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Bremner JD, Russo SJ, Gallagher R, Simon NM. Acute and long-term effects of COVID-19 on brain and mental health: A narrative review. Brain Behav Immun 2025; 123:928-945. [PMID: 39500417 PMCID: PMC11974614 DOI: 10.1016/j.bbi.2024.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 09/16/2024] [Accepted: 11/02/2024] [Indexed: 11/09/2024] Open
Abstract
BACKGROUND COVID infection has been associated with long term sequalae (Long COVID) which include neurological and behavioral effects in thousands of patients, but the etiology and scope of symptoms is not well understood. This paper reviews long term sequelae of COVID on brain and mental health in patients with the Long COVID syndrome. METHODS This was a literature review which queried databases for Pubmed, Psychinfo, and Medline for the following topics for January 1, 2020-July 15, 2023: Long COVID, PASC, brain, brain imaging, neurological, neurobiology, mental health, anxiety, depression. RESULTS Tens of thousands of patients have developed Long COVID, with the most common neurobehavioral symptoms anosmia (loss of smell) and fatigue. Anxiety and mood disorders are elevated and seen in about 25% of Long COVID patients. Neuropsychological testing studies show a correlation between symptom severity and cognitive dysfunction, while brain imaging studies show global decreases in gray matter and alterations in olfactory and other brain areas. CONCLUSIONS Studies to date show an increase in neurobehavioral disturbances in patients with Long COVID. Future research is needed to determine mechanisms.
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Affiliation(s)
- J Douglas Bremner
- Departments of Psychiatry & Behavioral Sciences and Radiology, Emory University School of Medicine, Atlanta Georgia, and the Atlanta VA Medical Center, Decatur, GA, USA; Nash Family Department Neuroscience and Brain-Body Research Center, Icahn School of Medicine at Mt. Sinai, New York, NY, USA; Department of Child and Adolescent Psychiatry, New York University (NYU) Langone Health, New York, NY, USA.
| | - Scott J Russo
- Nash Family Department Neuroscience and Brain-Body Research Center, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
| | - Richard Gallagher
- Department of Child and Adolescent Psychiatry, New York University (NYU) Langone Health, New York, NY, USA; Department of Psychiatry, New York University (NYU) Langone Health, New York, NY, USA
| | - Naomi M Simon
- Department of Psychiatry, New York University (NYU) Langone Health, New York, NY, USA
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Chatterjee S, Kordbacheh R, Sin J. Extracellular Vesicles: A Novel Mode of Viral Propagation Exploited by Enveloped and Non-Enveloped Viruses. Microorganisms 2024; 12:274. [PMID: 38399678 PMCID: PMC10892846 DOI: 10.3390/microorganisms12020274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 01/24/2024] [Accepted: 01/26/2024] [Indexed: 02/25/2024] Open
Abstract
Extracellular vesicles (EVs) are small membrane-enclosed structures that have gained much attention from researchers across varying scientific fields in the past few decades. Cells secrete diverse types of EVs into the extracellular milieu which include exosomes, microvesicles, and apoptotic bodies. These EVs play a crucial role in facilitating intracellular communication via the transport of proteins, lipids, DNA, rRNA, and miRNAs. It is well known that a number of viruses hijack several cellular pathways involved in EV biogenesis to aid in their replication, assembly, and egress. On the other hand, EVs can also trigger host antiviral immune responses by carrying immunomodulatory molecules and viral antigens on their surface. Owing to this intricate relationship between EVs and viruses, intriguing studies have identified various EV-mediated viral infections and interrogated how EVs can alter overall viral spread and longevity. This review provides a comprehensive overview on the EV-virus relationship, and details various modes of EV-mediated viral spread in the context of clinically relevant enveloped and non-enveloped viruses.
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Affiliation(s)
| | | | - Jon Sin
- Department of Biological Sciences, University of Alabama, 1325 Hackberry Lane, Tuscaloosa, AL 35401, USA; (S.C.); (R.K.)
