Konwar, S., Hunyadvari, N., Venneri, A. et al. (2 more authors) (2025) Neuroanatomical normative modelling in frontotemporal lobar degeneration: higher heterogeneity in the behavioural variant. Journal of Neurology, 272 (10). 642. ISSN: 0340-5354
Abstract
Introduction
Frontotemporal lobar degeneration (FTLD) includes heterogenous diseases: behavioural variant frontotemporal dementia (bvFTD), primary progressive aphasias (PPA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We applied neuroanatomical normative modelling to quantify individual atrophy patterns and heterogeneity within and between FTLD forms.
Methods
We included 160 participants across FTLDNI and 4RTNI studies: controls (n = 15), bvFTD (n = 22), nfvPPA (n = 14), svPPA (n = 21), CBS (n = 43) and PSP (n = 45). Using cortical thickness and subcortical volumes from 3T MRIs, we applied normative modelling with a large healthy reference dataset (n = 58,836), further accounting for age, sex, and scanner. Outlier regions (z < – 1.96) were used to compute total outlier counts (tOC) and Hamming distances, capturing individual atrophy patterns and inter-subject dissimilarity.
Results
bvFTD, svPPA, CBS and PSP showed significantly higher cortical tOC than controls, with all groups showing higher subcortical tOC than controls, especially svPPA and PSP. bvFTD, svPPA, CBS and PSP had significantly higher cortical Hamming distance scores than controls, with higher scores in bvFTD and svPPA than nfvPPA and PSP. svPPA and PSP had significantly higher subcortical scores than controls and CBS. Greater disease severity (measured using the Clinical Dementia Rating—CDR for PSP and CBS, and the CDR® plus NACC-FTLD global scores for FTD variants) was associated with increased tOC and dissimilarity, highlighting the link between clinical progression and neuroanatomical heterogeneity.
Conclusions
The pronounced heterogeneity within and between FTLD subtypes (particularly in bvFTD) increases with disease progression and may reflect distinct underlying pathologies. This supports the development of subtype-specific biomarkers and emphasize the need for personalized diagnostic and therapeutic strategies.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2025. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
Keywords: | Frontotemporal lobar degeneration; Neuroanatomical normative modelling; Individual neuroimaging biomarkers; MRI |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) |
Date Deposited: | 29 Sep 2025 14:09 |
Last Modified: | 29 Sep 2025 14:09 |
Status: | Published |
Publisher: | Springer Science and Business Media LLC |
Refereed: | Yes |
Identification Number: | 10.1007/s00415-025-13378-5 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:232321 |