Biophysical properties and clinical applications of ...

1995, The British Journal of Radiology, 68, 225-247

Invited review: Biophysical properties and clinical applications of magnetic resonance imaging contrast agents 1

R MATHUR-DE VRE, PhD and 2 M LEMORT, MD

1

lnstitut d'hygiene et d'epidemiologie, 14 Rue J Wytsman, 1050 Brussels, Belgium, and institute J Bordet, Centre des tumeurs, Universite Libre de Bruxelles, Rue H Bordet 1, 1000 Brussels, Belgium Abstract Contrast enhanced magnetic resonance imaging (MRI) is a very versatile and effective technique for detecting and characterizing lesions, for identifying a variety of patho-physiological abnormalities, and for providing perfusion and functional information. The application of contrast enhanced MRI to many clinical and research indications has emerged because of the rapid evolution in imaging techniques, improved methodology, and the development of efficient and specific contrast agents. Problems related to optimizing parameters and dosage have been due to complex interplay of relaxation times, biophysical mechanisms and acquisition parameters. A knowledge of basic biophysical aspects is therefore essential for a full understanding of the results obtained for different organs under different conditions, and for optimizing the image parameters and dosage of contrast agents. This article underlines the biophysical basis of the effects of contrast agents in MRI, identifies the problems involved in optimizing the parameters for maximum efficiency, and presents a general overview of the clinical studies and research applications in the central nervous system, perfusion abnormalities, hepatobiliary system, musculoskeletal system and the gastrointestinal tract. The section on perfusion studies includes a discussion of quantitative analysis and kinetic models describing the effects of contrast agents. Finally, a critical evaluation of the scope and limitations of contrast enhanced MRI is presented.

The differences in intrinsic 7i and T2 values of tissues are often insufficient to provide significant image contrast for clinical diagnosis and to characterize the lesions in non-enhanced magnetic resonance imaging (NE-MRI). Contrast agents are administered in order to enhance tissue contrast, to characterize lesions and to evaluate perfusion and flow-related abnormalities. However, the administration of contrast agents is not a basic condition for the generation of tissue contrast in MRI. The distribution of exogenous magnetic substances is detected indirectly by their effects on the relaxation times of tissue water. The scope of contrast enhanced MRI (CE-MRI) has considerably widened in recent years due to the development of agents with improved properties, together with the availability of fast and ultrafast imaging techniques. This article outlines certain biophysical and physicochemical aspects of contrast agents used in MRI, and reviews their clinical and research applications. General aspects The magnetic resonance signal is influenced by the longitudinal or spin-lattice relaxation time (71) and the transverse or spin-spin relaxation time (T2). The administration of contrast agents in living systems lowers the 71 Received 11 October 1993 and in final form 10 June 1994, accepted 13 July 1994. Vol. 68, No. 807

and/or T2 values of tissues that retain them, thereby influencing their signal intensities and the image contrast. Relaxation rates Different biophysical processes influence [ 1 ] the relaxation rates Rl = l/T1 and R2=l/T2. In the presence of inhomogeneous fields the T2 rate is given by: \/T2* — l/T2+l/T2', where \/T2* includes the transverse relaxation rate (1/T2) due to spin-spin interaction, and (1/T2') arises from the effects of inhomogeneities in the static magnetic field and local magnetic susceptibility. The enhancement of relaxation rates by contrast agents in simple solutions is expressed quantitatively by relaxivities rl s and r2s (s" 1 mmol" 1 L), where (C) = concentration of the species rl g = 1/(71 x C )

(1)

r2s =

(2)

l/(T2xC)

Relaxation mechanisms In the presence of contrast agents, the relaxation rates Rl and R2 of tissue water are dominated by highly efficient paramagnetic or susceptibility mechanisms. The paramagnetic mechanism originates from short-range dipolar interactions dominated by the high magnetic moment of unpaired electrons present in paramagnetic substances. The compartmentation of high susceptibility agents creates local field gradients in tissues and results 225

R Mathur-De Vre and M Lemort

in long-range susceptibility effects that lower T2* and T2 values. The R2 rate is enhanced by the diffusion of spins through inhomogeneous fields. Image contrast The image contrast obtained from local signal intensities is a combined function of proton density (N), 7i and T2 values of tissues, as well as pulse parameters. In spin echo (SE) images, the signal intensity (SI) in each voxel is given by the following equation [2]:

Quantification The quantitative evaluation of contrast agents in vivo is carried out either by quantification of image signal intensity or by direct measurements of Tx and T2 values. Parameters for quantitative image analysis. The parameters required for quantification of image contrast are: image intensities, contrast-to-noise ratio (C/N), and signal-to-noise ratio (S/N). (i) The normalized image intensity is given by: W^post or prior/

= AT(H).exp(-TE/T 2 ){l+exp(-TR/r 1 ) - 2 e x p ( - T R + TE/2).l/T 1 }

(3)

