052181166X cambridge university press neurodegenerative diseases neurobiology pathogenesis and therapeutics jul 2005

This page intentionally left blank


Neurodegenerative Diseases
Neurobiology, Pathogenesis and Therapeutics

Neurodegenerative diseases are among the major contributors to disability and disease, with Alzheimer’s and Parkinson’s diseases the most prevalent among many in this category. This major reference reviews the rapidly advancing
knowledge of pathogenesis and treatment of neurodegenerative diseases in the context of a comprehensive survey of
each disease and its clinical features. The editors and contributors are among the leading experts in the field internationally.
Covering basic science, diagnostic tools and therapeutic
approaches, the book focuses on all aspects of neurodegenerative disease, including the normal aging process. The
dementias, prion diseases, Parkinson’s disease and atypical
parkinsonisms, neurodegenerative ataxias, motor neuron
diseases, degenerative diseases with chorea, iron and copper disorders, and mitochondrial diseases, are all methodically presented and discussed, with extensive illustrations.
In each case the underlying genetics, neuropathological
and clinical issues are fully reviewed, making this the most
complete as well as the most authoritative reference available to clinicians and neuroscientists.
M. Flint Beal is Anne Parrish Titzell Professor and Chairman
of the Department of Neurology and Neuroscience at the
Weill Medical College of Cornell University, and Director of
Neurology at the New York Presbyterian Cornell Campus.
An internationally recognized authority on neurodegenerative disorders, his research has focused on the mechanism
of neuronal degeneration in Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and amyotrophic lateral
sclerosis.
Anthony E. Lang is Professor in the Department of Medicine,
Division of Neurology, University of Toronto. A founding
member of the Parkinson Study Group and the Movement
Disorders Society, his research has included clinical trials
of poorly recognized neurological disorders, clinical trials
of new therapeutic modalities, and studies in molecular

biology, neurophysiology, neuropsychology and imaging.
Albert C. Ludolph is Professor of Neurology, Chair of Neurology, and Chairman of the Neuroscience Center of the University of Ulm, Germany. A neurologist and psychiatrist, his
major interest is in toxicological models of vulnerability and
genetic models for the pathogenesis of neurodegenerative
diseases.



Neurodegenerative Diseases
Neurobiology, Pathogenesis and Therapeutics

M. Flint Beal
Weill Medical College of Cornell University

Anthony E. Lang
University of Toronto

Albert C. Ludolph
University of Ulm


  
Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo
Cambridge University Press
The Edinburgh Building, Cambridge  , UK
Published in the United States of America by Cambridge University Press, New York
www.cambridge.org
Information on this title: www.cambridge.org/9780521811668
© Cambridge University Press 2005
This book is in copyright. Subject to statutory exception and to the provision of

relevant collective licensing agreements, no reproduction of any part may take place
without the written permission of Cambridge University Press.
First published in print format 2005
-
-

---- eBook (EBL)
--- eBook (EBL)

-
-

---- hardback
--- hardback

Cambridge University Press has no responsibility for the persistence or accuracy of
s for external or third-party internet websites referred to in this book, and does not
guarantee that any content on such websites is, or will remain, accurate or appropriate.
Every effort has been made in preparing this book to provide accurate and up-to-date
information that is in accord with accepted standards and practice at the time of
publication. Nevertheless, the authors, editors and publisher can make no warranties that
the information contained herein is totally free from error, not least because clinical
standards are constantly changing through research and regulation. The authors, editors
and publisher therefore disclaim all liability for direct or consequential damages
resulting from the use of material contained in this book. Readers are strongly advised
to pay careful attention to information provided by the manufacturer of any drugs or
equipment that they plan to use.


Contents

List of contributors
Preface

page ix
xxi

Part I Basic aspects of neurodegeneration
1

2

3

4

Endogenous free radicals and antioxidants in
the brain
Stefan L. Marklund

3

Biological oxidants and therapeutic
antioxidants
John P. Crow

18

Mitochondria, metabolic inhibitors and
neurodegeneration

James G. Greene and J. Timothy Greenamyre

33

Excitoxicity and excitatory amino acid
antagonists in chronic neurodegenerative
diseases
Chrysanthy Ikonomidou and Lechoslaw Turski

5

Glutamate transporters
Davide Trotti and Stuart L. Gibb

6

Calcium binding proteins in selective
vulnerability of motor neurons
´ o´ Siklos
´ and Stanley H. Appel
Laszl

44

57

65

7

Apoptosis in neurodegenerative diseases
Jorg B. Schulz

80

8

Neurotrophic factors
Michael Sendtner

94

v


vi

Contents

9

10

Protein misfolding and cellular defense
mechanisms in neurodegenerative
diseases
Michael Y. Sherman and Alfred L. Goldberg
Neurodegenerative disease and the repair of
oxidatively damaged DNA
Marcus S. Cooke

