Serum Phosphorylated Neurofilament Heavy Chain Is a Marker of Axonal Loss in Experimental Optic Neuritis (original) (raw)
Related papers
Serum phosphorylated neurofilament-heavy chain levels in multiple sclerosis patients
Journal of Neurology, Neurosurgery & Psychiatry, 2014
Objectives We evaluated whether the measurement of serum phosphorylated neurofilament heavy chain ( pNF-H) titre is likely to be a valid biomarker of axonal injury in multiple sclerosis (MS). Methods Serum pNF-H concentrations were measured by ELISA in cases with relapsing-remitting (RR)-MS (n=81), secondary progressive (SP) MS (n=13) and primary progressive (PP)-MS; n=6) MS; first demyelinating event (FDE; n=82); and unaffected controls (n=135). A subset of MS cases (n=45) were resampled on one or multiple occasions. The Multiple Sclerosis Severity Score (MSSS) and MRI measures were used to evaluate associations between serum pNF-H status, disease severity and cerebral lesion load and activity.
F1000 - Post-publication peer review of the biomedical literature
Objective: Neurofilament light chains (NfL) are unique to neuronal cells, are shed to the cerebrospinal fluid (CSF), and are detectable at low concentrations in peripheral blood. Various diseases causing neuronal damage have resulted in elevated CSF concentrations. We explored the value of an ultrasensitive single-molecule array (Simoa) serum NfL (sNfL) assay in multiple sclerosis (MS). Methods: sNfL levels were measured in healthy controls (HC, n 5 254) and two independent MS cohorts: (1) crosssectional with paired serum and CSF samples (n 5 142), and (2) longitudinal with repeated serum sampling (n 5 246, median follow-up 5 3.1 years, interquartile range [IQR] 5 2.0-4.0). We assessed their relation to concurrent clinical, imaging, and treatment parameters and to future clinical outcomes. Results: sNfL levels were higher in both MS cohorts than in HC (p < 0.001). We found a strong association between CSF NfL and sNfL (b 5 0.589, p < 0.001). Patients with either brain or spinal (43.4pg/ml, IQR 5 25.2-65.3) or both brain and spinal gadolinium-enhancing lesions (62.5pg/ml, IQR 5 42.7-71.4) had higher sNfL than those without (29.6pg/ml, IQR 5 20.9-41.8; b 5 1.461, p 5 0.005 and b 5 1.902, p 5 0.002, respectively). sNfL was independently associated with Expanded Disability Status Scale (EDSS) assessments (b 5 1.105, p < 0.001) and presence of relapses (b 5 1.430, p < 0.001). sNfL levels were lower under disease-modifying treatment (b 5 0.818, p 5 0.003). Patients with sNfL levels above the 80th, 90th, 95th, 97.5th, and 99th HC-based percentiles had higher risk of relapses (97.5th percentile: incidence rate ratio 5 1.94, 95% confidence interval [CI] 5 1.21-3.10, p 5 0.006) and EDSS worsening (97.5th percentile: OR 5 2.41, 95% CI 5 1.07-5.42, p 5 0.034). Interpretation: These results support the value of sNfL as a sensitive and clinically meaningful blood biomarker to monitor tissue damage and the effects of therapies in MS.
Ultrasensitive immunoassay allows measurement of serum neurofilament heavy in multiple sclerosis
Multiple Sclerosis and Related Disorders, 2021
Background: Neurofilament heavy (NfH) is a promising biomarker for neuro-axonal damage in Multiple Sclerosis (MS). We compared the performance of high-sensitivity serum-NfH immunoassays, with as aim to investigate the value of serum-NfH as biomarker for MS. Methods: We measured serum-NfH in 76 MS patients with Simoa (one commercial, one in-house) or Luminex assays. Serum-NfH measured by the immunoassay with greatest sensitivity was related to clinical and radiological outcomes with age and sex-adjusted linear regression analysis, and to biological outcomes cerebrospinal fluid (CSF)-NfH, serum neurofilament light (NfL) and CSF-NfL with Spearman's correlation analysis. Results: With the commercial Simoa assay, we obtained 100% serum-NfH detectability (in-house Simoa: 70%, Luminex: 61%), with lowest coefficient of variation (CV) between duplicates of 11%CV (in-house Simoa: 22%CV, Luminex: 30%CV). Serum-NfH quantified with the commercial Simoa assay was associated with disease duration (standardized beta (sβ) = 0.28, p = 0.034), T2 lesion volume (sβ = 0.23, p = 0.041), and tended to associate with black hole count (sβ = 0.21, p = 0.084) but not with Expanded Disease Disability Score (EDSS) or normalized brain volume (all: p>0.10). Furthermore, serum-NfH showed correlations with CSF-NfH (rho = 0.27, p = 0.018) and serum-NfL (rho=0.44, p < 0.001), but not with CSF-NfL. Conclusions: Serum-NfH can be quantified with high-sensitivity technology. Cross-sectionally, we observed some weak correlations of serum-NfH with MS disease burden parameters, suggesting there might be some utility for serum-NfH as biomarker for MS disease burden.
