Advancing the Understanding of Postoperative Delirium Mechanisms via Multi-Omics

通过多组学促进对术后谵妄机制的理解

• 批准号: 9204773
• 负责人: TOWIA A. LIBERMANN
• 金额: $ 60.25万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204773
• 关键词: Acute; Acute-Phase Proteins; Address; Aging; Biological; Biological Markers; Blood; Blood - brain barrier anatomy; Cerebrospinal Fluid; Clinical; Clinical Management; Cognitive; Cohort Studies; Complex; Confusion; Data Set; Delirium; Dependence; Development; Diagnosis; Disease; Elderly; Enzyme-Linked Immunosorbent Assay; Functional disorder; Funding; Goals; Health Care Costs; Hip region structure; Impaired cognition; Incidence; Inflammation; Inflammatory; Inflammatory Response; Intervention; Knowledge; Lead; Link; Lipids; Mass Spectrum Analysis; Measures; Membrane; Methods; Modeling; Monitor; NIH Program Announcements; National Institute on Aging; Neuronal Injury; Operative Surgical Procedures; Orthopedic Surgery procedures; Orthopedics; Participant; Pathway interactions; Patients; Plasma; Plasma Proteins; Postoperative Period; Preventive; Proteins; Proteomics; Recovery; Research; Sampling; Schedule; Severities; Specimen; Syndrome; System; Systems Biology; Translating; Work; base; biobank; biomarker discovery; clinical Diagnosis; cognitive change; cohort; cost; cytokine; design; experience; functional disability; improved; metabolomics; mortality; neuroinflammation; neuron loss; postoperative delirium; predictive signature; prevent; programs; protein metabolite; public health relevance; response; secondary analysis; stressor

 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.

 描述(申请人提供)：精神错乱导致15%-53%的老年人大手术并发，导致死亡率增加2-20倍，长期认知和功能障碍，以及增加的医疗费用。然而，精神错乱仍然是一个完全的临床诊断；其病理生理学仍在很大程度上尚不清楚，没有生物标记物来指导其诊断或治疗。在过去的4.5年里，我们在美国国家老龄研究所(NIA)资助SAGS(选择性手术后成功老龄化)研究的项目中开展了“Delirium的生物标记物发现”项目。使用SAGS血浆生物库和包括蛋白质组学在内的最先进的方法，我们发现与匹配的对照组相比，精神错乱患者的促炎细胞因子、急性时相反应物和神经元损伤标志物持续升高。这些结果支持一种精神错乱的模型，在该模型中，易感的全身性炎症前状态会导致对应激源(大手术)的功能障碍反应，导致血脑屏障破坏、小胶质细胞激活、神经炎症、神经元损伤和死亡。作为对NIA计划公告PA-13-168“对现有数据集和存储的生物样本进行二次分析以解决临床衰老研究问题”的回应，我们现在提出一套新的具体目标，与我们P01资助的项目没有科学或预算上的重叠。我们将利用SAGES的标本，以及一个独立的骨科队列，HiPOR(更健康的术后恢复)，收集和存储血浆和术前脑脊液(CSF)。我们将应用尖端系统水平的“OMICS”方法来定义融合了来自血浆和脑脊液的蛋白质、脂类和代谢物的精神错乱症状。我们将寻求证实并进一步阐明上述功能失调的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妄想的其他机制。在此背景下，我们提出了以下具体目标：目标1：定义和验证用于精神错乱的血浆蛋白质特征；目标2：定义血浆脂类和代谢物精神错乱的特征，与蛋白质特征相结合，并在SAGES队列和独立的HiPOR样本中验证这一综合特征；目标3：定义基于脑脊液的蛋白质、脂质和代谢物的综合特征用于精神错乱。影响：我们的近期目标是利用来自两个老年骨科患者队列研究的资料库标本，开发综合的(蛋白质、代谢物、脂肪)血浆和脑脊液生物标记物标记。我们将进一步阐明上述炎症途径，并通过提出的目的揭示其他途径，这将从根本上促进我们对精神错乱的病理生理学的了解。最终，我们的目标是通过改进精神错乱的诊断和监测方法，以及设计有针对性的、基于病理生理学的干预措施，将我们的发现转化为床边的研究结果。因此，拟议工作的长期影响将是改变这种常见的、病态的和昂贵的综合征的临床管理。