Evidence of altered polyamine concentrations in cerebral cortex of suicide completers.
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ABSTRACT:
SUBMITTER: Chen GG
PROVIDER: S-EPMC2874419 | biostudies-other | 2010 Jun
REPOSITORIES: biostudies-other
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Project description:BackgroundThe polyamines are a group of ubiquitous low-molecular-weight aliphatic molecules that play an essential role in various physiological functions of the mammalian CNS. Previous literature has indicated alterations in the expression of polyamine-related genes in the brains of individuals who died by suicide, including downregulation of spermidine/spermine N1-acetyltransferase, a key enzyme involved in polyamine catabolism. One such polyamine, agmatine, has been shown to act as an antidepressant in animal models of depressive-like behavior. However, agmatine concentrations have not been explored in postmortem human brain of individuals who died by suicide.MethodsTo measure agmatine in postmortem human brain tissue, we employed our previously published high-resolution capillary gas chromatography in combination with mass spectrometry method. Using this method, we analyzed agmatine levels in a total of 120 tissue samples from Brodmann areas 4, 11, and 44 of 40 male subjects comprising controls (n=13), individuals who died by suicide and met criteria for major depressive disorder (n=14), and subjects who died by suicide and did not meet criteria for major depressive disorder (n=13).ResultsAgmatine fell within the expected nanomolar range and was significantly reduced in the cortex of suicides, irrespective of meeting criteria for major depressive disorder compared with controls.ConclusionsThis is the first gas chromatography-mass spectrometry study to analyze agmatine concentrations in human postmortem brain of individuals who died by suicide. These results add to our mechanistic understanding of the role that the polyamine stress response pathway may play in the neurobiology of major depression and/or suicide.
| S-EPMC6165952 | biostudies-literature
Project description:Suicide is a significant worldwide public health problem. Understanding the neurobiology is important as it can help us to better elucidate underlying etiological factors and provide opportunities for intervention. In recent years, many lines of research have suggested that the polyamine system may be dysregulated in suicidal behaviors. Initial research in animals provided evidence of a dysfunctional polyamine stress response system, while later work using post-mortem human brain tissue has suggested that molecular mechanisms may be at play in the suicide brain. In this review, we will describe the research that suggests the presence of alterations in the polyamine system in mental disorders and behavioral phenotypes, with particular attention to work on suicide. In addition, we will also describe potential avenues for future work.
| S-EPMC5293545 | biostudies-literature
Project description:Probing molecular brain mechanisms related to increased suicide risk is an important issue in biological psychiatry research. Gene expression studies on post mortem brains indicate extensive changes prior to a successful suicide attempt; however, proteomic studies are scarce. Thus, we performed a DIGE proteomic analysis of post mortem tissue samples from the prefrontal cortex and amygdala of suicide victims to identify protein changes and biomarker candidates of suicide. Among our matched spots we found 46 and 16 significant differences in the prefrontal cortex and amygdala, respectively; by using the industry standard t test and 1.3 fold change as cut off for significance. Because of the risk of false discoveries (FDR) in these data, we also made FDR adjustment by calculating the q-values for all the t tests performed and by using 0.06 and 0.4 as alpha thresholds we reduced the number of significant spots to 27 and 9 respectively. From these we identified 59 proteins in the cortex and 11 proteins in the amygdala. These proteins are related to biological functions and structures such as metabolism, the redox system, the cytoskeleton, synaptic function, and proteolysis. Thirteen of these proteins (CBR1, DPYSL2, EFHD2, FKBP4, GFAP, GLUL, HSPA8, NEFL, NEFM, PGAM1, PRDX6, SELENBP1 and VIM,) have already been suggested to be biomarkers of psychiatric disorders at protein or genome level. We also pointed out 9 proteins that changed in both the amygdala and the cortex, and from these, GFAP, INA, NEFL, NEFM and TUBA1 are interacting cytoskeletal proteins that have a functional connection to glutamate, GABA, and serotonin receptors. Moreover, ACTB, CTSD and GFAP displayed opposite changes in the two examined brain structures that might be a suitable characteristic for brain imaging studies. The opposite changes of ACTB, CTSD and GFAP in the two brain structures were validated by western blot analysis.
