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

项目摘要 尽管它影响公共健康和一个世纪的生物学研究，精神分裂症的病理生理学 (深圳)仍然知之甚少。一个主要的障碍是缺乏在体内经过验证的和生物学上相关的 反映深圳进程的措施。越来越多的证据表明，一种中枢“免疫氧化” 涉及氧化还原失调、氧化应激和NMDA受体功能低下的通路可能起着关键作用 在出现神经元功能障碍和信息处理异常的特点 无序。氧化还原状态是关键，氧化NAD和还原NADH之间的平衡反映了氧化还原状态 生物系统中表示系统产生能量的能力的参数；氧化还原比 (RR=NAD/NADH)因此与ATP合成过程密切相关。存款准备金率在 人脑，我们最活跃的新陈代谢器官，其脆弱的氧化还原平衡很容易 打乱了。在密集的能量新陈代谢过程中，会形成有毒的活性氧物种；这些物种会被清除。 通过抗氧化剂谷胱甘肽(GSH)，这是抵抗氧化应激的关键分子。此外，强势 氧化还原平衡与能量代谢之间存在双向影响； 谷氨酸能传递和NMDA受体在另一端发挥作用。因此，被广泛报道的异常情况 SZ的谷氨酸能功能可能与氧化还原平衡异常和生物能量学有关。在这份提案中， 我们实施了最近开发的磁共振波谱(MRS)技术来测量RR， GSH和谷氨酸/谷氨酰胺水平在同一扫描中的相同大脑区域，提供收敛 SZ氧化还原失调和谷氨酸能功能同时存在的证据。当代文学 提示这些异常在SZ的早期阶段是至关重要的，但尚不清楚它们是如何演变和 随着时间的推移相互影响。为了解决这一关键问题，我们将在临床招募一批个人 高危(CHR)和经历第一次精神病发作(FE)的另一组，并跟踪这两组超过2- 一年期间。由于慢性阻塞性肺病患者转化为坦率精神病的比率较低，我们将对社区进行调查。 这一组的结果以及换算。我们还会将此组中的结果与FE的结果进行比较 所有人都患上了坦率的精神病。这将使我们能够观察到正在展开的异常 深圳出现的关键阶段。我们的目标是在早期勾勒出生物发展的轨迹 目的是研究精神障碍的不同阶段，并找出一个敏感的先兆和向精神病过渡的预测因子。 可以预测后续功能障碍的与CHR相关的生物标记物的鉴定将是 大力推动制定早期干预和预防战略，以及衡量 早期干预的影响。该提案使用创新的MRS方法来提出机械性的问题 采用纵向研究设计。它可能会产生很大的影响，因为它专注于活动性疾病 SZ关键早期阶段的过程。

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.