New Compound Identifies Alzheimer's Disease Brain Toxins, Study Shows

Until now, the beta-amyloid deposits to which PiB binds have been confirmed, without question, only in the autopsied brains of patients afflicted with Alzheimer's. The new findings, which correlate PiB-identified beta-amyloid deposits from living patients to their post-mortem autopsy results, will ultimately aid in the early diagnosis of Alzheimer's, help clinicians monitor the progression of the disease and further the development of potential treatments.

"This is final confirmation of what we have believed all along -- that Pittsburgh Compound-B allows us to accurately assess the amount of beta-amyloid plaques in brains of people afflicted with Alzheimer's," said senior author Steven DeKosky, M.D., professor of neurology, psychiatry, neurobiology and human genetics and director of the Alzheimer's Disease Research Center at the University of Pittsburgh.

Invented and developed by Pitt researchers Chester Mathis, Ph.D., professor of radiology and pharmaceutical sciences, and William Klunk, M.D., Ph.D., professor of psychiatry and neurology, PiB is a radioactive compound that, when coupled with positron emission tomography (PET) imaging, can be injected into the bloodstream to enable researchers to visualize the brains of people with the memory-stealing illness and see the location and distribution of the beta-amyloid plaque deposits associated with Alzheimer's. The distinguishing factor between Alzheimer's disease and other dementias is the presence of these amyloid plaques, which are thought to kill brain cells.

In the study, a 63-year-old woman with a clinical diagnosis of Alzheimer's underwent PiB PET imaging. The PET scan showed significant retention of PiB in distinct regions of her brain. Upon her death 10 months later, her autopsied brain was analyzed using histological and biochemical assays to detect a variety of amyloid deposits, including the beta-amyloid plaques. The regions of her brain where the PET scans had identified the highest PiB levels before death correlated precisely with the regions of high beta-amyloid plaque concentrations in her autopsied brain. 

Beta-amyloid plaques, the hallmark of Alzheimer's disease, are just one type of amyloid structure that can be found in diseased brains. However, other forms of amyloid are not thought to be specific for Alzheimer's, or they have significantly different roles in the pathogenesis of this disease. To further validate the binding properties of PiB to beta-amyloid and the presence of Alzheimer's disease, sophisticated laboratory studies were performed on the autopsied brains of 27 other patients with confirmed Alzheimer's disease.

"In every subject, and with each test that we performed, our results supported the idea that PiB binds almost exclusively to beta-amyloid, which means that we can, with confidence, look to PiB to indicate the troublesome beta-amyloid deposits in brains of living patients," said the lead author Milos Ikonomovic, M.D., assistant professor of neurology and psychiatry at the University of Pittsburgh.

"This patient who selflessly and generously agreed to PiB PET scanning and who gave us the gift of her brain has enabled us to compare what we detected during her life to what we confirmed after her death. The findings from our study of her brain, coupled with the further confirmation of the other 27 brains, tell us without a doubt that PiB binds to beta-amyloid and that it is a reliable indicator of the presence of Alzheimer's disease in those who are suffering its cruel effects," said Dr. Klunk.

"This work is an important step forward in the development of new tools for both research and clinical care," noted Neil Buckholtz, Ph.D., chief of the Dementias of Aging Branch of the National Institute on Aging, National Institutes of Health, which supported the study. "It provides additional evidence validating the use of PiB to identify beta-amyloid deposits in living individuals and advancing the potential use of PiB as an outcome measure in clinical trials of anti-beta-amyloid therapeutics."

It is estimated that up to 4.5 million people in the United States have Alzheimer's, including 50 percent of those older than age 85 and 10 percent of those over age 65. The number of those affected is expected to triple over the next 50 years.

Journal reference: Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease. Brain. Advance Access published online on March 12, 2008 Brain, doi:10.1093/brain/awn016

In addition to Drs. DeKosky, Ikonomovic, Klunk and Mathis, the research team included Eric Abrahamson, Ph.D., Julie Price, Ph.D., Nicholas Tsopelas, M.D., Brian Lopresti, B.S., Scott Ziolko, B.S., Wenzhu Bi, B.S., William Paljug, M.Sc., Manik Debnath, M.S., Caroline Hope, M.Sc., Barbara Isanski, M.Sc., and Ronald Hamilton, M.D., all of the University of Pittsburgh School of Medicine.

The study was supported by grants from the National Institutes of Health, the Alzheimer's Association, The U.S. Department of Energy and the Dana Foundation.