Toxoplasma gondi, the kynurenine pathway, and suicidal behavior in veterans

弓形虫、犬尿氨酸途径和退伍军人的自杀行为

• 批准号: 9033416
• 负责人: TEODOR T POSTOLACHE
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9033416
• 关键词: Adult; Aggressive behavior; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Baltimore; Biological; Biological Markers; Biological Process; Biology; Blood; Boxing; Brain; Carboxy-Lyases; Chronic; Clinic; Clinical Trials; Color; Communities; Data; Decision Making; Delayed Memory; Diagnosis; Enzyme-Linked Immunosorbent Assay; Epidemic; Equation; FDA approved; Feeling hopeless; Feeling suicidal; Future; Gambling; Goals; Health; High Pressure Liquid Chromatography; Immune; Immunoglobulin G; Impulsivity; Individual; Infection; Inflammation; Inpatients; Intervention; Iowa; Iraq; Knowledge; Kynurenine; Linear Regressions; Link; Logistic Regressions; Longitudinal Studies; Mass Fragmentography; Measures; Mediating; Mediation; Mental Health; Mental Health Services; Methods; Middle East; Modeling; Molecular; Monitor; Neuropsychological Tests; Neuropsychology; Outpatients; Parasites; Participant; Pathway interactions; Patients; Performance; Personality Traits; Pharmaceutical Preparations; Phenotype; Picolinic Acids; Plasma; Population; Production; Questionnaires; Quinolinic Acid; Recording of previous events; Recruitment Activity; Reporting; Research Personnel; Resistance; Risk; Risk Management; Role; Seroprevalences; Short-Term Memory; Statistical Methods; Subgroup; Suicide; Suicide attempt; Suicide prevention; Testing; Time; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Tryptophan; Veterans; Violence; base; clinical research site; cytokine; design; enzyme activity; executive function; high risk; immune activation; improved; inclusion criteria; indexing; inflammatory marker; insight; latent infection; middle age; neuroinflammation; neuropsychological; neurotoxic; novel; outcome forecast; personalized approach; premature; prevent; public health relevance; reducing suicide; research study; resilience; response; suicidal; suicidal behavior; suicidal morbidity; suicidal risk; suicide mortality; trait; trait impulsivity

 DESCRIPTION (provided by applicant): Background As suicide epidemics appear resilient to current organizational and individual approaches, and as our pharmacological arsenal for suicide prevention is stagnant, there is a fundamental need to increase our understanding about the biological mechanisms underlying suicidal self-directed violence (SSDV). The goals of this proposal are therefore to investigate infectious and immune biological processes that contribute to SSDV. Infection with Toxoplasma gondii (T. gondii), markers of inflammation and elevations of kynurenines have been separately associated with SSDV. However, no studies have investigated T. gondii, inflammation, and kynurenine (KYN) interdependently, and in interaction with traits of impulsivity and aggression as well as neuropsychological deficits considered as intermediate phenotypes for SSDV. Moreover no previous study has examined these associations in higher lethality attempts by Veterans, a population at higher risk for both suicide as well as, through deployment to Middle East, T. gondii exposure. From a molecular standpoint, the project will test whether T. gondii IgG seropositivity, and high levels of proinflammatory cytokines, KYN and its neurotoxic metabolite quinolinic acid (QUIN) are associated with SSDV. Conceptually, the project will explore molecular resilience supported by our preliminary data that a high index of activity of the enzyme aminocarboxy-muconate semialdehyde decarboxylase (ACMSD) leading to the production of a neuroprotective molecule, picolinic acid (PIC) at the expense of QUIN may provide resilience to suicide elevating effects of infection and inflammation. Finally, the potentil capacity of trait aggression mediating role of aggression and decision making deficits to mediate the link between T gondii seropositivity, inflammation and SSDV will be examined. Aims The specific aims are to a) estimate associations between SSDV and T. gondii IgG seropositivity (Aim 1) and Kynurenine and its metabolite levels (Aim 2), in interaction with markers of immune activation; b) investigate associations between T. gondii and impulsivity, aggression, decision making deficits, previously described as intermediate phenotypes for SSDV (Aim 3), and c) to analyze interactions between infection, inflammation, kynurenines, intermediate phenotypes and SSDV (Integrative Aim 4). Methods We will compare T. gondii seropositivity, KYN and its metabolites QUIN and PIC, and inflammation markers in Veterans who receive mental health services with (N=300) vs. those without (N=300) history of SSDV who had at least one suicide attempt of high lethality. Veterans will be recruited on the inpatient units, outpatient mental health clinics and in the community at Baltimore, Atlanta, or Denver VAs. All participants will be carefully diagnosed, and evaluated for history of suicidal behavior and suicidal ideation, as well as factors known to interact with inflammation or SSDV. T. gondii seropositivity will be measured by enzyme-linked Immunosorbent assay, KYN with High Pressure Liquid Chromatography, KYN metabolites with Gas chromatography-mass spectrometry, impulsivity and aggression with well-validated questionnaires. Neuropsychological tests will include Iowa Gambling Test, The Immediate and Delayed Memory Test, and the Stroop Color and Word Test. Statistical methods will be based on multivariable logistic regression and linear regression methods with GEE for clustering within VA clinical sites. Direct and indirect associations among the variables, and testing the strength of the hypothesized associations will be done using structural equation modeling. Impact We expect that this study with broad inclusion criteria, and thus generalizability for Veterans and higher lethality attempters will contribute to future predictive and interventional studies to discover combinations of bio- and neuropsychological markers to improve prognosis of SSDV, and potentially identify novel intervention targets for specific subgroups of Veterans at increased risk.

