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Cognitive deficits in long-term Covid-19

Cognitive deficits in long-term Covid-19

Some patients who have recovered from infection have reported transient or even permanent cognitive dysfunction. This includes patients who have been infected with SARS-CoV-2, many of whom, including those with mild disease, have reported deficits in attention, executive functioning, language, processing speed and memory – symptoms collectively referred to as “brain fog”. ” Together with the increased frequency of anxiety, depression, sleep disorders and fatigue, this syndrome of cognitive impairment contributes significantly to the morbidity of the post-Covid-19 condition (also called “long Covid”).

However, it is difficult to diagnose and separate Covid-related brain fog from other causes of symptoms in an individual patient, as longitudinal neurocognitive data for patients is rarely available. (At a population level, however, post-Covid cognitive decline has been documented.1) Doctors are generally reluctant to accept the condition as an organic disease without a pathobiological concept or the ability to measure the disease in a given patient, as is the case with post-Covid brain fog. The results of a study recently published by Fernández-Castañeda and colleagues may represent a pivot in our understanding of this consequence.2

Effect of mild respiratory infection SARS-CoV-2 on neural cells.

In a recent study, Fernández-Castañeda et al.2 investigated the effects of a mild respiratory infection of SARS-CoV-2 in a mouse model. They found changes in neuroinflammatory cytokines and chemokines, including the protein CC motif chemokine 11 (CCL11), in cerebrospinal fluid and serum over a period of 7 weeks after initiation of infection. They also observed brain region-specific changes in subcortical white matter, with activation of microglia and subsequent loss of oligodendrocytes, oligodendrocyte precursor cells, and myelin. Intraperitoneal delivery of CCL11 to unaffected mice induced microglia activation and inhibited neurogenesis. Taken together, these mechanisms may explain brain dysfunction and cognitive impairment.

Using a mouse model, researchers investigated how mild respiratory infections with SARS-CoV-2 can lead to neuroinflammation and subsequent brain damage due to multilineage dysregulation of neuronal cells (Figure 1). The researchers modeled mild respiratory Covid in a mouse that expresses the viral entry receptor for SARS-CoV-2 (angiotensin-converting enzyme 2 in humans) in the trachea and lungs by delivering SARS-CoV-2 intranasally. They did not detect SARS-CoV-2 in the brain, but they did find signs of neuroinflammation in elevated levels of chemokines in CSF and serum, each with a different time course. These changes led to the activation of microglia in the subcortical and hippocampal regions of the white matter (but not in the gray matter), with distinct effects on specific populations of nerve cells. It should be noted that these findings are supported by similar results in a small group of patients who were found to have SARS-CoV-2 infection and did not have severe lung damage at the time of death.

Microglia are resident macrophage cells in the central nervous system. Although they contribute to central nervous system homeostasis and the purification of neuronal networks by removing dendritic spines and synapses during neuronal development, microglia can transition into an activated, neurotoxic state, as seen in this mouse model. In the subcortical white matter, microglial activation was associated with the loss of both oligodendrocyte precursors and mature oligodendrocytes; consistent with this loss, there was also a loss of myelin and myelinated axons at least 7 weeks after the onset of infection. Myelin insulates axons and is crucial for the speed of electrical conduction along neurons and for axonal metabolism. Loss of myelinated axons disrupts the structure and function of neuronal networks.

In the hippocampus, activation of microglia was associated with inhibition of neurogenesis, which could explain impaired memory formation in patients. Microglial activation appeared to be mediated by persistently elevated levels of a molecule called CC motif chemokine 11 (CCL11). CCL11 is associated with aging and inhibition of neurogenesis.3 Systemic intraperitoneal injection of CCL11 into mice resulted in activation of hippocampal microglia but not microglia in the subcortical white matter. Consistent with these findings, individuals with long Covid and cognitive deficits had higher levels of serum CCL11 than those with long Covid who did not have cognitive symptoms. The patients, like the mice, had a mild disease, and were infected before the availability of vaccines, but their number was small (48 with cognitive deficits and 15 without them).

The effect of CCL11 on microglial activation in the hippocampus and inhibition of neurogenesis warrants further investigation of circuit-specific effects of chemokines and cytokines and potentially offers a framework for the study, prevention, and treatment of neurological and psychiatric symptoms of long-term Covid. The findings of Fernández-Castañeda et al. they also have pathobiological parallels with cognitive impairment syndromes that occur after cancer therapy4 and after H1N1 influenza infection. (The researchers also found a temporal correlation between elevated levels of chemokines and cytokines and impaired hippocampal neurogenesis after H1N1 infection in a mouse model.)

Could these findings lead to a cure for brain fog caused by Covid? Several drugs targeting activated microglia have been tested in preclinical models of mechanistically similar cognitive impairment syndromes. Pexidartinib, a CSF1 receptor inhibitor, is approved by the Food and Drug Administration for the treatment of symptomatic tenosynovial giant cell tumors and can deplete microglia. Certain non-steroidal anti-inflammatory agents and tetracyclines can inhibit microglia. The findings of the study by Fernández-Castañeda and colleagues support the testing of microglial modulators for the treatment of brain fog associated with Covid. Studying the targeting of upstream regulators of microglial activation such as CCL11 may also be beneficial.

The study also implicates CCL11 as a candidate biomarker. If this finding is confirmed through a future study, CCL11 levels in plasma or cerebrospinal fluid could potentially identify patients with Covid-related cognitive impairment. The CCL11 assays could also be used to study the effect of the Covid vaccination on fog-related changes in the brain. However, since only small groups of patients were studied and factors such as patient gender and history of autoimmune disease may influence CCL11 serum levels, large cohort clinical studies are needed to rule out confounding variables and further substantiate CCL11 as a biomarker. Specificity may be increased when other cytokine or chemokine profiles are included or with a narrower focus on CCL11 levels in cerebrospinal fluid, as there is significant overlap in serum CCL11 levels in individuals with and without brain fog.

The discovery of axonal demyelination (or impaired myelination) in sections of the mouse brain could spur the development of new MRI biomarkers for humans.1 However, it should be noted that Fernández-Castañeda et al. used the earliest strain of SARS-CoV-2 (known as the original isolate Wuhan-Hu-1 or USA-WA1/2020); The relevance of their findings to brain fog associated with infection with other SARS-CoV-2 variants seems likely but uncertain. Moreover, as the authors themselves note, the contribution of other cell types, such as astrocytes, to the brain fog associated with Covid may be significant. Finally, there is the usual caveat that mice are not humans, so these findings warrant robust replication tests in studies involving larger numbers of patients. Although the findings of brain dysfunction and patterns of damage during and after Covid are concerning, especially given the similarities to changes in human neurodegenerative diseases,5 translational research, such as that reported by Fernández-Castañeda, may point the way toward accurate diagnoses and treatments.



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