Neuromethods 137 Robert Perneczky Editor Biomarkers for Preclinical Alzheimer ’s Disease N euromethods Series Editor Wolfgang Walz University of Saskatchewan Saskatoon, SK, Canada For further volumes: http://www.springer.com/series/7657 Biomarkers for Preclinical Alzheimer’s Disease Edited by Robert Perneczky Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, Munich, Germany Editor Robert Perneczky Department of Psychiatry and Psychotherapy Ludwig-Maximilians-Universität München Munich, Germany ISSN 0893-2336 ISSN 1940-6045 (electronic) Neuromethods ISBN 978-1-4939-7673-7 ISBN 978-1-4939-7674-4 (eBook) https://doi.org/10.1007/978-1-4939-7674-4 Library of Congress Control Number: 2017964263 © Springer Science+Business Media, LLC 2018 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Printed on acid-free paper This Humana Press imprint is published by Springer Nature The registered company is Springer Science+Business Media, LLC The registered company address is: 233 Spring Street, New York, NY 10013, U.S.A. Series Preface Experimental life sciences have two basic foundations: concepts and tools. The Neuromethods series focuses on the tools and techniques unique to the investigation of the nervous system and excitable cells. It will not, however, shortchange the concept side of things as care has been taken to integrate these tools within the context of the concepts and questions under investigation. In this way, the series is unique in that it not only collects protocols but also includes theoretical background information and critiques which led to the methods and their development. Thus it gives the reader a better understanding of the origin of the techniques and their potential future development. The Neuromethods publishing program strikes a balance between recent and exciting developments like those concerning new ani- mal models of disease, imaging, in vivo methods, and more established techniques, includ- ing, for example, immunocytochemistry and electrophysiological technologies. New trainees in neurosciences still need a sound footing in these older methods in order to apply a critical approach to their results. Under the guidance of its founders, Alan Boulton and Glen Baker, the Neuromethods series has been a success since its first volume published through Humana Press in 1985. The series continues to flourish through many changes over the years. It is now published under the umbrella of Springer Protocols. While methods involving brain research have changed a lot since the series started, the publishing environment and technology have changed even more radically. Neuromethods has the distinct layout and style of the Springer Protocols program, designed specifically for readability and ease of reference in a laboratory setting. The careful application of methods is potentially the most important step in the process of scientific inquiry. In the past, new methodologies led the way in developing new disci- plines in the biological and medical sciences. For example, Physiology emerged out of Anatomy in the nineteenth century by harnessing new methods based on the newly discov- ered phenomenon of electricity. Nowadays, the relationships between disciplines and meth- ods are more complex. Methods are now widely shared between disciplines and research areas. New developments in electronic publishing make it possible for scientists that encounter new methods to quickly find sources of information electronically. The design of individual volumes and chapters in this series takes this new access technology into account. Springer Protocols makes it possible to download single protocols separately. In addition, Springer makes its print-on-demand technology available globally. A print copy can there- fore be acquired quickly and for a competitive price anywhere in the world. Saskatoon, Canada Wolfgang Walz v Preface The constantly increasing number of individuals with dementia due to Alzheimer’s disease (AD) poses a significant financial and emotional burden on the affected families and the global society. Therapeutic strategies designed to treat symptoms or alter the disease course have so far failed to make a positive impact, despite billions of US dollars of R&D invest- ments and massive efforts of the industry and academic communities. These failures in treatment have led many to believe that symptomatic AD, including its earliest clinical stages, is resistant to drug interventions. The recently increased focus on biomarkers to diagnose early disease is fuelled by the hope of identifying a therapeutic window, in which the brain is still largely intact and there- fore amenable to treatment effects. The ability of biomarkers to adequately define the pre- clinical (i.e., at risk of AD dementia) disease stage may ultimately allow novel or repurposed drugs to finally achieve clinically meaningful results for the affected individuals and to help to prevent dementia and associated disability. This book discusses the usefulness of established biomarkers (imaging, fluid, and genetic) to detect preclinical AD, providing detailed protocols for state-of-the-art biomarker mea- surement and analysis. It is also explained how cutting-edge technology is used to develop novel improved biomarkers for the earliest, presymptomatic stages of AD. Our book aims to provide a comprehensive overview specifically of biomarkers for the earliest detectable dis- ease stages. All previous publications cover biomarkers for clinical, symptomatic AD. This publication comprises five parts: In Part I (Chaps. 