NeurimmiRs and Postoperative Delirium in Elderly Patients Undergoing Total Hip/Knee Replacement: A Pilot Study

Rui Dong, Lingling Sun, Yayuan Lu, Xi Yang, Mian Peng, Zongze Zhang, Rui Dong, Lingling Sun, Yayuan Lu, Xi Yang, Mian Peng, Zongze Zhang

Abstract

Objective: Postoperative delirium (POD) is a frequent complication after surgery and its occurrence is associated with poor outcomes. The pathophysiology of this complication is not clear, but identification of risk factors is important for positive postoperative outcomes. The purpose of this study was to investigate the associations between the preoperative expression levels of microRNA (miR)-146a, miR-125b, and miR-181c in cerebrospinal fluid (CSF) and serum and the development and severity of POD. Methods: Forty elderly patients aged 65 years old and older admitted for elective total hip/knee replacement under spinal anesthesia. Preoperatively, baseline cognitive function was assessed using the Mini-Mental State Examination. Each patient was interviewed daily on the first and second postoperative days. Delirium was diagnosed using the Confusion Assessment Method, and delirium severity was measured using the Memorial Delirium Assessment Scale (MDAS). Preoperative serum and CSF miR levels were determined by quantitative real-time PCR (qRT-PCR). Results: POD was detected in 27.5% (11/40) of patients. Up-regulation of miR-146a and miR-181c in CSF and down-regulation of miR-146a in serum were observed preoperatively in patients who developed POD, while patients with and without POD did not differ in serum or CSF levels of miR-125b. Delirious patients had higher CSF/serum ratios of miR-146a and miR-181c levels than non-delirious patients. The lower CSF miR-146a and CSF/serum miR-146a ratios were significantly associated with milder POD severity, represented by a lower MDAS score. Conclusion: The dysregulation of preoperative miR-146a and miR-181c in CSF and serum was associated with the development and severity of POD. These NeurimmiRs might participate in the neuropathogenesis of POD, pending further investigations. Clinical trial registration: this study was registered at ClinicalTrials.gov (NCT02817386).

Keywords: elderly patients; microRNA; neuroinflammation; postoperative delirium; surgery.

Figures

FIGURE 1
FIGURE 1
Flow diagram. The flow diagram shows that 86 patients were initially screened for the studies, and 40 patients were finally included in the data analysis.
FIGURE 2
FIGURE 2
Expression of candidate NeurimmiRs in the CSF and serum of patients with or without POD. Scatter plots of mean Ct-values of U6 (A) and expression levels of miR-146a (B), miR-125b (C), and miR-181c (D) in the CSF and serum of patients with or without POD. Rel was calculated after normalization using U6 snRNA. The black horizontal lines represent median Rel values ± 95% CIs. Each point represents the mean of triplicate samples. P-values were determined using the Mann–Whitney U-test. POD, postoperative delirium; Rel, relative expression level; CSF, cerebrospinal fluid.
FIGURE 3
FIGURE 3
POD severity in the first quartile and the combination of the other three quartiles of levels of miRs and miR CSF/serum ratios. We found that the median of the highest MDAS score (4, 2–5) of the patients in the first quartile of miRNA-146a in CSF was significantly lower than that of the patients in the combination of the second, third, and fourth quartiles of miRNA-146a in CSF (9, 6–13) (A). In contrast, the median of the highest MDAS score (12, 8–14) of the patients in the first quartile of miRNA-146a in serum was significantly higher than that of the patients in the combination of the second, third, and fourth quartiles of miRNA-146a in serum (6, 5–8) (B). The median of the highest MDAS score in the first quartile of miR-146a cell-free CSF/serum ratio (5, 2–7) was significantly lower than that of the patients in the combination of the second, third, and fourth quartiles of miR-146a CSF/serum ratio (9, 6–13) (C). No significant difference in the highest MDAS score was observed between the patients in the first quartile and the patients in the combination of the second, third, and fourth quartiles of CSF miR-181c or CSF/serum miR-181c ratio (D,E). The black horizontal lines represent median MDAS scores ± interquartile ranges. Each point represents the highest MDAS score. P-values were determined using the Mann–Whitney U-test. POD, postoperative delirium; CSF, cerebrospinal fluid; MDAS, Memorial Delirium Assessment Scale.

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