{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T02:32:37Z","timestamp":1787884357030,"version":"build-2784847793"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T00:00:00Z","timestamp":1745452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["AG062429"],"award-info":[{"award-number":["AG062429"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute on Neurological Disease and Stroke","award":["NS120038"],"award-info":[{"award-number":["NS120038"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Digital histology offers a more objective, continuous definition of neuropathological severity than traditional staging systems, but its reliability remains underexplored. We calculated regional percentage areas occupied by phosphorylated tau (p-Tau, AT8), amyloid-\u03b2 (A\u03b2, NAB228), and phosphorylated \u03b1-synuclein (p-\u03b1Syn, 81A) pathology in 24 autopsied cases with varying degrees of Alzheimer disease neuropathological change and Lewy body disease (LBD) using manual and automated immunostaining methods to investigate variability across protocols. We then compared natural log-transformed percent area occupied values (ln%AO) to blinded ordinal severity scores, Braak stages, Thal phases, and McKeith LBD stages. p-Tau ln%AO from methodologically similar runs had the highest correlations (R2 = 0.91-0.95, \u03b2 \u2009=\u2009 0.95-0.97 for manual and automated methods, respectively); p-\u03b1Syn ln%AO from disparate immunostaining methods had the lowest (R2 = 0.16-0.34 \u03b2 \u2009=\u2009 0.40-0.59). p-Tau and A\u03b2 ln%AO increased regionally with higher Braak and Thal stages (p-Tau: z\u2009=\u20092.06 P\u2009=\u2009.04. A\u03b2: z\u2009=\u20093.70 P\u2009&amp;lt;\u2009.001). Regional p-\u03b1Syn ln%AO increased from limbic to neocortical stages (z\u2009=\u20095.86 P\u2009&amp;lt;\u2009.001); amygdala-predominant type LBD cases peaked in the amygdala and dropped in other limbic regions. These findings show the potential to quantify differences in p-Tau, A\u03b2, and p-\u03b1Syn pathologies using digital histological methods in single-center studies.<\/jats:p>","DOI":"10.1093\/jnen\/nlaf047","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T12:18:34Z","timestamp":1745497114000},"page":"725-733","source":"Crossref","is-referenced-by-count":4,"title":["Reliability and modeling of digital histological measurements in Alzheimer\u2019s disease neuropathologic change and Lewy body disease"],"prefix":"10.1093","volume":"84","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4501-3660","authenticated-orcid":false,"given":"Yongya","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Neurosciences, University of California San Diego , La Jolla , CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thea","family":"Andreasson","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of California San Diego , La Jolla , CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Namitha","family":"Vishupad","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of California San Diego , La Jolla , CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avani","family":"Benegal","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of California San Diego , La Jolla , CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald","family":"Pizzo","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California San Diego , La Jolla , CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California San Diego , La Jolla , CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Hiniker","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Southern California , Los Angeles, CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4111-0102","authenticated-orcid":false,"given":"David","family":"Coughlin","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of California San Diego , La Jolla , CA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,4,24]]},"reference":[{"key":"2025072103523853100_nlaf047-B1","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s00401-006-0127-z","article-title":"Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry","volume":"112","author":"Braak","year":"2006","journal-title":"Acta Neuropathol"},{"key":"2025072103523853100_nlaf047-B2","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1212\/WNL.41.4.479","article-title":"The Consortium to Establish a Registry for Alzheimer\u2019s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer\u2019s disease","volume":"41","author":"Mirra","year":"1991","journal-title":"Neurology"},{"key":"2025072103523853100_nlaf047-B3","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1212\/WNL.58.12.1791","article-title":"Phases