Neurodegenerative Diseases ADVANCES in EXPERIMENTAL MEDICINE and BIOLOGY

Neurodegenerative Diseases ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY

Editorial Board: NATHAN BACK, State University of New York at Buffalo IRUN R. COHEN, The Weizmann Institute of Science ABEL LAJTHA, N.S. Kline Institute for Psychiatric Research JOHN D. LAMBRIS, University of Pennsylvania RODOLFO PAOLETTI, University of Milan

Recent Volumes in this Series

Volume 716 MAST CELL BIOLOGY: CONTEMPORARY AND EMERGING TOPICS

Volume 717 KAINATE RECEPTORS: NOVEL SIGNALING INSIGHTS Antonio Rodriguez-Moreno and Talvinder S. Sihra

Volume 718 BRAIN INSPIRED COGNITIVE SYSTEMS 2010 Ricardo Sanz, Jaime Gomez and Carlos Hernandez

Volume 719 HOT TOPICS IN INFECTION AND IMMUNITY IN CHILDREN VIII Nigel Curtis

Volume 720 HUMAN CELL TRANSFORMATION Johng S. Rhim and Richard Kremer

Volume 721 SPHINGOLIPIDS AND METABOLIC DISEASE L. Ashley Cowart

Volume 722 RNA INFRASTRUCTURE AND NETWORKS Lesley J. Collins

Volume 723 RETINAL DEGENERATIVE DISEASES !"" and John D. Ash

Volume 724 NEURODEGENERATIVE DISEASES Shamim I. Ahmad

!#$%&#'&&#" ""#((##"#(#(")#"( (# Neurodegenerative Diseases

Shamim I. Ahmad, BSc, MSc, PhD School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom

Springer Science+Business Media, LLC Landes Bioscience Springer Science+Business Media, LLC Landes Bioscience

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Neurodegenerative Diseases/""5"{+/('/q{# Media, LLC dual imprint / Springer series: Advances in Experimental Medicine and Biology.

ISBN: 978-1-4614-0652-5

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Library of Congress Cataloging-in-Publication Data

*#'&+/""5" (;"<<=&>(""';?@QX 5#'(> ISBN 978-1-4614-0652-5 1. Nervous system--Degeneration. I. Ahmad, Shamim I. II. Series: Advances in experimental medicine and ';&?@Q[[\]<@]^_ [DNLM: 1. Neurodegenerative Diseases. W1 AD559 v.724 2011 / WL 358.5] RC365.N473 2011 616.8’0442--dc23 2011021159 DEDICATION

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vii viii PREFACE

"""(((k<k (=/X("##(#(#( disease, Rett syndrome and Down syndrome covered in this volume. The genetic causes #'R2(#"##(2& #(!#(!'#"( !#('#"=(X>'#"(# '#(''##" interactions with other proteins leading to the diseases.7*& k((8 $/&("#;$/#'#(>

(O2BLX>=L$X'(>=2O2X(#'# ((&###"'&'"# (''"('&$/(# '(("#&##' #"##'*"'''(&"'&# #"(*((#'#(&& mechanisms to eliminate O2BL2O2Rk'' k#(#&'#>#&"&L$ &&''&##'L$9 &#"&'$/(# "'#"#""'L$ &''&((### ">(" /&"][<~[[(( !(@]/&(#'# ((""#&>" (;##"#&(( hyperlexics, 3-D drawings, map memory, poetry, painting and sculpturing. One savant ##&#%@@~]Q(/&" ((#>=X(" k##"(#&(( 5"*#)"*#'' #(('#'(("' #&"''#"*'k" ("'(("##'("((' "" " #"("=X&# "####'"'" =!(~X"k&"(>= '>X""#"(#({((## (+(#+#({'&/" ""##'"&"# '&&""( #""""#'&!( Q&#### k/>"#""#" #(&(>'#(# PREFACE ix

