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Principal Investigator: Kristen Knutson
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2022
Award: $631,557
Funding agency: National Institute on Aging
There is a fundamental gap in our understanding of the neurological manifestations of post-acute sequelae of
SARS-CoV-2 infection (Neuro-PASC). Neuro-PASC consists in a wide array of symptoms affecting patient’s
cognition and quality of life, as well as their ability to work. Up to 85% of Neuro-PASC patients complain of severe
fatigue and 33% from insomnia. Of particular interest, subjective impression of fatigue correlates with low
cognitive performance. A major obstacle to our understanding of one key aspect of Neuro-PASC pathogenesis
is the complex interplay between sleep difficulties, profound fatigue and cognitive dysfunction presented by those
patients. A key gap in our knowledge is the lack of data on the impact of Neuro-PASC in older adults, a population
who are vulnerable for sleep disruption, fatigue, and cognitive dysfunction, and whether they are at increased
risk for early onset of Alzheimer’s or other types of dementia. The overall objective of this supplement application
is to leverage the research infrastructure of the parent project “An Epidemiologic Study of Disparities in Sleep
and Cognition in Older Adults (DISCO)” to characterize sleep-wake disturbances, fatigue, and cognitive
dysfunction in older adults with Neuro-PASC and decipher their immunopathogenic mechanisms. Our
preliminary data indicate that Neuro-PASC patients have cognitive dysfunction, sleep disturbance and broad
dysfunction in memory T cell generation against SARS-CoV-2 proteins and response to vaccination. The
emerging immunologic picture in Neuro-PASC is consistent with dysregulation of T cell function is the setting of
a persistent infection in hidden reservoirs. Since SARS-CoV-2 binds angiotensin converting enzyme -2 (ACE-2)
receptors located on endothelial cells, this may result in an endotheliitis affecting the central nervous system,
leading to alteration of sleep/wakefulness centers. In addition, there is ample evidence that sleep disruption has
a detrimental impact on cellular immune responses, especially on regulatory T cells (Tregs). We hypothesize that
sleep and circadian rhythm disruption and associated fatigue affects cognitive abilities in older Neuro-PASC
patients. Moreover, poor sleep may have a compounding effect on the alterations of the cellular immune
response to SARS-CoV-2, leading to an altered function of Tregs and development of autoimmunity, which may
be a key long-term mechanism of Neuro-PASC. The rationale is that the proposed studies will enable us to
understand a central aspect of Neuro-PASC pathogenesis in older adults and open new avenues to develop
therapeutic and preventive interventions. We will test our hypothesis by pursuing the following Specific Aim:
Aim 1: Characterize the pathogenic mechanisms of Neuro-PASC in adults ≥ 65 yo.
We will determine the interplay of sleep and circadian rhythm disruption and T cell dysregulation on cognitive
dysfunction in non-hospitalized Neuro-PASC patients ≥ 65 yo. The proposed supplement is within the scope of
the parent grant, which is to study the effects of sleep on cognition in older adults. These results will positively
impact the clinical management of older patients with Neuro-PASC and advance the field of Aging research.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><ACE2><Acute><Adult><Adult Human><Affect><Aging><Amentia><Autoimmune Status><Autoimmunity><Binding><CNS Nervous System><COVID><COVID associated pneumonia><COVID induced pneumonia><COVID pneumonia><COVID related pneumonia><COVID survivors><COVID-19><COVID-19 associated pneumonia><COVID-19 induced pneumonia><COVID-19 infection survivors><COVID-19 long hauler><COVID-19 pneumonia><COVID-19 related pneumonia><COVID-19 survivors><COVID-19 virus><COVID19><COVID19 virus><CV-19><CV19><Cell Function><Cell Process><Cell physiology><Cellular Function><Cellular Physiology><Cellular Process><Central Nervous System><Cessation of life><Circadian Rhythms><Clinic><Clinical Management><CoV disease><CoV-2><CoV2><Cognition><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Communication><Complex><Coughing><Country><Data><Death><Dementia><Development><Diagnosis><Diagnostic><Disease><Disorder><Disturbance in cognition><Dysfunction><EOAD><Early Onset Alzheimer Disease><Elderly><Endothelial Cells><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Fatigue><Female><Functional disorder><Generations><Hospital Admission><Hospitalization><Immune response><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Impaired cognition><Individual><Insomnia><Insomnia Disorder><Knowledge><Lack of Energy><Long COVID><Long COVID-19><Long coronavirus disease><Long coronavirus disease 2019><Mission><Molecular Interaction><Nature><Nervous System Diseases><Neuraxis><Neurologic