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Molecular Imaging Series |
1 From the Department of Radiology, Molecular Imaging Program, Stanford University School of Medicine, 300 Pasteur Dr, S-062B, Stanford, CA 94305 (S.B.); Department of Radiology, University of California, San Diego, Calif (D.L.R); Departments of Radiology and Neurology, University of Utah School of Medicine, Salt Lake City, Ut (J.M.H.); and Departments of Radiology and Bioengineering, Molecular Imaging Program, and Bio-X Program, Stanford University School of Medicine, Stanford, Calif (S.S.G.). Received February 15, 2006; revision requested April 20; revision received October 31; final version accepted December 11. Address correspondence to S.B. (e-mail: biswals{at}stanford.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRHEUMATOID ARTHRITISOSTEOARTHRITISPAIN AND INFLAMMATIONMUSCULOSKELETAL NEOPLASMSOTHER APPLICATIONSSUMMARYReferences |
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© RSNA, 2007
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRHEUMATOID ARTHRITISOSTEOARTHRITISPAIN AND INFLAMMATIONMUSCULOSKELETAL NEOPLASMSOTHER APPLICATIONSSUMMARYReferences |
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Furthermore, the fusion of functional and molecular imaging procedures with conventional anatomic imaging methods will no doubt add to the specificity and sensitivity of imaging diagnosis, just as fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT has done for general tumor screening and staging. Molecular imaging procedures should be viewed as important complementary tools to an already powerful armamentarium of clinical imaging devices. For the near future, hybrid imaging technologies such as PET/CT and single photon emission computed tomography (SPECT)/CT will be the workhorses for the molecular imager. New molecular contrast agents for MR imaging and ultrasonography (US) will further enhance their potential. There is also an emerging imaging technology involving optical methods (fluorescence and bioluminescence) that are now commonly used in preclinical animal models of disease and in the drug development and discovery process; we are already seeing the first applications of these methods in humans. The detailed use of these systems within the context of molecular imaging has been described elsewhere in this series. Please refer to the earlier article in the Molecular Imaging Series entitled "Molecular Imaging: The Vision and Opportunity for Radiology in the Future" in the July 2007 issue of Radiology.
Perhaps another important reason to increase one's understanding of this evolving discipline of molecular imaging is that, in this modern era of molecular medicine, therapies, including gene therapy and cell-based therapies, can be directly and indirectly studied by using molecular imaging procedures and techniques. Basic scientists and molecular imagers are combining forces to find better ways to design and monitor such therapies in living subjects. Ultimately, clinical imagers will be asked to determine whether a certain gene or cell therapy is working in the targeted location in the manner in which it was designed to work.
We have limited our discussion of molecular imaging procedures and techniques to their application in four important chronic musculoskeletal disease entities: RA, OA, pain and/or inflammation, and musculoskeletal malignancy. Other diseases and phenomena, such as osteoporosis, endocrine disorders, fracture healing, growth disorders, and infection, that are equally amenable to study with molecular imaging procedures and techniques are not discussed here.
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RHEUMATOID ARTHRITIS |
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TOPABSTRACTINTRODUCTIONRHEUMATOID ARTHRITISOSTEOARTHRITISPAIN AND INFLAMMATIONMUSCULOSKELETAL NEOPLASMSOTHER APPLICATIONSSUMMARYReferences |
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Patients with RA would greatly benefit from early detection and treatment of disease. MR imaging and US are being used successfully to depict early RA-related changes in patients and in preclinical animal models. MR imaging enables early detection of osseous and soft-tissue changes—including joint effusions, synovitis, tenosynovitis, tendon and/or ligament damage, bone marrow signal intensity changes, and cartilage destruction—in RA, and it is currently considered the superior method in the evaluation of this disease (4–7). MR imaging can be applied to the analysis of relatively early changes and chronic periods of the disease. Gadolinium-enhanced MR imaging allows detection of synovitis with great sensitivity and aids in the differentiation of soft-tissue inflammation from joint effusion.
High-frequency US (7.5–10 MHz for conventional studies and 20 MHz for fine-detail musculoskeletal studies), which can depict synovial thickening, and power Doppler US, which indirectly measures hyperemia related to capillary flow, have been used to assess the thickened, hypervascularized synovium of the inflamed small joints of the hands and feet in RA. US techniques are believed to have superior sensitivity to MR imaging with regard to the detection of effusions and tenosynovial fluid but are thought to be inferior to MR imaging in the assessment of synovitis, tendon and/or ligament damage, and bone erosions (8). US is particularly useful during earlier stages of disease and serves as a relatively accessible and inexpensive procedure, involving no ionizing radiation, for assessing small joints.
Radionuclide techniques can also be used to detect early changes in RA. When important cellular and protein mediators are specifically "tagged," or labeled, RA can be visualized in a cellular or molecular context (as described below). The white blood cell or leukocyte scan, for example, is a classic assay for studying the migration and trafficking of these specialized cells to sites of inflammation. Preliminary studies of rheumatoid wrists have shown that MR measurements of synovial volume correlate with the metabolic rate of the inflamed tissue as measured with the radionuclide study FDG PET (FDG is 2-[18F]fluoro-2-deoxy-D-glucose) (r > 0.86; P < .0001) (9).
Pathogenesis of RA
Despite extensive reviews on the subject, the cause of RA remains a mystery (10,11). Presumably, an unidentified arthritogenic antigen stimulates or activates CD4+ T cells that normally reside in synovium. Neighboring cells, such as dendritic cells, monocytes, synovial fibroblasts, and macrophages, are induced to produce the proinflammatory cytokines interleukin-1, tumor necrosis factor 
, and interleukin-6. These same cells are also stimulated to secrete the matrix metalloproteinases, which cause degradation of the synovial, cartilaginous, and osseous extracellular matrix tissue. Activated T cells also stimulate B cells to produce immunoglobins, the most notorious of which is rheumatoid factor. Rheumatoid factor may play a role in the pathogenesis of RA by binding and activating complement that further contributes to the inflammatory process. Furthermore, activated T cells also possess the ability to directly activate osteoclasts, cells that are responsible for the bone erosions typical of the disease. Angiogenesis, an eventual prominent feature in the synovial membrane, can be attributed to activated macrophages, lymphocytes, and fibroblasts. It is this proliferation of vascular elements that gives rise to the synovial enhancement seen with gadolinium-enhanced MR imaging and power Doppler US. Within the context of ongoing inflammation, endothelial cells, which line both the newly created and the preexisting vessels, produce proinflammatory proteins (such as receptors) and adhesion molecules that have also become imaging targets.
