STOCKHOLM —Significant advances in understanding how amyloid plaques form in the brain are providing researchers with new opportunities to study the causes of Alzheimer’s disease and how to treat or prevent it. “Much of the most promising Alzheimer’s disease research is looking at how we can reduce the buildup of amyloid plaques in the brain,” said William Thies, PhD, Vice President of Medical and Scientific Affairs of the Alzheimer’s Association. “The more we learn about how to interfere with the creation of beta amyloid, the closer we come to determining whether this is the right approach to fighting Alzheimer’s disease.”

A study presented at the Alzheimer’s Association’s 8th International Conference on Alzheimer’s Disease and Related Disorders focused on reducing amyloid plaque buildup in the brain. Patrick May, PhD, of Eli Lilly, and researchers at Elan Pharmaceuticals identified a compound that inhibits the function of gamma secretase. When they treated transgenic mice during a 90-day period when the mice would normally be accumulating large amounts of amyloid, the gamma secretase inhibitor produced an 80% to 90% reduction in beta amyloid without any adverse reactions.

Earlier this year, clinical tests of a vaccine designed to create antibodies to beta amyloid were halted when some participants developed inflammation of the central nervous system. “It is encouraging to see another approach to reducing amyloid buildup,” Dr. Thies said. “Additional research will be necessary to replicate the findings and reproduce them in other animals and eventually in humans. While we have made tremendous progress, we still have a long way to go before we can say we have conquered this devastating disease.”

BREAKTHROUGH BRAIN IMAGING

The first human studies of the compound 6-OH-BTA-1, used with positron emission tomography (PET) imaging, indicate that researchers now can, for the first time, successfully highlight amyloid plaques in the brains of individuals in the early stages of Alzheimer’s disease. “Having the ability to quantify amyloid deposition in the brain will have a profound impact on our ability to monitor the progression of Alzheimer’s disease as well as gauge the effectiveness of medical treatments,” said Dr. Thies. Prior to this discovery, the scientific community could view and study amyloid plaques only in postmortem brain tissue.

The collaboration leading to this breakthrough took 10 years, beginning with researchers at the University of Pittsburgh School of Medicine, under the leadership of Professor of Radiology Chester Mathis, PhD. Dr. Mathis and his colleagues synthesized more than 100 compounds and examined their properties to identify an agent that could safely cross the blood-brain barrier.

After conducting research using synthetic amyloid fibrils in normal mice and baboons, the investigators selected the 6-OH-BTA-1 compound, based on its ability to bind specifically to amyloid plaques, cross the blood-brain barrier, and clear from normal brain tissue. The compound’s successful demonstration of these properties led researchers to conclude that the imaging agent held promise for use in studying individuals with Alzheimer’s disease.

Building on the University of Pittsburgh research, Bengt Långström, Professor of Organic Chemistry at the Uppsala Universitet PET Center, led colleagues from the PET Center and Karolinska Institutet in Huddinge, Sweden, in the first human amyloid imaging studies. Fourteen individuals were recruited for the Uppsala study. Nine of the participants (ages 55 to 70) had a diagnosis of Alzheimer’s disease and were in relatively mild stages of the disease. Five additional individuals with no cognitive impairment were selected to serve as the controls.

After receiving the compound intravenously, the study participants underwent a 60-minute PET scan. Investigators were able to gather valuable images that showed that the compound entered the brain and was retained in specific regions of the brain consistent with the accumulation of plaques previously seen only during autopsy in the brains of people with Alzheimer’s disease. In addition, the researchers found that very little of the compound was retained in the brains of the control individuals who had no cognitive impairment. According to Professor Långström, “This research, which has been conducted very carefully over several years, is especially promising for the development of new treatments in that there is now a tool that can be used to validate and expand our understanding of the mechanisms of this disease.”

NR

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