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. 2020 Oct 20;21(20):7758.
doi: 10.3390/ijms21207758.

Saliva microRNA Biomarkers of Cumulative Concussion

Steven D Hicks  1 , Robert P Olympia  2 , Cayce Onks  3 , Raymond Y Kim  4 , Kevin J Zhen  1 , Gregory Fedorchak  5 , Samantha DeVita  5 , Aakanksha Rangnekar  5 , Matthew Heller  6 , Hallie Zwibel  6 , Chuck Monteith  7 , Zofia Gagnon  8 , Callan D McLoughlin  8 , Jason Randall  8 , Miguel Madeira  8 , Thomas R Campbell  9 , Elise Fengler  10 , Michael N Dretsch  11 , Christopher Neville  12 , Frank A Middleton  13
Affiliations

Saliva microRNA Biomarkers of Cumulative Concussion

Steven D Hicks et al. Int J Mol Sci. .

Abstract

Recurrent concussions increase risk for persistent post-concussion symptoms, and may lead to chronic neurocognitive deficits. Little is known about the molecular pathways that contribute to persistent concussion symptoms. We hypothesized that salivary measurement of microribonucleic acids (miRNAs), a class of epitranscriptional molecules implicated in concussion pathophysiology, would provide insights about the molecular cascade resulting from recurrent concussions. This hypothesis was tested in a case-control study involving 13 former professional football athletes with a history of recurrent concussion, and 18 age/sex-matched peers. Molecules of interest were further validated in a cross-sectional study of 310 younger individuals with a history of no concussion (n = 230), a single concussion (n = 56), or recurrent concussions (n = 24). There was no difference in neurocognitive performance between the former professional athletes and their peers, or among younger individuals with varying concussion exposures. However, younger individuals without prior concussion outperformed peers with prior concussion on three balance assessments. Twenty salivary miRNAs differed (adj. p < 0.05) between former professional athletes and their peers. Two of these (miR-28-3p and miR-339-3p) demonstrated relationships (p < 0.05) with the number of prior concussions reported by younger individuals. miR-28-3p and miR-339-5p may play a role in the pathophysiologic mechanism involved in cumulative concussion effects.

Keywords: biomarker; microRNA; mild traumatic brain injury; saliva; sports-related concussion.

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Conflict of interest statement

S.D.H. is a paid consultant for Quadrant Biosciences Inc., Syracuse, NY, USA. S.D.H. is a scientific advisory board member for Quadrant Biosciences and is named as a co-inventor on intellectual property related to saliva RNA biomarkers in concussion that are patented by The Penn State College of Medicine and licensed to Quadrant Biosciences. S.D.V., G.F., and A.R. are paid employees of Quadrant Biosciences. C.N. is a member of the scientific advisory board and has equity interest in Quadrant Bioscience Inc.

Figures

Figure 1
Figure 1
Salivary miRNA profiles differentiate former professional football athletes from peers. Partial least squares discriminant analysis (PLSDA) was applied to individual salivary miRNA profiles (A), balance performance measures (B), and neurocognitive scores (C) among professional athletes in the National Football League (NFL; n = 13; green) and control participants (CTRL; n = 18; red). The two-dimensional PLSDA plot based on saliva miRNA levels achieved complete separation of groups, while accounting for 27.5% of variance in the miRNA data.
Figure 2
Figure 2
Twenty salivary miRNAs differ between former professional football athletes and peers. The heatmap displays salivary levels of 20 miRNAs with significant differences (adj p < 0.05) in salivary expression between former professional football athletes (n = 13; green) and control participants (n = 18; red). Hierarchical clustering of both participants and miRNAs is based on a Ward clustering algorithm with a Euclidean distance measure. V statistics and adjusted p values on non-parametric analysis of variance are presented for each miRNA.
Figure 3
Figure 3
Three miRNA candidates differ among individuals with prior concussion. A non-parametric analysis of variance comparing levels of the 20 miRNA candidates identified in former professional football athletes, identified three miRNAs (miR-339-3p, miR-361-5p, and miR-28-3p) nominal differences (p < 0.05; adjusted p < 0.15) between individuals with prior concussion, and those without prior concussion. Red denotes increased expression, while blue denotes decreased expression. Notably, for 2/3 miRNAs (miR-339-3p and miR-361-5p), expression levels among individuals with prior concussion mirrored differences observed in former professional football athletes.
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