Postoperative Delirium and Alzheimer's Disease Related Dementias

术后谵妄和阿尔茨海默病相关的痴呆

基本信息

批准号：
10113503
负责人：
Zhongcong Xie
金额：
$ 70.97万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10113503
关键词：
AD transgenic mice Abdomen Acute Adult Age Aging Alzheimer&apos s disease related dementia Anesthesia procedures Anesthetics Animal Model Anti-Inflammatory Agents Behavior Behavioral Biochemical Genetics Biosensing Techniques Blood Brain Calcium Caring Cell Culture Techniques Clinical Confusion Data Delirium Dementia Development Elderly Electrophysiology (science)Enzyme-Linked Immunosorbent Assay Funding Opportunities Gene Mutation General Anesthesia Generations Genetic Genetic Predisposition to Disease Goals Harvest Hour Human Image Immunohistochemistry Impaired cognition In Vitro Interleukin-6 Intervention Studies Isoflurane Knock-out Knockout Mice Knowledge Label Lead Lithium Methods Microdialysis Microglia Modeling Morbidity - disease rate Mus Naproxen Nerve Degeneration Neuronal Dysfunction Neurons Neuropathogenesis Operative Surgical Procedures Outcome Pathogenesis Patients Pharmaceutical Preparations Pharmacology Plasma Postoperative Complications Postoperative Period Precipitating Factors Predisposing Factor Prevention Research Risk Risk Factors Rodent Model Role System Technology Testing Time Transgenic Organisms Wild Type Mouse aged behavior test care costs confusion assessment method desflurane experience experimental study high risk in vivo in vivo calcium imaging inhibitor/antagonist innovation insight mortality nano neuroinflammation new technology novel older patient patient subsets post-operative cognitive dysfunction postoperative delirium prevent sevoflurane tau Proteins tau phosphorylation tau-1 tool trafficking

项目摘要

Postoperative delirium (POD), a clinical phenomenon different from postoperative cognitive dysfunction, is the most common postoperative complication among older patients and is associated with substantially increased rates of morbidity and mortality, as well as an increased cost of care, and risk of developing Alzheimer's disease and related dementias (ADRD). Specifically, people with ADRD are at an increased risk of developing delirium, and dementia-free patients who experience delirium are at higher risk of developing ADRD. However, the pathogenesis of POD is still largely unknown, and this gap in knowledge impedes current efforts in preventing and treating POD. To further study the POD pathogenesis, we have established a rodent model, called the Confusion Assessment Method (CAM) in mice, to assess the delirium-like behavior in mice. Consistent with the notion that Tau phosphorylation and neuroinflammation are part of ADRD neuropathogenesis and are associated with cognitive impairments, our preliminary studies showed that open abdominal surgery under general anesthesia (anesthesia/surgery) induced neuroinflammation and POD-like behavior in aged mice which had elevated levels of brain phosphorylated Tau (pTau). Thus, the proposed research will extend these studies to define a potential multifactorial model of POD pathogenesis by testing the following hypothesis: anesthesia/surgery-induced neuroinflammation is exacerbated by aging- or AD gene mutation-associated accumulation of brain pTau, leading to neuronal dysfunction and POD-like behavior in mice. We will employ biochemical and genetic tools through both in vivo (mice) and in vitro (neuron and microglia) approaches to accomplish three Specific Aims: 1) We will evaluate the effects of abdominal surgery under anesthesia with 1.4% isoflurane, 3% sevoflurane or 9% desflurane for two hours on plasma and brain levels of IL-6 and pTau, microglia activation, neuronal dysfunction, and POD-like behavior in mice. 2) We will perform in vitro studies to determine the trafficking of neuronal pTau and microglia IL-6, and their effects on each other's generation and consequent neuronal dysfunction, using the neurons and microglia harvested from wild-type, IL-6 knockout and Tau knockout mice. 3) We will assess whether knockout of IL-6 or Tau, anti- inflammatory treatments (naproxen and parecoxib) or Tau phosphorylation inhibitor (lithium) can mitigate the anesthesia/surgery-induced neuronal dysfunction and POD-like behavior in mice. We will include adult wild- type (3 months-old) mice versus age matched (3 months-old) AD transgenic and aged wild-type (18 months- old) mice (with higher pTau levels), and employ a label-free nano-biosensing system for biomolecular analysis (nanobeam technology), calcium imaging, in vitro electrophysiology, microdialysis, and CAM in mice. This proposal aims to investigate an understudied topic in innovative systems through testing novel hypotheses. Our efforts could ultimately help to develop prevention and treatment methods towards POD, leading to safer surgical care and better post-operative outcomes for senior and ADRD patients.

术后谵妄（POD）是一种不同于术后认知功能障碍的临床现象，老年患者中最常见的术后并发症，与发病率和死亡率增加，护理费用增加，罹患疾病的风险也增加阿尔茨海默病和相关痴呆症（ADRD）。具体来说，患有 ADRD 的人患以下疾病的风险增加：发生谵妄，而经历过谵妄的无痴呆患者发生谵妄的风险更高 ADRD。然而，POD 的发病机制仍然很大程度上未知，这种知识差距阻碍了当前的研究努力预防和治疗POD。为了进一步研究 POD 发病机制，我们建立了啮齿类动物模型，称为小鼠混乱评估方法（CAM），用于评估小鼠的谵妄样行为。与 Tau 磷酸化和神经炎症是 ADRD 一部分的观点一致神经发病机制并与认知障碍相关，我们的初步研究表明开放全身麻醉（麻醉/手术）下的腹部手术引起的神经炎症和 POD 样大脑磷酸化 Tau (pTau) 水平升高的老年小鼠的行为。因此，建议的研究将扩展这些研究，通过测试以下因素来定义 POD 发病机制的潜在多因素模型：以下假设：衰老或 AD 基因会加剧麻醉/手术引起的神经炎症突变相关的脑 pTau 积累，导致神经元功能障碍和 POD 样行为老鼠。我们将通过体内（小鼠）和体外（神经元和神经元）使用生化和遗传工具。小胶质细胞）方法来实现三个具体目标：1）我们将评估腹部手术的效果用 1.4% 异氟醚、3% 七氟醚或 9% 地氟醚麻醉血浆和大脑两小时小鼠中 IL-6 和 pTau 水平、小胶质细胞激活、神经元功能障碍和 POD 样行为。 2）我们会进行体外研究以确定神经元 pTau 和小胶质细胞 IL-6 的运输及其对使用从细胞中收获的神经元和小胶质细胞来研究彼此的产生和随之而来的神经元功能障碍野生型、IL-6 敲除小鼠和 Tau 敲除小鼠。 3) 我们将评估是否敲除 IL-6 或 Tau、抗炎症治疗（萘普生和帕瑞昔布）或 Tau 磷酸化抑制剂（锂）可以缓解麻醉/手术引起的小鼠神经元功能障碍和 POD 样行为。我们将包括成年野生- 类型（3 个月大）小鼠与年龄匹配（3 个月大）AD 转基因和老年野生型（18 个月- 老）小鼠（具有较高的 pTau 水平），并采用无标记纳米生物传感系统进行生物分子分析（纳米束技术）、钙成像、体外电生理学、微透析和小鼠 CAM。这该提案旨在通过测试新的假设来调查创新系统中尚未研究的主题。我们的努力最终可能有助于开发 POD 的预防和治疗方法，从而实现更安全的治疗为老年和 ADRD 患者提供手术护理和更好的术后结果。