Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS
- 7 July 2020
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Neurology
- Vol. 95 (1), e59-e69
- https://doi.org/10.1212/wnl.0000000000009559
Abstract
Objective To identify preferred neurofilament assays and clinically validate serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) as prognostic and potential pharmacodynamic biomarkers relevant to amyotrophic lateral sclerosis (ALS) therapy development. Methods In this prospective, multicenter, longitudinal observational study of patients with ALS (n = 229), primary lateral sclerosis (n = 20), and progressive muscular atrophy (n = 11), biological specimens were collected, processed, and stored according to strict standard operating procedures (SOPs). Neurofilament assays were performed in a blinded manner by independent contract research organizations. Results For serum NfL and pNfH measured using the Simoa assay, there were no missing data (i.e., technical replicates below the lower limit of detection were not encountered). For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in ∼4% and ∼10% of serum samples, respectively. Mean coefficients of variation for NfL in serum and CSF were both ∼3%. Mean coefficients of variation for pNfH in serum and CSF were ∼4%–5% and ∼2%–3%, respectively, in all assays. Baseline serum NfL concentration, but not pNfH, predicted the future Revised ALS Functional Rating Scale (ALSFRS-R) slope and survival. Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of ∼8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings. Conclusions Serum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, has potential utility as a pharmacodynamic biomarker of treatment effect.Keywords
This publication has 29 references indexed in Scilit:
- Neurofilament light chainNeurology, 2015
- Crowdsourced analysis of clinical trial data to predict amyotrophic lateral sclerosis progressionNature Biotechnology, 2014
- Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal studyJournal of Neurology, Neurosurgery & Psychiatry, 2014
- Phosphorylated neurofilament heavy subunit (pNF-H) in peripheral blood and CSF as a potential prognostic biomarker in amyotrophic lateral sclerosisJournal of Neurology, Neurosurgery & Psychiatry, 2012
- Plasma Neurofilament Heavy Chain Levels Correlate to Markers of Late Stage Disease Progression and Treatment Response in SOD1G93A Mice that Model ALSPLOS ONE, 2012
- Phase I Clinical Trial of Systemically Administered TUSC2(FUS1)-Nanoparticles Mediating Functional Gene Transfer in HumansPLOS ONE, 2012
- Clinical significance in the change of decline in ALSFRS-RAmyotrophic Lateral Sclerosis, 2010
- Immunoreactivity of the phosphorylated axonal neurofilament H subunit (pNF‐H) in blood of ALS model rodents and ALS patients: evaluation of blood pNF‐H as a potential ALS biomarkerJournal of Neurochemistry, 2009
- Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALSNeurology, 2006
- STATISTICAL METHODS FOR ASSESSING AGREEMENT BETWEEN TWO METHODS OF CLINICAL MEASUREMENTThe Lancet, 1986