{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T18:05:56Z","timestamp":1791223556108,"version":"4.1.0"},"reference-count":20,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2023,4,19]],"date-time":"2023-04-19T00:00:00Z","timestamp":1681862400000},"content-version":"vor","delay-in-days":108,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["K99AG068602"],"award-info":[{"award-number":["K99AG068602"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Massachusetts Alzheimer Disease Research Center","award":["P30AG062421"],"award-info":[{"award-number":["P30AG062421"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Studies of post-mortem human tissue provide insight into pathological processes, but are inherently limited by practical considerations that limit the scale at which tissue can be examined, and the obvious issue that the tissue reflects only one time point in a continuous disease process. We approached this problem by adapting new tissue clearance techniques to an entire cortical area of human brain, which allows surveillance of hundreds of thousands of neurons throughout the depth of the entire cortical thickness. This approach allows detection of \u2018rare\u2019 events that may be difficult to detect in standard 5 micrometre-thick paraffin sections. For example, it is well established that neurofibrillary tangles begin within a neuron, and ultimately, in at least some instances, persist in the brain even after the neuron has died. These are referred to as \u2018ghost tangles\u2019, a term that appropriately implies their \u2018difficult to see\u2019 ephemeral qualities. We set out to find ghost tangles as one example of the power of the tissue clearance\/image analysis techniques to detect rare events, and to learn what happens at the end-point of a tangle\u2019s life history. We were able to identify 8103 tau tangles, 132 465 neurons and 299 640 nuclei in tissue samples from three subjects with severe Alzheimer\u2019s disease (Braak V\u2013VI) and 4 tau tangles, 200 447 neurons and 462 715 nuclei in tissue samples from three subjects with no significant tau pathology (Braak 0\u2013I). Among these data, we located 57 ghost tangles, which makes them only 0.7% of the total tau tangles observed. We found that ghost tangles are more likely to be found in cortical layers 3 and 5 (49\/57), with a select few scattered across other layers 1, 2, 4 and 6. This ability to find rare events, such as ghost tangles, in large enough quantities to statistically test their distribution exemplifies how tissue clearing can be used as a powerful tool for studying selective vulnerability or resilience to pathology across brain regions.<\/jats:p>","DOI":"10.1093\/braincomms\/fcad130","type":"journal-article","created":{"date-parts":[[2023,4,19]],"date-time":"2023-04-19T08:19:26Z","timestamp":1681892366000},"source":"Crossref","is-referenced-by-count":16,"title":["Spatial characterization of tangle-bearing neurons and ghost tangles in the human inferior temporal gyrus with three-dimensional imaging"],"prefix":"10.1093","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6815-4482","authenticated-orcid":false,"given":"Theodore J","family":"Zwang","sequence":"first","affiliation":[{"name":"Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital , Charlestown, MA , USA"},{"name":"Harvard Medical School , Boston, MA , USA"},{"name":"Massachusetts Alzheimer\u2019s Disease Research Center , Charlestown, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Woost","sequence":"additional","affiliation":[{"name":"Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital , Charlestown, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Bailey","sequence":"additional","affiliation":[{"name":"Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital , Charlestown, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary","family":"Hoglund","sequence":"additional","affiliation":[{"name":"Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital , Charlestown, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3189-2190","authenticated-orcid":false,"given":"Douglas S","family":"Richardson","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology and Harvard Center for Biological Imaging, Harvard University , Cambridge, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel E","family":"Bennett","sequence":"additional","affiliation":[{"name":"Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital , Charlestown, MA , USA"},{"name":"Harvard Medical School , Boston, MA , USA"},{"name":"Massachusetts Alzheimer\u2019s Disease Research Center , Charlestown, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley T","family":"Hyman","sequence":"additional","affiliation":[{"name":"Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital , Charlestown, MA , USA"},{"name":"Harvard Medical School , Boston, MA , USA"},{"name":"Massachusetts Alzheimer\u2019s Disease Research Center , Charlestown, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,4,19]]},"reference":[{"issue":"1","key":"2023050608312104700_fcad130-B1","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a006189","article-title":"Neuropathological alterations in Alzheimer disease","volume":"1","author":"Serrano-Pozo","year":"2011","journal-title":"Cold Spring Harb Perspect Med"},{"issue":"9","key":"2023050608312104700_fcad130-B2","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1002\/alz.12321","article-title":"Visualization of neurofibrillary tangle maturity in Alzheimer\u2019s disease: A clinicopathologic perspective for biomarker research","volume":"17","author":"Moloney","year":"2021","journal-title":"Alzheimers 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