Enlarged perivascular spaces are associated with white matter injury and cognition in an autosomal dominant vascular neurodegenerative disease (CADASIL)

Abstract Background Enlarged perivascular spaces (EPVS), quantified on brain imaging, can reflect structural changes of blood vessels or of the surrounding fluid filled spaces. EPVS measures are emerging as promising biomarkers of cerebral small vessel disease, especially in dementia research. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a vascular neurodegenerative disease (VNDD) caused by mutations in the NOTCH3 gene. CADASIL involves disease of small vessels and presents with headaches, early onset strokes, and progressive neuropsychiatric dysfunction. We asked whether “burden” of EPVS is associated with clinical outcomes in CADASIL. Method Brain MRIs were obtained in a CADASIL cohort (n = 27) and age/sex matched controls (n = 27). EPVS and WMH (white matter hyperintensity, measure of injury) were quantified with a semi‐ automated pipeline, using T1/T2 and FLAIR images, respectively. Participants underwent clinical and neuropsychological tests measuring executive function. Linear regression models were built to test associations between EPVS with WMH (a classical biomarker in CADASIL) and executive function. All models were adjusted for age and sex. Result We found no group differences in total EPVS volumes between CADASIL and the control group (β = 0.04, p = 0.73). Age was significantly associated with EPVS only in the control group (β = 0.018, p < 0.05). We found a significant inverse association of EPVS with executive function in CADASIL (β = ‐0.11, p < 0.05) and a positive association of EPVS with WMH (β = 0.28, p = 0.05). Conclusion CADASIL, a vasculo‐centric neurodegenerative disease includes prominent SVD pathology that may be driving total EPVS volumes. This may represent an accelerated vascular aging phenotype. Associations with cognition and MRI measure of white matter injury (WMH) in CADASIL confirm that EPVS may be a relevant biomarker to track in CADASIL. Longitudinal studies will be of great value in determining the utility of EPVS as a disease‐relevant biomarker in future therapeutic trials in CADASIL.