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Principal Investigator: JENNIFER M LOFTIS
Organization: PORTLAND VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Among the concerns of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the
development of neurological manifestations of post-acute sequelae of SARS-CoV-2 infection (PASC) or neuro-
PASC. Research shows that neuropsychiatric impairments, including cognitive problems, depression, and
anxiety are among the most common persistent symptoms (following fatigue), occurring in approximately 50%-
80% of individuals. In this Merit Review project, our multi-disciplinary team will test an overarching hypothesis
that specific inflammatory factors [e.g., monokine induced by gamma interferon (MIG)], signaling pathways [e.g.,
interferon (IFN-)], genotypes (APOE4), and immunosuppressive cells contribute to the development and
persistence of neuro-PASC. Our preliminary results and published studies provide rationale for the research. We
found that individuals with neuro-PASC who experienced more severe COVID-19 have increased levels of
circulating inflammatory factors [e.g., MIG, tumor necrosis factor-alpha (TNF-)] and report increased anxiety
and depression, as compared to those with mild disease. Further, lower levels of cortisol, a stress hormone that
helps the body control inflammation, have been observed in individuals with long COVID. In addition, carriers of
the APOE4 genotype appear to be at greater risk for severe COVID-19 and PASC fatigue. Based on these and
other findings, we hypothesize that inflammatory factors in the interferon (IFN)-signaling pathway will be
positively associated with cognitive injury and severity of neuropsychiatric symptoms (including increased
depression and anxiety). We also hypothesize that APOE genotype will modify the severity of neuro-PASC. We
propose three specific aims to test these hypotheses: Aim 1 will monitor and evaluate neuro-PASC symptoms
over time (baseline, 6 months and 12 months) and determine whether APOE genotype modulates severity of
neuro-PASC. Neuropsychological evaluations will assess domains most relevant to neuro-PASC (e.g., learning
and memory, attention/concentration, decision-making, and executive function). Mental health symptoms known
to be induced by inflammation and developing as a result of COVID-19 will also be evaluated. APOE genotyping
will be determined based on saliva or blood samples. Aim 2 will identify immune-related biomarkers associated
with neuro-PASC symptoms. Saliva and blood (plasma and PBMCs) samples will be collected at three timepoints
(baseline, 6 months, and 12 months) from Veterans with and without neuro-PASC. Samples will be analyzed
using a combination of ELISAs, Luminex-based multiplex assays, and Olink proteomics. Aim 3 (exploratory) will
assess neuroimaging correlates of neuro-PASC symptoms using whole brain voxel-based morphometry,
diffusion-tensor imaging, and task-based and resting-state functional connectivity. To accomplish these aims,
we have teamed up with East Tennessee VA collaborators who have unique resources (e.g., Long COVID
registry, Olink proteomics) and diverse expertise (e.g., virology, infectious diseases) to accelerate the translation
of our new advances and knowledge into clinical practice.
