Contrast Agents In Conjunction Research Articles

Cerebral Vascular Density and Its Possible Correlation with Alzheimer Disease Progression in Elderly Individuals with Rheumatoid Arthritis

BackgroundRheumatoid Arthritis (RA) is characterized by chronic systemic inflammation, primarily affecting the joints. In RA patients, high concentrations of inflammatory cytokines are found within the synovial fluid and serum (PMID: 1700672). These cytokines reduce the blood brain barrier (BBB) integrity by decreasing the expression of tight junction proteins (PMID: 29910805). In a RA animal model such decreased BBB integrity has been shown to affect the transport of amyloid beta peptide (Aβ) between the peripheral circulation and the brain, thereby promoting accumulation of Aβ within the cerebral vasculature followed by the endothelial cell degeneration (PMID: 22029666). In humans, a similar pathologic process is a major risk factor for Alzheimer’s Disease (AD) which accelerates neuronal loss and cognitive impairment associated with AD (PMID: 29377008). Assessment of cerebral vascular density is an emerging modality for detection and monitoring the progression of cerebrovascular disease (CVD) (PMID: 15564412). Advancements in computed tomography (CT) imaging technology and the development of novel contrast agents should provide more accurate assessment for CVD in humans.The main objective of this study was to test high‐resolution CT imaging using a recently developed BriteVu contrast agent in conjunction with conventional histological techniques for postmortem assessment of CVD and pathology in the cerebral cortex and hippocampus of two male cadavers. The first, 74‐year‐old (D1) was diagnosed with RA and AD, while the second, 90‐year‐old (D2) had RA.ResultsThe D1 and D2 cadavers were fixed and perfused with BriteVu contrast agent. Heads were removed and scanned with a VimagoGT30 CT scanner at 300 µm. The images were subjected to volumetric analysis using Radiant software. The results showed that scans of the cerebral cortex from D2, specifically the middle frontal, inferior parietal, and superior temporal gyri, had significantly lower mean Hounsfield unit densities (MHUD) than those from the same regions of D1. The MHUD from the hippocampal scans revealed no significant difference. The lower MHUD count in the D2 cortex in comparison to D1 most likely reflects a lower vascular density in the respective brain region. The AD related pathology in both donors was assessed by histochemical and immunohistochemical techniques. To that end, the brains were extracted and fixed in formalin solution for 12‐16 weeks. The brain hippocampal and cortical sections were paraffin processed followed by H&E and immunohistochemical staining for Aβ 1‐42, phospho‐tau, and phospho‐TDP‐43. Analysis of the data confirmed the AD diagnosis in D1 and demonstrated distinct AD pathology in D2. The AD staging could be characterized as mild in D1 and intermediate in D2.Conclusionsi) The vascular density within the cerebral cortex of elderly individuals with RA could correlate with the AD progression. ii) The adaptation of the reported CT imaging technique for its use in live individuals could provide more sensitive and accurate method for assessing AD in RA patients at the early AD stage(s).

Towards controlled drug delivery in brain tumors with microbubble-enhanced focused ultrasound.

Brain tumors are particularly challenging malignancies, due to their location in a structurally and functionally distinct part of the human body - the central nervous system (CNS). The CNS is separated and protected by a unique system of brain and blood vessel cells which together prevent most bloodborne therapeutics from entering the brain tumor microenvironment (TME). Recently, great strides have been made through microbubble (MB) ultrasound contrast agents in conjunction with ultrasound energy to locally increase the permeability of brain vessels and modulate the brain TME. As we elaborate in this review, this physical method can effectively deliver a wide range of anticancer agents, including chemotherapeutics, antibodies, and nanoparticle drug conjugates across a range of preclinical brain tumors, including high grade glioma (glioblastoma), diffuse intrinsic pontine gliomas, and brain metastasis. Moreover, recent evidence suggests that this technology can promote the effective delivery of novel immunotherapeutic agents, including immune check-point inhibitors and chimeric antigen receptor T cells, among others. With early clinical studies demonstrating safety, and several Phase I/II trials testing the preclinical findings underway, this technology is making firm steps towards shaping the future treatments of primary and metastatic brain cancer. By elaborating on its key components, including ultrasound systems and MB technology, along with methods for closed-loop spatial and temporal control of MB activity, we highlight how this technology can be tuned to enable new, personalized treatment strategies for primary brain malignancies and brain metastases.

