Characterizing the Clinical Features and Atrophy Patterns of MAPT-Related Frontotemporal Dementia With Disease Progression Modeling

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background and objective: Mutations in the MAPT gene cause frontotemporal dementia (FTD). Most previous studies investigating the neuroanatomical signature of MAPT mutations have grouped all different mutations together and shown an association with focal atrophy of the temporal lobe. However, the variability in atrophy patterns between each particular MAPT mutation is less well characterised. We aimed to investigate whether there were distinct groups of MAPT mutation carriers based on their neuroanatomical signature. Methods: We applied Subtype and Stage Inference (SuStaIn), an unsupervised machine learning technique that identifies groups of individuals with distinct progression patterns, to characterise patterns of regional atrophy in MAPT-associated FTD within the Genetic FTD Initiative (GENFI) cohort study. Results: 82 MAPT mutation carriers were analysed, the majority of whom had P301L, IVS10+16 or R406W mutations, along with 48 healthy non-carriers. SuStaIn identified two groups of MAPT mutation carriers with distinct atrophy patterns: a 'temporal' subtype in which atrophy was most prominent in the hippocampus, amygdala, temporal cortex and insula, and a 'frontotemporal' subtype in which atrophy was more localised to the lateral temporal lobe and anterior insula, as well as the orbitofrontal and ventromedial prefrontal cortex and anterior cingulate. There was a one-to-one mapping between IVS10+16 and R406W mutations and the temporal subtype, and a near one-to-one mapping between P301L mutations and the frontotemporal subtype. There were differences in clinical symptoms and neuropsychological test scores between subtypes: the temporal subtype was associated with amnestic symptoms, whereas the frontotemporal subtype was associated with executive dysfunction. Discussion: Our results demonstrate that different MAPT mutations give rise to distinct atrophy patterns and clinical phenotype, providing insights into the underlying disease biology, and potential utility for patient stratification in therapeutic trials.
The Dementia Research Centre is supported by Alzheimer's Research UK, Brain Research Trust, and The Wolfson Foundation. This work was supported by the NIHR Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and Kings College London, as well as an Alzheimer's Society grant (AS-PG-16-007). This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Italian Ministry of Health (CoEN015 and Ricerca Corrente), and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, a Canadian Institutes of Health Research operating grant and The Bluefield Project, and the JPND GENFI-PROX grant (2019-02248). 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). Nonfinancial support was also provided through the European Reference Network for Rare Neurologic Diseases (ERN-RND), 1 of 24 ERNs funded by the European Commission (ERNRND: 3HP 767231).