Multimodal neuroimaging in post-COVID syndrome and correlation with cognition.

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.

Transcranial direct current stimulation for post-COVID fatigue: a randomized, double-blind, controlled pilot study.

Fatigue is one of the most frequent and disabling symptoms of the post-COVID syndrome. In this study, we aimed to assess the effects of transcranial direct current stimulation on fatigue severity in a group of patients with post-COVID syndrome and chronic fatigue. We conducted a double-blind, parallel-group, sham-controlled study to evaluate the short-term effects of anodal transcranial direct current stimulation (2 mA, 20 min/day) on the left dorsolateral prefrontal cortex. The modified fatigue impact scale score was used as the primary endpoint. Secondary endpoints included cognition (Stroop test), depressive symptoms (Beck depression inventory) and quality of life (EuroQol-5D). Patients received eight sessions of transcranial direct current stimulation and were evaluated at baseline, immediately after the last session, and one month later. Forty-seven patients were enrolled (23 in the active treatment group and 24 in the sham treatment group); the mean age was 45.66 ± 9.49 years, and 37 (78.72%) were women. The mean progression time since the acute infection was 20.68 ± 6.34 months. Active transcranial direct current stimulation was associated with a statistically significant improvement in physical fatigue at the end of treatment and 1 month as compared with sham stimulation. No significant effect was detected for cognitive fatigue. In terms of secondary outcomes, active transcranial direct current stimulation was associated with an improvement in depressive symptoms at the end of treatment. The treatment had no effects on the quality of life. All the adverse events reported were mild and transient, with no differences between the active stimulation and sham stimulation groups. In conclusion, our results suggest that transcranial direct current stimulation on the dorsolateral prefrontal cortex may improve physical fatigue. Further studies are needed to confirm these findings and optimize stimulation protocols.

Development of criteria for cognitive dysfunction in post-COVID syndrome: the IC-CoDi-COVID approach.

BACKGROUND: We aimed to develop objective criteria for cognitive dysfunction associated with the post-COVID syndrome. METHODS: Four hundred and four patients with post-COVID syndrome from two centers were evaluated with comprehensive neuropsychological batteries. The International Classification for Cognitive Disorders in Epilepsy (IC-CoDE) framework was adapted and implemented. A healthy control group of 145 participants and a complementary data-driven approach based on unsupervised machine-learning clustering algorithms were also used to evaluate the optimal classification and cutoff points. RESULTS: According to the developed criteria, 41.2% and 17.3% of the sample were classified as having at least one cognitive domain impaired using -1 and -1.5 standard deviations as cutoff points. Attention/processing speed was the most frequently impaired domain. There were no differences in base rates of cognitive impairment between the two centers. Clustering analysis revealed two clusters, although with an important overlap (silhouette index 0.18-0.19). Cognitive impairment was associated with younger age and lower education levels, but not hospitalization. CONCLUSIONS: We propose a harmonization of the criteria to define and classify cognitive impairment in the post-COVID syndrome. These criteria may be extrapolated to other neuropsychological batteries and settings, contributing to the diagnosis of cognitive deficits after COVID-19 and facilitating multicenter studies to guide biomarker investigation and therapies.

Fatigue and Cognitive Dysfunction Are Associated with Occupational Status in Post-COVID Syndrome.

Post-COVID syndrome (PCS) is a medical condition characterized by the persistence of a wide range of symptoms after acute infection by SARS-CoV-2. The work capacity consequences of this disorder have scarcely been studied. We aimed to analyze the factors associated with occupational status in patients with PCS. This cross-sectional study involved 77 patients with PCS on active work before SARS-CoV-2 infection. Patients were evaluated 20.71 ± 6.50 months after clinical onset. We conducted a survey on occupational activity and cognitive and clinical symptoms. The association between occupational activity and fatigue, depression, anxiety, sleep quality, and cognitive testing was analyzed. Thirty-eight (49.4%) patients were working, and thirty-nine (50.6%) patients were not. Of those not working at the moment of the assessment, 36 (92.3%) patients were on sick leave. In 63 patients (81.8% of the sample), sick leave was needed at some point due to PCS. The mean duration of sick leave was 12.07 ± 8.07 months. According to the patient's perspective, the most disabling symptoms were cognitive complaints (46.8%) and fatigue (31.2%). Not working at the moment of the assessment was associated with higher levels of fatigue and lower cognitive performance in the Stroop test. No association was found between occupational status with depression and anxiety questionnaires. Our study found an influence of PCS on work capacity. Fatigue and cognitive issues were the most frequent symptoms associated with loss of work capacity.

