Temporal order of clinical and biomarker changes in familial frontotemporal dementia.

Adam M Staffaroni ORCID logo ; Melanie Quintana ORCID logo ; Barbara Wendelberger ORCID logo ; Hilary W Heuer ; Lucy L Russell ORCID logo ; Yann Cobigo ORCID logo ; Amy Wolf ; Sheng-Yang Matt Goh ; Leonard Petrucelli ; Tania F Gendron ORCID logo ; +95 more... Carolin Heller ORCID logo ; Annie L Clark ; Jack Carson Taylor ORCID logo ; Amy Wise ; Elise Ong ; Leah Forsberg ; Danielle Brushaber ; Julio C Rojas ; Lawren VandeVrede ORCID logo ; Peter Ljubenkov ; Joel Kramer ; Kaitlin B Casaletto ; Brian Appleby ; Yvette Bordelon ; Hugo Botha ORCID logo ; Bradford C Dickerson ; Kimiko Domoto-Reilly ORCID logo ; Julie A Fields ; Tatiana Foroud ORCID logo ; Ralitza Gavrilova ; Daniel Geschwind ORCID logo ; Nupur Ghoshal ORCID logo ; Jill Goldman ; Jonathon Graff-Radford ; Neill Graff-Radford ; Murray Grossman ; Matthew GH Hall ; Ging-Yuek Hsiung ORCID logo ; Edward D Huey ; David Irwin ; David T Jones ORCID logo ; Kejal Kantarci ; Daniel Kaufer ; David Knopman ORCID logo ; Walter Kremers ; Argentina Lario Lago ; Maria I Lapid ORCID logo ; Irene Litvan ORCID logo ; Diane Lucente ; Ian R Mackenzie ; Mario F Mendez ORCID logo ; Carly Mester ; Bruce L Miller ; Chiadi U Onyike ; Rosa Rademakers ORCID logo ; Vijay K Ramanan ORCID logo ; Eliana Marisa Ramos ; Meghana Rao ; Katya Rascovsky ; Katherine P Rankin ; Erik D Roberson ORCID logo ; Rodolfo Savica ; M Carmela Tartaglia ORCID logo ; Sandra Weintraub ; Bonnie Wong ; David M Cash ORCID logo ; Arabella Bouzigues ORCID logo ; Imogen J Swift ; Georgia Peakman ORCID logo ; Martina Bocchetta ORCID logo ; Emily G Todd ; Rhian S Convery ; James B Rowe ORCID logo ; Barbara Borroni ; Daniela Galimberti ORCID logo ; Pietro Tiraboschi ; Mario Masellis ; Elizabeth Finger ; John C van Swieten ; Harro Seelaar ORCID logo ; Lize C Jiskoot ; Sandro Sorbi ORCID logo ; Chris R Butler ; Caroline Graff ; Alexander Gerhard ORCID logo ; Tobias Langheinrich ORCID logo ; Robert Laforce ORCID logo ; Raquel Sanchez-Valle ORCID logo ; Alexandre de Mendonça ; Fermin Moreno ; Matthis Synofzik ; Rik Vandenberghe ; Simon Ducharme ; Isabelle Le Ber ; Johannes Levin ; Adrian Danek ORCID logo ; Markus Otto ; Florence Pasquier ORCID logo ; Isabel Santana ; John Kornak ; Bradley F Boeve ORCID logo ; Howard J Rosen ; Jonathan D Rohrer ; Adam L Boxer ORCID logo ; Frontotemporal Dementia Prevention Initiative (FPI) Investigator ; (2022) Temporal order of clinical and biomarker changes in familial frontotemporal dementia. Nature medicine, 28 (10). pp. 2194-2206. ISSN 1078-8956 DOI: 10.1038/s41591-022-01942-9
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Unlike familial Alzheimer's disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects.


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