Commissural Fiber Disruption Is Associated With Symptom Onset in Cerebral Autosomal-Dominant Arteriopathy With...

Extensive white matter hyperintensities are a hallmark of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a monogenic small-vessel disease caused by pathogenic NOTCH3 variants. This study aimed to assess microstructural white matter integrity in symptomatic and premanifest CADASIL individuals utilizing peak width of skeletonized mean diffusivity (PSMD), a diffusion tensor imaging-based metric.

A total of 161 participants were recruited, including 60 patients with symptomatic CADASIL, 67 preclinical NOTCH3 variant carriers, and 34 healthy controls. All participants underwent brain magnetic resonance imaging and PSMD analysis. Cognitive function and disability were assessed using the Mini-Mental State Examination, Trail Making Test Part A, and modified Rankin Scale. Longitudinal magnetic resonance imaging scans were available for 35 participants, and their radiological progression was assessed. PSMD was analyzed in projection, association, and commissural fibers.

Among fiber tracts, commissural fiber PSMD exhibited the strongest correlations with cognitive function and disability, explaining the most variance (40%-60%). Symptomatic patients with CADASIL had significantly higher commissural fiber PSMD values (5.78±1.94×10^-4 mm²/s) compared with preclinical carriers (2.79±0.68×10^-4 mm²/s) and healthy controls (2.82±0.68×10^-4 mm²/s). Higher commissural fiber PSMD distinguished patients with symptomatic CADASIL from preclinical carriers (odds ratio, 13.59 [95% CI, 5.25-35.20]; P <0.001) and predicted faster disease progression, including increased lacune numbers, cerebral microbleed counts, and advancing brain atrophy.

Commissural fiber PSMD may serve as a robust biomarker for assessing disease severity and progression in CADASIL. These findings highlight its potential clinical utility in patient stratification and prognostication.