EXPERT REACTION: “Significant” brain changes documented after mild COVID-19

This is a landmark study. Not only does it document the impact of the SARS-CoV-19 virus on brain tissue, but it also demonstrates the tremendous scientific potential of big data analytics applied to brain MRI scans.

Surely, this should serve as a wake-up call for Australia to acquire all imaging data in a standardised and reproducible way, on calibrated instruments, and collect these data in an Australian imaging biobank.

This will enable advanced data analytics to open new avenues for diagnosis, treatment monitoring, and possibly even prevention of diseases.

This landmark study shows that people who experience even mild COVID can have brain changes months after their infection. These were mainly shown in areas of brain scans involved in smell and memory. Losses were more marked in older individuals (~> 60-70 years old).

Given COVID is now widespread in the general population further research is key to determine whether these changes persist in the longer term, whether these brain changes also occur with the omicron variant, and whether vaccination status can protect against these changes.

This study indicates that even in patients with mild infections, long COVID can include neurological consequences. Further research is needed to help us examine whether in addition to smell, other neural sensory systems such as sight may also be effected, the latter is an area our group is investigating.

Douaud and colleagues have accessed the UK Brain Biobank and found individuals who had already had brain scans prior to the COVID-19 pandemic. They then found 401 of these individuals who had subsequently returned a positive COVID diagnosis within an average of 38 months, either via their health records or reports from two consecutive rapid antigen tests. They found that SARS-CoV2 infection results in a 1.3-1.8% loss of grey matter in the brain, compared to an estimated loss of ~0.2% of brain volume per year in normal middle-aged individuals. These changes are associated with decline in cognition, with affected individuals taking longer to answer questions in standard cognitive tests.

The unique aspect of this study is that the authors have assessed brain images of the same individuals before and after COVID-19 infection, therefore eliminating the possibility that any findings could be due to pre-existing brain changes. It is also interesting that although the severity of the disease was not documented for each individual, there were no significant differences amongst 15 of these individuals who were hospitalised due to COVID-19. This suggests that any episode of SARS-CoV2  infection, whether resulting in severe disease requiring hospitalisation or not, can cause brain damage. It remains to be determined whether the Delta variant and all other subsequent variants of the virus have caused similar or worse damage to the brain.

The results from this article are unfortunately what we expected. Numerous pathogens are now known to be able to enter the brain using the olfactory nerve within the nasal cavity, and they can contribute to a range of neurological and neurodegenerative conditions including stroke and Alzheimer’s disease. It is still not certain whether SARS-CoV-2 virus can enter the brain, but at a minimum it certainly can destroy the nerve cells responsible for the sense of smell which may then set off a cascade of events that lead to pathologies further in the brain. We suspected that there would be deficits in the brain for patients with severe illness.

However, this paper has focused on people with mild COVID-19 and shows that they have significant deleterious decreases in the size of various brain regions, and not just in those regions associated with the sense of smell, but in other regions too. The patients also had cognitive decline which may explain the long-COVID brain fog that so many people report. What we still don’t know are the long-term effects such as whether there will be ongoing deficits that lead to chronic illnesses or neurodegeneration – I hope not, but I suspect there will be.

The study is rigorous in its methodology, controlling for thousands of confounding variables. It uniquely captures the effects of COVID-19 on the brain via access to a large (785 in total, 401 who’d had COVID-19 and matched to a control sample) middle-aged UK population who had been brain scanned and cognitively assessed three years prior to, and five months after, infection. The study provides strong evidence of a subtle reduction in brain size (ranging from 0.2 per cent to 2 per cent), particularly in frontal and temporal brain regions important to cognitive abilities such as self-control and memory. For comparison, adults in the sample age range would usually show reductions of 0.2 per cent per year.

The subtle brain changes however were not associated with declines in cognitive performance overall, although a subtle decline was found in speed of thinking, but are of a level that would be unlikely to affect everyday function (or potentially be noticed). The limited period for follow-up makes it unclear whether these changes are recoverable. The study findings also appear to suggest that the brain and cognitive declines were related to the severity of COVID-19 illness, although only a small study sub-group had been hospitalised (15 people). Given the timing of the study, none of the sample are believed to have been infected with the Delta variant.

This excellent study of brain scans before and after a COVID-19 infection reveals that the brain is damaged by the infection, even in mild cases. The brain loses some mass and the shrinkage occurs in areas that are reminiscent of the changes seen in Alzheimer’s disease and Parkinson’s disease.

While the changes are not large over the three years of the study, they are accompanied by a loss in cognitive processing. The cognitive losses appear to be similar to accelerated ageing. These are troubling findings, which indicate that the brain is not spared damage in COVID-19, and potentially could be at risk of dementia with time. More work is needed to understand the biological mechanism that damages the brain in COVID-19 to see whether there might be any treatment ideas possible.

