Gravesteijn G.Rutten J.W.Cerfontaine M.N.Hack R.J.Liao Y.C.Jolly A.A.Guey S.Hsu S.L.Park J.Y.Yuan Y.Kopczak A.Rifino N.Neilson S.J.Poggesi A.Shourav M.M.I.Saito S.Ishiyama H.Domínguez Mayoral A.Nogueira R.Muiño E.Andersen P.De Stefano N.Santo G.Sukhonpanich N.Mele F.Park A.Lee J.S.Rodríguez-Girondo M.Vonk S.J.J.Brodtmann A.Börjesson-Hanson A.Pantoni L.Fernández-Cadenas I.Silva A.R.Montanaro V.V.A.Kalaria R.N.Lopergolo D.Ihara M.Meschia J.F.Muir K.W.Bersano A.Pescini F.Duering M.Choi J.C.Ling C.Kim H.Markus H.S.Chabriat H.Lee Y.C.Lesnik Oberstein S.A.J.Mahidol University2025-01-272025-01-272025-01-01JAMA neurology Vol.82 No.1 (2025) , 49-60https://repository.li.mahidol.ac.th/handle/20.500.14594/103049Importance: Typical cysteine-altering NOTCH3 (NOTCH3cys) 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 NOTCH3cys variant, availability of brain magnetic resonance imaging, and modified Rankin Scale score. The discovery cohort consisted of 195 NOTCH3cys-positive cases from families with CADASIL; the validation set included 1713 NOTCH3cys-positive cases from 15 countries. The UK Biobank cohort consisted of 101 NOTCH3cys-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 NOTCH3cys-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 NOTCH3cys 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.MedicineArticleSCOPUS10.1001/jamaneurol.2024.44872-s2.0-852156474862168615739610302