Pathogenesis of Postoperative Cognitive Dysfunction

描述（由申请人提供）：随着老年人数量的增加，预计在不久的将来，认知能力下降将成为对患者和提供者最苛刻的医疗保健问题之一，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，与发病率、死亡率和护理费用的大幅增加有关。然而，POCD的发病机制在很大程度上仍是未知的，这一知识空白阻碍了对POCD的进一步研究。神经炎症包括小胶质细胞激活和促炎细胞因子如肿瘤坏死因子(TNF)-¿、白细胞介素-6 （IL-6）和IL-1在大脑中的增加。淀粉样蛋白（A¿）是阿尔茨海默病（AD）患者老年斑的关键成分，AD患者和老年人大脑中的A¿水平升高。与神经炎症和A¿积累与认知功能障碍相关的观点一致，并且未经全身麻醉的手术也可能导致人类POCD，我们对小鼠的初步研究表明，局部麻醉下的腹部开放手术诱导神经炎症、A¿积累和神经行为缺陷。因此，本研究将扩展这些研究，通过验证以下假设来定义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¿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）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中TNF-、IL-6和IL-1水平的时间依赖性影响；脑内TNF-¿、IL-6、IL- 1¿、磷酸化真核生物翻译起始因子2¿（eIF2¿- p）、app -site切割酶（BACE）1、A¿、小胶质细胞活化和淀粉样斑块的水平；以及小鼠术后的行为变化。2)我们将通过研究TNF-、IL-6和IL-1对eIF2 - p相关A -生成途径和潜在的CD33（一种新提出的阿尔茨海默病基因）相关A -降解途径的影响，解剖手术诱导神经炎症后A -积累的途径。3)我们将评估敲除TNF-、IL-6或IL-1受体、抗炎或抗a -积累治疗是否能抑制手术引起的神经毒性。我们将野生型和幼年（9个月）小鼠与年龄匹配的AD转基因小鼠和老年（18个月）小鼠（基线A¿水平较高）进行比较，并采用Western blot、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。本提案旨在通过检验新的假设来研究创新系统中一个未被充分研究的主题。我们的努力将最终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)-¿, interleukin-6 (IL-6), and IL-1¿ in the brain. ¿-Amyloid protein (A¿) is th key component of senile plaques in Alzheimer's disease (AD) patients, and A¿ levels are elevated in the brains of AD patients as well as older adults. Consistent with the notion that neuroinflammation and A¿ 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, A¿ 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 A¿ 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- ¿, IL-6, and IL-1¿; the brain levels of TNF- ¿, IL-6, IL- 1¿, phosphorylated eukaryotic translation initiatin factor 2¿ (eIF2 ¿-P), ¿-site APP-cleaving enzyme (BACE)1, A¿, microglia activation, and amyloid plaques; and postoperative behavioral changes in mice. 2) We will dissect the pathways contributing to A¿ accumulation following surgery-induced neuroinflammation by investigating the effects of TNF-¿, IL-6, and IL-1¿ on eIF2 ¿-P-associated A¿ generation pathway and potential CD33 (a newly suggested Alzheimer's disease gene)-associated A¿ degradation pathway. 3) We will assess whether the knockout of TNF-¿, IL-6 or IL-1¿ receptor, anti-inflammatory, or anti-A¿ 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 A¿ 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.