This new study provides some of the strongest evidence yet that infection with the SARS-CoV-2 virus (which causes COVID-19) can affect brain structure and function, and associated cognition. It utilises the power of the UK Biobank, so that a large group (approximately 800 people) having had two brain (MRI) scans were divided into those who were infected with SARS-CoV-2 between brain scans, and those who did not. Key questions arising from this new study include whether the brain (and cognitive) changes were directly due to the virus invading the brain, versus inflammation in the body spreading to the brain (‘neuro-inflammation’), accelerated neurodegeneration or perhaps even sensory deprivation (loss of taste and smell are highly common symptoms of COVID-19).

However, there are other potential causes of these brain changes in those 401 individuals (aged 51-81 years) who were infected with SARS-CoV-2. COVID-19 can be highly stressful, and we know that chronic stress can cause reduction in volume of some brain regions. There may have been other shared aspects of experience in those infected with SARS-CoV-2, such as reduced physical activity (during and after illness), which has also been associated with decreases in specific brain regions.

Further relevant questions include whether COVID-19 could increase risk of degenerative brain disorders such Parkinson’s disease, Alzheimer’s disease and other forms of dementia. It is essential that further research is urgently carried out, regarding our understanding of ‘neuro-COVID’, ‘long COVID’ and other chronic consequences of the global COVID-19 pandemic.

The difficulty in understanding the effects of a disease is that you don’t ordinarily have data collected prior to disease onset, so it is difficult to say definitively whether research findings reflect that disease. This research leverages the large-scale UK Biobank, which is a collection of health data and imaging such as MRI scans amassed from volunteers over the previous years.

This research is really novel because the scientists could compare MRI scans from people who had previously joined the UK Biobank study to their MRI scans after a mild COVID-19 infection. This group was then directly compared with matching before-and-after MRI sets of people who did not have COVID-19, to allow researchers to determine the effects of mild COVID-19 infection on brain structure and cognition.

The findings of the study are remarkable. The authors show that people who had mild COVID-19 infection an average of five months prior had thinning of brain tissue in several key brain regions including those related to behaviour and emotion, as well as those located close to the nose. They also had alterations in their white matter connections between different brain regions, and slight decreases in cognitive function.

These findings may also apply to Australians, but people need not panic if they have had COVID-19. The brain changes observed were relatively small and on a group level, so not everyone had the same effects. More research is needed to know whether these changes remain, reverse or get worse over time, and whether there are treatments which could help.

Despite the various challenges that inevitably lead to some shortcomings, this is as good a study as is possible to evaluate the effects over time of SARS-CoV-2 infection on the brain after supposedly ‘recovering’ from COVID-19. The existence of baseline data prior to the pandemic has been a boon that the authors have leveraged brilliantly.

The study suggests that long-term effects of COVID-19 on the brain are not to be taken lightly even in those with milder disease who did not need hospitalisation during the acute illness. The loss of grey matter extends across many critical regions of the brain that are together responsible for a raft of functions, such as decision making, attention, emotions and empathy. We don’t yet know whether the functional effects of the observed anatomical changes will get worse and how much the brain’s capacity for plasticity will help in the recovery. We do not also know whether the results apply to a lesser or greater degree to the later variants, namely Delta and Omicron.

The authors postulate three possible mechanisms for the effect: degenerative spread starting with olfactory nerves, body’s inflammatory reaction to the virus or simply sensory deprivation from the loss of smell sensation on various brain regions. It is crucial that the basic mechanism is better understood before effective treatment and preventive measures can be developed.

This study investigated the effect that COVID-19 can have on the brain in mild cases, with results showing small but significant losses in multiple brain regions, which were linked to cognitive decline. Importantly, the study used brain scans from people both before and after the infection, meaning that this was a very well controlled study. What does this mean for the community?

Some have a view that it is good for people to contract the virus and have a mild case, however, these results strongly suggest to avoid viral infection, and rather be vaccinated. Importantly, the authors have an opportunity to perform further scans in the future, to determine if the reduction in brain areas is maintained, increased, or recovered. These will be critical studies for our understanding of how COVID-19, like other viruses, can affect our brains.

This study adds to the mounting evidence of significant damage to neurological systems after SARS-CoV-2 infection. The lack of adequate controls on widespread disease is set to damage the cognitive capacity of the workforce of Australia significantly. We could lose key business, medical and scientific personnel to cognitive dulling or dementia earlier than otherwise.

