Diagnosis of diabetes mellitus, presence of hyperglycemia, and/or insulin resistance confer cardiovascular risk, particularly for diastolic dysfunction. Diabetes is associated with elevated myocardial norepinephrine (NE) content, enhanced sympathetic nervous system (SNS) activity, altered resting heart rate, and depressed heart rate variability. Positron emission tomography (PET) using the NE analogue [11C]meta-hydroxyephedrine ([11C]HED) provides an index of myocardial sympathetic neuronal integrity at the NE reuptake transporter (NET). The hypothesis of this project is that (i) hyperglycemia imparts heightened sympathetic tone and NE release, leading to abnormal sympathetic neuronal function in the hearts of diabetic rats, and (ii) these abnormalities may be reversed or prevented by treatments to normalize glycemia. Sprague Dawley rats were rendered insulin resistant by high fat feeding and diabetic by a single dose of streptozotocin (STZ). Diabetic rats were treated for 8 weeks with insulin, metformin or rosiglitazone, starting from either 1 week (prevention) or 8 weeks (reversal) after STZ administration. Sympathetic neuronal integrity was evaluated longitudinally by [11C]HED PET. Echocardiography measures of systolic and diastolic function were completed at serial timepoints. Plasma NE levels were evaluated serially and expression of NET and β-adrenoceptors were tested at the terminal endpoints. Diabetic rats exhibited a 52-57% reduction of [11C]HED standardized uptake value (SUV) at 8 weeks after STZ, with a parallel 2.5-fold elevation of plasma NE and a 17-20% reduction in cardiac NET expression. These findings were confirmed by ex vivo biodistribution studies. Transmitral pulse wave Doppler echocardiography established an extension of mitral valve deceleration time and elevated early to atrial velocity ratio, suggesting diastolic dysfunction. Subsequent treatment with insulin but not metformin restored glycemia, reduced plasma NE by 50%, normalized NET expression, and recovered [11C]HED SUV towards non-diabetic age-matched control. Diastolic dysfunction in these rats persisted. By contrast, early treatment with insulin, metformin, or rosiglitazone delayed the progression of diastolic dysfunction, but had no effect on elevated NE and reduced [11C]HED SUV in diabetic rats, potentially owing to a latent decrease in blood glucose. In conclusion, diabetes is associated with heightened circulating and tissue NE levels which can be effectively reversed by lowering glycemia with insulin. Noninvasive interrogation of sympathetic neuronal integrity using [11C]HED PET may have added value in the stratification of cardiovascular risk among diabetic patients and in determining the myocardial effects of glycemic therapy.

Growing evidence from animal and clinical studies suggests that cardiac cell therapy can restore perfusion and improve function in the ischemic/infarcted myocardium. However, cell therapy is hindered by insufficient cell numbers, inefficient cell homing and engraftment, and inadequate cellular interactions. Furthermore, the biological mechanisms and local effects of transplanted cells have not been well-elucidated. The research presented herein attempts to address some of these issues. In manuscript #1, a new subpopulation of circulating progenitor cells (CPCs), termed derived CD133+ cells, was generated from the CD133- fraction of human peripheral blood. The derived CD133+ progenitors appeared to have superior vasculogenic potential in vitro, which may prove to be beneficial in inducing vasculogenesis in ischemic tissues. Positron emission tomography (PET) with direct cell labeling and reporter gene techniques were employed to assess the fate of transplanted human CPCs in vivo at different subjects of investigation, and different stages of cell transplantation. In manuscript #2, PET imaging with 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) direct cell labeling was used to demonstrate that collagen-based matrices improve the early homing and retention of delivered CPCs in a rat ischemic hindlimb model. This mechanism conferred by the matrix may have implications on cell therapy at the early stages after transplantation. In manuscript #3, a more efficient, stable and accurate labeling method, hexadecyl-4-[18F]fluorobenzoate (18F-HFB) direct cell labeling, was developed to quantify cell distribution of transplanted CPCs in a rat myocardial infarction model. PET imaging of 18F-HFB-CPCs revealed significant cell washout from the myocardium immediately after intramyocardial injection, with only a small proportion of transplanted CPCs remaining in the target area in the first 4 hours after delivery. In manuscript #4, human CPCs transduced with lentiviral vectors showed stable expression of PET reporter genes. This reporter gene based-cell labeling technique can be developed for noninvasive tracking cells within a bioengineered matrix by PET, while preserving cell phenotype, viability and function. These studies contribute important insights into the biology and physiology of transplanted stem cells and the ability of delivery matrices to improve transplanted cell engraftment, survival, and function. I believe with further refinement, cell expansion, tissue engineering and PET imaging could facilitate the clinical applications of cell therapies in years to come.

