Neurologic manifestations associated with COVID-19: a multicentre registry.

OBJECTIVES: To provide an overview of the spectrum, characteristics and outcomes of neurologic manifestations associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: We conducted a single-centre retrospective study during the French coronavirus disease 2019 (COVID-19) epidemic in March-April 2020. All COVID-19 patients with de novo neurologic manifestations were eligible. RESULTS: We included 222 COVID-19 patients with neurologic manifestations from 46 centres in France. Median (interquartile range, IQR) age was 65 (53-72) years and 136 patients (61.3%) were male. COVID-19 was severe or critical in 102 patients (45.2%). The most common neurologic diseases were COVID-19-associated encephalopathy (67/222, 30.2%), acute ischaemic cerebrovascular syndrome (57/222, 25.7%), encephalitis (21/222, 9.5%) and Guillain-Barré syndrome (15/222, 6.8%). Neurologic manifestations appeared after the first COVID-19 symptoms with a median (IQR) delay of 6 (3-8) days in COVID-19-associated encephalopathy, 7 (5-10) days in encephalitis, 12 (7-18) days in acute ischaemic cerebrovascular syndrome and 18 (15-28) days in Guillain-Barré syndrome. Brain imaging was performed in 192 patients (86.5%), including 157 magnetic resonance imaging (70.7%). Among patients with acute ischaemic cerebrovascular syndrome, 13 (22.8%) of 57 had multiterritory ischaemic strokes, with large vessel thrombosis in 16 (28.1%) of 57. Brain magnetic resonance imaging of encephalitis patients showed heterogeneous acute nonvascular lesions in 14 (66.7%) of 21. Cerebrospinal fluid of 97 patients (43.7%) was analysed, with pleocytosis found in 18 patients (18.6%) and a positive SARS-CoV-2 PCR result in two patients with encephalitis. The median (IQR) follow-up was 24 (17-34) days with a high short-term mortality rate (28/222, 12.6%). CONCLUSIONS: Clinical spectrum and outcomes of neurologic manifestations associated with SARS-CoV-2 infection were broad and heterogeneous, suggesting different underlying pathogenic processes.

Close to me but unreachable: spotting the link between peripersonal space and empathy.

The space surrounding the body [i.e. peripersonal space (PPS)] has a crucial impact on individuals' interactions with the environment. Research showed that the interaction within the PPS increases individuals' behavioral and neural responses. Furthermore, individuals' empathy is affected by the distance between them and the observed stimuli. This study investigated empathic responses to painfully stimulated or gently touched faces presented within the PPS depending on the presence vs absence of a transparent barrier erected to prevent the interaction. To this aim, participants had to determine whether faces were painfully stimulated or gently touched, while their electroencephalographic signals were recorded. Brain activity [i.e. event-related potentials (ERPs) and source activations] was separately compared for the two types of stimuli (i.e. gently touched vs painfully stimulated faces) across two barrier conditions: (i) no-barrier between participants and the screen (i.e. no-barrier) and (ii) a plexiglass barrier erected between participants and the screen (i.e. barrier). While the barrier did not affect performance behaviorally, it reduced cortical activation at both the ERP and source activation levels in brain areas that regulate the interpersonal interaction (i.e. primary, somatosensory, premotor cortices and inferior frontal gyrus). These findings suggest that the barrier, precluding the possibility of interacting, reduced the observer's empathy.

Thinking Clearly: The History of Brain Dysfunction in Critical Illness.

Brain dysfunction during critical illness (ie, delirium and coma) is extremely common, and its lasting effect has only become increasingly understood in the last two decades. Brain dysfunction in the intensive care unit (ICU) is an independent predictor of both increased mortality and long-term impairments in cognition among survivors. As critical care medicine has grown, important insights regarding brain dysfunction in the ICU have shaped our practice including the importance of light sedation and the avoidance of deliriogenic drugs such as benzodiazepines. Best practices are now strategically incorporated in targeted bundles of care like the ICU Liberation Campaign's ABCDEF Bundle.

Pathogenesis and Management of Acute Necrotizing Encephalopathy.

