Microglia are immune brain cells implicated in stress-related mental illnesses including posttraumatic stress disorder (PTSD). Their role in the pathophysiology of PTSD, and on neurobiological ...systems that regulate stress, is not completely understood. We tested the hypothesis that microglia activation, in fronto-limbic brain regions involved in PTSD, would be elevated in participants with occupation-related PTSD. We also explored the relationship between cortisol and microglia activation. Twenty participants with PTSD and 23 healthy controls (HC) completed positron emission tomography (PET) scanning of the 18-kDa translocator protein (TSPO), a putative biomarker of microglia activation using the probe
FFEPPA, and blood samples for measurement of cortisol.
FFEPPA V
was non-significantly elevated (6.5-30%) in fronto-limbic regions in PTSD participants.
FFEPPA V
was significantly higher in PTSD participants reporting frequent cannabis use compared to PTSD non-users (44%, p = 0.047). Male participants with PTSD (21%, p = 0.094) and a history of early childhood trauma (33%, p = 0.116) had non-significantly higher
FFEPPA V
. Average fronto-limbic
FFEPPA V
was positively related to cortisol (r = 0.530, p = 0.028) in the PTSD group only. Although we did not find a significant abnormality in TSPO binding in PTSD, findings suggest microglial activation might have occurred in a subgroup who reported frequent cannabis use. The relationship between cortisol and TSPO binding suggests a potential link between hypothalamic-pituitary-adrenal-axis dysregulation and central immune response to trauma which warrants further study.
Increasing evidence suggests inflammation is an important component of concussion pathophysiology. However, its etiology, restitution, and potential clinical repercussions remain unknown. The purpose ...of the current study was to compare the blood concentrations of interleukin (IL) -6, a prominent inflammatory cytokine, between healthy athletes and athletes with a sport-related concussion (SRC), while addressing the potential confounds of sex, recent physical activity, and the interacting effect of concussion history.
A prospective, observational cohort study was conducted on athletes at a single academic institute participating across 13 interuniversity sports. Follow-up of 96 athletes who agreed to provide a blood sample was completed: 41 athletes with a physician diagnosed SRC, and 55 healthy athletes. Ella™, the high sensitivity immunoassay system by ProteinSimple was used to measure peripheral plasma concentrations of IL-6 within the first week (median = 4 days, range = 2-7) following injury. A resampled ordinary least squares regression was used to evaluate the relationship between IL-6 concentrations and concussion status, while partial least squares regression was used to evaluate the relationship between IL-6 and both symptom burden and time to clinical recovery.
Regression analysis identified a negative relationship between plasma IL-6 concentrations and the interaction between an acute SRC and a history of concussion (β = -0.29, p = 0.029). IL-6 did not differ between healthy athletes and those with an acute SRC independent of concussion history, and was not correlated with either recovery time or symptom burden in athletes with SRC.
Perturbations to circulating IL-6 concentrations, a key inflammatory cytokine, may be more pronounced following SRC in athletes who have a history of concussion. These results add to a growing body of evidence supporting the involvement of inflammation at all phases of recovery following SRC, and potentially support a concomitant effect of prior concussion on acute SRC pathophysiology.
The long-term health effects of concussion and sub-concussive impacts in sport are unknown. Growing evidence suggests both inflammation and neurodegeneration are pivotal to secondary injury processes ...and the etiology of neurodegenerative diseases. In the present study we characterized circulating brain injury and inflammatory mediators in healthy male and female athletes according to concussion history and collision sport participation. Eighty-seven university level athletes (male, n = 60; female, n = 27) were recruited before the start of the competitive season. Athletes were healthy at the time of the study (no medications, illness, concussion or musculoskeletal injuries). Dependent variables included 29 inflammatory and 10 neurological injury analytes assessed in the peripheral blood by immunoassay. Biomarkers were statistically evaluated using partial least squares multivariate analysis to identify possible relationships to self-reported previous concussion history, number of previous concussions and collision sport participation in male and female athletes. Multiple concussions were associated with increases in peripheral MCP-1 in females, and MCP-4 in males. Collision sport participation was associated with increases in tau levels in males. These results are consistent with previous experimental and clinical findings that suggest ongoing inflammatory and cerebral injury processes after repetitive mild head trauma. However, further validation is needed to correlate systemic biomarkers to repetitive brain impacts, as opposed to the extracranial effects common to an athletic population such as exercise and muscle damage.
