gait), studied prospectively, between two study clinicians who independently assessed gait in 30 subjects was good (κ = 0.8) (Verghese et al., 2004). At each visit, study clinicians observe gait patterns and turns while subjects walk up and down a well-lit path (Verghese et al., 2002b, 2006, 2010; Oh-Park et al., 2010). The first step in clinical gait analysis is the recognition that gaits are either normal or abnormal; then abnormal gaits are subtyped as either neurologic (one of eight subtypes discussed shortly) or non-neurologic (arthritic, vascular claudication, or secondary to cardiopulmonary issues, and so on). In our large community-based study (the Bronx Aging Study, now known as the Einstein Aging Study (Verghese et al., 2002b, 2006, 2010; Oh-Park et al., 2010), neurologic gaits are subtyped. Neurologic gait abnormalities are subtyped as unsteady if subjects experienced marked swaying or lost balance under two or more of the following conditions: while walking in a straight line or in tandem or while making turns. Ataxic (cerebellar) gait is wide based, with other cerebellar signs such as intention tremor. Ataxic and unsteady gaits were combined, because they share clinical features such as wide base and poor balance. Patients with neuropathic gaits have foot drop, sensory loss, and depressed deep tendon reflexes. Short steps, wide base, and difficulty lifting the feet off the floor characterize frontal gait. Older people with parkinsonian gaits have small shuffling steps, flexed posture, absent arm swing, en bloc turns, and festination. Frontal gait is characterized by short steps, wide base, and difficulty in lifting the feet off the floor. Patients with hemiparetic gait swing a leg outward and in a semicircle from the hip (circumduction). In addition to lower motor neuron/lower-level causes of foot drop, ankle dorsiflexion can be affected in patients with upper motor neuron disorders. Ankle dorsiflexion plays a role in the initial stance phase of the gait cycle and the wing phase, and can be impaired in upper motor neuron lesions, as part of the hemiparetic gait (Verghese et al., 2007). In spastic gait, both legs circumduct and, when severe, cross in front of

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one another (scissoring). See web links (Verghese et al., 2002b) to videos of abnormal neurologic gait subtypes.

Psychogenic gait disorders Gait disorders that are nonorganic/nonphysiologic/ functional are called psychogenic gait disorders. Astasiaabasia is a Greek term that means “inability to stand and to walk.” Paul Blocq described this phenomenon in the late 1800s, which he characterized in a series of patients who did not have the ability to maintain an upright posture, despite normal function of the legs in bed (Blocq, 1888). Sudarsky et al. found that, in elderly patients, 3.3% of gait disorders were psychogenic (Sudarsky and Tideiksaar, 1997). A functional disorder has several features, such as momentary fluctuations, excessive slowness of movement or hesitation, “psychogenic” Romberg with a silent delay or improvement with distraction, uneconomic postures (wasting of energy), small cautious steps with fixed ankle joints (“walking on ice”), and sudden buckling of knees with and without falls. The caveat is that gait disorders develop over time, and repeated examination and history taking is necessary to truly characterize a gait disorder as psychogenic. Elderly patients may showcase a “cautious gait,” with reduced stride, widened base, and lowered center of gravity (Sudarsky and Tideiksaar, 1997). Cautious gait may be a reaction to a previous fall, may be psychogenic, or may be a representation of a larger gait disorder that has not manifested yet. The main risk factors for developing the fear of falling are at least one fall, female sex, and increasing age (Tinetti and Mendes de Leon, 1994; Sudarsky and Tideiksaar 1997; Scheffer et al., 2008). This can cause significant psychosocial limitations for an individual. Treatment relies on a multidisciplinary team, including psychiatry and rehabilitation experts. An additional syndrome important to discuss is camptocormia, or “bent spine syndrome.” This syndrome is characterized by forward flexion of the trunk in the erect position and reduced flexion when in the supine position (Azher and Jankovic, 2005). The etiology was originally thought to be a form of “conversion” or psychogenic disorder; however, the underlying cause encompasses many aspects of the neuraxis. The etiology involves neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), facioscapulohumeral muscular dystrophy (FSHD), mitochondrial myopathy, and dysferlinopathy, as well as PD and dystonia (Van Gerpen, 2001; Schabitz et al., 2003; Azher and Jankovic, 2005; Gomez-Puerta et al., 2007; Seror et al., 2008).

Quantitative assessment of gait: creating a scorecard for prediction of falls Walking is the repetitive sequence of limb motion to push the body forward while maintaining stance and stability

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(Perry, 1992). Although clinical observation alone is an important component of gait analysis, it depends on the examiner’s expertise. On the other hand, criticisms of quantitative gait analysis methods may state that the assessment protocols are cumbersome and vary in the level of detailed analysis required. Recent technologic advances in quantitative assessment of gait have enabled faster acquisition of kinematic data and an in-depth measurement of various gait variables (Verghese et al., 2002b; Abellan van Kan et al., 2009). It is important to measure variables such as normal gait measures, as well as variability within these measures. Gait speed has been associated with good health and functional status (Cesari et al., 2005; Rolland et al., 2006; Rosano et al., 2008; Abellan van Kan et al., 2009; Verghese et al., 2009). Normal older adults with increased stride-to-stride or stance time variability at baseline assessments were reported to have increased risk of falling, mobility disability, and dementia (Brach et al., 2005; Cesari et al., 2005; Perera et al., 2006; Verghese et al., 2009; Verghese and Xue, 2011).

Timed gait Simple timed gait is recommended by a number of studies and can be done in most clinical settings (Abellan van Kan et al., 2009; Studenski, 2009; Verghese et al., 2009). An abundance of gait norms exist for elderly individuals, which presents difficulty for clinical application because of the variation in the reported values. Mean gait velocity varied in older adults from 89  cm/s to 141  cm/s in previous community-based studies (Murray et al., 1969; Winter et al., 1990; Oberg et al., 1993; Samson et al., 2001; Bohannon, 2008). Gait velocity decreased with advancing age in the Einstein Aging cohort (Verghese et al., 2009). In this prospective study of a large, well-characterized cohort of community-residing elders, quantitative gait markers were independent and strong predictors of incident falls (Verghese et al., 2009). Each 10  cm/s decrease in gait speed was associated with a 7% increased risk for falls (Verghese et al., 2009). Participants with slow gait speed (≤70  cm/s) had a 1.5-fold increased risk for falls, compared with those with normal speed (Verghese et al., 2009). Computerized assessments for gait are varied. Subjects in the Einstein Aging Study protocol are asked to walk on a mat at their normal pace for two trials in a quiet, well-lit hallway with comfortable footwear on the GAITrite system. Footfalls are recorded and gait variables are recorded over two trials. Eight gait parameters are reported, based on previous studies of their associations with adverse outcomes: velocity (cm/s), cadence (steps/min), stride length (cm), swing time (s), stance time (s), and double support phase (%). (See Table 6.1 for definitions.) The standard deviation (SD) of stride length and swing time is used for variability (Verghese et al., 2007). Gait variability in each measure of gait was defined as the within-

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Table 6.1 Definition of quantitative gait parameters. Variable

Unit

Definition

Velocity Stride length

cm/s cm

Cadence Double support

steps/min s

Swing time

s

Stance time

s

Distance covered on two trials by the ambulation time Distance between heel points of two consecutive footfalls of the same foot. Variability in length between strides is reported as standard deviation (SD). Number of steps taken in a minute Time elapsed between the first contact of the current footfall and the last contact of the previous footfall, added to the time that elapsed between the last contact of the current footfall and the first contact of the next footfall Duration when the foot is in the air and is the time taken from toe-off to heel strike of the same foot. Variability in swing time is reported as SD. Duration when the foot is on the ground and is the time taken from heel strike to toe-off of the same foot

Source: Adapted from Snijders et al. (2007), with permission from Elsevier. All quantitative parameters described are automatically calculated as the mean of two trials by the gait software.

subject SD derived from all the right steps recorded over two trials (Brach et al., 2005). Gait variability is an important indicator of impaired mobility in older adults (Brach et al., 2005).

Performance-based tests A number of performance-based assessments can be used in any office setting to assess risks for falls. A quick tool that has been well validated is the Timed Up and Go test (Podsiadlo et al., 1991). The patient is timed from rising from a chair, walking 3 m, turning, and returning to the chair. A timing of 14 seconds or more has been shown to be an indicator for a fall risk (Podsiadlo et al., 1991). A unipedal stance of less than 5 seconds has been associated with increased risk of falls in the elderly (Vellas et al., 1997). Walking while talking The task of walking while talking (WWT) requires divided attention and harnesses the bridge between cognitive and motor disorders. Although walking at a normal pace is thought to be “reflexive,” WWT requires a shift of attentional resources and places cognitive demands on individuals. In subjects with imbalance, this can lead to postural instability and falls (Verghese et al., 2002a; Beauchet et al., 2009). In a review of dual-task conditions such as WWT, the pooled odds ratios showed a statistically significant increase in the risk of falls while performing the dual task of WWT (5.3 (95% CI, 3.1–9.1)) (Beauchet et al., 2009). Etiology of gait disorders: a window into diagnosis and workup General medical examinations, especially during visits to emergency rooms, often neglect gait examination. Yet it is a crucial part of the neurologic examination. The following discussion includes etiologies of six main subtypes of neurologic gait disorders, described in our

clinical gait classification in the previous sections and related investigations. The cause of spasticity can be multifactorial in the elderly. Myelopathy from structural causes such as spondylotic ridges and ligamentous hypertrophy contribute to spinal canal narrowing and cord impingement. As a result of cord compression, especially in the posterior columns, which contain vibration and proprioception fibers, patients often complain of imbalance. The physical examination includes mild spasticity (especially in the legs), hand numbness, reports of urinary urgency and incontinence, and a positive Romberg test. The gait is described as stiff-legged with reduced toe clearance and a tendency toward circumduction. Patients may also have pseudoathetosis, or abnormal writhing movements, usually of the fingers, caused by a failure of joint position sense (proprioception). It is important to keep in mind that presentations may be asymmetric or may appear as a central cord syndrome with possible associated syringomyelia, with sensory deficits in a cape-like distribution. Nonstructural causes of myelopathy can be caused by demyelinating diseases such as multiple sclerosis, vitamin B12 deficiency, trauma to the spinal cord, vitamin E deficiency, post-radiation, herpes zoster infection, or copper deficiency. Further evaluation of the brain and spine with MRI, as well as screening bloodwork for nonstructural causes, may be indicated. Parkinsonism is characterized by bradykinesia, resting tremor, rigidity, and loss of postural reflexes. PD is common in the elderly population, with a prevalence of approximately 0.5–1% among persons 65–69 years of age, rising to 1–3% among persons 80 years of age and older (Tanner and Goldman, 1996). Other disorders, including those from neuroleptic drugs and arteriosclerotic parkinsonism as a result of multiple subcortical infarcts, may cause similar gait and balance problems mimicking idiopathic PD. If idiopathic PD is suspected, no further workup is necessary unless secondary causes are suspected.

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Hemiparetic gait is characterized by asymmetric weakness and may be attributable to vascular causes; however, other structural causes, such as AVM, subdural hematoma, metastases, must be ruled out with imaging of the head. Frontal gait includes the disorders of normal pressure hydrocephalus (NPH), as well as multiple strokes. As previously discussed, patients may have a “magnetic gait,” with difficulty lifting the feet off the floor (Sudarsky and Simon, 1987). Imaging of the brain often reveals extensive white matter disease when the etiology is vascular. NPH is characterized by frontal gait disorder, urinary incontinence, and cognitive impairment. This syndrome requires a lumbar puncture for diagnosis, and improvement in gait monitored by the clinician underscores the NPH diagnosis. The response to the removal of 30–50 cc or a large volume of the cerebrospinal fluid is characterized by improvement of gait. The response or rating of improvement to spinal tap is not well standardized. Treatment requires shunting of the cerebrospinal fluid. Ataxic gait includes unsteady gait and includes disorders of the cerebellum. The disorders can be because of neurodegenerative causes, as in olivopontocerebellar degeneration, a disorder that is within the category of Parkinson’s plus syndromes. Paraneoplastic degeneration of the cerebellum associated with antibodies against different cells can cause ataxic gaits. One example includes Anti-Yo antibodies, found mostly in women with cerebellar degeneration accompanying gynecologic and breast malignancies (Peterson et al., 1992). The antibodies recognize cytoplasmic proteins of Purkinje cells, contributing to their degeneration. Anti-Hu antibody, found predominantly in paraneoplastic neurologic syndromes associated with small-cell carcinoma of the lung, reacts with proteins present in nuclei and cytoplasm of virtually all neurons (Mason et al., 1997). Chronic alcoholism can contribute to atrophy of the anterior vermis of the cerebellum (Victor et al., 1959). Treatment includes elimination if thought to be because of toxins. Screening for underlying malignancy and with labwork to identify antibodies is crucial in ataxia as a result of paraneoplastic degeneration. Individuals with neuropathic gait have unilateral or bilateral foot drop and may have a “stocking” pattern of sensory loss and absent deep tendon reflexes. Etiology depends on the type of neuropathy. Several causes of subacute/chronic sensorimotor axonal polyneuropathy include, but are not limited to, diabetes, hypothyroidism, vitamin B12 deficiency, connective tissue disease (Sjorgren, rheumatoid arthritis), paraproteinemia, and toxic neuropathy (alcohol). Clinical cues must be taken from the history and examination. Workup as suggested for the first tier by Herskovitz et al. is complete blood count, chemistry, HgA1C, oral glucose tolerance test, vitamin B12 (methylmalonic acid/homocysteine), ESR, serum protein immunofixation, and toxic exposure his-

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tory (Herskovitz et al., 2010). The authors encourage consideration of urinalysis, chest X-ray, thyroid testing, lipid profile, antinuclear antibody (ANA), rheumatoid factor, Lyme disease, hepatitis C titre, and angiotensin-converting enzyme (ACE) level (Herskovitz et al., 2010).

Summary A detailed history taking that includes an assessment of home safety, complemented with a complete cognitive and gait examination, is crucial to identifying patients with gait disorders. Prevention strategies should be tailored to each individual, depending on the etiology such as stroke, neurodegenerative, neuropathic, psychogenic, or ataxic. Treatment is targeted at controlling underlying conditions that have caused the gait disturbance. Close follow-up is important to ascertain changes in gait patterns over time. Gait disorders follow the same evolutionary principle as the development of man. They evolve over time. The astute clinician must help the patient identify the underlying problem, highlight the obstacles, and help the patient adapt to the environment.

Suggested citations Nutt, J.G., Marsden, C.D., and Thompson, P.D. (1993) Human walking and higher-level gait disorders, particularly in the elderly. Neurology, 43: 268–279. Snijders, A.H., van de Warrenburg, B.P., Giladi, N., and Bloem, B.R. (2007) Neurological gait disorders in elderly people: clinical approach and classification. Lancet Neurol, 6: 63–74. Sudarsky, L. (1990) Geriatrics: gait disorders in the elderly. N Engl J Med, 322 (20): 1441–1446. Verghese, J., Lipton, R., et al. (2002) Abnormality of gait as a predictor of non-Alzheimer’s dementia. N Engl J Med, 347: 1761–1768. Verghese, J., Wang, C., Lipton, R.B., et al. (2007) Quantitative gait dysfunction and risk of cognitive decline and dementia. J Neurol Neurosurg Psychiatry, 78: 929–935. Verghese J., Holtzer, R. et al. (2009) Quantitiative gait markers and incident fall risk in older adults. J Gerontol A Biol Sci Med Sci, 64: 896–901.

Case discussions The following section illustrates the major subtypes of gait disorders. It is a useful tool for teaching and can be utilized with the videos from Verghese et al. ( 2002b).

Case 1: history The patient is a 65-year-old right-handed man with a four-year history of intermittent distal symmetric paresthesias of the legs. Over the past year, the

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paresthesias has caused his legs to become numb to the mid-calf at all times. He had a recent fall in which he “tripped over the curb.” Over the last several months, he has complained of difficulty buttoning his shirt and opening jars. He denies bowel/bladder symptoms or autonomic symptoms. There is no allodynia. There are no constitutional symptoms. He remarked that although it is winter, he finds it uncomfortable to sleep with the sheet on the bed. He denies a family history of neuropathy, high arches, or hammer toes. He has significant thirst, but he attributes it to the use of his inhaler for chronic obstructive pulmonary disease (COPD).

The general medical examination is unremarkable except for poor dentition. The mental status examination was normal. Cranial nerves were normal. The strength examination was normal. Deep tendon reflexes were absent at the toes and brisk 3+ knees but present and normal at the arms. Plantar responses were extensor. There was no tremor or other adventitious movements. Light touch and pinprick were affected to midshin bilaterally. Vibration was decreased to anterior iliac spine, and proprioception required large excursions. Tone was increased throughout. Romberg was positive. There was significant pseudoathetosis.

Physical examination

Gait

The general medical examination is unremarkable. The mental status examination was normal. Cranial nerves were normal. The strength examination revealed a weakness of toe flexion and extension, with an MRC grading of 4, with slight asymmetry or worsening on the right. Deep tendon reflexes were absent at the toes and knees but were present and normal at the arms. Plantar responses were flexor. There was no tremor or other adventitious movements. Light touch and vibration were decreased to midshin bilaterally with pinprick and proprioception mildly affected. There was sensitivity to touch at the soles of the feet. He was able to toe-walk and heel-walk but had extreme difficulty. Romberg showed swaying. There was no pseudoathetosis. Tone was normal. The lower legs were significantly atrophic.

Sways slightly while walking with occasional misstep. Worse with tandem. Wide-based ataxic gait with spasticity.

Gait Bilateral foot drop—neuropathic. There is a “stocking” pattern of sensory loss and absent deep tendon reflexes. Comment on case: Upon further questioning, there was significant erectile dysfunction for 5 years beforehand. Labwork revealed significantly elevated HgA1C.

Case 2: history This is an 85-year-old woman with a history of “unsteadiness” for several months. She reports intermittent paresthesias of the hands, which began several months ago and now has affected the feet. She reports that when she is in the shower, she is unable to wash her hair with her eyes closed. She feels as though she will fall over, and she reports “electricity” in both arms with tilting of her head and neck in a certain direction. There are no bowel/bladder symptoms or constitutional symptoms. She reports recent dental work with injection only (no gas) for poorly fitting dentures. There are no falls. She is on Coumadin for an “abnormal heart rate. She also notes that she has been forgetting where she put her keys a lot more often and got lost driving home on her usual route.

Physical examination

Diagnosis Myeloneuropathy secondary to hyperzincemia causing hypocupremia (Kumar et al., 2004; Nations et al., 2008). Comment on case: Vitamin B12 levels were normal. The patient admitted to using denture cream in significant amounts over the past several months (Herskovitz et al., 2010). Copper levels were low. Serum zinc levels were high. There was an associated anemia on complete blood count. The previous discussion includes description of two subtypes of gait: ataxic and spastic gait.

Case 3: history This 78-year-old right-handed writer presents with a two-year history of changes in his handwriting. He used to take notes throughout the day and night to keep track of new book ideas. His handwriting has become progressively smaller. He notes that, at nighttime, he has increasing difficulty turning in bed. While watching television, he also noted a right-hand tremor. He has lost his balance occasionally but has no falls. He denies hallucinations or autonomic symptoms. Family history is noncontributory. Past medical history is significant for depression without neuroleptic use.

Physical examination The general medical examination is unremarkable. The mental status examination was normal. Cranial nerves were normal. The strength examination was normal. Deep tendon reflexes were normal. Plantar responses were flexor. There was a rest tremor on the right hand. Light touch, pinprick, vibration, and proprioception were normal. There was cogwheeling with activation of the right upper extremity. Pull test was positive. Romberg was negative. He pushed with arms to elevate from a seat. Frontal release signs were negative. Fine finger movements were slowed throughout.

Gait Disorders in the Graying Population

(a)

(b)

(c)

(d)

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Figure 6.1 Footfall patterns recorded on an

instrumented walkway: (a) frontal gait; (b) parkinsonism; (c) ataxic gait; (d) left hemiparetic.

Gait Small shuffling steps, flexed posture, absent arm swing on right, turns en bloc, and festination (acceleration while walking). He does not swing his arms and has difficulty with initiating a turn. (See Figure 6.1.)

Diagnosis Idiopathic PD. Comment on case: The patient exhibits typical features of PD that hallmark symptoms of tremor, bradykinesia, rigidity, and postural instability. His gait was parkinsonian.

Case 4: history This 85-year-old right-handed woman presents with a two-year history of difficulty walking. She feels as though she just cannot move forward or that there is glue under her feet. She is independent at home; however, she recently stopped going to the movies with friends because of incontinence over the last several months. She spends her time reading multiple books at a time and has no trouble keeping up with them.

Physical examination The general medical examination is unremarkable. The mental status examination was normal. Cranial nerves were normal. The strength examination was normal. Deep tendon reflexes were normal. Plantar responses were flexor. There were no adventitious movements. Light touch, pinprick, vibration, and proprioception were normal. Tone and bulk were normal. Pull test was positive. Romberg was negative. She pushed with arms to elevate from a seat. Frontal release signs showed positive snout and palmomental. Fine finger movements were slowed throughout. No pseudobulbar affect.

Gait Frontal gait is characterized by short steps, wide base, and difficulty lifting the feet off the floor (magnetic response).

Diagnosis NPH (Figure 6.1–-the wide base can be visualized).

Case 5: history This is a 65-year-old left-handed woman with history of hypertension who had acute onset of “inability to speak” and weakness of her right-side arm/leg. She was unable to lift her right leg and arm at first. She noted that her drink was coming out of her mouth. She went to the emergency room after 48 hours of symptoms. After further questioning, she noted an increasing headache over the past several weeks, with a “worse” headache the day of maximal symptoms. She has a remote history of melanoma. She was noted to have an elevated blood pressure.

Physical examination The general medical examination is unremarkable. The mental status examination was normal. Cranial nerves revealed a right central facial. Strength examination showed right triceps, right hamstring, psoas weakness grade 4/5. There was a positive fixed arm roll, as well as pronator drift. Coordination showed difficulty with finger–nose–finger test not out of proportion to weakness. Deep tendon reflexes were hypoactive on the right. Plantar responses were extensor on the right. There were no adventitious movements. Light touch and pinprick were decreased on the right upper and lower extremity. Vibration and proprioception were normal. Tone and bulk were normal.

Gait She swings her leg outward and in a semicircle from the hip (circumduction) and displays external rotation of the right foot. She does not swing her right arm, and her right leg is slower than the left (see Figure 6.1).

Diagnosis Hemiparetic gait. Imaging revealed a hemorrhage in the left basal ganglia; detailed imaging with MRI revealed an underlying lesion with hemorrhage, likely because of metastatic melanoma.

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Seror, P., Krahn, M., et al. (2008) Complete fatty degeneration of lumbar erector spinae muscles caused by a primary dysferlinopathy. Muscle Nerve, 37: 410–414. Snijders, A.H., Van De Warrenburg, B.P., Giladi, N., and Bloem, B.R. (2007) Neurological gait disorders in elderly people: clinical approach and classification. Lancet Neurol, 6: 63–74. Stevens, J.A., Mack, K.A., et al. (2006) The costs of fatal and nonfatal falls among older adults. Inj Prev, 12 (5): 290–295. Stevens, J.A., Mack, K.A., et al. (2008) Self-reported falls and fallrelated injuries among persons aged > or = 65 years–-United States, 2006. J Safety Res, 39 (3): 345–349. Studenski, S. (2009) Bradypedia: is gait speed ready for clinical use? J Nutr Health Aging, 13 (10): 878–880. Studenski, S., Perera, S., et al. (2011) Gait speed and survival in older adults. J Am Med Assoc, 305 (1): 50–58. Sudarsky, L. (1990) Geriatrics: gait disorders in the elderly. N Engl J Med, 322 (20): 1441–1446. Sudarsky, L. (2001) Gait disorders: prevalence, morbidity, and etiology. Adv Neurol, 87: 111–117. Sudarsky, L. and Simon, S. (1987) Gait disorder in late-life hydrocephalus. Arch Neurol, 44: 263–267. Sudarsky, L. and Tideiksaar, R. (1997) The cautious gait, fear of falling, and psychogenic gait disorders. In: Gait Disorders of Aging. Philadelphia: Lippincott Raven. Tanner, C.M. and Goldman, S.M. (1996) Epidemiology of Parkinson’s disease. Neurol Clin, 14: 317–335. Tattersall, I. (1998) Becoming Human: Evolution and Human Uniqueness. New York: Harcourt Brace and Company. Tinetti, M. and Mendes de Leon, C. (1994) Fear of falling and fallrelated efficacy in relationship to functioning among community elders. J Gerontol, 49 (3): M140–M147. Tinetti, M.E., Baker, D.I., et al. (1994) A multifactorial intervention to reduce the risk of falling among elderly living in the community. N Engl J Med, 331: 821–827. Tinetti, M.E., Doucette, J., et al. (1995) Risk factors for serious injury during falls by older persons in the community. J Am Geriatr Soc, 43 (11): 1214–1221.

