Epigenetic age estimations based on DNA methylation (DNAm) can predict human chronological age with a high level of accuracy. These DNAm age algorithms can also be used to index advanced cellular age, when estimated DNAm age exceeds chronological age. Advanced DNAm age has been associated with several diseases and metabolic and inflammatory pathology, but the causal direction of this association is unclear. The goal of this study was to examine potential bidirectional associations between advanced epigenetic age and metabolic and inflammatory markers over time in a longitudinal cohort of 179 veterans with a high prevalence of posttraumatic stress disorder (PTSD) who were assessed over the course of two years. Analyses focused on two commonly investigated metrics of advanced DNAm age derived from the Horvath (developed across multiple tissue types) and Hannum (developed in whole blood) DNAm age algorithms. Results of cross-lagged panel models revealed that advanced Hannum DNAm age at Time 1 (T1) was associated with increased (i.e., accounting for T1 levels) metabolic syndrome (MetS) severity at Time 2 (T2; p = 0.001). This association was specific to worsening lipid panels and indicators of abdominal obesity (p = 0.001). In contrast, no baseline measures of inflammation or metabolic pathology were associated with changes in advanced epigenetic age over time. No associations emerged between advanced Horvath DNAm age and any of the examined biological parameters. Results suggest that advanced epigenetic age, when measured using an algorithm developed in whole blood, may be a prognostic marker of pathological metabolic processes. This carries implications for understanding pathways linking advanced epigenetic age to morbidity and mortality.

OBJECTIVE: Cognitive performance in trauma-exposed populations, such as combat Veterans, has been shown to be worse than in nonexposed peers. However, cognitive performance has typically been within the normal range (within 1 SD of normative mean), and the prevalence of clinically significant cognitive dysfunction (i.e., performance more than 1 SD below the mean on multiple measures in a domain) in younger adults with trauma exposure remains unknown. The objective of our study was to measure this. METHOD: We applied Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) cutoffs for clinically significant cognitive dysfunction (>1 SD below the mean in multiple measures within a domain) in the domains of memory, executive function, and attention to a sample of combat-exposed Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND; N = 368, mean age = 31.7 years, 90% men) Veterans. We then compared psychiatric, physiological, and neural measures, as well as functional outcomes, between those with and without cognitive dysfunction. RESULTS: Veterans with cognitive dysfunction (n = 129, 35.1%) had lower premorbid reading ability and more severe psychological distress, including increased anxiety, depression, posttraumatic stress disorder (PTSD), sleep difficulties, pain, and alcohol consumption. Those with cognitive dysfunction also had worse functional outcomes, with mild but significant disability. In contrast, we found associations between outcome and age, traumatic brain injury, physiological and neural measures to be weak or not significant. CONCLUSIONS: Together, this suggests that premorbid abilities and trauma-related psychological symptoms contribute significantly to cognitive dysfunction in OEF/OIF/OND Veterans, and that neurological insult and aging may play less of a role. Cognitive dysfunction may be at least partially ameliorated by treating trauma-related symptoms. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Military personnel are often exposed to multiple instances of various types of head trauma. As a result, there has been increasing concern recently over identifying when head trauma has resulted in a brain injury and what, if any, long-term consequences those brain injuries may have. Efforts to develop equipment to protect soldiers from these long-term consequences will first require understanding the types of head trauma that are likely responsible. In this study, we sought to identify the types of head trauma most likely to lead to the deposition of tau, a protein identified as a likely indicator of long-term negative consequences of brain injury. To define the types of head trauma in a military population, we applied a factor analysis to interviews from a larger cohort of 428 Veterans enrolled in the Translational Research Center for Traumatic Brain Injury and Stress Disorders. Three factors were identified: Blast Exposure, Symptom Duration, and Blunt Concussion. Sixteen male Veterans from this study and one additional male civilian (aged 25–69, mean 35.2 years) underwent simultaneous positron emission tomography/magnetic resonance imaging using a tracer that binds to tau protein, the ligand T807/AV-1451 (Flortaucipir). Standard uptake value ratios to the isthmus of the cingulate were calculated from a 20-minute time frame 70 min post-injection. We found that tracer uptake throughout the brain was associated with Blast Exposure factor beta weights, but not with either Symptom Duration or Blunt Concussion. Associations with uptake were located primarily in the cerebellar, occipital, inferior temporal and frontal regions. The data suggest that in this small, relatively young cohort of Veterans, elevated T807/AV-1451 uptake is associated with exposure to blast neurotrauma. These findings are unanticipated, as they do not match histopathological descriptions of tau pathology associated with head trauma. Continued work will be necessary to understand the nature of the regional T807/AV-1451 uptake and any associations with clinical symptoms.

