Whole-Body Imaging Using Low Frequency Transmission Ultrasound.

RATIONALE AND OBJECTIVES: To indicate that 3D low-frequency ultrasound tomography with 3D data acquisition (volography) is a safe, low-cost, high-resolution, whole-body meso-scale medical imaging modality that gives high-resolution quantitatively accurate clinically relevant images. MATERIALS AND METHODS: We compare the speed of sound accuracy in various organs in situ. We validate our 3D ultrasound tomography images using MRI and gross section anatomy as ground truth in 10-day old piglets. Data acquisition is accomplished with the QT Scanner at ∼1 MHz center frequency, and array transceivers for reflection data @3.6 MHz. Images are generated with unique model-based 3D ultrasound tomography algorithms. In reflection, we use 3D refraction-corrected ray tracing to allow 360° compounding with sub-mm resolution. Four 10-12 day old pigs were anesthetized and whole-body images were acquired via low-frequency transmitted ultrasound and 3T MRI. RESULTS: Tissue values were within an average of 1.07% (0.5%) of the literature values. We also show the detailed correlation of our images with MRI images in axial, coronal, and sagittal views. Volography images of a piglet show high resolution and quantitative accuracy, showing more contrast &resolution than 3T MRI, including the kidney showing medulla, cortex and fibrous cover, and small intestines with ileal lumen detail visible. CONCLUSION: We establish that 3D ultrasound tomography (volography), yields high-resolution quantitatively accurate images whole-body images in presence of bone and air which are potentially clinically useful but have not appeared in the literature.

Natural History of Cardiomyopathy in Adult Dogs With Golden Retriever Muscular Dystrophy.

Background Duchenne muscular dystrophy (DMD) is an X-linked disease that causes progressive muscle weakness. Affected boys typically die from respiratory or cardiac failure. Golden retriever muscular dystrophy (GRMD) is genetically homologous with DMD and causes analogous skeletal and cardiac muscle disease. Previous studies have detailed features of GRMD cardiomyopathy in mostly young dogs. Cardiac disease is not well characterized in adult GRMD dogs, and cardiac magnetic resonance (CMR) imaging studies have not been completed. Methods and Results We evaluated echocardiography and CMR in 24 adult GRMD dogs at different ages. Left ventricular systolic and diastolic functions, wall thickness, and myocardial strain were assessed with echocardiography. Features evaluated with CMR included left ventricular function, chamber size, myocardial mass, and late gadolinium enhancement. Our results largely paralleled those of DMD cardiomyopathy. Ejection fraction and fractional shortening correlated well with age, with systolic dysfunction occurring at ≈30 to 45 months. Circumferential strain was more sensitive than ejection fraction in early disease detection. Evidence of left ventricular chamber dilatation provided proof of dilated cardiomyopathy. Late gadolinium enhancement imaging showed DMD-like left ventricular lateral wall lesions and earlier involvement of the anterior septum. Multiple functional indexes were graded objectively and added, with and without late gadolinium enhancement, to give cardiac and cardiomyopathy scores of disease severity. Consistent with DMD, there was parallel skeletal muscle involvement, as tibiotarsal joint flexion torque declined in tandem with cardiac function. Conclusions This study established parallels of progressive cardiomyopathy between dystrophic dogs and boys, further validating GRMD as a model of DMD cardiac disease.

Quantitative assessment of breast density using transmission ultrasound tomography.

