In late 2019, a new variant of Coronaviruses called SARS-CoV-2 or COVID-19 emerged as a severe acute respiratory syndrome, rapidly spreading worldwide and becoming a global health concern. While primarily characterized as a respiratory pathogen transmitted through respiratory droplets, COVID-19 has also been associated with abnormalities in various organs, including the brain, heart, kidneys, liver, skeletal muscle, and skin.
Neurological symptoms, such as dizziness, headache, and impaired consciousness, have been observed in a significant percentage of COVID-19 patients.
Moreover, long-term cognitive dysfunction has been detected in patients who have recovered from COVID-19 infection. This article explores the long-lasting neuro-cognitive impairment caused by SARS-CoV-2 and the possible role of vascular dysfunction in its development.
Neurological and Cognitive Symptoms in COVID-19
A meta-analysis study of COVID-19 patients reported fever, cough, fatigue, and hyposmia (impaired sense of smell) as the most common symptoms. Neurological abnormalities, including dizziness, headache, and impaired consciousness, were observed in 36.4% of hospitalized COVID-19 patients.
Furthermore, cognitive deficits have been reported in non-hospitalized COVID-19 patients, with the most common symptoms being fatigue, memory impairment, decision-making difficulties, and concentration problems. Patients have often described these cognitive deficits as “brain fog” or “mental clouding.” Long-term cognitive impairment has been found to persist even after recovery from the infection.
COVID-19 and Cognitive Function
Cognition refers to the processing of information necessary for acquiring knowledge and generating a response. It involves perception, attention, understanding, memory, reasoning, and judgment. Fatigue, memory impairment, difficulties in decision-making, and concentration problems are frequently reported cognitive injuries in non-hospitalized COVID-19 patients.
Cognitive deficits can persist for several weeks or even months after the acute onset of the disease. Studies have shown significant differences in sustained attention, executive function, visuospatial processing, memory, and language between COVID-19 patients and healthy controls.
Mechanisms of COVID-19 Penetration into the Central Nervous System (CNS)
While direct evidence of SARS-CoV-2 virus in the cerebrospinal fluid is lacking, both direct and indirect mechanisms may contribute to CNS dysfunction in COVID-19. The virus enters host cells by binding to the ACE2 receptor on the cell surface.
ACE2 is expressed in various cells in the central nervous system, including neurons, astrocytes, oligodendrocytes, and endothelial cells. This widespread expression of ACE2 makes the CNS susceptible to SARS-CoV-2 invasion. Other receptors, such as CD147 and neuropilin-1 (NRP1), have also been implicated in the virus’s entry into the brain. Furthermore, proteases like TMPRSS2, cathepsin B and L, and furin play a role in facilitating viral entry and replication.
Endothelial Cell Infection and Endotheliitis in COVID-19
Vascular endothelial cells line the innermost layer of blood vessels and play a crucial role in maintaining vascular integrity and homeostasis. COVID-19 has been associated with endothelial dysfunction and inflammation. Autopsy studies have shown evidence of endothelial cell damage and microthrombi formation, particularly in small vessels like capillaries.
The expression of ACE2, TMPRSS2, and other receptors involved in SARS-CoV-2 infection has been detected in endothelial cells. Inflammatory mediators released during infection can lead to endothelial cell activation, impairing vascular integrity.
Impaired Vascular Function and Neurological Consequences
Endothelial dysfunction and inflammation in COVID-19 can lead to vascular abnormalities, including microthrombi formation, increased permeability, and impaired blood flow regulation. These vascular changes can have detrimental effects on the brain, potentially leading to neurological symptoms and cognitive impairment. Reduced blood flow and oxygen delivery to the brain can result in neuronal damage and cognitive dysfunction.
Ischemic Stroke and COVID-19
COVID-19 has been associated with an increased risk of ischemic stroke, which occurs when a blood clot blocks a blood vessel in the brain. The endothelial dysfunction, inflammation, and procoagulant state observed in COVID-19 contribute to this increased stroke risk. Ischemic stroke can result in focal neurological deficits and cognitive impairments, depending on the affected brain region.
Small Vessel Disease and Cognitive Impairment
Small vessel disease (SVD) refers to the damage or dysfunction of small blood vessels in the brain. It is commonly associated with hypertension, diabetes, and aging. COVID-19 may exacerbate SVD through endothelial dysfunction and inflammation, leading to cognitive impairment. SVD-related cognitive impairment typically manifests as difficulties in executive function, attention, processing speed, and memory.
Neuroinflammation and Cytokine Storm
COVID-19 triggers a systemic immune response, including the release of proinflammatory cytokines. This immune response, often referred to as a cytokine storm, can also affect the brain and contribute to cognitive dysfunction. Neuroinflammation, characterized by the activation of immune cells and release of inflammatory molecules in the brain, has been observed in COVID-19 patients. Elevated levels of cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) have been associated with cognitive impairment.
