Background: Injuries from single or repetitive blast explosions are among the most common type of brain trauma in the US military. Multiple studies have indicated that mild Traumatic Brain Injury (TBI) induced by exposure to repetitive blasts is frequently associated with an increased risk of mental health disorders, chronic pain or headaches, and substance abuse disorders. In the civilian population, it is estimated that nearly 1.7 million civilians are affected by TBI every year and many of them live with long term TBI related disabilities. Mild TBI (mTBI) may not have immediate clinical symptoms, hence patients are released from emergency rooms with basic discharge instructions without further medical intervention. Imaging methods such as CT and MRI are currently used for TBI diagnosis, however, these are of limited use for diagnosis of mTBI. The recently approved protein biomarkers GFAP and UCH-L1 can only provide information for acute injuries and cannot be used for chronic injury diagnosis/evaluation. Currently there are no effective therapeutics for treatment and management of TBI despite dozens of attempted clinical trials. It has been suggested that future clinical trials should employ biofluid biomarkers to determine treatment effects and better understand the pathophysiology of the therapy on brain function. Lack of a biomarker which can track the effectiveness of treatment further impedes the translation of potential treatments into the clinical setting. With the absence of an approved biomarker or effective neuroimaging test for mTBI, self-reporting outcome tools are utilized to assess the outcome of the injury. A non-invasive, sensitive and specific diagnostic assay is desirable which can be used assess the therapeutic efficacy of the treatment for TBI. The objective of this study is to identify miRNA biomarker candidates for chronic repetitive TBI.
Methods: This observational clinical study recruited US service members with a prior history of single or multiple mild TBIs. The participants in the TBI groups sustained multiple injuries that included motor vehicle accidents, falls, fights, and blast explosions. We performed global miRNA expression profiles from serum samples from control and TBI groups (N=40/ group) to identify biomarkers for chronic repetitive TBI. Statistical analysis was performed to identify significant miRNAs. MiRNAs that were significantly upregulated in the TBI groups were correlated with the PTSD checklist scores of the participants to identify significant correlations.
Results: We analyzed miRNA expression in two groups of participants. Group 1 participants experienced 1 or 2 TBIs whereas group 2 participants experienced 3 or more TBIs. After the statistical analysis and correction to multiple comparisons, we identified a set of 5 and 4 miRNAs in group 1 TBI (1 or 2) and group e TBI (3 and more) respectiviely. In both the groups, miR-383 was identified as a central nervouls system (CNS) specific miRNA with elevated expression compared to matched controls. Correlation analysis showed that the concentration of serum miR-383 positively and significantly correlated with the PCL scores. Pathway analysis showed that PPARĪ³ and PRDX3 are the two main targets of miR-383, that are critical mediators in secondary neuronal injury.
Conclusions: Our data suggest that CNS specific miR-383 is a biomarker of chronic repetitive TBI and may be indicative of underlying neuronal injury. Disclaimers: The opinions and assertions expressed herein are those of the authors and do not necessarily reflect the official policy or position of the Uniformed Services University or the Department of Defense or the U.S. Government.
The opinions and assertions expressed herein are those of the authors and do not necessarily reflect the official policy or position of the Henry M. Jackson Foundation for the Advancement of Military Medicine.
