One of the challenges to diagnosing Alzheimer's disease is the lack of a nonbehavioral clinical test. The definitive diagnosis can only be made when amyloid plaques and neurofibrillary tangles are seen at autopsy. Virginia Lee, Daniel Skovronsky, and colleagues at the University of Pennsylvania report that they have synthesized a molecule that may be the first step toward evaluating Alzheimer's pathology in living patients using current radiological techniques.
The hurdle has been to find a molecular probe that attaches itself to fibrillar β-amyloid with a high degree of specificity (i.e., it doesn't label other compounds) and also sensitivity (i.e., it picks up even low levels of plaques). Furthermore, in order to be useful as a clinical probe, the molecule will have to be tagged with a radioactive tracer and delivered in a noninvasive manner, meaning intravenously rather than directly into the brain. This means that the molecular probe must be able to get through the blood-brain barrier, the natural filter that protects the brain.
Lee's group has synthesized a probe called BSB [for (trans,trans),-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene] that has a high affinity for Aβ aggregates in vitro. Writing in the Proceedings of the National Academy of Sciences, they report that this molecule labeled amyloid plaques in human AD autopsy sections with great sensitivity and penetrated cells in vitro to label intracellular Aβ42 aggregates with high specificity. When administered to living transgenic Tg2576 mice, which express human amyloid in plaque aggregates, BSB labeled those plaques with great sensitivity and specificity. This was true when it was administered directly into the brain, but more importantly, when it was administered intravenously, as well.
Clearly, say the authors, much remains to determine if this probe is safe and stable enough to use in patients. But if it were to be effective, it would give clinicians, first, a test to definitively diagnose AD, and second, a way to monitor the effectiveness of drugs designed to break up and eliminate plaques. "This research is an enormously important step toward developing an imaging method that could pinpoint telltale signs of plaque development associated with Alzheimer's disease in a living brain," opines Marcelle Morrison-Bogorad of the National Institute of Aging.—Hakon Heimer
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- Skovronsky DM, Zhang B, Kung MP, Kung HF, Trojanowski JQ, Lee VM. In vivo detection of amyloid plaques in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7609-14. PubMed.