Neuropsychological Predictors of Fatigue in Post-COVID Syndrome.

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.

Persistent olfactory dysfunction after COVID-19 is associated with reduced perfusion in the frontal lobe.

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.

Cognitive dysfunction associated with COVID-19: A comprehensive neuropsychological study.

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.

Examining Association of Personality Characteristics and Neuropsychiatric Symptoms in Post-COVID Syndrome.

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.

The effects of the COVID-19 pandemic on neuropsychiatric symptoms in dementia and carer mental health: an international multicentre study.

As a global health emergency, the rapid spread of the novel coronavirus disease (COVID-19) led to the implementation of widespread restrictions (e.g., quarantine, physical/social distancing measures). However, while these restrictions reduce the viral spread of COVID-19, they may exacerbate behavioural and cognitive symptoms in dementia patients and increase pressure on caregiving. Here, we aimed to assess the impact of COVID-19 and related restrictions on both carers and people living with dementia across the world. We conducted an international survey (Australia, Germany, Spain, and the Netherlands) to assess the impact of COVID-19 on carers and people living with dementia. People with dementia experienced worsened neuropsychiatric symptoms since the outbreak of COVID-19, most commonly, depression, apathy, delusions, anxiety, irritability, and agitation. Regression analyses revealed that limited understanding of the COVID-19 situation and not living with the carer was associated with worsened neuropsychiatric symptoms. Carers also reported a decline in their own mental health, increased stress and reduced social networks as a result of COVID-19 and related restrictions. Regression analyses revealed uncertainty about the future and loneliness were associated with worsened carer mental health. Findings from this study will inform strategies for the development of support services and compassionate protocols that meet the evolving needs of those living with dementia and their carers.

"Brain Fog" by COVID-19 or Alzheimer's Disease? A Case Report.

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.

ACE2, TMPRSS2, and Furin variants and SARS-CoV-2 infection in Madrid, Spain.

It has been suggested that some individuals may present genetic susceptibility to SARS-CoV-2 infection, with particular research interest in variants of the ACE2 and TMPRSS2 genes, involved in viral penetration into cells, in different populations and geographic regions, although insufficient information is currently available. This study addresses the apparently reasonable hypothesis that variants of these genes may modulate viral infectivity, making some individuals more vulnerable than others. Through whole-exome sequencing, the frequency of exonic variants of the ACE2, TMPRSS2, and Furin genes was analyzed in relation to presence or absence of SARS-CoV-2 infection in a familial multiple sclerosis cohort including 120 individuals from Madrid. The ACE2 gene showed a low level of polymorphism, and none variant was significantly associated with SARS-CoV-2 infection. These variants have previously been detected in Italy. While TMPRSS2 is highly polymorphic, the variants found do not coincide with those described in other studies, with the exception of rs75603675, which may be associated with SARS-CoV-2 infection. The synonymous variants rs61735792 and rs61735794 showed a significant association with infection. Despite the limited number of patients with SARS-CoV-2 infection, some variants, especially in TMPRSS2, may be associated with COVID-19.

Death Rate Due to COVID-19 in Alzheimer's Disease and Frontotemporal Dementia.

We aimed to evaluate the frequency and mortality of COVID-19 in patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD). We conducted an observational case series. We enrolled 204 patients, 15.2% of whom were diagnosed with COVID-19, and 41.9% of patients with the infection died. Patients with AD were older than patients with FTD (80.36±8.77 versus 72.00±8.35 years old) and had a higher prevalence of arterial hypertension (55.8% versus 26.3%). COVID-19 occurred in 7.3% of patients living at home, but 72.0% of those living at care homes. Living in care facilities and diagnosis of AD were independently associated with a higher probability of death. We found that living in care homes is the most relevant factor for an increased risk of COVID-19 infection and death, with AD patients exhibiting a higher risk than those with FTD.

Experimental Models for the Study of Central Nervous System Infection by SARS-CoV-2.

