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.

项目摘要 尽管精神分裂症对公众健康的影响和世纪的生物学研究， (SZ)仍然知之甚少。一个主要的障碍是缺乏经验证的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，一个中央“免疫氧化” 包括氧化还原失调、氧化应激和NMDA受体功能低下的通路可能起关键作用 在出现神经元功能障碍和信息处理异常的特点， disorder.由氧化的NAD+和还原的NADH之间的平衡所反映的氧化还原状态是关键。 生物系统中的一个参数，表示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。经常资源特别重要， 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 被打乱了在密集的能量代谢过程中，形成有毒的活性氧;这些被消除 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双向影响， 另一方面是神经递质传递和NMDA受体功能。因此，广泛报道的异常 SZ的神经功能可能与氧化还原平衡异常和生物能量学有关。在这项提案中， 我们实施最近开发的磁共振波谱（MRS）技术来测量RR， GSH和谷氨酸/谷氨酰胺水平在相同的大脑区域在同一扫描，提供收敛 SZ中氧化还原失调和代谢能功能同时存在的证据。当前文献 表明这些异常在SZ的早期阶段是至关重要的，但尚不清楚它们是如何演变的， 随着时间的推移相互影响。为了解决这个关键问题，我们将招募一批临床研究人员， 高风险（ESTA）和另一个经历精神病的第一次发作（FE），并遵循两组超过2- 年期间。由于转化为坦率的精神病的比率是低的，我们将研究社区 在这一组的成果，以及转换。我们还将比较这一组的结果与FE的结果 所有人都有明显的精神病这将使我们能够观察到在 深圳出现的关键阶段。我们的目标是勾勒出早期生物发展的轨迹， 精神障碍的阶段，并确定一个敏感的预测前驱症状和过渡到精神病。 鉴定与可预测随后功能障碍的脑卒中相关的生物标志物将是一个重要的研究方向。 大大推动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 采用纵向研究设计。它可能具有很高的影响力，因为它侧重于活动性疾病 在深圳的关键早期阶段的过程。