Clues to Progression of Alzheimer's Disease
A novel imaging agent heralded for its potential to diagnose Alzheimer's disease during life is now giving scientists information never before available about how and where the disease progresses in the brain. Results of this new research involving Pittsburgh Compound-B (PIB), which binds to the telltale beta-amyloid deposits in the brain of Alzheimer's patients, were presented by University of Pittsburgh scientists November 15 at Neuroscience 2005, the 35th Annual Meeting of the Society for Neuroscience in Washington, DC.
Prior to this study using PIB there had not been a way to monitor non-invasively what is happening in the brains of people with Alzheimer's disease, a significant barrier to studying disease progression and monitoring the efficacy of treatments.
Developed by scientists at the University of Pittsburgh, PIB, when coupled with positron emission tomography (PET), gives scientists a picture of beta-amyloid, or amyloid plaque, deposits in the brain. The distinguishing factor between Alzheimer's disease and other dementias is the presence of amyloid plaques that are thought to cause the death of brain cells. Studies have demonstrated that PIB can detect the accumulation of amyloid plaques when patients are alive. This could lead to accurate diagnosis of Alzheimer's disease at very early stages. Previously, a definitive diagnosis of the disease could only be made through an autopsy after the patient's death, typically at a very late stage of the illness.
According to one University of Pittsburgh study reported at the Society for Neuroscience meeting, the pattern of PIB retention in the brain suggests that amyloid plaques deposit sequentially. Amyloid plaques first appear in the brain's cingulate cortex/precuneus and frontal cortex areas, then progresses to the parietal and temporal cortex and caudate. Finally, the disease ravages the occipital cortex and sensory-motor cortex. These findings may explain why memory and judgment are often the brain functions first affected in Alzheimer's disease.
"We've had hints about the time course of brain changes in Alzheimer's disease from autopsy studies but the current findings in living patients take these observations further," said William E. Klunk, MD, PhD, associate professor of psychiatry at the University of Pittsburgh School of Medicine and co-inventor of PIB, who presented the findings. "If we can delineate the natural history of brain changes in Alzheimer's disease, we then have a baseline against which to judge the success of therapies designed to prevent these changes."
The scientists hope that PIB will be used in clinical trials of Alzheimer's therapies within the next year or two. To meet this goal, they have developed a more simplified method for analyzing data from PIB studies, which is described in a second study presented by SNM members Chester A. Mathis, Ph.D., and Julie C. Price, Ph.D.
The original approach for using PIB mandatory patients to have arterial blood samples drawn over the span of 90 minutes. The blood samples were used to define how much PIB actually got to the brain. Scientists then used a complex modeling analysis to determine where PIB had accumulated in the brain, signaling the location of amyloid plaque deposits. In the current study, the Pittsburgh scientists found that it may eventually be possible to replace the arterial blood sampling by data that can be recovered from the PET scan itself. While this approach appears promising, arterial sampling may continue to be necessary for some uses of PIB.
By using a method that eliminates the need for arterial blood draws, the scientists think that patients will be more comfortable participating in PIB research; the more simple approach also will allow scientists at other centers to use PIB for large-scale investigation.
"Pittsburgh Compound-B allowed us to see what was happening in the living brain during Alzheimer's disease. Before this compound we had no way to judge the progression of amyloid deposition in real-time, making it hard to assess the degree of pathology in the brain, especially in the early stages. The compound should prove especially useful for ascertaining how new therapies are actually working to eliminate amyloid plaques in the brain," said Dr. Mathis, who is a professor of radiology at the University of Pittsburgh School of Medicine and co-inventor of PIB. "Making use of this compound easier on both patients and scientists alike could help accelerate the pace of clinical trials of Alzheimer's disease."
Alzheimer's is a debilitating brain disease that affects memory and cognitive function in an estimated 4.5 million Americans, and if advances in treatments are not realized, will strike as a number of as 14 million over the next 50 years.