Objective: Confirmatory factor analysis (CFA) has previously been employed to examine the latent factor structure of posttraumatic stress disorder (PTSD) symptoms with mixed results. A limited number of studies examined PTSD factor structure among veterans of recent military conflicts. This study examined the relationship between PTSD factor structure and the hallmark conditions of these conflicts, mild traumatic brain injury (mTBI) and close-range blast exposure (CBE).Method: The fit of previously proposed PTSD factor models was compared in a cohort of 387 combat-exposed veterans, with stratified analyses comparing factor structure models between those with a history of military-related mTBI and CBE (n = 106) and those without either of these antecedents (n = 151). CFAs were conducted using criteria from the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994).Results: The 4-factor emotional numbing (EN) model yielded the best fit when using a clinician-administered assessment of PTSD symptoms regardless of mTBI/CBE exposure status. However, when using a self-report measure of PTSD symptom severity, the EN model yielded best fit for those with mTBI/CBE exposure history while the 5-factor dysphoric arousal (DA) model was preferable among combat-exposed veterans with no history of mTBI/CBE exposure.Conclusions: Factors including mTBI and blast exposure and type of assessment tools must be considered when determining preferable PTSD latent factor structure models. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

BACKGROUND: Externalizing disorders are known to be partly heritable, but the biological pathways linking genetic risk to the manifestation of these costly behaviors remain under investigation. This study sought to identify neural phenotypes associated with genomic vulnerability for externalizing disorders. METHODS: One-hundred fifty-five White, non-Hispanic veterans were genotyped using a genome-wide array and underwent resting-state functional magnetic resonance imaging. Genetic susceptibility was assessed using an independently developed polygenic score (PS) for externalizing, and functional neural networks were identified using graph theory based network analysis. Tasks of inhibitory control and psychiatric diagnosis (alcohol/substance use disorders) were used to measure externalizing phenotypes. RESULTS: A polygenic externalizing disorder score (PS) predicted connectivity in a brain circuit (10 nodes, nine links) centered on left amygdala that included several cortical [bilateral inferior frontal gyrus (IFG) pars triangularis, left rostral anterior cingulate cortex (rACC)] and subcortical (bilateral amygdala, hippocampus, and striatum) regions. Directional analyses revealed that bilateral amygdala influenced left prefrontal cortex (IFG) in participants scoring higher on the externalizing PS, whereas the opposite direction of influence was observed for those scoring lower on the PS. Polygenic variation was also associated with higher Participation Coefficient for bilateral amygdala and left rACC, suggesting that genes related to externalizing modulated the extent to which these nodes functioned as communication hubs. CONCLUSIONS: Findings suggest that externalizing polygenic risk is associated with disrupted connectivity in a neural network implicated in emotion regulation, impulse control, and reinforcement learning. Results provide evidence that this network represents a genetically associated neurobiological vulnerability for externalizing disorders.

Evidence suggests that blast exposure has profound negative consequences for the health of the human brain, and that it may confer risk for the development of neurodegenerative diseases such as chronic traumatic encephalopathy and Alzheimer's disease (AD). Although the molecular mechanisms linking blast exposure to subsequent neurodegeneration is an active focus of research, recent studies suggest that genetic risk for AD may elevate the risk of neurodegeneration following traumatic brain injury (TBI). However, it is currently unknown if blast exposure also interacts with AD risk to promote neurodegeneration. In this study we examined whether apolipoprotein (APOE) ɛ4, a well-known genetic risk factor for AD, influenced the relationship between blast exposure and white matter integrity in a cohort of 200 Iraq and Afghanistan war veterans. Analyses revealed a significant interaction between close-range blast exposure (CBE) (close range being within 10 m) and APOE ɛ4 carrier status in predicting white matter abnormalities, measured by a voxelwise cluster-based method that captures spatial heterogeneity in white matter disruptions. This interaction remained significant after controlling for TBI, pointing to the specificity of CBE and APOE in white matter disruptions. Further, among veteran ɛ4 carriers exposed to close-range blast, we observed a positive association between the number of CBEs and the number of white matter abnormalities. These results raise the possibility that CBE interacts with AD genetic influences on neuropathological processes such as the degradation of white matter integrity.