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Chapter 7 Imaging of the Geriatric Brain 7.1 Structural Neuroimaging in Degenerative Dementias

Liana G. Apostolova1 7.2 Functional Imaging in Dementia

Adam S. Fleisher2 and Alexander Drzezga2 7.3 Amyloid Imaging

Anil K. Nair3 and Marwan N. Sabbagh4 1

Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

2

Banner Alzheimer’s Institute, Department of Neurosciences, University of California, San Diego, CA, USA and Department of Nuclear Medicine, University Hospital of Cologne, Cologne, Germany 3Clinic

for Cognitive Disorders and Alzheimer’s Disease Center, Quincy Medical Center, Quincy, MA, USA

4Banner

Sun Health Research Institute, Sun City, AZ, USA

Summary Structural Neuroimaging in Degenerative Dementias • Neurodegenerative disorders cause brain changes that can be detected with structural imaging. • Hippocampal atrophy, cortical atrophy, ventricular enlargement, and white matter changes are structural biomarkers for the presence of AD. • Structural biomarkers for frontotemporal dementias (FTDs) (differ by phenotype) are as follows: • fvFTD: frontal atrophy, which is often asymmetrical. • Nonfluent PPA: left perisylvian atrophy. • Fluent PPA: anterior temporal lobe involvement. • Structural biomarkers for dementia with Lewy bodies (DLB): • Mild-to-moderate, nonspecific, generalized brain atrophy. • Atrophy of dorsal midbrain, hypothalamus, and substantia innominata. • Structural biomarkers of Parkinson’s disease dementia: • Widespread cortical atrophy of the limbic, temporal, parietal, frontal, and occipital regions. • Atrophy of caudate nuclei and lateral and third ventricular enlargement. • Structural biomarkers of corticobasal degeneration: • Asymmetric frontoparietal atrophy that involves the sensorimotor strip. • Structural biormarkers of progressive supranuclear palsy: • Atrophy of the midbrain tegmentum, enlargement of the third ventricle. • Structural biomarkers in Creutzfeldt–Jakob disease: • Increased T2, fluid attenuation inversion recovery (FLAIR) and diffusion-weighted abnormalities in the cortical ribbon and basal ganglia.

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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Functional Imaging in Dementia FDG-PET • Currently a complementary procedure in the diagnostic evaluation of dementia. • Progressive reduction of complete metabolic response (CMR) in hippocampal, temporoparietal, and posterior cingulate areas occur years before the onset of clinical AD. • It is 94% sensitive and 73% specific for AD and shows reduced temporoparietal glucose utilization may be detectable before notable amyloid pathology. • In frontotemporal dementias (FTDs), it shows frontal or temporal hypometabolism with relative sparing of the parietal lobes. • In dementia with Lewy bodies (DLB), glucose utilization is impaired in the primary visual and occipital association cortices in addition to the precuneus and posterior cingulate areas; and dopamine PET scans may show reduced striatal dopaminergic activity. SPECT • Shows decreased temporoparietal perfusion in AD with sparing of primary sensorimotor strip and basal ganglia. • Isoflupane(IFP)-CIT-SPECT shows nigrostriatal hypoperfusion and is useful to distinguish DLB from Alzheimer’s disease (AD) and Parkinson’s disease (PD). • Metaiodobenzylguanine(MIBG)-SPECT may be a good measure of cardiac sympathetic denervation in DLB. • Vascular dementia shows nonspecific patchy hypoperfusion in the neocortex, subcortical regions, and cerebellum. • Frontal blood flow has 80% sensitivity and 65% specificity in distinguishing FTDs from AD. fMRI • Research tools such as blood-oxygenation-level-dependent (BOLD) imaging and arterial spin labeling (ASL) are magnetic resonance imaging (MRI) techniques to magnetically tag blood and may have superior temporal and spatial resolution compared with PET and SPECT. • Hippocampal and parahippocampal regions show reduced BOLD activations during episodic encoding tasks in clinical AD. • In early mild cognitive impairment (MCI) and in APOE4 carriers, there may be a compensatory increase in hippocampal BOLD response that precedes clinical worsening. • Default mode networks (DMNs) show reduced resting state connectivity as well as alterations in task-induced deactivation in MCI, AD, and in APOE4 carriers. Amyloid Imaging • Amyloid imaging may help identify individuals at high risk for AD as well as test the efficacy of anti-amyloid therapeutics in clinical trials. • It uses two types of radio-labeled agents, (11)C—Pittsburgh Compound B (PiB) and (18)F— florbetapir, florbetaben, flutemetamol. • Plasma or cerebrospinal fluid (CSF) amyloid measurements indirectly estimate the extent of cerebral amyloidosis, but imaging can directly assess amyloid plaque pathology. • Amyloid imaging will soon supplement clinical evaluation in the diagnosis of AD, while MRI and FDG-PET may supplant cognitive tests as markers of disease progression. (11)C LABELED AGENTS • (11)C has a half-life of only 20 minutes, making large-scale distribution difficult. • PiB, the most extensively studied isotope, is an analog of the amyloid-binding dye Thioflavin-T. • It has an on-and-off accumulation pattern unlike the progression of pathologic brain changes. • BF227 labels dense amyloid deposits like Abeta plaques in AD as well as Lewy bodies in PD. (18)F LABELED AGENTS • The 2-hour half-life allows distribution from regional cyclotron facilities to local scanners for up to 10 hours post manufacture. • FDDNP-PET provides detailed visualization of both Abeta plaques and neurofibrillary tangles (NFTs) in AD. • Florbetapir, florbetaben, and flutemetamol show high affinity specific binding to amyloid deposits in the brain.

Chapter 7.1 Structural Neuroimaging in Degenerative Dementias Liana G. Apostolova Disclosures: This project was supported by a grant from the National Institute on Aging for the UCLA Alzheimer’s Disease Research Center (P50 16570) and the Jim Easton Consortium for Alzheimer’s Drug Discovery and Biomarker Development.

Dementia is the persistent state of serious cognitive, functional, and emotional deterioration from a previously higher level of functioning, leading to impaired abilities of self-care and independent living. Dementia most commonly results from insidiously progressive neurodegenerative disorders such as Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). These disorders invariably cause irreversible brain parenchymal changes, which can be frequently detected with structural imaging. In recent decades, the predementia stages of neurodegeneration have attracted significant attention and have led to the recognition of a state called mild cognitive impairment (MCI). MCI (Petersen et al., 2001) and the related construct of prodromal AD (Dubois and Albert, 2004; Dubois et al., 2007) are increasingly important foci of research and clinical attention in our efforts to identify and treat patients early. The 2001 American Academy of Neurology (AAN) guidelines (Knopman et al., 2001) recommend structural neuroimaging as part of the routine clinical evaluation of patients with cognitive impairment supported by class II evidence of nondegenerative lesions, such as a slowgrowing brain neoplasm, subdural hematomas, or normal-pressure hydrocephalus, being the culprit for cognitive decline (Chui and Zhang, 1997). Although magnetic resonance imaging (MRI) is preferred, if MRI technology is not available or an MRI is contraindicated (such as in patients with pacemakers), computed tomography (CT) should be used. Recently, the role of structural and functional neuroimaging in the initial assessment and outcome prediction for subjects with cognitive decline has expanded with the newly proposed prodromal AD diagnostic criteria. This criteria is based on a combination of characteristic cognitive features and a well-established positive disease biomarker such as hippocampal atrophy or cerebrospinal fluid Abeta, and tau levels or a positive amyloid PET scan suggestive of AD (Dubois et al., 2007).

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The role of structural neuroimaging in Alzheimer’s disease Hippocampal atrophy Atrophy of the medial temporal lobe structures—the entorhinal cortex and the hippocampus—are considered the classic structural imaging hallmark of AD (Jack et al., 2004; Apostolova et al., 2006b; see Figure 7.1). These changes can be easily appreciated as early as the prodromal AD stages. As the disease evolves into a full-blown dementia syndrome, significant global brain atrophy with temporoparietal predilection and ventricular enlargement develops (see Figures 7.1 and 7.2; Thompson et al., 2003; Apostolova et al., 2007). These are easily appreciated on conventional CT or structural MRI sequences. In addition, MRI gradient echo sequences can reveal another common finding in AD patients—multiple small hemorrhages in the brain and spinal cord. These are due to accompanying amyloid angiopathy, which can also result in large, lifethreatening lobar hemorrhages in late life. The hippocampal imaging research field has been particularly productive in the past decade. Imaging biomarkers are presently being developed as diagnostic and prognostic biomarkers and as surrogate biomarkers for clinical trials. Hippocampal atrophy, the most validated structural biomarker, is already being accepted as a biomarker criterion for AD presence in the prodromal AD stages (Dubois et al., 2007). The hippocampus undergoes age-related structural changes. Hippocampal atrophy has been found to accompany normal aging with an estimated volume loss rate of around 1.6–1.7% annually (Jack et al., 1998, 2000). MCI subjects who eventually convert to dementia and AD subjects show a hippocampal volume loss of 3.7% and 3.5–4% per year, respectively, but MCI subjects who remain cognitively stable show an annual atrophy rate of 2.8% (Jack et al., 1998, 2000). Although this volumetric measure is seemingly useful and intuitive, it cannot capture the complex pattern of disease progression within the hippocampal structure (Schonheit et al., 2004).

Structural Neuroimaging in Degenerative Dementias

AD

Coronal view hippocampal head

Mid-sagittal view

NC

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images from a normal elderly person (normal control (NC), left column) and an advanced AD patient (right column). Significant hippocampal atrophy can be easily appreciated in the sagittal (top row) and coronal sections through the hippocampal head (middle row) and body (bottom row). Cortical thinning of the entorhinal and parahippocampal cortex is also evident in AD.

Coronal view hippocampal body

Figure 7.1 7T structural MRI hippocampal

Figure 7.2 Brain atrophy in prodromal and advanced AD. In the

prodromal stages, mild hippocampal and global brain atrophy and mild ventriculomegaly are noted. In advanced AD, severe hippocampal and global brain atrophy and ventriculomegaly are easily identified.

New and advanced methodologies provide a unique opportunity to study the earliest AD-associated changes in the hippocampal structure. Advanced computational anatomy, hippocampal shape, and deformation techniques allow us to study the subregional hippocampal changes (Csernansky et al., 2000; Thompson et al., 2004). For example, the hippocampal radial distance mapping approach (which models the hippocampal structure in 3D) computes hippocampal thickness at each surface point. Using the radial distance or other conceptually related approaches, researchers have now mapped the progression of AD pathology through the hippocampal structure in vivo (Csernansky et al., 2000, 2005; Apostolova et al., 2006a, 2006b, 2010c) and documented the spread of hippocampal atrophy from the subiculum and CA1 subfield to the CA2-3 region—a pattern that was previously captured in only postmortem studies (Schonheit et al., 2004). The unsurpassed precision of surface-based approaches has allowed us to also document subtle hippocampal structural changes years before the onset of cognitive decline, suggesting a potential role of such technologies in presymptomatic diagnosis and risk assessment. For example, subtle atrophy can be readily detected in the prodromal AD stages as early as 3 years before evident cognitive impairment, warranting a diagnosis of MCI in cognitively normal elderly patients who eventually

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Figure 7.3 3D hippocampal atrophy maps showing the amount of atrophy (in %) accumulated over a 3-year period in cognitively normal elderly patients who remained cognitively normal for 6 years or longer since baseline (NL–NL) and cognitively normal elderly patients who were diagnosed with amnestic MCI at 3 years and AD at 6 years (NL–MCIAD). (For a color version, see the color plate section.)

develop full-blown dementia syndrome of the Alzheimer’s type (Apostolova et al., 2010b; see Figure 7.3). In addition, CA1 atrophy of the hippocampus at baseline was recently shown to increase the future risk of conversion to dementia in the MCI stage (Apostolova et al., 2010c). The next major advance in structural hippocampal imaging is the recent development of automated hippocampal segmentation techniques (Fischl et al., 2002, 2004; Yushkevich et al., 2006; Morra et al., 2008a), which has allowed rapid and successful analyses of very large datasets such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI; Morra et al., 2009a). ADNI data analyses have confirmed previous findings from smaller studies and helped us map the expected associations between hippocampal atrophy and cognitive deterioration (Apostolova et al., 2006d; Morra et al., 2008b; Mormino et al., 2009; Beckett et al., 2010). Important observations from the ADNI study have also linked genetic risk factors and rates of hippocampal atrophy. The hippocampi of APOE ε4 allele carriers were reported to atrophy faster than those of noncarriers (Morra et al., 2009b; Schuff et al., 2009; Beckett et al., 2010). MCI subjects with a maternal history of dementia had greater atrophy at baseline and greater 12-month atrophy rates relative to those who had a negative maternal history of dementia (Andrawis et al., 2012).

Cortical atrophy Cortical atrophy, a classic feature of AD, has also been heavily researched in recent years with advanced and more precise techniques and approaches. The contemporary cortical thickness approaches currently offer the most precise cortical mapping (Fischl et al., 1999; Fischl and Dale, 2000; Thompson et al., 2003). Using these techniques has allowed us to document in vivo the progressive spread of cortical atrophy in subjects with AD

(Thompson et al., 2003), to identify the excess cortical damage in subjects with very mild AD compared with those with MCI (see Figure 7.4; Apostolova et al., 2007), and to ascertain the cortical subregions that most sensitively predict AD type dementia in the elderly (Lerch et al., 2005; Bakkour et al., 2009). Cortical areas that are affected early include the entorhinal, parahippocampal, inferior, and lateral temporal cortices, with disease changes spreading next to the parietal and frontal association cortices (see Figure 7.4; Thompson et al., 2003). It is now well established that MCI subjects have intermediate cortical thickness relative to cognitively normal elderly and AD subjects in the normal aging–dementia continuum (Singh et al., 2006). Similar to hippocampal atrophy, cortical atrophy shows robust correlations with cognitive impairment (Thompson et al., 2003; Apostolova et al., 2006c, 2008a). Because the association cortex is highly specialized, the observed brain–behavioral associations have been very insightful. Global measures of cognitive decline, such as the mini– mental state examination (MMSE), show a widely distributed pattern of association with cortical atrophy, including the entorhinal, parahippocampal, precuneal, superior parietal, and subgenual cingulate association cortices (Apostolova et al., 2006c). However, impaired language function showed associations with the perisylvian cortical areas thought to play an important role in lexical and semantic storage and retrieval and language processing (Apostolova et al., 2008a). Investigating the effects of APOE4 genotypes on cortical atrophy has resulted in several interesting reports. Several groups recently reported that APOE4 carriers show a more aggressive involvement of the temporal association cortices relative to noncarriers (Filippini et al., 2009; Gutierrez-Galve et al., 2009; Pievani et al., 2009).

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Figure 7.4 Cortical atrophy in AD. Relative to patients with amnestic MCI, patients with very mild AD show extensive cortical atrophy of the entorhinal, parahippocampal, inferior, and lateral temporal cortices, with disease changes spreading next to the parietal and frontal association cortices (left column). The pattern is strikingly similar to the amyloid deposition described in Braak and Braak amyloid stage B (right column). (For a color version, see the color plate section.)

Ventricular enlargement Ventricular enlargement is another consistent finding in AD. The radial distance approach has also been applied to study the changes in the ventricular system in AD. Although ventricular enlargement is largely nonspecific and occurs in many degenerative and nondegenerative neurologic conditions, it is a robust imaging biomarker in AD. MCI subjects show a posterior-predominant enlargement of the lateral ventricles; however, when subjects are in the dementia stages of AD, a panventricular enlargement is readily observed (Chou et al., 2008). APOE4 carriers show a frontal-predominant dilatation pattern relative to APOE4 noncarriers. Cognitive measures show the expected strong linkage in an AD-like pattern (Chou et al., 2008). White matter changes White matter changes have been long implicated in neurodegeneration (Bartzokis et al., 2004; Bartzokis, 2007) and have been associated with cognitive decline in the elderly (Debette et al., 2010). In the ADNI sample, greater white matter hyperintensity burden at baseline was associated with greater cognitive decline during the following 12 months (Carmichael et al., 2010). Diffusion-weighted imaging (DWI) sequences have been recently utilized to study white matter integrity. Microstructural changes in the myelin sheath result in greater diffusivity and reduced fractional anisotropy on DWI sequences, and are positively correlated with worsening cognition in MCI and AD (Wang et al., 2010). A comprehensive meta-analysis recently revealed that the white matter changes in AD are nonuniform. The greatest changes in fractional anisotropy and mean diffusivity were seen in the uncinate fasciculus (the white matter

tract connecting the hippocampus and amygdala with the anterior temporal lobe) and the superior longitudinal fasciculus (a white matter tract connecting the anterior (frontal) with the posterior (temporal, parietal, and occipital) association cortices; Sexton et al., 2011.). Medium effect size was seen in the genu and splenium of the corpus callosum and the frontal and temporal white matter (Sexton et al., 2011). Among subjects with MCI, the most pronounced differences relative to normal controls were seen in the hippocampus and parietal white matter (Sexton et al., 2011). Decreased fractional anisotropy has been reported in preclinical presenilin mutation carriers in the fornix and orbitofrontal white matter, suggesting that brain parenchymal changes begin years and possibly decades before dementia onset (Ringman et al., 2007).

The role of structural neuroimaging in the frontotemporal dementia (FTD) spectrum The FTDs are a group of neurodegenerative disorders affecting the frontal or temporal lobes disproportionately to the rest of the brain with variable post-mortem pathologic findings. The group comprises several distinct phenotypes: the classic frontal or behavioral variant FTD (fvFTD), two language variants—primary progressive aphasia (PPA) and semantic dementia (SD)—and one variant with associated motor neuron disease (MND), FTD-MND. At the time of diagnosis patients with fvFTD usually reveal substantial frontal or temporal (often asymmetrical) atrophy (see Figure 7.5). The classic MRI feature of nonfluent PPA is left perisylvian atrophy, particularly in

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Figure 7.5 Brain atrophy in FTD. Frontal variant FTD is characterized by prominent frontal lobe atrophy. Primary progressive aphasia subjects have asymmetric left-predominant perisylvian atrophy most pronounced in the posterior portions of the inferior frontal gyrus. SD patients characteristically present with left-predominant anterior temporal atrophy.

the inferior frontal cortex and insula; however, fluent PPA patients tend to show inferior, middle, and polar temporal lobe involvement. SD patients usually present with bilateral anterior temporal lobe involvement (Gorno-Tempini et al., 2004; Chao et al., 2007). DWI imaging in FTD has also shown abnormalities. Reduced fractional anisotropy has been reported in the frontal and temporal lobe white matter and the anterior cingulate (Zhang et al., 2009). Reduced fractional anisotropy in the uncinate fasciculus and the occipitofrontal fasciculus have recently been reported in still asymptomatic Progranulin mutation carriers, suggesting that brain parenchymal changes begin years and possibly decades before the onset of dementia (Borroni et al., 2008).

The role of structural neuroimaging in dementia with Lewy bodies On the basis of structural imaging alone, DLB is difficult to distinguish from AD. Upon visual inspection of clinical CT or MRI scans, patients with DLB often have mild-tomoderate nonspecific, generalized brain atrophy. Hippocampal involvement may be present. After a larger number of DLB subjects scans are analyzed, some atrophy patterns emerge. DLB has been associated with diffuse temporal, parietal, and frontal cortical atrophy (Burton et al., 2002; Ballmaier et al., 2004; Beyer et  al., 2007b), as well as with atrophy of the dorsal midbrain, hypothalamus, and substantia innominata (Whitwell et al., 2007). Diffusion tensor imaging (DTI) signal changes in DLB are somewhat similar to patients with AD. Decreased fractional anisotropy was found in the inferior longitudinal fasciculus—the white matter tract connecting the temporal with the occipital lobes—in both disorders (Kantarci et al., 2010). In the DLB group, this finding showed a strong association with visual hallucinations (Kantarci et al., 2010). Another study compared the DTI characteristics between DLB and Parkinson’s disease dementia (PDD). Relative to the PDD group, DLB subjects showed more severe and more extensive abnormalities, with fractional

anisotropy decreases in the posterior cingulate and visual cortices (Lee et al., 2010).

The role of structural neuroimaging in Parkinson’s disease dementia Cognitive impairment is arguably the most understudied nonmotor syndrome in Parkinson’s disease (PD). Yet as many as 90% of all PD subjects develop dementia during the disease course (Buter et al., 2008). In PD, the clinical indications for obtaining an MRI would be to rule out basal ganglia strokes, diffuse white matter ischemic changes, features associated with other parkinsonian disorders, such as midbrain atrophy, which is commonly seen in progressive supranuclear palsy (PSP), or an asymmetric frontoparietal atrophy that could suggest corticobasal degeneration (CBD). Yet widespread cortical atrophy in PDD- and PD-associated MCI does occur and involves the limbic, temporal, parietal, frontal, and occipital cortical regions and caudate nuclei (Burton et al., 2004; Beyer et al., 2007a; Meyer et al., 2007; Apostolova et al., 2010a; Hwang et al., 2013). These cortical changes are also accompanied by atrophy of the caudate nuclei and lateral and third ventricular enlargement (Meyer et al., 2007; Apostolova et al., 2010a). As previously mentioned, PDD subjects also show decreased fractional anisotropy in the frontal, temporal, and parietal white matter (Lee et al., 2010).

The role of structural neuroimaging in other parkinsonian dementias and Creutzfeldt–Jakob disease The frequently asymmetric clinical cortical features of CBD—cortical sensory loss, and limb apraxia—are reflected in often strikingly asymmetric contralateral frontoparietal atrophy, with clear involvement of the motor and sensory cortices. High T1 signal intensity of the subthalamic nucleus, midbrain atrophy, and T2 striatal hypointensity can also be seen (Sitburana and Ondo, 2009; Tokumaru et al., 2009).

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promising disease-modifying agents in the pharmaceutical pipeline, AD researchers are hopeful to soon be able to cure and prevent this most devastating neurodegenerative disorder.

References

Figure 7.6 Diffusion-weighted imaging findings in CJD. Extensive cortical hyperintensities can be identified in the right temporal, the bilateral insular and frontal cortex, and the caudates.

The classic structural MRI abnormalities of PSP are atrophy of the midbrain tegmentum, enlargement of the third ventricle, hyperintensity of the midbrain, and inferior olives (Oba et al., 2005; Boxer et al., 2006). Some studies have also reported frontal and temporal cortical atrophy and hypointensity of the red nucleus and putamen (Gupta et al., 2010). The classic MRI findings in Creutzfeldt–Jakob disease (CJD) are increased T2, fluid attenuation inversion recovery (FLAIR), and diffusion signal of the basal ganglia and the cortical ribbon. Such findings are essentially pathognomonic for CJD (see Figure 7.6; Milton et al., 1991; Hirose et al., 1998; Yee et al., 1999; Zeidler et al., 2000; Matoba et al., 2001).

Conclusions Structural neuroimaging almost invariably shows significant abnormalities in most neurodegenerative disorders. The most prevalent neurodegenerative disorder—AD— is one of the leading health concerns of the twenty-first century, with an increasing elderly population and its exponentially increasing social and economic impact. Researchers are already tuned into developing powerful biomarker strategies that can potentially identify the cognitively normal elderly who have entered the presymptomatic (prodromal) AD stages, as these subjects would be the ideal therapeutic target for any disease-modifying drug. In the recent two decades, neuroimaging researchers have developed major revolutionary technologic advances in both structural and functional neuroimaging fields. The rapid development of new promising techniques capable of reliable, sensitive, and powerful detection of focal disease-induced changes instills optimism that disease course and therapeutic response could be carefully monitored and appraised. With several

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Chapter 7.2 Functional Imaging in Dementia Adam S. Fleisher and Alexander Drzezga Alzheimer’s disease (AD) is pathologically manifested as synaptic loss and neuronal death, with subsequent reduction of metabolic activity and brain volume loss. Although the specific neurodegenerative pathway in AD is unknown, it is believed to predominantly be an amyloid protein-mediated process (Braak and Braak, 1991, 1994; Selkoe, 2000). It is most widely accepted that beta amyloid (Aβ) is poorly cleared in AD patients, leading to increased soluble and insoluble extracellular Aβ, also leading to fibrillar amyloid plaque deposition and downstream neurotoxic pathways (Selkoe, 2008). According to this hypothesis, excess Aβ leads to loss of neuronal synapses, intracellular neurofibrillary tangles (NFTs), and cellular toxicity, resulting in mitochondrial dysfunction and, ultimately, cell death (Mirra et al., 1991, 1993). This pathologic process progresses in predictable regional patterns predominantly involving structures in the basal forebrain, medial temporal lobes (MTLs), and parietal cortex (Braak and Braak, 1996). In addition, neuropathology and synaptic dysfunction may occur several decades before clinical manifestations (Braak and Braak, 1991; Reiman et al., 2004; Engler et al., 2006; Mintun et al., 2006). And it is likely that neuronal synaptic dysfunction precedes Aβ plaque deposition and the gross pathologic changes associated with AD (Selkoe, 2002). If physiologic changes can be identified before clinical and gross pathologic changes, this provides a potential opportunity for sensitive presymptomatic imaging biomarkers of disease. Standards for the diagnosis of dementia today are based entirely on clinical symptoms (McKhann et al., 1984). Medical history of progressive cognitive decline consistent with AD, ruling out active confounding comorbidities, and neuropsychological evaluations are the mainstays for establishing a diagnosis of dementia. Neuropsychological evaluations, however, have a relatively low sensitivity and specificity of 80% and 70%, respectively, for identifying pathologically confirmed dementia of the Alzheimer’s type (Jobst et al., 1998; Knopman et al., 2001; Silverman et al., 2002b; Lopponen et al., 2003; Petrella et al., 2003; Zamrini et al., 2004). Guidelines recommend imaging predominantly as a tool for excluding other causes of dementia, such as cerebrovascular disease, infection, normal pressure hydrocephalus, and other structural lesions (Knopman et al., 2001; http://www. aan.com/professionals/practice/pdfs/dementia_guideline. pdf). New advancements in functional imaging may provide tools for identifying neurodegenerative brain disease

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for clinical decision making and treatment development. Recently, the European Federation of the Neurological Societies (EFNS) recommended the use of functional imaging as part of the routine diagnostic workup of clinically questionable dementia cases (Hort et al., 2010).

What is functional imaging? Unlike imaging of gross brain structures or even micropathology, functional imaging is defined as any imaging modality that represents an underlying physiologic process. This type of imaging can capture static average brain function while a participant is resting with eyes open or closed, or can identify dynamic brain activity in response to a task being performed during image acquisition. Such tasks may be cognitive in nature, such as with memory or language, or reflect sensory-, motor-, visual-, or even smell-related brain activity. Common physiologic targets of functional imaging include brain oxygen utilization, blood perfusion, and glucose metabolism. Various modalities of imaging can be used to identify these physiologic brain functions. In dementia, the most frequently utilized imaging modalities include magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET). All three of these techniques are capable of imaging brain pathology and functional brain physiology. In addition, imaging methods that identify pathologic and physiologic changes associated with disease progression may be superior to neuropsychological testing regarding early and reliable diagnosis of AD (Lim et al., 1999; Hoffman et al., 2000; Silverman et al., 2001). But many techniques in dementia imaging are predominantly used for research and are not approved for clinical purposes. Therefore, this chapter focuses on functional imaging techniques that are available and practical in clinical dementia evaluations for the purpose of guiding physicians in clinical decision making. Structural MRI and amyloid imaging are addressed elsewhere.

