{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T16:54:17Z","timestamp":1787849657153,"version":"build-2784847793"},"reference-count":77,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,26]],"date-time":"2023-01-26T00:00:00Z","timestamp":1674691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>For most, staying \u201cmentally sharp\u201d as they age is a very high priority that may be thwarted by the consequences of a postoperative complication unrelated to the disorder which necessitated the surgical intervention. Perioperative neurocognitive disorder (PND) is an overarching term for cognitive impairment in surgical patients, that includes conditions from delirium to dementia, affecting more than 7 million patients annually in the US, and which threatens both functional independence and life. Clinical trials and meta-analyses have identified the association between PNDs and increased perioperative levels of Interleukin-6 (IL-6), a pleiotropic cytokine that is both necessary and sufficient for postoperative memory decline in a preclinical model of PND. Recently, we reported that, in adult male wild-type mice subjected to tibial fracture under general anesthesia, IL-6 trans-signaling in hippocampal CA1 neurons mediates surgery-induced memory impairment. As there are no therapeutic options for preventing or reversing PNDs, patients and their caregivers, as well as the healthcare industry, endure staggering costs. Olamkicept, a highly selective IL-6 trans-signaling blocker has shown to be efficacious and safe in clinical trials involving patients with inflammatory bowel disease, another condition for which IL-6 trans-signaling is the mediating mechanism. Subject to a demonstration that olamkicept is effective in preventing cognitive impairment in vulnerable (aged and Alzheimer\u2019s Disease) preclinical PND models, clinical trials involving aged and\/or cognitively impaired surgical patients should be undertaken to study olamkicept\u2019s utility for PNDs.<\/jats:p>","DOI":"10.3389\/fnagi.2022.1097606","type":"journal-article","created":{"date-parts":[[2023,1,25]],"date-time":"2023-01-25T23:46:58Z","timestamp":1674690418000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Defining the role of Interleukin-6 for the development of perioperative neurocognitive disorders: Evidence from clinical and preclinical studies"],"prefix":"10.3389","volume":"14","author":[{"given":"Odmara L.","family":"Barreto Chang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mervyn","family":"Maze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,26]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1296","DOI":"10.1111\/j.1540-8167.2008.01257.x","article-title":"Effects of gender and aging on differential autonomic responses to orthostatic maneuvers","volume":"19","author":"Barantke","year":"2008","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref10","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-051921-112525","article-title":"Age-related perioperative neurocognitive disorders: experimental models and Druggable targets","author":"Barreto Chang","year":"","journal-title":"Annu. Rev. Pharmacol. Toxicol"},{"key":"ref11","doi-asserted-by":"publisher","DOI":"10.1111\/jgs.18033","article-title":"A novel approach for the detection of cognitive impairment and delirium risk in older patients undergoing spine surgery","author":"Barreto Chang","year":"","journal-title":"J. Am. Geriatr. Soc"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"e150","DOI":"10.1213\/ANE.0000000000004179","article-title":"Flow cytometry characterization of cerebrospinal fluid monocytes in patients with postoperative cognitive dysfunction: A pilot study","volume":"129","author":"Berger","year":"2019","journal-title":"Anesth. Analg."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1406","DOI":"10.1213\/ANE.0000000000003841","article-title":"Best practices for postoperative brain health: recommendations from the fifth international perioperative neurotoxicity working group","volume":"127","author":"Berger","year":"2018","journal-title":"Anesth. Analg."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1007\/s12035-014-8657-1","article-title":"Body fluid cytokine levels in mild cognitive impairment and Alzheimer\u2019s disease: a comparative overview","volume":"50","author":"Brosseron","year":"2014","journal-title":"Mol. Neurobiol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1016\/j.bbi.2011.10.008","article-title":"Interleukin-6 trans-signaling in the senescent mouse brain is involved in infection-related deficits in contextual fear conditioning","volume":"26","author":"Burton","year":"2012","journal-title":"Brain Behav. Immun."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.bbi.2013.01.002","article-title":"Central inhibition of interleukin-6 trans-signaling during peripheral infection reduced neuroinflammation and sickness in aged mice","volume":"30","author":"Burton","year":"2013","journal-title":"Brain Behav. Immun."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1016\/j.jalz.2016.02.010","article-title":"Neuroinflammation in Alzheimer\u2019s disease: current evidence and future directions","volume":"12","author":"Calsolaro","year":"2016","journal-title":"Alzheimers Dement."