Concurrent Assessment of Cartilage Morphology and Bone Microarchitecture in the Human Knee Using Contrast-Enhanced HR-pQCT Imaging

Osteoarthritis (OA) is a prevalent articular disease characterized by whole joint degradation, including articular cartilage and bone. Presently, no single imaging modality is well suited to concurrently capture these changes. Recent ex vivo animal studies have demonstrated the efficacy of utilizing contrast agents in conjunction with micro-CT as a means of evaluating cartilage and bone alterations concurrently, though no work as of yet has been performed in large animal models or humans. This study sought to develop and validate a novel joint imaging technique, contrast enhanced high resolution peripheral quantitative computed tomography (CEHR-pQCT), to concurrently assess bone microarchitecture and cartilage morphology in the whole human knee. Fresh frozen cadaveric knees were harvested (n = 10) and scanned using magnetic resonance imaging (MRI), HR-pQCT without contrast, and HR- pQCT following intra-articular injection of nonionic contrast media. Cartilage morphology and bone microarchitecture were evaluated in weight bearing regions of interest in both the tibia and femur. Joints were then disarticulated, and the articular cartilage thickness measured by needle probe. Measures of cartilage morphology, thickness and volume, were found to be significantly less when measured by CEHR- pQCT compared to magnetic resonance imaging in all regions. Compared to needle probing, cartilage thickness measured by CEHR-pQCT was less in the lateral tibia and greater in the medial tibia. Bone microarchitecture was found to be significantly different when measured with CEHR-pQCT compared to HR-pQCT, where cortical bone mineral density (BMD) was depressed, and trabecular bone mineral density was greater. This study demonstrates that CEHR-pQCT can be used to concurrently measure cartilage morphology and bone microarchitecture; however, systematic errors impact both measures. This is the first study using contrast media in combination with HR-pQCT in whole joints. Additionally, all imaging parameters, as well as the contrast media, were selected to be directly transferable to in vivo studies, laying the foundation to perform in vivo scanning of knee cartilage and bone.

Contrast-enhanced ultrasound: clinical applications in patients with atherosclerosis.

Contrast-enhanced ultrasound (CEUS) is increasingly being used to evaluate patients with known or suspected atherosclerosis. The administration of a microbubble contrast agent in conjunction with ultrasound results in an improved image quality and provides information that cannot be assessed with standard B-mode ultrasound. CEUS is a high-resolution, noninvasive imaging modality, which is safe and may benefit patients with coronary, carotid, or aortic atherosclerosis. CEUS allows a reliable assessment of endocardial borders, left ventricular function, intracardiac thrombus and myocardial perfusion. CEUS results in an improved detection of carotid atherosclerosis, and allows assessment of high-risk plaque characteristics including intraplaque vascularization, and ulceration. CEUS provides real-time bedside information in patients with a suspected or known abdominal aortic aneurysm or aortic dissection. The absence of ionizing radiation and safety of the contrast agent allow repetitive imaging which is particularly useful in the follow-up of patients after endovascular aneurysm repair. New developments in CEUS-based molecular imaging will improve the understanding of the pathophysiology of atherosclerosis and may in the future allow to image and directly treat cardiovascular diseases (theragnostic CEUS). Familiarity with the strengths and limitations of CEUS may have a major impact on the management of patients with atherosclerosis.

