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By Jamshed Arslan, Pharm D, PhD
There is good news and bad news related to COVID-19, a disease caused by SARS-COV-2 infection. Good news first: the vast majority of otherwise healthy individuals remain asymptomatic. The bad news though is that even the asymptomatic population is at risk for COVID-19-related brain damage called NeuroCOVID. The neurological manifestations related to COVID-19 may be less severe and less frequent in milder cases as compared to the hospitalized patients. This article will outline the mechanism behind NeuroCOVID and COVID-19-related neuropsychological symptoms including headache, anosmia (loss of smell), ageusia (loss of taste), mental confusion, impaired consciousness, seizures, delirium, dizziness, agitation, cognitive impairment, aberrant psychomotor activity, coma, and a potential propensity for neurodegeneration. These mental complications can be due to the direct brain infection and/or a secondary impact of SARS-COV-2 infection on the central nervous system (CNS).
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ACE‑2 was detected in immersion fixed paraffin-embedded sections of human kidney using Mouse Anti-ACE‑2 Monoclonal Antibody (MAB933) at 15 µg/mL overnight at 4 °C. Before incubation with the primary antibody, tissue was subjected to heat-induced epitope retrieval using Antigen Retrieval Reagent-Basic (CTS013). Tissue was stained using the Anti-Mouse HRP-DAB Cell & Tissue Staining Kit (CTS002; brown) and counterstained with hematoxylin (blue). Specific staining was localized to cell surface of epithelial cells in convoluted tubules.
SARS-COV-2 can directly infect the brain through nasal entry or by crossing the blood-brain barrier (BBB). The nasal passage is rich in angiotensin-converting enzyme 2 (ACE-2) receptors that the virus uses to attach its spike (S) protein and then inject its RNA to replicate inside the infected cell. When the virus enters the nose from the respiratory droplets of an infected person, it attaches to ACE-2 receptors in the olfactory epithelium of the new host. SARS-CoV-2 infects the olfactory nerve and invades the brain through axonal transport, reaching from the piriform cortex up to the brainstem. Anosmia and respiratory complications of COVID-19 can be explained by the viral invasion of rhinencephalon and the respiratory centers of brainstem. Interestingly, it is mainly the damage to the olfactory supporting cells such as the sustentacular and basal cells that cause anosmia, rather than the olfactory neurons. The phylogenetic similarity and anatomical connectivity of the allocortex of hippocampus with the olfactory and piriform cortices can provide the rationale behind hippocampus-related symptoms like cognitive impairment and mental confusion.
The ubiquitousness of ACE-2 receptors explains the myriad of COVID-19 symptoms. The virus infects multiple organs and leaks into the blood to ultimately reach the brain after crossing BBB. Since the brain has relatively low ACE-2 receptor expression, SARS-COV-2 uses additional receptors, including EMMPRIN/CD147, also known by basigin, to infect various brain areas.
Western blot shows lysates of human brain (cerebellum) tissue, human heart tissue, and human liver tissue. PVDF membrane was probed with 0.2 µg/mL of Mouse Anti-Human EMMPRIN/CD147 Monoclonal Antibody (MAB972) followed by HRP-conjugated Anti-Mouse IgG Secondary Antibody (HAF018). A specific band was detected for EMMPRIN/CD147 at approximately 40-60 kDa (as indicated). This experiment was conducted under reducing conditions and using Immunoblot Buffer Group 1.
SARS-COV-2 can activate peripheral trigeminal nerve endings, either directly or through vascular damage, contributing to COVID-19-related headaches. The virus also promotes the release of pro-inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-alpha), into the blood. The exaggerated immune response leads to an attack on the myelin sheath and the consequent white matter damage is the underlying mechanism behind impaired cognition and aberrant sensory/motor activity. Combined with the respiratory failure/distress-induced hypoxia and the hypoxic/anoxic-related encephalopathy, patients feel symptoms of headache and dizziness. Moreover, attachment of the virus to endothelial ACE-2 receptors makes the blood vessels prone to inflammatory attack and coagulopathy. This provides the rationale behind ischemic and hemorrhagic cerebrovascular events observed in older patients.
Overall, neuropsychiatric symptoms associated with COVID-19 can be the result of a combination of both direct neuroinvasion and indirect pathological cascade resulting from the infection. To facilitate the diagnosis, research and treatment of neurological complications from COVID-19 and longitudinal follow-ups of infected patients is highly warranted.
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Jamshed Arslan, Pharm D, PhD
Dr Arslan is an Assistant Professor at Barrett Hodgson University, Pakistan,
where he uses various pedagogical methods to teach Pharm D students.
Research in focus
Bolay, H., et al. (2020). COVID-19 is a real headache! Journal of Head and Face Pain. https://doi.org/10.1111/head.13856.
Bougakov, D., Podell, K., & Goldberg, E. (2020). Multiple neuroinvasive pathways in COVID-19. Molecular Neurobiology. https://doi.org/10.1007/s12035-020-02152-5.
Brann, D.H., et al. (2020). Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia. Science Advances. https://doi.org/10.1126/sciadv.abc5801.
Otmani, H.E., & Moutaouakil, F. (2020). Neuro-COVID-19: What are we talking about? Revue Neurologique. https://doi.org/10.1016/j.neurol.2020.05.004.
Román, G.C., et al. (2020). The neurology of COVID-19 revisited: A proposal from the Environmental Neurology Specialty Group of the World Federation of Neurology to implement international neurological registries. Journal of the Neurological Sciences. https://doi.org/10.1016/j.jns.2020.116884.
