Insufficient Memory
Can a pill boost your brain’s ability to hold information? By Jamie Talan (c)
Newsday.com Nov. 18, 2003
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Just around the corner looms a brave new
world where people of all ages could reach for a pill that would strengthen
the brain, enabling it to learn faster and make the lessons last.
Swallowing pills to make learning easier or to make memories stick is no
longer pie-in-the-sky thinking. Scientists have learned so much about the
way the human brain learns and remembers that they are fashioning the first
generation of memory enhancers.
"It's no longer just about correcting an abnormality," said Steven Ferris,
executive director of the Silberstein Aging and Dementia Research Center at
New York University School of Medicine. "The idea that we only use drugs to
treat disease is changing."
No one thinks twice, he said, about spending to correct age-related body
changes affecting hair, the eyes, bones, skin, even erectile dysfunction.
"Why should the brain be any different?" he asked. "We are on the threshold
to see if we can improve memory and cognition in AAMI."
AAMI stands for age-associated memory impairment and it encompasses the
kinds of things that any older person would understand: periodic
forgetfulness, occasionally misplacing an item, slips in mental agility. By
comparison, doctors are now diagnosing a condition called mild cognitive
impairment, or MCI, in more and more older people. This label defines
symptoms that include difficulty recognizing friends or family, temporarily
forgetting what everyday items are used for, increasing problems with
short-term memory, but problems not severe enough to signify Alzheimer's
disease.
Some experts say MCI is the earliest stage of Alzheimer's, but not everyone
agrees.
Still, the hunt is on for medicines to target every level of poor memory --
from losing a word to missing large chunks of information. Scientists also
are developing medicines to enhance normal memory -- a pill to help with the
SATs, for instance -- something that could make learning easier for the
masses, regardless of age.
Thomas Crook has been testing experimental memory medicines for 10 years.
"There is this idea that we could create a mental version of Viagra," said
Crook, a psychologist whose company, Psychologix Inc. of Fort Lauderdale,
Fla., tests memory in healthy adults and then works with pharmaceutical
companies to test experimental compounds. "One day soon, you could take such
a pill when you have a challenging intellectual task."
Dr. Randall Carpenter, chief executive of Sention Inc., a biotech company in
Providence, says the company is testing a substance that helps information
move from short-term to long- term memory. When this journey is successful,
neural connections are established so that just-learned information is
stored and available on command. When those connections aren't made, the
information is forgotten.
"Forgetting is a universal experience," said Carpenter, who is 50. "I'm
getting to the age where I can use something."
Most of the medicines now in development target the brain's search and
retrieval system. The most likely first candidates for boosting insufficient
memory seem to be drugs developed for memory at its worst, as seen in
Alzheimer's. These medicines help patients retain and retrieve new
information by allowing a brain chemical called acetylcholine -- one of
hundreds of neurotransmitters, agents that ferry information from cell to
cell within the brain -- to work more efficiently. The Alzheimer's process
depletes stores of the chemical, but research is showing that normal aging
may do so as well.
The human brain takes in enormous amounts of information every second and
must decide which parts are worth remembering. Researchers say that,
generally, information that gets stored as long-term memory is coupled with
an emotional experience. The stronger the emotional signal, the easier the
memory is to retrieve. So, for example, most adults over 45 remember clearly
the day President John F. Kennedy was assassinated.
But there's a fine line between how much memory is enough and too much. Tim
Tully, a memory researcher at Cold Spring Harbor Laboratory, worries that
memory-enhancing medicine taken over a long period of time could result in
the storage of too much information.
"Maybe we forget things for a reason," said Tully, who started a company
that's designing memory drugs based on his research findings. "Do we want to
remember everything that goes on in a given day? Absolutely not."
And he cautioned there might be risks attached to altering the brain's
ability to learn and remember. "If you are diabetic, restoring insulin does
good things," he said, by comparison. "For normal people, it can do a lot of
harm."
Earlier this month, scientists at Yale University published a study that
found certain experimental drugs improve long-term memory but damage working
memory -- the ability to remember short-term in order to carry out a
specific task. In essence, said Yale neurobiologist Amy Arnsten, who led the
research, people might have access to long- term memories but not know what
to do with them.
The first stages of testing a drug developed for enhancing memory in humans
have been completed at Sention, one that's based on another
neurotransmitter. But reaching conclusions about whether it works may take
years.
It's been well-established that memory machinery doesn't work as well in the
older brain.
The phrase "age-associated memory impairment" was coined in 1986 by Crook,
who had spent years as a research program director at the National Institute
of Mental Health. He believed there was strong evidence that key brain
systems are harmed by the normal aging process, not as a disease per se, but
as a mental state that needs fixing.
"The body ages, and so does the brain," Crook said, and he set out to prove
it. Such signs of aging are noted as early as in the 30s, he said, and grow
worse with each decade. The biggest impact is on the ability to learn and
remember new things.
In 1990, Crook opened memory clinics around the country to gather data on
normal brain aging, and he found that with each decade of age over 50, a
higher proportion of people met criteria for AAMI. By 70, more than half of
those arriving at the clinics showed working memory deficits that hampered
some aspects of their daily lives -- but not so much that they would be
diagnosed with Alzheimer's.