Positron emission tomography in dementia PET imaging facilitates the detection of subtle changes in brain physiology. PET uses positron emitters to label

Functional Imaging in Dementia

target physiologic or pathologic brain processes. Positrons are positively charged unstable particles that interact with electrons while traveling through brain tissue. This interaction produces photons. These coincident tissue interactions are detected by sensitive detector rings in the PET scanner that make it possible to identify both spatial and intensity information. Various types of positron-emitting nuclei can be used to label tracers to identify physiologic targets of interest in vivo. The most common are 15O, 11C, and 18F, with 18F being the most widely used in clinical practice, mostly because its longer half-life makes it a more practical molecular isotope. In particular, PET imaging with a glucose analog, 18F fluorodeoxy glucose (FDG), has been used to identify subtle changes in metabolic glucose utilization in the brain. In AD, reductions in regional glucose metabolism, representing cellular metabolic activity, may be one of the earliest detectable brain dysfunctions accompanying the onset of AD pathology. In fact, there is reason to believe that FDG-PET may be able to detect brain dysfunction prior to notable amyloid pathology in the brain (Reiman et al., 2001; Alexander et al., 2002; Caselli et al., 2008; Langbaum et al., 2009). However, this idea is somewhat controversial, given our poor understanding of the relationship between amyloid deposition and glucose metabolism. In fact, there are examples of comparable FDG-PET uptake in amyloid PET positive healthy patients compared with amyloid negative patients, and areas of increased glucose metabolism associated with increased amyloid binding in mild cognitive impairment (MCI) patients (Cohen et al.,

147

2009). Currently, the use of FDG-PET is recommended as only an optional complementary procedure in the diagnostic evaluation of dementia. However, as more information becomes available, it is more likely that functional imaging will play a more prominent role in early clinical diagnosis, risk assessment, and treatment–response monitoring. As a measure of neuronal dysfunction, radiolabeled glucose using FDG-PET allows tracking of glucose metabolism in the brain. It is well understood that glucose utilization parallels neuronal activity as its primary energy source. After intravenous injection, FDG is phosphorylized and incorporated into cells. The amount of regional FDG uptake then provides a spatial and intensity representation of brain cell cerebral metabolic rates of glucose metabolism (CMRgl; Phelps et al., 1983). Synaptic activity of neurons drives glucose utilization, perhaps indirectly, with increased glucose uptake in surrounding glial cells. Lactate is subsequently transferred to neurons for energy metabolism (Magistretti and Pellerin, 1999). In the resting state, FDG uptake is driven mostly by basal neuronal activity. In general, basal state FDG-PET imaging represents underlying neuronal integrity, with decreased function leading to regional reduction in glucose turnover (Rocher et al., 2003). In AD, patients have characteristic patterns of glucose hypometabolism. This consists of reduced FDG-PET signal in temporal–parietal, posterior cingulated, and frontal cortices (see Figure 7.7). These regions are well known to be associated with cognitive function such as memory

92 AD < 104 NC

Figure 7.7 FDG-PET in 92 AD and 184 MCI participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI; Mueller et al., 2006; Jack et al., 2008a), compared with 104 cognitively normal elderly controls. Top images show typical patterns of glucose hypometabolism in Alzheimer’s disease (AD), compared with normal. Bottom images show similar AD-like patterns, but to a less spatial and intensity extent in MCI. See Langbaum et al. (2009) for methodology details. (For a color version, see the color plate section.)

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Assessment of the Geriatric Neurology Patient

and spatial orientation. Likewise, brain regions spared of early hypometabolism in AD include the primary visual, sensory, and motor cortices, consistent with spared associated symptoms in clinical AD (Herholz, 1995; Silverman et al., 2001; Minoshima, 2003). This pattern is also consistent with known patterns of AD pathology (Braak and Braak, 1996; Klunk et al., 2004). Minoshima et al. (2001) found that patients with postmortem histopathologic proof of AD showed typical temporal–parietal, posterior cingulate, and frontal hypometabolic changes in prior FDG-PET scans. Hoffman et al. (2000) reported that temporal–parietal hypometabolism is the typical abnormality in patients with pathologically verified AD. Recently, one autopsy comparison study demonstrated longitudinal decline in FDG-PET CMRgl in cognitively normal individuals followed an average of 13 years (Mosconi et al., 2009b). Two of four patients declined to clinical AD in that time period. The authors observed that progressive CMRgl reductions on FDG-PET occurred years in advance of clinical AD symptoms in patients with pathologically verified disease. Deficits in CMRgl demonstrated progressive AD-like patterns, with most prominent reductions in the hippocampus, temporal–parietal, and posterior cingulate cortices. The FDG-PET profiles in life also were consistent with the postmortem diagnosis of AD. This small case series supports the idea that FDG-PET is a valuable preclinical marker of AD pathophysiology.

Disease severity and cognitive decline is strongly associated with glucose hypometabolism in AD (Kawano et al., 2001; Alexander et al., 2002; Bokde et al., 2005; Langbaum et al., 2009). In fact, regions of brain glucose hypometabolism that correlate with measures of global cognition are similar to patterns characteristic for AD (Langbaum et al., 2009). Figure 7.8 shows patterns of glucose hypometabolism correlated with the mini–mental state examination (MMSE) scores (Folstein et al., 1975), a brief global test of cognition commonly used in clinical practice, and the Clinical Diagnostic Rating scale (CDR; Berg, 1988), which is a functional and global cognitive assessment tool commonly used as an endpoint measure in AD clinical treatment trials. FDG-PET is highly sensitive and moderately specific for dementia of the Alzheimer’s type, with superior accuracy compared with neuropsychological testing. In a large multicenter trial, Silverman et al. (2001) found a sensitivity of 94% and a specificity of 73% for identifying histopathologically proven AD. Comparatively, when using pathologically confirmed AD as a diagnostic gold standard, neuropsychological testing has shown a sensitivity of 85% and specificity of 55% (Lim et al., 1999; Hoffman et al., 2000). These studies provide convincing evidence that diagnostic workups for AD that include FDG-PET are more accurate than neuropsychological and medical evaluation alone. In addition, it has been demonstrated

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Figure 7.8 FDG-PET in 298 participants with varying degrees of MCI and AD, and cognitively normal elderly from ADNI ( Mueller et al., 2006; Jack et al., 2008a). (a) Areas of correlated FDG-PET binding representing glucose hypometabolism associated with CDR scores. (b) Areas of correlated FDG-PET binding representing glucose hypometabolism associated with MMSE scores. Regions associated with cognitive impairment are similar to those associated with a diagnosis of clinical AD (Figure 7.7). See Langbaum et al., 2009 for methodology details. (For a color version, see the color plate section.)

Functional Imaging in Dementia

that FDG-PET is cost-efficient and can lead to improved management, including therapeutic decision-making and overall patient care (Silverman et al., 2002a, 2002b; Moulin-Romsee et al., 2005). Although there is some controversy regarding whether glucose hypometabolism is a cause or consequence of AD, FDG-PET represents a valuable tool for early diagnosis and differential diagnosis in AD (Silverman et al., 2002b; Minoshima, 2003). FDG-PET is the most validated functional imaging technique available to most clinicians for evaluating dementia patients. AD is a clinical diagnosis in evolution, with a push to define the disease by pathologic biomarkers as part of clinical diagnostic criteria (Dubois et al., 2007). Efforts are currently underway by the National Institute on Aging and the Alzheimer’s Association to revise existing NINCDS-ADRDA diagnostic criteria to better reflect this emphasis on biomarker evidence of disease. Recent recommendations from the EFNS include use of FDG-PET or perfusion SPECT in patients where there is diagnostic doubt in clinical dementia presentation (Hort et al., 2010). Functional imaging also may play an important role in identifying the earliest clinical stages of the disease processes. FDG-PET has been shown to be valuable in detecting early disease such as MCI, as a transitional stage between normal aging and clinical dementia. In addition, FDG-PET may be capable of identifying AD-like hypometabolism in asymptomatic people at increased risk factors for AD, suggesting its potential use as a presymptomatic predictor of future cognitive decline.

FDG-PET in MCI A clinical diagnosis of MCI is defined as a loss of cognitive function that exceeds common age-associated changes but does not meet the diagnostic criteria for dementia (Petersen et al., 1999, 2001; Petersen, 2000). Thus, MCI is regarded as a risk population for AD. Consequently, current guidelines of the American Academy of Neurology recommend that patients with MCI be identified and monitored for progression to AD (Knopman et al., 2001). Glucose hypometabolism occurs in MCI patients in patterns similar to those with AD, but to a lesser degree (see Figure 7.7). A number of studies have evaluated the value of FDG-PET in the diagnostic assessment of MCI. Several cross-sectional studies (some of them large, multicenter studies with more than 100 MCI subjects) have consistently demonstrated that FDG-PET imaging can reliably differentiate groups of MCI patients from healthy controls and on the basis of specific hypometabolic patterns (Minoshima et al., 1997; Drzezga et al., 2003, 2005; Del et al., 2008; Nobili et al., 2008). A number of studies have identified a predictive value of FDG-PET as a biomarker for determining future AD (Herholz et al., 1999; Arnaiz et al., 2001; Silverman et al., 2001; Chetelat et al.,

149

2003; Drzezga et al., 2003, 2005; Mosconi et al., 2004; Hunt et al., 2007; Nobili et al., 2008; Landau et al., 2011). All these studies were able to identify typical hypometabolic changes in FDG-PET baseline examinations of MCI patients, associated with later conversion to AD dementia, whereas stable subjects showed fewer or no abnormalities. Generally, high sensitivity and specificity values were calculated (75–100%). Drzezga et al. (2005) demonstrated a sensitivity of 92% and a specificity of 89% (positive predictive value 85%, negative predictive value 94%) for predicting conversion to AD within 16 months. A number of studies were also able to demonstrate higher accuracy of FDG-PET for prediction of AD dementia in MCI patients, compared with neuropsychological examination (Silverman et al., 2001; Mosconi et al., 2004). While postmortem neuropathologic evaluation was considered as the gold standard, it is clear that adding FDG to the diagnostic evaluation improves prediction accuracy (Silverman et al., 2001). It is commonly agreed that brain pathology in AD begins many years prior to clinical symptoms of cognitive impairment. In fact, this pathologic burden may begin as many as 20 years before clinical manifestations (Mintun et al., 2006; Fagan et al., 2007). Functional imaging therefore affords us the opportunity to potentially identify AD before clinical symptoms develop. This is critically important for developing treatments to prevent future dementia and screening for individuals at increased risk for AD. Current diagnostic guidelines recommend against cognitive screening in asymptomatic individuals. Therefore, use of known risk factors for AD in healthy elderly individuals may provide guidance in determining which individuals should be screened for the pathologic hallmarks of AD. For example, patients with a strong family history of dementia and those with known genetic risk factors may have detectible presymptomatic biomarkers of AD pathology and represent such a risk population (Fratiglioni et al., 1993; Corder et al., 1998; Ghebremedhin et al., 1998).

FDG-PET in the evaluation of presymptomatic risk for AD Early-onset familial Alzheimer’s disease (FAD) is associated with autosomal-dominant inheritance of mutations in the presenilin and amyloid precursor protein genes (Goate, 1997; Ermak and Davies, 2002). Regional glucose hypometabolism on FDG-PET has been associated with asymptomatic FAD gene carriers, consistent with the typical AD PET pattern in the relative absence of structural brain atrophy (Mosconi et al., 2006; Nikisch et al., 2008). However, cases of FAD with autosomal-dominant inheritance represent only a small percentage of all AD cases and have a very different clinical onset and course

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compared with the more common late-onset sporadic AD (LOAD). Thus, findings obtained in this population may not be generalizable to LOAD. The apolipoprotein E (APOE) e4allele (ε4) is currently the most potent known genetic risk factor for LOAD (Corder et al., 1993; Farrer et al., 1997). It is associated with the subsequent presence of NFTs and amyloid plaques in the brain (Corder et al., 2004) and plays a key role in coordinating the mobilization and redistribution of cholesterol, phospholipids, and fatty acids. It also is implicated in the mechanisms of neuronal development, brain plasticity, and repair (Mahley, 1988; Mahley and Rall, 2000). Evidence indicates that it promotes formation of the beta-pleated sheet conformation of Aβ peptides into amyloid fibers and inhibits the neurotoxic effect of Aβ in an allele-specific manner (E3 > E4; Strittmatter et al., 1993; Ma et al., 1996; Jordan et al., 1998). The APOEε4 gene also appears to modulate Aβ toxicity to vascular endothelium (Folin et al., 2006). Having a family history of dementia is independent and additive to the risk associated with the APOE ε4 allele (Cupples, Farrer et al., 2004). For these reasons, presymptomatic pathologic and physiologic brain changes may be identifiable in individuals with genetic risk factors for AD by using FDG-PET. Several studies have been able to demonstrate hypometabolic abnormalities in cognitively impaired individuals at increased risk for AD, including carriers of the APOE ε4 allele and those with family histories of AD. For example,

Left lateral Parietal Prefrontal

Temporal

Right lateral Parietal Prefrontal

Temporal

Left medial Cingulate

Reiman et al. (1996) showed reduced glucose metabolism in ε4 homozygotes, compared with age- and educationmatched noncarriers (ages 50–65 years). This occurred in the same brain regions as in patients with probable AD (posterior cingulate, parietal, temporal, and prefrontal regions). These same authors later demonstrated that even relatively young (20–39 years) ε4 homozygotes had abnormally low rates of glucose metabolism bilaterally in the posterior cingulate, parietal, temporal, and prefrontal cortex, and that the ε4-gene dose is correlated with lower glucose metabolism in each of these brain regions (see Figure 7.9; Reiman et al., 2004, 2005). Furthermore, in several studies, decline of glucose metabolism over time in AD-typical regions has been demonstrated in cognitively healthy ε4 carriers (Small et al., 2000; Reiman et al., 2001). Correspondingly, more pronounced hypometabolism was detected in ε4-positive subjects with clinical AD, compared with age-matched ε4–negative AD patients (Drzezga et al., 2005). Recent studies have also shown hypometabolic changes in subjects with maternal history of AD who are at higher risk for dementia, suggesting additional genetic or environmental risks for LOAD (Mosconi et al., 2007, 2009a). For these reasons, functional brain imaging may be useful for evaluating putative AD prevention therapies in cognitively normal individuals at increased genetic risk for AD near the age of mean clinical dementia onset (Reiman, 2007; Fleisher et al., 2009a; Reiman et al., 2010).

Right medial Cingulate

Figure 7.9 Regions of the brain with abnormally low CMRgl in young adult carriers of two copies of the APOE ε4-allele and their relationship to brain regions with abnormally low CMRgl in patients with probable AD. Purple areas are regions in which CMRgl was abnormally low only in patients with AD. Bright blue areas are regions in which CMRgl was abnormally low in both the young adult e4 carriers and patients with probable AD. The muted blue areas are regions in which CMRgl was abnormally low only in the ε4 carriers. Source: Reiman et al. (2004). Reproduced with permission from National Academy of Sciences. (For a color version, see the color plate section.)

Functional Imaging in Dementia

FDG-PET and other dementias FDG-PET may be particularly useful to clinicians in distinguishing AD from other dementias. As seen, typical patterns of hypometabolism can be identified in patients with AD. Likewise, other dementias show patterns of glucose metabolism that distinguish them from normal controls and AD patients. These disease-specific patterns can be used for differential diagnosis decisions and subsequent clinical management. However, much less data is available on other neurodegenerative dementias, given their relatively low prevalence compared with AD. FDG-PET can often be useful for diagnostic differential conclusions based on patterns of hypometabolism in individual patients. Yet, in common clinical dementia evaluation guidelines(Knopman et al., 2001), routine FDG-PET scans are not recommended in dementia evaluations because the added value over structural imaging has not been well established in individual patients. However it is reimbursable under Medicare, as noted, to distinguish clinically ambiguous cases of AD versus frontal temporal lobar dementia (FTLD). The EFNS guidelines now support its use in such cases (Hort et al., 2010).

Frontal temporal lobar dementia FTLD is a heterogeneous disorder representing a mix of pathologies and clinical presentations (Rabinovici and Miller, 2010). Pathologic features in FTLD syndromes include either tau-positive (FTLD-TAU) or TAR DNAbinding protein 43 (TDP-43)-positive (FTLD-TDP) inclusion bodies. FTLDs are clinical syndromes of progressive dysfunction of the frontal and/or temporal lobes, bilaterally or unilaterally, with clinical decline in behavior and/ or language, resulting in dementia. It is recognized as one of the leading causes of dementia before age 65. These disorders are clinically distinct from AD in most cases, but have overlapping syndromes with atypical parkinsonism, such as corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), as well as with amyotrophic lateral sclerosis. Three primary types of FTLD syndromes exist, including behavioral variant (bvFTD), FTD associated with motor neuron disease (FTD-MND), and primary progressive aphasia (PPA). PPA is subsequently broken down into three aphasia variants: semantic, logopenic, and nonfluent/agrammatic. It has been demonstrated that forms of AD with atypical clinical appearance can be confused with the FTLD syndromes. Diagnosis based on neuropsychological criteria alone cannot assess underlying pathology or reliably differentiate such cases of nonamyloid pathology in atypical AD clinically presenting with FTLD-like symptoms (Neary et al., 1998). Postmortem studies demonstrate that clinical diagnosis alone may lead to confusion of FTLD and AD in some cases (Godbolt et al., 2005). With this degree of clinical and pathologic

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variability, it is not surprising that functional imaging may be just as heterogeneous in presentation. In many cases, functional neuroimaging can improve diagnostic accuracy in distinguishing clinical syndromes of FTLD with AD. Typical patterns of hypometabolism in FTLD include a combination of frontal or temporal predominant CMRgl reductions. At least early on in the course of the disease, these patterns show relative sparing of the parietal lobes, distinguishing them from AD (Ishii et al., 1998, 2000; Silverman et al., 2001; Ishii, 2002; Foster et al., 2007). When seen in individual patients, these patterns are useful in distinguishing FTLD from AD (see Figure 7.10). Foster et al. (2007) demonstrated that adding FDG-PET to clinical diagnostic criteria can significantly increase the accuracy of diagnosis. In comparison of 31 AD patients to 14 FTD patients, they were able to achieve a specificity of 97.6% and sensitivity of 86% for distinguishing AD from FTD. This was particularly true with visual inspections of individual images projected onto stereotactic brain surface projections. Unfortunately, this holds true at the group level but cannot always be identified in individual patients (Silverman et al., 2001). Nonetheless, when typical frontal and/or anterior frontal hypometabolism is seen, it can improve clinical diagnostic accuracy. Figure 7.10D demonstrates an example of frontal hypometabolism on FDG-PET in a patient with bvFTD.

Dementia with Lewy bodies Approximately 15% of dementias occurring over the age of 65 result from dementia with Lewy bodies (DLB), as the second most common type of late-onset dementia (Heidebrink, 2002). DLB involves widespread neuronal degeneration with deposition of Lewy bodies and Lewy neurites, which contain alpha-synuclein as a major filamentous component (Galvin et al., 1999). Similar to AD in its progression with prominent memory dysfunction, DLB also typically presents with fluctuations in cognitive impairment, prominent visuospatial dysfunction and visual hallucinations, and early parkinsonism (McKeith et al., 2005). In fact, DLB is often an overlap syndrome with the majority of DLB patients also meeting pathologic CERAD criteria for AD, with the addition of diffuse cortical Lewy bodies (Fleisher and Olichney, 2005). There have been relatively few investigations of DLB with functional imaging, compared with AD. But consistent with structural findings, there appears to be a relative sparing of the MTL and an overall pattern of glucose hypometabolism, similar to AD (Burton et al., 2002; Weisman et al., 2007). In addition to precuneus and posterior cingulated hypometabolism, decreased glucose utilization is often seen in the primary visual and the occipital association cortices, consistent with the clinical presentation of DLB (see Figure 9.4; Minoshima et al., 2001; Gilman et al., 2005). This pattern of hypometabolism is consistent with a finding of diffuse

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Lewy bodies on autopsy (Albin et al., 1996; Minoshima et al., 2001; Gilman et al., 2005; Mosconi et al., 2009b). One such study by Minoshima et al. (2001) comparing 11 DLB with 10 AD patients, showed significant metabolic reductions in DLB compared with AD, with 90% sensitivity and 80% specificity. In addition, dopaminergic loss and dopamine transport loss in the striatum has been demonstrated at autopsy to be similar in magnitude in DLB to that seen in Parkinson’s disease (PD) (O’Brien et al., 2004). Experimentally, PET ligands that bind to dopamine ([18F] fluorodopa) and monoamine transporters ([11C]DTBZ) have demonstrated reduced striatal dopamine activity in DLB compared with AD, consistent with the high prevalence of parkinsonism in this dementia (Hu et al., 2000; Koeppe et al., 2008; Klein et al., 2010). These dopamine PET imaging techniques are not widely available and are not recommended for routine evaluations of DLB. However, SPECT tracers for imaging of dopamine transporters may have clinical value and have recently been demonstrated to reliably differentiate between DLB and AD.

Vascular dementia Vascular dementia is typically diagnosed with a combination of clinical and MRI findings (van Straaten et al., 2003). Functional imaging would be used only for cases with equivocal findings. In addition, 15–20% of vascular dementia patients will have a combination of AD and vascular pathology (Chui et al., 2000). Findings of patchy deficits rather than typical patterns of parietotemporal dysfunction may help distinguish vascular dementia from AD (Talbot et al., 1998; Jagust et al., 2001). However, MRI imaging for ischemic disease is routinely recommended over functional imaging for diagnostic evaluation.

FDG-PET in the clinic FDG-PET scanning, in general, is approved for clinical use. However, Medicare in the United States has specific National Coverage Determinations for use of FDG-PET as a diagnostic test for dementia and neurodegenerative diseases (Medicare Manual Section Number 220.6.13). In general, Medicare covers FDG-PET scans for the differential diagnosis of frontotemporal dementia (FTD) and AD. An FDG-PET scan is considered reasonable and necessary in patients with a recent diagnosis of dementia and documented cognitive decline of at least 6 months who meet diagnostic criteria for both AD and FTD. These patients have been evaluated for specific alternate neurodegenerative diseases or other causative factors, but the cause of the clinical symptoms remains uncertain. Coverage varies from state to state, and there is no guarantee that a private insurance carrier will cover the cost or approve the imaging procedure. Costs can be as high as $4000 if not covered

by the patient’s insurance, so it is important to have these discussions with patients before ordering scans. When used in individual patients in the clinic, the typical pattern of glucose hypometabolism for MCI, AD, FTLD, and DLB is often identifiable and potentially useful for diagnosis and clinical decision-making (see Figure 7.10).

Single photon emission computed tomography SPECT imaging uses gamma photon–emitting radioisotopes attached to biologically relevant molecules that have been injected intravenously and distributed throughout the body. As gamma-emitting molecules are dispersed in the body, they are attenuated as they pass through different types of tissue. This attenuation is assumed to be homogenous throughout the brain. A gamma camera is used to detect the photon signal, and collimators funnel photon activity to the camera as they are emitted in defined directions, allowing for the detection of spatial patterns. This directional filtering allows only a small portion of photons to be detected, which limits the sensitivity of SPECT compared with PET. The gamma camera rotates around the patient, generating 2D images projected from various angles. Three-dimensional reconstruction of these 2D images facilitates the modeling of biologically meaningful physiologic processes such as blood flow and receptor-binding capacity. Modern cameras use dual- or triple-head cameras to reduce acquisition times. With regard to neurologic indications, SPECT most commonly is used to measure cerebral blood flow by using common gamma-emitting tracers such as Technetium 99-hexamethylpropylene amine oxime (99mTcHMPAO) and 99mTc-ethylenedicysteine-folate (99mTcEC-folate; Shagam, 2009). SPECT has historically been widely available and well studied in AD (Silverman, 2004). It continues to be widely available and somewhat less expensive than FDG-PET scanning. It is approved by the FDA for general medical use but has no specific Medicare indication for dementia. Insurance coverage for use in dementia is therefore variable but generally good. Similar to hypometabolism seen on FDG-PET imaging, SPECT shows decreased cerebral perfusion in bilateral temporalparietal lobes (Table 7.1). As in PET, the frontal lobes are also affected in AD (often in the later stages of dementia), but the primary sensorimotor strips and basal ganglia are typically spared (Silverman et al., 2001; Dougall et al., 2004; Pakrasi and O’Brien, 2005). SPECT in MCI has likewise revealed consistent patterns of cerebral hypoperfusion, though to a lesser degree than that seen in AD, and has shown some predictive value for AD (Johnson et al., 1998; Huang et al., 2002; Staffen et al., 2006). One recent study demonstrated a limited

Functional Imaging in Dementia

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Figure 7.10 Individual FDG-PET

scans in a patient with (a) normal cognition, (b) MCI, (c) AD, (d) bvFTLD, and (e) DLB. Images on the left are individual FDGPET CMRgl binding, showing areas of significant glucose hypometabolism compared with normal controls (blue). An automated algorithm was used to transform individual patient images into the dimensions of a standard brain and compute statistical maps of significantly reduced glucose metabolism relative to 67 normal control subjects (mean age 64 years). Redoutlined regions represent areas of mean hypometabolism seen in FDG-PET scans from 14 patients with AD (mean age 64 years), compared with the same 67 normal controls. On the right are raw FDG-PET color maps from the same corresponding patients. Here we can see the use of FDGPET for identifying diseasespecific patterns of glucose metabolism for clinical use in individual patients, to assist with diagnostic decision-making. (For a color version, see the color plate section.)

