Neurological Impact of Cardiopulmonary Bypass Surgery

心肺搭桥手术对神经系统的影响

• 批准号: 7446775
• 负责人: KEVIN Scott LEE
• 金额: $ 33.1万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7446775
• 关键词: Address; Adult; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Area; Attenuated; Behavioral; Benchmarking; Brain; Bypass; Cardiac; Cardiopulmonary Bypass; Cell Death; Cells; Cognitive; Cognitive deficits; Complex; Count; Data; Development; Diffuse; Early Intervention; Event; Functional disorder; Future; Goals; Hippocampus (Brain); Impaired cognition; Impairment; Inflammation; Inflammatory Response; Injury; Knowledge; Lead; Life; Localized; Lung; Measures; Mediating; Memory; Memory impairment; Microglia; Modeling; Molecular; Nature; Nerve Degeneration; Nervous System Trauma; Neuraxis; Neurologic; Neurons; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Outcome; Outcome Measure; Patients; Performance; Play; Procedures; Protocols documentation; Rattus; Recovery; Rodent; Role; Techniques; Testing; Therapeutic; Time; Treatment Efficacy; Treatment Protocols; United States; Upper arm; base; behavior test; cognitive function; comparison group; concept; functional decline; gliogenesis; improved; middle age; neurogenesis; neurogenetics; neuroinflammation; neuron loss; novel; protective effect; research study; response

DESCRIPTION (provided by applicant): The long-term neurological impact of cardio-pulmonary bypass (CPB) surgery can be profound. Recent studies indicate that significant cognitive decline is observed in 42% of CPB-patients when assessed five years after the procedure. This is a substantial biomedical problem because over 500,000 cardiac bypass procedures are performed each year in the United States. The underlying causes of CPB-induced cognitive decline are controversial and not well understood. The overall goal of this application is to characterize mechanisms of CPB-related injury and to evaluate a therapeutic strategy for treating long-term cognitive deficits after CPB. Our preliminary findings indicate that performance on a complex cognitive task is impaired for at least 5-6 months in a rat model of CPB. Studies under Aim #1 will characterize the behavioral impact of CPB in this replicable animal model, and will establish benchmarks for assessing long-term cognitive dysfunction after CPB. Aim #2 will examine three cellular mechanisms proposed to underlie CPB-induced injury: neuroinflammation, suppressed adult neurogenesis, and selective neuronal loss. Preliminary data indicate that sustained, localized neuroinflammation occurs in the hippocampus for at least 6 months after CPB. The preliminary findings also indicate that a substantial decrease in adult neurogenesis occurs in the area of neuroinflammation. These findings, which will be confirmed and extended under Aim #2, spur the hypothesis that sustained neuroinflammation in the hippocampus suppresses adult neurogenesis, which in turn produces long-term cognitive impairment. Aim #3 will test this concept by evaluating the protective effects of anti-inflammatory therapy on the neurogenetic and cognitive consequences of CPB. The benchmarks for behavioral impairment, established under Aim #1, will be used as a measure of cognitive function in these studies. It is hypothesized that blocking the inflammatory response to CPB will attenuate the suppression of neurogenesis and improve cognitive outcome. Together, the proposed studies will: 1) establish a means for assessing long-term cognitive deficits in a rodent recovery model of CPB, 2) characterize fundamental cellular mechanisms that underlie the deleterious effects of CPB, and 3) evaluate a specific therapeutic strategy for blocking and/or reversing cognitive decline associated with CPB. The results will expand our fundamental understanding of the mechanisms underlying CPB-related injury and will assess a rational candidate therapy for limiting cognitive decline after CPB.

描述（由申请人提供）：体外循环 (CPB) 手术对神经系统的长期影响可能是深远的。最近的研究表明，在术后五年进行评估时，42% 的 CPB 患者出现了显着的认知能力下降。这是一个重大的生物医学问题，因为美国每年进行超过 500,000 例心脏搭桥手术。 CPB 引起的认知能力下降的根本原因存在争议，且尚未得到充分了解。本申请的总体目标是表征 CPB 相关损伤的机制，并评估治疗 CPB 后长期认知缺陷的治疗策略。我们的初步研究结果表明，在 CPB 大鼠模型中，复杂认知任务的表现至少会受到 5-6 个月的损害。目标 1 下的研究将描述体外循环 (CPB) 在这种可复制动物模型中的行为影响，并将建立评估体外循环 (CPB) 后长期认知功能障碍的基准。目标 #2 将研究 CPB 引起的损伤的三种细胞机制：神经炎症、抑制成体神经发生和选择性神经元丢失。初步数据表明，CPB 后至少 6 个月内，海马会发生持续的局部神经炎症。初步研究结果还表明，成人神经发生的显着减少发生在神经炎症区域。这些发现将在目标 2 下得到证实和扩展，激发了这样的假设：海马体中的持续神经炎症会抑制成人神经发生，进而产生长期认知障碍。目标 #3 将通过评估抗炎治疗对 CPB 的神经遗传和认知后果的保护作用来检验这一概念。根据目标 1 建立的行为障碍基准将在这些研究中用作认知功能的衡量标准。据推测，阻断体外循环的炎症反应将减弱对神经发生的抑制并改善认知结果。总之，拟议的研究将：1）建立一种评估体外循环啮齿动物恢复模型中长期认知缺陷的方法，2）描述构成体外循环有害影响的基本细胞机制，3）评估阻止和/或逆转与体外循环相关的认知衰退的特定治疗策略。结果将扩大我们对 CPB 相关损伤机制的基本理解，并将评估限制 CPB 后认知能力下降的合理候选疗法。

项目成果

Persistent cognitive deficits and neuroinflammation in a rat model of cardiopulmonary bypass.

• DOI: 10.1016/j.jtcvs.2019.12.070
• 发表时间: 2020-10
• 期刊: The Journal of thoracic and cardiovascular surgery
• 作者: Wang Y;Tache-Leon C;Machizawa MG;Lisle T;Williams C;Clarke RH;Anzivino MJ;Kron I;Lee KS
• 通讯作者: Lee KS