13 March 2005. Researchers from the RIKEN Brain Science Institute in Saitoma, Japan, are reporting a new MRI-based method for identifying amyloid deposits in living brain. A group led by Takaomi Saido used a fluorine-containing amyloidophilic dye and high-resolution MRI to detect individual plaques in live, anesthetized amyloid precursor protein (APP) transgenic mice.
The new technique, published in Nature Neuroscience online on March 13, gives researchers a valuable tool to investigate the pathology and possible prevention of amyloid buildup in mouse models of AD. Eventually, MRI could provide a cheaper, higher resolution, non-radioactive alternative to the recently developed PET-PIB technique (see related news story) first used in humans last year.
In PET-PIB scans, a short-lived radioactive tracer lights up amyloid deposits. For MRI, Saido's group and their collaborators at Dojin Laboratories in Kumamoto developed a stable contrast agent based on the Congo red-related amyloid stain bromostyrylbenzene (BSB). The researchers replaced the bromine with the naturally occurring isotope of fluorine, 19F, an atom that produces an MR signal nearly equal to that of 1H. Living tissues contain very little fluorine, assuring a low background. The researchers, led by first author Makoto Higuchi, showed the compound avidly labeled amyloid plaques in mouse and human brain tissue slices, and that FSB was not toxic to the heart, liver, kidneys or hippocampal neurons at the doses used for imaging.
Intravenous injection of FSB into Tg2576 APP transgenic mice, followed by live MRI, resulted in the appearance of 19F -MR bright spots in the cortex and hippocampus, and the enhancement of 1H resonance signals in the hippocampus. Post-mortem staining of brains confirmed that the MR changes after injection of FSB corresponded to areas of β-amyloid immunoreactivity.
Successive MRI scans of aging transgenic mice showed increased plaque burden with time, and the quantitation of plaque abundance by MRI correlated well with amyloid levels measured independently by immunohistochemistry. In the hippocampus, the lower limit for detection using 19F - and 1H -MRI was 2.5 percent of surface area covered with plaque, while in the entorhinal cortex the limit of detection was somewhere between 2 percent and 8 percent coverage.
This technique will be immediately useful for longitudinal studies looking at amyloid burden and pathology progression in mice but its clinical application to humans will require more development. The use of 19F for MRI holds great promise, according to the authors, because of the ease of incorporating fluorine into a wide variety of chemical compounds to create long-lived contrast agents. Improvements in MRI that could cut image collection times, which ranged up to two hours in the current study, are sure to continue apace, leading the authors to summarize their work this way: "Considering its sufficient sensitivity, specificity and cost effectiveness together with negating the need for radioactive materials, we propose that the MRI technology approach be seriously considered as a candidate for diagnostic amyloid imaging of human brains."—Pat McCaffrey
Pat McCaffrey is a freelance science writer in Newton, Massachusetts.
Higuchi, et al. 19F - and 1H-MRI detection of amyloid-β plaques in vivo. Nature Neuroscience 2005 March 13; advance online publication.