Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of “long COVID-19” syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell–derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike–NRP1 interaction. SARS-CoV-2–infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.

COVID-19 patients may exhibit neuropsychiatric and/or neurological symptoms. We found that anxiety and cognitive impairment are manifested by 28-56% of SARS-CoV-2-infected individuals with mild or no respiratory symptoms and are associated with altered cerebral cortical thickness. Using an independent cohort, we found histopathological signs of brain damage in 19% of individuals who died of COVID-19. All of the affected brain tissues exhibited foci of SARS-CoV-2 infection, particularly in astrocytes. Infection of neural stem cell-derived astrocytes changed energy metabolism, altered key proteins and metabolites used to fuel neurons and for biogenesis of neurotransmitters, and elicited a secretory phenotype that reduces neuronal viability. Our data support the model where SARS-CoV-2 reaches the brain, infects astrocytes and triggers neuropathological changes that contribute to the structural and functional alterations in the brain of COVID-19 patients.

COVID-19 patients may exhibit neuropsychiatric and neurological symptoms. We found that anxiety and cognitive impairment are manifested by 28-56% of SARS-CoV-2-infected individuals with mild respiratory symptoms and are associated with altered cerebral cortical thickness. Using an independent cohort, we found histopathological signs of brain damage in 25% of individuals who died of COVID-19. All of the affected brain tissues exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Infection of neural stem cell-derived astrocytes changed energy metabolism, altered key proteins and metabolites used to fuel neurons and for biogenesis of neurotransmitters, and elicited a secretory phenotype that reduces neuronal viability. Our data support the model where SARS-CoV-2 reaches the brain, infects astrocytes and triggers neuropathological changes that contribute to the structural and functional alterations in the brain of COVID-19 patients.

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.

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Calibration and prediction for NIR spectroscopy data are performed based on a functional interpretation of the Beer-Lambert formula. Considering that, for each chemical sample, the resulting spectrum is a continuous curve obtained as the summation of overlapped absorption spectra from each analyte plus a Gaussian error, we assume that each individual spectrum can be expanded as a linear combination of B-splines basis. Calibration is then performed using two procedures for estimating the individual analytes curves: basis smoothing and smoothing splines.Prediction is done by minimizing the square error of prediction. To assess the variance of the predicted values, we use a leave-one-out jackknife technique. Departures from the standard error models are discussed through a simulation study, in particular, how correlated errors impact on the calibration step and consequently on the analytes' concentration prediction. Finally, the performance of our methodology is demonstrated through the analysis of two publicly available datasets.

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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.