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.

项目概要/摘要 大约 5-8% 的人感染严重急性呼吸综合征冠状病毒 2 (SARS CoV-2) 因 2019 年冠状病毒 (COVID-19) 严重症状需要住院重症监护室 (ICU)。多于 80% 的 COVID-19 ICU 患者出现谵妄，这是一种注意力和认知的急性障碍，使他们陷入困境 轻度认知障碍 (MCI) 和阿尔茨海默病及其他相关痴呆症 (ADRD) 的风险较高。 迫切需要研究以确定可能降低潜在公共卫生风险的新治疗靶点 ICU 谵妄以及随后因 COVID-19 大流行而导致的 ADRD 的负担。一种这样有前途的治疗方法 目标可能是内皮细胞，它可以直接被SARS CoV-2感染。 内皮细胞排列在血管上，在炎症和血液调节中发挥着至关重要的作用 凝固。当这些内皮细胞被 SARS CoV-2 感染时，患者会出现急性炎症 血液发生变化，在各个器官中形成血栓（也称为高凝状态）。 然而，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 COVID-19 ICU 患者会出现某些脑部疾病，例如谵妄和 ADRD。还需要研究 了解 COVID-19 的炎症和高凝状态是否与内皮细胞相关 功能障碍可以解释谵妄与随后的 ADRD 之间的联系。 为了回答这些问题，我们建议进行一项前瞻性试点研究，比较 ICU 患者 未感染 SARS CoV-2 的 ICU 患者因严重 COVID-19 症状而住院 因急性呼吸衰竭和休克住院。总体假设是 SARS 的内皮感染 CoV-2 会导致内皮细胞功能障碍并伴随炎症，进而引发 高凝状态。这种与 COVID-19 相关的病理生理学最初表现为 ICU 谵妄，并且 持续导致脑血管损伤、神经退行性变，最后导致ADRD。此举的目标 提案旨在评估这些协会实现以下目标的实力，这将成为以下目标的基础： 未来的 R01 提案：1）检查内皮细胞功能障碍、炎症和 COVID-19 和非 COVID-19 ICU 患者之间的高凝状态； 2) 确定是否有COVID-19 相关的内皮功能障碍、炎症和高凝状态与 ICU 发生率较高有关 谵妄和/或 MCI 和 ADRD； 3) 检查COVID-19相关内皮细胞之间的关系 功能障碍、炎症、高凝状态以及神经退行性疾病的生物标志物。