{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T02:31:58Z","timestamp":1788402718266,"version":"build-2803163510"},"reference-count":128,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Postoperative neurocognitive disorders (PNDs) encompass a spectrum of cognitive dysfunction in the perioperative period. PNDs can present with hypoactive symptoms such as lethargy, hyperactive symptoms such as confusion and disorientation or a mix of both. PNDs can affect patients of all ages; however, the incidence of PNDs increases significantly as patients age. It is important to promptly recognize PNDs as patients can have higher morbidity and mortality, longer hospital stays, higher readmissions rates, and additional testing\/treatment after discharge. In this review, we explore the molecular basis involved in brain aging as well as the mechanisms involved in anesthesia exposure and the development of PNDs. Understanding the mechanisms behind brain aging and the parallels to the pathophysiology of PNDs such as neuroinflammation, oxidative stress, mitochondrial dysfunction, and synaptic disruption are integral to mitigating the incidence and severity of PNDs. Current research suggests possible clinical targets for management such as dexmedetomidine and NSAIDs due to their abilities to combat harmful neuroinflammatory effects. Additionally, EEG-guided anesthesia, careful choice of anesthetics, and supportive measures can aid in mitigating PNDs. By understanding the mechanisms of brain aging, the risk factors for and pathophysiology of PNDs, we can better tailor our management of PNDs.<\/jats:p>","DOI":"10.3390\/ijms262110272","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T01:14:02Z","timestamp":1761182042000},"page":"10272","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Molecular and Clinical Considerations for Anesthesia in the Aging Brain"],"prefix":"10.3390","volume":"26","author":[{"given":"George-Abraam","family":"Tawfik","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Stony Brook University Hospital, Stony Brook, NY 11794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Lu","sequence":"additional","affiliation":[{"name":"Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"De La Hoz","sequence":"additional","affiliation":[{"name":"Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Crugnola","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Stony Brook University Hospital, Stony Brook, NY 11794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2495-7048","authenticated-orcid":false,"given":"Zhaosheng","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Stony Brook University Hospital, Stony Brook, NY 11794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daryn","family":"Moller","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Stony Brook University Hospital, Stony Brook, NY 11794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,22]]},"reference":[{"key":"ref_1","unstructured":"National Institute on Aging, National Institutes of Health, and U.S. Department of Health and Human Services (2025, August 25). Global Health and Aging, Available online: https:\/\/www.nia.nih.gov\/sites\/default\/files\/2017-06\/global_health_aging.pdf."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"(2016). Global patient outcomes after elective surgery: Prospective cohort study in 27 low-, middle- and high-income countries. Br. J. Anaesth., 117, 601\u2013609.","DOI":"10.1093\/bja\/aew316"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"111320","DOI":"10.1016\/j.jclinane.2023.111320","article-title":"Postoperative neurocognitive disorders: A clinical guide","volume":"92","author":"Dilmen","year":"2024","journal-title":"J. Clin. Anesth."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1001\/jama.2010.1013","article-title":"Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: A meta-analysis","volume":"304","author":"Witlox","year":"2010","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.bjae.2020.10.004","article-title":"Postoperative cognitive dysfunction in clinical practice","volume":"21","author":"Brodier","year":"2021","journal-title":"BJA Educ."