Research Letter: Relationship of Blood Biomarkers of Inflammation With Acute Concussion Symptoms and Recovery in the CARE Consortium.

OBJECTIVE: Determine the association of inflammatory biomarkers with clinical measures and recovery in participants with concussion. SETTING: Multicenter study in National Collegiate Athletic Association member institutions including military service academies. PARTICIPANTS: Four hundred twenty-two participants with acute concussion. DESIGN: Clinical visits and blood draws were completed preinjury and at multiple visits postconcussion (0-12 hours, 12-36 hours, and 36-60 hours postinjury). Clinical measures included Sport Concussion Assessment Tool (SCAT) symptom severity, Balance Error Scoring System, Standardized Assessment of Concussion (SAC), Brief Symptom Inventory-18 (BSI-18) scores, time to initiation of graduated return-to-play (RTP) protocol, and time to RTP. Interleukin (IL)-6, IL-10, IL-8, IL-1 receptor antagonist (RA), tumor necrosis factor (TNF), c-reactive protein, and vascular endothelial growth factor (VEGF) were measured in serum. Prespecified analyses focused on IL-6 and IL-1RA at 0 to 12 hours; exploratory analyses were conducted with false discovery rate correction. RESULTS: For prespecified analyses, IL-1RA at 0 to 12 hours in female participants was positively associated with more errors on the SAC (B(standard error, SE) = 0.58(0.27), P < .05) and worse SCAT symptom severity (B(SE) = 0.96(0.44), P < .05). For exploratory analyses, higher levels of IL-1RA at 12 to 36 hours were associated with higher global (B(SE) = 0.55(0.14), q < 0.01), depression (B(SE) = 0.45(0.10), q < 0.005), and somatization scores on the BSI (B(SE) = 0.46(0.12), q < 0.01) in participants with concussion; Higher TNF at 12 to 36 hours was associated with fewer errors on the SAC (B(SE) = - 0.46(0.14), q < 0.05). Subanalyses showed similar results for male participants and participants who were athletes. No associations were discovered in nonathlete cadets. Higher IL-8 at 0 to 12 hours was associated with slower RTP in female participants (OR = 14.47; 95% confidence interval, 2.96-70.66, q < 0.05); no other associations with recovery were observed. CONCLUSIONS: Peripheral inflammatory markers are associated with clinical symptoms following concussion and potentially represent one mechanism for psychological symptoms observed postinjury. Current results do not provide strong support for a potential prognostic role for these markers.

Elevated Serum Tau and UCHL-1 Concentrations Within 12 Months of Injury Predict Neurobehavioral Functioning 2 or More Years Following Traumatic Brain Injury: A Longitudinal Study.

OBJECTIVE: Blood-based biomarkers have received considerable attention for their diagnostic and prognostic value in the acute and postacute period following traumatic brain injury (TBI). The purpose of this study was to examine whether blood-based biomarker concentrations within the first 12 months of TBI can predict neurobehavioral outcome in the chronic phase of the recovery trajectory. SETTING: Inpatient and outpatient wards from 3 military medical treatment facilities. PARTICIPANTS: A total of 161 service members and veterans classified into 3 groups: (a) uncomplicated mild TBI (MTBI; n = 37), (b) complicated mild, moderate, severe, penetrating TBI combined (STBI; n = 46), and (c) controls (CTRL; n = 78). DESIGN: Prospective longitudinal. MAIN MEASURES: Participants completed 6 scales from the Traumatic Brain Injury Quality of Life (ie, Anger, Anxiety, Depression, Fatigue, Headaches, and Cognitive Concerns) within 12 months (baseline) and at 2 or more years (follow-up) post-injury. Serum concentrations of tau, neurofilament light, glial fibrillary acidic protein, and UCHL-1 at baseline were measured using SIMOA. RESULTS: Baseline tau was associated with worse anger, anxiety, and depression in the STBI group at follow-up (R2 = 0.101-0.127), and worse anxiety in the MTBI group (R2 = 0.210). Baseline ubiquitin carboxyl-terminal hydrolase L1 (UCHL-1) was associated with worse anxiety and depression at follow-up in both the MTBI and STBI groups (R2Δ = 0.143-0.207), and worse cognitive concerns in the MTBI group (R2Δ = 0.223). CONCLUSIONS: A blood-based panel including these biomarkers could be a useful tool for identifying individuals at risk of poor outcome following TBI.

