Sex and race differences of cerebrospinal fluid metabolites in healthy individuals.

INTRODUCTION: Analyses of cerebrospinal fluid (CSF) metabolites in large, healthy samples have been limited and potential demographic moderators of brain metabolism are largely unknown. OBJECTIVE: Our objective in this study was to examine sex and race differences in 33 CSF metabolites within a sample of 129 healthy individuals (37 African American women, 29 white women, 38 African American men, and 25 white men). METHODS: CSF metabolites were measured with a targeted electrochemistry-based metabolomics platform. Sex and race differences were quantified with both univariate and multivariate analyses. Type I error was controlled for by using a Bonferroni adjustment (0.05/33 = .0015). RESULTS: Multivariate Canonical Variate Analysis (CVA) of the 33 metabolites showed correct classification of sex at an average rate of 80.6% and correct classification of race at an average rate of 88.4%. Univariate analyses revealed that men had significantly higher concentrations of cysteine (p < 0.0001), uric acid (p < 0.0001), and N-acetylserotonin (p = 0.049), while women had significantly higher concentrations of 5-hydroxyindoleacetic acid (5-HIAA) (p = 0.001). African American participants had significantly higher concentrations of 3-hydroxykynurenine (p = 0.018), while white participants had significantly higher concentrations of kynurenine (p < 0.0001), indoleacetic acid (p < 0.0001), xanthine (p = 0.001), alpha-tocopherol (p = 0.007), cysteine (p = 0.029), melatonin (p = 0.036), and 7-methylxanthine (p = 0.037). After the Bonferroni adjustment, the effects for cysteine, uric acid, and 5-HIAA were still significant from the analysis of sex differences and kynurenine and indoleacetic acid were still significant from the analysis of race differences. CONCLUSION: Several of the metabolites assayed in this study have been associated with mental health disorders and neurological diseases. Our data provide some novel information regarding normal variations by sex and race in CSF metabolite levels within the tryptophan, tyrosine and purine pathways, which may help to enhance our understanding of mechanisms underlying sex and race differences and potentially prove useful in the future treatment of disease.

Correction to: Low Life Course Socioeconomic Status (SES) Is Associated with Negative NEO PI-R Personality Patterns.

After the publication of the original article, the Editor was notified by Duke University that they have determined the authorship to be incomplete. Consequently, Dr Edward Suarez has been added as a co-author to represent his contribution to the conception and design of the work and acquisition of the data.

Mindfulness Meditation Targets Transdiagnostic Symptoms Implicated in Stress-Related Disorders: Understanding Relationships between Changes in Mindfulness, Sleep Quality, and Physical Symptoms.

Mindfulness-Based Stress Reduction (MBSR) is an 8-week meditation program known to improve anxiety, depression, and psychological well-being. Other health-related effects, such as sleep quality, are less well established, as are the psychological processes associated with therapeutic change. This prospective, observational study (n = 213) aimed to determine whether perseverative cognition, indicated by rumination and intrusive thoughts, and emotion regulation, measured by avoidance, thought suppression, emotion suppression, and cognitive reappraisal, partly accounted for the hypothesized relationship between changes in mindfulness and two health-related outcomes: sleep quality and stress-related physical symptoms. As expected, increased mindfulness following the MBSR program was directly correlated with decreased sleep disturbance (r = -0.21, p = 0.004) and decreased stress-related physical symptoms (r = -0.38, p < 0.001). Partial correlations revealed that pre-post changes in rumination, unwanted intrusive thoughts, thought suppression, experiential avoidance, emotion suppression, and cognitive reappraisal each uniquely accounted for up to 32% of the correlation between the change in mindfulness and change in sleep disturbance and up to 30% of the correlation between the change in mindfulness and change in stress-related physical symptoms. Results suggest that the stress-reducing effects of MBSR are due, in part, to improvements in perseverative cognition and emotion regulation, two "transdiagnostic" mental processes that cut across stress-related disorders.

The Relation of Light-to-Moderate Alcohol Consumption to Glucose Metabolism and Insulin Resistance in Nondiabetic Adults: the Moderating Effects of Depressive Symptom Severity, Adiposity, and Sex.