| S-EPMC3516509 | biostudies-literature
Project description:Linoleic acid (LA, 18:2n-6) is the most abundant polyunsaturated fatty acid in the North American diet and is a precursor to circulating bioactive fatty acid metabolites implicated in brain disorders. This exploratory study tested the effects of increasing dietary LA on plasma and cerebral cortex metabolites derived from LA, its elongation-desaturation products dihomo-gamma linolenic (DGLA, 20:3n-6) acid and arachidonic acid (AA, 20:4n-6), as well as omega-3 alpha-linolenic (?-LNA, 18:3n-3), eicosapentaenoic (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). Plasma and cortex were obtained from rats fed a 0.4%, 5.2% or 10.5% energy LA diet for 15 weeks and subjected to liquid chromatography tandem mass spectrometry analysis. Total oxylipin concentrations, representing the esterified and unesterified pool, and unesterified oxylipins derived from LA and AA were significantly increased and EPA metabolites decreased in plasma at 5.2% or 10.5% energy LA compared to 0.4% energy LA. Unesterified plasma DHA metabolites also decreased at 10.5% energy LA. In cortex, total and unesterified LA and AA metabolites increased and unesterified EPA metabolites decreased at 5.2% or 10.5% LA. DGLA and ?-LNA metabolites did not significantly change in plasma or cortex. Dietary LA lowering represents a feasible approach for targeting plasma and brain LA, AA, EPA or DHA-derived metabolite concentrations.
| S-EPMC5106341 | biostudies-literature
Project description:Background Immune dysregulation may play a role in the development of Rett syndrome (RTT), a neurodevelopmental disorder caused by mutations of the MECP2 gene. Abnormal cytokine concentrations have been documented in the serum of individuals with RTT. Measurement of salivary cytokines has been investigated as a potential alternative approach to measurement in blood and serum, but it is unclear whether salivary cytokine concentrations can provide valid information about systemic immune function in neurodevelopmental disorders. The goal of this study was to evaluate the potential validity of salivary cytokines as biomarkers of immune dysregulation in RTT. Methods Saliva samples from 16 individuals with RTT (all female; age range 2–40 years) and 16 healthy control females (age range 2–40 years) were analyzed for concentrations of 12 cytokines. Between-group differences in concentrations, and correlations with clinical severity in the RTT group were evaluated. Results Concentrations of several salivary cytokines (IL-1β, IL-6, IL-8, IL-10, GM-CSF, TNF-α, and VEGF) were increased in RTT compared to controls. The same cytokines showed significant positive correlations with clinical severity scores. There were no differences in concentrations of IL-2, IL-4, IL-5, IL-12p70, and IFN-γ. Conclusion The results suggest that salivary cytokines may be a possible indicator of immune dysregulation in RTT. Future research should investigate whether these results can be applied to other neurodevelopmental disorders. Highlights • Immune dysregulation may play a role in the development of Rett syndrome (RTT), a disorder caused by mutations of the MECP2 gene.• Concentrations of several salivary cytokines were increased in RTT compared to controls.• These same cytokines showed significant positive correlations with clinical severity scores.• Results suggest that salivary cytokines may be a possible indicator of immune dysregulation in RTT.
