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1
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Festa LK, Jordan-Sciutto KL, Grinspan JB. Neuroinflammation: An Oligodendrocentric View. Glia 2025; 73:1113-1129. [PMID: 40059542 PMCID: PMC12014387 DOI: 10.1002/glia.70007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 02/18/2025] [Accepted: 02/20/2025] [Indexed: 03/16/2025]
Abstract
Chronic neuroinflammation, driven by central nervous system (CNS)-resident astrocytes and microglia, as well as infiltration of the peripheral immune system, is an important pathologic mechanism across a range of neurologic diseases. For decades, research focused almost exclusively on how neuroinflammation impacted neuronal function; however, there is accumulating evidence that injury to the oligodendrocyte lineage is an important component for both pathologic and clinical outcomes. While oligodendrocytes are able to undergo an endogenous repair process known as remyelination, this process becomes inefficient and usually fails in the presence of sustained inflammation. The present review focuses on our current knowledge regarding activation of the innate and adaptive immune systems in the chronic demyelinating disease, multiple sclerosis, and provides evidence that sustained neuroinflammation in other neurologic conditions, such as perinatal white matter injury, traumatic brain injury, and viral infections, converges on oligodendrocyte injury. Lastly, the therapeutic potential of targeting the impact of inflammation on the oligodendrocyte lineage in these diseases is discussed.
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Affiliation(s)
- Lindsay K Festa
- Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Kelly L Jordan-Sciutto
- Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Judith B Grinspan
- Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
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2
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Remsik J, Tong X, Kunes RZ, Li MJ, Estrera R, Snyder J, Thomson C, Osman AM, Chabot K, Sener UT, Wilcox JA, Isakov D, Wang H, Bale TA, Chaligné R, Sun JC, Brown C, Pe'er D, Boire A. Interferon-γ orchestrates leptomeningeal anti-tumour response. Nature 2025:10.1038/s41586-025-09012-z. [PMID: 40369076 DOI: 10.1038/s41586-025-09012-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 04/11/2025] [Indexed: 05/16/2025]
Abstract
Metastasis to the cerebrospinal-fluid-filled leptomeninges, or leptomeningeal metastasis, represents a fatal complication of solid tumours1. Multimodal analyses of clinical specimens reveal substantial inflammatory infiltrate in leptomeningeal metastases with enrichment of IFNγ and resulting downstream signalling. Here, to investigate and overcome this futile anti-tumour response within the leptomeninges, we developed syngeneic lung cancer, breast cancer and melanoma leptomeningeal-metastasis mouse models. We show that transgenic host mice lacking IFNγ or its receptor fail to control the growth of leptomeningeal metastases growth. Leptomeningeal overexpression of Ifng through a targeted adeno-associated-virus-based system controls cancer cell growth independent of adaptive immunity. Using a suite of transgenic hosts, we demonstrate that leptomeningeal T cells generate IFNγ to actively recruit and activate peripheral myeloid cells, generating a diverse spectrum of dendritic cell subsets. Independent of antigen presentation, migratory CCR7+ dendritic cells orchestrate the influx, proliferation and cytotoxic action of natural killer cells to control cancer cell growth in the leptomeninges. This study identifies unique, leptomeninges-specific IFNγ signalling and suggests an immune-therapeutic approach against tumours within this space.
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Affiliation(s)
- Jan Remsik
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Laboratory for Immunology of Metastatic Ecosystems, Center for Cancer Biology, VIB, Leuven, Belgium
- Department of Oncology, KU Leuven, Leuven, Belgium
| | - Xinran Tong
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- BCMB Allied Program, Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA
| | - Russell Z Kunes
- Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Statistics, Columbia University, New York, NY, USA
| | - Min Jun Li
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Medical Scientist Training Program, University of California San Diego, La Jolla, CA, USA
| | - Rachel Estrera
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jenna Snyder
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Clark Thomson
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ahmed M Osman
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden
| | - Kiana Chabot
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- College of Osteopathic Medicine, New York Institute of Technology, Glen Head, NY, USA
| | - Ugur T Sener
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Neurology & Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | - Jessica A Wilcox
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Danielle Isakov
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Tri-Institutional MD-PhD Program, Weill Cornell Medicine, New York, NY, USA
| | - Helen Wang
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Tejus A Bale
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ronan Chaligné
- Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Joseph C Sun
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Chrysothemis Brown
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Immunology and Microbial Pathogenesis Program, Weill Cornell Medical College, New York, NY, USA
| | - Dana Pe'er
- Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Adrienne Boire
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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3
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Boluda-Navarro M. Olink ® Explore for High-Throughput Protein Biomarker Discovery in Cerebrospinal Fluid. Methods Mol Biol 2025; 2914:141-163. [PMID: 40167917 DOI: 10.1007/978-1-0716-4462-1_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
The Olink® Explore platform enables high-throughput protein biomarker discovery through Proximity Extension Assay (PEA) technology combined with Next Generation Sequencing (NGS) on Illumina instruments. This approach allows for the simultaneous measurement of thousands of human plasma proteins with minimal sample volumes. The Explore 3072 library offers approximately 3000 protein assays, while the smaller Explore 384-plex panels cater to more targeted studies. The platform excels in detecting low-abundance proteins, such as cytokines and chemokines, and is particularly effective for challenging sample types like cerebrospinal fluid (CSF), where protein content is typically low. In this chapter, we emphasize critical dry-lab considerations, including CSF handling, study design, sample size determination, instrumentation requirements, and post-experiment data management. Proper planning and execution of these factors are essential for optimizing performance and ensuring reliable outcomes when using Olink®'s platform.
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4
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Rudroff T. Frontal-striatal glucose metabolism and fatigue in patients with multiple sclerosis, long COVID, and COVID-19 recovered controls. Exp Brain Res 2024; 242:2125-2136. [PMID: 38970653 DOI: 10.1007/s00221-024-06882-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 06/20/2024] [Indexed: 07/08/2024]
Abstract
This study compared brain glucose metabolism using FDG-PET in the caudate nucleus, putamen, globus pallidus, thalamus, and dorsolateral prefrontal cortex (DLPFC) among patients with Long COVID, patients with fatigue, people with multiple sclerosis (PwMS) patients with fatigue, and COVID recovered controls. PwMS exhibited greater hypometabolism compared to long COVID patients with fatigue and the COVID recovered control group in all studied brain areas except the globus pallidus (effect size range 0.7-1.5). The results showed no significant differences in glucose metabolism between patients with Long COVID and the COVID recovered control group in these regions. These findings suggest that long COVID fatigue may involve non-CNS systems, neurotransmitter imbalances, or psychological factors not captured by FDG-PET, while MS-related fatigue is associated with more severe frontal-striatal circuit dysfunction due to demyelination and neurodegeneration. Symmetrical standardized uptake values (SUVs) between hemispheres in all groups imply that fatigue in these conditions may be related to global or network-level alterations rather than hemisphere-specific changes. Future studies should employ fine-grained analysis methods, explore other brain regions, and control for confounding factors to better understand the pathophysiology of fatigue in MS and long COVID. Longitudinal studies tracking brain glucose metabolism in patients with Long COVID could provide insights into the evolution of metabolic patterns as the condition progresses.
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Affiliation(s)
- Thorsten Rudroff
- Department of Health and Human Physiology, University of Iowa, E432 Field House, Iowa City, IA, 52242, USA.
- Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
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5
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da Silva R, Vallinoto ACR, dos Santos EJM. The Silent Syndrome of Long COVID and Gaps in Scientific Knowledge: A Narrative Review. Viruses 2024; 16:1256. [PMID: 39205230 PMCID: PMC11359800 DOI: 10.3390/v16081256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 07/24/2024] [Accepted: 07/28/2024] [Indexed: 09/04/2024] Open
Abstract
COVID-19 is still a major public health concern, mainly due to the persistence of symptoms or the appearance of new symptoms. To date, more than 200 symptoms of long COVID (LC) have been described. The present review describes and maps its relevant clinical characteristics, pathophysiology, epidemiology, and genetic and nongenetic risk factors. Given the currently available evidence on LC, we demonstrate that there are still gaps and controversies in the diagnosis, pathophysiology, epidemiology, and detection of prognostic and predictive factors, as well as the role of the viral strain and vaccination.
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Affiliation(s)
- Rosilene da Silva
- Laboratory of Genetics of Complex Diseases, Institute of Biological Sciences, Federal University of Pará, Belém 66075-110, Brazil;
- Graduate Program in Biology of Infectious and Parasitic Agents, Federal University of Pará, Belém 66075-110, Brazil;
| | - Antonio Carlos Rosário Vallinoto
- Graduate Program in Biology of Infectious and Parasitic Agents, Federal University of Pará, Belém 66075-110, Brazil;
- Laboratory of Virology, Institute of Biological Sciences, Federal University of Pará, Belém 66075-110, Brazil
| | - Eduardo José Melo dos Santos
- Laboratory of Genetics of Complex Diseases, Institute of Biological Sciences, Federal University of Pará, Belém 66075-110, Brazil;
- Graduate Program in Biology of Infectious and Parasitic Agents, Federal University of Pará, Belém 66075-110, Brazil;
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6
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Pan T, Gallo ME, Donald KA, Webb K, Bath KG. Elevated risk for psychiatric outcomes in pediatric patients with Multisystem Inflammatory Syndrome (MIS-C): A review of neuroinflammatory and psychosocial stressors. Brain Behav Immun Health 2024; 38:100760. [PMID: 38586284 PMCID: PMC10992702 DOI: 10.1016/j.bbih.2024.100760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 02/19/2024] [Accepted: 03/17/2024] [Indexed: 04/09/2024] Open
Abstract
Multisystem Inflammatory Syndrome in Children (MIS-C) is a secondary immune manifestation of COVID-19 involving multiple organ systems in the body, resulting in fever, skin rash, abdominal pain, nausea, shock, and cardiac dysfunction that often lead to hospitalization. Although many of these symptoms resolve following anti-inflammatory treatment, the long-term neurological and psychiatric sequelae of MIS-C are unknown. In this review, we will summarize two domains of the MIS-C disease course, 1) Neuroinflammation in the MIS-C brain and 2) Psychosocial disruptions resulting from stress and hospitalization. In both domains, we present existing clinical findings and hypothesize potential connections to psychiatric outcomes. This is the first review to conceptualize a holistic framework of psychiatric risk in MIS-C patients that includes neuroinflammatory and psychosocial risk factors. As cases of severe COVID-19 and MIS-C subside, it is important for clinicians to monitor outcomes in this vulnerable patient population.
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Affiliation(s)
- Tracy Pan
- Stanford University School of Medicine, Stanford, CA, USA
- Department of Cognitive, Linguistic, and Psychological Sciences, Brown University, Providence, RI 029112, USA
- The Neuroscience Institute, University of Cape Town, South Africa
- Division of Developmental Neuroscience, New York State Psychiatric Institute, New York, NY, 10032, USA
| | - Meghan E. Gallo
- Department of Cognitive, Linguistic, and Psychological Sciences, Brown University, Providence, RI 029112, USA
- Division of Developmental Neuroscience, New York State Psychiatric Institute, New York, NY, 10032, USA
- Department of Psychiatry, Columbia University Irving Medical College, New York, NY, 10032, USA
- Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, 10032, USA
| | - Kirsten A. Donald
- Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Cape Town, South Africa
- The Neuroscience Institute, University of Cape Town, South Africa
| | - Kate Webb
- Division of Paediatric Rheumatology, School of Child and Adolescent Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Cape Town, 7700, South Africa
- Crick African Network, Francis Crick Institute, London, UK
| | - Kevin G. Bath
- Division of Developmental Neuroscience, New York State Psychiatric Institute, New York, NY, 10032, USA
- Department of Psychiatry, Columbia University Irving Medical College, New York, NY, 10032, USA
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7
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Hu WT, Kaluzova M, Dawson A, Sotelo V, Papas J, Lemenze A, Shu C, Jomartin M, Nayyar A, Hussain S. Clinical and CSF single-cell profiling of post-COVID-19 cognitive impairment. Cell Rep Med 2024; 5:101561. [PMID: 38744274 PMCID: PMC11148803 DOI: 10.1016/j.xcrm.2024.101561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 02/15/2024] [Accepted: 04/17/2024] [Indexed: 05/16/2024]
Abstract
Natural history and mechanisms for persistent cognitive symptoms ("brain fog") following acute and often mild COVID-19 are unknown. In a large prospective cohort of people who underwent testing a median of 9 months after acute COVID-19 in the New York City/New Jersey area, we found that cognitive dysfunction is common; is not influenced by mood, fatigue, or sleepiness; and is correlated with MRI changes in very few people. In a subgroup that underwent cerebrospinal fluid analysis, there are no changes related to Alzheimer's disease or neurodegeneration. Single-cell gene expression analysis in the cerebrospinal fluid shows findings consistent with monocyte recruitment, chemokine signaling, cellular stress, and suppressed interferon response-especially in myeloid cells. Longitudinal analysis shows slow recovery accompanied by key alterations in inflammatory genes and increased protein levels of CXCL8, CCL3L1, and sTREM2. These findings suggest that the prognosis for brain fog following COVID-19 correlates with myeloid-related chemokine and interferon-responsive genes.
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Affiliation(s)
- William T Hu
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Center for Innovation in Health and Aging Research, Institute for Health, Health Care Policy, and Aging Research, New Brunswick, NJ, USA.
| | - Milota Kaluzova
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Alice Dawson
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Center for Innovation in Health and Aging Research, Institute for Health, Health Care Policy, and Aging Research, New Brunswick, NJ, USA
| | - Victor Sotelo
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Center for Innovation in Health and Aging Research, Institute for Health, Health Care Policy, and Aging Research, New Brunswick, NJ, USA
| | - Julia Papas
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA; Center for Innovation in Health and Aging Research, Institute for Health, Health Care Policy, and Aging Research, New Brunswick, NJ, USA
| | - Alexander Lemenze
- Department of Pathology and Laboratory Medicine, Rutgers-New Jersey Medical School, Newark, NJ, USA
| | - Carol Shu
- Department of Medicine-Pulmonary and Critical Care, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Mini Jomartin
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Ashima Nayyar
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Sabiha Hussain
- Department of Medicine-Pulmonary and Critical Care, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA
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8
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Kumar A, Tripathi P, Kumar P, Shekhar R, Pathak R. From Detection to Protection: Antibodies and Their Crucial Role in Diagnosing and Combatting SARS-CoV-2. Vaccines (Basel) 2024; 12:459. [PMID: 38793710 PMCID: PMC11125746 DOI: 10.3390/vaccines12050459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 04/20/2024] [Accepted: 04/22/2024] [Indexed: 05/26/2024] Open
Abstract
Understanding the antibody response to SARS-CoV-2, the virus responsible for COVID-19, is crucial to comprehending disease progression and the significance of vaccine and therapeutic development. The emergence of highly contagious variants poses a significant challenge to humoral immunity, underscoring the necessity of grasping the intricacies of specific antibodies. This review emphasizes the pivotal role of antibodies in shaping immune responses and their implications for diagnosing, preventing, and treating SARS-CoV-2 infection. It delves into the kinetics and characteristics of the antibody response to SARS-CoV-2 and explores current antibody-based diagnostics, discussing their strengths, clinical utility, and limitations. Furthermore, we underscore the therapeutic potential of SARS-CoV-2-specific antibodies, discussing various antibody-based therapies such as monoclonal antibodies, polyclonal antibodies, anti-cytokines, convalescent plasma, and hyperimmunoglobulin-based therapies. Moreover, we offer insights into antibody responses to SARS-CoV-2 vaccines, emphasizing the significance of neutralizing antibodies in order to confer immunity to SARS-CoV-2, along with emerging variants of concern (VOCs) and circulating Omicron subvariants. We also highlight challenges in the field, such as the risks of antibody-dependent enhancement (ADE) for SARS-CoV-2 antibodies, and shed light on the challenges associated with the original antigenic sin (OAS) effect and long COVID. Overall, this review intends to provide valuable insights, which are crucial to advancing sensitive diagnostic tools, identifying efficient antibody-based therapeutics, and developing effective vaccines to combat the evolving threat of SARS-CoV-2 variants on a global scale.
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Affiliation(s)
- Anoop Kumar
- Molecular Diagnostic Laboratory, National Institute of Biologicals, Noida 201309, India
| | - Prajna Tripathi
- Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY 10021, USA;
| | - Prashant Kumar
- R. Ken Coit College of Pharmacy, University of Arizona, Tucson, AZ 85721, USA
| | - Ritu Shekhar
- Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Rajiv Pathak
- Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA
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9
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Owens CD, Bonin Pinto C, Detwiler S, Olay L, Pinaffi-Langley ACDC, Mukli P, Peterfi A, Szarvas Z, James JA, Galvan V, Tarantini S, Csiszar A, Ungvari Z, Kirkpatrick AC, Prodan CI, Yabluchanskiy A. Neurovascular coupling impairment as a mechanism for cognitive deficits in COVID-19. Brain Commun 2024; 6:fcae080. [PMID: 38495306 PMCID: PMC10943572 DOI: 10.1093/braincomms/fcae080] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 02/08/2024] [Accepted: 03/05/2024] [Indexed: 03/19/2024] Open
Abstract
Components that comprise our brain parenchymal and cerebrovascular structures provide a homeostatic environment for proper neuronal function to ensure normal cognition. Cerebral insults (e.g. ischaemia, microbleeds and infection) alter cellular structures and physiologic processes within the neurovascular unit and contribute to cognitive dysfunction. COVID-19 has posed significant complications during acute and convalescent stages in multiple organ systems, including the brain. Cognitive impairment is a prevalent complication in COVID-19 patients, irrespective of severity of acute SARS-CoV-2 infection. Moreover, overwhelming evidence from in vitro, preclinical and clinical studies has reported SARS-CoV-2-induced pathologies in components of the neurovascular unit that are associated with cognitive impairment. Neurovascular unit disruption alters the neurovascular coupling response, a critical mechanism that regulates cerebromicrovascular blood flow to meet the energetic demands of locally active neurons. Normal cognitive processing is achieved through the neurovascular coupling response and involves the coordinated action of brain parenchymal cells (i.e. neurons and glia) and cerebrovascular cell types (i.e. endothelia, smooth muscle cells and pericytes). However, current work on COVID-19-induced cognitive impairment has yet to investigate disruption of neurovascular coupling as a causal factor. Hence, in this review, we aim to describe SARS-CoV-2's effects on the neurovascular unit and how they can impact neurovascular coupling and contribute to cognitive decline in acute and convalescent stages of the disease. Additionally, we explore potential therapeutic interventions to mitigate COVID-19-induced cognitive impairment. Given the great impact of cognitive impairment associated with COVID-19 on both individuals and public health, the necessity for a coordinated effort from fundamental scientific research to clinical application becomes imperative. This integrated endeavour is crucial for mitigating the cognitive deficits induced by COVID-19 and its subsequent burden in this especially vulnerable population.
