In the U.K. cognition survey, a portion of those who had a confirmed case of COVID-19 but were not hospitalized had cognitive deficits as well, though not as severe as the hospitalized group. Other studies confirm that people who experienced “mild” or “moderate” COVID-19 can have lingering cognitive issues that have a profound impact on daily life.
Davis and others like her have formed the Patient-Led Research Collaborative, a self-organized group of long COVID-19 patients who are collecting data on neurological and other lasting symptoms. In a peer-reviewed paper published on July 15, Davis’s group found that out of nearly 3,800 people surveyed who suffered from long COVID, 85 percent reported “brain fog” — which the authors define as poor attention, problem-solving, executive-functioning, and decision-making. Only a small portion of those—317 people—were previously hospitalized with severe COVID-19.
In one post-COVID-19 clinic at Northwestern Memorial Hospital in Chicago, researchers found that many individuals with long COVID were never hospitalized yet had neurologic symptoms lasting longer than six weeks. Out of 100 patients, the most common neurologic manifestations were brain fog, and numbness and tingling, which affected 81 percent and 60 percent of patients respectively, according to a study published in March. These individuals also performed worse in attention and working-memory cognitive tasks compared to people their age who hadn’t gotten sick with COVID-19.
Probing the brain
Other viruses like West Nile, Zika, herpes simplex, and the virus that causes chickenpox and shingles are known to directly infect the brain. When COVID-19 patients first started reporting cognitive and neurological side effects last year, scientists wondered if SARS-CoV-2 might do the same thing.
Researchers started probing the brains of people who died of COVID-19 looking for traces of the virus. But brain tissue is hard to come by. Few people donate their brains to research, and strict protocols for handling potentially infectious brain tissue make studying it even more difficult. As a result, these studies are small, often involving just a handful to a few dozen patients.
While a few studies have detected the presence of the virus in neurons and their supportive glia cells, which hold neurons together like glue, scientists now think it’s unlikely that SARS-CoV-2 infects brain cells, at least in large enough quantities to cause neurological damage. If the virus is present there at all, it’s likely in very small amounts or is contained within the brain’s blood vessels.
A Columbia University study of 40 people who died of COVID-19 found no evidence of viral RNA or proteins in samples of patient brain cells. The results were published in April in the journal Brain. The authors suggest that previous reports of virus detected in brain cells may be due to contamination during the autopsy.
“The fact that SARS-CoV-2 is potentially causing these cognitive effects at a distance makes it a bit unusual,” says Christopher Bartley, a postdoctoral fellow in immunopsychiatry at the University of California, San Francisco, who wasn’t involved in the Columbia study.
Biological mechanisms
If SARS-CoV-2 doesn’t infect brain cells, how is so destructive to cognition? There are two leading hypotheses.
The first is that the infection somehow triggers inflammation in the brain. Some COVID-19 patients have suffered encephalitis, or swelling of the brain, which can cause confusion and double vision, and in serious cases, speech, hearing, or vision problems. If left untreated, patients can develop cognitive problems. Viruses like West Nile and Zika can cause encephalitis by directly infecting the brain cells, but how COVID-19 may lead to brain inflammation is less clear.
An immune response run amok, known as autoimmunity, might be to blame for some instances of inflammation throughout the body, including the brain. When the immune system is fighting a disease like COVID-19, it unleashes antibodies to do battle against the infection. But sometimes a person’s immune system becomes hyperactive and instead starts making self-attacking antibodies, known as autoantibodies, which can contribute to inflammation and blood clots. These autoantibodies have been found in the cerebrospinal fluid of COVID-19 patients with neurological symptoms.
In the Columbia study, researchers found clusters of microglia—special immune cells in the brain whose job is to clear out damaged neurons—that appeared to be attacking healthy neurons. The phenomenon is called neuronophagia. Most of these rogue microglia were in the brain stem, which regulates heartbeat, breathing, and sleeping. The researchers think these microglia may get activated by signaling molecules called inflammatory cytokines found in patients with severe COVID-19. These molecules are supposed to help regulate the immune system, but some people’s bodies release too many inflammatory cytokines in response to a viral infection.
When researchers at Stanford looked at brain tissue from eight patients who died of COVID-19, they also observed signs of inflammation compared to 14 control brains. Using a technique called single-cell RNA sequencing, they found that hundreds of genes associated with inflammation were activated in brain cells from COVID-19 patients compared to controls.
They also noted molecular changes in the cerebral cortex, the part of the brain involved in decision-making and memory that suggested signaling imbalances in neurons. Similar imbalances have been seen in patients with Alzheimer’s disease. The results were published in Nature in June.
A second explanation for cognitive issues is that COVID-19 may restrict blood flow to the brain and deprive it of oxygen. In patients who have died of COVID-19, researchers have found evidence of brain tissue damagecaused by hypoxia, or the lack of oxygen.
