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CSF protein predicts development of Alzheimer's.

CHICAGO -- A combination of specialized brain imaging and cerebrospinal amyloid beta42 measurements powerfully predicts the presence--and absence--of Alzheimer's-type dementia.

For several years researchers have focused on A[[beta].sub.42] in cerebrospinal fluid (CSF) as a possible biomarker of Alzheimer's disease: Higher levels indicate the protein is still soluble, whereas lower levels suggest that it might be building up in the brain as neuropathologic plaque. But an unpredictable overlap of CSF A[[beta].sub.42] among controls, Alzheimer's patients, and those with mild cognitive impairment has confounded any definitive conclusions, Anne Fagan, Ph.D., said at the International Conference on Alzheimer's Disease.

The advent of Pittsburgh imaging compound B (PIB), an imaging agent that lights up amyloid plaques during PET scanning, has allowed Dr. Fagan to more fully explore the associations of A[[beta].sub.42] in the brain and the CSF. She presented the results of a prospective study of 132 subjects who underwent PIB scanning and a lumbar puncture for CSF A[[beta].sub.42] levels within a 2-year period. These volunteers had a mean age of 66 years; 113 were cognitively normal, 14 had very mild Alzheimer's dementia, and 5 had mild Alzheimer's dementia.

Dr. Fagan, of Washington University, St. Louis, and her colleagues found what she called "a striking inverse relationship between the levels of amyloid in the brain and levels of A[[beta].sub.42] in the CSF."

Of the 37 subjects whose PIB-PET scans showed high levels of brain amyloid, 36 (97%) had low CSF A[[beta].sub.42]. Conversely, 80 of the 95 with low levels of brain amyloid (84%) had high CSF A[[beta].sub.42]. These relationships were strong regardless of cognitive status at the time of testing. "Low CSF A[[beta].sub.42] appears to be an excellent marker for the presence of brain amyloid, regardless of whether people have dementia or not. Low CSF A[[beta].sub.42] combined with PIB-positivity in the brain may be antecedent biomarkers of Alzheimer's disease, predicting who will develop future dementia."

Some independent clinical follow-up data seem to confirm this, Dr. Fagan said. Three subjects who were cognitively normal at the time of testing, but were PIB-positive and had low CSF A[[beta].sub.42], have since developed very mild Alzheimer's dementia.

Four with diagnoses of very mild Alzheimer's who were PIB-negative and had high CSF A[[beta].sub.42] have had their diagnoses changed to no dementia or non-Alzheimer's dementia. "High CSF A[[beta].sub.42] and cortical PIB-negativity may be useful for a differential diagnosis, identifying possible Alzheimer's misdiagnoses in the very early stages."

Of four subjects who were PIB-negative but had low CSF A[[beta].sub.42], "one subject is now PIB-positive, indicating the presence of cortical amyloid, and two others may have PIB-positivity in some select brain regions. Levels of CSF A[[beta].sub.42] may decrease prior to cortical amyloid becoming detectable by PIB, and thus may be a very sensitive biomarker for the earliest, preclinical stages of Alzheimer's," she noted.

The clinical impact could be profound, Dr. Fagan said at the meeting sponsored by the Alzheimer's Association. "Disease-modifying treatments ... will have the best chance of preserving normal brain function if they are initiated in the early, or even in the preclinical, stages, prior to any cognitive symptoms."

BY MICHELE G. SULLIVAN Mid-Atlantic Bureau
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Title Annotation:News; cerebrospinal fluid
Author:Sullivan, Michele G.
Publication:Internal Medicine News
Article Type:Clinical report
Geographic Code:1USA
Date:Sep 15, 2008
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