Cell proliferation detected using [18F]FLT PET/CT as an early marker of abdominal aortic aneurysm.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a focal aortic dilatation progressing towards rupture. Non-invasive AAA-associated cell proliferation biomarkers are not yet established. We investigated the feasibility of the cell proliferation radiotracer, fluorine-18-fluorothymidine ([18F]FLT) with positron emission tomography/computed tomography (PET/CT) in a progressive pre-clinical AAA model (angiotensin II, AngII infusion). METHODS AND RESULTS: Fourteen-week-old apolipoprotein E-knockout (ApoE-/-) mice received saline or AngII via osmotic mini-pumps for 14 (n = 7 and 5, respectively) or 28 (n = 3 and 4, respectively) days and underwent 90-minute dynamic [18F]FLT PET/CT. Organs were harvested from independent cohorts for gamma counting, ultrasound scanning, and western blotting. [18F]FLT uptake was significantly greater in 14- (n = 5) and 28-day (n = 3) AAA than in saline control aortae (n = 5) (P < 0.001), which reduced between days 14 and 28. Whole-organ gamma counting confirmed greater [18F]FLT uptake in 14-day AAA (n = 9) compared to saline-infused aortae (n = 4) (P < 0.05), correlating positively with aortic volume (r = 0.71, P < 0.01). Fourteen-day AAA tissue showed increased expression of thymidine kinase-1, equilibrative nucleoside transporter (ENT)-1, ENT-2, concentrative nucleoside transporter (CNT)-1, and CNT-3 than 28-day AAA and saline control tissues (n = 3 each) (all P < 0.001). CONCLUSIONS: [18F]FLT uptake is increased during the active growth phase of the AAA model compared to saline control mice and late-stage AAA.

Analyzing the blood-brain barrier: the benefits of medical imaging in research and clinical practice.

A dysfunctional BBB is a common feature in a variety of brain disorders, a fact stressing the need for diagnostic tools designed to assess brain vessels' permeability in space and time. Biological research has benefited over the years various means to analyze BBB integrity. The use of biomarkers for improper BBB functionality is abundant. Systemic administration of BBB impermeable tracers can both visualize brain regions characterized by BBB impairment, as well as lead to its quantification. Additionally, locating molecular, physiological content in regions from which it is restricted under normal BBB functionality undoubtedly indicates brain pathology-related BBB disruption. However, in-depth research into the BBB's phenotype demands higher analytical complexity than functional vs. pathological BBB; criteria which biomarker based BBB permeability analyses do not meet. The involvement of accurate and engineering sciences in recent brain research, has led to improvements in the field, in the form of more accurate, sensitive imaging-based methods. Improvements in the spatiotemporal resolution of many imaging modalities and in image processing techniques, make up for the inadequacies of biomarker based analyses. In pre-clinical research, imaging approaches involving invasive procedures, enable microscopic evaluation of BBB integrity, and benefit high levels of sensitivity and accuracy. However, invasive techniques may alter normal physiological function, thus generating a modality-based impact on vessel's permeability, which needs to be corrected for. Non-invasive approaches do not affect proper functionality of the inspected system, but lack in spatiotemporal resolution. Nevertheless, the benefit of medical imaging, even in pre-clinical phases, outweighs its disadvantages. The innovations in pre-clinical imaging and the development of novel processing techniques, have led to their implementation in clinical use as well. Specialized analyses of vessels' permeability add valuable information to standard anatomical inspections which do not take the latter into consideration.

Potential of Nuclear Imaging Techniques to Study the Oral Delivery of Peptides.

Peptides are small biomolecules known to stimulate or inhibit important functions in the human body. The clinical use of peptides by oral delivery, however, is very limited due to their sensitive structure and physiological barriers present in the gastrointestinal tract. These barriers can be overcome with chemical and mechanical approaches protease inhibitors, permeation enhancers, and polymeric encapsulation. Studying the success of these approaches pre-clinically with imaging techniques such as fluorescence imaging (IVIS) and optical microscopy is difficult due to the lack of in-depth penetration. In comparison, nuclear imaging provides a better platform to observe the gastrointestinal transit and quantitative distribution of radiolabeled peptides. This review provides a brief background on the oral delivery of peptides and states examples from the literature on how nuclear imaging can help to observe and analyze the gastrointestinal transit of oral peptides. The review connects the fields of peptide delivery and nuclear medicine in an interdisciplinary way to potentially overcome the challenges faced during the study of oral peptide formulations.