 描述（由申请人提供）： 背景 由于自杀流行病似乎对当前的组织和个人方法具有弹性，并且由于我们预防自杀的药物库停滞不前，因此我们迫切需要加深对自杀性自我导向暴力（SSDV）背后的生物学机制的了解。因此，该提案旨在研究导致 SSDV 感染的感染和免疫生物学过程，炎症标志物和犬尿氨酸升高分别与该感染相关。然而，尚无研究探讨弓形虫、炎症和犬尿氨酸 (KYN) 之间的相互依赖性，以及与被视为 SSDV 中间表型的冲动和攻击性特征以及神经心理缺陷的相互作用。在退伍军人的更高致死率尝试中，该人群自杀风险较高，并且通过部署到中东，从分子角度来看，该项目将测试弓形虫是否存在。 IgG 血清阳性和高水平的促炎细胞因子、KYN 及其神经毒性代谢物喹啉酸 (QUIN) 从概念上讲，该项目将探索由我们初步数据支持的分子弹性，即高活性指数。 氨基羧基粘康酸半醛脱羧酶（ACMSD）导致以 QUIN 为代价产生神经保护分子吡啶甲酸（PIC），这可能会增强感染和炎症的自杀效应。最后，特质攻击介导作用的潜在能力。将检查攻击性和决策缺陷介导弓形虫血清阳性、炎症和 SSDV 之间的联系。 a) 评估 SSDV 与弓形虫 IgG 血清阳性（目标 1）和犬尿氨酸及其代谢物水平（目标 2）之间的关联，以及与免疫激活标记物的相互作用；b) 研究弓形虫与冲动、攻击性、决策之间的关联；缺陷，之前被描述为 SSDV 的中间表型（目标 3），以及 c) 分析感染、炎症、犬尿氨酸、中间表型和 SSDV 之间的相互作用（综合目标 4）我们将比较接受心理健康服务的退伍军人 (N=300) 与没有 (N=300) 病史的退伍军人的弓形虫血清阳性、KYN 及其代谢物 QUIN 和 PIC 以及炎症标志物。巴尔的摩、亚特兰大或丹佛的住院部、门诊心理健康诊所和社区将招募至少有过一次自杀未遂经历的退伍军人。所有参与者都将被仔细诊断，并评估自杀行为和自杀意念的历史，以及已知与炎症或弓形虫血清阳性相互作用的因素，将通过酶联免疫吸附试验、高压 KYN 进行测量。液相色谱法、气相色谱-质谱法测定 KYN 代谢物、冲动性和攻击性以及经过充分验证的神经心理学测试。爱荷华州赌博测试、即时和延迟记忆测试以及 Stroop 颜色和单词测试将基于多变量逻辑回归和线性回归方法，并使用 GEE 对 VA 临床站点内的变量进行聚类，以及将使用结构方程模型来测试开创性关联的强度。影响我们预计这项研究具有广泛的纳入标准，因此对退伍军人和更高致死率尝试者的普遍适用性将有助于未来的预测和干预研究，以发现生物和杀伤力的组合。神经心理学标志物可改善 SSDV 的预后，并可能为风险较高的退伍军人特定亚群确定新的干预目标。