Background:Evidence suggests that single nucleotide polymorphisms (SNPs) in genes involved in serotonergic signaling and stress response pathways moderate associations between PTSD and cortical thickness. This study examined a genetic regulator of these pathways, the PPM1F gene, which has also been implicated in mechanisms of stress responding and is differentially expressed in individuals with comorbid PTSD and depression compared to controls.Methods:Drawing from a sample of 240 white non-Hispanic trauma-exposed veterans, we tested 18 SNPs spanning the PPM1F gene for association with PTSD and cortical thickness.Results:Analyses revealed six PPM1F SNPs that moderated associations between PTSD symptom severity and cortical thickness of bilateral superior frontal and orbitofrontal regions as well as the right pars triangularis (all corrected p’s0.05) such that greater PTSD severity was related to reduced cortical thickness as a function of genotype. A whole-cortex vertex-wise analysis using the most associated SNP (rs9610608) revealed this effect to be localized to a cluster in the right superior frontal gyrus (cluster-corrected p0.02).Limitations:Limitations of this study include the small sample size and that the sample was all-white, non-Hispanic predominately male veterans.Conclusions:These results extend prior work linking PPM1F to PTSD and suggest that variants in this gene may have bearing on the neural integrity of the prefrontal cortex (PFC).

BACKGROUND: Posttraumatic stress disorder (PTSD) and stress/trauma exposure are cross-sectionally associated with advanced DNA methylation age relative to chronological age. However, longitudinal inquiry and examination of associations between advanced DNA methylation age and a broader range of psychiatric disorders is lacking. The aim of this study was to examine if PTSD, depression, generalized anxiety, and alcohol-use disorders predicted acceleration of DNA methylation age over time (i.e. an increasing pace, or rate of advancement, of the epigenetic clock). METHODS: Genome-wide DNA methylation and a comprehensive set of psychiatric symptoms and diagnoses were assessed in 179 Iraq/Afghanistan war veterans who completed two assessments over the course of approximately 2 years. Two DNA methylation age indices (Horvath and Hannum), each a weighted index of an array of genome-wide DNA methylation probes, were quantified. The pace of the epigenetic clock was operationalized as change in DNA methylation age as a function of time between assessments. RESULTS: Analyses revealed that alcohol-use disorders (p = 0.001) and PTSD avoidance and numbing symptoms (p = 0.02) at Time 1 were associated with an increasing pace of the epigenetic clock over time, per the Horvath (but not the Hannum) index of cellular aging. CONCLUSIONS: This is the first study to suggest that posttraumatic psychopathology is longitudinally associated with a quickened pace of the epigenetic clock. Results raise the possibility that accelerated cellular aging is a common biological consequence of stress-related psychopathology, which carries implications for identifying mechanisms of stress-related cellular aging and developing interventions to slow its pace.

BACKGROUND: Longevity gene klotho (KL) is associated with age-related phenotypes but has not been evaluated against a direct human biomarker of cellular aging. We examined KL and psychiatric stress, including posttraumatic stress disorder (PTSD), which is thought to potentiate accelerated aging, in association with biomarkers of cellular aging. METHODS: The sample comprised 309 white, non-Hispanic genotyped veterans with measures of epigenetic age (DNA methylation age), telomere length (n = 252), inflammation (C-reactive protein), psychiatric symptoms, metabolic function, and white matter neural integrity (diffusion tensor imaging; n = 185). Genotyping and DNA methylation were obtained on epi/genome-wide beadchips. RESULTS: In gene by environment analyses, two KL variants (rs9315202 and rs9563121) interacted with PTSD severity (peak corrected p = 0.044) and sleep disturbance (peak corrected p = 0.034) to predict advanced epigenetic age. KL variant, rs398655, interacted with self-reported pain in association with slowed epigenetic age (corrected p = 0.048). A well-studied protective variant, rs9527025, was associated with slowed epigenetic age (p = 0.046). The peak PTSD interaction term (with rs9315202) also predicted C-reactive protein (p = 0.049), and white matter microstructural integrity in two tracts (corrected ps = 0.005 - 0.035). This SNP evidenced a main effect with an index of metabolic syndrome severity (p = 0.015). Effects were generally accentuated in older subjects. CONCLUSIONS: Rs9315202 predicted multiple biomarkers of cellular aging such that psychiatric stress was more strongly associated with cellular aging in those with the minor allele. KL genotype may contribute to a synchronized pathological aging response to stress and could be a therapeutic target to alter the pace of cellular aging.