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Long Covid

Long COVID Looks Like Acute Infection in the Brain

Research finds immune pathway for the 50 percent who recover from long COVID.

Key points

  • Long COVID patients with brain fog have the biological signature of an acute infection in the brain.
  • 50 percent of people with cognitive impairment from Long COVID improve after two years, but very slowly.
  • An effective interferon lambda response in the brain helps recovery from Long COVID cognitive impairment.
  • Researchers call for a clinical trial on the use of interferon lambda to treat Long COVID brain fog.
Mel Lituañas / Unsplash
Long COVID brain fog is an inflammatory condition and is not "all in your head."
Source: Mel Lituañas / Unsplash

Long COVID has the biological signature of an acute infection in the brain, according to a new research study. For patients with difficulty thinking or concentrating due to Long COVID, which has lasted over four years in some, this may be caused by ongoing COVID-19 infection. In addition, 50 percent of people with Long COVID brain fog do not get better, but in the 50 percent that do, the critical immune system pathway involves interferon.

A research team from Rutgers has isolated the molecular makeup of the immune system’s response to Long COVID in the brain by extensively testing cerebral spinal fluid (CSF). By mapping the proteomics of the CSF in Long COVID patients, the team has made an important step toward resolving an ongoing debate about the cause of Long COVID. Long COVID looks like an acute infection. It does not fit the pattern of a post-infectious autoimmune process or Alzheimer’s disease. Further, brain fog is not caused by anxiety or depression and is not “all in the patient’s head.”

Since evidence is growing that about 24 million Americans have had some form of Long COVID, and that we can develop long COVID even after several infections, these findings are important for all of us.

Alzheimer’s researchers tackle Long COVID

The research team, led by William Hu, M.D., Ph.D., associate professor and division chief of cognitive neurology at Rutgers-Robert Wood Johnson Medical School, has had extensive experience in studying the cognitive changes and biology associated with Alzheimer’s disease. When Long COVID emerged as a new disease, and patients reported brain fog, one of the leading theories was that Long COVID produced an Alzheimer’s dementia-like picture in the brain.

This piqued Hu’s interest. “We recruited a group of people [with Long COVID] who were coming here to Rutgers for care, and we follow them over time to see what happened to their memory issues, or what many people call brain fog over time. And over the course of two years, about half of the people experienced improvement in their cognition...the other half did not,” Hu told a reporter at PBS. This allowed them to see that there was some recovery, but the recovery was slow.

Why did some patients improve while others did not? To answer this question, Hu’s team recruited a subgroup of people to undergo spinal fluid collection and analysis. By collecting all the immune cells in the CSF that were in contact with the brain, the team was able to study the genes in those cells. They learned that long COVID was very similar to acute infection with the SARS-CoV2 virus.

Because of the team’s experience with Alzheimer’s, they already had precise markers for the disease. “We did not find Alzheimer’s signatures in any way in the group of people with long COVID,” said Hu.

Fifty percent of people with Long COVID brain fog recover slowly

Once the researchers determined that the spinal fluid’s genetic and protein pattern was consistent with acute COVID-19 infection, they wanted to know what was different about the people whose brain fog was slowly improving. They compared the proteomic signature, or protein pattern, in the CSF of the study subjects with existing databases to see which patterns they matched.

This analysis made it clear that the difference between those who were improving and those who were not was in the immune system’s interferon-led response to the virus. Interferons are proteins that act like the body’s alarm system against viruses and other harmful invaders. When a virus infects a cell, the cell sends out interferons to warn nearby cells. These nearby cells then prepare to defend themselves, making it harder for the virus to spread. All of these responses produce specific biological signatures that have been determined in various experiments and exist in databases.

Interferon responses are critical to Long COVID recovery

By comparing the study samples with existing databases, Hu’s team found that the three interferon pathways, which are intermixed and interrelated, were all important in Long COVID. Both interferon alpha and gamma were under-activated in people with long COVID, but it was interferon lambda that differentiated the people who got better from those who did not.

Interferon lambda is the least studied and least understood of the three interferons. Yet, this was the critical pathway for Long COVID. Hu’s team found that interferon lambda-2 levels were actually higher in people who do not recover. But higher levels are not always better: In this case, Hu’s team believes that the higher interferon lambda levels are a sign of something going wrong. Lambda remained high because it was not sufficiently activating the defense pathways that were needed to fight off the COVID-19 infection.

“People who did recover have a successful interferon process,” Hu explained. Interferon lambda levels had normalized in the patients who were getting better, which suggested that they had already recruited all the biological defenses they needed and were on their way to healing.

We should believe patients who report brain fog

Many people with Long COVID report being met with disbelief by friends, family, their workplaces, and healthcare professionals when they shared their difficulty thinking and concentrating from Long COVID brain fog. Hu says this is nothing new and has been happening to people with early Alzheimer’s dementia all along. “A lot of people with early Alzheimer’s will come with very mild memory issues. And some doctors might say, ‘You’re just isolated because you’re retired,’ or ‘You’re just sad because you’ve lost your spouse,” and they get ignored,” says Hu.

Because Hu was aware of the way people with Long COVID have, at times, been neglected or ignored in traditional healthcare systems, his team took special care to evaluate their brain fog.

To evaluate the role of mood disorders or other factors that can impact cognitive function, Hu’s team looked carefully at the study participants’ memory function, depression, anxiety, fatigue, and sleep. They found that anxiety and depression were not correlated with brain fog or cognitive difficulties. Also, there was no difference in levels of anxiety and depression in the group with Long COVID cognitive impairments who did not improve as compared to those who did.

The team also objectively verified study participants’ complaints of brain fog. Some of the study participants who reported brain fog showed documented cognitive deficits in performance on short testing, the kind that might be used in a doctor’s office. Other study participants complained of brain fog but obtained normal results on the short tests.

Yet, when Hu’s team ran complete neuropsychological testing on the participants, both groups showed objective cognitive impairments. “It’s just a matter of what domain and how extensively you look,” says Hu. “When somebody complains about something, they’re usually right.”

In people with even mild cognitive symptoms, the team demonstrated significant biological changes in the CSF that cannot be explained just by depression or other mood disorders. “It was really empowering both for us and for the participants,” says Hu.

What does this mean for Long COVID patients?

Since this testing was done on spinal fluid in a research lab, it is not something that patients can ask their doctor for. However, the Rutgers team is in the midst of studying whether blood tests could be used to evaluate the interferon-gamma response in individuals with Long COVID.

Still, patients can show their doctor the study, which provides strong evidence that Long COVID cognitive impairment has an inflammatory basis in the brain.

Directions for research into Long COVID treatment

In February 2023, a study was published in the New England Journal of Medicine on the use of Pegylated Interferon Lambda for acute COVID-19 infection. That study found that administering the pegylated interferon lambda to outpatients with acute COVID-19 reduced their later need for ER visits or hospitalization.

Based on their own findings, Hu’s team suspects that interferon lambda needs to be supplemented. “That is going to be very difficult either in the human model or the animal model,” says Hu. “The easiest path to determine whether interferon lambda works would be in a clinical trial.” To that end, Hu’s team is reaching out to other researchers and to those involved with the NIH RECOVER efforts to make them aware of this exciting lead.

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