McCandless Metabolic Encephalopathy

1. Auflage 2009
ISBN: 978-0-387-79112-8
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 601 Seiten

Metabolic Encephalopathy is meant to combine and correlate animal and human studies. It is hoped that increased awareness of the importance of early diagnosis and treatment of these disorders may result in a lowering of the incidence of structural changes and morbidity. These disorders hold a special fascination for both basic scientists and clinical investigators because they are accessible, treatable and there exists good animal models for study. Therefore, this book will pull together basic and clinical neuroscience issue in the treatment of specific metabolic encephalopathies.

Autoren/Hrsg.

McCandless, David W.

Inhaltsverzeichnis

1;Title Page;3
2;Copyright Page;4
3;Preface;6
4;Contents;8
5;Contributors;11
6;Chapter 1;15
6.1;Functional Anatomy of the Brain;15
6.1.1;Introduction;15
6.1.1.1;Protective Structures;15
6.1.1.2;Organization of the Central Nervous System;17
6.1.1.3;Vascular Supply;22
6.1.1.4;Functions of Brain Regions;25
6.1.2;Physically Induced Alterations in Consciousness;26
6.1.3;Conclusion;27
6.1.4;References Cited;28
6.1.5;General References;28
7;Chapter 2;29
7.1;Brain Metabolic Adaptations to Hypoxia;29
7.1.1;Introduction;29
7.1.1.1;Oxygen, Brain, and Energy Metabolism;29
7.1.2;Hypoxia;30
7.1.3;Acute and Chronic Exposure;30
7.1.4;Metabolic Adaptations to Hypoxia;31
7.1.4.1;Glucose Metabolism;31
7.1.4.2;Activation of Glycolysis: Ph Paradox;32
7.1.4.3;Enzyme Related Changes in Oxidative Metabolism;33
7.1.5;Intrinsic Brain Tissue Oxygen Sensors and Regulators;34
7.1.5.1;Hypoxic Inducible Factor: Energy Metabolism;34
7.1.5.2;Brain Metabolic Indicators of Hypoxia: Glucose and Ketone Body Transporters;34
7.1.5.3;Glutamate Transporters;35
7.1.5.4;Ketosis and Hypoxia;36
7.1.5.5;Hypoxic-Tolerance with Ketosis;37
7.1.6;Conclusions;39
7.1.7;References;41
8;Chapter 3;45
8.1;Hypoglycemic Brain Damage;45
8.1.1;Historical Aspects of Hypoglycemia;45
8.1.2;The EEG in Hypoglycemia;46
8.1.3;Neurochemistry;47
8.1.4;Neuropathology;50
8.1.5;References;52
9;Chapter 4;54
9.1;Experimental Ischemia: Summary of Metabolic Encephalopathy;54
9.1.1;Introduction;54
9.1.2;Energy Metabolism in the Brain;55
9.1.3;Biochemical and Physiological Consequences of Experimental Ischemia;56
9.1.4;Flow Thresholds;56
9.1.5;Ischemia Impact on Intermediary Metabolism;58
9.1.6;Triggered Events Secondary to Energy Failure;60
9.1.7;Ion Homeostasis;61
9.1.8;Acidosis;62
9.1.9;Second Messengers;63
9.1.10;Recirculation Postischemia;64
9.1.11;Free Radicals;65
9.1.12;Metabolic Consequence of Reperfusion: Reversal of Ischemic Process?;67
9.1.13;Recovery: Mitochondrial Dysfunction;69
9.1.14;Reperfusion: Molecular Events and Cell Death;71
9.1.14.1;Necrosis;71
9.1.14.2;Autophagy;72
