Contrast-Enhanced Magnetic Resonance Imaging of Central... : Topics in Magnetic Resonance Imaging (original) (raw)
With 10 to 15 per 100,000 persons diagnosed both in Europe and United States per year, brain tumors are among the top causes of cancer-related deaths.1
Brain tumors are categorized into primary versus secondary tumors based on the origin tissue and intra-axial versus extra-axial tumors based on the origin of growth.2-4 The most common primary intra-axial tumors are neuroepithelial tumors, including astrocytomas, oligodendrogliomas, mixed gliomas, and other more rare neuronal-glial tumors with the glioblastoma multiforme as the most common brain tumor.5,6 Meningiomas are the most common primary extra-axial tumors7 and account for approximately 20% of all brain tumors. In adults, however, secondary metastatic brain lesions far outnumber the primary tumors with a high incidence of systemic cancer such as lung and breast cancer.8
The goals and requirements for brain tumor imaging are multiplex and involve making a diagnosis and a differential diagnosis, while accurate lesion grading is needed in the case of brain tumor imaging. Neuroimaging is an essential part of the decision-making process for therapy and later for precise planning of surgical interventions. In the case of neurosurgery, neuroimaging can precisely define the location and accurately delineate the lesion before intervention. In the case of radiotherapy, it can precisely define and demarcate the margins for targeted intervention. Neuroimaging is also mandatory after therapeutic intervention for monitoring of disease and possible side effects.
Because of its high tissue contrast and its noninvasiveness, magnetic resonance imaging (MRI) is accepted as the most sensitive method of diagnosing brain tumors.9,10 Magnetic resonance imaging enables to recognize and determine accurately the dimensions of a tumor and its surrounding tissue. This requires as high a central nervous system (CNS)-to-lesion contrast as possible, which depends on the signal intensity of the lesion relative to that of the surrounding normal tissue.10 Furthermore, detailed information on the internal morphology of the lesion is essential for differential diagnosis, grading, and selection and planning of therapy. For most diseases and for many of the currently available functional MRI (fMRI) methods, the use of magnetic resonance (MR) contrast media (CM) is mandatory. The standard dose used for MRI of the CNS is 0.1 mmol/kg body weight, although numerous studies have shown that lesion detection may be improved with the use of higher doses and dedicated sequences.11,12 Contrast-enhanced MRI also helps in distinguishing tumors from other pathological processes and in depicting basic signs of tumor response to therapy, such as change in size, morphology, and degree of contrast material enhancement.
In the past few years, however, a number of advanced, mostly contrast-enhanced MRI techniques have been developed that provide new insights into the pathophysiology of brain tumors. One of these techniques, perfusion MRI, is now recognized as an important new means of assessing tumor grading and follow-up of various treatment strategies. Another of these techniques, dynamic contrast-enhanced MRI (DCE-MRI), is also gaining acceptance for the same purposes. In the following review, the reader will be provided with the fundamental features of the contrast mechanisms and their influences in brain tumor assessment. The different properties of currently available CM and the dosage and field dependencies will be discussed. Basic methodologies and the first clinical experience with the contrast-enhanced functional imaging tools, perfusion MRI and DCE-MRI, will be presented.
MECHANISMS OF CONTRAST ENHANCEMENT IN BRAIN TUMORS
Because of the presence of the blood-brain barrier (BBB), the currently available MR CM do not leak into the brain tissue.13,14 The BBB consists of a complex of capillary endothelial cells, pericytes, and astroglial and perivascular macrophages and serves as an effective physical barrier to the entry of lipophobic substances into the brain.13 The BBB blocks all molecules except those that cross cell membranes by means of lipid solubility (such as oxygen, carbon dioxide, ethanol, and steroid hormones) and those that are allowed in by specific transport systems (such as sugars and some amino acids). Substances with a molecular weight higher than 180 d, which include all available imaging CM, generally cannot cross the BBB.15
The integrity of the BBB can be altered by a variety of circumstances which increase the permeability both for CM and drug delivery. A disruption of the BBB may be caused by osmotic means, for example, steroids, biochemically by the use of vasoactive substances such as bradykinin, or even by localized exposure to focused ultrasound.16-19
In intra-axial primary tumors, mainly gliomas, the BBB can be compromised by neovascularization and direct tumorous damage. Because nonneoplastic astrocytes are required to induce BBB features of cerebral endothelial cells, it is conceivable that malignant astrocytes have lost this ability because of dedifferentiation. Alternatively, glioma cells might actively degrade previously intact BBB tight junctions.20,21 Although the integrity of the barrier is often compromised within the tumor, this alteration in permeability is variable and dependent on the tumor type and size. Moreover, it is extremely heterogeneous in a given lesion.22 Although the BBB is frequently leaky in the center of malignant brain tumors, the well-vascularized, actively proliferating edge of the tumor, in the brain adjacent to tumor area, has been shown to have variable and complex barrier integrity.
In secondary metastatic intra-axial tumors and extra-axial tumors, the vessels are different from normal cerebral vasculature and have no or strongly disturbed BBB.23-25 Those entities normally have a strong enhancement pattern, presenting the whole tumor as enhancing mass.
As brain edema is also thought to be caused by the breakdown of the BBB, one can expect a correlation between the degree of enhancement and the volume of the peritumoral edema. Holodny et al26-28 studied this correlation in malignant gliomas as a representative of primary intra-axial tumors and meningiomas as a representative of extra-axial tumors. In their study, no correlation was found for meningiomas which proved that the meningioma vessels have no BBB or no effect on the BBB in the surrounding brain tissue. For malignant gliomas, a strong correlation was found which offers evidence that the defect of the BBB is directly related both to the degree of lesion enhancement and amount of edema, and both should interfere in between each other. The interference may influence both the conventional contrast-enhanced MRI as well as some of the flow-dependent functional imaging techniques. The contrast enhancement patterns change substantially after corticosteroid treatment as first presented by the group of Wilkinson et al.29 The enhancement is less both in intensity and size (Fig. 1).
Pharmacokinetic analysis of a high-grade glioma before (A and C) and after (B and D) glucocorticoid administration. The perfusion enhancement of the BBB decreased 3 days after therapeutic intervention which can be appreciated by the color-coded maps. The corticoid treatment has a direct influence on the integrity of the BBB which has to be considered in the evaluation of brain tumor MRI, especially in the treatment follow-up.
However, the concept of permeability across a disrupted or disturbed BBB in patients with brain tumor has recently gained further interest in monitoring modern treatment strategies. First, changes in permeability may serve as a surrogate marker for other important physiological processes in brain tumors, such as angiogenesis. Second, an understanding of permeability can elucidate the mechanisms by which therapeutic agents enter the brain parenchyma. Third, an understanding of methods for increasing permeability can help in the development of methods to selectively alter the BBB to enhance drug delivery.
Modern MR neuroimaging strategies such as DCE-MRI focus on the visualization and quantification of the blood-brain barrier breakdown which will be described in detail in the section on dynamic MRI.
