Magnetic resonance imaging (MRI) is a technique that is capable of providing three-dimensional imaging of an object. A conventional MRI system typically includes a main or primary magnet that provides the main static magnetic field Bo, magnetic field gradient coils and radio frequency (RF) coils, which are used for spatial encoding, exciting and detecting the nuclei for imaging. Typically, the main magnet is designed to provide a homogeneous magnetic field in an internal region within the main magnet, for example, in the air space of a large central bore of a solenoid or in the air gap between the magnetic pole plates of a C-type magnet. The patient or object to be imaged is positioned in the homogeneous field region located in such air space. The gradient field and the RF coils are typically located external to the patient or object to be imaged and inside the geometry of the main or primary magnet(s) surrounding the air space. There is shown in U.S. Pat. Nos. 4,689,563; 4,968,937 and 5,990,681, the teachings of which are incorporated herein by reference, some exemplary MRI systems.
In MRI, high-resolution information is obtained on liquids such as intracellular or extra-cellular fluid, tumors such as benign or malignant tumors, inflammatory tissues such as muscles and the like through the medium of a nuclear magnetic resonance (NMR) signal of a nuclear magnetic resonance substance such a proton, fluorine, magnesium, phosphorous, sodium, calcium or the like found in the area (e.g., organ, muscle, etc.) of interest. In addition to being a non-invasive technique, the MRI images contain chemical information in addition to the morphological information, which can provide physiological information.
Most clinical uses of MRI of biological tissue, however, employ the water content and water relaxation properties to image anatomy and function with micro-liter resolution. The relaxation properties of water (1H nuclei) are the basis for most of the contrast obtained by NMR imaging techniques. Conventional 1H NMR images of biological tissues usually reflect a combination of spin-lattice (T1) and spin-spin (T2) water 1H relaxation. The variations in water 1H relaxation rate generate image contrast between different tissue and pathologies depending upon how the NMR image is collected.
With MRI based on 1H water relaxation properties, the system typically detects signals from mobile protons (1H) that have sufficiently long T2 relaxation times so that spatial encoding gradients can be played out between excitation and acquisition before the signal has completely decayed. The T2-values of less mobile protons associated with immobile macromolecules (including solid-like bound cellular proteins) and membranes in biological tissues are too short (e.g., less than 1 ms) to be detected directly in the MRI process.
As has become known to those skilled in the art, however, coupling between the immobile, solid-like macromolecular protons and the mobile or “liquid” protons of water allows the spin state of the macromolecular protons to influence the spin state of the liquid protons through exchange processes. As is known in the art, it is possible to saturate the spins of the immobile, solid-like macromolecular protons (“immobile macromolecular spins”) preferentially using an off-resonance radio frequency (RF) pulse. The immobile macromolecular spins have a much broader absorption lineshape than the spins of the liquid protons (“liquid spins”), making them as much as 106 times more sensitive to an appropriately placed off-resonance RF irradiation, as illustrated in FIG. 1. This saturation of the immobile, solid-like macromolecular spins can be transferred to the liquid spins, depending upon the rate of exchange between the two spin populations, and hence is detectable with MRI. This process also is typically referred to as magnetization transfer (MT) process. See also Magnetization Transfer in MRI: A Review; R. M. Henkelman, G. J. Stanisz and S. J. Graham; NMR Biomed 14, 57-64 (2001), the teachings of which are incorporated herein by reference in its entirety and U.S. Pat. No. 5,050,609, the teachings of which also are incorporated herein by reference in its entirety.
Magnetization transfer is more than just a probe into the proton spin interactions within tissues as it also provides a mechanism that can be used to provide additional advantageous contrast in MR images. One application for use of the magnetization technique is in magnetic resonance angiography (MRA). In MRA specific imaging sequences are used to suppress the signal from static tissues while enhancing signal from blood by means of inflow or phase effects. The signal contrast between the blood and other tissue can always be enhanced by using MT (which need not affect blood) to further suppress the background tissue signal. Better contrast between blood and tissue leads to better angiograms.
Another application of MT is characterization of white matter disease in the brain, such as multiple sclerosis (MS) and brain tumors. Multiple sclerosis is a diffuse, progressive disease, grossly characterized by the presence of lesions in brain white matter tissue with pathological characteristics that vary as the lesions evolve. The evolution and history of specific MS lesions is difficult to resolve with conventional T1-weighted or T2-weighted MRI, and so some lesions are unobservable. Using MT imaging for the region of-interest analyses, MS lesions are more conspicuous and the magnetization transfer ratio values provide information on lesion evolution.
More recently, the diffuse characteristics of multiple sclerosis have been characterized by plotting the MTR histogram of the whole brain. This process indicates that there are significant differences between the MTR ratio of the so-called ‘normal-appearing white matter’ in MS patients and the white matter of healthy individuals. Histogram-based measures of MTR show strong correlation with cognitive decline in MS patients and may provide a useful method to study the natural course of MS or to evaluate the effect of drug treatments.
