Mild COVID-19 infection may still lead to nerve cell and myelin disorders

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Stanford-Yale research: Mild COVID-19 infection may still lead to nerve cell and myelin disorders

Stanford-Yale research: Mild COVID-19 infection may still lead to nerve cell and myelin disorders.
　　

With at least 500 million people infected with Covid-19 worldwide, the ensuing “Long Covid” has become another pandemic.

The U.S. Centers for Disease Control and Prevention (CDC) defines “coronavirus” as a variety of new, recurring, or persistent health problems that may occur in people four weeks or more after they were first infected with the new coronavirus.

People with “coronavirus” often cite lingering neurological symptoms.

The latest research from Stanford University, Yale University and other teams from top universities in the United States has found that these neurological symptoms of “long COVID-19” patients are similar to the cognitive impairment (“chemo brain”) that occurs in cancer treatment.

The microglial reactivity in the white matter of the COVID-19 infection and the consequent neurological dysregulation are the core of the syndrome.

The study focused on the neurobiological effects of respiratory tract infection with SARS-CoV-2 and identified white matter-selective microglial reactivity in mice and humans.

Following the onset of mild respiratory COVID in mice, their hippocampal neurogenesis was persistently impaired, with reduced oligodendrocytes and loss of myelin and markedly elevated CSF cytokines/chemokines, including CCL11.

We found that systemic CCL11 leads to impaired microglial reactivity and neurogenesis in the hippocampus. Likewise, humans with persistent cognitive symptoms following SARS-CoV-2 infection also showed elevated CCL11 levels.

The study also found that mild respiratory influenza in mice similarly elicited similar white matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis and CCL11 at earlier time points compared to SARS-CoV-2 elevated pattern, but only CCL11 and hippocampal pathological elevations persisted after influenza recovery.

These findings illustrate similar neuropathology following cancer treatment and respiratory SARS-CoV-2 infection, implying that even mild SARS-CoV-2 infection can lead to cognitive impairment.

The corresponding authors of the aforementioned research are big names in the field of neurology and immunity in the United States: Michelle Monje, a professor in the Department of Neurology and Neuroscience at Stanford University in California, and Akiko Iwasaki, a professor in the Department of Immunobiology at Yale University.

Research institutions also include New York University, the National Institute of Neurological Disorders and Stroke, and the National Cancer Institute.

The research was published in the top international academic journal CELL on June 12, local time.

Persistent cognitive impairment affects about one in four people with Covid-19, according to previous research.

While people with COVID-19 who require hospitalization are more likely to experience cognitive impairment, even those with mild symptoms during the acute infection phase may experience lasting cognitive impairment, commonly known as “COVID-fog” (COVID-19 brain fog). , this COVID-related syndrome of cognitive impairment is characterized by impaired attention, information processing speed, memory, and executive function.

The latest research shows that this cognitive impairment syndrome greatly increases the incidence of “long COVID-19” along with increased rates of anxiety, depression, sleep disturbance and fatigue, and makes it difficult for infected people to return to their previous occupational levels.

Given the scale of global SARS-CoV-2 infection, this persistent cognitive impairment syndrome has become a major public health crisis. The syndrome of cognitive symptoms often experienced by people with Covid-19 is similar to the syndrome of cognitive impairment associated with cancer treatment, often referred to as the “chemo brain.”

Neuroinflammation is at the core of the pathophysiology of cognitive impairment associated with cancer therapy, suggesting that there may be similar pathophysiological mechanisms in SARS-CoV-2 infection.

The inflammatory response to mild COVID may also induce elevations in neurotoxic cytokines/chemokines, a pattern of white matter microglial reactivity, and consequent myelinating oligodendrocytes and dysregulation of hippocampal neural precursor cells.

Stanford-Yale research: Mild COVID-19 infection may still lead to nerve cell and myelin disorders

Important findings of the study

• Respiratory infection with 2019-nCoV induces elevation of cerebrospinal fluid cytokines and microglia reactivity

• CCL11 factor activates microglia in the hippocampus and impairs neurogenesis

• Respiratory infection with 2019-nCoV leads to persistent loss of oligodendrocytes and myelin axons

• Respiratory infection with influenza virus can cause a similar reaction, but with a shorter duration

Important knowledge points

Oligodendrocyte (oligodendrocyte) : distributed in the central nervous system.

Smaller than astrocytes, its cytoplasm is short and few, the nucleus is round, small and dense, and the cytoplasm has a high electron density under electron microscope, mainly containing mitochondria, ribosomes and microtubules.

In gray matter, oligodendrocytes are mainly located near the perinuclear body; in white matter, they exist side by side between myelinated nerve fibers and form the myelin sheath.

Active movement of oligodendrocytes can be seen in tissue culture.

The main function of oligodendrocytes is to wrap axons in the central nervous system, form insulating myelin structures, assist in the efficient transmission of bioelectrical signals, and maintain and protect the normal function of neurons.

Its abnormality will not only lead to demyelinating lesions of the central nervous system, but also cause neuronal damage or psychiatric diseases, and even brain tumors.

