Neurofilament protein in cerebrospinal fluid: a potential marker of activity in multiple sclerosis (original) (raw)
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Neurofilament protein in cerebrospinal fluid: A marker of white matter changes
Journal of Neuroscience Research, 2001
The neurofilament protein is a major structural protein of neurons and a marker for axonal damage. The concentrations of the light subunit of the neurofilament triplet protein (NFL) in CSF were significantly increased in patients with relapsing-remitting multiple sclerosis compared with healthy controls (p<0.001). Seventy eight per cent of patients with multiple sclerosis showed increased NFL concentrations. Significant correlations between the NFL concentration in CSF and clinical indices were discerned for disability, exacerbation rate, and time from the start of the previous exacerbation to the time of the lumbar puncture. The results suggest that axonal damage occurs during relapsing-remitting multiple sclerosis and that the damage contributes to disability and the appearance of clinical exacerbations. The concentration of NFL in CSF is a potential marker of disease activity in multiple sclerosis and might be useful in future clinical trials of multiple sclerosis.
Neurofilament Proteins as Body Fluid Biomarkers of Neurodegeneration in Multiple Sclerosis
Multiple Sclerosis International, 2011
Biomarkers of axonal degeneration have the potential to improve our capacity to predict and monitor neurological outcome in multiple sclerosis (MS) patients. Neurofilament proteins, one of the major proteins expressed within neurons and axons, have been detected in cerebrospinal fluid and blood samples from MS patients and are now being actively investigated for their utility as prognostic indicators of disease progression in MS. In this paper, we summarize the current literature on neurofilament structure, assembly, and degeneration and discuss their potential utility as biomarkers for monitoring neurological decline in MS. We also discuss the need to further develop sensitive methods for assaying neurofilaments in blood to improve clinical applicability.
Cytoskeletal proteins in the cerebrospinal fluid as biomarker of multiple sclerosis
Neurological Sciences, 2013
The axonal cytoskeleton is a finely organized system, essential for maintaining the integrity of the axon. Axonal degeneration is implicated in the pathogenesis of unremitting disability of multiple sclerosis (MS). Purpose of this study is to evaluate levels of cytoskeletal proteins such as neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), and b-tubulin (b-Tub) isoforms II and III in the cerebrospinal fluid (CSF) of MS patients and their correlation with MS clinical indices. CSF levels of cytoskeletal proteins were determined in 51 patients: 33 with MS and 18 with other neurological diseases (OND). NFL, GFAP and b-Tub II proteins were significantly higher (p \ 0.0001) in MS than in OND group; no significant difference (p [ 0.05) was found between MS and OND with regard to b-Tub III. Interestingly, levels of b-Tub III and NFL were higher in progressive than in remitting MS forms; on the contrary, higher levels of b-Tub II and GFAP were found in remitting MS forms. However, with the exception of b-Tub III, all proteins tend to decrease their CSF levels concomitantly with the increasing disability (EDSS) score. Overall, our results might indicate b-Tub II as a potential candidate for diagnostic and b-Tub III as a possible prognostic biomarker of MS. Therefore, further analyses are legitimated and desirable.
European Journal of Neurology, 2017
Background and purposeImproved biomarkers are needed to facilitate clinical decision‐making and as surrogate endpoints in clinical trials in multiple sclerosis (MS). We assessed whether neurodegenerative and neuroinflammatory markers in cerebrospinal fluid (CSF) at initial sampling could predict disease activity during 2 years of follow‐up in patients with clinically isolated syndrome (CIS) and relapsing–remitting MS.MethodsUsing multiplex bead array and enzyme‐linked immunosorbent assay, CXCL1, CXCL8, CXCL10, CXCL13, CCL20, CCL22, neurofilament light chain (NFL), neurofilament heavy chain, glial fibrillary acidic protein, chitinase‐3‐like‐1, matrix metalloproteinase‐9 and osteopontin were analysed in CSF from 41 patients with CIS or relapsing–remitting MS and 22 healthy controls. Disease activity (relapses, magnetic resonance imaging activity or disability worsening) in patients was recorded during 2 years of follow‐up in this prospective longitudinal cohort study.ResultsIn a logis...
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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.
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...
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...
Neurofilament levels, disease activity and brain volume during follow-up in multiple sclerosis
Journal of Neuroinflammation
Background: There is a need for clinically useful biomarkers of disease activity in clinically isolated syndrome (CIS) and relapsing remitting MS (RRMS). The aim of this study was to assess the correlation between neurofilament light chain (NFL) in cerebrospinal fluid (CSF) and serum and the relationship between NFL and other biomarkers, subsequent disease activity, and brain volume loss in CIS and RRMS. Methods: A panel of neurodegenerative and neuroinflammatory markers were analyzed in repeated CSF samples from 41 patients with CIS or RRMS in a prospective longitudinal cohort study and from 22 healthy controls. NFL in serum was analyzed using a single-molecule array (Simoa) method. "No evidence of disease activity-3" (NEDA-3) status and brain volume (brain parenchymal fraction calculated using SyMRI®) were recorded during 4 years of follow-up. Results: NFL levels in CSF and serum correlated significantly (all samples, n = 63, r 0.74, p < 0.001), but CSF-NFL showed an overall stronger association profile with NEDA-3 status, new T2 lesions, and brain volume loss. CSF-NFL was associated with both new T2 lesions and brain volume loss during follow-up, whereas CSF-CHI3L1 was associated mainly with brain volume loss and CXCL1, CXCL10, CXCL13, CCL22, and MMP-9 were associated mainly with new T2 lesions. Conclusions: Serum and CSF levels of NFL correlate, but CSF-NFL predicts and reflects disease activity better than S-NFL. CSF-NFL levels are associated with both new T2 lesions and brain volume loss. Our findings further add to the accumulating evidence that CSF-NFL is a clinically useful biomarker in CIS and RRMS and should be considered in the expanding NEDA concept. CSF-CXCL10 and CSF-CSF-CHI3L1 are potential markers of disease activity and brain volume loss, respectively.
Journal of Clinical Medicine
Background: Given the significant role of neurodegeneration in the progression of multiple sclerosis (MS) and insufficient therapies, there is an urgent need to better understand this pathology and to find new biomarkers that could provide important insight into the biological mechanisms of the disease. Thus, the present study aimed to compare different neurodegeneration and axonal dysfunction biomarkers in MS and verify their potential clinical usefulness. Methods: A total of 59 patients, who underwent CSF analysis during their diagnostics, were enrolled in the study. Quantitative analysis of neurodegeneration biomarkers was performed through immunological tests. Oligoclonal bands were detected by isoelectric focusing on agarose gel, whereas the concentrations of immunoglobulins and albumin were measured using nephelometry. Results: Our studies showed that NfL, RTN4, and tau protein enabled the differentiation of MS patients from the control group. Additionally, the baseline CSF Nf...
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