Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia

Andre Altmann; David M. Cash; Martina Bocchetta; Carolin Heller; Regina Reynolds; Katrina Moore; Rhian S. Convery; David L. Thomas; John C. Van Swieten; Fermin Moreno; Raquel Sanchez-Valle; Barbara Borroni; Robert Laforce; Mario Masellis; Maria Carmela Tartaglia; Caroline Graff; Daniela Galimberti; James B. Rowe; Elizabeth Finger; Matthis Synofzik; Rik Vandenberghe; Alexandre De Mendonça; Fabrizio Tagliavini; Isabel Santana; Simon Ducharme; Chris R. Butler; Alex Gerhard; Johannes Levin; Adrian Danek; Giovanni Frisoni; Roberta Ghidoni; Sandro Sorbi; Markus Otto; Mina Ryten; Jonathan D. Rohrer; Caroline Greaves; Georgia Peakman; Rachelle Shafei; Emily Todd; Martin N. Rossor; Jason D. Warren; Nick C. Fox; Henrik Zetterberg; Rita Guerreiro; Jose Bras; Jennifer Nicholas; Simon Mead; Lize Jiskoot; Lieke Meeter; Jessica Panman; Janne M. Papma; Rick Van Minkelen; Yolanda Pijnenburg; Myriam Barandiaran; Begoa Indakoetxea; Alazne Gabilondo; Mikel Tainta; Maria De Arriba; Ana Gorostidi; Miren Zulaica; Jorge Villanua; Zigor Diaz; Sergi Borrego-Ecija; Jaume Olives; Albert Lladó; Mircea Balasa; Anna Antonell; Nuria Bargallo; Enrico Premi; Maura Cosseddu; Stefano Gazzina; Alessandro Padovani; Roberto Gasparotti; Silvana Archetti; Sandra Black; Sara Mitchell; Ekaterina Rogaeva; Morris Freedman; Ron Keren; David Tang-Wai; Linn Öijerstedt; Christin Andersson; Vesna Jelic; Hakan Thonberg; Andrea Arighi; Chiara Fenoglio; Elio Scarpini; Giorgio Fumagalli; Thomas Cope; Carolyn Timberlake; Timothy Rittman; Christen Shoesmith; Robart Bartha; Rosa Rademakers; Carlo Wilke; Hans Otto Karnarth; Benjamin Bender; Rose Bruffaerts; Philip Van Damme; Mathieu Vandenbulcke; Catarina B. Ferreira; Gabriel Miltenberger; Carolina Maruta; Ana Verdelho; Sónia Afonso; Ricardo Taipa; Paola Caroppo; Giuseppe Di Fede; Giorgio Giaccone; Sara Prioni; Veronica Redaelli; Giacomina Rossi; Pietro Tiraboschi; Diana Duro; Maria Rosario Almeida; Miguel Castelo-Branco; Maria João Leitão; Miguel Tabuas-Pereira; Beatriz Santiago; Serge Gauthier; Pedro Rosa-Neto; Michele Veldsman; Paul Thompson; Tobias Langheinrich; Catharina Prix; Tobias Hoegen; Elisabeth Wlasich; Sandra Loosli; Sonja Schonecker; Elisa Semler; Sarah Anderl-Straub; Luisa Benussi; Giuliano Binetti; Michela Pievani; Gemma Lombardi; Benedetta Nacmias; Camilla Ferrari; Valentina Bessi; Cristina Polito

