Article

Circulating miRNA Biomarkers for Alzheimer's Disease

University of Melbourne, Australia
PLoS ONE (Impact Factor: 3.23). 07/2013; 8(7):e69807. DOI: 10.1371/journal.pone.0069807
Source: PubMed

ABSTRACT

A minimally invasive diagnostic assay for early detection of Alzheimer's disease (AD) is required to select optimal patient groups in clinical trials, monitor disease progression and response to treatment, and to better plan patient clinical care. Blood is an attractive source for biomarkers due to minimal discomfort to the patient, encouraging greater compliance in clinical trials and frequent testing. MiRNAs belong to the class of non-coding regulatory RNA molecules of ∼22 nt length and are now recognized to regulate ∼60% of all known genes through post-transcriptional gene silencing (RNAi). They have potential as useful biomarkers for clinical use because of their stability and ease of detection in many tissues, especially blood. Circulating profiles of miRNAs have been shown to discriminate different tumor types, indicate staging and progression of the disease and to be useful as prognostic markers. Recently their role in neurodegenerative diseases, both as diagnostic biomarkers as well as explaining basic disease etiology has come into focus. Here we report the discovery and validation of a unique circulating 7-miRNA signature (hsa-let-7d-5p, hsa-let-7g-5p, hsa-miR-15b-5p, hsa-miR-142-3p, hsa-miR-191-5p, hsa-miR-301a-3p and hsa-miR-545-3p) in plasma, which could distinguish AD patients from normal controls (NC) with >95% accuracy (AUC of 0.953). There was a >2 fold difference for all signature miRNAs between the AD and NC samples, with p-values<0.05. Pathway analysis, taking into account enriched target mRNAs for these signature miRNAs was also carried out, suggesting that the disturbance of multiple enzymatic pathways including lipid metabolism could play a role in AD etiology.

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    • "↑ in AD 0.01 miR-101-3p ↑ in AD NS miR-15a-5p ↑ in AD 0·04 miR-20a-5p ↑ in AD 0.02 miR-93-5p ↑ in AD 0.03 miR-106b-5p ↑ in AD NS miR-18b-5p ↑ in AD 0·01 miR-106a-5p ↑ in AD 0.05 miR-1306-5p ↓ in AD 0·01 miR-582-5p ↑ in AD 0·01 miR-143-3p ↑ in AD 0·02 miR-335-5p ↑ in AD 0.02 miR-361-5p ↑ in AD 0.03 miR-424-5p ↑ in AD 0·01 miR-342-3p ↓ in AD 0·01 miR-15b-3p ↓ in AD 0.03 Panel of 16 miRNAs 0.87 0.77 – Kumar [9] 2013 miR-15b-5p * ↓ in AD <0.0001 0.85 0.88 0.96 miR-142-3p-3p ↓ in AD <0.0001 0.65 1.00 0.96 miR-191-5p ↓ in AD <0.0001 0.95 0.76 0.95 Let-7g-5p * ↓ in AD <0.0001 0.95 0.53 0.93 Let-7d-5p ↓ in AD <0.0001 0.75 0.88 0.92 miR-545-3p * ↓ in AD 0.01 0.20 0.88 0.74 miR-301a-3p ↓ in AD NS – – – Combination of 3 miRNAs ( * ) 0.95 0.94 0.95 (Continued) "
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    ABSTRACT: Background: In recent years, microRNAs (miRNA), a class of non-coding RNA known to regulate protein expression post-transcriptionally, have been recognized as novel biomarkers of diseases. Objective: In this systematic review, we identify miRNAs that are differentially expressed in Alzheimer's disease (AD) and/or mild cognitive impairment (MCI) and evaluate their accuracy as potential blood biomarkers. Methods: Eligible studies of miRNAs in peripheral blood distinguishing patients with AD or MCI from cognitively normal controls were identified through standardized search strategies in Medline, PubMed, and Embase. MiRNAs that were differentially expressed were identified and where available their sensitivity and specificity for AD or MCI extracted from the retrieved studies. Results: Eighteen studies investigated the diagnostic value of miRNAs as peripheral biomarkers of AD/MCI. Twenty miRNAs were significantly upregulated and 32 miRNAs downregulated in AD compared to controls in ten AD studies. Nine miRNAs were consistently dysregulated in more than one study. Of the 8 MCI studies, only one miRNA, miR-132, was consistently upregulated in three independent studies. Of the studies that reported diagnostic accuracy data, the majority of miRNA panels and individual miRNAs had a sensitivity and specificity greater than 0.75. Conclusion: Individual studies suggest that microRNAs can differentiate patients with AD/MCI from cognitively normal controls with modest accuracy. However, the literature is constrained by methodological differences between studies, with few studies assessing the same miRNAs. To become potential biomarkers for AD, further studies with standardized study designs for replication and validation are required. Results from this review may help researchers select candidate miRNAs for further investigation.
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