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By
Michael Purdy
June
25, 2006 -- Science is now poised to answer an important
and longstanding question about the origins of Alzheimer's
disease: Do Alzheimer's patients have high levels of
a brain protein because they make too much of it or
because they can't clear it from their brains quickly
enough?
Researchers
from the Alzheimer's Disease Research Center (ADRC)
at Washington University School of Medicine in St. Louis
have developed the first safe and sensitive way to monitor
the production and clearance rates of amyloid beta peptide
(Abeta) in the human central nervous system. According
to the authors, the new testing process opens a valuable
window into the genesis of Alzheimer's disease that,
in addition to helping scientists better understand
the origins of the condition, will likely help them
improve its diagnosis and treatment.
The
scientists' results will be published online on June
25 by Nature Medicine.
High
levels of Abeta in the brain are a hallmark of Alzheimer's
disease and believed to be a pivotal cause of the condition.
Tests that measure Abeta levels in the cerebrospinal
fluid have been available for some time. However, those
fixed assessments of Abeta gave no indication of whether
the flood of Abeta in patient's brains came from an
increase in the mechanisms that make the protein or
a reduction in the processes that regularly clear it
from the brain.
Because
Alzheimer's symptoms take many years to develop, some
researchers had assumed that the creation and clearance
rates for Abeta were very slow. But the initial test
of the new technique, applied to six healthy volunteers,
suggests the opposite.
"Abeta
has the second-fastest production rate of any protein
whose production rate has been measured so far,"
says lead author Randall Bateman, M.D., assistant professor
of neurology. "In a time span of about six or seven
hours, you make half the amyloid beta found in your
central nervous system."
Ideally,
the production and clearance rates stay balanced, causing
the overall amount of Abeta in the central nervous system
to remain constant. In the healthy volunteers who were
the first test subjects, Bateman found the production
and clearance rates were the same. He is now applying
the technique to individuals with Alzheimer's disease.
Researchers
are developing Alzheimer's drugs that either decrease
Abeta production or increase its clearance, Bateman
notes, and the new test could be very important in determining
which approach is most effective.
Prior
to the new test, the only way to assess the effectiveness
of a new Alzheimer's drug was to follow the mental performance
of patients receiving the treatment over many months
or years.
"This
new test could let us directly monitor patients in clinical
trials to see if the drug is really doing what we want
it to do in terms of Abeta metabolism," Bateman
says. "If further study confirms the validity of
our test, it could be very valuable for determining
which drugs go forward in clinical trials and at what
doses."
The
test also may be useful in diagnosis of Alzheimer's
prior to the onset of clinical symptoms, which occurs
after Alzheimer's has inflicted widespread and largely
irreversible damage to the brain.
"We
hope to study whether we can develop ways to identify
potential Alzheimer's patients on the basis of a metabolic
imbalance between Abeta synthesis and clearance rates,"
Bateman says.
The
test combines technologies that have been available
for some time but only through recent technical and
procedural advances has become sufficiently sensitive.
Via an intravenous drip, scientists give test subjects
a form of the amino acid leucine that has been very
slightly altered to label it. Inside the leucine are
carbon atoms with 13 neutrons and protons in their nucleus
instead of the more common 12 neutrons and protons—in
scientific parlance, carbon 13 instead of carbon 12.
"Normally
only about 1.1 percent of the carbon atoms in our bodies
are carbon 13—the vast majority is carbon 12,"
Bateman notes. "Physiologically and biochemically,
carbon 13 acts just like carbon 12, meaning it won't
alter the normal Abeta production and clearance processes
and is very safe to use."
Over
the course of hours, cells in the brain pick up the
labeled leucine and incorporate it into the new copies
they make of Abeta and other proteins. Scientists take
periodic samples of the subjects' cerebrospinal fluid
through a lumbar catheter, purify the Abeta from the
samples and then use a device known as a mass spectrometer
to determine how much of the Abeta includes carbon-13-labeled
leucine.
Tracking
the rise of the percentage of Abeta with labeled leucine
over time gives scientists the subject's Abeta production
rate. When the percentage of Abeta containing labeled
leucine plateaus, scientists remove the IV drip supplying
the labeled leucine. Periodic sampling of the patients'
CSF continues, allowing scientists to get a measurement
of how quickly the nervous system clears out the labeled
Abeta. In the first test subjects, the test procedure
lasted for 36 hours.
Other
research groups have expressed an interest in applying
the new test to Alzheimer's research and to other neurological
disorders such as Huntington's disease.
This
study was performed in the laboratories of David M.
Holtzman, M.D., the Andrew and Gretchen Jones Professor
and chair of Neurology, and Kevin E. Yarasheski, Ph.D.,
associate professor of medicine and assistant director
of the Washington University Biomedical Mass Spectrometry
Resource. It was also supported by the ADRC, directed
by John C. Morris, M.D., the Friedman Distinguished
Professor of Neurology.
Bateman
RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman
DM. Human amyloid-b synthesis and clearance rates as
measured in cerebrospinal fluid in vivo. Nature Medicine,
June 25, 2006.
Funding
from the American Academy of Neurology and the National
Institutes of Health supported this research.
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