Even Mild Cases of Covid-19 Pose Serious Risks to Brain Health

By Dr. Ziyad Al-Aly

From the very early days of the pandemic, “brain fog” emerged as a significant health condition that many experience after COVID-19.

Brain fog is a colloquial term that describes a state of mental sluggishness or lack of clarity and haziness that makes it difficult to concentrate, remember things and think clearly.

Fast-forward four years and there is now abundant evidence that being infected with SARS-CoV-2 – the virus that causes COVID-19 – can affect brain health in many ways.

In addition to brain fog, COVID-19 can lead to an array of problems, including headaches, seizure disorders, strokes, sleep problems, and tingling and paralysis of the nerves, as well as several mental health disorders.

A large and growing body of evidence amassed throughout the pandemic details the many ways that COVID-19 leaves an indelible mark on the brain. But the specific pathways by which the virus does so are still being elucidated, and curative treatments are nonexistent.

Now, two new studies published in the New England Journal of Medicine shed further light on the profound toll of COVID-19 on cognitive health.

I am a physician scientist, and I have been devoted to studying long COVID since early patient reports about this condition – even before the term “long COVID” was coined. I have testified before the U.S. Senate as an expert witness on long COVID and have published extensively on this topic.

Here are some of the most important studies to date documenting how COVID-19 affects brain health:

• Large epidemiological analyses showed that people who had COVID-19 were at an increased risk of cognitive deficits, such as memory problems.

• Imaging studies done in people before and after their COVID-19 infections show shrinkage of brain volume and altered brain structure after infection.

• A study of people with mild to moderate COVID-19 showed significant prolonged inflammation of the brain and changes that are commensurate with seven years of brain aging.

• Severe COVID-19 that requires hospitalization or intensive care may result in cognitive deficits and other brain damage that are equivalent to 20 years of aging.

• Laboratory experiments in human and mouse brain organoids designed to emulate changes in the human brain showed that SARS-CoV-2 infection triggers the fusion of brain cells. This effectively short-circuits brain electrical activity and compromises function.

• Autopsy studies of people who had severe COVID-19 but died months later from other causes showed that the virus was still present in brain tissue. This provides evidence that contrary to its name, SARS-CoV-2 is not only a respiratory virus, but it can also enter the brain in some individuals. But whether the persistence of the virus in brain tissue is driving some of the brain problems seen in people who have had COVID-19 is not yet clear.

• Studies show that even when the virus is mild and exclusively confined to the lungs, it can still provoke inflammation in the brain and impair brain cells’ ability to regenerate.

• COVID-19 can also disrupt the blood brain barrier, the shield that protects the nervous system – which is the control and command center of our bodies – making it “leaky.” Studies using imaging to assess the brains of people hospitalized with COVID-19 showed disrupted or leaky blood brain barriers in those who experienced brain fog.

• A large preliminary analysis pooling together data from 11 studies encompassing almost 1 million people with COVID-19 and more than 6 million uninfected individuals showed that COVID-19 increased the risk of development of new-onset dementia in people older than 60 years of age.

Autopsies have revealed devastating damage in the brains of people who died with COVID-19.

Drops in IQ

Most recently, a new study published in the New England Journal of Medicine assessed cognitive abilities such as memory, planning and spatial reasoning in nearly 113,000 people who had previously had COVID-19. The researchers found that those who had been infected had significant deficits in memory and executive task performance.

This decline was evident among those infected in the early phase of the pandemic and those infected when the delta and omicron variants were dominant. These findings show that the risk of cognitive decline did not abate as the pandemic virus evolved from the ancestral strain to omicron.

In the same study, those who had mild and resolved COVID-19 showed cognitive decline equivalent to a three-point loss of IQ. In comparison, those with unresolved persistent symptoms, such as people with persistent shortness of breath or fatigue, had a six-point loss in IQ. Those who had been admitted to the intensive care unit for COVID-19 had a nine-point loss in IQ. Reinfection with the virus contributed an additional two-point loss in IQ, as compared with no reinfection.

Generally the average IQ is about 100. An IQ above 130 indicates a highly gifted individual, while an IQ below 70 generally indicates a level of intellectual disability that may require significant societal support.

