Abstract There are currently no validated peripheral biomarkers for the diagnosis, differentiation or progression of the neurodegenerative synucleinopathies, Parkinson’s disease (PD) and multiple system atrophy (MSA). Diagnostic biomarkers that reflect the disease mechanisms, or progression biomarkers that change with disease severity would be extremely valuable for assessing disease modifying therapies. Our objective was to explore putative protein biomarkers of PD and MSA, in relation to clinical disease severity, using Nucleic Acid Linked Immuno-Sandwich Assay (NULISA) central nervous system disease panel for biomarker quantification. We used the NULISA CNS disease panel to test plasma from 161 PD patients collected at 3 timepoints (0, 48, 96 weeks) and serum from 43 MSA patients at 3 timepoints (0, 24, 48 weeks) and compared results to paired plasma and serum samples collected from (n=39) age matched healthy control (HC) individuals at a single timepoint. We also tested paired CSF samples collected on 2 occasions, separated by 96 weeks from a subgroup of PD (n=51) and after an interval of 48 weeks in a subgroup MSA (n=23) participants. All samples were taken contemporaneously with objective clinical assessments of disease severity. Biomarker comparisons were made across disease status, and in relation to disease severity using linear modelling. Multiple proteins showed significantly different quantitative levels (False Discovery Rate (FDR) corrected p value 0.05) between peripheral samples from PD and HC, and MSA and HC. For PD, we identified three key classes of proteins that showed significant differences between PD and controls: (i) Amyloidogenic proteins, specifically, oligomeric alpha-synuclein was significantly higher in PD compared to controls. A number of other aggregating proteins also exhibited differences. (ii) Metabolic pathways, including the adipokine (Chemokine-like protein TAFA-5) were associated with PD diagnosis and (iii) Inflammatory pathways (Interleukin-7) were associated with PD diagnosis. Importantly, some of these same proteins were significantly associated with PD severity including oligomeric and phosphorylated forms of alpha-synuclein and Insulin-like Growth Factor-1 receptor. We also confirmed as expected that Neurofilament Light levels strongly distinguish MSA patients from HC, while also demonstrating that serum inflammatory proteins (Interleukin-6) as well as the phosphorylated alpha synuclein ratio are strongly associated with MSA severity. These results from the NULISA multiplex platform provide additional insights into the complex pathogenetic mechanisms associated with alpha-synucleinopathy related neurodegeneration. Individual protein levels or the combination of multiple protein candidates may usefully serve as diagnostic biomarkers, or as biomarkers for disease progression in trials of potential disease modifying interventions.
Vijiaratnam et al. (Tue,) studied this question.