Immune-mediated Pathogenic Mechanisms of Neuro-PASC in Veterans (PASC)

March 25, 2026 updated by: VA Office of Research and Development
Mental health symptoms, including cognitive impairment ("brain fog"), following COVID-19 are of great concern to Veterans. This research seeks to advance understanding of the long-term effects of COVID-19 on neuropsychiatric and neurological functions, identifying clinically relevant biomarkers and directions for developing and testing therapeutic interventions. To accomplish these objectives the investigators are conducting a longitudinal study at two VA medical centers to: 1) assess and monitor cognitive function and psychiatric symptoms in Veterans post-COVID; 2) evaluate biomarkers of inflammation and signaling pathways associated with viral infection and neuropsychiatric function; and 3) integrate neuropsychiatric and neurological findings with biological data to identify biomarkers and clinical endpoints associated with disease progression or severity, as well as those for promoting brain repair and attenuating those symptoms.

Study Overview

Status

Recruiting

Conditions

Detailed Description

The goal of this research project is to identify the neuroinflammatory mechanisms contributing to post-COVID cognitive deficits and neuropsychiatric symptoms [neuro-PASC (post-acute sequelae of SARS CoV-2 infection)]. This collaborative research effort will also characterize new or worsened mental health symptoms and genetic and environmental risk factors for the incidence and severity of post-COVID neuropsychiatric impairments. Aim 1 will monitor and evaluate cognitive injury and neuro-PASC symptoms and determine whether APOE genotype modulates severity of the cognitive injury and neuro-PASC symptoms. Cognitive functioning will be evaluated over time using neuropsychological measures assessing domains most relevant to PASC: learning and memory, attention/concentration, social cognition/emotions, and executive function; assessments will include standardized measures. Mental health symptoms known to be induced and exacerbated by inflammation and potentially 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 cognitive injury and neuro-PASC symptoms. Blood (plasma and cells) will be used to identify biomarkers associated with PASC progression or severity, promotion of brain repair, attenuation of symptoms. Plasma will be used for Olink proteomics, followed by confirmatory multiplex assays or enzyme-linked immunosorbent assays (ELISAs). The investigators will assess relationships among biomarkers and cognitive injury and neuro-PASC symptoms across APOE genotypes and contribute data and samples to the repository managed by Dr. Moorman (Co-Investigator). Aim 3 (exploratory aim; conducted in Portland only) will assess neuroimaging correlates of cognitive injury and neuro-PASC symptoms. Neuroimaging evaluations (i.e., whole brain voxel-based morphometry, diffusion-tensor imaging, resting-state connectivity, and task-based assessments) will be conducted at baseline and at 12 months to correlate magnetic resonance imaging (MRI) measures with symptoms of long COVID (e.g., cognitive impairment and neuropsychiatric symptoms) across APOE genotypes.

Study Type

Observational

Enrollment (Estimated)

200

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Oregon
      • Portland, Oregon, United States, 97207-2964
        • Recruiting
        • VA Portland Health Care System, Portland, OR
        • Principal Investigator:
          • Jennifer M Loftis, MA PhD
        • Contact:
        • Contact:
    • Tennessee
      • Mountain Home, Tennessee, United States, 37684
        • Not yet recruiting
        • James H. Quillen VA Medical Center, Mountain Home, TN
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Veterans

Description

Inclusion Criteria:

Eligible participants will:

  • have a history of SARS-CoV-2 infection 4 weeks prior to enrollment, defined as a positive PCR or home antigen test
  • be able to give informed consent as determined by brief cognitive exam and evaluation of understanding of the risks, benefits, and voluntary nature of the study

Additionally, participants enrolled as part of the neuro-PASC group must also:

  • currently experience neuro-PASC symptoms, not present prior to infection, as confirmed by the "Long COVID-19 Symptom Assessment" scale, a self-report measure that consists of 46 common COVID-19 sequela symptoms

Exclusion Criteria:

Exclusion criteria for all groups:

  • diagnosed with dementia, traumatic brain injury, a neurological syndrome (e.g. Parkinson disease, Alzheimer disease), or other progressive cognitive disorder before SARS-CoV-2 infection
  • diagnosed with a mood or psychotic disorder before SARS-CoV-2 infection
  • history of fibromyalgia or chronic fatigue syndrome prior to SARS-CoV-2 infection
  • unstable medical conditions or active uncontrolled autoimmune or inflammatory conditions

