Neurodegenerative diseases : neurobiology, pathogenesis, and therapeutics

Neurodegenerative diseases are major contributors to disability and disease, with Alzheimer's and Parkinson's diseases the most prevalent. 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. Cover 1 Half-Title 3 Title 5 Copyright 6 Contents 7 Preface 23 Contributors 11 Part I Basic aspects of neurodegeneration 25 1 Endogenous free radicals and antioxidants in the brain 27 Formation of oxygen free radicals 27 Superoxide anion radical 27 Mitochondria 27 Autoxidations 28 Xanthine oxidase 28 Nitric oxide synthase 28 Prostanoid metabolism 28 CYP450 28 RAGE 28 Reactions of the superoxide radical 28 Hydrogen peroxide 29 Hydroxyl radical 29 Singlet oxygen 29 Lipid peroxidation and vitamin E 30 Transition metal ions 30 Hemoprotein peroxidases and oxidants 31 Low-molecular weight scavengers 31 Endogenous 31 GSH 31 Bilirubin and heme oxygenases 32 Urate 32 Exogenous 32 Ascorbate 32 Flavonoids and other plant antioxidants 32 Antioxidant proteins and enzymes 33 Superoxide dismutases (SOD) 33 Catalase 34 Glutathione peroxidases (GPX) 34 Peroxyredoxins 35 Markers of free radical damage 35 Chemical analysis 35 Cellular and histochemical analyses 36 REFERENCES 36 2 Biological oxidants and therapeutic antioxidants 42 Introduction 42 Why is identification of reactive species and biomolecular targets so difficult? 42 The good, the bad, and the unknown of NO 43 Interminable terminology 43 Common oxidative pathways 44 Mitochondria as primary source of ROS 44 How can superoxide be toxic? 44 Reactive oxygen versus reactive nitrogen species 45 Why does “how” matter? 45 Physical/chemical properties of nitric oxide 45 Nitric oxide does not react directly with thiols 46 Peroxynitrite – the predominant NO-derived oxidant (NODO) 46 Nitrotyrosine as marker of NODOs 47 Other oxidative modifications by peroxynitrite 47 MnSOD is a ubiquitous target of peroxynitrite in vivo 48 Protein nitration in neurodegenerative diseases 48 Scavenging of reactive species: basic concepts 49 Direct-acting vs. indirect-acting scavengers 49 Sacrificial vs. catalytic scavengers 49 Scavengers based on pharmacophores in proteins 50 Metalloporphyrins 51 Selenium- and tellurium-based scavengers 51 Superoxide, NO, H2O2, and peroxynitrite are inextricably intertwined with SODs 51 Why do we need so much SOD activity? 51 More SOD does not mean more H2O2 52 In the presence of NO, SODs can use H2O2 to run in reverse 52 Copper-binding proteins as a generic mechanism of toxicity in neurodegenerative disease 53 ENDNOTES 53 REFERENCES 54 3 Mitochondria, metabolic inhibitors and neurodegeneration 57 Mitochondrial energy production and sites of action for metabolic inhibitors 57 Mitochondrial calcium homeostasis 59 Mitochondrial free radical production 59 Mitochondrial permeability transition 60 Mitochondria and cell death: necrosis 60 Mitochondrial and cell death: apoptosis 62 Mitochondrial inhibition and neurodegeneration 63 Concluding remarks 64 REFERENCES 64 4 Excitotoxicity and excitatory amino acid antagonists in chronic neurodegenerative diseases 68 Introduction 68 NMDA receptors 68 Non-NMDA ionotropic glutamate receptors 69 Metabotropic glutamate receptors 69 The neurotoxin glutamate 69 Slow onset excitotoxicity 70 Excitotoxicity and neurodegenerative diseases 70 Excitotoxicity and Parkinson's disease 70 Huntington's disease 72 Glutamate in Alzheimer's disease 73 Amyotrophic lateral sclerosis 73 Conclusions 74 REFERENCES 75 5 Glutamate transporters 81 Introduction 81 High affinity, Na+-dependent glutamate transporters: localization, functional properties and topology 81 Localization 81 Functional properties 81 Topology 82 Regulation of glutamate transporters 83 Excitatory neurotransmission and glutamate transporters 83 Excitotoxicity and glutamate transporters 84 Neurodegenerative diseases and glutamate transporters 84 Amyotrophic lateral sclerosis (ALS) 84 Alzheimer's disease 85 Huntington's disease 85 Parkinson's disease 86 Ischemia 86 Glutamate transporters and mercury neurotoxicity 86 Concluding remarks 86 REFERENCES 86 6 Calcium binding proteins in selective vulnerability of motor neurons 89 Introduction 89 Increased calcium in motor neurons in ALS 89 Cellular calcium homeostasis and calcium binding proteins 90 Calcium binding proteins in motor neurons 92 AMPA/kainate receptors and selective vulnerability 92 Mechanism of protection of motor neurons by calcium binding proteins: axon terminals 93 Mechanism of protection of motor neurons by calcium binding proteins: cell bodies 94 In vitro transfection study 95 In vivo studies 95 Stress-related changes of CaBPs in motoneurons and glial cells 96 Neuroprotective role of CaBPs in other systems 96 Conclusions: calcium-mediated degeneration of motor neurons 98 Acknowledgements 98 REFERENCES 98 7 Apoptosis in neurodegenerative diseases 104 Introduction 104 Apoptosis 104 Caspases 105 Death receptor, exogenous pathway of apoptosis 105 Mitochondrial, endogenous pathway of apoptosis 105 Evidence for apoptosis and caspase activation in human diseases 107 Studies in animal models 108 Stroke 108 Trauma 108 Multiple sclerosis 109 Huntington's disease 109 Parkinson's disease 109 Amyotrophic lateral sclerosis 112 Caspase inhibition and inflammation 112 Limitations and cautions 112 REFERENCES 113 8 Neurotrophic factors 118 Introduction 118 Developmental motoneuron cell death 118 Neurotrophic factors for motoneurons 119 Identification of cellular signaling pathways responsible for neurotrophic factor mediated survival of motoneurons 120 The role of neuronal activity and glutamate for motoneuron survival 121 An active role of NGF signaling in motoneuron cell death? 122 Downstream signals which mediate the neuronal survival response to neurotrophins and CNTF: the role of members of the IAP family 124 Animal models for human motoneuron disease 125 REFERENCES 127 9 Protein misfolding and cellular defense mechanisms in neurodegenerative diseases 132 Introduction 132 Protective functions of heat shock proteins 134 Selective degradation of abnormal proteins 134 Protein inclusions and aggresome formation 136 Proteasomal hydrolysis of polyQ-containing proteins 139 Protein damage can induce apoptosis 140 Key unresolved issues 141 Neuronal protection by molecular chaperones 143 Abnormal protein inclusions in Parkinson's disease 143 Apoptosis and inclusions in other neurodegenerative diseases 144 Aging, Hsps, and susceptibility to neurodegenerative diseases 145 Acknowledgements 147 REFERENCES 147 10 Neurodegenerative disease and the repair of oxidatively damaged DNA 155 Free radicals and oxidative damage to DNA 155 Maintenance of genome integrity 155 Prevention of incorporation 155 Removal of oxidative lesions from DNA 155 Base excision repair 156 Nucleotide excision repair 157 Transcription coupled repair 157 DNA repair abnormalities and neurological symptoms 157 Xeroderma pigmentosum 157 Cockayne’s syndrome 157 Trichothiodystrophy 159 Repair of mitochondrial DNA damage and neurodegenerative disease 159 Defects in the DNA damage response and neurological symptoms 161 Concluding remarks 161 Acknowledgements 161 REFERENCES 162 11 Compounds acting on ion channels 165 Sodium channel blockers 165 Potassium channel openers 166 Calcum channel antagonists 167 Concluding remarks 168 REFERENCES 168 12 The role of nitric oxide and PARP in neuronal cell death 170 Nitric oxide 170 Poly(ADP-ribose) polymerase-1 170 PARP-1 mediated