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1176\/appi.psy.50.3.248","article-title":"Phenomenological subtypes of delirium in older persons: Patterns, prevalence, and prognosis","volume":"50","author":"Yang","year":"2009","journal-title":"Psychosomatics"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1213\/ANE.0000000000004641","article-title":"American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on Postoperative Delirium Prevention","volume":"130","author":"Hughes","year":"2020","journal-title":"Anesth. Analg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.bpa.2012.07.003","article-title":"Epidemiology and risk factors for delirium across hospital settings","volume":"26","author":"Vasilevskis","year":"2012","journal-title":"Best Pract. Res. Clin. Anaesthesiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2703","DOI":"10.1001\/jama.286.21.2703","article-title":"Delirium in mechanically ventilated patients: Validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU)","volume":"286","author":"Ely","year":"2001","journal-title":"JAMA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1001\/archoto.2011.1456","article-title":"Alcohol-related predictors of delirium after major head and neck cancer surgery","volume":"138","author":"Shah","year":"2012","journal-title":"Arch. Otolaryngol. Head Neck Surg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1002\/bjs.5053","article-title":"Postoperative delirium in elderly patients after major abdominal surgery","volume":"92","author":"Olin","year":"2005","journal-title":"Br. J. Surg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"R238","DOI":"10.1186\/cc9393","article-title":"High serum cortisol level is associated with increased risk of delirium after coronary artery bypass graft surgery: A prospective cohort study","volume":"14","author":"Mu","year":"2010","journal-title":"Crit. Care"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"279","DOI":"10.2310\/6670.2010.00052","article-title":"Delirium after emergency\/elective open and endovascular aortoiliac surgery at a surgical ward with a high-standard delirium care protocol","volume":"18","author":"Koebrugge","year":"2010","journal-title":"Vascular"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1093\/ageing\/afp024","article-title":"Predicting the onset of delirium in the post-operative patient","volume":"38","author":"Noimark","year":"2009","journal-title":"Age Ageing"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1213\/ANE.0000000000006893","article-title":"The Association of Preoperative Diabetes With Postoperative Delirium in Older Patients Undergoing Major Orthopedic Surgery: A Prospective Matched Cohort Study","volume":"138","author":"Shang","year":"2024","journal-title":"Anesth. Analg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1186\/s12871-025-03110-1","article-title":"Association between combinations of preoperative comorbidities and postoperative delirium in older patients: A matched cohort study","volume":"25","author":"Li","year":"2025","journal-title":"BMC Anesthesiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1002\/bjs.6843","article-title":"Risk factors and incidence of postoperative delirium in elderly patients after elective and emergency surgery","volume":"97","author":"Ansaloni","year":"2010","journal-title":"Br. J. Surg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1097\/SLA.0b013e3181c1cfc9","article-title":"Impaired mobility, ASA status and administration of tramadol are risk factors for postoperative delirium in patients aged 75 years or more after major abdominal surgery","volume":"251","author":"Brouquet","year":"2010","journal-title":"Ann. Surg."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2306","DOI":"10.1111\/j.1532-5415.2011.03725.x","article-title":"Predisposing factors for postoperative delirium after hip fracture repair in individuals with and without dementia","volume":"59","author":"Lee","year":"2011","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1093\/ejcts\/ezr031","article-title":"Preoperative and operative predictors of delirium after cardiac surgery in elderly patients","volume":"41","author":"Bakker","year":"2012","journal-title":"Eur. J. Cardiothorac. Surg."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0022-5223(03)01281-9","article-title":"Predictors of delirium after cardiac surgery delirium: Effect of beating-heart (off-pump) surgery","volume":"127","author":"Bucerius","year":"2004","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/S0003-4975(03)01358-4","article-title":"Predictors of cognitive decline following coronary artery bypass graft surgery","volume":"77","author":"Ho","year":"2004","journal-title":"Ann. Thorac. Surg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1093\/bja\/ael094","article-title":"Emergence delirium in adults in the post-anaesthesia care unit","volume":"96","author":"Lautner","year":"2006","journal-title":"Br. J. Anaesth."},{"key":"ref_24","first-page":"394","article-title":"Risk factors for inadequate emergence after anesthesia: Emergence delirium and hypoactive emergence","volume":"76","author":"Radtke","year":"2010","journal-title":"Minerva. Anestesiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1016\/j.ijnurstu.2012.03.008","article-title":"The association between nurse-administered midazolam following cardiac surgery and incident delirium: An observational study","volume":"49","author":"Taipale","year":"2012","journal-title":"Int. J. Nurs. Stud."