Dynamic 129Xe gas exchange spectroscopy

Abstract

To provide non-invasive methods and systems for aiding in diagnosing and / or monitoring pulmonary hypertension and interstitial lung disease including pulmonary hypertension and pulmonary arterial hypertension (PAH).SOLUTION: The present invention provides non-invasive systems and methods for generating multiple dynamic spectroscopic parameters of a gas exchange region of a lung associated with three different 129Xe resonances, namely, a 129Xe gas resonance, a 129Xe barrier resonance and 129Xe red blood cells ("RBCs" or "RBC") resonance.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] (Related Applications) This application claims the benefit and priority of U.S. Patent Application No. 16 / 406,630, filed on May 8, 2019, and U.S. Provisional Application No. 62 / 673,175, filed on May 18, 2018, the contents of both applications are hereby incorporated by reference as if fully set forth herein.

[0002] (Government Approval) This invention was made with government support under Grant Nos. NHLB1 R01 HL 105643 and NHLBI R01 HL 126771 from the National Institutes of Health and Grant No. HHSN268201700001C from the Department of Health and Human Services. The U.S. government has certain rights in this invention.

[0003] (Copyright Retention) A portion of the disclosure of this patent document contains material to which copyright protection is claimed. Since it is recorded in the patent files or records of the Patent and Trademark Office, the copyright owner does not object to the facsimile or reproduction of the patent document or patent disclosure by any party, but reserves all other rights.

[0004] This invention relates to medical evaluation using in vivo NMR spectroscopy.

Background Art

[0005] Hyperpolarization (HP) 129 Xe MIR has emerged as a useful means of imaging lung structure and function. See Non-Patent Document 1 and Non-Patent Document 2. Perhaps the most significant feature as a probe of lung function relates to its solubility in blood and biological tissues combined with individual in vivo chemical shifts that reflect the local environment. See Non-Patent Document 3. Dissolved in human blood 129 Xe shows separate resonances approximately 22 ppm apart for red blood cells (RBCs) and plasma. See Non-Patent Document 4 and Non-Patent Document 5. Obtained in the human lung129 In the Xe spectrum, resonances composed of Xe dissolved in both plasma and parenchymal tissue are also present. 129 With the resonance composed of Xe, an RBC peak characteristic of the gas-phase resonance at 0 ppm is observed at 217 ppm. See Non-Patent Document 6. These environments also form barriers to the diffusion of Xe or O2 into RBCs, and are often called barrier resonances. See Non-Patent Document 7. Recent high-resolution spectroscopy has suggested that barrier resonances contain additional structures, but they are generally thought to have a frequency shift of about 198 ppm. See Non-Patent Document 8. The contents of the cited documents are hereby incorporated by reference as if fully set forth herein. 129 Since they also form barriers to Xe or O2 transport, they are often called barrier resonances. See Non-Patent Document 7. Recent high-resolution spectroscopy has suggested that barrier resonances contain additional structures, but they are generally thought to have a frequency shift of about 198 ppm. See Non-Patent Document 8. The contents of the cited documents are hereby incorporated by reference as if fully set forth herein.

[0006] Recently, 129 The spectroscopic properties unique to Xe have been used to obtain 3D images of pulmonary gas exchange. See Non-Patent Document 9. Such imaging reveals gas exchange disorders in various diseases affecting the cardiopulmonary system. For example, in patients with idiopathic pulmonary fibrosis (IPF), Xe uptake in the barrier is significantly higher in most of the lungs, but local dysfunction is observed in the transport to RBCs. See Non-Patent Document 10. In contrast, in the situation of chronic obstructive pulmonary disease (COPD) including emphysema, both barrier uptake and RBC transport decrease. See Non-Patent Document 11. Also, 129 Xe uptake is significantly higher in most of the lungs, but local dysfunction is observed in the transport to RBCs. See Non-Patent Document 10. In contrast, in the situation of chronic obstructive pulmonary disease (COPD) including emphysema, both barrier uptake and RBC transport decrease. See Non-Patent Document 11. Also, 129 Recently, RBC transport disorders in pulmonary vascular diseases have been demonstrated by Xe gas exchange MRI. See Non-Patent Document 12. The contents of the documents cited in the "Background" are hereby incorporated by reference as if fully set forth herein.

[0007] A wide range of coexisting conditions such as asthma-COPD overlap syndrome (ACOS), fibrosis-emphysema comorbidity (CPFE), or secondary pulmonary hypertension (PH) may be seen in patients, and it may be important to distinguish the underlying pathophysiology that causes gas exchange disorders.

[0008] Pulmonary vascular diseases (PVDs), such as pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease (PVOD), result in obstruction of blood flow in the pulmonary vasculature, which consequentially causes right heart failure. Even with current treatment methods, PVDs are associated with substantial morbidity and mortality, with a 5-year survival rate of only ~50%. However, the management of PVDs is greatly limited by diagnostic criteria and non-invasive disease monitoring methods. The most common PVD, PAH, can only be diagnosed by invasive right heart catheterization (RHC). Also, pulmonary hypertension (PH) is defined as mean pulmonary artery pressure (mPAP) ≥25 mmHg and pulmonary capillary wedge pressure (PCWP) ≤15 mmHg, provided that specific hemodynamic and clinical criteria are met and there are no significant cardiac, pulmonary, or systemic diseases. Other PVDs are diagnosed by either pathology or the exclusion method. These strict criteria can exclude patients who actually have the pathological lesions of PVDs in whom treatment with pulmonary vasodilators may potentially be beneficial. For example, patients with diastolic heart failure or lung diseases can develop severe precapillary PH associated with high pulmonary vascular resistance (PVR). Unfortunately, the secondary causes of such increased resistance generally prevent a definitive diagnosis of PVD by invasive catheterization. However, scenarios of suspected PVD in patients with comorbidities are becoming more common in the elderly population.

Prior Art Documents

Non-Patent Documents

[0009]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Summary of the Invention

Problems to be Solved by the Invention

[0010] Therefore, there is a need for non-invasive techniques that can assist in the diagnosis and / or monitoring of pulmonary hypertension and interstitial lung diseases, including PVD (pulmonary vascular disease), for many patients for whom specific treatment for PAH (pulmonary arterial hypertension) is effective or who would otherwise remain untreated.

