Role of Endothelial and Brain Injury in Acute and Long-term Brain Dysfunction

描述(申请人提供)：脑功能障碍在重症老年人中普遍存在，在急性情况下表现为精神错乱或昏迷，或在长期表现为整体认知和执行功能的损害。这种大脑功能障碍会导致住院费用、住院时间、功能依赖和死亡率的增加。这种脑功能障碍的病理生理学机制尚不清楚，但可能涉及内皮功能障碍和血脑屏障和神经元的损伤。随着人口年龄的增加和危重疾病的持续高发，必须研究老年人特有危重疾病的急性和长期认知效应，并阐明内皮功能障碍和神经损伤等潜在的病理生理通路在老年人脑功能障碍中的机制作用。因此，这项研究项目的总体目标是检验全球假说，即全身内皮功能障碍和神经损伤会导致危重疾病期间的急性脑功能障碍和幸存者的长期认知功能障碍。这项研究将为危重病脑功能障碍的病理生理学提供新的见解，这笔赠款将使首席研究员能够深入研究这些病理生理机制，同时在研究老年人脑功能障碍的独特挑战中积累经验。在这一资助期间获得的数据将导致主要研究人员对老年人脑功能障碍进行更详细的机制研究。重要的是，这一系列研究的结果可能会导致未来的治疗试验 内皮或血脑屏障调节旨在改善老年ICU患者的认知结果。

DESCRIPTION (provided by applicant): Brain dysfunction is prevalent in the critically ill elderly, presenting in the acute setting as delirium or coma or in the long-term as impairment in global cognition and executive functioning. This brain dysfunction results in increased hospital cost, length of stay, functional dependence, and mortality. The pathophysiology of this brain dysfunction remains unclear but likely involves endothelial dysfunction and injury to the blood brain barrier and neurons. With the increasing age of the population and continued high morbidity from critical illness states, the acute and long-term cognitive effects of critical illnes that are unique to the elderly must be studied, and the mechanistic roles of potential pathophysiological pathways such as endothelial dysfunction and neurologic injury in this brain dysfunction of the elderly must be elucidated. The overall objectives of this research project, therefore, focus on testing the global hypothesis that systemic endothelial dysfunction and neurologic injury lead to acute brain dysfunction during critical illness and long-term cognitive impairment after in survivors. This research will provide new insights into the pathophysiology of critical illness brain dysfunction, and this grant will allow the principal investigator to delve ito these pathophysiological mechanisms while gaining experience in the unique challenges of researching brain dysfunction in the elderly. The data obtained during this grant period will lead toward more detailed mechanistic studies by the principal investigator of brain dysfunction in the elderly. Importantly, the results of this line of research may lead to future therapeutic trials of endothelial or blood brain barrier modulation designed to improve the cognitive outcomes our elderly ICU patients.