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utility of SPECT for predicting progression to AD from MCI. The authors found that visual ratings of SPECT in the temporal and parietal lobes did not distinguish eventual MCI converters to AD (N = 31) from nonconverters (N = 96), whereas a global rating of dementia did (41.9% sensitivity and 82.3% specificity, Fisher’s exact test p = 0.013; Devanand et al., 2010). Only when dichotomized at the median value of the patients with MCI did low flow increase the hazard of conversion to AD for parietal (hazard ratio: 2.96, 95% CI: 1.16–7.53, p = 0.023) and medial temporal regions (hazard ratio: 3.12, 95% CI: 1.14–8.56, p = 0.027). In a 3-year follow-up sample, low parietal (p 40

>40

No

100 in P102L mutation; much less common in other mutations

100

DWI/FLAIR MRI positive

Yes, >92%

Yes, pulvinar sign

Yes for most mutations

Variable; some positive in deep nuclei or cerebellum

Unclear

Variable; most negative

N/A

PSW on EEG

Yes, 65%

No (rarely at end stage)

Yes

Yes

No

No

N/A

Amyloidosis

Sparse plaques Severe in all in 5–10% cases

Sporadically seen

Sporadically seen

No

Very severe

75% of cases

Presence of PrPSc in the lymphoreticular system

No

No

Yes

No

No

Unlikely

Yes

Source: Geschwind (2011). Reproduced with permission from Elsevier. Parchi et al. (1999), Brown et al. (2000, 2006), Valleron et al. (2001), Huillard d’Aignaux et al. (2002), Collie et al. (2003), Will (2003), Kong et al. (2004), Collinge et al. (2006), Collins et al. (2006), Lewis et al. (2006), Brandner et al. (2008), Vitali et al. (2008), and Heath et al. (2010). CJD, Creutzfeldt–Jakob disease; EEG, electroencephalogram; FFI, familial fatal insomnia; GSS, Gerstmann–Sträussler–Scheinker syndrome; mo., months; N/A, not available or not applicable; PSW, paroxysmal sharp waves; yr, years.

a classical sign in CJD, this abnormality may also be found in dementia with Lewy bodies, AD, and corticobasal degeneration. Subtle behavioral and psychiatric changes and constitutional symptoms (e.g., fatigue, malaise, headache, dry cough, lightheadedness, vertigo) can also be seen early, very subtle symptoms (irritability, anxiety, depression, or other changes in personality) in the disease course. Preliminary research at our center shows that sCJD presents as prominently with behavioral symptoms as behavioral variant FTD. These symptoms are often overlooked and should be given more weight in the diagnosis of sCJD. Problems processing visual information lead to visual symptoms such as blurred or double vision,

cortical blindness, or other perceptual problems. Such patients often are referred to ophthalmologists. As the age of onset in sCJD is also the common age for cataracts, many sCJD patients with visual symptoms have cataract operations, which, of course, do not improve the visual symptoms that have brain origin. Less frequently, other symptoms, such as aphasia, neglect, or apraxia (inability to do learned movements) due to parietal dysfunction occur and can be presenting features. Sensory symptoms such as numbness, tingling, and/or pain are less well-recognized symptoms and are probably under-reported, given the magnitude of the other symptoms in sCJD (Geschwind and Jay, 2003; Will,

Prion Diseases

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2004; Lomen-Hoerth et al., 2010; Prusiner and Bosque, 2001).

Diagnosing sCJD A diagnosis of sCJD can be considered definite, probable, or possible based on level of certainty. Definite criteria require pathologic evidence of PrPSc in brain tissue (by biopsy or autopsy; Kretzschmar et al. 1996; Budka, 2003). Several criteria exist for the diagnosis of possible or probable sCJD. Unfortunately, most of these criteria are geared toward the purpose of surveillance and epidemiologic studies for patients who were not definitely diagnosed pathologically and thus are intended to catch most patients at the end of their disease course (Figure 9.14). Most of these criteria, therefore, are not very helpful when evaluating a patient early in the disease course (Table 9.14). The most commonly used “probable” criteria are World Health Organization (WHO) Revised criteria (WHO, 1998). In the criteria, pyramidal symptoms might include hyperreflexia, focal weakness, and a positive Babinski (extensor) response. Extrapyramidal symptoms include rigidity, slowed movement (bradykinesia), tremor, and dystonia, for example. Akinetic mutism describes the state when patients are without purposeful movement and mute. Possible CJD criteria are the same as for probable but do not require the ancillary testing (e.g., EEG or CSF 14-3-3 tests; WHO, 1998). Many patients will not meet revised WHO criteria for probable sCJD until late in the disease course. UCSF criteria, utilizing brain MRI, were proposed in 2007 (Geschwind et al., 2007a); in 2009, Modified European sCJD criteria also allowed inclusion of brain MRI.

Figure 9.14 Neuropathology of prion disease. (a) In sCJD, some

brain areas may have no (hippocampal end plate, left), mild (subiculum, middle), or severe (temporal cortex, right) spongiform change. Haematoxylin and eosin (H&E) stain. (b) Cortical sections immunostained for PrPSc in sCJD: synaptic (left), patchy/perivacuolar (middle), or plaque type (right) patterns of PrPSc deposition. (c) Large Kuru-type plaque, H&E stain. (d) Typical “florid” plaques in vCJD, H&E stain. Source: Budka (2003). Reproduced with permission from Oxford University Press. (For a color version, see the color plate section.)

Table 9.14 Current diagnostic criteria for probable sCJD European criteria 2009a (Zerr et al., 2009)

UCSF 2007 criteria (Geschwind et al., 2007a)

1 1 Progressive dementia 2 2 At least two of these four features: Myoclonus Visual or cerebellar disturbance Pyramidal/extrapyramidal signs Akinetic mutism 3 And one of more of the following: PSWCs on the EEG A positive 14-3-3 CSF assay and a clinical duration to death R), and left temporal–parietal–occipital junction (dashed arrow). (e, f) A 76-year-old woman with MRI showing diffuse hyperintense signal mainly in bilateral temporoparietal (solid arrows) and occipital cortex (dotted arrow), right posterior insula (dashed arrow), and left inferior frontal cortex (arrowhead), but no significant subcortical abnormalities. (g, h) A 21-year-old woman with probable vCJD, with MRI showing bilateral thalamic hyperintensity in the mesial pars (mainly dorsomedian nucleus) and posterior pars (pulvinar) of the thalamus, the so-called “double hockey stick sign.” Also note the “pulvinar sign,” with the posterior thalamus (pulvinar; arrow) being more hyperintense than the anterior putamen. CJD, Creutzfeldt–Jakob disease; MRI, magnetic resonance imaging; DWI, diffusionweighted imaging; FLAIR, fluid-attenuated inversion recovery. Source: Geschwind (2011). Reproduced with permission from Elsevier.

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with the MRI findings indicative of CJD, and a majority of sCJD MRIs are misread (Geschwind et al., 2010; Carswell et al., 2012). Diagnostic MRI criteria for sCJD have been proposed. Some allow the use of FLAIR or DWI and do not include abnormalities in the frontal lobes (Zerr et al., 2009); others require diffusion abnormalities and do not exclude frontal lobe involvement (Vitali et al., 2011).

Other laboratory testing Basic laboratory studies, such as CBC, chemistry, liver function tests, ESR, and ANA, are generally unremarkable in sCJD. CSF might show a mildly elevated protein (typically less than 100 mg/dL) with normal glucose level. Red and white blood cell counts usually are normal. Pleiocytosis, an elevated IgG index, or increased oligoclonal bands rarely occur in sCJD and should prompt evaluation for other conditions, particularly infectious or autoimmune disorders. At our center, we frequently rule out reversible causes of RPD that sometimes mimic sCJD, including autoimmune paraneoplastic (such as anti-Hu, anti-CV2, anti-Ma2, anti-Ri, and anti-NMDA antibodies) and nonparaneoplastic diseases (such as Hashimoto’s encephalopathy; antithyroid peroxidase and antithyroglobulin antibodies, and antivoltage gated-associated encephalopathy (anti-VGKC antibodies).

Genetic prion disease Mutations in the prion protein gene, PRNP, are responsible for about 15% of all human prion disease cases. They are always autosomal dominant, and most are 100% penetrant (i.e., almost everyone with a mutation develops the disease if they live a normal lifespan). More than 40  mutations, including point mutations, stop codons, insertions, and deletions, have been identified. Testing and diagnosis can be achieved through DNA testing of blood while a patient is alive or through autopsy tissue (Kong et al., 2004). Despite the high penetrance, more than 60% of patients with gPrD do not have a positive family history of prion disease. In most of these cases, relatives were misdiagnosed with other dementias, families hid their medical history, or there was reduced mutation penetrance (Kovacs et al., 2005). Based on clinical, genetic, and pathologic characteristics, three forms of gPrDs have been identified: fCJD, GSS, and FFI. This classification is not absolute, as some mutations have features that blend fCJD and GSS. Patients with gPrD typically have a younger age of onset (typically from 40s to 60s), a slower progressive course, and a longer lifespan (typically a few years) than sCJD patients. Depending on the PRNP mutation and other genetic and epigenetic factors, gPrDs often present identically (clinically and pathologically) to sCJD with rapid onset of clinical symptoms and short survival of weeks to months (Kong et al., 2004). Common early symptoms include parkinsonism or ataxia with only mild personality or early cognitive changes. Other mutations, such as those causing GSS, bring

about a slower illness, often with behavioral and motor abnormalities early on and dementia later in the disease. Some less common PRNP mutations result in an older age of onset, in the 70s or 80s. There is often great variability in presentation and disease course of the several mutations causing gPrDs; in fact, even within the same family members carrying the same mutation, there might be great clinical variability. Polymorphism within PRNP, such as at codon 129, also alters the presentation of gPrDs (Kong et al., 2004). It is generally thought that the mechanism for gPrDs is that mutations in PRNP make PrPC more susceptible to changing conformation into the abnormally shaped, disease-causing form, PrPSc. It is thought that this conformational change occurs throughout life but that these are cleared by the cell; as one ages, the body’s ability to clear abnormal proteins declines, leading to the accumulation of PrPSc (Kong et al., 2004; van der Kamp and Daggett, 2010).

Familial CJD (fCJD) More than 15 mutations are known to cause fCJD. Most are point (missense) mutations, but some are insertion mutations and a deletion (Kong et al., 2004; Meissner et al., 2009). Most fCJD patients present similarly to sCJD, with overlapping clinical MRI and EEG findings. The most common fCJD mutation worldwide is E200K, found most commonly among Libyan Jews and Slovakians.

Gerstmann–Sträussler–Scheinker (GSS) Gerstmann-Sträussler-Scheinker is caused by at least 10 PRNP mutations, including several missense mutations, a stop mutation, and insertion mutations (Kong et al., 2004). The age of onset for GSS mutations is often under the age of 65, typically in the 50s or younger, so we will not delve into too much detail, as the likelihood of a geriatric presentation is low. GSS often presents as a slowly progressive ataxic and/or parkinsonian disorder. Cognitive impairment often comes only later, although some mutations are present with early dementia and/or behavioral abnormalities. However, considerable phenotypic variability exists within and between mutations and families (Kong et al., 2004; Giovagnoli et al., 2008; Webb et al., 2008). Due to the slow course (up to several years), persons with GSS can be mistaken to have other neurodegenerative conditions, such as multiple-system atrophy, spinocerebellar ataxias, idiopathic Parkinson’s disease, AD, or HD (refer to Table 9.13).

Fatal familial insomnia Fatal familial insomnia is one of the rarest gPrDs and is caused by a single PRNP point mutation, D178N, with codon 129 having methionine (129M) on the same

Prion Diseases

30 MM blood

Number of deaths

25

MV primary

20

Untyped primary MM primary

15 10 5 0

1995

1997

1999

2001 2003

2005

2007

2009

Year Figure 9.17 Times series of observed vCJD cases in the United

Kingdom by genotype and presumed transmission route. Bar graph depicting number of deaths from vCJD per year in the United Kingdom through 2009. Bars refer to codon 129 polymorphism of decedent and their method of infection, primary, through consumption of BSE, or blood, through blood transfusion. Three persons, all codon 129 MM, died from vCJD from blood transfusion (black bars). One probable vCJD subject who died in 2009 (lighter bar) was codon 129MV and had primary infection. The number of deaths from vCJD has been relatively stable over the past five years. but it is not clear whether there will be another rise in the number of cases. Source: Garske and Ghani (2010). Reproduced with permission from Public Library of Science.

chromosome (cis; see Figure 9.17). Patients with D178N but cis valine at codon 129 (129V) usually present with fCJD, clinically more similar to sCJD than FFI. FFI usually at a mean age of 49 (range 20–72) presents with progressive, severe insomnia and dysautonomia (tachycardia, hyperhydrosis, and hyperpyrexia), with motor and cognitive problems appearing later in the course. Most FFI patients survive slightly longer than sCJD patients, about one and a half years. Although brain MRI is usually normal, FDG– PET imaging reveals thalamic and cingulate hypometabolism, often even before disease onset (Kong et al., 2004). Confirming a PRNP mutation by DNA extraction is important in diagnosing a gPrD, as pathology alone often cannot confirm a genetic etiology. As many gPrDs appear similar to sCJD and can have obscured family histories, this testing is important after the appropriate genetic counseling (Huntington’s Disease Society of America, 1994).

Acquired CJD Acquired forms of CJD occur because prions are transmissible and infectious. A relatively large number of prions (estimated several thousand proteins) probably are necessary to transmit prion disease, so they are not highly infectious or contagious.

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Acquired prion diseases include Kuru (now essentially extinct, occurring in the Fore tribe in Papua New Guinea due to endocannibalism); iatrogenic CJD (iCJD); and the highly publicized vCJD, occurring primarily in the United Kingdom and France, caused by consumption of bovine spongiform encephalopathy (BSE or mad cow disease), contaminated beef (Will et al., 2000; Prusiner and Bosque, 2001; Will, 2003; Collinge et al., 2006), and, in a few cases, blood transfusion. As prions are proteins, typical sterilization methods do not render them inactive (Bellinger-Kawahara et al., 1987a, 1987b; Prusiner, 1998); inactivation requires other methods or longer times at higher pressure and temperatures than typically used for standard sterilization (Peretz et al., 2006). This difficulty has led to approximately 400 cases of iCJD, from the use of cadaveric-derived human pituitary hormones, dura mater grafts, corneal transplants, the reuse of cleaned and sterilized EEG depth electrodes implanted directly into the brain and other neurosurgical equipment, and blood transfusion (Brown et al., 2000; Will, 2003). Most of the pituitary-derived (human grown hormone [hGH] and gonadotrophin) cases occurred from contaminated batches in France, the United Kingdom, and the United States. Methods have since been instituted to prevent prion transmission through such hormones (Brown et al., 2006). Thankfully, it appears that the number of iCJD cases is declining. Despite WHO recommended practices, however, for managing potential prion-contamination tissues (WHO, 1999, 2003), this still occurs and leaves patients at risk for iCJD. As most persons treated with these materials were children and incubation period is from one year at the shortest and up to one to two decades, such cases of iCJD do not occur in the geriatric population. The most notorious form of CJD is vCJD, first identified in 1995 (Will et al., 1996). It is caused by inadvertent ingestion of BSE (mad cow disease) or, in a few cases, blood transfusion from asymptomatic patients who were unknowing carriers of vCJD (Zou et al., 2008). Cattle are thought to have contracted BSE from being fed scrapieinfected sheep products used as feed (Bruce et al., 1997; Scott et al., 1999). Differing from sCJD, patients with vCJD are generally younger, with a median age of around 27 (range 12–74), and almost all cases have occurred in persons younger than 50. The mean disease duration is longer, about 14.5 months, versus about 7 months for sCJD. Early psychiatric symptoms are more characteristic in vCJD as compared to sCJD (Wall et al., 2005; Rabinovici et al., 2006) and might occur several months before obvious neurologic symptoms begin. Painful paresthesias, relatively persistent through the disease course, often occur in vCJD, although such pain rarely is seen in other prion diseases. The EEG does not show the classic periodic sharp wave complexes, except in rare cases at the end of the disease (Binelli et al., 2006). The best diagnostic marker currently is the brain MRI that usually shows the “pulvinar sign,” in which the pulvinar (posterior thalamus) is

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brighter than the anterior putamen on T2-weighted or DWI MRI (refer to Figure 9.17; Collie et al., 2003); this MRI pattern is very rare in the other prion diseases (Petzold et al., 2004). More specific tests, including detecting vCJD prions in the CSF, are under development. The younger age of onset, MRI findings, prominent early psychiatric features, persistent painful sensory symptoms, and chorea help differentiate vCJD from sCJD. As with sCJD, definitive diagnosis of vCJD is based on pathologic evidence of PrPSc in brain biopsy or autopsy. As the prions in vCJD are present in high numbers in the lymphoreticular system (unlike other human prion diseases, in which there are high prion numbers only in the central nervous system), tonsils and other lymphoid tissue can also be used for pathologic diagnosis. As of November 2013, approximately 225 cases of probable or definite cases of vCJD have been documented, mostly in the United Kingdom, and no cases of vCJD have been acquired in the Western Hemisphere, including the United States or Canada (three patients in the United States and two in Canada have been diagnosed with vCJD, but those cases are thought to have been acquired elsewhere; CDC, 2006; UK National CJD Surveillance Unit, 2013). Following the United Kingdom, France has the second highest number of vCJD cases, which probably have the same origin as those in the United Kingdom (Brandel et al., 2009). The height of the vCJD epidemic passed in 2000. Experts fear that there may be further peaks due to people with different genetic susceptibility who were infected at the same time or the continuing risk of iatrogenic spread of vCJD (Andrews, 2010). One British study found vCJD prions in three of 11,246 appendix samples collected from 1995 to 2000 by immunostaining. Another similar study, the National Anonymous Tonsil Archive, found one positive sample among a subset of 10,000 tested (Garske and Ghani, 2010). Thus, some people in the population are not sick and carry variant prions, but the risk is unclear. These asymptomatic carriers of vCJD might pose the greatest risk for spread of vCJD, through transfusion of blood products or invasive procedures. Most alarmingly, it seems that infected asymptomatic vCJD donors are capable of transmitting the disease 1.5–6 years before they became symptomatic (Health Protection Agency, 2007). As of December 2010, four patients have acquired vCJD through non-leukodepleted (white blood cells removed) blood transfusions received before 1999 (Health Protection Agency, 2007). Figure 9.18 graphs presumed vCJD cases in the United Kingdom.

Prion decontamination Decontamination of prions requires methods that will denature proteins, as prions resist normal inactivation methods used to kill viruses and bacteria. Some

recommended methods for prion decontamination include very high temperatures with steam and caustic denaturing agents—methods that often damage equipment and instrumentation (WHO, 2003). Due to the risk of transmission to subsequent patients, some medical centers opt for the more secure method of preventing iCJD by destroying neurosurgical equipment (through incineration) rather than attempting to decontaminate and reuse. Research into improved methods of decontamination of prions is ongoing (Peretz et al., 2006).

Animal prion diseases In addition to BSE as a cause of acquired human CJD, a relatively new animal form of prion disease is raising similar concerns in North America: chronic wasting disease (CWD). CWD is a prion disease of mule deer, white-tailed deer, elk, and moose. The first clinical cases were recognized in the late 1960s in North America. The disease primarily has been reported in the United States and Canada, with the highest concentrations occurring in the Central Mountain region of the United States, especially Colorado and Montana, as well as the Canadian provinces of Saskatchewan and Alberta. Figure 9.18 shows the distribution of CWD in North America. A most concerning aspect of CWD is its

Chronic wasting disease in North America

Areas with CWD infected cervid populations States/provinces where CWD has been found incaptive populations Figure 9.18 Map of the distribution of CWD in North America.

Darkest areas denotes areas where wild populations have been infected. Medium dark denotes states and provinces with captive herds contaminated with CWD. Reproduced from Chronic Wasting Disease Alliance (www.cwd-info.org) with permission.

Prion Diseases

ease of horizontal transmission between cervids. This might be in part due to the fact that CWD appears to be transmittable through blood, urine, and saliva (Haley et al., 2009). This feature makes it difficult to prevent spread of the disease in free-ranging cervid populations (Williams, 2005). It still is not clear whether CWD can spread to humans or whether there is a species barrier, but there has been no reported increase in human prion cases in states where CWD rates have been highest (Sigurdson et al., 2009).

Molecular and pathologic findings of human prion diseases The key pathologic features of sCJD are the presence of PrPSc deposition (by either immunohistochemistry or Western blot), neuronal loss, gliosis (proliferation of astrocytes), and vacuolation (spongiform changes; see Figure 9.15). We now know that the spongiform changes are due to fluid-filled vesicles formed in distal dendrites near synapses and are not air-filled holes (as in a sponge), so the term vacuolation probably is more appropriate than spongiform. GSS has a distinct neuropathology from most other prion diseases, with large unicentric or multicentric plaques of PrPSc amyloid the unicentric plaques, however, also are seen in a minority of sCJD cases, whereas the multicentric plaques are more specific for GSS. Neuropathology of FFI includes profound thalamic gliosis and neuronal loss, causing atrophy. Involvement of regions outside the thalamus is greater in FFI with codon 129 MV than MM (Cortelli et al., 1997, 2006; Budka, 2003). Because vCJD is typically acquired peripherally, PrPSc can be found in the lymphoreticular system, including tonsillar tissue (Will, 2004). Brain pathology of vCJD shows abundant PrPSc deposition, particularly multiple fibrillary PrP plaques surrounded by a halo of spongiform vacuoles (“florid” plaques) and other PrP plaques, and amorphous pericellular and perivascular PrP deposits, especially prominent in the cerebellar molecular layer; the pathognomonic plaques in vCJD are called florid because they have the appearance of a flower with a dense center and surrounding ring of vacuoles (refer to Figure 9.15; Budka, 2003). The Western blot characteristics of vCJD PrPSc also are different from those seen in other forms of prion disease (Will et al., 2000; Will, 2003, 2004).

Molecular classification of sCJD Sporadic Jakob–Creutzfeldt disease has been divided into approximately six molecular subtypes based on the genetic polymorphism at codon 129 in the prion gene and the type of protease-resistant prion (type 1

277

Table 9.15 Distribution of PRNP codon 129 polymorphism in normal population and several human prion diseases

Normal population sCJD iCJD vCJDa

MV (%)

MM (%)

VV (%)

51 12–17 20 0

37 ~66 to 72 57 100

12 17 23 0

Source: Reproduced from Geschwind (2011) with permission from Elsevier. sCJD, sporadic Jakob-Creutzfeldt disease; iCJD, iatrogenic CJD; vCJD, variant CJD. a All but one clinical case of vCJD have been MM; one probable vCJD case was codon 129 MV, and some subclinical cases with vCJD prions in the lymphoreticular system have been identified (Parchi et al., 1999; Brown et al., 2000; Collins et al., 2006; Garske and Ghani, 2010; Peden et al., 2010).

or 2). Codon 129 polymorphisms are comprised of different combinations of either methionine (M) or valine (V) at location 129 of PRNP (e.g., MM, MV, or VV; see Table 9.15 and Figure 9.18). Additionally, upon extraction from the brain and partial digestion with proteinase, PrPSc may be cleaved at two possible sites (codon 82 or 97; refer to Figure 9.14), resulting in either a longer, 21 kDa (type 1) or a shorter, 19 kDa (type 2) peptide on a Western blot. To some extent, this classification separates sCJD cases based on their clincopathologic features. MM1 and MV1 are the most common forms (70%) and present as classic sCJD, with RPD and a duration of just a few months. VV2 (16%) starts with ataxia, later-onset dementia, and a short duration. The remaining four types, MV2 (9%), MM2-thalamic (2%), MM2cortical (2%), and VV1 (1%), have a duration of about 1–1.5 years. MV2 presents similarly to VV2 with ataxia, but these cases have focal amyloid kuru plaques in the cerebellum. MM2-thalamic presents often with insomnia, followed later by ataxia and dementia, with most pathology confined to the thalamus and inferior olives with very little vacuolation; some call this form sporadic fatal insomnia (sFI) because it presents similarly to the genetic prion disease, FFI. MM2-cortical patients have progressive dementia with large confluent vacuoles in all cortical layers. sCJD patients with VV1 also present with progressive dementia, but these cases have severe cortical and striatal pathology, with sparing of the brainstem nuclei and cerebellum. Unlike with MM2-cortical, sCJD VV1 patients do not have large confluent vacuoles, but there is faint synaptic PrPSc staining (Parchi et al., 1999). Curiously, as shown in Table 9.15, heterozygosity at codon 129 in the prion gene, PRNP, is somewhat protective against prion disease. Recently, however, it has been found that many sCJD patients have a mix of both type 1 and type 2 prions (Kobayashi et al., 2011), so this classification scheme must be revised.

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Proteinase-sensitive proteinopathy (PSPr): a new form of sCJD Until recently, one marker of prion disease has been the resistance of PrPSc to proteases, enzymes that digest proteins. A new form of sCJD has recently been identified in which the vast majority of patients’ PrPSc is protease sensitive. Thus, standard immunohistochemical techniques that depend on identifying protease-resistant PrPSc for diagnosis are now considered insufficient. These subjects had a different clinical phenotype based on their codon 129 genotype (VV, MV, and MV). These cases presented with psychiatric symptoms and a frontal dementia syndrome (with predominant behavioral symptoms and executive deficits), and most had negative ancillary tests (MRIs, EEGs, and 14-3-3). Although their mean age was commensurate with classic sCJD (late 60s), their mean disease duration was much longer, at 2.5 years (Zou et al., 2010).