Ultimately, the conventional methods described earlier reflect abnormalities that are relatively downstream to the inciting event—activation of the T cell. Effusions, hypervascularity, erosions, and synovial proliferations are changes seen only after the activation of T cells and macrophages. Molecular imaging protocols attempt to image these cells and the related acute mediators of disease.
Molecular Imaging of RA
A fundamental explanation for the frustration of clinicians in defining appropriate therapeutic options in patients with RA is the variety of clinical manifestations and responses to treatment of the disease. Adding to the complexity of this disease are the seemingly uncoupled events of synovitis and bone destruction (12). For these reasons, clinicians and molecular imagers alike are interested in finding consistent, reliable biomarkers of RA. Identifying common cellular and molecular denominators of disease that can be applied broadly during the course of the disease is of great importance. Rather than focusing on anatomic changes in the disease, molecular imaging attempts to depict cellular and molecular perturbations by exploiting the stereotypic changes seen in this disease. Inflammatory cells, for example, are recruited to an affected joint, an event that in turn is followed by a cascade of inflammation-related biochemical processes such as the upregulation of certain cell surface receptors. By specifically tagging inflammatory cells or carefully selected ligands, one may be able to define specific and discrete aspects of the inflammatory process. Furthermore, by tailoring molecular imaging protocols in light of current molecular therapies, we may be able to better assist our colleagues who are designing therapies to deal specifically with the action of T cells, autoantibodies, cytokines, or other effector cells. A summary of both conventional and molecular methods for imaging RA is provided in the Table.
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T-cell trafficking.—One particularly exciting method of monitoring the pathogenesis of RA will be to track one of the main cellular culprits associated with this autoimmune disease—namely, the reactive CD4+ T-cell lymphocytes (39). There are means of isolating and purifying such cells from a subject by using sophisticated cell-sorting techniques. Once isolated from peripheral blood, these cells can be "marked" with a contrast agent and then reintroduced into the same subject. After a period of incubation, the subject can undergo serial imaging to determine the distribution of the cells. Traditional cell labeling techniques have been founded on radionuclide methods (111In-oxine, 111In-tropolonate, and 99mTc-HMPAO) (13,40); however, a number of PET, optical, and MR imaging–compatible methods are currently available.
In animal models of collagen-induced RA, localization of collagen-reactive CD4+ cells has been performed with imaging assays in living mice. To track the cells, investigators transfected reactive CD4+ T-cell hybridomas with a recombinant retroviral vector encoding green fluorescent protein, or gfp, and firefly luciferase optical-based reporter genes (14). For a review of reporter genes, please see an earlier installment of this series and other publications (41,42). With use of a cooled optical charge-coupled device camera designed for optical imaging, images obtained from nonarthritic control animals showed that optically labeled T cells resided in axillary and inguinal lymph nodes (Fig 1). By comparison, images in animals with polyarticular inflammation showed that the specially marked cells migrated from the lymph nodes to the inflamed joints. Investigators also used these cells to specifically deliver antiinflammatory gene therapy to the joints in the form of cytokine antagonist interleukin-12 p40. Injection of collagen-specific interleukin-12 p40–producing T cells retarded the development of collagen-induced RA.
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Recently, this cell-labeling contrast agent has undergone a modification that facilitates its entry into target cells. The superparamagnetic core of the iron oxide particle has been linked with peptide sequences of the transactivator protein (Tat) of human immunodeficiency virus 1 (HIV-1), resulting in CLIO-Tat particles (48,49). The HIV-1 Tat protein is an 86-amino-acid protein required for replication of the virus. It appears to be involved in translocating the viral particle freely across cellular and nuclear membranes. A short segment of the peptide, amino acid residues 48–57, is largely responsible for this transport phenomenon, and, when this short peptide segment is attached to a CLIO particle, it increases the cell labeling efficiency 100-fold. This agent has been tested in animals, in which the expected migration of CLIO-Tat–labeled T cells to the reticuloendothelial system was seen, and in an animal model of autoimmune diabetes, in which labeled T cells trafficked to the pancreas (15). Other recent cell labeling techniques involve directly labeling cells with 99mTc or with MR imaging–detectable DNA-binding chelates (50–53). Many of these methods have not yet been applied to arthritis models but have great potential.
Macrophage trafficking.—SPIO particles can also be used to monitor monocytic/macrophage migration patterns in the setting of RA. After intravenous injection of SPIO particles, cells that reside in the reticuloendothelial system, including macrophages, engulf the agent. Because macrophages are recruited to inflamed joints, monitoring their distribution with SPIO-based techniques can be helpful, especially during early phases of the disease. MR imaging can be used to study the migration of these cells from the reticuloendothelial system to inflamed joints. Investigators have successfully documented the migration of SPIO-labeled macrophages to the synovium in a rat model of RA (Fig 1) (25).
Activated macrophages are also known to express a large number of folic acid receptors, and this characteristic has been exploited by several investigators as a means to study the distribution of macrophages in the inflamed joints of animals. The ligand for the receptor, folic acid, has been coupled to a variety of optical and radionuclide labels, and early studies with intravenously administered labeled folate in animal models have shown localization of the tracer in inflamed joints (27,28,54).
Leukocyte trafficking.—Leukocytes include neutrophils, basophils, eosinophils, monocytes, macrophages, and lymphocytes. They participate in a host of inflammatory reactions in diseases such as RA, infection, and trauma. Imaging leukocyte trafficking, better known as white blood cell scanning, has been a staple procedure among the radionuclide-based imaging examinations for the past few decades. A variety of methods have been developed for successfully labeling leukocytes with 99mTc, 67Ga, and 111In, and these methods have been specifically applied to the study of RA (21). Because of its relatively low cost, ease of use, low radiation burden, general accessibility, and high sensitivity and because of the significant correlation of accumulated activity at sites of active disease (as measured with the swollen joint count), 99mTc-HMPAO–labeled leukocyte scintigraphy is one of the methods of choice for studying migration of these cells into inflamed joints (29).
