Disease Severity Staging System for NOTCH3-Associated Small Vessel Disease, Including CADASIL

Importance Typical cysteine-altering NOTCH3 (NOTCH3(cys)) variants are highly prevalent (approximately 1 in 300 individuals) and are associated with a broad spectrum of small vessel disease (SVD), ranging from early-onset stroke and dementia (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) to nonpenetrance. A staging system that captures the full NOTCH3-SVD severity spectrum is needed and currently lacking. Objective To design a simple disease severity staging system that captures the broad clinicoradiological NOTCH3-SVD severity spectrum. Design, Setting, and Participants A cohort study was performed in which the NOTCH3-SVD severity staging system was developed using a discovery cohort (2019-2020) and validated in independent international CADASIL cohorts (1999-2023) and the UK Biobank. Clinical and imaging data were collected from participants originating from 23 international CADASIL cohorts and from the UK Biobank. Eligibility criteria were presence of a NOTCH3(cys) variant, availability of brain magnetic resonance imaging, and modified Rankin Scale score. The discovery cohort consisted of 195 NOTCH3(cys)-positive cases from families with CADASIL; the validation set included 1713 NOTCH3(cys)-positive cases from 15 countries. The UK Biobank cohort consisted of 101 NOTCH3(cys)-positive individuals. Data from 2-year (2019-2023) and 18-year (1999-2017) follow-up studies were also analyzed. Data analysis was performed from July 2023 to August 2024. Main Outcomes and Measures Percentage of cases following the sequence of events of the NOTCH3-SVD stages, and the association between the stages and ischemic stroke, intracerebral hemorrhage, global cognition, processing speed, brain volume, brain microstructural damage, and serum neurofilament light chain (NfL) level. Results The NOTCH3-SVD staging system encompasses 9 disease stages or substages, ranging from stage 0 (premanifest stage) to stage 4B (end stage). Of all 1908 cases, which included 195 in the discovery cohort (mean [SD] age, 52.4 [12.2] years) and 1713 in the validation cohorts (mean [SD] age, 53.1 [13.0] years), 1789 (94%) followed the sequence of events defined by the NOTCH3-SVD staging system. The NOTCH3-SVD stages were associated with neuroimaging outcomes in the NOTCH3(cys)-positive cases in the CADASIL cohorts and in the UK Biobank and with cognitive outcomes and serum NfL level in cases from the CADASIL cohorts. The NOTCH3-SVD staging system captured disease progression and was associated with 18-year survival. Conclusions and Relevance The NOTCH3-SVD staging system captures the full disease spectrum, from asymptomatic individuals with a NOTCH3(cys) variant to patients with end-stage disease. The NOTCH3-SVD staging system is a simple but effective tool for uniform disease staging in the clinic and in research.