{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:26Z","timestamp":1787028566265,"version":"build-2736575974"},"reference-count":73,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,14]],"date-time":"2025-06-14T00:00:00Z","timestamp":1749859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hallym University Research Fund"},{"name":"Hana Pharmacy (Seoul, Republic of Korea)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Perioperative neurocognitive disorder (PND) is a concern following anesthesia, particularly in individuals at risk for Alzheimer\u2019s disease (AD). This study compared the cognitive and pathological effects of propofol and remimazolam in a mouse model with AD following surgery. Five-month-old male ApoE4-KI mice underwent abdominal surgery under either propofol (170 mg\/kg) or remimazolam (85 mg\/kg) anesthesia. Cognitive function was assessed using the Morris water maze and Y-maze, and neuronal apoptosis and amyloid-beta (A\u03b2) deposition in the CA3 and dentate gyrus (DG) of the hippocampus were evaluated preoperatively and at 2, 4, and 7 days postoperatively. Both groups showed similar postoperative cognitive functions, with increased relative escape latency at day 2 and decreased relative spontaneous alternation at days 4 and 7. However, the neuropathological analysis revealed that propofol-induced significantly more neuronal death in the CA3 (days 4 and 7) and DG (days 2, 4, and 7), and greater A\u03b2 accumulation in the CA3 (days 2 and 4) and DG (days 2 and 7) compared to remimazolam (p &lt; 0.05). Propofol was associated with more pronounced neuropathologic changes in the hippocampus compared to remimazolam. These findings suggest remimazolam may be a safer anesthetic for patients at risk for neurodegenerative disorders, as it is associated with less severe hippocampal pathology, which is characteristic of AD.<\/jats:p>","DOI":"10.3390\/ijms26125718","type":"journal-article","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T09:51:22Z","timestamp":1750067482000},"page":"5718","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Comparison of Cognitive Deterioration Between Propofol and Remimazolam Anesthesia in ApoE4 Knock-In Mouse Model"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3818-2239","authenticated-orcid":false,"given":"Jong-Ho","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Chuncheon Sacred Heart Hospital, College of Medicine, Hallym University, Chuncheon 24253, Republic of Korea"},{"name":"Institute of New Frontier Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songyi","family":"Park","sequence":"additional","affiliation":[{"name":"Institute of New Frontier Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harry","family":"Jung","sequence":"additional","affiliation":[{"name":"Institute of New Frontier Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Hae","family":"Lee","sequence":"additional","affiliation":[{"name":"Institute of New Frontier Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Seo","family":"Lee","sequence":"additional","affiliation":[{"name":"Institute of New Frontier Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2656-9222","authenticated-orcid":false,"given":"Jae-Jun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Chuncheon Sacred Heart Hospital, College of Medicine, Hallym University, Chuncheon 24253, Republic of Korea"},{"name":"Institute of New Frontier Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong-Hee","family":"Sohn","sequence":"additional","affiliation":[{"name":"Institute of New Frontier Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea"},{"name":"Department of Neurology, Chuncheon Sacred Heart Hospital, College of Medicine, Hallym University, Chuncheon 24253, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,14]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/S0140-6736(97)07382-0","article-title":"Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction","volume":"351","author":"Moller","year":"1998","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1111\/anae.13308","article-title":"Peri-operative cognitive dysfunction and protection","volume":"71","author":"Steinmetz","year":"2016","journal-title":"Anaesthesia"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.exger.2006.01.014","article-title":"Alzheimer\u2019s disease and post-operative cognitive dysfunction","volume":"41","author":"Xie","year":"2006","journal-title":"Exp. Gerontol."