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1.
Clinical & Experimental Neuroimmunology ; : 1, 2022.
Article in English | Academic Search Complete | ID: covidwho-2192455
2.
Asian Journal of Psychiatry ; : 103373, 2022.
Article in English | ScienceDirect | ID: covidwho-2122282
3.
ACS Chem Neurosci ; 13(20): 2934-2938, 2022 Oct 19.
Article in English | MEDLINE | ID: covidwho-2050258

ABSTRACT

With reports of diverse neurological deficits in the acute phase of COVID-19, there is a surge in neurological findings in Long-COVID─a protracted phase of SARS-CoV-2 infection. Very little is known regarding the pathogenic mechanisms of Neuro-COVID in the above two settings in the current pandemic. Herein, we hint toward the possible molecular mechanism that can contribute to the signs and symptoms of patients with neurological deficits and possible treatment and prevention modalities in the acute and chronic phases of COVID-19.


Subject(s)
COVID-19 , Humans , SARS-CoV-2 , Pandemics
4.
Cells ; 11(16)2022 08 10.
Article in English | MEDLINE | ID: covidwho-2032864

ABSTRACT

Neurofilament light chain (NfL) is a specific biomarker of neuro-axonal damage. Matrix metalloproteinases (MMPs) are zinc-dependent enzymes involved in blood-brain barrier (BBB) integrity. We explored neuro-axonal damage, alteration of BBB integrity and SARS-CoV-2 RNA presence in COVID-19 patients with severe neurological symptoms (neuro-COVID) as well as neuro-axonal damage in COVID-19 patients without severe neurological symptoms according to disease severity and after recovery, comparing the obtained findings with healthy donors (HD). Overall, COVID-19 patients (n = 55) showed higher plasma NfL levels compared to HD (n = 31) (p < 0.0001), especially those who developed ARDS (n = 28) (p = 0.0005). After recovery, plasma NfL levels were still higher in ARDS patients compared to HD (p = 0.0037). In neuro-COVID patients (n = 12), higher CSF and plasma NfL, and CSF MMP-2 levels in ARDS than non-ARDS group were observed (p = 0.0357, p = 0.0346 and p = 0.0303, respectively). SARS-CoV-2 RNA was detected in four CSF and two plasma samples. SARS-CoV-2 RNA detection was not associated to increased CSF NfL and MMP levels. During COVID-19, ARDS could be associated to CNS damage and alteration of BBB integrity in the absence of SARS-CoV-2 RNA detection in CSF or blood. CNS damage was still detectable after discharge in blood of COVID-19 patients who developed ARDS during hospitalization.


Subject(s)
Blood-Brain Barrier , COVID-19 , Axons , Humans , RNA, Viral , SARS-CoV-2
6.
Eur J Nucl Med Mol Imaging ; 50(1): 90-102, 2022 12.
Article in English | MEDLINE | ID: covidwho-1999921

ABSTRACT

PURPOSE: We evaluated brain metabolic dysfunctions and associations with neurological and biological parameters in acute, subacute and chronic COVID-19 phases to provide deeper insights into the pathophysiology of the disease. METHODS: Twenty-six patients with neurological symptoms (neuro-COVID-19) and [18F]FDG-PET were included. Seven patients were acute (< 1 month (m) after onset), 12 subacute (4 ≥ 1-m, 4 ≥ 2-m and 4 ≥ 3-m) and 7 with neuro-post-COVID-19 (3 ≥ 5-m and 4 ≥ 7-9-m). One patient was evaluated longitudinally (acute and 5-m). Brain hypo- and hypermetabolism were analysed at single-subject and group levels. Correlations between severity/extent of brain hypo- and hypermetabolism and biological (oxygen saturation and C-reactive protein) and clinical variables (global cognition and Body Mass Index) were assessed. RESULTS: The "fronto-insular cortex" emerged as the hypometabolic hallmark of neuro-COVID-19. Acute patients showed the most severe hypometabolism affecting several cortical regions. Three-m and 5-m patients showed a progressive reduction of hypometabolism, with limited frontal clusters. After 7-9 months, no brain hypometabolism was detected. The patient evaluated longitudinally showed a diffuse brain hypometabolism in the acute phase, almost recovered after 5 months. Brain hypometabolism correlated with cognitive dysfunction, low blood saturation and high inflammatory status. Hypermetabolism in the brainstem, cerebellum, hippocampus and amygdala persisted over time and correlated with inflammation status. CONCLUSION: Synergistic effects of systemic virus-mediated inflammation and transient hypoxia yield a dysfunction of the fronto-insular cortex, a signature of CNS involvement in neuro-COVID-19. This brain dysfunction is likely to be transient and almost reversible. The long-lasting brain hypermetabolism seems to reflect persistent inflammation processes.


