Association of Serum Neurofilament Light Levels With Long-term Brain Atrophy in Patients With a First Multiple Sclerosis Episode

Plavina, Tatiana; Singh, Carol M.; Sangurdekar, Dipen; Moor, Carl de; Engle, Bob; Gafson, Arie; Goyal, Jaya; Fisher, Elizabeth; Szak, Suzanne; Kinkel, Revere P.; Sandrock, Alfred; Su, Ray; Kieseier, Bernd C.; Rudick, Richard A.

doi:10.1001/jamanetworkopen.2020.16278

Cited by 21 publications

(21 citation statements)

References 39 publications

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“…The increased axonal damage assessed by sNfL in IRL patients complements the knowledge of the destructiveness of IRLs ( 17 ) in terms of their association with higher lesion burden, atrophy, prominent black holes, and the worse clinical and neuropsychological outcome described earlier ( 8 , 9 ). Our findings, therefore, are consistent with chronic inflammation and increased sNfL ( 44 ) and with the reported associations between increased sNfL, increased lesion burden, and atrophy ( 14 , 42 ). Furthermore, neurofilament is assigned a value as a predictor of long-term clinical outcome ( 12 ) and is thought to be weakly associated with neuropsychological impairment ( 48 ).…”

Section: Discussionsupporting

confidence: 92%

“…sNfL is reported to have a prognostic value for the conversion from clinically isolated syndrome to clinical-definite MS ( 46 ). Furthermore, sNfL levels assessed early from disease onset are reported to correlate significantly with 10-year follow-up MRI parameters, such as T2 lesion load and whole-brain atrophy and fatigue ( 14 , 37 , 47 ) and with long-term clinical motor outcome after 15 years ( 12 ) but only weakly with the long-term evolution of cognitive performance ( 48 ). Nevertheless, sNfL research is currently in its early stages, and a normative database of sNfL in healthy individuals is still needed including the effects of age and comorbidities ( 41 , 49 ).…”

Section: Introductionmentioning

confidence: 99%

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Iron Rims in Patients With Multiple Sclerosis as Neurodegenerative Marker? A 7-Tesla Magnetic Resonance Study

Dal‐Bianco¹,

Schranzer

Gräβner

et al. 2021

Front. Neurol.

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Introduction: Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease of the central nervous system, characterized by inflammatory-driven demyelination. Symptoms in MS manifest as both physical and neuropsychological deficits. With time, inflammation is accompanied by neurodegeneration, indicated by brain volume loss on an MRI. Here, we combined clinical, imaging, and serum biomarkers in patients with iron rim lesions (IRLs), which lead to severe tissue destruction and thus contribute to the accumulation of clinical disability.Objectives: Subcortical atrophy and ventricular enlargement using an automatic segmentation pipeline for 7 Tesla (T) MRI, serum neurofilament light chain (sNfL) levels, and neuropsychological performance in patients with MS with IRLs and non-IRLs were assessed.Methods: In total 29 patients with MS [15 women, 24 relapsing-remitting multiple sclerosis (RRMS), and five secondary-progressive multiple sclerosis (SPMS)] aged 38 (22–69) years with an Expanded Disability Status Score of 2 (0–8) and a disease duration of 11 (5–40) years underwent neurological and neuropsychological examinations. Volumes of lesions, subcortical structures, and lateral ventricles on 7-T MRI (SWI, FLAIR, and MP2RAGE, 3D Segmentation Software) and sNfL concentrations using the Simoa SR-X Analyzer in IRL and non-IRL patients were assessed.Results: (1) Iron rim lesions patients had a higher FLAIR lesion count (p = 0.047). Patients with higher MP2Rage lesion volume exhibited more IRLs (p <0.014) and showed poorer performance in the information processing speed tested within 1 year using the Symbol Digit Modalities Test (SDMT) (p <0.047). (2) Within 3 years, patients showed atrophy of the thalamus (p = 0.021) and putamen (p = 0.043) and enlargement of the lateral ventricles (p = 0.012). At baseline and after 3 years, thalamic volumes were lower in IRLs than in non-IRL patients (p = 0.045). (3) At baseline, IRL patients had higher sNfL concentrations (p = 0.028). Higher sNfL concentrations were associated with poorer SDMT (p = 0.004), regardless of IRL presence. (4) IRL and non-IRL patients showed no significant difference in the neuropsychological performance within 1 year.Conclusions: Compared with non-IRL patients, IRL patients had higher FLAIR lesion counts, smaller thalamic volumes, and higher sNfL concentrations. Our pilot study combines IRL and sNfL, two biomarkers considered indicative for neurodegenerative processes. Our preliminary data underscore the reported destructive nature of IRLs.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Iron Rims in Patients With Multiple Sclerosis as Neurodegenerative Marker? A 7-Tesla Magnetic Resonance Study

Dal‐Bianco¹,

Schranzer

Gräβner

et al. 2021

Front. Neurol.

