MAGNETIC RESONANCE IN MEDICINE
22,268-272 ( 1991)
Contrast Agents for Fast Imaging * GERALD L. WOLF AND JADWIGAROGOWSKA Center for Imaging and Pharmaceutical Research, Massachirsetts General Hospital, Building 149, 13th Street, Charlestown, Massachusetts 02129 Received July 18, 1991
Many new pulse sequences are available that can be completed in less time than conventional spin-echo MRI. However, an operational definition of “fast” is twice the speed of the (dynamic) process of interest. Adequate speed is necessary, but may not be sufficient. The imaging must also have satisfactory spatial resolution and safety and must report the signal of interest with sufficient reliability to be interpretable. Frequently, quantitative or semiquantitative measurements must be feasible, even when the outcome is only expressed relative to a control or compared to a previous assessment of the same parameter. Contrary to earlier speculations, MR contrast agents have provided useful characterizations of tissue anatomy or function when utilized with slower imaging methods. The purpose of this paper is to examine some generalities that influence the utility of contrast agents when MR technology allows faster imaging. The measurement of tissue perfusion will serve as the illustrative example of the general principles. THE FREQUENCY DOMAIN
The Nyquist theorem states that a dynamic signal must be sampled at least twice as fast as the information is changing. Table 1 demonstrates the broad range of signal domains of potential interest. For measures of tissue perfusion, the imaging sequence must be able to image in the range of 0.3-3 per second. Thus, many sequences that are called “fast” are not fast enough for this application. For those that are, the user needs to be aware of the details of signal collection, e.g., the need for a preparation pulse, the order of k-space sampling, the T 1, T2, T2 * sensitivity, etc. In some cases, this impacts upon the selection of a contrast agent formulation, dose, or administration profile. MINIMAL CRITERIA FOR “FAST” CONTRAST AGENTS
Investigators have become familiar with indicator-dilution methodology ( 1-3), where contrast agents with appropriate biodistributions are functional indicators with in vivo detection by the MRI device. Most often, the agent is given by bolus and * Presented at the SMRM Workshop on Contrast Enhanced Magnetic Resonance, Napa. CA, May 2325. 1991. 0740-3194/91 $3.00 Copyright 0 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.
268
CONTRAST AGENTS FOR FAST IMAGING
269
TABLE 1 Some Signal Domains Electrophysiology Contraction Perfusion Excretion Innovation Change
100 Hz 10 Hz 1 Hz 0.01 Hz 1x
IO-~HZ
1 X lo-’ Hz
mathematical analysis appropriate to this injection method is applied. The cautions and methodologic details are well-considered elsewhere ( 2 , 3 ) .However, for the bolus case, the Nyquist theorem also applies to the input function; when the agent is administered on the venous side, its arterial concentration profile must have a bolus with a good amplitude and a width that provides twice the frequency of the physiologic signal. For example, where kidney function is of interest, our studies show the cortical perfusion response peaks at 10 s, the proximal tubule excretory response at 50 s, and the distal tubule excretory response at 120 s. For tissue perfusion measurements in this case, the bolus must be prominent and the contrast agent must be safe enough for an effective dose to be entirely injected within 3-5 s. It is uncommon for such injection profiles to be used for acute toxicity tests. Table 2 summarizes a few general criteria for contrast agents in fast tissue perfusion measures. Many agents are available that provide a satisfactory bolus and their distribution within the tissue commences with the “first pass.” There are important trade-offs of the ideal properties for an MR contrast agent when one intends to sample the dynamic signal change in a tissue region; extracellular agents, blood pool agents, and targeted agents may offer differences in acceptability on a case by case basis ( 4 - 6 ) . INTENSITY-CONCENTRATION RELATIONSHIPS
As the bolus moves through the tissue of interest, it must change the MR signal from the sampled region by a detectable and measurable amount. The latter process is facilitated if there is a known relation between local indicator concentration and local MR signal. MR signal intensities are notoriously dependent upon many influences, many of which are either unmeasurable or lumped in somewhat simplified MR algebra relating signal to tissue content and motion ( 5 , 7, 8). Similarly, there is a
TABLE 2 Contrast Agents for Fast Imaging Safe enough for rapid injection Reasonable Biodistribution (Economical and Reimbursable) (Not an orphan)
270
WOLF AND ROGOWSKA
compartment
VCV
FIG. 1 . Biologic prediction of compartment effect. An MR contrast agent with a magnetic susceptibility center is distributed within a biologic compartment. Nuclei with magnetic moments outside the compartment are dephased by the magnetic susceptibility gradient created by the compartmentation.