of a beta-deposition in the human brain and its relevance for the development of AD","volume":"58","author":"Thal","year":"2002","journal-title":"Neurology"},{"key":"2025072103523853100_nlaf047-B4","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1212\/01.wnl.0000187889.17253.b1","article-title":"Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium","volume":"65","author":"McKeith","year":"2005","journal-title":"Neurology"},{"key":"2025072103523853100_nlaf047-B5","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/S0197-4580(02)00065-9","article-title":"Staging of brain pathology related to sporadic Parkinson\u2019s disease","volume":"24","author":"Braak","year":"2003","journal-title":"Neurobiol Aging"},{"key":"2025072103523853100_nlaf047-B6","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1097\/00005072-199405000-00012","article-title":"Interlaboratory comparison of neuropathology assessments in Alzheimer's disease","volume":"53","author":"Mirra","year":"1994","journal-title":"J Neuropathol Exp Neurol"},{"key":"2025072103523853100_nlaf047-B7","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1159\/000106639","article-title":"Staging of Alzheimer-type pathology: an interrater-intrarater study","volume":"8","author":"Nagy","year":"1997","journal-title":"Dement Geriatr Cogn Disord"},{"key":"2025072103523853100_nlaf047-B8","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1111\/j.1750-3639.2008.00147.x","article-title":"Staging of neurofibrillary pathology in Alzheimer\u2019s disease: a study of the BrainNet Europe Consortium","volume":"18","author":"Alafuzoff","year":"2008","journal-title":"Brain Pathol"},{"key":"2025072103523853100_nlaf047-B9","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s00401-009-0485-4","article-title":"Assessment of \u03b2-amyloid deposits in human brain: a study of the BrainNet Europe Consortium","volume":"117","author":"Alafuzoff","year":"2009","journal-title":"Acta Neuropathol"},{"key":"2025072103523853100_nlaf047-B10","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1007\/s00401-009-0523-2","article-title":"Staging\/typing of Lewy body related alpha-synuclein pathology: a study of the BrainNet Europe Consortium","volume":"117","author":"Alafuzoff","year":"2009","journal-title":"Acta Neuropathol"},{"key":"2025072103523853100_nlaf047-B11","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.jalz.2015.07.492","article-title":"Multisite assessment of NIA-AA guidelines for the neuropathologic evaluation of Alzheimer\u2019s disease","volume":"12","author":"Montine","year":"2016","journal-title":"Alzheimers Dement"},{"key":"2025072103523853100_nlaf047-B12","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s00401-020-02255-2","article-title":"Neuropathological consensus criteria for the evaluation of Lewy pathology in post-mortem brains: a multi-centre study","volume":"141","author":"Attems","year":"2021","journal-title":"Acta Neuropathol"},{"key":"2025072103523853100_nlaf047-B13","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/s00401-009-0538-8","article-title":"Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction","volume":"117","author":"Beach","year":"2009","journal-title":"Acta Neuropathol"},{"key":"2025072103523853100_nlaf047-B14","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1097\/01.jnen.0000171652.40083.15","article-title":"Staging of sporadic Parkinson disease-related alpha-synuclein pathology: inter- and intra-rater reliability","volume":"64","author":"Muller","year":"2005","journal-title":"J Neuropathol Exp Neurol"},{"key":"2025072103523853100_nlaf047-B15","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1111\/j.1750-3639.2007.00117.x","article-title":"Empiric refinement of the pathologic assessment of Lewy-related pathology in the dementia patient","volume":"18","author":"Leverenz","year":"2008","journal-title":"Brain Pathol"},{"key":"2025072103523853100_nlaf047-B16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00401-011-0910-3","article-title":"National Institute on Aging-Alzheimer\u2019s Association guidelines for the neuropathologic assessment of Alzheimer\u2019s disease: a practical approach","volume":"123","author":"Montine","year":"2012","journal-title":"Acta Neuropathol"},{"key":"2025072103523853100_nlaf047-B17","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1097\/NEN.0b013e3182768de4","article-title":"Digital pathology and image analysis for robust high-throughput quantitative assessment of Alzheimer disease