SERUM NOTCH3 EXTRACELLULAR DOMAIN LEVEL AS A BLOOD BIOMARKER FOR SCREENING CADASIL

초록

Background and Aims: We aimed to investigate serum levels of NOTCH3 extracellular domain (N3ECD) as a potential biomarker for screening cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and assessment of the disease severity by comparing those serum levels to healthy control and as well as to sporadic ischemic stroke patients. Methods: The study participants consisted of 64 patients with genetically proven CADASIL patients (Jeju CADASIL cohort), age- and sex-matched 64 healthy individuals and same number of patients with sporadic ischemic stroke. We enrolled additional 19 CADASIL patients from other institutions with various pathogenic variants for validation.The N3ECD levels were determined in serum using a sandwich enzyme-linked immunosorbent assay (ELISA). Results: Of 64 patients in the Jeju CADASIL cohort (mean age: 66 years, men: 47%), 58 patients (90.6%) had the same p.Arg544Cys mutation. Serum N3ECD level was significantly decreased in the Jeju CADASIL cohort compared to healthy participants and sporadic stroke controls (19.5±10.4 ng/ml vs. 78.9±36.3 ng/ml vs. 74.2±.43.5 ng/ml, P <0.001). The area under ROC curve was 0.989 (95% Confidence Interval [CI], 0.997-1.000) for CADASIL vs. healthy controls and 0.933 (95% CI, 0.888-0.978) for CADASIL vs. sporadic stroke with a cut-off value of 35.0ng/ml. Conclusions: The serum N3ECD showed high sensitivity and reasonable specificity in differentiating CADASIL from healthy control or sporadic stroke. Unlike other blood biomarker for cerebral small blood vessel, this ELISA-based serum N3NCD measurement is specific for CADASIL and can be used as a screening test for CADASIL.