Majbour, Nour; Aasly, Jan; Abdi, Ilham; Ghanem, Simona; Erskine, Daniel; van de Berg, Wilma; El-Agnaf, Omar; (2022) Disease-Associated α-Synuclein Aggregates as Biomarkers of Parkinson Disease Clinical Stage. Neurology 10.1212/WNL.0000000000201199. (In press).

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Abstract

BACKGROUND AND OBJECTIVES: There's an unmet need to identify robust diagnostic biomarker that can mirror Parkinson's disease (PD) clinical course. Here we present a novel approach to investigate disease associated αSyn aggregates as biomarkers of PD clinical stage. METHODS: We combined both seed amplification assay (SAA) and enzyme-linked immunosorbent assay (ELISA) to provide a quantitative test readout that reflects the clinical severity of PD patients. To attain this goal, we initially explored the potential of our test using two sets of human brain homogenates (pilot and validation sets), and then verified it with two independent human CSF cohorts; discovery (62 PD, and 34 control) and validation (49 PD and 48 control). RESULTS: We showed that oligomers-specific ELISA robustly quantified SAA end product from subjects with PD or DLB with high sensitivity and specificity scores (100%). Analysis also demonstrated that seeding activity could be detected earlier with oligomeric ELISA as the test readout rather than SAA alone. More importantly, multiplexing the assays provided robust information about the patients' clinical disease stage. In the discovery cohort, levels of CSF seeded αSyn oligomers correlated with the severity of the clinical symptoms of PD as measured by UPDRS-motor (r= 0.58, p <0.001) and H&Y scores (r= 0.43, p <0.01). Similar correlations were observed in the validation cohort between the concentrations of CSF seeded αSyn oligomers and both UPDRS-motor (r= 0.50, p <0. 01) and H&Y scores (r= 0.49, p <0.01). At 20 h, ROC analysis yielded a sensitivity of 91.9% (95% CI, 82.4%-96.5%) and a specificity of 85.3% (95% CI,69.8 %-93.5%), with an area under the curve of 0.969 for CSF seeded αSyn oligomers differentiating PD from controls in the Discovery CSF cohort, whereas, a sensitivity of 80.7% (95% CI, 69.1 %-88.5%), a specificity of 76.5% (95% CI, 60.0 %-87.5%), and area under the curve of 0.860 were generated with ThT Imax at the same time-point. DISCUSSION: We showed that combining SAA and ELISA assays is more promising diagnostic tool than SAA alone, providing information about the disease stage by correlating with clinical measures of disease severity.

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