Positron Emission Tomography (PET) is a widely used imaging modality for diagnosing patients with cancer. Recently, there have been three novel developments in PET imaging aiming to increase PET image quality and quantification. This thesis focuses on the optimization of PET image quality on these three developments. The first development is the fully 3D PET data acquisition and reconstruction. 3D Acquisitions are not constrained in collecting events in single 2D planes and can span across different planes. 3D acquisition provides better detection since it can accept more events. Also it can result in lower radiation dose to the patient and shorter imaging times. With the application of 3D acquisition, a fully 3D iterative reconstruction algorithm was also developed. The aim of the first project in this thesis is to evaluate the PET image and raw data quality when this fully 3D iterative reconstruction algorithm is applied. The second development in PET imaging is the time-of-flight (TOF) PET data acquisition and reconstruction. TOF imaging has the ability to measure the difference between the detection times, thus localize the event location more accurately to increase the image quality. The second project in this thesis focuses on optimizing the TOF reconstruction parameters on a newly developed TOF PET scanner. Then the improvement of TOF information on image quality is assessed using the derived optimal parameters. Finally the effect of scan duration is evaluated to determine whether similar image quality could be obtained between TOF and non-TOF while using less scan time for TOF. The third development is the interest in building PET / magnetic resonance (MR) multi-modality scanner. MR imaging has the ability to show high soft tissue contrast and can assess physiological processes, which cannot be achieved on PET images. One problem in developing PET/MR system is that it is not possible with current MR acquisition schemes to translate the MR image into an attenuation map to correct for PET attenuations. The third project in this thesis proposed and assessed an approach for the attenuation correction of PET data in potential PET/MR systems to improve PET image quality and quantification.

<p>Positron emission tomography (PET) is a nuclear medicine diagnostic imaging exam of metabolic processes in the body. Radiotracers, which consist of positron emitting radioisotopes and a molecular probe, are introduced into the body, emitted radiation is detected, and tomographic images are reconstructed. The primary clinical PET application is in oncology using a glucose analogue radiotracer, which is avidly taken up by some cancers.</p><p>It is well known that PET performance and image quality degrade as body size increases, and epidemiological studies over the past two decades show that the adult US population's body size has increased dramatically and continues to increase. Larger patients have more attenuating material that increases the number of emitted photons that are scattered or absorbed within the body. Thus, for a fixed amount of injected radioactivity and acquisition duration, the number of measured true coincidence events will decrease, and the background fractions will increase. Another size-related factor, independent of attenuation, is the volume throughout which the measured coincidence counts are distributed: for a fixed acquisition duration, as the body size increases, the counts are distributed over a larger area. This is true for both a fixed amount of radioactivity, where the concentration decreases as size increases, and a fixed concentration, where the amount radioactivity increases with size.</p><p>Time-of-flight (TOF) PET is a recently commercialized technology that allows the localization, with a certain degree of error, of a positron annihilation using timing differences in the detection of coincidence photons. Both heuristic and analytical evaluations predict that TOF PET will have improved performance and image quality compared to non-TOF PET, and this improvement increases as body size increases. The goal of this dissertation is to parameterize the image quality improvement of TOF PET compared to non-TOF PET as a function of body size. Currently, no standard for comparison exists.</p><p>Previous evaluations of TOF PET's improvement have been made with either computer-simulated data or acquired data using a few discrete phantom sizes. A phantom that represents a range of attenuating dimensions, that can have a varying radioactivity distribution, and that can have radioactive inserts positioned throughout its volume would facilitate characterizing PET system performance and image quality as a function of body size. A fillable, tapered phantom, was designed, simulated, and constructed. The phantom has an oval cross-section ranging from 38.5 &times; 49.5 cm to 6.8 &times; 17.8 cm, a length of 51.1 cm, a mass of 6 kg (empty), a mass of 42 kg (water filled), and 1.25-cm acrylic walls.