Extracellular vesicle-associated cytokines in sport-related concussion.

Growing evidence suggests that sport-related concussion results in a robust inflammatory response that can be measured in serum or plasma and is predictive of symptom recovery. Recently, extracellular vesicles (EV) derived from serum or plasma have emerged as a promising source of biomarkers for neurological disorders like concussion because they may better reflect central immunological activity. However, the association of acute concussion with EV-associated cytokines has not yet been systematically studied in humans. We tested the hypothesis that EV-associated cytokines are elevated acutely and predictive of symptom duration following concussion in a cohort of high-school and collegiate football players. Players were enrolled and provided serum samples at a preseason baseline visit (N = 857). An additional blood draw was obtained in players that subsequently suffered a concussion (N = 23) within 6-hours post-injury and in matched, uninjured players (N = 44). Concentrations of Interleukin-6 (IL-6), IL-1ß, IL-1 receptor antagonist (IL-1RA), IL-10, and tumor necrosis factor were measured in EV and EV-depleted serum samples. EV-associated IL-6 was significantly elevated post-injury relative to baseline levels and controls (ps < 0.01). In EV-depleted samples, IL-1RA was significantly elevated post-injury relative to baseline levels and controls (ps < 0.01). Time-to-event analyses showed that post-injury EV-associated IL-6 levels were positively associated with the number of days that injured athletes reported symptoms (p < 0.05). These results highlight the potential of EV-associated cytokines as biomarkers of concussion.

ErbB Signaling Pathway Genes Are Differentially Expressed in Monozygotic Twins Discordant for Sports-Related Concussion.

Transcriptional changes involved in neuronal recovery after sports-related concussion (SRC) may be obscured by inter-individual variation in mRNA expression and nonspecific changes related to physical exertion. Using a co-twin study, the objective of this study was to identify important differences in mRNA expression among a single pair of monozygotic (MZ) twins discordant for concussion. A pair of MZ twins were enrolled as part of a larger study of concussion biomarkers among collegiate athletes. During the study, Twin A sustained SRC, allowing comparison of mRNA expression to the nonconcussed Twin B. Twin A clinically recovered by Day 7. mRNA expression was measured pre-injury and at 6 h and 7 days postinjury using Affymetrix HG-U133 Plus 2.0 microarray. Changes in mRNA expression from pre-injury to each postinjury time point were compared between the twins; differences >1.5-fold were considered important. Kyoto Encyclopedia of Genes and Genomes identified biologic networks associated with important transcripts. Among 38,000 analyzed genes, important changes were identified in 153 genes. The ErbB (epidermal growth factor receptor) signaling pathway was identified as the top transcriptional network from pre-injury to 7 days postinjury. Genes in this pathway with important transcriptional changes included epidermal growth factor (2.41), epiregulin (1.73), neuregulin 1 (1.54) and mechanistic target of rapamycin (1.51). In conclusion, the ErbB signaling pathway was identified as a potential regulator of clinical recovery in a MZ twin pair discordant for SRC. A co-twin study design may be a useful method for identifying important gene pathways associated with concussion recovery.

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

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.

The Effect of Virtual Mindfulness-Based Interventions on Sleep Quality: A Systematic Review of Randomized Controlled Trials.

PURPOSE OF REVIEW: We summarized peer-reviewed literature investigating the effect of virtual mindfulness-based interventions (MBIs) on sleep quality. We aimed to examine the following three questions: (1) do virtual MBIs improve sleep quality when compared with control groups; (2) does the effect persist long-term; and (3) is the virtual delivery method equally feasible compared to the in-person delivery method? RECENT FINDINGS: Findings suggest that virtual MBIs are equivalent to evidence-based treatments, and to a limited extent, more effective than non-specific active controls at reducing some aspects of sleep disturbance. Overall, virtual MBIs are more effective at improving sleep quality than usual care controls and waitlist controls. Studies provide preliminary evidence that virtual MBIs have a long-term effect on sleep quality. Moreover, while virtual MBI attrition rates are comparable to in-person MBI attrition rates, intervention adherence may be compromised in the virtual delivery method. This review highlights virtual MBIs as a potentially effective alternative to managing sleep disturbance during pandemic-related quarantine and stay-at-home periods. This is especially relevant due to barriers of accessing in-person interventions during the pandemic. Future studies are needed to explore factors that influence adherence and access to virtual MBIs, with a particular focus on diverse populations.

