Emerging biomarkers for Parkinson's disease in biological fluids

Early and accurate diagnosis of Parkinson's disease (PD) remains a challenge, hindering the efficient recruitment of patients into clinical trials aimed at disease modification. This underscores the urgent need for validated and clinically applicable biomarkers. Research continues to expand our knowledge of fluid biomarkers for detecting and monitoring PD progression. Cerebrospinal fluid α-synuclein (α-syn) seed amplification assays (SAA) have emerged as highly sensitive and specific biomarkers for the diagnosis of PD. The development of less invasive procedures using biological fluids such as serum or saliva would be more practical for routine clinical use. Recent data demonstrate the presence of pathogenic α-synuclein in the serum of PD patients compared with healthy controls, detected using real-time quaking-induced conversion (RT-QuIC) assays. Elevated ratios of pS129-α-syn and/or oligomeric α-syn to total α-syn have also been reported in PD. Future research should clarify differences in protein aggregate formation across various synucleinopathies. Promising advances toward a clinically useful blood-based diagnostic test for PD include the quantification of proteins released from neural-derived extracellular vesicles (NDEVs), such as oligomeric and phosphorylated α-syn, tau, and disease-associated microRNAs. Given the role of neuroinflammation in PD pathogenesis, inflammatory biomarkers, including interleukin (IL)-6, IL-10, tumor necrosis factor-α(TNF-α), glial fibrillary acidic protein (GFAP), chitinase-3-like protein 1 (YKL-40), and monocyte chemoattractant protein-1 (MCP-1), are under active investigation. Furthermore, fluid biomarkers associated with Alzheimer's disease pathology are being explored for their potential to predict motor and cognitive decline in PD and related synucleinopathies. Salivary EVs hold promise as a non-invasive source of PD biomarkers; however, robust validation in large, well-characterized cohorts is essential to improve the diagnostic and prognostic accuracy of PD.