Severe COVID-19 infection enhanced specific molecular pathways associated with brain aging and cognitive decline, according to study findings published online preprint in medRxiv.

After obtaining consent from next-of-kin, researchers at Brigham and Women’s Hospital in Boston, Massachusetts conducted 54 postmortem autopsies between September 1, 2020 to December 31, 2020.

They obtained brain tissue samples from 22 individuals aged 23 to 84 years who died following complications due to polymerase chain reaction (PCR)-confirmed COVID-19 infections (21 severe infections and 1 asymptomatic infection). Most individuals in the COVID-infected postmortem group had no history of neurological or psychiatric disorders, except 2 people (1 with epilepsy and 1 with Alzheimer disease [AD]).

For comparison, the researchers also obtained brain tissue samples from 22, age- and sex-matched control individuals who were not infected with COVID-19, 1 uninfected person with AD, and 9 uninfected individuals with history of intensive care unit (ICU) or ventilator treatment.

We found striking similarities between individuals with COVID-19 and aged individuals …

They studied frontal cortex tissue samples from these 54 individuals using whole-transcriptome analysis with total RNA-sequencing. Upon analysis, the researchers noticed that results from the individuals with severe COVID-19 infections were segregated away from the control individuals. Outliers included the infected, asymptomatic person and the infected individual with epilepsy.   

Comparison between individuals infected with COVID-19 and control individuals note infected revealed differential expression of 6993 genes with 3330 upregulated and 3663 downregulated genes. In particular, those infected with COVID-19 exhibited upregulated S100A8 and S100A9 genes which encode calprotectin, a circulating blood biomarker that distinguishes severe from mild COVID-19 infection.

The researchers also noted that severe COVID-19 infection promoted molecular pathways associated with aging of the human brain, including positive enrichment of immune-related pathways and negative enrichment of synaptic activity, cognition, and memory pathways.

Severe COVID-19 infection correlated significantly with changes in pathways responsible for cellular response to DNA damage, mitochondrial function, calcium homeostasis, vesicular transport, insulin signaling and secretion, and regulation of responses to stress (including oxidative stress). These biological pathways are also known to change due to natural aging in the brain.

Overall, the researchers’ findings suggest that COVID-19 is associated with the molecular signatures of brain aging. The researchers acknowledged that their findings also highlight the importance of neurological follow-up among individuals who have recovered from the virus.

They concluded, “We found striking similarities between individuals with COVID-19 and aged individuals: genes upregulated in aging were upregulated in severe COVID-19; likewise, genes downregulated in aging were also downregulated in severe COVID-19.”

Study limitations include variability of illness duration, imperfect quality of brain tissue samples in several cases, and problems with specificity of findings due to COVID-19.

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