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Brain changes have been reported in the first weeks after SARS-CoV-2 infection. However, limited literature exists about brain alterations in post-COVID syndrome, a condition increasingly associated with cognitive impairment. The present study aimed to evaluate brain functional and structural alterations in patients with post-COVID syndrome, and assess whether these brain alterations were related to cognitive dysfunction. Eighty-six patients with post-COVID syndrome and 36 healthy controls were recruited and underwent neuroimaging acquisition and a comprehensive neuropsychological assessment. Cognitive and neuroimaging examinations were performed 11 months after the first symptoms of SARS-CoV-2. Whole-brain functional connectivity analysis was performed. Voxel-based morphometry was performed to evaluate grey matter volume, and diffusion tensor imaging was carried out to analyse white-matter alterations. Correlations between cognition and brain changes were conducted and Bonferroni corrected. Post-COVID syndrome patients presented with functional connectivity changes, characterized by hypoconnectivity between left and right parahippocampal areas, and between bilateral orbitofrontal and cerebellar areas compared to controls. These alterations were accompanied by reduced grey matter volume in cortical, limbic and cerebellar areas, and alterations in white matter axial and mean diffusivity. Grey matter volume loss showed significant associations with cognitive dysfunction. These cognitive and brain alterations were more pronounced in hospitalized patients compared to non-hospitalized patients. No associations with vaccination status were found. The present study shows persistent structural and functional brain abnormalities 11 months after the acute infection. These changes are associated with cognitive dysfunction and contribute to a better understanding of the pathophysiology of the post-COVID syndrome.
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COVID-19 , Substância Branca , Humanos , Imagem de Tensor de Difusão/métodos , Imageamento por Ressonância Magnética/métodos , SARS-CoV-2 , Encéfalo , Neuroimagem/métodos , Cognição/fisiologia , Substância Cinzenta , SíndromeRESUMO
BACKGROUND: Olfactory dysfunction is common during SARS-CoV-2 infection. The pathophysiology of the persistence of this symptom and the potential relationship with central nervous system involvement is unknown. AIM OF THE STUDY: To evaluate the neural correlates of persistent olfactory dysfunction in a series of patients with post-COVID syndrome. METHODS: Eighty-two patients with post-COVID syndrome were assessed with the Brief Smell Identification Test and a multimodal MRI study including 3D-T1, T2-FLAIR, diffusion-tensor imaging, and arterial spin labeling. Olfactory and neuroimaging examinations were performed 11.18 ± 3.78 months after the acute infection. Voxel-based brain mapping analyses were conducted to correlate the olfactory test with brain volumes, white matter microstructure, and brain perfusion. RESULTS: Olfactory dysfunction was associated with lower tissue perfusion in the orbital and medial frontal regions in the arterial spin labeling sequence. Conversely, no statistically significant findings were detected in brain volumes and diffusion-tensor imaging. Mild changes in paranasal sinuses and nasal cavities were detected in 9.75% of cases, with no association with olfactory deficits. CONCLUSIONS: We provide new insights regarding the pathophysiology of persistent olfactory dysfunction after COVID-19, involving the main brain regions associated with the olfactory system.
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COVID-19 , Transtornos do Olfato , COVID-19/complicações , Lobo Frontal/diagnóstico por imagem , Humanos , Transtornos do Olfato/diagnóstico por imagem , Transtornos do Olfato/etiologia , Perfusão , SARS-CoV-2 , OlfatoRESUMO
The main objective was to evaluate structural and functional connectivity correlates of fatigue in post-COVID syndrome, and to investigate the relationships with an objective measure of mental fatigue and with subjective cognitive complaints. One-hundred and twenty-nine patients were recruited after 14.79 ± 7.17 months. Patients were evaluated with fatigue, neuropsychological, and subjective cognitive complaints assessments. Structural and functional magnetic resonance imaging were acquired, and functional connectivity, white matter diffusivity and grey matter volume were evaluated. Fatigue was present in 86 % of patients, and was highly correlated to subjective cognitive complaints. Fatigue was associated with structural and functional connectivity mostly in frontal areas but also temporal, and cerebellar areas, showing mental fatigue different pattern of functional connectivity correlates compared to physical fatigue. White matter diffusivity correlates were similar in fatigue and subjective cognitive complaints, located in the forceps minor, anterior corona radiata and anterior cingulum. Findings confirm that fatigue in post-COVID syndrome is related to cerebral connectivity patterns, evidencing its brain substrates. Moreover, results highlight the relationship between fatigue and subjective cognitive complaints. These findings point out the relevance of the multidisciplinary assessment of post-COVID syndrome patients with subjective cognitive complaints, in order to unravel the symptomatology beneath the patient's complaints.
