Inflammation resolving mechanism dysregulation in postoperative cognitive decline

描述（由申请人提供）：有人担心，高龄手术患者可能会出现信息处理问题（“认知功能障碍”），并在手术后长期存在。除了年龄之外，最近的一项研究显示，患有代谢综合征（一组包括内脏肥胖、胰岛素抵抗、血脂异常和高血压的疾病）的手术患者特别容易发生术后认知功能障碍，发生频率几乎为三分之一。在过去的5年里，我们积累了一系列已发表的研究数据，这些研究涉及接受手术的健康啮齿动物，揭示了海马体中短暂炎症的发展，海马体是一个对认知功能至关重要的大脑区域。结果，手术前即刻获得的急性记忆回忆被中断。通常情况下，大脑炎症和记忆力下降都会在几天内修复，不会产生长期的后果。然而，如果参与解决炎症的过程被禁用，那么正常认知功能的恢复将不会发生。我们已经进行了涉及代谢综合征大鼠模型的术后研究，其中先天和后天的影响都导致了严重的后果，包括预期寿命大大缩短。术后急性期，这些大鼠出现夸大的认知能力下降，以及与更严重的脑部炎症相关的持久性而非短暂的认知能力下降。我们注意到，认知能力的下降与这些动物解决手术创伤后炎症的方式异常有关。我们的新项目测试了一个假设，即炎症消退的异常是代谢综合征大鼠模型中夸大和持续的术后认知下降的原因。当我们测试这种因果关系时，我们将发现免疫系统中可能的目标，这将使我们能够干预并希望中断异常。特别值得一提的是，我们注意到的一些异常通过运动可能是可逆的，因此我们还将探讨运动训练对术后认知功能下降的机制和表达的影响。由于大鼠模型和人类代谢综合征状况之间的相似性，我们随后计划研究患有这种状况的手术患者是否表现出与我们在大鼠中注意到的相同的异常;如果是这样，我们可以将本研究中注意到的成功治疗干预扩展到人类，特别是术前锻炼。

DESCRIPTION (provided by applicant): There is a concern that surgical patients of advanced age may develop problems processing information ("cognitive dysfunction") that persist long after the operation. Apart from age a recent study revealed that surgical patients with the Metabolic Syndrome (a clustering of conditions that include visceral obesity, insulin resistance, dyslipidemia and hypertension) are particularly prone to develop postoperative cognitive dysfunction occurring with a frequency of almost one in three. Over the last 5 years we have accumulated data from a series of published studies involving healthy rodents undergoing surgery that reveal the development of short-lived inflammation in the hippocampus, a brain region that is vital for cognitive function. As a consequence acute recall of memories, acquired immediately before the surgery, is disrupted. Normally, both the brain inflammation and the memory decline are repaired within days with no long-lasting consequence. However, if the processes involved in resolving the inflammation are disabled then restoration of normal cognitive function will not occur. We have undertaken postoperative studies involving a rat model of the Metabolic Syndrome in which both the influences of nature and nurture contribute to serious consequences including a considerably shorter life expectancy. Acutely postoperatively, these rats develop exaggerated cognitive decline, and remotely a persistent, rather than short-lived, cognitive decline that is associated with more severe brain inflammation. We noted that the cognitive deterioration was associated with abnormalities in the manner that these animals resolve the inflammation that follows the trauma of surgery. Our new project tests the hypothesis that the abnormalities in inflammation-resolution are the cause for the exaggerated and persistent postoperative cognitive decline in this rat model of the Metabolic Syndrome. As we test this cause and effect relationship we will uncover possible targets in the immune system that will allow us to intervene and hopefully interrupt the abnormality. In particular, we are encouraged that some of the abnormalities that we have noted are potentially reversible with exercise and therefore we will also explore the effect of exercise training on the mechanisms and expression of postoperative cognitive decline. Because of the similarity between the rat model and the human condition of Metabolic Syndrome we subsequently plan to study whether surgical patients with this condition exhibit the same abnormalities as we noted in the rat; if so, we can extend to humans successful therapeutic interventions noted in this study, in particular pre-operative exercise.