Experiments in mice link common anesthetic to Alzheimer's-like brain changes

Mice given an anesthetic widely used in surgery on people suffered changes to their brains similar to the damage found in Alzheimer's disease, researchers from Massachusetts General Hospital report in the online Annals of Neurology. The results need to be tested in humans, the authors caution, but the findings raise questions about administering this kind of anesthesia to elderly patients with or without Alzheimer's.

Dr. Zhongcong Xie and his colleagues at the MassGeneral Institute for Neurodegenerative Disease had already seen how the anesthetic gas isoflurane spurred production of amyloid-beta protein, based on human nerve cell experiments in lab dishes. Amyloid-beta protein is toxic to nerve cells and can short-circuit the synapses where impulses pass between nerve cells. In Alzheimer's disease, amyloid-beta protein builds up in the brain in clusters called plaques.

The next step for the Xie team was to test what happened at the cellular level in mice. They already knew that anesthesia is a risk factor for delirium, particularly in older people who sometimes have cognitive problems for up to a week after long surgeries such as cardiac bypass operations. The researchers gave mice doses of isoflurane for two hours, the equivalent of what people would receive in general surgery. They then compared them to mice that did not receive the anesthetic.

After six hours, there were signs that programmed cell death was beginning and levels of an enzyme that makes amyloid beta protein were rising in the brains of mice that were given isoflurane. After 24 hours, the enzyme was four times higher in mice who had received isoflurane than in untreated mice, supporting the idea that the anesthetic not only triggers cell death but also spurs excessive production of amyloid-beta protein.

"It may put elderly patients at risk for Alzheimer's disease if -- and it's a very big if --- this happens in humans under conditions of surgery. You could be triggering disease or exacerbating disease," Rudolph E. Tanzi, the paper's senior author and director of the Genetics and Aging Research Unit at Mass. General, said in an interview. "We are not saying 'Take this anesthetic out of the operating room,' but it does say to the astute anesthesiologist who keeps track of the literature, we need to be a little careful and we need to keep track of this. It could later be validated" in humans.

In another part of the study, a group of mice were given clioquinol, a drug that prevents the buildup of amyloid-beta protein. When these mice received the anesthetic isoflurane a week later, they had significantly lower levels of the enzyme that leads to amyloid-beta production.

Both Xie and Tanzi declared conflicts of interest in the study, which was funded by the National Institutes of Health, the American Geriatrics Society, the Alzheimer's Association, Harvard University, and the Cure Alzheimer's Fund. Xie is a consultant of Baxter Healthcare, which makes isoflurane, and Tanzi is a co-founder of Prana Biotechnology Ltd., an Australian company that is testing a derivative of clioquinol. Neither Baxter nor Prana paid for the study or had a role in how it was conducted.

Research is mixed on isoflurane, with some studies saying it's better than other agents in cardiac bypass surgery.

Tanzi recommends caution: "Even though I say it's too early to say anything to the operating room or to anesthesiologists about isoflurane, we just don't know. For family and friends, I say don't risk it. Just use another agent."