{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:57:56Z","timestamp":1791928676792,"version":"4.3.4"},"reference-count":68,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01\u2010AG37491"],"award-info":[{"award-number":["R01\u2010AG37491"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Brain Pathology"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>TAR DNA\u2010binding protein 43 (TDP\u201043) inclusions are often associated with hyperphosphorylated tau, thus neurofibrillary tangles as the hallmark of Alzheimer's disease (AD) and primary age\u2010related tauopathy (PART). TDP\u201043 in AD is associated with cognitive impairment, and while staging is known, the localization, cellular and inclusion characteristics of TDP\u201043 are yet to be elucidated. We investigate relationships between TDP\u201043 inclusions and the tangle maturation continuum in AD, PART, and co\u2010pathologies by multiplex immunostaining combined with artificial intelligence (AI)\u2013based segmentation via object recognition, reconstruction, and quantification. We performed anti\u2010phosphorylated TDP\u201043 immunofluorescence with phosphorylated tau labeling different stages and modifications of tangles (AT8, pS396, TauC3, MN423, GT38) in three controls, three cases with PART and TDP\u201043 (PART\u2010TDP), five cases with high likelihood AD and TDP\u201043 (AD\u2010TDP), and four cases of high likelihood AD with TDP\u201043 and Lewy Body disease (AD\u2010TDP\u2010LBD). Confocal imaging was taken from eight regions: amygdala (amygdala\u2010BL and amygdala\u2010CM) and hippocampus (Cornu Ammonis (CA)\u20101, CA2\/3, CA4, dentate gyrus (DG), subiculum (SUB)), and entorhinal cortex (ERC) and quantified with AI segmentation to identify 3D spatial relations, thus the maturity of neurofibrillary tangle associated TDP\u201043 (TAT) inclusions. TATs, which were either identified by pTDP\u201043 and AT8 or pTDP\u201043 and pS396 double positivity, were also investigated by Thioflavin S (ThioS) histochemistry. We found pS396 labeled mature TATs predominated in PART and AD in every region. Basolateral and centromedial amygdala displayed overall greatest number of pre\u2010TATs and mature TATs. Mature TATs were homogenously distributed among hippocampal subfields whereas CA4 and DG had the greatest mature TAT composition. ERC revealed closer numbers of pre\u2010TATs and mature TATs yet mature TATs predominated all groups. Unbiased AI\u2010based object identification, reconstruction, and TAT maturation analysis pipeline in conjunction with TDP\u201043, tau, and ThioS multiplex immunostaining demonstrated unique aggregation and maturation patterns, highlighting region\u2010specific dynamics in the neurodegenerative processes of PART and AD.<\/jats:p>","DOI":"10.1111\/bpa.70131","type":"journal-article","created":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T05:46:52Z","timestamp":1786168012000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Artificial intelligence\u2013based\n                    <scp>3D<\/scp>\n                    segmentation of tangle\u2010associated\n                    <scp>TDP<\/scp>\n                    \u201043 in neurodegeneration"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8706-9443","authenticated-orcid":false,"given":"Gokhan","family":"Uruk","sequence":"first","affiliation":[{"name":"Department of Neurology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8876-8038","authenticated-orcid":false,"given":"Hossam","family":"Youssef","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2170-6662","authenticated-orcid":false,"given":"Rodolfo G.","family":"Gatto","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9202-1172","authenticated-orcid":false,"given":"Nadia","family":"Hossain","sequence":"additional","affiliation":[{"name":"Department of Neurology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6914-1563","authenticated-orcid":false,"given":"Jennifer L.","family":"Whitwell","sequence":"additional","affiliation":[{"name":"Department of Radiology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert R.","family":"Reichard","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology (Neuropathology) Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2930-8634","authenticated-orcid":false,"given":"Keith 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