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1.
J Neurol ; 269(11): 5691-5701, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-1971703

ABSTRACT

BACKGROUND: Increased serum levels of neurofilament light chain (sNFL), a biomarker of neuroaxonal damage, have been reported in patients with Covid-19. We aimed at investigating whether sNFL is increased in Covid-19 patients without major neurological manifestations, is associated with disease severity, respiratory and routine blood parameters, and changes longitudinally in the short term. METHODS: sNFL levels were measured with single molecule array (Simoa) technology in 57 hospitalized Covid-19 patients without major neurological manifestations and in 30 neurologically healthy controls. Patients were evaluated for PaO2/FiO2 ratio on arterial blood gas, Brescia Respiratory Covid Severity Scale (BRCSS), white blood cell counts, serum C-reactive protein (CRP), plasma D-dimer, plasma fibrinogen, and serum creatinine at admission. In 20 patients, NFL was also measured on serum samples obtained at a later timepoint during the hospital stay. RESULTS: Covid-19 patients had higher baseline sNFL levels compared to controls, regardless of disease severity. Baseline sNFL correlated with serum CRP and plasma D-dimer in patients with mild disease, but was not associated with measures of respiratory impairment. Longitudinal sNFL levels tended to be higher than baseline ones, albeit not significantly, and correlated with serum CRP and plasma D-dimer. The PaO2/FiO2 ratio was not associated with longitudinal sNFL, whereas BRCSS only correlated with longitudinal sNFL variation. CONCLUSIONS: We provide neurochemical evidence of subclinical axonal damage in Covid-19 also in the absence of major neurological manifestations. This is apparently not fully explained by hypoxic injury; rather, systemic inflammation might promote this damage. However, a direct neurotoxic effect of SARS-CoV-2 cannot be excluded.


Subject(s)
COVID-19 , Respiratory Distress Syndrome , Biomarkers , C-Reactive Protein , COVID-19/complications , Creatinine , Fibrinogen , Humans , Intermediate Filaments , Neurofilament Proteins , SARS-CoV-2
2.
Int J Mol Sci ; 23(10)2022 May 10.
Article in English | MEDLINE | ID: covidwho-1875638

ABSTRACT

We would like to make readers of the second edition of the Special Issue from the International Journal of Molecular Sciences on the Recent Advances in Intermediate Filaments aware of the content of the first edition on this same topic [...].


Subject(s)
Cytoskeleton , Intermediate Filaments
3.
Ann Clin Transl Neurol ; 9(5): 622-632, 2022 05.
Article in English | MEDLINE | ID: covidwho-1825806

ABSTRACT

OBJECTIVE: Given the continued spread of coronavirus 2, the early predictors of coronavirus disease 19 (COVID-19) associated mortality might improve patients' outcomes. Increased levels of circulating neurofilament light chain (NfL), a biomarker of neuronal injury, have been observed in severe COVID-19 patients. We investigated whether NfL provides non-redundant clinical value to previously identified predictors of COVID-19 mortality. METHODS: We measured serum or plasma NfL concentrations in a blinded fashion in 3 cohorts totaling 338 COVID-19 patients. RESULTS: In cohort 1, we found significantly elevated NfL levels only in critically ill COVID-19 patients. Longitudinal cohort 2 data showed that NfL is elevated late in the course of the disease, following the two other prognostic markers of COVID-19: decrease in absolute lymphocyte count (ALC) and increase in lactate dehydrogenase (LDH). Significant correlations between ALC and LDH abnormalities and subsequent rise of NfL implicate that the multi-organ failure is the most likely cause of neuronal injury in severe COVID-19 patients. The addition of NfL to age and gender in cohort 1 significantly improved the accuracy of mortality prediction and these improvements were validated in cohorts 2 and 3. INTERPRETATION: A substantial increase in serum/plasma NfL reproducibly enhanced COVID-19 mortality prediction. Combined with other prognostic markers, such as ALC and LDH that are routinely measured in ICU patients, NfL measurements might be useful to identify the patients at a high risk of COVID-19-associated mortality, who might still benefit from escalated care.


