J Stroke.  2021 May;23(2):162-182. 10.5853/jos.2020.05085.

Diagnostic and Prognostic Circulating MicroRNA in Acute Stroke: A Systematic and Bioinformatic Analysis of Current Evidence

• Bejleri J
• Jirström E
• Donovan P
• Williams DJ
• Pfeiffer S

• KMID: 2516407
• DOI: http://doi.org/10.5853/jos.2020.05085

Abstract

Background and Purpose
Stroke is the second leading cause of death and disability worldwide and its diagnosis, and assessment of prognosis, remains challenging. There is a need for improved diagnostic and prognostic biomarkers. MicroRNAs (miRNAs) play important roles in the post-transcriptional regulation of gene expression and their secretion and remarkable stability in biofluids highlights their potential as sensitive biomarkers in the diagnosis and prognosis of acute stroke.
Methods
We carried out a systematic review to assess current evidence supporting the potential of miRNAs to act as unique diagnostic and prognostic biomarkers in blood samples collected from patients suffering acute stroke within 24 hours of symptoms onset.
Results
We identified 22 studies eligible for inclusion with 33 dysregulated miRNAs having diagnostic potential in the acute phase of the disease. We identified miR-16, miR-126, and miR-335 as having the highest sensitivity as diagnostic and prognostic biomarkers in acute ischaemic stroke and present original bioinformatic and pathway enrichment analysis of putative miRNA–target interactions.
Conclusions
miRNAs represent unique biomarkers which have a promising future in stroke diagnosis and prognosis. However, there is a need for more standardized and consistent methodology for the accurate interpretation and translation of miRNAs as novel specific and sensitive biomarkers into clinical practice.

Keyword

miRNA; Ischaemic stroke; Stroke; Biomarker; Diagnostic; Prognostic

Figure

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  Figure 1. Flow chart detailing study screening and selection process.

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  Figure 2. Clinical utility of identified miRNAs in acute stroke. (A) Diagnostic accuracy of acutely expressed miRNAs within or at 24 hours of stroke symptoms onset. Study reference indicated in brackets. (B) Clinical utility of dysregulated miRNAs. LAAS, large artery atherosclerosis stroke; TACI, total anterior circulation infarct; PACI, partial anterior circulation infarct. *Denotes combination of miRNAs.

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  Figure 3. Bioinformatic miRNA gene target prediction and pathway enrichment. (A) Total and shared predicted mRNA targets of miR-16-5p, miR-126-5p, and miR-335-5p, identified as having highest sensitivity and specificity with diagnostic and prognostic potential. Barplots showing the top (B) Kyoto Encyclopedia of Genes and Genomes (KEGG) terms and (C), enriched gene ontology (GO) terms per group. The fraction in each bar represents the number of predicted gene targets/total number of genes associated with a given pathway or GO. Adjusted P values (Benjamini-Hochberg corrected) <0.05 were considered significant. GnRH, gonadotropin-releasing hormone; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; TNF, tumor necrosis factor; ErbB, epidermal growth factor; RISC, RNA‐induced silencing complex; MF, molecular function; BP, biological process; CC, cellular component.

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  Figure 4. Potential roles for miR-16-5p, miR-126-5p, and miR-335-5p in the pathogenesis of ischaemic stroke. Putative targets for miR-16-5p were significantly enriched in mammalian target of rapamycin (mTOR), insulin, Wnt, and Ras/mitogen-activated protein kinases (MAPK) signalling pathways involved in regulation of roles central to neuronal survival and death and infarct development following stroke. Ras/MAPK is a common signalling pathway significantly enriched for the targets of both miR-16-5p and miR-126-5p. Also enriched in targets of miR-126-5p were tumor necrosis factor (TNF) and epidermal growth factor (ErbB) signalling pathways related to immune and inflammatory responses and endothelial cell growth, survival and proliferation. miR-335-5p regulation of Rho associated protein kinase 1 (ROCK1), involved in vascular inflammation, and NOTCH1 regulation of human endothelial cell calcification, is linked to aortic valve calcification and stenosis, common causes of cardiovascular morbidity and mortality. Figure produced in Biorender.

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