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BACKGROUND: Cognitive deficits are among the main disabling symptoms in COVID-19 patients and post-COVID syndrome (PCS). Within brain regions, the hippocampus, a key region for cognition, has shown vulnerability to SARS-CoV-2 infection. Therefore, in vivo detailed evaluation of hippocampal changes in PCS patients, validated on post-mortem samples of COVID-19 patients at the acute phase, would shed light into the relationship between COVID-19 and cognition. METHODS: Hippocampal subfields volume, microstructure, and perfusion were evaluated in 84 PCS patients and compared to 33 controls. Associations with blood biomarkers, including glial fibrillary acidic protein (GFAP), myelin oligodendrocyte glycoprotein (MOG), eotaxin-1 (CCL11) and neurofilament light chain (NfL) were evaluated. Besides, biomarker immunodetection in seven hippocampal necropsies of patients at the acute phase were contrasted against eight controls. FINDINGS: In vivo analyses revealed that hippocampal grey matter atrophy is accompanied by altered microstructural integrity, hypoperfusion, and functional connectivity changes in PCS patients. Hippocampal structural and functional alterations were related to cognitive dysfunction, particularly attention and memory. GFAP, MOG, CCL11 and NfL biomarkers revealed alterations in PCS, and showed associations with hippocampal volume changes, in selective hippocampal subfields. Moreover, post mortem histology showed the presence of increased GFAP and CCL11 and reduced MOG concentrations in the hippocampus in post-mortem samples at the acute phase. INTERPRETATION: The current results evidenced that PCS patients with cognitive sequalae present brain alterations related to cognitive dysfunction, accompanied by a cascade of pathological alterations in blood biomarkers, indicating axonal damage, astrocyte alterations, neuronal injury, and myelin changes that are already present from the acute phase. FUNDING: Nominative Grant FIBHCSC 2020 COVID-19. Department of Health, Community of Madrid. Instituto de Salud Carlos III through the project INT20/00079, co-funded by European Regional Development Fund "A way to make Europe" (JAMG). Instituto de Salud Carlos III (ISCIII) through Sara Borrell postdoctoral fellowship Grant No. CD22/00043) and co-funded by the European Union (MDC). Instituto de Salud Carlos III through a predoctoral contract (FI20/000145) (co-funded by European Regional Development Fund "A way to make Europe") (MVS). Fundación para el Conocimiento Madri+d through the project G63-HEALTHSTARPLUS-HSP4 (JAMG, SOM).
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Hipocampo/patologia , Atrofia , Síndrome , BiomarcadoresRESUMO
BACKGROUND: Primary progressive aphasia (PPA) is a clinical syndrome characterized by gradual loss of language skills. This study aimed to evaluate the diagnostic capacity of a connected speech task for the diagnosis of PPA and its variants, to determine the main components of spontaneous speech, and to examine their neural correlates. METHODS: A total of 118 participants (31 patients with nfvPPA, 11 with svPPA, 45 with lvPPA, and 31 healthy controls) were evaluated with the Cookie Theft picture description task and a comprehensive language assessment protocol. Patients also underwent 18F-fluorodeoxyglucose positron emission tomography and magnetic resonance imaging studies. Principal component analysis and machine learning were used to evaluate the main components of connected speech and the accuracy of connected speech parameters for diagnosing PPA. Voxel-based analyses were conducted to evaluate the correlation between spontaneous speech components and brain metabolism, brain volumes, and white matter microstructure. RESULTS: Discrimination between patients with PPA and controls was 91.67%, with 77.78% discrimination between PPA variants. Parameters related to speech rate and lexical variables were the most discriminative for classification. Three main components were identified: lexical features, fluency, and syntax. The lexical component was associated with ventrolateral frontal regions, while the fluency component was associated with the medial superior prefrontal cortex. Number of pauses was more related with the left parietotemporal region, while pauses duration with the bilateral frontal lobe. The lexical component was correlated with several tracts in the language network (left frontal aslant tract, left superior longitudinal fasciculus I, II, and III, left arcuate fasciculus, and left uncinate fasciculus), and fluency was linked to the frontal aslant tract. CONCLUSION: Spontaneous speech assessment is a useful, brief approach for the diagnosis of PPA and its variants. Neuroimaging correlates suggested a subspecialization within the left frontal lobe, with ventrolateral regions being more associated with lexical production and the medial superior prefrontal cortex with speech rate.