Antibody- and cytokine-based imaging.—Autoantibodies that develop during the course of RA have been labeled and injected, and their distribution has been studied. Additionally, specific antibodies to T cells, general leukocytes, cytokines, and receptors have also been utilized in this manner. A variety of specific and nonspecific antibodies of interest have been radiolabeled or fluorescently labeled and imaged in animal models of RA (Table). One example is an antibody to the glycolysis enzyme, glucose-6-phosphate isomerase (GPI), which has been the subject of intense interest because 50% of patients with RA have serum antibodies to GPI. By labeling anti-GPI immunoglobulin G with the positron emitter 64Cu, investigators have studied the biodistribution of this antibody in animal models of RA. PET imaging reveals accumulation of the labeled antibody in the front paws, hind ankles, and rear feet of animals with RA, while control animals showed negligible articular uptake (16). Other antibodies, including polyclonal nonspecific immunoglobulin G, have been similarly interrogated by using scintigraphic methods (55–57). Although their exact mechanisms remain poorly understood, the use of nonspecific antibodies is encouraged by their high sensitivity. However, the lack of specificity (<50%) and the relatively high cost compared with that of more conventional scintigraphic techniques (such as leukocyte scintigraphy) probably prevents the routine utilization of radiolabeled antibody–based techniques at the current time.
Another way to track antibodies is through fluorescence labeling. Using a fluorescently labeled (Cy5.5) monoclonal antibody to F4/80 antigen, investigators have demonstrated the localization of this antibody in the inflamed joints of mice by using optical imaging strategies (Fig 1) (24). The antigen F4/80 is present on the surface of macrophages that infiltrate an inflamed joint, and targeted imaging of these macrophages by using antibodies represents yet another approach to RA imaging. Numerous other antibodies (Table) have been developed to bind to the various mediators of disease, including T cells, cytokines, and receptors. Recent evidence, however, suggests that the use of antibody-based imaging techniques may be problematic because only a fraction of the radiolabeled monoclonal antibodies (directed CD4+ T lymphocytes) actually bind to target cells, while a majority of the dose gets trapped in the reticuloendothelial system (eg, in the liver) (58). Modifications to antibodies (ie, diabodies, tetrabodies, and minibodies) are currently being performed and evaluated in the hope of avoiding such problems in the future (59).
Just as antibodies can be labeled, so can inflammatory cytokines or receptor antagonists. Investigators have labeled a receptor antagonist to the interleukin-1 receptor with 123I, and the tracer has been tested in humans. Gamma camera images show localization of the tracer to affected joints in patients with RA (Fig 1) (30).
Protease-specific activated near-infrared probes.—The production of matrix metalloproteinases and cathepsins is also enhanced in active stages of joint inflammation. In the optical imaging world, a "smart" fluorescent probe has recently been developed to detect elevated levels of matrix metalloproteinases and cathepsins (31). This probe, or contrast agent, will emit light only when it is cleaved by its specific target enzyme; otherwise, the probe is optically invisible. This breed of fluorescent probe is dependent on the close proximity of multiple Cy5.5 near-infrared fluorochromes, which are bound to a synthetic graft copolymer backbone—that is, partially methoxy poly(ethylene glycol) modified poly-L-lysine (60).
When placed in close proximity, a pair of these fluorochromes will "quench" each other and will therefore be "invisible." Once the fluorochromes achieve a minimal physical separation, they will begin to fluoresce. The basis of this physical phenomenon is called mutual fluorescence energy transfer. When cathepsin B, which has lysine-lysine substrate specificity, interacts with the Cy5.5-loaded near-infrared fluorochrome "contrast agent," the lysine backbone is cleaved and the Cy5.5 fluorochromes spatially dissociate to fluoresce. These contrast agents are red shifted, and, thus, fluoresce in the near-infrared portion of the electromagnetic spectrum (excitation wavelength, 673 nm; emissions wavelength, 689 nm). Red-shifted fluorochromes are ideal fluorescent agents for use in intact organisms because longer wavelengths penetrate tissues such as bone better than do green-fluorescing agents.
Because many of the arthritides (as well as tumors) necessarily elaborate certain matrix-digesting proteases during stages of progression and angiogenesis, these "smart" biocompatible autoquenched near-infrared fluorescent probes can potentially be used to depict a variety of arthritic processes (including OA), as well as cancers. The successful application of a cathepsin B-sensitive probe has been demonstrated in an animal model of RA (61). After intravenous administration of the near-infrared fluorochrome probe, light was seen to arise from the inflamed knees and ankles of animals with RA but not from the joints of normal animals.
Cell stress/apoptosis imaging.—The inflammation of RA is an event that is stressful to cells involved in the process. Furthermore, an abnormal rate of apoptosis appears to occur in synovial tissue in RA. Whether the level of apoptosis is excessive or reduced remains a matter of considerable debate (62). Imaging of cell stress and apoptosis is now possible in living subjects by using an endogenous molecule called annexin V. Annexin V recognizes a cell membrane component that presents itself during times of increased metabolic stress, apoptosis, and necrosis (see next).
In the collagen-induced RA model, increased uptake of radiolabeled 99mTc hydrazinonicotinamide annexin V is seen in the paws of arthritic animals compared with control animals (63). Steroid treatment in the arthritic model not only alleviates clinical manifestations of collagen-induced RA but also results in diminished uptake of annexin V, suggesting that the steroids provide some type of cytoprotective effect.
Metabolic imaging.—The process of inflammation is a glucose-avid oxidative process and, thus, FDG PET enables quantitative measurements that correlate positively with the degree of inflammation in patients with RA. FDG PET has recently been found to correlate with the degree of disease activity as measured with clinical scores, swelling, tenderness, serum markers (erythrocyte sedimentation rate and C-reactive protein level), and synovial thickness as measured with US; thus, this method is a useful tool for quantifying the extent of metabolic activity in the joints of patients with RA (33) (Fig 1). Furthermore, the uptake of FDG was higher in patients with positive synovial Power Doppler signals. Such quantitative measurements provide potential help in gauging the effectiveness of various therapies designed to alleviate inflammation.
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OSTEOARTHRITIS |
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TOPABSTRACTINTRODUCTIONRHEUMATOID ARTHRITISOSTEOARTHRITISPAIN AND INFLAMMATIONMUSCULOSKELETAL NEOPLASMSOTHER APPLICATIONSSUMMARYReferences |
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A majority of persons with early disease are asymptomatic or have only minor clinical problems. Thus, only a small proportion of these individuals seek medical attention, while most will seek medical assistance only after they have entered the irreparable phase of disease. The impetus to detect early lesions is to allow timely intervention so as to prevent the eventual evolution of radiographically evident joint space narrowing, osteophytosis, subchondral sclerosis, and cyst formation.
Recent efforts to image OA have been focused on developing improved techniques for identifying early cartilage loss. Until the advent of MR imaging, many of the standard methods, including conventional radiography, arthrography, arthrotomography, and US, have been limited in their ability to allow evaluation of articular cartilage (66).
