Long COVID Brain Fog Isn’t “All in Your Head.” Scientists Now Know the Cause.

  

REMEMBER COVID? PLENTY of people have already moved past the lockdowns, social distancing, and other protective measures. But for people with long COVID—symptoms that continue to linger for months or years—the pandemic isn’t over.

According to the World Health Organization, for every 100 people infected, 6 developed long COVID. One of the most common and debilitating symptoms was brain fog—severe difficulty in thinking or concentrating. For years, researchers have tried to uncover the mystery behind this debilitating symptom. And finally we have some answers.

A new study published in Brain Communications earlier this month pinpoints the first biological evidence to explain why long COVID brain fog happens, and potentially provides a new target for treatments.

The study identified changes in a type of receptor in the brain called AMPA, which help brain cells communicate with each other and are important in connections related to memory and learning. Changes in AMPA receptor activity have been previously associated with depression, schizophrenia, and dementia.

Since people with brain fog have trouble processing and remembering information, the researchers of the new study hypothesized that COVID may have disrupted AMPA receptor activity.

The team used a new type of PET imaging brain scans to examine the number of AMPA receptors in living human brains of 30 people with long COVID. They compared their brain scans to 80 individuals without long COVID.

Amongst people with long COVID, there was an abnormally high density of AMPA receptors. And the more AMPA receptor activity there was, the more severe people reported their cognitive impairments.

“This is a potentially promising study that raises an interesting hypothesis about a risk factor for mild cognitive impairment ("brain fog"). The specific receptor (AMPA) seems to be upregulated in this small cohort of patients who have brain fog, and normal in healthy controls,” says Deepak Nair, MD, a neurologist at OSF Healthcare in Illinois who was not involved in the study.

Increases in AMPA activity is only one half of the story. The other half is something researchers have long suspected—that COVID infections provoke an overactive brain immune response.

In the study, they found several inflammatory markers linked to increases in AMPA receptor levels. According to the researchers, the immune response may be behind these changes in AMPA receptor numbers.

Keep in mind, this new study is in its early phases. Dr. Nair notes it would have been helpful to know if the control group—people who did not have long COVID—had prior COVID infections and how that might have affected the results. Still, the new findings align with research from earlier this year that found people with brain fog experience chronic inflammation.

So where does this leave people who are currently still dealing with long COVID brain fog? The study didn’t make or suggest a new treatment but instead could provide scientists with guidance on what to target. For example, doctors may want to prescribe drugs that block AMPA receptor activity to lessen brain fog symptoms.

"Our findings clearly demonstrate that long COVID brain fog should be recognized as a legitimate clinical condition,” adds Takuya Takahashi, a professor at Yokohama City University in Japan and senior study author. “This could encourage the healthcare industry to accelerate the development of diagnostic and therapeutic approaches for this disorder."

 

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You Could Have Long COVID and Not Even Know It

t took a long time for Rachel Bean to fully accept that she has Long COVID. Bean, 35, caught the virus in May 2020, when most experts were still saying that COVID-19 either causes life-threatening illness or milder symptoms that resolve within a few weeks. Bean’s acute case was asymptomatic—so as time passed and she felt unwell, with a rapid heart rate and unrelenting fatigue, she figured there had to be another explanation.

Then, in August 2020, she joined an online Long COVID support group and found that plenty of other people hadn’t fully recovered from COVID-19, either. But many of their symptoms seemed different than hers, so she kept pushing through. Finally, in late 2020—shortly before her illness forced her to leave her job as a social worker—Bean asked her doctor to refer her to a Long COVID treatment clinic.

Today, Bean is struck by how many people still don’t realize that their health issues could be signs of Long COVID. She’s talked to people who insist they’ve fully recovered from COVID-19, but also complain of classic Long COVID symptoms like fatigue and cognitive dysfunction. “People aren’t necessarily connecting the dots,” Bean says.

Experts say that lack of recognition could be causing some Long COVID cases to go undiagnosed. “People are bad at correlation if they’re not thinking about it all the time,” says Hannah Davis, a machine learning expert who is part of the Long COVID Patient-Led Research Collaborative. “When you had COVID…and then two months later you stop being able to drive, you’re not necessarily going to tie it to that.”

Not every health issue is a sign of Long COVID. Thousands of people around the world are diagnosed with COVID-19 every day, and many recover without lingering issues. Others experience health problems following but unrelated to their infections, because all the things that made people sick before the pandemic haven’t gone away.

But Long COVID affects more people than many realize. In the U.S. alone, roughly one in five adults with a known previous case of COVID-19 currently has Long COVID symptoms, according to a recent data from the National Center for Health Statistics. Others could be living with the condition without realizing it.

