While we often hear an argument about “mild cases” of COVID-19 in the pandemic that don’t require individuals to seek hospitalization, many of the after effects still remain an elusive mystery to researchers. One of the more horrific effects first noted in people who suffered from long-term COVID is a phenomenon known as brain fog and this attracted the attention of Stanford-based oncologist Michelle Monje who specializes in cancers of the brain. The cognitive effects of brain fog on COVID patients reminded her of a disorder known as “chemo brain,” in her cancer patients who underwent radiation treatment and experienced inflammation in their brains.
While Monje has written a great deal of literature on the cognitive impairment of cancer therapy over the last two decades, she has dedicated the last two to studying COVID and its overall effect on the body. What’s going on in the brain that makes it hard to do math in your head or stumble for the right word?
Monje assembled a team consisting of the Yale virologist Akiko Iwasaki and the founder of Mount Sinai long-term COVID clinic, David Putrino and with a new study, demonstrated that the impacts of COVID and chemo on neuro-inflammation in the brain are very similar. Their study, based on data from mouse experiments as well as autopsy findings, was published in January as a preprint on the server bioRxiv and has been submitted for publication to a peer-reviewed journal (the publication’s rules do not permit authors to disclose its name before their work is accepted). With that caveat aside, the comparison offered by Monje and her co-authors still provides new insight into what is an often debilitating symptom that up to almost one-third of people suffering from long-term COVID may experience their symptoms for months or even for several years after they were initially infected. The link is a glimmer of optimism that one day a treatment could be found to benefit these same hot spots within the brain.
“While the link is not immediately obvious, in light of the roles that neuroinflammation plays in the neurobiology of ‘chemo brain,’ it makes a lot of sense that there would be these similarities with the cognitive impairment after an inflammatory challenge like Covid,” says Beth Stevens, who is an associate professor of neurology at Harvard Medical School and at Boston Children’s Hospital. In 2012, Stevens discovered that microglia, small connective brain cells neglected by medicine since they were first described in the 1920s, are in fact, very powerful immune cells. She was not one of the researchers in Monje’s study.
Deciphering the basic biology involved is a crucial first step toward an effective therapy, Stevens said, both for chemo brain and also for that post-COVID brain fog. “Monje and team have been working on therapeutic interventions for cancer therapy-related cognitive impairment for some time, so they can now test those possible therapies for long Covid. There are clear next steps.”
Therapies for the chemo brain condition are still a long way off in the future, Monje warns, so potential remedies for long-term COVID brain fog would also be, but the latest findings could still give them a much needed push.
As Monje set out to analyze chemo brain and long Covid brain fog, her starting point was neuroinflammation and the cognitive impairment it causes. Cancer therapies can lead to persistent activation of microglia, which normally help in brain development and later in maintaining brain health. But these cells can go into overdrive in disease, particularly an immunogenic one like Covid-19, known for sparking cytokine release syndrome and other kinds of inflammatory dysregulation.
“I worried back in the spring of 2020 that we would perhaps see a syndrome very similar to what we see after cancer therapy, that we might start to see a cognitive syndrome characterized by things like impairment in memory, executive function, attention, speed of information processing, multitasking,” Monje said in a STAT News interview. “And then, you know, within months, reports of exactly that sort of complaint started to emerge.”
By that point in the pandemic, it was already clear that a severe enough case of COVID-19 could affect the brain, resulting in strokes or even in some cases, lead to a direct viral infection. But what made Monje curious was the way in which milder infection and inflammation occurring somewhere else in the body could impact the brain the way in which cancer chemotherapy targets all tumors within the body.
She knew that there is a commonly prescribed cancer drug called methotrexate, designed to target specific microglia cells within the white matter of the brain that then render connective cells called astrocytes neurotoxic. Together, these properties damage the production of myelin — an insulative sheath around the nerves that speeds up brain circuit signals. The result is cognitive impairment, even if only temporarily. Experiments have demonstrated that the depletion of any overactive microglia is able to reverse the process. Monje sought to determine whether or not there is a similar physiological process that could be at work when an individual suffers from long COVID brain fog, and if so, whether the process might be reversible. The primary end goal for the researchers would be to restore the balance between the white matter brain cells and restore normal cognition.