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Norouzi-Barough L, Asgari Khosroshahi A, Gorji A, Zafari F, Shahverdi Shahraki M, Shirian S. COVID-19-Induced Stroke and the Potential of Using Mesenchymal Stem Cells-Derived Extracellular Vesicles in the Regulation of Neuroinflammation. Cell Mol Neurobiol 2023; 43:37-46. [PMID: 35025001 PMCID: PMC8755896 DOI: 10.1007/s10571-021-01169-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 11/09/2021] [Indexed: 02/07/2023]
Abstract
Ischemic stroke (IS) is a known neurological complication of COVID-19 infection, which is associated with high mortality and disability. Following IS, secondary neuroinflammation that occurs can play both harmful and beneficial roles and lead to further injury or repair of damaged neuronal tissue, respectively. Since inflammation plays a pivotal role in the pathogenesis of COVID-19-induced stroke, targeting neuroinflammation could be an effective strategy for modulating the immune responses following ischemic events. Numerous investigations have indicated that the application of mesenchymal stem cells-derived extracellular vesicles (MSC-EVs) improves functional recovery following stroke, mainly through reducing neuroinflammation as well as promoting neurogenesis and angiogenesis. Therefore, MSC-EVs can be applied for the regulation of SARS-CoV-2-mediated inflammation and the management of COVID-19- related ischemic events. In this study, we have first described the advantages and disadvantages of neuroinflammation in the pathological evolution after IS and summarized the characteristics of neuroinflammation in COVID-19-related stroke. Then, we have discussed the potential benefit of MSC-EVs in the regulation of inflammatory responses after COVID-19-induced ischemic events.
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Affiliation(s)
- Leyla Norouzi-Barough
- Acquired Immunodeficiency Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Ali Gorji
- Epilepsy Research Center, Department of Neurosurgery, Westfälische Wilhelms-Universitat Münster, Munster, Germany
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran
| | - Fariba Zafari
- Cellular and Molecular Research Center, Research Institute for Prevention of Non- Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
| | | | - Sadegh Shirian
- Department of Pathology, School of Veterinary Medicine, Shahrekord University, Shahrekord, Iran.
- Shiraz Molecular Pathology Research Center, Dr. Daneshbod Pathol Lab, Shiraz, Iran.
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Wais T, Hasan M, Rai V, Agrawal DK. Gut-brain communication in COVID-19: molecular mechanisms, mediators, biomarkers, and therapeutics. Expert Rev Clin Immunol 2022; 18:947-960. [PMID: 35868344 PMCID: PMC9388545 DOI: 10.1080/1744666x.2022.2105697] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 07/21/2022] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Infection with COVID-19 results in acute respiratory symptoms followed by long COVID multi-organ effects presenting with neurological, cardiovascular, musculoskeletal, and gastrointestinal (GI) manifestations. Temporal relationship between gastrointestinal and neurological symptoms is unclear but warranted for exploring better clinical care for COVID-19 patients. AREAS COVERED We critically reviewed the temporal relationship between gut-brain axis after SARS-CoV-2 infection and the molecular mechanisms involved in neuroinvasion following GI infection. Mediators are identified that could serve as biomarkers and therapeutic targets in SARS-CoV-2. We discussed the potential therapeutic approaches to mitigate the effects of GI infection with SARS-CoV-2. EXPERT OPINION Altered gut microbiota cause increased expression of various mediators, including zonulin causing disruption of tight junction. This stimulates enteric nervous system and signals to CNS precipitating neurological sequalae. Published reports suggest potential role of cytokines, immune cells, B(0)AT1 (SLC6A19), ACE2, TMRSS2, TMPRSS4, IFN-γ, IL-17A, zonulin, and altered gut microbiome in gut-brain axis and associated neurological sequalae. Targeting these mediators and gut microbiome to improve immunity will be of therapeutic significance. In-depth research and well-designed large-scale population-based clinical trials with multidisciplinary and collaborative approaches are warranted. Investigating the temporal relationship between organs involved in long-term sequalae is critical due to evolving variants of SARS-CoV-2.