Subject(s)
COVID-19 , Positron-Emission Tomography , Humans , COVID-19/diagnostic imaging , Fluorodeoxyglucose F18/metabolism , Brain/diagnostic imaging , Brain/metabolism , Inflammation/metabolism
7.
Brain Disord ; 4: 100021, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1426913

ABSTRACT

Coronaviruses have emerged as alarming pathogens owing to their inherent ability of genetic variation and cross-species transmission. Coronavirus infection burdens the endoplasmic reticulum (ER.), causes reactive oxygen species production and induces host stress responses, including unfolded protein response (UPR) and antioxidant system. In this study, we have employed a neurotropic murine ß-coronavirus (M-CoV) infection in the Central Nervous System (CNS) of experimental mice model to study the role of host stress responses mediated by interplay of DJ-1 and XBP1. DJ-1 is an antioxidant molecule with established functions in neurodegeneration. However, its regulation in virus-induced cellular stress response is less explored. Our study showed that M-CoV infection activated the glial cells and induced antioxidant and UPR genes during the acute stage when the viral titer peaks. As the virus particles decreased and acute neuroinflammation diminished at day ten p.i., a significant up-regulation in UPR responsive XBP1, antioxidant DJ-1, and downstream signaling molecules, including Nrf2, was recorded in the brain tissues. Additionally, preliminary in silico analysis of the binding between the DJ-1 promoter and a positively charged groove of XBP1 is also investigated, thus hinting at a mechanism behind the upregulation of DJ-1 during MHV-infection. The current study thus attempts to elucidate a novel interplay between the antioxidant system and UPR in the outcome of coronavirus infection.

8.
J Neurol ; 269(9): 4581-4603, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1971704

ABSTRACT

The SARS-CoV-2 pandemic has raised particular concern for people with Multiple Sclerosis, as these people are believed to be at increased risk of infection, especially those being treated with disease-modifying therapies. Therefore, the objective of this review was to describe how COVID-19 affects people who suffer from Multiple Sclerosis, evaluating the risk they have of suffering an infection by this virus, according to the therapy to which they are subjected as well as the immune response of these patients both to infection and vaccines and the neurological consequences that the virus can have in the long term. The results regarding the increased risk of infection due to treatment are contradictory. B-cell depletion therapies may cause patients to have a lower probability of generating a detectable neutralizing antibody titer. However, more studies are needed to help understand how this virus works, paying special attention to long COVID and the neurological symptoms that it causes.


Subject(s)
COVID-19 , Multiple Sclerosis , Antibodies, Viral , COVID-19/complications , COVID-19 Vaccines/adverse effects , Humans , Multiple Sclerosis/complications , Multiple Sclerosis/therapy , SARS-CoV-2
9.
Colloidal Nanoparticles for Biomedical Applications XVII 2022 ; 11977, 2022.
Article in English | Scopus | ID: covidwho-1962038

ABSTRACT

Quantum dots were encapsulated in polymeric phospholipid micelles conjugated to multiple ligands of SARS-CoV-2 spike protein to form fluorescent biomimetic nanoparticles for SARS-CoV-2 (COVID-QDs). Phosphatidylethanolaminepolyethylene glycol (PE:PEG) was appended with bis(4-methylphenyl)sulfone to form PE:PEG:bis-sulfone and self-assembled into micelles around CdSe/CdS core/shell quantum dots via thin-film rehydration. The introduction of the bis-sulfone group the surface of the micelle-encapsulated quantum dots provides multiple sites for conjugation to his-tagged SARS-CoV-2 spike protein via a bisalkylation mechanism. Based on the eluted unconjugated fraction, we estimate that an average of seven spike proteins are conjugated per COVID-QD. We treated an in-vitro model system for the neurovascular unit (NVU) with these COVID-QD constructs to investigate the COVID-QDs, and by proxy SARS-CoV-2, may modulate the NVU leading to the COVID-19 associated neuropathophysiology. © 2022 SPIE

