Aykan Sanem Aslihan, Lai James Han, Sugimoto Kazutaka, Aykan Orhan, Fung Wai Yee, Ho David, Joutel Anne, Sakadzic Sava, Chung David Y, Ayata Cenk
Neurovascular Research Unit, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown (S.A.A., J.H.L., K.S., O.A., D.Y.C., C.A.).
Hovid Berhad, Ipoh, Malaysia (W.Y.F., D.H.).
Stroke. 2025 Apr;56(4):987-995. doi: 10.1161/STROKEAHA.124.049772. Epub 2025 Jan 30.
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.
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) compared with wild type littermates (Notch3), 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.
At baseline, resting-state interhemispheric and intrahemispheric functional connectivity was significantly lower in Notch3 than in Notch3 (=0.004), and the grid walk test revealed a higher number of foot faults in the Notch3 group compared with Notch3. 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 genotypes to a similar extent; lesion volumes did not differ between the genotypes. Tocotrienol treatment did not show any protective effect on any end point.
These data show impaired resting-state functional connectivity and increased foot faults in the Notch3 mutant model of cerebral autosomal-dominant arteriopathy, subcortical infarcts, and leukoencephalopathy. Future work will aim to test therapeutic or preventive interventions in cerebral autosomal-dominant arteriopathy, subcortical infarcts, and leukoencephalopathy mutants using these measures.
大脑常染色体显性动脉病伴皮质下梗死和白质脑病是脑小血管病最常见的单基因遗传性病因。尽管其发病率高，但目前尚无经证实的疗法可预防或逆转该疾病的进展。
本研究旨在通过光学静息态功能连接成像及行为学检查，比较表达R169C突变体（Notch3）的大脑常染色体显性动脉病伴皮质下梗死和白质脑病转基因小鼠与野生型同窝小鼠（Notch3）长白质束的功能完整性，这些小鼠有无叠加的胼胝体局灶性白质病变。此外，我们研究了生育三烯酚的疗效，生育三烯酚是一种从棕榈油中提取的维生素E神经保护衍生物，在涉及小血管病患者的临床试验中已显示出预防白质疾病进展的前景。
在基线时，Notch3小鼠的静息态半球间和半球内功能连接显著低于Notch3小鼠（P=0.004），网格行走试验显示Notch3组的脚步失误次数高于Notch3小鼠。性别在主要结局上与基因型无相互作用。在胼胝体引入病变在相似程度上损害了两种基因型的功能连接和行为结局；基因型之间的病变体积无差异。生育三烯酚治疗对任何终点均未显示出任何保护作用。
这些数据表明，在大脑常染色体显性动脉病伴皮质下梗死和白质脑病的Notch3突变模型中，静息态功能连接受损且脚步失误增加。未来的工作将旨在使用这些指标测试大脑常染色体显性动脉病伴皮质下梗死和白质脑病突变体的治疗或预防干预措施。