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Affiliation(s)
- Cameron D Owens
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Camila Bonin Pinto
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Sam Detwiler
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
| | - Lauren Olay
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
| | - Ana Clara da C Pinaffi-Langley
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
| | - Peter Mukli
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, 1089, Hungary
| | - Anna Peterfi
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, 1089, Hungary
| | - Zsofia Szarvas
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, 1089, Hungary
| | - Judith A James
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Arthritis & Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
- Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Veronica Galvan
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
| | - Stefano Tarantini
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, 1089, Hungary
- The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Anna Csiszar
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, 1089, Hungary
| | - Zoltan Ungvari
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, 1089, Hungary
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Angelia C Kirkpatrick
- Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
- Cardiovascular Section, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
| | - Calin I Prodan
- Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
- Department of Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Andriy Yabluchanskiy
- Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA
- Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health, Translational Medicine and Physiology, Semmelweis University, Budapest, 1089, Hungary
- Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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10
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Kiyak C, Ijezie OA, Ackah JA, Armstrong M, Cowen J, Cetinkaya D, Burianová H, Akudjedu TN. Topographical Distribution of Neuroanatomical Abnormalities Following COVID-19 Invasion : A Systematic Literature Review. Clin Neuroradiol 2024; 34:13-31. [PMID: 37697012 PMCID: PMC10881816 DOI: 10.1007/s00062-023-01344-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 08/14/2023] [Indexed: 09/13/2023]
Abstract
PURPOSE This systematic review is aimed at synthesising the literature base to date on the frequency and topographical distribution of neuroanatomical changes seen on imaging following COVID-19 invasion with a focus on both the acute and chronic phases of the disease. METHODS In this study, 8 databases were systematically searched to identify relevant articles published from December 2019 to March 2022 and supplemented with a manual reference search. Data were extracted from the included studies and narrative synthesis was employed to integrate the findings. RESULTS A total of 110 studies met the inclusion criteria and comprised 119,307 participants (including 31,073 acute and 143 long COVID-19 patients manifesting neurological alterations) and controls. Considerable variability in both the localisation and nature of neuroanatomical abnormalities are noted along the continuum with a wide range of neuropathologies relating to the cerebrovascular/neurovascular system, (sub)cortical structures (including deep grey and white matter structures), brainstem, and predominant regional and/or global alterations in the cerebellum with varying degrees of spinal involvement. CONCLUSION Structural regional alterations on neuroimaging are frequently demonstrated in both the acute and chronic phases of SARS-CoV‑2 infection, particularly prevalent across subcortical, prefrontal/frontal and cortico-limbic brain areas as well as the cerebrovascular/neurovascular system. These findings contribute to our understanding of the acute and chronic effects of the virus on the nervous system and has the potential to provide information on acute and long-term treatment and neurorehabilitation decisions.
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Affiliation(s)
- Ceyda Kiyak
- Faculty of Science and Technology, Bournemouth University, Bournemouth, UK
- School of Psychology, University of East Anglia, Norwich, UK
| | | | - Joseph A Ackah
- Institute of Medical Imaging and Visualisation, Faculty of Health and Social Sciences, Bournemouth University, 8 8GP, Bournemouth, UK
| | - Matthew Armstrong
- Department of Rehabilitation & Sports Sciences, Faculty of Health and Social Sciences, Bournemouth University, Bournemouth, UK
| | - Jake Cowen
- Department of Radiology, Queen Alexandra Hospital, Portsmouth Hospitals University NHS Trust, Portsmouth, UK
| | - Deniz Cetinkaya
- Faculty of Science and Technology, Bournemouth University, Bournemouth, UK
| | - Hana Burianová
- Faculty of Science and Technology, Bournemouth University, Bournemouth, UK
| | - Theophilus N Akudjedu
- Institute of Medical Imaging and Visualisation, Faculty of Health and Social Sciences, Bournemouth University, 8 8GP, Bournemouth, UK.
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11
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Kanberg N, Grahn A, Stentoft E, Bremell D, Yilmaz A, Studahl M, Nilsson S, Schöll M, Gostner JM, Blennow K, Zetterberg H, Padmanabhan N, Cohen R, Misaghian S, Romero D, Campbell C, Mathew A, Wang M, Sigal G, Stengelin M, Edén A, Gisslén M. COVID-19 Recovery: Consistent Absence of Cerebrospinal Fluid Biomarker Abnormalities in Patients With Neurocognitive Post-COVID Complications. J Infect Dis 2024; 229:493-501. [PMID: 37874918 PMCID: PMC10873166 DOI: 10.1093/infdis/jiad395] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 09/08/2023] [Indexed: 10/26/2023] Open
Abstract
BACKGROUND To investigate evidence of residual viral infection, intrathecal immune activation, central nervous system (CNS) injury, and humoral responses in cerebrospinal fluid (CSF) and plasma in patients recovering from coronavirus disease 2019 (COVID-19), with or without neurocognitive post-COVID condition (PCC). METHODS Thirty-one participants (25 with neurocognitive PCC) underwent clinical examination, lumbar puncture, and venipuncture ≥3 months after COVID-19 symptom onset. Healthy volunteers were included. CSF and plasma severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid and spike antigen (N-Ag, S-Ag), and CSF biomarkers of immune activation and neuronal injury were analyzed. RESULTS SARS-CoV-2 N-Ag or S-Ag were undetectable in all samples and no participant had pleocytosis. We detected no significant differences in CSF and plasma cytokine concentrations, albumin ratio, IgG index, neopterin, β2M, or in CSF biomarkers of neuronal injury and astrocytic damage. Furthermore, principal component analysis (PCA1) analysis did not indicate any significant differences between the study groups in the marker sets cytokines, neuronal markers, or anti-cytokine autoantibodies. CONCLUSIONS We found no evidence of ongoing viral replication, immune activation, or CNS injury in plasma or CSF in patients with neurocognitive PCC compared with COVID-19 controls or healthy volunteers, suggesting that neurocognitive PCC is a consequence of events suffered during acute COVID-19 rather than persistent viral CNS infection or residual CNS inflammation.
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Affiliation(s)
- Nelly Kanberg
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Infectious Diseases, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Anna Grahn
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Infectious Diseases, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Erika Stentoft
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Infectious Diseases, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Daniel Bremell
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Infectious Diseases, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Aylin Yilmaz
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Infectious Diseases, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Marie Studahl
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Infectious Diseases, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Staffan Nilsson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Michael Schöll
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
- Department of Neurodegenerative Disease, Dementia Research Centre, Institute of Neurology, University College London, London, United Kingdom
| | - Johanna M Gostner
- Institute of Medical Biochemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Kaj Blennow
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
| | - Henrik Zetterberg
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Neurodegenerative Disease, Dementia Research Centre, Institute of Neurology, University College London, London, United Kingdom
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
- UK Dementia Research Institute, University College London, London, United Kingdom
- Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China
- Wisconsin Alzheimer's Disease Research Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | | | - Rachel Cohen
- Meso Scale Diagnostics, LLC, Rockville, Maryland, USA
| | | | - Daniel Romero
- Meso Scale Diagnostics, LLC, Rockville, Maryland, USA
| | | | - Anu Mathew
- Meso Scale Diagnostics, LLC, Rockville, Maryland, USA
| | - Mingyue Wang
- Meso Scale Diagnostics, LLC, Rockville, Maryland, USA
| | - George Sigal
- Meso Scale Diagnostics, LLC, Rockville, Maryland, USA
| | | | - Arvid Edén
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Infectious Diseases, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Magnus Gisslén
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Infectious Diseases, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
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12
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Qin H, Duan G, Zhou K, Qin L, Lai Y, Liu Y, Lu Y, Peng B, Zhang Y, Zhou X, Huang J, Huang J, Liang L, Wei Y, Zhang Q, Li X, OuYang Y, Bin B, Zhao M, Yang J, Deng D. Alteration of white matter microstructure in patients with sleep disorders after COVID-19 infection. Sleep Med 2024; 114:109-118. [PMID: 38181582 DOI: 10.1016/j.sleep.2023.12.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 12/10/2023] [Accepted: 12/25/2023] [Indexed: 01/07/2024]
Abstract
BACKGROUND The pathophysiology of coronasomnia remains unclear. This study aimed to investigate changes in white matter (WM) microstructure and inflammatory factors in patients with sleep disorders (SD) characterized by poor sleep quantity, quality, or timing following coronavirus disease 2019 (COVID-19) infection in the acute phase (within one month) and whether these changes could be recovered at 3-month follow-up. METHODS 29 acute COVID-19 patients with SD (COVID_SD) and 27 acute COVID-19 patients without SD (COVID_NonSD) underwent diffusion tensor imaging (DTI), tested peripheral blood inflammatory cytokines level, and measured Pittsburgh Sleep Quality Index (PSQI), and matched 30 uninfected healthy controls. Analyzed WM abnormalities between groups in acute phase and explored its changes in COVID_SD at 3-month follow-up by using tract-based spatial statistics (TBSS). Correlations between DTI and clinical data were examined using Spearman partial correlation analysis. RESULTS Both COVID_SD and COVID_NonSD exhibited widespread WM microstructure abnormalities. The COVID_SD group showed specific WM microstructure changes in right inferior fronto-occipital fasciculus (IFOF) (lower fractional anisotropy [FA]/axial diffusivity [AD] and higher radial diffusivity [RD]) and left corticospinal tract (CST) (higher FA and lower RD) and higher interleukin-1β (IL-1β) compared with COVID_NonSD group. These WM abnormalities and IL-1β levels were correlated PSQI score. After 3 months, the IFOF integrity and IL-1β levels tended to return to normal accompanied by symptom improvement in the COVID_SD relative to baseline. CONCLUSION Abnormalities in right IFOF and left CST and elevated IL-1β levels were important neurophenotypes correlated with COVID_SD, which might provide new insights into the pathogenesis of neuroinflammation in SD patients induced by COVID-19.
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Affiliation(s)
- Haixia Qin
- Medical College of Guangxi University, Guangxi University, Nanning, 530004, Guangxi, China; Department of Radiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 530021, Guangxi, China
| | - Gaoxiong Duan
- Department of Radiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 530021, Guangxi, China
| | - Kaixuan Zhou
- Department of Radiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 530021, Guangxi, China
| | - Lixia Qin
- Department of Sleep Medicine, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning, 530021, Guangxi, China
| | - Yinqi Lai
- Department of Radiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 530021, Guangxi, China
| | - Ying Liu
- Department of Radiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 530021, Guangxi, China
| | - Yian Lu
- Department of Sleep Medicine, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning, 530021, Guangxi, China
| | - Bei Peng
- Department of Radiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 530021, Guangxi, China
| | - Yan Zhang
- Department of Radiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 530021, Guangxi, China
| | - Xiaoyan Zhou
- Department of Radiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 530021, Guangxi, China
| | - Jiazhu Huang
- Department of Radiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 530021, Guangxi, China
| | - Jinli Huang
- Department of Radiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 530021, Guangxi, China
| | - Lingyan Liang
- Department of Radiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 530021, Guangxi, China
| | - Yichen Wei
- Department of Radiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 530021, Guangxi, China
| | - Qingping Zhang
- Department of Radiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 530021, Guangxi, China
| | - Xiaocheng Li
- Department of Radiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 530021, Guangxi, China
| | - Yinfei OuYang
- Department of Radiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 530021, Guangxi, China
| | - Bolin Bin
- Department of Radiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 530021, Guangxi, China
| | - Mingming Zhao
- Department of Sleep Medicine, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, Nanning, 530021, Guangxi, China.
| | - Jianrong Yang
- Guangxi Clinical Reserch Center for Sleep Medicine, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, Guangxi, China.
| | - Demao Deng
- Medical College of Guangxi University, Guangxi University, Nanning, 530004, Guangxi, China; Department of Radiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Guangxi Academy of Medical Sciences, 530021, Guangxi, China.
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13
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Devlin L, Gombolay GY. Cerebrospinal fluid cytokines in COVID-19: a review and meta-analysis. J Neurol 2023; 270:5155-5161. [PMID: 37581633 PMCID: PMC10591843 DOI: 10.1007/s00415-023-11928-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 08/05/2023] [Accepted: 08/08/2023] [Indexed: 08/16/2023]
Abstract
INTRODUCTION Neurological involvement can occur in patients with SARS-CoV-2 infections, resulting in coronavirus disease 2019 (COVID-19). Cytokine alterations are associated with neurological symptoms in COVID-19. We performed a review of cytokines in the cerebrospinal fluid (CSF) of patients with COVID-19. METHODS Two reviewers independently searched PubMed for all relevant articles published prior to November 11, 2022. Active SARS-CoV-2 infection and CSF cytokine analyses were required for inclusion. RESULTS Three-hundred forty-six patients with COVID-19 and 356 controls from 28 studies were included. SARS-CoV-2 PCR was positive in the CSF of 0.9% (3/337) of patients with COVID-19. Thirty-seven different cytokines were elevated in the CSF of patients with COVID-19 when compared to controls and the standards set forth by individual assays used in each study. Of the 37 cytokines, IL-6 and IL-8 were most commonly elevated. CSF IL-6 is elevated in 60%, and CSF IL-8 is elevated in 51% of patients with COVID-19. CONCLUSION Levels of several inflammatory cytokines are elevated in the CSF of patients with COVID-19, and SARS-CoV-2 PCR is often not isolated in the CSF of patients with COVID-19. Many patients with COVID-19 have neurological symptoms and given the cytokine elevations in the absence of detectable viral RNA in cerebrospinal fluid; further study of the CSF cytokine profiles and pathogenesis of neurological symptoms in COVID-19 is needed.
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Affiliation(s)
- Lily Devlin
- Emory University School of Medicine, Atlanta, GA, USA
| | - Grace Y Gombolay
- Children's Healthcare of Atlanta, Division of Pediatric Neurology, Emory University, 1400 Tulle Road NE, 8th Floor, Atlanta, GA, USA.
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14
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Lou N, Wang G, Wang Y, Xu M, Zhou Y, Tan Q, Zhong Q, Zhang L, Zhang X, Liu S, Luo R, Wang S, Tang L, Yao J, Zhang Z, Shi Y, Yu X, Han X. Proteomics Identifies Circulating TIMP-1 as a Prognostic Biomarker for Diffuse Large B-Cell Lymphoma. Mol Cell Proteomics 2023; 22:100625. [PMID: 37500057 PMCID: PMC10470290 DOI: 10.1016/j.mcpro.2023.100625] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 06/24/2023] [Accepted: 07/24/2023] [Indexed: 07/29/2023] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, although disease stratification using in-depth plasma proteomics has not been performed to date. By measuring more than 1000 proteins in the plasma of 147 DLBCL patients using data-independent acquisition mass spectrometry and antibody array, DLBCL patients were classified into four proteomic subtypes (PS-I-IV). Patients with the PS-IV subtype and worst prognosis had increased levels of proteins involved in inflammation, including a high expression of metalloproteinase inhibitor-1 (TIMP-1) that was associated with poor survival across two validation cohorts (n = 180). Notably, the combination of TIMP-1 with the international prognostic index (IPI) identified 64.00% to 88.24% of relapsed and 65.00% to 80.49% of deceased patients in the discovery and two validation cohorts, which represents a 24.00% to 41.67% and 20.00% to 31.70% improvement compared to the IPI score alone, respectively. Taken together, we demonstrate that DLBCL heterogeneity is reflected in the plasma proteome and that TIMP-1, together with the IPI, could improve the prognostic stratification of patients.