11

Compounds acting on ion channels
Holger Lerche and Frank Lehmann-Horn

12

The role of nitric oxide and PARP in neuronal
cell death
Mika Shimoji, Valina L. Dawson and
Ted M. Dawson

13

14

15

Copper and zinc in Alzheimer’s disease and
amyotrophic lateral sclerosis
Avi L. Friedlich and Ashley I. Bush
The role of inflammation in Alzheimer’s
disease neuropathology and clinical
dementia. From epidemiology to treatment
Guilio Maria Pasinetti
Selected genetically engineered models
relevant to human neurodegenerative disease
Donald Price, David R. Borchelt, Michael K. Lee and
Philip C. Wong

16

Toxic animal models
Serge Przedborski and Kim Tieu

17

A genetic outline of the pathways to cell death
in Alzheimer’s disease, Parkinson’s disease,
frontal dementias and related disorders
John Hardy

18

Neurophysiology of Parkinson’s disease,
levodopa-induced dyskinesias, dystonia,
Huntington’s disease and myoclonus
` Rocco Agostino and
Antonio Curra,
Alfredo Berardelli

21
108

131

141

22

Gene therapy
Chamsy Sarkis and Jacques Mallet

23

Stem cells and cell-based therapy in
neurodegenerative disease
Eva Chmielnicki and Steven A. Goldman

24

157

20

Structural and functional magnetic
resonance imaging in neurodegenerative
diseases
Michael Samuel and Alan Colchester
PET/SPECT
ˇ Vijay Dhawan, Andrew Feigin and
Maja Trost,
David Eidelberg

Necessary methodological and stem cell
advances for restoration of the dopaminergic
system in Parkinson’s disease patients
Ole Isacson, Kwang-Soo Kim, Ivar Mendez, Craig
van Horne, Lars M. Bjorklund and

Rosario Sanchez-Pernaute

329

347

363

Part IV Normal aging
25

Clinical aspects of normal aging
Marilyn S. Albert

26

Neuropathology of normal aging in cerebral
cortex
John H. Morrison, Patrick Hof and
Peter R. Rapp

176

196

383

396

Part V Alzheimer’s disease

222

227

27

Mild cognitive impairment
Keith A. Josephs, David F. Tang-Wai and
Ronald C. Petersen

409

28

Alzheimer’s disease: overview
David F. Tang-Wai, Keith A. Josephs and
Ronald C. Petersen

416

29

The neuropathology of Alzheimer’s disease in
the year 2005
Colin L. Masters and Konrad Beyreuther

Part II Neuroimaging in neurodegeneration
19

301

Part III Therapeutic approaches in
neurodegeneration

146

166

Magnetic resonance spectroscopy of
neurodegenerative illness
Bruce G. Jenkins, Ji-Kyung Choi and M. Flint Beal

433

30

Genetics of Alzheimer’s disease
Lars Bertram and Rudolph E. Tanzi

441

31

The role of ß-amyloid in Alzheimer’s disease
Roger M. Nitsch

452

32

Treatment of Alzheimer’s disease
Mary Sano

459

253

290


Contents

Part VI Other dementias

Part VIII Cerebellar degenerations

33

Dementia with Lewy bodies
Norman Relkin

473

46

Approach to the patient with ataxia
Thomas Klockgether

699

34

Frontotemporal lobar degeneration
Adam L. Boxer, John Q. Trojanowski, Virginia M.-Y.
Lee and Bruce L. Miller

481

47

Autosomal dominant cerebellar ataxia
Henry L. Paulson

709

48

35

Frontotemporal dementia with parkinsonism
linked to Chromosome 17
Mark S. Forman, Virginia M.-Y. Lee and
John Q. Trojanowski

Friedreich’s ataxia and other autosomal
recessive ataxias
´ ene
` Puccio and Michel Koenig
Hel

36

Prion diseases

494
49
512

I The clinical approach to human prion
disease
II The pathogenesis and mechanisms of
prion diseases

Ataxia telangiectasia
Richard A. Gatti, Tom O. Crawford, Alan
S. Mandir, Susan Perlman and
Howard T. J. Mount

719

738

Part IX Motor neuron diseases

Adriano Aguzzi, H. Tumani and Albert C. Ludolph
50

Part VII Parkinson’s and related
movement disorders
37

Approach to the patient presenting with
parkinsonism
Katie Kompoliti and Christopher G. Goetz

