Inflammatory Biomarkers in First Episode Psychosis: A Mexico/US Collaboration

描述(由申请人提供)：目前的提案是针对标准杆11-031，发展中国家的大脑疾病：跨寿命研究(R21)，将建立在加州大学圣地亚哥分校(UCSD)和墨西哥城国家神经研究所(INNN)之间现有的合作基础上。进一步的合作，重点是了解和治疗早期精神病的神经病理变化，可能会对墨西哥的早期精神病研究产生重大影响，因为Innn是这座拥有2000多万人口的城市的中心培训地点。拟议的R21将1)提供资源以 为墨西哥城可能大量使用抗精神病药物的首发精神病患者建立招募基础设施。此外，墨西哥工厂将通过从加州大学圣迭戈分校获得磁共振成像(MRI)分析技术方面的培训，加强其在Innn的神经成像计划，包括皮质厚度的分割分析和扩散张量成像(DTI)数据的自由水分析。为了确保神经成像生物标记物在现场之间的可靠性，我们将在项目的前三个月进行一项旅行受试者研究。最后，2)我们还将在两个地点获得抗精神病药物初发患者和正常对照的先导性神经成像和炎症生物标记物数据，为在同一人群中调查神经炎症和抗炎治疗的纵向研究做准备。最终，我们计划提交一份翻译的R01，该报告将研究早期精神病的人类和动物模型中的神经炎症机制。据推测，早期接触感染和/或炎症有可能诱发潜在的神经炎性异常，这些异常可以通过暴露于应激刺激、激活小胶质细胞和促进中枢神经系统中促炎细胞因子的产生而显露出来。动物模型已经证明，针对激活的炎症反应系统或相关的生理过程的干预可以减轻产前感染/炎症对神经发育的影响。与基础科学研究一致的是，最近对早期精神病患者的研究表明，抗炎干预可能会减轻阴性症状和认知症状。相比之下，抗炎策略对慢性精神分裂症并不有效，这表明神经炎性过程在疾病的早期阶段是活跃的，也是干预的重要目标。本申请中提出的多模式神经生物学技术的使用可以进一步深入了解精神病发生的机制。随着对精神病发病时异常神经发育过程的了解不断增加，有可能开发出更好的治疗干预措施来改善疾病的结局、发病率和死亡率。

DESCRIPTION (provided by applicant): The current proposal in response to PAR 11-031, Brain Disorders in the Developing World: Research Across the Lifespan (R21) will build on an existing collaboration between University of California San Diego (UCSD) and the Instituto Nacional de Neurolog¿a y Neurocirug¿a (INNN), Mexico City. Further collaboration, with an emphasis on understanding and treating the neuropathological changes in early psychosis could have a significant impact on early psychosis research in Mexico since INNN is a central training site in this city of over 20 million people. The proposed R21 will 1) provide resources to develop the recruitment infrastructure for potentially very large numbers of antipsychotic na¿ve first episode psychosis patients in Mexico City. In addition, the Mexican site will enhance their neuroimaging program at the INNN by obtain training from UCSD in Magnetic resonance imaging (MRI) analysis techniques including segmentation analysis of cortical thickness and free water analysis of Diffusion Tensor Imaging (DTI) data. To assure between site reliability of neuroimaging biomarkers, we will perform a traveling subjects study during the first three months of the project. Finally, 2) we will also obtain pilot neuroimaging and inflammatory biomarker data in antipsychotic naive first episode patients and normal controls at both sites in preparation for a longitudinal study that investigates neuroinflammation and anti-inflammatory treatment in the same population. Ultimately we plan to submit a translational R01 that will investigate neuroinflammatory mechanisms in human and animal models of early psychosis. It has been postulated that early-life exposure to infection and/or inflammation has the potential to induce latent neuroinflammatory abnormalities that can be unmasked by exposure to stressful stimuli, activating microglia and enhancing the production of pro-inflammatory cytokines in the CNS. Animal models have demonstrated that the neurodevelopment effects of prenatal infection/inflammation can be attenuated by interventions targeting activated inflammatory response systems or associated physiologically processes. Consistent with the basic science research, recent studies in early psychosis patients suggest that anti-inflammatory interventions may attenuate negative and cognitive symptoms. In contrast, anti-inflammatory strategies are not effective in chronic schizophrenia, suggesting that neuroinflammatory processes are active during the early phase of disease and an important target for intervention. The use of multimodal neurobiological techniques as proposed in this application can provide further insight into the mechanism by which psychosis emerges. With increasing knowledge of the aberrant neurodevelopmental processes at the onset of psychosis, it may become possible to develop better treatment interventions to modify the disease outcome, morbidity and mortality.