RESEARCH AND PERSPECTIVES IN ALZHEIMER'S DISEASE

Fondation Ipsen

Editor

Yves Christen, Fondation Ipsen, Paris (France)

Editorial Board

Yves Agid, H6pital Pitie Salpetriere, Paris (France) Albert Aguayo, McGill University, Montreal (Canada) Brian H. Anderton, Institute of Psychiatry, London (GB) Raymond T. Bartus, Alkermes, Cambridge (USA) Anders Bjorklund, University of Lund (Sweden) Floyd Bloom, Scripps Clinic and Research Foundation, La Jolla (USA) Franrois Boller, Inserm U 324, Paris (France) Carl Cotman, University of California, Irvine (USA) Peter Davies, Albert Einstein College of Medicine, New York (USA) Andre Delacourte, Inserm U 422, Lille (France) Steven Ferris, New York University Medical Center, New York (USA) Jean-Franrois Foncin, H6pital Pitie Salpetriere, Paris (France) Franroise Forette, H6pital Broca, Paris (France) Fred Gage, Salk Institute, La Jolla (USA) Dmitry Goldgaber, State University of New York Stone Brook (USA) John Hardy, National Institute of Health, Bethesda (USA) Jean-Jacques Hauw, H6pital Pitie Salpetriere, Paris (France) Claude Kordon, Inserm U 159, Paris (France) Kenneth S. Kosik, Harvard Medical School, Center for Neurological

Diseases and Brigham and Women's Hospital, Boston (USA) Jacques Mallet, H6pital Pitie Salpetriere, Paris (France) Colin L. Masters, University of Melbourne, Parkville (Australia) Stanley 1. Rapoport, National Institute on Aging, Bethesda (USA) Andre Rascol, H6pital Purpan, Toulouse (France) Barry Reisberg, New York University Medical Center, New York (USA) Allen Roses, Duke University Medical Center, Durham (USA) Dennis J. Selkoe, Harvard Medical School, Center of Neurological

Diseases and Brigham and Women's Hospital, Boston (USA) Michael L. Shelanski, Columbia University, New York (USA) Pierre-Marie Sinet, H6pital Necker, Paris (France) Peter St. George-Hyslop, University of Toronto, Toronto (Canada) Robert Terry, University of California, La Jolla (USA) Edouard Zarifian, Centre Hospitalier Universitaire, Caen (France)

B.T. Hyman J.-F. Demonet Y. Christen (Eds.)

The Living Brain and Alzheimer's Disease

With 49 Figures and 8 Tables

~ Springer

Hyman. Bradley T., M.D, Ph.D. Neurology Service, Warren 408 Massachusetts General Hospital/Harvard Medical School Fruit Street Boston, MA 02114 USA E-mail: b-hyman@helix.mgh.harvard.edu

Demonet, Jean-Franfois, M.D. Service Neurologie - Inserm U.455 CHU Hopital Purpan Place du Dr. Baylac 31059 Toulouse Cedex 3 France E-mail: demonet@purpan.inserm.fr

ISSN 0945-6066 ISBN -13: 978-3-642-63927-2

Library of Congress-Cataloging-in-Publication-Data

Christen, Yves, Ph.D. Fondation IPSEN Pour la Recherche Therapeutique 24, rue Erlanger 75781 Paris Cedex 16 France e-mail: yves.christen@beaufour-ipsen.com

The living brain and Alzheimer's disease 1 B.T. Hyman, J.-F. Demont, Y. Christen (eds.). p. ; cm. (Research and perspectives in Alzheimer's disease) Proceedings of an intenational meeting, organized by Fondation Ipsen, which took place in March 17,2003. Includes bibliographical references and index.