INTRODUCTION: During the COVID-19 pandemic, many cases of acute necrotizing encephalopathy (ANE) secondary to COVID-19 have been reported. ANE is characterized by a rapid onset, a fulminant course, and low morbidity and fatality rates. Therefore, clinicians need to be vigilant for such disorders, especially during the influenza virus and COVID-19 epidemics. AREAS COVERED: The authors summarize the most recent studies on the clinical spectrum and treatment essentials of ANE to provide references for prompt diagnosis and improved treatment of this rare but fatal disease. EXPERT OPINION: ANE is a type of necrotizing lesion of the brain parenchyma. There are two major types of reported cases. One is isolated and sporadic ANE, which is primarily caused by viral infections, particularly influenza and HHV-6 virus. The other type is familial recurrent ANE, which is caused by RANBP2 gene mutations. ANE patients have rapid progression and a very poor prognosis, with acute brain dysfunction occurring within days of viral infection and requiring admission to the intensive care unit. Clinicians still need to investigate and find solutions for the problems of early detection and treatment of ANE.

Neurobiological Correlates of Psilocybin Response in Depression.

Objective: To synthesize the neurobiological basis of brain-resetting effects of psilocybin and identify neuroimaging correlates of psilocybin response in depressed patients.Data Sources: MEDLINE(R), Embase, APA PsycINFO, Cochrane, and CINAHL were systematically searched on June 3, 2022, with no date restrictions using the following string: (psilocybin) AND (psychedelics) AND (MRI) OR (fMRI)) OR (PET)) OR (SPECT)) OR (imaging)) OR (neuroimaging)).Study Selection: After duplicates were removed from 946 studies, 391 studies remained, of which 8 qualified for full-text analysis, but only 5 fulfilled the eligibility criteria of randomized, double-blind, or open-label neuroimaging study with psilocybin treatment in depressed patients.Data Extraction: The Covidence platform was used for deduplication and bias assessment. The a priori data points included concomitant psychological intervention, modality of neuroimaging technique, changes in depression scores, brain functional changes, and association between functional and psilocybin response. Assessment bias was assessed with the standard risk of bias tool for randomized controlled trials and the tool for risk of bias in nonrandomized studies of interventions.Results: Four studies were open-label, and one was a combined open-label and randomized controlled trial using functional magnetic resonance imaging. Psilocybin-assisted psychotherapy was administered in 3 studies, 1 in refractory and 2 in nonrefractory patients. The remaining 2 studies were in refractory patients. The transient increase in psilocybin-induced global connectivity in major neural tracts and specific areas of brain activation was associated with antidepressant response.Conclusions: Transient functional brain changes with psilocybin therapy resemble the "brain reset" phenomenon and may serve as the putative predictors of psilocybin antidepressant response.

SARS-CoV-2 and the nervous system: current perspectives.

SARS-CoV-2 infection frequently causes neurological impairment in both adults and children. Recent publications have described significant aspects of the viral pathophysiology associated with neurological dysfunction. In theory, neurological manifestations following SARS-CoV-2 infection may be caused directly by the effects of the virus infecting the brain or indirectly by the local and systemic immune responses against the virus. Neurological manifestations can occur during the acute phase as well as in the post-acute phase of the infection. In this review, we discuss recent literature describing the association of nervous system disorders with COVID-19.

SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity.

Numerous viruses use specialized surface molecules called fusogens to enter host cells. Many of these viruses, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can infect the brain and are associated with severe neurological symptoms through poorly understood mechanisms. We show that SARS-CoV-2 infection induces fusion between neurons and between neurons and glia in mouse and human brain organoids. We reveal that this is caused by the viral fusogen, as it is fully mimicked by the expression of the SARS-CoV-2 spike (S) protein or the unrelated fusogen p15 from the baboon orthoreovirus. We demonstrate that neuronal fusion is a progressive event, leads to the formation of multicellular syncytia, and causes the spread of large molecules and organelles. Last, using Ca2+ imaging, we show that fusion severely compromises neuronal activity. These results provide mechanistic insights into how SARS-CoV-2 and other viruses affect the nervous system, alter its function, and cause neuropathology.

Cellular Metabolism: A Fundamental Component of Degeneration in the Nervous System.

It is estimated that, at minimum, 500 million individuals suffer from cellular metabolic dysfunction, such as diabetes mellitus (DM), throughout the world. Even more concerning is the knowledge that metabolic disease is intimately tied to neurodegenerative disorders, affecting both the central and peripheral nervous systems as well as leading to dementia, the seventh leading cause of death. New and innovative therapeutic strategies that address cellular metabolism, apoptosis, autophagy, and pyroptosis, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), growth factor signaling with erythropoietin (EPO), and risk factors such as the apolipoprotein E (APOE-ε4) gene and coronavirus disease 2019 (COVID-19) can offer valuable insights for the clinical care and treatment of neurodegenerative disorders impacted by cellular metabolic disease. Critical insight into and modulation of these complex pathways are required since mTOR signaling pathways, such as AMPK activation, can improve memory retention in Alzheimer's disease (AD) and DM, promote healthy aging, facilitate clearance of ß-amyloid (Aß) and tau in the brain, and control inflammation, but also may lead to cognitive loss and long-COVID syndrome through mechanisms that can include oxidative stress, mitochondrial dysfunction, cytokine release, and APOE-ε4 if pathways such as autophagy and other mechanisms of programmed cell death are left unchecked.

