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 ,   on behalf of the Genetic FTD Initiative, GENFI
Published: December 2019

Frontotemporal dementia (FTD) 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 FTD, 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 gray matter atrophy in symptomaticC9orf72,GRNandMAPTmutation carriers obtained from the Genetic FTD Initiative study. No significant association was seen between (C9orf2,GRNandMAPTexpression and the atrophy patterns in the respective genetic groups. Between 1,000 and 5,000 genes showed a negative or positive correlation with the atrophy pattern within each individual genetic group, with the most significantly associated genes beingTREM2,SSBP3andGPR158(negative association inC9orf72,GRNandMAPTrespectively) andRELN, MXRA8andLPA(positive association inC9orf72,GRNandMAPTrespectively). An overrepresentation analysis identified a negative correlation with genes involved in mitochondrial function, and a positive correlation with genes involved in vascular and glial cell function in each of the genetic groups. After adjusting for spatial autocorrelation, a set of 423 and 700 genes showed significant positive and negative correlation, 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 FTD 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.

Abbreviated summary

Altmann et al. investigated the concordance between spatial cortical gene expression in healthy subjects and atrophy patterns in genetic frontotemporal dementia. They found that elevated gene expression of endothelial cell and astrocyte-related genes in regions with atrophy, suggesting a role of these cell types in the aetiology of frontotemporal dementia.