Means for Solving the Problem

[0011] Embodiments of the present invention provide a non-invasive system and method for creating a number of dynamic spectroscopic parameters of the gas exchange region of the lung related to three different 129 Xe resonances, namely 129 Xe gas resonance and 129 Xe barrier resonance and 129 Xe red blood cell (「RBCs」 or 「RBC」) resonance.

[0012] Embodiments of the present invention can provide non-invasive methods and systems for assisting in the diagnosis and / or monitoring of pulmonary hypertension and interstitial lung diseases including PAH.

[0013] Embodiments of the present invention can use markers related to dynamic spectroscopy of Xe to distinguish pre-capillary (i.e., pulmonary arterial hypertension) and post-capillary vascular diseases. 129

[0014] Embodiments of the present invention provide disease-specific signature patterns that include peak height values and / or shapes of one or more oscillations of RBC amplitude, chemical shift, and phase.

[0015] The oscillations can be related to one or more of inhalation, apnea, and / or exhalation time.

[0016] Embodiments of the present invention provide a library of disease signature patterns that can be useful for diagnosing lung diseases or injuries, considering or evaluating interstitial lung diseases and injuries and / or their progression or remission, and / or evaluating targeted therapies, side effects or accidental negative effects of treatment or drug treatment and / or drug discovery.

[0017] Embodiments of the present invention can be used to discriminate vascular system symptoms or diseases of pre-capillaries and post-capillaries 129 Xe MRI gas exchange ventilation, barriers, and RBC images can be used together with dynamic spectroscopy, and / or, for example, it can be determined how many capillary beds are damaged or injured.

[0018] Embodiments of the present invention can modify and / or adjust the RBC oscillation amplitude based on the stroke volume and the pulmonary exchange volume.

[0019] Embodiments of the present invention relate to a method for creating dynamic spectroscopy parameters. This method involves obtaining the free induction decay (FID) of the gas exchange region of one or both lungs of a subject during a respiratory motion that includes one or more of inspiration / inhalation, apnea, and expiration / exhalation 129 of the Xe NMR signal 129 obtaining the Xe NMR spectrum, approximating the obtained Xe spectrum for the FID with a curve approximation function, and electronically creating a plurality of dynamic 129 Xe spectrum parameters based on the approximation. 129 The Xe spectrum is modeled with one or more non-Lorentzian lines, and the plurality of dynamic 129 Xe spectrum parameters include at least one time-course plot of (i) the barrier amplitude, the barrier chemical shift (ppm), one or more barrier full-width at half-maximum (FWHM) (ppm) parameters, (ii) the gas amplitude, the gas chemical shift (ppm), the gas FWHM (ppm), the gas phase (degrees), and (iii) the red blood cell (RBC) amplitude, the RBC chemical shift (ppm), the RBC FWHM (ppm), the RBC phase (degrees). 129 This method may include extracting the temporal variation of the Xe RBC resonance occurring at the cardiac frequency before the approximation and creation steps.

[0020] 129

[0021] The Xe barrier resonance modeled as a Voigt line and each modeled using a Lorentzian line 129 129 129 129129 Xe RBC and 129 Xe gas phase resonance allows for an approximation to be performed. The barrier resonance is characterized by both the Lorentz FWHM parameter and the Gaussian FWHM (FWHM G )(ppm) parameter.

[0022] This method may further include adjusting the amplitude “A RBC ” of the RBC amplitude plot by multiplying (V_stroke_ref / V_stroke)*(PEV / PEV_ref). V_stroke_ref is a reference stroke volume such as 94 ml or 95 ml (for adults), V_stroke is the actual stroke volume of the subject, PEV_ref is the reference pulmonary exchange volume, and PEV is the pulmonary exchange volume of the subject by measurement.

[0023] This method may further include, during the apnea period of the respiratory motion, for the magnetization decay caused by T1 and RF-induced depolarization, dividing the RBC amplitude “A” by the calculated apparent T1 decay constant (T1app) to 129 correct the amplitude of the RBC amplitude plot of the Xe spectral parameters. By approximating the RBC amplitude “t” over time to Ae -t√T1app , T1app can be quantified.

[0024] This method may further include 129 removing the trend from the amplitude of the Xe spectral parameters and then calculating the variation over time between peaks.

[0025] This method may further include calculating the rate of change of the signal amplitude of the RBC amplitude (A) from the baseline as rbc_amp_percent: rbc_amp_percent = (rbc_amp - A*exp(-t / T1 app )) / (A*exp(-t / T1 app ))). T1 app is the T1 decay constant and t is the time in seconds.

[0026] This method may further include calculating the temporal variation of the signal amplitude of the RBC amplitude (A) using peak - to - peak analysis of the difference between the maximum and minimum values of the oscillation signal of the RBC amplitude.

[0027] This method may further include removing residual baseline fluctuations by high - pass filtering each of the RBC amplitude, RBC chemical shift, RBC phase, and RBC FWHM at a 0.5 Hz cut - off frequency to provide a filtered parameter plot of the RBC spectral parameters.

[0028] This method may further include approximating the filtered parameter plot to a sine curve including a phase offset.

Number

[0029] f c can be used for the temporal approximation of all other RBC spectral parameters (chemical shift, line width, phase).

[0030] This method may further include normalizing the RBC amplitude spectral parameters, the barrier amplitude spectral parameters, and the gas amplitude spectral parameters according to the 129 Xe signal in the barrier phase or gas phase.

[0031] This method may further include preprocessing the raw FID with Fourier transform raw data in the indirect time domain regarding the apnea time of the apnea of the respiratory motion before the approximation and creation steps, retaining only the coefficients exceeding a specified threshold, filtering out non-dominant frequencies from the indirect time domain to smooth the temporal variations between different FIDs by providing an FID with a high SNR for the raw FID for the approximation while keeping the spectral frequency domain unchanged, and performing an inverse Fourier transform in the indirect frequency domain.

[0032] This method may further include using an FID sliding boxcar window filter and averaging a plurality of time-domain filtered FIDs to provide an FID with a high SNR for the approximation.

[0033] The acquisition can provide high sensitivity to cardiac oscillations by being at least partially responsive to a pulse sequence having a TR in the range of 20 milliseconds to 300 milliseconds and a flip angle of about 20 to 90 degrees.

[0034] The acquisition may be at least partially responsive to a pulse sequence having a TR in the range of 200 to 30 ms and a flip angle in the range of 20 to 90 degrees.