neurotoxicity is executed by apoptosis inducing factor 171 Excitotoxicity and experimental stroke 172 Parkinson's disease 173 Inflammatory neurodegenerative diseases 173 Inhibitors of nitric oxide synthase 174 PARP inhibitors 174 REFERENCES 176 13 Copper and zinc in Alzheimers disease and amyotrophic lateral sclerosis 181 Introduction 181 Protein interactions in brain copper and zinc metabolism 181 Alzheimer's disease 182 Beta amyloid protein 183 Amyotrophic lateral sclerosis 184 Superoxide dismutase 1 184 Future prospects 185 Acknowledgements 185 REFERENCES 185 14 The role of inflammation in Alzheimers disease neuropathology and clinical dementia. From epidemiology to treatment 190 Inflammation as a function of clinical progression of AD dementia 191 Implications for the potential beneficial role of NSAIDs in cases with MCI 191 AD anti-inflammatory prevention trial (ADAPT) 192 COX: a target for NSAIDs in AD 192 Novel evidence for the beneficial role of NSAIDs in AD neuropathology 193 Hypothesis for the role of COX-2 in ABeta-amyloid plaques 194 Paradoxical role of inflammatory mediators in the brain. Implications for AD dementia 194 The role of COX derived prostaglandin in the cell cycle 195 Cell cycle, COX-2 and AD neuropathology 195 Inflammation and ABeta vaccination therapy in AD 196 Research in progress and outstanding research questions: is there a “better” NSAID for AD? 196 Acknowledgements 197 REFERENCES 197 15 Selected genetically engineered models relevant to human neurodegenerative disease 200 Introduction 200 Alzheimer's disease 200 Clinical features, pathology and genetics 200 Models of ABeta amyloidosis 203 Gene targeting relevant to Alzheimer's disease 204 Alzeimer's disease, a neuronal disease 204 Potential therapeutics for Alzheimer's disease 206 Amyotrophic lateral sclerosis 207 Clinical features, pathology and genetics 207 Other forms of motor neuron degeneration or motor axonopathies have been linked to mutations 208 SOD1 mutant mice 208 Potential therapies for ALS 209 Parkinson's disease 210 Clinical features, pathology and genetics 210 α-syn transgenic mice 211 α-Syn gene targeted mice 212 The tauopathies 212 Clinical features, pathology and genetics 212 Gene targeting of tau 213 Models of tauopathies 213 Experimental therapeutics 213 Conclusions 214 REFERENCES 215 16 Toxic Animal Models 220 Introduction 220 1-Methy-4-phenyl-1,2,3,6-tetrahydropyridine 220 MPTP mode of action 222 MPTP mechanism of action 223 Early events 223 Late events 223 Secondary events 224 Reactive oxygen species-producing neurotoxins 224 6-Hydroxydopamine and related compounds 224 Paraquat 227 Mitochondrial neurotoxins 228 Rotenone 228 Malonate and 3-nitropropionic acid 229 Other ETC mitochondrial toxins 231 Neurotoxic amphetamines 232 Isoquinolines derivatives 234 Glutamate and analogues 234 Acknowledgements 236 REFERENCES 236 17 A genetic outline of the pathways to cell death in Alzheimers disease, Parkinsons disease, frontal dementias and related disorders 246 Gaps in our knowledge 246 First, to what extent do the entities represent single pathogenic processes? 246 Second: what other genes are involved in disease pathogeneses? 247 Third, what are the relationships between the molecules involved in these pathogenic processes? 247 Fourth, what are the toxic species of these pathogenic molecules? 247 Experimental therapies based on the amyloid cascade hypothesis 248 Conclusions 249 REFERENCES 249 18 Neurophysiology of Parkinsons disease, levodopainduced dyskinesias, dystonia, Huntingtons disease and myoclonus 251 Introduction 251 Parkinson's disease (PD) 251 Neurophysiological findings obtained in experimental parkinsonism and in patients undergoing surgery 252 Bradykinesia: EMG, movement studies, sensorimotor integration studies, movement-related potentials, transcranial magnetic stimulation 252 Bradykinesia-: cortical function (reaction times, movement-related potentials, magnetic stimulation) 256 Conclusions on bradykinesia 257 Tremor: neuroimaging and TMS studies 257 Rigidity: spinal and long loop reflexes, spinal inhibitory mechanisms 258 EMG of the external anal sphincter for the differential diagnosis of parkinsonism 259 Levodopa-induced dyskinesias (LIDs) 259 Neurophysiological findings in experimental dyskinesias and during surgery 259 EMG recordings 260 Blinking and brainstem function in patients with LIDs 260 Primary dystonia 260 Neurophysiological findings in experimental dystonia and during surgery 260 EMG recordings 260 Brainstem reflexes 260 Spinal reflexes and spinal inhibitory circuits 261 Movement studies 262 Sensory function and sensorimotor integration 262 Cortical function (LLR, somatosensory evoked potentials, movement-related potentials, magnetic stimulation) 263 Conclusions 264 Huntington's disease (HD) 264 Findings from experimental chorea 264 EMG recordings 264 Brainstem function 265 Spinal cord function 265 Movement studies 265 Sensorimotor integration 265 Cortical function (LLR, SEPs, premotor potentials and TMS) 266 Conclusions 267 Myoclonus 267 REFERENCES 269 Part II Neuroimaging in neurodegeneration 275 19 Structural and functional magnetic resonance imaging in neurodegenerative diseases 277 Introduction 277 Structural MRI in neurodegenerative disorders 277 Structural MRI acquisition and postprocessing techniques 277 Manual segmentation 278 Automated segmentation by analysis of image intensities 278 Automated measurement of volume differences using deformation analysis 278 Diffusion-weighted imaging (DWI) 279 Diffusion tensor imaging (DTI): quantitative analysis of DWI 279 Structural MRI in neurodegenerative diseases 280 Dementias 281 Alzheimer’s disease 281 Dementia with Lewy bodies (DLB) 282 Fronto-temporal dementia (FTD) 283 Huntington’s disease 284 Extrapyramidal disorders 284 Parkinson’s Disease 284 Atypical forms of parkinsonism and their differentiation from PD 284 Disorders of copper, iron and calcium Figs. 19.3(16)) 287 Motor system disorders 287 Ataxias 289 Prion diseases 291 Variant CJD (vCJD) 292 Variant CJD (vCJD) 292 Iatrogenic and familial CJD 294 Functional MRI (fMRI) in neurodegenerative diseases 295 Introduction 295 Does a structurally abnormal area of cerebral tissue activate normally? 295 Can fMRI detect subclinical or preclinical states? 296 Does a cerebral region overactivate during task performance? 296 What is the time scale of the rCBF changes? 296 Are discrete regions functionally related? 