PURPOSE: Breast density is important in the evaluation of breast cancer risk. At present, breast density is evaluated using two-dimensional projections from mammography with or without tomosynthesis using either (a) subjective assessment or (b) a computer-aided approach. The purpose of this work is twofold: (a) to establish an algorithm for quantitative assessment of breast density using quantitative three-dimensional transmission ultrasound imaging; and (b) to determine how these quantitative assessments compare with both subjective and objective mammographic assessments of breast density. METHODS: We described and verified a threshold-based segmentation algorithm to give a quantitative breast density (QBD) on ultrasound tomography images of phantoms of known geometric forms. We also used the algorithm and transmission ultrasound tomography to quantitatively determine breast density by separating fibroglandular tissue from fat and skin, based on imaged, quantitative tissue characteristics, and compared the quantitative tomography segmentation results with subjective and objective mammographic assessments. RESULTS: Quantitative breast density (QBD) measured in phantoms demonstrates high quantitative accuracy with respect to geometric volumes with average difference of less than 0.1% of the total phantom volumes. There is a strong correlation between QBD and both subjective mammographic assessments of Breast Imaging - Reporting and Data System (BI-RADS) breast composition categories and Volpara density scores - the Spearman correlation coefficients for the two comparisons were calculated to be 0.90 (95% CI: 0.71-0.96) and 0.96 (95% CI: 0.92-0.98), respectively. CONCLUSIONS: The calculation of breast density using ultrasound tomography and the described segmentation algorithm is quantitatively accurate in phantoms and highly correlated with both subjective and Food and Drug Administration (FDA)-cleared objective assessments of breast density.

Quantitative transmission ultrasound tomography: Imaging and performance characteristics.

PURPOSE: Quantitative Transmission (QT) ultrasound has shown promise as a breast imaging modality. This study characterizes the performance of the latest generation of QT ultrasound scanners: QT Scanner 2000. METHODS: The scanner consists of a 2048-element ultrasound receiver array for transmission imaging and three transceivers for reflection imaging. Custom fabricated phantoms were used to quantify the imaging performance parameters. The specific performance parameters that have been characterized are spatial resolution (as point spread function), linear measurement accuracy, contrast to noise ratio, and image uniformity, in both transmission and reflection imaging modalities. RESULTS: The intrinsic in-plane resolution was measured to be better than 1.5 mm and 1.0 mm for transmission and reflection modalities respectively. The linear measurement accuracy was measured to be, on average, approximately 1% for both the modalities. Speed of sound image uniformity and measurement accuracy were calculated to be 99.5% and <0.2% respectively. Contrast to noise ratio (CNR) measurements vary as a function of object size. CONCLUSIONS: The results show an improvement in the imaging performance of the system in comparison to earlier ultrasound tomography systems, which are applicable to clinical applications of the system, such as breast imaging.

3-D Nonlinear Acoustic Inverse Scattering: Algorithm and Quantitative Results.

We describe a novel 3-D ultrasound technology, the quantitative transmission ultrasound system and algorithm to image a pendent breast in a water bath. Quantitative accuracy is verified using phantoms. Morphological accuracy is verified using cadaveric breast and in vivo images, and spatial resolution is estimated. This paper generalizes an earlier 2-D algorithm to a full 3-D inversion algorithm and shows the importance of such a 3-D algorithm for artifact suppression as compared with the 2-D algorithm. The resultant high-resolution ultrasound images, along with quantitative information regarding tissue speed of sound/stiffness, provide a more accurate depiction of the breast anatomy and lesions, contributing to improved breast care.

Objective breast tissue image classification using Quantitative Transmission ultrasound tomography.

Quantitative Transmission Ultrasound (QT) is a powerful and emerging imaging paradigm which has the potential to perform true three-dimensional image reconstruction of biological tissue. Breast imaging is an important application of QT and allows non-invasive, non-ionizing imaging of whole breasts in vivo. Here, we report the first demonstration of breast tissue image classification in QT imaging. We systematically assess the ability of the QT images' features to differentiate between normal breast tissue types. The three QT features were used in Support Vector Machines (SVM) classifiers, and classification of breast tissue as either skin, fat, glands, ducts or connective tissue was demonstrated with an overall accuracy of greater than 90%. Finally, the classifier was validated on whole breast image volumes to provide a color-coded breast tissue volume. This study serves as a first step towards a computer-aided detection/diagnosis platform for QT.

Maternal choline supplementation in a sheep model of first trimester binge alcohol fails to protect against brain volume reductions in peripubertal lambs.