Subject(s)
COVID-19 , Biomarkers , Cohort Studies , Humans , Intermediate Filaments , Prognosis
4.
Sci Transl Med ; 13(602)2021 07 14.
Article in English | MEDLINE | ID: covidwho-1270875

ABSTRACT

Brain imaging studies of patients with COVID-19 show evidence of macro- and microhemorrhagic lesions, multifocal white matter hyperintensities, and lesions consistent with posterior reversible leukoencephalopathy. Imaging studies, however, are subject to selection bias, and prospective studies are challenging to scale. Here, we evaluated whether serum neurofilament light chain (NFL), a neuroaxonal injury marker, could predict the extent of neuronal damage in a cohort of 142 hospitalized patients with COVID-19. NFL was elevated in the serum of patients with COVID-19 compared to healthy controls, including those without overt neurological manifestations. Higher NFL serum concentrations were associated with worse clinical outcomes. In 100 hospitalized patients with COVID-19 treated with remdesivir, a trend toward lower NFL serum concentrations was observed. These data suggest that patients with COVID-19 may experience neuroaxonal injury and may be at risk for long-term neurological sequelae. Neuroaxonal injury should be considered as an outcome in acute pharmacotherapeutic trials for COVID-19.


Subject(s)
COVID-19 , Tumor Necrosis Factor Ligand Superfamily Member 14 , Biomarkers , Humans , Intermediate Filaments , Magnetic Resonance Imaging , Neurofilament Proteins , Prospective Studies , SARS-CoV-2
7.
J Neurol ; 268(12): 4436-4442, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1222771

ABSTRACT

BACKGROUND AND AIMS: Patients infected with SARS-CoV-2 range from asymptomatic, to mild, moderate or severe disease evolution including fatal outcome. Thus, early predictors of clinical outcome are highly needed. We investigated markers of neural tissue damage as a possible early sign of multisystem involvement to assess their clinical prognostic value on survival or transfer to intensive care unit (ICU). METHODS: We collected blood from 104 patients infected with SARS-CoV-2 the day of admission to the emergency room and measured blood neurofilament light chair (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and total tau protein levels. RESULTS: We found that NfL, GFAP, and tau were significantly increased in patients with fatal outcome, while NfL and UCH-L1 in those needing ICU transfer. ROC and Kaplan-Meier curves indicated that total tau levels at admission accurately predict mortality. CONCLUSIONS: Blood neural markers may provide additional prognostic value to conventional biomarkers used to predict COVID-19 outcome.


Subject(s)
COVID-19 , Intermediate Filaments , Neurofilament Proteins/blood , tau Proteins/blood , Biomarkers , COVID-19/mortality , Glial Fibrillary Acidic Protein/blood , Humans , Ubiquitin Thiolesterase/blood
8.
J Neurol ; 268(11): 3969-3974, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1210701

ABSTRACT

BACKGROUND: Serum neurofilament light chain (sNfL) is an established biomarker of neuro-axonal damage in multiple neurological disorders. Raised sNfL levels have been reported in adults infected with pandemic coronavirus disease 2019 (COVID-19). Levels in children infected with COVID-19 have not as yet been reported. OBJECTIVE: To evaluate whether sNfL is elevated in children contracting COVID-19. METHODS: Between May 22 and July 22, 2020, a network of outpatient pediatricians in Bavaria, Germany, the Coronavirus antibody screening in children from Bavaria study network (CoKiBa), recruited healthy children into a cross-sectional study from two sources: an ongoing prevention program for 1-14 years, and referrals of 1-17 years consulting a pediatrician for possible infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We determined sNfL levels by single molecule array immunoassay and SARS-CoV-2 antibody status by two independent quantitative methods. RESULTS: Of the 2652 included children, 148 (5.6%) were SARS-CoV-2 antibody positive with asymptomatic to moderate COVID-19 infection. Neurological symptoms-headache, dizziness, muscle aches, or loss of smell and taste-were present in 47/148 cases (31.8%). Mean sNfL levels were 5.5 pg/ml (SD 2.9) in the total cohort, 5.1 (SD 2.1) pg/ml in the children with SARS-CoV-2 antibodies, and 5.5 (SD 3.0) pg/ml in those without. Multivariate regression analysis revealed age-but neither antibody status, antibody levels, nor clinical severity-as an independent predictor of sNfL. Follow-up of children with pediatric multisystem inflammatory syndrome (n = 14) showed no association with sNfL. CONCLUSIONS: In this population study, children with asymptomatic to moderate COVID-19 showed no neurochemical evidence of neuronal damage.


