Multimodality Small Animal Imaging Research Articles

Bridging the translational gap: Implementation of multimodal small animal imaging strategies for tumor burden assessment in a co-clinical trial.

In designing co-clinical cancer studies, preclinical imaging brings unique challenges that emphasize the gap between man and mouse. Our group is developing quantitative imaging methods for the preclinical arm of a co-clinical trial studying immunotherapy and radiotherapy in a soft tissue sarcoma model. In line with treatment for patients enrolled in the clinical trial SU2C-SARC032, primary mouse sarcomas are imaged with multi-contrast micro-MRI (T1 weighted, T2 weighted, and T1 with contrast) before and after immune checkpoint inhibition and pre-operative radiation therapy. Similar to the patients, after surgery the mice will be screened for lung metastases with micro-CT using respiratory gating. A systems evaluation was undertaken to establish a quantitative baseline for both the MR and micro-CT systems against which others systems might be compared. We have constructed imaging protocols which provide clinically-relevant resolution and contrast in a genetically engineered mouse model of sarcoma. We have employed tools in 3D Slicer for semi-automated segmentation of both MR and micro-CT images to measure tumor volumes efficiently and reliably in a large number of animals. Assessment of tumor burden in the resulting images was precise, repeatable, and reproducible. Furthermore, we have implemented a publicly accessible platform for sharing imaging data collected during the study, as well as protocols, supporting information, and data analyses. In doing so, we aim to improve the clinical relevance of small animal imaging and begin establishing standards for preclinical imaging of tumors from the perspective of a co-clinical trial.

NEMA NU4-2008 Performance Evaluation of Albira: A Two-Ring Small-Animal PET System Using Continuous LYSO Crystals

Goals:This paper presents the performance review based on a dual-ring Positron Emission Tomography (PET) scanner being a part of Bruker Albira: a multi-modal small-animal imaging platform. Each ring of Albira PET contains eight detectors arranged as octagon, and each detector is built using a single continuous lutetium-yttrium oxyorthosilicate crystal and multi-anode photo multiplier tube. In two-ring configuration, the scanner covers 94.4 mm in axial- and 80´80 mm in trans-axial direction, which is sufficient to acquire images of small animals (e.g.mice) without the need of moving the animal bed during the scan.Methods:All measurements and majority of data processing were performed according to the NEMA NU4-2008 standard with one exception. Due to the scanner geometry, the spatial resolution test was reconstructed using iterative algorithm instead of the analytical one. The main performance characteristics were compared with those of the other PET sub-systems of tri-modal small-animal scanners.Results:The measured spatial resolution at the centre of the axial field of view in radial, tangential and axial directions was 1.72, 1.70 and 2.45 mm, respectively. The scatter fraction for the mouse-like phantom was 9.8% and for the rat-like phantom, 21.8%. The maximum absolute sensitivity was 5.30%. Finally, the recovery co-efficients for 5, 4, 3, 2, 1 mm diameter rods in image quality phantom were: 0.90, 0.77, 0.66, 0.30 and 0.05, respectively.Conclusion:The Bruker Albira is a versatile small-animal multi-modal device that can be used for variety of studies. Overall the PET sub-system provides a good spatial resolution coupled with better-than average sensitivity and the ability to produce good quality animal images when administering low activities.

Multimodal imaging analysis of an orthotopic head and neck cancer mouse model and application of anti-CD137 tumor immune therapy.

Recent technical progress makes sophisticated noninvasive imaging methods available for murine models. For the first time, in this study, we applied fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT and FDG-PET-MRI to a murine orthotopic model of head and neck cancer immunotherapy. Tumor growth of floor of the mouth tumors was evaluated by multimodal small-animal imaging using FDG-PET-CT and FDG-PET-MRI. The immunotherapeutic effects of anti-CD137 antibody therapy were examined on body weight, tumor growth, and tumor-infiltrating immune cells in longitudinal imaging studies and immunohistochemical analyses. Imaging revealed aggressive, fast-growing tumors without evidence of local or distant metastases. CD137 immunotherapy decreased tumor take and growth and stabilized body weight over time. A clear case of tumor regression was demonstrated by longitudinal PET-CT. The murine model mimics the characteristics of head and neck cancer in humans and offers excellent opportunities to investigate immunomodulatory anticancer drugs. The CD137 antibody showed antitumor effects in some therapy-responsive mice.

