Stephen H. Boyle

Metabolomics in early Alzheimer's disease: identification of altered plasma sphingolipidome using shotgun lipidomics.

Background The development of plasma biomarkers could facilitate early detection, risk assessment and therapeutic monitoring in Alzheimers disease (AD). Alterations in ceramides and sphingomyelins have been postulated to play a role in amyloidogensis and inflammatory stress related neuronal apoptosis; however few studies have conducted a comprehensive analysis of the sphingolipidome in AD plasma using analytical platforms with accuracy, sensitivity and reproducibility. Methods and Findings We prospectively analyzed plasma from 26 AD patients (mean MMSE 21) and 26 cognitively normal controls in a non-targeted approach using multi-dimensional mass spectrometry-based shotgun lipidomics [1], [2] to determine the levels of over 800 molecular species of lipids. These data were then correlated with diagnosis, apolipoprotein E4 genotype and cognitive performance. Plasma levels of species of sphingolipids were significantly altered in AD. Of the 33 sphingomyelin species tested, 8 molecular species, particularly those containing long aliphatic chains such as 22 and 24 carbon atoms, were significantly lower (p<0.05) in AD compared to controls. Levels of 2 ceramide species (N16:0 and N21:0) were significantly higher in AD (p<0.05) with a similar, but weaker, trend for 5 other species. Ratios of ceramide to sphingomyelin species containing identical fatty acyl chains differed significantly between AD patients and controls. MMSE scores were correlated with altered mass levels of both N20:2 SM and OH-N25:0 ceramides (p<0.004) though lipid abnormalities were observed in mild and moderate AD. Within AD subjects, there were also genotype specific differences. Conclusions In this prospective study, we used a sensitive multimodality platform to identify and characterize an essentially uniform but opposite pattern of disruption in sphingomyelin and ceramide mass levels in AD plasma. Given the role of brain sphingolipids in neuronal function, our findings provide new insights into the AD sphingolipidome and the potential use of metabolomic signatures as peripheral biomarkers.

Cognitive ability in early adulthood and risk of 5 specific psychiatric disorders in middle age: the Vietnam Experience Study

CONTEXT Lower cognitive ability is a risk factor for some forms of psychopathology, but much of the evidence for risk is based on individuals who required specialist care. It is unclear whether lower ability influences the risk of particular patterns of comorbidity. OBJECTIVE To examine the relation between premorbid cognitive ability in early adulthood and the risk of major depression, generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), alcohol and other drug abuse or dependence, and comorbid forms of these conditions in midlife. DESIGN Prospective cohort study in which cognitive ability was measured on enlistment into military service at a mean age of 20.4 years and psychiatric disorder was assessed by structured diagnostic interview at a mean age of 38.3 years. SETTING The United States. PARTICIPANTS A total of 3258 male veterans, participants in the Vietnam Experience Study. MAIN OUTCOME MEASURES Major depression, GAD, PTSD, and alcohol or other drug abuse or dependence since enlistment and currently, diagnosed according to the DSM-III. RESULTS Lower cognitive ability was associated with an increased risk of depression, GAD, alcohol abuse or dependence, and PTSD and with some patterns of comorbidity. For a 1-SD decrease in cognitive ability, unadjusted odds ratios (95% confidence interval) for having these disorders currently were 1.32 (1.12-1.56) for depression, 1.43 (1.27-1.64) for GAD, 1.20 (1.08-1.35) for alcohol abuse or dependence, 1.39 (1.18-1.67) for PTSD, 2.50 (1.41-4.55) for PTSD plus GAD, 2.17 (1.47-3.22) for PTSD plus GAD plus depression, and 2.77 (1.12-6.66) for all 4 disorders. Most associations remained statistically significant after adjustment for confounders. CONCLUSIONS Lower cognitive ability is a risk factor for several specific psychiatric disorders, including some forms of comorbidity. Understanding the mechanisms whereby ability is linked to individual patterns of psychopathology may inform intervention.

