Biomarkers for Alzheimer’s Disease Drug Development

362 Pages·2018·11.67 MB·English

by  Robert Perneczky (eds.)

Methods in
Molecular Biology 1750
Robert Perneczky Editor
Biomarkers
for Alzheimer’s
Disease Drug
Development
M M B
ethods in olecular iology
Series Editor
John M. Walker
School of Life and Medical Sciences
University of Hertfordshire
Hatfield, Hertfordshire, AL10 9AB, UK
For further volumes:
http://www.springer.com/series/7651
Biomarkers for Alzheimer’s
Disease Drug Development
Edited by
Robert Perneczky
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München,
Munich, Germany
German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
Neuroepidemiology and Ageing Research Unit, School of Public Health, The Imperial College of Science,
Technology and Medicine, London, UK
West London Mental Health NHS Trust, London, UK
Editor
Robert Perneczky
Department of Psychiatry and Psychotherapy
Ludwig-Maximilians-Universität München
Munich, Germany
German Center for Neurodegenerative Diseases (DZNE) Munich
Munich, Germany
Neuroepidemiology and Ageing Research Unit, School of Public Health
The Imperial College of Science, Technology and Medicine
London, UK
West London Mental Health NHS Trust
London, UK
ISSN 1064-3745 ISSN 1940-6029 (electronic)
Methods in Molecular Biology
ISBN 978-1-4939-7703-1 ISBN 978-1-4939-7704-8 (eBook)
https://doi.org/10.1007/978-1-4939-7704-8
Library of Congress Control Number: 2018932034
© 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.
Preface
The prevalence of Alzheimer’s disease and its healthcare and socioeconomic impact are
exploding worldwide, and drug development success rates need to be improved urgently;
the traditional linear model of pharmaceutical R&D has become outdated and virtually all
new drugs have failed since the cholinesterase inhibitors were introduced to the markets
two decades ago. Drug development has been more successful in other fields of medicine
such as infectious diseases and cancer, in which translational models are applied, linking
population-based cohorts and genetic data with potential drug targets and study endpoints.
This powerful translational approach is fuelled by technology platforms such as n euroimaging,
-omics, and fluid biomarkers. The Alzheimer’s disease field requires a significant cultural
change to discover and develop effective disease-modifying treatment options (until 2025,
as postulated at the 2013 G8 Dementia Summit).
The main objective of this book is to bridge and converge population, -omics, and
imaging sciences (typically owned by academia) with R&D approaches for new t echnologies
and novel, effective drugs (the traditional remit of industry). The book will help building a
new generation of experts with a broader understanding of key topics to initiate the
disruptive innovation required to make real progress. Given the high complexity and
multifactorial disease nature related to dementias, a precision/personalized medicine
approach in designing the next generation R&D strategies is now urgently required.
This publication comprises nine parts: In Part I (Chapters 1–3) we explain why Alzheimer’s
disease is one of the major challenges for the global societies and healthcare systems, and how
population-based and systems biology approaches can be leveraged to develop more effective
treatments. In Part II (Chapters 4–6) we present innovative approaches to the discovery of novel
biomarkers in cerebrospinal fluid, whereas in Part III (Chapters 7–9) innovation in blood-based
biomarkers is discussed. Part IV (Chapters 10–12) and Part V (Chapters 13–16) provide a
comprehensive overview of magnetic resonance imaging and molecular imaging approaches and
their value for developing drugs for Alzheimer’s disease, respectively. In Part VI (Chapters 17 and
18) cutting-edge d evelopments in neuropathology and their relevance for Alzheimer’s disease
trials are presented. Part VII (Chapters 19–21) covers novel genomic strategies for biomarker
development. Part VIII (Chapters 22 and 23) highlights the contribution of preclinical research
to the development of novel b iomarkers and drugs. Finally, in Part IX (Chapters 24 and 25), we
consider r elevant related topics including neuropsychological testing and advanced analytical
methods.