ISBN -13:978-3-642-63927 -2 e-ISBN-13 :978-3-642-59300-0 DOl: 10.1007/978-3-642-59300-0

1. Alzheimer's disease - Diagnosis - Congresses. 2. Alzheimer's disease - Imaging - Congresses. 3. Brain - Diseseases - Congresses. 4. Alzheimer's disease - Animal models - Congresses. 5. Brain - Animal mod­els - Congresses. 6. Brain - Pathophysiology - Congresses. 7. Nervous system - Diseases - Diagnosis - Congresses. I. Hyman, B.T. II. Demont, J.-F. (Jean-Francois) III. Christen, Yves. IV. Series. [DNLM: 1. Alzheimer Disease - diagnosis. 2. Alzheimer Disease - physiopathology. 3. Brain - physiopa­thology. 4. Diagnosis Techniques, Neurological. WT 155 L 785 2004]

This work is subject to copyright. All rights are reserved, 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 way, and storage in data banks. Duplication of this publication or parts thereofis permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law.

Springer-Verlag is a part of Springer Science+ Business Media

springeronline.com

©Springer-Verlag Berlin Heidelberg 2004 Softcover reprint of the hardcover 1st edition 2004

The use of general descriptive names, registered names, trademarks, 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.

Product liability: The publishers cannot guarantee the accuracy of any information about dosage and appli­cation contained in this book. In every individual case the user must check such information by consulting the relevant literature.

Production: PRO EDIT GmbH, 69126 Heidelberg, Germany Cover design: design & production, 69121 Heidelberg, Germany Printed on acid-free paper 27/3130Re - 5 4 3 2 1 0

Preface

Throughout the history of studies of Alzheimer's disease, there has been a dicho­tomy between the observations made by careful clinicians evaluating patients' symptoms, cognitive function, and progression, weighing diagnostic and research issues, and the neuropathologist on the other hand, who has the final say with re­gard to diagnosis, but has very little to say about what has happened to the brain prior to autopsy. From large cross-sectional studies of autopsy material, it seems as if a time course of disease, at least on average, can be mapped out: a pattern of hierarchical vulnerability for neuronal loss and neurofibrillary tangles beginning in medial temporal lobe structures like the entorhinal cortex and hippocampus, proceeding through association areas. Plaques follow their own temporal course, with widespread cortical deposits occurring even early in a disease process. The whole process may well take twenty years, the first half of which may be without overt symptoms.

How can we link the critical observations performed at autopsy with the events that occur over the previous twenty years of the illness? This is the problem posed to a group of our colleagues who are using state-of-the-art neural imaging me­thods in patients and in animal models to illuminate the natural history of the disease - in the living brain.

The Fondation Ipsen thus organized an international meeting on this topic in March 17,2003, and the proceedings are contained herein. The editors wish to thank Mrs. Jacqueline Mervaillie for the organization of the meeting and Mary­Lynn Gage for the editing of the book.

May 2004 Bradley T. Hyman Jean-Franr;ois Demonet

Yves Christen

Contents

Neuropathology of Alzheimer's disease, as Seen in Fixed Tissues Charles Duyckaerts, Dominique Langui, Nadege Girardot, Jean-Jacques Hauw, Benoit Delatour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1

Cerebrospinal Fluid Biomarkers for the Diagnosis of Alzheimer's Disease Andreas Papassotiropoulos, Alessia Maddalena, Danielle Gretener, Roger M. Nitsch, Christoph Hock .. ...................................... 17

The Living Brain and Alzheimer's Disease Bradley T. Hyman . .................................................... 25

In Vivo Imaging of Alzheimer Pathology in Transgenic Mice Using Multiphoton Microscopy Brian J. Bacskai, William E. Klunk, Gregory A. Hickey, Jesse Skoch, Stephen T. Kajdasz, Megan E. McLellan, Matthew P. Frosch, Manik Debnath, Daniel Holt, Yanming Wang, Guo-feng Huang, Chester A. Mathis, and Bradley T. Hyman . ............................... 33

