The search for new measures, or "biomarkers," to detect Alzheimer's disease (AD) before signs of memory loss appear has advanced an important step in a study by researchers at Washington University in St. Louis, MO, and the University of Pittsburgh.
The researchers combined high-tech brain imaging with measurement of beta-amyloid protein fragments in cerebrospinal fluid (CSF). They found that greater amounts of beta-amyloid containing plaques in the brain were associated with lower levels of a specific protein fragment, amyloid-beta 1-42, in CSF. Prior research indicates that amyloid-beta 1-42 is central to AD development. The fragment is a major component of amyloid plaques in the brain, which are believed to influence cell-to-cell communication and are considered a hallmark of the Alzheimer's brain.
The study, published online December 21, 2005, by the Annals of Neurology, is the first to examine the relationship between levels of amyloid plaque deposits in the brain and different forms of beta-amyloid in CSF in living humans. It was supported by the National Institute on Aging (NIA), a component of the National Institutes of Health (NIH) at the U.S. Department of Health and Human Services, and by the Washington University General Clinical Research Center, funded by the NIH.
The method studied might one day help to more accurately diagnose AD, even before the appearance of cognitive symptoms, and to monitor disease progression. In the near term, the findings could be useful in a research context, allowing scientists to track the effects of potential beta-amyloid lowering treatments in clinical trials.
"We presently don't have fully validated imaging or biomarker measures that can help us monitor the development or progression of Alzheimer's in living people," explains Neil Buckholtz, Ph.D., chief of the Dementias of Aging Branch at the NIA. "This study represents one step in the progress being made toward identifying clinically useful biological measures for AD."
The research was conducted by Anne M. Fagan, Ph.D., and colleagues David M. Holtzman, M.D., Mark A. Mintun, M.D., and John C. Morris, M.D., of the Alzheimer's Disease Research Center (ADRC) at Washington University School of Medicine and used a newly developed imaging tracer for beta-amyloid from investigators at the ADRC at the University of Pittsburgh. Both ADRCs are funded by the NIA.
The study included 24 people ages 48 to 83 years who were cognitively normal or had very mild, mild, or moderate dementia. The researchers used positron emission tomography (PET), a brain imaging technique, with a tracing substance called Pittsburgh Compound B (PIB), to determine the amount of plaques in the participants' brains. PIB travels through the bloodstream into the brain and then binds to beta-amyloid containing plaques in the brain. PIB makes it possible to see on PET images any areas of the brain with high concentrations of plaques.
The researchers also analyzed samples of study participants' CSF and blood plasma for levels of specific protein fragments, including two forms of beta-amyloid and the protein tau.
The seven participants whose PET scans showed PIB binding -- and therefore deposits of beta-amyloid containing plaques in the brain -- had the lowest levels of amyloid-beta 1-42 in their CSF. Those without PIB binding had the highest levels of CSF amyloid-beta 1-42. No relationship was seen between PIB binding and the other CSF or blood-plasma biomarkers studied, including plasma amyloid-beta 1-42. As shown in previous studies of mice, decreases in CSF beta-amyloid may result from plaques acting as a "sink," hindering movement of soluble beta-amyloid between the brain and CSF, the researchers hypothesize.
Importantly, three of the participants had normal cognitive evaluations but had high PIB binding and low CSF amyloid-beta 1-42, suggesting the possibility that this combination of methods may be useful as "antecedent" biomarkers of AD, identifying the presence of AD amyloid pathology before the development of cognitive impairments. Alternatively, if these subjects never develop cognitive decline, it is possible that plaque number is not always a predictor of the disease.
"Although this study involved a very small sample, the findings suggest that amyloid imaging and CSF beta-amyloid measures together may have utility as biomarkers of AD before symptoms develop and as the disease progresses," says Fagan. "These measures hold potential for identifying individuals with AD pathology before cognitive symptoms, improving the accuracy of clinical diagnosis of AD and facilitating the testing of future therapies."
However, she cautions, "It is important to recognize that this is still a research study and the findings must be carefully validated before this approach can be considered for clinical use."
The search for biomarkers to detect AD and to monitor disease progression was accelerated recently when the NIA, in conjunction with more than a dozen other Federal Government and private-sector organizations, launched the 5-year, $60 million Alzheimer's Disease Neuroimaging Initiative. The initiative is the most comprehensive effort to date to study and correlate neuroimaging and fluid biomarkers with the changes associated with mild cognitive impairment and AD. It will examine whether serial magnetic resonance imaging (MRI), PET, other biomarkers, and clinical and neuropsychological assessment can be combined to assess mild cognitive impairment and early AD progression.
The Neuroimaging Initiative has begun recruiting people ages 55 to 90 to participate in the study. Participants may be cognitively normal or have MCI or early AD. Further information about the study and a list of the 58 local study sites in the U.S. and Canada may be obtained by calling the NIA's Alzheimer's Disease Education and Referral (ADEAR) Center toll free at 1-800-438-4380 or visiting the ADNI section of the ADEAR website at www.alzheimers.org/imagine. Anyone interested in learning more about enrollment in the project may contact the study site closest to them. Spanish-language capabilities are available at some of the study sites.
For information on participation in other AD clinical trials, visit http://www.clinicaltrials.gov/ (search for Alzheimer's disease trials) or the ADEAR Center website at http://www.alzheimers.org, or call the ADEAR Center toll free at 1-800-438-4380. The ADEAR Center is sponsored by the NIA to provide information to the public and health professionals about AD and age-related cognitive change and may be contacted at the website and phone number above for a variety of publications and fact sheets, as well as information on clinical trials.
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