51

551
52

38

Parkinson’s disease
Christopher G. Goetz and Katie Kompoliti

561

39

Neuropathology of Parkinson’s disease
Dennis W. Dickson

575

40

Genetics of parkinsonism
Thomas Gasser

586

41

Pathophysiology: biochemistry of
Parkinson’s disease
Daniela Berg, Olaf Riess and
Peter Riederer

42

43

Current and potential treatments of
Parkinson’s disease
Clifford W. Shults
Multiple system atrophy
Felix Geser, Carlo Colosimo and
Gregor. K. Wenning

623

44

Progressive supranuclear palsy
Lawrence I. Golbe

663

45

Corticobasal degeneration
Kailish P. Bhatia and Anthony E. Lang

682

751

The genetics of amyotrophic lateral
sclerosis
Ammar Al-Chalabi and Robert Brown

758

Current and potential therapeutics
in motor neuron diseases
Clare Wood-Allum and Pamela J. Shaw

772

53

The hereditary spastic paraplegias
John K. Fink

54

Spinal and bulbar muscular atrophy
(Kennedy’s disease): a sex-limited,
polyglutamine repeat expansion
disorder

Patrick S. Thomas and Albert R. La Spada

598

612

An approach to the patient with motor
neuron dysfunction
Matthew J. Parton and P. Nigel Leigh

55

Spinal muscular atrophies
¨
Klaus Zerres and Sabine Rudnik-Schoneborn

56

Western Pacific ALS/parkinsonism–dementia
complex
Daniel P. Perl and Patrick R. Hof

794

803

817

827

Part X Other neurodegenerative
diseases
57

Huntington’s disease
Christoph M. Kosinski and
Bernhard Landwehrmeyer

847

vii


viii

Contents

58

Dentatorubral-pallidoluysian atrophy
(DRPLA): model for Huntington’s disease and
other polyglutamine diseases
Christopher A. Ross, Lisa M. Ellerby,
Jonathan D. Wood and Frederick C. Nucifara Jr.

61
861
62

59

Neuroacanthocytosis
Alexander Storch

871

60

Brain iron disorders
Satoshi Kono, Hiroaki Miyajima and
Jonathan D. Gitlin

880

Neurological aspects of Wilson’s
disease
Peter A. LeWitt and George J. Brewer

890

Disorders of the mitochondrial
respiratory chain
Anthony H. V. Schapira

909

Index

927

Contributors

Editors
M. Flint Beal
The New York Hospital
525 E. 68th Street
New York
NY 10021
USA
Anthony E. Lang
Toronto Western Hospital
7 McLaughlin
Room 304, 11th floor
399 Bathhurst Street
Toronto
ON M5T 2S8
Canada
Albert C. Ludolph
Neurologische
Universitatsklinik Ulm
Steinhovelstrasse 9
89075 Ulm
Germany

List of contributors
Rocco Agostino
Department of Neurological Sciences and INM Neuromed
IRCCS
University of Rome “La Sapienza”

Viale de’ll Universita 30
00185 Rome
Italy

ix


x

List of contributors

Adriano Aguzzi
Institute of Neuropathology
Universitatsspital Zurich
Schmelzbergstrasse 12
Zurich CH-8091
Switzerland

Marilyn S. Albert
Department of Neurology (Meyer 6-113)
Johns Hopkins University School of
Medicine
600 N Wolfe Street
Baltimore
MD 21287
USA

Ammar Al-Chalabi
Department of Neurology
Institute of Psychiatry

London SE5 8AF
UK

Stanley H. Appel
Department of Neurology
Baylor College of Medicine
6501 Fannin, Suite NB302
Houston
TX

M. Flint Beal
Department of Neurology
Weill Medical College
Cornell University
New York
NY
USA

Alfredo Berardelli
Department of Neurological Sciences
University of Rome “La Sapienza”
Viale de’ll Universit`a 30
00185 Rome
Italy
Daniela Berg
Hertie Institute for Clinical Brain Research,
Hoppe–Seyler Strasse 3
¨
D-72076 Tubingen,
Germany

Lars Bertram
Genetics and Aging Research Unit
Department of Neurology
Massachusetts General Hospital
114 16th Street
Charlestown
MA 02129
USA
Konrad Beyreuther
Centre for Molecular Biology
The University of Heidelberg
Heidelberg
Germany
Kailish P. Bhatia
Sobell Department of Movement
Neuroscience
Institute of Neurology
Queen Square
London WC1N 3BG
UK
Lars M. Bjorklund
Udall Parkinson’s Disease Research
Center of Excellence
Neuroregeneration Laboratories
McLean Hospital/Harvard Medical
School
115 Mill Street
Belmont
MA 02478

