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This suggests a prolonged prodromal phase with accumulation of neuropathology and minimal symptoms, about which little is known. To study early and presymptomatic SD, we first examine a well-characterized cohort of people with SD recruited from the Cambridge Centre for Frontotemporal Dementia. Five people with early SD had coincidental MRI prior to the onset of symptoms or were healthy volunteers in research with anterior temporal lobe atrophy as an incidental finding. We model longitudinal imaging changes in left- and right-lateralized SD to predict atrophy at symptom onset. We then assess 61 203 participants with structural brain MRI in the UK Biobank to find individuals with imaging changes in keeping with SD but with no neurodegenerative diagnosis. To identify these individuals in the UK Biobank, we design an ensemble-based classifier, differentiating baseline structural MRI in SD from healthy controls and patients with other neurodegenerative diseases, including other causes of frontotemporal lobar degeneration. We train the classifier on a Cambridge-based cohort (SD n = 47, other neurodegenerative diseases n = 498, healthy controls n = 88) and test it on a combined cohort from the Neuroimaging in Frontotemporal Dementia study and the Alzheimer\u2019s Disease Neuroimaging Initiative (SD n = 42, other neurodegenerative disease n = 449, healthy controls n = 127).<\/jats:p>\n                  <jats:p>From our case series, we find people with marked atrophy 3 to 5 years before recognition of symptom onset in left- or right-predominant SD. We present right-lateralized cases with subtle multimodal semantic impairment, found concurrently with only mild behavioural disturbance. We show that imaging measures can reliably and accurately differentiate clinical SD from other neurodegenerative diseases (recall: 0.88, precision: 0.95, F1 score: 0.91). We find individuals with no neurodegenerative diagnosis in the UK Biobank with striking left-lateralized (prevalence ages 45\u201385, 4.8\/100 000) or right-lateralized (5.9\/100 000) anterior temporal lobe atrophy, with deficits on cognitive testing suggestive of semantic impairment. These individuals show progressive involvement of other cognitive domains in longitudinal follow-up. Together, our findings suggest that (i) there is a burden of incipient early anterior temporal lobe atrophy in older populations, with comparable prevalence of left- and right-sided cases from this prospective unbiased approach to identification; (ii) substantial atrophy is required for manifest symptoms, particularly in right-lateralized cases; and (iii) semantic deficits across multiple domains can be detected in the early symptomatic phase.<\/jats:p>","DOI":"10.1093\/brain\/awaf351","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T12:05:26Z","timestamp":1758283526000},"page":"1663-1678","source":"Crossref","is-referenced-by-count":2,"title":["The presymptomatic and early manifestations of semantic dementia"],"prefix":"10.1093","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5890-9220","authenticated-orcid":false,"given":"David J","family":"Whiteside","sequence":"first","affiliation":[{"name":"Department of Clinical Neurosciences, University of Cambridge , Cambridge CB2 0SZ ,","place":["UK"]},{"name":"Department of Neurology, Cambridge University Hospitals NHS Foundation Trust , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3157-4301","authenticated-orcid":false,"given":"Matthew A","family":"Rouse","sequence":"additional","affiliation":[{"name":"Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge , Cambridge CB2 7EF ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P Simon","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, University of Cambridge , Cambridge CB2 0SZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Coyle-Gilchrist","sequence":"additional","affiliation":[{"name":"Department of Neurology, Norfolk and Norwich University Hospital NHS Trust , Norwich NR4 7UY ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0813-0670","authenticated-orcid":false,"given":"Alexander G","family":"Murley","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, University of Cambridge , Cambridge CB2 0SZ ,","place":["UK"]},{"name":"Department of Neurology, Cambridge University Hospitals NHS Foundation Trust , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Stockton","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, University of Cambridge , Cambridge CB2 0SZ ,","place":["UK"]},{"name":"Department of Neurology, Cambridge University Hospitals NHS Foundation Trust , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E","family":"Hughes","sequence":"additional","affiliation":[{"name":"Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge , Cambridge CB2 7EF ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0714-0685","authenticated-orcid":false,"given":"Richard A I","family":"Bethlehem","sequence":"additional","affiliation":[{"name":"Department of Psychology, University of Cambridge , Cambridge CB2 3EB ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varun","family":"Warrier","sequence":"additional","affiliation":[{"name":"Department of Psychology, University of Cambridge , Cambridge CB2 3EB ,","place":["UK"]},{"name":"Department of Psychiatry, University of Cambridge , Cambridge CB2 0SZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5907-2488","authenticated-orcid":false,"given":"Matthew A","family":"Lambon Ralph","sequence":"additional","affiliation":[{"name":"Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge , Cambridge CB2 7EF ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1063-6937","authenticated-orcid":false,"given":"Timothy","family":"Rittman","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, University of Cambridge , Cambridge CB2 0SZ ,","place":["UK"]},{"name":"Department of Neurology, Cambridge University Hospitals NHS Foundation Trust , Cambridge CB2 0QQ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James B","family":"Rowe","sequence":"additional","affiliation":[{"name":"Department of Clinical Neurosciences, University of Cambridge , Cambridge CB2 0SZ ,","place":["UK"]},{"name":"Department of Neurology, Cambridge University Hospitals NHS Foundation Trust , Cambridge CB2 0QQ ,","place":["UK"]},{"name":"Medical Research Council Cognition and Brain Sciences Unit, University of 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