</p><p>For this dissertation research, PET image quality was measured using multiple, small spheres with diameters near the spatial resolution of clinical whole-body PET systems. Measurements made on a small sphere, which typically include a small number of image voxels, are susceptible to fluctuations over the few voxels, so using multiple spheres improves the statistical power of the measurements that, in turn, reduces the influence of these fluctuations. These spheres were arranged in an array and mounted throughout the tapered phantom's volume to objectively measure image quality as a function of body size. Image quality is measured by placing regions of interest on images and calculating contrast recovery, background variability, and signal to noise ratio.</p><p>Image quality as a function of body size was parameterized for TOF compared to non-TOF PET using 46 1.0-cm spheres positioned in six different body sizes in a fillable, tapered phantom. When the TOF and non-TOF PET images were reconstructed for matched contrast, the square of the ratio of the images' signal-to-noise ratios for TOF to non-TOF PET was plotted as a function, <italic>f</italic>(<italic>D</italic>), of the radioactivity distribution size, <italic>D</italic>, in cm. A linear regression was fit to the data: <italic>f</italic>(<italic>D</italic>) = 0.108<italic>D</italic> - 1.36. This was compared to the ratio of <italic>D</italic> and the localization error, <italic>&sigma;_d</italic>, based on the system timing resolution, which is approximately 650 ps for the TOF PET system used for this research. With the image quality metrics used in this work, the ratio of TOF to non-TOF PET fits well to a linear relationship and is parallel to <italic>D/&sigma;_d</italic>. For <italic>D</italic> < 20 cm, there is no image quality improvement, but for radioactivity distributions <italic>D</italic> > 20 cm, TOF PET improves image quality over non-TOF PET. PET imaging's clinical use has increased over the past decade, and TOF PET's image quality improvement for large patients makes TOF an important new technology because the occurrence of obesity in the US adult population continues to increase.</p> / Dissertation

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Medical imaging is the main tool to extract a 3D modelling of the human body or specific organs within it. In order to accomplish this, various imaging modalities have been developed over the years, such as X-Ray Computed Tomography (CT), Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET). Each one is based on a particular energy source that passes through the body and on specific physical laws, which define the meaning of noise and the sensitivity of the imaging process. In all medical imaging systems the main goal is to increase resolution since higher resolution is a key factor in increased information content, which is critical for increased accuracy in the understanding of the anatomy and in the assessment of size and morphological structure of organs, for early detection of abnormalities, suspected pathologies and more. In order to overcome the resolution limitations, one promising idea is to use signal processing techniques to enhance the spatial resolution. This approach proposes the acquisition of a high-resolution (HR) image from observed multiple low-resolution (LR) images. This image restoration approach is called super resolution (SR) image reconstruction (or restoration). It is the process of combining multiple low resolution images to form a high resolution image. The basic requirement in order to apply SR restoration techniques is the availability of multiple LR images captured from the same scene, which are sub-sampled (aliased) as well as shifted with subpixel precision. Each observed LR image is expressed as the result of a sequence of operators on the original HR image source, consisting of a geometrical warp, blurring and down-sampling. The SR image reconstruction method consists of three stages, registration, interpolation and restoration (i.e., inverse procedure). In the registration stage, the relative shifts between LR images, with reference to a certain LR image, are estimated with fractional pixel accuracy. Accurate sub-pixel motion estimation is a very important factor in the success of the SR image reconstruction algorithm. Since the shifts between LR images are arbitrary, the registered HR image will not always match up to a uniformly spaced HR grid. Thus, non-uniform interpolation is necessary, to obtain a uniformly spaced HR image from a non-uniformly spaced composite of LR images. Finally, image