17α-Ethinyl estradiol-3-sulfate increases survival and hemodynamic functioning in a large animal model of combined traumatic brain injury and hemorrhagic shock: a randomized control trial.

BACKGROUND: Traumatic brain injury (TBI) and severe blood loss resulting in hemorrhagic shock (HS) represent leading causes of trauma-induced mortality, especially when co-occurring in pre-hospital settings where standard therapies are not readily available. The primary objective of this study was to determine if 17α-ethinyl estradiol-3-sulfate (EE-3-SO4) increases survival, promotes more rapid cardiovascular recovery, or confers neuroprotection relative to Placebo following TBI + HS. METHODS: All methods were approved by required regulatory agencies prior to study initiation. In this fully randomized, blinded preclinical study, eighty (50% females) sexually mature (190.64 ± 21.04 days old; 28.18 ± 2.72 kg) Yucatan swine were used. Sixty-eight animals received a closed-head, accelerative TBI followed by removal of approximately 40% of circulating blood volume. Animals were then intravenously administered EE-3-SO4 formulated in the vehicle at 5.0 mg/mL (dosed at 0.2 mL/kg) or Placebo (0.45% sodium chloride solution) via a continuous pump (0.2 mL/kg over 5 min). Twelve swine were included as uninjured Shams to further characterize model pathology and replicate previous findings. All animals were monitored for up to 5 h in the absence of any other life-saving measures (e.g., mechanical ventilation, fluid resuscitation). RESULTS: A comparison of Placebo-treated relative to Sham animals indicated evidence of acidosis, decreased arterial pressure, increased heart rate, diffuse axonal injury and blood-brain barrier breach. The percentage of animals surviving to 295 min post-injury was significantly higher for the EE-3-SO4 (28/31; 90.3%) relative to Placebo (24/33; 72.7%) cohort. EE-3-SO4 also restored pulse pressure more rapidly post-drug administration, but did not confer any benefits in terms of shock index. Primary blood-based measurements of neuroinflammation and blood brain breach were also null, whereas secondary measurements of diffuse axonal injury suggested a more rapid return to baseline for the EE-3-SO4 group. Survival status was associated with biological sex (female > male), as well as evidence of increased acidosis and neurotrauma independent of EE-3-SO4 or Placebo administration. CONCLUSIONS: EE-3-SO4 is efficacious in promoting survival and more rapidly restoring cardiovascular homeostasis following polytraumatic injuries in pre-hospital environments (rural and military) in the absence of standard therapies. Poly-therapeutic approaches targeting additional mechanisms (increased hemostasis, oxygen-carrying capacity, etc.) should be considered in future studies.

Apolipoprotein e (APOE) ε4 genotype influences memory performance following remote traumatic brain injury in U.S. military service members and veterans.

The purpose of this study was to examine the association between the apolipoprotein E (APOE) ε4 allele and neurocognitive functioning following traumatic brain injury (TBI) in military service members and veterans (SMVs). Participants included 176 SMVs with a history of remote TBI (≥1 year post-injury), categorized into mild (n = 100), moderate (n = 40), and severe (n = 36) TBI groups. Participants completed a neuropsychological assessment and APOE genotyping (n = 46 ε4+, n = 130 ε4-). Neurocognitive composite scores representing memory, executive functioning, and visual processing speed were computed. ANCOVAs adjusting for race, education, combat exposure, and PTSD symptom severity showed a significant main effect of ε4 on the memory composite, such that ε4+ SMVs exhibited poorer memory performance than ε4- SMVs. When ε2 allele carriers were removed from the analyses, associations with memory were strengthened, demonstrating a possible protective effect of the ε2 allele. No main effect of TBI group was identified on any cognitive composite, nor were there any significant TBI group × Îµ4 status interactions for any cognitive composite. Future studies with larger samples are needed to verify these findings, but our results suggest an important relationship between ε4 status and memory functioning following remote TBI of all severities.

Fluid Biomarkers for Chronic Traumatic Encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neuropathological condition that has been described in individuals who have been exposed to repetitive head impacts, including concussions and subconcussive trauma. Currently, there is no fluid or imaging biomarker for diagnosing CTE during life. Based on retrospective clinical data, symptoms of CTE include changes in behavior, cognition, and mood, and may develop after a latency phase following the injuries. However, these symptoms are often nonspecific, making differential diagnosis based solely on clinical symptoms unreliable. Thus, objective biomarkers for CTE pathophysiology would be helpful in understanding the course of the disease as well as in the development of preventive and therapeutic measures. Herein, we review the literature regarding fluid biomarkers for repetitive concussive and subconcussive head trauma, postconcussive syndrome, as well as potential candidate biomarkers for CTE. We also discuss technical challenges with regard to the current fluid biomarkers and potential pathways to advance the most promising biomarker candidates into clinical routine.