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Affiliation(s)
- Ning Lou
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Guibin Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences-Beijing (PHOENIX Center), Beijing Institute of Lifeomics, Beijing, China
| | - Yanrong Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Meng Xu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences-Beijing (PHOENIX Center), Beijing Institute of Lifeomics, Beijing, China
| | - Yu Zhou
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Qiaoyun Tan
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Qiaofeng Zhong
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Lei Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Xiaomei Zhang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences-Beijing (PHOENIX Center), Beijing Institute of Lifeomics, Beijing, China
| | - Shuxia Liu
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Rongrong Luo
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Shasha Wang
- Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Le Tang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Jiarui Yao
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Zhishang Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China
| | - Yuankai Shi
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
| | - Xiaobo Yu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences-Beijing (PHOENIX Center), Beijing Institute of Lifeomics, Beijing, China.
| | - Xiaohong Han
- Clinical Pharmacology Research Center, Peking Union Medical College Hospital, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK & PD Investigation for Innovative Drugs, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
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15
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Solomon IH, Singh A, Folkerth RD, Mukerji SS. What Can We Still Learn from Brain Autopsies in COVID-19? Semin Neurol 2023. [PMID: 37023787 DOI: 10.1055/s-0043-1767716] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
Neuropathological findings have been published from ∼900 patients who died with or from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, representing less than 0.01% of the close to 6.4 million deaths reported to the World Health Organization 2 years into the coronavirus disease 2019 (COVID-19) pandemic. In this review, we extend our prior work summarizing COVID-19 neuropathology by including information on published autopsies up to June 2022, and neuropathological studies in children, COVID-19 variants, secondary brain infections, ex vivo brain imaging, and autopsies performed in countries outside of the United States or Europe. We also summarize research studies that investigate mechanisms of neuropathogenesis in nonhuman primates and other models. While a pattern of cerebrovascular pathology and microglial-predominant inflammation remains the primary COVID-19-associated neuropathological finding, there is no singular understanding of the mechanisms that underlie neurological symptoms in acute COVID-19 or the post-acute COVID-19 condition. Thus, it is paramount that we incorporate microscopic and molecular findings from brain tissue into what we know about the clinical disease so that we attain best practice guidance and direct research priorities for the study of the neurological morbidity of COVID-19.
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Affiliation(s)
- Isaac H Solomon
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Arjun Singh
- Division of Neuroimmunology and Neuro-Infectious Diseases, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts
- Healing Hospital, Chandigarh, India
| | - Rebecca D Folkerth
- Office of Chief Medical Examiner and Department of Forensic Medicine, New York University School of Medicine, New York, New York
| | - Shibani S Mukerji
- Harvard Medical School, Boston, Massachusetts
- Division of Neuroimmunology and Neuro-Infectious Diseases, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts
- Division of Infectious Diseases, Vaccine and Immunotherapy Center, Massachusetts General Hospital, Charlestown, Massachusetts
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16
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Maity S, Mayer MG, Shu Q, Linh H, Bao D, Blair RV, He Y, Lyon CJ, Hu TY, Fischer T, Fan J. Cerebrospinal Fluid Protein Markers Indicate Neuro-Damage in SARS-CoV-2-Infected Nonhuman Primates. Mol Cell Proteomics 2023; 22:100523. [PMID: 36870567 PMCID: PMC9981268 DOI: 10.1016/j.mcpro.2023.100523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 02/18/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
Neurologic manifestations are among the most frequently reported complications of COVID-19. However, given the paucity of tissue samples and the highly infectious nature of the etiologic agent of COVID-19, we have limited information to understand the neuropathogenesis of COVID-19. Therefore, to better understand the impact of COVID-19 on the brain, we used mass-spectrometry-based proteomics with a data-independent acquisition mode to investigate cerebrospinal fluid (CSF) proteins collected from two different nonhuman primates, Rhesus Macaque and African Green Monkeys, for the neurologic effects of the infection. These monkeys exhibited minimal to mild pulmonary pathology but moderate to severe central nervous system (CNS) pathology. Our results indicated that CSF proteome changes after infection resolution corresponded with bronchial virus abundance during early infection and revealed substantial differences between the infected nonhuman primates and their age-matched uninfected controls, suggesting these differences could reflect altered secretion of CNS factors in response to SARS-CoV-2-induced neuropathology. We also observed the infected animals exhibited highly scattered data distributions compared to their corresponding controls indicating the heterogeneity of the CSF proteome change and the host response to the viral infection. Dysregulated CSF proteins were preferentially enriched in functional pathways associated with progressive neurodegenerative disorders, hemostasis, and innate immune responses that could influence neuroinflammatory responses following COVID-19. Mapping these dysregulated proteins to the Human Brain Protein Atlas found that they tended to be enriched in brain regions that exhibit more frequent injury following COVID-19. It, therefore, appears reasonable to speculate that such CSF protein changes could serve as signatures for neurologic injury, identify important regulatory pathways in this process, and potentially reveal therapeutic targets to prevent or attenuate the development of neurologic injuries following COVID-19.
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Affiliation(s)
- Sudipa Maity
- Center for Cellular and Molecular Diagnostics, Tulane University School of Medicine, New Orleans, Louisiana, USA; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Meredith G Mayer
- Division of Comparative Pathology, National Primate Research Center, Covington, Louisiana, USA
| | - Qingbo Shu
- Center for Cellular and Molecular Diagnostics, Tulane University School of Medicine, New Orleans, Louisiana, USA; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Hellmers Linh
- Division of Comparative Pathology, National Primate Research Center, Covington, Louisiana, USA
| | - Duran Bao
- Center for Cellular and Molecular Diagnostics, Tulane University School of Medicine, New Orleans, Louisiana, USA; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Robert V Blair
- Division of Comparative Pathology, National Primate Research Center, Covington, Louisiana, USA
| | - Yanlin He
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Christopher J Lyon
- Center for Cellular and Molecular Diagnostics, Tulane University School of Medicine, New Orleans, Louisiana, USA; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Tony Y Hu
- Center for Cellular and Molecular Diagnostics, Tulane University School of Medicine, New Orleans, Louisiana, USA; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Tracy Fischer
- Division of Comparative Pathology, National Primate Research Center, Covington, Louisiana, USA; Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Jia Fan
- Center for Cellular and Molecular Diagnostics, Tulane University School of Medicine, New Orleans, Louisiana, USA; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana, USA.
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17
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Remsik J, Tong X, Kunes RZ, Li MJ, Osman A, Chabot K, Sener UT, Wilcox JA, Isakov D, Snyder J, Bale TA, Chaligné R, Pe'er D, Boire A. Leptomeningeal anti-tumor immunity follows unique signaling principles. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.17.533041. [PMID: 36993586 PMCID: PMC10055207 DOI: 10.1101/2023.03.17.533041] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
Abstract
Metastasis to the cerebrospinal fluid (CSF)-filled leptomeninges, or leptomeningeal metastasis (LM), represents a fatal complication of cancer. Proteomic and transcriptomic analyses of human CSF reveal a substantial inflammatory infiltrate in LM. We find the solute and immune composition of CSF in the setting of LM changes dramatically, with notable enrichment in IFN-γ signaling. To investigate the mechanistic relationships between immune cell signaling and cancer cells within the leptomeninges, we developed syngeneic lung, breast, and melanoma LM mouse models. Here we show that transgenic host mice, lacking IFN-γ or its receptor, fail to control LM growth. Overexpression of Ifng through a targeted AAV system controls cancer cell growth independent of adaptive immunity. Instead, leptomeningeal IFN-γ actively recruits and activates peripheral myeloid cells, generating a diverse spectrum of dendritic cell subsets. These migratory, CCR7+ dendritic cells orchestrate the influx, proliferation, and cytotoxic action of natural killer cells to control cancer cell growth in the leptomeninges. This work uncovers leptomeningeal-specific IFN-γ signaling and suggests a novel immune-therapeutic approach against tumors within this space.
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18
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Do SARS-CoV-2 Variants Differ in Their Neuropathogenicity? mBio 2023; 14:e0292022. [PMID: 36651750 PMCID: PMC9973339 DOI: 10.1128/mbio.02920-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Neurological complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are a huge societal problem. Although the neuropathogenicity of SARS-CoV-2 is not yet fully understood, there is evidence that SARS-CoV-2 can invade and infect cells of the central nervous system. Kong et al. (https://doi.org/10.1128/mbio.02308-22) shows that the mechanism of virus entry into astrocytes in brain organoids and primary astrocytes differs from entry into respiratory epithelial cells. However, how SARS-CoV-2 enters susceptible CNS cells and whether there are differences among SARS-CoV-2 variants is still unclear. In vivo and in vitro models are useful to study these important questions and may reveal important differences among SARS-CoV-2 variants in their neuroinvasive, neurotropic, and neurovirulent potential. In this commentary we address how this study contributes to the understanding of the neuropathology of SARS-CoV-2 and its variants.
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19
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Huang JJ, Wang CW, Liu Y, Zhang YY, Yang NB, Yu YC, Jiang Q, Song QF, Qian GQ. Role of the extracellular matrix in COVID-19. World J Clin Cases 2023; 11:73-83. [PMID: 36687194 PMCID: PMC9846981 DOI: 10.12998/wjcc.v11.i1.73] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 12/14/2022] [Accepted: 12/23/2022] [Indexed: 01/04/2023] Open
Abstract
An outbreak of coronavirus disease 2019 (COVID-19) has spread globally, with over 500 million cases and 6 million deaths to date. COVID-19 is associated with a systemic inflammatory response and abnormalities of the extracellular matrix (ECM), which is also involved in inflammatory storms. Upon viral infection, ECM proteins are involved in the recruitment of inflammatory cells and interference with target organ metabolism, including in the lungs. Additionally, serum biomarkers of ECM turnover are associated with the severity of COVID-19 and may serve as potential targets. Consequently, understanding the expression and function of ECM, particularly of the lung, during severe acute respiratory syndrome of the coronavirus 2 infection would provide valuable insights into the mechanisms of COVID-19 progression. In this review, we summarize the current findings on ECM, such as hyaluronic acid, matrix metalloproteinases, and collagen, which are linked to the severity and inflammation of COVID-19. Some drugs targeting the extracellular surface have been effective. In the future, these ECM findings could provide novel perspectives on the pathogenesis and treatment of COVID-19.
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Affiliation(s)
- Jia-Jia Huang
- School of Medicine, Ningbo University, Ningbo 315000, Zhejiang Province, China
| | - Chu-Wen Wang
- School of Medicine, Ningbo University, Ningbo 315000, Zhejiang Province, China
| | - Ying Liu
- School of Medicine, Ningbo University, Ningbo 315000, Zhejiang Province, China
| | - Ying-Ying Zhang
- School of Medicine, Ningbo University, Ningbo 315000, Zhejiang Province, China
| | - Nai-Bin Yang
- Department of Infectious Diseases, Ningbo First Hospital, Ningbo 315000, Zhejiang Province, China
| | - Yu-Chun Yu
- Department of Endocrinology, Ningbo Ninth Hospital, Ningbo 315000, Zhejiang Province, China
| | - Qi Jiang
- Department of Digestive, Ningbo First Hospital, Ningbo 315000, Zhejiang Province, China
| | - Qi-Fa Song
- Medical Data Center, Ningbo First Hospital, Ningbo 315000, Zhejiang Province, China
| | - Guo-Qing Qian
- Department of Infectious Diseases, Ningbo First Hospital, Ningbo 315000, Zhejiang Province, China
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20
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Ramezani S, Ezzatifar F, Hojjatipour T, Hemmatzadeh M, Shabgah AG, Navashenaq JG, Aslani S, Shomali N, Arabi M, Babaie F, Jadidi-Niaragh F, Hosseinzadeh R, Feizisani F, Khodayar S, Safari R, Mohammadi H. Association of the matrix metalloproteinases (MMPs) family gene polymorphisms and the risk of coronavirus disease 2019 (COVID-19); implications of contribution for development of neurological symptoms in the COVID-19 patients. Mol Biol Rep 2023; 50:173-183. [PMID: 36319784 PMCID: PMC9628292 DOI: 10.1007/s11033-022-07907-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 08/31/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND Seemingly, the Matrix metalloproteinases (MMPs) play a role in the etiopathogenesis of coronavirus disease 2019 (COVID-19). Here in this study, we determined the association of MMP9 rs3918242, MMP3 rs3025058, and MMP2 rs243865 polymorphisms with the risk of COVID-19, especially in those with neurological syndrome (NS). METHODS We enrolled 500 patients with COVID-19 and 500 healthy individuals. To genotype the target SNPs, the Real-time allelic discrimination technique was used. To determine serum levels of MMPs, Enzyme-linked immunosorbent assay (ELISA) was exerted. RESULTS The MMP9 gene rs3918242 and MMP3 gene rs3025058 SNP were significantly associated with increased COVID-19 risk and susceptibility to COVID-19 with NS. The serum level of MMP-9 and MMP-3 was significantly higher in COVID-19 cases compared with the healthy controls. Serum MMP-9 and MMP-3 levels were also higher in COVID-19 subjects with NS in comparison to the healthy controls. The polymorphisms in MMP genes were not associated with serum level of MMPs. CONCLUSION MMP9 and MMP3 gene polymorphisms increases the susceptibility to COVID-19 as well as COVID-19 with neurologic syndrome, but they probably have no role in the regulation of serum MMP-9 and MMP-3 levels.
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Affiliation(s)
- Samaneh Ramezani
- Immunology Research Center, Inflammation and Inflammatory Diseases Division, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Ezzatifar
- Molecular and Cell Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
| | - Tahereh Hojjatipour
- Department of Hematology and Blood Transfusion, Students Research Centre, School of Allied Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Hemmatzadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Saeed Aslani
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Navid Shomali
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohsen Arabi
- Department of Physiology, Pharmacology and Medical Physics, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Farhad Babaie
- Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ramin Hosseinzadeh
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fahimeh Feizisani
- Student Research Committee, Sarab Faculty of Medical Sciences, Sarab, Iran
| | - Sara Khodayar
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Roghaiyeh Safari
- Molecular and Cellular Epigenetics (GIGA), Belgium. Molecular and Cellular Biology (TERRA), Gembloux Agro-Bio Tech, University of Liege, Sart-Tilman Liège, University of Liege, Gembloux, Belgium.
- Molecular and Cellular Biology (TERRA), Gembloux Agro-Bio Tech, University of Liege, Gembloux, Belgium.
| | - Hamed Mohammadi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.
- Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
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21
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Tan PH, Ji J, Hsing CH, Tan R, Ji RR. Emerging Roles of Type-I Interferons in Neuroinflammation, Neurological Diseases, and Long-Haul COVID. Int J Mol Sci 2022; 23:ijms232214394. [PMID: 36430870 PMCID: PMC9696119 DOI: 10.3390/ijms232214394] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/11/2022] [Accepted: 11/15/2022] [Indexed: 11/22/2022] Open
Abstract
Interferons (IFNs) are pleiotropic cytokines originally identified for their antiviral activity. IFN-α and IFN-β are both type I IFNs that have been used to treat neurological diseases such as multiple sclerosis. Microglia, astrocytes, as well as neurons in the central and peripheral nervous systems, including spinal cord neurons and dorsal root ganglion neurons, express type I IFN receptors (IFNARs). Type I IFNs play an active role in regulating cognition, aging, depression, and neurodegenerative diseases. Notably, by suppressing neuronal activity and synaptic transmission, IFN-α and IFN-β produced potent analgesia. In this article, we discuss the role of type I IFNs in cognition, neurodegenerative diseases, and pain with a focus on neuroinflammation and neuro-glial interactions and their effects on cognition, neurodegenerative diseases, and pain. The role of type I IFNs in long-haul COVID-associated neurological disorders is also discussed. Insights into type I IFN signaling in neurons and non-neuronal cells will improve our treatments of neurological disorders in various disease conditions.
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Affiliation(s)
- Ping-Heng Tan
- Department of Anesthesiology, Chi Mei Medical Center, Tainan 701, Taiwan
- Correspondence: (P.-H.T.); (C.-H.H.)
| | - Jasmine Ji
- Neuroscience Department, Wellesley College, Wellesley, MA 02482, USA
| | - Chung-Hsi Hsing
- Department of Anesthesiology, Chi Mei Medical Center, Tainan 701, Taiwan
- Correspondence: (P.-H.T.); (C.-H.H.)
| | - Radika Tan
- Kaohsiung American School, Kaohsiung 81354, Taiwan
| | - Ru-Rong Ji
- Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA
- Departments of Cell Biology and Neurobiology, Duke University Medical Center, Durham, NC 27710, USA
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22
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Bernard-Valnet R, Favre E, Bernini A, Oddo M, Chiche JD, Du Pasquier RA, Rossetti AO. Delirium in Adults With COVID-19-Related Acute Respiratory Distress Syndrome: Comparison With Other Etiologies. Neurology 2022; 99:e2326-e2335. [PMID: 36376086 PMCID: PMC9695422 DOI: 10.1212/wnl.0000000000201162] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 07/11/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Neurologic complications have been associated with COVID-19, including delirium. Such complications have been reported to be frequent among intensive care unit (ICU)-admitted patients. We hypothesized that the rate of neurologic complications would be higher in COVID-19 associated acute respiratory distress syndrome (ARDS) than those who develop ARDS from a different cause. METHODS We conducted a retrospective cohort study in the adult ICU of Lausanne University Hospital, including all consecutive patients fulfilling the Berlin criteria for ARDS hospitalized between December 2017 and June 2021, stratifying exposure between COVID-19 or not. The primary outcome was delirium onset during ICU stay, defined by the confusion assessment method (CAM-ICU). Exploratory outcomes included development of neurologic complications of the central nervous system (stroke, hemorrhage, and vasculitis), critical illness weakness, and 30- and 180-day all-cause mortality. RESULTS Three hundred eleven patients were included in the study (253 with COVID-19 and 58 with other causes) and CAM-ICU could be assessed in 231 (74.3% in COVID-19 vs 74.1% in non-COVID-19). The proportion of patients developing delirium was similar in patients with COVID-19 and controls in univariate comparison (69.1% vs 60.5%, p = 0.246). Yet, patients with COVID-19 had a higher body mass index, lower ICU severity, longer mechanical ventilation, and higher sedation doses (propofol and dexmedetomidine). After adjusting for these factors in a multivariable analysis, the risk of delirium remained comparable across groups (adjusted OR [95% CI]: 0.86 [0.35-2.1]). Similarly, COVID-19-related ARDS had no effect on all-cause mortality at 30 days (adjusted OR: 0.87 [0.39-1.92]) and 180 days (adjusted OR: 0.67 [0.33-1.35]). Finally, neurologic complications affecting the CNS (adjusted OR: 1.15 [0.25-5.29]) and critical illness weakness (adjusted OR: 2.99 [0.97-9.1]) were not higher in the COVID-19 group. DISCUSSION Compared with other etiologies, patients with COVID-19 did not have higher incidence of delirium and other neurologic complications, after accounting for underlying disease severity in patients with ARDS. Management of COVID-19-associated ARDS needed longer invasive ventilation and higher sedation, which could explain higher rates of delirium in uncontrolled studies.
