Technique could provide the first non-invasive, definitive diagnosis before death
A team of chemists at the Harvard Institutes of Medicine is at work on a non-invasive method to show images of plaque deposits in the brains of Alzheimer's disease (AD) patients as the disease progresses. Currently, the only way to definitively diagnose both the plaque formation and the disease is to examine the patient's brain after death.
The laboratory studies are currently underway with animals, and have been published in the July 29 issue of the peer-reviewed Journal of Medicinal Chemistry, published by the American Chemical Society, the world's largest scientific society. (The report initially was published on the journal's Web site on July 2, 1999.)
"We envision a time when individuals who may be at risk to develop AD because of a family history, the presence of a susceptibility genetic marker, or an epidemiological risk will routinely be imaged" using the new technology, said Peter T. Lansbury, Ph.D., leader of the Harvard research team. He noted that this would allow definitive diagnosis and therapy faster than is now possible.
The Alzheimer's disease brain is characterized by abnormal amyloid plaque deposit in an amount that roughly correlates with the severity of symptoms at the time of death. While many factors strongly suggest that amyloid formation precedes neurodegeneration, a direct proof is lacking, Lansbury notes. For that reason, he says, "we sought to elucidate the relationship between amyloid formation and neurodegeneration by designing amyloid probes that could be used to measure brain amyloid noninvasively" and compare the course of amyloid deposition with symptom progression.
Lansbury's strategy involves coupling an isotope of the element technetium to large organic molecules that are known to have an affinity for amyloid of the type that characterizes the AD brain. The imaging is then done with single-photon computed tomography (SPECT) that relies on the detection of gamma particles emitted by the trace amounts of radioactive technetium probe.
"Our goal," Lansbury states, "is to prepare compounds that can cross the blood-brain barrier effectively and bind to brain amyloid, allowing its precise quantitation." In this paper, his group reports the synthesis of a group of compounds that have the solubility properties that are commonly associated with effective brain imaging agents. "Our compounds are also shown to effectively label amyloid plaques in tissue slices from postmortem AD brain," he adds.
"Studies are in progress to determine whether these compounds will reach the brain of a live animal, as suggested by their solubility properties, and bind brain amyloid. In addition, a novel series of analogs that is expected to have improved qualities for in vivo application have been synthesized and are also being tested in animals." A patent application, originally filed in 1996, is under review.
A nonprofit organization with a membership of nearly 159,000 chemists and chemical engineers, the American chemical Society publishes scientific journals and databases, convenes major research conferences, and provides educational, science policy and career programs in chemistry. Its main offices are in Washington, D.C., and Columbus, Ohio. ( http://www.acs.org )
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