[0035] This method may further include 129 providing a plurality of diverse predefined disease pattern signatures of Xe spectral parameters that correlate with various pulmonary hypertension and interstitial lung diseases.

[0036] This method may further include 129 electronically evaluating the created Xe spectral parameters to determine whether the subject has one or more of the predefined diverse disease pattern signatures.

[0037] One or more of the predefined diverse disease patterns may include one or more oscillations of RBC spectral parameters exceeding a predefined peak-to-peak threshold.

[0038] One or more of the specified diverse disease patterns may include oscillations of one or more RBC spectral parameters below a specified peak-to-peak threshold.

[0039] One or more of the specified diverse disease patterns 129 may be based on the shape of oscillations of one or more of the Xe spectral parameters.

[0040] At least one interstitial lung disease may have a disease pattern signature with an RBC frequency shift that decreases during the breath-hold of the respiratory motion relative to the inhalation and / or exhalation portions of the respiratory motion.

[0041] The specified diverse disease patterns can distinguish precapillary occlusion by decreased RBC amplitude oscillations relative to a specified level.

[0042] The specified diverse disease patterns can distinguish postcapillary disease from precapillary disease by increased RBC amplitude oscillations relative to a specified level.

[0043] One or more of the specified diverse disease patterns can optionally determine complex precapillary and postcapillary disease by the shape of the RBC amplitude oscillations.

[0044] This method may further include comparing the RBC amplitude oscillations of one or more RBC plots before and after administration of a pharmaceutical, and determining vascular reactivity and / or changes based on changes in the RBC amplitude oscillations.

[0045] The pharmaceutical is a vasodilator, and optionally the vasodilator is an inhaled vasodilator.

[0046] The pharmaceutical may include prostacyclin.

[0047] This method may further include the gas exchange of the subject 129Detecting pulmonary hypertension associated with a decrease in RBC transport that affects a fraction of the lung that is more unevenly large than can be explained by fractions with abnormal barrier uptake by comparing Xe MRI images.

[0048] The data acquired can be acquired between every 20 milliseconds and every 300 milliseconds during the respiratory motion. The respiratory motion can include breath-holding, full inspiration, and full expiration over a period of 10 to 30 seconds.

[0049] An approximation is performed for each resonance characterized by four spectral parameters, namely amplitude (α), frequency (f), phase (φ), and Lorentz linewidth (FWHM). For the barrier resonance, which is the fifth parameter, the Gaussian linewidth (FWHM G ) is also extracted, and an approximation is performed with the barrier resonance initialized with equal Lorentz and Gaussian linewidths. The approximation is performed using the following equation.

Equation

[0050] This method further includes determining whether the subject has IPF, which is characterized by a disease signature pattern with RBC amplitude oscillations that are significantly larger (at least about 1.25-fold or 1.5-fold larger) than those of a healthy cohort, and RBC frequency (chemical shift / ppm) and phase oscillations that are at least 1.5-fold, generally at least 2-fold larger than those of a healthy cohort.

[0051] The RBC amplitude fluctuations are at least 1.5-fold larger than those of the healthy cohort (optionally 16.8 ± 5.2% and 9.7 ± 2.9%; P = 0.008), the chemical shift oscillations are more than 5-fold higher than those of the healthy cohort (optionally 0.43 ± 0.33 ppm and 0.083 ± 0.05 ppm; P < 0.001), and the RBC phase oscillations are more than 5-fold higher than those of the healthy cohort (optionally 7.7 ± 5.6° and 1.4 ± 0.8°; P < 0.001).

[0052] This method may further include transmitting data obtained from an imaging site equipped with an MR scanner to a remote server. The remote server can perform approximation and creation operations. The remote server may include or be in communication with a database of various disease pattern signatures defining Xe spectral parameters correlated with pulmonary hypertension and interstitial lung disease. 129 It may include or be in communication with a database of various disease pattern signatures defining Xe spectral parameters correlated with pulmonary hypertension and interstitial lung disease.

[0053] This method involves obtaining a plurality of 129 Xe imaging parameters for one or both lungs of a subject, including at least two of the RBC impairment rate, ventilation impairment rate, and barrier impairment rate, and 129 determining whether the patient has a cardiopulmonary disease based on the obtained 129 Xe imaging parameters and at least two of a plurality of dynamic

[0054] IPF is characterized by a disease signature pattern that includes an RBC chemical shift (ppm) below 217 ppm.

[0055] A method for determining a patient's cardiopulmonary disease involves obtaining a plurality of 129 Xe imaging parameters including the red blood cell (RBC) impairment rate, ventilation impairment rate, and barrier impairment rate, and obtaining a plurality of 129 Xe dynamic spectroscopy parameters including RBC shift oscillation and RBC amplitude oscillation, and 129 determining whether the patient has a cardiopulmonary disease based on the obtained 129 Xe imaging parameters and

[0056] This method may further include 129 creating a graphic signature regarding the health or disease state of the patient's cardiopulmonary system based on the obtained 129 Xe imaging parameters and

[0057] This method may further include comparing the created graphic signature with a library of graphic signatures that includes graphic signatures specific to each of chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), left heart failure (LHF), and pulmonary arterial hypertension (PAH).

[0058] This method may further include providing a diagnostic model that defines predictions of various diseases based on various thresholds between the peak of RBC oscillation and the peak of chemical shift (ppm) oscillation. A determination may be made using the provided diagnostic model.

[0059] Yet other embodiments relate to an MRI scanner system configured to perform any of the methods of the present invention, including an MRI scanner that includes an MRI receiver and at least one processor in communication with the MRI scanner.

[0060] Other embodiments relate to a medical evaluation system having at least one processor configured to perform any of the methods of the present invention, including a server in communication with at least one MRI scanner.

[0061] Although the method aspects of the present invention have been described, it will be understood that the present invention may also be embodied as a system and a computer program product.

[0062] Other systems, methods, and / or computer program products according to embodiments of the present invention will be or become apparent to those of ordinary skill in the art upon examination of the following drawings and detailed description. Such additional systems, methods, and / or computer program products are all included within this description, are within the scope of the present invention, and are intended to be protected by the accompanying claims.

Brief Description of the Drawings

[0063] This patent or application file includes at least one drawing depicted in color. Copies of this patent or patent application publication that include color drawings will be provided by the Patent Office upon request and payment of the necessary fees. The features of the present invention will be more readily understood from the following detailed description of the exemplary embodiments when interpreted in conjunction with the accompanying drawings.