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1001\/jamasurg.2024.6602","article-title":"Benzodiazepine-Free Cardiac Anesthesia for Reduction of Postoperative Delirium: A Cluster Randomized Crossover Trial","volume":"160","author":"Spence","year":"2025","journal-title":"JAMA Surg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.bja.2022.12.001","article-title":"Effect of perioperative benzodiazepine use on intraoperative awareness and postoperative delirium: A systematic review and meta-analysis of randomised controlled trials and observational studies","volume":"131","author":"Wang","year":"2023","journal-title":"Br. J. Anaesth."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1097\/ALN.0000000000002334","article-title":"Recommendations for the Nomenclature of Cognitive Change Associated with Anaesthesia and Surgery-2018","volume":"129","author":"Evered","year":"2018","journal-title":"Anesthesiology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"147","DOI":"10.14336\/AD.2018.0326","article-title":"Elevated Inflammatory Status and Increased Risk of Chronic Disease in Chronological Aging: Inflamm-aging or Inflamm-inactivity?","volume":"10","author":"Flynn","year":"2019","journal-title":"Aging Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/imcb.12301","article-title":"The role of innate immune responses and neuroinflammation in amyloid accumulation and progression of Alzheimer\u2019s disease","volume":"98","author":"Webers","year":"2020","journal-title":"Immunol. Cell. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1152\/physiolgenomics.00129.2015","article-title":"Age-dependent differences in microglial responses to systemic inflammation are evident as early as middle age","volume":"48","author":"Nikodemova","year":"2016","journal-title":"Physiol. Genom."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.stem.2010.08.014","article-title":"Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis","volume":"7","author":"Sierra","year":"2010","journal-title":"Cell Stem Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1097\/00001756-199406020-00016","article-title":"Effects of ageing on microglia in the normal rat brain: Immunohistochemical observations","volume":"5","author":"Ogura","year":"1994","journal-title":"Neuroreport"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"E1896","DOI":"10.1073\/pnas.1800165115","article-title":"Normal aging induces A1-like astrocyte reactivity","volume":"115","author":"Clarke","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/npp.2016.185","article-title":"Microglia Priming with Aging and Stress","volume":"42","author":"Niraula","year":"2017","journal-title":"Neuropsychopharmacology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.tins.2013.12.001","article-title":"The human side of microglia","volume":"37","author":"Smith","year":"2014","journal-title":"Trends Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1111\/j.1532-5415.2008.01851.x","article-title":"Time-course of cytokines during delirium in elderly patients with hip fractures","volume":"56","author":"Korevaar","year":"2008","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s00540-023-03273-6","article-title":"Association between preoperative neutrophil-lymphocyte ratio, uric acid, and postoperative delirium in elderly patients undergoing degenerative spine surgery","volume":"38","author":"Kato","year":"2024","journal-title":"J. Anesth."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.jpsychores.2014.06.014","article-title":"Cerebrospinal fluid markers of neuroinflammation in delirium: A role for interleukin-1\u03b2 in delirium after hip fracture","volume":"77","author":"Cape","year":"2014","journal-title":"J. Psychosom. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1038\/s41380-022-01878-z","article-title":"Neuroinflammation is independently associated with brain network dysfunction in Alzheimer\u2019s disease","volume":"28","author":"Leng","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1093\/brain\/awaa088","article-title":"Microglial activation and tau burden predict cognitive decline in Alzheimer\u2019s disease","volume":"143","author":"Malpetti","year":"2020","journal-title":"Brain"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7218","DOI":"10.1523\/JNEUROSCI.2574-18.2019","article-title":"Neuroinflammation and Functional Connectivity in Alzheimer\u2019s Disease: Interactive Influences on Cognitive Performance","volume":"39","author":"Passamonti","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"101854","DOI":"10.1016\/j.arr.2023.101854","article-title":"Does oxidative stress shorten telomeres in vivo? A meta-analysis","volume":"85","author":"Armstrong","year":"2023","journal-title":"Ageing Res. