2/2 - Inflammation and Stress Response in Familial and Nonfamilial Youth Suicidal Behavior

自杀是美国年轻人的第二大死因，自杀比率在17年内上升了33%。临床危险因素 单独的预测能力令人失望，生物预测显示出希望，但很少分开长期的- 由于在自杀行为前不久检测生物学特征的挑战而导致的长期和短期预测因素 (某人)我们提出了一种新的实用方法，用于在急性事件发生后立即检查生物风险概况。 自杀危机，然后将他们分为家族性和非家族性风险档案。我们的协作工作表明 一种与致命性和家族性SB相关的应激反应生物学表型，其中炎症 通过将色氨酸从5-羟色胺分流到5-羟色胺，激活犬尿氨酸途径消耗大脑5-羟色胺 犬尿氨酸合成。炎症和神经性炎症可能由HPA轴和 线粒体失调。我们还发现HPA轴调节失调和炎症在 有某人病史的人和某人的家族史我们假设家族性因素大多是长期的和非家族性的。 影响因素多为短期风险因素。我们建议检查短期或近端的生物风险概况。 在应激反应和炎症途径中的自杀行为(SB)，外周和大脑中，以及 研究青壮年SB的家族和非家族生物学机制。我们将招募120名年轻人 精神科住院或门诊患者，年龄18-30岁，80岁为SB的高危人群，定义为向 急诊科(ED)或因有自杀意念(SI)而入院并有计划和意图的或在最后两次中的某人 风险较低的40例，在过去3个月内没有计划/意图的SB或SI。组将进行频率匹配 关于家族风险。我们将收集：1)临床数据；2)头发测量皮质醇浓度(HCC)；3)进行 Trier社会应激任务(TSST)测量皮质醇、外周炎症(细胞因子、犬尿氨酸 代谢产物)和循环中无细胞线粒体DNA(CCF-mtDNA)；4)使用[11C]ER176配体进行PET成像 5)近红外光谱(NIRS)检测PFC氧化状态 细胞色素-c-氧化酶(OxCOX)，线粒体功能的大脑标志。患者将在1，3， 还有12个月。出院后一年/急诊室出院对某人来说是一个高风险时期，前3个月是 最高风险期。我们假设高危患者会表现出较高的[11C]ER176 PET结合率和较低的oxCOX 在基线上。他们还将表现出较低的肝细胞癌和较高的皮质醇对压力的反应和较高的炎症和 Ccf-mtDNA在基线和应激反应之前。未遂者的后代将表现出更严重的生物学特征 由于短期和长期风险因素的影响而产生的影响。我们还将研究这些关系 外周和大脑测量之间的关系，并探索它们是否可以预测某人。这项研究将改善我们的 了解家族性和非家族性SB更好地区分长期和短期的生物学机制 期限风险生物学表型，这将有助于指导风险检测和新的即时方法。

Suicide is 2nd leading cause of death in the US youth, and rates have risen 33% in 17 years. Clinical risk factors alone have disappointing predictive power and biological predictors show promise but rarely separated into long- term and short-term predictors due to the challenge of detecting biological profiles shortly before suicide behavior (SB). We propose a novel pragmatic approach of examining biological risk profiles immediately after an acute suicidal crisis and then separating them into familial and nonfamilial risk profiles. Our collaborative work indicates a stress responsive biological phenotype associated with more lethal and familial SB where inflammation activates the kynurenine pathway depleting brain serotonin by shunting tryptophan away from serotonin toward kynurenine synthesis. Inflammation and neuroinflammation can potentially result from HPA axis and mitochondrial dysregulations. We also find HPA axis dysregulation and inflammation to be more pronounced in those with SB and family history of SB. We hypothesize familial factors to be mostly long-term and nonfamilial factors to be mostly short-term risk factors. We propose to examine short-term or proximal biological risk profiles for suicidal behavior (SB) in stress response and inflammatory pathways, peripherally and in the brain, and examine familial and nonfamilial biological mechanisms for SB in young adults. We will recruit 120 young adult psychiatric inpatients or outpatients, aged 18-30 years, 80 at high-risk for SB defined as those presenting to the emergency department (ED) or admitted for suicidal ideation (SI) with a plan and intent or SB in the last two weeks; and 40 at lower risk with no SB or SI with plan/intent in past 3 months. Groups will be frequency-matched on familial risk. We will collect: 1) clinical data; 2) hair to measure hair cortisol concentrations (HCC); 3) conduct the Trier Social Stress Task (TSST) to measure cortisol, peripheral inflammation (cytokines, kynurenine metabolites) and circulating cell free mitochondrial DNA (ccf-mtDNA); 4) PET imaging using [11C]ER176 ligand to measure neuroinflammation; and 5) near-infrared spectroscopy (NIRS) to measure in PFC oxidation state of cytochrome-c-oxidase (oxCOX), a brain marker of mitochondrial function. Patients will be followed up at 1, 3, and 12 months. The year post-hospital/ED discharge is a high-risk period for SB and the first 3 months is the highest risk period. We hypothesize high-risk patients will show higher [11C]ER176 PET binding and lower oxCOX at baseline. They will also show lower HCC and higher cortisol response to stress and higher inflammation and ccf-mtDNA prior and in response to stress at baseline. Offspring of attempters will show more severe biological profiles due to the contribution of short and longer-term risk factors. We will also examine the relationships between peripheral and brain measures and explore whether they predict SB. This study will improve our understanding of familial and nonfamilial biological mechanisms for SB to better separate long-term and short- term risk biological phenotypes, which will help guide risk detection and novel just-in-time approaches.