NfL reliability across laboratories, stage-dependent diagnostic performance and matrix comparability in genetic FTD: a large GENFI study

Linnemann, Christoph; Wilke, Carlo; Mengel, David; Zetterberg, Henrik; Heller, Carolin; Kuhle, Jens; Bouzigues, Arabella; Russell, Lucy L; Foster, Phoebe H; Ferry-Bolder, Eve; Van Swieten, John Cornelis; Jiskoot, Lize C; Seelaar, Harro; Moreno, Fermin; Borroni, Barbara; Sánchez-Valle, Raquel; Galimberti, Daniela; Laforce, Robert; Graff, Caroline; Masellis, Mario; Tartaglia, Maria Carmela; Rowe, James Benedict; Finger, Elizabeth; Vandenberghe, Rik; de Mendonca, Alexandre; Butler, Chris R; Gerhard, Alexander; Ducharme, Simon; Ber, Isabelle L E; Tiraboschi, Pietro; Santana, Isabel; Pasquier, Florence; Levin, Johannes; Otto, Markus; Sorbi, Sandro; Rohrer, Jonathan Daniel; Synofzik,; Matthis Annabel Nelson,; Bocchetta, Martina; Cash, David; David, L Thomas; Todd, Emily; Benotmane, Hanya; Nicholas, Jennifer; Samra, Kiran; Shafei, Rachelle; Timberlake, Carolyn; Cope, Thomas; Rittman, Timothy; Alberici, Antonella; Premi, Enrico; Gasparotti, Roberto; Cantoni, Valentina; Buratti, Emanuele; Arighi, Andrea; Fenoglio, Chiara; Scarpini, Elio; Fumagalli, Giorgio; Borracci, Vittoria; Rossi, Giacomina; Giaccone, Giorgio; Giuseppe Di Fede,; Caroppo, Paola; Tiraboschi, Pietro; Prioni, Sara; Redaelli, Veronica; Tang-Wai, David; Rogaeva, Ekaterina; Castelo-Branco, Miguel; Freedman, Morris; Keren, Ron; Black, Sandra; Mitchell, Sara; Shoesmith, Christen; Bartha, Robart; Rademakers, Rosa; Poos, Jackie; Janne, M Papma; Giannini, Lucia; Rick van Minkelen,; Pijnenburg, Yolande; Nacmias, Benedetta; Ferrari, Camilla; Polito, Cristina; Lombardi, Gemma; Bessi, Valentina; Veldsman, Michele; Andersson, Christin; Thonberg, Hakan; Öijerstedt, Linn; Jelic, Vesna; Thompson, Paul; Langheinrich, Tobias; Lladó, Albert; Antonell, Anna; Olives, Jaume; Balasa, Mircea; Bargalló, Nuria; Borrego-Ecija, Sergi; Verdelho, Ana; Maruta, Carolina; Catarina, B Ferreira; Miltenberger, Gabriel; Coelho, Tiago; Frederico Simões do Couto,; Gabilondo, Alazne; Gorostidi, Ana; Villanua, Jorge; Cañada, Marta; Tainta, Mikel; Zulaica, Miren; Barandiaran, Myriam; Alves, Patricia; Bender, Benjamin; Graf, Lisa; Vogels, Annick; Vandenbulcke, Mathieu; Van Damme Philip,; Bruffaerts, Rose; Poesen, Koen; Rosa-Neto, Pedro; Gauthier, Serge; Camuzat, Agnès; Brice, Alexis; Bertrand, Anne; Funkiewiez, Aurélie; Rinaldi, Daisy; Saracino, Dario; Colliot, Olivier; Sayah, Sabrina; Prix, Catharina; Wlasich, Elisabeth; Wagemann, Olivia; Loosli, Sandra; Schönecker, Sonja; Hoegen, Tobias; Lombardi, Jolina; Anderl-Straub, Sarah; Rollin, Adeline; Kuchcinski, Gregory; Bertoux, Maxime; Lebouvier, Thibaud; Deramecourt, Vincent; Santiago, Beatriz; Duro, Diana; Maria João Leitão,; Maria Rosario Almeida,; Tábuas-Pereira, Miguel; Afonso, Sónia