spectrum of MR contrast agents available, all of which change tissue T 1, T2, and T2 * ( 5 , 9 ) . As proton relaxation is a summation of all local influences, it can become quite complicated to relate tissue MR signal to local concentration of MR contrast agent. However, measuring tissue signal change and/or comparison of dynamic response of the target tissue to an appropriate control usually provides sufficient simplification of the intensity-concentration relationship to encourage biological investigations. Available MR contrast agents range in size from small (70 nanometer) ferromagnetic particles with more than 10 lo iron oxide molecules. The size and distribution of relaxing centers within the molecule, as well as the choice of inorganic or organic electron spin donor determine the agent’s R 1, R2, and susceptibility effects. However, the agent’s biodistribution in tissues can have a significant influence upon the biologic efficacy. MAGNETIC SUSCEPTIBILITY AGENTS
There is a special interest in MR contrast agents that reduce tissue MR signal due to their asymmetric distribution or compartmentation in tissues. There are several apparent benefits to such agents for fast imaging and tissue characterization using MR contrast agents as indicators. First, the MR imaging sequences that have subsecond temporal response with good spatial resolution are especially sensitive to T2 * and can be used without a preparatory pulse to introduce T1 sensitivity. Second, there is often a surprising linear (and incompletely understood) relation between change in MR
TABLE 3 Influence of Compartmental Susceptibility Agents Contrast agent Distribution volume Pulse sequences
Gd, Dy, SP large > small (nonlinear) sharp > fuzzy gradient GE > SE Maximal at TE 20-100 ms
-
271
CONTRAST AGENTS FOR FAST IMAGING
Normalized MR signal 1 intensity FeO -100
concentration
nc. 2. Impact of compartmented susceptibility agent upon MR signal change. The decrease in signal caused by the dephasing effect of the magnetic susceptibility gradient is created by the compartmented MR contrast agent. The effect is predicted to be nonlinearly related to local tissue concentration and to the magnetic susceptibility of the active agent; Gd < Dy < iron oxide. signal and tissue MR contrast agent concentration ( 6 , 10-12). We believe this results from tissue compartmentation that creates conditions where proton relaxation is neither at the fast exchange or slow exchange limit but rather in an intermediate exchange case. Fortuitously, the change in a T2*-weighted MR signal is reduced in proportion to the compartmented contrast agent concentration for t h s intermediate regime. Figure 1 diagrammatically depicts the dephasing effect of a compartmented contrast agent upon tissue MR signal. Third, this proportional response of MR signal to compartmented contrast agent is well-suited to the bolus case of a dynamic study to assess tissue function with indicator dilution methods. There are important details that determine the best choice of MR contrast agent for a particular application. The potency (effect per amount) of the agent depends upon the choice of the active ingredient; gadolinium is less potent that dysprosium which is less potent than iron oxide particles (Table 3 ) . This factor can be approximated by knowledge of relative magnetic properties of the formulation. However, Table 3 also emphasizes that compartmentation and pulse sequence are important as well. Unfortunately, though the susceptibility effect causes a unimodal decrease in signal intensity, we can anticipate that the relation versus concentration may well be nonlinear (Figure 2 ) . Finally, the details of MR contrast agent compartmentation are importantly determined by the tissue biodistribution of the agent. This depends upon both the agent TABLE 4 The Influence of Tissue Physiology upon Compartmentation
Tissue
ECF"
Blood volume
Blood flow (ml/min/100 g)
Brain Heart Kidney
4% 20% 3 0 + 10%
4%
55
8% 15%
400
As measured with
22,268-272 ( 1991)
Contrast Agents for Fast Imaging * GERALD L. WOLF AND JADWIGAROGOWSKA Center for Imaging and Pharmaceutical Research, Massachirsetts General Hospital, Building 149, 13th Street, Charlestown, Massachusetts 02129 Received July 18, 1991
