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Platelet miRNA bio-signature discriminates between dementia with Lewy bodies and Alzheimer’s disease

ABSTRACT: Dementia with Lewy bodies (DLB) is the second most common cause of degenerative dementia after Alzheimer’s disease (AD) and presents several overlapping pathological and clinical features with both AD and Parkinson’s disease (PD). Consequently, only one in three DLB cases is diagnosed correctly. Platelets are anucleate cells containing cellular structures and molecules, such as microRNA (miRNA), the analysis of which provides biomarkers for several disorders. In this cross-sectional study, we profiled the whole platelet miRNA transcriptome from 7 DLB patients and 7 healthy controls using Next-Generation Sequencing (NGS) and found 22 differentially expressed miRNAs. These miRNAs were further validated with miRCURY LNA miRNA Custom PCR panels in three consecutive validation studies carried out from 2017-2019 with a total of 162 individuals including DLB (n=59), AD (n=28), and PD patients (n=24), and healthy controls (n=51). As a result, three different groups of miRNAs were identified as related to DLB, AD and PD, all in comparison with controls. Additionally, our results demonstrated a significant down-regulation of hsa-miR-26b-5p and hsa-miR-150-5p in DLB compared to PD; and a signature composed of seven miRNAs that had lower expression in DLB compared to AD. The predictive diagnostic value of this bio-signature for the differentiation of DLB from AD was assessed calculating the corresponding ROC curve, which yielded an area under the curve of 1.00. Predictive analyses using specialized software (miRTarbase, miRGate) were performed for the disease-specific miRNAs to identify target genes and corresponding pathways. Three disease-specific clusters of pathways and biological processes were identified 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, and protein metabolism and degradation were identified. In conclusion, we describe the identification of a novel, highly specific and sensitive platelet-associated miRNA-based bio-signature, which permits us to distinguish between DLB and AD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147218 | GEO | 2020/07/01

REPOSITORIES: GEO

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Project description:Results: MiRNA expression profiling of 1281 human miRNAs revealed relevant expression of 221 miRNAs consistently expressed in all samples at all time points. Correlation of platelet miRNA ranks was highly significant with data from other studies. Global distribution of miRNA expression was relatively similar in all subjects. No miRNA exhibited a significant effect of time at level 0.05. This finding was supported by exploratory analysis of predicted time effects from the mixed effects models. Furthermore, no significant effect of ASA could be found. Concerning the functional implication of the 20 most abundantly expressed miRNAs, we found 6 functional themes: nuclear import, cell cycle, transmembrane receptor protein serine/threonine kinase signaling pathway, regulation of kinase activity, pathways in cancer, and leukocyte differentiation. Conclusion: Our study shows that the platelet miRNA profile is remarkably stable in healthy subjects and is not affected by single-dose ASA treatment. For this reason, single-point analysis of platelet miRNA profile is reasonable when inter-individual differences are studied. The functional annotation network points toward additional extra-platelet effects of platelet miRNAs. We assessed the platelet miRNA profile blood in 5 volunteers at five time points over a time course of 10 days; 24 h prior to the last blood sampling, all subjects took 500 mg acetylsalicylic acid (ASA) once. Platelet miRNA was isolated from platelet-rich plasma which was leucocyte-depleted by negative bead separation. Then miRNA array analysis was performed on the isolated platelet miRNA. Temporal patterns and the effect of ASA were explored by a linear mixed effects model for each miRNA. For the 20 most abundantly expressed platelet miRNAs, a target gene search was performed by using miRWalk for validated and predicted targets. To visualize which molecular functions arerelated to those miRNAs, an annotation network was created by ClueGO, a Cytoscape plug-in.

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Platelet miRNA bio-signature discriminates between dementia with Lewy bodies and Alzheimer’s disease

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