296 Method of fMRI 296 Basic principles 296 Exogenous contrast 297 Endogenous contrast 297 Image pre-processing and analysis 297 Presentation of results 299 Pitfalls in fMRI for neurodegenerative disorders 299 Experimental design 299 Inter-subject variability 299 Differing analytical software 300 The brain–vein issue 300 Dementias 300 Alzheimer’s disease 300 Other dementias 301 Extrapyramidal disorders 302 Parkinson’s Disease 302 Other extra-pyramidal syndromes 303 Motor system disorders 304 Ataxias 305 Prion diseases 305 Acknowledgement 305 REFERENCES 305 20 PET/SPECT 314 Introduction 314 Presynaptic dopaminergic function 314 Dopamine transporter imaging 314 Dopa decarboxylase activity 315 Vesicular monoamine transporter 316 Postsynaptic dopaminergic function 316 Functional brain imaging 317 Interventional modulation of brain glucose metabolism in PD 319 Huntington's disease 320 Conclusions 320 Acknowledgements 321 REFERENCES 321 21 Magnetic resonance spectroscopy of neurodegenerative illness 325 Introduction 325 Evaluation of neurochemistry 327 NAA 331 Lactate 332 Glutamate and Aspartate 333 Choline, creatine and myo-Inositol 334 Quantification of proton spectroscopy 334 31P spectroscopy 336 13C NMR spectroscopy 338 Use of MRS in studies of therapeutics in humans 339 Neuroprotection in animal models 341 Combined MRS and MRI of excitotoxicity 344 31P spectroscopy 345 Acknowledgements 345 REFERENCES 345 Part III Therapeutic approaches in neurodegeneration 351 22 Gene therapy 353 Delivery vectors for gene transfer into the nervous system 353 Adenovirus derived vectors 354 Herpes simplex virus (HSV)-derived vectors 356 Adeno-associated virus (AAV) derived vectors 357 Retrovirus derived vectors 359 Examples of therapeutic strategies 360 Parkinson’s disease 361 Mucopolysaccharidosis type VII (MPS-VII) 362 Conclusions 363 REFERENCES 363 23 Stem cells and cellbased therapy in neurodegenerative disease 371 Neural stem cells of the mammalian forebrain 371 Neuronal progenitor cells of the adult brain 372 Stem cell-based transplant strategies in the neurodegenerative diseases 372 Derivation and expansion of implantable human neural stem cells 372 Huntington’s disease as a prototypic target for neural stem cell-based therapy 372 Progenitor cell-mediated restoration of striatal dopamine: Parkinson’s as a disease target 374 Embryonic stem cells as a replenishable source of dopaminergic neurons 374 Stem and progenitor cell-mediated treatment of Alzheimer’s and the cholinergic depletions 375 Neurogenesis from endogenous progenitor cells in the adult brain 376 Compensatory neurogenesis as a predictor of inducible neuronal replacement 376 Forebrain progenitor cells can be induced to expand and generate neurons in vivo 377 Intraventricular viral expression vectors can target subependymal progenitor cells 377 BDNF overexpression induces heterotopic neuronal recruitment to the adult neostriatum 378 Induced neurogenesis may be a therapeutic strategy in animal models of Huntington’s disease 379 Synergistic strategies for inducing striatal neurogenesis from endogenous progenitor cells 379 Additional strategies for mobilizing striatal progenitor cells 380 Beyond the VZ: induction of non-striatal progenitor cell pools 380 Induction of resident progenitors as a means of restoring dopaminergic input to the striatum 380 Progenitor stimulation as a restorative strategy for the hippocampal atrophies 381 Conclusions 382 Acknowledgements 382 REFERENCES 382 24 Necessary methodological and stem cell advances for restoration of the dopaminergic system in Parkinson’s disease patients 387 Introduction 387 It is necessary to obtain structural reconstitution of terminal synaptic function and regulated dopamine release by new dopamine neurons 388 Technical developments of a new technology for regeneration of neural function and pathways in patients 392 Subpopulations of midbrain dopaminergic neurons perform different functions and reach different targets: its potential relevance to repair of PD brains 393 Evidence that tissue type, surgical cell preparation or specific surviving dopaminergic neuronal phenotype influence the degree of functional recovery 394 Can we produce better therapies with fewer sideeffects by accomplishing a more specific cellular and synaptic dopamine replacement? 394 Generation of a stem cell derived therapy for Parkinson's disease 396 How can stem cell biology research help Parkinson patients? 396 Acknowledgements 398 REFERENCES 398 Part IV Normal aging 405 25 Clinical aspects of normal aging 407 Overview 407 Epidemiologic aspects of aging 407 Changes in cognitive function with age 408 Memory 408 Memory in humans 408 Memory in non-human primates 409 Memory in rodents 409 Executive function 410 Executive function in humans 410 Executive function in monkeys 410 Imaging studies of age-related changes in cognition 410 Changes in motor function with age 412 Underlying neural mechanisms that contribute to age-related changes in cognitive and physical function 413 Neuronal number 413 Neuronal loss and neurotransmitter changes 413 Synaptic integrity 414 Neuronal proliferation in the adult brain 414 White matter changes 414 Implications for clinical evaluation of older persons 415 REFERENCES 415 26 Neuropathology of normal aging in cerebral cortex 420 Introduction 420 Selective vulnerability in Alzheimer's disease 420 Overview 420 Hippocampal pathology in AD 420 Neocortical pathology in AD 421 Lesion types and cortical distribution 421 Neurofilament protein is a marker of neuronal vulnerability in Alzheimer’s disease 422 Summary: AD and cortical circuitry 422 Age-associated memory impairment: functional decline without neuron loss 423 The aging synapse: non-human primate studies 423 Age-related changes in rat hippocampus 425 Interactions between neural and endocrine senescence 426 Conclusions and future directions 427 Acknowledgements 428 REFERENCES 428 Part V Alzheimer's disease 431 27 Mild cognitive impairment 433 Overview 433 Normal aging and evolution to MCI 433 Clinical description 434 Heterogeneity of MCI 435 Approach to the diagnosis of MCI 435 History and examination 435 Laboratory tests 436 Neuropsychometric test 436 Neuroimaging 436 Biomarkers 436 Neuropathology 437 Genetics and predictors of progression 437 Clinical trials 437 AAN practice parameters 437 Future directions 438 REFERENCES 438 28 Alzheimer’s disease – overview 440 Dementia 440 First description/historical overview 440 Epidemiology 441 Risk factors for Alzheimer's disease 441 Clinical features 441 Clinical diagnosis 442 Clinical criteria of Alzheimer's disease 442 History, bedside mental status examination, neurological examination 442 Laboratory evaluation 443 Spinal fluid examination 444 Other testing 444 Neuroimaging 444 Neuropsychological testing 445 Pathogenesis/mechanisms of disease 445 Biomarkers 447 CSF ABeta and tau 447 Amyloid precursor protein isoforms in platelets 447 Neuronal thread protein (NTP) 448 AAN guidelines on biomarkers 448 Clinical variants of Alzheimer's disease 448 Progressive aphasia 448 Progressive visual disturbance 448 Progressive apraxic syndrome 449 Treatments of Alzheimer's disease 449 Symptomatic treatment: acetylcholinesterase inhibitors 449 Disease modifying 450 Selegiline and alpha-tocopherol (vitamin E) 450 Memantine 451 Secretases and immunotherapy 451 Conclusions 452 REFERENCES 452 29 The neuropathology of Alzheimer's disease in the year 2005 457 Introduction 457 The ABeta theory of Alzheimer’s disease and the problem of selective vulnerability 457 The basic neuropathology of Alzheimer's disease 458 Macroscopic changes 458 Classical histological changes ABeta amyloid plaques 458 Tau-related neurofibrillary tangles (NFT) 459 Granulovacuolar degeneration (GVD) and Hirano bodies 460 Neuronal and synaptic loss 460 Astrocytic and microglial changes 460 The morphometric approach to the neuropathology of AD 460 The clinical biochemistry of ABeta in AD 460 The place of genetic diagnostics in the neuropathology of AD 461 Neuroimaging of ABeta 461 REFERENCES 461 30 Genetics of Alzheimer's disease 465 Introduction 465 Early-onset Alzheimer's disease 465 Late-onset Alzheimer's disease 468 The APOE locus on chromosome 19 468 Chromosome 12 469 Chromosome 10 471 Findings on other chromosomes 472 Conclusions 472 REFERENCES 473 31 The role of Beta-amyloid in Alzheimer’s disease 476 Introduction 476 Beta-amyloid plaques are major histophathological hallmarks of Alzheimer’s disease 476 Neurofibrillary