Waking up demented: New ideas about anesthesia-induced cognitive impairment
In an intriguing paper just published in Anesthesiology, Eckenhoff et al. seek an explanation for the commonly observed transitory, and sometimes persistent, cognitive impairment that is observed following surgeries involving the use of inhaled anesthetics. This observation, along with results of a number of studies suggesting, but not proving, a link between surgery and increased risk of Alzheimer’s and Parkinson’s disease in the elderly, led Eckenhoff et al. to study whether inhaled anesthetics might have direct effects on amyloid-β protein (Aβ) self-assembly. To do so, the authors used a combination of biophysical methods to study peptide assembly. These methods included turbidity measurements, filtration, electron microscopy, Thioflavin T (ThT) binding, and size exclusion chromatography. In addition, lactate dehydrogenase (LDH) assays were done on PC12 cells to assess peptide-mediated cytotoxicity. The basic experimental design used groups including anesthetic alone, peptide alone, and...  Read more

Waking up demented: New ideas about anesthesia-induced cognitive impairment
In an intriguing paper just published in Anesthesiology, Eckenhoff et al. seek an explanation for the commonly observed transitory, and sometimes persistent, cognitive impairment that is observed following surgeries involving the use of inhaled anesthetics. This observation, along with results of a number of studies suggesting, but not proving, a link between surgery and increased risk of Alzheimer’s and Parkinson’s disease in the elderly, led Eckenhoff et al. to study whether inhaled anesthetics might have direct effects on amyloid-β protein (Aβ) self-assembly. To do so, the authors used a combination of biophysical methods to study peptide assembly. These methods included turbidity measurements, filtration, electron microscopy, Thioflavin T (ThT) binding, and size exclusion chromatography. In addition, lactate dehydrogenase (LDH) assays were done on PC12 cells to assess peptide-mediated cytotoxicity. The basic experimental design used groups including anesthetic alone, peptide alone, and mixtures of the two. Anesthetics included halothane, isoflurane, propofol, and ethanol.

Halothane increased Aβ42 aggregation in a concentration-dependent manner. This anesthetic also augmented ThT binding during Aβ42 self-assembly. Electron microscopy of the assemblies present at the termination of these experiments showed fibrils and protofibrils. Examination of the amount of peptide filterable through a 100 kDa molecular mass membrane revealed that halothane-treated Aβ assembly reactions were least filterable, followed in rank order by isoflurane, propofol, and ethanol. Halothane also facilitated the formation of high molecular weight assemblies, as assessed by size exclusion chromatography. In addition, halothane, as well as isoflurane, potentiated the toxic effect of Aβ42 on PC12 cells.

The authors conclude that inhaled anesthetics enhance oligomerization and cytotoxicity of Alzheimer's disease-associated peptides, and that this effect may underlie the clinically observed surgery (anesthetic)-associated cognitive impairment often observed in the elderly. This is an intriguing notion worthy of further study.

How can the suggestive work of Eckenhoff et al. be placed on a rigorous experimental foundation? As with any structure-activity study of Aβ, the key requirement will be determination of the distribution of Aβ assemblies and a correlation of that distribution with a specific peptide-associated behavior, whether that behavior is biophysical (filterability, morphology, dye binding, turbidity) or biological (cytotoxicity). The method of peptide preparation used here (DMSO solubilization and dissolution into buffer) produces a heterogeneous population of assemblies, complicating data interpretation. In particular, although the role of oligomers was discussed explicitly, the presence of protofibrils and fibrils in the peptide preparations used precludes determination of the effects of anesthetics on oligomer formation and activity. Eckenhoff et al. may be right. However, greater confidence in the conclusions will come through examination of oligomer-specific assembly processes and effects. The application of more sophisticated spectroscopic methods to monitor directly anesthetic-peptide interactions would provide additional support for the authors’ postulations that hydrophobic interactions are central to the effects observed.

View all comments by David Teplow