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Association Between Vascular NOTCH3 Aggregation and Disease Severity in a CADASIL Cohort - Implications for NOTCH3

Minne N Cerfontaine1, Gido Gravesteijn1, Remco J Hack1

  • 1Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Annals of Neurology
|April 23, 2025
PubMed

Insights

NOTCH3 protein aggregation in skin vessels correlates with disease severity in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This finding aids in predicting stroke and dementia risk for patients with NOTCH3 variants.

Area of Science:

  • Neurology
  • Genetics
  • Vascular Biology

Background:

  • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic small vessel disease.
  • NOTCH3 protein ectodomain aggregation is a key pathological feature of CADASIL.
  • Cysteine-altering NOTCH3 variants are common genetic contributors to stroke and vascular dementia.

Purpose of the Study:

  • To investigate the association between NOTCH3 aggregation load in skin vessels and disease severity in CADASIL patients.
  • To explore the relationship between specific NOTCH3 variants, aggregation load, and clinical/neuroimaging outcomes.
  • To determine if NOTCH3 aggregation propensity explains variability in disease severity.

Main Methods:

  • A prospective cohort study of 212 CADASIL patients with 39 distinct NOTCH3 variants.
  • Quantification of NOTCH3 aggregation load using a NOTCH3 score in skin vessels.
  • Analysis of associations using multivariable linear mixed models, Cox regression, and mediation analyses.

Main Results:

  • The NOTCH3 score was significantly associated with lifetime stroke probability and small vessel disease neuroimaging outcomes.
  • Variant-specific NOTCH3 scores correlated with differences in disease severity linked to distinct NOTCH3 variants.
  • No significant association was found between the NOTCH3 score and age.

Conclusions:

  • Differences in NOTCH3 aggregation propensity explain disease severity variations linked to NOTCH3 variants in CADASIL.
  • NOTCH3-variant specific scores can enhance individualized disease prediction for CADASIL.
  • This study provides insights into the pathogenic mechanisms of CADASIL and potential therapeutic targets.
Abstract

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