June 2005, VOLUME 184
NUMBER 6

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June 2005, Volume 184, Number 6

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Review

Getting Small Is Suddenly Very Big: Review of the Proceedings of the Third Annual Meeting of the Society for Molecular Imaging

+ Affiliation:
Department of Radiology, Duke University Medical Center, Box 3808, Durham, NC 27710.

Citation: American Journal of Roentgenology. 2005;184: 1736-1739. 10.2214/ajr.184.6.01841736

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The field of molecular imaging, defined here as imaging that provides information on cellular processes and molecular pathways in vivo, is rapidly growing. In this context, the term “molecular imaging” has been used for barely a decade and, until recently, few radiologists were aware of the term. The remarkable progress occurring during this short interval is, quite literally, leading to a revolution in thought. Anatomic imaging is being replaced by functional imaging, in which the underlying biochemical pathways can be directly interrogated to confirm the presence or absence of pathology. It is clear that many new techniques and insights gained from molecular imaging in animal models will play a role in imaging of human disease processes. However, which applications will bear fruit, and when, remain unclear.

In the past few years, many scientific societies have formed to advance molecular imaging techniques. One of the major ones, the Society for Molecular Imaging (SMI), founded in 2000, held its third annual meeting September 9-12, 2004, in St. Louis, MO. The mission of the SMI is “to advance our understanding of biology and medicine through noninvasive in vivo investigation of cellular molecular events involved in normal and pathologic processes” [1]. Attendance at SMI's annual meetings has grown significantly during the society's short history. The first meeting in 2002 drew approximately 550 attendees; in 2004, the meeting had approximately 850 registrants.

The goal of the 2004 meeting, to highlight the increasing ability to view disease processes in vivo, was accomplished through six plenary sessions, 16 symposia, two seminars, and more than 100 oral presentations. In addition, more than 300 posters were presented during two sessions. The meeting was called to order by David Piwnica-Worms, Washington University School of Medicine, after which Britton Chance, University of Pennsylvania, delivered the keynote lecture.

This review highlights the presentations that are likely to be of special interest to radiologists. Those seeking more information should visit SMI's Web site [1].

In his presentation, “How to Integrate `Molecular Imaging' into Clinical Radiology,” King Li, National Institutes of Health, addressed the misconception that molecular imaging is an esoteric topic that will not contribute significantly to radiologic imaging of humans. Li defined molecular imaging as “the practice of medical imaging in an era of molecular medicine,” a description that should arouse the interest of radiologists in the field. He outlined the preliminary steps radiologists can take while they await the transition of molecular imaging from the animal-imaging environment to the clinical-human environment. The first step is to understand the molecular biology that underlies the morphologic features seen on conventional imaging studies. The next step is to combine imaging information with the molecular diagnostic information available through numerous sources.

One of the more interesting presentations explained how molecular imaging can advance our understanding of a common disease process—bone metastases from a remote primary tumor. Because development of metastases in bone marrow is dependent on expression of various growth factors normally released during bone resorption, therapies aimed at pharmacologic interference with bone turnover would be expected to decrease the rate of formation of these metastases. Several investigators are examining methods for early detection of bone metastases and assessment of therapies aimed at slowing the rate of formation. In “Optical Imaging in Early Detection and Therapy Follow-Up of Experimental Bone Metastasis Models,” Clemens Lowik, Leiden University Medical Center, explored novel imaging techniques in this common disease process. By transfecting breast cancer cells with the luciferase enzyme, which causes the cells to become bioluminescent, Lowik developed a technique by which deposition of tumor cells within bone marrow can be detected in a mouse model using whole-body bioluminescence imaging (Figs. 1A, 1B, 1C, and 1D). He then treated mice with biphosphonates that decrease the rate of bone turnover and measured tumor response with bioluminescence imaging. He found that biphosphonates only transiently decrease the rate of growth of previously established metastases. However, prophylactic therapy before establishment substantially decreases the rate of development and growth of metastases. An important finding is that bioluminescence imaging is much more sensitive than conventional radiography in detecting metastases when cortical bone is not involved.

