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Vascular NOTCH3 Deposition Load: Association With NOTCH3 Genotype and CADASIL Disease Severity

Yu-Wen Cheng1, Chih-Hao Chen1, Chi-Chao Chao1

  • 1Department of Neurology, National Taiwan University Hospital, Taipei.

Neurology. Genetics
|September 5, 2025
PubMed

Insights

The NOTCH3 variant genotype significantly impacts vascular NOTCH3 extracellular domain (NOTCH3ECD) deposition in CADASIL. Higher NOTCH3ECD load correlated with increased cerebral microbleeds, but not overall disease severity.

Area of Science:

  • Neurology
  • Genetics
  • Pathology

Background:

  • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by vascular NOTCH3 extracellular domain (NOTCH3ECD) deposition.
  • Understanding the relationship between NOTCH3ECD deposition, genotype, and cerebral small vessel disease (SVD) is crucial for CADASIL research.

Purpose of the Study:

  • To investigate the correlation between NOTCH3ECD deposition load and different NOTCH3 variant genotypes.
  • To explore the association between NOTCH3ECD deposition load and the severity of cerebral SVD in patients with CADASIL.

Main Methods:

  • Fifty-four individuals with pathogenic NOTCH3 variants underwent skin biopsies to quantify dermal vascular NOTCH3ECD deposition.
  • NOTCH3ECD deposition load was compared across different genotypes: p.R544C heterozygotes, p.R544C homozygotes, and variants in EGFr 1-6 and 8.
  • Regression models analyzed associations between NOTCH3ECD load and SVD severity measures in p.R544C heterozygotes.

Main Results:

  • Individuals with NOTCH3 variants in EGFr 1-6 and 8 and p.R544C homozygotes exhibited significantly higher NOTCH3ECD deposition loads compared to p.R544C heterozygotes.
  • In p.R544C heterozygotes, higher NOTCH3ECD load was associated with an increased number of cerebral microbleeds.
  • No significant associations were found between NOTCH3ECD load and overall disease severity, cognitive function, or other SVD imaging markers in p.R544C heterozygotes.

Conclusions:

  • The NOTCH3 genotype is a primary determinant of vascular NOTCH3ECD deposition load in CADASIL.
  • The limited correlation between NOTCH3ECD load and SVD severity suggests that other modifying factors influence the clinical presentation of CADASIL.
Abstract

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