Oxidative Stress Biomarkers in Anhedonia and Major Depression

描述(由申请者提供)：这个以患者为导向的导师研究职业发展奖(K23)的长期目标是支持候选人作为情绪障碍翻译神经科学的研究人员的发展。这将通过有组织的、有监督的研究经验以及专注于(1)临床研究方法论(包括MRS方法、数据分析、生物统计学和伦理学)和(2)情感神经科学的正式教学指导来实现。严重抑郁障碍(MDD)是一个严重的公共卫生问题，与严重的发病率和死亡率有关。严重抑郁障碍(MDD)的异质性阻碍了神经生物学相关因素的识别。为了应对这一挑战，拟议的项目利用了一种维度调查方法，专注于快感丧失--MDD的核心症状，与自杀和预后不良相关。快感缺乏症表现出一系列的严重性，从根本上说与神经奖赏回路有关。我们的 研究小组报告称，外周炎症与人类快感缺乏的严重程度之间存在强烈的关联。利用质子磁共振波谱(1HMRS)，我们发现快感厌食症患者的外周炎症与纹状体总胆碱(膜翻转生物标志物)呈正相关。最近，我们的团队报告了MDD患者谷胱甘肽(GSH，最重要的大脑抗氧化剂)的减少，以及大脑GSH与快感缺失严重程度之间的负相关。在这些有希望的初步数据的基础上，拟议的研究将检验总体假设，即炎症介导的GSH和OS变化与MDD和快感缺乏严重程度特别相关。我们将招募50名患有MDD的非精神药物受试者和25名年龄在21-65岁之间的匹配的健康对照。这项研究将包括一个全面、系统的诊断程序，其中包括对快感缺乏症的结构化维度评估。我们将使用~1H MRS测量神经回报回路的前扣带皮质和纹状体中GSH的浓度，以及血浆细胞因子和OS标记的水平。相关性和影响：为了解决MDD的异质性，拟议的研究重点放在快感缺乏症的良好量化表型上，同时采用免疫学和神经化学成像的综合研究策略。拟议的研究可以导致对这种严重的精神障碍的更机械性的、基于神经科学的理解(与NIH RDoC倡议一致)。这项研究的结果还将证实炎症和OS是真正的疾病生物标志物和潜在的治疗目标，最终将导致临床试验 对人类的新干预。重要的是，在K23颁奖期间获得的技能和数据将为候选人提供所需的工具，以实现成为情绪障碍翻译神经科学研究的独立研究员的长期目标。

DESCRIPTION (provided by applicant): The long-term objective of this Patient-Oriented Mentored Research Career Development Award (K23) is to support the development of the candidate as an investigator in translational neuroscience of mood disorders. This will be accomplished through a structured, supervised research experience along with formal didactic instruction focused on (1) Clinical Research Methodology (including MRS Methods, Data Analysis, Biostatistics, and Ethics) and (2) Affective Neuroscience. Major depressive disorder (MDD) is a serious public health concern associated with significant morbidity and mortality. The identification of neurobiological correlates of major depressive disorder (MDD) has been hampered by the disorder's heterogeneity. To address this challenge, the proposed project utilizes a dimensional investigative approach focusing on anhedonia - the loss of pleasure - a core symptom of MDD that is associated with suicide and less favorable prognosis. Anhedonia manifests a full range of severity and is fundamentally related to the neural reward circuitry. Our team reported strong associations between peripheral inflammation, known to induce oxidative stress (OS), and anhedonia severity in humans. Using proton magnetic resonance spectroscopy (1H MRS) we found positive correlations between peripheral inflammation and striatal total choline (membrane turnover biomarker) in anhedonic patients. More recently, our team reported decreased glutathione (GSH, the most important brain antioxidant) in MDD, as well as negative associations between brain GSH and anhedonia severity. Building upon these promising preliminary data, the proposed study will test the overall hypothesis that inflammation-mediated changes in GSH and OS are specifically linked to MDD and anhedonia severity. We will enroll 50 psychotropic-medication free subjects with MDD and 25 matched healthy controls, ages 21-65. The study will consist of a comprehensive, systematic diagnostic procedure that includes structured dimensional assessments of anhedonia. We will measure concentrations of GSH in the anterior cingulate cortex and striatum, regions of the neural reward circuitry, using 1H MRS, along with plasma levels of cytokines and OS markers. RELEVANCE AND IMPACT: To address the heterogeneous nature of MDD, the proposed research focuses on the well-quantified phenotype of anhedonia while employing an integrated investigative strategy of immunological and neurochemical imaging. The proposed research can lead to more mechanistic, neuroscience-based understanding (consistent with the NIH RDoC initiative) of this severe psychiatric disorder. The results of this study will also validate inflammation and OS as bona fide disease biomarkers and potential treatment targets, ultimately leading to clinical trials of novel interventions in humans. Importantly, the skills and data acquired during the K23 award period will provide the candidate with the tools required to achieve the long-term goal of becoming an independent investigator in translational neuroscience research of mood disorders.