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

Article type: Research Article

Authors: Berger, Miles^{a; *} | Nadler, Jacob W.^b | Friedman, Allan^c | McDonagh, David L.^d | Bennett, Ellen R.^e | Cooter, Mary^a | Qi, Wenjing^f | Laskowitz, Daniel T.^{a; e; g} | Ponnusamy, Vikram^h | Newman, Mark F.^{a; i} | Shaw, Leslie M.^j | Warner, David S.^{a; c; g} | Mathew, Joseph P.^a | James, Michael L.^{a; e} | MAD-PIA trial team

Collaborators: Radhakrishnan, Senthil | Carter, James | Lad, Shivanandan | Zomorodi, Ali | Sampson, John | Fukushima, Takanori | Adogwa, Owoicho | Clemmons, Karen | Conde, Carlos | Olaleye, Omowunmi | Balajonda, Naraida | Aquino, Jhoanna | Funk, Bonita | Li, Yi-Ju | White, William D.

Affiliations: [a] Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA | [b] Division Chief, Neurosurgical Anesthesiology Medical Director, Postanesthesia Care Unit; Department of Anesthesiology, University of Rochester, Rochester, NY, USA | [c] Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA | [d] Department of Anesthesiology & Pain Management, Neurological Surgery, Neurology and Neurotherapeutics, University of Texas, Southwestern, Dallas, TX, USA | [e] Department of Neurology, Duke University Medical Center, Durham, NC, USA | [f] Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA | [g] Department of Neurobiology, Duke University Medical Center, Durham, NC, USA | [h] College of Arts and Sciences, Duke University, Durham, NC, USA | [i] Private Diagnostic Clinic, Duke University Medical Center, Durham, NC, USA | [j] Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

Correspondence: [*] Correspondence to: Miles Berger, MD, PhD, Duke South Orange Zone, Room 4317, Duke University Medical Center, Durham, NC 27710, USA. Tel.: +1 919 684 8679; Fax: +1 919 613 5264; E-mail: [email protected].

Abstract: 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 24 h 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.

Keywords: Amyloid-beta, anesthesia, cerebrospinal fluid, isoflurane, propofol, surgery, tau protein

DOI: 10.3233/JAD-151190

Journal: Journal of Alzheimer's Disease, vol. 52, no. 4, pp. 1299-1310, 2016