In order to test their concept, Iwasaki developed a model at Yale that was used to infect lab mice with a mild strain of COVID-19. In another trial, the researchers examined brain samples extracted from nine patients who had died from COVID. Putrino at Mount Sinai collected serum samples taken from patients who have long Covid – both with and without signs of cognitive impairment. The scientists discovered that there were high levels of both cytokines and chemokines — the proteins responsible for regulating the body’s immune system response. More importantly, this coincided with signs of microglial reactivity occurring within the brain’s white matter – and showed reactions similar to what happens in the brains of people undergoing chemotherapy. One particular chemokine commonly associated with cognitive impairment was found in larger concentrations in the patients who experienced long COVID brain fog than in the people whose long-term COVID did not consist of cognitive issues.
Monje wasn’t too surprised to discover this pattern, but she does see it as a harbinger for things to come. “It was not subtle,” she says, noting that recent discoveries in the interaction between neurons and glial cells were critical to her team’s efforts – particularly when it comes to maintaining health and plasticity. “That basic work is going to really hopefully inform the cognitive function after Covid,” she said. “What’s exciting about that is we’re not starting from ground zero.”
At long-term Covid clinics, which have surfaced in just about every state besides North and South Dakota in the U.S., symptom relief is paramount in treating the many persistent problems affecting both body and mind.
“In rehabilitation medicine, we always have been focused on addressing people’s current symptoms and their impairments and improving their quality of life and getting their functioning back,” says John Baratta, who is the founder and co-director of the UNC COVID Recovery Clinic in Chapel Hill, N.C., as well as a physician whose field is stroke rehabilitation. “Certainly if a magic drug becomes available in the future that treats whatever the underlying issues are with long Covid, then we would love to have access to that. But until that time, if that time comes, we’ll continue focusing on managing the symptoms and helping people improve as much as they can.”
That can mean a neuropsychiatric evaluation along with cognitive rehabilitation, which uses exercises to help patients with processing speed as well as memory and attention. Sometimes stimulants can help, especially if brain fog and fatigue come together.
The next step in Monje’s research is a matter of building on the basic science. Among the remaining questions are whether the COVID-19 vaccines play any role in the inflammatory response to mild Covid – a topic already being looked at by Stevens of Boston Children’s Hospital, and also on whether or not being exposed to COVID in early childhood has an effect on the brain’s development. Depending on the nature of their discoveries, they could potentially help people recover from COVID brain fog using similar therapies already used to treat chemo brain.
Monje said it’s still a bit early to discuss any potential brain fog treatments.
“I don’t want to speculate about what therapies might be useful because I can’t recommend anything we haven’t tested,” Monje says. “We will be testing potential interventions first in preclinical models and then there will be carefully controlled clinical trials so that we can identify the best and safest. But I wouldn’t want people to think, ‘Oh, I read somewhere that x y z, you know, calms down microglia.’ I’ve seen that happen on Twitter.”
For the time being, Monje suspects that because an infection from the Omicron variant is often milder for those who are vaccinated or boosted, that could put a limit on the spread of long-term COVID. At least, she definitely hopes it’s the case. She and a majority of her family were diagnosed with COVID-19 after a long six-hour plane ride back home to the east coast.
“I was vaccinated and boosted and incredibly grateful for that because, wow, just having a taste of how bad the disease is — I was pretty sick for a few days,” she recalls. “But one thing that I am taking some personal solace in are these emerging preprints that suggest that being vaccinated is protective, potentially against long Covid, but that needs to be peer-reviewed. I’m not an epidemiologist, but I’m hopeful that we will find that vaccination changes the neuro immunogenicity of fighting this infection.”