Abstract
BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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). DISCUSSION: 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.