restoration is applied to the up-sampled image to remove blurring and noise. In order to evaluate the performance of SR reconstruction, a ‘simulate and correct’ approach to reconstruction is selected. First, simulated images of a computer generated phantom are formed and processed in order to comply with the observation model for the LR images. These are used as the images from which the HR image is constructed through the SR method. The iterative back-projection (IBP) algorithm suggested by Irani and Peleg has been chosen to be utilized, which belongs in the spatial domain methods and it is an easily and intuitively understood method. The results of the SR reconstruction are presented separately for the axial and the transaxial case. The evaluation relies on qualitative measures of image enhancement and on objective quantitative measures, such as the resolution (FWHM), the signal-to-noise ratio, the contrast ratio and the contrast-to-noise ratio. The performed trials demonstrated improvement in both the axial and transaxial resolution. The super-resolution images also provide a significantly improved contrast ratio, which is important for improving sensitivity for detection of small details and features. The improvement in resolution can be achieved without using any hardware changes or any increase in the patient radiation procedure. An important contribution of super-resolution is also the reduction of partial volume effects in the reconstructed image. The loss in SNR, which is a typical characteristic of all resolution enhancement algorithms, was not that considerable to preclude the clinical application of super-resolution. The overall evaluation demonstrated that the SR reconstruction is a post-processing method, which can provide medical images of higher resolution and better contrast ratio, without increasing the amount of radiation or the duration of the scan. / Η ιατρική απεικόνιση είναι το κύριο εργαλείο για την τρισδιάστατη μοντελοποίηση του ανθρώπινου σώματος και συγκεκριμένων οργάνων. Για να επιτευχθεί αυτό, διάφορες μέθοδοι απεικόνισης έχουν αναπτυχθεί, όπως η Υπολογιστική Τομογραφία, η Μαγνητική Τομογραφία και η Τομογραφία Εκπομπής Ποζιτρονίου. Η κάθε μία βασίζεται σε μια συγκεκριμένη πηγή ενέργειας η οποία διαπερνά το ανθρώπινο σώμα και έχει συγκεκριμένες φυσικές ιδιότητες. Σε όλα τα συστήματα ιατρικής απεικόνισης, ο βασικός στόχος είναι η βελτίωση της διακριτικής ικανότητας και κατα συνέπεια της παρεχόμενης πληροφορίας, η οποία είναι σημαντική για την ακρίβεια στην κατανόηση της ανατομίας και στην εκτίμηση του μεγέθους και της μορφολογίας των οργάνων, για την έγκαιρη διάγνωση ανωμαλιών κλπ. Μια από τις μεθόδους που έχουν προταθεί για τη βελτίωση της διακριτικής ικανότητας είναι η χρήση τεχνικών επεξεργασίας εικόνας. Σύμφωνα με αυτή τη μέθοδο, η οποία λέγεται Super Resolution, μια εικόνα υψηλής διακριτικής ικανότητας προκύπτει από πολλαπλές εικόνες χαμηλής διακριτικής ικανότητας. Η βασική προϋπόθεση για την εφαρμογή της μεθόδου είναι η ύπαρξη πολλαπλών εικόνων χαμηλής διακριτικής ικανότητας από την ίδια σκηνή, οι οποίες είναι μετατοπισμένες με ακρίβεια ενός κλάσματος píxel. Κάθε εικόνα χαμηλής διακριτικής ικανότητας εκφράζεται σαν το αποτέλεσμα ενός γεωμετρικού μετασχηματισμού, παραμόρφωσης και υπο-δειγματοληψίας της εικόνας υψηλής διακριτικής ικανότητας. Η ανακατασκευή μιας εικόνας με τη μέθοδο Super Resolution περιλαμβάνει τρία στάδια. Στο πρώτο στάδιο, υπολογίζονται οι σχετικές μετατοπίσεις μεταξύ των εικόνων. Η ακριβής εκτίμηση αυτής της σχετικής κίνησης είναι κρίσιμος παράγοντας για την απόδοση του αλγορίθμου ανακατασκευής. Για την εκτίμηση της απόδοσης της ανακατασκευής χρησιμοποιείται ένας αλγόριθμος ‘προσομοίωσης και διόρθωσης’. Αρχικά παράγονται οι εικόνες που θα χρησιμοποιηθούν σαν βάση για την ανακατασκευή της εικόνας υψηλής διακριτικής ικανότητας. Ο αλγόριθμος που χρησιμοποιείται είναι ο IBP (iterative back-projection), όπως προτάθηκε από τους Irani, Peleg. Η εκτίμηση της απόδοσης της μεθόδου βασίζεται σε ποιοτικά και ποσοτικά κριτήρια, όπως η διακριτική ικανότητα (FWHM), το SNR και η διακριτική ικανότητα αντίθεσης. Οι δοκιμές έδειξαν βελτίωση στην διακριτική ικανότητα και στην διακριτική ικανότητα αντίθεσης, η οποία είναι σημαντική για τη βελτίωση της ικανότητας ανίχνευσης λεπτομερειών. Οι βελτιώσεις αυτές επιτυγχάνονται χωρίς αλλαγές στο επίπεδο του υλικού και χωρίς αύξηση του χρόνου έκθεσης του ασθενούς στην ακτινοβολία. Η απώλεια σε SNR, η οποία είναι τυπική συνέπεια όλων των αλγορίθμων ανακατασκευής, δεν είναι απαγορευτική για τη χρήση της μεθόδου. Η συνολική εκτίμηση της μεθόδου, δείχνει ότι είναι μια μέθοδος επεξεργασίας, μέσω της οποίας μπορούν να προκύψουν ιατρικές εικόνες υψηλής διακριτικής ικανότητας, χωρίς την αύξηση της ποσότητας της ακτινοβολίας και του χρόνου έκθεσης του ασθενούς.

