GENETICS, INFLAMMATION & POST-OP COGNITIVE DYSFUNCTION

我们的研究团队最近发现晚发性阿尔茨海默病与载脂蛋白 E（APOE，基因；apoE，蛋白质）epsilon-4 基因之间存在遗传关联。这一发现引发了许多最近的研究，表明 apoE 在确定各种急性缺血性损伤（包括脑出血、闭合性脑损伤、急性中风和拳击员痴呆（慢性创伤性脑损伤））后的神经损伤和恢复中发挥着重要作用。我们工作的一个重要方面是发现 APOE4 与心脏手术后神经认知能力下降之间的关联。尽管越来越多的证据表明 apoE 在急性和慢性神经系统疾病中发挥作用，但这些观察结果背后的机制以及衰老的影响尚不完全清楚。 我们假设麻醉和手术后观察到的容易记录的神经系统和神经认知功能障碍存在遗传倾向。 ApoE 可能在调节缺血和围手术期应激的炎症反应中发挥作用。 我们最近确定 ApoE 在体内调节神经胶质细胞中一氧化氮和 TNF-α 的释放。 这可能会加剧我们最近在老年人中报道的自主神经失调。 这两个因素的结合可能会调节过度的炎症反应，增加围手术期损伤的易感性。 我们将 APOE4 与心脏手术后认知障碍相关的试点数据支持了这一假设。 因此，我们建议确定接受胸部和血管手术的患者术后神经认知功能障碍、神经认知恢复和 APOE4 基因型之间的关联。 统一的假设是，手术后对神经功能障碍的遗传易感性要么是由于免疫失调的倾向，正常基因​​编码的修复过程的失败，要么是这些机制的组合导致神经认知功能障碍的发生率和严重程度更高，以及手术后老年人口的生活质量和独立性下降。 因此，我们广泛的前期工作以及我们扩大的跨学科合作研究小组（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）独特地能够研究术后神经认知功能障碍的遗传倾向。 这种关联是阐明缺血性损伤遗传易感性机制和设计干预策略以改善结果的重要的第一步。

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.