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 Endogenous free radicals and antioxidants in the brain Stefan L Marklund 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 Glutamate transporters Davide Trotti and Stuart L Gibb Calcium binding proteins in selective vulnerability of motor neurons ´ o´ Siklos ´ and Stanley H Appel Laszl 44 57 65 Apoptosis in neurodegenerative diseases Jorg B Schulz 80 Neurotrophic factors Michael Sendtner 94 v vi Contents 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 ă 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 Index coenzyme Q10 therapy 612–13 cognitive complication treatment 617 cognitive function 279 complex I activity decrease 39, 601, 612 deficiency 915, 916 complex IV impairment 602 cortical function 232–3 deep brain stimulation 279, 618 dementia 564–5, 582 depression 564–5, 582 diagnostic markers 563–4 differential diagnosis 576 DNA oxidative damage 136 donor grafts 368–9 dopa decarboxylase activity 291–2 dopamine 599–600 replacement 296, 370–1 transmission 367–8 dopamine cell replacement 364 dopamine receptors 186 binding loss 293–4 function measurement 293 dopamine transporters binding 290–1 loss 291 dopaminergic agonists 615–16 dopaminergic neurons embryonic stem cells as source 350–1 functions 369–70 regional sparing 371 dysautonomia 565 dyskinesias 566 effective connectivity 279 electromyography 228 enzymes protecting from oxidative damage 110 epidemiology 567 etiology 562–4 excitotoxicity 46–8 calcium 602 exotoxins 602–3 familial 579, 586–7 non-monogenic 591–2 free radical damage 562 functional MRI 278–9 gene therapy 337–8 genetic linkages 223 genetically-defined forms 587 genetics 186–7, 562–3, 579, 586–93 glial cells 603 glial pathology 581 glutamate 310 glutamate transporters 62 hallucinations 564–5, 582 heat-shock proteins in development retardation 120 hereditary 292 historical background 561 hypometria 228, 232 infections 602–3 inflammation 603, 613–14 inhibitor of apoptosis proteins 86 interstimulus intervals 233, 239 interventional modulation of brain glucose 295–6 iron accumulation 880 levodopa-induced dyskinesias 235–6 Lewy bodies 149, 186, 478, 577–8, 582–3, 604–5, 613 early pathology 580–1 Lewy neurites 186, 577–8, 580 life expectancy 566–7 long-distance nigrostriatal axogenesis 350 magnetic resonance spectroscopy 316 malfunctioning circuitry interventions 617–18 microglial activation 577 midbrain 576 mitochondria disruption 149 dysfunction 47, 87, 601–2, 612–13, 915–16 genetics 563 role 135 monoamine oxidase activity monoamine oxidase B inhibitors 616–17 monogenic 587–8 morphometry 271 motor disorders 228–9, 564 motor evoked potentials 232–3, 240 motor fluctuations 566 levodopa-induced 614–15 motor performance 231 MPTP modeling 196–200 MPTP-induced 47, 602 multiple system atrophy differentiation 263 muscle force underscaling 233 NAA loss 307 measurement 316 neural function regeneration 368–9 neural progenitor induction to restore dopaminergic input to striatum 356–7 neurochemistry 561–2 neurodegeneration 599 neuroimaging 367, 567–8 neuromelanin 600 pigmentation loss 575 neuron loss 561, 577, 582 neuropathology 149, 575–83 neurophysiology 227–40 tests 230 new synapse growth 367–8 971 972 Index Parkinson’s disease (cont.) nigrostriatal dopaminergic system function 292 augmentation 614–17 nigrostriatal tract reformation 350 nitric oxide 601 non-monogenic 591–2 oxidative stress 562, 598–601, 613 factors diminishing 601 paraquat model 203 parkinsonism differentiation 551 pathogenesis 223 pathogenic molecules 223–4 pathology 186, 561, 575–7, 579 early 580–1 pathophysiology 598–605 patients undergoing surgery 228 peroxynitrite formation 120, 149 phosphocreatine in resting muscle 313 postsynaptic dopaminergic function 292–4 postural reflexes 564 premotor potential 232 presynaptic dopaminergic function 290–1 prevalence 567 primary dystonia 236–9 progenitor cell-mediated restoration of striatal dopamine 350 progression slowing/stopping 567, 612–14 protective gene therapy 337–8 protein aggregation 604–5, 613 degradation impairment 613 nitration 24 psychiatric complication treatment 617 quality of life 565, 566 rapid eye movement sleep disorder 564–5, 582 rapid movement 232 reaction times 232 reciprocal inhibition of agonist/antagonist muscles 234–5, 237 restorative gene therapy 337 rigidity 234–5, 564 rotenone 567, 602, 603–4 features 47 model 204–5 sensorimotor integration 231–2, 238–9 sensory information for motor performance 231 sequential movements 229–31 shortening reaction 234 silent period 233, 239 sleep disorders 582, 616 slow excitotoxicity 47 sporadic 593 staging system 581, 581 stem cell therapy 372–4, 619 striatal synuclein lesions 577 structural MRI 260 subcortical activation 279 substantia nigra 269 changes 260 iron 600 iron accumulation 577, 577 subthalamic nucleus 260 subtypes 565 surgical interventions 617–18 susceptible neuronal population 116 symptoms advanced 564 asymmetry 564 early 564 moderate 564 α-syn fragments 187 synuclein 580 α-synuclein 916 mutations 562–3, 586, 588–9, 604 thalamus 263 time course 566–7 transcranial magnetic stimulation 232–3 transplantation clinical trials 365 treatment 279, 612–19 anticholinergic drugs 617 catecholamine-o-methyl transferase inhibitors 616 cell replacement 619 cognitive complications 617 deep brain stimulation 