Researchers at the Blanchette Rockefeller Neurosciences Institute in West Virginia say they've identified a biomarker for Alzheimer's that may allow for an early diagnosis of the debilitating disease with a brief, painless skin test.
Alzheimer's is a notoriously difficult disease to diagnose. Standard methods today involve a battery of imperfect psychiatric evaluations or postmortems that are of no help to the living. When the disease begins, it is also hard to distinguish from other impairments with similar symptoms, delaying therapy that could provide significant benefits in slowing the progression of Alzheimer's.
But a new scientific study says that Alzheimer's spurs changes in the enzymes MAP Kinase Erk 1/2. The researchers' work was based on skin tissue samples taken from the bodies of patients who had suffered a range of ailments including Alzheimer's, and it points the way to crucial early diagnosis.
"Potential treatments of Alzheimer's," says Dr. Daniel L. Alkon, scientific director of BRNI and co-author of the study with Tapan K. Khan, PhD, assistant professor, "are likely to have their greatest efficacy before the devastating and widespread impairment of brain function that inevitably develops after four or more years."
The researchers exposed the skin tissue samples to Bradykinin, a natural chemical secreted by the skin, and found that the Erk 1/2 response in the skin of Alzheimer's patients reacted in a unique manner, distinct from the reactions recorded for age-matched controls … and even more importantly, different from the skin cells of patients with non-Alzheimer's dementias such as Parkinson's disease, multiple infarct dementia and Huntington's chorea.
Using a mathematical formula, the researchers converted the skin reaction to a numerical score. They found when that score from the Alzheimer's Index agrees with a clinical diagnosis of Alzheimer's, then the probability of an accurate diagnosis is high.
In addition, says Dr. Alkon, the skin test could be delivered by any nurse or physician's assistant in an outpatient clinic or doctor's office.
"We've been studying memory cascades involving upstream regulators of those two enzymes for 25 years," says Dr. Alkon. The knowledge that the enzymes play a role in memory dates back to the 1980s. Later it was confirmed that the enzymes also played a role in Alzheimer's.
"We had the idea that they formed a crucial convergence between memory and the actual pathology of Alzheimer's," he continues, "and we started in the '90s, developing a series of tests. This is the culmination of that work, where we were able to chase down specific protein targets of those enzymes."
The Alzheimer's Association noted that the research work was "interesting but preliminary." Clearly worried that some patients or family members might overreact to the news, the association quickly emphasized that the skin test research had a number of limitations, and the group noted that there is no actual test on the market for people.
"As of today, the validity of this 'skin test' technology for making or confirming any dementia diagnosis is unproven. Claims to the contrary are misleading and overstated," says Sam Gandy, MD, PhD, chair of the Alzheimer's Association's Medical & Scientific Advisory Council. Gandy is also director of the Farber Institute for Neurosciences at Thomas Jefferson University, Philadelphia.
Today, about 4.5 million people in the United States suffer from Alzheimer's, but that number is rising quickly. Some analysts estimate that the number could hit 15 million in a decade.
Alzheimer's groups in the United Kingdom reacted more positively to the news than their counterparts here. "If the skin test can be successfully developed, it will revolutionize early diagnosis of dementia," Dr. Susanne Sorensen, head of research for the Alzheimer's Society in London, told the BBC, adding that current tests were far from completely effective.
For Dr. Alkon, the proof will be in the data drawn by expanding the test to thousands of people.
"We have another study after this one that has already been completed, with another 100 patients, that confirms these findings," he says. "But it's clear we need to work together with partnerships –– with hospitals, universities, drug companies –– to expand this to thousands of people. If it is validated with thousands of patients, and I'm optimistic it will be, it could then be available to everyone. It could be a year, a couple years or a few years away. The proof will be in the expansion and scaling up."
And the scientists say they may be onto something even more significant than an accurate test. The molecular pathway measured by the BRNI biomarker includes the same enzyme, PKC, which is targeted by the drug bryostatin. BRNI is currently seeking approval to begin clinical trials of bryostatin to determine if it is useful in treating both the symptoms and neurodegeneration of Alzheimer's disease.
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October 2006
