PET Neuroimaging in Vivo in Mood Disorders and Suicidal Behavior

摘要--项目3 自杀是美国第十大死因，第三大死因 年龄在35-44岁的人，在15-34岁的人中是第二大死因。完全自杀率 在过去的十年里，在美国每年都在上升。分子途径有助于 抑郁症和自杀风险尚未得到很好的了解，这阻碍了新的治疗方法的开发。在 在之前的资助期间，我们使用正电子发射断层扫描(PET)来定量5-羟色胺中的蛋白质 系统、5-羟色胺转运体和5-羟色胺1A受体及其与抑郁、自杀的关系 尝试历史，以及对情绪刺激的神经反应。在此续期申请中，我们建议扩展 我们对几个似乎与抑郁症的神经生物学高度相关的分子通路的研究 和自杀。神经炎症是由应激引起的，涉及中枢神经中小胶质细胞的激活。 并导致几种下游效应，包括大脑神经可塑性的损害 AS对多种神经递质系统的影响。它可能与大脑相关区域的突触丢失有关 抑郁症和自杀的病理生理学，包括前额叶皮质和海马体。我们的 研究小组发现，有证据表明抑郁症患者存在外周自杀高危人群的炎症反应 血液中炎性细胞因子的测量，以及炎症升高的趋同发现 通过对自杀受害者的尸检研究发现大脑中的细胞因子。我们现在建议研究一下 既往有和没有抑郁症病史的患者体内的神经炎症 自杀未遂(MDD+SA和MDD-SA)，并将这些组与健康志愿者(HV)进行比较。 我们还将收集试点数据，以检查神经炎症的潜在下游后果，即 在MDD+SA、MDD-SA和HV参与者的子集中，使用带有新型放射性示踪剂的PET，突触密度 用作标记或突触密度。我们将对上一个资助期的调查结果采取后续行动 单胺氧化酶A酶，由压力诱导，分解5-羟色胺， 多巴胺和去甲肾上腺素。已发现MAO-A在MDD中升高，并随着自杀倾向的增加而增加 我们将研究它与抑郁症和自杀未遂病史的关系。最后，我们将 将该项目的PET结果与临床炎症和HPA轴活动的外周测量进行比较 症状描述，以及在拟建的康特中心的其他项目中获得的功能磁共振数据。确实有 已知的现有临床干预措施针对该提案中量化的每个分子过程， 如果我们验证它们之间的关系，针对这些靶点的额外治疗开发的巨大潜力 抑郁和自杀风险，这将大大推进更有效的干预目标，以减少 MDD导致的发病率和死亡率。

SUMMARY - PROJECT 3 Suicide is the 10th leading cause of death in the United States, the 3rd leading cause of death among individuals age 35-44, and the 2nd leading cause of death among those age 15-34. Completed suicide rates have risen annually in the United States over the past decade. The molecular pathways contributing to depression and suicide risk are not well understood, which has hampered novel treatment development. In the previous period of funding, we used positron emission tomography (PET) to quantify proteins in the serotonin system, the serotonin transporter and the serotonin 1A receptor, and their association to depression, suicide attempt history, and neural responses to emotional stimuli. In this renewal application, we propose to expand our studies to several molecular pathways that appear to be highly relevant to the neurobiology of depression and suicide. Neuroinflammation is induced by stress, involves activation of microglia in the central nervous system, and leads to several downstream effects, including impairments in neuroplasticity in the brain as well as effects on multiple neurotransmitter systems. It may contribute to loss of synapses in brain regions relevant to the pathophysiology of depression and suicide, including the prefrontal cortex and the hippocampus. Our group has identified evidence of inflammation in depressed individuals at high risk for suicide from peripheral blood measurements of inflammatory cytokines, as well as convergent findings of elevated inflammatory cytokines in the brain through postmortem studies in suicide victims. We now propose to examine neuroinflammation in vivo in individuals with current major depressive disorder with and without a history of previous suicide attempt (MDD+SA and MDD-SA), and to compare these groups to healthy volunteers (HV). We will also gather pilot data to examine a potentially downstream consequence of neuroinflammation, loss of synaptic density, in a subset of MDD+SA, MDD-SA and HV participants using PET with a novel radiotracer that serves as a marker or synaptic density. We will follow-up on our findings from the previous funding period by quantifying the monoamine oxidase A enzyme, which is induced by stress and catabolizes serotonin, dopamine and norepinephrine. MAO-A has been found to be elevated in MDD and to scale with suicidal ideation; we will examine its relationship to both depression and suicide attempt history. Lastly, we will compare PET findings from this project to peripheral measures of inflammation and HPA-axis activity, clinical symptom profiles, and functional MRI data acquired in other projects of the proposed Conte Center. There are existing clinical interventions known to target each of the molecular processes being quantified in this proposal, and great potential for additional treatment development aimed at these targets if we validate their relationship to depression and suicide risk, which would greatly advance the goal of intervening more effectively to reduce the morbidity and mortality that results from MDD.