{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T15:31:45Z","timestamp":1784043105725,"version":"3.55.0"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T00:00:00Z","timestamp":1665532800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T00:00:00Z","timestamp":1665532800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japanese Society for Promotion of Science","doi-asserted-by":"crossref","award":["19H03749"],"award-info":[{"award-number":["19H03749"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Science Research Grant for research on chronic pain","award":["H26-Cancer-060"],"award-info":[{"award-number":["H26-Cancer-060"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Older adult surgical patients are susceptible to developing delirium. Early intervention can be initiated if a potential biomarker associated with delirium can be identified during the acute phase of surgery. Therefore, we investigated the changes in the levels of serum inflammatory mediators responsible for delirium. Serum biomarkers were measured preoperatively to postoperative day 3 in 96 patients who underwent esophageal cancer surgery and compared between patients who did and did not develop delirium. Serum concentrations of the brain-derived phosphorylated neurofilament heavy subunit remained at higher levels throughout the entire perioperative period in patients with delirium (n\u2009=\u200915) than in those without delirium (n\u2009=\u200981). The interaction between delirium and non-delirium was significant for plasminogen activator inhibitor-1 (including age as a covariate, F\u2009=\u200913.360,<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001, \u03b7<jats:sup>2<\/jats:sup><jats:sub>p<\/jats:sub>\u2009=\u20090.134, observed power 1.000) during the perioperative periods. Plasminogen activator inhibitor-1 level discriminated between patients with and without clinically diagnosed delirium with significantly high accuracy (area under curve, 0.864; sensitivity, 1.00: negative predictive value, 1.000;<jats:italic>p<\/jats:italic>\u2009=\u20090.002). Rapid increases in the levels of serum plasminogen activator inhibitor-1 may enable clinicians to identify patients at risk of developing postoperative delirium and initiate early prevention and intervention.<\/jats:p>","DOI":"10.1038\/s41598-022-21682-7","type":"journal-article","created":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T12:07:15Z","timestamp":1665576435000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Elevation of serum plasminogen activator inhibitor-1 predicts postoperative delirium independent of neural damage: a sequential analysis"],"prefix":"10.1038","volume":"12","author":[{"given":"Kazuhito","family":"Mietani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maiko","family":"Hasegawa-Moriyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Yagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reo","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Ogata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobutake","family":"Shimojo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuyuki","family":"Seto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanji","family":"Uchida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiko","family":"Sumitani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,10,12]]},"reference":[{"key":"21682_CR1","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1016\/S0140-6736(13)60688-1","volume":"383","author":"SK Inouye","year":"2014","unstructured":"Inouye, S. K. et al. Delirium in elderly people. Lancet 383, 911\u2013922 (2014).","journal-title":"Lancet"},{"key":"21682_CR2","doi-asserted-by":"publisher","first-page":"1134","DOI":"10.1001\/jamasurg.2015.2606","volume":"150","author":"LJ Gleason","year":"2015","unstructured":"Gleason, L. J. et al. Effect of delirium and other major complications on outcomes after elective surgery in older adults. JAMA Surg. 150, 1134\u20131140 (2015).","journal-title":"JAMA Surg."},{"key":"21682_CR3","doi-asserted-by":"publisher","first-page":"e208931","DOI":"10.1001\/jamanetworkopen.2020.8931","volume":"3","author":"MD Boone","year":"2020","unstructured":"Boone, M. D. et al. Economic burden of postoperative neurocognitive disorders among US medicare patients. JAMA Netw. Open 3, e208931 (2020).","journal-title":"JAMA Netw. Open"},{"key":"21682_CR4","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/j.bja.2020.10.037","volume":"126","author":"CJ Peden","year":"2021","unstructured":"Peden, C. J. et al. Improving perioperative brain health: An expert consensus review of key actions for the perioperative care team. Br. J. Anaesth. 126, 423\u2013432 (2021).","journal-title":"Br. J. Anaesth."},{"key":"21682_CR5","doi-asserted-by":"publisher","first-page":"1456","DOI":"10.1056\/NEJMcp1605501","volume":"377","author":"ER Marcantonio","year":"2017","unstructured":"Marcantonio, E. R. Delirium in hospitalized older adults. N. Engl. J. Med. 377, 1456\u20131466 (2017).","journal-title":"N. Engl. J. Med."