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Affiliation(s)
- Tameena Wais
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences. Pomona, CA 91766
| | - Mehde Hasan
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences. Pomona, CA 91766
| | - Vikrant Rai
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences. Pomona, CA 91766
| | - Devendra K. Agrawal
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences. Pomona, CA 91766
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Abdolahi S, Ashayeri Ahmadabad R, Gorji A, Mirzaasgari Z. Status epilepticus and the presence of SARS-COV-2 in the cerebrospinal fluid: A case report. Clin Case Rep 2022; 10:e6214. [PMID: 35957773 PMCID: PMC9361715 DOI: 10.1002/ccr3.6214] [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: 04/08/2022] [Revised: 07/01/2022] [Accepted: 07/24/2022] [Indexed: 12/02/2022] Open
Abstract
A growing number of studies indicate a broad range of neurological manifestations, including seizures, occur in patients with COVID-19 infection. We report a 29-year-old female patient with status epilepticus and positive SARS-CoV-2 in the cerebrospinal fluid. Our findings support previous reports suggesting seizure as a possible symptom of COVID-19 infection.
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Affiliation(s)
- Sara Abdolahi
- Shefa Neuroscience Research CenterKhatam Alanbia HospitalTehranIran
| | | | - Ali Gorji
- Shefa Neuroscience Research CenterKhatam Alanbia HospitalTehranIran
- Neuroscience Research CenterMashhad University of Medical SciencesMashhadIran
- Department of Neurosurgery and NeurologyWestfälische Wilhelms‐Universitat MünsterMünsterGermany
- Epilepsy Research Center, Department of NeurosurgeryWestfälische Wilhelms‐Universitat MünsterMünsterGermany
| | - Zahra Mirzaasgari
- Shefa Neuroscience Research CenterKhatam Alanbia HospitalTehranIran
- Department of Neurology, Firoozgar hospital, School of MedicineIran University of Medical ScienceTehranIran
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de Mello AJ, Moretti M, Rodrigues ALS. SARS-CoV-2 consequences for mental health: Neuroinflammatory pathways linking COVID-19 to anxiety and depression. World J Psychiatry 2022; 12:874-883. [PMID: 36051596 PMCID: PMC9331446 DOI: 10.5498/wjp.v12.i7.874] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 05/03/2022] [Accepted: 06/17/2022] [Indexed: 02/06/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has been linked to an increased prevalence of mental health disorders, particularly anxiety and depression. Moreover, the COVID-19 pandemic has caused stress in people worldwide due to several factors, including fear of infection; social isolation; difficulty in adapting to new routines; lack of coping methods; high exposure to social media, misinformation, and fake reports; economic impact of the measures implemented to slow the contagion and concerns regarding the disease pathogenesis. COVID-19 patients have elevated levels of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, and other inflammation-related factors. Furthermore, invasion of the central nervous system by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may potentially contribute to neuroinflammatory alterations in infected individuals. Neuroinflammation, a consequence of psychological stress due to the COVID-19 pandemic, may also play a role in the development of anxiety and depressive symptoms in the general population. Considering that neuroinflammation plays a significant role in the pathophysiology of depression and anxiety, this study investigated the effects of SARS-CoV-2 on mental health and focused on the impact of the COVID-19 pandemic on the neuroinflammatory pathways.
