New Evidence Points To Role For Free Radicals In Alzheimer's Disease

Additionally, the frontal and temporal lobes were the only parts of the brains where the levels of two recently identified biochemical markers of free-radical tissue damage were seen to be elevated. This is an important observation because these two areas of the brain, critical for memory and intellectual function, are the ones most affected by the disease. A report on the new findings appears in the December issue of the FASEB Journal.

"The strength of what we found was that, firstly, these markers were elevated only in the affected parts of the brains of people who died of Alzheimer's disease," says Garret A. FitzGerald, MD, chairman of the department pharmacology and senior author on the report. "And, secondly, the markers were not elevated in the same parts of the brains of people who died of other causes. This suggests that what we're looking at are sensitive, quantitative indicators of disease activity."

The most abundant of the two markers was also found to be significantly elevated in the cerebrospinal fluid, or CSF. The importance of this finding is that the CSF is a relatively accessible body fluid, so that extensions of the current work into living patients presumed to have Alzheimer's disease will be possible. Indeed, such studies have already begun at Penn. Likely to emerge from these investigations will be more accurate methods for disease diagnosis, improved assessments of drugs against the disease, and a clearer overall picture of the disease process.

For example, results from epidemiological studies suggest that anti-inflammatory drugs (e.g., ibuprofen) and antioxidant compounds (e.g., vitamin E) both offer some protection against Alzheimer's disease. Although inflammation is linked to oxidant stress and its associated tissue damage, it would be useful to know whether and to what degree these processes, independently or in concert, drive the progression of the disease. And which class of drugs -- anti-inflammatories or antioxidants -- offers the greatest potential benefit to patients?

"People debate the initiating cause of Alzheimer's disease, but there's general agreement that there is an inflammatory component, and inflammation is associated with oxidant stress," says FitzGerald. "So, it becomes relevant whether drug targets associated with inflammation will represent distinct or overlapping targets from those involved in oxidation. In other words, if we give a patient an anti-inflammatory, should we expect any additional benefit from an antioxidant vitamin or drug? Currently, we don't know the answer. Our ongoing studies should begin to address that question."

The innovative measurement technique used in all of these experiments was developed in FitzGerald's laboratory in collaboration with Joshua Rokach, PhD, a chemist at the Florida Institute of Technology and coauthor on the current report. It assesses the levels in body fluids or tissues of certain biochemicals called isoprostanes. These isoprostanes are stable byproducts of free-radical catalyzed damage to lipids, or fatty molecules, found throughout the body, and they serve as quantitative markers for that damage.

The lead author on the study is Domenico Pratico, MD, an assistant professor of pharmacology at Penn. Coauthors on the study, in addition to Rokach, include Virginia M.-Y. Lee, PhD, and John Q. Trojanowski, MD, PhD, both professors of pathology and laboratory medicine at Penn. Funding for the work was provided by the National Institutes of Health.