Impaired Resting State Functional Connectivity in CADASIL Mutant Mice

Background: Cerebral autosomal-dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) 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 CADASIL transgenic mice, both with and without focal white matter lesions in the corpus callosum added on, utilizing optical resting-state functional connectivity imaging alongside behavioral examinations. Additionally, 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 inter 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 to 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 endpoint. Conclusion: These data show impaired resting-state functional connectivity and increased foot faults in the Notch3R169C mutant model of CADASIL. Future work will aim to test therapeutic or preventive interventions in CADASIL mutants using these measures.