Back in the first wave of the pandemic, Michelle Monje worried about the power of Covid-19 to confuse the brain. Seeing the massive inflammatory response to the virus and the first signs of what has become known as Covid’s long brain fog, she was reminded of the ‘chemo brain’ that cancer patients have mind-numbing side effects endure when therapy to burn tumors also inflames the brain.

Monje is neither a virologist nor an epidemiologist. She is a neuro-oncologist at Stanford and has studied the neurobiological underpinnings of cognitive impairment after cancer treatment for 20 years. But like scientists around the world, over the past two years his research has pivoted to include Covid and its far-reaching impact on the whole body. This includes brain fog, when people can’t do simple calculations, 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 trigger neuroinflammation in much the same way. Their study, based on mouse experiments and autopsy results, was recently published as a preprint on the bioRxiv server and submitted to a peer-reviewed journal (which does not allow the 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-term Covid experience for months or even years later the initial infection. And the link holds out hope that one day a treatment could put out the fire in the same brain hotspots.


“While the connection is not immediately obvious, in light of the roles neuroinflammation plays in the neurobiology of the ‘chemo brain’, it makes perfect sense that there are these similarities to cognitive impairment after an inflammatory challenge. like Covid,” Beth Stevens, 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 their discovery in the 1920s, were actually powerful immune cells. She was not involved in Monje’s study, but is aware of his research.

Understanding basic biology is a first step toward effective therapy, Stevens said, for both chemo brain and post-Covid brain fog. “Monje and his team have been working on therapeutic interventions for cognitive impairment related to cancer treatment for some time, so they can now test these possible therapies for a long time Covid. There are clear next steps.


Therapies for the chemo brain are still a long way off, Monje warned, so the cures for Covid’s long brain fog would be too, but these findings could pave the way for them.

It’s no secret to anyone like Simone Bowles, a special education teacher’s assistant in Naperville, Illinois, 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 helpful. A doctor suggested she take Claritin to see if the taste or smell could come back, but nothing worked.

The fog sowed confusion in daily tasks: she lost her bank card once to get gas. “And I never forget my credit card. Now I’m constantly checking, like, where is it?” she told STAT.

Her sense of taste and smell have always disappeared and she faces fatigue every day. She is devoted to her 9-year-old daughter, she takes heart from people she talks to online in a black long-mail group and said her faith in God keeps her going.

“I mean, I get up and go to work because I have to go to work,” she said. “I planned a trip just because I’m trying to force myself to start doing things again. I do not want to do anything.

As Monje set out to analyze the chemo brain and long Covid brain fog, her starting point was neuroinflammation and the cognitive impairment it causes. Cancer therapies can cause persistent activation of microglia, which normally helps in brain development and later in maintaining brain health. But these cells can overload into disease, especially an immunogenic disease like Covid-19, which is known to trigger cytokine release syndrome and other types of inflammatory dysregulation.

“In the spring of 2020, I was concerned that we might be seeing a syndrome very similar to what we see after cancer treatment, that we might start to see a cognitive syndrome characterized by things like impaired memory , executive functions, attention, processing speed, multitasking,” Monje told STAT. “And then, you know, within a few months, reports of exactly those kinds of complaints started to emerge.”

It was then clear that severe Covid could damage the brain, cause strokes or, in rare cases, direct viral infection. But what she wanted to understand was how milder infection and inflammation elsewhere in the body could affect the brain in similar ways to cancer chemotherapy targeting tumors throughout the body.

She knew that the commonly used cancer drug methotrexate directly stimulates certain microglia in the white matter of the brain, which then makes cells called astrocytes neurotoxic. Together they damage the formation of myelin – a sheath around nerves that speeds up brain circuit signals – in a way that leads to cognitive impairment. Experiments have shown that depleting overactive microglia can reverse this process. Monje sought to understand whether a similar physiological process might be at play in Covid’s long brain fog, and whether it might be potentially reversible. The aim would be to restore the balance between brain cells in order to save 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 limited to the airways. They also studied brain samples taken from nine people who died of Covid-19. And Putrino at Mount Sinai had collected serum samples from people with long Covid with or without cognitive impairment. Scientists found elevated 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 people’s brains after chemotherapy. A particular chemokine linked to cognitive impairment was higher in people with long Covid brain fog than in people whose long Covid did not include cognitive symptoms.

Monje wasn’t surprised to find this similarity, but she found it quite striking. “It wasn’t subtle,” she said. She credits advances in the fundamental understanding of how neurons and glial cells work with each other to maintain neuronal health and plasticity. “This groundwork will hopefully really inform cognitive function after Covid,” she said. “What’s exciting about this is that we’re not starting from scratch.”

In the long-running Covid clinics, which have sprung up in every state except North and South Dakota in the US, symptom relief is the mainstay for treating the range of lingering issues spanning body and mind. .

“In rehabilitation medicine, our focus has always been on managing people’s current symptoms and impairments, improving their quality of life and restoring their functioning, said John Baratta, Founder and co-director of the UNC COVID Recovery Clinic in Chapel Hill, North Carolina. , and a physician specializing in post-stroke rehabilitation. “Certainly if a magic medicine becomes available in the future that addresses whatever the underlying issues with long Covid are, then we would love to have access to it. But until then, if that time comes, we will continue to focus on symptom management and helping people get as well as possible.

This may mean neuropsychiatric evaluation as well as 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 combine.

The next step in Monje’s research is to build on basic science. Questions to be answered could include how vaccination affects the inflammatory response to mild Covid, Boston Children’s Stevens said, and whether early childhood exposure to Covid influences brain development, and whether chemo brain therapies could help people recover from Covid brain fog.

Monje said it was too early to talk about treatments.

“I don’t want to speculate on which therapies might be helpful because I can’t recommend anything that we haven’t tested,” she said. “We will first test potential interventions in preclinical models and then there will be carefully controlled clinical trials so that we can identify the best and safest ones. But I wouldn’t want people to think, “Oh, I read somewhere that xyz, you know, calms microglia.” I saw this happen on Twitter.

In the meantime, she suspects that infection with the Omicron variant is milder for vaccinated and boosted people, which could limit the duration of Covid. She certainly hopes so. She and most of her family members tested positive for Covid-19 after a harrowing six-hour plane ride home after the holiday season in the east.

“I was vaccinated and boosted and incredibly grateful for that because, wow, just getting a taste of how bad it was – I was pretty sick for a few days,” she said. “But one thing that gives me personal comfort is these emerging preprints that suggest being vaccinated is protective, potentially against long Covid, but that needs to be peer reviewed. I’m not an epidemiologist, but I hope we find that vaccination changes the neuroimmunogenicity of the fight against this infection..