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Fig. 1A. Images showing growth of metastasis after direct inoculation of 100.000 luciferase-expressing breast cancer cells (MDA-MB231-luc) into bone marrow cavity of nude mouse. Bioluminescent image 2 weeks after tumor inoculation shows region of luciferase activity (indicating a tumor focus) in the right leg as a colored focus.

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Fig. 1B. Images showing growth of metastasis after direct inoculation of 100.000 luciferase-expressing breast cancer cells (MDA-MB231-luc) into bone marrow cavity of nude mouse. Bioluminescent image 4 weeks after tumor inoculation shows increase in size of region of luciferase activity (indicating enlargement of tumor focus) and development of a focus of very high luciferase activity (white area).

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Fig. 1C. Images showing growth of metastasis after direct inoculation of 100.000 luciferase-expressing breast cancer cells (MDA-MB231-luc) into bone marrow cavity of nude mouse. Bioluminescent image 6 weeks after tumor inoculation shows further enlargement of tumor focus and development of a focus of very high luciferase activity (white area).

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Fig. 1D. Images showing growth of metastasis after direct inoculation of 100.000 luciferase-expressing breast cancer cells (MDA-MB231-luc) into bone marrow cavity of nude mouse. Radiograph shows severe osteolytic lesions. (Courtesy of G. van der Pluijm, C. Lowik, Leiden University Medical Center, The Netherlands)

Treatment of Alzheimer's disease is a subject of intense investigation by medical scientists and many pharmaceutical companies. For that reason, increased importance is being placed on early detection of this previously untreatable disorder. Beta-amyloid aggregates are considered a hallmark of the disease. At present, the definitive diagnosis of Alzheimer's disease is made by postmortem visualization of plaques in the brain. A noninvasive test that depicts plaques during life would be a true advance. In “Probes for Imaging β-Amyloid Plaques in the Brain,” Hank Kung, University of Pennsylvania, described the development of biomarkers that show the density of plaques in the brain of affected patients. In vivo tests of plaque-specific binding agents in transgenic mice that overexpress β-amyloid plaques have been performed. Kung described several agents that can cross the intact blood-brain barrier and showed the presence of plaques in mouse models (Fig. 2), a finding that may prove useful in monitoring the effects of potential therapies [2]. On a related note, Mark Mintun, Washington University School of Medicine, in “Potential Clinical Impact of PET Amyloid Imaging in Aging and Alzheimer's Disease,” described testing of a PET imaging agent (11C-PIB) developed at the University of Pittsburgh. In preliminary tests, the agent markedly increased uptake in the brains of patients with Alzheimer's disease. This agent, and similar ones, may prove useful for early diagnosis of Alzheimer's disease and for distinguishing disease states that mimic Alzheimer's.

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Fig. 2. In vitro mouse brain autoradiograph shows binding of β-amyloid plaques using 125I-radiolabeled 6-iodo-2-(4'-dimethylamino-)phenyl-imidazo[1,2-a]pyridine (arrows), which has shown promise as a SPECT agent for depiction of amyloid plaques in Alzheimer's disease [2]. (Courtesy of H. F. Kung, Philadelphia, PA)

As development of stem cells to treat various diseases progresses, creating methods to track these cells to their targets will become increasingly important. Several presentations addressed stem-cell issues. In “Optical/MRI Dual-Modality, Cell-Concentrating Contrast Agents for Stem Cell Tracking,” John Frangioni, Beth Israel Deaconess Medical Center, described probes designed to diffuse into cells in culture at high concentrations. These probes can serve as both MR agents and bioluminescent markers that can be detected using near-infrared fluorescence imaging. These two complementary techniques can then be used to track stem-cell migration. Several other presenters also explored the use of dual-technique contrast agents that provide at least two types of information (e.g., anatomic detail and physiologic function). In “The Fate and Function of Individual Hematopoietic Stem Cells,” Christopher Contag, Stanford University, described an alternative method of bioluminescence imaging using luciferase-labeled stem cells. In “Fate of SPIO Nanoparticles in Magnetically Labeled Cells: Physiologic, Metabolic, and Imaging Studies,” Ali Arbab, National Institutes of Health, discussed the use of super-paramagnetic iron oxide particles for tracking stem-cell migration using MRI and addressed the important issue of the potential toxicity of these (and other) particles used for labeling cells.