'&#(('"#'#'"5 '#"'&(&" ('& 5"("#"&!<< #(=!(]X"("(>'#("][ and is the most commonly inherited neuropathy. Twenty-nine genes and more than 30 & (((("&""#'' #]["((&>(!(_ "#&&"(>"( (("@[[['&kk"* #((#"((#'&"k #(&((((''"#(=# ("'(('X<""> #""#&("(((& ((%"&<"('=)X !(_"&(()''* ''"k(##' #k(!(~|&'#"( #'<k#k(""#k( %#<>!&"'( #k((#&'" )#"#"#k( &##' '#"#'#' "#&'"+#&'' ">#' /(><("(> &>#&&!(@?~Q(&k """("'" &k###&#' (('##>(#''('"" &"""<""&' associated with neuronal damage. In Chapter 15, Hargreaves has addressed this issue '>"('(("#"" ""(###'( "'"#####"(# "k#&" In the editor’s view, Chapter 16 on mitochondrial importance in certain NDs is one k(((k/"=5"" ('>>>X'##'k&k*&"R #'R%kR""= !(@@X&k"#$/$>& #'&((=!(@~X ((>"# apoptosis and cell death in neuron systems. #(#""# >&=!(~?X x PREFACE

"/>"#( ">&'$/ excellently presented in the chapter. *#(k("#>( !(~^"'k#""#k ###((@(5R &#((## '">=~X& Chapter 22 covers the important and commonly prevailing disease, Down syndrome, #(#"##>& >(("(("""@~( &#((((("&<>( !#<#(>"#=/$<~X"/$<~ and glutathione peroxidase, thus more H2O2 is generated giving rise to oxidative stress. Premature ageing syndrome includes two NDs: Werner’s syndrome and progeria. &>#!(@Q)!((( /'M"=//X'"'# ;#"#"" !(@\ 5("(Neurodegenerative Diseases will stimulate >(&>&&## (##'!#" '&#""('' (''#&###' "#&#&(""k &'"&(##'(" &'

Shamim I. Ahmad, BSc, MSc, PhD School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom

REFERENCES

1. Bredesen DE, Rao RV, Mehlen P. Cell death in nervous system. Nature 2006; 443:796-802 @"/5*({+/('/q{#@[~[ |"/5k)#""%'"#"#+*}k Landes Bioscience/Springer Science+Business Media, 2008. Q"/5#"!k/"#+*}k{+ Springer Science+Business Media, 2009. ]"/5#">'#+*}k{+ Springer Science+Business Media, 2009. \" /5 k / # " ) " #+* }k Bioscience/Springer Science+Business Media, 2007. ?"(*#'#*#@[[_;QQ|?[?(~{!"@[[^;@_Q?Q@](> Phys Chem Chem Phts 2011; 13:7178-7188. ABOUT THE EDITOR...

SHAMIM I. AHMAD'R'{"% &{5%#"& '*'"%~###(" /(*'"%##"*'"& &'#|?k"("'" 'k#'#<")"k '#'"' #"&("<5/#'" #('"("!# accident. But his primary interest, which started 27 years ago, is DNA damage and repair, (#('"(#(#&>' ("(#"#'k>" ('"#"&''(<'"(## as 8-methoxypsoralen+UVA, mitomycin C, and nitrogen mustard and their importance in psoriasis treatment and in Fanconi anemia. In 2003 he received a prestigious “Asian P{O>#PMolecular Mechanisms of Fanconi Anaemia, Molecular Mechanisms of Xeroderma Pigmentosum, Molecular Mechanisms of Ataxia Telangiectasia, Molecular Mechanisms of Cockayne Syndrome and Diseases of DNA Repair(#{

xi PARTICIPANTS

Shamim I. Ahmad Eduardo Calpena //' Unit 732 Nottingham Trent University Centro de Investigación Biomédica en Red Nottingham "=!5{X UK and # Orlando Graziani Povoas Barsottini 5#{"=5{X ("*#' !/#(5&' and Neurosurgery !=!/5!X )&/ %# Valencia / %# Spain Brazil Giuseppe Castello {{ CROM !''{ Cancer Research Center and Neurodegenerative Disorders Mercoglianao Neurology Unit Italy &{ Brescia Andrea E. Cavanna Italy ("*#( &{"'"{/) Pedro Braga-Neto Birmingham ("*#' and and Neurosurgery /("&" )&/ %# 5#*#' / %# University College London Brazil London UK Paul Brown CEA/DSV/iMETI/SEPIA Jocelyn Cherry Fontenay-aux-Roses ("!*# France Southampton General Hospital Southampton UK

