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Microbleed clustering in thalamus sign in CADASIL patients with NOTCH3 R75P mutation
Jun Takei1, Yujiro Higuchi1, Masahiro Ando1
1Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Insights
Japanese Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) patients with the NOTCH3 R75P mutation show more cerebral microbleeds. A new imaging sign, microbleed clustering in thalamus (MCT sign), may characterize this genetic subtype.
Area of Science:
- Neurology
- Genetics
- Medical Imaging
Background:
- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a genetic cerebrovascular disorder.
- It leads to vascular dementia and recurrent strokes due to cerebral microvascular disease.
Purpose of the Study:
- To investigate the genetic and clinical characteristics of CADASIL in Japan.
- To identify specific imaging markers associated with NOTCH3 gene mutations.
Main Methods:
- Genetic analysis of 32 patients diagnosed with CADASIL.
- Brain MRI analysis, including assessment of cerebral microbleeds (CMBs) using established scales.
- Correlation of NOTCH3 mutations with clinical and imaging findings.
Main Results:
- Twenty-four of 32 patients harbored the NOTCH3 R75P mutation, suggesting a founder effect.
- Patients with the R75P mutation exhibited significantly more CMBs, especially in the thalamus.
- A novel imaging finding, the microbleed clustering in thalamus (MCT) sign, was observed in 15 R75P mutation carriers.
Conclusions:
- The MCT sign may be a characteristic imaging feature of NOTCH3 R75P-related CADASIL.
- This study enhances understanding of genotype-phenotype correlations in CADASIL.
Background And Objective:
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral microvascular disease characterized by the development of vascular dementia and lacunar infarctions. This study aimed to identify the genetic and clinical features of CADASIL in Japan.
Methods:
We conducted genetic analysis on a case series of patients clinically diagnosed with CADASIL. Clinical and imaging analyses were performed on 32 patients with pathogenic mutations in the NOTCH3 gene. To assess the presence of cerebral microbleeds (CMBs), we utilized several established rating scales including the Fazekas scale, Scheltens rating scale, and Microbleed Anatomical Rating Scale, based on brain MRI images.
Results:
Among the 32 CADASIL patients, 24 cases were found carrying the R75P mutation in NOTCH3, whereas the remaining eight cases had other NOTCH3 mutations (R75Q, R110C, C134F, C144F, R169C, and R607C). The haplotype analysis of the R75P mutation uncovered the presence of a founder effect. A brain MRI analysis revealed that cases with the R75P mutation had a significantly higher total number of CMBs, particularly in the thalamus when compared to patients with other NOTCH3 mutations. Among 15 out of 24 cases with the R75P mutation, we observed a notable clustering of CMBs in the thalamus, termed microbleed clustering in thalamus sign (MCT sign).
Conclusion:
We propose that the MCT sign observed in NOTCH3 R75P-related CADASIL patients may serve as a potentially characteristic imaging feature. This finding offers further insights into the interactions between genotypes and phenotypes between NOTCH3 and CADASIL.
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