Update on the Epidemiology, Pathogenesis, and Biomarkers of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic disorder of the cerebral small blood vessels. It is caused by mutations in the NOTCH3 gene on chromosome 19, and more than 280 distinct pathogenic mutations have been reported to date. CADASIL was once considered a very rare disease with an estimated prevalence of 1.3-4.1 per 100,000 adults. However, recent large-scale genomic studies have revealed a high prevalence of pathogenic NOTCH3 variants among the general population, with the highest risk being among Asians. The disease severity and age at onset vary significantly even among individuals who carry the same NOTCH3 mutations. It is still unclear whether a significant genotype-phenotype correlation is present in CADASIL. The accumulation of granular osmiophilic material in the vasculature is a characteristic feature of CADASIL. However, the exact pathogenesis of CADASIL remains largely unclear despite various laboratory and clinical observations being made. Major hypotheses proposed so far have included aberrant NOTCH3 signaling, toxic aggregation, and abnormal matrisomes. Several characteristic features have been observed in the brain magnetic resonance images of patients with CADASIL, including subcortical lacunar lesions and white matter hyperintensities in the anterior temporal lobe or external capsule, which were useful in differentiating CADASIL from sporadic stroke in patients. The number of lacunes and the degree of brain atrophy were useful in predicting the clinical outcomes of patients with CADASIL. Several promising blood biomarkers have also recently been discovered for CADASIL, which require further research for validation.

Keywords: CADASIL; NOTCH3 mutation; biomarker; magnetic resonance imaging.

Fig. 1. Variable neuroimaging severity among patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) carrying different NOTCH3 mutations. Representative fluid-attenuated inversion recovery (FLAIR) images showing (A) typical magnetic resonance imaging (MRI) features including lacunar infarct, diffuse white-matter hyperintensities (WMHs) involving the corona radiata, periventricular regions, and anterior temporal poles in a patient with CADASIL carrying a heterozygous NOTCH3 p.Ser118Cys mutation located within epidermal growth factor-like repeat (EGFR)2 of the NOTCH3 protein; (B and C) variable severity of WMHs without anterior temporal pole involvement in a middle-age-onset patient with CADASIL and an elderly paucisymptomatic individual, both of whom carried a heterozygous p.Arg544Cys NOTCH3 mutation that altered the amino acid residue between EGFR13 and EGFR14; and (D) typical MRI features of CADASIL in a late-onset patient with a heterozygous p.Cys1250Arg mutation located within the EGFR32. AE, age at examination; AO, age at stroke onset; HTN, hypertension; DM, diabetes mellitus; lipid, hypercholesterolemia.

Fig. 2. Pathogenesis of CADASIL-causing NOTCH3 mutations. There is currently still no consensus on the pathogenesis of CADASIL. Major hypotheses proposed so far are aberrant NOTCH3 signaling, toxic NOTCH3 extracellular domain (NECD) aggregation, and matrisomes. ECM, extracellular matrix; ER, endoplasmic reticulum; GOM, granular osmiophilic material; IPAD, intramural periarterial drainage; NEXT, Notch3 extracellular truncation; NICD, Notch3 intracellular domain.

Fig. 3. Characteristic brain MRI features of CADASIL. Axial FLAIR MRI images of a 59-year-old male present prominent WMHs in the right anterior temporal lobe (arrow) (A). WMHs involving right external capsule (arrows) were noted in a 66-year-old female (B). Axial FLAIR MRI images of a 68-year-old male presented subcortical lacunar lesions at the junction between the white matter and the gray matter in the left anterior temporal lobe (arrowheads and the enlarged figure in the white box) (C). Multiple lacunar infarctions (arrows) at the bilateral subcortical white matter (D). Several cerebral microbleeds (arrows) with a right thalamic hematoma (arrowhead) (E) and marked brain atrophy (F). All patients had the same p.Arg544Cys mutation.