Temporal order of clinical and biomarker changes in familial frontotemporal dementia

Adam M. Staffaroni, Melanie Quintana, Frontotemporal Dementia Prevention Initiative (FPI) Investigators, Barbara Wendelberger, Hilary W. Heuer, Lucy L. Russell, Yann Cobigo, Amy Wolf, Sheng Yang Matt Goh, Leonard Petrucelli, Tania F. Gendron, Carolin Heller, Annie L. Clark, Jack Carson Taylor, Amy Wise, Elise Ong, Leah Forsberg, Danielle Brushaber, Julio C. Rojas, Lawren VandeVredePeter Ljubenkov, Joel Kramer, Kaitlin B. Casaletto, Brian Appleby, Yvette Bordelon, Hugo Botha, Bradford C. Dickerson, Kimiko Domoto-Reilly, Julie A. Fields, Tatiana Foroud, Ralitza Gavrilova, Daniel Geschwind, Nupur Ghoshal, Jill Goldman, Jonathon Graff-Radford, Neill Graff-Radford, Murray Grossman, Matthew G.H. Hall, Ging Yuek Hsiung, Edward D. Huey, David Irwin, David T. Jones, Kejal Kantarci, Daniel Kaufer, David Knopman, Walter Kremers, Argentina Lario Lago, Maria I. Lapid, John C. van Swieten, Harro Seelaar, Lize C. Jiskoot, Jonathan D. Rohrer, Adam L. Boxer

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Web of Science)

Abstract

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.

Original languageEnglish
Pages (from-to)2194-2206
Number of pages13
JournalNature Medicine
Volume28
Issue number10
Early online date22 Sep 2022
DOIs
Publication statusPublished - 1 Oct 2022

Bibliographical note

Publisher Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

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