xiii xiv PARTICIPANTS

)!(( Aristea S. Galanopoulou ("#"&" /#("*#' Sciences and / "k%%#(#(" &% *# Rome !' Italy {>*}k USA Marc Corral-Juan Basic, Translational and Neurogenetics Alan J. Hargreaves Research Unit //' ("*# Nottingham Trent University Health Sciences Research Institute Nottingham "%#=5%X UK Universitat Autònoma de Barcelona Barcelona Masaharu Hayashi Spain ("!*#(' k(5# Sónia C. Correia *# !*#!{' k and Japan )#/' ("/ k &!" ("(' !" )# Portugal Interdisciplinary Graduate School '' Lívia Almeida Dutra &}" ("*#' Yamanashi and Neurosurgery Japan )&/ %# / %# John R. Hughes Brazil ("*#' &5! <5'# Chicago, Illinois ("*##' USA & #' #' James W. Ironside Germany National CJD Surveillance Unit Western General Hospital Carmen Espinós #' Unit 732 UK Centro de Investigación Biomédica en Red "=!5{X Michaela Jelen Valencia & Spain " Canada PARTICIPANTS xv

Sam Khandhadia Vincenzo Lupo ("!*# Unit 732 Southampton General Hospital Centro de Investigación Biomédica en Red Southampton "=!5{X UK and # }#k" 5#{"=5{X ("*#( !/#(5&' $k"&#/ !=!/5!X Valencia Dentistry and Pharmaceutical Sciences Spain /k<$k" Japan Soe Mar &%&(" Richard Knight Neurology National CJD Surveillance Unit ("*#' Western General Hospital '&/ #' Saint Louis, Missouri UK USA

Tsuyoshi Koide <# ("#"# Unit 732 Centro de Investigación Biomédica *5# " /#k =!5{X Japan and # k# 5#{"=5{X ("(' !/#(5&' )# !=!/5!X Interdisciplinary Graduate School Valencia '' Spain &}" Yamanashi Antoni Matilla-Dueñas Japan Basic, Translational and Molecular Neurogenetics Research Unit %%k ("*# ( Health Sciences Research Institute and Neuropathology "%#=5%X ("#%' Universitat Autònoma de Barcelona and Neuropathology Barcelona Medical University Lodz Spain Lodz Poland

Andrew John Lotery ("!*# Southampton General Hospital Southampton UK xvi PARTICIPANTS

b Giovanni Pagano *# CROM 555( Cancer Research Center Lodz Mercogliano and Italy ("!"! Biochemistry Joy B. Parrish &{' *#'5# Bydgoszcz ("*#' Poland /{" Sciences #k &{# ("(' {#*}k )# USA Interdisciplinary Graduate School '' Stephanie Patterson &}" &!' Yamanashi '! Japan USA

Rie Miyata José Luiz Pedroso ("!*#(' ("*#' k(5# and Neurosurgery *# )&/ %# k / %# Japan Brazil

Paula I. Moreira Seth J. Perlman !*#!{' &%&(" and Neurology )# ("*#' 5#%' '&/ &!" Saint Louis, Missouri !" USA Portugal George Perry Tomonori Ono ("%' /#("*#' Case Western Reserve University !' Cleveland, Ohio {>*}k and USA UTSA Neurosciences Institute ("{' Alessandro Padovani &>/ !''{ San Antonio, Texas and Neurodegenerative Disorders USA Neurology Unit &{ Brescia Italy PARTICIPANTS xvii

/%k {/kk Massachusetts General Hospital ( Stephen E. and Catherine Pappas Center and Neuropathology *#<$' ("#%' Boston, Massachusetts and Neuropathology USA & Lodz Enrico Premi Poland !''{ and Neurodegenerative Disorders k/" Neurology Unit ("%' &{ Case Western Reserve University Brescia Cleveland, Ohio Italy USA

