Longitudinal biomarkers in amyotrophic lateral sclerosis

• Type of Material: Article
• Authors: Fen Huang, Denali Therapeutics; Yuda Zhu, Denali Therapeutics; Jennifer Hsiao-Nakamoto, Denali Therapeutics; Xinyan Tang, Denali Therapeutics; Jason C. Dugas, Denali Therapeutics; Miriam Moscovitch-Lopatin, Massachusetts General Hospital; Jonathan Glass, Emory University; Robert H. Brown, University of Massachusetts; Shafeeq S. Ladha, Barrow Neurological Institute; David Lacomis, University of Pittsburgh; Jeffrey M. Harris, Denali Therapeutics; Kimberly Scearce-Levie, Denali Therapeutics; Carole Ho, Denali Therapeutics; Robert Bowser, Barrow Neurological Institute; James D. Berry, Massachusetts General Hospital
• Language: English
• Date: 2020-06-09
• Publisher: Wiley
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/acn3.51078
• Title of Journal or Parent Work: Annals of Clinical and Translational Neurology
• Volume: 7
• Issue: 7
• Start Page: 1103
• End Page: 1116
• Grant/Funding Information: This work was funded by Denali Therapeutics grant.
• Keywords: Neurosciences & Neurology; Chain; Science & Technology; Survival; Double blind; Neurofilament light levels; Neurosciences; Diagnosis; Life Sciences & Biomedicine; Efficacy; Cerebrospinal fluid; ALS; Prognostic biomarker; Clinical Neurology; Edaravone
• Research Categories: Biology, Neuroscience; Health Sciences, Rehabilitation and Therapy; Health Sciences, Pathology

Abstract

Objective To investigate neurodegenerative and inflammatory biomarkers in people with amyotrophic lateral sclerosis (PALS), evaluate their predictive value for ALS progression rates, and assess their utility as pharmacodynamic biomarkers for monitoring treatment effects. Methods De‐identified, longitudinal plasma, and cerebrospinal fluid (CSF) samples from PALS (n = 108; 85 with samples from ≥2 visits) and controls without neurological disease (n = 41) were obtained from the Northeast ALS Consortium (NEALS) Biofluid Repository. Seventeen of 108 PALS had familial ALS, of whom 10 had C9orf72 mutations. Additional healthy control CSF samples (n = 35) were obtained from multiple sources. We stratified PALS into fast‐ and slow‐progression subgroups using the ALS Functional Rating Scale‐Revised change rate. We compared cytokines/chemokines and neurofilament (NF) levels between PALS and controls, among progression subgroups, and in those with C9orf72 mutations. Results We found significant elevations of cytokines, including MCP‐1, IL‐18, and neurofilaments (NFs), indicators of neurodegeneration, in PALS versus controls. Among PALS, these cytokines and NFs were significantly higher in fast‐progression and C9orf72 mutation subgroups versus slow progressors. Analyte levels were generally stable over time, a key feature for monitoring treatment effects. We demonstrated that CSF/plasma neurofilament light chain (NFL) levels may predict disease progression, and stratification by NFL levels can enrich for more homogeneous patient groups. Interpretation Longitudinal stability of cytokines and NFs in PALS support their use for monitoring responses to immunomodulatory and neuroprotective treatments. NFs also have prognostic value for fast‐progression patients and may be used to select similar patient subsets in clinical trials.