To put the finding of the New England Journal of Medicine study into perspective, I estimate that a three-point downward shift in IQ would increase the number of U.S. adults with an IQ less than 70 from 4.7 million to 7.5 million – an increase of 2.8 million adults with a level of cognitive impairment that requires significant societal support.

Another study in the same issue of the New England Journal of Medicine involved more than 100,000 Norwegians between March 2020 and April 2023. It documented worse memory function at several time points up to 36 months following a positive SARS-CoV-2 test.

Memory and Cognitive Decline

Taken together, these studies show that COVID-19 poses a serious risk to brain health, even in mild cases, and the effects are now being revealed at the population level.

A recent analysis of the U.S. Current Population Survey showed that after the start of the COVID-19 pandemic, an additional 1 million working-age Americans reported having “serious difficulty” remembering, concentrating or making decisions than at any time in the preceding 15 years. Most disconcertingly, this was mostly driven by younger adults between the ages of 18 to 44.

Data from the European Union shows a similar trend – in 2022, 15% of people in the EU reported memory and concentration issues.

Looking ahead, it will be critical to identify who is most at risk. A better understanding is also needed of how these trends might affect the educational attainment of children and young adults and the economic productivity of working-age adults. And the extent to which these shifts will influence the epidemiology of dementia and Alzheimer’s disease is also not clear.

The growing body of research now confirms that COVID-19 should be considered a virus with a significant impact on the brain. The implications are far-reaching, from individuals experiencing cognitive struggles to the potential impact on populations and the economy.

Lifting the fog on the true causes behind these cognitive impairments, including brain fog, will require years if not decades of concerted efforts by researchers across the globe. And unfortunately, nearly everyone is a test case in this unprecedented global undertaking.

Ziyad Al-Aly, MD, is Chief of Research and Development at VA St. Louis Health Care System and a Senior Clinical Epidemiologist at Washington University in St. Louis.

Dr. Al-Aly’s laboratory was the first to produce evidence on the effects of vaccines on Long Covid, the health consequences of repeated infections with SARS-CoV-2, and the effect of antivirals on the short- and long-term outcomes of SARS-CoV-2 infection. He also co-chaired the Biden Administration committee that developed the National Research Action Plan for Long Covid.

This article originally appeared in The Conversation and is republished with permission.

Brain Changes Found in Patients with Long-Term Lyme Disease

By Pat Anson, PNN Editor

Researchers at Johns Hopkins University have documented changes in the brains of patients with post-treatment Lyme disease that may explain symptoms such as brain fog, memory loss and other cognitive issues. The finding could also have implications for patients with long covid, fibromyalgia, multiple sclerosis, chronic fatigue and other health conditions who have cognitive problems.    

Lyme disease is a bacterial illness spread by ticks that causes a rash, flu-like aches and fever, joint pain and fatigue. Most patients fully recover when treated early with antibiotics, but up to 20% of those with post-treatment Lyme disease (PTLD) have long-term symptoms, including depression, insomnia and cognitive difficulties. There is usually no clinical or laboratory evidence to explain their ongoing issues.

“Objective biologic measures of post-treatment Lyme symptoms typically can’t be identified using regular MRIs, CT scans, or blood tests,” says John Aucott, MD., director of the Johns Hopkins Lyme Disease Clinical Research Center.

Aucott and his colleagues recruited 12 PTLD patients and 18 people without a history of Lyme to undergo functional MRI (fMRI) scans while performing a short-term memory task. The scans allow investigators to track blood flow and other changes in the brain in real time.

Their findings, published in the journal PLOS ONE, suggest that cognitive difficulties in PTLD patients are linked to functional and structural changes in the “white matter” of the brain, which is crucial for processing and relaying information. The imaging tests revealed unusual activity in the frontal lobe, an area of the brain responsible for memory recall and concentration. Patients with post-treatment Lyme needed longer periods of time to complete the memory task.

“We saw certain areas in the frontal lobe under-activating and others that were over-activating, which was somewhat expected,” said lead author Cherie Marvel, PhD, an associate professor of neurology at Johns Hopkins.