Several presentations showed the capability of molecular techniques to provide exquisite anatomic imaging. Alan Koretsky, National Institute of Neurological Disorders and Stroke, in “Molecular Imaging of Functional Architecture in the Brain with MRI,” explored the roles of two molecular and cellular imaging agents, manganese-enhanced MR particles and micron-sized iron oxide particles, in defining brain microarchitecture in the mouse. Magnetically enhanced MR particles enter cells on voltage-gated calcium channels and provide information related to calcium influx, which allows them to depict cells in areas of brain activation; potential areas of activation include learning, memory tasks, motor activity, and sensory activity. These particles can also migrate along neuronal pathways, allowing delineation of neuronal pathways on MR images. These features might be used in combination; for example, by showing areas of brain activation and then depicting the neuronal pathways connecting the region of activation to other brain regions. Finally, these particles allow finely detailed depiction of brain cytoarchitecture (e.g., various layers of cortex) of the mouse brain with 100-μm resolution on a high-field MR scanner. Iron oxide particles are also useful for cell tracking. For example, important cell pathways (e.g., olfactory) in the mouse could potentially be outlined using this tracer. The implications for increased understanding of neurologic and psychiatric disorders in the human brain, initially through animal models and perhaps later in humans, are clear.

A revealing seminar, “Research and Industrial Collaborations,” included short presentations by representatives of three major instrument vendors: Siemens, GE Healthcare, and Philips. These were followed by a discussion by a panel of experts comprising nearly a dozen individuals representing contrast agent, pharmaceutical, and biotechnology concerns who responded to queries by audience members. Many of the major themes are of interest to all imaging specialists. The evolution of imaging techniques into the functional or molecular realm clearly is continuing, however, not to the detriment of anatomic imaging. In fact, anatomic-based techniques such as CT and even MRI continue to show intrinsic value. This is particularly evident in the realm of stand-alone PET scanners, which have been almost completely replaced by combined PET-CT. Other multimodal approaches—for example, CT-SPECT—have significance in both human and animal imaging. A second major theme was new contrast agents or “molecular probes” that will show greater specificity in binding. These probes are blurring the traditional borders among instrument vendors, contrast companies, and pharmaceutical companies, yielding new collaborations among these once separate entities. Moreover, many probes will have the capability of delivering drugs, making the distinction among imaging agents/instruments and therapeutic agents less well defined.

Several developers introduced new instrumentation. Philips and Siemens showed hybrid CT-SPECT systems that combine the anatomic and functional capabilities of both traditional approaches. For small-animal imaging, GE Healthcare exhibited the first volumetric flat-panel CT system. This instrument can image in the microscale and allows acquisition times as rapid as 1 sec in perfusion mode; this will open the world of high-temporal resolution perfusion imaging that was unavailable on microCT systems. This technology highlights the effort of all major instrument manufacturers to provide capabilities that range from “mouse to man.” Optical imaging, an area of nontraditional imaging that is becoming prevalent in molecular laboratories, uses techniques that range from fluorescence to bioluminescence. Although not currently practical in humans, these techniques can be used to determine whether genes have been incorporated into the genome, are expressing proteins, or are exhibiting features of specific phases of the cellular cycle. Although unlikely to become everyday fixtures in most radiology departments in the foreseeable future, these systems will aid in the development of agents that will become commonplace in the clinical setting.

The role of molecular imaging is increasingly featured at many mainstream radiology and nuclear medicine meetings. The next opportunity for a dedicated look at molecular imaging will be the fourth meeting of the SMI, which will be held in Cologne, Germany, on September 7-10, 2005, and will likely provide new insights into this exciting field.

Address correspondence J. M. Provenzale.

References
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1. Society of Molecular Imaging Web site. Available at: www.molecularimaging.org. Accessed February 19, 2005 [Google Scholar]
2. Zhuang ZP, Kung MP, Wilson A, et al. Structure-activity relationship of imidazo[1,2-a]pyridines as ligands for detecting beta-amyloid plaques in the brain. J Med Chem 2003; 46:237-243 [Google Scholar]

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Getting Small Is Suddenly Very Big: Review of the Proceedings of the Third Annual Meeting of the Society for Molecular Imaging

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American Journal of Roentgenology. 2005;184:1868-1872. 10.2214/ajr.184.6.01841868
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