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><APOE e4><APOE-ε4><APOEε4><Acceleration><Address><Adhesions><Adverse effects><Aeroseb-HC><Americans with Disabilities Act><Anatomic Sites><Anatomic structures><Anatomy><Anisotropy><Anxiety><Apo-E><ApoE><ApoE protein><Apolipoprotein E><Attention><Behavior><Biological><Biological Markers><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood Sample><Blood specimen><Brain><Brain Nervous System><CNS Nervous System><COVID disease severity><COVID severity><COVID-19><COVID-19 disease severity><COVID-19 infection><COVID-19 neural sequela><COVID-19 predisposition><COVID-19 severity><COVID-19 susceptibility><COVID-19 virus><COVID-19 virus infection><COVID-19 vulnerability><COVID19 disease severity><COVID19 infection><COVID19 severity><COVID19 virus><CV-19><Cachectin><Cell Body><Cells><Central Nervous System><Cetacort><Chemotaxis><Clinical><CoV-2><CoV2><Cognition><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Communicable Diseases><Coronaviridae><Coronavirus><Coronavirus Infectious Disease 2019><Coronavirus disease 2019 predisposition><Coronavirus disease 2019 susceptibility><Coronavirus disease 2019 vulnerability><Cort-Dome><Cortef><Cortenema><Cortisol><Cortispray><Cortril><DWI (diffusion weighted imaging)><DWI-MRI><Data><Decision Making><Dermacort><Development><Diffusion MRI><Diffusion Magnetic Resonance Imaging><Diffusion Weighted MRI><Diffusion weighted imaging><Diffusion-weighted Magnetic Resonance Imaging><Disease><Disorder><Disturbance in cognition><ELISA><Eldecort><Encephalon><Endocrine Gland Secretion><Ensure><Enzyme-Linked Immunosorbent Assay><Evaluation><Exclusion Criteria><Fatigue><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Functional impairment><Future><Genetic predisposing factor><Genotype><Health><Health Care Systems><Healthcare Systems><History><Hormones><Human><Hydrocortisone><Hydrocortone><Hytone><IFN><Immune><Immunes><Impaired cognition><Impairment><In Vitro><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Inflammatory><Injury><Interferons><Isoforms><Knowledge><Lack of Energy><Learning><Long COVID><Long COVID-19><Long coronavirus disease><Long coronavirus disease 2019><MR Imaging><MR Tomography><MRI><MRIs><Macrophage><Macrophage-Derived TNF><Magnetic Resonance Imaging><Measures><Mediating><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medical center><Memory><Memory Deficit><Memory impairment><Mental Depression><Mental Health><Mental Hygiene><Modern Man><Monitor><Monocyte-Derived TNF><Monokine Induced by Gamma Interferon><Moods><Mφ><NMR Imaging><NMR Tomography><Nervous System Physiology><Neuraxis><Neurologic><Neurologic Manifestations><Neurologic Signs and Symptoms><Neurologic Symptoms><Neurologic function><Neurological><Neurological Manifestations><Neurological Signs and Symptoms><Neurological function><Neuropsychologies><Neuropsychology><Nuclear Magnetic Resonance Imaging><Nutracort><On-Line Systems><Online Systems><PASC><PBMC><Pathogenicity><Pathway interactions><Peripheral Blood Mononuclear Cell><Phenotype><Plasma><Plasma Proteins><Plasma Serum><Population><Post Acute Sequelae of COVID19><Post Acute Sequelae of SARS-CoV-2><Post Acute Sequelae of SARS-CoV2><Post Acute Sequelae of severe acute respiratory syndrome coronavirus 2><Post-Acute Sequelae of SARS-CoV-2 Infection><Predisposed to COVID-19><Predisposed to SARS-CoV-2><Predisposed to Severe acute respiratory syndrome coronavirus 2><Proctocort><Protein Isoforms><Proteomics><Psychological Health><Publishing><Reaction><Recommendation><Recording of previous events><Registries><Reporting><Research><Research Resources><Resources><Rest><Reticuloendothelial System, Serum, Plasma><Risk><SARS corona virus 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coronavirus 2 predisposition><Severe acute respiratory syndrome coronavirus 2 susceptibility><Severe acute respiratory syndrome coronavirus 2 vulnerability><Severe acute respiratory syndrome related corona virus 2><Severities><Signal Pathway><Small Inducible Cytokine B9><Stress><Structure><Symptoms><T-Cells><T-Lymphocyte><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Tennessee><Testing><Therapeutic Hormone><Therapeutic Intervention><Thick><Thickness><Time><Translations><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Vaccination><Veterans><Viral Burden><Viral Load><Viral Load result><Virus><Wuhan coronavirus><Zeugmatography><adverse sequelae of COVID><adverse sequelae of COVID-19><adverse sequelae of coronavirus disease><adverse sequelae of coronavirus disease 2019><apo E-4><apo E4><apo epsilon4><apoE epsilon 4><apoE-4><apoE4><apolipoprotein E epsilon 4><apolipoprotein E-4><apolipoprotein E4><attenuation><bio-markers><biologic><biologic marker><biomarker><biomarker 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