Cerebral Cortex : Neurodegenerative and Age-Related Changes in Structure and Function of Cerebral Cortex

This volume of Cerebral Cortex is dedicated to Sir John Eccles, who was an active member of the advisory board for the series until his death in May 1997. His input as to what topics should be covered in future volumes of this series will be sorely missed. The present volume is concerned with neurodegenerative disorders and age­ related changes in the structure and function of the cerebral cortex, a topic that has attracted increasing interest as longevity and the number of aged individuals in the population increase. Although much of the research on the neurodegenerative effects of aging has been centered on Alzheimer's disease, most of the aging popu­ lation will not be afflicted by this disease. They will, however, be affected by the consequences of normal aging, so the first few chapters of this volume are con­ cerned with that topic. Chapter 1, by Marilyn S. Albert and Mark B. Moss, gives an account of the cognitive changes that accompany normal human aging. Chapter 2, by Mark B.

1 Cognitive Profiles of Normal Human Aging.- 1. Introduction.- 2. Domains of Cognitive function.- 3. Memory.- 3.1. Types of Memory.- 3.2. Explicit Memory Performance and Aging.- 3.3. Implicit Memory Performance and Aging.- 4. Executive function.- 5. Visuospatial function.- 6. Language.- 7. Attention.- 8. General Intelligence.- 9. Age-Related Changes in Brain Structure and function.- 10. Conclusion.- 11. References.- 2 Age-Related Cognitive Decline in the Rhesus Monkey.- 1. Introduction.- 2. Life Span of the Rhesus Monkey.- 3. Cognitive function.- 3.1. Attention.- 3.2. Learning and Memory.- 3.3. Executive System function.- 3.4. Motor Skills.- 4. Performance Patterns.- 5. Longitudinal Studies.- 6. Neurobiological Considerations.- 7. Conclusions.- 8. References.- 3 Normal Aging in the Cerebral Cortex of Primates.- 1. Introduction.- 2. Neurons in the Cerebral Cortex.- 3. Variation in the Sizes of Cortical Areas.- 4. Changes in Volume: Gray and White Matter with Age.- 5. Effects of Age on Dendrites.- 6. Effects of Age on Layer I.- 7. Age-Related Changes in Synapses.- 8. Effects of Aging on Axons and Their Sheaths.- 9. Effects of Aging on Neuroglial Cells.- 10. Neuritic Plaques and Amyloid.- 11. Conclusions.- 12. References.- 4 Age-Related Neuronal Loss in the Cerebral Cortex.- 1. Background.- 1.1. Historical Confusion.- 1.2. A More Clear but Still Incomplete View.- 2. Recent Studies with Improved Methods.- 3. Differences in Neuronal Loss Patterns: Normal Aging and Alzheimer’s Disease.- 4. Interspecies Differences.- 5. Factors other than Neuronal Loss.- 6. The Emerging View and Its Implications.- 7. References.- 5 Age-Related Cognitive Deficits and Neurotransmitters: The Role of Catecholamine Mechanisms in Prefrontal Cortical Cognitive Decline.- 1. Introduction.- 2. Pattern of Cognitive Deficits with Normal Aging.- 2.1. Monkeys.- 2.2. Humans.- 3. Pattern of Neuropathological and Neurochemical Changes.- 3.1. Neuropathological Changes.- 3.2. Neurochemical Changes.- 4. Neurotransmitter Modulation of the Prefrontal Cortex.- 4.1. Dopamine.- 4.2. Norepinephrine.- 4.3. Serotonin.- 4.4. Acetylcholine.- 5. The Cholinergic Hypothesis of Age-Related Cognitive Decline.- 6. Functional Evidence for PFC Catecholamine Loss with Age.- 6.1. Dopamine Loss.