Η Τομογραφία Εκπομπής Ποζιτρονίων, η οποία συχνά αναφέρεται με βάση το ακρωνύμιό της, PET (Positron Emission Tomography), αποτελεί μία πρωτοποριακή τεχνική απεικόνισης η οποία παρέχει εγκάρσιες τομές της λειτουργίας των διαφόρων δομών του ανθρωπίνου σώματος. Η Τομογραφία PET επιτρέπει την μεταβολική απεικόνιση αυτών των δομών (σε αντίθεση με τις ακτίνες-Χ και την Υπολογιστική Τομογραφία (CT – Computer Tomography) οι οποίες παρέχουν ανατομική απεικόνιση), σε μοριακό επίπεδο, και αυτός είναι ο λόγος που συχνά η Τομογραφία PET αναφέρεται ως μοριακή απεικόνιση. Ειδικότερα, οι τομογράφοι PET για μικρά ζώα (Small Animal PET) οι οποίοι απαιτούν ιδιαίτερα υψηλή διακριτική ικανότητα, διαδραματίζουν σημαντικό ρόλο στην βιολογία και στις in-vivo μελέτες της φαρμακοκινητικής των ιχνηθετών και του μεταβολισμού. Σύμφωνα με τη βιβλιογραφία έχουν αναφερθεί διάφοροι τύποι τομογράφων PET, στους οποίους χρησιμοποιήθηκαν διάφοροι τύποι ανιχνευτικών διατάξεων, με διαφορετικό σχεδιασμό σε κάθε περίπτωση. Η τεχνολογία αυτών των τομογράφων βασίζεται στη χρήση μικρών ανόργανων κρυστάλλων, κυρίς αποτελούμενων από BGO, GSO και LSO, οι οποίοι σχηματίζουν ένα block στο οποίο έχει προσαρτηθεί ένας φωτοπολλαπλασιαστής είτε με ευαισθησία θέσης (PS – PMT: Position Sensitive PhotoMultiplier Tube), είτε με πολλαπλές ανόδους (multianode PMT). To BGO (Bismuth Germanate Oxide) είναι το υλικό που χρησιμοποιείται σε αρκετούς εμπορικούς Τομογράφους, έχοντας πλέον αντικαταστήσει το ιωδιούχο νάτριο (ΝαΙ). Ένα πρότυπο σύστημα small animal PET χαμηλού κόστους βρίσκεται υπό ανάπτυξη, προκειμένου να μελετήσουμε τα επιμέρους σχεδιαστικά χαρακτηριστικά του και να μετρήσουμε την απόδοσή του. Ο βασικός block ανιχνευτής αποτελείται από μία 16×16 διάταξη επιμέρους BGO κρυστάλλων διαστάσεων 3.75×3.75×20 mm3, ο οποίος έχει τοποθετηθεί με ειδική διεργασία στην επιφάνεια ενός Hamamatsu R-2486 PSPMT. Με τη χρήση κατάλληλων ηλεκτρονικών διατάξεων και την ανάπτυξη ειδικού λογισμικού πραγματοποιήθηκαν μετρήσεις της απόδοσης των επιμέρους ανιχνευτών καθώς επίσης και μετρήσεις σχετικές με τους φωτοπολλαπλασιαστές. / Positron Emission Tomography, often referred to by its acronym, PET, is an emerging radiologic modality that yields transverse tomographic images of functioning organs in the human body. PET enables the metabolic imaging of organs (as opposed to the anatomic imaging provided by techniques such as the X-ray imaging or the Computerized Tomography (CT)), in molecular level, and this is the reason why it is characterized as molecular imaging. Especially, small animal PET tomographs which require high spatial resolution can play an important role in biology and studies of in vivo tracer pharmacokinetics and metabolism. Various implementations have been reported in the literature using a variety of detector and design technologies. The basic technology for these scanners is based on small inorganic crystals, mainly from BGO, GSO, and LSO, forming detector blocks read out by position sensitive and multianode PMTs. BGO is the material used in a lot of commercial scanners, having replaced NaI, mainly because BGO has higher stopping power and it is not hygroscopic. We have been developing a low-cost small animal PET prototype, in order to study specific design characteristics and measure its performance. The basic block detector design consists of a 16×16 array of 3.75×3.75×20 mm3 individual BGO crystals coupled to a Hamamatsu R-2486 PSPMT. Measurements of the individual detector performance as well as measurements of the PSPMTs have been performed.

