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