Plasma Biomarkers, Brain Volume, and Cognitive Performance in Service Members and Veterans With mTBI: A LIMBIC-CENC Study.

Importance: Repetitive mild traumatic brain injury (mTBI) may result in neurobiological changes that contribute to persistent symptoms of cognitive dysfunction. Elevations in plasma biomarkers (glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL], total-tau [t-tau], and ubiquitin C-terminal hydrolase-L1 [UCH-L1]) have been reported acutely after mTBI, but few studies have assessed these biomarkers during the chronic phase of mTBI. Objective: To examine whether the associations among plasma biomarkers, brain volume, and cognition varied by mTBI among US active-duty service members and veterans. Design, Setting, and Participants: This cross-sectional study used data from the Long-Term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC), a prospective, multicenter study of US active-duty service members and veterans (SMVs). Data collection began in January 2015, and only enrollment data (collected 2015 to September 2023) were analyzed. Recruitment occurred across several different VA medical centers and military sites across the United States. Participants were aged 18 years or older; had a history of deployment in Operation Enduring Freedom, Operation Iraqi Freedom, or Operation New Dawn; and had combat exposure during deployment. Exclusion criteria were major neurologic or psychiatric disorder, history of moderate to severe TBI, coma lasting more than 30 minutes, posttraumatic amnesia lasting more than 24 hours, and intracranial lesion on computed tomography scan. Exposure: History of blast- or combat-related mTBI. Main Outcomes and Measures: Plasma biomarkers were analyzed using Quanterix SIMOA assays. History of mTBI was ascertained using structured clinical interview. Regional brain volume was derived from T1-weighted magnetic resonance imaging scans. Cognitive performance was assessed using neuropsychological measures. Correlations were computed for associations between mTBI, brain volume, and cognition, and separate covariate-adjusted linear regression models we used to examine the association between each plasma biomarker and brain volume as well as cognition. Additional linear regression models were used to examine whether the number of combat-related and blast-related mTBIs moderated the association between each plasma biomarker, brain volume, and cognition. Results: The cohort included 1160 participants (mean [SD] age, 41.9 [10.2] years; 1025 [88.4%] male; mean [SD] years since last mTBI, 12.1 [9.5]). Less than half of the sample was exposed to at least 1 blast-related (475 [40.9%]) or combat-related mTBI (490 [42.2%]). The association between enrollment biomarker concentration and brain volume and cognitive performance differed by the number of mTBIs. Among those with 2 mTBIs, higher UCH-L1 concentrations were associated with smaller anterior cingulate volume (blast-related mTBI: b = -0.08; 95% CI, -0.16 to -0.01; P = .04; combat-related mTBI: b = -0.09; 95% CI, -0.17 to -0.01; P = .03). Among those with 2 blast-related mTBIs, higher t-tau was associated with poorer performance on immediate and delayed visual memory (eg, performance on the Brief Visuospatial Memory Test-Revised, immediate recall: b = -0.11; 95% CI, -0.19 to -0.04; P = .003; delayed recall: b = -0.08; 95% CI, -0.16 to -0.01; P = .03), and higher GFAP and NfL concentration were associated with worse executive functioning (performance on Trail Making Testing B: GFAP concentration: b = 0.20; 95% CI, 0.03 to 0.37; P = .02; NfL concentration, b = 0.14; 95% CI, 0.01 to 0.26; P = .04), while no biomarker-cognition associations were observed for those with no mTBIs. However, most findings did not pass multiple comparison correction and should be interpreted with caution. Conclusions and Relevance: In this cross-sectional study of 1160 SMVs, plasma biomarkers of neuronal injury and astrogliosis were associated with brain volume and cognitive performance based on mTBI.