USA
David R. Borchelt
Department of Pathology and Division
of Neuropathology
The Johns Hopkins University School
of Medicine
558 Ross Research Building
72 Rutland Avenue
Baltimore
MD 21205-2196
USA
Adam L. Boxer
Memory and Aging Center
Department of Neurology
University of California
350 Parnassus Ave
Suite 800, Box 1207
San Francisco
CA 94143-1207
USA


List of contributors

George J. Brewer
Department of Human Genetics and
Department of Internal Medicine
University of Michigan School of
Medicine
Ann Arbor

MI
USA
Robert H. Brown
Cecil B Day Neuromuscular Laboratory
Massachusetts General Hospital East
Bldg 114 The Navy Yard, 16th St, Rm
2125
Charlestown
MA 02129
USA
Ashley I. Bush
Laboratory for Oxidation Biology
Genetics and Aging Research Unit
Building 114, 16th Street
Charlestown
MA 02129-4404
USA
and
Mental Health Research Institute of
Victoria, and
Department of Pathology
University of Melbourne
Parkville
Victoria
Australia
Eva Chmielnicki
Department of Neurology and
Neuroscience
Cornell University Medical Center
1300 York Avenue, Room E607

New York
NY 10021
USA
Ji-Kyung Choi
Department of Radiology
Athinoula A Martinos Center for
Biomedical Imaging
Massachusetts General Hospital and
Harvard Medical School
Building 149, 13th Street Charlestown
MA 02129
USA

Alan Colchester
Kent Institute of Medicine and Health Sciences
University of Kent
Canterbury CT2 7PD
UK
Carlo Colosimo
Department of Neurology
University “La Sapienza”
I-00185 Rome
Italy
Marcus S. Cooke
Genome Instability Group
Departments of Cancer Studies and Genetics
University of Leicester
Leicester Royal Infirmary
University Hospitals of Leicester
NHS Trust

Leicester LE2 7LX
UK
Tom O. Crawford
Department of Neurology
Johns Hopkins University School of Medicine
600 N Wolfe Street
Baltimore
MD 21287-3923
USA
John P. Crow
Department of Pharmacology and Toxicology
University of Arkansas College of Medicine
Little Rock, AR
USA
Antonio Curr`a
Department of Neurological
Sciences and INM Neuromed
IRCCS
University of Rome “La Sapienza”
00185 Rome
Italy
Ted M. Dawson
Department of Neurology
Johns Hopkins University School of Medicine
600 N Wolfe Street, Pathol 2-210
Baltimore
MD 21205
USA

xi

xii

List of contributors

Valina L. Dawson
Department of Neurology
Johns Hopkins University School of
Medicine
600 N Wolfe Street, Pathol 2-210
Baltimore
MD 21205
USA
Vijay Dhawan
Institute for Medical Research
Long Shore – Long Island
Jewish Health System
350 Community Drive
Manhasset
NY 11030
USA
Dennis W. Dickson
Department of Pathology
Mayo Clinic Jacksonville
4500 San Pablo Road
Jacksonville
FL 32224
USA
David Eidelberg

Institute for Medical Research
North Shore – Long Island
Jewish Health System
350 Community Drive
Manhasset
NY 11030
USA
Lisa M. Ellerby
Buck Institute for Research
in Aging
8001 Redwood Blvd
Novato
CA 94945
USA
Andrew Feigin
Institute for Medical Research
Long Shore – Long Island
Jewish Health System
350 Community Drive
Manhasset
NY 11030
USA

John K. Fink
5214 CCGCB Box 0940
1500 E Medical Center Drive
Ann Arbor
MI 481099-0940
USA
Mark S. Forman

Center for Neurodegenerative Disease Research
Department of Pathology and Laboratory Medicine
University of Pennsylvania School of Medicine
HUP, Maloney Bldg, Room A009
Philadelphia
PA 19104-4283
USA
Avi L. Friedlich
Laboratory for Oxidation Biology
Genetics and Aging Research Unit
Building 114, 16th Street
Charlestown
MA 02190-4404
USA
Thomas Gasser
Department of Neurodegenerative Disorders
Hertie-Institute for Clinical Brain Research
Center of Neurology
¨
University of Tubingen
Germany
Richard A. Gatti
Department of Pathology and Laboratory Medicine
David Geffen School of Medicine at
UCLA
Los Angeles
CA 90095-1732
USA
Felix Geser
Department of Neurology

University Hospital
A-6020 Innsbruck
Austria
Stuart L. Gibb
Department of Neurology
Massachusetts General Hospital
Harvard Medical School
16th Street, Bldg 114
Charlestown
MA 02129
USA


