Higher exosomal phosphorylated tau and total tau among veterans with combat-related repetitive chronic mild traumatic brain injury

ABSTRACT

Objective: The objective of the study is to measure plasma and exosomal levels of tau, phosphorylated tau (p-tau), and amyloid beta (Aβ) in Veterans with historical mild traumatic brain injury (mTBI) and chronic neuropsychological symptoms.

Methods: Tau, p-tau, Aβ40, and Aβ42 were measured by ultrasensitive immunoassay in plasma and exosomes from 195 Veterans enrolled in the Chronic Effects of Neurotrauma Consortium Multicenter Observational Study. Protein biomarkers were compared among groups with and without mTBI with loss of consciousness (LOC) or post-traumatic amnesia (PTA), and also in those with and without repetitive (≥3) mTBI (rTBI) compared to those with 0 (TBI-neg) and 1–2 mTBI.

Results: There were no differences in measures of plasma and exosomal protein levels among mTBI with LOC or PTA, mTBI with alteration of consciousness only or TBI-neg. Exosomal tau and exosomal p-tau were elevated in rTBI compared to those with 2 or fewer mTBIs and TBI-neg (p < 0.05). Elevations of exosomal tau and p-tau significantly correlated with post-traumatic and post-concussive symptoms, with exosomal tau also relating specifically to cognitive, affective, and somatic post-concussive symptoms (p < 0.05).

Conclusion: rTBI is associated with elevations of exosomal p-tau and exosomal tau, suggesting that blood-based exosomes may provide a peripheral source of informative, centrally derived biomarkers in remote mTBI and that rTBI may contribute to chronic neuropsychological symptoms.

KEYWORDS:

• Exosomes
• traumatic brain injury (TBI)
• tau
• phosphorylated tau (p-tau)
• biomarker

Acknowledgements

The CENC Observational Study Group members include Study leadership: William C. Walker MD (CENC Observational Study Chairman), David X. Cifu MD (consortium PI); Site PIs or co-PIs: Heather G. Belanger PhD (Tampa), Randall Scheibel PhD (Houston), Blessen C. Eapen MD (San Antonio), Carlos Jaramillo MD (San Antonio), Ajit Pai MD (Richmond), Melissa Geurra MD (Fort Belvoir), Terri Pogoda PhD (Boston), Scott Sponheim PhD (Minneapolis), and Kathleen Carlson PhD (Portland). We also acknowledge the efforts of the entire CENC Observational Study Leadership Working Group and Core Team members who also include: Justin Alicea, Jessica Berumen, Cody Blankenship, Jennifer Boyce, Linda Brunson, Katrina Burson, William Carne, Julia Christensen, Margaret Clarke, Sureyya Dikmen, Esra Doud, Connie Duncan, Stephanie Edmunds, Robyn Endsley, Elizabeth Fogleman, Cheryl Ford-Smith, Laura M. Franke, George Gitchel, Katelyn Gormley, Brenda Hair, Jim Henry, Sidney R. Hinds (consortium co-PI), Shawn Hirsch, Nancy Hsu, Caitlin Jones, Sunchai Khemalaap, Valerie Larson, Henry Lew, Tiffany Lewis, Scott McDonald, Tamara McKenzie-Hartman, Frank Mierzwa, Alison Molitor, Joe Montanari, Johnnie Mortenson, Lauren Nagusuki, Nicholas Pastorek, Judy Pulliam, Risa Richardson, Callie Riggs, Rachel Rosenfield, Sara Salkind, Robert Shin, James K. Sickinger, Taylor Swankie, Nancy Temkin, Doug Theriaque, Maya Troyanskaya, Rodney Vanderploeg, Carmen Vasquez, and Rick Williams (consortium Co-PI). 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 Michael E. DeBakey VA Medical Center, Houston, 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).

Declaration of interest

The authors report no conflicts of interest. The views, opinions, and/or findings contained in this article are those of the authors and should not be construed as an official Veterans Affairs or Department of Defense position, policy or decision, unless so designated by other official documentation.

Additional information

Funding

This work was supported by grant funding from Department of Defense, Chronic Effects of Neurotrauma Consortium (CENC) Award W81XWH-13-2-0095 and Department of Veterans Affairs CENC Award I01 CX001135.