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Principal Investigator: LINDA CHANG
Organization: UNIVERSITY OF MARYLAND BALTIMORE
Fiscal Year: 2021
Award: $424,875
Funding agency: National Institute of Neurological Disorders and Stroke
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.
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><3-10C><ACE2><AMCF-I><Acquired brain injury><Acute><Affect><Affinity><Age><Angiotensins><Anxiety><Attention><Award><B cell differentiation factor><B cell growth factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-1><B-Cell Differentiation Factor-2><B-Cell Growth Factor-1><B-Cell Growth Factor-I><B-Cell Proliferating Factor><B-Cell Stimulating Factor><B-Cell Stimulating Factor-1><B-Cell Stimulation Factor-1><B-Cell Stimulatory Factor-1><B-Cell Stimulatory Factor-2><BCDF><BCDF-1><BCGF><BCGF-1><BCSF 1><BSF-1><BSF-2><BSF1><BSF2><Back><Basal Ganglia><Basal Nuclei><Behavior><Behavioral><Beta Proprotein Interleukin 1><Binding><Binetrakin><Blood><Blood Reticuloendothelial System><Blood Serum><Blood monocyte><Brain><Brain Inflammation><Brain Injuries><Brain Nervous System><Brain imaging><Brain region><C-reactive protein><CCL2><CCL2 gene><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 infected patient><COVID-19 negative><COVID-19 patient><COVID-19 positive patient><COVID-19 test><COVID-19 tests><COVID-19 virus><COVID19><COVID19 negative><COVID19 patient><COVID19 positive patient><COVID19 test><COVID19 tests><COVID19 virus><CSIF><CSIF-10><CV-19><CV19><CXCL8><Cachectin><Cell Body><Cells><Cerebrospinal Fluid><Chemokine, CC Motif, Ligand 2><Chemotactic Cytokines><Choline><Co-Stimulator><CoV-2><CoV2><Cognitive><Cognitive deficits><Convalescence><Costimulator><Creatine><Cytokine Synthesis Inhibitory Factor><D-dimer><D-dimer fibrin><D-dimer fragments><DWI (diffusion weighted imaging)><DWI-MRI><Data><Data Systems><Development><Diffuse><Diffusion MRI><Diffusion Magnetic Resonance Imaging><Diffusion Weighted MRI><Diffusion weighted imaging><Diffusion-weighted Magnetic Resonance Imaging><Disease><Disorder><Dorsum><ELISA><Emergencies><Emergency Situation><Emotions><Encephalitis><Encephalon><Endothelium><Enzyme Gene><Enzyme-Linked Immunosorbent Assay><Enzymes><Epidermal Thymocyte Activating Factor><Fatigue><Fibrin fragment D><Functional MRI><Functional Magnetic Resonance Imaging><Future><GCP1><Gamma interferon><Globus Pallidus><Glutamates><H+ element><HPGF><Health><Hepatocyte-Stimulating Factor><Homologous Chemotactic Cytokines><Hortega cell><Hospital Admission><Hospitalization><Human><Hybridoma Growth Factor><Hydrogen Ions><IFN-Gamma><IFN-beta 2><IFN-g><IFN-γ><IFNB2><IFNG><IFNγ><IL-1 beta><IL-1 β><IL-1-b><IL-10><IL-13><IL-1β><IL-2><IL-4><IL-6><IL-7><IL-7 Gene><IL-8><IL1-Beta><IL1-β><IL10><IL10A><IL13><IL1B Protein><IL1F2><IL1β><IL2 Protein><IL4 Protein><IL6 Protein><IL7><IL7 Protein><IL7 gene><IL8><IL8 gene><IT Systems><Immediate Memory><Immune><Immune Interferon><Immunes><Inflammation><Inflammatory><Information Systems><Information Technology Systems><Intercrines><Interferon Gamma><Interferon Type II><Interferon-gamma><Interleukin 10 Precursor><Interleukin 1beta><Interleukin 2><Interleukin 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negative><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 test><SARS-CoV-2 tests><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SCYA2><SCYB8><SIS cytokines><Serum><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Short-Term Memory><Shortterm Memory><Small Inducible Cytokine A2><Socio-economic status><Socioeconomic Status><Spectroscopy><Spectrum Analyses><Spectrum 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