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“…We found that the volume reduction of the gray matter, bilateral putamen, caudate nucleus, and nucleus accumbens was correlated with the increase in plasma NfL concentration. Previous studies have shown that the decrease in brain volume is the result of a variety of pathological mechanisms, including irreversible demyelination, axonal and neuronal damage [19]. Recent studies have shown that a reduction in the cortical, and deep nucleus volumes, mainly in the putamen, caudate, and globus pallidus, was correlated to the increased Global Assessment Scale (GAS), Bold: results significant (p＜0.05).…”

Section: Discussionmentioning

confidence: 99%

Plasma neurofilament light chain as a biomarker in Wilson's disease

Yang

Huang

Yang

et al. 2022

Parkinsonism & Related Disorders

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Introduction: Neurofilament light chain (NfL) was recently proposed as a promising blood biomarker for nervous system diseases, including Wilson's disease (WD). In this study, we investigated plasma NfL concentrations in patients with different types of WD and their correlations with clinical manifestations and brain atrophy. Methods: Seventy-five WD cases (54 neurological type, 21 hepatic type) and 27 age-matched healthy controls were included in this study. We compared plasma NfL concentrations between the different types and correlated them with Unified Wilson's Disease Rating Scale (UWDRS) scores. Patients were allocated to stable and unstable groups according to changes in UWDRS scores and clinical assessment. We compared the differences in plasma NfL concentrations between groups. Voxel-based morphometry (VBM) and FreeSurfer software were used to analyze MRI images. We investigated the correlation between plasma NfL concentrations and volume of gray matter, white matter, and several areas of interest in the brain MRI of 24 patients. Results: Plasma NfL concentrations were significantly higher in neurological type WD than in hepatic type WD (8.16 vs. 3.19 pg/mL, p < 0.001). Plasma NfL concentrations were positively correlated with UWDRS scores (r = 0.291, p = 0.035) in patients with neurological type WD. Plasma NfL was significantly higher in unstable patients than in stable patients (10.74 vs. 7.23 pg/mL, p = 0.004). Significant negative associations were found between plasma NfL level and the volumes of total gray matter, bilateral caudate nucleus, putamen, and nucleus accumbens. Conclusion: Plasma NfL is valuable as a biomarker for neurological damage in patients with WD.

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“…The stability of reagents stored at their recommended storage conditions of 2-8°C was assessed by monitoring the measured drift of QC samples. QCs were tested on Day 0, 3,7,10,14,17,21,24,28,31,72,123. Linear regression analysis of concentration versus time for each sample was performed.…”

Section: Reagent Storage Stabilitymentioning

confidence: 99%

Development of a Highly Sensitive Serum Neurofilament Light Chain Assay on an Automated Immunoassay Platform

Uzgiris

Calabresi

Stevenson

et al. 2022

Preprint

Self Cite

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Background: Neurofilament light chain (NfL) is an axonal cytoskeletal protein that is released into the extracellular space following neuronal or axonal injury associated with neurological conditions such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and other diseases. NfL is detectable in cerebrospinal fluid (CSF) and blood. Numerous studies in MS have demonstrated that NfL correlates with disease activity, predicts disease progression, and is reduced by treatment with MS disease-modifying drugs, making NfL an attractive candidate to supplement existing clinical and imaging measures in MS. However, for NfL to achieve its potential as a clinically useful biomarker for clinical decision-making or drug development, a standardized, practical, widely accessible assay is needed. Our objective was to validate the analytical performance of the novel serum neurofilament light (sNfl) assay on the ADVIA Centaur(r) XP immunoassay system. Methods: The research assay was evaluated on the ADVIA Centaur XP immunoassay system from Siemens Healthineers. The lower limit of quantitation (LLoQ), intra-assay variation, assay range, cross-reactivity with neurofilament medium and heavy chains, and effect of interfering substances were determined. NfL assay values in serum and CSF were compared with radiological and clinical disease activity measures in patients with MS and ALS, respectively. This assay was further optimized to utilize serum, plasma, and CSF sample types and transferred to Siemens' CLIA laboratory, where it was analytically validated as a laboratory-developed test. Results: In this study, a LLoQ of 1.85 pg/mL, intra-assay variation of <6%, and an assay range of up to 646 pg/mL were demonstrated. A cross-reactivity of <0.7% with neurofilament medium and heavy chains was observed, and the assay was not significantly affected by various interfering substances encountered in clinical specimens. Serum and CSF NfL assay values were associated with radiological and clinical disease activity measures in patients with MS and ALS, respectively. Conclusion: The analytical performance of the NfL assay fulfilled all acceptance criteria; therefore, we believe the assay is acceptable for use in both research and clinical practice settings to determine elevated sNfL levels in patients.

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Association of Serum Neurofilament Light Levels With Long-term Brain Atrophy in Patients With a First Multiple Sclerosis Episode

Cited by 21 publications

References 39 publications

Iron Rims in Patients With Multiple Sclerosis as Neurodegenerative Marker? A 7-Tesla Magnetic Resonance Study

Iron Rims in Patients With Multiple Sclerosis as Neurodegenerative Marker? A 7-Tesla Magnetic Resonance Study

Plasma neurofilament light chain as a biomarker in Wilson's disease

Development of a Highly Sensitive Serum Neurofilament Light Chain Assay on an Automated Immunoassay Platform

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