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Methods for in vivo evaluation of physiological conditions and/or organ or system function including methods to evaluate cardiopulmonary disorders such as chronic heart failure using polarized 129xeRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, In Vivo Diagnosis Or In Vivo TestingMethods for in vivo evaluation of physiological conditions and/or organ or system function including methods to evaluate cardiopulmonary disorders such as chronic heart failure using polarized 129xe description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060002856, Methods for in vivo evaluation of physiological conditions and/or organ or system function including methods to evaluate cardiopulmonary disorders such as chronic heart failure using polarized 129xe. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The present invention relates to magnetic resonance imaging ("MRI") and MR spectroscopy using hyperpolarized noble gases. More particularly, the present invention relates to techniques to assess certain physiology, conditions, and/or functions of organs or body systems in vivo using polarized noble gases. BACKGROUND OF THE INVENTION [0002] Conventionally, MRI has been used to produce images by exciting the nuclei of hydrogen molecules (present in water protons) in the human body. However, it has recently been discovered that polarized noble gases can produce improved images of certain areas and regions of the body that have heretofore produced less than satisfactory images in this modality. Polarized Helium 3 (".sup.3He") and Xenon-129 (".sup.129Xe") have been found to be particularly suited for this purpose. See U.S. Pat. No. 5,545,396 to Albert et al., entitled "Magnetic Resonance Imaging Using Hyperpolarized Noble Gases", the disclosure of which is hereby incorporated by reference herein as if recited in full herein. [0003] In order to obtain sufficient quantities of the polarized gases necessary for imaging, hyperpolarizers are used to produce and accumulate polarized noble gases. Hyperpolarizers artificially enhance the polarization of certain noble gas nuclei (such as .sup.129Xe or .sup.3He) over the natural or equilibrium levels, i.e., the Boltzmann polarization. Such an increase is desirable because it enhances and increases the Magnetic Resonance Imaging ("MRI") signal intensity, thereby potentially allowing physicians to obtain better images of many tissues and organs in the body. [0004] Generally stated, in order to produce the hyperpolarized gas, the hyperpolarizer is configured such that the noble gas is blended with optically pumped alkali metal vapors such as rubidium ("Rb"). These optically pumped metal vapors collide with the nuclei of the noble gas and hyperpolarize the noble gas through a phenomenon known as "spin-exchange". The "optical pumping" of the alkali metal vapor is produced by irradiating the alkali-metal vapor with circularly polarized light (typically provided by lasers) at the wavelength of the first principal resonance for the alkali metal (e.g., 795 nm for Rb). Generally described, the ground state atoms become excited, then subsequently decay back to the ground state. In the presence of non-zero nuclear spin noble gases, the alkali-metal vapor atoms can collide with the noble gas atoms in a manner in which the polarization of the valence electrons is transferred to the noble-gas nuclei through a mutual spin flip "spin-exchange". After the spin-exchange has been completed, the hyperpolarized gas is separated from the alkali metal prior to introduction into a patient. [0005] Conventionally, gas-phase imaging has been possible using both .sup.3He and .sup.129Xe, and has been particularly useful in producing ventilation-driven images of the lungs, a region where proton images have produced signal voids. However, in contrast to gas phase imaging, dissolved phase imaging has proven to be problematic. Dissolved phase imaging uses the solubility characteristic of .sup.129Xe in blood and lipid rich tissue. The gas phase is thus absorbed or "dissolved" into surrounding tissue or blood vessels and may allow perfusion imaging of the brain, lung, or other regions. Such images can potentially allow for the performance of non-invasive studies of the pulmonary vasculature to detect emboli and other circulatory system problems. Unfortunately, once the polarized gas has been dissolved (such as into the blood vessels), it has proven difficult to generate clinically useful images using the dissolved phase gas. [0006] For example, MRI images using gas-space-imaging techniques have been generated using hyperpolarized .sup.129Xe gas. See Mugler III et al., MR Imaging and Spectroscopy Using Hyperpolarized .sup.129Xe gas: Preliminary Human Results, 37 Magnetic Resonance in Medicine, pp. 809-815 (1997). While good correlation is seen between the gas-space signal in the xenon images and the gas-space