618 malfunctioning circuitry interventions 617–18 monoamine oxidase B inhibitors 616–17 nigrostriatal dopaminergic system function augmentation 614–17 progression slowing/stopping 567, 612–14 psychiatric complications 617 regeneration 618–19 surgical interventions 617–18 tremor 233–4, 552, 564 metabolic substrates 294 ubiquination system mutations 120 ubiquitin proteasomal system 916 unregulated dopamine levels 367 visuospatial dysfunction 582 volumetry 270 well water drinking 567, 602 X-linked inhibitor of apoptosis proteins (XIAP) 86 see also levodopa Parkinson’s disease-related covariance pattern (PDRP) 294–5 modulation in antiparkinsonian interventions 295–6 parvalbumin 68 amyotrophic lateral sclerosis 68 motor neuron protection 71–2 neuron protection 73–4 in vivo study 71–2 PAX2 gene 729 pedunculopontine nucleus 235 Index Peliazaeus–Merzbacher disease 799 Pen-2 179 penicillamine provocative test 897–8 Wilson’s disease 900, 901 penile implants, multiple system atrophy 648 pentoxifylline, amyotrophic lateral sclerosis 782 peptides polyQ-containing co-aggregation with normal essential proteins 118 toxicity mechanisms 118 unfolded 111 percutaneous endoscopic gastrostomy, motor neuron dysfunction 755 pergolide multiple system atrophy 648–9 Parkinson’s disease 615, 616 periodic vestibular ataxia 716 peripheral neuropathy ataxia–telangiectasia 739 cerebellar ataxia 730–2 Machado–Joseph disease/SCA3 713 neurogenic muscle weakness ataxia and retinitis pigmentosa 913–14 permeability transition pore, mitochondrial 67 peroxidases peroxyl (LOO) peroxynitrite 4, 19, 21 activity 22–3 anion production 22 biomolecular target modification 23 dopamine hydroxylation 24 excitotoxicity 45, 148 formation 601 generation by nitric oxide 148 hydroxyl radical formation metalloporphyrin scavenging 27 neurotoxicity 148, 151–2 nitric oxide toxic actions 146 oxidative modifications 23, 24 Parkinson’s disease 120, 149 production 22 scavengers 22–3 SOD relationship 27 SOD1 gain-of-function reaction 160 SOD2 targeting 24 superoxide reaction with NO 28 tyrosine phosphatase reactions 23–4 peroxyredoxins 11 personality change, Alzheimer’s disease 418 phenylbutyrate 783 phosphate, inorganic 312–13 phosphocreatine (PCr) measurement in phosphorus-31 spectroscopy 312–13 phosphodiesterase 4B (PDE4B) inhibitor 782 phospholipase A2 45 phospholipid hydroperoxide glutathione peroxidase (PHGPX) 10 phosphorus-31 spectroscopy 312–13, 321 photosensitizing reactions, type II physical therapy ataxia 705–6 corticobasal degeneration 693 hereditary spastic paraplegia 798 motor neuron dysfunction 753 progressive supranuclear palsy 674 physostigmine, progressive supranuclear palsy 674 phytanic acid accumulation 728, 729 phytanoyl-CoA hydroxylase (PAHX) gene 729 phytol 729 PI-3K signaling pathway 97 Pick bodies 483 frontotemporal dementia with parkinsonism linked to chromosome 17 501 tau 483, 484 Pick’s disease see frontotemporal lobar degeneration Pisa syndrome 633 Plank–Einstein equation 303 plant antioxidants 8–9 platelet-derived growth factor (PDGF) 629–30 platelets, amyloid precursor protein isoforms 423–4 PLAU gene 447, 448 PLCγ1 activation 97 pneumonia aspiration 671 ataxia–telangiectasia 741 Huntington’s disease 852 polyglutamine 111 aggregate hypothesis 808 amyloid-like aggregates in Huntington’s disease 855 expansion 807 androgen receptor protein 811–12 toxicity 808 instability 854 mutant misfolded 856 neurotoxicity 807–8 protein aggregation 808 polyglutamine disorders 710, 709–11 ataxia 711 polyneuropathy, Machado–Joseph disease/SCA3 713 polypeptides, nonsense generation in aged brain 122 poly(ADP-ribose) polymerase-1 (PARP-1) 146–7 abundance 147 activation 147 cell death promotion 150–1 DNA damage 152 neurotoxicity 148 NO formation 148 activity 147 cell death 150–1 DNA repair 146–7 973 974 Index poly(ADP-ribose) polymerase-1 (PARP-1) (cont.) energetic cost of activation 147 excitotoxicity 148 inhibitors 150–2 agents 151 neuroprotection 151 neurotoxicity and apoptosis inducing factor 147–8 peroxynitrite neurotoxicity 148 release from DNA 147 stroke 148 structure 147 polyQ aggregates 113–14 suppression 711 polyQ expansion diseases 710–11 chaperones 710 enhanced autophagy 117 inclusion bodies 112, 113–14 onset 122 proteins 710 proteolysis reduction 122 toxic fragment hypothesis 710 yeast model 114–15 polyQ-containing proteins 112 polysomnography, fatal familial insomnia 517 polyubiquitin gene 111 Pompe’s disease, adult 821 pontine ocular motor area, progressive supranuclear palsy 669–70 porphyrins catalytic antioxidant activity 26, 27 positron emission tomography (PET) 290 Alzheimer’s disease 421, 475 β-amyloid imaging 455 brain functional imaging 293–6 chorea-acanthocytosis 872 cognitive function change with age 387–8 corticobasal degeneration 688, 692 deep brain stimulation 295 dementia with Lewy bodies 475 dopa decarboxylase activity 291–2 dopamine transporter imaging 290–1 frontotemporal dementia frontal lobe variant 488 Huntington’s disease 295, 296 McLeod syndrome 873–4 multiple system atrophy 644–5 parkinsonism 558 Parkinson’s disease 367, 567–8 Parkinson’s disease-related covariance pattern 294–5 postsynaptic dopaminergic function 292–4 presynaptic dopamine transporters 368 principal component analysis 294 progressive supranuclear palsy 664 semantic dementia 488 statistical