CONTRAST MEDIA AND DOSAGE
Contrast material-enhanced MR imaging is the accepted standard of reference for assessment of the integrity of the BBB. Compared with contrast-enhanced computed tomography, MRI with gadolinium (Gd)-based contrast agents is far more sensitive and depicts even subtle disruptions of the BBB that are caused by a variety of noxious agents, neoplastic or inflammatory processes, or ischemic stress.28
The use of Gd CM is therefore standard in the assessment of cerebral tumors. Although in the beginning of MRI only 1 CM (Gd-diethylenetriamine pentaacetic acid [DTPA] [Magnevist]; Berlex, Wayne, NJ) was available, there are several Gd-based contrast agents available today and used up to a dosage of 0.3 mmol/kg body weight. The currently available agents are described below, and the different dosage strategies are discussed.
Types of Contrast Media
Paramagnetic Contrast Media
Figure 2 shows an overview of brand names and categories of the currently available MR CM. Table 1 lists application areas and first launch date and location of the most common CM; Table 2 lists the pharmacokinetics.
Magnetic resonance CM available for clinical imaging. However, the paramagnetic Gd chelates and the Mn chelates as well as the superparamagnetic CM ultrasmall particles of iron oxide (USPIO) and superparamagnetic (or small particles) of iron oxide (SPIO) have different labeled indications. The molarity of the Gd-based compounds is 0.5 mol/L if not mentioned different. Second- and third-generation Gd-based compounds are also available in a lower (Vasovist, Primovist) and higher (Gd-BT-DO3A) concentration. Superparamagnetic particles of iron oxide show differences in their distribution because of their coating material. The contrast agent framed with a double line (Vasovist) has a prolonged half-life in the vascular system (Table 1). Note: not all listed CM are labeled for neuroapplications (Table 2).
List of Magnetic Resonance Contrast Media That Are Available on the Market for Clinical Use
List of Magnetic Resonance Contrast Media That Are Available on the Market for Clinical Use: Overview of the Chemical Structure, Ionic Charge, Stability Constant (log K and log K′), Molecular Weight and Concentration, Vascular Half-Life, and Distribution
Since the first MR contrast agent, gadopentetate dimeglumine (Gd-DTPA [Magnevist]) entered clinical trials of MRI brain studies30 and was marketed initially in parts of Europe and Asia in 1988, and later in the United States, 6 other Gd chelate-based compounds were developed and are now available in many countries. The CM currently approved in Europe for the diagnosis of CNS diseases are Gd-DTPA (gadopentetate dimeglumine [Magnevist]), Gd-HP-DO3A (gadoteridol [ProHance]), Gd-DTPA-BMA (gadodiamide [Omniscan]), Gd-DOTA (gadoterate meglumine [Dotarem]), Gd-BT-DO3A (gadobutrol [Gadovist]), Gd-DTPA-BMEA (gadoversetamide [OptiMARK]), and Gd-BOPTA (gadobenate dimeglumine MultiHance). All of them are paramagnetic; that is, they gain magnetic properties in a strong magnet field reducing the T1 and T2 relaxation times of nearby water protons.31 Using a T1-weighted MR sequence, these agents increase signal-to-noise ratio (SNR) of perfused tissue and improve contrast-to-noise ratio (CNR). They are so called "positive enhancers."
The above-mentioned CM have the lanthanide ion Gd3+ as its central metal ion, building a chelate of small molecular weight of 1000 d or less. The diameter of these small molecular CM (SMCM) is approximately 1 nm.32 Therefore, SMCM extravasate fast into the interstitial space already in normal tissue during first-pass effect. They belong also to the group of extracellular fluid agents. The vascular half-life is relatively short (~90 minutes). This generation of Gd chelates does not show any cellular uptake and no binding characteristics with regard to serum proteins. Excretion is predominantly renal, 1% or less via the hepatobiliary system. Each agent of this group behaves very similar regarding this group's pharmacokinetic and vascular enhancement characteristics.33,34 After an intravenous bolus injection or infusion, SMCM do not cross the BBB, but in the event of any BBB alterations, increased extravasation of contrast medium into the CNS can occur quite rapidly.35
The metal Gd has been mainly used as the paramagnetic center of these chelates. However, also the transition metal Mn2+ was introduced in Mn-DPDP (Teslacan) with a more specific distribution pattern accumulating in the liver and pancreas.36 Mn-DPDP does not have a label for CNS imaging. In an animal study, however, Lin and Koretsky37 used Mn2+ in fMRI in a rat model. This agent, being transported into cells in a similar manner to Ca2+ ions, can be viewed as a marker of neuronal activity. Once inside the cell, it can be visualized by its T1-shortening effect. Moreover, Stieltjes et al38 used Mn2+ in an animal model for spinal cord imaging. Because of severe cell toxicity, there is no suggestion that Mn2+ is appropriate for clinical use.
Small Molecular Contrast Media With a Higher Molarity
The first Gd chelates were all produced in the concentration of 0.5 mol/L, which is considered as the standard. However, quite recently, a compound with a higher concentration became available on the market as 1.0 mol/L Gadobutrol (Gd-BT-DO3A, Gadovist).39 The size of this compound is comparable with that of conventional Gd chelates. Its in vitro relaxivity (r1) has been shown to be higher (~20%-25% in plasma at 1.5 T) compared with other non-protein-binding Gd chelates.40 The doubled concentration of this agent reduces the bolus volume, which can be preferential for neuroimaging depending upon the technique being used.41,42 Imaging techniques such as T2* perfusion seem to benefit from this high-molar agent.
Small Molecular Contrast Media With a Weak Protein Affinity
Recently, the small molecular Gd-BOPTA (gadobenate dimeglumine; MultiHance) has become available for CNS imaging. Initially designed for advanced liver imaging, this agent has shown to be useful for CNS imaging as well.43,44 Studies by Cavagna et al45 showed that Gd-BOPTA leads to a stronger T1 shortening because of a weak affinity for human serum albumin (HSA). Human serum albumin that is approximately 13 nm in diameter and approximately 67,000 d in size serves as macromolecule carrier for Gd-BOPTA demonstrating a stronger enhancing effect at equivalent dose and serum concentration to conventional extracellular agents in MRI of the liver,46-48 in brain tumors,49 and in the vascular system.49,50 Multiple studies on liver imaging using Gd-BOPTA have been published since it was found that approximately 4% of these Gd chelates are excreted from the hepatocytes into the hepatobiliary system.51 The protein-binding effect depends on the field strength40 and on the amount of HSA as proven in vitro by Giesel et al.52
Since recently, also Gd-EOB-DOTA is available on the European market as a weak protein-binding agent.53 This agent is produced as 0.25 mol/L Primovist and labeled only for liver imaging because approximately 40% of its excretion pathway is via the hepatobiliary system.54,55 There are no publications available suggesting that this compound can be preferentially used for CNS imaging.
