The Impact of COVID-19 on Cognitive Decline and the Potential Role of miRNAs as Biomarkers


Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), manifests as a multi-organ condition with both immediate and protracted effects, extending its reach to the central nervous system (CNS). Studies, including one with a four-month follow-up period on patients who were hospitalized due to COVID-19, revealed that 30-40% of these individuals exhibited cognitive impairments such as memory dysfunction, attention deficits, and dysexecutive syndrome.

The term ‘COVID-19 brain fog’ has since been coined to describe a constellation of symptoms post-infection, including fatigue, diminished attention span, memory issues, lack of motivation, and difficulties in sustaining long working hours. Notably, younger individuals seem more susceptible to COVID-19-related cognitive declines, independent of the severity of their infection.

The long-term trajectory of these cognitive symptoms post-COVID-19 infection remains uncertain, with questions lingering about the potential for lasting neurological deficits or the gradual worsening of cognitive impairments. Another area of concern is whether COVID-19 exacerbates dementia symptoms in individuals with pre-existing conditions. The hypothesis that direct brain infection by SARS-CoV-2 could impair cognitive functions is under investigation.

A critical question in the understanding of COVID-19’s cognitive impact is whether the observed symptoms result from systemic inflammatory responses, direct viral encephalitis, tissue hypoxia, microvascular damage affecting cerebral perfusion and the blood-brain barrier, autoimmune reactions, or the deterioration of peripheral organs. The consequential cognitive impairments can significantly affect patients’ life quality and functionality, potentially leading to a cycle of deteriorating mental health and cognitive function. Therefore, understanding the mechanisms behind COVID-19-related cognitive decline is vital for developing effective prevention and treatment strategies.

Biomarkers, objectively measurable indicators of biological or pathogenic processes, play a crucial role in this context. Given the invasive nature of brain specimen collection and the informativeness of cerebrospinal fluid (CSF), the latter is considered a prime source for identifying biomarkers that reflect brain pathology. This necessitates the discovery of minimally invasive, disease-specific diagnostic biomarkers for early detection of pathological protein aggregations.

MicroRNAs (miRNAs), small non-coding RNAs of 19-23 nucleotides, regulate gene expression and are pivotal in post-transcriptional gene regulation. They function by binding to complementary sequences in the 3′-untranslated region (3′-UTR) of target mRNAs, leading to mRNA degradation or inhibition of protein synthesis. With over 2,500 miRNAs identified in humans, these molecules play essential roles in various biological processes, including metabolism, cell differentiation, and apoptosis. Their dysregulation has been linked to a range of diseases, including neurodegenerative conditions like Parkinson’s disease (PD). miRNAs, present in various biological fluids, have emerged as promising biomarkers for PD and other diseases, offering insights into pathophysiology and potential therapeutic targets.

The interplay between COVID-19 and cognitive decline potentially involves miRNAs in bodily fluids affecting disease pathogenesis. Identifying plasma biomarker changes across different cognitive domains is crucial for addressing the disabling effects of post-COVID cognitive decline. This review underscores the importance of researching circulating miRNAs as diagnostic tools and therapeutic targets for COVID-19-induced cognitive impairments, aiming to enhance clinical outcomes and inform neurological practice.

Exploring the Role of miRNAs in Cognitive Decline: Insights from Exosomal miR-146a to miR-21

Exosomal miR-146a: A Neuroprotective Agent in Cognitive Decline

Exosomal miR-146a, originating from bone marrow-derived mesenchymal stem cells, plays a crucial role in neuroprotection, particularly in the context of seizure-related cognitive impairment. Upon being absorbed by activated astrocytes in the hippocampal region, miR-146a exhibits protective effects against cognitive damage. Its lower blood levels in Alzheimer’s disease (AD) patients correlate with increased neuroinflammation, signifying its potential as a biomarker for AD progression. Overexpression of miR-146a in microglia contributes to improved learning/memory functions and reduced neuroinflammation and amyloid plaques, partly by inhibiting NF-κB nuclear translocation. Furthermore, it modulates microglial phenotype, reducing pro-inflammatory cytokines and aiding in β-amyloid and tau clearance. The downregulation of miR-146a in chronic conditions like diabetes, obesity, and hypertension may link to severe COVID-19 outcomes, with the overproduction of IL-6 potentially inactivating specific anti-COVID drugs.

miR-155: A Pro-Inflammatory Modulator in the CNS

miR-155, significantly expressed in Down’s syndrome-related dementia, acts as a central modulator of inflammatory responses in the CNS, affecting microglia activation. It mediates inflammation through NF-κB and induces the release of IFN-γ, promoting pro-inflammatory effects. This miRNA is associated with the progression of cognitive impairments by stimulating T-cell responses, leading to β-amyloid accumulation and cognitive deficits. In AD, miR-155 is linked to impaired cell migration and β-amyloid clearance, potentially contributing to neuroinflammation and cognitive decline. Elevated serum miR-155 levels in COVID-19 patients hint at its diagnostic potential for the disease.

Let-7b: A Potential Therapeutic Target in Cognitive Decline

Let-7b’s increased expression in various cognitive impairments, including mild cognitive impairment (MCI), AD, and Parkinson’s disease (PD), highlights its role in cognitive decline. Its elevated levels in SARS-CoV-2 infected individuals suggest a potential therapeutic angle, given its regulatory effects on angiotensin-converting enzyme 2. Let-7b’s modulation of immune responses in chronic inflammatory conditions and its association with cognitive dysfunction make it a notable candidate for further research in COVID-19 and cognitive decline.

miR-31: A Therapeutic Option for Alzheimer’s Disease

miR-31, with its reduced serum levels in AD, holds promise as a biomarker for distinguishing AD from vascular dementia. Its role in reducing β-amyloid deposition in AD models, alongside its impact on amyloid precursor protein (APP) and β-secretase cleavage, underscores its potential as a therapeutic agent for AD. However, low miR-31 levels in COVID-19 patients imply a complex interplay between this miRNA, cognitive dysfunction, and the viral infection, necessitating more extensive research to clarify its role.

miR-21: Modulating Neuroinflammation and Cognitive Decline

miR-21, known for its significant modulation of apoptosis and neuroinflammation, shows decreased levels in extracellular vesicles from AD patients. It acts as an anti-inflammatory agent by regulating NF-κB signaling and has been shown to improve dementia outcomes in brain injury contexts. The downregulation of miR-21 in COVID-19 patients, leading to increased systemic inflammation and potential neurodegeneration, indicates its critical role in the nexus of inflammation, neurodegeneration, and cognitive decline post-COVID-19.

In summary, the intricate network of miRNAs, including miR-146a, miR-155, Let-7b, miR-31, and miR-21, plays pivotal roles in the regulation of neuroinflammatory and neurodegenerative processes, impacting cognitive functions. Their interactions with COVID-19 further complicate their roles, presenting them as potential biomarkers and therapeutic targets in the fight against COVID-19-associated cognitive decline. Further research is essential to unravel the detailed mechanisms of these miRNAs and their therapeutic potential in cognitive diseases, especially in the context of COVID-19.

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