Small cerebral vessel disease in familial amyloid and non-amyloid angiopathies: FAD-PS-1 (P117L) mutation and CADASIL. Immunohistochemical and ultrastructural studies.

Three patients (of two unrelated Polish families) with early-adult onset dementia were subjects of the study. Two cases, previously diagnosed as familial Alzheimer's disease (FAD) with cerebral amyloid angiopathy (CAA), were confirmed by genetic and neuropathological studies, and one case of CADASIL was ultrastructurally confirmed by the presence of vascular granular osmiophilic material. Now the brain autopsy material has been reinvestigated using immunohistochemical (IHC) markers for vascular smooth muscle cells, paying special attention to collagen markers for extracellular matrix components and ultrastructural microvascular changes. In both diseases, IHC examination showed a reduction or loss of expression of smooth muscle actin (SMA) in tunica media of the cerebral arterioles. Fibrous thickening of the wall of the small meningeal arteries, intracerebral arterioles and numerous capillaries, with amyloid or granular deposits, drew our attention. In these vessels, marked expression of fibrillar collagen type III as well as strong immunoreactivity of the basement membrane (BM) component collagen type IV were found. The most damage was observed in the FAD/CAA double-barrel vessel wall and in some CADASIL arterioles changed by fibrinoid necrosis. The fibrous changes of the small vessels were more distinct in CADASIL t han in FAD/CAA. In FAD,electronmicroscopic examination revealed both amyloid and collagen fibres within the thickened BM of capillaries and the small arterioles. Clusters of collagen fibres between lamellae of BM, frequently in a pericyte position,were observed,and some were seen in the degenerated pericytes as well. Typical changes of the pericytes were accumulation of lipofuscin-like material and their degeneration. The mitochondria of the pericytes and of the endothelium were rare and swollen, with damaged and reduced cristae. The VSMCs of the arteriolar walls exhibited degenerative changes with atrophy of the cellular organelles. The fibrous,collagen-richCADASILsmallcerebralvessels,despite the weakness of the vessel wall due to reduction of VSMCs, appeared to be stronger than in FAD/CAA. These findings may suggest an accelerated process of transformation of the small cerebral vessels in which early onset of VSMCs loss is a predominant feature of the vascular changes in both presented diseases.