A neuroimmune-enriched multibiofluid proteomic index associated with cognitive-motor progression in early Parkinson’s disease: a longitudinal PPMI cohort study

Abstract

Progression in early Parkinson's disease (PD) is heterogeneous, motivating transparent biological markers of group-level progression context. We analyzed longitudinal Parkinson’s Progression Markers Initiative (PPMI) data downloaded on 31 May 2026. The neuroimmune-enriched multibiofluid proteomic index (NEMPI) used 718 quality-control-eligible cerebrospinal fluid and plasma markers, organized into four source-context modules with equal marker and module weights. Direct normalized protein quantification (NPQ) z-standardization was used for the primary reporting implementation, with the log1p implementation examined as a preprocessing sensitivity analysis. Among the 521 participants in the same-sample Cox comparison (173 first observed cognitive-status abnormalities), adding NEMPI to demographic, clinical, alpha-synuclein seed amplification assay, dopamine-transporter imaging, and apolipoprotein E (APOE) epsilon4 covariates yielded an NEMPI hazard ratio (HR) of 1.287 per 1-SD higher value (95% confidence interval (CI): 1.102–1.502; P = 0.001) and improved likelihood-based fit, but the C-index increment was small (0.0032; bootstrap 95% CI: -0.0093 to 0.0239). The consecutive-abnormality association was stronger but had fewer events, with fewer than 10 events per parameter; the persistent/irreversible estimate was weaker, and its confidence interval crossed 1. Higher NEMPI was also associated with a modest group-average Montreal Cognitive Assessment (MoCA) and motor trajectory differences, with 5-year translations below published minimal clinically important difference (MCID) ranges. Results were similar under 5-year censoring, discrete-time analysis, stabilized inverse-probability weighting, age analyses, and measured confounder or preanalytic adjustments. NEMPI is therefore interpreted as an abundance-based, neuroimmune-enriched, multibiofluid proteomic composite associated with broad cognitive-motor progression, not as a patient-level prediction tool, clinical threshold, cognition-specific biomarker, or causal mechanism.