Back in the pandemic’s first wave, Michelle Monje was worried about Covid-19’s power to muddle the brain. Seeing the massive inflammatory response to the virus and early signs of what became known as long Covid’s brain fog, she was reminded of “chemo brain,” that mind-numbing side effect cancer patients endure when therapy to burn tumors away also inflames the brain.
Monje’s not a virologist or an epidemiologist. She’s a neuro-oncologist at Stanford who has studied the neurobiological underpinnings of cognitive impairment after cancer therapy for 20 years. But like scientists around the world, for the last two years her research has pivoted to include Covid and its far-reaching impact throughout the body. That includes brain fog, when people can’t do simple math, concentrate for more than a few minutes, or find the right words.
Working with a team that includes Yale virologist Akiko Iwasaki and Mount Sinai long Covid clinic founder David Putrino, she discovered that chemo and Covid spark neuro-inflammation in much the same way. Their study, based on mouse experiments and autopsy findings, was recently published as a preprint on the bioRxiv server and it’s been submitted to a peer-reviewed journal (one that does not allow authors to disclose its name before acceptance). But with that caveat, the comparison Monje and her co-authors draw still offers new insight into an often debilitating symptom that up to a third of people with long Covid experience for months or even years after initial infection. And the link raises hopes that a treatment one day could put out the fire in the same hot spots in 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,” Beth Stevens, an associate professor of neurology at Harvard Medical School and Boston Children’s Hospital, told STAT. In 2012, Stevens discovered that microglia, brain cells ignored since they were first noted in the 1920s, were actually powerful immune cells. She was not involved in Monje’s study, but is familiar with her research.
Understanding the basic biology is a first step toward an effective therapy, Stevens said, both for chemo brain and brain fog after Covid. “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 chemo brain are a long way off, Monje cautioned, so remedies for long Covid’s brain fog would be too, but these findings could pave the way toward them.
It’s no secret to people like Simone Bowles, a special education teacher’s assistant in Naperville, Ill., that there are no treatments available. She has lived with long Covid and brain fog for almost two years and said she has not found medical care to be helpful. One doctor suggested she take Claritin to see if taste or smell could come back, but it did no good.
The fog has thrown confusion into everyday tasks: She lost her bank card getting gas once. “And I never forget my bank card. Now I’m checking constantly, like, where is this?” she told STAT.
Her sense of taste and smell are still gone, and she deals with fatigue every day. She is devoted to her 9-year-old daughter, she takes heart from people she talks with online in a Black long haulers group, and said her faith in God keeps her going.
“I mean, I get up and go to work because I’ve got to go to work,” she said. “I do have a trip planned just because I’m trying to force myself to get back to doing things. I don’t want to do nothing.”
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 told STAT. “And then, you know, within months, reports of exactly that sort of complaint started to emerge.”
It was clear then that severe Covid could harm the brain, causing strokes or in rare cases direct viral infection. But what she wanted to understand was how milder infection and inflammation elsewhere in the body might affect the brain in ways similar to cancer chemotherapy targeting tumors throughout the body.
She knew the commonly used cancer drug methotrexate directly stimulates certain microglia in the brain’s white matter that then turn cells called astrocytes neurotoxic. Together they damage formation of myelin — a sheath around nerves that speeds brain circuit signals — in ways that result in cognitive impairment. Experiments have shown that depleting overactive microglia can reverse this process. Monje set out to understand if a similar physiological process might be at play in long Covid brain fog, and if it might be a potentially reversible one. The goal would be to restore balance between brain cells in order to rescue cognition.
To test this idea, Monje’s team used a model developed by Iwasaki at Yale to infect mice with a mild form of Covid-19 that was limited to the airways. They also studied brain samples taken from nine people who had died of Covid-19. And Putrino at Mount Sinai had been collecting serum samples from people suffering from long Covid with or without cognitive impairment. The scientists found high levels of cytokines and chemokines — proteins that regulate immune responses — as well as signs of microglial reactivity in the brain’s white matter that mirror what appears in the brains of people after chemotherapy. One particular chemokine linked to cognitive impairment was higher in people experiencing long Covid’s brain fog than in people whose long Covid didn’t include cognitive symptoms.
Monje wasn’t surprised to find this similarity, but she did find it quite striking. “It was not subtle,” she said. She credits advances made in the fundamental understanding of how neurons and glial cells work with each other to maintain neuronal 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 Covid clinics, which have sprung up in every state but North and South Dakota in the U.S., symptom relief is the mainstay to treat the array of persistent problems spanning the 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,” said John Baratta, founder and co-director of UNC COVID Recovery Clinic in Chapel Hill, N.C., and a physician who specializes in 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.
What’s next for Monje’s research is to build on the basic science. Questions to answer could include how vaccination affects the inflammatory response to mild Covid, Stevens of Boston Children’s said, and whether early childhood exposure to Covid influences brain development, and could therapies for chemo brain help people recover from Covid’s brain fog.
Monje said it’s too soon to talk about any treatments.
“I don’t want to speculate about what therapies might be useful because I can’t recommend anything we haven’t tested,” she said. “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.”
Meanwhile, she suspects because infection with the Omicron variant is milder for vaccinated and boosted people that might limit long Covid. She certainly hopes so. She and most of her family tested positive for Covid-19 after a distressing six-hour plane ride home from holiday celebrations back east.
“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 said. “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.”