Serum neurofilament light chain as a biomarker of inflammatory activity in relapsing-remitting multiple sclerosis: a real-world longitudinal cohort study
Aug 2026· Clinical Chemistry and Laboratory Medicine· 0 citations· 46 references
Medicine
Abstract
Abstract Objectives Serum neurofilament light chain (sNfL) reflects neuroaxonal injury in relapsing-remitting multiple sclerosis (RRMS), but its clinical utility is limited by high interindividual variability and confounders such as renal function. Population-based thresholds may therefore be suboptimal for longitudinal monitoring. The reference change value (RCV), an intraindividual approach based on biological variation, remains insufficiently validated in real-world settings. Methods In this retrospective cohort study, 967 sNfL determinations from 295 RRMS patients were analyzed (LUMIPULSE G600II). Measurements were matched to clinical relapse and MRI activity within ±90 days. Associations with log-sNfL were assessed using linear mixed-effects models. RCV and population-based threshold (PBT) were compared as factors associated with inflammatory activity using cluster-robust logistic regression and ROC analysis. Correlation with new MRI lesion count was also evaluated. Results The intraclass correlation coefficient was 0.536. RCV elevation showed a highly significant association with active MRI (OR 4.93, 95 % CI 2.49–9.77) and clinical relapse (OR 6.48, 95 % CI 2.75–15.25), whereas PBT elevation did not reach statistical significance for either outcome (active MRI: OR 1.52, p=0.290; clinical relapse: OR 2.38, p=0.073). Clinical relapse and MRI activity were independently associated with mean sNfL increases of +72.1 % (95 % CI +53.7 %, +92.7 %) and +24.5 % (95 % CI +13.7 %, +36.3 %), respectively. Renal impairment was a major confounder, with sNfL elevations of +16.0 % in eGFR G2 and +67.8 % in G3–G5. Negative predictive values exceeded 91 % across all markers and outcomes. sNfL correlated with new MRI lesion count (Spearman ρ=0.498, p<0.0001), with a Youden-optimal threshold of ≥4 lesions. Conclusions sNfL measured on the LUMIPULSE platform is a valid real-world biomarker of inflammatory activity in RRMS. Its high interindividual variability makes RCV-based intraindividual interpretation substantially more informative than population-based thresholding for longitudinal monitoring. The consistently high negative predictive value supports its use as a rule-out tool for active neuroinflammation and provides a rational basis for risk-adapted MRI surveillance in clinically stable patients.
ZUSAMMENFASSUNG Serum-Neurofilament-Leichtkette (sNfL) ist ein Biomarker für neuroaxonalen Schaden und korreliert mit klinischer und bildgebender Krankheitsaktivität, Hirnatrophie und Behinderungsprogression, ist jedoch nicht krankheitsspezifisch. Diese Übersichtsarbeit fasst aktuelle Aspekte der Messmethodik, Präanalytik und Interpretation von sNfL zusammen. Besondere Bedeutung haben zentrale Einflussfaktoren wie Alter, Body-Mass-Index beziehungsweise Verteilungsvolumen, Nierenfunktion sowie andere Einflussfraktoren. Für die klinische Anwendung ist daher eine standardisierte Bewertung anhand alters- und BMI-korrigierter Referenzdaten, etwa über Z-Scores oder Perzentile, entscheidend. Klinisch kann sNfL die initiale Risikostratifizierung und Therapieplanung unterstützen, im Verlauf als Frühwarnsignal für subklinische Krankheitsaktivität dienen, die Abgrenzung von Schub und Pseudoschub erleichtern, progrediente Verläufe ergänzend charakterisieren und Entscheidungen in besonderen Situationen wie Schwangerschaft, höherem Lebensalter oder Deeskalation begleiten. Dabei sind serielle Messungen einzelnen Bestimmungen überlegen. Zukünftige Prioritäten sollten in der Harmonisierung der Assays sowie in prospektiven Studien zu NfL-gestützten, multimodalen Entscheidungsstrategien liegen.
Hernan Inojosa, Katja Akgün, L. Masanneck et al.· Fortschritte der Neurologie...· 0 citations
BACKGROUND AND OBJECTIVES
Serum neurofilament light chain (sNfL) reflects inflammatory axonal damage in relapsing multiple sclerosis (RMS). Longitudinal sNfL dynamics may aid treatment response assessment, although data on expected changes under disease-modifying treatments remain limited, particularly in real-world practice. This study evaluated whether on-treatment changes in sNfL were associated with subsequent evidence of disease activity (EDA) and whether they provided complementary information to established treatment response scoring systems (TRSS).
