Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: A GENFI study

Enrico Premi; Mario Grassi; John Van Swieten; Daniela Galimberti; Caroline Graff; Mario Masellis; Carmela Tartaglia; Fabrizio Tagliavini; James B. Rowe; Robert Laforce; Elizabeth Finger; Giovanni B. Frisoni; Alexandre De Mendonça; Sandro Sorbi; Stefano Gazzina; Maura Cosseddu; Silvana Archetti; Roberto Gasparotti; Marta Manes; Antonella Alberici; Manuel J. Cardoso; Martina Bocchetta; David M. Cash; Sebastian Ourselin; Alessandro Padovani; Jonathan D. Rohrer; Barbara Borroni

doi:10.1093/brain/awx103

Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: A GENFI study

Enrico Premi, Mario Grassi, John Van Swieten, Daniela Galimberti, Caroline Graff, Mario Masellis, Carmela Tartaglia, Fabrizio Tagliavini, James B. Rowe, Robert Laforce, Elizabeth Finger, Giovanni B. Frisoni, Alexandre De Mendonça, Sandro Sorbi, Stefano Gazzina, Maura Cosseddu, Silvana Archetti, Roberto Gasparotti, Marta Manes, Antonella AlbericiManuel J. Cardoso, Martina Bocchetta, David M. Cash, Sebastian Ourselin, Alessandro Padovani, Jonathan D. Rohrer, Barbara Borroni^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

48 Citations (Scopus)

Abstract

Frontotemporal dementia is a heterogeneous neurodegenerative disorder with around a third of cases having autosomal dominant inheritance. There is wide variability in phenotype even within affected families, raising questions about the determinants of the progression of disease and age at onset. It has been recently demonstrated that cognitive reserve, as measured by years of formal schooling, can counteract the ongoing pathological process. The TMEM106B genotype has also been found to be a modifier of the age at disease onset in frontotemporal dementia patients with TDP-43 pathology. This study therefore aimed to elucidate the modulating effect of environment (i.e. cognitive reserve as measured by educational attainment) and genetic background (i.e. TMEM106B polymorphism, rs1990622 T/C) on grey matter volume in a large cohort of presymptomatic subjects bearing frontotemporal dementia-related pathogenic mutations. Two hundred and thirty-one participants from the GENFI study were included: 108 presymptomatic MAPT, GRN, and C9orf72 mutation carriers and 123 non-carriers. For each subject, cortical and subcortical grey matter volumes were generated using a parcellation of the volumetric T1-weighted magnetic resonance imaging brain scan. TMEM106B genotyping was carried out, and years of education recorded. First, we obtained a composite measure of grey matter volume by graph-Laplacian principal component analysis, and then fitted a linear mixed-effect interaction model, considering the role of (i) genetic status; (ii) educational attainment; and (iii) TMEM106B genotype on grey matter volume. The presence of a mutation was associated with a lower grey matter volume (P = 0.002), even in presymptomatic subjects. Education directly affected grey matter volume in all the samples (P = 0.02) with lower education attainment being associated with lower volumes. TMEM106B genotype did not influence grey matter volume directly on its own but in mutation carriers it modulated the slope of the correlation between education and grey matter volume (P = 0.007). Together, these results indicate that brain atrophy in presymptomatic carriers of common frontotemporal dementia mutations is affected by both genetic and environmental factors such that TMEM106B enhances the benefit of cognitive reserve on brain structure. These findings should be considered in evaluating outcomes in future disease-modifying trials, and support the search for protective mechanisms in people at risk of dementia that might facilitate new therapeutic strategies.

Original language	English
Pages (from-to)	1784-1791
Number of pages	8
Journal	Brain
Volume	140
Issue number	6
Early online date	27 Apr 2017
DOIs	https://doi.org/10.1093/brain/awx103
Publication status	Published - Jun 2017

Keywords

Cognitive reserve
Frontotemporal dementia
Genetics
Structural MRI
TMEM106b

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10.1093/brain/awx103Licence: CC BY

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Premi, E., Grassi, M., Van Swieten, J., Galimberti, D., Graff, C., Masellis, M., Tartaglia, C., Tagliavini, F., Rowe, J. B., Laforce, R., Finger, E., Frisoni, G. B., De Mendonça, A., Sorbi, S., Gazzina, S., Cosseddu, M., Archetti, S., Gasparotti, R., Manes, M., ... Borroni, B. (2017). Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: A GENFI study. Brain, 140(6), 1784-1791. https://doi.org/10.1093/brain/awx103