MR imaging is currently considered the best imaging method for the direct, noninvasive evaluation of articular cartilage. Its dynamic range, spatial resolution, and multiplanar capabilities have permitted it to be applied clinically and to serve as the focus of research endeavors. During the past 2 decades, numerous pulse sequences have had their moment in the spotlight. These have included two- and three-dimensional gradient-recalled-echo sequences, spin-echo sequences, fast spin-echo sequences, T1-weighted inversion recovery sequences, magnetization transfer contrast sequences, and fat-suppressed sequences; reports of the value of these sequences have indicated variable sensitivities (31%–100%) and specificities (50%–100%) for detecting cartilage lesions (66). Lesions that are generally substantial (ie, those that show marked thinning, full thickness cartilage loss, and/or fissuring) are accurately depicted with MR imaging. However, smaller lesions, such as superficial fraying and subsurface cartilage softening, are more challenging to assess at MR imaging, especially compared with arthroscopy, and the results are highly dependent on the sequence that is utilized (67). MR imaging techniques such as driven-equilibrium Fourier transform, short echo time methods, proton density or T2 mapping, steady-state free precession, three-dimensional T1
relaxation mapping, diffusion-weighted imaging, and iterative decomposition of water and fat with echo asymmetry and least-squares estimation, or IDEAL, hold promise in this regard. They measure parameters such as water content, proteoglycan concentration, and collagen structure, and they have been nicely reviewed elsewhere (68–73). Other attempts, including ones involving MR imaging techniques, to better characterize these small and early cartilage lesions from a molecular and cellular standpoint are described below.
Pathogenesis of Early OA
To detect early cartilage damage, molecular imaging research has focused on the identification of better ways to either visualize extracellular matrix depletion or measure events that are associated with cartilage damage, such as chondrocyte death and the elaboration of matrix-degrading enzymes. In OA, there is general acceptance that abnormal chondrocyte apoptosis is a pivotal event in the eventual destruction of articular cartilage (74,75).
The major constituents of articular cartilage are water (75% by weight), collagen (predominantly type II; 20% by weight), aggrecan (5% by weight), and a variety of other extracellular matrix molecules, all of which are maintained by resident chondrocytes. From a mechanical standpoint, collagen acts as "rebar," contributing to the tensile strength of cartilage, while aggrecan, a macromolecule consisting of negatively charged glycosaminoglycan (GAG) molecules, acts as electrostatic springs, providing the compressive strength of cartilage. Chondrocytes maintain a very intimate relationship with the extracellular matrix through a variety of adhesion molecules and proteins; they are integral to homeostasis of the extracellular matrix, and their survival dictates the health of the tissue.
In fact, a focal cartilage injury, complete with matrix derangement, matrix depletion, and chondrocyte apoptosis, can be viewed as the beginning of a vicious cycle. The natural history of OA-related cartilage loss seen in serial studies of joints is a reflection of this downward course. Trauma results in matrix disruption, chondrocyte apoptosis, or a combination of both. Chondrocytic apoptosis is thought to arise from abnormal acute or chronic mechanical loads. In the setting of trauma or microtrauma, there are two fundamental means of chondrocytic apoptosis: (a) Traumatic events that directly result in a substantial mechanical load on the chondrocyte itself can cause apoptosis and (b) traumatic loads can disrupt the extracellular matrix, causing the chondrocyte to be physically isolated from its immediate surroundings. For reasons not entirely clear, chondrocyte detachment causes the cell to undergo programmed cell death. With regard to the latter phenomenon, investigators have proposed that the denuded, exposed chondrocyte is vulnerable to Fas-mediated killing or nitric oxide toxicity once it has been released from its protective surroundings (76,77).
Chondrocyte apoptosis leads to matrix dysregulation and an inability to sufficiently regenerate the matrix, causing local mechanical deficiencies. Chondrocytes that have survived the local insult attempt to proliferate and synthesize new matrix elements, but, if the injury was too great, cartilage repair will be outpaced by chondral loss. Injured areas also produce active degradative enzymes, matrix metalloproteinases, aggrecanase, and cathepsins; interestingly, these enzymes may reside in an inert state in the extracellular matrix and become activated once cartilage injury ensues (78). The injured area of cartilage becomes mechanically insufficient, and loads are transferred to the more normal peripheral regions of the injured area.
Subsequently, viable chondrocytes at the border of an injured area are subject to abnormal forces and undergo apoptosis. These "border" chondrocytes eventually undergo apoptosis themselves once abnormal forces become excessive, perpetuating the paradigm between matrix loss and chondrocyte apoptosis and resulting in an expanded area of matrix decomposition. The cycle of apoptosis and matrix loss is perpetuated over time, resulting in the progressive changes seen either as joint space loss with joint space narrowing on serial radiographs or as actual cartilage loss at MR imaging. Imaging research and development are focused on the detection of very early cartilage derangement, protease elaboration, and chondrocyte apoptosis.
Molecular and Functional Techniques for Early OA
Charge-based methods.—Hyaline cartilage, with its intricate network of negatively charged, hydrophilic GAG molecules, possesses a fixed charge density (FCD). Diseased, GAG-depleted areas of osteoarthritic cartilage correlate with areas of diminished FCD. Methods of measuring changes in charge density distribution are possible through the use of charged contrast agents.
As one example, delayed gadolinium-enhanced MR imaging of cartilage utilizes the negatively charged T1-shortening agent gadopentate dimeglumine (79). Because it is similar in charge to the FCD, gadopentate dimeglumine is repulsed by normal, intact cartilage and is found in extracartilaginous tissues such as the synovial fluid or subchondral bone after its intravenous administration. Injured cartilage, which contains GAG-deficient areas, permits penetration of gadopentate dimeglumine within the cartilage proper; thus, the local concentration of gadopentate dimeglumine is inversely related to FCD. T1 relaxation measurements of damaged cartilage show redistribution of the contrast agent in specific GAG-depleted areas. Thus, with the delayed gadolinium-enhanced MR imaging of cartilage technique, T1 relaxation times are lower in areas of cartilage damage than in normal, intact cartilage. The clinical application of this method is not without challenges (eg, a requirement for intraarticular injection of gadopentate dimeglumine, a 30 minute to 3 hour time delay after injection before imaging can be performed, and a requirement for exercise of the joint), but this technique has already proved useful in the evaluation of early OA in dysplastic hips (Fig 2) (80,82).
