Neuroimaging of the Biological Correlates of Early Psychosis: A MR-PET Study

项目摘要 在重新提交这份K01申请时，我们建议进行混合横断面和 旨在了解生物学性质和时间的纵向多模式神经成像研究 先前在首发精神分裂症患者中观察到的急性脑反应的过程。急性期 首发患者的大脑反应以细胞外游离水的全球增加为特征，一直以来 以前与神经炎有关。最近的证据表明，急性大脑反应可能是 与恢复或恢复力有关的代偿性免疫相关行为。在这项提案中，我们建议和 研究这种代偿反应可能与Group表达增加有关的假说 I亚型代谢型谷氨酸受体5(MGluR5)，已被证明对 中枢神经系统中的免疫调节作用。这项K01提案的中心科学目标是 利用全面的数据收集范例1)了解生物的本质和轨迹 通过研究其与mGluR5的联系研究早期精神病的急性脑反应和2)调查 假设FEP中大脑免疫激活的这些标记物与弹性有关。为了实现这一目标， 我们将利用最先进的、同时收集结构、扩散和正电子发射的技术 使用mGluR5放射性配体[18F]FPEB的断层扫描(PET)图像。与我们的混合，横截面和 纵向研究设计，我们将收集多模式成像、血液、神经认知和临床数据 来自一组首发患者和健康的配对对照组。我们假设患有这种疾病的患者 更大的急性脑反应和mGluR5表达将显示出更少的结构损伤和更好的临床和 6个月后进行认知功能测试。这将是第一个研究mGluR5在早期 精神病和这项先导性研究的结果将有助于更好地了解 疾病发作后潜在的弹性的神经生物学成分。 为了实现提出的科学目标，我确定了四个主要的培训领域和相关的 导师/顾问：1)在Jacob Hooker博士(主要)的指导下采集和分析PET图像 导师)和顾问Julie Price博士和Ciprian Catana博士；2)临床和神经认知评估 威廉·斯通博士(共同导师)和马切里·凯沙万博士的指导；3)生物统计学 顾问马克·范格尔博士；4)在马雷克·库比基博士(共同导师)的指导下进行专业发展。 该项目将在哈佛医学院内的多个机构进行，这些机构加在一起，将创造一个 为执行科学目标和拟议的培训计划提供理想的环境。在完成此操作后 K01，我将获得成为一名独立研究员的专业知识和一个 未来的R01。

Project Summary In the resubmission of this K01 application, we propose to conduct a hybrid cross-sectional and longitudinal multi-modal neuroimaging study aimed at understanding the biological nature and time course of an acute brain response previously observed in first-episode schizophrenia patients. The acute brain response, characterized by a global increase in extracellular free water in first-episode patients, has been previously linked to neuroinflammation. Recent evidence suggests that the acute brain response may be part of a compensatory immune-related action related to recovery or resiliency. In this proposal, we suggest and investigate the hypothesis that this compensatory response may be related to the increased expression of Group I subtype metabotropic glutamate receptor 5 (mGluR5), which have been shown to serve a beneficial immunomodulatory role in the central nervous system. The central scientific goal of this K01 proposal is to utilize a comprehensive data collection paradigm to 1) understand the biological nature and trajectory of the acute brain response in early psychosis by investigating its connection to mGluR5 and 2) investigate the hypothesis that these markers of cerebral immune activation in FEP are linked to resiliency. To achieve this goal, we will leverage the state-of-the-art, simultaneous collection of structural, diffusion, and positron emission tomography (PET) images utilizing the mGluR5 radioligand [18F] FPEB. With our hybrid, cross-sectional and longitudinal study design, we will collect multi-modal imaging, blood, neurocognitive, and clinical data from a cohort of first-episode patients and healthy matched controls. We hypothesize that patients with greater acute brain responses and mGluR5 expression will exhibit less structural damage and better clinical and cognitive performance after 6 months. This will be the first study to investigate the role of mGluR5 in early psychosis and the results of this pilot study will be valuable for gaining a greater understanding of the neurobiological components underlying resiliency after illness onset. To carry out the proposed scientific aims, I identified four principal areas of training and associated mentors/advisors: 1) PET image acquisition and analysis under the mentorship of Dr. Jacob Hooker (primary mentor) and advisors Drs. Julie Price and Ciprian Catana; 2) clinical and neurocognitive assessments under the mentorship of Dr. William Stone (co-mentor) and advisor Dr. Matcheri Keshavan; 3) biostatistics with advisor Dr. Mark Vangel; 4) professional development under the mentorship of Dr. Marek Kubicki (co-mentor). This project will take place at multiple institutions within Harvard Medical School, which, combined, create an ideal environment for the execution of the scientific aims and proposed training plan. Upon completion of this K01, I will have acquired the expertise to become an independent researcher and the preliminary data for a future R01.