The U.S. Food and Drug
Administration and physicians continue to document that some patients
experience fuzzy thinking and memory loss while taking statins, a class of
global top-selling cholesterol-lowering drugs
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.
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.
"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 barrier.
"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 outcomes."
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.
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 disorders.
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 be."
"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 physicians."
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."
University of Arizona. "Possible reason for cholesterol-drug side effects such as memory loss." ScienceDaily, 10 May 2013. Web. 12 Jun. 2013.