Researchers Solve Why COVID-19 Can Cause Long-term Neurological Disorders

COVID-19 affects hundreds of millions of people worldwide and often causes long-term neurological symptoms such as loss of taste and smell, dizziness, headaches, confusion, memory disorder, chronic fatigue, or autonomic dysfunction. Researchers at HUN-REN Institute of Experimental Medicine (IEM) have identified the role of microglial cells, the main regulators of brain inflammatory processes in the development of COVID-19-related brain damage, reads the Hungarian Research Network’s website.

Clinical imaging studies have shown that lesions can develop in many areas of the brain even in the acute phase of the disease, while in post-COVID cases, a reduction in cortical thickness or disturbance of cerebral circulation may persist for many months. However, the causes of brain lesions are currently unknown. Their findings are of major clinical importance, and have been published in the prestigious Nature Neuroscience journal.

The Neuroimmunology research team, led by HUN-REN IEM’s Ádám Dénes, aimed to understand the role of the brain’s immune cells, i.e. microglia cells, in the development of inflammation and neurological symptoms induced by SARS-CoV-2 infection. To do this, they developed a new method that allowed detailed histological and molecular biological studies to be carried out on samples of brain tissue and peripheral organs from patients who died as a result of COVID-19.

One of the main findings of the research program is that microglial cell dysfunction and inflammatory processes in the surrounding cerebral blood vessels are strongly correlated with the extent of neuronal damage in brain areas affected by COVID-19.

The researchers found that the so-called P2Y12R receptors, that play a key role in microglial cell communication with nerve cells and brain blood vessels, were greatly reduced in brain areas where vascular inflammation was present alongside viral proteins.

It has also been found that functional disruption of microglia is associated with damage to mitochondria, which are also responsible for cellular energy production. The damage to microglial cells was most pronounced in brain regions where, in parallel with the inflammation of blood vessels, there was also significant damage to synapses and myelin sheaths that play a crucial role in neuronal communication. The neurological abnormalities identified developed in very different areas and to very different degrees in the brain of each patient, especially in the brainstem, where the main respiratory and circulatory centers are located. In addition, the cerebral cortex, hypothalamus, and thalamus were also affected, and damage to these areas may be associated with the development of hormonal, autonomic nervous system, memory, or sleep disorders as a result of COVID-19.

HUN-REN IEM researchers have also observed that SARS-CoV-2 virus proteins are expressed in blood vessel wall cells and circulating immune cells that accumulate in inflamed brain areas. In these areas, there was not only a dysfunction of microglial cells, but also damage to the so-called blood-brain barrier, which separates circulating blood from brain tissue.

Surprisingly, the researchers found that the elevated levels of inflammatory proteins in the circulation and peripheral organs also showed a strong correlation with the amount of inflammation and viral hereditary material (viral RNA) in the brain tissue of each patient.

They also showed a response of inflammasomes, that regulate the recognition of viral proteins and RNA and control inflammation, in brain tissue, lungs, the liver, and spleen. However, no significant evidence was found that large numbers of nerve cells were infected. This suggests that COVID-19 does not spread as a traditional neurological infection, but primarily induces neurological lesions through vascular inflammation and metabolic dysfunction and injury of brain glial cells.

The observed inflammatory processes may contribute to the development of neurological symptoms such as memory disorder, concentration difficulties, chronic fatigue, and depression, which affect many people, both in acute SARS-CoV-2 infection and in post-COVID syndrome,”

said Dénes, the leader of the research. He added that further studies are needed to explore the extent to which the identified brain inflammatory changes contribute to the development of long-term cognitive and neurological disorders, and how targeted inhibition of these changes could help develop more effective therapies to alleviate the neurological symptoms of COVID-19.

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