N(H) is proportional to (N). Equation (3) indicates that (SI) is related to relaxation times; the 7j, T2 or iV-weighting is governed by the magnitude of pulse parameters TR (repetition time) and TE (echo time) relative to 7^ and T2 of tissues. It may be noted that the Tx and T2 values of tissues vary over a wide range [1] and can be lowered in specific tissues by administering contrast agents. Therefore, Tx and T2 serve as highly sensitive contrast parameters in MRI. Imaging methods The following methods [3-12] are commonly employed for CE-MRI: the conventional slow and faster SE methods; fast methods such as gradient echo (GE), echo planar imaging (EPI) and fast low-angle shot (FLASH) imaging, as well as ultrafast Turbo-FLASH and IR-MBEST/EPI imaging methods. Fast and ultrafast imaging methods provide high quality images and significantly reduce the imaging time. In GE pulse sequences the gradient pulses replace the 180° refocusing pulses employed in the SE sequence. This allows the use of much shorter TE values but results in the sensitivity of GE images to magnetic field inhomogeneities [ 4 ] . The FLASH method employs gradient refocusing pulses, very short TR and TE values and a small flip angle (a) resulting in T2* sensitivity. The optimum flip angle, the Ernst angle, maximizes the image signal but does not optimize the Tx contrast [13]. Turbo-FLASH [3, 5] and IR-MBEST/EPI [12] methods combine the advantages of 7j sensitivity and very short imaging time (Is). In these methods the 7i contrast is obtained by applying a 180° inversion pulse preceding the acquisition of data. Image parameters and tissue 7j and T2. The use of long TR and long TE sequences provides high T2 sensitivity in conventional spin echo imaging. Consequently, the agents that lower T2* or T2 values attenuate the signal intensity (negative effect). The 7i sensitivity can be optimized by using short TR (TR< TJ and short TE values (to minimize the loss of signal due to T2 effects). In this case, lowering the Tj values of tissues by agents enhances the signal intensity (positive effect). In imaging by the FLASH sequence, 7i weighting is minimized by setting small values of (a), whereas the GE images obtained with long TE values exhibit a marked sensitivity to T2* effects [ 4 ] .

226

^sample/^reference

\^)

where SI post and SI prior are signal intensities of images obtained after and before, respectively, the administration of contrast agents, and normalized to the intensity of a reference signal (SIreference: internal or external). (ii) Percentage signal change induced by contrast agents is given by: (£SI) = (SI p o s t -SI p r i o r ) x 100/SIprior

(5)

The (£SI) values give an indication of the efficiency of agents to enhance the contrast. (hi) Contrast/noise (C/N): The (C/N) ratio between tissue 1 and tissue 2 is given by: (C/N) = (SI 1 -SI 2 )/(a 1 2 + ( r 2 2 ) 1/2

(6)

Where SIX and SI2 are the signal intensities, and ax and a2 are the standard deviation of pixel values in the same region of interest (ROI). The magnitude and sign of C/N indicate relative contrast enhancement of tissues and are indicators of lesion detectability by agents. (iv)

Signal/noise (S/N) = SI/noise Sd

(7)

Sd = standard deviation of the background noise. The increase in S/N observed after administering contrast agents reflects the sensitivity of CE-MRI to detect uptake of the agent by tissues. Quantitative measurement of Tt and T2 in vivo. The effects of contrast agents in tissues can be quantitated either by accurate measurements of relative differences in Tx and T2 values of tissues or by monitoring the temporal evolution of Tx and T2 values by using fast or ultrafast methods of measurements [8, 10, 14-16]. It is possible to obtain highly reliable in vivo data by an appropriate choice of parameters and controlled protocols [17-19]. Problems of quantification. The following factors contribute to problems involved in quantification of the Table I. Log K values of complexes Compound

LogK

Gd-DTPA Gd-DOTA Gd-BOPTA Gd-(DTPA-NMA)

28 >22

22.5 18.4

Reference [24] [25] [26] [27]

The British Journal of Radiology, March 1995

Invited review: MRI contrast agents

effects of contrast agents in vivo: (i) difficulties in establishing biodistribution of the agent, particularly in pathological tissues; (ii) competing positive and negative effects of agents [20-23] at low and high doses, respectively; (iii) partial volume effects; (iv) lack of a linear relationship between the degree of contrast enhancement and the administered dose.