Interleukin-6 is associated with acute concussion in military combat personnel.

BACKGROUND: Concussion is the most common type of TBI, yet reliable objective measures related to these injuries and associated recovery processes remain elusive, especially in military personnel. The purpose of this study was to characterize the relationship between cytokines and recovery from acute brain injury in active duty service members. Inflammatory cytokines (IL-6, IL-10, and TNFα) were measured acutely in blood samples within 8 h following a medically diagnosed concussion and then 24 h later. METHODS: Participants (n = 94) were categorized into two groups: 1) military personnel who sustained provider-diagnosed concussion, without other major medical diagnosis (n = 45) and 2) healthy control participants in the same deployment environment who did not sustain concussion or other illness or injuries (n = 49). IL-6, IL-10, and TNFα concentrations were measured using an ultrasensitive single-molecule enzyme-linked immunosorbent assay. Differences in cytokine levels between concussed and healthy groups were evaluated at two time points (time point 1 ≤ 8 h after injury; time point 2 = 24 h following time point 1). RESULTS: At time point 1, IL-6 median (IQR) concentrations were 2.62 (3.62) in the concussed group, which was greater compared to IL-6 in the healthy control group (1.03 (0.90); U = 420.00, z = - 5.12, p < 0.001). Compared to healthy controls, the concussed group did not differ at time point 1 in IL-10 or TNFα concentrations (p's > 0.05). At time point 2, no differences were detected between concussed and healthy controls for IL-6, IL-10, or TNFα (p's > 0.05). The median difference between time points 1 and 2 were compared between the concussed and healthy control groups for IL-6, IL-10, and TNFα. Change in IL-6 across time was greater for the concussed group than healthy control (- 1.54 (3.12); U = 315.00, z = - 5.96, p < 0.001), with no differences between groups in the change of IL-10 or TNFα (p's > 0.05). CONCLUSION: Reported here is a significant elevation of IL-6 levels in concussed military personnel less than 8 h following injury. Future studies may examine acute and chronic neurological symptomology associated with inflammatory cytokine levels, distinguish individuals at high risk for developing neurological complications, and identify underlying biological pathways to mitigate inflammation and improve outcomes.

Recent Advances in Blood-Based Biomarkers of Remote Combat-Related Traumatic Brain Injury.

PURPOSE OF REVIEW: Traumatic brain injury (TBI) is highly prevalent among service members and Veterans (SMVs) and associated with changes in blood-based biomarkers. This manuscript reviews candidate biomarkers months/years following military-associated TBI. RECENT FINDINGS: Several blood-based biomarkers have been investigated for diagnostic or prognostic use to inform care years after military-associated TBI. The most promising include increased levels of plasma/serum and exosomal proteins reflecting neuronal, axonal and/or vascular injury, and inflammation, as well as altered microRNA expression and auto-antibodies of central nervous system markers. Diagnostic and prognostic biomarkers of remote TBI outcomes remain in the discovery phase. Current evidence does not yet support single or combination biomarkers for clinical diagnostic use remotely after injury, but there are promising candidates that require validation in larger, longitudinal studies. The use of prognostic biomarkers of future neurodegeneration, however, holds much promise and could improve treatments and/or preventive measures for serious TBI outcomes.

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.

Gene expression differences in PTSD are uniquely related to the intrusion symptom cluster: A transcriptome-wide analysis in military service members.