Many new pulse sequences are available that can be completed in less time than conventional spin-echo MRI. However, an operational definition of “fast” is twice the speed of the (dynamic) process of interest. Adequate speed is necessary, but may not be sufficient. The imaging must also have satisfactory spatial resolution and safety and must report the signal of interest with sufficient reliability to be interpretable. Frequently, quantitative or semiquantitative measurements must be feasible, even when the outcome is only expressed relative to a control or compared to a previous assessment of the same parameter. Contrary to earlier speculations, MR contrast agents have provided useful characterizations of tissue anatomy or function when utilized with slower imaging methods. The purpose of this paper is to examine some generalities that influence the utility of contrast agents when MR technology allows faster imaging. The measurement of tissue perfusion will serve as the illustrative example of the general principles. THE FREQUENCY DOMAIN
The Nyquist theorem states that a dynamic signal must be sampled at least twice as fast as the information is changing. Table 1 demonstrates the broad range of signal domains of potential interest. For measures of tissue perfusion, the imaging sequence must be able to image in the range of 0.3-3 per second. Thus, many sequences that are called “fast” are not fast enough for this application. For those that are, the user needs to be aware of the details of signal collection, e.g., the need for a preparation pulse, the order of k-space sampling, the T 1, T2, T2 * sensitivity, etc. In some cases, this impacts upon the selection of a contrast agent formulation, dose, or administration profile. MINIMAL CRITERIA FOR “FAST” CONTRAST AGENTS
Investigators have become familiar with indicator-dilution methodology ( 1-3), where contrast agents with appropriate biodistributions are functional indicators with in vivo detection by the MRI device. Most often, the agent is given by bolus and * Presented at the SMRM Workshop on Contrast Enhanced Magnetic Resonance, Napa. CA, May 2325. 1991. 0740-3194/91 $3.00 Copyright 0 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.
268
CONTRAST AGENTS FOR FAST IMAGING
269
TABLE 1 Some Signal Domains Electrophysiology Contraction Perfusion Excretion Innovation Change
100 Hz 10 Hz 1 Hz 0.01 Hz 1x
IO-~HZ
1 X lo-’ Hz
mathematical analysis appropriate to this injection method is applied. The cautions and methodologic details are well-considered elsewhere ( 2 , 3 ) .However, for the bolus case, the Nyquist theorem also applies to the input function; when the agent is administered on the venous side, its arterial concentration profile must have a bolus with a good amplitude and a width that provides twice the frequency of the physiologic signal. For example, where kidney function is of interest, our studies show the cortical perfusion response peaks at 10 s, the proximal tubule excretory response at 50 s, and the distal tubule excretory response at 120 s. For tissue perfusion measurements in this case, the bolus must be prominent and the contrast agent must be safe enough for an effective dose to be entirely injected within 3-5 s. It is uncommon for such injection profiles to be used for acute toxicity tests. Table 2 summarizes a few general criteria for contrast agents in fast tissue perfusion measures. Many agents are available that provide a satisfactory bolus and their distribution within the tissue commences with the “first pass.” There are important trade-offs of the ideal properties for an MR contrast agent when one intends to sample the dynamic signal change in a tissue region; extracellular agents, blood pool agents, and targeted agents may offer differences in acceptability on a case by case basis ( 4 - 6 ) . INTENSITY-CONCENTRATION RELATIONSHIPS
As the bolus moves through the tissue of interest, it must change the MR signal from the sampled region by a detectable and measurable amount. The latter process is facilitated if there is a known relation between local indicator concentration and local MR signal. MR signal intensities are notoriously dependent upon many influences, many of which are either unmeasurable or lumped in somewhat simplified MR algebra relating signal to tissue content and motion ( 5 , 7, 8). Similarly, there is a
TABLE 2 Contrast Agents for Fast Imaging Safe enough for rapid injection Reasonable Biodistribution (Economical and Reimbursable) (Not an orphan)
270
WOLF AND ROGOWSKA
compartment
VCV
FIG. 1 . Biologic prediction of compartment effect. An MR contrast agent with a magnetic susceptibility center is distributed within a biologic compartment. Nuclei with magnetic moments outside the compartment are dephased by the magnetic susceptibility gradient created by the compartmentation.
