Temporal order of clinical and biomarker changes in familial frontotemporal dementia

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...

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Published in	Nature Medicine Vol. 28; no. 10; pp. 2194 - 2206
Main Authors	Staffaroni, Adam M., Quintana, Melanie, Wendelberger, Barbara, Heuer, Hilary W., Russell, Lucy L., Cobigo, Yann, Wolf, Amy, Petrucelli, Leonard, Gendron, Tania F., Heller, Carolin, Clark, Annie L., Taylor, Jack Carson, Wise, Amy, Ong, Elise, Forsberg, Leah, Brushaber, Danielle, Rojas, Julio C., VandeVrede, Lawren, Ljubenkov, Peter, Kramer, Joel, Casaletto, Kaitlin B., Appleby, Brian, Botha, Hugo, Dickerson, Bradford C., Domoto-Reilly, Kimiko, Fields, Julie A., Foroud, Tatiana, Gavrilova, Ralitza, Geschwind, Daniel, Ghoshal, Nupur, Goldman, Jill, Graff-Radford, Jonathon, Graff-Radford, Neill, Grossman, Murray, Hall, Matthew G. H., Hsiung, Ging-Yuek, Huey, Edward D., Irwin, David, Jones, David T., Kantarci, Kejal, Kaufer, Daniel, Knopman, David, Kremers, Walter, Lago, Argentina Lario, Lapid, Maria I., Litvan, Irene, Lucente, Diane, Mackenzie, Ian R., Mendez, Mario F., Mester, Carly, Miller, Bruce L., Onyike, Chiadi U., Rademakers, Rosa, Ramanan, Vijay K., Ramos, Eliana Marisa, Rao, Meghana, Rascovsky, Katya, Rankin, Katherine P., Roberson, Erik D., Savica, Rodolfo, Tartaglia, M. Carmela, Weintraub, Sandra, Wong, Bonnie, Cash, David M., Bouzigues, Arabella, Swift, Imogen J., Peakman, Georgia, Bocchetta, Martina, Todd, Emily G., Convery, Rhian S., Rowe, James B., Borroni, Barbara, Tiraboschi, Pietro, Masellis, Mario, Finger, Elizabeth, van Swieten, John C., Seelaar, Harro, Jiskoot, Lize C., Sorbi, Sandro, Butler, Chris R., Graff, Caroline, Gerhard, Alexander, Langheinrich, Tobias, Laforce, Robert, Sanchez-Valle, Raquel, de Mendonça, Alexandre, Moreno, Fermin, Synofzik, Matthis, Vandenberghe, Rik, Ducharme, Simon, Levin, Johannes, Danek, Adrian, Otto, Markus, Pasquier, Florence, Santana, Isabel, Kornak, John, Boeve, Bradley F., Rosen, Howard J., Rohrer, Jonathan D., Boxer, Adam. L.
Format	Journal Article Magazine Article
Language	English
Published	New York Nature Publishing Group US 01.10.2022 Nature Publishing Group
Subjects	692/53 692/617/375/132 Alzheimer's disease Atrophy Biomarkers Biomedical and Life Sciences Biomedicine C9orf72 Protein C9orf72 Protein - genetics Cancer Research Clinical trials Clinical Trials as Topic Dementia Dementia disorders Disease prevention Disease Progression Frontotemporal Dementia Frontotemporal Dementia - genetics Genotypes Humans Infectious Diseases Life Sciences Medical imaging Metabolic Diseases Molecular Medicine Mutation Mutation - genetics Neurodegenerative diseases Neuroimaging Neurons and Cognition Neurosciences tau Proteins tau Proteins - genetics Temporal variations
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ISSN	1078-8956 1546-170X 1546-170X 1744-7933
DOI	10.1038/s41591-022-01942-9

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Summary:	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. Empirically based models of disease progression in familial frontotemporal dementia reveal the relative ordering of clinical, neuroimaging, and fluid biomarker changes and facilitate novel clinical trial designs
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC9951811 Author Contributions Statement A.M.S., M.Q., and B.W. had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. A.M.S., M.Q., B.W., H.W.H., L.R., H.J.R., J.D.R., and A.L.B. were responsible for concept development and design. A.M.S., M.Q., and B.W. conducted statistical analyses. M.Q. and B.W. developed the custom code for the disease progression models. L.P., T.F.G., and C.H. processed the neurofilament light chain data. Y.C., A.W., and S.Y.M.G. processed the neuroimaging data. A.M.S., M.Q. and B.W. drafted the manuscript. A.M.S., M.Q., B.W., H.W.H, L.R., H.J.R., J.D.R, and A.L.B critically revised the manuscript. A.L.B. supervised the research. B.F.B, H.J.R, J.D.R, & A.L.B obtained funding. All authors contributed to acquisition, analysis, or interpretation of data or revision of the manuscript.
ISSN:	1078-8956 1546-170X 1546-170X 1744-7933
DOI:	10.1038/s41591-022-01942-9