The Handbook of Alzheimer’s Disease and Other Dementias Wiley-Blackwell Handbooks of Behavioral Neuroscience The rapidly expanding field of behavioral neuroscience examines neurobiological aspects of behavior, utilizing techniques from molecular biology, neuropsychology, and psychology This series of handbooks provides a cutting-edge overview of classic research, current scholarship, and future trends in behavioral neuroscience The series provides a survey of representative topics in this field, suggesting implications for basic research and clinical applications Series editor: David Mostofsky, Boston University The Handbook of Stress: Neuropsychological Effects on the Brain Edited by Cheryl D Conrad The Handbook of Alzheimer’s Disease and Other Dementias Edited by Andrew E Budson and Neil W Kowall The Handbook of the Neuropsychology of Language (2 Volumes) Edited by Miriam Faust The Handbook of Alzheimer’s Disease and Other Dementias Edited by Andrew E Budson and Neil W Kowall A John Wiley & Sons, Ltd., Publication This edition first published 2011 © 2011 Blackwell Publishing Ltd Blackwell Publishing was acquired by John Wiley & Sons in February 2007 Blackwell’s publishing program has been merged with Wiley’s global Scientific, Technical, and Medical business to form Wiley-Blackwell Registered Office John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial Offices 350 Main Street, Malden, MA 02148-5020, USA 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 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 Andrew E Budson and Neil W Kowall to be identified as the editors of the editorial material in 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 Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic books 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 This publication is designed to provide accurate and authoritative information in regard to the subject matter covered 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 Library of Congress Cataloging-in-Publication Data The handbook of Alzheimer’s disease and other dementias / edited by Andrew E Budson and Neil W Kowall p ; cm – (Wiley-Blackwell handbooks of behavioral neuroscience) Includes bibliographical references and index ISBN 978-1-4051-6828-1 (hardcover : alk paper) Dementia I Budson, Andrew E II Kowall, Neil W III Series: Wiley-Blackwell handbooks of behavioral neuroscience [DNLM: Dementia WM 220] RC521.H34 2011 616.8'3–dc22 2011010575 A catalogue record for this book is available from the British Library This book is published in the following electronic formats: ePDFs 9781444344080; Wiley Online Library 9781444344103; ePub 9781444344097 Set in 10.5/13 pt Minion by Toppan Best-set Premedia Limited 2011 We wish to dedicate this book to our families: Amy, Leah, and Danny And Miriam, Elisheva, Charlotte, Jenny, Mischa, and Jonah Contents Contributors ix Foreword xii Preface xv Part I Common Dementias Alzheimer’s Disease Alan M Mandell and Robert C Green Vascular Dementia Angela L Jefferson, Amanda M Gentile, and Ravi Kahlon Dementia with Lewy Bodies Tamara G Fong and Daniel Z Press 92 131 Frontotemporal Dementia Adam L Boxer 145 Other Dementias Peter Morin 179 Part II Pathogenesis and Disease Mechanisms Genetic Risk Factors for Dementia Paul Hollingworth and Julie Williams 195 197 The Neuropathology of the Dementing Disorders Ann C McKee and Brandon E Gavett 235 Amyloid Beta Peptide and the Amyloid Cascade Hypothesis Carmela R Abraham 262 viii Contents Other Mechanisms of Neurodegeneration Marina Boziki, Vassilis Papaliagkas, and Magda Tsolaki 277 10 Rational Therapeutics for Alzheimer’s Disease and Other Dementias Neil W Kowall 301 Part III 313 Cognitive and Behavioral Dysfunction 11 Memory Dysfunction in Dementia Andrew E Budson 315 12 336 Language Processing in Dementia Jamie Reilly, Joshua Troche, and Murray Grossman 13 Executive Functioning Robert A Stern, Stacy L Andersen, and Brandon E Gavett 369 14 Emotion and Behavior in Alzheimer’s Disease and Other Dementias Christopher I Wright 416 15 Visuospatial Function in Alzheimer’s Disease and Related Disorders Alice Cronin-Golomb 457 16 483 Sleep and Circadian Rhythms in Dementia David G Harper Part IV Neuroimaging in Dementia 505 17 Glimpses of the Living Brain with Alzheimer’s Disease Ronald J Killiany 507 18 535 Functional MRI in Alzheimer’s Disease and Other Dementias Maija Pihlajamäki and Reisa A Sperling 19 Molecular Neuroimaging of the Dementias Bradford C Dickerson 557 20 Using EEG and MEG to Understand Brain Physiology in Alzheimer’s Disease and Related Dementias Brandon A Ally 575 Index 604 a b c Figure 2.3 Vascular lesions evident upon gross pathological examination (a) Atherosclerosis; (b) Infarcts; (c) Lacunes Source: Courtesy of Dr Ann McKee, Boston University School of Medicine a b Figure 3.3 (a) On the left are two Lewy bodies, seen as spherical, eosinophilic (pink) intracellular inclusions in a pigmented neuron from the substantia nigra (picture courtesy of