“However, we didn’t see this same white matter activity in the group without post-treatment Lyme.”

To confirm their finding, researchers used another form of imaging called diffusion tensor imaging (DTI) on all 12 patients with Lyme and 12 of the non-Lyme participants. DTI detects the direction of water movement within brain tissue. Water was diffusing, or leaking, in the the same white matter regions identified in the fMRI.

Researchers believe the increased activity they saw in white matter may reflect an immune system response in the PTLD patients, which may also explain cognitive issues in patients with other chronic health conditions.

PLOS ONE

“Results reported here may have implications for other diseases in which white matter pathology has been demonstrated (e.g., multiple sclerosis) or in illnesses in which cognitive complaints follow disease onset,” researchers said. “The use of multimodal neuroimaging methods, like the ones used in the current study, may be a viable approach for obtaining information on brain function and structure to identify biomarkers of disease burden.”

Researchers say larger studies with more patients will be needed to confirm their findings, as well as long-term tracking of brain changes from the initial Lyme infection through development of PTLD.

Nearly 500,000 people are believed to get Lyme disease each year in the United States. Diagnoses of Lyme have soared over the past 15 years, according to a recent analysis of insurance claims that found Lyme cases rose 357% in rural areas and 65% in urban areas. The highest rates of Lyme were in New Jersey, Vermont, Maine, Rhode Island and Connecticut.

‘Cognitive Rehab’ May Help Clear Brain Fog

By Judith Graham, Kaiser Health News

Eight months after falling ill with covid-19, the 73-year-old woman couldn’t remember what her husband had told her a few hours before. She would forget to remove laundry from the dryer at the end of the cycle. She would turn on the tap at a sink and walk away.

Before covid, the woman had been doing bookkeeping for a local business. Now, she couldn’t add single-digit numbers in her head. Was it the earliest stage of dementia, unmasked by covid? No. When a therapist assessed the woman’s cognition, her scores were normal.

What was going on? Like many people who’ve contracted covid, this woman was having difficulty sustaining attention, organizing activities, and multitasking. She complained of brain fog. She didn’t feel like herself.

But this patient was lucky. Jill Jonas, an occupational therapist associated with the Washington University School of Medicine in St. Louis who described her to me, has been providing cognitive rehabilitation to the patient, and she is getting better.

Cognitive rehabilitation is therapy for people whose brains have been injured by concussions, traumatic accidents, strokes, or neurodegenerative conditions such as Parkinson’s disease. It’s a suite of interventions designed to help people recover from brain injuries, if possible, and adapt to ongoing cognitive impairment. Services are typically provided by speech and occupational therapists, neuropsychologists and neurorehabilitation experts.

In a recent development, some medical centers are offering cognitive rehabilitation to patients with long covid, who have symptoms that persist several months or longer after the initial infection. According to the Centers for Disease Control and Prevention, about 1 in 4 older adults who survive covid have at least one persistent symptom.

“Anecdotally, we’re seeing a good number of people make significant gains with the right kinds of interventions,” said Monique Tremaine, director of neuropsychology and cognitive rehabilitation at Hackensack Meridian Health’s JFK Johnson Rehabilitation Institute in New Jersey.

Among the post-covid cognitive complaints being addressed are problems with attention, language, information processing, memory, and visual-spatial orientation. A recent review in JAMA Psychiatry found that up to 47% of patients hospitalized in intensive care with covid developed problems of this sort.

Seniors More Vulnerable

There’s emerging evidence that seniors are more likely to experience cognitive challenges post-covid than younger people — a vulnerability attributed, in part, to older adults’ propensity to have other medical conditions. Cognitive challenges arise because of small blood clots, chronic inflammation, abnormal immune responses, brain injuries such as strokes and hemorrhages, viral persistence, and neurodegeneration triggered by covid.

Getting help starts with an assessment by a rehabilitation professional to pinpoint cognitive tasks that need attention and determine the severity of a person’s difficulties. One person may need help finding words while speaking, for instance, while another may need help with planning and yet another may not be processing information efficiently. Several deficits may be present at the same time.