doi:10.1093/braincomms/fcaa122

Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia

Andre Altmann, David M. Cash, Martina Bocchetta, Carolin Heller, Regina Reynolds, Katrina Moore, Rhian S. Convery, David L. Thomas, John C. Van Swieten, Fermin Moreno, Raquel Sanchez-Valle, Barbara Borroni, Robert Laforce, Mario Masellis, Maria Carmela Tartaglia, Caroline Graff, Daniela Galimberti, James B. Rowe, Elizabeth Finger, Matthis SynofzikRik Vandenberghe, Alexandre De Mendonça, Fabrizio Tagliavini, Isabel Santana, Simon Ducharme, Chris R. Butler, Alex Gerhard, Johannes Levin, Adrian Danek, Giovanni Frisoni, Roberta Ghidoni, Sandro Sorbi, Markus Otto, Mina Ryten, Jonathan D. Rohrer, Caroline Greaves, Georgia Peakman, Rachelle Shafei, Emily Todd, Martin N. Rossor, Jason D. Warren, Nick C. Fox, Henrik Zetterberg, Rita Guerreiro, Jose Bras, Jennifer Nicholas, Simon Mead, Lize Jiskoot, Lieke Meeter, Jessica Panman, Janne M. Papma, Rick Van Minkelen, Yolanda Pijnenburg, Myriam Barandiaran, Begoa Indakoetxea, Alazne Gabilondo, Mikel Tainta, Maria De Arriba, Ana Gorostidi, Miren Zulaica, Jorge Villanua, Zigor Diaz, Sergi Borrego-Ecija, Jaume Olives, Albert Lladó, Mircea Balasa, Anna Antonell, Nuria Bargallo, Enrico Premi, Maura Cosseddu, Stefano Gazzina, Alessandro Padovani, Roberto Gasparotti, Silvana Archetti, Sandra Black, Sara Mitchell, Ekaterina Rogaeva, Morris Freedman, Ron Keren, David Tang-Wai, Linn Öijerstedt, Christin Andersson, Vesna Jelic, Hakan Thonberg, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Thomas Cope, Carolyn Timberlake, Timothy Rittman, Christen Shoesmith, Robart Bartha, Rosa Rademakers, Carlo Wilke, Hans Otto Karnarth, Benjamin Bender, Rose Bruffaerts, Philip Van Damme, Mathieu Vandenbulcke, Catarina B. Ferreira, Gabriel Miltenberger, Carolina Maruta, Ana Verdelho, Sónia Afonso, Ricardo Taipa, Paola Caroppo, Giuseppe Di Fede, Giorgio Giaccone, Sara Prioni, Veronica Redaelli, Giacomina Rossi, Pietro Tiraboschi, Diana Duro, Maria Rosario Almeida, Miguel Castelo-Branco, Maria João Leitão, Miguel Tabuas-Pereira, Beatriz Santiago, Serge Gauthier, Pedro Rosa-Neto, Michele Veldsman, Paul Thompson, Tobias Langheinrich, Catharina Prix, Tobias Hoegen, Elisabeth Wlasich, Sandra Loosli, Sonja Schonecker, Elisa Semler, Sarah Anderl-Straub, Luisa Benussi, Giuliano Binetti, Michela Pievani, Gemma Lombardi, Benedetta Nacmias, Camilla Ferrari, Valentina Bessi, Cristina Polito

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

19 Scopus citations

Abstract

Frontotemporal dementia is a heterogeneous neurodegenerative disorder characterized by neuronal loss in the frontal and temporal lobes. Despite progress in understanding which genes are associated with the aetiology of frontotemporal dementia, the biological basis of how mutations in these genes lead to cell loss in specific cortical regions remains unclear. In this work, we combined gene expression data for 16 772 genes from the Allen Institute for Brain Science atlas with brain maps of grey matter atrophy in symptomatic C9orf72, GRN and MAPT mutation carriers obtained from the Genetic Frontotemporal dementia Initiative study. No significant association was seen between C9orf72, GRN and MAPT expression and the atrophy patterns in the respective genetic groups. After adjusting for spatial autocorrelation, between 1000 and 5000 genes showed a negative or positive association with the atrophy pattern within each individual genetic group, with the most significantly associated genes being TREM2, SSBP3 and GPR158 (negative association in C9Orf72, GRN and MAPT respectively) and RELN, MXRA8 and LPA (positive association in C9Orf72, GRN and MAPT respectively). An overrepresentation analysis identified a negative association with genes involved in mitochondrial function, and a positive association with genes involved in vascular and glial cell function in each of the genetic groups. A set of 423 and 700 genes showed significant positive and negative association, respectively, with atrophy patterns in all three maps. The gene set with increased expression in spared cortical regions was enriched for neuronal and microglial genes, while the gene set with increased expression in atrophied regions was enriched for astrocyte and endothelial cell genes. Our analysis suggests that these cell types may play a more active role in the onset of neurodegeneration in frontotemporal dementia than previously assumed, and in the case of the positively associated cell marker genes, potentially through emergence of neurotoxic astrocytes and alteration in the blood-brain barrier, respectively.