“The brain is an organ that requires a lot of oxygen to do its job,” says Billie Schultz, a physiatrist at the Mayo Clinic in Rochester, Minnesota, who specialized in rehabilitating stroke and traumatic brain injury patients before COVID-19 hit.
Other symptoms that accompany post-COVID-19 syndrome—pain, fatigue, and shortness of breath—can negatively affect cognition too, Schultz says. “It’s not just a brain issue; it's a multi-system body issue that needs to be addressed.”
Schultz is hopeful that many people experiencing persistent cognitive issues from COVID-19 will eventually improve. Many stroke and traumatic brain injury patients experience spontaneous recovery, in which the brain heals itself within three to six months.
But others worry that cognitive issues caused by COVID-19 may lead to dementia. At the Alzheimer’s Association International Conference in July, scientists presented research showing that hospitalized COVID-19 patients had similar blood biomarkers, neurodegeneration, and inflammation to those with Alzheimer’s disease. The research has not yet been peer-reviewed.
Heather Snyder, vice president of medical and scientific relations at the Alzheimer's Association, cautions that the findings don’t necessarily mean someone who gets COVID-19 is more likely to develop Alzheimer’s or another type of dementia. “We’re still trying to understand those associations,” she says.
For now, there are no specific treatments for COVID-related brain fog, memory loss, and other cognitive effects. Instead, doctors are using cognitive therapy, occupational therapy, or speech-language pathology to treat symptoms. Many studies, like the NIH one, are trying to understand the underlying mechanisms of cognitive dysfunction in long COVID patients in hopes of identifying potential treatments.
“We and others are collecting anecdotal data from patients on what has helped them, but we are far from definitive therapeutics,” Frontera says.
In the U.S. alone, millions of people have developed lasting cognitive and neurological problems long after an initial COVID-19 infection. Some of these patients may be permanently disabled and need long-term care. “My concern is that we're going to have huge numbers of the population who aren't able to function at their cognitive baseline. They can't go back to work, or at least not to what they did before,” Frontera says. “We haven’t even thought of the long-term implications. It could be an incredible blow to the economy.”
Davis says the scariest part about COVID-19’s cognitive effects is that people of all ages and health status are affected. “This is something everyone is at risk for, and it's completely debilitating.”
Editor's Note: This article has been updated to correct the number of patients in studies regarding COVID-19 and cognition.
Unexpected effects
In the U.K. cognition survey, a portion of those who had a confirmed case of COVID-19 but were not hospitalized had cognitive deficits as well, though not as severe as the hospitalized group. Other studies confirm that people who experienced “mild” or “moderate” COVID-19 can have lingering cognitive issues that have a profound impact on daily life.
Davis and others like her have formed the Patient-Led Research Collaborative, a self-organized group of long COVID-19 patients who are collecting data on neurological and other lasting symptoms. In a peer-reviewed paper published on July 15, Davis’s group found that out of nearly 3,800 people surveyed who suffered from long COVID, 85 percent reported “brain fog” — which the authors define as poor attention, problem-solving, executive-functioning, and decision-making. Only a small portion of those—317 people—were previously hospitalized with severe COVID-19.
In one post-COVID-19 clinic at Northwestern Memorial Hospital in Chicago, researchers found that many individuals with long COVID were never hospitalized yet had neurologic symptoms lasting longer than six weeks. Out of 100 patients, the most common neurologic manifestations were brain fog, and numbness and tingling, which affected 81 percent and 60 percent of patients respectively, according to a study published in March. These individuals also performed worse in attention and working-memory cognitive tasks compared to people their age who hadn’t gotten sick with COVID-19.
Probing the brain
Other viruses like West Nile, Zika, herpes simplex, and the virus that causes chickenpox and shingles are known to directly infect the brain. When COVID-19 patients first started reporting cognitive and neurological side effects last year, scientists wondered if SARS-CoV-2 might do the same thing.
Researchers started probing the brains of people who died of COVID-19 looking for traces of the virus. But brain tissue is hard to come by. Few people donate their brains to research, and strict protocols for handling potentially infectious brain tissue make studying it even more difficult. As a result, these studies are small, often involving just a handful to a few dozen patients.
While a few studies have detected the presence of the virus in neurons and their supportive glia cells, which hold neurons together like glue, scientists now think it’s unlikely that SARS-CoV-2 infects brain cells, at least in large enough quantities to cause neurological damage. If the virus is present there at all, it’s likely in very small amounts or is contained within the brain’s blood vessels.
A Columbia University study of 40 people who died of COVID-19 found no evidence of viral RNA or proteins in samples of patient brain cells. The results were published in April in the journal Brain. The authors suggest that previous reports of virus detected in brain cells may be due to contamination during the autopsy.