Type 1 and 2 Diabetes Mellitus are a growing health problem throughout the world. There is an increasing  need for methodologies, which are both reliable and non-invasive to measure the amount of insulin-producing tissue (Beta-cell mass, or BCM), as well as rapidly quantify changes in the BCM due to the onset of disease, beta-cell replacement therapy, or other treatments. Positron Emission Tomography (PET) is a non-invasive, quantitative functional imaging technique which can be used to study dynamical or static processes inside the body. In this thesis, we present a study protocol for in vivo imaging of the most common form of beta- cell replacement therapy; islet transplantation. Islets were labeled with the PET tracer, 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG), and administered intra-portally, while the recipient was monitored by PET/CT. The hepatic distribution of the islets was highly heterogeneous, and around 25% (human) or 50% (porcine) of the administered islets could not be found in the liver after completed transplantation, confirming previous reports of considerable cell injury during the procedure leading to low hepatic engraftment. Native BCM in the pancreas can potentially be quantified using a PET tracer with sufficiently high specificity, but the major obstacle is the relative low amounts of insulin producing tissue (only 1-2% of the pancreatic volume). Two tetrabenazine analogues, [18F]FE-(+)-DTBZ and [18F]FE-(+)-DTBZ-d4, are ligands to VMAT2, which is expressed in islet tissue. Both analogues were investigated and characterized as potential BCM imaging agents both in vitro and in vivo.  Both tracers exhibited high preferential binding to islet tissue compared to exocrine pancreatic tissue. However, the specificity was not high enough to overcome the obscuring exocrine signal in vivo (7-10% of the signal originating from specific islet tracer uptake). This thesis demonstrates that it is possible to quantitatively assess islet transplantation by PET imaging. In vivo determination of native pancreatic BCM is, in theory, possible with both [18F]FE-(+)-DTBZ and [18F]FE-(+)-DTBZ-d4, but tracer analogues with higher islet specificity is needed for quantification of smaller BCM changes with physiological impact.

Although mammals are the most commonly utilized laboratory animal, laboratory animal medicine continually seeks to replace them with animals of lower phylogenic classification. Fish are becoming increasingly important as investigators seek alternative animal models for research. Fish can provide an economical and feasible alternative to typical mammalian models; moreover, many fish, which have comparatively short life spans, can easily reproduce in the laboratory. One key area of animal health research in which fish have been underutilized is the field of advanced imaging. Although many images of fish have been captured through the use of computed tomography (CT), radiography, and ultrasonography, these images have been primarily utilized for anatomical study. In addition, fish have never before been studied with positron emission tomography/ computed tomography (PET/CT). My objectives were to determine if these imaging techniques can be used to obtain physiological information from fish, therefore making it more likely that fish can be utilized as replacement animals using these new imaging techniques (CT, PET/CT). I performed two different types of studies to assess the potential application of advanced imaging techniques to fish. In the first experiment, microCT was used to characterize otolith deformity in vitamin C deficient captive-raised red drum and relate the deformity to behavioral and physiological changes. I found that the normal and abnormal fish had statistically significant differences in behavior, cortisol levels, and otolith volume and density. MicroCT assessment of abnormal fish revealed operculum abnormalities, malocclusions, and several types of otolith malformations. Therefore, the affected fish had not only an abnormal skeletal appearance but also significantly abnormal behavior and cortisol responses. In the second experiment, fluorodeoxyglucose-positron emission tomography/ computed tomography (FDG-PET/CT) was used to quantify glucose uptake in select organs prior to carcinogenesis studies in fish. The quantified glucose uptake was compared to published data on humans, mice, and dogs. Rapid, quantifiable glucose uptake was demonstrated, particularly in brain, kidneys, and liver in all imaged fish species. Glucose uptake in the major organ systems of fish was closer to that in humans than uptake in mice or dogs, indicating that fish may serve as an effective alternative animal model for tumor studies using this technology. Other applications for this technique in fish may include metabolism studies and screening for environmental carcinogenesis. I found that both microCT and PET/CT imaging provided useful and meaningful results. In addition, the use of non-invasive scanning allows for re-use of fish, thus reducing the number of animal models used in experiments. These experiments suggest that fish will be good replacement models for mammals using these advanced imaging techniques.

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