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The hippocampus and cingulate gyrus are strongly interconnected brain regions that have been implicated in the neurobiology of post-traumatic stress disorder (PTSD). These brain structures are comprised of functionally distinct subregions that may contribute to the expression of PTSD symptoms or associated cardio-metabolic markers, but have not been well investigated in prior studies.Two divisions of the cingulate cortex (i.e., rostral and caudal) and 11 hippocampal subregions were investigated in 22 male combat-exposed veterans with PTSD and 22 male trauma-exposed veteran controls (TC). Cardio-metabolic measures included cholesterol, body mass index, and mean arterial pressure.Individuals with PTSD had less caudal cingulate area compared to TC even after controlling for caudal cingulate thickness. Total hippocampus volume was lower in PTSD compared to TC, accounted for by differences in CA1-CA4, granule cell layer of the dentate gyrus, molecular layer, and subiculum. Individuals with PTSD had higher mean arterial pressure compared to TC, which correlated with hippocampus volume only in the PTSD group.Sample size, cross-sectional analysis, no control for medications and findings limited to males.These data demonstrate preferential involvement of caudal cingulate area (vs. thickness) and hippocampus subregions in PTSD. The inverse association between hippocampus volume and mean arterial pressure may contribute to accelerated aging known to be associated with PTSD.

Despite experiencing a significant trauma, only a subset of World Trade Center (WTC) rescue and recovery workers developed posttraumatic stress disorder (PTSD). Identification of biomarkers is critical to the development of targeted interventions for treating disaster responders and potentially preventing the development of PTSD in this population. Analysis of gene expression from these individuals can help in identifying biomarkers of PTSD. We established a well-phenotyped sample of 371 WTC responders, recruited from a longitudinal WTC responder cohort using stratified random sampling, by obtaining blood, self-reported and clinical interview data. Using bulk RNA-sequencing from whole blood, we examined the association between gene expression and WTC-related PTSD symptom severity on (i) highest lifetime Clinician-Administered PTSD Scale (CAPS) score, (ii) past-month CAPS score, and (iii) PTSD symptom dimensions using a 5-factor model of re-experiencing, avoidance, emotional numbing, dysphoric arousal and anxious arousal symptoms. We corrected for sex, age, genotype-derived principal components and surrogate variables. Finally, we performed a meta-analysis with existing PTSD studies (total N = 1016), using case/control status as the predictor and correcting for these variables. We identified 66 genes significantly associated with total highest lifetime CAPS score (FDR-corrected p 0.05), and 31 genes associated with total past-month CAPS score. Our more granular analyses of PTSD symptom dimensions identified additional genes that did not reach statistical significance in our analyses with total CAPS scores. In particular, we identified 82 genes significantly associated with lifetime anxious arousal symptoms. Several genes significantly associated with multiple PTSD symptom dimensions and total lifetime CAPS score (SERPINA1, RPS6KA1, and STAT3) have been previously associated with PTSD. Geneset enrichment of these findings has identified pathways significant in metabolism, immune signaling, other psychiatric disorders, neurological signaling, and cellular structure. Our meta-analysis revealed 10 genes that reached genome-wide significance, all of which were downregulated in cases compared to controls (CIRBP, TMSB10, FCGRT, CLIC1, RPS6KB2, HNRNPUL1, ALDOA, NACA, ZNF429 and COPE). Additionally, cellular deconvolution highlighted an enrichment in CD4 T cells and eosinophils in responders with PTSD compared to controls. The distinction in significant genes between total lifetime CAPS score and the anxious arousal symptom dimension of PTSD highlights a potential biological difference in the mechanism underlying the heterogeneity of the PTSD phenotype. Future studies should be clear about methods used to analyze PTSD status, as phenotypes based on PTSD symptom dimensions may yield different gene sets than combined CAPS score analysis. Potential biomarkers implicated from our meta-analysis may help improve therapeutic target development for PTSD.

Background Posttraumatic Stress Disorder (PTSD) is an increasingly prevalent condition among older adults and may escalate further as the general population including veterans from recent conflicts grow older. Despite growing evidence of higher medical comorbidity, cognitive impairment and dementia, and disability in older individuals with PTSD, there are very few studies examining brain cortical structure in this population. Hence, we examined cortical volumes in a cross-sectional study of veterans and civilians aged ≥50 years, of both sexes and exposed to trauma (interpersonal, combat, non-interpersonal). Methods Cortical volumes were obtained from T1-weighted structural MRI and compared between individuals with PTSD and Trauma Exposed Healthy Controls (TEHC) adjusting for age, sex, estimated intracranial volume, depression severity, and time elapsed since trauma exposure. Results The PTSD group (N = 55) had smaller right parahippocampal gyrus compared to TEHC (N = 36), corrected p(pFWER) = 0.034, with an effect size of 0.75 (Cohen's d), with no significant group differences in other cortical areas. Conclusions These findings are different from the structural brain findings reported in studies in younger age groups (larger parahippocampal volume in PTSD patients), suggesting a possible significant change in brain structure as PTSD patients age. These results need replication in longitudinal studies across the age-span to test whether they are neuroanatomical markers representing disease vulnerability, trauma resilience or pathological neurodegeneration associated with cognitive impairment and dementia.

ImportanceTo date, no psychopharmacologic treatment has been found to be uniformly effective in veterans with posttraumatic stress disorder (PTSD); novel targets and approaches are needed to treat this disabling disorder.ObjectiveTo examine whether treatment with the glucocorticoid receptor antagonist mifepristone yields a signal for clinical efficacy in male veterans with PTSD.Design, Setting, and ParticipantsThis phase 2a, double-blind, parallel-group randomized clinical trial was conducted from November 19, 2012 (accrual started), through November 16, 2016 (final follow-up), within the US Department of Veterans Affairs. Participants were male veterans with chronic PTSD and a screening Clinician-Administered PTSD Scale score of 50 or higher. A total of 181 veterans consented to participation. Statistical analysis was conducted between August 2014 and May 2017.InterventionsParticipants were randomized in a 1:1 ratio to mifepristone (600 mg) or matched placebo taken orally for 7 days.Main Outcomes and MeasuresThe clinical outcome was whether a veteran achieved a clinical response status (a reduction of ≥30% of total Clinician-Administered PTSD Scale score from baseline) at 4- and 12-week follow-up. On the basis of a binary statistical selection rule, a difference in the proportion of treatment vs control group responders of 15% would be a clinically relevant difference. Self-report measures of PTSD and associated symptoms were also obtained. Neuroendocrine outcomes and plasma levels of mifepristone were measured. Safety was assessed throughout the study. The primary analysis was based on a multiple imputation technique to address missing outcome data; thus, some participant numbers may not appear as whole numbers.ResultsA total of 81 veterans were enrolled and randomized. Excluding 1 participant randomized in error, 80 were included in the modified intention-to-treat analysis (41 randomized to mifepristone and 39 to placebo). The mean (SD) age was 43.1 (13.7) years. A total of 15.6 (38.1%) in the mifepristone group and 12.1 (31.1%) in the placebo group were clinical responders at 4 weeks in the analysis using the multiple imputation technique. The group difference in the proportion of clinical responders (7.0%) was less than the predefined margin of 15% indicating signal for clinical efficacy. In an exploratory analysis, the difference in response to mifepristone vs placebo in the subgroup with no lifetime history of traumatic brain injury (TBI) (7.0 [50.0%] vs 3.0 [27.3%]; difference, 22.7%) exceeded the efficacy margin at 4 weeks and was sustained at 12 weeks. In contrast, in veterans with PTSD and lifetime TBI, the response rate to mifepristone was lower than placebo at 12 weeks (7.4 [27.4%] vs 13.5 [48.3%]; difference, −20.9%).Conclusions and RelevanceThis study did not detect a signal for efficacy for mifepristone at 600 mg/d for 1 week in male veterans with chronic PTSD. Thus, this study does not support a phase 3 trial in this population. Future studies of mifepristone for the treatment of PTSD may be of interest in those without a history of TBI or in samples with a low base rate of lifetime head trauma.Trial RegistrationClinicalTrials.gov Identifier: NCT01946685