Neurofilament light in CSF and serum is a sensitive marker for axonal white matter injury in MS
Neurology - Neuroimmunology Neuroinflammation, 2016
Objective: In an ongoing, open-label, phase 1b study on the intrathecal administration of rituximab for progressive multiple sclerosis, an intraventricular catheter was inserted for drug delivery. The objective of this study was to characterize the limited white matter axonal injury evoked by catheter insertion by analyzing a panel of markers for tissue damage in CSF and serum. Methods: Lumbar CSF and serum were collected before catheter insertion and at regular intervals during the follow-up period of 1 year. Levels of neurofilament light polypeptide (NF-L), glial fibrillary acidic protein, microtubule-associated protein tau, and S100 calcium binding protein B were measured in the CSF, and NF-L was also quantified in serum at each time point. Results: One month after neurosurgical trauma, there was a distinct peak in NF-L concentration in both CSF and serum. In contrast, the biomarkers S100 calcium binding protein B, glial fibrillary acidic protein, and microtubule-associated protein tau did not show any significant changes. NF-L levels in both CSF and serum peaked at 1 month post surgery, returning to baseline after 6 to 9 months. A strong correlation was observed between the concentrations of NF-L in CSF and serum. Conclusions: The NF-L level, in CSF and serum, appears to be both a sensitive and specific marker for white matter axonal injury. This makes NF-L a valuable tool with which to evaluate acute white matter axonal damage in a clinical setting. Serum analysis of NF-L may become a convenient way to follow white matter axonal damage longitudinally.
Axonal damage accumulates in the progressive phase of multiple sclerosis: three year follow up study
Journal of Neurology Neurosurgery and Psychiatry, 2005
BACKGROUND: Neurofilament phosphoforms (Nf) are principal components of the axoskeleton released during axonal injury. Cerebrospinal fluid (CSF) levels of Nf phosphoforms might be useful surrogate markers for disability in multiple sclerosis (MS), aid in distinguishing clinical subtypes, and provide valuable prognostic information. METHOD: Thirty four patients with MS were included in a three year follow up study along with 318
International Journal of Molecular Sciences
Neurofilament light chain (NfL), is a neuron-specific cytoskeletal protein detected in extracellular fluid following axonal damage. Extensive research has focused on NfL quantification in CSF, establishing it as a prognostic biomarker of disability progression in Multiple Sclerosis (MS). Our study used a new commercially available Enzyme-Linked Immunosorbent Assay (ELISA) kit and Single Molecular Array (Simoa) advanced technology to assess serum NfL levels in MS patients and Healthy Controls (HC). Verifying the most accurate, cost-effective methodology will benefit its application in clinical settings. Blood samples were collected from 54 MS patients and 30 HC. Protocols accompanying the kits were followed. The ELISA thershold was set as 3 S.D. above the mean of the HC. For Simoa, the Z-score calculation created by Jens Kuhle’s group was applied (with permission). Samples exceeding the threshold or z-score ≥1.5 indicated subclinical disease activity. To our knowledge, this is the fi...