Concussion is associated with disrupted cerebral blood flow (CBF), although there appears to be substantial inter-individual variability in CBF response. At present, the mechanisms of variable CBF ...response remain incompletely understood, but one potential contributor is matrix metalloproteinase (MMP) expression. In more severe forms of acquired brain injury, MMP up-regulation contributes to CBF impairments via increased blood-brain barrier permeability. A similar relationship is hypothesized for concussion, where recently concussed individuals with higher MMP levels have lower CBF. To test this hypothesis, 35 concussed athletes were assessed longitudinally at early symptomatic injury (median: 5 days post-injury) and at medical clearance (median: 24 days post-injury), along with 71 athletic controls. For all athletes, plasma MMPs were measured and arterial spin labelling was used to measure CBF. Consistent with our hypothesis, higher concentrations of MMP-2 and MMP-3 were correlated with lower global CBF. The correlations between MMPs and global CBF were also significantly diminished for concussed athletes at medical clearance and for athletic controls. These results indicate an inverse relationship between plasma MMP levels and CBF that is specific to the symptomatic phase of concussion. Analyses of regional CBF further showed that correlations with MMP levels exhibited some spatial specificity, with greatest effects in occipital, parietal and temporal lobes. These findings provide new insights into the mechanisms of post-concussion cerebrovascular dysfunction.
Posttraumatic stress disorder (PTSD) is a debilitating mental health condition that results from exposure to traumatic event(s). Decreased astrocyte-related proteins (e.g., glial fibrillary acidic ...protein, GFAP) and atrophic astrocytes in corticolimbic brain areas implicated in PTSD have been reported in experimental models suggesting that astrocyte pathology may be a feature of this disorder. We used positron emission tomography (PET) of the monoamine oxidase (MAO)-B probe 11CSL25.1188 to test the hypothesis that levels of MAO-B, an index of astrocyte levels is decreased in PTSD. MAO-B availability (11CSL25.1188 distribution volume) was measured in 13 participants with PTSD (∼39 years, 6F) and 17 healthy controls (HC) (∼31 years, 9F). A magnetic resonance image was acquired to delineate 6 cortiolimbic brain regions. PTSD was associated with a trending reduction in 11CSL25.1188 availability across regions (8-17%; p = 0.067) implicating the ventral striatum (p uncorrected = 0.015) and medial prefrontal cortex (p uncorrected = 0.060). 11CSL25.1188 availability was ∼30% lower in corticolimbic regions in PTSD with co-morbid major depressive disorder (MDD) (n = 4) vs HC (p = 0.001) and vs PTSD without MDD (p = 0.005). Our preliminary results do not suggest astrogliosis (inferred from elevated availability) in PTSD, but rather point to a loss of astrocytes or an independent downregulation of MAO-B in PTSD with more severe negative affect. These exploratory findings, which are partly in line with preclinical literature and recent PET observations of decreased microglia marker, Translocator Protein, in PTSD, warrant replication in a larger PTSD cohort.
Inflammation is considered a hallmark of concussion pathophysiology in experimental models, yet is understudied in human injury. Despite the growing use of blood biomarkers in concussion, ...inflammatory biomarkers have not been well characterized. Furthermore, it is unclear if the systemic inflammatory response to concussion differs from that of musculoskeletal injury. The purpose of this paper was to characterize systemic inflammation after injury in athletes with sport-related concussion or musculoskeletal injury.
A prospective, observational cohort study was conducted employing 175 interuniversity athletes (sport-related concussion, n = 43; musculoskeletal injury, n = 30; healthy, n = 102) from 12 sports at a sports medicine clinic at an academic institution. High-sensitivity immunoassay was used to evaluate 20 inflammatory biomarkers in the peripheral blood of athletes within 7 days of injury (subacute) and at medical clearance. Healthy athletes were sampled prior to the start of their competitive season. Partial least squares regression analyses were used to identify salient biomarker contributions to class separation between injured and healthy athletes, as well as to evaluate the relationship between biomarkers and days to recovery in injured athletes.
