Exosomal MicroRNAs in Military Persons with Mild Traumatic Brain Injury: Preliminary Results from a Chronic Effects of Neurotrauma Consortium (CENC) Biomarker Discovery Project.

BACKGROUND Chronic symptoms after mild traumatic brain injury (mTBI) are common among Veterans and service members represent a significant source of morbidity, with those who sustain multiple mTBIs at greatest risk. Exosomal miRNAs, mediator of intercellular communication, may be involved with chronic TBI symptom persistence. METHODS Exosomal miRNA (exomiR) was extracted from 153 participants enrolled in the Chronic Effect of Neurotrauma Consortium (CENC) longitudinal study (no TBI, n=35; ≥ 3 mTBIs (rTBI), n=45; 1-2 mTBI, n=73). Analyses were performed with nCounter® Human miRNA Expression Panels and Ingenuity pathway analysis (IPA) for identification of gene networks associated with TBI. Generalized linear models were used to analyze the predictive value of exomiR dysregulation and remote neurobehavioral symptoms. RESULTS Compared to controls, there were 17 dysregulated exomiRs in the entire mTBI group and 32 dysregulated exomiRs in the rTBI group. Two miRNAs, hsa-miR-139-5p and hsa-miR-18a-5p, were significantly differentially expressed in the rTBI and 1-2 mTBI groups. IPA analyses showed that these dysregulated exomiRs correlated with pathways of inflammatory regulation, neurological disease, and cell development. Within the rTBI group, exomiRs correlated with gene activity for hub-genes of TP53, insulin like growth factor (IGF-1), and tumor growth factor. TBI history and neurobehavioral symptom survey scores negatively and significantly correlated with hsa-miR-103a-3p expression. CONCLUSION Participants with remote mTBI have distinct exomiR profiles, which are significantly in pathways linked to inflammatory and neuronal repair pathways. These profiles suggest that analysis of exosomal miRNA expression may provide novel insights into the underlying pathobiology of chronic TBI symptom persistence.