Targeted nanoparticles for quantitative imaging of sparse molecular epitopes with MRI.

Before molecular imaging with MRI can be applied clinically, certain problems, such as the potential sparseness of molecular epitopes on targeted cell surfaces, and the relative weakness of conventional targeted MR contrast agents, must be overcome. Accordingly, the conditions for diagnostic conspicuity that apply to any paramagnetic MRI contrast agent with known intrinsic relaxivity were examined in this study. A highly potent paramagnetic liquid perfluorocarbon nanoparticle contrast agent ( approximately 250 nm diameter, >90,000 Gd3+/particle) was imaged at 1.5 T and used to successfully predict a range of sparse concentrations in experimental phantoms with the use of standard MR signal models. Additionally, we cultured and targeted the smooth muscle cell (SMC) monolayers that express "tissue factor," a glycoprotein of crucial significance to hemostasis and response to vascular injury, by conjugating an anti-tissue factor antibody fragment to the nanoparticles to effect specific binding. Quantification of the signal from cell monolayers imaged at 1.5 T demonstrated, as predicted via modeling, that only picomolar concentrations of paramagnetic perfluorocarbon nanoparticles were required for the detection and quantification of tissue factor at clinical field strengths. Thus, for targeted paramagnetic agents carrying high payloads of gadolinium, it is possible to quantify molecular epitopes present in picomolar concentrations in single cells with routine MRI.     

Evaluation of signal formation in local arterial input function measurements of dynamic susceptibility contrast MRI

Correct arterial input function (AIF) measurements in dynamic susceptibility contrast‐MRI are crucial for quantification of the hemodynamic parameters. Often a single global AIF is selected near a large brain‐feeding artery. Alternatively, local AIF measurements aim for voxel‐specific AIFs from smaller arteries. Because local AIFs are measured higher in the arterial‐tree, it is assumed that these will reflect the true input of the microvasculature much better. However, do the measured local AIFs reflect the true concentration‐time curves of small arteries? To answer this question, in vivo data were used to evaluate local AIF candidates selected based on two different types of angiograms. For interpretation purposes, a 3D numerical model that simulated partial‐volume effects in local AIF measurements was created and the simulated local AIFs were compared to the ground truth. The findings are 2‐fold. First, the in vivo data showed that the shape‐characteristics of local AIFs are similar to the shape‐characteristics of gray matter concentration‐time curves. Second, these findings are supported by the simulations showing broadening of the measured local AIFs compared to the ground truth. These findings are suggesting that local AIF measurements do not necessarily reflect the true concentration‐time curve in small arteries. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc.     

Early depiction of brain ischaemia with MRI and dysprosium-dota injection

The effects of a pure shift reagent (dysprosium-DOTA [Dy-DOTA]) and a relaxation agent (gadolinium-DOTA [Gd-DOTA]) administered as IV bolus (1 mmol/kg) were compared to visualize early stroke in a feline model of middle-cerebral-artery occlusion. The T2-weighted fast sequences showed a transient decrease of 44% ± 19 (mean ±SD; P = 0.009) in the intensity of the normal cortex after Dy and 28% ± 7 (P = 0.014) after Gd (vs 5% ± 8 and 5% ± 6 nonsignificant decrease in the intensity of the injury). This allowed depiction of the damaged zones within the first hour of ischaemia. Although the changes in signal intensity are less pronounced after Gd than after Dy, this difference did not reach statistical significance in this group. Nevertheless, this difference, smaller than expected only from the magnetic moments, suggests that the T2 relaxation effect specific to Gd is also partly responsible for the signal loss, and that the commercially available Gd chelates should be suitable for MRI of brain vascularity. Correspondence to: I. Berry     

In vivo detection of single cells by MRI.

The use of high-relaxivity, intracellular contrast agents has enabled MRI monitoring of cell migration through and homing to various tissues, such as brain, spinal cord, heart, and muscle. Here it is shown that MRI can detect single cells in vivo, homing to tissue, following cell labeling and transplantation. Primary mouse hepatocytes were double-labeled with green fluorescent 1.63-microm iron oxide particles and red fluorescent endosomal labeling dye, and injected into the spleens of recipient mice. This is a common hepatocyte transplantation paradigm in rodents whereby hepatocytes migrate from the spleen to the liver as single cells. One month later the animals underwent in vivo MRI and punctuated, dark contrast regions were detected scattered through the livers. MRI of perfused, fixed samples and labeled hepatocyte phantoms in combination with histological evaluation confirmed the presence of dispersed single hepatocytes grafted into the livers. Appropriate controls were used to determine whether the observed contrast could have been due to dead cells or free particles, and the results confirmed that the contrast was due to disperse, single cells. Detecting single cells in vivo opens the door to a number of experiments, such as monitoring rare cellular events, assessing the kinetics of stem cell homing, and achieving early detection of metastases.     

