Aoife O’Donovan

Pessimism correlates with leukocyte telomere shortness and elevated interleukin-6 in post-menopausal women

The combination of less positive and more negative expectations for the future (i.e., lower optimism and higher pessimism) increases risk for disease and early mortality. We tested the possibility that expectancies might influence health outcomes by altering the rate of biological aging, specifically of the immune system (immunosenescence). However, no studies to date have examined associations between optimism or pessimism and indicators of immunosenescence such as leukocyte telomere length (TL) and interleukin-6 (IL-6) levels. We investigated whether dispositional tendencies towards optimism and pessimism were associated with TL and IL-6 in a sample of 36 healthy post-menopausal women. Multiple regression analyses where optimism and pessimism were entered simultaneously, and chronological age and caregiver status were controlled, indicated that pessimism was independently associated with shorter TL (beta=-.68, p=.001) and higher IL-6 concentrations (beta=.50, p=.02). In contrast, optimism was not independently associated with either measure of immunosenescence. These findings suggest that dispositional pessimism may increase IL-6 and accelerate rate of telomere shortening. Mechanistic causal relationships between these parameters need to be investigated.

Stress appraisals and cellular aging: A key role for anticipatory threat in the relationship between psychological stress and telomere length

Chronic psychological stress is a risk factor for multiple diseases of aging. Accelerated cellular aging as indexed by short telomere length has emerged as a potential common biological mechanism linking various forms of psychological stress and diseases of aging. Stress appraisals determine the degree and type of biological stress responses and altered stress appraisals may be a common psychological mechanism linking psychological stress and diseases of aging. However, no previous studies have examined the relationship between stress appraisals and telomere length. We exposed chronically stressed female caregivers and non-caregiving controls (N=50; M age=62.14±6.10) to a standardized acute laboratory stressor and measured their anticipatory and retrospective threat and challenge appraisals of the stressor. We hypothesized that threat and challenge appraisals would be associated with shorter and longer telomere length respectively, and that chronic caregiving stress would influence telomere length through altered stress appraisals. Higher anticipatory threat appraisals were associated with shorter age-adjusted telomere length (β=-.32, p=.03), but challenge appraisals and retrospective threat appraisals showed no independent association with telomere length. Caregivers reported significantly higher anticipatory (β=-.36, p=.006) and retrospective (β=-.29, p=.03) threat appraisals than controls, but similar challenge appraisals. Although there was no significant main effect of caregiver status on telomere length, caregiving had a significant indirect effect on telomere length through anticipatory threat appraisals. Exaggerated anticipatory threat appraisals may be a common and modifiable psychological mechanism of psychological stress effects on cellular aging.

Elevated Risk for Autoimmune Disorders in Iraq and Afghanistan Veterans with Posttraumatic Stress Disorder

BACKGROUND Posttraumatic stress disorder (PTSD) is associated with endocrine and immune abnormalities that could increase risk for autoimmune disorders. However, little is known about the risk for autoimmune disorders among individuals with PTSD. METHODS We conducted a retrospective cohort study of 666,269 Iraq and Afghanistan veterans under age 55 who were enrolled in the Department of Veterans Affairs health care system between October 7, 2001, and March 31, 2011. Generalized linear models were used to examine if PTSD, other psychiatric disorders, and military sexual trauma exposure increased risk for autoimmune disorders, including thyroiditis, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and lupus erythematosus, adjusting for age, gender, race, and primary care visits. RESULTS PTSD was diagnosed in 203,766 veterans (30.6%), and psychiatric disorders other than PTSD were diagnosed in an additional 129,704 veterans (19.5%). Veterans diagnosed with PTSD had significantly higher adjusted relative risk (ARR) for diagnosis with any of the autoimmune disorders alone or in combination compared with veterans with no psychiatric diagnoses (ARR = 2.00; 95% confidence interval, 1.91-2.09) and compared with veterans diagnosed with psychiatric disorders other than PTSD (ARR = 1.51; 95% confidence interval, 1.43-1.59; p < .001). The magnitude of the PTSD-related increase in risk for autoimmune disorders was similar in women and men, and military sexual trauma exposure was independently associated with increased risk in both women and men. CONCLUSIONS Trauma exposure and PTSD may increase risk for autoimmune disorders. Altered immune function, lifestyle factors, or shared etiology may underlie this association.