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Classification of MRI contrast agents The contrast agents used in MRI can be classified on the basis of several criteria: (i) physical properties— paramagnetic and susceptibility agents; (ii) relaxation properties—Tt or T2 agents, depending on whether they lower predominantly the Tx or T2 values of tissues; (iii) relative intensity changes—positive or negative agents, depending on whether the signal intensity is increased or diminished in the presence of agents; (iv) structure of agents; (vi) bio-distribution behaviour— for example, extracellular, intravascular and tissue specific agents. General requirements of contrast agents The general requirements of an efficient MRI contrast agent are: high relaxivity, low toxicity and high tolerance, low effective dose, thermodynamic stability (high logK) of complexes (Table I), in vivo stability [28], and reduced competition of complexes with indigenous metal ions [29]. Structure and properties of contrast agents Three types of compounds are commonly employed as contrast agents: metaHigand complexes (ML), polymers-complex conjugates (P-ML), and particulate iron oxide. The structure of some metal complexes used as MRI contrast agents are given in Table II and in Appendix 1. The physicochemical properties of metal complexes used as MR contrast agents have been discussed in detail elsewhere [30, 31]. The relaxivity of a complex is significantly lower than the corresponding metal ion (Table III). The metal complexes interact with macromolecules via covalent linkage, non-covalent linkages with binding sites of serum proteins in vivo [43], or complexes entrapped in liposomes. The contrast agents AMI25, AMI-121, and ultra small paramagnetic iron oxide (USPIO) particles are very small ferromagnetic iron oxide particles. These particles consist of microscopic volume or "domain" and exhibit much greater magnetic susceptibility (superparamagnetic properties) than the paramagnetic complexes. The nature of coating and particle size (Table IV) are important factors governing their properties. The permeability values of USPIO and AMI25 indicate that their flux across endothelial monolayers depends on the particle size [40]. Biodistribution of agents The biodistribution and pharmacokinetic properties of contrast agents in living systems are related to: the size and structure of agents, their interactions with 227


Table III. Relaxivity of contrast agents Compound

Temperature (°Q

GdCl3 MnCl2 Gd-DTPA H2O solution Dog serum Gd-DOTA Gd-BOPTA Gadoteridol Gadodiamide Mn-DPDP Polylysine-(Gd-DTPA) Albumin-(Gd-DTPA) Dextran-(Gd-DTPA) AMI25 USPIO Magnetic starch micro-spheres (MSM) Iron oxide nanoparticles (MD): dextran coated

Frequency (MHz)"

rl

(mM" 1 s"1)*"

39 35 40 39 40 39 39 40 40 39 39 37 40 39 39 37 37 37

20 20 20 20 20 20 20 20 20 20 20 10 20 20 17

10.6 10.6 10.6 85.2

15

37 37 37 37

20 20 20

23.9 21.6

10.2

4

20

Reference

r\

(mM" 1 s"1)6 7.2 9.1 8.5

—

3.67 + 0.02 4.5

62.8 4.07 + 0.1 5.9 — — 5.8 —

3.7 + 0.11 4.1+0.42 3.8 3.4

4.63 + 0.01 3.1 4.6 2.8

5.65 + 0.01 — 5.1 3.7

13.1+0.36 13.1

14.3 + 0.46 14.9 22 — —

18.9 10.5 6.6

16.6 98.3 44.1

24 17

70 218

(mM Fe" 1 s"1)

(mM Fe" 1 s"1)

43.6

368.4

[32] [30] [33] [34] [33] [31] [33] [35] [26] [32] [36] [33] [34] [37] [38] [39] [21] [40] [40] [22] [41] [42]

" IT = 42.58 MHz. 6 per gadolinium ion in the case of polymer-(Gd-DTPA) species. Table IV. Particle size of iron oxide contrast agents Compound

Description

Size

Reference

AMI25 AMI25 (superparamagnetic iron oxide) USPIO USPIO AMI-121 Iron oxide (DM) Iron oxide (MSM)

Colloidal solution Crystalline Polycrystalline Surrounded by a dextran surfactant Submicroscopic particles bound by an inert polymer Dextran coated Starch coated, 30% w/w iron

72 nm 35-1.000 nm 11.4 nm + 6.3 20 nm 200 nm 10-70 nm 400 urn

[44] [45] [40] [22] [46] [42] [41]

inherent biochemical components, perfusion and physiological state of tissues, as well as the administered dose. The half-life values of agents are summarized in Table V. After intravenous (iv) administration, Gd-DTPA is rapidly distributed in the extravascular compartment; it has a short half-life in blood and fast renal clearance, even in the presence of renal insufficiency [50]. The manganese complexes are distributed in the intracellular space [51]. The AMI25 particles are specifically retained in the liver due to their large size and rapid clearance from the blood [42, 52]. The distribution [53] of AMI25 after iv administration shows two phases: firstly, a dynamic distribution phase during the first 15min and, secondly, a retention phase as the 228

contrast material clears from the blood stream and is retained by tissues. The long half-life of USPIO particles favours their distribution in the lymphatic system [54]. The USPIO particles and polylysine-( Gd-DTPA) are distributed in the intravascular space and have distribution volumes of 28.7 + 1.5 and 51+ 9 ml kg" 1 , respectively; the latter value corresponds to the vascular space (Vc = 50 ml kg"1) [22, 34]. Toxicity of contrast agents