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Affiliation(s)
- Anna Julie de Mello
- Department of Biochemistry, Universidade Federal de Santa Catarina, Florianópolis 88040-200, Brazil
| | - Morgana Moretti
- Department of Biochemistry, Universidade Federal de Santa Catarina, Florianópolis 88040-200, Brazil
| | - Ana Lúcia S Rodrigues
- Department of Biochemistry, Universidade Federal de Santa Catarina, Florianópolis 88040-200, Brazil
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Domingues RB, Leite FBVDM, Senne C. Cerebrospinal fluid analysis in patients with COVID-19-associated central nervous system manifestations: a systematic review. ARQUIVOS DE NEURO-PSIQUIATRIA 2022; 80:296-305. [DOI: 10.1590/0004-282x-anp-2021-0117] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/22/2021] [Indexed: 12/14/2022]
Abstract
ABSTRACT Background: Central nervous system (CNS) symptoms may occur in patients with acute COVID-19. The role of CSF examination in these patients remains to be established. Objective: A systematic review of CSF findings relating to COVID-19 was carried out. Methods: CSF parameters, including cytological and biochemical analyses, SARS-CoV-2 RT-PCR and other CSF markers, were recorded and analyzed among patients with acute COVID-19 and one of the following CNS syndromes: stroke, encephalopathy, encephalitis, inflammatory syndromes, seizure, headache and meningitis. Results: Increased white blood cells and/or increased protein concentration were found in 52.7% of the patients with encephalitis, 29.4% of the patients with encephalopathy and 46.7% of the patients with inflammatory syndromes (P < 0.05). CSF RT-PCR for SARS-CoV-2 was positive in 17.35% of the patients with encephalitis and less than 3.5% of the patients with encephalopathy or inflammatory syndromes (P < 0.05). Intrathecal production of immunoglobulins was found in only 8% of the cases. More than 85% of the patients had increased CSF cytokines and chemokines. Increased CSF neurofilament light chain (NfL) and CSF Tau were found in 71% and 36% of the cases, respectively. Conclusion: Non-specific inflammatory CSF abnormalities were frequently found in patients with COVID-19 CNS syndromes. The increase in neurodegeneration biomarkers suggests that neuronal damage occurs, with long-term consequences that are still unknown.
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Sepehrinezhad A, Gorji A, Sahab Negah S. SARS-CoV-2 may trigger inflammasome and pyroptosis in the central nervous system: a mechanistic view of neurotropism. Inflammopharmacology 2021; 29:1049-1059. [PMID: 34241783 PMCID: PMC8266993 DOI: 10.1007/s10787-021-00845-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 06/21/2021] [Indexed: 01/08/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can enter the central nervous system and cause several neurological manifestations. Data from cerebrospinal fluid analyses and postmortem samples have been shown that SARS-CoV-2 has neuroinvasive properties. Therefore, ongoing studies have focused on mechanisms involved in neurotropism and neural injuries of SARS-CoV-2. The inflammasome is a part of the innate immune system that is responsible for the secretion and activation of several pro-inflammatory cytokines, such as interleukin-1β, interleukin-6, and interleukin-18. Since cytokine storm has been known as a major mechanism followed by SARS-CoV-2, inflammasome may trigger an inflammatory form of lytic programmed cell death (pyroptosis) following SARS-CoV-2 infection and contribute to associated neurological complications. We reviewed and discussed the possible role of inflammasome and its consequence pyroptosis following coronavirus infections as potential mechanisms of neurotropism by SARS-CoV-2. Further studies, particularly postmortem analysis of brain samples obtained from COVID-19 patients, can shed light on the possible role of the inflammasome in neurotropism of SARS-CoV-2.
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Affiliation(s)
- Ali Sepehrinezhad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Gorji
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran
- Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Epilepsy Research Center, Westfälische Wilhelms-Universität, Münster, Germany
- Department of Neurosurgery, Westfälische Wilhelms-Universität, Münster, Germany
- Department of Neurology, Westfälische Wilhelms-Universität, Münster, Germany
| | - Sajad Sahab Negah
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran.
- Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
- Society for Brain Mapping and Therapeutics, Iranian Chapter, SBMT, Los Angeles, USA.
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