Dr Jeffrey Joseph) (b) On the right is a demonstration of changes seen in perfusion MRI with arterial spin labeling in DLB The top row represents normal perfusion imaging, the second row shows mild decreases seen in mild AD, the third row shows greater decreases seen in DLB matched for severity Figure 7.1 Cerebral atrophy and microscopic pathology in AD Source: Courtesy of Dr Ann McKee, Boston University School of Medicine Figure 7.2 Chronic traumatic encephalopathy Source: Courtesy of Dr Ann McKee, Boston University School of Medicine Image not available in the electronic edition Figure 11.1 Episodic memory The medial temporal lobes, including the hippocampus and parahippocampus, form the core of the episodic memory system Other brain regions are also necessary for episodic memory to function correctly In addition to being involved in episodic memory, the amygdala is also important for the autonomic conditioning Source: From Budson, A E., & Price, B H (2005) Memory dysfunction New England Journal of Medicine, 352, 692–699; permission granted by the New England Journal of Medicine Image not available in the electronic edition Figure 11.6 Semantic, procedural, and working memory The inferolateral temporal lobes are important in the naming and categorization tasks by which semantic memory is typically assessed However, in the broadest sense, semantic memory may reside in multiple and diverse cortical areas that are related to various types of knowledge The basal ganglia, cerebellum, and supplementary motor area are critical for procedural memory The prefrontal cortex is active in virtually all working memory tasks; other cortical and subcortical brain regions will also be active, depending on the type and complexity of the working memory task In addition to being involved in procedural memory, the cerebellum is also important for the motoric conditioning Source: From Budson, A E., & Price, B H (2005) Memory dysfunction New England Journal of Medicine, 352, 692–699; permission granted by the New England Journal of Medicine Figure 12.2 A cascade model of the cognitive-linguistic decline in semantic dementia Figure 14.3 The amygdala structure and function Coronal gross section (left), high resolution T1 weighted MRI (middle), and fMRI activation map demonstrating responses to fearful versus neutral faces A B C D Figure 14.5 Alzheimer’s disease (A) Axial FLAIR MRI showing medial temporal lobe atrophy (B) Axial FDG PET showing parietotemrporal hypometabolism (C) Coronal crosssection showing medial temporal lobe atrophy (D) Silver stained histopathological section showing plaques and tangles A B C D Figure 14.7 Frontotemporal dementia (A) Saggital PET subtraction image showing areas of medial PFC hypometabolism relative to a normative database (B) Axial PET subtraction image showing areas of medial and lateral PFC hypometabolism (courtesy of Keith Johnson) (C) Gross pathological whole-brain specimen showing frontotemporal atrophy (D) Histopathological specimen showing Pick bodies A B C Figure 14.8 Lewy body dementia (A) Axial T2 weighted MRI scan showing lack of atrophy in early LBD (B) Axial PET image showing areas of occipitopatietal hypometabolism (courtesy of Keith Johnson) (C) Microscopic pathological tissue specimen showing Lewy bodies in pigmented nerve cell of substantia nigra Figure 17.6 Axial T2 relaxation map from a non-demented elderly individual showing areas of T2 signal shortening in red superimposed over a corresponding T2 weighted axial scan Certain areas of the brain such as the globus pallidus (G) are known to accumulate iron with age and this is the likely cause for the T2 signal shortening in this area Less clear is why smaller areas of T2 signal shortening (white arrow indicates an example) can be found These may be markers of oxidative damage Figure 17.9 Example of an axial FA map generated by the post processing of a DTI scan The different colors to the white matter represent the preferred direction of diffusion for each voxel with red representing the medial/lateral direction, green the rostral/caudal direction and blue the ventral/dorsal direction A B C Figure 18.1 This figure illustrates typical inferotemporal BOLD fMRI responses during a “block design” memory paradigm, that is, associative encoding of Novel (N) face–name pairs compared to visual Fixation (+) in young (A) and older (B) healthy subjects and in AD patients (C) FMRI time courses also show the smaller fMRI BOLD response amplitude during blocks of Repeated (R) stimuli than during Novel blocks P-values range from 0.0001 (in dark blue) to 0.0000001 (in yellow) Figure 18.2 This figure shows the right hippocampal area of significantly decreased fMRI activation (P < 0.001) in mild AD patients compared to healthy older subjects when contrasting encoding of Novel face–name pairs to visual Fixation Z-scores range from 0.0 (in dark red) to 3.0 (in white) A B Figure 18.3 Subjects with “early” MCI (A), i.e., CDR-SB scores of 0.5–1.5, demonstrate