scholarly journals Association of intrathecal pleocytosis and IgG synthesis with axonal damage in early MS

2020 ◽  
Vol 7 (3) ◽  
pp. e679 ◽  
Author(s):  
Sinah Engel ◽  
Falk Steffen ◽  
Timo Uphaus ◽  
Peter Scholz-Kreisel ◽  
Frauke Zipp ◽  
...  
Keyword(s):  
Single Molecule ◽  
Leukocyte Count ◽  
Cross Sectional Study ◽  
Axonal Damage ◽  
Oligoclonal Bands ◽  
Neurofilament Light Chain ◽  
Cross Sectional ◽  
Neurofilament Light ◽  
Igg Synthesis ◽  
Healthy Donors

ObjectiveTo investigate the association of serum neurofilament light chain (sNfL) levels with CSF parameters in clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS), taking into account radiologic and clinical parameters of disease activity.MethodsSimultaneously collected serum and CSF samples of 112 untreated patients newly diagnosed with CIS or RRMS were included in this cross-sectional study. CSF parameters were obtained as part of routine diagnostic tests. sNfL levels of patients and of 62 healthy donors were measured by highly sensitive single molecule array (SiMoA) immunoassay.ResultsPatients with RRMS (n = 91, median 10.13 pg/mL, interquartile range [IQR] 6.67–17.77 pg/mL) had higher sNfL levels than healthy donors (n = 62, median 5.25 pg/mL, IQR 4.05–6.81 pg/mL, p < 0.001) and patients with CIS (n = 21, median 5.69 pg/mL, IQR 4.73–9.07 pg/mL, p < 0.001). Patients positive for oligoclonal bands (OCBs) (n = 101, median 9.19 pg/mL, IQR 6.34–16.38 pg/mL) had higher sNfL levels than OCB-negative patients (n = 11, median 5.93 pg/mL, IQR 2.93–8.56 pg/mL, p = 0.001). sNfL levels correlated with CSF immunoglobulin G (IgG) levels (r = 0.317, p = 0.002), IgG ratio (QIgG) (r = 0.344, p < 0.001), and CSF leukocyte count (r = 0.288, p = 0.002). In linear regression modeling, the CSF leukocyte count combined with the number of contrast-enhancing lesions in MRI predicted sNfL levels best.ConclusionsIn active MS, sNfL levels correlate with intrathecal pleocytosis and IgG synthesis, indicating that axonal damage is associated with both acute and chronic CNS-intrinsic inflammation.

scholarly journals Cerebrospinal fluid in COVID-19 neurological complications: no cytokine storm or neuroinflammation

2021 ◽  
Author(s):  
Maria A. Garcia ◽  
Paula V. Barreras ◽  
Allie Lewis ◽  
Gabriel Pinilla ◽  
Lori J. Sokoll ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
High Sensitivity ◽  
Neurological Complications ◽  
Cross Sectional Study ◽  
Neurofilament Light Chain ◽  
Cross Sectional ◽  
Neurofilament Light ◽  
Reactive Protein ◽  
D Dimer

ABSTRACTBACKGROUNDNeurological complications occur in COVID-19. We aimed to examine cerebrospinal fluid (CSF) of COVID-19 subjects with neurological complications and determine presence of neuroinflammatory changes implicated in pathogenesis.METHODSCross-sectional study of CSF neuroinflammatory profiles from 18 COVID-19 subjects with neurological complications categorized by diagnosis (stroke, encephalopathy, headache) and illness severity (critical, severe, moderate, mild). 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.RESULTSCSF from COVID-19 subjects showed a paucity of neuroinflammatory changes, absence of pleocytosis or specific increases in pro-inflammatory markers or cytokines (IL-6, ferritin, or D-dimer). Anti-SARS-CoV2 antibodies in CSF of COVID-19 subjects (77%) were observed despite no evidence of SARS-CoV2 viral RNA. A similar increase of pro-inflammatory cytokines (IL-6, TNFα, IL-12p70) and IL-10 in CSF of COVID-19 and non-COVID-19 stroke subjects was observed compared to controls. CSF-NF-L was elevated in subjects with stroke and critical COVID-19. CSF-hsCRP was present almost exclusively in COVID-19 cases.CONCLUSIONThe 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. Elevated CSF-NF-L indicates neuroaxonal injury in COVID-19 cases. The role of CSF SARS-CoV2 IgG antibodies is still undetermined.FUNDINGThis work was supported by NIH R01-NS110122 and The Bart McLean Fund for Neuroimmunology Research.

