Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia
Authors: Altmann Andre , Cash David M , Bocchetta Martina , Heller Carolin , Reynolds Regina , Moore Katrina , Convery Rhian S , Thomas David L , van Swieten John C , Moreno Fermin , Sanchez-Valle Raquel , Borroni Barbara , Laforce Robert , Masellis Mario , Tartaglia Maria Carmela , Graff Caroline , Galimberti Daniela , Rowe James B , Finger Elizabeth , Synofzik Matthis , Vandenberghe Rik , de Mendonça Alexandre , Tagliavini Fabrizio , Santana Isabel , Ducharme Simon , Butler Chris R , Gerhard Alex , Levin Johannes , Danek Adrian , Frisoni Giovanni , Ghidoni Roberta , Sorbi Sandro , Otto Markus , Ryten Mina , Rohrer Jonathan D ,   the Genetic FTD Initiative, GENFI, Greaves Caroline , Peakman Georgia , Shafei Rachelle , Todd Emily , Rossor Martin N , Warren Jason D , Fox Nick C , Zetterberg Henrik , Guerreiro Rita , Bras Jose , Nicholas Jennifer , Mead Simon , Jiskoot Lize , Meeter Lieke , Panman Jessica , Papma Janne M , van Minkelen Rick , Pijnenburg Yolanda , Barandiaran Myriam , Indakoetxea Begoa , Gabilondo Alazne , Tainta Mikel , de Arriba Maria , Gorostidi Ana , Zulaica Miren , Villanua Jorge , Diaz Zigor , Borrego-Ecija Sergi , Olives Jaume , Lladó Albert , Balasa Mircea , Antonell Anna , Bargallo Nuria , Premi Enrico , Cosseddu Maura , Gazzina Stefano , Padovani Alessandro , Gasparotti Roberto , Archetti Silvana , Black Sandra , Mitchell Sara , Rogaeva Ekaterina , Freedman Morris , Keren Ron , Tang-Wai David , Öijerstedt Linn , Andersson Christin , Jelic Vesna , Thonberg Hakan , Arighi Andrea , Fenoglio Chiara , Scarpini Elio , Fumagalli Giorgio , Cope Thomas , Timberlake Carolyn , Rittman Timothy , Shoesmith Christen , Bartha Robart , Rademakers Rosa , Wilke Carlo , Karnarth Hans-Otto , Bender Benjamin , Bruffaerts Rose , Van Damme Philip , Vandenbulcke Mathieu , Ferreira Catarina B , Miltenberger Gabriel , Maruta Carolina , Verdelho Ana , Afonso Sónia , Taipa Ricardo , Caroppo Paola , Di Fede Giuseppe , Giaccone Giorgio , Prioni Sara , Redaelli Veronica , Rossi Giacomina , Tiraboschi Pietro , Duro Diana , Almeida Maria Rosario , Castelo-Branco Miguel , Leitão Maria João , Tabuas-Pereira Miguel , Santiago Beatriz , Gauthier Serge , Rosa-Neto Pedro , Veldsman Michele , Thompson Paul , Langheinrich Tobias , Prix Catharina , Hoegen Tobias , Wlasich Elisabeth , Loosli Sandra , Schonecker Sonja , Semler Elisa , Anderl-Straub Sarah , Benussi Luisa , Binetti Giuliano , Pievani Michela , Lombardi Gemma , Nacmias Benedetta , Ferrari Camilla , Bessi Valentina , Polito Cristina 
Published: August 2020

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.