Oxytocin administration enhances controlled social cognition in patients with schizophrenia

BACKGROUND Individuals with schizophrenia have functionally significant deficits in automatic and controlled social cognition, but no currently available pharmacologic treatments reduce these deficits. The neuropeptide oxytocin has multiple prosocial effects when administered intranasally in humans and there is growing interest in its therapeutic potential in schizophrenia. METHODS We administered 40 IU of oxytocin and saline placebo intranasally to 29 male subjects with schizophrenia and 31 age-matched, healthy controls in a randomized, double-blind, placebo-controlled, cross-over study. Social cognition was assessed with The Awareness of Social Inference Test (TASIT) and the Reading the Mind in the Eyes Test (RMET). We examined the effects of oxytocin administration on automatic social cognition (the ability to rapidly interpret and understand emotional cues from the voice, face, and body); controlled social cognition (the ability to comprehend indirectly expressed emotions, thoughts, and intentions through complex deliberations over longer time periods); and a control task (the ability to comprehend truthful dialog and perform general task procedures) in individuals with and without schizophrenia using mixed factorial analysis of variance models. RESULTS Patients with schizophrenia showed significant impairments in automatic and controlled social cognition compared to healthy controls, and administration of oxytocin significantly improved their controlled, but not automatic, social cognition, F(1, 58)=8.75; p=0.004. Conversely, oxytocin administration had limited effects on social cognition in healthy participants. Patients and controls performed equally well and there were no effects of oxytocin administration on the control task. DISCUSSION Intact social cognitive abilities are associated with better functional outcomes in individuals with schizophrenia. Our data highlight the potentially complex effects of oxytocin on some but not all aspects of social cognition, and support the exploration of intranasal oxytocin as a potential adjunct treatment to improve controlled social cognition in schizophrenia.

Suppressed monocyte gene expression profile in men versus women with PTSD

There have been several attempts to use gene microarrays from peripheral blood mononuclear cells to identify new biological pathways or targets for therapy in Posttraumatic Stress Disorder (PTSD). The few studies conducted to date have yielded an unclear pattern of findings, perhaps reflecting the use of heterogeneous samples of circulating immune cells for analysis. We used gene microarrays on a homogeneous sample of circulating monocytes to test the hypothesis that chronic PTSD would be associated with elevated inflammatory activity and to identify new pathways dysregulated in the disorder. Forty-nine men (24 PTSD+ and 25 age-matched trauma-exposed PTSD- controls) and 18 women (10 PTSD+ and 8 age-matched PTSD- controls) were recruited. Gene expression microarray analysis was performed on CD14+ monocytes, immune cells that initiate and respond to inflammatory signaling. Male subjects with PTSD had an overall pattern of under-expression of genes on monocytes (47 under-expressed versus 4 over-expressed genes). A rigorous correction for multiple comparisons and verification with qPCR showed that of only 3 genes that were differentially expressed, all were under-expressed. There was no transcriptional evidence of chronic inflammation in male PTSD+ subjects. In contrast, preliminary data from our pilot female PTSD+ subjects showed a relatively balanced pattern of increased and decreased expression of genes and an increase in activity of pathways related to immune activation. The results indicate differential patterns of monocyte gene expression in PTSD, and the preliminary data from our female pilot subjects are suggestive of gender dimorphism in biologic pathways activated in PTSD. Changes in immune cell gene expression may contribute to medical morbidity in PTSD.