Plasma proteome of Long-COVID patients indicates HIF-mediated vasculo-proliferative disease with impact on brain and heart function.

AIMS: Long-COVID occurs after SARS-CoV-2 infection and results in diverse, prolonged symptoms. The present study aimed to unveil potential mechanisms, and to inform prognosis and treatment. METHODS: Plasma proteome from Long-COVID outpatients was analyzed in comparison to matched acutely ill COVID-19 (mild and severe) inpatients and healthy control subjects. The expression of 3072 protein biomarkers was determined with proximity extension assays and then deconvoluted with multiple bioinformatics tools into both cell types and signaling mechanisms, as well as organ specificity. RESULTS: Compared to age- and sex-matched acutely ill COVID-19 inpatients and healthy control subjects, Long-COVID outpatients showed natural killer cell redistribution with a dominant resting phenotype, as opposed to active, and neutrophils that formed extracellular traps. This potential resetting of cell phenotypes was reflected in prospective vascular events mediated by both angiopoietin-1 (ANGPT1) and vascular-endothelial growth factor-A (VEGFA). Several markers (ANGPT1, VEGFA, CCR7, CD56, citrullinated histone 3, elastase) were validated by serological methods in additional patient cohorts. Signaling of transforming growth factor-ß1 with probable connections to elevated EP/p300 suggested vascular inflammation and tumor necrosis factor-α driven pathways. In addition, a vascular proliferative state associated with hypoxia inducible factor 1 pathway suggested progression from acute COVID-19 to Long-COVID. The vasculo-proliferative process predicted in Long-COVID might contribute to changes in the organ-specific proteome reflective of neurologic and cardiometabolic dysfunction. CONCLUSIONS: Taken together, our findings point to a vasculo-proliferative process in Long-COVID that is likely initiated either prior hypoxia (localized or systemic) and/or stimulatory factors (i.e., cytokines, chemokines, growth factors, angiotensin, etc). Analyses of the plasma proteome, used as a surrogate for cellular signaling, unveiled potential organ-specific prognostic biomarkers and therapeutic targets.

Delayed engagement of host defenses enables SARS-CoV-2 viremia and productive infection of distal organs in the hamster model of COVID-19.

Clinical presentations that develop in response to infection result from interactions between the pathogen and host defenses. SARS-CoV-2, the etiologic agent of COVID-19, directly antagonizes these defenses, leading to delayed immune engagement in the lungs that materializes only as cells succumb to infection and are phagocytosed. Leveraging the golden hamster model of COVID-19, we sought to understand the dynamics between SARS-CoV-2 infection in the airways and the systemic host response that ensues. We found that early SARS-CoV-2 replication was largely confined to the respiratory tract and olfactory system and, to a lesser extent, the heart and gastrointestinal tract but generated a host antiviral response in every organ as a result of circulating type I and III interferons. Moreover, we showed that diminishing the response in the airways by immunosuppression or administration of SARS-CoV-2 intravenously resulted in decreased immune priming, viremia, and increased viral tropism, including productive infection of the liver, kidney, spleen, and brain. Last, we showed that productive infection of the airways was required for mounting an effective and system-wide antiviral response. Together, these data illustrate how COVID-19 can result in diverse clinical presentations in which disease outcomes can be a by-product of the speed and strength of immune engagement. These studies provide additional evidence for the mechanistic basis of the diverse clinical presentations of COVID-19 and highlight the ability of the respiratory tract to generate a systemic immune defense after pathogen recognition.

Neurodegenerative and Neurodevelopmental Diseases and the Gut-Brain Axis: The Potential of Therapeutic Targeting of the Microbiome.

