Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 143
Filter
Add filters

Document Type
Year range
1.
Nat Med ; 27(9): 1600-1606, 2021 09.
Article in English | MEDLINE | ID: covidwho-1526089

ABSTRACT

Clinical evidence suggests the central nervous system is frequently impacted by SARS-CoV-2 infection, either directly or indirectly, although the mechanisms are unclear. Pericytes are perivascular cells within the brain that are proposed as SARS-CoV-2 infection points. Here we show that pericyte-like cells (PLCs), when integrated into a cortical organoid, are capable of infection with authentic SARS-CoV-2. Before infection, PLCs elicited astrocytic maturation and production of basement membrane components, features attributed to pericyte functions in vivo. While traditional cortical organoids showed little evidence of infection, PLCs within cortical organoids served as viral 'replication hubs', with virus spreading to astrocytes and mediating inflammatory type I interferon transcriptional responses. Therefore, PLC-containing cortical organoids (PCCOs) represent a new 'assembloid' model that supports astrocytic maturation as well as SARS-CoV-2 entry and replication in neural tissue; thus, PCCOs serve as an experimental model for neural infection.


Subject(s)
Astrocytes/virology , Brain/virology , COVID-19/pathology , Pericytes/virology , Viral Tropism/physiology , Astrocytes/cytology , Brain/pathology , Cell Differentiation/physiology , Cells, Cultured , Humans , Interferon Type I/immunology , SARS-CoV-2 , Virus Replication/physiology
2.
Alzheimers Dement ; 17(2): 318-319, 2021 02.
Article in English | MEDLINE | ID: covidwho-1516716
3.
J Gen Virol ; 102(10)2021 10.
Article in English | MEDLINE | ID: covidwho-1490495

ABSTRACT

The highly pathogenic Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a severe respiratory virus. Recent reports indicate additional central nervous system (CNS) involvement. In this study, human DPP4 transgenic mice were infected with MERS-CoV, and viral antigens were first detected in the midbrain-hindbrain 4 days post-infection, suggesting the virus may enter the brainstem via peripheral nerves. Neurons and astrocytes throughout the brain were infected, followed by damage of the blood brain barrier (BBB), as well as microglial activation and inflammatory cell infiltration, which may be caused by complement activation based on the observation of deposition of complement activation product C3 and high expression of C3a receptor (C3aR) and C5a receptor (C5aR1) in neurons and glial cells. It may be concluded that these effects were mediated by complement activation in the brain, because of their reduction resulted from the treatment with mouse C5aR1-specific mAb. Such mAb significantly reduced nucleoprotein expression, suppressed microglial activation and decreased activation of caspase-3 in neurons and p38 phosphorylation in the brain. Collectively, these results suggest that MERS-CoV infection of CNS triggers complement activation, leading to inflammation-mediated damage of brain tissue, and regulating of complement activation could be a promising intervention and adjunctive treatment for CNS injury by MERS-CoV and other coronaviruses.


Subject(s)
Brain/pathology , Complement System Proteins/immunology , Coronavirus Infections/pathology , Dipeptidyl Peptidase 4/genetics , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Animals , Blood-Brain Barrier/immunology , Blood-Brain Barrier/pathology , Brain/blood supply , Brain/immunology , Brain/virology , Complement Activation/drug effects , Complement Inactivating Agents/therapeutic use , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Coronavirus Infections/virology , Disease Models, Animal , Humans , Inflammation , Mice , Mice, Transgenic , Microglia/immunology , Microglia/pathology
4.
Nat Neurosci ; 24(11): 1522-1533, 2021 11.
Article in English | MEDLINE | ID: covidwho-1500484

ABSTRACT

Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/metabolism , Coronavirus 3C Proteases/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Microvessels/metabolism , SARS-CoV-2/metabolism , Animals , Blood-Brain Barrier/pathology , Brain/pathology , Chlorocebus aethiops , Coronavirus 3C Proteases/genetics , Cricetinae , Female , Humans , Intracellular Signaling Peptides and Proteins/genetics , Male , Mesocricetus , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Microvessels/pathology , SARS-CoV-2/genetics , Vero Cells
5.
Int J Mol Sci ; 22(21)2021 Oct 27.
Article in English | MEDLINE | ID: covidwho-1488609

