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

项目摘要 由于急性呼吸衰竭或休克引起的心力衰竭是最常见的综合征， 重症监护室服务。心肺功能衰竭患者通常会出现神经认知负担 影响短期和长期结果的后遗症。在短期内，这些患者经常会出现 谵妄，注意力和认知的严重改变，与死亡率增加以及 机械通气和ICU停留时间更长。康复后，四分之一的幸存者长期遭受 认知障碍（LTCI），类似于痴呆。尽管谵妄和LTCI对这些患者有影响， 目前还没有经过证实的旨在预防这些神经认知后遗症的药物疗法。 脓毒症占每年超过100万次住院治疗，并且是心肺功能衰竭的最常见原因。 失败，使其成为研究谵妄和LTCI潜在机制的理想人群。我们集团 其他研究表明，谵妄和LTCI的特征是海马和额叶损伤， 皮层动物模型显示出类似的神经元损伤模式，并暗示谷氨酸的改变。 稳态和犬尿氨酸代谢作为神经元损伤的关键下游途径， 治疗靶向。然而，由于缺乏关于人类这些途径的数据， 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， 将这些发现用于临床试验。为了弥补这些知识差距，本提案将探讨以下方面的作用： 心肺衰竭脓毒症患者中谷氨酸和犬尿氨酸失调的研究 他们被前瞻性地跟踪谵妄和随后的认知障碍。除了拟议的 研究，候选人将参加一个严格的培训计划，旨在支持他过渡到一个 独立科学家本提案的具体目标是：1）确定谷氨酸的关联 与犬尿氨酸失调伴谵妄和认知功能障碍的心肺功能衰竭患者 失败，2）识别认知障碍的风险因素，并开发可用于指导的预测工具 在未来的临床试验中招募，3）在认知神经科学，神经元的机制， 损伤和修复，队列研究设计和进行，分子实验室技术和先进的统计学， （4）为候选人提供个性化辅导，以支持其向独立过渡。的 导师会定期检讨申请人在研究及训练方面的表现 咨询委员会。通过完成这份建议书，候选人将加深我们对以下方面的理解： 这些患者中谵妄和LTCI的潜在机制，并将自己定位为成功地 竞争R01基金的未来项目旨在测试神经保护疗法。

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.