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Imaging apoptosis.—Programmed cell death, also known as apoptosis, is a normal physiologic phenomenon required for biologic growth and development, homeostasis, and immune surveillance. Many disease processes, however, can be characterized as having too much or too little apoptosis. Diseases with excessive cell death include neurodegenerative disorders, myelodysplastic syndromes, ischemia-reperfusion injury, viral infections, transplant rejection, and OA. Diseases exemplified by a paucity of apoptosis include cancer (uncontrolled cell growth and proliferation) and autoimmune diseases such as RA, although the latter association is controversial. Thus, it can be easily seen that having the ability to image programmed cell death in patients can help clinicians better understand the pathogenesis of and treatment response in a variety of disease processes.
Most procedures and techniques for directly assaying cell death require tissue sampling and employ histologic and other in vitro techniques. Recently, a method has become available for the study of this phenomenon in living subjects. This method takes advantage of an endogenous protein, annexin V, whose function is not clearly understood but which is thought to play a role in coagulation (83). Annexin V has an extremely strong affinity for the cell membrane phospholipid phosphotidylserine, which is "externalized," or expressed, to the outer surface of the cell membrane during the apoptotic cascade. Annexin V, a 35-kd extracellular protein, binds the negatively charged externalized phosphotidylserine with an extremely high affinity (10–9 mol/L). It is this interaction that is the basis for programmed cell death imaging (34,84,85). In normal conditions, healthy cells have relatively little annexin V bound to the cell membrane, because most phosphotidylserine molecules are located in the inner leaflet. In contrast, a cell undergoing apoptosis externalizes its phosphotidylserine, thereby increasing annexin V binding approximately 100- to 1000-fold. The use of annexin V, labeled with either a radioisotope or a fluorescent marker, provides an excellent opportunity to image programmed cell death. To date, annexin V has been labeled with 99mTc, iodine (125I, 124I, 123I), 111In, 11C, 67Ga, 68Ga, and 18F, making it appropriate for either SPECT or PET imaging (34,86–89). Annexin V has also been conjugated with CLIO particles for use with MR imaging and with Cy5.5 fluorescent dye for use with optical techniques (34,35). Any organ or structure demonstrating increased annexin V uptake is thought to be experiencing substantial apoptosis or tremendous metabolic stress.
Annexin V imaging has yet to be applied to the assessment of human OA. In part, the clinical use of this tracer faces challenges with regard to its crossing the blood-synovial barrier. Perhaps direct intraarticular injection of the agent will be needed. Alternatively, mutants or modifications of annexin V may be designed to cross such barriers. Radiolabeled annexin V has been studied in animal models of collagen-induced RA (63). Radiolabeled annexin V has been used as an imaging agent in clinical trials in humans that dealt with myocardial ischemia, cardiac transplant rejection, and cancer chemotherapy (90–93).
Annexin V imaging will face other challenges as well. The externalization of phosphotidylserine to the outer leaflet is not limited to apoptotic cells. Viable cells in severe stress or those undergoing necrosis will also present phosphotidylserine molecules to the outer membrane for annexin V binding. Because of this, annexin V imaging loses specificity. Also, there appears to be a biphasic, temporally dependent pattern of phosphotidylserine externalization after an apoptotic signal, a phenomenon that restricts the timing of optimal imaging periods (94). A better understanding of annexin V biology will help determine specific imaging requirements in the future. Additionally, other techniques for imaging apoptosis, including lipid hydrogen 1 MR spectroscopy and the use of anti–annexin V monoclonal antibodies, anti-phosphotidylserine monoclonal antibodies, and radiolabeled caspase inhibitors/substrates as imaging agents, are being explored (Fig 2) (34). Apoptotic chondrocytes have been found in mechanically injured cartilage (74,75).
Imaging matrix-degrading enzymes.—Details of this method are provided in the earlier section of this article on RA. Just as in RA, in OA, certain proteases are elaborated during the course of the disease. As mentioned earlier, damaged cartilage appears to activate hibernating proteases such as matrix metalloproteinases and cathepsins. Using a cathepsin B–sensitive near-infrared fluorescent probe, researchers have found significant amounts of signal arising from an arthritic knee compared with normal knees in an animal model of OA (Fig 2) (81).
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PAIN AND INFLAMMATION |
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TOPABSTRACTINTRODUCTIONRHEUMATOID ARTHRITISOSTEOARTHRITISPAIN AND INFLAMMATIONMUSCULOSKELETAL NEOPLASMSOTHER APPLICATIONSSUMMARYReferences |
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Alternatively, patients with chronic pain who undergo imaging may demonstrate multifocal disease. For example, in the patient with chronic lumbar pain, numerous abnormalities are often detected with MR imaging, including multiple bulging, dessicated disks and multilevel facet arthropathy. It is often difficult to determine which particular abnormality, if any, is the cause of symptoms. Because therapy for the patient will be partly dictated by the image interpretation, the lack of specificity in the diagnosis can indirectly or directly contribute to delayed or inadequate treatment regimens in some cases.
Pathogenesis
Persons suffering from chronic pain often experience hypersensitivity to a stimulus, which clinically manifests as allodynia (pain arising from non-noxious stimuli) and hyperalgesia (a noxious stimulus causing increased and prolonged pain). The molecular neurobiology of pain and nociception is extremely complex (100). Simplistically, chronic pain, sometimes referred to as inflammatory pain, is thought to arise from a progressive exchange of inflammatory mediators between peripheral pain-sensing (nociceptive) neurons and surrounding chronic soft-tissue and/or bone inflammation. A complicated network of various molecular pathways are differentially modulated or recruited among the local ensemble of inflammatory cells, vascular endothelium, and peripheral nociceptive neurons at the site of injury. Inflamed nociceptive neurons chronically transmit excitatory signals through the dorsal root ganglion to the dorsal horn neurons of the spinal cord, and, from there, through ascending spinothalamic neurons to the brainstem, hypothalamus, thalamus, and, ultimately, the cerebral cortex, where the sensation is perceived. Descending inhibitory neurons from the brain send modulatory signals to the dorsal horn neurons and signals to the periphery through sympathetic neurons (100).
At the peripheral site of tissue damage, inflammatory mediators, such as protons, neurotrophic growth factor, prostaglandin E2, bradykinin, cytokines, and chemokines, are necessarily released, stimulating the peripheral ends of peripheral neurons, local mast (and other inflammatory) cells, and vascular endothelium. These biochemical mediators ultimately interact with their receptive receptors or ion channels. Subsequently, a variety of intracellular kinases are activated, which, in turn, phosphorylate a number of targets that lower activation thresholds and improve synaptic transmission efficiency between the primary afferent neurons and the secondary dorsal horn neurons.