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Affiliation(s)
- Raphael Bernard-Valnet
- From the Neurology Service (R.B.-V., R.A.D.P., A.O.R.), Department of Clinical Neurosciences; Department of Intensive Care Medicine (E.F., J.-D.C.); Neuroscience Critical Care Research Group (A.B.), Department of Intensive Care Medicine; and Medical Direction (M.O.), Lausanne University Hospital (Centre Hospitalier Universitaire Vaudois) and University of Lausanne, Switzerland.
| | - Eva Favre
- From the Neurology Service (R.B.-V., R.A.D.P., A.O.R.), Department of Clinical Neurosciences; Department of Intensive Care Medicine (E.F., J.-D.C.); Neuroscience Critical Care Research Group (A.B.), Department of Intensive Care Medicine; and Medical Direction (M.O.), Lausanne University Hospital (Centre Hospitalier Universitaire Vaudois) and University of Lausanne, Switzerland
| | - Adriano Bernini
- From the Neurology Service (R.B.-V., R.A.D.P., A.O.R.), Department of Clinical Neurosciences; Department of Intensive Care Medicine (E.F., J.-D.C.); Neuroscience Critical Care Research Group (A.B.), Department of Intensive Care Medicine; and Medical Direction (M.O.), Lausanne University Hospital (Centre Hospitalier Universitaire Vaudois) and University of Lausanne, Switzerland
| | - Mauro Oddo
- From the Neurology Service (R.B.-V., R.A.D.P., A.O.R.), Department of Clinical Neurosciences; Department of Intensive Care Medicine (E.F., J.-D.C.); Neuroscience Critical Care Research Group (A.B.), Department of Intensive Care Medicine; and Medical Direction (M.O.), Lausanne University Hospital (Centre Hospitalier Universitaire Vaudois) and University of Lausanne, Switzerland
| | - Jean-Daniel Chiche
- From the Neurology Service (R.B.-V., R.A.D.P., A.O.R.), Department of Clinical Neurosciences; Department of Intensive Care Medicine (E.F., J.-D.C.); Neuroscience Critical Care Research Group (A.B.), Department of Intensive Care Medicine; and Medical Direction (M.O.), Lausanne University Hospital (Centre Hospitalier Universitaire Vaudois) and University of Lausanne, Switzerland
| | - Renaud A Du Pasquier
- From the Neurology Service (R.B.-V., R.A.D.P., A.O.R.), Department of Clinical Neurosciences; Department of Intensive Care Medicine (E.F., J.-D.C.); Neuroscience Critical Care Research Group (A.B.), Department of Intensive Care Medicine; and Medical Direction (M.O.), Lausanne University Hospital (Centre Hospitalier Universitaire Vaudois) and University of Lausanne, Switzerland
| | - Andrea O Rossetti
- From the Neurology Service (R.B.-V., R.A.D.P., A.O.R.), Department of Clinical Neurosciences; Department of Intensive Care Medicine (E.F., J.-D.C.); Neuroscience Critical Care Research Group (A.B.), Department of Intensive Care Medicine; and Medical Direction (M.O.), Lausanne University Hospital (Centre Hospitalier Universitaire Vaudois) and University of Lausanne, Switzerland
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23
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Abstract
Persistent neurological and neuropsychiatric symptoms affect a substantial fraction of people after COVID-19 and represent a major component of the post-acute COVID-19 syndrome, also known as long COVID. Here, we review what is understood about the pathobiology of post-acute COVID-19 impact on the CNS and discuss possible neurobiological underpinnings of the cognitive symptoms affecting COVID-19 survivors. We propose the chief mechanisms that may contribute to this emerging neurological health crisis.
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Affiliation(s)
- Michelle Monje
- Department of Neurology, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, USA.
| | - Akiko Iwasaki
- Department of Immunobiology, Yale University, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University, USA.
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24
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Rossi E, Mutti L, Morrione A, Giordano A. Neuro-Immune Interactions in Severe COVID-19 Infection. Pathogens 2022; 11:1256. [PMID: 36365007 PMCID: PMC9699641 DOI: 10.3390/pathogens11111256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/26/2022] [Accepted: 10/28/2022] [Indexed: 12/15/2022] Open
Abstract
SARS-CoV-2 is a new coronavirus that has affected the world since 2019. Interstitial pneumonia is the most common clinical presentation, but additional symptoms have been reported, including neurological manifestations. Severe forms of infection, especially in elderly patients, present as an excessive inflammatory response called "cytokine storm", which can lead to acute respiratory distress syndrome (ARDS), multiorgan failure and death. Little is known about the relationship between symptoms and clinical outcomes or the characteristics of virus-host interactions. The aim of this narrative review is to highlight possible links between neurological involvement and respiratory damage mediated by pathological inflammatory pathways in SARS-CoV-2 infection. We will focus on neuro-immune interactions and age-related immunity decline and discuss some pathological mechanisms that contribute to negative outcomes in COVID-19 patients. Furthermore, we will describe available therapeutic strategies and their effects on COVID-19 neurological symptoms.
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Affiliation(s)
- Elena Rossi
- Department of Medicine, Surgery and Neuroscience, University of Siena, 53100 Siena, Italy
| | - Luciano Mutti
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
- Italian Group for Research and Therapy for Mesothelioma (GIMe), 27058 Voghera, Italy
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Via Vetoio, Coppito 2, 67100 L’Aquila, Italy
| | - Andrea Morrione
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
| | - Antonio Giordano
- Department of Medicine, Surgery and Neuroscience, University of Siena, 53100 Siena, Italy
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
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25
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Gutierrez-Martinez L, Karten J, Kritzer MD, Josephy-Hernandez S, Kim D, Newhouse A, Pasinski M, Praschan N, Razafsha M, Rubin DB, Sonni A, Fricchione G, Rosand MPHJ, Chemali Z. Post-Acute Sequelae of SARS-CoV-2 Infection: A Descriptive Clinical Study. J Neuropsychiatry Clin Neurosci 2022; 34:393-405. [PMID: 35686346 DOI: 10.1176/appi.neuropsych.21070193] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
OBJECTIVE The investigators aimed to describe the clinical experience of a single center reporting on neuropsychiatric findings among patients experiencing persistent symptoms as part of post-acute sequelae of SARS-CoV-2 (PASC) infection. METHODS Data were collected retrospectively (between February 2020 and May 2021) from a cohort (N=100) within a COVID-19 survivors study of patients with persistent symptoms enrolled after a short inpatient stay or who had been outpatients never hospitalized. Patients without confirmatory positive PCR or antibody diagnostic test results were grouped separately as presumptive cases (N=13). RESULTS Of the 87 patients with confirmed SARS-CoV-2, 63 (72.4%) were female, and 65 (74.7%) were White. The mean age was 49.2 years (SD=14.9). The most prevalent symptoms after COVID-19 infection were fatigue, "brain fog," headache, anxiety, and sleep issues. Attention and executive function were frequently impaired. The mean Montreal Cognitive Assessment score was 26.0 (SD=2.8). Concentration and attention as well as memory issues were both significantly correlated with the complaint of brain fog. CONCLUSIONS These preliminary findings suggest that post-acute sequelae of SARS-CoV-2 vary in frequency and duration with relation to premorbid history and that these conditions affect functional domains and patients' ability to return to work. Longitudinal research with larger cohorts is needed to characterize PASC and to optimize care, especially for vulnerable populations.
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Affiliation(s)
- Leidys Gutierrez-Martinez
- Henry and Allison McCance Center for Brain Health (Gutierrez-Martinez, Karten, Newhouse, Pasinski, Rubin, Sonni, Fricchione, Rosand, Chemali); Department of Psychiatry, Division of Neuropsychiatry (Kritzer, Josephy-Hernandez, Kim, Newhouse, Praschan, Razafsha, Fricchione, Chemali); Department of Neurology (Josephy-Hernandez, Kim, Pasinski, Rubin, Rosand, Chemali); Department of Medicine (Newhouse); and Benson-Henry Mind-Body Institute (Fricchione), Massachusetts General Hospital, Boston
| | - Jordan Karten
- Henry and Allison McCance Center for Brain Health (Gutierrez-Martinez, Karten, Newhouse, Pasinski, Rubin, Sonni, Fricchione, Rosand, Chemali); Department of Psychiatry, Division of Neuropsychiatry (Kritzer, Josephy-Hernandez, Kim, Newhouse, Praschan, Razafsha, Fricchione, Chemali); Department of Neurology (Josephy-Hernandez, Kim, Pasinski, Rubin, Rosand, Chemali); Department of Medicine (Newhouse); and Benson-Henry Mind-Body Institute (Fricchione), Massachusetts General Hospital, Boston
| | - Michael D Kritzer
- Henry and Allison McCance Center for Brain Health (Gutierrez-Martinez, Karten, Newhouse, Pasinski, Rubin, Sonni, Fricchione, Rosand, Chemali); Department of Psychiatry, Division of Neuropsychiatry (Kritzer, Josephy-Hernandez, Kim, Newhouse, Praschan, Razafsha, Fricchione, Chemali); Department of Neurology (Josephy-Hernandez, Kim, Pasinski, Rubin, Rosand, Chemali); Department of Medicine (Newhouse); and Benson-Henry Mind-Body Institute (Fricchione), Massachusetts General Hospital, Boston
| | - Sylvia Josephy-Hernandez
- Henry and Allison McCance Center for Brain Health (Gutierrez-Martinez, Karten, Newhouse, Pasinski, Rubin, Sonni, Fricchione, Rosand, Chemali); Department of Psychiatry, Division of Neuropsychiatry (Kritzer, Josephy-Hernandez, Kim, Newhouse, Praschan, Razafsha, Fricchione, Chemali); Department of Neurology (Josephy-Hernandez, Kim, Pasinski, Rubin, Rosand, Chemali); Department of Medicine (Newhouse); and Benson-Henry Mind-Body Institute (Fricchione), Massachusetts General Hospital, Boston
| | - David Kim
- Henry and Allison McCance Center for Brain Health (Gutierrez-Martinez, Karten, Newhouse, Pasinski, Rubin, Sonni, Fricchione, Rosand, Chemali); Department of Psychiatry, Division of Neuropsychiatry (Kritzer, Josephy-Hernandez, Kim, Newhouse, Praschan, Razafsha, Fricchione, Chemali); Department of Neurology (Josephy-Hernandez, Kim, Pasinski, Rubin, Rosand, Chemali); Department of Medicine (Newhouse); and Benson-Henry Mind-Body Institute (Fricchione), Massachusetts General Hospital, Boston
| | - Amy Newhouse
- Henry and Allison McCance Center for Brain Health (Gutierrez-Martinez, Karten, Newhouse, Pasinski, Rubin, Sonni, Fricchione, Rosand, Chemali); Department of Psychiatry, Division of Neuropsychiatry (Kritzer, Josephy-Hernandez, Kim, Newhouse, Praschan, Razafsha, Fricchione, Chemali); Department of Neurology (Josephy-Hernandez, Kim, Pasinski, Rubin, Rosand, Chemali); Department of Medicine (Newhouse); and Benson-Henry Mind-Body Institute (Fricchione), Massachusetts General Hospital, Boston
| | - Marie Pasinski
- Henry and Allison McCance Center for Brain Health (Gutierrez-Martinez, Karten, Newhouse, Pasinski, Rubin, Sonni, Fricchione, Rosand, Chemali); Department of Psychiatry, Division of Neuropsychiatry (Kritzer, Josephy-Hernandez, Kim, Newhouse, Praschan, Razafsha, Fricchione, Chemali); Department of Neurology (Josephy-Hernandez, Kim, Pasinski, Rubin, Rosand, Chemali); Department of Medicine (Newhouse); and Benson-Henry Mind-Body Institute (Fricchione), Massachusetts General Hospital, Boston
| | - Nathan Praschan
- Henry and Allison McCance Center for Brain Health (Gutierrez-Martinez, Karten, Newhouse, Pasinski, Rubin, Sonni, Fricchione, Rosand, Chemali); Department of Psychiatry, Division of Neuropsychiatry (Kritzer, Josephy-Hernandez, Kim, Newhouse, Praschan, Razafsha, Fricchione, Chemali); Department of Neurology (Josephy-Hernandez, Kim, Pasinski, Rubin, Rosand, Chemali); Department of Medicine (Newhouse); and Benson-Henry Mind-Body Institute (Fricchione), Massachusetts General Hospital, Boston
| | - Mahdi Razafsha
- Henry and Allison McCance Center for Brain Health (Gutierrez-Martinez, Karten, Newhouse, Pasinski, Rubin, Sonni, Fricchione, Rosand, Chemali); Department of Psychiatry, Division of Neuropsychiatry (Kritzer, Josephy-Hernandez, Kim, Newhouse, Praschan, Razafsha, Fricchione, Chemali); Department of Neurology (Josephy-Hernandez, Kim, Pasinski, Rubin, Rosand, Chemali); Department of Medicine (Newhouse); and Benson-Henry Mind-Body Institute (Fricchione), Massachusetts General Hospital, Boston
| | - Daniel B Rubin
- Henry and Allison McCance Center for Brain Health (Gutierrez-Martinez, Karten, Newhouse, Pasinski, Rubin, Sonni, Fricchione, Rosand, Chemali); Department of Psychiatry, Division of Neuropsychiatry (Kritzer, Josephy-Hernandez, Kim, Newhouse, Praschan, Razafsha, Fricchione, Chemali); Department of Neurology (Josephy-Hernandez, Kim, Pasinski, Rubin, Rosand, Chemali); Department of Medicine (Newhouse); and Benson-Henry Mind-Body Institute (Fricchione), Massachusetts General Hospital, Boston
| | - Akshata Sonni
- Henry and Allison McCance Center for Brain Health (Gutierrez-Martinez, Karten, Newhouse, Pasinski, Rubin, Sonni, Fricchione, Rosand, Chemali); Department of Psychiatry, Division of Neuropsychiatry (Kritzer, Josephy-Hernandez, Kim, Newhouse, Praschan, Razafsha, Fricchione, Chemali); Department of Neurology (Josephy-Hernandez, Kim, Pasinski, Rubin, Rosand, Chemali); Department of Medicine (Newhouse); and Benson-Henry Mind-Body Institute (Fricchione), Massachusetts General Hospital, Boston
| | - Gregory Fricchione
- Henry and Allison McCance Center for Brain Health (Gutierrez-Martinez, Karten, Newhouse, Pasinski, Rubin, Sonni, Fricchione, Rosand, Chemali); Department of Psychiatry, Division of Neuropsychiatry (Kritzer, Josephy-Hernandez, Kim, Newhouse, Praschan, Razafsha, Fricchione, Chemali); Department of Neurology (Josephy-Hernandez, Kim, Pasinski, Rubin, Rosand, Chemali); Department of Medicine (Newhouse); and Benson-Henry Mind-Body Institute (Fricchione), Massachusetts General Hospital, Boston
| | - M P H Jonathan Rosand
- Henry and Allison McCance Center for Brain Health (Gutierrez-Martinez, Karten, Newhouse, Pasinski, Rubin, Sonni, Fricchione, Rosand, Chemali); Department of Psychiatry, Division of Neuropsychiatry (Kritzer, Josephy-Hernandez, Kim, Newhouse, Praschan, Razafsha, Fricchione, Chemali); Department of Neurology (Josephy-Hernandez, Kim, Pasinski, Rubin, Rosand, Chemali); Department of Medicine (Newhouse); and Benson-Henry Mind-Body Institute (Fricchione), Massachusetts General Hospital, Boston
| | - Zeina Chemali
- Henry and Allison McCance Center for Brain Health (Gutierrez-Martinez, Karten, Newhouse, Pasinski, Rubin, Sonni, Fricchione, Rosand, Chemali); Department of Psychiatry, Division of Neuropsychiatry (Kritzer, Josephy-Hernandez, Kim, Newhouse, Praschan, Razafsha, Fricchione, Chemali); Department of Neurology (Josephy-Hernandez, Kim, Pasinski, Rubin, Rosand, Chemali); Department of Medicine (Newhouse); and Benson-Henry Mind-Body Institute (Fricchione), Massachusetts General Hospital, Boston
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26
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Latorre D. Autoimmunity and SARS-CoV-2 infection: Unraveling the link in neurological disorders. Eur J Immunol 2022; 52:1561-1571. [PMID: 35833748 PMCID: PMC9350097 DOI: 10.1002/eji.202149475] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 05/14/2022] [Accepted: 07/12/2022] [Indexed: 12/14/2022]
Abstract
According to the World Health Organization, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has already infected more than 400 million people and caused over 5 million deaths globally. The infection is associated with a wide spectrum of clinical manifestations, ranging from no signs of illness to severe pathological complications that go beyond the typical respiratory symptoms. On this note, new-onset neurological and neuropsychiatric syndromes have been increasingly reported in a large fraction of COVID-19 patients, thus potentially representing a significant public health threat. Although the underlying pathophysiological mechanisms remain elusive, a growing body of evidence suggests that SARS-CoV-2 infection may trigger an autoimmune response, which could potentially contribute to the establishment and/or exacerbation of neurological disorders in COVID-19 patients. Shedding light on this aspect is urgently needed for the development of effective therapeutic intervention. This review highlights the current knowledge of the immune responses occurring in Neuro-COVID patients and discusses potential immune-mediated mechanisms by which SARS-CoV-2 infection may trigger neurological complications.