Treatments of human prion diseases Human prion diseases have no known cure or diseasemodifying treatment. All cases are uniformly fatal. Some hypothetical mechanisms for treating prion diseases include removing or reducing the endogenous substrate, PrPC; blocking the interaction of PrPC with PrPSc; and removing PrPSc or blocking its toxicity (Korth and Peters, 2006). An immunotherapy approach to treating prion diseases is currently under investigation, and it may be that some antibodies that are effective against prions could be useful in other neurodegenerative diseases as well (Freir et al., 2011). Several medicines have been used to treat human prion disease, but only flupirtine, quinacrine and doxycycline, given orally, have been tested in randomized, double-blinded, placebocontrolled trials. None were effective in prolonging survival (Korth and Peters, 2006; Geschwind et al., 2013). Intraventricular pentosan polysulfate has been used on a compassionate basis in the United Kingdom, Japan, and a few other countries, but observational data suggest that it does not affect survival. The doxycycline treatment trial for human prion disease in Italy and France completed in 2013 and did not show any positive effect in survival or other outcomes. (www.agenziafarmaco.it/en). Other drugs will likely be tested in the near future (Stewart et al., 2008). Several laboratories around the world are screening drug libraries and using medicinal chemistry to identify and develop antiprion therapies. In the absence of any curative treatments, management of prion diseases involves treating symptoms as they arise and providing comfort care.

Differential diagnosis The differential of prion diseases includes RPDs (Geschwind et al., 2007b) and other slower, more common

neurodegenerative diseases, such as AD and Lewy body disease (Tschampa et al., 2001). A useful mnemonic to use when evaluating a patient with an RPD or suspected prion disease is VITAMINS, for vascular, infectious, toxicmetabolic, autoimmune, metastatic-metabolic, iatrogenic, neurodegenerative-neoplastic, and systemic etiologies (Geschwind et al., 2007b, 2008; Vernino et al., 2007).

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Chapter 9.8 Normal Pressure Hydrocephalus Norman R. Relkin

Introduction Normal pressure hydrocephalus (NPH) is a chronic neurologic disorder in older adults characterized by enlargement of the cerebral ventricles and progressive disturbances of gait, urinary continence, and cognition. Hakim and Adams first described the classic symptom triad of shuffling gait, urinary incontinence, and dementia in 1965 and identified NPH as a surgically treatable condition (Hakim and Adams, 1965). NPH is now widely recognized as a potentially reversible cause of physical disability and cognitive impairment in the elderly.

Classification of hydrocephalus The term hydrocephalus is used to describe a number of pathologic conditions in which the size of the cerebral ventricles is increased. NPH is a particular type of hydrocephalus with certain distinguishing features: • NPH is a “communicating” form of hydrocephalus because it develops chronically in the absence of a macroscopic obstruction to the flow of cerebrospinal fluid (CSF). This distinguishes NPH from acute, obstructive forms of hydrocephalus that result from lesions such as brain tumors and intracerebral hematomas. NPH can occur in the aftermath of conditions such as intracranial hemorrhage, meningitis, or head trauma. Such cases are called secondary NPH (sNPH) because hydrocephalus arises as the distal consequences of a brain insult rather than from an obstructive mass lesion. When there is no identifiable antecedent cause for adult hydrocephalus, it is called idiopathic NPH (iNPH). • Enlargement of the ventricles in NPH is not exclusively the result of brain atrophy (so-called hydrocephalus ex vacuo). In practice, differentiating NPH from ex vacuo enlargement of the ventricles can be challenging. The current approach involves subjective judgment of the extent to which ventricular enlargement is disproportionate brain atrophy as assessed from signs such as the degree of sulcal widening on brain imaging. Other potentially distinguishing signs have been identified (see the upcoming section “Neuroimaging”). • NPH is a different disorder than hydrocephalus in neonates and children. However, possible links between certain types of childhood hydrocephalus and NPH have been identified. According to the so-called

“two hit” hypothesis of NPH, benign congenital external hydrocephalus combined with the development of deep white matter ischemia later in life may lead to NPH in older adults (Bradley et al., 2006). Because skull size becomes fixed after the fontanelles close in early childhood, this could help explain why head circumference is significantly increased in a subset of patients with NPH (Krefft et al., 2004). Another NPH-like syndrome related to childhood hydrocephalus is called longstanding overt ventriculomegaly in adults (LOVA) (Kiefer et al., 2002). LOVA is thought to begin with childhood hydrocephalus that is initially compensated but progresses later in life to cause symptoms. Associated findings include an enlarged head circumference and, in some cases, an empty sella turcica. • Aqueductal stenosis (AS) can closely resemble NPH but differs in cause and treatment. In AS, congenital or acquired narrowing of the aqueduct of Silvius leads to ventricular enlargement and symptoms quite similar to those of NPH. Stenosis of the aqueduct can be identified on a midsagittal MRI scan and by flow-sensitive MRI techniques that document diminished CSF flow rates.

Demographics Idiopathic NPH most commonly affects persons over 40  years of age and may occur alone or in combination with Alzheimer’s disease, Parkinson’s disease, and other age-related disorders. NPH occurs in males and females in roughly equal proportions. Familial association has been anecdotally reported but is only rarely encountered in practice. The precise incidence and prevalence of NPH has not been rigorously determined. A Norwegian study in over 200,00 subjects estimated the incidence of NPH at 5.5 per 100,000 population and estimated prevalence at 21.9 per 100,000 population (Brean and Eide, 2008).

Pathophysiology Not surprisingly, the most consistent finding in NPH patients at autopsy is enlargement of the cerebral ventricles. Pathologic studies have failed to identify lesions at

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the gross or molecular levels that are universally diagnostic of NPH or unequivocally explain its etiology. Increased resistance to the clearance of CSF has been documented in some cases, but its cause has yet to be determined. Likewise, it remains unclear how disturbances in the CSF compartment translate into brain dysfunction and clinical symptoms in NPH. Intracranial pressure is only mildly elevated in NPH, typically to 130 mm H2O or slightly higher. Although this pressure is inadequate to cause cerebral dysfunction in normals, it has been argued that the effects are multiplied by the expanded ventricular surface over which it is exerted in NPH. Ventricular expansion, transependymal fluid movement, and age-associated reductions in cerebral compliance may make the brain more susceptible to the repeated impact of the CSF pulsations. A provocative hypothesis has been recently forwarded that implicates disturbances in CSF pulsatility in the pathogenesis of NPH (Bateman, 2008) According to this hypothesis, altered brain compliance and CSF pulsatility leads to cyclical compression of the tributary veins that empty into the sagittal sinus, resulting in increased resistance to CSF outflow (Ro). “Hydrodynamic” interference in CSF clearance could explain the increased Ro documented by CSF infusion studies in many NPH patients, in the absence of an identifiable obstruction of CSF flow. Physical distortion of neurons and their processes caused by ventricular enlargement has been hypothesized to delay or disrupt neuronal transmission in NPH. However, motor-evoked response studies have failed to show alterations in central conduction latencies, as would be expected if physical stretching were the cause of cerebral dysfunction in NPH (Zaaroor et al., 1997). Reduced cerebral blood flow has also been reported in NPH, but brain perfusion is not universally compromised, nor is it consistently improved after treatment. Small-vessel ischemic cerebrovascular disease has been linked to progression of NPH. As the burden of cerebrovascular disease increases, NPH generally becomes more refractory to treatment. In chronically untreated cases, small-vessel infarction occurs throughout the periventricular region, giving rise to a condition that is indistinguishable from Binswanger’s disease.

Neuroimaging A brain imaging study is necessary to identify ventricular enlargement in NPH. However, diagnosis also requires documentation of appropriate clinical findings. X-ray computed tomography (CT) or nuclear medicine scans such as cisternography can be used for this purpose, but MRI is the preferred modality for evaluating NPH. The use of MRI is limited by contraindications such as pacemakers, metallic implants, and claustrophobia, as well as in some venues by cost and availability. A T1-weighted

or other MRI pulse sequence that highlights ventricular and cortical anatomy can readily be used for this purpose. The Evans’ index, a measure of ventricular size calculated from the ratio of the diameter of the skull to the diameter of the lateral ventricle at its widest point, is 0.3 or greater in NPH. Because ventricular enlargement also occurs in aging and neurodegenerative diseases, evaluation of possible NPH requires determining whether the enlargement of the ventricles is disproportionate to cerebral atrophy. This is currently accomplished by visual inspection of brain images to identify widened sulcal markings as proxy measures of brain atrophy. This method is highly subjective and may soon be supplanted by quantitative MRI volumetric techniques that provide more accurate measures of cortical atrophy. Advances in MRI methods and other imaging techniques are likely to contribute to improved differential diagnosis of NPH in the future. Imaging can also be useful for verifying whether there is any obstruction to CSF flow. In some cases, imaging of the spine is useful for identifying obstructive causes for hydrocephalus. Inspection of a midline sagittal T1-weighted image is recommended for examining the patency of the cerebral aqueduct and fourth ventricle. In equivocal cases, a phase contrast CSF flow study can provide useful information about CSF movement. Aqueductal flow rates are low or undetectable in aqueductal stenosis, while in NPH, normal or increased (hyperdynamic) flow is observed. Hyperdynamic flow can sometimes be identified as a fourth ventricular flow void on proton density images or nonwater-suppressed echo planar images. Other structural findings associated with NPH that can be identified on CT scans or MRIs include enlargement of the temporal horns of the lateral ventricles not attributable to hippocampal atrophy, upward doming of the roof of the body of lateral ventricles, enlargement of the Sylvian fissure, and compression of the paramedian sulci of the frontoparietal region near the cranial convexity (see Figure 9.20).

Symptoms Although NPH is associated with gait ataxia, urinary incontinence, and dementia, symptoms fall on a continuum from very mild to severe and are not limited to those of the classic triad. Symptoms are stage dependent and may be minimal early in the disease or confined to just one or two domains. It is therefore important for clinicians to become familiar with the full spectrum of presentations and stages of NPH: • Gait and balance: Impairments of walking and balance are the most readily observed symptoms of NPH and the most reliably reversed by treatment. The characteristic gait disturbance in NPH is often described as

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(a)

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(b)

Figure 9.20 Midsagittal MRIs taken 5 years apart in a patient with Alzheimer’s disease who subsequently developed symptoms of NPH. Note the expansion of ventricles without a commensurate increase in sulcal markings, and the apparent narrowing of sulci at the parietal convexity. (a) Initial presentation of AD. (b) Five years later, coincident with onset of NPH symptoms.

“shuffling” or “magnetic.” Patients with NPH typically show a reduced foot–floor clearance and a widened base, walking in short steps with their toes point outward. There is reduced counter-rotation of the hips and shoulders while walking. Accelerometer studies show an increased tendency to sway while walking and while standing in place. There may be a prolonged latency when starting ambulation or stopping. Tandem gait is frequently disturbed. It takes symptomatic NPH patients longer than normal to rise from a chair and to walk a short distance. The number of steps required to cover a given distance is also increased. Patients with NPH frequently retropulse, either spontaneously or as a consequence of being pulled backward on the “Pull Test.” Turning in place may require multiple small steps, so-called “en-bloc” turning. NPH patients frequently fall directly forward or backward when bending or on uneven terrain but may fall in any direction. Parkinsonism may be present in NPH patients either as a comorbid illness or as a consequence of NPH itself. Parkinsonism secondary to NPH is less responsive to treatment with dopamine precursors or agonists than idiopathic Parkinson’s disease. A timed walking test is an inexpensive and sensitive method for identifying and following the gait disturbances in NPH. Clinical gait scales such as the one published by Boon and colleagues (Boon, 1971) can be useful for rating the full range of associated gait and balance disturbances. • Control of urination: The most common urinary symptoms associated with NPH are urinary frequency, urgency, and nocturia. These early stage symptoms may progress to urinary incontinence as the disease progresses. In most cases, incontinence is confined to micturition, but in advanced stages, defecation may be involved as well. NPH patients are often aware of their urinary symptoms and embarrassed when incontinence develops. With progression of the disease, and particularly with advancing dementia, they may develop indifference to incontinence. Asking subjects or spouses to keep a bladder diary indicating frequency/

urgency of urination and incidents of incontinence can provide useful diagnostic information. Urologic evaluation is recommended to rule out other causes of urinary dysfunction. Urodynamic studies in NPH patients tend to show a neurogenic-type pattern and may reveal an increased post-void residual. Persons with untreated NPH may be at increased risk of urinary tract infections (UTIs), owing to incomplete voiding. Those with recurrent UTIs may benefit from an antimicrobial prophylaxis. • Cognition: The cognitive profile of NPH is typically subcortical with frontally weighted deficits and relative sparing of language function. Not infrequently, NPH occurs in combination with diseases such as Alzheimer’s which may add elements of cortical, limbic, and paralimbic disturbances to the profile of cognitive dysfunction. Cognitive impairments in NPH usually manifest as disturbances of executive function, including difficulties carrying out multistep tasks, multitasking, formulating abstractions, and dividing attention. Memory can fail secondary to impaired information retrieval. Recognition memory is relatively preserved, as evidenced by performance improving with cues or multiple choice. This contrasts with Alzheimer’s disease, in which the information is rapidly lost from memory and may be neither recalled nor recognized. Language ability usually remains intact, although phonemic (letter) fluency and confrontational naming are decreased in conjunction with frontal systems deficits. Ideomotor praxis may be preserved, but some patients with NPH have difficulty transitioning from a standing to recumbent position, such as on an examining table. Screening tests such as the Folstein Minimental State examination may not be sufficiently sensitive to detect subtle frontal systems deficits in NPH. Timed performance-based tasks and tasks with frontal weightings are recommended to assess impairments in suspected cases of NPH. Tests such as Trails A and B, The Digit-Symbol test, tend to be sensitive to NPH-related deficits and improve with treatment. Certain tests of

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upper extremity function (Maze Drawing and Serial Dotting) have recently been found sensitive to impairments in NPH and are responsive to CSF drainage (Tsakanikas et al., 2009). Neuropsychological testing can be useful in documenting subtle cognitive dysfunction in mild stages of NPH and for tracking response to treatment. • Other findings: A variety of psychiatric disturbances ranging from psychosis and agitation to depression and anxiety disorders have been reported in association with NPH, either as exacerbation of pre-existing conditions or arising de novo. In some cases, psychiatric symptoms are responsive to treatment of hydrocephalus. Recent onset of hypertension has been reported in an unexpected fraction of patients with newly diagnosed NPH, leading to the speculation of a possible causal relationship. Decreased hearing and frank deafness have been rarely associated with NPH, but primarily in the aftermath of shunt placement instead of as a presenting symptom. The same is true of epilepsy, which may occur in as many as 10% of shunted NH patients.

Diagnostic criteria International consensus criteria for the diagnosis of iNPH were published in 2005 (Relkin et al., 2005). These evidence-based guidelines divide NPH into probable and possible subcategories, to reflect the level of certainty about the diagnosis. The guidelines also identify shuntresponsive NPH as the subset of cases that have a positive outcome from treatment.

Differential diagnosis The symptoms of NPH overlap those of several conditions that are common in elderly individuals. Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative conditions can manifest similar symptoms and may occur comorbidly with NPH. Spinal stenosis, arthritic conditions, and orthopedic disorders can cause gait and balance disturbances resembling those of NPH. Prostatic enlargement and a number of other urologic conditions can give rise to the urgency, frequency, and incontinence that is also associated with NPH. Differential diagnosis of NPH therefore requires careful exclusion of other conditions, and, in the cases with comorbidities, a determination of the extent to which symptoms are attributable to NPH.

Prognostication Some generalizations can be made about the likelihood of a positive response to shunt treatment based on demographic and medical history, and additional prognostication can be made on the basis of clinical tests:

• Prognosis for a positive response to neurosurgical treatment in NPH is better for patients aged 75 years or less, with duration of symptoms less than 2 years and a lack of serious medical comorbidities. A less favorable prognosis is associated with atypical presentations, advanced dementia, longstanding symptoms, confluent subcortical cerebrovascular changes, and concomitant anticoagulation therapy. • Several tests have been developed to estimate the likelihood that a person with NPH will respond positively to a shunt. These include techniques high volume (30–50 cc) lumbar puncture (LP) “tap tests,” 24- to 72hour external lumbar or ventricular catheter drainage, CSF dynamics studies, MRI CSF flow measurements, B-wave monitoring, radionuclide cisternography, and others. Positive results on these tests can indicate a more favorable prognosis for shunt response, but negative outcomes do not preclude benefit from a shunt. For that reason, these tests tend to be used selectively when the decision about whether to proceed to shunt must be balanced against increased risks. The likelihood of shunt responsiveness can be determined with up to 90% accuracy when prognostic tests are positive (Marmarou et al., 2005).

Treatment A distinctive feature of NPH is that its symptoms can be rapidly reversed by procedures that divert CSF out of the central nervous system. Temporary improvements can occur after LP, external lumbar drainage (ELD), and ventriculostomy. Lasting reversal of symptoms follows neurosurgical implantation of a ventricular shunt. Shunt placement is the standard of care for NPH and fosters excellent recovery in well-selected patients. Shunts are permanent implanted devices that serve as an alternative physical conduit for the outflow of CSF from the central nervous system. Shunts have many different designs and configurations, the full scope of which is beyond the scope of this chapter. The most basic configuration is a tube running from the cerebral ventricles to another location in the body in which drainage occurs by gravity. In most cases, however, a shunt valve is introduced between the two ends to control the rate and volume of drainage of CSF as the position of the head relative to the rest of the body changes. The most common types of shunts in use today are differential pressure valves that open when a certain pressure difference exists between the ventricular side of the shunt and its distal end, which is most often placed intra-abdominally. The shunt valve may be supplemented by an antisiphon device that prevents the valve from remaining open when gravity induces a rapid flow (siphon) effect.

Normal Pressure Hydrocephalus

Until the 1990s, most shunt valves had fixed opening pressures (low, medium, and high). An important innovation that changed the management of NPH was the advent of programmable valves that can be noninvasively adjusted post-operatively. Present-day programmable valves can be adjusted by magnetic or electromagnetic programming devices and can be set noninvasively to a wide range of opening pressures. This provides an opportunity to optimize the shunt function in individual cases and a way to adjust the extent of drainage. The settings of a programmable shunt can be interrogated by various means that are valve dependent, including magnetic compass devices, acoustic devices, and X-rays. The value of programmable shunts relative to reduction of shunt morbidity compared to fixed-pressure shunts has not been conclusively established, but they have given NPH patients and their physicians greater latitude to manage symptoms that would otherwise require repeated surgery. Although shunts can provide relief to well-chosen surgical candidates that persist for several years, the outcome of shunt placement is not uniformly positive. Shunts fail to provide improvement in some cases and are associated with operative and post-operative morbidity rates ranging from 10% to 80% in different case series (Bergsneider et al., 2005). Complications such as subdural hematomas, infections, and shunt blockage take a devastating toll on frail, elderly NPH patients and dramatically increase the costs of NPH care. Maximizing successful treatment of NPH requires accurate diagnosis and skillful clinical management by specifically trained healthcare professionals. LOVA may be treatable by endoscopic third ventriculostomy (ETV), a procedure that creates an alternative conduit for CSF flow through the floor of the third ventricle. ETV may be associated with lower morbidity than using a shunt to treat NPH, but it does not reverse symptoms in all cases. AS can also be treated by ETV instead of a shunt, making it an important condition to recognize and distinguish from NPH. Nonsurgical aspects of management are also extremely important for the care of patients with NPH. In both the pre- and post-surgical periods, vulnerability to falling is increased and appropriate steps should be taken to reduce fall risk. This can be promoted by prescription of a cane, walker, or, when appropriate, wheelchair. Modifications to the household should be considered for safety purposes, including but not limited to installation of grab bars in the bathroom and handrails on ramps and stairwells. Suitable candidates should be referred for physical therapy. A program of scheduled toileting may help those prone to UTIs or daytime incontinence, and prescription of prophylaxis against UTIs should be considered in some cases. Medications such as cholinesterase inhibitors that are approved to treat Alzheimer’s disease and dementia in Parkinson’s disease have not been formally evaluated

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in NPH but may have adjunct therapeutic value in some patients. The same may be said about dopamine precursors such as levodopa. Focal or generalized seizure may emerge after shunt surgery and should be addressed with antiepileptic medication if recurrent. Depression and other behavioral disturbances also occur in the NPH population and may require medication and/or psychotherapy. In patients with advanced symptoms or those who are not candidates for surgery, a home health aide or even institutionalization may become necessary. This is particularly the case for individuals who live alone or are more physically frail or severely demented.

Summary • NPH is a chronic form of adult hydrocephalus that is treatable and sometimes reversible. Idiopathic and secondary forms exist. Pathophysiology is incompletely understood. • Diagnosis of NPH requires evidence of ventricular enlargement disproportionate to cerebral atrophy on a brain imaging study and impairment in gait, balance, continence, and/or cognition. MRI or another brain imaging study is required. Clinical assessment must include appropriate history and physical examination. • The classic triad of gait ataxia, incontinence, and dementia is sometimes, but not always, present in NPH patients and can occur in other disorders. Impairments may be mild and/or in a single domain. Symptoms of NPH may overlap those of Parkinson’s disease, Alzheimer’s disease, and other disorders even when NPH occurs in isolation. • The cognitive profile of NPH is typically subcortical with predominant frontally weighted deficits. Not infrequently, NPH occurs in combination with diseases such as Alzheimer’s, which may add elements of cortical, limbic, and paralimbic disturbances to the cognitive profile. • Gait disturbance tends to be the most responsive to treatment. Balance, control of urination, and cognition follow, respectively, in terms of likelihood and time to improvement. • Invasive examinations such as lumbar drainage, infusion tests, and ICP monitoring may add to diagnostic and prognostic certainty but are not required in every case. • Neurosurgical placement of a shunt that diverts CSF away from the brain in a controlled fashion is the current treatment of choice for NPH. Ventriculoperitoneal shunt is the most common configuration. Shunt valves may be fixed- or adjustable-pressure types. Success rate can be as high as 90% but varies across centers. ETV, devices to alter CSF pulsatility, and medications are under study by are not of proven value in NPH.

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• Although mortality attributable to shunt surgery is generally low, post-operative morbidity from shunts is 10–15% or higher. Subdural hematomas and effusions are common complications. Seizures, infections, and shunt failures are among other serious adverse consequences. Factors such as advanced age, multiple medical comorbidities, extreme frailty, anticoagulation, and severe dementia increase the risk of adverse outcomes from shunt surgery. Accurate diagnosis, skilled surgical intervention, and careful long-term management are required to minimize morbidity and treat NPH successfully.

References Bateman, G. (2008) The pathophysiology of idiopathic normal pressure hydrocephalus: cerebral ischemia or altered venous hemodynamics? Am J Neuroradiol, 29: 198–203. Bergsneider, M., Black, P.M., Klinge, P., et al. (2005) Surgical management of idiopathic normal-pressure hydrocephalus. Neurosurgery, 57 (Suppl. 3): S29–S39. Boon, W. (1971) Steplength measurement for the objective evaluation of the pathological gait. Proc K Ned Akad Wet C, 74 (5): 444–448. Bradley, W., Bahl, G., and Alksne, J. (2006) Idiopathic normal pressure hydrocephalus may be a “two hit” disease: benign external hydrocephalus in infancy followed by deep white matter ischemia in late adulthood. J Magn Reson Imaging, 24 (4): 747–755.

Brean, A. and Eide, P.K. (2008) Prevalence of probable idiopathic normal pressure hydrocephalus in a Norwegian population. Acta Neurol Scand, 118 (1): 48–53. Hakim, S. and Adams, R.D. (1965) The special clinical problem of symptomatic hydrocephalus with normal cerebrospinal fluid pressure: observations on cerebrospinal fluid hydrodynamics. J Neurol Sci, 2 (4): 307–327. Kiefer, M., Eymann, R., and Steudel, W.I. (2002) LOVA hydrocephalus: a new entity of chronic hydrocephalus. Nervenarzt, 73 (10): 972–981. Krefft, T., Graff-Radford, N., Lucas, J., and Mortimer, J. (2004) Normal pressure hydrocephalus and large head size. Alzheimer Dis Assoc Disord, 18 (1): 35–37. Marmarou, A., Bergsneider, M., Klinge, P., et al. (2005) The value of supplemental prognostic tests for the preoperative assessment of idiopathic normal-pressure hydrocephalus. J Neurosurg, 57 (3): S17–S28. Relkin, N., Marmarou, A., Klinge, P., et al. (2005) Diagnsosing idiopathic normal-pressure hydrocephalus. J Neurosurg, 57 (3): S2-4–S2-16. Tsakanikas, D., Katzen, H., Ravdin, L., and Relkin, N. (2009) Upper extremity motor measures of tap test response in normal pressure hydrocephalus. Clin Neurol Neurosurg, 111 (9): 752–757. Zaaroor, M., Bleich, N., Chistyakov, A., et al. (1997) Motor evoked potentials in the preoperative and postoperative assessment of normal pressure hydrocephalus. J Neurol Neurosurg Psychiatry, 62 (5): 517–521.

Chapter 10 Depression in the Elderly: Interactions with Aging, Stress, Chronic Pain, Inflammation, and Neurodegenerative Disorders Douglas F. Watt Department of Neuropsychology, Cambridge City Hospital, Harvard Medical School and Alzheimer’s Disease Center/Clinic for Cognitive Disorders, Quincy Medical Center, Quincy, MA, USA

Summary • The separation-distress hypothesis of depression suggests that depression reflects a conserved neurobiological mechanism to terminate protracted separation distress. • Evolutionary perspectives also suggest that depressive withdrawal may have been selected to protect organisms from intrinsically unreachable goals, particularly, potentially fatal dominance conflicts and terminating other maladaptive forms of motivation and goal seeking. • Depressive illness may reflect hypertrophy and disinhibition of basic depressive shutdown mechanisms and/or disturbance of mechanisms that normally terminate depression upon social re-immersion. • DSM-IV criteria for depression emphasize a depressed mood (which is a fundamentally circular criterion) along with loss of interest and pleasure. • Chronic stresses of wide varieties but, most particularly, chronic forms of separation distress, chronic pain, or other chronic social stressors are potent depressogenic stimuli. Chronic pain combined with virtually any kind of chronic separation distress results in an extremely high incidence of depression. • The elderly are at elevated risk for depression due to their increased exposure to chronic pain, cognitive decline, loss of social supports, and other prototype stressors for depression. • Although SSRIs and other aminergic pharmacology are regarded as first-line treatments and are often times the only treatment patients receive, they are modestly effective at best, while individual psychotherapy, social support, and reduction of social isolation and other forms of chronic stress are underutilized and underappreciated as antidepressant interventions.