In the subacute period after injury, compared to healthy athletes, athletes with sport-related concussion had higher levels of the chemokines' monocyte chemoattractant protein-4 (p < 0.001) and macrophage inflammatory protein-1β (p = 0.001); athletes with musculoskeletal injury had higher levels of thymus and activation-regulated chemokine (p = 0.001). No significant differences in biomarker profiles were observed at medical clearance. Furthermore, concentrations of monocyte chemoattractant protein-1 (p = 0.007) and monocyte chemoattractant protein-4 (p < 0.001) at the subacute time point were positively correlated with days to recovery in athletes with sport-related concussion, while thymus and activation-regulated chemokine was (p = 0.001) positively correlated with days to recovery in athletes with musculoskeletal injury.
Sport-related concussion is associated with perturbations to systemic inflammatory chemokines that differ from those observed in athletes with a musculoskeletal injury. These results support inflammation as an important facet of secondary injury after sport-related concussion that can be measured systemically in a human model of injury.
Background
Hemorrhage is a leading cause of preventable death in civilian and military trauma. Freeze‐dried plasma is promising for hemostatic resuscitation in remote prehospital settings, given its ...potential benefits in reducing blood loss and mortality, long storage at ambient temperatures, high portability, and rapid reconstitution for transfusion in austere environments. Here we assess the ex vivo characteristics of a novel Terumo's freeze‐dried plasma product (TFDP).
Study design and methods
Rotational thromboelastometry (ROTEM) tests (INTEM, EXTEM, and FIBTEM) were conducted on plasma samples at 37°C with a ROTEM delta‐machine using standard reagents and procedures. The following samples were analyzed: pooled plasma to produce TFDP, TFDP reconstituted, and stored immediately at −80°C, reconstituted TFDP stored at 4°C for 24 h and room temperature (RT) for 4 h before freezing at −80°C. Analysis of plasma concentrations of selected cytokines, chemokines, and vascular molecules was performed using a multiplex immunoassay system. One‐way ANOVA with post hoc tests assessed differences in hemostatic and inflammatory properties.
Results
No significant differences in ROTEM variables (coagulation time CT, clot formation time, α‐angle, maximum clot firmness, and lysis index 30) between the TFDP‐producing plasma and reconstituted TFDP samples were observed. Compared to control plasma, reconstituted TFDP stored at 4°C for 24 h or RT for 4 h showed a longer INTEM CT. Levels of immuno‐inflammatory mediators were similar between frozen plasma and TFDP.
Conclusions
TFDP is equivalent to frozen plasma with respect to global hemostatic and immuno‐inflammatory mediator profiles. Further investigations of TFDP in trauma‐induced coagulopathy models and bleeding patients are warranted.
Background
Freeze‐dried plasma (FDP) is a promising blood component for prehospital resuscitation given its logistic advantages over fresh frozen plasma (FFP). COVID‐19 convalescent (CC) plasma has ...been used to treat coronavirus disease 2019 (COVID‐19) patients, and its corresponding FDP has potential use during future pandemics. Therefore, we conducted the study to determine if the hemostatic and immunological properties of plasma can be retained after lyophilization.
Study design and methods
Hemostatic tests were conducted with Rotational Thromboelastometry (ROTEM) and a Stago analyzer. Anti‐severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) IgG (Immunoglobulin G) and neutralizing activity were analyzed using Meso Scale Diagnostics immunoassay kits.
Results
There were no differences in ROTEM parameters and Stago measurements for prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen and D‐dimer concentrations, and antithrombin, factor V, VIII, and protein S activities between FFP and FDP for either pre‐COVID‐19 or CC samples. Differences were observed in INTEM clotting time and PT and PTT when comparing reconstituted FDP stored at 4°C for 24 h or room temperature for 4 h to healthy control. Both CC‐FFP and CC‐FDP showed two orders of magnitude higher concentrations of IgG antibodies against SARS‐CoV‐2 antigens than pre‐COVID‐19‐FFP and pre‐COVID‐19‐FDP and healthy control. Similarly, the CC samples showed approximately 4‐fold higher %‐inhibition of receptor binding than the pre‐COVID‐19 samples. There were no differences in either the antibody levels or neutralization activity between CC‐FFP and CC‐FDP.