Journal of Neurology, 2014
Background and purpose: Primary and secondary progressive forms of multiple sclerosis (PPMS and SPMS) have different pathological characteristics. However, it is unknown whether neurodegenerative mechanisms are shared. Methods: We measured cerebrospinal fluid (CSF) levels of neurofilament (Nf) light and heavy isoforms and N-acetylaspartic acid (NAA) in 21 PP, 10 SPMS patients and 15 non-inflammatory neurological disease controls (NINDC). Biomarkers were related to EDSS (Expanded Disability Status Scale) and MSSS (Multiple Sclerosis Severity Score) over a long period of follow-up (median (interquartile range) 9 (5.5-12.5) years) in 19 PPMS and 4 SPMS patients, and to T2 lesion load (T2LL), T1 lesion load (T1LL), and brain parenchymal fraction (BPF) at time of lumbar puncture. Results: Nf light was higher in PPMS (p<0.005) and Nf heavy was increased in both SPMS and PPMS (p<0.05 and p<0.01) compared to NINDC, but were comparable between the two MS subtypes. Nf heavy was a predictor of the ongoing disability
Multiple sclerosis: Neurofilament light chain antibodies are correlated to cerebral atrophy
Neurology, 2003
To evaluate markers of axonal damage in CSF and serum of patients with different subtypes of MS in relation to measures of disease progression on MRI. Methods: In 51 patients with MS (21 relapsing-remitting, 20 secondary progressive, 10 primary progressive), levels of heavy and light neurofilaments (NfH and NfL) and antibodies to neurofilaments (anti-NfL and-NfH) as well as the total immunoglobulin G (IgG) were analyzed. MRI analysis included T2 hyperintense, T1 hypointense, and gadolinium enhancing lesions and markers of cerebral atrophy (ventricular and parenchymal fractions). Results: For the total group, correlations were found between the anti-NfL index and the parenchymal fraction (PF) (r ϭ Ϫ0.51, p Ͻ 0.001), T2 lesion load (r ϭ 0.41, p Ͻ 0.05), ventricular fraction (r ϭ 0.37, p Ͻ 0.05), and T1 lesion load (r ϭ 0.37, p Ͻ 0.05). For the anti-NfH index, a correlation was found with the PF (r ϭ Ϫ0.39, p Ͻ 0.05). No correlations were found between the IgG index and MRI measures. Conclusions: Intrathecal production of anti-NfL antibodies may serve as a marker of tissue damage, particularly axonal loss, in MS.
Validation of a novel biomarker for acute axonal injury in experimental autoimmune encephalomyelitis
Journal of Neuroscience Research, 2008
In multiple sclerosis, inflammatory axonal injury is a key pathological mechanism responsible for the development of progressive neurological dysfunction. The injured axon represents a therapeutic target in this disease; however, therapeutic trials of neuroprotective candidates will initially require preclinical testing in an animal model of inflammatory axonal injury and subsequently the development of a reliable paraclinical measure of axonal degeneration in humans. In the present study, we demonstrate the validity of serum phosphorylated neurofilament H (pNF-H) as a marker of axonal injury in murine experimental autoimmune encephalomyelitis (EAE). At the time of maximum disease severity (EAE day 22), the average serum pNF-H level reached 5.7 ng/ml, correlating significantly with the EAE paraplegia score (r 5 0.75, P < 0.001). On average, 40% of axons in the spinal cord were lost in EAE, and serum pNF-H levels were highly correlated with axon loss (r 5 0.8, P < 0.001). Axonal injury was a severe and acute event, insofar as serum pNF-H levels were not significantly elevated at early (EAE day 12) or late (EAE days 35 and 50) disease time points. Our results demonstrate that acute inflammatory axonal injury is a pathological feature of murine MOG 35-55 EAE, indicating that this model may mirror the acute pathological events in active multiple sclerosis lesions. Furthermore, we have validated the serum pNF-H assay as an unbiased measurement of axonal injury in EAE, facilitating rapid screening of potential neuroprotective therapies in this model. V V C 2008 Wiley-Liss, Inc.
A comparative study of CSF neurofilament light and heavy chain protein in MS
Multiple Sclerosis Journal, 2013
Background: There is a lack of reliable biomarkers of axonal degeneration. Neurofilaments are promising candidates to fulfil this task. We compared two highly sensitive assays to measure two subunits of the neurofilament protein (neurofilament light (NfL) and neurofilament heavy chain (NfH)). Methods: We evaluated the analytical and clinical performance of the UmanDiagnostics NF-light® enzyme-linked immunosorbent assay (ELISA) in the cerebrospinal fluid (CSF) of a group of 148 patients with clinically isolated syndrome (CIS) or multiple sclerosis (MS), and 72 controls. We compared our results with referring levels of our previously-developed CSF NfHSMI35 assay. Results: Exposure to room temperature (up to 8 days) or repetitive thawing (up to 4 thaws) did not influence measurement of NfL concentrations. Values of NfL were higher in all disease stages of CIS/MS, in comparison to controls ( p ≤ 0.001). NfL levels correlated with the Expanded Disability Status Scale (EDSS) score in pati...