Apathy in presymptomatic genetic frontotemporal dementia predicts cognitive decline and is driven by structural brain changes

• Published in: Alzheimer's & dementia 2021-06, Vol.17 (6), p.969-983
• Main Authors: Malpetti, Maura, Jones, P. Simon, Tsvetanov, Kamen A., Rittman, Timothy, Swieten, John C., Borroni, Barbara, Sanchez‐Valle, Raquel, Moreno, Fermin, Laforce, Robert, Graff, Caroline, Synofzik, Matthis, Galimberti, Daniela, Masellis, Mario, Tartaglia, Maria Carmela, Finger, Elizabeth, Vandenberghe, Rik, de Mendonça, Alexandre, Tagliavini, Fabrizio, Santana, Isabel, Ducharme, Simon, Butler, Chris R., Gerhard, Alexander, Levin, Johannes, Danek, Adrian, Otto, Markus, Frisoni, Giovanni B., Ghidoni, Roberta, Sorbi, Sandro, Heller, Carolin, Todd, Emily G., Bocchetta, Martina, Cash, David M., Convery, Rhian S., Peakman, Georgia, Moore, Katrina M., Rohrer, Jonathan D., Kievit, Rogier A., Rowe, James B., GENFI - Genetic Frontotemporal dementia Initiative
• Format: Article
• Language: English
• Subjects: Apathy; Atrophy - pathology; Brain - pathology; Cognitive decline; Cognitive Dysfunction - pathology; Female; Frontotemporal Dementia - genetics; Genetic frontotemporal dementia; Gray Matter - pathology; Humans; Longitudinal design; Magnetic Resonance Imaging; Male; Middle Aged; MRI; Mutation - genetics; Presymptomatic carriers; Prodromal Symptoms
• ISSN: 1552-5260; 2352-8729; 1552-5279
• DOI: 10.1002/alz.12252

© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Introduction: Apathy adversely affects prognosis and survival of patients with frontotemporal dementia (FTD). We test whether apathy develops in presymptomatic genetic FTD, and is associated with cognitive decline and brain atrophy. Methods: Presymptomatic carriers of MAPT, GRN or C9orf72 mutations (N = 304), and relatives without mutations (N = 296) underwent clinical assessments and MRI at baseline, and annually for 2 years. Longitudinal changes in apathy, cognition, gray matter volumes, and their relationships were analyzed with latent growth curve modeling. Results: Apathy severity increased over time in presymptomatic carriers, but not in non-carriers. In presymptomatic carriers, baseline apathy predicted cognitive decline over two years, but not vice versa. Apathy progression was associated with baseline low gray matter volume in frontal and cingulate regions. Discussion: Apathy is an early marker of FTD-related changes and predicts a subsequent subclinical deterioration of cognition before dementia onset. Apathy may be a modifiable factor in those at risk of FTD. This work is co‐funded by the UK Medical Research Council (MR/M023664/1), the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, a Canadian Institutes of Health Research operating grant and the Bluefield Project, as well as a JPND grant “GENFI‐prox” (by DLR/BMBF to MS, joined with JDR, JvS, MO, BB and CG). MM is supported by the Cambridge Trust & Sidney Sussex College Scholarship. PSJ is supported by the Cambridge Centre for Parkinson Plus. KAT is supported by the British Academy Postdoctoral Fellowship (KAT: PF160048) and Guarantors of Brain (KAT: 101149). TR is supported by the Cambridge Centre for Parkinson Plus and Cambridge Biomedical Resource Centre. RAK is supported by Medical Research Council (RAK: SUAG/047/G101400). JBR reports grants from the NIHR Cambridge Biomedical research centre, Wellcome Trust (103838), and Medical Research Council (SUAG051/G101400; MR/T033371/1); personal fees from Asceneuron, WAVE, Astex, and Biogen; and grants from Janssen, AZ Medimmune, and Eli Lilly, outsid