Small Molecular Contrast Media With Stronger Protein Affinity
Recently, MS-325 (Vasovist) has been marketed in Europe. This compound is also a small (938 d) Gd chelate but with a stronger affinity to HSA as compared with Gd-BOPTA or Gd-EOB-DOTA.56 Depending on the dose administered and the type of HSA (human vs animal), the majority of the injected compound binds to HSA noncovalently.57 The unbound fraction behaves like a conventional Gd chelate. The nonbound amount extravasates into the nonvascular space like any other small molecular contrast agent. However, this "hermaphrodite" is defined to belong to the group of intravascular contrast agents. The binding effect can be explained also by the so-called receptor-induced magnetization enhancement strategy. The binding to HSA causes an increase in relaxivity of the molecule, an approximately 9-fold increase at 20 MHz and a 4- to 5-fold increase at 64 MHz.40,58 Excretion is via the urinary system. Clinical trials need to show how CNS imaging may benefit from its enhancement characteristics and its special pharmacokinetics. First results are published for body CE MRA.59 However, Vasovist is currently labeled only for vascular imaging of peripheral vessels.
B-22956 is also an SMCM showing affinity to HSA exhibiting an increased T1 relaxivity with an even stronger binding effect compared with MS-325 with a bound fraction of HSA of approximately 94%.60 The excretion pathway of B-22956 is via the hepatobiliary (~45%) and the urinary (~55%) system.61 Its usage is being under clinical (phases 2 and 3) investigation for coronary artery imaging.62,63
Superparamagnetic Contrast Media
A long history of iron oxide particle usage can be found.64 These colloid-based nanoparticles are produced with a core of 50 to 180 nm as superparamagnetic or small particles of iron oxide (SPIO), with a core of 10 to 50 nm as ultrasmall or less than 10 nm as very small superparamagnetic iron oxide particles contrast agents. These particles are "super"-paramagnetic offering a strong magnetic moment with a higher r2; that is, they belong to the group of "negative enhancers," because in a strong magnetic field, they predominantly cause strong susceptibility effects.
Early on, MRI showed specific uptake by of the reticuloendothelial system of the liver and spleen.65,66 Superparamagnetic or small particles of iron oxide have been available on the market as ferumoxides (Feridex/Endorem); however, they are only labeled for liver imaging.67 After biodegradation, the iron is handled by the usual metabolic pathways. In preclinical and clinical trials as well as in the clinical routine (as "off-label" use), these iron oxides have been successfully used for CNS applications. In clinical studies, improved differentiation and characterization of brain tumors using iron oxides have been shown as promising CNS applications.68,69
The ultrasmall and very small superparamagnetic particles of iron oxide have been used for T1-weighted CE-MRA; however, for NC100150, clinical trials have been stopped.70-72
A variety of novel MR CM are under development. Quite advanced in the development are macromolecular Gd-based agents (typically 15-100 d). Known macromolecular CM (MMCM) are with an intermediate size ranging between 6473 d for Gadomelitol (P-792; Guerbet, Aulnay-sous-Bois, France) and 17,500 d for the 0.05 mol/L Gadomer-17 (Schering AG, Berlin, Germany).73 P-792 would be considered as a rather small MMCM with rapid renal excretion being under investigation to evaluate tumor angiogenesis in breast carcinoma.74 Other MMCM are so-called dendrimers that have been investigated in preclinical settings as prognostic markers and surrogates for pharmacokinetics of organs and tumors.75 With regard to the field of "molecular imaging" CM which are only of preclinical utilization (animal studies) became of more interest. Especially the field of stem cell research for effective "cell labeling" and "cell tracking" gained importance, and apart from common iron-labeled cell, other T1-positive contrast mechanisms are nowadays investigated such as Gd@C8276 or Gadofluorine M.77
CONTRAST MEDIA DOSAGE
This topic is ongoing in MRI and will be continuing with further improvement of the hardware technology and changes in sequence design and more advanced CM application strategies. By looking only at gadopentetate dimeglumine, the pioneer being used now worldwide in more than 45 million applications,78 we find the same dosage recommendations in the package inserts for the minimum dose by looking at France, Germany, Italy, Japan, the United Kingdom, and the United States, but different results if the maximal dose is considered. The maximum dose of 0.3 mmol/kg body weight did not gain approval in Japan or in the United States.78
However, it has been shown that a higher dose of Gd chelate-based contrast agents may help reveal more subtle disease states of the BBB (Fig. 3).79,80
Single-dose (A) and double-dose (B) imaging in a patient with metastases of a cerebral ependymoma. The single-dose imaging was only able to detect a solitary lesion in the right lateral ventricle (arrow heads), whereas the double-dose imaging 4 days after the initial scan revealed additional lesions in the left lateral ventricle (arrows) which were not reported and detected on the single-dose imaging study. High-dose imaging is able to increase the detection rate in cerebral tumors and allows a better delineation of enhancing tissue.
Several studies exist both for detection and characterization of focal CNS lesions. Initial investigations by Yuh et al81 have demonstrated that dosages of 0.2 mmol/kg and up to 0.3 mmol/kg allow detection of additional brain metastases in approximately 20% of patients. Although they detected highly significant differences in small lesions, there was no difference in the detection rate for lesions larger than 10 mm. The application of a triple dose was also superior compared with a delayed imaging. In between the highest dose group, the detection rate did not correlate with the application scheme. For screening of metastases, Sze et al82 compared single- and triple-dose contrast-enhanced MRI quantifying lesion load at single and triple doses in patients with risk of cerebral metastases and those who could benefit from the possible increased sensitivity in lesion detection. In their series, of all 70 negative single-dose studies, the triple-dose studies depicted no additional metastases in terms of the standard of reference. No statistically significant difference was seen between the results of the single- and triple-dose studies. For 10 equivocal single-dose studies, the triple-dose study helped clarify the presence or absence of metastases in 50% of the cases. In 12 patients with a solitary metastasis seen on the single-dose study, the triple-dose study depicted additional metastases in 25% of the cases. In the results of 1 of the 2 blinded readers, use of triple-dose contrast led to a statistical difference by decreasing the number of equivocal readings but at the expense of increasing the number of false-positive readings. The authors therefore conclude that routine triple-dose contrast administration in all cases of suspected brain metastasis is not helpful.
The effect of higher dosage on lesion size in metastatic brain tumors was assessed in the study of Van et al.83 The contrast of brain metastases after cumulative doses of Gd chelate was quantified and compared to assess the clinical utility of high dosage in a series of 39 patients with metastatic brain tumors. The post-Gd MRI contrast doubled with dose escalation from 0.1 to 0.3 mmol/kg and also increased with lesion size, by a factor of 2.5 between metastases of 3 and 16 mm diameter. At 0.2 and 0.3 mmol/kg, the respective numbers of visible metastases increased by 15% and 43% compared with 0.1 mmol/kg (P < 0.0001). Image contrast figures differed significantly between doses (P = 0.018). Both the number of metastases and the image contrast are significantly higher when dose escalation is performed. It is indicated that the number of detected metastases will increase further at Gd doses beyond 0.3 mmol/kg. Post-Gd MRI contrast increases with lesion size, to an extent that cannot be attributed to partial volume attenuation.
