TY  - JOUR
AU  - Planche, Vincent
AU  - Mansencal, Boris
AU  - Fonov, Vladimir
AU  - Manjon, José V
AU  - Tourdias, Thomas
AU  - Bouzigues, Arabella
AU  - Russell, Lucy L
AU  - Foster, Phoebe H
AU  - Ferry-Bolder, Eve
AU  - van Swieten, John C
AU  - Jiskoot, Lize C
AU  - Seelaar, Harro
AU  - Sanchez-Valle, Raquel
AU  - Laforce, Robert
AU  - Graff, Caroline
AU  - Galimberti, Daniela
AU  - Vandenberghe, Rik
AU  - de Mendonça, Alexandre
AU  - Tiraboschi, Pietro
AU  - Santana, Isabel
AU  - Gerhard, Alexander
AU  - Levin, Johannes
AU  - Sorbi, Sandro
AU  - Otto, Markus
AU  - Bertoux, Maxime
AU  - Lebouvier, Thibaud
AU  - Butler, Chris R
AU  - Le Ber, Isabelle
AU  - Finger, Elizabeth
AU  - Tartaglia, Maria Carmela
AU  - Masellis, Mario
AU  - Rowe, James B
AU  - Synofzik, Matthis
AU  - Moreno, Fermin
AU  - Borroni, Barbara
AU  - Rohrer, Jonathan D
AU  - Collins, D Louis
AU  - Ducharme, Simon
AU  - Coupé, Pierrick
AU  - Consortium, ALLFTD
TI  - Anatomical progression of genetic frontotemporal lobar degeneration across the lifespan.
JO  - Brain
VL  - 148
IS  - 11
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2025-01248
SP  - 3880 - 3892
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Middle Aged
KW  - Adult
KW  - Male
KW  - Frontotemporal Lobar Degeneration: genetics
KW  - Frontotemporal Lobar Degeneration: pathology
KW  - Female
KW  - Progranulins
KW  - Aged
KW  - C9orf72 Protein: genetics
KW  - Disease Progression
KW  - tau Proteins: genetics
KW  - Magnetic Resonance Imaging
KW  - Adolescent
KW  - Aged, 80 and over
KW  - Young Adult
KW  - Mutation: genetics
KW  - Brain: pathology
KW  - Atrophy: pathology
KW  - Longitudinal Studies
KW  - Intercellular Signaling Peptides and Proteins: genetics
KW  - Proteins: genetics
KW  - C9orf72 (Other)
KW  - GRN (Other)
KW  - MAPT (Other)
KW  - brain charts (Other)
KW  - frontotemporal lobar degeneration (Other)
KW  - lifespan (Other)
KW  - Progranulins (NLM Chemicals)
KW  - C9orf72 Protein (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
KW  - C9orf72 protein, human (NLM Chemicals)
KW  - GRN protein, human (NLM Chemicals)
KW  - MAPT protein, human (NLM Chemicals)
KW  - Intercellular Signaling Peptides and Proteins (NLM Chemicals)
KW  - Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40424598
DO  - DOI:10.1093/brain/awaf195
UR  - https://pub.dzne.de/record/281877
ER  -