- 6.2. Norepinephrine Loss.- 7. Summary.- 8. References.- 6 Neurotransmitter Receptor Changes in the Hippocampus and Cerebral Cortex in Normal Aging.- 1. Introduction.- 2. Technical Considerations.- 3. Age-Related Changes in Cholinergic Receptors.- 4. Age-Related Changes in GABAergic Receptors.- 5. Age-Related Changes in Glutamatergic Receptors.- 6. Age-Related Changes in Monkey Temporal Lobe.- 7. Possible Mechanisms of Receptor Changes.- 7.1. Membrane Loss.- 7.2. Functional or Metabolic Down-Regulation.- 7.3. Masking of Loss by Up-Regulation.- 7.4. Changes in Affinity and Gene Regulation of Subunits.- 8. Summary and Conclusions.- 9. References.- 7 Trophic Factors in Experimental Models of Adult Central Nervous System Injury.- 1. Introduction.- 1.1. The Trophic Hypothesis.- 1.2. Trophic Factor Diversity.- 1.3. Trophic Influence Assessment in Vivo.- 2. Experimental Approaches.- 2.1. Injury Models.- 2.2. Trophic Factor Delivery Systems.- 3. Nerve Growth Factor.- 3.1. Nerve Growth Factor and Its Receptors.- 3.2. In Vitro Activity.- 3.3. In Vivo Activity.- 3.4. Clinical Experience with Nerve Growth Factor Administration.- 4. Other Neurotrophins.- 4.1. Neurotrophins and Their Receptors.- 4.2. In Vitro Activity.- 4.3. In Vivo Activity.- 4.4. Clinical Experience with Neurotrophin Administration.- 5. Ciliary Neurotrophic Factor.- 6. Fibroblast Growth Factors.- 6.1. Fibroblast Growth Factors and Their Receptors.- 6.2. In Vitro Activity.- 6.3. In Vivo Activity.- 7. Trophic Factor Administration and Adult Neurogenesis.- 7.1. In Vitro Evidence.- 7.2. In Vivo Evidence.- 8. Conclusions.- 8.1. Reliability of Phenotypic Expression.- 8.2. Caveats Regarding Quantification of Tissue Sections.- 8.3. Broad Effects of Trophic Factor Administration.- 9. References.- 8 Cortical Neuropathology in Aging and Dementing Disorders: Neuronal Typology, Connectivity, and Selective Vulnerability.- 1. Introduction.- 2. Neuropathological Evidence of Selective Neuronal Vulnerability in Aging and Alzheimer’s Disease.- 2.1. Neuropathological Changes.- 2.2. Distribution of Cortical Neurofibrillary Tangles and Senile Plaques.- 2.3. Correlations between Lesion Distribution and Specific Circuits.- 3. Morphologic and Neurochemical Correlates of Neuronal Vulnerability in AD.- 3.1. Neuronal Types and Development of Neurofibrillary Tangles.- 3.2. Abundance of Nonphosphorylated Neurofilament Protein in Subsets of Vulnerable Neurons.- 3.3. Glutamate Receptor Implication.- 3.4. Other Proteins Associated with Neuronal Degeneration.- 3.5. Morphologic and Molecular Characteristics of Resistant Neuron Subpopulations.- 4. Other Dementing Disorders: Evidence for Disease-Specific Involvement of Cortical Circuitry.- 4.1. Down’s Syndrome.- 4.2. Guamanian Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex.- 4.3. Progressive Supranuclear Palsy and Corticobasal Degeneration.- 4.4. Postencephalitic Parkinsonism.- 4.5. Dementia Pugilistica and Posttraumatic Dementia.- 4.6. Pick’s Disease.- 4.7. Frontal Lobe Dementia.- 4.8. Lewy Body Dementia.- 4.9. Other Neurodegenerative Disorders Involving Cytoskeletal Alterations.- 5. Conclusions and Future Prospects.- 6. References.- 9 The Anatomy of Dementias.- 1. Introduction.- 2. Alzheimer’s Disease and the Primary Involvement Pattern of the Temporal Lobe.- 3. Progressive Subcortical Gliosis.- 4. Dementia of the Frontal Type.- 5. Pick’s Disease.