In Vivo Magnetic Resonance of Amyloid Plaques in Alzheimer's Disease Model Mice Einar M. Sigurdsson, YoussefZaim Wadghiri, Marcin Sadowski, James 1. Elliott, Yongsheng Li, Henrieta Scholtzova, Cheuk Ying Tang, Gilbert Aguilnaldo, Karen Duff, Daniel H. Turnbull, Thomas Wisniewski . .................................................. 47

Measuring Progression in Alzheimer's Disease Using Sserial MRI: 4DMRI NC Fox, JM Schott, RI Scahill . .......................................... 61

Validating MRI Measures of Disease Stage and Progression in Alzheimer's Disease Clifford R. Jack, Jr., M.D ............................................... 75

VIII Contents

Dynamic Mapping of Alzheimer's Disease Paul M. Thompson, Kiralee M. Hayashi, Greig de Zubicaray, Andrew L. Janke, Elizabeth R. Sowell, Stephen E. Rose, James Semple, David Herman, Michael S. Hong, Stephanie S. Dittmer, David M. Doddrell, Arthur W. Toga ................................... 87

Development of Benzothiazole Amyloid-Imaging Agents William E. Klunk, Yanming Wang and Chester A. Mathis ..... ............. 113

First PET Study with a Benzothiazol Amyloidimaging Agent (PIB) in Alzheimer's Disease Patients and Hhealthy Volunteers Henry Engler, Agneta Nordberg, William Klunk, Gunnar Blomqvist, Daniel Holt, Yanming Wang, Mats Bergstrom, Guo-feng Huang, Sergio Estrada, Manik Debnath, Julien Barletta, Johan Sandell, Anders Wall,Gunnar Antoni, Chester Mathis, Bengt Langstrom . ............ 123

Mild Cognitive Impairment (MCI): Predicting Conversion to Clinically Probable Alzheimer's Disease with Fluoro-Deoxy-Glucose PET J-C Baron, G. Chitelat, B. Desgranges, F. Eustache ........................ 139

Positron Emission Tomography and Magnetic Resonance Imaging in the Study of Cognitively Normal Persons at Differential Genetic Risk for Alzheimer's Dementia Eric M. Reiman, Richard J. Caselli, Kewei Chen, and Gene E. Alexander .. ............................................. 151

Subject Index ...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 179

Contributors

Aguilnaldo, Gilbert Departments of Radiology and Psychiatry, Mount Sinai School of Medicine, New York, NY, USA

Alexander, Gene E. Department of Psychology, Arizona Alzheimer's Disease Consortium, 1111 East Mc Dowell Road, Phoenix, AZ 85006, USA

Antoni, Gunnar Uppsala University, PET Centre/Uppsala Research Imaging Solutions AB, Uppsala, Sweden

Bacskai, Brian, J. Massachusetts General Hospital, Department of Neurology/Alzheimer's Disease Research Laboratory, 114 16th Street, No 2850, Charlestown, MA 02129, USA

Barlettta, Julien Department of Organic Chemistry, Uppsala University, Uppsala, Sweden

Baron, Jean-Claude University of Cambridge, Department of Neurology, Addenbrooke's Hospital, Box 83, Cambridge CB2 2QQ, UK

Bergstrom, Mats Uppsala University, PET Centre/Uppsala Research Imaging Solutions AB, Uppsala, Sweden

Blomqvist, Gunnar Uppsala University, PET Centre/Uppsala Research Imaging Solutions AB, Uppsala, Sweden

Caselli, Richard J. Department of Neurology, Mayo Clinic Scottsdale, and Arizona Alzheimer's Disease Consortium, 1111 East McDowell Road, Phoenix, AZ 85006, USA

X Contributors

Chen, Kewei Department of Mathematics, Arizona State University, Good Samaritan Positron Emission Tomography Center, 1111 East McDowell Road, Phoenix, AZ 85006, USA

