In Conversation: The neurocognitive impact of long COVID

What is long COVID brain fog?

Long COVID, post-COVID syndrome, or PASC (post-acute sequelae of COVID-19 infection) describe ongoing physical, cognitive, or both symptoms at least 6-12 weeks after having a positive test for COVID-19 or symptoms of acute COVID-19.

Some researchers and clinicians use the term neuro-COVID to describe the acute manifestations of COVID-19 in the brain, including the commonly occurring headache and loss of smell and rarer problems, such as stroke, encephalopathy, and Guillain-Barré syndrome.

Neuro-COVID in long-haulers, or long-neuro-COVID, describes the lasting neurological symptoms following acute infection with SARS-CoV-2. Those with neuro COVID usually complain of brain fog — the inability to think as clearly as usual.

Prof. de Erausquin cautioned against using a single term as people may develop neurocognitive symptoms with or without having severe or obvious symptoms of COVID-19 infection:

“The notion of long COVID assumes the person had acute COVID. So you are having a continuance of symptoms that has an onset at the time of the acute infection. The idea of neuro COVID, on the other hand, may or may not [imply] acute respiratory system illness; you may have de novo emergence of neurological symptoms, regardless of the status of the acute illness. So they don’t necessarily mean the same thing.”

The closest we get in medical terms to understand brain fog is that it represents a loss of executive function. It is a symptom that has associations with anxiety, as have many of the respiratory and cardiovascular symptoms of long COVID, such as breathlessness, palpitations, and dizziness.

The overlap with psychiatric diagnoses and post-viral fatigue has made it difficult for people with long COVID to obtain a formal cognitive assessment.

However, people who have post-COVID-19 symptoms are eight times more likely to have contracted the virus than people who have not and are three times more likely to have those symptoms consistently over 12 weeks.

Can we measure brain fog after COVID-19?

Dr. Smith never managed to get a formal test for her brain fog, but, in desperation, she turned to a new online study called the Great British Wellbeing Survey, which focused on how COVID-19 impacted brain function.

The research group responsible for the survey had previously designed the Great British Intelligence Test to map cognitive strengths in a general sample of people in England.

In response to the pandemic, the researchers added additional questions about health and COVID-19 infection. In total, 81,337 people, average age 46.75 years, completed the online tests and questionnaire. Of these. 12,689 (15.6%) had confirmed or suspected COVID-19.

The team found that even people who were no longer reporting symptoms had “significant cognitive deficits versus controls when controlling for age, gender, education level, income, racial-ethnic group, pre-existing medical disorders, tiredness, depression, and anxiety.”

The cognitive deficit was especially noticeable in those with worse respiratory symptoms, but it still occurred in those with no respiratory symptoms during the acute phase of the illness.

Because this research was a cross-sectional study, it could not establish that the cognitive deficit was the result of contracting COVID-19. In contrast, the U.K. Biobank study, which maps genetic and health data of 500,000 people over time, had invited a subset of people to have an MRI brain scan before the pandemic with subsequent follow-up scans.

The results have not yet undergone peer review, though they are available online in preprint form. By May 2021, the Biobank study had identified 401 participants who had tested positive for SARS-CoV-2 and who also had useable pre- and post-COVID-19 scans.

Most did not spend time in the hospital, representing a group of people with mild to moderate COVID-19 infection. The researchers matched these individuals to 384 other people who showed no evidence of COVID-19 and similar risk factors for COVID-19 infection.

Using fine-grain automated analysis of the brain scan images to pick up changes that would not be visible to the naked eye, the researchers found that compared to controls, participants who had COVID-19 showed:

• a greater loss of grey matter in the lateral orbitofrontal cortex
• an increase in signs of tissue damage in various regions in the brain, including in the brain’s smell center (the olfactory nucleus and tubercle)
• more signs of generalized brain atrophy.

Individuals who had COVID-19 also showed a larger cognitive decline on several cognitive function tests.

The authors explain that their findings strongly suggest that the loss of brain function is related to infection with SARS-CoV-2

Who is most at risk of neuro-COVID?

Prof. de Erausquin described two groups of patients from his clinics who showed different forms of neuro-COVID. The first group of younger individuals had a more severe respiratory illness in the acute phase. Over time, these patients tended to improve.

