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

描述（申请人提供）：脑功能障碍普遍存在于危重老年患者中，急性表现为谵妄或昏迷，长期表现为整体认知和执行功能障碍。这种脑功能障碍导致住院费用、住院时间、功能依赖和死亡率增加。这种脑功能障碍的病理生理学尚不清楚，但可能涉及内皮功能障碍和血脑屏障和神经元的损伤。随着人口年龄的增长和危重疾病状态的持续高发病率，必须研究老年人特有的危重疾病的急性和长期认知影响，并阐明内皮功能障碍和神经损伤等潜在病理生理途径在老年人这种脑功能障碍中的机制作用。因此，本研究项目的总体目标集中在验证系统性内皮功能障碍和神经损伤导致危重疾病期间急性脑功能障碍和幸存者后长期认知障碍的全球假设。这项研究将为危重疾病脑功能障碍的病理生理提供新的见解，这项资助将允许首席研究员深入研究这些病理生理机制，同时获得研究老年人脑功能障碍的独特挑战的经验。在此资助期间获得的数据将引导首席研究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

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.