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

Abstract

In certain embodiments, methods of the present invention obtain NMR spectroscopy signal data that corresponds to the behavior of the polarized 129 Xe at a selected site(s) in selected environments in vivo. The gas exchange signal data can be used to evaluate: (a) the thickness of a barrier, such as a membrane, lining, wall or width of a lumen; (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.

1 . A minimally or non-invasive in vivo method for evaluating the thickness or width of a physiological barrier such as a membrane, lining, lumen, channel, or wall in a subject using dissolved-phase polarized  129 Xe, comprising: 
 delivering polarized  129 Xe 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  129 Xe travels serially through the first environment, the barrier, and into the second environment, wherein the polarized  129 Xe has an associated different NMR signal chemical shift frequency in the first and second environments and the barrier; destroying the polarization of the  129 Xe in the barrier and the second environment;    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 values over time representative of the behavior of the polarized  129 Xe as it crosses the barrier and enters the second environment;    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    determining the thickness or width of the barrier based on data provided by said evaluating step.    
     
     
         2 . A method according to  claim 2 , wherein the physiological barrier is the alveolar-capillary membrane, and wherein said obtaining and evaluating steps are carried out when the subject is at rest and then repeated while the subject is under stress by actual or simulated exercise to elevate the heart rate, and wherein said method further comprises comparing the gas transit times at rest and stress to thereby assess the function of the alveolar-capillary membrane.  
     
     
         3 . A method according to  claim 1 , wherein the step of determining is used to measure barriers having a thickness or width in the range of about 1 micron to about 100 microns.  
     
     
         4 . A method according to  claim 1 , wherein the first environment is the lung air space or pulmonary vasculature tissue, wherein the barrier comprises the alveolar-capillary membrane, and wherein the second environment is pulmonary blood.  
     
     
         5 . A method according to  claim 1 , wherein the physiological barrier is one of the glomerular capillary membrane, bowel membrane, placental membrane, and blood brain barrier.  
     
     
         6 . A method according to  claim 1 , wherein the obtaining step is carried out a plurality of times, including at least once while the subject is at rest and at least once when the subject is under actual or simulated physical activity.  
     
     
         7 . A method according to  claim 1 , wherein the obtaining and evaluating steps are carried out to monitor the efficacy of a therapeutic agent administered to the subject.  
     
     
         8 . A method according to  claim 1 , further comprising assessing the function of the alveolar-capillary membrane.  
     
     
         9 . A method according to  claim 1 , further comprising generating an MR image of the anatomy of interest using a dual tuned  129 Xe and  1 H RF excitation coil.  
     
     
         10 . A method according to  claim 1 , further comprising obtaining a polarized noble gas  129 Xe ventilation distribution MRI.  
     
     
         11 . A method according to  claim 2 , further comprising determining the presence or absence of chronic heart failure based at least in part on said calculating step.  
     
     
         12 . A method according to  claim 1 , further comprising: 
 generating a signal strength versus time curve to fit the dynamic data;    identifying a time constant of the curve; and    evaluating the amplitude of the signal strength at a time along the curve corresponding to the time constant.    
     
     
         13 . A method according to  claim 1 , further comprising obtaining a second NMR spectroscopic signal of the polarized gas in the subject at the first chemical shift in the first environment to generate at least one dynamic data set of the NMR spectroscopic signal values over time; and generating a signal strength versus time curve to fit the dynamic data for the first environment.  
     
     
         14 . A method according to  claim 2 , further comprising evaluating pulmonary fibrosis or pulmonary edema.  
     
     
         15 . A method according to  claim 1 , further comprising evaluating at least one of glomerular filtration rate, acute and chronic renal failure, nephrotic syndrome, glomerulonephritis and other renal diseases.  
     
     
         16 . A method according to  claim 1 , further comprising evaluating large and small bowel wall thickness, integrity or function.  
     
     
         17 . A method according to  claim 1 , further comprising quantitatively evaluating placental membrane function.  
     
     
         18 . A method according to  claim 1 , further comprising evaluating the blood brain barrier.  
     
     
         19 . A method according to  claim 1 , further comprising evaluating the patient for respiratory ailments.  
     
     
         20 . A method according to  claim 9 , wherein said delivering step is carried out via breath-hold inhalation.  
     
     
         21 . A method according to  claim 1 , wherein the physiological barrier is a membrane or lining in the body of the subject.  
     
     
         22 . A method according to  claim 1 , wherein the physiological barrier is the bowel wall.  
     
