The Potential of MicroRNAs as Diagnostic and Prognostic Biomarkers for Mild Traumatic Brain Injury: A Systematic Review and Meta-analysis

Main Article Content

Ghea Mangkuliguna
Rexel Kuatama
Nikolaus Tobian
Yulian Prastisia
Laurentius Pramono
Yuda Turana

Abstract

Background: At least 80% of traumatic brain injuries (TBI) are classified as mild. Repetitive mTBI might lead to long-term cognitive and behavioural alterations, or even increasing risks of neurocognitive disorders. Current diagnostic techniques have little benefits on patients with no obvious brain lesions. Altered expression of miRNAs in humans’ biofluids are related to the pathological processes of TBI and can be molecular signature.


Objective: Investigate the potential of miRNAs as diagnostic and prognostic biomarkers for mTBI.


Material and Methods: This study was reported following the PRISMA criteria. Literature search was carried out in PubMed, ScienceDirect, and ProQuest for relevant articles published prior to January 2021. Both qualitative and quantitative analysis were conducted to determine the diagnostic and prognostic value of miRNAs. Quality of included studies was assessed using Newcastle-Ottawa Scale (NOS).


Results: Ten clinical studies reported various miRNAs from serum/plasma, cerebrospinal fluid, and saliva as potential diagnostic and prognostic biomarkers. miRNAs secured from the saliva had the highest diagnostic accuracy (Pooled AUC=0.843; 95% CI [0.802,0.883]; I2=0%; P<0.001). The diagnostic accuracy was higher among pediatrics and athletes (AUC>0.850) who were more vulnerable to head trauma without apparent lesions on neuroimaging. A common miRNA reported across studies, miR-92a, had very good diagnostic accuracy even when used as a single biomarker (AUC>0.890). Qualitative studies showed that the concentration of miR-425, miR-103a-3p, miR-219a-5p, miR-302d-3p, miR-422a, miR-518f-3p, miR-520d-3p, miR-93, miR-191 and miR-499 were correlated with patients’ clinical outcome. All of included studies showed good quality in terms of selection, comparability and outcome domains.


Conclusion: The present study suggested the use of salivary miRNAs as an early diagnostic tool for mTBI. Even though its prognostic value was still undermined, miR-92a was a promising candidate for future diagnostic biomarkers in mTBI.

Article Details

How to Cite
Mangkuliguna, G., Kuatama, R., Tobian, N., Prastisia, Y., Pramono, L. and Turana, Y. (2021) “The Potential of MicroRNAs as Diagnostic and Prognostic Biomarkers for Mild Traumatic Brain Injury: A Systematic Review and Meta-analysis”, Journal of Asian Medical Students’ Association. Kuala Lumpur, Malaysia. Available at: https://jamsa.amsa-international.org/index.php/main/article/view/303 (Accessed: 26July2021).
Section
Scientific Papers (AMSC Academic Competition)
Author Biographies

Laurentius Pramono, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Pluit Raya No. 2, North Jakarta 14440, Indonesia

Department of Public Health and Nutrition, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Pluit Raya No. 2, North Jakarta 14440, Indonesia

Department of Internal Medicine, Saint Carolus Hospital, Salemba Raya No.41, Senen, Jakarta 10440, Indonesia

Yuda Turana, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Pluit Raya No. 2, North Jakarta 14440, Indonesia

Department of Neurology, School of Medicine and Health Sciences, Atma Jaya Catholic University of Indonesia, Pluit Raya No. 2, North Jakarta 14440, Indonesia

References

Hyder AA, Wunderlich CA, Puvanachandra P, Gururaj G, Kobusingye OC. The impact of traumatic brain injuries: a global perspective. NeuroRehabilitation. 2007;22(5):341-353.

Dewan MC, Rattani A, Gupta S, Baticulon RE, Hung YC, Punchak M, et al. Estimating the global incidence of traumatic brain injury [published online ahead of print, 2018 Apr 1]. J Neurosurg. 2018;1-18. doi:10.3171/2017.10.JNS17352

Maas AIR, Menon DK, Adelson PD, Andelic N, Bell MJ, Belli A, et al. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 2017;16(12):987-1048. doi:10.1016/S1474-4422(17)30371-X

Gardner RC, Yaffe K. Epidemiology of mild traumatic brain injury and neurodegenerative disease. Mol Cell Neurosci. 2015;66(Pt B):75-80. doi:10.1016/j.mcn.2015.03.001

McInnes K, Friesen CL, MacKenzie DE, Westwood DA, Boe SG. Mild Traumatic Brain Injury (mTBI) and chronic cognitive impairment: A scoping review. PLoS One. 2017;12(4):e0174847. doi: 10.1371/journal.pone.0174847.

Prince C, Bruhns ME. Evaluation and treatment of mild traumatic brain injury: the role of neuropsychology. Brain Sci. 2017;7(8):105. doi: 10.3390/brainsci7080105.

Bhomia M, Balakathiresan NS, Wang KK, Papa L, Maheshwari RK. A Panel of Serum MiRNA Biomarkers for the Diagnosis of Severe to Mild Traumatic Brain Injury in Humans. Sci Rep. 2016;6:28148. Published 2016 Jun 24. doi:10.1038/srep28148

LaRocca D, Barns S, Hicks SD, Brindle A, Williams J, Uhlig R, et al. Comparison of serum and saliva miRNAs for identification and characterization of mTBI in adult mixed martial arts fighters. PLoS One. 2019;14(1):e0207785. Published 2019 Jan 2. doi:10.1371/journal.pone.0207785

Yan J, Bu X, Li Z, Wu J, Wang C, Li D, et al. Screening the expression of several miRNAs from TaqMan Low Density Array in traumatic brain injury: miR-219a-5p regulates neuronal apoptosis by modulating CCNA2 and CACUL1. J Neurochem. 2019;150(2):202-217. doi:10.1111/jnc.14717

Yang T, Song J, Bu X, Wang C, Wu J, Cai J, et al. Elevated serum miR-93, miR-191, and miR-499 are noninvasive biomarkers for the presence and progression of traumatic brain injury. J Neurochem. 2016;137(1):122-129. doi:10.1111/jnc.13534

Pogoda TK, Hendricks AM, Iverson KM, Stolzmann KL, Krengel MH, Baker E, et al. Multisensory impairment reported by veterans with and without mild traumatic brain injury history. J Rehabil Res Dev. 2012;49(7):971-984. doi:10.1682/jrrd.2011.06.0099

Delouche A, Attyé A, Heck O, Grand S, Kastler A, Lamalle L, et al. Diffusion MRI: Pitfalls, literature review and future directions of research in mild traumatic brain injury. Eur J Radiol. 2016;85(1):25-30. doi:10.1016/j.ejrad.2015.11.004

Levin HS, Diaz-Arrastia RR. Diagnosis, prognosis, and clinical management of mild traumatic brain injury. Lancet Neurol. 2015;14(5):506-517. doi:10.1016/S1474-4422(15)00002-2

Maegele M, Schöchl H, Menovsky T, Maréchal H, Marklund N, Buki A, et al. Coagulopathy and haemorrhagic progression in traumatic brain injury: advances in mechanisms, diagnosis, and management. Lancet Neurol. 2017;16(8):630-647. doi:10.1016/S1474-4422(17)30197-7

Qin X, Li L, Lv Q, Shu Q, Zhang Y, Wang Y. Expression profile of plasma microRNAs and their roles in diagnosis of mild to severe traumatic brain injury. PLoS One. 2018;13(9):e0204051. Published 2018 Sep 18. doi:10.1371/journal.pone.0204051

Shin SS, Bales JW, Edward Dixon C, Hwang M. Structural imaging of mild traumatic brain injury may not be enough: overview of functional and metabolic imaging of mild traumatic brain injury. Brain Imaging Behav. 2017;11(2):591-610. doi:10.1007/s11682-017-9684-0

Adrian H, Mårten K, Salla N, Lasse V. Biomarkers of Traumatic Brain Injury: Temporal Changes in Body Fluids. eNeuro. 2016;3(6):ENEURO.0294-16.2016. Published 2016 Dec 21. doi:10.1523/ENEURO.0294-16.2016

Papa L, Robertson CS, Wang KK, Brophy GM, Hannay HJ, Heaton S, et al. Biomarkers improve clinical outcome predictors of mortality following non-penetrating severe traumatic brain injury. Neurocrit Care. 2015;22(1):52-64. doi:10.1007/s12028-014-0028-2

Di Pietro V, Yakoub KM, Scarpa U, Di Pietro C, Belli A. MicroRNA signature of traumatic brain injury: from the biomarker discovery to the point-of-care. Front Neurol. 2018;9:429. doi: 10.3389/fneur.2018.00429.

