Research Article
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Published Online: 1 January 2018

Overlapping MicroRNA Expression in Saliva and Cerebrospinal Fluid Accurately Identifies Pediatric Traumatic Brain Injury

Publication: Journal of Neurotrauma
Volume 35, Issue Number 1

Abstract

To assess the accuracy and physiological relevance of circulating microRNA (miRNA) as a biomarker of pediatric concussion, we compared changes in salivary miRNA and cerebrospinal fluid (CSF) miRNA concentrations after childhood traumatic brain injury (TBI). A case-cohort design was used to compare longitudinal miRNA concentrations in CSF of seven children with severe TBI against three controls without TBI. The miRNAs “altered” in CSF were interrogated in saliva of 60 children with mild TBI and compared with 18 age- and sex-matched controls. The miRNAs with parallel changes (Wilcoxon rank sum test) in CSF and saliva were interrogated for predictive accuracy of TBI status using a multivariate regression technique. Spearman rank correlation identified relationships between miRNAs of interest and clinical features. Functional analysis with DIANA mirPath identified related mRNA pathways. There were 214 miRNAs detected in CSF, and 135 (63%) were also present in saliva. Six miRNAs had parallel changes in both CSF and saliva (miR-182-5p, miR-221-3p, mir-26b-5p, miR-320c, miR-29c-3p, miR-30e-5p). These miRNAs demonstrated an area under the curve of 0.852 for identifying mild TBI status. Three of the miRNAs exhibited longitudinal trends in CSF and/or saliva after TBI, and all three targeted mRNAs related to neuronal development. Concentrations of miR-320c were directly correlated with child and parent reports of attention difficulty. Salivary miRNA represents an easily measured, physiologically relevant, and accurate potential biomarker for TBI. Further studies assessing the influence of orthopedic injury and exercise on peripheral miRNA patterns are needed.

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References

1.
McCarthy M.T. and Kosofsky B.E. (2015). Clinical features and biomarkers of concussion and mild traumatic brain injury in pediatric patients. Ann. N.Y. Acad. Sci. 1345, 89–98.
2.
Kirkwood M.W., Yeates K.O., and Wilson PE. (2006). Pediatric sport-related concussion: a review of the clinical management of an oft-neglected population. Pediatrics 117,1359–1371.
3.
Zonfrillo M.R., Master C.L., Grady M.F., Winston F.K., Callahan J.M., and Arbogast K.B. (2012). Pediatric providers' self-reported knowledge, practices, and attitudes about concussion. Pediatrics 130, 1120–1125.
4.
Bauer R. and Fritz H. (2004). Pathophysiology of traumatic injury in the developing brain: an introduction and short update. Exp. Toxicol. Pathol. 56, 65–73.
5.
McCrory P., Meeuwisse W.H., Aubry M., Cantu B., Dvorak J., Echemendia R.J., Engebretsen L., Johnston K., Kutcher J.S., Raftery M., Sills A., Benson B.W., Davis G.A., Ellenbogen R., Guskiewicz K.M., Herring S.A., Iverson G.L., Jordan B.D., Kissick J., McCrea M., McIntosh A.S., Maddocks D., Makdissi M., Purcell L., Putukian M., Schneider K., Tator C.H., and Turner M. (2013). Consensus statement on concussion in sport: the 4th International Conference on Concussion in Sport, Zurich, November 2012. J. Athl. Train. 48, 554–575.
6.
Rogelj B. and Giese K.P. (2004). Expression and function of brain-specific small RNAs. Rev. Neurosci. 15, 185–198.
7.
Gilad S., Meiri E., Yogev Y., Benjamin S., Lebanony D., Yerushalmi N., Benjamin H., Kushnir M., Cholakh H., Melamed N., Bentwich Z., Hod M., Goren Y., and Chajut A. (2008). Serum microRNAs are promising novel biomarkers. PLoS One 3, e3148.
8.
Redell J.B., Zhao J., and Dash P.K. (2011). Altered expression of miRNA-21 and its targets in the hippocampus after traumatic brain injury. J. Neurosci. Res. 89, 212–221.
9.
Pasinetti G.M., Ho L., Dooley C., Abbi B., and Lange G. (2012). Select non-coding RNA in blood components provide novel clinically accessible biological surrogates for improved identification of traumatic brain injury in OEF/OIF Veterans. Am. J. Neurodegen. Dis. 1, 88–98.
10.
Redell J.B., Moore A.N., Ward III N.H., Hergenroeder G.W., and Dash P.K. (2010). Human traumatic brain injury alters plasma microRNA levels J. Neurotrauma 27, 2147–2156.
11.
Zetterberg H., Smith D.H., and Blennow K. (2013). Biomarkers of mild traumatic brain injury in cerebrospinal fluid and blood. Nat. Rev. Neurology 9, 201–210.
12.
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.
13.
Bahn J.H., Zhang Q., Li F., Chan T.M., Lin X., Kim Y., Wong D.T., and Xiao X. (2015). The landscape of microRNA, Piwi-interacting RNA, and circular RNA in human saliva. Clin. Chem. 61, 221–230.
14.
Weber J.A., Baxter D.H., Zhang S., Huang D.Y., Huang K.H., Lee M.J., Galas D.J., and Wang K. (2010). The microRNA spectrum in 12 body fluids. Clin. Chem. 56, 1733–1741.
15.
Hicks S.D., Ignacio C., Gentile K., and Middleton F.A. (2016). Salivary miRNA profiles identify children with autism spectrum disorder, correlate with adaptive behavior, and implicate ASD candidate genes involved in neurodevelopment. BMC Pediatr 16, 52.
16.
Varma S., Janesko K.L., Wisniewski S.R., Bayir H., Adelson P.D., Thomas N.J., and Kochanek P.M. (2003). F2-isoprostane and neuron-specific enolase in cerebrospinal fluid after severe traumatic brain injury in infants and children. J. Neurotrauma 20, 781–786.
17.
Yokobori S., Hosein K., Burks S., Sharma I., Gajavelli S., and Bullock R. (2013). Biomarkers for the clinical differential diagnosis in traumatic brain injury—a systematic review. CNS Neurosci Ther 19, 556–565.
18.
Xia J., and Wishart D.S. (2016). Using MetaboAnalyst 3.0 for comprehensive metabolomics data analysis. Curr. Protoc. Bioinformatics 55,1014–1019.
19.
Vlachos I.S., Zagganas K., Paraskevopoulou M.D., Georgakilas G., Karagkouni D., Vergoulis T., Dalamagas T., and Hatzigeorgiou A.G. (2015). DIANA-miRPath v3. 0: deciphering microRNA function with experimental support. Nucleic Acids Res. 43, 460–466.
20.
Szklarczyk D., Franceschini A., Wyder S., Forslund K., Heller D., Huerta-Cepas J., Simonovic M., Roth A., Santos A., Tsafou K.P., Kuhn M., Bork P., Jensen L.J., and von Mering C. (2015). STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 43, 447–452.
21.
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.
22.
Valadi H., Ekström K., Bossios A., Sjöstrand M., Lee J.J., and Lötvall J.O. (2007). Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659.
23.
Majem B., Rigau M., Reventós J., and Wong D.T. (2015). Non-coding RNAs in saliva: emerging biomarkers for molecular diagnostics. Intt J Mol Sci 16, 8676–8698.
24.
Yan W., Apweiler R., Balgley B.M., Boontheung P., Bundy J.L., Cargile B.J., Cole S., Fang X., Gonzalez‐Begne M., Griffin T.J., Hagen F., Hu S., Wolinsky L.E., Lee C.S., Malamud D., Melvin J.E., Menon R., Mueller M., Qiao R., Rhodus N.L., Sevinsky J.R., States D., Stephenson J.L., Than S., Yates J.R., Yu W., Xie H., Xie Y., Omenn G.S., Loo J.A., and Wong D.T. (2009). Systematic comparison of the human saliva and plasma proteomes. Proteomics Clin. Appl. 3, 116–134.
25.
Plog B.A., Dashnaw M.L., Hitomi E., Peng W., Liao Y., Lou N., Deane R., and Nedergaard M. (2015). Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system. J. Neurosci. 35, 518–526.
26.
Savaskan N.E., Bräuer A.U., and Nitsch R. (2004). Molecular cloning and expression regulation of PRG‐3, a new member of the plasticity‐related gene family. Eur. J. Neurosci. 19, 212–220.
27.
Lopez J.P., Fiori L.M., Gross J.A., Labonte B., Yerko V., Mechawar N., and Turecki G. (2014). Regulatory role of miRNAs in polyamine gene expression in the prefrontal cortex of depressed suicide completers. Int. J. Neuropsychopharmacol. 17, 23–32.
28.
Ziats M.N. and Rennert O.M. (2014) Identification of differentially expressed microRNAs across the developing human brain. Mol. Psychiatry 19, 848–852.

