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UNT System: Resource magazine >> The aging of the brain

A fThe aging brain: researchers study Alzheimer's causes, treatments and preventionsIt's diagnosed in the United States every two minutes and takes a life every five minutes. It's Alzheimer's disease, a progressive, irreversible disorder that kills brain cells and eventually kills its victims. But researchers at the University of North Texas Health Science Center at Fort Worth are working to determine what causes Alzheimer's and how to treat and prevent the disease.
James Simpkins, left, visits with residents of the James L. West Alzheimer Center in Fort Worth.     The symptoms of Alzheimer's disease, or AD, are well known: a gradual loss of memory, confusion and impaired judgment, changes in personality and behavior, dependence on others for the routine tasks of living. Four million Americans, most of them elderly, have been diagnosed with AD; without a cure or method of prevention, that number will rise to 14 million by mid-century. Worldwide, many millions more will suffer from the disease that some researchers are already calling the epidemic of the 21st century.
UNT's Texas Academy of Mathematics and Science student Priscilla Pang prepares to test estrogen-like compounds for their ability to protect brain cells.   While the exact cause of AD is still unknown, scientists' understanding of the underlying mechanisms is growing. Researchers believe that processing of certain proteins in the brain goes awry, resulting in the production of toxic proteins that invade nerve cells (causing what are called neurofibrillary tangles) and the spaces between nerve cells (leading to the accumulation of insoluble deposits known as amyloid plaques).

Risk factors
   As researchers examine how and why the processing of these proteins is altered, they continue to learn more about the risk factors associated with AD. James Simpkins, Ph.D., chair of the Department of Pharmacology and Neuroscience and director of the Institute for Aging and Alzheimer's Disease Research at the Health Science Center, says there are several known risk factors.
    "Family history a first-degree relative (a parent or sibling) who has the disease puts you in a high-risk group," he says. "Being female is a risk factor. Women are two to three times as likely to have AD as men. We believe that's because of the estrogen reduction during menopause. Low educational attainment is a risk factor, as is a history of head injuries that have resulted in loss of consciousness. Having had a stroke is a risk factor. And an obvious, major risk factor is age."
    Without question, the likelihood of contracting AD rises dramatically as a person ages. The increase in average life expectancy over the past century from 48 to 76 years has brought with it a marked rise in the number of cases of Alzheimer's, a disease that strikes most frequently between the ages of 65 and 75.

Free radicals
   Research is under way at the Health Science Center that uses protein biological markers (biomarkers) in the blood to identify people who are at risk for developing the disease. The goal of this research is to develop a test that can provide a diagnosis for Alzheimer's before symptoms appear. An accurate, early diagnosis gives affected individuals a greater chance of benefiting from existing treatments.
    "One such marker," says Robert W. Gracy, Ph.D., Alzheimer's researcher and associate vice president for research and biotechnology at the Health Science Center, "is damaged proteins that show up in blood due to oxidative damage to cells in the brain."
    As a consumer of a full fifth of the oxygen we take in, the brain is exposed to potentially toxic oxygen free radicals, which contribute to the production of the toxic proteins that can kill brain cells, Gracy explains. Our body makes antioxidants to combat the oxygen free radicals, and we obtain some in our diet. Research at the Health Science Center is aimed at understanding why the body's defenses against oxidative damage appear to diminish with age and which antioxidants are the most effective and in what quantities. For example, vitamin E has shown promise in slowing down the progression of AD, Gracy says.
    "The goal of our research here is to treat what we call preventable brain aging," says Simpkins. "We're looking at using a number of therapies that we think are going to preserve brain health and hopefully delay brain aging as well as delay or prevent AD. We believe that if we can prevent nerve cell death, we can preserve cognitive function."