1 and 2) we explain why AD is one of the major challenges for the global societies and healthcare systems, which highlights the urgent need for improved approaches for early diagnosis enabling disease prevention. In Part II (Chaps. 3–5) clinical and research concepts are presented, which are important to improve early recognition of AD. Part III (Chaps. 6–10) provides a comprehensive over- view of methods currently used in the AD diagnostic work-up, and it is explained how these methods can be applied to preclinical disease. In Part IV (Chaps. 11–15) cutting-edge tech- nology innovations and their value for early AD diagnosis are discussed. Finally, in Part V (Chaps. 16–18), we consider important ethical considerations in relation to biomarker-based early diagnosis, and we also discuss the meaningfulness of biomarker endpoints in clinical AD research. The book is targeted at individuals with an interest in the use of advanced biomarker strategies to significantly improve the early diagnosis of AD, and thereby to accelerate the development of effective, disease-modifying drugs. This includes researchers, clinicians, and those interested in regulatory and medical affairs, both from academia and industry. We wish to present biomarker development approaches as a strategy for the study of AD with the hope and expectation that the results will translate into more effective diagnosis and treatment and improved public health policies. We expect this book to complement other excellent volumes and monographs on AD that cover basic science or clinical aspects of the disease. London, UK Robert Perneczky vii Contents Series Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi Part I alzheImer’s DIsease as a socIetal challenge 1 Worldwide Economic Costs and Societal Burden of Dementia................. 3 Junfang Xu and Chengxuan Qiu 2 Epidemiology and Risk Factors of Alzheimer’s Disease: A Focus on Diet......... 15 Cécilia Samieri Part II DIagnostIc concePts 3 The Dimensional Structure of Subjective Cognitive Decline .................. 45 Miguel A. Fernández-Blázquez, Marina Ávila-Villanueva, and Miguel Medina 4 Deriving and Testing the Validity of Cognitive Reserve Candidates............. 63 Yaakov Stern and Christian Habeck 5 Methods for Pathological Classification of Alzheimer’s Disease................ 71 Johannes Attems, Kirsty E. McAleese, and Lauren Walker Part III establIsheD markers of PathoPhysIology anD rIsk 6 Cerebrospinal Fluid Biomarkers of Preclinical Alzheimer’s Disease ............. 93 Panagiotis Alexopoulos and Chaido Sirinian 7 Brain Structural Imaging in Alzheimer’s Disease........................... 107 Sven Haller, Davide Zanchi, Cristelle Rodriguez, and Panteleimon Giannakopoulos 8 Brain Functional Imaging in Preclinical Alzheimer’s Disease . . . . . . . . . . . . . . . . . . 119 Peter Häussermann, Thorsten Bartsch, and Oliver Granert 9 Imaging of Brain Amyloid Load in Early Alzheimer’s Disease ................. 149 Timo Grimmer and Jennifer Grace Perryman 10 Functional EEG Connectivity Alterations in Alzheimer’s Disease............... 157 Florian Hatz and Peter Fuhr Part IV bIomarker DIscoVery 11 A Selected Reaction Monitoring Protocol for the Measurement of sTREM2 in Cerebrospinal Fluid..................................... 169 Amanda J. Heslegrave, Wendy E. Heywood, Kevin M. Mills, and Henrik Zetterberg ix x Contents 12 Soluble Amyloid Precursor Proteins in Blood: Methods and Challenges ......... 179 Robert Perneczky and Panagiotis Alexopoulos 13 Tau Imaging in Preclinical Alzheimer’s Disease............................ 189 Paul Edison 14 Retinal Imaging in Early Alzheimer’s Disease ............................. 199 Tom MacGillivray, Sarah McGrory, Tom Pearson, and James Cameron 15 In Vivo Volumetry of the Cholinergic Basal Forebrain ...................... 213 Michel J. Grothe, Ingo Kilimann, Lea Grinberg, Helmut Heinsen, and Stefan Teipel Part V PatIent benefIt anD ethIcal consIDeratIons 16 Clinical Meaningfulness of Biomarker Endpoints in Alzheimer’s Disease Research................................................... 235 Kok Pin Ng, Tharick A. Pascoal, Xiaofeng Li, Pedro Rosa-Neto, and Serge Gauthier 17 The Ethics of Biomarker-Based Preclinical Diagnosis of Alzheimer’s Disease...... 249 Alexander F. Kurz and Nicola T. Lautenschlager 18 Shared Decision-Making and Important Medical and Social Decisions in the Context of Early Diagnosis of Alzheimer’s Disease .................... 