- 6. Huntington’s Disease.- 7. Parkinson’s Disease and Diffuse Lewy Body Disease.- 8. Corticobasal Degeneration.- 9. Multiple System Atrophy.- 10. Progressive Supranuclear Palsy.- 11. Schizophrenia.- 12. Discussion.- 12.1. General.- 12.2. Alzheimer’s Disease and Progressive Subcortical Gliosis: Head Brain /Body Brain and Architectonics.- 12.3. Embryology of the Cerebral Cortex and Progressive Subcortical Gliosis.- 12.4. Frontal-Type Dementia, Pick’s Disease, and the Selective Vulnerability of the Frontal and Temporal Lobes.- 12.5. Huntington’s Disease and Diffuse Lewy Body Disease: Dementias with Cerebral Cortical Pathology and Prominent Subcortical Changes.- 12.6. Corticobasal Degeneration, Multiple System Atrophy, and Progressive Supranuclear Palsy: Dementias with Predominately Subcortical Involvement.- 12.7. Schizophrenia.- 12.8. Conclusion.- 13. References.- 10 Age-Related Changes in Subcortical Nuclei that Project to the Cerebral Cortex.- 1. Introduction.- 2. Subcortical Areas.- 2.1. Cholinergic Basal Forebrain.- 2.2. Dopaminergic Ventral Mesencephalon.- 2.3. Locus Coeruleus.- 2.4. Median and Dorsal Raphe Nuclei.- 3. Discussion.- 3.1. Age-Related Changes.- 3.2. Disease-Related Changes.- 4. Summary and Conclusions.- 5. References.- 11 Ultrastructural Changes in Dementing Illnesses.- 1. Introduction.- 2. Alzheimer’s Disease.- 2.1. Alzheimer’s Neurofibrillary Tangles.- 2.2. Ghost Tangles.- 2.3. Astrocytic Paired Helical Filaments.- 2.4. Anchorage Densities of Perivascular Astrocytes.- 2.5. Senile Plaques.- 2.6. Hirano Bodies (Eosinophilic Rodlike Structures).- 2.7. Granulovacuolar Degeneration.- 3. Pick’s Disease.- 4. Progressive Supranuclear Palsy and Corticobasal Degeneration.- 4.1. Progressive Supranuclear Palsy.- 4.2. Corticobasal Degeneration.- 5. Diffuse Lewy Body Disease.- 6. Cruetzfeldt-Jakob Disease.- 7. Amyotrophic Lateral Sclerosis with Dementia.- 8. AIDS-Dementia Complex.- 9. Conclusion.- 10. References.- 12 Locating Genetic Modifiers for Inherited Neurodegenerative Diseases.- 1. Introduction.- 2. Conceptualization of Genetic Modifiers.- 3. Wilson’s Disease.- 4. Huntington’s Disease.- 5. Machado-Joseph Disease.- 6. Approaches for Identifying Genetic Modifiers.- 6.1. Genetic Case-Control Paradigms.- 6.2. Genetic Linkage Analysis.- 6.3. Special Case: Primary Mutation and Its Modifier in One Genetic System.- 7. Conclusions.- 8. References.- 13 Early Features of Alzheimer’s Disease.- 1. Introduction.- 2. Memory Changes in Early Alzheimer’s Disease.- 3. Executive Function Changes in Early Alzheimer’s Disease.- 4. Changes in Brain Structure and Function in Early Alzheimer’s Disease that May Underly the Memory Deficit.- 5. Changes in Brain Structure in Early Alzheimer’s Disease Related to Executive Function Deficits.- 6. Summary.- 7. References.- 14 Temporal Sequence of Alzheimer’s Disease-Related Pathology.- 1. Introduction.- 2. Anatomical Considerations.- 3. Extracellular Amyloid Deposits.- 3.1. Transiently Developed Forms of Amyloid Deposits.- 3.2. Mature Forms of Amyloid Deposits.- 3.3. Evolutionary Stages of A?-Amyloid Deposition.- 4. Intraneuronal Neurofibrillary Changes.- 4.1. Neurofibrillary Tangles, Neuropil Threads, and Neuritic Plaques.- 4.2. Evolutionary Stages of Neurofibrillary Tangles and Neuropil Threads.- 4.3. Stages I to VI: Development Repeats Cortical Myelination Progression in Reverse Order.