MRI of tumor angiogenesis

Angiogenesis has long been established as a key element in the pathophysiology of tumor growth and metastasis. Increasingly, new molecularly targeted antiangiogenic drugs are being developed in the fight against cancer. These drugs bring with them a need for an accurate means of diagnosing tumor angiogenesis and monitoring response to treatment. Imaging techniques can offer this in a noninvasive way, while also providing functional information about the tumor. Among the many clinical imaging techniques available, MRI alone can provide relatively good spatial resolution and specificity, without ionizing radiation and with limited side effects. Arterial spin labeling (ASL) and blood oxygenation level-dependent (BOLD) imaging techniques can be employed to confer indirect measures of angiogenesis, such as blood flow and blood volume, without the need for external contrast agents. Dynamic contrast-enhanced (DCE)-MRI is rapidly emerging as a standard method for directly measuring angiogenesis during angiogenesis-inhibitor drug trials. As macromolecular MR contrast agents become available, they will inevitably be utilized in the assessment of tumor perfusion and vessel permeability. Meanwhile, technological advances have made imaging at a molecular level a possibility. They have brought the potential to directly target MR contrast agents to markers of angiogenesis, such as the alpha(v)beta(3) integrin. Before this is used clinically, however, substantial gains in sensitivity brought about by improved coils, pulse sequences, and contrast agents will be needed. Herein we discuss the techniques currently available for MRI of angiogenesis, along with their respective advantages and disadvantages, and what the future holds for this evolving field of imaging.     

Principles of T2*‐weighted dynamic susceptibility contrast MRI technique in brain tumor imaging

Dynamic susceptibility contrast magnetic resonance imaging (DSC‐MRI) is used to track the first pass of an exogenous, paramagnetic, nondiffusible contrast agent through brain tissue, and has emerged as a powerful tool in the characterization of brain tumor hemodynamics. DSC‐MRI parameters can be helpful in many aspects, including tumor grading, prediction of treatment response, likelihood of malignant transformation, discrimination between tumor recurrence and radiation necrosis, and differentiation between true early progression and pseudoprogression. This review aims to provide a conceptual overview of the underlying principles of DSC‐MRI of the brain for clinical neuroradiologists, scientists, or students wishing to improve their understanding of the technical aspects, pitfalls, and controversies of DSC perfusion MRI of the brain. Future consensus on image acquisition parameters and postprocessing of DSC‐MRI will most likely allow this technique to be evaluated and used in high‐quality multicenter studies and ultimately help guide clinical care. J. Magn. Reson. Imaging 2015;41:296–313. © 2013 Wiley Periodicals, Inc .     

3．OT MRI定量动态对比增强对乳腺疾病的应用价值研究

目的 研究3.0T MRI动态对比增强定量参数对乳腺疾病的诊断价值.方法 采用3.0T MRI扫描仪和16通道乳腺相控阵线圈对45例怀疑乳腺肿瘤患者进行动态对比增强MRI检查,共发现病灶52个,其中5例为2个病灶（1例为双侧,4例为单侧）,1例为3个病灶（双侧）,所有2个以上病灶都取最大的病灶纳入研究.分别测量定量血流动力学参数,包括容量转移常数（volume transfer constant,Kttrans）和血管外细胞外间隙容积比（extravascular extracellular space distribute volume per unit tissue volume,Ve）.采用单因素方差分析比较乳腺癌、纤维瘤和其他良性病变的组间差异,受试者特性曲线（receiver operating characteristic curve,ROC）分析良、恶性病变的组间差异.结果 乳腺癌（n=23）的Ktrans和Ve均值分别为（10.18±2.65） min-1和7.64±1.20;良性病变（n=22）的Ktrans和Ve均值分别为（5.68±1.15）nind和8.44±2.01;良性病变中纤维瘤（n=12）的上述均值分别为（7.31±1.42） min1和11.25±2.75,其他良性病变（n=10）的上述均值分别为（3.73±0.83） min1和5.07±1.13.乳腺癌与良性病变间Ktrans的差异有统计学意义（F值为4.271,P值＜0.05）,Ve的差异无统计学意义（F值为1.553,P值＞0.05）;乳腺癌、乳腺纤维瘤与其他良性病变3组间Ktrans和Ve的差异均有统计学意义（F值分别为4.316和3.944,P值均＜0.05）.以最大约登指数为最佳诊断切点值,Ktrans和Ve判断乳腺良恶性病变的敏感度分别为87.5％和8l.3％;特异度分别为55.6％和38.9％.综合2个定量参数作为联合指标诊断良、恶性病变的敏感度、特异度和准确度分别为91..％（21/23）,77.3％ （17/22）和84.4％（38/45）.结论 3.0T MRI动态对比增强定量血流动力学参数Ktrans对乳腺良恶性病变的鉴别诊断具有很高的诊断价值,Ve对鉴别乳腺癌与纤维瘤具有一定的诊断价值.     

