Neurocognitive Impairment in Acute Respiratory Failure and Shock: Understanding the Role of Neuronal Excitotoxicity

项目摘要 由急性呼吸衰竭或休克引起的心肺衰竭是最常见的综合征 重症监护病房服务。心肺衰竭患者经常出现神经认知功能障碍。 威胁短期和长期结果的后遗症。在短期内，这些患者经常发展为 精神错乱，注意力和认知的严重改变，与死亡率增加和 机械通气量和ICU停留时间较长。康复后，每4名幸存者中就有1人遭受长期痛苦 类似于痴呆症的认知障碍(LTCI)。尽管精神错乱和LTCI对这些患者有影响， 目前还没有经过验证的药物疗法来预防这些神经认知后遗症。 脓毒症每年导致100多万人住院，是心肺疾病最常见的原因。 失败，使它成为一个理想的人群来研究精神错乱和LTCI的潜在机制。我们的团队 其他研究表明，精神错乱和LTCI的特征是海马体和额叶的损伤。 大脑皮层。动物模型显示出类似的神经元损伤模式，并牵涉到谷氨酸的变化 动态平衡和犬尿氨酸代谢作为神经元损伤的关键下游通路 在治疗上有针对性。然而，由于缺乏关于人类这些通路的数据，并且无法识别 哪些患者最有可能从早期治疗中受益是限制翻译的关键知识差距 将这些发现提交给临床试验。为了解决这些知识差距，这项提案将调查 败血症心肺衰竭患者中的谷氨酸和犬尿氨酸失衡 他们会因精神错乱和随后的认知障碍而被前瞻性地跟踪。除了建议的 研究，候选人将参与一项严格的培训计划，以支持他过渡到 独立科学家。这项提案的具体目标是：1)确定谷氨酸的结合 合并心肺功能障碍的脓毒症患者的犬尿氨酸调节障碍和认知功能障碍 失败，2)确定认知障碍的风险因素并开发可用于指导的预测工具 参加未来的临床试验，3)培训候选人在认知神经科学，神经机制 损伤和修复、队列研究设计和实施、分子实验室技术和高级统计学， 以及4)为候选人提供个性化的指导，以支持他向独立的过渡。这个 候选人的导师将定期审查候选人达到特定研究和培训基准的情况 和咨询委员会。通过完成这项建议，候选人将增进我们对 这些患者精神错乱和LTCI的潜在机制，并将自己定位为成功 为未来旨在测试神经保护疗法的项目争夺R01资金。

Project Summary Cardiopulmonary failure due to acute respiratory failure or shock is the most common syndrome necessitating intensive care unit services. Patients with cardiopulmonary failure often develop burdensome neurocognitive sequelae that threaten both short and long-term outcomes. In the short-term, these patients frequently develop delirium, a severe alteration in attention and cognition that is associated with increased mortality as well as longer durations of mechanical ventilation and ICU stay. After recovering, 1 in 4 survivors suffer long-term cognitive impairment (LTCI) similar to dementia. Despite the impact delirium and LTCI have on these patients, there are currently no proven pharmacologic therapies aimed at preventing these neurocognitive sequelae. Sepsis accounts for over 1 million hospitalizations per year and is the most common cause of cardiopulmonary failure, making it an ideal population to investigate the underlying mechanisms of delirium and LTCI. Our group and others have shown that delirium and LTCI are characterized by injury to the hippocampus and frontal cortex. Animal models show a similar pattern of neuronal injury, and implicate alterations in glutamate homeostasis and kynurenine metabolism as key downstream pathways of neuronal injury that can be therapeutically targeted. However, a lack of data on these pathways in humans and an inability to identify which patients would most likely benefit from early therapy are key knowledge gaps limiting the translation of these findings to clinical trials. To address these knowledge gaps, this proposal will investigate the role of glutamate and kynurenine dysregulation in an ongoing cohort of septic patients with cardiopulmonary failure who are followed prospectively for delirium and subsequent cognitive impairment. In addition to the proposed research, the candidate will engage in a rigorous training program designed to support his transition into an independent scientist. The specific objectives of this proposal are to: 1) determine the association of glutamate and kynurenine dysregulation with delirium and cognitive impairment in septic patients with cardiopulmonary failure, 2) identify risk factors for cognitive impairment and develop a predictive tool that could be used to guide enrollment in future clinical trials, 3) train the candidate in cognitive neuroscience, mechanisms of neuronal injury and repair, cohort study design and conduct, molecular laboratory techniques and advanced statistics, and 4) provide the candidate with individualized mentoring to support his transition to independence. The candidate's attainment of specific research and training benchmarks will be regularly reviewed by his mentors and advisory committee. Through completion of this proposal, the candidate will enhance our understanding of the underlying mechanisms of delirium and LTCI in these patients, and position himself to successfully compete for R01 funding of future projects aimed at testing neuroprotective therapies.