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Age and surgery type have been identified as risk factors. However, what caused the increased risk in the\u00a0elderly is poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We utilized a PND model in aged mice undergoing experimental laparotomy with general anesthesia to evaluate the causal relationship between hyperhomocysteinemia and increased PND susceptibility. PND was assessed by Novel Object Tasks, Fear Conditioning Tests, and Barnes Maze Tests. Serum homocysteine (Hcy) as well as vitamin B12 and folate acid levels were tested before, immediately after surgery and from day 1 to day 29 after surgery by ELISA. The effectiveness of preventative strategy including diet supplementation of vitamin B12\u00a0+\u00a0folic acid (Vit B12\u00a0+\u00a0FA) and S\u2010adenosylmethionine (SAM) injection targeting hyperhomocysteinemia were also tested.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PND in aged mice lasted for at least 2\u00a0weeks after experimental laparotomy, which was not observed in young adult mice. Serum Hcy results indicated a significant correlation between postoperative cognitive performance and perioperative Hcy level. Preoperative supplementation with VB12 and folic acid (FA) in the diet or S\u2010adenosylmethionine (SAM) injection reduced perioperative serum Hcy level and inhibited the development of PND in aged mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Serum homocysteine accumulation is a fundamental cause for increased susceptibility of PND in aged mice. Preoperative diet supplementation of VitB12\u00a0+\u00a0FA can effectively reduce PND in aged mice, which may be a promising prophylaxis treatment in clinical settings.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.50838","type":"journal-article","created":{"date-parts":[[2019,7,29]],"date-time":"2019-07-29T07:08:46Z","timestamp":1564384126000},"page":"1435-1444","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Hyperhomocysteinemia is key for increased susceptibility to PND in aged mice"],"prefix":"10.1002","volume":"6","author":[{"given":"Guangchao","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine Xijing Hospital, the Fourth Military Medical University 127th West Changle Road Xi'an 710032 Shaanxi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7559-0047","authenticated-orcid":false,"given":"Jiao","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine Xijing Hospital, the Fourth Military Medical University 127th West Changle Road Xi'an 710032 Shaanxi China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuan","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Tenth People's Hospital of Tongji University 301 Yanchang Rd. 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