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<p>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 <i>n</i> = 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 <i>C9orf72</i>, <i>GRN</i> or <i>MAPT</i> genes, and 287 non-carriers, collected from 24 GENFI sites. A subset of <i>n</i> = 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 <i>n</i> = 403 individuals (239 carriers, 164 non-carriers) with Cambridge Behavioural Inventory-Revised scores during 2.8 ± 1.6 years, and <i>n</i> = 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 <i>C9orf72</i> carriers, followed by <i>MAPT</i> carriers (from CDR = 0.5 stage), and by <i>GRN</i> 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.</p>

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Cortical microstructure is associated with disease severity and clinical progression in genetic frontotemporal dementia: a GENFI study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月9日

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  • Elena Rodriguez-Vieitez,
  • Melissa T. Rydell,
  • Abbe Ullgren,
  • Victor Montal,
  • Ignacio Illán-Gala,
  • Juan Fortea,
  • Vesna Jelic,
  • 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,
  • Daniela Galimberti,
  • Rik Vandenberghe,
  • Alexandre de Mendonça,
  • Pietro Tiraboschi,
  • Isabel Santana,
  • Alexander Gerhard,
  • Johannes Levin,
  • Sandro Sorbi,
  • Markus Otto,
  • Florence Pasquier,
  • Simon Ducharme,
  • 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,
  • Eric Westman,
  • Caroline Graff,
  • John C. van Swieten,
  • Alexandre de Mendonça,
  • Isabelle Le Ber

摘要

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.