Neuroimaging and Behavioral Studies to Assess For Neuroinflammation in COVID-19 During Convalescence

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Project Summary This R21 Exploratory/Developmental Research Grant is written in response to PAR-20-177: Emergency Awards: Rapid Investigation of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19). SARS-CoV2 is the virus that causes COVID-19, and is known to have high affinity binding to the angiotensin-coverting enzyme 2 (ACE-2) receptors. This receptor is expressed on endothelial lining, innate immune cells, including monocytes and macrophages, as well as astroglial and microglial cells in the brain. SARS-CoV2 virus was shown to be neuroinvasive, but whether it causes persistent or residual neuroinflammation or neuronal injury is unknown. We will use a multi-parametric MRI approach to evaluate markers of neuroinflammation and neural integrity in COVID-19 patients, and a comprehensive NIH Toolbox® and PROMIS® battery to assess cognitive performance, emotional distress, fatigue, pain, motor function and global health outcomes in convalescent COVID-19 patients. We will also determine whether serum and cerebrospinal fluid (CSF) levels of neuroinflammatory markers, i.e. cytokines and chemokines, would predict the neuroimaging and behavioral measures. We propose three specific Aims: Aim 1: Structural MRI, proton spectroscopy (1H-MRS) and diffusion tensor imaging (DTI), will be used to evaluate regional neuroinflammation or neuronal injury in convalescent COVID-19 patients and in healthy controls with negative COVID-19 tests. Aim 2: Cognitive and motor function will be evaluated using the NIH Toolbox®, while emotional distress, fatigue, pain and overall health will be assessed using PROMIS®. Neural correlates of these behaviors will also be assessed with blood oxygenation level dependent-functional MRI (BOLD-fMRI). Aim 3: CSF and blood will be collected during early convalescence to quantify soluble markers of inflammation using a multiplex ELISA cytokine panel. Levels of D-dimer and C-reactive protein will also be repeated to compare with those obtained during the patients’ acute hospitalization. This project will generate novel data regarding possible residual or ongoing neuroinflammation or brain injury in convalescent COVID-19 patients. We will also investigate whether such brain abnormalities might be related to cognitive or behavioral outcomes that might affect their overall health. Furthermore, we will determine whether the soluble inflammatory markers night predict brain or neurobehavioral outcomes. Findings from these studies can lead to a larger study that may guide future treatments to ameliorate neuronal injury or neuroinflammation in COVID-19 patients.