Methylation of the AIM2 gene: An epigenetic mediator of PTSD-related inflammation and neuropathology plasma biomarkers.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with inflammation and various forms of chronic disease. The Absent in Melanoma 2 (AIM2) gene has been implicated in mechanisms of inflammation and anxiety, and methylation at a particular locus in this gene (cg10636246) has previously been shown to influence the association between PTSD and elevated C-reactive protein levels in blood. METHOD: We tested if this association might extend to other indicators of inflammation and to plasma-based measures of neuropathology in a cohort of post-9/11 US military veterans. Using a Bayesian approach, mediation models were tested cross-sectionally (n = 478) and longitudinally (n = 298). Peripheral markers of inflammation and neuropathology were measured with ultra-sensitive Single Molecule Array (Simoa®) technology. RESULTS: Analyses revealed indirect effects of PTSD symptom severity on peripheral indices of both inflammation (interleukin [IL]6, IL-10, tumor necrosis factor-α; indirect standardized [std.] ß range = 0.018-0.023, all p-values adjusted for multiple testing [padj ] < 0.05) and neuropathology (neurofilament light [NFL]; indirect std. ß = -0.018, padj = 0.02) via AIM2 methylation. This indirect effect was also evident when predicting IL-10 at a follow-up assessment (indirect std. ß = -0.018, padj = 0.04) controlling for baseline IL-10. CONCLUSIONS: Given that AIM2 methylation mediated the association between PTSD symptoms and multiple inflammatory and neuropathology markers, our results suggest that AIM2 methylation may offer clinical utility for indexing risk for adverse health outcomes associated with these peripheral indices of inflammation and neuropathology. Results also suggest a possible shared etiology underlying the frequent co-occurrence of inflammation and neuropathology.

Test-retest reliability of FreeSurfer automated hippocampal subfield segmentation within and across scanners.

The human hippocampus is vulnerable to a range of degenerative conditions and as such, accurate in vivo measurement of the hippocampus and hippocampal substructures via neuroimaging is of great interest for understanding mechanisms of disease as well as for use as a biomarker in clinical trials of novel therapeutics. Although total hippocampal volume can be measured relatively reliably, it is critical to understand how this reliability is affected by acquisition on different scanners, as multiple scanning platforms would likely be utilized in large-scale clinical trials. This is particularly true for hippocampal subregional measurements, which have only relatively recently been measurable through common image processing platforms such as FreeSurfer. Accurate segmentation of these subregions is challenging due to their small size, magnetic resonance imaging (MRI) signal loss in medial temporal regions of the brain, and lack of contrast for delineation from standard neuroimaging procedures. Here, we assess the test-retest reliability of the FreeSurfer automated hippocampal subfield segmentation procedure using two Siemens model scanners (a Siemens Trio and Prismafit Trio upgrade). T1-weighted images were acquired for 11 generally healthy younger participants (two scans on the Trio and one scan on the Prismafit). Each scan was processed through the standard cross-sectional stream and the recently released longitudinal pipeline in FreeSurfer v6.0 for hippocampal segmentation. Test-retest reliability of the volumetric measures was examined for individual subfields as well as percent volume difference and Dice overlap among scans and intra-class correlation coefficients (ICC). Reliability was high in the molecular layer, dentate gyrus, and whole hippocampus with the inclusion of three time points with mean volume differences among scans less than 3%, overlap greater than 80%, and ICC >0.95. The parasubiculum and hippocampal fissure showed the least improvement in reliability with mean volume difference greater than 5%, overlap less than 70%, and ICC scores ranging from 0.78 to 0.89. Other subregions, including the CA regions, were stable in their mean volume difference and overlap (<5% difference and >75% respectively) and showed improvement in reliability with the inclusion of three scans (ICC â€‹> â€‹0.9). Reliability was generally higher within scanner (Trio-Trio), however, Trio-Prismafit reliability was also high and did not exhibit an obvious bias. These results suggest that the FreeSurfer automated segmentation procedure is a reliable method to measure total as well as hippocampal subregional volumes and may be useful in clinical applications including as an endpoint for future clinical trials of conditions affecting the hippocampus.

Lower stress-reactive cortisol in female veterans associated with military status but not PTSD.

