Pittsburgh Compound B, towards diagnosing Alzheimer’s disease
by Scott Perkins
The first thing that comes to mind when you think of medical breakthroughs in Pittsburgh might be the polio vaccine, but what about Alzheimer’s disease research? About eight years ago, a team of Pitt researchers consisting of William Klunk, MD, PhD and Chester Mathis, PhD, had their first successes with a compound that enabled them to visualize amyloid plaques in living human brain tissue – the first time this has been accomplished with strong correlation by anyone in the world. This molecule came to be known as Pittsburgh Compound B (PiB).
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that targets our elderly population and, at present, has no cure. AD symptoms include dementia, confusion, and memory loss among other things. Its pathology in the brain is largely characterized by amyloid-beta plaques and neurofibrillary tangles which are usually observed during post-mortem analysis. However, knowing that a deceased individual had plaques and tangles in their brain does not help physicians to understand the timely progression of Alzheimer’s disease before a diagnosis is made. For this reason, researchers began to search for ways to visualize the presence of AD indicators in live patients.
Currently, the best diagnostic tool for measuring in vivo receptor binding is with positron emission tomography (PET). In order for PET scans to work effectively, a suitable tracer is needed that can cross the blood brain barrier, bind to a specific receptor or protein, and then be cleared from the brain efficiently. Radiochemist, Dr. Mathis, synthesizes a tracer like this by attaching a radioactive isotope to the compound of interest, injecting it into a patient through an IV, and then using a PET scanner and computer to analyze what areas of the brain have the most accumulation of tracer. This is the sum total of about fifteen years of work performed by Dr. Mathis after he first began to look for a compound to observe AD progression in the brain.
So how was Dr. Mathis able to have so much success in his research during this amount of time? “Perseverance and learning from your failures,” Mathis told me during a phone interview. When he first started in 1986, he was using Congo Red, a charged dye that was used for staining amyloid plaques in histological tissue sections. He quickly learned that Congo Red was unsuitable as an in vivo binding agent because it could not cross the blood brain barrier. At the suggestion of Dr. Klunk, a Pitt geriatric psychiatrist, he moved to a more lipophilic (or “fat-loving”) molecule named Chrysamine G. The two doctors started working together and created over 300 Chrysamine G derivatives between 1994 and 1999. Many of these compounds had the properties that Klunk and Mathis were looking for but were still unsuitable for PET studies. After switching to derivatives of thioflavin-T, a fluorescent radiolabel, the two researchers settled on a molecule that would later become known internationally as Pittsburgh Compound B.
AD is extremely rare in individuals younger than 60 years old; in fact, only 5% of 60-70 year-olds have a diagnosis of Alzheimer’s. However, 10-20% of people in this age group show amyloid plaque positivity. Pittsburgh Compound B (PiB) is a useful tool because it allows researchers to observe pathological changes in the brain before symptoms appear, and subsequently allows us to potentially help these patients before it is too late. According to Dr. Mathis, it takes about ten years from the time amyloid plaques become evident in the brain until a diagnosis of Alzheimer’s can be made. PiB allows us to be able to learn from patients that are at risk for AD (those positive for amyloid plaques), but who have not yet started experiencing symptoms.
When I asked Dr. Mathis if PiB would be eventually used for screening purposes the way breast exams or colonoscopies are administered, he answered that it was a possibility. However, before widespread screening can be applied, we need to find a cure for Alzheimer’s disease in order to make screening worthwhile. For now, patients benefit from knowing they have amyloid positivity because it allows them to plan for the future. Mathis likened it to a sort of “peace of mind” about knowing what is in store for your future and knowing what kind of arrangements to make with your family.
The discovery of Pittsburgh Compound B has had enormous impacts on the careers of Chester Mathis and William Klunk. When they first started, they were assistant and associate professors; now they are tenured, full professors working as directors of various associations related to their disciplines. Over the past few years, they have received over ten substantial grants from the National Institute of Health, drug companies, and other institutions in addition to receiving royalties from the patent that Pitt has on PiB. Not to mention, that they have garnered considerable prestige and fame for both our university and Pittsburgh.
Currently, Dr. Mathis is working on a tracer to study the progression of the neurofibrillary tangles that are also associated with AD. Dr. Klunk still works as a psychiatrist at UPMC. Their work with Alzheimer’s disease remains influential around the world, and they are continually invited to give speeches all over the country. The large community of individuals affected by Alzheimer’s disease is indebted to Dr. Mathis and Klunk for the progress they have made in this important field of study. Hopefully, these two Pitt researchers will continue their progress until we have a cure for this unfortunate disease.