Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia. Issue 5 (15th January 2021)

• Record Type: Journal Article
• Authors: Panman, Jessica L; Venkatraghavan, Vikram; van der Ende, Emma L; Steketee, Rebecca M E; Jiskoot, Lize C; Poos, Jackie M; Dopper, Elise G P; Meeter, Lieke H H; Donker Kaat, Laura; Rombouts, Serge A R B; Vernooij, Meike W; Kievit, Anneke J A; Premi, Enrico; Cosseddu, Maura; Bonomi, Elisa; Olives, Jaume; Rohrer, Jonathan D; Sánchez-Valle, Raquel; Borroni, Barbara; Bron, Esther E; Van Swieten, John C; Papma, Janne M; Klein, Stefan
• Other Names: author non-byline.; Afonso Sónia author non-byline.; Almeida Maria Rosario author non-byline.; Anderl-Straub Sarah author non-byline.; Andersson Christin author non-byline.; Antonell Anna author non-byline.; Archetti Silvana author non-byline.; Arighi Andrea author non-byline.; Balasa Mircea author non-byline.; Barandiaran Myriam author non-byline.; Bargalló Nuria author non-byline.; Bartha Robart author non-byline.; Bender Benjamin author non-byline.; Black Sandra author non-byline.; Butler Chris author non-byline.; Bocchetta Martina author non-byline.; Borrego-Ecija Sergi author non-byline.; Bras Jose author non-byline.; Bruffaerts Rose author non-byline.; Caroppo Paola author non-byline.; Cash David author non-byline.; Castelo-Branco Miguel author non-byline.; Convery Rhian author non-byline.; Cope Thomas author non-byline.; Danek Adrian author non-byline.; Arriba María de author non-byline.; Mendonça Alexandre de author non-byline.; Fede Giuseppe Di author non-byline.; Díaz Zigor author non-byline.; Ducharme Simon author non-byline.; Duro Diana author non-byline.; Fenoglio Chiara author non-byline.; Ferreira Catarina B author non-byline.; Finger Elizabeth author non-byline.; Flanagan Toby author non-byline.; Fox Nick author non-byline.; Freedman Morris author non-byline.; Fumagalli Giorgio author non-byline.; Gabilondo Alazne author non-byline.; Galimberti Daniela author non-byline.; Gasparotti Roberto author non-byline.; Gauthier Serge author non-byline.; Gazzina Stefano author non-byline.; Gerhard Alexander author non-byline.; Giaccone Giorgio author non-byline.; Gorostidi Ana author non-byline.; Graff Caroline author non-byline.; Greaves Caroline author non-byline.; Guerreiro Rita author non-byline.; Heller Carolin author non-byline.; Hoegen Tobias author non-byline.; Indakoetxea Begoña author non-byline.; Jelic Vesna author non-byline.; Karnath Hans-Otto author non-byline.; Keren Ron author non-byline.; Laforce Robert author non-byline.; Leitão Maria João author non-byline.; Levin Johannes author non-byline.; Lladó Albert author non-byline.; Loosli Sandra author non-byline.; Maruta Carolina author non-byline.; Masellis Mario author non-byline.; Mead Simon author non-byline.; Miltenberger Gabriel author non-byline.; Minkelenm Rick van author non-byline.; Mitchell Sara author non-byline.; Moore Katrina author non-byline.; Moreno Fermin author non-byline.; Nicholas Jennifer author non-byline.; Öijerstedt Linn author non-byline.; Otto Markus author non-byline.; Ourselin Sebastian author non-byline.; Padovani Alessandro author non-byline.; Peakman Georgia author non-byline.; Pijnenburg Yolande author non-byline.; Polito Cristina author non-byline.; Prioni Sara author non-byline.; Prix Catharina author non-byline.; Rademakers Rosa author non-byline.; Redaelli Veronica author non-byline.; Rittman Tim author non-byline.; Rogaeva Ekaterina author non-byline.; Rosa-Neto Pedro author non-byline.; Rossi Giacomina author non-byline.; Rosser Martin author non-byline.; Rowe James author non-byline.; Santana Isabel author non-byline.; Santiago Beatriz author non-byline.; Scarpini Elio author non-byline.; Schönecker Sonja author non-byline.; Semler Elisa author non-byline.; Shafei Rachelle author non-byline.; Shoesmith Christen author non-byline.; Synofzik Matthis author non-byline.; Tábuas-Pereira Miguel author non-byline.; Tagliavini Fabrizio author non-byline.; Tartaglia Carmela author non-byline.; Tainta Mikel author non-byline.; Taipa Ricardo author non-byline.; Tang-Wai David author non-byline.; Thomas David L author non-byline.; Thonberg Hakan author non-byline.; Timberlake Carolyn author non-byline.; Tiraboschi Pietro author non-byline.; Todd Emily author non-byline.; Vandamme Philip author non-byline.; Vandenberghe Rik author non-byline.; Vandenbulcke Mathieu author non-byline.; Veldsman Michele author non-byline.; Verdelho Ana author non-byline.; Villanua Jorge author non-byline.; Warren Jason author non-byline.; WilkeIone Carlo author non-byline.; Elisabeth Woollacott author non-byline.; Henrik Wlasich author non-byline.; Zulaica Zetterberg Miren author non-byline.;
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 92:Issue 5(2021)
• Page Start: 494
• Page End: 501
• Publication Date: 2021-01-15
• Subjects: Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2020-323541
• Languages: English
• ISSNs: 0022-3050

Abstract

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.