By Gabriella Martinez
COVID-19’s impact persists beyond the initial infection, with post-COVID syndrome (PCS, also known as Long COVID) affecting 10-20% of those infected (World Health Organization, 2022). The Centers for Disease Control Prevention (2024) define PCS as a chronic illness caused by COVID-19 that presents with symptoms for at least three months after a COVID-19 infection, impacting multiple organ systems. One of the most common symptoms, brain fog, is raising serious concerns about cognitive impairments in those living with Long COVID. This article will be exploring possible mechanisms that cause PCS-related brain fog as a way to spark conversation and generate interest for more research into this issue.
What Is PCS-Related Brain Fog? Why Does It Matter?
More than 200 PCS symptoms have been identified, with neurological and psychiatric issues being common (CDC, 2024). Taquet et al. (2021) found that a third of PCS patients received a neurological or psychiatric diagnosis within six months of infection. Brain fog, a term for neurocognitive symptoms affecting the prefrontal cortex, impacts working memory, abstract reasoning, and executive functioning (Zadeh et al., 2023).
Even mild COVID-19 cases can lead to cognitive impairments, with these deficits often appearing within the first month post-infection (Krishnan et. al., 2022). This is concerning as the prefrontal cortex’s functions are vital to daily life. PCS-related brain fog can severely impact professional, academic, and personal relationships. One in four adults with PCS experience significant limitations to their daily activities (CDC, 2024), making it crucial to understand its potential causes– neuroinflammation, vascular dysfunction, and reduced neuronal firing– so effective treatments can be developed.
Neuroinflammation
When COVID-19 infects a host, it gains access to the host’s cells by binding a Spike protein to their angiotensin converting enzyme 2 (ACE2) receptors (Shabani et al., 2023). Due to ACE2 receptors being located throughout the body, the virus quickly gains access to various types of cells, including those in the central nervous system (CNS). Normally, this enzyme is supposed to help regulate blood pressure and protect the brain by transforming angiotensin I to angiotensin II, which leads to the stimulation of the angiotensin II type 1 receptor (AT1R) (Shabani et al., 2023). However, when AT1R is activated, it can promote inflammation and neurodegeneration, leaving the CNS extremely susceptible to an invasion of COVID-19 (Shabani et al., 2023).
As this occurs, microglia– cells that eliminate any potential threats to the CNS– release pro-inflammatory cytokines which contribute heavily to the body’s immune response (Colonna & Butovsky, 2017). As the microglia continue to overcompensate with more and more cytokines, the cells can experience mitochondrial dysfunction, oxidative stress, and ultimately, a severe neuroinflammatory response called a “cytokine storm”, increasing the risk of more inflammation developing in the brain (Gorenshtein et al., 2024).
Vascular Dysfunction and the Blood-Brain Barrier
Cytokines can also compromise the blood-brain barrier (BBB), a selective membrane that lines the brain’s blood vessels and protects the brain by preventing harmful substances from entering. The BBB is composed of tight junction proteins that hold together vascular endothelial cells, ensuring the barrier’s integrity (Shabani et al., 2023). However, Shabani et al. (2023) found the release of pro-inflammatory cytokines like IL-1, IL-6, and TNF-ɑ can degrade these proteins, making the BBB more permeable. This increased permeability allows more cytokines and the virus itself to enter the brain (Shabani et al., 2023). Additionally, cytokines stimulate Vascular Endothelial Growth Factor (VEGF) in astrocytes, which further disrupts tight junctions and exacerbates inflammation, contributing to brain fog in PCS patients (Shabani et al., 2023).
Because of the weakened BBB, it can no longer effectively protect the brain and may lead to long-term neurological issues, even after the infection clears (Shabani et al., 2023). Shabani et al.'s research also mentions how elevated levels of pro-inflammatory chemokines, molecules previously linked to age-related cognitive decline, were found in Long COVID patients with cognitive deficits. Furthermore, it is also stated that changes in the brain’s white matter were found postmortem, which could explain the persistent cognitive impairment seen in those with PCS (Shabani et al., 2023).
