Reason for Fuzzy Memories for Seniors Taking Statins
May Be Explained
Memory loss that is reversible sometimes caused by
cholesterol-lowering drugs, one of most widely prescribed medications
for senior citizens in the world.
drugs tested, only four caused nodules to form inside the neurites,
resembling beads on a string. All four drugs were statins.
May 10, 2013 - A University of Arizona research
team has made a novel discovery in brain cells being treated with statin
drugs: unusual swellings within neurons, which the team has termed the
"beads-on-a-string" effect. It may explain the continued documentation
that some patients experience fuzzy thinking and memory loss while
taking statins, a class of global top-selling cholesterol-lowering drugs
used primarily by older people.
The team is not entirely sure why the beads form,
said UA neuroscientist Linda L. Restifo, who leads the investigation.
However, the team believes that further investigation of the beads will
help inform why some people experience cognitive declines while taking
statins. Which has been documented by the Food and Drug Administration
"What we think we've found is a laboratory
demonstration of a problem in the neuron that is a more severe version
for what is happening in some peoples' brains when they take statins,"
said Restifo, a UA professor of neuroscience, neurology and cellular and
molecular medicine, and principal investigator on the project.
Restifo and her team's co-authored study and
findings recently were published in Disease Models & Mechanisms, a
peer-reviewed journal. Robert Kraft, a former research associate in the
department of neuroscience, is lead author on the article.
Restifo and Kraft cite clinical reports noting that
statin users often are told by physicians that cognitive disturbances
experienced while taking statins were likely due to aging or other
effects. However, the UA team's research offers additional evidence that
the cause for such declines in cognition is likely due to a negative
response to statins.
The team also has found that removing statins
results in a disappearance of the beads-on-a-string, and also a
restoration of normal growth. With research continuing, the UA team
intends to investigate how genetics may be involved in the bead
formation and, thus, could cause hypersensitivity to the drugs in
people. Team members believe that genetic differences could involve
neurons directly, or the statin interaction with the blood-brain
"This is a great first step on the road toward more
personalized medication and therapy," said David M. Labiner, who heads
the UA department of neurology. "If we can figure out a way to identify
patients who will have certain side effects, we can improve therapeutic
For now, the UA team has multiple external grants
pending, and researchers carry the hope that future research will
greatly inform the medical community and patients.
"If we are able to do genetic studies, the goal
will be to come up with a predictive test so that a patient with high
cholesterol could be tested first to determine whether they have a
sensitivity to statins," Restifo said.
Cause Mitochondria to Pile Up
whose mitochondria are labeled with green fluorescent protein (GFP)
reveal that statins cause mitochondria to pile up inside the branches
that neurons use to connect with each other. By Linda Restifo/University
Detecting, Understanding a Drugs' Side Effects
Restifo used the analogy of traffic to explain what
she and her colleagues theorize.
The beads indicate a sort of traffic jam, she
described. In the presence of statins, neurons undergo a "dramatic
change in their morphology," said Restifo, also a BIO5 Institute member.
"Those very, very dramatic and obvious swellings
are inside the neurons and act like a traffic pileup that is so bad that
it disrupts the function of the neurons," she said.
It was Kraft's observations that led to team's
novel discovery. Restifo, Kraft and their colleagues had long been
investigating mutations in genes, largely for the benefit of advancing
discoveries toward the improved treatment of autism and other cognitive
At the time, and using a blind-screened library of
1,040 drug compounds, the team ran tests on fruit fly neurons,
investigating the reduction of defects caused by a mutation when neurons
were exposed to different drugs. The team had shown that one mutation
caused the neuron branches to be curly instead of straight, but certain
drugs corrected this. The research findings were published in 2006 in
the Journal of Neuroscience.
Then, something serendipitous occurred: Kraft
observed that one compound, then another and then two more all created
the same reaction – "these bulges, which we called beads-on-a-string,'"
Kraft said. "And they were the only drugs causing this effect."
At the end of the earlier investigation, the team
decoded the library and found that the four compounds that resulted in
the beads-on-a-string were, in fact, statins.
"The 'beads' effect of the statins was like a bonus
prize from the earlier experiment," Restifo said. "It was so striking,
we couldn't ignore it."
