JPWO2005039646A1 - Contrast agents and apparatus for magnetic resonance tissue perfusion imaging - Google Patents

Abstract

To provide a contrast medium and a magnetic resonance diagnostic apparatus for highly safe magnetic resonance tissue perfusion imaging. A contrast agent for magnetic resonance tissue perfusion imaging, comprising air-containing microparticles based on sugar, is provided. Preferably, the sugar is galactose, the galactose content is 99% to 99.99% in the fine particles, and the fine particles further contain 0.01% to 1% palmitic acid. This contrast agent can be safely used in magnetic resonance perfusion imaging, particularly to measure blood flow in the blood vessels in the body. Furthermore, according to this invention, the magnetic resonance diagnostic apparatus which can measure the change of the magnetic field in the body by the air in the said contrast agent is also provided.

Description

  The present invention relates to a contrast agent used for diagnosis using a nuclear magnetic resonance (hereinafter also referred to as “MR”) technique and a nuclear magnetic resonance imaging (hereinafter also referred to as “MRI”) technique. In particular, the present invention relates to a contrast agent for nuclear magnetic resonance imaging capable of safely obtaining tissue perfusion information such as blood flow in various parts of a human body. The contrast agent of the present invention can be widely used for animals in general, but is particularly effective for mammals, particularly humans, and is extremely effective for blood flow diagnosis in subjects having allergic diseases among humans.

(MRI diagnostic method and its contrast agent)
Conventionally, information related to blood flow in each part of a living body has been studied as important information for diagnosing a state related to a circulatory organ in a human body. As one of the techniques, in recent years, a nuclear magnetic resonance diagnostic method has been developed, and research on the perfusion information of each part of the body, for example, blood flow information such as brain, liver, kidney, muscle, and tumor, and its circulation. Used to diagnose vessel and tissue conditions.

  For the measurement of such tissue perfusion information, a gadolinium (Gd) chelate preparation has been widely used as a contrast agent. For example, a product having a trade name of Magnevist (registered trademark) is known.

  However, it is known that gadolinium contrast agents are not sufficiently safe for the human body and involve considerable risks.

Specifically, administration of gadolinium contrast agent may cause nausea even in healthy humans, requiring treatment in the intensive care unit at a rate of 1 in 5,000 to 10,000 people. It is known that fatal accidents caused by the administration of gadolinium contrast agent occur at a rate of about 1 in 50,000 people. In Magnevist (registered trademark), the incidence of side effects of 1.21%, specifically, nausea (0.29%), vomiting (0.13%), heat sensation (0.06%), urticaria ( Side effects such as 0.29%) have been reported. Serious side effects include shock, seizures, anaphylactoid symptoms (dyspnea, throat / laryngoedema, facial edema), and 3 fatal cases have been confirmed so far.
This risk is particularly noticeable for subjects with allergic diseases. For example, a subject having bronchial asthma, which is one of allergic diseases, is highly likely to cause a serious disorder, and a gadolinium contrast agent cannot be used. In fact, the Magnevist® product documentation includes (1) extremely poor subjects in general condition, (2) subjects with bronchial asthma, (3) subjects with severe liver damage, and (4 ) In principle, contraindicated for subjects with severe renal impairment, (1) Subjects with allergic predisposition to allergic rhinitis, rash, urticaria, etc. (2) Bronchial asthma in parents and siblings, allergies (3) Subjects with a history of drug hypersensitivity, (4) Subjects with a history of convulsions, epilepsy and their predisposition, including past history, ( It states that it should be administered carefully to 5) elderly people and (6) young children and young children.

  The possibility of using liposomes as contrast agents has also been suggested. Patent Documents 4 to 6 suggest that liposomes can be used as MR contrast agents. However, no specific research has been reported as a specific contrast agent for MRI, particularly as a contrast agent in tissue perfusion imaging.

(Ultrasound diagnostic method and its contrast agent)
On the other hand, an ultrasonic diagnostic method is known as a method for measuring a state in a human body. This method measures how ultrasound is reflected in the human body. What is nuclear magnetic resonance based on the principle of measuring the change in magnetic field based on the interaction between the magnetic field and the state of nuclei existing in the body? The mechanism is completely different.

  Patent Documents 7 to 11 describe contrast agents suitable for such ultrasonic diagnosis. Patent document 7 describes the composition for blood-flow infusion which forms a microbubble which consists of a physiologically acceptable material. Galactose is described as a specific example of the material. This composition is used to enhance the ultrasound image. Patent Document 8 describes an ultrasound diagnostic contrast agent comprising a surfactant and a non-surfactant solid substance and containing bubbles. Patent Document 9 describes an ultrasound diagnostic contrast agent that is composed of a surfactant and a non-surfactant solid substance and contains bubbles. Patent Document 10 describes small particles of galactose containing bubbles for use in ultrasonic manometry. Patent Document 11 describes a contrast agent for ultrasonic diagnosis composed of a fatty acid (for example, palmitic acid) and a non-surface active solid (for example, galactose).