Chetelat, Gael. INSERM E 218-University-Cyceron, 1400 Caen, France

De Zubicaray, Greig Centre for Magnetic Resonance, University of Queensland, Brisbane, QLD 4072, Australia

Debnath, Manik Departments of Radiology and Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA

Delatour, Benoit Laboratoire NAMC CNRS UMR 8620, 91405 Orsay, France

Desgranges, B. INSERM E 218-University-Cyceron, 1400 Caen, France

Dittmer, Stephanie S. Laboratory of Neuro Imaging, Brain Mapping Division, Department of Neurology, UCLA School of Medicine, 710 Westwood Plaza, Los Angeles, CA 90095, USA

Doddrell, David M. Centre for Magnetic Resonance, University of Queensland, Brisbane, QLD 4072, Australia

Duff, Karen Nathan S. Kline Institutes, New York University, Orangeburg, NY 10962, USA

Duyckaerts, Charles Laboratoire de Neuropathologie Raymond Escourolle, Association Claude Bernard, CHU Pitie-Salpetriere, 75013 Paris, and INSERM U 106, France

Elliott, James, I. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06510, USA

Engler, Henry Uppsala University, PET Centre/Uppsala Research Imaging Solutions AB, Uppsala , Sweden

Contributors XI

Estrada, Sergio Uppsala University, PET Centre/Uppsala Research Imaging Solutions AB, Uppsala, Sweden

Eustache, F. INSERM E 218-University-Cyceron, 1400 Caen, France

Fox, NickC National Hospital for Neurology and Neurosurgery, Queen Square, London WCIN 3BG, UK

Frosch, Matthew P. Massachusetts General Hospital, Department of Neurology/Alzheimer's Disease Research Laboratory, 114 16th Street, No 2850, Charlestown, MA 02129, USA

Girardot, Nadege Laboratoire de Neuropathologie Raymoand Escourolle, Association Claude Bernard, CHU Pitie-Salpetriere, 75013 Paris, and INSERM U 106, France

Gretener, Danielle Division of Psychiatry Research, University of Zurich, Lenggstr. 31, 8029 Zurich, Switzerland

Hauw, Jean-Jacques Laboratoire de Neuropathologie Raymond Escourolle, Association Claude Bernard, CHU Pitie-Salpetriere, 75013 Paris, and INSERM U 360, France

Hayashi, Kiralee M. Laboratory ofNeuro Imaging, Brain Mapping Division, Department of Neurology, UCLA School of Medicine, 710 Westwood Plaza, os Angeles, CA 90095, USA

Herman, David Laboratory of Neuro Imaging, Brain Mapping Division, Department of Neurology, UCLA School of Medicine, 710 Westwood Plaza, Los Angeles, CA 90095, USA

Hickey, Gregory, A. Massachusetts General Hospital, Department of Neurology/Alzheimer's Disease Research Laboratory, 114 16th Street, No 2850, Charlestown, MA 02129, USA

Hock, Christoph Division of Psychiatry Research, University of Zurich, Lenggstr. 31, 8029 Zurich, Switzerland

XII Contributors

Holt, Daniel Departments of Radiology and Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA

Hong, Michael S. Laboratory of Neuro Imaging, Brain Mapping Division, Department of Neurology, UCLA School of Medicine, 710 Westwood Plaza, Los Angeles, CA 90095, USA

Huang, Guo-Feng Departments of Radiology and Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA

Hyman, Bradley, T. Neurology Service, Warren 408, Massachusetts General Hospital/Harvard Medical School, Fruit Street, Boston, MA 02114, USA

Jack, Clifford R. Jr. Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

Janke, Andrew L. Centre for Magnetic Resonance, University of Queensland, Brisbane, QLD 4072, Australia

Kajdasz, Stephen T. Massachusetts General Hospital, Department of Neurology/Alzheimer's Disease Research Laboratory, 114 16th Street, No 2850, Charlestown, MA 02129, USA

