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 (Notch3R169C) compared with wild type littermates (Notch3WT), 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 Notch3R169C than in Notch3WT (P=0.004), and the grid walk test revealed a higher number of foot faults in the Notch3R169C group compared with Notch3WT. 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.
CONCLUSIONS: These data show impaired resting-state functional connectivity and increased foot faults in the Notch3R169C 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.