Other areas of application for MT include, but are not limited to, imaging of the breast, knee, muscle and cartilage. Within cartilage, it may be possible using Gd-DTPA to separate the effect of proteoglycan degradation, from the effect of collagen disruption, which is the major contributor to MT in this tissue.
MRI of acute stroke is becoming an increasingly important procedure for rapid assessment of treatment options. Despite many available MRI modalities, it is presently difficult to assess the viability of the ischemic penumbra (i.e., a zone of reduced flow around the ischemic core). Also, impaired oxygen metabolism and concomitant pH changes are crucial in the progress of the ischemic cascade, however, pH effects cannot be ascertained using the water signal.
As is known to those skilled in the art, phosphorous magnetic resonance spectroscopy (MRS) can be used to assess absolute pH and pH changes, however, this particular technique has low spatial resolution (e.g., 20-30 ml) in part because the strength of the NMR signal from phosphorous is significantly less than that for the water signal. Phosphorous MRS, however, is not available on standard clinical equipment, which as noted above, is limited predominatly to those that use the water proton (1H) signals. Also, given the time constraints usu9ly involved with making timely diagnoses for purposes of treatment, such as for when dealing with acute stroke victims, it is not a practical option or practice to re-configure clinical equipment configured to use the water signal so it can perform phosphorous MRS to assess pH. Thus, measurement of pH and assessment of pH effects cannot be practically performed in connection with the NMR imaging process.
In sum, it has become possible to use the water (1H) signal in MRI for non-invasive assessment of functional and physiological parameters as well as for providing a mechanism for contrasting tissues being imaged. It has not been possible, however, to use this water signal for purposes of imaging pH effects.
Efforts have been undertaken to develop exogenous contrast agents for pH detection via the water resonance. These techniques attempt to indirectly detect exchangeable protons through the water resonance in solution using such contrast agents. Discussions of such techniques are found in NMR Imaging of Labile Proton Exchange, S. Wolff and R. Balaban, JMR 86, p. 164 (1990); Detection of Proton Chemical Exchange Between Metabolites and Water in Biological Tissues, V. Guivel-Scharen, T. Sinnwell, S. D. Wolff and R. S. Balaban, J. Magn Reson 133, 36 (1998); A New Class of Contrast Agents for MRI Based Proton Chemical Exchange Dependent Saturation Transfer (CEST), K. M. Ward, A. H. Aletras and R. S. Balaban, J Magn Reson 143, 79 (2000); and K. M. Ward and R. S. Balaban, Determination of pH Using Water Protons and Chemical Exchange Dependent Saturation Transfer (CEST), Magn Reson Med 44(5): 799 (2000).
In the article entitled Detection of Proton Chemical Exchange Between Metabolites and Water in Biological Tissues, it is suggested that small endogenous metabolites with exchangeable protons can be used for pH detection, while the marcomolecule solid-like phase cannot be so used. Further, the article includes no discussion or suggestion of the use of mobile proteins/peptides for this purpose as well. As to the article entitle, Determination of pH Using Water Protons and Chemical Exchange Dependent Saturation Transfer (CEST), the discussion describes or relates to the exogenous agents being given to the subject.
In addition to the foregoing, there is found in Sensitive Detection of Solvent-Saturable Resonances by Proton NMR Spectroscopy in Situ; A New Approach to study pH Effects, S. Mori, et al., Magn Reson Med 40, 36 (1998), the use of exchangeable protons for studying pH in vivo. This document shows such a use with spectroscopy but not through detection with and/or using the water signal. There also have been other studies undertaken that involve the study of proton-like spectra in vivo using chemical shifts but these studies also were not based on detection through the use of the water signal.
Mobile cellular proteins and peptides are some of the building blocks of cells. The cellular content and amide proton exchange properties of these endogenous proteins and peptides may change dramatically during ischemia and in cancer and many other pathologies. Although papers have pointed to the presence of mobile proteins in NMR spectra, there are presently no practical MRI approaches to selectively detect mobile proteins and peptides because of interference with bound metabolites, more rigid-like proteins and other slow-moving macromolecules.
It thus would be desirable to provide MRI methods to detect mobile proteins and peptides using the water signal. In addition, it would be desirable to monitor pH, to detect pH changes, and to assess associated effects using the water signal. It would be particularly desirable to provide magnetic resonance imaging methods that would produce pH sensitive MRI contrast by exploiting for example the magnetization exchange between water protons and the labile amide protons of endogenous mobile cellular proteins and peptides. It also would be desirable to provide MRI methods that would provide a mechanism to monitor, detect and assess mobile protein and peptide content using the amide protons. Further, it would be desirable to use such methods for monitoring, detecting and assessing pH and labile amide proton content in connection with treatment of brain related disorders and diseases, cardiac disorders and diseases, and cancer and to use such methods for monitoring, detecting and assessing pH as well as mobile protein and peptide content in vivo and pathologically for any of a number of diseases or disorders of a human body, including but not limited to cancers, ischemia, Alzheimers and Parkinsons.