Rodriguez-Vieitez, Elena;
Rydell, Melissa T;
Ullgren, Abbe;
Montal, Victor;
Illan-Gala, Ignacio;
Fortea, Juan;
Jelic, Vesna;
... Genetic Frontotemporal Dementia Initiative (GENFI); + view all
(2025)
Cortical microstructure is associated with disease severity and clinical progression in genetic frontotemporal dementia: a GENFI study.
Molecular Psychiatry
10.1038/s41380-025-03280-x.
(In press).
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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.
| Type: | Article |
|---|---|
| Title: | Cortical microstructure is associated with disease severity and clinical progression in genetic frontotemporal dementia: a GENFI study |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41380-025-03280-x |
| Publisher version: | https://doi.org/10.1038/s41380-025-03280-x |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10216413 |
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