Cadasil

Loss of arterial smooth muscle cells (SMCs) and abnormal accumulation of the extracellular domain of the NOTCH3 receptor (Notch3ECD) are the two core features of CADASIL, a common cerebral small vessel disease caused by highly stereotyped dominant mutations in NOTCH3. Yet, the relationship between NOTCH3 receptor activity, Notch3ECD accumulation and arterial SMC loss has remained elusive, hampering the development of disease-modifying therapies. Using dedicated histopathological and multiscale imaging modalities, we could detect and quantify previously undetectable CADASIL-driven arterial SMC loss in the central nervous system of mice expressing the archetypal Arg169Cys mutation. We found that arterial pathology was more severe and Notch3ECD accumulation greater in transgenic mice overexpressing the mutation on a wild-type Notch3 background (TgNotch3R169C) than in knock-in Notch3R170C/R170C mice expressing this mutation without a wild-type Notch3 copy. Notably, expression of Notch3-regulated genes was essentially unchanged in TgNotch3R169C arteries. We further showed that wild-type Notch3ECD co-aggregated with mutant Notch3ECD and that elimination of one copy of wild-type Notch3 in TgNotch3R169C was sufficient to attenuate Notch3ECD accumulation and arterial pathology. These findings suggest that Notch3ECD accumulation, involving mutant and wild-type NOTCH3, is a major driver of arterial SMC loss in CADASIL, paving the way for NOTCH3-lowering therapeutic strategies.

This study aimed to assess alterations in retinal vascular density in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients using optical coherence tomography angiography (OCTA) and investigate their association with MRI and cognitive features.

Twenty-five patients with CADASIL and forty healthy controls were evaluated by Cirrus HD-OCT 5000 with AngioPlex OCTA to determine changes in macular retinal vasculature. Retinal vasculature parameters between two groups were compared. The MRI lesion burden and neuropsychological scales were also examined in patients. The association between OCTA parameters and MRI/cognitive features was evaluated using partial Spearman rank correlation.

The vessel density and perfusion density of whole image in macular region (vessel density: t =  - 2.834, p = 0.005; perfusion density: t =  - 2.691, p = 0.007) were significantly decreased in patients with CADASIL. Moreover, vessel density of whole image in macular region was negatively associated with Fazekas scores (ρ =  - 0.457; p = 0.025) and the number of lacunar infractions (ρ =  - 0.425, p = 0.038) after adjustment for age. Decreased macular vessel density and perfusion density of whole image were also associated with MoCA scores (vessel density: ρ = 0.542, p = 0.006; perfusion density: ρ = 0.478, p = 0.018) and other domain-specific neuropsychological tests (p < 0.05) after adjustment for age.

Decreased retinal vascular density was associated with increased MRI lesion burden and cognitive impairment in patients with CADASIL. Our findings suggest that the degree of retinal vascular involvement, as demonstrated by OCTA, may be consistent with the severity of MRI lesions and the degree of cognitive impairment in patients.