Peripheral Inflammatory Biomarkers in Parkinson's Disease: A Systematic Review and Meta-Analysis Revealing Inconsistent Alterations and Limited Diagnostic Utility

Background: Neuroinflammation is recognized as a central feature of Parkinson's disease (PD), but whether peripheral inflammatory biomarkers reliably reflect central immune dysregulation remains unclear. Objective: To clarify whether circulating cytokines differ between individuals with PD and healthy controls. Methods: We conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. Case-control studies reporting quantitative serum or plasma inflammatory biomarkers in PD were identified through PubMed, Web of Science, Embase, and Scopus databases. Studies providing extractable data (mean, SD, and sample size) were included. Standardized mean differences (Hedges' g) were pooled using random-effects models with Hartung-Knapp adjustment. Subgroup analyses, meta-regression (age and sample size), publication bias assessment, and leave-one-out sensitivity analysis were performed. Results: Eight studies met the inclusion criteria. The overall pooled effect showed no significant difference in peripheral inflammatory biomarker levels between PD and controls (SMD = 0.18, 95% CI -0.71 to 1.08; I² = 96.9%). Subgroup analyses revealed marker-dependent heterogeneity, with inconsistent findings for IL-6, TNF-α, and IL-8. Meta-regression identified age as a positive moderator and sample size as a negative moderator of effect size. Funnel-plot asymmetry suggested potential publication bias or small-study effects. Sensitivity analyses confirmed the robustness of the overall null result. Conclusion: Current evidence does not support a consistent alteration of peripheral inflammatory biomarkers in PD. The substantial heterogeneity and moderating effects of age and sample size indicate that peripheral cytokines do not reliably reflect central neuroinflammatory processes and cannot serve as universal biomarkers for PD. Future studies should adopt standardized assay procedures, stratified designs, and longitudinal approaches to better characterize PD-related immune alterations.