Next comes an effort to understand how patients’ cognitive issues affect their daily lives. Among the questions that therapists will ask, according to Jason Smith, a rehabilitation psychologist at the University of Texas Southwestern Medical Center in Dallas: “Is this showing up at work? At home? Somewhere else? Which activities are being affected? What’s most important to you and what do you want to work on?”

To try to restore brain circuits that have been damaged, patients may be prescribed a series of repetitive exercises. If attention is the issue, for instance, a therapist might tap a finger on the table once or twice and ask a patient to do the same, repeating it multiple times. This type of intervention is known as restorative cognitive rehabilitation.

“It isn’t easy because it’s so monotonous and someone can easily lose attentional focus,” said Joe Giacino, a professor of physical medicine and rehabilitation at Harvard Medical School. “But it’s a kind of muscle building for the brain.”

A therapist might then ask the patient to do two things at once: repeat the tapping task while answering questions about their personal background, for instance.

“Now the brain has to split attention — a much more demanding task — and you’re building connections where they can be built,” Giacino explained.

To address impairments that interfere with people’s daily lives, a therapist will work on practical strategies with patients. Examples include making lists, setting alarms or reminders, breaking down tasks into steps, balancing activity with rest, figuring out how to conserve energy, and learning how to slow down and assess what needs to be done before taking action.

A growing body of evidence shows that “older adults can learn to use these strategies and that it does, in fact, enhance their everyday life,” said Alyssa Lanzi, a research assistant professor who studies cognitive rehabilitation at the University of Delaware.

Along the way, patients and therapists discuss what worked well and what didn’t, and practice useful skills, such as using calendars or notebooks as memory aids.

“As patients become more aware of where difficulties occur and why, they can prepare for them and they start seeing improvement,” said Lyana Kardanova Frantz, a speech therapist at Johns Hopkins University. “A lot of my patients say, ‘I had no idea this could be so helpful.’”

Johns Hopkins has been conducting neuropsychiatric exams on patients who come to its post-covid clinic. About 67% have mild to moderate cognitive dysfunction at least three months after being infected, said Dr. Alba Miranda Azola, co-director of Johns Hopkins’ Post-Acute COVID-19 Team. When cognitive rehabilitation is recommended, patients usually meet with therapists once or twice a week for two to three months.

Before this kind of therapy can be tried, other problems may need to be addressed. “We want to make sure that people are sleeping enough, maintaining their nutrition and hydration, and getting physical exercise that maintains blood flow and oxygenation to the brain,” Frantz said. “All of those impact our cognitive function and communication.”

Depression and anxiety — common companions for people who are seriously ill or disabled — also need attention. “A lot of times when people are struggling to manage deficits, they’re focusing on what they were able to do in the past and really mourning that loss of efficiency,” Tremaine said. “There’s a large psychological component as well that needs to be managed.”

Medicare usually covers cognitive rehabilitation, but Medicare Advantage plans may differ in the type and length of therapy they’ll approve and how much they’ll reimburse providers — an issue that can affect access to care.

Still, Tremaine noted, “not a lot of people know about cognitive rehabilitation or understand what it does, and it remains underutilized.” She and other experts don’t recommend digital brain-training programs marketed to consumers as a substitute for practitioner-led cognitive rehabilitation because of the lack of individualized assessment, feedback, and coaching.

Also, experts warn, while cognitive rehabilitation can help people with mild cognitive impairment, it’s not appropriate for people who have advanced dementia.

If you’re noticing cognitive changes of concern, ask for a referral from your primary care physician to an occupational or speech therapist, said Erin Foster, an associate professor of occupational therapy, neurology, and psychiatry at Washington University School of Medicine in St. Louis. Be sure to ask therapists if they have experience addressing memory and thinking issues in daily life, she recommended.

“If there’s a medical center in your area with a rehabilitation department, get in touch with them and ask for a referral to cognitive rehabilitation,” said Smith, of UT Southwestern Medical Center. “The professional discipline that helps the most with cognitive rehabilitation is going to be rehabilitation medicine.”

Kaiser Health News is a national newsroom that produces in-depth journalism about health issues.