9.1.14.3;Apoptosis;73
9.1.15;Ischemic Neuroprotection;74
9.1.16;Summary;74
9.1.17;References;75
10;Chapter 5;81
10.1;Metabolic Encephalopathy Stroke - Clinical Features;81
10.1.1;Introduction;81
10.1.2;Predictors of Good Outcome;81
10.1.2.1;Duration of Ischemia;81
10.1.2.2;Infarct Size and Stroke Severity;82
10.1.2.3;Collateral Flow;83
10.1.2.4;Patient’s Age;84
10.1.2.5;Hyperglycemia and History of Diabetes;84
10.1.2.6;Hypertension;85
10.1.2.7;Role of Preconditioning;85
10.1.3;Acute Stroke Treatment;86
10.1.3.1;Recanalization;87
10.1.3.2;Neuroprotection;88
10.1.4;Beyond Clot Removal;88
10.1.4.1;Maintenance of Perfusion Pressure;88
10.1.4.2;Management of Hyperthermia, Hypothermic Treatments;89
10.1.4.3;Management of Hyperglycemia;90
10.1.5;Future in Stroke Therapies;90
10.1.6;References;90
11;Chapter 6;96
11.1;The Role of Animal Models in the Study of Epileptogenesis;96
11.1.1;Introduction;96
11.1.2;Epileptogenesis in Human Epilepsies and Experimental Models;96
11.1.2.1;Hippocampal Sclerosis;98
11.1.3;Animal Models of Epilepsy;99
11.1.3.1;Post-status Epilepticus Models;100
11.1.3.1.1;Pilocarpine Model;101
11.1.3.1.2;Perforant Path Stimulation;101
11.1.3.2;Tetanus Toxin Model;102
11.1.3.3;The Kindling Model;102
11.1.4;Cellular Alterations During Epileptogenesis;103
11.1.4.1;Neuronal Loss;103
11.1.4.2;The Creation of New Circuits: Mossy Fibre Sprouting;104
11.1.4.3;Growth Factors;106
11.1.4.4;The Dormant Basket Cell Hypothesis;106
11.1.4.5;Gliogenesis;107
11.1.4.6;Neurogenesis;108
11.1.4.7;Altered Inhibition;108
11.1.4.8;Non-synaptic Mechanisms in Epileptogenesis;109
11.1.4.9;Receptor/Acquired Channel Changes;110
11.1.4.9.1;GABA A Receptors;110
11.1.4.9.2;GABA B Receptors;111
11.1.4.9.3;Metabotropic Glutamate Receptors (mGluRs);111
11.1.4.9.4;NMDA Receptors;112
11.1.4.9.5;Kainate Receptors;112
11.1.4.9.6;Channelopathies;113
11.1.5;Interventions to Prevent Epileptogenesis;113
11.1.5.1;Initial Insult Modification;113
11.1.5.2;Neuroprotection to Prevent Epileptogenesis;114
11.1.5.3;Antiepileptogenesis;114
11.1.6;Conclusion;115
11.1.7;References;115
12;Chapter 7;124
12.1;Seizure-Induced Neuronal Plasticity and Metabolic Effects;124
12.1.1;Introduction;124
12.1.2;Historical Perspective;124
12.1.3;Insights from Experimental Models and Human Studies;125
12.1.3.1;Neuronal Loss;126
12.1.3.1.1;Mitochondrial Dysfunction;128
12.1.3.1.2;Role of Free Radicals;129
12.1.3.1.3;Activation of Proteolytic and Catabolic Enzymes;129
12.1.3.2;Neurogenesis;129
12.1.3.3;Axonal Sprouting and Dendritic Changes;130
12.1.3.4;Astrocyte Dysfunction;130
12.1.3.5;Altered Gene Expression;131
12.1.3.6;Altered Neurotransmitter Receptors Within Epileptic Foci;132
12.1.3.7;Altered Ion Channel Function;132
12.1.3.8;Altered Neurochemistry;132
12.1.3.9;Do Seizures Cause More Seizures?;133
12.1.3.10;Seizure-Associated Changes in the Developing Brain;133