Posttraumatic stress disorder (PTSD) is associated with wide-spread immune dysregulation; however, little is known about the gene expression differences attributed to each PTSD symptom cluster. This is an important consideration when identifying diagnostic and treatment response markers in highly comorbid populations with mental and physical health conditions that share symptoms. To this aim, we utilized a transcriptome-wide analysis of differential gene expression in peripheral blood by comparing military service members: (1) with vs. without PTSD, (2) with high vs. low PTSD cluster symptom severity, and (3) with improved vs. not improved PTSD symptoms following 4-8 weeks of evidenced-based sleep treatment. Data were analyzed at a ±2.0-fold change magnitude with subsequent gene ontology-based pathway analysis. In participants with PTSD (n = 39), 89 differentially expressed genes were identified, and 94% were upregulated. In participants with high intrusion symptoms (n = 22), 1040 differentially expressed genes were identified, and 98% were upregulated. No differentially expressed genes were identified for the remaining two PTSD symptom clusters. Ten genes (C5orf24, RBAK, CREBZF, CD69, PMAIP1, AGL, ZNF644, ANKRD13C, ESCO1, and ZCCHC10) were upregulated in participants with PTSD and high intrusion symptoms at baseline and downregulated in participants with improved PTSD symptoms following treatment. Pathway analysis identified upregulated immune response systems and metabolic networks with a NF-kB hub, which were downregulated with symptom reduction. Molecular biomarkers implicated in intrusion symptoms and PTSD symptom improvement may inform the development of therapeutic targets for precise treatment of PTSD.

Concurrent Mild Traumatic Brain Injury and Posttraumatic Stress Disorder Is Associated With Elevated Tau Concentrations in Peripheral Blood Plasma.

Concurrent mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) are common in U.S. military service members and veterans. Tau and amyloid-beta-42 (Aß42) are proteins that have been linked to cognitive impairment, neurological hallmarks of Alzheimer's disease, and may also relate to recovery from mTBI. However, the role of these proteins in the maintenance or resolution of chronic symptoms has not yet been determined. Participants in the current study were 102 service members and veterans who had sustained an mTBI (n = 84) or injured controls (IC) without TBI (n = 18). They were categorized into three groups based on the presence or absence of mTBI and PTSD: IC/PTSD-Absent (n = 18), mTBI/PTSD-Absent (n = 63), and mTBI/PTSD-Present (n = 21). Concentrations of tau and Aß42 in peripheral blood plasma were measured using SimoaTM , an ultrasensitive technology, and compared across groups. Tau concentrations were highest in the mTBI/PTSD-Present group, F(2, 99) = 4.33, p = .016, compared to the other two groups. Linear multiple regression was conducted to determine the independent effects of PTSD and mTBI on tau concentrations, controlling for gender and sleep medication. PTSD was a significant and independent predictor of tau concentrations, ß = .25, p = .009, ηp 2 = .26. Aß42 concentrations did not differ between the groups. The results indicated that PTSD was associated with an elevation of tau in peripheral blood and suggest that there may be increased biological effects of PTSD in this young cohort of service members and veterans following mTBI.

Spanish Abstracts by Asociación Chilena de Estrés Traumático (ACET) La Lesión Cerebral Traumática Leve Concurrente con Trastorno de Estrés Postraumático se asocia a elevadas concentraciones de Tau en Plasma de Sangre Periférica TRASTORNO DE ESTRÉS POSTRAUMÁTICO Y TAU ELEVADA La comorbilidad entre lesión cerebral traumática leve (mTBI por su sigla en inglés) y Trastorno de Estrés Postraumático (TEPT) es común en miembros del ejército estadounidense en servicio y en veteranos. Tau y beta-amiloide-42 (Aß42) son proteínas que han sido relacionadas a deterioro cognitivo, son marcadores neurológicos de Enfermedad de Alzheimer, y pueden también relacionarse a la recuperación de mTBI. Sin embargo, el rol de estas proteínas en la mantención o resolución de síntomas crónicos aún no ha sido determinado. Los participantes del presente estudio fueron 102 miembros en servicio y veteranos que habían sufrido una mTBI (n = 84) o controles heridos (CH) sin TBI (n = 18). Fueron categorizados en tres grupos de acuerdo con la presencia o ausencia de mTBI y TEPT; CH/TEPT-Ausente (n = 18), mTBI/TEPT-Ausente (n = 63) y mTBI-TEPT Presente (n = 21). Se midieron las concentraciones de Tau y Aß42 en plasma de sangre periférica usando SimoaTM , una tecnología ultrasensible, y fueron comparadas entre grupos. Las concentraciones de Tau fueron más altas en el grupo mTBI/TEPT-Presente, F(2, 99) = 4.33, p = .016, en comparación a los otros dos grupos. Se realizó una regresión lineal múltiple para determinar los efectos independientes del TEPT y mTBI sobre la concentración de Tau, controlando el género y la medicación para dormir. El TEPT fue un predictor significativo e independiente de concentraciones de Tau, ß = .25, p = .009, ηp 2 = .26. Las concentraciones de Aß42 no difirieron entre los grupos. Los resultados indicaron que el TEPT se asoció a una elevación de Tau en sangre periférica y sugieren que puede haber efectos biológicos del TEPT incrementados en esta joven cohorte de miembros en servicio y veteranos luego de una mTBI.

