Journal Article

Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications

Dorgham, Karim, Chen, Yaohua, Hannequin, Didier, Formaglio, Maïté, Bombois, Stéphanie, Vercelletto, Martine, Habert, Marie-Odile, Rametti-Lacroux, Armelle, Toullec, Benjamin Le, Rollin-Sillaire, Adeline, Dubois, Bruno, Martinaud, Olivier, Clot, Fabienne, Forlani, Sylvie, Le Ber, Isabelle, Bissery, Anne, Pallardy, Amandine, Bertin, Hugo, Gerardin, Emmanuel, Lautrette, Géraldine, Funkiewiez, Aurélie, Masmanian, Merry, Camuzat, Agnès, Benchetrit, Eve, Chastan, Mathieu, Migliaccio, Raffaella, Didic, Mira, Wallon, David, Bertrand, Anne, Michel, Bernard-François, Mackowiak, Marie-Anne, Saracino, Dario, Jornea, Ludmila, Bardinet, Eric, Delmaire, Christine, Sauvée, Mathilde, Oya, Assi-Hervé, Monteil, Jacques, Houot, Marion, Berry, Isabelle, Golfier, Véronique, Sellal, François, Colliot, Olivier, Martin-Hardy, Philippe, Ceccaldi, Mathieu, Causse-Lemercier, Valérie, Azuar, Carole, Chupin, Marie, Sayah, Sabrina, Ber, Isabelle Le, Levy, Richard, Belliard, Serge, Auriacombe, Sophie, Delbeuck, Xavier, Payoux, Pierre, Thauvin-Robinet, Christel, Lacomblez, Lucette, Couratier, Philippe, Pasquier, Florence, Kuchinski,

2021

Overview

ObjectiveNeurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72 and GRN cohorts from presymptomatic to clinical stages.MethodsWe analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72 and GRN patients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical–genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index.ResultspNfL levels increased with age in controls, from ~5 to~18 pg/mL (p<0.0001), progressing over time (mean annualised rate of change (ARC): +3.9%/year, p<0.0001). Patients displayed higher levels and greater longitudinal progression (ARC: +26.7%, p<0.0001), with gene-specific trajectories. GRN patients had higher levels than C9orf72 (86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In C9orf72 patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades.ConclusionsThis study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression.Trial registration numbers NCT02590276 and NCT04014673.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adult / Age / Aged / Aged, 80 and over / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - blood / Amyotrophic Lateral Sclerosis - diagnosis / Amyotrophic Lateral Sclerosis - genetics / Biomarkers / C9orf72 Protein - genetics / Dementia / Disease / Disease Progression / Female / Frontotemporal Dementia - blood / Frontotemporal Dementia - diagnosis / Frontotemporal Dementia - genetics / Gender / Humans / Life Sciences / Male / Middle Aged / Mutation / Neurobiology / Neurofilament Proteins - blood / Neurogenetics / Neurons and Cognition / Physiology / Plasma / Progranulins - genetics