Related Experiment Video
Updated: Jun 6, 2025
Signal Acquisition, Score Interpretation, and Economics of a Non-Invasive Point-of-Care Test for Coronary Artery Disease
Published on: August 9, 2024
Disease Severity Staging System for NOTCH3-Associated Small Vessel Disease, Including CADASIL
Gido Gravesteijn1, Julie W Rutten1, Minne N Cerfontaine1
1Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
Insights
A new staging system for NOTCH3-related small vessel disease (SVD) effectively categorizes disease severity from premanifest to end-stage. This validated system aids in clinical and research settings for understanding NOTCH3-SVD progression.
Area of Science:
- Neurology
- Genetics
- Vascular Medicine
Background:
- Cysteine-altering NOTCH3 (NOTCH3cys) variants are common, affecting ~1 in 300 individuals.
- These variants are linked to a wide range of small vessel disease (SVD) severities, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), stroke, dementia, and asymptomatic cases.
- A standardized system to classify NOTCH3-SVD severity is currently lacking.
Purpose of the Study:
- To develop a straightforward staging system for disease severity that encompasses the full clinicoradiological spectrum of NOTCH3-SVD.
- To validate this staging system in independent cohorts.
Main Methods:
- A cohort study was conducted, developing the NOTCH3-SVD staging system in a discovery cohort and validating it in international CADASIL cohorts and the UK Biobank.
- Data from 2,000+ participants with NOTCH3cys variants, including brain MRI and clinical assessments, were analyzed.
- Follow-up data spanning up to 18 years were incorporated.
Main Results:
- The developed NOTCH3-SVD staging system includes 9 stages (0 to 4B), capturing the spectrum from premanifest to end-stage disease.
- Ninety-four percent of participants (1789/1908) followed the defined sequence of disease events.
- The stages correlated significantly with neuroimaging findings, cognitive function, serum neurofilament light chain levels, and 18-year survival.
Conclusions:
- The NOTCH3-SVD staging system effectively captures the complete disease spectrum in individuals with NOTCH3cys variants.
- This system provides a simple, validated tool for consistent disease staging in both clinical practice and research.
- It aids in understanding disease progression and outcomes associated with NOTCH3-SVD.
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.