  Patent Documents 1 to 3 refer to the possibility that such hollow microparticles can be used for MRI. This possibility is based on the theory that the magnetic field inhomogeneity between the gas in the hollow microparticles and the outside of the hollow microparticles can be detected by MRI. However, there are no examples in which hollow microparticles other than liposomes have been actually studied for details of specific MRI measurement. One reason may be that for intravascular use such as blood vessels, it is advantageous that the gas is stabilized with a soft compound such as a liposome.

(Contrast agent in tissue perfusion imaging)
As described above, only a liposome has been studied as a contrast agent in the tissue perfusion imaging method of the nuclear magnetic resonance method, and no research using other substances as a contrast agent has been conducted. In this field, it was still common to use gadolinium as a contrast agent.

  The reason is as follows, for example. In the tissue perfusion imaging method of the nuclear magnetic resonance method, it is usually necessary that the intravenously injected contrast agent is transported to a desired tissue at a high concentration. In order to obtain an image in the tissue perfusion imaging method, the contrast agent is used. The contrast agent needs to be stable over the travel time of. In particular, in order to measure tissue perfusion dominated by systemic circulation (eg, blood flow in cerebral blood vessels), intravenously administered contrast agents must travel through the pulmonary circulation to the systemic circulation, which is longer. Time is expected to be needed for travel. However, a contrast agent having high in vivo stability is not known as a contrast agent other than gadolinium or liposome. For example, Levovist (registered trademark) is known as a low-toxicity ultrasound contrast agent, but its in vitro half-life is less than 1 minute (Patent Document 1), so that tissue perfusion imaging of nuclear magnetic resonance is used. It is considered unsuitable for.

  Furthermore, when performing tissue perfusion imaging, the contrast agent should be as flexible as possible, such as liposomes, to pass through fine capillaries and to minimize the negative effects of interaction with the tissue. It is thought that.

However, contrast agents that satisfy these requirements have not yet been developed, and therefore, contrast agents for MR (particularly for perfusion) that do not have the disadvantages of gadolinium are desired.
Patent 3383954 (Claim 1, column 3, lines 32 to 50) Special table 7-505136 (Claims 1, 2 lower right column lines 4-24) Special table 7-505137 (Claims 1, 2 lower right column lines 7-9) 9-510204 (Claim 1, Claim 2, Claim 8) 10-505900 (Claim 29, Claim 31, page 7 from the bottom to the third line to the second line from the bottom) Special table hei 11-501839 (Claim 1, claim 11, page 16, lines 6-8) JP-B 63-44731 (Claim 1, Claim 2, Column 3, lines 35-44) Japanese Patent Publication No. 4-25934 (Claim 1) Japanese Patent Publication No. 4-17164 (Claim 1) 3-500010 (Claim 20) Japanese Patent Publication No. 7-37394 (Claim 1)

  An object of this invention is to provide the contrast agent for a nuclear magnetic resonance diagnosis excellent in safety. Furthermore, an object of the present invention is to provide a nuclear magnetic resonance diagnostic apparatus that can use a contrast agent excellent in safety.

  In particular, the present invention relates to subjects with extremely poor general conditions, subjects with bronchial asthma, subjects with severe liver damage, subjects with severe renal impairment, allergic rhinitis, rash , Subjects with allergic predisposition to cause urticaria, parents, siblings with bronchial asthma, allergic rhinitis, rash, urticaria, etc., history of drug hypersensitivity An extremely safe contrast agent that can be administered to patients with convulsions, epilepsy and their predispositions, elderly people, and young children, including side effects, without worrying about side effects. Is intended to apply.

  According to the present invention, the following contrast medium and apparatus are provided, whereby the above-mentioned problems are solved.

  (1) A contrast agent for magnetic resonance tissue perfusion imaging, comprising gas-containing fine particles mainly composed of sugar.

  (2) The contrast agent according to Item 1, which is applicable to a subject having an allergic disease.

  (3) The contrast agent according to item 1, wherein the gas-containing fine particles are composed only of sugar and fatty acid.

(4) The contrast agent according to item 3, wherein the fatty acid is a _C10-20 fatty acid.

  (5) The contrast agent according to item 1, wherein the sugar is galactose, the galactose content is 99% to 99.99% in the fine particles, and the fine particles are in the range of 0. A contrast agent comprising 01% to 1% palmitic acid.

  (6) The contrast agent according to (1), wherein the contrast agent is used for measuring blood flow in a body tissue.

