Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications. Issue 12 (4th August 2021)

• Record Type: Journal Article
• Authors: Saracino, Dario; Dorgham, Karim; Camuzat, Agnès; Rinaldi, Daisy; Rametti-Lacroux, Armelle; Houot, Marion; Clot, Fabienne; Martin-Hardy, Philippe; Jornea, Ludmila; Azuar, Carole; Migliaccio, Raffaella; Pasquier, Florence; Couratier, Philippe; Auriacombe, Sophie; Sauvée, Mathilde; Boutoleau-Bretonnière, Claire; Pariente, Jérémie; Didic, Mira; Hannequin, Didier; Wallon, David; Colliot, Olivier; Dubois, Bruno; Brice, Alexis; Levy, Richard; Forlani, Sylvie; Le Ber, Isabelle
• Other Names: author non-byline.; Auriacombe Sophie author non-byline.; Belliard Serge author non-byline.; Blanc Frédéric author non-byline.; Boutoleau-Bretonnière Claire author non-byline.; Brice Alexis author non-byline.; Ceccaldi Mathieu author non-byline.; Couratier Philippe author non-byline.; Didic Mira author non-byline.; Dubois Bruno author non-byline.; Duyckaerts Charles author non-byline.; Etcharry-Bouyx Frédérique author non-byline.; Formaglio Maïté author non-byline.; Golfier Véronique author non-byline.; Hannequin Didier author non-byline.; Lacomblez Lucette author non-byline.; Ber Isabelle Le author non-byline.; Michel Bernard-François author non-byline.; Pariente Jérémie author non-byline.; Pasquier Florence author non-byline.; Rinaldi Daisy author non-byline.; Sauvée Mathilde author non-byline.; Sellal François author non-byline.; Thauvin-Robinet Christel author non-byline.; Thomas-Anterion Catherine author non-byline.; Vercelletto Martine author non-byline.; author non-byline.; Auffray-Calvier Elisabeth author non-byline.; Bardinet Eric author non-byline.; Benchetrit Eve author non-byline.; Berry Isabelle author non-byline.; Bertin Hugo author non-byline.; Bertrand Anne author non-byline.; Bissery Anne author non-byline.; Bombois Stéphanie author non-byline.; Boncoeur Marie-Paule author non-byline.; Brice Alexis author non-byline.; Boutoleau-Bretonnière Claire author non-byline.; Camuzat Agnès author non-byline.; Causse-Lemercier Valérie author non-byline.; Chastan Mathieu author non-byline.; Chen Yaohua author non-byline.; Chupin Marie author non-byline.; Colliot Olivier author non-byline.; Couratier Philippe author non-byline.; Delbeuck Xavier author non-byline.; Delmaire Christine author non-byline.; Deramecourt Vincent author non-byline.; Didic Mira author non-byline.; Funkiewiez Aurélie author non-byline.; Gerardin Emmanuel author non-byline.; Girard Nadine author non-byline.; Guedj Eric author non-byline.; Habert Marie-Odile author non-byline.; Hannequin Didier author non-byline.; Kas Aurélie author non-byline.; Kuchinski Gregory author non-byline.; Lautrette Géraldine author non-byline.; Ber Isabelle Le author non-byline.; Toullec Benjamin Le author non-byline.; Mackowiak Marie-Anne author non-byline.; Martinaud Olivier author non-byline.; Masmanian Merry author non-byline.; Monteil Jacques author non-byline.; Oya Assi-Hervé author non-byline.; Pallardy Amandine author non-byline.; Pariente Jérémie author non-byline.; Pasquier Florence author non-byline.; Petyt Grégory author non-byline.; Payoux Pierre author non-byline.; Rinaldi Daisy author non-byline.; Rollin-Sillaire Adeline author non-byline.; Sayah Sabrina author non-byline.; Wallon David author non-byline.;
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 92:Issue 12(2021)
• Page Start: 1278
• Page End: 1288
• Publication Date: 2021-08-04
• Subjects: Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2021-326914
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : Objective: Neurofilament 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. Methods: We 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. Results: pNfL 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. Conclusions: This 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 .