Cheng Yu-Wen, Chen Chih-Hao, Chao Chi-Chao, Chen Ya-Fang, Jeng Jiann-Shing, Tang Sung-Chun, Hsieh Sung-Tsang
Department of Neurology, National Taiwan University Hospital, Taipei.
Department of Medical Imaging, National Taiwan University Hospital, Taipei.
Neurol Genet. 2025 Aug 27;11(5):e200288. doi: 10.1212/NXG.0000000000200288. eCollection 2025 Oct.
Vascular NOTCH3 extracellular domain (NOTCH3ECD) deposition is the pathologic hallmark of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We aimed to explore the relationships among the NOTCH3ECD deposition load, the variant genotype, and cerebral small vessel disease (SVD) severity.
Fifty-four individuals carrying pathogenic variants were enrolled and underwent skin biopsy for the quantification of dermal vascular NOTCH3ECD deposition load using immunohistochemical staining. The NOTCH3ECD deposition load, defined as the percentage of the NOTCH3ECD-stained area within the vessel area marked by smooth muscle actin staining, was compared among p.R544C heterozygotes (n = 46), p.R544C homozygotes (n = 3), and individuals with pathogenic variants in epidermal growth factor-like repeats (EGFr) 1-6 and 8 (n = 5). In p.R544C heterozygotes, we further investigated the associations between the NOTCH3ECD deposition load and various clinical and imaging severity measures of cerebral SVD using regression models adjusted for age, sex, and hypertension.
The NOTCH3ECD deposition load was greater in individuals with variants located in EGFr 1-6 and 8 (93.21%) and in p.R544C homozygotes (56.63%) than in p.R544C heterozygotes (16.37%, = 0.0004 and 0.0296, respectively). In p.R544C heterozygotes, no statistically significant associations were found between NOTCH3ECD load and disease severity stage, stroke incidence, Mini-Mental State Examination score, or functional independence. Regarding MRI features, a greater NOTCH3ECD load was associated with an increased cerebral microbleed count (B = 0.074, 95% CI = 0.014-0.135, = 0.018) but was not associated with white matter hyperintensity burden, lacune count, or brain parenchymal fraction after adjustment for age, sex, and hypertension.
The variant genotype is a key determinant of the vascular NOTCH3ECD deposition load. The weak association between CADASIL disease severity and NOTCH3ECD deposition load suggests the importance of modifying factors that contribute to the diverse clinical spectrum of NOTCH3 vasculopathy.
血管性NOTCH3细胞外结构域（NOTCH3ECD）沉积是伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病（CADASIL）的病理标志。我们旨在探讨NOTCH3ECD沉积负荷、变异基因型与脑小血管病（SVD）严重程度之间的关系。
纳入54名携带致病变异的个体，进行皮肤活检，采用免疫组织化学染色定量真皮血管NOTCH3ECD沉积负荷。比较p.R544C杂合子（n = 46）、p.R544C纯合子（n = 3）以及表皮生长因子样重复序列（EGFr）1-6和8存在致病变异的个体（n = 5）的NOTCH3ECD沉积负荷，NOTCH3ECD沉积负荷定义为NOTCH3ECD染色面积占平滑肌肌动蛋白染色标记的血管面积的百分比。在p.R544C杂合子中，我们进一步使用调整了年龄、性别和高血压因素的回归模型，研究NOTCH3ECD沉积负荷与脑SVD的各种临床和影像学严重程度指标之间的关联。
位于EGFr 1-6和8的变异个体（93.21%）和p.R544C纯合子（56.63%）的NOTCH3ECD沉积负荷高于p.R544C杂合子（16.
