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Studies have shown that the presence of acute inflammation during recovery is indicative of poor outcomes after a traumatic brain injury (TBI); however, the role of chronic inflammation in predicting post-TBI-related symptoms remains poorly understood. The purpose of this study was to compare inflammatory biomarkers (tumor necrosis factor [TNF]-α, interleukin [IL]-6, and IL-10) in active duty personnel who either sustained or did not sustain a TBI. Service members were also assessed for post-traumatic stress disorder (PTSD), depression, and quality of life through self-reported measures. IL-6 and TNF-α concentrations were greater in the TBI group than in the control group. Of those with a TBI, IL-6 and TNF-α concentrations were greater in the high-PTSD group than the low-PTSD group. No significant differences were found in IL-10 or the IL-6/IL-10 ratios between those with low and high PTSD. Exploratory factor analysis was conducted to describe the latent structure of variables relating to emotional and physical health (i.e., Short Form 36 subcomponents, etc.) and their relationships within the TBI group with inflammatory cytokines. Four symptom profiles were found, with the third component most relating to PTSD and depression symptoms and high inflammation. This study indicates that the comorbidity of TBI and PTSD is associated with inflammation in a military sample, emphasizing the necessity for intervention in order to mitigate the risks associated with inflammation.

Traumatic brain injury (TBI) is linked to long-term symptoms in a sub-set of patients who sustain an injury, but this risk is not universal, leading us and others to question the nature of individual variability in recovery trajectories. Extracellular vesicles (EVs) are a promising, novel avenue to identify blood-based biomarkers for TBI. Here, our aim was to determine if glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) measured 1-year postinjury in EVs could distinguish patients from controls, and whether these biomarkers relate to TBI severity or recovery outcomes. EV GFAP and EV NfL were measured using an ultrasensitive assay in 72 TBI patients and 20 controls. EV GFAP concentrations were elevated in moderate and severe TBI compared to controls ( p ’s < 0.001) and could distinguish controls from moderate (AUC = 0.86) or severe TBI (AUC = 0.88). Increased EV GFAP and EV NfL levels were associated with lower 1-year Glasgow Outcome Scale–Extended (GOS-E) score ( p ’s < 0.05). These findings suggest that blood-derived EV concentrations of GFAP and NfL drawn even 1 year after injury are higher in TBI patients compared to controls, and are related to injury severity and poor recovery outcomes, suggesting that TBIs alter the activity of these biomarkers, likely contributing to individual variability in recovery.

Traumatic brain injury (TBI) can be associated with long-term neurobehavioral symptoms. Here, we examined levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in extracellular vesicles isolated from blood, and their relationship with TBI severity and neurobehavioral symptom reporting. Participants were 218 service members and veterans who sustained uncomplicated mild TBIs (mTBI, n = 107); complicated mild, moderate, or severe TBIs (smcTBI, n = 66); or Injured controls (IC, orthopedic injury without TBI, n = 45). Within one year after injury, but not after, NfL was higher in the smcTBI group than mTBI (p = 0.001, d = 0.66) and IC (p = 0.001, d = 0.35) groups, which remained after controlling for demographics and injury characteristics. NfL also discriminated the smcTBI group from IC (AUC:77.5%, p < 0.001) and mTBI (AUC:76.1%, p < 0.001) groups. No other group differences were observed for NfL or GFAP at either timepoint. NfL correlated with post-concussion symptoms (r s  = − 0.38, p = 0.04) in the mTBI group, and with PTSD symptoms in mTBI (r s  = − 0.43, p = 0.021) and smcTBI groups (r s  = − 0.40, p = 0.024) within one year after injury, which was not confirmed in regression models. Our results suggest the potential of NfL, a protein previously linked to axonal damage, as a diagnostic biomarker that distinguishes TBI severity within the first year after injury.

