Pathogenesis of Postoperative Cognitive Dysfunction

描述(申请人提供)：随着老年人数量的增加，预计在不久的将来，认知能力下降将成为患者及其提供者面临的最严峻的医疗问题之一，消耗越来越多的医疗资源。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，并与显著增加的发病率、死亡率和护理费用有关。然而，POCD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对POCD的进一步研究。神经炎症包括脑内小胶质细胞的激活和促炎细胞因子如肿瘤坏死因子α、白介素6和白介素1的增加。B-淀粉样蛋白是阿尔茨海默病(AD)患者老年斑的关键成分，AD患者和老年人的大脑中A？水平均升高。我们在小鼠身上的初步研究表明，局部麻醉下的开腹手术会导致神经炎症、Aü积聚和神经行为缺陷，这一观点与神经炎症和A？积聚与认知功能障碍有关，以及在没有全身麻醉的情况下手术也会导致人类POCD。因此，这项拟议的研究将扩展这些研究，通过检验以下假设来定义POCD发病的潜在多因素模型：手术诱导的神经炎症将与基因突变或衰老诱导的Aü水平升高相互作用，导致学习/记忆和注意力/执行功能的损害。我们将通过体外(神经元)和体内(小鼠)方法使用化学和遗传工具来实现三个特定目标：1)我们将评估手术对血浆肿瘤坏死因子-α、IL-6和IL-1？水平的时间依赖性影响；脑部肿瘤坏死因子-α、IL-6、IL-1？、磷酸化真核细胞翻译起始因子2α(eIF2α-P)、？位应用裂解酶1、A？、小胶质细胞激活和淀粉样蛋白斑块的影响；以及术后小鼠的行为变化。2)我们将通过研究肿瘤坏死因子-α、IL-6和IL-1？对eIF2-α-P相关的A？生成通路和潜在的CD33(一种新发现的阿尔茨海默病基因)相关的A？降解通路的影响，来剖析手术诱导的神经炎症后A？积聚的途径。3)我们将评估剔除肿瘤坏死因子-α、IL-6或IL-1？受体、抗炎或抗A？蓄积治疗是否能抑制手术所致的神经毒性。我们将包括野生型和较年轻(9个月大)的小鼠与年龄匹配的AD转基因小鼠和较大(18个月大)的小鼠(基线水平较高)，并使用Western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度内/维度外挖掘任务。这项提议旨在通过测试新的假设来研究创新系统中一个未被研究的话题。我们的努力最终将为老年患者带来更安全的外科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.