The book is targeted at individuals with an interest in the use of advanced biomarker strategies
to accelerate the development of effective, disease-modifying drugs for Alzheimer’s disease. 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 Alzheimer’s disease with the hope and expectation that the results will translate into
more effective treatments. We expect this book to complement other excellent volumes and
monographs on Alzheimer’s disease that cover basic science or clinical aspects of the disease.
Munich, Germany Robert Perneczky
v
Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
Part I the Need for alzheImer’s dIsease BIomarkers
1 Epidemiology of Dementia: The Burden on Society,
the Challenges for Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Frank J. Wolters and M. Arfan Ikram
2 Population-Based Approaches to Alzheimer’s Disease Prevention . . . . . . . . . . . 15
Robert Perneczky
3 Systems Biology Methods for Alzheimer’s Disease Research
Toward Molecular Signatures, Subtypes, and Stages
and Precision Medicine: Application in Cohort Studies and Trials . . . . . . . . . . . 31
Juan I. Castrillo, Simone Lista, Harald Hampel, and Craig W. Ritchie
Part II INNovatIve aPProaches to cereBrosPINal
fluId BIomarker dIscovery
4 CSF Lipidomics Analysis: High-Resolution Mass
Spectrometry Analytical Platform . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Paul L. Wood and Randall L. Woltjer
5 CSF N-Glycomics Using MALDI MS Techniques
in Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Angelo Palmigiano, Angela Messina, Rosaria Ornella Bua,
Rita Barone, Luisa Sturiale, Mario Zappia, and Domenico Garozzo
6 MicroRNA Profiling of Alzheimer’s Disease Cerebrospinal Fluid . . . . . . . . . . . 93
Johannes Denk and Holger Jahn
Part III Novel Blood-Based BIomarkers
7 Validation of a Chemiluminescence Immunoassay
for Measuring Amyloid-β in Human Blood Plasma . . . . . . . . . . . . . . . . . . . . . . 111
Jonathan Vogelgsang, Jens Wiltfang, and Hans W. Klafki
8 Mass Spectrometry-Based Metabolomic Multiplatform
for Alzheimer’s Disease Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Raúl González-Domínguez, Álvaro González-Domínguez, Ana Sayago,
and Ángeles Fernández-Recamales
9 Blood-Based Biomarker Screening with Agnostic Biological
Definitions for an Accurate Diagnosis Within the Dimensional
Spectrum of Neurodegenerative Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Filippo Baldacci, Simone Lista, Sid E. O’Bryant, Roberto Ceravolo,
Nicola Toschi, Harald Hampel, and for the Alzheimer Precision Medicine
Initiative (APMI)
vii
viii Contents
Part Iv magNetIc resoNaNce ImagINg methods
10 Functional Magnetic Resonance Imaging in Alzheimer’
Disease Drug Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Stefan Holiga, Ahmed Abdulkadir, Stefan Klöppel, and Juergen Dukart
11 Neuroimaging Methods for MRI Analysis in CSF Biomarkers Studies . . . . . . . . 165
Carles Falcon, Grégory Operto, José Luis Molinuevo,
and Juan Domingo Gispert
12 Hybrid PET-MRI in Alzheimer’s Disease Research . . . . . . . . . . . . . . . . . . . . . . 185
Ismini C. Mainta, Maria I. Vargas, Sara Trombella,
Giovanni B. Frisoni, Paul G. Unschuld, and Valentina Garibotto
Part v molecular ImagINg aPProaches
13 Amyloid PET Imaging: Standardization and Integration
with Other Alzheimer’s Disease Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
Silvia Morbelli and Matteo Bauckneht
14 The Use of 18F-FDG PET in the Diagnostic Workup
of Alzheimer’s Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Marion M. Ortner
15 Quantification of Tau Load in Alzheimer’s Disease Clinical
Trials Using Positron Emission Tomography . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Tessa Timmers, Bart N.M. van Berckel, Adriaan A. Lammertsma,
