By Duke Medicine News and Communications

DURHAM, N.C. -- A drug that helps memory and cognition in patients with Alzheimer's disease also seems to improve attention span, communication, behavior and mood in adults with Down Syndrome. A larger, controlled study is underway to confirm the finding.

Duke University Medical Center researchers tried the Alzheimer's drug on individuals with Down Syndrome because they realized both disorders result, in part, from an insufficient supply of a brain neurotransmitter called acetylcholine

Although the study, published in the March 27 issue of The Lancet, was conducted with only four patients, the researchers say it may represent a significant advance because no drug now exists that can help both the adaptive and mental impairments associated with Down Syndrome.

"There is no proven treatment for cognitive problems in Down Syndrome, which is the most common genetic cause of retardation worldwide," said Duke pediatric geneticist Dr. Priya Kishnani. "While these are preliminary data, if it continues to prove beneficial to these patients, this may be a therapy we could start early in their lives and use on a continuing basis."

All four patients experienced improved cognitive, adaptive and behavioral functioning during the 26 weeks they took the drug, known as donepezil (the trade name is Aricept). Kishnani said one patient who has continued the medication (and has been on it now for almost two years) has experienced "the best years of his life," according to his caregiver.

Based on that study's success, Duke researchers are now testing Aricept in a randomized and double-blind group of 20 adults with the disorder. In this study, each patient will be given the drug and the placebo at different times, and their performance in these periods will be compared. Kishnani also will soon start a third trial examining use of the drug in children, 7 to 12 years old, with Down Syndrome.

The research was funded by both the National Institutes of Health (the National Center for Research Resources) and an unrestricted grant from Pfizer Inc. and Eisai America, makers of donepezil, which received U.S. Food and Drug Administration approval for use by Alzheimer's disease patients in 1996.

"There is a great need for therapy for Down Syndrome. Up to now, patients and their caregivers have resorted to such things as use of megavitamins and antioxidants in an effort to improve brain functioning," said Duke psychiatrist Dr. Murali Doraiswamy, who collaborated with Kishnani and her team. "We have a lot of experience now with using Aricept in Alzheimer's disease patients and we hope this novel use of it will focus attention on the needs of Down Syndrome patients."

Down Syndrome is caused by the inheritance of an extra copy of chromosome 21, and it occurs in about one of every 600-700 births. More than 10,000 infants are born each year with the disorder, and nationwide about 300,000 people have it.

Due to improved care for the heart conditions that afflict many children with Down Syndrome, as well as overall advances in medical technology, the life span of a patient with the disorder has increased from age 9 in 1925 to an average age today of 56 years. More than one-quarter of people with Down Syndrome will be alive at age 67.

As they live longer, improving their quality of life and maximizing their abilities is of paramount importance, Kishnani said.

Both Alzheimer's disease and Down Syndrome patients share a common problem in that their brains do not produce enough of a chemical known as acetylcholine. This malady occurs much earlier in people with Down Syndrome. In fact, individuals with Down Syndrome develop Alzheimer's disease at a much earlier age (usually in the fourth decade) compared to the general population. "But the idea here is not to treat the Alzheimer's disease that may be developing, or have developed, in Down Syndrome patients, but to provide the brain chemicals that are missing in both disorders," Kishnani said.

Acetylcholine is a neurotransmitter that carries a number of vital signals from one neuron to another. Normally, when a certain type of signal needs to travel through the brain, nerve cells release a supply of acetylcholine to transport the signal across the synaptic junction, the space that exists between the cells, and then to an area on the connecting neuron called the post-synaptic receptor site. There the signal connects in a process akin to turning on a lamp by plugging it in. But if there isn't enough acetylcholine available to a nerve cell to allow it to pass a signal on, a person will experience problems with learning and memory, among other deficits.

Aricept is known as a cholinesterase inhibitor. It works by blocking a brain enzyme that typically breaks down acetylcholine, thus leaving more of the neurotransmitter available in the synaptic junction for use at the post synaptic receptor site.

Trials of the drug in Alzheimer's disease patients have shown that Aricept improves overall functioning and cognition, which can result in improved use of language and behavior. It is also less toxic than tacrine, an earlier type of cholinesterase inhibitor and the only other approved drug to treat Alzheimer's.

To test the ability of Aricept to help Down Syndrome, Kishnani enrolled three men and one woman, age 27 to 64, as well as their primary caregivers. To measure improvements, the Duke team developed a battery of tests, which they administered to the volunteers and their caregivers at the beginning of the study, and then at three and six months. They also asked the patient's caregivers to keep diaries, and the researchers interviewed the caregivers throughout the trial.

None of the four patients experienced serious adverse effects, worsened cognitively or dropped out of the study, Kishnani said. In fact, improvements in communication, expressive language, attention and mood stability were noted by the caregivers and the physicians, and were also documented on the tests, she said.

Those patients who did not continue using Aricept after the study ended appeared not to have any withdrawal symptoms or further deterioration, although caregivers noted changes in the patients' ability to communicate and express themselves, Kishnani said.

"I see more than 200 families with children who have Down Syndrome, and they always ask me to recommend anything that will help," said Kishnani, who co-directs Duke's Down Syndrome Clinic. "I hope I will be able to give them some assistance in the future, should trials of Aricept continue to prove beneficial."