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health and economic burden of postoperative delirium. Previous studies have typically used single omics approaches to identify such biomarkers. Preoperative cerebrospinal fluid (CSF) from the Healthier Postoperative Recovery study of adults \u2265 63 years old undergoing elective major orthopedic surgery was used in a matched pair delirium case\u2013no delirium control design. We performed metabolomics and lipidomics, which were combined with our previously reported proteomics results on the same samples. Differential expression, clustering, classification, and systems biology analyses were applied to individual and combined omics datasets. Probabilistic graph models were used to identify an integrated multi-omics interaction network, which included clusters of heterogeneous omics interactions among lipids, metabolites, and proteins. The combined multi-omics signature of 25 molecules attained an AUC of 0.96 [95% CI: 0.85\u20131.00], showing improvement over individual omics-based classification. We conclude that multi-omics integration of preoperative CSF identifies potential risk markers for delirium and generates new insights into the complex pathways associated with delirium. With future validation, this hypotheses-generating study may serve to build robust biomarkers for delirium and improve our understanding of its pathophysiology.<\/jats:p>","DOI":"10.3390\/biom14080924","type":"journal-article","created":{"date-parts":[[2024,8,1]],"date-time":"2024-08-01T12:38:20Z","timestamp":1722515900000},"page":"924","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Integrated Multi-Omics Analysis of Cerebrospinal Fluid in Postoperative Delirium"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3205-5917","authenticated-orcid":false,"given":"Bridget A.","family":"Tripp","sequence":"first","affiliation":[{"name":"Department of Electrical and Computer Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4417-178X","authenticated-orcid":false,"given":"Simon T.","family":"Dillon","sequence":"additional","affiliation":[{"name":"Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA"},{"name":"Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Yuan","sequence":"additional","affiliation":[{"name":"Division of Signal Transduction and Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7450-2589","authenticated-orcid":false,"given":"John M.","family":"Asara","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, MA 02215, USA"},{"name":"Division of Signal Transduction and Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarinnapha M.","family":"Vasunilashorn","sequence":"additional","affiliation":[{"name":"Harvard Medical School, Boston, MA 02215, USA"},{"name":"Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA"},{"name":"Harvard T.H. 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J. Geriatr. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1016\/j.jagp.2013.09.005","article-title":"Neuropathogenesis of delirium: Review of current etiologic theories and common pathways","volume":"21","author":"Maldonado","year":"2013","journal-title":"Am. J. Geriatr. Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1152\/physiol.00011.2010","article-title":"Epithelial pathways in choroid plexus electrolyte transport","volume":"25","author":"Damkier","year":"2010","journal-title":"Physiology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.anorl.2011.03.002","article-title":"Anatomy and physiology of cerebrospinal fluid","volume":"128","author":"Sakka","year":"2011","journal-title":"Eur. Ann. Otorhinolaryngol. Head. Neck Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/nrn3921","article-title":"Development and functions of the choroid plexus-cerebrospinal fluid system","volume":"16","author":"Lun","year":"2015","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.expneurol.2015.07.027","article-title":"A balanced view of the cerebrospinal fluid composition and functions: Focus on adult humans","volume":"273","author":"Spector","year":"2015","journal-title":"Exp. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1093\/chromsci\/bmw167","article-title":"Proteomics: Technologies and their applications","volume":"55","author":"Aslam","year":"2017","journal-title":"J. Chromatogr. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"30.34.31","DOI":"10.1002\/0471142727.mb3004s114","article-title":"Metabolomics by gas chromatography-mass spectrometry: Combined targeted and untargeted profiling","volume":"114","author":"Fiehn","year":"2016","journal-title":"Curr. Protoc. Mol. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/jssc.201700709","article-title":"Mass-spectrometry-based lipidomics","volume":"41","author":"Hu","year":"2018","journal-title":"J. Sep. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.semcdb.2020.08.012","article-title":"The role of lipids in the central nervous system and their pathological implications in amyotrophic lateral sclerosis","volume":"112","author":"Tracey","year":"2021","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Han, Y., Zhang, W., Liu, J., Song, Y., Liu, T., Li, Z., Wang, X., Yang, N., Li, Y., and Han, D. (2020). Metabolomic and lipidomic profiling of preoperative CSF in elderly hip fracture patients with postoperative delirium. Front. Aging Neurosci., 12.","DOI":"10.3389\/fnagi.2020.570210"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1038\/s41598-020-80412-z","article-title":"Targeted metabolomics analysis of postoperative delirium","volume":"11","author":"Tripp","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Watne, L.O., Idland, A.V., Fekkes, D., Raeder, J., Frihagen, F., Ranhoff, A.H., Chaudhry, F.A., Engedal, K., Wyller, T.B., and Hassel, B. (2016). Increased CSF levels of aromatic amino acids in hip fracture patients with delirium suggests higher monoaminergic activity. BMC Geriatr., 16.","DOI":"10.1186\/s12877-016-0324-0"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e477","DOI":"10.1038\/tp.2014.114","article-title":"Quantitative proteomics of delirium cerebrospinal fluid","volume":"4","author":"Poljak","year":"2014","journal-title":"Transl. Psychiatry"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1093\/gerona\/gly036","article-title":"Development of a dynamic multi-protein signature of postoperative delirium","volume":"74","author":"Vasunilashorn","year":"2019","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1093\/gerona\/glaa326","article-title":"Proteome-wide analysis using SOMAscan identifies and validates chitinase-3-like protein 1 as a risk and disease marker of delirium among older adults undergoing major elective surgery","volume":"77","author":"Vasunilashorn","year":"2022","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1097\/SLA.0b013e318298b077","article-title":"Cerebrospinal fluid a\u03b2 to tau ratio and postoperative cognitive change","volume":"258","author":"Xie","year":"2013","journal-title":"Ann. Surg."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1186\/s12974-016-0681-9","article-title":"Perioperative cerebrospinal fluid and plasma inflammatory markers after orthopedic surgery","volume":"13","author":"Hirsch","year":"2016","journal-title":"J. Neuroinflammation"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Lin, X., Tang, J., Liu, C., Li, X., Cao, X., Wang, B., Dong, R., Xu, W., Yu, X., and Wang, M. (2020). Cerebrospinal fluid cholinergic biomarkers are associated with postoperative delirium in elderly patients undergoing Total hip\/knee replacement: A prospective cohort study. BMC Anesthesiol., 20.","DOI":"10.1186\/s12871-020-01166-9"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/0022-3956(75)90026-6","article-title":"\u201cMini-mental state\u201d. A practical method for grading the cognitive state of patients for the clinician","volume":"12","author":"Folstein","year":"1975","journal-title":"J. Psychiatr. Res."},{"key":"ref_24","first-page":"314","article-title":"The modified mini-mental state (3MS) examination","volume":"48","author":"Teng","year":"1987","journal-title":"J. Clin. Psychiatry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"941","DOI":"10.7326\/0003-4819-113-12-941","article-title":"Clarifying confusion: The confusion assessment method. A new method for detection of delirium","volume":"113","author":"Inouye","year":"1990","journal-title":"Ann. Intern. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1177\/002383099200500103","article-title":"The delirium symptom interview: An interview for the detection of delirium symptoms in hospitalized patients","volume":"5","author":"Albert","year":"1992","journal-title":"J. Geriatr. Psychiatry Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/j.jalz.2016.03.005","article-title":"The short-term and long-term relationship between delirium and cognitive trajectory in older surgical patients","volume":"12","author":"Inouye","year":"2016","journal-title":"Alzheimers Dement."