and Rik Ossenkoppele
16 Imaging Neuroinflammation: Quantification of Astrocytosis
in a Multitracer PET Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
Elena Rodriguez-Vieitez and Agneta Nordberg
Part vI NeuroPathology
17 Unbiased Lipidomics and Metabolomics of Human Brain Samples . . . . . . . . . . 255
Giuseppe Astarita, Matteo Stocchero, and Giuseppe Paglia
18 Neuropathological Assessment as an Endpoint in Clinical Trial Design . . . . . . . 271
Steve Gentleman and Alan King Lun Liu
Part vII geNomIc methods
19 Analysis of Micro-RNA Expression by qPCR on a Microfluidics Platform
for Alzheimer’s Disease Biomarker Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . 283
Petros Takousis
20 Telomere Length Shortening in Alzheimer’s Disease: Procedures
for a Causal Investigation Using Single Nucleotide Polymorphisms
in a Mendelian Randomization Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
Yiqiang Zhan and Sara Hägg
21 Quantifying miRNA Deregulation in Alzheimer’s Disease . . . . . . . . . . . . . . . . 307
Ana L. Cardoso and Joana R. Guedes
Contents ix
Part vIII PreclINIcal research
22 Imaging of Microglial Activation in Alzheimer’s Disease
by [11C]PBR28 PET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
Cornelius K. Donat, Nazanin Mirzaei, Sac-Pharm Tang,
Paul Edison, and Magdalena Sastre
23 In Vivo Two-Photon Calcium Imaging of Hippocampal Neurons
in Alzheimer Mouse Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
Marc Aurel Busche
Part IX related coNcePts: cogNItIve testINg
aNd advaNced aNalytIcs
24 Cognitive Assessment in Alzheimer’s Disease Clinical Trials . . . . . . . . . . . . . . . 355
Geraint Price
25 Data Mining and Machine Learning Methods for Dementia Research . . . . . . . 363
Rui Li
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
Contributors
ahmed aBdulkadIr · University Hospital of Old Age Psychiatry and Psychotherapy Bern,
Bern, Switzerland
m. arfaN Ikram · Departments of Epidemiology, Radiology, Neurology, Erasmus
University Medical Center Rotterdam, Rotterdam, The Netherlands
gIusePPe astarIta · Department of Biochemistry and Molecular and Cellular Biology,
Georgetown University, Washington, DC, USA
fIlIPPo BaldaccI · AXA Research Fund & UPMC Chair, Paris, France; Sorbonne
Université, AP-HP, GRC n° 21, Alzheimer Precision Medicine (APM), Hôpital de la
Pitié-Salpêtrière, Boulevard de l’hôpital, Paris, France; Institut du Cerveau et de la
Moelle Épinière (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l’hôpital,
Paris, France; Institut de la Mémoire et de la Maladie d’Alzheimer (IM2A),
Département de Neurologie, Hôpital de la Pitié-Salpêtrière, AP-HP, Boulevard de
l’hôpital, Paris, France; Department of Clinical and Experimental Medicine,
University of Pisa, Pisa, Italy
rIta BaroNe · CNR, Istituto per i Polimeri, Compositi e i Biomateriali Catania,
Catania, Italy; Pediatric Neurology Unit, Department of Pediatrics,
University of Catania, Catania, Italy
matteo BauckNeht · Nuclear Medicine Unit, Polyclinic San Martino Hospital, Genova,
Italy; Department of Health Sciences, University of Genoa, Genoa, Italy
Bart N.m. vaN Berckel · Department of Radiology and Nuclear Medicine, Neuroscience
Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
rosarIa orNella Bua · CNR, Istituto per i Polimeri, Compositi e i Biomateriali
Catania, Catania, Italy
marc aurel Busche · Department of Neurology, Massachusetts General Hospital,
Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease,
Charlestown, MA, USA; Department of Psychiatry and Psychotherapy, Technical
University of Munich, Munich, Germany; Munich Cluster for Systems Neurology, Munich,
Germany