In addition to detecting the beads effect, the team
came upon yet another major finding: when statins are removed, the
beads-on-a-string effect disappears, offering great promise to those
being treated with the drugs.
"For some patients, just as much as statins work to
save their lives, they can cause impairments," said Monica Chaung, who
has been part of the team and is a UA undergraduate researcher studying
molecular and cellular biology and physiology.
"It's not a one drug fits all," said Chaung, a UA
junior who is also in the Honors College. "We suspect different gene
mutations alter how people respond to statins."
Having been trained by Kraft in techniques to
investigate cultured neurons, Chuang was testing gene mutations and
found variation in sensitivity to statins. It was through the work of
Chuang and Kraft that the team would later determine that, after
removing the statins, the cells were able to repair themselves; the
neurotoxicity was not permanent, Restifo said.
"In the clinical literature, you can read reports
on fuzzy thinking, which stops when a patient stops taking statins. So,
that was a very important demonstration of a parallel between the
clinical reports and the laboratory phenomena," Restifo said.
The finding led the team to further investigate the
neurotoxicity of statins.
"There is no question that these are very important
and very useful drugs," Restifo said. Statins have been shown to lower
cholesterol and prevent heart attacks and strokes.
But too much remains unknown about how the drugs'
effects may contribute to muscular, cognitive and behavioral changes.
"We don't know the implications of the beads, but
we have a number of hypotheses to test," Restifo said, adding that
further studies should reveal exactly what happens when the
transportation system within neurons is disrupted.
Also, given the move toward prescribing statins to
children, the need to have an expanded understanding of the effects of
statins on cognitive development is critical, Kraft said.
"If statins have an effect on how the nervous
system matures, that could be devastating," Kraft said. "Memory loss or
any sort of disruption of your memory and cognition can have quite
severe effects and negative consequences."
Restifo and her colleagues have multiple grants
pending that would enable the team to continue investigating several
facets related to the neurotoxicity of statins. Among the major
questions is, to what extent does genetics contribute to a person's
sensitivity to statins?
"We have no idea who is at risk. That makes us
think that we can use this genetic laboratory assay to infer which of
the genes make people susceptible," Restifo said.
"This dramatic change in the morphology of the
neurons is something we can now use to ask questions and experiment in
the laboratory," she said. "Our contribution is to find a way to ask
about genetics and what the genetic vulnerability factors are."
The Possibility for Future Research, Advice
The team's findings and future research could have
important implications for the medical field and for patients with
regard to treatment, communication and improved personalized medicine.
"It's important to look into this to see if people
may have some sort of predisposition to the beads effect, and that's
where we want to go with this research," Kraft said. "There must be more
research into what effects these drugs have other than just controlling
a person's elevated cholesterol levels."
And even as additional research is ongoing,
suggestions already exist for physicians, patients and families.
"Most physicians assume that if a patient doesn't
report side effects, there are no side effects," Labiner said. "The
paternalistic days of medication are hopefully behind us. They should
"We can treat lots of things, but the problem is if
there are side effects that worsen the treatment, the patient is more
likely to shy away from the medication. That's a bad outcome," he said.
"There's got to be a give and take between the patient and physician."
Patients should feel empowered to ask questions,
and deeper questions, about their health and treatment and physicians
should be very attentive to any reports of cognitive decline for those
patients on statins, she said.
For some, it starts early after starting statins;
for others, it takes time. And the signs vary. People may begin losing
track of dates, the time or their keys.
"These are not trivial things. This could have a
significant impact on your daily life, your interpersonal relationships,
your ability to hold a job," Restifo said.
"This is the part of the brain that allows us to
think clearly, to plan, to hold onto memories," she said. "If people are
concerned that they are having this problem, patients should ask their
Restifo said open and direct patient-physician
communication is even more important for those on statins who have a
family history of side effects from statins.
Also, physicians could work more closely with
patients to investigate family history and determine a better dosage
plan. Even placing additional questions on the family history
questionnaire could be useful, she said.
"There is good clinical data that every-other-day
dosing give you most of the benefits, and maybe even prevents some of
the accumulation of things that result in side effects," Restifo said,
suggesting that physicians should try and get a better longitudinal
picture on how people react while on statins.
"Statins have been around now for long enough and
are widely prescribed to so many people," she said. "But increased
awareness could be very helpful."
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