Association of Skin Denervation With Brain Atrophy and Cognitive Impairment in Patients With Parkinson Disease

BACKGROUND AND OBJECTIVES: Small fiber pathology is an intrinsic feature of Parkinson disease (PD), yet its relevance to central neurodegeneration remains unclear. Given that cognitive impairment is a major manifestation of disease progression closely linked to cortical structural changes, we aimed to determine whether peripheral skin denervation is associated with cognitive impairment and brain atrophy in PD. METHODS: In this cross-sectional study at a movement disorders center in China, patients with PD and healthy controls (HCs) were recruited. Key inclusion criteria included a clinical PD diagnosis based on the Movement Disorder Society criteria and an age range of 50-99 years. Patients were classified into normal cognition (PD-NC), mild cognitive impairment (PD-MCI), and patients develop dementia (PDD). All participants underwent skin biopsy for quantification of intraepidermal nerve fiber density (IENFD), neuropsychological assessments, and structural MRI. Multivariable regression and mediation analyses examined associations among IENFD, cognition, and brain volumes. DISCUSSION: Our study suggests that skin denervation is closely associated with cognitive impairment in PD and that regional brain atrophy statistically mediates this relationship. These findings provide novel evidence for the peripheral-central axis in PD, suggesting that small fiber pathology may mirror central neurodegeneration. Future multicenter and longitudinal studies are required for validation.