The lethal dose (LD50) values of some exogenous MR contrast agents are summarized in Table VI. Hyperosmolarity of ionic compounds (Table VII) is a major factor contributing to their low tolerance and The British Journal of Radiology, March 1995

Invited review: MRI contrast agents Table V. Half-life in vitro of some contrast agents Compound

Blood half-life (min)

GD-DTPA

36 ±5.2

GD-BOPTA Polylysine-(Gd-DTPA) SPIO (AMI25) USPIO Albumin-(Gd-DTPA) Liposome-(Gd-DTPA) Dextran-(Gd-DTPA)

14.4 + 10.2 93.6 + 11.4 17.4+12.0 89.4+1777 5.5 22 8.04 + 0.12 144 + 6 6 12.8+10.3 161 + 102 81 117.5 + 3.17 108 240 366 + 3.6

System and conditions

Reference

Rabbits Patients: iv 0.1 mmol kg" 1 , 2-components Normal renal function

[34] [47]

Impaired renal function Rat (250jimolkg- 1 )

[48]

Rabbits, 2-components characteristics, iv I

[34]

Rats, — distribution phase — late retention phase Rats Rats (monoexponential kinetics) Rats Rats Rats

[40] [45] [40] [22] [39] [49] [21]

Table VI. LD50 values of some contrast agents Compound GdCl3 MnCl2 Gd-DTPA Gd-DOTA Gd-BOPTA Gadoteridol (non-ionic) Gadodiamide (non-ionic) Mn-DPDP Polylysine-(Gd-DTPA) Iron oxide nanoparticle USPIO Dextran coated magnetite (DM)

LD 50 " (mmol kg

1

System

Reference

Mice (iv) Mice (iv)

[32] [31] [32] [32] [31] [32] [27] [55] [55] [32] [32] [29] [33] [34] [37] [56] Private communication (Guerbet Lab., 1993) [57]

)

0.4 0.38 0.3 6.0 8.2 18 15 5.8 1.02 7.5 the distinction of haemangioblastomas and metastases from oedema, the differentiation of suspected neoplasms from other lesions, and the characterization of gliomas [118]. In a multicentre study [119] involving patients with suspected spinal tumours, additional information was obtained after iv administration of Gd-DTPA in 96% of intradural extramedullary and intramedullary tumours, as well as 53% of extradural tumours (0.1 mmol kg" 1 at 10 ml min" 1 , Tx and T2 weighted SE sequences). Perfusion agents The principal applications of intravascular contrast agents are the distinction of poorly perfused regions from normally perfused tissues in the brain and heart, the quantification of perfusion parameters, and the evaluation of tumour vascularity and permeability. Mechanism for contrast enhancement After iv administration the dynamic behaviour of perfusion agents in the intravascular space depends on their The British Journal of Radiology, March 1995


compartmentation, the intravascular retention time and tissue vascularity. The compartmentation of susceptibility agents induces local field gradients by changing the magnetic susceptibility {%) in and around the blood vessels carrying the agents [120, 121], consequently the T2* and T2 values of tissues are lowered, resulting in enhanced image contrast. Quantification and models Kinetic models. After a bolus injection of susceptibility agents, the initial distribution phase ("first-pass" kinetics) is characterized by transient changes in signal intensity. Kinetic models were developed to quantify perfusion (blood flow and blood volume) from the transient curves [121-125]. The quantitative evaluation of tissue perfusion is based on the indicator-dilution technique involving the following steps: (i) experimental determination of intensity-time curves following a bolus injection of contrast agent, a rapid bolus injection is necessary [126] for accurate mathematical analysis; (ii) conversion of intensity-time changes to concentration-time curves by using models; (iii) finally, the use of concentration-time curves to derive regional blood flow and blood volume since the concentration of agents in tissues is directly proportional to blood flow, and the integral of concentration-time curves varies in proportion to the local regional blood volume (RBV). In a brain with an intact BBB the kinetics of contrast agents are a function of cerebral blood volume (CBV). After a bolus iv injection, the concentration of Gd-DTPA in the brain was described [105] by a model comprising a plasma volume connected to a large extracellular space distributed throughout the body, except in the brain due to BBB. Several constraints are involved in absolute quantification of RBV and flow [121, 127, 128]. The quantification of flow requires the mean transit time (MTT) of the agent, relating tissue blood volume to blood flow. The uncertainties in estimating area and MTT derived from concentration-time curves were evaluated by a Monte Carlo simulation method [129]. Pre-clinical and clinical applications The qualitative and quantitative information about the state of perfusion is derived either from the first-pass dynamic MRI or from the perfusion-dependent differential retention effects of agents in tissues. The following compounds are employed as perfusion agents: nonspecific and myocardial specific metal complexes, conjugates of Gd-DTPA with biopolymers, iron oxide particles and endogenous blood oxygen. Cerebral perfusion and tumour vascularity Gd-DTPA enhanced dynamic MRI has proved useful for identifying cerebral perfusion deficient regions in patients, for instance unenhanced white matter can be distinguished [130] from blood pool and grey matter the signal intensities of which are enhanced to varying degrees (0.1 mmol kg" 1 ; Tx sensitive; FLASH 5/25 ). Different patterns of time-intensity curves have been observed [4] in the case of stroke, vascular stenosis,

