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Effect of NOTCH3 EGFr Group, Sex, and Cardiovascular Risk Factors on CADASIL Clinical and Neuroimaging Outcomes
Remco J Hack1, Minne N Cerfontaine1, Gido Gravesteijn1
1Department of Clinical Genetics (R.J.H., M.N.C., G.G., S.T., F.B., J.W.R., S.A.J.L.O.), Leiden University Medical Center, the Netherlands.
Insights
The NOTCH3 EGFr group is the primary modifier of CADASIL disease progression, influencing stroke age and white matter hyperintensity volume. Sex and cardiovascular risk factors like hypertension also significantly impact disease severity.
Area of Science:
- Neurology
- Genetics
- Vascular Disease
Background:
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic small vessel disease.
- NOTCH3 gene variants, specifically the EGFr group, are known modifiers of CADASIL.
- The influence of other factors like sex and cardiovascular risk on CADASIL severity in conjunction with NOTCH3 EGFr group requires further investigation.
Purpose of the Study:
- To determine the relative disease-modifying effects of NOTCH3 EGFr group, sex, and cardiovascular risk factors on CADASIL disease severity.
- To analyze the impact of these modifiers on clinical outcomes and neuroimaging markers in a prospective CADASIL cohort.
Main Methods:
- Prospective cohort study (DiViNAS) of 200 CADASIL patients.
- Clinical assessment, neuropsychological testing, and brain MRI were performed.
- Multivariable regression models analyzed the association between modifiers and disease severity.
Main Results:
- NOTCH3 EGFr 1-6 group was the strongest modifier of age at first stroke, lacune volume, white matter hyperintensity (WMH) volume, and mean diffusivity.
- Patients with EGFr 1-6 variants showed increased WMH volume and enlarged perivascular spaces.
- Male sex and hypertension emerged as the next most significant modifiers after the NOTCH3 EGFr group.
Conclusions:
- The NOTCH3 EGFr group is the most critical determinant of CADASIL disease progression across multiple clinical and imaging measures.
- Sex and cardiovascular risk factors, including hypertension, diabetes, and smoking, are also important CADASIL disease modifiers.
- These findings highlight the complex interplay of genetic and environmental factors in CADASIL pathogenesis.
Background:
A retrospective study has shown that EGFr (epidermal growth factor-like repeat) group in the NOTCH3 gene is an important cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) disease modifier of age at first stroke and white matter hyperintensity (WMH) volume. No study has yet assessed the effect of other known CADASIL modifiers, that is, cardiovascular risk factors and sex, in the context of NOTCH3 EGFr group. In this study, we determined the relative disease-modifying effects of NOTCH3 EGFr group, sex and cardiovascular risk factor on disease severity in the first genotype-driven, large prospective CADASIL cohort study, using a comprehensive battery of CADASIL clinical outcomes and neuroimaging markers.
Methods:
Patients with CADASIL participated in a single-center, prospective cohort study (DiViNAS [Disease Variability in NOTCH3 Associated Small Vessel Disease]) between 2017 and 2020. The study protocol included a clinical assessment, neuropsychological test battery and brain magnetic resonance imaging on a single research day. Multivariable linear, logistic and Cox regression models were used to cross-sectionally assess the effect of CADASIL modifiers on clinical severity (stroke, disability, processing speed) and neuroimaging markers (WMH volume, peak width of skeletonized mean diffusivity, lacune volume, brain volume, cerebral microbleed count).
Results:
Two hundred patients with CADASIL participated, of which 103 harbored a NOTCH3 EGFr 1-6 variant and 97 an EGFr 7-34 variant. NOTCH3 EGFr 1-6 group was the most important modifier of age at first stroke (hazard ratio, 2.45 [95% CI, 1.39-4.31]; P=0.002), lacune volume (odds ratio, 4.31 [95% CI, 2.31-8.04]; P=4.0×10-6), WMH volume (B=0.81 [95% CI, 0.60-1.02]; P=1.1×10-12), and peak width of skeletonized mean diffusivity (B=0.65 [95% CI, 0.44-0.87]; P=1.6×10-8). EGFr 1-6 patients had a significantly higher WMH volume in the anterior temporal lobes and superior frontal gyri and a higher burden of enlarged perivascular spaces. After NOTCH3 EGFr group, male sex and hypertension were the next most important modifiers of clinical outcomes and neuroimaging markers.
Conclusions:
NOTCH3 EGFr group is the most important CADASIL disease modifier not only for age at first stroke and WMH volume but also strikingly so for a whole battery of clinically relevant disease measures such as lacune volume and peak width of skeletonized mean diffusivity. NOTCH3 EGFr group is followed in importance by sex, hypertension, diabetes, and smoking.
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