Harvard study links severe COVID to genetic signs of brain aging

A study of post-mortem brain tissue samples found that 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 that potential long-term neurological problems could emerge in the years following the death. pandemic.

As we approach the third 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, an outbreak of COVID-19 may present as a mild flu-like respiratory illness, however, it has become increasingly clear that this virus can affect the whole body broadly, ranging from heart tissue damage to increased risk of diabetes.

The impact of SARS-CoV-2 on the brain has perhaps been one of the most concerning areas of research over the past two years. COVID has long been associated with neurological symptoms such as brain fog or loss of smell, so it’s been clear since 2020 that the disease impacts the brain. But exactly how it affects the brain has not been clear.

Earlier this year, a study, dubbed “one of the largest” in the pandemic to date, identified long-term brain changes in hundreds of recovered COVID patients. The study offered one of the first longitudinal imaging analyzes of brain changes associated with SARS-CoV-2 infections.

Shortly after the publication of this study, another investigation appeared on the long-term cognitive impacts of severe COVID-19. This research, led by scientists from Imperial College London and the University of Cambridge, estimated that one severe case of COVID was cognitively equivalent to around 20 years of brain aging.

A barrage of cognitive assessments in COVID patients six months after discharge from hospital found that survivors were slower to respond to tasks and less accurate in their answers, compared to their matched controls. Essentially, a 50-year-old man hospitalized with severe COVID showed cognitive test scores similar to what one would see in a healthy 70-year-old man.

Maria Mavrikaki, a researcher at Harvard Medical School, had been following emerging studies linking COVID to persistent cognitive problems since the start of the pandemic and set out to investigate what specifically might be causing these brain problems. Along with several colleagues, Mavrikaki analyzed more than 50 brain tissue samples, including 21 samples from people who died of 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, providing insight into which specific genes were turned on or off in a person at the time of death.

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, the activity of genes related to immune pathways was up-regulated, but perhaps of more concern was the amount of down-regulated genes related to synaptic activity, cognition, and memory pathways.

“We also observed significant associations of cellular response to DNA damage, mitochondrial function, regulation of stress and oxidative stress response, vesicular transport, calcium homeostasis and pathways. insulin signaling/secretion previously associated with aging processes and brain aging,” the researchers write. in the new study. “Overall, our analyzes suggest that many biological pathways that change with natural aging in the brain also change in severe cases of COVID-19.

Research has also looked at the mechanisms that might trigger these specific age-related changes in gene expression. So far, the debate about the effects of COVID on the brain has offered two distinct hypotheses. One school of thought argues that SARS-CoV-2 can directly infiltrate the brain, while the other argument suggests that the neurological symptoms of COVID are due to systemic inflammatory effects caused by the disease.

Looking at both hypotheses, the new research could not detect any SARS-CoV-2 viral RNA in the brain tissue samples. Instead, the study identified the upregulation 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 that these specific immune cells can directly influence the expression of several age-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 said in the study. “Taken together, our data suggest that COVID-19-induced TNF and type I/II interferons can cause significant deteriorating effects in the brain in the absence of neuroinvasion by SARS-CoV-2.”

So what does all this mean?

Commenting on the new study by Nature, neuropathologist Marianna Bugiani said it’s difficult to predict the long-term effects of COVID on the brain, pointing out that it’s too early to tell if these brain changes are permanent or what their consequences might be for the risk of COVID-19. neurodegenerative disease of a person. And we don’t know how much these kinds of gene expression changes affect the brains of those who experience mild bouts of COVID.

“It opens up a plethora of questions that are important, not just for understanding the disease, but for preparing society for what the consequences of the pandemic might be,” said Bugiani, who did not work on this new study. “And those consequences may not be clear for years.”

In 2020, shortly after the emergence of SARS-CoV-2, a team of researchers from the Florey Institute of Neuroscience & Mental Health in Australia warned that rates of Parkinson’s disease could rise in the years following the pandemic. Understanding how virus-induced neuroinflammation can increase a person’s risk of neurological disease, the Florey researchers cited the fallout from the 1918 Spanish flu pandemic as an example of what could happen as a result of this pandemic. COVID.

Five years after the end of the Spanish flu pandemic, global diagnoses of Parkinson’s disease had nearly tripled. And so far, three years into the COVID pandemic, preliminary studies are already detecting small increases in rates of Alzheimer’s, Parkinson’s and dementia.

Mavrikaki and his colleagues are careful not to draw any explicit conclusions in their latest study. They note that these findings are only a small piece of the larger puzzle of the long-term effects of COVID, but they also point out that their findings appear to be directly related to SARS-CoV-2, and are not simply a relic of a critically ill patient. .

A particularly novel analysis from the study compares gene expression data from COVID patients to brain tissue samples from critically ill patients in intensive care and/or ventilated but who have not been infected with COVID. This analysis confirmed that the brain aging identified in COVID patients was disease-specific and not just due to the trauma of severe hospitalization.

The researchers ultimately recommend that physicians be aware that COVID could be considered a risk factor for dementia in the future, especially in patients with pre-existing susceptibilities.

“The generalizability of our findings to people who had mild COVID-19 or who have recovered from COVID-19 remains to be determined,” the researchers conclude. “Given our findings, we advocate neurological follow-up of people who have recovered from COVID-19 and suggest potential clinical value in modifying risk factors to reduce the risk or delay the development of age-related neurological pathologies and of cognitive decline.

The new study has been published in the journal natural aging.