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@ARTICLE{RodriguezVieitez:282289,
author = {Rodriguez-Vieitez, Elena and Rydell, Melissa T and Ullgren,
Abbe and Montal, Victor and Illán-Gala, Ignacio and Fortea,
Juan and Jelic, Vesna 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 Galimberti,
Daniela and Vandenberghe, Rik and de Mendonça, Alexandre
and Tiraboschi, Pietro and Santana, Isabel and Gerhard,
Alexander and Levin, Johannes and Sorbi, Sandro and Otto,
Markus and Pasquier, Florence and Ducharme, Simon 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 Westman, Eric
and Graff, Caroline},
collaboration = {Initiative, Genetic Frontotemporal Dementia},
othercontributors = {van Swieten, John C and de Mendonça, Alexandre and Le Ber,
Isabelle},
title = {{C}ortical microstructure is associated with disease
severity and clinical progression in genetic frontotemporal
dementia: a {GENFI} study.},
journal = {Molecular psychiatry},
volume = {30},
number = {12},
issn = {1359-4184},
address = {[London]},
publisher = {Springer Nature},
reportid = {DZNE-2025-01260},
pages = {5800 - 5812},
year = {2025},
abstract = {The study of genetic frontotemporal dementia (FTD) allows
investigating its earliest presymptomatic stages. Using
cross-sectional T1-weighted and diffusion-weighted MRI, we
test the hypothesis that cortical microstructural
alterations, quantified as cortical mean diffusivity (cMD),
are detectable earlier and are more strongly associated with
clinical progression than cortical thickness (CTh). The
sample comprised n = 710 individuals (47.8 ± 13.5 years,
$56.6\%$ female, 14.1 ± 3.3 years of education), including
118 symptomatic carriers and 305 presymptomatic carriers
with mutations in C9orf72, GRN or MAPT genes, and 287
non-carriers, collected from 24 GENFI sites. A subset of n =
453 individuals (289 carriers, 164 non-carriers) were
investigated across Clinical Dementia Rating (CDR) = 0, 0.5
and ≥1 stages. Two subsets had longitudinal clinical
outcome measures, including n = 403 individuals (239
carriers, 164 non-carriers) with Cambridge Behavioural
Inventory-Revised scores during 2.8 ± 1.6 years, and n =
261 individuals (164 carriers, 97 non-carriers) with CDR
Sum-of-Boxes scores during 2.0 ± 0.8 years. Regional cMD
and CTh were entered into linear mixed-effects models
incorporating age, sex and education as covariates; site,
and individual nested within site were random intercepts.
The results demonstrated that cMD is more sensitive than CTh
to track early cortical injury, with elevated cMD first
observed at CDR = 0 in C9orf72 carriers, followed by MAPT
carriers (from CDR = 0.5 stage), and by GRN carriers
(beginning at CDR ≥ 1). At all stages, cortical
microstructural injury had stronger effect size and was more
widespread than cortical thinning. In all mutation carrier
types, cMD was more strongly associated than CTh with
subsequent clinical progression. Cortical microstructure is
a promising biomarker to identify at-risk individuals before
atrophy and clinical progression, with utility in
therapeutic trials.},
keywords = {Humans / Female / Male / Frontotemporal Dementia: genetics
/ Frontotemporal Dementia: pathology / Frontotemporal
Dementia: diagnostic imaging / Middle Aged / Disease
Progression / tau Proteins: genetics / C9orf72 Protein:
genetics / Progranulins: genetics / Adult / Cerebral Cortex:
pathology / Cerebral Cortex: diagnostic imaging /
Cross-Sectional Studies / Aged / Mutation: genetics /
Magnetic Resonance Imaging: methods / Severity of Illness
Index / Diffusion Magnetic Resonance Imaging: methods / tau
Proteins (NLM Chemicals) / C9orf72 Protein (NLM Chemicals) /
Progranulins (NLM Chemicals) / MAPT protein, human (NLM
Chemicals) / GRN protein, human (NLM Chemicals) / C9orf72
protein, human (NLM Chemicals)},
cin = {Clinical Research (Munich) / AG Levin / AG Gasser},
ddc = {610},
cid = {I:(DE-2719)1111015 / I:(DE-2719)1111016 /
I:(DE-2719)1210000},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41068257},
pmc = {pmc:PMC12602311},
doi = {10.1038/s41380-025-03280-x},
url = {https://pub.dzne.de/record/282289},
}