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 Alzheimer's disease 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 in 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.
The method studied might one day help to more accurately diagnose Alzheimer's disease , 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.
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" 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,
chief of the Dementias of Aging Branch at the NIA. "T his
study represents one step in the progress being made
toward identifying clinically useful biological measures
for Alzheimer's disease."
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 Alzheimer's disease, identifying the
presence of Alzheimer's disease 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
Alzheimer's disease before symptoms develop and as the
disease progresses," says Fagan. " These measures hold
potential for identifying individuals with Alzheimer's
disease pathology before cognitive symptoms, improving the
accuracy of clinical diagnosis of Alzheimer's disease 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."
Source: National Institutes of Health, 2005