OBJECTIVE The present study evaluated distinct facets of impulsivity related to cardiometabolic risk (CMR) to identify specific behavioral mechanisms driving these relationships. METHOD Community adults (N = 1,295) between 30 and 54 years old (53% female, 84% White) completed a battery of impulsivity measures, reported their engagement in health behaviors over the past week (i.e., cigarette smoking, alcohol use, physical activity, and dietary intake), and were assessed for CMR factors (i.e., blood pressure, insulin resistance, adiposity, and blood lipids). Structural equation modeling was used to estimate previously established hierarchical models of distinct facets of impulsivity and CMR. Indirect effects through the observed health behaviors were examined for each association between the latent impulsivity factors identified and the latent CMR factor. RESULTS Neuroticism/negative emotionality was the only latent impulsivity factor directly related to heightened CMR (β = 0.09, 95% confidence interval [CI] [0.01, 0.16], p = .020). Extraversion/positive emotionality indirectly related to lower CMR through greater physical activity (β = -0.04, 95% CI [-0.06, -0.02], p < .001), and measures of inhibition (β = 0.02, 95% CI [0.001, 0.04], p = .045) and delay discounting (β = 0.08, 95% CI [0.001, 0.15], p = .049) indirectly related to CMR through saturated fat intake. CONCLUSIONS These findings indicate that distinct facets of impulsivity differentially relate to CMR through varied behavioral pathways and identify physical activity and saturated fat intake as being particularly important health behaviors to target when tailoring treatment approaches to the unique behavioral characteristics of individuals high on certain facets of impulsivity. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Although glucocorticoid resistance contributes to increased inflammation, individuals with posttraumatic stress disorder (PTSD) exhibit increased glucocorticoid receptor (GR) sensitivity along with increased inflammation. It is not clear how inflammation coexists with a hyperresponsive hypothalamic-pituitary-adrenal (HPA) axis. To understand this better, we developed and analyzed an integrated mathematical model for the HPA axis and the immune system. We performed mathematical simulations for a dexamethasone (DEX) suppression test and IC50-dexamethasone for cytokine suppression by varying model parameters. The model analysis suggests that increasing the steepness of the dose-response curve for GR activity may reduce anti-inflammatory effects of GRs at the ambient glucocorticoid levels, thereby increasing proinflammatory response. The adaptive response of proinflammatory cytokine-mediated stimulatory effects on the HPA axis is reduced due to dominance of the GR-mediated negative feedback on the HPA axis. To verify these hypotheses, we analyzed the clinical data on neuroendocrine variables and cytokines obtained from war-zone veterans with and without PTSD. We observed significant group differences for cortisol and ACTH suppression tests, proinflammatory cytokines TNFα and IL6, high-sensitivity C-reactive protein, promoter methylation of GR gene, and IC50-DEX for lysozyme suppression. Causal inference modeling revealed significant associations between cortisol suppression and post-DEX cortisol decline, promoter methylation of human GR gene exon 1F ( NR3C1-1F), IC50-DEX, and proinflammatory cytokines. We noted significant mediation effects of NR3C1-1F promoter methylation on inflammatory cytokines through changes in GR sensitivity. Our findings suggest that increased GR sensitivity may contribute to increased inflammation; therefore, interventions to restore GR sensitivity may normalize inflammation in PTSD.

DNA methylation patterns at specific cytosine-phosphate-guanine (CpG) sites predictably change with age and can be used to derive “epigenetic age”, an indicator of biological age, as opposed to merely chronological age. A relatively new estimator, called “DNAm GrimAge”, is notable for its superior predictive ability in older populations regarding numerous age-related metrics like time-to-death, time-to-coronary heart disease, and time-to-cancer. PTSD is associated with premature mortality and frequently has comorbid physical illnesses suggestive of accelerated biological aging. This is the first study to assess DNAm GrimAge in PTSD patients. We investigated the acceleration of GrimAge relative to chronological age, denoted “AgeAccelGrim” in combat trauma-exposed male veterans with and without PTSD using cross-sectional and longitudinal data from two independent well-characterized veteran cohorts. In both cohorts, AgeAccelGrim was significantly higher in the PTSD group compared to the control group (N = 162, 1.26 vs −0.57, p = 0.001 and N = 53, 0.93 vs −1.60 Years, p = 0.008), suggesting accelerated biological aging in both cohorts with PTSD. In 3-year follow-up study of individuals initially diagnosed with PTSD (N = 26), changes in PTSD symptom severity were correlated with AgeAccelGrim changes (r = 0.39, p = 0.049). In addition, the loss of CD28 cell surface markers on CD8 + T cells, an indicator of T-cell senescence/exhaustion that is associated with biological aging, was positively correlated with AgeAccelGrim, suggesting an immunological contribution to the accelerated biological aging. Overall, our findings delineate cellular correlates of biological aging in combat-related PTSD, which may help explain the increased medical morbidity and mortality seen in this disease.

Post-traumatic stress disorder (PTSD) can develop following severe trauma, but the extent to which genetic and environmental risk factors contribute to individual clinical outcomes is unknown. Here, we compared transcriptional responses to hydrocortisone exposure in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and peripheral blood mononuclear cells (PBMCs) from combat veterans with PTSD (n = 19 hiPSC and n = 20 PBMC donors) and controls (n = 20 hiPSC and n = 20 PBMC donors). In neurons only, we observed diagnosis-specific glucocorticoid-induced changes in gene expression corresponding with PTSD-specific transcriptomic patterns found in human postmortem brains. We observed glucocorticoid hypersensitivity in PTSD neurons, and identified genes that contribute to this PTSD-dependent glucocorticoid response. We find evidence of a coregulated network of transcription factors that mediates glucocorticoid hyper-responsivity in PTSD. These findings suggest that induced neurons represent a platform for examining the molecular mechanisms underlying PTSD, identifying biomarkers of stress response, and conducting drug screening to identify new therapeutics.