parametric mapping analysis 294 vesicular monoamine transporters 292 Wilson’s disease 898 posterior cortical atrophy 424–5 postpoliomyelitis muscular atrophy 821 postsynaptic dopaminergic function, Parkinson’s disease 292–4 postural control 389 postural instability parkinsonism 553 progressive supranuclear palsy 669 postural reflexes, Parkinson’s disease 564 potassium channel openers 142–3 neuroprotective effect 143 potassium channels activation 142–3 ATP-dependent 142, 143 crystallized bacterial 142 inward rectifier 142 large-conductance calcium-activated 142, 143 two P domain 142, 143 voltage-gated 142–3 PPP2R2B gene 711, 715 pramipexole Parkinson’s disease 615–16 sleep disorders 616 pravastatin, Alzheimer’s disease 466–7 prazosin, multiple system atrophy 647–8 prednisone 465 prefrontal cortex, aging 399–400 pregnancy, Wilson’s disease 901 premotor potential 232 presenilin aggresomes 112 conserved 178 mouse models 180 mutation 109, 122, 443 Alzheimer’s disease 122, 454 Alzheimer’s disease risk factor 177 autosomal dominant Alzheimer’s disease 178, 416–17 early-onset Alzheimer’s disease 177–8 γ-secretase activity 179, 182 presenilin conserved 178 mouse models 180 mutation 178 Alzheimer’s disease 454 Alzheimer’s disease risk factor 177 autosomal dominant Alzheimer’s disease 178, 416–17 presenilin gene mutations 222 missense 178 presynaptic dopaminergic function 290–4 Parkinson’s disease 290–1 presynaptic inhibition 237–8 Huntington’s disease 241 Index principal component analysis (PCA) 294 prion diseases 267–8, 512–20 clinical diagnostic features 513–19 differential diagnosis 519 neuropathology 513 structural MRI 267–71 therapy 519–20 transmissibility 513 prion proteins copper binding 19, 29 self-perpetuating in neurons 109 see also PRNP gene; PrPsc PRKCG gene 711–12 PRNP gene codon 129 513 mutations 513 proapoptotic pathways, neurotrophic factor effects 103 procaspase-9 38–9, 83 progestins, Alzheimer’s disease 417 programmed cell death 80 progressive aphasia 424, 481–2 progressive apraxic syndrome 425 progressive autonomic failure see multiple system atrophy progressive hepatolenticular degeneration see Wilson’s disease progressive myoclonus epilepsy (PME) 705 progressive nonfluent aphasia 485, 487 imaging 488 neuropsychology 489 progressive supranuclear palsy 188, 663–75 age at onset 671 anatomic distribution of degeneration 667–71 animal models 667 anticholinergic drugs 673–4 antidepressants 674 apraxia 668 astrocytes 666, 669 atypical 556, 663–4 auditory blink reflex 670–1 auditory startle response 670–1 behavioral change 667 botulinum toxin 674 cerebral cortex 667–8 cholinergic drugs 673–4 clinical evaluation 664 clinical features 188 clinical presentation 663–4 clinicopathological correlates 668 combined 556 complex I deficiency 673 corticobasal degeneration differential diagnosis 685 corticobasal degeneration-like syndrome 690–1 daytime hypersomnolence 670 diagnosis 556 diagnostic criteria 664, 665 differential diagnosis 664, 666 dopaminergic agonists 673 dysarthria 671, 671 dysphagia 671, 674 epidemiology 671–2 executive function 668 exercise 674 external anal sphincter 671 eyelid movement 670 eyelid paresis 674 gait 553, 663, 669 gaze palsy 669–70, 674 genetics 673 clinical 672 nuclear molecular 672–3 geographic clusters 672 globus pallidus 669 granulovacuolar degeneration 667 grumose degeneration 667 hippocampus 669 hummingbird sign 260 imaging 664–6 incidence 672, 671–2 levodopa 673 locomotory aids 674 mesencephalic area 669–70 microglia activation 667 mitochondrial mechanisms 673 neurofibrillary tangles 556, 663, 666 neurons 667 neuropathologic criteria 556 neuropathology 666–7 neurophysiologic tests 230 neuropil threads 666–7 nigrostriatal system 669 oculomotor findings 670 onset of disease 664 Onuf’s nucleus degeneration 671 oxidative stress 673 patient resources 674–5 physical therapy 674 Pick’s disease overlap 481 pontine ocular motor area 669–70 possible 556 postsynaptic dopaminergic function 292–3 postural instability 669 prevalence 555, 671 probable 556 rapid eye movement sleep 670 rating scale 664 reflex gaze 670 rigidity 669 risk factors 672 saccades 670 sex ratio 672 sleep disorders 670 speech impairment 671, 671, 674 spinal cord involvement 671 975 976 Index progressive supranuclear palsy (cont.) sporadic 673 striatum 669 structural MRI 260 substantia nigra 669 subthalamic nucleus 669 supranuclear ophthalmoplegia 553 surgical implants 674 survival 671 swallowing 671, 674 tau gene allelic variant 673 haplotypes 673 tau protein 666–7 isoforms 672 transglutaminases 673 treatment 673–4 tremor 669 typical 556 ubiquitin accumulation 121 urinary incontinence 671 vertical gaze restriction 663, 669–70 vestibulo-ocular reflex 670 volumetry 270 pro-inflammatory cascade induction 172 prolactin, pituitary release regulation 640 promyelocytic leukemia oncogenic domains (PODS) 112 proposagnosia, semantic dementia 487 proprioception 389 prostaglandin Emultiple system atrophy 648 prostaglandins, COX-derived 171 prostanoids, metabolism prostate apoptosis response-4 (Par-4) 87 proteasome(s) inhibition by abnormal protein accumulation 115–16 oxidative stress effect on function 604 α-synuclein inclusion bodies 120 trapping in inclusion bodies 114, 118 proteasome, 20S 110–11, 115 peptidase sites 115 proteasome, 26S 110–11 extended polyQ sequence interference with degradation 115 inclusion body association 112 proteasome inhibitors 112, 113 JNK-dependent apoptotic pathway 116–17 proteasome-associated peptidase 115–16 protein kinases activation 116–17 tau phosphorylation 171 protein misfolding, spinal and bulbar muscular atrophy 812–13 protein tyrosine phosphatases proteins abnormal amyotrophic lateral sclerosis 120–1 selective degradation 110–11 stressed cells 114 apoptosis induction by damage 116–17 β-sheet aggregates 112, 115 calcium-binding domain 66 copper-binding 29 degradation inhibition 115–16 in non-stressed cells 114 reduction with aging 122–3 inclusions 112–15 abnormal in Parkinson’s disease 119–20 nitrated 23 nitration 24–5 pharmacophores 26–7 polyQ domains 114 polyQ-containing apoptosis induction 117 co-aggregation with normal essential proteins 118 proteasomal hydrolysis 115–16 proteasome digestion 115 signaling pathway activation 117 toxicity mechanisms 118 refolding 111 thiol-containing 26–7 ubiquinated inclusion body association 112 loss from aggresomes 113 unfolded 108, 111 accumulation in cell 108–9 accumulation in endoplasmic reticulum 109 aggregation 119 binding by molecular chaperones 110 cell processing mechanism inadequacy 116 proteolipid protein (PLP) gene mutations 799 proton motive force 34–5 proximal myotonic myopathy (PROMM) 821 PrPsc 513 antiprion agent effects 520 detection 516 Gerstmann–Straussler–Scheinker syndrome 517 variant Creutzfeldt–Jakob disease 518 PSEN1 gene 443 mutation 443, 445 Alzheimer’s disease 442 PSEN2 gene 443, 443 mutation in Alzheimer’s disease 442 pseudobulbar crying/laughing multiple system atrophy 635 Wilson’s disease 893 psychiatric changes, Huntington’s disease 853 psychomotor skills, Huntington’s disease 853 PTP pore complex 36 mitochondrial 38 pulvinar sign 268, 268, 269 Purkinje cells ataxia–telangiectasia 738, 739 corticobasal degeneration 683 Index putamen, multiple system atrophy 624 pyramidal signs corticobasal degeneration 689 multiple system atrophy 633 pyruvate 33 quantitative sudomotor axon reflex test 641 quetiapine dementia with Lewy bodies 478 frontotemporal lobar degeneration 490 Parkinson’s disease 617 quinolinic acid 48, 210–12 raclopride 293 radiofrequency pulse 310 radiologically-inserted gastrostomy, motor neuron dysfunction 755 RAGE ragged red fibers 912 chronic progressive external ophthalmoplegia 910 Kearns–Sayre syndrome 911–12 MELAS syndrome 912 Ramsay Hunt syndrome 705 Rap1 GTP-binding protein 97 raphe nuclei, serotonergic neurons in Parkinson’s disease 582 rapid eye movement sleep, progressive supranuclear palsy 670 rapid eye movement sleep disorder 477, 635 management 479 multiple system atrophy 634–5 Parkinson’s disease 564–5, 582 Ras/MAP-kinase pathway, trk-signaling 96–7 Raynaud’s phenomenon, multiple system atrophy 635 reactive nitrogen species (RNS) 21 reactive oxygen species (ROS) 3, 19, 21, 131 6-OHDA produced 201 amphetamine produced 209 Cockayne’s syndrome 135 complex I inhibition by MPP+ 199 generation 20 glutamate transporter downregulation 62 ischemia–reperfusion injury 110 mitochondrial function impairment 37 mitochondrial production 35–6, 37–8 mitochondrial source 20 neurotoxin-produced 200–4 paraquat-induced 203 transmutation 18 xeroderma pigmentosa 133 reactive species 19 scavenging 25 reciprocal inhibition (RI), agonist/antagonist muscles in Parkinson’s disease 234–5 red blood cells, copper toxicity 899 reflex gaze, progressive supranuclear palsy 670 Refsum’s disease 719, 728–9 diagnosis 701 remacemide 47, 48–9 replication competent adenovirus (RCA) 331 RERE protein 862 restless leg syndrome 713 retinal degeneration ataxia 705, 705 SCA7 714 retinitis pigmentosa neurogenic muscle weakness ataxia and retinitis pigmentosa 913–14 retinoblastoma (Rb) protein 171 retrovirus-derived vectors 335–6 rigidity corticobasal degeneration 688 Huntington’s disease 851–2 Machado–Joseph disease/SCA3 713 multiple system atrophy 631–2 parkinsonism 552–3 parkinsonism–dementia complex of Guam 828 Parkinson’s disease 234–5, 564 progressive supranuclear palsy 669 riluzole 48 amyotrophic lateral sclerosis 50, 98, 186, 316, 756, 774–7 drug combination 782 guidelines for use 776 neuroprotective effect 142 clinical trials 775–6 Cochrane review 776 dosage 777 mechanism of action 775 neuroprotective effects 142 prescribing 776–7 side effects 777 spinal muscular atrophy treatment 784 structure 774 TRAAK activation 143 TREK-1 activation 143 risperidone 277–8 frontotemporal lobar degeneration 490 Parkinson’s disease 617 risus sardonicus 634 rivastigmine 277 Alzheimer’s disease treatment 425, 426, 426, 460 dementia with Lewy bodies treatment 474 Rnq1 yeast prion 114–15 rofecoxib 172 Alzheimer’s disease prevention 465 amyotrophic lateral sclerosis drug combination 782 ropinirole Parkinson’s disease 615–16 sleep disorders 616 977 978 Index rotenone administration route 205 complex I inhibition 39, 567, 602 mitochondrial toxicity 205 Parkinson’s disease 567, 602, 603–4 features 47 model 204–5 Russell mechanism S100 proteins 72 amyotrophic lateral sclerosis 72 saccades autosomal recessive spastic ataxia of Charlevoix–Saguenay 731 corticobasal degeneration 689 oculomotor apraxia 701–2 progressive supranuclear palsy 670 SCA2 712, 713 sago palm, false, Guam ALS/parkinsonism–dementia complex 837–8 salicylate 12 (R)salsolinol 210 SCA1 703, 710, 712 protein interactions 808 SCA1 gene 712 SCA2 703, 710, 712–13 mutations 703–4 saccades 712 SCA2 gene 713 SCA3 703, 710 mutations 703–4 nuclear inclusions 808 see also Machado–Joseph disease/SCA3 SCA4 713 SCA5 714 SCA6 703, 710, 714 disease protein 711, 711 mutations 703–4 SCA7 710, 714 protein interactions 808 SCA7 gene 714 SCA8 711, 714 SCA8 gene 714 SCA10 711, 714–15 SCA10 gene 714–15 SCA11 711–15 SCA12 711, 715 SCA13 gene 715 SCA14 711–12 SCA14 gene 715 SCA15 715 SCA16 715 SCA17 710, 715 SCA18 715 SCA19 715 SCA21 715 schizophreniform disorders, Wilson’s disease 893 Schwann cells motor neuron signaling 95 motor neuron survival 94 scintigraphy, multiple system atrophy 645–6 scrapie 512 secretase(s) Alzheimer’s disease treatment 427 amyloid precursor protein cleavage 181 α-secretase 180–1, 467 stimulators 455 β-secretase 467 Alzheimer’s disease 444 β-amyloid peptide generation 454 inhibition 224 see also BACE gene; BACE1; BACE2 γ-secretase 467 activity 182 β-amyloid peptide generation 454 assays 437 inhibition 224, 455 Alzheimer’s disease treatment 427 presenilin requirement for activity 179 transmembrane protein proteolysis 179 seizures MERFF 913 neurogenic muscle weakness ataxia and retinitis pigmentosa 913–14 SCA10 714–15 selective serotonin reuptake inhibitors (SSRIs) dementia with Lewy bodies 479 frontotemporal lobar degeneration 490 selegiline Alzheimer’s disease 426–7 amyotrophic lateral sclerosis 778 Parkinson’s disease 567, 616–17 selenium deficiency 10 selenium-based scavengers 27 selenomethionine 27 semantic dementia 485, 487 imaging 488 memory 487 neuropsychology 489 senescence, neural/endocrine interactions 402–3 senile plaques see amyloid plaques sensory evoked potentials corticobasal degeneration 692–3 Wilson’s disease 895 D-serine 44 serotonergic neurons 351 serotonin, Parkinson’s disease 562 serotonin transporter, MPP+ affinity 198 SETX gene 762 Index sexual dysfunction, multiple system atrophy 632–3, 641, 648 Shc adapter protein 96–7 binding site in trk-B 97 isoforms 97 Short Test of Mental Status (STMS) 412 Shy–Drager syndrome see multiple system atrophy sildenafil, multiple system atrophy 648 silent period (SP) 233 Silver syndrome 797 simvastatin, Alzheimer’s disease 466–7 single photon emission computed tomography (SPECT) 290 Alzheimer’s disease 421 brain functional imaging 293–6 compounds 290 corticobasal degeneration 688, 692 dementia with Lewy bodies 477 dopamine transporter imaging 290–1 frontotemporal dementia frontal lobe variant 488 Huntington’s disease 305, 308, 312, 313, 320 McLeod syndrome 873–4 multiple system atrophy 294, 644, 645 parkinsonism 558 Parkinson’s disease 294, 568, 644 postsynaptic dopaminergic function 292–4 progressive supranuclear palsy 665 semantic dementia 488 vesicular monoamine transporters 292 Wilson’s disease 898 β-sitosterol β-D-glycoside 838 sleep disorders multiple system atrophy 634–5 Parkinson’s disease 582, 616 progressive supranuclear palsy 670 see also rapid eye movement sleep disorder slow Wallerian degeneration mutant mouse 184 Smac/DIABLO 81, 83 small interfering RNA (siRNA) 711 SMN gene deletions 823 screening 819 SMN protein 823 SMN1 gene 783, 818 conversion events to SMN2 822 deletions 821–2 mutations 821–2 SMN2 gene 783, 818 centrometric copies 822 conversion events from SMN1 822 deletion 822 high number of copies 823, 824–5 smoking, multiple system atrophy 639, 649 SOD1 7, 9, 160–1, 760–1 A4V variant 760 copper chaperone 121 D90A mutation 760, 765 D90V mutation 760–1 discovery 18 E100K variant 760 G93C variant 760 gain-of-function redox reactions 160 gene location 759 genetic studies 764–5 I112T mutation 760–1, 765 inclusion bodies in amyotrophic lateral sclerosis 121 low penetrance variants 760 motor neuron death 786 MPP+ neurotoxicity 199 mutant mice 184–5 mutations 9, 19, 760 amyotrophic lateral sclerosis 28, 49–50, 61, 101, 121, 160, 183, 185–6, 758, 764–5 Guam ALS/parkinsonism–dementia complex 839 motor neuron disease 756 motor neuron selective degeneration 185 phenotype correlation with genotype 760 toxic properties 185 pathogenicity 160–1 copper involvement 161 transgenic mice 773 variants 760 zinc deficient 28, 50 SOD2 9–10, 20 amyotrophic lateral sclerosis 767 nitration by peroxynitrite 24 oxidative injury 24 peroxynitrite target 24 SOD3 10 sodium butyrate, spinal muscular atrophy treatment 783–4 sodium channel blockers 141–2 neuroprotective effects 142 neuroprotective mechanisms 142 types 141 use-dependent 141 sodium channels, voltage-gated 141 block 141 sodium influx into neurons 141–2 sodium valproate, spinal muscular atrophy treatment 784 sodium/calcium exchangers 65 reversal 142 somatosensory evoked potentials (SEPs) dystonia 239 hereditary spastic paraplegia 797 Huntington’s disease 242 sonic hedgehog (SHH) 351, 357 Spartin 799 spasticity autosomal recessive spastic ataxia of Charlevoix–Saguenay 731 hereditary spastic paraplegia 796 spastin protein 798–9 979 980 Index speech impairment corticobasal degeneration 689 Huntington’s disease 852 motor neuron dysfunction 753 multiple system atrophy 633–4 progressive supranuclear palsy 671, 671, 674 Wilson’s disease 892 see also dysarthria; dysphonia; language disturbance speech therapy ataxia 705–6 motor neuron dysfunction 753, 755 SPG3A gene 799 SPG4 gene 798–9 SPG7 gene mutation 799 