Research Article
No access
Published Online: 5 April 2019

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

Publication: Journal of Neurotrauma
Volume 36, Issue Number 8


This prospective controlled observational cohort study assessed the performance of a novel panel of serum microRNA (miRNA) biomarkers on indicators of concussion, subconcussive impacts, and neurocognitive function in collegiate football players over the playing season. Male collegiate student football athletes participating in a Division I Football Bowl Subdivision of the National Collegiate Athletic Association (NCAA) were enrolled. There were a total of 53 participants included in the study, 30 non-athlete control subjects and 23 male collegiate student football athletes. Neurocognitive assessments and blood samples were taken within the week before the athletic season began and within the week after the last game of the season and measured for a panel of pre-selected miRNA biomarkers. All the athletes had elevated levels of circulating miRNAs at the beginning of the season compared with control subjects (p < 0.001). Athletes with the lowest standard assessment of concussion (SAC) scores at the beginning of the season had the highest levels of miRNAs. The area under the curve (AUC) for predicting pre-season SAC scores were miR-195 (0.90), miR-20a (0.89), miR-151-5p (0.86), miR-505* (0.85), miR-9-3p (0.77), and miR-362-3p (0.76). In athletes with declining neurocognitive function over the season, concentrations of miRNAs increased over same period. There were significant negative correlations with miR-505* (p = 0.011), miR-30d (p = 0.007), miR-92 (p = 0.033), and (p = 0.008). The miRNAs correlating with balance problems were miR-505* (p = 0.007), miR-30d (p = 0.028), and miR-151-5p (p = 0.023). Those correlating with poor reaction times were miR-20a (0.043), miR-505* (p = 0.049), miR-30d (p = 0.031), miR-92 (p = 0.015), and miR-151-5p (p = 0.044). Select miRNAs were associated with baseline concussion assessments at the beginning of the season and with neurocognitive changes from pre to post-season in collegiate football players. Should these findings be replicated in a larger cohort of athletes, these markers could potentially serve as measures of neurocognitive status in athletes at risk for concussion and subconcussive injuries.

Get full access to this article

View all available purchase options and get full access to this article.