Epigenetic changes are currently invoked as explanations for both the chronicity and tenacity of post-traumatic stress disorder (PTSD), a heterogeneous condition showing varying, sometimes idiosyncratic responses to treatment. This study evaluated epigenetic markers in the context of a randomized clinical trial of PTSD patients undergoing prolonged-exposure psychotherapy with and without a hydrocortisone augmentation prior to each session. The purpose of the longitudinal epigenome-wide analyses was to identify predictors of recovery (from pretreatment data) or markers associated with symptom change (based on differences between pre- and post-therapy epigenetic changes). The results of these analyses identified the CREB–BDNF signaling pathway, previously linked to startle reaction and fear learning and memory processes, as a convergent marker predicting both symptom change and severity. Several previous-reported resilience markers were also identified (FKBP5, NR3C1, SDK1, and MAD1L1) to associate with PTSD recovery in this study. Especially, the methylation levels of FKBP5 in the gene body region decreased significantly as CAPS score decreased in responders, while no changes occurred in nonresponders. These biomarkers may have future utility in understanding clinical recovery in PTSD and potential applications in predicting treatment effects.

Posttraumatic stress disorder (PTSD) is associated with neuroendocrine alterations and metabolic abnormalities; however, how metabolism is affected by neuroendocrine disturbances is unclear. The data from combat-exposed veterans with PTSD show increased glycolysis to lactate flux, reduced TCA cycle flux, impaired amino acid and lipid metabolism, insulin resistance, inflammation, and hypersensitive hypothalamic-pituitary-adrenal (HPA) axis. To analyze whether the co-occurrence of multiple metabolic abnormalities is independent or arises from an underlying regulatory defect, we employed a systems biological approach using an integrated mathematical model and multiomic analysis. The models for hepatic metabolism, HPA axis, inflammation, and regulatory signaling were integrated to perform metabolic control analysis (MCA) with respect to the observations from our clinical data. We combined the metabolomics, neuroendocrine, clinical laboratory, and cytokine data from combat-exposed veterans with and without PTSD to characterize the differences in regulatory effects. MCA revealed mechanistic association of the HPA axis and inflammation with metabolic dysfunction consistent with PTSD. This was supported by the data using correlational and causal analysis that revealed significant associations between cortisol suppression, high-sensitivity C-reactive protein, homeostatic model assessment of insulin resistance, γ-glutamyltransferase, hypoxanthine, and several metabolites. Causal mediation analysis indicates that the effects of enhanced glucocorticoid receptor sensitivity (GRS) on glycolytic pathway, gluconeogenic and branched-chain amino acids, triglycerides, and hepatic function are jointly mediated by inflammation, insulin resistance, oxidative stress, and energy deficit. Our analysis suggests that the interventions to normalize GRS and inflammation may help to manage features of metabolic dysfunction in PTSD.

Attempts to correlate blood levels of brain-derived neurotrophic factor (BDNF) with post-traumatic stress disorder (PTSD) have provided conflicting results. Some studies found a positive association between BDNF and PTSD diagnosis and symptom severity, while others found the association to be negative. The present study investigated whether serum levels of BDNF are different cross-sectionally between combat trauma-exposed veterans with and without PTSD, as well as whether longitudinal changes in serum BDNF differ as a function of PTSD diagnosis over time. We analyzed data of 270 combat trauma-exposed veterans (230 males, 40 females, average age: 33.29 ± 8.28 years) and found that, at the initial cross-sectional assessment (T0), which averaged 6 years after the initial exposure to combat trauma (SD=2.83 years), the PTSD positive group had significantly higher serum BDNF levels than the PTSD negative controls [31.03 vs. 26.95 ng/mL, t(268) = 3.921, p

We sought to find clinical subtypes of posttraumatic stress disorder (PTSD) in veterans 6–10 years post-trauma exposure based on current symptom assessments and to examine whether blood biomarkers could differentiate them. Samples were males deployed to Iraq and Afghanistan studied by the PTSD Systems Biology Consortium: a discovery sample of 74 PTSD cases and 71 healthy controls (HC), and a validation sample of 26 PTSD cases and 36 HC. A machine learning method, random forests (RF), in conjunction with a clustering method, partitioning around medoids, were used to identify subtypes derived from 16 self-report and clinician assessment scales, including the clinician-administered PTSD scale for DSM-IV (CAPS). Two subtypes were identified, designated S1 and S2, differing on mean current CAPS total scores: S2 = 75.6 (sd 14.6) and S1 = 54.3 (sd 6.6). S2 had greater symptom severity scores than both S1 and HC on all scale items. The mean first principal component score derived from clinical summary scales was three times higher in S2 than in S1. Distinct RFs were grown to classify S1 and S2 vs. HCs and vs. each other on multi-omic blood markers feature classes of current medical comorbidities, neurocognitive functioning, demographics, pre-military trauma, and psychiatric history. Among these classes, in each RF intergroup comparison of S1, S2, and HC, multi-omic biomarkers yielded the highest AUC-ROCs (0.819–0.922); other classes added little to further discrimination of the subtypes. Among the top five biomarkers in each of these RFs were methylation, micro RNA, and lactate markers, suggesting their biological role in symptom severity.

Despite experiencing a significant trauma, only a subset of World Trade Center (WTC) rescue and recovery workers developed posttraumatic stress disorder (PTSD). Identification of biomarkers is critical to the development of targeted interventions for treating disaster responders and potentially preventing the development of PTSD in this population. Analysis of gene expression from these individuals can help in identifying biomarkers of PTSD.We established a well-phenotyped sample of 371 WTC responders, recruited from a longitudinal WTC responder cohort, by obtaining blood, self-reported and clinical interview data. Using bulk RNA-sequencing from whole blood, we examined the association between gene expression and WTC-related PTSD symptom severity on (i) highest lifetime Clinician-Administered PTSD Scale (CAPS) score, (ii) past-month CAPS score, and (iii) PTSD symptom dimensions using a 5-factor model of re-experiencing, avoidance, emotional numbing, dysphoric arousal and anxious arousal symptoms. We corrected for sex, age, genotype-derived principal components and surrogate variables. Finally, we performed a meta-analysis with existing PTSD studies (total N=1,016), using case/control status as the predictor and correcting for these variables.We identified 66 genes significantly associated with highest lifetime CAPS score (FDR-corrected pSERPINA1, RPS6KA1,andSTAT3) have been previously associated with PTSD. Geneset enrichment of these findings has identified pathways significant in metabolism, immune signaling, other psychiatric disorders, neurological signaling, and cellular structure. Our meta-analysis revealed 10 genes that reached genome-wide significance, all of which were down-regulated in cases compared to controls (CIRBP, TMSB10, FCGRT, CLIC1, RPS6KB2, HNRNPUL1, ALDOA, NACA, ZNF429 and COPE). Additionally, cellular deconvolution highlighted an enrichment in CD4 T cells and eosinophils in responders with PTSD compared to controls.The distinction in significant genes between lifetime CAPS score and the anxious arousal symptom dimension of PTSD highlights a potential biological difference in the mechanism underlying the heterogeneity of the PTSD phenotype. Future studies should be clear about methods used to analyze PTSD status, as phenotypes based on PTSD symptom dimensions may yield different gene sets than combined CAPS score analysis. Potential biomarkers implicated from our meta-analysis may help improve therapeutic target development for PTSD.

