THE CORTICAL NEURITIC PATHOLOGY OF HUNTINGTONS-DISEASE

We have studied the brains of 10 patients with clinically and pathologically defined Huntington's disease and graded the degree of striatal pathology according to the Vonsattel grading system. Sections from nine cerebral cortical areas (Brodmann areas 8, 10, 24, 33, 28, 38, 7, 39, 18), the cerebellum, hypothalamus, medulla and caudate nucleus were stained with antibodies to ubiquitin and ubiquitin C-terminal hydrolase (PGP 9.5). Dystrophic neurites, immunoreactive with ubiquitin and PGP 9.5 were detected in all cortical areas, in layers 3, 5 and 6, of all brains studied. No dystrophic neurites were found in subcortical areas or cerebellum. Sections from cortical areas 8 and 24 from the two brains with the most and least ubiquitin-immunoreactive neurites were stained with antibodies to beta-amyloid precursor protein, tau, glial fibrillary acidic protein, neurofilament protein, alpha B crystallin, GABA, cholecystokinin and somatostatin. The dystrophic neurites were found to also react with P-amyloid precursor protein. Electron microscopy showed the abnormal neurites to contain granulofilamentous material. Granular deposits with a diameter of 40-100nm were interspersed between randomly orientated 'fuzzy' or coated, straight or slightly curved filaments measuring 10-15 nm in diameter. These structures have not been seen in control brain and differ from age-related neuritic degeneration and neurites associated with amyloid. Immunohistochemically these structures most resemble CA 2/3 neurites seen in Lewy body disease, and, ultrastructurally, the intraneuronal filamentous inclusions in motor neuron disease. The areal density of these neurites was quantified in 20 microscopic fields in the superior frontal and anterior cingulate sections (Brodmann areas 8 and 24) and did not correlate with the Vonsattel grade, suggesting that they are an independent and possibly primary cortical pathology in Huntington's disease.