New tool
detects Alzheimer’s protein, may help identify brain changes, assess treatment
effects
Credit:
Ping Yan and Jin-Moo Lee
Researchers at Washington University School of Medicine in St.
Louis have developed a chemical compound that detects the Alzheimer’s protein
amyloid beta better than current FDA-approved agents. The compound potentially
may be used in brain scans to identify people in the earliest stages of
Alzheimer’s disease. In the image, the compound has passed from the bloodstream
of a living mouse into its brain, where it is detected by a positron emission
tomography (PET) scan. Arrows indicate clumps of amyloid beta.
Newswise, November 7, 2016 — By the time unambiguous signs of
memory loss and cognitive decline appear in people with Alzheimer’s disease,
their brains already are significantly damaged, dotted with clumps of a
destructive protein known as amyloid beta. For years, scientists have sought
methods and clues to help identify brain changes associated with Alzheimer’s
earlier in the disease process, so they can try to stop or even reverse the
changes before they severely affect people’s lives.
Now, researchers at Washington University School of Medicine
in St. Louis have developed a chemical compound, named Fluselenamyl, that
detects amyloid clumps better than current FDA-approved compounds.
If a radioactive atom is incorporated into the compound, its
location in a living brain can be monitored using positron emission tomography
(PET) scans.
The compound, described in a paper published Nov. 2 in Scientific
Reports, one of the Nature journals, potentially could be used in brain
scans to identify the signs of early-stage Alzheimer’s disease or to monitor
response to treatment.
“Fluselenamyl is both more sensitive and likely more specific
than current agents,” said Vijay Sharma, PhD, a professor of radiology, of
neurology and of biomedical engineering, and the study’s senior author.
“Using this compound, I think we can reduce false negatives,
potentially do a better job of identifying people in the earliest stages of
Alzheimer’s disease and assess the effects of treatments.”
Amyloid plaques are one of the most telltale findings in the
brains of people with Alzheimer’s disease. The neurons near such plaques are
often dead or damaged, and this loss of brain cells is thought to account for
difficulty with thinking, memory loss and confusion experienced by Alzheimer’s
patients.
Amyloid plaques can be either diffuse or compact. The compact
kind has long been associated with the disease, but conventional wisdom has
held that diffuse plaques are benign, since they can be found in the brains of
elderly people without any symptoms of Alzheimer’s disease, as well as the
brains of those with Alzheimer’s. Sharma believes that diffuse plaques may mark
the earliest stages of the disease.
“It is a relatively underexplored area in the development of
Alzheimer’s pathology,” Sharma said.
“Since current approved agents don’t detect diffuse plaques,
there is no reliable noninvasive imaging tool to investigate this aspect in
animal models or in patients. Our compound could be used to study the role of
diffuse plaques.”
Using human amyloid beta proteins, Sharma and colleagues
showed that Fluselenamyl bound to such proteins two to 10 times better than
each of the three FDA-approved imaging agents for detecting amyloid beta.
In other words, Fluselenamyl detected much smaller clumps of
the protein, indicating that it may be able to detect the brain changes
associated with Alzheimer’s disease earlier.
To determine whether Fluselenamyl can detect plaques in the
brain, the researchers used the compound to stain brain slices from people who
had died of Alzheimer’s disease and, as controls, people of similar ages who
had died of other causes.
The brain slices from the Alzheimer’s patients, but not the
controls, were identified as containing plaques.
When a radioactive atom was incorporated into the compound,
the researchers found very little interaction between Fluselenamyl and the
healthy white matter in the human brain slices.
“A huge obstacle with existing state-of-the-art PET agents
approved for plaque detection is that they tend to bind indiscriminately to the
brain’s white matter, which creates false positives on the scans,” Sharma said.
Nonspecific binding to other parts of the brain creates
“noise,” which makes it difficult to distinguish samples with plaques from
those without.
A similar experiment comparing mice genetically predisposed to
develop amyloid plaques with normal control mice showed the same pattern of
high sensitivity for amyloid beta and low binding to healthy white matter.
Furthermore, Sharma and colleagues showed that when
Fluselenamyl with the radioactive atom is injected intravenously into mice, the
compound can cross the blood-brain barrier, bind to any plaques in their brains
and be detected by PET scan.
In mice without plaques, the compound is quickly flushed from
the brain and then excreted from the body.
The next step is to move to testing in patients. Sharma
already has submitted an application to the National Institutes of Health (NIH)
for a phase 0 trial, to establish whether Fluselenamyl is safe for use in
humans and behaves in the human body the same way it behaves in mice.
Phase 0 trials involve a low dose given to a small number of
people to learn how a molecule is processed in the body and how it affects the
body.
“Ideally, we’d like to look at patients with very mild
symptoms who are negative for Alzheimer’s by PET scan to see if we can identify
them using Fluselenamyl,” Sharma said.
“One day, we may be
able to use Fluselenamyl as part of a screening test to identify segments of
the population that are going to be at risk for development of Alzheimer’s
disease. That’s the long-term goal.”
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