ABSTRACT

A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69.5 years; n = 7 control, median age = 68 years) and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in perivascular cells. Viral dsRNA was identified in the vascular wall and paralleled by perivascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood-brain barrier. Notably, cerebrospinal fluid from additional 16 individuals (n = 8 COVID-19, median age = 67 years; n = 8 control, median age = 69.5 years) exhibited significantly lower levels of the pericyte marker PDGFRß in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to perivascular inflammation and a locally compromised blood-brain barrier.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Brain/virology , COVID-19/physiopathology , Encephalitis, Viral/virology , Pericytes/virology , Angiotensin-Converting Enzyme 2/genetics , Animals , Blood-Brain Barrier , Brain/pathology , COVID-19/etiology , Case-Control Studies , Encephalitis, Viral/pathology , Fibrinogen/metabolism , Humans , Immunohistochemistry/methods , Mice , Pericytes/metabolism , Pericytes/pathology , Receptor, Platelet-Derived Growth Factor beta/cerebrospinal fluid
6.
Int J Mol Sci ; 22(14)2021 Jul 06.
Article in English | MEDLINE | ID: covidwho-1485149

ABSTRACT

Chronic neurodegenerative diseases are complex, and their pathogenesis is uncertain. Alzheimer's disease (AD) is a neurodegenerative brain alteration that is responsible for most dementia cases in the elderly. AD etiology is still uncertain; however, chronic neuroinflammation is a constant component of brain pathology. Infections have been associated with several neurological diseases and viruses of the Herpes family appear to be a probable cause of AD neurodegenerative alterations. Several different factors may contribute to the AD clinical progression. Exogeneous viruses or other microbes and environmental pollutants may directly induce neurodegeneration by activating brain inflammation. In this paper, we suggest that exogeneous brain insults may also activate retrotransposons and silent human endogenous retroviruses (HERVs). The initial inflammation of small brain areas induced by virus infections or other brain insults may activate HERV dis-regulation that contributes to neurodegenerative mechanisms. Chronic HERV activation in turn may cause progressive neurodegeneration that thereafter merges in cognitive impairment and dementia in genetically susceptible people. Specific treatment for exogenous end endogenous pathogens and decreasing pollutant exposure may show beneficial effect in early intervention protocol to prevent the progression of cognitive deterioration in the elderly.


Subject(s)
Alzheimer Disease/pathology , Alzheimer Disease/virology , Brain/pathology , Brain/virology , Endogenous Retroviruses/pathogenicity , Virus Diseases/pathology , Virus Diseases/virology , Animals , Cognition Disorders/pathology , Cognition Disorders/virology , Encephalitis/pathology , Encephalitis/virology , Humans
7.
Nat Commun ; 12(1): 5739, 2021 10 19.
Article in English | MEDLINE | ID: covidwho-1475293

ABSTRACT

Protein aggregates associated with neurodegenerative diseases have the ability to transmit to unaffected cells, thereby templating their own aberrant conformation onto soluble homotypic proteins. Proteopathic seeds can be released into the extracellular space, secreted in association with extracellular vesicles (EV) or exchanged by direct cell-to-cell contact. The extent to which each of these pathways contribute to the prion-like spreading of protein misfolding is unclear. Exchange of cellular cargo by both direct cell contact or via EV depends on receptor-ligand interactions. We hypothesized that enabling these interactions through viral ligands enhances intercellular proteopathic seed transmission. Using different cellular models propagating prions or pathogenic Tau aggregates, we demonstrate that vesicular stomatitis virus glycoprotein and SARS-CoV-2 spike S increase aggregate induction by cell contact or ligand-decorated EV. Thus, receptor-ligand interactions are important determinants of intercellular aggregate dissemination. Our data raise the possibility that viral infections contribute to proteopathic seed spreading by facilitating intercellular cargo transfer.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Extracellular Vesicles/metabolism , Membrane Glycoproteins/metabolism , Protein Aggregation, Pathological/virology , Spike Glycoprotein, Coronavirus/metabolism , Viral Envelope Proteins/metabolism , Adult , Aged , Brain/pathology , Case-Control Studies , Cell Line , Endocytosis , Female , Humans , Intravital Microscopy , Male , Middle Aged , Prions/metabolism , Protein Aggregation, Pathological/pathology , Protein Folding , tau Proteins/metabolism
8.
Sci Rep ; 11(1): 20476, 2021 10 14.
Article in English | MEDLINE | ID: covidwho-1469981