Accurate measures of changes in regional lung air volumes from chest x-rays of small animals.

Objective. To develop a robust technique for calculating regional volume changes within the lung from x-ray radiograph sequences captured during ventilation, without the use of computed tomography (CT).Approach. This technique is based on the change in transmitted x-ray intensity that occurs for each lung region as air displaces the attenuating lung tissue.Main results. Lung air volumes calculated from x-ray intensity changes showed a strong correlation (R2= 0.98) against the true volumes, measured from high-resolution CT. This correlation enables us to accurately convert projected intensity data into relative changes in lung air volume. We have applied this technique to measure changes in regional lung volumes from x-ray image sequences of mechanically ventilated, recently-deceased newborn rabbits, without the use of CT.Significance. This method is suitable for biomedical research studies,enabling quantitative regional measurement of relative lung air volumes at high temporal resolution, and shows great potential for future clinical application.

Performance assessment of the ALBIRA II pre-clinical SPECT S102 system for 99mTc imaging.

OBJECTIVE: The performance characteristics of the SPECT sub-system S102 of the ALBIRA II PET/SPECT/CT are analyzed for the 80 mm field of view (FOV) to evaluate the potential in-vivo imaging in rats, based on measurements of the system response for the commonly used Technetium-99 m (99mTc) in small animal imaging. METHODS: The ALBIRA II tri-modal µPET/SPECT/CT pre-clinical system (Bruker BioSpin, Ettlingen, Germany) was used. The SPECT modality is made up of two opposite gamma cameras (Version S102) with Sodium doped Cesium Iodide (CsI(Na)) single continuous crystal detectors coupled to position-sensitive photomultipliers (PSPMTs). Imaging was performed with the NEMA NU-4 image quality phantom (Data Spectrum Corporation, Durham, USA). Measurements were performed with a starting activity concentration of 4.76 MBq/mL 99mTc. An energy window of 20% at 140 keV was selected in this study. The system offers a 20 mm, 40 mm, 60 mm and an 80 mm field of view (FOV) and in this study the 80 mm FOV was used for all the acquisitions. The data were reconstructed with an ordered subset expectation maximization (OSEM) algorithm. Sensitivity, spatial resolution, count rate linearity, convergence of the algorithm and the recovery coefficients (RC) were analyzed. All analyses were performed with PMOD and MATLAB software. RESULTS: The sensitivities measured at the center of the 80 mm FOV with the point source were 23.1 ± 0.3 cps/MBq (single pinhole SPH) and 105.6 ± 5.5 cps/MBq (multi pinhole MPH). The values for the axial, tangential and radial full width at half maximum (FWHM) were 2.51, 2.54, and 2.55 mm with SPH and 2.35, 2.44 and 2.32 mm with MPH, respectively. The corresponding RC values for the 5 mm, 4 mm, 3 mm and 2 mm rods were 0.60 ± 0.28, 0.61 ± 0.24, 0.29 ± 0.11 and 0.20 ± 0.06 with SPH and 0.56 ± 0.20, 0.50 ± 0.18, 0.38 ± 0.09 and 0.23 ± 0.06 with MPH. To obtain quantitative imaging data, the image reconstructions should be performed with 12 iterations. CONCLUSION: The ALBIRA II preclinical SPECT sub-system S102 has a favorable sensitivity and spatial resolution for the 80 mm FOV setting for both the SPH and MPH configurations and is a valuable tool for small animal imaging.

Capsules for biomedical image segmentation.

Our work expands the use of capsule networks to the task of object segmentation for the first time in the literature. This is made possible via the introduction of locally-constrained routing and transformation matrix sharing, which reduces the parameter/memory burden and allows for the segmentation of objects at large resolutions. To compensate for the loss of global information in constraining the routing, we propose the concept of "deconvolutional" capsules to create a deep encoder-decoder style network, called SegCaps. We extend the masked reconstruction regularization to the task of segmentation and perform thorough ablation experiments on each component of our method. The proposed convolutional-deconvolutional capsule network, SegCaps, shows state-of-the-art results while using a fraction of the parameters of popular segmentation networks. To validate our proposed method, we perform experiments segmenting pathological lungs from clinical and pre-clinical thoracic computed tomography (CT) scans and segmenting muscle and adipose (fat) tissue from magnetic resonance imaging (MRI) scans of human subjects' thighs. Notably, our experiments in lung segmentation represent the largest-scale study in pathological lung segmentation in the literature, where we conduct experiments across five extremely challenging datasets, containing both clinical and pre-clinical subjects, and nearly 2000 computed-tomography scans. Our newly developed segmentation platform outperforms other methods across all datasets while utilizing less than 5% of the parameters in the popular U-Net for biomedical image segmentation. Further, we demonstrate capsules' ability to generalize to unseen handling of rotations/reflections on natural images.

