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.

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