IQ in late adolescence/early adulthood, risk factors in middle age and later all-cause mortality in men: the Vietnam Experience Study

Objective: To examine the role of potential mediating factors in explaining the IQ–mortality relation. Design, setting and participants: A total of 4316 male former Vietnam-era US army personnel with IQ test results at entry into the service in late adolescence/early adulthood in the 1960/1970s (mean age at entry 20.4 years) participated in a telephone survey and medical examination in middle age (mean age 38.3 years) in 1985–6. They were then followed up for mortality experience for 15 years. Main results: In age-adjusted analyses, higher IQ scores were associated with reduced rates of total mortality (hazard ratio (HR)per SD increase in IQ 0.71; 95% CI 0.63 to 0.81). This relation did not appear to be heavily confounded by early socioeconomic position or ethnicity. The impact of adjusting for some potentially mediating risk indices measured in middle age on the IQ–mortality relation (marital status, alcohol consumption, systolic and diastolic blood pressure, pulse rate, blood glucose, body mass index, psychiatric and somatic illness at medical examination) was negligible (<10% attenuation in risk). Controlling for others (cigarette smoking, lung function) had a modest impact (10–17%). Education (0.79; 0.69 to 0.92), occupational prestige (0.77; 0.68 to 0.88) and income (0.86; 0.75 to 0.98) yielded the greatest attenuation in the IQ–mortality gradient (21–52%); after their collective adjustment, the IQ–mortality link was effectively eliminated (0.92; 0.79 to 1.07). Conclusions: In this cohort, socioeconomic position in middle age might lie on the pathway linking earlier IQ with later mortality risk but might also partly act as a surrogate for cognitive ability.

Hostility as a predictor of survival in patients with coronary artery disease.

Objective: This article presents a reanalysis of an earlier study that reported a nonsignificant relation between the 50-item Cook-Medley Hostility Scale (CMHS) and survival in a sample of coronary patients. Since publication of those results, there have been significant developments in the measurement of hostility that suggest that an abbreviated scale may be a better predictor of health outcomes. This study examined the ability of the total CMHS and an abbreviated form of the CMHS (ACM) to predict survival in a sample of patients with documented coronary artery disease (CAD) with increased statistical power. Methods: Nine hundred thirty-six patients (83% were male; mean age = 51.48) with CAD who were followed for an average of 14.9 years. The ACM consisted of the combination of the cynicism, hostile attribution, hostile affect, and aggressive responding subscales that were identified in an earlier study (Barefoot et al. [1989]) by a rational analysis of the item content. The relation between hostility and survival was examined with Cox proportional hazard models (hazard ratios [HRs] based on a two standard deviation difference). Results: Controlling for disease severity, the ACM was a significant predictor for both CHD mortality (HR = 1.33, p < .009) and total mortality (HR = 1.28, p < .02). The total CMHS was only a marginally significant predictor of either outcome (p values < 0.06). Conclusion: The results of this study suggest that hostility is associated with poorer survival in CAD patients, and it may be possible to refine measures of hostility in order to improve prediction of health outcomes. CMHS = Cook-Medley Hostility Scale; CHD = coronary heart disease; CAD = coronary artery disease; MI = myocardial infarction; ACM = abbreviated Cook-Medley Hostility Scale; SD = standard deviation; HR = hazard ratio; CI = confidence interval.

Pretreatment metabotype as a predictor of response to sertraline or placebo in depressed outpatients: a proof of concept

