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.

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

  1. This interesting paper describes modification of a probe that crosses the blood brain barrier to become an MRI contrast agent. The exact specificity and sensitivity of the probe are still below what one would want to see in a
    clinical reagent, and the imaging times a bit long, so it appears that the development of this probe is a step or two behind the PET ligand PIB. Nonetheless, it is exciting to see the revolution in amyloid imaging that has occurred after the demonstration by Klunk and colleagues that small molecules based on histological dyes could cross the blood brain barrier and act as specific contrast agents for amyloid plaques. The current paper advances the
    field considerably by expanding to MRI the potential imaging modalities that could one day be used to track progression of plaque deposition in patients.

  2. Alzheimer's disease is diagnosed definitively by the presence of amyloid and tau pathology in the context of dementia. Because plaques and tangles (the canonical AD lesions) can be detected with certainty only by histological analysis, a method of visualizing either or both of these lesions non-invasively in the living brain would be a boon to patients, physicians, and researchers. In vivo imaging would permit a longitudinal analysis of the amplification and spread of the lesions, as well as the relationship of the lesions to specific behavioral impairments; Furthermore, the ability to detect Aβ plaques early in the course of the illness could help to rule out other causes of cognitive decline, and the amyloid signal would be invaluable as a biomarker for assessing the effects of disease-modifying treatments for AD. At present, the most promising imaging method for AD is a PET method using radiolabeled Pittsburgh compound-B. The drawbacks of this method are the exposure of the patient to radiation, short half-life of the compound's radioactivity, expense, low resolution, background noise and (from a research standpoint) the relatively poor binding of the compound to Aβ deposits in experimental transgenic mice.

    The ideal imaging technique, then, would be safe, sensitive, specific, uncomplicated and inexpensive; comparable binding in humans and animal models also would be a plus. While we are still far from the ultimate imaging method, Higuchi et al. make important advances in several of these domains. Specifically, they have developed a non-radioactive, 19F-containing compound (FSB) that crosses the blood-brain barrier, binds selectively to amyloid deposits in transgenic mouse brain, and can be visualized by MRI both in the 19F and 1H modes. The compound is comparatively safe, selective, long-lived, and works well in a transgenic murine model of cerebral β-amyloidosis. The brain structures affected can be visualized with high resolution MRI. As the authors note, there is still need for improvement before this method becomes practical for use in humans. Relatively long imaging times in a powerful (9.4T) magnet are employed to achieve the reported results in mice. The differential sensitivity of T1-weighted 1HMRI for detecting plaques in different brain areas requires further analysis, and the sensitivity of the protocol for diffuse vs. dense deposits as well as for vascular β-amyloid in vivo is unclear. It would also be useful to know if the compound, or similar compounds, binds to pre-fibrillar Aß structures. Higuchi and colleagues note that experiments are in progress to assess the binding of the compound to tangle-like lesions in a mouse model of tauopathy. As a bridge between mice and humans, MR imaging of FSB could be profitably undertaken in larger animals such as aged nonhuman primates, which naturally develop senile plaques and cerebral amyloid angiopathy (and, in some instances, tauopathy). It is heartening to note the acceleration of progress in imaging AD pathology in vivo; it appears likely that clinicians and scientists soon may have multiple options for visualizing proteopathic lesions in the living brain.

  3. This is a very significant paper. It represents an important new chapter in AD imaging by developing and testing novel non-radioactive ligands for Aβ plaques. The authors show they can visualize the plaque burden in experimental animal models of AD-like Aβ brain amyloidosis without the need for specialized radioligands, some of which have limited availability, so I expect this new advance in neuroimaging methods will accelerate the pace of neuroimaging studies for AD.

References

News Citations

  1. Pittsburgh Compound-B Zooms into View

Further Reading

Primary Papers

  1. . 19F and 1H MRI detection of amyloid beta plaques in vivo. Nat Neurosci. 2005 Apr;8(4):527-33. PubMed.