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.

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.

Hostility, anger, and depression predict increases in C3 over a 10-year period.

We examined the relation of hostility, anger, and depression to 10-year changes in the third (C3), and fourth (C4) complement in 313, apparently healthy male participants enrolled in the Air Force Health Study (AFHS), a 20-year study designed to evaluate the health consequences of dioxin exposure. Hostility, depression, and anger were assessed using subscales from the Minnesota Multiphasic Personality Inventory (MMPI), which was administered in 1985. Given the high intercorrelations among these psychological scales, we used a principal component analysis to generate a composite score representing the linear combination of the hostility, anger, and depression scales. The dependent variables, C3 and C4 levels, were determined from samples collected in 1992, 1997, and 2002. Regression analyses controlling for age, race, alcohol use, body mass index, and cigarette use as well as onset of disease, and use of lipid lowering and blood pressure medications during follow-up revealed a significant timexcomposite score interaction for C3 complement (p<.0003), but not C4. Post-hoc analyses revealed that high composite scores were associated with larger 10-year increases in C3. These observations suggest that men who are hostile and are prone to experience frequent and intense feelings of anger, and depression show activation of the complement system, and specifically increases in C3, that may contribute to the development of coronary heart disease.

Increases in stimulated secretion of proinflammatory cytokines by blood monocytes following arousal of negative affect: the role of insulin resistance as moderator.

We examined the effect of negative affect on changes in stimulated secretion of cytokines by blood monocytes and determined whether insulin resistance (IR), as indexed by the Homeostasis Model Assessment (HOMA), moderated these associations in 58 healthy men (aged 18-65 years). Blood samples and ratings of negative affect were collected at rest and 15min following subjects' participation in the Anger Recall Interview (ARI). Assessment of lipopolysaccharide (LPS)-stimulated secretion of IL-1beta, IL-6, and TNF-alpha was accomplished by ELISA of supernatant. Regression models controlling for age, body mass index, and race/ethnicity revealed that higher HOMA-IR values were associated with larger stress-induced increases in IL-1beta and TNF-alpha (p<.05). Furthermore, arousal of negative affect during the ARI was differentially associated with stress-induced changes in stimulated secretion of TNF-alpha and IL-6 as a function of HOMA-IR (p<.05). Increases in stimulated cytokine secretion were associated with arousal of negative affect, but only among men with higher HOMA-IR values. Among men with lower HOMA-IR values, arousal of negative affect was associated with diminished cytokine secretion. Collectively, these data suggest that the HOMA-IR moderates the impact that arousal of negative affect has on the ability of blood monocytes to secrete inflammatory cytokines in response to LPS. Stress-induced increases in cytokine secretion among high HOMA-IR men are consistent with the role of inflammation in cardiovascular disease, hypertension, type 2 diabetes as well as the metabolic syndrome and underscore the relevance of negative affect in the etiology of these inflammatory conditions.

Enhanced expression of cytokines and chemokines by blood monocytes to in vitro lipopolysaccharide stimulation are associated with hostility and severity of depressive symptoms in healthy women.

The current study investigated the relation of hostility and severity of depressive symptoms, separately and jointly, to the capacity of blood monocytes to secrete an array of cytokines when stimulated by bacterial lipopolysaccharide (LPS). Subjects were 44 healthy, non-smoking, premenopausal women (aged 23-49 years) not currently taking oral contraceptives. Data were collected during the follicular phase of the menstrual cycle. The Cook-Medley Hostility (Ho) scale and the Beck Depression Inventory (BDI) were used to assess hostility and severity of depressive symptoms, respectively. Dual-color flow cytometry was used to measure the total expression of interleukin (IL)-1alpha, IL-1beta, IL-8, tumor necrosis factor (TNF)-alpha, monocyte chemotactic protein (MCP)-1 and monocyte inflammatory protein (MIP)-1alpha in blood monocytes following 4 h in vitro LPS stimulation of whole blood. In analyses adjusting for age, body mass index (BMI), fasting cholesterol, alcohol use, race and 17beta-estradiol (E(2)), higher Ho scores were associated with greater LPS-stimulated expression of IL-1alpha (beta = 0.033, p = 0.02), IL-8 (beta = 0.046, p = 0.01) and IL-1beta (beta = 0.024, p = 0.06). Higher BDI scores were associated with greater expression of TNF-alpha (beta = 0.042, p = 0.02) and IL-8 (beta = 0.045, p = 0.04). The linear combination of Ho and BDI scores was significantly associated with IL-1beta (beta = 0.18, p = 0.057), IL-8 (beta = 0.36, p = 0.01), TNF-alpha (beta = 0.25, p = 0.03), and IL-1alpha (beta = 0.18, p < 0.07). Thus, in healthy women, these psychological risk factors, alone and in combination, induce a proinflammatory phenotype in circulating monocytes characterized by the up-regulation of proinflammatory cytokines, supporting the hypothesis that inflammation may be a key pathway whereby hostility and depressive symptoms contribute to atherosclerosis and subsequent coronary heart disease (CHD).

Joint effect of hostility and severity of depressive symptoms on plasma interleukin-6 concentration.

