Use Of Molecular Imaging Techniques Research Articles

Positron Emission Tomography Techniques to Measure Active Inflammation, Fibrosis and Angiogenesis: Potential for Non-invasive Imaging of Hypertensive Heart Failure

Heart failure, which is responsible for a high number of deaths worldwide, can develop due to chronic hypertension. Heart failure can involve and progress through several different pathways, including: fibrosis, inflammation, and angiogenesis. Early and specific detection of changes in the myocardium during the transition to heart failure can be made via the use of molecular imaging techniques, including positron emission tomography (PET). Traditional cardiovascular PET techniques, such as myocardial perfusion imaging and sympathetic innervation imaging, have been established at the clinical level but are often lacking in pathway and target specificity that is important for assessment of heart failure. Therefore, there is a need to identify new PET imaging markers of inflammation, fibrosis and angiogenesis that could aid diagnosis, staging and treatment of hypertensive heart failure. This review will provide an overview of key mechanisms underlying hypertensive heart failure and will present the latest developments in PET probes for detection of cardiovascular inflammation, fibrosis and angiogenesis. Currently, selective PET probes for detection of angiogenesis remain elusive but promising PET probes for specific targeting of inflammation and fibrosis are rapidly progressing into clinical use.

Abstract 11497: Focal Hibernating Myocardium -A Novel Method to Assess Ventricular Arrhythmogencity Using Molecular Imaging

Introduction: Hibernating myocardium is associated with increased ventricular tachyarrhythmias and sudden cardiac death. Current algorithms aim to detect only large areas of left ventricular hibernation, likely to respond to revascularization and improve LV EF. However, no current tools allow the determination of small and focal hibernating areas within the ischemic substrate, which could act as VT trigger and substrate modulators, and initiate or maintain ventricular arrhythmias. Methods: Custom-made Matlab-based software was developed to perform quantitative segmental analysis. Patients with ischemic cardiomyopathy undergoing VT ablation underwent pre-procedural FDG and Rubidium-PET/Technicum SPECT to determine the metabolic and perfusion characteristics of the LV myocardium. After co-registering the voxel-based tracer intensity information was transferred into a 36 x 21 +1 matrix (757 segments analysis). After normalization comparative analysis identified functional categories of LV myocardium (normal:>75% uptake perfusion[p]/metabolism[M]; hibernation: P and MP+20% or P>50% but P+20%; matched scar P and M<50%). Results: Software was evaluated on metabolism/perfusion scans of 8 patients undergoing VT ablation. While all patients had reported scar, only 2/8 patients (25%) had clinically identified area of hibernation using the currently clinically employed nuclear medicine algorithm. All DICOM files were successfully uploaded into the software module, transformed and analyzed using the pre-specified functional categories of LV myocardium. Post-analysis polar plots of all patients demonstrated matched scar as seen during the clinical read. However, focal areas of hibernation were detected in all patients using the 757 algorithm analytical tool (100% vs. 25% for 757 segmental vs. standard clinical analysis, P<0.001) often adjacent to pre-specified scar category. ConclusioN: The novel quantitative 757 segmental analysis is able to detect and localize focal areas of hibernation in all patients with ischemic VT substrate. This allows the use of molecular imaging techniques to identify potentially proarrhythmic VT trigger and modulators and design novel diagnostic and therapeutic strategies.

A portable device for small animal SPECT imaging in clinical gamma-cameras

Molecular imaging is reshaping clinical practice in the last decades, providing practitioners with non-invasive ways to obtain functional in-vivo information on a diversity of relevant biological processes. The use of molecular imaging techniques in preclinical research is equally beneficial, but spreads more slowly due to the difficulties to justify a costly investment dedicated only to animal scanning. An alternative for lowering the costs is to repurpose parts of old clinical scanners to build new preclinical ones. Following this trend, we have designed, built, and characterized the performance of a portable system that can be attached to a clinical gamma-camera to make a preclinical single photon emission computed tomography scanner. Our system offers an image quality comparable to commercial systems at a fraction of their cost, and can be used with any existing gamma-camera with just an adaptation of the reconstruction software.

The Impact of Oxidative Stress on Islet Transplantation and Monitoring the Graft Survival by Non-Invasive Imaging

