Early neurotransmitters changes in prodromal frontotemporal dementia: A GENFI study

Enrico Premi, Marta Pengo, on behalf of the Genetic Frontotemporal dementia Initiative (GENFI), Irene Mattioli, Valentina Cantoni, Juergen Dukart, Roberto Gasparotti, Emanuele Buratti, Alessandro Padovani, Martina Bocchetta, Emily G. Todd, Arabella Bouzigues, David M. Cash, Rhian S. Convery, Lucy L. Russell, David L. Thomas, John C. van Swieten, Lize C. Jiskoot, Harro Seelaar, Daniela GalimbertiRaquel Sanchez-Valle, Robert Laforce, Fermin Moreno, Matthis Synofzik, Caroline Graff, Mario Masellis, Maria Carmela Tartaglia, James B. Rowe, Kamen A. Tsvetanov, Rik Vandenberghe, Elizabeth Finger, Fabrizio Tagliavini, Alexandre de Mendonça, Isabel Santana, Chris R. Butler, Simon Ducharme, Alexander Gerhard, Adrian Danek, Johannes Levin, Markus Otto, Sandro Sorbi, Isabelle Le Ber, Florence Pasquier, Jonathan D. Rohrer, Barbara Borroni*

*Corresponding author for this work

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Abstract

Background: Neurotransmitters deficits in Frontotemporal Dementia (FTD) are still poorly understood. Better knowledge of neurotransmitters impairment, especially in prodromal disease stages, might tailor symptomatic treatment approaches. Methods: In the present study, we applied JuSpace toolbox, which allowed for cross-modal correlation of Magnetic Resonance Imaging (MRI)-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, GABAergic and glutamatergic neurotransmission. We included 392 mutation carriers (157 GRN, 164 C9orf72, 71 MAPT), together with 276 non-carrier cognitively healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in mutation carriers (relative to HC) are correlated with specific neurotransmitter systems in prodromal (CDR® plus NACC FTLD = 0.5) and in symptomatic (CDR® plus NACC FTLD≥1) FTD. Results: In prodromal stages of C9orf72 disease, voxel-based brain changes were significantly associated with spatial distribution of dopamine and acetylcholine pathways; in prodromal MAPT disease with dopamine and serotonin pathways, while in prodromal GRN disease no significant findings were reported (p < 0.05, Family Wise Error corrected). In symptomatic FTD, a widespread involvement of dopamine, serotonin, glutamate and acetylcholine pathways across all genetic subtypes was found. Social cognition scores, loss of empathy and poor response to emotional cues were found to correlate with the strength of GMV colocalization of dopamine and serotonin pathways (all p < 0.01). Conclusions: This study, indirectly assessing neurotransmitter deficits in monogenic FTD, provides novel insight into disease mechanisms and might suggest potential therapeutic targets to counteract disease-related symptoms.

Original languageEnglish
Article number106068
JournalNeurobiology of Disease
Volume179
DOIs
Publication statusPublished - Apr 2023

Bibliographical note

Funding Information:
This work is supported by JPND grant “GENFI-prox” ( 2019–02248 ), the Centre d'Investigation Clinique (ICM, France) and the Centre pour l'Acquisition et le Traitement des Images platform (CATI, France), the UK Medical Research Council , the Italian Ministry of Health (CoEN015 and Ricerca Corrente), 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 Italian Ministry of Health (GR- 2018-12365105 ). This work was also supported by the MRC UK GENFI grant ( MR/M023664/1 ), the Alzheimer's Society grant ( AS-PG-16-007 ), and the Bluefield Project. This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198 ).

Funding Information:
MB is supported by a Fellowship award from the Alzheimer's Society, UK (AS-JF-19a-004-517). RS-V was funded at the Hospital Clinic de Barcelona by Instituto de Salud Carlos III, Spain (grant code PI20/00448 to RSV) and Fundació Marató TV3, Spain (grant code 20143810 to RSV). RL is supported by the Canadian Institutes of Health Research and the Chaire de Recherche sur les Aphasies Primaires Progressives Fondation Famille Lemaire. MS has been supported by the German Federal Ministry of Education and Research (BMBF) by a grant given to the German FTLD Consortium (FKZ O1GI1007A), and by the German Research Foundation DFG (SCHR 774/5–1). CG is supported by the Swedish Frontotemporal Dementia Initiative Schӧrling Foundation, Swedish Research Council, JPND Prefrontals, 2015–02926,2018–02754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Karolinska Institutet Doctoral Funding, KI Strat-Neuro, Swedish Dementia Foundation, and Stockholm County Council ALF/Region Stockholm. MM was, in part, funded by the UK Medical Research Council, the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, and also Canadian Institutes of Health Research operating grants (Grant #s: MOP- 371851 and PJT-175242) and funding from the Weston Brain Institute to Mario Masellis. JBR is supported by the Wellcome Trust (103,838;220,258), Medical Research Council (SUAG/092 G116768) and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20,014; the views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care). RV's work is supported by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie. SD receives salary funding from the Fonds de Recherche du Québec - Santé. JL is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). JDR is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). BB is supported by JPND grant “GENFI-prox” (2019–02248). Several authors of this publication (JCvS, MS, RSV, MO, RV, JDR) are members of the European Reference Network for Rare Neurological Diseases (ERN-RND) - Project ID No 739510. All other authors report no biomedical financial interests or potential conflicts of interest.

Publisher Copyright:
© 2023

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