Pathogenesis of Postoperative Cognitive Dysfunction

描述（由申请人提供）：随着老年人数量的增加，预计认知能力下降将成为患者及其提供者在不久的将来最需要解决的医疗保健问题之一，消耗越来越多的医疗保健资源。术后认知功能障碍或下降（POCD）是老年患者最常见的术后并发症之一，与发病率、死亡率和护理成本的大幅增加相关。然而，POCD的发病机制在很大程度上仍然是未知的，这种知识的差距阻碍了POCD的进一步研究。神经炎症包括脑中小胶质细胞活化和促炎细胞因子（如肿瘤坏死因子（TNF）-α、白细胞介素-6（IL-6）和IL-1 β）增加。β-淀粉样蛋白（A β-Amyloid protein，A β）是阿尔茨海默病（Alzheimer's disease，AD）患者老年斑的主要成分，A β-Amyloid protein在AD患者和老年人的脑中水平升高。与神经炎症和ApoA累积与认知功能障碍相关的概念一致，并且没有全身麻醉的手术也可能导致人类的POCD，我们在小鼠中的初步研究表明，局部麻醉下的开腹手术诱导神经炎症，ApoA累积和神经行为缺陷。因此，拟议的研究将扩展这些研究，通过测试以下假设来定义POCD发病机制的潜在多因素模型：手术诱导的神经炎症将与基因突变或衰老诱导的A β水平升高相互作用，导致学习/记忆和注意力/执行功能受损。我们将通过体外（神经元）和体内（小鼠）两种方法使用化学和遗传工具来实现三个具体目标：1）我们将评估手术对血浆TNF-α、IL-6和IL-1 β水平的时间依赖性影响;脑组织TNF-α、IL-6、IL-1 β、磷酸化真核细胞翻译起始因子2α（eIF 2 α-P）、β-位APP裂解酶（BACE）1、AAP 13、小胶质细胞活化和淀粉样斑块;以及小鼠的术后行为变化。2)我们将通过研究TNF-α、IL-6和IL-1 β对eIF 2 α-P相关的Ablast生成途径和潜在的CD 33（一种新提出的阿尔茨海默病基因）相关的Ablast降解途径的影响，来剖析导致手术诱导的神经炎症后Ablast蓄积的途径。3)我们将评估TNF-α、IL-6或IL-1 β受体的敲除、抗炎或抗A β积聚治疗是否可以抑制手术诱导的神经毒性。我们将包括野生型和较年轻（9个月大）小鼠与年龄匹配的AD转基因和较年长（18个月大）小鼠（具有较高的基线ApoE水平），并采用蛋白质印迹、ELISA、免疫组织化学、RT-PCR、微透析、RNAi、恐惧条件反射测试和维内/维外挖掘任务。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。我们的努力最终将为老年患者带来更安全的手术护理和更好的术后结果。

DESCRIPTION (provided by applicant): With an increase in the number of aged people, it is predicted that cognitive decline will be one of the most demanding healthcare problems in the near future for both patients and their providers, consuming a growing fraction of healthcare resources. Post-operative cognitive dysfunction or decline (POCD) is one of the most common post-operative complications in older patients, and is associated with substantially increased morbidity, mortality, and cost of care. However, the pathogenesis of POCD is still largely unknown, and this gap in knowledge impedes further studies of POCD. Neuroinflammation includes microglia activation and increases in pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), and IL-1ß in the brain. ß-Amyloid protein (Aß) is th key component of senile plaques in Alzheimer's disease (AD) patients, and Aß levels are elevated in the brains of AD patients as well as older adults. Consistent with the notion that neuroinflammation and Aß accumulation are associated with cognitive dysfunction, and that surgery without general anesthesia can also lead to POCD in humans, our Preliminary studies in mice have shown that open abdominal surgery under local anesthesia induced neuroinflammation, Aß accumulation, and neurobehavioral deficits. Thus, the proposed research will extend these studies to define a potential multifactorial model of POCD pathogenesis by testing the hypothesis that: surgery-induced neuroinflammation will interact with the gene mutation- or aging-induced elevation of Aß levels, leading to impairment of learning/memory and attention/executive function. We will employ chemical and genetic tools through both in vitro (neurons) and in vivo (mice) approaches to accomplish three Specific Aims: 1) We will evaluate the time- dependent effects of the surgery on plasma levels of TNF-α, IL-6, and IL-1ß; the brain levels of TNF-α, IL-6, IL- 1ß, phosphorylated eukaryotic translation initiatin factor 2α (eIF2α-P), ß-site APP-cleaving enzyme (BACE)1, Aß, microglia activation, and amyloid plaques; and postoperative behavioral changes in mice. 2) We will dissect the pathways contributing to Aß accumulation following surgery-induced neuroinflammation by investigating the effects of TNF-α, IL-6, and IL-1ß on eIF2α-P-associated Aß generation pathway and potential CD33 (a newly suggested Alzheimer's disease gene)-associated Aß degradation pathway. 3) We will assess whether the knockout of TNF-α, IL-6 or IL-1ß receptor, anti-inflammatory, or anti-Aß accumulation treatment can inhibit the surgery-induced neurotoxicity. We will include wild-type and younger (9 month-old) mice versus age matched AD transgenic and older (18 month-old) mice (with higher baseline Aß levels), and employ Western blot, ELISA, immunohistochemistry, RT-PCR, microdialysis, RNAi, the Fear Conditioning Test, and an intra-dimensional/extra-dimensional digging task. This proposal aims to investigate an understudied topic in an innovative system by testing novel hypotheses. Our efforts would ultimately lead to safer surgical care and better post-operative outcomes for senior patients.