Remote blast-related mild traumatic brain injury is associated with differential expression of exosomal microRNAs identified in neurodegenerative and immunological processes

ABSTRACT

Background

Blast traumatic brain injury (TBI) and subconcussive blast exposure have been associated, pathologically, with chronic traumatic encephalopathy (CTE) and, clinically, with cognitive and affective symptoms, but the underlying pathomechanisms of these associations are not well understood. We hypothesized that exosomal microRNA (miRNA) expression, and their relation to neurobehavioral outcomes among Veterans with blunt or blast mild TBI (mTBI) may provide insight into possible mechanisms for these associations and therapeutic targets.

Methods

This is a subanalysis of a larger Chronic Effects of Neurotrauma Consortium Biomarker Discovery Project. Participants (n = 152) were divided into three groups: Controls (n = 35); Blunt mTBI only (n = 54); and Blast/blast+blunt mTBI (n = 63). Postconcussive and post-traumatic stress symptoms were evaluated using the NSI and PCL-5, respectively. Exosomal levels of 798 miRNA expression were measured.

Results

In the blast mTBI group, 23 differentially regulated miRNAs were observed compared to the blunt mTBI group and 23 compared to controls. From the pathway analysis, significantly dysregulated miRNAs in the blast exposure group correlated with inflammatory, neurodegenerative, and androgen receptor pathways.

Discussion

Our findings suggest that chronic neurobehavioral symptoms after blast TBI may pathomechanistically relate to dysregulated cellular pathways involved with neurodegeneration, inflammation, and central hormonal regulation.

KEYWORDS:

• Blast
• military
• neurological symptoms

Acknowledgments

We thank the military Servicemembers and Veterans who participated in this study. The CENC Observational Study Site PIs or co-PIs also include: Heather Belanger PhD (Tampa), Carlos Jaramillo MD (SanAntonio), Ajit Pai MD (Richmond), Melissa Guerra MD (Fort Belvoir), Randall Scheibel PhD (Houston), Terri Pogoda PhD (Boston), Scott Sponheim PhD (Minneapolis), Kathleen Carlson PhD (Portland). We also acknowledge the efforts of the entire CENC Observational Study Leadership Working Group and Core Team members who besides the authors also include: Justin Alicea, Jessica Berumen, Cody Blankenship, Jennifer Boyce, Linda Brunson, Katrina Burson, Julia Christensen, Margaret Clarke, Doreen Collins, Sureyya Dikmen, Esra Doud, Connie Duncan, Stephanie Edmunds, Robyn Endsley, Elizabeth Fogleman, Laura M. Franke, Katelyn Gormley, Brenda Hair, Jim Henry, Nancy Hsu, Cheryl Ford-Smith, George Gitchel, Col. Sidney Hinds (Consortium Co-PI), Caitlin Jones, Sunchai Khemalaap, Valerie Larson, Tiffany Lewis, Scott McDonald, Tamara McKenzie-Hartman, Frank Mierzwa, Alison Molitor, Joe Montanari, Johnnie Mortenson, Nicholas Pastorek, Judy Pulliam, Risa Richardson, Callie Riggs, Rachel Rosenfield, Sara Salkind, James K. Sickinger, Taylor Swankie, Nancy Temkin, Doug Theriaque, Maya Troyanskaya, Rodney Vanderploeg, and Carmen Vasquez. This material is based upon work supported with resources and the use of facilities at: Hunter Holmes McGuire Veterans Affairs Medical Center (VAMC) in Richmond, VA; James A. Haley Veterans Hospital (VH), Tampa, FL; Audie L. Murphy Memorial VH, San Antonio, TX; and is based upon work supported in part by the Defense and Veterans Brain Injury Center, US Army Medical Research and Material Command (USAMRMC).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Disclaimer

The views expressed in this manuscript are those of the authors and do not necessarily represent the official policy or position of the Department of Defense (DoD), Departments of Army/Navy/Air Force, Veterans Health Administration (VHA), Uniformed Services University of the Health Sciences, United States government, or any other United States government agency. The identification of specific products or scientific instrumentation is considered an integral part of the scientific endeavor and does not constitute endorsement or implied endorsement on the part of the author(s), DoD, or any component agency. No official endorsement should be inferred.

Additional information

Funding

This work was supported by the Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense, through the Psychological Health/Traumatic Brain Injury Research Program Long-Term Impact of Military-Relevant Brain Injury Consortium (LIMBIC) Award/W81XWH-18-PH/TBIRP-LIMBIC under Awards No. W81XWH1920067 and W81XWH-13-2-0095, and by the U.S. Department of Veterans Affairs Awards No. I01 CX002097, I01 CX002096, I01 HX003155, I01 RX003444, I01 RX003443, I01 RX003442, I01 CX001135, I01 CX001246, I01 RX001774, I01 RX 001135, I01 RX 002076, I01 RX 001880, I01 RX 002172, I01 RX 002173, I01 RX 002171, I01 RX 002174, and I01 RX 002170. The U.S. Army Medical Research Acquisition Activity, 839 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office. NIH, National Institute of Nursing Research Intramural Research Program.