PURPOSE: We examined the relation of alcohol consumption to glucose metabolism and insulin resistance (IR) as a function of depressive symptoms, adiposity, and sex. METHOD: Healthy adults (aged 18-65 years) provided fasting blood samples and information on lifestyle factors. Alcohol intake was categorized as never, infrequent (1-3 drinks/month), occasional (1-7 drinks/week), and regular (≥2 drinks/day) drinkers. The Beck Depression Inventory (BDI) was used to assess symptom severity. Primary outcomes were fasting insulin, glucose, and IR assessed by the homeostasis model assessment (HOMA). RESULTS: In univariate analysis, alcohol consumption was negatively associated with HOMA-IR (p = 0.03), insulin (p = 0.007), and body mass index (BMI) (p = 0.04), but not with glucose or BDI. Adjusting for potential confounders including BMI, alcohol consumption was associated with HOMA-IR (p = 0.01) and insulin (p = 0.009) as a function of BDI and sex. For women with minimal depressive symptoms, light-to-moderate alcohol consumption was associated with lower HOMA-IR and insulin. Alcohol consumption was not associated with metabolic markers in women with higher depressive symptoms and in men. In analysis using BMI as a continuous moderator, alcohol consumption was only associated with insulin (p = 0.004). Post-hoc comparisons between BMI groups (<25 vs ≥25 kg/m2) revealed that light-to-moderate alcohol consumption was associated with lower insulin but only in subjects with BMI ≥ 25 kg/m2. CONCLUSIONS: The benefits of light-to-moderate alcohol consumption on fasting insulin and IR are sex dimorphic and appear to be independently moderated by adiposity and depressive symptom severity.

The cortisol:C-reactive protein ratio and negative affect reactivity in depressed adults.

OBJECTIVE: We evaluated the effect of the cortisol (CORT) to high sensitivity C-reactive protein (hsCRP) ratio on stress-induced negative affect (NA) reactivity and whether the association was moderated by depressive symptom severity and gender. The CORT/CRP ratio was used to evaluate the integrity of the negative feedback loop between the hypothalamic-pituitary-adrenal axis and inflammatory response system. METHOD: Basal CORT and hsCRP levels were measured in fasting blood samples from 198 medication-free and nonsmoking healthy men and women. Depressive symptom severity was assessed using the Hamilton Rating Scale for Depression (HAMD). NA ratings were collected at baseline and at the completion of the laboratory stressors, the Anger Recall Interview (ARI) and reading. RESULTS: Adjusting for potential confounders and baseline NA, analysis revealed a significant relationship between CORT/CRP ratio and NA reactivity to ARI as a function of depressive symptom severity. Simple effects revealed that for participants with high HAMD, decreasing CORT/CRP ratio, suggestive of an insufficient CORT release relative to higher hsCRP, predicted increasing stress-induced NA reactivity. For participants with low HAMD, the CORT/CRP ratio failed to predict NA reactivity. Gender did not moderate the joint effect of depressive symptom severity and the CORT/CRP ratio on stress-induced NA reactivity. CONCLUSIONS: This is the first study to document that a premorbid dysregulation of the neuro-immune relationship, characterized by an insufficient release of CORT in conjunction with higher CRP, plays a role in stress sensitivity, and specifically NA reactivity, in individuals with elevated levels of depression symptoms. (PsycINFO Database Record

Decreased symptoms of depression after mindfulness-based stress reduction: potential moderating effects of religiosity, spirituality, trait mindfulness, sex, and age.

OBJECTIVE: Mindfulness-based stress reduction (MBSR) is a secular meditation training program that reduces depressive symptoms. Little is known, however, about the degree to which a participant's spiritual and religious background, or other demographic characteristics associated with risk for depression, may affect the effectiveness of MBSR. Therefore, this study tested whether individual differences in religiosity, spirituality, motivation for spiritual growth, trait mindfulness, sex, and age affect MBSR effectiveness. METHODS: As part of an open trial, multiple regression was used to analyze variation in depressive symptom outcomes among 322 adults who enrolled in an 8-week, community-based MBSR program. RESULTS: As hypothesized, depressive symptom severity decreased significantly in the full study sample (d=0.57; p<0.01). After adjustment for baseline symptom severity, moderation analyses revealed no significant differences in the change in depressive symptoms following MBSR as a function of spirituality, religiosity, trait mindfulness, or demographic variables. Paired t tests found consistent, statistically significant (p<0.01) reductions in depressive symptoms across all subgroups by religious affiliation, intention for spiritual growth, sex, and baseline symptom severity. After adjustment for baseline symptom scores, age, sex, and religious affiliation, a significant proportion of variance in post-MBSR depressive symptoms was uniquely explained by changes in both spirituality (ß=-0.15; p=0.006) and mindfulness (ß=-0.17; p<0.001). CONCLUSIONS: These findings suggest that MBSR, a secular meditation training program, is associated with improved depressive symptoms regardless of affiliation with a religion, sense of spirituality, trait level of mindfulness before MBSR training, sex, or age. Increases in both mindfulness and daily spiritual experiences uniquely explained improvement in depressive symptoms.