Islet transplantation is an attractive strategy to treat severe diabetic conditions in patients suffering from autoimmune derived diabetes, and it has currently been considered a forefront research arena in diabetes. Major aim of islet transplantation is to achieve successful insulin independent disease free survival. The key challenges in transplanted islets are the generation of reactive oxygen species (ROS) and associated oxidative stress, pro-inflammatory cytokine - (TNFα) mediated apoptotic induction, attack by immune cells, and achieving revascularization with minimal hypoxic microenvironment. Free radicals and their derivatives are constantly produced in living systems, but at relatively low level, and in a balanced state. Oxidative stress, which occurs as a result of an imbalance between the intracellular free radicals production and the cellular antioxidant defense mechanisms in the transplanted islets, can lead to cell death. The balance between oxidants and antioxidants in a cell can be easily disturbed by increase in ROS production or reduction in the level of cellular antioxidant defensive substances, which can cause many metabolic complications, including pancreatic β-cell damage. Antioxidants function as blockers of radical processes by eliminating harmful ROS produced during normal cellular metabolism. A complex antioxidant defense mechanism has been developed by nature in cells to protect the cellular homeostasis. This system mainly includes antioxidant enzymes, vitamins and minerals. As transplanted islet survival is crucial for achieving successful therapy, most of these antioxidants can be used as a supplement to scavenge the local ROS thereby improving the survival of transplanted islets. Currently, very few techniques have been routinely used to qualitatively and quantitatively assess the survival and function of islet grafts, especially to confirm the success of treatment, which includes metabolic parameters such as blood glucose, insulin and C-peptide levels. These biochemical measurements provide markers at only the late stages of islet rejection. Use of molecular imaging techniques has the potential for real-time non-invasive monitoring of the functional status and viability of transplanted islet grafts in living animals. This review mainly focuses on the current status of islet transplantations, potential preventive strategies used to reduce oxidative stress-mediated toxicity in islet grafts, and use of molecular imaging as a tool to quantitatively evaluate the functional status of the transplanted islets in living animals.

Islet Transplantation &β-Cell Replacement Therapies for Diabetes

Restoration of physiologic metabolic control is the ultimate therapeutic goal for patients with diabetes but is difficult to achieve by means of medical therapy. Transplantation of islets of Langerhans represents a viable therapeutic option for patients with insulin-dependent diabetes. It is currently offered to patients with a brittle form of diabetes and hypoglycemia unawareness. Current limitations of islet transplantation include scarcity of deceased donor pancreata, partially effective islet isolation and purification protocols, need for life-long systemic immunosuppression, inadequate implantation sites, lack of predictive tests, and noninvasive graft monitoring protocols. Great progress has been recorded in different research areas aimed at overcoming current limitations of islet cell transplantation. These areas include stem cells technology, xenotransplantation, development of novel immunosuppressive regimens, immune tolerance, immunoisolation protocols, alternative sites for islet implantation, immune monitoring, and noninvasive imaging techniques. This special issue was open to the scientific community working on the development of beta-cell replacement. Of the several papers received, ten received favorable peer reviews and were selected for publication in this issue to cover specific topics of general interest in this field. The paper by C. Jahansouz et al. provides a comprehensive and historical overview of beta-cell replacement therapies. The paper by P. Chhabra and K. L. Brayman reviews emerging clinical and preclinical approaches toward enhancing the clinical outcome of islet cell transplantation and includes aspects related to cytoprotection and immune interventions. The paper by H. Wang et al. is focused on important cytoprotective pathways such as carbon monoxide and heme oxygenase-1 and their ability to enhance islet cell viability and engraftment. The paper by X. Wang et al. offers a perspective on the B7-H4 co-stimulation pathway and its potential toward enhancing immune regulation and prolonging islet graft survival. Recognizing the current limitations of human pancreas donation after brain death, alternative cellular-based approaches are actively being explored to widen the clinical application of beta-cell replacement therapies. The paper by M. R. Hammerman provides interesting new experimental data on porcine islet cell engraftment in xenogeneic recipients without immunosuppression. In his paper H. Noguchi shares an overview of his experience with novel protocols aimed at ameliorating pancreas preservation injury and improving the yield and quality of islets obtained for transplantation. I. Meivar-Levy et al. explore the use of hepatic cells expressing albumin and mesenchymal properties that have been engineered to produce insulin as an alternative and potentially unlimited source of transplantable insulin-producing cells. F. Carlotti et al. assess the important issue of the pros and cons related to the translatability of results obtained in rodent studies to humans when studying beta-cell regeneration. There are increasing efforts aimed at developing novel implantation sites for islet cells. The paper by D. Espes et al. describes the promising properties of intramuscular site which makes of it a viable option for islet cell implantation. P. Wang et al. review the important and rapidly evolving field in vivo islet imaging. The use of molecular imaging techniques may be of invaluable assistance toward monitoring islet grafts as well as a tool to better understand the physiopathological changes that occur after transplantation. Thierry Berney Olle Korsgren Andrew Posselt Antonello Pileggi

Noninvasive Imaging of Cell-Mediated Therapy for Treatment of Cancer

Cell-mediated therapy (immunotherapy) for the treatment of cancer is an active area of investigation in animal models and clinical trials. Despite many advances, objective responses to immunotherapy are observed in a small number of cases, for certain tumor types. To better understand differences in outcomes, it is critical to develop assays for tracking effector cell localization and function in situ. The fairly recent use of molecular imaging techniques to track cell populations has presented researchers and clinicians with a powerful diagnostic tool for determining the efficacy of cell-mediated therapy for the treatment of cancer. This review highlights the application of whole-body noninvasive radioisotopic, magnetic, and optical imaging methods for monitoring effector cells in vivo. Issues that affect sensitivity of detection, such as methods of cell marking, efficiency of cell labeling, toxicity, and limits of detection of imaging modalities, are discussed.

