Enhanced tumor detection in the presence of liver cirrhosis: experimental study on the diagnostic value of a superparamagnetic iron oxide MR imaging contrast agent (NSR 0430)

The purpose of this study was to determine the diagnostic value of the superparamagnetic iron oxide NSR 0430 for the detection of focal liver lesions in the presence of advanced cirrhosis. Cirrhosis and growth of cholangiofibromas were induced in 22 rats by administration of thioacetamide. Sixteen non-cirrhotic animals served as controls. T1 and T2 relaxation times of liver and tumor tissue of 12 animals were measured spectroscopically. In 10 animals in vivo MRI was performed before and 1 hour after contrast administration, and then the tumor-to-liver contrast-to-noise ratio (CNR) was calculated. All specimens were evaluated histologically. After contrast administration, T1 and T2 values of liver tissue showed a significant decrease of 18% (P = 0.01) and 31% (P = 0.009), respectively, whereas relaxation times of tumor tissue did not change. On precontrast turbo spin-echo images, 40 tumors could be identified; after contrast administration, 95 lesions were visible. CNR increased significantly after contrast administration by 297% at a TE of 50 msec and by 254% at a TE of 90 msec. In conclusion, our in vitro and in vivo results demonstrate that administration of NSR 0430 substantially improves liver-to-tumor CNR and lesion detection on T2-weighted magnetic resonance images even in the presence of severe cirrhosis.     

Assessment of a superparamagnetic iron oxide (AMI-25) as a brain contrast agent

We have applied a superparamagnetic iron oxide formulation (AMI-25, Advanced Magnetics, Inc., Cambridge, MA) to image the cerebral vasculature. Contrast-enhanced images of normal anesthetized rats demonstrated excellent gray/white matter differentiation, consistent with known differences in blood perfusion, and cerebrospinal fluid spaces were clearly seen. Alterations in normal perfusion patterns due to barbiturate anesthesia and ischemia were clearly visible. We propose the use of this agent as an adjunct to MRI for the imaging of conditions with perfusion abnormalities.     

超顺磁性氧化铁灌注T_2WI诊断超急性脑缺血的实验研究

目的观察国产超顺磁性氧化铁（ＳＰＩＯ）灌注Ｔ２ＷＩ诊断超急性期脑缺血的可行性。方法正常大鼠５只和右侧大脑中动脉闭塞（ＭＣＡＯ）大鼠２６只,行ＳＰＩＯ灌注前后Ｔ２ＷＩ,后者在ＭＣＡＯ后４０～５０分钟行ＭＲ检查。ＭＲ检查后４只行墨汁灌注检查,６只在ＭＣＡＯ后２４小时行ＭＲ复查和病理检查。ＳＰＩＯＩ颗粒直径２０ｎｍ、ＳＰＩＯＩ颗粒直径６～９ｎｍ,剂量为０６ｍｍｏｌ／ｋｇ。采用ＳＰＩＯＩ做了６只、ＳＰＩＯＩ做了２０只灌注检查。结果在ＭＣＡＯ后５０分钟,平扫Ｔ２ＷＩ仅３７％表现右侧大脑中动脉（ＭＣＡ）供血区信号稍高;两种型号的ＳＰＩＯ灌注后１００％或８０％的右侧ＭＣＡ供血区呈相对高信号,与墨汁灌注检查的灌注缺损区及ＭＣＡＯ后２４小时复查Ｔ２ＷＩ的高信号范围一致。病理检查证实右侧ＭＣＡ供血区的缺血、梗死。在剂量相同情况下,ＳＰＩＯＩ灌注Ｔ２ＷＩ显示缺血区与非缺血区的对比度明显高于ＳＰＩＯＩ。结论ＳＰＩＯ相当于一种阴性造影剂,国产ＳＰＩＯ“灌注”常规Ｔ２ＷＩ可以诊断血管闭塞５０分钟的急性脑缺血,ＳＰＩＯＩ灌注的诊断效果优于ＳＰＩＯＩ。     

MRI in acute cerebral ischaemia: perfusion imaging with superparamagnetic iron oxide in a rat model