10.
Life (Basel) ; 12(7)2022 Jul 19.
Article in English | MEDLINE | ID: covidwho-1938890

ABSTRACT

The COVID-19 era has prompted several researchers to search for a linkage between COVID-19 and its associated neurological manifestation. Toll-like receptor 4 (TLR-4) acts as one such connecting link. spike protein of SARS-CoV-2 can bind either to ACE-2 receptors or to TLR-4 receptors, leading to aggregation of α-synuclein and neurodegeneration via the activation of various cascades in neurons. Recently, dithymoquinone has been reported as a potent multi-targeting candidate against SARS-CoV-2. Thus, in the present study, dithymoquinone and its six analogues were explored to target 3CLpro (main protease of SARS-CoV-2), TLR4 and PREP (Prolyl Oligopeptidases) by using the molecular docking and dynamics approach. Dithymoquinone (DTQ) analogues were designed in order to investigate the effect of different chemical groups on its bioactivity. It is noteworthy to mention that attention was given to the feasibility of synthesizing these analogues by a simple photo-dimerisation reaction. The DTQ analogue containing the 4-fluoroaniline moiety [Compound (4)] was selected for further analysis by molecular dynamics after screening via docking-interaction analyses. A YASARA structure tool built on the AMBER14 force field was used to analyze the 100 ns trajectory by taking 400 snapshots after every 250 ps. Moreover, RMSD, RoG, potential energy plots were successfully obtained for each interaction. Molecular docking results indicated strong interaction of compound (4) with 3CLpro, TLR4 and PREP with a binding energy of -8.5 kcal/mol, -10.8 kcal/mol and -9.5 kcal/mol, respectively, which is better than other DTQ-analogues and control compounds. In addition, compound (4) did not violate Lipinski's rule and showed no toxicity. Moreover, molecular dynamic analyses revealed that the complex of compound (4) with target proteins was stable during the 100 ns trajectory. Overall, the results predicted that compound (4) could be developed into a potent anti-COVID agent with the ability to mitigate neurological manifestations associated with COVID-19.

11.
Front Neurol ; 13: 884449, 2022.
Article in English | MEDLINE | ID: covidwho-1933727

ABSTRACT

It is increasingly acknowledged that Coronavirus Disease 2019 (COVID-19) can have neurological manifestations, and cerebral microbleeds (CMBs) have been observed in this setting. The aim of this study was to characterize CMBs patterns on susceptibility-weighted imaging (SWI) in hospitalized patients with COVID-19 with neurological manifestations. CMBs volume was quantified and correlated with clinical and laboratory parameters. The study included patients who were hospitalized due to COVID-19, exhibited neurological manifestations, and underwent a brain MRI between March and May 2020. Neurological, clinical, and biochemical variables were reported. The MRI was acquired using a 3T scanner, with a standardized protocol including SWI. Patients were divided based on radiological evidence of CMBs or their absence. The CMBs burden was also assessed with a semi-automatic SWI processing procedure specifically developed for the purpose of this study. Odds ratios (OR) for CMBs were calculated using age, sex, clinical, and laboratory data by logistic regression analysis. Of the 1,760 patients with COVID-19 admitted to the ASST Papa Giovanni XXIII Hospital between 1 March and 31 May 2020, 116 exhibited neurological symptoms requiring neuroimaging evaluation. Of these, 63 patients underwent brain MRI and were therefore included in the study. A total of 14 patients had radiological evidence of CMBs (CMBs+ group). CMBs+ patients had a higher prevalence of CSF inflammation (p = 0.020), a higher white blood cell count (p = 0.020), and lower lymphocytes (p = 0.010); the D-dimer (p = 0.026), LDH (p = 0.004), procalcitonin (p = 0.002), and CRP concentration (p < 0.001) were higher than in the CMBs- group. In multivariable logistic regression analysis, CRP (OR = 1.16, p = 0.011) indicated an association with CMBs. Estimated CMBs volume was higher in females than in males and decreased with age (Rho = -0.38; p = 0.18); it was positively associated with CRP (Rho = 0.36; p = 0.22), and negatively associated with lymphocytes (Rho = -0.52; p = 0.07). CMBs are a frequent imaging finding in hospitalized patients with COVID-19 with neurological manifestations and seem to be related to pro-inflammatory status.

