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Discovery may lead to skin tests for Alzheimer's disease

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By Press Release by National Institutes of Health • • August 31, 1993

Scientists at the National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, MD, and the Burke Medical Research Institute at Cornell Medical College in White Plains, NY, have discovered physiological differences in the skin cells of those with Alzheimer's disease (AD), a finding that could lead to a standard battery of skin tests for diagnosing the disease. The scientific basis of one possible test is published in the September 1 issue of the Proceedings of the National Academy of Sciences (PNAS)*. The results also offer hope that physicians will ultimately be able to predict who is at risk for getting AD and could point scientists toward the underlying cause of the disease, says Daniel L. Alkon, M.D., chief of the NINDS Neural Systems Section and the lead scientist in the research group.

The tests are based on the group's discovery that skin cells in AD patients have defects that upset the cells' ability to properly regulate critical potassium and calcium ions. The fact that the cell defects are present in the skin suggests that AD results from physiological changes throughout the body. Dementia may be the first noticeable effect of these changes as the defects affect cells in the brain, the scientists say.

AD is the single greatest cause of intellectual impairment in older Americans, affecting more than 2.5 million people in the United States alone. It is a devastating disorder that causes a progressive and irreversible dementia. One of the earliest and most common symptoms of the disease is memory loss. As AD progresses, patients get disoriented, confused, and forget what was said only a moment previously. Patients in the late stages of the disease often become totally isolated from the world and may lose control of basic bodily functions.

Currently, doctors make a diagnosis of AD by eliminating all other possible causes of dementia, and have no way to confirm the diagnosis until an autopsy is done. "Since Alois Alzheimer described the disease nearly a century ago, people have been trying to find a way to accurately diagnose it in its early stages," says Patricia Grady, Ph.D., acting director of the NINDS. "This discovery, if confirmed, could provide a big step forward in our efforts to deal with and understand the disease."

In the PNAS paper, Alkon and colleagues report that, of 50 people tested, skin cells from the 15 who were clinically diagnosed as having AD were missing a certain type of microscopic tunnel that governs the flow of potassium in and out of the cells. Nearly all the age-matched controls, and many of the younger controls, had functional potassium channels of this type. When this test and three others were done together, the results were 100 percent accurate in separating those with clinically diagnosed AD from those without the disease. In blind tests of skin samples from controls and those with AD, Alkon says, "we didn't miss any."

The researchers at the Burke Medical Research Institute have long been searching for a skin test for AD under the direction of Gary Gibson, Ph.D., and with financial support from the National Institute on Aging (NIA). In the past, Gibson and coworkers have found other intriguing cell changes that may eventually be diagnostically significant and could help scientists understand the deficits associated with AD.

Alkon emphasizes that a broad clinical trial is necessary to determine whether the current finding will hold for all AD patients, but the research team is encouraged by the results so far. "With these statistics it is extremely promising that the result will hold up in the population at large," Alkon says. The director for Alzheimer's disease research at the NIA, Zaven Khachaturian, Ph.D., also notes the need to confirm the result with a much larger study, but comments that a simple skin test for Alzheimer's would be "an extremely important finding."

The NINDS scientists made the discoveries through a unique line of scientific reasoning. Most scientists who study AD concentrate on the fibrillary tangles and amyloid plaques prevalent in the brain tissue of those with the disease. Alkon and his colleagues, on the other hand, are memory researchers: they study how the flow of ions and the interactions of neural signals allow the brain to remember. They originally intended to study memory loss in AD, not find a clinical test for the disease. "We started off with the idea that since difficulty in forming memories is one of the earliest and most common effects of Alzheimer's disease, the common denominator for AD patients might be a defect in the cellular processes of memory," Alkon says. Furthermore, Alkon theorized, such changes in cell physiology might be present throughout the body.

In the present study the scientists discovered that the AD patients had a missing or dysfunctional channel that usually governs the flow of potassium in and out of cells. The flow of potassium is especially critical in cells responsible for memory formation. The scientists then went on to find two other defects that affect cells' supply of calcium, another critical ion. The scientists detected the same cell defects in nerve cells of the olfactory system, a good sign that the defects are also present in other brain cells.
If their discovery is substantiated by further research, the investigators may have found a key clue to the cause of AD. But even a diagnostic test alone could translate into savings of millions of dollars in medical costs, Alkon says. Early diagnosis may also allow early intervention as effective treatments for AD are discovered.

National Institutes of Health
U.S. Department of Health and Human Services
Press Release
August 31, 1993

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