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1038\/s41386-020-00863-w","article-title":"Telomere length and human hippocampal neurogenesis","volume":"45","author":"Palmos","year":"2020","journal-title":"Neuropsychopharmacology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2859","DOI":"10.1002\/jnr.22450","article-title":"Deficiency of telomerase activity aggravates the blood-brain barrier disruption and neuroinflammatory responses in a model of experimental stroke","volume":"88","author":"Zhang","year":"2010","journal-title":"J. Neurosci. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"527658","DOI":"10.3389\/fnagi.2020.527658","article-title":"The Association Between Leukocyte Telomere Length and Cognitive Performance Among the American Elderly","volume":"12","author":"Linghui","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1038\/nature02661","article-title":"Gene regulation and DNA damage in the ageing human brain","volume":"429","author":"Lu","year":"2004","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"7466","DOI":"10.1093\/nar\/gkm756","article-title":"Changes in DNA repair during aging","volume":"35","author":"Gorbunova","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.mrfmmm.2016.02.004","article-title":"DNA double strand break repair, aging and the chromatin connection","volume":"788","author":"Gorbunova","year":"2016","journal-title":"Mutat. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e13905","DOI":"10.1111\/acel.13905","article-title":"The role of aging and brain-derived neurotrophic factor signaling in expression of base excision repair genes in the human brain","volume":"22","author":"Lautrup","year":"2023","journal-title":"Aging Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.neurobiolaging.2021.07.014","article-title":"Emerging roles of oxidative stress in brain aging and Alzheimer\u2019s disease","volume":"107","author":"Cotman","year":"2021","journal-title":"Neurobiol. Aging"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.3233\/JAD-161088","article-title":"Oxidative Stress, Synaptic Dysfunction, and Alzheimer\u2019s Disease","volume":"57","author":"Trushina","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1196\/annals.1427.015","article-title":"The role of mitochondria in reactive oxygen species metabolism and signaling","volume":"1147","author":"Starkov","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1089\/ars.2006.8.2021","article-title":"Protein oxidation and lipid peroxidation in brain of subjects with Alzheimer\u2019s disease: Insights into mechanism of neurodegeneration from redox proteomics","volume":"8","author":"Sultana","year":"2006","journal-title":"Antioxid. Redox Signal."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1016\/j.cmet.2018.05.011","article-title":"Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States","volume":"27","author":"Mattson","year":"2018","journal-title":"Cell Metab."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"931536","DOI":"10.3389\/fnagi.2022.931536","article-title":"Normal Aging Induces Changes in the Brain and Neurodegeneration Progress: Review of the Structural, Biochemical, Metabolic, Cellular, and Molecular Changes","volume":"14","author":"Lee","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"6021","DOI":"10.1038\/s41467-021-26310-y","article-title":"A metabolome atlas of the aging mouse brain","volume":"12","author":"Ding","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"15","DOI":"10.3389\/fnagi.2019.00015","article-title":"Links Between Metabolic and Structural Changes in the Brain of Cognitively Normal Older Adults: A 4-Year Longitudinal Follow-Up","volume":"11","author":"Castellano","year":"2019","journal-title":"Front. Aging Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/nrn3200","article-title":"The ageing cortical synapse: Hallmarks and implications for cognitive decline","volume":"13","author":"Morrison","year":"2012","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/nrn1809","article-title":"Neural plasticity in the ageing brain","volume":"7","author":"Burke","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.neurobiolaging.2024.05.013","article-title":"Testing the structural disconnection hypothesis: Myelin content correlates with memory in healthy aging","volume":"141","author":"Thomas","year":"2024","journal-title":"Neurobiol. Aging"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Abdelhamid, R.F., and Nagano, S. (2023). Crosstalk