Monitoring disease activity in multiple sclerosis using serum neurofilament light protein.
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ABSTRACT: Objective
To examine the effects of disease activity, disability, and disease-modifying therapies (DMTs) on serum neurofilament light (NFL) and the correlation between NFL concentrations in serum and CSF in multiple sclerosis (MS).Methods
NFL concentrations were measured in paired serum and CSF samples (n = 521) from 373 participants: 286 had MS, 45 had other neurologic conditions, and 42 were healthy controls (HCs). In 138 patients with MS, the serum and CSF samples were obtained before and after DMT treatment with a median interval of 12 months. The CSF NFL concentration was measured with the UmanDiagnostics NF-light enzyme-linked immunosorbent assay. The serum NFL concentration was measured with an in-house ultrasensitive single-molecule array assay.Results
In MS, the correlation between serum and CSF NFL was r = 0.62 (p < 0.001). Serum concentrations were significantly higher in patients with relapsing-remitting MS (16.9 ng/L) and in patients with progressive MS (23 ng/L) than in HCs (10.5 ng/L, p < 0.001 and p < 0.001, respectively). Treatment with DMT reduced median serum NFL levels from 18.6 (interquartile range [IQR] 12.6-32.7) ng/L to 15.7 (IQR 9.6-22.7) ng/L (p < 0.001). Patients with relapse or with radiologic activity had significantly higher serum NFL levels than those in remission (p < 0.001) or those without new lesions on MRI (p < 0.001).Conclusions
Serum and CSF NFL levels were highly correlated, indicating that blood sampling can replace CSF taps for this particular marker. Disease activity and DMT had similar effects on serum and CSF NFL concentrations. Repeated NFL determinations in peripheral blood for detecting axonal damage may represent new possibilities in MS monitoring.
SUBMITTER: Novakova L
PROVIDER: S-EPMC5705244 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveTo understand how longitudinal serum neurofilament light chain (sNfL) patterns can inform its use as a prognostic biomarker in multiple sclerosis (MS) and evaluate whether sNfL reflects MS disease activity and disease-modifying therapy usage.MethodsThis was a post hoc analysis of longitudinal data and samples from the ADVANCE trial (NCT00906399) of patients with relapsing-remitting MS (RRMS). sNfL was measured every 3 months for 2 years, then every 6 months for 4 years. Regression models explored how sNfL data predicted 4-year values of brain volume, expanded disability status scale score, and T2 lesions. sNfL levels were assessed in those receiving placebo, peginterferon beta-1a, and those with disease activity.ResultsBaseline sNfL was a predictor of 4-year brain atrophy and development of new T2 lesions. Clinical (p = 0.02) and magnetic resonance imaging (MRI) (p < 0.01) outcomes improved in those receiving peginterferon beta-1a whose sNfL decreased to <16 pg/mL after 12 months versus those whose sNfL remained ⩾16 pg/mL. Mean sNfL levels decreased in peginterferon beta-1a-treated patients and increased in placebo-treated patients (-9.5% vs. 6.8%; p < 0.01). sNfL was higher and more variable in patients with evidence of active MS.ConclusionThese data support sNfL as a prognostic and disease-monitoring biomarker for RRMS.
| S-EPMC8414824 | biostudies-literature
Project description: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).sNfL levels were measured in healthy controls (HC, n = 254) and two independent MS cohorts: (1) cross-sectional with paired serum and CSF samples (n = 142), and (2) longitudinal with repeated serum sampling (n = 246, median follow-up = 3.1 years, interquartile range [IQR] = 2.0-4.0). We assessed their relation to concurrent clinical, imaging, and treatment parameters and to future clinical outcomes.sNfL levels were higher in both MS cohorts than in HC (p < 0.001). We found a strong association between CSF NfL and sNfL (? = 0.589, p < 0.001). Patients with either brain or spinal (43.4pg/ml, IQR = 25.2-65.3) or both brain and spinal gadolinium-enhancing lesions (62.5pg/ml, IQR = 42.7-71.4) had higher sNfL than those without (29.6pg/ml, IQR = 20.9-41.8; ? = 1.461, p = 0.005 and ? = 1.902, p = 0.002, respectively). sNfL was independently associated with Expanded Disability Status Scale (EDSS) assessments (? = 1.105, p < 0.001) and presence of relapses (? = 1.430, p < 0.001). sNfL levels were lower under disease-modifying treatment (? = 0.818, p = 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 = 1.94, 95% confidence interval [CI] = 1.21-3.10, p = 0.006) and EDSS worsening (97.5th percentile: OR = 2.41, 95% CI = 1.07-5.42, p = 0.034).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. Ann Neurol 2017;81:857-870.