Regarding the effect of field strength, no differences were described. In a study comparing 3.0 and 1.5 T, cumulative triple-dose images of both field strengths were superior to standard field strengths. However, administration of a better CM such as gadodiamide contrast agent produces higher contrast between tumor and normal brain on 3.0 than on 1.5 T, resulting in better detection of brain metastases and leptomeningeal involvement.84
Besides better detection, the high dose may also allow a better characterization of gliomas. In suspected low-grade tumors, a mild enhancement pattern might be better visualized, and a tumor recurrence may be better visualized as has been shown by Erickson et al.11
In a prospective study protocol, they evaluated if there is a subset of brain tumors that demonstrate contrast enhancement with triple dose and magnetization transfer saturation (MTS) that do not enhance with standard imaging and standard contrast dose. In 15 patients with either newly diagnosed primary brain tumor or brain tumor that had been followed for more than 2 years, T1-weighted MTS images without intravenous contrast, with 0.1 mmol/kg without MTS (single-dose images) and with additional 0.2 mmol/kg Gd and MTS ("TD/MTS") were obtained. None of the patients had enhancement on single-dose imaging, although 6 patients had areas of enhancement on triple-dose MTS images. So far, it might be possible that those small areas of enhancement seen only with triple-dose MTS might represent areas of higher-grade tumor which may benefit form a more intensive initial tumor therapy.
CONTRAST AGENTS USED AT DIFFERENT FIELD STRENGTH
During the past decade, most clinical experience in the field of cerebral MRI has been with 1.5-T systems with a dose of 0.1 mmol/kg body weight of the conventional Gd chelates, as this combination seems to be an acceptable compromise between imaging expense and diagnostic sensitivity.85,86 The number of 3.0-T systems in clinical settings has been increasing during the past few years, and systems operating at even higher field strengths are being used in clinical trials already.87
One of the main features of MRI at 3.0 T is the general gain in SNR compared with that at lower field strengths. Therefore, one may anticipate that the increased SNR associated with a higher magnetic field will translate, at least to a certain degree, into a higher CNR between enhancing and nonenhancing tissues. The increased CNR should improve the delineation of contrast agent-induced changes and, thus, could increase the sensitivity of detection of such signal intensity changes.
In addition, the effectiveness of the T1-shortening effect of a Gd-based contrast agent depends on the baseline T1 relaxation time of local tissue. With the longer baseline T1 relaxation times brought about by a higher magnetic field strength, the T1-shortening effect of Gd-based contrast agents will be greater, as the relaxivity of such contrast agents changes only marginally between 1.5-T and 3.0-T MRI.88,89 Accordingly, the signal intensity changes caused by contrast enhancement observable in T1-weighted images should generally be stronger at 3.0 T than they are at 1.5 T.
Giesel et al90 described that CM with affinity to serum HSA, for example, weak protein-binding Gd chelates, cause a decrease in T1 relaxation rate with higher field strength.
At a study comparing 1.5- and 3.0-T imaging by Krautmacher et al91 showed that the CNR increased more than 2-fold with respect to 1.5-T imaging, with a median relative CNR (ratio of change in CNR with full dose) of 2.8. Moreover, even with the reduced contrast agent dose, CNR at 3.0 T was significantly higher (ratio of change in CNR with half dose; median, 1.3-fold) compared with the same patient's examination at 1.5 T with the full dose of contrast agent (P < 0.01). Trattnig et al92 found that the cumulative triple dose at 3.0 T still shows the best results in the detection of brain metastases but that CM dose for dynamic susceptibility- weighted CE perfusion MRI can be reduced to 0.1 mmol compared with 0.2 mmol at 1.5 T.
There are 2 different clinical strategies to exploit this CNR increase. First, the higher CNR can be invested to improve the visualization of subtle disruptions of the BBB, thus possibly improving the sensitivity for depiction of small metastases or early inflammatory changes. Second, the higher CNR could, in principle, be traded to reduce the dose of contrast agent for contrast-enhanced brain imaging at 3.0 T.
In regard to the first approach, that of a possible improvement in sensitivity, this may be said. In standard clinical settings, a dose of 0.10 mmol/kg Gd chelate is generally considered sufficient for contrast-enhanced MRI of the brain at 1.5 T,85,86,93 as this dose delivers acceptable diagnostic sensitivity at a reasonable cost. Imaging for certain indications, however, has been shown to benefit from double or triple the dose of contrast agent. Typically, these indications include clinical situations in which the detection of even subtle disruptions in the BBB has an effect on patient treatment.94-96 Yuh et al80 found that studies at 1.5 T with triple the dose of contrast agent were more effective in the detection of metastatic brain lesions than were studies with the full dose of Gd chelate.
In regard to the second approach, that of a reduction in the dose of contrast agent, this may be said. By using the reduced contrast agent dose at 3.0-T MRI, CNR was still higher compared with that at 1.5-T imaging with the full dose of contrast agent. This suggests that even with half the contrast agent dose, the diagnostic sensitivity in the depiction of disruptions of the BBB should be maintained at 3.0 T compared with the 1.5-T standard setting. In fact, all lesions depicted at 1.5 T with the full dose of contrast agent were also diagnosed prospectively and independently at 3.0 T with half the dose of contrast agent; lesion conspicuity was rated to be equivalent.
Haba et al97 showed that dose can be reduced by using MTS by 50% without loss of contrast enhancement in investigation of meningiomas. No matter which dose is used, MTS can also be helpful to further improve detection of small areas of enhancement.11
Awareness of the field strength is crucial for the optimal choice of contrast agents. Comparison of in vitro relaxivity values has shown relevant changes in relaxivities depending on field strength.40 These results show that, for example, protein-binding CM are most efficient at 0.47 T with a relatively high r1 (L · mmol−1 · s−1) and a relatively low r2 (L · mmol−1 · s−1) compared with 4.7 T, where r2 is found to be increased and r1 is decreased. This effect is less with the conventional agent. The r1/r2 ratio from an SPIO, for example, Resovist, changes from 0.15 at 0.47 T to 0.01 at 4.7 T measured in plasma at 37°C.40
COMPARATIVE CONTRAST MEDIA STUDIES
Recently approved in the United States, protein interactive contrast agent Gd-BOPTA (gadobenate dimeglumine; MultiHance) demonstrated a stronger enhancing effect at equivalent dose and serum concentration to conventional extracellular agents both in MRI of the liver98,99 and in animal models of brain tumors.100 Studies by Cavagna et al100 have shown that the stronger contrasting behavior of Gd-BOPTA is caused by an increased T1 relaxivity in blood arising from an affinity that the Gd-BOPTA molecule has for serum albumin.
Runge et al101 have demonstrated that a 0.2-mmol/kg dose of Gd-BOPTA is equivalent to a 0.3-mmol/kg dose of Gd-DTPA-BMA for MRI of CNS lesions. In an intraindividual crossover clinical study, Gd-BOPTA was compared with other Gd agents at equivalent dose.102 By comparison with the standard contrast agents, Gd-DTPA and Gd-DOTA, Gd-BOPTA demonstrated an up to 30% stronger signal intensity enhancement and a better CNS-to-lesion contrast (Fig. 4).
