Disease Severity Staging System for NOTCH3-Associated Small Vessel Disease, Including CADASIL
Authors: Gravesteijn Gido , Rutten Julie W. , Cerfontaine Minne N. , Hack Remco J. , Liao Yi-Chu , Jolly Amy A. , Guey Stéphanie , Hsu Shao-Lun , Park Jae-young , Yuan Yun , Kopczak Anna , Rifino Nicola , Neilson Sam J. , Poggesi Anna , Shourav Md Manjurul Islam , Saito Satoshi , Ishiyama Hiroyuki , Domínguez Mayoral Ana , Nogueira Renata , Muiño Elena , Andersen Pia , De Stefano Nicola , Santo Gustavo , Sukhonpanich Nontapat , Mele Francesco , Park Ashley , Lee Jung Seok , Rodríguez-Girondo Mar , Vonk Sebastiaan J. J. , Brodtmann Amy , Börjesson-Hanson Anne , Pantoni Leonardo , Fernández-Cadenas Israel , Silva Ana Rita , Montanaro Vinícus V. A. , Kalaria Rajesh N. , Lopergolo Diego , Ihara Masafumi , Meschia James F. , Muir Keith W. , Bersano Anna , Pescini Francesca , Duering Marco , Choi Jay Chol , Ling Chen , Kim Hyunjin , Markus Hugh S. , Chabriat Hugues , Lee Yi-Chung , Lesnik Oberstein Saskia A. J. 
Published: November 2024

ImportanceTypical 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.ObjectiveTo design a simple disease severity staging system that captures the broad clinicoradiological NOTCH3-SVD severity spectrum.Design, Setting, and ParticipantsA 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 MeasuresPercentage 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.ResultsThe 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 RelevanceThe 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.