},{"key":"ref_5","doi-asserted-by":"crossref","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":"ref_6","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1097\/ALN.0b013e318195b569","article-title":"Long-term consequences of postoperative cognitive dysfunction","volume":"110","author":"Steinmetz","year":"2009","journal-title":"Anesthesiology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"20518","DOI":"10.1073\/pnas.1014557107","article-title":"Tumor necrosis factor-\u03b1 triggers a cytokine cascade yielding postoperative cognitive decline","volume":"107","author":"Terrando","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6232","DOI":"10.2174\/138161212803832344","article-title":"Neurotoxicity of general anesthetics: An update","volume":"18","author":"Vlisides","year":"2012","journal-title":"Curr. Pharm. Des."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1097\/00000542-200410000-00009","article-title":"Apolipoprotein E genotype and cognitive dysfunction after noncardiac surgery","volume":"101","author":"Abildstrom","year":"2004","journal-title":"Anesthesiology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1111\/j.1365-2044.2010.06244.x","article-title":"Anaesthetics and postoperative cognitive dysfunction: A pathological mechanism mimicking Alzheimer\u2019s disease","volume":"65","author":"Fodale","year":"2010","journal-title":"Anaesthesia"},{"key":"ref_11","first-page":"711","article-title":"Exposure to general anesthesia and the risk of dementia","volume":"8","author":"Yang","year":"2015","journal-title":"J. Pain Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1126\/science.8346443","article-title":"Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer\u2019s disease in late onset families","volume":"261","author":"Corder","year":"1993","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/nrneurol.2012.263","article-title":"Apolipoprotein E and Alzheimer disease: Risk, mechanisms and therapy","volume":"9","author":"Liu","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1001\/jama.1997.03550160069041","article-title":"Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium","volume":"278","author":"Farrer","year":"1997","journal-title":"Jama"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hsiao, W.J., Chen, C.Y., Kang, Y.N., Hu, C.J., Chen, C.H., Lin, P.L., and Lin, Y.C. (2023). Apolipoprotein E4 allele is genetically associated with risk of the short- and medium-term postoperative cognitive dysfunction: A meta-analysis and trial sequential analysis. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0282214"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S1474-4422(10)70325-2","article-title":"Apolipoprotein E in Alzheimer\u2019s disease and other neurological disorders","volume":"10","author":"Verghese","year":"2011","journal-title":"Lancet Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Fernandez, C.G., Hamby, M.E., McReynolds, M.L., and Ray, W.J. (2019). The Role of APOE4 in Disrupting the Homeostatic Functions of Astrocytes and Microglia in Aging and Alzheimer\u2019s Disease. Front. Aging Neurosci., 11.","DOI":"10.3389\/fnagi.2019.00014"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/s41392-023-01484-7","article-title":"Amyloid \u03b2-based therapy for Alzheimer\u2019s disease: Challenges, successes and future","volume":"8","author":"Zhang","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1111\/jnc.15904","article-title":"Detection of early Alzheimer\u2019s disease-like molecular alterations in a mouse model expressing human ApoE4","volume":"166","author":"Rai","year":"2023","journal-title":"J. Neurochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1750-1326-8-16","article-title":"ApoE4 induces A\u03b242, tau, and neuronal pathology in the hippocampus of young targeted replacement apoE4 mice","volume":"8","author":"Liraz","year":"2013","journal-title":"Mol. Neurodegener."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kim, J.H., Jung, H., Lee, Y., and Sohn, J.H. (2021). Surgery Performed Under Propofol Anesthesia Induces Cognitive Impairment and Amyloid Pathology in ApoE4 Knock-In Mouse Model. Front. Aging Neurosci., 13.","DOI":"10.3389\/fnagi.2021.658860"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"115123","DOI":"10.1016\/j.bbr.2024.115123","article-title":"Cognitive deficits in human ApoE4 knock-in mice: A systematic review and meta-analysis","volume":"471","author":"Alferink","year":"2024","journal-title":"Behav. Brain Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1097\/ALN.0b013e31823d0c36","article-title":"An allosteric coagonist model for propofol effects on \u03b11\u03b22\u03b32L \u03b3-aminobutyric acid type A receptors","volume":"116","author":"Ruesch","year":"2012","journal-title":"Anesthesiology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1021\/acsptsci.4c00745","article-title":"Propofol: Current Updates, Challenges, and Strategies for Improved Self-Nanoemulsifying Formulation","volume":"8","author":"Kazi","year":"2025","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1007\/s40262-018-0672-3","article-title":"Clinical Pharmacokinetics and Pharmacodynamics of Propofol","volume":"57","author":"Sahinovic","year":"2018","journal-title":"Clin. Pharmacokinet."