Antiangiogenic mechanisms and factors in breast cancer treatment.

Breast cancer is known to metastasize in its latter stages of existence. The different angiogenic mechanisms and factors that allow for its progression are reviewed in this article. Understanding these mechanisms and factors will allow researchers to design drugs to inhibit angiogenic behaviors and control the rate of tumor growth.

A Pilot Study Investigating the Use of Serum Glial Fibrillary Acidic Protein to Monitor Changes in Brain White Matter Integrity After Repetitive Head Hits During a Single Collegiate Football Game.

Repetitive head hits (RHHs) in sports and military settings are increasingly recognized as a risk factor for adverse neurological outcomes, but they are not currently tracked. Blood-based biomarkers of concussion have recently been shown to increase after nonconcussive RHHs during a single sporting contest, raising the possibility that they could be used in real time to monitor the brain's early response to repeated asymptomatic head hits. To test this hypothesis, we measured GFAP in serum immediately before (T0), immediately after (T1) and 45 min (T2) after a single collegiate football game in 30 athletes. Glial fibrillary acidic protein (GFAP) changes were correlated with three measures of head impact exposure (number of hits, total linear acceleration, and total rotational acceleration captured by helmet impact sensors) and to changes in brain white matter (WM) integrity, estimated by regional changes in fractional anisotropy (FA) and mean diffusivity (MD) on diffusion tensor imaging from 24 h before (T1) to 48 h after (T3) the game. To account for the potentially confounding effects of physical exertion on GFAP, correlations were adjusted for kilocalories of energy expended during the game measured by wearable body sensors. All 30 participants were male with a mean age of 19.5 ± 1.2 years. No participant had a concussion during the index game. We observed a significant increase in GFAP from T0 to T1 (mean 79.69 vs. 91.95 pg/mL, p = 0.008) and from T0 to T2 (mean 79.69 vs. 99.21 pg/mL, p < 0.001). WM integrity decreased in multiple WM regions but was statistically significant in the right fornix (mean % FA change -1.43, 95% confidence interval [CI]: -2.20, -0.66). T0 to T2 increases in GFAP correlated with reduced FA in the left fornix, right fornix, and right medical meniscus and with increased MD in the right fornix (r-values ranged from 0.59 to 0.61). Adjustment for exertion had minimal effect on these correlations. GFAP changes did not correlate to head hit exposure, but after adjustment for exertion, T0 to T2 increases correlated with all three hit metrics (r-values ranged from 0.69 to 0.74). Thus, acute elevations in GFAP after a single collegiate football game of RHHs correlated with in-game head hit exposure and with reduced WM integrity 2 days later. These results suggest that GFAP may be a biologically relevant indicator of the brain's early response to RHHs during a single sporting event. Developing tools to measure the neurological response to RHHs on an individual level has the potential to provide insight into the heterogeneity in adverse outcomes after RHH exposure and for developing effective and personalized countermeasures. Owing to the small sample size, these findings should be considered preliminary; validation in a larger, independent cohort is necessary.

Association of Blood Biomarkers of Inflammation With Acute Concussion in Collegiate Athletes and Military Service Academy Cadets.

