The Golden Rule - Do Unto Others

We are who we are in good measure because of what we have learned and what we remember.”

By: Dr. Eric R. Kandel



THE 76-YEAR-OLD CALIFORNIA LAWYER appears to be the very model of healthy aging. C.L., (who asked that his name not be used) , hikes two miles up a nearby mountain four times a week, is always reading two or more nonfiction books at a time, and boasts that his waist and chest measurements haven’t changed since he was 25.

But his memory hasn’t kept pace. In the last six years, since 1997, C.L. has begun to forget names. He loses his train of thought when there are distractions, and he has walked away (forgot) from six pairs of expensive sunglasses. “You notice when you begin to lose that ability to grab onto every word, every concept,” he says. “It’s like a significant part of your life is erased.” C.L. yearns for some kind of treat- ment. Although he is functioning very well for his age, he lobbied hard to enter a study for an experimental memory drug developed by Cortex Pharmaceuticals Inc. of Irvine, California. The compound, called CX516, is directed at people who suffer from frequent short-term memory lapses, known as mild cognitive impairment (MCI). The condition isn’t serious, but can be an early sign of Alzheimer’s:

EVERY YEAR, some 15 % of those with MCI go on to develop the disease. In spring 2002, C.L. took nine capsules of CX516 daily for four weeks. The impact was immediate. “At the start of the trial, I could remember less than 5 words out of a list of 15. By the second week, I could get 14. There was a very exciting, appreciable enhancement.” He has since finished his part in the study and says it was “heartbreaking” to go off the drug. “I’ve been thinking of some other way to get it, and I don’t give a damn if it’s legal or illegal.”

It won’t be that long before C.L. can solve his problem legally. At least 60 pharmaceutical and biotech companies around the world are working on novel memory pills. Some 40 are in human trials, and the first of these could be on the market within the next few years. These drugs are aimed both at the occasional “senior moment” and at the diagnosis people fear most, Alzheimer’s disease.

THE FIRST DRUG able to improve the thinking abilities of people with advanced Alzheimer’s was approved by the FDA last fall. Memantine, from the German company Merz, is no miracle cure, and it has yet to show an effect on early Alzheimer’s. But clinical trials indicate the drug allows some patients to live independently for six months to a year longer than they would otherwise. That’s more significant than it may sound: Dementia is the top cause of nursing home institutionalization in the United States.

The new drug marks a big payoff of brain research carried out over the past decade. And while some researchers are studying already available substances such as ginkgo biloba, blood pressure medications, and even curry (India has the lowest incidence of Alzheimer’s in the world), many experts believe that a new drug specifically designed for memory loss will prove most effective in the long run.

However, new treatments bring new risks. Two years ago, a trial of an Alzheimer’s vaccine was halted when it caused brain inflammation. Infamously, it was a new treatment for seizures that provided a breakthrough in memory research. Back in 1953, a Hartford surgeon attempted to relieve seizures in a 27-year-old man by removing a small structure deep in the brain called the hippocampus The seizures lessened, but the patient known as H.M., never formed another memory. He can recall events from before the operation but has no memory at all of a conversation held minutes earlier. H.M.'s case helped prove the hippocampus is where fleeting impressions turn into permanent memories.

Each sensation that enters the hippocampus, be it a spoken name, a visual impression, or a phone number, sets off electrical charges inside neurons, the cells that make up the brain. The charge stimulates the cell to release a stew of neurotransmitters, which carry the information across tiny gaps called synapses that connect the neurons to one another. The longer these signals flash back and forth, the stronger the connections become and the more synapses are created—a single neuron can have as many as 10,000. Finally, a set of neurons bands together to retain the data, and the brain remolds itself to create storage space. The entire process, from the time a number is heard until it is permanently stored, can take hours or even days.

AS WE AGE, the brain performs this intricate dance slower and slower, though by challenging ourselves mentally, research suggests some of us may be able to offset that decline. So how will we know whether we’ll suffer debilitating memory loss? Doctors still can’t accurately predict who is at risk for Alzheimer’s; they can’t even diagnose it with absolute certainty until after the patient’s death. It is then that clumps of sticky plaque in the brain can be detected during autopsy. Scientists are fairly certain that the plaque starts accumulating 10 to 20 years before mental decline is evident, by which point it is too late to halt or reverse the process. “The current Alzheimer’s treatments are an act of despair,” says Eric R. Kandel, professor of psychiatry at Columbia University. “We have to start intervening much earlier if we want to make a real difference.”

Which explains the intense focus on early memory loss, when the brain may still have a chance to save itself. Kandel shared the 2000 Nobel Prize in medicine for his discoveries about memory that grew out of painstaking work with sea slugs. Kandel’s discoveries were amplified by Tim Tully, a professor at Cold Spring Harbor Laboratory on Long Island, whose research is based on fruit flies.

Work on these two lowly life forms led to a revolution in the understanding of memory. Kandel discovered that a signaling molecule known as cyclic-AMP, or cAMP, plays a key role in strengthening synapses. The cAMP molecule activates a protein called CREB, which in turn switches on the genes that control the release of neurotransmitters essential to long-term memory. “Think of CREB as a general contractor that organizes the genes that build memories,” says Tully.

The Golden Rule - Do Unto Others

Once CREB was discovered, Tully went to work designing a strain of fruit flies with the CREB protein permanently “on.” The result: flies with photographic memories. The CREB flies remembered how to avoid a certain smell after only one try, while average flies required multiple training sessions. Both Kandel and Tully have formed companies to pursue their discoveries, specifically targeting mild cognitive impairment and age-associated memory loss. The reputations of Kandel and Tully give their companies cachet, but they’re joining a crowded field (see “Memory Magic,” above).

Most of the drugs in development can be divided into two camps, defensive and offensive. They either amplify brain signals that strengthen memory formation or block those that get in the way of that process. Cortex Pharmaceuticals, for example, is investigating a group of drugs that amplify a neurotransmitter, which seems to stimulate it to produce more synapses. The farthest along is CX516, the drug tested on C.L., the 76-year-old lawyer from California. In early trials, CX516 boosted memories in healthy 65- to 76-year- olds more than twofold over a placebo group. The drug also improved mental performance in a group of Swedish medical students, an intriguing hint that the drug may work on the young as well as the old. Cortex is now conducting a 150-patient trial in patients with mild cognitive impairment.

The defensive strategy is being pursued by Saegis Pharmaceuticals Inc. of Half Moon Bay, California. Its drug, SGS742, blocks GABA, a neurotransmitter that can interfere with memory consolidation. Study results have yet to be published, but Saegis chief executive Rodney Pearlman says, “We did see a statistical significance over the placebo group.”

There are plenty of existing compounds under investigation as well. One closely watched trial sponsored by the NIH will try to determine if the popular cholesterol -lowering statin drugs, such as Zocor and Lipitoi; can slow memory loss. Such a connection makes sense, says Dr. Kenneth Davis, former head of the Alzheimer’s s Disease Research Center at Mount Sinai School of Medicine in New York. because the risk factors associated with the plaque that clogs arteries in patients s with high cholesterol could have certain similarities with the risk factors that lead to the plaque found in the brains of Alzheimer’s patients.

At some point in the not-too -distant future, people who suspect declining memory might visit a special clinic where they will take a battery of brain tests. Based on the results, they will be given a set of mental exercises and prescribed a memory drug. This effort,” says Tully, ‘will yield lasting improvements in our abilities to perceive the world around us and remember our contributions to it.” It is a vision everyone on the far side of 40 can embrace.

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