Original language	English
Article number	fcaa122
Journal	Brain Communications
Volume	2
Issue number	2
DOIs	https://doi.org/10.1093/braincomms/fcaa122
State	Published - 2020
Externally published	Yes

Keywords

Astrocytes
Atrophy
Frontotemporal dementia
Gene expression
Imaging genetics

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10.1093/braincomms/fcaa122

Cite this

Altmann, A., Cash, D. M., Bocchetta, M., Heller, C., Reynolds, R., Moore, K., Convery, R. S., Thomas, D. L., Van Swieten, J. C., Moreno, F., Sanchez-Valle, R., Borroni, B., Laforce, R., Masellis, M., Tartaglia, M. C., Graff, C., Galimberti, D., Rowe, J. B., Finger, E., ... Polito, C. (2020). Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia. Brain Communications, 2(2), Article fcaa122. https://doi.org/10.1093/braincomms/fcaa122

@article{61ef441af5634b398817e1f825a18fee,

title = "Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia",

abstract = "Frontotemporal dementia is a heterogeneous neurodegenerative disorder characterized by neuronal loss in the frontal and temporal lobes. Despite progress in understanding which genes are associated with the aetiology of frontotemporal dementia, the biological basis of how mutations in these genes lead to cell loss in specific cortical regions remains unclear. In this work, we combined gene expression data for 16 772 genes from the Allen Institute for Brain Science atlas with brain maps of grey matter atrophy in symptomatic C9orf72, GRN and MAPT mutation carriers obtained from the Genetic Frontotemporal dementia Initiative study. No significant association was seen between C9orf72, GRN and MAPT expression and the atrophy patterns in the respective genetic groups. After adjusting for spatial autocorrelation, between 1000 and 5000 genes showed a negative or positive association with the atrophy pattern within each individual genetic group, with the most significantly associated genes being TREM2, SSBP3 and GPR158 (negative association in C9Orf72, GRN and MAPT respectively) and RELN, MXRA8 and LPA (positive association in C9Orf72, GRN and MAPT respectively). An overrepresentation analysis identified a negative association with genes involved in mitochondrial function, and a positive association with genes involved in vascular and glial cell function in each of the genetic groups. A set of 423 and 700 genes showed significant positive and negative association, respectively, with atrophy patterns in all three maps. The gene set with increased expression in spared cortical regions was enriched for neuronal and microglial genes, while the gene set with increased expression in atrophied regions was enriched for astrocyte and endothelial cell genes. Our analysis suggests that these cell types may play a more active role in the onset of neurodegeneration in frontotemporal dementia than previously assumed, and in the case of the positively associated cell marker genes, potentially through emergence of neurotoxic astrocytes and alteration in the blood-brain barrier, respectively.",

keywords = "Astrocytes, Atrophy, Frontotemporal dementia, Gene expression, Imaging genetics",

author = "Andre Altmann and Cash, {David M.} and Martina Bocchetta and Carolin Heller and Regina Reynolds and Katrina Moore and Convery, {Rhian S.} and Thomas, {David L.} and {Van Swieten}, {John C.} and Fermin Moreno and Raquel Sanchez-Valle and Barbara Borroni and Robert Laforce and Mario Masellis and Tartaglia, {Maria Carmela} and Caroline Graff and Daniela Galimberti and Rowe, {James B.} and Elizabeth Finger and Matthis Synofzik and Rik Vandenberghe and {De Mendon{\c c}a}, Alexandre and Fabrizio Tagliavini and Isabel Santana and Simon Ducharme and Butler, {Chris R.} and Alex Gerhard and Johannes Levin and Adrian Danek and Giovanni Frisoni and Roberta Ghidoni and Sandro Sorbi and Markus Otto and Mina Ryten and Rohrer, {Jonathan D.} and Caroline Greaves and Georgia Peakman and Rachelle Shafei and Emily Todd and Rossor, {Martin N.} and Warren, {Jason D.} and Fox, {Nick C.} and Henrik Zetterberg and Rita Guerreiro and Jose Bras and Jennifer Nicholas and Simon Mead and Lize Jiskoot and Lieke Meeter and Jessica Panman and Papma, {Janne M.} and {Van Minkelen}, Rick and Yolanda Pijnenburg and Myriam Barandiaran and Begoa Indakoetxea and Alazne Gabilondo and Mikel Tainta and {De Arriba}, Maria and Ana Gorostidi and Miren Zulaica and Jorge Villanua and Zigor Diaz and Sergi Borrego-Ecija and Jaume Olives and Albert Llad{\'o} and Mircea Balasa and Anna Antonell and Nuria Bargallo and Enrico Premi and Maura Cosseddu and Stefano Gazzina and Alessandro Padovani and Roberto Gasparotti and Silvana Archetti and Sandra Black and Sara Mitchell and Ekaterina Rogaeva and Morris Freedman and Ron Keren and David Tang-Wai and Linn {\"O}ijerstedt and Christin Andersson and Vesna Jelic and Hakan Thonberg and Andrea Arighi and Chiara Fenoglio and Elio Scarpini and Giorgio Fumagalli and Thomas Cope and Carolyn Timberlake and Timothy Rittman and Christen Shoesmith and Robart Bartha and Rosa Rademakers and Carlo Wilke and Karnarth, {Hans Otto} and Benjamin Bender and Rose Bruffaerts and {Van Damme}, Philip and Mathieu Vandenbulcke and Ferreira, {Catarina B.} and Gabriel Miltenberger and Carolina Maruta and Ana Verdelho and S{\'o}nia Afonso and Ricardo Taipa and Paola Caroppo and {Di Fede}, Giuseppe and Giorgio Giaccone and Sara Prioni and Veronica Redaelli and Giacomina Rossi and Pietro Tiraboschi and Diana Duro and Almeida, {Maria Rosario} and Miguel Castelo-Branco and Leit{\~a}o, {Maria Jo{\~a}o} and Miguel Tabuas-Pereira and Beatriz Santiago and Serge Gauthier and Pedro Rosa-Neto and Michele Veldsman and Paul Thompson and Tobias Langheinrich and Catharina Prix and Tobias Hoegen and Elisabeth Wlasich and Sandra Loosli and Sonja Schonecker and Elisa Semler and Sarah Anderl-Straub and Luisa Benussi and Giuliano Binetti and Michela Pievani and Gemma Lombardi and Benedetta Nacmias and Camilla Ferrari and Valentina Bessi and Cristina Polito",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s) (2020).",