The paper by Douaud et al is a uniquely valuable contribution to understanding COVID-19 and its neurological effects. Despite the large number of MRI brain scans that were reviewed pre and post COVID-19 there are some caveats: there were sparse clinical details available for the analyses; the cognitive testing that was employed was brief and somewhat insensitive; the effects of ethnicity and education level were difficult to address; the data do not relate to other SARS-CoV-2 variants most particularly Omicron.

Nonetheless, the results firmly establish that particular parts of the brain can be damaged by the virus even in those with mild disease. Further, they provide a platform on which more targeted studies can be performed using other MRI imaging techniques and more comprehensive neuropsychological testing. These may afford a real-time biomarker to monitor potential therapies. The long term implications of the brain changes will require careful studies in to the future.

The findings from this important study by Douaud and colleagues demonstrate that even mild cases of COVID-19 can have significant effects on brain health, with the authors showing atrophy (shrinking) of brain regions essential for processing smell, memory, cognition and emotion. While more research is needed to determine the mechanism through which the virus impacts the brain in this way, it is likely to be via a range of direct (i.e., the direct action of the virus on brain cells) and indirect (activation of neuroinflammation) processes. We have long known that inflammation plays a role in neuropsychiatric and neurodegenerative conditions.

The data from this study highlights the need for further research into the long term neurobiological effects of COVID-19, and how factors such as reinfection and/or vaccination impact this risk. Long term follow up is also needed to determine whether these effects are reversed over time. However, these data clearly show that even when only causing mild respiratory illness, the COVID-19 virus can directly target and damage the brain.

These data highlight the need for sustained preventative measures to reduce the viral transmission, as well as further development of treatments that can target and protect the brain from COVID-19. Also any clinical intervention for mood, anxiety or cognitive symptoms resulting from COVID-19 exposure will need to account for neuroinflammation as a potential causative factor and treatment target. Standard antidepressant treatments, for example, may not be effective under these conditions.

This is a very interesting study, which shows that mild acute infection is associated with brain atrophy and cognitive decline. I note that the authors stated that the group who got infected had lower performance cognitive and brain volume than the controls at baseline. I interpret this as meaning that SARS-CoV2 brain impact may be the strongest in those with existing neurocognitive vulnerabilities. This is concerning of course for the potential added dementia risk. It will be important that this study provides more details about the comorbid conditions of their sample.

In Australia, the ADAPT COVID-19 study at Sydney St. Vincent’s Hospital has similar results showing cognitive decline or lack of expected improvement on repeated cognitive testing. We presented these results at CROI 2022 and linked it to immune/inflammatory biomarkers.

This is a well performed longitudinal study, the results look very interesting, but worrying as well. It is a very good example of what Covid-19 can do to the human system long term.

This study looked at the different brain regions and changes in the brain size. Our research team is looking at the molecular and cellular level – what's going on inside the brain cells when they are exposed to the virus. The results from our experiments will help us understand what is happening inside the cells, which could be leading to the changes in the brain that are highlighted in this study.

Our preliminary data shows some infection in brain cells, including neurons. However we still don't know if the virus can enter these cells after crossing the blood-brain barrier, or if the symptoms we're seeing inside the cells are because of some other reason. For example, there is an immune response when the virus is infecting our bodies, which could be causing secondary effects that affect the brain cells as well.

There are definitely several cases where patients infected with the virus started getting neurological symptoms like dizziness, disturbed consciousness, headache, loss of smell and taste, seizure, encephalitis and there have been links with Parkinson's disease.

From this research and our own, it is clear there is an effect on the brain from Covid-19 infection, and this could lead to some Long Covid effects. We still don't know how to treat this, because no one has looked at it yet. But we do know that the virus directly, or indirectly, can affect the human brain.

This is carefully performed work that utilises the data from about 780 people who had had an MRI brain scan as part of a bio-banking initiative prior to the pandemic who have then had their brain imaged again after they have had Covid-19. In addition a similar age group of participants have been scanned  with the same time interval that had not had Covid-19, as a comparison.

The findings demonstrate that the brain pathways that relate to the sense of smell and the pathways that relate to memory formation and recall have shrunk in those that had had Covid-19. The shrinkage or loss of brain volume was significant and exceeded a 6% difference on average.

Furthermore those who demonstrated this shrinkage, performed significantly worse on executive function, visual searching and mental flexibility tests (Trails tests). We know that loss of the sense of smell very early on in Covid-19 is a key sign of infection and some people never get their sense of smell back. The smell pathway and the memory pathway in the brain are connected and these are the same pathways affected in some dementias including Alzheimer’s disease.

From the available data the researchers also conclude that Covid-19 causes the shrinkage whereas being infected with the seasonal flu did not cause brain shrinkage.

This study demonstrates that there is a long term consequence to getting Covid-19 and it highlights the importance of taking all measures possible to reduce Covid-19’s impact on the body and especially the brain.