People with “chemo brain” and covid brain fog could not seem more different: Those with “chemo brain” have a life-threatening disease for which they’ve taken toxic drugs or radiation. Many of those with covid brain fog, in contrast, describe themselves as previously healthy people who have had a relatively mild infection that felt like a cold.

So when Stanford University neuroscientist Michelle Monje began studies on long covid, she was fascinated to find similar changes among patients in both groups, in specialized brain cells that serve as the organ’s surveillance and defense system.

“It was really quite striking,” Monje said.

In cancer patients undergoing treatment, a malfunction in those same cells, known as microglia, are believed to be a cause of the fuzzy thinking that many describe. Scientists have also theorized that in Alzheimer’s disease, these cells may be impeded, making it difficult for them to counteract the cellular wear and tear of aging.

Monje’s project is part of a crucial and growing body of research that suggests similarities in the mechanisms of post-covid cognitive changes and other long-studied brain conditions, including “chemo brain,” Alzheimer’s and other post-viral syndromes following infections with influenza, Epstein-Barr, HIV or Ebola.

“There is humongous overlap” between long covid and these other conditions, said Avindra Nath, intramural clinical director of the neurological disorders and stroke unit of the National Institutes of Health.

Pre-covid, much of the medical research into brains (as well as other organs) was siloed by disease. But during the pandemic, as diverse scientists banded together to understand a complex, multi-organ disease, commonalities among the conditions began coming to light.

One such collaboration — among Monje, a recent MacArthur “genius” grant recipient; Yale’s Akiko Iwasaki, an immunobiologist who has become one of the leading voices on the coronavirus; and David Putrino, director of rehabilitation innovation for the Mount Sinai Health System in New York — has led to the discovery that the brain inflammation from covid-19 looks a lot like the inflammation after cancer therapy.

Monje believes that knowing those similarities gives the field of research into long covid “a real foundation.” She’s optimistic that some of the symptoms people are experiencing post-covid are reversible, and there’s already talk about testing drugs in clinical trials to treat “chemo brain” for those suffering from severe covid brain fog.

“We are not starting from nothing,” she said, “and I think that’s very hopeful.”

Another team of researchers from Harvard and Johns Hopkins University School of Medicine have highlighted how both in covid-19 and chronic fatigue syndrome, too many oxygen molecules pile up in a cell — possibly resulting in inflammation that leads to cognitive issues. And an examination of brain autopsy tissue by a Columbia University professor from 10 patients who died of covid-19 turned up a molecular change bearing the distinct signature of Alzheimer’s.

Most of the studies so far are so small and preliminary that they raise more questions than answers. But they also underscore the potential seriousness of covid-19 in producing short- and long-term brain effects, and provide hope that treatments to reverse or reduce those may be developed more quickly.

“We as a research community are very interested to see how whatever knowledge we have about other diseases can make a difference with long covid,” Nath said.

Gray matter

Scans from brains of people previously infected with the coronavirus show a loss in gray matter mostly concentrated in the regions highlighted in yellow and red, which correlate with sense of smell. (Nature)

The most complex object in the known universe, the human brain is a jellylike mass of about three pounds made up of hundreds of billions of cells connected in trillions of ways we barely understand. Researchers are still in the early stages of defining covid brain fog, the maddening feeling of slow thinking and confusion described post-infection by some people, but a study published this month provided the strongest evidence so far of biological changes following coronavirus infection.

Using data from the UK Biobank project, a long-term study of half a million people, researchers compared brain scans of 400 people before and after covid infections. They found that gray matter in key areas, mostly related to smell, was shrunken, and there was a higher-than-expected number of abnormalities in the tissue. The work was published March 7 in the journal Nature.

Scientist Gwenaëlle Douaud, an associate professor at the University of Oxford’s Wellcome Centre for Integrative Neuroimaging who led the study, said in an interview that she was “quite surprised to see such clear effects” in the pattern of damage, given that nearly everyone had experienced only mild illness. But she cautioned that it’s still unclear what the effects of these biological changes might mean in terms of a person’s functioning and whether they might be temporary or longer-lasting.

“We need to see whether, in time, the damage will resolve itself or give people greater vulnerability,” she said.

Gray matter is tissue made up of neurons that are thought to be responsible for thinking, white matter consists of cells supporting and connecting those neurons. All humans lose gray matter as part of healthy aging, but those with previous coronavirus infections in the study showed 0.2 to 2 percent additional reduction in brain size on average, compared with those who were not infected, between scans. They also had greater tissue damage in regions connected to the primary olfactory cortex linked to smell, and greater cognitive decline.

Although the study has been called one of the most important of the pandemic, it has key limitations. One is that the coronavirus-infected group was older, ages 51 to 81, and mostly White, so the results may not apply to other groups.

Still, some of the world’s top brain scientists have been struck by how the affected areas were the same ones their research had zeroed in on.

Alzheimer’s disease

In New York, Columbia University professor Andrew Marks conducted autopsies of the brains of 10 people, ages 38 to 80, who died of covid-19 in the first wave of the pandemic. He was taken aback when he noticed high levels of something known as phosphorylated tau, typically seen in Alzheimer’s patients.