12.1.4;Contributions of Neuroimaging;134
12.1.4.1;Volumetric MRI;134
12.1.4.2;Positron Emission Topography (PET);135
12.1.4.3;Magnetic Resonance Spectroscopy (MRS);135
12.1.4.4;Diffusion Tensor Imaging (DTI);135
12.1.4.5;Functional MRI;136
12.1.5;Clinical Perspective and Future Considerations;137
12.1.6;Conclusion;138
12.1.7;References;139
13;Chapter 8;147
13.1;Metabolic Encephalopathies in Children;147
13.1.1;Metabolic Encephalopathies in Children;147
13.1.2;Inborn Errors of Metabolism;148
13.1.3;Valproate: Induced Hyperammonemic Encephalopathy;148
13.1.4;Hepatic Encephalopathy;149
13.1.5;Astrocytes and Ammonia;149
13.1.6;Therapy for Hyperammonemic and Hepatic Encephalopathy;149
13.1.7;Plasma Filtration or Removal;150
13.1.8;Charcoal Hemoperfusion;151
13.1.9;MARS;151
13.1.10;Hepatocyte Columns;151
13.1.11;Hepatectomy;152
13.1.12;Common Strategies in Hepatic Encephalopathy;152
13.1.13;Diabetic Ketoacidosis;153
13.1.14;Conclusion;156
13.1.15;References;156
14;Chapter 9;159
14.1;Pathophysiology of Hepatic Encephalopathy: Studies in Animal Models;159
14.2;Introduction;159
14.3;Neuropathology of HE;160
14.3.1;The Astrocyte;160
14.3.2;Neuronal Cell Death in HE;161
14.4;Pathogenesis of HE: Role of Blood-Borne Toxins;162
14.4.1;Ammonia;162
14.4.2;Manganese;166
14.5;Brain Glucose Metabolism in HE;167
14.6;Astrocyte Metabolism and Function in HE;168
14.6.1;Astrocyte Structural Proteins;168
14.6.2;Glutamine Synthesis, the Glutamate-Glutamine Cycle;169
14.6.3;Glutamate and Glycine Transporters;169
14.6.4;“ Peripheral-Type ” Benzodiazepine Receptors, Neurosteroids;171
14.6.5;Astrocyte - Astrocyte “ Crosstalk ”;172
14.7;Neurotransmitter Function in HE;173
14.7.1;Glutamate;173
14.7.2;GABA;173
14.7.3;Serotonin;175
14.7.4;Dopamine;176
14.7.5;Histamine;177
14.7.6;Opioid System;177
14.8;Oxidative/Nitrosative Stress and Inflammation;178
14.8.1;Nitric Oxide;178
14.8.2;Inflammation;178
14.9;Therapeutic Advances;179
14.9.1;Ammonia-Lowering Strategies;179
14.9.2;Neuropharmacologic Advances;180
14.9.3;Hypothermia;181
14.9.4;Liver Support Systems;181
14.10;Summary;182
14.11;References;183
15;Chapter 10;191
15.1;Hepatic Encephalopathy;191
15.1.1;Clinical Features of Hepatic Encephalopathy;191
15.1.1.1;Acute Liver Failure;191
15.1.1.1.1;Seizures and Intracranial Hypertension are Frequent in Acute Liver Failure;192
15.1.1.1.2;Brain Edema: the Most Severe Complication of Acute Liver Failure;193
15.1.1.1.3;Prognosis of Acute Liver Failure;196
15.1.1.2;Encephalopathy Associated with Cirrhosis and Portal Hypertension (Type C);196
15.1.1.3;Minimal Hepatic Encephalopathy;198
15.1.1.3.1;Chronic Persistent Hepatic Encephalopathy;199
15.1.1.3.2;Hepatic Myelopathy;200
15.1.1.4;Diagnosis and Differential Diagnosis of Type C HE;200
15.1.1.4.1;Imaging;200
15.1.1.4.2;Laboratory Findings;201
15.1.1.4.3;EEG and Evoked Potentials;201
