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LATE-NC is most commonly found in the amygdala and hippocampus and is associated with progressive amnestic decline in individuals with a neurodegenerative disease. Since LATE-NC can only be diagnosed post-mortem, there is a need for pathology-validated neuroimaging biomarkers for LATE-NC. In the current study we assessed MRI-measured amygdalar and hippocampal volume in brain donors with Alzheimer's disease or Lewy body diseases with and without co-occurring LATE-NC pathology.<\/jats:p>\n                  <jats:p>Post-mortem in situ 3D-T1 3T-MRI data were collected for 51 cases (27 Alzheimer's disease and 24 Lewy body disease) of whom 17 had post-mortem confirmed LATE-NC and 34 were non-LATE-NC (matched on age, sex and neurodegenerative disease). Amygdalar and hippocampal volumes were calculated using FreeSurfer. Within-subject amygdalar and hippocampal tissue sections were immunostained for TDP-43 (pTDP-43), phosphorylated tau (AT8), amyloid-\u03b2 (4G8) and \u03b1-synuclein (pSer129). Positive cell density (TDP-43 and \u03b1-synuclein) and area percentage immunoreactivity (p-tau and amyloid-\u03b2) outcome measures were quantified using QuPath. Group differences between LATE-NC and non-LATE-NC donors were assessed with univariate analyses and correlations were assessed with linear regression models, all adjusting for intracranial volume and post-mortem delay and if applicable for primary pathology.<\/jats:p>\n                  <jats:p>Brain donors with LATE-NC showed significantly lower amygdalar (\u221226%, P = 0.014) and hippocampal (\u221219%, P = 0.003) volumes than non-LATE-NC brain donors, even when correcting for regional phosphorylated tau, amyloid-\u03b2 and \u03b1-synuclein burden. These group differences remained significant in the Alzheimer's disease group (amygdala \u221224%, P = 0.028; hippocampus \u221221%, P = 0.002), but in the Lewy body diseases group only the amygdala was smaller in LATE-NC donors compared with non-LATE-NC donors (18%, P = 0.030). These results suggest that severity of TDP-43 burden plays a role in amygdala and hippocampus atrophy on MRI, even when correcting for effects of primary pathology. This study proposes that exceptionally low amygdalar and hippocampal volumes could indicate LATE-NC and that this may serve as a potential biomarker for in vivo studies.<\/jats:p>","DOI":"10.1093\/brain\/awaf201","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T07:46:54Z","timestamp":1749714414000},"page":"3913-3923","source":"Crossref","is-referenced-by-count":19,"title":["Amygdalar and hippocampal volume loss in limbic-predominant age-related TDP-43 encephalopathy"],"prefix":"10.1093","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8989-507X","authenticated-orcid":false,"given":"Alex","family":"Wesseling","sequence":"first","affiliation":[{"name":"Department of Anatomy and Neurosciences, Amsterdam UMC , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Amsterdam Neuroscience, Neurodegeneration , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Alzheimer Center Amsterdam UMC , Department of Neurology, Amsterdam 1081 HV ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismael L","family":"Calandri","sequence":"additional","affiliation":[{"name":"Amsterdam Neuroscience, Neurodegeneration , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Alzheimer Center Amsterdam UMC , Department of Neurology, Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Amsterdam Neuroscience, Brain Imaging , Amsterdam 1081 HV ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maud M A","family":"Bouwman","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurosciences, Amsterdam UMC , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Amsterdam Neuroscience, Neurodegeneration , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Amsterdam Neuroscience, Brain Imaging , Amsterdam 1081 HV ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels","family":"Reijner","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurosciences, Amsterdam UMC , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Amsterdam Neuroscience, Neurodegeneration , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Amsterdam Neuroscience, Brain Imaging , Amsterdam 1081 HV ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasja A C","family":"Deshayes","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurosciences, Amsterdam UMC , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Amsterdam Neuroscience, Neurodegeneration , Amsterdam 1081 HV ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Barkhof","sequence":"additional","affiliation":[{"name":"Amsterdam Neuroscience, Brain Imaging , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Department of Radiology and Nuclear Medicine, Amsterdam UMC , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London , London WC1N 3BG ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rik","family":"Ossenkoppele","sequence":"additional","affiliation":[{"name":"Amsterdam Neuroscience, Neurodegeneration , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Alzheimer Center Amsterdam UMC , Department of Neurology, Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Amsterdam Neuroscience, Brain Imaging , Amsterdam 1081 HV ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilma D J","family":"van de Berg","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurosciences, Amsterdam UMC , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Amsterdam Neuroscience, Neurodegeneration , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Amsterdam Neuroscience, Brain Imaging , Amsterdam 1081 HV ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemieke J M","family":"Rozemuller","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam UMC , Amsterdam 1081 HV ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolande A L","family":"Pijnenburg","sequence":"additional","affiliation":[{"name":"Amsterdam Neuroscience, Neurodegeneration , Amsterdam 1081 HV ,","place":["The Netherlands"]},{"name":"Alzheimer Center Amsterdam UMC , Department of Neurology, Amsterdam 1081 HV ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen J M","family":"Hoozemans","sequence":"additional","affiliation":[{"name":"Department of Pathology, 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