April 21, 2008
An imaging agent developed by researchers at the University of Pittsburgh Medical Center that attaches to brain areas damaged by Alzheimer's disease may allow doctors to diagnose Alzheimer's at an earlier stage. The substance, named Pittsburgh compound B, attaches to deposits of beta-amyloid, the toxic protein that builds up in the brains of those with Alzheimer's.
Currently, Alzheimer's disease can be diagnosed with certainty only on autopsy, when doctors examine the brain. The development of a test that could diagnose the disease earlier would be valuable because doctors could prescribe drugs to slow progression of the disease (when such drugs are developed) at an early stage, when they may be most useful.
Early diagnosis could also allow researchers to test to see if experimental drugs are helping to prevent the progressive downward spiral that inevitably occurs in Alzheimer's. In this case, disease progression, or remission, could be measured by changes in the beta-amyloid content of the brain. Instead of waiting until autopsy, such changes in the brain can be detected during life by the Pittsburgh compound.
Beta-amyloid deposits in the brain, called plaques, are a hallmark of Alzheimer's. Until now, scientists could identify beta-amyloid plaques with certainty only when examining brain tissue on autopsy.
"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 Research Center at the University of Pittsburgh.
From Bloodstream to Brain
Pittsburgh compound B is a radioactive substance that is injected into the bloodstream. It then travels to the brain, where it binds to the beta-amyloid plaques that build up in the Alzheimer's-addled brain. Using an advanced brain scan technique called positron emission tomography, or PET, scientists can produce computer-generated images that show beta-amyloid deposits in the living brain.
In the study, a 63-year-old woman with a clinical diagnosis of Alzheimer's underwent Pittsburgh compound B injections and PET imaging. The PET scan showed significant retention of the compound in distinct regions of her brain.
When she died, 10 months later, her autopsied brain was analyzed using a variety of scientific techniques to detect beta-amyloid. Areas of her brain where the PET scans had identified the highest levels of the compound before death correlated precisely with the regions of high beta-amyloid plaque concentrations in her autopsied brain.
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 Pittsburgh compound B (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," Dr. Klunk said.
This is not a fool-proof indicator, however. Many people with heavy plaque load, as indicated by the Pittsburgh compound, do not display the outward symptoms of Alzheimer's and are able to function normally. However, many of these individuals may go on to develop the severe cognitive loss of Alzheimer's.
Further testing will be needed to confirm these findings. And it may take years before a reliable test to diagnose Alzheimer's disease at its earlier stages becomes routinely available at clinics across the country. In addition to Pittsburgh compound B, scientists are investigating other tests and brain imaging techniques to diagnose Alzheimer's at an earlier stage.
As those with relatives and friends of people with Alzheimer's know, the diagnosis of Alzheimer's disease is difficult to determine with certainty. An accurate test to diagnose Alzheimer's could help to distinguish the future course of symptom progression in people with memory-robbing ailments. People with mild cognitive impairment, for example, a form of memory loss that can impair day-to-day living, sometimes go on to develop the more severe symptoms of Alzheimer's. An accurate diagnostic test could help to determine who actually has early Alzheimer's, and who might benefit from Alzheimer's drugs.
A diagnostic test would also help researchers to monitor patients who are taking various medications, including experimental drugs. If brain scans showed that new deposits of beta-amyloid plaque were not growing in the brain, it might be a signal that a new Alzheimer's drug was working.
"Our results underscore the validity of using Pittsburgh compound B PET scanning not only to detect and follow the progression of beta-amyloid-containing deposits in clinically defined subject populations, but also to assess effectiveness of therapies aimed at clearing these potentially toxic deposits from the brain," the authors conclude.
University of Pittsburgh Medical Center, University of Pittsburgh Schools of the Health Sciences.
Milos D. Ikonomovic, William E. Klunk, Eric E. Abrahamson, et al: "Post-Mortem Correlates of In-Vivo PiB-PET Amyloid Imaging in a Typical Case of Alzheimer's Disease." Brain, published online, March 12, 2008.