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Published In

cover image Journal of Neurotrauma
Journal of Neurotrauma
Volume 35Issue Number 1January 1, 2018
Pages: 64 - 72
PubMed: 28762893

History

Published in print: January 1, 2018
Published online: 1 January 2018
Published ahead of print: 27 October 2017
Published ahead of production: 1 August 2017

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Steven D. Hicks
Department of Pediatrics, Penn State College of Medicine, Hershey, Pennsylvania.
Jeremiah Johnson
Department of Pediatrics, Penn State College of Medicine, Hershey, Pennsylvania.
Molly C. Carney
Department of Pediatrics, Penn State College of Medicine, Hershey, Pennsylvania.
Harry Bramley
Department of Pediatrics, Penn State College of Medicine, Hershey, Pennsylvania.
Robert P. Olympia
Department of Pediatrics, Penn State College of Medicine, Hershey, Pennsylvania.
Department of Emergency Medicine, Penn State College of Medicine, Hershey, Pennsylvania.
Andrea C. Loeffert
Department of Pediatrics, Penn State College of Medicine, Hershey, Pennsylvania.
Neal J. Thomas
Department of Pediatrics, Penn State College of Medicine, Hershey, Pennsylvania.
Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania.

Notes

Address correspondence to:Steven D. Hicks, MD, PhDPenn State College of MedicineMail Code HS83500 University Drive, PO Box 850Hershey, PA 17033-0850E-mail: [email protected]

Author Disclosure Statement

Dr. Hicks is a co-inventor of preliminary patents for microRNA biomarkers in disorders of the central nervous system that is assigned to the SUNY Upstate and Penn State Research Foundations and licensed to Quadrant Biosciences (formerly Motion Intelligence). Dr. Hicks is also a consultant for Quadrant Biosciences. These conflicts of interest are currently managed by the Penn State College of Medicine. For the remaining authors, no competing financial interests exist.

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