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

急性呼吸衰竭和休克中的神经认知损伤：了解神经元兴奋性毒性的作用

• 批准号: 9898435
• 负责人: Brian J. Anderson
• 金额: $ 19.57万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898435
• 关键词: Acute; Acute respiratory failure; Address; Admission activity; Advisory Committees; Animal Model; Animals; Area; Attention; Behavior; Benchmarking; Brain; Brain Injuries; Cardiopulmonary; Clinical; Clinical Trials; Cognition; Cohort Studies; Coma; Critical Care; Critical Illness; Data; Delirium; Dementia; Early treatment; Electroencephalography; Enrollment; Failure; Funding; Future; Glial Fibrillary Acidic Protein; Glutamates; Hippocampus (Brain); Homeostasis; Hospitalization; Hospitals; Human; Image; Impaired cognition; Inflammation; Injury; Intensive Care Units; Knowledge; Kynurenine; Laboratories; Lead; Link; Measures; Mechanical ventilation; Mentors; Metabolism; Methods; Molecular; Morbidity - disease rate; Neurocognitive; Neurocognitive Deficit; Neurologic; Neuron-Specific Enolase; Neuronal Injury; Neurons; Outcome; Oxygen; Pathogenesis; Pathway interactions; Patients; Pharmacological Treatment; Pharmacology; Phase; Phenotype; Plasma; Population; Positioning Attribute; Public Health; Recovery; Research; Research Design; Research Personnel; Research Training; Risk; Risk Factors; Role; Scientist; Sedation procedure; Sepsis; Services; Shock; Subgroup; Survivors; Syndrome; Techniques; Testing; Time; Training; Training Programs; Translations; Tryptophan; clinical risk; clinical trial enrollment; cognitive neuroscience; cognitive testing; cohort; confusion assessment method; design; excitotoxicity; frontal lobe; high risk; injury and repair; innovation; mortality; neuronal patterning; neuroprotection; new therapeutic target; patient oriented; patient stratification; predictive modeling; predictive tools; prevent; prospective; septic patients; statistics; targeted treatment; therapeutic target

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.

项目概要 急性呼吸衰竭或休克引起的心肺衰竭是最常见的综合征 重症监护室服务。心肺衰竭患者常常会出现沉重的神经认知障碍 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，四分之一的幸存者遭受长期痛苦 认知障碍（LTCI）与痴呆症类似。尽管谵妄和 LTCI 对这些患者有影响， 目前尚无经过验证的药物疗法旨在预防这些神经认知后遗症。 脓毒症每年导致超过 100 万人住院，是心肺疾病的最常见原因 失败，使其成为研究谵妄和 LTCI 潜在机制的理想人群。我们组 等人表明谵妄和 LTCI 的特点是海马体和额叶损伤 皮质。动物模型显示出类似的神经元损伤模式，并暗示谷氨酸的变化 稳态和犬尿氨酸代谢是神经元损伤的关键下游途径 治疗有针对性。然而，缺乏关于人类这些途径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转化的关键知识差距 将这些发现用于临床试验。为了解决这些知识差距，本提案将调查 一组患有心肺衰竭的脓毒症患者中谷氨酸和犬尿氨酸失调 对谵妄和随后的认知障碍进行前瞻性随访。除了提议的 研究期间，候选人将参加严格的培训计划，旨在支持他过渡到 独立科学家。该提案的具体目标是：1）确定谷氨酸的关联 心肺脓毒症患者中犬尿氨酸失调伴谵妄和认知障碍 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 参加未来的临床试验，3）对候选人进行认知神经科学、神经元机制方面的培训 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、 4) 为候选人提供个性化指导，以支持他向独立过渡。这 候选人的导师将定期审查其特定研究和培训基准的达到情况 和咨询委员会。通过完成本提案，候选人将增强我们对以下方面的理解： 这些患者发生谵妄和 LTCI 的根本机制，并让自己成功地 竞争旨在测试神经保护疗法的未来项目的 R01 资金。