Neuroinflammation and Oxidative Stress in Veterans with Schizophrenia

退伍军人事务职业发展奖(CDA-2)建议检查神经炎症水平 以及精神分裂症退伍军人大脑中的氧化应激，并将这些过程相互联系 以及重要的功能结果。神经炎症，指的是免疫细胞在脑组织中的招募 对伤害的反应，以及抗氧化防御系统(AODs)，指的是分子和酶 中和过量的自由基(氧化应激)，是对损伤的重要保护性反应 大脑。研究表明，与健康对照组相比，精神分裂症患者两者均发生了改变，可能与此有关 精神分裂症的发病机制。此外，它们与脑功能障碍的关系 精神分裂症，包括职业状况、住房状况和社会关系，仍然相对 没有经过研究。直到最近，神经炎的标志物和AOD只在 患者的死后组织、外周血或脑脊液(CSF)。这份CDA-2报告建议 直接检测退伍军人精神分裂症患者和对照组的神经炎症反应和AOD 使用两种相对较新的技术的受试者：1)神经炎症将用第二代 放射配基结合分子转位蛋白(TSPO)，使用正电子发射断层扫描(PET)； 受试者将在进入研究之前进行基因分型，以排除低亲和力结合表型，以及 2)AOD将用大脑中最重要的抗氧化剂分子谷胱甘肽的水平来衡量， 使用磁共振波谱(MRS)。具体的焦点区域将是前额背外侧 考虑到这一区域对精神分裂症患者认知功能的重要性。该项目有三个科学依据 目标：a)脑内神经炎症水平和AOD将在以下患者之间进行比较 精神分裂症和健康对照。B)神经炎症和氧化应激两者之间的关系 其他住院患者将接受检查，以及他们与认知表现和社区的关系 通过临床评估和访谈发挥作用。C)外周炎症标志物肿瘤坏死因子-α、白介素6、白介素10、 将测量Inf-g和CRP，并检查它们与上述中央标志物的关系。这 信息将阐明精神分裂症患者大脑中两个关键过程的作用及其影响 关于患有精神分裂症的退伍军人的生活质量。除了这些科学目标外，这项提案还将提供 申请人，Yvonne Yang博士，在PET神经成像和MRS神经成像方面拥有专业知识，并在 精神分裂症的神经炎症领域。杨医生的培训计划包括定期与她会面 导师：PET神经成像专家Mark Mandelkern博士，物理学家阿尔伯特·托马斯博士，精神病学家和 谷胱甘肽代谢综合征专家理查德·马多克博士，精神神经免疫学专家迈克尔·欧文博士，以及 她的主要导师迈克尔·格林博士。它还包括研讨会、会议、正式的教学和培训 以负责任的态度进行研究。所描述的科学项目、培训计划和指导计划 以上将为杨博士提供独立领导进一步研究的技能和专业知识 神经炎症在精神分裂症中的作用，并为个性化药物治疗奠定了基础 使用抗炎和抗氧化剂的范例，通过退伍军人事务部优异奖提案。

This Veterans Affairs Career Development Award (CDA-2) proposes to examine levels of neuroinflammation and oxidative stress in the brains of Veterans with schizophrenia, and to relate these processes to each other and to important functional outcomes. Neuroinflammation, which refers to the recruitment of immune cells in response to injury, and the antioxidant defense system (AODS), which refers to the molecules and enzymes that neutralize an excess of free radicals (oxidative stress), are important protective responses to injury in the brain. Both have been shown to be altered in schizophrenia compared to healthy controls, and may be related to the pathogenesis of schizophrenia. Furthermore, their relationship to disrupted functional outcomes in schizophrenia including occupational status, housing status, and social relationships, remains relatively unstudied. Until recently, markers for neuroinflammation and the AODS have only been examined in postmortem tissue, peripheral blood, or cerebrospinal fluid (CSF) of patients. This CDA-2 proposes to examine both neuroinflammation and the AODS directly in brain of Veterans with schizophrenia and control subjects with two relatively novel techniques: 1) neuroinflammation will be measured with second-generation radioligand binding to the molecule translocator protein (TSPO), using positron emission tomography (PET); subjects will be genotyped in order to exclude the low affinity binding phenotype prior to entering the study, and 2) the AODS will be measured with levels of glutathione, the most important antioxidant molecule in the brain, using magnetic resonance spectroscopy (MRS). The specific area of focus will be dorsolateral prefrontal cortex in light of this area’s importance for cognitive function in schizophrenia. The project has three scientific goals: a) Brain levels of neuroinflammation and the AODS will be compared between patients with schizophrenia and healthy controls. b) The relationship of neuroinflammation and oxidative stress to each other in patients will be examined, along with their relationship to cognitive performance and community function via clinical assessments and interviews. c) The peripheral inflammatory markers TNF-a, IL-6, IL-10, INF-g and CRP will be measured, and their relationship to the above central markers will be examined. This information will shed light on the roles of two key processes in the brain in schizophrenia, and their influence on quality of life for Veterans with schizophrenia. In addition to these scientific aims, this proposal will provide the applicant, Dr. Yvonne Yang, with expertise in PET neuroimaging and MRS neuroimaging, and expertise in the field of neuroinflammation in schizophrenia. Dr. Yang’s training plan includes regular meetings with her mentors: expert in PET neuroimaging Dr. Mark Mandelkern, MRS physicist Dr. Albert Thomas, psychiatrist and expert in MRS of glutathione Dr. Richard Maddock, expert in psychoneuroimmunology Dr. Michael Irwin, and her primary mentor Dr. Michael Green. It also includes workshops, conferences, formal didactics, and training in the responsible conduct of research. The scientific project, training plan, and mentoring plan described above will provide Dr. Yang with the skills and expertise to independently lead further studies investigating the role of neuroinflammation in schizophrenia, and lay the groundwork for a personalized medicine treatment paradigm using anti-inflammatory and antioxidant agents, through a VA Merit Award proposal.