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tumour and arteriovenous malformations, indicating differences in cerebral blood flow (1.5 T; GE35/25/io°; temporal resolution 1 s). Contrast enhanced MRI with Dy-(DTPA-BMA) detected perfusion deficient regions in parts of the brain in a cat model [131] within 1 h after MCA occlusion, whereas unenhanced MRI generally required up to 2-3 h to detect the injury (0.251.0 mmol kg" 1 ; 2 T; SE 1800/80 ). Quantitative studies have been performed using metal complexes and albumin-(Gd-DTPA). The ratio of regional CBV in normal grey and white matter in baboons [132], using Gd-DTPA, was estimated as 1.8 (0.3 mmol kg" 1 , 1.5 T; GE22/34/2o°)- C*ne method for quantitating cerebral blood flow [133] employed a perfused organ model that simulated blood flow in the brain. The absolute values of RBV were measured [134] in a rat model of very reduced cerebral perfusion using "blood pool" albumin-(Gd-DTPA). The differences in cerebral perfusion could be identified prior to the increase in brain water content (4.7 T; SE TR=235 . 6135 ). Methods employing ultrafast MRI techniques (dual TURBOFLASH) were developed to quantify rCBV, flow and BBB permeability [135, 136] by simultaneously measuring the changes in signal intensities of cerebral tissues and blood during the passage of Gd-DTPA. Vascular tumours rapidly accumulate contrast agents as a function of their blood supply and provide the basis for first-pass dynamic MRI. This method [137, 138] revealed that different tumours accumulate Gd-DTPA at different rates [138] during the first 100 s, indicating varying degrees of vascularity (0.2 mmol kg" 1 bolus; 0.52 T; IR-MBEST/EPI mean TI/TE6Oo/32; temporal resolution < 1 s). The kinetic behaviour was defined by a model comprising vascular, diffusion, and washout phases of the tumour. A study of the microvasculature of glioblastoma in rats [139], following the uptake of intravascular polylysine-(Gd-DTPA), showed that the most conspicuous enhancement occurred at the margin of tumours (1-100 umol animal" 1 ; 1.5 T; SE 400/20 ). It is possible to use Gd-DTPA to monitor the changes in tumour vascularity after radiation therapy [108, 119] because the treated areas of tumours often become fibrotic and poorly vascularized, resulting in reduced uptake of contrast agents. The evaluation of tumour vascularity bears important clinical implications for chemotherapy and radiotherapy. Albumin-(Gd-DTPA) has been employed in animal models to identify and follow the evolution of cerebral ischaemia and infarction [38, 140, 141], and to identify [142] poorly vascularized tumours and necrotic areas that do not readily accumulate contrast agents. Functional imaging Functional MRI is generated by subtracting precontrast images from the first-pass images obtained after the administration of susceptibility agents, or from the differences in images arising from different blood oxygen levels. Several applications of functional imaging in the brain have been reported, while functional imaging of 235


the heart is likely to undergo a rapid evolution in future due to the recent progress in ultrafast MRI techniques. The susceptibility effects are a function of the fractional volume occupied by capillaries carrying the agent and are independent of the integrity of the BBB [125, 143]. Attenuation of the MR signal from the brain induced by compartmentalized susceptibility agents is quantitatively correlated with CBV and arterial pCO 2 [120, 123, 125]. Therefore, functional MRI provides a useful method for determining CBV, and for differentiating perfusion deficient pathologies from those with an impaired BBB. The importance of measuring CBV lies in the fact that changes in the regional CBV are related to variations in the functional activity of the brain. Functional imaging of the dog brain [123] employing the agent Dy-DTPA showed a linear relationship between the MRI-derived CBV values and pCO 2 during hypocapnic, isocapnic and hypercapnic stress conditions (0.2mmol kg" 1 , 2T; GE 1000/14 ; temporal resolution 25 ms). The regional changes in CBV during resting and activated cognitive states have been observed [143] after administering Gd-DTPA in patients with intracranial pathology, and in normal human subjects (0.1 mmol kg" 1 in 4 s; EPI 750/10O ). The application of AMI25 in anaesthetized rats identified [144] altered blood perfusion in the case of barbiturate anaesthesia and in experimental cerebral ischaemia (4.7 T; multislice SE250o/6o)- Further applications [145] of functional MRI using Gd-DTPA and gadodiamide include the evaluation of the response of regional CBV to physiological activation (bolus 0.1 mmol kg" 1 , 2.0 T; FLASH 47/38/40 °; time resolution 3 s), a study [146] of cerebral haemodynamics in children (0.1 mmol kg" 1 , 1.5 T; GE24/i5/10o) and an assessment of brain tumours and metastases [147]. In the cerebral blood pool, deoxygenated blood behaves as an effective endogenous susceptibility contrast agent because of paramagnetic deoxyhaemoglobin. Changes in the state of brain oxygenation have been monitored by fast imaging techniques in studies of brain function in animal models subjected to challenge [148], and in [149] activation maps of normal human visual cortex (2.0 T; FLASH 15/6/20°). The response of signal to stimulators that increase the regional blood volume has been estimated in rat brain [150]. Myocardial perfusion The perfusion agents are useful for evaluating ischaemic heart diseases and reperfusion, and for quantifying myocardial infarcts. Studies using metal complexes. Gd-DTPA accumulates preferentially in the infarcted area of myocardium and enhances the Tt weighted contrast between normally perfused and abnormal myocardium [151-154]. A linear correlation has been observed [155] between sequential changes in image intensity of myocardium in a nephrectomized rat model (steady-state model) and gadoteridol concentration in tissue up to a dose of 0.5 mmol kg" 1 (2.0 T; SE 2 2 4 ± 2 0 / 2 0 ). Gd-DTPA enhanced dynamic MRI has been used [156] to differentiate normal myocardium from acute and chronic myocardial infarction. An 236

