Neurofilament levels, disease activity and brain volume during follow-up in multiple sclerosis (original) (raw)
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The CSF Profile Linked to Cortical Damage Predicts Multiple Sclerosis Activity
Annals of Neurology, 2020
Objective. Intrathecal inflammation correlates with the grey matter damage since the early stages of Multiple Sclerosis (MS), but whether the cerebrospinal fluid (CSF) profile can help to identify patients at risk of disease activity is still unclear. Methods. We evaluated the association between CSF levels of 18 cytokines, previously found to be associated to grey matter damage, and the disease activity, among 99 relapsing-remitting MS patients, who underwent blinded clinical and 3T-MRI evaluations for 4 years. Groups with (EDA) or without (NEDA) evidence of disease activity (occurrence of relapses, new white matter lesions, EDSS change) were identified. Cortical lesions and the annualized cortical thinning were also evaluated. Results. Fortyone patients experienced EDA and, compared to the NEDA group, had at diagnosis higher CSF levels of CXCL13, CXCL12, IFNγ, TNF, sCD163, LIGHT and APRIL (p<0.001). In the multivariate analysis, CXCL13 (HR=1.35, p=0.0002), LIGHT (HR=1.22, p=0.005) and APRIL (HR=1.78, p=0.0001) were the CSF molecules more strongly associated with the risk of EDA. The model including CSF variables predicted more accurately the occurrence of disease activity than the model with only clinical/MRI parameters (C-index at 4 years= 71% vs 44%). Finally, higher CSF levels of CXCL13 (β=4.7*10-4 ,p<0.001), TNF (β=3.1*10-3 ,p=0.004), LIGHT (β=2.6*10-4 ,p=0.003), sCD163 (β=4.3*10-3 ,p=0.009) and TWEAK (β=3.4*10-3 ,p=0.024) were associated with more severe cortical thinning.
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.
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...
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 chain serum levels correlate with 10‐year MRI outcomes in multiple sclerosis
Annals of Clinical and Translational Neurology, 2018
Objective: To assess the value of annual serum neurofilament light (NfL) measures in predicting 10-year clinical and MRI outcomes in multiple sclerosis (MS). Methods: We identified patients in our center's Comprehensive Longitudinal Investigations in MS at Brigham and Women's Hospital (CLIMB) study enrolled within 5 years of disease onset, and with annual blood samples up to 10 years (n = 122). Serum NfL was measured using a single molecule array (SIMOA) assay. An automated pipeline quantified brain T2 hyperintense lesion volume (T2LV) and brain parenchymal fraction (BPF) from year 10 high-resolution 3T MRI scans. Correlations between averaged annual NfL and 10-year clinical/MRI outcomes were assessed using Spearman's correlation, univariate, and multivariate linear regression models. Results: Averaged annual NfL values were negatively associated with year 10 BPF, which included averaged year 1-5 NfL values (unadjusted P < 0.01; adjusted analysis P < 0.01), and averaged values through year 10. Linear regression analyses of averaged annual NfL values showed multiple associations with T2LV, specifically averaged year 1-5 NfL (unadjusted P < 0.01; adjusted analysis P < 0.01). Approximately 15-20% of the BPF variance and T2LV could be predicted from early averaged annual NfL levels. Also, averaged annual NfL levels with fatigue score worsening between years 1 and 10 showed statistically significant associations. However, averaged NfL measurements were not associated with year 10 EDSS, SDMT or T25FW in this cohort. Interpretation: Serum NfL measured during the first few years after the clinical onset of MS contributed to the prediction of 10-year MRI brain lesion load and atrophy.
Multiple sclerosis (Houndmills, Basingstoke, England), 2015
Background: 'No evidence of disease activity' (NEDA), defined as absence of magnetic resonance imaging activity (T2 and/or gadolinium-enhanced T1 lesions), relapses and disability progression ('NEDA-3'), is used as a comprehensive measure of treatment response in relapsing multiple sclerosis (RMS), but is weighted towards inflammatory activity. Accelerated brain volume loss (BVL) occurs in RMS and is an objective measure of disease worsening and progression. Objective: To assess the contribution of individual components of NEDA-3 and the impact of adding BVL to NEDA-3 ('NEDA-4') Methods: We analysed data pooled from two placebo-controlled phase 3 fingolimod trials in RMS and assessed NEDA-4 using different annual BVL mean rate thresholds (0.2%-1.2%). Results: At 2 years, 31.0% (217/700) of patients receiving fingolimod 0.5 mg achieved NEDA-3 versus 9.9% (71/715) on placebo (odds ratio (OR) 4.07; p < 0.0001). Adding BVL (threshold of 0.4%), the respective proportions of patients achieving NEDA-4 were 19.7% (139/706) and 5.3% (38/721; OR 4.41; p < 0.0001). NEDA-4 status favoured fingolimod across all BVL thresholds tested (OR 4.01-4.41; p < 0.0001). Conclusion: NEDA-4 has the potential to capture the impact of therapies on both inflammation and neurodegeneration, and deserves further evaluation across different compounds and in long-term studies.