| S-EPMC8474566 | biostudies-literature
Project description:We yoked anatomical brain magnetic resonance imaging to a randomized, double-blind, placebo-controlled trial (RCT) of antidepressant medication for 10-week's duration in patients with dysthymia. The RCT study design mitigated ascertainment bias by randomizing patients to receive either duloxetine or placebo, and it supported true causal inferences about treatment effects on the brain by controlling treatment assignment experimentally. We acquired 121 anatomical scans: at baseline and end point in 41 patients and once in 39 healthy controls. At baseline, patients had diffusely thicker cortices than did healthy participants, and patients who had thicker cortices had proportionately less severe symptoms. During the trial, symptoms improved significantly more in medication-compared with placebo-treated patients; concurrently, thicknesses in medication-treated patients declined toward values in healthy controls, but they increased slightly, away from control values, in placebo-treated patients. Changes in symptom severity during the trial mediated the association of treatment assignment with the change in thickness, suggesting that the beneficial effects of medication on symptom severity were at least partially responsible for normalizing cortical thickness. Together our findings suggest that baseline cortical hypertrophy in medication-free patients likely represented a compensatory, neuroplastic response that attenuated symptom severity. Medication then reduced symptoms and lessened the need for compensation, thereby normalizing thickness. This is to the best of our knowledge the first study to report within an RCT a differential change in cortical morphology during medication treatment for depressive illness and the first to provide within an RCT in vivo evidence for the presence of neuroanatomical plasticity in humans.
| S-EPMC5589468 | biostudies-literature
Project description:IntroductionThe microbiota plays a critical role in modulating various aspects of host physiology, particularly through the microbiota-gut-brain (MGB) axis. However, the mechanisms that transduce and affect gut-to-brain communication are still not well understood. Recent studies have demonstrated that dysbiosis of the microbiome is associated with anxiety and depressive symptoms, which are common complications of metabolic syndrome. Germ-free (GF) animal models offer a valuable tool for studying the causal effects of microbiota on the host.MethodsWe employed gene expression and nuclear magnetic resonance (NMR)-based metabolomic techniques to investigate the relationships between brain plasticity and immune gene expression, peripheral immunity, and cerebral and liver metabolism in GF and specific pathogen-free (SPF) mice.ResultsOur principal findings revealed that brain acetate (p = 0.012) was significantly reduced in GF relative to SPF mice, whereas glutamate (p = 0.0013), glutamine (p = 0.0006), and N-acetyl aspartate (p = 0.0046) metabolites were increased. Notably, cFOS mRNA expression, which was significantly decreased in the prefrontal cortex of GF mice relative to SPF mice (p = 0.044), correlated with the abundance of a number of key brain metabolites altered by the GF phenotype, including glutamate and glutamine.DiscussionThese results highlight the connection between the GF phenotype, altered brain metabolism, and immediate-early gene expression. The study provides insight into potential mechanisms by which microbiota can regulate neurotransmission through modulation of the host's brain and liver metabolome, which may have implications for stress-related psychiatric disorders such as anxiety.
| S-EPMC10157641 | biostudies-literature
Project description:BACKGROUND:A growing body of evidence suggests that deficits in long-chain omega-3 (LCn-3) fatty acids may contribute to major depressive disorder (MDD) and principal causes of excess mortality including suicide and cardiovascular disease. In the present study we compared concentrations of docosahexaenoic acid (DHA, 22:6n-3), the principal LCn-3 fatty acid in brain, in the postmortem prefrontal cortex (BA10) of adult depressed suicide victims and controls with and/or without cardiovascular disease. METHODS:DHA concentrations (?mol/g) in the prefrontal cortex (PFC, BA10) of adult male and female suicide victims (n = 20) and controls with (n = 8) or without (n = 12) cardiovascular disease were determined by gas chromatography. RESULTS:There was a non-significant trend for lower DHA concentrations in suicide victims compared with all controls (-10%, p = 0.06, d = 0.5). Significantly lower DHA concentrations were observed in suicide victims compared with controls without cardiovascular disease (-14%, p = 0.03, d = 0.7) but not controls with cardiovascular disease (-4%, p = 0.71, d = 0.1). There was a non-significant trend for lower DHA concentrations in controls with cardiovascular disease compared with controls without cardiovascular disease (-11%, p = 0.1, d = 0.6). CONCLUSIONS:Adult depressed suicide victims exhibit lower postmortem PFC DHA concentrations compared with controls without cardiovascular disease. These data add to a growing body of evidence implicating DHA deficits in the pathophysiology of MDD, suicide, and cardiovascular disease.