  (7) A magnetic resonance imaging apparatus for imaging a blood flow containing the contrast agent according to (1) above, the means for irradiating an RF pulse to excite a magnetic field in the body, and the RF pulse irradiation being completed Then, after relaxing the magnetic field in the body until a predetermined time elapses, the apparatus has means for collecting MR signals and measuring changes in the magnetic field in the body due to the gas.

  (8) The apparatus according to item 7, wherein a time sufficient for causing a significant difference between the signal intensity at the place where the gas is present and the signal intensity at the place where the gas is not present. An apparatus in which the process of relaxing the magnetic field is continued until it has elapsed.

  As described above, the present invention provides a contrast agent for diagnosing nuclear magnetic resonance produced from a material that is harmless to the human body, so that it is possible to perform a nuclear magnetic resonance diagnosis without any practical side effects. Play.

It is a flowchart of the MRI measuring method using the contrast agent of this invention. It is a flowchart of the MRI measuring method using the contrast agent of this invention. It is a graph which shows a time-dependent change of MR signal. It is a graph which shows a time-dependent change of MR signal. 1 is a schematic diagram showing an outline of a phantom used in Example 1. FIG. 4 is a graph showing the results of T2 ^* relaxation characteristics of Example 1. It is the graph and signal strength image which show the result of the signal strength of Example 1. 2 is a graph and a phase image showing the result of phase shift in Example 1. FIG.

  The present invention will be described below. Throughout this specification, it should be understood that the singular forms also include the plural concept unless specifically stated otherwise. Thus, it should be understood that singular articles (eg, “a”, “an”, “the”, etc. in the case of English) also include the plural concept unless otherwise stated. In addition, it is to be understood that the terms used in the present specification are used in the meaning normally used in the art unless otherwise specified. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification, including definitions, will control.

(Definition of terms)
Listed below are definitions of terms particularly used in the present specification.

  As used herein, “contrast agent” refers to a contrast agent used for diagnosis using nuclear magnetic resonance (MR) technology and nuclear magnetic resonance imaging (MRI) technology. The magnetic resonance (MR) phenomenon is also called a nuclear magnetic resonance phenomenon (NMR), and there is a magnetic resonance diagnostic method (or magnetic resonance imaging method or magnetic resonance imaging method) (MRI) as a method for imaging it. MRI is synonymous with nuclear magnetic resonance diagnostic, nuclear magnetic resonance imaging, or nuclear magnetic resonance imaging. MR described in the present specification should be understood to include all concepts such as magnetic resonance, magnetic resonance phenomenon, and nuclear magnetic resonance phenomenon, which are used as a Japanese translation of Magnetic Resonance. Also, MRI should be understood to include all concepts such as magnetic resonance imaging, magnetic resonance diagnostics, and magnetic resonance imaging that are used as the Japanese translation of Magnetic Resonance Imaging in English.

A clinical MR apparatus generally utilizes the magnetic resonance phenomenon of hydrogen nuclei ( ¹ H, also called protons). However, the magnetic resonance phenomenon is observed if either the number of protons or the number of neutrons is an odd-numbered nuclide and can be applied to imaging. In this specification, when referring to nuclides that cause a magnetic resonance phenomenon, they may be described as hydrogen nuclei on behalf of them, but unless otherwise noted, it includes all nuclides that cause a magnetic resonance phenomenon. Should be understood.

  In magnetic resonance (MR), the spin of an atomic nucleus is observed as a magnetic field. However, when measuring the magnetic field in the body of a subject, the spins of many atomic nuclei are necessarily measured simultaneously. The spin states of many nuclei observed in this way are called spin systems.

  Magnetic resonance imaging (MRI), unlike X-rays, is an imaging technique that does not use ionizing radiation. Similar to computed tomography (CT), MRI captures a tomographic image of the body, but MRI is at any scan plane (ie, transverse, coronal, sagittal, or oblique). It has the additional advantage of being able to take an image. Unfortunately, the use of MRI for diagnostics to the body is limited due to the toxicity of common gadolinium contrast agents. Therefore, without an appropriate drug, it is often difficult to distinguish target tissue from adjacent tissue using MRI.

MRI uses magnetic fields, high-frequency energy and magnetic field gradients to take images of the body. The contrast or signal intensity difference between tissues is T1 (longitudinal) relaxation value (time), T2 and T2 ^* (transverse) relaxation values (time), tissue proton density (effectively free water content), Reflects the diffusion and flow effects of the molecules that make up the tissue. The difference between the T2 relaxation value and the T2 ^* relaxation value is due to the imaging method described later. That is, the former is a lateral relaxation value observed when the spin echo method is used, and the latter is observed when the gradient echo method is used. Say. Hereinafter, it should be understood that the T2 relaxation value includes the concept of T2 ^* relaxation value unless otherwise specified.

  Several approaches are utilized in changing the signal intensity at the site of the subject through the use of contrast agents. For example, contrast agents are designed to change either or some of T1, T2 or proton density.

