Circulating MicroRNAs and Extracellular Vesicle-Derived MicroRNAs as Predictors of Functional Recovery in Ischemic Stroke Patients: A Systematic Review and Meta-Analysis

Abstract

Stroke accounts for the second leading cause of death and a major cause of disability, with limited therapeutic strategy in both the acute and chronic phases. Blood-based biomarkers are intensively researched and widely recognized as useful tools to predict the prognoses of patients confronted with therapeutically limited diseases. We performed a systematic review of the circulating biomarkers in IS patients with prognostic value, with a focus on microRNAs and exosomes as predictive biomarkers of motor and cognitive recovery. We identified 63 studies, totalizing 72 circulating biomarkers with prognostic value in stroke recovery, as follows: 68 miRNAs and exosomal-miRNAs being identified as predictive for motor recovery after stroke, and seven biomarkers being predictive for cognitive recovery. Twelve meta-analyses were performed using effect sizes (random-effects and fixed-effects model). The most significant correlation findings obtained after pooling were with miR-21, miR-29b, miR-125b-5p, miR-126, and miR-335. We identified several miRNAs that were correlated with clinical outcomes of stroke severity and recovery after ischemic stroke, providing predictive information on motor and cognitive recovery. Based on the current state of research, we identified serum miR-9 and neutrophil miR-29b as the most promising biomarkers for in-depth follow-up studies, followed by serum miR-124 and plasma miR-125b.

Programming of cardiac metabolism by miR-15b-5p, a miRNA released in cardiac extracellular vesicles following ischemia-reperfusion injury

“…MiRNAs are promising biomarkers of CVD [ 21 ], possessing the main required properties including: being detectable in easily accessible human fluids (e.g., blood, serum, saliva, urine), being present before disease pathology thus predicting the future onset of diseases in high-risk individuals and being stably measurable in the circulation. Furthermore, they can be secreted by diseased tissues; indeed, unique signatures of circulating miRNAs have been associated with a wide range of human pathologies [ 42 , 43 ]. The current data show the novel findings that maternal obesity/adiposity is associated with a sex-dependent increase in miRNA-15b in both humans and mice.…”

Small RNA signatures of acute ischemic stroke in L1CAM positive extracellular vesicles

“…Many of the differentially expressed miRNAs or those identified to be module drivers of diagnosis have previously been implicated in AIS including miR-27b, miR-125a-5p, miR-125b-5p, miR-126, and miR-4448 11 , 25 – 27 . These miRNAs are highly expressed in brain tissue and/or arteries providing a rationale for further studying their pathophysiological functions in AIS 22 .…”

Circulating microRNA miR-425-5p Associated with Brain White Matter Lesions and Inflammatory Processes

“…Overexpression could reduce Aβ plaque area and neuroinflammation in the hippocampus [38] Associated with inflammation in the pathogenesis of AD [39] Involved in neurogenesis [40] Upregulated in plasma of AD patients [41] Altered regulation in brain of AD male rats [42] Involved in neuronal accumulation of AD [43] Decreased in plasma of AD subjects [44] Part of a nine-miRNA signature as potential biomarker for AD [45] Dysregulated in plasma of AMD rats [46] Associated with stroke recovery [47] Negative correlation with cognitive function [48] Dysregulated in AD NMV [49] Cardiovascular events (including stroke) [50] Regulation of BDNF synthesis [51] hsa-miR-374a-5p…”