Inflammatory Networks Mediating Cognitive Decline In Preclinical Alzheimers Disease

项目概要/摘要 阿尔茨海默病（AD）是一种破坏性的神经退行性疾病， 认知能力下降到痴呆美国65岁以上的人中有九分之一患有AD，这是第五位- 是这个年龄段的主要死因到2050年，65岁以上的人口预计将翻一番。划定 预测和预防与AD相关的认知能力下降的因素非常重要，但仍然很差。 明白 这个职业发展奖将提供额外的培训和研究机会， Pillai博士的生物信息学和神经炎症，以提高他的临床研究技能，以解决目前的 炎症因子在AD进展中作用的知识缺口。他是行为神经学家 在认知神经科学研究方面经验丰富，长期目标是建立一个程序化的机构， 研究使用生物信息学工具来描述支持认知能力下降的分子因素， 神经退行性疾病中的疾病进展。 对驱动AD进展的炎症因子的了解将是设计新颖的治疗方案的关键。 预防认知能力下降的治疗策略。这个奖项将帮助他通过一个 结构化的培训计划，包括生物信息学和统计技术方面的正式课程，以及 AD免疫生物学的相关实验室和临床研究。他还将接受额外的培训， 资助写作和临床试验研究的设计和管理，以促进他未来的重点， 生物信息学的见解，从大数据承担卓有成效的影响，在临床上。 本申请的基础研究是一项临床转化研究，旨在 表征神经炎症、血脑屏障（BBB）完整性和 AD中的神经变性。皮莱博士在这方面的初步研究，由阿尔茨海默病协会资助， 提示，在AD患者中，上述三个领域之间存在很强的相关性， 轻度认知障碍（MCI）目前的奖项将帮助皮莱博士确认和扩展这些见解 在APOE ε4风险基因携带者的健康、认知完整的老年人中， 可能处于AD的临床前阶段。我们假设，较高水平的特定基线脑脊液 炎症标记物和BBB破坏标记物与更高水平的神经变性相关， 影响了这些受试者24个月的认知能力下降。我们将确认并验证 炎症蛋白变化的过程与纵向多重生物标志物和基因组范围的表达 变化超过24个月，并与其他大型国家数据（阿尔茨海默病神经影像学）的数据 倡议，加速药物伙伴关系-AD）。这项研究将描述个人的倾向， 有害的炎症反应，这将有助于未来的精确医学干预， AD中的神经炎症以预防疾病进展和认知下降

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is a devastating neurodegenerative disease that causes progressive cognitive decline towards dementia. One in nine people over 65 yrs of age in the US has AD and it is the fifth- leading cause of death in this age group. The over 65 population is expected to double by 2050. Delineating factors that predict and prevent cognitive decline related to AD are hugely important but are still poorly understood. This Career Development Award will provide additional training and research opportunities in bioinformatics and neuroinflammation for Dr. Pillai to advance his clinical research skills to address a current knowledge gap in the role for inflammatory factors in AD progression. He is a behavioral neurologist experienced in cognitive neuroscience research with a long-term goal to establish a programmatic body of research using bioinformatics tools to delineate the molecular factors that underpin cognitive decline and disease progression among neurodegenerative diseases. Knowledge of inflammatory factors that drive AD progression will be critical in designing novel therapeutic strategies to prevent cognitive decline. This award will aid him in achieving these goals through a structured training plan that includes formal course work in bioinformatics and statistical techniques, as well as relevant laboratory and clinical research in the immunobiology of AD. He will also receive additional training in grant writing and the design and administration of clinical trials research to facilitate his future focus on bringing bioinformatics insights from large data to bear fruitful impact in the clinic. The research at the foundation of the current application is a clinical translational study that aims to characterize the temporal course of neuroinflammation, blood brain barrier (BBB) integrity and neurodegeneration in AD. Dr.Pillai's preliminary studies in this direction, funded by the Alzheimer Association, suggest that there is a strong relationship between the above three domains, among AD patients at the stage of mild cognitive impairment (MCI). The current award will help Dr.Pillai confirm and extend these insights among healthy, cognitively intact elders who are APOE ε4 risk gene carriers, a significant percentage of whom may be in the preclinical stage of AD. We hypothesize that higher levels of specific baseline cerebrospinal fluid inflammatory markers and BBB break down markers correlate with higher levels of neurodegeneration and impacts cognitive decline over 24 months among these subjects. We will confirm and validate the temporal course of inflammatory protein changes with longitudinal multiplex biomarker and genome wide expression changes over 24 months and against data from other large national data (Alzheimer's Disease Neuroimaging Initiative, Accelerating Medicines Partnership-AD). This research will characterize individual propensities for deleterious inflammatory responses that would be useful for future precision medicine interventions against neuroinflammation in AD to prevent disease progression and cognitive decline