Association of NOTCH3 variant risk category with 2-year clinical and radiologic small vessel disease progression in patients with CADASIL

Abstract

Background and ObjectivesPathogenic variants in NOTCH3 are the main cause of hereditary cerebral small vessel disease (SVD). SVD-associated NOTCH3 variants have recently been categorized into high risk (HR), moderate risk (MR), or low risk (LR) for developing early-onset severe SVD. The most severe NOTCH3-associated SVD phenotype is also known as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to investigate whether NOTCH3 variant risk category is associated with 2-year progression rate of SVD clinical and neuroimaging outcomes in CADASIL.

MethodsA single-center prospective 2-year follow-up study was performed of patients with CADASIL. Clinical outcomes were incident stroke, disability (modified Rankin Scale), and executive function (Trail Making Test B given A t-scores). Neuroimaging outcomes were mean skeletonized mean diffusivity (MSMD), normalized white matter hyperintensity volume (nWMHv), normalized lacune volume (nLV), and brain parenchymal fraction (BPF). Cox regression and mixed-effect models, adjusted for age, sex, and cardiovascular risk factors, were used to study 2-year changes in outcomes and differences in disease progression between patients with HR-NOTCH3 and MR-NOTCH3 variants.

ResultsOne hundred sixty-two patients with HR (n = 90), MR (n = 67), and LR (n = 5) NOTCH3 variants were included. For the entire cohort, there was 2-year mean progression for MSMD (β = 0.20, 95% CI 0.17–0.23, p = 7.0 × 10−24), nLV (β = 0.13, 95% CI 0.080–0.19, p = 2.1 × 10−6), nWMHv (β = 0.092, 95% CI 0.075–0.11, p = 8.8 × 10−20), and BPF (β = −0.22, 95% CI −0.26 to −0.19, p = 3.2 × 10−22), as well as an increase in disability (p = 0.002) and decline of executive function (β = −0.15, 95% CI −0.30 to −3.4 × 10−5, p = 0.05). The HR-NOTCH3 group had a higher probability of 2-year incident stroke (hazard ratio 4.3, 95% CI 1.4–13.5, p = 0.011), and a higher increase in MSMD (β = 0.074, 95% CI 0.013–0.14, p = 0.017) and nLV (β = 0.14, 95% CI 0.034–0.24, p = 0.0089) than the MR-NOTCH3 group. Subgroup analyses showed significant 2-year progression of MSMD in young (n = 17, β = 0.014, 95% CI 0.0093–0.019, p = 1.4 × 10−5) and premanifest (n = 24, β = 0.012, 95% CI 0.0082–0.016, p = 1.1 × 10−6) individuals. DiscussionIn a trial-sensitive time span of 2 years, we found that patients with HR-NOTCH3 variants have a significantly faster progression of major clinical and neuroimaging outcomes, compared with patients with MR-NOTCH3 variants. This has important implications for clinical trial design and disease prediction and monitoring in the clinic. Moreover, we show that MSMD is a promising outcome measure for trials enrolling premanifest individuals.