The Neuropathology of Huntington’s Disease: Classical Findings, Recent Developments and Correlation to Functional Neuroanatomy (Advances in Anatomy, Embryology and Cell Biology Book 217)

This monograph describes the progress in neuropathological HD research made during the last century, the neuropathological hallmarks of HD and their pathogenic relevance. Starting with the initial descriptions of the progressive degeneration of the striatum as one of the key events in HD, the worldwide practiced Vonsattel HD grading system of striatal neurodegeneration will be outlined. Correlating neuropathological data with results on the functional neuroanatomy of the human brain, subsequent chapters will highlight recent HD findings: the neuronal loss in the cerebral neo-and allocortex, the neurodegeneration of select thalamic nuclei, the affection of the cerebellar cortex and nuclei, the involvement of select brainstem nuclei, as well as the pathophysiological relevance of these pathologies for the clinical picture of HD. Finally, the potential pathophysiological role of neuronal huntingtin aggregations and the most important and enduring challenges of neuropathological HD research are discussed. Abstract 6 Acknowledgments 8 Contents 10 Non-neuroanatomical Abbreviations 14 Chapter 1: Introduction 16 Chapter 2: The Neuropathological Grading of Huntington’s Disease (HD) 21 2.1 Neuropathological Base for the Grading System of Huntington’s Disease (HD) 21 2.2 Grading of Striatal Neuropathology in Huntington’s Disease (HD) 23 2.3 Functional Neuroanatomy of the Striatum 33 2.4 Relationship Between Neostriatal Degeneration and Changes in Other Brain Regions in Huntington’s Disease (HD) 34 Chapter 3: The Cerebral Cortex in Huntington’s Disease (HD) 38 3.1 Establishment of Cortical Neuronal Loss as a Main Neuropathological Hallmark of Huntington’s Disease (HD) and Its Clinical Relevance 38 3.2 Confirmation and Extension of Very Early Descriptions of Cortical Neurodegeneration in Huntington’s Disease (HD) by Modern Quantitative Approaches 43 3.3 Application of Advanced, Unbiased Stereological Methods for the Assessment of Nerve Cell Loss 46 3.4 Pathomechanisms of the Involvement of the Cerebral Cortex in Huntington’s Disease (HD) 50 3.5 Voxel-Based Morphometric Magnet Resonance Imaging (MRI) In Vivo Studies of the Cerebral Cortex in Presymptomatic Huntington’s Disease (HD) Patients 52 Chapter 4: Degeneration of Select Motor and Limbic Nuclei of the Thalamus in Huntington’s Disease (HD) 53 4.1 The Thalamus in Huntington’s Disease (HD) 53 4.2 Functional Neuroanatomy of the Centromedian-­Parafascicular Complex (CM-PF) of the Human Thalamus 54 4.3 Functional Neuroanatomy of the Mediodorsal Nucleus (MD) of the Human Thalamus 58 4.4 Degeneration of the Thalamic Centromedian-­Parafascicular Complex (CM-PF) and Mediodorsal Nucleus (MD) in Huntington’s Disease (HD) 60 4.5 The Involvement of the Thalamic Centromedian-­Parafascicular Complex (CM-PF) and Mediodorsal Nucleus (MD) in Huntington’s Disease (HD) and its Pathogenetic Implications 60 4.6 Functional Implications of the Involvement of the Thalamic Centromedian-Parafascicular Complex (CM-PF) and Mediodorsal Nucleus (MD) in Huntington’s Disease (HD) 64 Chapter 5: Consistent and Widespread Degeneration of the Cerebellum in Huntington’s Disease (HD) 66 5.1 Clinical Symptoms Pointing to an Involvement of the Cerebellum in Huntington’s Disease (HD) 66 5.2 Neurodegeneration of the Cerebellum in Huntington’s Disease (HD) 67 5.3 The Functional Relevance of Cerebellar Affection in Huntington’s Disease (HD) 73 Chapter 6: Elucidation of the Role of the Premotor Oculomotor Brainstem Nuclei in the Pathogenesis of Oculomotor Dysfunctions in Huntington’s Disease (HD) 78 6.1 Types of Eye Movements that Guarantee Stabilization of the Images of Objects of the Visual World Onto the Central Foveal Region of the Retina 78 6.2 Oculomotor Dysfunctions in Huntington’s Disease (HD) 80 6.3 The Human Premotor Oculomotor Brainstem Network 81 6.4 The Human Premotor Oculomotor Brainstem Nuclei in Pigment-Nissl Stained Thick Serial Tissue Sections 89 6.5 In Search for the Morphological Correlates of Oculomotor Dysfunctions in Huntington’s Disease (HD) 91 6.6 Degeneration of Select Nuclei of the Human Premotor Oculomotor Brainstem Network in Huntington’s Disease (HD) and its Clinical Significance 93 Chapter 7: Widespread Brainstem Neurodegeneration in Huntington’s Disease (HD) 94 7.1 Systematic Pathoanatomical Investigations of the Brainstem in Huntington’s Disease (HD) 94 7.2 Neurodegenerative Brainstem Features in Huntington’s Disease (HD) 99 7.3 Clinical Relevance of Brainstem Neurodegeneration in Huntington’s Disease (HD) 100 Chapter 8: Intraneuronal Transport and Defense Mechanisms with Possible Pathogenetic Relevance in Huntington’s Disease (HD) 102 8.1 Axonal Transport Mechanisms in Healthy Nerve Cells 102 8.2 The Neuronal Protein Quality Control Machinery: Molecular Chaperones and the Ubiquitin-Proteasome Pathway 106 8.3 The Proteasomal Shuttle and Ubiquitin-Interacting Protein p62 111 Chapter 9: The Disease Protein Huntingtin and Neuronal Protein Aggregations in Huntington’s Disease (HD) 112 9.1 The Disease Protein Huntingtin 112 9.2 Types, Composition, and Pathogenetic Relevance of Neuronal Protein Aggregations in Huntington’s Disease (HD) 115 Chapter 10: Pathological Nerve Cell Alterations in Huntington’s Disease (HD) and Their Possible Role for the Demise of Nerve Cells 129 10.1 Morphological Alterations of Vulnerable Nerve Cells in Huntington’s Disease (HD) 129 10.2 Detection of Ballooned or Chromatolytic Nerve Cells 130 Chapter 11: Conclusions and Outlook 134 References 141 Front Matter....Pages i-xiv Introduction....Pages 1-5 The Neuropathological Grading of Huntington’s Disease (HD)....Pages 7-23 The Cerebral Cortex in Huntington’s Disease (HD)....Pages 25-39 Degeneration of Select Motor and Limbic Nuclei of the Thalamus in Huntington’s Disease (HD)....Pages 41-53 Consistent and Widespread Degeneration of the Cerebellum in Huntington’s Disease (HD)....Pages 55-66 Elucidation of the Role of the Premotor Oculomotor Brainstem Nuclei in the Pathogenesis of Oculomotor Dysfunctions in Huntington’s Disease (HD)....Pages 67-82 Widespread Brainstem Neurodegeneration in Huntington’s Disease (HD)....Pages 83-90 Intraneuronal Transport and Defense Mechanisms with Possible Pathogenetic Relevance in Huntington’s Disease (HD)....Pages 91-100 The Disease Protein Huntingtin and Neuronal Protein Aggregations in Huntington’s Disease (HD)....Pages 101-117 Pathological Nerve Cell Alterations in Huntington’s Disease (HD) and Their Possible Role for the Demise of Nerve Cells....Pages 119-123 Conclusions and Outlook....Pages 125-131 Back Matter....Pages 133-146