The human gut microbiome contains the largest number of bacteria in the body and has the potential to greatly influence metabolism, not only locally but also systemically. There is an established link between a healthy, balanced, and diverse microbiome and overall health. When the gut microbiome becomes unbalanced (dysbiosis) through dietary changes, medication use, lifestyle choices, environmental factors, and ageing, this has a profound effect on our health and is linked to many diseases, including lifestyle diseases, metabolic diseases, inflammatory diseases, and neurological diseases. While this link in humans is largely an association of dysbiosis with disease, in animal models, a causative link can be demonstrated. The link between the gut and the brain is particularly important in maintaining brain health, with a strong association between dysbiosis in the gut and neurodegenerative and neurodevelopmental diseases. This link suggests not only that the gut microbiota composition can be used to make an early diagnosis of neurodegenerative and neurodevelopmental diseases but also that modifying the gut microbiome to influence the microbiome-gut-brain axis might present a therapeutic target for diseases that have proved intractable, with the aim of altering the trajectory of neurodegenerative and neurodevelopmental diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorder, and attention-deficit hyperactivity disorder, among others. There is also a microbiome-gut-brain link to other potentially reversible neurological diseases, such as migraine, post-operative cognitive dysfunction, and long COVID, which might be considered models of therapy for neurodegenerative disease. The role of traditional methods in altering the microbiome, as well as newer, more novel treatments such as faecal microbiome transplants and photobiomodulation, are discussed.

The Blood-Brain Barrier in Health and Disease.

The blood-brain barrier (BBB) is a complex network of tightly regulated cells and transport proteins that separate the circulating blood from the brain tissue [...].

Brain imaging and neuropsychological assessment of individuals recovered from a mild to moderate SARS-CoV-2 infection.

As severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infections have been shown to affect the central nervous system, the investigation of associated alterations of brain structure and neuropsychological sequelae is crucial to help address future health care needs. Therefore, we performed a comprehensive neuroimaging and neuropsychological assessment of 223 nonvaccinated individuals recovered from a mild to moderate SARS-CoV-2 infection (100 female/123 male, age [years], mean ± SD, 55.54 ± 7.07; median 9.7 mo after infection) in comparison with 223 matched controls (93 female/130 male, 55.74 ± 6.60) within the framework of the Hamburg City Health Study. Primary study outcomes were advanced diffusion MRI measures of white matter microstructure, cortical thickness, white matter hyperintensity load, and neuropsychological test scores. Among all 11 MRI markers tested, significant differences were found in global measures of mean diffusivity (MD) and extracellular free water which were elevated in the white matter of post-SARS-CoV-2 individuals compared to matched controls (free water: 0.148 ± 0.018 vs. 0.142 ± 0.017, P < 0.001; MD [10-3 mm2/s]: 0.747 ± 0.021 vs. 0.740 ± 0.020, P < 0.001). Group classification accuracy based on diffusion imaging markers was up to 80%. Neuropsychological test scores did not significantly differ between groups. Collectively, our findings suggest that subtle changes in white matter extracellular water content last beyond the acute infection with SARS-CoV-2. However, in our sample, a mild to moderate SARS-CoV-2 infection was not associated with neuropsychological deficits, significant changes in cortical structure, or vascular lesions several months after recovery. External validation of our findings and longitudinal follow-up investigations are needed.

A year in review: brain barriers and brain fluids research in 2022.

This aim of this editorial is to highlight progress made in brain barrier and brain fluid research in 2022. It covers studies on the blood-brain, blood-retina and blood-CSF barriers (choroid plexus and meninges), signaling within the neurovascular unit and elements of the brain fluid systems. It further discusses how brain barriers and brain fluid systems are impacted in CNS diseases, their role in disease progression and progress being made in treating such diseases.

Brain hypoxia, neurocognitive impairment, and quality of life in people post-COVID-19.