Reduced Neuronal Firing
Neuroinflammation from COVID-19 affects neurons firing in the brain, particularly in the prefrontal cortex, which is highly vulnerable to inflammation due to its reliance on calcium-dependent feedback loops (Zadeh et al., 2023). Proper neuronal function requires balanced calcium levels; too much calcium causes nearby potassium channels to open, reducing neuronal firing. They further discuss how inflammation increases calcium release within neurons through the use of cytokines, leading to reduced firing and loss of dendritic spines necessary for synaptic connections and cognitive function.
Additionally, COVID-19 increases kynurenine levels in the brain, which can be converted into either the harmful kynurenic acid (KYNA) or the protective quinolinic acid. KYNA blocks receptors (NMDAR and nic-ɑ7R) pivotal for neuron protection, contributing to cognitive issues like memory loss (Zadeh et al., 2023). Their study suggests the virus also raises GCPII levels, disrupting normal brain signaling by reducing the effectiveness of the neurotransmitter NAAG– the combined increase of KYNA and GCPII leads to more frequent potassium channel openings, further impairing neuronal firing and perpetuating cognitive dysfunction.
Conclusion
The cognitive impairments associated with post-COVID syndrome, specifically PCS-related brain fog, highlight the complex interplay between neuroinflammation, vascular dysfunction, and reduced neuronal firing. COVID-19’s ability to invade the CNS, disrupt the BBB, and alter neuronal signaling barely scratches the surface on the virus’s far-reaching effects on brain health. The health and wellbeing of these patients can vary, but many describe feeling hopeless about how this illness has ravaged their body. For those living with PCS or caring for someone who does, it can be disheartening. My mom has had Long COVID since 2021 and watching her struggle with her memory and be unable to do the things she once loved has been incredibly difficult.
At the beginning of this article, I spoke of how I wished to spark interest and conversation on this subject out of professional courtesy. However, personally, I wanted to explore these mechanisms so that I could understand PCS’s potential etiologies and help alleviate the challenges faced by my loved ones and others affected by this condition. These findings emphasize the urgency needed to understand this chronic illness so adequate interventions can be discovered and used to improve quality of life in PCS patients. As research continues, it is imperative to address these neurocognitive challenges and mitigate the long-term impacts of COVID-19 on mental and neurological health.
References
Centers for Disease Control Prevention: COVID-19. (2024, July 12). CDC Science and the Public Health approach to long COVID. https://www.cdc.gov/covid/php/long-covid/index.html
Colonna, M., & Butovsky, O. (2017). Microglia function in the central nervous system during health and neurodegeneration. Annual Review of Immunology, 35(1), 441–468. https://doi.org/10.1146/annurev-immunol-051116-052358
Gorenshtein, A., Liba, T., Leibovitch, L., Stern, S., & Stern, Y. (2024). Intervention modalities for brain fog caused by long-COVID: systematic review of the literature. Neurological Sciences. https://doi.org/10.1007/s10072-024-07566-w
Krishnan, K., Lin, Y., Prewitt, K. M., & Potter, D. A. (2022). Multidisciplinary Approach to Brain fog and related Persisting Symptoms Post COVID-19. Journal of Health Service Psychology, 48(1), 31–38. https://doi.org/10.1007/s42843-022-00056-7
Shabani, Z., Liu, J., & Su, H. (2023). Vascular dysfunctions contribute to the Long-Term cognitive deficits following COVID-19. Biology, 12(8), 1106. https://doi.org/10.3390/biology12081106
Taquet, M., Geddes, J. R., Husain, M., Luciano, S., & Harrison, P. J. (2021). 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. The Lancet Psychiatry, 8(5), 416–427. https://doi.org/10.1016/s2215-0366(21)00084-5
World Health Organization: WHO. (2022, December 7). Post COVID-19 condition (Long COVID). https://www.who.int/europe/news-room/fact-sheets/item/post-covid-19-condition
Zadeh, A. F., Arnsten, A. F. T., & Wang, M. (2023). Scientific Rationale for the Treatment of Cognitive Deficits from Long COVID. Neurology International, 15(2), 725–742. https://doi.org/10.3390/neurolint15020045
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