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Whittington, R.A., Vir\u00e1g, L., Marcouiller, F., Papon, M.A., El Khoury, N.B., Julien, C., Morin, F., Emala, C.W., and Planel, E. (2011). Propofol directly increases tau phosphorylation. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016648"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.3233\/JAD-151190","article-title":"The Effect of Propofol Versus Isoflurane Anesthesia on Human Cerebrospinal Fluid Markers of Alzheimer\u2019s Disease: Results of a Randomized Trial","volume":"52","author":"Berger","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1093\/bja\/aew397","article-title":"Effects of propofol and surgery on neuropathology and cognition in the 3xTgAD Alzheimer transgenic mouse model","volume":"119","author":"Mardini","year":"2017","journal-title":"Br. J. Anaesth."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1538\/expanim.21-0120","article-title":"Morris water maze: A versatile and pertinent tool for assessing spatial learning and memory","volume":"71","author":"Othman","year":"2022","journal-title":"Exp. Anim."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Prieur, E.A.K., and Jadavji, N.M. (2019). Assessing Spatial Working Memory Using the Spontaneous Alternation Y-maze Test in Aged Male Mice. Bio-Protocol, 9.","DOI":"10.21769\/BioProtoc.3162"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"153","DOI":"10.2147\/IJGM.S242230","article-title":"Reducing Perioperative Neurocognitive Disorders (PND) Through Depth of Anesthesia Monitoring: A Critical Review","volume":"14","author":"Evered","year":"2021","journal-title":"Int. J. Gen. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s40265-020-01299-8","article-title":"Remimazolam: First Approval","volume":"80","author":"Keam","year":"2020","journal-title":"Drugs"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3957","DOI":"10.2147\/DDDT.S384155","article-title":"Remimazolam: An Updated Review of a New Sedative and Anaesthetic","volume":"16","author":"Hu","year":"2022","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Jhuang, B.J., Yeh, B.H., Huang, Y.T., and Lai, P.C. (2021). Efficacy and Safety of Remimazolam for Procedural Sedation: A Meta-Analysis of Randomized Controlled Trials with Trial Sequential Analysis. Front. Med., 8.","DOI":"10.3389\/fmed.2021.641866"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1515\/tnsci-2022-0220","article-title":"Remimazolam induced cognitive dysfunction in mice via glutamate excitotoxicity","volume":"13","author":"Zhou","year":"2022","journal-title":"Transl. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1213\/00000539-199607000-00027","article-title":"Propofol and ethanol produce additive hypnotic and anesthetic effects in the mouse","volume":"83","author":"Garfield","year":"1996","journal-title":"Anesth. Analg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1093\/bja\/64.6.734","article-title":"Potency of propofol for loss of consciousness after a single dose","volume":"64","author":"Leslie","year":"1990","journal-title":"Br. J. Anaesth."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1186\/s40001-024-02142-6","article-title":"Effect of remimazolam toluene sulfonate on the cognitive function of juveniles and its mechanism of action","volume":"29","author":"Shi","year":"2024","journal-title":"Eur. J. Med. Res."},{"key":"ref_39","first-page":"12","article-title":"Intraperitoneal Route of Drug Administration: Should it Be Used in Experimental Animal Studies?","volume":"37","author":"Archie","year":"2019","journal-title":"Pharm. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1097\/01.anes.0000267503.85085.c0","article-title":"CNS 7056: A novel ultra-short-acting Benzodiazepine","volume":"107","author":"Kilpatrick","year":"2007","journal-title":"Anesthesiology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1111\/anae.15613","article-title":"Acute peri-operative neurocognitive disorders: A narrative review","volume":"77","author":"Evered","year":"2022","journal-title":"Anaesthesia"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3233\/JAD-132258","article-title":"The impact of surgery and anesthesia on post-operative cognitive decline and Alzheimer\u2019s disease development: Biomarkers and preventive