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27
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Chu JY, Moe GW, Vyas MV, Chen R, Chow CM, Gupta M, Kaliwal Y, Koh M, Ko DT, Liu PP. Epidemiology of COVID-19 and Its Cardiac and Neurologic Complications Among Chinese and South Asians in Ontario: Waves 1, 2, and 3. CJC Open 2022; 4:894-904. [PMID: 36254328 PMCID: PMC9568686 DOI: 10.1016/j.cjco.2022.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 06/21/2022] [Indexed: 11/21/2022] Open
Abstract
Background Although we had previously reported the cardiac and neurologic outcomes of Chinese and South Asian Ontarians in wave 1 of COVID-19, data on subsequent waves of COVID-19 remain unexamined. This is an extension study of this cohort in waves 2 and 3. Methods We identified adult Ontarians with a positive COVID-19 polymerase chain reaction test from January 1, 2020 to June 30, 2021, and they were classified as being Chinese or South Asian using a validated surname algorithm; we compared their outcomes of mortality, and cardiac and neurologic complications with those of the general population using multivariable logistic regression models. Results Compared to the general population (n = 439,977), the Chinese population (n = 15,208) was older (mean age 44.2 vs 40.6 years, P < 0.001) and the South Asian population (n = 46,333) was younger (39.2 years, P < 0.001). The Chinese population had a higher 30-day mortality (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.61) and more hospitalization or emergency department visits (OR, 1.14; 95% CI, 1.09-1.28), with a trend toward a higher incidence of cardiac complications (OR, 1.03; 95% CI, 0.87-1.12) and neurologic complications (OR, 1.23; 95% CI, 0.96-1.58). South Asians had a lower 30-day mortality (OR, 0.88; 95% CI, 0.78-0.98) but a higher incidence of hospitalization or emergency department visits (OR, 1.17; 95% CI, 1.14-1.20) with a trend toward a lower incidence of cardiac complications (OR, 0.76; 95% CI, 0.67-0.87) and neurologic complications (OR, 0.89; 95% CI, 0.73-1.09). There was also a significant difference in these outcomes between wave 1, 2 and 3, with a greater mortality in all groups in waves 2 and 3. Conclusions Ethnicity continues to be an important determinant of mortality, cardiac and neurologic outcomes, and healthcare use among patients with COVID-19, requiring further studies to understand factors driving these differences.
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Affiliation(s)
- Joseph Y. Chu
- Division of Neurology, Department of Medicine, William Osler Health System, Toronto, Ontario, Canada
- Division of Neurology, Department of Medicine, Toronto Western Hospital-University Health Network, Toronto, Ontario, Canada
| | - Gordon W. Moe
- Division of Cardiology, Department of Medicine, St. Michael’s Hospital, Toronto, Ontario, Canada
- Division of Cardiology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Manav V. Vyas
- Division of Neurology, Department of Medicine, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Robert Chen
- Division of Neurology, Department of Medicine, Toronto Western Hospital-University Health Network, Toronto, Ontario, Canada
| | - Chi-Ming Chow
- Division of Cardiology, Department of Medicine, St. Michael’s Hospital, Toronto, Ontario, Canada
- Division of Cardiology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Milan Gupta
- Division of Cardiology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | | | | | - Dennis T. Ko
- ICES, Toronto, Ontario, Canada
- Schulich Heart Program, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Peter P. Liu
- Division of Cardiology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- University of Ottawa Heart Institute, University of Ottawa, Ottawa, Ontario, Canada
- Department of Medicine and Cellular & Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
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28
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Harada T, Schmitz K, Helsper CW, Campbell G, Nekhlyudov L. Long-COVID and long-term cancer survivorship-Shared lessons and opportunities. Eur J Cancer Care (Engl) 2022; 31:e13712. [PMID: 36151916 PMCID: PMC9539058 DOI: 10.1111/ecc.13712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 09/07/2022] [Indexed: 12/04/2022]
Abstract
As of 2022, close to 90 million persons in the United States, 243 million persons in Europe and 585 million worldwide have been infected with the novel SARS‐CoV‐2 (COVID‐19) virus and survived. Estimates vary but suggest that up to 50% may experience long‐term sequelae, termed ‘Long‐COVID’. While Long‐COVID is a new condition, the phenomenon of disabling long‐term effects following an illness requiring ongoing surveillance and management is not. In this commentary, we discuss how Long‐COVID parallels the experiences of long‐term cancer survivors, highlight shared challenges and offer opportunities to improve research and clinical care for both growing populations of patients as well as other long‐term chronic, disabling conditions.
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Affiliation(s)
- Taku Harada
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Kathryn Schmitz
- College of Medicine, Penn State University, Hershey, Pennsylvania, USA
| | - Charles W Helsper
- Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Grace Campbell
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Duquesne University School of Nursing and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Larissa Nekhlyudov
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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29
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Laurence J, Nuovo G, Racine-Brzostek SE, Seshadri M, Elhadad S, Crowson AN, Mulvey JJ, Harp J, Ahamed J, Magro C. Premortem Skin Biopsy Assessing Microthrombi, Interferon Type I Antiviral and Regulatory Proteins, and Complement Deposition Correlates with Coronavirus Disease 2019 Clinical Stage. THE AMERICAN JOURNAL OF PATHOLOGY 2022; 192:1282-1294. [PMID: 35640675 PMCID: PMC9144849 DOI: 10.1016/j.ajpath.2022.05.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 05/20/2022] [Accepted: 05/23/2022] [Indexed: 01/08/2023]
Abstract
Apart from autopsy, tissue correlates of coronavirus disease 2019 (COVID-19) clinical stage are lacking. In the current study, cutaneous punch biopsy specimens of 15 individuals with severe/critical COVID-19 and six with mild/moderate COVID-19 were examined. Evidence for arterial and venous microthrombi, deposition of C5b-9 and MASP2 (representative of alternative and lectin complement pathways, respectively), and differential expression of interferon type I-driven antiviral protein MxA (myxovirus resistance A) versus SIN3A, a promoter of interferon type I-based proinflammatory signaling, were assessed. Control subjects included nine patients with sepsis-related acute respiratory distress syndrome (ARDS) and/or acute kidney injury (AKI) pre-COVID-19. Microthrombi were detected in 13 (87%) of 15 patients with severe/critical COVID-19 versus zero of six patients with mild/moderate COVID-19 (P < 0.001) and none of the nine patients with pre-COVID-19 ARDS/AKI (P < 0.001). Cells lining the microvasculature staining for spike protein of severe acute respiratory syndrome coronavirus 2, the etiologic agent of COVID-19, also expressed tissue factor. C5b-9 deposition occurred in 13 (87%) of 15 patients with severe/critical COVID-19 versus zero of six patients with mild/moderate COVID-19 (P < 0.001) and none of the nine patients with pre-COVID-19 ARDS/AKI (P < 0.001). MASP2 deposition was also restricted to severe/critical COVID-19 cases. MxA expression occurred in all six mild/moderate versus two (15%) of 13 severe/critical cases (P < 0.001) of COVID-19. In contrast, SIN3A was restricted to severe/critical COVID-19 cases co-localizing with severe acute respiratory syndrome coronavirus 2 spike protein. SIN3A was also elevated in plasma of patients with severe/critical COVID-19 versus control subjects (P ≤ 0.02). In conclusion, the study identified premortem tissue correlates of COVID-19 clinical stage using skin. If validated in a longitudinal cohort, this approach could identify individuals at risk for disease progression and enable targeted interventions.
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Affiliation(s)
- Jeffrey Laurence
- Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, New York.
| | - Gerard Nuovo
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio; Discovery Life Sciences, Inc., Powell, Ohio
| | | | - Madhav Seshadri
- Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, New York
| | - Sonia Elhadad
- Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, New York
| | - A Neil Crowson
- Department of Pathology, Regional Medical Laboratories, Tulsa, Oklahoma
| | - J Justin Mulvey
- Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Joanna Harp
- Department of Dermatology, Weill Cornell Medicine, New York, New York
| | - Jasimuddin Ahamed
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma
| | - Cynthia Magro
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
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30
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Prasad K, Gour P, Raghuvanshi S, Kumar V. The SARS-CoV-2 targeted human RNA binding proteins network biology to investigate COVID-19 associated manifestations. Int J Biol Macromol 2022; 217:853-863. [PMID: 35907451 PMCID: PMC9328843 DOI: 10.1016/j.ijbiomac.2022.07.200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 07/22/2022] [Accepted: 07/25/2022] [Indexed: 11/21/2022]
Abstract
The global coronavirus disease 2019 (COVID-19) pandemic caused by the SARS-CoV-2 virus has had unprecedented social and economic ramifications. Identifying targets for drug repurposing could be an effective means to present new and fast treatments. Furthermore, the risk of morbidity and mortality from COVID-19 goes up when there are coexisting medical conditions, however, the underlying mechanisms remain unclear. In the current study, we have adopted a network-based systems biology approach to investigate the RNA binding proteins (RBPs)-based molecular interplay between COVID-19, various human cancers, and neurological disorders. The network based on RBPs commonly involved in the three disease conditions consisted of nine RBPs connecting 10 different cancer types, 22 brain disorders, and COVID-19 infection, ultimately hinting at the comorbidities and complexity of COVID-19. Further, we underscored five miRNAs with reported antiviral properties that target all of the nine shared RBPs and are thus therapeutically valuable. As a strategy to improve the clinical conditions in comorbidities associated with COVID-19, we propose perturbing the shared RBPs by drug repurposing. The network-based analysis presented hereby contributes to a better knowledge of the molecular underpinnings of the comorbidities associated with COVID-19.
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Affiliation(s)
- Kartikay Prasad
- Amity Institute of Neuropsychology & Neurosciences, Amity University, Noida, UP 201303, India
| | - Pratibha Gour
- Dept. of Plant Molecular Biology, University of Delhi, South Campus, New Delhi 110021, India
| | - Saurabh Raghuvanshi
- Dept. of Plant Molecular Biology, University of Delhi, South Campus, New Delhi 110021, India.
| | - Vijay Kumar
- Amity Institute of Neuropsychology & Neurosciences, Amity University, Noida, UP 201303, India.
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31
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de Oliveira LG, de Souza Angelo Y, Yamamoto P, Carregari VC, Crunfli F, Reis-de-Oliveira G, Costa L, Vendramini PH, Almeida ÉD, Dos Santos NB, Firmino EM, Paiva IM, Almeida GM, Sebollela A, Polonio CM, Zanluqui NG, de Oliveira MG, da Silva P, Gastão Davanzo G, Ayupe MC, Loureiro Salgado C, de Souza Filho AF, de Araújo MV, Silva-Pereira TT, de Almeida Campos AC, Góes LGB, Dos Passos Cunha M, Caldini EG, Lima MRDI, Fonseca DM, de Sá Guimarães AM, Minoprio PC, Munhoz CD, Mori CMC, Moraes-Vieira PM, Cunha TM, Martins-de-Souza D, Peron JPS. SARS-CoV-2 Infection Impacts Carbon Metabolism and Depends on Glutamine for Replication in Syrian Hamster Astrocytes. J Neurochem 2022; 163:113-132. [PMID: 35880385 PMCID: PMC9350388 DOI: 10.1111/jnc.15679] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 07/10/2022] [Accepted: 07/12/2022] [Indexed: 01/08/2023]
Abstract
COVID‐19 causes more than million deaths worldwide. Although much is understood about the immunopathogenesis of the lung disease, a lot remains to be known on the neurological impact of COVID‐19. Here we evaluated immunometabolic changes using astrocytes in vitro and dissected brain areas of SARS‐CoV‐2 infected Syrian hamsters. We show that SARS‐CoV‐2 alters proteins of carbon metabolism, glycolysis, and synaptic transmission, many of which are altered in neurological diseases. Real‐time respirometry evidenced hyperactivation of glycolysis, further confirmed by metabolomics, with intense consumption of glucose, pyruvate, glutamine, and alpha ketoglutarate. Consistent with glutamine reduction, the blockade of glutaminolysis impaired viral replication and inflammatory response in vitro. SARS‐CoV‐2 was detected in vivo in hippocampus, cortex, and olfactory bulb of intranasally infected animals. Our data evidence an imbalance in important metabolic molecules and neurotransmitters in infected astrocytes. We suggest this may correlate with the neurological impairment observed during COVID‐19, as memory loss, confusion, and cognitive impairment.
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Affiliation(s)
- Lilian Gomes de Oliveira
- Neuroimmune Interactions Laboratory, Institute of Biomedical Science, Department of Immunology, University of São Paulo, São Paulo, SP, Brazil.,Neuroimmunology of Arboviruses Laboratory, Scientific Platform Pasteur, University of São Paulo, São Paulo, SP, Brazil
| | - Yan de Souza Angelo
- Neuroimmune Interactions Laboratory, Institute of Biomedical Science, Department of Immunology, University of São Paulo, São Paulo, SP, Brazil.,Neuroimmunology of Arboviruses Laboratory, Scientific Platform Pasteur, University of São Paulo, São Paulo, SP, Brazil
| | - Pedro Yamamoto
- Neuroimmune Interactions Laboratory, Institute of Biomedical Science, Department of Immunology, University of São Paulo, São Paulo, SP, Brazil.,Neuroimmunology of Arboviruses Laboratory, Scientific Platform Pasteur, University of São Paulo, São Paulo, SP, Brazil
| | - Victor Corasolla Carregari
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Fernanda Crunfli
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Guilherme Reis-de-Oliveira
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Lícia Costa
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Pedro Henrique Vendramini
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Érica Duque Almeida
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Nilton Barreto Dos Santos
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Egidi Mayara Firmino
- Center for Research in Inflammatory Diseases (CRID); Department of Pharmacology - Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil
| | - Isadora Marques Paiva
- Center for Research in Inflammatory Diseases (CRID); Department of Pharmacology - Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil
| | - Glaucia Maria Almeida
- Department of Biocehmistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Adriano Sebollela
- Department of Biocehmistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Carolina Manganeli Polonio
- Neuroimmune Interactions Laboratory, Institute of Biomedical Science, Department of Immunology, University of São Paulo, São Paulo, SP, Brazil.,Neuroimmunology of Arboviruses Laboratory, Scientific Platform Pasteur, University of São Paulo, São Paulo, SP, Brazil
| | - Nagela Ghabdan Zanluqui
- Neuroimmune Interactions Laboratory, Institute of Biomedical Science, Department of Immunology, University of São Paulo, São Paulo, SP, Brazil.,Neuroimmunology of Arboviruses Laboratory, Scientific Platform Pasteur, University of São Paulo, São Paulo, SP, Brazil
| | - Marília Garcia de Oliveira
- Neuroimmune Interactions Laboratory, Institute of Biomedical Science, Department of Immunology, University of São Paulo, São Paulo, SP, Brazil
| | - Patrick da Silva
- Neuroimmune Interactions Laboratory, Institute of Biomedical Science, Department of Immunology, University of São Paulo, São Paulo, SP, Brazil.,Neuroimmunology of Arboviruses Laboratory, Scientific Platform Pasteur, University of São Paulo, São Paulo, SP, Brazil
| | - Gustavo Gastão Davanzo
- Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Marina Caçador Ayupe
- Laboratory of Mucosal Immunology, Department of Immunology - Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Caio Loureiro Salgado
- Laboratory of Mucosal Immunology, Department of Immunology - Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Antônio Francisco de Souza Filho
- Laboratory of Applied Research in Mycobacteria, Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Marcelo Valdemir de Araújo
- Laboratory of Applied Research in Mycobacteria, Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | - Taiana Tainá Silva-Pereira
- Laboratory of Applied Research in Mycobacteria, Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | | | | | | | - Elia Garcia Caldini
- Laboratory of Cellular Biology (LIM 59), School of Medicine, University of São Paulo, São Paulo, SP, Brazil
| | | | - Denise Morais Fonseca
- Laboratory of Mucosal Immunology, Department of Immunology - Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Ana Márcia de Sá Guimarães
- Laboratory of Applied Research in Mycobacteria, Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil
| | | | - Carolina Demarchi Munhoz
- Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Cláudia Madalena Cabrera Mori
- Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, São Paulo, SP, Brazil
| | - Pedro Manoel Moraes-Vieira
- Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Thiago Mattar Cunha
- Center for Research in Inflammatory Diseases (CRID); Department of Pharmacology - Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, Brazil
| | - Daniel Martins-de-Souza
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil.,Experimental Medicine Research Cluster (EMRC), University of Campinas, Campinas, SP, Brazil.,D'Or Institute for Research and Education (IDOR), São Paulo, SP, Brazil.,Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBION), Conselho Nacional de Desenvolvimento Científico e Tecnológico, São Paulo, SP, Brazil
| | - Jean Pierre Schatzmann Peron
- Neuroimmune Interactions Laboratory, Institute of Biomedical Science, Department of Immunology, University of São Paulo, São Paulo, SP, Brazil.,Neuroimmunology of Arboviruses Laboratory, Scientific Platform Pasteur, University of São Paulo, São Paulo, SP, Brazil.,Immunopathology and Allergy Post Graduate Program, School of Medicine, University of São Paulo, São Paulo, SP, Brazil
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32
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Fernández-Castañeda A, Lu P, Geraghty AC, Song E, Lee MH, Wood J, O'Dea MR, Dutton S, Shamardani K, Nwangwu K, Mancusi R, Yalçın B, Taylor KR, Acosta-Alvarez L, Malacon K, Keough MB, Ni L, Woo PJ, Contreras-Esquivel D, Toland AMS, Gehlhausen JR, Klein J, Takahashi T, Silva J, Israelow B, Lucas C, Mao T, Peña-Hernández MA, Tabachnikova A, Homer RJ, Tabacof L, Tosto-Mancuso J, Breyman E, Kontorovich A, McCarthy D, Quezado M, Vogel H, Hefti MM, Perl DP, Liddelow S, Folkerth R, Putrino D, Nath A, Iwasaki A, Monje M. Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation. Cell 2022; 185:2452-2468.e16. [PMID: 35768006 PMCID: PMC9189143 DOI: 10.1016/j.cell.2022.06.008] [Citation(s) in RCA: 308] [Impact Index Per Article: 102.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 05/04/2022] [Accepted: 06/07/2022] [Indexed: 12/13/2022]
Abstract
COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared with SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white-matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 at early time points, but after influenza, only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.