Symptoms of post-traumatic stress disorder (PTSD) are common in military populations, and frequently associated with a history of combat-related mild traumatic brain injury (mTBI). In this study, we examined relationships between severity of PTSD symptoms and levels of extracellular vesicle (EV) proteins and miRNAs measured in the peripheral blood in a cohort of military service members and Veterans (SMs/Vs) with chronic mTBI(s). Participants ( n = 144) were divided into groups according to mTBI history and severity of PTSD symptoms on the PTSD Checklist for DSM-5 (PCL-5). We analyzed EV levels of 798 miRNAs (miRNAs) as well as EV and plasma levels of neurofilament light chain (NfL), Tau, Amyloid beta (Aβ) 42, Aβ40, interleukin (IL)-10, IL-6, tumor necrosis factor-alpha (TNFα), and vascular endothelial growth factor (VEGF). We observed that EV levels of neurofilament light chain (NfL) were elevated in participants with more severe PTSD symptoms (PCL-5 ≥ 38) and positive mTBI history, when compared to TBI negative controls ( p = 0.024) and mTBI participants with less severe PTSD symptoms ( p = 0.006). Levels of EV NfL, plasma NfL, and hsa-miR-139–5p were linked to PCL-5 scores in regression models. Our results suggest that levels of NfL, a marker of axonal damage, are associated with PTSD symptom severity in participants with remote mTBI. Specific miRNAs previously linked to neurodegenerative and inflammatory processes, and glucocorticoid receptor signaling pathways, among others, were also associated with the severity of PTSD symptoms. Our findings provide insights into possible signaling pathways linked to the development of persistent PTSD symptoms after TBI and biological mechanisms underlying susceptibility to PTSD.

Military and law enforcement breachers are exposed to many low-level blasts during their training and occupational experiences in which they detonate explosives to force entry into secured structures. There is a concern that exposure to these repetitive blast events in career breachers could result in cumulative neurological effects. This study aimed to determine concentrations of neurofilament light (NF-L), tau, and amyloid-beta 42 (Aβ42) in serum and in neuronal-derived extracellular vesicles (EVs) in an experienced breacher population, and to examine biomarker associations with neurobehavioral symptoms. Thirty-four participants enrolled in the study: 20 experienced breachers and 14 matched military or civilian law enforcement controls. EV tau concentrations were significantly elevated in experienced breachers (0.3301 ± 0.5225) compared to controls (−0.4279 ± 0.7557; F = 10.43, p = 0.003). No statistically significant changes were observed in EV levels of NF-L or Aβ42 or in serum levels of NF-L, tau, or Aβ42 (p’s > 0.05). Elevated EV tau concentrations correlated with increased Neurobehavioral Symptom Inventory (NSI) score in experienced breachers (r = 0.596, p = 0.015) and predicted higher NSI score ( F (1,14) = 7.702,  p  = 0.015,  R 2  = 0.355). These findings show that neuronal-derived EV concentrations of tau are significantly elevated and associated with neurobehavioral symptoms in this sample of experienced breachers who have a history of many low-level blast exposures.

