Journal article
Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS
Neurology, Vol.95(1), pp.e59-e69
07/07/2020
DOI: 10.1212/WNL.0000000000009559
PMCID: PMC7371380
PMID: 32385188
Abstract
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.
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.
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.
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.
Details
- Title: Subtitle
- Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS
- Creators
- Michael Benatar - University of Miami*Lanyu Zhang - University of Miami*Lily Wang - University of MiamiVolkan Granit - University of Miami*Jeffrey Statland - University of KansasRichard Barohn - University of KansasAndrea Swenson - University of IowaJohn Ravits - University of California, San DiegoCarlayne Jackson - The University of Texas Health Science Center at San AntonioTed M Burns - University of VirginiaJaya Trivedi - The University of Texas Southwestern Medical CenterErik P Pioro - Cleveland ClinicJames Caress - Wake Forest UniversityJonathan Katz - California Pacific Medical CenterJacob L McCauley - University of Miami*Rosa Rademakers - Mayo ClinicAndrea Malaspina - Queen Mary University of LondonLyle W Ostrow - Johns Hopkins UniversityJoanne Wuu - University of Miami*CReATe Consortium
- Resource Type
- Journal article
- Publication Details
- Neurology, Vol.95(1), pp.e59-e69
- DOI
- 10.1212/WNL.0000000000009559
- PMID
- 32385188
- PMCID
- PMC7371380
- NLM abbreviation
- Neurology
- ISSN
- 0028-3878
- eISSN
- 1526-632X
- Grant note
- UL1 TR002366 / NCATS NIH HHS U54 NS092091 / NINDS NIH HHS UL1 TR000001 / NCATS NIH HHS U01 NS107027 / NINDS NIH HHS
- Language
- English
- Date published
- 07/07/2020
- Academic Unit
- Neurology
- Record Identifier
- 9984303016802771
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