Impaired Resting-State Functional Connectivity in Cerebral Autosomal-Dominant Arteriopathy, Subcortical Infarcts, and Leukoencephalopathy Mutant Mice

作者：Sanem A Aykan, James Han Lai, Kazutaka Sugimoto, Orhan Aykan, Wai-Yee Fung, David Joon Ho, Anne Joutel, Sava Sakadžić, David Y. Chung, Cenk Ayata · 发表于：Stroke · 年份：2025 · DOI：10.1161/strokeaha.124.049772 · 被引用次数：1 · 研究领域：Cerebrovascular and genetic disorders、Neurological Disease Mechanisms and Treatments、Intracerebral and Subarachnoid Hemorrhage Research

BACKGROUND: Cerebral autosomal-dominant arteriopathy, subcortical infarcts, and leukoencephalopathy is the most prevalent monogenic inherited cause of cerebral small vessel disease. Despite its prevalence, there is currently no proven therapy to prevent or reverse the progression of the disease. METHODS: This study aimed to characterize the functional integrity of long white matter tracts in cerebral autosomal-dominant arteriopathy, subcortical infarcts, and leukoencephalopathy transgenic mice expressing R169C mutant Notch3 (Notch3 R169C ) compared with wild type littermates (Notch3 WT ), both with and without a superimposed focal white matter lesion in the corpus callosum, utilizing optical resting-state functional connectivity imaging alongside behavioral examinations. In addition, we examined the efficacy of tocotrienol, a neuroprotective derivative of vitamin E derived from palm oil, which has shown promise in preventing white matter disease progression in clinical trials involving patients with small vessel disease. RESULTS: At baseline, resting-state interhemispheric and intrahemispheric functional connectivity was significantly lower in Notch3 R169C than in Notch3 WT ( P =0.004), and the grid walk test revealed a higher number of foot faults in the Notch3 R169C group compared with Notch3 WT . Sex did not interact with the genotype on the primary outcomes. Introducing a lesion in the corpus callosum compromised functional connectivity and behavior outcomes in both genot...