Anatomical progression of genetic frontotemporal lobar degeneration across the lifespan. Planche, V., Mansencal, B., Fonov, V., Manjon, J. V, Tourdias, T., Bouzigues, A., Russell, L. L, Foster, P. H, Ferry-Bolder, E., van Swieten, J. C, Jiskoot, L. C, Seelaar, H., Sanchez-Valle, R., Laforce, R., Graff, C., Galimberti, D., Vandenberghe, R., de Mendonça, A., Tiraboschi, P., Santana, I., Gerhard, A., Levin, J., Sorbi, S., Otto, M., Bertoux, M., Lebouvier, T., Butler, C. R, Le Ber, I., Finger, E., Tartaglia, M. C., Masellis, M., Rowe, J. B, Synofzik, M., Moreno, F., Borroni, B., Rohrer, J. D, Collins, D L., Ducharme, S., & Coupé, P. Brain : a journal of neurology, 148(11):3880–3892, nov, 2025.
doi  abstract   bibtex   
The recent development of brain charts for the human lifespan offers an ideal modelling framework for pathologies such as genetic frontotemporal lobar degeneration (FTLD) which likely involve both neurodevelopmental and neurodegenerative processes over a lifetime. We have therefore combined this new methodological approach with MRI data from asymptomatic and symptomatic subjects, carrying C9orf72, MAPT or GRN mutations from the Genetic FTD Initiative (GENFI) and the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study. We analysed 37 532 MRIs from control subjects covering the entire lifespan and a total of 1341 MRIs from subjects with a pathogenic FTLD mutation, aged from 18 to 86 years old. We detected the first significant regional brain volume differences on average at 27 years old in C9orf72 and MAPT mutation carriers, and at 42 years old in GRN mutation carriers. The delay between the onset of anatomical changes and the average age of symptom onset (i.e. the presymptomatic phase) was 13 years for MAPT, 17 years for GRN and 34 years for C9orf72 mutation carriers. In terms of effect size, cumulative atrophy over the lifespan was twice as severe in affected brain regions in MAPT than in GRN or C9orf72 mutation carriers. However, the neurodegenerative process was spatially more extensive in C9orf72 (35 brain regions affected out of the 61 tested) compared with GRN or MAPT mutation carriers (25 and 18 regions, respectively). Schematically, the chronological staging of atrophy progression showed an initial involvement of the thalamus in C9orf72 expansion carriers, followed by the fronto-temporo-insular regions, the striatum and the amygdala. In GRN mutation carriers, atrophy began in fronto-insular areas, before progressing toward subcortical structures. In MAPT mutation carriers, atrophy affected the anterior temporal pole with the amygdala and hippocampus, before progressing to fronto-insular regions and the striatum. Our results using brain charts for the human lifespan show that C9orf72 is the most diffuse but also the slowest to emerge among genetic FTLD. MAPT FTLD is more aggressive and focal, while GRN FTLD is also rapidly progressive but with a later onset of the presymptomatic phase. Beyond quantification of the anatomical progression of genetic FTLD over the lifespan, these results may help determine the best timing to model and test disease-modifying strategies in FTLD, and monitor their effect in future clinical trials.
@article{Planche2025,
abstract = {The recent development of brain charts for the human lifespan offers an ideal  modelling framework for pathologies such as genetic frontotemporal lobar degeneration (FTLD) which likely involve both neurodevelopmental and neurodegenerative processes over a lifetime. We have therefore combined this new methodological approach with MRI data from asymptomatic and symptomatic subjects, carrying C9orf72, MAPT or GRN mutations from the Genetic FTD Initiative (GENFI) and the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study. We analysed 37 532 MRIs from control subjects covering the entire lifespan and a total of 1341 MRIs from subjects with a pathogenic FTLD mutation, aged from 18 to 86 years old. We detected the first significant regional brain volume differences on average at 27 years old in C9orf72 and MAPT mutation carriers, and at 42 years old in GRN mutation carriers. The delay between the onset of anatomical changes and the average age of symptom onset (i.e. the presymptomatic phase) was 13 years for MAPT, 17 years for GRN and 34 years for C9orf72 mutation carriers. In terms of effect size, cumulative atrophy over the lifespan was twice as severe in affected brain regions in MAPT than in GRN or C9orf72 mutation carriers. However, the neurodegenerative process was spatially more extensive in C9orf72 (35 brain regions affected out of the 61 tested) compared with GRN or MAPT mutation carriers (25 and 18 regions, respectively). Schematically, the chronological staging of atrophy progression showed an initial involvement of the thalamus in C9orf72 expansion carriers, followed by the fronto-temporo-insular regions, the striatum and the amygdala. In GRN mutation carriers, atrophy began in fronto-insular areas, before progressing toward subcortical structures. In MAPT mutation carriers, atrophy affected the anterior temporal pole with the amygdala and hippocampus, before progressing to fronto-insular regions and the striatum. Our results using brain charts for the human lifespan show that C9orf72 is the most diffuse but also the slowest to emerge among genetic FTLD. MAPT FTLD is more aggressive and focal, while GRN FTLD is also rapidly progressive but with a later onset of the presymptomatic phase. Beyond quantification of the anatomical progression of genetic FTLD over the lifespan, these results may help determine the best timing to model and test disease-modifying strategies in FTLD, and monitor their effect in future clinical trials.},
author = {Planche, Vincent and Mansencal, Boris and Fonov, Vladimir and Manjon, Jos{\'{e}} V and Tourdias, Thomas and Bouzigues, Arabella and Russell, Lucy L and Foster, Phoebe H and Ferry-Bolder, Eve and van Swieten, John C and Jiskoot, Lize C and Seelaar, Harro and Sanchez-Valle, Raquel and Laforce, Robert and Graff, Caroline and Galimberti, Daniela and Vandenberghe, Rik and de Mendon{\c{c}}a, Alexandre and Tiraboschi, Pietro and Santana, Isabel and Gerhard, Alexander and Levin, Johannes and Sorbi, Sandro and Otto, Markus and Bertoux, Maxime and Lebouvier, Thibaud and Butler, Chris R and {Le Ber}, Isabelle and Finger, Elizabeth and Tartaglia, Maria Carmela and Masellis, Mario and Rowe, James B and Synofzik, Matthis and Moreno, Fermin and Borroni, Barbara and Rohrer, Jonathan D and Collins, D Louis and Ducharme, Simon and Coup{\'{e}}, Pierrick},
doi = {10.1093/brain/awaf195},
institution = {ALLFTD Consortium and the Genetic FTD Initiative (GENFI)},
issn = {1460-2156 (Electronic)},
journal = {Brain : a journal of neurology},
keywords = {Adolescent,Adult,Aged,Aged, 80 and over,Atrophy,Brain,C9orf72 Protein,Disease Progression,Female,Frontotemporal Lobar Degeneration,Humans,Intercellular Signaling Peptides and Proteins,Longitudinal Studies,Magnetic Resonance Imaging,Male,Middle Aged,Mutation,Progranulins,Proteins,Young Adult,genetics,pathology,tau Proteins},
language = {eng},
month = {nov},
number = {11},
pages = {3880--3892},
pmid = {40424598},
title = {{Anatomical progression of genetic frontotemporal lobar degeneration across the  lifespan.}},
volume = {148},
year = {2025}
}
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