Shared Pathophysiology of Postoperative Delirium and Alzheimer's Disease and Related Dementias

项目总结/摘要 K 01职业发展奖将支持初级研究员的培训和职业发展， 博士Sarinnapha Vasunilashorn，在面向患者的老龄化研究中。该提案的总体目标是提供 博士Vasunilashorn作为一个独立的， 精神错乱和阿尔茨海默病及相关痴呆症（ADRD）的翻译研究员。具体培训 目标包括：1）在临床环境中获得原始数据收集的经验，2）扩大她的 先进的纵向方法和遗传数据分析的分析技能，以及3）建立一个深入的 ADRD知识库。这些培训目标将与一套具体的 基于Vasunilashorn博士的初步数据的研究项目，报告了 血浆炎症标志物与老年患者术后谵妄的发生率和严重程度 接受非心脏手术的ADRD。谵妄和ADRD有很强的流行病学关联：ADRD 长期以来被认为是谵妄的一个危险因素，最近谵妄被认为是一种风险， ADRD事件的系数。虽然这表明谵妄和ADRD之间存在明确的联系，但共享的 这些关系背后的病理生理学仍然很大程度上未知。在拟议的K 01具体目标中， 博士Vasunilashorn将解决这一知识差距，并大大扩展她的初步研究， 只关注基于血浆的炎症标志物， 基于脑脊液（CSF）的神经炎症和神经元损伤指标与术后 谵妄、长期认知能力下降和ADRD事件，并评估遗传风险是否会改变这些 协会.这些研究将利用以下方面的大量资源：1）国家情报局资助的项目， 择期手术后成功老化研究（SAGES; P01 AG 031720），和2）更健康的 术后恢复研究（HiPOR; R21 AG 048600）。这一建议在检查 神经炎症和神经元损伤，这将促进我们对病理生理学的理解， 谵妄-ADRD关系的潜在机制，这是一个很大程度上未被探索的领域，代表了一个顶部 NIH的优先领域（PAR-17-038）。重要的是，这些结果将告知病理生理学靶向 治疗炎症以提供神经保护并确定重要变量以改善谵妄风险 预测策略，从而潜在地预防谵妄和减少ADRD。最终，这项工作将为 Vasunilashorn博士的独立研究生涯的启动，将提供基础的方式， 探讨谵妄和ADRD的病理生理联系，这是独立性的两个主要威胁， 所有老年人的生活质量。

PROJECT SUMMARY/ABSTRACT This K01 Career Development Award will support the training and career development of a junior investigator, Dr. Sarinnapha Vasunilashorn, in patient-oriented aging research. The overall goal of the proposal is to provide Dr. Vasunilashorn with critical skills and development of experience and competence as an independent, translational researcher in delirium and Alzheimer's Disease and Related Dementias (ADRD). Specific training goals include: 1) obtaining experience in primary data collection within a clinical setting, 2) expansion of her analytic skillset in advanced longitudinal methods and genetic data analysis, and 3) building an in-depth knowledge base of ADRD. These training goals will be conducted in coordination with a set of specific research projects based on Dr. Vasunilashorn's preliminary data that reports on the association between plasma inflammatory markers and the incidence and severity of postoperative delirium in older patients without ADRD undergoing non-cardiac surgery. Delirium and ADRD have strong epidemiological associations: ADRD has long-been recognized as a risk factor for delirium, and recently delirium has been implicated as a risk factor for incident ADRD. Although this points to a clear link between delirium and ADRD, the shared pathophysiology underlying these relationships remains largely unknown. In the proposed K01 Specific Aims, Dr. Vasunilashorn will address this gap in knowledge and substantially extend her preliminary studies that have focused only on plasma-based markers of inflammation by examining whether both plasma and cerebrospinal fluid (CSF)-based measures of neuroinflammation and neuronal injury are associated with postoperative delirium, long-term cognitive decline, and incident ADRD, and evaluate whether genetic risk modifies these associations. These studies will leverage the considerable resources of: 1) the NIA-funded program project, the Successful Aging after Elective Surgery Study (SAGES; P01AG031720), and 2) the Healthier Postoperative Recovery Study (HiPOR; R21AG048600). This proposal is highly novel in examining markers of neuroinflamamtion and neuronal injury that will advance our understanding of the pathophysiologic mechanisms underlying the delirium-ADRD relationship, a largely underexplored area that represents a top priority area of the NIH (PAR-17-038). Importantly, the results will inform pathophysiologically targeted treatment for inflammation to provide neuroprotection and identify important variables to refine delirium risk prediction strategies thereby potentially preventing delirium and reducing ADRD. Ultimately, this work will pave the way and provide the foundation for the launch of Dr. Vasunilashorn's independent research career that will explore the pathophysiologic linkages of delirium and ADRD, two major threats to the independence and quality of life of all older adults.