ABSTRACT

The increased frequency of neurological manifestations, including central nervous system (CNS) manifestations, in patients with coronavirus disease 2019 (COVID-19) pandemic is consistent with the virus's neurotropic nature. In most patients, brain magnetic resonance imaging (MRI) is a sensitive imaging modality in the diagnosis of viral encephalitides in the brain. The purpose of this study was to determine the frequency of brain lesion patterns on brain MRI in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia patients who developed focal and non-focal neurological manifestations. In addition, it will compare the impact of the Glasgow Coma Scale (GCS) as an index of deteriorating cerebral function on positive brain MRIs in both neurological manifestations. This retrospective study included an examination of SARS-CoV-2 pneumonia patients with real-time reverse transcription polymerase chain reaction (RT-PCR) confirmation, admitted with clinicoradiologic evidence of COVID-19 pneumonia, and who were candidates for brain MRI due to neurological manifestations suggesting brain involvement. Brain imaging acquired on a 3.0 T MRI system (Skyra; Siemens, Erlangen, Germany) with a 20-channel receive head coil. Brain MRI revealed lesions in 38 (82.6%) of the total 46 patients for analysis and was negative in the remaining eight (17.4%) of all finally enclosed patients with RT-PCR confirmed SARS-CoV-2 pneumonia. Twenty-nine (63%) patients had focal neurological manifestations, while the remaining 17 (37%) patients had non-focal neurological manifestations. The patients had a highly significant difference (p = 0.0006) in GCS, but no significant difference (p = 0.4) in the number of comorbidities they had. Brain MRI is a feasible and important imaging modality in patients with SARS-CoV-2 pneumonia who develop neurological manifestations suggestive of brain involvement, particularly in patients with non-focal manifestations and a decline in GCS.


Subject(s)
Brain Diseases/etiology , Brain/diagnostic imaging , COVID-19/complications , Adult , Aged , Brain/pathology , Brain Diseases/diagnostic imaging , Brain Diseases/pathology , COVID-19/pathology , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Retrospective Studies , SARS-CoV-2/isolation & purification
9.
Folia Neuropathol ; 59(3): 219-231, 2021.
Article in English | MEDLINE | ID: covidwho-1463956

ABSTRACT

Coronavirus disease 2019 (COVID-19) poses a global challenge to healthcare and society in the early 21st century. We report neuropathological changes in 52 patients aged between 22 years and 88 years (median 58 years) who were infected with the CoV-2 coronavirus. Patients died under various circumstances and had various pre-existing diseases. The inclusion criteria for this study were: positive result for the nasopharyngeal swab for SARS-CoV-2 RNA, diagnosis of pneumonia of SARS-CoV-2 or nucleoproteins of SARS-CoV-2 in pulmonary tissue confirmed by immunohistochemical methods (IHC). Samples from all brain structures and lung specimens were taken for histopathological examinations. Brain and pulmonary samples were stained typically with histological and immunohistochemical methods and small tissue fragments were examined with the transmission electron microscope (TEM). The light and electron microscopy examination confirmed the numerous neuropathological changes in the brains of the patients infected with the CoV-2. Many of these changes were caused by pre-existing diseases of patients and/or by necessary treatment. However, vascular lesions and the inflammatory process seem to be characteristic of the CoV-2 infection. In all of the structures of 52 brains of patients, damage of the vessel walls and morphological feature of the damage to the blood-brain barrier were observed. Lymphocytic and microglial infiltrates, both perivascular and diffuse, were also observed. Hence, the brain changes due to COVID-19 infection, could be called COVID-19 cerebral angiopathy with diffuse inflammation.


Subject(s)
Brain/pathology , COVID-19/pathology , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , SARS-CoV-2
10.
Viruses ; 13(10)2021 10 08.
Article in English | MEDLINE | ID: covidwho-1463838

