Cadasil

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is the most common heritable cause of stroke and vascular dementia in adults. Clinical and neuroimaging features resemble those of sporadic small-artery disease, although patients with CADASIL have an earlier age at onset of stroke events, an increased frequency of migraine with aura, and a slightly variable pattern of ischaemic white-matter lesions on brain MRI. NOTCH3 (Notch homolog 3), the gene involved in CADASIL, encodes a transmembrane receptor primarily expressed in systemic arterial smooth-muscle cells. Pathogenetic mutations alter the number of cysteine residues in the extracellular domain of NOTCH3, which accumulates in small arteries of affected individuals. Functional and imaging studies in cultured cells, genetically engineered mice, and patients with CADASIL have all provided insights into the molecular and vascular mechanisms underlying this disease. A recent multicentre trial in patients with cognitive impairment emphasises the feasibility of randomised trials in patients with CADASIL. In this Review, we summarise the current understanding of CADASIL, a devastating disorder that also serves as a model for the more common forms of subcortical ischaemic strokes and pure vascular dementia.

Consensus statement for diagnosis of subcortical small vessel disease

“…The clinical presentation of CADASIL is characterized by migraine with aura, subcortical ischemic events, mood disturbances, apathy, and cognitive impairment. 45 Migraine with aura is usually the first symptom. Transient ischemic attacks and ischemic strokes are the most frequent manifestations in CADASIL, often occurring in the absence of conventional vascular risk factors.…”

“…Eventually, multiple strokes cause gait problems, urinary incontinence, depression, and pseudobulbar palsy. 45,46 Leukoaraiosis Leukoaraiosis was derived from the Greek words for 'white' and 'rarified', and was originally proposed to describe the low signal seen on CT in the white matter for which a concise etiology was lacking. 47 The attenuated signal on CT corresponds to high signal on T2-weighted MRI.…”

Differences in proliferation rate between CADASIL and control vascular smooth muscle cells are related to increased TGFβ expression

“…Cerebral autosomal‐dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary small vessel disease and is the most common genetic cause of stroke and vascular dementia in adults 1, 2. The clinical presentation of CADASIL is characterized by migraine with aura, transient neurological symptoms, mood disturbances and cognitive impairment 3, 4, 5, 6, 7.…”

CADASIL: two new cases with intracerebral hemorrhage

“…Neuroimaging abnormalities such as cerebral white matter lesions (WMLs), lacunes, and microbleeds in the CADASIL patients are related to this cerebral small‐vessel histopathology 1. While CADASIL is considered a primarily ischemic form of vascular dementia, spontaneous intracerebral hemorrhage (ICH) has recently been reported in association with CADASIL,2, 3, 4, 5, 6 suggesting that the structural fragility of arterial walls may lead to ICH attacks.…”