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8A1

Figure 8A2

Figure 8B

Figure 8C

Figure 8D

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

Figure 19

Figure 20

Figure 21

Figure 22

Figure 23

Figure 24

Figure 25

Figure 26

Figure 27

Figure 28

Figure 29

Figure 30

Figure 31

Figure 32

DETAILED DESCRIPTION OF THE INVENTION

[0064] The present invention may be made in modified and alternative forms, and specific embodiments thereof are shown by way of example in the drawings and described in detail below. However, it is not intended to limit the present invention to the specific forms disclosed, but rather it should be understood that the present invention encompasses all modifications, equivalents, and alternatives within the spirit and scope of the present invention. Like reference numerals throughout the drawings mean like elements.

[0065] In the figures, the thickness of a certain line, layer, component, element, or feature may be exaggerated for clarity. Dashed lines indicate any feature or operation unless otherwise specified. The sequence of operations (or steps) is not limited to the order presented in the claims or figures unless otherwise explicitly stated.

[0066] The terms used in this document are for the sole purpose of describing particular embodiments and are not intended to limit the invention. As used herein, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Further, "comprises" and / or "comprising", when used in this specification, specify the presence of the described features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. As used in this document, the phrase "and / or" includes any and all combinations of one or more of the associated listed items. As used herein, phrases such as "between X and Y" and "between about X and Y" should be construed to include X and Y. As used herein, "between about X and Y" means "between about X and about Y". As used herein, phrases such as "from about X to Y" mean "from about X to about Y".

[0067] Unless otherwise defined, all terms (including technical and scientific terms) used in this book shall have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, terms as defined in commonly used dictionaries shall be interpreted as having a meaning consistent with the context of this specification and the related art, and shall not be interpreted in an idealized or overly formal sense unless so clearly defined herein. Well-known functions or structures are not described in detail for the sake of brevity and / or clarity.

[0068] The terms first, second, etc. may be used herein to describe various elements, components, regions, layers, and / or sections, but it will be understood that these elements, components, regions, layers, and / or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer, or section from another. Thus, a first element, component, region, layer, or section described below may be referred to as a second element, component, region, layer, or section without departing from the teachings of the present invention.

[0069] The term "MRI scanner" refers to a magnetic resonance imaging and / or NMR spectroscopy system. As is well known, an MRI scanner includes a low magnetic field strength magnet (generally between about 0.1T and about 0.5T), a superconducting magnet of intermediate or high magnetic field strength, an RF pulse excitation system, and a gradient magnetic field system. MRI scanners are well known to those skilled in the art. Examples of commercially available clinical MRI scanners include those provided by, for example, General Electric Medical System, Siemens, Philips, Varian, Bruker, Marconi, Hitachi, and Toshiba. The MRI system may be at any suitable magnetic field strength, such as about 1.5T, and may be a high magnetic field system between about 2.0T and 10.0T.

[0070] The term "high magnetic field strength" refers to a magnetic field strength greater than about 1.0 T, generally greater than about 1.5 T such as 2.0 T or 3.0 T. However, the present invention is not limited to these magnetic field strengths and is suitable for use with high magnetic field strength magnets such as 3.0 T or more.

[0071] "Hyperpolarization" 129 The term Xe refers to Xe having a polarization higher than the natural or equilibrium level. As is well known to those skilled in the art, hyperpolarization can be induced by spin exchange with an optically pumped alkali metal vapor. See U.S. Patent No. 5,545,396 to Albert et al. and U.S. Patents Nos. 5,642,625 and 5,809,801 to Cates et al. These cited examples are hereby incorporated by reference as if fully set forth. Hyperpolarization 129 One polarizer suitable for the generation of hyperpolarized Xe is the 9800, 9810, 9820 polarizer models manufactured by Polarean, Imaging, plc of Durham, North Carolina. Thus, as used herein, the terms "hyperpolarization", "polarization" and other terms mean artificially increasing the polarization of certain noble gas nuclei above the natural and equilibrium levels. 129 The term "automatically" means that the operation is performed substantially and generally completely without human or manual input and is generally directed or executed according to a program. The term "electronically" includes both wireless and wired connections between components. The term "according to a program" means communicating with an electronic circuit and other hardware and / or software under the instructions of a computer program.

[0072]

[0073] ​The term "3D image" refers to a 2D visualization that appears like a 3D image using volumetric data that can represent features with various visual characteristics such as diverse intensities, opacities, colors, textures, and others. For example, a 3D image of the lungs can be created to show differences in wall thickness using differences in color or opacity in the image volume. Thus, the term "3D" for an image does not require actual 3D visibility (such as through 3D glasses, etc.), but only the 3D appearance in a 2D viewing space such as a display. A 3D image includes a number of 2D slices. A 3D image can be a series of 2D slices that can be volumetrically rendered and / or visually paged in a manner well-known in the art.

[0074] The term "trend removing" and its derivatives mean adjusting the amplitude signal that decays during apnea by correcting the apparent T1 relaxation caused by a combination of true relaxation due to oxygen induction and relaxation due to the application of radio frequency pulses. This flattens the amplitude signal relative to the non-trend-removed amplitude signal, making it easier to determine and / or quantify oscillations.

[0075] The term "normalizing" and its derivatives regarding the oscillation of the RBC spectrum of various spectral parameters means normalizing the RBC signal by dividing its amplitude by the amplitude of another spectral parameter (i.e., the amplitude of the barrier or gas phase resonance), and can generally be performed as normalization for displaying the dynamics of RBCs, barriers, and gases prior to trend removal.

[0076] The actual RBC oscillation amplitude can also be "normalized" for a particular patient / subject by adjusting the stroke volume and / or effective capillary exchange volume of the individual patient.

[0077] The terms "raw data", "raw FID", and "raw NMR signal" refer to the complex NMR signal acquired in the time domain prior to Fourier transform.

[0078] The term "about" with respect to flip angle means that the number can vary within + / - 10%. The term "about" with respect to time means that the stated number can vary by + / - 20%. The term "about" with respect to resonance frequency means 2 - 5 ppm (the RBC chemical shift varies from about 214.5 to 219).