INTRODUCTION: The response to the SARS-CoV-2 coronavirus epidemic requires increased research efforts to expand our knowledge of the disease. Questions related to infection rates and mechanisms, the possibility of reinfection, and potential therapeutic approaches require us not only to use the experimental models previously employed for the SARS-CoV and MERS-CoV coronaviruses but also to generate new models to respond to urgent questions. DEVELOPMENT: We reviewed the different experimental models used in the study of central nervous system (CNS) involvement in COVID-19 both in different cell lines that have enabled identification of the virus' action mechanisms and in animal models (mice, rats, hamsters, ferrets, and primates) inoculated with the virus. Specifically, we reviewed models used to assess the presence and effects of SARS-CoV-2 on the CNS, including neural cell lines, animal models such as mouse hepatitis virus CoV (especially the 59 strain), and the use of brain organoids. CONCLUSION: Given the clear need to increase our understanding of SARS-CoV-2, as well as its potential effects on the CNS, we must endeavor to obtain new information with cellular or animal models, with an appropriate resemblance between models and human patients.

Spectrum of Headaches Associated With SARS-CoV-2 Infection: Study of Healthcare Professionals.

BACKGROUND: Series of patients with SARS-CoV-2 infection report headache in 6%-15% of cases, although some data suggest that the actual frequency is higher, and that headache is not associated with fever. No study published to date has analyzed the characteristics of headache in these patients. OBJECTIVE: To analyze the characteristics of COVID-19 related headaches. METHODS: We conducted a survey of Spaniard healthcare professionals who have been infected by SARS-CoV-2 and presented headache during the course of the disease. The survey addressed respondents' medical history and headache characteristics, and we analyzed the association between both. RESULTS: We analyzed the responses of a sample of 112 healthcare professionals. History of migraine was reported by 20/112 (17.9%) of respondents, history of tension-type headache by 8/112 (7.1%), and history of cluster headache was reported by a single respondent; 82/112(73.2%) of respondents had no history of headache. Headache presented independently of fever, around the third day after symptom onset. The previous history of migraine was associated with a higher frequency of pulsating headache (20% in patients with previous migraine vs 4.3% in those with no history of migraine, P = .013). CONCLUSION: Headache is often holocranial, hemicranial, or occipital, pressing, and worsens with physical activity or head movements. Because the characteristics of the headache and the associated symptoms are heterogeneous in our survey, we suggest that several patterns with specific pathophysiological mechanisms may underlie the headache associated with COVID-19.

Clinical exacerbation of SARS-CoV2 infection after fingolimod withdrawal.

The role of disease-modifying therapies in patients with autoimmune disorders during severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection is controversial. Immunocompromised patients could have a more severe coronavirus disease-2019 (COVID-19) due to the absence of an adequate immune response against the SARS-CoV-2. However, therapies that act on immune response could play a protective role by dampening the cytokine-release syndrome. Fingolimod is a drug used for immune therapy in patients with multiple sclerosis (MS) through the sequestration of activated lymphocytes in the lymph nodes. We report the case of a 57-year-old man with relapsing-remitting MS treated with fingolimod that showed a reactivation of COVID-19 with signs of hyperinflammation syndrome after fingolimod withdrawal. Our case suggests that discontinuation of fingolimod during COVID-19 could imply a worsening of SARS-CoV2 infection.

An Online Observational Study of Patients With Olfactory and Gustory Alterations Secondary to SARS-CoV-2 Infection.

Introduction: Since the beginning of the Covid-19 epidemic produced by SARS2-Cov virus, olfactory alterations have been observed at a greater frequency than in other coronavirus epidemics. While olfactory alterations may be observed in patients with rhinovirus, influenza virus, or parainfluenza virus infection, they are typically explained by nasal obstruction with mucus or direct epithelial damage; in the case of SARS-CoV-2, olfactory alterations may present without nasal congestion with mucus. We performed a study of patients presenting olfactory/gustatory alterations in the context of SARS-CoV-2 infection in order to contribute to the understanding of this phenomenon. Material and Methods: We performed a descriptive, cross-sectional, observational study of the clinical characteristics of olfactory/gustatory alterations using a self-administered, anonymous online questionnaire. Results: A total of 909 patients with SARS-CoV-2 infection and olfactory/gustatory alterations responded to the questionnaire in the 4-day data collection period; 824 cases (90.65%) reported simultaneous olfactory and gustatory involvement. Patients' responses to the questionnaire revealed ageusia (581, 64.1% of respondents), hypogeusia (256, 28.2%), dysgeusia (22, 2.4%), anosmia (752 82.8%), hyposmia (142, 15.6%), and dysosmia (8, 0.9%). Fifty-four percent (489) did not report concomitant nasal congestion or mucus. Conclusion: Olfactory alterations are frequent in patients with SARS-CoV-2 infection and is only associated with nasal congestion in half of the cases.