eprintid: 10130164 rev_number: 22 eprint_status: archive userid: 608 dir: disk0/10/13/01/64 datestamp: 2021-06-29 15:45:54 lastmod: 2021-12-06 23:43:56 status_changed: 2021-06-29 15:45:54 type: article metadata_visibility: show creators_name: Young, AL creators_name: Bocchetta, M creators_name: Russell, LL creators_name: Convery, RS creators_name: Peakman, G creators_name: Todd, E creators_name: Cash, DM creators_name: Greaves, CV creators_name: Van Swieten, J creators_name: Jiskoot, L creators_name: Seelaar, H creators_name: Moreno, F creators_name: Sanchez-Valle, R creators_name: Borroni, B creators_name: Laforce, R creators_name: Masellis, M creators_name: Tartaglia, MC creators_name: Graff, C creators_name: Galimberti, D creators_name: Rowe, JB creators_name: Finger, E creators_name: Synofzik, M creators_name: Vandenberghe, R creators_name: De Mendonça, A creators_name: Tagliavini, F creators_name: Santana, I creators_name: Ducharme, S creators_name: Butler, C creators_name: Gerhard, A creators_name: Levin, J creators_name: Danek, A creators_name: Otto, M creators_name: Sorbi, S creators_name: Williams, SC creators_name: Alexander, DC creators_name: Rohrer, JD creators_name: Genetic FTD Initiative (GENFI), title: Characterizing the Clinical Features and Atrophy Patterns of MAPT-Related Frontotemporal Dementia With Disease Progression Modeling ispublished: inpress divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F86 divisions: B04 divisions: C05 divisions: F48 keywords: Frontotemporal dementia, Association studies in genetics, Neuropsychological assessment, Volumetric MRI note: 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) (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract: 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. date: 2021-06-22 official_url: https://doi.org/10.1212/WNL.0000000000012410 oa_status: green full_text_type: other language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1872480 doi: 10.1212/WNL.0000000000012410 pii: WNL.0000000000012410 lyricists_name: Alexander, Daniel lyricists_name: Bocchetta, Martina lyricists_name: Cash, David lyricists_name: Convery, Rhian lyricists_name: Greaves, Caroline lyricists_name: Rohrer, Jonathan lyricists_name: Russell, Lucy lyricists_name: Young, Alexandra lyricists_id: DALEX06 lyricists_id: MBOCC01 lyricists_id: DMCAS28 lyricists_id: RSCON91 lyricists_id: CVGRE00 lyricists_id: JDROH34 lyricists_id: LLRUS40 lyricists_id: YOUNG96 actors_name: Bocchetta, Martina actors_id: MBOCC01 actors_role: owner full_text_status: public publication: Neurology event_location: United States citation: Young, AL; Bocchetta, M; Russell, LL; Convery, RS; Peakman, G; Todd, E; Cash, DM; ... Genetic FTD Initiative (GENFI); + view all <#> Young, AL; Bocchetta, M; Russell, LL; Convery, RS; Peakman, G; Todd, E; Cash, DM; Greaves, CV; Van Swieten, J; Jiskoot, L; Seelaar, H; Moreno, F; Sanchez-Valle, R; Borroni, B; Laforce, R; Masellis, M; Tartaglia, MC; Graff, C; Galimberti, D; Rowe, JB; Finger, E; Synofzik, M; Vandenberghe, R; De Mendonça, A; Tagliavini, F; Santana, I; Ducharme, S; Butler, C; Gerhard, A; Levin, J; Danek, A; Otto, M; Sorbi, S; Williams, SC; Alexander, DC; Rohrer, JD; Genetic FTD Initiative (GENFI); - view fewer <#> (2021) Characterizing the Clinical Features and Atrophy Patterns of MAPT-Related Frontotemporal Dementia With Disease Progression Modeling. Neurology 10.1212/WNL.0000000000012410 <https://doi.org/10.1212/WNL.0000000000012410>. (In press). Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10130164/1/WNL.0000000000012410.full.pdf