{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T11:20:53Z","timestamp":1788780053508,"version":"build-2803163510"},"reference-count":22,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T00:00:00Z","timestamp":1637193600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T00:00:00Z","timestamp":1637193600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AG017586"],"award-info":[{"award-number":["AG017586"]}],"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":["NS053488"],"award-info":[{"award-number":["NS053488"]}],"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":["AG052943"],"award-info":[{"award-number":["AG052943"]}],"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":["2-P30-EY01583-26"],"award-info":[{"award-number":["2-P30-EY01583-26"]}],"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":["NS109260"],"award-info":[{"award-number":["NS109260"]}],"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":["P01-AG066597"],"award-info":[{"award-number":["P01-AG066597"]}],"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":["P30-AG072979"],"award-info":[{"award-number":["P30-AG072979"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["K08-EY025742"],"award-info":[{"award-number":["K08-EY025742"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Research to Prevent Blindness, Block grant to Scheie Eye Institute"},{"DOI":"10.13039\/100008556","name":"Paul MacKall and Evanina Bell MacKall Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008556","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["acta neuropathol commun"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Alzheimer\u2019s disease (AD) is associated with inner retina (nerve fiber and ganglion cell layers) thinning. In contrast, we have seen outer retina thinning driven by photoreceptor outer nuclear layer (ONL) thinning with antemortem optical coherence tomography (OCT) among patients considered to have a frontotemporal degeneration tauopathy (FTLD-Tau). Our objective was to determine if postmortem retinal tissue from FTLD-Tau patients demonstrates ONL loss observed antemortem on OCT. Two probable FTLD-Tau patients that were deeply phenotyped by clinical and genetic testing were imaged with OCT and followed to autopsy. Postmortem brain and retinal tissue were evaluated by a neuropathologist and ocular pathologist, respectively, masked to diagnosis. OCT findings were correlated with retinal histology. The two patients had autopsy-confirmed FTLD-Tau neuropathology and had antemortem OCT measurements showing ONL thinning (66.9\u00a0\u03bcm, patient #1; 74.9\u00a0\u03bcm, patient #2) below the 95% confidence interval of normal limits (75.1\u2013120.7\u00a0\u03bcm) in our healthy control cohort. Postmortem, retinal tissue from both patients demonstrated loss of nuclei in the ONL, matching ONL loss visualized on antemortem OCT. Nuclei counts from each area of ONL loss (2 \u2013 3 nuclei per column) seen in patient eyes were below the 95% confidence interval (4 \u2013 8 nuclei per column for ONL) of 3 normal control retinas analyzed at the same location. Our evaluation of retinal tissue from FTLD-Tau patients confirms ONL loss seen antemortem by OCT. Continued investigation of ONL thinning as a biomarker that may distinguish FTLD-Tau from other dementias is warranted.<\/jats:p>","DOI":"10.1186\/s40478-021-01290-8","type":"journal-article","created":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T11:03:20Z","timestamp":1637233400000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Retina tissue validation of optical coherence tomography determined outer nuclear layer loss in FTLD-tau"],"prefix":"10.1186","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0230-3868","authenticated-orcid":false,"given":"Benjamin J.","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward B.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrienne","family":"Saludades","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Q.","family":"Trojanowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua L.","family":"Dunaief","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murray","family":"Grossman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Irwin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,18]]},"reference":[{"key":"1290_CR1","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1109\/RBME.2010.2084567","volume":"3","author":"MD Abramoff","year":"2010","unstructured":"Abramoff MD, Garvin MK, Sonka M (2010) Retinal imaging and image analysis. IEEE Rev Biomed Eng 3:169\u2013208","journal-title":"IEEE Rev Biomed Eng"},{"issue":"9","key":"1290_CR2","doi-asserted-by":"publisher","first-page":"1814","DOI":"10.1016\/j.ajpath.2019.05.022","volume":"189","author":"BH Baumann","year":"2019","unstructured":"Baumann BH, Shu W, Song Y, Sterling J, Kozmik Z, Lakhal-Littleton S et al (2019) Liver-specific, but not retina-specific, hepcidin knockout causes