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.
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.
Public concern has been a catalyst for an emerging body of research investigating the potential long-term negative health consequences associated with sport-related concussion and subconcussive ...impacts. We conducted a systematic review of the literature on mental health measures associated with sport-related brain injuries in former athletes. Ovid MEDLINE, EMBASE, CINAHL, and PsychINFO databases were used. Thirteen studies were included in the final review. We identified a consistent positive association between a history of concussion and depression among former athletes, although the underlying causation remains unclear. Limited and inconsistent findings were observed in studies that evaluated subconcussive impacts. Overall, several methodological shortcomings were noted, including selection bias, research design, operational definitions, and measurement tools. Future research will benefit from employing prospective longitudinal studies, surveillance data systems and standardized collection methods, and should attempt to account for psychosocial modifiers or confounders when reporting the mental health status of former athletes. This area would also benefit from studies that include equal representation of male and female athletes, examine mental health disorders beyond depression, and assess a variety of sports and competition levels.
•A consistent, positive association was identified between concussion history and depression among former athletes.•Limited and inconsistent findings were observed in studies that evaluated subconcussive impacts and mental health.•Several methodological shortcomings were noted, leading to numerous recommendations for future studies.
Oxidative stress has been implicated in psychiatric disorders, including posttraumatic stress disorder (PTSD). Currently, the status of glutathione (GSH), the brain's most abundant antioxidant, in ...PTSD remains uncertain. Therefore, the current study investigated brain concentrations of GSH and peripheral concentrations of blood markers in individuals with PTSD vs. Healthy Controls (HC).
GSH spectra was acquired in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) using MEGA-PRESS, a J-difference-editing acquisition method. Peripheral blood samples were analyzed for concentrations of metalloproteinase (MMP)-9, tissue inhibitors of MMP (TIMP)-1,2, and myeloperoxidase (MPO).
There was no difference in GSH between PTSD and HC in the ACC (
= 30 PTSD,
= 20 HC) or DLPFC (
= 14 PTSD,
= 18 HC). There were no group differences between peripheral blood markers (
> 0.3) except for (non-significantly) lower TIMP-2 in PTSD. Additionally, TIMP-2 and GSH in the ACC were positively related in those with PTSD. Finally, MPO and MMP-9 were negatively associated with duration of PTSD.
We do not report altered GSH concentrations in the ACC or DLPFC in PTSD, however, systemic MMPs and MPO might be implicated in central processes and progression of PTSD. Future research should investigate these relationships in larger sample sizes.
Preclinical data suggest methamphetamine (MA), a widely used stimulant drug, can harm the brain by causing oxidative stress and inflammation, but only limited information is available in humans. We ...tested the hypothesis that levels of glutathione (GSH), a major antioxidant, would be lower in the brains of chronic human MA preferring polysubstance users. We also explored if concentrations of peripheral immunoinflammatory blood biomarkers were related with brain GSH concentrations.
20 healthy controls (HC) (33 years; 11 M) and 14 MA users (40 years; 9 M) completed a magnetic resonance spectroscopy (MRS) scan, with GSH spectra obtained by the interleaved J-difference editing MEGA-PRESS method in anterior cingulate cortex (ACC) and left dorsolateral prefrontal cortex (DLPFC). Peripheral blood samples were drawn for measurements of immunoinflammatory biomarkers. Independent samples
-tests evaluated MA vs. HC differences in GSH.
GSH levels did not differ between HC and MA users (ACC
= 0.30; DLPFC
= 0.85). A total of 17 of 25 immunoinflammatory biomarkers were significantly elevated in MA users and matrix metalloproteinase (MMP)-2 (
= 0.577,
= 0.039), myeloperoxidase (MPO) (
= -0.556,
= 0.049), and MMP-9 (
= 0.660,
= 0.038) were correlated with brain levels of GSH.
Normal brain GSH in living brain of chronic MA users is consistent with our previous postmortem brain finding and suggests that any oxidative stress caused by MA, at the doses used by our participants, might not be sufficient to cause either a compensatory increase in, or substantial overutilization of, this antioxidant. Additionally, more research is required to understand how oxidative stress and inflammatory processes are related and potentially dysregulated in MA use.
Our limited understanding of biological mechanisms underpinning Posttraumatic Stress Disorder (PTSD) is preventing effective drug development. Inflammation and oxidative stress have been implicated ...in brain pathology of PTSD and research suggests systemic immune dysfunction might be implicated as well. To date there is a lack of in vivo studies assessing these biological processes in humans with PTSD. The aim of the current thesis was to investigate inflammation and oxidative stress in PTSD using multimodal imaging and stimulated blood sampling.17 PTSD and 20 HC participants completed positron emission tomography (PET) imaging of the Translocator Protein (TSPO, index of microglia activation); Glutathione (GSH, antioxidant) was acquired via magnetic resonance spectroscopy (MRS) in 32 PTSD and 24 HC participants; and Lipopolysaccharide (LPS, innate immune system activator) stimulated whole blood samples were collected in 21 PTSD and 20 HC participants.No group differences in TSPO binding were observed, however frontal-limbic TSPO binding was higher in PTSD cannabis users and positively related with serum cortisol concentrations in PTSD participants. Brain GSH was not altered in PTSD but was positively correlated with plasma TIMP-2 in PTSD participants. Additionally, plasma MPO and MMP-9 were negatively correlated with duration of PTSD. Finally, men with PTSD exhibited reduced innate immune function, and lower resting inflammatory state, while females exhibited a higher resting inflammatory state. There were no relationships reported between study outcomes and PTSD symptoms.The current thesis highlighted the importance of considering sample heterogeneity in PTSD and sex specific data analysis, and draws attention to the systemic aspect of the disorder. While no group differences were observed in central proteins between PTSD and HC, subgroups of PTSD exhibited higher TSPO binding and GSH. Additionally, several sex specific findings emerged that suggest sex differences in the neurobiology of PTSD. To achieve therapeutic treatment that will benefit all with PTSD, future studies need to 1) study larger sample sizes to understand how sample heterogeneity in PTSD affects biological outcomes; 2) conduct sex stratified analysis to understand sex differences in PTSD; and 3) pursue systemic dysregulation in the disorders and investigate the potential role MMPs might have.
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