| S-EPMC5519945 | biostudies-literature
Project description:ImportanceUnrecognized demyelinating events often precede the clinical onset of multiple sclerosis (MS). Identification of these events at the time of occurrence would have implications for early diagnosis and the search of causal factors for the disease.ObjectiveTo assess whether serum neurofilament light chain (sNfL) levels are elevated before the clinical MS onset.Design, setting, and participantsNested case-control study among US military personnel who have serum samples stored in the US Department of Defense Serum Repository. Serum samples were collected from 2000 to 2011; sNfL assays and data analyses were performed from 2018 to 2019. We selected 60 case patients with MS who either had 2 samples collected before onset (mean follow-up, 6.3 years) or 1 sample collected before and 1 after onset (mean follow-up, 1.3 years), among 245 previously identified case patients. For each case, we randomly selected 1 of 2 previously identified control individuals matched by age, sex, race/ethnicity, and dates of sample collection. The sample size was chosen based on the available funding.ExposuresSerum NfL concentrations measured using an ultrasensitive single-molecule array assay (Simoa).Main outcomes and measurementsLog-transformed sNfL concentrations in case patients and control individuals compared using conditional logistic regression and linear mixed models.ResultsMean age at baseline was 27.5 years, and 92 of 120 participants (76.7%) were men. Serum NfL levels were higher in case patients with MS compared with their matched control individuals in samples drawn a median of 6 years (range, 4-10 years) before the clinical onset (median, 16.7 pg/mL; interquartile range [IQR], 12.6-23.1 pg/mL vs 15.2 pg/m; IQR, 10.3-19.9 pg/mL; P = .04). This difference increased with decreasing time to the case clinical onset (estimated coefficient for interaction with time = 0.063; P = .008). A within-person increase in presymptomatic sNfL levels was associated with higher MS risk (rate ratio for ≥5 pg/mL increase, 7.50; 95% CI, 1.72-32.80). The clinical onset was associated with a marked increase in sNfL levels (median, 25.0; IQR, 17.1-41.3 vs 45.1; IQR, 27.0-102.7 pg/mL for presymptomatic and postonset MS samples; P = .009).Conclusions and relevanceThe levels of sNfL were increased 6 years before the clinical MS onset, indicating that MS may have a prodromal phase lasting several years and that neuroaxonal damage occurs already during this phase.
| S-EPMC6745051 | biostudies-literature
Project description:Background and Objectives Adapted ketogenic diet (AKD) and caloric restriction (CR) have been suggested as alternative therapeutic strategies for multiple sclerosis (MS), but information on their impact on neuroaxonal damage is lacking. Thus, we explored the impact of diets on serum neurofilament light chain (sNfL) levels in patients with relapsing-remitting MS. Methods We retrospectively evaluated a prospective randomized controlled trial of 60 patients with MS who were on a common diet or ketogenic diet or fasting. We examined sNfL levels of 40 participants at baseline and at the end of the study after 6 months using single molecule array assay. Results sNfL levels were investigated in 9 controls, 14 participants on CR, and 17 participants on AKD. Correlation analysis showed an association of sNfL with age and disease duration; an association was also found between sNfL and the Multiple Sclerosis Functional Composite. AKD significantly reduced sNfL levels at 6 months compared with the common diet group (p = 0.001). Discussion For clinical or study use, consider that AKD may incline sNfL levels independent of relapse activity up to 3 months after initiation. At 6 months, AKD, which complements current therapies, reduced sNfL levels, therefore suggesting potential neuroprotective effects in MS. A single cycle of seven-day fasting did not affect sNfL. AKD may be an addition to the armamentarium to help clinicians support patients with MS in a personalized manner with tailored diet strategies.
| S-EPMC8587737 | biostudies-literature
Project description:ObjectiveTo investigate the association of combined serum neurofilament light chain (sNfL) and retinal optical coherence tomography (OCT) measurements with future disease activity in patients with early multiple sclerosis (MS).MethodsWe analyzed sNfL by single molecule array technology and performed OCT measurements in a prospective cohort of 78 patients with clinically isolated syndrome and early relapsing-remitting MS with a median (interquartile range) follow-up of 23.9 (23.3-24.7) months. Patients were grouped into those with abnormal or normal sNfL levels, defined as sNfL ≥/<80th percentile of age-corrected reference values. Likewise, patients were grouped by a median split into those with thin or thick ganglion cell and inner plexiform layer (GCIP), peripapillary retinal nerve fiber layer, and inner nuclear layer in nonoptic neuritis eyes. Outcome parameters were violation of no evidence of disease activity (NEDA-3) criteria or its components.ResultsPatients with abnormal baseline sNfL had a higher risk of violating NEDA-3 (hazard ratio [HR] 2.28, 95% CI 1.27-4.09, p = 0.006) and developing a new brain lesion (HR 2.47, 95% CI 1.30-4.69, p = 0.006), but not for a new relapse (HR 2.21, 95% CI 0.97-5.03, p = 0.058). Patients with both abnormal sNfL and thin GCIP had an even higher risk for NEDA-3 violation (HR 3.61, 95% CI 1.77-7.36, p = 4.2e-4), new brain lesion (HR 3.19, 95% CI 1.51-6.76, p = 0.002), and new relapse (HR 5.38, 95% CI 1.61-17.98, p = 0.006) than patients with abnormal sNfL alone.ConclusionsIn patients with early MS, the presence of both abnormal sNfL and thin GCIP is a stronger risk factor for future disease activity than the presence of each parameter alone.