Testing for COVID-19 is now as easy as swabbing your nose at home. Diagnosing Long COVID is more complicated, as no single test can detect it.

Public-health groups define the condition slightly differently, but their criteria usually boil down to having symptoms that didn’t exist prior to a confirmed or suspected SARS-CoV-2 infection, last at least a couple months after infection, and can’t be explained by anything else.

In the summer of 2020, an estimated half of cases weren’t formally diagnosed, according to an article  co-authored by U.K. researcher Trish Greenhalgh. It’s hard to say exactly what that percentage is today, but it’s probably still significant. There are an estimated 2 million people with Long COVID in the U.K., which by Greenhalgh’s estimate means each full-time general practitioner there cares for about 65 long-haulers. But fewer are properly diagnosed, due to factors like patients not seeking care, doctors missing the condition, or doctors entering it into patient records as something else, she explains

Elisa Perego, an honorary research fellow in archaeology at University College London who is credited with coining the term “Long Covid” to describe her own condition, says there’s another problem: many people genuinely have no idea they might have Long COVID.

Policymakers, public-health officials, and the media “have often portrayed covid as a short, flu-like disease, especially in the young,” Perego wrote in an email. As a result, people might not make the connection between a case of COVID-19 and health issues months later, especially if they had a mild initial illness or are fully vaccinated; other people may have been asymptomatically infected or got a false-negative test result, so they don’t know they had COVID-19 at all.

Long COVID also isn’t always a linear condition. Some people catch COVID-19 and never fully recover, while others seem to get better and then relapse—sometimes multiple times.

There’s also a common misconception that Long COVID symptoms are a continuation of the issues people experience right after getting sick, like coughing or fever. That’s the case for some people, but many others develop new symptoms, including fatigue, chronic pain, and neurological or cognitive issues. “It is commonly more than one symptom and commonly more than one system in the body,” says Nisreen Alwan, an associate professor in public health at the U.K.’s University of Southampton who has had Long COVID herself.

These symptoms are also often oversimplified. Labels like “fatigue” or “brain fog” don’t always capture the more distinctive experiences of long-haulers—like crashing after physical activity (known as post-exertional malaise) or experiencing cognitive dysfunction such as memory loss. Plus, media coverage doesn’t always reflect the range of severity associated with Long COVID, focusing on only the most dire cases. If people don’t see their experiences reflected in news articles or lists of symptoms, they might assume something else is going on, Alwan says.

Research shows that more people are found to have post-COVID fatigue and cognitive impairment when studies screen for these symptoms using objective, as opposed to subjective or self-reported, measures. That finding suggests some people either miss or minimize their own symptoms, Davis says.

People of color seem most likely to be missed, says Dr. Zeina Chemali, director of neuropsychiatry clinics at Massachusetts General Hospital and co-author of a recent study on Long COVID symptoms. Three-quarters of the people in her study were white, educated women, which “speaks volumes about the disparities in care and access,” she says.

While some people don’t realize they could have Long COVID, others refuse to accept it—and ableism plays a part in that, Perego says. “Discrimination of disabled people in society and the fear of being permanently ill may render it more difficult to accept prolonged disease and the risk of never recovering,” she wrote.

Almost all long-haulers experience stigma at some point, according to a study. Alwan co-authored that has yet to be peer-reviewed. That could mean stigma from others—like loved ones being uncomfortable with or not believing a Long COVID diagnosis—or internalized stigma, like being embarrassed about one’s illness or physical limitations.

The medical establishment often doesn’t make matters easier, as some patients still face disbelief or a lack of knowledge from their doctors. “This is an area where you really have to be on top of research,” Davis says. “Your average clinician just doesn’t seem to be doing that,” which leads to cases being missed, dismissed, or misunderstood.

Even people who are correctly diagnosed with Long COVID don’t have great treatment options; there is no known cure for the condition, though some of its associated symptoms can be managed. But Alwan says getting a diagnosis is important for other reasons. It could make people eligible for disability benefits and sick pay, and a diagnosis might prompt a patient’s physicians to do more thorough physical exams that could uncover treatable issues.

Better recognition, diagnosis, and public education about Long COVID could help people who might currently be suffering in silence. “The fear is that you might be missing those most in need of support,” Alwan says. “It might be that people recognizing they’ve got Long COVID are not the only people who really need access to care.” 

 

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Golden-Age Fatigue: Why Does it Happen?

Susan K. Smith of Louisville was caught off-guard by the relentless fatigue that hit her after her stage 4 lung cancer diagnosis in early 2020. Initially, Smith, now 77, considered it might be depression. It was a herculean task just to get dressed every morning. On some days, even getting out of bed seemed impossible. 