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title = "Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: A GENFI study",

abstract = "Frontotemporal dementia is a heterogeneous neurodegenerative disorder with around a third of cases having autosomal dominant inheritance. There is wide variability in phenotype even within affected families, raising questions about the determinants of the progression of disease and age at onset. It has been recently demonstrated that cognitive reserve, as measured by years of formal schooling, can counteract the ongoing pathological process. The TMEM106B genotype has also been found to be a modifier of the age at disease onset in frontotemporal dementia patients with TDP-43 pathology. This study therefore aimed to elucidate the modulating effect of environment (i.e. cognitive reserve as measured by educational attainment) and genetic background (i.e. TMEM106B polymorphism, rs1990622 T/C) on grey matter volume in a large cohort of presymptomatic subjects bearing frontotemporal dementia-related pathogenic mutations. Two hundred and thirty-one participants from the GENFI study were included: 108 presymptomatic MAPT, GRN, and C9orf72 mutation carriers and 123 non-carriers. For each subject, cortical and subcortical grey matter volumes were generated using a parcellation of the volumetric T1-weighted magnetic resonance imaging brain scan. TMEM106B genotyping was carried out, and years of education recorded. First, we obtained a composite measure of grey matter volume by graph-Laplacian principal component analysis, and then fitted a linear mixed-effect interaction model, considering the role of (i) genetic status; (ii) educational attainment; and (iii) TMEM106B genotype on grey matter volume. The presence of a mutation was associated with a lower grey matter volume (P = 0.002), even in presymptomatic subjects. Education directly affected grey matter volume in all the samples (P = 0.02) with lower education attainment being associated with lower volumes. TMEM106B genotype did not influence grey matter volume directly on its own but in mutation carriers it modulated the slope of the correlation between education and grey matter volume (P = 0.007). Together, these results indicate that brain atrophy in presymptomatic carriers of common frontotemporal dementia mutations is affected by both genetic and environmental factors such that TMEM106B enhances the benefit of cognitive reserve on brain structure. These findings should be considered in evaluating outcomes in future disease-modifying trials, and support the search for protective mechanisms in people at risk of dementia that might facilitate new therapeutic strategies.",

keywords = "Cognitive reserve, Frontotemporal dementia, Genetics, Structural MRI, TMEM106b",

author = "Enrico Premi and Mario Grassi and {Van Swieten}, John and Daniela Galimberti and Caroline Graff and Mario Masellis and Carmela Tartaglia and Fabrizio Tagliavini and Rowe, {James B.} and Robert Laforce and Elizabeth Finger and Frisoni, {Giovanni B.} and {De Mendon{\c c}a}, Alexandre and Sandro Sorbi and Stefano Gazzina and Maura Cosseddu and Silvana Archetti and Roberto Gasparotti and Marta Manes and Antonella Alberici and Cardoso, {Manuel J.} and Martina Bocchetta and Cash, {David M.} and Sebastian Ourselin and Alessandro Padovani and Rohrer, {Jonathan D.} and Barbara Borroni",

year = "2017",

month = jun,

doi = "10.1093/brain/awx103",

language = "English",

volume = "140",

pages = "1784--1791",

journal = "Brain",

issn = "0006-8950",

publisher = "Oxford University Press (OUP)",

number = "6",

}

Premi, E, Grassi, M, Van Swieten, J, Galimberti, D, Graff, C, Masellis, M, Tartaglia, C, Tagliavini, F, Rowe, JB, Laforce, R, Finger, E, Frisoni, GB, De Mendonça, A, Sorbi, S, Gazzina, S, Cosseddu, M, Archetti, S, Gasparotti, R, Manes, M, Alberici, A, Cardoso, MJ, Bocchetta, M, Cash, DM, Ourselin, S, Padovani, A, Rohrer, JD & Borroni, B 2017, 'Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: A GENFI study', Brain, vol. 140, no. 6, pp. 1784-1791. https://doi.org/10.1093/brain/awx103

TY - JOUR

T1 - Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia

T2 - A GENFI study

AU - Premi, Enrico

AU - Grassi, Mario

AU - Van Swieten, John

AU - Galimberti, Daniela

AU - Graff, Caroline

AU - Masellis, Mario

AU - Tartaglia, Carmela

AU - Tagliavini, Fabrizio

AU - Rowe, James B.

AU - Laforce, Robert

AU - Finger, Elizabeth

AU - Frisoni, Giovanni B.

AU - De Mendonça, Alexandre

AU - Sorbi, Sandro

AU - Gazzina, Stefano

AU - Cosseddu, Maura

AU - Archetti, Silvana

AU - Gasparotti, Roberto

AU - Manes, Marta

AU - Alberici, Antonella

AU - Cardoso, Manuel J.

AU - Bocchetta, Martina

AU - Cash, David M.

AU - Ourselin, Sebastian

AU - Padovani, Alessandro

AU - Rohrer, Jonathan D.