Discussion
We demonstrated that FDP and CC‐FDP retained the same hemostatic and antibody functional activities relative to their initial plasma sources, supporting clinical evaluation of their benefits in severe trauma and COVID‐19 patients.
Elevated catecholamine levels might be associated with unfavorable outcome after traumatic brain injury (TBI). We investigated the association between catecholamine levels in the first 24 h ...post-trauma and functional outcome in patients with isolated moderate-to-severe TBI.
A cohort of 174 patients who sustained isolated blunt TBI was prospectively enrolled from three Level-1 Trauma Centers. Epinephrine (Epi) and norepinephrine (NE) concentrations were measured at admission (baseline), 6, 12 and 24 h post-injury. Outcome was assessed at 6 months by the extended Glasgow Outcome Scale (GOSE) score. Fractional polynomial plots and logistic regression models (fixed and random effects) were used to study the association between catecholamine levels and outcome. Effect size was reported as the odds ratio (OR) associated with one logarithmic change in catecholamine level.
At 6 months, 109 patients (62.6%) had an unfavorable outcome (GOSE 5-8 vs. 1-4), including 51 deaths (29.3%). Higher admission levels of Epi were associated with a higher risk of unfavorable outcome (OR, 2.04, 95% CI: 1.31-3.18, p = 0.002) and mortality (OR, 2.86, 95% CI: 1.62-5.01, p = 0.001). Higher admission levels of NE were associated with higher risk of unfavorable outcome (OR, 1.59, 95% CI: 1.07-2.35, p = 0.022) but not mortality (OR, 1.45, 95% CI: 0.98-2.17, p = 0.07). There was no relationship between the changes in Epi levels over time and mortality or unfavorable outcome. Changes in NE levels with time were statistically associated with a higher risk of mortality, but the changes had no relation to unfavorable outcome.
Elevated circulating catecholamines, especially Epi levels on hospital admission, are independently associated with functional outcome and mortality after isolated moderate-to-severe TBI.
No new therapies for traumatic brain injury (TBI) have been officially translated into current practice. At the tissue and cellular level, both inflammatory and oxidative processes may be exacerbated ...post-injury and contribute to further brain damage.
acetylcysteine (NAC) has the potential to downregulate both processes. This review focuses on the potential neuroprotective utility of NAC and
-acetylcysteine amide (NACA) post-TBI.
Medline, Embase, Cochrane Library, and ClinicalTrials.gov were searched up to July 2017. Studies that examined clinical and laboratory effects of NAC and NACA post-TBI in human and animal studies were included. Risk of bias was assessed in human and animal studies according to the design of each study (randomized or not). The primary outcome assessed was the effect of NAC/NACA treatment on functional outcome, while secondary outcomes included the impact on biomarkers of inflammation and oxidation. Due to the clinical and methodological heterogeneity observed across studies, no meta-analyses were conducted.
Our analyses revealed only three human trials, including two randomized controlled trials (RCTs) and 20 animal studies conducted using standardized animal models of brain injury. The two RCTs reported improvement in the functional outcome post-NAC/NACA administration. Overall, the evidence from animal studies is more robust and demonstrated substantial improvement of cognition and psychomotor performance following NAC/NACA use. Animal studies also reported significantly more cortical sparing, reduced apoptosis, and lower levels of biomarkers of inflammation and oxidative stress. No safety concerns were reported in any of the studies included in this analysis.
Evidence from the animal literature demonstrates a robust association for the prophylactic application of NAC and NACA post-TBI with improved neurofunctional outcomes and downregulation of inflammatory and oxidative stress markers at the tissue level. While a growing body of scientific literature suggests putative beneficial effects of NAC/NACA treatment for TBI, the lack of well-designed and controlled clinical investigations, evaluating therapeutic outcomes, prognostic biomarkers, and safety profiles, limits definitive interpretation and recommendations for its application in humans at this time.
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