Zetterberg H, Blennow K. Fluid biomarkers for mild traumatic brain injury and related conditions. Nat Rev Neurol. 2016;12(10):563-574. doi:10.1038/nrneurol.2016.127

Ji W, Jiao J, Cheng C, Shao J. MicroRNA-21 in the Pathogenesis of Traumatic Brain Injury. Neurochem Res. 2018;43(10):1863-1868. doi:10.1007/s11064-018-2602-z

Martinez B, Peplow PV. MicroRNAs as diagnostic markers and therapeutic targets for traumatic brain injury. Neural Regen Res. 2017;12(11):1749-1761. doi:10.4103/1673-5374.219025

Flynt AS, Lai EC. Biological principles of microRNA-mediated regulation: shared themes amid diversity. Nat Rev Genet. 2008;9(11):831-842. doi:10.1038/nrg2455

Di Pietro V, Ragusa M, Davies D, Su Z, Hazeldine J, Lazzarino G, et al. MicroRNAs as Novel Biomarkers for the Diagnosis and Prognosis of Mild and Severe Traumatic Brain Injury. J Neurotrauma. 2017;34(11):1948-1956. doi:10.1089/neu.2016.4857

Di Pietro V, Porto E, Ragusa M, Barbagallo C, Davies D, Forcione M, et al. Salivary MicroRNAs: Diagnostic Markers of Mild Traumatic Brain Injury in Contact-Sport. Front Mol Neurosci. 2018;11:290. Published 2018 Aug 20. doi:10.3389/fnmol.2018.00290

Hicks SD, Johnson J, Carney MC, Bramley H, Olympia RP, Loeffert AC, et al. Overlapping MicroRNA Expression in Saliva and Cerebrospinal Fluid Accurately Identifies Pediatric Traumatic Brain Injury. J Neurotrauma. 2018;35(1):64-72. doi:10.1089/neu.2017.5111

Papa L, Slobounov SM, Breiter HC, Walter A, Bream T, Seidenberg P, et al. Elevations in MicroRNA Biomarkers in Serum Are Associated with Measures of Concussion, Neurocognitive Function, and Subconcussive Trauma over a Single National Collegiate Athletic Association Division I Season in Collegiate Football Players. J Neurotrauma. 2019;36(8):1343-1351. doi:10.1089/neu.2018.6072

Redell JB, Moore AN, Ward NH 3rd, Hergenroeder GW, Dash PK. Human traumatic brain injury alters plasma microRNA levels. J Neurotrauma. 2010;27(12):2147-2156. doi:10.1089/neu.2010.1481

Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi:10.1371/journal.pmed.1000097

Heather NL, Derraik JG, Beca J, Hofman PL, Dansey R, Hamill J, et al. Glasgow Coma Scale and outcomes after structural traumatic head injury in early childhood. PLoS One. 2013;8(12):e82245. Published 2013 Dec 2. doi:10.1371/journal.pone.0082245

Irimia A, Goh SM, Wade AC, Patel K, Vespa PM, Van Horn JD. Traumatic Brain Injury Severity, Neuropathophysiology, and Clinical Outcome: Insights from Multimodal Neuroimaging. Front Neurol. 2017;8:530. Published 2017 Oct 5. doi:10.3389/fneur.2017.00530

Teasdale G, Maas A, Lecky F, Manley G, Stocchetti N, Murray G. The Glasgow Coma Scale at 40 years: standing the test of time [published correction appears in Lancet Neurol. 2014 Sep;13(9):863]. Lancet Neurol. 2014;13(8):844-854. doi:10.1016/S1474-4422(14)70120-6

Simundic AM. Measures of diagnostic accuracy: Basic definition. EJIFCC. 2016;19(4):203–11.

Wells G, Shea B, O’Connell D, Peterson je, Welch V, Losos M, et al. The Newcastle–Ottawa Scale (NOS) for Assessing the Quality of Non-Randomized Studies in Meta-Analysis. 2000.

Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane handbook for systematic reviews of interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from www.training.cochrane.org/handbook.

Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088-1101.

Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629-34. doi: 10.1136/bmj.315.7109.629.

MedCalc Software. 2020. MedCalc Version 19.5.1. Belgium: MedCalc Software Ltd.

Papa L, Edwards D, Ramia M. Exploring Serum Biomarkers for Mild Traumatic Brain Injury. In: Kobeissy FH, editor. Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton (FL): CRC Press/Taylor & Francis; 2015. Chapter 22. Available from: https://www.ncbi.nlm.nih.gov/books/NBK299199/

Albicini M, McKinlay A. Mild traumatic brain injury: A review of terminology, symptomatology, clinical considerations and future directions. Traumatic brain injury. 2014.

Eierud C, Craddock RC, Fletcher S, Aulakh M, King-Casas B, Kuehl D, et al. Neuroimaging after mild traumatic brain injury: review and meta-analysis. Neuroimage Clin. 2014 Jan 4;4:283-94. doi: 10.1016/j.nicl.2013.12.009.

