CADASIL: do the clinical and MRI profiles differ for women and men?

See related article, page 137. In 1977, Sourander and Walinder1 described a family with neuropsychiatric disease, a relapsing course, and cognitive impairment. The disorder began in early adulthood, affected women and men, and lasted for 10 to 15 years. At brain necropsy, there were multiple small infarcts, particularly of the basal ganglia, thalamus, periventricular white matter, and pons. Vascular changes were prominent in small muscular arteries and in arterioles of the pia-arachnoid, basal ganglia, thalamus, mesencephalon, pons, and cerebellum and in small vessels of the cerebral and cerebellar white matter. The disorder was thought to be genetically transmitted by an autosomal-dominant mechanism and was called hereditary multi-infarct dementia. In 1993, the monogenic disorder, cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), was mapped to chromosome 19q12 by Tournier-Lasserve et al.2 Now, CADASIL is recognized as the most common hereditary cause of vascular cognitive impairment and may present clinically as migraine with aura, mood disturbance, recurrent strokes, cognitive impairment, and MRI-based extensive white matter lesions, lacunar infarcts, cerebral microbleeds, and brain atrophy.3–5 Most cases are caused by missense mutations of the Notch3 gene that create or eliminate cysteine residues.6 Characteristic ultrastructural changes in skin and muscle vessels include granular osmophilic material in the arteriolar media. During the past several decades, our understanding of CADASIL has advanced. In relation to clinical manifestations, it has been suggested that: cardiovascular risk factors (eg, hypertension, smoking) may modulate clinical expression of CADASIL7; migraine with atypical aura may be a distinguishing feature of the disorder8; and overall burden of lacunar infarcts may importantly impact on the occurrence of cognitive impairment and disability, whereas white matter lesions may not be predictive of these domains.9,10 In relation to structural brain changes elucidated by neuroimaging studies: diffusion tensor imaging may define microstructural tissue alterations in asymptomatic and symptomatic brain areas affected by CADASIL11,12; brain parenchymal fraction may be predicted by volume of lacunar lesions and increase in mean cerebral apparent diffusion coefficient13; however, individual lacunar volume may not be related to other CADASIL neuroimaging lesions or vascular risk factors14; and there may be segmentation of lacunar infarcts.15 When neuropathological examination is taken into account, neuronal apoptosis may be associated with the burden of subcortical ischemic lesions.16 Furthermore, fibrotic thickening of arteriolar walls that supply the lenticular nucleus may occur without stenosis of the vessel lumen and differs from that of stenotic vessels supplying the white matter. Therefore, stenosis of vessels supplying the white matter and hemodynamic factors may be the basis of white matter lesions and lacunar infarcts, respectively.17 Finally, the following physiological parameters may be abnormal: endothelial-dependent vasodilatation in resistance arteries and vasoconstrictor responses18,19; heart rate variability20; systemic blood pressure profile (lower than expected)21; and cerebrovascular CO2 reactivity.22 A recently published guidance statement recommends genetic testing for CADASIL as being reasonable in patients with progressive cognitive impairment, appropriate imaging findings, and a family history suggestive of autosomaldominant inheritance (class IIa and level of evidence A), and it may be considered in sporadic patients with suggestive clinical and imaging findings (class IIb and level of evidence B).3 In this issue of Stroke, Gunda et al23 advance our knowledge of CADASIL by providing a comparison of clinical and neuroimaging features in women and men.