Female veterans are a growing yet understudied population. Currently, 14.6% of all troops deployed to Afghanistan and Iraq are female. Military service is associated with an increased risk for trauma exposure and subsequent development of posttraumatic stress disorder (PTSD). Dysregulation of the hypothalamic-pituitary-adrenal axis is frequently associated with PTSD. Few studies have examined females diagnosed with PTSD and only one study, to our knowledge, has examined HPA-axis dysregulation in female veterans. This study examined salivary cortisol in 52 female veterans and civilians both with and without PTSD. We collected saliva samples at bedtime and awakening, as well as in response to the Trier social stress test (TSST). We found that female veterans had blunted cortisol concentrations at all time points during the TSST compared to female civilians, regardless of PTSD status. Even though all groups showed the expected diurnal decline in cortisol, the difference between awakening and bedtime samples were significant only in civilians without PTSD. The results of our study suggest that stressors specific to the military may lead to lower than normal cortisol, which may not be associated with the expressions of PTSD.

Referent-oriented interactions in infancy: A naturalistic, longitudinal case study from an English-speaking household.

Caregivers use a of combination labeling, pointing, object grasping, and gaze to communicate with infants about referents in their environment. By two years of age, children reliably use these referent-oriented cues to communicate and learn. While there is some evidence from lab-based studies that younger infants attend to and use referent-oriented cues during communication, some more naturalistic studies have found that in the first year of life, infants do not robustly leverage these cues during dyadic interactions. The current study examined parent and infant gaze, touching, pointing, and reaching to referents for a wide range of nouns, verbs, adjectives, and other early-learned words during 59 one-hour head-camera recordings sampled from one English-learning infants' life between 6 and 12 months of age. We found substantial variability across individual words for all cues. Some variability was explained by referent concreteness and the grammatical category of the label. The parent's touching of labeled referents increased across months, suggesting that parent-infant-referent interactions may change with development. Future studies should investigate the trajectories of specific types of words and contexts, rather than attempting to discover possibly non-existent universal trajectories of parent and infant referent-oriented behaviors.

Genetic Risk for Alzheimer Disease and Plasma Tau Are Associated With Accelerated Parietal Cortex Thickness Change in Middle-Aged Adults.

Background and Objectives: Neuroimaging and biomarker studies in Alzheimer disease (AD) have shown well-characterized patterns of cortical thinning and altered biomarker concentrations of tau and ß-amyloid (Aß). However, earlier identification of AD has great potential to advance clinical care and determine candidates for drug trials. The extent to which AD risk markers relate to cortical thinning patterns in midlife is unknown. The first objective of this study was to examine cortical thickness change associated with genetic risk for AD among middle-aged military veterans. The second objective was to determine the relationship between plasma tau and Aß and change in brain cortical thickness among veterans stratified by genetic risk for AD. Methods: Participants consisted of post-9/11 veterans (N = 155) who were consecutively enrolled in the Translational Research Center for TBI and Stress Disorders prospective longitudinal cohort and were assessed for mild traumatic brain injury (TBI) and posttraumatic disorder (PTSD). Genome-wide polygenic risk scores (PRSs) for AD were calculated using summary results from the International Genomics of Alzheimer's Disease Project. T-tau and Aß40 and Aß42 plasma assays were run using Simoa technology. Whole-brain MRI cortical thickness change estimates were obtained using the longitudinal stream of FreeSurfer. Follow-up moderation analyses examined the AD PRS × plasma interaction on change in cortical thickness in AD-vulnerable regions. Results: Higher AD PRS, signifying greater genetic risk for AD, was associated with accelerated cortical thickness change in a right hemisphere inferior parietal cortex cluster that included the supramarginal gyrus, angular gyrus, and intraparietal sulcus. Higher tau, but not Aß42/40 ratio, was associated with greater cortical thickness change among those with higher AD PRS. Mild TBI and PTSD were not associated with cortical thickness change. Discussion: Plasma tau, particularly when combined with genetic stratification for AD risk, can be a useful indicator of brain change in midlife. Accelerated inferior parietal cortex changes in midlife may be an important factor to consider as a marker of AD-related brain alterations.

Intimate Partner Violence Predicts Posttraumatic Stress Disorder Severity Independent of Early Life and Deployment-Related Trauma in Deployed Men and Women Veterans.