sphingomyelin, hypobetalipoproteinemia 875 spinal and bulbar muscular atrophy (SBMA) 752, 756, 803–13 androgen ablation 812 insensitivity 804–5 animal models 812 autosomal 762 CAG trinucleotide repeat expansion 785, 805–6 chaperone proteins 812–13 clinical features 785, 803 endocrinology tests 805 female carriers 809 genetic instability 805–6 genetics 805–7 glutamine aggregates 785 heat-shock proteins 812–13 inheritance 803, 805, 809 laboratory tests 805 loss-of-function 807 molecular biology 805–7 motor neuron degeneration molecular basis 808–12 neuropathology 805 nuclear inclusions 808–9 pathology 803–4 polyglutamine CAG repeat expansion 710, 807 neurotoxicity 807–8 prevalence 805 protein misfolding 812–13 spinal muscular atrophy differential diagnosis 821 stem cell therapy 787 therapy development 812–13 transcriptional regulation 812 transgenic mouse model 785 see also androgen receptor (AR) gene spinal cord injury and apoptosis 84–5 ischemia 84 posterior column degeneration in Friedreich’s ataxia 720 progressive supranuclear palsy 671 spinal muscular atrophy 821 spinal muscular atrophy (SMA) 817–25 aclarubicin 784 age of onset 818 animal models 823 classification 817, 818, 819, 823–4 clinical features 817–18 definition 817 diagnosis 819–21 diagnostic criteria 821 differential diagnosis 821 distal 824 epidemiology 817 gabapentin 784 genetics 783, 821–3 high throughput screening 787 management 823 molecular biology 821–3 neurotrophic factors 784–5 non-proximal 824 pathogenesis 783 prognosis 819 proximal 817–23 riluzole 784 severity 822 sodium butyrate 783–4 sodium valproate 784 spinal cord 821 splice enhancers 823 stem cell therapy 787 thyrotropin-releasing hormone 784 transgenic mouse models 783 treatment 783–5 type I 817–18 type II 818 type III 818 type IV 818 spinal reflexes, dystonia 237–8 spin-echo sequence 310–11 spinocerebellar ataxia 266, 712, 711–16 clinical phenotypes 702 genetic tests 702 mutations 702, 702–3 polyglutamine expansion 807 progressive type animal model 114 see also SCAs spinocerebellar ataxia + neuropathy (SCAN1) 719, 730–1 spongiform encephalopathy 512 see also bovine spongiform encephalopathy (BSE) Ssq1 gene 724 Stat-3 95 statins, Alzheimer’s disease 466–7 statistical parametric mapping (SPM) analysis 294 Index stem cell(s) biology 372–4 pluripotent in neurogenesis 390 transplant strategies 348–52 see also embryonic stem cells; neural stem cell(s) stem cell therapy 787 Parkinson’s disease 372–4, 619 rejection 787 stereology 254 sterol β-D-glycosides 838 sticky DNA 721–2 stretch reflex, long-latency 234 striatal progenitor cells, mobilizing 356 striatonigral degeneration see multiple system atrophy striatum amphetamine effects 209 atrophy in parkinsonism 260–3 progressive supranuclear palsy 669 synuclein lesions in Parkinson’s disease 577 see also nigrostriatal dopaminergic pathway stridor multiple system atrophy 648 nocturnal 634 stroke apoptosis 84 caspase-3 84 experimental and excitotoxicity 148 PARP-1 role 148 subependymal progenitor cells 353–4 substance P, multiple system atrophy 626, 627 substantia nigra 227 corticobasal degeneration 686 dopaminergic neuron decline 46 frontotemporal dementia with parkinsonism linked to chromosome 17 500 iron pigment 577 Lewy bodies in Guam ALS/parkinsonism–dementia complex 831 neuromelanin pigmentation loss in Parkinson’s disease 575 neuronal loss 577 Parkinson’s disease 260, 269, 561 iron 600 iron accumulation 577 oxidative stress 598 progressive supranuclear palsy 669 subthalamic nucleus 227 bilateral high-frequency stimulation 649 neurons 235–6 Parkinson’s disease 260 progressive supranuclear palsy 669 succinate malonate effects 206 3-NP effects 206 succinate dehydrogenase 33 inhibition 321 malonate inhibition of succinate binding 205 NAA neuroprotection marker 319 3-NP inhibition of succinate binding 205 sunflower cataracts, Wilson’s disease 894 superoxide 20 activity 18 conversion to hydrogen peroxide 36 Fe(III) reduction to Fe(II) 20–1 mitochondrial production 20 NO reaction 22, 28 reaction with hypochlorite rate 28 SOD relationship 27 steady-state concentration in cells 28 toxicity 20–1 vital stains 12 superoxide anion radical 3–5 autoxidations CYP450 formation 3–4 mitochondria 3–4 prostanoid metabolism RAGE reactions 4–5 superoxide anions, excitotoxicity 148 superoxide dismutases (SOD) 9–10 activity 27–8, 598–9 Friedreich’s ataxia 725 hydrogen peroxide relationship 27, 28 induction in heat shock response 110 NO relationship 27 oxidative damage defense 601 peroxidase activity 28–9 peroxynitrite relationship 27 reverse reaction with hydrogen peroxide 28–9 superoxide relationship 27 superoxide scavenging 22 toxicity in overexpression 28 zinc-deficient 102–3 supranuclear gaze palsy, corticobasal degeneration 689 supranuclear ophthalmoplegia 553 survival motor neuron (SMN) gene amyotrophic lateral sclerosis 766–7 spinal muscular atrophy 821 association 783 survival motor neuron (SMN) protein 95 SVCT2 Na-couple transporter swallowing Huntington’s disease 852 motor neuron dysfunction 753 progressive supranuclear palsy 671, 674 see also dysphagia α-syn gene A53T mutation 187–8 brainstem P2 fraction 187 fragments in Parkinson’s disease 187 981 982 Index α-syn gene (cont.) mutations 186–8 targeted mice 188 α-syn transgenic mice 187–8 synapses aging hippocampal changes 401 