BACKGROUND AND OBJECTIVES: The objective was to characterize the acute effects of concussion (a subset of mild traumatic brain injury) on serum interleukin (IL)-6 and IL-1 receptor antagonist (RA) and 5 additional inflammatory markers in athletes and military service academy members from the Concussion Assessment, Research, and Education Consortium and to determine whether these markers aid in discrimination of concussed participants from controls. METHODS: Athletes and cadets with concussion and matched controls provided blood at baseline and postinjury visits between January 2015 and March 2020. Linear models investigated changes in inflammatory markers measured using Meso Scale Discovery assays across time points (baseline and 0-12, 12-36, 36-60 hours). Subanalyses were conducted in participants split by sex and injury population. Logistic regression analyses tested whether acute levels of IL-6 and IL-1RA improved discrimination of concussed participants relative to brain injury markers (glial fibrillary acidic protein, tau, neurofilament light, ubiquitin c-terminal hydrolase-L1) or clinical data (Sport Concussion Assessment Tool-Third Edition, Standardized Assessment of Concussion, Balance Error Scoring System). RESULTS: Participants with concussion (total, N = 422) had elevated IL-6 and IL-1RA at 0-12 hours vs controls (n = 345; IL-6: mean difference [MD] (standard error) = 0.701 (0.091), p < 0.0001; IL-1RA: MD = 0.283 (0.042), p < 0.0001) and relative to baseline (IL-6: MD = 0.656 (0.078), p < 0.0001; IL-1RA: MD = 0.242 (0.038), p < 0.0001), 12-36 hours (IL-6: MD = 0.609 (0.086), p < 0.0001; IL-1RA: MD = 0.322 (0.041), p < 0.0001), and 36-60 hours (IL-6: MD = 0.818 (0.084), p < 0.0001; IL-1RA: MD = 0.317 (0.040), p < 0.0001). IL-6 and IL-1RA were elevated in participants with sport (IL-6: MD = 0.748 (0.115), p < 0.0001; IL-1RA: MD = 0.304 (0.055), p < 0.0001) and combative-related concussions (IL-6: MD = 0.583 (0.178), p = 0.001; IL-1RA: MD = 0.312 (0.081), p = 0.0001). IL-6 was elevated in male (MD = 0.734 (0.105), p < 0.0001) and female participants (MD = 0.600 (0.177), p = 0.0008); IL-1RA was only elevated in male participants (MD = 0.356 (0.047), p < 0.0001). Logistic regression showed the inclusion of IL-6 and IL-1RA at 0-12 hours improved the discrimination of participants with concussion from controls relative to brain injury markers (χ2(2) = 17.855, p = 0.0001; area under the receiver operating characteristic curve [AUC] 0.73 [0.66-0.80] to 0.78 [0.71-0.84]), objective clinical measures (balance and cognition; χ2(2) = 40.661, p < 0.0001; AUC 0.81 [0.76-0.86] to 0.87 [0.83-0.91]), and objective and subjective measures combined (χ2(2) = 13.456, p = 0.001; AUC 0.97 [0.95-0.99] to 0.98 [0.96-0.99]), although improvement in AUC was only significantly relative to objective clinical measures. DISCUSSION: IL-6 and IL-1RA (male participants only) are elevated in the early-acute window postconcussion and may aid in diagnostic decisions beyond traditional blood markers and common clinical measures. IL-1RA results highlight sex differences in the immune response to concussion which should be considered in future biomarker work.

Feasibility and acceptability for LION, a fully remote, randomized clinical trial within the VA for light therapy to improve sleep in Veterans with and without TBI: An MTBI2 sponsored protocol: LION: A remote RCT protocol within VA.

Sleep-wake disturbances frequently present in Veterans with mild traumatic brain injury (mTBI). These TBI-related sleep impairments confer significant burden and commonly exacerbate other functional impairments. Therapies to improve sleep following mTBI are limited and studies in Veterans are even more scarce. In our previous pilot work, morning bright light therapy (MBLT) was found to be a feasible behavioral sleep intervention in Veterans with a history of mTBI; however, this was single-arm, open-label, and non-randomized, and therefore was not intended to establish efficacy. The present study, LION (light vs ion therapy) extends this preliminary work as a fully powered, sham-controlled, participant-masked randomized controlled trial (NCT03968874), implemented as fully remote within the VA (target n=120 complete). Randomization at 2:1 allocation ratio to: 1) active: MBLT (n=80), and 2) sham: deactivated negative ion generator (n=40); each with identical engagement parameters (60-min duration; within 2-hrs of waking; daily over 28-day duration). Participant masking via deception balanced expectancy assumptions across arms. Outcome measures were assessed following a 14-day baseline (pre-intervention), following 28-days of device engagement (post-intervention), and 28-days after the post-intervention assessment (follow-up). Primary outcomes were sleep measures, including continuous wrist-based actigraphy, self-report, and daily sleep dairy entries. Secondary/exploratory outcomes included cognition, mood, quality of life, circadian rhythm via dim light melatonin onset, and biofluid-based biomarkers. Participant drop out occurred in <10% of those enrolled, incomplete/missing data was present in <15% of key outcome variables, and overall fidelity adherence to the intervention was >85%, collectively establishing feasibility and acceptability for MBLT in Veterans with mTBI.