scholarly journals Serum neurofilament light chains in MS

2020 ◽  
Vol 7 (6) ◽  
pp. e895
Author(s):  
Gilles Allali ◽  
Jens Kuhle ◽  
Gautier Breville ◽  
David Leppert ◽  
Stephane Armand ◽  
...  
Keyword(s):  
Cross Sectional Study ◽  
Behavioral Measures ◽  
Timed Up And Go ◽  
Neurofilament Light Chain ◽  
Cross Sectional ◽  
Neurofilament Light ◽  
Neuropsychological Measures ◽  
Low Level ◽  
Neurologic Disability ◽  
Edss Score

ObjectiveThis cross-sectional study aims to assess the association between neuroaxonal damage assessed by serum neurofilament light chain (sNfL) and the Timed Up and Go (TUG)—a reliable and rapid measure of global neurologic disability—in patients with MS.MethodsA total of 41 consecutive patients with MS (38.0 ± 10.4 years; 57% women) with low level of disability (Expanded Disability Status Scale [EDSS] score 0–3) (EDSS score 1.0, interquartile range [IQR] 0.0–2.0) were included in this study. The TUG and sNfL were measured in a 6-month interval, together with a comprehensive neuropsychological and quantitative gait evaluation. The association of sNfL (dependant variable) with TUG, and other gait, cognitive, and behavioral measures (independent variables) were evaluated with multiple linear regressions adjusted for age, sex, and EDSS score.ResultsThe sNfL concentration was 23.51 pg/mL (IQR 16.51–32.21 pg/mL), and the mean TUG was 9.27 ± 1.70 seconds. Only the TUG was associated with sNfL (β = 0.021; 95% CI 0.003–0.037; p = 0.022) (after adjusting for age, sex, and EDSS score), whereas this was not the case for gait and neuropsychological measures.ConclusionsThe TUG—an easy and unexpansive measure of disability—is associated with the degree of neuroaxonal damage, as measured by sNfL, in patients with MS with low level of disability. These findings confirm the validity of the TUG as a reliable bedside measure of global neurologic disability as a result of neuroaxonal damage.

scholarly journals Brain disconnectome mapping and serum neurofilament light levels in multiple sclerosis

2021 ◽  
Author(s):  
Henning H. Rise ◽  
Synne Brune ◽  
Claudia Chien ◽  
Tone Berge ◽  
Steffan D. Bos ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Single Molecule ◽  
Brain Network ◽  
Axonal Damage ◽  
Base Line ◽  
Lesion Volume ◽  
Neurofilament Light Chain ◽  
Random Factor ◽  
Neurofilament Light ◽  
Multiple Sclerosis Patients

AbstractThe pathophysiological mechanisms for classical plaque characteristics and their predictive value for clinical course and outcome in multiple sclerosis is unclear. Connectivity-based approaches incorporating the distribution and magnitude of the extended brain network aberrations caused by lesions may offer higher sensitivity for axonal damage. Using individual brain disconnectome mapping, we tested the longitudinal associations between putative brain network aberrations and levels of serum neurofilament light chain (sNfL) as a neuroaxonal injury biomarker.Multiple sclerosis patients (n = 328, mean age 42.9 years, 71 % female) were prospectively enrolled at four European multiple sclerosis centres, and reassessed after two years (n = 280). Post-processing of 3 Tesla (3T) MRI data was performed at one centre using a harmonized pipeline, and disconnectome maps were calculated using BCBtoolkit based on individual lesion maps. Global disconnectivity (GD) was defined as the average disconnectome probability in each patient’s white matter. Serum NfL concentrations were measured by single molecule array (Simoa). Robust linear mixed models (rLMM) with GD or T2-lesion volume (T2LV) as dependent variables, patient and centre as a random factor, sNfL, age, sex, timepoint for visit, diagnosis, and treatment as fixed factors were run.Robust LMM revealed significant associations between higher levels of GD and increased sNfL (t = 2.30, β = 0.03, p = 0.02), age (t = 5.01, β = 0.32, p < 5.5 × 10−7), and diagnosis progressive multiple sclerosis (PMS); t = 1.97, β = 1.06, p = 0.05), but not for sex (t = 0.78, p = 0.43), treatments (effective; t = 0.85, p = 0.39, highly-effective; t = 0.86, p = 0.39) or sNfL change between base line and two-year follow up (t = −1.65, p = 0.10). Voxel-wise analyses revealed distributed associations in cerebellar and brainstem regions.In our prospective multi-site multiple sclerosis cohort, rLMMs demonstrated that the extent of global brain disconnectivity is sensitive to a systemic biomarker of axonal damage, sNfL, in patients with multiple sclerosis. These findings provide a neuropathological correlate of advanced disconnectome mapping and provide a platform for further investigations of the functional and clinical relevance in patients with brain disorders.