OBJECTIVE: Although interleukin (IL)-6 plays a significant role in cardiovascular disease, little is known about its relation to psychological risk factors, such as hostility and severity of depressive symptoms. The current study examined the joint effects of severity of depressive symptoms and hostility on plasma IL-6 in a sample of 90 healthy, nonsmoking men. METHODS: After an overnight fast, blood samples for plasma IL-6 and fasting lipids were collected on the same day that the Beck Depression Inventory (BDI) and the Cook-Medley hostility (Ho) scale were administered. Plasma IL-6 was determined using enzymatic-linked immunosorbent assay (ELISA). RESULTS: Analyses of logarithmically normalized plasma IL-6 adjusting for age, body mass index (BMI), fasting total cholesterol, high density lipoprotein (HDL), and resting diastolic blood pressure (DBP) revealed a significant BDI by Ho interaction (p =.026). Post hoc decomposition revealed that Ho was correlated with log-normalized plasma IL-6 (r = 0.59, p =.025) but only among men with BDI scores of 10 and above. Alternatively, BDI was correlated with log-normalized plasma IL-6 (r = 0.61, p =.003) but only among men with Ho scores of 23 and higher. Comparisons among BDI/Ho groups indicated that men with high scores on both the BDI and the Ho exhibited the highest median levels of plasma IL-6. CONCLUSION: Hostile men who exhibited above normal levels of depressive symptoms had higher plasma levels of IL-6 suggestive of a subpopulation at increased risk for future cardiac events.

Plasma interleukin-6 is associated with psychological coronary risk factors: moderation by use of multivitamin supplements.

The current study examined the relation of plasma IL-6 to anger, hostility, and severity of depressive symptoms as a function of multivitamin supplement use in 96 healthy, nonsmoking men (aged 18-46). Plasma IL-6 was independently associated with anger, hostility, and severity of depressive symptoms, as well as with a composite factor score, but only among nonusers. Among users, these associations were not significant. Multivitamin use was associated with lower plasma IL-6 levels, but only among men with high composite factor scores. Statistical adjustments for age, body mass index, resting diastolic blood pressure, fasting total cholesterol, high-density lipoprotein cholesterol, alcohol use, exercise frequency, and educational level did not alter these results. These data suggest that plasma IL-6 is elevated among healthy men characterized by a propensity for anger, a hostile disposition, and greater severity of depressive symptoms and that multivitamin supplements could ameliorate plasma IL-6 levels among these men.

The relation of severity of depressive symptoms to monocyte-associated proinflammatory cytokines and chemokines in apparently healthy men.

OBJECTIVE: We examined the relation of severity of depressive symptoms to lipopolysaccharide-stimulated expression of monocyte-associated proinflammatory cytokines and chemokines in 53 nonsmoking, healthy men. METHODS: Assessments of cytokine and chemokine expression and severity of depressive symptoms were conducted on the same day. The 21-item Beck Depression Inventory (BDI) was used to assess severity of depressive symptoms experienced during the week before study participation. Dual-color flow cytometry was used to determine monocyte-associated (CD14+) expression of interleukin-1alpha (IL-1alpha), IL-1beta, tumor necrosis factor-alpha (TNF-alpha), IL-8, and monocyte chemotactic protein-1 (MCP-1) after in vitro lipopolysaccharide stimulation of undiluted whole blood. RESULTS: Calculations of partial correlation coefficients controlling for age, race, body mass index, and alcohol use indicated that BDI score was significantly associated with IL-1alpha (r = 0.27), IL-1beta (r = 0.44), TNF-alpha (r = 0.57), MCP-1 (r = 0.52), and IL-8 (r = 0.33). In addition, relative to men with BDI scores below 10, men with BDI scores of 10 or above exhibited an overexpression of IL-1beta (p =.004), TNF-alpha (p =.005), IL-8 (p =.002), and MCP-1 (p =.025). CONCLUSIONS: Relative to men with no or minimal symptoms of depression, men with mild to moderate levels of depressive symptoms showed overexpression of monocyte-associated proinflammatory cytokines and chemokines.

The relation of aggression, hostility, and anger to lipopolysaccharide-stimulated tumor necrosis factor (TNF)-alpha by blood monocytes from normal men.

Aggression, hostility, and anger significantly predict morbidity and mortality from atherosclerotic cardiovascular disease (ACVD). ACVD is believed to be an inflammatory disease characterized by increased expression of a number of proinflammatory cytokines, such as tumor necrosis factor (TNF)-alpha. This study examined the relation of aggression, hostility, and anger to monocyte-associated TNF-alpha expression following lipopolysaccharide (LPS) stimulation. Participants were 62 healthy, non-smoking men (aged 18-45 years). Hostility, anger, verbal, and physical aggression were assessed using the Buss-Perry aggression questionnaire (BPAQ). LPS-stimulated TNF-alpha expression was determined using dual-color flow cytometry gating for CD14(+) cells. After controlling for age, race, education, and alcohol use, scores on the hostility (p=.013), physical aggression (p=.010), and verbal aggression (p=.034) subscales, and the total score (p=.007) on the BPAQ were positively associated with LPS-stimulated TNF-alpha expression. The results suggest that hostility and aggression are associated with an increased expression of TNF-alpha, a cytokine implicated in ACVD.