neuropathologic changes","volume":"71","author":"Neltner","year":"2012","journal-title":"J Neuropathol Exp Neurol"},{"key":"2025072103523853100_nlaf047-B18","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1369\/0022155415614303","article-title":"Semi-automated digital image analysis of pick\u2019s disease and TDP-43 proteinopathy","volume":"64","author":"Irwin","year":"2016","journal-title":"J Histochem Cytochem"},{"key":"2025072103523853100_nlaf047-B19","doi-asserted-by":"crossref","first-page":"e12759","DOI":"10.1111\/nan.12759","article-title":"Deep learning-based model for diagnosing Alzheimer\u2019s disease and tauopathies","volume":"48","author":"Koga","year":"2022","journal-title":"Neuropathol Appl Neurobiol"},{"key":"2025072103523853100_nlaf047-B20","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1093\/jnen\/nlab005","article-title":"Deep Learning-based image classification in differentiating tufted astrocytes, astrocytic plaques, and neuritic plaques","volume":"80","author":"Koga","year":"2021","journal-title":"J Neuropathol Exp Neurol"},{"key":"2025072103523853100_nlaf047-B21","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1186\/s40478-024-01827-7","article-title":"Machine learning quantification of amyloid-\u03b2 deposits in the temporal lobe of 131 brain bank cases","volume":"12","author":"Scalco","year":"2024","journal-title":"Acta Neuropathol Commun"},{"key":"2025072103523853100_nlaf047-B22","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.1038\/s41467-019-10212-1","article-title":"Interpretable classification of Alzheimer\u2019s disease pathologies with a convolutional neural network pipeline","volume":"10","author":"Tang","year":"2019","journal-title":"Nat Commun"},{"key":"2025072103523853100_nlaf047-B23","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1002\/ana.25392","article-title":"Cognitive and pathological influences of tau pathology in Lewy body disorders","volume":"85","author":"Coughlin","year":"2019","journal-title":"Ann Neurol"},{"key":"2025072103523853100_nlaf047-B24","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1111\/nan.12659","article-title":"Hippocampal subfield pathologic burden in Lewy body diseases vs. Alzheimer\u2019s disease","volume":"46","author":"Coughlin","year":"2020","journal-title":"Neuropathol Appl Neurobiol"},{"key":"2025072103523853100_nlaf047-B25","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1093\/jnen\/nlac094","article-title":"Digital histological study of neocortical grey and white matter tau burden across tauopathies","volume":"81","author":"Coughlin","year":"2022","journal-title":"J Neuropathol Exp Neurol"},{"key":"2025072103523853100_nlaf047-B26","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1002\/ana.25465","article-title":"Divergent patterns of TDP-43 and tau pathologies in primary progressive aphasia","volume":"85","author":"Giannini","year":"2019","journal-title":"Ann Neurol"},{"key":"2025072103523853100_nlaf047-B27","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1007\/s00401-015-1406-3","article-title":"Neuropathologically mixed Alzheimer\u2019s and Lewy body disease: burden of pathological protein aggregates differs between clinical phenotypes","volume":"129","author":"Walker","year":"2015","journal-title":"Acta Neuropathol"},{"key":"2025072103523853100_nlaf047-B28","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1038\/s41374-019-0202-4","article-title":"Artificial intelligence in neuropathology: deep learning-based assessment of tauopathy","volume":"99","author":"Signaevsky","year":"2019","journal-title":"Lab Investig"},{"key":"2025072103523853100_nlaf047-B29","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1186\/s40478-022-01457-x","article-title":"Artificial intelligence-derived neurofibrillary tangle burden is associated with antemortem cognitive impairment","volume":"10","author":"Marx","year":"2022","journal-title":"Acta Neuropathol Commun"},{"key":"2025072103523853100_nlaf047-B30","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s40478-021-01129-2","article-title":"Frontotemporal lobar degeneration proteinopathies have disparate microscopic patterns of white and grey matter pathology","volume":"9","author":"Giannini","year":"2021","journal-title":"Acta Neuropathol Commun"},{"key":"2025072103523853100_nlaf047-B31","doi-asserted-by":"crossref","first-page":"682","DOI":"10.3389\/fnins.2019.00682","article-title":"Empiric methods to account for pre-analytical variability in digital histopathology in frontotemporal lobar degeneration","volume":"13","author":"Giannini","year":"2019","journal-title":"Front