The Holy Grail for researchers studying Alzheimer's disease is an imaging
system or biomarker to help diagnose the illness or at least document its
A new study from researchers at Washington University in St. Louis takes a
step in that direction by combining PET scan imaging and cerebrospinal fluid
(CSF) analysis. The process compared the extent of beta-amyloid plaques in the
brain with levels of related protein fragments in CSF or blood plasma.
Using PET technology, researchers led by Anne Fagan, Ph.D., a research
associate professor of neurology at the Washington University School of
Medicine, scanned the brains of 24 people aged 48 to 83 to find concentrations
of plaques containing beta-amyloid. They used an amyloid-binding agent,
Pittsburgh Compound B (PIB), provided by investigators at the University of
Pittsburgh. Some participants were cognitively normal while others had very
mild, mild, or moderate dementia.
Fagan and her colleagues from the Washington University Alzheimer's Disease
Research Center also tested CSF and blood plasma for several proteins using
enzyme-linked immunosorbent assays.
They found no relation between PIB binding and the proteins amyloid-40,
tau, phosphor-tau181 in CSF, and amyloid-40 and amyloid-42 in plasma. However,
they did observe an inverse relationship between amyloid-42 in CSF and PIB
binding at beta-amyloid plaques in the brain.
"Subjects fell into two nonoverlapping groups: those with positive
PIB binding had the lowest CSF amyloid-42 level, and those with negative PIB
binding had the highest level," wrote the researchers in an online
publication of their paper in the Annals of Neurology.
Seven subjects showed positive PIB binding and low CSF amyloid-42 levels.
Three of those subjects were diagnosed with mild or moderate Alzheimer's-type
dementia, and another with very mild symptoms.
However, three participants were cognitively normal but had high PIB
binding and low CSF levels of amyloid-42, hinting that they were in such a
preclinical state. If these subjects eventually develop dementia, this
combined technique may indeed prove useful for identifying cases before they
reach clinical status. However, if patients such as these never decline
cognitively, it may show that plaque number does not always predict the
Prior animal studies have suggested that amyloid plaques in the brain may
bind beta-amyloid, reducing the movement of soluble beta-amyloid between the
brain and the CSF, possibly accounting for the inverse relationship, said the
authors. Heavy deposits of beta-amyloid plaques at autopsy are diagnostic for
"These observations suggest that brain amyloid deposition results in
low CSF amyloid-42 and that amyloid imaging and CSF amyloid-42 levels may
potentially serve as antecedent biomarkers of preclinical Alzheimer's
disease," Fagan said. "[They] support the hypothesis that amyloid
deposition in the brain acts as a `sink,' resulting in a new equilibrium
between soluble and deposited amyloid-42 in the central nervous
"These measures hold potential for identifying individuals with
Alzheimer's disease pathology before cognitive symptoms [appear], improving
the accuracy of clinical diagnosis, and facilitating the testing of future
therapies," said Fagan in a prepared statement. "But 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
"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," commented Neil Buckholtz, Ph.D., chief of
the Dementias of Aging Branch at the National Institute on Aging. "This
study represents one step in the progress being made toward identifying
clinically useful biological measures for AD."
The study was supported by the National Institute on Aging and the
Washington University General Clinical Research Center, which is funded by the
National Institutes of Health.
An abstract of "Inverse Relation Between in Vivo Amyloid
Imaging Load and Cerebrospinal Fluid A42 in Humans" is posted at<www3.interscience.wiley.com/cgi-bin/abstract/112219062/ABSTRACT>.▪