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1080\/01621459.1989.10478868","article-title":"Optimal matching for observational studies","volume":"84","author":"Rosenbaum","year":"1989","journal-title":"J. Am. Stat. Assoc."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ngo, L.H., Inouye, S.K., Jones, R.N., Travison, T.G., Libermann, T.A., Dillon, S.T., Kuchel, G.A., Vasunilashorn, S.M., Alsop, D.C., and Marcantonio, E.R. (2017). Methodologic considerations in the design and analysis of nested case-control studies: Association between cytokines and postoperative delirium. BMC Med. Res. Methodol., 17.","DOI":"10.1186\/s12874-017-0359-8"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/s41597-019-0324-y","article-title":"Blood proteome profiling using aptamer-based technology for rejection biomarker discovery in transplantation","volume":"6","author":"Shubin","year":"2019","journal-title":"Sci. Data"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Dillon, S.T., Vasunilashorn, S.M., Otu, H.H., Ngo, L., Fong, T., Gu, X., Cavallari, M., Touroutoglou, A., Shafi, M., and Inouye, S.K. (2023). Aptamer-based proteomics measuring preoperative cerebrospinal fluid protein alterations associated with postoperative delirium. Biomolecules, 13.","DOI":"10.3390\/biom13091395"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.nbt.2011.11.016","article-title":"Advances in human proteomics at high scale with the SOMAscan proteomics platform","volume":"29","author":"Gold","year":"2012","journal-title":"N. Biotechnol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"14248","DOI":"10.1038\/s41598-017-14755-5","article-title":"Assessment of variability in the SOMAscan assay","volume":"7","author":"Candia","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1038\/nprot.2012.024","article-title":"A positive\/negative ion-switching, targeted mass spectrometry-based metabolomics platform for bodily fluids, cells, and fresh and fixed tissue","volume":"7","author":"Yuan","year":"2012","journal-title":"Nat. Protoc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.aca.2018.08.002","article-title":"statTarget: A streamlined tool for signal drift correction and interpretations of quantitative mass spectrometry-based omics data","volume":"1036","author":"Luan","year":"2018","journal-title":"Anal. Chim. Acta"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1109\/TIT.1967.1053964","article-title":"Nearest neighbor pattern classification","volume":"13","author":"Cover","year":"1967","journal-title":"IEEE Trans. Inf. Theory"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1007\/s11306-018-1347-7","article-title":"NormalizeMets: Assessing, selecting and implementing statistical methods for normalizing metabolomics data","volume":"14","author":"Olshansky","year":"2018","journal-title":"Metabolomics"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: A practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Society. Ser. B"},{"key":"ref_39","unstructured":"Hoaglin, D. (2001). Understanding Robust and Exploratory Data Analysis, Taylor & Francis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"14.10.11","DOI":"10.1002\/cpbi.11","article-title":"Using MetaboAnalyst 3.0 for comprehensive metabolomics data analysis","volume":"55","author":"Xia","year":"2016","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_41","unstructured":"(2020, October 18). Lipid Pathway Enrichment Analysis (LIPEA). Available online: https:\/\/hyperlipea.org."},{"key":"ref_42","first-page":"1","article-title":"Integration of multi-omics data using probabilistic graph models and external knowledge","volume":"16","author":"Tripp","year":"2021","journal-title":"Curr. Bioinform."},{"key":"ref_43","first-page":"e949","article-title":"KEGG2Net: Deducing gene interaction networks and acyclic graphs from KEGG pathways","volume":"26","author":"Chanumolu","year":"2021","journal-title":"EMBnetjournal"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/nbt.4072","article-title":"Recon3D enables a three-dimensional view of gene variation in human metabolism","volume":"36","author":"Brunk","year":"2018","journal-title":"Nat. Biotechnol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2860","DOI":"10.1093\/bioinformatics\/btv285","article-title":"The SwissLipids knowledgebase for lipid biology","volume":"31","author":"Aimo","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_47","unstructured":"Friedman, N., Goldszmidt, M., and Wyner, A.J. (1999). Data Analysis with Bayesian Networks: A Bootstrap Approach. arXiv."