NEUROSCIENTIST MICHELLE MONJE of Stanford University in California has spent two decades studying cancer- related cognitive impairment (CRCI), also known as chemo brain. Her research revealed how cancer treatments such as the widely used chemotherapy drug methotrexate activate immune cells called microglia in the brain. When activated, microglia trigger brain inflammation and cell dysregulation in brain cells needed for normal neural function.

The result is impaired attention, concentration, memory and executive function, Monje explains. “It’s a very common report from survivors that after their cancer therapy, they were not able to go back to the same level of either educational or occupational function that they previously were able to do,” she says. For some people, the brain fog lifts with time, but others are not so lucky.

So when neurologists and patients began to share reports of memory problems after COVID-19 infection, Monje dove into new research revealing potential overlap between symptoms of long COVID-19 and chemo brain. Monje spoke with Cancer Today about how new research collaborations sparked by the pandemic could benefit people with memory problems related to both COVID-19 and cancer.

CT: What led you to pursue COVID-19 research?
MONJE: I was already thinking about systemic inflammation and the central mechanism of inflammatory-mediated disruption of neuroplasticity. When I started thinking about the pandemic in March of 2020, it very quickly became clear that this was a profoundly immunogenic virus. With my particular perspective on this, it seemed obvious that we were going to see a chemo brain-like syndrome. By the summer, every neurologist I talked to was telling me about this severe brain fog that people had, even when they weren’t that sick from the initial infection. They were left with what sounded to me like chemo brain: impaired attention, concentration, memory function, multitasking, executive dysfunction. It was the same syndrome.

I thought, well, it must be [triggered by] systemic inflammation, even if you don’t have brain involvement or disease enough to cause some of the more severe [effects of COVID-19], like strokes and clots. That would be really important to understand, because we already [have tools to treat] this in mice who are given methotrexate. Maybe the same strategies would help with this syndrome. I reached out to Akiko Iwasaki [an immunobiologist at Yale University in New Haven, Connecticut], who had developed this beautiful mouse model of respiratory-restricted COVID. Her lab would infect the mice with SARS-CoV-2 [the virus that causes COVID-19].

CT: What did you find?
MONJE: It was exactly what we hypothesized: These mice looked OK. They were running around their cages … and not exhibiting sickness behavior. But their brains were not normal. There was a neuroinflammatory effect that was persistent. And just as we anticipated, when we looked at the microglial reactivity, there was the exact same pattern of white matter-specific microglial reactivity that we saw in the methotrexate mouse model and in people who had been previously exposed to chemotherapy. It really fit the same sort of cellular dysregulation that we had anticipated.

CT: Does this research suggest new ways to treat chemo brain?
MONJE: Right now, chemo brain research is informing COVID fog research more. Chemo brain is something that affects a huge number of cancer survivors, but I have never seen as much interest in any single paper that I ever published as there is in this COVID paper, because COVID is literally affecting the entire world. One in four people has cognitive impairment after COVID, and everybody is getting COVID. So there is more interest and I think more momentum to find the solution for the brain fog induced by this glial dysregulation, which is relevant to cancer therapy and COVID and probably many other inflammatory contexts as well.

One of the really beautiful things about this particular moment in science is that the terribleness of this pandemic—the tragedy and the incredible urgency to find solutions—has made scientists from very different areas come together to work together, to try to meet the moment and find solutions quickly.

I think there is just such intense interest in COVID fog that it will advance therapy for chemo brain. For people with CRCI, what we need to do now is translate some of the regenerative strategies that have proven helpful for mice and see if they indeed are helpful for our patients. I would love for somebody to take this forward. It just takes people who are able to focus on it and the funding to do it.

A lot of people have written to me: “This is so validating. I’m not crazy. I’m not lazy. There’s something really biologically wrong.” It’s helpful to acknowledge that there’s a neurobiological basis for these persistent cognitive symptoms. It’s real, it should be accommodated, and there’s potential to fix it.