TY - JOUR
T1 - Temporal order of clinical and biomarker changes in familial frontotemporal dementia
AU - Frontotemporal Dementia Prevention Initiative (FPI) Investigators
AU - ALLFTD Investigators
AU - GENFI Investigators
AU - Staffaroni, Adam M.
AU - Quintana, Melanie
AU - Wendelberger, Barbara
AU - Heuer, Hilary W.
AU - Russell, Lucy L.
AU - Cobigo, Yann
AU - Wolf, Amy
AU - Goh, Sheng Yang Matt
AU - Petrucelli, Leonard
AU - Gendron, Tania F.
AU - Heller, Carolin
AU - Clark, Annie L.
AU - Taylor, Jack Carson
AU - Wise, Amy
AU - Ong, Elise
AU - Forsberg, Leah
AU - Brushaber, Danielle
AU - Rojas, Julio C.
AU - VandeVrede, Lawren
AU - Ljubenkov, Peter
AU - Kramer, Joel
AU - Casaletto, Kaitlin B.
AU - Appleby, Brian
AU - Bordelon, Yvette
AU - Botha, Hugo
AU - Dickerson, Bradford C.
AU - Domoto-Reilly, Kimiko
AU - Fields, Julie A.
AU - Foroud, Tatiana
AU - Gavrilova, Ralitza
AU - Geschwind, Daniel
AU - Ghoshal, Nupur
AU - Goldman, Jill
AU - Graff-Radford, Jonathon
AU - Graff-Radford, Neill
AU - Grossman, Murray
AU - Hall, Matthew G.H.
AU - Hsiung, Ging Yuek
AU - Huey, Edward D.
AU - Irwin, David
AU - Jones, David T.
AU - Kantarci, Kejal
AU - Kaufer, Daniel
AU - Knopman, David
AU - Kremers, Walter
AU - Lago, Argentina Lario
AU - Lapid, Maria I.
AU - Litvan, Irene
AU - Lucente, Diane
AU - Mackenzie, Ian R.
AU - Mendez, Mario F.
AU - Mester, Carly
AU - Miller, Bruce L.
AU - Onyike, Chiadi U.
AU - Rademakers, Rosa
AU - Ramanan, Vijay K.
AU - Ramos, Eliana Marisa
AU - Rao, Meghana
AU - Rascovsky, Katya
AU - Rankin, Katherine P.
AU - Roberson, Erik D.
AU - Savica, Rodolfo
AU - Tartaglia, M. Carmela
AU - Weintraub, Sandra
AU - Wong, Bonnie
AU - Cash, David M.
AU - Bouzigues, Arabella
AU - Swift, Imogen J.
AU - Peakman, Georgia
AU - Bocchetta, Martina
AU - Todd, Emily G.
AU - Convery, Rhian S.
AU - Rowe, James B.
AU - Borroni, Barbara
AU - Galimberti, Daniela
AU - Tiraboschi, Pietro
AU - Masellis, Mario
AU - Finger, Elizabeth
AU - van Swieten, John C.
AU - Seelaar, Harro
AU - Jiskoot, Lize C.
AU - Sorbi, Sandro
AU - Butler, Chris R.
AU - Graff, Caroline
AU - Gerhard, Alexander
AU - Langheinrich, Tobias
AU - Laforce, Robert
AU - Sanchez-Valle, Raquel
AU - de Mendonça, Alexandre
AU - Moreno, Fermin
AU - Synofzik, Matthis
AU - Vandenberghe, Rik
AU - Ducharme, Simon
AU - Le Ber, Isabelle
AU - Levin, Johannes
AU - Danek, Adrian
AU - Otto, Markus
AU - Pasquier, Florence
AU - Santana, Isabel
AU - Kornak, John
AU - Boeve, Bradley F.
AU - Rosen, Howard J.
AU - Rohrer, Jonathan D.
AU - Boxer, Adam L.
AU - Apostolova, Liana
AU - Barmada, Sami
AU - Boeve, Bradley
AU - Bozoki, Andrea
AU - Clark, David
AU - Coppola, Giovanni
AU - Darby, Ryan
AU - Dickson, Dennis
AU - Faber, Kelley
AU - Fagan, Anne
AU - Galasko, Douglas R.
AU - Grant, Ian M.
AU - Huang, Eric
AU - Kerwin, Diana
AU - Lapid, Maria
AU - Lee, Suzee
AU - Leger, Gabriel
AU - Masdeux, Joseph C.
AU - McGinnis, Scott
AU - Onyike, Chiadi
AU - Pascual, M. Belen
AU - Pressman, Peter
AU - Rademakers, Rosa
AU - Ramanan, Vijay
AU - Ritter, Aaron
AU - Seeley, William W.
AU - Syrjanen, Jeremy
AU - Taylor, Jack C.
AU - Weintraub, Sandra
AU - Esteve, Aitana Sogorb
AU - Nelson, Annabel
AU - Greaves, Caroline V.
AU - Thomas, David L.
AU - Benotmane, Hanya
AU - Zetterberg, Henrik
AU - Nicholas, Jennifer
AU - Samra, Kiran
AU - Shafei, Rachelle
AU - Timberlake, Carolyn
AU - Cope, Thomas
AU - Rittman, Timothy
AU - Benussi, Alberto
AU - Premi, Enrico
AU - Gasparotti, Roberto
AU - Archetti, Silvana
AU - Gazzina, Stefano
AU - Cantoni, Valentina
AU - Arighi, Andrea
AU - Fenoglio, Chiara
AU - Scarpini, Elio
AU - Fumagalli, Giorgio
AU - Borracci, Vittoria
AU - Rossi, Giacomina
AU - Giaccone, Giorgio
AU - Di Fede, Giuseppe
AU - Caroppo, Paola
AU - Prioni, Sara
AU - Redaelli, Veronica
AU - Tang-Wai, David
AU - Rogaeva, Ekaterina
AU - Castelo-Branco, Miguel
AU - Freedman, Morris
AU - Keren, Ron
AU - Black, Sandra
AU - Mitchell, Sara
AU - Shoesmith, Christen
AU - Bartha, Robart
AU - Poos, Jackie
AU - Papma, Janne M.
AU - Giannini, Lucia
AU - van Minkelen, Rick
AU - Pijnenburg, Yolande
AU - Nacmias, Benedetta
AU - Ferrari, Camilla
AU - Polito, Cristina
AU - Lombardi, Gemma
AU - Bessi, Valentina
AU - Veldsman, Michele
AU - Andersson, Christin
AU - Thonberg, Hakan
AU - Öijerstedt, Linn
AU - Jelic, Vesna
AU - Thompson, Paul
AU - Lladó, Albert
AU - Antonell, Anna
AU - Olives, Jaume
AU - Balasa, Mircea
AU - Bargalló, Nuria
AU - Borrego-Ecija, Sergi
AU - Verdelho, Ana
AU - Maruta, Carolina
AU - Ferreira, Catarina B.
AU - Miltenberger, Gabriel
AU - Simões do Couto, Frederico
AU - Gabilondo, Alazne
AU - Gorostidi, Ana
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/10
Y1 - 2022/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85139804219&partnerID=8YFLogxK
U2 - 10.1038/s41591-022-01942-9
DO - 10.1038/s41591-022-01942-9
M3 - Article
C2 - 36138153
AN - SCOPUS:85139804219
SN - 1078-8956
VL - 28
SP - 2194
EP - 2206
JO - Nature medicine
JF - Nature medicine
IS - 10
ER -