RT Journal Article SR Electronic T1 Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS JF Neurology JO Neurology FD Lippincott Williams & Wilkins SP e59 OP e69 DO 10.1212/WNL.0000000000009559 VO 95 IS 1 A1 Benatar, Michael A1 Zhang, Lanyu A1 Wang, Lily A1 Granit, Volkan A1 Statland, Jeffrey A1 Barohn, Richard A1 Swenson, Andrea A1 Ravits, John A1 Jackson, Carlayne A1 Burns, Ted M. A1 Trivedi, Jaya A1 Pioro, Erik P. A1 Caress, James A1 Katz, Jonathan A1 McCauley, Jacob L. A1 Rademakers, Rosa A1 Malaspina, Andrea A1 Ostrow, Lyle W. A1 Wuu, Joanne YR 2020 UL http://n.neurology.org/content/95/1/e59.abstract 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