15.1.1.4.4;Wernicke’s Disease is the Most Important Differential Diagnosis of HE;201
15.1.1.4.5;Diagnosis of Minimal Hepatic Encephalopathy;202
15.1.1.5;Therapy for Hepatic Encephalopathy;203
15.1.2;References;205
16;Chapter 11;210
16.1;Uremic and Dialysis Encephalopathies;210
16.1.1;Introduction;210
16.1.2;Uremic Encephalopathy;211
16.1.3;Diagnosis of Uremic Encephalopathy;212
16.1.3.1;Acute Renal Failure;212
16.1.3.2;Chronic Renal Failure;213
16.1.3.3;Psychological Testing;214
16.1.4;Biochemical Changes in the Brain;215
16.1.5;Central Nervous System Pathology with Uremia;216
16.1.6;Pathophysiology of Uremic Encephalopathy;217
16.1.7;Uremic Neurotoxins;218
16.1.7.1;Central Nervous System;218
16.1.7.2;Guanidine Compounds;219
16.1.7.3;Advanced Glycation End Products;220
16.1.8;Neurologic Complications of End-Stage Renal Disease and Its Therapy;221
16.1.8.1;Dialysis Disequilibrium Syndrome;221
16.1.9;Chronic Dialysis Dependent Encephalopathy;222
16.1.9.1;Radiologic and Pathologic Examination of Uremic Brain;222
16.1.10;Dialysis Dementia;224
16.1.11;Alternative Etiologies;229
16.1.12;Other Central Nervous System Complications of Dialysis;230
16.1.13;Stroke in Patients Treated with Chronic Hemodialysis;231
16.1.14;Sexual Dysfunction in Uremia;234
16.1.15;References;235
17;Chapter 12;244
17.1;Thiamine Deficiency: A Model of Metabolic Encephalopathy and of Selective Neuronal Vulnerability;244
17.1.1;Introduction;244
17.1.2;Thiamine-Dependent Processes are Altered in Multiple Human Diseases;246
17.1.3;Thiamine-Dependent Processes are also Diminished in Animal Models of Neurological Disease;247
17.1.4;TD Models Both the Acute and Chronic Effects of Mild Impairment of Oxidative Metabolism;248
17.1.5;Behavioral Deficits due to TD Precede Neuronal Death (Acute Treatment);249
17.1.6;TD-Induced Behavioral Deficits are Altered by Age and Genetics;250
17.1.7;Reversal of TD-Induced Behavioral Deficits Provides Insight into Underlying Mechanisms;250
17.1.8;TD-Induced Neurological Deficits that are Not Reversed by Thiamine Administration;251
17.1.9;Impairing Thiamine-Dependent Processes Alters Cholinergic Function and Behavioral Performance, and Induces Cell Death;252
17.1.10;The Temporal Sequence of Selective Neuronal Death in TD Can Be Used to Study Mechanism;252
17.1.11;Immunocytochemical, Histochemical and Message Studies to Evaluate Selective Vulnerability;253
17.1.12;Ex Vivo Studies to Evaluate Selective Vulnerability;255
17.1.13;TD-Induced Changes in Inflammation and Oxidative Stress Support their Role in the Selective Neuronal Death During TD;255
17.1.14;Selective Changes in the Blood-Brain Barrier Suggest that they are Involved in Selective Neurodegeneration;258
17.1.15;Changes in Amyloid Precursor Protein in Response to TD;259
17.1.16;Prevention of Cell Death as a Test of Mechanism;260