List of contributors

Jonathan D. Gitlin
Washington University School of Medicine
McDonnell Pediatric Research
Building
660 South Euclid Avenue
St Louis
MO 63110
USA
Christopher G. Goetz
Section of Movement Disorders
Department of Neurological Sciences
Rush University Medical Center
1725 W Harrison Street, Suite 755
Chicago
IL 60612

USA
Lawrence I. Golbe
Department of Neurology
97 Paterson Street
New Brunswick
NJ 08901
USA
Alfred L. Goldberg
Department of Cell Biology
Harvard Medical School
240 Longwood Ave
Boston
MA 02115
USA
Steven A. Goldman
Division of Cell and Gene Therapy
University of Rochester Medical
Center
601 Elmwood Avenue
MRBX, Box 645
Rochester
NY 14642
USA
J. Timothy Greenamyre
Pittsburgh Institute for Neurodegenerative Diseases
University of Pittsburgh
S-506 Biomedical Science Tower
203 Lothrop Street
Pittsburgh
PA 15213

USA

James G. Greene
Center for Neurodegenerative
Disease and Department of Neurology
Emory University
Whitehead Building
Room 505M
615 Michael Street
Atlanta
GA 30322
USA
John Hardy
Laboratory of Neurogenetics
National Institute on Aging
National Institutes of Health
Building 10, Room 6C103,
MSC1589
Bethesda
MD 20892
USA
Patrick Hof
Department of Neuroscience
Mount Sinai School of Medicine
One Gustave Levy Place
New York
NY 10029
USA
Hrissanthi Ikonomidou
Department of Pediatric Neurology

Carl Gustav Carus University
Fetscherstrasse 74
Dresden D-01307
Germany
Ole Isacson
Neuroregeneration Laboratories
McLean Hospital/Harvard Medical School
114 Mill Street
Belmont
MA 02478
USA
Bruce G. Jenkins
Department of Radiology
Athinoula A Martinos Center for Biomedical Imaging
Massachusetts General Hospital and
Harvard Medical School
Building 149, 13th Street Charlestown
MA 02129
USA

xiii


xiv

List of contributors

Julene Johnson
Keith A. Josephs
Mayo Alzheimer’s Disease Research

Center
Department of Neurology
Mayo Clinic
200 First Street
SW Rochester
MN 55905-0001
USA

Kwang-Soo Kim
Udall Parkinson’s Disease Research
Center of Excellence
Molecular Neurobiology Laboratory
McLean Hospital/Harvard Medical
School
115 Mill Street
Belmont
MA 02478
USA

Thomas Klockgether
Department of Neurology
University of Bonn
Sigmund-Freud-Str. 25
D-53105 Bonn
Germany

Michel Koenig
Institut de G´en´etique et de Biologie
Mol´eculaire et Cellulaire
1 rue Laurent Fries

BP 10142
674 Illkirch Cedex
France

Katie Kompoliti
Section of Movement Disorders
Department of Neurological
Sciences
Rush University Medical Center
1725 W Harrison Street, Suite 755
Chicago
IL 60612
USA

Satoshi Kono
Edward Mallinckrodt Department of
Pediatrics
Washington University School of
Medicine
St Louis
MO
USA and
First Department of Medicine
Hamamatsu University School of
Medicine
Hamamatsu
Japan
Christoph M. Kosinski
Department of Neurology
University Hospital Aachen

Pauwelsstrasse 30
Aachen 52074
Germany
Bernhard Landwehrmeyer
Department of Neurology
University of Ulm
Steinhoevelstrasse 9
Ulm 89079
Germany
Albert R. La Spada
Department of Laboratory Medicine
Medicine and Neurology
Centre for Neurogenetics and Neurotherapeutics
University of Washington Medical
Center
Box 357 110, Room NW120
Seattle
WA 98195-7110
USA
Michael K. Lee
Department of Pathology and Division of
Neuropathology
The Johns Hopkins University School of
Medicine
558 Ross Research Building
72 Rutland Avenue
Baltimore
MD 21205-2196
USA

List of contributors

Virginia M.-Y. Lee
Center for Neurodegenerative Disease
Research
Department of Pathology and
Laboratory Medicine
University of Pennsylvania School of
Medicine
HUP, Maloney Bldg, Room A009
Philadelphia
PA 19104-4283
USA
Frank Lehmann-Horn
¨ Angewandte Physiologie
Abteilung fur
Albert-Einstein-Allee 11
Universit¨at Ulm
D-89069
Germany
Nigel Leigh
Department of Clinical Neurology
Guy’s, King’s and St Thomas’
School of Medicine and Institute of
Psychiatry
DeCrespigny Park
London SE5 8AF
UK
Holger Lerche

