FORGET ME NOT
While physicians seek a better understanding of Alzheimer's disease, a new center helps patients and their families grapple with the difficult and frustrating effects of dementia.
by Alfred KildowAfter graduating from USC with a degree in business in 1949, Raymond McCarron started an advertising firm specializing in business and industry product promotion. When his firm became extraordinarily successful, he credited the education he received at USC with helping him reach his business goals, and dreamed that he would one day establish a scholarship in his name that would make it possible for others to get the same education.
Today, however, the McCarron name is attached to a different cause. On his 74th birthday last year, Raymond McCarron and his wife, Betty, dedicated the Raymond and Betty McCarron Chair in Neurology, currently held by USC professor Helena Chui, M.D. They also funded the McCarron Clinical Research and Education Center on Alzheimer's disease at USC.
A series of medical problems had brought McCarron to USC doctors who specialize in Alzheimer's disease at Rancho Los Amigos National Rehabilitation Center in Downey, Calif. "The care we received was extraordinary, and we wanted to further the research that helped us so much," explains Betty McCarron.
The new McCarron Center is part of a major USC effort in Alzheimer's disease. Central to that effort is the Alzheimer's Disease Research Center (ADRC), which is one of a small number of such national centers across the nation that are funded by the National Institutes on Aging. The ADRC, headquartered at the USC University Park Campus, is under the leadership of world-renowned gerontologist Caleb E. Finch, Ph.D., the ARCO/William F. Kieschnick Chair in the Neurobiology of Aging.
Alzheimer's research, clinical care, education and training takes place on campuses and at hospitals throughout the USC system. The McCarron Center, headquartered at Rancho Los Amigos, is a project under development that intends to focus its educational and training efforts on both caregivers and patients. Bryan Kemp, Ph.D., USC professor of family medicine, psychiatry and gerontology, directs the center. The co-directors are USC's Chui, and Laura Mosqueda, M.D., who is now on the faculty at the University of California, Irvine, but continues her affiliation with USC as an adjunct professor. It is literally a "center without walls," according to Kemp.
Part of their work is devoted to directing one of the seven state-funded Alzheimer's Disease Research Centers of California. The Research Center is located at Rancho Los Amigos and includes patient assessment, patient management, research, education and adult day care components.
As more families like the McCarrons come face-to-face with the debilitating illness called Alzheimer's, interest in the disease-and a cure-is skyrocketing. Almost four million Americans today have the progressive, degenerative disease that attacks the brain, and an estimated 14 million will have Alzheimer's early in the next century, according to the Alzheimer's Association.
"The baby boomers are starting to feel the brunt of this with their parents," says Kemp. "It has moved from a niche medical problem to a broader social concern."
A popular research front in the battle against Alzheimer's at USC and elsewhere involves prevention: are there substances, lifestyle choices or other interventions that can stop the disease before it starts? Lon Schneider, M.D., professor of psychiatry, neurology and gerontology, leads a team involved in an ongoing clinical trial involving vitamin E, the cholinesterase inhibitor donepezil (Aricept) and a placebo to see if the incidence of Alzheimer's dementia can be reduced in people with mild cognitive impairment-half of whom will go on to develop more severe Alzheimer's. Dementia is a term describing the impairment of intellectual function, or cognition, that interferes with normal social and occupational activities. The condition is usually progressive.
Some of the best hope for prevention, however, rests in a better understanding of the molecular and biological origins of the disease itself. The USC ADRC provides core facilities and resources for those investigating Alzheimer's at all USC institutions.
Among those leading the effort is Carol A. Miller, M.D., professor of pathology and a co-director of the ADRC. Her focus: why the disease causes the selective death of some neurons and spares others. Most recently she has worked to characterize the biochemical differences between these so-called vulnerable neurons and protected neurons. "Understanding this could be the first step towards developing a treatment that would halt the destruction of brain cells early enough to keep an Alzheimer's patient healthy and functional," she says.
USC neuroscientist Zoltan Tokes, Ph.D., has been studying enzyme changes in brains affected by Alzheimer's disease. In one communications pathway in the brain, nerve impulses are transmitted from a cell, across a synapse, to another cell by the neurotransmitter acetylcholine. Acetylcholine is a neurotransmitter that helps the efficiency of thinking. Too much, or too little acetylcholine, can result in faulty transmissions. To shut down or reduce transmissions, an enzyme, cholinesterase, acts as a sort of housekeeper, destroying excess acetylcholine. In 1996, Tokes and his colleagues discovered that cholinesterase, which is produced in a region of the brain important in short term memory and learning, was inactive in Alzheimer's patients, leading them to speculate that uninhibited acetylcholine would cause too much signaling, resulting in loss of memory or other symptoms of dementia in Alzheimer's patients.
