By the time a person begins to experience symptoms of Alzheimer's disease, several brain structures already are dotted with the plaques and tangles that characterize the illness. So researchers are working to identify changes in brain structures as early as possible in the course of the disease — at a time when it might soon be possible to halt the progress of the disease before people become severely impaired.
Even the best brain imaging techniques can't yet reveal the presence of plaques and tangles, but a team of neuroscientists at the Silvio Conte Center for Neuroscience Research and the Alzheimer's Disease Research Center at Washington University in St. Louis have been working with state-of-the-art imaging techniques to see whether they can identify subtle changes in brain structures that are present in the earliest stages of the disease.
At the time of the first MRI scans, the turquoise color shows areas of the hippocampus in patients with mild Alzheimer's disease that are shaped differently than in healthy older people. Two years later, even more changes have occurred, represented by the purple color.
Reporting online and in an upcoming issue of the journal NeuroImage, Lei Wang, Ph.D., research associate in psychiatry, and colleagues say they have identified changes in the brain that appear to distinguish Alzheimer's disease from healthy aging.
Because learning and memory are greatly affected by Alzheimer's disease, the team focused on a structure important for learning and memory: the hippocampus, a seahorse-shaped structure deep inside the brain.
They compared healthy people with those in the early stages of Alzheimer's disease. To identify differences, they conducted magnetic resonance imaging (MRI) scans two years apart on 18 patients with mild Alzheimer's disease and 26 healthy individuals of about the same age.
The team measured differences in the volume and shape of the hippocampus and the differences in the way the volume and shape of the hippocampus became more abnormal over time.
In people who didn't have Alzheimer's disease, the volume of the hippocampus decreased by about 4 percent over two years. But in people with early Alzheimer's disease, the volume of the hippocampus decreased by 10 percent.
In addition, the changes in shape in healthy people tended to be confined to a small part of the structure. But in people with Alzheimer's disease, shape changes involved larger parts of the hippocampus, including an area where plaques and tangles are known to appear..
"There were changes in normal people, too," Wang says, "but the changes were more pronounced in people with mild Alzheimer's disease. At the start of the study, there were some differences between the two groups, but at the two-year follow-up, the pattern of changes had spread to a wider region of the hippocampus in people with Alzheimer's disease."
Much of the research at Washington University's Silvio Conte Center for Neuroscience Research uses imaging to try to identify subtle anatomical differences that demonstrate a person is at risk for a particular disease. In diseases like schizophrenia or autism, researchers believe that differences in the shape of various brain structures probably show up very early. People may even be born with them.
"But in Alzheimer's disease, presumably brain structures have a normal size and shape until the disease cascade begins," says John G. Csernansky, M.D., the Gregory B. Couch Professor of Psychiatry and director of the Conte Center. "Changes in hippocampal shape represent early evidence of damage to a part of the brain that previously was normal. Those changes in shape happened at the same time that patients were first showing symptoms of Alzheimer's disease, so that provides strong evidence that the shape changes that we observed in the hippocampus may be actually causing at least some of the symptoms of Alzheimer's disease."
Alzheimer's disease causes volume changes, too. But those are more difficult to interpret because people of various sizes also tend to have different sized brains. By using imaging scans to measure subtle changes in the shape of brain structures, the researchers believe they have a more sensitive indicator of the presence of disease.
"Tangles and plaques occur early in a part of the hippocampus called the CA1 region and in another sub-field of the hippocampus called the subiculum," Wang says. "In our study, we were able to see changes occurring in those same sub-fields as the disease progressed over time. So our findings seem to correspond to what others have found in post-mortem studies."
In past imaging studies, Wang and Csernansky have found that the hippocampus tends to be slightly smaller in people with Alzheimer's disease than in those without the disorder. They also noted that even healthy older adults had some changes in the shape of the hippocampus when compared to younger adults. But they still had difficulty distinguishing normal changes in volume and shape from atrophy that might be associated with disease. This study helped to clarify that by demonstrating people with Alzheimer's disease tended to change more — and in more parts of the hippocampus — as their disease progressed over time.
"There was a logical progression of the shape change — it initially involved a smaller portion of the hippocampus and later grew to involve a larger portion," Csenansky says.
The ultimate goal, they say, is to identify differences in volume and shape of brain structures such as the hippocampus that can predict the future onset of Alzheimer's disease. Detecting disease before clinical symptoms appear will be critical when there are treatments that can prevent more extensive damage and halt the progression of the disease.
Wang L, Swank JS, Glick IE, Gado MH, Miller MI, Morris JC, Csernansky JG. Changes in hippocampal volume and shape across time distinguish dementia of the Alzheimer type from healthy aging. NeuroImage vol. 19, 2003. Available online by clicking here.
Funding from the National Institutes of Health, the Gregory B. Couch Endowment at Washington University and a grant from the American Health Assistance Foundation supported this research.