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

Abstract

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 <i>Notch3</i> (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. At baseline, resting-state interhemispheric and intrahemispheric functional connectivity was significantly lower in Notch3^R169C than in Notch3^WT (<i>P</i>=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 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^R169C 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.