The Neuropathology of Huntington´s disease: classical findings, recent developments and correlation to functional neuroanatomy

Abstract

Huntington’s disease (HD) is a severe, autosomal dominantly inherited, gradually worsening neurological disorder, the clinical features of which were first described in 1863 by Irving W. Lyon and with additional details, in 1872, by George Huntington. Progress in molecular biological research has shown that HD is caused by meiotically unstable CAG-repeats in the mutated HD gene (the so-called IT 15 gene) on chromosome 4p16.3, which encodes the mutated protein huntingtin (Htt). This monograph provides a survey of the stepwise progress in neuropathological HD research made during a time period of more than hundred years, the currently known neuropathological hallmarks of HD, as well as their pathogenic and clinical relevance. Starting with the initial descriptions of the progressive degeneration of the neostriatum (i.e., caudate nucleus and putamen) as one of the key events in HD, the worldwide practiced Vonsattel HD grading system of striatal neurodegeneration will be outlined. Correlating qualitative and quantitative neuropathological data with characteristics pertaining to the functional neuroanatomy of the human brain, subsequent chapters will highlight the latest neuropathological HD findings: the area- and layer-specifi c neuronal loss in the cerebral neo- and allocortex, the neurodegeneration of select thalamic nuclei, the affection of the cerebellar cortex and the deep cerebellar nuclei, the involvement of distinct brainstem nuclei, and the pathophysiological relevance of these pathologies for the clinical phenotype of HD. Finally, the potential pathophysiological role of axonal transport deficit