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.artmed.2012.12.006","article-title":"Identifying significant edges in graphical models of molecular networks","volume":"57","author":"Scutari","year":"2013","journal-title":"Artif. Intell. Med."},{"key":"ref_49","unstructured":"Sneath, P.H.A., and Sokal, R.R. (1973). Numerical Taxonomy: The Principles and Practice of Numerical Classification, W. H. Freeman."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1080\/14786440109462720","article-title":"On lines and planes of closest fit to systems of points in space","volume":"2","author":"Pearson","year":"1901","journal-title":"Lond. Edinb. Dublin Philos. Mag. J. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1109\/72.991427","article-title":"A comparison of methods for multiclass support vector machines","volume":"13","author":"Hsu","year":"2002","journal-title":"IEEE Trans. Neural Netw."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5938","DOI":"10.1002\/ece3.5177","article-title":"Machine learning of large-scale spatial distributions of wild turkeys with high-dimensional environmental data","volume":"9","author":"Farrell","year":"2019","journal-title":"Ecol. Evol."},{"key":"ref_53","first-page":"362","article-title":"Individualized multi-omic pathway deviation scores using multiple factor analysis","volume":"23","author":"Rau","year":"2022","journal-title":"Biostatistics"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/j.1467-9868.2005.00503.x","article-title":"Regularization and variable selection via the Elastic Net","volume":"67","author":"Zou","year":"2005","journal-title":"J. R. Stat. Soc. Ser. B Stat. Methodol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Sammut, C., and Webb, G.I. (2010). Leave-one-out cross-validation. Encyclopedia of Machine Learning, Springer US.","DOI":"10.1007\/978-0-387-30164-8"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/S0031-3203(96)00142-2","article-title":"The use of the area under the ROC curve in the evaluation of machine learning algorithms","volume":"30","author":"Bradley","year":"1997","journal-title":"Pattern Recognit."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Gao, J., Xu, K., Liu, H., Liu, G., Bai, M., Peng, C., Li, T., and Yin, Y. (2018). Impact of the gut microbiota on intestinal immunity mediated by tryptophan metabolism. Front. Cell Infect. Microbiol., 8.","DOI":"10.3389\/fcimb.2018.00013"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/s12986-017-0233-z","article-title":"The metabolism and significance of homocysteine in nutrition and health","volume":"14","author":"Kumar","year":"2017","journal-title":"Nutr. Metab."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"167","DOI":"10.15698\/cst2020.07.225","article-title":"The role of lipids in autophagy and its implication in neurodegeneration","volume":"4","author":"Soukup","year":"2020","journal-title":"Cell Stress"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Graham, S.F., Chevallier, O.P., Elliott, C.T., H\u00f6lscher, C., Johnston, J., McGuinness, B., Kehoe, P.G., Passmore, A.P., and Green, B.D. (2015). Untargeted metabolomic analysis of human plasma indicates differentially affected polyamine and L-arginine metabolism in mild cognitive impairment subjects converting to Alzheimer\u2019s disease. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119452"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1093\/ajcn\/80.2.483","article-title":"Plasma amino acid concentrations in patients with amnestic mild cognitive impairment or Alzheimer disease","volume":"80","author":"Ravaglia","year":"2004","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Amand, J., Fehlmann, T., Backes, C., and Keller, A. (2019). DynaVenn: Web-based computation of the most significant overlap between ordered sets. BMC Bioinform., 20.","DOI":"10.1186\/s12859-019-3320-5"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Campbell, B., Charych, E., Lee, A., and M\u00f6ller, T. (2014). Kynurenines in CNS disease: Regulation by inflammatory cytokines. Front. Neurosci., 8.","DOI":"10.3389\/fnins.2014.00012"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.jcrc.2021.09.025","article-title":"Activation of the kynurenine pathway predicts mortality and neurological outcome in cardiac arrest patients: A validation study","volume":"67","author":"Loretz","year":"2022","journal-title":"J. Crit. Care"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"157","DOI":"10.4137\/IJTR.S4294","article-title":"Understanding the roles of the kynurenine pathway in multiple sclerosis progression","volume":"3","author":"Lim","year":"2010","journal-title":"Int. J. Tryptophan Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"204","DOI":"10.2478\/v10039-010-0023-6","article-title":"Kynurenine and its metabolites in Alzheimer\u2019s disease patients","volume":"55","author":"Gulaj","year":"2010","journal-title":"Adv. Med. Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e2022857118","DOI":"10.1073\/pnas.2022857118","article-title":"Whole-blood metabolomics of dementia patients reveal classes of disease-linked metabolites","volume":"118","author":"Teruya","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1038\/nm.3951","article-title":"Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits","volume":"21","author":"Min","year":"2015","journal-title":"Nat. Med."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Tracy, T.E., and Gan, L. (2017). Acetylated tau in Alzheimer\u2019s disease: An instigator of synaptic dysfunction underlying memory loss: Increased levels of acetylated tau blocks the postsynaptic signaling required for plasticity and promotes memory deficits associated with tauopathy. Bioessays, 39.","DOI":"10.1002\/bies.201600224"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13024-022-00548-6","article-title":"Microbial-derived metabolites as a risk factor of age-related cognitive decline and dementia","volume":"17","author":"Connell","year":"2022","journal-title":"Mol. Neurodegener."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1146\/annurev.arplant.50.1.473","article-title":"The shikimate pathway","volume":"50","author":"Herrmann","year":"1999","journal-title":"Annu. Rev. Plant Physiol. Plant Mol. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Jenkins, T.A., Nguyen, J.C.D., Polglaze, K.E., and Bertrand, P.P. (2016). Influence of tryptophan and serotonin on mood and cognition with a possible role of the gut-brain axis. Nutrients, 8.","DOI":"10.3390\/nu8010056"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1093\/gerona\/glad074","article-title":"Association between gut microbiota and delirium in acutely ill older adults","volume":"78","author":"Garcez","year":"2023","journal-title":"J. Gerontol. Ser. A"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/s41398-023-02450-1","article-title":"The association between gut microbiota and postoperative delirium in patients","volume":"13","author":"Zhang","year":"2023","journal-title":"Transl. Psychiatry"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Ticinesi, A., Parise, A., Nouvenne, A., Cerundolo, N., Prati, B., and Meschi, T. (2023). The possible role of gut microbiota dysbiosis in the pathophysiology of delirium in older persons. Microbiome Res. Rep., 2.","DOI":"10.20517\/mrr.2023.15"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.jalz.2018.01.003","article-title":"Association of branched-chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer\u2019s disease: A prospective study in eight cohorts","volume":"14","author":"Tynkkynen","year":"2018","journal-title":"Alzheimers Dement."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13195-017-0270-x","article-title":"One-carbon metabolism, cognitive impairment and CSF measures of Alzheimer pathology: Homocysteine and beyond","volume":"9","author":"Dayon","year":"2017","journal-title":"Alzheimers Res. Ther."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"561","DOI":"10.3233\/JAD-171042","article-title":"Homocysteine and dementia: An international consensus statement","volume":"62","author":"Smith","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Ma, X., Mei, X., Tang, T., Wang, M., Wei, X., Zheng, H., Cao, J., Zheng, H., Cody, K., and Xiong, L. (2022). Preoperative homocysteine modifies the association between postoperative C-reactive protein and postoperative delirium. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.963421"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/nrm3249","article-title":"Canonical and non-canonical autophagy: Variations on a common theme of self-eating?","volume":"13","author":"Codogno","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1007\/s12264-022-00861-6","article-title":"Correlation of ferroptosis and other types of cell death in neurodegenerative diseases","volume":"38","author":"Dang","year":"2022","journal-title":"Neurosci. Bull."