Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia

Aurélie Bussy, Jake P Levy, Tristin Best, Raihaan Patel, Lani Cupo, Tim Van Langenhove, Jørgen E Nielsen*, Yolande Pijnenburg, Maria Landqvist Waldö, Anne M Remes, Matthias L Schroeter, Isabel Santana, Florence Pasquier, Markus Otto, Adrian Danek, Johannes Levin, Isabelle Le Ber, Rik Vandenberghe, Matthis Synofzik, Fermin MorenoAlexandre de Mendonça, Raquel Sanchez-Valle, Robert Laforce, Tobias Langheinrich, Alexander Gerhard, Caroline Graff, Chris R Butler, Sandro Sorbi, Lize Jiskoot, Harro Seelaar, John C van Swieten, Elizabeth Finger, Maria Carmela Tartaglia, Mario Masellis, Pietro Tiraboschi, Daniela Galimberti, Barbara Borroni, James B Rowe, Martina Bocchetta, Jonathan D Rohrer, Gabriel A Devenyi, M Mallar Chakravarty, Simon Ducharme, GENetic Frontotemporal dementia Initiative (GENFI)

*Corresponding author af dette arbejde
4 Citationer (Scopus)

Abstract

Recent studies have reported early cerebellar and subcortical impact in the disease progression of genetic frontotemporal dementia (FTD) due to microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72). However, the cerebello-subcortical circuitry in FTD has been understudied despite its essential role in cognition and behaviors related to FTD symptomatology. The present study aims to investigate the association between cerebellar and subcortical atrophy, and neuropsychiatric symptoms across genetic mutations. Our study included 983 participants from the Genetic Frontotemporal dementia Initiative including mutation carriers and noncarrier first-degree relatives of known symptomatic carriers. Voxel-wise analysis of the thalamus, striatum, globus pallidus, amygdala, and the cerebellum was performed, and partial least squares analyses (PLS) were used to link morphometry and behavior. In presymptomatic C9orf72 expansion carriers, thalamic atrophy was found compared to noncarriers, suggesting the importance of this structure in FTD prodromes. PLS analyses demonstrated that the cerebello-subcortical circuitry is related to neuropsychiatric symptoms, with significant overlap in brain/behavior patterns, but also specificity for each genetic mutation group. The largest differences were in the cerebellar atrophy (larger extent in C9orf72 expansion group) and more prominent amygdalar volume reduction in the MAPT group. Brain scores in the C9orf72 expansion carriers and MAPT carriers demonstrated covariation patterns concordant with atrophy patterns detectable up to 20 years before expected symptom onset. Overall, these results demonstrated the important role of the subcortical structures in genetic FTD symptom expression, particularly the cerebellum in C9orf72 and the amygdala in MAPT carriers.

OriginalsprogEngelsk
TidsskriftHuman Brain Mapping
Vol/bind44
Udgave nummer7
Sider (fra-til)2684-2700
Antal sider17
ISSN1065-9471
DOI
StatusUdgivet - maj 2023

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