Depressogenic vulnerability and gender-specific patterns of neuro-immune dysregulation: What the ratio of cortisol to C-reactive protein can tell us about loss of normal regulatory control.

We examined whether the ratio of cortisol (CORT) to high-sensitivity C-reactive protein (hsCRP), an index that captures the integrity of homeostatic regulation between the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory processes, is associated with vulnerability to depression in a gender specific manner and whether glucocorticoid receptor (GR) sensitivity plays a role in these associations. Fasting blood samples were collected between 08:45 and 09:15 and assayed for CORT, hsCRP, and leukocyte count in 213 healthy, medication-free men and women. The NEO-Personality Inventory was used to assess neuroticism, extraversion and anxiety. We used the Hamilton Depression Interview to assess depressive symptoms, the Buss-Perry anger subscale to measure anger, and the Pittsburgh Sleep Quality Index to evaluate subjective sleep quality and its components. Log-transformed CORT/CRP values were analyzed using multiple regression with Holms' adjusted p-values and age, body mass index (BMI), and race as covariates. GR sensitivity was estimated using the log-transformed ratio of neutrophils (N)-to-monocytes (M). The log-transformed ratio of CORT/CRP did not differ between men and women but was significantly and negatively associated with age and BMI. Severity of depressive symptoms, extraversion, anxiety, and sleep quality were associated with the CORT/CRP ratio in a gender-specific manner. For women, decreasing CORT/CRP ratios, suggestive of an insufficient release of CORT coupled with a heightened inflammatory state, were associated with increasing severity of depressive symptoms, decreasing quality of sleep, increasing frequency of sleep disturbance, and decreasing extraversion. For men, increasing frequency of daytime disturbance and levels of anxiety were associated with increasing CORT/CRP ratio, suggestive of an enhanced release of CORT relative to attenuated levels of hsCRP. For both genders, increasing anger was associated with decreasing CORT/CRP ratios. Although results suggested GR downregulation in women but not men, such differences did not mediate the observed associations. With the use of the CORT/CRP ratio, we showed that vulnerability factors for depression are associated with a loss of normal regulatory controls resulting in gender-specific patterns of neuro-immune dysregulation. That GR downregulation did not influence these associations suggests that the loss of regulatory controls in at risk individuals is primarily at the level of the hormone. Beyond the individual contribution of each component of the CORT/CRP ratio, disruption of normal neuroimmune regulatory feedback provides a plausible biological framework useful in understanding biobehavioral vulnerabilities to depression in a gender specific manner. The CORT/CRP ratio may be a viable biomarker not only for delineating risk for MDD but also progression and treatment responses among patients with MDD; possibilities that are testable in future studies.

Race differences in the relation of vitamins A, C, E, and ß-carotene to metabolic and inflammatory biomarkers.

Using archival data, we conducted a secondary analysis to examine race differences in the relation of serum vitamins A, C, E and ß-carotene to insulin resistance (IR), fasting insulin and glucose, high sensitivity C-reactive protein (hs-CRP), and leukocyte count in 176 non-smoking, healthy, white, and African American (AA) adults aged 18 to 65 years (48% women, 33% AA). We hypothesized that micronutrient concentrations would be associated with early risk markers of cardiometabolic diseases in a race-dependent manner. Fasting blood samples were analyzed for micronutrients, insulin, glucose, hs-CRP, and leukocyte count. Insulin resistance was estimated using the homeostatic model assessment. After adjusting for age, body mass index, gender, educational level, use of vitamin supplements, alcohol intake, leisure time physical activity, menopausal status, and total cholesterol, we observed that ß-carotene was significantly associated with insulin resistance and fasting insulin in a race-dependent manner. Among AA, lower ß-carotene levels were associated with higher estimates of insulin resistance and fasting insulin; whereas, these same associations were not significant for whites. Race also significantly moderated the relation of vitamin C to leukocyte count, with lower vitamin C being associated with higher leukocyte count only in AA but not whites. For all subjects, lower ß-carotene was associated with higher hs-CRP. In AA, but not whites, lower levels of ß-carotene and vitamin C were significantly associated with early risk markers implicated in cardiometabolic conditions and cancer. Whether or not lower levels of micronutrients contribute uniquely to racial health disparities is a worthwhile aim for future research.

Depression inhibits the anti-inflammatory effects of leisure time physical activity and light to moderate alcohol consumption.

