MRI Probe Combined with Magnetic Nanostructure and Antibody can Detect Alzheimer’s Disease Early

A noninvasive magnetic resonance imaging (MRI) application has been designed that can detect the Alzheimer’s disease (AD) in a living animal, well before typical Alzheimer’s symptoms appear. The researchers created an MRI probe that combines a magnetic nanostructure with an antibody that searches for the amyloid beta brain toxins responsible for onset of the disease. The accumulated toxins, because of the associated magnetic nanostructures, are revealed as dark areas in MRI scans of the brain.

The interdisciplinary team of Northwestern University (Evanston, IL, USA) scientists and engineers developed the noninvasive MRI approach that can detect the disease in a living animal, and can do so at the earliest stages of AD, well before typical symptoms appear.

The research was led by neuroscientist William L. Klein, a professor of neurobiology in the Weinberg College of Arts and Sciences and materials scientist Vinayak P. Dravid, a professor of materials science and engineering at the McCormick School of Engineering and Applied Science, the researchers developed the MRI probe that pairs a magnetic nanostructure (MNS). This capability to identify the molecular toxins may one day enable scientists to both identify problems early and better design drugs or therapies to fight and track the disease. Furthermore, while not the focus of the study, early evidence suggests the MRI probe improves memory, too, by binding to the toxins to render them “tied up” to do additional damage.

“We have a new brain imaging method that can detect the toxin that leads to Alzheimer’s disease,” said Prof. Klein, who first identified the amyloid beta oligomer in 1998. “Using MRI, we can see the toxins attached to neurons in the brain,” Prof. Klein commented. “We expect to use this tool to detect this disease early and to help identify drugs that can effectively eliminate the toxin and improve health.”

With the successful demonstration of the MRI probe, Northwestern researchers now have established the molecular basis for the cause, detection by noninvasive MR imaging and treatment of AD. Dr. Dravid introduced this magnetic nanostructure MRI contrast enhancement approach for Alzheimer's following his earlier work utilizing MNS as smart nanotechnology carriers for targeted cancer diagnostics and therapy. (A MNS is typically 10–15 nm in diameter.)

The study’s findings were published online December 22, 2014, in the journal Nature Nanotechnology. This new MRI probe technology is identifying something different from conventional technology: toxic amyloid beta oligomers instead of plaques, which occur at a stage of AD when therapeutic intervention would be very late. Amyloid beta oligomers now are widely believed to be the cause in the onset of AD and subsequent memory loss.

The mobile amyloid beta oligomers, in a disease brain, attack the synapses of neurons, destroying memory and ultimately resulting in neuron death. As time progresses, the amyloid beta accumulates and starts to adhere together, forming the amyloid plaques that current probes target. Oligomers may appear more than 10 years before plaques are detected. “Noninvasive imaging by MRI of amyloid beta oligomers is a giant step forward towards diagnosis of this debilitating disease in its earliest form,” said Prof. Dravid.

There is a great need for what the Northwestern research team is doing—identifying and detecting the correct biomarker for new drug discovery. In spite of extraordinary efforts, no effective drugs exist yet for Alzheimer’s disease. “This MRI method could be used to determine how well a new drug is working,” Prof. Dravid said. “If a drug is effective, you would expect the amyloid beta signal to go down.”

The nontoxic MRI probe was delivered intranasally to mouse models with AD and control animals without the disease. In animals with Alzheimer’s, the toxins’ presence can be seen clearly in the hippocampus in MRI scans of the brain. No dark areas, however, were seen in the hippocampus of the control group.

The ability to detect amyloid beta oligomers, according to Prof. Klein, is significant for two reasons: amyloid beta oligomers are the toxins that damage neurons, and the oligomers are the first indication of trouble in the disease process, appearing before any other pathology. Moreover, the investigators observed that the behavior of animals with AD improved even after receiving a single dose of the MRI probe. “While preliminary, the data suggests the probe could be used not only as a diagnostic tool but also as a therapeutic,” said Kirsten L. Viola, a co-first author of the study and a research manager in Prof. Klein’s laboratory.

Along with the studies in live animals, the researchers also examined human brain tissue from Northwestern’s Cognitive Neurology and Alzheimer’s Disease Center. The samples were from individuals who died from AD and those who did not have the disease. After introducing the MRI probe, the researchers observed large dark areas in the Alzheimer brains, indicating the presence of amyloid beta oligomers.

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