  Paramagnetic contrast agents contain unpaired electrons that act as small local magnets in the main magnetic field to shorten the longitudinal (T1) and transverse (T2) relaxation values. Most paramagnetic contrast agents are often toxic metal ions. In order to reduce toxicity, these metal ions are generally chelated using a ligand. Metal oxides, most notably iron oxide, have also been tested as MRI contrast agents. For example, iron oxide small particles smaller than 20 nm diameter have paramagnetic relaxation properties, but the dominant effect is due to volume magnetic sensitivity. For this reason, magnetic powder has a dominant effect in T2 relaxation. All of these contrast agents can be toxic in certain use situations, and none of these are ideal for use as perfusion contrast agents.

  As used herein, the “sugar” may be any monosaccharide, oligosaccharide, or polysaccharide, and is preferably a monosaccharide. Preferred as the sugar of the present invention is a monosaccharide such as galactose or a mixture thereof, most preferably galactose.

In the present invention, if necessary, a sugar derivative may be used in addition to the sugar. As used herein, “gas” contained in gas-containing microparticles is any gas that can cause changes in the internal magnetic field in MRI tissue perfusion imaging and is harmless to the human body. The gas can be used. For example, not only air but Ne, Xe, O ₂ , SF ₆ , Ar, and N ₂ can be mentioned, but not limited thereto. Air and O ₂ are preferable.

As a method for incorporating a gas into the microparticles, a method similar to that of a conventional contrast agent for ultrasonic diagnosis can be used, and such a method is well known:
As used herein, “fatty acid” refers to aliphatic monocarboxylic acids and aliphatic dicarboxylic acids obtained by hydrolysis of natural lipids. The fatty acid of the present invention may be a saturated fatty acid or an unsaturated fatty acid, and may or may not contain a branched chain. Preferably, the fatty acid has a chain length of 10 to 20 carbon atoms, more preferably the fatty acid is palmitic acid. Mixtures of these fatty acids may be used.

(Methods for obtaining and preparing contrast media)
The contrast agent used in the present invention is produced by adding a necessary amount of other components, for example, fatty acids and the like, if necessary, containing sugar as a main component. Preferably, the sugar content is about 50% by weight or more, more preferably 80% by weight or more, still more preferably 90% by weight or more, and particularly preferably 95% by weight or more.

  When a fatty acid is used for the contrast agent, the amount is preferably 0.01 to 10% by weight, more preferably 0.03 to 3% by weight.

  In a preferred embodiment, the contrast agent is substantially free of components other than sugars, fatty acids, and encapsulated gases. Even if used, components other than sugar, fatty acid and encapsulated gas are preferably 20% by weight or less, more preferably 10% by weight or less, and particularly preferably 1% by weight or less. preferable.

  As a specific contrast agent used in the present invention, a known contrast agent can be used as a conventional contrast agent for ultrasonic diagnosis. For example, the gas-containing contrast agents described in Patent Documents 7 to 11 can be used.

  More specifically, for example, Levovist (registered trademark) commercially available from Schering is listed.

(Dose and administration method of contrast medium)
The dose of the contrast agent can be approximately the same as the dose administered in the conventional ultrasonic diagnostic diagnosis. The dose of the contrast agent of the present invention is not limited per body weight as in the case of a gadolinium contrast agent that is generally used, and is approximately 5 to 25 ml, preferably approximately 8 to 25 ml, more preferably for an adult. Is 10 to 25 ml. However, it is not limited to these depending on the size (volume) and concentration of the contained gas, the magnetic field strength of the MR apparatus used, and the imaging method. Preferably, the contrast agent is administered as a carrier suspended in a liquid such as physiological saline. The concentration in the liquid to be administered is preferably about 10 mg / ml to 500 mg / ml, more preferably about 100 mg / ml to 400 mg / ml. However, it is not limited to these depending on the size and concentration of the contained gas, the magnetic field strength of the MR apparatus to be used, and the imaging method. The contrast agent of the present invention is administered by a method basically similar to the conventional method for administering a contrast agent for ultrasonic diagnosis. A typical administration method is intravenous injection. The timing of administration is preferably from 5 minutes before the start of MRI measurement to the end of MRI measurement, more preferably from 1 minute before the start of MRI measurement to 1 minute after the start of measurement, Particularly preferably, it is from the same time as the start of MRI measurement to 10 seconds after the start of measurement. The number of administrations may be once or may be divided into multiple times. Administration may be performed manually by the practitioner holding a syringe containing the contrast medium, and the automatic contrast medium injector or an alternative injection assisting device may be loaded with the syringe containing the contrast medium, or The contrast agent may be aspirated and mechanical injection may be performed. Preferably, high-speed injection is performed by an automatic contrast medium injector or an injection assist device instead.

