scholarly journals Plasma neurofilament light levels are associated with risk of disability in multiple sclerosis

Neurology ◽  
2020 ◽  
Vol 94 (23) ◽  
pp. e2457-e2467 ◽  
Author(s):  
Ali Manouchehrinia ◽  
Pernilla Stridh ◽  
Mohsen Khademi ◽  
David Leppert ◽  
Christian Barro ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Single Molecule ◽  
Progressive Multiple Sclerosis ◽  
Population Based ◽  
Neurofilament Light Chain ◽  
Permanent Disability ◽  
Neurofilament Light ◽  
Increased Risk ◽  
Edss Score ◽  
The Impact

ObjectiveTo investigate the association between plasma neurofilament light chain (pNfL) levels and the risk of developing sustained disability worsening.MethodsConcentrations of pNfL were determined in 4,385 persons with multiple sclerosis (MS) and 1,026 randomly selected population-based sex- and age-matched controls using the highly sensitive Single Molecule Array (SimoaTM) NF-Light Advantage Kit. We assessed the impact of age-stratified pNfL levels above the 80th, 95th, and 99th percentiles among controls on the risk of Expanded Disability Status Scale (EDSS) worsening within the following year and reaching sustained EDSS scores of 3.0, 4.0, and 6.0 and conversion to secondary progressive multiple sclerosis (SPMS).ResultsThe median (interquartile range [IQR]) pNfL was 7.5 (4.1) pg/mL in controls and 11.4 (9.6) pg/mL in MS (p < 0.001). The median (IQR) duration of follow-up was 5 (5.1) years. High pNfL was associated with increased adjusted rates of EDSS worsening ranging between 1.4 (95% confidence intervals [CIs]: 1.1–1.8) and 1.7 (95% CI: 1.4–2.3). High pNfL was also associated with the risk of reaching a sustained EDSS score of 3.0, with adjusted rates ranging between 1.5 (95% CI: 1.2–1.8) and 1.55 (95% CI: 1.3–1.8) over all percentile cutoffs (all p < 0.001). Similar increases were observed for the risk of sustained EDSS score 4.0. In contrast, the risk of reaching sustained EDSS score 6.0 and conversion to SPMS was not consistently significant.ConclusionsElevated pNfL levels at early stages of MS are associated with an increased risk of reaching sustained disability worsening. Hence, pNfL may serve as a prognostic tool to assess the risk of developing permanent disability in MS.

scholarly journals Impact of Dietary Intervention on Serum Neurofilament Light Chain in Multiple Sclerosis

2021 ◽  
Vol 9 (1) ◽  
pp. e1102
Author(s):  
Markus Bock ◽  
Falk Steffen ◽  
Frauke Zipp ◽  
Stefan Bittner
Keyword(s):  
Multiple Sclerosis ◽  
Ketogenic Diet ◽  
Single Molecule ◽  
Light Chain ◽  
Dietary Intervention ◽  
Controlled Trial ◽  
Trial Registration ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
The Impact

Background and ObjectivesAdapted 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.MethodsWe 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.ResultssNfL 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).DiscussionFor 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.Trial Registration InformationClinical trial registration number NCT01538355.

scholarly journals Supplementary medication in multiple sclerosis: Real-world experience and potential interference with neurofilament light chain measurement

2020 ◽  
Vol 6 (3) ◽  
pp. 205521732093631
Author(s):  
Katrin Pape ◽  
Falk Steffen ◽  
Frauke Zipp ◽  
Stefan Bittner
Keyword(s):  
Multiple Sclerosis ◽  
Dietary Supplements ◽  
Single Molecule ◽  
Light Chain ◽  
Neurofilament Light Chain ◽  
Over The Counter ◽  
Neurofilament Light ◽  
The Impact ◽  
Different Doses ◽  
Supplementary Medication

Background As vitamins and dietary supplements are obtainable without prescription, treating physicians often ignore their intake by patients with multiple sclerosis (MS) and may therefore miss potential adverse effects and interactions. Objective We aimed to assess the spectrum and intake frequency of supplementary medication in a cohort of MS patients and to analyse the effect of biotin intake on measurement of serum neurofilament light chain (sNfL), an emerging marker of disease activity. Methods MS patients visiting our neurology outpatient clinic completed a questionnaire on their past or present use of vitamins or dietary supplements. In addition, the impact of two different doses of biotin (10 and 300 mg/day) on sNfL was studied in healthy volunteers. Results Of 186 patients, 72.6% reported taking over-the-counter vitamins or dietary supplements currently or previously. Most frequently used was vitamin D (60.0%), followed by biotin. Female patients and patients with primary progressive MS tended to use supplements more frequently. Biotin intake did not interfere with sNfL measurement by single molecule array (Simoa). Conclusions The use of vitamins and dietary supplements is frequent among patients with MS. Thus, treating physicians should be aware of the pitfalls of supplementary treatment and educate their patients accordingly.