定量动态增强MRI在脊柱肿瘤中的研究进展

Spinal tumor used to be a kind of disease which was hard to diagnose by neuroi mage. Because of some overlap of benign and malignant tumor, it was also difficult to tell the classification directly. In recent years, with the continuous development of new techniques of imaging, especially MRI in clinical application, the diagnostic accuracy of spinal tumor gradually improved. Quantitative dynamic contrast enhanced MRI (DCE MRI) was conducted by different parameters, and then applied in the diagnosis, differential diagnosis, and the classification of tumors and therapeutic evaluations. In this review we summarized the applications of the quantitative DCE MRI in the spinal lesions.     

Quantitative "magnetic resonance immunohistochemistry" with ligand-targeted (19)F nanoparticles.

Unstable atherosclerotic plaques exhibit microdeposits of fibrin that may indicate the potential for a future rupture. However, current methods for evaluating the stage of an atherosclerotic lesion only involve characterizing the level of vessel stenosis, without delineating which lesions are beginning to rupture. Previous work has shown that fibrin-targeted, liquid perfluorocarbon nanoparticles, which carry a high payload of gadolinium, have a high sensitivity and specificity for detecting fibrin with clinical (1)H MRI. In this work, the perfluorocarbon content of the targeted nanoparticles is exploited for the purposes of (19)F imaging and spectroscopy to demonstrate a method for quantifiable molecular imaging of fibrin in vitro at 4.7 T. Additionally, the quantity of bound nanoparticles formulated with different perfluorocarbon species was calculated using spectroscopy. Results indicate that the high degree of nanoparticle binding to fibrin clots and the lack of background (19)F signal allow accurate quantification using spectroscopy at 4.7 T, as corroborated with proton relaxation rate measurements at 1.5 T and trace element (gadolinium) analysis. Finally, the extension of these techniques to a clinically relevant application, the evaluation of the fibrin burden within an ex vivo human carotid endarterectomy sample, demonstrates the potential use of these particles for uniquely identifying unstable atherosclerotic lesions in vivo.     

Added value of breathhold diffusion‐weighted MRI in detection of small hepatocellular carcinoma lesions compared with dynamic contrast‐enhanced MRI alone using receiver operating characteristic curve analysis

Purpose

To evaluate the added value of single‐breathhold diffusion‐weighted MRI (DWI) in detection of small hepatocellular carcinoma (HCC) lesions (≤2 cm) in patients with chronic liver disease, by comparing the detection sensitivity of combined DWI/conventional dynamic contrast‐enhanced (DCE)‐MRI to that of conventional DCE‐MRI alone.

Materials and Methods

A total of 37 patients with chronic liver diseases underwent abdominal MRI at 1.5T, including T1‐weighted imaging (T1WI), T2‐weighted imaging (T2WI), and 2D conventional DCE. For each patient study, axial DWI was performed with a single‐shot echo‐planar imaging (EPI) sequence using a modified sensitivity‐encoding (mSENSE) technique with b‐value of 500 seconds/mm². A total of 20–24 slices were obtained during a 15–17‐second breathhold. Two observers independently interpreted the combined DWI/conventional DCE‐MRI images and the conventional DCE‐MRI images alone in random order. For all small HCC lesions, the diagnostic performance using each imaging set was evaluated by receiver operating characteristic (ROC) curve analysis. Sensitivity and positive predictive values were also calculated and analyzed.

Results

A total of 47 small HCCs were confirmed as final result. The area under the ROC curve (Az) of combined DWI/conventional DCE‐MRI images (observer 1, 0.922; observer 2, 0.918) were statistically higher than those of conventional DCE‐MRI alone (observer 1, 0.809; observer 2, 0.778) for all small HCC lesions (P < 0.01). The lesion detection sensitivities using the combined technique for both observers were significantly higher than those using conventional DCE‐MRI alone (P < 0.01). The sensitivity values for two observers using the combined technique were 97.87% and those using conventional DCE‐MRI alone were 85.11% to 82.98%. The positive predictive values for two observers using the combined imaging technique (97.87%) were slightly higher than those using conventional DCE‐MRI alone (92.86–93.02%), but there was no significant difference between the two imaging sets.

Conclusion

Combined use of breathhold DWI with conventional DCE‐MRI helped to provide higher sensitivities than conventional DCE‐MRI alone in the detection of small HCC lesions in patients with chronic liver disease. J. Magn. Reson. Imaging 2009;29:341–349. © 2009 Wiley‐Liss, Inc.     

