Severe COVID-19 causes aging-like changes in the human brain

By Neha MathurReviewed by Benedette Cuffari, M.Sc.Dec 11 2022

In a recent article published in Nature Aging, researchers found that severe coronavirus disease 2019 (COVID-19) triggers aging-like changes in the brain's frontal cortex region, resulting in cognitive deficits. These findings highlight the importance of neurological examination of individuals who have recovered from COVID-19.

Study: Severe COVID-19 is associated with molecular signatures of aging in the human brain. Image Credit: Naeblys / Shutterstock.com

Background

Previous studies have reported an average 10-year reduction in global cognitive performance post-severe COVID-19. Similarly, some reports have shown that COVID-19 damages the frontal cortex, the brain region responsible for cognition.

Despite these observations, there remains inadequate molecular evidence for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced effects on the brain, which the researchers of the current study have hypothesized are similar to accelerated aging effects.

About the study

In the present study, researchers analyzed frontal cortex samples obtained from 54 individuals through ribonucleic acid sequencing (RNA-seq) to identify molecular signatures similar to aging associated with severe COVID-19.

After collection during the autopsy, frozen brain samples were prepared using biosafety level 2+ procedures before RNA extraction by phase separation. Subsequently, SARS-CoV-2 genome alignment was assessed by aligning raw sequencing reads to a SARS-CoV-2 reference genome. Likewise, the researchers determined differential gene expression (DGE) by aligning raw sequencing reads to a reference transcriptome.

The team identified frontal cortex samples whose whole-transcriptome analysis yielded DEGs with a false discovery rate (FDR) of less than 0.05 for gene-set enrichment analysis (GSEA). To reduce bias in transcriptome profiling methods, an 'aging index' was devised using the aging and control cohorts as a training and test set.

The aging cohort comprised 21 people with severe COVID-19. One individual had a history of Alzheimer's disease (AD) and another one of epilepsy, while the remaining 19 had no known neurological disorders.

The aging group also consisted of one 23-year-old individual with an asymptomatic SARS-CoV-2 infection. The control group included 22 age- and gender-matched SARS-CoV-2-uninfected controls with no neurological disorders and an age- and gender-matched uninfected individual with AD.

Another independent control cohort comprised of nine SARS-CoV-2-uninfected people between 22 and 85 years old with a history of ventilator (VENT) or intensive care unit (ICU) treatment was also included in the final analysis.

Furthermore, frontal cortex transcriptomic data from another subset of 633 people who donated their brains for the Religious Order Study and the Memory and Aging Project (ROSMAP) were studied. These individuals were subjected to Mini-Mental State Examination (MMSE) while alive.

This subset of people were categorized according to their average MMSE score, wherein a score of 25 indicated high cognitive performance and less than 25 indicated low cognitive performance, respectively. This exercise helped the researchers further assess the relationship between COVID-19-related transcriptomic changes and cognitive function.

Study findings

Except for the 62-year-old individual with epilepsy and the 23-year-old with asymptomatic infection, all COVID-19 cases in the aging cohort were segregated farther from controls, as assessed by clustering analyses. Aged adults in the ICU/VENT cohort also clustered near SARS-CoV-2-infected individuals in the aging cohort.

A total of 6,993 DEGs were identified between COVID-19 cases of the aging cohort and their age- and gender-matched controls. Between these two cohorts, 3,330 and 3,663 DEGs were substantially up- and down-regulated, respectively.

While severe COVID-19 led to positive gene enrichment of immune pathways, it negatively enriched memory and cognition pathways. The disease also perturbed cellular responses to several biological pathways associated with brain aging, such as deoxyribonucleic acid (DNA) damage and calcium homeostasis. GSEA also revealed a consistent correlation between severe COVID-19 and poor cognitive performance.

Additional analyses leveraging the aging index confirmed that severe COVID-19 shifted the molecular age of brains relative to uninfected ICU/VENT and age- and gender-matched controls.

Intriguingly, the observed gene expression changes in samples from individuals with severe COVID-19 were not due to the presence of SARS-CoV-2 RNA in the frontal cortex. Instead, these changes likely occurred due to the upregulation of interferon (IFN) and tumor necrosis factor (TNF) response pathways in the frontal cortex that subsequently caused aging-like cognitive deficits.

Conclusions

The current study identified aging-like gene expression changes in individuals with severe COVID-19 that explain the cognitive deficits observed in recovered cases. Furthermore, the results showed that circulating pro-inflammatory cytokines mediated these aging-related gene expression changes, which suggests that severe COVID-19-induced inflammation might be neuroprotective.

Based on these findings, the researchers recommend that those who have recovered from severe COVID-19 undergo neurological follow-up. Monitoring and early interventions could potentially impede aging-like neurological pathologies and subsequent cognitive decline in these individuals.