Disease Severity Staging System for NOTCH3-Associated Small Vessel Disease, Including CADASIL
Por:
Gravesteijn, G, Rutten, JW, Cerfontaine, MN, Hack, RJ, Liao, YC, Jolly, AA, Guey, S, Hsu, SL, Park, JY, Yuan, Y, Kopczak, A, Rifino, N, Neilson, SJ, Poggesi, A, Shourav, MMI, Saito, S, Ishiyama, H, Mayoral, AD, Nogueira, R, Muino, E, Andersen, P, De Stefano, N, Santo, G, Sukhonpanich, N, Mele, F, Park, A, Lee, JS, Rodriguez-Girondo, M, Vonk, SJJ, Brodtmann, A, Boerjesson-Hanson, A, Pantoni, L, Fernandez-Cadenas, I, Silva, AR, Montanaro, VVA, Kalaria, RN, Lopergolo, D, Ihara, M, Meschia, JF, Muir, KW, Bersano, A, Pescini, F, Duering, M, Choi, JC, Ling, C, Kim, H, Markus, HS, Chabriat, H, Lee, YC, Oberstein, SAJL
Publicada:
1 ene 2025
Ahead of Print:
1 nov 2024
Resumen:
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.
Filiaciones:
Gravesteijn, G:
Leiden Univ, Med Ctr, Dept Clin Genet, POB 9600, NL-2300 RC Leiden, Netherlands
Rutten, JW:
Leiden Univ, Med Ctr, Dept Clin Genet, POB 9600, NL-2300 RC Leiden, Netherlands
Cerfontaine, MN:
Leiden Univ, Med Ctr, Dept Clin Genet, POB 9600, NL-2300 RC Leiden, Netherlands
Hack, RJ:
Leiden Univ, Med Ctr, Dept Clin Genet, POB 9600, NL-2300 RC Leiden, Netherlands
Liao, YC:
Taipei Vet Gen Hosp, Dept Neurol, Taipei, Taiwan
Natl Yang Ming Chiao Tung Univ, Brain Res Ctr, Taipei, Taiwan
Jolly, AA:
Univ Cambridge, Dept Clin Neurosci, Stroke Res Grp, Cambridge Biomed Campus, Cambridge, England
Guey, S:
Univ Paris Diderot, Ctr Reference Malad Vasc Rares Cerveau & OEil CER, Paris, France
Inst Natl St & Rech Medicale INSERM, Neuroctr Magendie U1215, Paris, France
Hsu, SL:
Natl Yang Ming Chiao Tung Univ, Brain Res Ctr, Taipei, Taiwan
Park, JY:
Univ Ulsan, Coll Med, Asan Med Ctr, Dept Neurol, Seoul, South Korea
Yuan, Y:
Peking Univ First Hosp, Dept Neurol, Beijing, Peoples R China
Kopczak, A:
Ludwig Maximilians Univ Hosp Munich, Inst Stroke & Dementia Res, Munich, Germany
Rifino, N:
Fdn IRCCS Ist Neurol Carlo Besta, Cerebrovascular Unit, Milan, Italy
Neilson, SJ:
Univ Glasgow, Inst Neurosci & Psychol, Ctr Stroke & Brain Imaging, Glasgow G12 8QQ, Lanark, Scotland
Poggesi, A:
Careggi Univ Hosp, Stroke Unit, Florence, Italy
Univ Florence, Dipartimento Neurosci, Psicol, Area Farmaco & Salute Bambino, Florence, Italy
Shourav, MMI:
Mayo Clin, Dept Neurol, Jacksonville, FL USA
Saito, S:
Natl Cerebral & Cardiovasc Ctr, Dept Neurol, Suita, Japan
Ishiyama, H:
Natl Cerebral & Cardiovasc Ctr, Dept Neurol, Suita, Japan
Mayoral, AD:
Hosp Univ Virgen Macarena, Seville, Spain
Nogueira, R:
Hosp Lagoa, Dept Neurol, Rio De Janeiro, Brazil
Muino, E:
Hosp St Creu i St Pau, Inst Recerca St Pau, Dept Gastroenterol, Barcelona, Spain
Andersen, P:
Karolinska Univ Hosp, Theme Inflammat & Aging, Stockholm, Sweden
Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden
De Stefano, N:
Univ Siena, Dept Med Surg & Neurosci, Siena, Italy
Santo, G:
Hosp Univ Coimbra, Dept Gastroenterol, Unidade Local Saude Coimbra, Coimbra, Portugal
Sukhonpanich, N:
Univ Cambridge, Dept Clin Neurosci, Stroke Res Grp, Cambridge Biomed Campus, Cambridge, England
Mahidol Univ, Fac Med, Dept Med, Siriraj Hosp, Bangkok, Thailand
Mele, F:
Luigi Sacco Univ Hosp, Neurol & Stroke Unit, Milan, Italy
Park, A:
Royal Melbourne Hosp, Dept Neurol, Melbourne, Vic, Australia
Lee, JS:
Jeju Natl Univ, Coll Med, Dept Pediat, Jeju, South Korea
Rodriguez-Girondo, M:
Leiden Univ, Med Ctr, Dept Biomed Data Sci, Leiden, Netherlands
Vonk, SJJ:
DENSO Int Europe, Weesp, Netherlands
Brodtmann, A:
Monash Univ, Sch Translat Med, Melbourne, Australia
Boerjesson-Hanson, A:
Karolinska Univ Hosp, Theme Inflammat & Aging, Stockholm, Sweden
Karolinska Inst, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden
Pantoni, L:
Univ Milan, Neurosci Res Ctr, Dept Biomed & Clin Sci, Milan, Italy
Fernandez-Cadenas, I:
Hosp St Creu i St Pau, Inst Recerca St Pau, Dept Gastroenterol, Barcelona, Spain
Silva, AR:
Univ Coimbra, Ctr Res Neuropsychol & Cognit Behav Intervent, Coimbra, Portugal
Montanaro, VVA:
Hosp Sarah Kubitschek, Brasilia, DF, Brazil
Kalaria, RN:
Newcastle Univ, Translat & Clin Res Inst, Newcastle Upon Tyne, Northumberland, England
Lopergolo, D:
Univ Siena, Dept Med Surg & Neurosci, Siena, Italy
Ihara, M:
Natl Cerebral & Cardiovasc Ctr, Dept Neurol, Suita, Japan
Meschia, JF:
Mayo Clin, Dept Neurol, Jacksonville, FL USA
Muir, KW:
Univ Glasgow, Sch Cardiovasc & Metab Hlth, Glasgow City, Scotland
Bersano, A:
Fdn IRCCS Ist Neurol Carlo Besta, Cerebrovascular Unit, Milan, Italy
Pescini, F:
Careggi Univ Hosp, Stroke Unit, Florence, Italy
Univ Florence, Dipartimento Neurosci, Psicol, Area Farmaco & Salute Bambino, Florence, Italy
Duering, M:
Ludwig Maximilians Univ Hosp Munich, Inst Stroke & Dementia Res, Munich, Germany
Univ Basel, Med Image Anal Ctr MIAC, Basel, Switzerland
Choi, JC:
Jeju Natl Univ, Coll Med, Dept Pediat, Jeju, South Korea
Ling, C:
Peking Univ First Hosp, Dept Neurol, Beijing, Peoples R China
Kim, H:
Univ Ulsan, Coll Med, Asan Med Ctr, Dept Neurol, Seoul, South Korea
Markus, HS:
Univ Cambridge, Dept Clin Neurosci, Stroke Res Grp, Cambridge Biomed Campus, Cambridge, England
Chabriat, H:
Univ Paris Diderot, Ctr Reference Malad Vasc Rares Cerveau & OEil CER, Paris, France
Inst Natl St & Rech Medicale INSERM, Neuroctr Magendie U1215, Paris, France
Lee, YC:
Taipei Vet Gen Hosp, Dept Neurol, Taipei, Taiwan
Natl Yang Ming Chiao Tung Univ, Brain Res Ctr, Taipei, Taiwan
Natl Yang Ming Chiao Tung Univ, Ctr Intelligent Drug Syst & Smart Biodevices IDS2B, Hsinchu, Taiwan
Oberstein, SAJL:
Leiden Univ, Med Ctr, Dept Clin Genet, POB 9600, NL-2300 RC Leiden, Netherlands
Green Submitted, hybrid
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