Fetal alcohol spectrum disorder (FASD) is a leading potentially preventable birth defect. Poor nutrition may contribute to adverse developmental outcomes of prenatal alcohol exposure, and supplementation of essential micronutrients such as choline has shown benefit in rodent models. The sheep model of first-trimester binge alcohol exposure was used in this study to model the dose of maternal choline supplementation used in an ongoing prospective clinical trial involving pregnancies at risk for FASD. Primary outcome measures including volumetrics of the whole brain, cerebellum, and pituitary derived from magnetic resonance imaging (MRI) in 6-month-old lambs, testing the hypothesis that alcohol-exposed lambs would have brain volume reductions that would be ameliorated by maternal choline supplementation. Pregnant sheep were randomly assigned to one of five groups - heavy binge alcohol (HBA; 2.5 g/kg/treatment ethanol), heavy binge alcohol plus choline supplementation (HBC; 2.5 g/kg/treatment ethanol and 10 mg/kg/day choline), saline control (SC), saline control plus choline supplementation (SCC; 10 mg/kg/day choline), and normal control (NC). Ewes were given intravenous alcohol (HBA, HBC; mean peak BACs of ∼280 mg/dL) or saline (SC, SCC) on three consecutive days per week from gestation day (GD) 4-41; choline was administered on GD 4-148. MRI scans of lamb brains were performed postnatally on day 182. Lambs from both alcohol groups (with or without choline) showed significant reductions in total brain volume; cerebellar and pituitary volumes were not significantly affected. This is the first report of MRI-derived volumetric brain reductions in a sheep model of FASD following binge-like alcohol exposure during the first trimester. These results also indicate that maternal choline supplementation comparable to doses in human studies fails to prevent brain volume reductions typically induced by first-trimester binge alcohol exposure. Future analyses will assess behavioral outcomes along with regional brain and neurohistological measures.

Anatomy-Correlated Breast Imaging and Visual Grading Analysis Using Quantitative Transmission Ultrasound™.

Objectives. This study presents correlations between cross-sectional anatomy of human female breasts and Quantitative Transmission (QT) Ultrasound, does discriminate classifier analysis to validate the speed of sound correlations, and does a visual grading analysis comparing QT Ultrasound with mammography. Materials and Methods. Human cadaver breasts were imaged using QT Ultrasound, sectioned, and photographed. Biopsies confirmed microanatomy and areas were correlated with QT Ultrasound images. Measurements were taken in live subjects from QT Ultrasound images and values of speed of sound for each identified anatomical structure were plotted. Finally, a visual grading analysis was performed on images to determine whether radiologists' confidence in identifying breast structures with mammography (XRM) is comparable to QT Ultrasound. Results. QT Ultrasound identified all major anatomical features of the breast, and speed of sound calculations showed specific values for different breast tissues. Using linear discriminant analysis overall accuracy is 91.4%. Using visual grading analysis readers scored the image quality on QT Ultrasound as better than on XRM in 69%-90% of breasts for specific tissues. Conclusions. QT Ultrasound provides accurate anatomic information and high tissue specificity using speed of sound information. Quantitative Transmission Ultrasound can distinguish different types of breast tissue with high resolution and accuracy.

Imaging Performance of Quantitative Transmission Ultrasound.

Quantitative Transmission Ultrasound (QTUS) is a tomographic transmission ultrasound modality that is capable of generating 3D speed-of-sound maps of objects in the field of view. It performs this measurement by propagating a plane wave through the medium from a transmitter on one side of a water tank to a high resolution receiver on the opposite side. This information is then used via inverse scattering to compute a speed map. In addition, the presence of reflection transducers allows the creation of a high resolution, spatially compounded reflection map that is natively coregistered to the speed map. A prototype QTUS system was evaluated for measurement and geometric accuracy as well as for the ability to correctly determine speed of sound.

Computed tomography assessment of peripubertal craniofacial morphology in a sheep model of binge alcohol drinking in the first trimester.

