Inflammatory Networks Mediating Cognitive Decline In Preclinical Alzheimers Disease

项目摘要/摘要 阿尔茨海默病(AD)是一种破坏性的神经退行性疾病，导致进行性 对痴呆症的认知能力下降。在美国，65岁以上的人中每九人中就有一人患有阿尔茨海默病，这是第五位-- 这个年龄段的主要死因。预计到2050年，65岁以上的人口将翻一番。划定 预测和预防与阿尔茨海默病相关的认知衰退的因素非常重要，但仍然很差 明白了。 这项职业发展奖将在以下方面提供更多的培训和研究机会 生物信息学和神经炎症为Pillai博士提高他的临床研究技能，以解决当前 在炎症因子在AD进展中的作用方面的知识差距。他是一名行为神经学家 在认知神经科学研究方面经验丰富，长期目标是建立一个 研究使用生物信息学工具来描绘支持认知能力下降和 神经退行性疾病之间的疾病进展。 对推动阿尔茨海默病进展的炎症因素的了解将是设计小说的关键 预防认知衰退的治疗策略。这个奖项将帮助他通过一个 结构化培训计划，包括生物信息学和统计技术方面的正式课程工作，以及 阿尔茨海默病免疫生物学相关实验室和临床研究。他还将接受额外的培训 格兰特的写作以及临床试验研究的设计和管理，以促进他未来的工作重点 来自大数据的生物信息学见解在临床上产生了丰硕的影响。 目前应用的基础研究是一项临床翻译研究，旨在 描述神经炎、血脑屏障(BBB)完整性和 阿尔茨海默病的神经退行性变。皮莱博士在这个方向上的初步研究，由阿尔茨海默氏症协会资助， 提示AD患者在上述三个领域之间存在较强的相关性 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 在健康、认知正常的老年人中，有相当比例的人是载脂蛋白Eε4风险基因携带者 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 炎症标记物和血脑屏障分解标记物与较高水平的神经变性和 影响这些受试者24个月的认知能力下降。我们将确认和验证时间 炎性蛋白变化过程的纵向多重生物标志物和全基因组表达 24个月的变化和来自其他大型国家数据的数据(阿尔茨海默病神经成像 倡议，加速药品伙伴关系(AD)。这项研究将表征个人倾向于 有害的炎症反应，这将有助于未来的精确医学干预 阿尔茨海默病患者的神经炎症可防止疾病进展和认知能力下降

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