Vincenzo Romeo Veronica Smith ("*# & &%& " Padova Canada Italy *k Ivelisse Sanchez ("*#( Basic, Translational and Neurogenetics $k"&#/ Research Unit ("*# Dentistry and Pharmaceutical Sciences Health Sciences Research Institute /k<$k" "%#=5%X Japan Universitat Autònoma de Barcelona Barcelona *#k#" Spain ("!*#(' k(5# Renato X. Santos *# !*#!{' k and Japan )#/' ("/ Cristiano Termine &!" Child Neuropsychiatry Unit !" (">(" Portugal &5# Varese Tilmann Schweitzer Italy ("*##' & #' k" #' Massachusetts General Hospital Germany Stephen E. and Catherine Pappas Center *#<$' Boston, Massachusetts USA xviii PARTICIPANTS

#k"'k E. Ann Yeh (" *#'5# Nagoya University Graduate School ("*#' /{" Nagoya, Aichi Sciences Japan &{# {#*}k Victor Volpini USA Molecular Diagnosis Center 5 $"#}k 5#R5&'{" # ("*#( {&'=55{X $k"&#/ R(' Barcelona Dentistry and Pharmaceutical Sciences Spain /k<$k" Japan Shiyao Wang %k'& Xiongwei Zhu People’s Hospital ("%' {' Case Western Reserve University China Cleveland, Ohio USA Thomas Westermaier ("*##' & #' #' Germany CONTENTS

1. ACUTE DISSEMINATED ENCEPHALOMYELITIS ...... 1 Joy B. Parrish and E. Ann Yeh

Abstract ...... 1 Introduction ...... 1 Incidence and Prevalence ...... 2 Differential Diagnosis of Multiple Sclerosis and Acquired Central Nervous System Demyelinating Disorders in Children and Adolescents ...... 4 Diagnostic Testing ...... 5 Clinical and Demographic Predictors of the Risk to Develop MS after an Initial Demyelinating Event ...... 7 Treatment ...... 8 Prognosis ...... 10 Conclusion ...... 11

2. AGE-RELATED MACULAR DEGENERATION ...... 15 Sam Khandhadia, Jocelyn Cherry and Andrew John Lotery

Abstract ...... 15 Introduction ...... 15 Epidemiology ...... 16 Normal Anatomy ...... 16 AMD and the Retina ...... 17 Symptoms of AMD ...... 18 Clinical Management of AMD ...... 20 Prognosis of AMD ...... 22 Pathology of AMD ...... 23 AMD and Alzheimer’s Disease...... 26 Ongoing Research and Anticipated Developments ...... 27 Conclusion ...... 33

xix xx CONTENTS

3. ARACHNOID CYSTS ...... 37 " ""/<5'#

Abstract ...... 37 Introduction ...... 37 Natural Behavior of Arachnoid Cysts ...... 39 Mechanisms of Cyst-Growth...... 41 Clinical Symptoms ...... 42 Diagnostic Procedures ...... 44 Indication for Treatment ...... 46 Treatment ...... 46 Conclusion ...... 48

4. AUTISM SPECTRUM DISORDERS: INFORMATION FOR PEDIATRICIANS SUPPORTING FAMILIES OF YOUNG CHILDREN ON THE SPECTRUM ...... 51 Stephanie Patterson, Veronica Smith and Michaela Jelen

Abstract ...... 51 Introduction ...... 51 Prevalence of Autism Spectrum Disorders ...... 52 Etiology ...... 52 Early Diagnosis: Screening of ‘Red Flags’ ...... 53 Diagnosis: Getting it Right ...... 54 First Steps into Early Intervention ...... 56 The Impact of ASD on the Family ...... 58 Conclusion ...... 59

5. AUTOSOMAL RECESSIVE CHARCOT-MARIE-TOOTH NEUROPATHY ...... 61 !"(#!(<# and Vincenzo Lupo

Abstract ...... 61 Introduction ...... 61 The Most Prevalent AR-CMT Forms ...... 64 The Most Severe AR-CMT Forms ...... 66 Founder Mutations Related to AR-CMT Forms ...... 68 Conclusion ...... 70