Identification of facial dysmorphology is essential for the diagnosis of fetal alcohol syndrome (FAS); however, most children with fetal alcohol spectrum disorders (FASD) do not meet the dysmorphology criterion. Additional objective indicators are needed to help identify the broader spectrum of children affected by prenatal alcohol exposure. Computed tomography (CT) was used in a sheep model of prenatal binge alcohol exposure to test the hypothesis that quantitative measures of craniofacial bone volumes and linear distances could identify alcohol-exposed lambs. Pregnant sheep were randomly assigned to four groups: heavy binge alcohol, 2.5 g/kg/day (HBA); binge alcohol, 1.75 g/kg/day (BA); saline control (SC); and normal control (NC). Intravenous alcohol (BA; HBA) or saline (SC) infusions were given three consecutive days per week from gestation day 4-41, and a CT scan was performed on postnatal day 182. The volumes of eight skull bones, cranial circumference, and 19 linear measures of the face and skull were compared among treatment groups. Lambs from both alcohol groups showed significant reduction in seven of the eight skull bones and total skull bone volume, as well as cranial circumference. Alcohol exposure also decreased four of the 19 craniofacial measures. Discriminant analysis showed that alcohol-exposed and control lambs could be classified with high accuracy based on total skull bone volume, frontal, parietal, or mandibular bone volumes, cranial circumference, or interorbital distance. Total skull volume was significantly more sensitive than cranial circumference in identifying the alcohol-exposed lambs when alcohol-exposed lambs were classified using the typical FAS diagnostic cutoff of ≤10th percentile. This first demonstration of the usefulness of CT-derived craniofacial measures in a sheep model of FASD following binge-like alcohol exposure during the first trimester suggests that volumetric measurement of cranial bones may be a novel biomarker for binge alcohol exposure during the first trimester to help identify non-dysmorphic children with FASD.

Dosimetry of a (90)Y-hydroxide liquid brachytherapy treatment approach to canine osteosarcoma using PET/CT.

A new treatment strategy based on direct injections of (90)Y-hydroxide into the tumor bed in dogs with osteosarcoma was studied. Direct injections of the radiopharmaceutical into the tumor bed were made according to a pretreatment plan established using (18)F-FDG images. Using a special drill, cannulas were inserted going through tissue, tumor and bone. Using these cannulas, direct injections of the radiopharmaceutical were made. The in vivo biodistribution of (90)Y-hydroxide and the anatomical tumor bed were imaged using a time-of-flight (TOF) PET/CT scanner. The material properties of the tissues were estimated from corresponding CT numbers using an electron-density calibration. Radiation absorbed dose estimates were calculated using Monte Carlo methods where the biodistribution of the pharmaceutical from PET images was sampled using a collapsing 3-D rejection technique. Dose distributions in the tumor bed and surrounding tissues were calculated, showing significant heterogeneity with multiple hot spots at injection sites. Dose volume histograms showed that approximately 33.9% of bone and tumor and 70.2% of bone marrow and trabecular bone received an absorbed dose over 200Gy; approximately 3.2% of bone and tumor and 31.0% of bone marrow and trabecular bone received a total dose of over 1000Gy.

Improving paclitaxel delivery: in vitro and in vivo characterization of PEGylated polyphosphoester-based nanocarriers.

