Cadasil.

Area of Science:

• Neurology
• Genetics
• Vascular Biology

Background:

• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is the leading inherited cause of stroke and vascular dementia.
• CADASIL shares features with sporadic small-artery disease but presents with earlier stroke onset, migraine with aura, and distinct white-matter lesions on MRI.
• The NOTCH3 gene, encoding a transmembrane receptor in arterial smooth muscle cells, is implicated in CADASIL pathogenesis.

Purpose of the Study:

• To review current understanding of CADASIL, including its molecular and vascular mechanisms.
• To highlight CADASIL as a model for common forms of subcortical ischemic strokes and vascular dementia.
• To discuss the feasibility of randomized clinical trials in CADASIL patients.

Main Methods:

• Review of functional and imaging studies in cell cultures, genetically engineered mice, and human patients.
• Analysis of pathogenetic mutations in the NOTCH3 gene.
• Examination of findings from a recent multicenter trial in patients with cognitive impairment.

Main Results:

• NOTCH3 mutations lead to cysteine alterations and accumulation in small arteries, driving CADASIL pathology.
• Studies reveal insights into the molecular and vascular mechanisms underlying the disease.
• A multicenter trial demonstrated the feasibility of conducting randomized trials in CADASIL patients.

Conclusions:

• CADASIL is a significant heritable cerebrovascular disorder with implications for understanding common stroke and dementia forms.
• Further research into NOTCH3 and vascular smooth muscle cell biology is crucial.
• Randomized clinical trials are feasible and necessary for advancing CADASIL treatment strategies.