12.
Eur J Immunol ; 52(10): 1561-1571, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-1929796

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.


Subject(s)
COVID-19 , Nervous System Diseases , Autoimmunity , COVID-19/complications , Humans , Nervous System Diseases/etiology , SARS-CoV-2
13.
Clinics (Sao Paulo) ; 77: 100064, 2022.
Article in English | MEDLINE | ID: covidwho-1885698

ABSTRACT

Guillain-Barre Syndrome (GBS) has been repeatedly reported as a neurological complication of COVID-19 (post-COVID GBS [PCG]). Whether the introduction of SARS-CoV-2 vaccines reduced the prevalence of PCG is unknown. This narrative review aimed to compare the number of published PCG cases between the second half of 2020 (no vaccination available) with those of the first half of 2021 (vaccination available). A total of 124 articles reported 300 patients with PCG between January 2020 and June 2021. The ages ranged from 7 to 94y. There was male dominance. The latency between the onset of COVID-19 and the onset of PCG ranged from -10 to 90d Acute, inflammatory, demyelinating polyneuropathy was diagnosed in 171 patients, acute, motor axonal neuropathy in 24, and acute, motor, and sensory axonal neuropathy in 16 patients. Regarding treatment, 241 patients received immunoglobulins, 28 patients' plasmaphereses, and 7 patients' steroids. Artificial ventilation was required in 59 patients. Full recovery was achieved in 42 cases, partial recovery in 163 cases, and 17 patients died. The number of published PCG patients fell from 192 in the second half of 2020 to 75 patients in the first half of 2021. It is concluded that the prevalence of PCG has decreased since the introduction of SARS-CoV-2 vaccines. SARS-CoV-2 vaccinations have a positive effect on the prevalence of PCG.


Subject(s)
COVID-19 , Guillain-Barre Syndrome , COVID-19 Vaccines , Humans , Male , Prevalence , SARS-CoV-2
14.
Crit Care Clin ; 38(3): 553-570, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1878086

ABSTRACT

Neurologic complications can be seen in mild to severe COVID-19 with a higher risk in patients with severe COVID-19. These can occur as a direct consequence of viral infection or consequences of treatments. The spectrum ranges from non-life-threatening, like headache, fatigue, malaise, anosmia, dysgeusia, to life-threatening complications, like stroke, encephalitis, coma, Guillain-Barre syndrome. A high index of suspicion can aid in early recognition and treatment. Outcomes depend on severity of underlying COVID-19, patient age, comorbidities, and severity of the complication. Postacute sequelae of COVID-19 range from fatigue, headache, dysosmia, brain fog, anxiety, depression to an overlap with postintensive care syndrome.


Subject(s)
COVID-19 , Nervous System Diseases , Stroke , COVID-19/complications , Disease Progression , Fatigue/complications , Headache/complications , Humans , Nervous System Diseases/etiology , Nervous System Diseases/therapy
15.
Front Immunol ; 13: 866153, 2022.
Article in English | MEDLINE | ID: covidwho-1817943

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.


Subject(s)
COVID-19 , Encephalitis , Biomarkers , COVID-19/complications , Cytokines , Humans , Interleukin 1 Receptor Antagonist Protein , Interleukin-18 , Interleukin-8 , SARS-CoV-2
16.
Archives of Pediatric Infectious Diseases ; 10, 2022.
Article in English | Scopus | ID: covidwho-1789630

ABSTRACT

Serious, and sometimes, deadly complications of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are devastating. Whereas most manifestations of COVID-19 are respiratory (fever, dry cough, fatigue, pneumonia), it is getting to be progressively recognized that numerous organ functions can be affected by this disease, and the nervous system is one of them as neurological complications can affect up to 36% of adult patients. However, the prevalence and pathophysiology of these complications have yet to be fully elucidated in children. Here, we discuss an infant with neurological symptoms manifested as chronic isolated aseptic meningitis associated with COVID-19, which was unresponsive to ordinary treatments and dramatically responsive to dexamethasone. Immune-mediated reactions may have had a major pathophysiologic role in this case. © 2021, Author(s).