An imaging technique capable of detecting ischaemic cerebral injury at an early stage could improve diagnosis in acute or transient cerebral ischaemia. We compared the ability of superparamagnetically contrastenhanced MRI and conventional T2-weighted MRI to detect ischaemic injury early after unilateral occlusion of the middle cerebral artery in 12 male Wistar rats. Permanent vessel occlusion was achieved by a transvascular approach, which has the advantage of not requiring a craniectomy. At 45–60 min after the procedure, the animals had conventional T2-weighted MRI before and after administration of a superparamagnetic contrast agent (iron oxide particles). Unenhanced images were normal in all animals. After administration of iron oxide particles, the presumed ischaemic area was clearly visible, as relatively increased signal, in all animals; this high signal area corresponded to the area of ischaemic brain infarction seen on histological studies. Magnetic susceptibility effects of iron particles cause low signal in normally perfused cerebral tissue, whereas tissue with reduced or absent blood flow continues to give relatively high signal. Our results suggest that superparamagnetic iron particles may significantly reduce the interval between an ischaemic insult and the appearance of parenchymal changes on MRI.     

Early MR detection of experimentally induced cerebral ischemia using magnetic susceptibility contrast agents: comparison between gadopentetate dimeglumine and iron oxide particles.

PURPOSETo evaluate early patterns of MR changes in a rat model of cerebral ischemia using the first pass of two magnetic susceptibility contrast agents.METHODSOne hours after endovascular middle cerebral artery occlusion, all animals were examined in an experimental MR unit. After bolus application of gadopentetate dimeglumine and, 10 minutes later, of iron oxide particles, the MR changes of the first pass of these contrast agents were followed using a T2*-weighted fast low-angle shot sequence. Time-density curves of both contrast agents were analyzed and compared.RESULTSAfter bolus injection of either (paramagnetic) gadopentetate dimeglumine or superparamagnetic particles, nonischemic brain parenchyma decreased markedly in signal, whereas the ischemic brain area remained relatively hyperintense (and thus became clearly delineated). Only after application of gadopentetate dimeglumine did a mild reduction in signal occur in the ischemic hemisphere, although the main artery was occluded. An explantation for this phenomenon might be residual capillary perfusion (plasma flow), which is detectable only when the smaller (paramagnetic) contrast molecules are being used.CONCLUSIONSCerebral perfusion deficits can be detected 1 hour after vascular occlusion with T2*-weighted fast low-angle shot sequences and bolus injection of paramagnetic or superparamagnetic MR contrast agents. Gadopentetate dimeglumine may be used as a marker of microcirculatory plasma flow.     

MR contrast agents in acute experimental cerebral ischemia: potential adverse impacts on neurologic outcome and infarction size

The purpose of the study was to investigate the effects of magnetic resonance (MR) contrast agents on neurologic outcome and infarction size in a rat stroke model. Focal cerebral ischemia was induced in 80 rats using an endovascular occlusion technique of the middle cerebral artery. Four hours after occlusion, 64 animals (4 groups of 16 each) received gadodiamide (Gd-DTPA-BMA) in a single (0.1 mmol/kg) or triple (0.3 mmol/kg) clinical dose or the ultrasmall superparamagnetic iron oxide particles contrast agent NC 100150 in a single (0.03 mmol/kg, 1.5 mg Fe(2+)/kg) or double (0.06 mmol/kg, 3.0 mg Fe(2+)/kg) clinical dose, respectively. Sixteen animals received equivolumetric saline (control group). Neurologic score and body weight were recorded every 8 hours. Twenty-four hours after vessel occlusion, infarction size was measured by 2,3, 5-triphenyl-tetrazolium-chloride (TTC) staining. Neither the normal nor the triple clinical dose of gadodiamide or NC 100150 in the single or double dose had any statistically significant effects on infarction volume, mortality, body weight, or neurologic outcome (P > 0.05). Our results suggest that bolus injection of gadodiamide and the ultrasmall superparamagnetic iron oxide particles NC 100150 in clinically relevant doses does not significantly affect infarction volume and clinical outcome of acute cerebral ischemia.     