tangles 477 Beta-amyloid-related toxicity causes the formation of neurofibrillary tangles 477 Genetic evidence links ß-amyloid formation to familial Alzheimer’s disease 478 ABetapeptides are generated by s-and γ-secretases that function in APP signalling 478 Aggregation of soluble ABeta into insoluble Beta-amyloid fibrils 478 Imaging of Beta-amyloid in living people 479 Beta-Amyloid is a therapeutic target for the treatment and prevention of AD 479 Immunization against Beta-amyloid 479 Other treatments of Alzheimer's disease 480 Acknowledgements 480 REFERENCES 480 32 Treatment of Alzheimer's disease 483 Overview 483 Introduction 483 Treatment with agents approved for Alzheimer's disease 484 Cholinergic stimulation 484 Tacrine 484 Donepezil 484 Rivastigmine 484 Galantamine 484 Quality of life and economic benefit of cholinesterase inhibitors 485 Glutamate and the NMDA receptor 486 Memantine 486 Treatment of vascular and mixed dementia with agents approved for AD 486 Other pharmacologic approaches to treating AD 487 Anti-oxidants 487 Vitamin E 487 Gingko biloba 488 Anti-inflammatory agents 488 Lowering homocysteine 489 Lowering lipids 490 Theoretical approaches based on attacking amyloid 491 Conclusions: the challenge of managing a neurodegenerative disease 491 Acknowledgement 492 REFERENCES 492 Part VI Other dementias 495 33 Dementia with Lewy bodies 497 Introduction 497 Pathogenesis and heritability 498 Neuropathology 499 Clinical characterization 499 Laboratory evaluations and brain imaging 501 Management 502 Conclusions 503 REFERENCES 503 34 Frontotemporal lobar degeneration 505 Introduction 505 First description and history of FTLD 505 Gross morphological pattern of vulnerability 507 Biochemical findings (microscopic pattern of vulnerability) 507 Pick's disease 507 Corticobasal ganglionic degeneration (CBD; see also Chapter 45) 507 Demential lacking distinctive histopathology (DLDH) 508 Frontotemporal dementia with motor neuron disease (FTD-MND) 508 Molecular biology 508 The role of tau protein in FTLD pathogenesis 508 Pathogenesis/mechanisms of disease (animal models) 509 Clinical picture 509 Core clinical characteristics of FTLD 509 FTLD clinical syndromes 509 Clinical presentation and differentiation from AD 510 Clinical variants 510 Time course of the disease 511 Epidemiology 511 Investigations 512 Imaging 512 Neuropsychology 513 Semantic dementia (SD) 513 Progressive non-fluent aphasia (PNFA) 513 Genetics 513 Treatment 514 Acknowledgements 514 REFERENCES 514 35 Frontotemporal dementia with parkinsonism linked to chromosome 17 518 Introduction 518 Familial frontotemporal dementia 518 Frontotemporal dementia with parkinsonism linked to chromosome 17 520 Biology of the tau protein 521 Clinical features of FTDP-17 522 Neuropathology of FTDP-17 524 Effects of FTDP-17 mutations 525 Animal models of FTDP-17 529 Conclusions 529 Acknowledgements 530 REFERENCES 530 36 PRION DISEASES 536 I The clinical approach to human prion diseases 536 Introduction 536 Epidemiology 536 Transmissibility and neuropathology 537 Clinical diagnostic features 537 Sporadic CJD 537 Clinical variants 538 Late symptomatology, course of the disease 538 Diagnostic procedures 538 EEG (Fig. 36.2) 539 Magnetic resonance imaging (MRI) 540 Cerebrospinal fluid (CSF) analysis 540 Genetic CJD (gCJD) 540 GSS 541 vCJD 541 Epidemiology 541 Course of the disease – late stages 542 Relation to BSE 542 Diagnostic procedures (MRI, tonsil biopsy, neuropathology) 542 Kuru 542 Differential diagnosis (Table) 543 Therapeutic aspects 543 Symptomatic treatment 543 Disease-specific treatment, anti-prion approach 544 REFERENCES 544 II The pathogenesis and mechanisms of prion diseases 547 Introduction 547 Prion biology: some basic facts 547 Stanley Prusiner's protein-only hypothesis 548 Some major open questions in prion biology 548 Brain damage in prion diseases 549 Peripheral entry sites of prions 549 The pathway of orally administered prions 550 Oral prion susceptibility correlates with number but not structure of Peyer's patches 550 Diagnosis of prion disease: identification of the infectious agent 551 Transepithelial enteric passage of prions: a role for Mcells? 551 Lymphocytes and prion pathogenesis 552 Straining the lymphocytes 553 Prion hideouts in lymphoid organs 553 Neuroinvasion proper: the role of sympathetic nerves 556 Spread of prions within the central nervous system 558 Innate immunity and antiprion defense 558 Macrophages and toll-like receptors 558 The role of the complement system 559 Adaptive immunity and pre-exposure prophylaxis against prions 559 Prion immunization and its reduction to practice 560 The prion doppelganger 561 Phenotypes of Prnp deficient mice: a paradox resolved 562 Consequences of Doppel deficiency: a detour to reproductive pathology 562 Perspectives in prion therapy 565 A prion glossary 565 Acknowledgments 565 REFERENCES 565 Part VII Parkinson's and related movement disorders 573 37 Approach to the patient presenting with parkinsonism 575 General symptomatology of patients with parkinsonism 575 Clinical signs constituting the syndrome of parkinsonism 576 Other signs to evaluate 577 Differential diagnosis of parkinsonism 578 The epidemiology of the differential forms of parkinsonism 578 Anatomy, physiology and biochemistry as they apply to the clinical signs of parkinsonism 579 Clinical approach to the investigation of parkinsonism 581 REFERENCES 582 38 Parkinson's disease 585 Historical background 585 Morphological patterns of vulnerability (pathology) 585 Biochemical patterns of vulnerability (neurochemistry) 585 Concepts regarding etiology 586 Cardinal motor features 588 Other clinical features 588 Subtypes of Parkinson's disease 589 Time course of the disease 590 Epidemiology 591 Neuroimaging 591 Future perspectives 592 REFERENCES 592 39 Neuropathology of Parkinson's disease 599 Introduction 599 Pathology of PD 599 Lewy bodies (LBs) and Lewy neurites (LNs) 601 Composition of LBs 602 Biochemical changes in synuclein in PD 604 What is the earliest pathology in PD? 604 Other pathology in PD 605 Clinicopathologic correlations in PD 606 Acknowledgements 607 REFERENCES 607 40 Genetics of parkinsonism 610 Overview 610 Introduction and historical background 610 Monogenic forms of Parkinson's disease 611 Autosomal dominant parkinsonism 612 PARK1: Parkinson’s disease caused by mutations in the gene for Alpha-synuclein (PARK1) 612 Cellular and animal models 612 PARK3: Parkinson's disease linked to chromosome 2 613 PARK4: Parkinsonism-dementia caused by α-synuclein triplication 613 PARK5: Parkinsonism associated with a mutation in the gene for ubiquitin hydrolase L1 613 PARK8, PARK10 614 Autosomal-recessive forms of parkinsonism 614 PARK2: autosomal recessive juvenile parkinsonism (AR-JP) caused by mutations in the gene for parkin 614 Recessive early-onset parkinsonism linked to chromosome 1 (PARK6 and PARK7) 615 Non-monogenic forms of familial PD 615 Genetic contribution to sporadic PD 617 Conclusions 617 REFERENCES 617 41 Pathophysiology: biochemistry of Parkinsons disease 622 Oxidative stress 622 Factors contributing to the generation of oxidative stress 623 Dopamine 623 Iron 624 Neuromelanin 624 Nitric oxide 625 Factors diminishing oxidative stress 625 Factors diminishing oxidative stress 625 Mitochondrial dysfunction 625 Calcium homeostasis and excitotoxicity 626 Exotoxins 626 Glial cells and inflammation 627 Apoptosis 627 Lewy bodies and protein aggregation 628 REFERENCES 