     
         23 . A method according to  claim 1 , wherein the physiological barrier is the blood brain barrier.  
     
     
         24 . A method according to  claim 1 , further comprising evaluating organ or brain perfusion based at least in part on said obtaining and evaluating steps.  
     
     
         25 . A method according to  claim 1 , further comprising obtaining an NMR spectroscopic signal of the polarized gas in the subject at the first chemical shift to generate a second dynamic data set of the NMR spectroscopic signal values over time at the first chemical shift frequency, and wherein the first dynamic data defines a slope of the signal of polarized  129 Xe in tissue over time in millisecond resolution, generating curves fit to each of the dynamic data sets.  
     
     
         26 . A method according to  claim 25 , wherein the second dynamic data set corresponds to polarized  129 Xe behavior in tissue, and wherein the peak amplitude of the associated curve represents tissue volume.  
     
     
         27 . A method according to  claim 1 , further comprising generating a line of signal strength over time fit to the dynamic data, wherein the line has an associated time constant, an associated linear portion with a slope, and signal strength amplitude over time, and wherein said evaluating step considers parameters associated with the line, including at least one of, the time constant, the signal amplitude at a time corresponding to the time constant, the peak signal amplitude, and the slope associated with the linear portion of the curve.  
     
     
         28 - 33 . (canceled)  
     
     
         34 . A method of obtaining cerebral perfusion information, comprising: 
 administering polarized  129 Xe to a subject in vivo;    concurrently obtaining a plurality dynamic data sets of NMR spectrographic signal strength of the polarized  129 Xe in the brain of the subject representative of perfusion in the brain, each dynamic data set corresponding to a different chemical shift frequency;    repeating the obtaining step for a plurality of different compartments across the brain; and    generating at least one perfusion image of the brain based on the obtaining step, wherein the image comprises a plurality of voxels associated therewith, and wherein each voxel corresponds to a measure of perfusion in a predetermined number of compartmentalized regions in the brain.    
     
     
         35 . A method according to  claim 34 , wherein the dynamic data sets correspond to the dynamic behavior of polarized  129 Xe in gray matter, polarized  129 Xe in white matter, and polarized  129 Xe in cerebral blood.  
     
     
         36 . An in vivo method for evaluating at least one of the thickness of adequacy of function of a membrane or lining, comprising: 
 delivering polarized  129 Xe in vivo to a subject such that the polarized  129 Xe moves across the membrane or wall, the polarized gas in the membrane or wall having a corresponding polarized gas NMR chemical shift signal frequency;    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    evaluating at least one of (a) the adequacy of function of the membrane or lining and (b) determining the thickness of the membrane or lining based on the data provided by said obtaining step.    
     
     
         37 . A method according to  claim 36 , further comprising generating a line of signal strength over time best fit to the dynamic data, the line having an associated time constant, and wherein the step of obtaining is carried out for a time which is greater than about two times the length of the time constant.  
     
     
         38 . A method according to  claim 37 , wherein the evaluating step measures a membrane or lining with a thickness in the range of about 1 micron to about 100 microns.  
     
     
         39 . A method according to  claim 37 , wherein the membrane is the glomerular capillary membrane.  
     
     
         40 . A method according to  claim 37 , wherein the membrane is the bowel membrane.  
     
     
         41 . A method according to  claim 37 , wherein the membrane is the placental membrane.  
     
     
         42 . A method according to  claim 37 , wherein the membrane is the blood brain barrier.  
     
     
         43 . A method according to  claim 39 , wherein the function evaluated comprises measuring glomerular filtration rate.  
     
     
         44 . A method according to  claim 39 , wherein the method is used to monitor disease progression and therapy in subjects having one of glomerulonephritides, acute and chronic renal failure, nephrotic syndrome, and glomerulonephritis.  
     
     
         45 . A method according to  claim 40 , wherein the method is carried out to evaluate at least one of large and small bowel wall function.  
     
     
         46 . A method according to  claim 37 , wherein the evaluating step comprises assessing bowel membrane integrity and function for gastroenterological diseases.  
     
     
         47 . A method according to  claim 36 , wherein the obtaining step is carried out to monitor the efficacy of a therapeutic administered to the subject.  
     
     
         48 . A computer program product for evaluating bioactivity, physiology, and/or perfusion in vivo in a subject, the computer program product comprising: 
 a computer readable storage medium having computer readable program code embodied in said medium, said computer-readable program code comprising:    computer readable program code that obtains an NMR spectroscopic signal of polarized  129 Xe 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 values over time; and    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 tissue, membrane, or lining (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.