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 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 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 5-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 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 NOTCH3 variant carriers and noncarriers. In addition, we compared the WMH probability map and vertex-wise cortex maps at a voxel/vertex-wise level.

Results: A total of 1,054 participants were included in baseline analysis (13.56% carried rare NOTCH3 variants), among whom 661 had a follow-up brain MRI (13.76% carried rare NOTCH3 variants). Rare NOTCH3 variant 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 rare NOTCH3 variant 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 rare NOTCH3 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.

Figure 1. Study Flow Diagram

EGFr = epidermal growth factor-like repeat; WES = whole-exome sequencing; WMH = white matter hyperintensity.

Figure 2. Rare NOTCH3 Variants and Aging-Related Alterations of White Matter Hyperintensity Volume and Brain Parenchymal Fraction

(A) The left plot depicts the dynamic change in white matter hyperintensity volume (WMH) volume (mL) over the follow-up period along with age at the individual level and stratified by variant groups. (B) The dynamic change in brain parenchymal fraction (BPF) stratified by variant groups. β groups denote the estimated effect of age*group interaction in the linear fit of longitudinal change; β time denotes the estimated change in WMH volume or BPF for every 1-year increase in age.

Figure 3. Rare NOTCH3 Variants and Spatial Patterns of WMH

(A) The distribution of baseline WMH in different variant groups, and (B) the distribution of WMH progression in different variant groups. The total volumes of baseline WMH or WMH progression in different groups were shown as a box plot on the left. Brain slices show the average WMH probability map for the NOTCH3(+) group (yellow scale, upper panel) or the EGFr(+) group (red scale, lower panel) on top of that of the NOTCH3(−) group (blue scale). The threshold for the NOTCH3(+) group is set at 0.007 to 0.3 in baseline maps and 0.011 to 0.1 in progression maps while for the EGFr(+) group, it is set at 0.014 to 0.3 in baseline maps and 0.023 to 0.1 in progression maps. The percentage of participants who had WMH in a particular voxel is depicted in the color bar. (C) The significant clusters where the baseline WMH is positively related to rare NOTCH3 variants (upper panel) or EGFr-involving variants (lower panel) (threshold-free cluster enhancement corrected p < 0.05, adjusted for age, sex, hypertension, diabetes, hyperlipidemia, and any smoking history). The p values of correlation tests between the variant status and probability of WMH in a particular voxel are depicted in the red-blue color bar. No significant clusters were found comparing WMH progression rate maps between variant groups. EGFr = epidermal growth factor-like repeat; WMH = white matter hyperintensities.

Figure 4. Rare NOTCH3 Variants and Spatial Patterns of Cortical Atrophy

(A) The baseline cortex volume map related to EGFr-involving variant status. (B) The cortex volume rate map related to the NOTCH3 variant of EGFr-involving variant status, in raw models (model 1) and adjusted models for age and sex (model 2). (C) Significant clusters of cortex volume rate map related to the progression of WMH volume, in the NOTCH3 (−) group and the NOTCH3 (−) group, respectively (adjusted for age and sex). The color scale at the bottom represents the statistical significance of a positive or negative relationship (cluster-wise p-value <0.05, multicomparison corrected). Significant clusters were labeled according to the Desikan-Killiany atlas. EGFr = epidermal growth factor-like repeat; WMH = white matter hyperintensities.