Objective Determination of biomarker and neuropathogenesis of postoperative cognitive change (POCC) or postoperative cognitive dysfunction. Background POCC is one of the most common postoperative complications in elderly patients. Whether preoperative cerebrospinal fluid (CSF) β-amyloid protein (Aβ) to tau ratio, an Alzheimer disease biomarker, is a biomarker for risk of POCC remains unknown. We therefore set out to assess the association between preoperative CSF Aβ42 or Aβ40 to tau ratio and POCC. Methods Patients who had total hip/knee replacement were enrolled. The CSF was obtained during the administration of spinal anesthesia. Cognitive tests were performed with these participants at 1 week before and at 1 week and 3 to 6 months after the surgery. Z scores of the changes from preoperative to postoperative on several key domains of the cognitive battery were determined. We then examined the association between preoperative CSF Aβ42/tau or Aβ40/tau ratio and the outcome measures described earlier, adjusting for age and sex. Results Among the 136 participants (mean age = 71 ± 5 years; 55% men), preoperative CSF Aβ42/tau ratio was associated with postoperative Hopkins Verbal Learning Test Retention [Z score 8.351; age, sex-adjusted (adj.) P = 0.003], and the Benton Judgment of Line= Orientation (Z score 1.242; adj. p = 0.007). Aβ40/tau ratio was associated with Brief Visuospatial Memory Test Total Recall (Z score = 1.045; adj. P = 0.044). Conclusions Preoperative CSF Aβ/tau ratio is associated with postoperative changes in specific cognitive domains. The presence of the Alzheimer's disease biomarker, specifically the Aβ/tau ratio, may identify patients at higher risk for cognitive changes after surgery.

Background β-amyloid protein (Aβ) accumulation, caspase activation, apoptosis, and hypoxia-induced neurotoxicity have been suggested to be involved in Alzheimer disease neuropathogenesis. Aβ is produced from amyloid precursor protein (APP) through proteolytic processing by the aspartyl protease β-site APP-cleaving enzyme (BACE) and γ-secretase. Inhaled anesthetics have long been considered to protect against neurotoxicity. However, recent studies have suggested that the inhaled anesthetic isoflurane may promote neurotoxicity by inducing caspase activation and apoptosis, and by increasing levels of BACE and Aβ. We therefore sought to determine whether isoflurane can induce concentration-dependent dual effects on hypoxia-induced caspase-3 activation and increases in BACE levels: protection versus promotion. Methods H4 human neuroglioma cells were treated with hypoxia (3% O2) alone, different concentrations of isoflurane (0.5% and 2%), and the combination of hypoxia and 0.5% or 2% isoflurane. The levels of caspase-3 cleavage (activation), BACE, and Bcl-2 were determined by Western blot analysis. Results Here we show for the first time that treatment with 0.5% isoflurane for eight hours attenuated, whereas treatment with 2% isoflurane for eight hours enhanced, hypoxia-induced caspase-3 activation and increases in BACE levels. The 2% isoflurane treatment also enhanced a hypoxia-induced decrease in Bcl-2 levels. Conclusions These results suggest a potential concept that isoflurane has dual effects (protection versus promotion) on hypoxia-induced toxicity, which may act through Bcl-2 family proteins. These findings could lead to more systematic studies to determine the potential dual effects of anesthetics on Alzheimer disease-associated neurotoxicity.