CADASIL: what component of the vessel wall is really a target for Notch 3 gene mutations?

Abstract

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease leading to cognitive decline, dementia and recurrent strokes. The underlying angiopathy of the small vessels is characterized by basophilic degeneration of the media, Notch 3 protein accumulation in vessel wall and a unique type of ultrastructural deposits located nearby the basal lamina. In some cases of CADASIL, morphological changes similar to those observed in panarteritis nodosa (PAN) were found. PAN-like changes manifested as fibrinoid necrosis of the tunica media and perivascular inflammatory infiltrates were found in arteries not only in the central nervous system but also in internal organs. Presence of PAN-like changes indicates that some autoimmunological mechanisms can participate in the CADASIL process. Although vascular smooth muscle cells seem to be a primary target of the pathogenic process triggered by mutations in Notch 3 gene they are probably not the only target. This article gives a brief overview on the morphologic spectrum of the vascular pathological changes in CADASIL and discusses some of the relevant mechanisms that lead from Notch 3 mutations to ischemic infarcts.