[0079] As is well known, basic NMR spectral lines have amplitude, chemical shift (sometimes called frequency), linewidth, and phase (in degrees). The FID is a time-domain signal (damped oscillation). Frequency and chemical shift are the same. Chemical shift is a frequency, usually expressed in ppm rather than Hz, relative to some standard frequency. Similarly, the FWHM / linewidth can be expressed in Hz or ppm. The conversion of FWHM / linewidth from Hz to ppm is 129 performed by dividing by the Xe Larmor frequency.

[0080] Embodiments of the present invention are particularly suitable for use in human patients, but can also be used on animal or other mammalian subjects.

[0081] Generally, in embodiments of the present invention, hyperpolarization 129 Xe exchange spectral parameters are acquired and quantified during a respiratory motion (i.e., protocol) associated with one or all of inhalation, apnea, and exhalation in the gas exchange region of the lung. The gas exchange region of the lung is a space sensitive to the pathophysiology of the lung, the interstitial barrier, and the 129 Xe gas exchange between red blood cells (RBCs). In embodiments of the present invention, particular attention is paid to the quantification of the cardiac oscillation of RBC resonance 129 to obtain and evaluate the dynamics of Xe spectroscopy.

[0082] As described in the "Background", 129 the spectral characteristics of Xe had distinct features in vitro and in vivo. There is promise in the surprisingly high sensitivity of Xe diffusion barrier uptake and RBC transport to a wide range of pathologies, but new challenges also arise. 129 Although there is promise in the surprisingly high sensitivity of Xe diffusion barrier uptake and RBC transport to a wide range of pathologies, new challenges also arise. 129In addition to the characterization of the Xe gas transport spectrum by static parameters, its temporal dynamics provide an opportunity to obtain additional clinically important findings. For this purpose, interesting observations about the heartbeat in the amplitude of RBC resonance have been reported in preliminary studies. See "Hyperpolarized 129 Xe NMR of human blood 129 Xe chemical shift and pulmonary blood oxygenation measurement in humans ([[]] 129 Xe chemical shift in human blood and pulmonary blood oxygenation measurement in humans using hyperpolarized 129 Xe NMR)" by Norquay et al., Magnetic Resonance in Medicine 2017;77(4):1399-1408, and "Detecting pulmonary capillary blood pulsations using hyperpolarized xenon-129 chemical shift saturation recovery (CSSR) MR spectroscopy" by Ruppert et al., Magnetic Resonance in Medicine 2015. The contents of these documents are hereby incorporated by reference as if fully set forth herein. However, this study mainly focused on the characteristics of 129 Xe uptake in alveolar septal units on a time scale of 0 to 100 milliseconds via the chemical shift saturation recovery (CSSR) method. See "Assessment of lung function in asthma and COPD using hyperpolarized 129 Xe chemical shift saturation recovery spectroscopy and dissolved-phase MRI" by Qing et al. 129Xe chemical shift saturation recovery spectroscopy and dissolved-phase MRI)」NMR in biomedicine 2014a;27(12):1490 - 1501, and "Experimental validation of the hyperpolarized 129 Xe chemical shift saturation recovery technique in healthy volunteers and subjects with interstitial lung disease)" by Stewart et al. in Magnetic resonance in medicine 2015;74(1):196 - 207. Thus, these studies were limited by relatively low temporal resolution, did not employ robust curve fitting methods for quantification, and did not investigate the dynamics of other spectral parameters. 129 Although 3D gas exchange MRI is an important technique for characterizing the spatial distribution of gas exchange impairment, it is not sufficient on its own to determine the underlying cause. For example, dyspnea can occur due to interstitial lung disease or underlying heart or pulmonary vascular disease. Among PVDs, it is difficult to determine whether the obstruction is pre - capillary or post - capillary, and this is even more difficult in the context of other lung diseases. Also, existing PVD assessment methods require invasive right - heart catheterization. 3D

[0083] By combining Xe gas exchange MRI 129 with the assessment of cardiopulmonary dynamics by Xe spectroscopy, a non - invasive approach unique to these problems is achieved. 129

[0084] ​However, as recently as 2017, "Proc. Intl. Soc. Mag. Reson. Med." 25(2017)2152 by Bier et al. reported on RBC chemical shifts that are physically impossible considering in vitro RBC chemical shift values. That is, anything below approximately 214.5 is not considered physically possible. For example, the 2017 study showed that the RBC frequency was as low as 212 ppm. Embodiments of the present invention provide a robust acquisition and processing framework for clinically relevant RBC spectral parameters for dissolved phase 129 Xe that improves the quantification of spectral parameters. For example, using the improved processing method and system according to the present invention, the RBC chemical shift in 7 healthy volunteer subjects changed from 213.8±0.5 to 217.6±0.6 ppm, and in subjects with IPF, it changed from 213.7±1.3 to 216.3±0.9 ppm.

[0085] The inventors recognized that in order to develop robust quantification methods and algorithms, 129 Xe barrier resonance's complex underlying spectral structure, and / or the relatively low spectral resolution of the dissolved phase 129 Xe signal oscillations. The inventors also recognized that in addition to the variation in RBC amplitude, there are other dynamic 129 Xe spectral parameters (4 - 5 per resonance) that can be analyzed to gain insights into underlying conditions and / or discriminate between various conditions.

[0086] To gain insights into the interpretation of patients with pulmonary vascular diseases, comparison of one or more healthy subject cohorts (i.e., population level) can be used. Thus, embodiments of the present invention, to facilitate clinical interpretation, a) with sufficient time and spectral resolution 129Strategies for obtaining the temporal dynamics of Xe transport to obtain clinically useful and / or statistically reliable results, b) a robust analysis framework for quantifying dynamics such as cardiac oscillations, and c) representative data from healthy cohorts and diseased patients can be provided.

[0087] The population level is established using one or more healthy subjects, i.e., humans, and can be provided based on age and gender or age only or gender only.

[0088] Embodiments of the present invention acquire Xe free induction decay (FID) at 5 to 400 milliseconds per respiratory cycle, more generally from about 20 milliseconds per respiratory cycle to about 300 milliseconds per respiratory cycle, so as to fully characterize the dynamics of each resonance (gas, barrier, RBC). 129 In this way, "dynamic spectroscopy", i.e., Xe NMR signal parameters, are obtained over a time period associated with a respiratory motion that includes at least one of inhalation / breath-hold and exhalation. Then, in embodiments of the present invention, complex time-domain curve approximation methods and / or algorithms that can robustly quantify each Xe resonance (gas, barrier, RBC) by amplitude, chemical shift, line width, and phase can be applied. 129 Xe NMR signal parameters are obtained. Then, in embodiments of the present invention, complex time-domain curve approximation methods and / or algorithms that can robustly quantify each Xe resonance (gas, barrier, RBC) by amplitude, chemical shift, line width, and phase can be applied. 129 Xe NMR signal parameters are obtained. Then, in embodiments of the present invention, complex time-domain curve approximation methods and / or algorithms that can robustly quantify each Xe resonance (gas, barrier, RBC) by amplitude, chemical shift, line width, and phase can be applied.

