Self-reported health, neuropsychological tests & biomarkers in fully recovered COVID-19 pts vs pts with post-COVID cognitive symptoms,2025,

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0315486
Michael R. Lawrence, Judith E. Arnetz , Scott E. Counts, Aiesha Ahmed, Bengt B. Arnetz

• https://doi.org/10.1371/journal.pone.0315486

Abstract

Substantial numbers of individuals who contract COVID-19 experience long-lasting cognitive symptoms such as brain fog.

Yet research to date has not compared these patients with healthy controls with a history of laboratory-confirmed COVID-19 infection, making it difficult to understand why certain COVID patients develop post-COVID cognitive symptoms while others do not.

The objective of this pilot study was to compare two groups of laboratory-confirmed post-COVID patients, with and without cognitive symptoms, on measures of cognitive and psychological functioning, self-reported perceptions of functional status and quality of life, and biomarkers of stress, inflammation, and neuroplasticity.

Using a case-control design, 17 participants were recruited from a healthcare system in western Michigan, USA in 2022–2024.

All participants were aged 25–65 and had a positive polymerase chain reaction (PCR) test confirming previous COVID-19 infection.

Ten participants reported cognitive symptoms (long COVID group) while seven were fully recovered with no residual symptoms (controls).

All participants underwent an interview on their self-rated health and quality of life, a battery of neurocognitive tests, and blood draw for biomarker analysis.

No group differences were detected for neuropsychological test measures except for letter fluency where the long COVID group scored significantly lower (p < .05).

The long COVID group had significantly lower ratings than controls on quality of life, physical health, emotional functioning, and psychological well-being.

Serum levels of nerve growth factor (NGF), a biomarker of brain plasticity, were significantly lower in the long COVID group, which was significantly more likely than controls to have serum levels of inflammatory marker (interleukin (IL)-10) values greater than or equal to the median (p = 0.015).

Biomarker analyses suggest possible prolonged inflammatory processes in long COVID patients compared to fully recovered patients.

Results of decreased neuroplastic functioning give credence to patients’ reports of post-COVID changes in brain function.

 

https://www.eurekalert.org/news-releases/1083190

News Release 15-May-2025
Scientists find two brain biomarkers in long COVID sufferers may be what’s causing their brain fog, other cognitive issues

Study is the first to compare inflammation and stress responses in infected patients

Peer-Reviewed Publication
Corewell Health

image:

Dr. Michael Lawrence, neuropsychologist at Corewell Health in Grand Rapids, Michigan.

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Credit: Corewell Health

EMBARGOED: May 15, 2025, at 2 p.m. ET

Grand Rapids, Mich., May 15, 2025 – A new study that is the first to compare inflammation and brain stress responses in long COVID-19 patients with individuals who have fully recovered shows that those with continued brain fog and other cognitive issues have a lower ability to adapt to stress and higher levels of inflammation in their brains. While previous long COVID studies have shown changes in these markers in mice, this study evaluated the infection’s impact on the brain in documented COVID-positive patients.

Up until now, physicians have found it difficult to understand why certain patients develop post-COVID cognitive symptoms while others do not. Recent studies estimate tens of millions of people worldwide still have not recovered from the COVID infection, even five years later.

“We compared our long COVID participants to our healthy, fully recovered control group based on neurocognitive measures, emotional functioning, measures of quality of life as well as specific changes in blood markers assessing stress response,” said lead author Michael Lawrence, Ph.D., neuropsychologist at Corewell Health in Grand Rapids, Michigan. “To our knowledge, this is the first controlled study that shows specific self-reported neurocognitive and central nervous systems changes in long COVID patients which validates the symptoms they’ve been experiencing.”

The pilot study, published in PLOS One, included 17 confirmed COVID patients (10 with long COVID and seven who were fully recovered with no lingering symptoms) and found the following:

• Serum levels of nerve growth factor, a biomarker of the brain’s ability to change and adapt by forming new connections, were significantly lower in the long COVID group. This group was also more likely to have higher serum levels of interleukin (IL)-10, a marker of inflammation.
• While there was virtually no difference between groups related to neuropsychological test outcomes, long COVID participants did score significantly lower on letter fluency, meaning they had more difficulty with quickly and accurately accessing language centers in the brain and producing words beginning with various letters.
• The long COVID group also had significantly lower ratings than healthy controls on quality of life, physical health, emotional functioning and psychological well-being responses.

“Although this is a small study and more work needs to be done, from a clinical application standpoint, physicians potentially can identify individuals who are struggling sooner and provide wrap-around care that could be helpful to them,” said Judith Arnetz, Ph.D., professor emerita at Michigan State University College of Human Medicine and corresponding author of the study.

According to the study authors, the struggle physicians have with evaluating long COVID patients is that when asked to complete various written diagnostic tests, they tend to look normal.

“These patients experience significant frustration, and their symptoms often may be minimized by friends, family and even the medical community,” Dr. Lawrence said. “It’s tough when everything looks normal on paper, but our patients continue to struggle and report a multitude of difficulties.”

Dr. Arnetz agreed and indicated that physicians might want to take a multidisciplinary approach to care and assess inflammatory and brain biomarkers, which could ultimately offer a better path forward in treating patients with long COVID.

“Additional services such as speech therapy, psychotherapy for stress reduction and incorporating medications that target fatigue and mental fogginess could all be elements of creating a successful treatment plan as well,” Dr. Lawrence said.

About Corewell Health™

People are at the heart of everything we do, and the inspiration for our legacy of outstanding outcomes, innovation, strong community partnerships, philanthropy and transparency. Corewell Health is a not-for-profit health system that provides health care and coverage with an exceptional team of 65,000+ dedicated people—including more than 12,000 physicians and advanced practice providers and more than 16,000 nurses providing care and services in 21 hospitals, 300+ outpatient locations and several post-acute facilities—and Priority Health, a provider-sponsored health plan serving more than 1.3 million members. Through experience and collaboration, we are reimagining a better, more equitable model of health and wellness. For more information, visit corewellhealth.org.



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Journal
PLOS One

Method of Research
Case study

Subject of Research
People

Article Title
Self-reported health, neuropsychological tests and biomarkers in fully recovered COVID-19 patients vs patients with post-COVID cognitive symptoms: a pilot study

Article Publication Date
15-May-2025

 

I don't understand how no one still can't find a single damn cognitive test that shows anything. It's completely unbelievable, it's one of the most significant problems. How can someone go from being able to function normally to literally not being able to understand work they did themselves and this doesn't show up on any standard tests?!&*@#$!

The only reasonable explanation would be that cognitive problems make it too difficult to even participate in such studies, but even that's a stretch. When we look at simple tests of basic functioning, the difference in, say, the 6 minute walking test is huge. Any test worth a damn should be at least as wide as this between controls.

It's just not credible that standard tests are inadequate for this, just test the wrong things. This is all-encompassing impairment.

 

The problem is a basis for comparison. The people who participate in these studies are generally of higher functioning than a typical patient and often have IQs outside of one or even two SD of the norm (IQ is an imperfect measure, so I don't want to get into that debate, but...).

Studies that are self-controlled, that is induce fatigue and then re-test note substantial latencies in the fatigued condition compared to the fresh condition.

Studies that don't explicitly induce fatigue when doing trying to test for cognitive deficits are done by idiots.