To investigate the longitudinal imaging features of cerebral small vessel disease (SVD) in relation to rare NOTCH3 variants, including spatial patterns, dynamic patterns, and the interaction between the cortical atrophy and white matter lesions.

Previous studies reported that rare NOTCH3 variants were identified in over 10% of the general population and the carriers have a susceptibility to heavy SVD burden. The correlating imaging characteristics deserve in-depth investigation to uncover the important genetic predisposition in age-related SVD in the general population.

Rare NOTCH3 variants were identified through Whole-Exome Sequencing. The White matter hyperintensities (WMH) volume and WMH probability maps were assessed through quantitative segmentation. Brain structural volumes and vertex-wise cortex maps were obtained from the longitudinal FreeSurfer analysis suite. Between-group differences were compared through data statistical analysis of global measurements, and voxel/vertex-wise analysis of WMH maps or cortex maps.

A total of 1054 patients were included in the baseline analysis (13.56% rare NOTCH3 variant carriers), while 661 included in the longitudinal analysis (13.76% rare NOTCH3 variant carriers). We found that rare NOTCH3 variant carriers had heavier WMH burden (1.65 vs 0.85ml, P=0.025) and more presence of lacunes (23.78% vs 14.84, P=0.010). More importantly, rare NOTCH3 variant carriers had a distinct WMH distribution and progression pattern in periventricular areas. These features appeared more prominent in the EGFr-involving subgroup. Also, we found that rare NOTCH3 variant carriers showed susceptibility to worse cortical atrophy (β=-0.004, SE=0.002, adjusted for age and sex). Of most interest, the progressing of frontal brain atrophy is related to WMH progression, which indicated the role of rare NOTCH3 variant in age-related SVD and a structural network disconnection phenomenon.

Our findings posed a distinct MRI profile of age-related SVD in rare NOTCH3variant carriers and shed new light on the pathogenic mechanisms of rare NOTCH3 SNPs.