Phoebe H. Foster, UCL Queen Square Institute of Neurology
Lucy L. Russell, UCL Queen Square Institute of Neurology
Georgia Peakman, UCL Queen Square Institute of Neurology
Rhian S. Convery, UCL Queen Square Institute of Neurology
Arabella Bouzigues, UCL Queen Square Institute of Neurology
Caroline V. Greaves, UCL Queen Square Institute of Neurology
Martina Bocchetta, UCL Queen Square Institute of Neurology
David M. Cash, UCL Queen Square Institute of Neurology
John C. van Swieten, Erasmus MC
Lize C. Jiskoot, Erasmus MC
Fermin Moreno, Osakidetza, Donostia University Hospital
Raquel Sanchez-Valle, Universitat de Barcelona
Robert Laforce, CHU de Québec - Université Laval
Caroline Graff, Karolinska Institutet
Mario Masellis, University of Toronto
Carmela Tartaglia, Tanz Centre for Research in Neurodegenerative Diseases
James B. Rowe, Department of Clinical Neurosciences
Barbara Borroni, Università degli Studi di Brescia
Elizabeth Finger, Western UniversityFollow
Matthis Synofzik, Hertie-Institut für klinische Hirnforschung
Daniela Galimberti, Ospedale Maggiore Policlinico Milano
Rik Vandenberghe, Departement Neurowetenschappen
Alexandre de Mendonça, Faculdade de Medicina, Universidade de Lisboa
Chris R. Butler, University of Oxford Medical Sciences Division
Alex Gerhard, The University of Manchester
Simon Ducharme, School of Medicine
Isabelle Le Ber, Sorbonne Universite
Fabrizio Tagliavini, Foundation IRCCS Neurological Institute "C. Besta"
Isabel Santana, Centro Hospitalar e Universitário de Coimbra
Florence Pasquier, Université de Lille

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Background: Reduced empathy is a common symptom in frontotemporal dementia (FTD). Although empathy deficits have been extensively researched in sporadic cases, few studies have explored the differences in familial forms of FTD. Methods: Empathy was examined using a modified version of the Interpersonal Reactivity Index (mIRI) in 676 participants from the Genetic FTD Initiative: 216 mutation-negative controls, 192 C9orf72 expansion carriers, 193 GRN mutation carriers and 75 MAPT mutation carriers. Using global scores from the CDR® plus NACC FTLD, mutation carriers were divided into three groups, asymptomatic (0), very mildly symptomatic/prodromal (.5), or fully symptomatic (1 or more). The mIRI Total score, as well as the subscores of Empathic Concern (EC) and Perspective Taking (PT) were assessed. Linear regression models with bootstrapping were used to assess empathy ratings across genetic groups, as well as across phenotypes in the symptomatic carriers. Neural correlates of empathy deficits were examined using a voxel-based morphometry (VBM) analysis. Results: All fully symptomatic groups scored lower on the mIRI Total, EC, and PT when compared to controls and their asymptomatic or prodromal counterparts (all p <.001). Prodromal C9orf72 expansion carriers also scored significantly lower than controls on the mIRI Total score (p =.046). In the phenotype analysis, all groups (behavioural variant FTD, primary progressive aphasia and FTD with amyotrophic lateral sclerosis) scored significantly lower than controls (all p <.007). VBM revealed an overlapping neural correlate of the mIRI Total score across genetic groups in the orbitofrontal lobe but with additional involvement in the temporal lobe, insula and basal ganglia in both the GRN and MAPT groups, and uniquely more posterior regions such as the parietal lobe and thalamus in the GRN group, and medial temporal structures in the MAPT group. Conclusions: Significant empathy deficits present in genetic FTD, particularly in symptomatic individuals and those with a bvFTD phenotype, while prodromal deficits are only seen using the mIRI in C9orf72 expansion carriers.