{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T09:12:32Z","timestamp":1787735552577,"version":"build-2784847793"},"reference-count":58,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2024,10,7]],"date-time":"2024-10-07T00:00:00Z","timestamp":1728259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ESRC-funded UCL, Bloomsbury and East London Doctoral Training Partnership","award":["ES\/P000592\/1"],"award-info":[{"award-number":["ES\/P000592\/1"]}]},{"DOI":"10.13039\/501100017506","name":"Alzheimer\u2019s Society","doi-asserted-by":"publisher","award":["AS-JF-19a-004-517"],"award-info":[{"award-number":["AS-JF-19a-004-517"]}],"id":[{"id":"10.13039\/501100017506","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002283","name":"Alzheimer\u2019s Research UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002283","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020172","name":"Royal National Institute for Deaf People","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020172","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIHR UCLH Biomedical Research Centre"},{"name":"Frontotemporal Dementia Research Studentship"},{"DOI":"10.13039\/501100000143","name":"Alzheimer\u2019s Society, UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000143","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013790","name":"Miriam Marks Brain Research UK Senior Fellowship","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013790","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MRC Clinician Scientist Fellowship","award":["MR\/M008525\/1"],"award-info":[{"award-number":["MR\/M008525\/1"]}]},{"name":"NIHR Rare Disease Translational Research Collaboration","award":["BRC149\/NS\/MH"],"award-info":[{"award-number":["BRC149\/NS\/MH"]}]},{"name":"NIHR Rare Disease Translational Research Collaboration","award":["MR\/M023664\/1"],"award-info":[{"award-number":["MR\/M023664\/1"]}]},{"name":"Bluefield Project"},{"name":"JPND GENFI-PROX","award":["2019-02248"],"award-info":[{"award-number":["2019-02248"]}]},{"name":"UKRI Future Leaders Fellow","award":["MR\/S03546X\/1"],"award-info":[{"award-number":["MR\/S03546X\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,3,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The primary progressive aphasias are rare, language-led dementias, with three main variants: semantic, non-fluent\/agrammatic and logopenic. Although the semantic variant has a clear neuroanatomical profile, the non-fluent\/agrammatic and logopenic variants are difficult to discriminate from neuroimaging. Previous phenotype-driven studies have characterized neuroanatomical profiles of each variant on MRI. In this work, we used a machine learning algorithm known as SuStaIn to discover data-driven neuroanatomical \u2018subtype\u2019 progression profiles and performed an in-depth subtype\u2013phenotype analysis to characterize the heterogeneity of primary progressive aphasia.<\/jats:p>\n                  <jats:p>Our study included 270 participants with primary progressive aphasia seen for research in the UCL Queen Square Institute of Neurology Dementia Research Centre, with follow-up scans available for 137 participants. This dataset included individuals diagnosed with all three main variants (semantic, n = 94; non-fluent\/agrammatic, n = 109; logopenic, n = 51) and individuals with unspecified primary progressive aphasia (n = 16). A dataset of 66 patients (semantic, n = 37; non-fluent\/agrammatic, n = 29) from the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Research Study was used to validate our results. MRI scans were segmented, and SuStaIn was used on 19 regions of interest to identify neuroanatomical profiles independent of the diagnosis. We assessed the assignment of subtypes and stages, in addition to their longitudinal consistency.<\/jats:p>\n                  <jats:p>We discovered four neuroanatomical subtypes of primary progressive aphasia, labelled S1 (left temporal), S2 (insula), S3 (temporoparietal) and S4 (frontoparietal), exhibiting robustness to statistical scrutiny. S1 was correlated strongly with the semantic variant, whereas S2, S3 and S4 showed mixed associations with the logopenic and non-fluent\/agrammatic variants. Notably, S3 displayed a neuroanatomical signature akin to a logopenic-only signature, yet a significant proportion of logopenic cases were allocated to S2. The non-fluent\/agrammatic variant demonstrated diverse associations with S2, S3 and S4. No clear relationship emerged between any of the neuroanatomical subtypes and the unspecified cases. At first follow-up, subtype assignment was stable for 84% of patients, and stage assignment was stable for 91.9% of patients. We partially validated our findings in the ALLFTD dataset, finding comparable qualitative patterns.<\/jats:p>\n                  <jats:p>Our study, leveraging machine learning on a large primary progressive aphasia dataset, delineated four distinct neuroanatomical patterns. Our findings suggest that separable spatiotemporal neuroanatomical phenotypes do exist within the primary progressive aphasia spectrum, but that these are noisy, particularly for the non-fluent\/agrammatic non-fluent\/agrammatic and logopenic variants. Furthermore, these phenotypes do not always conform to standard formulations of clinico-anatomical correlation. Understanding the multifaceted profiles of the disease, encompassing neuroanatomical, molecular, clinical and cognitive dimensions, has potential implications for clinical decision support.<\/jats:p>","DOI":"10.1093\/brain\/awae314","type":"journal-article","created":{"date-parts":[[2024,10,4]],"date-time":"2024-10-04T15:22:17Z","timestamp":1728055337000},"page":"955-968","source":"Crossref","is-referenced-by-count":10,"title":["Data-driven neuroanatomical subtypes of primary progressive aphasia"],"prefix":"10.1093","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3630-5047","authenticated-orcid":false,"given":"Beatrice","family":"Taylor","sequence":"first","affiliation":[{"name":"Centre for Medical Image Computing, Department of Computer Science, University College London , London WC1V 6LJ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1814-5024","authenticated-orcid":false,"given":"Martina","family":"Bocchetta","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London , London WC1N 3AR ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron","family":"Shand","sequence":"additional","affiliation":[{"name":"Centre for Medical Image Computing, Department of Computer Science, University College London , London WC1V 6LJ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily G","family":"Todd","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London , London WC1N 3AR ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthipa","family":"Chokesuwattanaskul","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London , London WC1N 3AR ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian J","family":"Crutch","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London , London WC1N 3AR ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason D","family":"Warren","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London , London WC1N 3AR ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan D","family":"Rohrer","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London , London WC1N 3AR ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris J D","family":"Hardy","sequence":"additional","affiliation":[{"name":"Dementia Research Centre, UCL Queen Square Institute of Neurology, University College London , London WC1N 3AR ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0203-3909","authenticated-orcid":false,"given":"Neil P","family":"Oxtoby","sequence":"additional","affiliation":[{"name":"Centre for Medical Image Computing, Department of Computer Science, University College London , London WC1V 6LJ 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