The Effect of Propofol Versus Isoflurane Anesthesia on Human Cerebrospinal Fluid Markers of Alzheimer's Disease: Results of a Randomized Trial

Background: Preclinical studies have found differential effects of isoflurane and propofol on the Alzheimer's disease (AD)-associated markers tau, phosphorylated tau (p-tau) and amyloid-β (Aβ). Objective: We asked whether isoflurane and propofol have differential effects on the tau/Aβ ratio (the primary outcome), and individual AD biomarkers. We also examined whether genetic/intraoperative factors influenced perioperative changes in AD biomarkers. Methods: Patients undergoing neurosurgical/otolaryngology procedures requiring lumbar cerebrospinal fluid (CSF) drain placement were prospectively randomized to receive isoflurane (n=21) or propofol (n=18) for anesthetic maintenance. We measured perioperative CSF sample AD markers, performed genotyping assays, and examined intraoperative data from the electronic anesthesia record. A repeated measures ANOVA was used to examine changes in AD markers by anesthetic type over time. Results: The CSF tau/Aβ ratio did not differ between isoflurane- versus propofol-treated patients (p=1.000). CSF tau/Aβ ratio and tau levels increased 10 and 24h after drain placement (p=2.002×10^-6 and p=1.985×10^-6, respectively), mean CSF p-tau levels decreased (p=0.005), and Aβ levels did not change (p=0.152). There was no interaction between anesthetic treatment and time for any of these biomarkers. None of the examined genetic polymorphisms, including ApoE4, were associated with tau increase (n=9 polymorphisms, p>0.05 for all associations). Conclusion: Neurosurgery/otolaryngology procedures are associated with an increase in the CSF tau/Aβ ratio, and this increase was not influenced by anesthetic type. The increased CSF tau/Aβ ratio was largely driven by increases in tau levels. Future work should determine the functional/prognostic significance of these perioperative CSF tau elevations.