Myocardial suppression in vivo by spin locking with composite pulses

Improved myocardium-blood contrast by myocardial suppression resulting from T₁ρ-weighting in contrast-enhanced, gradient-echo, bright-blood cine images, acquired at 1.5T, is shown. In the standard images, blood has twice the intensity of muscle. In similar T₁ρ-weighted images, it has 3–4 times the intensity of muscle. A composite spin-lock pulse before each observation pulse provides T₁ρ-weighting. A typical pulse was: 90y-135x-360x-135x-90(-y) with element durations: 0.84, 1.26, 8.12, 1.26, and 0.84 ms. The tolerance of this composite pulse to shimming and frequency errors allows spin locking with comparatively weak RF and therefore low specific absorption rate (SAR). Initial clinical evaluation on patients with poor ventricular function demonstrates both a qualitative and quantitative improvement in delineation of myocardial borders.     

Characterization of estrogen‐receptor‐targeted contrast agents in solution,breast cancer cells,and tumors in vivo

The estrogen receptor (ER) is a major prognostic biomarker of breast cancer, currently determined in surgical specimens by immunohistochemistry. Two new ER‐targeted probes, pyridine‐tetra‐acetate‐Gd chelate (PTA‐Gd) conjugated either to 17β‐estradiol (EPTA‐Gd) or to tamoxifen (TPTA‐Gd), were explored as contrast agents for molecular imaging of ER. In solution, both probes exhibited a micromolar ER binding affinity, fast water exchange rate (～10⁷ s^?1), and water proton‐relaxivity of 4.7–6.8 mM^?1 s^?1. In human breast cancer cells, both probes acted as estrogen agonists and enhanced the water protons T₁ relaxation rate and relaxivity in ER‐positive as compared to ER‐negative cells, with EPTA‐Gd showing a higher ER‐specific relaxivity than TPTA‐Gd. In studies of breast cancer tumors in vivo, EPTA‐Gd induced the highest enhancement in ER‐positive tumors as compared to ER‐negative tumors and muscle tissue, enabling in vivo detection of ER. TPTA‐Gd demonstrated the highest enhancement in muscle tissue indicating nonspecific interaction of this agent with muscle components. The extracellular contrast agents, PTA‐Gd and GdDTPA, showed no difference in the perfusion capacity of ER‐positive and ‐negative tumors confirming the specific interaction of EPTA‐Gd with ER. These findings lay a basis for the molecular imaging of the ER using EPTA‐Gd as a template for further developments. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.     

Magnetic resonance imaging of vulnerable atherosclerotic plaques: current imaging strategies and molecular imaging probes

The vulnerability or destabilization of atherosclerotic plaques has been directly linked to plaque composition. Imaging modalities, such as magnetic resonance (MR) imaging, that allow for evaluation of plaque composition at a cellular and molecular level, could further improve the detection of vulnerable plaque and may allow for monitoring the efficacy of antiatherosclerotic therapies. In this review we focus on MR imaging strategies for the detection and evaluation of atherosclerotic plaques and their composition. We highlight recent advancements in the development of MR pulse sequences, computer image analysis, and the use of commercially available MR contrast agents, such as gadopentic acid (Gd-DTPA), for plaque characterization. We also discuss molecular imaging strategies that are currently being used to design specific imaging probes targeted to biochemical and cellular markers of atherosclerotic plaque vulnerability.     

Differentiation of nonmetastatic and metastatic rodent prostate tumors with high spectral and spatial resolution MRI.

MR images can be acquired with high spectral and spatial resolution to precisely measure lineshapes of the water and fat resonances in each image voxel. Previous work suggests that the high-resolution spectral information can be used to improve image contrast, SNR, sensitivity to contrast agents and to physiologic and biochemical processes that affect local magnetic susceptibility gradients. The potential advantages of high-resolution spectroscopic imaging (SI) suggest that it might be useful for early detection and characterization of tumors. The present experiments evaluate the use of high-resolution SI to discriminate between metastatic and nonmetastatic rodent Dunning prostate tumors. SI datasets were obtained at 4.7 Tesla with an in-plane resolution of 350-500 micron in a single 1.0-mm slice, and 6-8 Hz spectral resolution, before and after i.v. injection of an iron oxide contrast agent. Images of water signal peak height in nonmetastatic tumors were smoother in the tumor interior than images of metastatic tumors (P <.004 by t-test) before contrast media injection. This difference was stronger in contrast-enhanced images (P <.0004). In addition, the boundary between the tumor and muscle was more clearly demarcated in nonmetastatic than metastatic tumors. Combinations of image texture, tumor edge morphology, and changes in T2* following contrast media injection improved discrimination between metastatic and nonmetastatic tumors. The data presented here do not demonstrate that effective discrimination between metastatic and nonmetastatic tumors depends on the use of high-resolution SI. However, the results suggest that SI and/or other MR methods that provide similar contrast might be used clinically for early and accurate detection of metastatic disease.