METHODS
This prospective, real-world cohort study was conducted at the Multiple Sclerosis Center of Catalonia (Cemcat). Adult RMS patients initiating disease-modifying treatments (DMTs) with serum samples at treatment initiation (baseline) and after 1 year (Y1) were included. The primary exposure was change in sNfL z-scores (ΔzNfL = zNfLY1 - zNfL-baseline) analyzed using data-derived thresholds (ΔzNfL ≥0 and <0.5-point reduction). At Y1, Expanded Disability Status Scale progression, clinical/radiologic activity, and TRSS (Rio [RS], modified Rio [mRS], and MAGNIMS) were assessed. The primary outcome was EDA between years 1 and 2 (EDA-Y2). Multivariable logistic regression models evaluated associations between ΔzNfL and EDA-Y2, as well as the added value of ΔzNfL across TRSS strata.
RESULTS
A total of 329 patients (66.3% female; median age 39 years) initiated 352 DMTs; 342 remained on treatment for ≥1 year and 182 had complete EDA-Y2 data. Mean (SD) ΔzNfL at Y1 was -0.62 (1.2), with greater reductions in monoclonal antibody-treated and treatment-naïve patients. Lack of zNfL reduction over the first year (ΔzNfL ≥0) was associated with higher odds of EDA-Y2 in the overall cohort (OR [95% CI], p: 3.07 [1.47-6.39], 0.003), in treatment-naïve cases (14.04 [2.47-79.93], 0.003), and in those achieving No Evidence of Disease Activity (NEDA-3) at Y1 (4.54 [1.26-16.30], 0.02). Similar associations were observed for <0.5-point reductions. Adding ΔzNfL to TRSS showed persistent associations with EDA-Y2 despite otherwise favorable scores [e.g., RS: 2.26 (1.12-4.59), 0.024].
DISCUSSION
Failure to reduce zNfL levels after 1 year of treatment was associated with subsequent disease activity, even in patients otherwise considered stable, providing complementary information to clinical and MRI-based monitoring. Limitations include incomplete follow-up and the modest discriminative performance of ΔzNfL, supporting a complementary rather than stand-alone role for zNfL dynamics.
Victoria Fernández, Agustín Pappolla, Pere Carbonell-Mirabent et al.· Neurology· 0 citations
ABSTRACT Objective Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous neurodegenerative disease requiring reliable biomarkers to improve patient stratification and trial design. While serum neurofilament light chain (sNfL) reflects neuroaxonal stress and disease aggressiveness, troponin T (TnT) may capture complementary aspects of neuromuscular involvement. We assessed the associations of TnT and sNfL with D50‐derived measures of disease aggressiveness (D50) and disease accumulation (rD50) in ALS. Methods In this retrospective observation, TnT and sNfL levels from ALS patients in two independent German cohorts were analyzed using the D50 disease progression model; discovery cohort (Essen, n = 433) and an independent replication cohort (Bonn, n = 185). Results TnT levels were strongly associated with rD50‐defined disease phases in the discovery cohort (p < 0.001). While not all subgroup‐specific associations were replicated, the overall relationship between TnT and disease accumulation was supported in the independent replication cohort. In contrast, sNfL showed no consistent relationship with rD50‐derived disease phases. sNfL concentrations demonstrated a significant inverse association with D50, supporting a relationship with disease aggressiveness across both cohorts (p < 0.001). Associations between TnT levels and D50‐defined disease aggressiveness were generally weaker and less consistent. Interpretation TnT was associated with measures of disease accumulation (rD50), whereas sNfL was more closely associated with disease aggressiveness (D50). Our results suggest that TnT and sNfL capture different dimensions of disease status within the D50 framework. Further longitudinal studies are needed to determine whether combining these biomarkers improves disease stratification or prognostic assessment in clinical practice and therapeutic trials.
Julia Sellin, Sofia Waldorf, Janina von der Gablentz et al.· Annals of Clinical and Trans...· 0 citations
BACKGROUND
Progression independent of relapse activity (PIRA) is increasingly appreciated as one of the important factors contributing to disability accumulation in MS. sGFAP and sNfL could represent markers reflecting two separate biological processes related to relapse-independent progression in MS.
OBJECTIVE
To perform a systematic review of the literature on blood GFAP and/or NfL measured in relation to PIRA or other similar relapse-independent progression endpoints in people with MS.
METHODS
PubMed, Scopus, and Web of Science databases were searched from inception to 1 June 2026. The eligible studies were original human studies measuring blood GFAP and/or NfL concentrations in serum, plasma, or any other type of blood-derived material and assessing PIRA, PIRMA, CDP/CDW without relapses, relapse-free EDSS progression, non-inflammatory progression, or comparable relapse-independent disability worsening outcomes. Methodological quality was assessed according to the Newcastle-Ottawa scale and the QUIPS instrument for bias detection in the body of evidence on prognostic factors. Due to heterogeneity of outcomes, biomarker measurements and effect estimates, results were synthesized qualitatively rather than quantitatively.
