Biomarkers Reveal Neurological Basis for Long COVID
Brain fog, fatigue and anxiety in long COVID may be linked to brain inflammation and lower nerve growth factors.
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Why do some people recover from COVID-19 while others remain foggy, anxious and exhausted months later?
A small pilot study from Corewell Health looked into this question by comparing long COVID patients to people who had fully recovered.
Published in PLOS One, the researchers found biological differences in brain health and inflammation that help explain lingering symptoms.
The problem with testing long COVID brain symptoms
Since the early days of the pandemic, millions have reported long-term symptoms after COVID-19, with ~30% of those infected continuing to experience problems months later. “Brain fog” is one of the most common complaints, affecting attention, memory and language. But despite these reports, most patients perform within the normal range on standard cognitive tests. This mismatch makes diagnosis harder, and many patients feel dismissed.
Until now, few studies have addressed why some people develop long-term cognitive symptoms while others don’t. Many studies didn’t include proper control groups, often comparing long COVID patients with people who never had COVID at all. Others looked at biomarkers like inflammatory proteins, but they rarely linked them directly to cognitive symptoms.
Persistent symptoms affect people’s ability to work, maintain relationships and feel mentally well. Without clear evidence of what’s happening, patients are often left in limbo.
“These patients experience significant frustration, and their symptoms often may be minimized by friends, family and even the medical community,” said lead author Dr. Michael Lawrence, a neuropsychologist at Corewell Health.
“It’s tough when everything looks normal on paper, but our patients continue to struggle and report a multitude of difficulties,” said Lawrence.
The new pilot study set out to address this gap in research. Instead of comparing long COVID patients to healthy people, the researchers matched them with others who also had confirmed COVID-19 but made a full recovery. The aim was to look at objective cognitive performance, self-reported symptoms and markers in the blood related to stress, inflammation and brain health.
Long COVID patients show signs of brain inflammation
The participants were recruited from a health system in Michigan between 2022 and 2024 and split into two groups: those who still had ongoing cognitive symptoms like brain fog (10 participants) and those that had recovered fully, with no lingering effects (7 participants).
Each participant completed a standard set of cognitive tests, answered questionnaires about their mood, energy and daily functioning and gave a blood sample. The team looked at markers of inflammation and stress, such as IL-6, IL-10 and cortisol, and brain health, including nerve growth factor (NGF).
Participants with long COVID scored much lower on physical and emotional health. They reported more pain, fatigue and worse overall quality of life. They also had much higher levels of depression and anxiety than those who had fully recovered.
On the cognitive tests, both groups scored in the normal range overall. However, the long COVID group performed worse on a task that measured how quickly and fluently they could generate words starting with a certain letter.
In the blood samples, the long COVID group had lower levels of NGF, which supports brain cell growth and repair. They also showed more signs of ongoing inflammation, with 8 out of 10 long COVID participants having IL-10 levels above the median, compared to just 1 out of 7 in the control group.
IL-10 (Interleukin 10)
IL-10 is an immune system protein that helps regulate inflammation. While it’s often described as anti-inflammatory, high IL-10 levels can also reflect the body’s attempt to counter ongoing inflammation, which is why it’s sometimes elevated in chronic conditions like long COVID.
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When combining IL-6 and IL-10 into a pro-inflammatory score, 9 out of 10 long COVID participants fell into the high-inflammation category, vs only 1 control.
The future of long COVID care
“To our knowledge, this is the first controlled study that shows specific self-reported neurocognitive and central nervous system changes in long COVID patients, which validates the symptoms they’ve been experiencing,” said Lawrence.
The drop in NGF suggests the brain’s ability to adapt and repair may be affected, and high levels of IL-10 add to growing evidence of ongoing inflammation.
“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 co-author Dr. Judith Arnetz, a professor in the Department of Family Medicine at Michigan State University.
“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,” Lawrence added.
Larger, longer-term studies will be needed to confirm the patterns, test interventions and refine assessment tools.
Reference: Lawrence MR, Arnetz JE, Counts SE, Ahmed A, Arnetz BB. Self-reported health, neuropsychological tests and biomarkers in fully recovered COVID-19 patients vs patients with post-COVID cognitive symptoms: A pilot study. PLOS One. 2025. doi: 10.1371/journal.pone.0315486
This article is a rework of a press release issued by Corewell Health. Material has been edited for length and content.