“The fact that SARS-CoV-2 is potentially causing these cognitive effects at a distance makes it a bit unusual,” says Christopher Bartley, a postdoctoral fellow in immunopsychiatry at the University of California, San Francisco, who wasn’t involved in the Columbia study.
Biological mechanisms
If SARS-CoV-2 doesn’t infect brain cells, how is so destructive to cognition? There are two leading hypotheses.
The first is that the infection somehow triggers inflammation in the brain. Some COVID-19 patients have suffered encephalitis, or swelling of the brain, which can cause confusion and double vision, and in serious cases, speech, hearing, or vision problems. If left untreated, patients can develop cognitive problems. Viruses like West Nile and Zika can cause encephalitis by directly infecting the brain cells, but how COVID-19 may lead to brain inflammation is less clear.
An immune response run amok, known as autoimmunity, might be to blame for some instances of inflammation throughout the body, including the brain. When the immune system is fighting a disease like COVID-19, it unleashes antibodies to do battle against the infection. But sometimes a person’s immune system becomes hyperactive and instead starts making self-attacking antibodies, known as autoantibodies, which can contribute to inflammation and blood clots. These autoantibodies have been found in the cerebrospinal fluid of COVID-19 patients with neurological symptoms.
In the Columbia study, researchers found clusters of microglia—special immune cells in the brain whose job is to clear out damaged neurons—that appeared to be attacking healthy neurons. The phenomenon is called neuronophagia. Most of these rogue microglia were in the brain stem, which regulates heartbeat, breathing, and sleeping. The researchers think these microglia may get activated by signaling molecules called inflammatory cytokines found in patients with severe COVID-19. These molecules are supposed to help regulate the immune system, but some people’s bodies release too many inflammatory cytokines in response to a viral infection.
When researchers at Stanford looked at brain tissue from eight patients who died of COVID-19, they also observed signs of inflammation compared to 14 control brains. Using a technique called single-cell RNA sequencing, they found that hundreds of genes associated with inflammation were activated in brain cells from COVID-19 patients compared to controls.
They also noted molecular changes in the cerebral cortex, the part of the brain involved in decision-making and memory that suggested signaling imbalances in neurons. Similar imbalances have been seen in patients with Alzheimer’s disease. The results were published in Nature in June.
A second explanation for cognitive issues is that COVID-19 may restrict blood flow to the brain and deprive it of oxygen. In patients who have died of COVID-19, researchers have found evidence of brain tissue damagecaused by hypoxia, or the lack of oxygen.
“The brain is an organ that requires a lot of oxygen to do its job,” says Billie Schultz, a physiatrist at the Mayo Clinic in Rochester, Minnesota, who specialized in rehabilitating stroke and traumatic brain injury patients before COVID-19 hit.
Other symptoms that accompany post-COVID-19 syndrome—pain, fatigue, and shortness of breath—can negatively affect cognition too, Schultz says. “It’s not just a brain issue; it's a multi-system body issue that needs to be addressed.”
The next health crisis
Schultz is hopeful that many people experiencing persistent cognitive issues from COVID-19 will eventually improve. Many stroke and traumatic brain injury patients experience spontaneous recovery, in which the brain heals itself within three to six months.
But others worry that cognitive issues caused by COVID-19 may lead to dementia. At the Alzheimer’s Association International Conference in July, scientists presented research showing that hospitalized COVID-19 patients had similar blood biomarkers, neurodegeneration, and inflammation to those with Alzheimer’s disease. The research has not yet been peer-reviewed.
Heather Snyder, vice president of medical and scientific relations at the Alzheimer's Association, cautions that the findings don’t necessarily mean someone who gets COVID-19 is more likely to develop Alzheimer’s or another type of dementia. “We’re still trying to understand those associations,” she says.
For now, there are no specific treatments for COVID-related brain fog, memory loss, and other cognitive effects. Instead, doctors are using cognitive therapy, occupational therapy, or speech-language pathology to treat symptoms. Many studies, like the NIH one, are trying to understand the underlying mechanisms of cognitive dysfunction in long COVID patients in hopes of identifying potential treatments.
“We and others are collecting anecdotal data from patients on what has helped them, but we are far from definitive therapeutics,” Frontera says.
In the U.S. alone, millions of people have developed lasting cognitive and neurological problems long after an initial COVID-19 infection. Some of these patients may be permanently disabled and need long-term care. “My concern is that we're going to have huge numbers of the population who aren't able to function at their cognitive baseline. They can't go back to work, or at least not to what they did before,” Frontera says. “We haven’t even thought of the long-term implications. It could be an incredible blow to the economy.”
Davis says the scariest part about COVID-19’s cognitive effects is that people of all ages and health status are affected. “This is something everyone is at risk for, and it's completely debilitating.”
Editor's Note: This article has been updated to correct the number of patients in studies regarding COVID-19 and cognition.