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

Background: Blood 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. Methods: Comparative 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. Results: NfL 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. Conclusions: Our 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 / Christoph, Linnemann; Carlo, Wilke; David, Mengel; Henrik, Zetterberg; Carolin, Heller; Jens, Kuhle; Arabella, Bouzigues; Lucy L, Russell; Phoebe H, Foster; Eve, Ferry-Bolder; John Cornelis, Van Swieten; Lize C, Jiskoot; Harro, Seelaar; Fermin, Moreno; Barbara, Borroni; Raquel, Sánchez-Valle; Daniela, Galimberti; Robert, Laforce; Caroline, Graff; Mario, Masellis; Maria Carmela, Tartaglia; James Benedict, Rowe; Elizabeth, Finger; Rik, Vandenberghe; Alexandre, de Mendonca; Chris R, Butler; Alexander, Gerhard; Simon, Ducharme; Isabelle L E, Ber; Pietro, Tiraboschi; Isabel, Santana; Florence, Pasquier; Johannes, Levin; Markus, Otto; Sandro, Sorbi; Jonathan Daniel, Rohrer; Synofzik, ; Annabel Nelson, Matthis; Bocchetta, Martina; Cash, David; L Thomas, David; 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; Di Fede, Giuseppe; 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; M Papma, Janne; Giannini, Lucia; van Minkelen, Rick; 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; B Ferreira, Catarina; Miltenberger, Gabriel; Coelho, Tiago; Simões do Couto, Frederico; Gabilondo, Alazne; Gorostidi, Ana; Villanua, Jorge; Cañada, Marta; Tainta, Mikel; Zulaica, Miren; Barandiaran, Myriam; Alves, Patricia; Bender, Benjamin; Graf, Lisa; Vogels, Annick; Vandenbulcke, Mathieu; Damme Philip, Van; 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; João Leitão, Maria; Rosario Almeida, Maria; Tábuas-Pereira, Miguel; Afonso, Sónia. - In: JOURNAL OF NEUROLOGY, NEUROSURGERY AND PSYCHIATRY. - ISSN 0022-3050. - 2024:(2024), pp. 1-7. [10.1136/jnnp-2023-332464]