Disorders><Neurologic Manifestations><Neurologic Signs and Symptoms><Neurologic Symptoms><Neurological Disorders><Neurological Manifestations><Neurological Signs and Symptoms><Neurology><Neurovirology><Nyctohemeral Rhythm><Outcome><PASC><Pathogenesis><Pathogenicity><Patients><Persons><Physiopathology><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><Preventative intervention><Proteins><Public Health><QOL><Quality of life><Receptor Protein><Regulatory T-Lymphocyte><Research><Research Infrastructure><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Risk><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 associated pneumonia><SARS-CoV-2 induced pneumonia><SARS-CoV-2 pneumonia><SARS-CoV-2 related pneumonia><SARS-CoV-2 survivors><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><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-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><Sleep><Sleep disturbances><Sleeplessness><Sore Throat><Subcellular Process><Symptoms><Syndrome><T memory cell><T-Cells><T-Lymphocyte><Testing><Therapeutic Intervention><Treg><Twenty-Four Hour Rhythm><Vaccination><Wakefulness><Work><Wuhan coronavirus><aberrant sleep><adulthood><advanced age><adverse sequelae of COVID><adverse sequelae of COVID-19><adverse sequelae of coronavirus disease><adverse sequelae of coronavirus disease 2019><angiotensin converting enzyme 2><angiotensin converting enzyme II><burden of disease><burden of illness><chronic COVID><chronic COVID-19><chronic COVID-19 sequelae><chronic infection><chronic novel coronavirus disease 2019><circadian process><cognitive ability><cognitive dysfunction><cognitive loss><cognitive performance><corona virus disease><corona virus disease 2019><coronavirus disease><coronavirus disease 2019><coronavirus disease 2019 associated pneumonia><coronavirus disease 2019 induced pneumonia><coronavirus disease 2019 long hauler><coronavirus disease 2019 pneumonia><coronavirus disease 2019 related pneumonia><coronavirus disease 2019 virus><coronavirus disease associated pneumonia><coronavirus disease induced pneumonia><coronavirus disease pneumonia><coronavirus disease related pneumonia><coronavirus disease-19><coronavirus disease-19 pneumonia><coronavirus disease-19 virus><coronavirus infectious disease-19><daily biorhythm><developmental><disease burden><disrupted sleep><disturbed sleep><early onset AD><early onset Alzheimer's><elderly patient><elders><epidemiologic investigation><epidemiology study><geriatric><hCoV19><host response><immune system response><immunoneurology><immunoresponse><impaired sleep><impression><improved><interest><intervention for prevention><intervention therapy><irregular sleep><late life><later life><long haul COVID><long haul COVID-19><long haul coronavirus disease><long haul coronavirus disease 2019><long haul sequelae of COVID-19><long haul sequelae of coronavirus disease 2019><long hauler><long-hauler COVID><long-hauler COVID-19><long-hauler coronavirus disease 2019><long-hauler syndrome><long-term COVID><long-term COVID-19><long-term coronavirus disease><long-term coronavirus disease 2019><long-term sequelae of COVID-19><long-term sequelae of SARS-CoV-2><long-term sequelae of coronavirus disease 2019><long-term sequelae of severe acute respiratory syndrome coronavirus 2><longterm COVID><longterm COVID-19><longterm coronavirus disease><longterm coronavirus disease 2019><memory T lymphocyte><nCoV2><nervous system disorder><neural manifestation><neuroimmunology><neurological disease><older adult><older patient><older person><parent grant><parent project><pathophysiology><persistent infection><pneumonia due to COVID><pneumonia due to COVID-19><pneumonia due to SARS-CoV-2><pneumonia due to coronavirus disease><pneumonia due to coronavirus disease 2019><pneumonia due to severe acute respiratory syndrome coronavirus 2><pneumonia in COVID><pneumonia in COVID-19><pneumonia in SARS-CoV-2><pneumonia in coronavirus disease><pneumonia in coronavirus disease 2019><pneumonia in severe acute respiratory syndrome coronavirus 2><poor sleep><post COVID syndrome><post COVID-19 syndrome><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 phases of COVID-19><post-acute sequelae following SARS-CoV-2 infection><post-acute sequelae of COVID-19><post-acute sequelae of acute COVID infection><post-acute sequelae of coronavirus disease 2019><prevention intervention><preventional intervention strategy><preventive intervention><receptor><regulatory T-cells><response><senior citizen><severe acute respiratory syndrome coronavirus 2 associated pneumonia><severe acute respiratory syndrome coronavirus 2 induced pneumonia><severe acute respiratory syndrome coronavirus 2 pneumonia><severe acute respiratory syndrome coronavirus 2 related pneumonia><sleep difficulty><sleep disruption><sleep dysregulation><survive COVID-19><survive SARS-CoV-2><thymus derived lymphocyte><years of life lost to disability><years of life lost to disease>