Prognostic Significance of NOTCH3 Small Vessel Disease Staging for the NOTCH3 p.R544C Variant

The NOTCH3-SVD staging system was developed to characterize NOTCH3-related small vessel disease (SVD), but it has not been validated in cohorts carrying a single pathogenic variant. We applied this system to Taiwanese individuals with the NOTCH3 p.R544C variant to evaluate its clinical relevance and prognostic value.

We enrolled individuals carrying the NOTCH3 p.R544C variants from 2 sources: the Taiwan Precision Medicine Initiative, a hospital-based volunteer cohort undergoing genetic screening, and the Taiwan CADASIL Registry, which includes individuals with symptomatic SVD and confirmed NOTCH3 pathogenic variants. Participants were classified using the NOTCH3-SVD staging system, ranging from stage 0 (premanifest stage) to stage 4B (end stage). Baseline characteristics were compared across stages. Multivariable models were used to identify factors associated with prior stroke or cognitive impairment. Stroke-free survival was analyzed using Kaplan-Meier curves and Cox proportional hazards models. Cognitive decline, assessed by Mini-Mental State Examination, was evaluated using a generalized estimating equation.

Among 260 individuals (median age 62 years; 49% male), the median stage was 2A. Higher stages were positively associated with prior stroke, cognitive impairment, gait disturbance, and psychiatric symptoms and inversely associated with headache (all p values < 0.05). Fewer years of education (OR 0.90, 95% CI 0.83-0.98, p = 0.012), hypertension (OR 2.34, 95% CI 1.18-4.67, p = 0.016), and higher NOTCH3-SVD stage (OR 3.70 per 1-substage increase, 95% CI 2.61-5.25, p < 0.001) were significantly associated with prior stroke or cognitive impairment. During a median follow-up of 1.9 years, individuals with stage ≥2B had a higher risk of incident stroke than those with stage <2B (annual risk 6.7% vs 2.0%, log-rank p = 0.023; adjusted hazard ratio 3.38; 95% CI 1.10-10.4, adjusted for age and hypertension). MMSE scores declined progressively over 2 years in individuals with stage ≥2B, whereas those with stage <2B remained cognitively stable (p for interaction = 0.024).

The NOTCH3-SVD staging system effectively stratified disease burden and predicted incident stroke and cognitive decline in individuals with NOTCH3 p.R544C, with stage ≥2B indicating a higher risk.