6. CREUTZFELDT-JAKOB DISEASE ...... 76 {/kk'" 5%%k

Abstract ...... 76 Introduction ...... 76 Clinical Features ...... 77 Sporadic CJD (sCJD) ...... 77 Genetics of Prion Disease (gPD) ...... 83 Iatrogenic CJD (iCJD) ...... 84 Variant Creutzfeldt-Jakob Disease (vCJD) ...... 84 Conclusion ...... 88 CONTENTS xxi

7. EPIGENETICS IN AUTISM AND OTHER NEURODEVELOPMENTAL DISEASES ...... 91 #kk#k#

Abstract ...... 91 Introduction ...... 91 Congenital Neurodevelopmental Diseases Associated with Epigenetic Mechanism ...... 93 Environmental Factors Which Affect Brain Function via Epigenetic Mechanism ...... 93 Epigenetic Treatments for Patients with Neurodevelopmental Diseases ...... 95 Conclusion ...... 97

8. EPILEPSY AND EPILEPTIC SYNDROME ...... 99 Tomonori Ono and Aristea S. Galanopoulou

Abstract ...... 99 Introduction ...... 99 Clinical Features of Epilepsy: Is Epilepsy A Neurodegenerative Disorder/Syndrome? ...... 100 Neurodegenerative Changes in Epilepsies: Cellular and Molecular Mechanisms ...... 102 Current State of Diagnosis and Treatment of Neurodegeneration in Epilepsy ...... 106 Conclusion ...... 108

9. FRONTOTEMPORAL LOBAR DEGENERATION ...... 114 %"%&{{

Abstract ...... 114 Introduction ...... 114 Epidemiology ...... 115 Clinical Presentation ...... 115 Histopathology...... 119 Genetics ...... 121 Treatment ...... 122 Conclusion ...... 123

10. GERSTMANN-STRÄUSSLER-SCHEINKER DISEASE...... 128 %%k

Abstract ...... 128 Introduction ...... 128 Codon 102 Mutation (102Leu 129Met) ...... 130 Mutation of Codon 105 (105Leu 129Val) ...... 131 Mutation of Codon 117 (117Val 129Val) ...... 131 Mutation of Codon 131 (131Met 129Val) ...... 131 Mutation of Codon 145 (145Stop) ...... 132 Mutation of Codon 187 (187Arg 129Val) ...... 132 Mutation of Codon 198 (198Ser 129Val) ...... 132 Mutation of Codon 202 (202Asn 129Val) and Mutation of Codon 212 (212Pro 129Met) ...... 133 Mutation of Codon 217 (217Arg 129Val) ...... 133 Mutation of Codon 232 (232Thr) ...... 133 Unknown Mutations ...... 133 Biology of GSS ...... 133 xxii CONTENTS

PrP Peptides in GSS ...... 134 Conclusion ...... 134

11. JUVENILE NEURONAL CEROID LIPOFUSCINOSES ...... 138 Shiyao Wang

Abstract ...... 138 Introduction ...... 138 Genetic and Biochemical Basis ...... 139 Pathogenesis...... 139 Clinical Features ...... 139 Histopathology...... 140 Diagnosis ...... 140 Therapeutic Strategy ...... 141 Conclusion ...... 142

12. KURU: THE FIRST PRION DISEASE ...... 143 %%k{/kk%#{

Abstract ...... 143 Introduction ...... 143 Background and Ethnographic Setting ...... 144 Cannibalism ...... 144 Kuru Etiology—The Insight into a Novel Class of Pathogens ...... 145 Epidemiology of Kuru—A Strong Support of the Cannibalism Theory ...... 145 Clinical Manifestations ...... 146 Neuropathology ...... 147 Genetics and Molecular Biology of Kuru ...... 150 Conclusion ...... 151