scholarly journals Long-term prognostic value of longitudinal measurements of blood neurofilament levels

2020 ◽  
Vol 7 (5) ◽  
pp. e856 ◽  
Author(s):  
Dieter A. Häring ◽  
Harald Kropshofer ◽  
Ludwig Kappos ◽  
Jeffrey A. Cohen ◽  
Anuja Shah ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Light Chain ◽  
Prognostic Value ◽  
Long Term Outcomes ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Longitudinal Measurements ◽  
Relapsing Remitting ◽  
Edss Score

ObjectiveTo assess the long-term prognostic value of an integral of longitudinal measurements of plasma neurofilament light chain levels (NfLlong) over 12 and 24 months vs single neurofilament light chain (NfL) measurements in patients with relapsing-remitting MS (RRMS) and its additional value when combined with clinical and MRI measures.MethodsThis analysis included continuously fingolimod-treated patients with RRMS from the 24-month FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS)/12-month Trial Assessing Injectable Interferon vs FTY720 Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS) phase 3 trials and their long-term extension, LONGTERMS. Patients were classified into high (≥30 pg/mL, n = 110) and low (<30 pg/mL, n = 164) NfL categories based on the baseline (BL) NfL value or the geometric mean NfLlong calculated over 12 and 24 months to predict disability-related outcomes and brain volume loss (BVL). The additional prognostic value of NfL was quantified using the area under the receiver operating characteristic (ROC) curve.ResultsA single high (vs low) NfL measure at BL was prognostic of a higher risk of reaching Expanded Disability Status Scale (EDSS) score ≥4 earlier (hazard ratio [HR] = 2.19; 95% CI = 1.21–3.97) and higher BVL over 120 months (difference: −1.12%; 95% CI = −2.07 to −0.17). When NfLlong was measured over 24 months, high NfL was associated with a higher risk of reaching EDSS score ≥4 (HR = 7.91; 95% CI = 2.99–20.92), accelerated 6-month confirmed disability worsening (HR = 3.14; 95% CI = 1.38–7.11), and 20% worsening in the Timed 25-Foot Walk Test (HR = 3.05; 95% CI = 1.38–6.70). Area under the ROC curve was consistently highest in models combining NfL with clinical and MRI measures.ConclusionsNfLlong had a higher prognostic value than single NfL assessments on long-term outcomes in RRMS. Combining it with clinical and MRI measures increased sensitivity and specificity to predict long-term disease outcomes.Classification of evidenceThis study provides Class I evidence that NfLlong was more strongly associated with long-term outcomes than single NfL assessments in patients with RRMS.

scholarly journals Serum neurofilament light as a biomarker in progressive multiple sclerosis

Neurology ◽  
2020 ◽  
Vol 95 (10) ◽  
pp. 436-444 ◽  
Author(s):  
Raju Kapoor ◽  
Kathryn E. Smith ◽  
Mark Allegretta ◽  
Douglas L. Arnold ◽  
William Carroll ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Unmet Need ◽  
Progressive Multiple Sclerosis ◽  
Response To Treatment ◽  
Tissue Fluid ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Novel Biomarkers ◽  
Active Inflammation

There is an unmet need in multiple sclerosis (MS) therapy for treatments to stop progressive disability. The development of treatments may be accelerated if novel biomarkers are developed to overcome the limitations of traditional imaging outcomes revealed in early phase trials. In January 2019, the International Progressive MS Alliance convened a standing expert panel to consider potential tissue fluid biomarkers in MS in general and in progressive MS specifically. The panel focused their attention on neurofilament light chain (NfL) in serum or plasma, examining data from both relapsing and progressive MS. Here, we report the initial conclusions of the panel and its recommendations for further research. Serum NfL (sNfL) is a plausible marker of neurodegeneration that can be measured accurately, sensitively, and reproducibly, but standard procedures for sample processing and analysis should be established. Findings from relapsing and progressive cohorts concur and indicate that sNfL concentrations correlate with imaging and disability measures, predict the future course of the disease, and can predict response to treatment. Importantly, disease activity from active inflammation (i.e., new T2 and gadolinium-enhancing lesions) is a large contributor to sNfL, so teasing apart disease activity from the disease progression that drives insidious disability progression in progressive MS will be challenging. More data are required on the effects of age and comorbidities, as well as the relative contributions of inflammatory activity and other disease processes. The International Progressive MS Alliance is well positioned to advance these initiatives by connecting and supporting relevant stakeholders in progressive MS.

scholarly journals No Early Effect of Intrathecal Rituximab in Progressive Multiple Sclerosis (EFFRITE Clinical Trial)