MRT letter: Contrast‐enhanced computed tomographic imaging of soft callus formation in fracture healing

Formation of a cartilaginous soft callus at the site of a bone fracture is a pivotal stage in the healing process. Noninvasive, or even nondestructive, imaging of soft callus formation can be an important tool in experimental and pre-clinical studies of fracture repair. However, the low X-ray attenuation of cartilage renders the soft callus nearly invisible in radiographs. This study utilized a recently developed, cationic, iodinated contrast agent in conjunction with micro-computed tomography to identify cartilage in fracture calluses in the femora of C57BL/6J and C3H/HeJ mice. Fracture calluses were scanned before and after incubation in the contrast agent. The set of pre-incubation images was registered against and then subtracted from the set of post-incubation images, resulting in a three-dimensional map of the locations of cartilage in the callus, as labeled by the contrast agent. This map was then compared to histology from a previous study. The results showed that the locations where the contrast agent collected in relatively high concentrations were similar to those of the cartilage. The contrast agent also identified a significant difference between the two strains of mice in the percentage of the callus occupied by cartilage, indicating that this method of contrast-enhanced computed tomography may be an effective technique for nondestructive, early evaluation of fracture healing.

Safety and positive predictive value of high-dose dipyridamole stress-echocardiography with or without contrast flash-replenishment perfusion imaging in patients with suspected or known coronary artery disease

⁎ Corresponding author at: Parma University Hospital, Cardiology Department, Via Gramsci, 14-43100 PARMA, Italy. E-mail address: ngaibazzi@gmail.com (N. Gaibazzi). A growing body of literature has demonstrated the safety of ultrasound contrast agents in conjunction with low mechanical-index imaging during echocardiography, although most studies reported on contrast use during rest echocardiography for left ventricle opacification and rarely on its use during stress-echo (SE) with flash-replenishment myocardial perfusion imaging (MPI). Flash-replenishment sequences, bymeans of high-mechanical index pulses, represent a specificmodel of interaction among ultrasound, microbubbles and myocardial tissue, which could theoretically portend specific safety concerns. We retrospectivelyanalyzedour prospectively collected SEdatabase to evaluate the safetyof a contrast agent (SonoVue©Bracco Imaging Italia srl, Milan, Italy) routinely administered for flash-replenishment high-dose (0.84 mg/kg) dipyridamole echocardiography (cDipSE) and compared this cDipSE groupwith a reference cohortwho underwent standard highdose dipyridamole echocardiography without contrast administration (sDipSE) in the same time frame. According to CTCAE v3.0 standardized terminology (1), moderate (grade 2), severe (grade 3), life-threatening (grade 4) or deadly (grade 5) adverse events (AEs) were recorded during and after SE directly by the physicianperforming the test and after 24 hby contacting the patient. True and false positive figures for coronary artery disease (CAD) detectionwere also calculated in the selected patients who underwent coronary angiography. The database includes 1953 patients who presented between January 2008 and June 2011 and underwent DipSE with (n=1342) or without contrast, (n=611) for suspected or known CAD. Standard DipSE exclusion criteria were used, while pregnancy, knownallergy to sulfonamides or previous anaphylactoid reactions were considered contraindications to contrast administration (cDipSE). The decision to proceed to coronary angiography after DipSE was left to the referring physician, based on clinical judgment and hence influenced by DipSE results. The primary endpoint of the studywas the short-term safety of DipSE (any AENgrade 1 taking place b24 h after the test) and secondarily of sDipSE compared with cDipSE. ContrastDipSE:PatientswhounderwentDipSEwith contrast andflashreplenishment perfusion imaging were 1342; 771 underwent bolus contrast administration,while 571underwent continuous infusion of contrast using a dedicated rotating pump; repeated 0.5 ml boluses (4 to 5 boluses for each test) or infusion at 0.8–1 ml/minute of SonoVue© was used. Myocardial perfusion was studied activating low-MI power-modulation imaging and acquiring flash-replenishment cine-loops in the apical four, three and two-chamber views. Baseline characteristics of the entire DipSE group and of the 2 subgroups based on the use of contrast administration for flash-replenishment perfusion imaging are shown in Table 1. The demographic data and the prevalence of CAD risk factors did not differ significantly between the 2 subgroups, but there were significantly (pb0.001) more abnormal cDipSE than sDipSE—371/ 1342 (28%) vs 55/611 (9%), which was largely expected due to cDipSE taking advantage of wall motion+perfusion imaging analysis. Table 2 reports AEs in the study groups. No fatalities (AEs grade 5) were recorded during the SE study or in the next 24 h. Three lifeTable 1 Baseline clinical characteristics, stress-echocardiography results and coronary angiography data. DipSE = high-dose dipyridamole echocardiography, sDipSE = standard high-dose dipyridamole echocardiography, cDipSE = contrast flash-replenishment dipyridamole echocardiography, CAD = coronary artery disease, MI = myocardial infarction.