The heart asks pleasure first And then, excuse from pain And then, those little anodynes That deaden suffering; And then, to go to sleep; And then, if it should be The will of its Inquisitor, The liberty to die. Emily Dickenson

Introduction and overview: the problem space of depression Depression is our most common mental health condition, yet its fundamental underpinnings remain mysterious. It is also a condition to which the elderly may be exposed disproportionately, perhaps for many reasons. Factors may include increasing exposure to multiple and

profound social losses, increased psychosocial isolation, the stress of multiple age-related chronic and more acute illnesses, chronic pain syndromes, increased financial stress, and perhaps even just the intrinsic degradations and humiliations of aging itself. The biology of depression also appears to interdigitate with many other comorbidities of aging, including an intrinsic upregulation of inflammation (“inflammaging”)

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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and multiple neurodegenerative disorders, notably Alzheimer’s disease, a major comorbidity of depression in the elderly. A basic organizing hypothesis of this review is that depression reflects an evolutionarily conserved mechanism in mammalian brains, selected as a shutdown mechanism to terminate protracted separation distress, which, if sustained, would be dangerous for infant mammals. This fundamental shutdown mechanism remains available to more mature mammalian and human brains, particularly, those with certain polymorphisms in genetic endowment, early loss/separation trauma, or other predisposing factors, which can promote reactivation in relationship to almost any chronic stressor. Although depression must have an adaptive and evolutionary basis (or else it surely could not be so ubiquitous), depressive shutdown mechanisms can become “hypertrophied” and released from normal control mechanisms in vulnerable individuals to potentially yield the full spectrum of depressive illness, which is not adaptive. The neurobiology of depression remains a challenging puzzle box of correlates, involving changes in many biogenic amine and neuropeptide systems and alterations in neuroendocrine and immune function. We suggest that core factors form an interactive and even synergistic “depressive matrix,” arguing against any “single-factor” theory. We review core contributions to the biology of depression from stress cascades, inflammation, and alterations in multiple neuropeptide and monoamine systems. In contrast to single-factor theories, this review suggests synergisms between core neurobiological factors, as well as a recursive (looping) control architecture regulating both entry to and exit from depression. Such an interactive matrix of factors may help explain why such an enormous multiplicity of potential treatments are antidepressant, ranging from psychotherapy and exercise to multiple drugs, vagal and deep brain stimulation, and electroconvulsive therapy (ECT). Unfortunately, traditional biological psychiatric perspectives are almost totally “bottom up” (neglecting relationships between depression and social isolation and stress) and typically cannot explain why depression is such a pervasive problem or why evolution could have ever selected for such a mechanism. This hypothesis suggests, in practical terms, that a primary reduction of social isolation and increased social support might be a fundamental and highly cost-effective preventative measure in elderly at-risk populations. Exercise and diet may also have protective and preventative effects. Depression in the elderly must be understood in the context of the problem of depression in general. In addition, we must appreciate the unique constellation of factors that might promote depression in late life. Depression is surely an ancient issue for human beings at virtually every stage of the lifecycle, with references to depression appearing in many classical sources onward

from the earliest recorded human history. Depression may be both our most common and our most “mystified” emotional condition bringing patients into clinical contact with a health professional, not just in this country, but in most, if not all, Western technologic societies. Not only is it the most common emotional issue bringing patients to physicians and mental health professionals, but it is also probably substantially underdiagnosed (Lecrubier, 2007), with the true epidemiologic incidence of depression poorly charted, due to significant underreporting bias. According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV; American Psychiatric Association [APA], 1994), lifetime risk for major depression is roughly 10–25% for women and 5–12% for men; given the many who never seek treatment and have highly motivated underreporting, however, these numbers are probably serious underestimates. If one were to include its milder forms or briefer depressive episodes, the lifetime incidence of some form of depressive-spectrum disorder would likely be much higher, perhaps as high as 80% or more. For unknown reasons, there is perhaps a twofold higher prevalence in females, potentially indicating that their emotional systems are more sensitive or more affected by the abundant stressors that promote depression. From a societal perspective, depression may exact a staggering human and economic cost—recent estimates place major depression as the third leading cause of disability worldwide and, overall, the single most expensive disorder confronting Western societies (including both the costs of treatment and lost productivity; World Psychiatric Association [WPA], 2002). Because depression may worsen many other medical conditions (Kessler et al., 2003), including being a significant risk factor for cardiac disease, immune dysregulation, obesity, and addiction, to name a few, the total human and economic costs associated with depression may be larger than what have yet been estimated. Although the popular media typically conceptualize depression as an “illness caused by a chemical imbalance,” with major pharmaceutical firms highly motivated to advance similar notions, most scientific literature suggests that depression should be treated as a syndrome and not as a distinct illness. Additionally, popular depictions of depression as “a chemical imbalance” are trivial, without a concurrent functional–psychological analysis, as all biologic conditions, including death, are accompanied by “chemical imbalances.” The “illness” categorization also begs the question of why evolution might have permitted, or even selected for, such a common process in the first place, a question rarely asked due to the equation of depression with maladaptive behavior. Equating clinical depression with maladaptation (implying that no selection processes would be involved), while understandable, is scientifically problematic if two core questions are thereby obscured: (1) Why is depression so common?

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(2) What evolutionarily conserved brain mechanisms promote depression? The neglect of such evolutionary perspectives may reflect, in part, psychiatry’s attempt to map psychiatric syndromes directly onto brain mechanisms while simultaneously ignoring the intervening neural systems that generate the core prototype emotional states in mammalian brains. (For a summary of these core affective processes, including fear, rage, playfulness, separation distress, lust, and maternal care, see Panksepp, 1998.) Curiously, this long-standing neglect of potential relationships between depression and mammalian-brain emotional systems exists side-by-side with vigorous ongoing efforts to develop and use multiple animal models in preclinical antidepressant drug discovery and testing. Although it is frequently presented in almost exclusively molecular and reductionist terms in mainstream psychiatry, evidence suggests that depression is a conserved mammalian brain process, with correspondingly ancient origins, possibly emerging concomitant with many other aspects of a highly social brain (Insel and Young, 2001; Baron-Cohen, 1999; Watt, 2007; Watt and Panksepp, 2009). It indeed may reflect an intrinsic and dark vulnerability in all highly social brains. Such considerations suggest a possible logic to the greater incidence of depression in females, as several authors have suggested that the female brain is intrinsically more social. It has already been argued that depression may represent a conserved mechanism to terminate protracted separation distress (Watt and Panksepp, 2009), a potentially fatal state for infant mammals separated from their conspecifics. It may also serve additional adaptive purposes in adult mammals, as a mechanism to withdraw from and terminate potentially fatal dominance conflicts (Neese, 2000). Our lack of an integrated picture of depression is evident in the dozens of neurobiologic correlates for depression presented in a voluminous literature, yet without any clearly defined mechanistic integration that might allow clinicians and researchers to link disparate facts to central generative mechanisms. So far, candidate “driving” mechanisms in depression are envisioned largely in neuromodulatory and biochemical terms, including some form of monoamine deficiency (Schildkraut, 1965), cholinergic overactivity (Janowsky et al., 1972), hypothalamic-pituitary-adrenal (HPA) stress axis alterations (Holsboer, 2000; de Kloet et al., 2005) that promote atrophic change in the hippocampus (Dranovsky and Hen, 2006), potential deficits in neuronal growth factors (Duman and Monteggia, 2006), and associated alterations in corticotropin-releasing factor (CRF), glucocorticoid receptor function, and brainderived neurotrophic factor (BDNF). A recent reappraisal of the role played by stress cascades has emphasized fundamental changes in the hippocampus associated with cortisol, effects countered by BDNF (Holsboer, 2000), coincident with the finding that antidepressants promote

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or restore neuronal proliferation and neuroplasticity in this brain region. Additionally, more recent ideas emphasize multiple alterations in other neuropeptide systems besides CRF, especially substance P, opioids, and oxytocin (Holsboer, 2003), as well as upregulation of dynorphin (the “dysphoric” or “paradoxical” opioid), which modulates the nucleus accumbens (Todtenkopf et al., 2004) and decreases motivation to seek rewards. There is also evidence for significant functional alterations in both glutamate and γ-aminobutyric acid (GABA), with evidence for both GABAergic downregulation and glutamatergic upregulation. However, the basis for these changes in both GABA and glutamate is unclear. Glutamatergic changes may be driven in part by possible upregulation of quinolinic acid, which acts as an N-methylD-aspartate (NMDA) agonist, due to alterations in pathways associated with upregulated pro-inflammatory cytokines (for review, see Muller and Schwartz, 2007). Because of the prolific roles in all brain functions of GABA and glutamate, so far with limited therapeutic implication for depression (Matsumoto, Puia, Dong, and Pinna, 2007) except for the mood-stabilizing ability of certain antiepileptic agents that inhibit excitatory drive/processes (such as affecting sodium channels), we note only the most promising new lines of evidence in this enormous field of research. Because of preclinical reports suggesting that blockade of glutamate might have antidepressant effects, recent clinical reports have now indicated that intravenous administration of ketamine, which blocks one of the glutamatergic receptors (the NMDA receptor), yields robust and rapid (within 2 hours, after a short dissociative effect) antidepressant effects that could last for several days to a week (Zarate et al., 2006). This study is part of a larger body of work suggesting that, in a variety of preclinical models, metabotropic glutamate receptor (mGluR1 and mGluR5) antagonists, as well as agonists at alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors, have antidepressant-like activity. Of course, how this antidepressant effect from NMDA antagonism is transduced in the brain remains uncertain, but it must be noted that glutamatergic stimulation of many subcortical brain sites can produce strong negative emotional arousals (Panksepp, 1998). In short, there is a complex panoply of neuromodulatory changes in depression, with very uncertain leading versus trailing edges, particularly given the enormous (and still incompletely mapped) interactions between many modulatory systems. In contrast with any simplistic notion about a primary “chemical imbalance” in depression, virtually every modulatory system that has been closely studied shows complex alterations in depression. A “prime mover” in this complex symphony of changes remains elusive. In addition to these traditional bottom-up neurochemical/neuromodulatory perspectives, there has been increasing evidence that depression involves fundamental

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changes in large-scale corticolimbic emotional networks (particularly, hyperactivity in Brodmann’s area 25, the subcallosal cingulate, particularly, in severe refractory depressions; Mayberg et al., 2005), along with shifts in baseline activation of a wide variety of corticolimbic systems, some appearing upregulated and some, downregulated. However, any putative functional integration of all these disparate candidate mechanisms is rarely, if ever, evident in the currently available literature. Might a more concerted focus on conserved mammalian emotional systems potentially coordinate many disparate and otherwise fragmented lines of biologic thinking about depression? If so, such approaches may eventually significantly improve biologic treatments of depression and better clarify and refine psychotherapeutic practices as well. It may also help eventually coordinate the growing numbers of putative neurochemical correlates and causes into a more coherent theoretical framework than presently exists.

A multifaceted separation-distress hypothesis of depression The many brain changes in depression may be differential manifestations—different “faces”—of a fundamental shutdown process, reflecting ancient and evolutionarily conserved mammalian brain mechanisms aimed at the termination of separation-distress responses (see Watt and Panksepp, 2009 for a comprehensive review). In Bowlby’s (1980) terms, the shift from a “protest” to a “despair” phase following social losses suggests a conserved psychobehavioral shutdown mechanism that may initiate and promote depression. The evolutionary adaptation (“purpose”) of such a shutdown mechanism may have been the benefits of terminating protracted separation distress, particularly in younger and infant mammals. Sustained separation distress (crying) would likely prove fatal, either by alerting predators to prey availability or by metabolically exhausting small infants if they remained in a protracted panic phase. Analogously, the protest that follows the loss of other rewards, as well as other homeostatic losses (such as illness and chronic pain), may also engender depressive shutdown. Depression is fundamentally connected to social attachment, social status, and comfort and its many vicissitudes. This is not a new idea, but the possibility that the fundamental neuroscience of depression could be better integrated under this affective neuroscience umbrella is a relatively novel idea within biologic psychiatry. One could contrast this potential social biology view of depression with classic molecular reductionism and argue that mere “brute-force” cataloging of dozens of neurochemical changes is not optimally heuristic or integrative. The prevailing radical reductionism in mainstream psychiatry still envisions that one can jump from molecules and similar brain details all the way to highly complex psychiatric

diagnostic categories and organized behavior, with no psychologically meaningful or evolutionarily grounded neuroscience of emotions in between, almost as if the psychological properties of the brain and its adaptive mandates are irrelevant to the predominantly molecular analysis.

Previous evolutionary views of depression Evolutionary perspectives on depression have not been prominently featured in mainline psychiatric journals. The first major volley occurred at the beginning of this new century. Neese (2000) argued that depression might serve several adaptive purposes, including communicating a need for help, as well as signaling submission in social hierarchy conflicts, where one has little chance of winning and considerable chance of losing and being seriously injured or even killed (Malatynska et al., 2005). Thus, depression might provide a mechanism for disengaging from unreachable goals and for regulating patterns of maladaptive emotional investment and motivation. The idea that social loss leads to depression was perhaps first articulated in the 1970s and 1980s (Bowlby, 1980; Reite et al., 1981), but it remained without substantive neuroscientific foundations until fairly recently. Since then, several other contributions, following themes advanced by Nesse, have emphasized that brain mechanisms promoting depressive states must have an evolutionary basis; otherwise, they could not exist. More recently, Keller and Nesse (2006) have argued that not only was there selection for depressive mood, but also that depression may come in subtypes according to the particular type of adaptive challenges for which an organism has no viable solution to cope with, especially when sustained efforts to pursue difficult goals may result in danger, loss, injury, or wasted effort. In such situations, depressive “pessimism” and lack of motivation may provide a fitness advantage by virtue of inhibiting actions when one has inadequate resources or plans, particularly when challenges to dominant figures may be hazardous. Depression could thus confer a significant fitness advantage by terminating risky or damaging dominance conflicts. These arguments are complementary to our main hypothesis, which focuses on the adaptive value of terminating protracted separation distress, especially for young and vulnerable infants. Separation distress is indeed intimately coordinated with the generalized HPA stress response that has been a mainstay of depression research, in humans as well as animal models (Henn and Vollmayr, 2005; Keck et al., 2005; Maier and Watkins, 2005). Shutdown mechanisms activated in early-life separation-distress episodes could be recruited later in life in relation to social losses experienced in dominance–hierarchy conflicts. Indeed, it seems more likely that evolution would select a mechanism if it could “kill several birds with one stone,” so to speak.

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A critical review of DSM-IV criteria for major depressive episode As with every syndrome in DSM-IV (APA, 1994), there are no objective or laboratory diagnostic tests for the presence of depression, even though biomarkers—abundant brain abnormalities—have been demonstrated at both structural and biochemical levels. Indeed, given the lack of bona fide objective tests for depression beyond a compilation of symptoms approach favored in DSM-IV, there is probably no absolutely clear line distinguishing someone with a mild form of clinical depression from those who are simply having a difficult time in the course of day-to-day existence and are simply mildly to moderately dysphoric. This may further underline the ubiquitous nature of depressive-spectrum phenomena. The DSM-IV criteria for a major depressive episode are the following: (a) Five (or more) of the following symptoms have been present during the same 2-week period and represent a change. At least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. 1 Depressed mood most of the day, nearly every day (NED), as indicated by either subjective report (feels sad or empty) or observation made by others (appears tearful). Note: In children and adolescents, it can be irritable mood. 2 Markedly diminished interest or pleasure in all, or almost all, activities most of the day, NED (as indicated by subjective account or observation). 3 Significant weight loss when not dieting or weight gain (a change of more than 5% of body weight in a month), or decrease or increase in appetite NED. Note: In children, consider failure to make expected weight gains. 4 Insomnia or hypersomnia nearly every day. 5 Psychomotor agitation or retardation NED (observable). 6 Fatigue or loss of energy NED. 7 Feelings of worthlessness or excessive or inappropriate guilt (may be delusional) (not merely self-reproach or guilt about being sick) NED. 8 Diminished ability to think or concentrate, or indecisiveness NED (either by subjective account or as observed by others). 9 Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a plan, or a suicide attempt or a specific plan for committing suicide. (b) The symptoms do not meet criteria for a mixed episode. (c) The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. (d) The symptoms are not due to the direct physiologic effects of a substance (such as a drug of abuse or a medication) or a general medical condition (such as hypothyroidism). (e) The symptoms are not better accounted for by bereavement (APA, 1994).

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Several issues are worth noting in regard to these criteria. First, the criteria cut across the entire hierarchy of functional domains of the brain (cognition, emotion, and homeostasis) and involve cognitive disruption (especially criteria 8 and, to a lesser extent, 9), obvious changes in emotion/mood (criteria 1, 2, 7, and 9), and altered homeostasis (criteria 3–6), with sleep and appetite typically disrupted, but also sexual functioning, endocrine status, and, more recently appreciated, immune status, all altered in depression. Core criteria emphasize either (1) depressed mood or (2) loss of interest or pleasure as required for a diagnosis of major depression. Unfortunately, the notion of a “depressed mood” as a central diagnostic criterion for depression is strikingly circular, a circularity rarely commented on or even acknowledged in psychiatric circles. Also, unfortunately, the criteria fail to make a careful distinction between sadness and depression, using them as rough synonyms, a recurrent problem in the psychiatric literature. We argue instead that these states have to be viewed as quite distinct, albeit potentially related. They are commonly conflated in part because they are found together, in many instances. In other words, patients are simultaneously both sad and depressed, a coincidence of states underlining that depressions are often reactions to losses; many depressions, however, especially retarded and more severe ones, show no sadness whatsoever, suggesting that sadness is actually terminated by deepening depression and supporting our core hypothesis. Additionally, we argue that the core criteria of depressed mood necessarily indexes a fundamental loss of hopefulness—in other words, “depressed mood” means an intrinsically less hopeful mood and orientation. Depression means that we no longer anticipate or expect good things to happen. Indeed, in our judgment, it is a curious omission that hopelessness is not specified at all in the DSM-IV criteria, even though despair and loss of hope probably have a quite fundamental connection to suicidal ideation and wishes to die. Earlier, DSM II and DSM III criteria did reference hopelessness, but for uncertain reasons, this notion has been pulled out of the more recent versions of DSM diagnostic criteria. Although “hopefulness” is not easily defined and operationalized (perhaps leading recent revisers of DSM to drop hopelessness as a criterion), hopefulness is traditionally contrasted with its antonyms, hopelessness and despair. Although depression is, in a sense, more complex than simple despair, these considerations suggest intrinsically close linkages between loss of hope and depression. Perhaps one of the clearest operational indices of hopefulness may be an organism’s willingness to struggle with adversity. Indeed, this ability to struggle with adversity without giving up the pursuit of rewarding activities or abandoning our social connections may directly index a fundamental emotional resilience and resistance to depression. This intrinsic connection between hopefulness and a willingness to struggle is implicit in one of the most important behavioral

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tests frequently used to evaluate potential antidepressants in the animal literature—the “forced swim test.” In this very important sense, depressed individuals lose their fundamental willingness and ability to struggle with challenging circumstances and basically give up. This “giving up” of core organism goals is a fundamental dimension to depression that any candidate theory must at least attempt to explain, and it certainly suggests that depression must have fundamental inhibitory effects on basic motivational systems in the brain, especially the complex brain network “energized” by the ventral tegmental mesolimbic dopamine system (conceptualized in Panksepp, 1998 as a generalized motivational arousal, or “seeking” system). Indeed, if our core hypothesis about depression is correct—namely, that it emerges from an evolutionarily selected mechanism to terminate protracted separation distress—such a putative shutdown mechanism would have to negatively feed back on central motivational arousal mechanisms in the brain and attenuate the ability of those mechanisms to energize behavior. Dynophin appears ideally positioned between chronic stress and VTA modulation to help achieve such a shutdown of motivational machinery. The second core criterion in DSM-IV for major depression (after depressed mood) is anhedonia and loss of interest. Interest in a wide variety of stimuli and pursuits in the world, and the anticipation of reward, may be intrinsically related both to the operation of the ventral tegmental mesolimbic–mesocortical “seeking” system (Panksepp, 1998) and to social rewards garnered in individuals with low activity in separation-distress systems and high activity in maternal care and “play” systems. Taken together, this suggests that depression may fundamentally disrupt both the anticipation and the pursuit of rewards (“interest”), along with a diminished ability to experience pleasure, even when rewards are available and obtained. We argue that this loss of interest and anhedonia are also fundamental phenomena that any heuristic theory must attempt to explain. Although loss of interest and loss of pleasure are treated as one homogeneous entity in this important criterion, evidence suggests that these are probably separate issues, with loss of interest more dopamine-related and loss of pleasure more opioidergic (for a thorough review, see Berridge, 2004). None of the subsequent seven criteria after these first two are necessarily required for the diagnosis of depression, but one must have at least four of the other “subordinate” criteria and either depressed mood or loss of interest/pleasure to meet diagnostic criteria. This approach (“at least one from column A” and “at least four from column B”), with two core criteria and seven secondary criteria, allows the DSM-IV diagnostic criteria to at least partially cover the challenging heterogeneity of depression, without prematurely committing to a subtyping paradigm (when subtypes are still not completely understood or extensively validated in the literature).

A brief neuroscientific overview of depression Due to space considerations, in-depth coverage of neurobiologic work on depression is not feasible. We instead emphasize heuristic (“big picture”) summation, particularly how multiple neurobiologic processes may interdigitate and form recursive and looping control factors that regulate both entry into and exit from depressive states. Aside from the general acceptance that severe life stress is a prominent factor in the genesis of depression (see Holsboer, 2000; Vollmayr and Henn, 2003), the largest “bin” in the neurobiology of depression “box” would clearly be classic neurotransmitter perspectives. Classically, the earliest hypotheses about depression centered on the first three monoamines characterized in the brain—norepinephrine, serotonin, and dopamine—along with the first transmitter discovered in the brain, in the 1920s, acetylcholine. The monoamine deficiency hypothesis, with a focus on norepinephrine deficits, is the oldest neurochemical hypothesis about depression (Schildkraut, 1965; for an update of the classic monoamine hypothesis, see Harro and Oreland, 2001). However, simple aminergic deficiency as an explanatory hypothesis has fallen by the wayside and been largely discredited, in the context of enormous evidence that depression is significantly more complicated than a simple “deficiency” state in any monoaminergic system, singly or even collectively (for a summary of the history, see Healy, 1997). The strongest data points against a simple noradrenergic (NE)/serotonergic (5-HT) deficiency hypothesis are: (1) the failure of norepinephrine or serotonin synthesis inhibition to create depressive symptoms in normal individuals, even though it can diminish mood in recently depressed individuals (Delgado et al., 1990); and (2) the lack of rapid amelioration of depression following the rapid onset of reuptake inhibition of various noradrenergic and serotonergic antidepressant drugs, resulting in significantly more synaptic availability of biogenic amines in forebrain areas within hours of ingestion (Delgado, 2000, 2004). Antidepressant efficacy for these classic amine facilitators occurs weeks later. Although the classical viewpoint has been that the therapeutic effects are associated with an active downregulation of receptors and/or their active pruning in the forebrain, more recent hypotheses have focused on a variety of neuronal growth and neuroplasticity factors modulated by aminergic tone (Stone et al., 2003, 2008). In addition to older hypotheses emphasizing the role of norepinephrine and serotonin, more recently, monoamine perspectives have increasingly focused on dopamine as well, particularly given its superordinate role in motivated behavior (Panksepp, 1998; Ikemoto and Panksepp, 1999; Alcaro, Huber, and Panksepp, 2007; Berridge, 2007). Also, mounting evidence now indicates that multiple other neurotransmitter systems, including GABA,

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glutamate, and multiple neuropeptides (CRF, substance P, cholecystokinin, dynorphin and other opioids, and oxytocin), may also be centrally involved in depression. Many aminergic and peptidergic neurotransmitter systems intimately coregulate each other in ways still incompletely understood, adding layers of complexity to any purely ‘modulator-centric’ neuroscientific understanding and treatment of depression (Wong and Licinio, 2001; Norman and Burrows, 2007; Stone et al., 2008). Additionally, much thinking about depression has been guided by depression’s intimate connection to alterations of the HPA axis (for example, hypercortisolemia promoting hippocampal atrophy; McEwen, 2004; Warner-Schmidt and Duman, 2006; Drew and Hen, 2007). Moreover, increasing evidence argues for an important role for pro-inflammatory cytokines in the modulation of mood and for a primary role in depression, including critical effects on the HPA axis that prevent hypercortisolemia from renormalizing the stress axis by negative feedback on CRF (Leonard, 2006). In addition to these more traditional bottom-up neuromodulatory perspectives, the neuroscientific and clinical literature on depression has increasingly focused on the possibility that depression may reflect some kind of fundamental alteration in corticolimbic networks. Recent work suggests that mood and self-related emotional information processing probably reflect changes and dynamics within highly distributed medial subcortical–cortical networks (Northoff and Panksepp, 2008). Regions of interest in such distributed network formulations would centrally include the prefrontal systems, the hippocampus, the ventral or limbic stratum, and particularly the shell of the nucleus accumbens/olfactory tubercle, along with several other subcortical limbic and paleocortical paralimbic structures, including periaqueductal gray (PAG) (Watt, 2000; Liotti and Panksepp, 2004; Northoff et  al., 2006). Such a distributed network effect is seen when stress reduces reward-seeking through a global reduction of mesolimbic dopamine transmission, partly by the capacity of upregulated dynorphin to make this whole hedonic network less responsive (Nestler and Carlezon, 2006). Considered jointly, these distributed network and neuromodulatory perspectives suggest that depression may reflect global changes in large-scale reticular-limbic– cortical networks critical to “seeking” (basic motivational arousal) and associated exploratory behavior. Therefore, they would also be critical to energizing primary attachment behavior. Attachment behaviors centrally involve the seeking of proximity to objects of attachment and an associated pursuit of multiple rewarding of positive affective states in the context of those social connections, particularly the rewards of playfulness and affection, and the seeking of comfort when distressed. All of these fundamental aspects of social seeking and attachment are shut down, if not profoundly unavailable, to depressed

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individuals (but not to individuals who are merely sad, underlining this distinction). Basic neurobiologic perspectives emerging from our current penchant for molecular reductionism must be integrated with the long-standing intuitive insight that depression is fundamentally related to the brain’s reaction to emotional/social loss. This is particularly noteworthy when the subject feels a keen helplessness to mitigate the loss or when the loss is especially penetrating and hurtful. This is not to suggest that molecular perspectives and a view of depression as related to the vicissitudes of attachment are in any way mutually exclusive. On the contrary, we believe that this more social view of depression, in which depression becomes a dark vulnerability of a highly pro-social brain, dependent on intimate social connection for its fundamental sense of well-being, may eventually better integrate an enormous amount of molecular data.

