Dec. 12, 2006
Protein 'bar code' in spinal fluid could lead to first diagnostic test for Alzheimer's patients, researchers say
Imagine the ability to use a simple spinal tap to diagnose Alzheimer's in people living with the disease.
With the power of proteomics -- the study of the structure and function of proteins -- that ability could be close at hand.
Kelvin Lee, Cornell associate professor of chemical and biomolecular engineering; Norman Relkin, clinical neurology associate professor at Weill Cornell Medical College; and researchers Erin Finehout, Ph.D. '05, Zsofia Franck and Leila Choe have discovered that Alzheimer's is identifiable through a specific pattern of proteins, a "bar code," so to speak -- found in cerebrospinal fluid, or CSF.
Their findings, published in the December online issue of Annals of Neurology, are the culmination of research efforts involving both neurology and engineering on Cornell's two campuses that began in 1999.
The researchers discovered a panel of 23 proteins specific to the neurodegenerative disease when comparing CSF samples from a group of patients suffering from Alzheimer's, with samples from a control group of asymptomatic patients and patients with other forms of dementia. The discovery holds promise for developing a diagnostic test for Alzheimer's.
Currently, the only definitive diagnosis is a postmortem biopsy on brain tissue. The ability to accurately identify the disease in living patients would have major implications for everything from personalized medical care to clinical drug trials, Lee said.
The Cornell researchers are not the first, nor the only scientists looking to proteomics as the key to unlocking an Alzheimer's diagnosis. The Cornell study, however, differs in many ways from research elsewhere, not only through its unique engineering/neurology collaboration, but also the quality of its samples, the researchers noted.
"Some other studies have met with limited success, but most have correlated their findings with patients' clinical symptoms, rather than working with the gold standard of autopsy-proven Alzheimer's," Relkin said.
To start, Lee said, the research group called every brain bank and Alzheimer's research center in the country to solicit samples that met criteria for the disease, taken while the patients were still alive. They also needed proof that the patients, after they died, were later confirmed to have had the illness.
Their control group comprised healthy individuals who donated spinal fluid, as well as people who exhibited signs of dementia but were unlikely to be suffering from Alzheimer's. The composition of the control group was critical, according to Lee, so that the right comparisons could be made to the Alzheimer's samples.
To separate and quantify the proteins, the scientists used gel electrophoresis, which allowed them to see the proteins as two-dimensional bar code patterns on a given sample. This led to analysis of how the bar code patterns changed in ways relevant to the disease.
Using mass spectrometry, the researchers then analyzed the individual proteins to figure out what the underlying genes were.
Although identifying the presence of the 23 proteins was a huge step forward for diagnosing Alzheimer's, there is more work to be done before a spinal-tap procedure for diagnosis of the disease can become available for physicians in their offices, Lee said. Among the further studies needed is confirmation of these results using different sets of patients, he said.
Despite the preliminary nature of the Cornell researchers' results, the presence of the protein biomarkers holds important implications for Alzheimer's diagnosis and treatment down the road, Lee said.
"You can imagine a situation where, if treatment strategies are available, physicians can start to treat and look at the response to these markers, and see if the individual is responding or not to the treatment," Lee said. "If not, physicians can try a different dosage or switch to a different strategy."
The Institute for the Study of Aging is continuing the research by funding the group to develop nanotechnology based on the discovery of the 23 proteins, Lee said. The group's original research was funded by the Michael J. Fox Foundation, the O'Neill Foundation, the New York State Office of Science, Technology and Academic Research, the National Institutes of Health and Cornell's intercampus seed grant program.
Lee said that the synergy created by the research group collaboration bridging Cornell's two campuses played a major role in the team's success. The balance of having a physician/neuroscientist working together with a biochemical engineer provided the key perspectives needed to reach their conclusions.
"Each kept the other side on their toes," Lee said.