year = "2020",

doi = "10.1093/braincomms/fcaa122",

language = "English",

volume = "2",

journal = "Brain Communications",

issn = "2632-1297",

publisher = "Oxford University Press",

number = "2",

}

Altmann, A, Cash, DM, Bocchetta, M, Heller, C, Reynolds, R, Moore, K, Convery, RS, Thomas, DL, Van Swieten, JC, Moreno, F, Sanchez-Valle, R, Borroni, B, Laforce, R, Masellis, M, Tartaglia, MC, Graff, C, Galimberti, D, Rowe, JB, Finger, E, Synofzik, M, Vandenberghe, R, De Mendonça, A, Tagliavini, F, Santana, I, Ducharme, S, Butler, CR, Gerhard, A, Levin, J, Danek, A, Frisoni, G, Ghidoni, R, Sorbi, S, Otto, M, Ryten, M, Rohrer, JD, Greaves, C, Peakman, G, Shafei, R, Todd, E, Rossor, MN, Warren, JD, Fox, NC, Zetterberg, H, Guerreiro, R, Bras, J, Nicholas, J, Mead, S, Jiskoot, L, Meeter, L, Panman, J, Papma, JM, Van Minkelen, R, Pijnenburg, Y, Barandiaran, M, Indakoetxea, B, Gabilondo, A, Tainta, M, De Arriba, M, Gorostidi, A, Zulaica, M, Villanua, J, Diaz, Z, Borrego-Ecija, S, Olives, J, Lladó, A, Balasa, M, Antonell, A, Bargallo, N, Premi, E, Cosseddu, M, Gazzina, S, Padovani, A, Gasparotti, R, Archetti, S, Black, S, Mitchell, S, Rogaeva, E, Freedman, M, Keren, R, Tang-Wai, D, Öijerstedt, L, Andersson, C, Jelic, V, Thonberg, H, Arighi, A, Fenoglio, C, Scarpini, E, Fumagalli, G, Cope, T, Timberlake, C, Rittman, T, Shoesmith, C, Bartha, R, Rademakers, R, Wilke, C, Karnarth, HO, Bender, B, Bruffaerts, R, Van Damme, P, Vandenbulcke, M, Ferreira, CB, Miltenberger, G, Maruta, C, Verdelho, A, Afonso, S, Taipa, R, Caroppo, P, Di Fede, G, Giaccone, G, Prioni, S, Redaelli, V, Rossi, G, Tiraboschi, P, Duro, D, Almeida, MR, Castelo-Branco, M, Leitão, MJ, Tabuas-Pereira, M, Santiago, B, Gauthier, S, Rosa-Neto, P, Veldsman, M, Thompson, P, Langheinrich, T, Prix, C, Hoegen, T, Wlasich, E, Loosli, S, Schonecker, S, Semler, E, Anderl-Straub, S, Benussi, L, Binetti, G, Pievani, M, Lombardi, G, Nacmias, B, Ferrari, C, Bessi, V & Polito, C 2020, 'Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia', Brain Communications, vol. 2, no. 2, fcaa122. https://doi.org/10.1093/braincomms/fcaa122

TY - JOUR

T1 - Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia

AU - Altmann, Andre

AU - Cash, David M.

