Disease Severity Staging System for NOTCH3-Associated Small Vessel Disease, Including CADASIL
Issued Date
2025-01-01
Resource Type
eISSN
21686157
Scopus ID
2-s2.0-85215647486
Pubmed ID
39610302
Journal Title
JAMA neurology
Volume
82
Issue
1
Start Page
49
End Page
60
Rights Holder(s)
SCOPUS
Bibliographic Citation
JAMA neurology Vol.82 No.1 (2025) , 49-60
Suggested Citation
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. Disease Severity Staging System for NOTCH3-Associated Small Vessel Disease, Including CADASIL. JAMA neurology Vol.82 No.1 (2025) , 49-60. 60. doi:10.1001/jamaneurol.2024.4487 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/103049
Title
Disease Severity Staging System for NOTCH3-Associated Small Vessel Disease, Including CADASIL
Author(s)
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.
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.
Author's Affiliation
Siriraj Hospital
National Yang Ming Chiao Tung University
Université Paris Cité
Peking University First Hospital
Department of Clinical Neurosciences
Asan Medical Center
Università degli Studi di Milano
Universität Basel
Azienda Ospedaliera Careggi
Università degli Studi di Firenze
Universidade de Coimbra
Monash University
Karolinska Universitetssjukhuset
Centro Hospitalar e Universitário de Coimbra
Foundation IRCCS Neurological Institute "C. Besta"
National Cerebral and Cardiovascular Center
Leids Universitair Medisch Centrum
Taipei Veterans General Hospital
Karolinska Institutet
Hospital de La Santa Creu I Sant Pau
Jeju National University School of Medicine
Newcastle University
Royal Melbourne Hospital
Università degli Studi di Siena
Mayo Clinic in Jacksonville, Florida
Ospedale Luigi Sacco - Polo Universitario
Hospital Universitario Virgen Macarena
SARAH Network of Rehabilitation Hospitals
University of Glasgow
Inserm
Klinikum der Universität München
Software developer in personal capacity
Hosp. Julia Kubitschek
National Yang Ming Chiao Tung University
Université Paris Cité
Peking University First Hospital
Department of Clinical Neurosciences
Asan Medical Center
Università degli Studi di Milano
Universität Basel
Azienda Ospedaliera Careggi
Università degli Studi di Firenze
Universidade de Coimbra
Monash University
Karolinska Universitetssjukhuset
Centro Hospitalar e Universitário de Coimbra
Foundation IRCCS Neurological Institute "C. Besta"
National Cerebral and Cardiovascular Center
Leids Universitair Medisch Centrum
Taipei Veterans General Hospital
Karolinska Institutet
Hospital de La Santa Creu I Sant Pau
Jeju National University School of Medicine
Newcastle University
Royal Melbourne Hospital
Università degli Studi di Siena
Mayo Clinic in Jacksonville, Florida
Ospedale Luigi Sacco - Polo Universitario
Hospital Universitario Virgen Macarena
SARAH Network of Rehabilitation Hospitals
University of Glasgow
Inserm
Klinikum der Universität München
Software developer in personal capacity
Hosp. Julia Kubitschek
Corresponding Author(s)
Other Contributor(s)
Abstract
Importance: 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.