Serum neurofilament light chain is a biomarker of acute and chronic neuronal damage in early multiple sclerosis

2018 ◽  
Vol 25 (5) ◽  
pp. 678-686 ◽  
Author(s):  
Nelly Siller ◽  
Jens Kuhle ◽  
Muthuraman Muthuraman ◽  
Christian Barro ◽  
Timo Uphaus ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Single Molecule ◽  
Light Chain ◽  
Neuronal Damage ◽  
Axonal Damage ◽  
Lesion Volume ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Magnetic Resonance Imaging Mri ◽  
Brain Parenchymal

Background: Monitoring neuronal injury remains one key challenge in early relapsing-remitting multiple sclerosis (RRMS) patients. Upon axonal damage, neurofilament – a major component of the neuro-axonal cytoskeleton – is released into the cerebrospinal fluid (CSF) and subsequently peripheral blood. Objective: To investigate the relevance of serum neurofilament light chain (sNfL) for acute and chronic axonal damage in early RRMS. Methods: sNfL levels were determined in 74 patients (63 therapy-naive) with recently diagnosed clinically isolated syndrome (CIS) or RRMS using Single Molecule Array technology. Standardized 3 T magnetic resonance imaging (MRI) was performed at baseline and 1–3 consecutive follow-ups (42 patients; range: 6–37 months). Results: Baseline sNfL correlated significantly with T2 lesion volume ( r = 0.555, p < 0.0001). There was no correlation between baseline sNfL and age, Expanded Disability Status Scale (EDSS) score or other calculated MRI measures. However, T2 lesion volume increased ( r = 0.67, p < 0.0001) and brain parenchymal volume decreased more rapidly in patients with higher baseline sNfL ( r = −0.623, p = 0.0004). Gd-enhancing lesions correlated positively with sNfL levels. Initiation of disease-modifying treatment led to a significant decrease in sNfL levels. Conclusion: sNfL indicates acute inflammation as demonstrated by correlation with Gd+ lesions. It is a promising biomarker for neuro-axonal damage in early multiple sclerosis (MS) patients, since higher baseline sNfL levels predicted future brain atrophy within 2 years.

scholarly journals Serum Neurofilament Light in Patients with Frontotemporal Dementia Caused by CHMP2B Mutation

2020 ◽  
Vol 49 (6) ◽  
pp. 533-538
Author(s):  
Anders Toft ◽  
Peter Roos ◽  
Olli Jääskeläinen ◽  
Christian Sandøe Musaeus ◽  
Emil Elbæk Henriksen ◽  
...  
Keyword(s):  
Serum Albumin ◽  
Frontotemporal Dementia ◽  
Single Molecule ◽  
Surrogate Marker ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
Neurofilament Light ◽  
Mutation Carriers ◽  
Healthy Family ◽  
Highly Correlated

<b><i>Introduction:</i></b> The potential of neurofilament light (NfL) as a blood-based biomarker is currently being investigated in autosomal dominant neurodegenerative disease. This study explores the clinical utility of serum-NfL in frontotemporal dementia due to <i>CHMP2B</i> mutation (FTD-3). <b><i>Methods:</i></b> This cross-sectional study included serum and CSF data from 38 members of the Danish FTD-3 family: 12 affected <i>CHMP2B</i> mutation carriers, 10 presymptomatic carriers, and 16 noncarriers. Serum-NfL levels measured by single-molecule array (Simoa) technology were tested for associations with the clinical groups and clinical parameters. Serum and CSF data were compared, and CSF/serum-albumin ratio was included as a measure of blood-brain barrier (BBB) function. <b><i>Results:</i></b> Serum-NfL concentrations were significantly increased in symptomatic <i>CHMP2B</i> mutation carriers compared to presymptomatic carriers and in both groups compared to healthy family controls. Serum-NfL levels appear to increase progressively with age in presymptomatic carriers, and this is perhaps followed by a change in trajectory when patients become symptomatic. Measurements of NfL in serum and CSF were highly correlated and fold-changes in serum and CSF between clinical groups were similar. Increase in serum-NFL levels was correlated with reduced ACE-score. Higher CSF/serum-albumin ratios were demonstrated in FTD-3 patients, but this did not affect the significant associations between serum-NfL and clinical groups. <b><i>Conclusion:</i></b> Serum-NfL could be utilized as an accurate surrogate marker of CSF levels to segregate symptomatic <i>CHMP2B</i> carriers, presymptomatic carriers, and non-carriers. The observed indication of BBB dysfunction in FTD-3 patients did not confound this use of serum-NfL. The results support the occurrence of mutation-related differences in NfL dynamics in familial FTD.