Intimate partner violence (IPV) refers to emotional, physical, and/or sexual abuse perpetrated by a current or former partner. IPV affects both genders, though little is known about its effects on men as victims. The aims of this study were to determine if IPV is a factor contributing to posttraumatic stress disorder (PTSD) severity independently of deployment-related trauma, and to determine if there are gender differences in these associations. Participants were 46 female and 471 male post-9/11 veterans. Four sequential regressions were employed to examine the independent contribution of IPV among multiple trauma types on PTSD severity in men and women at two epochs, post-deployment (participants were anchored to deployment-related PTSD symptoms) and current (within the past month). Models were significant for both epochs in men (ps < .001) but not in women (ps > .230). In men, IPV independently predicted PTSD severity in both epochs (ß > .093). However, in women, early life trauma (ß = .284), but not IPV was a significant and independent predictor for current PTSD. Thus, there are distinct gender differences in how trauma type contributes to PTSD symptom severity. Although the statistical models were not significant in women, we observed similar patterns of results as in men and, in some cases, the ß was actually higher in women than in men, suggesting a lack of power in our analyses. More research is clearly needed to follow-up these results; however, our findings indicate that IPV is a contributing factor to PTSD severity in veterans.

Plasma biomarkers associated with deployment trauma and its consequences in post-9/11 era veterans: initial findings from the TRACTS longitudinal cohort.

Mild traumatic brain injury (mTBI) is among the most common injuries sustained by post-9/11 veterans; however, these injuries often occur within the context of psychological trauma. Blast exposure, even in the absence of a diagnosable TBI, leads to changes in neural connectivity and congitive functioning. Therefore, considering clinical comorbidities and injury characteristics is critical to understanding the long-term effects of mTBI. Research is moving towards identifying diagnostic and prognostic blood-based biomarkers for TBI; however, few studies include other prevalent clinical and medical comorbidities related to deployment. Here, we present the initial cross-sectional relationships between plasma biomarkers, clinical, and medical comorbidities in a well-characterized longitudinal sample of 550 post-9/11 veteran men and women. We examined biomarkers associated with inflammation (interleukin 6 and 10, tumor necrosis factor α, and eotaxin) and neurodegeneration (neurofilament light, glial fibrillary acidic protein (GFAP), tau, brain derived neurotrophic factor, amyloid ß 40 and 42, phosphorylated neurofilament heavy chain, and neuron specific enolase). Univariate analyses of covariance (ANCOVA) were conducted to determine mean level differences between close blast (blasts that occur within 0-10 meters) and mTBI groups. Our primary findings were twofold: (1) Inflammatory markers were consistently higher in participants exposed to close blasts and were strongly related to deployment-related psychopathology. (2) GFAP was consistently lower in participants exposed to blast and mTBI and lower GFAP was associated with more severe psychological symptoms. More research is clearly needed; however, our findings indicate that chronic increased inflammation and decreased GFAP may be related to close blast exposure.

The association between blast exposure and transdiagnostic health symptoms on systemic inflammation.

Chronic elevation of systemic inflammation is observed in a wide range of disorders including PTSD, depression, and traumatic brain injury. Although previous work has demonstrated a link between inflammation and various diagnoses separately, few studies have examined transdiagnostic symptoms and inflammation within the same model. The objective of this study was to examine relationships between psychiatric and health variables and systemic inflammation and to determine whether mild traumatic brain injury (mTBI) and/or exposure to blast munitions moderate these relationships. Confirmatory factor analysis in a large sample (N = 357) of post-9/11 Veterans demonstrated a good fit to a four-factor model reflecting traumatic stress, affective, somatic, and metabolic latent variables. Hierarchical regression models revealed that each of the latent variables were associated with higher levels of systemic inflammation. However, the strongest relationship with inflammation emerged among those who had both war-zone blast exposures and metabolic dysregulation, even after adjusting for mental health latent variables. Exploratory analyses showed that blast exposure was associated with metabolic dysregulation in a dose-response manner, with self-reported closer blast proximity associated with the greatest metabolic dysregulation. Together, these results provide a greater understanding of the types of symptoms most strongly associated with inflammation and underscore the importance of maintaining a healthy lifestyle to reduce the impact of obesity and other metabolic symptoms on future chronic disease in younger to middle-aged Veterans.

Trauma-related psychiatric and behavioral conditions are uniquely associated with sustained attention dysfunction.