Drugs and mental exercise
   In addition to its research on amyloid plaques and neurofibrillary tangles and its development of genetic and biological tests to detect the early stages of AD, the Institute of Aging is researching ways to prevent brain damage from stroke. And one of the most exciting areas of future research at the institute is behavioral intervention the idea that simply using your brain may help keep it healthy.
    "There is anecdotal evidence and hard data that what I like to call 'mental exercise' is good for the aging brain and is probably very good for the Alzheimer's brain, particularly if it's instituted prior to the onset of the disease," Simpkins explains.
    "We don't know the kind of mental exercise that's best, nor the amount that's best. We don't know if it's a short bout daily or long bouts less frequently that are more effective. We will be able to design studies that get at those issues. Hopefully we'll be able to come up with prescribed behavioral modifications for people who are showing evidence of dementia."
    The Health Science Center is also developing new drugs for the treatment of Alzheimer's and plans a facility in which to conduct clinical trials to establish their effectiveness, Simpkins says.
    "We have coming out of our lab 50 different compounds, some of which we hope to start in clinical development," he says.
    Such optimism characterizes Simpkins' view of the future of Alzheimer's research and treatment at the Health Science Center.
    "The issues we're looking at are not being addressed today anywhere else," he says. "They're very important subjects."

 The estrogen connection

Women appear to be two to three times more likely than men to develop Alzheimer's, says James Simpkins, Ph.D., chair of the Department of Pharmacology and Neuroscience and director of the Institute for Aging and Alzheimer's Disease Research at the UNT Health Science Center.
   The fact that women tend to outlive men makes women more likely to reach the age at which the risk of getting AD increases dramatically. But Simpkins believes another factor is at play: estrogen reduction during menopause.
   "Being post-menopausal and not on estrogen replacement is a risk factor," he says.
   A study being conducted at the Health Science Center is examining the estrogen-Alzheimer's link. A team led by Janice Knebl, D.O., chief of geriatrics and director of the Gerontology Assessment and Planning Program, is evaluating the effectiveness of hormone replacement therapy coupled with the drug donepezil hydrochloride, which helps conserve the brain's neurotransmission chemical, acetylcholine.
   It's an area that has engaged Simpkins for more than 15 years. In tests, he says, estrogens have reduced the deposition in the brain of beta amyloid, a cause of senile plaques commonly found in Alzheimer's patients. Estrogens also appear to stabilize microtubules, which Simpkins describes as small canals that run up and down the nerve cells and transport materials to the cells. The canals become twisted and tangled in Alzheimer's patients, and estrogens appear to maintain the function of these canals.
   "If you take estrogens away from a woman or animal," Simpkins says, "the brain doesn't seem to do as well. Therefore, loss of estrogens at menopause is having some fundamental effect on the ability of the brain to age well."
   "The clinical evidence is that if you're on estrogen replacement therapy, you have about a 50 percent lower incidence of AD," Simpkins says. "That's been seen again and again in epidemiological studies that look back and ask who got the disease and what is interesting about their life related to getting or not getting the disease."
   The goal, he says, is to design therapies that take advantage of estrogen's apparent positive effects on Alzheimer's while minimizing potential negative effects. He says compounds are being produced containing estrogen that may protect nerve cells without the risk of cancer associated with the use of estrogen.
   In ongoing prevention trials at the Health Science Center, women who appear to be cognitively normal but have risk factors for developing Alzheimer's are being studied.
   "If you put part of the group on estrogens," Simpkins says, "is there a difference in the incidence of AD after four or five years? We're trying to determine if a compound or behavior can prevent a disease from happening."




 What can we do?

Recent progress in Alzheimer's disease research has been dramatic, but there is still much to learn before a cure can be discovered. In the meantime, according to the latest research, there are several ways to reduce the risk of developing the disease.
    "We're approaching the time when we can say, 'Here are the things you ought to be doing by the age of 55 or 60,'" says Simpkins.
   "Certainly, keeping mentally engaged is one. With people who are cognitively active, the prediction is and the data support that they're less likely to show up with cognitive decline."
   Keeping physically active also appears to be beneficial, Simpkins says. Exercising, as well as keeping one's blood pressure in check and quitting smoking, can help reduce the risk of stroke, which is strongly associated with Alzheimer's disease.
   The incidence of head trauma, another risk factor, can be reduced through the use of sports helmets and seat belts.
It appears likely that antioxidant supplements such as vitamin E have a positive effect. "But to get the effect, you probably need a much higher dose than that found in typical multivitamins," Simpkins says.
   In addition, some studies have shown anti-inflammatories, such as ibuprofen, to be beneficial in treating or slowing the progression of the disease.



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