Lessons from CADASIL

Abstract

Vascular dementia (VaD) includes several different vascular mechanisms and changes in the brain. Among VaD, CADASIL is an inherited angiopathy caused by mutations in the Notch3 gene. The pathological hallmark of CADASIL is a granular osmiophilic material deposit (GOM) that is not only found in the brain, but also in the peripheral vascular tree. Consequently, a window into the brain was opened from a strictly neurological disease with tremendous consequences thanks to a skin biopsy. The latter was and continues to be used as a diagnostic tool for CADASIL, despite an immunohistochemical test that is now available. The skin biopsy first used as a diagnostic tool revealed the existence of numerous other VaDs presenting systemic vascular changes. Later, skin biopsy became a research tool, and a morphological skin vessel change classification was proposed on 300 patients. Interestingly, similar skin vessel lesions appear to be related to the same biological modifications. In addition, an early destruction of the medial muscle cells was noticed in 74% of cases. Because vascular smooth muscle cells secrete a powerful endothelial permeability factor (VEGF), their destruction could lead to a decrease in vascular permeability. Cocultures of endothelial cells with vascular muscle cells showed that their presence doubled vascular permeability. Thus, alteration or the loss of vascular muscle cells likely results in hypopermeability, in addition to vessel wall hypotonia and a watershed hypoperfusion. The wealth of information brought forth by knowledge of CADASIL provided new tools for research and clues for understanding the consequences of vascular impairments in dementia.