scholarly journals NT1-Tau Is Increased in CSF and Plasma of CJD Patients, and Correlates with Disease Progression

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3514
Author(s):  
David Mengel ◽  
Tze How Mok ◽  
Akin Nihat ◽  
Wen Liu ◽  
Robert A. Rissman ◽  
...  
Keyword(s):  
Disease Progression ◽  
Rating Scale ◽  
Functional Decline ◽  
Cross Sectional Study ◽  
Clinical Severity ◽  
Neurofilament Light Chain ◽  
Cross Sectional ◽  
Neurofilament Light ◽  
Custom Made ◽  
Jakob Disease

This study investigates the diagnostic and prognostic potential of different forms of tau in biofluids from patients with Creutzfeldt-Jakob disease (CJD). Extracellular tau, which is molecularly heterogeneous, was measured using ultra-sensitive custom-made Simoa assays for N-terminal (NT1), mid-region, and full-length tau. We assessed cross-sectional CSF and plasma from healthy controls, patients with Alzheimer’s disease (AD) and CJD patients. Then, we evaluated the correlation of the best-performing tau assay (NT1-tau) with clinical severity and functional decline (using the MRC Prion Disease Rating Scale) in a longitudinal CJD cohort (n = 145). In a cross-sectional study, tau measured in CSF with the NT1 and mid-region Simoa assays, separated CJD (n = 15) from AD (n = 18) and controls (n = 21) with a diagnostic accuracy (AUCs: 0.98–1.00) comparable to or better than neurofilament light chain (NfL; AUCs: 0.96–0.99). In plasma, NT1-measured tau was elevated in CJD (n = 5) versus AD (n = 15) and controls (n = 15). Moreover, in CJD plasma (n = 145) NT1-tau levels correlated with stage and rate of disease progression, and the effect on clinical progression was modified by the PRNP codon 129. Our findings suggest that plasma NT1-tau shows promise as a minimally invasive diagnostic and prognostic biomarker of CJD, and should be further investigated for its potential to monitor disease progression and response to therapies.

scholarly journals Plasma neurofilament light chain concentration in the inherited peripheral neuropathies

Neurology ◽  
2018 ◽  
Vol 90 (6) ◽  
pp. e518-e524 ◽  
Author(s):  
Åsa Sandelius ◽  
Henrik Zetterberg ◽  
Kaj Blennow ◽  
Rocco Adiutori ◽  
Andrea Malaspina ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Disease Severity ◽  
Light Chain ◽  
Cross Sectional Study ◽  
Healthy Controls ◽  
Neurofilament Light Chain ◽  
Cross Sectional ◽  
Neurofilament Light ◽  
Charcot Marie Tooth Disease ◽  
Inherited Neuropathies

ObjectiveTo perform a cross-sectional study to determine whether plasma neurofilament light chain (NfL) concentration is elevated in patients with Charcot-Marie-Tooth disease (CMT) and if it correlates with disease severity.MethodsBlood samples were collected from 75 patients with CMT and 67 age-matched healthy controls over a 1-year period. Disease severity was measured using the Rasch modified CMT Examination and neuropathy scores. Plasma NfL concentration was measured using an in-house-developed Simoa assay.ResultsPlasma NfL concentration was significantly higher in patients with CMT (median 26.0 pg/mL) compared to healthy controls (median 14.6 pg/mL, p < 0.0001) and correlated with disease severity as measured using the Rasch modified CMT examination (r = 0.43, p < 0.0001) and neuropathy (r = 0.37, p = 0.044) scores. Concentrations were also significantly higher when subdividing patients by genetic subtype (CMT1A, SPTLC1, and GJB1) or into demyelinating or axonal forms compared to healthy controls.ConclusionThere are currently no validated blood biomarkers for peripheral neuropathy. The significantly raised plasma NfL concentration in patients with CMT and its correlation with disease severity suggest that plasma NfL holds promise as a biomarker of disease activity, not only for inherited neuropathies but for peripheral neuropathy in general.

scholarly journals Serum Neurofilament Light Chain Levels and Myelin Oligodendrocyte Glycoprotein Antibodies in Pediatric Acquired Demyelinating Syndromes