signal void in the proton images, the spectra associated with the dissolved phase signal components were significantly lower than the gas-phase signal. [0007] There remains a need to provide clinically useful methods for using polarized gas to perform in vivo evaluations of the body. SUMMARY OF THE INVENTION [0008] In certain embodiments, methods of the present invention obtain dynamic NMR spectroscopy signal data that corresponds to the behavior of polarized .sup.129Xe at a selected site(s) or environment in vivo. The signal data can be used to evaluate: (a) the physiology (tissue volume or thickness/width) of a membrane, organ, tissue, or other physiological structure or environment; (b) the operational condition or function of a membrane, body system, or portion thereof; (c) cerebral perfusion; and/or (c) the efficacy of a therapeutic treatment used to treat a diagnosed disorder, disease, or condition. Thus, the present invention provides methods for screening and/or diagnosing a disorder or disease, and/or methods for monitoring the efficacy of therapeutics administered to subject to treat a disorder or disease. [0009] Particular embodiments of the present invention use .sup.129Xe as a tracer for oxygen. A curve can be best-fit to the dynamic data to represent the behavior of the polarized .sup.129Xe at selected chemical shifts or frequencies. The curve can have various characterizing parameters including: an associated time constant, peak amplitude, amplitude at the time constant, slope of linear portions, and the like. These characterizing parameters can be used to evaluate the target of interest. [0010] For example, the curve can illustrate the transit time of polarized .sup.129Xe in a target in the body. Delayed (longer) transit times may represent thicker tissue, or poor perfusion to help evaluate whether the subject may be hypoxic (in one or more areas such as in the pulmonary blood, the cardiac region, or in the brain). The polarized .sup.129Xe can be used to determine whether low oxygen saturation is the result of poor ventilation, poor perfusion, and/or poor gas diffusing capacity across tissue or membranes. Such an analysis can be used to monitor therapeutic efficacy or disease progression. [0011] In certain embodiments, a dynamic data set of the signal strength of the .sup.129Xe in selected tissue or environments over time can be generated and evaluated. Such information can be used in various manners such as to assess perfusion uptake, or the function of selected membranes, linings, and biosystems. The dynamic data set corresponds to the accrual, build up, or increase in signal strength over time of .sup.129Xe at one or more chemical shift frequencies or ppm. [0012] Particular embodiments of the present invention are directed to minimally or non-invasive in vivo methods for evaluating the thickness or width of a physiological barrier such as a membrane, lining, lumen, channel, or wall in a subject using polarized .sup.129Xe. The method includes: (a) delivering polarized .sup.129Xe gas in vivo to a subject having a first environment, a physiological barrier having a thickness, and a second environment opposing the first environment such that the polarized .sup.129Xe travels serially through the first environment, the barrier, and into the second environment, wherein the polarized .sup.129Xe has an associated different NMR signal chemical shift frequency in the first and second environments and the barrier; (b) destroying the polarization of the .sup.129Xe in the barrier and the second environment; (c) obtaining an NMR spectroscopic signal of the polarized gas in the subject at the second chemical shift to generate at least one dynamic data set of the NMR spectroscopic signal strength values over time representative of the behavior of the polarized .sup.129Xe as it crosses the barrier and enters the second environment; (d) evaluating the polarized gas transit time of the polarized gas, the gas transit time corresponding to the time it takes the polarized gas to travel across the barrier and then enter the second environment, based on data provided by said obtaining step; and (e) determining the thickness or width of the barrier based on data provided by the calculating step. [0013] The method may further include (a) generating a signal strength versus time curve to fit the dynamic data; (b) identifying a time constant of the curve; and (c) evaluating the amplitude of the signal strength at a time along the curve corresponding to the time constant. [0014] In other embodiments, the operation or function of the membrane can be evaluated without determining the thickness of the membrane. In particular embodiments, the method can be used to measure membranes having a thickness in the range of about 1 micron to about 100 microns. [0015] Another embodiment is directed to in vivo methods for evaluating the blood brain barrier in a subject. The