A compact frequency-domain photon migration system for integration into commercial hybrid small animal imaging scanners for fluorescence tomography

The work presented herein describes the system design and performance evaluation of a miniaturized near-infrared fluorescence (NIRF) frequency-domain photon migration (FDPM) system with non-contact excitation and homodyne detection capability for small animal fluorescence tomography. The FDPM system was developed specifically for incorporation into a Siemens micro positron emission tomography/computed tomography (microPET/CT) commercial scanner for hybrid small animal imaging, but could be adapted to other systems. Operating at 100 MHz, the system noise was minimized and the associated amplitude and phase errors were characterized to be ±0.7% and ±0.3°, respectively. To demonstrate the tomographic ability, a commercial mouse-shaped phantom with 50 µM IRDye800CW and 68Ga containing inclusion was used to associate PET and NIRF tomography. Three-dimensional mesh generation and anatomical referencing was accomplished through CT. A third-order simplified spherical harmonics approximation (SP3) algorithm, for efficient prediction of light propagation in small animals, was tailored to incorporate the FDPM approach. Finally, the PET-NIRF target co-localization accuracy was analyzed in vivo with a dual-labeled imaging agent targeting orthotopic growth of human prostate cancer. The obtained results validate the integration of time-dependent fluorescence tomography system within a commercial microPET/CT scanner for multimodality small animal imaging.

Performance characterization of the Inveon preclinical small-animal PET/SPECT/CT system for multimodality imaging

We investigated the performance of the Inveon small-animal PET/SPECT/CT system and compared the imaging capabilities of the SPECT and PET components. For SPECT, the energy resolution, tomographic spatial resolution and system sensitivity were evaluated with a (99m)Tc solution using a single pinhole collimator. For PET, the spatial resolution, absolute sensitivity, scatter fraction and peak noise equivalent count were evaluated. Phantoms and a normal rat were scanned to compare the imaging capabilities of SPECT and PET. The SPECT spatial resolution was 0.84mm full-width at half-maximum (FWHM) at a radius of rotation of 25mm using a 0.5-mm pinhole aperture collimator, while the PET spatial resolution was 1.63mm FWHM at the centre. The SPECT system sensitivity at a radius of rotation of 25mm was 35.3cps/MBq (4 × 10(-3)%) using the 0.5-mm pinhole aperture, while the PET absolute sensitivity was 3.2% for 350-650keV and 3.432ns. Accordingly, the volume sensitivity of PET was three orders of magnitude higher than that of SPECT. This integrated PET/SPECT/CT system showed high performance with excellent spatial resolution for SPECT and sensitivity for PET. Based on the tracer availability and system performance, SPECT and PET have complementary roles in multimodality small-animal imaging.

Performance study of a fan beam collimator designed for a multi-modality small animal imaging device

This paper describes the methodology to design and conduct the performances of a fan beam collimator. This fan beam collimator was designed to use with a multi-modality small animal imaging device and the performance of the collimator was studied for a 3D geometry. Analytical expressions were formulated to calculate the parameters for the collimator. A Monte Carlo model was developed to analyze the scattering and image noises for a 3D object. The results showed that the performance of the fan beam collimator was strongly dependent on the source distribution and position. The fan beam collimator showed increased counting efficiency in comparison to a parallel hole collimator. Inside attenuating medium, the increased attenuating effect outweighed the fan beam increased counting efficiency.

Articulated Whole-Body Atlases for Small Animal Image Analysis: Construction and Applications

PurposeUsing three publicly available small-animal atlases (Sprague–Dawley rat, MOBY, and Digimouse), we built three articulated atlases and present several applications in the scope of molecular imaging.ProceduresMajor bones/bone groups were manually segmented for each atlas skeleton. Then, a kinematic model for each atlas was built: each joint position was identified and the corresponding degrees of freedom were specified.ResultsThe articulated atlases enable automated registration into a common coordinate frame of multimodal small-animal imaging data. This eliminates the postural variability (e.g., of the head, back, and front limbs) that occurs in different time steps and due to modality differences and nonstandardized acquisition protocols.ConclusionsThe articulated atlas proves to be a useful tool for multimodality image combination, follow-up studies, and image processing in the scope of molecular imaging. The proposed models were made publicly available.

Registration Method for the Detection of Tumors in Lung and Liver Using Multimodal Small Animal Imaging

Small animal PET scanning with <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">18</sup> F-FDG has been increasingly used in the studies using murine tumor models. The aim of this study was to obtain multimodal tumor images with the use of small animal PET and clinical CT by using hardware guidance and a registration method. PET imaging studies were performed with a dedicated small animal PET scanner. Static PET images of mice with liver and lung tumors were scanned for 20 minute by the use of hardware guidance with 1% activity of the injected dose. The CT images obtained with the use of a clinical CT scanner can be used to improve the anatomical localization of uptake in PET images. <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">124</sup> I -FIAU-PET was obtained from mice containing an orthotopic hepatocellular carcinoma (HCC). Contrast enhanced CT images were obtained at three hours after injection of contrast agent. The PET and CT images were fused using hardware fiducial markers that were manually identified in both data sets. The PET and CT images were precisely registered by the use of a small animal contour point in both data sets to perform a point-based rigid registration. The registered images in the HCC model and a lung metastatic tumor model showed good agreement of tumor region on the both PET and CT images. The use of PET and contrast enhanced CT allowed a precise and improved detection of tumors in liver and lung models. Multimodal imaging with small animal PET and clinical CT images was useful in the detection of metastatic tumors and this multimodal imaging registration method can improve the quantitative accuracy and interpretation of tracer.