greater task-related hippocampal activation than clinically more impaired “late” MCI subjects (B) with CDR-SB scores of 2.0–3.5 during associative encoding of Novel and Repeated face–name pairs T-values range from (in dark red) to 10 (in white) A B C Figure 18.4 This figure shows increasingly disrupted fMRI task-induced deactivation pattern during processing of Novel and Repeated face–name pairs, as revealed by independent component analysis, across the continuum from healthy older controls (A) to MCI subjects (B) to patients with mild AD (C) T-values range from (in dark blue) to 14 (in white) Figure 19.1 In mild Alzheimer’s disease, cortical glucose metabolism is typically reduced in the temporoparietal region, as well as posterior midline and orbitofrontal regions This now classic finding is useful clinically in differential diagnosis and may be valuable as an imaging biomarker for early detection of the metabolic signature of the disease in patients with minimal or no symptoms This figure shows the largest reduction in metabolism in yellow, with lesser reductions in red hues from a single patient with mild AD, displayed on that patient’s cortical surface as reconstructed from the anatomic MRI Image not available in the electronic edition Figure 19.2 Regional brain metabolism can be used in the differential diagnosis of AD versus vascular dementia This map shows the areas of relative hypometabolism in AD along the yellow-red end of the spectrum, including temporoparietal, posterior midline, and orbitofrontal regions, and areas of relative hypometabolism in vascular dementia along the violetblue end of the spectrum Areas of relative hypometabolism in vascular dementia include frontal cortex, primary sensorimotor cortices, basal ganglia, and cerebellar regions Source: Kerrouche, N., Herholz, K., Mielke, R., Holthoff, V., & Baron, J C (2006) 18FDG PET in vascular dementia: Differentiation from Alzheimer’s disease using voxel-based multivariate analysis Journal of Cerebral Blood Flow & Metabolism, 26, 1213–1221 Figure reproduced with permission from the International Society of Cerebral Blood Flow and Metabolism Figure 19.3 The variety of dopaminergic PET tracers highlight different abnormalities at different clinical stages of Parkinson’s disease and in other movement disorders, such as multiple system atrophy (MSA-P) Top row illustrates dopamine synthesis and storage as measured by F-DOPA, middle row illustrates D2 receptor binding as measured by raclopride (RACLO) Dopamine synthesis and storage is reduced in the putamen in all conditions (red star), while D2 receptor binding is increased at an early clinical stage of PD (HY I, yellow plus sign), returns to normal in advanced PD (HY IV), and is reduced in MSA-P (red plus sign) Source: Heiss, W.D., & Herholz, K (2006) Brain receptor imaging Journal of Nuclear Medicine, 47, 302–312 Figure reproduced with permission from the Society of Nuclear Medicine Normal control subject Mild Alzheimer’s: reduced neocortical and amygdaloid AChE activity normal AChE activity in nbM region Figure 19.4 Cholinergic PET tracers highlight the reduction of acetylcholinesterase (AChE) in mild Alzheimer’s disease, particularly in cortex and amygdala with relative preservation in basal forebrain (nucleus basalis of Meynert, nbM), suggesting a dying-back of cholinergic neurons rather than initial loss of cell bodies Source: Heiss, W.D., & Herholz, K (2006) Brain receptor imaging Journal of Nuclear Medicine, 47, 302–312 Figure reproduced with permission from the Society of Nuclear Medicine Figure 19.5 In vivo PET-based detection of beta amyloid Increased retention of Pittsburgh Compound B (PiB) is found in frontal and temporoparietal regions in a patient with clinical AD dementia (left), compared with a control (right) PIB-PET images are shown in color with yellow-red hues indicating relatively high amyloid binding and blue indicating essentially no amyloid binding Source: Dickerson, B C., & Sperling, R A (2005) Neuroimaging biomarkers for clinical trials of disease-modifying therapies in Alzheimer’s sisease Neurorx, 2, 348–360 Figure courtesy of William E Klunk, M.D., Ph.D., and reproduced with permission from Elsevier, Inc 3µV 500 550 600 650 700 750 800 –3µV Figure 20.3 Hit–correct rejection scalp topographies during the recollection of words for patients with mild cognitive impairment and healthy older adults ... Handbook of Stress: Neuropsychological Effects on the Brain Edited by Cheryl D Conrad The Handbook of Alzheimer’s Disease and Other Dementias Edited by Andrew E Budson and Neil W Kowall The Handbook. .. The Handbook of Alzheimer’s Disease and Other Dementias Wiley-Blackwell Handbooks of Behavioral Neuroscience The rapidly expanding field of behavioral neuroscience examines... Neil W Kowall The Handbook of the Neuropsychology of Language (2 Volumes) Edited by Miriam Faust The Handbook of Alzheimer’s Disease and Other Dementias Edited by Andrew E Budson and Neil W Kowall