Traumatic brain injury (TBI) affects millions of Americans each year and has been shown to disproportionately impact those subject to greater disparities in health. Female sex is one factor that has been associated with disparities in health outcomes, including in TBI, but sex differences in biomarker levels and behavioral outcomes after TBI are underexplored. This study included participants with both blunt and blast TBI with majority rating their TBI as mild. Time since injury was 5.4 (2.0, 15.5) years for females and 6.8 (2.4, 11.3) years for males. The aim of this cross sectional study is to investigate the relationship between postconcussive, depression, and post-traumatic stress disorder (PTSD) symptoms, as well as health related quality of life (HRQOL), and the levels of glial fibrillary acidic protein (GFAP), total tau (t-tau), neurofilament light chain (NfL), and ubiquitin C-terminal hydrolase-L1 (UCH-L1). Behavioral outcomes were evaluated with the Neurobehavioral Symptom Inventory (NSI), Patient Health Questionnaire-9 (PHQ-9), PTSD Checklist- Civilian Version (PCL-C), short form (SF)-36, and plasma levels of total tau, GFAP, NfL, and UCHL-1 measured with the Simoa-HDX. We observed that females had significantly higher levels of GFAP and tau ( ps < 0.05), and higher PHQ-9 scores, NSI total scores, NSI- vestibular, NSI-somatosensory, NSI-affective sub-scale scores ( ps < 0.05)), than males. In addition, females had lower scores in HRQOL outcomes of role limitations due to emotional problems, vitality, emotional well-being, social functioning, and pain compared to males ( ps < 0.05). Correlation analysis showed positive associations between levels of tau and the NSI-total and NSI-cognitive sub-scale scores ( ps < 0.05) in females. No significant associations were found for NfL or GFAP with NSI scores. For female participants, negative correlations were observed between tau and NfL concentrations and the SF-36 physical function subscale ( ps < 0.05), as well as tau and the social function subscale ( p < 0.001), while GFAP levels positively correlated with role limitations due to emotional problems ( p = 0.004). No significant associations were observed in males. Our findings suggest that sex differences exist in TBI-related behavioral outcomes, as well as levels of biomarkers associated with brain injury, and that the relationship between biomarker levels and behavioral outcomes is more evident in females than males. Future studies are warranted to corroborate these results, and to determine the implications for prognosis and treatment. The identification of candidate TBI biomarkers may lead to development of individualized treatment guidelines.

Background: Elevations of inflammatory cytokine levels occur immediately after mild traumatic brain injury (mTBI) and can persist for years. These elevations have been associated with neuropsychological outcomes, including depression and PTSD symptoms. Sleep disorders, another common sequelae of mTBI, are independently associated with inflammation in otherwise healthy individuals. However, whether sleep and inflammation are linked in chronic mTBI has not been reported. Methods: A retrospective cross-sectional cohort of warfighters was used to investigate the hypothesis that inflammation may be linked to sleep quality in chronic mTBI. Clinical history, peripheral blood samples, and sleep quality scores were collected from 182 warfighters ( n = 138 mTBI; n = 44 controls) during enrollment in the Chronic Effects of Neurotrauma Consortium study. Biomarkers of inflammation (IL-6, IL-10, TNFα cytokines) from plasma and plasma-derived extracellular vesicles (EVs) were quantified using single molecule array. Relationships between sleep quality and cytokine levels were assessed, controlling for age, sex, and BMI. Using clinical cutoff scores for sleep quality, mTBI patients were then divided into “good” and “poor” sleepers and cytokine levels compared between groups. Results: In mTBI participants, sleep quality was significantly associated with EV levels of IL-10 [ß (SE) = 0.11 (0.04), p = 0.01] and TNFα [ß (SE) = 0.07 (0.03), p < 0.01]. When divided according to “good” versus “poor” sleepers, those reporting poor sleep had significantly elevated EV IL-10 compared to those reporting good sleep [ß (SE) = 0.12 (0.04), p < 0.01]. Plasma-derived associations were not significant. No associations were found between sleep quality and cytokine levels in controls. Conclusion: These results suggest a significant relationship between sleep quality and chronic inflammation in mTBI patients. Clinically, mTBI patients with a high likelihood of sleep disorders demonstrate elevated levels of inflammatory cytokines. Signal from EVs, though smaller in magnitude, may have stronger clinical associations than from plasma. Sleep-focused interventions may also serve to regulate chronic inflammatory processes in these patients. Larger prospective studies are needed to investigate the mechanisms and therapeutic implications of the likely bi-directional relationship between sleep and inflammation following mTBI.