17.1.17;The Cellular Basis of Cell Death in Response to Mild Impairment of Oxidative Metabolism (Fig. 12.2 );261
17.1.17.1;Cell Culture;261
17.1.17.2;Protein Processing;263
17.1.17.3;Translocation of Proteins to the Nucleus;264
17.1.18;Other Roles of Thiamine May also Be Critical in TD-Induced Cell Death;264
17.1.19;Conclusion;265
17.1.20;References;265
18;Chapter 13;270
18.1;Alcohol, Neuron Apoptosis, and Oxidative Stress;270
18.1.1;Introduction;270
18.1.2;Ethanol Damage and Neuron Loss in the “ Developing ” Brain;270
18.1.2.1;Ethanol Effects on the Developing Brain;270
18.1.2.2;Ethanol Elicits Neuron Death;271
18.1.3;Oxidative Stress;271
18.1.3.1;Oxidative Stress in Biological Systems;271
18.1.3.2;Ethanol-Related Origins of Oxidative Stress;272
18.1.3.3;Ethanol and the Adult Brain;273
18.1.3.4;Ethanol and the Developing Brain;273
18.1.4;Apoptotic Death of Neurons;275
18.1.4.1;Mitochondria and Apoptosis;275
18.1.4.2;Caspases;276
18.1.4.3;Bcl-2 Family Proteins;276
18.1.5;Ethanol Induction of Apoptotic Death of Neurons in the Developing Brain;277
18.1.5.1;Bcl-2 Family Proteins in Ethanol-Mediated Apoptosis;277
18.1.5.2;Caspases in Ethanol-Mediated Apoptosis;278
18.1.5.3;Summary;279
18.1.6;Ethanol-Mediated Apoptosis and Antioxidant Interventions;279
18.1.6.1;Ethanol and Oxidative Stress-Mediated Apoptosis;279
18.1.6.2;Neuron Glutathione Homeostasis, a Key Role for Astrocytes;280
18.1.7;Summary and Conclusions;282
18.1.8;References;283
19;Chapter 14;289
19.1;Wernicke’s Encephalopathy;289
19.1.1;Introduction;289
19.1.2;Prevalence;290
19.1.3;Clinical Features;291
19.1.4;Diagnosis;294
19.1.5;Neuroimaging;295
19.1.6;Pathology;296
19.1.7;Role of Thiamine;297
19.1.8;Thiamine Absorption;299
19.1.9;Pathogenesis of Wernicke’s Encephalopathy;300
19.1.10;Treatment;303
19.1.11;Prevention;304
19.1.12;Conclusion;304
19.1.13;References;305
20;Chapter 15;310
20.1;The Genetics of Myelination in Metabolic Brain Disease: The Leukodystrophies;310
20.1.1;Introduction;310
20.1.2;Leukodystrophies;310
20.1.2.1;Globoid Cell Leukodystrophy (Krabbe Disease);310
20.1.2.2;X-linked Adrenoleukodystrophy (X-ALD);313
20.1.2.3;Canavan Disease;316
20.1.3;Impacts of Leukodystrophies;319
20.1.3.1;Economic Impacts of Genetic Metabolic Brain Diseases;319
20.1.3.2;Social Impacts;319
20.1.4;Conclusion;319
20.1.5;References;320
21;Chapter 16;327
21.1;Bilirubin Encephalopathy;327
21.1.1;Bilirubin Metabolism;327
21.1.2;Bilirubin Toxicity;328
21.1.3;In-Vivo Animal Studies;329
21.1.4;The Gunn Rat Model;330
21.1.5;Human Bilirubin Encephalopathy-Pathology;332
21.1.6;Bilirubin Encephalopathy-Treatment;334
21.1.7;References;335
22;Chapter 17;339
22.1;Infectious and Inflammatory Metabolic Encephalopathies;339
22.1.1;Normal Brain Homeostasis;339
22.1.2;CNS Viral Infections;341
22.1.2.1;Acute Lytic Infections of the Brain with Focal or Regional Necrosis, Edema and Brain Herniation;341
