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

Background

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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.

Results

A total of 155 patients with PD (mean age, 63.4 years; 52% female; PD-NC: n = 75; PD-MCI: n = 40; PDD: n = 40) and 50 HCs (mean age, 60.3 years; 50% female) were included. IENFD demonstrated a progressive decline across the PD cognitive spectrum (HC: 7.18 ± 2.44; PD-NC: 5.89 ± 2.05; PD-MCI: 4.65 ± 1.33; PDD: 3.40 ± 1.15 fibers/mm). IENFD positively correlated with global and 5 domain-specific cognitive scores (β = 0.170-0.387, p < 0.05). Lower IENFD was independently associated with an increased risk of cognitive impairment (odds ratio = 0.541, 95% CI 0.420-0.697) and showed good diagnostic performance in distinguishing PD-MCI and PDD from PD-NC (area under the ROC curve = 0.772, 95% CI 0.697-0.838). Furthermore, IENFD correlated with frontal and insular gray matter volumes (β = 0.155-0.195, p < 0.05), which statistically mediated the associations between IENFD and cognitive performance (proportion mediated for global cognition: 8.0%-10.2%).

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.