Cytokine Profiles Differentiate Symptomatic from Asymptomatic PTSD in Service Members and Veterans with Chronic Traumatic Brain Injury.

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.

Sex Differences in Behavioral Symptoms and the Levels of Circulating GFAP, Tau, and NfL in Patients With Traumatic Brain Injury.

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.

High IL-6 in military personnel relates to multiple traumatic brain injuries and post-traumatic stress disorder.

Repetitive traumatic brain injuries (TBIs) among military personnel have been linked to chronic behavioral and neurological symptoms, and poor health outcomes. Repetitive TBIs may impact inflammation, which may offer some explanation of the biological basis of these long-term risks, and may improve the care that is provided to these individuals. This study examines the concentrations of TNFα, IL-6 and IL-10 and associations with behavioral symptoms, including post-traumatic stress disorder symptoms and depression in a cohort of 106 military personnel and Veterans with a history of TBI. Group comparisons conducted for those with repetitive TBIs (> 3; n = 44), to participants with less than three TBIs (n = 29), and controls with no TBIs (n = 33). The primary outcomes were serum levels of inflammatory related proteins TNF-α, IL-6 and IL-10, TBI history, and PTSD symptoms. IL-6 mean concentration was significantly higher in the repetitive TBI group compared to those with 1-2 TBI or no TBI history (p = 0.050). Additionally, for participants with a history of TBI, PTSD symptom severity, specifically, intrusion (p = .006 and p = .007) and avoidance (p = .034 and .009), were significant predictors of higher IL-6 and IL-10 concentrations respectively. These findings suggest that repetitive TBIs concurrent with high PTSD symptoms in military personnel and Veterans are associated with chronic inflammation, and specifically elevated concentrations of IL-6. Examining the changes in inflammatory processes may identify potential therapeutic targets for early intervention after TBI in order to prevent the development of neurological deficits and disorders.

Excessive daytime sleepiness is associated with altered gene expression in military personnel and veterans with posttraumatic stress disorder: an RNA sequencing study.

STUDY OBJECTIVES: Posttraumatic stress disorder (PTSD) is a common condition for military personnel and veterans. PTSD has been shown to impact gene expression, however, to date no study has examined comorbid conditions which may also impact gene expression, for example, excessive daytime sleepiness (EDS). As such, this study sought to examine gene expression using RNA sequencing across three group comparisons of military personnel and veterans: (1) PTSD with EDS (PTSDwEDS) versus PTSD without EDS (PTSDw/outEDS), (2) Controls (no PTSD or EDS) versus PTSDwEDS, and (3) Controls versus PTSDw/outEDS. METHODS: We performed experimental RNA-seq using Illumina's HiSeq 2500 Sequencing System. We also used Ingenuity Pathway Analysis (IPA), a bioinformatics application, to identify gene pathways and networks which may be disrupted. RESULTS: There were only two genes that were significantly dysregulated between the Controls and PTSDw/outEDS, therefore IPA analysis was not conducted. However, comparisons revealed that there was significant gene dysregulation between Controls and the PTSDwEDS (251 genes), and the PTSDwEDS versus the PTSDw/outEDS (1,873 genes) groups. Four candidate networks were identified via the IPA software for analysis. Significantly dysregulated genes across the four candidate networks were associated with sleep and circadian function, metabolism, mitochondrial production and function, ubiquitination, and the glutamate system. CONCLUSIONS: These results suggest that PTSD with concurrent EDS is associated with gene dysregulation. This dysregulation may present additional biological and health consequences for these military personnel and veterans. Further research, to track these gene changes over time and to determine the cause of the EDS reported, is vital.

Elevated Tau in Military Personnel Relates to Chronic Symptoms Following Traumatic Brain Injury.

OBJECTIVE: To understand the relationships between traumatic brain injury (TBI), blood biomarkers, and symptoms of posttraumatic stress disorder (PTSD), depression, and postconcussive syndrome symptoms. DESIGN: Cross-sectional cohort study using multivariate analyses. PARTICIPANTS: One hundred nine military personnel and veterans, both with and without a history of TBI. MAIN MEASURES: PTSD Checklist-Civilian Version (PCL-C); Neurobehavioral Symptom Inventory (NSI); Ohio State University TBI Identification Method; Patient Health Questionnaire-9 (PHQ-9); Simoa-measured concentrations of tau, amyloid-beta (Aß) 40, Aß42, and neurofilament light (NFL). RESULTS: Controlling for age, sex, time since last injury (TSLI), and antianxiety/depression medication use, NFL was trending toward being significantly elevated in participants who had sustained 3 or more TBIs compared with those who had sustained 1 or 2 TBIs. Within the TBI group, partial correlations that controlled for age, sex, TSLI, and antianxiety/depression medication use showed that tau concentrations were significantly correlated with greater symptom severity, as measured with the NSI, PCL, and PHQ-9. CONCLUSIONS: Elevations in tau are associated with symptom severity after TBI, while NFL levels are elevated in those with a history of repetitive TBIs and in military personnel and veterans. This study shows the utility of measuring biomarkers chronically postinjury. Furthermore, there is a critical need for studies of biomarkers longitudinally following TBI.

Distinguishing the Relative Impact of Post-Traumatic Stress Disorder and Traumatic Brain Injury on iPad-Measured Cognitive Function.

Traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are highly prevalent, and frequently comorbid, among active and retired military service members. Both TBI and PTSD may contribute to impaired cognitive function, but it remains insufficiently clear what the relative impact of each is on overall cognition and whether multiple TBIs may further impair cognitive function. To understand the relative impact of TBI and symptoms of PTSD on cognitive function we examined data from 326 active or retired military service members, or dependents, either with or without a history of TBI, using questionnaires and the NIH Toolbox Cognitive Battery (NIH-TB), a brief iPad-based assessment that measures the cognitive domains most important to daily functioning. The NIH-TB was developed for use as a "common currency" among research studies, and was more recently adapted to the iPad for ease of use. To our knowledge, this is the first report of its application to evaluate the relative impact of TBI and PTSD. Our results indicate that cognitive function remains largely intact after multiple TBIs if symptoms of PTSD are not evident, and that measures of literacy and overall intelligence are relatively impervious to both TBI and PTSD. When cognitive impairment is observed after TBI, it is predominantly associated with the presence of significant symptoms of PTSD in most domains. However, TBI alone may impair some aspects of executive function. These findings need to be validated in other populations.

Streamlining Participant Recruitment for TBI and PTSD Research Studies.

OBJECTIVES: Recruitment of participants for traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) studies is a major challenge, causing delays in study timelines and even study failures. To address this challenge, the Center for Neuroscience and Regenerative Medicine (CNRM) Recruitment Core developed procedures for identification, screening, and referral of participants from screening studies to a broad range of TBI and PTSD studies. METHODS: Participants were recruited from civilian hospitals, Military Treatment Facilities, and through various events and presentations. Enrolled participants were referred to other studies during initial enrollment, follow-up visits, or ad hoc as new CNRM studies became active. A centralized online database was used to streamline the eligibility and referral process. RESULTS: As of October 25, 2016, 1,040 enrolled participants from the two screening studies have been assessed for eligibility for active CNRM studies. Referrals have led to 197 total enrollments into other CNRM studies. Common reasons for exclusion from studies included age, date of injury, injury severity, contraindication to Magnetic Resonance Imaging, state of residence, and military status. CONCLUSION: Collaborative work with multiple disciplines and institutions, and the use of diverse media, was critical to augmenting participant enrollment, and significantly diversified the demographics of the participant population. Streamlining the referral process helps studies meet their timelines and target enrollment.