Inflammatory Protein Landscape in the CSF of Mid- to Late- Stage Parkinson’s Disease: Associations with Motor Severity and Subtypes

Purpose: Parkinson’s disease is a progressive neurodegenerative disorder in which neuroinflammation is recognized as a contributor to clinical progression. This study aimed to characterize the cerebrospinal fluid (CSF) inflammatory profile in mid- to late-stage PD patients and identify specific inflammatory proteins with potential clinical relevance to motor symptoms and disease severity. Methods: In this retrospective cross-sectional study, CSF samples were obtained from 25 patients with mid-to late- stage PD (mean disease duration: 10.24 ± 4.65 years) and 15 non-PD controls. The levels of 92 inflammation-related proteins were quantified using the Olink proximity extension assay (PEA). Based on the identified differentially expressed proteins (DEPs), we next compared inflammatory profiles between the postural instability and gait difficulty (PIGD, n = 10) and tremor-dominant (TD, n = 10) PD subtypes. Additionally, correlation analyses were performed between the DEPs and Unified Parkinson’s Disease Rating Scale Part III (UPDRS-III) scores to identify inflammatory biomarkers with potential clinical relevance. Results: Using the Olink platform, 28 DEPs were identified between the PD and non-PD groups ( p < 0.05). Subsequent protein–protein interaction network analysis identified IFN-γ as the central hub. Comparative analysis between the PIGD and TD subgroups revealed five DEPs (IFN-γ, ST1A1, TNFSF14, MMP-1, TRANCE) ( p < 0.05). Among all DEPs, IL-10RB (r = 0.440, p = 0.028), CD8A (r = 0.414, p = 0.039), and CXCL9 (r = 0.414, p = 0.040) showed the strongest correlations with UPDRS-III scores. Conclusion: This study identifies IFN-γ as the central hub protein within the CSF inflammatory network in mid- to late-stage PD and highlights specific T cell-related DEPs that are strongly associated with motor dysfunction. These proteins may represent potential targets for future anti-inflammatory therapies and serve as biomarkers for tracking disease progression.