Neurologischen Klinik und
¨
Abteilung fur
Angewandte Physiologie
Universit¨at Ulm
Helmholtzstrasse 8/1
Ulm
D-89081
Germany
Peter A. LeWitt
Clinical Neuroscience Center
26400 West Twelve Mile Road
Suite 110
Southfield
MI 48034
USA
Albert C. Ludolph
Department of Neurology
University of Ulm
Germany

Jacques Mallet
Hˆopital Piti´e-Salp´etri`ere (Batiment
CERVI)
83 Boulevard de l’Hˆopital
75013 Paris
France
Alan S. Mandir
Department of Neurology
Johns Hopkins University School of

Medicine
600 N Wolfe Street, Path 219
Baltimore
MD 21287
USA
Stefan L. Marklund
Department of Medical Biosciences
Clinical Chemistry
Umea University Hospital
Umea SE-90185
Sweden
Colin L. Masters
Department of Pathology
The University of Melbourne
Parkville 3010
Australia
Ivar Mendez
Division of Neurosurgery
Dalhousie University
Halifax
NS
Canada
Hiroaki Miyajima
Edward Mallinckrodt Department of
Pediatrics
Washington University School of
Medicine
St Louis
MO
USA and

First Department of Medicine
Hamamatsu University School of
Medicine
Hamamatsu
Japan

xv


xvi

List of contributors

Bruce L. Miller
Memory and Aging Center
Department of Neurology
University of California
350 Parnassus Ave
Suite 800, Box 1207
San Francisco
CA 94143-1207
USA

Guilio Maria Pasinetti
Neuroinflammation Research
Laboratories
Department of Psychiatry
Mount Sinai School of Medicine
One Gustave Levy Place
New York

NY 10029
USA

John H. Morrison
Department of Neuroscience
Mount Sinai School of Medicine
One Gustave Levy Place
New York
NY 10029
USA

Henry L. Paulson
Department of Neurology
University of Iowa Hospitals and Clinics
Iowa City
IA 52242
USA

Howard T. J. Mount
CRND
Department of Medicine
Division of Neurology
University of Toronto
Toronto
ON
Canada
Roger M. Nitsch
Division of Psychiatry Research
University of Zurich
August Forel Strasse 1

Zurich 8008
Switzerland
Frederick C. Nucifora
Division of Neurobiology
Department of Psychiatry
Johns Hopkins University School of
Medicine
Ross Research Building, Room 618
720 Rutland Avenue
Baltimore
MD 21205
USA
Matthew J. Parton
Department of Neurology
The Institute of Psychiatry and Guy’s,
King’s & St Thomas’ School of Medicine
De Crespigny Park
London SE5 8AF
UK

Daniel Perl
Department of Neuropathology
Mount Sinai Medical Center
Box 1134
One Gustave Levy Place
New York
NY 10029-6500
USA
Susan Perlman
Department of Neurology

David Geffen School of Medicine at
UCLA
Los Angeles
CA
USA
Ronald C. Petersen
Mayo Alzheimer’s Disease Research Center
Department of Neurology
Mayo Clinic
200 First Street
SW Rochester
MN 55905-0001
USA
Donald Price
Departments of Pathology, Neurology
and Neurosciences and Division of Neuropathology
The Johns Hopkins University School of Medicine
558 Ross Research Building
72 Rutland Avenue
Baltimore
MD 21205-2196
USA


List of contributors

Serge Przedborski
Departments of Neurology and Pathology, and
Center for Neurobiology and Behavior
BB-307 Columbia University

650 West 168th Street
New York
NY 10032
USA
H´el`ene Puccio
Institut de G´en´etique et de Biologie
Mol´eculaire et Cellulaire
1 rue Laurent Fries
BP 10142
674 Illkirch Cedex
France
Peter R. Rapp
Department of Neuroscience
Mount Sinai School of Medicine
One Gustave Levy Place
New York
NY 10029
USA
Normal Relkin
Weill Cornell Medical College
New York
NY
USA
Peter Riederer
Clinic and Poliklinik of Psychiatry and Psychotherapy
Department of Clinical Neurochemistry
University of Wurzburg
Fuchsleinstrasse 15
97080 Wurzburg Germany
Olaf Riess

Institute for Medical Genetics
Calwerstrasse 7
¨
D-72076 Tubingen
Germany
Christopher A. Ross
Division of Neurobiology
Department of Psychiatry
Johns Hopkins University School of Medicine
Ross Research Building, Room 618
720 Rutland Avenue
Baltimore
MD 21205
USA

Sabine Rudnik-Sch¨
oneborn
Institute for Human Genetics
University of Technology
Pauwelsstr. 30
52074 Aachen
Germany
Michael Samuel
Department of Neurology
King’s College Hospital
Denmark Hill
Camberwell
London SE5 9RS
UK
Rosario Sanchez-Pernaute