MRI susceptometry: image-based measurement of absolute susceptibility of MR contrast agents and human blood.

We present a novel NMR imaging technique that allows absolute determination of the magnetic susceptibility constant, chi, of a solution. By comparing the phase difference of MR images produced with an instant (echo planar) "offset" spin-echo sequence, we obtain a direct measure of the magnetic field perturbations caused by the solution. We demonstrate this method with Gd(DTPA), Dy(DTPA), human red blood cells, and superparamagnetic iron oxide particles.     

超顺磁性氧化铁胶体用作网状内皮系统磁共振对比剂的实验研究

作者报道一种自制的超顺磁性氧化铁胶体磁共振对比剂，其选择性分布于网状内皮系统吞噬细胞内起阴性对比作用，初步研究表明，这种对比剂对肝组织不造成损伤，毒性小，稳定性好，能显著增加肝组织和肝内肿瘤间的信号反差，有效增强时间长于５ｄ，应用后将有助于肿瘤病变的早期检出和鉴别诊断。     

CT灌注成像对大鼠脑梗死半暗带的时间依赖性

目的：应用CT灌注成像对急性脑梗死缺血半暗带阈值进行判定,并着重探讨其时间依赖性。方法：取110只Wister大鼠,随机分为3组：对照组（10只）、缺血组（50只,分为5个亚组）、缺血再灌注组（50只,分为5个亚组）。用栓线法制作大鼠脑缺血动物模型,后2组于手术后5个时间点（2、4、6、8和10 h）分别行CT灌注成像检查,再灌注组经再灌注24 h后还需再次行CT灌注成像检查。检查结束后对图像进行判定,确定半暗带和最终梗死区的rCBF值,并取大鼠的脑组织进行病理观察。结果：缺血2 h和4 h的中心区及边缘区,缺血6、8和10 h的边缘区为半暗带,在缺血4 h之前,即使此区域的rCBF低至0.143,仍可逆;缺血6 h之后rCBF〉0.223以及10 h之后rCBF〉0.271的区域才有挽救的意义。病理检查显示在缺血6 h后,光镜和电镜发现有坏死神经细胞。结论：CT灌注成像能够判断半暗带及其阈值,预测其转归。在判断阈值应考虑到阈值与缺血时间的关系。     

Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging

An ultrasmall superparamagnetic iron oxide (USPIO) preparation was developed that is small enough to migrate across the capillary wall, a prerequisite in the design of targetable particulate pharmaceuticals. Seventy percent of particles were smaller than 10 nm; 26%, smaller than 5 nm. The blood half-life of USPIO in rats was 81 minutes, considerably longer than that of larger superparamagnetic iron oxide preparations such as AMI-25 (6 minutes). Electron microscopy demonstrated that USPIO particles transmigrate the capillary wall by means of vesicular transport and through interendothelial junctions. Twenty-four hours after intravenous administration, 3.6% of the injected dose per gram of tissue was found in lymph nodes, 2.9% per gram in bone marrow, 6.3% per gram in liver, and 7.1% per gram in spleen. The major potential applications for USPIO are as (a) an intravenous contrast agent for the lymphatic system, (b) a bone marrow contrast agent, (c) a long-half-life perfusion agent for brain and heart, and (d) the magnetic moiety in organ-targeted superparamagnetic contrast agents for magnetic resonance imaging.     

320排动态容积CT全脑灌注成像在脑梗死缺血半暗带分期中的应用

目的 应用320排动态容积CT全脑灌注成像探讨脑梗死缺血半暗带分期的可行性.资料与方法 测量18例存在缺血半暗带脑梗死患者的梗死核心区、缺血半暗带区及其镜像对侧脑血容量(CBV)、脑血流量(CBF)、平均通过时间(MTT)及达峰时间(TTP),按脑梗死前期分期标准对缺血半暗带进行分期.结果 18例缺血半暗带区表现为MTT、TTP延长,CBF降低,CBV轻度升高、正常或轻度降低.与梗死核心区比较,缺血半暗带区CBV、CBF升高,MTT延长,TTP缩短(P＜0.05);与健侧对应区比较,CBF降低,MTT及TTP延长(P＜0.05),而CBV无显著差异(P＞0.05).缺血半暗带分期:Ⅰ2期3例,Ⅱ1期9例,Ⅱ2期6例.结论 应用320排动态容积CT全脑灌注成像可明确脑梗死患者的病变部位、范围以及有无缺血半暗带存在,并可对缺血半暗带进行分期.     

