BackgroundThe development of plasma biomarkers could facilitate early detection, risk assessment and therapeutic monitoring in Alzheimer's 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 FindingsWe 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.ConclusionsIn 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.

The short (s) variant of the serotonin transporter (5-HTT) gene linked functional polymorphic region (5-HTTLPR) is associated with depression. Stressful life events, gender, and race have been shown to moderate this association. We examined the relationship between 5-HTTLPR genotype and symptoms of depression in two samples. Study 1 = 288 participants from a study of caregiver stress; and Study 2 = 142 participants from a study examining psychosocial stressors, genetics, and health. Main effects of 5-HTTLPR on symptoms of depression were examined, along with moderation by stress (care-giving status or low childhood socioeconomic status (SES), gender, and race. The 5-HTTLPR × stress group × gender interaction was significant in both samples (P < 0.003, and P < 0.008, respectively). For females, the s allele, combined with caregiving stress (Study 1) or low

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.

Therapeutic response to selective serotonin (5-HT) reuptake inhibitors in Major Depressive Disorder (MDD) varies considerably among patients, and the onset of antidepressant therapeutic action is delayed until after 2 to 4 weeks of treatment. The objective of this study was to analyze changes within methoxyindole and kynurenine (KYN) branches of tryptophan pathway to determine whether differential regulation within these branches may contribute to mechanism of variation in response to treatment. Metabolomics approach was used to characterize early biochemical changes in tryptophan pathway and correlated biochemical changes with treatment outcome. Outpatients with MDD were randomly assigned to sertraline (n = 35) or placebo (n = 40) in a double-blind 4-week trial; response to treatment was measured using the 17-item Hamilton Rating Scale for Depression (HAMD17). Targeted electrochemistry based metabolomic platform (LCECA) was used to profile serum samples from MDD patients. The response rate was slightly higher for sertraline than for placebo (21/35 [60%] vs. 20/40 [50%], respectively, χ2(1)  = 0.75, p = 0.39). Patients showing a good response to sertraline had higher pretreatment levels of 5-methoxytryptamine (5-MTPM), greater reduction in 5-MTPM levels after treatment, an increase in 5-Methoxytryptophol (5-MTPOL) and Melatonin (MEL) levels, and decreases in the (KYN)/MEL and 3-Hydroxykynurenine (3-OHKY)/MEL ratios post-treatment compared to pretreatment. These changes were not seen in the patients showing poor response to sertraline. In the placebo group, more favorable treatment outcome was associated with increases in 5-MTPOL and MEL levels and significant decreases in the KYN/MEL and 3-OHKY/MEL; changes in 5-MTPM levels were not associated with the 4-week response. These results suggest that recovery from a depressed state due to treatment with drug or with placebo could be associated with preferential utilization of serotonin for production of melatonin and 5-MTPOL.

Background Expectations of patients regarding their prospects for recovery have been shown to predict subsequent physical and social functioning. Evidence regarding the impact of expectations on clinical outcomes is limited. Methods At the inpatient service of a tertiary care hospital, we evaluated beliefs of patients undergoing coronary angiography about their prognosis as predictors of long-term survival and 1-year functional status. Baseline assessments, including a measure of expectations for recovery, were obtained during hospitalization with mortality follow-up for approximately 15 years. Patients with significant obstructive coronary artery disease were interviewed while in the hospital and enrolled in follow-up. Functional status was assessed at baseline and 1 year later with questionnaires reflecting physical capabilities. Analyses controlled for age, sex, disease severity, comorbidities, treatments, demographics, depressive symptoms, social support, and functional status. There were 1637 total deaths, 885 from cardiovascular causes, in the 2818 patients in these analyses. The outcomes were total mortality, cardiovascular mortality, and 1-year functional status. Results Expectations were positively associated with survival after controlling for background and clinical disease indicators. For a difference equivalent to an inter-quartile range of expectations, the hazard ratio (HR) for total mortality was 0.76 (95% confidence interval [CI], 0.71–0.82) and 0.76 (95% CI, 0.69–0.83) for cardiovascular mortality. The HRs were 0.83 (95% CI, 0.76–0.91) and 0.79 (95% CI, 0.70–0.89) with further adjustments for demographic and psychosocial covariates. Similar associations (P<.001) were observed for functional status. Conclusion Recovery expectations at baseline were positively associated with long-term survival and functioning in patients with coronary artery disease.

These findings suggest that greater emotional awareness and high curiosity, as indicated by the NEO PI Feelings and Actions facets, are associated with increased patient longevity independently of other risk factors and educational achievement.

Targeted metabolomics provides an approach to quantify metabolites involved in specific molecular pathways. We applied an electrochemistry-based, targeted metabolomics platform to define changes in tryptophan, tyrosine, purine and related pathways in the depressed and remitted phases of major depressive disorder (MDD). Biochemical profiles in the cerebrospinal fluid of unmedicated depressed (n = 14; dMDD) or remitted MDD subjects (n = 14; rMDD) were compared against those in healthy controls (n = 18; HC). The rMDD group showed differences in tryptophan and tyrosine metabolism relative to the other groups. The rMDD group also had higher methionine levels and larger methionine-to-glutathione ratios than the other groups, implicating methylation and oxidative stress pathways. The dMDD sample showed nonsignificant differences in the same direction in several of the metabolic branches assessed. The reductions in metabolites associated with tryptophan and tyrosine pathways in rMDD may relate to the vulnerability this population shows for developing depressive symptoms under tryptophan or catecholamine depletion.

The serotonin 5HTR2C receptor has been shown to mediate HPA axis activation during stress. We hypothesized that a functional polymorphism (rs6318) of the 5HTR2C gene would be associated with HPA axis response to a laboratory stress protocol. The present sample consisted of 41 men (22 African Americans, 19 Caucasians). We found that at rest men with the more active rs6318 Ser23 C allele had similar cortisol values compared to those with the less active sys23 G allele. During laboratory stress, however, men with the Ser23 C allele exhibited the predicted significantly higher cortisol levels (p < .001), as well as larger increases in anger (P=0.08) and depressive mood (P=0.006) ratings, compared to the sys23 G carriers. The increase in cortisol was significantly related to the increases in ratings of anger and depression assessed before and after the emotion induction, and these correlations became nonsignificant when rs6318 genotype was covaried. We conclude that genetic variation in 5HTR2C may be associated with HPA axis activation and stimulated by emotional stress, and also with both psychological and physiological endophenotypes that increase the risk of cardiovascular disease and type 2 diabetes.