AU - Borroni, Barbara

PY - 2017/6

Y1 - 2017/6

N2 - Frontotemporal dementia is a heterogeneous neurodegenerative disorder with around a third of cases having autosomal dominant inheritance. There is wide variability in phenotype even within affected families, raising questions about the determinants of the progression of disease and age at onset. It has been recently demonstrated that cognitive reserve, as measured by years of formal schooling, can counteract the ongoing pathological process. The TMEM106B genotype has also been found to be a modifier of the age at disease onset in frontotemporal dementia patients with TDP-43 pathology. This study therefore aimed to elucidate the modulating effect of environment (i.e. cognitive reserve as measured by educational attainment) and genetic background (i.e. TMEM106B polymorphism, rs1990622 T/C) on grey matter volume in a large cohort of presymptomatic subjects bearing frontotemporal dementia-related pathogenic mutations. Two hundred and thirty-one participants from the GENFI study were included: 108 presymptomatic MAPT, GRN, and C9orf72 mutation carriers and 123 non-carriers. For each subject, cortical and subcortical grey matter volumes were generated using a parcellation of the volumetric T1-weighted magnetic resonance imaging brain scan. TMEM106B genotyping was carried out, and years of education recorded. First, we obtained a composite measure of grey matter volume by graph-Laplacian principal component analysis, and then fitted a linear mixed-effect interaction model, considering the role of (i) genetic status; (ii) educational attainment; and (iii) TMEM106B genotype on grey matter volume. The presence of a mutation was associated with a lower grey matter volume (P = 0.002), even in presymptomatic subjects. Education directly affected grey matter volume in all the samples (P = 0.02) with lower education attainment being associated with lower volumes. TMEM106B genotype did not influence grey matter volume directly on its own but in mutation carriers it modulated the slope of the correlation between education and grey matter volume (P = 0.007). Together, these results indicate that brain atrophy in presymptomatic carriers of common frontotemporal dementia mutations is affected by both genetic and environmental factors such that TMEM106B enhances the benefit of cognitive reserve on brain structure. These findings should be considered in evaluating outcomes in future disease-modifying trials, and support the search for protective mechanisms in people at risk of dementia that might facilitate new therapeutic strategies.

AB - Frontotemporal dementia is a heterogeneous neurodegenerative disorder with around a third of cases having autosomal dominant inheritance. There is wide variability in phenotype even within affected families, raising questions about the determinants of the progression of disease and age at onset. It has been recently demonstrated that cognitive reserve, as measured by years of formal schooling, can counteract the ongoing pathological process. The TMEM106B genotype has also been found to be a modifier of the age at disease onset in frontotemporal dementia patients with TDP-43 pathology. This study therefore aimed to elucidate the modulating effect of environment (i.e. cognitive reserve as measured by educational attainment) and genetic background (i.e. TMEM106B polymorphism, rs1990622 T/C) on grey matter volume in a large cohort of presymptomatic subjects bearing frontotemporal dementia-related pathogenic mutations. Two hundred and thirty-one participants from the GENFI study were included: 108 presymptomatic MAPT, GRN, and C9orf72 mutation carriers and 123 non-carriers. For each subject, cortical and subcortical grey matter volumes were generated using a parcellation of the volumetric T1-weighted magnetic resonance imaging brain scan. TMEM106B genotyping was carried out, and years of education recorded. First, we obtained a composite measure of grey matter volume by graph-Laplacian principal component analysis, and then fitted a linear mixed-effect interaction model, considering the role of (i) genetic status; (ii) educational attainment; and (iii) TMEM106B genotype on grey matter volume. The presence of a mutation was associated with a lower grey matter volume (P = 0.002), even in presymptomatic subjects. Education directly affected grey matter volume in all the samples (P = 0.02) with lower education attainment being associated with lower volumes. TMEM106B genotype did not influence grey matter volume directly on its own but in mutation carriers it modulated the slope of the correlation between education and grey matter volume (P = 0.007). Together, these results indicate that brain atrophy in presymptomatic carriers of common frontotemporal dementia mutations is affected by both genetic and environmental factors such that TMEM106B enhances the benefit of cognitive reserve on brain structure. These findings should be considered in evaluating outcomes in future disease-modifying trials, and support the search for protective mechanisms in people at risk of dementia that might facilitate new therapeutic strategies.

KW - Cognitive reserve

KW - Frontotemporal dementia

KW - Genetics

KW - Structural MRI

KW - TMEM106b

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U2 - 10.1093/brain/awx103

DO - 10.1093/brain/awx103

M3 - Article

C2 - 28460069

AN - SCOPUS:85022080675

SN - 0006-8950

VL - 140

SP - 1784

EP - 1791

JO - Brain

JF - Brain

IS - 6

ER -

Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: A GENFI study

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