2021 ◽  
Vol 12 ◽  
Author(s):  
Marta Simone ◽  
Claudia Palazzo ◽  
Mariangela Mastrapasqua ◽  
Luca Bollo ◽  
Francesco Pompamea ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Single Molecule ◽  
Light Chain ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Oligoclonal Bands ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Significant Difference ◽  
The Relationship

Introduction: The relationship between serum neurofilament light chain (sNfL) and myelin oligodendrocyte glycoprotein antibody (MOG-Ab) status has not been yet investigated in children with the acquired demyelinating syndrome (ADS).Objective and Methods: The sNfL levels and MOG-Abs were measured by ultrasensitive single-molecule array and cell-based assay in a cohort of 37 children with ADS and negativity for serum anti-aquaporin 4 (AQP4) antibodies. The sNfL levels were compared in MOG-Ab+/MOG-Ab– and in two subgroups MOG-Ab+ with/without encephalopathy.Results: About 40% ADS resulted in MOG-Ab+. MOG-Ab+ were younger at sampling (median = 9.8; range = 2.17–17.5 vs. 14.7/9–17; p = 0.002) with lower frequency of cerebrospinal fluid oligoclonal bands positivity (27% vs. 70%; p = 0.013) compared to MOG-Ab–. About 53% of MOG-Ab+ presented encephalopathy at onset, 1/22 of MOG-Ab– (p = 0.0006). Higher sNfL levels (p = 0.0001) were found in MOG-Ab+ (median/range = 11.11/6.8–1,129) and MOG-Ab– (median/range = 11.6/4.3–788) compared to age-matched controls (median/range = 2.98/1–4.53), without significant difference. MOG-Ab+ with encephalopathy resulted significantly younger at sampling (median/range: 4.5/2.17–11.17 vs. 14.16/9.8–17.5; p = 0.004), had higher sNfL levels (median/range:75.24/9.1–1,129 vs. 10.22/6.83–50.53; p = 0.04), and showed a trend for higher MOG-Ab titer (0.28/0.04–0.69 vs. 0.05/0.04–0.28; p = 0.1) in comparison to those without encephalopathy.Discussion: We confirmed high sNfL levels in pediatric ADS independently from the MOG-Ab status. Encephalopathy at onset is associated more frequently with MOG Ab+ children with higher sNfL levels and MOG titer. These findings suggest a role of acute demyelination in association with axonal damage in the pathogenesis of encephalopathy in pediatric ADS.

scholarly journals Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19

Neurology ◽  
2020 ◽  
Vol 95 (12) ◽  
pp. e1754-e1759 ◽  
Author(s):  
Nelly Kanberg ◽  
Nicholas J. Ashton ◽  
Lars-Magnus Andersson ◽  
Aylin Yilmaz ◽  
Magnus Lindh ◽  
...  
Keyword(s):  
Single Molecule ◽  
Severe Disease ◽  
Plasma Concentrations ◽  
Neuronal Injury ◽  
Cns Injury ◽  
Neurofilament Light Chain ◽  
Cross Sectional ◽  
Neurofilament Light ◽  
Plasma Biomarkers

ObjectiveTo test the hypothesis that coronavirus disease 2019 (COVID-19) has an impact on the CNS by measuring plasma biomarkers of CNS injury.MethodsWe recruited 47 patients with mild (n = 20), moderate (n = 9), or severe (n = 18) COVID-19 and measured 2 plasma biomarkers of CNS injury by single molecule array, neurofilament light chain protein (NfL; a marker of intra-axonal neuronal injury) and glial fibrillary acidic protein (GFAp; a marker of astrocytic activation/injury), in samples collected at presentation and again in a subset after a mean of 11.4 days. Cross-sectional results were compared with results from 33 age-matched controls derived from an independent cohort.ResultsThe patients with severe COVID-19 had higher plasma concentrations of GFAp (p = 0.001) and NfL (p < 0.001) than controls, while GFAp was also increased in patients with moderate disease (p = 0.03). In patients with severe disease, an early peak in plasma GFAp decreased on follow-up (p < 0.01), while NfL showed a sustained increase from first to last follow-up (p < 0.01), perhaps reflecting a sequence of early astrocytic response and more delayed axonal injury.ConclusionWe show neurochemical evidence of neuronal injury and glial activation in patients with moderate and severe COVID-19. Further studies are needed to clarify the frequency and nature of COVID-19–related CNS damage and its relation to both clinically defined CNS events such as hypoxic and ischemic events and mechanisms more closely linked to systemic severe acute respiratory syndrome coronavirus 2 infection and consequent immune activation, as well as to evaluate the clinical utility of monitoring plasma NfL and GFAp in the management of this group of patients.

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