integrity change 390 memory impairment 396 non-human primate studies 399–401 estrogen receptor α 403 loss in Alzheimer’s disease 436 remodeling 70–1 synaptic cleft, glutamate molecules 60 synaptic nerve action potentials (SNAPs) 805 synaptophysin 436 immunoreactivity 401 synphilin 591 Lewy bodies 186 synphilin-1 120, 629 synuclein(s) gene mutations 742 parkinsonism 555–6 Parkinson’s disease 580 α-synuclein 119–20 accumulation and chaperones 629 β-sheet configuration 588 calcium binding 602 E46K mutation 474 glial cytoplasmic inclusions in multiple system atrophy 626, 628–9 heat-shock proteins defects 122 effects 120 inclusion bodies 120 Guam ALS/parkinsonism–dementia complex 831 interference with aggregation 613 iron interaction 600 Lewy bodies 149, 186, 454–5, 579–80, 604, 613 multiple system atrophy 628–9 mutations 222 animal models 588–9 cellular models 588–9 Parkinson’s disease 562–3, 586, 588–9, 604 O-glycosylated form 591 parkinsonism 555–6 Parkinson’s disease 916 tau pathology 190 up-regulation by paraquat 203 synucleopathies 563 T cells, ataxia–telangiectasia 743 T8893G mutation 914 tacrine 460 Alzheimer’s disease treatment 425, 426 dementia with Lewy bodies 474, 478–9 TAFII130 864 tamoxifen, amyotrophic lateral sclerosis 778 TATA binding protein gene (TBP) 715 tau gene 497 allelic variant in progressive supranuclear palsy 673 exon 10 splicing 502–3 mutations 189, 222, 454, 496 frontotemporal dementia 494–5 frontotemporal dementia with parkinsonism linked to chromosome 17 495, 501–5 Pick’s disease 484, 485 targeting 189 tau protein 3R/4Rtau ratio 503 abnormal processing 423 abnormalities in altered transport 184 Alzheimer’s disease 423, 453 argyrophilic grain disease 686 banding pattern 502 biology 497–8 cerebrospinal fluid levels 423 corticobasal degeneration 683, 684, 685 H1 haplotype 686, 691 frontotemporal dementia with parkinsonism linked to chromosome 17 501 aggregation formation 504 mutations 501–5 pathology 499, 503 phosphorylation alteration 505 frontotemporal lobar degeneration 489 functions 497–8 glial cell pathology in corticobasal degeneration 684–5 H1 haplotype 686, 691 hypophosphorylated filamentous inclusions 190 isoforms 188–9 corticobasal degeneration 685 progressive supranuclear palsy 672 Lewy bodies 579–80 mild cognitive impairment biomarker 413 mouse endogenous 189 neurofibrillary tangles 435–6 parkinsonism 555 pathway in frontal dementias 223 phosphorylation alteration in frontotemporal dementia with parkinsonism linked to chromosome 17 505 COX-2 171–2 protein kinases 171 Pick bodies 483, 484 Pick’s disease 484–5 pathogenesis 484–5 progressive supranuclear palsy 666–7, 685 H1 haplotype 686, 691 α-synuclein association with pathology 190 tau transgene mutations 222 Index tauopathies 188–90, 484, 494, 685 animal models 505 experimental therapeutics 189–90 geographic clusters 672 inclusions 188 neurofibrillary tangles 453, 454–5 pathogenesis 190 transgenic models 189 tellurium-based scavengers 27 tendon stimulation 237–8 tetracyclines tetrahydrobiopterin 1, 2, 3, 4-tetrahydroisoquinolones (TIQ) 210 tetrodotoxin (TTX) 141 neuroprotective effects 142 thalamotomy, Parkinson’s disease 617 thalamus dystonia pathogenesis 236 gray matter intensity 263 Parkinson’s disease 263 tremor 233–4 thermoregulation amphetamines 209–10 multiple system atrophy 641 thermoregulatory sweat test 641 thiamine, multiple system atrophy 627 thiobarbituric acid 11 oxidative stress 598–9 thiols, hyperactive 27 thioredoxin 11 thioredoxin reductases 11 L-threo-dihydroxy-phenylserine, multiple system atrophy 647 L-threonine 777 thyroid peroxidase thyrotropin-releasing hormone (TRH) 784 TNFA gene in Alzheimer’s disease 448 α-tocopherol see vitamin E α-tocopherol transfer protein (α-TTP) 727 tolcapone 616 tonic vibration reflex 237 topiramate dementia with Lewy bodies 479 Total Functional Capacity (TFC) scale 853 TRAAK activation 143 transcription factors huntingtin 855 neuronal nuclear inclusions 855 transcription-coupled repair 131–2, 133 Cockayne’s syndrome 133–5 deficiency 135 transferrin 880, 882 transferrin receptors 880 transforming growth factor α (TGF-α) compensatory neurogenesis 352 striatal dopaminergic neuron recruitment 356 transglutaminases, progressive supranuclear palsy 673 transition metal ions 6–7 transmembrane protein, γ-secretase proteolysis 179 transmissible spongiform encephalopathy 704 trauma apoptosis 84–5 multiple sclerosis 85 traumatic head injury, NAA/Cr ratio 316 TREK-1 activation 143 tremor essential dopamine transporter binding 291 neurophysiologic tests 230 metabolic substrates 294 multiple system atrophy 631–2 neuroimaging 233–4 palatal 266 Parkinson’s disease 552, 564 progressive supranuclear palsy 669 Wilson’s disease 552, 892, 893 triacylglycerols 875 tricarboxylic acid (TCA) cycle 33 dynamics assay 303 flux 314–15 glucose metabolism 314 glycolysis 35 trichothiodystrophy, defective DNA repair 135 trien, Wilson’s disease 900, 901 triglycerides abetalipoproteinemia 874 hypobetalipoproteinemia 875 trkB receptor 97 Troyer syndrome 797, 799 tumor necrosis factor α (TNF-α) gene in Alzheimer’s disease 448 multiple system atrophy 629 Parkinson’s disease 603 tumor necrosis factor receptor (TNFR1) 81 Parkinson’s disease 614 tyrosine nitration 23 oxidant attack 25 tyrosine phosphatases 23–4 tyrosyl radical 25 tyrosyl-DNA