| Title: | Anatomical progression of genetic frontotemporal lobar degeneration across the lifespan |
| Journal: | Brain |
| Published: | 27 May 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40424598/ |
| DOI: | https://doi.org/10.1093/brain/awaf195 |
| URL: | https://hal.science/hal-05090549 |
Publication 16613
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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.</p>
21 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
- tau Proteins
139 Authors
- Vincent Planche
- Boris Mansencal
- Vladimir Fonov
- José V Manjon
- Thomas Tourdias
- Arabella Bouzigues
- Lucy L Russell
- Phoebe H Foster
- Eve Ferry-Bolder
- John C van Swieten
- Lize C Jiskoot
- Harro Seelaar
- Raquel Sanchez-Valle
- Robert Laforce
- Caroline Graff
- Daniela Galimberti
- Rik Vandenberghe
- Alexandre de Mendonça
- Pietro Tiraboschi
- Isabel Santana
- Alexander Gerhard
- Johannes Levin
- Sandro Sorbi
- Markus Otto
- Maxime Bertoux
- Thibaud Lebouvier
- Chris R Butler
- Isabelle Le Ber
- Elizabeth Finger
- Maria Carmela Tartaglia
- Mario Masellis
- James B Rowe
- Matthis Synofzik
- Fermin Moreno
- Barbara Borroni
- Jonathan D Rohrer
- D Louis Collins
- Simon Ducharme
- Pierrick Coupé
- Rhian Convery
- Martina Bocchetta
- David Cash
- Sophie Goldsmith
- Kiran Samra
- David L Thomas
- Maura Malpetti
- Antonella Alberici
- Enrico Premi
- Roberto Gasparotti
- Valentina Cantoni
- Andrea Arighi
- Chiara Fenoglio
- Vittoria Borracci
- Maria Serpente
- Tiziana Carandini
- Emanuela Rotondo
- Giacomina Rossi
- Giorgio Giaccone
- Giuseppe Di Fede
- Paola Caroppo
- Sara Prioni
- Veronica Redaelli
- David Tang-Wai
- Ekaterina Rogaeva
- Johanna Krüger
- Miguel Castelo-Branco
- Morris Freedman
- Ron Keren
- Sandra Black
- Sara Mitchell
- Christen Shoesmith
- Robart Bartha
- Rosa Rademakers
- Jackie Poos
- Janne M Papma
- Lucia Giannini
- Liset de Boer
- Julie de Houwer
- Rick van Minkelen
- Yolande Pijnenburg
- Benedetta Nacmias
- Camilla Ferrari
- Cristina Polito
- Gemma Lombardi
- Valentina Bessi
- Enrico Fainardi
- Stefano Chiti
- Mattias Nilsson
- Henrik Viklund
- Melissa Taheri Rydell
- Vesna Jelic
- Linn Öijerstedt
- Tobias Langheinrich
- Albert Lladó
- Anna Antonell
- Jaume Olives
- Mircea Balasa
- Sergi Borrego-Ecija
- Ana Verdelho
- Carolina Maruta
- Tiago Costa-Coelho
- Gabriel Miltenberger
- Frederico Simões do Couto
- Alazne Gabilondo
- Ioana Croitoru
- Mikel Tainta
- Myriam Barandiaran
- Patricia Alves
- Benjamin Bender
- David Mengel
- Lisa Graf
- Annick Vogels
- Mathieu Vandenbulcke
- Philip Van Damme
- Rose Bruffaerts
- Koen Poesen
- Pedro Rosa-Neto
- Maxime Montembeault
- Raphaella Lara Migliaccio
- Ninon Burgos
- Daisy Rinaldi
- Catharina Prix
- Elisabeth Wlasich
- Olivia Wagemann
- Sonja Schönecker
- Alexander Maximilian Bernhardt
- Anna Stockbauer
- Jolina Lombardi
- Sarah Anderl-Straub
- Adeline Rollin
- Gregory Kuchcinski
- Vincent Deramecourt
- João Durães
- Marisa Lima
- Maria João Leitão
- Maria Rosario Almeida
- Miguel Tábuas-Pereira
- Sónia Afonso
- João Lemos
1 Application
| Application ID | Title |
|---|---|
| 80509 | Holistic bigdata lifespan modeling of brain trajectory for automatic diagnostic of neurodegenerative diseases based on advanced deep learning methods |
Enabling scientific discoveries that improve human health