Document text
Principal Investigator: Emilie T. Reas
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $781,184
Funding agency: National Institute on Aging
PROJECT SUMMARY
COVID-19 is associated with cognitive impairment that may persist long after infection. COVID-19 risk
factors overlap with those for Alzheimer’s disease (AD), including older age, the APOE4 allele, and vascular
dysfunction, suggesting that pathology from one condition may exacerbate pathogenesis of the other. Blood-
brain barrier (BBB) dysfunction may serve as a common pathogenic mechanism, as BBB breakdown has been
identified in individuals at risk for AD and may facilitate COVID-19-related neural injury via binding of SARS-
CoV-2 to cerebrovascular endothelial cells or via virally-mediated neuroinflammation. Sex is also a risk factor
for both diseases, with increased AD risk for women and sex-specific risk for acute and chronic COVID-19
symptoms, which may be partially mediated by sex hormone regulation of SARS-CoV-2 binding, inflammation,
immune activity, or BBB dysfunction. The intersection of latent AD neuropathology with neuroinflammation or
cerebrovascular dysfunction triggered by COVID-19 among the aging population may ignite a perfect storm of
neurodegenerative changes. Yet despite potential for convergence of the COVID-19 pandemic upon a pre-
existing public health crisis of dementia, little research has been devoted to understanding the mechanistic
overlap between these conditions or the potentially catastrophic public health consequences of their synergy.
The proposed investigation will assess the neurobiological sequalae of COVID-19 in older adults along with
their modification by sex, AD pathology, and AD genetic risk. Restriction spectrum imaging to measure brain
microstructure and dynamic contrast-enhanced MRI to estimate BBB permeability will be conducted on adults
aged 50 years or older with previous COVID-19 infection (CV) and disease-related cognitive impairment, and
on uninfected healthy controls. Cognitive testing will be conducted at time of neuroimaging and annually for up
to four additional years. AD polygenic hazard scores (PHS), estrogen and testosterone levels, and plasma p-
tau181, will be measured for all participants, and lifetime estrogen exposure will be calculated for women. This
project will test the hypotheses that CV exhibit greater BBB breakdown, microstructural damage, and more
severe cognitive impairment and decline than controls (Aim 1). AD risk (Aim 2) and sex (Aim 3) are predicted
to modify effects of COVID-19 on brain and cognitive measures, with more severe disease-related brain injury,
BBB permeability, and cognitive decline for those with high PHS or abnormal p-tau181 and for women. In sex-
stratified analyses, testosterone and estrogen are expected to correlate with brain injury, BBB breakdown, and
cognitive deficits (Aim 3). This study will pioneer the most advanced diffusion and permeability MRI techniques
to clarify the yet elusive neurobiological effects of COVID-19 underlying its cognitive symptoms in older adults
at elevated risk for neurodegenerative changes. It will advance our understanding of the currently speculative
synergy between COVID-19 and AD pathogenesis as well as the complex role of sex and hormonal regulation
in COVID-19-related neurological sequalae.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><ACE2><AD dementia><AD pathology><APOE e4><APOE-ε4><APOEε4><Acceleration><Acquired brain injury><Acute><Adult><Adult Human><Age><Age-associated cognitive decline><Age-associated memory impairment><Age-related cognitive decline><Aged 65 and Over><Aging><Alleles><Allelomorphs><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease pathology><Alzheimer's disease risk><Alzheimer's pathology><Alzheimers Dementia><Amentia><Ammon Horn><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Attention><BBB permeabilization><BBB permeable><Benign senescent forgetfulness><Binding><Blood><Blood - brain barrier anatomy><Blood Plasma><Blood Reticuloendothelial System><Blood brain barrier dysfunction><Blood-Brain Barrier><Brain><Brain Injuries><Brain Nervous System><Brain Vascular><Brain Vascular Disorders><CNS Nervous System><COVID crisis><COVID disease severity><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID severity><COVID survivors><COVID-19><COVID-19 affected><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 consequence><COVID-19 crisis><COVID-19 death><COVID-19 disease severity><COVID-19 effect><COVID-19 epidemic><COVID-19 era><COVID-19 fatality><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 impact><COVID-19 impacted><COVID-19 induced death><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 infected patient><COVID-19 infection><COVID-19 infection survivors><COVID-19 mortality><COVID-19 neural sequela><COVID-19 pandemic><COVID-19 patient><COVID-19 period><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 related death><COVID-19 related fatality><COVID-19 related mortality><COVID-19 related risk><COVID-19 risk><COVID-19 risk factor><COVID-19 sequelae><COVID-19 severity><COVID-19 survivors><COVID-19 virus><COVID-19 virus infection><COVID-19 years><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 death><COVID19 disease severity><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 infection><COVID19 mortality><COVID19 patient><COVID19 positive patient><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 severity><COVID19 virus><CV-19><Central Nervous System><Cerebrovascular