retinal iron accumulation and degeneration. Am J Pathol 189(9):1814\u20131830","journal-title":"Am J Pathol"},{"issue":"4","key":"1290_CR3","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/j.ophtha.2018.08.009","volume":"126","author":"VTT Chan","year":"2019","unstructured":"Chan VTT, Sun Z, Tang S, Chen LJ, Wong A, Tham CC et al (2019) Spectral domain-optical coherence tomography measurements in Alzheimer\u2019s disease: a systematic review and meta-analysis. Ophthalmology 126(4):497\u2013510. https:\/\/doi.org\/10.1016\/j.ophtha.2018.08.009","journal-title":"Ophthalmology"},{"issue":"6","key":"1290_CR4","doi-asserted-by":"publisher","first-page":"1206","DOI":"10.1074\/mcp.M800406-MCP200","volume":"8","author":"R Fridlich","year":"2009","unstructured":"Fridlich R, Delalande F, Jaillard C, Lu J, Poidevin L, Cronin T et al (2009) The thioredoxin-like protein rod-derived cone viability factor (RdCVFL) interacts with TAU and inhibits its phosphorylation in the retina. Mol Cell Proteom 8(6):1206\u201318. https:\/\/doi.org\/10.1074\/mcp.M800406-MCP200","journal-title":"Mol Cell Proteom"},{"issue":"1","key":"1290_CR5","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1136\/bjo.65.1.23","volume":"65","author":"S Gartner","year":"1981","unstructured":"Gartner S, Henkind P (1981) Aging and degeneration of the human macula. 1. Outer nuclear layer and photoreceptors. Br J Ophthalmol 65(1):23\u201328","journal-title":"Br J Ophthalmol"},{"key":"1290_CR6","doi-asserted-by":"publisher","first-page":"1436","DOI":"10.1109\/TMI.2009.2016958","volume":"28","author":"MK Garvin","year":"2009","unstructured":"Garvin MK, Abramoff MD, Wu X, Russell SR, Burns TL, Sonka M (2009) Automated 3-D intraretinal layer segmentation of macular spectral-domain optical coherence tomography images. IEEE Trans Med Imaging 28:1436\u20131447","journal-title":"IEEE Trans Med Imaging"},{"key":"1290_CR7","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1056\/NEJM198608213150804","volume":"315","author":"DR Hinton","year":"1986","unstructured":"Hinton DR, Sadun AA, Blanks JC, Miller CA (1986) Optic-nerve degeneration in Alzheimer\u2019s disease. N Engl J Med 315:485\u2013487. https:\/\/doi.org\/10.1056\/NEJM198608213150804","journal-title":"N Engl J Med"},{"key":"1290_CR8","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1007\/s00401-014-1380-1","volume":"129","author":"DJ Irwin","year":"2015","unstructured":"Irwin DJ, Cairns NJ, Grossman M, McMillan CT, Lee EB, Van Deerlin VM et al (2015) Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine. Acta Neuropathol 129:469\u2013491","journal-title":"Acta Neuropathol"},{"key":"1290_CR9","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1093\/brain\/awx319","volume":"141","author":"DJ Irwin","year":"2018","unstructured":"Irwin DJ, McMillan CT, Xie SX, Rascovsky K, Van Deerlin VM, Coslett HB et al (2018) Asymmetry of post-mortem neuropathology in behavioural-variant frontotemporal dementia. Brain 141:288\u2013301","journal-title":"Brain"},{"key":"1290_CR10","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1109\/TPAMI.2006.19","volume":"28","author":"L Kang","year":"2006","unstructured":"Kang L, Wu X, Chen DZ, Sonka M (2006) Optimal surface segmentation in volumetric images: a graph-theoretic approach. IEEE Trans Pattern Anal Mach Intell 28:119\u2013134","journal-title":"IEEE Trans Pattern Anal Mach Intell"},{"key":"1290_CR11","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-021-02318-y","author":"B Kim","year":"2021","unstructured":"Kim B, Mikytuck B, Suh E, Gibbons GS, Van Deerlin VM, Vaishnavi SN et al (2021) Tau immunotherapy is associated with glial responses in FTLD-Tau. Acta Neuropathol. https:\/\/doi.org\/10.1007\/s00401-021-02318-y","journal-title":"Acta Neuropathol"},{"key":"1290_CR12","doi-asserted-by":"publisher","first-page":"1604","DOI":"10.1212\/WNL.0000000000004500","volume":"89","author":"BJ Kim","year":"2017","unstructured":"Kim BJ, Irwin DJ, Song D, Daniel E, Leveque JD, Raquib AR et al (2017) Optical coherence tomography identifies outer retina thinning in frontotemporal degeneration. Neurology 89:1604\u20131611. https:\/\/doi.org\/10.1212\/WNL.0000000000004500","journal-title":"Neurology"},{"key":"1290_CR13","doi-asserted-by":"publisher","first-page":"298","DOI":"10.3389\/fnins.2019.00298","volume":"13","author":"BJ Kim","year":"2019","unstructured":"Kim BJ, Grossman M, Song D, Saludades S, Pan W, Dominguez-Perez S et al (2019) Persistent and progressive outer retina thinning in frontotemporal degeneration. Front Neurosci 13:298","journal-title":"Front Neurosci"},{"issue":"4","key":"1290_CR14","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1097\/00006982-200208000-00012","volume":"22","author":"SY Kim","year":"2002","unstructured":"Kim SY, Sadda S, Pearlman J, Humayun MS, de Juan E, Melia BM et al (2002) Morphometric analysis of the macula in eyes with disciform age-related macular