(MRI equipment)
As hardware of the MRI apparatus used in the present invention, conventionally known hardware of the MRI apparatus can be used.

  However, since the software of a conventionally known MRI apparatus is generally set to use a conventional gadolinium contrast agent, it is not preferable to use the contrast agent of the present invention. For this reason, it is preferable to modify a part of the software settings related to the measurement conditions. Such measurement conditions will be described later.

(Tissue perfusion imaging method)
The tissue perfusion imaging method is remarkably different from other imaging methods of MRI in that a state where a fluid such as blood flow is flowing is imaged. Specifically, for example, there are the following features. In general, MRI uses an imaging method that obtains a high signal intensity to maintain sufficient contrast between tissues or between normal and lesioned areas and to increase the signal-to-noise ratio, and eliminates noise that hinders diagnosis as much as possible. In addition, the image is picked up so that the clearness of the image, that is, the spatial resolution is sufficiently maintained. The time required for one imaging is approximately several minutes to several tens of minutes. In addition, in MRI using a gadolinium contrast agent, a high concentration gadolinium contrast agent is known to cause a decrease in signal of the surrounding tissue, that is, a decrease in image quality due to the magnetic susceptibility effect. When diagnosing inflammatory diseases and inflammatory diseases, it is necessary to perform imaging after the contrast medium has sufficiently penetrated into the lesion or surrounding tissue and has been diluted to a concentration that does not cause a decrease in signal. It is preferable in terms of enhancement. The degree of signal decrease due to the gadolinium contrast agent varies depending not only on the contrast agent concentration but also on the magnetic field strength, the imaging method and imaging parameters described later. For example, among the imaging methods, the spin echo method is less susceptible to the magnetic susceptibility effect than the gradient echo method, that is, less susceptible to signal degradation, and is therefore widely used in general MRI. TE (echo time) which is one of the imaging parameters is an important factor. Even when the gadolinium contrast agent is present at a high concentration, the effect of signal decrease can be suppressed by setting the TE short, and the gadolinium contrast agent can be suppressed. The signal enhancement effect is obtained by the interaction of the surrounding spin system. On the other hand, tissue perfusion imaging using a gadolinium contrast agent measures perfusion blood flow and the like by measuring the amount of signal decrease due to the magnetic susceptibility effect caused by gadolinium. More specifically, a gadolinium contrast agent is rapidly administered, and a state in which a high concentration contrast agent reaches a blood vessel that perfuses a desired organ (for example, the brain) and decreases the signal of surrounding brain tissue is observed. Assume that the amount of signal reduction caused by gadolinium contrast agent reflects the volume of perfused blood. At this time, in order to effectively observe the signal decrease to be caused by the gadolinium contrast agent, it is preferable to perform imaging using a gradient echo method that is easily affected by the magnetic susceptibility effect. For the same reason, it is preferable to set TE slightly longer. In addition, in order to observe in detail how the contrast agent perfuses the desired tissue, it is preferable to shorten the imaging time as much as possible and to perform repeated imaging of the same part, and the gradient echo method is effective in reducing the imaging time. is there. As described above, in the tissue perfusion imaging method, the gradient echo method that is sensitive to the magnetic susceptibility effect and can shorten the imaging time is widely used.

(MRI measurement method)
In the MR tissue perfusion imaging method, a contrast medium is generally rapidly administered intravenously, and MR tomographic images of a target site (for example, the head) are taken over time. Immediately after rapid administration, the contrast agent is carried to the brain at a high concentration, and decreases the signal intensity (pixel value) of the MR image. Based on this action, quantifying how much the signal has decreased due to the administration of the contrast agent, the blood flow at that site (eg, the brain) will be measured. More specifically, the MR signal intensity does not decrease in a portion where blood is not flowing. On the other hand, the MR signal intensity decreases in the portion where blood flows. By observing this difference, the blood flow volume at the site can be evaluated.

In the tissue perfusion imaging method, generally, as shown in the flowchart of FIG. 1, an excitation step of irradiating an RF pulse, a relaxation step of relaxing a magnetic field (spin system) after the irradiation of the RF pulse is terminated, and an MR signal It can be designed to perform a restoration process for restoring and a recording process for recording the current induced in the coil by the electromagnetic field generated by each of these processes. The excitation process, the relaxation process, and the restoration process form one cycle, and this cycle is repeated a desired number of times. Then, signals are collected at arbitrary timings in these processes. As shown in FIG. 2, the time from excitation to signal acquisition is described as TE (echo time) in this specification, and the time required for one cycle from excitation to excitation is referred to as TR (repetition time).

