Vascular NOTCH3 Deposition Load: Association With NOTCH3 Genotype and CADASIL 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.