Age-related plaque morphology and C-terminal heterogeneity of amyloid β in Dutch-type hereditary cerebral hemorrhage with amyloidosis

The evolvement of amyloid β (Aβ) deposition in the frontal cerebral cortex of 24 patients of increasing age with Dutch-type hereditary cerebral hemorrhage with amyloidosis (HCHWA-D) was studied using end-specific monoclonal antibodies to Aβx-42 (Aβ42) or Aβx-40 (Aβ40) and markers for degenerating neurites. Aβ42 immunostaining revealed parenchymal Aβ deposits with a heterogeneous morphology and distribution, i.e., clouds, fine/dense diffuse, coarse, and homogeneous plaques. Clouds and diffuse plaques were associated with glial Aβ granules. Aβ40 labeling was absent in clouds/fine diffuse plaques, inconsistent and variably intense in dense diffuse/¶coarse plaques and consistent in homogeneous plaques. In a subset of Aβ40-positive plaques, degenerating neurites – without tauopathy – and/or amyloid cores were observed. Electron microscopy revealed no apparent amyloid fibrils in fine diffuse plaques, small bundles of fibrils in dense diffuse/homogeneous plaques, and amyloid masses in coarse plaques. The parenchymal Aβ pathology was age-related: the ratio of fine to dense diffuse plaques decreased with age, clouds were limited to younger patients; coarse plaques to the oldest old. Homogeneous/cored plaques were present most consistently in older patients. Plaque density did not increase with age. Vascular Aβ deposits stained for both Aβ species, but exclusively Aβ42-positive, presumably recent deposits were also observed. This study suggests that HCHWA-D is a model of plaque evolution in which clouds leave fine diffuse plaques, which may become dense diffuse and ultimately coarse or homogeneous plaques.