Inflammatory, mitochondrial and serotonergic interrelationships in the pathogenesis of major depression

大多数关于重度抑郁障碍(MDD)病理生理学的研究都考察了一个单一的、推定的病因 域。在这项关于MDD发病机制的拟议研究中，我们将评估三条途径之间的关系- 与MDD相关的起源结构域，这些结构域在很大程度上是未知的，因为这三个结构域从未 在一个抑郁的人群中一起学习。这些领域包括：神经炎症、5-羟色胺能 调节失调和线粒体功能障碍。该项目是一项横断面研究，将直接评估 用正电子发射断层扫描(PET)测量所有三个病理生理域的脑功能 神经炎症和5-HT1a自身受体结合，以及近红外光谱(NIRS)检测丝裂原 线粒体功能：MDD(N=45)和健康志愿者(HV；N=20)。第三代高亲和力聚酯 示踪剂[11C]ER176将测量与转运蛋白(TSPO)的结合，TSPO是胶质细胞激活和有丝分裂的标志。 软骨功能。大脑线粒体功能也将通过经颅近红外光谱进行评估。 复制(NIR)。带有[11C]Way-100635的PET将对调节5-羟色胺神经元的5-HT1a自身受体进行量化 开火并释放。大脑测量将在MDD和HV组之间以及MDD内进行比较，因为他们 与抑郁症的严重程度有关。大脑指数也将与外周血液指标相关联，这将 包括犬尿氨酸途径组件、一组细胞/趋化因子和线粒体健康指数(MHI)， 外周线粒体功能的标量单位。此丰富的数据集将用于生成描述性 病理生理域之间的相互关系模型以及每个域与 抑郁症状严重程度。探索性分析将寻求确定表现为DO-DO的患者亚组。 主特异型病理学。 目的1：比较45例未服药、抑郁、非精神病型DSM5 MDD患者与20例HV患者的神经炎情况。 在体内测量大脑的运动、5-羟色胺能和线粒体效应。确定大脑的相关性 MDD组中MDD严重程度的测量。目标2：在与目标1相同的组中，确定关系- 脑组织TSPO结合和oxCOX活性与周围神经炎症指标的相关性 和线粒体的功能。血细胞/趋化因子、犬尿氨酸途径成分和线粒体 健康指数(MHI)。目标3：开发描述性模型。 这项研究在结合神经炎症、线粒体功能和5-羟色胺的评估方面具有创新性。 在使用第三代TSPO放射示踪剂的单组受试者中的HT自身受体结合，以及在 采用新的近红外光谱和MHI方法。研究团队在翻译方面有很强的记录 使用所有建议的模式进行搜索，并配备进行这项建议的研究。这项研究的发现 将有可能统一抑郁症病理生理学的主要理论，并指导新的， 更加个体化的治疗方法。

Most studies of major depressive disorder (MDD) pathophysiology have examined a single, putative causative domain. In this proposed study of MDD pathogenesis, we will evaluate relationships between three path- ogenic domains related to MDD, that are largely unknown because these three domains have never been studied together in a single depressed population. The domains are: neuroinflammation, serotonergic dysregulation and mitochondrial dysfunction. This project is a cross-sectional study that will directly assess brain functioning in all three pathophysiologic domains by using positron emission tomography (PET) to measure neuroinflammation and 5-HT1A autoreceptor binding, and near infrared spectrometry (NIRS) to measure mito- chondrial function, in MDD (N=45) and healthy volunteers (HV; N=20). A third-generation, high-affinity PET tracer, [11C]ER176, will measure binding to translocator protein (TSPO), a marker of glial activation and mito- chondrial function. Brain mitochondrial function also will be assessed with transcranial near infrared spectros- copy (NIRS). PET with [11C]WAY-100635 will quantify 5-HT1A autoreceptors which regulate serotonin neuron firing and release. Brain measures will be compared between MDD and HV groups and within MDD as they relate to depression severity. Brain indices also will be correlated with peripheral blood measures, which will include kynurenine pathway components, a panel of cyto/chemokines, and the mitochondrial health index (MHI), a scalar measure of peripheral mitochondrial function. This rich dataset will be used to generate descriptive models of interrelationships between pathophysiologic domains and the relative correlation of each domain with depressive symptom severity. Exploratory analyses will seek to identify subgroups of patients who exhibit do- main-specific pathology. AIM 1: Compare 45 unmedicated, depressed, non-psychotic DSM5 MDD patients with 20 HVs, on neuroinflam- matory, serotonergic and mitochondrial effects measured in vivo in brain. Determine correlations of brain measures with MDD severity in the MDD group. AIM 2: In the same groups from Aim 1, determine the relation- ships of brain TSPO binding and oxCOX activity to the respective peripheral measures of neuroinflammation and mitochondrial functioning. blood cyto/chemokines, kynurenine pathway components, and the mitochondrial health index (MHI). AIM 3: Develop descriptive models. This study is innovative in combining assessment of neuroinflammation, mitochondrial function, and 5- HT autoreceptor binding in a single set of subjects, in using a third-generation TSPO radiotracer, and in employing novel NIRS and MHI methodologies. The research team has a strong record of translational re- search with all proposed modalities and is equiped to carry out this proposed study. Findings from this study would have potential to unify major theories of depression pathophysiology, and guide the development of new, more individualized treatment approaches.