{"doi":"10.1093/brain/awaf201","title":"Amygdalar and hippocampal volume loss in limbic-predominant age-related TDP-43 encephalopathy","abstract":"Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) refers to the aberrant accumulation of TDP-43 in the brains of ageing individuals either in isolation or in combination with neurodegenerative disease. 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. 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-β (4G8) and α-synuclein (pSer129). Positive cell density (TDP-43 and α-synuclein) and area percentage immunoreactivity (p-tau and amyloid-β) 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. Brain donors with LATE-NC showed significantly lower amygdalar (-26%, P = 0.014) and hippocampal (-19%, P = 0.003) volumes than non-LATE-NC brain donors, even when correcting for regional phosphorylated tau, amyloid-β and α-synuclein burden. These group differences remained significant in the Alzheimer's disease group (amygdala -24%, P = 0.028; hippocampus -21%, 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.","journal":"Brain","year":2025,"id":511571,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":226598,"name":"Ismael Luis Calandri","orcid":"0000-0002-6983-1430","position":1,"is_corresponding":false},{"id":1369595,"name":"Maud M.A. Bouwman","orcid":"0000-0002-9481-0332","position":2,"is_corresponding":false},{"id":1370330,"name":"Niels Reijner","orcid":null,"position":3,"is_corresponding":false},{"id":1370331,"name":"Natasja A. C. Deshayes","orcid":null,"position":4,"is_corresponding":false},{"id":242544,"name":"Frederik Barkhof","orcid":"0000-0003-3543-3706","position":5,"is_corresponding":false},{"id":230944,"name":"Rik Ossenkoppele","orcid":"0000-0003-1584-7477","position":6,"is_corresponding":false},{"id":7252,"name":"Wilma D. J. van de Berg","orcid":"0000-0002-6175-5357","position":7,"is_corresponding":false},{"id":282551,"name":"Annemieke J.M. Rozemüller","orcid":"0000-0003-2528-4428","position":8,"is_corresponding":false},{"id":233807,"name":"Yolande A.L. Pijnenburg","orcid":"0000-0003-2464-1905","position":9,"is_corresponding":false},{"id":282552,"name":"Jeroen J.M. Hoozemans","orcid":"0000-0002-2888-8967","position":10,"is_corresponding":false},{"id":1369596,"name":"Laura E. Jonkman","orcid":"0000-0003-1479-3649","position":11,"is_corresponding":false},{"id":1370329,"name":"Alex J. Wesseling","orcid":null,"position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T02:47:55.918021Z","pmid":"40512809","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}