13. LEUKODYSTROPHIES ...... 154 Seth J. Perlman and Soe Mar

Abstract ...... 154 Introduction ...... 154 Demyelinating and Dysmyelinating Disorders ...... 155 Hypomyelinating Disorders ...... 160 Spongiform Disorders ...... 164 Cystic Disorders ...... 167 Conclusion ...... 168

14. MACHADO-JOSEPH DISEASE AND OTHER RARE SPINOCEREBELLAR ATAXIAS ...... 172 Antoni Matilla-Dueñas

Abstract ...... 172 Introduction ...... 172 Spinocerebellar Ataxia Type 3 (SCA3) [MIM #109150] ...... 173 Dentatorubral-Pallidoluysian Atrophy (DRPLA) [MIM #125370] ...... 175 Fragile X Tremor and Ataxia Syndrome (FXTAS) (MIM #300623) ...... 176 Episodic Ataxia Type 1 (EA1) (MIM #160120) ...... 176 CONTENTS xxiii

Episodic Ataxia Type 2 (EA2) [MIM #108500] ...... 177 Episodic Ataxia Type 3 (EA3) [MIM #606554] ...... 177 Episodic Ataxia Type 4 (EA4) [MIM #606552] ...... 178 Episodic Ataxia Type 5 (EA5) [MIM #601949] ...... 178 Episodic Ataxia Type 6 (EA6) [MIM #612656] ...... 178 Episodic Ataxia Type 7 (EA7) [MIM# 611907] ...... 179 Autosomal Dominant Spastic Ataxia (ADSA) [MIM #108600] ...... 179 Other Autosomal Dominant Spinocerebellar Ataxias ...... 179 Therapeutic Strategies in the Spinocerebellar Ataxias ...... 180 Conclusion ...... 184

15. NEURODEGENERATIONS INDUCED BY ORGANOPHOSPHOROUS COMPOUNDS ...... 189 Alan J. Hargreaves

Abstract ...... 189 Introduction ...... 189 Mechanisms of Acute and Delayed Neurotoxicity of OPs ...... 192 Molecular Targets of OPs ...... 196 Neuropathy Target Esterase (NTE) ...... 196 Other Potential Molecular Targets of Organophosphates ...... 198 Other Potential ‘Non-Esterase’ OP Binding Proteins ...... 199 Conclusion ...... 200

16. MITOCHONDRIAL IMPORTANCE IN ALZHEIMER’S, HUNTINGTON’S AND PARKINSON’S DISEASES ...... 205 Sónia C. Correia, Renato X. Santos, George Perry, Xiongwei Zhu, %#5k/"

Editor’s Note ...... 205 Abstract ...... 205 Introduction ...... 206 Mitochondrial Dysfunction in the Limelight of Neurodegenerative Diseases ...... 206 Conclusion ...... 215

17. MULTIPLE SCLEROSIS ...... 222 b

Abstract ...... 222 Introduction ...... 222 Symptoms and the Clinical Phenotypes of MS...... 223 Structures of Brain Involved in Immunopathology of MS ...... 224 Immunopathogenesis of MS ...... 226 Disruption of BBB ...... 227 Axonal Injury ...... 229 Remyelination and Repair...... 229 Gliosis ...... 229 Oxidative Stress and Excititoxicity ...... 230 Blood Platelets in MS Etiology...... 231 Biomarkers of MS ...... 232 Treatment ...... 233 Conclusion ...... 233 xxiv CONTENTS

18. MYOTONIC DYSTROPHY TYPE 1 OR STEINERT’S DISEASE ...... 239 Vincenzo Romeo

Abstract ...... 239 Introduction ...... 240 Clinical Features ...... 242 Muscle Pathology ...... 249 Pathogenesis of DM ...... 251 Management, Treatment and Future Perspectives ...... 255 Conclusion ...... 255

19. NEURODEGENERATION IN DIABETES MELLITUS ...... 258 #k"'k

Abstract ...... 258 Introduction ...... 258 Brain Imaging Studies in Type 2 Diabetes ...... 259 Underlying Mechanism of Cognitive Dysfunction in T2DM ...... 259 Vascular Contribution to T2DM-Associated Cognitive Dysfunction ...... 261 The Effects of Blood Glucose Control ...... 262 Future Direction ...... 262 Conclusion ...... 263

