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

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.