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"2503","DOI":"10.1523\/JNEUROSCI.2830-13.2014","article-title":"Trans-signaling is a dominant mechanism for the pathogenic actions of interleukin-6 in the brain","volume":"34","author":"Campbell","year":"2014","journal-title":"J. Neurosci."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1186\/s12871-019-0735-5","article-title":"Effects of an abnormal mini-mental state examination score on postoperative outcomes in geriatric surgical patients: a meta-analysis","volume":"19","author":"Cao","year":"2019","journal-title":"BMC Anesthesiol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.1111\/cns.13718","article-title":"Cholecystokinin octapeptide improves hippocampal glutamatergic synaptogenesis and postoperative cognition by inhibiting induction of A1 reactive astrocytes in aged mice","volume":"27","author":"Chen","year":"2021","journal-title":"CNS Neurosci. Ther."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"699329","DOI":"10.3389\/fnins.2021.699329","article-title":"Spatial memory and microglia activation in a mouse model of chronic Neuroinflammation and the anti-inflammatory effects of Apigenin","volume":"15","author":"Chesworth","year":"2021","journal-title":"Front. Neurosci."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1042\/EBC20200018","article-title":"Specialized pro-resolving mediator network: an update on production and actions","volume":"64","author":"Chiang","year":"2020","journal-title":"Essays Biochem."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1002\/ana.22082","article-title":"Role of interleukin-1beta in postoperative cognitive dysfunction","volume":"68","author":"Cibelli","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/S0009-9120(76)80028-8","article-title":"The use of o-dianisidine for serum haptoglobin electrophoresis using cellulose acetate","volume":"9","author":"Compton","year":"1976","journal-title":"Clin. Biochem."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1186\/1742-2094-9-179","article-title":"Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study","volume":"9","author":"Cribbs","year":"2012","journal-title":"J. Neuroinflammation"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1186\/s12974-018-1318-y","article-title":"Effects of methylprednisolone on blood-brain barrier and cerebral inflammation in cardiac surgery-a randomized trial","volume":"15","author":"Danielson","year":"2018","journal-title":"J. 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Soc."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1002\/ana.24909","article-title":"The immune response of the human brain to abdominal surgery","volume":"81","author":"Forsberg","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1111\/j.1749-6632.2000.tb06651.x","article-title":"Inflamm-aging. An evolutionary perspective on immunosenescence","volume":"908","author":"Franceschi","year":"2000","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1196\/annals.1358.024","article-title":"Immunologic role of the cholinergic anti-inflammatory pathway and the nicotinic acetylcholine alpha 7 receptor","volume":"1062","author":"Gallowitsch-Puerta","year":"2005","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1038\/nrd.2018.45","article-title":"Interleukin-6: designing specific therapeutics for a complex cytokine","volume":"17","author":"Garbers","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.jneuroim.2018.09.002","article-title":"Microglia priming by interleukin-6 signaling is enhanced in aged mice","volume":"324","author":"Garner","year":"2018","journal-title":"J. Neuroimmunol."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1007\/s00406-004-0558-2","article-title":"Pattern of interleukin-6 receptor complex immunoreactivity between cortical regions of rapid autopsy normal and Alzheimer\u2019s disease brain","volume":"255","author":"Hampel","year":"2005","journal-title":"Eur. Arch. Psychiatry Clin. 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Immunol."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1038\/s41398-021-01349-z","article-title":"Pro-inflammatory interleukin-6 signaling links cognitive impairments and peripheral metabolic alterations in Alzheimer\u2019s disease","volume":"11","author":"Lyra","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1038\/nature07201","article-title":"Origin and physiological roles of inflammation","volume":"454","author":"Medzhitov","year":"2008","journal-title":"Nature"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1016\/j.biopsych.2008.11.029","article-title":"Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression","volume":"65","author":"Miller","year":"2009","journal-title":"Biol. Psychiatry"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1097\/01.anes.0000296071.19434.1e","article-title":"Predictors of cognitive dysfunction after major noncardiac surgery","volume":"108","author":"Monk","year":"2008","journal-title":"Anesthesiology"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1097\/00000542-199209000-00004","article-title":"Responses of plasma adrenocorticotropic hormone, cortisol, and cytokines during and after upper abdominal surgery","volume":"77","author":"Naito","year":"1992","journal-title":"Anesthesiology"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"1456","DOI":"10.1111\/jgs.14238","article-title":"Associations between delirium and preoperative cerebrospinal fluid C-reactive protein, Interleukin-6, and Interleukin-6 receptor in individuals with acute hip fracture","volume":"64","author":"Neerland","year":"2016","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/0090-1229(89)90147-5","article-title":"Elevation of serum interleukin 6 prior to acute phase proteins on the inflammation by surgical operation","volume":"50","author":"Nishimoto","year":"1989","journal-title":"Clin. Immunol. Immunopathol."