Preliminary aspects of this work were presented in mid-2002 in the "Hot Topics" session of the widely attended International Conference on Alzheimer’s disease and Related Disorders in Stockholm, Sweden and were very well received by the scientific community. Subsequently, this preliminary report received much publicity, such as coverage in the "News of the Week" section of Science and inclusion in the Discover magazine "100 Top Science Stories of 2002." Thus, most of the imaging community was aware that a full report was in progress. We had many inquiries about when and where this first full report would be published from scientists who were writing papers and reviews and wanted to include reference to the work in their manuscripts. Thus, in a sense, there was a group of investigators waiting for this publication.

Beyond this, the images of Alzheimer’s disease (AD) brain produced by this technology are very easily understood by the non-imaging community since the distribution of amyloid is very similar to what one would expect from autopsy studies. The visual, photogenic nature of the in vivo brain imaging work carries a certain inherent validity and appeal. The application of this technology to early diagnosis and drug development is very evident, so it is often referenced in general discussions regarding AD that do not focus on imaging.

Yes, this paper describes the first human imaging studies with Pittsburgh Compound-B. PIB provides a tool to non-invasively image beta-amyloid in the brain of living human subjects using positron emission tomography (PET). The compound has great potential as a surrogate endpoint to help determine the efficacy of anti-amyloid drug therapies currently in (or soon to enter) clinical trials, as a basic science tool to help test the amyloid cascade hypothesis, and someday as a diagnostic agent for AD.

Prior to the development of this brain imaging technology, AD could be diagnosed with certainty only by examining brain tissue itself, and this was performed after death with an autopsy. A consistent autopsy finding in AD is the presence of protein deposits in the brain called plaques. Plaques can be seen with tissue dyes that specifically bind to the proteins comprising the plaques. The plaques are composed of amyloid-beta proteins, and some scientists believe that an excess of amyloid-beta protein causes AD. Therefore, many drug companies are developing drugs aimed at preventing the accumulation or reversing deposits of amyloid-beta in the brain.

Researchers face several difficulties in their quest to successfully treat AD. One difficulty is that evidence suggests that the deposition of amyloid-beta protein begins years before the first symptoms of mild AD. The inability to detect the pre-symptomatic development of AD could mean that the brain pathology is fairly well advanced by the time of AD clinical diagnosis. In addition, advanced AD will likely to be more difficult to treat than during very early stages of the disease. Therefore, it is difficult to know who to treat prior to the onset of memory problems without the ability to detect pre-symptomatic amyloid-beta deposition. Another difficulty is designing drugs to combat amyloid-beta without being able to measure the direct effects of the drug on the target. This would be like developing a drug for diabetes without being able to measure blood sugar levels.

PIB is a variation of one of the tissue dyes used to positively diagnose AD after death. Unlike the tissue dyes, PIB can enter the brain in living humans, bind to the amyloid-beta protein plaques, and be detected by the scanning technique called positron emission tomography (PET). This allows one to detect and measure the amount of amyloid-beta in the brain of a living person. PIB imaging technology may one day allow screening for early amyloid pathology. It might be these very early, pre-symptomatic cases that would stand the best chance of responding to the therapeutic treatments of many kinds now under development. PIB imaging technology is currently being added to several new drug trials in order to improve our ability to find the most effective drugs more quickly and, thereby, make them available for the treatment of AD more quickly.

Drs. Klunk (at the University of Pittsburgh) and Mathis (at Lawrence Berkeley Laboratory) independently began working on the development of non-invasive brain-imaging methods to quantify brain amyloid deposition in AD in the late 1980’s. Each progressed this work slowly, until they met in the mid-1990’s after Mathis moved to the University of Pittsburgh. With a more focused commitment, they worked together to combine their expertise on the problem and evaluated several hundred compounds for this purpose along the way to PIB.