Background and ObjectivesThis study investigated the cutaneous small fiber pathology of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and its clinical significance, that is, the NOTCH3 deposition in cutaneous vasculatures and CNS neurodegeneration focusing on cognitive impairment.MethodsThirty-seven patients with CADASIL and 59 age-matched healthy controls were enrolled to evaluate cutaneous small fiber pathology by quantitative measures of intraepidermal nerve fiber density (IENFD), sweat gland innervation, and vascular innervation. Cognitive performance of patients with CADASIL was evaluated by a comprehensive neuropsychological assessment, and its association with small fiber pathology was tested using multivariable linear regression analysis adjusted for age and diabetes mellitus. We further assessed the relationships of IENFD with cutaneous vascular NOTCH3 ectodomain (NOTCH3ECD) deposition and biomarkers of neurodegeneration including structural brain MRI measures, serum neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin carboxy-terminal hydrolase L1.ResultsPatients with CADASIL showed reduced IENFD (5.22 ± 2.42 vs 7.88 ± 2.89 fibers/mm,p= 0.0001) and reduced sweat gland (p< 0.0001) and vascular (p< 0.0001) innervations compared with age-matched controls. Reduced IENFD was associated with impaired global cognition measured by Mini-Mental State Examination (B= 1.062, 95% CI = 0.370–1.753,p= 0.004), and this association remained after adjustment for age and diabetes mellitus (p= 0.043). In addition, IENFD in patients with CADASIL was associated with mean cortical thickness (Pearsonr= 0.565,p= 0.0023) but not white matter hyperintensity volume, total lacune count, or total microbleed count. Reduced IENFD was associated with cutaneous vascular NOTCH3ECD deposition amount among patients harboring pathogenic variants in exon 11 (mainly p.R544C) (B= −0.092, 95% CI = −0.175 to −0.009,p= 0.031). Compared with those with normal cognition, patients with CADASIL with cognitive impairment had an elevated plasma NfL level regardless of concurrent small fiber denervation, whereas only patients with both cognitive impairment and small fiber denervation showed an elevated plasma GFAP level.DiscussionCutaneous small fiber pathology correlates with cognitive impairment and CNS neurodegeneration in patients with CADASIL, indicating a peripheral neurodegenerative process related to NOTCH3ECD aggregation.