GENETICS, INFLAMMATION & POST-OP COGNITIVE DYSFUNCTION

我们的研究小组最近发现了迟发性阿尔茨海默病与载脂蛋白E(apoE，基因；apoE，蛋白质)epsilon-4基因之间的遗传关联。这一发现引发了许多最近的研究，表明载脂蛋白E在确定脑出血、闭合性脑损伤、急性中风和痴呆(慢性创伤性脑损伤)等各种急性缺血性损伤后的神经损伤和康复方面发挥着重要作用。我们工作的一个重要方面是发现载脂蛋白4与心脏手术后神经认知功能下降之间的联系。尽管越来越多的证据表明载脂蛋白E在急性和慢性神经疾病中发挥作用，但这些观察结果背后的机制和衰老的影响并不完全清楚。我们假设在麻醉和手术后观察到的容易被证实的神经和神经认知功能障碍存在遗传易感性。APOE可能在调节对缺血和围术期应激的炎症反应中发挥作用。我们最近确定，在体内，载脂蛋白E调节神经胶质细胞中一氧化氮和肿瘤坏死因子-α的释放。这可能会加剧我们最近在老年人中报告的自主神经失调。这两个因素的结合可能会调节过度的炎症反应，增加围术期损伤的易感性。我们将载脂蛋白4与心脏手术后认知损害联系起来的先导数据支持这一假设。因此，我们建议确定胸部和血管手术患者术后神经认知功能障碍、神经认知恢复和APOE4基因之间的关系。统一的假设是，手术后神经功能障碍的遗传易感性要么是由于免疫功能失调的易感性，要么是正常的基因编码修复过程的失败，要么是这些机制的结合导致手术后神经认知功能障碍的发生率和严重性更高，以及老年人口手术后生活质量和独立性的下降。因此，我们广泛的前期工作以及我们扩大的跨学科协作研究小组，包括心脏麻醉师、心脏外科医生、神经科学家、遗传学家和神经学家，能够独一无二地调查手术后神经认知功能障碍的遗传易感性。这种关联是阐明缺血性损伤遗传易感性的机制，并设计干预策略以改善结果的重要第一步。

Our investigative team has recently discovered a genetic association between late-onset Alzheimer's disease and the apolipoprotein E (APOE, gene; apoE, protein) epsilon-4 gene. This finding has triggered many recent studies showing an important role of apoE in the determination of neurologic injury and recovery following a variety of acute ischemic insults including intracerebral hemorrhage, closed head injury, acute stroke and dementia pugilistica (chronic traumatic brain injury). An important aspect of our work is the finding of an association between APOE4 and neurocognitive decline after cardiac surgery. Although mounting evidence suggests apoE plays a role in acute and chronic neurological disease, the mechanism underlying these observations and the influence of aging is not completely understood. We hypothesize that a genetic predisposition exists for the easily documented neurologic and neurocognitive dysfunction observed after anesthesia and surgery. ApoE may play a role in modulating the inflammatory response to ischemia and perioperative stress. We have recently determined that ApoE, in vivo, modulates the release of nitric oxide and TNF-alpha in glial cells. This may compound the autonomic dysregulation that we recently reported in the elderly. The combination of these two factors may modulate an exaggerated inflammatory response increasing the susceptibility to perioperative injury. Our pilot data associating APOE4 with cognitive impairment after cardiac surgery support this hypothesis. Therefore, we propose to determine the association between post-operative neurocognitive dysfunction, neurocognitive recovery, and APOE4 genotype in patients undergoing thoracic and vascular surgery. The unifying hypothesis is that a genetic susceptibility to neurologic dysfunction after surgery results either from a predisposition to immunologic dysregulation, the failure of normal genetically encoded reparative processes, or a combination of these mechanisms resulting in a greater incidence and severity of neurocognitive dysfunction and reduction in quality of life and independence in the aging population after surgery. Thus, our extensive preliminary work as well as our expanded collaborative interdisciplinary research group including cardiac anesthesiologists, cardiac surgeons, neuroscientists, geneticists and neurologists is uniquely able to investigate the genetic predisposition to neurocognitive dysfunction after surgery. Such an association is an important first step in elucidating the mechanism underlying genetic susceptibility to ischemic insults, and designing interventional strategies to improve outcome.