Effects of Physical Exertion on Early Changes in Blood-Based Brain Biomarkers: Implications for the Acute Point of Care Diagnosis of Concussion.

Blood-based brain biomarkers (BBM) such as glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) have potential to aid in the diagnosis of concussion. Recently developed point-of-care test devices would enable BBMs to be measured in field settings such military and sport environments within minutes of a suspicious head hit. However, head hits in these environments typically occur in the setting of vigorous physical exertion, which can itself increase BBMs levels. Thus, efforts to develop BBMs as acute concussion aids in field settings need to account for the effects of physical exertion. To determine the acute effects of physical exertion on the BBMs, we measured GFAP, UCH-L1, tau, and neurofilament light chain (NF-L) immediately before, immediately after, and 45 min after a single workout session consisting of aerobic and resistance exercises in 30 collegiate football players. Subjects wore body sensors measuring several aspects of exertion and underwent diffusion tensor imaging 24 h before and 48 h after exertion. All subjects were male with a mean age of 19.5 ± 1.2 years. The mean duration of activity during the workout session was 94 ± 31 min. There was a significant decrease in serum GFAP immediately after (median decrease of 27.76%, p < 0.0001) and a significant increase in serum UCH-L1 45 min after (median increase of 37.11%, p = 0.016) exertion, compared with pre-exertion baseline. No significant changes in tau or NF-L were identified. The duration of exertion had a significant independent linear correlation to the increase in serum UCHL1 from pre-exertion to 45 min after exertion (r = 0.68, p = 0.004). There were no significant pre- to post-exertional changes in any of the 39 examined brain white matter regions, and biomarker changes did not correlate to variation in white matter integrity in any of these regions. Thus, exertion appeared to be associated with immediate decreases in serum GFAP and very acute (45 min) increases in UCH-L1. These changes were related to the duration of exertion, but not to changes in brain white matter integrity. Our results have important implications for how these BBMs might be used to aid in the on-scene diagnosis of concussion occurring in the setting of physical exertion.

Serum GFAP, NfL, and tau concentrations are associated with worse neurobehavioral functioning following mild, moderate, and severe TBI: a cross-sectional multiple-cohort study.

Introduction: The purpose of this study was to examine whether blood-based biomarkers associate with neurobehavioral functioning at three time points following traumatic brain injury (TBI). Materials and methods: Participants were 328 United States service members and veterans (SMVs) prospectively enrolled in the Defense and Veterans Brain Injury Center-Traumatic Brain Injury Center of Excellence (DVBIC-TBICoE) 15-Year Longitudinal TBI Study, recruited into three groups: uncomplicated mild TBI (MTBI, n = 155); complicated mild, moderate, severe TBI combined (STBI, n = 97); non-injured controls (NIC, n = 76). Participants were further divided into three cohorts based on time since injury (≤12 months, 3-5 years, and 8-10 years). Participants completed the Minnesota Multiphasic Personality Inventory-2-Restructured Format (MMPI-2-RF) and underwent blood draw to measure serum concentrations of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and tau. A total of 11 MMPI-2-RF scales were examined (e.g., depression, anxiety, anger, somatic, cognitive symptoms). Stepwise hierarchical regression models were conducted within each group. Results: Significant associations were found between biomarkers and MMPI-2-RF scales (all p < 0.05; R2Δ > 0.10). GFAP was inversely related to (a) neurological complaints in the MTBI group at ≤12 months, (b) demoralization, anger proneness in the STBI group at ≤12 months, and (c) head pain complaints in the STBI group at 8-10 years. NfL was (a) related to low positive emotions in the NIC group; and inversely related to (b) demoralization, somatic complaints, neurological complaints, cognitive complaints in the MTBI group at ≤12 months, (c) demoralization in the STBI group at ≤12 months, and (d) demoralization, head pain complaints, stress/worry in the STBI group at 3-5 years. In the STBI group, there were meaningful findings (R2Δ > 0.10) for tau, NFL, and GFAP that did not reach statistical significance. Discussion: Results indicate worse scores on some MMPI-2-RF scales (e.g., depression, stress/worry, neurological and head pain complaints) were associated with lower concentrations of serum GFAP, NfL, and tau in the sub-acute and chronic phase of the recovery trajectory up to 5 years post-injury, with a reverse trend observed at 8-10 years. Longitudinal studies are needed to help elucidate any patterns of association between blood-based biomarkers and neurobehavioral outcome over the recovery trajectory following TBI.