Neurological Consequences of Hypoxia
In severe cases of COVID-19, hypoxia (oxygen deprivation) can occur due to respiratory distress or acute respiratory distress syndrome (ARDS). Hypoxia can lead to neuronal injury and cognitive impairment. The hippocampus, a brain region critical for memory formation, is particularly vulnerable to hypoxic damage. Hypoxia-related cognitive impairment may manifest as memory deficits, attention problems, and difficulties with executive function.
The Blood-Brain Barrier and its Role
The BBB is a highly selective barrier that separates the blood circulation from the brain parenchyma, protecting the delicate neural tissue from harmful substances and pathogens. It consists of brain endothelial cells connected by tight junctions, along with other supporting cells such as pericytes, astrocytes, and microglia. This complex structure, collectively known as the neurovascular unit (NVU), regulates the exchange of molecules and maintains the homeostasis of the CNS.
Endothelial Cell Inflammation and BBB Disruption
SARS-CoV-2 is unable to easily penetrate the brain parenchyma through the endothelial cells that line the capillaries of the systemic circulatory system due to the unique physiology of the BBB. However, in the context of COVID-19, the hyper-inflammatory condition induced by the infection can contribute to BBB damage. Studies have shown that human brain microvascular endothelial cells infected with SARS-CoV-2 exhibit overexpression of pro-inflammatory cytokines, chemokines, and adhesion molecules, along with decreased expression of tight junction proteins. This disruption of endothelial tight junctions can lead to increased BBB permeability, allowing the virus and inflammatory molecules to enter the CNS.
Role of Pro-inflammatory Cytokines
Elevated levels of pro-inflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), have been observed in COVID-19 patients and are known to affect BBB integrity. These cytokines can impair the function of tight junction proteins and increase BBB permeability, facilitating the infiltration of immune cells and viral particles into the CNS. Additionally, cytokines like IL-1β can upregulate matrix metalloproteinase-9 (MMP-9), which further disrupts tight junction proteins through the activation of signaling cascades.
Disseminating Intravascular Coagulation and BBB Disruption
COVID-19 is associated with both overactive coagulation and hyper-inflammation, which can contribute to endothelial cell damage and thrombus formation. Intravascular coagulation and thromboembolic events have been reported in severe COVID-19 cases, and these events can potentially lead to the occlusion of cerebral blood vessels, causing neurological manifestations and cognitive deficits. The release of pro-inflammatory cytokines and activation of the complement system in COVID-19 further contribute to the coagulation process and can lead to the activation of platelets and the formation of blood clots. These processes can indirectly disrupt the BBB by promoting inflammation, coagulation, and platelet aggregation.
Pneumonia and BBB Disruption
Pneumonia, a common complication of COVID-19, can also contribute to BBB disruption and cognitive impairment. Hypoxemia and hypoxia resulting from pneumonia can cause neuronal atrophy, cognitive dysfunction, and memory loss. CT scans of COVID-19 patients with acute respiratory distress syndrome (ARDS) have revealed cerebral atrophy and widening of the ventricles, indicating brain damage.
The brain damage observed in these cases may be attributed to a combination of factors, including hypoxia-induced inflammation, cytokine release, and oxidative stress, all of which can disrupt the BBB and compromise neuronal function.
Implications of BBB Disruption in COVID-19
The disruption of the BBB in COVID-19 can have significant implications for CNS involvement and neurological complications. Here are a few key implications:
- Neuroinvasion: BBB disruption allows the entry of SARS-CoV-2 into the CNS, leading to direct viral invasion and potential neuronal damage. The presence of the virus in the brain can trigger neuroinflammatory responses and activate immune cells, exacerbating CNS damage.
- Neurological Symptoms: COVID-19 patients with BBB disruption may experience a range of neurological symptoms, including headaches, dizziness, altered mental status, delirium, and seizures. These symptoms can arise due to direct viral effects on the CNS, neuroinflammation, or secondary effects of systemic inflammation.
- Long-Term Neurological Consequences: BBB disruption and associated CNS damage may contribute to long-term neurological consequences in COVID-19 survivors. Cognitive impairment, memory deficits, mood disorders, and other neurodegenerative conditions have been observed in individuals recovering from severe COVID-19.
- Therapeutic Considerations: Understanding the mechanisms of BBB disruption can inform the development of targeted therapies. Strategies aimed at reducing neuroinflammation, restoring BBB integrity, and preventing viral entry into the CNS may help mitigate neurological complications in COVID-19.
COVID-19 can result in long-term neurological and cognitive impairment, even in individuals who have recovered from the acute infection. Vascular dysfunction, including endothelial cell infection, endotheliitis, and small vessel disease, likely plays a crucial role in the development of these neurological consequences. Understanding the mechanisms underlying COVID-19-associated cognitive impairment can inform targeted interventions and treatments for affected individuals. Further research is needed to unravel the complex interactions between the virus, vascular dysfunction, and neurological sequelae in COVID-19.
reference link :https://www.preprints.org/manuscript/202306.0170/v1