The purpose of this study was to determine whether the baseline metabolic profile (that is, metabotype) of a patient with major depressive disorder (MDD) would define how an individual will respond to treatment. Outpatients with MDD were randomly assigned to sertraline (up to 150 mg per day) (N=43) or placebo (N=46) in a double-blind 4-week trial. Baseline serum samples were profiled using the liquid chromatography electrochemical array; the output was digitized to create a ‘digital map’ of the entire measurable response for a particular sample. Response was defined as ⩾50% reduction baseline to week 4 in the 17-item Hamilton Rating Scale for Depression total score. Models were built using the one-out method for cross-validation. Multivariate analyses showed that metabolic profiles partially separated responders and non-responders to sertraline or to placebo. For the sertraline models, the overall correct classification rate was 81% whereas it was 72% for the placebo models. Several pathways were implicated in separation of responders and non-responders on sertraline and on placebo including phenylalanine, tryptophan, purine and tocopherol. Dihydroxyphenylacetic acid, tocopherols and serotonin were common metabolites in separating responders and non-responders to both drug and placebo. Pretreatment metabotypes may predict which depressed patients will respond to acute treatment (4 weeks) with sertraline or placebo. Some pathways were informative for both treatments whereas other pathways were unique in predicting response to either sertraline or placebo. Metabolomics may inform the biochemical basis for the early efficacy of sertraline.

Dimensions of anger-hostility and cardiovascular reactivity in provoked and angered men.

This study investigated the relationship between two dimensions of anger-hostility-the expression of anger-hostility and the experience of anger-hostility-and cardiovascular reactivity in provoked and angered men. A serial subtraction task was administered to 41 male undergraduates who were provoked and angered. A measure of the expression of anger-hostility correlated positively and significantly with systolic and diastolic blood pressure (BP) reactivity. There were no significant correlations between a measure of the experience of anger-hostility and cardiovascular reactivity. The two types of anger-hostility were also found to relate differentially to life-style variables that have been identified as risk factors for coronary heart disease (CHD), with only the expression of anger-hostility showing positive relationships with these life-style CHD risk factors. These findings are discussed within the context of a similar differential relationship between the two dimensions of anger-hostility and CAD and CHD. Finally, significant negative relationships were obtained between the experience of anger-hostility and resting BP and heart rate levels. These findings are discussed within the context of other data suggesting that trait anxiety-neuroticism may have protective properties.

Positive affect is associated with cardiovascular reactivity, norepinephrine level, and morning rise in salivary cortisol.

Positive affect was examined as a predictor of (1) cardiovascular reactivity during a sadness and an anger recall task and recovery following the protocol, (2) epinephrine (EPI) and norepinephrine (NOREPI) reactivity and level during the recall protocol, and (3) the diurnal pattern of salivary cortisol. Sample was 328 individuals. Negative affect, age, race, sex, smoking status, income, and BMI were adjusted. During sadness recall, positive affect was inversely related to systolic blood pressure (p=.007) and diastolic blood pressure (p=.049) reactivity, and unrelated to heart rate (p=.226). Positive affect was unrelated to reactivity during anger recall (ps>.19), and was unrelated to recovery at the end of the recall protocol. Positive affect was inversely related to the mean level of NOREPI (p=.046), and unrelated to EPI (p=.149). Positive affect was inversely related to the increase in cortisol 30 min post awakening (p=.042), and unrelated to the evening decline in cortisol levels (p=.174). Positive emotions may be relevant to good health.

Effect of Escitalopram on Mental Stress–Induced Myocardial Ischemia: Results of the REMIT Trial