A second group he describes as more worrying. They tend to be over 60 years of age and have developed a “dementia-like” syndrome:

“And it’s a much more dense memory impairment, with a component of also executive dysfunction and language impairment. That is very reminiscent of Alzheimer’s disease.”

Links with genetic dementia risk

Dementia is a risk factor for severe COVID-19, increasing the chances of being hospitalized more than three times. Another study from the U.K. Biobank has shown a link between the ApoE e4 genotype, associated with Alzheimer’s disease and severe COVID-19.

A paper presented at the Alzheimer’s Association International Conference (AAIC) 2021 by Prof. M. Wisniewski showed that hospitalized patients with COVID-19 and neurological symptoms were more likely to have serum biomarkers of neuronal injury, neuroinflammation, and Alzheimer’s disease, indicating an acceleration of Alzheimer’s pathology.

Moreover, a study whose results appeared in Brain in October 2021 found a further link between the genetic risk for dementia and the risk of developing severe COVID-19.

Namely, a specific variant of the OAS1 gene — which influences the risk of Alzheimer’s disease — is also tied to an increased risk of severe COVID-19.

According to the study authors, this is because a lowered expression of OAS1 in microglia, a type of neural cells found in the brain and spinal cord, is associated with a heightened pro-inflammatory response at cellular level.

In a comment for Science Media Centre, Dr. David Strain, Senior Clinical Lecturer at the University of Exeter in the U.K., notes that “[t]his is robust research that supports some of the early observations that people with Alzheimer’s disease were at an increased risk of poor outcomes from COVID-19.”

“At first, we thought that was because people with dementia were less likely to be able to adhere to physical distancing and mask-wearing, or were exposed in their care institutions when there was a mass discharge from hospitals. However, even after adjustment for these risk factors, those with even early dementia were still at a much higher risk,” meaning that a biological mechanism was most likely at play, he explains.

Links with loss of sense of smell

Another study presented at this year’s AAIC linked loss of sense of smell with ongoing dementia-like symptoms in those who had a positive test for COVID-19. This corresponds with Professor de Erausquin’s opinion that in adults with a dementia-like syndrome, “persistent loss of sense of smell is a much better predictor of cognitive impairment than the severity of the acute illness.”

Prof. de Erausquin found in a group of 300 randomly selected older Argentine Amerindians (average age 66.7 years) that regardless of the severity of COVID-19, more than one-third (34.4%) had signs of multidomain cognitive impairment.

Impairments included severe short-term memory, semantic memory (ability to recall a word, concept, number), executive function failure, and reduced attention times.

The severity of the cognitive impairment correlated with the persistent loss of sense of smell, rather than the severity of acute illness as found in the younger age group studied in the Great British Intelligence study, suggesting different causal mechanisms of harm.

Further research, published in Science Translational Medicine, found that contrary to the accepted view that people with ongoing loss of smell no longer have active SARS-CoV-2 present; it was present inside cells of the olfactory epithelium up to 6 months after the initial acute infection.

Swab samples from the nose and throat were negative, but cells retrieved from the nasal cavity at the level of olfactory apparatus — the smelling organ in the nose — were 100% positive for SARS-CoV-2.

Could SARS-CoV-2 “travel” from the nasal cavity to various parts of the brain then? Dr. Visvabharathy was unsure.

“[T]he ability of the virus to invade and persist in other areas of the brain is much less supported [by existing evidence], at least in human studies,” she noted.

However, there are suggestions that the virus could reach the brain stem, the part that connects the cerebrum — the “bulk” of the brain — to the spinal cord.

“Because what we’ve seen with the previous SARS infection [epidemic] in China in 2002 and 2003 is that if you took post mortem [samples] from patients who had died from SARS, you could very readily detect a virus in the brain stem, whereas [in the case of SARS-CoV-2] it’s very up and down,” she explained.

Theories about how neuro-COVID happens

Many hypotheses seek to explain the pathological pathways for the long-term neurological effects of COVID-19. Generic explanations include fatigue post-illness, but these do not explain the changes in brain scans of individuals who have contracted SARS-CoV-2.

Another explanation focuses on post ITU syndrome, but studies show that these symptoms occur in people who have not spent time in the hospital.

Another suggestion for cognitive dysfunction is that microthrombi damage the brain when oxygen levels are low during the acute phase of the illness. However, while this may contribute to the risk, it does not explain the waxing and waning nature of the symptoms nor the ongoing signs of neuroinflammation.