Many biochemical mediators are important to the development of chronic pain syndromes. Cyclooxygenase-2 (COX-2) is considered a major facilitator of tissue inflammation because of its role in prostanoid production from the metabolism of arachidonic acid into prostaglandin H; prostaglandin H is eventually converted into prostaglandin E2 by catalytic enzymes. The success of COX-2 inhibitors among patients with chronic pain is evidence of its importance in the inflammatory cascade.
A number of "pain receptors" have been implicated in chronic pain phenomena. In models of chronic pain, many of these receptors, which form a diverse group of receptors involved in nociception, have been found in increased quantities, leading to increased sensitization and spontaneous activation of the nociceptive axis. In particular, substance P and its receptor, substance P receptor, or neurokinin-1 receptor, have been studied extensively in a variety of animal pain models because these receptors are thought to play a major role in the development of hypersensitivity in the pain pathway. Upregulation of the substance P receptor has been demonstrated in a variety of animal pain models, and substance P receptor kinetics may serve as a marker for the transition from acute to persistent pain states (101–103). Substance P receptor upregulation in the dorsal root ganglion and dorsal horn of the spinal cord is seen in persistent pain models such as those demonstrated in the complete Freund adjuvant model.
Other ligand-receptor systems that are generally increased in inflammatory pain are believed to play important roles. These include calcitonin gene–related peptide, serotonin, bradykinin, brain-derived neurotrophic factor, vanilloid receptor VR1, N-methyl-D-aspartate, tyrosine kinase B, neurotensin, and cholecystokinin, to list a few (104). Additional ligand-receptor systems, including the opioid-based systems and those involving galanin, vasoactive intestinal peptide, and somatostatin, are thought to have important modulatory roles (105,106).
Because of the large number and complexity of biochemical pathways that are involved, identifying a common molecular mechanism for chronic pain will be a challenge (if not impossible)—not only from an imaging standpoint, but from a therapeutic one as well. Adding to the challenge will be the fact that different types of pain (eg, inflammatory vs neuropathic) arise from unique physiologic and molecular changes. For example, patients with knee OA respond to COX-2 inhibitors, but those with spinal cord injury do not. These observations suggests that COX-2 plays an important role in inflammatory pain and a lesser role in neuropathic pain. Therefore, a tracer designed to identify elevated COX-2 levels may localize sites of inflammatory pain only.
Molecular Imaging of Pain and Related Inflammation
In general, little has been accomplished in the way of imaging pain modulators directly in the peripheral nervous system and the distal central nervous system. Rather, numerous "pain imaging" studies that have focused primarily on central (brain) manifestations of pain have been performed in the past decade. Specifically, functional MR imaging and FDG PET have been helpful in localizing a number of structures in the brain (107–109). For the musculoskeletal radiologist, peripheral manifestations of nociceptive activity are more relevant, if not more important. Additionally, with regard to inflammation, much more work has been performed in the areas of joint and vascular inflammation. Protocols for imaging inflamed joints have been touched on in the earlier RA section of this article. Additional information about vascular inflammation is provided below.
Labeled neuropeptides and analogs.—Just as radiolabeled octreotide has been helpful in identifying somatostatin receptor–positive neuroendocrine tumors, radiolabeled neuropeptides may be able to help negotiate the receptor-dependent network that is chronic pain. For example, substance P and some of its analogs have been radiolabeled and studied in animal models of pain. Investigators using [111In-DTPA-Arg1] substance P and a gamma camera found that this radiolabeled peptide localizes to normal substance P receptor–positive tissues such as the salivary gland, as well as to arthritic joints induced by an inflammatory adjuvant (110). Recently, a substance P antagonist, SPA-RQ, has been radiolabeled and studied in humans. Normally used to treat chemotherapy-induced nausea and vomiting, this antagonist to the substance P receptor is specifically selective to the NK1 receptor and has been labeled with 18F (111). NK1 receptors, which are present in increased amounts in inflammatory tissue, may serve as targets for inflammatory (and thus painful) foci. In normal physiologic conditions, a number of these receptors are present in the striatum of the brain. Preliminary PET imaging of the brain in healthy volunteers shows its expected striatal localization in a dose-dependent fashion (112). Imaging studies with this tracer in patients with chronic pain may eventually prove to be helpful in localizing sites of inflammation and local pain generators.
Radiolabeled opioids have also been the subject of study for the past decade, during which much of opioid receptor imaging has focused on the analogs of the effects of addiction on the brain. PET imaging with 11C-diphrenorphine, for example, showed that patients with central poststroke pain have reduced regional binding in the neural structures associated with nociceptive processing, suggesting an imbalance between excitatory and inhibitory mechanisms of pain as the cause for the syndrome (113). Studies with this tracer and other radiolabeled opioids, such as 11C-carfentanil, [6-O-[11C]methyl]buprenorphine, and 6-O-(2-[18F]fluoroethyl)-6-O-desmethyldiprenorphine, may help provide a better comprehension of more distal mechanisms of pain in the future (114,115).
Other labeled neuropeptides have been developed for the detection of certain cancers. Currently, many of these peptides have not been applied for purposes of identifying pain generators, but further analysis may prove helpful. These radiolabeled peptides include somatostatin, vasoactive intestinal peptide (123I–vasoactive intestinal peptide, 99mTc-TP3654), cholecystokinin, or 111In-DTPA-[Nle28,31]-CCK(26-33), neurotensin, or 99mTc-neurotensin(8-13), and substance P (90Y-DOTA-substance P); their application to cancer imaging has been reviewed (116).
COX-2 tracers.—A few selective COX-2 inhibitors have been radiolabeled and may potentially be useful in imaging the type of inflammation that is characterized by increased COX-2 enzyme expression. To date, such tracers as 99mTc-celebrex, 18F-SC51825, and 18F-desbromo-DuP-697 have been developed and studied in a preliminary fashion (117–119). Planar images with 99mTc-celebrex showed the localization of this tracer to xenografts in tumor-bearing animals. To date, the localization of this tracer to inflammation models has not been reported. Imaging with 18F-desbromo-DuP-697 has been attempted in an animal model of paw inflammation model with little success, in part due to the relatively low level of COX-2 enzyme generated in this model. Additional studies will be needed to verify whether COX-2 can serve as a peripheral marker for pain and pain generators.