Nanomaterials have great potential to offer effective treatment against devastating diseases by providing sustained release of high concentrations of therapeutic agents locally, especially when the route of administration allows for direct access to the diseased tissues. Biodegradable polyphosphoester-based polymeric micelles and shell cross-linked knedel-like nanoparticles (SCKs) have been designed from amphiphilic block-graft terpolymers, PEBP-b-PBYP-g-PEG, which effectively incorporate high concentrations of paclitaxel (PTX). Well-dispersed nanoparticles physically loaded with PTX were prepared, exhibiting desirable physiochemical characteristics. Encapsulation of 10 wt% PTX, into either micelles or SCKs, allowed for aqueous suspension of PTX at concentrations up to 4.8 mg/mL, as compared to <2.0 µg/mL for the aqueous solubility of the drug alone. Drug release studies indicated that PTX released from these nanostructures was defined through a structure-function relationship, whereby the half-life of sustained PTX release was doubled through cross-linking of the micellar structure to form SCKs. In vitro, physically loaded micellar and SCK nanotherapeutics demonstrated IC50 values against osteosarcoma cell lines, known to metastasize to the lungs (CCH-OS-O and SJSA), similar to the pharmaceutical Taxol formulation. Evaluation of these materials in vivo has provided an understanding of the effects of nanoparticle structure-function relationships on intratracheal delivery and related biodistribution and pharmacokinetics. Overall, we have demonstrated the potential of these novel nanotherapeutics toward future sustained release treatments via administration directly to the sites of lung metastases of osteosarcoma.

The effects of continuous and intermittent reduced speed modes on renal and intestinal perfusion in an ovine model.

The effects of the continuous-flow output on renal and intestinal microcirculation have not been extensively studied. To address this, the Heartware HVAD pump loaded with continuous and intermittent reduced speed (IRS) modes was implanted in four sheep and then operated at low and high speeds to mimic partial and complete unloading of the left ventricle. Then microsphere and positron emission tomography/computed tomography (PET/CT) studies were used to assess renal and intestinal tissue perfusion at various pump speeds and flow modes as compared with baseline (pump off). Arterial and venous oxygen (T02) and carbon dioxide (TCO2) contents were measured to assess changes in intestinal metabolism. Renal and intestinal regional blood flows did not produce any significant changes compared with baseline values in either continuous or IRS modes and speeds. The venous TO2 and TCO2 significantly increased in continuous and IRS modes and speeds compared with baseline. Our data suggested that renal and intestinal tissue perfusions were not adversely affected by continuous and IRS modes either in partial or complete unloading. Intestinal venous hyperoxia and increased TCO2 may be the evidence of intestinal arteriovenous shunting along with increased intestinal tissue metabolism. Longer-term studies are warranted in chronic heart failure models.

MR angiography of carotid artery aneurysms in a porcine model at 3 Tesla: comparison of two different macrocyclic gadolinium chelates and of dynamic and conventional techniques.

PURPOSE: To evaluate the differences in image quality of two macrocyclic gadolinium-based contrast agents, gadobutrol and gadoterate meglumine, using time-resolved, contrast-enhanced MR angiography (CE-MRA) in a porcine carotid artery aneurysm model and to compare image quality between dynamic and conventional, single acquisition CE-MRA. MATERIALS AND METHODS: Bilateral carotid aneurysms were created surgically in this Institutional Animal Care and Use Committee approved study. Dynamic CE-MRA studies optimized for high temporal resolution were performed at 3 Tesla. Scans using equivalently dosed (on a per mmol basis) gadobutrol and gadoterate meglumine were compared qualitatively and quantitatively in terms of contrast-to-noise ratio (CNR). Higher spatial resolution dynamic and conventional CE-MRA were also compared. RESULTS: N = 16 aneurysms were assessed. Qualitative evaluation of dynamic CE-MRA scans demonstrated a preference for gadobutrol over gadoterate meglumine. Significantly higher aneurysm CNR was found with gadobutrol (133 ± 44) versus gadoterate meglumine, the latter at both equivalent and double injection rates (94 ± 35 and 102 ± 38). In a blinded assessment, conventional CE-MRA was preferred qualitatively when compared with dynamic CE-MRA. However, dynamic CE-MRA was generally capable of providing diagnostic image quality. CONCLUSION: Gadobutrol is preferred to gadoterate meglumine for high temporal resolution dynamic CE-MRA, a fact with important clinical implications for low dose CE-MRA protocols in patients at risk for nephrogenic systemic fibrosis. Conventional high resolution CE-MRA provides superior image quality when compared with dynamic CE-MRA.

NEMA NU 2-2007 performance measurements of the Siemens Inveon preclinical small animal PET system.