Clinical utility of contrast-enhanced echocardiography.

Over the past three decades, echocardiography has become a major diagnostic tool in the arsenal of clinical cardiology for real-time imaging of cardiac dynamics. More and more, cardiologists' decisions are based on images created from ultrasound wave reflections. From the time ultrasound imaging technology provided the first insight into a human heart, our diagnostic capabilities have increased exponentially as a result of our growing knowledge and developing technologies. One of the most intriguing developments that brought about a decade-long combination of expectations and disappointments was the introduction of echocardiographic contrast agents. Despite repeated waves of controversy regarding the readiness of this technology for clinical use, it has overcome multiple hurdles and currently provides useful clinical information that helps cardiologists to diagnose heart disease accurately. Since the initial reports on the use of ultrasound contrast media such as agitated saline or renografin, the major advances in the field of contrast echocardiography have included (1) the development of stable perfluorocarbon-filled microbubbles, frequently referred to as second-generation contrast agents; and (2) the development of contrast-targeted nonlinear imaging modes, such as harmonic imaging, pulse inversion, and power modulation, which allow consistent real-time visualization of these agents. These contrast agents in conjunction with the new imaging technology constitute powerful tools that improve our ability to evaluate left ventricular function and myocardial perfusion, and allow differential diagnosis of thrombi and intravascular masses. In this manuscript, we briefly review some of the literature that has provided the scientific basis for the use of echocardiographic contrast agents in the context of these important variables.

Targeted ultrasound contrast agents for the imaging of biofilm infections.

Targeted ultrasound contrast agents (UCA) offer a novel, potential method for diagnostic imaging of biofilm infections. Currently, there is no established method for molecular imaging of in vitro biofilm infections with any type of modality. For infective endocarditis, the case of biofilm formation on damaged or diseased heart valves, an early diagnostic method might greatly reduce the associated high mortality rate. Fluorescently labeled lectins were used with targeted ultrasound contrast agents in conjunction with epifluorescence microscopy and time-resolved scanning acoustic microscopy for visualization and characterization of the extracellular polymeric substances (EPS) of two types of infectious biofilms (Staphylococcus aureus and Pseudomonas aeruginosa). Noninvasive acoustic measurements of the biofilms were conducted at high-frequency (100 MHz) with a time-resolved scanning acoustic microscope. Measurements of the reflection and transmission coefficients, over a broad frequency spectrum for a range of biofilm growth stages in both, the presence and absence of targeted UCA were obtained. The biofilm morphology and structure were also investigated with acoustic microscopy as a function of growth. [This work was supported by the National Institutes of Health Grants NIH 2 P20 RR016453-05A1 and NIH 2 G12 RR0030161-21.]

First clinical experience of contrast enhanced digital mammography (CEDM) for the detection of breast carcinomas.

Abstract Abstract #5001 Purpose: CEDM is a recent development of digital mammography using the intra-venous injection of an iodinated contrast agent in conjunction with a mammography examination. The objective of this paper is to present two techniques developed to perform CEDM examinations, the preliminary clinical experiences and potential clinical applications of this new breast imaging procedure.
 Material and methods: Between 2005 and 2008, 140 consenting women with suspicious findings on mammography and or ultrasonography underwent CEDM using modified full-field digital mammography systems (GE Healthcare, Chalfont St-Giles, UK). A temporal subtraction sequence with acquisition of high-energy images before and after contrast medium injection was used for the first 20 patients. A dual energy technique with acquisition of a pair of low and high-energy images only after contrast medium injection was used for the other 120 patients.
 Results: CEDM, either using temporal or dual energy technique, improved the probability of malignancy and the BIRADS assessment compared to conventional mammography alone. The temporal subtraction technique offered the possibility to analyze the kinetic curve of enhancement of breast lesions, similar to breast MRI. Dual energy technique did not provide information about the kinetic of tumor enhancement but allowed the acquisition of multiples views of the same breast or bilateral examination and was less sensitive to patient motion than temporal CEDM. The potential clinical applications are the determination of the extent of disease, the assessment of recurrent disease, the clarification of mammographically equivocal lesions, the detection of occult lesions on standard mammography, particularly in dense breast, and the monitoring of the response to chemotherapy.
 