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Affiliation(s)
| | - Peiwen Lu
- Department of Immunobiology, Yale University, New Haven, CT, USA
| | - Anna C Geraghty
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Eric Song
- Department of Immunobiology, Yale University, New Haven, CT, USA
| | - Myoung-Hwa Lee
- National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
| | - Jamie Wood
- Abilities Research Center, Department of Rehabilitation and Human Performance, Mount Sinai School of Medicine, New York, NY, USA
| | - Michael R O'Dea
- Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, USA
| | - Selena Dutton
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Kiarash Shamardani
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Kamsi Nwangwu
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Rebecca Mancusi
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Belgin Yalçın
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Kathryn R Taylor
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Lehi Acosta-Alvarez
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Karen Malacon
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Michael B Keough
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Lijun Ni
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Pamelyn J Woo
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | | | | | | | - Jon Klein
- Department of Immunobiology, Yale University, New Haven, CT, USA
| | | | - Julio Silva
- Department of Immunobiology, Yale University, New Haven, CT, USA
| | | | - Carolina Lucas
- Department of Immunobiology, Yale University, New Haven, CT, USA
| | - Tianyang Mao
- Department of Immunobiology, Yale University, New Haven, CT, USA
| | | | | | - Robert J Homer
- Department of Pathology, Yale University, New Haven, CT, USA
| | - Laura Tabacof
- Abilities Research Center, Department of Rehabilitation and Human Performance, Mount Sinai School of Medicine, New York, NY, USA
| | - Jenna Tosto-Mancuso
- Abilities Research Center, Department of Rehabilitation and Human Performance, Mount Sinai School of Medicine, New York, NY, USA
| | - Erica Breyman
- Abilities Research Center, Department of Rehabilitation and Human Performance, Mount Sinai School of Medicine, New York, NY, USA
| | - Amy Kontorovich
- Cardiovascular Research Institute, Mount Sinai School of Medicine, New York, NY, USA
| | - Dayna McCarthy
- Abilities Research Center, Department of Rehabilitation and Human Performance, Mount Sinai School of Medicine, New York, NY, USA
| | | | - Hannes Vogel
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Marco M Hefti
- Department of Pathology, University of Iowa, Iowa City, IA, USA
| | - Daniel P Perl
- Department of Pathology, Uniformed Services University of Health Sciences, Bethesda, MD, USA
| | - Shane Liddelow
- Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, USA; Departments of Neuroscience & Physiology and of Ophthalmology, NYU Grossman School of Medicine, New York, NY, USA; Parekh Center for Interdisciplinary Neurology, NYU Grossman School of Medicine, New York, NY, USA
| | | | - David Putrino
- Abilities Research Center, Department of Rehabilitation and Human Performance, Mount Sinai School of Medicine, New York, NY, USA
| | - Avindra Nath
- National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
| | - Akiko Iwasaki
- Department of Immunobiology, Yale University, New Haven, CT, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT, USA.
| | - Michelle Monje
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA; Department of Pathology, Stanford University, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
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Chu JY, Kaliwal Y, Koh M, Chen R, Chow CM, Ko DT, Liu PP, Moe GW. COVID-19 and its Cardiac and Neurological Complications among Ontario Visible Minorities. Can J Neurol Sci 2022; 49:504-513. [PMID: 34162448 PMCID: PMC8365110 DOI: 10.1017/cjn.2021.148] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 06/19/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND Due to lack of data on the epidemiology, cardiac, and neurological complications among Ontario visible minorities (Chinese and South Asians) affected by coronavirus disease (COVID-19), this population-based retrospective study was undertaken to study them systematically. METHODS From January 1, 2020 to September 30, 2020 using the last name algorithm to identify Ontario Chinese and South Asians who were tested positive by PCR for COVID-19, their demographics, cardiac, and neurological complications including hospitalization and emergency visit rates were analyzed compared to the general population. RESULTS Chinese (N = 1,186) with COVID-19 were found to be older (mean age 50.7 years) compared to the general population (N = 42,547) (mean age 47.6 years) (p < 0.001), while South Asians (N = 3,459) were younger (age of 42.1 years) (p < 0.001). The 30-day crude rate for cardiac complications among Chinese was 169/10,000 (p = 0.069), while for South Asians, it was 64/10,000 (p = 0.008) and, for the general population, it was 112/10,000. For neurological complications, the 30-day crude rate for Chinese was 160/10,000 (p < 0.001); South Asians was 40/10,000 (p = 0.526), and general population was 48/10,000. The 30-day all-cause mortality rate was significantly higher for Chinese at 8.1% vs 5.0% for the general population (p < 0.001), while it was lower in South Asians at 2.1% (p < 0.001). CONCLUSIONS Chinese and South Asians in Ontario affected by COVID-19 during the first wave of the pandemic were found to have a significant difference in their demographics, cardiac, and neurological outcomes.
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Affiliation(s)
- Joseph Y. Chu
- Division of Neurology, Department of Medicine, Toronto Western Hospital-University Health Network and William Osler Health System, University of Toronto, Toronto, Canada
| | | | | | - Robert Chen
- Krembil Research Institute, University Health Network and Division of Neurology, Department of Medicine, University of Toronto, Toronto, Canada
| | - Chi-Ming Chow
- Division of Cardiology, Department of Medicine, St. Michael’s Hospital, University of Toronto, Toronto, Canada
| | - Dennis T. Ko
- ICES, Toronto, Canada
- Schulich Heart Program, Sunnybrook Health Sciences Centre, Sunnybrook Research Institute, University of Toronto, Toronto, Canada
| | - Peter P. Liu
- University of Ottawa Heart Institute and Department of Medicine and Cellular & Molecular Medicine, University of Ottawa and Division of Cardiology, Department of Medicine, University of Toronto, Toronto, Canada
| | - Gordon W. Moe
- Division of Cardiology, Department of Medicine, St. Michael’s Hospital, University of Toronto, Toronto, Canada
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Löscher W, Howe CL. Molecular Mechanisms in the Genesis of Seizures and Epilepsy Associated With Viral Infection. Front Mol Neurosci 2022; 15:870868. [PMID: 35615063 PMCID: PMC9125338 DOI: 10.3389/fnmol.2022.870868] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 04/05/2022] [Indexed: 12/16/2022] Open
Abstract
Seizures are a common presenting symptom during viral infections of the central nervous system (CNS) and can occur during the initial phase of infection ("early" or acute symptomatic seizures), after recovery ("late" or spontaneous seizures, indicating the development of acquired epilepsy), or both. The development of acute and delayed seizures may have shared as well as unique pathogenic mechanisms and prognostic implications. Based on an extensive review of the literature, we present an overview of viruses that are associated with early and late seizures in humans. We then describe potential pathophysiologic mechanisms underlying ictogenesis and epileptogenesis, including routes of neuroinvasion, viral control and clearance, systemic inflammation, alterations of the blood-brain barrier, neuroinflammation, and inflammation-induced molecular reorganization of synapses and neural circuits. We provide clinical and animal model findings to highlight commonalities and differences in these processes across various neurotropic or neuropathogenic viruses, including herpesviruses, SARS-CoV-2, flaviviruses, and picornaviruses. In addition, we extensively review the literature regarding Theiler's murine encephalomyelitis virus (TMEV). This picornavirus, although not pathogenic for humans, is possibly the best-characterized model for understanding the molecular mechanisms that drive seizures, epilepsy, and hippocampal damage during viral infection. An enhanced understanding of these mechanisms derived from the TMEV model may lead to novel therapeutic interventions that interfere with ictogenesis and epileptogenesis, even within non-infectious contexts.
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Affiliation(s)
- Wolfgang Löscher
- Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Hannover, Germany
- Center for Systems Neuroscience, Hannover, Germany
| | - Charles L. Howe
- Division of Experimental Neurology, Department of Neurology, Mayo Clinic, Rochester, MN, United States
- Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN, United States
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Edén A, Grahn A, Bremell D, Aghvanyan A, Bathala P, Fuchs D, Gostner J, Hagberg L, Kanberg N, Kanjananimmanont S, Lindh M, Misaghian S, Nilsson S, Schöll M, Sigal G, Stentoft E, Studahl M, Yilmaz A, Wang M, Stengelin M, Zetterberg H, Gisslén M. Viral Antigen and Inflammatory Biomarkers in Cerebrospinal Fluid in Patients With COVID-19 Infection and Neurologic Symptoms Compared With Control Participants Without Infection or Neurologic Symptoms. JAMA Netw Open 2022; 5:e2213253. [PMID: 35604688 PMCID: PMC9127556 DOI: 10.1001/jamanetworkopen.2022.13253] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
IMPORTANCE Neurologic symptoms are common in COVID-19, but the central nervous system (CNS) pathogenesis is unclear, and viral RNA is rarely detected in cerebrospinal fluid (CSF). OBJECTIVE To measure viral antigen and inflammatory biomarkers in CSF in relation to neurologic symptoms and disease severity. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study was performed from March 1, 2020, to June 30, 2021, in patients 18 years or older who were admitted to Sahlgrenska University Hospital, Gothenburg, Sweden, with COVID-19. All patients had CSF samples taken because of neurologic symptoms or within a study protocol. Healthy volunteer and prepandemic control groups were included. EXPOSURE SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES Outcomes included CSF SARS-CoV-2 nucleocapsid antigen (N-Ag) using an ultrasensitive antigen capture immunoassay platform and CSF biomarkers of immune activation (neopterin, β2-microglobulin, and cytokines) and neuronal injury (neurofilament light protein [NfL]). RESULTS Forty-four patients (median [IQR] age, 57 [48-69] years; 30 [68%] male; 26 with moderate COVID-19 and 18 with severe COVID-19 based on the World Health Organization Clinical Progression Scale), 10 healthy controls (median [IQR] age, 58 [54-60] years; 5 [50%] male), and 41 patient controls (COVID negative without evidence of CNS infection) (median [IQR] age, 59 [49-70] years; 19 [46%] male) were included in the study. Twenty-one patients were neuroasymptomatic and 23 were neurosymptomatic (21 with encephalopathy). In 31 of 35 patients for whom data were available (89%), CSF N-Ag was detected; viral RNA test results were negative in all. Nucleocapsid antigen was significantly correlated with CSF neopterin (r = 0.38; P = .03) and interferon γ (r = 0.42; P = .01). No differences in CSF N-Ag concentrations were found between patient groups. Patients had markedly increased CSF neopterin, β2-microglobulin, interleukin (IL) 2, IL-6, IL-10, and tumor necrosis factor α compared with controls. Neurosymptomatic patients had significantly higher median (IQR) CSF interferon γ (86 [47-172] vs 21 [17-81] fg/mL; P = .03) and had a significantly higher inflammatory biomarker profile using principal component analysis compared with neuroasymptomatic patients (0.54; 95% CI, 0.03-1.05; P = .04). Age-adjusted median (IQR) CSF NfL concentrations were higher in patients compared with controls (960 [673-1307] vs 618 [489-786] ng/L; P = .002). No differences were seen in any CSF biomarkers in moderate compared with severe disease. CONCLUSIONS AND RELEVANCE In this study of Swedish adults with COVID-19 infection and neurologic symptoms, compared with control participants, viral antigen was detectable in CSF and correlated with CNS immune activation. Patients with COVID-19 had signs of neuroaxonal injury, and neurosymptomatic patients had a more marked inflammatory profile that could not be attributed to differences in COVID-19 severity. These results highlight the clinical relevance of neurologic symptoms and suggest that viral components can contribute to CNS immune responses without direct viral invasion.
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Affiliation(s)
- Arvid Edén
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Region Västra Götaland, Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Anna Grahn
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Region Västra Götaland, Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Daniel Bremell
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Region Västra Götaland, Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden
| | | | | | - Dietmar Fuchs
- Institute of Biological Chemistry, Medical University of Innsbruck, Biocenter, Austria
| | - Johanna Gostner
- Institute of Medical Biochemistry, Medical University of Innsbruck, Biocenter, Austria
| | - Lars Hagberg
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Region Västra Götaland, Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Nelly Kanberg
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Region Västra Götaland, Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden
| | | | - Magnus Lindh
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | | | - Staffan Nilsson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Michael Schöll
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London, England
| | | | - Erika Stentoft
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Region Västra Götaland, Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Marie Studahl
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Region Västra Götaland, Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Aylin Yilmaz
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Region Västra Götaland, Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden
| | | | | | - Henrik Zetterberg
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London, England
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
- UK Dementia Research Institute at UCL, London, England
- Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China
| | - Magnus Gisslén
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Region Västra Götaland, Department of Infectious Diseases, Sahlgrenska University Hospital, Gothenburg, Sweden
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Guasp M, Muñoz-Sánchez G, Martínez-Hernández E, Santana D, Carbayo Á, Naranjo L, Bolós U, Framil M, Saiz A, Balasa M, Ruiz-García R, Sánchez-Valle R, The Barcelona Neuro-COVID Study Group. CSF Biomarkers in COVID-19 Associated Encephalopathy and Encephalitis Predict Long-Term Outcome. Front Immunol 2022; 13:866153. [PMID: 35479062 PMCID: PMC9035899 DOI: 10.3389/fimmu.2022.866153] [Citation(s) in RCA: 63] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 03/18/2022] [Indexed: 12/15/2022] Open
Abstract
Patients with coronavirus disease 2019 (COVID-19) frequently develop acute encephalopathy and encephalitis, but whether these complications are the result from viral-induced cytokine storm syndrome or anti-neural autoimmunity is still unclear. In this study, we aimed to evaluate the diagnostic and prognostic role of CSF and serum biomarkers of inflammation (a wide array of cytokines, antibodies against neural antigens, and IgG oligoclonal bands), and neuroaxonal damage (14-3-3 protein and neurofilament light [NfL]) in patients with acute COVID-19 and associated neurologic manifestations (neuro-COVID). We prospectively included 60 hospitalized neuro-COVID patients, 25 (42%) of them with encephalopathy and 14 (23%) with encephalitis, and followed them for 18 months. We found that, compared to healthy controls (HC), neuro-COVID patients presented elevated levels of IL-18, IL-6, and IL-8 in both serum and CSF. MCP1 was elevated only in CSF, while IL-10, IL-1RA, IP-10, MIG and NfL were increased only in serum. Patients with COVID-associated encephalitis or encephalopathy had distinct serum and CSF cytokine profiles compared with HC, but no differences were found when both clinical groups were compared to each other. Antibodies against neural antigens were negative in both groups. While the levels of neuroaxonal damage markers, 14-3-3 and NfL, and the proinflammatory cytokines IL-18, IL-1RA and IL-8 significantly associated with acute COVID-19 severity, only the levels of 14-3-3 and NfL in CSF significantly correlated with the degree of neurologic disability in the daily activities at 18 months follow-up. Thus, the inflammatory process promoted by SARS-CoV-2 infection might include blood-brain barrier disruption in patients with neurological involvement. In conclusion, the fact that the levels of pro-inflammatory cytokines do not predict the long-term functional outcome suggests that the prognosis is more related to neuronal damage than to the acute neuroinflammatory process.
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Affiliation(s)
- Mar Guasp
- Neuroimmunology Program, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Neurology Service, Hospital Clinic de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red, Enfermedades Raras (CIBERER), Madrid, Spain
| | | | - Eugenia Martínez-Hernández
- Neuroimmunology Program, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Neurology Service, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Daniel Santana
- Neurology Service, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Álvaro Carbayo
- Neurology Service, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Laura Naranjo
- Immunology Department, Centre Diagnòstic Biomèdic, Hospital Clínic, Barcelona, Spain
| | - Uma Bolós
- Immunology Department, Centre Diagnòstic Biomèdic, Hospital Clínic, Barcelona, Spain
| | - Mario Framil
- Department of Immunology, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain
| | - Albert Saiz
- Neuroimmunology Program, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Neurology Service, Hospital Clinic de Barcelona, Barcelona, Spain
| | - Mircea Balasa
- Neurology Service, Hospital Clinic de Barcelona, Barcelona, Spain
- Alzheimer’s Disease and Other Cognitive Disorders Unit, Hospital Clínic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Raquel Ruiz-García
- Neuroimmunology Program, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Immunology Department, Centre Diagnòstic Biomèdic, Hospital Clínic, Barcelona, Spain
- *Correspondence: Raquel Ruiz-García, ; Raquel Sánchez-Valle,
| | - Raquel Sánchez-Valle
- Neurology Service, Hospital Clinic de Barcelona, Barcelona, Spain
- Alzheimer’s Disease and Other Cognitive Disorders Unit, Hospital Clínic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
- *Correspondence: Raquel Ruiz-García, ; Raquel Sánchez-Valle,
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Acharjee A, Stephen Kingsly J, Kamat M, Kurlawala V, Chakraborty A, Vyas P, Vaishnav R, Srivastava S. Rise of the SARS-CoV-2 Variants: can proteomics be the silver bullet? Expert Rev Proteomics 2022; 19:197-212. [PMID: 35655386 DOI: 10.1080/14789450.2022.2085564] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
INTRODUCTION The challenges posed by emergent strains of SARS-CoV-2 need to be tackled by contemporary scientific approaches, with proteomics playing a significant role. AREAS COVERED In this review, we provide a brief synthesis of the impact of proteomics technologies in elucidating disease pathogenesis and classifiers for the prognosis of COVID-19 and propose proteomics methodologies that could play a crucial role in understanding emerging variants and their altered disease pathology. From aiding the design of novel drug candidates to facilitating the identification of T cell vaccine targets, we have discussed the impact of proteomics methods in COVID-19 research. Techniques varied as mass spectrometry, single-cell proteomics, multiplexed ELISA arrays, high-density proteome arrays, surface plasmon resonance, immunopeptidomics, and in silico docking studies that have helped augment the fight against existing diseases were useful in preparing us to tackle SARS-CoV-2 variants. We also propose an action plan for a pipeline to combat emerging pandemics using proteomics technology by adopting uniform standard operating procedures and unified data analysis paradigms. EXPERT OPINION The knowledge about the use of diverse proteomics approaches for COVID-19 investigation will provide a framework for future basic research, better infectious disease prevention strategies, improved diagnostics, and targeted therapeutics.
