Oxidative Stress Biomarkers in Anhedonia and Major Depression

快感缺失和重度抑郁症的氧化应激生物标志物

• 批准号: 9021877
• 负责人: Kyle Alexander Blumberg Lapidus
• 金额: $ 17.82万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9021877
• 关键词: Oxidative; Stress; Biomarkers; Anhedonia; Major

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.

描述（由申请人提供）：这个以患者为导向的指导研究职业发展奖（K23）的长期目标是支持候选人作为心境障碍转化神经科学研究者的发展。这将通过一个结构化的，有监督的研究经验沿着正式的教学指导，重点是（1）临床研究方法（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。重度抑郁症（MDD）是一种严重的公共卫生问题，与显着的发病率和死亡率。重性抑郁障碍（MDD）的神经生物学相关因素的识别一直受到障碍的异质性的阻碍。为了应对这一挑战，拟议的项目采用了一种维度调查方法，重点关注快感缺失-快感丧失-MDD的核心症状，与自杀和不良预后相关。快感缺失表现出全方位的严重性，并从根本上与神经奖励回路有关。我们 研究小组报告了外周炎症（已知可诱导氧化应激（OS））与人类快感缺乏严重程度之间的密切联系。使用质子磁共振波谱（1H MRS），我们发现外周炎症和纹状体总胆碱（膜周转生物标志物）在快感缺失患者之间呈正相关。最近，我们的团队报道了MDD患者谷胱甘肽（GSH，最重要的脑抗氧化剂）的减少，以及脑GSH与快感缺失严重程度之间的负相关性。基于这些有希望的初步数据，拟议的研究将测试炎症介导的GSH和OS变化与MDD和快感缺乏严重程度特异性相关的总体假设。我们将入组50名无精神药物治疗的MDD受试者和25名匹配的健康对照者，年龄21-65岁。该研究将包括一个全面的，系统的诊断程序，包括结构化的维度评估快感缺失。我们将使用1H MRS，沿着血浆细胞因子和OS标记物水平，测量前扣带皮层和纹状体（神经奖赏回路区域）中GSH的浓度。相关性和影响：为了解决MDD的异质性，拟议的研究重点是快感缺乏症的量化表型，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精神疾病的更机械的、基于神经科学的理解（与NIH RDoC倡议一致）。这项研究的结果也将验证炎症和OS作为真正的疾病生物标志物和潜在的治疗靶点，最终导致临床试验 新的干预措施。重要的是，在K23奖励期间获得的技能和数据将为候选人提供实现成为心境障碍转化神经科学研究的独立研究者的长期目标所需的工具。