strategies","volume":"41","author":"Kapila","year":"2014","journal-title":"J. Alzheimers Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S1474-4422(09)70299-6","article-title":"Hypothetical model of dynamic biomarkers of the Alzheimer\u2019s pathological cascade","volume":"9","author":"Jack","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"369","DOI":"10.3233\/JAD-2009-1173","article-title":"Mini-forum: Roles of amyloid-\u03b2 and tau phosphorylation in neuronal repair and protection","volume":"18","author":"Bissette","year":"2009","journal-title":"J. Alzheimers Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2633","DOI":"10.1016\/j.bbamem.2008.07.002","article-title":"A\u03b2 peptide interactions with isoflurane, propofol, thiopental and combined thiopental with halothane: A NMR study","volume":"1778","author":"Mandal","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1002\/ana.21548","article-title":"The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid \u03b2-protein level in vivo","volume":"64","author":"Xie","year":"2008","journal-title":"Ann. Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1097\/00000542-200605000-00015","article-title":"The common inhalation anesthetic isoflurane induces apoptosis and increases amyloid \u03b2 protein levels","volume":"104","author":"Xie","year":"2006","journal-title":"Anesthesiology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1523\/JNEUROSCI.5320-06.2007","article-title":"The inhalation anesthetic isoflurane induces a vicious cycle of apoptosis and amyloid \u03b2-protein accumulation","volume":"27","author":"Xie","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s12974-021-02089-z","article-title":"Sirtuin 3 protects against anesthesia\/surgery-induced cognitive decline in aged mice by suppressing hippocampal neuroinflammation","volume":"18","author":"Liu","year":"2021","journal-title":"J. Neuroinflammation"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1111\/cns.13053","article-title":"SIRT3 activator honokiol ameliorates surgery\/anesthesia-induced cognitive decline in mice through anti-oxidative stress and anti-inflammatory in hippocampus","volume":"25","author":"Ye","year":"2019","journal-title":"CNS Neurosci. Ther."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.neubiorev.2006.07.007","article-title":"Modeling behavioral and neuronal symptoms of Alzheimer\u2019s disease in mice: A role for intraneuronal amyloid","volume":"31","author":"Johansson","year":"2007","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1093\/hmg\/ddh019","article-title":"Mutant presenilins specifically elevate the levels of the 42 residue \u03b2-amyloid peptide in vivo: Evidence for augmentation of a 42-specific \u03b3 secretase","volume":"13","author":"Jankowsky","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/nrn.2016.128","article-title":"Lasting impact of general anaesthesia on the brain: Mechanisms and relevance","volume":"17","author":"Vutskits","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Woodhouse, A., Fernandez-Martos, C.M., Atkinson, R.A.K., Hanson, K.A., Collins, J.M., O\u2019Mara, A.R., Terblanche, N., Skinner, M.W., Vickers, J.C., and King, A.E. (2018). Repeat propofol anesthesia does not exacerbate plaque deposition or synapse loss in APP\/PS1 Alzheimer\u2019s disease mice. BMC Anesthesiol., 18.","DOI":"10.1186\/s12871-018-0509-5"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Chen, Y., Dai, C.L., Wu, Z., Iqbal, K., Liu, F., Zhang, B., and Gong, C.X. (2017). Intranasal Insulin Prevents Anesthesia-Induced Cognitive Impairment and Chronic Neurobehavioral Changes. Front. Aging Neurosci., 9.","DOI":"10.3389\/fnagi.2017.00136"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.neuro.2022.08.003","article-title":"Novel benzodiazepine remimazolam tosylate delays neurodegeneration of aged mice via decreasing tau phosphorylation","volume":"92","author":"Liu","year":"2022","journal-title":"Neurotoxicology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"115268","DOI":"10.1016\/j.bbr.2024.115268","article-title":"Remimazolam attenuates lipopolysaccharide-induced neuroinflammation and cognitive dysfunction","volume":"476","author":"Zhou","year":"2025","journal-title":"Behav. Brain Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1996","DOI":"10.1053\/j.jvca.2023.06.027","article-title":"Propofol Versus Remimazolam on Cognitive Function, Hemodynamics, and Oxygenation During One-Lung Ventilation in Older Patients Undergoing Pulmonary Lobectomy: A Randomized Controlled Trial","volume":"37","author":"Kuang","year":"2023","journal-title":"J. Cardiothorac. Vasc. Anesth."