1. Roderic G. Eckenhoff, MD Dept. Anesthesiology & Critical Care, University of Pennsylvania roderic.eckenhoff@uphs.upenn.edu Hypothesis: Inhaled anesthetics promote aggregation and toxicity of disease-associated peptides, and thereby accelerate the onset of neurodegenerative disorders, like Alzheimers. Methods: 1.In vitro protein studies – Aβ. 1-40 and Aβ 1-42. 2.Cell culture models – exogenous and endogenous. 3.Transgenic animal models of enhanced Aβ expression. Background: 1.Durable post-operative cognitive decline in older people. 2.Positive odds ratio for Alzheimer disease and prior surgery. 3.Biophysical basis for enhanced protein oligomerization. Disclosure: No conflicts

2. Anesthesiology 2004;101:703 Current Alzheimer Research 2007 (in press) Isolated proteins

3. LDH release, % change from control * # † * # † * * * Cell Culture Anesthesiology 2004;101:703

4. Animals: Tg2576 WTTg C H I

5. Impact of Prior Anesthesia History on AD Silber & Rosenbaum analysis of Bohnen papers P=0.08 one sided P=0.11 one sided

6. Conclusions: 1.Inhaled anesthetics accelerate aggregation of Aβ. Halo>Iso 2.Inhaled anesthetics stabilize the toxic Aβ oligomer. 3.Aβ plus anesthetic is more cytotoxic than either alone. 4.Inhaled anesthetics enhance plaque in transgenic mouse brain. 5.Isoflurane causes learning/memory impairment in old WT mice. Future directions: 1.Rank-order effects for all these actions. 2.Effects at pre-symptomatic stage. 3.Large epidemiologic studies. 4.Biomarker studies.