microRNA ‐7‐5p and α‐Synuclein SAA Predict Parkinson's Disease Phenoconversion

ABSTRACT Objective Corroborate blood neuron‐derived extracellular vesicle (NDEV) alpha‐synuclein (αSyn), the CSF αSyn seed amplification assay (αSyn‐SAA), and blood microRNA‐7‐5p (miR‐7‐5p) as markers for Parkinson's disease (PD) phenoconversion and determine if combining these markers would help select subjects who would be more likely to phenoconvert. Methods Using Parkinson Progression Marker Initiative data, time to PD phenoconversion was determined by Hoehn and Yahr scores. Log‐rank analysis was used to find cutpoints. Cox regression analysis was used with log[miR‐7‐5p], log[NDEV αSyn], and the αSyn‐SAA. Models included age and sex. Results In a Cox model with baseline log[miR‐7‐5p], for each unit increase in log[miR‐7‐5p], there was 1.57 times increased PD phenoconversion ( p = 0.003). In a model with baseline log[NDEV αSyn], only baseline age was associated with increased phenoconversion ( p < 0.05). Using Cox regression analysis, the cutpoints for miR‐7‐5p and NDEV αSyn were 27.39 reads per million mapped ( p < 0.01) and 18.36 pg/mL ( p = 0.01), respectively. In separate models using log[miR‐7‐5p] and log[NDEV αSyn] cutpoints, higher levels of log[miR‐7‐5p] and log[NDEV αSyn] resulted in 2.26 ( p < 0.001) and 4.46 ( p < 0.05) times increased PD phenoconversion, respectively. A positive αSyn‐SAA was associated with 3.62 times increased phenoconversion ( p < 0.001). Having log[miR‐7‐5p] higher than its cutpoint and a positive αSyn‐SAA was associated with 4.31 times phenoconversion ( p < 0.001). Interpretation Blood miR‐7‐5p, NDEV αSyn, and αSyn‐SAA could be used to enrich for prodromal patients likely to develop PD earlier in disease‐modifying clinical trials and combining them could further enrich for this population.