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the coronavirus disease (COVID-19), is currently infecting millions of people worldwide and is causing drastic changes in people's lives. Recent studies have shown that neurological symptoms are a major issue for people infected with SARS-CoV-2. However, the mechanism through which the pathological effects emerge is still unclear. Brain endothelial cells (ECs), one of the components of the blood-brain barrier, are a major hurdle for the entry of pathogenic or infectious agents into the brain. They strongly express angiotensin converting enzyme 2 (ACE2) for its normal physiological function, which is also well-known to be an opportunistic receptor for SARS-CoV-2 spike protein, facilitating their entry into host cells. First, we identified rapid internalization of the receptor-binding domain (RBD) S1 domain (S1) and active trimer (Trimer) of SARS-CoV-2 spike protein through ACE2 in brain ECs. Moreover, internalized S1 increased Rab5, an early endosomal marker while Trimer decreased Rab5 in the brain ECs. Similarly, the permeability of transferrin and dextran was increased in S1 treatment but decreased in Trimer, respectively. Furthermore, S1 and Trimer both induced mitochondrial damage including functional deficits in mitochondrial respiration. Overall, this study shows that SARS-CoV-2 itself has toxic effects on the brain ECs including defective molecular delivery and metabolic function, suggesting a potential pathological mechanism to induce neurological signs in the brain.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/pathology , COVID-19/pathology , Endothelial Cells/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Animals , Brain/metabolism , Brain/virology , Endothelial Cells/virology , Humans , Mice , Mitochondria/metabolism , Protein Domains , SARS-CoV-2/metabolism , rab5 GTP-Binding Proteins/metabolism
12.
J Alzheimers Dis ; 83(2): 523-530, 2021.
Article in English | MEDLINE | ID: covidwho-1459395

ABSTRACT

Coronavirus (COVID-19) has emerged as a human catastrophe worldwide, and it has impacted human life more detrimentally than the combined effect of World Wars I and II. Various research studies reported that the disease is not confined to the respiratory system but also leads to neurological and neuropsychiatric disorders suggesting that the virus is potent to affect the central nervous system (CNS). Moreover, the damage to CNS may continue to rise even after the COVID-19 infection subsides which may further induce a long-term impact on the brain, resulting in cognitive impairment. Neuroimaging techniques is the ideal platform to detect and quantify pathological manifestations in the brain of COVID-19 survivors. In this context, a scheme based on structural, spectroscopic, and behavioral studies could be executed to monitor the gradual changes in the brain non-invasively due to COVID-19 which may further help in quantifying the impact of COVID-19 on the mental health of the survivors. Extensive research is required in this direction for identifying the mechanism and implications of COVID-19 in the brain. Cohort studies are urgently required for monitoring the effects of this pandemic on individuals of various subtypes longitudinally.


Subject(s)
Brain/diagnostic imaging , COVID-19/complications , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/virology , Brain/pathology , Brain Mapping/methods , COVID-19/diagnostic imaging , COVID-19/pathology , Cognitive Dysfunction/pathology , Humans , Magnetic Resonance Spectroscopy , Oxidative Stress/physiology , SARS-CoV-2 , Survivors
13.
Biomed Res Int ; 2021: 7880448, 2021.
Article in English | MEDLINE | ID: covidwho-1455779

ABSTRACT

COVID-19-associated neuropsychiatric complications are soaring. There is an urgent need to understand the link between COVID-19 and neuropsychiatric disorders. To that end, this article addresses the premise that SARS-CoV-2 infection results in gut dysbiosis and an altered microbiota-gut-brain (MGB) axis that in turn contributes to the neuropsychiatric ramifications of COVID-19. Altered MGB axis activity has been implicated independently as a risk of neuropsychiatric disorders. A review of the changes in gut microbiota composition in individual psychiatric and neurological disorders and gut microbiota in COVID-19 patients revealed a shared "microbial signature" characterized by a lower microbial diversity and richness and a decrease in health-promoting anti-inflammatory commensal bacteria accompanied by an increase in opportunistic proinflammatory pathogens. Notably, there was a decrease in short-chain fatty acid (SCFA) producing bacteria. SCFAs are key bioactive microbial metabolites with anti-inflammatory functions and have been recognized as a critical signaling pathway in the MGB axis. SCFA deficiency is associated with brain inflammation, considered a cardinal feature of neuropsychiatric disorders. The link between SARS-CoV-2 infection, gut dysbiosis, and altered MGB axis is further supported by COVID-19-associated gastrointestinal symptoms, a high number of SARS-CoV-2 receptors, angiotensin-cleaving enzyme-2 (ACE-2) in the gut, and viral presence in the fecal matter. The binding of SARS-CoV-2 to the receptor results in ACE-2 deficiency that leads to decreased transport of vital dietary components, gut dysbiosis, proinflammatory gut status, increased permeability of the gut-blood barrier (GBB), and systemic inflammation. More clinical research is needed to substantiate further the linkages described above and evaluate the potential significance of gut microbiota as a diagnostic tool. Meanwhile, it is prudent to propose changes in dietary recommendations in favor of a high fiber diet or supplementation with SCFAs or probiotics to prevent or alleviate the neuropsychiatric ramifications of COVID-19.