Intraindividual comparative study between the high relaxivity contrast agent Gd-BOPTA (MultiHance) (A) and the standard contrast agent Gd-DOTA (Dotarem) (B) in a patient with cerebral glioma. The scan with the high relaxivity agent presented a significant higher lesion contrast and was able to visualize an enhancing satellite lesion, suggestive of a high-grade tumor part, which could not be detected with the use of a standard agent (arrow). The higher relaxivity influences substantially stronger the T1 relaxation of the pathological tissue which results in an up to 30% stronger enhancement of the lesions.
In 2 intraindividual crossover studies, Gd-BOPTA has been compared with other Gd agents at equivalent dose.44,102
In the first 2 centric study, 22 patients with either high-grade glioma or metastases were examined with 0.1-mmol/kg body weight doses of 0.5 mol/L Gd-DTPA and 0.5 mol/L Gd-BOPTA in a controlled randomized fashion. Imaging was performed before injection (T1-weighted spin-echo (SE) and T2-weighted fast spin-echo (FSE) acquisitions) and at 1, 3, 5, 7, 9, and 16 minutes after injection (T1-weighted SE acquisitions). All available studies were evaluated on-site by the investigators and off-site by 2 independent, highly experienced radiologists who were blinded to the results of the on-site evaluations and to all patient and contrast agent information. The qualitative assessment was performed in terms of lesion-to-brain contrast, lesion delineation, morphology and vascularization, and global image preference. Additional qualitative assessment of global enhancement, as well as quantitative region-of-interest comparison, was performed. The region-of-interest data were used to calculate lesion-to-brain contrast and differences from precontrast to postcontrast in lesion signal intensity.
The same protocol was used for the second study which compared Gd-DOTA with Gd-BOPTA (unpublished data).
In both studies, Gd-BOPTA demonstrates better CNS-to-lesion contrast and a signal intensity enhancement that was up to 30% stronger (Fig. 1). In the first study, significant (P < 0.05) preference for Gd-BOPTA over Gd-DTPA was noted by both off-site readers for the global assessment of contrast enhancement (Gd-BOPTA preferred in 13 and 17 cases; Gd-DTPA in 4 and 4 cases and equivalence in 5 and 1 case; readers 1 and 2, respectively). Similar preference for Gd-BOPTA was noted by off-site readers and on-site investigators alike for lesion-to-brain contrast and all other qualitative parameters (Fig. 2). Off-site and on-site quantitative evaluation revealed significantly superior enhancement by Gd-BOPTA compared with Gd-DTPA from 3-minute postinjection (P < 0.05).
In the second study, both blinded readers considered the global contrast enhancement to be significantly superior after Gd-BOPTA administration. Reader 1 considered the contrast enhancement to be superior after Gd-BOPTA administration in all 13 patients, whereas reader 2 considered the enhancement to be superior after Gd-BOPTA administration in 11 patients and equal in 2 patients. Similar results were obtained in terms of the global contrast agent preference; for none of the 13 patients was Gd-DOTA preferred over Gd-BOPTA, whereas Gd-BOPTA was preferred over Gd-DOTA in 13 and 12 patients, respectively.
Evaluation of specific enhancement parameters revealed clear superiority for Gd-BOPTA over Gd-DOTA. Reader 1 considered Gd-BOPTA to be superior in a significantly higher number of patients for all evaluations on all sequences. Reader 2 similarly considered Gd-BOPTA to be superior to Gd-DOTA for CNS-to-lesion contrast and lesion delineation, but did not note significant differences on any sequence for the evaluations of internal lesion morphology or tumor vascularization. Neither reader considered Gd-DOTA to be superior for any evaluation in any patient.
In the qualitative evaluation, both blinded readers determined the lesion-to-white matter contrast to be significantly greater with Gd-BOPTA compared with Gd-DOTA at all time points after contrast agent administration.
CONTRAST-ENHANCED PERFUSION MAGNETIC RESONANCE IMAGING IN BRAIN TUMORS
Perfusion-weighted imaging (PWI) in brain tumors has benefits for 3 major fields: differential diagnosis, biopsy planning, and treatment monitoring. In this section, we will focus on the role of perfusion MRI in improving accurate diagnosis and monitoring brain tumors during therapy. For differential diagnosis, biopsy planning, and treatment monitoring of brain tumors, besides PWI, other imaging methods, such as diffusion-weighted imaging and spectroscopic imaging, are beneficial (for reviews about these techniques, see Law103 and Provenzale et al104). Together with PWI, MRI now has the ability to provide quantitative cellular, hemodynamic, and metabolic information about brain tumor biology. Perfusion-weighted imaging in neuro-oncology is mostly performed using first-pass, dynamic susceptibility- weighted, contrast-enhanced (DSC) MR echo-planar imaging approaches.105 Perfusion imaging approaches, such as arterial spin labeling, which do not need extrinsic CM application but are only able to measure cerebral blood flow (CBF) as perfusion-related parameter,106 will not be reviewed in this work.
The basic principle of PWI using DSC MRI is as follows: the first-pass effect of a contrast bolus in brain tissue is monitored by a series of T2*-weighted MR images. The susceptibility effect of the paramagnetic contrast agent leads to a signal loss that can be converted, using the principles of the indicator dilution theory, into an increase of the contrast agent concentration. From these data, parameter maps of cerebral blood volume (CBV) and CBF can be derived. Regional CBF and CBV values can be obtained by region-of-interest analysis. For in-depth review article that described physical basics of DSC MRI, we refer the reader to Reference 107. In neuro-oncological issues, mainly the parameter CBV has been investigated.105 For in-depth review articles about the basic principles of perfusion imaging in neuro-oncology, we refer the reader to References.104,105,108
Brain tumors are a heterogeneous group of neoplasms with a correspondingly wide variation in histology and a variety of imaging features. Accurate diagnosis and grading of brain tumors, however, are critical to determine prognosis and therapy schemes that base on the 3 main columns: surgery, radiotherapy, and chemotherapy. Magnetic resonance imaging is the modality of choice for depiction and delineation of intracerebral neoplasms. However, tumor specification is limited, and sometimes, conventional MRI cannot discriminate glioblastomas from solitary metastases, CNS lymphomas, or other glioma grades. Because their management and prognosis are different, early differentiation is important. The results of the available studies in literature, all with relatively limited patient numbers, indicate that DSC MRI is useful in the preoperative diagnosis of gliomas, CNS lymphomas, and solitary metastases, as well as in the differentiation of these neoplastic lesions from infections and tumorlike manifestations of demyelinating disease.105,109-111 For these issues, it delivers higher predicting values than does conventional MRI.
Our experience on brain tumor differentiation is that PWI has superior diagnostic performance in predicting glioma grade and in differentiating glioblastoma from other tumor entities (metastases, meningiomas, and CNS lymphomas) when compared with spectroscopic imaging and DCE-MRI.111 Because of the shorter acquisition time and the better predictive values in differential diagnosis, we would favor the use of perfusion over spectroscopic imaging and DCE-MRI on a 1.5-T MR unit. This may be the case in patients with reduced physical condition and compliance, often encountered in brain tumor patients, which results in a limited imaging time.