aNa l. cardoso · Center for Neuroscience and Cell Biology, University of Coimbra,
Coimbra, Portugal
JuaN I. castrIllo · Genetadi Biotech S .L . Parque Tecnológico de Bizkaia, Derio, Bizkaia,
Spain
roBerto ceravolo · Department of Clinical and Experimental Medicine, University of
Pisa, Pisa, Italy
JohaNNes deNk · Department of Psychiatry and Psychotherapy, University Medical Center
Hamburg-Eppendorf, Hamburg, Germany
corNelIus k. doNat · Division of Brain Sciences, Imperial College London,
Hammersmith Hospital, London, UK
JuergeN dukart · F . Hoffmann-La Roche, Pharma Research Early Development, Roche
Innovation Centre Basel, Basel, Switzerland; Roche Pharmaceutical Research and Early
Development, Neuroscience, Ophthalmology and Rare Diseases, Discovery and
Translational Area, Roche Innovation Center Basel, Basel, Switzerland
xi
xii Contributors
Paul edIsoN · Division of Brain Sciences, Imperial College London, Hammersmith
Hospital, London, UK
carles falcoN · Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation,
Barcelona, Spain; Centro de Investigación Biomédica en Red de Bioingeniería,
Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain
ÁNgeles ferNÁNdez-recamales · Department of Chemistry, Faculty of Experimental
Sciences, University of Huelva, Huelva, Spain; International Campus of Excellence
CeiA3, University of Huelva, Huelva, Spain
gIovaNNI B. frIsoNI · Faculty of Medicine, Nuclear Medicine Department, Geneva
University Medical Center, University of Geneva, Geneva, Switzerland; Department of
Internal Medicine, Geneva University Hospitals, Geneva, Switzerland
valeNtINa garIBotto · Division of Nuclear Medicine and Molecular Imaging, Geneva
University Hospitals, Geneva, Switzerland; Faculty of Medicine, Nuclear Medicine
Department, Geneva University Medical Center, University of Geneva, Geneva,
Switzerland
domeNIco garozzo · CNR, Istituto per i Polimeri, Compositi e i Biomateriali Catania,
Catania, Italy
steve geNtlemaN · Division of Brain Sciences, Department of Medicine, Imperial College
London, London, UK
JuaN domINgo gIsPert · Barcelonaβeta Brain Research Center, Pasqual Maragall
Foundation, Barcelona, Spain; Centro de Investigación Biomédica en Red de
Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain
raúl goNzÁlez-domíNguez · Department of Chemistry, Faculty of Experimental
Sciences, University of Huelva, Huelva, Spain; International Campus of Excellence
CeiA3, University of Huelva, Huelva, Spain
Álvaro goNzÁlez-domíNguez · Department of Chemistry, Faculty of Experimental
Sciences, University of Huelva, Huelva, Spain; International Campus of Excellence
CeiA3, University of Huelva, Huelva, Spain
JoaNa r. guedes · Center for Neuroscience and Cell Biology, University of Coimbra,
Coimbra, Portugal
sara hägg · Department of Medical Epidemiology and Biostatistics, Karolinska Institutet,
Stockholm, Sweden
harald hamPel · AXA Research Fund & UPMC Chair, Paris, France; Sorbonne
Université, AP-HP, GRC n° 21, Alzheimer Precision Medicine (APM), Hôpital de la
Pitié-Salpêtrière, Boulevard de l’hôpital, Paris, France; Institut du Cerveau et de la
Moelle Épinière (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l’hôpital,
Paris, France; Institut de la Mémoire et de la Maladie d’Alzheimer (IM2A),
Département de Neurologie, Hôpital de la Pitié-Salpêtrière, AP-HP, Boulevard de
l’hôpital, Paris, France
stefaN holIga · F . Hoffmann-La Roche, pharma Research Early Development, Roche
Innovation Centre Basel, Basel, Switzerland
holger JahN · Department of Psychiatry and Psychotherapy, University Medical Center
Hamburg-Eppendorf, Hamburg, Germany
haNs W. klafkI · Department of Psychiatry and Psychotherapy, University Medical Center
Goettingen, Georg-August-University, Goettingen, Germany