Udall Parkinson’s Disease Research
Center of Excellence
Neuroregeneration Laboratories
McLean Hospital/Harvard Medical
School
115 Mill Street
Belmont
MA 02478
USA
Mary Sano
Alzheimer’s Disease Research Center
Department of Psychiatry
Mount Sinai School of Medicine
New York
USA
and
Bronx VA Medical Center
139 W Kingsbridge Road
Code 151/Rm 1F01
Bronx
New York
NY 10468
USA
Chamsy Sarkis
Laboratoire de G´en´etique
Moleculaire de la Neurotransmission et
des Processus Neurod´eg´eneratiffs
(LGN)
Centre National de la Recherche
Scientifique

UMR 7091
Paris
France

xvii


xviii

List of contributors

Anthony H. V. Schapira
Royal Free and University College
Medical School
University College London
Rowland Hill Street
London NW3 2PF
UK
and
Institute of Neurology
University College London
Queen Square
London WC1N 3BG
UK
Jorg B. Schulz
Department of Neurodegeneration and
Restorative Research
Center of Neurological Medicine
University of G¨ottingen
Waldweg 33

D-37073 G¨ottingen
Germany
Michael Sendtner
Institute for Clinical Neurobiology JosefSchneider-Str. 11
97080 Wurzburg
Germany
Pamela J. Shaw
Academic Neurology Unit
E Floor
Sheffield University Medical
School
Beech Hill Road
Sheffield S10 2RX
UK
Michael Y. Sherman
Department of Biochemistry
Bldg K323
Boston University Medical School
715 Albany Street
Boston
MA 02118
USA
Mika Shimoji
Department of Neurology
Johns Hopkins University School of Medicine
600 N Wolfe Street, Pathol 2-210

Baltimore
MD 21205
USA

Clifford W. Shults
Department of Neurosciences
University of California San Diego
Neurology Service
3350 La Jolla Village Drive
San Diego
CA 92101
USA
L´aszl´
o Sikl´
os
Department of Neurology
Baylor College of Medicine
Houston
TX
USA
Alexander Storch
Department of Neurology
Technical University of Dresden
Fetscherstrasse 74
01307 Dresden
Germany
David F. Tang-Wai
Division of Neurology
University Health Network
Toronto Western Hospital
Toronto
Ontario
Canada
Rudolph E. Tanzi

Genetics and Aging Research Unit
Department of Neurology
Massachusetts General Hospital
114 16th Street
Charlestown
MA 02129
USA
Patrick S. Thomas, Jr.
Department of Laboratory Medicine
and Center for Neurogenetics and Neurotherapeutics
University of Washington Medical Center
Seattle
WA
USA


List of contributors

Kim Tieu
Department of Environmental Medicine
and Center for Aging and Developmental Biology
University of Rochester
Rochester
NY 14642
USA
John Q. Trojanowski
Center for Neurodegenerative Disease
Research
Department of Pathology and
Laboratory Medicine

University of Pennsylvania School of
Medicine
3400 Spruce Street
Maloney Building, 3rd floor
Philadelphia
PA 19104
USA
Maja Troˇst
Institute for Medical Research
Long Shore – Long Island
Jewish Health System
350 Community Drive
Manhasset
NY 11030
USA
Davide Trotti
Department of Neurology
Massachusetts General Hospital
Harvard Medical School
16th Street, Bldg 114
Charlestown
MA 02129
USA

Craig van Horne
Udall Parkinson’s Disease Research
Center of Excellence
Neuroregeneration Laboratories
McLean Hospital/Harvard Medical School
115 Mill Street

Belmont
MA 02478
USA
Gregor K. Wenning
Department of Neurology
University Hospital
A-6020 Innsbruck
Austria
Philip C. Wong
Department of Pathology and Division of
Neuropathology
The Johns Hopkins University School
of Medicine
558 Ross Research Building
72 Rutland Avenue
Baltimore
MD 21205-2196
USA
Jonathan D. Wood
The University of Sheffield
Academic Neurology Unit
E Floor, Medical School
Beech Hill Road
Sheffield S10 2RX
UK

Hayrettin Tumani
Department of Neurology
University of Ulm
Germany

Clare Wood-Allum
Academic Neurology Unit
E Floor
Sheffield University Medical School
Beech Hill Road
Sheffield S10 2RX
UK

Lechoslaw Turski
Solvay Pharmaceuticals Research
Laboratories
C J van Houtenlaan 36
1831 CP Weesp
The Netherlands