Neurosci"},{"key":"2025072103523853100_nlaf047-B32","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1523\/JNEUROSCI.3047-16.2016","article-title":"Hippocampal alpha-synuclein in dementia with Lewy bodies contributes to memory impairment and is consistent with spread of pathology","volume":"37","author":"Adamowicz","year":"2017","journal-title":"J Neurosci"},{"key":"2025072103523853100_nlaf047-B33","doi-asserted-by":"crossref","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: open source software for digital pathology image analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Sci Rep"},{"key":"2025072103523853100_nlaf047-B34","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1002\/ana.24559","article-title":"Deep clinical and neuropathological phenotyping of pick disease","volume":"79","author":"Irwin","year":"2016","journal-title":"Ann Neurol"},{"key":"2025072103523853100_nlaf047-B35","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/0022-3956(75)90026-6","article-title":"\u201cMini-mental state\u201d: a practical method for grading the cognitive state of patients for the clinician","volume":"12","author":"Folstein","year":"1975","journal-title":"J Psychiatr Res"},{"key":"2025072103523853100_nlaf047-B36","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1212\/WNL.44.5.964","article-title":"The Mattis Dementia Rating Scale: normative data from 1,001 healthy volunteers","volume":"44","author":"Schmidt","year":"1994","journal-title":"Neurology"},{"key":"2025072103523853100_nlaf047-B37","doi-asserted-by":"crossref","first-page":"141","DOI":"10.11613\/BM.2015.015","article-title":"Understanding Bland Altman analysis","volume":"25","author":"Giavarina","year":"2015","journal-title":"Biochem Medica"},{"key":"2025072103523853100_nlaf047-B38","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0140-6736(86)90837-8","article-title":"Statistical methods for assessing agreement between two methods of clinical measurement","volume":"327","author":"Bland","year":"1986","journal-title":"Lancet"},{"key":"2025072103523853100_nlaf047-B39","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s00401-021-02402-3","article-title":"Signature laminar distributions of pathology in frontotemporal lobar degeneration","volume":"143","author":"Ohm","year":"2022","journal-title":"Acta Neuropathol"},{"key":"2025072103523853100_nlaf047-B40","doi-asserted-by":"publisher","first-page":"e043916","DOI":"10.1002\/alz.043916","article-title":"The status of digital pathology and machine learning within Alzheimer\u2019s Disease Centers","volume":"16","author":"Dugger","year":"2020","journal-title":"Alzheimer Dement"},{"key":"2025072103523853100_nlaf047-B41","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1093\/jnen\/nlad086","article-title":"High-throughput digital quantification of Alzheimer disease pathology and associated infrastructure in large autopsy studies","volume":"82","author":"Kapasi","year":"2023","journal-title":"J Neuropathol Exp Neurol"},{"key":"2025072103523853100_nlaf047-B42","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.neurobiolaging.2020.08.003","article-title":"Multimodal in vivo and postmortem assessments of tau in Lewy body disorders","volume":"96","author":"Coughlin","year":"2020","journal-title":"Neurobiol Aging"},{"key":"2025072103523853100_nlaf047-B43","doi-asserted-by":"crossref","first-page":"2342","DOI":"10.1002\/acn3.51183","article-title":"Tau pathology associates with in vivo cortical thinning in Lewy body disorders","volume":"7","author":"Spotorno","year":"2020","journal-title":"Ann Clin Transl Neurol. Ann Clin Transl Neurol"}],"container-title":["Journal of Neuropathology &amp; Experimental Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jnen\/article-pdf\/84\/8\/725\/63001589\/nlaf047.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jnen\/article-pdf\/84\/8\/725\/63001589\/nlaf047.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T07:52:49Z","timestamp":1753084369000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jnen\/article\/84\/8\/725\/8119282"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,24]]},"references-count":43,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,4,24]]},"published-print":{"date-parts":[[2025,8,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jnen\/nlaf047","relation":{},"ISSN":["0022-3069","1554-6578"],"issn-type":[{"value":"0022-3069","type":"print"},{"value":"1554-6578","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,8]]},"published":{"date-parts":[[2025,4,24]]}}}