Roderic G. Eckenhoff, MD Dept. Anesthesiology & Critical Care, University of Pennsylvania [email protected]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
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Roderic G. Eckenhoff, MD Dept. Anesthesiology & Critical Care, University of Pennsylvania
Roderic G. Eckenhoff, MD Dept. Anesthesiology & Critical Care, University of Pennsylvania [email protected]. Disclosure: No conflicts. Background: Durable post-operative cognitive decline in older people. Positive odds ratio for Alzheimer disease and prior surgery. - PowerPoint PPT Presentation
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Roderic G. Eckenhoff, MDDept. Anesthesiology & Critical Care, University of [email protected]
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 Aβ1-42 .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
Anesthesiology 2004;101:703Anesthesiology 2004;101:703Current Alzheimer Research 2007 (in press)Current Alzheimer Research 2007 (in press)
Impact of Prior Anesthesia History on ADImpact of Prior Anesthesia History on ADSilber & Rosenbaum analysis of Bohnen papersSilber & Rosenbaum analysis of Bohnen papers
0
0.5
1
1.5
2
Odds Ratio
None 1-5 >6
Number of Anesthetics
Number of Prior Anesthetics
0
0.5
1
1.5
2
Odds Ratio
None <10 hr >10 hr
Hours of Anesthesia
Hours of Prior Anesthesia
P=0.08 one sided P=0.11 one sided
Conclusions:
1. Inhaled anesthetics accelerate aggregation of Aβ. Halo>Iso2. 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.