Select small nucleolar RNAs in blood components as novel biomarkers for improved identification of comorbid traumatic brain injury and post-traumatic stress disorder in veterans of the conflicts in Afghanistan and Iraq

Background: The present study was designed to validate the ability of our recently identified set of small noncoding RNA candidate mild traumatic brain injury (mTBI) biomarkers to diagnose mTBI in the presence or absence of post-traumatic stress disorder (PTSD) comorbidity. Using qPCR, we explored the regulation of the candidate biomarkers in peripheral blood mononuclear cells (PBMC) from 58 veterans. Results: We confirmed that 4 small nucleolar RNAs (snoRNAs), ACA48, U35, U55, and U83A, are significantly down-regulated in PBMC from veterans with mTBI and PTSD compared to non-TBI, control subjects with PTSD only. We found that the snoRNA biomarkers are able to dissect subjects with comorbid mTBI and PTSD from PTSD subjects without mTBI with 100% sensitivity, 81% accuracy, and 72% specificity. No significant differential expression of snoRNA biomarkers was found in mTBI subjects without comorbid PTSD. However, we found significantly lower U55 contents in subjects with PTSD. We explored the regulation of ACA48 in rodent models of PTSD or blast-induced mTBI to gather proof-of-concept evidence that would connect the regulation of the biomarkers and the development of mTBI or PTSD. We found no change in the regulation of ACA48 in the mTBI rat model. We did, however, find significant down-regulation of ACA48 in the PTSD mouse model 24 hours following psychological trauma exposure. This may reflect a short-term response to trauma exposure, since we found no change in the regulation of ACA48 in veteran PTSD subjects 3.6 years post-deployment. Conclusions: Additional application of the 4 snoRNA biomarker to current diagnostic criteria may provide an objective biomarker pattern to help identify veterans with comorbid mTBI and PTSD. Our observations suggest that biological interactions between TBI and PTSD may contribute to the clinical features of veterans with comorbid mTBI and PTSD. Future investigations on mTBI mechanisms or TBI biomarkers should consider their interactions with PTSD.