In Conversation: The neurocognitive impact of long COVID
Accessed from the world wide web at 09:00 hrs 01.09.21.
For many people, long COVID has associations with serious neurological and neurocognitive impairments, a phenomenon sometimes known as neuro-COVID. Why does this happen, and who is most at risk? In this Special Feature and podcast, we speak to two researchers and a person with lived experience of neuro-COVID to find out more.
“Pointy orange things, and of course, they’re carrots. I was just struggling to search for the names of things.”
This is Dr. Kerry Smith, a family doctor from the United Kingdom, talking about her post-COVID symptoms. She has not worked for the past 18 months since contracting COVID-19 from a patient who had returned from Wuhan, China, with a fever and persistent cough.
Talking to Medical News Today, she explained why she has been unable to return to her job:
“The thing that’s really preventing me [from] going back to work as a [family doctor] is my cognitive issues or brain fog. Ummm [silence] Sorry, sorry, that’s it, you see, I lose my train of thought, Hilary [interviewer’s name, ed.], that’s the problem. With, with my brain fog, I have problems concentrating, keeping up with conversations, multitasking. I lose my train of thought easily. And I have difficulties with my memory.”
Dr. Smith has long COVID, which the Centers for Disease Control and Prevention (CDC) defineTrusted Source as “new, returning or ongoing health problems” occurring 4 weeks or more after contracting SARS-CoV-2, the virus that causes COVID-19.
As the COVID-19 pandemic progresses, there is growing awareness that around 1 in 3 people who tested positive for COVID-19 and who were usually not admitted to the hospital for treatment do not recover fully by 3 months.
An international studyTrusted Source of people with long COVID documented 203 different symptoms across 10 body systems. More than 88% of the 3,762 people who completed the online survey reported memory problems and cognitive dysfunction, making these the “most persistent and pervasive symptoms in this cohort, equally common across all age groups.”
Two-thirds (65%) reported experiencing symptoms for 6 months. Cognitive dysfunction was one of the top three most debilitating symptoms, alongside fatigue and breathlessness.
Brain fog is the most common symptom described by people with cognitive dysfunction following COVID-19 illness.
In this feature in the MNT: In Conversation series and associated podcast, Prof. Gabriel de Erausquin and Dr. Lavanya Visvabharathy discuss the latest research and hypotheses regarding long-term cognitive dysfunction after COVID-19.
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-COVIDTrusted Source 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.
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 TestTrusted Source 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
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 riskTrusted Source 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.