Klaus Zerres
Institute for Human Genetics
University of Technology
Pauwelsstr. 30
52074 Aachen
Germany

xix



Preface

Neurodegenerative diseases are becoming increasingly

prevalent with the aging of the general population. The
twentieth century witnessed a significant demographic
change in the human population of the industrialized world
that is currently followed by a similar shift of life expectancy
to upper age ranges in Asia, Africa, and Middle and South
America. Quality of life of the aging population of the world
is, to a great extent, determined by the normal aging process of neurons in the central nervous system and especially
by the occurrence of diseases characterized by accelerated
neuronal loss: diseases which are traditionally designated
as being neurodegenerative. They are presently amongst
the major contributors to disability and disease in human
populations.
Alzheimer’s disease is the most prevalent of the neurodegenerative diseases followed by Parkinson’s disease. Amyotrophic lateral sclerosis and Huntington’s disease affect
smaller numbers of patients but have devastating consequences. A large number of other rarer neurodegenerative diseases have similar profound effects on the patients
and families who are afflicted by these illnesses. Research
into the pathogenesis and treatment for these disorders
is exploding exponentially. To a great extent this has been
fostered by major advances in genetics, since we now know
mutations that are associated with a large number of these
illnesses. This includes familial forms of Alzheimer’s disease, Parkinson’s disease, fronto-temporal dementia, ALS,
Huntington’s disease and a variety of ataxias. Most of the
sporadic cases of the common neurodegenerations such as
Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis appear to be polygenetic and are influenced
by poorly characterized environmental factors.
The discovery of causative genetic mutations has led
to the development of transgenic animal models of
these disorders, which has enhanced our understanding of disease pathogenesis. Transgenic models are also

xxi

xxii

Preface

useful for experimental therapeutics. Already, this is having a major impact on the development of novel therapeutic strategies for the treatment of these disorders.
The ultimate goal is to either prevent these diseases in
at-risk individuals before the onset of clinical manifestations or to develop effective neuroprotective therapies
that slow down or halt disease progression in the earliest
stages.
Given the pace of research and the burgeoning interest in the field, it appeared to be an auspicious time to
put together a major textbook placing the neurodegenerative diseases into modern prospective. The objective of
the present text is to present the latest research into the
genetics, pathogenesis, biochemistry, animal models, clinical features, and treatment of neurodegenerative diseases.
As such, we have been very fortunate to obtain the assistance of an internationally recognized group of authors
who are amongst the foremost experts in neurodegenerative diseases.
In the first section we have compiled state-of-the-art
chapters that reflect on basic aspects of neurodegeneration, including the roles of free radicals, mitochondria,
excitotoxicity, calcium binding proteins, apoptosis, neurotrophins, protein aggregation, DNA repair systems, trace
elements, nitric oxide/PARP, and inflammation. We have
also obtained outstanding chapters on utilizing diagnostic and therapeutic tools in neurodegenerative diseases.
This includes chapters on transgenic animal models, toxic
animal models, strategies for molecular genetics, electrophysiological assessment, MRI, PET/SPECT, and MRI spectroscopy. Gene therapy, stem cells and transplantation are
also covered.

The book then focuses on major aspects of neurodegenerative diseases, including normal aging of the nervous
system. There are specific approaches to diseases dominated by dementia or behavioral disturbances, including
Alzheimer’s disease, Dementia with Lewy bodies, Pick’s
disease, fronto-temporal dementias, and fronto-temporal
dementia with parkinsonism. There is also a chapter on

prion diseases. The approach to the patient presenting
with Parkinsonian symptoms is addressed, as well as more
detailed chapters dealing with the clinical aspects, neuropathology and treatment of Parkinson’s disease. There
are also chapters on the so-called “atypical parkinsonisms”
including multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration. Subsequent
sections deal with the neurodegenerative ataxias, motor
neuron diseases, degenerative diseases with chorea (Huntington’s disease, DRPLA, neurocanthocytosis), iron and
copper disorders and finally mitochondria diseases. In each
section we attempted to obtain chapters that detail the
genetics and the clinical and neuropathologic features of
these illnesses, as well as modern approaches to treatment.
Although the rapid pace of research in the field challenges
the ability of any textbook to maintain its currency, we have
conscripted a superlative group of contributors and compiled a text that we believe will be the most authoritative in
the field for the forthcoming near future. We hope that this
text will be useful to both neurologists and neuroscientists
who are interested in the pathogenesis, clinical aspects, and
treatment of these disorders. We also hope that this work
will stimulate the further research necessary to relieve the
human suffering caused by these tragic and devastating
illnesses.
Flint Beal
Anthony Lang
Albert Ludolph


Part I
Basic aspects of neurodegeneration