Lee YK, Hou SW, Lee CC, Hsu CY, Huang YS, Su YC. Increased risk of dementia in patients with mild traumatic brain injury: a nationwide cohort study. PLoS One. 2013;8(5):e62422. doi:10.1371/journal.pone.0062422

Lehman EJ, Hein MJ, Baron SL, Gersic CM. Neurodegenerative causes of death among retired National Football League players. Neurology. 2012;79(19):1970-1974. doi:10.1212/WNL.0b013e31826daf50

Bedreag OH, Rogobete AF, Dumache R, Sarandan M, Cradigati AC, Papurica M, et al. Use of circulating microRNAs as biomarkers in critically ill polytrauma patients. Biomark Genomic Med. 2015 Dec;7(4):131–8.

Weber JA, Baxter DH, Zhang S, Huang DY, Huang KH, Lee MJ, et al. The microRNA spectrum in 12 body fluids. Clin Chem. 2010;56(11):1733-1741. doi:10.1373/clinchem.2010.147405

Han Z, Chen F, Ge X, Tan J, Lei P, Zhang J. miR-21 alleviated apoptosis of cortical neurons through promoting PTEN-Akt signaling pathway in vitro after experimental traumatic brain injury. Brain Res. 2014;1582:12-20. doi:10.1016/j.brainres.2014.07.045

Li D, Huang S, Yin Z, Zhu J, Ge X, Han Z, et al. Increases in miR-124-3p in Microglial Exosomes Confer Neuroprotective Effects by Targeting FIP200-Mediated Neuronal Autophagy Following Traumatic Brain Injury. Neurochem Res. 2019;44(8):1903-1923. doi:10.1007/s11064-019-02825-1

Li D, Huang S, Zhu J, Hu T, Han Z, Zhang S, et al. Exosomes from MiR-21-5p-Increased Neurons Play a Role in Neuroprotection by Suppressing Rab11a-Mediated Neuronal Autophagy In Vitro After Traumatic Brain Injury. Med Sci Monit. 2019;25:1871-1885. Published 2019 Mar 12. doi:10.12659/MSM.915727

Sabirzhanov B, Stoica BA, Zhao Z, Loane DJ, Wu J, Dorsey SG, et al. miR-711 upregulation induces neuronal cell death after traumatic brain injury. Cell Death Differ. 2016;23(4):654-668. doi:10.1038/cdd.2015.132

Sun L, Zhao M, Wang Y, Liu A, Lv M, Li Y, et al. Neuroprotective effects of miR-27a against traumatic brain injury via suppressing FoxO3a-mediated neuronal autophagy. Biochem Biophys Res Commun. 2017;482(4):1141-1147. doi:10.1016/j.bbrc.2016.12.001

Balakathiresan N, Bhomia M, Chandran R, Chavko M, McCarron RM, Maheshwari RK. MicroRNA let-7i is a promising serum biomarker for blast-induced traumatic brain injury. J Neurotrauma. 2012;29(7):1379-1387. doi:10.1089/neu.2011.2146

Chandran R, Sharma A, Bhomia M, Balakathiresan NS, Knollmann-Ritschel BE, Maheshwari RK. Differential expression of microRNAs in the brains of mice subjected to increasing grade of mild traumatic brain injury. Brain Inj. 2017;31(1):106-119. doi:10.1080/02699052.2016.1213420

Ge XT, Lei P, Wang HC, Zhang AL, Han ZL, Chen X, et al. miR-21 improves the neurological outcome after traumatic brain injury in rats. Sci Rep. 2014;4:6718. Published 2014 Oct 24. doi:10.1038/srep06718

Liu L, Sun T, Liu Z, Chen X, Zhao L, Qu G, et al. Traumatic brain injury dysregulates microRNAs to modulate cell signaling in rat hippocampus. PLoS One. 2014;9(8):e103948. Published 2014 Aug 4. doi:10.1371/journal.pone.0103948

Wang P, Ma H, Zhang Y, Zeng R, Yu J, Liu R, et al. Plasma Exosome-derived MicroRNAs as Novel Biomarkers of Traumatic Brain Injury in Rats. Int J Med Sci. 2020;17(4):437-448. Published 2020 Feb 4. doi:10.7150/ijms.39667

Chen Q, Xu J, Li L, Li H, Mao S, Zhang F, et al. MicroRNA-23a/b and microRNA-27a/b suppress Apaf-1 protein and alleviate hypoxia-induced neuronal apoptosis. Cell Death Dis. 2014 Mar 20;5(3):e1132. doi: 10.1038/cddis.2014.92.

Guerriero RM, Giza CC, Rotenberg A. Glutamate and GABA imbalance following traumatic brain injury. Curr Neurol Neurosci Rep. 2015 May;15(5):27. doi: 10.1007/s11910-015-0545-1.