[0089] In some particular embodiments, signal acquisition and processing algorithms and / or methods that address the low signal-to-noise ratio (SNR) and spectral resolution of the data thus dynamically acquired in two ways can be used. First, one or more preprocessing steps can be incorporated that are tuned (prescribed) to remove high-frequency noise outside of physiologically reasonable regions. Second, preferably, innovative processing of the Xe spectrum is performed using one or more non-Lorentzian linearly modeled curve approximations that require one or two additional degrees of approximation freedom to maintain (not only Lorentzian) temporal and / or spatial resolution. 129 Innovative processing of the Xe spectrum is performed.

[0090] In some presently preferred embodiments, the barrier resonance linearity is approximated to incorporate known complexities using a fork spectrum profile, while only one additional degree of approximation is needed. Here, the terms "fork spectrum profile" and "fork linearity" are described interchangeably with the "fork curve approximation function".

[0091] In embodiments of the present invention, by acquiring NMR raw signal data during the process of a respiratory motion that may include each of inspiration / inhalation, apnea, and expiration / exhalation, spectral parameters sensitive to gas exchange in the lungs can be created.

[0092] Figure 1 shows the temporal changes in the spectral parameters of 129 Xe gas, the barrier, and RBC resonance in a representative healthy subject during inspiration, apnea (gray bar / center of the plot), and expiration. In this graph / plot, all amplitudes are normalized according to the 129 Xe barrier signal amplitude. For example, if the maximum barrier amplitude = 10 and the maximum RBC amplitude = 5, the RBC graph shows a maximum signal of 0.5, while the barrier graph shows a maximum amplitude of 1. This can be implemented by first determining the value of the maximum barrier signal and then dividing the signal amplitudes of the gas, barrier, and RBC by this value. According to another example, the maximum raw barrier signal is a constant value of about 3.0×10 3 and all amplitudes are divided by this constant value. Alternatively, the RBC amplitude may be divided by the barrier amplitude at each time point to create a time-dependent RBC:barrier ratio that represents the overall gas exchange efficiency. The arrows in Figure 1 highlight / indicate some of the spectral changes associated with the respiratory motion and the line above the RBC amplitude (Figures 1 and 2 highlight / emphasize cardiac oscillations).

[0093] 129 Xe gas amplitude or 129 It should be noted that other normalization factors may be used, such as normalizing according to the

[0094] In another approach to normalizing the amplitudes of various spectral parameters, it is possible to employ a time-related barrier / gas phase (i.e., normalization based on time points). As a result, a plot of the time-related RBC:barrier ratio or RBC:gas ratio is obtained.

[0095] Figure 1 shows the temporal changes in the spectral parameters of Xe gas, barrier, and RBC resonance in an IPF subject (Subject 13) between inhalation, apnea (gray bar), and exhalation. Again, all amplitudes are normalized according to the maximum Xe signal in the barrier compartment. Unlike healthy volunteer subjects, RBC resonance shows significant oscillations in heart rate not only in amplitude but also in chemical shift and phase, as represented by the black bars. 129 Xe gas, barrier, RBC resonance shows the temporal changes in the spectral parameters of Xe gas, barrier, and RBC resonance in an IPF subject (Subject 13) between inhalation, apnea (gray bar), and exhalation. Again, all amplitudes are normalized according to the maximum Xe signal in the barrier compartment. Unlike healthy volunteer subjects, RBC resonance shows significant oscillations in heart rate not only in amplitude but also in chemical shift and phase, as represented by the black bars. 129 Unlike healthy volunteer subjects, RBC resonance shows significant oscillations in heart rate not only in amplitude but also in chemical shift and phase, as represented by the black bars.

[0096] Figure 2 shows the RBC spectral parameter dynamics after normalization and trend removal during apnea from a representative healthy volunteer, two IPF subjects, two PAH subjects, and one left heart failure (LHF) subject. The solid lines represent the sine curve approximation. Note the large RBC amplitude oscillations in IPF combined with large RBC frequency / phase oscillations. In contrast, small RBC oscillations are seen in PAH patients. Large RBC amplitude oscillations are seen in left heart failure (LHF) patients, but the frequency (shift / ppm) and phase oscillations are decreased and / or not significant.

[0097] Figures 3A - 4D show the interbeat cardiogenic oscillations of RBC spectral parameters during apnea for healthy subjects and IPF subjects. Oscillations in RBC amplitude, chemical shift, and phase are significantly greater for IPF subjects (red / dashed line, right side of the plot) than for healthy volunteer subjects (P = 0.008, P = 0.001, P = 0.002). * represents the statistical difference between groups (P < 0.05).

[0098] Figures 5A to 5D are comparisons of RBC amplitude, chemical shift, and phase oscillations between the healthy cohort (green data on the left side of each plot), IPF (red in the center of each plot), and PAH (red-violet data on the right side of each plot) cohorts. IPF is discriminated by significantly larger RBC amplitude, frequency, and phase oscillations than the normal cohort. PAH is discriminated by significantly smaller RBC amplitude oscillations than the normal cohort.

[0099] Figure 6A is a set of relaxation approximation sets for the large average of FID where the minimum residual error is seen for the 3-Lorentz approximation (left plot) and the barrier fork model approximation (right panel). Figure 6B is a set of plots of dynamic acquisition spectroscopy for healthy volunteers where poor condition approximation occurs for the barrier resonance of the 3-Lorentz model (left and central panels) but is overcome by the barrier fork model (right panel). The FWHM (ppm) panel of the barrier using the fork model has an FWHM G line and a Lorentz line (Lorentz is shown by a solid line above the FWHM G line) and provides a more reliable RBC approximation (e.g., Figures 1 and 2).

