Serum NOTCH3 Extracellular Domain in Patients With CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease caused by variants in the NOTCH3 gene. The extracellular domain of NOTCH3 (N3ECD) has been proposed as a potential serum biomarker for CADASIL. However, its diagnostic utility remains uncertain. The aim of this study was to evaluate serum N3ECD levels in patients with CADASIL and assess their potential as a diagnostic or prognostic biomarker.

Serum N3ECD levels were measured using ELISA in 2 independent CADASIL cohorts: a Korean cohort (n = 78) and a Japanese cohort (n = 64). Each group included patients with genetically confirmed CADASIL. In addition, the Korean cohort included age-matched and sex-matched healthy controls and patients with sporadic ischemic stroke. Statistical analyses assessed group differences and correlations with clinical and radiologic features.

Serum N3ECD levels did not differ significantly among patients with CADASIL, healthy controls, and patients with ischemic stroke in the Korean cohort (p = 0.149). However, in the Korean cohort, N3ECD levels showed a positive correlation with age (r = 0.329, p = 0.001), particularly in individuals carrying the p.Arg544Cys variant. Similarly, in the Japanese cohort, age-related increases in N3ECD levels were observed in p.Arg75Pro variant carriers (r = 0.661, p = 0.014). No significant associations were found between N3ECD levels and MRI markers or clinical outcomes such as stroke occurrence or cognitive impairment.

These findings suggest that serum N3ECD alone has limited value as a standalone diagnostic marker for CADASIL. However, the age-dependent increase in N3ECD levels observed in specific variant carriers may reflect underlying pathophysiologic changes and could serve as a clue to disease progression. Further studies are warranted to clarify the mechanistic role of N3ECD in CADASIL and to evaluate its potential as a marker for monitoring disease progression or therapeutic response. Continued biomarker discovery efforts are needed to improve diagnosis and management of CADASIL.