Pattern of Brain Parenchymal Damage Related to Cerebral Small Vessel Disease in Carriers of Rare <i>NOTCH3</i> Variants.

Abstract

Previous studies reported that carriers of rare <i>NOTCH3</i> variants comprised more than 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 <i>NOTCH3</i> variants and the interaction between cortical atrophy and white matter lesions from a longitudinal view, with respect to spatial and dynamic patterns. 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 5-year follow-up MRI, and those who did not complete the follow-up were excluded from the longitudinal analysis. <i>NOTCH3</i> variants with minor allele frequency <1% in all 4 public population databases were defined as rare variants. We used general linear models to compare the volume of white matter hyperintensity (WMH) volume and brain parenchymal fraction between rare <i>NOTCH3</i> variant carriers and noncarriers. In addition, we compared the WMH probability map and vertex-wise cortex maps at a voxel/vertex-wise level. A total of 1,054 participants were included in baseline analysis (13.56% carried rare <i>NOTCH3</i> variants), among whom 661 had a follow-up brain MRI (13.76% carried rare <i>NOTCH3</i> variants). Rare <i>NOTCH3</i> variant carriers had a heavier white matter hyperintensity burden (1.65 vs 0.85 mL, <i>p</i> = 0.025) and had more extensive WMH distributed in the periventricular areas. We also found that rare <i>NOTCH3</i> variant carriers were susceptible to worse cortical atrophy (β = -0.004, SE = 0.002, <i>p</i> = 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. Individuals with rare <i>NOTCH3</i> variants 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.