average enhancement of 40% for normal myocardium and 90% for infarcted regions has been reported (1.5 T; FLASH 3 9/2 4/15°). The possibility of assessing [157] myocardial perfusion by Gd-DTPA enhanced ultrafast MRI has been shown in an animal model (0.05 mmol kg" 1 into left atrium; Turbo-FLASH r = 100ms)- The administration of Gd-DTPA in piglets showed [158] infarcted myocardium early (1 week) and late (3 weeks) after coronary artery occlusion (0.15 mmol kg" 1 ; 1.5 T; standard and dynamic MRI). In a study of recent infarction in patients, Gd-DOTA helped to identify tissue oedema as the hyperintense signal [159]. Acute myocardial infarction in patients was detected and quantified by using Gd-DTPA [160, 161], whereas chronically infarcted areas of myocardium did not show significant enhancement (0.1-0.15 mmol kg" 1 ; 1.5 T; SE6Oo-i2oo/35:7o)Myocardial infarction has also been quantitatively evaluated by measuring the myocardial blood flow and the distribution volume of Gd-DTPA [162, 163]. Two types of specific complexes have been employed to study myocardial perfusion using conventional MRI: (i) complexes with phosphonate and pyrophosphate moities (Ca + + seeking agents) localize in soft tissue calcification present in the infarcted regions of myocardium and other necrotic tissues [164, 165]; (ii) M n + + complexes accumulate more efficiently in normal than in ischaemic myocardium, thereby detecting abnormalities in myocardial perfusion [51]. The use of Mn-DPDP in a rat model [166] led to the discrimination of reversible from irreversible injury (greater enhancement) in reperfused myocardium (0.4 mmol kg" 1 ; 2 T; SE 170 . 240/20 ; Dt = 3-60 min). There are no available reports of the use of these agents in human studies. Studies using iron oxide particles. Unlike Gd-DTPA, the bolus administration of AMI25 in rats [167] produced a greater transient loss of signal from normal myocardium (during 1 h) than from ischaemic regions (36 umol Fe kg" 1 ; 4.7 T; SE 1500/20 ). However, a positive enhancement of myocardial signal was observed [5, 22] at lower doses of USPIO and AMI25 (Turbo-FLASH). The demarcation of perfusion deficient regions by contrast enhanced cardiovascular MRI [5,152,167] allowed differentiation of reperfused from non-perfused infarcts. The clinical importance of these studies lies in their possible application in patients undergoing reperfusion therapy. Studies using polymer-(Gd-DTPA). During myocardial damage the blood pool polymer agents leak out into the extracellular space and accumulate in tissues. Early studies [38, 140, 141] employed albumin-(Gd-DTPA) to investigate myocardial ischaemia and infarction in rat models. Quantitative measurements of in vivo plasma volume [39] and RBV [127] showed higher values for myocardium relative to the skeletal muscle. These results account for the higher sensitivity of myocardial MRI to contrast enhancement by perfusion agents. Perfusion of lymphatic system The prolonged retention time and optimal size of intravascular agents such as USPIO particles and

