A nanotechnology process developed by researchers at Northwestern University can detect miniscule quantities of an important marker for Alzheimer disease in the CSF, offering the promise of a test that might one day allow diagnosis of the disease long before clinical symptoms appear.
Bio-barcode amplification (BCA) technology, which was introduced in 2003 and is already being used clinically to detect a marker for prostate cancer, detects amyloid beta-derived diffusible ligands or ADDLs. ADDLs are soluble aggregated proteins that, when concentrated in brain tissue, become the signature fibrous plaques of Alzheimer disease. (See “More about Nanotechnology Detection.”)
A team of investigators led by Chad A. Mirkin, MD, PhD, Director of Northwestern's Institute for Nanotechnology, used BCA to measure ADDL levels in the CSF of 30 patients. They discovered that ADDL concentrations were consistently and significantly greater among patients with Alzheimer's dementia than in healthy controls. The findings were reported in the Proceedings of the National Academy of Sciences (2005; 102: 2273–2276).
A MORE SENSITIVE MEASURE
According to Dr. Mirkin, BCA technology is much more sensitive than other diagnostic tests in identifying ADDLs in CSF. Currently Alzheimer disease can only be confirmed by autopsy. The test could one day enable therapeutic intervention long before plaques begin to damage the brain and patients develop dementia, he said.
“This is a pretty spectacular advance not only because we're able to test new markers in CSF, but we may be able to look for markers in other environments such as blood, urine and brain tissue samples,” Dr. Mirkin said. “We hope to develop a blood test over the course of the year,” he added.
In addition to Alzheimer disease and prostate cancer, BCA technology could be used to target known biomarkers for a wide variety of diseases, such as HIV, various other cancers, and Creutzfeldt-Jakob disease, he added.
Although not yet approved by the Food and Drug Administration (FDA) for Alzheimer disease, Dr. Mirkin said investigators at the NIH and the FDA already are using BCA technology in laboratory research.
Neurobiologist Stephan Snyder, PhD, Director of the Neuroscience and Neuropsychology of Aging Program at the National Institute on Aging, told Neurology Today in a phone interview: “There is a lot of work that remains to be done, of course, but I think that if we can detect ADDLs in the CSF they are also likely to be present in plasma or serum.”
“This test is the first in a long process to make sure we have a valid marker or markers for Alzheimer disease, but it seems that BCA has certainly met the [initial] test,” Dr. Snyder said. “Whether it has the same sensitivity in blood has yet to be determined. But then again, that may not be necessary. As long as theirs is a bona fide marker it can be turned into a clinical diagnostic tool.”
PRIONS, OTHER APPLICATIONS
Dr. Mirkin noted that the technology may have applications for detection of other diseases, including Creutzfeldt-Jakob disease and stroke. “We're working with prions and are excited,” said Dr. Mirkin. “It's our big target, but for screening purposes you need very high sensitivity.”
Dr. Mirkin added that while developing an accurate blood test for Alzheimer disease is “the ultimate goal” of the researchers, it is equally important to make sure that ADDLs are the right markers for disease. “There's evidence that it is, but we don't yet know at what concentrations.” He said it is likely that multiple markers will ultimately need to be identified for definite diagnosis of the disease, but the technology can simultaneously measure many markers at very low concentrations in a variety of media.
ADDITIONAL RESEARCH NEEDS
Samuel Gandy, MD, Vice-chair of the National Medical and Scientific Advisory Council of the Alzheimer's Association, said the report needs to be repeated with larger numbers of subjects. Dr. Gandy, who was not part of the research team, is Director of the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia.
“The paper in PNAS focuses on a small number of subjects but appears quite promising for distinguishing Alzheimer CSF from that of age-matched controls,” he said. “Now independent studies of larger numbers of subjects are required to establish whether the apparent accuracy of the test can be validated. If so, this would be an important step toward a single affirmative test for Alzheimer disease – rather than diagnosing by exclusion – and would also greatly facilitate the evaluation of anti-amyloid drugs that are currently in human clinical trials.”
While there are no proven effective medicines for the underlying cause of Alzheimer disease, development of effective anti-amyloid drugs is “an essential step in that direction,” he said.
“Finally, but importantly, successful anti-amyloid therapies are required to establish the extent to which cerebral a-beta accumulation contributes to the cognitive decline of Alzheimer disease.”
According to NIH Alzheimer disease expert Stephan Snyder, “It's clear that we may now be able to do something early on in the process, which is extremely important. Maybe not for a patient who is say 85 years old, but for patients in their 50s and 60s, it's an entirely different thing.”
ARTICLE IN BRIEF
✓ Using a new technology, investigators were able to detect miniscule quantities of amyloid beta-derived diffusible ligands - ADDLs - an important marker for Alzheimer disease in the CSF.