Vascular inflammation.—Vascular endothelial cells associated with the area of inflammation, whether related to trauma, infection, arthritis or other causes, become "activated," and their activation is integral to the process of leukocytic recruitment. These stimulated endothelial cells necessarily amplify a number of adhesion molecules, such as P-selectin, E-selectin, ICAM-1, and VCAM-1, to attract and bind inflammatory cells (120,121). In efforts to improve detection of inflammatory processes, a number of contrast agents that target endothelial epitopes have been developed for US, MR, and radionuclide-based imaging. For example, echogenic microbubbles have been conjugated to antibodies for ICAM-1, fibrinogen, or P-selectin (122,123). These agents will localize to the endothelium of an organ that has sustained an ischemia-reperfusion injury. Alternatively, these agents will diffusely localize to the endothelium when systemic tumor necrosis factor is administered. Echogenic liposomal agents have also been coated with anti–ICAM-1, resulting in their localization to atheromatous plaques during US (124,125).
MR imaging researchers have also created agents for the identification of inflammatory processes. One group of investigators has produced liposomes containing a gadolinium lipid chelator, which becomes paramagnetic in the presence of gadolinium (126). By biotinylating these paramagnetic liposomes, biotinylated antibodies can be conjugated to the liposomes through an avidin linker, creating an antibody-conjugated paramagnetic liposome, or ACPL. In an animal model of experimental autoimmune encephalitis, localization of ICAM-1 ACPL in the brain leads to increased signal intensity. Another MR-based imaging agent involves the conjugation of monocrystalline iron oxide nanoparticles to anti–human E-selectin (127). In cell culture, umbilical vein endothelial cells avidly bind this MR contrast agent compared with controls when exposed to the inflammatory mediator interleukin-1ß.
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FDG PET has some important advantages in cases of tumor, although the method is not without its limitations. One particular advantage of FDG PET imaging is that it is a quantitative study from which statistical measurements can be determined. Two different types of tumor measurements of FDG uptake can be taken. One is referred to as the standardized uptake value (SUV), and the other is referred to as a tumor-to-background ratio (TBR). In both cases, regions of interest (ROIs) are individually defined for each lesion. Maximum radiotracer uptake is determined from the ROI. In the case of TBR, maximum uptake values are normalized to a background ROI such as normal muscle tissue. While TBR is more practical and independent of transmission scanning, it is considered to be less accurate than the SUV, for which radioactive concentration in the tumor is normalized to the injected dose and patient's body weight. Because these quantitative measurements can be performed, PET protocols can be rigorously tested, and new radiotracers can be compared easily with others.
FDG PET of Musculoskeletal Neoplasms
The ability to distinguish viable tumor from nonviable tumor is perhaps the most powerful attribute of FDG PET imaging and forms the basis for its increasing use among clinicians in recent years. Although it still requires further exploration and clarification, the role of FDG PET in the early clinical studies of musculoskeletal tumors has shown this method to be helpful in the determination of biopsy harvest sites, evaluation of posttreatment response, and assessment of tumor recurrence (133–135).
Grading musculoskeletal neoplasms.—Whether FDG PET allows prediction of the grade and malignant potential of musculoskeletal tumors is not clear (136–138). Although the majority of high-grade and intermediate-grade sarcomas avidly take up FDG (tumor-to-background ratio, >3), other benign lesions, such as myositis ossificans, pigmented villonodular synovitis, aggressive fibromatosis, fasciitis nodularis, and glomangioma, also demonstrate increased uptake in a subset of cases. In contrast, tumors that display a low tumor-to-background ratio (<1.5) are limited to latent or benign lesions such as lipoma, myxoma, and hemangioma. Those lesions with an intermediate tumor-to-background ratio (between 1.5 and 3.0) include a mixture of benign and aggressive lesions, including low-grade liposarcoma, hemangiopericytoma, spindle cell lipoma, neurofibroma, hemangioma, pigmented villonodular synovitis, schwannoma, and angiolipoma.
A study involving standardized uptake values for analysis found similar findings with FDG PET (137). While a significant positive correlation between standardized uptake value and tumor grade exists, strong FDG accumulation (standardized uptake value, >1.9) can also be seen in benign tumors such as giant cell tumor of bone, chondroblastoma, xanthofibroma, and sarcoidosis, as well as soft-tissue tumors like giant cell tumor of tendon sheath, schwannoma, and desmoid tumor of soft tissue.
Further clouding the issue is the occurrence of a few malignant tumors that display low standardized uptake value values (<1.9), such as grade I liposarcomas and grade II chondrosarcomas. In some studies, variable uptake was seen in liposarcomas; FDG uptake in this malignant tumor appears to be significantly higher in pleomorphic, mixed, and higher grade lesions than in lesions that are well differentiated (139). Perhaps by restricting one's analysis to a specific cell lineage, one may have better accuracy in gauging malignancy, as one group of investigators have found in the evaluation of cartilage neoplasms (140). Using a threshold standardized uptake value of 2.0, these investigators found that FDG PET was 97% accurate in separating chondrosarcomas from benign lesions, such as enchondromas and exostoses, in 26 surgical cases.
Despite the difficulties in grading tumors and predicting malignant potential, FDG PET appears to offer exciting opportunities for research and serves as the impetus for the development of more specific radiotracers, such as 18F--methyltyrosine or radiolabeled antibody derivatives (137). Also, technical and software improvements in uptake measurements are certain to improve the specificity of current techniques (141).
Response to therapy.—Recent studies have also shown the capability of FDG PET to help determine favorable versus unfavorable responses after neoadjuvant chemotherapy for primary tumors of bone (Fig 3) (133,142,143). These studies, using either pre- or posttherapeutic tumor-to-background ratios or standardized uptake values, confirm accurate prediction of a favorable or unfavorable response in 70%–92% of cases. The cause of the discrepant results is not entirely clear, but may be related in part to inflammatory and fibrotic reactions associated with the tumor necrosis after therapy, an effect that can potentially cause increased FDG uptake (146). Another possible reason explaining the discrepancy is that histologic grades are averaged across the entire lesion, which may not be representative of a small viable focus that is detected with FDG PET. Furthermore, it appears that the ability of FDG PET to predict the behavior of certain tumors is dependent on the precise histologic nature of the neoplasm. The ability of FDG PET findings to predict the fate of a Ewing sarcoma, for example, is more accurate than its ability to predict an outcome of an ostesarcoma (133,147). The reason for this is not entirely clear at this time.