[0100] Previously, Robertson et al. proposed managing the complexity of barrier resonance by using two rather than one Lorentz resonance. "Discovery of the third relaxation phase of 129 Xe resonance in the human lung: Quantification of spectroscopic features in healthy subjects and patients with idiopathic pulmonary fibrosis" by Robertson et al. 129See "Xe resonance in the human lung: Quantifying spectroscopic features in healthy subjects and patients with idiopathic pulmonary fibrosis)", Magnetic resonance in medicine 2017;78(4):1306 - 1315. The entire content is hereby incorporated by reference as if fully set forth herein. However, this approach results in a poor - condition approximation of dynamic spectroscopy because it requires more degrees of freedom for approximation. The Voigt profile has a shape that is a convolution of a Lorentzian peak with a Gaussian distribution and requires only one additional degree of freedom for approximation. Specifically, two separate line - width parameters, the Lorentzian and Gaussian parameters, result. By Marshall et al., "Use of Voigt lineshape for quantification of in vivo 1 H spectra)", Magnetic resonance in medicine 1997;37(5):651 - 657. The entire content is hereby incorporated by reference as if fully set forth herein. 1 In other embodiments, other curve - fitting functions that provide sufficient time and spectral resolution to obtain accurate barrier resonance data may be used, i.e., the Xe spectrum can be modeled by one or more non - Lorentzian line shapes or a combination of one or more non - Lorentzian line shapes and Lorentzian line shapes.

[0101] 129

[0102] FIG. 7A is a color-coded image set of a COPD patient with severe ventilation disorder (ventilation, barrier: gas, RBC: gas), and the barrier uptake and RBC uptake are relatively well matched. FIG. 7B is a corresponding color-coded image set for a COPD patient in whom RBC transport disorder is disproportionately low compared to barrier uptake, suggesting the possibility of precapillary pulmonary hypertension.

[0103] FIG. 8A is an example of a flowchart of a signal processing operation that can be used to create dynamic spectrum parameters according to an embodiment of the present invention. Data in a certain frequency range is acquired. The data is dissolved gas phase so as to obtain the entire range of curve approximation and determine the frequency / chemical shift of each resonance at a time related to a respiratory motion including one or more of inhalation, apnea, and exhalation. 129 including Xe resonance (resonance of gas, barrier, and RBC) (block 100). The free induction decay (FID) of the NMR signal acquired over this time is curve approximated to a function that models the RBC and gas peaks as Lorentz curves having amplitude, frequency, FWHM, and phase, and models the barrier resonance as a fork profile with additional Gaussian FWHM (block 110). That is, 129 the Xe barrier resonance is modeled (approximated) using a fork line shape, 129 Xe-RBC and 129 Xe-gas phase resonances can be modeled (approximated) using their respective Lorentz line shapes (only). The barrier resonance has only one frequency, and when this is approximated to a fork function, it is possible to have simultaneous Lorentz and Gaussian FWHMs, but the amplitude, frequency, and phase are only one. Independent Lorentz and Gaussian curves are not necessary. The barrier signal is simply approximated to a single line shape having two line width parameters. This addresses the complexity of the barrier line shape while additionally limiting the required approximation degrees of freedom. Curve approximation can be performed to identify the barrier, RBC, and gas signals so as to minimize the error between the model function and the data.

[0104] 129The spectral parameters of Xe gas, the barrier, and RBC are created based on curve fitting. Each of the gas, barrier, and RBC spectral parameters includes amplitude, chemical shift (ppm), FWHM (ppm), and phase (degrees), and the barrier spectral parameters further include the FWHM at that time G including (block 120).

[0105] Estimation of at least amplitude, frequency, FWHM, and phase by at least frequency and FWHM based on the median or mean of one or more healthy subjects can be provided and used as an initial input for curve fitting (block 102).

[0106] The FID can include the mean value of a selected subset of raw data dynamic FIDs that are averaged together at corresponding various time points to generate a first high SNR FID for initial curve fitting (block 112). For example, 3 to 10 FIDs such as 3, 4, 5, 6, 7, 8, 9, 10 FIDs are averaged together at corresponding time points during the respiratory motion to improve the SNR.

[0107] The amplitude is normalized according to the (maximum) barrier amplitude and / or gas amplitude 129 according to the Xe signal (block 122).

[0108] 129 The Xe gas phase frequency can be defined as a 0 ppm reference frequency (block 114).

[0109] The resonance frequency is converted to chemical shift (ppm) by using the gas phase frequency as the reference frequency, and the 129 Xe Larmor frequency or 129 central frequency of Xe is used to convert the FWHM from Hertz to ppm (block 115). For example, when the scanner transmit frequency is 34 MHz and the gas phase signal is detected at 0 Hz while the RBC signal is detected at 7.378 kHz, the RBC chemical shift is 7.378 kHz / 34 MHz or 217 ppm.

[0110] The curve fitting results are electronically evaluated (block 116) to determine whether the RBC chemical shift is ≧ 214.5 ppm and the barrier chemical shift is ≧ 196.0 ppm. If this condition is not met, the initial estimate or input may be updated and / or a second curve fitting may be performed after averaging multiple FIDs to provide an averaged FID for the corrected first high SNR FID (block 117). If yes, the curve fitting is acceptable and no iterative changes or further curve fitting or adjustment is necessary. If no, the initial estimate may be updated / corrected. Also, the RBC frequency may be evaluated to confirm that it is in the range of 215 - 220 ppm, the barrier frequency may be evaluated to confirm that it is in the range of 195 - 198 ppm, and the FWHM may be evaluated to confirm that it is less than 20 (block 118).

[0111] The frequency (chemical shift) of the gas phase reference can also be electronically evaluated for accuracy (block 119) to ensure that it is not artificially determined based on signal acquisition artifacts and / or approximation errors due to low SNR.

[0112] Cardiopulmonary or pulmonary disease states or symptoms may be identified (block 124) based on correlated disease signature patterns associated with dynamic 129 Xe spectroscopy parameters.

[0113] Predictions of the presence or absence of PAH, LHF, IPH may be identified (block 126) based on signature patterns that do not include significant oscillatory increases or decreases and / or peak-to-peak variations by statistical validation from the population level (normal cohort) in one or more of amplitude oscillation, phase oscillation, FWHM oscillation, chemical shift oscillation (ppm) among one or more of the RBC, gas, barrier spectral parameters.

[0114] The amplitudes of the spectral parameters associated with the breath hold time between 1 - 30 seconds are normalized and detrended, and optionally, sine curve fitting may be applied to at least some of the RBC spectral parameters (block 128).