degeneration. Retina 22(4):471\u2013477","journal-title":"Retina"},{"issue":"1","key":"1290_CR15","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1097\/NEN.0b013e31820376cc","volume":"70","author":"F Leger","year":"2011","unstructured":"Leger F, Fernagut P, Canron M, Leoni S, Vital C, Tison F et al (2011) Protein aggregation in the aging retina. J Neuropathol Exp Neurol 70(1):63\u201368","journal-title":"J Neuropathol Exp Neurol"},{"issue":"9","key":"1290_CR16","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1167\/iovs.62.9.22","volume":"62","author":"RA Masri","year":"2021","unstructured":"Masri RA, Weltzien F, Purushothuman S, Lee SCS, Martin PR, Grunert U (2021) Composition of the inner nuclear layer in human retina. Invest Oph Vis Sci 62(9):22","journal-title":"Invest Oph Vis Sci"},{"key":"1290_CR17","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1093\/brain\/awu024","volume":"137","author":"MM Mesulam","year":"2014","unstructured":"Mesulam MM, Weintraub S, Rogalski EJ, Wieneke C, Geula C, Bigio EH (2014) Asymmetry and heterogeneity of Alzheimer\u2019s and frontotemporal pathology in primary progressive aphasia. Brain 137:1176\u20131192","journal-title":"Brain"},{"key":"1290_CR18","doi-asserted-by":"publisher","first-page":"e201960187","DOI":"10.1002\/jbio.201960187","volume":"13","author":"JQ Sun","year":"2020","unstructured":"Sun JQ, McGeehan B, Firn K, Irwin D, Grossman M, Ying GS et al (2020) Comparison of the Iowa Reference Algorithm to the Heidelberg Spectralis optical coherence tomography segmentation algorithm. J Biophotonics 13:e201960187. https:\/\/doi.org\/10.1002\/jbio.201960187","journal-title":"J Biophotonics"},{"issue":"4","key":"1290_CR19","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/j.jalz.2013.06.003","volume":"10","author":"JB Toledo","year":"2014","unstructured":"Toledo JB, Van Deerlin VM, Lee EB, Suh ER, Baek Y, Robinson JL et al (2014) A platform for discovery: The University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Alzheimers Dement 10(4):477\u2013484","journal-title":"Alzheimers Dement"},{"key":"1290_CR20","doi-asserted-by":"publisher","first-page":"2768","DOI":"10.1167\/iovs.17-23240","volume":"59","author":"A Uchida","year":"2018","unstructured":"Uchida A, Pillai JA, Bermel R, Bonner-Jackson A, Rae-Grant A, Fernandez H et al (2018) Outer retinal assessment using spectral-domain optical coherence tomography in patients with alzheimer\u2019s and parkinson\u2019s disease. Invest Ophthalmol Vis Sci 59:2768\u20132777. https:\/\/doi.org\/10.1167\/iovs.17-23240","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"11","key":"1290_CR21","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1001\/jamaneurol.2013.3956","volume":"70","author":"EM Wood","year":"2013","unstructured":"Wood EM, Falcone D, Suh E, Irwin DJ, Chen-Plotkin AS, Lee EB et al (2013) Development and validation of pedigree classification criteria for frontotemporal lobar degeneration. JAMA Neurol 70(11):1411\u20131417. https:\/\/doi.org\/10.1001\/jamaneurol.2013.3956 (PMID: 24081456)","journal-title":"JAMA Neurol"},{"key":"1290_CR22","doi-asserted-by":"publisher","first-page":"5979","DOI":"10.1167\/iovs.14-15025","volume":"55","author":"L Zhao","year":"2014","unstructured":"Zhao L, Wang C, Song D, Li Y, Song Y, Su G et al (2014) Systemic Administration of the Antioxidant\/Iron Chelator alpha-Lipoic Acid Protects Against Light-Induced Photoreceptor Degeneration in the Mouse Retina. Invest Oph Vis Sci 55:5979\u20135988","journal-title":"Invest Oph Vis Sci"}],"container-title":["Acta Neuropathologica Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-021-01290-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40478-021-01290-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40478-021-01290-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T11:28:59Z","timestamp":1637234939000},"score":1,"resource":{"primary":{"URL":"https:\/\/actaneurocomms.biomedcentral.com\/articles\/10.1186\/s40478-021-01290-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,18]]},"references-count":22,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["1290"],"URL":"https:\/\/doi.org\/10.1186\/s40478-021-01290-8","relation":{},"ISSN":["2051-5960"],"issn-type":[{"value":"2051-5960","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,18]]},"assertion":[{"value":"12 September 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 November 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 November 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the University of Pennsylvania Institutional Review Board (#819894). All patients (or caregivers when appropriate) gave informed consent for this study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The cases described are of patients that have expired. Consent for publication has been given by the appropriate family member of each patient.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"184"}}