Journal
NATURE MEDICINE
Volume 28, Issue 10, Pages 2194-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41591-022-01942-9
Keywords
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Funding
- National Institute on Aging [U19: AG063911, U01 AG045390]
- National Institute of Neurological Diseases and Stroke [U19: AG063911, U01 AG045390, U54 NS092089]
- National Center for Advancing Translational Sciences [U54 NS092089]
- Association for Frontotemporal Degeneration (FTD Biomarkers Initiative)
- Bluefield Project to Cure FTD
- Larry L. Hillblom Foundation [2018-A-025-FEL]
- National Institutes of Health [AG038791, AG032306, AG016976, AG062677, AG019724, AG058233, AG072122, P30 AG062422, K12 HD001459, K23AG061253, AG062422, K24AG045333]
- Rainwater Charitable Foundation
- National Centralized Repository for Alzheimer Disease and Related Dementias (NCRAD) - National Institute on Aging (NIA) [U24 AG021886]
- Medical Research Council UK GENFI grant [MR/M023664/1]
- Bluefield Project
- National Institute for Health Research
- JPND GENFI-PROX grant [2019-02248]
- European Reference Network for Rare Neurologic Diseases [739510]
- National Institute for Health and Care Research (NIHR) UCL/H Biomedical Research Centre
- Leonard Wolfson Experimental Neurology Centre Clinical Research Facility
- UK Dementia Research Institute from UK DRI Ltd - UK Medical Research Council
- Alzheimer's Society
- Alzheimer's Research UK
- Miriam Marks Brain Research UK Senior Fellowship
- MRC Clinician Scientist Fellowship [MR/M008525/1]
- NIHR Rare Disease Translational Research Collaboration [BRC149/NS/MH]
- Alzheimer's Society, UK [AS-JF-19a-004-517]
- Frontotemporal Dementia Research Studentships in Memory of David Blechner through The National Brain Appeal [RCN 290173]
- NIHR Cambridge Biomedical Research Centre [BRC-121520014]
- Wellcome Trust [220258]
- Cambridge Centre for Parkinson-plus
- Medical Research Council [SUAG/092 G116768]
- ANR-PRTS PREV-DemAls
- PHRC PREDICT-PGRN
- European Reference Network for Rare Neurological Diseases [739510]
- Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany's Excellence Strategy [EXC 2145, 390857198]
- Hospital Clinic de Barcelona by Instituto de Salud Carlos III, Spain [PI20/00448]
- Fundacio Marato TV3, Spain [20143810]
- UK Medical Research Council
- Italian Ministry of Health
- Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant
- Canadian Institutes of Health Research [MOP-371851, PJT-175242]
- Weston Brain Institute
- Chaire de Recherche sur les Aphasies Primaires Progressives Fondation Famille Lemaire
- Swedish Frontotemporal Dementia Initiative Schorling Foundation
- Swedish Research Council
- JPND Prefrontals [2015-02926,2018-02754]
- Swedish Alzheimer Foundation
- Swedish Brain Foundation
- Karolinska Institutet Doctoral Funding
- KI Strat-Neuro
- Swedish Dementia Foundation
- Stockholm County Council ALF/Region Stockholm
- German Research Foundation [EXC 2145, 390857198]
- Brain Research UK
- Wolfson Foundation
- National Institute for Health Research UCL/H Biomedical Research Centre
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This study developed multimodal models for familial frontotemporal dementia (f-FTD) progression and found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations, atrophy and NfL were identified as the best endpoints, with clinical measures potential endpoints in early symptomatic trials.
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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