AU - Bocchetta, Martina

AU - Heller, Carolin

AU - Reynolds, Regina

AU - Moore, Katrina

AU - Convery, Rhian S.

AU - Thomas, David L.

AU - Van Swieten, John C.

AU - Moreno, Fermin

AU - Sanchez-Valle, Raquel

AU - Borroni, Barbara

AU - Laforce, Robert

AU - Masellis, Mario

AU - Tartaglia, Maria Carmela

AU - Graff, Caroline

AU - Galimberti, Daniela

AU - Rowe, James B.

AU - Finger, Elizabeth

AU - Synofzik, Matthis

AU - Vandenberghe, Rik

AU - De Mendonça, Alexandre

AU - Tagliavini, Fabrizio

AU - Santana, Isabel

AU - Ducharme, Simon

AU - Butler, Chris R.

AU - Gerhard, Alex

AU - Levin, Johannes

AU - Danek, Adrian

AU - Frisoni, Giovanni

AU - Ghidoni, Roberta

AU - Sorbi, Sandro

AU - Otto, Markus

AU - Ryten, Mina

AU - Rohrer, Jonathan D.

AU - Greaves, Caroline

AU - Peakman, Georgia

AU - Shafei, Rachelle

AU - Todd, Emily

AU - Rossor, Martin N.

AU - Warren, Jason D.

AU - Fox, Nick C.

AU - Zetterberg, Henrik

AU - Guerreiro, Rita

AU - Bras, Jose

AU - Nicholas, Jennifer

AU - Mead, Simon

AU - Jiskoot, Lize

AU - Meeter, Lieke

AU - Panman, Jessica

AU - Papma, Janne M.

AU - Van Minkelen, Rick

AU - Pijnenburg, Yolanda

AU - Barandiaran, Myriam

AU - Indakoetxea, Begoa

AU - Gabilondo, Alazne

AU - Tainta, Mikel

AU - De Arriba, Maria

AU - Gorostidi, Ana

AU - Zulaica, Miren

AU - Villanua, Jorge

AU - Diaz, Zigor

AU - Borrego-Ecija, Sergi

AU - Olives, Jaume

AU - Lladó, Albert

AU - Balasa, Mircea

AU - Antonell, Anna

AU - Bargallo, Nuria

AU - Premi, Enrico

AU - Cosseddu, Maura

AU - Gazzina, Stefano

AU - Padovani, Alessandro

AU - Gasparotti, Roberto

AU - Archetti, Silvana

AU - Black, Sandra

AU - Mitchell, Sara

AU - Rogaeva, Ekaterina

AU - Freedman, Morris

AU - Keren, Ron

AU - Tang-Wai, David

AU - Öijerstedt, Linn

AU - Andersson, Christin

AU - Jelic, Vesna

AU - Thonberg, Hakan

AU - Arighi, Andrea

AU - Fenoglio, Chiara

AU - Scarpini, Elio

AU - Fumagalli, Giorgio

AU - Cope, Thomas

AU - Timberlake, Carolyn

AU - Rittman, Timothy

AU - Shoesmith, Christen

AU - Bartha, Robart

AU - Rademakers, Rosa

AU - Wilke, Carlo

AU - Karnarth, Hans Otto

AU - Bender, Benjamin

AU - Bruffaerts, Rose

AU - Van Damme, Philip

AU - Vandenbulcke, Mathieu

AU - Ferreira, Catarina B.

