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

André Altmann ,Maria Carmela Tartaglia,Barbara Borroni,Mario Masellis,Johannes Levin,Martina Bocchetta,Alexandre De Mendonça,Mina Ryten,Elizabeth Finger,Caroline Graff,Adrian Danek,Sandro Sorbi,Isabel Santana,Matthis Synofzik,Carolin Heller,Daniela Galimberti,Alex Gerhard,Rik Vandenberghe,Katrina Moore,Robert Laforce,Markus Otto,Fabrizio Tagliavini,Roberta Ghidoni,Simon Ducharme,James B Rowe ,Chris Butler ,Raquel Sánchez‐Valle ,John C Van Swieten ,Regina H Reynolds ,Rhian S Convery ,David M Cash ,David L Thomas ,Fermín Moreno ,Jonathan D Rohrer ,Giovanni B Frisoni ,Genfi Genetic Ftd Initiative

doi:10.1093/braincomms/fcaa122

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.

Highlights

Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder characterized by neuronal loss in the frontal and temporal lobes, with clinical symptoms including behavioural, language and motor deficits (Seelaar et al, 2011)
We investigated the gene expression correlates of the cortical regions atrophic in the three main genetic causes of FTD
Whilst there was no association with expression of the gene itself (i.e. chromosome 9 open reading frame 72 (C9orf72), genes: progranulin (GRN) and microtubule-associated protein tau (MAPT)), our analysis revealed that groups of genes commonly associated with astrocytes and endothelial cells showed higher expression levels in regions with more atrophy and genes commonly associated with neurons and microglia showed higher expression levels in the relatively spared regions

Summary

Introduction

Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder characterized by neuronal loss in the frontal and temporal lobes, with clinical symptoms including behavioural, language and motor deficits (Seelaar et al, 2011). Despite progress in understanding the pathophysiological basis of genetic FTD, the biological basis of how mutations in these genes leads to cell loss in specific cortical regions and subsequently to specific clinical phenotypes is unclear. An alternative approach to elucidating the molecular biology of autosomal dominant FTD is to study the gene expression profiles of brain regions which are atrophic in symptomatic mutation carriers. This approach has been enabled by publicly available data from the Allen Institute for Brain Science which features post-mortem high-resolution brain-wide gene expression data (i.e. the Allen Atlas) from cognitively normal individuals (Hawrylycz et al, 2012, 2015). In the case of neurodegenerative disorders, one study investigated the link between gene expression and both regional patterns of atrophy and amyloid deposition, finding a positive correlation of APP gene expression and amyloid (Grothe et al, 2018), whilst another study showed that expression of the MAPT gene was associated with changes in functional connectivity in Parkinson’s disease (Rittman et al, 2016)

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