Post-traumatic stress disorder (PTSD) results from severe trauma exposure, but the extent to which genetic and epigenetic risk factors impact individual clinical outcomes is unknown. We assessed the impact of genomic differences following glucocorticoid administration by examining the transcriptional profile of human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons and live cultured peripheral blood mononuclear cells from combat veterans with PTSD (n=5) and without PTSD (n=5). This parallel examination in baseline and glucocorticoid-treated conditions resolves cell-type specific and diagnosis-dependent elements of stress response, and permits discrimination of gene expression signals associated with PTSD risk from those induced by stress. Computational analyses revealed neuron-specific glucocorticoid-response expression patterns that were enriched for transcriptomic patterns observed in clinical PTSD samples. PTSD-specific signatures, albeit underpowered, accurately stratify veterans with PTSD relative to combat-exposed controls. Overall, in vitro PTSD and glucocorticoid response signatures in blood and brain cells represent exciting new platforms with which to test the genetic and epigenetic mechanisms underlying PTSD, identify biomarkers of PTSD risk and onset, and conduct drug-screening to identify novel therapeutics to prevent or ameliorate clinical phenotypes.

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition triggered by exposure to trauma. The study of PTSD is complicated by highly heterogeneous presentations and experiences of trauma between individuals. Capitalizing on the existence of the World Trade Center General Responder Cohort (WTC-GRC) of rescue, recovery and clean-up workers who responded during and in the aftermath of the World Trade Center (WTC) 9/11/2001 attacks, we studied genetic correlates of PTSD in a sample of 371 WTC responders, selected from the WTC-GRC utilizing stratified random sampling. This deeply phenotyped sample of WTC responders – ranging from no/low PTSD symptom levels to severe PTSD– provide a unique opportunity to study genetic risk factors for PTSD severity and chronicity following a single, shared, well-documented trauma, also incorporating measures of childhood and other lifetime traumas.We examined associations of polygenic risk scores (PRS) –derived from a range of genome-wide association studies (GWAS) of behavioral traits, psychiatric disorders, and brain volumetric phenotypes– with PTSD severity and chronicity among these 371 individuals. Our results demonstrate significant genetic regulation of lifetime PTSD severity, assessed with the lifetime version Clinician-Administered PTSD Scale (CAPS), and chronicity, assessed with the past-month CAPS. PRS derived from GWAS of attention deficit-hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and brain imaging phenotypes (amygdala and putamen volumes) were associated with several PTSD symptom dimensions. Interestingly, we found greater genetic contribution to PTSD among cases compared to our full sample. In addition, we tested for associations between exposures to traumatic stressors, including WTC-related exposures, childhood trauma, and other lifetime traumatic life events in our full sample. Together, polygenic risk and exposures to traumatic stress explained ~45% of variance in lifetime CAPS (R2=0.454), and ~48% of variance in past-month CAPS (R2=0.480) in the full sample.These participants represent a highly vulnerable population, with exposures to severe trauma during 9/11 and the following days and months. These novel identified associations between PTSD and PRS of behavioral traits and brain volume phenotypes, as well as replicated associations with PRS of other psychiatric disorders, may contribute to understanding the biological factors associated with risk for and chronicity of PTSD. In particular, the identification of neuroimaging phenotypes indicates that coupling of neuroimaging with genetic risk score calculations may predict PTSD outcomes.

Objective Cognitive behavioral therapies such as Prolonged Exposure (PE) are considered first line treatments for posttraumatic stress disorder (PTSD). Nonetheless, many continue to experience significant symptoms following treatment and there is interest in enhancing treatment effectiveness. Glucocorticoid alterations in PTSD are well documented, and these steroids have been shown to enhance extinction learning. Methods Augmentation of PE with the synthetic glucocorticoid hydrocortisone (HCORT) was tested in a randomized, double-blind, placebo-controlled trial in 60 veterans of wars in Iraq or Afghanistan with PTSD (NCT01525680). Participants ingested 30 mg oral HCORT or placebo 30 min prior to exposure sessions. Primary outcome measure: PTSD severity assessed by the CAPS; secondary outcome measures: self reported PTSD symptoms assessed by the PDS and depression assessed by the BDI; all administered at pretreatment, posttreatment, and 3-month follow up. Results Across conditions, there was a robust effect of PE over time. An intent-to-treat analysis showed that HCORT did not measurably improve PTSD symptoms or secondary outcomes. However, exploratory analyses indicated that veterans with mild TBI exposure and current postconcussive symptoms showed a greater reduction in hyperarousal symptoms following PE treatment with HCORT augmentation. Additionally, veterans with higher baseline glucocorticoid sensitivity showed a greater reduction in avoidance symptoms with HCORT augmentation. Conclusions Treatment matching based on cognitive or biological vulnerabilities might lead to greater efficacy of PE with glucocorticoid augmentation.

DNA methylation patterns at specific cytosine-phosphate-guanine (CpG) sites predictably change with age and can be used to derive "epigenetic age", an indicator of biological age, as opposed to merely chronological age. A relatively new estimator, called "DNAm GrimAge", is notable for its superior predictive ability in older populations regarding numerous age-related metrics like time-to-death, time-to-coronary heart disease, and time-to-cancer. PTSD is associated with premature mortality and frequently has comorbid physical illnesses suggestive of accelerated biological aging. This is the first study to assess DNAm GrimAge in PTSD patients. We investigated the acceleration of GrimAge relative to chronological age, denoted "AgeAccelGrim" in combat trauma-exposed male veterans with and without PTSD using cross-sectional and longitudinal data from two independent well-characterized veteran cohorts. In both cohorts, AgeAccelGrim was significantly higher in the PTSD group compared to the control group (N = 162, 1.26 vs -0.57, p = 0.001 and N = 53, 0.93 vs -1.60 Years, p = 0.008), suggesting accelerated biological aging in both cohorts with PTSD. In 3-year follow-up study of individuals initially diagnosed with PTSD (N = 26), changes in PTSD symptom severity were correlated with AgeAccelGrim changes (r = 0.39, p = 0.049). In addition, the loss of CD28 cell surface markers on CD8 + T cells, an indicator of T-cell senescence/exhaustion that is associated with biological aging, was positively correlated with AgeAccelGrim, suggesting an immunological contribution to the accelerated biological aging. Overall, our findings delineate cellular correlates of biological aging in combat-related PTSD, which may help explain the increased medical morbidity and mortality seen in this disease.

Background Traumatic stress can adversely affect physical and mental health through neurobiological stress response systems. We examined the effects of trauma exposure and posttraumatic stress disorder (PTSD) on telomere length, a biomarker of cellular aging, and volume of the amygdala, a key structure of stress regulation, in combat-exposed veterans. In addition, the relationships of psychopathological symptoms and autonomic function with telomere length and amygdala volume were examined. Methods Male combat veterans were categorized as having PTSD diagnosis (n = 102) or no lifetime PTSD diagnosis (n = 111) based on the Clinician-Administered PTSD Scale. Subjects were assessed for stress-related psychopathology, trauma severity, autonomic function, and amygdala volumes by magnetic resonance imaging. Results A significant interaction was found between trauma severity and PTSD status for telomere length and amygdala volume after adjusting for multiple confounders. Subjects with PTSD showed shorter telomere length and larger amygdala volume than those without PTSD among veterans exposed to high trauma, while there was no significant group difference in these parameters among those exposed to low trauma. Among veterans exposed to high trauma, greater telomere shortening was significantly correlated with greater norepinephrine, and larger amygdala volume was correlated with more severe psychological symptoms and higher heart rates. Conclusions These data suggest that the intensity of the index trauma event plays an important role in interacting with PTSD symptomatology and autonomic activity in predicting telomere length and amygdala volume. These results highlight the importance of trauma severity and PTSD status in predicting certain biological outcomes.

