Postoperative Delirium and Alzheimer's Disease Related Dementias

术后谵妄和阿尔茨海默病相关的痴呆

• 批准号: 10565910
• 负责人: Zhongcong Xie
• 金额: $ 59.13万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565910
• 关键词: AD transgenic mice; Abdomen; Acute; Adult; Age; Aging; Alzheimer' s disease related dementia; Anesthesia procedures; Anesthetics; Animal Model; Anti-Inflammatory Agents; Behavior; Behavioral; Biochemical; 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; Lithium; Methods; Microdialysis; Microglia; Modeling; Morbidity - disease rate; Mus; Naproxen; Nerve Degeneration; Neuronal Dysfunction; Neurons; Neuropathogenesis; Operative Surgical Procedures; Outcome; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Plasma; Postoperative Complications; Postoperative Period; Precipitating Factors; Predisposing Factor; Prevention; Research; Risk; Risk Factors; Rodent Model; Role; System; Technology; Testing; Time; Transgenic Mice; 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; innovation; insight; mortality; nano; neuroinflammation; new technology; novel; older patient; patient subsets; pharmacologic; post-operative cognitive dysfunction; postoperative delirium; prevent; sevoflurane; tau Proteins; tau-1; tool; trafficking

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， 发病率和死亡率增加，护理费用增加， 阿尔茨海默病和相关痴呆症（ADRD）。具体来说，ADRD患者的风险增加， 发生谵妄，而经历谵妄的无痴呆患者发生谵妄的风险更高。 ADRD。然而，POD的发病机制在很大程度上仍然是未知的，这种知识上的差距阻碍了目前的研究。 预防和治疗POD。为了进一步研究POD的发病机制，我们建立了一个啮齿动物模型， 模型，称为混乱评估方法（CAM）在小鼠中，以评估小鼠的谵妄样行为。 与Tau磷酸化和神经炎症是ADRD的一部分的观点一致 神经发病机制，并与认知障碍，我们的初步研究表明，开放 全身麻醉下的腹部手术（麻醉/手术）诱导神经炎症和POD样 在具有升高的脑磷酸化Tau（pTau）水平的老年小鼠中的行为。因此，拟议的 研究将扩展这些研究，以确定一个潜在的多因素模型的POD发病机制，通过测试 以下假设：麻醉/手术诱导的神经炎症因衰老或AD基因而加剧 突变相关的脑pTau积累，导致神经元功能障碍和POD样行为， 小鼠我们将通过体内（小鼠）和体外（神经元和 小胶质细胞）的方法来实现三个具体的目的：1）我们将评估腹部手术的效果 用1.4%异氟烷、3%七氟烷或9%地氟烷麻醉血浆和脑2小时 小鼠中IL-6和pTau水平、小胶质细胞活化、神经元功能障碍和POD样行为。2)我们将 进行体外研究，以确定神经元pTau和小胶质细胞IL-6的运输，以及它们对 彼此的产生和随之而来的神经元功能障碍，使用神经元和小胶质细胞收获， 野生型、IL-6敲除和Tau敲除小鼠。3)我们将评估是否敲除IL-6或Tau，抗- 炎性治疗（那普利和帕瑞昔布）或Tau磷酸化抑制剂（锂）可以减轻 麻醉/手术诱导的小鼠神经元功能障碍和POD样行为。我们将包括成年野生- 型（3个月大）小鼠与年龄匹配的（3个月大）AD转基因和老年野生型（18个月- 老年）小鼠（具有较高的pTau水平），并采用无标记的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、微透析和小鼠中的CAM。这 该提案旨在通过测试新的假设来研究创新系统中未充分研究的主题。 我们的努力最终可能有助于开发POD的预防和治疗方法，从而更安全地 为老年人和ADRD患者提供手术护理和更好的术后结果。