259 Katharina Bronner and Johannes Hamann Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 Contributors marIna ÁVIla-VIllanueVa • Alzheimer Disease Research Unit, CIEN Foundation, Carlos III Institute of Health, Queen Sofía Foundation Alzheimer Center, Madrid, Spain PanagIotIs alexoPoulos • Department of Psychiatry, University Hospital of Patras, University of Patras, Patras, Greece; Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany Johannes attems • Institute for Neuroscience, Newcastle University, Newcastle upon Tyne, UK thorsten bartsch • Department of Neurology, Memory Disorders and Plasticity Group, Dementia and Alzheimer’s Clinic, University Hospital Schleswig-Holstein, Kiel, Germany katharIna bronner • Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany James cameron • Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK Paul eDIson • Division of Brain Sciences, Department of Medicine, Neurology Imaging Unit, Imperial College London, Hammersmith Hospital, London, UK; Department of Psychological Medicine, Cardiff University School of Medicine, Cardiff, UK mIguel a. fernÁnDez-blÁzquez • Alzheimer Disease Research Unit, CIEN Foundation, Carlos III Institute of Health, Queen Sofía Foundation Alzheimer Center, Madrid, Spain Peter fuhr • Section of Clinical Neurophysiology, Department of Neurology, Hospital of the University of Basel, Basel, Switzerland serge gauthIer • The McGill University Research Centre for Studies in Aging, McGill University, Montreal, QC, Canada PanteleImon gIannakoPoulos • Department of Psychiatry, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Division of Institutional Measures, Medical Direction, University Hospitals of Geneva, Belle-Idée, Chêne-Bourg, Switzerland olIVer granert • Department of Neurology, Memory Disorders and Plasticity Group, Dementia and Alzheimer’s Clinic, University Hospital Schleswig-Holstein, Kiel, Germany tImo grImmer • Centre for Cognitive Disorders, Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany lea grInberg • Department of Neurology, University of California, San Francisco, CA, USA mIchel J. grothe • German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany chrIstIan habeck • Cognitive Neuroscience Division, Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA sVen haller • Affidea Carouge Radiologic Diagnostic Center, Geneva, Switzerland; Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, Sweden; Department of Neuroradiology, University Hospital Freiburg, Freiburg, Germany; Department of Neuroradiology, Faculty of Medicine, University of Geneva, Geneva, Switzerland xi xii Contributors Johannes hamann • Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany florIan hatz • Section of Clinical Neurophysiology, Department of Neurology, Hospital of the University of Basel, Basel, Switzerland Peter häussermann • Department of Geriatric Psychiatry, LVR Klinik Köln, Academic Teaching Hospital, University of Cologne, Köln, Germany helmut heInsen • Universidade de Sao Paulo Faculdade de Medicina, Sao Paulo, Brazil; Department of Psychiatry, Psychosomatics and Psychotherapy, Julius-Maximilians- University, Würzburg, Germany amanDa J. heslegraVe • Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK WenDy e. heyWooD • Centre for Translational Omics, University College London Institute of ChildHealth, London, UK Ingo kIlImann • German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany; Department of Psychosomatic Medicine, University of Rostock, Rostock, Germany alexanDer f. kurz • Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technische Universität München, Munich, Germany nIcola t. lautenschlager • Academic Unit for Psychiatry of Old Age, Department of Psychiatry, The University of Melbourne and NorthWestern Mental Health, Mental Health, Melbourne, Australia xIaofeng lI • The McGill University Research Centre for Studies in Aging, McGill University, Montreal, QC, Canada; Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China tom macgIllIVray • Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK kIrsty e. mcaleese • Institute for Neuroscience, Newcastle University, Newcastle upon Tyne, UK sarah mcgrory • Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK mIguel meDIna • Alzheimer Disease Research Unit, CIEN Foundation, Carlos III Institute of Health, Queen Sofía Foundation Alzheimer Center, Madrid, Spain; CIBERNED (Network Center for Biomedical Research in Neurodegenerative Diseases), Universidad Autónoma de Madrid, Madrid, Spain keVIn m. mIlls • Centre for Translational Omics, University College London Institute of ChildHealth, London, UK kok PIn ng • The McGill University Research Centre for Studies in Aging, McGill University, Montreal, QC, Canada; Department of Neurology, National Neuroscience Institute, Singapore, Singapore tharIck a. Pascoal • The McGill University Research Centre for Studies in Aging, McGill University, Montreal, QC, Canada tom Pearson • Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK robert Perneczky • Department of Psychiatry and Psychotherapy, Ludwig-Maximilians- Universität München, Munich, Germany JennIfer grace Perryman • Ludwig-Maximilians-University Munich, Munich, Germany