Feb. 2, 2005 ARLINGTON, Va. -- Using their novel bio-bar-code amplification (BCA) technology, researchers analyzing fluid from around the brain and spinal cord have detected a protein linked in recent studies to Alzheimer's disease.
If proven successful in further clinical studies, the procedure could become the first tool for early diagnosis of Alzheimer's, and the first test to conclusively identify the disease in living patients.
Chad Mirkin and William Klein of the National Science Foundation (NSF) Nanoscale Science and Engineering Center (NSEC) for Nanopatterning and Detection Technologies at Northwestern University, and their colleagues, announce their findings the week of Jan. 31 in the online edition of the Proceedings of the National Academy of Sciences.
Because of the extreme sensitivity of the BCA process that Mirkin's team developed, the researchers were able to detect within each fluid sample a miniscule amount of proteins called amyloid ß-derived diffusible ligands (ADDLs). The goal is to detect and validate infinitesimal amounts of the biomarkers in blood.
Research by Klein and his colleagues suggests that ADDLs first appear in the earliest stages of Alzheimer's. If the BCA process can identify the markers before symptoms develop, doctors may be able to combat the illness in its nascent form when treatments may be most effective.
In the first steps of the BCA process, unique microparticles latch onto the biomarker targets – in this study, the ADDLs. The particles are magnetic, a property that aids collection at the end of the procedure. Researchers then add a second ingredient that consists of a gold nanoparticle core surrounded by hundreds of identical DNA strands, which serve as hundreds of "bio-bar-codes" the researchers can detect at the end of the test. Ultimately, the gold-DNA particles and magnetic particles sandwich the biomarker targets.
A magnet separates the sandwich complexes from the rest of the sample. The complexes are then heated to release the DNA bar codes, which are then measured by an extremely sensitive detector. Each DNA piece greatly increases the sensitivity of the test and its potential to tell doctors a patient carries the ADDLs.
According to the researchers, BCA is about 1 million times more sensitive than the next best thing – standard enzyme-linked immunoassays (ELISAs). ELISAs do not have the sensitivity required to detect ADDLs in cerebrospinal fluid.
BCA could eventually be configured to detect hundreds of diseases simultaneously – with a single procedure, doctors could quickly and inexpensively test a blood sample for any number of ailments. The researchers developed BCA to detect a mere few dozen molecules amongst a sample filled with billions and have already experimented with biomarkers for AIDS and prostate cancer.
This research was supported by both NSF's Engineering Research Centers program and the NSF Office on International Science and Engineering.
Comments from the researchers:
"This study is a major step forward in identifying a routine diagnostic tool for Alzheimer's disease, and it validates our hypothesis that there are many biomarkers for disease that go under the radar of conventional diagnostic tools. The extraordinary sensitivity of the bar code assay has a chance to change the way the medical community thinks about molecular diagnostics and the markers they consider for many types of diseases." – Chad Mirkin, Northwestern University Department of Chemistry and Institute for Nanotechnology
"It's a good bet that the very earliest stage of AD memory loss begins when ADDLs attack key synapses in the brain. We predicted some of these ADDLs would leak into the cerebrospinal fluid, but until now we couldn't detect them. Thanks to the extraordinary sensitivity of the BCA it's been possible to validate the prediction, and maybe even set the stage for creating the first clinical lab test for Alzheimer's disease. " -- William Klein, Northwestern University Institute for Neuroscience
Comments from NSF:
"The researchers have pioneered a promising new technology in the emerging area of nanobioengineering. These nanoengineered particles have the capability to effectively interface with biological molecules." – Sohi Rastegar, a bioengineering expert and the NSF program director who oversees the agency's support of the Northwestern NSEC and several other bioengineering centers.
"This will be a biosensing system with high sensitivity and specificity that can help health professionals diagnose many debilitating diseases. This is particularly important for diseases like Alzheimer's where a reliable diagnostic tool is lacking and early intervention could have a significant impact on the lives of patients and their loved ones, in addition to lowering health care costs." – Sohi Rastegar
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