Pattern of Brain Parenchymal Damage Related to Cerebral Small Vessel Disease in Carriers of Rare NOTCH3 Variants

Abstract

Background and objectives:Previous studies reported that carriers of rare NOTCH3 variants comprised over 10% of the general population and are susceptible to a heavy overall burden of cerebral small vessel disease, while the injury patterns remain uncovered. This study aimed to investigate the imaging features in relation to rare NOTCH3 variants and the interaction between cortical atrophy and white matter lesions from a longitudinal view, with respect to spatial and dynamic patterns.Methods:As part of a community-based cohort, we included participants with complete Whole-Exome Sequencing and brain MRI in the baseline analysis. All participants were invited for a five-year follow-up MRI, and those who did not complete the follow-up were excluded from the longitudinal analysis. NOTCH3 variants with minor allele frequency <1% in all four public population databases were defined as rare variants. We utilized general linear models to compare the volume of white matter hyperintensity volume (WMH) and brain parenchymal fraction between rare NOTCH3 variant carriers and non-carriers. Additionally, we compared the WMH probability map and vertex-wise cortex maps at a voxel/vertex-wise level.Results:1054 participants were included in baseline analysis (13.56% carried rareNOTCH3variants), among whom 661 had a follow-up brain MRI (13.76% carried rareNOTCH3variants). RareNOTCH3variant carriers had a heavier white matter hyperintensity burden (1.65 vs 0.85 ml, p=0.025) and had more extensive WMH distributed in the periventricular areas. We also found that rareNOTCH3variant carriers were susceptible to worse cortical atrophy (β=-0.004, SE=0.002, p=0.057, adjusted for age and sex). Cortical atrophy of multiple regions in the frontal and parietal lobes was related to white matter hyperintensity progression.Discussion:Individuals with rareNOTCH3variants have a distinct pattern of brain parenchymal damage related to CSVD. Our findings uncover the important genetic predisposition in age-related cerebral small vessel disease in the general population.