CCL11: Chemokine ligand 11, also known as eosinophil chemokine (Eotaxin), is a small molecular weight cytokine in the CC chemokine family.

It is selectively recruited by inducing chemotaxis of eosinophils and thus involved in allergic reactions. Elevated expression of CCL11 in human and mouse plasma is associated with aging.

Hippocampus: A key memory center in the brain that is involved in short-term memory formation and is often the focus of research on age-related cognitive decline.

Myelin sheath: A membrane that wraps around the axon of a nerve cell.

Its function is to insulate, similar to the sheath of a wire, preventing nerve electrical impulses from being transmitted from a neuron axon to another neuron axon, avoiding interference.

White matter: It is the place where nerve fibers gather in the brain. Because its area is lighter in color than the surface layer of the brain where the cell bodies gather, it is named white matter.

The researchers demonstrated through a series of experiments that even mild respiratory infections with SARS-CoV-2 can lead to persistent neuroinflammatory changes that lead to dysregulation of nerve cell types important for healthy cognitive function.

Such neuroinflammatory changes, particularly white matter-selective/enriched microglial reactivity, impaired hippocampal neurogenesis, oligodendrocyte lineage dysregulation, and loss of myelin in other disease settings have been implicated.

Details

Various immune stimuli induce distinct immune responses that differentially involve specific subsets of immune cells and induce disease-specific cytokine and chemokine profiles in the systemic and central nervous system.

This principle is underscored by differences in neuroinflammatory signatures observed in mouse models of SARS-CoV-2 and H1N1 influenza respiratory tract infections. SARS-CoV-2 infection induces a broad inflammatory response – well beyond the typical type 1 immune response to other respiratory viral infections.

Similarly, we found here that even mild respiratory COVID induces marked elevations of multiple cytokines and chemokines, as well as persistent reactivity of white matter microglia in subcortical and hippocampal regions. In contrast, H1N1 influenza caused a partially overlapping but distinct CSF cytokine/chemokine profile and a more restricted pattern of persistent cellular changes.

Systemic inflammation-induced neuroinflammation with consequent glial dysregulation and impaired neurological function is beyond the usual symptoms of COVID. Other viral syndromes such as influenza can also cause microglial reactivity, elevated levels of central nervous system cytokines, and impair cognitive function, even in the absence of neural invasion.

However, the oligodendrocyte deficits observed in the present study after the acute infection phase of SARS-CoV-2 were more persistent than those of H1N1 influenza, and were more consistent with persistent changes after methotrexate chemotherapy.

In general, people with COVID-19 who have recovered from critical illness experience higher rates of long-term cognitive impairment, the researchers said, and persistent cognitive impairment is also a post-intensive care syndrome.

The specific immunogenicity of SARS-CoV-2 and the persistence of the neuroinflammatory changes observed here, given the size of the infected population globally during this pandemic, have contributed to the crisis of persistent cognitive impairment associated with COVID.

Elevated levels of CCL11 were found in mice infected with either SARS-CoV-2 or H1N1 influenza in the respiratory tract. Elevated levels of CCL11 were found in humans with cognitive symptoms after COVID-19 infection, which can lead to insufficient hippocampal neurogenesis and induce microglial reactivity in the hippocampus.

But this finding means that the hippocampus is particularly vulnerable to the neuroinflammation of respiratory infections, consistent with recent reports of structural changes in the limbic nervous system in COVID survivors: This region/circuit-specific role of CCL11 highlights distinct cytokines Potential for the /chemokine profile to exert disease-specific effects on the nervous system, resulting in variable prevalence of certain cognitive or neuropsychiatric symptoms.

Consistent with the clinical similarities of the “COVID-19 brain fog” and “chemo brain” syndromes of cognitive impairment, the findings here illustrate many pathophysiological similarities, including depletion of myelinating oligodendrocytes and loss of myelin sheath .

Myelin regulates the speed of nerve impulse conduction, provides metabolic support for axons, and exhibits adaptive plasticity; even small changes in myelination can have profound effects on neural circuit dynamics and thus cognitive function influences. Subcortical white matter microglia/macrophage reactivity and associated loss of oligodendrocyte and myelin axons in a mouse model of SARS-CoV-2 respiratory infection and methotrexate chemotherapy-associated cognitive impairment are similar.

Although methotrexate directly stimulates microglial responsiveness, the mechanism mediating respiratory infection-induced subcortical white matter microglial responsiveness remains to be fully elucidated and may involve cytokine/chemokine signaling.

The conduction mechanism or the cellular neuroimmune interaction requires further study.

In addition to the neuropathological changes caused by a relatively mild acute respiratory infection and consequent neuroinflammation, more severe COVID may lead to additional neuropathological consequences.

These include microvascular thrombosis, neuronal loss, cortical inflammation, and in some cases outright brain infection. Consequently, the neurological sequelae of SARS-CoV-2 infection have proven to be common and debilitating.

While the inflammation-induced multicellular dysregulation described here may be reversed by therapeutic interventions, these more severe complications of COVID, such as stroke, may cause irreversible damage to the brain.

Stanford-Yale research: Mild COVID-19 infection may still lead to nerve cell and myelin disorders

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