The outbreak of SARS-CoV-2 in 2019 has resulted in numerous variants with high transmissibility. The emergence of the Omicron variant has led to over 0.7 billion infectious cases worldwide. Despite high vaccination rates in many countries, breakthrough infections of the Omicron variant in vaccinated individuals have been reported.
Additionally, a significant percentage of SARS-CoV-2 patients experience post-COVID-19 symptoms, known as Long-COVID syndrome. These symptoms, including fatigue, shortness of breath, headache, loss of smell or taste, myalgia, anxiety, and cognitive impairment, have been observed in patients with both severe and mild clinical courses.
The incidence of dementia and psychiatric disorders is also higher in SARS-CoV-2 patients compared to those infected with other respiratory viruses.
This review aims to explore the molecular evidence of SARS-CoV-2 infection in the brain, the effects of spike-mediated syncytia formation, the long-term impact of SARS-CoV-2 on the human brain and memory, and the strategies for preventing Long-COVID syndrome.
Routes of SARS-CoV-2 Invasion in the Brain
SARS-CoV-2 primarily infects the respiratory tract. However, there are three possible routes through which the virus can invade the brain.
Firstly, the virus can spread directly from the nasal cavity to the olfactory bulb of the brain through the olfactory nerves. The high expression of the ACE2 receptor in the nasal cavity facilitates this direct neuroinvasion.
Secondly, viral infection in the respiratory tract can lead to significant pathological changes, allowing the virus to enter the bloodstream. From there, the virus can cross the blood-brain barrier and invade the central nervous system (CNS) through different pathways.
Lastly, SARS-CoV-2 can potentially infect the eyes and reach the occipital cortex through the optic nerve. Although eyes are not the main site of infection, this route is still a possibility.
Effects of SARS-CoV-2 Infection on the Nervous System
Long-COVID syndrome has been observed in a significant number of patients, both with severe and mild COVID-19. Symptoms include fatigue, neurological and psychiatric manifestations, frequent headaches, shortness of breath, memory and concentration difficulties, autonomic dysfunction, and other neurological symptoms.
Studies have demonstrated the presence of ACE2, NRP1, and TMPRSS2, the receptors and protease required for SARS-CoV-2 entry, in human nerves near the medulla and other CNS regions. Brain imaging studies have shown greater brain size reduction and volume loss in patients with SARS-CoV-2 infection, even in mild cases.
While SARS-CoV-2 RNA detection in cerebrospinal fluid is rare, immune activation and inflammation within the CNS are believed to be the primary causes of neurological symptoms. However, brain organoid and non-human primate studies have demonstrated SARS-CoV-2 replication in brain tissues, suggesting a direct impact on the nervous system. SARS-CoV-2 infection has also been associated with the activation of Alzheimer’s-like neuropathology and an increased incidence of parkinsonism.
Effects of SARS-CoV-2-Mediated Syncytia Formation
In addition to viral replication, the spike protein of SARS-CoV-2 can induce cell-cell fusion, leading to the formation of syncytia. Syncytia formation has been linked to severe pneumonia and immune responses in patients. Spike-mediated fusion can cause apoptosis and cell death, and it has been associated with immunosuppression and the evasion of host defenses.
The formation of syncytia in the brain can disrupt normal neuronal communication and contribute to the neurological symptoms observed in SARS-CoV-2 patients. The syncytia formation can lead to the loss of functional neuronal networks and impair cognitive functions, memory, and overall brain health.
Long-Term Impact on Memory and Cognitive Function
Several studies have reported cognitive impairments in individuals recovering from SARS-CoV-2 infection. These impairments include difficulties with memory, attention, executive function, and processing speed. The exact mechanisms underlying these cognitive deficits are not yet fully understood, but it is believed to involve a combination of direct viral invasion, neuroinflammation, and vascular abnormalities. The involvement of the hippocampus, a brain region crucial for memory formation and consolidation, has been suggested as a potential mechanism for the memory impairments observed in Long-COVID syndrome.
Inflammation and immune dysregulation induced by SARS-CoV-2 infection can contribute to neuronal damage and disrupt neuroplasticity, leading to long-term cognitive deficits. The activation of pro-inflammatory cytokines and the dysregulation of immune responses can further exacerbate the neuroinflammatory processes and contribute to neuronal dysfunction. Additionally, the disruption of the blood-brain barrier, which has been observed in COVID-19 patients, can allow immune cells and inflammatory mediators to enter the brain, leading to further neuroinflammation and neuronal damage.
Strategies for Preventing Long-COVID Syndrome
Given the potential long-term impact of SARS-CoV-2 on the brain and memory, it is crucial to develop strategies for preventing Long-COVID syndrome. This includes early diagnosis and treatment of SARS-CoV-2 infection, as well as monitoring and managing post-COVID-19 symptoms.
Vaccination against SARS-CoV-2 remains a key preventive measure to reduce the risk of infection and subsequent neurological complications. Additionally, promoting a healthy lifestyle that includes regular exercise, a balanced diet, and mental stimulation can support brain health and potentially mitigate the cognitive effects of SARS-CoV-2 infection.
SARS-CoV-2 infection can have significant impacts on the human brain and memory. The virus can invade the brain through various routes, leading to neuroinflammation, neuronal damage, and cognitive impairments. Syncytia formation induced by the spike protein of the virus can further contribute to the disruption of normal neuronal function. Long-COVID syndrome, characterized by persistent symptoms such as fatigue, headaches, and cognitive impairments, highlights the need for comprehensive management and preventive strategies. Further research is necessary to better understand the underlying mechanisms and develop effective interventions to mitigate the long-term neurological consequences of SARS-CoV-2 infection.