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、护理费用增加以及患病风险相关 然而，阿尔茨海默病 (AD) 和 AD 相关痴呆 (AD/ADRD) 的发病机制。 POD 在很大程度上仍然未知，这种知识差距阻碍了当前预防和治疗的努力 为了进一步研究POD发病机制，我们建立了纳米针技术来测量POD。 苏氨酸 217 (Tau-pT217) 和苏氨酸 181 (Tau-pT181) 处 Tau 磷酸化的血液浓度。 与 Tau-pT217 和 Tau-pT181 是新发现的早期阶段生物标志物的观点一致 AD，我们的初步研究表明，在异氟烷麻醉下进行开腹手术 （麻醉/手术）血液、肺和脑中 Tau-pT217 和 Tau-pT181 含量增加，并伴有 因此，拟议的研究将这些研究扩展到老年小鼠血液中的 B 细胞减少。 通过测试确定 Tau-pT217 和 Tau-pT181 从血液到大脑的转运是 POD 的发病机制 以下假设：麻醉/手术增强 Tau-pT217 和 Tau-pT181 的生成并促进 Tau-pT217 和 Tau-pT181 从血液转运至大脑，导致小鼠出现类似谵妄的行为。 通过体内（小鼠）方法使用生化和遗传工具来实现三个具体目标：1) 我们将评估麻醉/手术对血液中 Tau-pT217 和 Tau-pT181 含量的影响， 成年（3个月大）和老年（18个月大）野生型小鼠以及成年（3个月大）AD的肺和大脑 2) 我们将进行研究以确定 Tau-pT217 和 Tau-pT181 的转运情况。 使用条件化血液合成 Tau-pT217，将野生型小鼠和 Tau 基因敲除小鼠的血液输送至大脑 和 Tau-pT181 肽或小鼠的联体共生 3) 我们将评估是否使用 WS635 或维生素 K2 进行治疗。 （线粒体功能的保护者），或 B 细胞可以减轻麻醉/手术引起的 Tau- 增加 pT217 和 Tau-pT181 的量，以及老年野生型小鼠和 AD 转基因小鼠的谵妄样行为。 我们将包括成年野生型（3 个月大）小鼠与年龄匹配（3 个月大）AD 转基因小鼠和 老年野生型（18 个月大）小鼠（具有较高的 pTau 水平），并采用无标记纳米生物传感 生物分子分析系统（纳米针技术）。 通过测试新的假设，我们的努力最终可以帮助开发创新系统的主题。 POD 的预防和治疗方法，使手术护理更安全，术后效果更好 老年和 AD/ADRD 患者的结果，从而制定预防 AD/ADRD 的策略。

项目成果

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

导尿管通过小鼠葡萄糖代谢损伤诱导谵妄样行为。

• 发表时间: 2022-09-01
• 影响因子: 5.7
• 作者: Jiang, Zhangjie;Liang, Feng;Zhang, Yida;Dong, Yuanlin;Song, Annie;Zhu, Xiaoping;Zhang, Yiying;Xie, Zhongcong
• 通讯作者: Xie, Zhongcong

The association between gut microbiota and postoperative delirium in patients.

肠道微生物群与患者术后谵妄之间的关联。

• 发表时间: 2023-05-09
• 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