Advancing the Understanding of Postoperative Delirium Mechanisms via Multi-Omics

 描述（由申请人提供）：谵妄使15-53%的老年人大手术复杂化，导致死亡率增加2-20倍，长期认知和功能障碍，并增加医疗费用。然而，谵妄仍然是一个完全的临床诊断;其病理生理学仍然在很大程度上是未知的，没有生物标志物来指导其诊断或管理。在过去的4.5年中，我们在国家老龄化研究所（NIA）项目中进行了“谵妄生物标志物发现”项目，该项目资助了SAGES（择期手术后成功老化）研究。使用SAGES血浆生物储存库和最先进的方法，包括蛋白质组学，我们发现促炎细胞因子，急性期反应物和神经元损伤标记物在谵妄患者中相对于匹配的对照组持续升高。这些结果支持谵妄模型，其中易感的全身性炎症前状态导致对应激源（大手术）的功能障碍性反应，导致血脑屏障破坏、小胶质细胞活化、神经炎症、神经元损伤和死亡。为了响应NIA计划公告PA-13-168“现有数据集和存储生物样本的二次分析以解决临床老化研究问题”，我们现在提出一套新的特定目标，与我们的P01资助项目没有科学或预算重叠。我们将利用来自SAGES的标本，以及一个独立的骨科队列，HiPOR（更健康的术后恢复），收集和储存血浆和术前脑脊液（CSF）。我们将应用尖端系统水平的“组学”方法来定义整合血浆和CSF中蛋白质、脂质和代谢物的谵妄特征。我们将寻求证实和进一步阐明上述功能失调性炎症病理生理学模型，并探索可能与上述途径相互作用或独立于上述途径的谵妄的其他机制。在这种情况下，我们提出了以下具体目标：目标1：定义和验证谵妄的血浆蛋白质特征目标2：定义血浆脂质和代谢物谵妄特征，与蛋白质特征整合，并在SAGES队列和独立的HiPOR样本中验证该整合特征目标3：定义谵妄的整合的基于CSF的蛋白质、脂质和代谢物特征。影响：我们的近期目标是使用来自两项老年骨科患者队列研究的库存标本，开发综合（蛋白质，代谢物，脂质）血浆和CSF为基础的谵妄生物标志物签名。我们将进一步阐明上述炎症通路，并通过提出的目标揭示其他通路，这将从根本上推进我们对谵妄病理生理学的认识。最终，我们的目标是通过改进诊断和监测谵妄的方法，并通过设计有针对性的、基于病理生理学的干预措施，将我们的发现转化为床边研究。因此，拟议工作的长期影响将是改变这种常见，病态和昂贵的综合征的临床管理。

 DESCRIPTION (provided by applicant): Delirium complicates 15-53% of major surgery in older adults, resulting in 2-20 fold increased mortality, long term cognitive and functional impairment, and increased healthcare costs. Yet, delirium remains a wholly clinical diagnosis; its pathophysiology remains largely unknown, with no biomarkers to guide its diagnosis or management. Over the past 4.5 years, we conducted the "Biomarker Discovery for Delirium" project within a National Institute on Aging (NIA) program project that funded the SAGES (Successful Aging after Elective Surgery) study. Using the SAGES plasma biorepository and state-of-the-art approaches, including proteomics, we found that pro-inflammatory cytokines, acute phase reactants, and neuronal injury markers are consistently elevated in delirious patients relative to matched controls. These results support a model for delirium in which a predisposing, systemic pre-inflammatory state results in a dysfunctional response to a stressor (major surgery), leading to blood brain barrier breakdown, microglial activation, neuro-inflammation, neuronal injury and death. Responding to NIA Program Announcement PA-13-168 "Secondary analysis of existing data sets and stored biospecimens to address clinical aging research questions", we now propose a new set of Specific Aims with no scientific or budgetary overlap with our P01-funded project. We will leverage specimens from SAGES, and an independent orthopedic cohort, HiPOR (Healthier Postoperative Recovery) that collected and stored both plasma and preoperative cerebrospinal fluid (CSF). We will apply cutting edge systems level "Omics" methods to define delirium signatures that integrate proteins, lipids, and metabolites from both plasma and CSF. We will seek to confirm and further elucidate the dysfunctional inflammation pathophysiological model described above, and probe additional mechanisms for delirium that might interact with, or be independent of the above pathways. In this context, we propose the following Specific Aims: Aim 1: Define and validate a plasma protein signature for delirium Aim 2: Define plasma lipid and metabolite delirium signatures, integrate with the protein signature, and validate this integrated signature across the SAGES cohort and in the independent HiPOR sample Aim 3: Define an integrated CSF-based protein, lipid, and metabolite signature for delirium. Impact: Our immediate goals are to develop integrated (protein, metabolite, lipid) plasma and CSF-based biomarker signatures for delirium using banked specimens from two cohort studies of older orthopedic patients. We will further elucidate the inflammatory pathway described above and uncover others through the proposed Aims, which will fundamentally advance our knowledge of the pathophysiology of delirium. Ultimately, our goal is to translate our findings to the bedside through improved methods of diagnosis and monitoring of delirium, and though the design of targeted, pathophysiologically based interventions. Therefore, the long term impact of the proposed work will be to transform clinical management of this common, morbid, and costly syndrome.