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000281877 0247_ $$2doi$$a10.1093/brain/awaf195
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000281877 1001_ $$00000-0003-3713-227X$$aPlanche, Vincent$$b0
000281877 245__ $$aAnatomical progression of genetic frontotemporal lobar degeneration across the lifespan.
000281877 260__ $$aOxford$$bOxford Univ. Press$$c2025
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000281877 520__ $$aThe 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.
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000281877 650_7 $$2Other$$aC9orf72
000281877 650_7 $$2Other$$aGRN
000281877 650_7 $$2Other$$aMAPT
000281877 650_7 $$2Other$$abrain charts
000281877 650_7 $$2Other$$afrontotemporal lobar degeneration
000281877 650_7 $$2Other$$alifespan
000281877 650_7 $$2NLM Chemicals$$aProgranulins
000281877 650_7 $$2NLM Chemicals$$aC9orf72 Protein
000281877 650_7 $$2NLM Chemicals$$atau Proteins
000281877 650_7 $$2NLM Chemicals$$aC9orf72 protein, human
000281877 650_7 $$2NLM Chemicals$$aGRN protein, human
000281877 650_7 $$2NLM Chemicals$$aMAPT protein, human
000281877 650_7 $$2NLM Chemicals$$aIntercellular Signaling Peptides and Proteins
000281877 650_7 $$2NLM Chemicals$$aProteins
000281877 650_2 $$2MeSH$$aHumans
000281877 650_2 $$2MeSH$$aMiddle Aged
000281877 650_2 $$2MeSH$$aAdult
000281877 650_2 $$2MeSH$$aMale
000281877 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: genetics
000281877 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: pathology
000281877 650_2 $$2MeSH$$aFemale
000281877 650_2 $$2MeSH$$aProgranulins
000281877 650_2 $$2MeSH$$aAged
000281877 650_2 $$2MeSH$$aC9orf72 Protein: genetics
000281877 650_2 $$2MeSH$$aDisease Progression
000281877 650_2 $$2MeSH$$atau Proteins: genetics
000281877 650_2 $$2MeSH$$aMagnetic Resonance Imaging
000281877 650_2 $$2MeSH$$aAdolescent
000281877 650_2 $$2MeSH$$aAged, 80 and over
000281877 650_2 $$2MeSH$$aYoung Adult
000281877 650_2 $$2MeSH$$aMutation: genetics
000281877 650_2 $$2MeSH$$aBrain: pathology
000281877 650_2 $$2MeSH$$aAtrophy: pathology
000281877 650_2 $$2MeSH$$aLongitudinal Studies
000281877 650_2 $$2MeSH$$aIntercellular Signaling Peptides and Proteins: genetics
000281877 650_2 $$2MeSH$$aProteins: genetics
000281877 7001_ $$00000-0002-9190-4819$$aMansencal, Boris$$b1
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000281877 7001_ $$aConsortium, ALLFTD$$b39
000281877 7001_ $$aInitiative, the Genetic FTD$$b40$$eCollaboration Author
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