| S-EPMC3710518 | biostudies-literature
Project description:A total of 36 postmortem brain samples (23 suicide completers, 13 control sudden death) were collected. We evaluated the proteome profile in the prefrontal cortex (Brodmann area 9, 10) with TMT-based quantification using LC-MS/MS. Several bioinformatics tools were used to elucidate biological mechanisms related to suicide. Subgroup analysis was conducted to find common differentially expressed proteins (DEPs) among various clinically different groups. Among the 9801 proteins identified in our dataset, 295 proteins were differentially expressed between suicide completers and sudden death subjects. Various bioinformatics analysis revealed that suicide completion is predominately enriched in synaptic functions and synaptogenesis especially in endocannabinoid and GABA signaling pathway. Our finding presents the largest protein pools related to suicide completion, and suggests that newly emerging neurotransmitter systems such as endocannabinoid system and synaptogenesis processes may have an impact upon the biological cascade leading to suicide.
2022-05-20 | PXD029845 | Pride
Project description:ImportancePresently, 81 countries mandate the fortification of grain products with folic acid to lessen the risk of neural tube defects in the developing fetus. Epidemiologic data on severe mental illness suggest potentially broader effects of prenatal folate exposure on postnatal brain development, but this link remains unsubstantiated by biological evidence.ObjectiveTo evaluate associations among fetal folic acid exposure, cortical maturation, and psychiatric risk in youths.Design, setting, and participantsA retrospective, observational clinical cohort study was conducted at Massachusetts General Hospital (MGH) among 292 youths 8 to 18 years of age born between January 1993 and December 2001 (inclusive of folic acid fortification rollout ±3.5 years) with normative results of clinical magnetic resonance imaging, divided into 3 age-matched groups based on birthdate and related level of prenatal folic acid fortification exposure (none, partial, or full). Magnetic resonance imaging was performed between January 2005 and March 2015. Two independent, observational, community-based cohorts (Philadelphia Neurodevelopmental Cohort [PNC] and National Institutes of Health Magnetic Resonance Imaging Study of Normal Brain Development [NIH]) comprising 1078 youths 8 to 18 years of age born throughout (PNC, 1992-2003) or before (NIH, 1983-1995) the rollout of folic acid fortification were studied for replication, clinical extension, and specificity. Statistical analysis was conducted from 2015 to 2018.ExposuresUnited States-mandated grain product fortification with folic acid, introduced in late 1996 and fully in effect by mid-1997.Main outcomes and measuresDifferences in cortical thickness among nonexposed, partially exposed, and fully exposed youths (MGH) and underlying associations between age and cortical thickness (all cohorts). Analysis of the PNC cohort also examined the association of age-cortical thickness slopes with the odds of psychotic symptoms.ResultsThe MGH cohort (139 girls and 153 boys; mean [SD] age, 13.3 [2.3] years) demonstrated exposure-associated cortical thickness increases in bilateral frontal and temporal regions (9.9% to 11.6%; corrected P < .001 to P = .03) and emergence of quadratic (delayed) age-associated thinning in temporal and parietal regions (β = -11.1 to -13.9; corrected P = .002). The contemporaneous PNC cohort (417 girls and 444 boys; mean [SD] age, 13.5 [2.7] years) also exhibited exposure-associated delays of cortical thinning (β = -1.59 to -1.73; corrected P < .001 to P = .02), located in similar regions and with similar durations of delay as in the MGH cohort. Flatter thinning profiles in frontal, temporal, and parietal regions were associated with lower odds of psychosis spectrum symptoms in the PNC cohort (odds ratio, 0.37-0.59; corrected P < .05). All identified regions displayed earlier thinning in the nonexposed NIH cohort (118 girls and 99 boys; mean [SD] age, 13.3 [2.6] years).Conclusions and relevanceThe results of this study suggest an association between gestational exposure to fortification of grain products with folic acid and altered cortical development and, in turn, with reduction in the risk of psychosis in youths.
| S-EPMC6142921 | biostudies-literature