Another decade of photoacoustic imaging.

Photoacoustic imaging-a hybrid biomedical imaging modality finding its way to clinical practices. Although the photoacoustic phenomenon was known more than a century back, only in the last two decades it has been widely researched and used for biomedical imaging applications. In this review we focus on the development and progress of the technology in the last decade (2011-2020). From becoming more and more user friendly, cheaper in cost, portable in size, photoacoustic imaging promises a wide range of applications, if translated to clinic. The growth of photoacoustic community is steady, and with several new directions researchers are exploring, it is inevitable that photoacoustic imaging will one day establish itself as a regular imaging system in the clinical practices.

Rapid, efficient, and economical synthesis of PET tracers in a droplet microreactor: application to O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET).

BACKGROUND: Conventional scale production of small batches of PET tracers (e.g. for preclinical imaging) is an inefficient use of resources. Using O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET), we demonstrate that simple microvolume radiosynthesis techniques can improve the efficiency of production by consuming tiny amounts of precursor, and maintaining high molar activity of the tracers even with low starting activity. PROCEDURES: The synthesis was carried out in microvolume droplets manipulated on a disposable patterned silicon "chip" affixed to a heater. A droplet of [18F]fluoride containing TBAHCO3 was first deposited onto a chip and dried at 100 °C. Subsequently, a droplet containing 60 nmol of precursor was added to the chip and the fluorination reaction was performed at 90 °C for 5 min. Removal of protecting groups was accomplished with a droplet of HCl heated at 90 °C for 3 min. Finally, the crude product was collected in a methanol-water mixture, purified via analytical-scale radio-HPLC and formulated in saline. As a demonstration, using [18F]FET produced on the chip, we prepared aliquots with different molar activities to explore the impact on preclinical PET imaging of tumor-bearing mice. RESULTS: The microdroplet synthesis exhibited an overall decay-corrected radiochemical yield of 55 ± 7% (n = 4) after purification and formulation. When automated, the synthesis could be completed in 35 min. Starting with < 370 MBq of activity, ~ 150 MBq of [18F]FET could be produced, sufficient for multiple in vivo experiments, with high molar activities (48-119 GBq/µmol). The demonstration imaging study revealed the uptake of [18F]FET in subcutaneous tumors, but no significant differences in tumor uptake as a result of molar activity differences (ranging 0.37-48 GBq/µmol) were observed. CONCLUSIONS: A microdroplet synthesis of [18F]FET was developed demonstrating low reagent consumption, high yield, and high molar activity. The approach can be expanded to tracers other than [18F]FET, and adapted to produce higher quantities of the tracer sufficient for clinical PET imaging.

A simple device to convert a small-animal PET scanner into a multi-sample tissue and injection syringe counter.

INTRODUCTION: We describe a simple fixture that can be added to the imaging bed of a small-animal PET scanner that allows for automated counting of multiple organ or tissue samples from mouse-sized animals and counting of injection syringes prior to administration of the radiotracer. The combination of imaging and counting capabilities in the same machine offers advantages in certain experimental settings. METHODS: A polyethylene block of plastic, sculpted to mate with the animal imaging bed of a small-animal PET scanner, is machined to receive twelve 5-ml containers, each capable of holding an entire organ from a mouse-sized animal. In addition, a triangular cross-section slot is machined down the centerline of the block to secure injection syringes from 1-ml to 3-ml in size. The sample holder is scanned in PET whole-body mode to image all samples or in one bed position to image a filled injection syringe. Total radioactivity in each sample or syringe is determined from the reconstructed images of these objects using volume re-projection of the coronal images and a single region-of-interest for each. We tested the accuracy of this method by comparing PET estimates of sample and syringe activity with well counter and dose calibrator estimates of these same activities. RESULTS: PET and well counting of the same samples gave near identical results (in MBq, R2=0.99, slope=0.99, intercept=0.00-MBq). PET syringe and dose calibrator measurements of syringe activity in MBq were also similar (R2=0.99, slope=0.99, intercept=- 0.22-MBq). CONCLUSION: A small-animal PET scanner can be easily converted into a multi-sample and syringe counting device by the addition of a sample block constructed for that purpose. This capability, combined with live animal imaging, can improve efficiency and flexibility in certain experimental settings.