Because of a significantly higher tumor perfusion in glioblastomas compared with CNS lymphomas,105,109,111 a threshold value of 1.4 for relative CBV provided sensitivity, specificity, and positive and negative predicting values of 100%, 50%, 90%, and 100%.111 Although conventional MRI characteristics of solitary metastases and primary high-grade gliomas may sometimes be similar, MR perfusion and spectroscopic imaging enable distinction between the two.111,112 Although both intratumoral metabolite ratios and rrCBV or rrCBF values did not allow for discrimination between the 2 entities, analyzing the peritumoral T2-weighted-hyperintense region enables the discrimination between high-grade gliomas and metastases, because CBV was significantly higher in peritumoral nonenhancing T2-weighted-hyperintense regions of glioblastomas compared with metastases. Thus, elevated perfusion in the peritumoral region of the lesion represents high-specificity glioma in differentiation of glioma from metastasis or grade 1 meningioma.111,112 Hence, PWI allows us to readily appreciate tumor extension past obvious gross anatomic boundaries on conventional MRI.
Correct grading of gliomas has significant clinical impact, because adjuvant therapy after surgery is usually administered to high-grade but not low-grade gliomas. Histopathology as gold standard based on biopsy samples is limited because of the inherent sampling error in these heterogeneous tumors.103 Several studies reported that high-grade gliomas had higher relative regional CBV (rrCBV)110,111,113-115 and relative regional CBF (rrCBF)111,116,117 than low-grade gliomas, and glioblastomas have the highest tumor perfusion among all other glioma grades (Fig. 5). However, there is a significant overlap of tumor perfusion between high- and low-grade gliomas, which may be explained by the inherent glioma heterogeneity and the sampling error of biopsy samples.103,105,111 This overlap leads to a low specificity, especially when differentiating grade 3 from grade 2 gliomas. Thus, PWI has limited utility for an individual patient in making a specific diagnosis, but they may be of great clinical value for biopsy guidance because of the potential glioma heterogeneity with high-grade components that might be interspersed among low-grade components. Nevertheless, PWI increases the sensitivity, specificity, and positive and negative predicting values compared with conventional MRI, which is only 73%, 65%, 86%, and 44%,110 for discriminating high-grade from low-grade gliomas. Future work has to focus on the optimum threshold values to be used in a clinical setting to evaluate tumors preoperatively for histological grade.
A 73-year-old patient with histologically proven glioblastoma multiforme at first presentation. A, Contrast-enhanced T1-weighted MR image. Parameter maps for CBV (B), CBF (C), and percent susceptibility (D). Tumor perfusion is highly above gray and white matter, indicating increased microcirculation typical of high-grade glioma. The parameter "percent susceptibility can be easily calculated delivering similar information as blood volume and flow maps and might be used for clinical purposes whenever absolute quantification of CBV and flow is not important, for example, biopsy targeting.
Although PWI has a better diagnostic performance than conventional MRI techniques in distinguishing different tumor entities, PWI cannot eliminate the need for a biopsy and histological confirmation because modern treatment regimens also take genetic mutations of tumor cells into account.
Because histopathology as gold standard based on biopsy samples is limited because of the inherent sampling error in these heterogeneous tumors, biopsy guidance by fMRI methods, especially in the homogeneous appearing low-grade gliomas, is crucial. Perfusion-weighted imaging is suitable for determining tumor areas of increased microcirculation that very well correspond to anaplastic areas of active tumor growth. These areas should be the target of stereotactic biopsy.108 Several recent studies report that, by using PWI, it may become possible to reduce potential errors caused by sampling bias from a stereotactic biopsy.105,108,111,118
It is very important to evaluate for tumor status during therapy to assess for therapeutic response and treatment-related complications, for example, the differentiation between recurrent tumor and treatment-related complications. Studies on PWI for these issues show that it helps better assessing the tumor response to therapy, residual tumor after therapy, and possible treatment failure and therapy-related complications, such as radiation necrosis.105,108 In case of the latter, new enhancing lesions might appear years after radiotherapy that are indistinguishable from tumor recurrence with conventional MRI. In this issue, an enhancing lesion with rrCBV ratios of higher than 2.6 suggests tumor recurrence, whereas ratios lower than 0.6 suggest therapy-related nonneoplastic contrast enhancement114 (Fig. 6). Problematic is contrast-enhancing tissue with a CBV ratio between 0.6 and 2.6. Then, additional nuclear medicine or spectroscopic imaging approaches must be performed.
Standard contrast-enhanced T1-weighted SE imaging (A) and rCBF map of perfusion MRI (B) using a single dose of MR CM (MultiHance) in a patient with follow-up after irradiation of a temporoparietal fibrillary (World Health Organization [WHO] grade 2) astrocytoma. The standard imaging presents a new area of contrast enhancement at the dorsal border of the tumor. Standard imaging is not able to differentiate a malignant transformation of the tumor from treatment-related changes. The perfusion scan confirms a high blood flow of the lesion which is suggestive of a malignant transformation as has been shown in a vast number of studies.
Perfusion-weighted imaging has tremendous impact on treatment monitoring of low-grade gliomas, besides the advantages in biopsy planning. Because of the intact BBB, valid quantification of perfusion is possible in these entities. In case of a disrupted BBB, leakage of contrast agents from tumor vessels causes underestimation of tumor CBV in PWI.119 In low-grade gliomas, determination of rrCBV measurements can be used to predict clinical response. In a recent study, low-grade gliomas that had progressed more rapidly (mean time to progression of 245 days) had significantly higher CBV than those with stable tumor volumes at follow-up (mean time to progression of 4620 days). The authors proposed a threshold value of rrCBV (>1.75) to indicate a propensity for malignant transformation.120 The reason for this finding is presumably-as in biopsy planning-that PWI depicts focal anaplastic areas in low-grade gliomas that have not yet led to a disruption of the BBB and therefore to a contrast enhancement on conventional MRI. The same applies for low-grade gliomas after radiotherapy. Perfusion-weighted imaging also detects a subset of patients with higher tumor CBV and shorter progression-free survival.121 Thus, PWI enables a better prediction of prognosis after radiotherapy than conventional MRI, but also after antiangiogenic chemotherapy for gliomas, PWI has shown its potential to better predict treatment outcome than tumor volume determined on conventional MRI.122 For other intra-axial lesions, such as brain metastases,123,124 perfusion-weighted imaging has also shown its potential to better predict treatment outcome than tumor volume. In this context, a reduction of CBV was highly predictive of treatment response, whereas an increase in CBV was a hint for nonresponse. In extra-axial lesions, such as meningiomas, DCE-MRI might be a good alternative to DSC MRI for treatment monitoring125,126 (see also the following section), because the technique is not as susceptible to susceptibility artifacts arising from bone and air as DSC MRI.