Light to moderate alcohol consumption and leisure time physical activity (LTPA) are independently associated with lower levels of high sensitivity C-reactive protein (CRP), a predictor of cardiometabolic risk. In contrast, depression, ranging from low mood disturbance to major depressive disorder, has been associated with elevated CRP. To test the hypothesis that depression attenuates the anti-inflammatory effects of LTPA and alcohol consumption, the current study tested the moderating effect of severity of depressive symptomatology on the relation of alcohol consumption and LTPA to CRP in 222 healthy adult men and women (18-65 years of age). Given the known effects of gender on inflammation, we also examined the effects of gender on the tested interactions. Depression was assessed using the Beck Depression Inventory. Frequency of alcohol consumption, hours of LTPA per week and other coronary risk/protective factors were assessed via self-report and structured interview. Fasting blood samples were used to measure CRP and lipids. As predicted, the interaction between LTPA and depressive symptomatology was significant (F=5.29, p<.03) such that lower CRP was associated with the combination of decreased depressive symptomatology and increased LTPA. Among those with increased depressive symptoms, increased LTPA was not associated with higher CRP. Similarly, depression interacted with alcohol consumption in predicting CRP in men but not women (F=5.03, p<.008) such that for men light to moderate alcohol consumption was associated with lower CRP but only among those with decreased depressive symptoms. Light to moderate alcohol consumption was not associated with lower CRP in those with increased depressive symptom severity. The pattern of the interactions between anti-inflammatory activities such as light to moderate alcohol consumption and LTPA and psychological distress as indexed by severity of depressive symptomatology suggests an important new avenue for future research.

Changes in spirituality partly explain health-related quality of life outcomes after Mindfulness-Based Stress Reduction.

Mindfulness-Based Stress Reduction is a secular behavioral medicine program that has roots in meditative spiritual practices. Thus, spirituality may partly explain Mindfulness-Based Stress Reduction outcomes. Participants (N = 279; M (SD) age = 45(12); 75% women) completed an online survey before and after an 8-week Mindfulness-Based Stress Reduction program. Structural equation modeling was used to test the hypothesis that, following Mindfulness-Based Stress Reduction, the relationship between enhanced mindfulness and improved health-related quality of life is mediated by increased daily spiritual experiences. Changes in both spirituality and mindfulness were significantly related to improvement in mental health. Although the initial mediation hypothesis was not supported, an alternate model suggested that enhanced mindfulness partly mediated the association between increased daily spiritual experiences and improved mental health-related quality of life (indirect effect: ß = 0.07, P = 0.017). Effects on physical health-related quality of life were not significant. Findings suggest a novel mechanism by which increased daily spiritual experiences following Mindfulness-Based Stress Reduction may partially explain improved mental health as a function of greater mindfulness.

Cardiovascular and psychological reactivity and recovery from harassment in a biracial sample of high and low hostile men and women.

BACKGROUND: This study emphasizes the importance of studying the emotional, motivational, and cognitive characteristics accompanying and the potential hemodynamic mechanisms underlying cardiovascular reactivity to and recovery from interpersonal conflict. PURPOSE: The relation of dispositional hostility to cardiovascular reactivity during a frustrating anagram task and post-task recovery was investigated. METHODS: The sample was composed of 99 healthy participants (age, 18-30 years; 53% women; 51% Caucasian; 49% African American)-half randomly assigned to a harassment condition. High and low hostility groups were created by a median split specific to sex and race subgroup score distributions on the Cook-Medley Hostility Scale. It was hypothesized that hostility would interact with harassment such that harassed, high hostile individuals would display the greatest cardiovascular and emotional reactivity and slowest recovery of the four groups. Participants completed a 10-min baseline, a 6-min anagram task, and a 5-min recovery period with blood pressure, heart rate, pre-ejection period, stroke index, cardiac index, and total peripheral resistance index measured. RESULTS: Harassed participants displayed significantly greater cardiovascular responses and lower positive affect to the task and slower systolic blood pressure (SBP) recovery than did nonharassed participants. The high hostile group, irrespective of harassment, showed blunted cardiovascular responses during the task and delayed SBP recovery than the low hostile group. CONCLUSION: Although the predicted interaction between hostility and harassment was not supported in the context of cardiovascular responses, such an interaction was observed in the context of blame attributions, whereby harassed hostile participants were found to blame others for their task performance than the other subgroups.

Central nervous system serotonin and clustering of hostility, psychosocial, metabolic, and cardiovascular endophenotypes in men.