20. NEUROFIBROMATOSES ...... 266 k"/%k

Abstract ...... 266 Introduction ...... 266 Epidemiology ...... 267 Clinical Features ...... 267 Genetic Basis ...... 271 Biochemical and Molecular Mechanism of Disease ...... 271 Pathology ...... 272 Diagnostic Criteria ...... 272 Therapeutic Strategy and Prognosis ...... 273 Conclusion ...... 275

21. OXIDATIVE STRESS IN DEVELOPMENTAL BRAIN DISORDERS ...... 278 #*#k#"

Abstract ...... 278 Introduction ...... 279 Hereditary DNA Repair Disorders ...... 279 Congenital Metabolic Errors ...... 283 Childhood-Onset Neurodegenerative Disorders ...... 285 Conclusion ...... 288 CONTENTS xxv

22. OXIDATIVE STRESS AND MITOCHONDRIAL DYSFUNCTION IN DOWN SYNDROME...... 291 Giovanni Pagano and Giuseppe Castello

Abstract ...... 291 Introduction ...... 291 ...... 292 Mitochondrial Dysfunctions in DS ...... 293 Mitochondria-Targeted Chemoprevention ...... 295 Conclusion: Research Perspectives ...... 296

23. PICK’S DISEASE ...... 300 *k}#k"$"#}k

Abstract ...... 300 Introduction ...... 300 Pick’s Disease and Clinicopathological Concept of FTLD ...... 301 History of ‘Pick’s Disease without Pick Bodies’ and Present !...... 302 Frequencies of Pathological Subtypes of FTLD ...... 304 Pick’s Disease and FTLD-TDP ...... 305 Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP) ...... 309 Basophilic Inclusion Body Disease (BIBD) and Neuronal Intermediate Filament Inclusion Disease (NIFID) ...... 311 Argyrophilic Grain Disease (AGD) ...... 312 Conclusion ...... 313

24. PREMATURE AGING SYNDROME ...... 317 )!((

Abstract ...... 317 Introduction ...... 317 Epidemiology ...... 318 Clinical Features ...... 318 Aetiology: Genetic and Biochemical Basis ...... 320 Molecular Mechanisms ...... 323 Neuropathogenesis ...... 327 Diagnosis and Therapeutical Approaches ...... 328 Conclusion ...... 328

25. THE SAVANT SYNDROME AND ITS POSSIBLE RELATIONSHIP TO EPILEPSY ...... 332 John R. Hughes

Abstract ...... 332 Introduction ...... 332 Method ...... 333 Different Forms ...... 333 Possible Causes of the SS ...... 337 xxvi CONTENTS

Characteristics of Savants ...... 339 Anatomical Relationships ...... 339 Incidence ...... 340 Conclusion ...... 340

26. SJOGREN-LARSSON SYNDROME ...... 344 Lívia Almeida Dutra, Pedro Braga-Neto, José Luiz Pedroso and Orlando Graziani Povoas Barsottini

Abstract ...... 344 Introduction ...... 344 Clinical Manifestations ...... 345 Molecular Insights into Lipid Metabolism ...... 346 Diagnosis ...... 347 Differential Diagnosis ...... 347 Treatment ...... 349 Conclusion ...... 349

27. THE SPINOCEREBELLAR ATAXIAS: CLINICAL ASPECTS AND MOLECULAR GENETICS ...... 351 Antoni Matilla-Dueñas, Marc Corral-Juan, Victor Volpini and Ivelisse Sanchez

