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Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS

2020; Lippincott Williams & Wilkins; Volume: 95; Issue: 1 Linguagem: Inglês

10.1212/wnl.0000000000009559

1526-632X

Michael Benatar, Lanyu Zhang, Lily Wang, Volkan Granit, Jeffrey Statland, Richard J. Barohn, Andrea Swenson, John Ravits, Carlayne E. Jackson, Ted M. Burns, Jaya Trivedi, Erik P. Pioro, James B. Caress, Jonathan Katz, Jacob L. McCauley, Rosa Rademakers, Andrea Malaspina, Lyle W. Ostrow, Joanne Wuu, Sumaira Hussain, Anne Cooley, Yindi Li, Marielle Wallace, Julie Steele, Jessica Hernandez, Jéssica Medina, Maria Elena Paredes, Ashley Manso, Natalia Ravelo, Wendy Levy, Patrice L. Whitehead, Stephan Züchner, Mamatha Pasnoor, Omar Jawdat, Duaa Jabari, Constantine Farmakidis, Melanie Glenn, Mazen M. Dimachkie, Laura Herbelin, Hellen Tanui, Sherri Anderson, Michaela Walker, Tina Liu, Ayla McCally, Andrew Heim, Melissa Currence, Yolanda Harness, Jeri Sieren, Emilee Gibson, G. Garcia Gutierrez, Danielle Bussey, Rose Previte, Pamella Kittrell, Amruta Joshi, Amy Conger, Debbie Hastings, Irys Caristo, Mozhdeh Marandi, Simon Carty, J. Paul Taylor, Gang Wu, Evadnie Rampersaud, Rebecca Schüle, Marka van Blitterswijk,

Neurogenetic and Muscular Disorders Research

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.