Subject(s)
COVID-19/psychology , Fatty Acids, Volatile/metabolism , Gastrointestinal Microbiome/physiology , Bacteria/metabolism , Brain/metabolism , Brain/pathology , COVID-19/metabolism , COVID-19/microbiology , COVID-19/virology , Diet , Dysbiosis , Feces/microbiology , Gastrointestinal Diseases/microbiology , Gastrointestinal Microbiome/immunology , Humans , Inflammation , Probiotics/pharmacology , SARS-CoV-2/isolation & purification
14.
Int J Mol Sci ; 22(19)2021 Sep 28.
Article in English | MEDLINE | ID: covidwho-1444228

ABSTRACT

For a yet unknown reason, a substantial share of patients suffering from COVID-19 develop long-lasting neuropsychiatric symptoms ranging from cognitive deficits to mood disorders and/or an extreme fatigue. We previously reported that in non-neural cells, angiotensin-1 converting enzyme 2 (ACE2), the gene coding for the SARS-CoV2 host receptor, harbors tight co-expression links with dopa-decarboxylase (DDC), an enzyme involved in the metabolism of dopamine. Here, we mined and integrated data from distinct human expression atlases and found that, among a wide range of tissues and cells, enterocytes of the small intestine express the highest expression levels of ACE2, DDC and several key genes supporting the metabolism of neurotransmitters. Based on these results, we performed co-expression analyses on a recently published set of RNA-seq data obtained from SARS-CoV2-infected human intestinal organoids. We observed that in SARS-CoV2-infected enterocytes, ACE2 co-regulates not only with DDC but also with a specific group of genes involved in (i) the dopamine/trace amines metabolic pathway, (ii) the absorption of microbiota-derived L-DOPA and (iii) the absorption of neutral amino acids serving as precursors to neurotransmitters. We conclude that in patients with long COVID, a chronic infection and inflammation of small intestine enterocytes might be indirectly responsible for prolonged brain alterations.


Subject(s)
Brain/pathology , COVID-19/complications , Gene Expression Regulation , Intestine, Small/pathology , Angiotensin-Converting Enzyme 2/genetics , Aromatic-L-Amino-Acid Decarboxylases/genetics , Brain/metabolism , COVID-19/genetics , COVID-19/pathology , Cells, Cultured , Enterocytes/metabolism , Enterocytes/pathology , Humans , Intestine, Small/metabolism , SARS-CoV-2/isolation & purification
15.
Virulence ; 12(1): 2430-2442, 2021 12.
Article in English | MEDLINE | ID: covidwho-1406439

ABSTRACT

Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is currently causing a worldwide threat with its unusually high transmission rates and rapid evolution into diverse strains. Unlike typical respiratory viruses, SARS-CoV-2 frequently causes systemic infection by breaking the boundaries of the respiratory systems. The development of animal models recapitulating the clinical manifestations of COVID-19 is of utmost importance not only for the development of vaccines and antivirals but also for understanding the pathogenesis. However, there has not been developed an animal model for systemic infection of SARS-CoV-2 representing most aspects of the clinical manifestations of COVID-19 with systemic symptoms. Here we report that a Roborovski hamster strain SH101, a laboratory inbred hamster strain of P. roborovskii, displayed most symptoms of systemic infection upon SARS-CoV-2 infection as in the case of the human counterpart, unlike current COVID-19 animal models. Roborovski hamster strain SH101 post-infection of SARS-CoV-2 represented most clinical symptoms of COVID-19 such as snuffling, labored breathing, dyspnea, cough, hunched posture, progressive weight loss, ruffled fur, and high fever following shaking chills. Histological examinations also revealed initial right-predominated pneumonia as well as slight organ damages in the brain and liver, manifesting systemic COVID-19 cases. Considering the merit of a small animal as well as its clinical manifestations of SARS-CoV-2 infection in human, this hamster model seems to provide an ideal tool to investigate COVID-19.