IMPORTANCE Mental stress can induce myocardial ischemia and also has been implicated in triggering cardiac events. However, pharmacological interventions aimed at reducing mental stress-induced myocardial ischemia (MSIMI) have not been well studied. OBJECTIVE To examine the effects of 6 weeks of escitalopram treatment vs placebo on MSIMI and other psychological stress-related biophysiological and emotional parameters. DESIGN, SETTING, AND PARTICIPANTS The REMIT (Responses of Mental Stress Induced Myocardial Ischemia to Escitalopram Treatment) study, a randomized, double-blind, placebo-controlled trial of patients with clinically stable coronary heart disease and laboratory-diagnosed MSIMI. Enrollment occurred from July 24, 2007, through August 24, 2011, at a tertiary medical center. INTERVENTIONS Eligible participants were randomized 1:1 to receive escitalopram (dose began at 5 mg/d, with titration to 20 mg/d in 3 weeks) or placebo over 6 weeks. MAIN OUTCOMES AND MEASURES Occurrence of MSIMI, defined as development or worsening of regional wall motion abnormality; left ventricular ejection fraction reduction of 8% or more; and/or horizontal or down-sloping ST-segment depression of 1 mm or more in 2 or more leads, lasting for 3 or more consecutive beats, during 1 or more of 3 mental stressor tasks. RESULTS Of 127 participants randomized to receive escitalopram (n = 64) or placebo (n = 63), 112 (88.2%) completed end point assessments (n = 56 in each group). At the end of 6 weeks, more patients taking escitalopram (34.2% [95% CI, 25.4%-43.0%]) had absence of MSIMI during the 3 mental stressor tasks compared with patients taking placebo (17.5% [95% CI, 10.4%-24.5%]), based on the unadjusted multiple imputation model for intention-to-treat analysis. A significant difference favoring escitalopram was observed (odds ratio, 2.62 [95% CI, 1.06-6.44]). Rates of exercise-induced ischemia were slightly lower at 6 weeks in the escitalopram group (45.8% [95% CI, 36.6%-55.0%]) than in patients receiving placebo (52.5% [95% CI, 43.3%-61.8%]), but this difference was not statistically significant (adjusted odds ratio; 1.24 [95% CI, 0.60-2.58]; P = .56). CONCLUSIONS AND RELEVANCE Among patients with stable coronary heart disease and baseline MSIMI, 6 weeks of escitalopram, compared with placebo, resulted in a lower rate of MSIMI. There was no statistically significant difference in exercise-induced ischemia. Replication of these results in multicenter settings and investigations of other medications for reducing MSIMI are needed. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00574847.

The effectiveness of psychological debriefing with vicarious trauma: A meta-analysis

Post-traumatic psychiatric reactions to physical trauma are readily acknowledged and accepted. However, there is a relatively new phenomenon of developing similar reactions after providing emergency care to such patients. The purpose of this study was to examine the effectiveness of a crisis intervention technique known as group psychological debriefing, which is designed to mitigate the impact of post-traumatic morbidity in individuals exposed to vicarious traumatization. Using adequately controlled, peer-reviewed journal articles and clinical proceedings as the database, 698 subjects from 10 investigations were submitted to a meta-analysis. The results support the effectiveness of group psychological debriefings in alleviating the effects of vicarious psychological distress in emergency care providers. Copyright

Pharmacometabolomics reveals racial differences in response to atenolol treatment.

Antihypertensive drugs are among the most commonly prescribed drugs for chronic disease worldwide. The response to antihypertensive drugs varies substantially between individuals and important factors such as race that contribute to this heterogeneity are poorly understood. In this study we use metabolomics, a global biochemical approach to investigate biochemical changes induced by the beta-adrenergic receptor blocker atenolol in Caucasians and African Americans. Plasma from individuals treated with atenolol was collected at baseline (untreated) and after a 9 week treatment period and analyzed using a GC-TOF metabolomics platform. The metabolomic signature of atenolol exposure included saturated (palmitic), monounsaturated (oleic, palmitoleic) and polyunsaturated (arachidonic, linoleic) free fatty acids, which decreased in Caucasians after treatment but were not different in African Americans (p<0.0005, q<0.03). Similarly, the ketone body 3-hydroxybutyrate was significantly decreased in Caucasians by 33% (p<0.0001, q<0.0001) but was unchanged in African Americans. The contribution of genetic variation in genes that encode lipases to the racial differences in atenolol-induced changes in fatty acids was examined. SNP rs9652472 in LIPC was found to be associated with the change in oleic acid in Caucasians (p<0.0005) but not African Americans, whereas the PLA2G4C SNP rs7250148 associated with oleic acid change in African Americans (p<0.0001) but not Caucasians. Together, these data indicate that atenolol-induced changes in the metabolome are dependent on race and genotype. This study represents a first step of a pharmacometabolomic approach to phenotype patients with hypertension and gain mechanistic insights into racial variability in changes that occur with atenolol treatment, which may influence response to the drug.