The British Journal of Radiology, March 1995


polylysine-(Gd-DTPA) result in selective retention of agents by lymph nodes and bone marrow, whereas metastatic lymph nodes do not phagocytose USPIO particles [40, 54, 168]. USPIO particles were used to differentiate benign from malignant adenopathy [54] (200yumol Fekg" 1 , 0.6 T; SE200.2000/16_4o, GE12O/16/7o°:2o°)> and to determine [168] the microstructural anatomy of lymph nodes in rats (9.4 T; SE 500/6 2 ; SE 6000/15 2 ). In the presence of USPIO [169] and polylysine-(Gd-DTPA) [170], the ability to detect small intramedullary tumours was improved by preferential changes in the signal intensity of bone marrow. Contrast enhanced angiography MR angiography with Gd complexes has been used to identify blood vessels [171] (LOT; 3D FLASH30^40/9_14/40°) and to image the vascular structures [3] (Turbo-FLASH 6 5/3/u =). MR angiography employing blood-pool agents constitutes a vast clinical potential. Hepatobiliary contrast agents Hepatobiliary contrast agents are used to improve the detection sensitivity of focal lesions in the liver and spleen, and to evaluate diffuse liver diseases and renal function. Mechanism for contrast enhancement Normal liver is a highly vascular organ that readily takes up contrast agents from the blood stream. The Kupffer cells and hepatocytes of normal liver interact with specific agents via biliary metabolic pathways and by macrophage activity, resulting in specific retention of these agents. Pre-clinical and clinical applications Different types of hepatobiliary contrast agents employed are: non-specific and specific metal complexes, iron oxide particles, and Gd-DTPA entrapped in liposomes serving as carrier. Studies using metal complexes Non-specific complexes. After iv bolus injection, Gd-DTPA is rapidly distributed in the interstitial space of normal liver as well as in tumours [172-174], resulting in a sharp decline of the initial contrast enhancement. Using conventional MRI, Gd-DTPA is therefore inefficient in improving the diagnosis of focal hepatic lesions. With the advent of dynamic MRI employing fast imaging techniques, the efficiency of Gd-DTPA for detecting and identifying hepatic lesions has significantly improved. Different types of lesions with vascular characteristics, for instance hepatic haemangiomas, can be distinguished by dynamic MRI 5 min after the injection of Gd-DTPA [175, 176]. All haemangiomas less than 3 cm in size showed prolonged contrast enhancement compared with hepatocellular carcinoma (0.05 mmol kg" 1 , 1.5 T; FLASH19/12/90°). The diagnosis of hepatic tumours and metastases in patients is significantly improved by combining the dynamic and delayed MRI methods [177] (0.05-0.2 mmol kg" 1 ; 0.5 T; delayed GE 315/14/90 °; dynamic-FLASH40/14/40°). A high dose of gadoteridol

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[80] significantly enhanced the rim of focal liver lesions in a rabbit model (0.3 mmol kg" 1 ; 1.5 T; TurboFLASH8/4/520/10»). Abnormal renal function in patients could be identified [178] by Gd-DTPA enhanced dynamic MRI (0.05 and 0.1 mmol kg" 1 ; 1.5 T; GRE2o/ii/io°; SPGR18/5/60°). Specific-complexes. The complexes: MnDPDP, Gd-BOPTA and Gd-EOB-DTPA are specifically taken up by normal functioning liver tissues. The use of MnDPDP resulted in a five-fold increase in tumour/liver contrast (C/N) relative to the contrast observed in unenhanced images of rat liver [33]. The time-dependent enhancement pattern produced by Mn-DPDP [179] at different doses and pulse sequences (SE, GE, IR, 1.5 T) with several pulse intervals indicated that the optimum conditions are: 8 umol kg" 1 of Mn-DPDP and a heavily Tx weighted sequence for imaging 5-60 min after the administration of contrast agent. Mn-DPDP has the advantage in clinical practice of providing a wider time frame (30 min) for optimal lesion-to-liver contrast [33] compared with Gd-DTPA. In studies [62] involving healthy subjects, significant enhancement of liver parenchyma was observed after the administration of Mn-DPDP (15 umol kg" 1 ; 1.5 T; SE 150/20 ; Dt = 10min). Improved contrast has been reported [180] for hepatocellular carcinoma, focal nodular hyperplasia and regenerative nodules; whereas metastases, cholangiocarcinomas or lymphomas remained unenhanced (5 and 10 umol kg" 1 ; 1.5 T; SE2OOo/23oo/9o; SE5OO/15; GE120_160/5_6/80»; D t = 30min). In general, Mn-DPDP is a useful agent for assessing hepatocyte function and is well tolerated [180] when infused slowly (1 ml min" 1 ). However, side effects have been reported [62] following faster rates of administration (0.016-0.25 ml s" 1 ). Other promising hepato-specific complexes have been reported in animal studies. Gd-EOB-DTPA [181] was found to enhance the liver signal by 270% with an effective dose as low as 50 umol kg" 1 . The possibility of using Gd-BOPTA [48] for detecting focal liver diseases has also been suggested (250 umol kg" 1 ; 0.5 T; SE2Oo/i6)Iron oxide particles Intravenously injected iron oxide particles (AMI25) are phagocytosed by Kupffer cells and exhibit high specificity for normal functioning liver and spleen [182]. The hepatic uptake of AMI25 is reduced within tumours, in inflammatory tissue and in diffuse liver disease [183]. AMI25 has been found to facilitate the detection of focal liver lesions [45], and to improve [184] the diagnostic accuracy for liver carcinoma and small metastases in animal models (20 umol Fekg"" 1 ; 1.4T; SE15OO/6O; SE 250/15 ; SE 500/30 ) and in humans [53] (20 umol Fe kg" 1 ; 0.6 T; SE 1500/40 ; SE5OO/3o)- However, in one clinical study [185] it was reported that AMI25-enhanced MRI failed to identify any more metastases than nonenhanced T2 weighted imaging (20 umol Fe kg" 1 ; 1.5 T; SE'820/30:60 ;SE 2200/22:70 ) Retention phase images after the administration of AMI25 and USPIO particles exhibit higher sensitivity than distribution phase images in the detection of hepatic 237