Disease><Cerebrovascular Disorders><CoV-2><CoV2><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive Manifestations><Cognitive Symptoms><Cognitive decline><Cognitive deficits><Cognitive function abnormal><Complex><Confusion><Confusional State><Cornu Ammonis><Coronavirus Infectious Disease 2019><DWI (diffusion weighted imaging)><DWI-MRI><Dementia><Differences between sexes><Differs between sexes><Diffusion><Diffusion MRI><Diffusion Magnetic Resonance Imaging><Diffusion Weighted MRI><Diffusion weighted imaging><Diffusion-weighted Magnetic Resonance Imaging><Disease><Disorder><Disturbance in cognition><Drops><Encephalon><Endothelial Cells><Estrogens><Exhibits><Extravasation><Genetic><Genetic Risk><Genetic predisposing factor><Gonadal Steroid Hormones><Hemato-Encephalic Barrier><Hippocampus><Hyperactivity><Immune><Immune response><Immunes><Immunological response><Impaired cognition><Individual><Infection><Infiltration><Inflammation><Inflammatory><Injury><Intracranial Vascular Diseases><Intracranial Vascular Disorders><Investigation><Leakage><Long COVID><Long COVID-19><Long coronavirus disease><Long coronavirus disease 2019><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Measures><Medial><Mediating><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Memory><Menopause><Mental Confusion><Methods><Mission><Modification><Molecular Interaction><NIH><NMR Imaging><NMR Tomography><National Institutes of Health><Nerve Cells><Nerve Degeneration><Nerve Unit><Neural Cell><Neuraxis><Neurobehavioral Manifestations><Neurobehavioral Signs and Symptoms><Neurobiology><Neurocyte><Neurologic><Neurologic Effect><Neurologic Manifestations><Neurologic Signs and Symptoms><Neurologic Symptoms><Neurologic outcome><Neurological><Neurological Manifestations><Neurological Signs and Symptoms><Neurological outcome><Neuron Degeneration><Neurons><Nuclear Magnetic Resonance Imaging><Outcome><Participant><Pathogenesis><Pathogenicity><Pathologic><Pathology><Pathway interactions><Patients><Permeability><Personalized medical approach><Plasma><Plasma Serum><Predisposition><Primary Senile Degenerative Dementia><Public Health><Reporting><Research><Restriction Spectral Imaging><Restriction Spectrum Imaging><Reticuloendothelial System, Serum, Plasma><Risk><Risk Assessment><Risk Estimate><Risk Factors><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 disease severity><SARS-CoV-2 epidemic><SARS-CoV-2 fatality><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 mortality><SARS-CoV-2 neurological sequelae><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><SARS-CoV-2 sequelae><SARS-CoV-2 severity><SARS-CoV-2 survivors><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><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 CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><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 coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Sex Differences><Sex Hormones><Sex Steroid Hormones><Sexual differences><Spillage><Structure><Susceptibility><Symptoms><Techniques><Testing><Testosterone><Therapeutic Estrogen><Therapeutic Testosterone><Time><Trans-Testosterone><United States National Institutes of Health><Vascular Diseases><Vascular Disorder><Viral><Woman><Wuhan coronavirus><Zeugmatography><abnormal brain function><above age 65><acute COVID-19><acute SARS-CoV-2 infection><acute phase of COVID-19><acute phase of SARS-CoV-2 infection><adulthood><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after age 65><after infection by SARS-CoV-2><after severe acute respiratory distress syndrome CoV-2 infection><age 65 and greater><age 65 and older><age 65 or older><age > 65><age associated><age associated memory decline><age correlated><age dependent><age linked><age of 65 years onward><age related><age related cognitive deficit><age related cognitive impairment><age related memory dysfunction><age specific><age-induced cognitive decline><age-related decline in cognition><age-related decline in cognitive function><aged><aged 65 and greater><aged 65+><aged group><aged groups><aged individual><aged individuals><aged people><aged person><aged persons><aged population><aged populations><aged ≥65><ages><aging population><alzheimer risk><angiotensin converting enzyme 2><angiotensin converting enzyme II><apo E-4><apo E4><apo epsilon4><apoE epsilon 4><apoE-4><apoE4><apolipoprotein E epsilon 4><apolipoprotein E-4><apolipoprotein E4><biomarker identification><blood vessel disorder><blood-brain barrier permeabilization><blood-brain barrier permeable><bloodbrain barrier><bloodbrain barrier permeabilization><bloodbrain barrier permeable><brain abnormalities><brain damage><brain dysfunction><brain health><brain impairment><brain tissue><brain vascular disease><brain vascular dysfunction><brain-injured><cerebral vascular><cerebral vascular disease><cerebral vascular dysfunction><cerebro-vascular><cerebrovascular><cerebrovascular dysfunction><chronic COVID><chronic COVID-19><chronic effect of COVID-19><chronic novel coronavirus disease 2019><co-morbid><co-morbidity><cognitive assessment><cognitive defects><cognitive dysfunction><cognitive function><cognitive loss><cognitive recovery><cognitive testing><comorbidity><contrast enhanced><coronavirus disease 2019><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 consequence><coronavirus disease 2019 crisis><coronavirus disease 2019 death><coronavirus disease 2019 disease severity><coronavirus disease 2019 effect><coronavirus disease 2019 epidemic><coronavirus disease 2019 