Following an infection, some individuals have experienced short-term or even long-term cognitive damage. This includes SARS-CoV-2 infected patients, many of whom have reported deficits in attention, executive functioning, language, processing speed, and memory — symptoms collectively referred to as "brain fog" Together with increased incidence of anxiety, depression, sleep disorder, and fatigue, this syndrome of cognitive impairment contributes significantly to the morbidity of post-Covid-19 conditions (also known as "lo" conditions).
Nevertheless, because neurocognitive longitudinal data for patients are infrequently accessible, it might be challenging to identify Covid-related brain fog and to distinguish it from other causes of symptoms in a specific patient. Physicians are typically reluctant to acknowledge a symptom as an organic disease without a pathobiologic notion or the ability to assess the disease in a given patient, as is the case with post-Covid brain fog. Cognitive deterioration after Covid has, however, been observed on a population level. The findings of a study that Fernández-Castaeda and colleagues recently described may mark a turning point in our comprehension of this sequela.
The researchers investigated how multilineage neural cell dysregulation in moderate SARS-CoV-2 respiratory infections could result in neuroinflammation and eventual brain injury (Figure 1). By administering SARS-CoV-2 intravenously, the researchers were able to simulate moderate 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 lung. No SARS-CoV-2 was found in the brain, but they did find evidence of neuroinflammation in the form of raised chemokine levels in the serum and cerebrospinal fluid, each with a distinctive time course. In the subcortical and hippocampal white-matter regions (but not in the gray matter), these modifications induced microglia activation, which had unique impacts on particular neuronal cell types.Notably, similar outcomes in a small number of patients who were determined to have SARS-CoV-2 infection and no substantial lung damage at the time of death validated these findings.
The central nervous system's resident macrophage cells are known as microglia. Microglia can change into an active, neurotoxic state, as observed in this mouse model, despite the fact that they help maintain the homeostasis of the central nervous system and refine neuronal networks by eliminating dendritic spines and synapses during the formation of neurons. Both oligodendrocyte precursors and mature oligodendrocytes were lost in the subcortical white matter as a result of microglial activation; in line with this loss, myelin and myelinated axons were also lost until at least 7 weeks after the infection started. Axonal metabolism and the speed of electrical conduction along neurons depend on myelin, which protects axons. The structure and operation of neural networks are hampered by the loss of myelinated axons.
Microglia activation was linked to decreased neurogenesis in the hippocampus, which may account for patients' poor memory development. The molecule known as C-C motif chemokine 11 seems to be the mediator of the activation of microglia (CCL11). CCL11 has been connected to neurogenesis suppression and aging. Mice receiving a systemic intraperitoneal dose of CCL11 had their subcortical white matter microglia activated but not their hippocampus microglia. Persons with long Covid and cognitive abnormalities showed higher blood CCL11 levels than those with long Covid but no cognitive symptoms, which is consistent with our findings. The patients, like the mice, had a mild illness and were infected before vaccines were available, although they were few in number(48 with cognitive deficits and 15 without them).
Further investigation of the effects of chemokines and cytokines specific to brain circuits is warranted in light of CCL11's impact on microglial activation in the hippocampus and inhibition of neurogenesis. This research may also provide a framework for studying, preventing, and treating the neurologic and psychiatric symptoms of long-term COVID. The results of Fernandez-Castaeda et al. also share pathobiologic similarities with cognitive impairment syndromes that have been reported following cancer therapy and H1N1 infection. (The researchers discovered a temporal relationship between increased chemokine and cytokine levels and reduced hippocampus neurogenesis following H1N1 infection in a mouse model.)
Could a remedy for Covid-related brain fog result from these discoveries?
In preclinical models of mechanistically comparable syndromes of cognitive impairment, a number of medicines that target activated microglia have been explored. The Food and Drug Administration has approved pexidartinib, an inhibitor of the CSF1 receptor, for the treatment of symptomatic tenosynovial giant-cell tumors. It has the ability to deplete microglia. Tetracyclines and specific nonsteroidal anti-inflammatory drugs can stop microglia from functioning. The research on microglial modulators to treat Covid-related brain fog is supported by the findings of the study by Fernández-Castaeda and colleagues. Another useful area of research is the targeting of CCL11 and other upstream regulators of microglial activation.
The study suggests CCL11 as a potential biomarker as well. Levels of CCL11 in the plasma or CSF fluid may be able to identify people with Covid-related cognitive impairment if this finding is confirmed by further research. The impact of Covid vaccinations on alterations related to changes in brain fog might also be investigated using assays of CCL11. Large cohort clinical investigations are required to rule out confounding variables and further substantiate CCL11 as a biomarker, however, as only small patient cohorts were examined and characteristics including a patient's sex and history of autoimmune disease may influence serum levels of CCL11. When additional cytokine or chemokine profiles are taken into account, or when the amount of CCL11 in the cerebrospinal fluid is specifically targeted, specificity may rise，since there is a substantial overlap of CCL11 serum levels in persons with brain fog and those without.
It should be noted, however, that Fernández-Castaeda et al. used the earliest strain of SARS-CoV-2 (known as the original Wuhan-Hu-1 isolate or USA-WA1/2020); the relevance of their findings to brain fog associated with infection by other SARS-CoV-2 variants seems likely but uncertain. The discovery of axonal demyelination (or impaired myelination) in sections of mouse brain could inspire the development of new magnetic Additionally, as the authors themselves acknowledged, astrocytes and other cell types may contribute significantly to the mental fog associated with Covid. The findings demand rigorous tests of replication in studies with a greater number of patients due to the typical caveat that mice are not people.Although the findings of brain dysfunction and damage patterns during and after Covid are concerning, particularly in light of the similarities with changes in human neurodegenerative diseases, translational studies like the one described by Fernández-Castaeda may point to avenues toward precise diagnoses and treatments.