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Affiliation(s)
- Arup Acharjee
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India
| | | | - Madhura Kamat
- Department of Biological Sciences, Sunandan Divatia School of Science, SVKM's NMIMS (Deemed-to-be University), Mumbai, India
| | - Vishakha Kurlawala
- Department of Biological Sciences, Sunandan Divatia School of Science, SVKM's NMIMS (Deemed-to-be University), Mumbai, India
| | | | - Priyanka Vyas
- Department of Biotechnology and Botany, Mahila PG Mahavidyalaya, J. N. V University, Jodhpur, India
| | - Radhika Vaishnav
- Department of Life Sciences, Ivy Tech Community College, Indianapolis, Indiana, USA
| | - Sanjeeva Srivastava
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, India
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Fernández-Castañeda A, Lu P, Geraghty AC, Song E, Lee MH, Wood J, Yalçın B, Taylor KR, Dutton S, Acosta-Alvarez L, Ni L, Contreras-Esquivel D, Gehlhausen JR, Klein J, Lucas C, Mao T, Silva J, Peña-Hernández MA, Tabachnikova A, Takahashi T, Tabacof L, Tosto-Mancuso J, Breyman E, Kontorovich A, McCarthy D, Quezado M, Hefti M, Perl D, Folkerth R, Putrino D, Nath A, Iwasaki A, Monje M. Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2022:2022.01.07.475453. [PMID: 35043113 PMCID: PMC8764721 DOI: 10.1101/2022.01.07.475453] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Survivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing and memory. This long-COVID cognitive syndrome shares many features with the syndrome of cancer therapy-related cognitive impairment (CRCI). Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection. Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection - without neuroinvasion - and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function. Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.
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Affiliation(s)
| | - Peiwen Lu
- Department of Immunobiology, Yale University, New Haven CT USA
| | - Anna C. Geraghty
- Department of Neurology and Neurological Sciences, Stanford University, Stanford CA USA
| | - Eric Song
- Department of Immunobiology, Yale University, New Haven CT USA
| | - Myoung-Hwa Lee
- National Institute of Neurological Disorders and Stroke, Besthesda MD USA
| | - Jamie Wood
- Abilities Research Center, Department of Rehabilitation and Human Performance, Mount Sinai School of Medicine, New York, NY USA
| | - Belgin Yalçın
- Department of Neurology and Neurological Sciences, Stanford University, Stanford CA USA
| | - Kathryn R. Taylor
- Department of Neurology and Neurological Sciences, Stanford University, Stanford CA USA
| | - Selena Dutton
- Department of Neurology and Neurological Sciences, Stanford University, Stanford CA USA
| | - Lehi Acosta-Alvarez
- Department of Neurology and Neurological Sciences, Stanford University, Stanford CA USA
| | - Lijun Ni
- Department of Neurology and Neurological Sciences, Stanford University, Stanford CA USA
| | | | | | - Jon Klein
- Department of Immunobiology, Yale University, New Haven CT USA
| | - Carolina Lucas
- Department of Immunobiology, Yale University, New Haven CT USA
| | - Tianyang Mao
- Department of Immunobiology, Yale University, New Haven CT USA
| | - Julio Silva
- Department of Immunobiology, Yale University, New Haven CT USA
| | | | | | | | - Laura Tabacof
- Abilities Research Center, Department of Rehabilitation and Human Performance, Mount Sinai School of Medicine, New York, NY USA
| | - Jenna Tosto-Mancuso
- Abilities Research Center, Department of Rehabilitation and Human Performance, Mount Sinai School of Medicine, New York, NY USA
| | - Erica Breyman
- Abilities Research Center, Department of Rehabilitation and Human Performance, Mount Sinai School of Medicine, New York, NY USA
| | - Amy Kontorovich
- Cardiovascular Research Institute, Mount Sinai School of Medicine, New York, NY USA
| | - Dayna McCarthy
- Abilities Research Center, Department of Rehabilitation and Human Performance, Mount Sinai School of Medicine, New York, NY USA
| | | | - Marco Hefti
- Department of Pathology, University of Iowa, Iowa City, IA USA
| | - Daniel Perl
- Department of Pathology, Uniformed Services University of Health Sciences, Bethesda MD USA
| | | | - David Putrino
- Abilities Research Center, Department of Rehabilitation and Human Performance, Mount Sinai School of Medicine, New York, NY USA
| | - Avi Nath
- National Institute of Neurological Disorders and Stroke, Besthesda MD USA
| | - Akiko Iwasaki
- Department of Immunobiology, Yale University, New Haven CT USA
- Howard Hughes Medical Institute, Yale University, New Haven CT USA
| | - Michelle Monje
- Department of Neurology and Neurological Sciences, Stanford University, Stanford CA USA
- Howard Hughes Medical Institute, Stanford University, Stanford CA USA
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Characterization, isolation, and in vitro culture of leptomeningeal fibroblasts. J Neuroimmunol 2021; 361:577727. [PMID: 34688068 DOI: 10.1016/j.jneuroim.2021.577727] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 09/08/2021] [Accepted: 09/26/2021] [Indexed: 11/22/2022]
Abstract
Meninges, or the membranous coverings of the brain and spinal cord, play host to dozens of morbid pathologies. In this study we provide a method to isolate the leptomeningeal cell layer, identify leptomeninges in histologic slides, and maintain leptomeningeal fibroblasts in in vitro culture. Using an array of transcriptomic, histological, and cytometric analyses, we identified ICAM1 and SLC38A2 as two novel markers of leptomeningeal cells in vivo and in vitro. Our results confirm the fibroblastoid nature of leptomeningeal cells and their ability to form a sheet-like layer that covers the brain and spine parenchyma. These findings will enable researchers in central nervous system barriers to describe leptomeningeal cell functions in health and disease.
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Intrathecal inflammatory responses in the absence of SARS-CoV-2 nucleic acid in the CSF of COVID-19 hospitalized patients. J Neurol Sci 2021; 430:120023. [PMID: 34678659 PMCID: PMC8489278 DOI: 10.1016/j.jns.2021.120023] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 09/06/2021] [Accepted: 09/30/2021] [Indexed: 11/21/2022]
Abstract
OBJECTIVE Little is known about CSF profiles in patients with acute COVID-19 infection and neurological symptoms. Here, CSF was tested for SARS-CoV-2 RNA and inflammatory cytokines and chemokines and compared to controls and patients with known neurotropic pathogens. METHODS CSF from twenty-seven consecutive patients with COVID-19 and neurological symptoms was assayed for SARS-CoV-2 RNA using quantitative reverse transcription PCR (RT-qPCR) and unbiased metagenomic sequencing. Assays for blood brain barrier (BBB) breakdown (CSF:serum albumin ratio (Q-Alb)), and proinflammatory cytokines and chemokines (IL-6, IL-8, IL-15, IL-16, monocyte chemoattractant protein -1 (MCP-1) and monocyte inhibitory protein - 1β (MIP-1β)) were performed in 23 patients and compared to CSF from patients with HIV-1 (16 virally suppressed, 5 unsuppressed), West Nile virus (WNV) (n = 4) and 16 healthy controls (HC). RESULTS Median CSF cell count for COVID-19 patients was 1 white blood cell/μL; two patients were infected with a second pathogen (Neisseria, Cryptococcus neoformans). No CSF samples had detectable SARS-CoV-2 RNA by either detection method. In patients with COVID-19 only, CSF IL-6, IL-8, IL-15, and MIP-1β levels were higher than HC and suppressed HIV (corrected-p < 0.05). MCP-1 and MIP-1β levels were higher, while IL-6, IL-8, IL-15 were similar in COVID-19 compared to WNV patients. Q-Alb correlated with all proinflammatory markers, with IL-6, IL-8, and MIP-1β (r ≥ 0.6, p < 0.01) demonstrating the strongest associations. CONCLUSIONS Lack of SARS-CoV-2 RNA in CSF is consistent with pre-existing literature. Evidence of intrathecal proinflammatory markers in a subset of COVID-19 patients with BBB breakdown despite minimal CSF pleocytosis is atypical for neurotropic pathogens.
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Tan PH, Ji J, Yeh CC, Ji RR. Interferons in Pain and Infections: Emerging Roles in Neuro-Immune and Neuro-Glial Interactions. Front Immunol 2021; 12:783725. [PMID: 34804074 PMCID: PMC8602180 DOI: 10.3389/fimmu.2021.783725] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 10/19/2021] [Indexed: 12/24/2022] Open
Abstract
Interferons (IFNs) are cytokines that possess antiviral, antiproliferative, and immunomodulatory actions. IFN-α and IFN-β are two major family members of type-I IFNs and are used to treat diseases, including hepatitis and multiple sclerosis. Emerging evidence suggests that type-I IFN receptors (IFNARs) are also expressed by microglia, astrocytes, and neurons in the central and peripheral nervous systems. Apart from canonical transcriptional regulations, IFN-α and IFN-β can rapidly suppress neuronal activity and synaptic transmission via non-genomic regulation, leading to potent analgesia. IFN-γ is the only member of the type-II IFN family and induces central sensitization and microglia activation in persistent pain. We discuss how type-I and type-II IFNs regulate pain and infection via neuro-immune modulations, with special focus on neuroinflammation and neuro-glial interactions. We also highlight distinct roles of type-I IFNs in the peripheral and central nervous system. Insights into IFN signaling in nociceptors and their distinct actions in physiological vs. pathological and acute vs. chronic conditions will improve our treatments of pain after surgeries, traumas, and infections.
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Affiliation(s)
- Ping-Heng Tan
- Department of Anesthesiology, Chi Mei Medical Center, Tainan City, Taiwan
| | - Jasmine Ji
- Neuroscience Department, Wellesley College, Wellesley, Massachusetts, MA, United States
- Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, United States
| | - Chun-Chang Yeh
- Department of Anesthesiology of Tri-Service General Hospital & National Defense Medical Center, Taipei City, Taiwan
| | - Ru-Rong Ji
- Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, United States
- Department of Neurobiology, Duke University Medical Center, Durham, NC, United States
- Department of Cell Biology, Duke University Medical Center, Durham, NC, United States
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Manifestations and mechanisms of central nervous system damage caused by SARS-CoV-2. Brain Res Bull 2021; 177:155-163. [PMID: 34571039 PMCID: PMC8462004 DOI: 10.1016/j.brainresbull.2021.09.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 09/14/2021] [Accepted: 09/16/2021] [Indexed: 01/08/2023]
Abstract
The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its threat to humans have drawn worldwide attention. The acute and long-term effects of SARS-CoV-2 on the nervous system pose major public health challenges. Patients with SARS-CoV-2 present diverse symptoms of the central nervous system. Exploring the mechanism of coronavirus damage to the nervous system is essential for reducing the long-term neurological complications of COVID-19. Despite rapid progress in characterizing SARS-CoV-2, the long-term effects of COVID-19 on the brain remain unclear. The possible mechanisms of SARS-CoV-2 injury to the central nervous system include: 1) direct injury of nerve cells, 2) activation of the immune system and inflammatory cytokines caused by systemic infection, 3) a high affinity of the SARS-CoV-2 spike glycoprotein for the angiotensin-converting enzyme ACE2, 4) cerebrovascular disease caused by hypoxia and coagulation dysfunction, and 5) a systemic inflammatory response that promotes cognitive impairment and neurodegenerative diseases. Although we do not fully understand the mechanism by which SARS-CoV-2 causes nerve injury, we hope to provide a framework by reviewing the clinical manifestations, complications, and possible mechanisms of neurological damage caused by SARS-CoV-2. With hope, this will facilitate the early identification, diagnosis, and treatment of possible neurological sequelae, which could contribute toward improving patient prognosis and preventing transmission.
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43
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Matos ADMB, Dahy FE, de Moura JVL, Marcusso RMN, Gomes ABF, Carvalho FMM, Fernandes GBP, Felix AC, Smid J, Vidal JE, Frota NAF, Casseb J, Easton A, Solomon T, Witkin SS, Malta Romano C, de Oliveira ACP. Subacute Cognitive Impairment in Individuals With Mild and Moderate COVID-19: A Case Series. Front Neurol 2021; 12:678924. [PMID: 34421788 PMCID: PMC8371908 DOI: 10.3389/fneur.2021.678924] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 06/30/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Previous reported neurologic sequelae associated with SARS-CoV-2 infection have mainly been confined to hospital-based patients in which viral detection was restricted to nasal/throat swabs or to IgM/IgG peripheral blood serology. Here we describe seven cases from Brazil of outpatients with previous mild or moderate COVID-19 who developed subacute cognitive disturbances. Methods: From June 1 to August 15, 2020, seven individuals 18 to 60 years old, with confirmed mild/moderate COVID-19 and findings consistent with encephalopathy who were observed >7 days after respiratory symptom initiation, were screened for cognitive dysfunction. Paired sera and CSF were tested for SARS-CoV-2 (IgA, IgG ELISA, and RT-PCR). Serum and intrathecal antibody dynamics were evaluated with oligoclonal bands and IgG index. Cognitive dysfunction was assessed by the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and the Clock Drawing Test (CDT). Results: All but one of our patients were female, and the mean age was 42.6 years. Neurologic symptoms were first reported a median of 16 days (IQR 15–33) after initial COVID-19 symptoms. All patients had headache and altered behavior. Cognitive dysfunction was observed mainly in phonemic verbal fluency (MoCA) with a median of six words/min (IQR 5.25–10.75) and altered visuospatial construction with a median of four points (IQR 4–9) (CDT). CSF pleocytosis was not detected, and only one patient was positive for SARS-Co Conclusions: A subacute cognitive syndrome suggestive of SARS-CoV-2-initiated damage to cortico-subcortical associative pathways that could not be attributed solely to inflammation and hypoxia was present in seven individuals with mild/moderate COVID-19.