The challenging multifactorial nature of depression: depression and the social brain Although play, empathy, social bonding, contagion (the social  “infectiousness” of prototype emotions), and separation distress are all largely viewed as discrete processes in neuroscience and investigated quite independent of one another, we argue that these putatively disparate phenomena could be considered interlocking threads, somehow jointly forming the full fabric of a deeply social brain. Therefore, it seems reasonable to us that these processes were selected in an integrated manner by related evolutionary pressures. Each of these phenomena is part and parcel of a truly social brain, in which the pleasures of social connection and the pains of social loss are all first-rank motivators. Consistent with this viewpoint emphasizing the multicomponent nature of a highly social brain, one might suggest that a vulnerability to depression is probably intrinsic within this complex multidimensional fabric of a social brain. Some social brains are clearly more vulnerable to this; some are more resilient and resistant. Individuals with fortunate genetic endowments and supportive and loving upbringings may have intrinsic and robust protection against depression, but even those with more resilient genetic endowments and environmental good fortunes are never totally or permanently protected from the reach of intrinsic depressive mechanisms. At least some degree of depression lies only a major catastrophe away for almost everyone. At present, where radical reductionism and individual neurochemical vectors are receiving primary attention in psychiatry, more integrated (big-picture) psychobiologic views of depression are badly needed. However, typical modes of scientific analysis are obviously not well suited

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for conducting the massive multifactorial studies that such integration would require. Thus, we are left to patch together more holistic levels of understanding from the many factual parts that scientific empirical treatments can spew out in abundance. However, the current tendency to de-emphasize possible primary psychological dimensions in depression within much of molecular psychiatry is, in our estimation, not as likely to lead to a satisfactory integration of all the available pieces of this challenging puzzle. Future work will need to better integrate the many factors that have been identified by existing molecular approaches, summarized earlier and encompassing three monoamine systems: the cholinergic system, multiple neuropeptide systems including multiple opioid systems, the neuroendocrine/stress axes, and immune/cytokine issues. Although it is easy to assume by the current state of the art that these factors constitute all the important pieces of the puzzle, further research may underline that even this impressive collection of factors falls well short of a complete story. This brings us to another touchstone concept. Attempting to delineate unitary “first causes” or “prime movers” in a system as massively recursive and interactive as the brain may be a mostly doomed enterprise. From this perspective, the potential interactions between factors has received overall far less “air time” in the history

of writings on depression than the many proposals promoting single- or primary-factor theories. In general, however, recent work seems more open to multifactorial points of view. Instead, it may be more heuristic and much more practical to think in terms of an interactive matrix of factors that can lead to depression, but where individual variability might map to differential loading of various core factors (suggesting, among other things, that future optimal treatment of depression may require individually tuned multidimensional approaches). As Table 10.1 delineates, these presumed core neurobiologic factors regulate and massively influence one another. This suggests that any individual mind “lurches,” in a sense, sometimes rather unpredictably through a complex trajectory of neurochemical–neurodynamic space as these factors cascade and reverberate in one direction or another, in any particular instance of depression. This multifactorial nature may also help to explain why so many different therapies, ranging from exercise and psychotherapy to ECT and deep brain stimulation, are antidepressant. Although we are a long way from being able to explain why one antidepressant therapy works in one depressed individual and not in another, we suspect that an answer to this also lies somewhere in a deeper understanding of the dynamic relationships between these primary core factors in a depressive matrix. Although it has been long

Table 10.1 Neurobiologic factors: an interactive depressive matrix Depressive factor

Driven by

Producing

Behaviorial and symptomatic correlates

Increased CRF, hypercortisolemia, choleocystokinin, and reduced BDNF

Multifactorial limbic influences on paraventricular nucleus, promoting activation of HPA stress axis

Increased dynorphin, decreased 5-HT, reduced neuroplasticity/HC atrophy, intensification of separation distress, disrupted ventral HC feedback on core affective regions

Dysphoria, sleep and appetite loss, reduced short-term memory, and other cognitive deficits

Increased acetylcholine

Reduction of social and other rewards, opioid withdrawal, and any other social punishment

Facilitation of separation distress circuitry and other negative emotions, effects on other core variables

Negative affect and excess attention to negativistic perceptions and thoughts

Decreased μ-opioids and oxytocin

Separation distress and other stressors, including physical illness and pain

Disinhibition/release of stress cascades, decreased 5-HT and DA, overdriven NE, promotion of cytokine generation

Anhedonia and sadness, reduced positive affect, reduced sense of connection, suicidality

Increased dynorphin in accumbens/VTA

Stress cascades

Downregulation of VTA and mesolimbic DA system

Anhedonia, dysphoria, loss of motivation

Increased cytokines

Acute but probably not chronic stress, acute reduction of opioids

Promotion of stress cascades, decreased serotonergic and increased glutamatergic tone, impairment of HPA axis negative feedback

Fatigue, malaise, and appetitive losses; increased cognitive disruption; anhedonia

Reduced serotonergic drive/vulnerability

Stress, increased corticosteroids, cytokines, decreased μ-opioids

Lowered dopaminergic and increased noradrenergic drive, less functional segregation among brain systems

Poor affective regulation, impulsivity, obsessive thoughts, possible disinhibition of suicidality

Diminished catecholaminergic (DA and NE) tone

Constitutional vulnerability, stress and poor reward availability

Reduced “signal-to-noise” processing in all sensory–perceptual and motor/ executive systems

Fatigue, diminished psychic “energy,” appetitive sluggishness, dysphoria, impaired coordination of cognitive and emotional information processing

HC, hippocampus; 5-HT, serotonin; NE, noradrenergic; DA, dopamine; VTA, ventral tegmental area.

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thought in psychopharmacology that everyone’s chemoarchitecture is different, interactions between these core factors in a depressive matrix may also be differentially “gated” across different individuals. This may eventually allow us to answer the long-standing question of why, in an individual clinical instance, one treatment works and another does not. This review underscores an oft-neglected relevance of opioids and oxytocin for understanding depressive cascades, as critical modulators for social connection and social bonding, and how a strong social connection protects brains against depression-generating chronic stress states. Table 10.1 underlines what we consider to be the handful of core factors constituting this “depressive matrix.” Core factors may consist of (1) diminished tone in opioid and oxytocin systems associated with separation distress; (2) altered and chronic stress neurophysiology promoting upregulation of CRF and hypercortisolemia, leading to hippocampal atrophy and the failure of negative feedback on the stress axis; (3) alterations in numerous amine as well as peptidergic neuromodulatory systems, and choleocystokinin- and dynorphin-induced negative affects, creating inhibitory feedback on the ventral tegmental system dopamine and other catecholamine systems that sustain “energized,” goal-directed bodily and mental activities; (4) a critical role played by the immune system, specifically pro-inflammatory cytokines, which appear synergistic with stress cascades. Cytokines may directly or indirectly promote glutamatergic overdrive and contribute to a hypotonic serotonin system as well (Muller and Schwartz, 2007); they further promote withdrawal, fatigue, and behavioral and affective shutdown, impairing HPA axis regulation by disrupting negative feedback inhibition of CRF (Schiepers et al., 2005). Evidence indicates that social disconnection and separation distress (associated with changes in both μ- and κ-opioid systems) result in potentiated stress cascades and increased cytokine generation (Hennessy et al., 2001). We believe that these interlocking pieces of a puzzle fit together, as differential facets of a basic depressive cascade, although the seams between the pieces cannot be completely stitched together at this time. This view of depression emphasizes the critical importance of social support, in both the long-term protection against depression and its more acute and subacute therapeutic management. Our perspective underlines that social relations have a close relationship to the neurobiology of depression due to their intrinsic connections of social biology to the stress axis, cytokine promotion, modulation of critical growth and neurotrophic factors, and modulation of multiple neuropeptide and amine systems. We believe that the current treatment climate in psychiatry could significantly benefit from such an adjustment in emphasis. Psychotherapy and social support have fallen off the radar in the treatment of many

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patients with depression, due to a largely bottom-up neurochemical view of both etiology and treatment, often to the detriment of basic patient care (Rush, 2007); many patients with depression receive only psychopharmacology, with classic aminergic agents often being modestly effective, at best (see the section “Treatment algorithms in relationship to depression in the elderly”). Opioids and oxytocin, maintained tonically in securely attached creatures, exercise a powerfully inhibitory effect on basic stress cascades. The protracted downregulation of these systems in the context of protracted separation distress may tonically facilitate stress responsivity. The promotion of CRF and the downregulation of opioids and oxytocin may rapidly shift the affective state of the brain from a more euthymic to a more dysthymic one. The older view of stress cascades failed to adequately credit their role in affective changes, viewing changes in the HPA axis as if they were just physiologic changes instead of ones that created psychological change. For a long time, there has been comparative neglect of factors known to regulate separation distress and social attachments, namely opioids and oxytocin systems, in preference for noradrenergic- and serotonergic-centered viewpoints. Also generally neglected until recently within the overall puzzle were peptidergic variables most intimately and directly related to mood (μ- and κ-opioids, cannabinoids, cholecystokinin, CRF, dynorphin, and oxytocin). Protracted stress, the most prototypical being separation distress arising from social loss, may create an altered balance in μ-, δ-, and κ-opioids and oxytocin. Promotion of dynorphin and cholecystokinin tone, especially in the nucleus accumbens and VTA, and the resulting loss of motivation, including centrally the inhibition of attachment-related needs/drives, potentially transform separation distress from an acute (protest) phase to a sustained chronic (despair) phase. This shutdown is assisted by the potential fatigue/sickness-promoting effects of pro-inflammatory cytokines. These parallel changes drive global inhibition of many specific motivations, from food appetite to erotic pursuits, generating a generalized anhedonia (with active dysphoria) and, thereby, loss of a more hopeful orientation toward life opportunities and normal reward seeking. Altered homeostasis, particularly sleep and appetite, may be caused not only by elevated CRF effects on several homeostatic and circadian hypothalamic systems, but also by the diminished influence of prosocial neuropeptides. Such a sustained dysthymic mood may promote negative cognition (which, in turn, may help sustain negative mood via positive feedback effects of sustained ruminations). The hypofunction in prefrontal and hippocampal systems, perhaps associated with several neuromodulatory shifts and the effects of excessive cortisol, results in the characteristic attentional, executive, and mildly amnestic cognitive deficits of depression. Thus, even the most generous allowance

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for the causal role of a single factor may not come close to explaining all the changes that constitute a full-blown depressive episode. The variety of brain–mind factors that can contribute to depressive affect also underscores that surely not every depression is precipitated simply by attachment losses, or even by symbolic (such as social status) losses. Anhedonia and dysphoria can have various causes, including endogenous neurochemical imbalances of the brain and withdrawal from various drugs of abuse. Polymorphisms of multiple genes involved in the neurochemical underpinnings of affective homeostasis can also presumably modify the thresholds for the induction of the various stress and affective cascades. However, it is now also clear that early separation distress can promote lifelong dysregulation of hedonic homeostasis, leading to the disinhibition of negative affective processes and stress cascades. This combination of incompletely mapped genetic and somewhat better understood early environmental factors results in the potentiation of future depressive processes more easily triggered by any severe chronic form of stress, besides the classic precipitation by various forms of separation distress. In fully considering the long-term consequences of early stress, we can envision how the whole system of regulatory controls over intrinsic depressive mechanisms becomes epigenetically more fragile over the entire lifespan (Mann and Courier, 2010). The precise manner in which that happens remains important chapters for both future animal-brain and human developmental research. Of course, due to the challenging heterogeneity of depression (and virtually every other Axis I condition in psychiatry), we must remain open to the possibility of several distinct types of unipolar depression that we cannot yet clearly differentiate unambiguously, either with differential symptom clusters or with biomarkers. Just as the neurobiologic correlates of depression appear very multifactorial, developmental issues contributing to lifetime vulnerability in depression appear equally so. Recent developmental modeling (Kendler et al., 2006) confirms this multifactorial nature of developmental pathways into depression, outlining a host of “outside the skin” factors that presumably interact with multiple “inside the skin” neurobiologic variables in a fashion still poorly plotted. Kendler et al. (2006), found, using a sophisticated statistical algorithm, that roughly half of the variance for major depression in males can be explained by 18 factors and their interactions: genetic risk, low parental warmth, childhood sexual abuse, and parental loss (early childhood factors); neuroticism, low self-esteem, early-onset anxiety, and conduct disorder (early adolescence factors); low educational achievement, lifetime traumas, low social support, and substance misuse/abuse (late adolescence factors); history of divorce and past history of major depression (adult fac-

tors); and factors taking place in the last year (last-year marital problems, other personal difficulties, and stressful life events). How these factors might intersect in the brain remains uncertain. Similar modeling was done for females in an earlier study, with slightly more than 50% of the variance explainable in terms of a similar complex of factors (Kendler et al., 2002). Given that even with such a complex matrix of predisposing variables, they could explain only slightly less than 50% of the variance further underlines the challenging heterogeneity of depression in terms of its multifactorial developmental pathways. In addition to the risk factors outlined in these models, it seems obvious that chronic pain and perhaps numerous other chronic illnesses can be powerfully depressogenic, by virtue of chronic activation of stress and immunologic/cytokine cascades and relative hypoactivation of μ-opioid systems that may require not just social comfort and secure attachment, but also general physical wellness for their maximum tonic promotion (Panksepp, 1998).

Implications for an understanding of common factors promoting late-life depression Such a pleiotropic view of depression suggests several potential bridges to the problem of depression in the elderly. Elderly women again show a greater incidence of depression than elderly men, consistent with the greater penetration of this syndrome in females throughout the entire lifecycle. The elderly who undergo loss of loved ones (especially spouses), increased social isolation due to loss of friends or other social supports, loss of meaningful and rewarding activities (often due to illness or disability), or virtually any major health problem (Kaji et al., 2010) appear most at risk overall. Most obviously and probably most importantly, many elderly are exposed to severe and even catastrophic social losses, in terms of the death of their spouses and friends. In our view, this is a primary and powerful trigger for depressive episodes. Many elderly must deal with primary losses of critical attachment figures, which then leads to significantly increased social isolation, and from there, to significantly increased risk of depression (Cacioppo et al., 2010). Evidence indicates that social isolation also increases the risk for acute medical illness, with acute illness representing an additional pro-depressive stressor to which the elderly are differentially exposed, relative to younger adults (Kaji et al., 2010; Molloy et al., 2010.) An additional major point of intersection between aging and depression may rest in extensive comorbidities between pain and depression. Recent work shows that chronic pain syndromes, recently found to be the most common degrading influence in overall health status and sense of well-being in the elderly over 75 (at

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least in Europe—this has not yet been replicated in the United States), are a powerful pro-depressive influence to which the elderly are differentially exposed (Konig et al., 2010). Comorbidity of depression with chronic pain has been associated with both poorer prognosis and greater functional impairment, compared with those suffering from each illness separately (Arnow et al., 2006). Rates of depression in patients with chronic pain have been reported to range from 30% to 60% (Miller and Cano, 2009), many times higher than incidence in the general population. More severe and persistent pain also increases the incidence of more severe depression and, not surprisingly, is concomitant, with a stronger association toward suicidality (Fishbain et al., 1997). Depressed patients have a four times greater risk of chronic pain, compared with nondepressed patients (Simon et al., 1999). Chronic pain is a risk factor for subsequent development of major depression, while depression is a risk factor for the development of chronic pain (Maletic and Raison, 2009). These fundamental intersections between pain and depression are still incompletely understood but may rest in significant neuromodulatory, stress axis, neural network, and even genetic factors that overlap between the two conditions. Both depression and pain are associated with key alterations in opioid and other neuropeptide systems; increased stress axis activation; changes in dopamine, serotonin, and glutamate systems; and promotion of cytokine/inflammatory processes. Both conditions also recruit functional changes in similar distributed corticolimbic networks (involving prefrontal, medial frontal, insular, and several classic limbic system structures such as hippocampus, amygdala, and nucleus accumbens; see Narasimhan and Campbell, 2010 for a detailed review). In relation to the most immediately relevant neuromodulatory system, that of μ-opioids, both pain and depression might reflect low ebbs in complex subcortical/paleocortical opioidergic systems, signaling basic homeostatic wellness (see de Kloet et al., 2005 for confirmation of primary opioidergic involvement in sadness and separation distress). An intriguing hypothesis about an evolutionary continuity between pain and depression is suggested by the hypothesis that separation distress may have emerged from pain systems (Panksepp, 1998). If our earlier evolutionary hypothesis is correct (that depression was selected as a way of terminating protracted separation distress), pain, as an evolutionary antecedent to separation distress, might constitute a potential primary trigger for depression. Of course, much work remains to clarify (or falsify) such intriguing hypotheses, yet the importance of the common clinical comorbidity of pain and depression cannot be denied, however incompletely we may understand their intersection. An additional nontrivial point of intersection is that both conditions are probably significantly underdiagnosed and all too frequently missed in primary care.

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Additionally, given the relationship between depression and pro-inflammatory signaling cited earlier (also see Pasco et al., 2010), the increased level of inflammatory “tone,” thought to be possibly intrinsic to aging (“inflammaging”; Franceschi et al., 2007), suggests another important potential relationship between aging and increased intrinsic vulnerability to depression. Pro-inflammatory cytokines can function as regulatory signals, with a substantial inhibitory effect on various hormones and neural growth factors, many thought to sustain neuroplasticity and mood. Sustained pro-inflammatory activity has been thought to be a potential pathologic factor in the development of many diseases of aging, including IBS (inflammatory bowel disease), type II diabetes, cardiovascular and cerebrovascular diseases, rheumatoid arthritis and osteoarthritis, major depression, Alzheimer’s disease, and even aging itself (Franceschi et al., 2007). Additionally, recent work shows that classic growth factors (such as Insulin like growth factor [IGF]) and pro-inflammatory cytokines have mutually inhibitory influences on one another and can even induce resistance to the effects of one another (O’Connor et al., 2008). O’Connor et al., hypothesized that a balance between these inflammatory and growth factor processes is essential to optimal aging, with growth factors generally declining and inflammation increasing. This suggests that anti-inflammatory lifestyle variables, such as exercise; a diet rich in polyphenols, fiber, and an adequate ω-3/ω-6 ratio (an “antiinflammatory diet”); adequate sleep; positive social engagement (which has been shown to promote growth factors); and not too much stress especially chronic stress, are all likely to help retain an adaptive balance between pro-inflammatory and growth factor signaling. Additionally, there are potential relationships between dementing disorders and depression, particularly Alzheimer’s disease. Although it has been long known that recurrent major depression is a risk factor for Alzheimer’s disease, recent work suggests a reciprocal relationship, with Alzheimer’s disease also constituting a risk factor for depression (Aznar and Knudsen, 2011). The basis for this association remains to be fully clarified, but evidence indicates that Alzheimer’s disease intrinsically deteriorates affective regulation (Nash et al., 2007), a critical capacity in the resistance to depression in the face of life stresses. Alzheimer’s disease also promotes pro-inflammatory signaling and inhibits neuroplasticity, which has critical links to mood regulation (McEwen, 2004). Comorbidities may also exist between other dementing disorders and depression, although these have been less closely studied. Frontotemporal dementia may predispose to more primary apathy states, frequently misdiagnosed as depression, but also may predispose to depression as well (Chow et al., 2009; Huang et al., 2010). Last, but certainly not least, both acute medical illnesses and more chronic diseases of aging (heart disease, cancer,

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diabetes, arthritis, and all neurodegenerative disorders) have been found to be significant risk factors for depression, perhaps particularly when combined with financial and socioeconomic stress (Almeida et al., 2010; Baldwin, 2010; Kaji et al., 2010).

Treatment algorithms in relationship to depression in the elderly A comprehensive presentation of research into treatment of depression is well beyond the scope of this brief chapter summary. However, outside of paying particular attention to the unique lifestyle and developmental/adaptive challenges facing the elderly, and addressing and mitigating the unique set of stresses that contribute to the risk for depression in the elderly, there is no systematic evidence that either the prevention or the treatment of depression in the elderly is necessarily substantively different from those considerations in a younger adult (although medicine interactions can be significantly more challenging, given that many elderly patients are often on multiple medicines that can interact with psychotropic medicines in a variety of ways). In general, we argue that social support (particularly including reduction of social isolation), both psychodynamically oriented and cognitive behavioral psychotherapy, and careful attention to precipitating stressors (helping patients to generate more adaptive behaviors in response to those stresses) are often neglected in primary care interventions with depressed elderly; often physicians simply hand out a prescription for the latest selective serotonin reuptake inhibitors (SSRI). Current research suggests that psychopharmacology alone is not nearly as effective as a combination of psychopharmacology and psychotherapy (STAR D work—see Rush, 2007). In general, psychopharmacology of depression works best with adopting a flexible empiricism and fitting patient characteristics and symptomatology to drug effect profiles. A detailed review of these issues is well beyond the scope of this chapter, and clinicians looking for a review of specific approaches to the psychopharmacology of depression should consult standard texts (such as APA Publishing Textbook of Psychopharmacology). Recently, published work has suggested that big pharma may have deliberately exaggerated effect sizes for classic aminergic antidepressants. A recent meta-analysis in the New England Journal of Medicine (Turner et al., 2008) suggested widespread exaggeration of effect sizes in relation to many blockbuster (billion-dollar) antidepressant compounds. It further stated that with the inclusion of previously suppressed negative trials, effect sizes for popular antidepressant drugs are significantly less impressive than initially reported. According to the published studies, roughly 94% of the trials conducted on mainline

antidepressant drugs showed positive results. However, if one included unpublished studies in the analysis, only 51% of the trials were positive. Separate meta-analyses of the Federal Drug Administration (FDA) and journal data sets demonstrated an increase in effect size from 11% to 69% for individual drugs, with a 32% overall inflation of effect size across all studies. This recalibration shows that effect sizes for many antidepressant drugs may be relatively modest (0.31 on average, where a 0.5 effect size might be the threshold for a clinically important effectiveness, according to a meta-analysis by Ioannidis (2008). This suggests that the current practice trends, particularly within primary care of an exclusive reliance on popular SSRIs and other related aminergic agents (selective noradrenergic reuptake inhibitors [SNRI] and mixed serotonergic noradrenergic drugs), may have a substantially weaker evidence base than most medical practitioners generally assume. In an insightful study emphasizing a multivariate view of depression and practical ability to predict risk in patient populations, Almeida et al. (2010) showed that a matrix of risk factors predicted a likelihood of minor to major depression. A multivariate logistic regression showed depression was “independently associated with age older than 75 years, childhood adverse experiences, adverse lifestyle practices (smoking, alcohol use, physical inactivity), intermediate health hazards (obesity, diabetes and hypertension), comorbid medical conditions (clinical history of coronary heart disease, stroke, asthma, chronic obstructive pulmonary disease, emphysema, or cancers), as well as social or financial strain.” The authors stratified the risk factors to build a predictive matrix demonstrating a probability of depression increasing progressively with an accumulation of risk factors, from less than 3% for those with no adverse factors to more than 80% for people reporting the maximum number of risk factors. Primary care physicians and other clinicians dealing with the elderly might be able to more accurately gauge the total level of biologic stress, determine the subsequent risk for depression in their patients, and identify the need for early and potentially mitigating, if not completely preventative, interventions. In terms of common lifestyle variables that might prevent depression, fish consumption (Lin et al., 2010), vitamin D levels (Milaneschi et al., 2010; Stewart and Hirani, 2010), and regular aerobic exercise (Cotman et al., 2007; Bots et. al., 2008) appear to have the best empirical support, but conclusive data is still lacking. Unfortunately, systematic studies into preventing late-life depression have been relatively modest, at best (Baldwin, 2010). Hyperhomocysteinemia, an inflammatory marker increasingly viewed as a risk factor for all diseases of aging, and contributing to increased oxidative stress in aging (Wu, 2007), may be a meaningful target for prevention/reduction of systemic inflammation, multiple diseases of aging, and depression as well (Almeida et al.,

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2008). Vitamin D deficiency, sedentary lifestyles, obesity, and sleep deprivation, all risk factors for inflammatory diseases and other diseases of aging, may also be useful prevention targets for delimiting penetration of depressive disorders. Additional prevention targets may include improved management of chronic pain and, of course, reduction of social isolation.