OBJECTIVE: It is increasingly recognized that trauma victims, particularly Veterans, have co-occurring psychological and physical conditions that impact cognition, especially the domains of sustained attention and executive functioning. Although previous work has generally attempted to isolate the unique cognitive effects of common combat-related comorbidities, less work has been done to examine how these conditions co-occur, and whether unique cognitive signatures accompany certain clinical combinations. METHOD: To address this gap, we examined how several deployment-related conditions were associated with performance on a well-validated measure of sustained attention (i.e., gradual onset continuous performance task [gradCPT]) and a battery of standard neuropsychological measures in 123 Veterans from the Translational Research Center for TBI and Stress Disorders. Initially, a Principal component analysis was conducted to investigate how comorbid conditions grouped together. RESULTS: Several sustained attention measures from the gradCPT were differentially associated with four unique combinations of trauma-related pathology. Specifically, a somatic component representing the combination of current pain, sleep disturbance, and mild traumatic brain injury was associated with a higher rate of failures of attentional engagement. On the other hand, a comorbid posttraumatic stress disorder (PTSD) and mood disorder component (moodPTSD), as well as a substance use disorder component, were associated with higher rates of inhibitory control failures. Increased attentional instability was associated with moodPTSD as well as an anxiety disorder component. In contrast, the cognitive effects of deployment-related trauma were not observed on standard neuropsychological measures. CONCLUSION: These findings suggest that unique combinations of trauma-related pathology have dissociable effects on sustained attentional control. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

A non-enzyme cascade amplification strategy for colorimetric assay of disease biomarkers.

A non-enzyme cascade amplification strategy, based on the dissolution of Ag nanoparticles and a Pt nanocube-catalyzed reaction, for colorimetric assay of disease biomarkers was developed. This strategy overcomes the intrinsic limitations of enzymes involved in conventional enzymatic amplification techniques, thanks to the utilization of noble-metal nanostructures with superior properties.

Structural and Functional MRI Differences in Master Sommeliers: A Pilot Study on Expertise in the Brain.

Our experiences, even as adults, shape our brains. Regional differences have been found in experts, with the regions associated with their particular skill-set. Functional differences have also been noted in brain activation patterns in some experts. This study uses multimodal techniques to assess structural and functional patterns that differ between experts and non-experts. Sommeliers are experts in wine and thus in olfaction. We assessed differences in Master Sommeliers' brains, compared with controls, in structure and also in functional response to olfactory and visual judgment tasks. MRI data were analyzed using voxel-based morphometry as well as automated parcellation to assess structural properties, and group differences between tasks were calculated. Results indicate enhanced volume in the right insula and entorhinal cortex, with the cortical thickness of the entorhinal correlating with experience. There were regional activation differences in a large area involving the right olfactory and memory regions, with heightened activation specifically for sommeliers during an olfactory task. Our results indicate that sommeliers' brains show specialization in the expected regions of the olfactory and memory networks, and also in regions important in integration of internal sensory stimuli and external cues. Overall, these differences suggest that specialized expertise and training might result in enhancements in the brain well into adulthood. This is particularly important given the regions involved, which are the first to be impacted by many neurodegenerative diseases.

The Chest Pain Choice trial: a pilot randomized trial of a decision aid for patients with chest pain in the emergency department.

BACKGROUND: Chest pain is a common presenting complaint in the emergency department (ED). Despite the frequency with which clinicians evaluate patients with chest pain, accurately determining the risk of acute coronary syndrome (ACS) and sharing risk information with patients is challenging. The aims of this study are (1) to develop a decision aid (CHEST PAIN CHOICE) that communicates the short-term risk of ACS and (2) to evaluate the impact of the decision aid on patient participation in decision-making and resource use. METHODS/DESIGN: This is a protocol for a parallel, 2-arm randomized trial to compare an intervention group receiving CHEST PAIN CHOICE to a control group receiving usual ED care. Adults presenting to the Saint Mary's Hospital ED in Rochester, MN USA with a primary complaint of chest pain who are being considered for admission for prolonged ED observation in a specialized unit and urgent cardiac stress testing will be eligible for enrollment. We will measure the effect of CHEST PAIN CHOICE on six outcomes: (1) patient knowledge regarding their short-term risk for ACS and the risks of radiation exposure; (2) quality of the decision making process; (3) patient and clinician acceptability and satisfaction with the decision aid; (4) the proportion of patients who decided to undergo observation unit admission and urgent cardiac stress testing; (5) economic costs and healthcare utilization; and (6) the rate of delayed or missed ACS. To capture these outcomes, we will administer patient and clinician surveys after each visit, obtain video recordings of the clinical encounters, and conduct 30-day phone follow-up. DISCUSSION: This pilot randomized trial will develop and evaluate a decision aid for use in ED chest pain patients at low risk for ACS and provide a preliminary estimate of its effect on patient participation in decision-making and resource use. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT01077037.