Immobilization using dental material casts facilitates accurate serial and multimodality small animal imaging

Custom disposable patient immobilization systems that conform to the patient's body contours are commonly used to facilitate accurate repeated patient setup for imaging and treatment in radiation therapy. However, in small-animal imaging, immobilization is often overlooked or done in a way that is not conducive to reproducible positioning. This has a negative impact on the potential for accurate analysis of serial or multimodality imaging. We present the use of vinyl polysiloxane dental impression material for immobilization of mice for imaging. Four different materials were examined to identify any potential artifacts using magnetic resonance techniques. A water phantom placed inside the cast was used at 4.7 T with magnetic resonance imaging and showed no effect at the center of the image when compared with images without the cast. A negligible effect was seen near the ends of the coil. Each material had no detectable signal using electron paramagnetic resonance imaging at 9 mT. The use of dental material also greatly enhances the use of fiducial markers that can be embedded in the mold. Therefore, image registration is simplified as the immobilization of the animal and fiducials together helps in translating from one image coordinate system to another.

A Three-Dimensional Registration Method for MicroUS/MicroPET Multimodality Small-Animal Imaging

Small-animal models are used extensively in disease research, genomics research, drug development and developmental biology. The development of noninvasive small-animal imaging techniques with adequate spatial resolution and sensitivity is therefore of prime importance. In particular, multimodality small-animal imaging can provide complementary information. This paper presents a method for registering high-frequency ultrasonic (microUS) images with small-animal positron-emission tomography (microPET) images. Registration is performed using six external multimodality markers, each being a glass bead with a diameter of 0.43-0.60 mm, with 0.1 microl of [18F]FDG placed in each marker holder. A small-animal holder is used to transfer mice between the microPET and microUS systems. Multimodality imaging was performed on C57BL/6J black mice bearing WF-3 ovary cancer cells in the second week after tumor implantation and rigid-body image registration of the six markers was also performed. The average registration error was 0.31 mm when all six markers were used and increased as the number of markers decreased. After image registration, image segmentation and fusion are performed on the tumor. Our multimodality small-animal imaging method allows structural information from microUS to be combined with functional information from microPET, with the preliminary results showing it to be an effective tool for cancer research.

WE‐D‐I‐609‐08: Multimodality Small Animal Imaging: Registration of Functional EPR Images with MRI Anatomy

Purpose: Electron paramagnetic resonance imaging (EPRI) is a spectroscopic imaging modality being developed for functional and molecular imaging in small animals, and has potential for ultimate translation to clinical imaging. By utilizing contrast agents (“spin probes”) whose EPR spectra are modified by the local environment, it is possible to produce images which directly measure important physiologic quantities. In studies of tumor response to radiation‐mediated gene therapy we have utilized EPR oxygen images, which provide 3D oxygen maps with resolution of ∼1mm spatially and ∼3 Torr in oxygen partial pressure. Like functional nuclear medicine images, EPR oxygen images do not depict anatomy directly. Analysis is facilitated by the ability to use an anatomic image as a “roadmap” for interpretation of the functional images. We have developed methods for registration of EPRI with MRI to allow anatomically‐based analysis of these functional images. Method and Materials: EPRI is performed using locally developed spectroscopic imaging systems. MRI is performed on a 4.7T dedicated small animal system. Several registration techniques have been newly developed or adapted from clinical multimodality imaging. Fiducial markers visible in both EPRI and MRI can be attached to the animal or to the immobilization device. Simple point‐to‐point registration is possible using this method. Surface‐based and intensity‐based registration methods have also been applied. Customized immobilization devices are fabricated using a polymer dental impression material, analogous to foam cradles used in radiotherapy. Results: Both anatomically directed analysis of functional EPR images and analysis of serial changes in defined anatomical regions during a course of therapy are enabled by the use of customized immobilization and anatomic/functional image registration. Conclusion: Image registration is critical for accurate interpretation of multimodality anatomic/functional small animal imaging. Techniques analogous to those in clinical use can be used with success in this setting.

Non-Invasive imaging of small-animal tumors: high-frequency ultrasound vs. MicroPET.

Tumor volume measurement on small animals is important but currently invasive. We employ ultrasonic micro-imaging (UMI) in this study and demonstrate its feasibility. In addition, we use small animal positron emission tomography (microPET) as a preliminary effort to develop multi-modality small animal imaging techniques. The tumor growth curve from UMI is also compared to radioactivity from microPET. Both UMI and [18F] FDG microPET imaging were performed on C57BL/6J black mice bearing WF-3 ovary cancer cells at various stages from the second week till up to the eighth week. Segmentation and 3D reconstruction were also done. The growth curve was obtained in vivo noninvasively by UMI. The cell doubling time was 7.46 days according to UMI. This result was compared with vernier caliper measurement and radioactivity counting by microPET. In microPET, we obtained the time-activity curves from the tumor and the tumor-surrounding tissue. The tumor-to-normal-tissues ratios reached maximum at the fifth week after tumor cell implantation.