@article {Panman494, author = {Jessica L Panman and Vikram Venkatraghavan and Emma L van der Ende and Rebecca M E Steketee and Lize C Jiskoot and Jackie M Poos and Elise G P Dopper and Lieke H H Meeter and Laura Donker Kaat and Serge A R B Rombouts and Meike W Vernooij and Anneke J A Kievit and Enrico Premi and Maura Cosseddu and Elisa Bonomi and Jaume Olives and Jonathan D Rohrer and Raquel S{\'a}nchez-Valle and Barbara Borroni and Esther E Bron and John C Van Swieten and Janne M Papma and Stefan Klein}, editor = {, and , and Afonso, S{\'o}nia and Almeida, Maria Rosario and Anderl-Straub, Sarah and Andersson, Christin and Antonell, Anna and Archetti, Silvana and Arighi, Andrea and Balasa, Mircea and Barandiaran, Myriam and Bargall{\'o}, Nuria and Bartha, Robart and Bender, Benjamin and Black, Sandra and Butler, Chris and Bocchetta, Martina and Borrego-Ecija, Sergi and Bras, Jose and Bruffaerts, Rose and Caroppo, Paola and Cash, David and Castelo-Branco, Miguel and Convery, Rhian and Cope, Thomas and Danek, Adrian and Arriba, Mar{\'\i}a de and Mendon{\c c}a, Alexandre de and Fede, Giuseppe Di and D{\'\i}az, Zigor and Ducharme, Simon and Duro, Diana and Fenoglio, Chiara and Ferreira, Catarina B and Finger, Elizabeth and Flanagan, Toby and Fox, Nick and Freedman, Morris and Fumagalli, Giorgio and Gabilondo, Alazne and Galimberti, Daniela and Gasparotti, Roberto and Gauthier, Serge and Gazzina, Stefano and Gerhard, Alexander and Giaccone, Giorgio and Gorostidi, Ana and Graff, Caroline and Greaves, Caroline and Guerreiro, Rita and Heller, Carolin and Hoegen, Tobias and Indakoetxea, Bego{\~n}a and Jelic, Vesna and Karnath, Hans-Otto and Keren, Ron and Laforce, Robert and Leit{\~a}o, Maria Jo{\~a}o and Levin, Johannes and Llad{\'o}, Albert and Loosli, Sandra and Maruta, Carolina and Masellis, Mario and Mead, Simon and Miltenberger, Gabriel and Minkelenm, Rick van and Mitchell, Sara and Moore, Katrina and Moreno, Fermin and Nicholas, Jennifer and {\"O}ijerstedt, Linn and Otto, Markus and Ourselin, Sebastian and Padovani, Alessandro and Peakman, Georgia and Pijnenburg, Yolande and Polito, Cristina and Prioni, Sara and Prix, Catharina and Rademakers, Rosa and Redaelli, Veronica and Rittman, Tim and Rogaeva, Ekaterina and Rosa-Neto, Pedro and Rossi, Giacomina and Rosser, Martin and Rowe, James and Santana, Isabel and Santiago, Beatriz and Scarpini, Elio and Sch{\"o}necker, Sonja and Semler, Elisa and Shafei, Rachelle and Shoesmith, Christen and Synofzik, Matthis and T{\'a}buas-Pereira, Miguel and Tagliavini, Fabrizio and Tartaglia, Carmela and Tainta, Mikel and Taipa, Ricardo and Tang-Wai, David and Thomas, David L and Thonberg, Hakan and Timberlake, Carolyn and Tiraboschi, Pietro and Todd, Emily and Vandamme, Philip and Vandenberghe, Rik and Vandenbulcke, Mathieu and Veldsman, Michele and Verdelho, Ana and Villanua, Jorge and Warren, Jason and WilkeIone, Carlo and Elisabeth, Woollacott and Henrik, Wlasich and Zulaica, Zetterberg Miren}, title = {Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia}, volume = {92}, number = {5}, pages = {494--501}, year = {2021}, doi = {10.1136/jnnp-2020-323541}, publisher = {BMJ Publishing Group Ltd}, abstract = {Objective Progranulin-related frontotemporal dementia (FTD-GRN) is a fast progressive disease. Modelling the cascade of multimodal biomarker changes aids in understanding the aetiology of this disease and enables monitoring of individual mutation carriers. In this cross-sectional study, we estimated the temporal cascade of biomarker changes for FTD-GRN, in a data-driven way.Methods We included 56 presymptomatic and 35 symptomatic GRN mutation carriers, and 35 healthy non-carriers. Selected biomarkers were neurofilament light chain (NfL), grey matter volume, white matter microstructure and cognitive domains. We used discriminative event-based modelling to infer the cascade of biomarker changes in FTD-GRN and estimated individual disease severity through cross-validation. We derived the biomarker cascades in non-fluent variant primary progressive aphasia (nfvPPA) and behavioural variant FTD (bvFTD) to understand the differences between these phenotypes.Results Language functioning and NfL were the earliest abnormal biomarkers in FTD-GRN. White matter tracts were affected before grey matter volume, and the left hemisphere degenerated before the right. Based on individual disease severities, presymptomatic carriers could be delineated from symptomatic carriers with a sensitivity of 100\% and specificity of 96.1\%. The estimated disease severity strongly correlated with functional severity in nfvPPA, but not in bvFTD. In addition, the biomarker cascade in bvFTD showed more uncertainty than nfvPPA.Conclusion Degeneration of axons and language deficits are indicated to be the earliest biomarkers in FTD-GRN, with bvFTD being more heterogeneous in disease progression than nfvPPA. Our data-driven model could help identify presymptomatic GRN mutation carriers at risk of conversion to the clinical stage.Data are available upon reasonable request. The raw data of this project are part of Genetic Frontotemporal dementia Initiative and are not publicly available. Data can be accessed upon reasonable request to JCVS (j.c.vanswieten@erasmusmc.nl) and JDR (j.rohrer@ucl.ac.uk). The code for discriminative event-based modelling is available and can be downloaded from https://github.com/88vikram/pyebm/.}, issn = {0022-3050}, URL = {https://jnnp.bmj.com/content/92/5/494}, eprint = {https://jnnp.bmj.com/content/92/5/494.full.pdf}, journal = {Journal of Neurology, Neurosurgery \& Psychiatry} }