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1111\/jgh.15761","article-title":"Effect of remimazolam tosilate on early cognitive function in elderly patients undergoing upper gastrointestinal endoscopy","volume":"37","author":"Tan","year":"2022","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1007\/s00540-022-03148-2","article-title":"Effect of remimazolam on the incidence of delirium after transcatheter aortic valve implantation under general anesthesia: A retrospective exploratory study","volume":"37","author":"Kaneko","year":"2023","journal-title":"J. Anesth."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"143","DOI":"10.2147\/DDDT.S392569","article-title":"Effect of Remimazolam on Postoperative Delirium in Older Adult Patients Undergoing Orthopedic Surgery: A Prospective Randomized Controlled Clinical Trial","volume":"17","author":"Yang","year":"2023","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1097\/ALN.0000000000000762","article-title":"Brain maturation in neonatal rodents is impeded by sevoflurane anesthesia","volume":"123","author":"Makaryus","year":"2015","journal-title":"Anesthesiology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e1053","DOI":"10.1542\/peds.2011-0351","article-title":"Cognitive and behavioral outcomes after early exposure to anesthesia and surgery","volume":"128","author":"Flick","year":"2011","journal-title":"Pediatrics"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1097\/01.anes.0000344728.34332.5d","article-title":"Early exposure to anesthesia and learning disabilities in a population-based birth cohort","volume":"110","author":"Wilder","year":"2009","journal-title":"Anesthesiology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.jalz.2016.02.002","article-title":"Preclinical Alzheimer\u2019s disease: Definition, natural history, and diagnostic criteria","volume":"12","author":"Dubois","year":"2016","journal-title":"Alzheimers Dement."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.jalz.2011.03.003","article-title":"Toward defining the preclinical stages of Alzheimer\u2019s disease: Recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"Sperling","year":"2011","journal-title":"Alzheimers Dement."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Li, Y., Li, Y.J., Fang, X., Chen, D.Q., Yu, W.Q., and Zhu, Z.Q. (2024). Peripheral inflammation as a potential mechanism and preventive strategy for perioperative neurocognitive disorder under general anesthesia and surgery. Front. Cell Neurosci., 18.","DOI":"10.3389\/fncel.2024.1365448"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/0166-4328(88)90157-X","article-title":"A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data","volume":"31","author":"Ennaceur","year":"1988","journal-title":"Behav. Brain Res."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Steiner, A.R., Rousseau-Blass, F., Schroeter, A., Hartnack, S., and Bettschart-Wolfensberger, R. (2020). Systematic Review: Anaesthetic Protocols and Management as Confounders in Rodent Blood Oxygen Level Dependent Functional Magnetic Resonance Imaging (BOLD fMRI)-Part A: Effects of Changes in Physiological Parameters. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.577119"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.brainresprot.2004.04.001","article-title":"Quantification of sPLA2-induced early and late apoptosis changes in neuronal cell cultures using combined TUNEL and DAPI staining","volume":"13","author":"Daniel","year":"2004","journal-title":"Brain Res. Brain Res. Protoc."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1002\/ana.22082","article-title":"Role of interleukin-1\u03b2 in postoperative cognitive dysfunction","volume":"68","author":"Cibelli","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbr.2004.09.019","article-title":"Human apoE targeted replacement mouse lines: H-apoE4 and h-apoE3 mice differ on spatial memory performance and avoidance behavior","volume":"159","author":"Grootendorst","year":"2005","journal-title":"Behav. Brain Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1111\/j.1471-4159.2010.06608.x","article-title":"Partial reduction of BACE1 improves synaptic plasticity, recent and remote memories in Alzheimer\u2019s disease transgenic mice","volume":"113","author":"Kimura","year":"2010","journal-title":"J. Neurochem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/12\/5718\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:52:06Z","timestamp":1760032326000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/12\/5718"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,14]]},"references-count":73,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["ijms26125718"],"URL":"https:\/\/doi.org\/10.3390\/ijms26125718","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,14]]}}}