22.1.2.2;Acute Viral Encephalopathy Without Significant Necrosis or Inflammation;341
22.1.2.3;Oxidative Stress from Reactive Oxygen Species/Intermediates;342
22.1.2.4;Acute Excitotoxicity and Coma;342
22.1.2.5;Viral Infection and Neuronal Apoptosis;343
22.1.2.6;Chronic Virus Persistence in the Brain;344
22.1.2.7;Role of Astrocytes in Viral Encephalitis;344
22.1.3;Hiv Related Encephalopathy;345
22.1.4;West Nile Virus Encephalitis;346
22.1.5;CNS Bacterial Infections;347
22.1.5.1;Bacterial Meningitis;347
22.1.6;Metabolic Encephalopathy with Systemic Infections/Inflammation;347
22.1.7;Post Infectious Encephalomyelitis;348
22.1.8;Encephalopathy in the Transplant Recipient;349
22.1.9;Progressive Multifocal Leukoencephalopathy;350
22.1.10;Summary;351
22.1.11;References;351
23;Chapter 18;355
23.1;Major Depression and Metabolic Encephalopathy: Syndromes More Alike Than Not?;355
23.1.1;Introduction;355
23.1.2;Metabolic Encephalopathy: A Brief Overview;357
23.1.3;Is Depressive Illness a Metabolic Encephalopathy?;360
23.1.4;Glutamate and GABA in Disorders of Mood and Their Association with Encephalopathy;362
23.1.4.1;The Role of GABA;363
23.1.4.2;The Role of Glutamate;363
23.1.5;Depression as an Encephalopathy: Implications for Onset of Antidepressant Action;365
23.1.6;Conclusion;366
23.1.7;References;367
24;Chapter 19;376
24.1;Attention-Deficit/Hyperactivity Disorder as a Metabolic Encephalopathy;376
24.1.1;Attention-Deficit Hyperactivity Disorder;376
24.1.2;Developmental Aspects;376
24.1.3;Genetics;377
24.1.4;Environmental Risk Factors;378
24.1.5;Ubiquitous Nature of ADHD Symptoms;379
24.1.6;Structural Abnormalities;379
24.1.7;Functional Abnormalities;379
24.1.8;Neurophysiology;381
24.1.9;Treatment;382
24.1.10;Animal Models of ADHD;384
24.1.11;Energetics;386
24.1.12;Conclusion;387
24.1.13;References;387
25;Chapter 20;397
25.1;Brain Damage in Phenylalanine, Homocysteine and Galactose Metabolic Disorders;397
25.1.1;Introduction;397
25.1.2;Disorders of Phenylalanine Metabolism;398
25.1.2.1;Clinical Features;398
25.1.2.2;Biochemical Defects;398
25.1.2.3;Pathogenesis of Mental Retardation in Phenylketonuria;400
25.1.2.4;Laboratory Diagnosis;400
25.1.2.5;Variant Forms of Hyperphenylalaninemia;401
25.1.2.6;Treatment;402
25.1.2.7;Dihydropteridine Reductase Deficiency;403
25.1.2.7.1;Clinical Features;403
25.1.2.7.2;Biochemical Defects;403
25.1.2.7.3;Biopterin Deficiency: Hyperphenylalaninemia;403
25.1.2.8;Treated PKU;404
25.1.2.9;Neuropsychological Effects Despite Treatment;405
25.1.2.10;Factors Related to Neuropsychological Performance in Treated PKU;406
25.1.2.11;Neuropsychological Tests;407
25.1.2.12;Phenylketonuria vs Dopamine;408
25.1.2.12.1;Animal Studies;410
25.1.2.12.2;Phenylalanine vs. Blood – Brain Barrier;411
25.1.2.13;Brain Magnetic Resonance Spectrometry;415
25.1.2.13.1;Conclusion;416
