Roderic G. Eckenhoff, MDDept. Anesthesiology & Critical Care, University of Pennsylvaniaroderic.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 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)

0 10 20 30 40 50 60 700

250

500

750

0

1

2

3

4

5

6

time, hrs

Flu

ore

sc

en

ce

@ 4

80

nm

[Ha

loth

an

e], m

M

0 5 10 150

25

50

75

100

125HalothaneIsofluraneEthanol (X100)

Propofol (100)

concentration, mM

"So

lub

le"

A 1-

42,

% r

emai

nin

g

0 10 20 300

5.0×10 3

1.0×10 4

1.5×10 4

2.0×10 4

2.5×10 4

Time (minutes)

Abs

orba

nce

Isolated proteinsIsolated proteins

LD

H r

ele

ase,

%

ch

an

ge

from

con

trol

Halothane

-25

0

25

50

Isoflurane

-25

0

25

50

1 M

AC

2 M

AC A

A

+ 1M

AC

A

+ 2

MA

C

* #

†

*#†

Propofol, ethanol

-25

0

25

50

prop

ofol

etha

nol A

A

+ pr

opof

ol

A

+ et

hano

l

* * *

Cell CultureCell Culture

Anesthesiology 2004;101:703Anesthesiology 2004;101:703

WT Vector L286V0

50

100

150

- Isoflurane + Isoflurane

***

*+

LD

H (

% C

ont

rol)

WT Vector L286V0

25

50

75

100

125

- Isoflurane + Isoflurane

*+

**

MT

T (%

Co

ntro

l)

WT Vector L286V0

50

100

150

-Halothane +Halothane

***

*+

LD

H (

% C

ont

rol)

WT Vector L286V0

25

50

75

100

125

- Halothane + Halothane

***

MT

T (%

Co

ntro

l)

Animals: Tg2576Animals: Tg2576

Tg-Con Tg-Iso Tg-Hal0.0

2.5

5.0

7.5

10.0

To

tal

# P

laq

ues

WT Tg

C H I C H I

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.