Altered inflammatory activity associated with reduced hippocampal volume and more severe posttraumatic stress symptoms in Gulf War veterans

BACKGROUND Inflammation may reduce hippocampal volume by blocking neurogenesis and promoting neurodegeneration. Posttraumatic stress disorder (PTSD) has been linked with both elevated inflammation and reduced hippocampal volume. However, few studies have examined associations between inflammatory markers and hippocampal volume, and none have examined these associations in the context of PTSD. METHODS We measured levels of the inflammatory markers interleukin-6 (IL-6) and soluble receptor II for tumor necrosis factor (sTNF-RII) as well as hippocampal volume in 246 Gulf War veterans with and without current and past PTSD as assessed with the Clinician Administered PTSD Scale (CAPS). Enzyme-linked immunosorbent assays were used to measure inflammatory markers, and 1.5Tesla magnetic resonance imaging (MRI) and Freesurfer version 4.5 were used to quantify hippocampal volume. Hierarchical linear regression and analysis of covariance models were used to examine if hippocampal volume and PTSD status would be associated with elevated levels of IL-6 and sTNF-RII. RESULTS Increased sTNF-RII, but not IL-6, was significantly associated with reduced hippocampal volume (β=-0.14, p=0.01). The relationship between sTNF-RII and hippocampal volume was independent of potential confounds and covariates, including PTSD status. Although we observed no PTSD diagnosis-related differences in either IL-6 or sTNF-RII, higher PTSD severity was associated with significantly increased sTNF-RII (β=0.24, p=0.04) and reduced IL-6 levels (β=-0.24, p=0.04). CONCLUSIONS Our results indicate that specific inflammatory proteins may be associated with brain structure and function as indexed by hippocampal volume and PTSD symptoms.

Posttraumatic stress Disorder, adverse childhood events, and Buccal cell Telomere length in elderly swiss Former indentured child laborers

Posttraumatic stress disorder (PTSD) is associated with increased risk for age-related diseases and early mortality. Accelerated biological aging could contribute to this elevated risk. The aim of the present study was to assess buccal cell telomere length (BTL) – a proposed marker of biological age – in men and women with and without PTSD. The role of childhood trauma was assessed as a potential additional risk factor for shorter telomere length. The sample included 62 former indentured Swiss child laborers (age: M = 76.19, SD = 6.18) and 58 healthy controls (age: M = 71.85, SD = 5.97). Structured clinical interviews were conducted to screen for PTSD and other psychiatric disorders. The Childhood Trauma Questionnaire (CTQ) was used to assess childhood trauma exposure. Quantitative polymerase chain reaction was used to measure BTL. Covariates include age, sex, years of education, self-evaluated financial situation, depression, and mental and physical functioning. Forty-eight (77.42%) of the former indentured child laborers screened positive for childhood trauma, and 21 (33.87%) had partial or full-blown PTSD. Results did not support our hypotheses that PTSD and childhood trauma would be associated with shorter BTL. In fact, results revealed a trend toward longer BTL in participants with partial or full PTSD [F(2,109) = 3.27, p = 0.04, η2 = 0.06], and longer BTL was marginally associated with higher CTQ scores (age adjusted: β = 0.17 [95% CI: −0.01 to 0.35], t = 1.90, p = 0.06). Furthermore, within-group analyses indicated no significant association between BTL and CTQ scores. To the best of our knowledge, this is the first study exploring the association between childhood trauma and BTL in older individuals with and without PTSD. Contrary to predictions, there were no significant differences in BTL between participants with and without PTSD in our adjusted analyses, and childhood adversity was not associated with BTL. Possible explanations and future research possibilities are discussed.

Current posttraumatic stress disorder and exaggerated threat sensitivity associated with elevated inflammation in the Mind Your Heart Study

OBJECTIVE Elevated inflammation has been repeatedly observed in posttraumatic stress disorder (PTSD), and it may drive the development of both psychiatric symptoms and physical comorbidities. However, it is not clear if elevated inflammation is a feature of both remitted and current PTSD, and little is known about relationships between specific clusters of PTSD symptoms and inflammation. Exaggerated threat sensitivity, as indexed by threat reactivity and avoidance of perceived threats, may be particularly closely associated with inflammation. METHODS We assessed PTSD symptoms and threat sensitivity using the Clinician Administered PTSD Scale in 735 Veterans Affairs patients (35% current PTSD; 16% remitted PTSD) who participated in the Mind Your Heart Study (mean age=59±11; 94% male). High sensitivity C-reactive protein (hsCRP), white blood cell count (WBC), and fibrinogen were used as indices of inflammation. Analysis of covariance models with planned contrasts were used to examine differences in inflammation by PTSD status, adjusting for age, sex, race, kidney function and socioeconomic status. RESULTS Individuals with current PTSD had significantly higher hsCRP and WBC than patients with no history of PTSD, but there were no significant differences in inflammatory markers between those with remitted versus no history of PTSD. Within patients with current PTSD, higher threat reactivity was independently associated with higher hsCRP (β=0.16, p=0.01) and WBC count (β=0.24, <0.001), and higher effortful avoidance was associated with higher fibrinogen (β=0.13, p=0.04). CONCLUSION Our data indicate that elevated inflammation may be a feature of current, but not remitted, PTSD. Within patients with PTSD, higher threat reactivity was also associated with elevated inflammation. A better understanding of the relationship between threat sensitivity and inflammation may inform interventions for patients with PTSD.