急性脑缺血脑血流变化与脑组织死亡概率间关系的实验研究

目的采用自体血栓栓塞模型计算超急性期脑缺血时脑组织的死亡概率曲线,并通过概率曲线计算缺血半暗带的阈值。材料与方法12只新西兰大白兔行自体血栓栓塞制成局灶性脑缺血模型。采用GELightspeed16层螺旋CT,于栓塞后20min和10h各行CT灌注扫描1次。以CT灌注软件绘出每个时间点的脑血流图。在脑缺血12h后,取脑标本行TTC染色,并根据血流速图和染色结果将梗死侧分为中心梗死区,半暗带区和相对正常区三部分。结果缺血20min时中心梗死区、半暗带区和相对正常区各区域pCBF均值分别为29.33%,47.86%和94.32%,对应的死亡概率分别为67%,27%和1%,缺血10h各区域pCBF均值分别为16.87%,50.17%和85.49%,对应的死亡概率分别为100%,95%和43%。各时间点梗死侧的3个区域间差别有显著的统计学意义(P<0.0001)。缺血20minP=0.5时对应的pCBF值等于31.14%,而缺血10hP=0.5时对应的pCBF值等于40.89%。结论缺血10h的脑组织死亡概率明显高于缺血20min,证明了早期诊断和治疗的重要性,提出利用概率进行半暗带判定的方法,但其有效性还需进一步研究与证实。     

Effectiveness of micron‐sized superparamagnetic iron oxide particles as markers for detection of migration of bone marrow‐derived mesenchymal stromal cells in a stroke model

Purpose:

To evaluate the feasibility of using micron‐sized superparamagnetic iron oxide particles (MPIOs) as an effective labeling agent for monitoring bone marrow‐derived mesenchymal stromal cell (BMSC) migration in the brain using magnetic resonance imaging (MRI) in a rat model of stroke and whether the accumulation of MPIO‐labeled BMSCs can be differentiated from the accumulation of free MPIO particles or hemoglobin breakdown at a site of neuronal damage.

Materials and Methods:

In this study BMSCs were labeled with iron oxide and their pattern of migration following intravenous injection in a rat stroke model was monitored using a clinical MRI system followed by standard histopathology. The migration pattern was compared between intravenous injection of BMSCs alone, BMSCs labeled with MPIOs, and MPIO particles alone.

Results:

The results demonstrated that while MRI was highly sensitive in the detection of iron oxide particle‐containing cells in areas of neuronal ischemia, the true origin of cells containing iron oxide particles remains ambiguous. Therefore, detection of iron particles may not be a suitable strategy for the detection of BMSCs in the brain in a stroke model.

Conclusion:

This study suggests that the use of MPIOs as labeling agents are insufficient to conclusively determine the localization of iron within cells in regions of neuronal ischemia and hemorrhage. J. Magn. Reson. Imaging 2013;37:1409–1418. © 2012 Wiley Periodicals, Inc.     

Effect of Gd-DTPA-BMA on choline signals of HT29 tumors detected by in vivo 1H MRS

Purpose

To study the impact of Gd‐DTPA‐BMA on choline signals of HT29 colon carcinomas determined by localized ¹H MRS in vivo at 4.7T.

Materials and Methods

PRESS ¹H MR spectra (2‐second repetition time and echo times of 20–272 msec) were acquired from HT29 xenografts prior to and following intravenous administration of 0.1 or 0.2 mmol/kg Gd‐DTPA‐BMA. The magnetic resonance spectroscopy (MRS) data were analyzed by 1) normalizing choline and water peak areas to their precontrast values; and 2) estimating absolute choline concentration relative to tissue water.

