# Pathogenic mechanisms of Neuro-PASC in older adults

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $631,557

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10554897
- **Project number:** 3R01AG059291-04S1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Kristen Knutson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $631,557
- **Award type:** 3
- **Project period:** 2019-07-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10554897

## Citation

> US National Institutes of Health, RePORTER application 10554897, Pathogenic mechanisms of Neuro-PASC in older adults (3R01AG059291-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10554897. Licensed CC0.

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