Investigation of the imaging characteristics of the ALBIRA II small animal PET system for 18F, 68Ga and 64Cu.

AIM: In this study the performance characteristics of the Albira II PET sub-system and the response of the system for the following radionuclides 18F, 68Ga and 64Cu was analyzed. MATERIALS AND METHODS: The Albira II tri-modal system (Bruker BioSpin MRI GmbH, Ettlingen, Germany) is a pre-clinical device for PET, SPECT and CT. The PET sub-system uses single continuous crystal detectors of lutetium yttrium orthosilicate (LYSO). The detector assembly consists of three rings of 8 detector modules. The transaxial field of view (FOV) has a diameter of 80mm and the axial FOV is 148mm. A NEMA NU-4 image quality phantom (Data Spectrum Corporation, Durham, USA) having five rods with diameters of 1, 2, 3, 4 and 5mm and a uniform central region was used. Measurements with 18F, 68Ga and 64Cu were performed in list mode acquisition over 10h. Data were reconstructed using a maximum-likelihood expectation-maximization (MLEM) algorithm with iteration numbers between 5 and 50. System sensitivity, count rate linearity, convergence and recovery coefficients were analyzed. RESULTS: The sensitivities for the entire FOV (non-NEMA method) for 18F, 68Ga and 64Cu were (3.78±0.05)%, (3.97±0.18)% and (3.79±0.37)%, respectively. The sensitivity based on the NEMA protocol using the 22Na point source yielded (5.53±0.06)%. Dead-time corrected true counts were linear for activities ≤7MBq (18F and 68Ga) and ≤17MBq (64Cu) in the phantom. The radial, tangential and axial full widths at half maximum (FWHMs) were 1.52, 1.47 and 1.48mm. Recovery coefficients for the uniform region with a total activity of 8MBq in the phantom were (0.97±0.05), (0.98±0.06), (0.98±0.06) for 18F, 68Ga and 64Cu, respectively. CONCLUSION: The Albira II pre-clinical PET system has an adequate sensitivity range and the system linearity is suitable for the range of activities used for pre-clinical imaging. Overall, the system showed a favorable image quality for pre-clinical applications.

Imaging in pleural mesothelioma: A review of the 12th International Conference of the International Mesothelioma Interest Group.

Imaging of malignant pleural mesothelioma is essential to patient management, prognostication, and response assessment. From animal models to clinical trials, the gamut of research activities and clinical standards relies on imaging to provide information on lesion morphology and the growing number of physiologic characteristics amenable to capture through imaging techniques. The complex morphology, growth pattern, and biological mechanisms of mesothelioma, however, present challenges for image acquisition and interpretation. Nevertheless, novel approaches to image acquisition and subsequent image analysis have expanded the opportunities for (as well as the need for) imaging in this disease. This paper summarizes the imaging-based research presented orally at the 2014 International Conference of the International Mesothelioma Interest Group (iMig) in Cape Town, South Africa, October 2014. Presented topics include the imaging of hypoxia in a murine model through positron emission tomography (PET), the use of diffusion-weighted magnetic resonance imaging (MRI) to assess the histologic composition of biphasic mesothelioma and to assess early response to chemotherapy, the correlation of CT-based tumor volume with the volume of the post-surgical tumor specimen, the development of volumetric tumor response criteria, and pre-treatment tumor volume growth considerations for tumor response assessment.

PET, SPECT, CT, and MRI in Mouse Cardiac Phenotyping: An Overview.

This overview first summarizes the last decade of continuous developments and improvements in pre-clinical imaging methods that are now essential tools for in vivo evaluation of cardiac morphology and function in living mice, involving nuclear emission of labeled molecules (micro-PET and micro-SPECT) and electromagnetic wave interactions with biological tissues (micro-CT and micro-MRI). In the following, and for better understanding, the basic physical principles and specific technical innovations of the aforementioned imaging methods are reviewed. Specificity, sensitivity, and spatial and temporal resolutions, together with the corresponding advantages and weaknesses of each method are then discussed, and cardiac image-acquisition protocols and illustrative examples are given for each modality. Emerging hybrid cardiac imaging is also presented and illustrated. Then, recent biological insights provided by mouse cardiac imaging are presented. Finally, imaging strategies in mouse cardiac phenotyping involving the aforementioned methods, adding metabolic and molecular information to morphological data, are emphasized and discussed. Curr. Protoc. Mouse Biol. 2:129-144 © 2012 by John Wiley & Sons, Inc.