Abstract ...... 351 Introduction ...... 351 Spinocerebellar Ataxia Type 1 (SCA1) [MIM #164400] ...... 353 Spinocerebellar Ataxia Type 2 (SCA2) [MIM #183090] ...... 354 Spinocerebellar Ataxia Type 3 (SCA3) [MIM #109150] ...... 355 Spinocerebellar Ataxia Type 4 (SCA4) [MIM #600223] ...... 355 Spinocerebellar Ataxia Type 5 (SCA5) [MIM# 600224] ...... 356 Spinocerebellar Ataxia Type 6 (SCA6) [MIM #183086] ...... 356 Spinocerebellar Ataxia Type 7 (SCA7) [MIM #164500] ...... 357 Spinocerebellar Ataxia Type 8 (SCA8) [MIM #60876] ...... 359 Spinocerebellar Ataxia Type 10 (SCA10) [MIM #603516] ...... 360 Spinocerebellar Ataxia Type 11 (SCA11) [MIM #604432] ...... 360 Spinocerebellar Ataxia Type 12 (SCA12) [MIM #604326] ...... 361 Spinocerebellar Ataxia Type 13 (SCA13) [MIM #605259] ...... 362 Spinocerebellar Ataxia Type 14 (SCA14) [MIM #605361] ...... 362 Spinocerebellar Ataxia Type 15 (SCA15) [MIM #606658] ...... 363 Spinocerebellar Ataxia Type 17 (SCA17) [MIM #607136] ...... 363 Spinocerebellar Ataxia Type 18 (SCA18) [MIM #607458] ...... 364 Spinocerebellar Ataxia Type 19 (SCA19) [MIM #607346] ...... 364 Spinocerebellar Ataxia Type 20 (SCA20) [MIM #608687] ...... 365 Spinocerebellar Ataxia Type 21 (SCA21) [MIM #607454] ...... 365 Spinocerebellar Ataxia Type 23 (SCA23) [MIM #610245] ...... 366 Spinocerebellar Ataxia Type 25 (SCA25) [MIM #608703] ...... 366 Spinocerebellar Ataxia Type 26 (SCA26) [MIM #609306] ...... 367 Spinocerebellar Ataxia Type 27 (SCA27) [MIM #609307] ...... 367 Spinocerebellar Ataxia Type 28 (SCA28) [MIM #610246] ...... 368 Spinocerebellar Ataxia Type 29 (SCA29) [MIM #117360] ...... 368 Spinocerebellar Ataxia Type 30 (SCA30) [MIM #613371] ...... 368 Spinocerebellar Ataxia Type 31 (SCA31) [MIM #117210] ...... 369 Treatment ...... 369 Conclusion ...... 370 CONTENTS xxvii

28. TOURETTE SYNDROME ...... 375 Andrea E. Cavanna and Cristiano Termine

Abstract ...... 375 Introduction ...... 375 Epidemiology ...... 376 Aetiology ...... 376 Clinical Aspects and Diagnostic Criteria ...... 377 Assessment and Management ...... 380 Conclusion ...... 381

INDEX ...... 385 ACKNOWLEDGEMENTS

k#k'# #(#'<(k' (k#(#k # (#&((###( k5#kk'!!"!! $R{$k{k (((k5"k# {""k)5k """")""" "&#((#'"#'(# k

xxix IN MEMORIAM

MARK ANTHONY SMITH (August 15, 1965 – December 19, 2010)

An Inspiration for Alzheimer’s Disease

k/"(("=X''& (' k#'" hypothesis,1#"#"" '"''"&"" (#(# $'''' leading to the two-hit hypothesis2#(( ('('"# #&"#!&((! ""##"'##"#' "(## kR!#('<;# '##&5#(' k#''&'#!&3 which he elegantly #'(#'(' '"("""" "'"!"&k'' "#(''('# ("

xxxi {#'"(kR#(" '>&<#'(" ""$&(~["(# "4 k#"##')<%"" /*#"$#'5&'""/ 5&'&%'""""'' ""R"<# "*/##"%' /{5k)" &"/"''/ !'%') American Philosophical Society. kR'(&''"<#&"''' #"#"'((*5#R" '&""&@[[#(#' """#'##'" 'kR#'&"'( &=(++<"+"k""X kR""<~^^["#"k&& #'>(#"""#k#"'&' k #>&" ('((5>&(( induced, heme oxygenase,6&#k#>& #(''' """&#' #(#&R&"' (&kR&(# #&"'""' ' ##(kR#'# &&('&(" #

Xiongwei Zhu, Hyoung-gon Lee and George Perry

REFERENCES

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