Traumatic brain injuries (TBI) and posttraumatic stress disorder (PTSD) are commonly observed comorbid occurrences among military service members and veterans (SMVs). In this cross-sectional study, SMVs with a history of TBI were stratified into symptomatic and asymptomatic PTSD groups based on posttraumatic stress checklist-civilian (PCL-C) total scores. Blood-based biomarkers were assessed, and significant differential markers were associated with scores from multiple neurobehavioral self-report assessments. PCL-C cutoffs were total scores >50 (PTSD symptomatic) and <25 (asymptomatic). Cytokines IL6, IL8, TNFα, and IL10 were significantly elevated (p < 0.05–0.001) in the TBI+/PTSD symptomatic group compared to the TBI+/asymptomatic group. Cytokine levels of IL8, TNFα, and IL10 were strongly associated with PCL-C scores (0.356 < r > 0.624 for all, p < 0.01 for all), while TNFα and IL10 were additionally associated with NSI totals (r = 0.285 and r = 0.270, p < 0.05, respectively). This is the first study focused on PTSD symptom severity to report levels of circulating pro-inflammatory IL8, specifically in SMVs with TBI. These data suggest that within the military TBI population, there are unique cytokine profiles that relate to neurobehavioral outcomes associated with TBI and PTSD.

Repetitive low-level blast exposure is one of the major occupational health concerns among US military service members and law enforcement. This study seeks to identify gene expression using microRNA and RNA sequencing in whole-blood samples from experienced breachers and unexposed controls. We performed experimental RNA sequencing using Illumina’s HiSeq 2500 Sequencing System, and microRNA analysis using NanoString Technology nCounter miRNA expression panel in whole-blood total RNA samples from 15 experienced breachers and 14 age-, sex-, and race-matched unexposed controls. We identified 10 significantly dysregulated genes between experienced breachers and unexposed controls, with FDR corrected <0.05: One upregulated gene, LINC00996 (long intergenic non-protein coding RNA 996); and nine downregulated genes, IGLV3-16 (immunoglobulin lambda variable 3-16), CD200 (CD200 molecule), LILRB5 (leukocyte immunoglobulin-like receptor B5), ZNF667-AS1 (ZNF667 antisense RNA 1), LMOD1 (leiomodin 1), CNTNAP2 (contactin-associated protein 2), EVPL (envoplakin), DPF3 (double PHD fingers 3), and IGHV4-34 (immunoglobulin heavy variable 4-34). The dysregulated gene expressions reported here have been associated with chronic inflammation and immune response, suggesting that these pathways may relate to the risk of lasting neurological symptoms following high exposures to blast over a career.

Chronic symptoms after mild traumatic brain injury (mTBI) are common among veterans and service members, and represent a significant source of morbidity, with those who sustain multiple mTBIs at greatest risk. Exosomal micro-RNAs (miRNAs), mediators of intercellular communication, may be involved in chronic TBI symptom persistence. Exosomal miRNA (exomiR) was extracted from 153 participants enrolled in the Chronic Effect of Neurotrauma Consortium (CENC) longitudinal study (no TBI, n = 35; ≥ 3 mTBIs (rTBI), n = 45; 1–2 mTBIs, n = 73). Analyses were performed with nCounter® Human miRNA Expression Panels and Ingenuity Pathway Analysis (IPA) for identification of gene networks associated with TBI. Generalized linear models were used to analyze the predictive value of exomiR dysregulation and remote neurobehavioral symptoms. Compared with controls, there were 17 dysregulated exomiRs in the entire mTBI group and 32 dysregulated exomiRs in the rTBI group. Two miRNAs, hsa-miR-139-5p and hsa-miR-18a-5p, were significantly differentially expressed in the rTBI and 1–2 mTBI groups. IPA analyses showed that these dysregulated exomiRs correlated with pathways of inflammatory regulation, neurological disease, and cell development. Within the rTBI group, exomiRs correlated with gene activity for hub-genes of tumor protein TP53, insulin-like growth factor 1 receptor, and transforming growth factor beta. TBI history and neurobehavioral symptom survey scores negatively and significantly correlated with hsa-miR-103a-3p expression. Participants with remote mTBI have distinct exomiR profiles, which are significantly linked to inflammatory and neuronal repair pathways. These profiles suggest that analysis of exosomal miRNA expression may provide novel insights into the underlying pathobiology of chronic TBI symptom persistence.