Journal Article

FZJ-2023-05140

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Early neurotransmitters changes in prodromal frontotemporal dementia: A GENFI study

Premi, E. ; Pengo, M. ; Mattioli, I. ; Cantoni, V. ; Dukart, J.FZJ* ; Gasparotti, R. ; Buratti, E. ; Padovani, A. ; Bocchetta, M. ; Todd, E. G. ; Bouzigues, A. ; Cash, D. M. ; Convery, R. S. ; Russell, L. L. ; Foster, P. ; Thomas, D. L. ; van Swieten, J. C. ; Jiskoot, L. C. ; Seelaar, H. ; Galimberti, D. ; Sanchez-Valle, R. ; Laforce, R. ; Moreno, F. ; Synofzik, M. ; Graff, C. ; Masellis, M. ; Tartaglia, M. C. ; Rowe, J. B. ; Tsvetanov, K. A. ; Vandenberghe, R. ; Finger, E. ; Tiraboschi, P. ; de Mendonça, A. ; Santana, I. ; Butler, C. R. ; Ducharme, S. ; Gerhard, A. ; Levin, J. ; Otto, M. ; Sorbi, S. ; Le Ber, I. ; Pasquier, F. ; Rohrer, J. D. ; Borroni, B. (Corresponding author) ; Esteve, A. S. ; Heller, C. ; Greaves, C. V. ; Zetterberg, H. ; Swift, I. J. ; Samra, K. ; Shafei, R. ; Timberlake, C. ; Cope, T. ; Rittman, T. ; Arighi, A. ; Fenoglio, C. ; Scarpini, E. ; Fumagalli, G. ; Borracci, V. ; Rossi, G. ; Giaccone, G. ; Di Fede, G. ; Caroppo, P. ; Tiraboschi, P. ; Prioni, S. ; Redaelli, V. ; Tang-Wai, D. ; Rogaeva, E. ; Castelo-Branco, M. ; Freedman, M. ; Keren, R. ; Black, S. ; Mitchell, S. ; Shoesmith, C. ; Bartha, R. ; Rademakers, R. ; Poos, J. ; Papma, J. M. ; Giannini, L. ; van Minkelen, R. ; Pijnenburg, Y. ; Nacmias, B. ; Ferrari, C. ; Polito, C. ; Lombardi, G. ; Bessi, V. ; Veldsman, M. ; Andersson, C. ; Thonberg, H. ; Öijerstedt, L. ; Jelic, V. ; Thompson, P. ; Langheinrich, T. ; Lladó, A. ; Antonell, A. ; Olives, J. ; Balasa, M. ; Bargalló, N. ; Borrego-Ecija, S. ; Verdelho, A. ; Maruta, C. ; Ferreira, C. B. ; Miltenberger, G. ; do Couto, F. S. ; Gabilondo, A. ; Gorostidi, A. ; Villanua, J. ; Cañada, M. ; Tainta, M. ; Zulaica, M. ; Barandiaran, M. ; Alves, P. ; Bender, B. ; Wilke, C. ; Graf, L. ; Vogels, A. ; Vandenbulcke, M. ; Van Damme, P. ; Bruffaerts, R. ; Poesen, K. ; Rosa-Neto, P. ; Gauthier, S. ; Camuzat, A. ; Brice, A. ; Bertrand, A. ; Funkiewiez, A. ; Rinaldi, D. ; Saracino, D. ; Colliot, O. ; Sayah, S. ; Prix, C. ; Wlasich, E. ; Wagemann, O. ; Loosli, S. ; Schönecker, S. ; Hoegen, T. ; Lombardi, J. ; Anderl-Straub, S. ; Rollin, A. ; Kuchcinski, G. ; Bertoux, M. ; Lebouvier, T. ; Deramecourt, V. ; Santiago, B. ; Duro, D. ; Leitão, M. J. ; Almeida, M. R. ; Tábuas-Pereira, M. ; Afonso, S.

2023
Elsevier [Amsterdam]

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Please use a persistent id in citations: doi:10.1016/j.nbd.2023.106068  doi:10.34734/FZJ-2023-05140

Abstract: BackgroundNeurotransmitters deficits in Frontotemporal Dementia (FTD) are still poorly understood. Better knowledge of neurotransmitters impairment, especially in prodromal disease stages, might tailor symptomatic treatment approaches.MethodsIn 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.ResultsIn 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).ConclusionsThis 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.

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Contributing Institute(s):

1. Gehirn & Verhalten (INM-7)

Research Program(s):

1. 5252 - Brain Dysfunction and Plasticity (POF4-525) (POF4-525)

Appears in the scientific report 2023

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