},{"key":"21682_CR6","doi-asserted-by":"publisher","first-page":"1370","DOI":"10.1097\/00003246-200107000-00012","volume":"29","author":"EW Ely","year":"2001","unstructured":"Ely, E. W. et al. Evaluation of delirium in critically ill patients: Validation of the confusion assessment method for the intensive care unit (CAM-ICU). Crit. Care Med. 29, 1370\u20131379 (2001).","journal-title":"Crit. Care Med."},{"key":"21682_CR7","doi-asserted-by":"publisher","first-page":"2721","DOI":"10.1097\/01.CCM.0000292011.93074.82","volume":"35","author":"JW Devlin","year":"2007","unstructured":"Devlin, J. W. et al. Use of a validated delirium assessment tool improves the ability of physicians to identify delirium in medical intensive care unit patients. Crit. Care Med. 35, 2721\u20132724 (2007).","journal-title":"Crit. Care Med."},{"key":"21682_CR8","doi-asserted-by":"publisher","first-page":"2022","DOI":"10.1097\/CCM.0b013e318250acc0","volume":"40","author":"ML Gunther","year":"2012","unstructured":"Gunther, M. L. et al. The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: The VISIONS cohort magnetic resonance imaging study. Crit. Care Med. 40, 2022\u20132032 (2012).","journal-title":"Crit. Care Med."},{"key":"21682_CR9","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1097\/ALN.0b013e318246ec0b","volume":"116","author":"RP Kline","year":"2012","unstructured":"Kline, R. P. et al. Surgery and brain atrophy in cognitively normal elderly subjects and subjects diagnosed with mild cognitive impairment. Anesthesiology 116, 603\u2013612 (2012).","journal-title":"Anesthesiology"},{"key":"21682_CR10","doi-asserted-by":"publisher","first-page":"e0222721","DOI":"10.1371\/journal.pone.0222721","volume":"14","author":"K Mietani","year":"2019","unstructured":"Mietani, K. et al. Dysfunction of the blood-brain barrier in postoperative delirium patients, referring to the axonal damage biomarker phosphorylated neurofilament heavy subunit. PLoS ONE 14, e0222721 (2019).","journal-title":"PLoS ONE"},{"key":"21682_CR11","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.neulet.2017.05.023","volume":"653","author":"R Inoue","year":"2017","unstructured":"Inoue, R. et al. Direct evidence of central nervous system axonal damage in patients with postoperative delirium: A preliminary study of pNF-H as a promising serum biomarker. Neurosci. Lett. 653, 39\u201344 (2017).","journal-title":"Neurosci. Lett."},{"key":"21682_CR12","doi-asserted-by":"crossref","first-page":"169","DOI":"10.36150\/2499-6564-N488","volume":"70","author":"K Mietani","year":"2022","unstructured":"Mietani, K. et al. Preoperative detection of serum phosphorylated neurofilament heavy chain subunit predicts postoperative delirium: A prospective observational study. J. Geriatrics Gerontol. 70, 169\u2013177 (2022).","journal-title":"J. Geriatrics Gerontol."},{"key":"21682_CR13","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1186\/s12974-016-0681-9","volume":"13","author":"J Hirsch","year":"2016","unstructured":"Hirsch, J. et al. Perioperative cerebrospinal fluid and plasma inflammatory markers after orthopedic surgery. J. Neuroinflamm. 13, 211 (2016).","journal-title":"J. Neuroinflamm."},{"key":"21682_CR14","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1097\/00000542-200603000-00005","volume":"104","author":"A Buvanendran","year":"2006","unstructured":"Buvanendran, A. et al. Upregulation of prostaglandin E2 and interleukins in the central nervous system and peripheral tissue during and after surgery in humans. Anesthesiology 104, 403\u2013410 (2006).","journal-title":"Anesthesiology"},{"key":"21682_CR15","first-page":"557","volume":"24","author":"MP Yeager","year":"1999","unstructured":"Yeager, M. P. et al. Cerebrospinal fluid cytokine levels after surgery with spinal or general anesthesia. Reg. Anesth. Pain Med. 24, 557\u2013562 (1999).","journal-title":"Reg. Anesth. Pain Med."},{"key":"21682_CR16","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1213\/ANE.0000000000001403","volume":"123","author":"K Yuki","year":"2016","unstructured":"Yuki, K. et al. Mechanisms of the immunological effects of volatile anesthetics: A review. Anesth. Analg. 123, 326\u2013335 (2016).","journal-title":"Anesth. Analg."},{"key":"21682_CR17","doi-asserted-by":"publisher","first-page":"688090","DOI":"10.3389\/fnins.2021.688090","volume":"15","author":"B Hussain","year":"2021","unstructured":"Hussain, B. et al. Blood-brain barrier breakdown: An emerging biomarker of cognitive impairment in normal aging and dementia. Front. Neurosci. 15, 688090 (2021).","journal-title":"Front. Neurosci."},{"key":"21682_CR18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0226412","volume":"14","author":"JB McNeil","year":"2019","unstructured":"McNeil, J. B. et al. Plasma biomarkers of inflammation, coagulation, and brain injury as predictors of delirium duration in older hospitalized patients. PLoS ONE 14, e0226412 (2019).","journal-title":"PLoS ONE"},{"key":"21682_CR19","doi-asserted-by":"publisher","first-page":"1348","DOI":"10.1158\/1078-0432.CCR-14-2775","volume":"21","author":"A Natori","year":"2015","unstructured":"Natori, A. et al. Potential role of pNF-H, a biomarker of axonal damage in the central nervous system, as a predictive marker of chemotherapy-induced cognitive impairment. Clin. Cancer Res. 21, 1348\u20131352 (2015).","journal-title":"Clin. Cancer Res."