lesions and for correlating tumour type with variations in image intensity [53]. A 7 1 % average loss of liver signal was observed in the retention phase of AMI25 compared with a 57% loss in the distribution phase [53]. The signal loss for haemangiomas, with their higher vascularity, was greater than for any metastases in late images. The dynamic enhancement patterns of liver after intravascular USPIO particles in pigs [23] showed an enhancement of 42.8% after 1-3 min and a signal loss of 75.8% after 8-17 min (10-20 umol Fe kg ; 1.5 T; SE 140/10 ; SE 2000/50:100 ; SE3OoO/15O; and Turbo field-echo). These results also indicate that USPIO particles are more efficient for enhancing the contrast in late images. The threshold size of lesions detected in animal models by AMI25-enhanced MRI [186] was less than 2 mm (50 umol Fekg" 1 ; 0.6 T; SE 500/32 ), compared with greater than 4 mm on unenhanced MRI (SE 260/21 ). The threshold size of lesions detectable by Mn-DPDP in clinical trials is much larger at 10 mm diameter [180]. This is probably due to slow diffusion of the MnDPDP complex into small tumours with vascular structures reducing the effectiveness of contrast agents. The efficiency of AMI25 in the diagnosis of diffuse liver diseases has been evaluated [183]. The reduction in signal intensities observed 1 h after the administration of AMI25 was as follows: normal liver 75 + 9%, cirrhotic liver 52±13%, and liver tissues with hepatitis 11 + 2% (20u.mol Fekg" 1 , 0.3 T; SE15Oo/42:84; SE5Oo/28:42)- The relatively higher enhancement of tissues from diffuse liver diseases by AMI25 particles is particularly important [187] because, in the absence of contrast agents, the Tj and T2 values of cirrhotic and normal liver tissues are closely similar. Therefore, non-enhanced images are generally inefficient for studying cirrhosis. Coated AMI25 particles were developed to improve specificity, efficiency and tolerance. Starch coated iron oxide particles (MSM) exhibited [41] a high degree of hepatosplenic targeting in rat models whereas dextran coated magnetite (DM) particles increased the detection sensitivity [57] of hepatocellular carcinoma to less than 2 mm in diameter within a rat model (1.25— 50 umol kg" 1 ; 1.5 T; SE400/2(?; SE2OOo/7o)- The USPIO particles coated with arabinogalactan (AG-USPIO) target on hepatocytes via receptors. Consequently, these agents are useful for evaluating hepatic functional abnormalities and for assessing liver transplants [44, 188]. Liposome-complex agents Liposomes labelled with Gd-DTPA were developed [49, 189, 190] to improve the ability of MRI in delineating tumours and detecting metastases in rat models (0.1-0.5 mmol kg" 1 ; 0.5-1.5 T; SE 400/16 _ 20 ). The maximum enhancement was observed [191] within 1-2 h after injecting liposome-(Gd-DTPA) (1.5 T; SE 500/20:25 ; fat suppression sequences). Contrast agents for musculoskeletal system and other soft tissues Gadolinium complexes combined with dynamic MRI techniques have been extensively used in the evaluation, 238

discrimination, and characterization of mass lesions, vascular tumours and inflammatory joint diseases. Mechanism for contrast enhancement The extravascular distribution of Gd complexes allows well perfused regions in soft tissues and vascular tumours to be distinguished from the unenhanced perfusion deficient areas such as fatty tissue, muscle and bone marrow. Pre-clinical and clinical studies Musculoskeletal systems. Dynamic MRI after the administration of Gd-DTPA identifies malignant tumours [192, 193] and synovial proliferation in rheumatoid arthritis (0.1 mmol kg" 1 ; 1.5 T; SE 600/15:20 ; SE 2500/90 ; FLASH40/15/90») [194]. Neoplastic recurrence was detected in a follow-up study [195] of primary musculoskeletal tumours in patients, using Gd-DTPA or Gd-DOTA in conjunction with dynamic MRI techniques and computerized factorial analysis of dynamic structures (1.5 T; SE