The acetylcholine pathway is now a high-priority target for pharmaceutical intervention. Drugs are being tested that in effect augment the diminished supply of cholinesterase so that signals in the acetylcholine pathway can be reduced, hopefully with a resulting diminishment of the dementia.
USC researchers are also looking at environmental exposures that may increase risk of Alzheimer's. A study of more than 300 Southern California patients by Eugene Sobel, Ph.D., professor of preventive medicine and neurology, suggested occupational exposure to electromagnetic fields (EMFs) can lead to an increased risk of developing Alzheimer's. Individuals in high-risk occupations-such as seamstresses, because sewing machines emit high levels of EMFs-had nearly four times the risk of developing the disease than individuals who had little or no occupational EMF exposure.
At USC and elsewhere, the increased interest in Alzheimer's has translated to unprecedented research-both in the laboratory and in the clinic, where patients and their families grapple with the impaired memory, thinking and behavior that result from the condition.
Helena Chui devotes part of her time to researching the anatomical and biochemical basis for differences in Alzheimer's behavior and natural history. While all patients with Alzheimer's experience severe memory loss, some may develop depression while others become agitated, suspicious or aggressive. Chui and her colleagues have painstakingly correlated the anatomical pattern of nerve cell loss with clinical symptoms, hoping to find clues to improve treatment.
Chui also devotes significant effort to defining which clinical treatments work for both the Alzheimer's patient and the caregiver family. In this area, she notes, there have been some significant improvemnts. In the past it was generally acknowledged that in Alzheimer's patients there are nerve cells with abnormal accumulations of proteins called "tangles." In 1982, says Chui, it was discovered that when nerve cells develop tangles and die out, the levels of acetylcholine decrease in the brain. Subsequent research has found that medications that raise levels of neurotransmitters like acetylcholine, serotonin or norepinephrine in the brain offer some symptomatic improvement.
Chui says that "families notice some improvement with the two FDA-approved memory-aiding drugs, Cognex and Aricept. There are also some medicines that can help depression, reduce agitation and reduce the vividness of hallucinations."
The reason clinicians who treat Alzheimer's are so focused on therapies to help symptoms is that, as yet, there is no cure in sight for Alzheimer's. According to Schneider, "There is preclinical work to develop medication that will interfere with the disease process before symptoms develop. But at this time there are no specific drugs that look promising as a cure."
Adds Chui: "We don't know if the cure is right around the corner or 15 years away. But great strides are being made."
In the meantime, research is making progress in terms of symptomatic treatment, with much of the focus on drugs that are active in signaling pathways in the brain.
Schneider, who has pioneered some of the most promising clinical trials in Alzheimer's-including studying the effects of such substances as estrogen, vitamin E, melatonin and the antioxidant drug selegiline-points to the enormous benefits such research brings to both patients and families.
"The first, most obvious therapeutic goal is to delay onset of the illness," Schneider says. "If you delay it even by five years, you cut in half the prevalence of the disease and the number of people in nursing homes."
Second, he says, slowing the rate of symptomatic decline effectively improves the quality of life for both patient and caregiver. It allows patients to function better and longer in the community, increases self-esteem and reduces stress.
Third, the goal of most treatments is to improve or correct cognition, memory and behavioral disorders for those who have severe dementia. Most current clinical research efforts, says Schneider, fall into the third category: improving symptoms in people who already have the illness.
For example, Schneider and his group recently took the lead in a multi-center clinical trial of the herb ginkgo biloba in Alzheimer's patients. "People who are alternative medicine advocates argue it may improve cognition and memory, but to date there has been only one poorly-designed study," he says. "Some of the ingredients in ginkgo could inhibit the breakdown of acetylcholine in the body and may also increase acetylcholine in the brain. Other aspects of ginkgo are that it may influence serotonin in ways that definitely improve mood. Our trial will involve some 500 to 600 patients to be followed over the course of six months to see whether gingko is more effective than the placebo."
The effect of hormones on memory is one of the major contributions being made by USC scientists toward achieving an understanding of Alzheimer's and providing relief to those afflicted. USC physicians led by Victor W. Henderson, M.D., holder of the Kenneth and Bette Volk Professorship in Neurology, discovered that women on estrogen replacement (Premarin) therapy were at reduced risk for Alzheimer's. Roberta D. Brinton, Ph.D., associate professor of molecular pharmacology and toxicology in the USC School of Pharmacy, is examining which components of Premarin are active on nerve cells. In addition, colleagues Annlia Paganini-Hill, Ph.D., professor of preventive medicine, and J. Galen Buckwalter, Ph.D., assistant professor in the Andrus Gerontology Center are contributing to this research in ongoing clinical studies.