Existential aspects of aging and their impact on mood Although it has not been systematically studied to our knowledge, one might suspect that intrinsic features of aging pose “depressogenic” challenges for many individuals with less than optimal family and social histories. Older individuals face the shrinking sense of any future or substantial time to make up for previous mistakes, disappointments, and lost opportunities, while often struggling with an existential awareness of the inevitability of death and physical decline. In contrast, in individuals who have been most successfully and securely socially connected, and for whom life has presented ample opportunities for both social and work-related rewards, these intrinsic challenges of mortality and aging are substantially buffered by an ongoing affirmation of deep ties to spouses, friends, and other loved ones; devotion to children and grandchildren; and continuing involvement in a cultural and intellectual heritage to which one feels connected and may have substantially contributed in the past. Those without such resources, and lacking successful social and work histories, may inevitably face what Erik Erikson (1950) called, in his eighth stage of life, the crisis of “integrity versus despair.” Instead of having an accumulated wisdom and a reverence for life despite all its many painful limitations, individuals who have not successfully negotiated previous developmental challenges enter the final stage of life with conflicted, traumatic, or simply absent relationships. Instead of affirmation of continuing social, professional, and cultural connections, they may feel a keen sense of despair over their failures and multiple losses, and regret the absence of youthful opportunities for substantially mitigating a negative past. This suggests that, in old age, those who have failed to achieve a secure sense of self-esteem and associated social connection are particularly disadvantaged, as they face their own mortality and, inevitably, declining health and function, intrinsically difficult challenges for even the most resilient elders. Such self-esteem and chronic psychosocial and characterologic deficits in these less fortunate individuals pose enormous burdens on mood and mood regulation in the context of these existential challenges of aging and form a critical and often underappreciated vulnerability to depression in all its forms.

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Chapter 11 Cerebrovascular Diseases in Geriatrics Patrick Lyden, Khalil Amir, and Ilana Tidus Department of Neurology, Cedars-Sinai Medical Centre, Los Angeles, CA, USA

Summary • Aging is influenced by diet, environment, personal habits, and genetic factors. Abrupt decline in any system or function is always due to disease and is not considered “normal aging.” • Symptoms of atypical aging include incontinence, memory disturbance or intellectual impairment, immobility and falls, and instability. • Delirium is defined as an acute decline in attention and cognition and requires the presence of acute onset and fluctuating course, inattention and disorganized thinking, or altered level of consciousness. • Stroke pathology includes cerebral infarction, primary intracerebral hemorrhage, and subarachnoid hemorrhage. National Institutes of Health Stroke Scale (NIHSS) indicates stroke severity with a score more than 24, indicating severe stroke. • In previous studies, carotid endarterectomy (CEA) has been known to reduce the risk of recurrent disabling stroke or death in patients with severe ipsilateral internal carotid artery stenosis. • Biologic therapies, multimodality neuroprotection therapies, therapeutic hypothermia, and sonothrombolysis may possibly help stroke treatment in the future. • Cerebrovascular risk factors (CVRFs) predispose the patient to stroke or heart attack and are more likely to cause depressive symptoms after stroke.

“Care of the elderly” arbitrarily refers to patients older than 65 years of age. The clinical approach to the elderly person is much different than the medical evaluation of a younger adult person. These important differences have many implications for correct diagnoses, appropriate investigations, clinical outcome measures, quality of care, hospital length of stay (LOS), and cost to health care and the general public. Several physiologic and biologic changes take place during aging that have implications for medication-related adverse effects, atypical disease presentations, and the way the aging body responds to stress. Other important factors to consider in the care of the elderly are high prevalence of comorbidities, multiple coexisting and interacting chronic diseases (such as diabetes, ischemic heart disease, heart failure, arthritis, dementia, cerebrovascular and cardiovascular diseases, social isolation, and polypharmacy). As a result of these complex and interactive factors and biologic changes with associated features, the manifestations of diseases are more subtle and present with atypical and nonspecific features. Barriers to physical examinations exist, as do limitations in the correct diagnostic and prognostic tests and therapeutic interventions. The other important variable is the current and future demographic changes that

are more pronounced in the older population, particularly with a significant increase in those 85 years and older. All these changes, whether biologic, iatrogenic, or demographic, have a direct impact on health-related outcomes, quality of life, cost of health care, rate of hospitalizations, the patient, families and caregivers, and medical staff satisfaction. They also impact morbidity and mortality (Warshaw, et al., 1982; Hirsch et al., 1990; Inouye et al., 1993; Brennan et al., 1991).

Biologic changes with aging Physiologically, human aging is characterized by a progressive constriction of the homeostatic reserve of every organ system, called homeostenosis. Evident by the third decade, it is gradual and progressive, but the extent of decline may vary. It is also influenced by diet, environment, personal habits, and genetic factors. Individuals become more dissimilar as they age, belying any stereotype of aging. In addition, it is important to note that an abrupt decline in any system or function is always due to disease, not to “normal aging.” “Normal aging” can be attenuated by modifying risk factors (such as hypertension, smoking, and exercise).

Geriatric Neurology, 1st Edition. Edited by Anil K. Nair and Marwan N. Sabbagh. © 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

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Generally, as one ages, the relative total body fat increases and the total body water decreases. This has a direct relationship to the volume of distribution (VD) for fat-soluble and water-soluble medications. It increases the VD for fat-soluble medications (such as benzodiazepines and many other cardiac or central nervous system (CNS)-acting drugs), hence increases the half-life and side effects, and decreases the VD for water-soluble medications (such as alcohol, digoxin, and theophylline), with increased concentrations and toxic effects. In terms of cardiac and central nervous systems, several neuroendocrine metabolites are altered such as with a decrease in brain catecholamine synthesis and decreased dopaminergic synthesis, among others, causing stiffer gait, increased body sway, early wakening insomnia, and decreased resting temperatures. In the cardiovascular system, there is decreased arterial compliance, increased systolic blood pressure, decreased β-adrenergic responsiveness, decreased baroreceptor sensitivity, and decreased sinoatrial node automaticity. These, in turn, can cause reduced response to volume depletion, decreased cardiac output and heart rate because of stress, and impaired BP response to standing (Kasper et al., 2005; Evans et al., 2000).

Clinical presentations in the elderly “Healthy old age” is not an oxymoron. In fact, in the absence of diseases, the decline in homeostatic reserve causes no symptoms and imposes few restrictions on activities of daily living (ADL), regardless of age. However, as individuals age, they are more likely to suffer from disease, disability, and the side effects of drugs. When combined with the decrease in physiologic reserves, these compounded factors can make the older person more vulnerable to environmental, pathologic, and pharmacologic challenges. Therefore, managing elder patients involves distinct considerations. In caring for geriatric patients, one typically manages multiple chronic conditions. Similarly, more of an emphasis falls on care versus cure. Coupled with comprehensive geriatric assessment (CGA), dealing with a whole patient rather than disease specifics and using a team approach with coordinated care across multiple sites is essential for continuity of care (Kasper et al., 2005; Evans et al., 2000).

General approach to hospitalized elderly patients Although only 13% of the American population is elderly, they account for 38% of all discharges and 46% of all hospital inpatient days. This means longer hospital stays, greater costs, and more adverse outcomes. Basically, acute

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care is geriatric care (Kozak et al., 2004, 2005; Warshaw et al., 1982; Hirsch et al., 1990).

Atypical presentations in the elderly As mentioned earlier, care of the elderly involves atypical and different clinical presentations. For example, simple and mild hyperthyroidism can present with confusion, atrial fibrillation, depression, syncope, and weakness—all at the same time. In addition, a limited number of symptoms predominates because of the “weakest link” phenomenon. These include confusion, depression, incontinence, falls, and syncope. What constitutes geriatric giants is as follows: • Incontinence (made worse by urinary tract infections, immobility, diuretics, and many other disease processes) • Memory disturbance or intellectual impairment (affected by many disorders such as stroke, Parkinson’s disease (PD), delirium, and medication-related adverse effects) • Immobility and falls (affected by arthritis, postural hypotension, osteoporosis, stroke, PD, Alzheimer’s disease (AD), and medication) • Instability (such as with decreased muscle mass and visual impairment) Other important and complicating factors in terms of the clinical evaluation of an elderly person are that the general rules of clinical approach may not strictly apply. For example, an organ system-related symptom is less likely to be the source of that symptom. Likewise, a clinical depression is not likely strictly due to a psychiatric illness, as would probably be the case for a younger adult with major depression. Similarly, an acute confusional state or delirium would likely not be the result of a new CNS lesion. More likely, the problem is multifactorial, perhaps a contributing risk factor with causative agents playing the major role. Another example of atypical clinical presentation in the elderly is that an older person who presents with syncope or a brief period of loss of consciousness is unlikely to have the illness due to a structural heart disease, unlike a younger adult. It may well be due to postural hypotension, compounded by medication-related adverse effects such as the simple antihistamine, anticholinergic medication diphenhydramine. It is crucial that a clinician’s approach to older patients be proactive and preventative in nature. Because elder persons have decreased physiologic reserves, they can have earlier presentations and manifestations of their illness. An illustration is clinical congestive heart failure exacerbated or caused by mild hyperthyroidism. In addition, a cognitive dysfunction may be related to mild hyperparathyroidism or related to increased drug side effects. For example, diphenhydramine may cause confusion, digoxin may contribute to depression, and

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much-overlooked over-the-counter sympathomimetics can cause urinary retention. Knowing these factors can reduce unnecessary investigations and invasive or risky procedures. Correctly identifying the risk factors and properly diagnosing the clinical condition helps determine appropriate management strategies. All of these are related to improved outcomes, improved quality of life, and decreased morbidity and mortality. In addition, this has cost savings implications and results in improved satisfaction for the patients, their caregivers, and staff. Care of the elderly also involves multiple abnormalities, but small improvements in each may yield dramatic benefits overall. Another aspect of care of the elderly in general involves the theory that there is no anemia, impotence, depression, or confusion of old age. The diagnostic “law of parsimony” often does not apply. As an example, imagine that a patient is admitted to the hospital with a constellation of signs and symptoms consisting of fever, anemia, retinal emboli, and heart murmur. In a young person, this would indicate endocarditis. However, in an elderly person, it could be an aspirin side effect, cholesterol emboli, aortic sclerosis, or simply a viral illness. Even if the correct diagnosis is made, treating a single disease is unlikely to result in a cure or a better outcome. Therefore, the “whole person” approach is much more important than the diseasespecific approach because it addresses other issues related to the care of the elderly (Kasper et al., 2004; Evanse et al., 2000; Kozak et al., 2004, 2005).

Hospitalization of elderly patients We know that hospitalization contributes to a decline in the older patient’s functional status or the ability to function independently in the physical, mental, and social activities of daily life. These include bathing, dressing, toileting, continence, and instrumental activities of daily life (shopping, housekeeping, preparing meals, taking medications, using public transportation, and so on). Therefore, older patients are more likely to depend on ADLs at admission and to suffer functional decline. As we discussed, the elderly have diminished homeostatic reserves and can have multiple comorbid conditions, decreased muscle mass, and strength. This is further compromised by sustained bed rest. Moreover, independent self-care is further threatened in patients with cognitive impairment, stroke, PD, arthritis, and heart and respiratory failure. Studies show that 25–60% of elderly hospitalized patients experience loss of independent function during hospitalization. This increases LOS, nursing home placement, and mortality, with associated high cost.

Table 11.1 Geriatric principles of geriatric medicine Primum non nocere (first, do no harm) Pay attention Avoid causing discomfort or indignity Use meticulous clinical observations and proper technique Actively search for signs and symptoms of dysfunction and disability Evaluate the whole person, including physical, mental, and social functions Emphasize prevention, rehabilitation, and enhanced quality of life Eliminate iatrogenic causes Maintain function and independence at all times Source: Courtesy of Professor Mark E. Williams (with minor modifications).

In summary, the current hospital model can be a restrictive, unfamiliar, and threatening environment, particularly for a patient with mild dementia, poor mobility, decreased hearing, or visual disturbances. In addition, there is significant iatrogenesis, and unnecessary tests and procedures are carried out with related adverse outcomes. The prescription of inappropriate medications in hospitalized elderly is well documented and, again, is related to increased hospital LOS, increased cost, and negative outcomes. To improve all outcomes for elderly hospitalized patients, we can turn to several effective models of care that have been shown to improve morbidity, improve mortality, be cost-effective, reduce LOS, and improve patient and staff satisfaction. These comprehensive models are run with a multidisciplinary team approach and care pathways geared to the care of the elderly. Examples are stroke units, acute care of the elderly (ACE) units, program of all-inclusive care of the elderly (PACE), delirium preventions intervention, and multidisciplinary falls and fracture prevention models (Warshaw et al., 1982; Hirsch et al., 1990; Inouye et al., 1993; Brennan et al., 1991; Landefeld et al., 1995). I want to specifically highlight the geriatric principles in Table 11.1, which I adopted from one of my mentors and role models in the care of the elderly at the University of Virginia in Charlottesville, Virginia.

Specific diseases Several issues need to be addressed while dealing with specific disease, particularly considering the increasing aging population and the high prevalence of delirium in hospitalized elderly patients with associated increased morbidity, mortality, increased LOS, increased cost, patient and caregiver grief, and increased institutionalization.

Delirium or acute confessional state Delirium is defined as an acute decline in attention and cognition. Delirium is often underdiagnosed, has serious implications, and is preventable.

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The key features of delirium are as follows: Acute onset and fluctuating course Inattention Disorganized thinking Altered level of consciousness The Confusion Assessment Method (CAM) has been well validated and is used for rapid assessment and detection of delirium. It has a sensitivity of 94–100% and specificity of 90–95%, and uses the four criteria given below. 1 Acute onset and fluctuating course 2 Inattention 3 Disorganized thinking 4 Altered level of consciousness The diagnosis of delirium requires the presence of criteria 1, 2, and 3, or 4. As we discussed, the prevalence of delirium ranges (on admission) between 10% and 40%, with an incidence (in hospital) of 25–60%. This is associated with significant hospital mortality between 10% and 65% and annual health-care expenditures of more than $8 billion. Clinically, many risk factors predispose older patients to developing delirium. These have been well validated in studies and include the following: • Cognitive impairment • Sleep deprivation • Immobilization • Vision impairment • Hearing impairment • Dehydration Recognizing these risk factors and being alert about them, upon admission, enables health-care professionals to intervene early in each of these steps and potentially prevent delirium. Interventions may include reality orientations, nonpharmacologic sleep protocols, early mobilization protocols, vision aids, amplifying devices (hearing aids), and appropriate hydration. Apart from the previously mentioned risk factors, several etiologies for delirium exist. The pneumonic delirium can be useful. • • • •

Dementia Electrolyte abnormalities Lungs, liver, heart, kidney, brain Infection Rx Injury, pain, stress Unfamiliar environment Metabolic In particular, the list of medications causing delirium is large and important. Some culprits include benzodiazepines, anticholinergics, antihistamines, antidepressants, and many cardiac medications. In terms of management, once risk factors or causative agents are identified, emphasis should be on prevention, risk factor evaluation on admission, and early intervention.

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Generally, treatment is geared toward eliminating these etiologies and treating the underlying condition. A good clinical history including a medication list, a thorough physical examination, a targeted metabolic panel, and a search for occult infection, may be all that is required and will have the greatest yield, as opposed to EEG and CT/MRI–brain. Emphasis is on nonpharmacologic approaches and less invasive investigations. However, low doses of haloperidol (0.5–1.0 mg IM/PO, with a maximum dose of 3–5 mg) or short-acting benzodiazepines (such as lorazepam) can be useful in alleviating symptoms. In summary, delirium should be considered a medical emergency and must be coupled with a thorough history and physical examination. Emphasis should be put on early prevention and risk evaluation and less invasive tests or investigations. Treatment must focus on eliminating the causative agents and using fewer pharmacologic agents (Inouye et al., 1990, 1993,1999a,1999b; Inouye and Charpentier, 1996; Cole et al., 2002; Francis et al., 1990).

Stroke It is suggested and widely believed, though no concrete evidence exists, that Hippocrates may have defined stroke 2400 years ago as apoplexy (struck down by violence), although the term was used for different conditions. Stroke is a clinical syndrome characterized by rapidly developing clinical symptoms or signs of focal—and, at times, global—loss of cerebral function; symptoms last more than 24 hours or lead to death, with no apparent cause other than that of vascular origin. Not long ago, patients with stroke were either treated at home or admitted for compassionate observation. Doctors made an effort to localize lesions and describe vascular syndromes and pathology. An aura of therapeutic hopelessness surrounded stroke care. Fortunately, those days are over and optimism about the benefits of treatment (stroke care units (SCUs) and thrombolysis), coupled with a sense of urgency in dealing quickly with every patient with acute stroke, has swept away that nihilism (Barnett et al., 2000; Lyden 2008, 2009).

Risk factors for stroke The risk factors for stroke are the usual suspects. Such modifiable risks include hypertension, diabetes mellitus, tobacco abuse, hyperlipidemia, atrial fibrillation, transient ischemic attack (TIA), certain medications and recreational drugs, and alcohol. Other risks include nonmodifiable risks such as age, sex, and genetics. Importantly and interestingly, when compared to the risk identification for stroke, only 60% of the time-specific risk factors are identified in stroke versus 90% in ischemic heart disease (Whisnant, 1997; Yusuf et al., 2004).

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Stroke classifications Stroke is classified pathologically, clinically, or by etiology. Pathology/subtypes are as follows: • Cerebral infarction • Primary intracerebral hemorrhage • Subarachnoid hemorrhage (Warlow et al., 2003)

Etiology The etiologic classification of ischemic stroke, which is sometimes referred to as the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, includes the following: • Atherosclerotic • Cardioembolic • Small vessel thrombotic • Other pathology (vasculitis, hypercoagulable state) • Undetermined cause Strokes can be classified into four clinical subtypes according to the (Bamford) Oxfordshire Community Stroke Project (OCSP) classification (Table 11.2). Other causes of stroke and differential diagnosis include the following: • Migraine • Seizure disorder/postictal • GA/TA • Intracranial structural lesions • Tumor • Aneurysm • Arteriovenous malformation • Chronic subdural hematoma • Head injury • Encephalitis • Cerebral abscess • Multiple sclerosis • Labyrinthine disorder • Metabolic disturbance • Hypoglycemia • Hyponatremia • Hypocalcemia • Alcohol and drugs • Myasthenia gravis • Psychological cause • Panic • Hyperventilation • Somatization disorder Another important clinical aspect of stroke is ruling out stroke mimics. This differentiation was illustrated in separate studies that showed an alternative final diagTable 11.2 Stroke clinical subtypes 1 2 3 4

Total anterior circulation syndrome (TACS) Partial anterior circulation syndrome (PACS) Posterior circulation syndrome (POCS) Lacunar syndrome (LACS)

nosis among patients admitted to the hospital with an admission diagnosis of stroke. A retrospective study by Hemmen et al. (2008) reviewed the discharge diagnoses of all patients who presented to the emergency department as a code stroke (411 patients). A patient was considered a stroke mimic, if a code stroke was activated, but none of the first three International Classification of Diseases, Ninth Revision codes on discharge were related to TIA or ischemic stroke. In all, 104 patients (25.3%) were discharged without a diagnosis of stroke or TIA. The diagnoses in this group were intracranial hemorrhage (19 patients), subarachnoid hemorrhage (6), subdural hematoma (3), old deficit (11), hypotension (11), seizure (10), intoxication (8), hypoglycemia (7), mass lesion (6), migraine (5), and others (18). In all, 33 of 307 eligible patients (10.7%) were treated with tissue-type plasminogen activator. None of the patients with a stroke mimic received tissue-type plasminogen activator. In 44 of 104 stroke mimics (42.3%), the acute disease was caused by a severe neurologic condition other than ischemic cerebrovascular disease. Only 60 of 411 code strokes (14.6%) were initiated for patients without a severe and acute neurologic condition. The study concluded that, in their community, 25.5% of all code strokes were initiated for stroke mimics. Most mimic patients had an illness likely to benefit from urgent neurologic evaluation (Adams et al., 1993; Bamford et al., 1991).

Bottom of form Another study by Nor et al. (2005) showed the percentages of final diagnosis of patients admitted with an admission diagnosis of stroke. Seizure disorder (24%) Sepsis (23%) Migraine (10%) Somatization (6%) Labyrinthitis/vestibulitis/vertigo (5%) Metabolic disorder (4%) Brain tumor (4%) Dementia (3%) Encephalopathy (2%) Neuropathy/radiculopathy (1%) Transient global amnesia (1%) Again, similar to the study by Hemmen et al., none of these patients received thrombolysis (Nor et al., 2005; Hemmen et al., 2008).

Stroke care Stroke care is a true interdisciplinary and multidisciplinary approach that has shown to be effective and improve outcomes of stroke, including reducing mortality. It involves

Cerebrovascular Diseases in Geriatrics

the patient, the community, the family, general and family practitioners, emergency response services, the emergency department, geriatricians, neurologists, general physicians, psychologists, nurses, and the rehabilitation team. The interdisciplinary team consists of the following: • Physiotherapist • Occupational therapist • Speech and language therapist • Dietician • Pharmacist • Social worker • Bed manager • Coordinator The diagnosis of stroke is clinical and several aids can help with the diagnosis, the severity of stroke, and functional outcomes or prognosis. • Clinical history and examination • Los Angeles Pre Stroke Scale (LAPSS) • Cincinnati Stroke Scale • Face, Arm, Speech Test (FAST) • Recognition of Stroke in the Emergency Room (ROSIER) • Modified Rankin Scale (mRS) • National Institutes of Health Stroke Scale (NIHSS) • Scandinavian Stroke Scale (SSS) • Barthel Index (BI) • Glasgow Coma Scale (GCS) NIHSS, a serial measure of neurologic deficit, is a 42-point scale that quantifies neurologic deficits in 11 categories. Normal function without a neurologic deficit is scored as 0, and the scale is repeated at regular intervals. The NIH designed the NIHSS; the National Institute of Neurological Disorders and Stroke (NINDS), with Dr Patrick D Lyden as one of its leaders, developed the video materials it uses. It is quick (can be done in less than 7 minutes), has good interobserver reliability, and can be administered by non-neurologists. An NIHSS score of more than 24 indicates a severe stroke; a score of less than 4 denotes a mild stroke. Both of these scores are relative contraindications for thrombolysis. The NIHSS has 11 parts as given below. • Level of consciousness (1a, b, c) • Best gaze and vision (2, 3) • Facial palsy (4) • Motor arm and legs (5a, b; 6a, b) • Limb ataxia (7) • Sensory (8) • Language and dysarthria (9, 10) • Extinction/neglect and inattention (11) The mRS is a simplified overall assessment of function that has been widely accepted as an outcome measure in stroke studies. A score of 0 indicates the absence of symptoms, a score of 5 indicates severe disability, and a score of 6 indicates that the patient is dead. Table 11.3 describes the scores for the mRS.

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Table 11.3 Modified rankin scale Score

Measurement

0 1

No symptoms No significant disability, despite symptoms; able to carry out all usual duties and activities Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance Moderate disability; requires some help, but able to walk without assistance Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance Severe disability; bedridden, incontinent, and requires constant nursing care and attention Dead

2 3 4

5 6

The BI is a simple index of independence to score the ability of a patient with a neuromuscular or musculoskeletal disorder to care for him- or herself and, by repeating the test periodically, to assess improvement. A patient scoring 100 BI is continent; eats, dresses, and bathes independently; gets up out of bed and chairs; walks at least a block; and can ascend and descend stairs. This does not mean that the person is able to live alone. He or she may not be able to cook, keep house, or meet the public, although he or she is able to get along without attendant care. As with the mRS, the advantage of the BI is its simplicity. It is useful in evaluating a patient’s state of independence before treatment, progress while undergoing treatment, and status at maximum benefit. It can easily be understood by all who work with the patient and anyone who adheres to the definitions of the items listed, can quickly and accurately score it. The total score is not as significant or meaningful as the breakdown into individual items, because these indicate where the deficiencies are. Management goals for stroke are as follows: • Minimize brain injury • Maximize patient recovery • Improve mortality • Improve functional independence • Increase patient, family, and staff satisfaction • Prevent complications Best practices, recommendations, and full guidelines for stroke care are available from the American Heart Association (AHA)/American Stroke Association (ASA) and many other stroke organizations online (Stroke Unit Trialists’ Collaboration, 2007; Brott, 1989; Bonita and Beaglehole 1988; Van Swieten et al., 1988; Mahoney and Barthel, 1965; Wade and Collin, 1988; Granger et al., 1979; Shah et al., 1989; Sulter et al., 1999).

Stroke outcome data Thrombolysis The original NINDS rt-PA Stroke Study Group study was a randomized controlled trial (RCT) that administered t-PA

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0.9 mg/kg within 3 hours versus placebo, with strict inclusion and exclusion criteria. The primary outcome measures were functional independence as measured by mRS. It showed a 32% relative risk reduction (RRR) and a 12% absolute risk reduction (ARR) at 90 days, with minimal or no disability as per mRS. The number needed to treat (NNT) was 8 to prevent one bad outcome. The odds ratio (OR) for improvement was 2 (95% CI 1.3–3.1). It also showed that at 1 year, 30% were more likely to have a favorable outcome. Mortality was the same, even though the risk of symptomatic intracranial hemorrhage (sICH) was much higher in the intervention group (6.4% vs. 0.6% in placebo). The European Cooperative Acute Stroke Study (ECASS) 3 was a similar, recently published study that increased the timeline from within 3 hours to within 4.5 hours. The RRR was 16% (CI 1.01–1.34); p = 0.04 and 7.2% ARR at 90 days with minimal or no disability as per mRS. The NNT was 14 and OR for improvement was 1.34 (95% CI 1.02–1.76; p = 0.04). Mortality was the same (7.7% vs. 8.4%; p = 0.68), and sICH was 2.4% vs. 0.2% (p = 0.008). For every 100 patients treated, 14 additional patients have a favorable outcome (The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995; Hacke et al., 2004, 2008).

Stroke care units The Cochrane Review under Stroke Unit Trialists’ conducted a meta-analysis of more than 3500 patients in 20 trials. Outcome measures were of patients in stroke units versus general units, with reduction in death OR 0.83 (95% CI 0.71–0.87), reduction in death and dependency OR 0.77 (95% CI 0.65–0.87), ARR 5.6%, and NNT 18. Similarly, other studies showed stroke unit care versus medical ward was associated with reduced mortality at 30 days (39% vs. 63%; p = 0.007) and at 1 year (52% vs. 69%; p = 0.013). Organized inpatient MDT rehabilitation was associated with reduced odds of death OR 0.66 (95% CI 0.49–0.88; p = 0.01) and reduced death of dependency OR 0.65 (95% CI 0.50–0.85; p = 0.001). Patients who were treated in SCU versus general medical wards were discharged home versus NH (47% vs. 19%; p