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Mickael Bonnan ◽  
Sylvie Ferrari ◽  
Henri Courtade ◽  
Paul Money ◽  
Pauline Desblache ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Progressive Multiple Sclerosis ◽  
Immunosuppressive Drugs ◽  
Control Group ◽  
Csf Biomarkers ◽  
Open Label ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Early Effect ◽  
Mri Changes

Background. The progressive phase of multiple sclerosis (MS) is characterized by an intrathecal (IT) compartmentalization of inflammation, involving B-cells within meningeal follicles, and resisting all the available immunosuppressive treatments. A new therapeutic paradigm may be to target this inflammation by injecting immunosuppressive drugs inside the central nervous system compartment. Methods. We designed a single-center, open-label, randomized, controlled, phase II study designed to evaluate the safety and efficacy of IT rituximab in progressive MS (EFFRITE trial; ClinicalTrial Registration NCT02545959). Patients were randomized into three arms (1 : 1 : 1): control group, IT rituximab (20 mg, IT) group, and intravenous+IT (IV+IT) group. The main outcome was a change in levels of CSF biomarkers of inflammation (osteopontin). Secondary outcomes were changes in levels of CSF biomarkers of axonal loss (neurofilament light chain) and clinical and MRI changes. Results. Ten patients were included (2 : 4 : 4). No adverse event occurred. OPN level remained stable in CSF at each time point, whereas NFL had slightly decreased (-8.7%) at day 21 ( p = 0.02 ). Clinical parameters remained stable and leptomeningeal enhancements remained unchanged. Conclusion. Clinical outcome and biomarkers of inflammation were not dramatically modified after IT injection of rituximab, probably due to its limited efficiency in CSF. Drug issues for future studies are discussed.

scholarly journals Case Report: Successful Stabilization of Marburg Variant Multiple Sclerosis With Ocrelizumab Following High-Dose Cyclophosphamide Rescue

2021 ◽  
Vol 12 ◽  
Author(s):  
Valeria Koska ◽  
Moritz Förster ◽  
Katja Brouzou ◽  
Maryam Hatami ◽  
Ercan Arat ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Neurological Deficits ◽  
High Dose ◽  
B Cell Depletion ◽  
Neurofilament Light Chain ◽  
Permanent Disability ◽  
Neurofilament Light ◽  
Aggressive Form ◽  
Rescue Treatment ◽  
Marked Decline

The Marburg variant of multiple sclerosis (Marburg MS) is the most aggressive form of MS, often leading to death soon after onset. Here we describe the case of a 26-year-old Marburg MS patient presenting with severe neurological deficits requiring intensive care. In spite of more than 100 gadolinium-enhancing MRI lesions, the patient recovered almost completely upon high-dose cyclophosphamide (HiCy) rescue treatment (four consecutive days with 50 mg/kg/day, cumulative absolute dose of 14 g). Following the acute treatment, her disease was stabilized by B cell depletion using ocrelizumab. Clinical amelioration was reflected by a decrease of MRI activity and a marked decline of serum neurofilament light chain levels. HiCy rescue treatment followed by ocrelizumab as a maintenance therapy prevented permanent disability and achieved an almost complete clinical and drastic radiological improvement in this Marburg MS patient.

Defining active progressive multiple sclerosis

2017 ◽  
Vol 23 (13) ◽  
pp. 1727-1735 ◽  
Author(s):  
Finn Sellebjerg ◽  
Lars Börnsen ◽  
Cecilie Ammitzbøll ◽  
Jørgen Erik Nielsen ◽  
Tua Vinther-Jensen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Progressive Multiple Sclerosis ◽  
Csf Biomarkers ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Cell Counts ◽  
Igg Index ◽  
Show Evidence ◽  
Leukocyte Counts ◽  
Nitric Oxide Metabolites

Background: It is unknown whether disease activity according to consensus criteria (magnetic resonance imaging activity or clinical relapses) associate with cerebrospinal fluid (CSF) changes in progressive multiple sclerosis (MS). Objective: To compare CSF biomarkers in active and inactive progressive MS according to consensus criteria. Methods: Neurofilament light chain (NFL), myelin basic protein (MBP), IgG-index, chitinase-3-like-1 (CHI3L1), matrix metalloproteinase-9 (MMP-9), chemokine CXCL13, terminal complement complex, leukocyte counts and nitric oxide metabolites were measured in primary ( n = 26) and secondary progressive MS ( n = 26) and healthy controls ( n = 24). Results: Progressive MS patients had higher CSF cell counts, IgG-index, CHI3L1, MMP-9, CXCL13, NFL and MBP concentrations. Active patients were younger and had higher NFL, CXCL13 and MMP-9 concentrations than inactive patients. Patients with active disease according to consensus criteria or detectable CXCL13 or MMP-9 in CSF were defined as having combined active progressive MS. These patients had increased CSF cell counts, IgG-index and MBP, NFL and CHI3L1 concentrations. Combined inactive patients only had increased IgG-index and MBP concentrations. Conclusion: Patients with combined active progressive MS show evidence of inflammation, demyelination and neuronal/axonal damage, whereas the remaining patients mainly show evidence of active demyelination. This challenges the idea that neurodegeneration independent of inflammation is crucial in disease progression.