In summary, PWI delivers higher predicting values than conventional MRI by providing maps of the regional variations in cerebral microvasculature of normal and diseased brains. Perfusion-weighted imaging can easily be incorporated as part of the routine clinical evaluation of intracranial mass lesions because of the relatively short imaging and data-processing times and the use of a standard dose of contrast agent. Thus, PWI together with conventional MRI should be regarded as the test of choice to diagnose and monitor brain tumors before, during, and after therapy.
Dynamic contrast-enhanced MRI is the acquisition of serial images before, during, and after the administration of extracellular, low-molecular, weighted MR CM. The resulting signal intensity measurements of the tumor reflect a composite of tumor perfusion, vessel permeability, and the extravascular-extracellular space.127,128
Dynamic contrast-enhanced MRI has been investigated for a range of clinical oncological applications, including cancer detection, diagnosis, staging, and assessment of treatment response.33,126,129-132 Dynamic contrast-enhanced MRI parameters measure permeability and its aberrations, whereas microvascular density (MVD) measures only the histopathologically partial picture of the tissue microvasculature. Furthermore, MVD also measures the heterogeneous property of tumors, is limited by histopathologic sampling, and is generally hotspot value. Tumor microvascular measurements by DCE-MRI have been found to correlate with prognostic factors, such as tumor grade, MVD, and vascular endothelial growth factor expression, and with recurrence and survival outcomes.133,134
In addition, changes in DCE-MRI in follow-up studies during therapeutic intervention have been shown to correlate with outcome,130,132 suggesting a role for DCE-MRI as a predictive marker.130,132
In contrast to conventional (static postcontrast T1-weighted) enhanced MRI, which simply presents a snapshot of enhancement at 1 time point, DCE-MRI permits a fuller depiction of the wash-in and wash-out contrast kinetics within tumors, and this provides insight into the nature of the bulk tissue properties on its microvascular level. Such data are ready to 2-compartment pharmacokinetic modeling from which parameters based on the rates of exchange between the compartments can be generated. These modeling condenses the 4-dimensional information (3-dimensional CM delivery over time) via parametric mapping into a 3-dimensional image data set. These color codes aid the visual assessment of tumor microvascular environment.
Although DCE-MRI is in clinical use, there are also a number of limitations, including overlapping between malignant and benign inflammatory tissue, drug intervention (Fig. 1),29 failure to resolve microscopic disease, and the inconsistent predictive value of enhancement characteristics with respect to clinical outcome.
The accuracy of DCE-MRI relies on the ability to model the pharmacokinetics of an injected CM, using the signal intensity changes on sequential MRI. Signal intensity changes can be rapid immediately after contrast injection (depending on its size and surface property), and the temporal sampling rate is of major importance. However, increasing the temporal sampling rate of the images has direct consequences on critical image characteristics, that is, spatial resolution, SNR, and volume of coverage. There is always the trade between the temporal resolution and spatial resolution.
With the strong demand in drug development (especially with the introduction of anti-vascular endothelial growth factor trials) to identify a biomarker that can assess tumor microvascular properties noninvasively in animal135 as well in human studies,136-139 this technique seems to be most appealing as a possible "imaging biomarker."
PRINCIPLES, METHODOLOGY, AND TECHNICAL ASPECTS
Dynamic contrast-enhanced MRI is performed by obtaining sequential MRI before, during, and after the injection of CM. For human investigations, CM are generally of small molecular weighted Gd-containing compound such as Gd-DTPA or Gd-EOB-DTPA. In contrast to this, T1-weighted imaging technique commonly used in neuroimaging is T2* or dynamic susceptibility-weighted MRI. This can be used early after contrast injection (in the first few seconds) to observe the transient first-pass effect of CM, which provides information about perfusion.
The T2* effect is measured as a rapid drop and subsequent recovery of signal intensity after bolus injection. Measurement of first-pass T2* effects necessitates a rapid imaging method that is performed over 5 to 15 slices through the target tissue (see DYNAMIC CONTRAST-ENHANCED MAGNETIC RESONANCE IMAGING) and needs especially the convention of 1-compartment microvascular properties.
Therefore, the T2* imaging technique is commonly used in ischemic stroke imaging for characterizing the "tissue at risk." These techniques are not really appropriate for intra-axial tumors with BBB defect (high-grade gliomas) and extra-axial tumors (ie, meningioma and acoustic neurinomas).
Dynamic contrast-enhanced MRI is used during a longer time course (several minutes) to observe the extravasation of CM from the vascular space (first compartment) to the interstitial space (second compartment), providing information about blood volume and the vascular permeability. The accumulation of the CM in the second compartment results in a signal increase on T1-weighted MRI: a subsequent wash-out effect can be observed if the vascular permeability is higher and there is reflux of CM back to the vascular space.136-139
Signal intensity will change in proportion to the CM concentration in the volume element of measurement or voxel. The principles of tracer pharmacokinetics can be applied to DCE-MRI if the dependence of signal intensity on CM concentration is known.
To accurately relate the change in signal intensity (Δ_S_) to CM concentration in the tissue (_C_t), the precontrast tissue (_T_1) value is essential. The tissue contrast as a function of time [_C_t(t)] also depends on the arterial blood plasma concentration as a function of time [_C_p(t)], which varies depending on the mode of injection (bolus vs long injection rate). This can effect the pharmacokinetic behavior and its parameters (see also Tofts et al140).
To adequately apply a pharmacokinetic 2-compartment model on the basis of DCE-MRI time course, measurement of the intrinsic T1 value and arterial input function are essentially needed. The arterial input function requirement is often addressed using average values measured in healthy control subjects from blood samples, which have been reported in the literature.140
Improved quantization of estimated Gd concentration necessitates the acquisition of T1 map of the target tissue before injection. This finally enables an estimation of the concentration of Gd chelate present in tissue but requires additional time both to acquire and calculate. However, linearity of contrast concentration in the targeted tissue is important but is not an absolute necessity as many clinically important characteristics can be observed with slightly nonlinear Gd concentration-signal intensity relationships.136
However, both T1- and T2*-weighted MRI sequences can be designed to detect the initial vascular phase of contrast medium delivery and thus enable the estimation of tissue perfusion and blood volume. Signal enhancement caused by shortening of T1 relaxation time can be quantified using T1-weighted sequence.141-143 Concentrated intravascular CM also produce magnetic field inhomogeneities that reduce the signal intensity of surrounding tissues, and T2*-weighted sequences can be used to quantify these effects.144,145
T1-weighted DCE-MRI sequences are also used to detect the presence of CM in the extravascular fluid space. This allows the estimation of permeability and extracellular leakage space. The analysis methods for evaluating these techniques have their foundations in the basic physiological and pathological assumptions.146
Dynamic contrast-enhanced MRI is relatively simple to perform and should be within the reach of virtually any MRI center. To optimize imaging, dedicated coils should be considered whenever possible. The patient must be comfortably positioned such that the same position can be maintained during the entire study without excessive motion. Furthermore, an adequate peripheral access should be in place before entering the MRI suite. After routine preliminary T1- and T2-weighted images have been performed, the DCE-MRI sequence can be performed.