Subject(s)
COVID-19 , Cricetinae/classification , Disease Models, Animal , SARS-CoV-2 , Animals , Body Temperature , Brain/pathology , COVID-19/pathology , COVID-19/physiopathology , Female , Liver/pathology , Lung/pathology , Male , Mesocricetus , Mice , Mice, Transgenic
16.
Neurodegener Dis Manag ; 11(5): 387-409, 2021 10.
Article in English | MEDLINE | ID: covidwho-1394696

ABSTRACT

Teriflunomide, a once daily, oral disease-modifying therapy, has demonstrated consistent efficacy, safety and tolerability in patients with relapsing forms of multiple sclerosis (MS) and with a first clinical episode suggestive of MS treated up to 12 years. This review is an update to a previous version that examined data from the teriflunomide core clinical development program and extension studies. Data have since become available from active comparator trials with other disease-modifying therapies, treatment-related changes in brain volume (analyzed using structural image evaluation using normalization of atrophy) and real-world evidence including patient-reported outcomes. Initial data on the potential antiviral effects of teriflunomide in patients with MS, including case reports of patients infected with the 2019 novel coronavirus (SARS-CoV-2), are also presented.


Subject(s)
Crotonates/therapeutic use , Hydroxybutyrates/therapeutic use , Immunosuppressive Agents/therapeutic use , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Nitriles/therapeutic use , Toluidines/therapeutic use , Brain/diagnostic imaging , Brain/pathology , Humans , Multiple Sclerosis, Relapsing-Remitting/diagnostic imaging , Multiple Sclerosis, Relapsing-Remitting/physiopathology , Organ Size
17.
Cells ; 10(9)2021 08 31.
Article in English | MEDLINE | ID: covidwho-1390541

ABSTRACT

COVID-19 presents with a wide range of clinical neurological manifestations. It has been recognized that SARS-CoV-2 infection affects both the central and peripheral nervous system, leading to smell and taste disturbances; acute ischemic and hemorrhagic cerebrovascular disease; encephalopathies and seizures; and causes most surviving patients to have long lasting neurological symptoms. Despite this, typical neuropathological features associated with the infection have still not been identified. Studies of post-mortem examinations of the cerebral cortex are obtained with difficulty due to laboratory safety concerns. In addition, they represent cases with different neurological symptoms, age or comorbidities, thus a larger number of brain autoptic data from multiple institutions would be crucial. Histopathological findings described here are aimed to increase the current knowledge on neuropathology of COVID-19 patients. We report post-mortem neuropathological findings of ten COVID-19 patients. A wide range of neuropathological lesions were seen. The cerebral cortex of all patients showed vascular changes, hyperemia of the meninges and perivascular inflammation in the cerebral parenchyma with hypoxic neuronal injury. Perivascular lymphocytic inflammation of predominantly CD8-positive T cells mixed with CD68-positive macrophages, targeting the disrupted vascular wall in the cerebral cortex, cerebellum and pons were seen. Our findings support recent reports highlighting a role of microvascular injury in COVID-19 neurological manifestations.


Subject(s)
COVID-19/pathology , Cerebral Cortex/pathology , Aged , Aged, 80 and over , Autopsy , Brain/pathology , Brain/virology , Brain Diseases/pathology , Brain Diseases/virology , CD8-Positive T-Lymphocytes/pathology , Cerebral Cortex/virology , Female , Humans , Inflammation , Macrophages/pathology , Male , Microvessels/pathology , Microvessels/virology , Middle Aged , Nervous System Diseases/pathology , Nervous System Diseases/virology , SARS-CoV-2/pathogenicity
18.
CNS Neurosci Ther ; 27(1): 36-47, 2021 01.
Article in English | MEDLINE | ID: covidwho-1388231

ABSTRACT

The blood-brain barrier (BBB) is an important physiological barrier that separates the central nervous system (CNS) from the peripheral circulation, which contains inflammatory mediators and immune cells. The BBB regulates cellular and molecular exchange between the blood vessels and brain parenchyma. Normal functioning of the BBB is crucial for the homeostasis and proper function of the brain. It has been demonstrated that peripheral inflammation can disrupt the BBB by various pathways, resulting in different CNS diseases. Recently, clinical research also showed CNS complications following SARS-CoV-2 infection and chimeric antigen receptor (CAR)-T cell therapy, which both lead to a cytokine storm in the circulation. Therefore, elucidation of the mechanisms underlying the BBB disruption induced by peripheral inflammation will provide an important basis for protecting the CNS in the context of exacerbated peripheral inflammatory diseases. In the present review, we first summarize the physiological properties of the BBB that makes the CNS an immune-privileged organ. We then discuss the relevance of peripheral inflammation-induced BBB disruption to various CNS diseases. Finally, we elaborate various factors and mechanisms of peripheral inflammation that disrupt the BBB.