1. NCAA. (2018). Estimated Probability of Competing in College Athletics. NCAA Research. (last accessed October 16, 2018).
2. Bailes J.E., Petraglia A.L., Omalu B.I., Nauman E., and Talavage T. (2013). Role of subconcussion in repetitive mild traumatic brain injury. J. Neurosurg. 119, 1235–1245.
3. Slobounov S.M., Walter A., Breiter H.C., Zhu D.C., Bai X., Bream T., Seidenberg P., Mao X., Johnson B., and Talavage T.M. (2017). The effect of repetitive subconcussive collisions on brain integrity in collegiate football players over a single football season: a multi-modal neuroimaging study. Neuroimage Clin. 14, 708–718.
4. Reynolds B.B., Stanton A.N., Soldozy S., Goodkin H.P., Wintermark M., and Druzgal T.J. (2017). Investigating the effects of subconcussion on functional connectivity using mass-univariate and multivariate approaches. Brain Imaging Behav. [Epub ahead of print].
5. Johnson B., Neuberger T., Gay M., Hallett M., and Slobounov S. (2014). Effects of subconcussive head trauma on the default mode network of the brain. J. Neurotrauma 31, 1907–1913.
6. Bahrami N., Sharma D., Rosenthal S., Davenport E.M., Urban J.E., Wagner B., Jung Y., Vaughan C.G., Gioia G.A., Stitzel J.D., Whitlow C.T., and Maldjian J.A. (2016). Subconcussive head impact exposure and white matter tract changes over a single season of youth football. Radiology 281, 919–926.
7. Gavett B.E., Stern R.A., and McKee A.C. (2011). Chronic traumatic encephalopathy: a potential late effect of sport-related concussive and subconcussive head trauma. Clin. Sports Med. 30, 179–188, xi.
8. Bailes J.E., Dashnaw M.L., Petraglia A.L., and Turner R.C. (2014). Cumulative effects of repetitive mild traumatic brain injury. Prog. Neurol. Surg. 28, 50–62.
9. Papa L. (2016) Potential blood-based biomarkers for concussion. Sports Med. Arthrosc. Rev. 24, 108–115.
10. Papa L., Mittal M.K., Ramirez J., Ramia M., Kirby S., Silvestri S., Giordano P., Weber K., Braga C.F., Tan C.N., Ameli N.J., Lopez M., and Zonfrillo M. (2016). In children and youth with mild and moderate traumatic brain injury, glial fibrillary acidic protein out-performs S100beta in detecting traumatic intracranial lesions on computed tomography. J. Neurotrauma 33, 58–64.
11. Papa L., Zonfrillo M.R., Ramirez J., Silvestri S., Giordano P., Braga C.F., Giordano P., Weber K., Braga C.F., Tan C.N., Ameli N.J., Lopez M., and Zonfrillo M. (2015). Performance of glial fibrillary acidic protein in detecting traumatic intracranial lesions on computed tomography in children and youth with mild head trauma. Acad Emerg Med 22, 1274–1282.
12. Papa L., Ramia M.M., Kelly J.M., Burks S.S., Pawlowicz A., and Berger R.P. (2013). Systematic review of clinical research on biomarkers for pediatric traumatic brain injury. J. Neurotrauma 30, 324–338.
13. Papa L., Ramia M.M., Edwards D., Johnson B.D., nd Slobounov S.M. (2015). Systematic review of clinical studies examining biomarkers of brain injury in athletes after sports–related concussion. J. Neurotrauma 32, 661–673.
14. Jin X.F., Wu N., Wang L., and Li J. (2013). Circulating microRNAs: a novel class of potential biomarkers for diagnosing and prognosing central nervous system diseases. Cell Mol. Neurobiol. 33, 601–613.
15. Balakathiresan N., Bhomia M., Chandran R., Chavko M., McCarron R.M., and Maheshwari R.K. (2012). MicroRNA let-7i is a promising serum biomarker for blast-induced traumatic brain injury. J. Neurotrauma 29, 1379–1387.
16. Bhomia M., Balakathiresan N.S., Wang K.K., Papa L., and Maheshwari R.K. (2016). A panel of serum MiRNA biomarkers for the diagnosis of severe to mild traumatic brain injury in humans. Sci. Rep. 6, 28148.
17. Hicks S.D., Johnson J., Carney M.C., Bramley H., Olympia R.P., Loeffert A.C., and Thomas N.J. (2017). Overlapping microRNA expression in saliva and cerebrospinal fluid accurately identifies pediatric traumatic brain injury. J Neurotrauma 35, 64–72.
18. Johnson J.J., Loeffert A.C., Stokes J., Olympia R.P., Bramley H., and Hicks S.D. (2018). Association of salivary microRNA changes with prolonged concussion symptoms. JAMA Pediatr. 172, 65–73.
19. Mitra B., Rau T.F., Surendran N., Brennan J.H., Thaveenthiran P., Sorich E., Fitzgerald M.C., Rosenfeld J.V., and Patel S.A. (2017). Plasma micro–RNA biomarkers for diagnosis and prognosis after traumatic brain injury: a pilot study. J. Clin. Neurosci. 38, 37–42.
20. McCrea M. (2001). Standardized mental status assessment of sports concussion. Clin. J. Sport. Med. 11, 176–181.
21. Teel E., Gay M., Johnson B., and Slobounov S. (2016). Determining sensitivity/specificity of virtual reality-based neuropsychological tool for detecting residual abnormalities following sport-related concussion. Neuropsychology 30, 474–483.
22. Teel E.F., and Slobounov S.M. (2015). Validation of a virtual reality balance module for use in clinical concussion assessment and management. Clin. J. Sport Med. 25, 144–148.
23. Centers for Disease Control and Prevention (2017). HEADS UP to Health Care Providers: Tools for Providers. Centers for Disease Control and Prevention, HEADS UP Concussion Prevention Initiative: Atlanta
24. Abbas K., Shenk T.E., Poole V.N., Breedlove E.L., Leverenz L.J., Nauman E.A., Talavage T.M., and Robinson M.E. (2015). Alteration of default mode network in high school football athletes due to repetitive subconcussive mild traumatic brain injury: a resting-state functional magnetic resonance imaging study. Brain Connect. 5, 91–101.
25. Campolettano E.T., Gellner R.A., and Rowson S. (2017). High-magnitude head impact exposure in youth football. J. Neurosurg. Pediatr. 20, 604–612.
26. Tsushima W.T., Ahn H.J., Siu A.M., Yoshinaga K., Choi S.Y., and Murata N.M. (2018). Effects of repetitive subconcussive head trauma on the neuropsychological test performance of high school athletes: a comparison of high, moderate, and low contact sports. Appl. Neuropsychol. Child. 2, 1–8.
27. Chrisman S.P., Quitiquit C., and Rivara F.P. (2013). Qualitative study of barriers to concussive symptom reporting in high school athletics. J. Adolesc. Health 52, 330–335.
28. Papa L., Robicsek S.A., Brophy G.M., Wang K.K.W., Hannay H.J., Heaton S., Schmalfuss I., Gabrielli A., Hayes R.L., and Robertson C.S. (2018). Temporal profile of microtubule-associated protein 2: a novel indicator of diffuse brain injury severity and early mortality after brain trauma. J Neurotrauma 35, 32–40.
29. Fehlmann T., Ludwig N., Backes C., Meese E., and Keller A. (2016). Distribution of microRNA biomarker candidates in solid tissues and body fluids. RNA Biol. 13, 1084–1088.

