# Immune-mediated pathogenic mechanisms of Neuro-PASC in Veterans

> **NIH VA I01** · PORTLAND VA MEDICAL CENTER · 2024 · —

## Abstract

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
reg...

## Key facts

- **NIH application ID:** 10806775
- **Project number:** 1I01CX002668-01A1
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** JENNIFER M LOFTIS
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10806775

## Citation

> US National Institutes of Health, RePORTER application 10806775, Immune-mediated pathogenic mechanisms of Neuro-PASC in Veterans (1I01CX002668-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10806775. Licensed CC0.

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