COVID-19 primarily causes respiratory illness and has also been linked to neurological symptoms in certain vulnerable communities.
COVID-19 causes frontal brain dysfunction, which is critical for cognitive function, according to neuroimaging and cognitive testing. COVID-19 may also cause long-term cognitive damage. But the biochemical changes caused by COVID-19 that cause cognitive impairment are unknown.
Natrual aging reduces frontal brain activity, causing cognitive deficits. In the human brain, aging is related with increased immunological signaling and decreasing synaptic activity.
Since COVID-19 causes frontal cortex damage similar to aging, researchers recently investigated if severe COVID-19 caused aging-related molecular signatures in the brain.
This study’s findings are available as a preprint on medRxiv.
The study compared the postmortem frontal cortex of twelve COVID-19 patients to that of twelve age- and sex-matched uninfected controls using full transcriptome analysis.
Clustering analysis using t-distributed stochastic neighbor embedding (TSNE) revealed that the COVID-19 patients’ transcriptome profiles were distinct from controls. Interestingly, the transcriptome profiles of two controls, ages 71 and 84, matched those of the COVID-19 patients.
Quantitative polymerase chain reaction (qPCR) study revealed that SARS-CoV-2 was not present in the frontal brain of COVID-19 patients or controls at the time of death. This shows that the changes in gene expression reported in COVID-19 patients were not caused by the virus’s direct influence on the frontal brain.
Additionally, when the COVID-19 transcriptome profiles were compared to age- and sex-matched controls, the scientists identified 2,809 differentially expressed genes (DEGs) with unique Ensembl gene IDs. 1,397 DEGs were discovered to be upregulated, while 1,412 were found to be downregulated.
Calprotectin levels in the blood are a biomarker that distinguishes severe COVID-19 from mild disease, and the S100A8/S100A9 genes that produce calprotectin were increased in the COVID-19 patient cohort studied in this work.
Additionally, as previously reported in COVID-19 patients, SYNGR1 levels were decreased in the patient cohort. The variations in gene expression found in COVID-19 patients in this investigation are consistent with prior results.
To ascertain the functional significance of reported gene expression variations in the transcriptome, pathway enrichment analysis was done using annotated Gene Ontology (GO) Biological processes. The input gene set is compared to each of the GO words or bins, and a statistical test is done to evaluate if each term or bin is enriched for the input genes.
Notably, the investigators discovered considerable enrichment of numerous DEGs and GO keywords associated with human brain aging. Along with positive enrichment of words associated with immune response in the COVID-19 patient cohort, relevant genes such as BCL2, IFI16, and CFH were elevated.
IFITM1-3, which is involved with the interferon response, has a significantly dysregulated expression pattern with higher levels of expression. Synaptic function GO keywords such as synaptic signaling, synaptic plasticity control, glutamatergic, GABAergic, and dopaminergic synaptic transmission were found to be negatively enriched, which corroborated the reported downregulation of synaptic signaling genes such as SST, GRIA1, and GRIN2B.
Notably, SST is a gene previously associated with aging in the human frontal brain, and it was found to be the most downregulated gene in the COVID-19 patient group in this investigation.
The researchers observed a significant enrichment of GO terms relating to the cellular response to DNA damage, mitochondrial function, stress and oxidative stress regulation, vesicular transport, calcium homeostasis, apoptosis, and insulin signaling, as well as pathways known to be associated with aging, specifically brain aging. Additionally, GO keywords associated with cognitive function, memory, and learning were enriched.
The DEGs that overlapped with these enriched pathways were analyzed, and genes associated with aging, such as brain-derived neurotrophic factor (BDNF), were discovered.
The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathway enrichment studies were done, and the results indicate that immunological activation pathways are enriched positively, while synaptic function pathways are enriched negatively.
Notably, the “Coronavirus Disease – COVID-19” route was discovered as a significantly enriched pathway in the COVID-19 patient group in this investigation.
The findings suggest that changes in biological pathways that are related to natural aging are also observed in COVID-19 patients with severe disease.
The researchers then examined whether the significant COVID-19-induced changes in the transcriptome are comparable to those caused by aging in the human brain. They examined transcriptome-wide datasets from five patients for aging-related alterations and discovered that genes that were up- or down-regulated during aging were also up- or down-regulated in COVID-19 patients with severe illness. This study found that a gene set previously related with aging was highly elevated in the COVID-19 patient group.
Quantitative PCR (qPCR) investigations supported the findings, revealing that genes S100A9, MYL12A, and RHOBTB3 were elevated in the frontal cortex of COVID-19 patients, while genes CALM3, INPP4A, GRIA1, and GRIN3A were downregulated.
Interestingly, the same set of genes was also differentially expressed in older persons’ frontal brain.
Additionally, the researchers sought to determine whether the aging gene signature differs between younger COVID-19 patients aged 65 years or less and older COVID-19 patients aged 65 years or more.
Interestingly, the scientists identified more alterations in gene expression in younger COVID-19 patients than in older COVID-19 patients.
In younger COVID-19 patients, 1,631 upregulated and 2,073 downregulated genes were discovered that corresponded to numerous DEGs in age/sex-matched controls. However, in older COVID-19 patients, we identified an upregulation of 19 genes, including the HBA1, HBA2, and HBB genes, and a downregulation of four genes.
Additionally, these DEGs reflect the same tendencies as aging-related genes in the frontal brain. These findings suggest that the aging effects of COVID-19 are more prominent in the brains of younger COVID-19 patients than in those of older COVID-19 patients.
Additional research with young COVID-19 patient cohorts will corroborate the observed findings.
Additionally, the researchers examined whether the COVID-19-induced molecular alterations were gender-specific. They discovered that COVID-19 had a consistent effect on aging-related genes and pathways in male and female COVID-19 patients.
The current work is the first to establish parallels between the frontal cortex of COVID-19 patients and the aging human brain in terms of transcriptome profiles.
The current study’s findings show that severe COVID-19 infection may cause brain alterations associated with age and may result in premature aging. These alterations are more noticeable in younger patients than in older patients. Earlier reports indicate that recovered COVID-19 patients have a persistent cognitive loss.
Additionally, the study reveals that prolonged COVID exposure may result in elevated rates of cognitive impairment and neurotoxicity. As a result, it may be required to follow recovered COVID-19 patients for neurological problems associated with aging on a frequent basis.
Source: 10.1101/2021.11.24.21266779
Image Credit: Getty
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*Important Note
medRxiv provides unpeer-reviewed preliminary scientific studies that should not be considered definitive, guide clinical practice/health-related behavior, or taken as established information.