| Title: | Disease Severity Staging System for NOTCH3-Associated Small Vessel Disease, Including CADASIL |
| Journal: | JAMA Neurology |
| Published: | 1 Jan 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39610302/ |
| DOI: | https://doi.org/10.1001/jamaneurol.2024.4487 |
| URL: | https://jamanetwork.com/journals/jamaneurology/articlepdf/2827600/jamaneurology_gravesteijn_2024_oi_240081_1732701289.58533.pdf |
Publication 14226
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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.</p>
Objective: To design a simple disease severity staging system that captures the broad clinicoradiological NOTCH3-SVD severity spectrum.</p>
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.</p>
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.</p>
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.</p>
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.</p>
12 Keywords
- Adult
- Aged
- CADASIL
- Cerebral Small Vessel Diseases
- Cohort Studies
- Female
- Humans
- Magnetic Resonance Imaging
- Male
- Middle Aged
- Receptor, Notch3
- Severity of Illness Index
50 Authors
- Gido Gravesteijn
- Julie W. Rutten
- Minne N. Cerfontaine
- Remco J. Hack
- Yi-Chu Liao
- Amy A. Jolly
- Stéphanie Guey
- Shao-Lun Hsu
- Jae-young Park
- Yun Yuan
- Anna Kopczak
- Nicola Rifino
- Sam J. Neilson
- Anna Poggesi
- Manjurul Islam Shourav
- Satoshi Saito
- Hiroyuki Ishiyama
- Ana Domínguez Mayoral
- Renata Nogueira
- Elena Muiño
- Pia Andersen
- Nicola De Stefano
- Gustavo Santo
- Nontapat Sukhonpanich
- Francesco Mele
- Ashley Park
- Jung Seok Lee
- Mar Rodríguez-Girondo
- Sebastiaan J. J. Vonk
- Amy Brodtmann
- Anne Börjesson-Hanson
- Leonardo Pantoni
- Israel Fernández-Cadenas
- Ana Rita Silva
- Vinícus V. A. Montanaro
- Rajesh N. Kalaria
- Diego Lopergolo
- Masafumi Ihara
- James F. Meschia
- Keith W. Muir
- Anna Bersano
- Francesca Pescini
- Marco Duering
- Jay Chol Choi
- Chen Ling
- Hyunjin Kim
- Hugh S. Markus
- Hugues Chabriat
- Yi-Chung Lee
- Saskia A. J. Lesnik Oberstein
1 Application
| Application ID | Title |
|---|---|
| 74162 | The full phenotypic spectrum of hereditary small vessel diseases and its modifiers |
Enabling scientific discoveries that improve human health