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Insufficient Memory
Can a pill boost your brainís 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."

Copyright © 2003, Newsday, Inc.