spectrum of MR contrast agents available, all of which change tissue T 1, T2, and T2 * ( 5 , 9 ) . As proton relaxation is a summation of all local influences, it can become quite complicated to relate tissue MR signal to local concentration of MR contrast agent. However, measuring tissue signal change and/or comparison of dynamic response of the target tissue to an appropriate control usually provides sufficient simplification of the intensity-concentration relationship to encourage biological investigations. Available MR contrast agents range in size from small (70 nanometer) ferromagnetic particles with more than 10 lo iron oxide molecules. The size and distribution of relaxing centers within the molecule, as well as the choice of inorganic or organic electron spin donor determine the agent’s R 1, R2, and susceptibility effects. However, the agent’s biodistribution in tissues can have a significant influence upon the biologic efficacy. MAGNETIC SUSCEPTIBILITY AGENTS
There is a special interest in MR contrast agents that reduce tissue MR signal due to their asymmetric distribution or compartmentation in tissues. There are several apparent benefits to such agents for fast imaging and tissue characterization using MR contrast agents as indicators. First, the MR imaging sequences that have subsecond temporal response with good spatial resolution are especially sensitive to T2 * and can be used without a preparatory pulse to introduce T1 sensitivity. Second, there is often a surprising linear (and incompletely understood) relation between change in MR
TABLE 3 Influence of Compartmental Susceptibility Agents Contrast agent Distribution volume Pulse sequences
Gd, Dy, SP large > small (nonlinear) sharp > fuzzy gradient GE > SE Maximal at TE 20-100 ms
-
271
CONTRAST AGENTS FOR FAST IMAGING
Normalized MR signal 1 intensity FeO -100
concentration
nc. 2. Impact of compartmented susceptibility agent upon MR signal change. The decrease in signal caused by the dephasing effect of the magnetic susceptibility gradient is created by the compartmented MR contrast agent. The effect is predicted to be nonlinearly related to local tissue concentration and to the magnetic susceptibility of the active agent; Gd < Dy < iron oxide. signal and tissue MR contrast agent concentration ( 6 , 10-12). We believe this results from tissue compartmentation that creates conditions where proton relaxation is neither at the fast exchange or slow exchange limit but rather in an intermediate exchange case. Fortuitously, the change in a T2*-weighted MR signal is reduced in proportion to the compartmented contrast agent concentration for t h s intermediate regime. Figure 1 diagrammatically depicts the dephasing effect of a compartmented contrast agent upon tissue MR signal. Third, this proportional response of MR signal to compartmented contrast agent is well-suited to the bolus case of a dynamic study to assess tissue function with indicator dilution methods. There are important details that determine the best choice of MR contrast agent for a particular application. The potency (effect per amount) of the agent depends upon the choice of the active ingredient; gadolinium is less potent that dysprosium which is less potent than iron oxide particles (Table 3 ) . This factor can be approximated by knowledge of relative magnetic properties of the formulation. However, Table 3 also emphasizes that compartmentation and pulse sequence are important as well. Unfortunately, though the susceptibility effect causes a unimodal decrease in signal intensity, we can anticipate that the relation versus concentration may well be nonlinear (Figure 2 ) . Finally, the details of MR contrast agent compartmentation are importantly determined by the tissue biodistribution of the agent. This depends upon both the agent TABLE 4 The Influence of Tissue Physiology upon Compartmentation
Tissue
ECF"
Blood volume
Blood flow (ml/min/100 g)
Brain Heart Kidney
4% 20% 3 0 + 10%
4%
55
8% 15%
400
As measured with