scholarly journals Serum Neurofilament Light Chain Levels are Associated with Lower Thalamic Perfusion in Multiple Sclerosis

Diagnostics ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 685
Author(s):  
Dejan Jakimovski ◽  
Niels Bergsland ◽  
Michael G. Dwyer ◽  
Deepa P. Ramasamy ◽  
Murali Ramanathan ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Single Molecule ◽  
Cerebral Blood Volume ◽  
Mean Transit Time ◽  
Dynamic Susceptibility ◽  
Linear Regression Models ◽  
Dynamic Susceptibility Contrast ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Normal Appearing White Matter

Both perfusion-weighted imaging (PWI) measures and serum neurofilament light (sNfL) chain levels have been independently associated with disability in multiple sclerosis (MS) patients. This study aimed to determine whether these measures are correlated to each other or independently describe different MS processes. For this purpose, 3T MRI dynamic susceptibility contrast (DSC)–PWI and single-molecule assay (Simoa)-based sNfL methods were utilized when investigating 86 MS patients. The perfusion measures of mean transit time (MTT), cerebral blood volume (CBV), and cerebral blood flow (CBF) were derived for the normal-appearing whole brain (NAWB), the normal-appearing white matter (NAWM), the gray matter (GM), the deep GM (DGM), and the thalamus. The normalized CBV and CBF (nCBV and nCBV) were calculated by dividing by the corresponding NAWM measure. Age- and sex-adjusted linear regression models were used to determine associations between the DSC–PWI and sNfL results. False discovery rate (FDR)-adjusted p-values < 0.05 were considered statistically significant. A greater age and thalamic MTT were independently associated with higher sNfL levels (p < 0.001 and p = 0.011) and explained 36.9% of sNfL level variance. NAWM MTT association with sNfL levels did not survive the FDR correction. In similar models, a lower thalamic nCBF and nCBV were both associated with greater sNfL levels (p < 0.001 and p = 0.022), explaining 37.8% and 44.7% of the variance, respectively. In conclusion, higher sNfL levels were associated with lower thalamic perfusion.

scholarly journals Serum neurofilament light chain is a useful biomarker in pediatric multiple sclerosis

2020 ◽  
Vol 7 (4) ◽  
pp. e749 ◽  
Author(s):  
Marie-Christine Reinert ◽  
Pascal Benkert ◽  
Jens Wuerfel ◽  
Zuzanna Michalak ◽  
Esther Ruberte ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Treatment Response ◽  
Single Molecule ◽  
Light Chain ◽  
Interferon Beta ◽  
Class Iii ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Potential Biomarker

ObjectiveTo investigate serum neurofilament light chain (sNfL) as a potential biomarker for disease activity and treatment response in pediatric patients with multiple sclerosis (MS).MethodsIn this retrospective cohort study, sNfL levels were measured in a pediatric MS cohort (n = 55, follow-up 12–105 months) and in a non-neurologic pediatric control cohort (n = 301) using a high-sensitivity single-molecule array assay. Association of sNfL levels and treatment and clinical and MRI parameters were calculated.ResultsUntreated patients had higher sNfL levels than controls (median 19.0 vs 4.6 pg/mL; CI [4.732, 6.911]), p < 0.001). sNfL levels were significantly associated with MRI activity (+9.1% per contrast-enhancing lesion, CI [1.045, 1.138], p < 0.001; +0.6% per T2-weighted lesion, CI [1.001, 1.010], p = 0.015). Higher values were associated with a relapse <90 days ago (+51.1%; CI [1.184, 1.929], p < 0.001) and a higher Expanded Disability Status Scale score (CI [1.001, 1.240], p = 0.048). In patients treated with interferon beta-1a/b (n = 27), sNfL levels declined from 14.7 to 7.9 pg/mL after 6 ± 2 months (CI [0.339, 0.603], p < 0.001). Patients with insufficient control of clinical or MRI disease activity under treatment with interferon beta-1a/b or glatiramer acetate who switched to fingolimod (n = 18) showed a reduction of sNfL levels from 16.5 to 10.0 pg/mL 6 ± 2 months after switch (CI [0.481, 0.701], p < 0.001).ConclusionssNfL is a useful biomarker for monitoring disease activity and treatment response in pediatric MS. It is most likely helpful to predict disease severity and to guide treatment decisions in patients with pediatric MS. This study provides Class III evidence that sNfL levels are associated with disease activity in pediatric MS.

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