},{"key":"21682_CR20","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/j.bbadis.2015.10.011","volume":"1862","author":"A Mehra","year":"2016","unstructured":"Mehra, A. et al. The plasminogen activation system in neuroinflammation. Biochim. Biophys. Acta 1862, 395\u2013402 (2016).","journal-title":"Biochim. Biophys. Acta"},{"key":"21682_CR21","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1016\/j.bja.2020.08.061","volume":"126","author":"T Ballweg","year":"2021","unstructured":"Ballweg, T. et al. Association between plasma tau and postoperative delirium incidence and severity: A prospective observational study. Br. J. Anaesth. 126, 458\u2013466 (2021).","journal-title":"Br. J. Anaesth."},{"key":"21682_CR22","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.exger.2014.10.004","volume":"60","author":"J Oh","year":"2014","unstructured":"Oh, J. et al. Plasminogen activator inhibitor-1 as an early potential diagnostic marker for Alzheimer\u2019s disease. Exp. Gerontol. 60, 87\u201391 (2014).","journal-title":"Exp. Gerontol."},{"key":"21682_CR23","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/0165-0173(95)00011-9","volume":"21","author":"PL McGeer","year":"1995","unstructured":"McGeer, P. L. et al. The inflammatory response system of brain: Implications for therapy of Alzheimer and other neurodegenerative disease. Brain Res. Brain Res. Rev. 21, 195\u2013218 (1995).","journal-title":"Brain Res. Brain Res. Rev."},{"key":"21682_CR24","doi-asserted-by":"publisher","first-page":"e809","DOI":"10.1097\/CCM.0000000000001739","volume":"44","author":"CG Hughes","year":"2016","unstructured":"Hughes, C. G. et al. Endothelial activation and blood-brain barrier injury as risk factors for delirium in critically Ill patients. Crit. Care Med. 44, e809\u2013e817 (2016).","journal-title":"Crit. Care Med."},{"key":"21682_CR25","doi-asserted-by":"publisher","first-page":"4560","DOI":"10.2174\/1381612825666191210154535","volume":"25","author":"Y Lee","year":"2020","unstructured":"Lee, Y. et al. Neurofilament proteins as prognostic biomarkers in neurological disorders. Curr. Pharm. Des. 25, 4560\u20134569 (2020).","journal-title":"Curr. Pharm. Des."},{"key":"21682_CR26","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1160\/TH08-04-0259","volume":"100","author":"S Soeda","year":"2008","unstructured":"Soeda, S. et al. Anti-apoptotic roles of plasminogen activator inhibitor-1 as a neurotrophic factor in the central nervous system. Thromb. Haemost. 100, 1014\u20131020 (2008).","journal-title":"Thromb. Haemost."},{"key":"21682_CR27","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1016\/j.bja.2021.04.033","volume":"127","author":"AM Noah","year":"2021","unstructured":"Noah, A. M. et al. Preoperative inflammatory mediators and postoperative delirium: Systematic review and meta-analysis. Br. J. Anaesth. 127, 424\u2013434 (2021).","journal-title":"Br. J. Anaesth."},{"key":"21682_CR28","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1097\/ALN.0000000000003834","volume":"135","author":"YW Li","year":"2021","unstructured":"Li, Y. W. et al. Delirium in older patients after combined epidural-general anesthesia or general anesthesia for major surgery: A randomized trial. Anesthesiology 135, 218\u2013232 (2021).","journal-title":"Anesthesiology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-21682-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-21682-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-21682-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T01:03:44Z","timestamp":1678237424000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-022-21682-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,12]]},"references-count":28,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["21682"],"URL":"https:\/\/doi.org\/10.1038\/s41598-022-21682-7","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,12]]},"assertion":[{"value":"1 July 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 September 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 October 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The department to which M.H-M. belongs is supported by Nippon Zoki Pharmaceutical Co., Ltd. (Osaka, Japan), Shionogi Co., Ltd. (Osaka, Japan), Heartfelt Co., Ltd. (Kumamoto, Japan) and Aiwa Hospital (Nagano, Japan). K.U. has collaborative research agreement accompanied with research funding with Nipro Corporation (Osaka, Japan) and Nihon Kohden Corporation (Tokyo, Japan) on topics unrelated to the present study. Other authors K.M., K.Y., R.I., T.O., N.S., Y.S., and M.S. declare that they have no competing interest to report.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"17091"}}