This Article was originally published without the correct Supplemental Table file (Table S1 was missing). In total, there are seven Supplemental Tables, and six were in the original submission. Furthermore, Fig. 1 was misplaced in the main text; it was embedded in the manuscript file even before the results section. Both issues have now been fixed in the HTML and PDF versions of this Article.

Post-traumatic stress disorder (PTSD) is a heterogeneous condition evidenced by the absence of objective physiological measurements applicable to all who meet the criteria for the disorder as well as divergent responses to treatments. This study capitalized on biological diversity observed within the PTSD group observed following epigenome-wide analysis of a well-characterized Discovery cohort (N = 166) consisting of 83 male combat exposed veterans with PTSD, and 83 combat veterans without PTSD in order to identify patterns that might distinguish subtypes. Computational analysis of DNA methylation (DNAm) profiles identified two PTSD biotypes within the PTSD+ group, G1 and G2, associated with 34 clinical features that are associated with PTSD and PTSD comorbidities. The G2 biotype was associated with an increased PTSD risk and had higher polygenic risk scores and a greater methylation compared to the G1 biotype and healthy controls. The findings were validated at a 3-year follow-up (N = 59) of the same individuals as well as in two independent, veteran cohorts (N = 54 and N = 38), and an active duty cohort (N = 133). In some cases, for example Dopamine-PKA-CREB and GABA-PKC-CREB signaling pathways, the biotypes were oppositely dysregulated, suggesting that the biotypes were not simply a function of a dimensional relationship with symptom severity, but may represent distinct biological risk profiles underpinning PTSD. The identification of two novel distinct epigenetic biotypes for PTSD may have future utility in understanding biological and clinical heterogeneity in PTSD and potential applications in risk assessment for active duty military personnel under non-clinician-administered settings, and improvement of PTSD diagnostic markers.

Introduction Several lines of evidence indicate that increased inflammation is associated with Post-Traumatic Stress Disorder (PTSD). We have previously reported that peripheral inflammatory markers are significantly higher in combat-exposed veterans with than without PTSD. This study was designed to replicate these findings in a new study cohort using the same population and recruitment strategies. Methods Sixty-one male war veterans (31 PTSD and 30 control subjects) were included in this replication study. Levels of Interleukin-6, Tumor Necrosis Factor-alpha, Gamma interferon, and high-sensitivity C-reactive protein were quantified in blood samples. A standardized “total pro-inflammatory score” was calculated to limit the number of statistical comparisons. The Clinician Administered PTSD Scale (CAPS) rating scale was used to assess PTSD symptom severity. Results PTSD subjects had significantly higher total pro-inflammatory scores compared to non-PTSD subjects in unadjusted analysis (Cohen’s d = 0.75, p = 0.005) as well as after adjusting for potentially confounding effects of age, BMI, smoking, and potentially interfering medications and somatic co-morbidities (p = 0.023). There were no significant correlations between inflammatory markers and severity of symptoms within the PTSD group. Conclusions We replicated, in a new sample, our previous finding of increased inflammatory markers in combat-exposed PTSD subjects compared to combat-exposed non-PTSD controls. These findings strongly add to the growing literature suggesting that immune activation may be an important aspect of PTSD pathophysiology, although not directly correlated with current PTSD symptom levels in the PTSD group.

Trait domains of the five-factor model are not orthogonal, and two metatraits have often been estimated from their covariation. Here, we focus on the stability metatrait, which reflects shared variance in conscientiousness, agreeableness, and (inversely) neuroticism. It has been hypothesized that stability manifests, in part, because of individual differences in central serotonergic functioning. We explored this possibility in a community sample ( N = 441) using a multiverse analysis of (a) multi-informant five-factor-model traits and (b) stability as a predictor of individual differences in central serotonergic functioning. Differences in serotonergic functioning were assessed by indexing change in serum prolactin concentration following intravenous infusion of citalopram, a selective serotonin reuptake inhibitor. Results were mixed, showing that trait neuroticism, agreeableness, and conscientiousness, as well as the stability metatrait, were significantly associated with prolactin response but that these findings were contingent on a number of modeling decisions. Specifically, these effects were nonlinear, emerging most strongly for participants with the highest levels (or lowest, for neuroticism) of the component traits.

Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to 1) identify genetic variation associated with reported childhood maltreatment, 2) calculate the relevant SNP-based heritability estimates, and 3) quantify the genetic overlap of reported childhood maltreatment with mental and physical health-related phenotypes. Genome-wide association analysis for childhood maltreatment was undertaken, using a discovery sample from the UK Biobank (UKBB) (n=124,000) and a replication sample from the Psychiatric Genomics Consortium–posttraumatic stress disorder working group (PGC-PTSD) (n=26,290). Heritability estimations for childhood maltreatment and genetic correlations with mental/physical health traits were calculated using linkage disequilibrium score regression (LDSR). Two genome-wide significant loci associated with childhood maltreatment, located on chromosomes 3p13 (rs142346759, beta=0.015, p=4.35×10−8,FOXP1) and 7q31.1 (rs10262462, beta=-0.016, p=3.24×10−8,FOXP2), were identified in the discovery dataset but were not replicated in the PGC-PTSD sample. SNP-based heritability for childhood maltreatment was estimated to be ∼6%. Childhood maltreatment was most significantly genetically correlated with depressive symptoms (rg=0.70, p=4.65×10−40). This is the first large-scale genetic study to identify specific variants associated with self-reported childhood maltreatment.FOXPgenes could influence traits such as depression and thereby be relevant to childhood maltreatment. Alternatively, these variants may be associated with a greater likelihood of reporting maltreatment. A clearer understanding of the genetic relationships of childhood maltreatment, including particular abuse subtypes, with various psychiatric disorders, may ultimately be useful in in developing targeted treatment and prevention strategies.

Combat veterans are at elevated suicide risk. The goal of this study was to test the hypothesis that combat veterans who have made a suicide attempt post-deployment can be distinguished from combat veterans who have never made a suicide attempt based on differences in psychological and biological variables. For the latter, we focused on endogenous cannabinoids, neuroendocrine markers that are associated with stress. Demographic and clinical parameters of suicide attempters and non-attempters were assessed. Blood samples were assayed for anandamide (AEA), 2-arachidonoylglycerol (2-AG), and cortisol. Suicide attempters had higher Scale for Suicidal Ideation (SSI) scores in comparison to non-attempters. Controlling for gender, 2-AG levels were higher among suicide attempters in comparison to non-attempters. Cortisol levels positively correlated with 2-AG levels and negatively correlated with SSI scores among non-attempters but not among attempters. AEA levels negatively correlated with SSI scores among attempters but not among non-attempters. Our results indicate that there are psychological and biological differences between combat veterans with or without a history of suicidal attempt. Our findings also suggest that clinically observed differences between the groups may have a neurobiological basis.

