Anesthesia-Alzheimer Disease Link ProbedAnesthesia-Alzheimer Disease Link Probed

Some commonly used inhaled anesthetics may cause brain damage that accelerates the onset of Alzheimer disease, according to recent findings from two separate groups of scientists.

For more than a decade, physicians and scientists have searched for clues to why some people experience cognitive dysfunction after undergoing anesthesia and surgery (Brewer K et al. Anesthesia exposure as a possible risk factor for cognitive decline in the elderly. In: Alzheimer's Disease. Paris: Serdi Publishing Company;1996:161-171). Some studies also have suggested that age of onset of Alzheimer disease may be associated with previous anesthetic exposure during surgery, although the results from these small studies were not significant (Bohnen N et al. Int J Neurosci. 1994;77:181-185; Gasparini M et al. Neurol Sci. 2002;23:11-14; Lee TA et al. J Alzheimers Dis. 2005:7:319-324). Now, scientists are beginning to tease out the mechanisms behind anesthesia's ill effects on the brain and to understand how these mechanisms might lead to cognitive dysfunction and speed the development of Alzheimer disease.

In 2004, a team of researchers from the University of Pennsylvania demonstrated that the inhaled anesthetic agents isoflurane and halothane caused amyloid β proteins to stick together in cell cultures (Eckenhoff RG et al. Anesthesiology. 2004;101:703-709). The findings were provocative because such amyloid β buildup is toxic, and amyloid β plaques have been implicated in the pathogenesis of Alzheimer disease. The findings suggested a possible molecular explanation for cognitive dysfunction following anesthesia.

Recently, the researchers took the research a step further. They exposed 2 types of mice—transgenic mice predisposed to develop Alzheimer diseaselike cognitive dysfunction and wild-type mice—to isoflurane or halothane for 5 days (Bianchi SL et al. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2007 .02.009 [published online ahead of issue March 7, 2007]). They then measured amyloid β aggregation in the brains of these mice and of control mice of both types that were not exposed to anesthetic. The cognitive function of the mice was measured before and after anesthetic exposure.

The researchers found that the transgenic mice that were exposed to the anesthetics developed more plaques, with the mice exposed to halothane developing the most plaques. However, they were unable to document any additional cognitive decline in these mice compared with transgenic mice that were not exposed to anesthesia, despite greater plaque buildup.

Roderic G. Eckenhoff, MD, professor of anesthesiology at the University of Pennsylvania School of Medicine in Philadelphia, said the lack of discernable cognitive decline was likely due to the fact that the transgenic mice were severely cognitively compromised even before exposure to anesthetic, making it difficult to document further small declines in cognition. He said the research team plans to confirm whether this true by testing younger transgenic mice that are not as cognitively impaired.

However, wild-type mice that were exposed to isoflurane did experience cognitive decline. Eckenhoff said this suggests the isoflurane might cause cognitive decline through a mechanism other than plaque deposition.

Eckenhoff said he does not believe that anesthetics cause Alzheimer disease, but that they may subtly affect the course of the disease in individuals who have it or are predisposed to it. Because of this, he said, individuals who have a family history of early Alzheimer disease or those who have discovered through genetic testing that they have a mutation that predisposes them to the disorder should discuss the potential risks with their surgeon and anesthesiologist.

In other work, a Massachusetts-based team of researchers has demonstrated that exposure to isoflurane triggers amyloid β accumulation and cell death in human cell cultures, suggesting a potential molecular mechanism of anesthesia-related cognitive decline (Xie Z et al. J Neurosci. 2007;27:1247-1254).

“It's a vicious cycle between apoptosis induced by isoflurane and also increased by amyloid β levels,” explained lead author Zhongcong Xie, MD, PhD, of Massachusetts General Hospital in Boston.

The findings may apply to a wider array of anesthetics because many of the most commonly used anesthetics, including isoflurane, desflurane, and sevoflurane, have similar structures, said Xie, but further studies are necessary to confirm such an association.

He cautioned that patients and physicians should not panic about the potential damaging effects of these drugs. “It is alarming, but we have to do much more study before we have any conclusion,” he said.