AU - Miltenberger, Gabriel

AU - Maruta, Carolina

AU - Verdelho, Ana

AU - Afonso, Sónia

AU - Taipa, Ricardo

AU - Caroppo, Paola

AU - Di Fede, Giuseppe

AU - Giaccone, Giorgio

AU - Prioni, Sara

AU - Redaelli, Veronica

AU - Rossi, Giacomina

AU - Tiraboschi, Pietro

AU - Duro, Diana

AU - Almeida, Maria Rosario

AU - Castelo-Branco, Miguel

AU - Leitão, Maria João

AU - Tabuas-Pereira, Miguel

AU - Santiago, Beatriz

AU - Gauthier, Serge

AU - Rosa-Neto, Pedro

AU - Veldsman, Michele

AU - Thompson, Paul

AU - Langheinrich, Tobias

AU - Prix, Catharina

AU - Hoegen, Tobias

AU - Wlasich, Elisabeth

AU - Loosli, Sandra

AU - Schonecker, Sonja

AU - Semler, Elisa

AU - Anderl-Straub, Sarah

AU - Benussi, Luisa

AU - Binetti, Giuliano

AU - Pievani, Michela

AU - Lombardi, Gemma

AU - Nacmias, Benedetta

AU - Ferrari, Camilla

AU - Bessi, Valentina

AU - Polito, Cristina

PY - 2020

Y1 - 2020

N2 - Frontotemporal dementia is a heterogeneous neurodegenerative disorder characterized by neuronal loss in the frontal and temporal lobes. Despite progress in understanding which genes are associated with the aetiology of frontotemporal dementia, the biological basis of how mutations in these genes lead to cell loss in specific cortical regions remains unclear. In this work, we combined gene expression data for 16 772 genes from the Allen Institute for Brain Science atlas with brain maps of grey matter atrophy in symptomatic C9orf72, GRN and MAPT mutation carriers obtained from the Genetic Frontotemporal dementia Initiative study. No significant association was seen between C9orf72, GRN and MAPT expression and the atrophy patterns in the respective genetic groups. After adjusting for spatial autocorrelation, between 1000 and 5000 genes showed a negative or positive association with the atrophy pattern within each individual genetic group, with the most significantly associated genes being TREM2, SSBP3 and GPR158 (negative association in C9Orf72, GRN and MAPT respectively) and RELN, MXRA8 and LPA (positive association in C9Orf72, GRN and MAPT respectively). An overrepresentation analysis identified a negative association with genes involved in mitochondrial function, and a positive association with genes involved in vascular and glial cell function in each of the genetic groups. A set of 423 and 700 genes showed significant positive and negative association, respectively, with atrophy patterns in all three maps. The gene set with increased expression in spared cortical regions was enriched for neuronal and microglial genes, while the gene set with increased expression in atrophied regions was enriched for astrocyte and endothelial cell genes. Our analysis suggests that these cell types may play a more active role in the onset of neurodegeneration in frontotemporal dementia than previously assumed, and in the case of the positively associated cell marker genes, potentially through emergence of neurotoxic astrocytes and alteration in the blood-brain barrier, respectively.

AB - Frontotemporal dementia is a heterogeneous neurodegenerative disorder characterized by neuronal loss in the frontal and temporal lobes. Despite progress in understanding which genes are associated with the aetiology of frontotemporal dementia, the biological basis of how mutations in these genes lead to cell loss in specific cortical regions remains unclear. In this work, we combined gene expression data for 16 772 genes from the Allen Institute for Brain Science atlas with brain maps of grey matter atrophy in symptomatic C9orf72, GRN and MAPT mutation carriers obtained from the Genetic Frontotemporal dementia Initiative study. No significant association was seen between C9orf72, GRN and MAPT expression and the atrophy patterns in the respective genetic groups. After adjusting for spatial autocorrelation, between 1000 and 5000 genes showed a negative or positive association with the atrophy pattern within each individual genetic group, with the most significantly associated genes being TREM2, SSBP3 and GPR158 (negative association in C9Orf72, GRN and MAPT respectively) and RELN, MXRA8 and LPA (positive association in C9Orf72, GRN and MAPT respectively). An overrepresentation analysis identified a negative association with genes involved in mitochondrial function, and a positive association with genes involved in vascular and glial cell function in each of the genetic groups. A set of 423 and 700 genes showed significant positive and negative association, respectively, with atrophy patterns in all three maps. The gene set with increased expression in spared cortical regions was enriched for neuronal and microglial genes, while the gene set with increased expression in atrophied regions was enriched for astrocyte and endothelial cell genes. Our analysis suggests that these cell types may play a more active role in the onset of neurodegeneration in frontotemporal dementia than previously assumed, and in the case of the positively associated cell marker genes, potentially through emergence of neurotoxic astrocytes and alteration in the blood-brain barrier, respectively.

KW - Astrocytes

KW - Atrophy

KW - Frontotemporal dementia

KW - Gene expression

KW - Imaging genetics

UR - http://www.scopus.com/inward/record.url?scp=85115903326&partnerID=8YFLogxK

U2 - 10.1093/braincomms/fcaa122

DO - 10.1093/braincomms/fcaa122

M3 - Article

AN - SCOPUS:85115903326

SN - 2632-1297

VL - 2

JO - Brain Communications

JF - Brain Communications

IS - 2

M1 - fcaa122

ER -

Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia

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