25.1.2.14;Efficiency of Long-Term Tetrahydrobiopterin Monotherapy in Phenylketonuria;417
25.1.2.15;Brain Abnormalities in Maternal PKU;417
25.1.3;Disorders of Homocysteine Metabolism;418
25.1.3.1;Clinical Features;418
25.1.3.1.1;Biochemical Defects;420
25.1.3.2;Pathophysiology;422
25.1.3.3;Laboratory Diagnosis;423
25.1.3.3.1;Treatment;423
25.1.3.4;Defects in Homocystine Remethylation;423
25.1.3.4.1;Defective Activity of N 5 -Methyltetrahydrofolate: Homocysteine Methyl-Transferase and Cobalamin Activation;423
25.1.3.5;Decreased N 5,10 Methylenetetrahydrofolate Reductase Activity;424
25.1.3.6;Animal Studies;425
25.1.3.7;Neuropsychologic Disturbances;428
25.1.3.7.1;The Effect of Vitamin Supplementations on Plasma tHcy Concentrations;435
25.1.4;Galactosemia;437
25.1.4.1;Genetics and Epidemiology;437
25.1.4.2;Metabolic Derangement and Intoxication;438
25.1.4.3;Evidence From Animal Models;440
25.1.4.4;Autopsy Studies;440
25.1.4.5;Central Nervous System White Matter;441
25.1.4.6;Influence of Genotype on Cognitive Outcome;442
25.1.4.7;Acute Neonatal Presentation and Diagnosis Presentation;443
25.1.4.8;Diagnosis;443
25.1.4.9;Non-Neurologic Sequelae;443
25.1.4.10;Neurologic Sequelae;444
25.1.4.10.1;Acute Elevated Intracranial Pressure in Infants;444
25.1.4.10.2;Cognitive Impairment: Gender Effects and Possible Regression with Age;444
25.1.4.10.3;Speech Apraxia Commonly Occurs;445
25.1.4.10.4;Motor Function: A Subgroup Develops More Severe Ataxia and Tremor;445
25.1.4.10.5;Seizures are Uncommon;445
25.1.4.10.6;Pathophysiology of Neurology Dysfunction in Galactosemia;446
25.1.5;Treatment: Standard of Care, Controversies, and Clinical Trials;446
25.1.5.1;Treatment of Symptomatic Infants – Standard of Care;446
25.1.5.2;Long-term Nutrition Management: Standard of Care and Recent Issues;446
25.1.5.3;Effects of Dietary Treatment: Does Strict Dietary Treatment After Early Childhood Improve Adult Outcomes?;447
25.1.6;References;448
26;Chapter 21;462
26.1;Wilson Disease;462
26.1.1;The Wilson Disease Gene;462
26.1.2;He´patic Copper Metabolism and the Role of ATP7B;463
26.1.3;Pathogenesis;465
26.1.4;Clinical Presentations;467
26.1.4.1;Kayser-Fleischer Rings;467
26.1.4.2;Liver Disease;468
26.1.4.2.1;Acute Wilsonian Hepatitis and Fulminant Wilson Disease;468
26.1.4.2.2;Chronic Hepatitis due to Wilson Disease;469
26.1.4.3;Psychiatric Presentation;470
26.1.4.4;Other Clinical Manifestations;470
26.1.5;Diagnosis;471
26.1.5.1;Patients with Neurological Disease;471
26.1.5.2;Patients with Liver Disease and Hemolytic Anemia;472
26.1.5.3;Laboratory Parameters;472
26.1.5.3.1;Routine Laboratory Parameters of Liver Disease;472
26.1.5.3.2;Serum Ceruloplasmin;472
26.1.5.3.3;Serum Copper;473
26.1.5.3.4;Urinary Copper Excretion;473
26.1.5.3.5;Hepatic Copper Content;473
26.1.5.4;Liver Biopsy;475
26.1.5.4.1;Light Microscopy;475
