Molecular Mechanisms and Biomarkers for Disease Progression from Prodrome to Early Psychosis

从前驱症状到早期精神病的疾病进展的分子机制和生物标志物

• 批准号: 10312102
• 负责人: FEI DU
• 金额: $ 49.61万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-18 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312102
• 关键词: ATP Synthesis Pathway; Address; Antioxidants; Biochemical Process; Bioenergetics; Biological; Biological Assay; Biological Markers; Blood; Blood specimen; Brain; Brain region; Characteristics; Chlorpromazine; Chronic; Chronic Schizophrenia; Clinical; Clinical Trials; Cognition; Cognitive; Collaborations; Communities; Computer software; Creatine Kinase; DSM-V; Data; Data Set; Development; Diagnosis; Disease; Disease Progression; Early Intervention; Energy Metabolism; Equilibrium; Functional disorder; Future; Glutamates; Glutamine; Glutathione; Glutathione Disulfide; Glycolysis; Goals; Healthcare Systems; Heterogeneity; Human; Impairment; Individual; Inflammatory; Intervention; Lead; Link; Liquid substance; Literature; Longitudinal Studies; Longitudinal cohort; Magnetic Resonance Spectroscopy; Measurement; Measures; Medial; Medicine; Mental disorders; Metabolic; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; NADH; National Institute of Mental Health; Nature; Neuronal Dysfunction; Occipital lobe; Organ; Outcome; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Oxides; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Plasma; Play; Prefrontal Cortex; Prevention strategy; Process; Production; Psychoses; Psychotic Disorders; Public Health; Reactive Oxygen Species; Receptor Signaling; Reporting; Research Design; Research Domain Criteria; Scanning; Schizophrenia; Science; Series; System; Techniques; Testing; Time; Toxic effect; Treatment Efficacy; biological development; biological research; biological systems; burnout; clinical predictors; cohort; early psychosis; experience; family burden; first episode psychosis; first episode schizophrenia; follow-up; high risk; high risk population; improved; in vivo; indexing; information processing; innovation; neuroimaging; neurotransmission; nicotinamide-beta-riboside; non-affective psychoses; novel; patient subsets; pre-clinical; predictive marker; reaction rate; receptor function; recruit; response; stressor; synaptic function; transmission process

Project Summary Despite its public health impact and a century of biological research, the pathophysiology of Schizophrenia (SZ) remains poorly understood. One major barrier is the lack of validated and biologically relevant in vivo measures reflecting SZ progression. Accumulating evidence suggests that a central “immuno-oxidative” pathway involving redox dysregulation, oxidative stress, and NMDA receptor hypofunction, may play a key role in the emergence of neuronal dysfunction and information processing abnormalities characteristic of the disorder. The redox state, reflected by the balance between oxidized NAD+ and reduced NADH, is a key parameter in biological systems indicating the system's ability to carry out energy production; the redox ratio (RR=NAD+/NADH) is thus intimately linked to ATP synthesis processes. The RR is particularly important in the human brain, our most metabolically active organ whose fragile balance of oxidation-reduction is easily disrupted. During intensive energy metabolism, toxic reactive oxygen species are formed; these are eliminated by the antioxidant glutathione (GSH), a critical molecule in resisting oxidative stress. In addition, strong bidirectional influences exist between redox balance and energy metabolism on the one hand and glutamatergic transmission and NMDA receptor function on the other. Thus, the widely-reported abnormalities in glutamatergic function in SZ may be related to abnormal redox balance and bioenergetics. In this proposal, we implement recently developed Magnetic Resonance Spectroscopy (MRS) techniques to measure RR, GSH, and glutamate/glutamine levels in the same brain regions in the same scan, providing convergent evidence on redox dysregulation and glutamatergic function simultaneously in SZ. The current literature suggests that these abnormalities are critical in the early phases of SZ but it is not known how they evolve and influence one another over time. To address this key issue, we will recruit a cohort of individuals at clinical high risk (CHR) and another experiencing a first episode (FE) of psychosis and follow both groups over a 2- year period. Because rate of conversion to frank psychosis is low in CHR groups, we will examine community outcomes in this group as well as conversion. We will also compare findings in this group with those from FE where all individuals have developed frank psychosis. This will allow us to observe unfolding abnormalities at critical stages of the emergence of SZ. We aim to outline the trajectories of biological development in early phases of psychotic disorders and to identify a sensitive predictor for the prodrome and transition to psychosis. The identification of a biomarker associated with CHR which could predict subsequent dysfunction would be a major boost to the development of early intervention and prevention strategies as well as to measuring the impact of early intervention. This proposal uses innovative MRS approaches to ask mechanistic questions using a longitudinal study design. It is likely to be of high impact because it focuses on active disease processes in the critical early stage of SZ.

项目概要 尽管精神分裂症的病理生理学对公共卫生有影响，并且经过一个世纪的生物学研究，但 （SZ）仍然知之甚少。一个主要障碍是缺乏经过验证和生物学相关的体内 反映 SZ 进展的措施。越来越多的证据表明，中枢“免疫氧化” 涉及氧化还原失调、氧化应激和 NMDA 受体功能低下的途径可能发挥关键作用 神经元功能障碍和信息处理异常的出现 紊乱。氧化还原态，由氧化型 NAD+ 和还原型 NADH 之间的平衡反映，是关键 生物系统中的参数，表明系统进行能量生产的能力；氧化还原比 (RR=NAD+/NADH) 因此与 ATP 合成过程密切相关。 RR 在以下情况中尤为重要： 人脑是我们代谢最活跃的器官，其脆弱的氧化还原平衡很容易被破坏 扰乱了。在剧烈的能量代谢过程中，会形成有毒的活性氧；这些都被消除了 抗氧化剂谷胱甘肽（GSH）是抵抗氧化应激的关键分子。此外，强 氧化还原平衡与能量代谢之间存在着双向影响，一方面是 谷氨酸能传递和NMDA受体功能有关。因此，广泛报道的异常 SZ 谷氨酸功能的改变可能与异常的氧化还原平衡和生物能有关。在这个提案中， 我们采用最近开发的磁共振波谱 (MRS) 技术来测量 RR， 在同一扫描中相同大脑区域的 GSH 和谷氨酸/谷氨酰胺水平，提供收敛性 SZ 中同时存在氧化还原失调和谷氨酸能功能的证据。目前的文献 表明这些异常在 SZ 的早期阶段至关重要，但尚不清楚它们是如何演变和 随着时间的推移互相影响。为了解决这个关键问题，我们将招募一批临床人员 高风险 (CHR) 和另一个经历精神病首次发作 (FE) 的人，并在 2- 年期间。由于 CHR 群体中转化为坦率精神病的比率较低，因此我们将检查社区 该组的结果以及转化。我们还将比较该组的研究结果与 FE 的研究结果 那里的所有人都患有明显的精神病。这将使我们能够观察到正在发生的异常情况 SZ 出现的关键阶段。我们的目标是勾勒出早期生物发展的轨迹 精神障碍的各个阶段，并确定前驱症状和向精神病转变的敏感预测因素。 鉴定与 CHR 相关的生物标志物可以预测随后的功能障碍将是一个 极大地促进了早期干预和预防战略的制定以及衡量 早期干预的影响。该提案使用创新的 MRS 方法来提出机械问题 使用纵向研究设计。它可能会产生很大的影响，因为它重点关注活动性疾病 SZ 关键早期阶段的过程。