期刊
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
卷 92, 期 7, 页码 694-701出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jnnp-2020-325838
关键词
-
资金
- British Heart Foundation [RG/4/32218]
- Cambridge BHF Centre of Research Excellence
- MRC experimental medicine grant [MR/N026896/1]
- NIHR Senior Investigator award
- NIHR Cambridge Biomedical Research Centre [BRC-1215-20014]
- MRC [MR/N026896/1] Funding Source: UKRI
Cysteine-altering NOTCH3 variants, previously associated with CADASIL, are more common in the general population than expected, and are risk factors for stroke and vascular dementia. These variants are also associated with MRI changes indicative of small vessel disease.
Background Cysteine-altering NOTCH3 variants identical to those causing the rare monogenic form of stroke, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), have been reported more common than expected in the general population, but their clinical significance and contribution to stroke and dementia risk in the community remain unclear. Methods Cysteine-altering NOTCH3 variants were identified in UK Biobank whole-exome sequencing data (N=200 632). Frequency of stroke, vascular dementia and other clinical features of CADASIL, and MRI white matter hyperintensity volume were compared between variant carriers and non-carriers. MRIs from those with variants were visually rated, each matched with three controls. Results Of 200 632 participants with exome sequencing data available, 443 (similar to 1 in 450) carried 67 different cysteine-altering NOTCH3 variants. After adjustment for various covariates, NOTCH3 variant carriers had increased risk of stroke (OR: 2.33, p=0.0004) and vascular dementia (OR: 5.00, p=0.007), and increased white matter hyperintensity volume (standardised difference: 0.52, p<0.001) and white matter ultrastructural damage on diffusion MRI (standardised difference: 0.72, p<0.001). On visual analysis of MRIs from 47 carriers and 148 matched controls, variants were associated with presence of lacunes (OR: 5.97, p<0.001) and cerebral microbleeds (OR: 4.38, p<0.001). White matter hyperintensity prevalence was most increased in the anterior temporal lobes (OR: 7.65, p<0.001) and external capsule (OR: 13.32, p<0.001). Conclusions Cysteine-changing NOTCH3 variants are more common in the general population than expected from CADASIL prevalence and are risk factors for apparently 'sporadic' stroke and vascular dementia. They are associated with MRI changes of small vessel disease, in a distribution similar to that seen in CADASIL.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据