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expert reaction to preprint suggesting patients who recovered from COVID-19 could suffer serious cognitive decline

A preprint (unpublished non-peer reviewed paper) posted to MedRxiv, looked at cognitive deficits in people who have recovered from COVID-19.


Prof Joanna Wardlaw CBE, Professor of Applied Neuroimaging, Honorary Consultant Neuroradiologist, Head of Division, University of Edinburgh, said:

“While COVID-19 infection may affect cognitive function through its effects on the brain endothelium, the results of this study require some cautious interpretation. The cognitive function of the participants was not known pre COVID, and the results also do not reflect long term recovery so any effects on cognition may be short term. Premorbid cognitive ability is a powerful risk factor for stroke, cerebral small vessel disease and various other common neurological and vascular disorders, independent of vascular risk factors and education. It’s possible that the study has mainly detected a relationship between COVID infection and premorbid cognitive ability that is consistent with what we already know about risk profiles for symptomatic including severe COVID infection.”


Prof Derek Hill, Professor of Medical Imaging Science, UCL, said:

“This research – which is still undergoing peer review and has not yet been published – involves testing the cognition of people who have recovered from COVID-19, and comparing the results on those tests with a group of matched normal controls. Cognitive tests measure how well the brain performs certain tasks – like remembering words you heard a few moments earlier, or joining dots on a puzzle. Such tests are widely used to assess brain performance in diseases like Alzheimer’s, but cognitive tests can also assess temporary impairment of brain performance, for example due to tiredness, alcohol or certain medicines.

“This study involves more than 80,000 people, who self-reported their COVID symptom severity, the treatment they received for COVID (if any) and whether or not they had a positive COVID test. Statistical analysis was used to determine whether the cognitive performance was linked to symptom severity and treatment received. The authors found that COVID – especially severe COVID – was associated with worse performance on cognitive tests.

“This result must be treated with great caution. First of all, the study is based on individuals reporting their own symptoms, and only a tiny fraction had a positive COVID test. There is likely, therefore, to be some uncertainty about the reliability of the information about severity of symptoms.

“Secondly, this is what is called a “cross sectional” study. It does not look at whether COVID makes your cognition worse – it instead looks at whether people who have recovered from possible COVID do worse on the cognitive test than a control group. This type of methodology is more subject to error than a longitudinal study that looks at the same people before and after an illness.

“Thirdly, it is not clear whether the impaired cognition was permanent or not – it is well documented that many COVID symptoms can last months after the end of the serious part of the illness, and any cognitive deficit may eventually be reversed. Also, there is no comparison with people who suffer from other respiratory illnesses like flu – is this long term effect on cognition different from flu?

“Finally, there is no investigation of the biological effect on the brain, e.g. does COVID result in brain shrinkage? This approach is widely used to understand the biology underlying change in cognitive performance – for example, it is well known that cognitive decline in Alzheimer’s disease is associated with shrinkage of the brain as determined by MRI scans.

“Overall an intriguing but inconclusive piece of research into the effect of COVID on the brain. As researchers seek to better understand the long term impact of COVID, it will be important to further investigate the extent to which cognition is impacted in the weeks and months after the infection, and whether permanent damage to brain function results in some people.”


Dr David Strain, Senior Clinical Lecturer, University of Exeter, said:

“This manuscript suggests that the brains of people that have had COVID have aged approximately 10 years compared to those that haven’t – this is much worse than we usually see with other post viral syndromes. The main caveat is that it is cross sectional rather than longitudinal – i.e. it doesn’t show that individuals age quicker, it shows that people who’ve had it are biologically older. It’s a very small difference, but it’s entirely possible that people who start out with lower levels of brain function are more likely to catch it and/or have a bad outcome from it. An equally plausible hypothesis – an individual’s ability to reason predicts adherence to face masks, hand hygiene and social distancing. A lower IQ may mean more social interaction, less wearing face masks, higher viral loads and a higher likelihood to get really unwell. This is in keeping with the QCOVID report that pre-existing dementia is a really strong predictor of poor outcome if you catch COVID.

“Cognitive decline after severe infection is well recognised. The mechanisms for this are many-fold, through inflammation, oxidative stress (i.e. the body detects something is wrong and tries to do something about it, but overshoots and ends up damaging itself), lack of perfusion into the microcirculation (the smallest blood vessels that do most of the oxygen delivery and waste product removal), and hypoxia – reduced oxygen into the blood. This persists for at least five years and may be a lifelong step down in function. One manifestation that we see regularly in hospital is delirium during the acute infection. (Delirium is an acute and fluctuant alteration in mental function during an infection). COVID was associated with a degree of delirium that was substantially higher than we have seen in other similar viral illnesses. It also persisted much longer than previous experience would have predicted. Delirium is at one end of the spectrum of a virus affecting the brain. Knowing that this was much higher, it makes sense that all of the effects on brain function were more common, and this paper does talk about a ‘dose dependency’ type of effect (i.e. the more severe the original illness, the more the brain appears to be affected).

“With regards to the ‘long COVID’ symptoms, brain fog – which is effectively an individual not being able to function where they were previously – is the most common symptom that people are talking about in our study as well as being common in patients presenting to the long COVID services. This paper will certainly resonate with all of those affected. As to whether this is more common or more severe than in other post viral illnesses, it’s difficult to say, as the extremes are more likely to get referred or participate in these trials.”



* ‘Cognitive deficits in people who have recovered from COVID-19 relative to controls: An N=84,285 online study’ by Adam Hampshire et al. was uploaded to medRxiv on 21st October 2020. This paper has not been peer-reviewed.



All our previous output on this subject can be seen at this weblink:



Declared interests

Prof Derek Hill: “No conflict of interest.”

None others received.

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