629 42 Current and potential treatments of Parkinson's disease 636 Slowing or stopping the progression of PD 636 Mitochondrial dysfunction 636 Oxidative stress 637 Impaired protein degradation 637 Protein aggregation 6 Cover......Page 1 Half-Title......Page 3 Title......Page 5 Copyright......Page 6 Contents......Page 7 Preface......Page 23 Contributors......Page 11 Part I Basic aspects of neurodegeneration......Page 25 Mitochondria......Page 27 Reactions of the superoxide radical......Page 28 Singlet oxygen......Page 29 Transition metal ions......Page 30 GSH......Page 31 Flavonoids and other plant antioxidants......Page 32 Superoxide dismutases (SOD)......Page 33 Glutathione peroxidases (GPX)......Page 34 Chemical analysis......Page 35 REFERENCES......Page 36 Why is identification of reactive species and biomolecular targets so difficult?......Page 42 Interminable terminology......Page 43 How can superoxide be toxic?......Page 44 Physical/chemical properties of nitric oxide......Page 45 Peroxynitrite – the predominant NO-derived oxidant (NODO)......Page 46 Other oxidative modifications by peroxynitrite......Page 47 Protein nitration in neurodegenerative diseases......Page 48 Sacrificial vs. catalytic scavengers......Page 49 Scavengers based on pharmacophores in proteins......Page 50 Why do we need so much SOD activity?......Page 51 In the presence of NO, SODs can use H2O2 to run in reverse......Page 52 ENDNOTES......Page 53 REFERENCES......Page 54 Mitochondrial energy production and sites of action for metabolic inhibitors......Page 57 Mitochondrial free radical production......Page 59 Mitochondria and cell death: necrosis......Page 60 Mitochondrial and cell death: apoptosis......Page 62 Mitochondrial inhibition and neurodegeneration......Page 63 REFERENCES......Page 64 NMDA receptors......Page 68 The neurotoxin glutamate......Page 69 Excitotoxicity and Parkinson's disease......Page 70 Huntington's disease......Page 72 Amyotrophic lateral sclerosis......Page 73 Conclusions......Page 74 REFERENCES......Page 75 Functional properties......Page 81 Topology......Page 82 Excitatory neurotransmission and glutamate transporters......Page 83 Amyotrophic lateral sclerosis (ALS)......Page 84 Huntington's disease......Page 85 REFERENCES......Page 86 Increased calcium in motor neurons in ALS......Page 89 Cellular calcium homeostasis and calcium binding proteins......Page 90 AMPA/kainate receptors and selective vulnerability......Page 92 Mechanism of protection of motor neurons by calcium binding proteins: axon terminals......Page 93 Mechanism of protection of motor neurons by calcium binding proteins: cell bodies......Page 94 In vivo studies......Page 95 Neuroprotective role of CaBPs in other systems......Page 96 REFERENCES......Page 98 Apoptosis......Page 104 Mitochondrial, endogenous pathway of apoptosis......Page 105 Evidence for apoptosis and caspase activation in human diseases......Page 107 Trauma......Page 108 Parkinson's disease......Page 109 Limitations and cautions......Page 112 REFERENCES......Page 113 Developmental motoneuron cell death......Page 118 Neurotrophic factors for motoneurons......Page 119 Identification of cellular signaling pathways responsible for neurotrophic factor mediated survival of motoneurons......Page 120 The role of neuronal activity and glutamate for motoneuron survival......Page 121 An active role of NGF signaling in motoneuron cell death?......Page 122 Downstream signals which mediate the neuronal survival response to neurotrophins and CNTF: the role of members of the IAP family......Page 124 Animal models for human motoneuron disease......Page 125 REFERENCES......Page 127 Introduction......Page 132 Selective degradation of abnormal proteins......Page 134 Protein inclusions and aggresome formation......Page 136 Proteasomal hydrolysis of polyQ-containing proteins......Page 139 Protein damage can induce apoptosis......Page 140 Key unresolved issues......Page 141 Abnormal protein inclusions in Parkinson's disease......Page 143 Apoptosis and inclusions in other neurodegenerative diseases......Page 144 Aging, Hsps, and susceptibility to neurodegenerative diseases......Page 145 REFERENCES......Page 147 Removal of oxidative lesions from DNA......Page 155 Base excision repair......Page 156 Cockayne’s syndrome......Page 157 Repair of mitochondrial DNA damage and neurodegenerative disease......Page 159 Acknowledgements......Page 161 REFERENCES......Page 162 Sodium channel blockers......Page 165 Potassium channel openers......Page 166 Calcum channel antagonists......Page 167 REFERENCES......Page 168 Poly(ADP-ribose) polymerase-1......Page 170 PARP-1 mediated neurotoxicity is executed by apoptosis inducing factor......Page 171 Excitotoxicity and experimental stroke......Page 172 Inflammatory neurodegenerative diseases......Page 173 PARP inhibitors......Page 174 REFERENCES......Page 176 Protein interactions in brain copper and zinc metabolism......Page 181 Alzheimer's disease......Page 182 Beta amyloid protein......Page 183 Superoxide dismutase 1......Page 184 REFERENCES......Page 185 14 The role of inflammation in Alzheimers disease neuropathology and clinical dementia. From epidemiology to treatment......Page 190 Implications for the potential beneficial role of NSAIDs in cases with MCI......Page 191 COX: a target for NSAIDs in AD......Page 192 Novel evidence for the beneficial role of NSAIDs in AD neuropathology......Page 193 Paradoxical role of inflammatory mediators in the brain. Implications for AD dementia......Page 194 Cell cycle, COX-2 and AD neuropathology......Page 195 Research in progress and outstanding research questions: is there a “better” NSAID for AD?......Page 196 REFERENCES......Page 197 Clinical features, pathology and genetics......Page 200 Models of ABeta amyloidosis......Page 203 Alzeimer's disease, a neuronal disease......Page 204 Potential therapeutics for Alzheimer's disease......Page 206 Clinical features, pathology and genetics......Page 207 SOD1 mutant mice......Page 208 Potential therapies for ALS......Page 209 Clinical features, pathology and genetics......Page 210 α-syn transgenic mice......Page 211 Clinical features, pathology and genetics......Page 212 Experimental therapeutics......Page 213 Conclusions......Page 214 REFERENCES......Page 215 1-Methy-4-phenyl-1,2,3,6-tetrahydropyridine......Page 220 MPTP mode of action......Page 222 Late events......Page 223 6-Hydroxydopamine and related compounds......Page 224 Paraquat......Page 227 Rotenone......Page 228 Malonate and 3-nitropropionic acid......Page 229 Other ETC mitochondrial toxins......Page 231 Neurotoxic amphetamines......Page 232 Glutamate and analogues......Page 234 REFERENCES......Page 236 First, to what extent do the entities represent single pathogenic processes?......Page 246 Fourth, what are the toxic species of these pathogenic molecules?......Page 247 Experimental therapies based on the amyloid cascade hypothesis......Page 248 REFERENCES......Page 249 Parkinson's disease (PD)......Page 251 Bradykinesia: EMG, movement studies, sensorimotor integration studies, movement-related potentials, transcranial magnetic stimulation......Page 252 Bradykinesia-: cortical function (reaction times, movement-related potentials, magnetic stimulation)......Page 256 Tremor: neuroimaging and TMS studies......Page 257 Rigidity: spinal and long loop reflexes, spinal inhibitory mechanisms......Page 258 Neurophysiological findings in experimental dyskinesias and