between Oxidative Stress and Aging in Neurodegeneration Disorders. Cells, 12.","DOI":"10.3390\/cells12050753"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Liu, Y., Yang, W., Xue, J., Chen, J., Liu, S., Zhang, S., Zhang, X., Gu, X., Dong, Y., and Qiu, P. (2023). Neuroinflammation: The central enabler of postoperative cognitive dysfunction. Biomed. Pharmacother., 167.","DOI":"10.1016\/j.biopha.2023.115582"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"20518","DOI":"10.1073\/pnas.1014557107","article-title":"Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline","volume":"107","author":"Terrando","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1016\/j.bbi.2012.06.004","article-title":"Thinking through postoperative cognitive dysfunction: How to bridge the gap between clinical and pre-clinical perspectives","volume":"26","author":"Hovens","year":"2012","journal-title":"Brain Behav. Immun."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Yang, J., Dong, H.Q., Liu, Y.H., Ji, M.H., Zhang, X., Dai, H.Y., Sun, Z.C., Liu, L., Zhou, J., and Sha, H.H. (2022). Laparotomy-Induced Peripheral Inflammation Activates NR2B Receptors on the Brain Mast Cells and Results in Neuroinflammation in a Vagus Nerve-Dependent Manner. Front. Cell. Neurosci., 16.","DOI":"10.3389\/fncel.2022.771156"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1177\/1073858416687249","article-title":"Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons","volume":"23","author":"Skaper","year":"2017","journal-title":"Neuroscientist"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"112290","DOI":"10.1016\/j.intimp.2024.112290","article-title":"Anesthesia\/surgery activate MMP9 leading to blood-brain barrier disruption, triggering neuroinflammation and POD-like behavior in aged mice","volume":"135","author":"Hu","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s12916-022-02705-6","article-title":"Prolonged anesthesia induces neuroinflammation and complement-mediated microglial synaptic elimination involved in neurocognitive dysfunction and anxiety-like behaviors","volume":"21","author":"Xu","year":"2023","journal-title":"BMC Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.neuron.2014.02.040","article-title":"Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain","volume":"82","author":"Elmore","year":"2014","journal-title":"Neuron"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1213\/ANE.0000000000000989","article-title":"Intraoperative Electroencephalogram Suppression Predicts Postoperative Delirium","volume":"122","author":"Fritz","year":"2016","journal-title":"Anesth. Analg."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1242\/jcs.171017","article-title":"Mitochondrial dynamics in neuronal injury, development and plasticity","volume":"130","author":"Flippo","year":"2017","journal-title":"J. Cell Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1080\/13510002.2021.1891808","article-title":"Contribution of oxidative stress in the mechanisms of postoperative complications and multiple organ dysfunction syndrome","volume":"26","author":"Rodrigo","year":"2021","journal-title":"Redox Rep."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1007\/s00210-022-02338-9","article-title":"Inhibition of mitochondrial respiration by general anesthetic drugs","volume":"396","author":"Fedorov","year":"2023","journal-title":"Naunyn. Schmiedebergs Arch. Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"844","DOI":"10.18632\/aging.102659","article-title":"Surgery\/Anesthesia disturbs mitochondrial fission\/fusion dynamics in the brain of aged mice with postoperative delirium","volume":"12","author":"Lu","year":"2020","journal-title":"Aging"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e2023676118","DOI":"10.1073\/pnas.2023676118","article-title":"Prolonged anesthesia alters brain synaptic architecture","volume":"118","author":"Wenzel","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"505","DOI":"10.3233\/JAD-161268","article-title":"Anesthesia\/Surgery Induces Cognitive Impairment in Female Alzheimer\u2019s Disease Transgenic Mice","volume":"57","author":"Zhang","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Colucci-D\u2019Amato, L., Speranza, L., and Volpicelli, F. (2020). Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21207777"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s11658-024-00595-5","article-title":"Impaired synaptic plasticity and decreased glutamatergic neuron excitability induced by SIRT1\/BDNF downregulation in the hippocampal CA1 region are involved in postoperative cognitive dysfunction","volume":"29","author":"Wu","year":"2024","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.neuron.2014.01.028","article-title":"SIRT1 in neurodevelopment and brain senescence","volume":"81","author":"Herskovits","year":"2014","journal-title":"Neuron"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1038\/nature09271","article-title":"A novel pathway regulates memory and plasticity via SIRT1 and miR-134","volume":"466","author":"Gao","year":"2010","journal-title":"Nature"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1002\/dneu.22562","article-title":"Compartment-specific dynamics and functions of autophagy in neurons","volume":"78","author":"Kulkarni","year":"2018","journal-title":"Dev. Neurobiol."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Gao, S., Zhang, S., Zhou, H., Tao, X., Ni, Y., Pei, D., Kang, S., Yan, W., and Lu, J. (2021). Role of mTOR-Regulated Autophagy in Synaptic Plasticity Related Proteins Downregulation and the Reference Memory Deficits Induced by Anesthesia\/Surgery in Aged Mice. Front. Aging Neurosci., 13.","DOI":"10.3389\/fnagi.2021.628541"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/nature07672","article-title":"Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals","volume":"458","author":"Guttman","year":"2009","journal-title":"Nature"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1126\/science.1138341","article-title":"RNA maps reveal new RNA classes and a possible function for pervasive transcription","volume":"316","author":"Kapranov","year":"2007","journal-title":"Science"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"4511","DOI":"10.1038\/s41380-020-0662-3","article-title":"LncRNA-AC006129.1 reactivates a SOCS3-mediated anti-inflammatory response through DNA methylation-mediated CIC downregulation in schizophrenia","volume":"26","author":"Ni","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.brainresbull.2013.06.001","article-title":"Roles of long noncoding RNAs in brain development, functional diversification and neurodegenerative diseases","volume":"97","author":"Wu","year":"2013","journal-title":"Brain Res. Bull."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e17775","DOI":"10.7717\/peerj.17775","article-title":"The role of lncRNAs related ceRNA regulatory network in multiple hippocampal pathological processes during the development of perioperative neurocognitive disorders","volume":"12","author":"Zhou","year":"2024","journal-title":"PeerJ"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3082","DOI":"10.1038\/emboj.2010.199","article-title":"A long nuclear-retained non-coding RNA regulates synaptogenesis by modulating gene expression","volume":"29","author":"Bernard","year":"2010","journal-title":"EMBO J."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"120652","DOI":"10.1016\/j.lfs.2022.120652","article-title":"Long non-coding RNA MALAT1 protects against Abeta(1-42) induced toxicity by regulating the expression of receptor tyrosine kinase EPHA2 via quenching miR-200a\/26a\/26b in Alzheimer\u2019s disease","volume":"302","author":"Chanda","year":"2022","journal-title":"Life Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1007\/s11011-016-9838-6","article-title":"Aberrantly expressed long noncoding RNAs are involved in sevoflurane-induced developing hippocampal neuronal apoptosis: A microarray related study","volume":"31","author":"Chen","year":"2016","journal-title":"Metab. Brain Dis."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/S0896-6273(01)00238-0","article-title":"Induction of BIM, a proapoptotic BH3-only BCL-2 family member, is critical for neuronal apoptosis","volume":"29","author":"Putcha","year":"2001","journal-title":"Neuron"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Qu, Y., Li, H., Shi, C., Qian, M., Yang, N., Wang, L., Gao, X., and Ni, C. (2020). lncRNAs Are Involved in Sevoflurane Anesthesia-Related Brain Function Modulation through Affecting Mitochondrial Function and Aging Process. BioMed Res. Int., 2020.","DOI":"10.1155\/2020\/8841511"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1097\/ALN.0b013e318242a48c","article-title":"Propofol neurotoxicity is mediated by p75 neurotrophin receptor activation","volume":"116","author":"Pearn","year":"2012","journal-title":"Anesthesiology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1097\/ALN.0000000000000484","article-title":"Possible pathogenic mechanism of propofol infusion syndrome involves coenzyme q","volume":"122","author":"Vanlander","year":"2015","journal-title":"Anesthesiology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1177\/147323001003800403","article-title":"Remifentanil reduces the incidence of post-operative delirium","volume":"38","author":"Radtke","year":"2010","journal-title":"J. Int. Med. Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s11916-020-00853-z","article-title":"Dexmedetomidine in Enhanced Recovery After Surgery (ERAS) Protocols for Postoperative Pain","volume":"24","author":"Kaye","year":"2020","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3328","DOI":"10.4081\/ejh.2022.3328","article-title":"Sufentanil alleviates cerebral ischemia-reperfusion injury by inhibiting inflammation and protecting the blood-brain barrier in rats","volume":"66","author":"Wang","year":"2022","journal-title":"Eur. J. Histochem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1007\/s40520-019-01123-8","article-title":"Comparative effects of fentanyl versus sufentanil on cerebral oxygen saturation and postoperative cognitive function in elderly patients undergoing open surgery","volume":"31","author":"Zhang","year":"2019","journal-title":"Aging Clin. Exp. Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1001\/jama.2021.22647","article-title":"Effect of Regional vs General Anesthesia on Incidence of Postoperative Delirium in Older Patients Undergoing Hip Fracture Surgery: The RAGA Randomized Trial","volume":"327","author":"Li","year":"2022","journal-title":"JAMA"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1186\/s12871-023-02196-9","article-title":"Neuraxial versus general anesthesia in elderly patients undergoing hip fracture surgery and the incidence of postoperative delirium: A systematic review and stratified meta-analysis","volume":"23","author":"Cheung","year":"2023","journal-title":"BMC Anesthesiol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"147ra111","DOI":"10.1126\/scitranslmed.3003748","article-title":"A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta","volume":"4","author":"Iliff","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1126\/science.1240514","article-title":"Neuroscience. Garbage truck of the brain","volume":"340","author":"Nedergaard","year":"2013","journal-title":"Science"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"206","DOI":"10.7555\/JBR.37.20230264","article-title":"Functional aspects of the brain lymphatic drainage system in aging and neurodegenerative diseases","volume":"38","author":"Chen","year":"2024","journal-title":"J. Biomed. Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1177\/0271678X241237073","article-title":"Long-term isoflurane anesthesia induces cognitive deficits via AQP4 depolarization mediated blunted glymphatic inflammatory proteins clearance","volume":"44","author":"Dong","year":"2024","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/s41419-024-06845-w","article-title":"Dexmedetomidine improves the circulatory dysfunction of the glymphatic system induced by sevoflurane through the PI3K\/AKT\/DeltaFosB\/AQP4 pathway in young mice","volume":"15","author":"Wang","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"eaav5447","DOI":"10.1126\/sciadv.aav5447","article-title":"Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia","volume":"5","author":"Hablitz","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1097\/ALN.0000000000005360","article-title":"Impaired Macroscopic Cerebrospinal Fluid Flow by Sevoflurane in Humans during and after Anesthesia","volume":"142","author":"Zimmermann","year":"2025","journal-title":"Anesthesiology"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1038\/s41593-024-01638-y","article-title":"Brain clearance is reduced during sleep and anesthesia","volume":"27","author":"Miao","year":"2024","journal-title":"Nat. Neurosci."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/nri2015","article-title":"Systemic infections and inflammation affect chronic neurodegeneration","volume":"7","author":"Perry","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1097\/ALN.0000000000001888","article-title":"Anesthesia with Dexmedetomidine and Low-dose Isoflurane Increases Solute Transport via the Glymphatic Pathway in Rat Brain When Compared with High-dose Isoflurane","volume":"127","author":"Benveniste","year":"2017","journal-title":"Anesthesiology"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1126\/science.aax5440","article-title":"Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep","volume":"366","author":"Fultz","year":"2019","journal-title":"Science"},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Zeng, H., Li, Z., He, J., and Fu, W. (2019). Dexmedetomidine for the prevention of postoperative delirium in elderly patients undergoing noncardiac surgery: A meta-analysis of randomized controlled trials. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0218088"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1186\/s12871-025-03264-y","article-title":"Dexmedetomidine for the prevention of postoperative delirium in patients undergoing cardiac surgery: A systematic review and meta-analysis with trial sequential analysis","volume":"25","author":"Zhong","year":"2025","journal-title":"BMC Anesthesiol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/s41572-020-00223-4","article-title":"Delirium","volume":"6","author":"Wilson","year":"2020","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"The American Geriatrics Society Expert Panel on Postoperative Delirium in Older Adults (2015). American Geriatrics Society abstracted clinical practice guideline for postoperative delirium in older adults. J. Am. Geriatr. Soc., 63, 142\u2013150.","DOI":"10.1111\/jgs.13281"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"42","DOI":"10.33545\/26643766.2024.v7.i2a.475","article-title":"Effect of dexmedetomidine infusion on incidence of postoperative delirium in elderly patients undergoing total hip arthroplasty: Randomised controlled double-blinded trial","volume":"7","year":"2024","journal-title":"Int. J. Med. Anesthesiol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1016\/S0140-6736(16)30580-3","article-title":"Dexmedetomidine for prevention of delirium in elderly patients after non-cardiac surgery: A randomised, double-blind, placebo-controlled trial","volume":"388","author":"Su","year":"2016","journal-title":"Lancet"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"2506","DOI":"10.1056\/NEJMoa1904710","article-title":"Early Sedation with Dexmedetomidine in Critically Ill Patients","volume":"380","author":"Shehabi","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"546","DOI":"10.4097\/kja.24325","article-title":"The effect of non-steroidal anti-inflammatory drugs on postoperative delirium: A meta-analysis","volume":"77","author":"Kim","year":"2024","journal-title":"Korean J. Anesthesiol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1213\/ANE.0000000000006424","article-title":"The Perioperative Frontal Relative Ratio of the Alpha Power of Electroencephalography for Predicting Postoperative Delirium After Highly Invasive Surgery: A Prospective Observational Study","volume":"137","author":"Kinoshita","year":"2023","journal-title":"Anesth. Analg."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"111343","DOI":"10.1016\/j.jclinane.2023.111343","article-title":"Lower alpha frequency of intraoperative frontal EEG is associated with postoperative delirium: A secondary propensity-matched analysis","volume":"93","author":"Hight","year":"2024","journal-title":"J. Clin. Anesth."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1097\/ALN.0000000000002323","article-title":"Processed Electroencephalogram Monitoring and Postoperative Delirium: A Systematic Review and Meta-analysis","volume":"129","author":"MacKenzie","year":"2018","journal-title":"Anesthesiology"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1001\/jama.2018.22005","article-title":"Effect of Electroencephalography-Guided Anesthetic Administration on Postoperative Delirium Among Older Adults Undergoing Major Surgery: The ENGAGES Randomized Clinical Trial","volume":"321","author":"Wildes","year":"2019","journal-title":"JAMA"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"zsaa167","DOI":"10.1093\/sleep\/zsaa167","article-title":"Dexmedetomidine-induced deep sedation mimics non-rapid eye movement stage 3 sleep: Large-scale validation using machine learning","volume":"44","author":"Ramaswamy","year":"2021","journal-title":"Sleep"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1213\/ANE.0000000000007079","article-title":"Electroencephalographic Measures of Delirium in the Perioperative Setting: A Systematic Review","volume":"140","author":"Bruzzone","year":"2025","journal-title":"Anesth. Analg."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1007\/s40520-015-0492-3","article-title":"Dexmedetomidine reduces postoperative delirium after joint replacement in elderly patients with mild cognitive impairment","volume":"28","author":"Liu","year":"2016","journal-title":"Aging Clin. Exp. Res."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Zhang, S.S., Meng, F.G., Rong, Y.Y., Zhang, Y.W., and Liu, H.Q. (2025). Dexmedetomidine and the glymphatic system: A new perspective in managing postoperative cognitive dysfunction. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1648308"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10272\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T01:20:19Z","timestamp":1761182419000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10272"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,22]]},"references-count":128,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262110272"],"URL":"https:\/\/doi.org\/10.3390\/ijms262110272","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,22]]}}}