- 5. Age, Amyloid Deposits, and Neurofibrillary Changes.- 6. References.- 15 Neuropathological Correlates of Dementia in Alzheimer’s Disease.- 1. Introduction.- 1.1. Synapse Formation and Remodeling as the Microanatomical Correlate of Cognition.- 1.2. Pre- and Postsynaptic Damage as the Basis for Dementia.- 1.3. Approaches to Understanding the Structural Basis of Alzheimer’s Disease Dementia.- 2. Neuropathological Basis for Cognitive Decline in Alzheimer’s Disease.- 2.1. Characteristics of the Neurodegenerative Process.- 2.2. Clinico-Neuropathological Correlation in Alzheimer’s Disease and Related Disorders.- 2.3. Correlations with the Progression of Neurodegenerative Alterations.- 2.4. Correlations with Neuropathological Markers.- 2.5. Correlations with Neurofibrillary Cytoskeletal Alterations.- 2.6. Association with Lewy Bodies.- 2.7. Correlations with Amyloid Deposition.- 3. Mechanisms of Synaptic Pathology in Alzheimer’s Disease.- 3.1. Amyloid-? Precursor Protein and Synaptic Damage.- 3.2. Apolipoprotein E and Synaptic Damage.- 3.3. Non-A? Component Precursor and Presynaptic Damage.- 4. References.- 16 Multifocal Cortical Neurodegeneration in Alzheimer’s Disease.- 1. Introduction.- 2. Neuropsychological Subgroups.- 3. Genetic Factors: Subgroups or Subtypes?.- 3.1. Frank Genetic Subtypes: Autosomal Dominant Mutations.- 3.2. Different Clinical and Neuropathological Outcomes: PS and APP Mutations.- 3.3. Mitochondrial DNA Mutations.- 3.4. Genetic Risk Factor: The ApoE Gene.- 4. Models of Heterogeneity, Postmortem Measures, and A? Neurotoxicity.- 5. Laminar Patterns in Neocortical Neurochemistry.- 6. Laminar Patterns of Neuron Vulnerability in Frontal/Anterior Cingulate Dementias.- 7. Multifocal Atrophies and Subsystem Disruption in Alzheimer’s Disease.- 7.1. Frontotemporal Atrophy and Case FG.- 7.2. Parietotemporal Atrophy and Case WJ.- 7.3. Posterior Cortical Atrophy.- 8. Layer-Selective Neurodegeneration in Posterior Cingulate Cortex.- 9. Neocortical Neurochemistry and the Subtypes Hypothesis.- 10. Models of Multifocal Cortical Neurodegeneration and the Subtypes Hypothesis.- 11. References.- 17 Molecular Pathology of Alzheimer’s Disease and Related Disorders.- 1. Introduction.- 2. Genetics of Familial Alzheimer’s Disease and Sporadic Alzheimer’s Disease.- 2.1. Familial Alzheimer’s Disease Caused by Mutations in the Amyloid-? Precursor Protein and Presenilin Genes.- 2.2. ApoE as a Risk Factor for Alzheimer’s Disease.- 3. Neurofibrillary Tangles: Pathophysiological Alterations in Hippocampus and Neocortex.- 3.1. Tau Structure and function.- 3.2. Paired Helical Filament Tau Structure and Localization to Neurofibrillary Tangles and Dystrophic Processes in Alzheimer’s Disease.- 3.3. Neurofibrillary Pathology in Other Tangle-Bearing Diseases.- 4. Senile Plaques: Pathophysiological Alterations in Hippocampus and Neocortex.- 4.1. Amyloid Deposition and Alzheimer’s Disease.- 4.2. Amyloid Deposition and Other Neurological Disorders.- 4.3. Genetics and Proteolytic Processing of Amyloid-? Precursor Protein and Amyloid-? Protein.- 4.4. Function of Amyloid-? Protein.- 5. Other Lesions and Cytopathology: Pathology in Hippocampus and Neocortex.- 5.1. Hirano Bodies.- 5.2. AMY Plaques.- 5.3. Granulovacuolar Degeneration.- 5.4. Nonneuronal Cells and Inflammatory Changes in Alzheimer’s Disease.- 6. Analysis of Vulnerable Cell Types and Pathological Lesions in Diseased Brain.