during surgery......Page 259 Brainstem reflexes......Page 260 Spinal reflexes and spinal inhibitory circuits......Page 261 Sensory function and sensorimotor integration......Page 262 Cortical function (LLR, somatosensory evoked potentials, movement-related potentials, magnetic stimulation)......Page 263 EMG recordings......Page 264 Sensorimotor integration......Page 265 Cortical function (LLR, SEPs, premotor potentials and TMS)......Page 266 Myoclonus......Page 267 REFERENCES......Page 269 Part II Neuroimaging in neurodegeneration......Page 275 Structural MRI acquisition and postprocessing techniques......Page 277 Automated measurement of volume differences using deformation analysis......Page 278 Diffusion tensor imaging (DTI): quantitative analysis of DWI......Page 279 Structural MRI in neurodegenerative diseases......Page 280 Alzheimer’s disease......Page 281 Dementia with Lewy bodies (DLB)......Page 282 Fronto-temporal dementia (FTD)......Page 283 Atypical forms of parkinsonism and their differentiation from PD......Page 284 Motor system disorders......Page 287 Ataxias......Page 289 Prion diseases......Page 291 Variant CJD (vCJD)......Page 292 Iatrogenic and familial CJD......Page 294 Does a structurally abnormal area of cerebral tissue activate normally?......Page 295 Basic principles......Page 296 Image pre-processing and analysis......Page 297 Inter-subject variability......Page 299 Alzheimer’s disease......Page 300 Other dementias......Page 301 Parkinson’s Disease......Page 302 Other extra-pyramidal syndromes......Page 303 Motor system disorders......Page 304 REFERENCES......Page 305 Dopamine transporter imaging......Page 314 Dopa decarboxylase activity......Page 315 Postsynaptic dopaminergic function......Page 316 Functional brain imaging......Page 317 Interventional modulation of brain glucose metabolism in PD......Page 319 Conclusions......Page 320 REFERENCES......Page 321 Introduction......Page 325 Evaluation of neurochemistry......Page 327 NAA......Page 331 Lactate......Page 332 Glutamate and Aspartate......Page 333 Quantification of proton spectroscopy......Page 334 31P spectroscopy......Page 336 13C NMR spectroscopy......Page 338 Use of MRS in studies of therapeutics in humans......Page 339 Neuroprotection in animal models......Page 341 Combined MRS and MRI of excitotoxicity......Page 344 REFERENCES......Page 345 Part III Therapeutic approaches in neurodegeneration......Page 351 Delivery vectors for gene transfer into the nervous system......Page 353 Adenovirus derived vectors......Page 354 Herpes simplex virus (HSV)-derived vectors......Page 356 Adeno-associated virus (AAV) derived vectors......Page 357 Retrovirus derived vectors......Page 359 Examples of therapeutic strategies......Page 360 Parkinson’s disease......Page 361 Mucopolysaccharidosis type VII (MPS-VII)......Page 362 REFERENCES......Page 363 Neural stem cells of the mammalian forebrain......Page 371 Huntington’s disease as a prototypic target for neural stem cell-based therapy......Page 372 Embryonic stem cells as a replenishable source of dopaminergic neurons......Page 374 Stem and progenitor cell-mediated treatment of Alzheimer’s and the cholinergic depletions......Page 375 Compensatory neurogenesis as a predictor of inducible neuronal replacement......Page 376 Intraventricular viral expression vectors can target subependymal progenitor cells......Page 377 BDNF overexpression induces heterotopic neuronal recruitment to the adult neostriatum......Page 378 Synergistic strategies for inducing striatal neurogenesis from endogenous progenitor cells......Page 379 Induction of resident progenitors as a means of restoring dopaminergic input to the striatum......Page 380 Progenitor stimulation as a restorative strategy for the hippocampal atrophies......Page 381 REFERENCES......Page 382 Introduction......Page 387 It is necessary to obtain structural reconstitution of terminal synaptic function and regulated dopamine release by new dopamine neurons......Page 388 Technical developments of a new technology for regeneration of neural function and pathways in patients......Page 392 Subpopulations of midbrain dopaminergic neurons perform different functions and reach different targets: its potential relevance to repair of PD brains......Page 393 Can we produce better therapies with fewer sideeffects by accomplishing a more specific cellular and synaptic dopamine replacement?......Page 394 How can stem cell biology research help Parkinson patients?......Page 396 REFERENCES......Page 398 Part IV Normal aging......Page 405 Epidemiologic aspects of aging......Page 407 Memory in humans......Page 408 Memory in rodents......Page 409 Imaging studies of age-related changes in cognition......Page 410 Changes in motor function with age......Page 412 Neuronal loss and neurotransmitter changes......Page 413 White matter changes......Page 414 REFERENCES......Page 415 Hippocampal pathology in AD......Page 420 Lesion types and cortical distribution......Page 421 Summary: AD and cortical circuitry......Page 422 The aging synapse: non-human primate studies......Page 423 Age-related changes in rat hippocampus......Page 425 Interactions between neural and endocrine senescence......Page 426 Conclusions and future directions......Page 427 REFERENCES......Page 428 Part V Alzheimer's disease......Page 431 Normal aging and evolution to MCI......Page 433 Clinical description......Page 434 History and examination......Page 435 Biomarkers......Page 436 AAN practice parameters......Page 437 REFERENCES......Page 438 First description/historical overview......Page 440 Clinical features......Page 441 History, bedside mental status examination, neurological examination......Page 442 Laboratory evaluation......Page 443 Neuroimaging......Page 444 Pathogenesis/mechanisms of disease......Page 445 Amyloid precursor protein isoforms in platelets......Page 447 Progressive visual disturbance......Page 448 Symptomatic treatment: acetylcholinesterase inhibitors......Page 449 Selegiline and alpha-tocopherol (vitamin E)......Page 450 Secretases and immunotherapy......Page 451 REFERENCES......Page 452 The ABeta theory of Alzheimer’s disease and the problem of selective vulnerability......Page 457 Classical histological changes ABeta amyloid plaques......Page 458 Tau-related neurofibrillary tangles (NFT)......Page 459 The clinical biochemistry of ABeta in AD......Page 460 REFERENCES......Page 461 Early-onset Alzheimer's disease......Page 465 The APOE locus on chromosome 19......Page 468 Chromosome 12......Page 469 Chromosome 10......Page 471 Conclusions......Page 472 REFERENCES......Page 473 Beta-amyloid plaques are major histophathological hallmarks of Alzheimer’s disease......Page 476 Beta-amyloid-related toxicity causes the formation of neurofibrillary tangles......Page 477 Aggregation of soluble ABeta into insoluble Beta-amyloid fibrils......Page 478 Immunization against Beta-amyloid......Page 479 REFERENCES......Page 480 Introduction......Page 483 Galantamine......Page 484 Quality of life and economic benefit of cholinesterase inhibitors......Page 485 Treatment of vascular and mixed dementia with agents approved for AD......Page 486 Vitamin E......Page 487 Anti-inflammatory agents......Page 488 Lowering homocysteine......Page 489 Lowering lipids......Page 490 Conclusions: the challenge of managing a neurodegenerative disease......Page 491 REFERENCES......Page 492 Part VI Other dementias......Page 495 Introduction......Page 497 Pathogenesis