Functional and microstructural brain abnormalities, fatigue, and cognitive dysfunction after mild COVID-19 (preprint)

Background: Little is known about the underpinning mechanisms of neurological dysfunction in post-COVID syndrome. Methods: We conducted a cross-sectional study of 87 consecutive subjects after a mild infection, with a median of 54 days after diagnosis of COVID-19. We performed structured interviews, neurological examinations, 3T-MRI scans, and neuropsychological assessments. The MRI study included white matter investigation with diffusion tensor images (DTI) and functional connectivity with resting-state functional MRI (RS-fMRI). Results: Subjects self-reported headaches (40%) and memory difficulties (33%). The quantitative analyses confirmed symptoms of fatigue (68% of participants), excessive somnolence (35%), symptoms of anxiety (29%), impaired cognitive flexibility (40%), and language dysfunction (33%). Besides, we observed a correlation between DTI fractional anisotropy (FA) and abnormal attention and cognitive flexibility in the Trail Making Test part B. Elevated levels of fatigue and somnolence associated with higher connectivity of the posterior cingulate cortex (PCC) in the RS-fMRI study of the default mode network. While higher connectivity of the PCC with bilateral angular gyri was associated with higher fatigue levels, the elevated levels of somnolence correlated with higher connectivity between the PCC and both the left thalamus and putamen. Conclusions: COVID-19 is associated with long-term neuropsychiatric symptoms and cerebral functional and microstructural alterations.

Functional and microstructural brain abnormalities, fatigue, and cognitive dysfunction after mild COVID-19 (preprint)

Although post-acute cognitive dysfunction and neuroimaging abnormalities have been reported after hospital discharge in patients recovered from COVID-19, little is known about persistent, long-term alterations in people without hospitalization. We conducted a cross-sectional study of 87 non-hospitalized recovered individuals 54 days after the laboratory confirmation of COVID-19. We performed structured interviews, neurological examination, 3T-MRI scans with diffusion tensor images (DTI) and functional resting-state images (fMRI). Also, we investigated fatigue, anxiety, depression, somnolence, language, memory, and cognitive flexibility, using validated instruments. Individuals self-reported a high frequency of headache (40%) and memory difficulties (33%). The quantitative analyses confirmed symptoms of fatigue (68%), excessive somnolence (35%), anxiety (29%), impaired cognitive flexibility (40%) and language impairment (33%). There were widespread cerebral white matter alterations (mainly characterized by increased fractional anisotropy), which correlated with abnormal attention and cognitive flexibility. The resting-state fMRI networks analysis showed severely disrupted brain hyperconnectivity and loss of resting-state networks specificity.

Levels of SARS-CoV-2 Lineage P.1 Neutralization by Antibodies Elicited after Natural Infection and Vaccination (preprint)

Background: A new SARS-CoV-2 lineage, named P.1 (20J/501Y.V3), has recently been detected in Brazil. Mutations accrued by the P.1 lineage include amino acid changes in the receptor-binding domain of the spike protein that also are reported in variants of concern in the United Kingdom (B.1.1.7) and South Africa (B.1.325).Methods: We isolated two P.1-containing specimens from nasopharyngeal and bronchoalveolar lavage samples of patients of Manaus, Brazil. We measured neutralization of the P.1 virus after incubation with the plasma of 19 COVID-19 convalescent blood donors and recipients of the chemically-inactivated CoronaVac vaccine and compared these results to neutralization of a SARS-CoV-2 B-lineage previously circulating in Brazil.Findings: The immune plasma of COVID-19 convalescent blood donors had 6-fold less neutralizing capacity against the P.1 than against the B-lineage. Moreover, five months after booster immunization with CoronaVac, plasma from vaccinated individuals failed to efficiently neutralize P.1 lineage isolates.Interpretation: These data indicate that the P.1 lineage may escape from neutralizing antibodies generated in response to polyclonal stimulation against previously circulating variants of SARS-CoV-2.Funding: São Paulo Research Foundation, MCTI/FINEP, Medical Research Council, National Council for Scientific and Technological Development, National Institutes of Health.Conflict of Interest: M.S.D. is a consultant for Inbios, Vir Biotechnology, NGMBiopharmaceuticals, and Carnival Corporation, and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions.Ethical Approval: All procedures followed the ethical standards of the responsible committee on humanexperimentation and approved by the ethics committees from the University of Campinas, Brazil (Approval number CONEP 4.021.484 for plasma collection of blood donors, CAEE32078620.4.0000.5404 and 30227920.9.0000.5404 for the sampling of vaccinated and viral genome sequencing, respectively). All patient data were anonymized before study inclusion.Informed consent was obtained from all subjects for being included in the study.

Elevated Glucose Levels Favor Sars-Cov-2 Infection and Monocyte Response Through a Hif-1α/Glycolysis Dependent Axis (preprint)

COVID-19 can result in severe lung injury. It remained to be determined why diabetic individuals with uncontrolled glucose levels are more prone to develop the severe form of COVID-19. The molecular mechanism underlying SARS-CoV-2 infection and what determines the onset of the cytokine storm found in severe COVID-19 patients are unknown. Monocytes/macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and appear to have a central role in the pathogenicity of the disease. These cells adapt their metabolism upon infection and become highly glycolytic, which facilitates SARS-CoV-2 replication. The infection triggers mitochondrial ROS production, which induces stabilization of hypoxia-inducible factor- 1α (HIF - 1α) and consequently promotes glycolysis. HIF- 1α-induced changes in monocyte metabolism by SARS-CoV-2 infection directly inhibit T cell response and reduce epithelial cell survival. Targeting HIF-1 ɑ may have great therapeutic potential for the development of novel drugs to treat COVID-19.