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Afasia Primária Progressiva , Fluordesoxiglucose F18 , Afasia Primária Progressiva/diagnóstico por imagem , Humanos , Idioma , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , FalaRESUMO
BACKGROUND: We aimed to evaluate personality traits in patients with post-COVID syndrome, as well as the association with neuropsychiatric symptoms present in this disorder. METHODS: The Big Five Structure Inventory was administered to 93 consecutive patients with a diagnosis of post-COVID syndrome as defined by the WHO and to demographically matched controls. We also performed a comprehensive evaluation of depression, anxiety, fatigue, sleep quality, cognitive function, and olfactory function. RESULTS: Patients with post-COVID syndrome scored lower for emotional stability, equanimity, positive mood, and self-control. Extraversion, emotional stability, and openness correlated negatively with anxiety and depression levels. Conscientiousness correlated negatively with anxiety. No statistically significant correlations were observed between personality traits and cognitive function, sleep quality, olfactory function, or fatigue. Personality scores explained 36.3% and 41% of the variance in scores on the anxiety and depression scales, respectively. Two personality profiles with lower levels of emotional stability were associated with depression and anxiety. CONCLUSIONS: Our study shows higher levels of neuroticism in patients with post-COVID syndrome. Personality traits were predictive of the presence of depression and anxiety, but not cognitive function, sleep quality, or fatigue, in the context of post-COVID syndrome. These findings may have implications for the detection of patients at risk of depression and anxiety in post-COVID syndrome, and for the development of preventive and therapeutic interventions.
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OBJECTIVE: Recent evidence suggests that patients suffering post-acute COVID syndrome frequently report cognitive complaints, but their characteristics and pathophysiology are unknown. This study aims to determine the characteristics of cognitive dysfunction in patients reporting cognitive complaints after COVID-19 and to evaluate the correlation between cognitive function and anxiety, depression, sleep, and olfactory function. METHODS: Cross-sectional study involving 50 patients with COVID-19 reporting cognitive complaints 9.12 ± 3.46 months after the acute infection. Patients were evaluated with a comprehensive neuropsychological protocol, and scales of fatigue, depression, anxiety, sleep and an olfactory test. Normative data and an age- and education matched healthy control group were used for comparison. RESULTS: COVID-19 patients showed a diminished performance on several tests evaluating attention and executive function, with alterations in processing speed, divided attention, selective attention, visual vigilance, intrinsic alertness, working memory, and inhibition; episodic memory; and visuospatial processing. Cognitive performance was correlated with olfactory dysfunction, and sleep quality and anxiety to a lesser extent, but not depression. CONCLUSIONS: Patients with COVID-19 reporting cognitive symptoms showed a reduced cognitive performance, especially in the attention-concentration and executive functioning, episodic memory, and visuospatial processing domains. Future studies are necessary to disentangle the specific mechanisms associated with COVID-19 cognitive dysfunction.
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COVID-19 , Disfunção Cognitiva , COVID-19/complicações , Cognição/fisiologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/psicologia , Estudos Transversais , Função Executiva/fisiologia , Humanos , Testes Neuropsicológicos , Síndrome de COVID-19 Pós-AgudaRESUMO
Fatigue is one of the most disabling symptoms in several neurological disorders and has an important cognitive component. However, the relationship between self-reported cognitive fatigue and objective cognitive assessment results remains elusive. Patients with post-COVID syndrome often report fatigue and cognitive issues several months after the acute infection. We aimed to develop predictive models of fatigue using neuropsychological assessments to evaluate the relationship between cognitive fatigue and objective neuropsychological assessment results. We conducted a cross-sectional study of 113 patients with post-COVID syndrome, assessing them with the Modified Fatigue Impact Scale (MFIS) and a comprehensive neuropsychological battery including standardized and computerized cognitive tests. Several machine learning algorithms were developed to predict MFIS scores (total score and cognitive fatigue score) based on neuropsychological test scores. MFIS showed moderate correlations only with the Stroop Color-Word Interference Test. Classification models obtained modest F1-scores for classification between fatigue and non-fatigued or between 3 or 4 degrees of fatigue severity. Regression models to estimate the MFIS score did not achieve adequate R2 metrics. Our study did not find reliable neuropsychological predictors of cognitive fatigue in the post-COVID syndrome. This has important implications for the interpretation of fatigue and cognitive assessment. Specifically, MFIS cognitive domain could not properly capture actual cognitive fatigue. In addition, our findings suggest different pathophysiological mechanisms of fatigue and cognitive dysfunction in post-COVID syndrome.
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Cognitive symptoms after COVID-19 have been increasingly recognized several months after the acute infection and have been designated as "brain fog." We report a patient with cognitive symptoms that started immediately after COVID-19, in which cerebrospinal fluid biomarkers were highly suggestive of Alzheimer's disease. Our case highlights the need to examine patients with cognitive symptoms following COVID-19 comprehensively. A detailed assessment combining clinical, cognitive, and biomarker studies may help disentangle the underlying mechanisms associated with cognitive dysfunction in each case. The investigation of neurodegenerative processes in an early stage, especially in older patients, is probably warranted.