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. 2018 Jan 1;35(1):64-72.
doi: 10.1089/neu.2017.5111. Epub 2017 Oct 27.

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

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Free PMC article

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

Steven D Hicks et al. J Neurotrauma. .
Free PMC article

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.

Keywords: biomarker; concussion; microRNA; pediatrics; saliva.

Conflict of interest 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.

Figures

FIG. 1.
FIG. 1.
Methodological pipeline for identifying accurate and physiologically relevant microribonucleic acid markers of concussion. sTBI, severe traumatic brain injury; GCS, Glasgow Coma Scale; mTBI, mild traumatic brain injury; RNA, ribonucleic acid;
FIG. 2.
FIG. 2.
Whisker box plots depicting mean concentrations in cerebrospinal fluid (CSF) and saliva for the six microribonucleic acids (miRNAs) of interest across concussion and control groups. Nominally significant changes were detected for miR-29c-3p (CSF p = 0.032; saliva p = 0.008), miR-26b-5p (CSF p = 0.003; saliva p = 0.016), miR-30e-5p (CSF p = 0.045; saliva p = 0.009), miR-182-5p (CSF p = 0.009; saliva p = 0.013), miR-320c (CSF p = 0.037; saliva p = 0.016), and miR-221-3p (CSF p = 0.014; saliva p = 0.005) with Wilcoxon rank sum testing. False detection rate correction was ≤0.15 for all six miRNAs. mTBI, mild traumatic brain injury; sTBI, severe traumatic brain injury.
FIG. 3.
FIG. 3.
The six microribonucleic acids (miRNAs) of interest accurately identify mild traumatic brain injury (mTBI) status in a multivariate regression analysis. A receiver operator characteristics curve utilizing salivary concentrations of six miRNAs (miR-29c-3p, miR-26b-5p, miR-30e-5p, miR-182-5p, miR-320c, and miR-221-3p) demonstrated an area under the curve (AUC) of 0.852 on random forest testing of mTBI status (a). The established algorithm misclassified two control subjects and 15 mTBI subjects. The 100-fold cross-validation of this tool holding out one-fourth of control and mTBI subjects at random exhibited similar accuracy (b). CI, confidence interval.

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