 

But as she started to organize her affairs, Smith realized something else was at play. No matter how much she slept, she woke up feeling drained. She was exhausted, even if she didn't do much during the day. 

 

 "When people told me, 'It's just old age.' it didn't help at all. It made me feel there was nothing I could do mentally or physically to manage this," she explained.

Fatigue is a frequent symptom of many diseases that afflict the elderly, such as heart disease, cancer, rheumatoid arthritis, lung disease, kidney disease, and neurological conditions like multiple sclerosis. According to a 2021 review by researchers at the University of Massachusetts, it's one of the primary symptoms associated with chronic illness, affecting 40% to 74% of older people living with these conditions.

This goes beyond the tiredness after an extremely busy day or a sleepless night. It's a persistent feeling of exhaustion that envelopes the whole body, even without physical exertion. "I feel like a spent battery almost all the time," said a user named Amanda in a Facebook group for people with polycythemia vera, a rare blood cancer. "It's like being a thoroughly squeezed-out sponge." 

 

Dr. P., a research scientist at the Regenstrief Institute in Louisville and a professor at the University of Louisville School of Medicine, said that fatigue isn't about being tired for a day; it's about weeks or even months of tiredness. 

 

When he and his team surveyed nearly 3,500 older patients at a primary care clinic in Louisville about distressing symptoms, 55% mentioned fatigue — second only to musculoskeletal pain (65%) and more than back pain (45%) and shortness of breath (41%).

Meanwhile, a 2010 study in the Journal of the American Geriatrics Society estimated that 31% of people aged 51 and older had experienced fatigue in the past week. 

 

The consequences can be severe. Fatigue is the leading cause of limited activity in people aged 70 and above, according to a 2001 study by Yale researchers. Other studies have associated fatigue with impaired mobility, limitations in performing daily activities, the onset or exacerbation of disability, and premature death. 

 

Often, older adults with fatigue reduce their activity level and become deconditioned, leading to muscle loss and weakness, which intensifies fatigue. "It creates a vicious cycle that can lead to things like depression, which further increases fatigue," said Dr. Amy Harmon, a professor of medicine and chief medical officer at the University of Colorado Hospital. 

 

To break this cycle, Smith developed a strategy after learning her lung cancer had returned. Every morning, she set small goals. One day, she would get up and wash her face. The next, she would take a shower. Another day, she would go grocery shopping. She would rest after each activity.

In the three years since her cancer recurrence, Smith's fatigue has been relentless. But she said, "I'm doing better now" because she has learned to pace herself and find things that drive her, like teaching a virtual class to aspiring teachers and exercising under a personal trainer's supervision.

When should elderly individuals be concerned about fatigue? "If a person was doing fine but now feels constantly tired, it's crucial to get an evaluation," advised Dr. Jennifer Wilson, a physician at Scripps Mercy Hospital in San Diego and the incoming board president of the American Academy of Hospice and Palliative Medicine. 

 

"Fatigue is a warning signal that something is off in the body, but it's seldom one thing. Typically, several issues need addressing," noted Dr. Rohit Patel, section chief of the Center for Geriatric Medicine at the Cleveland Clinic. 

 

 He listed several factors doctors should investigate: Are thyroid levels normal? Is sleep a problem? Are underlying medical conditions well managed? Is there an underlying infection? Is there chronic dehydration? Is there anemia or an electrolyte imbalance? Are testosterone levels low? Is protein intake sufficient? Have feelings of anxiety or depression increased? Could current medications be causing fatigue? 

 

"Even if the medications and dosages haven't changed, your body's ability to process those medications and remove them from your system might have," Patel said, pointing out that such metabolic changes are common as people age. 

 

Many potential fatigue contributors can be addressed. However, often, fatigue can't be attributed to an underlying medical condition. 

 

This was the case for Lydia Gonzalez, 64, a retired nurse living just outside of Portland, Oregon. On a December trip to Arizona, she suddenly found herself winded and extremely tired during a hike, despite being fit. After being diagnosed with an asthma flare-up at an urgent care facility and prescribed steroids, she didn't find any relief. 

 

 Soon, Gonzalez was spending most of her day in bed, overwhelmed by intense tiredness and weakness. Even minor activities exhausted her. But none of the medical tests she received in Arizona or back in Portland — including a chest X-ray and CT scan, blood work, and a cardiac stress test — revealed anything abnormal. 

 

 "It's hard for anyone to believe you're ill when there's no objective evidence of disease," she shared with me.