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Affiliation(s)
| | | | | | | | - Andre Borges Ferreira Gomes
- Hospital Geral de Fortaleza, Serviço de Neurologia, Fortaleza, Brazil.,Programa de Pós-Graduação em Ciências Médicas, Universidade de Fortaleza, Fortaleza, Brazil
| | - Fernanda Martins Maia Carvalho
- Hospital Geral de Fortaleza, Serviço de Neurologia, Fortaleza, Brazil.,Programa de Pós-Graduação em Ciências Médicas, Universidade de Fortaleza, Fortaleza, Brazil
| | | | - Alvina Clara Felix
- Faculdade de Medicina, Instituto de Medicina Tropical, Universidade de São Paulo, São Paulo, Brazil
| | - Jerusa Smid
- Instituto de Infectologia Emilio Ribas, São Paulo, Brazil
| | - Jose Ernesto Vidal
- Faculdade de Medicina, Instituto de Medicina Tropical, Universidade de São Paulo, São Paulo, Brazil.,Instituto de Infectologia Emilio Ribas, São Paulo, Brazil
| | - Norberto Anizio Ferreira Frota
- Hospital Geral de Fortaleza, Serviço de Neurologia, Fortaleza, Brazil.,Programa de Pós-Graduação em Ciências Médicas, Universidade de Fortaleza, Fortaleza, Brazil
| | - Jorge Casseb
- Faculdade de Medicina, Instituto de Medicina Tropical, Universidade de São Paulo, São Paulo, Brazil
| | - Ava Easton
- Encephalitis Society, Malton, United Kingdom.,Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, United Kingdom
| | - Tom Solomon
- National Institute for Health Research Health Protection Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom.,Walton Centre National Health Service Foundation Trust, Liverpool, United Kingdom
| | - Steven S Witkin
- Faculdade de Medicina, Instituto de Medicina Tropical, Universidade de São Paulo, São Paulo, Brazil.,Weill Cornell Medicine, Department of Obstetrics and Gynecology, New York, NY, United States
| | - Camila Malta Romano
- Faculdade de Medicina, Instituto de Medicina Tropical, Universidade de São Paulo, São Paulo, Brazil.,Faculdade de Medicina, Hospital das Clinicas, Universidade de São Paulo, São Paulo, Brazil
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Garcia MA, Barreras PV, Lewis A, Pinilla G, Sokoll LJ, Kickler T, Mostafa H, Caturegli M, Moghekar A, Fitzgerald KC, Pardo CA. Cerebrospinal fluid in COVID-19 neurological complications: Neuroaxonal damage, anti-SARS-Cov2 antibodies but no evidence of cytokine storm. J Neurol Sci 2021; 427:117517. [PMID: 34090021 PMCID: PMC8166041 DOI: 10.1016/j.jns.2021.117517] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 05/25/2021] [Accepted: 05/28/2021] [Indexed: 12/23/2022]
Abstract
OBJECTIVE To study in cerebrospinal fluid (CSF) of COVID-19 subjects if a "cytokine storm" or neuroinflammation are implicated in pathogenesis of neurological complications. METHODS Cross-sectional study of CSF neuroinflammatory profiles from 18 COVID-19 subjects with neurological complications categorized by diagnosis (stroke, encephalopathy, headache) and illness severity. COVID-19 CSF was compared with CSF from healthy, infectious and neuroinflammatory disorders and stroke controls (n = 82). Cytokines (IL-6, TNFα, IFNγ, IL-10, IL-12p70, IL-17A), inflammation and coagulation markers (high-sensitivity-C Reactive Protein [hsCRP], ferritin, fibrinogen, D-dimer, Factor VIII) and neurofilament light chain (NF-L), were quantified. SARS-CoV2 RNA and SARS-CoV2 IgG and IgA antibodies in CSF were tested with RT-PCR and ELISA. RESULTS CSF from COVID-19 subjects showed absence of pleocytosis or specific increases in pro-inflammatory markers (IL-6, ferritin, or D-dimer). Although pro-inflammatory cytokines (IL-6, TNFα, IL-12p70) and IL-10 were increased in CSF of stroke COVID-19 subjects, a similar increase was observed in non-COVID-19 stroke subjects. Anti-SARS-CoV2 antibodies in CSF of COVID-19 subjects (77%) were observed despite no evidence of SARS-CoV2 viral RNA. CSF-NF-L was elevated in subjects with stroke and critical COVID-19 as compared to controls and other COVID-19 severity categories. CSF-hsCRP was present in all subjects with critical stages of COVID-19 (7/18) but only in 1/82 controls. CONCLUSION The paucity of neuroinflammatory changes in CSF of COVID-19 subjects and lack of SARS-CoV2 RNA do not support the presumed neurovirulence of SARS-CoV2 or neuroinflammation in pathogenesis of neurological complications in COVID-19. The role of CSF SARS-CoV2 IgG antibodies and mechanisms of neuronal damage are still undetermined.
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Affiliation(s)
- Maria A Garcia
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America; Bloomberg School of Public Health, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Paula V Barreras
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Allie Lewis
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | | | - Lori J Sokoll
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Thomas Kickler
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Heba Mostafa
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Mario Caturegli
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Abhay Moghekar
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Kathryn C Fitzgerald
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Carlos A Pardo
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
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Naidoo J, Schreck KC, Fu W, Hu C, Carvajal-Gonzalez A, Connolly RM, Santa-Maria CA, Lipson EJ, Holdhoff M, Forde PM, Douville C, Riemer J, Barnes A, Redmond KJ, Kleinberg L, Page B, Aygun N, Kinzler KW, Papadopoulos N, Bettegowda C, Venkatesan A, Brahmer JR, Grossman SA. Pembrolizumab for patients with leptomeningeal metastasis from solid tumors: efficacy, safety, and cerebrospinal fluid biomarkers. J Immunother Cancer 2021; 9:jitc-2021-002473. [PMID: 34380662 PMCID: PMC8359453 DOI: 10.1136/jitc-2021-002473] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/02/2021] [Indexed: 01/17/2023] Open
Abstract
Background The benefit of immune checkpoint inhibitors (ICIs) in patients with leptomeningeal metastases (LMM) is unknown. Methods We undertook a phase II trial of pembrolizumab in patients with LMM from solid tumors. Eligible patients had radiologic/cytologic LMM and Eastern Cooperative Oncology Group performance status 0–1. Pembrolizumab was administered intravenously at 200 mg q3W until disease progression/unacceptable toxicity. The primary endpoint was central nervous system (CNS) response after four cycles, defined radiologically/cytologically/clinically. Serial cerebrospinal fluid (CSF) was assessed for tumor-derived DNA (t-DNA) aneuploidy and cytokines. Results Thirteen of a planned 16 patients were treated between April 2017 and December 2019. The study closed early for poor accrual. Median age was 57 years (range: 22–79). Sixty-two percent of patients had tumors not traditionally ICI-responsive (hormone-receptor (HR)-positive breast carcinoma=39%; high-grade glioma=23%), while 38% had ICI-responsive tumors (non-small cell lung cancer (NSCLC)=23%, head and neck carcinoma=8%, cutaneous squamous carcinoma (CSC)=8%). CNS response was observed in 38% of patients at 12 weeks (95% CI 13.9% to 68.4%) by pre-defined criteria and LM-RANO, and 2 achieved durable complete responses (CSC=1, overall survival (OS) 3+ years; NSCLC=1, OS 9 months). Median CNS progression-free survival and OS was 2.9 months (95% CI 1.3 to NR) and 4.9 months (95% CI 3.7 to NR), respectively. Grade 3+ treatment-related adverse events occurred in 15% of patients. Sensitivity for LMM detection by t-DNA and cytopathology was 84.6% (95% CI 54.6% to 98.1%) and 53.9% (95% CI 25.1% to 80.8%), respectively. Pre-therapy and on-therapy CSF cytokine analysis demonstrated complete responders clustered together. Conclusions Pembrolizumab conferred a 38% CNS response rate in patients with LMM, a tolerable safety profile, and deep responses in selected patients with ICI-responsive tumors. CSF t-DNA may be sensitive for LMM detection, and immunologic subsets of CNS response warrant further study. Trial registration number NCT03091478
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Affiliation(s)
- Jarushka Naidoo
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA .,Department of Immunology, The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.,Department of Oncology, Beaumont Hospital and RCSI University of Health Sciences, Dublin, Ireland
| | - Karisa C Schreck
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.,Department of Neurology, John Hopkins Medicine, Johns Hopkins University, Baltimore, Maryland, USA.,Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland, USA
| | - Wei Fu
- Department of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, John Hopkins University, Baltimore, Maryland, USA
| | - Chen Hu
- Department of Biostatistics, Sidney Kimmel Comprehensive Cancer Center, John Hopkins University, Baltimore, Maryland, USA
| | | | - Roisin M Connolly
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.,Cancer Research@UCC, College of Medicine and Health, University College Cork, Cork, Ireland
| | - Cesar A Santa-Maria
- Department of Immunology, The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.,Department of Immunology, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
| | - Evan J Lipson
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.,Department of Immunology, The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA
| | - Matthias Holdhoff
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.,Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland, USA
| | - Patrick M Forde
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.,Department of Immunology, The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA
| | - Christopher Douville
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.,Department of Immunology, The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.,Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University, Baltimore, Maryland, USA.,Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland, USA
| | - Joanne Riemer
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.,Department of Immunology, The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA
| | - Amanda Barnes
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.,Department of Immunology, The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA
| | - Kristin J Redmond
- Department of Radiation Oncology, Sidney Kimmel Comprehensive Cancer. John Hopkins University, Baltimore, Maryland, USA
| | - Lawrence Kleinberg
- Department of Radiation Oncology, Sidney Kimmel Comprehensive Cancer. John Hopkins University, Baltimore, Maryland, USA
| | - Brandi Page
- Department of Radiation Oncology, Sidney Kimmel Comprehensive Cancer. John Hopkins University, Baltimore, Maryland, USA
| | - Nafi Aygun
- Division of Radiology, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Kenneth W Kinzler
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.,Department of Immunology, The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.,Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University, Baltimore, Maryland, USA.,Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland, USA
| | - Nickolas Papadopoulos
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.,Department of Immunology, The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.,Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University, Baltimore, Maryland, USA.,Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland, USA
| | - Chetan Bettegowda
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.,Department of Immunology, The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.,Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland, USA.,Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University, Baltimore, Maryland, USA.,Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland, USA
| | - Arun Venkatesan
- Department of Neurology, John Hopkins Medicine, Johns Hopkins University, Baltimore, Maryland, USA
| | - Julie R Brahmer
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.,Department of Immunology, The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA
| | - Stuart A Grossman
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA
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Jesuthasan A, Massey F, Manji H, Zandi MS, Wiethoff S. Emerging potential mechanisms and predispositions to the neurological manifestations of COVID-19. J Neurol Sci 2021; 428:117608. [PMID: 34391037 PMCID: PMC8332920 DOI: 10.1016/j.jns.2021.117608] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/10/2021] [Accepted: 08/01/2021] [Indexed: 12/23/2022]
Abstract
A spectrum of neurological disease associated with COVID-19 is becoming increasingly apparent. However, the mechanisms behind these manifestations remain poorly understood, significantly hindering their management. The present review subsequently attempts to address the evolving molecular, cellular and systemic mechanisms of NeuroCOVID, which we have classified as the acute and long-term neurological effects of COVID-19. We place particular emphasis on cerebrovascular, demyelinating and encephalitic presentations, which have been reported. Several mechanisms are presented, especially the involvement of a "cytokine storm". We explore the genetic and demographic factors that may predispose individuals to NeuroCOVID. The increasingly evident long-term neurological effects are also presented, including the impact of the virus on cognition, autonomic function and mental wellbeing, which represent an impending burden on already stretched healthcare services. We subsequently reinforce the need for cautious surveillance, especially for those with predisposing factors, with effective clinical phenotyping, appropriate investigation and, if possible, prompt treatment. This will be imperative to prevent downstream neurological sequelae, including those related to the long COVID phenotypes that are being increasingly recognised.
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Affiliation(s)
- Aaron Jesuthasan
- University College Hospital, University College London Hospitals NHS Foundation Trust, London, UK.
| | - Flavia Massey
- University College London Medical School, Gower Street, London, UK
| | - Hadi Manji
- National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
| | - Michael S Zandi
- National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
| | - Sarah Wiethoff
- UCL Institute of Neurology, Queen Square, London, UK; Klinik für Neurologie mit Institut für Translationale Neurologie, Albert Schweitzer Campus 1, Gebäude A1, D-48149 Münster, Germany
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47
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Barrantes FJ. The unfolding palette of COVID-19 multisystemic syndrome and its neurological manifestations. Brain Behav Immun Health 2021; 14:100251. [PMID: 33842898 PMCID: PMC8019247 DOI: 10.1016/j.bbih.2021.100251] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/23/2021] [Accepted: 03/28/2021] [Indexed: 02/07/2023] Open
Abstract
Although our current knowledge of the pathophysiology of COVID-19 is still fragmentary, the information so far accrued on the tropism and life cycle of its etiological agent SARS-CoV-2, together with the emerging clinical data, suffice to indicate that the severe acute pulmonary syndrome is the main, but not the only manifestation of COVID-19. Necropsy studies are increasingly revealing underlying endothelial vasculopathies in the form of micro-haemorrhages and micro-thrombi. Intertwined with defective antiviral responses, dysregulated coagulation mechanisms, abnormal hyper-inflammatory reactions and responses, COVID-19 is disclosing a wide pathophysiological palette. An additional property in categorising the disease is the combination of tissue (e.g. neuro- and vasculo-tropism) with organ tropism, whereby the virus preferentially attacks certain organs with highly developed capillary beds, such as the lungs, gastrointestinal tract, kidney and brain. These multiple clinical presentations confirm that the acute respiratory syndrome as described initially is increasingly unfolding as a more complex nosological entity, a multiorgan syndrome of systemic breadth. The neurological manifestations of COVID-19, the focus of this review, reflect this manifold nature of the disease.
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Affiliation(s)
- Francisco J. Barrantes
- Institute of Biomedical Research (BIOMED), UCA-CONICET, Av. Alicia Moreau de Justo 1600, C1107AFF, Buenos Aires, Argentina
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48
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Zhou Y, Xu J, Hou Y, Leverenz JB, Kallianpur A, Mehra R, Liu Y, Yu H, Pieper AA, Jehi L, Cheng F. Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment. Alzheimers Res Ther 2021; 13:110. [PMID: 34108016 PMCID: PMC8189279 DOI: 10.1186/s13195-021-00850-3] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 05/28/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive and therapeutic interventions. METHODS In this study, we conducted a network-based, multimodal omics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9-based genetic assay results and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer's disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2. RESULTS We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Overall, individuals with the AD risk allele APOE E4/E4 displayed reduced expression of antiviral defense genes compared to APOE E3/E3 individuals. CONCLUSION Our results suggest significant mechanistic overlap between AD and COVID-19, centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions, although causal relationship and mechanistic pathways between COVID-19 and AD need future investigations.
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Affiliation(s)
- Yadi Zhou
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Jielin Xu
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Yuan Hou
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - James B Leverenz
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA
- Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Asha Kallianpur
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA
| | - Reena Mehra
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA
- Neurological Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Yunlong Liu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Haiyuan Yu
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, 14850, USA
- Department of Computational Biology, Cornell University, Ithaca, NY, 14850, USA
- Tri-Institutional Training Program in Computational Biology and Medicine, Cornell University, Ithaca, NY, 14850, USA
| | - Andrew A Pieper
- Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA
- Department of Psychiatry, Case Western Reserve University, Cleveland, OH, 44106, USA
- Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center, Cleveland, OH, 44106, USA
- Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA
- Weill Cornell Autism Research Program, Weill Cornell Medicine of Cornell University, New York, NY, 10065, USA
- Department of Neuroscience, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Lara Jehi
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA
- Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, 44195, USA
| | - Feixiong Cheng
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, 44195, USA.
- Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA.
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Pensato U, Muccioli L, Cani I, Janigro D, Zinzani PL, Guarino M, Cortelli P, Bisulli F. Brain dysfunction in COVID-19 and CAR-T therapy: cytokine storm-associated encephalopathy. Ann Clin Transl Neurol 2021; 8:968-979. [PMID: 33780166 PMCID: PMC8045903 DOI: 10.1002/acn3.51348] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/03/2021] [Accepted: 03/07/2021] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVE Many neurological manifestations are associated with COVID-19, including a distinct form of encephalopathy related to cytokine storm, the acute systemic inflammatory syndrome present in a subgroup of COVID-19 patients. Cytokine storm is also associated with immune effector cell-associated neurotoxicity syndrome (ICANS), a complication of chimeric antigen receptor T-cell (CAR-T) therapy, a highly effective treatment for refractory hematological malignancies. We investigated whether COVID-19-related encephalopathy, ICANS, and other encephalopathies associated with cytokine storm, share clinical and investigative findings. METHODS Narrative literature review. RESULTS Comparisons between COVID-19-related encephalopathy and ICANS revealed several overlapping features. Clinically, these included dysexecutive syndrome, language disturbances, akinetic mutism and delirium. EEG showed a prevalence of frontal abnormalities. Brain MRI was often unrevealing. CSF elevated cytokine levels have been reported. A direct correlation between cytokine storm intensity and severity of neurological manifestations has been shown for both conditions. Clinical recovery occurred spontaneously or following immunotherapies in most of the patients. Similar clinical and investigative features were also reported in other encephalopathies associated with cytokine storm, such as hemophagocytic lymphohistiocytosis, sepsis, and febrile infection-associated encephalopathies. INTERPRETATION COVID-19-related encephalopathy and ICANS are characterized by a predominant electro-clinical frontal lobe dysfunction and share several features with other encephalopathies associated with cytokine storm, which may represent the common denominator of a clinical spectrum of neurological disorders. Therefore, we propose a unifying definition of cytokine storm-associated encephalopathy (CySE), and its diagnostic criteria.
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Affiliation(s)
- Umberto Pensato
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Lorenzo Muccioli
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Ilaria Cani
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Damir Janigro
- Department of Physiology, Case Western Reserve University, Cleveland, OH, USA
| | - Pier Luigi Zinzani
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Istituto di Ematologia "Seragnoli", Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy
| | - Maria Guarino
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Pietro Cortelli
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy.,IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Francesca Bisulli
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy.,IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
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50
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Zhou Y, Xu J, Hou Y, Leverenz JB, Kallianpur A, Mehra R, Liu Y, Yu H, Pieper AA, Jehi L, Cheng F. Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2021:2021.03.15.435423. [PMID: 33791705 PMCID: PMC8010732 DOI: 10.1101/2021.03.15.435423] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive interventions. METHODS In this study, we conducted a network-based, multimodal genomics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9 based genetic assay results, and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer's disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2. RESULTS We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors ( BSG and FURIN ) and antiviral defense genes ( LY6E , IFITM2 , IFITM3 , and IFNAR1 ) was significantly elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Notably, individuals with the AD risk allele APOE E4/E4 displayed reduced levels of antiviral defense genes compared to APOE E3/E3 individuals. CONCLUSION Our results suggest significant mechanistic overlap between AD and COVID-19, strongly centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions.
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Affiliation(s)
- Yadi Zhou
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Jielin Xu
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Yuan Hou
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - James B. Leverenz
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA
- Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Asha Kallianpur
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA
| | - Reena Mehra
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA
- Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Yunlong Liu
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Haiyuan Yu
- Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14850, USA
- Department of Computational Biology, Cornell University, Ithaca, NY 14850, USA
- Tri-Institutional Training Program in Computational Biology and Medicine, Cornell University, Ithaca, NY 14850, USA
| | - Andrew A. Pieper
- Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
- Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106, USA
- Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center; Cleveland, OH 44106, USA
- Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Weill Cornell Autism Research Program, Weill Cornell Medicine of Cornell University, New York, NY 10065, USA
- Department of Neuroscience, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA
| | - Lara Jehi
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA
- Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Feixiong Cheng
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
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