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1016\/j.bja.2021.04.033","article-title":"Preoperative inflammatory mediators and postoperative delirium: systematic review and meta-analysis","volume":"127","author":"Noah","year":"2021","journal-title":"Br. J. Anaesth."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"3458","DOI":"10.1016\/j.neuron.2022.10.020","article-title":"Microglia states and nomenclature: A field at its crossroads","volume":"110","author":"Paolicelli","year":"2022","journal-title":"Neuron"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"3575","DOI":"10.4049\/jimmunol.161.7.3575","article-title":"In vivo and in vitro activities of the gp130-stimulating designer cytokine hyper-IL-6","volume":"161","author":"Peters","year":"1998","journal-title":"J. Immunol."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1186\/s12974-021-02252-6","article-title":"Aging triggers an upregulation of a multitude of cytokines in the male and especially the female rodent hippocampus but more discrete changes in other brain regions","volume":"18","author":"Porcher","year":"2021","journal-title":"J. Neuroinflammation"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/S0169-328X(97)00356-2","article-title":"Enhancement of beta-amyloid precursor protein transcription and expression by the soluble interleukin-6 receptor\/interleukin-6 complex","volume":"55","author":"Ringheim","year":"1998","journal-title":"Brain Res. Mol. Brain Res."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1101\/cshperspect.a028415","article-title":"Interleukin-6 family cytokines","volume":"10","author":"Rose-John","year":"2018","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"155577","DOI":"10.1016\/j.cyto.2021.155577","article-title":"Therapeutic targeting of IL-6 trans-signaling","volume":"144","author":"Rose-John","year":"2021","journal-title":"Cytokine"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1038\/s41577-021-00508-z","article-title":"Neuromodulation by the immune system: a focus on cytokines","volume":"21","author":"Salvador","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref59","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1186\/s12871-020-01200-w","article-title":"Preoperative sedentary behavior is neither a risk factor for perioperative neurocognitive disorders nor associated with an increase in peripheral inflammation, a prospective observational cohort study","volume":"20","author":"Saxena","year":"2020","journal-title":"BMC Anesthesiol."},{"key":"ref60","doi-asserted-by":"crossref","first-page":"e2311","DOI":"10.1053\/j.gastro.2021.02.062","article-title":"Therapeutic Interleukin-6 trans-signaling inhibition by Olamkicept (sgp130Fc) in patients with active inflammatory bowel disease","volume":"160","author":"Schreiber","year":"2021","journal-title":"Gastroenterology"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1038\/nri3547","article-title":"Age-dependent dysregulation of innate immunity","volume":"13","author":"Shaw","year":"2013","journal-title":"Nat. Rev. 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Neurochem."},{"key":"ref65","doi-asserted-by":"publisher","first-page":"7","DOI":"10.15424\/bioelectronmed.2016.00007","article-title":"Cytokine-specific Neurograms in the sensory Vagus nerve","volume":"3","author":"Steinberg","year":"2016","journal-title":"Bioelectron. Med."},{"key":"ref66","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1213\/ANE.0000000000004053","article-title":"Neuroinflammation and perioperative neurocognitive disorders","volume":"128","author":"Subramaniyan","year":"2019","journal-title":"Anesth. 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Immunol."},{"key":"ref70","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1159\/000505099","article-title":"Interleukin-6: A Masterplayer in the cytokine network","volume":"98","author":"Uciechowski","year":"2020","journal-title":"Oncology"},{"key":"ref71","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1097\/ALN.0000000000000045","article-title":"High-mobility group box 1 protein initiates postoperative cognitive decline by engaging bone marrow-derived macrophages","volume":"120","author":"Vacas","year":"2014","journal-title":"Anesthesiology"},{"key":"ref72","doi-asserted-by":"publisher","first-page":"1464","DOI":"10.3389\/fimmu.2017.01464","article-title":"Impaired resolution of inflammation in Alzheimer\u2019s disease: a review","volume":"8","author":"Whittington","year":"2017","journal-title":"Front. 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