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: 10065526
• 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/10065526
• 关键词: ATP Synthesis Pathway; Address; Antioxidants; Biochemical Process; Bioenergetics; Biologic Development; 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 research; biological systems; burnout; clinical predictors; cohort; 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; 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.

项目摘要 尽管其公共卫生影响和一个世纪的生物学研究，但精神分裂症的病理生理学 （SZ）仍然很少了解。一个主要的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。积累的证据表明，中央“免疫氧化” 涉及氧化还原失调，氧化应激和NMDA受体功能障碍的途径可能起关键作用 在神经元功能障碍和信息处理异常的出现中 紊乱。氧化还原状态是​​由氧化的NAD+和还原NADH之间的平衡反映的，是一个钥匙 生物系统中的参数，表明该系统能够执行能源生产的能力；氧化还原比 （RR = NAD+/NADH）因此与ATP合成过程密切相关。 RR在 人脑，我们最具代谢活性的器官，其脆弱的氧化 - 还原平衡很容易 破坏了。在强化能量代谢期间，形成有毒的活性氧。这些被淘汰 通过抗氧化剂谷胱甘肽（GSH），这是抵抗氧化应激的临界分子。另外，很强 双向影响一方面存在于氧化还原平衡和能量代谢之间 谷氨酸能传播和NMDA受体的功能在另一个上。那是广泛报道的异常 在SZ中的谷氨酸能功能中，可能与异常的氧化还原平衡和生物能学有关。在此提案中， 我们实施了最近开发的磁共振光谱（MRS）技术来测量RR， 在同一扫描中的同一大脑区域中的GSH和谷氨酸/谷氨酰胺水平，提供转换 仅在SZ中，有关氧化还原失调和谷氨酸能功能的证据。当前的文献 表明这些异常在SZ的早期阶段至关重要，但尚不知道它们如何发展和 随着时间的流逝，彼此互相影响。为了解决这个关键问题，我们将在临床上招募一群人 高风险（CHR）和另一个经历了精神病的第一集（FE），并在2-上跟随这两个群体 年期。因为CHR组的转化率转换为Frank精神病率很低，我们将检查社区 该组的结果以及转换。我们还将将该小组中的发现与FE的发现进行比较 所有人都发展了坦率的精神病。这将使我们能够观察到不正常 SZ出现的关键阶段。我们的目标是早期概述生物发展的轨迹 精神病的阶段，并确定对前代的敏感预测因子并过渡到精神病。 与ChR相关的生物标志物的鉴定可以预测随后的功能障碍将是一个 重大促进早期干预和预防策略的发展以及衡量 早期干预的影响。该建议使用创新的MRS方法来提出机械问题 使用纵向研究设计。它可能会产生高影响，因为它专注于活动疾病 在SZ的关键早期阶段的过程。