Platelet miRNA bio-signature discriminates between dementia with Lewy bodies and Alzheimer disease: A cross-sectional study.

Abstract Background Dementia with Lewy bodies (DLB) is one of the most common causes of degenerative dementia after Alzheimer’s disease (AD) and presents pathological and clinical overlap with both AD and Parkinson’s disease (PD). Consequently, only one in three DLB cases is diagnosed correctly. Platelets have been previously related to neurodegeneration. They contain microRNAs (miRNAs), and their analysis may provide disease biomarkers. Methods Small RNAs from platelets of DLB patients and controls were analyzed by Next Generation Sequencing (NGS), and miRNAs deregulated in DLB were selected. Expression of these miRNAs was then determined and validated by LNA-based qRT-PCR in three consecutive studies from 2017 to 2019 enrolling 162 individuals, including DLB, AD, and PD patients, and healthy controls. Their predictive diagnostic potential was calculated by ROC curve analysis. miRTarbase and miRGate were used for target prediction. Results We profiled the whole platelet miRNA transcriptome from 7 DLB patients and 7 controls using NGS. Twenty-two selected miRNAs were further validated in independent studies (2017–2019) including DLB (n = 59), AD (n = 28), and PD (n = 24) patients, and control individuals (n = 51). Our results demonstrated downregulated expression levels for hsa-let-7d-5p (fold change 0.14; p = 0.006), hsa-miR-132-5p (0.12; p = 0.0015), hsa-miR-142-3p (0.07; p = 0.00047), hsa-miR-146a-5p (0.07; p = 0.00035), hsa-miR-150-5p (0.10; p = 0.0098), hsa-miR-25-3p (0.13; p = 0.0019) and hsa-miR-26b-5p (0.09; p = 0.0014) in DLB compared to AD. ROC curve for this seven-miRNA biosignature yielded an area under the curve (AUC) of 1. Both hsa-miR-142-3p and hsa-miR-150-5p, were down-regulated in DLB compared to controls (AUC = 0.85). Comparing AD and controls, miRNAs hsa-miR-132-5p, hsa-miR-146a-5p, hsa-miR-25-3p, and hsa-miR-6747-3p were up-regulated in AD (AUC = 0.94); and hsa-miR-128-3p and hsa-miR-139-5p were down-regulated in PD compared to controls (AUC = 0.81). Predictive target analysis identified three disease-specific pathway clusters as a result of platelet-miRNA deregulation. In DLB, pathways related to gene expression and small RNA metabolism; in AD, pathways related to stress response and RNA stress granules; and in PD pathways related to protein phosphorylation, metabolism and degradation were identified. Conclusion A platelet-associated bio-signature composed of 7 miRNAs is highly specific and sensitive for distinguishing DLB from AD.