PT  - JOURNAL ARTICLE
AU  - Benatar, Michael
AU  - Zhang, Lanyu
AU  - Wang, Lily
AU  - Granit, Volkan
AU  - Statland, Jeffrey
AU  - Barohn, Richard
AU  - Swenson, Andrea
AU  - Ravits, John
AU  - Jackson, Carlayne
AU  - Burns, Ted M.
AU  - Trivedi, Jaya
AU  - Pioro, Erik P.
AU  - Caress, James
AU  - Katz, Jonathan
AU  - McCauley, Jacob L.
AU  - Rademakers, Rosa
AU  - Malaspina, Andrea
AU  - Ostrow, Lyle W.
AU  - Wuu, Joanne
TI  - Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS
AID  - 10.1212/WNL.0000000000009559
DP  - 2020 Jul 07
TA  - Neurology
PG  - e59--e69
VI  - 95
IP  - 1
4099  - http://n.neurology.org/content/95/1/e59.short
4100  - http://n.neurology.org/content/95/1/e59.full
SO  - Neurology2020 Jul 07; 95
AB  - 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.ALS=amyotrophic lateral sclerosis; ALSFRS-R=Revised ALS Functional Rating Scale; CI=confidence interval; CReATe=Clinical Research in ALS and Related Disorders for Therapeutic Development; CRO=contract research organization; CV=coefficient of variation; IRB=institutional review board; LLD=lower limit of detection; NfL=neurofilament light; PAV=permanent assisted ventilation; PLS=primary lateral sclerosis; PMA=progressive muscular atrophy; pNfH=phosphorylated neurofilament heavy