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. 2021:29:102540.
doi: 10.1016/j.nicl.2020.102540. Epub 2020 Dec 29.

Disease-related cortical thinning in presymptomatic granulin mutation carriers

Sergi Borrego-Écija  1 , Roser Sala-Llonch  2 , John van Swieten  3 , Barbara Borroni  4 , Fermín Moreno  5 , Mario Masellis  6 , Carmela Tartaglia  7 , Caroline Graff  8 , Daniela Galimberti  9 , Robert Laforce Jr  10 , James B Rowe  11 , Elizabeth Finger  12 , Rik Vandenberghe  13 , Fabrizio Tagliavini  14 , Alexandre de Mendonça  15 , Isabel Santana  16 , Matthis Synofzik  17 , Simon Ducharme  18 , Johannes Levin  19 , Adrian Danek  20 , Alex Gerhard  21 , Markus Otto  22 , Chris Butler  23 , Giovanni Frisoni  24 , Sandro Sorbi  25 , Carolin Heller  26 , Martina Bocchetta  26 , David M Cash  26 , Rhian S Convery  26 , Katrina M Moore  26 , Jonathan D Rohrer  26 , Raquel Sanchez-Valle  27 ; Genetic FTD Initiative GENFI
Collaborators, Affiliations

Disease-related cortical thinning in presymptomatic granulin mutation carriers

Sergi Borrego-Écija et al. Neuroimage Clin. 2021.

Abstract

Mutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting an increased CTh loss associated with age and estimated proximity to symptoms onset in GRN carriers, even before the disease onset.

Keywords: Cortical thickness; Frontotemporal dementia; GRN; Genetic mutations; Presymptomatic.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Scatter plot showing correlation between whole CTh and age in presymptomatic GRN carriers (red) and noncarriers (blue). No statistical differences between trajectories were found. CTh: Cortical Thickness. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 2
Fig. 2
Relationship between CTh and age in the selected area of the cortex where significant differences between carriers and noncarriers where found: A) Brain maps showing the area with statistical differences between presymptomatic carriers and noncarriers (p < 0.05). B) Scatter plot showing relationship between CTh and age in presymptomatic GRN carriers (red) and noncarriers (blue) in the selected area. Lines represent estimated linear regression models for both groups. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3
Fig. 3
Relationship between CTh and EYO: (A) Brain maps showing areas with statistical differences between carriers and noncarriers. B) Scatter plot illustrates the relationship between CTh and EYO in carriers and noncarriers. The X-axis represents the EYO. The Y-axis represents the mean CTh of the ROI covering all areas with significant differences between carriers and noncarriers. CTh: Cortical Thickness; EYO: estimated years to onset; ROI: Region of Interest.
Fig. 4
Fig. 4
Scatter plot showing relationship between CTh and age in GRN carriers according their TMEM106B genotype and noncarriers in the left superior frontal cortex.
See this image and copyright information in PMC

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