Multimodal characterization of age-dependent neurovascular phenotypes in Notch3^R170C CADASIL mice by ultra-high-field...

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease caused by mutations in NOTCH3 and characterized by progressive neurovascular alterations. Although magnetic resonance imaging (MRI) can detect vascular and white matter abnormalities in CADASIL, the relationship between imaging findings and underlying cellular and molecular changes remains incompletely understood. Here, we established an integrative, multi-scale framework combining ultra-high-field MRI, quantitative histology, and single-cell RNA sequencing to characterize age-dependent neurovascular phenotypes in a Notch3^R170C CADASIL mouse model. We found that cerebral blood flow declined with age, with more pronounced reductions in R170C mice at later stages, whereas oxygen saturation showed relatively mild changes and vascular fraction remained stable. Regional analyses further revealed region-specific perfusion changes across brain regions. Histological analyses showed age-dependent changes in vascular and glial markers, together with mild corpus callosum vacuolation at 16 months, whereas neuronal and oligodendrocyte-associated alterations were comparatively limited. Single-cell transcriptomic analysis revealed subtle but coordinated cell type-specific transcriptional profiles, particularly in vascular and glial populations. Together, this study provides an integrated and age-resolved characterization of neurovascular phenotypes in a Notch3^R170C CADASIL mouse model, linking in vivo resting cerebral perfusion imaging with histological and molecular alterations. These findings highlight the value of multimodal approaches for characterizing experimental CADASIL.