17.
Med Res Arch ; 10(1)2022 Jan.
Article in English | MEDLINE | ID: covidwho-1706409

ABSTRACT

BACKGROUND: Hemorrhagic cerebrovascular events, either due to aneurysmal rupture or spontaneous subarachnoid hemorrhage (SAH), are not rare in COVID-19. Several mechanisms such as coagulopathy, cytokine storm, viral endotheliopathy, hypertension, and immune modulation might play a role in the pathogenesis of SAH in COVID-19. This study aimed to report the first case of spontaneous non-aneurysmal SAH associated with SARS-CoV-2 from India. We briefly discussed the possible pathogenetic mechanisms underlying this process and succinctly reviewed the relevant literature. CASE REPORT: We herein report a case of a non-comorbid young woman infected with SARS-CoV-2 presenting with thunderclap headache and eventually non-aneurysmal SAH, who recovered with conservative management. CONCLUSION: Headache, although a very common clinical feature of COVID-19 itself, must be investigated in detail to identify alternate causes that may be life-threatening. This case also incites further enquiry into the possible pathogenic mechanisms of neurovascular complications in COVID-19.

18.
NPG Neurologie - Psychiatrie - Geriatrie ; 2022.
Article in English, French | Scopus | ID: covidwho-1699081

ABSTRACT

SARS-CoV-2 responsible for Covid-19, although having a primary pulmonary tropism, also causes variable neurological damage that it is important to know. In this narrative review, after briefly recalling the particularities of SARS-CoV-2 infection in the elderly, the authors present the main hypotheses that explain the neurotropism of SARS-CoV-2, the main types of neurological damage and the possible interactions with Parkinson's disease and Alzheimer's disease. © 2022 Elsevier Masson SAS

19.
NPG Neurologie - Psychiatrie - Gériatrie ; 2022.
Article in English | ScienceDirect | ID: covidwho-1665324

ABSTRACT

Résumé Le SARS-CoV-2 responsable du Covid-19, bien qu'ayant un tropisme au premier plan pulmonaire, entraîne également des atteintes neurologiques diverses qu’il est important de connaître. Dans cette revue narrative, après avoir rappelé brièvement les particularités de l’infection à SARS-CoV-2 chez le sujet âgé, les auteurs présentent les hypothèses pouvant expliquer le neurotropisme du SARS-CoV-2, les principales atteintes neurologiques et les interactions possibles avec la maladie de Parkinson et la maladie d’Alzheimer. SARS-CoV-2 responsible for Covid-19, although having a primary pulmonary tropism, also causes variable neurological damage that it is important to know. In this narrative review, after briefly recalling the particularities of SARS-CoV-2 infection in the elderly, the authors present the main hypotheses that explain the neurotropism of SARS-CoV-2, the main types of neurological damage and the possible interactions with Parkinson's disease and Alzheimer's disease.

20.
ACS Chem Neurosci ; 13(3): 308-312, 2022 02 02.
Article in English | MEDLINE | ID: covidwho-1636567

ABSTRACT

The SARS-CoV-2 virus is notorious for its neuroinvasive capability, causing multiple neurological conditions. The neuropathology of SARS-CoV-2 is increasingly attributed to mitochondrial dysfunction of brain microglia cells. However, the changes in biochemical content of mitochondria that drive the progression of neuro-COVID remain poorly understood. Here we introduce a Raman microspectrometry approach that enables the molecular profiling of single cellular organelles to characterize the mitochondrial molecular makeup in the infected microglia cells. We found that microglia treated with either spike protein or heat-inactivated SARS-CoV-2 trigger a dramatic reduction in mtDNA content and an increase in phospholipid saturation levels. At the same time, no significant changes were detected in Golgi apparatus and in lipid droplets, the organelles that accommodate biogenesis and storage of lipids. We hypothesize that transformations in mitochondria are caused by increased synthesis of reactive oxygen species in these organelles. Our findings call for the development of mitochondria-targeted therapeutic approaches to limit neuropathology associated with SARS-CoV-2.


Subject(s)
COVID-19 , SARS-CoV-2 , Brain , Humans , Microglia , Mitochondria
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