CLINICAL EXPERIENCE
Analysis of enhancement seen on T1-weighted DCE-MRI has been investigated in a number of clinical areas. An established role in lesion characterization is described in distinguishing benign from malignant breast and musculoskeletal lesions.147,148 Already simple observation and characterization of the signal intensity time curves have presented malignant tissues generally enhanced early, with rapid and large increases in signal intensity compared with benign tissues, which, in general, show a slower increase in signal intensity. Interestingly, nonmalignant proliferating tissues, such as benign prostatic hyperplasia, are described as having enhancing characteristics similar to prostate cancer.149-151
INTRACRANIAL TUMORS
Intracranial tumors can be divided into benign entity (meningioma, 15%; pituitary adenoma, 10%; and acoustic neuroma, 8%), malignant entity (glioma, 25%; and metastases, 33%), and other (9%). Most of them (apart from low-grade gliomas, grades 1 and 2) are characterized in post-T1-weighted MRI with contrast enhancement. These characteristics can be especially applied for DCE-MRI (Fig. 7). Dynamic contrast-enhanced MRI allows further noninvasive characterization of brain lesion and its microcirculatory properties during therapeutic intervention (chemotherapy and/or radiotherapy) (Fig. 8) and biopsy planning (Fig. 9).
Optical nerve sheet meningioma with characteristic homogeneous contrast enhancement color coded on the basis of a 2-compartment model (B). Echoplanar imaging sequence (A) presenting in the skull base distortion which indicates a limited utilization for DSC-MRI in certain anatomical areas (arrows). In contrast, DCE-MRI and parametric mapping are not influenced by susceptibility artifacts and allow characteristic discrimination of the meningioma and the adjacent tissue, which can be used for high-precision radiotherapy planning, for example, in conjunction with positron emission tomography data (C and D).
A patient with a low-grade glioma (A--C) presenting no contrast enhancement on T1-weighted SE (A) and DCE-MRI (C). In contrast, DSC-MRI shows a hyperfused region (CBF) in the right frontoparietal hemisphere (B), indicating an anaplastic transformation, which could be histologically confirmed as a WHO grade 3 glioma. Three years after surgery and radiotherapy, a recurrent, strongly enhancing tumor was observed both with T1-weighted SE and DCE-MRI c (D and E). The DSC MRI, however, indicates anaplastic tissue at the border of the resection cavity, whereas the more dorsal parts are less malignant, although strongly enhancing.
DCE-MRI performed for biopsy planning in a patient with malignant glioma. Dynamic contrast-enhanced MRI is used to depict most strongly enhanced lesions which represent the most vascularized and malignant tumor parts.
Hawighorst et al152 described that, before and during radiotherapy, DCE-MRI is helpful to characterize lesion changes before structural changes and predict therapeutic response (Fig. 10). Furthermore, DCE-MRI in combination with DSC-MRI technique is helpful to assess functional tumor response which is in concordance to the glioma WHO grading, and in addition, it is helpful to differentiate gliomas from other brain tumors.153
Parametric mapping of a skull base meningioma before (A) and after radiotherapy (B). In contrast of the stable morphology of the tumor after radiotherapy, decreased enhancement characteristic using DCE-MRI can be observed (B). The changes in the signal intensity time curve represent a decreasing vascularization caused by radiation.
Meningiomas are the most common nonglial primary tumor and the most common intracranial extra-axial neoplasm. Almost all meningiomas are characterized with a rapid and intense contrast enhancement after the application of CM.125 Although the meningiomas are usually slow-growing alesions, their response to radiotherapy is often difficult to assess, and DCE-MRI techniques showed promising results during radiotherapy (Fig. 10). Changes in tumor volume are easily measured after therapy and demonstrate possible changes but do not provide information about the tumor microcirculation. This additional information can be assessed and evaluated by pharmacokinetic analysis on the basis of DCE-MRI technique.125
In summary, continuous advances in therapeutic approaches necessitate new concepts in noninvasive assessment and characterization of brain lesions. Nuclear medicine techniques, especially positron emission tomography with computed tomography, have gained clinical utilization to combine structural and functional information. Nowadays, DCE-MRI is not a competitive functional imaging technique, and it is providing complementary functional information along with high resolution of structural MR information. Dynamic contrast-enhanced MRI is increasingly used as a so-called noninvasive "biomarker" to monitor ongoing therapies, such as neoadjuvant chemotherapy,154,155 combined chemotherapy and radiotherapy,156 and, in particular, antiangiogenic or immunologic therapy.157 In addition, DCE-MRI could, in the next 5 years, establish its robustness and complementary functional information on microvascular level, as it is more and more discussed for possible radiotherapeutic planning.158,159
With the improvement of MR technologies such as faster image acquisition (parallel imaging), improvement of spatial resolution (introduction of high-field MRI >7 T), and the introduction of contrast agents with different properties (micromolecules and macromolecules), DCE-MRI will become irreplaceable, noninvasive, and cost-effective functional imaging technique for research and clinical environment.
SUMMARY AND CONCLUSIONS
Contrast media application is essential in MRI for the diagnostic workup of patients with cerebral tumors. The radiologist should know about the availability of different CM with different properties and potential.
The contrast is influenced by the dosage of the CM, the use of MR field strength, and the applications strategy.
In modern neuroimaging protocols, however, functional contrast-enhanced techniques, such as PWI and DCE, allow further insights into the pathophysiology of cerebral tumors and provide information that complements the superb morphological assessment with standard imaging techniques. Perfusion-weighted imaging delivers higher predicting values than conventional MRI by providing maps of the regional variations in cerebral microvasculature of normal and diseased brains. Perfusion-weighted imaging can easily be incorporated as part of the routine clinical evaluation of intracranial mass lesions because of the relatively short imaging and data-processing times and the use of a standard dose of contrast agent. Thus, PWI together with conventional MRI should be regarded as the test of choice to diagnose and monitor brain tumors before, during, and after therapy.
Dynamic contrast-enhanced imaging techniques also provide complementary functional information along with high resolution of structural MR information. Dynamic contrast-enhanced MRI is increasingly used as a so-called noninvasive "biomarker" to monitor ongoing therapies, such as neoadjuvant chemotherapy or radiotherapy. New treatment strategies, for example, antiangiogenic or immunologic therapy, would benefit from this technique. The method provides information on the tissue perfusion and permeability which allows the assessment of biological activity in pathological tissue and the effect of antivascular cancer drugs.
In addition, DCE-MRI could assist in the treatment planning process by adding information about the microvascular density, size, and grade of the tumor.
Dynamic contrast-enhanced MRI and PWI will become established methods to allow a noninvasive and cost-effective assessment of tumors including those of the brain.
ACKNOWLEDGMENTS
The authors thank P.D. Griffiths and I.D. Wilkinson from the Academic MR Unit, University of Sheffield, UK, and P. Choyke from the Molecular Imaging Program, NIH-NIC, for their support and collaboration. They also thank Mrs Reinhardt and Mr Neff for assisting in the intense pharmacokinetic analysis in brain tumor analysis for this article.
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Keywords:
brain tumors; contrast media; MRI; DSC-MRI; DCE-MRI
© 2006 Lippincott Williams & Wilkins, Inc.