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Currently, the management of Parkinson’s disease (PD), the second most common neurodegenerative disease, is challenging due to the lack of consensus on blood biomarkers for diagnostic, prognostic, and outcome purposes. The identification of specific and sensitive biomarkers could contribute to an early diagnosis and, consequently, facilitate management and improve prognosis. Several molecules are emerging as potential biomarkers, although current data seem preliminary and need further validation. Further, their combination in a panel seems to strengthen their diagnostic power, allowing them to identify PD cases with greater specificity and sensitivity. In this study, we evaluated the association of a panel of molecules, including shed syndecans, ELA peptides, CD141, VEGF, BDNF, and systemic inflammatory indices, in 30 PD cases and 30 matched healthy controls. Significant differences in the systemic levels of all the molecules studied were detected in the PD group when compared to the healthy participants. Univariate and multivariate regression analyses, as well as correlations with clinical indicators, including PD severity expressed by the Hoehn and Yahr (H&Y) scale, highlighted the key role of the studied molecules as independent risk factors. Finally, the use of receiver operating characteristic (ROC) curves demonstrated the diagnostic value of hs-CRP, NLR, BDNF, shed syndecans (1–3), and ELA-32 in PD. Interestingly, their diagnostic performance significantly improved when combined in a panel. Overall, our results suggest that hs-CRP, NLR, BDNF, shed syndecans (1–3), and ELA-32 are significantly associated with PD and could likely serve as appropriate diagnostic and prognostic biomarkers, especially if combined in a panel. Full article