Feb. 14, 2006 Brain scans may detect neurological changes in people who exhibit no outward signs of cognitive decline but who later develop dementia or mental impairment, according to the results of a new study led by researchers at the University of California, Berkeley.
The study, to be published Feb. 8 in the journal Annals of Neurology, provides encouraging evidence that positron emission tomography (PET) and magnetic resonance imaging (MRI) could eventually be used to detect preclinical signs of Alzheimer's disease.
"Our paper is one of the few to show that it is possible to detect changes in the brains of normal older people who experience subsequent cognitive decline," said Dr. William Jagust, UC Berkeley professor of neuroscience and public health and lead author of the paper. "We don't have enough data, yet, to say that the brain scans can predict Alzheimer's disease. However, the locations of the affected brain regions have been associated in other studies with Alzheimer's, so it's possible that we are picking up early signs of the disease."
Jagust, who has joint appointments at UC Berkeley's School of Public Health, the Helen Wills Neuroscience Institute and the Lawrence Berkeley National Laboratory, worked with Mary Haan, professor of epidemiology at the University of Michigan and principal investigator of the Sacramento Area Latino Study on Aging (SALSA).
The brain imaging study is a substudy of SALSA, the first and only representative study of dementia and cognitive functioning in a Latino population. SALSA, funded by the National Institute on Aging, includes 1,789 people, primarily Mexican American, who were recruited by mail, telephone and door-to-door solicitation.
For the imaging substudy, 60 cognitively normal participants received baseline PET and MRI brain scans and underwent a full battery of neuropsychological tests at enrollment. They were followed for an average of 3.8 years, taking cognition and memory tests approximately once a year. Individuals with significant declines in their scores were evaluated further for signs of cognitive decline.
The researchers found that lower glucose metabolism - as determined by the PET scans - was strongly linked to faster declines on the modified mini mental state examination (3MSE), a test that assesses global cognitive functions such as memory, language, spatial ability and judgment.
Specifically, the PET scans detected areas of lower glucose metabolism in the parietal and temporal lobes of the brain, the same regions shown in many other studies to have lower glucose metabolism in Alzheimer's patients and in some people with mild cognitive impairment.
In the imaging substudy, the MRI scans focused on the entorhinal cortex and hippocampus regions in the temporal lobe of the brain, areas that are involved in memory. Other post-mortem studies of the brains of Alzheimer's patients indicate that these regions are the first to become affected as the disease develops.
The researchers found that the smaller these brain regions were in the MRI scans, the more an individual's score declined on the delayed recall (DelRec) memory test. These results are also in line with findings from other studies that link the size of the entorhinal cortex and hippocampus in people with mild cognitive impairment with the eventual development of Alzheimer's disease.
The researchers point out that the different brain scans predicted declines on different types of cognitive tests. The PET scans predicted declines on the 3MSE, but they did not predict declines on the DelRec memory test. It was the reverse for the MRI scans, which predicted declines on the memory test, but not on the 3MSE.
"These results fit with what we know about the brain," said Jagust. "The brain regions picked up by the PET scans involve more generalized cognitive functions, while the regions studied in the MRI scans are associated with memory."
During the study, five people developed cognitive impairment and one person was diagnosed with Alzheimer's disease. One of the five who developed cognitive impairment showed the fastest decline on both tests.
"In a project of this size, it's not realistic to expect the brain scans to predict Alzheimer's," said Haan. "But there is enough information to say that PET and MRI scans can predict subsequent cognitive decline in a population of cognitively normal people."
The researchers note that prior research on Alzheimer's focused primarily on people who had already developed mild symptoms of cognitive loss or on post-mortem analyses of the brains of Alzheimer's patients.
"By the time people who are already sick are identified, it's often too late to slow down the progression of Alzheimer's," said Haan. "By identifying early changes that could predict the development of dementia, it may also be possible to link those changes to primary risk factors that could be altered."
According to the National Institutes of Health, approximately 4 million people suffer from Alzheimer's disease in the United States, and the proportion of people with the disease doubles every five years after the age of 65.
"In the last two to five years, there has been a real explosion of knowledge about the molecular basis of Alzheimer's that may lead to effective drugs to cure or prevent the disease, and those drugs would likely be more effective the earlier they are given," said Jagust. "That has given a new urgency to research in predicting as early as possible those who will go on to develop Alzheimer's."
Options are now limited for identifying those who may go on to develop Alzheimer's disease. Few genetic factors have been identified, and the ones that have are only applicable to a minority of people who go on to develop the disease.
For instance, research has identified an allele that codes for a protein called apolipoprotein E, or apoE, as a major genetic risk factor for Alzheimer's disease. ApoE is associated with the buildup of beta amyloid plaques in the brain's nerve cells.
However, researchers estimate that this gene is only present in 15 to 25 percent of populations with Northern European ancestry. Among the Mexican American and Asian American populations, the prevalence is closer to 10 percent.
Meanwhile, research is continuing on identifying other risk factors for mental decline. The SALSA study, for instance, is credited with first identifying type 2 diabetes as a risk factor for dementia and cognitive impairment.
"It's possible that people of Mexican descent have a higher genetic risk for type 2 diabetes," said Haan. She said that she is investigating whether genes known to be associated with type 2 diabetes are also related to an increased risk in cognitive impairment.
Other co-authors of the paper are Amy Gitcho, research assistant, and Felice Sun and Beth Kuczynski, research fellows, at UC Berkeley's Helen Wills Neuroscience Institute; and Dan Mungas, professor of neurology at UC Davis.
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