A study looking at post-mortem brain tissue samples has found severe COVID-19 is associated with molecular signs of brain aging. The study identified gene expression changes in the brains of deceased COVID patients that resemble what is seen in old age, and the researchers warn potential long-term neurological problems could emerge in the years following the pandemic.
As we come up to the three-year anniversary of the emergence of SARS-CoV-2 scientists are still trying to understand the long-term impacts of this novel coronavirus on the human body. For many people a bout with COVID-19 can present as a mild, flu-like respiratory illness, however, it has become increasingly clear this virus can broadly affect the entire body, from damaging heart tissue to increasing one's diabetes risk.
The impact of SARS-CoV-2 on the brain has perhaps been one of the most concerning areas of research over the past couple of years. COVID has long been associated with neurological symptoms such as brain fog or losing one's sense of smell, so it has been clear since 2020 that the disease impacts the brain. But exactly how it affects the brain hasn't been clear.
Earlier this year a study, dubbed "one of the most important" of the pandemic to date, identified long-term brain changes in hundreds of recovered COVID patients. The study offered one of the first longitudinal imaging analyses of brain changes associated with SARS-CoV-2 infections.
Not long after that study was published another investigation appeared looking at the long-term cognitive impacts of severe COVID-19. That research, led by scientists from Imperial College London and the University of Cambridge, estimated a severe case of COVID was cognitively equivalent to about 20 years of brain aging.
A barrage of cognitive assessments in COVID patients six months after being discharged from hospital revealed survivors were slower to respond to tasks and less accurate in their responses, compared to their matched controls. Essentially, a 50 year old hospitalized with severe COVID showed cognitive test scores similar to what would be seen in a healthy 70 year old.
Maria Mavrikaki, a Harvard Medical School researcher, had been following the emerging studies linking COVID to persistent cognitive problems since the beginning of the pandemic and set out to investigate what specifically could be causing these brain problems. Along with several colleagues, Mavrikaki analyzed more than 50 brain tissue samples, including 21 samples from individuals who died from severe COVID.
The research focused on a type of genetic sequencing called whole-transcriptome analysis. This analysis presents a snapshot of gene activity in a particular cell, allowing for insights into what specific genes were switched on or off in a person at their time of death.
... our analyses suggest that many biological pathways that change with natural aging in the brain also change in severe COVID-19.
Compared to similar brain tissue samples from age- and sex-matched controls, the researchers identified nearly 7,000 differentially expressed genes in the COVID cohort. Unsurprisingly, gene activity relating to immune pathways was up-regulated, but perhaps more concerning was the amount of down-regulated genes linked to synaptic activity, cognition and memory pathways.
"We also observed significant associations of cellular response to DNA damage, mitochondrial function, regulation of response to stress and oxidative stress, vesicular transport, calcium homeostasis, and insulin signaling/secretion pathways previously associated with aging processes and brain aging," the researchers write in the new study. "Altogether, our analyses suggest that many biological pathways that change with natural aging in the brain also change in severe COVID-19."
The research also examined the mechanisms that could be triggering these specific age-related gene expression changes. So far, the debate over the effects of COVID on the brain has offered up two distinct hypotheses. One school of thought argues SARS-CoV-2 can directly infiltrate the brain, while the other argument suggests the neurological symptoms of COVID are due to systemic inflammatory effects brought on by the disease.
Investigating both hypotheses, the new research could not detect any SARS-CoV-2 viral RNA in the brain tissue samples. Instead, the study did identify the up-regulation of several inflammatory pathways (tumor necrosis factor, aka TNF, and type I/II interferons), which have previously been implicated in brain aging. Further investigations by the researchers confirmed these specific immune cells can directly influence the expression of several aging-related genes.
"We also found that cytokines upregulated the expression of aging-regulated genes that were upregulated in individuals with COVID-19 such as TRIM22, CHI3L1, C1S and IFITM1 and downregulated the expression of aging-regulated genes that were downregulated in individuals with COVID-19 such as CCND2, ACTR3B and EPHA5," the researchers stated in the study. "Taken together, our data suggest that COVID-19-induced TNF and type I/II interferons may lead to significant deteriorating effects in the brain in the absence of SARS-CoV-2 neuroinvasion."
So what does all this mean?
Commenting on the new study to Nature, neuropathologist Marianna Bugiani said it's hard to predict the long-term effects of COVID on the brain, pointing out it's too soon to tell whether these brain changes are permanent, or what their consequences could be on a person's risk of neurodegenerative disease. And we don't know to what degree these kinds of gene-expression changes affect the brains of those experiencing mild bouts of COVID.
[The] consequences might not be clear for years.
“It opens a plethora of questions that are important, not only for understanding the disease, but to prepare society for what the consequences of the pandemic might be,” said Bugiani, who didn't work on this new study. “And these consequences might not be clear for years.”
Back in 2020, soon after SARS-CoV-2 emerged, a team of researchers at Australia's Florey Institute of Neuroscience & Mental Health warned rates of Parkinson's disease could increase in the years following the pandemic. Understanding how virus-induced neuroinflammation can increase a person's risk of neurological disease, the Florey researchers pointed to the fallout from the 1918 Spanish Flu pandemic as an example of what may come in the wake of this COVID pandemic.
Five years after the Spanish Flu pandemic ended, global Parkinson’s disease diagnoses had almost tripled. And so far, three years into the COVID pandemic, preliminary studies are already detecting mild increases in rates of Alzheimer's, Parkinson's and dementia.
Mavrikaki and colleagues are cautious not to jump to any explicit conclusions in their latest study. They note these findings are just a small piece in the larger puzzle of COVID's long-term effects, but they also stress their findings seem to be directly related to SARS-CoV-2, and are not simply a relic of a patient being seriously ill.
One particularly novel analysis in the study compares the gene expression data from COVID patients to brain tissue samples from patients who were severely ill in intensive care and/or placed on a ventilator but were not infected with COVID. That analysis confirmed that the brain aging identified in the COVID patients was unique to the illness and not just due to the trauma of severe hospitalization.
The researchers ultimately recommend doctors be aware that COVID could be considered a risk factor for dementia in the future, particularly in patients with pre-existing susceptibilities.
"The generalizability of our results to individuals who had mild COVID-19 or who recovered from COVID-19 remains to be determined," the researchers conclude. "Given our findings, we advocate for neurological follow-up of individuals who recovered from COVID-19 and suggest potential clinical value in modifying risk factors to reduce the risk or delay the development of aging-related neurological pathologies and cognitive decline."
The new study was published in the journal Nature Aging.