Although glucocorticoid resistance contributes to increased inflammation, individuals with post-traumatic stress disorder (PTSD) exhibit increased glucocorticoid receptor (GR) sensitivity along with increased inflammation. It is not clear how inflammation co-exists with a hyper-responsive hypothalamic pituitary adrenal axis (HPA axis). To understand this better, we developed and analyzed an integrated mathematical model for the HPA axis and the immune system. We performed mathematical simulations for a dexamethasone suppression test and IC50-dexamethasone for cytokine suppression, by varying model parameters. The model analysis suggests that increasing the steepness of the dose response curve for GR activity may reduce anti-inflammatory effects of GRs at the ambient glucocorticoid levels thereby increasing pro-inflammatory response. The adaptive response of pro-inflammatory cytokine mediated stimulatory effects on the HPA-axis is reduced due to dominance of the GR-mediated negative feedback on the HPA-axis. To verify these hypotheses we analyzed the clinical data on neuro-endocrine variables and cytokines obtained from war-zone veterans with and without PTSD. We observed significant group differences for cortisol and ACTH suppression tests, pro-inflammatory cytokines TNFα and IL6, hs-CRP, promoter methylation of GR gene and IC50-Dex for lysozyme suppression. Causal inference modelling revealed significant associations between cortisol suppression and post-dex cortisol decline, promoter methylation of NR3C1-1F, IC50-Dex and pro-inflammatory cytokines. We noted significant mediation effects of NR3C1-1F promoter methylation on inflammatory cytokines through changes in GR sensitivity. Our findings suggest that increased GR sensitivity may contribute to increased inflammation, therefore, interventions to restore GR sensitivity may normalize inflammation in PTSD.

Post-traumatic stress disorder (PTSD) is a psychiatric illness with a highly polygenic architecture without large effect-size common single-nucleotide polymorphisms (SNPs). Thus, to capture a substantial portion of the genetic contribution, effects from many variants need to be aggregated. We investigated various aspects of one such approach that has been successfully applied to many traits, polygenic risk score (PRS) for PTSD. Theoretical analyses indicate the potential prediction ability of PRS. We used the latest summary statistics from the largest published genome-wide association study (GWAS) conducted by Psychiatric Genomics Consortium for PTSD (PGC-PTSD). We found that the PRS constructed for a cohort comprising veterans of recent wars (n = 244) explains a considerable proportion of PTSD onset (Nagelkerke R2 = 4.68%, P = 0.003) and severity (R2 = 4.35%, P = 0.0008) variances. However, the performance on an African ancestry sub-cohort was minimal. A PRS constructed with schizophrenia GWAS also explained a significant fraction of PTSD diagnosis variance (Nagelkerke R2 = 2.96%, P = 0.0175), confirming previously reported genetic correlation between the two psychiatric ailments. Overall, these findings demonstrate the important role polygenic analyses of PTSD will play in risk prediction models as well as in elucidating the biology of the disorder.

PTSD is associated with metabolic comorbidities; however it is not clear how the neuroendocrine disturbances affect metabolism. To analyze this we employed a systems biological approach using an integrated mathematical model of metabolism, HPA axis and inflammation. We combined the metabolomics, neuroendocrine, clinical lab and cytokine data from combat-exposed veterans with and without PTSD, to characterize the differences in regulatory effects. We used the pattern of fold change in metabolites representing pathway level differences as reference for metabolic control analysis (MCA) using the model. MCA revealed parameters constituting the HPA axis, inflammation and GPCR pathway that yielded metabolic dysfunction consistent with PTSD. To support this, we performed causal analysis between regulatory components and the significantly different metabolites in our sample. Causal inference revealed that the changes in glucocorticoid receptor sensitivity were mechanistically associated with metabolic dysfunction and the effects were jointly mediated by insulin resistance, inflammation, oxidative stress and energy deficit.

Psychiatric, physical and biological aspects of posttraumatic stress disorder (PTSD) may be associated with dysfunctions in several cellular processes including nitric oxide (NO) production. NO is synthesized from arginine in a reaction carried out by NO synthase (NOS) enzymes. The recently introduced "global arginine bioavailability ratio" (GABR; ratio of arginine to [ornithine+citrulline]) has been proposed as a reliable approximation of NO synthetic capacity in vivo. The objectives of the present study were to test the hypotheses that (i) subjects with combat-related PTSD have lower GABR scores than combat controls, (ii) GABR score is inversely associated with the severity of psychopathological measures, (iii) GABR score is inversely associated with markers of inflammation.Metabolic profiling for plasma samples (i.e. arginine, citrulline and ornithine) and inflammation markers (interleukin [IL]-6, IL-1β, tumor necrosis factor [TNF]-α, interferon [IFN]-γ and C-reactive protein [CRP]) were assessed in 56 combat-exposed males with PTSD and 65 combat-exposed males without PTSD. We assessed severity of PTSD (Clinician Administered PTSD Scale [CAPS]) and depression (Beck Depression Inventory-II [BDI-II]) as well as history of early life trauma (Early Trauma Inventory [ETI]) and affectivity (Positive and Negative Affect Schedule [PANAS]).The GABR value was (i) significantly lower in PTSD subjects compared to controls (p=0.001), (ii) significantly inversely correlated with markers of inflammation including IL6 (p=0.04) and TNFα (p=0.02), and (iii) significantly inversely correlated with CAPS current (p=0.001) and lifetime (p0.001) subscales, ETI (p=0.045) and PANAS negative (p=0.006). Adding antidepressant use or MDD diagnosis as covariates led to similar results. Adding age and BMI as covariates also led to similar results, with the exception of IL6 and ETI losing their significant association with GABR.This study provides the first evidence that global arginine bioavailability, a marker of NO synthetic capacity in vivo, is lower in veterans with PTSD and is negatively associated with some markers of inflammation as well as with measures of PTSD symptom severity, negative affectivity and childhood adverse experiences. These findings add to the accumulating evidence that specific cellular dysfunction may be associated with the symptomatology of PTSD and may help to explain the higher burden of cardio-metabolic disturbances seen in this disorder.

Sexual dysfunction is not a symptom of PTSD but is a common clinical complaint in trauma survivors with this disorder. In that there are biological parallels in the neuroendocrine processes underlying both PTSD and sexual behavior, we conducted an exploratory investigation of the relationship of PTSD and related neuroendocrine indicators with sexual dysfunction in armed service veterans. Major Depressive Disorder, highly comorbid with PTSD and sexual dysfunction, was also assessed. In veterans with PTSD, sexual problems were associated with plasma DHEA and cortisol, urinary catecholamines, and glucocorticoid sensitivity, even when controlling for the effects of comorbid depression. In a subsample analysis, testosterone levels did not distinguish PTSD or sexual dysfunction, suggesting that sexual problems reported by veterans in this sample were not the result of organic disorder. PTSD did predict higher dihydrotestosterone (DHT) levels, which were associated with sexual problems. More detailed assessment of sexual dysfunction in biologically informed studies of PTSD is warranted to clarify the relationships of PTSD symptomatology and related neurobiology with sexual dysfunction.

Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinson’s Disease gene,PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.

Background: We sought to determine whether post-traumatic stress disorder (PTSD) is a risk factor for myocardial infarction (MI) and stroke, beyond the expected effects from recognized cardiovascular risk factors and depression. Methods and Results: World Trade Center–Heart is an observational prospective cohort study of 6481 blue-collar first responders nested within the World Trade Center Health Program in New York City. Baseline measures in 2012 and 2013 included blood pressure, weight and height, and blood lipids. PTSD, depression, smoking, and dust exposure during the 2001 cleanup were self-reported. During the 4-year follow-up, outcomes were assessed through (1) interview-based incident, nonfatal MI, and stroke, validated in medical charts (n=118); and (2) hospitalizations for MI and stroke for New York city and state residents (n=180). Prevalence of PTSD was 19.9% in men and 25.9% in women, that is, at least twice that of the general population. Cumulative incidence of MI or stroke was consistently larger for men or women with PTSD across follow-up. Adjusted hazard ratios (HRs) were 2.22 (95% confidence interval [CI], 1.30–3.82) for MI and 2.51 (95% CI, 1.39–4.57) for stroke. For pooled MI and stroke, adjusted HRs were 2.35 (95% CI, 1.57–3.52) in all and 1.88 (95% CI, 1.01–3.49) in men free of depression. Using hospitalization registry data, adjusted HRs were 2.17 (95% CI, 1.41–3.32) for MI; 3.01 (95% CI, 1.84–4.93) for stroke; and for pooled MI and stroke, the adjusted HR was 2.40 (95% CI, 1.73–3.34) in all, HR was 2.44 (95% CI, 1.05–5.55) in women, and adjusted HR was 2.27 (95% CI, 1.41–3.67) in men free of depression. World Trade Center dust exposure had no effect. Conclusions: This cohort study confirms that PTSD is a risk factor for MI and stroke of similar magnitude in men and women, independent of depression.

OBJECTIVE: The extent to which major depression is the outcome of a single biological mechanism or represents a final common pathway of multiple disease processes remains uncertain. Genetic approaches can potentially identify etiologic heterogeneity in major depression by dividing patients on their experience of major adverse events. METHOD: Data are from China, Oxford, and VCU Experimental Research on Genetic Epidemiology (CONVERGE), a study of Han Chinese women with recurrent major depression aimed at identifying genetic risk factors for major depression in a rigorously ascertained cohort carefully assessed for key environmental risk factors (n = 9599). To detect etiologic heterogeneity, genome-wide association studies (GWAS), heritability analyses, and gene-by-environment interaction analyses were performed. RESULTS: GWAS stratified by exposure to adversity revealed three novel loci associated with major depression only in subjects with no history of adversity. Significant GxE interactions were seen between adversity and genotype at all three loci and 13.2% of major depression liability can be attributed to genome-wide interaction with adversity exposure. The genetic risk in major depression for samples who reported major adverse life events (27%) was partially shared with that in samples who did not (73%) (genetic correlation = +0.64). Together with results from simulation studies, these findings suggest etiologic heterogeneity within major depression as a function of environmental exposures. CONCLUSIONS: The genetic contributions to major depression in women may differ in those with and without major adverse life events. These results have implications for the molecular dissection of major depression and other complex psychiatric and biomedical diseases.

Objective The goal of this study was to determine whether combat veterans who have made a suicide attempt postdeployment can be distinguished from combat veterans who have never made a suicide attempt based on differences in psychological and biological variables. Methods Demographic and clinical parameters of suicide attempters and non-attempters were assessed. Blood samples were assayed for dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS). Results Suicide attempters had higher Scale for Suicidal Ideation and Montgomery-Asberg Depression Rating Scale (MADRS)-suicidal thoughts item scores in comparison with non-attempters. There was a trend toward higher MADRS scores in the suicide attempter group compared with non-attempters. Suicide attempters had significantly lower levels of DHEA and DHEAS compared with non-attempters. Scale for Suicidal Ideation scores in all study participants combined negatively correlate with DHEA and DHEAS levels. DHEAS levels negatively correlate with Scale for Suicidal Ideation scores in suicide non-attempters but not in suicide attempters. DHEA/DHEAS ratios positively correlate with total adolescence aggression scores, total adulthood aggression scores, and total aggression scale scores in suicide attempters but not in suicide non-attempters. Conclusion There are psychobiological differences between combat veterans with or without a history of suicidal behaviour.

DNA methylation patterns change with age and can be used to derive an estimate of “epigenetic age,” an indicator of biological age. Several studies have shown associations of posttraumatic stress disorder (PTSD) with worse somatic health and early mortality, raising the possibility of accelerated biological aging. This study examined associations between estimated epigenetic age and various variables in 160 male combat-exposed war veterans with (n = 79) and without PTSD (n = 81). DNA methylation was assessed in leukocyte genomic DNA using the Illumina 450K DNA methylation arrays. Epigenetic age was estimated using Horvath’s epigenetic clock algorithm and Δage (epigenetic age-chronological age) was calculated. In veterans with PTSD (Δage = 3.2), Δage was on average lower compared to those without PTSD (Δage = 5.0; p = 0.02; Cohen’s d = 0.42). This between-group difference was not explained by race/ethnicity, lifestyle factors or childhood trauma. Antidepressant use, however, explained part of the association. In the PTSD positive group, telomerase activity was negatively related to Δage (β = –0.35; p = 0.007). In conclusion, veterans with PTSD had significantly lower epigenetic age profiles than those without PTSD. Further, current antidepressant use and higher telomerase activity were related to relatively less epigenetic aging in veterans with PTSD, speculative of a mechanistic pathway that might attenuate biological aging-related processes in the context of PTSD.

Posttraumatic stress disorder (PTSD) is characterized by atrophy within the prefrontal-limbic network. Graph analysis was used to investigate to what degree atrophy in PTSD is associated with impaired structural connectivity within prefrontal limbic network (restricted) and how this affects the integration of the prefrontal limbic network with the rest of the brain (whole-brain). 85 male veterans (45 PTSD neg, 40 PTSD pos) underwent volumetric MRI on a 3T MR. Subfield volumes were obtained using a manual labeling scheme and cortical thickness measurements and subcortical volumes from FreeSurfer. Regression analysis was used to identify regions with volume loss. Graph analytical Toolbox (GAT) was used for graph-analysis. PTSD pos had a thinner rostral anterior cingulate and insular cortex but no hippocampal volume loss. PTSD was characterized by decreased nodal degree (orbitofrontal, anterior cingulate) and clustering coefficients (thalamus) but increased nodal betweenness (insula, orbitofrontal) and a reduced small world index in the whole brain analysis and by orbitofrontal and insular nodes with increased nodal degree, clustering coefficient and nodal betweenness in the restricted analysis. PTSD associated atrophy in the prefrontal-limbic network results in an increased structural connectivity within that network that negatively affected its integration with the rest of the brain.