doi:10.1136/jnnp-2023-332464

BackgroundBlood neurofilament light chain (NfL) is increasingly considered as a key trial biomarker in genetic frontotemporal dementia (gFTD). We aimed to facilitate the use of NfL in gFTD multicentre trials by testing its (1) reliability across labs; (2) reliability to stratify gFTD disease stages; (3) comparability between blood matrices and (4) stability across recruiting sites.MethodsComparative analysis of blood NfL levels in a large gFTD cohort (GENFI) for (1)-(4), with n=344 samples (n=148 presymptomatic, n=11 converter, n=46 symptomatic subjects, with mutations in C9orf72, GRN or MAPT; and n=139 within-family controls), each measured in three different international labs by Simoa HD-1 analyzer.ResultsNfL revealed an excellent consistency (intraclass correlation coefficient (ICC) 0.964) and high reliability across the three labs (maximal bias (pg/mL) in Bland-Altman analysis: 1.12 +/- 1.20). High concordance of NfL across laboratories was moreover reflected by high areas under the curve for discriminating conversion stage against the (non-converting) presymptomatic stage across all three labs. Serum and plasma NfL were largely comparable (ICC 0.967). The robustness of NfL across 13 recruiting sites was demonstrated by a linear mixed effect model.ConclusionsOur results underline the suitability of blood NfL in gFTD multicentre trials, including cross-lab reliable stratification of the highly trial-relevant conversion stage, matrix comparability and cross-site robustness.

NfL reliability across laboratories, stage-dependent diagnostic performance and matrix comparability in genetic FTD: a large GENFI study / Linnemann, Christoph; Wilke, Carlo; Mengel, David; Zetterberg, Henrik; Heller, Carolin; Kuhle, Jens; Bouzigues, Arabella; Russell, Lucy L; Foster, Phoebe H; Ferry-Bolder, Eve; Van Swieten, John Cornelis; Jiskoot, Lize C; Seelaar, Harro; Moreno, Fermin; Borroni, Barbara; Sánchez-Valle, Raquel; Galimberti, Daniela; Laforce, Robert; Graff, Caroline; Masellis, Mario; Tartaglia, Maria Carmela; Rowe, James Benedict; Finger, Elizabeth; Vandenberghe, Rik; de Mendonca, Alexandre; Butler, Chris R; Gerhard, Alexander; Ducharme, Simon; Ber, Isabelle L E; Tiraboschi, Pietro; Santana, Isabel; Pasquier, Florence; Levin, Johannes; Otto, Markus; Sorbi, Sandro; Rohrer, Jonathan Daniel; Synofzik, Matthis Annabel Nelson, Martina Bocchetta, David Cash, David L Thomas, Emily Todd, Hanya Benotmane, Jennifer Nicholas, Kiran Samra, Rachelle Shafei, Carolyn Timberlake, Thomas Cope, Timothy Rittman, Antonella Alberici, Enrico Premi, Roberto Gasparotti, Valentina Cantoni, Emanuele Buratti, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Vittoria Borracci, Giacomina Rossi, Giorgio Giaccone, Giuseppe Di Fede, Paola Caroppo, Pietro Tiraboschi, Sara Prioni, Veronica Redaelli, David Tang-Wai, Ekaterina Rogaeva, Miguel Castelo-Branco, Morris Freedman, Ron Keren, Sandra Black, Sara Mitchell, Christen Shoesmith, Robart Bartha, Rosa Rademakers, Jackie Poos, Janne M Papma, Lucia Giannini, Rick van Minkelen, Yolande Pijnenburg, Benedetta Nacmias, Camilla Ferrari, Cristina Polito, Gemma Lombardi, Valentina Bessi, Michele Veldsman, Christin Andersson, Hakan Thonberg, Linn Öijerstedt, Vesna Jelic, Paul Thompson, Tobias Langheinrich, Albert Lladó, Anna Antonell, Jaume Olives, Mircea Balasa, Nuria Bargalló, Sergi Borrego-Ecija, Ana Verdelho, Carolina Maruta, Catarina B Ferreira, Gabriel Miltenberger, Tiago Coelho, Frederico Simões do Couto, Alazne Gabilondo, Ana Gorostidi, Jorge Villanua, Marta Cañada, Mikel Tainta, Miren Zulaica, Myriam Barandiaran, Patricia Alves, Benjamin Bender, Lisa Graf, Annick Vogels, Mathieu Vandenbulcke, Van Damme Philip, Rose Bruffaerts, Koen Poesen, Pedro Rosa-Neto, Serge Gauthier, Agnès Camuzat, Alexis Brice, Anne Bertrand, Aurélie Funkiewiez, Daisy Rinaldi, Dario Saracino, Olivier Colliot, Sabrina Sayah, Catharina Prix, Elisabeth Wlasich, Olivia Wagemann, Sandra Loosli, Sonja Schönecker, Tobias Hoegen, Jolina Lombardi, Sarah Anderl-Straub, Adeline Rollin, Gregory Kuchcinski, Maxime Bertoux, Thibaud Lebouvier, Vincent Deramecourt, Beatriz Santiago, Diana Duro, Maria João Leitão, Maria Rosario Almeida, Miguel Tábuas-Pereira, Sónia Afonso. - In: JOURNAL OF NEUROLOGY, NEUROSURGERY AND PSYCHIATRY. - ISSN 0022-3050. - ELETTRONICO. - (2024), pp. jnnp-2023-332464.822-jnnp-2023-332464.828. [10.1136/jnnp-2023-332464]