OBJECTIVE: To use measures of cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5HIAA) and genotype of a functional polymorphism of the monoamine oxidase A gene promoter (MAOA-uVNTR) to study the role of central nervous system (CNS) serotonin in clustering of hostility, other psychosocial, metabolic and cardiovascular endophenotypes. METHODS: In 86 healthy male volunteers, we evaluated CSF levels of the primary serotonin metabolite 5HIAA and MAOA-uVNTR genotype for association with a panel of 29 variables assessing hostility, other psychosocial, metabolic, and cardiovascular endophenotypes. RESULTS: The correlations of 5HIAA with these endophenotypes in men with more active MAOA-uVNTR alleles were significantly different from those of men with less active alleles for 15 of the 29 endophenotypes. MAOA-uVNTR genotype and CSF 5HIAA interacted to explain 20% and 22% of the variance, respectively, in scores on one factor wherein high scores reflected a less healthy psychosocial profile and a second factor wherein high score reflected increased insulin resistance, body mass index, blood pressure and hostility. In men with less active alleles, higher 5HIAA was associated with more favorable profiles of hostility, other psychosocial, metabolic and cardiovascular endophenotypes; in men with more active alleles, higher 5HIAA was associated with less favorable profiles. CONCLUSIONS: These findings indicate that, in men, indices of CNS serotonin function influence the expression and clustering of hostility, other psychosocial, metabolic and cardiovascular endophenotypes that have been shown to increase risk of developing cardiovascular disease. The findings are consistent with the hypothesis that increased CNS serotonin is associated with a more favorable psychosocial/metabolic/cardiovascular profile, whereas decreased CNS serotonin function is associated with a less favorable profile.

Socioeconomic status moderates the association between John Henryism and NEO PI-R personality domains.

OBJECTIVE: To investigate associations between John Henryism (JH) and NEO Personality Inventory-Revised (PI-R) personality domains. JH-a strong behavioral predisposition to engage in high-effort coping with difficult psychosocial and economic stressors-has been associated with poor health, particularly among persons in lower socioeconomic (SES) groups. Unfavorable personality profiles have also been frequently linked to poor health; however, no studies have yet examined what global personality traits characterize JH. METHODS: Hypotheses were examined, using data from a sample of 233 community volunteers (mean age, 33 years; 61% black and 39% white) recruited specifically to represent the full range of the SES gradient. Personality (NEO PI-R) and active coping (12-item JH scale) measures and covariates were derived from baseline interviews. RESULTS: In a multiple regression analysis, independent of SES, JH was positively associated with Conscientiousness (C) (p < .001) and Extraversion (E) (p < .001), whereas the combination of low JH and high SES was associated with Neuroticism (N) (p = .02) When examining associations between JH and combinations of NEO PI-R domains called "styles," high JH was most strongly associated with a high E/high C "Go-Getters" style of activity, whereas low JH was associated with the low E/high Openness (O) "Introspectors" style. In facet level data, the most robust associations with JH were found for five C and five E facets. CONCLUSIONS: High JH was associated with higher scores on C and E, but the combination of low JH and high SES was associated with higher scores on N.

Hostility and fasting glucose in African American women.

OBJECTIVE: To examine whether the relationship of hostility (HOST) to fasting glucose indices is moderated by sex and race. HOST has been associated with abnormalities in glucose metabolism. Prior studies suggested that this association may be more prevalent in women and in African American (AA) individuals. METHODS: A total of 565 healthy AA and white (W) men and women (mean age = 33 +/- 6 years) were assessed. HOST was measured by the 27-item version of the Cook Medley HOST Scale. The moderating effects of sex and race were evaluated for the associations of HOST to fasting glucose, insulin, and insulin sensitivity (HOMA-IR). RESULTS: Analysis showed a moderating effect of sex and race on the association of HOST to fasting glucose (p = .03), but not for insulin (p = .12). Analysis of HOMA-IR revealed a trend (p = .06) for the interaction. Stratified analyses by race and sex revealed a positive association between HOST and fasting glucose only in AA women, which remained significant after controlling for age and body mass index. CONCLUSION: A relationship between HOST and fasting glucose was evident in AA women only, a group that has twice the risk of developing Type 2 diabetes compared with W women. Further studies are needed to elucidate the mechanisms by which HOST may affect glucose metabolism in AA women.

Sex and gender in psychoneuroimmunology research: past, present and future.

To date, research suggests that sex and gender impact pathways central to the foci of psychoneuroimmunology (PNI). This review provides a historical perspective on the evolution of sex and gender in psychoneuroimmunology research. Gender and sexually dimorphic pathways may have synergistic effects on health differences in men and women. We provide an overview of the literature of sex and gender differences in brain structure and function, sex steroids, gender role identification, hypothalamic-pituitary-adrenal axis function, genetics, immunology and cytokine response. Specific examples shed light on the importance of attending to sex and gender methodology in PNI research and recommendations are provided.