{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T06:37:55Z","timestamp":1791959875014,"version":"4.3.4"},"reference-count":66,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2020,8,24]],"date-time":"2020-08-24T00:00:00Z","timestamp":1598227200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["P30 AG028383"],"award-info":[{"award-number":["P30 AG028383"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["P30 AG010124"],"award-info":[{"award-number":["P30 AG010124"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["P01 AG017586"],"award-info":[{"award-number":["P01 AG017586"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01 AG057187"],"award-info":[{"award-number":["R01 AG057187"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01 AG042475"],"award-info":[{"award-number":["R01 AG042475"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>TAR-DNA binding protein-43 (TDP-43) proteinopathy is seen in multiple brain diseases. A standardized terminology was recommended recently for common age-related TDP-43 proteinopathy: limbic-predominant, age-related TDP-43 encephalopathy (LATE) and the underlying neuropathological changes, LATE-NC. LATE-NC may be co-morbid with Alzheimer\u2019s disease neuropathological changes (ADNC). However, there currently are ill-defined diagnostic classification issues among LATE-NC, ADNC, and frontotemporal lobar degeneration with TDP-43 (FTLD-TDP). A practical challenge is that different autopsy cohorts are composed of disparate groups of research volunteers: hospital- and clinic-based cohorts are enriched for FTLD-TDP cases, whereas community-based cohorts have more LATE-NC cases. Neuropathological methods also differ across laboratories. Here, we combined both cases and neuropathologists\u2019 diagnoses from two research centres\u2014University of Pennsylvania and University of Kentucky. The study was designed to compare neuropathological findings between FTLD-TDP and pathologically severe LATE-NC. First, cases were selected from the University of Pennsylvania with pathological diagnoses of either FTLD-TDP (n\u2009=\u200933) or severe LATE-NC (mostly stage 3) with co-morbid ADNC (n\u2009=\u200930). Sections from these University of Pennsylvania cases were cut from amygdala, anterior cingulate, superior\/mid-temporal, and middle frontal gyrus. These sections were stained for phospho-TDP-43 immunohistochemically and evaluated independently by two University of Kentucky neuropathologists blinded to case data. A simple set of criteria hypothesized to differentiate FTLD-TDP from LATE-NC was generated based on density of TDP-43 immunoreactive neuronal cytoplasmic inclusions in the neocortical regions. Criteria-based sensitivity and specificity of differentiating severe LATE-NC from FTLD-TDP cases with blind evaluation was \u223c90%. Another proposed neuropathological feature related to TDP-43 proteinopathy in aged individuals is \u2018Alpha\u2019 versus \u2018Beta\u2019 in amygdala. Alpha and Beta status was diagnosed by neuropathologists from both universities (n\u2009=\u20095 raters). There was poor inter-rater reliability of Alpha\/Beta classification (mean \u03ba = 0.31). We next tested a separate cohort of cases from University of Kentucky with either FTLD-TDP (n\u2009=\u20098) or with relatively \u2018pure\u2019 severe LATE-NC (lacking intermediate or severe ADNC; n\u2009=\u200914). The simple criteria were applied by neuropathologists blinded to the prior diagnoses at University of Pennsylvania. Again, the criteria for differentiating LATE-NC from FTLD-TDP was effective, with sensitivity and specificity \u223c90%. If more representative cases from each cohort (including less severe TDP-43 proteinopathy) had been included, the overall accuracy for identifying LATE-NC was estimated at &amp;gt;98% for both cohorts. Also across both cohorts, cases with FTLD-TDP died younger than those with LATE-NC (P\u2009&amp;lt;\u20090.0001). We conclude that in most cases, severe LATE-NC and FTLD-TDP can be differentiated by applying simple neuropathological criteria.<\/jats:p>","DOI":"10.1093\/brain\/awaa219","type":"journal-article","created":{"date-parts":[[2020,6,17]],"date-time":"2020-06-17T03:24:28Z","timestamp":1592364268000},"page":"2844-2857","source":"Crossref","is-referenced-by-count":71,"title":["Limbic-predominant age-related TDP-43 encephalopathy differs from frontotemporal lobar degeneration"],"prefix":"10.1093","volume":"143","author":[{"given":"John L","family":"Robinson","sequence":"first","affiliation":[{"name":"Alzheimer\u2019s Disease Core Center, University of Pennsyvania, Philadelphia, PA, USA"},{"name":"Center for Neurodegenerative Disease Research, University of Pennsyvania, Philadelphia, PA, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of Pennsyvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00edlvia","family":"Porta","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Core Center, University of Pennsyvania, Philadelphia, PA, USA"},{"name":"Center for Neurodegenerative Disease Research, University of Pennsyvania, Philadelphia, PA, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of Pennsyvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filip G","family":"Garrett","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Kentucky, Lexington, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panpan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Core Center, University of Pennsyvania, Philadelphia, PA, USA"},{"name":"Department of Biostatistics, Epidemiology and Informatics, University of Pennsyvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon X","family":"Xie","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Core Center, University of Pennsyvania, Philadelphia, PA, USA"},{"name":"Department of Biostatistics, Epidemiology and Informatics, University of Pennsyvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"EunRan","family":"Suh","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Core Center, University of Pennsyvania, Philadelphia, PA, USA"},{"name":"Center for Neurodegenerative Disease Research, University of Pennsyvania, Philadelphia, PA, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of Pennsyvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivianna M","family":"Van Deerlin","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Core Center, University of Pennsyvania, Philadelphia, PA, USA"},{"name":"Center for Neurodegenerative Disease Research, University of Pennsyvania, Philadelphia, PA, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of Pennsyvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin L","family":"Abner","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, University of Kentucky, Lexington, KY, USA"},{"name":"Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory A","family":"Jicha","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Kentucky, Lexington, KY, USA"},{"name":"Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6247-1834","authenticated-orcid":false,"given":"Justin M","family":"Barber","sequence":"additional","affiliation":[{"name":"Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia M -Y","family":"Lee","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Core Center, University of Pennsyvania, Philadelphia, PA, USA"},{"name":"Center for Neurodegenerative Disease Research, University of Pennsyvania, Philadelphia, PA, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of Pennsyvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward B","family":"Lee","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Core Center, University of Pennsyvania, Philadelphia, PA, USA"},{"name":"Center for Neurodegenerative Disease Research, University of Pennsyvania, Philadelphia, PA, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of Pennsyvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Q","family":"Trojanowski","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Core Center, University of Pennsyvania, Philadelphia, PA, USA"},{"name":"Center for Neurodegenerative Disease Research, University of Pennsyvania, Philadelphia, PA, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of Pennsyvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter T","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Kentucky, Lexington, KY, USA"},{"name":"Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,8,24]]},"reference":[{"key":"2020111212331368700_awaa219-B1","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1002\/ana.21154","article-title":"TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease","volume":"61","author":"Amador-Ortiz","year":"2007","journal-title":"Ann Neurol"},{"key":"2020111212331368700_awaa219-B2","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s00401-014-1358-z","article-title":"Hippocampal sclerosis in Lewy body disease is a TDP-43 proteinopathy similar to FTLD-TDP Type A","volume":"129","author":"Aoki","year":"2015","journal-title":"Acta Neuropathol"},{"key":"2020111212331368700_awaa219-B3","doi-asserted-by":"crossref","first-page":"3621","DOI":"10.1093\/brain\/awz277","article-title":"Antemortem volume loss mirrors TDP-43 staging in older adults with non-frontotemporal lobar 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aging","volume":"128","author":"Crary","year":"2014","journal-title":"Acta Neuropathol"},{"key":"2020111212331368700_awaa219-B10","doi-asserted-by":"crossref","first-page":"e26286","DOI":"10.1371\/journal.pone.0026286","article-title":"Neuropathologic correlates of hippocampal atrophy in the elderly: a clinical, pathologic, postmortem MRI study","volume":"6","author":"Dawe","year":"2011","journal-title":"PLoS One"},{"key":"2020111212331368700_awaa219-B11","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1212\/01.wnl.0000472918.79256.a9","article-title":"The TMEM106B locus and TDP-43 pathology in older persons without FTLD","volume":"85","author":"Dickson","year":"2015","journal-title":"Neurology"},{"key":"2020111212331368700_awaa219-B12","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1093\/jnen\/nlz017","article-title":"Chronic Traumatic Encephalopathy (CTE) is absent from a European community-based aging cohort while cortical Aging-Related Tau Astrogliopathy (ARTAG) is highly prevalent","volume":"78","author":"Forrest","year":"2019","journal-title":"J Neuropathol Exp Neurol"},{"key":"2020111212331368700_awaa219-B13","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1093\/jnen\/nlx097","article-title":"Detergent insoluble proteins and inclusion body-like structures immunoreactive for PRKDC\/DNA-PK\/DNA-PKcs, FTL, NNT, and AIFM1 in the amygdala of cognitively impaired elderly persons","volume":"77","author":"Gal","year":"2018","journal-title":"J Neuropathol Exp Neurol"},{"key":"2020111212331368700_awaa219-B14","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1212\/WNL.0b013e31821103e6","article-title":"Classification of primary progressive aphasia and its variants","volume":"76","author":"Gorno-Tempini","year":"2011","journal-title":"Neurology"},{"key":"2020111212331368700_awaa219-B15","first-page":"337","author":"Hunter","year":"2020"},{"key":"2020111212331368700_awaa219-B100","first-page":"1095","volume-title":"J 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