Administrative Supplement: Postoperative Delirium and Alzheimer's Disease Related Dementias

行政补充：术后谵妄和阿尔茨海默病相关痴呆

• 批准号: 10625200
• 负责人: Zhongcong Xie
• 金额: $ 40.4万
• 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/10625200
• 关键词: AD transgenic mice; Abdomen; Acute; Administrative Supplement; Adult; Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; Anesthesia procedures; B-Lymphocytes; Behavior; Binding; Biochemical Genetics; Biosensing Techniques; Blood; Brain; British; Caring; Cells; Clinical; Confusion; Delirium; Development; Elderly; Flow Cytometry; Generations; Genus Hippocampus; Grant; Hour; Impairment; Incidence; Isoflurane; Journals; Knock-out; Knockout Mice; Knowledge; Label; Lung; Measures; Methods; Mitochondria; Morbidity - disease rate; Mus; Neurons; Operative Surgical Procedures; Outcome; Parabiosis; Pathogenesis; Patients; Peptides; Pharmaceutical Preparations; Positron-Emission Tomography; Postoperative Complications; Postoperative Period; Prevention; Proteins; Research; Risk; Severities; Stress Tests; System; Technology; Testing; Threonine; Transgenic Organisms; United States National Institutes of Health; Vitamin K 2; Wild Type Mouse; aged; base; behavior change; care costs; cell behavior; dementia risk; early detection biomarkers; human old age (65+); in vivo; innovation; innovative technologies; mortality; nano; nanoneedle; new technology; novel; older patient; post-operative cognitive dysfunction; postoperative delirium; prevent; tau Proteins; tau phosphorylation; tau-1; tool; trafficking

Postoperative delirium (POD) is the most common postoperative complication among older patients and is associated with substantially increased rates of morbidity and mortality, increased cost of care, and risk of developing Alzheimer’s disease (AD) and AD related dementias (AD/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 nanoneedle technology to measure blood concentrations of Tau phosphorylation at threonine 217 (Tau-pT217) and threonine 181 (Tau-pT181). Consistent with the notion that Tau-pT217 and Tau-pT181 are the newly identified biomarker of early stage of AD, our preliminary studies showed that open abdominal surgery under isoflurane anesthesia (anesthesia/surgery) increased Tau-pT217 and Tau-pT181 amounts in blood, lungs and brain, accompanied by decreases in B cells in blood of aged mice. Thus, the proposed research will extend these studies to establish trafficking of Tau-pT217 and Tau-pT181 from blood to brain as the pathogenesis of POD by testing the following hypothesis: anesthesia/surgery enhances Tau-pT217 and Tau-pT181 generation and promotes Tau-pT217 and Tau-pT181 trafficking from blood to brain, leading to delirium-like behavior in mice. We will employ biochemical and genetic tools through in vivo (mice) approach to accomplish three Specific Aims: 1) We will evaluate the effects of anesthesia/surgery on the amounts of Tau-pT217 and Tau-pT181 in blood, lungs and brain of adult (3 months-old) and aged (18 months-old) wild-type mice, and adult (3 months-old) AD transgenic mice. 2) We will perform studies to determine the trafficking of Tau-pT217 and Tau-pT181 from blood to brain in wild-type mice and Tau knockout mice by using conditioned blood, synthesized Tau-pT217 and Tau-pT181 peptides or parabiosis in mice. 3) We will assess whether treatment with WS635 or Vitamin K2 (protector of mitochondrial function), or B cells can mitigate the anesthesia/surgery-induced increases in Tau- pT217 and Tau-pT181 amounts, and delirium-like behaviors in aged wild-type mice and AD transgenic 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 (nanoneedle technology). 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 AD/ADRD patients, leading to the development of strategies to prevent AD/ADRD.

术后谵妄（POD）是老年患者最常见的术后并发症， 与发病率和死亡率大幅增加，护理成本增加， 发展为阿尔茨海默病（AD）和AD相关痴呆（AD/ADRD）。然而， POD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预防和治疗POD的努力。 POD。为了进一步研究POD的发病机制，我们建立了纳米针技术来测量 在苏氨酸217（Tau-pT 217）和苏氨酸181（Tau-pT 181）处的Tau磷酸化的血液浓度。 与Tau-pT 217和Tau-pT 181是新鉴定的早期肿瘤的生物标志物的观点一致， AD，我们的初步研究表明，异氟烷麻醉下的腹部开放手术 （麻醉/手术）增加血液、肺和脑中的Tau-pT 217和Tau-pT 181量， 通过老年小鼠血液中B细胞的减少。因此，拟议的研究将把这些研究扩展到 通过测试确定Tau-pT 217和Tau-pT 181从血液到脑的运输是POD的发病机制 以下假设：麻醉/手术增强了Tau-pT 217和Tau-pT 181的产生，并促进了 Tau-pT 217和Tau-pT 181从血液运输到大脑，导致小鼠的谵妄样行为。我们将 通过体内（小鼠）方法使用生物化学和遗传工具来实现三个特定目的：1） 我们将评估麻醉/手术对血液中Tau-pT 217和Tau-pT 181量的影响， 成年（3月龄）和老年（18月龄）野生型小鼠和成年（3月龄）AD小鼠的肺和脑 转基因小鼠2)我们将进行研究，以确定Tau-pT 217和Tau-pT 181从 在野生型小鼠和Tau敲除小鼠中，通过使用条件化血液，合成Tau-pT 217， 和Tau-pT 181肽或小鼠中的联体共生。3)我们将评估是否使用WS 635或维生素K2治疗 （线粒体功能的保护者）或B细胞可以减轻麻醉/手术诱导的Tau-1增加。 pT 217和Tau-pT 181的量，以及老年野生型小鼠和AD转基因小鼠中的谵妄样行为。 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转基因小鼠， 老年野生型（18个月大）小鼠（具有较高的pTau水平），并采用无标记的纳米生物传感 生物分子分析系统（纳米针技术）。该提案旨在调查一个未充分研究的 通过测试新的假设在创新系统的主题。我们的努力最终可以帮助发展 POD的预防和治疗方法，导致更安全的手术护理和更好的术后护理 老年人和AD/ADRD患者的结局，从而制定预防AD/ADRD的策略。

项目成果

The association between gut microbiota and postoperative delirium in patients.

• DOI: 10.1038/s41398-023-02450-1
• 发表时间: 2023-05-09
• 期刊: TRANSLATIONAL PSYCHIATRY
• 影响因子: 6.8
• 作者: Zhang, Yiying;Baldyga, Kathryn;Dong, Yuanlin;Song, Wenyu;Villanueva, Mirella;Deng, Hao;Mueller, Ariel;Houle, Timothy T.;Marcantonio, Edward R.;Xie, Zhongcong
• 通讯作者: Xie, Zhongcong

Urinary Catheterization Induces Delirium-Like Behavior Through Glucose Metabolism Impairment in Mice.

• DOI: 10.1213/ane.0000000000006008
• 发表时间: 2022-09-01
• 期刊: Anesthesia and analgesia
• 影响因子: 5.7