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: 9912693
• 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
• 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/9912693
• 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 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

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.

术后精神障碍(POD)是一种不同于术后认知功能障碍的临床现象。 老年患者最常见的术后并发症，与实质上 发病率和死亡率的增加，以及护理费用和发病风险的增加 阿尔茨海默病和相关痴呆(ADRD)。具体地说，患有ADRD的人患上 发展中的精神错乱和经历过精神错乱的非痴呆症患者有更高的发展风险。 阿德勒。然而，POD的发病机制在很大程度上仍不清楚，这种认识上的差距阻碍了目前 努力预防和治疗POD。为了进一步研究POD的发病机制，我们建立了一种啮齿动物 模型，在小鼠中被称为迷惑评估方法(CAM)，以评估小鼠的神志不清行为。 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，并与认知障碍有关，我们的初步研究表明 全麻下腹部手术(麻醉/手术)引起的神经炎症和POD样反应 脑内磷酸化Tau(Ptau)水平升高的老年小鼠的行为。因此，拟议的 研究将扩展这些研究，以确定POD发病的潜在多因素模型，通过测试 假设：衰老或AD基因加重了麻醉/手术引起的神经炎症 突变相关的脑内ptau积聚，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 小胶质细胞)实现三个特定目标的方法：1)我们将评估腹部手术的效果 1.4%异氟醚、3%七氟醚或9%地氟烷麻醉2小时对血浆和脑的影响 小鼠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的转运及其对 彼此的产生和随后的神经元功能障碍，使用从 野生型、IL-6基因敲除和Tau基因敲除小鼠。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动物- 类型(3个月大)小鼠与年龄匹配(3个月大)的AD转基因小鼠和老年野生型(18个月- 老年)小鼠(ptau水平较高)，并使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、微透析和小鼠的CAM。这 提案旨在通过测试新的假设来研究创新系统中一个未被充分研究的话题。 我们的努力最终可以帮助开发POD的预防和治疗方法，导致更安全 为老年和ADRD患者提供手术护理和更好的术后结果。