- 6.1. Cell Death in Alzheimer’s Disease.- 6.2. Elucidating Pathologic Mechanisms: RNA Species Assessment in Alzheimer’s Disease Lesions.- 6.3. mRNA Species in Single Profiles Isolated from the Alzheimer’s Disease Hippocampus.- 7. Conclusions.- 8. References.- 18 Glutamate Receptors and Excitotoxic Mechanisms in Alzheimer’s Disease.- 1. Introduction.- 2. Components of Glutamatergic Pathways.- 2.1. The Ionotropic Receptors.- 2.2. The Metabotropic Glutamate Receptors.- 2.3. The Transporters.- 3. Alzheimer’s Disease Neuropathology.- 4. Alterations in Glutamatergic Pathways in Alzheimer’s Disease.- 4.1. The NMDA Receptors.- 4.2. The Kainic Acid Receptors.- 4.3. The AMPA Receptors.- 4.4. The Metabotropic Receptors.- 4.5. In Situ Hybridization Studies of Glutamate Receptors.- 4.6. Immunohistochemical Studies of Glutamate Receptors.- 4.7. Glutamate Levels.- 4.8. Glutamate Transport.- 5. Glutamate Receptors and Excitotoxic Insult.- 6. Relationship between Glutamatergic Pathways and Alzheimer’s Disease Pathology?.- 7. Summary and Conclusions.- 8. References.- 19 Nerve Growth Factor Systems in Alzheimer’s Disease.- 1. Introduction.- 2. Nerve Growth Factor Receptor Subtypes.- 3. Nerve Growth Factor in Neurological Disease.- 4. Nerve Growth Factor Protein Levels in Normal Aged Human Brain.- 5. Nerve Growth Factor-Like Immunoreactivity in Hippocampus.- 6. Target-Derived Nerve Growth Factor within Aged Cholinergic Basal Forebrain Neurons.- 7. Nerve Growth Factor Receptors and Cholinergic Basal Forebrain Neurons.- 8. Low-Affinity p75NTR and High-Affinity trkA Receptor within the Basal Forebrain.- 9. Colocalization of p75NTR and trk within the Primate Basal Forebrain.- 10. Alterations in the Nerve Growth Factor System in Alzheimer’s Disease.- 10.1. Cytoskeletal Abnormalities within p75NTR Containing Cholinergic Basal Forebrain Neurons.- 10.2. Loss of p75NTR Protein- and mRNA-Containing Cholinergic Basal Forebrain Neurons.- 11. Altered Transport of Target-Derived Nerve Growth Factor.- 12. Increased Nerve Growth Factor Levels in Neo- and Limbic Cortex.- 13. trkA within Cholinergic Basal Forebrain Neurons.- 13.1. Alterations in trkA Gene and Protein Expression in Nucleus Basalis.- 13.2. Reverse Transcription Polymerase Chain Reaction and Western Blot Analysis of trkA.- 13.3. Is Nerve Growth Factor Off trk in Alzheimer’s Disease?.- 14. Neuroplasticity of the Nerve Growth Factor Receptor System in Alzheimer’s Disease.- 14.1. De Novo Expression of p75NTR Containing Cortical Neurons.- 14.2. Galanin Fiber Hypertrophy of Remaining p75NTR Basal Forebrain Neurons.- 15. Treatment Approaches for Preventing Cholinergic Cell Degeneration in Alzheimer’s Disease.- 15.1. Grafting Encapsulated Cells Secreting Human Nerve Growth Factor.- 15.2. Comments.- 16. Nerve Growth Factor Conjugated to an Antitransferrin Receptor Antibody.- 16.1. Actions of OX-26-NGF on Cholinergic Systems.- 16.2. OX-26-NGF Prevents Cholinergic Basal Forebrain Cell Degeneration in Animal Correlates of Alzheimer’s Disease.- 17. Conclusion.- 18. References.- 20 Vascular-Related and Mediated Alterations in Alzheimer’s Disease.- 1. Introduction.- 2. Imaging the Vasculature.- 3. Macroscopic Changes in the Vasculature.- 4. Microscopic Changes in the Vasculature.- 5. Pathologic Deposition in the Vasculature.- 6. Evidence for Vascular-Mediated Alterations.- 7. References.