Background Circulating phosphatidylserine (cPS) may reflect neuronal injury in Parkinson's disease (PD), yet its diagnostic and prognostic utility remains unvalidated. This study aimed to evaluate cPS as a plasma biomarker for PD staging and outcome prediction. Methods In this 24-month prospective cohort (STARD-compliant), 120 PD patients (40 early Hoehn and Yahr scale [H&Y] I-II, 40 moderate III, 40 advanced IV-V) and 40 matched controls were enrolled. cPS was quantified via ELISA. Disease severity was assessed by MDS-UPDRS-III and H&Y staging; outcomes included Barthel Index (BI≤40 defining poor prognosis) and cognitive decline (≥4-point Montreal Cognitive Assessment [MoCA] drop). Statistical analyses involved Spearman correlations, ROC curves, mixed-effects models, and multivariable regressions. Results Baseline cPS increased with PD severity (control: 35.2 ± 8.45 vs. advanced: 89.45 ± 15.20 ng/mL, P < 0.001), correlating strongly with H&Y stage (ρ = 0.862, P < 0.001), MDS-UPDRS-III (ρ = 0.793, P < 0.001), and BI decline (ρ = −0.817, P < 0.001). ROC analysis showed cPS differentiated advanced vs. early PD with the highest AUC (0.95, 95% CI: 0.90–0.99, cutoff = 67.7 ng/mL, sensitivity = 97.0%, specificity = 82.0%). Longitudinal cPS increases were stage-dependent (early: +6.10 ± 2.45, moderate: +10.30 ± 3.15, advanced: +14.25 ± 4.50 ng/mL/year, P < 0.001). Multivariate Cox regression identified baseline cPS as an independent predictor of 24-month functional decline (BI ≤40: adjusted HR = 1.620, 95% CI: 1.382–1.898, P < 0.001). Logistic regression showed cPS predicted cognitive decline (MoCA ≥4-point drop: adjusted OR = 1.485, P < 0.001), independent of age and education. Conclusions: cPS levels correlate with PD severity, predict functional and cognitive decline, and exhibit stage-specific longitudinal changes, supporting cPS as a candidate biomarker for PD monitoring, though further validation is required.