In the restoration process, the MR signal attenuated after excitation is restored and observed. As a method for restoring the MR signal, (1) the spin echo method (revitalized by the RF pulse) and (2) the gradient echo method (revitalized by the gradient magnetic field) are known and can be used in the present invention. is there. The spin echo method is the most basic pulse sequence, and has an advantage that an excellent signal-to-noise ratio can be obtained, and has a feature that an imaging time is relatively long. The gradient echo method is also called a field echo method, which restores the MR signal by reversing the magnetic field gradient. The signal-to-noise ratio is inferior to the spin echo method, but the MR signal is sharper than the spin echo method. There are features such as attenuation, and sensitivity to magnetic field inhomogeneity (significant decrease in signal due to magnetic susceptibility effect), and an advantage is that imaging time can be shortened by shortening TR.

  The imaging parameters such as TR and TE usually have different values to be set depending on the main magnetic field strength of the MR apparatus to be used. This specification assumes and describes a main magnetic field strength of 1.5 T (Tesla), which is often used in clinical applications of MR tissue perfusion imaging, but main magnetic field strengths other than 1.5 T (Tesla) are used. Even in this case, based on the principle of setting the measurement conditions described in the present specification, those skilled in the art can easily confirm the appropriate TR and TE at the respective main magnetic field strengths.

  A conventional apparatus using gadolinium is usually designed so that the time of one cycle is extremely short for the purpose of shortening the measurement time. Since the signal decrease due to the gadolinium contrast agent is very strong, it is preferable to set TE in a relatively short time for the purpose of improving the signal-to-noise ratio. Setting TE to approximately 150 milliseconds or more should be avoided because the signal strength decreases exponentially with respect to TE, as described below. Also in the present invention, it is preferable to shorten the time of one cycle as much as possible for the purpose of shortening the measurement time. For this purpose, TR is preferably set to approximately 500 milliseconds or less, more preferably approximately 150 milliseconds or less, and even more preferably approximately 100 milliseconds or less. Moreover, in order to catch sharply the signal fall which the magnetic field nonuniformity by air exists causes, it is preferable to set TE comparatively long in the range which does not exceed TR in a relaxation process. More specifically, TE is preferably set to approximately 10 to 100 milliseconds, more preferably approximately 20 to 100 milliseconds. Setting TE to approximately 150 milliseconds or more should be avoided because the signal strength is too low. The shorter the difference between TR and TE, the better the cycle can be shortened. Therefore, it can be shortened as long as the performance of a device such as hardware permits. For example, if a high-performance MRI apparatus is used, the difference between TE and TR can be set to about several milliseconds (for example, TE is set to 20 milliseconds and TR is set to (20 milliseconds + several milliseconds)). is there.

MR signal intensity varies depending on various factors, but in the case of perfusion imaging, it is mainly a function of “parameter: TE” and “time constant: T2 ^* ”. Is represented by the following equation.

Here, the definition of each coefficient is as follows.
k: Coefficient determined by many factors such as density and diffusion of hydrogen nuclei and molecular structure.
TE: Echo time [ms]. The time from the irradiation of the RF pulse to the acquisition of the MR signal.
T2 ^* : Time constant [ms] depending on the magnetic field inhomogeneity around the hydrogen nucleus. The smaller the magnetic field is, the smaller it becomes.
Note that “S” in the above formula is the same as “y” in the formula of FIG. 3, and “k” in the above formula is the same as “a” in the formula of FIG.

  An example of a graph represented by this mathematical formula is shown in FIG.

  FIG. 4 shows a graph showing changes over time in signal intensity when using a contrast agent. FIG. 4 schematically shows a change in signal intensity when the contrast medium is not used (or no contrast medium is present) as a curve A, and a change in signal intensity when the contrast medium of the present invention is present as a curve B. This is schematically shown, and the change in signal intensity in the presence of a conventional gadolinium type contrast agent is schematically shown by curve C.

  As shown by the curve C, the gadolinium contrast agent rapidly attenuates the MR signal intensity. For this reason, immediately after excitation, the difference in signal intensity between the place where the contrast agent exists and the place where the contrast agent does not exist becomes remarkable, and the presence or absence of the contrast agent is easily observed. For this reason, when a gadolinium contrast agent is used, TE is set relatively short, that is, signal acquisition is performed within a relatively quick time after excitation.

  However, the contrast agent of the present invention has less signal intensity attenuation than the gadolinium contrast agent. For this reason, as shown in FIG. 4, immediately after excitation, there is almost no difference in signal intensity from a place where no contrast agent is present. Therefore, even if measurement is performed with the TE setting as in the case of using gadolinium contrast agent, the difference in signal between the place where the contrast agent exists and the place where the contrast agent does not exist cannot be observed. It is extremely difficult to determine whether or not a contrast medium is present at a site (that is, whether or not blood is flowing).