Associations of childhood adversity and adulthood trauma with C-reactive protein: A cross-sectional population-based study.

Mounting evidence highlights specific forms of psychological stress as risk factors for ill health. Particularly strong evidence indicates that childhood adversity and adulthood trauma exposure increase risk for physical and psychiatric disorders, and there is emerging evidence that inflammation may play a key role in these relationships. In a population-based sample from the Health and Retirement Study (n=11,198, mean age 69 ± 10), we examine whether childhood adversity, adulthood trauma, and the interaction between them are associated with elevated levels of the systemic inflammatory marker high sensitivity C-reactive protein (hsCRP). All models were adjusted for age, gender, race, education, and year of data collection, as well as other possible confounds in follow-up sensitivity analyses. In our sample, 67% of individuals had experienced at least one traumatic event during adulthood, and those with childhood adversity were almost three times as likely to have experienced trauma as an adult. Childhood adversities and adulthood traumas were independently associated with elevated levels of hsCRP (β=0.03, p=0.01 and β=0.05, p<0.001, respectively). Those who had experienced both types of stress had higher levels of hsCRP than those with adulthood trauma alone, Estimate=-0.06, 95% CI [-0.003, -0.12], p=0.04, but not compared to those with childhood adversity alone, Estimate=-0.06, 95% CI [0.03, -0.16], p=0.19. There was no interaction between childhood and adulthood trauma exposure. To our knowledge, this is the first study to examine adulthood trauma exposure and inflammation in a large population-based sample, and the first to explore the interaction of childhood adversity and adulthood trauma with inflammation. Our study demonstrates the prevalence of trauma-related inflammation in the general population and suggests that childhood adversity and adulthood trauma are independently associated with elevated inflammation.

Hyperinsulinemic response to oral glucose challenge in individuals with posttraumatic stress disorder.

BACKGROUND Posttraumatic stress disorder (PTSD) is associated with a 2-4 fold increased risk of developing Type 2 diabetes mellitus. However, detailed assessments of glucose metabolism and insulin secretion in a study designed to minimize confounders are lacking. Furthermore, few studies examine potential mechanisms involved. We analyzed data from a case-control study of medically healthy, medication-free adults to determine whether individuals with PTSD had abnormal glucose or insulin response to oral glucose tolerance test (OGTT) compared to controls. Secondarily, we assessed potential mediators such as sleep, cortisol and adiponectin. METHODS Data was analyzed from 92 age and gender-matched subjects (44 PTSD, 48 controls). Chronic PTSD was diagnosed using the Structured Clinical Interview for DSM-IV and Clinician Administered PTSD Scale. Subjects underwent 75-g OGTT, actigraphy and sleep diary (to quantify sleep duration), polysomnography (to assess slow wave sleep [SWS] and delta power), and overnight blood sampling (for cortisol and adiponectin). RESULTS At baseline, individuals with PTSD had mildly increased insulin levels (by 19%, compared to controls, p=0.048) that was mediated primarily by weight. In response to OGTT, the PTSD group had higher levels of insulin at 120 min (by 44%, p=0.03) and insulin AUC (by 43%, p=0.015) compared to controls, after adjusting for confounders. Glucose levels were similar in the two groups. Although self-reported sleep duration, SWS, and delta power differed between PTSD subjects and controls, they did not mediate the effects of PTSD status on insulin response. CONCLUSION In this case-control study, individuals with PTSD had a hyperinsulinemic response to oral glucose challenge compared to controls, suggestive of insulin resistance.