phosphodiesterase (TDP1) gene 731 ubiquinone see coenzyme Q10 ubiquitin 110–11 aggregates in amyotrophic lateral sclerosis 183 Alzheimer’s disease accumulation 121 anomalous form 121, 122–3 conjugation 111 degradation requirement 111 α-synuclein inclusion bodies 120 ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) 120, 589–90 mutations 187, 586 983 984 Index ubiquitin-carrier proteins (E2s) 111 ubiquitin-conjugating enzymes 112 ubiquitin–proteasome pathway 86, 108, 110–11, 916 aging effects 122 ubiquitin-protein ligase (E3) 111 parkin mutations 120 unfolded protein response 109 Unified Huntington’s Disease Rating Scale (UHDRS) 853 upper motor neurons (UMN) 751–2 signs associated with damage 752 urate metabolites 12 urethral sphincter, multiple system atrophy 646 urinary incontinence, progressive supranuclear palsy 671 urinary urgency, hereditary spastic paraplegia 796 L-valine 777 valproate, frontotemporal lobar degeneration 490 vascular dementia treatment 462–3 vascular endothelial growth factors (VEGF) gene 766, 786–7 ventral intermediate nucleus (VIM) 233–4 very low density lipoprotein (VLDL) 727 abetalipoproteinemia 874 hypobetalipoproteinemia 875 vesicular monoamine transporters (VMAT) 199 imaging 292 vestibulo-ocular reflex, progressive supranuclear palsy 670 visual disorders progressive disturbance 424–5 Wilson’s disease 894 vitamin A abetalipoproteinemia treatment 728 deficiency in abetalipoproteinemia 728 vitamin B5 887 vitamin B6 466 vitamin B12 466 deficiency 704 vitamin C Alzheimer’s disease 455, 463 scavenging 25 vitamin E 6, abetalipoproteinemia 874 treatment 728 Alzheimer’s disease 426–7, 455, 463 treatment 426, 463–4 amyotrophic lateral sclerosis treatment 778 ataxia due to isolated vitamin E deficiency treatment 727 chylomicrons 727 Friedreich’s ataxia treatment 726 hypobetalipoproteinemia 875 inherited deficiencies 719 Parkinson’s disease 613 phytol 729 scavenging 25 volumetry 254 voxel-based morphometry 254 Wallerian degeneration 184 SOD1 mutant mice 185 water, well and Parkinson’s disease 567, 602 Wechsler Adult Intelligence Scale (WAIS) 386 Werdnig–Hoffmann disease 817–18 Wernicke’s encephalopathy 704 whispering dysphonia, Wilson’s disease 892 white matter changes with age 390–1 dementia with Lewy bodies 258 degeneration in dentatorubral-pallidoluysian atrophy 861 NAA concentration 307 Wilson’s disease 890–901 aceruloplasminemia differential diagnosis 884–5 affected siblings 897 age of onset 891 ammonium tetrathiomolybdate 900–1 behavioral disorders 893 behavioral manifestations 893 brain lesions 264 brainstem atrophy 895 chelating agents 900 clinical presentation 891–3, 896 cognitive function 893 copper absorption prevention 891 assay of liver 897 availability 882 chelation therapy 896 elimination failure 890 radioisotope copper tracer tests 897 copper deposition 890–1, 899 eye 894 copper urinary excretion 897, 901 siblings 897 creatine phosphokinase 896–7, 899 decoppering therapy 890, 894, 896 depression 893 diagnosis 892, 896–8 dopamine transporter binding 291 epilepsy 893–4 eye copper deposition 894 movement 894 frequency 898 genetics 898–9 hallucinations 893 hepatitis 896 Index Wilson’s disease (cont.) imaging 893, 898 incidence 898 inheritance 898 Kayser–Fleischer rings 893, 894 liver biopsy 897 damage 899 transplantation 891, 900 liver failure 896, 897, 899 treatment 900 metallothioneins 899, 900 mutations 890, 898–9 neurological manifestations 891–3 neuropathology 895–6 neurophysiologic abnormalities 894–5 oculogyric crises 894 parkinsonism 555, 557 pathophysiology 890 penicillamine 900, 901 provocative test 897–8 pregnancy 901 pseudosclerotic clinical phenotype 895 psychiatric disorders 893 siblings 898 urinary copper excretion 897 sunflower cataracts 894 systemic manifestations 891 treatment 891, 900, 900–1 initial 900–1 maintenance 901 pregnancy 901 presymptomatic 901 prophylaxis 901 trien 900, 901 visual disorders 894 zinc therapy 900, 901 maintenance 901 pregnancy 901 Wolman’s disease 875 writer’s cramp 237 corticomotor representation 239 xaliproden, amyotrophic lateral sclerosis 780 xanthine oxidase X-chromosome-linked IAP (XIAP) 83, 84 dopaminergic neurons 374 MPTP model 199–200 xeroderma pigmentosa DNA repair abnormalities 133 nucleotide excision repair defects 133 reactive oxygen species 133 XK gene 874 X-linked inhibitor of apoptosis proteins (XIAP) 101 Parkinson’s disease 86 yohimbine, multiple system atrophy 648 zinc Alzheimer’s disease 158–9, 183 therapeutic target 160, 224 amyloid levels 158 β-amyloid protein binding site affinity 159, 159 precipitation 159 amyotrophic lateral sclerosis 160 Aβ-associated proteins 159 brain levels 158 metabolism 157–8 concentration gradients 157 homeostatic regulation 157 neurotransmission 157 oxidant production sequestration 158 transport 158 Wilson’s disease therapy 900, 901 maintenance 901 pregnancy 901 zinc deficiency hypothesis, amyotrophic lateral sclerosis 28 zinc transporter protein 157 zinc transporter family 158 ZNF231 gene 631 zVAD-fmk 86 985 ... 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... neurologist and psychiatrist, his major interest is in toxicological models of vulnerability and genetic models for the pathogenesis of neurodegenerative diseases Neurodegenerative Diseases Neurobiology, ... 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