Nevertheless, "our ability to learn new things and store information doesn't
stop," Ferris said. The challenge is to figure out ways to strengthen the
necessary cellular connections.
Two years ago he helped organize a meeting to help put AAMI on the treatment
map. Pharmaceutical companies didn't express much interest, he said, until
recently. Now that companies have been testing the first generation of
medicines to treat Alzheimer's, they're moving on to interventions for the
aging brain.
And people in the beginning stages of Alzheimer's may have normal working
memory -- they can retain information for a short while -- but they have
problems making that information stick.
"They have trouble storing new memories," Carpenter said. "We think we know
how to turn the dial up and help store that information." Such medicines
could be used to push back the onset of Alzheimer's, he said, as well as
treat other memory problems caused by disease and trauma.
But there are many brain regions involved in learning and memory. The
prefrontal cortex, for instance, takes care of working memory and is
critical in carrying out everyday functions. Another region, the
hippocampus, regulates the formation of long-term memories.
"The cautionary note is that many neuroscientists and pharmaceutical
companies assume that the brain is homogeneous," Arnsten said. "You have to
respect that there are vast chemical differences and learn how to target
these drugs intelligently."
The first hint that Alzheimer's drugs might have other memory benefits comes
from the work of Dr. Jerome Yesavage of Stanford University and the Palo
Alto Veterans Affairs Health Care System in California. Yesavage gave
Aricept, approved for mild to moderate Alzheimer's disease, to healthy
middle- aged airplane pilots to test whether it could boost their
performance.
In the study, 18 pilots learned a complex series of instructions during
seven sessions on a flight simulator. Then half took Aricept, and they
performed better, suggesting that the memory drug played a role. The study
was published in the journal of the American Academy of Neurology.
Tully of Cold Spring Harbor Lab is using his findings from fruit flies to
develop substances that switch on gene products involved in memory formation
and storage. In 1997 Tully and colleagues found that a specific drug could
enhance memory in animals by blocking one of the brain's chemical agents.
Experiments found that mice given the drug didn't have to practice as much
to form a specific memory, Tully said.
"The performance of the older animals looked a lot like that of the younger
ones," he added. The safety of the substance is now being tested in rats and
dogs. The drug is set for human trials next year.
The substance also has been used to cure a form of mental retardation in
mice.
The human form of the condition is called Rubinstein-Taybi syndrome, and it
causes mental retardation in one in 125,000 newborns. After learning
scientists had identified the gene defect in this disorder, Tully said, "I
was willing to bet that these patients suffer mental retardation because the
memory switch in their brain is broken."
Several years ago, a Japanese team produced the same genetic defect in mice;
they had normal short-term memories but could not store the information
long-term. But animals given the experimental drug were able to make
long-term memories.
"This told us that we have to think differently about mental retardation,"
Tully said. "We thought that it is developmental and permanent. But this
shows that the deficits are biochemical and can be reversed. It's
revolutionary." He wants to conduct studies on humans with this condition
and said the real success would come if the medicines could eventually be
tested in children born with this defect.
Memory Pharmaceuticals, founded by Nobel laureate Eric Kandel of Columbia
University, also is developing memory drugs, working on the same memory
mechanisms as Tully's Farmingdale- based company, Helicon.
Other strategies are being pursued: Some companies are looking to enhance
the brain's nicotinic receptors, home to the brain chemical and
neurotransmitter acetylcholine. Statins used to lower cholesterol are being
tested for a possible memory role. The herbal supplement ginkgo biloba is
the subject of a federal-sponsored memory trial. And there's evidence that a
natural brain substance called phosphatidylserine, or PS, can improve
learning and memory.
But improving normal memory through better chemistry means that a substance
must pass rigorous federal safety regulations. "It has to be very safe to be
used for problems inherent in every aging person," Ferris said.
Several nondrug interventions are being used, Ferris said, some as obvious
as brain teasers. Neuropsychologist Elkhonon Goldberg, a clinical professor
of neurology at NYU Medical Center, has been designing computer software
that combines a series of challenging mental games with mathematical
calculations. Several times each week, older people with complaints of mild
memory problems come to Goldberg's lab to exercise their brains. Their
performance is being tracked.
"Does it translate into better cognitive function?" Ferris asked. "We don't
know yet. But we think it will."
Crook said his studies of healthy adults show that a 75-year-old trying to
remember someone's name performs 65 percent worse than a 25-year-old. "If a
14-year-old kid lost 65 percent of his ability to perform tasks in the
classroom, who wouldn't treat it?" he asked. "Why doesn't an older person
deserve the same?"
Dr. Barry Gordon, a professor of neurology and cognitive science at Johns
Hopkins University, is the author of a new book, "Intelligent Memory," which
addresses ways to solve everyday problems faster. Gordon said he believes
that age-related cognitive decline represents a slowing of the brain's
processing system -- "just as no one is the same athlete at 50 as they were
at 20."
