Nov. 23, 1999 DURHAM, N.C. -- For the first time, researchers have been able to produce three-dimensional images of plaque, the blobs of "garbage" that clog the brains of Alzheimer's disease patients. Previously, plaque could only be viewed after brain tissue was diced and sliced and put under a microscope.
This milestone, made possible by marrying high-resolution magnetic resonance microscopy (MRM) with powerful computers, is the first step toward non-invasive detection of plaques in Alzheimer's disease. The researchers, from Duke University Medical Center, hope ongoing studies in human and animal brain tissue will ultimately answer the central enigma in Alzheimer's disease: Which comes first -- changes in behavior or the build-up of plaque?
The scientists also say that, using the technique, it might be possible to watch the development of plaque as it occurs in transgenic mice altered to produce the substance in their brains. In this way, the effect of experimental drugs designed to treat Alzheimer's disease can be tested as the disease progresses.
"If you can visualize the plaque in vivo to see how its development relates to cognitive behavior, you can answer the question of cause and effect," said Dr. Helene Benveniste, a Duke anesthesiologist and department of radiology brain researcher. She is the lead author on the study, published in the Nov. 23 issue of the Proceedings of the National Academy of Sciences. She said in an interview that researchers who study Alzheimer's disease are divided over the question of whether the disorder results from the development of plaques or whether those deposits are just "gravestones" for damage that has occurred due to a different factor. Plaques are made up of amyloid, a fibrous network of protein not usually found in the body, as well as lots of neuronal debris.
Working with Benveniste on the study were Duke investigators G. Allan Johnson, director of the Center for In Vivo Microscopy, Gillian Einstein, Katie Kim, and Dr. Christine Hullette. The study was funded by the Paul Beeson Foundation, the Alzheimer's Association and by the National Institutes of Health, which supports Duke's Center for In Vivo Microscopy where the work was done.
MRM technology was designed by Duke researchers in order to create highly detailed images of tiny structures and specimens. The technique is a refined version of magnetic resonance imaging (MRI) used in hospitals, but is much more powerful, using higher magnetic fields to create superb resolution. To make their three-dimensional images of plaque, the researcher removed tiny "plugs" of brain tissue from patients who had agreed to a rapid autopsy when they died; that is, an autopsy performed with hours of death so that brain chemistry is still fresh.
To image plaque inside the centimeter-wide brain samples, a specially-engineered magnetic coil was developed by Johnson so that it could come as close to the tissue as possible. After a number of experimental tries, the team found the right combination of settings for spatial resolution that could image the plagues embedded inside the brain tissue without distortion. They then took hundreds of individual images while rotating the sample, so that when a computer blended all the images together, a high-resolution three-dimensional portrait of brain plaques was created.
"When reconstituted in a 3D image, plagues looks like small round balls, basically spots of garbage, floating in space," Benveniste said.
The researchers do not plan to use the technique to confirm a diagnosis of Alzheimer's disease in patients -- currently, the only way to make sure a person has died from the disorder is to examine brain tissue that has been laboriously sliced and stained. "Current clinical magnetic resonance technology does not have the resolution to allow visualization of plaques inside the brain of a living human," Benveniste said. "This kind of detailed imaging is only possible in small animals."
Rather, they are viewing the advance as a research tool. With the use of transgenic mice, they have moved closer to the goal of understanding the pathology of the disease. These mice contain a human gene known to produce excess amounts of plaque material in the brain and it offers a good animal model of how plaque may affect brain functioning, Benveniste said. To create images of living brains, the mice are briefly anesthetized so they don't move within the MRM machine and distort the image. In their ongoing benchmark study, the researchers are creating a library of images to chart growth and development of the mice brains. This effort helps them determine the best way to track changes in plaque growth as the mice age. They will then be able to correlate changes in cognitive behavior with plaque growth in future experiments.
In what Benveniste describes as the "next generation of molecular biology," the researchers might be able to track, in living animal brains, the success of experimental drugs aimed at stopping the growth of plaques. "The dream of every brain researcher is to be able to follow, over time, both development of brain disease and the effects of drugs designed to combat them," she said. "If it works for this disease, it could work for other disorders and therapies. Time will tell."
Note to editors: The photo is available in color as Beneviste.jpg at http://photo1.dukenews.duke.edu. An image of brain plaque is located at http://wwwcivm.mc.duke.edu/civmProjects/Alzheimers/alz.html.
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