and heritability......Page 498 Clinical characterization......Page 499 Laboratory evaluations and brain imaging......Page 501 Management......Page 502 REFERENCES......Page 503 First description and history of FTLD......Page 505 Corticobasal ganglionic degeneration (CBD; see also Chapter 45)......Page 507 The role of tau protein in FTLD pathogenesis......Page 508 FTLD clinical syndromes......Page 509 Clinical variants......Page 510 Epidemiology......Page 511 Imaging......Page 512 Genetics......Page 513 REFERENCES......Page 514 Familial frontotemporal dementia......Page 518 Frontotemporal dementia with parkinsonism linked to chromosome 17......Page 520 Biology of the tau protein......Page 521 Clinical features of FTDP-17......Page 522 Neuropathology of FTDP-17......Page 524 Effects of FTDP-17 mutations......Page 525 Conclusions......Page 529 REFERENCES......Page 530 Epidemiology......Page 536 Sporadic CJD......Page 537 Diagnostic procedures......Page 538 EEG (Fig. 36.2)......Page 539 Genetic CJD (gCJD)......Page 540 Epidemiology......Page 541 Kuru......Page 542 Symptomatic treatment......Page 543 REFERENCES......Page 544 Prion biology: some basic facts......Page 547 Some major open questions in prion biology......Page 548 Peripheral entry sites of prions......Page 549 Oral prion susceptibility correlates with number but not structure of Peyer's patches......Page 550 Transepithelial enteric passage of prions: a role for Mcells?......Page 551 Lymphocytes and prion pathogenesis......Page 552 Prion hideouts in lymphoid organs......Page 553 Neuroinvasion proper: the role of sympathetic nerves......Page 556 Macrophages and toll-like receptors......Page 558 Adaptive immunity and pre-exposure prophylaxis against prions......Page 559 Prion immunization and its reduction to practice......Page 560 The prion doppelganger......Page 561 Consequences of Doppel deficiency: a detour to reproductive pathology......Page 562 REFERENCES......Page 565 Part VII Parkinson's and related movement disorders......Page 573 General symptomatology of patients with parkinsonism......Page 575 Clinical signs constituting the syndrome of parkinsonism......Page 576 Other signs to evaluate......Page 577 The epidemiology of the differential forms of parkinsonism......Page 578 Anatomy, physiology and biochemistry as they apply to the clinical signs of parkinsonism......Page 579 Clinical approach to the investigation of parkinsonism......Page 581 REFERENCES......Page 582 Biochemical patterns of vulnerability (neurochemistry)......Page 585 Concepts regarding etiology......Page 586 Other clinical features......Page 588 Subtypes of Parkinson's disease......Page 589 Time course of the disease......Page 590 Neuroimaging......Page 591 REFERENCES......Page 592 Pathology of PD......Page 599 Lewy bodies (LBs) and Lewy neurites (LNs)......Page 601 Composition of LBs......Page 602 What is the earliest pathology in PD?......Page 604 Other pathology in PD......Page 605 Clinicopathologic correlations in PD......Page 606 REFERENCES......Page 607 Introduction and historical background......Page 610 Monogenic forms of Parkinson's disease......Page 611 Cellular and animal models......Page 612 PARK5: Parkinsonism associated with a mutation in the gene for ubiquitin hydrolase L1......Page 613 PARK2: autosomal recessive juvenile parkinsonism (AR-JP) caused by mutations in the gene for parkin......Page 614 Non-monogenic forms of familial PD......Page 615 REFERENCES......Page 617 Oxidative stress......Page 622 Dopamine......Page 623 Neuromelanin......Page 624 Mitochondrial dysfunction......Page 625 Exotoxins......Page 626 Apoptosis......Page 627 Lewy bodies and protein aggregation......Page 628 REFERENCES......Page 629 Mitochondrial dysfunction......Page 636 Inflammation......Page 637 Levodopa......Page 638 Dopaminergic agonists......Page 639 Monoamine oxidase B (MAO-B) inhibitors......Page 640 Intervention in the malfunctioning circuitry......Page 641 Regeneration......Page 642 REFERENCES......Page 643 Historical review......Page 647 Morphological pattern of vulnerability......Page 648 Biochemical findings......Page 650 Molecular biology......Page 652 Pathogenesis/mechanism of disease......Page 653 Parkinsonism......Page 655 Dysautonomia......Page 656 Other clinical features......Page 657 Clinical variants and their frequency......Page 659 Time course of the disease......Page 661 Prognosis......Page 662 Cardiovascular function......Page 663 Bladder function......Page 664 Magnetic resonance imaging (MRI)......Page 665 Functional imaging......Page 668 Other investigations......Page 670 Autonomic failure......Page 671 Motor disorder......Page 672 Acknowledgements......Page 673 REFERENCES......Page 674 Presentation......Page 687 Radiologic evaluation......Page 688 Tau protein......Page 690 Clinical correlates......Page 691 Pathoanatomy......Page 693 Brainstem centers controlling sleep and arousal......Page 694 Incidence......Page 695 A clue from FTD......Page 696 Cholinergics and anticholinergics......Page 697 Patient resources......Page 698 REFERENCES......Page 699 Historical review......Page 706 Anatomical pathology......Page 707 Molecular pathology......Page 709 Clinical features......Page 710 CBD-like syndromes due to other pathologies......Page 714 Imaging......Page 715 Electrophysiology......Page 716 REFERENCES......Page 717 Part VIII Cerebellar degenerations......Page 721 Diagnostic approach to the patient with ataxia......Page 723 Ataxia disorders with highly characteristic phenotypes......Page 724 Autosomal recessive inheritance......Page 725 Genetic causes of sporadic adult-onset ataxia......Page 727 Myoclonus......Page 728 Management of ataxia patients......Page 729 REFERENCES......Page 730 CAG repeat/polyglutamine ataxias......Page 733 The spinocerebellar ataxias......Page 735 SCA2......Page 736 SCA4......Page 737 SCA10......Page 738 Episodic ataxias......Page 739 REFERENCES......Page 740 Epidemiology......Page 743 Pathological features......Page 744 FRDA mutations......Page 745 Frataxin mitochondrial localization......Page 746 Frataxin and iron homeostasis......Page 747 Frataxin as an iron-storage protein......Page 748 Mouse models for FRDA......Page 749 Ataxia due to isolated vitamin E deficiency (AVED)......Page 750 Abetalipoproteinemia (ABL)......Page 751 Refsum disease (RD)......Page 752 Ataxia + blindness + deafness (SCABD)......Page 753 Spinocerebellar ataxia + neuropathy 1 (SCAN1)......Page 754 Spastic ataxia of Charlevoix-Saguenay (ARSACS)......Page 755 REFERENCES......Page 756 Neuropathogenesis......Page 762 Molecular genetics......Page 763 Cancer susceptibility......Page 765 Laboratory diagnosis......Page 766 Treatment......Page 768 REFERENCES......Page 769 Part IX Motor neuron diseases......Page 773 Examination......Page 775 Management of the patient......Page 776 Bulbar dysfunction......Page 777 Nutritional support......Page 778 Other common symptoms......Page 779 REFERENCES......Page 780 Familial ALS and the first descriptions......Page 782 Linked genetic loci in familial ALS......Page 783 Cytosolic Cu/Zn superoxide dismutase (SOD1)......Page 784 ALS2......Page 785 Sporadic ALS......Page 786 Epidemiological studies......Page 787 Genetic studies-SOD1......Page 788 Genetic studies-candidate gene association studies......Page 789 Conclusions......Page 791 REFERENCES......Page 792 Testing therapies in transgenic mice......Page 796 Current and future therapies for ALS......Page 797 Excitotoxicity......Page 