Abstract Body: Objectives: Cerebral autosomal-dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) is a leading monogenic cause of cerebral small-vessel disease. This study aimed to evaluate the functional integrity of long white matter tracts in CADASIL transgenic mice and assess the potential of tocotrienol (T3) as a therapeutic agent.
Methods: Optical resting-state functional connectivity imaging and behavioral examinations were employed to characterize white matter tracts in CADASIL transgenic mice, both with and without focal white matter lesions in the corpus callosum. Functional connectivity and behavioral outcomes were compared between Notch3^R169C and Notch3^WTmice. The efficacy of T3, a neuroprotective vitamin E derivative, was also evaluated based on findings from previous clinical trials in small vessel disease.
Results: After performing stepwise elimination using the Akaike Information Criterion (AIC), the diet variable was removed from the model and we pooled the data in the two diet arms for subsequent analyses of interhemispheric homotopic connectivity. At baseline, resting-state interhemispheric functional connectivity was significantly reduced in Notch3^R169C mice compared to Notch3^WT mice (p=0.004). No significant differences between genotypes were observed on day 1 and day 7 post-lesion. Behavioral analysis using the grid walk test revealed an increased number of foot faults in Notch3^R169C mice at baseline, with similar increases observed in both genotypes one week after lesion induction. Lesion volumes on day 7 did not differ between genotypes.
Conclusions: The Notch3^R169C CADASIL model demonstrated impaired resting-state functional connectivity and increased foot faults, indicating significant functional and behavioral deficits. Future research will focus on evaluating therapeutic and preventive interventions in CADASIL models using these parameters.