{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T08:34:24Z","timestamp":1777710864226,"version":"3.51.4"},"reference-count":45,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T00:00:00Z","timestamp":1621382400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007512","name":"Nancy and Buster Alvord Endowment","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007512","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K08AG065426"],"award-info":[{"award-number":["K08AG065426"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K23EY029246"],"award-info":[{"award-number":["K23EY029246"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30AG066509"],"award-info":[{"award-number":["P30AG066509"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P50AG05136"],"award-info":[{"award-number":["P50AG05136"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG060942"],"award-info":[{"award-number":["R01AG060942"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01AG006781"],"award-info":[{"award-number":["U01AG006781"]}],"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"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>People who have Alzheimer's disease neuropathologic change (ADNC) typically associated with dementia but not the associated cognitive decline can be considered to be \u201cresilient\u201d to the effects of ADNC. We have previously reported lower neocortical levels of hyperphosphorylated tau (pTau) and less limbic\u2010predominant age\u2010related TDP\u201043 encephalopathy neuropathologic change (LATE\u2010NC) in the resilient participants compared to those with dementia and similar ADNC as determined by current NIA\u2010AA recommendations using traditional semi\u2010quantitative assessments of amyloid \u03b2 and pathological tau burden. To better understand differences between AD\u2010dementia and resilient participants, we developed and applied a deep learning approach to analyze the neuropathology of 14 brain donors from the Adult Changes in Thought study, including seven stringently defined resilient participants and seven age\u2010matched AD\u2010dementia controls. We created two novel, fully automated deep learning algorithms to quantify the level of phosphorylated TDP\u201043 (pTDP\u201043) and pTau in whole slide imaging. The models performed better than traditional techniques for quantifying pTDP\u201043 and pTau. The second model was able to segment lesions staining for pTau into neurofibrillary tangles (NFTs) and tau neurites (neuronal processes positive for pTau). Both groups had similar quantities of pTau localizing to neurites, but the pTau burden associated with NFTs in the resilient group was significantly lower compared to the group with dementia. These results validate use of deep learning approaches to quantify clinically relevant microscopic characteristics from neuropathology workups. These results also suggest that the burden of NFTs is more strongly associated with cognitive impairment than the more diffuse neuritic tau commonly seen with tangle pathology and suggest that additional factors may underlie resilience mechanisms defined by traditional means.<\/jats:p>","DOI":"10.1111\/bpa.12974","type":"journal-article","created":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T16:39:11Z","timestamp":1621442351000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Application of deep learning to understand resilience to Alzheimer's disease pathology"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1994-7213","authenticated-orcid":false,"given":"Cecilia S.","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Ophthalmology University of Washington Seattle WA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caitlin S.","family":"Latimer","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington Seattle WA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan C.","family":"Henriksen","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington Seattle WA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marian","family":"Blazes","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology University of Washington Seattle WA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric B.","family":"Larson","sequence":"additional","affiliation":[{"name":"Kaiser Permanente Washington Health Research Institute Seattle WA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul K.","family":"Crane","sequence":"additional","affiliation":[{"name":"Division of General Internal Medicine Department of Internal Medicine University of Washington Seattle WA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. Dirk","family":"Keene","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology University of Washington Seattle WA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aaron Y.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology University of Washington Seattle WA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,5,19]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-011-0910-3"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneurol.2011.157"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e31825018f7"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-180942"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-144-2-200601170-00004"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-019-0743-1"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-42042-y"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2018.8029"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2019.00220"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41374-019-0202-4"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10212-1"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-020-00927-4"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.59.11.1737"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1017\/S1041610294001602"},{"key":"e_1_2_8_16_1","volume-title":"Diagnostic and statistical manual of mental disorders: DSM\u2010IV","author":"American Psychiatric Association","year":"1994"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.34.7.939"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21208"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1159\/000197389"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2009-1180"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-006-0127-z"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.41.4.479"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000187889.17253.b1"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz099"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2002.tb04794.x"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21208"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.0b013e3181f52db1"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1369\/jhc.2009.952812"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-16-0637"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/1746-1596-7-42"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13000-016-0511-5"},{"key":"e_1_2_8_32_1","article-title":"Pyramid scene parsing network","author":"Zhao H","year":"2016","journal-title":"arXiv [cs.CV]"},{"key":"e_1_2_8_33_1","article-title":"Deep residual learning for image recognition","author":"He K","year":"2015","journal-title":"arXiv [cs.CV]"},{"key":"e_1_2_8_34_1","doi-asserted-by":"crossref","unstructured":"DengJ DongW SocherR LiL LiK LiFF.ImageNet: a large\u2010scale hierarchical image database. In: 2009 IEEE Conference on Computer Vision and Pattern Recognition. ieeexplore.ieee.org;2009. p.248\u201355.","DOI":"10.1109\/CVPR.2009.5206848"},{"key":"e_1_2_8_35_1","article-title":"A method for stochastic optimization","author":"Kingma DP","year":"2014","journal-title":"arXiv [cs.LG]"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-019-0743-1"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0333-5"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41583\u2010019\u20100240\u20103"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aww224"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41374-019-0196-y"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2011.00542.x"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2019.00376"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401\u2010016\u20101558\u20109"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a006189"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2007.03.026"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/0021-9681(87)90171-8"}],"container-title":["Brain Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bpa.12974","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bpa.12974","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bpa.12974","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T04:19:58Z","timestamp":1721189998000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bpa.12974"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,19]]},"references-count":45,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2021,11]]}},"alternative-id":["10.1111\/bpa.12974"],"URL":"https:\/\/doi.org\/10.1111\/bpa.12974","archive":["Portico"],"relation":{},"ISSN":["1015-6305","1750-3639"],"issn-type":[{"value":"1015-6305","type":"print"},{"value":"1750-3639","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,19]]},"assertion":[{"value":"2021-03-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-04-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-05-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e12974"}}