  Therefore, when the contrast agent of the present invention is used, signal acquisition is performed at a timing when TE is set to be relatively long and the difference between curve A and curve B in FIG. 4 becomes sufficiently large. However, when TE is too long, the curve A approaches 0, so the difference between the curve A and the curve B is reduced, and in this case also, it is difficult to determine the presence of the contrast agent. . Therefore, when setting TE, an appropriate TE length is set so that the difference between the signal intensity at the site where the contrast agent of the present invention is present and the signal intensity at the site where no contrast agent is present can be sufficiently detected. Should be selected.

  Thus, in the apparatus of the present invention, it is necessary to install software capable of selecting an appropriate TE corresponding to the contrast agent of the present invention. In the case of software installed in a general commercially available MRI apparatus, it is possible to easily set the appropriate TE described above by correcting a part of the setting.

  Also, by measuring the phase shift, useful information regarding blood flow in the body can be obtained according to the present invention.

  An MR signal is a signal in the complex domain, and can be expressed as a vector when plotted on a complex plane. In clinical practice, an image in which the magnitude (absolute value) of this vector is expressed in shades is observed. Hydrogen nuclei precess in a static magnetic field. This precession can be considered as a circular motion when observed in the direction of the main magnetic field, and can be analyzed using a complex plane. The phase obtained from the excitation by the RF pulse until the signal is collected is obtained by time-integrating the angular frequency of precession (the product of angular frequency and TE in constant velocity circular motion). The contrast agent has a function of shifting the phase, and observing this shift can also provide useful information about the blood flow state in the body. However, the phase shift amount is hardly measured in clinical practice, and even if it is measured, useful information is hardly obtained from the measurement result. As described above, in principle, the magnetic field inhomogeneity of the contrast agent has a function of shifting the phase, and it is possible to know the contrast agent concentration from the change in the phase amount. Have difficulty. This is because, since the phase has only angle information of 0 degree or more and less than 360 degree, for example, 361 degree cannot be distinguished from 1 degree. More specifically, the phase expressed by θ + 2nπ radians (θ is a phase not less than 0 degrees and less than 360 degrees, and n is an integer) cannot be distinguished even if n is changed. Therefore, when the amount of phase shift exceeds 360 degrees due to inhomogeneity of the magnetic field, it is no longer possible to know the correct phase (this is called phase aliasing). Since the nonuniformity of the magnetic field due to the gadolinium contrast agent is very strong, n is easily 1 or −1 or more, phase aliasing occurs, and it is difficult to measure the correct phase shift amount. For this reason, it is not used clinically except for special purposes such as flow velocity measurement and management of magnetic field inhomogeneity of the apparatus. In the present invention, the inhomogeneity of the magnetic field due to the gas is much smaller than that due to the gadolinium contrast agent, so that it is easier to suppress phase aliasing than with the gadolinium contrast agent.

  Therefore, according to the present invention, it is possible to measure the phase shift without phase aliasing, and it is possible to analyze the obtained phase shift information and use it to analyze the state of tissue perfusion in the body. become. If the information obtained by analyzing the phase shift is added to the information based on the signal intensity measurement result, it becomes possible to know the state of the body of the subject in more detail. In order to more reliably suppress phase aliasing, setting of TE in the relaxation process is important. As described above, since the phase is represented by the product of the angular frequency of precession and TE, aliasing can be suppressed more strongly as TE is shorter. For this reason, when it is intended to evaluate perfusion even with a phase shift in addition to the normal signal strength, it is advantageous to set TE slightly shorter. More specifically, TE is preferably set to approximately 10 to 80 milliseconds, and more preferably approximately 10 to 60 milliseconds. Since the phase shift amount and the absolute value amount are obtained from the same measurement data, in the actual condition setting, an optimal TE that does not cause phase aliasing and can obtain a sufficient signal drop should be selected. It is.

(Specific parameter settings for MRI measurement)
In the case of an MRI apparatus of a type currently delivered to a hospital or the like in general, the above setting is specifically performed as follows, for example.
The clinical MRI apparatus is equipped with a control console for controlling it, and most of them are computer controlled. In general, it is possible to set parameters such as an imaging method (spin echo method or gradient echo method), TR, and TE by using control software installed in a control computer. However, since TR and TE are factors that directly affect the control of the magnetic field and radio waves generated by the MRI apparatus, the values that can be set may be limited due to physical reasons or apparatus reasons. More specifically, for example, a lower limit of TE is set so that the signal cannot be collected when the influence of the excitation RF pulse remains, or excitation by the next RF pulse can be performed during signal collection. There is a restriction on the values of TR and TE so that there is no such thing. In actual MRI imaging, in addition to those shown in FIGS. 1 and 2, many gradient magnetic fields are applied and RF pulses are irradiated. Therefore, TR and TE are also limited by the insertion timing thereof. . In actual clinical practice, the user sets an arbitrary value within the degree of freedom of TR and TE limited by physical factors and device factors.