Subject(s)
Blood-Brain Barrier/metabolism , Brain/metabolism , COVID-19/metabolism , Inflammation Mediators/metabolism , Animals , Blood-Brain Barrier/immunology , Blood-Brain Barrier/pathology , Brain/immunology , Brain/pathology , COVID-19/immunology , COVID-19/pathology , Endothelial Cells/immunology , Endothelial Cells/metabolism , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Inflammation Mediators/immunology
20.
Neurol Neuroimmunol Neuroinflamm ; 8(6)2021 11.
Article in English | MEDLINE | ID: covidwho-1376615

ABSTRACT

BACKGROUND AND OBJECTIVES: Since the onset of the COVID-19 pandemic, a growing number of reports have described cases of acute disseminated encephalomyelitis (ADEM) and acute hemorrhagic leukoencephalitis (AHLE) following infection with COVID-19. Given their relatively rare occurrence, the primary objective of this systematic review was to synthesize their clinical features, response to treatments, and clinical outcomes to better understand the nature of this neurologic consequence of COVID-19 infection. METHODS: Patients with a history of COVID-19 infection were included if their reports provided adequate detail to confirm a diagnosis of ADEM or AHLE by virtue of clinical features, radiographic abnormalities, and histopathologic findings. Cases purported to be secondary to vaccination against COVID-19 or occurring in the context of a preexisting relapsing CNS demyelinating disease were excluded. Case reports and series were identified via PubMed on May 17, 2021, and 4 additional cases from the authors' hospital files supplemented the systematic review of the literature. Summary statistics were used to describe variables using a complete case analysis approach. RESULTS: Forty-six patients (28 men, median age 49.5 years, 1/3 >50 years old) were analyzed, derived from 26 case reports or series originating from 8 countries alongside 4 patient cases from the authors' hospital files. COVID-19 infection was laboratory confirmed in 91% of cases, and infection severity necessitated intensive care in 67%. ADEM occurred in 31 cases, whereas AHLE occurred in 15, with a median presenting nadir modified Rankin Scale score of 5 (bedridden). Anti-MOG seropositivity was rare (1/15 patients tested). Noninflammatory CSF was present in 30%. Hemorrhage on brain MRI was identified in 42%. Seventy percent received immunomodulatory treatments, most commonly steroids, IV immunoglobulins, or plasmapheresis. The final mRS score was ≥4 in 64% of patients with adequate follow-up information, including 32% who died. DISCUSSION: In contrast to ADEM cases from the prepandemic era, reported post-COVID-19 ADEM and AHLE cases were often advanced in age at onset, experienced severe antecedent infection, displayed an unusually high rate of hemorrhage on neuroimaging, and routinely had poor neurologic outcomes, including a high mortality rate. Findings are limited by nonstandardized reporting of cases, truncated follow-up information, and presumed publication bias.


Subject(s)
COVID-19/complications , Encephalomyelitis, Acute Disseminated/etiology , Brain/diagnostic imaging , Brain/pathology , Encephalomyelitis, Acute Disseminated/mortality , Encephalomyelitis, Acute Disseminated/physiopathology , Encephalomyelitis, Acute Disseminated/therapy , Glucocorticoids/therapeutic use , Humans , Immunoglobulins, Intravenous/therapeutic use , Immunologic Factors/therapeutic use , Intensive Care Units , Leukoencephalitis, Acute Hemorrhagic/etiology , Leukoencephalitis, Acute Hemorrhagic/mortality , Leukoencephalitis, Acute Hemorrhagic/physiopathology , Leukoencephalitis, Acute Hemorrhagic/therapy , Magnetic Resonance Imaging , Plasmapheresis , SARS-CoV-2 , Severity of Illness Index
SELECTION OF CITATIONS
SEARCH DETAIL
...