Results

Changes in the T₁ and T₂ of choline and water were apparent following administration of Gd‐DTPA‐BMA. Administration of 0.1 mmol/kg Gd‐DTPA‐BMA induced significant increases in the choline peak area, concomitant with enhancements of the water peak area, whereas 0.2 mmol/kg Gd‐DTPA‐BMA induced no enhancement of choline peak area but significant increases in water peak area at short echo times.

Conclusion

The effect of Gd‐DTPA‐BMA on estimation of tumor choline concentration varied with the dose of contrast agent, the echo time, and the time after contrast agent administration. These data highlight the potential pitfalls associated with the modulation of choline and water signals post‐Gd‐DTPA‐BMA and may account for the apparently contradictory results previously reported. J. Magn. Reson. Imaging 2008;28:1201–1208. © 2008 Wiley‐Liss, Inc.     

Dynamic patterns of USPIO enhancement can be observed in macrophages after ischemic brain damage.

Cells of the mononuclear phagocytotic system (MPS) are often found near to or within ischemic tissue and can potentially aggravate cellular damage. Hence, visualization of those cells would allow demarcation of putatively affected from intact tissue. Experimental MRI studies have shown that ultrasmall particles of dextran-coated iron oxide (USPIO) are internalized into cells of the MPS. To test if this cell tagging method may be also applied to cerebral infarction, USPIOs were administered to Fisher rats 5.5 h after permanent occlusion of the middle cerebral artery (pMCAO). During the first 2 days USPIO were preferentially found in patches within the lesion and in surrounding areas. On day 4, USPIOs expanded within the core of the lesion. On day 7 they were found predominantly within the boundary area. Histological analysis showed large populations of macrophages containing iron particles in the infarcted tissue. We conclude, therefore, that it is possible to monitor MPS activity after focal cerebral ischemia using USPIOs.     

Perfusion measurements of the brain: using dynamic CT for the quantitative assessment of cerebral ischemia in acute stroke

Objective: Perfusion CT has been successfully used as a functional imaging technique for the differential diagnosis of patients with hyperacute stroke. We investigated to what extent this technique can also be used for the quantitative assessment of cerebral ischemia. Methods and material: We studied linearity, spatial resolution and noise behaviour of cerebral blood flow (CBF) determination with computer simulations and phantom measurements. Statistical ROI based analysis of CBF images of a subset of 38 patients from a controlled clinical stroke study with currently more than 75 patients was done to check the power of relative cerebral blood flow (rCBF) values to predict definite infarction and ischemic penumbra. Classification was performed using follow-up CT and MR data. Results: Absolute CBF values were systematically underestimated, the degree depended on the cardiac output of the patients. Phantom measurements and simulations indicated very good linearity allowing reliable calculation of rCBF values. Infarct and penumbra areas in 19 patients receiving standard heparin therapy had mean rCBF values of 0.19 and 0.62, respectively. The corresponding values for 19 patients receiving local intraarterial fibrinolysis were 0.18 and 0.57. The difference between infarct and penumbra values was highly significant (P<0.0001) in both groups. No penumbra area was found with an rCBF value of less than 0.20. While in the heparin group only 25% of all areas with an rCBF between 0.20 and 0.35 survived, in the fibrinolytic group 61% of these areas could be saved (P<0.05). Conclusion: Perfusion CT is a fast and practical technique for routine clinical application. It provides substantial and important additional information for the selection of the optimal treatment strategy for patients with hyperacute stroke. Relative values of cerebral blood flow discriminate very well between areas of reversible and irreversible ischemia; an rCBF value of 0.20 appears to be a definite lower limit for brain tissue to survive an ischemic injury.     