798 Trial data......Page 799 Prescription guidelines for riluzole......Page 800 Anti-oxidant drugs......Page 801 Bioenergetic modifiers......Page 802 Gingko biloba......Page 803 Xaliproden......Page 804 Celecoxib......Page 805 Diseasemodifying agents for other motor neuron disorders......Page 806 Sodium butyrate......Page 807 Neurotrophic factors......Page 808 Hereditary spastic paraplegia (HSP)......Page 809 Candidate approach via clarification of molecular biology......Page 810 REFERENCES......Page 811 Clinical signs and symptoms of uncomplicated HSP......Page 818 Neurologic examination......Page 820 Treatment......Page 821 HSP genes......Page 822 Conclusions......Page 823 REFERENCES......Page 824 Clinical background......Page 827 Genetics and molecular biology......Page 829 Molecular basis of polyglutamine neurotoxicity......Page 831 Molecular basis of motor neuron degeneration in SBMA......Page 832 Towards therapy......Page 836 REFERENCES......Page 837 Clinical picture......Page 841 Diagnostic findings......Page 843 Genetics/molecular biology......Page 845 Non-proximal SMA......Page 847 Future prospects......Page 848 REFERENCES......Page 849 Introduction......Page 851 Parkinsonism--dementia complex of Guam......Page 852 Neurofibrillary tangles......Page 853 Eosinophilic rod-like inclusions (Hirano bodies)......Page 854 Other microscopic features......Page 855 Neuropathologic studies of Chamorros of Guam with intact neurologic function......Page 856 Other foci of ALS/parkinsonism--dementia complex......Page 857 Nature vs. nurture......Page 858 Migration studies of the Chamorros of Guam......Page 859 Infectious organisms......Page 860 Cycad......Page 861 Toxic metals......Page 862 REFERENCES......Page 863 Part X Other neurodegenerative diseases......Page 869 Introduction......Page 871 HD as a Mendelian disorder......Page 872 Differential diagnosis......Page 874 The classic phenotype......Page 875 Assessment of neurological and functional decline......Page 876 Non-motor signs and symptoms......Page 877 The Huntington's disease gene, the Huntington's disease protein ("Huntingtin") and the Huntington's disease mutation......Page 878 REFERENCES......Page 880 Molecular biology......Page 885 Pathogenesis......Page 886 Proteolytic processing of atrophin-1......Page 887 Clinical picture......Page 888 Investigations......Page 889 Treatment......Page 890 REFERENCES......Page 891 Chorea-acanthocytosis (ChAc)......Page 895 McLeod syndrome......Page 897 Hypolipoproteinemias......Page 898 Other rare neuroacanthocytosis syndromes......Page 899 REFERENCES......Page 900 Neuroferritinopathy......Page 904 Ceruloplasmin......Page 905 Aceruloplasminemia: genetics......Page 906 Aceruloplasminemia: clinical features......Page 907 Aceruloplasminemia: pathogenesis......Page 909 Hallervorden--Spatz syndrome......Page 910 REFERENCES......Page 911 Introduction......Page 914 Neurological manifestations of WD......Page 915 Epilepsy in WD......Page 917 Abnormalities of clinical neurophysiology in WD......Page 918 Neuropathological changes in WD......Page 919 Making the diagnosis of WD......Page 920 Genetics and pathophysiology of WD......Page 922 The toxicity of copper......Page 923 Initial treatment......Page 924 REFERENCES......Page 925 Introduction......Page 933 CPEO and KSS......Page 934 Myopathy encephalopathy lactic acidosis and stroke-like episodes......Page 936 Neurogenic muscle weakness ataxia and retinitis pigmentosa (NARP)......Page 937 Myo-neuro-gastrointestinal encephalopathy (MNGIE)......Page 938 Parkinson's disease......Page 939 Huntington's disease......Page 940 Friedreich's ataxia......Page 941 REFERENCES......Page 942 Index......Page 951 Neurodegenerative Diseases Are Major Contributors To Disability And Disease, With Alzheimer's And Parkinson's Diseases The Most Prevalent. 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. Covering Basic Science, Diagnostic Tools And Therapeutic Approaches, This 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. Endogenous Free Radicals And Antioxidants In The Brain -- Biological Oxidants And Therapeutic Antioxidants -- Mitochondria, Metabolic Inhibitors And Neurodegeneration -- Excitoxicity And Excitatory Amino Acid Antagonists In Chronic Neurodegenerative Diseases -- Glutamate Transporters -- Calcium Binding Proteins In Selective Vulnerability Of Motor Neurons -- Apoptosis In Neurodegenerative Diseases -- Neurotrophic Factors -- Protein Misfolding And Cellular Defense Mechanisms In Neurodegenerative Diseases -- Neurodegenerative Disease And The Repair Of Oxidatively Damaged Dna -- Compounds Acting On Ion Channels -- The Role Of Nitric Oxide And Parp In Neuronal Cell Death -- Copper And Zinc In Alzheimer's Disease And Amyotrophic Lateral Sclerosis -- The Role Of Inflammation In Alzheimer's Disease Neuropathology And Clinical Dementia. From Epidemiology To Treatment -- Selected Genetically Engineered Models Relevant To Human Neurodegenerative Disease -- Toxic Animal Models -- A Genetic Outline Of The Pathways To Cell Death In Alzheimer's Disease, Parkinson's Disease, Frontal Dementias And Related Disorders -- Neurophysiology Of Parkinson's Disease, Levodopa-induced Dyskinesias, Dystonia, Huntington's Disease And Muyoclonus -- Structural And Functional Magnetic Resonance Imaging In Neurodegenerative Diseases -- Pet/spect -- Magnetic Resonance Spectroscopy Of Neurodegenerative Illness -- Gene Therapy -- Stem Cells And Cell-based Theapy In Neurodegenerative Disease -- Necessary Methodological And Stem Cell Advances For Restoration Of The Dopaminergic System In Parkinson's Disease Patients -- Clinical Aspects Of Normal Aging -- Neuropathology Of Normal Aging In Cerebral Cortex -- Mild Cognitive Impairment -- Alzheimer's Disease: Overview -- The Neuropathology Of Alzheimer's Disease In The Year 2005 -- Genetics Of Alzheimer's Disease -- The Role Of [beta]-amyloid In Alzheimer's Disease -- Treatment Of Alzheimer's Disease -- Dementia With Lewy Bodies -- Frontotemporal Lobar Degeneration -- Frontotemporal Dementia With Parkinsonism Linked To Chromosome 17 -- Prion Diseases -- Approach To The Patient Presenting With Parkinsonism -- Parkinson's Disease -- Neuropathology Of Parkinson's Disease -- Genetics Of Parkinsonism -- Pathophysiology: Biochemistry Of Parkinson's Disease -- Current And Potential Treatments Of Parkinson's Disease -- Current And Potential Treatments Of Parkonson's Disease -- Multiple System Atrophy -- Progressive Supranuclear Palsy -- Corticobasal Degeneration -- Approach To The Patient With Ataxia -- Autosomal Dominant Cerebellar Ataxia -- Friedreich's Ataxia And Other Autosomal Recessive Ataxias -- Ataxia Telangiectasia -- An Approach To The Patient With Motor Neuron Dysfunction -- The Genetics Of Amyotrophic Lateral Sclerosis -- Current And Potential Therapeutics In Motor Neuron Diseases -- The Hereditary Spastic Paraplegias -- Spinal And Bulbar Muscular Atrophy (kennedy's Disease): A Sex-limited, Polyglutamine Repeat Expansion Disorder -- Spinal Muscular Atrophies -- Western Pacific Als/parkinsonism-dementia Complex -- Huntington's Disease -- Dentatorubral-pallidoluysian Atrophy (drpla): Model For Huntington's Disease And Other Polyglutamine Diseases -- Neurocanthocytosis -- Brain Iron Disorders -- Neurological Aspects Of Wilson's Disease -- Disorders Of The Mitochondrial Respiratory Chain. [edited By] M. Flint Beal, Anthony E. Lang, Albert C. Ludolph. Includes Bibliographical References And Index.