Discovery and validation of blood microRNAs as molecular biomarkers of epilepsy: Ways to close current knowledge gaps

Abstract

SummaryThere is a major unmet need for biomarkers of epilepsy. Biofluids such as blood offer a potential source of molecular biomarkers. MicroRNAs (miRNAs) fulfill several key requirements for a blood‐based molecular biomarker being enriched in the brain and dysregulated in epileptic brain tissue, and manipulation of miRNAs can have seizure‐suppressive and disease‐modifying effects in preclinical models. Biofluid miRNAs also possess qualities that are favorable for translation, including stability and easy and cheap assay techniques. Herein we review findings from both clinical and animal models. Studies have featured a mix of unbiased profiling and hypothesis‐driven efforts. Blood levels of several brain‐enriched miRNAs are altered in patients with epilepsy and in patients with drug‐resistant compared to drug‐responsive seizures, with encouraging receiver‐operating characteristic (ROC) curve analyses, both in terms of sensitivity and specificity. Both focal and generalized epilepsies are associated with altered blood miRNA profiles, and associations with clinical parameters including seizure burden have been reported. Results remain preliminary, however. There is a need for continued discovery and validation efforts that include multicenter studies and attention to study design, sample collection methodology, and quality control. Studies focused on epileptogenesis as well as associations with covariables such as sex, etiology, and timing of sampling remain limited. We identify 10 knowledge gaps and propose experiments to close these. If adequately addressed, biofluid miRNAs may be an important future source of diagnostic biomarkers that could also support forthcoming trials of antiepileptogenesis or disease‐modifying therapies.

Extracellular Vesicles as Diagnostics and Therapeutics for Structural Epilepsies

“…microRNAs and other circulating small RNAs are common targets for biomarker discovery from liquid biopsy for different indications [3,40]. Most circulating miRNAs are apparently carried by the Argonaute protein complexes [41,42], and several articles have reported the presence of small RNA also in lipoproteins [43,44,45].…”

“…Several studies have reported altered miRNA profiles in brain tissue and plasma after status epilepticus (SE) and TBI, and these findings have been comprehensively reviewed earlier [3,40,79]. EVs contain an interesting composition of circulating small RNAs.…”

The Biochemical Profile of Post-Mortem Brain from People Who Suffered from Epilepsy Reveals Novel Insights into the Etiopathogenesis of the Disease

“…A study in 2018 used biofluids, specifically microRNAs in blood, to look at the dysregulation of epileptic brain tissue. However, as there is a limited mechanistic understanding of miRNAs, the implementation of relevant biomarkers cannot currently prevent epileptogenesis or alter treatment [32]. In addition, a recent study by Raoof et al (2018) report a dual-center, dual-platform approach, demonstrating the biomarker potential of circulating miRNAs for diagnosing epilepsy, while providing some mechanistic insights into the underlying pathological mechanisms [33].…”

Circulating microRNAs as Potential Novel Diagnostic Biomarkers to Predict Drug Resistance in Temporal Lobe Epilepsy: A Pilot Study

“…The identification of circulating biomarkers for resistant epilepsy could potentially improve the choice of correct treatment as well as the prognosis of epileptic patients. Indeed, many circulating miRNAs have been reported as differentially expressed in hippocampi and peripheral blood from both animal models and patients with temporal lobe epilepsy compared to nonepileptic subjects [ 13 , 14 , 15 , 16 ]. Considering that few studies have specifically examined correlations between miRNA and TLE, the objectives of this study are (i) to determine if changes in expression of six epilepsy-related miRNAs, namely, miR-146a-5p, miR-142-5p, miR-132-3p, miR-138-5p, miR-298, and miR-223-3p (from now on, they are named miR-146a, miR-142, miR-132, miR-138, miR-298, miR-223), are present in the serum of a TLE cohort (these miRNAs have been selected on the findings of a previous work [ 11 ]), and (ii) to verify if the serum levels of these miRNAs are potentially associated with failure of ASMs.…”