GENETICS, INFLAMMATION & POST-OP COGNITIVE DYSFUNCTION

遗传学、炎症

• 批准号: 6532517
• 负责人: Mark Franklin Newman
• 金额: $ 43.79万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6532517
• 关键词: aging; anesthesia; apolipoprotein E; cardiovascular surgery; clinical research; cognition; cognition disorders; genetic susceptibility; genotype; health care cost /financing; human genetic material tag; human middle age (35-64); human old age (65+); human subject; inflammation; neuropsychological tests; postoperative complications; quality of life; thoracic surgery

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.

我们的研究小组最近发现了晚发性阿尔茨海默病与载脂蛋白E（APOE，基因; apoE，蛋白质）β 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，apoE在确定神经系统损伤和恢复后的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）的重要作用。我们工作的一个重要方面是发现APOE 4与心脏手术后神经认知功能下降之间的关联。虽然越来越多的证据表明apoE在急性和慢性神经系统疾病中起作用，但这些观察结果的机制和衰老的影响尚未完全了解。 我们假设，麻醉和手术后观察到的容易记录的神经和神经认知功能障碍存在遗传易感性。 ApoE可能在调节缺血和围手术期应激的炎症反应中发挥作用。 我们最近已经确定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报道的老年人的自主神经失调。 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APOE 4与心脏手术后认知障碍联系起来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APOE 4基因型之间的关联。 统一的假设是，遗传易感性手术后神经功能障碍的结果，无论是从一个易感性免疫失调，正常的遗传编码修复过程的失败，或这些机制的组合，导致更大的发病率和严重程度的神经认知功能障碍和降低生活质量和独立性的老年人群手术后。 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，是唯一能够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机制的重要第一步，并设计干预策略以改善结果。