围术期锻炼对老年病人术后认知功能障碍的影响及机制研究

The occurrence of postoperative cognitive dysfunction (POCD) in the elderly surgical patients is closely associated with peripheral inflammation as a consequence of surgery. Our clinical study found that perioperative intervention improved cognitive functions overall and decreased the incidence of POCD among the elderly after unilateral total hip replacement surgery. At the same time, it also reduced the increase of blood HMGB1 and TNF-αinduced by surgery. Thus we assume that perioperative intervention prevents POCD of aged patients by modulating peripheral immunity. In this study, it will be detected in larger samples whether perioperative intervention is helpful to prevent POCD; and then the potential relationship will be investigated between intervention and peripheral inflammation factors and CD4+T cells. The study will also detect the effects of blood serum and CD4+T cells from aged patients, who are treated with or without perioperative intervention, on the cultured neurons derived from the induced pluripotent stem cells. Based on these, this study employs skills to reconstruct the main features of inflammation factors and CD4+T cells, in order to explore whether modulating the peripheral immunity plays an important roll in improvement of the elderly postoperative cognitive function by using perioperative intervention. Our data will provide an appropriate perioperative intervention strategy, which can reduce POCD of aged patients with only little risk and payment.

老年病人术后认知功能障碍(POCD)的发生与手术诱导的外周炎症密切相关。我们的临床研究发现对单侧全髋关节置换手术的老年病人进行围术期锻炼可全面改善病人术后的认知功能，显著降低POCD的发生。同时,围术期锻炼抑制了术后外周血炎症因子HMGB1和TNF-α水平的升高。据此我们推测：围术期锻炼通过调节老年病人外周免疫系统改善其认知功能。本项目拟在前期基础上增大样本，观察围术期锻炼预防POCD的效果及其与外周血炎症因子和CD4+T细胞（在适应性免疫反应中起关键作用）改变的关系。并以病人来源的诱导型多能干细胞分化的神经元作为实验对象，利用围术期锻炼和非锻炼条件下的外周血血浆和CD4+T细胞直接作用于神经元，探讨他们对神经元的影响；通过体外重构锻炼组病人的外周血并用它干预神经元,检测围术期锻炼是否通过调节外周免疫系统改善POCD。研究结果有望为老年病人POCD的预防提供一种低风险、低成本的锻炼方式。

本项目检测了围术期锻炼对老年病人术后认知功能障碍（POCD）的影响及其机制。另外，本项目还检测了脓毒血症对脑内NMDA受体的表达影响及其机制。发现：围术期智能体能锻炼显著降低了POCD的发生率(非锻炼组发生率为26.4%，锻炼组发生率为7.9% )，同时显著降低了外周血炎症因子的水平。用药物或特异性抗体阻止锻炼期间外周血T淋巴细胞进入脑内显著抑制了锻炼对小鼠学习记忆的改善作用。脓毒血症能选择性的损伤海马NMDA受体，腹腔内给予NMDA受体激动剂D-serine能改善脓毒血症脑病的病理改变和认知功能。这些表明围术期智能体能锻炼是一种老年病人POCD防治的有效方法，其作用机制与其外周免疫的调节作用有关。NMDA受体是防治脓毒血症脑病的重要靶点。