Gonzalez began frequenting long covid websites and chat rooms for chronic fatigue syndrome sufferers. She now believes she has post-viral syndrome from an infection. The Centers for Disease Control and Prevention report fatigue that hinders daily life as one of the most frequent symptoms of long covid. 

 

Several strategies exist for managing persistent fatigue. For cancer patients, Dr. Jason Fowler, an associate professor of palliative medicine at the University of Kansas Health System, said, "the best evidence supports physical activities like tai chi, yoga, walking, or low-impact exercises." The goal is to "gradually expand patients' stamina," he mentioned. 

 

For long Covid, though, overdoing it too soon can result in "post-exertional malaise." It's often advised to pace activities: do only what's most important when energy levels are at their peak, and rest afterward. "You learn how to set realistic goals," said Dr. Mark Ashton, senior education advisor at the Center to Advance Palliative Care. 

 

Cognitive behavioral therapy can help the elderly with fatigue learn to adjust expectations and tackle intrusive thoughts like, "I should be able to do more." At the University of Texas MD Anderson Cancer Center, plans for managing fatigue in older patients typically include strategies to address physical activity, sleep health, nutrition, emotional health, and support from family and friends. fatigue among seniors.

"Much of managing fatigue is about developing new habits," pointed out Dr. Sarah Green, a palliative care and integrative medicine physician at MD Anderson. "It's crucial to understand that this doesn't occur instantly: It takes time."

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Coronavirus: Abnormal proteins which cause Alzheimer's could be responsible for COVID-19 neurological symptoms, blood clots; study says

Finding cause behind complicated COVID-19 symptoms

The cause of the many mysterious and lingering symptoms brought on by COVID-19 has remained a difficult puzzle for scientists and health professionals. Researchers have been looking into various systems in the body to find the cause behind various short-term and long-term symptoms caused by SARS-CoV-2, the virus that causes COVID-19.

A recent study, published in the Journal of American Chemical Society, has provided a suggested mechanism to explain why some people develop complicated COVID-19 symptoms after infection. One such symptom has been micro clots in people with long COVID.

Researchers of the new study found that amyloids, the abnormal proteins that are also known to cause Alzheimer’s, could be formed during SARS-CoV-2 infection, which could explain some of the symptoms experienced. The research suggests that the immune system’s interaction with SARS-CoV-2 may be resulting in blood clots and neurological symptoms, due to the production of these misfolded spike proteins.

​Health problems caused by amyloids

Amyloids are fibrous, abnormal protein structures that can build up in the body. These amyloids are present in a variety of disorders, such as Alzheimer’s disease, a condition that affects thinking and memory. Certain amyloids are also associated with several other health problems, such as – cardiac arrhythmias (Improper beating of the heart when electrical impulses in the heart don't work properly), atherosclerosis (buildup of fats, cholesterol and other substances in and on artery walls), type 2 diabetes mellitus (a chronic disease characterized by high levels of sugar in the blood) and rheumatoid arthritis (an autoimmune and inflammatory disease wherein the immune system attacks healthy cells in the body by mistake).

​About the study

In the present study, researchers sought to examine if the spike protein in SARS-CoV-2 could be converted to amyloids in the body. The spike protein or S-protein plays a major role in the virus’ transmission and evolution. The researchers found that several components of the S-protein could potentially produce amyloids.

When the study authors combined the S-protein in vitro with neutrophil elastase—a proteolytic enzyme (protease) that is produced in the human body by a type of white blood cell released early in SARS-CoV-2 infection called neutrophils—the researchers found that the S-protein broke up into sections that could lead to amyloid production. They also found that combining the S-protein with protease neutrophil elastase formed amyloid-like fibrils. Further research in this study looked at the relationship between the S-protein and blood clot formation.

​What does this mean?

Study author Sofie Nystrom explained that under normal circumstances, when we get an injury, fibrinogen (that we have in our bloodstream) is transformed into fibrin to form clots. To prevent ‘overclotting,’ there is another blood component, plasmin, that will dissolve the fibrin clots when there are enough and ultimately get rid of all fibrin when it is not needed anymore. “Our experiment shows that if fibrin is formed in the presence of spike amyloid, the plasmin can not totally remove the fibrin clots.”

​More research needed

Dr. Arturo Casadevall, an infectious disease expert at John Hopkins University in Baltimore, who was not involved in the study, has expressed skepticism about amyloid production being the cause of the neurological side effects seen in people with COVID-19. “To infer that these amyloid structures are responsible for the neurological effects is too speculative at this time simply because there is no evidence that such structures are produced during human infection.” The findings of the study don’t infer that COVID-19 infection increases a person’s risk of developing dementia.

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