Cognitive impairment as a result of severe COVID-19 is similar to that sustained between 50 and 70 years of age and is the equivalent to losing 10 IQ points, say a team of scientists from the University of Cambridge and Imperial College London.
The findings, published in the journal eClinicalMedicine, emerge from the NIHR COVID-19 BioResource. The results of the study suggest the effects are still detectable more than six months after the acute illness, and that any recovery is at best gradual.
There is growing evidence that COVID-19 can cause lasting cognitive and mental health problems, with recovered patients reporting symptoms including fatigue, ‘brain fog’, problems recalling words, sleep disturbances, anxiety and even post-traumatic stress disorder (PTSD) months after infection.
While even mild cases can lead to persistent cognitive symptoms, between a third and three-quarters of hospitalized patients report still suffering cognitive symptoms three to six months later.
To explore this link in greater detail, researchers analyzed data from 46 individuals who received in-hospital care, on the ward or intensive care unit, for COVID-19 at Addenbrooke’s Hospital, part of Cambridge University Hospitals NHS Foundation Trust. 16 patients were put on mechanical ventilation during their stay in hospital. All the patients were admitted between March and July 2020 and were recruited to the NIHR COVID-19 BioResource.
The individuals underwent detailed computerized cognitive tests an average of six months after their acute illness using the Cognitron platform, which measures different aspects of mental faculties such as memory, attention and reasoning. Scales measuring anxiety, depression and post-traumatic stress disorder were also assessed. Their data were compared against matched controls.
This is the first time that such rigorous assessment and comparison has been carried out in relation to the after effects of severe COVID-19.
COVID-19 survivors were less accurate and with slower response times than the matched control population—and these deficits were still detectable when the patients were following up six months later. The effects were strongest for those who required mechanical ventilation.
By comparing the patients to 66,008 members of the general public, the researchers estimate that the magnitude of cognitive loss is similar on average to that sustained with 20 years aging, between 50 and 70 years of age, and that this is equivalent to losing 10 IQ points.
Survivors scored particularly poorly on tasks such as verbal analogical reasoning, a finding that supports the commonly-reported problem of difficulty finding words. They also showed slower processing speeds, which aligns with previous observations post COVID-19 of decreased brain glucose consumption within the frontoparietal network of the brain, responsible for attention, complex problem-solving and working memory, among other functions.
Professor David Menon from the Division of Anaesthesia at the University of Cambridge, the study’s senior author, said: “Cognitive impairment is common to a wide range of neurological disorders, including dementia, and even routine aging, but the patterns we saw—the cognitive ‘fingerprint’ of COVID-19 – was distinct from all of these.”
While it is now well established that people who have recovered from severe COVID-19 illness can have a broad spectrum of symptoms of poor mental health – depression, anxiety, post-traumatic stress, low motivation, fatigue, low mood, and disturbed sleep—the team found that acute illness severity was better at predicting the cognitive deficits.
The patients’ scores and reaction times began to improve over time, but the researchers say that any recovery in cognitive faculties was at best gradual and likely to be influenced by a number of factors including illness severity and its neurological or psychological impacts.
Professor Menon added: “We followed some patients up as late as ten months after their acute infection, so were able to see a very slow improvement. While this was not statistically significant, it is at least heading in the right direction, but it is very possible that some of these individuals will never fully recover.”
There are several factors that could cause the cognitive deficits, say the researchers. Direct viral infection is possible, but unlikely to be a major cause; instead, it is more likely that a combination of factors contribute, including inadequate oxygen or blood supply to the brain, blockage of large or small blood vessels due to clotting, and microscopic bleeds.
However, emerging evidence suggests that the most important mechanism may be damage caused by the body’s own inflammatory response and immune system.
While this study looked at hospitalized cases, the team say that even those patients not sick enough to be admitted may also have tell-tale signs of mild impairment.
Professor Adam Hampshire from the Department of Brain Sciences at Imperial College London, the study’s first author, said: “Around 40,000 people have been through intensive care with COVID-19 in England alone and many more will have been very sick, but not admitted to hospital. This means there is a large number of people out there still experiencing problems with cognition many months later. We urgently need to look at what can be done to help these people.”
Professor Menon and Professor Ed Bullmore from Cambridge’s Department of Psychiatry are co-leading working groups as part of the COVID-19 Clinical Neuroscience Study (COVID-CNS) that aim to identify biomarkers that relate to neurological impairments as a result of COVID-19, and the neuroimaging changes that are associated with these.
Our analyses provide converging evidence to support the hypothesis that COVID-19 infection is associated with cognitive deficits that persist into the recovery phase. The observed deficits varied in scale with respiratory symptom severity, related to positive biological verification of having had the virus even amongst milder cases, could not be explained by differences in age, education or other demographic and socioeconomic variables, remained in those who had no other residual symptoms and was of greater scale than common pre-existing conditions that are associated with virus susceptibility and cognitive problems.
