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 约5%至8%的人感染严重急性呼吸系统综合症冠状病毒(SARS CoV-2) 严重的冠状病毒2019(新冠肺炎)症状需要重症监护病房(ICU)住院。多过 80%的新冠肺炎重症监护室患者出现精神错乱，这是一种急性注意力和认知障碍，将他们置于 轻度认知障碍(MCI)、阿尔茨海默病和其他相关痴呆(ADRD)的风险较高。 迫切需要研究以确定可能降低潜在公共健康的新的治疗靶点 新冠肺炎大流行给重症监护病房精神错乱和随后的ADRD带来的负担。其中一个很有希望的治疗方法 靶细胞可能是内皮细胞，可以直接感染SARS CoV-2。 内皮细胞排列在血管中，在炎症和血液调节中起着至关重要的作用。 凝结。当这些内皮细胞被SARS CoV-2感染时，患者可能会发生急性炎症 以及血液中的变化，在其各个器官形成血块(也称为高凝状态)。 然而，一个主要的知识空白是，新冠肺炎相关的内皮细胞功能障碍能否解释 新冠肺炎重症监护室的患者会出现某些脑部疾病，如精神错乱和药物不良反应。研究也是需要的 了解新冠肺炎相关内皮细胞的炎症和高凝状态 功能障碍可能解释了精神错乱和随后的ADRD之间的联系。 为了回答这些问题，我们建议进行一项前瞻性的先导性研究，比较ICU患者 与未感染SARS CoV-2的ICU患者因严重新冠肺炎症状入院 因急性呼吸衰竭和休克入院治疗。总体假设是内皮细胞感染SARS CoV-2导致内皮细胞功能障碍和伴随的炎症，进而触发 高凝状态。这种新冠肺炎相关的病理生理最初表现为重症监护病房的妄想，并且 持续导致持续的脑血管损伤，神经变性，最后是ADRD。这样做的目的是 建议是评估这些协会的力量，以实现以下目标，这将成为 未来R01建议：1)检查内皮细胞功能障碍、炎症和 19例ICU患者新冠肺炎与非冠状病毒感染患者的高凝状态；2)确定新冠肺炎是否 相关的内皮功能障碍、炎症和高凝状态与较高的ICU发生率相关 3)新冠肺炎相关血管内皮细胞与 神经退行性疾病的功能障碍、炎症和高凝状态以及生物标记物。