CSF neurofilament and N-acetylaspartate related brain changes in clinically isolated syndrome
Multiple Sclerosis Journal, 2013
Background: Axonal damage is considered a major cause of disability in multiple sclerosis (MS) and may start early in the disease. Specific biomarkers for this process are of great interest. Objective: To study if cerebrospinal fluid (CSF) biomarkers for axonal damage reflect and predict disease progression already in the earliest stages of the disease, that is, in clinically isolated syndrome (CIS). Methods: We assessed CSF levels of neurofilament heavy (NFH), neurofilament light (NFL) and N-acetylaspartate (NAA) in 67 patients with CIS and 18 controls with neuropsychiatric diseases of non-inflammatory aetiology (NC). Patients with CIS underwent baseline magnetic resonance imaging (MRI) at 3T, and a follow-up MRI after 1 year was obtained in 28 of them. Results: Compared with NC, patients with CIS had higher NFH (p=0.05) and NFL (p<0.001) levels. No significant group differences were found for NAA. Patients' NFH levels correlated with physical disability (r=0.304, p<0.05) and with change in brain volume over 1 year of follow-up (r=-0.518, p<0.01) but not with change in T2 lesion load. Conclusion: Our results confirm increased neurofilament levels already in CIS being related to the level of physical disability. The association of NFH levels with brain volume but not lesion volume changes supports the association of these markers with axonal damage.
Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology
JAMA Neurology, 2019
; and the NFL Group IMPORTANCE Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date. OBJECTIVES To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions. DATA SOURCES PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC. STUDY SELECTION Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex. DATA EXTRACTION AND SYNTHESIS Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept. MAIN OUTCOME AND MEASURE The cNfL levels adjusted for age and sex across diagnoses. RESULTS Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes. CONCLUSIONS AND RELEVANCE These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia, 2021
BACKGROUND Neurofilament light chain is a promising biomarker of disease activity and treatment response in relapsing-remitting multiple sclerosis (MS). Its role in progressive MS is less clear. AIM The aim of the study was to assess the relationship between plasma neurofilament light chain (pNfL) and disease activity as defined by the concept NEDA-3 (No Evident Disease Activity), and brain volumetry, in a cohort of patients with the progressive disease form (PMS). METHODS Levels of pNfL (SIMOA technology) were examined in 52 PMS patients and analysed in relationship to NEDA-3 status and annual brain volume loss (BVL) during the last 12 months. The statistical model was developed using logistic regression analysis, including demographic, clinical and magnetic resonance imaging (MRI) data as independent variables. Dependent variables were NEDA-3 status and BVL. RESULTS The mean age of the study participants (n=52, 50% females) was 45.85 (SD, 9.82) and the median disability score was ...
Lancet EBiomedicine, 2024
Neurofilament light chain (NfL) is a long-awaited blood biomarker that can provide clinically useful information about prognosis and therapeutic efficacy in multiple sclerosis (MS). There is now substantial evidence for this biomarker to be used alongside magnetic resonance imaging (MRI) and clinical measures of disease progression as a decision-making tool for the management of patients with MS. Serum NfL (sNfL) has certain advantages over traditional measures of MS disease progression such as MRI because it is relatively noninvasive, inexpensive, and can be repeated frequently to monitor activity and treatment efficacy. sNfL levels can be monitored regularly in patients with MS to determine change from baseline and predict subclinical disease activity, relapse risk, and the development of gadolinium-enhancing (Gd+) lesions. sNfL does not replace MRI, which provides information related to spatial localisation and lesion stage. Laboratory platforms are starting to be made available for clinical application of sNfL in several countries. Further work is needed to resolve issues around comparisons across testing platforms (absolute values) and normalisation (reference ranges) in order to guide interpretation of the results.