Spotting brain inflation using iron oxide microparticles
Early detection often is the key to successful treatment of a condition. Now a team from the University of Oxford in the UK has shown that iron oxide microparticles can image acute brain inflammation in a mouse model at a time when the pathology otherwise is undetectable.
Team member Dr. Robin P. Choudhury, a clinical cardiologist at Oxford, said that the results are promising for the treatment of diseases such as multiple sclerosis. “The ultimate goal would be human imaging,” he said, although cautioning that that objective is far off for now.
Multiple sclerosis is characterized by tissue inflammation followed by loss of the protective sheath around the nerves — or demyelination — and eventually there is loss of nerve axons. Before tissue inflammation, however, white blood cells, or leukocytes, become involved in the disease process. A key mediator of the initial leukocyte recruitment process is the endothelial vascular cell adhesion molecule-1 (VCAM-1). Thus, the researchers decided to detect VCAM-1 via MRI.
Three-dimensional volumetric maps of the magnetic resonance contrast agent VCAM-MPIO (red) are binding to inflamed neural tissue in a mouse brain. In each mouse, 41 contiguous images were segmented by an automated analysis of signal intensity histograms. MPIO contrast effects delineated the architecture of cerebral vasculature in the IL-1ß–stimulated hemisphere (left half of image) with almost total absence of binding on the contralateral, nonactivated side. The midlines are indicated by vertical sections. Reprinted from Nature Medicine, copyright R.P. Choudhury.
To do this, they used iron oxide microparticles, which provide a strong magnetic resonance signal, that were a micron in size, too large to target some tissue but suitable for endovascular imaging.
To the microparticles, they conjugated antibodies to VCAM-1. Tests with in vitro cell lines that were exposed to various doses of a tumor necrosis factor showed that the conjugated microparticles had a high affinity for the exposed cells. What’s more, the affinity went up with the dose of the tumor necrosis factor, which provokes the expression of VCAM-1.
Tests on a mouse model showed that injected microparticles produced an increase in magnetic resonance contrast of more than a hundredfold, making it easy to spot and locate the microparticles inside the mouse. Choudhury characterized the setup they used, which included a 7-Tesla horizontal bore magnet with a Varian spectrometer, as standard for biomedical research. He said that the group is actively investigating the properties of the contrast agent in clinical magnetic resonance scanners.
The researchers confirmed that binding of the microparticles was specific to the tissue. They did this in various ways, including post-mortem optical staining and light microscopy using a Leica microscope. They also captured magnetic resonance images of mice brains injected with the contrast agent. For a control, some previously were injected with antibodies that blocked the contrast agent binding. Those samples where the microparticles could bind to the tissue easily were distinguishable from those where the microparticles could not.
The studies also indicated that the contrast agent was well-tolerated and did not seem to pose a toxicity risk. Further work in this and other areas will be needed before the conjugated iron oxide microparticles can be used in a clinical setting.&
Nature Medicine, October 2007, pp. 1253-1258.
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