Information & Authors


Published In

cover image Journal of Neurotrauma
Journal of Neurotrauma
Volume 36Issue Number 8April 15, 2019
Pages: 1343 - 1351
PubMed: 30343622


Published in print: April 15, 2019
Published online: 5 April 2019
Published ahead of print: 5 December 2018
Published ahead of production: 20 October 2018
Accepted: 18 October 2018


Request permissions for this article.




Department of Emergency Medicine, Orlando Regional Medical Center, Orlando, Florida.
Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Semyon M. Slobounov
Department of Kinesiology, Pennsylvania State University, University Park, Pennsylvania.
Hans C. Breiter
Department of Psychiatry and Behavioral Sciences, Warren Wright Adolescent Center, Northwestern University, Chicago, Illinois.
Alexa Walter
Department of Kinesiology, Pennsylvania State University, University Park, Pennsylvania.
Tim Bream
Athletic Department, Pennsylvania State University, University Park, Pennsylvania.
Peter Seidenberg
Department of Orthopaedics and Rehabilitation, Penn State College of Medicine, University Park, Pennsylvania.
Department of Family and Community Medicine, Penn State College of Medicine, University Park, Pennsylvania.
Julian E. Bailes
Department of Neurosurgery, Northshore University Health System, University of Chicago Pritzker School of Medicine, Chicago, Illinois.
Stephen Bravo
Sandlake Imaging, Orlando, Florida.
Brian Johnson
Department of Kinesiology, Pennsylvania State University, University Park, Pennsylvania.
David Kaufman
Department of Neurology and Ophthalmology, Michigan State University, East Lansing, Michigan.
Dennis L. Molfese
Department of Psychology, University of Nebraska–Lincoln, Lincoln, Nebraska.
Thomas M. Talavage
School of Electrical and Computer Engineering, Purdue University, West Lafayette, Indiana.
David C. Zhu
Department of Radiology and Psychology, Michigan State University, East Lansing, Michigan.
Barbara Knollmann-Ritschel
Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.
Manish Bhomia [email protected]
Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland.


Address correspondence to: Linda Papa, MDCM, MSc, Department of Emergency Medicine, Orlando Regional Medical Center, 86 W. Underwood (S-200), Orlando, FL 32806 [email protected]
Address correspondence on miRNA analysis to: Manish Bhomia, PhD, Uniformed Services University of the Health Sciences, Henry M Jackson Foundation (HJF), Building B, 3082, 4301 Jones Bridge Road, Bethesda, MD 20814 [email protected]

Author Disclosure Statement

Drs. Papa and Bhomia are inventors of a United States patent application filed by Uniformed Services University of the Health Sciences (USUHS) regarding the potential utilities of selected miRNAs as diagnostic biomarkers for TBI. The other authors have nothing to disclose. The opinions expressed herein are those of authors and are not necessarily representative of those of the USUHS, Department of Defense or, the United States Army, Navy, Air Force and Defense Medical Research and Development Program (DMRDP).

Metrics & Citations



Export citation

Select the format you want to export the citations of this publication.

View Options

Get Access

Access content

To read the fulltext, please use one of the options below to sign in or purchase access.

Society Access

If you are a member of a society that has access to this content please log in via your society website and then return to this publication.

Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

View options


View PDF/ePub

Full Text

View Full Text







Copy the content Link

Share on social media

Back to Top