 
 
 Conclusion: Initial clinical experience has shown the ability of CEDM to map the distribution of neovasculature induced by cancer using mammography. CEDM should result in a simple way to enhance the detection and the characterization of breast lesions and to provide some prognostic factors of breast carcinomas. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5001.

Contrast-enhanced digital mammography

CEDM is a recent development of digital mammography using the intra-venous injection of an iodinated contrast agent in conjunction with a mammography examination. Two techniques have been developed to perform CEDM examinations: the temporal subtraction technique with acquisition of high-energy images before and after contrast medium injection and the dual energy technique with acquisition of a pair of low and high-energy images only after contrast medium injection. The temporal subtraction technique offered the possibility to analyze the kinetic curve of enhancement of breast lesions, similarly to breast MRI. The dual energy technique do not provide information about the kinetic of tumor enhancement but allows the acquisition of multiples views of the same breast or bilateral examination and is less sensitive to patient motion than temporal CEDM. Initial clinical experience has shown the ability of CEDM to map the distribution of neovasculature induced by cancer using mammography. Moreover, previous studies have shown a superiority of MX + CEDM, either for the assessment of the probability of malignancy than for BIRADS assessment comparing to MX alone. The potential clinical applications are the clarification of mammographically equivocal lesions, the detection of occult lesions on standard mammography, particularly in dense breast, the determination of the extent of disease, the assessment of recurrent disease and the monitoring of the response to chemotherapy. CEDM should result in a simple way to enhance the detection and the characterization of breast lesions.

Transcutaneous contrast enhanced sonography of the chest for evaluation of pleural based pulmonary lesions: experience in 137 patients

Transcutaneous ultrasound enables visualization of pleural based lesions but with a poor correlation to specific pathology. Ultrasound contrast agents in conjunction with contrast specific imaging techniques are increasingly accepted in clinical use. Up to date there are no data about the use of contrast enhanced sonography (CES) in a large series of pleural based pulmonary lesions. From August 2004 to August 2005, 137 consecutive patients with pleural based pulmonary lesions on B-mode sonography were studied by CES using a transcapillary second-generation contrast agent (SonoVue(R)). The following CES parameters were retrospectively evaluated. Time to enhancement (TE) of contrast agent after i. v. application was determined and classified as short TE (< = 6 sec) vs. delayed TE (> 6 sec). Extent of enhancement (EE) was evaluated during the arterial phase (2 - 30 sec) and the parenchymal phase (1 - 5 minutes) by using the normal splenic tissue as an in vivo reference, and classified in reduced EE (anechoic/hypoechoic) vs. marked EE (isoechoic/hyperechoic) during both phases. Homogeneity of enhancement (HE) was classified as homogeneous vs. inhomogeneous. 60 patients had histologically confirmed malignant lesions due to central lung cancer (n = 31), and peripheral malignant lesions (n = 29). 77 patients had benign pleural based lesions including pneumonia (n = 32), pulmonary embolism (n = 20), compression atelectasis (17), and other benign pleural based lesions (n = 8). Malignant and benign lesions did not vary significantly regarding TE, EE, and HE. However, there were highly significant differences in the ratio of short vs. delayed TE and reduced vs. marked EE between the six disease groups. Characteristic patterns were short TE with marked EE in all compression atelectasis cases and in 62 % of patients with pneumonia. Delayed TE and reduced EE was seen in all patients with pulmonary embolism and in 62 % of patients with peripheral malignant lesions. Central lung cancer and benign nodules did not present with such specific patterns. No significant differences in HE were seen between subgroups. Pulmonary lesions are characterized by different CES-patterns of arterial supply as evidenced by TE and EE which depends on underlying causes, but CES does not allow to distinguish benign from malignant pleural based lesions in general.