Subject(s)
COVID-19 , Intermediate Filaments , Adult , Child , Cross-Sectional Studies , Humans , Neurofilament Proteins , SARS-CoV-2 , Systemic Inflammatory Response Syndrome
9.
J Neurol ; 268(10): 3574-3583, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1141418

ABSTRACT

OBJECTIVE: To test the hypotheses that blood biomarkers for nervous system injury, serum concentrations of neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAp) can serve as biomarkers for disease severity in COVID-19 patients. METHODS: Forty-seven inpatients with confirmed COVID-19 had blood samples drawn on admission for assessing serum biomarkers of CNS injury by Single molecule array (Simoa), NfL and GFAp. Concentrations of NfL and GFAp were analyzed in relation to symptoms, clinical signs, inflammatory biomarkers and clinical outcomes. We used multivariate linear models to test for differences in biomarker concentrations in the subgroups, accounting for confounding effects. RESULTS: In total, 21% (n = 10) of the patients were admitted to an intensive care unit, and the overall mortality rate was 13% (n = 6). Non-survivors had higher serum concentrations of NfL (p < 0.001) upon admission than patients who were discharged alive both in adjusted analyses (p = 2.6 × 10-7) and unadjusted analyses (p = 0.001). The concentrations of NfL in non-survivors increased over repeated measurements; whereas, the concentrations in survivors were stable. The GFAp concentration was also significantly higher in non-survivors than survivors (p = 0.02). CONCLUSION: Increased concentrations of NfL and GFAp in COVID-19 patients on admission may indicate increased mortality risk. Measurement of blood biomarkers for nervous system injury can be useful to detect and monitor CNS injury in COVID-19.


Subject(s)
COVID-19 , Biomarkers , Glial Fibrillary Acidic Protein , Humans , Intermediate Filaments , Neurofilament Proteins , Prognosis , SARS-CoV-2
10.
Bioessays ; 42(11): e2000078, 2020 11.
Article in English | MEDLINE | ID: covidwho-746167

ABSTRACT

Intermediate filaments (IFs) formed by vimentin are less understood than their cytoskeletal partners, microtubules and F-actin, but the unique physical properties of IFs, especially their resistance to large deformations, initially suggest a mechanical function. Indeed, vimentin IFs help regulate cell mechanics and contractility, and in crowded 3D environments they protect the nucleus during cell migration. Recently, a multitude of studies, often using genetic or proteomic screenings show that vimentin has many non-mechanical functions within and outside of cells. These include signaling roles in wound healing, lipogenesis, sterol processing, and various functions related to extracellular and cell surface vimentin. Extracellular vimentin is implicated in marking circulating tumor cells, promoting neural repair, and mediating the invasion of host cells by viruses, including SARS-CoV, or bacteria such as Listeria and Streptococcus. These findings underscore the fundamental role of vimentin in not only cell mechanics but also a range of physiological functions. Also see the video abstract here https://youtu.be/YPfoddqvz-g.


Subject(s)
Intermediate Filaments/physiology , Mechanotransduction, Cellular/physiology , Vimentin/physiology , Animals , Bacterial Physiological Phenomena , Host-Pathogen Interactions/physiology , Humans , Intermediate Filaments/chemistry , Mechanical Phenomena , Vimentin/chemistry , Virus Internalization
11.
J Mol Cell Biol ; 12(12): 968-979, 2020 07 01.
Article in English | MEDLINE | ID: covidwho-676855

ABSTRACT

The emerging coronavirus (CoV) pandemic is threatening the public health all over the world. Cytoskeleton is an intricate network involved in controlling cell shape, cargo transport, signal transduction, and cell division. Infection biology studies have illuminated essential roles for cytoskeleton in mediating the outcome of host‒virus interactions. In this review, we discuss the dynamic interactions between actin filaments, microtubules, intermediate filaments, and CoVs. In one round of viral life cycle, CoVs surf along filopodia on the host membrane to the entry sites, utilize specific intermediate filament protein as co-receptor to enter target cells, hijack microtubules for transportation to replication and assembly sites, and promote actin filaments polymerization to provide forces for egress. During CoV infection, disruption of host cytoskeleton homeostasis and modification state is tightly connected to pathological processes, such as defective cytokinesis, demyelinating, cilia loss, and neuron necrosis. There are increasing mechanistic studies on cytoskeleton upon CoV infection, such as viral protein‒cytoskeleton interaction, changes in the expression and post-translation modification, related signaling pathways, and incorporation with other host factors. Collectively, these insights provide new concepts for fundamental virology and the control of CoV infection.


Subject(s)
Coronavirus Infections/virology , Coronavirus/pathogenicity , Cytoskeleton/virology , Host Microbial Interactions/physiology , Actin Cytoskeleton/physiology , Actin Cytoskeleton/virology , Animals , Biological Transport, Active , Brain/pathology , Cilia/pathology , Coronavirus/classification , Coronavirus/physiology , Coronavirus Infections/pathology , Coronavirus Infections/physiopathology , Cytoskeleton/pathology , Cytoskeleton/physiology , Humans , Intermediate Filaments/physiology , Intermediate Filaments/virology , Microtubules/physiology , Microtubules/virology , Models, Biological , Phylogeny , Receptors, Virus/physiology , Signal Transduction , Virus Assembly , Virus Internalization , Virus Replication
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