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Project description: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.
| S-EPMC6292183 | biostudies-literature
Project description:Serum neurofilament light chains (sNfL) are biomarkers of disease activity in multiple sclerosis (MS), but their value to predict response to treatment, and their association with patient immunological profile, need to be further explored. We studied 80 relapsing-remitting MS patients initiating dimethyl fumarate (DMF) treatment. sNfL levels were explored at baseline and at 3, 6 and 12 months by single molecule array. Blood lymphocyte subsets were measured at baseline and at 6 months by flow cytometry. Patients were followed a year and classified as NEDA (no evidence of disease activity) or ODA (ongoing disease activity). NEDA patients had lower sNfL levels at baseline (p = 0.0001), and after three (p = 0.004) and six (p = 0.03) months of DMF treatment. Consequently, low baseline sNfL values (≤ 12 pg/ml) increased the probability of NEDA (OR 5.8; CI 1.82-15.6; p = 0.002, after correcting by disease activity in the previous year), and associated with significant reductions of central memory CD4+ T lymphocytes, interferon-gamma+ CD8+ T lymphocytes, Natural Killer T cells, and memory B cells upon DMF treatment, being the highest differences in memory B cells (p < 0.0001). This shows that low baseline sNfL values identify MS patients with higher probability of optimal response to DMF and of a reduction in effector immune cells.
| S-EPMC8085019 | biostudies-literature
Project description:ObjectivesSerum neurofilament light protein (NfL) is a promising marker of disease onset and progression in Huntington's disease (HD). This study investigated associations between lifestyle factors and NfL levels in HD mutation carriers compared to healthy age- and sex-matched controls.Materials and methodsParticipants included 29 HD mutation carriers and 15 healthy controls. Associations between serum NfL concentrations and lifestyle factors, including cardiorespiratory fitness, social network size and diversity, physical activity, cognitive reserve, smoking status, and alcohol consumption, were examined using a stepwise multivariable linear regression model.ResultsHigher NfL levels were associated with lower cognitive reserve, social network size and diversity and cardiorespiratory fitness in HD mutation carriers. Group × lifestyle factor effects were observed between lower serum NfL levels and a greater social network diversity.ConclusionThese findings highlight a relationship between lifestyle factors and NfL levels in HD mutations carriers; however, longitudinal studies are required to confirm if these observed relationships persist over time.
| S-EPMC7218250 | biostudies-literature
Project description:ImportanceBlood sample-based biomarkers that are associated with clinically meaningful outcomes for patients with multiple sclerosis (MS) have not been developed.ObjectiveTo evaluate the potential of serum neurofilament light chain (sNFL) measurements as a biomarker of disease activity and progression in a longitudinal MS data set.Design, setting, and participantsSingle-center, ongoing, prospective observational cohort study of 607 patients with MS from the longitudinal EPIC (Expression, Proteomics, Imaging, Clinical) study at the University of California, San Francisco from July 1, 2004, through August 31, 2017. Clinical evaluations and sample collection were performed annually for 5 years, then at different time points for up to 12 years, with a median follow-up duration of 10 (interquartile range, 7-11) years. Serum NFL levels were measured using a sensitive single molecule array platform and compared with clinical and magnetic resonance imaging variables with the use of univariable and multivariable analyses.Main outcomes and measuresThe main outcomes were disability progression defined as clinically significant worsening on the Expanded Disability Status Scale (EDSS) score and brain fraction atrophy.ResultsMean (SD) age of the 607 study participants at study entry was 42.5 (9.8) years; 423 (69.7%) were women; and all participants were of non-Hispanic European descent. Of 3911 samples sequentially collected, 3904 passed quality control for quantification of sNFL. Baseline sNFL levels showed significant associations with EDSS score (β, 1.080; 95% CI, 1.047-1.114; P < .001), MS subtype (β, 1.478; 95% CI, 1.279-1.707; P < .001), and treatment status (β, 1.120; 95% CI, 1.007-1.245; P = .04). A significant interaction between EDSS worsening and change in levels of sNFL over time was found (β, 1.015; 95% CI, 1.007-1.023; P < .001). Baseline sNFL levels alone were associated with approximately 11.6% of the variance in brain fraction atrophy at year 10. In a multivariable analysis that considered sex, age, and disease duration, baseline sNFL levels were associated with 18.0% of the variance in brain fraction atrophy at year 10. After 5 years' follow-up, active treatment was associated with lower levels of sNFL, with high-potency treatments associated with the greater decreases in sNFL levels compared with platform therapies (high-potency vs untreated: β, 0.946; 95% CI, 0.915-0.976; P < .001; high-potency vs platform: β, 0.972; 95% CI, 0.948-0.998; P = .04).Conclusions and relevanceThis study found that statistically significant associations of sNFL with relevant clinical and neuroimaging outcomes in MS were confirmed and extended, supporting the potential of sNFL as an objective surrogate of ongoing MS disease activity. In this data set of patients with MS who received early treatment, the prognostic power of sNFL for relapse activity and long-term disability progression was limited. Further prospective studies are necessary to assess the assay's utility for decision-making in individual patients.
| S-EPMC6692664 | biostudies-literature
Project description: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.
| S-EPMC6052680 | biostudies-literature