320排动态容积CT全脑灌注成像技术在脑梗死中的临床应用

目的:探讨320排动态容积CT全脑灌注成像技术在脑梗死诊断中的优势及临床应用价值。方法:对42例脑梗死患者行CT全脑灌注成像,一次对比剂注射得到平扫容积图像、CT血管成像图像及全脑灌注图像,综合运用这三种检查方法全面评估脑梗死。结果:42例脑梗死患者共发现18例存在缺血半暗带(IP),其中8例超急性期6例存在IP,19例急性期8例存在IP,15例亚急性期4例存在IP。42例梗死核心区与健侧对应区比较,脑血容量(CBV)、血流量(CBF)、平均通过时间(MTT)及达峰时间(TTP)值差异均具统计学意义(P<0.05)。18例IP区与梗死核心区比较,CBV、CBF、MTT及TTP值差异均具统计学意义(P<0.05),与健侧对应区比较,CBV值差异无统计学意义(P>0.05)。结论:急性期及亚急性期脑梗死仍可能存在IP。应用320排容积CT全脑灌注成像,对脑梗死患者可明确其责任血管的狭窄部位及程度,了解病变范围及有无IP存在,实现对脑梗死的全面评估。     

Use of gadolinium-DTPA as a myocardial perfusion agent: potential applications and limitations for magnetic resonance imaging

To establish the effect of the paramagnetic contrast agent gadolinium diethylenetriaminepentaacetic acid ([Gd]DTPA) on myocardial magnetic resonance relaxation parameters T1 and T2, and its relationship to myocardial perfusion, we administered [Gd] DTPA 0.2 mM/kg to two groups of dogs. Group I had severe, resting myocardial ischemia induced by coronary occlusion, followed in 2 min by [Gd]DTPA infusion and heart excision 1 min later. Group II had a variable reduction in blood flow. In Group II the coronary vasodilator dipyridamole was infused to enhance blood flow to the normal myocardium before [Gd]DTPA was given. In Group I [Gd]DTPA caused a significant difference in T1 between the normal and severely ischemic zones; changes in T1 correlated with the severity of myocardial ischemia. Although vasodilatation delivered more Gd-DTPA to the normal myocardium in Group II, the lack of further decrease in T1 suggested that it was cleared more rapidly. Thus, [Gd]DTPA permits the detection and characterization of severe, resting myocardial ischemia by magnetic resonance techniques. Using the experimental techniques described in this study, less severe flow differences caused by vasodilatation and resultant hyperemia are not detected.     

Application of a superparamagnetic iron oxide (Resovis®) for MR imaging of human cerebral blood volume

The authors describe the feasibility of dynamic MRI using a novel superparamagnetic iron oxide contrast agent. Resovist® was injected as a bolus at doses of 4, 8, and 16 μmol Fe/kg bodyweight in three consented patients participating in a Phase 2 clinical multicenter trial for hepatic MRI. Dynamic images of the brain were obtained with a conventional FLASH sequence. Results were analyzed by evaluation of dynamic images, cerebral blood volume maps, and normalized signal intensity time curves. Resovist® enabled rapid injections and a dose-dependent strong reduction in gray and white matter signal intensity. The small injection volume and good tolerability may enable Resovist® to serve as a perfusion agent. Dedicated clinical trials are warranted to assess the potentials of Resovist® for perfusion MRI and fMRI.     

CBF and CBV measurements by USPIO bolus tracking: reproducibility and comparison with Gd-based values

The authors measured cerebral blood flow (CBF) and cerebral blood volume (CBV) by bolus tracking of a novel ultrasmall superparamagnetic iron oxide (USPIO) contrast agent (NC100150) and compared absolute and relative perfusion measurements with those obtained by a standard gadolinium-based contrast agent. They found a linear correlation between the two methods. A dose of 0.4 mg Fe/kg body weight was found to produce a signal drop similar to that of a standard 0.2 mmol/kg gadodiamide injection using spin-echo echoplanar imaging (SE-EPI) at 1.0 T. The measurements showed a high degree of reproducibility of repeated absolute as well as relative CBF and CBV values, lending further hope to the possibility of using magnetic resonance bolus tracking for routine CBF and CBV measurements. Finally, the authors present their initial experience with high-resolution, non-EPI CBV maps obtained from steady-state levels of an intravascular superparamagnetic contrast agent.