Similarly, residual brain damage from an inflammatory response in the acute phase does not account for the pattern of symptoms and ongoing signs of inflammatory response in the brain.

Prof. de Erausquin and Dr. Visvabharathy discussed the two leading key hypotheses:

• neurotropism — direct infection of the brain with the virus, potentially precipitating protein misfolding and clumping of proteins similar to the pathological process that occurs in Alzheimer’s disease
• an inflammatory response possibly with an autoimmune or hyper-inflammatory component.

Neurotropism

A paper published in Naturein November 2020 confirmed the presence of intact SARS-CoV-2 particles together with their RNA in the olfactory mucosa.

The authors also found SARS-CoV-2 proteins along the olfactory tract and bulb in the brain and suggested this might be a route for the virus to infect the brain.

They also noted that it was very difficult to interpret single viral particles within individual neurons (brain cells).

Animal studies have shown widespread infection in the brain by SARS-CoV-2. However, because researchers genetically alter the animals to promote infection with the virus, they do not necessarily offer a good model for understanding how COVID-19 affects the human brain.

Several autopsy studies, including the recent studythat found evidence of disturbance of the blood-brain barrier and infiltration of T cells from outside the brain inside the functional area of the brain, have not found intact virus.

An alternative theory is that SARs-CoV-2 does, in fact, infect the brain — the olfactory bulb in particular — for just long enough to set off a chain of events, leading to disturbed protein production within neurons. The resulting protein clumps are similar to those found in Alzheimer’s disease.

Inflammation

Dr. Visvabharathy explained why she prefers an explanation of neuro-COVID that is based on invasion by T cells from the periphery or by secretions from these cells causing brain cell death of malfunction:

“In hyperinflammatory situations, you can have immune cells that can get into the brain and around the brain in the meningeal areas. And what can then happen is either through direct interaction of these immune cells with your brain cells or with basically these immune cells secreting various factors; both of these can impact brain function. There is a lot of evidence in other models to show that whether those secreted factors or the cells themselves getting into the brain actually induce cell death; basically, immune cells can kill cells that are important for brain function.”

Her original hypothesis was that SARS-CoV-2 instigated an autoimmune response where the body’s immune system turned on itself. She now thinks that ongoing low-grade infection outside the brain may explain what is happening.

She found evidence of sustained antibodies to the nucleocapsid body part of the virus — the N antibody — which usually wanes quickly after infection. The presence of this antibody confirms infection, as people who have immunity via vaccination will only have the S antibody to the spike protein.

“So basically, what that means is, if you have [the] anti-nucleocapsid antibody, you probably had [COVID-19] recently,” she explained. “In contrast, what we found was that with long COVID patients, the vast majority of them seemed to have [the] anti-nucleocapsid antibody for many, many, many months after their initial [COVID-19] diagnosis.”

Her research with Dr. Koralnik, currently shared as a preprint, shows that people with long-neuro-COVID symptoms have an abnormal memory T cell response insufficient to remove the virus.

‘The $1 million question’

We are in the very early stages of our understanding of this pandemic and its potential long-term consequences. Findings of cognitive harm from tests and scans in patients with even minimal symptoms in the early phases of the disease, albeit in small numbers, can have a major impact when multiplied to a whole population level.

The two researchers who spoke to MNT considered what actions people could take to address these long-term problems. Prof. De Erausquin advised maintaining brain health through the Mediterranean diet, exercise, and social interaction.

From the perspective of scientific research, Dr. Visvabharathy advised increased testing and searching for active ongoing infection with the virus and research into therapies to block viral replication.

This would involve not just the collection of nasal cell swabs but additional tests, including stool samples, to check if the virus could be present in other parts of the body.

“I think what this kind of tells me from a molecular perspective is that similar to what was done with HIV; perhaps we could do research into understanding how to block viral replication as a therapy. The first question is to say, do long COVID patients have [the] virus in them for a long period of time, and can we find that out by a test?”

– Dr. Lavanya Visvabharathy

Dr. Smith asked a final brave question: “People like myself who’ve got cognitive dysfunction following COVID-19 infection — will we get early onset dementia or Alzheimer’s?”

Professor de Erausquin replied with honesty that, at present: “That’s the $1 million question. I wish I could answer it for her, either positive or negative.”

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