Stratifying the Presymptomatic Phase of Genetic Frontotemporal Dementia by Serum NfL and pNfH: A Longitudinal Multicentre Study. Issue 1 (29th November 2021)

• Record Type: Journal Article
• Authors: Wilke, Carlo; Reich, Selina; van Swieten, John C.; Borroni, Barbara; Sanchez‐Valle, Raquel; Moreno, Fermin; Laforce, Robert; Graff, Caroline; Galimberti, Daniela; Rowe, James B.; Masellis, Mario; Tartaglia, Maria C.; Finger, Elizabeth; Vandenberghe, Rik; de Mendonça, Alexandre; Tagliavini, Fabrizio; Santana, Isabel; Ducharme, Simon; Butler, Chris R.; Gerhard, Alexander; Levin, Johannes; Danek, Adrian; Otto, Markus; Frisoni, Giovanni; Ghidoni, Roberta; Sorbi, Sandro; Bocchetta, Martina; Todd, Emily; Kuhle, Jens; Barro, Christian; Rohrer, Jonathan D.; Synofzik, Matthis;
• Other Names: Afonso Sónia investigator.; Almeida Maria Rosario investigator.; Anderl‐Straub Sarah investigator.; Andersson Christin investigator.; Antonell Anna investigator.; Archetti Silvana investigator.; Arighi Andrea investigator.; Balasa Mircea investigator.; Barandiaran Myriam investigator.; Bargalló Nuria investigator.; Bartha Robart investigator.; Bender Benjamin investigator.; Benussi Alberto investigator.; Benussi Luisa investigator.; Bessi Valentina investigator.; Binetti Giuliano investigator.; Black Sandra investigator.; Borrego‐Ecija Sergi investigator.; Bras Jose investigator.; Bruffaerts Rose investigator.; Cañada Marta investigator.; Cantoni Valentina investigator.; Caroppo Paola investigator.; Cash David investigator.; Castelo‐Branco Miguel investigator.; Convery Rhian investigator.; Cope Thomas investigator.; Di Fede Giuseppe investigator.; Díez Alina investigator.; Duro Diana investigator.; Fenoglio Chiara investigator.; Ferrari Camilla investigator.; Ferreira Catarina B. investigator.; Fox Nick investigator.; Freedman Morris investigator.; Fumagalli Giorgio investigator.; Gabilondo Alazne investigator.; Gasparotti Roberto investigator.; Gauthier Serge investigator.; Gazzina Stefano investigator.; Giaccone Giorgio investigator.; Gorostidi Ana investigator.; Greaves Caroline investigator.; Guerreiro Rita investigator.; Heller Carolin investigator.; Hoegen Tobias investigator.; Indakoetxea Begoña investigator.; Jelic Vesna investigator.; Jiskoot Lize investigator.; Karnath Hans‐Otto investigator.; Keren Ron investigator.; Langheinrich Tobias investigator.; Leitão Maria João investigator.; Lladó Albert investigator.; Lombardi Gemma investigator.; Loosli Sandra investigator.; Maruta Carolina investigator.; Mead Simon investigator.; Meeter Lieke investigator.; Miltenberger Gabriel investigator.; van Minkelen Rick investigator.; Mitchell Sara investigator.; Moore Katrina investigator.; Nacmias Benedetta investigator.; Nicholas Jennifer investigator.; Öijerstedt Linn investigator.; Olives Jaume investigator.; Ourselin Sebastien investigator.; Padovani Alessandro investigator.; Panman Jessica investigator.; Papma Janne M. investigator.; Peakman Georgia investigator.; Pievani Michela investigator.; Pijnenburg Yolande investigator.; Polito Cristina investigator.; Premi Enrico investigator.; Prioni Sara investigator.; Prix Catharina investigator.; Rademakers Rosa investigator.; Redaelli Veronica investigator.; Rittman Tim investigator.; Rogaeva Ekaterina investigator.; Rosa‐Neto Pedro investigator.; Rossi Giacomina investigator.; Rosser Martin investigator.; Santiago Beatriz investigator.; Scarpini Elio investigator.; Schönecker Sonja investigator.; Seelaar Harro investigator.; Semler Elisa investigator.; Shafei Rachelle investigator.; Shoesmith Christen investigator.; Tábuas‐Pereira Miguel investigator.; Tainta Mikel investigator.; Taipa Ricardo investigator.; Tang‐Wai David investigator.; Thomas David L. investigator.; Thompson Paul investigator.; Thonberg Hakan investigator.; Timberlake Carolyn investigator.; Tiraboschi Pietro investigator.; Van Damme Philip investigator.; Vandenbulcke Mathieu investigator.; Veldsman Michele investigator.; Verdelho Ana investigator.; Villanua Jorge investigator.; Warren Jason investigator.; Woollacott Ione investigator.; Wlasich Elisabeth investigator.; Zetterberg Henrik investigator.; Zulaica Miren investigator.;
• Is Part Of: Annals of neurology. Volume 91:Issue 1(2022)
• Page Start: 33
• Page End: 47
• Publication Date: 2021-11-29
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.26265
• Languages: English
• ISSNs: 0364-5134

Abstract

Abstract : Objective: Although the presymptomatic stages of frontotemporal dementia (FTD) provide a unique chance to delay or even prevent neurodegeneration by early intervention, they remain poorly defined. Leveraging a large multicenter cohort of genetic FTD mutation carriers, we provide a biomarker‐based stratification and biomarker cascade of the likely most treatment‐relevant stage within the presymptomatic phase: the conversion stage. Methods: We longitudinally assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in the Genetic FTD Initiative (GENFI) cohort (n = 444), using single‐molecule array technique. Subjects comprised 91 symptomatic and 179 presymptomatic subjects with mutations in the FTD genes C9orf72, GRN, or MAPT, and 174 mutation‐negative within‐family controls. Results: In a biomarker cascade, NfL increase preceded the hypothetical clinical onset by 15 years and concurred with brain atrophy onset, whereas pNfH increase started close to clinical onset. The conversion stage was marked by increased NfL, but still normal pNfH levels, while both were increased at the symptomatic stage. Intra‐individual change rates were increased for NfL at the conversion stage and for pNfH at the symptomatic stage, highlighting their respective potential as stage‐dependent dynamic biomarkers within the biomarker cascade. Increased NfL levels and NfL change rates allowed identification of presymptomatic subjects converting to symptomatic disease and capture of proximity‐to‐onset. We estimate stage‐dependent sample sizes for trials aiming to decrease neurofilament levels or change rates. Interpretation: Blood NfL and pNfH provide dynamic stage‐dependent stratification and, potentially, treatment response biomarkers in presymptomatic FTD, allowing demarcation of the conversion stage. The proposed biomarker cascade might pave the way towards a biomarker‐based precision medicine approach to genetic FTD. ANN NEUROL 2022;91:33–47