Kontrastverst�rkte Sonographie der Leber

The detection rate of liver lesions using ultrasonography is 53-77%, rendering this method inferior to CT and MRI. Despite well-known limitations, development of stable second-generation contrast agents in conjunction with new techniques of contrast display has led to increased diagnostic accuracy. Characterization of focal liver lesions with ultrasound contrast agents follows known features of iodine- and gadolinium-containing contrast agents, but compared to CT and MRI sensitive visualization of intratumoral vessels takes place in real time. In addition to very high diagnostic accuracy in differentiating benign from malignant lesions, detectability of tumors of nonhepatocellular origin is increased significantly and direct assessment of treatment success with minimally invasive tumor ablative interventions in the liver is possible. The active principle of ultrasound contrast agents, examination technique as well as distinguishing features and appearance of various, frequently observed focal liver lesions are illustrated by cases from our department.

CO2 and gadopentetate dimeglumine as alternative contrast agents for malfunctioning dialysis grafts and fistulas

Hemodialysis grafts and native fistulas are frequently evaluated angiographically utilizing iodinated contrast material to determine the cause of malfunction. Occasionally, patients are not able to receive iodinated contrast material due to a history of previous severe allergic reaction or concern that iodinated contrast material could worsen renal function requiring premature initiation of permanent dialysis. We set out to test the feasibility of gadopentetate dimeglumine as an alternative contrast agent in conjunction with carbon dioxide (CO2) angiography in the evaluation and treatment of hemodialysis grafts and native fistulas in patients who have a contraindication to iodinated contrast material. Six patients with a malfunctioning hemodialysis graft and native fistula were evaluated. Four patients were successfully evaluated using carbon dioxide and gadopentetate dimeglumine. Two additional patients underwent balloon angioplasty using gadopentetate dimeglumine alone as the alternative contrast agent. All six patients successfully were evaluated and treated using gadopentetate dimeglumine either alone or as a supplement to CO2 angiography. Five of these patients had lesions successfully treated using gadopentetate dimeglumine alone or in combination with CO2 as the angiographic contrast agents. One patient underwent a successful diagnostic angiogram using gadopentetate dimeglumine and CO2 as alternative contrast agents and was subsequently treated with surgical revision. The gadopentetate dimeglumine angiograms identified the arterial anastomosis and more clearly identified stenotic lesions and venous outflow anatomy compared to carbon dioxide angiograms. Gadopentetate dimeglumine is useful as an alternative contrast agent in conjunction with CO2 in patients with malfunctioning hemodialysis grafts and fistulas, who have a contraindication to the administration of iodinated contrast material.

Perioperative sonography.

Experience using intraoperative real-time sonographic examinations for over a thousand patients has delineated the advantages of this surgical adjunct for a number of cranial and spinal pediatric neurosurgical procedures. Unusual and unfamiliar angles of insonation call for careful attention to anatomy. The advantages of intraoperative sonography in localizing intracerebral tumors, brain abscesses, and foreign bodies are demonstrated. In addition, adequacy of tumor removal can be assessed better at the time of operation and the operative area can be inspected for bleeding even after dural closure. In the pediatric age group, intraoperative real-time sonography is used most commonly for placement of shunts, allowing positioning of the ventricular catheter tip away from the choroid plexus. The use of air as a contrast agent in conjunction with intraoperative sonography allows better identification of catheter tips and can demonstrate the intercommunication of potentially isolated cavities within the brain. Intraoperative sonography has been extremely helpful, especially for identifying cysts within and the extent of intramedullary spinal cord tumors. Visualization of a syrinx is exquisite. Some of the cases presented also serve to identify limitations of intraoperative sonography as a surgical adjunct.