Immunohistochemical study of cerebral amyloid angiopathy. III. Widespread Alzheimer A4 peptide in cerebral microvessel walls colocalizes with gamma trace in patients with leukoencephalopathy.

Brain tissue from 11 patients with cerebral amyloid angiopathy, changes of Alzheimer's disease, and variable degrees of subcortical leukoencephalopathy was examined by immunohistochemical methods, using primary antibodies to peptide segments representing portions of the Alzheimer A4 (beta-) peptide or gamma-trace peptide (seen most commonly in Icelandic patients with cerebral hemorrhage (hereditary cerebral hemorrhage with amyloidosis [HCHWA-I]). Variable A4 immunostaining was seen within cortical (and rarely white matter) parenchyma in the form of senile plaques (with or without central cores), and within capillary and arteriolar walls. Within individual patients, A4 deposits were often primarily parenchymal or vascular, and when they were vascular they tended to be more prominent in arteriolar than in capillary wall segments. Perivascular A4 deposits were often detected around strongly immunoreactive microvessels. Gamma-trace immunoreactivity was noted in many A4-positive microvessel walls, but staining was always less intense than with the anti-A4 antibody. We conclude that patients with severe cerebral amyloid angiopathy may show wide variation in the severity and topography of A4 deposits within brain parenchyma. A4 may colocalize with gamma-trace peptide, suggesting that A4 and gamma-trace forms of cerebral amyloid angiopathy may not be as biochemically distinctive as has been suggested. Other proteases or protease inhibitors may contribute to the pathogenesis of cerebral amyloid angiopathy or cerebral amyloid angiopathy-related stroke syndromes.