Kewei, Chen Department of Mathematics, Arizona State University, Good Samaritan Positron Emission Tomography Center and Arizona Alzheimer's Disease Consortium, 1111 East McDowell Road, Phoenix, AZ 85006, USA

Klunk, William E. Departments of Radiology and Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA

Langstrom, Bengt Uppsala University, PET Centre/Uppsala Research Imaging Solutions AB, and Department of Organic Chemistry, Uppsala University, Uppsala, Sweden

Langui, Dominique Laboratoire de Neuropathologie Raymond Escourolle, Association Claude Bernard, CHU Pitie-Salpetriere, 75013 Paris, and INSERM U 106, France

Contributors XIII

Li, Yongsheng Department of Neurology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA

Maddalena, Alessia Division of Psychiatry Research, University of Zurich, Lenggstr. 31, 8029 Zurich, Switzerland

Mathis, Chester A. Departments of Radiology and Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA

McLellan, Megan E. Massachusetts General Hospital, Department of Neurology/ Alzheimer's Disease Research Laboratory, 114 16th Street, No 2850, Charlestown, MA 02129, USA

Nitsch, Roger. M. Division of Psychiatry Research, University of Zurich, Lenggstr. 31, 8029 Zurich, Switzerland

Nordberg, Agneta Geriatric Department, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden

Papassotiropoulos, Andreas Division of Psychiatry Research, University of Zurich, Lenggstr. 31, 8029 Zurich, Switzerland

Reiman, Eric M. Good Samaritan PET Center, Arizona Alzheimer's Disease Consortium, 1111 East McDowell Road, Phoenix, AZ 85006, USA

Rose, Stephen E. Centre for Magnetic Resonance, University of Queensland, Brisbane, QLD 4072, Australia

Sadowski, Marcin Department of Neurology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA

Sandell, Johan Uppsala University, PET Centre/Uppsala Research Imaging Solutions AB, Uppsala, Sweden

Scahill, Rachael1. National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK

XIV Contributors

Scholtzova, Henrieta Department of Neurology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA

Schott, Jonathan M. National Hospital for Neurology and Neurosurgery, Queen Square, London WClN 3BG, UK

Semple, James Centre for Magnetic Resonance, University of Queensland, Brisbane, QLD 4072, Australia

Sigurdsson, Einar, M. Departments od Psychiatry and Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA

Skoch, Jesse Massachusetts General Hospital, Department of Neurology/Alzheimer's Disease Research Laboratory, 114 16th Street, No 2850, Charlestown, MA 02129, USA

Sowell, Elizabeth R. Laboratory of Neuro Imaging, Brain Mapping Division, Department of Neurology, UCLA School of Medicine, 710 Westwood Plaza, Los Angeles, CA 90095, USA

Tang, Cheuk Ying Departments of Radiology and Psychiatry, Mount Sinai School of Medicine, New York, NY, USA

Thompson, Paul, M. Reed Neurological Research Center, Laboratory of Neuro Imaging, Department of Neurology, UCLA School of Medicine, 710 Westwood Plaza, Los Angeles, CA 90095-1769, USA

Toga, Arthur W. Laboratory of Neuro Imaging, Brain Mapping Division, Department of Neurology, UCLA School of Medicine, 710 Westwood Plaza, Los Angeles, CA 90095, USA

Turnbull, Daniel H. Departments of Pathology, Radiology, and Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 550 First Avenue, New York, NY, 10016, USA

Contributors XV

Wadghiri, Yousse!Zaim Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA

Wall, Anders Uppsala University, PET Centre/Uppsala Research Imaging Solutions AB, Uppsala, Sweden

Wang, Yanming Departments of Radiology and Psychiatry, University of Pittsburgh, Pittsburgh, PA 152l3, USA

Wisniewski, Thomas Departments of Psychiatry, Neurology and Pathology, New York University School of Medicine, Milhauser Laboratory HN419, 550 First Avenue, New York, NY 10016, USA