RESULTS
After removing duplicates, 1206 records were screened, followed by full-text review of 120 reports. A total of 18 reports were included. Overall, sGFAP was associated more frequently with PIRA or PIRA-like disability progression, particularly in cohorts with suppressed or limited overt inflammatory activity. Evidence for sNfL was more variable and context-dependent: several studies reported associations with PIRA-like or relapse-independent disability worsening when acute inflammatory activity was absent, suppressed, or analytically separated, whereas other studies reported negative or inconclusive findings. Negative or inconclusive results were reported by several articles, particularly when broad outcomes were evaluated or the study population was small.
CONCLUSION
Blood GFAP and NfL give complementary but non-interchangeable information concerning PIRA in MS patients. The existing evidence base does not allow us to perform meta-analysis because of heterogeneity in terms of outcomes, standardization of biomarkers, and treatment context. Further prospective investigations with uniform criteria will be necessary for their use as biomarkers of PIRA in clinical settings.
A. Maazi, Yousef Moradi· Multiple Sclerosis and Relat...· 0 citations
Neurofilament light chain (NfL) is an established marker of neuronal injury and disease aggressiveness in amyotrophic lateral sclerosis (ALS). In contrast, the clinical and biological significance of cardiac troponin T (cTnT) in ALS is not fully understood. We aimed to evaluate the relationship between plasma cTnT and disease aggressiveness, progression stage, and clinical phenotype in comparison with NfL. Plasma cTnT and cerebrospinal fluid (CSF) NfL were analysed at diagnosis in a population-based cohort of 526 patients with ALS. Disease aggressiveness was modelled using the D50 framework, which quantifies the time taken to lose 50% of functional capacity (ALSFRS-R) and normalises individual disease trajectories. Biomarker associations with disease aggressiveness, phase, and clinical variables were assessed through group comparisons, logistic and linear regression, and receiver operating characteristic analyses. Neurofilament light chain in CSF was strongly associated with disease aggressiveness, with higher levels in patients with more aggressive disease. In contrast, plasma hs-cTnT did not correlate with D50. Across disease phases, CSF NfL remained relatively stable, whereas plasma hs-cTnT increased with advancing rD50, suggesting accumulation with disease progression. Plasma hs-cTnT levels were higher in patients with spinal compared to bulbar onset. Combined biomarker models improved sensitivity and negative predictive value for identifying less aggressive disease. Plasma hs-cTnT and CSF NfL capture distinct but complementary dimensions of ALS pathology. While NfL reflects disease aggressiveness, hs-cTnT aligns with disease phase and clinical phenotype, supporting its use as a complementary biomarker for ALS characterisation and monitoring.
Julia Sellin, Linn Öijerstedt, Janina von der Gablentz et al.· Journal of Neurology· 0 citations
Objective: Axonal injury is a key determinant in irreversible disability in multiple sclerosis (MS). Reliable biomarkers of neuroaxonal damage are essential for improving diagnosis, monitoring disease progression, and evaluating treatment response. This study investigated the relationship between phosphorylated neurofilament heavy chain (pNF-H), clinical characteristics, and conventional cerebrospinal fluid (CSF) and serum biomarkers in Algerian patients with MS. Methods: A total of 102 participants were enrolled. Clinical, immunological, and biochemical parameters were assessed, including the Expanded Disability Status Scale (EDSS), oligoclonal bands (OCBs), IgG index, albumin quotient, and pNF-H concentrations in paired CSF and serum samples. Results: OCBs were detected in 85.5% of patients, and 65.21% exhibited intrathecal immunoglobulin synthesis, with a median IgG index of 0.87. Patients with progressive MS were significantly older and more disabled than those with relapsing–remitting MS (age: p = 0.01; EDSS: p = 0.0007). OCB-positive patients had significantly higher IgG index values (p = 0.0004), but OCB status was not associated with age, EDSS, or albumin quotient. EDSS correlated positively with age (p = 0.0007), albumin quotient (p = 0.01), and IgG index (p = 0.001). Both CSF and serum pNF-H levels were significantly elevated in MS patients compared with NSDs group (p < 0.001). Increased pNF-H concentrations were associated with progressive disease and greater disability (EDSS ≥ 5). Conclusions: Elevated pNF-H levels in CSF and serum are associated with disease severity and progressive MS, supporting their potential as complementary biomarkers of neuroaxonal damage and clinical disability in routine MS assessment.
Bouchra Nour El Houda Baiski, Zoulikha Mokrani, S. Atmani et al.· Diseases· 0 citations