OBJECTIVE: Systemic hypoxia occurs in COVID-19 infection; however, it is unknown if cerebral hypoxia occurs in convalescent individuals. We have evidence from other conditions associated with central nervous system inflammation that hypoxia may occur in the brain. If so, hypoxia could reduce the quality of life and brain function. This study was undertaken to assess if brain hypoxia occurs in individuals after recovery from acute COVID-19 infection and if this hypoxia is associated with neurocognitive impairment and reduced quality of life. METHODS: Using frequency-domain near-infrared spectroscopy (fdNIRS), we measured cerebral tissue oxygen saturation (StO2) (a measure of hypoxia) in participants who had contracted COVID-19 at least 8 weeks prior to the study visit and healthy controls. We also conducted neuropsychological assessments and health-related quality of life assessments, fatigue, and depression. RESULTS: Fifty-six percent of the post-COVID-19 participants self-reported having persistent symptoms (from a list of 18), with the most reported symptom being fatigue and brain fog. There was a gradation in the decrease of oxyhemoglobin between controls, and normoxic and hypoxic post-COVID-19 groups (31.7 ± 8.3 µM, 27.8 ± 7.0 µM and 21.1 ± 7.2 µM, respectively, p = 0.028, p = 0.005, and p = 0.081). We detected that 24% of convalescent individuals' post-COVID-19 infection had reduced StO2 in the brain and that this relates to reduced neurological function and quality of life. INTERPRETATION: We believe that the hypoxia reported here will have health consequences for these individuals, and this is reflected in the correlation of hypoxia with greater symptomology. With the fdNIRS technology, combined with neuropsychological assessment, we may be able to identify individuals at risk of hypoxia-related symptomology and target individuals that are likely to respond to treatments aimed at improving cerebral oxygenation.

MRI of fatal course of acute hemorrhagic leukoencephalitis in a child with SARS-CoV-2 omicron BA 2.0 infection.

We present a pediatric case of acute hemorrhagic leukoencephalitis associated with SARS-CoV-2 Omicron BA 2.0 infection. A previously healthy girl presented with ataxia and diplopia three weeks after the COVID-19 confirmation from a nasopharyngeal swab. Acute and symmetrical motor weakness and drowsiness ensued within the following 3 days. She then became spastic tetraplegic. MRI revealed multifocal lesions in the cerebral white matter, basal ganglia, and brainstem, with hemorrhagic changes confirmed with T1-hyperintensity and hypointensity on susceptibility-weighted images. Peripheral areas of decreased diffusion, increased blood flow, and rim contrast enhancement were noted in the majority of lesions. She was treated with a combination of intravenous immunoglobulin and methylprednisolone pulse therapy. Neurological deterioration ensued with coma, ataxic respiratory pattern and decerebrate posture. Repeated MRI performed on day 31 revealed progression of abnormalities, hemorrhages and brain herniation. Despite the administration of plasma exchange, she died two months after admission.

Olfactory Loss and Brain Connectivity after COVID-19: Structural Follow-Up at One Year.

The structural connectivity from the primary olfactory cortex to the main secondary olfactory areas was previously reported as relatively increased in the medial orbitofrontal cortex in a cohort of 27 recently SARS-CoV-2-infected (COV+) subjects, of which 23/27 had clinically confirmed olfactory loss, compared to 18 control (COV-) normosmic subjects, who were not previously infected. To complement this finding, here we report the outcome of an identical high angular resolution diffusion MRI analysis on follow-up data sets collected in 18/27 COV+ subjects (10 males, mean age ± SD: 38.7 ± 8.1 years) and 10/18 COV- subjects (5 males, mean age ± SD: 33.1 ± 3.6 years) from the previous samples who repeated both the olfactory functional assessment and the MRI examination after ~1 year. By comparing the newly derived subgroups, we observed that the increase in the structural connectivity index of the medial orbitofrontal cortex was not significant at follow-up, despite 10/18 COV+ subjects were still found hyposmic after ~1 year from SARS-CoV-2 infection. We concluded that the relative hyperconnectivity of the olfactory cortex to the medial orbitofrontal cortex could be, at least in some cases, an acute or reversible phenomenon linked to the recent SARS-CoV-2 infection with associated olfactory loss.

Uncovering a neurological protein signature for severe COVID-19.

Coronavirus disease of 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has sparked a global pandemic with severe complications and high morbidity rate. Neurological symptoms in COVID-19 patients, and neurological sequelae post COVID-19 recovery have been extensively reported. Yet, neurological molecular signature and signaling pathways that are affected in the central nervous system (CNS) of COVID-19 severe patients remain still unknown and need to be identified. Plasma samples from 49 severe COVID-19 patients, 50 mild COVID-19 patients, and 40 healthy controls were subjected to Olink proteomics analysis of 184 CNS-enriched proteins. By using a multi-approach bioinformatics analysis, we identified a 34-neurological protein signature for COVID-19 severity and unveiled dysregulated neurological pathways in severe cases. Here, we identified a new neurological protein signature for severe COVID-19 that was validated in different independent cohorts using blood and postmortem brain samples and shown to correlate with neurological diseases and pharmacological drugs. This protein signature could potentially aid the development of prognostic and diagnostic tools for neurological complications in post-COVID-19 convalescent patients with long term neurological sequelae.