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Scientists Watch Nerve Cell Changes that may Signal Alzheimer's

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Duke Health News 919-660-1306

DURHAM, N.C. - They lose their keys, misplace their
checkbooks and forget they told you the same joke the day
before. The signs are universally recognized as those of
age-related memory loss, but even a clinical exam can't say for
sure if it is the dreaded Alzheimer's disease until the patient
is well on his way to cognitive collapse.

Now, researchers at Duke University Medical Center have
discovered they can use a novel imaging technique, magnetic
resonance spectroscopy (MRS), to literally see inside the brain
and watch the changes they believe mark the nerve cell loss
that occurs in the early stages of Alzheimer's disease.

If their preliminary research is confirmed, then
spectroscopy could one day provide the first reliable test for
a disease that defies easy detection, said Dr. R. Ranga
Krishnan, chairman of Duke's department of psychiatry.

Currently, there is no definitive brain test for Alzheimer's
disease. Only an autopsy can confirm with certainty a doctor's
clinical diagnosis, Krishnan said.

"Spectroscopy could lend the first non-invasive and
biochemical assessment of brain function to a condition that's
now determined by memory tests and patient histories alone,"
said Cecil Charles, co-director of the Center for Advanced
Magnetic Resonance Imaging at Duke. "While MRS is not yet ready
to be used as a diagnostic tool, we are using it in the
research setting to complement our clinical assessments of
patients."

In studies among patients who were clinically diagnosed with
Alzheimer's disease, the research team used MRS to detect
subtle changes inside nerve cells that signal their eventual
demise and death. MRS is an alternative type of magnetic
resonance imaging that can measure active brain chemicals
inside minute regions of the brain -- areas as small as 1
milliliter.

Similar to traditional MRI, spectroscopy uses a radio
frequency transmitter to selectively "tune in" to atoms inside
the brain and capture their behavior within a magnetic field.
Since each atom behaves differently in the magnet, scientists
can zero in on a particular type of atom - for example, a
hydrogen, phosphorus or sodium atom - within a given chemical
compound and record its behavior. The radio frequency each atom
emits is, in essence, its thumb print, providing scientists
with a detailed analysis of the tissue or chemical at hand.

Traditional MRI, however, generally is used to focus on
hydrogen atoms within tissues and water, with the goal of
illuminating brain structures but not the chemicals inside
them. Spectroscopy uses a novel software package and special
transmitter coil to hone in on a wide variety of brain
chemicals that illuminate brain function, not just
structure.

Using this technique, the researchers measured levels of a
brain chemical known to be vital to memory function. The
chemical, N-acetylaspartate, is found primarily inside nerve
cells within the brain, and its presence signals the health, or
lack thereof, of a nerve cell. It is generally accepted that
dying or stunned nerve cells have lower levels of
acetylaspartate, but little is known about the chemical's role
in a particular disease.

With this base of knowledge, the researchers decided to
compare the amount of N-acetylaspartate in Alzheimer's patients
with that in normal elderly people, expecting to find less of
it in memory-impaired patients. The patients with Alzheimer's
disease had 24 percent to 31 percent less of the chemical in
their living nerve cells compared with their healthy
counterparts, Charles said.

"We saw this decrease in many different brain regions
consistent with the pattern of widespread nerve cell loss in
the middle stages of this disease," said Krishnan.

Results of this study were presented Dec. 14 at the annual
meeting of the American College of Neuropsychopharmacology in
San Juan, Puerto Rico.

Based on their first study, the researchers designed a
second, small study to see if levels of the chemical could
predict a patient's memory and behavior function one year
later. Results of this study involving 12 Alzheimer's patients
were reported in a research letter in the Nov. 21 issue of The
Lancet.

"We found exactly what we had predicted: the patients with
the least amount of N-acetylaspartate at baseline showed the
most profound behavioral and memory deficits one year later,"
Krishnan said. "This means the chemical may be a good biologic
marker of nerve cell integrity, and that we could actually use
it in the future - together with a clinical exam - to predict
progression of disease."

For decades, physicians have sought a more precise way to
diagnose Alzheimer's disease, to assess what stage a patient is
in, and to predict the patient's rate of decline. Memory tests
lack sophistication because they are affected by socioeconomic
status, education, fatigue, stress and medical illnesses that
alter cognition, said Dr. Murali Doraiswamy, director of
clinical trials in the department of psychiatry at Duke.
Traditional magnetic resonance imaging techniques, while
helpful, provide only a snapshot of entire areas that have lost
function.

Spectroscopy, on the other hand, can measure the chemicals
being metabolized inside an individual nerve cell -- changes
that occur before the patient shows obvious clinical signs.

Moreover, spectroscopy is safer and more accessible than
currently available chemical imaging techniques, like positron
emission topography (PET), because it does not require
injections or exposure to radiation, Charles said. PET is an
imaging technique that illuminates radioactive "tracers" as
they travel through the bloodstream in the brain. Only brain
regions that can absorb the tracer will show up on the scan,
and the resulting image reveals only the peaks and valleys of
activity taking place at the moment, but no information on the
resting status of brain function or activity.

"Spectroscopy should help us predict who will decline and at
what rate, even among a group of patients who clinically appear
to be at the same stage of disease," Charles said.

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