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.neuron.2012.09.020","article-title":"Endocannabinoid signaling and synaptic function","volume":"76","author":"Castillo","year":"2012","journal-title":"Neuron"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1039\/C3MB70529C","article-title":"Relationship between the lipidome, inflammatory markers and insulin resistance","volume":"10","author":"Wallace","year":"2014","journal-title":"Mol. BioSystems"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e109","DOI":"10.1111\/jgs.14913","article-title":"High c-reactive protein predicts delirium incidence, duration, and feature severity after major non-cardiac surgery","volume":"65","author":"Vasunilashorn","year":"2017","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.biopsych.2016.03.2098","article-title":"Higher c-reactive protein levels predict postoperative delirium in older patients undergoing major elective surgery: A longitudinal nested case-control study","volume":"81","author":"Dillon","year":"2017","journal-title":"Biol. Psychiatry"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1093\/gerona\/glv083","article-title":"Cytokines and postoperative delirium in older patients undergoing major elective surgery","volume":"70","author":"Vasunilashorn","year":"2015","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Kar, A., Mehrotra, S., and Chatterjee, S. (2020). CD38: T cell immuno-metabolic modulator. Cells, 9.","DOI":"10.3390\/cells9071716"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Hu, Y., Huang, Y., Xing, S., Chen, C., Shen, D., and Chen, J. (2022). A\u03b2 promotes CD38 expression in senescent microglia in Alzheimer\u2019s disease. Biol. Res., 55.","DOI":"10.1186\/s40659-022-00379-1"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Guerreiro, S., Privat, A.L., Bressac, L., and Toulorge, D. (2020). CD38 in neurodegeneration and neuroinflammation. Cells, 9.","DOI":"10.3390\/cells9020471"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"14285","DOI":"10.1002\/jcb.29004","article-title":"Neuroprotection by glucose-6-phosphate dehydrogenase and the pentose phosphate pathway","volume":"120","author":"Tang","year":"2019","journal-title":"J. Cell Biochem."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1186\/s12974-019-1659-1","article-title":"The pentose phosphate pathway regulates chronic neuroinflammation and dopaminergic neurodegeneration","volume":"16","author":"Tu","year":"2019","journal-title":"J. Neuroinflammation"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"23086","DOI":"10.1074\/jbc.M114.570911","article-title":"Depletion of cyclophilins B and C leads to dysregulation of endoplasmic reticulum redox homeostasis","volume":"289","author":"Stocki","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e2513","DOI":"10.1038\/cddis.2016.374","article-title":"Hyperhomocysteinemia causes ER stress and impaired autophagy that is reversed by Vitamin B supplementation","volume":"7","author":"Tripathi","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1016\/S0140-6736(99)00309-8","article-title":"Homocysteine in cerebral macroangiography and microangiopathy","volume":"353","author":"Fassbender","year":"1999","journal-title":"Lancet"},{"key":"ref_95","first-page":"1422","article-title":"Homocysteine and neurologic disease","volume":"57","year":"2000","journal-title":"Arch. Neurol."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Price, B.R., Wilcock, D.M., and Weekman, E.M. (2018). Hyperhomocysteinemia as a risk factor for vascular contributions to cognitive impairment and dementia. Front. Aging Neurosci., 10.","DOI":"10.3389\/fnagi.2018.00350"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1001\/archneur.1997.00550220074017","article-title":"Features, symptoms, and neurophysiological findings in stroke associated with hyperhomocysteinemia","volume":"54","author":"Evers","year":"1997","journal-title":"Arch. Neurol."},{"key":"ref_98","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_99","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/s41582-022-00698-7","article-title":"The inter-relationship between delirium and dementia: The importance of delirium prevention","volume":"18","author":"Fong","year":"2022","journal-title":"Nat. Rev. Neurol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/8\/924\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:26:27Z","timestamp":1760109987000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/8\/924"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,30]]},"references-count":99,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["biom14080924"],"URL":"https:\/\/doi.org\/10.3390\/biom14080924","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,30]]}}}