26.1.5.4.2;Electron Microscopy;475
26.1.5.5;Mutation Analysis;475
26.1.5.5.1;Direct Mutation Analysis;475
26.1.5.5.2;Haplotype Analysis;476
26.1.5.5.3;Family Screening;477
26.1.5.5.4;Treatment;477
26.1.5.6;D-Penicillamine;477
26.1.5.7;Trientine;478
26.1.5.8;Ammonium Tetrathiomolybdate;479
26.1.5.9;Zinc;479
26.1.5.10;Monitoring Therapy;480
26.1.5.11;Liver Transplantation;480
26.1.6;Prognosis;481
26.1.6.1;Liver Disease;481
26.1.6.2;Neurological Disease;482
26.1.7;References;483
27;Chapter 22;486
27.1;Metabolic Abnormalities in Alzheimer Disease;486
27.1.1;Alzheimer’s Disease;486
27.1.1.1;History;486
27.1.1.2;Epidemiology;486
27.1.1.3;Diagnosis;487
27.1.1.3.1;Clinical;487
27.1.1.3.2;Pathological;487
27.1.1.4;Presentation and Metabolism;487
27.1.1.4.1;beta -Amyloid Precursor Protein;488
27.1.1.5;Tau;494
27.1.1.5.1;Function of Tau;495
27.1.1.5.2;Phosphorylation of Tau;496
27.1.1.5.3;Abnormal Tau;496
27.1.1.5.4;Mitogen-Activated Protein (MAP) Kinases;496
27.1.1.5.5;p38;497
27.1.1.5.6;c-Jun Kinase (JNK) also called Stress Activated Protein Kinases, SAPK;498
27.1.1.5.7;Glycogen Synthase Kinase 3 (GSK3);498
27.1.1.5.8;Cyclin-dependent Kinases;499
27.1.1.5.9;cAMP-dependent Protein Kinase A (PKA);500
27.1.1.5.10;Calcium/Calmodium-dependent Protein Kinase II (CaM Kinase II);500
27.1.1.5.11;Casein Kinase 1 (Ck 1);501
27.1.1.6;The Presenilins PS1 and PS2;501
27.1.1.7;Protein Phosphatases;502
27.1.1.8;Oxidative Stress;504
27.1.1.8.1;DNA Oxidation;505
27.1.1.8.2;Proteins;505
27.1.1.8.3;Hemeoxygenases;506
27.1.1.9;Glucose;507
27.1.1.10;Apoe;509
27.1.1.11;Insulin and Related Factors;510
27.1.1.12;Concluding Remarks;512
27.1.1.13;References;512
28;Chapter 23;534
28.1;Prions and the Transmissible Spongiform Encephalopathies;534
28.1.1;Introduction and Overview;534
28.1.2;Transmission of Prion Diseases Between Humans and Animals;535
28.1.3;Gaps and Enigmas in the Prion Concept;536
28.1.4;Prion Disease Prevention;537
28.1.5;The Mechanism of Protein Infectivity;538
28.1.6;Origin and Acceptance of the Prion Hypothesis;540
28.1.7;Function of Normal Prion Protein;541
28.1.8;Mechanism of the Prion Protein Misfolding and Disease;543
28.1.9;Progression from Exposure to Disease;546
28.1.10;Horizontal Spread of Prion Disease;547
28.1.11;Conclusions;547
28.1.12;References;548
29;Chapter 24;554
29.1;Lead Encephalopathy;554
29.1.1;Introduction;554
29.1.2;Clinical Lead Encephalopathy;555
29.1.3;Leaded Gasoline Encephalopathy;557
29.1.4;Delayed Effects in Adults;558
29.1.4.1;Occupational Exposures;558
29.1.4.2;Amyloidogenesis;558
29.1.4.3;Calcification;560
29.1.5;Vulnerability of the Injured Brain;560
29.1.5.1;Subclinical Effects in Children;561
29.1.5.2;Mechanisms of Action;563
29.1.6;Mechanisms Proposed for Brain Edema;564
29.1.7;Mechanisms Proposed Developmental Effects;565
29.1.8;Conclusions;566
29.1.9;References;567
30;Index;575