National Electrical Manufacturers Association (NEMA) NU 2-2007 performance measurements were conducted on the Inveon preclinical small animal PET system developed by Siemens Medical Solutions. The scanner uses 1.51 x 1.51 x 10 mm LSO crystals grouped in 20 x 20 blocks; a tapered light guide couples the LSO crystals of a block to a position-sensitive photomultiplier tube. There are 80 rings with 320 crystals per ring and the ring diameter is 161 mm. The transaxial and axial fields of view (FOVs) are 100 and 127 mm, respectively. The scanner can be docked to a CT scanner; the performance characteristics of the CT component are not included herein. Performance measurements of spatial resolution, sensitivity, scatter fraction and count rate performance were obtained for different energy windows and coincidence timing window widths. For brevity, the results described here are for an energy window of 350-650 keV and a coincidence timing window of 3.43 ns. The spatial resolution at the center of the transaxial and axial FOVs was 1.56, 1.62 and 2.12 mm in the tangential, radial and axial directions, respectively, and the system sensitivity was 36.2 cps kBq(-1) for a line source (7.2% for a point source). For mouse- and rat-sized phantoms, the scatter fraction was 5.7% and 14.6%, respectively. The peak noise equivalent count rate with a noisy randoms estimate was 1475 kcps at 130 MBq for the mouse-sized phantom and 583 kcps at 74 MBq for the rat-sized phantom. The performance measurements indicate that the Inveon PET scanner is a high-resolution tomograph with excellent sensitivity that is capable of imaging at a high count rate.

Metabolic rates in small brain nuclei determined by high-resolution PET.

UNLABELLED: Identification of small nuclei in the brain by PET has been limited by the spatial resolution of conventional scanners. The new detector technology and advanced signal analysis of a high-resolution research tomograph (HRRT) has improved 3-dimensional spatial resolution to 2.2 mm at sufficient efficiency and permitted the quantification of tracer concentrations in small volumes. METHODS: In 9 healthy volunteers, cerebral glucose metabolism was investigated after intravenous injection of 370 MBq of (18)F-FDG, and regional cerebral metabolic rates for glucose (rCMRGlc) were determined in various structures of the brain identified on coregistered MR images using stereotactic and topographic anatomic information. RESULTS: rCMRGlc values (in mumol/100 g/min) were higher in the cerebral cortex (33.5 +/- 2.98), the basal ganglia (32.6 +/- 3.04 in the nucleus caudatus and 40.2 +/- 3.50 in the putamen), the thalamus (36.6 +/- 4.72), and the cerebellum (29.8 +/- 2.20) and were lower in the cerebral white matter (12.3 +/- 1.45) than those reported previously with conventional scanners. This resulted in an increased ratio of cortical values to white-matter values. Various nuclei in the basal frontal lobe (21.4 +/- 3.19 in the basal forebrain and 32.3 +/- 2.39 in the nucleus accumbens), the temporal lobe (22.2 +/- 1.74 in the corpus amygdalae), the hippocampus (25.7 +/- 2.11), the diencephalon (23.1 +/- 3.33 in the corpus geniculatum laterale, 20.2 +/- 2.87 in the corpus geniculatum mediale, and 25.2 +/- 3.29 in the nucleus subthalamicus), and the brain stem (24.4 +/- 2.47 in the colliculus superior, 31.4 +/- 3.63 in the colliculus inferior, 31.0 +/- 3.10 in the nucleus ruber, and 22.8 +/- 2.35 in the substantia nigra) could be identified, and the metabolic rate was assessed in these structures. The effect of improved spatial resolution on quantified metabolic rates could directly be demonstrated in a few cases investigated on scanners of different generations. CONCLUSION: The improved spatial resolution of the HRRT decreased partial-volume effects in the quantification of metabolic rates in the brain and increased the accuracy of rCMRGlc values in large structures. For the first time, this scanner has permitted the determination of metabolic rates in small nuclei that are involved in various neurodegenerative disorders.