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Using antemortem MRI and pathological data, we investigated the etiology of SNAP and the association of neurodegenerative pathologies with structural medial temporal lobe (MTL) measures in \u03b2-amyloid-negative subjects.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Subjects with antemortem MRI and autopsy data were selected from ADNI (<jats:italic>n<\/jats:italic>=63) and the University of Pennsylvania (<jats:italic>n<\/jats:italic>=156). Pathological diagnoses and semi-quantitative scores of MTL tau, neuritic plaques, \u03b1-synuclein, and TDP-43 pathology and MTL structural MRI measures from antemortem T1-weighted MRI scans were obtained. \u03b2-amyloid status (A+\/A\u2212) was determined by CERAD score and neurodegeneration status (N+\/N\u2212) by hippocampal volume.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>SNAP reflects a heterogeneous group of pathological diagnoses. In ADNI, SNAP (A\u2212N+) had significantly more neuropathological diagnoses than A+N+. In the A\u2212 group, tau pathology was associated with hippocampal, entorhinal cortex, and Brodmann area 35 volume\/thickness and TDP-43 pathology with hippocampal volume.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>SNAP had a heterogeneous profile with more mixed pathologies than A+N+. Moreover, a role for TDP-43 and tau pathology in driving MTL neurodegeneration in the absence of \u03b2-amyloid was supported.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13195-021-00835-2","type":"journal-article","created":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T14:03:41Z","timestamp":1621001021000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Pathological drivers of neurodegeneration in suspected non-Alzheimer\u2019s disease pathophysiology"],"prefix":"10.1186","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7504-3943","authenticated-orcid":false,"given":"L. E. 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For the UPenn dataset, all procedures during life were performed with prior informed consent in accordance with Penn Institutional Review Board guidelines.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"D.A.W. has received grant support from Avid Radiopharmaceuticals\/Eli Lilly, Biogen, Functional Neuromodulation, and Merck.J.Q.T. may accrue revenue in the future on patents submitted by the University of Pennsylvania wherein he is a co-inventor, and he received revenue from the sale of Avid to Eli Lilly as a co-inventor on imaging-related patents submitted by the University of Pennsylvania.C.M receives research funding from Biogen, Inc and provides consulting services for Invicro and Axon Advisors on behalf of Translational Bioinformatics, LLC. He also receives an honorarium as Associate Editor of <i>NeuroImage: Clinical<\/i>.M.G. receives grant support from NIH; participates in treatment trials sponsored by Biogen, Eisai, and Alector; consultation fees from Biogen, UCB, Ionis, and PassageBio; and in-kind support from LMI.L.X. received personal consulting fees from Galileo CDS, Inc.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"100"}}