From the Department of Post-Baccalaureate Medicine (H.T., C.-C.C., Y.-M.C., W.-J.L.), College of Medicine, National Chung Hsing University; Center of Faculty Development (H.T.), Department of Medical Education, and Department of Neurology (H.T., W.-J.L.), Neurological Institute, Taichung Veterans General Hospital; Graduate Institute of Clinical Medicine (C.-C.C.), College of Medicine, National Taiwan University, Taipei; Department of Ophthalmology (C.-C.C.), Taichung Veterans General Hospital; School of Medicine (C.-C.C., Y.-M.C., H.-C.C.), National Yang Ming Chiao Tung University, Taipei; Center for Quantitative Imaging in Medicine (H.-M.C.), Department of Medical Research, Division of Allergy, Immunology and Rheumatology (Y.-M.C.), Department of Internal Medicine, and Department of Medical Research (Y.-M.C.), Taichung Veterans General Hospital; Institute of Biomedical Science and Rong Hsing Research Center for Translational Medicine & Program in Translational Medicine (Y.-M.C.), and Precision Medicine Research Center (Y.-M.C.), College of Medicine, National Chung Hsing University, Taichung; Department of Radiology (Y.-Y.W., J.-W.C., H.-C.C.), Taichung Veterans General Hospital; Department of Electrical Engineering (Y.-Y.W.), National Chung Hsing University, Taichung; Biostatistics Task Force of Taichung Veterans General Hospital (J.-P.C.), Taichung; Institute of Statistical Science (S.-C.C.), Academia Sinica, Taipei; Dementia Center (W.-J.L.), Taichung Veterans General Hospital; and Brain Research Center (W.-J.L.), National Yang Ming Chiao Tung University, Taipei, Taiwan.
Neurology. 2024 Nov 12;103(9):e209941. doi: 10.1212/WNL.0000000000209941. Epub 2024 Oct 7.
pathologic variants cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which presents with stroke and dementia and is characterized by white matter hyperintensities (WMHs) on brain MRI. The R544C variant is a common pathologic variant in Taiwan, but not all carriers exhibit significant symptoms. We investigated whether WMHs occur before clinical symptoms in carriers with pathogenic variants, examined factors associated with WMHs, and explored their relationship with cognitive functions.
We enrolled 63 R544C carriers without overt clinical disease (WOCD) and 37 age-matched and sex-matched noncarriers as controls from the Taiwan Precision Medicine Initiative data set. All participants underwent clinical interviews, comprehensive neuropsychological assessments, and brain MRI. We calculated total and regional WMH volumes, determined the age at which WMHs began increasing in carriers, and examined the relationship between WMHs and neuropsychological performance. Factors associated with WMH volumes were analyzed using multivariable linear regression models.
Compared with controls, R544C carriers WOCD had increased WMH volume, except in the occipital and midbrain areas, and showed a rapid increase in WMHs starting at age 48. They scored lower on the Mini-Mental State Examination (median = 28.4 vs 29.0, = 0.048), Montreal Cognitive Assessment (MoCA) (median = 28.3 vs 29.0, = 0.013), and memory and executive function tests than controls. After adjusting for age, sex, and education, MoCA scores were associated with whole-brain (r = -0.387, = 0.008) and regional WMHs (all < 0.05) except in the midbrain area. Age (β = 0.034, 95% CI 0.021-0.046, < 0.001), hypercholesterolemia (β = 0.375, 95% CI 0.097-0.653, = 0.009), and the vascular risk factor (VRF) index (β = 0.132, 95% CI 0.032-0.242, = 0.019) were associated with the WMH severity in carriers.
Our study revealed that WMHs are extensively distributed in R544C carriers WOCD. They exhibited a rapid increase in WMHs beginning at age 48, approximately 7 years earlier than the reported age at symptomatic onset. Age was the strongest predictive factor of WMHs, and VRF, particularly hypercholesterolemia, might be modifying factors of WMHs.
病理性变异导致伴有皮质下梗死和白质脑病的常染色体显性脑动脉病（CADASIL），其表现为中风和痴呆，并以脑 MRI 上的白质高信号（WMHs）为特征。R544C 变异在台湾是一种常见的病理性变异，但并非所有携带者都表现出明显的症状。我们研究了携带致病性变异的携带者是否在出现临床症状之前出现 WMHs，检查了与 WMHs 相关的因素，并探讨了它们与认知功能的关系。
我们从台湾精准医学计划数据集中招募了 63 名无明显临床疾病（WOCD）的 R544C 携带者和 37 名年龄和性别匹配的非携带者作为对照组。所有参与者都接受了临床访谈、全面的神经心理学评估和脑部 MRI。我们计算了总和区域 WMH 体积，确定了携带者中 WMHs 开始增加的年龄，并检查了 WMHs 与认知功能表现之间的关系。使用多变量线性回归模型分析与 WMH 体积相关的因素。
与对照组相比，R544C 携带者 WOCD 的 WMH 体积增加，除了枕叶和中脑区域，并且从 48 岁开始 WMHs 迅速增加。他们在 Mini-Mental State Examination（MMSE）（中位数=28.4 与 29.0，=0.048）和蒙特利尔认知评估（MoCA）（中位数=28.3 与 29.0，=0.013）中的得分低于对照组。与对照组相比，记忆和执行功能测试。在调整年龄、性别和教育程度后，MoCA 评分与全脑（r=-0.387，=0.008）和区域 WMHs（均<0.05）相关，除了中脑区域。年龄（β=0.034，95%CI 0.021-0.046，<0.001）、高胆固醇血症（β=0.375，95%CI 0.097-0.653，=0.009）和血管危险因素（VRF）指数（β=0.132，95%CI 0.032-0.242，=0.019）与携带者的 WMH 严重程度相关。
我们的研究表明，WMHs 在 R544C 携带者 WOCD 中广泛分布。他们在 48 岁左右开始出现 WMHs 的快速增加，比报告的症状出现年龄早约 7 年。年龄是 WMHs 的最强预测因素，VRF，特别是高胆固醇血症，可能是 WMHs 的修饰因素。