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Distinguishing active tumor from posttherapeutic inflammation.—Once a tumor is treated with radiation therapy, chemotherapy, or surgery, a substantial inflammatory response develops. It is often quite challenging to discriminate between small foci of residual cancer (or recurrent tumor) and inflammatory tissue, because tumor and inflammation share similar conventional imaging characteristics. Radiography and MR imaging techniques allow differentiation between areas of inflammation and areas of fibrosis in larger regions of active tumor, provided sufficient time has lapsed since the therapeutic intervention (134). However, this time period is often far too long. Indeed, a period of several weeks is needed for much of the posttherapeutic inflammation to subside or for a tumor to declare itself (usually by growing in size at the imaging examination). Naturally, it is ideal to know early on whether there is residual tumor after therapy (good responders vs poor responders) so that additional therapeutic measures can be taken if necessary.
Traditionally, referring physicians are dependent on the results of history taking, blood tests, tissue sampling, and frequent follow-up scans to confirm tumor recurrence, remission, or eradication. Prior to FDG PET imaging, thallium 201 and 99mTc-MIBI were used to differentiate between fibrosis, tumor necrosis, and tumor recurrence (149–151). In the detection of recurrence of soft-tissue and osseous sarcomas, sensitivities of MIBI and FDG PET are 81% and 98%, respectively. In comparison, one investigation has revealed that conventional CT and MR imaging techniques enable detection of musculoskeletal tumor recurrences with a sensitivity of 58% and 83%, respectively (152). Such results, however, have been contradicted by others that have concluded that FDG PET does not offer any advantage beyond current methods in the assessment of treatment response and discrimination of viable tumor from surrounding inflammation (153). In fact, inflammation and fibrosis of a tumor that are detected soon after therapeutic intervention with FDG PET share many features with recurrent areas of tumor, providing the stimulus for the development of more specific tracers such as 3'-deoxy-3'-18F-fluorothymidine or radiolabeled tetraphenylphosphonium. These last tracers have been found to preferentially localize to neoplastic tissue, not inflammatory tissue, in preclinical studies (Fig 3) (144,145). How well these tracers are able to help discriminate between active tumor populations amid treated, necrotic, and inflamed tumor masses remains to be seen.
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OTHER APPLICATIONS |
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Recognizing a clinical need in this cause, molecular imaging researchers have advanced the principles of reporter gene technology for use in living subjects (158). Using this technology, molecular imagers can couple a reporter gene to a therapeutic gene to measure the efficacy of gene delivery and to track the extent of gene expression. Alternatively, the therapeutic gene can be imaged directly (eg, herpes simplex virus 1 mutated thymidine kinase). Details of the use of reporter genes in living subjects have been provided in this Molecular Imaging Review Series and elsewhere (41,159). A number of reporter techniques are now compatible with current clinical and other in vivo imaging methods such as the radionuclide-based techniques (PET and SPECT), MR imaging, MR spectroscopy, and optical-based (fluorescence and bioluminescence) methods.
Bone Metabolism
In routine clinical practice, the bone scan (ie, 99mTc-labeled methylene diphosphonate) is a study that utilizes a gamma camera to examine bone metabolism. Advantages of this study include its relative availability and affordability, but disadvantages stem from the low resolution and lack of specificity of the radionuclide technique (ie, 99mTc may dissociate from the methylene diphosphonate tracer in bone tissues) (160). An alternative method utilizes a positron-emitting isotope fluoride ion (18F) that has a high affinity for bone (161). After capillary diffusion into the bone, the 18F fluoride ion exchanges with hydroxyl groups in bone crystal to form fluoroapatite; it becomes naturally incorporated into cortical bone (162). Turnover of the 18F fluoride ion in bone is thought to be related to the physiologic responsibility of osteoblasts and osteoclasts to maintain bone matrix. Thus, the 18F fluoride ion can be used as a tracer for the evaluation of bone metabolism with PET. Advantages of this method are that it offers a means to scan living subjects in a fully quantitative, noninvasive, and repetitive manner. PET imaging with 18F also allows higher sensitivity and, possibly, higher resolution compared with 99mTc-labeled methylene diphosphonate bone scintigraphy. Still, bone scanning with either a gamma camera/SPECT or PET usually results in imaging characteristics that are relatively nonspecific and in a philosophy that bone scans should usually accompany radiography, CT, or MR imaging.
An alternative to radionuclide-based bone scanning employs the optical imaging agent, Pam78, which is a near-infrared fluorescent biphosphonate derivative (163). Pam78 possesses excitiation and emission maxima at 771 and 796 nm, respectively. Early studies utilizing imaging with a charge-coupled device camera have been performed in mice.
Imaging Chronic Osteomyelitis
In addition to newer white blood cell labeling methods (including antibody-based techniques), several new protocols to image chronic osteomyelitis have become available for use in human subjects. For example, radiolabeled 99mTc-ciprofloxacin, a bacteria-specific imaging agent, has shown predilection for chronically infected bone, and it appears that an additional delayed 24-hour image after administration of this radionuclide will help discriminate between septic arthritis and osteomyelitis (164). The scintigraphic technique has a sensitivity and specificity of 97% and 80%, respectively, and positive and negative predictive values of 95% and 89%, respectively (165).
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SUMMARY |
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TOPABSTRACTINTRODUCTIONRHEUMATOID ARTHRITISOSTEOARTHRITISPAIN AND INFLAMMATIONMUSCULOSKELETAL NEOPLASMSOTHER APPLICATIONSSUMMARYReferences |
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It is likely, in the next decade, that PET/CT and SPECT/CT will be the major workhorses for molecular imaging. PET-based technologies have an advantage given their greater sensitivity, as well as the ability to use biologic molecules that nearly simulate the structure and interactions of the native molecule and can be radiolabeled. Future technical improvements are certain to aid optical and MR imaging–based protocols for human application. Increasing alliance between molecular biologists, rheumatologists, orthopedic surgeons, engineers, chemists, physicists, and pharmacologists will develop during the next generation of molecular imaging technologies and expand their capabilities in the diagnosis and treatment of musculoskeletal diseases. The current research and clinical environment provides a great opportunity for the continued study of molecular imaging protocols and the application of these protocols to the analysis of a large variety of musculoskeletal disorders.
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FOOTNOTES |
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Abbreviations: CLIO = cross-linked iron oxide • COX-2 = cyclooxygenase-2 • FCD = fixed charge density • FDG = fluorine 18 fluorodeoxyglucose • GAG = glycosaminoglycan • HMPAO = hexamethylpropyleneamine oxime • OA = osteoarthritis • RA = rheumatoid arthritis • SPIO = superparamagnetic iron oxide
Authors stated no financial relationship to disclose.
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