method comprises: (a) delivering polarized .sup.129Xe in vivo to a subject such that it diffuses into the blood stream, across the blood brain membrane, and is taken up in tissue in the brain across the membrane, the polarized gas in the blood, membrane, and brain tissue having distinct corresponding polarized gas NMR chemical shift signal frequencies; (b) destroying the polarization of the polarized .sup.129Xe in at least the brain tissue; (c) obtaining an NMR spectroscopic signal of the polarized gas in the subject over time at the brain tissue chemical shift frequency to generate at least one dynamic data set of the NMR spectroscopic signal strength values over time; (d) evaluating the dynamic data; and (e) assessing the blood brain barrier based on data provided by the obtaining and evaluating steps. [0016] Other embodiments of the present invention are directed at methods for monitoring gas exchange dynamics of .sup.129Xe at or across the blood brain barrier to evaluate inflammatory disorders of the brain such as meningitis, encephalitis, and the like and/or to provide methods that can distinguish between certain disorders such as between meningitis and cerebritis by analyzing the gas exchange reaction at the blood barrier membrane. Still other embodiments are directed to measurement of organ perfusion by monitoring xenon transport in, to, or through, that organ. [0017] Still other embodiments are directed to methods of obtaining cerebral perfusion information. The method comprises: (a) administering polarized .sup.129Xe to a subject in vivo; (b) concurrently obtaining a plurality dynamic data sets of NMR spectrographic signal strength of the polarized .sup.129Xe in a compartment of the brain of the subject representative of perfusion in the brain, each dynamic data set corresponds to a different chemical shift frequency; (c) repeating step (b) for a plurality of different compartments across the brain; and (d) generating at least one perfusion image of the brain based on the data provided by the obtaining steps, wherein the image comprises a plurality of voxels associated therewith, and wherein each voxel corresponds to a measure of perfusion in the associated compartment in the brain. [0018] Other embodiments are directed to in vivo methods for evaluating at least one of the thickness of adequacy of function of a membrane or lining, comprising: (a) delivering polarized .sup.129Xe in vivo to a subject such that the polarized .sup.129Xe moves across the membrane or wall, the polarized gas in the membrane or wall having a corresponding polarized gas NMR chemical shift signal frequency; (b) obtaining an NMR spectroscopic signal of the polarized gas in the subject over time at the chemical shift frequency to generate at least one dynamic data set of the NMR spectroscopic signal strength values over time; and (c) evaluating at least one of (1) the adequacy of function of the membrane or lining and (2) the thickness of the membrane or lining based on the data provided by said obtaining step. [0019] Another embodiment of the present invention is directed to a computer program product for evaluating bioactivity, physiology, and/or perfusion in vivo. The computer program product includes computer readable storage medium having computer readable program code embodied in the medium, the computer-readable program code comprises: (a) computer readable program code that obtains an NMR spectroscopic signal of polarized .sup.129Xe in the subject over time at at least one selected chemical shift frequency to generate at least one dynamic data set of the NMR spectroscopic signal strength over time; and (b) computer readable program code that analyzes the dynamic data set for at least one of: (a) quantifying the thickness of a physiologic barrier such as a tissue, membrane, or lining of interest (b) quantifying the width of a lumen or channel; (c) evaluating the adequacy of physiologic function of certain biosystems or membranes; (d) identify disruptions or compromised integrity of physiological barriers, structures, lumens, or channels and/or to identify disorders associated therewith; and (e) to provide a cerebral perfusion map of the brain based on a concurrent acquisition of dynamic data at multiple chemical shifts associated with the brain across a plurality of compartments of the brain. [0020] Further, the instant invention can use spectroscopic or MRI imaging techniques to obtain signal data corresponding to a quantity of dissolved polarized .sup.129Xe before and after a physiologically active substance is administered to a human or animal body to evaluate the efficacy of the drug treatment. Continue reading about Methods for in vivo evaluation of physiological conditions and/or organ or system function including methods to evaluate cardiopulmonary disorders such as chronic heart failure using polarized 129xe... 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