fatality><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 impact><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 mortality><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease 2019 risk><coronavirus disease 2019 risk factor><coronavirus disease 2019 severity><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease severity><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 impact><coronavirus disease-19 mortality><coronavirus disease-19 pandemic><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><dMRI><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><diffused><diffuses><diffusing><diffusion tensor imaging><diffusions><dysfunctional brain><executive control><executive function><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><following COVID-19 infection><following SARS-CoV-2 infection><following SARS-CoV2 infection><following infection by SARS-CoV-2><following severe acute respiratory distress syndrome CoV-2 infection><genetic risk factor><gonadal steroids><hCoV19><hazard><high risk group><high risk individual><high risk people><high risk population><hippocampal><hormonal regulation><hormone regulation><host response><human old age (65+)><identification of biomarkers><identification of new biomarkers><immune system response><immunoresponse><individualized approach><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><inherited factor><injuries><intracranial vascular dysfunction><late life><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><long haul COVID><long haul COVID-19><long haul coronavirus disease><long haul coronavirus disease 2019><long term consequences of COVID-19><long term consequences of SARS-CoV-2 infection><long term consequences of coronavirus disease-19><long term effects of COVID-19><long term health consequences of COVID-19><long term health consequences of SARS-CoV2 infection><long term impact of COVID-19><long term impact of SARS-CoV-2 infection><long-hauler COVID><long-hauler COVID-19><long-hauler coronavirus disease 2019><long-hauler syndrome><long-term COVID><long-term COVID-19><long-term consequence of severe acute respiratory distress syndrome-cov-2 infection><long-term coronavirus disease><long-term coronavirus disease 2019><long-term effects of coronavirus disease-19><longterm COVID><longterm COVID-19><longterm consequences of COVID-19><longterm consequences of SARS-CoV-2 infection><longterm coronavirus disease><longterm coronavirus disease 2019><longterm effects of COVID-19><longterm health consequences of COVID-19><longterm health consequences of SARS-CoV2 infection><longterm impact of COVID-19><longterm impact of SARS-CoV-2 infection><marker identification><men><mental state><mental status><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><multi-modal neuro-imaging><multi-modal neuroimaging><multimodal neuro-imaging><multimodal neuroimaging><nCoV2><nerve injury><neural degeneration><neural imaging><neural inflammation><neural injury><neural manifestation><neural sequela in COVID-19><neuro post-acute sequelae of SARS-CoV-2><neuro-imaging><neuro-vascular><neuroPASC><neurobehavioral symptom><neurobiological><neurodegeneration><neurodegenerative><neuroimaging><neuroinflammation><neuroinflammatory><neurologic post acute sequelae of SARS-CoV-2><neurologic sequelae of COVID-19><neurological degeneration><neurological imaging><neurological post-acute sequelae of SARS-CoV-2><neurological sequelae associated with SARS-CoV-2><neurological sequelae caused by SARS-CoV-2><neuronal><neuronal degeneration><neuropathologic><neuropathological><neuropathology><neurovascular><old age><older adult><older adulthood><outcome prediction><over 65 years><p-tau><p-τ><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><persistent COVID-19><personalized approach><phospho-tau><phospho-τ><phosphorylated tau><population aging><post COVID syndrome><post COVID-19 syndrome><post SARS-CoV-2 infection><post acute COVID syndrome><post acute COVID-19><post acute COVID-19 syndrome><post acute SARS-CoV-2><post acute coronavirus disease 2019><post acute coronavirus disease 2019 syndrome><post acute coronavirus disease syndrome><post acute severe acute respiratory syndrome coronavirus 2><post coronavirus disease 2019 syndrome><post coronavirus disease syndrome><post-acute CNS symptoms of SARS-CoV-2 infection><post-acute phases of COVID-19><post-translational modification of tau><posttranslational modification of tau><pre-clinical><precision approach><preclinical><preservation><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><primary degenerative dementia><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><prolonged COVID-19 symptoms><respiratory virus><response><risk associated with COVID-19><risk factor associated with COVID-19><risk factor related to COVID-19><risk related to COVID-19><senile dementia of the Alzheimer type><sequelae following COVID-19><sequelae following SARS-CoV-2 infection><sequelae of COVID-19><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 disease severity><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><severe acute respiratory syndrome coronavirus 2 severity><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><sex><sex based differences><sex steroid><sex-dependent differences><sex-related differences><sex-specific differences><social role><survive COVID-19><survive SARS-CoV-2><synergism><tailored approach><tau phosphorylation><tau posttranslational modification><tau-1><tool><vascular dysfunction><vasculopathy><τ phosphorylation><≥65 years>