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Alzheimer's, Dementia & Mental Health
Do Alzheimer's Victims Produce Too Much Harmful
Protein, or Not Clear It Fast Enough?
Chicken or egg study could lead to answers by
monitoring protein
By Michael Purdy
June 26, 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?
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Alzheimer's, Dementia
& Mental Health |
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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.
More about study:
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.
View online:
http://mednews.wustl.edu/news/page/normal/7348.html?emailID=9821
Washington University School of Medicine's
full-time and volunteer faculty physicians also are the medical staff of
Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine
is one of the leading medical research, teaching and patient care
institutions in the nation, currently ranked third in the nation by U.S.
News & World Report. Through its affiliations with Barnes-Jewish and St.
Louis Children's hospitals, the School of Medicine is linked to BJC
HealthCare.
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