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We investigated associations between neurodegenerative pathologies and the thickness of different MTL subregions measured using high-resolution post-mortem MRI. Tau, TAR DNA-binding protein 43 (TDP-43), amyloid-\u03b2 and \u03b1-synuclein pathology were rated on a scale of 0 (absent)\u20143 (severe) in the hippocampus and entorhinal cortex (ERC) of 58 individuals with and without neurodegenerative diseases (median age 75.0\u00a0years, 60.3% male). Thickness measurements in ERC, Brodmann Area (BA) 35 and 36, parahippocampal cortex, subiculum, cornu ammonis (CA)1 and the stratum radiatum lacunosum moleculare (SRLM) were derived from 0.2\u2009\u00d7\u20090.2\u2009\u00d7\u20090.2 mm\n                    <jats:sup>3<\/jats:sup>\n                    post-mortem MRI scans of excised MTL specimens from the contralateral hemisphere using a semi-automated approach. Spearman\u2019s rank correlations were performed between neurodegenerative pathologies and thickness, correcting for age, sex and hemisphere, including all four proteinopathies in the model. We found significant associations of (1) TDP-43 with thickness in all subregions (r\u2009=\u2009\u2009\u2212\u20090.27 to r\u2009=\u2009\u2009\u2212\u20090.46), and (2) tau with BA35 (r\u2009=\u2009\u2009\u2212\u20090.31) and SRLM thickness (r\u2009=\u2009\u2009\u2212\u20090.33). In amyloid-\u03b2 and TDP-43 negative cases, we found strong significant associations of tau with ERC (r\u2009=\u2009\u2009\u2212\u20090.40), BA35 (r\u2009=\u2009\u2009\u2212\u20090.55), subiculum (r\u2009=\u2009\u2009\u2212\u20090.42) and CA1 thickness (r\u2009=\u2009\u2009\u2212\u20090.47). This unique dataset shows widespread MTL atrophy in relation to TDP-43 pathology and atrophy in\u00a0regions affected early in Braak stageing and tau pathology. Moreover, the strong association of tau with thickness in early Braak regions in the absence of amyloid-\u03b2 suggests a role of Primary Age-Related Tauopathy in neurodegeneration.\n                  <\/jats:p>","DOI":"10.1186\/s40478-021-01225-3","type":"journal-article","created":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T05:03:07Z","timestamp":1626843787000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Downstream effects of polypathology on neurodegeneration of medial temporal lobe subregions"],"prefix":"10.1186","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7504-3943","authenticated-orcid":false,"given":"L. E. 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Where possible, pre-consent during life and, in all cases, next-of-kin consent at death was given.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors have reviewed the contents of the manuscript being submitted, approved of its contents and validated the accuracy of the data and consented to publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"A.W has received grant support from Merck, Biogen, and Eli Lilly\/Avid and consultation fees from Neuronix and is on the DSMB for a clinical trial run by Functional Neuromodulation. L.X. received personal consultation fees from Galileo CDS, Inc. 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