“It was an unexpected surprising finding,” he said. “This can lead to what are called tangles in the brain — a disruption in the normal architecture.”

On the other hand, the pattern he found is dissimilar to Alzheimer’s in other respects. In the covid patients, the unusual findings were mostly in the cerebellum, which helps control balance and movement. In Alzheimer’s patients, phosphorylated tau is more likely to be seen early on in areas that involve higher-order brain functions, such as sensory perception, spatial reasoning and language.

Writing in the journal Alzheimer’s and Dementia on Feb. 3, Marks and his colleagues emphasized the need for follow-up studies to determine whether what they observed is unique to SARS-CoV-2 infection or common to all other viral infections.

Marks, chair of the department of physiology and cellular biophysics at Columbia, said “the preponderance of data from the UK [BioBank] study agrees that there is involvement in the brain that could be similar to Alzheimer’s disease.” He noted, for example, that there was some shrinking, albeit modest, in what’s known as the brain’s limbic system, which is involved in behavioral and emotional responses, in the long covid patients. He also noted that one early symptom of Alzheimer’s is a loss of smell.

On the other side of the Atlantic Ocean, another team of researchers has also been puzzled by a possible Alzheimer’s link.

In March 2020, a 67-year-old woman had come to the Hospital Clinico San Carlo in Madrid with a fever, cough, breathing difficulties and muscle aches. Her body fought off the illness, and she was discharged seven days later. But her cognitive symptoms worsened, and seven months later, in October, she returned for an evaluation.

Before her illness, the patient had been very active in her community, giving lectures and doing volunteer work. Afterward, according to a case report published in Frontiers in Psychology in November by Jordi A. Matias-Guiu and co-authors, she suffered “memory loss, difficulties in concentration, especially during reading, and cognitive fatigue.”

The woman underwent imaging and other tests and was diagnosed with Alzheimer’s. The researchers wondered whether covid-19 could have sped up symptoms of the illness — or as they wrote, unmasked cognitive symptoms already underway.

“[T]he relationship between COVID-19 and its potential role in future neurodegeneration is currently under debate,” the researchers wrote.

Stanford University neuroscientist Michelle Monje is looking at the similarities between brain inflammation in those with long covid and cancer patients post treatment. (LiPo Ching/San Jose Mercury News/Getty Images)

‘Chemo brain’

Monje and her team approached their research on covid brain fog using data from mice and humans. They infected the respiratory systems of mice with SARS-CoV-2, looked at autopsied tissue from nine people who had died of covid-19, and studied 48 patients with cognitive symptoms they ascribed to long covid.

In all three groups, the researchers found signals of inflammation in the brain. The long covid patients had elevated levels of immune markers, compared with those without long covid. In the mice and deceased patients, researchers found high levels of proteins that regulate immune responses, as well as changes in the microglia, the brain’s primary immune cells.

Those changes, Monje said, “can really powerfully dysregulate the interactions between multiple cell types, and it’s very clear that the crux of what goes wrong after cancer therapy is this same neuro-inflammation.”

In a preprint of a study still under journal review, Monje and her co-authors wrote that, “taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection.”

Post-viral syndromes

One leading theory about long covid is that it is not a new phenomenon at all — that it’s the same type of reaction some people have after other infections.

Bindu Paul, an assistant professor of pharmacology and molecular sciences at Johns Hopkins University School of Medicine, suggested in an August paper that certain biological responses may be in “disarray” after infection, leading to slower cognitive responses and brain fog. In particular, Paul and her co-authors believe there is evidence that an imbalance known as oxidative stress may be occurring in the brain. Oxidative stress has been compared to rust — too much oxygen is believed to lead to the destruction of molecules, proteins and even DNA.

In the paper published in Proceedings of the National Academy of Sciences, Paul noted the symptoms of chronic fatigue syndrome are very similar to those of long covid, “so it may well be that the group of abnormalities seen” in the two illnesses is related or the same.

From his office at NIH just outside Washington, Nath has been tracking long-term brain symptoms in 200 Ebola patients and 400 HIV patients for years and has compared similarities between those patients and people with chronic fatigue syndrome.

Nath said more scientists are wondering whether the mechanisms causing these patients, as well as those with long covid, to experience long-term fatigue and other post-viral symptoms “are probably one and the same.”

His group is starting a trial of 40 long covid patients who will receive intravenous immune globulin (IVIG), which is made up of antibodies that help fight infections, or corticosteroids, which reduce inflammation, to see whether their cognitive functioning improves. These treatments have been used in patients with chronic fatigue with mixed success.

Nath is hopeful those treatments may offer some benefit to long covid patients with brain fog, and believes the trick will be finding the right mix.

The need for such therapies may grow as an evolving virus continues circulating around the world. A study of covid’s chronic effects in the United States published earlier in February shows that people have a significantly elevated risk of mental health issues — including brain fog — in the year following infection.

“We need to reframe our thinking,” said Ziyad Al-Aly, chief of research at VA St. Louis Health Care system who led the study, which analyzed data from 154,000 patients. “We need to stop thinking in the short term and focus on covid’s long-term consequences.”