Blood proteins track Parkinson’s worsening over time

Repeated blood tests may reveal which molecular processes accompany clinical worsening in Parkinson’s disease, according to a prospective study published in npj Parkinson’s Disease. Researchers analysed 166 patients from the PROMOVE registry who underwent repeated OFF-state clinical assessments alongside longitudinal serum proteomics covering 297 proteins. Instead of relying on a single baseline measurement, the team tracked how protein levels changed within individuals over time and linked those trajectories to worsening across motor, cognitive, non-motor, and treatment-related outcomes.

The study addressed a persistent problem in Parkinson’s research: the disease shows marked heterogeneity in clinical progression, and single baseline biomarkers have shown limited value for predicting these changes. To overcome this, participants were classified as worsening or non-worsening for each outcome based on their individual longitudinal slopes. In the worsening group, all proteins were then tested using linear mixed-effects models that separated within-subject protein effects from between-subject effects, a statistical distinction that helps clarify whether a protein’s change over time within a person relates to clinical change, rather than simply reflecting differences between individuals.

Six protein-clinical associations remained significant after false discovery rate correction. Higher levels of DDC, an enzyme involved in dopamine synthesis, were associated with increasing levodopa equivalent daily dose, pointing to a treatment-related signature. Higher CD276 and POSTN were associated with worse scores on the MDS-UPDRS Part II, which measures motor experiences of daily living, while higher VEGF-C and IL19 were associated with worse MDS-UPDRS Part III scores, the clinician-rated motor examination. Higher IL12 was associated with lower MMSE scores, linking an immune signalling protein to cognitive decline.

The five non-treatment associations remained significant even after additional adjustment for time-varying dopaminergic treatment, suggesting that immune, vascular, and extracellular-matrix processes track clinical worsening independently of medication changes. CD276 is an immune checkpoint molecule, POSTN is an extracellular-matrix protein, VEGF-C is involved in vascular and lymphatic signalling, and IL19 and IL12 are immune cytokines, so the findings point to several distinct biological domains rather than a single pathway.

The authors suggest that longitudinal proteomics may complement clinical measures when monitoring Parkinson’s disease progression. Because the associations were identified in patients already showing clinical worsening, the results describe molecular patterns that accompany progression rather than proving that these proteins drive the disease process. The study also focused on a specific cohort from a prospective registry, so broader populations and independent cohorts would need to be examined before any clinical application.

Nevertheless, the approach illustrates why repeated sampling may outperform single time-point measurements in a heterogeneous disease. By classifying participants according to their own rate of change and modelling protein dynamics within individuals, the design captured progression-specific molecular signatures that baseline snapshots could miss. The work adds to growing interest in blood-based biomarkers for Parkinson’s disease, where accessible, repeatable measures could eventually help stratify patients and monitor responses in clinical trials.

Subject of Research: Longitudinal blood-based proteomics identifying protein signatures associated with clinical worsening in Parkinson's disease

Article Title: Longitudinal blood-based proteomics reveal progression-specific molecular signatures in Parkinson’s disease

Article References: Suette, M., Hofer, E., Gattermeyer-Kell, L., Brazel, D. M., Boyle, E. A., Schneller, M., Kern, D., Katschnig-Winter, P., Koegl, M., Enzinger, C., Qureshi, F., Khalil, M., & Schwingenschuh, P. (2026). Longitudinal blood-based proteomics reveal progression-specific molecular signatures in Parkinson’s disease. npj Parkinson's Disease. https://doi.org/10.1038/s41531-026-01608-0

Image Credits: AI Generated

DOI: 10.1038/s41531-026-01608-0

Keywords: Parkinson's disease, blood-based proteomics, biomarkers, clinical progression, MDS-UPDRS, levodopa, immune signalling, vascular biology, longitudinal study, serum proteins, cognitive decline, PROMOVE registry