Molecular Neuroimaging: From Conventional to Emerging Techniques

The use of molecular imaging techniques in the central nervous system (CNS) has a rich history. Most of the important developments in imaging-such as computed tomography, magnetic resonance imaging, single photon emission computed tomography, and positron emission tomography-began with neuropsychiatric applications. These techniques and modalities were then found to be useful for imaging other organs involved with various disease processes. Molecular imaging of the CNS has enabled scientists and researchers to understand better the basic biology of brain function and the way in which various disease processes affect the brain. Unlike other organs, the brain is not easily accessible, and it has a highly selective barrier at the endothelial cell level known as the blood-brain barrier. Furthermore, the brain is the most complex cellular network known to exist. Various neurotransmitters act in either an excitatory or an inhibitory fashion on adjacent neurons through a multitude of mechanisms. The various neuronal systems and the myriad of neurotransmitter systems become altered in many diseases. Some of the most devastating diseases, including Alzheimer disease, Parkinson disease, brain tumors, psychiatric disease, and numerous degenerative neurologic diseases, affect only the brain. Molecular neuroimaging will be critical to the future understanding and treatment of these diseases. Molecular neuroimaging of the brain shows tremendous promise for clinical application. In this article, the current state and clinical applications of molecular neuroimaging will be reviewed.

Dominant-Negative Lox-1 Blocks Homodimerization of Wild-Type Lox-1–Induced Cell Proliferation Through Extracellular Signal Regulated Kinase 1/2 Activation

C-type lectin-like oxidized low-density lipoprotein (Ox-LDL) receptor-1 (Lox-1) belongs to the same family as natural killer cell receptors Ly49A and CD94 and functionally undergoes dimerization. Although Lys262 and Lys263 in the C terminus of bovine (b)Lox-1 play an important role in the uptake of Ox-LDL, mutation of these residues has not been suggested to be a potential source of the dominant-negative property. We hypothesize that dominant-negative human (h)Lox-1 forms a heterodimer with Lox-1-wild-type (WT) and blocks Lox-1-WT-induced cell signaling. Based on the use of molecular imaging techniques with laser scanning confocal microscopy and immunoprecipitation in an hLox-1-expressing Chinese hamster ovary cell system, homodimerization of hLox-1-WT was localized in the cell membrane, and Ox-LDL activated extracellular signal regulated kinase (ERK)1/2 without the translocation of hLox-1-WT. Lys266 and Lys267 of hLox-1, corresponding with Lys262 and Lys263 of bLox-1, were mutated (hLox1-K266A/K267A), and the mutant receptor inhibited hLox-1-WT-induced thymidine incorporation and ERK1/2 activation. Although Ox-LDL binds to the dominant-negative mutant receptor and is taken up by cytoplasm, ERK1/2 activation was blocked by heterodimerization with the mutant receptor and hLox-1-WT in the cell membrane. In addition, in human coronary artery smooth muscle cells, which express hLox-1-WT, we confirmed that the activation of ERK1/2 and [3H]-thymidine incorporation was caused by the addition of Ox-LDL, and these actions were blocked by hLox1-K266A/K267A. In conclusion, the present findings constitute the first evidence that strategies aimed at blocking cell-proliferative pathways at the receptor level could be useful for impairing Lox-1-induced cell proliferation.

Inflammation Imaging

Acute and chronic lung diseases are almost invariably associated with some degree of inflammation. Cells that evolved as an effective mechanism to counter infection and heal lung tissue may, in some circumstances, themselves be partially responsible for the pathogenesis of chronic lung disease that leads to irreversible lung damage and loss of lung function. Although standard measurements of lung function can document the progression of disease, the contributions of the numerous interacting elements to the process are difficult to measure in life. The use of molecular imaging techniques allows the different components of the inflammatory response to be monitored in situ in humans. In particular, positron emission tomography of selected markers targeted to specific cells and biochemical pathways can provide accurate measurements of disease activity, enabling a better understanding of inflammatory processes at all stages of disease. The practicability of sequential measurements allows one to monitor the natural history of different lung diseases. More importantly, imaging provides a unique tool for quantification of the modulation of discrete and specific aspects of inflammatory lung disease by targeted interventions. This should facilitate the development of new treatment strategies with better specificity for key elements of each disease.

Molecular imaging: the application of small animal positron emission tomography.

The extraordinary advances in genomic technologies over the last decade have led to the establishment of new animal models of disease. The use of molecular imaging techniques to examine these models, preferably with non-destructive imaging procedures, such as those offered by positron emission tomography (PET), are especially valuable for the timely advancement of research. With the use of small animal PET imaging it is possible to follow individual subjects of a sample population over an extended time period by using highly specific molecular probes and radiopharmaceuticals. In this Prospect small animal PET imaging will be described, specifically focusing on the current technologies, its applications in molecular imaging and the logistics of performing small animal PET.

National Cancer Institute and Imaging-Intersecting Scientific Opportunity with Clinical Need.

National Cancer Institute and Imaging-Intersecting Scientific Opportunity with Clinical Need.