The Role of COVID-19 Endothelial Cell Dysfunction and Hypercoagulability in the Development of Post-ICU Cognitive Impairment and Dementia

COVID-19 内皮细胞功能障碍和高凝状态在 ICU 后认知障碍和痴呆发展中的作用

• 批准号: 10301224
• 负责人: Sophia Wang
• 金额: $ 19.81万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301224
• 关键词: 2019-nCoV; Acute; Acute Disease; Acute respiratory failure; Address; Admission activity; African American; Alzheimer' s Disease; Alzheimer' s disease related dementia; Attention; Behavioral; Biological; Biological Markers; Blood; Blood Coagulation Disorders; Blood Vessels; Blood coagulation; Brain Diseases; COVID-19; COVID-19 pandemic; COVID-19 patient; Cell Line; Cerebrovascular Circulation; Clinical; Coagulation Process; Cognition; Coronavirus; Data; Delirium; Dementia; Development; Endothelial Cells; Endothelium; Fibrin fragment D; Functional disorder; Future; Goals; Hospitalization; Hospitals; Image; Impaired cognition; Impairment; Incidence; Infection; Inflammation; Intensive Care Units; Intercellular adhesion molecule 1; Interleukin-1 beta; Interleukin-10; Interleukin-6; Interleukin-8; Knowledge; Lacunar Infarctions; Lead; Light; Link; Liquid substance; Magnetic Resonance Imaging; Measures; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neuropsychology; Observational Study; Organ; Pathway interactions; Patients; Pilot Projects; Plasma; Plasminogen Activator Inhibitor 1; Play; Population; Public Health; Recovery; Regulation; Research; Risk Factors; Role; SARS-CoV-2 infection; Shock; Survivors; Symptoms; Thrombomodulin; Thrombophilia; Thromboplastin; Vascular Cell Adhesion Molecule-1; Vulnerable Populations; cerebral atrophy; cerebral microbleeds; cerebrovascular; clinical phenotype; cohort; confusion assessment method; cytokine; endothelial dysfunction; experience; high risk; innovation; insight; mild cognitive impairment; neurofilament; neuroimaging; new therapeutic target; novel; prospective; severe COVID-19; therapeutic target; white matter

Project Summary/Abstract About 5-8% of those who are infected with severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) require intensive care unit (ICU) hospitalization for severe coronavirus 2019 (COVID-19) symptoms. More than 80% of COVID-19 ICU patients develop delirium, an acute disorder of attention and cognition, placing them at higher risk for mild cognitive impairment (MCI) and Alzheimer's disease and other related dementias (ADRD). Research is urgently needed to identify novel therapeutic targets which may reduce the potential public health burden of ICU delirium and subsequent ADRD from the COVID-19 pandemic. One such promising therapeutic target may be endothelial cells, which can be directly infected by SARS CoV-2. Endothelial cells line the blood vessels and play a crucial role in the regulation of inflammation and blood coagulation. When these endothelial cells are infected by SARS CoV-2, patients can develop acute inflammation and changes in the blood to form blood clots throughout their various organs (also known as hypercoagulability). However, a major knowledge gap is whether COVID-19 associated endothelial cell dysfunction can explain how certain brain disorders, such as delirium and ADRD, arise in COVID-19 ICU patients. Studies are also needed to understand whether inflammation and hypercoagulability from COVID-19 associated endothelial cell dysfunction may explain the link between delirium and subsequent ADRD. To answer these questions, we propose to conduct a prospective pilot study that will compare ICU patients hospitalized for severe COVID-19 symptoms with ICU patients who are not infected with SARS CoV-2 hospitalized for acute respiratory failure and shock. The overall hypothesis is that endothelial infection with SARS CoV-2 causes endothelial cell dysfunction and accompanying inflammation which, in turn, trigger a hypercoagulable state. This COVID-19 associated pathophysiology initially manifests as ICU delirium, and persists to cause ongoing cerebrovascular damage, neurodegeneration, and, finally, ADRD. The goal of this proposal is to estimate the strength of these associations for the following aims that will be the groundwork for a future R01 proposal: 1) examine the differences in endothelial cell dysfunction, inflammation, and hypercoagulability between COVID-19 and non-COVID 19 ICU patients; 2) determine whether COVID-19 associated endothelial dysfunction, inflammation, and hypercoagulability are associated with higher rates of ICU delirium and/or MCI and ADRD; and 3) examine the relationship between COVID-19 associated endothelial cell dysfunction, inflammation, and hypercoagulability and biomarkers of neurodegenerative disorders.

项目摘要/摘要 在感染严重急性呼吸综合征2（SARS COV-2）的人中，约有5-8％ 要求重症监护病房（ICU）住院治疗严重的冠状病毒2019（COVID-19）症状。多于 80％的ICU患者中，有80％的ICU患者发展为del妄，这是一种急性关注和认知疾病，将其置于 轻度认知障碍（MCI）和阿尔茨海默氏病和其他相关痴呆症（ADRD）的风险更高。 迫切需要进行研究以识别新的治疗靶标，这可能会降低潜在的公共卫生 ICU del妄的负担以及随后的Covid-19大流行的ADRD。一个如此有前途的治疗 靶标可以是内皮细胞，可以直接被SARS COV-2感染。 内皮细胞排在血管中，并在调节炎症和血液中起着至关重要的作用 凝血。当这些内皮细胞被SARS COV-2感染时，患者会出现急性炎症 并在整个器官（也称为高凝性）中形成血块的血液变化。 但是，一个主要的知识差距是Covid-19相关的内皮细胞功能障碍是否可以解释如何解释如何 某些脑部疾病，例如del妄和ADRD，在Covid-19 ICU患者中出现。还需要研究 了解COVID-19相关内皮细胞的炎症和高凝性是否存在 功能障碍可以解释ir妄与随后的ADRD之间的联系。 为了回答这些问题，我们建议进行一项预期的试点研究，以比较ICU患者 不受SARS COV-2感染的ICU患者的严重COVID症状住院 因急性呼吸衰竭和冲击而住院。总体假设是用SARS的内皮感染 COV-2会引起内皮细胞功能障碍和随附的炎症，从而触发A 超凝状态。这次COVID-19相关的病理生理学最初表现为ICU del妄，并且 持续造成持续的脑血管损伤，神经变性，最后是ADRD。目标的目标 提案是估算这些关联的实力，以实现以下目的，这将是一个基础 未来R01建议：1）检查内皮细胞功能障碍，炎症和 共凝-19和非卵巢19个ICU患者之间的高凝性； 2）确定COVID是否19 相关的内皮功能障碍，炎症和高凝性与ICU的率较高有关 Delirium和/或MCI和Adrd; 3）检查Covid-19相关内皮细胞之间的关系 神经退行性疾病的功能障碍，炎症，高凝性和生物标志物。