The aim of this study is to evaluate how C-reactive protein (CRP) and homocysteine and their interaction contribute to postoperative delirium, based on our previous finding on the interactions of CRP, homocysteine and postoperative delirium.

Postoperative delirium is a common complication of patients who undergo major surgery. It is frequently accompanied by adverse outcomes like Alzheimer's disease, high risk of postoperative complications and poor long-term outcomes, but its pathogenesis and biomarkers remain undetermined. Neuroinflammation is emerging as a popular hypothesis of developing postoperative delirium, particularly via microglial activation and increased pro-inflammatory cytokines in the brain. However, not every patient with surgery-induced inflammation develops postoperative delirium. Thus, inflammation alone may be insufficient to explain postoperative delirium. Patients who develop postoperative delirium may have other changes (predisposing factors) that exacerbate surgery-induced inflammation (precipitating factor), leading to neuronal dysfunction.

A potential predisposing factor is hyperhomocysteine, a pathogenesis implicated in cardiovascular and Alzheimer's disease. Previous studies had indicated that preoperative hyperhomocysteine may be related to postoperative delirium, but the findings are conflicting. More importantly, the interaction between inflammation and hyperhomocysteine remains unknown, which may contribute more to postoperative delirium than the inflammation alone or hyperhomocysteine alone.

Thus, this study is a prospective observational cohort study to evaluate the interaction between CRP and hyperhomocysteine and their contribution to postoperative delirium. Patients scheduled for orthopedic surgeries will be included. Written informed consent will be obtained from all the patients.

Preoperative assessments：Participants recruited will receive preoperative assessments one day before the scheduled surgery by two well-trained researchers. The assessments include demographic characteristics (e.g., age, sex, education, marital status )，age-adjusted Charlson comorbidity index (ACCI) , cognitive function assessments (mini-mental state examination [MMSE] and Confusion Assessment Method [CAM]). And similarly venous blood samples of patient will be collected for homocysteine and C-reactive protein measurements.

Outcome measurement： Postoperative delirium will be assessed for the first, second and third day after surgery (twice daily, in the morning and afternoon respectively) using the CAM and CAM-Severity (CAM-S) long-form by two trained assessors. And venous blood samples of patients will be collected after the anesthesia/surgery for C-reactive protein measurements.

Inclusion Criteria:

1. were 60 years old or older
2. had a normal cognitive function at the time of enrollment, evidenced by a mini-mental state examination (MMSE) score above an education-adjusted threshold (18 for individuals with no school education, 20 for 1-6 years of education, or 24 for 7 or more years of education 27)
3. spoke Mandarin Chinese
4. were able to provide informed consent
5. scheduled for orthopaedic surgeries

Exclusion Criteria:

1. pre-existing delirium assessed according to the Confusion Assessment Method (CAM) algorithm;
2. prior neurologic diseases (Parkinson's disease, multiple sclerosis or stroke) according to the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10);
3. history of mental disorders, e.g., major depressive disorder and schizophrenia, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV);
4. unwillingness to comply with the assessments.

Patients 60 years old or older and scheduled for orthopedic surgeries with an expected duration ≥ 2 h