Improving Alzheimer's symptoms by studying sleep patterns is the goal of a clinical trial being conducted by Patricia Riccio, Ph.D., in USC's Department of Nursing Program. Sleep disruption occurs in 45 percent of Alzheimer's patients and leads to diminished daytime function and increased confusion. Riccio has designed a trial involving bright light therapy. She says that as aging occurs, the body's normal circadian rhythms-biological processes such as sleep and waking-speed up. "With Alzheimer's patients, it may be shifted even further," she says. In her study, Alzheimer's patients wear a special visor for a specific period to deliver light directly to the retinal fibers of the eye (the area that "signals" the hypothalamus, which regulates the circadian rhythms). Riccio expects to effectively slow down the sleep/wake cycle.
While the goal of laboratory research is to prevent Alzheimer's in the future, those patients who seek treatment today at Alzheimer's clinics already benefit from being affiliated with the ongoing investigations at an academic medical center.
Says Kemp, "Through USC, our patients have access to the most innovative clinical trials and newest medications. In addition, we have resources for doing clinical research and we have support services for families and patients all in one location. I don't know of any other facility where you can get these kinds of services in the same setting."
Indeed, Kemp says, the broader mission of the USC McCarron Center is to promote research on Alzheimer's that involves more than just the physician and the patient. "It's hard for a single provider to take care of someone with dementia," says Kemp. "It really takes teamwork-physicians, nurses, physical therapists, psychologists, occupational therapists, social workers, pharmacists and others. We need to promote good primary care so that you continue to help the patient with Alzheimer's. We need to promote helping the family in relieving the caregiver's burden. We need to educate the public, as well as health care professionals, about Alzheimer's and other dementias."
To that end, the USC McCarron Center is researching such topics as caregiver stress and the benefits of adult day care for Alzheimer's patients-and in training physicians in the diagnosis and treatment of dementia. "The things I think are among the most important are caring, well-trained in-home help and adult day care," Kemp says. "If a patient can be in an adult day care center three or four days a week, six-hours a day, it provides essential relief to the family."
The Alzheimer's Day Care program at Rancho Los Amigos includes such components as health monitoring, structured recreational activities tailored to level of ability, exercise and projects such as gardening.
"This is just tremendous in terms of how it helps patients to stay functional for longer periods of time," says Kemp. "And when a patient is functioning on a day-to-day basis, his or her mood does better.
"Because there is no cure for Alzheimer's, it's too easy for physicians, family members and even the patients themselves to give up. It is important that people know you can do a lot more for the patient and the family than just trying to cure an illness."
Thanks to the McCarrons' gift, this help is just a phone call away. n
For more information about Alzheimer's disease research and treatment and the USC McCarron Clinical Research and Education Center, or to learn about The Doctors of USC, call 1-800-USC-CARE (1-800-872-2273).
Stephanie DuBois, Ian Gregor and Monika Guttman contributed to this article.
MUSCLING IN ON ALZHEIMER'S DISEASE
Valerie Askanas, M.D., Ph.D., is studying a disease called inclusion body myositis, or IBM, which is the most common muscle disease among people over 55. The disease weakens muscles so that people have trouble getting up out of chairs, walking and using their fingers. Eventually, they become so disabled that they must use wheelchairs.
"I think many more people have IBM than are being diagnosed," she says.
Askanas' research on IBM could have a profound impact on the treatment of Alzheimer's disease. Many abnormalities found in the muscle tissue of people who suffer from IBM strongly resemble abnormalities found in Alzheimer's patients.
Askanas discovered in the muscle tissue of IBM sufferers a protein called amyloid-ß, which also is found in the brain cells of people suffering from Alzheimer's disease.
In an ideal world, Askanas, would spend all her time researching the causes of muscle disease among older people and none applying for the grant money that funds her work.
Askanas' vision of utopia snapped a little more into focus recently when the USC professor of neurology and pathology learned that she will receive a prestigious National Institutes of Health Method to Extend Research in Time Award. This MERIT award doubles the funding period for Askanas' research to 10 years from five, allowing her to concentrate on her work knowing that long-term funding will be available.
Askanas, who has been with the School of Medicine since 1981 and currently is vice-chair of the Department of Neurology, joins an elite group of researchers. Only 3.3 percent of the 27,637 grant applications made to the National Institutes of Health in fiscal 1998 were selected for MERIT Awards.
Askanas plans to use her MERIT Award to build upon her discovery linking IBM and Alzheimer's disease.
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