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Neuro-PASC
All participants enrolled in the study will attend 4 study visits: 1) Screening, 2) Baseline, 3) 6-Month Follow-up, and 4) 12-Month Follow-up. At the Baseline, 6-Month, and 12-Month follow-up, participants will complete an online neuropsychological assessment, questionnaires, blood draw, and saliva collection
Neuro-PASC-imaging
A subset (60) of Portland VA only participants will be provided with the opportunity to complete an MRI visit at baseline and the 12-month follow-up.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Fatigue Severity Scale (FSS)
Time Frame: Baseline, 6-Month, 12-Month
A nine-item self-report questionnaire designed to assess fatigue as a symptom of a variety of different chronic conditions and disorders.
Baseline, 6-Month, 12-Month
Prospective and Retrospective Memory Questionnaire (PRMQ)
Time Frame: Baseline, 6-Month, 12-Month
A self-report measure of everyday memory, assessing prospective (the ability to remember to do things in the future) and retrospective memory.
Baseline, 6-Month, 12-Month
Spatial Working Memory (SWM)
Time Frame: Baseline, 6-Months, 12-Months
Online cognitive assessment requiring retention and manipulation of visuospatial information; measures executive functioning (i.e., strategy) and working memory.
Baseline, 6-Months, 12-Months
Paired Associates Learning (PAL)
Time Frame: Baseline, 6-Month, 12-Month
Online cognitive assessment measuring visual memory and new learning.
Baseline, 6-Month, 12-Month
Stockings of Cambridge (SOC)
Time Frame: Baseline, 6-Month, 12-Month
Online cognitive assessment measuring problem-solving strategies.
Baseline, 6-Month, 12-Month
Delayed Matching Sample (DMS)
Time Frame: Baseline, 6-Month, 12-Month
Online cognitive assessment measuring visual matching ability and short-term visual recognition memory.
Baseline, 6-Month, 12-Month
Rapid Visual Information Processing (RVP)
Time Frame: Baseline, 6-Month, 12-Month
Online cognitive assessment measuring sustained attention.
Baseline, 6-Month, 12-Month
Apolipoprotein E (APOE) Genotyping
Time Frame: Baseline, 6-Months, 12-Months
A genetic test that determines a person's inherited variations in the APOE gene. This gene plays a role in cholesterol metabolism and brain health. Blood and saliva samples will be used.
Baseline, 6-Months, 12-Months
Long Covid Questionnaire
Time Frame: Baseline
Self-report measure that assesses the continued presence of Long-COVID symptomology.
Baseline
Delis-Kaplan Executive Functioning - Verbal Fluency (D-KEFS-VF)
Time Frame: Baseline, 6-Months, 12-Months
Neuropsychological assessment measure of verbal behavioral productivity and cognitive flexibility.
Baseline, 6-Months, 12-Months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Posttraumatic Stress Disorder Checklist - Civilian Version (PCL-C)
Time Frame: Baseline, 6-Month, 12-Month
A standardized self-report rating scale for PTSD comprising 17 items that correspond to the key symptoms of PTSD.
Baseline, 6-Month, 12-Month
Patient Health Questionnaire-9 (PHQ-9)
Time Frame: Baseline, 6-Months, 12-Months
Self-report questionnaire objectifying and assessing degree of depression severity.
Baseline, 6-Months, 12-Months
Generalized Anxiety Disorder-7 (GAD-7)
Time Frame: Baseline, 6-Month, 12-Month
A self-reported questionnaire used to assess the severity of anxiety symptoms.
Baseline, 6-Month, 12-Month
Biomarkers
Time Frame: Baseline, 6-Months, 12-Months
Obtained from collected blood samples and saliva, biomarkers (including viral variants, genetic susceptibility, inflammatory markers, diagnostic markers, etc.) associated with specific symptoms of post-COVID conditions will be identified.
Baseline, 6-Months, 12-Months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Neuroimaging
Time Frame: Baseline, 12-Months
To detect pathological and restorative changes in the brain of COVID-19 survivors, neuroimaging evaluations will correlate magnetic resonance imaging (MRI) measures with symptoms of neuro-PASC.
Baseline, 12-Months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

VA Office of Research and Development

Collaborators

James H. Quillen Department of Veterans Affairs Medical Center

Investigators

  • Principal Investigator: Jennifer M Loftis, MA PhD, VA Portland Health Care System, Portland, OR

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 20, 2025

Primary Completion (Estimated)

March 31, 2028

Study Completion (Estimated)

March 31, 2028

Study Registration Dates

First Submitted

April 9, 2025

First Submitted That Met QC Criteria

April 9, 2025

First Posted (Actual)

April 17, 2025

Study Record Updates

Last Update Posted (Actual)

March 31, 2026

Last Update Submitted That Met QC Criteria

March 25, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MHBC-006-23S
  • I01CX002668 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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