TY - JOUR

T1 - Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia

AU - Bussy, Aurélie

AU - Levy, Jake P.

AU - Best, Tristin

AU - Patel, Raihaan

AU - Cupo, Lani

AU - Van Langenhove, Tim

AU - Nielsen, Jørgen E.

AU - Pijnenburg, Yolande

AU - Waldö, Maria Landqvist

AU - Remes, Anne M.

AU - Schroeter, Matthias L.

AU - Santana, Isabel

AU - Pasquier, Florence

AU - Otto, Markus

AU - Danek, Adrian

AU - Levin, Johannes

AU - Le Ber, Isabelle

AU - Vandenberghe, Rik

AU - Synofzik, Matthis

AU - Moreno, Fermin

AU - de Mendonça, Alexandre

AU - Sanchez-Valle, Raquel

AU - Laforce, Robert

AU - Langheinrich, Tobias

AU - Gerhard, Alexander

AU - Graff, Caroline

AU - Butler, Chris R.

AU - Sorbi, Sandro

AU - Jiskoot, Lize

AU - Seelaar, Harro

AU - van Swieten, John C.

AU - Finger, Elizabeth

AU - Tartaglia, Maria Carmela

AU - Masellis, Mario

AU - Tiraboschi, Pietro

AU - Galimberti, Daniela

AU - Borroni, Barbara

AU - Rowe, James B.

AU - Bocchetta, Martina

AU - Rohrer, Jonathan D.

AU - Devenyi, Gabriel A.

AU - Chakravarty, M. Mallar

AU - Ducharme, Simon

AU - Esteve, Aitana Sogorb

AU - Nelson, Annabel

AU - Bouzigues, Arabella

AU - Heller, Carolin

AU - Greaves, Caroline V.

AU - Cash, David

AU - Thomas, David L.

AU - GENetic Frontotemporal dementia Initiative (GENFI)

N1 - Publisher Copyright: © 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - frontotemporal dementia

KW - genetics

KW - magnetic resonance imaging

KW - neuropsychiatry

UR - http://www.scopus.com/inward/record.url?scp=85150648466&partnerID=8YFLogxK

U2 - 10.1002/hbm.26220

DO - 10.1002/hbm.26220

M3 - Journal article

C2 - 36895129

AN - SCOPUS:85150648466

VL - 44

SP - 2684

EP - 2700

JO - Human Brain Mapping

JF - Human Brain Mapping

SN - 1065-9471

IS - 7

ER -