Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia
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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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Human Brain Mapping |
| Vol/bind | 44 |
| Udgave nummer | 7 |
| Sider (fra-til) | 2684-2700 |
| Antal sider | 17 |
| ISSN | 1065-9471 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
A. Bussy receives support from the Alzheimer Society of Canada. Dr Chakravarty is funded by the Weston Brain Institute, the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, Healthy Brains Healthy Lives and Fondation de Recherches Santé Québec. Dr Ducharme received salary funding from the Fonds de Recherche du Québec - Santé. This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Italian Ministry of Health (CoEN015 and Ricerca Corrente), the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, a Canadian Institutes of Health Research operating grant, the Alzheimer's Society grant (AS-PG-16-007), the Bluefield Project and the JPND GENFI-PROX grant (2019–02248). MB is supported by a Fellowship award from the Alzheimer's Society, UK (AS-JF-19a-004-517). MB's work was also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd., funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. JDR is an MRC Clinician Scientist (MR/M008525/1) and has received funding from the NIHR Rare Diseases Translational Research Collaboration (BRC149/NS/MH), the Bluefield Project and the Association for Frontotemporal Degeneration. 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). Several authors of this publication (JCvS, MS, RSV, AD, MO, JDR) are members of the European Reference Network for Rare Neurological Diseases (ERN-RND) - Project ID No 739510. 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). This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.
Funding Information:
This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC‐1215‐20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.
Funding Information:
Alzheimer Society of Canada; Weston Brain Institute; Fonds de Recherche du Québec ‐ Santé; MRC UK GENFI, Grant/Award Number: MR/M023664/1; Italian Ministry of Health, Grant/Award Number: CoEN015; Canadian Institutes of Health Research; Alzheimer's Society grant, Grant/Award Number: AS‐PG‐16‐007; Alzheimer's Society, Grant/Award Number: AS‐JF‐19a‐004‐517; NIHR Rare Diseases Translational Research Collaboration; Deutsche Forschungsgemeinschaft; NIHR Cambridge Biomedical Research Centre, Grant/Award Numbers: BRC‐1215‐20014, BRC149/NS/MH Funding information
Funding Information:
This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Italian Ministry of Health (CoEN015 and Ricerca Corrente), the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, a Canadian Institutes of Health Research operating grant, the Alzheimer's Society grant (AS‐PG‐16‐007), the Bluefield Project and the JPND GENFI‐PROX grant (2019–02248). MB is supported by a Fellowship award from the Alzheimer's Society, UK (AS‐JF‐19a‐004‐517). MB's work was also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd., funded by the UK Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. JDR is an MRC Clinician Scientist (MR/M008525/1) and has received funding from the NIHR Rare Diseases Translational Research Collaboration (BRC149/NS/MH), the Bluefield Project and the Association for Frontotemporal Degeneration. 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). Several authors of this publication (JCvS, MS, RSV, AD, MO, JDR) are members of the European Reference Network for Rare Neurological Diseases (ERN‐RND) ‐ Project ID No 739510. 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:
A. Bussy receives support from the Alzheimer Society of Canada. Dr Chakravarty is funded by the Weston Brain Institute, the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada, Healthy Brains Healthy Lives and Fondation de Recherches Santé Québec. Dr Ducharme received salary funding from the Fonds de Recherche du Québec ‐ Santé.
Publisher Copyright:
© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.
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