Varying associations are reported between Five-Factor Model (FFM) personality traits and cardiovascular disease risk. Here, we further examine dispositional correlates of cardiometabolic risk within a hierarchical model of personality that proposes higher-order traits of Stability (shared variance of Agreeableness, Conscientiousness, inverse Neuroticism) and Plasticity (Extraversion, Openness), and we test hypothesized mediation via biological and behavioral factors. In an observational study of 856 community volunteers aged 30-54 years (46% male, 86% Caucasian), latent variable FFM traits (using multiple-informant reports) and aggregated cardiometabolic risk (indicators: insulin resistance, dyslipidemia, blood pressure, adiposity) were estimated using confirmatory factor analysis (CFA). The cardiometabolic factor was regressed on each personality factor or higher-order trait. Cross-sectional indirect effects via systemic inflammation, cardiac autonomic control, and physical activity were tested. CFA models confirmed the Stability "meta-trait," but not Plasticity. Lower Stability was associated with heightened cardiometabolic risk. This association was accounted for by inflammation, autonomic function, and physical activity. Among FFM traits, only Openness was associated with risk over and above Stability, and, unlike Stability, this relationship was unexplained by the intervening variables. A Stability meta-trait covaries with midlife cardiometabolic risk, and this association is accounted for by three candidate biological and behavioral factors.

OBJECTIVE Elevated blood pressure and the Apolipoprotein e4 allele (APOE e4) are independent risk factors for Alzheimer's disease. We sought to determine whether the combined presence of the APOE e4 allele and elevated blood pressure is associated with lower cognitive performance in cognitively healthy middle-aged adults. METHODS A total of 975 participants aged 30-54 (mean age = 44.47) were genotyped for APOE. Cardiometabolic risk factors including blood pressure, lipids, and glucose were assessed and cognitive function was measured using the Trail Making Test and the Visual Reproduction and Logical Memory subtests from the Wechsler Memory Scale. RESULTS Multivariable regression analysis showed that the association between APOE e4 and episodic memory performance varied as a function of systolic blood pressure (SBP), such that elevated SBP was predictive of poorer episodic memory performance only in APOE e4 carriers (β = -.092; t = -2.614; p = .009). Notably, this association was apparent at prehypertensive levels (≥130 mmHg), even after adjusting for physical activity, depression, smoking, and other cardiometabolic risk factors. CONCLUSIONS The joint presence of APOE e4 and elevated SBP, even at prehypertensive levels, is associated with lower cognitive performance in healthy, middle-aged adults. Results of this study suggest that the combination of APOE e4 and elevated SBP may synergistically compromise memory function well before the appearance of clinically significant impairments. Interventions targeting blood pressure control in APOE e4 carriers during midlife should be studied as a possible means to reduce the risk of cognitive decline in genetically susceptible samples.

Approximately half of people with post-traumatic stress disorder (PTSD) also suffer from Major Depressive Disorder (MDD). The current paper examines evidence for two explanations of this comorbidity. First, that the comorbidity reflects overlapping symptoms in the two disorders. Second, that the co-occurrence of PTSD and MDD is not an artifact, but represents a trauma-related phenotype, possibly a subtype of PTSD. Support for the latter explanation is inferred from literature that examines risk and biological correlates of PTSD and MDD, including molecular processes. Treatment implications of the comorbidity are considered.Aproximadamente la mitad de las personas con trastorno por estrés postraumático (TEPT) también sufren de un trastorno depresivo mayor (TDM). Este artículo examina la evidencia para dos explicaciones de esta co-morbilidad. Primero, que la comorbilidad refleja una sobreposición de síntomas en los dos trastornos. Segundo, que la ocurrencia simultánea de TEPT y TDM no es un artefacto, sino que representa un fenotipo relacionado con el trauma, posiblemente un subtipo de TEPT. El soporte para esta última explicación se infiere de la literatura que revisa el riesgo y los correlatos biológicos del TEPT y el TDM, incluyendo los procesos moleculares. También se consideran las repercusiones terapéuticas de esta comorbilidad.Environ la moitié des personnes qui présentent un trouble stress post-traumatique (TSPT) souffrent aussi d'un trouble dépressif caractérisé (majeur) (TDM). Cet article analyse les données relatives à deux explications de cette comorbidité. Premièrement, dans les deux troubles, la comorbidité révèle des symptômes de chevauchement. Deuxièmement, l'apparition concomitante d'un TSPT et d'un TDM n'est pas un artefact, mais représente un phénotype lié au traumatisme, probablement un sous-type de TSPT. La littérature, qui analyse le risque et les liens biologiques du TSPT et du TDM, y compris les processus moléculaires qui s'y rapportent, est en faveur de cette dernière explication. Nous examinons attentivement les implications thérapeutiques de cette comorbidité.

Genetic factors appear to be highly relevant to predicting differential risk for the development of post-traumatic stress disorder (PTSD). In a discovery sample, we conducted a genome-wide association study (GWAS) for PTSD using a small military cohort (Systems Biology PTSD Biomarkers Consortium; SBPBC, N = 147) that was designed as a case-controlled sample of highly exposed, recently returning veterans with and without combat-related PTSD. A genome-wide significant single nucleotide polymorphism (SNP), rs717947, at chromosome 4p15 (N = 147, β = 31.34, P = 1.28 × 10−8) was found to associate with the gold-standard diagnostic measure for PTSD (the Clinician Administered PTSD Scale). We conducted replication and follow-up studies in an external sample, a larger urban community cohort (Grady Trauma Project, GTP, N = 2006), to determine the robustness and putative functionality of this risk variant. In the GTP replication sample, SNP rs717947 associated with PTSD diagnosis in females (N = 2006, P = 0.005), but not males. SNP rs717947 was also found to be a methylation quantitative trait locus (meQTL) in the GTP replication sample (N = 157, P = 0.002). Further, the risk allele of rs717947 was associated with decreased medial and dorsolateral cortical activation to fearful faces (N = 53, P

Background Enhanced glucocorticoid receptor (GR) sensitivity is present in people with posttraumatic stress disorder (PTSD), but the molecular mechanisms of GR sensitivity are not understood. Epigenetic factors have emerged as one potential mechanism that account for how trauma exposure leads to sustained PTSD symptoms given that PTSD develops in only a subset of trauma survivors. Methods Cytosine methylation of a relevant promoter of the GR gene ( NR3C1 -1 F promoter) and three functional neuroendocrine markers of hypothalamic-pituitary-adrenal axis function were examined in a sample of 122 combat veterans. Results Lower NR3C1 -1 F promoter methylation in peripheral blood mononuclear cells (PBMCs) was observed in combat veterans with PTSD compared with combat-exposed veterans who did not develop PTSD. NR3C1 -1 F promoter methylation was also associated with three functional measures of glucocorticoid activity that have been associated with PTSD in combat veterans: PBMCs' lysozyme inhibition on the lysozyme suppression test, plasma cortisol decline on the low-dose (.50 mg) dexamethasone suppression test, and 24-hour urinary cortisol excretion. Finally, NR3C1 -1 F promoter methylation was inversely correlated with clinical markers and symptoms associated with PTSD. Conclusions Alterations in NR3C1 -1 F promoter methylation may reflect enduring changes resulting from combat exposure that lead to functional neuroendocrine alterations. Because epigenetic measures are thought to reflect enduring effects of environmental exposures, they may be useful in distinguishing combat-exposed veterans who do or do not develop PTSD.