The scale of the observed deficit was not insubstantial; the 0.47 SD global composite score reduction for the hospitalized with ventilator sub-group was greater than the average 10-year decline in global performance between the ages of 20 to 70 within this dataset. It was larger than the mean deficit of 480 people who indicated they had previously suffered a stroke (−0.24SDs) and the 998 who reported learning disabilities (−0.38SDs). For comparison, in a classic intelligence test, 0.47 SDs equates to a 7-point difference in IQ.
In terms of cognitive profile, the assessment battery applied comprised tests that were designed to enable variance in different aspects of cognition to be examined at very large scale within the general population. The deficits affected multiple tests but to different degrees. When examining the entire population, the deficits were most pronounced for paradigms that tapped cognitive functions such as reasoning, problem solving, spatial planning and target detection whilst sparing tests of simpler functions such as working-memory span as well as emotional processing.
These results accord with reports of long-COVID, where ‘brain fog’, trouble concentrating and difficulty finding the correct words are common. Notably, this profile cannot be explained by differences in the general sensitivity of our tests; e.g., Spatial Span and Digit Span scores show robust age-related differences. Instead, recovery from COVID-19 infection may be associated with particularly pronounced problems in aspects of higher cognitive or ‘executive’ function, an observation that accords with preliminary reports of executive dysfunction in some patients at hospital discharge [], as well as previous studies of ventilated patients with acute respiratory distress syndrome pre-pandemic [].
It should be noted though, that when the analysis of individual test scores was constrained to people who had positive biological tests, the profile in milder non-hospitalized cases extended to spatial span.
It is important to be cautious in inferring a neurobiological or psychological basis of the observed deficits without brain imaging data, although the assessment tasks used here have been shown to map to different networks within the human brain in terms of normal functional activity and connectivity as well as structural network damage [27, 28, 29].
Speculatively, we believe there are likely to be multiple contributing factors. For example, previous studies in hospitalised patients with respiratory disease not only demonstrate objective and subjective cognitive deficits but suggest these remain for some at 5-year follow-up [].
Consequently, the observation of post-infection deficits in the subgroup who were put on a ventilator was not altogether surprising. Conversely, the scale of deficits in cases who were not put on a ventilator, particularly those who remained at home, was unexpected given the limited literature on other respiratory illnesses such as cold []
Although these deficits were on average of small scale for those who remained at home, they were more substantial for people who had received positive confirmation of COVID-19 infection. A corollary of this is that cognitive deficits associated with other respiratory illnesses that are mistakenly self-diagnosed as COVID-19 are likely to be negligible. One possibility is that these deficits in milder bio-confirmed cases may reflect the lower grade consequences of less severe hypoxia.
The observed correlation with severity of respiratory symptoms is in close concordance with this view; however, as noted in the introduction, there have been case reports of other forms of neurological damage in COVID-19 survivors, including some for whom such damage was the first detected symptom [].
Accordingly, in the current study, bio-positive cases who reported being ill but remained at home showed a 0.23SD magnitude cognitive deficit. Based on this, we propose that a timely challenge is to cross-relate the multi-dimensional profile of cognitive deficits observed here to imaging markers that can confirm and differentiate the underlying psychological and neuropathological sequelae of COVID-19.
An important consideration for any cross-group study is biased sampling.
Crucially, our study promotional material did not mention COVID-19. Instead, we raised the profile via a BBC2 Horizon documentary plus news features stating that people could undertake a free online assessment to identify their greatest cognitive strengths. This mitigated biased recruitment of people who suspected that COVID-19 had affected their cognitive faculties. Including the questionnaire post assessment also mitigated the potential for questionnaire items to bias expectations of poor self-performance due to COVID-19.
Normal limitations pertaining to inferences about cause and effect from cross-sectional studies also should be considered [,]. The large and socioeconomically diverse nature of the cohort enabled us to include many potentially confounding variables in our analysis, which goes some way to mitigating the possibility that observed differences were present prior to illness.
Premorbid estimates also indicate that those who were ill were likely to have had somewhat higher as opposed to lower cognitive ability pre-illness. Nonetheless, longitudinal research, including follow-up of this cohort, should further confirm the cognitive impact of COVID-19 infection and determine deficit longevity as a function of respiratory symptom severity. A further consideration is that our results rely on self-report as we do not have access to participant clinical records. We note that this reliance will apply broadly for studies of the many Covid-19 patients who did not receive medical assistance during the acute phase.
Cross comparison to hospital recruited cohorts will provide further confirmation using the same cognitive tests reported here. This study did not set out to determine the biological basis of the COVID-19 cognitive deficit association in terms of neural systems or psychological mechanisms, just to confirm whether there is such an association.
Further work is required to interrelate the deficits to underlying causes, e.g., neurological changes, fatigue and apathy. Relatedly, future studies should also examine the role of putatively protective population factors such as cognitive reserve. The observation of substantial associations reported here can guide assessment batteries applied in such studies. A fuller understanding of the marked deficits that our study shows will enable better preparedness in the post-pandemic recovery challenges.
reference link : https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00324-2/fulltext
More information: Adam Hampshire et al, Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohort, eClinicalMedicine (2022). DOI: 10.1016/j.eclinm.2022.101417