(Example using a phantom)
Experiments were performed using the following devices and contrast agents.
MR system Magneto Vision Plus 1.5T (registered trademark), and CP Head coil (registered trademark) (Siemens AG) is used as an RF pulse and MR signal transmission / reception device.
Workstation Octane2 (Silicon Graphics Inc.)
Microbubble contrast agent Galactose / palmitic acid mixture Levovist® (Schering AG, 99.9% galactose, 0.1% palmitic acid), conditioned phantom for suspension at 200 mg / ml: shown in FIG. Double container.

The relaxation time was measured as follows. A microbubble contrast medium was enclosed in a syringe and placed in the center of the magnet. Images were taken over time using two types of TE by the FLASH method. The condition settings were as follows. TR = 400 ms, TE = 10 ms and 52 ms, FA = 30 deg. Here, FA is a flip angle (nucleus excitation angle). The relationship between the above two types of parameters and the signal intensity was applied to a theoretical formula, T2 ^* was approximately estimated, and this was obtained as a function of elapsed time. The results are shown in FIG. It is observed that the slope of the graph immediately after the preparation of the contrast agent is started and the measurement is steep, T2 ^* is shortened by the high-concentration bubbles immediately after the adjustment, and T2 ^* is rapidly extended as the bubbles collapse. Yes.

  A microbubble contrast agent was sealed in a plastic test tube, and a phantom fixed in a container filled with pure water was placed at the center of the magnet, and images were taken over time by the FLASH method. A schematic diagram of the phantom used is shown in FIG. The condition settings were as follows. TR = 140 ms, TE = 60 ms, FA = 90 deg.

A signal intensity image and a phase image were reconstructed from the obtained raw data (two-dimensional array of MR signals), and the signal intensity and the phase shift were obtained as a function of elapsed time. The presence of microbubbles leads to local magnetic field inhomogeneity around it, which is thought to be the main cause of shortening T2 ^* , but the presence of microbubbles also affects signal strength and phase shift. This effect was recognized not only in the contrast agent-containing test tube but also outside the test tube.

  A graph and an image of the obtained signal intensity are shown in FIG. It was observed that the signal intensity changed not only in the test tube but also around the test tube.

  A graph and an image of the obtained phase shift are shown in FIG. A strong phase shift was observed inside the test tube, and a slight phase shift was observed outside the test tube.

From this result, when considering clinical application, rapid intravenous injection of contrast medium immediately after adjustment, and perfusion can be evaluated by signal decrease or phase shift inside or outside the blood vessel due to T2 ^* shortening at the first passage of the target organ it is conceivable that.

  As described above, in this study, the modification effect of the relaxation characteristic and the signal characteristic by the microbubble contrast agent can be confirmed, and the applicability to MR magnetic resonance imaging was confirmed. According to the present invention, nuclear magnetic resonance diagnosis by tissue perfusion imaging with virtually no side effects is possible, and the present invention is extremely important for technical progress in the field of nuclear magnetic resonance diagnosis. Furthermore, according to the present invention, the effect that phase shift information that could not be used conventionally can be used for nuclear magnetic resonance diagnosis is also achieved.

  As mentioned above, although this invention has been illustrated using preferable embodiment of this invention, this invention should not be limited and limited to this embodiment. It is understood that the scope of the present invention should be construed only by the claims. It is understood that those skilled in the art can implement an equivalent range based on the description of the present invention and the common general technical knowledge from the description of specific preferred embodiments of the present invention. Patents, patent applications, and documents cited herein should be incorporated by reference in their entirety, as if the contents themselves were specifically described herein. Understood.

Claims (8)

A contrast agent for magnetic resonance tissue perfusion imaging, comprising gas-containing fine particles mainly composed of sugar. The contrast agent according to claim 1, which is applicable to a subject having an allergic disease. The contrast agent according to claim 1, wherein the gas-containing fine particles are composed only of sugar and fatty acid. The contrast agent according to claim 3, wherein the fatty acid is a _C10-20 fatty acid. The contrast agent according to claim 1, wherein the sugar is galactose, the galactose content is 99% to 99.99% in the fine particles, and the fine particles are 0.01% to Contrast agent containing 1% palmitic acid. The contrast agent according to claim 1, which is used for measuring blood flow of a tissue in a body. A magnetic resonance imaging apparatus for imaging a blood flow containing the contrast agent according to claim 1, comprising: means for irradiating an RF pulse to excite a magnetic field in the body; An apparatus comprising means for collecting MR signals after relaxing the magnetic field in the body until the time elapses, and measuring a change in the magnetic field in the body due to the gas. 8. The apparatus of claim 7, wherein a sufficient time has elapsed to cause a significant difference between a signal intensity at a location where the gas is present and a signal intensity at a location where the gas is not present. An apparatus in which the process of relaxing the magnetic field is continued.

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