[0115] The condition or symptom can be identified based at least in part on the shape of the RBC amplitude oscillation (block 129). In embodiments of the present application, it is assumed that the actual shape of the RBC oscillation can reveal information about the underlying condition or symptom. The RBC oscillation is not necessarily purely sinusoidal, and information about the underlying disease symptom can be obtained from the way the oscillation goes up and down.

[0116] The time-dependent amplitude can be detrended over the apnea period such that the amplitude signal is flattened considering signal attenuation and the signal oscillation is increased for the detrended amplitude signal (block 130). That is, the RBC spectral parameters can be normalized and detrended or detrended and normalized. The apnea time can be between 1 and 30 seconds. Optionally, a sinusoidal approximation can be applied to at least some of the (adjusted) RBC spectral parameters.

[0117] Figure 8B is another flowchart example according to an embodiment of the present invention. Raw data is read (acquired) (block 150). SIFT technology can be applied for noise reduction (block 155). See "SIFT, a postprocessing method that increases the signal-to-noise ratio of spectra which vary in time" by Doyle et al., Journal of Magnetic Resonance, Series B 1994;103(2):128-133 and "AP, Spectral improvement by fourier thresholding of in vivo dynamic spectroscopy data" by Rowland et al., Magnetic resonance in medicine 2015. The entire content is hereby incorporated by reference as if fully set forth herein.

[0118] Optionally, a high SNR FID can be generated when the centers of the three equal parts of the FID of the raw data are averaged together (block 160). Amplitude, frequency, FWHM, FWHM G And initial estimated values (guessed values) of phase are provided / stipulated (block 163). The initial guessed values / estimated values of the high SNR FID are provided as a first curve approximation iteration method, and the result of this approximation is used to provide updated guessed values for small blocks of the average value including dynamics.

[0119] Frequency and FWHM and FWHM GThe estimated value can be obtained based on the average (or median) value of the healthy subject cohort (block 163). The high SNR FID can be approximated using a barrier fork model (block 165). The gas phase frequency can be defined as a reference frequency of 0 ppm (block 167). The result of the high SNR approximation can be converted to ppm units (block 170).

[0120] The RBC chemical shift can be evaluated to confirm that it is ≧214.5, and the barrier chemical shift can be evaluated to confirm that it is ≧196.0 ppm (block 172). If these conditions are not met (false), the approximation stops (block 174). For example, the stop decision can be made based on the number of trials or a specified SNR threshold. If true, the initial estimated value / speculated value can be updated using the result from the high SNR approximation and / or the high SNR FID (block 175). The FID with high or relatively high SNR can be approximated with the updated speculated value / estimated value (block 180). Each time point of the high SNR FID can have five averaged FIDs (block 182). Although five FIDs are considered to provide sufficient resolution, for some embodiments, a small number of FIDs such as three or four, or more than five FIDs in the range of six to ten can be averaged together.

[0121] Figure 8C is another operation flowchart that can be used to evaluate a subject according to an embodiment of the present invention. Gas, barrier, RBC 129 A database of the disease signature pattern of the oscillation of the 129Xe resonance is provided (block 200).

[0122] The hyperpolarization of the subject during a respiratory motion including one or more of inhalation, apnea, and exhalation 129 The raw (FID) NMR signal of 129Xe is acquired (block 210).

[0123] 129 A graph of the oscillations related to the 129Xe barrier, RBC, and gas resonances is created (block 220).

[0124] Based on the oscillations of RBC chemical shift and RBC amplitude, the subject can be identified as having pre- or post-capillary pulmonary vascular disease (block 230). For example, only patients with pure precapillary disease benefit from PH drugs, while patients with post-capillary obstruction are not candidates for treatment with PH drugs, so appropriate characterization is important.

[0125] The database may also include a disease threshold for the RBC:barrier ratio that decreases in IPF subjects relative to the population level (block 202).

[0126] The FID or averaged FID is pre-processed to filter out non-primary frequencies (i.e., frequencies associated with noise) from the indirect time dimension and smooth the temporal variations between FIDs while leaving the spectral frequency region unchanged (block 212).

[0127] The FID or averaged FID can be approximated by a composite in the time domain (block 214).

[0128] A model in which the RBC and gas peaks are Lorentzians with amplitude, chemical shift, FWHM and phase, and a barrier peak is a fork profile that includes an additional Gaussian linewidth (FWHM G ) for the barrier resonance (block 215).

[0129] Curve approximation can be performed using the following equation S fit (block 216).

Equation

[0130] The temporal variations of the 129 Xe RBC resonance occurring at the cardiac frequency (about 1 Hz) can be extracted (block 211).

[0131] The amplitude of the RBC peak can be corrected using T1app (block 217).

[0132] T1app can be calculated by approximating the RBC amplitude during the apnea period to Ae -t / T1app (block 218).

[0133] In other words, the amplitude "A" of the RBC signal is corrected by dividing the signal by exp(-t / T1 app )*exp(-t start / T1 app ), and the second term is a scaling term for adjusting the amplitude to match the raw signal. The signal amplitude is in arbitrary units.

[0134] The RBC amplitude can be calculated as the rate of change from the baseline (block 222). For example, the RBC signal during apnea can be approximated to the function of block 216. Then the value of the function at each time point t is calculated and can be used as the baseline. By finding the difference between the measured value and the calculated value and dividing by the calculated value, the RBC baseline can be regarded as the rate of change. The baseline is defined as the result of the exponential decay approximation of block 218 and is essentially the rate of change from the grand average in many oscillations. [Number]

[0135] The operation of block 222 can use the corrected amplitude from block 217.

[0136] The acquired signal may include pre- and post-drug efficacy or dosing data (block 210).

[0137] To identify the disease state or monitor the progression, the 129 Xe MRI image can be evaluated together with the oscillation graph (block 232).

[0138] The oscillation frequency can be used to determine the heart rate of the subject.

[0139] The static values of one or more spectral parameters may also be evaluated so as to obtain information regarding various medical conditions and / or symptoms, either alone or in combination with one or more dynamic spectral parameters.

[0140] FIG. 8D is a flowchart of an operation that may be used to adjust the amplitude of RBC oscillations, which may be important for interpreting RBC amplitude oscillations. The RBC amplitude oscillations of a subject are obtained (block 300). The obtained RBC oscillations may be adjusted for cardiac output and a new parameter called "lung exchange volume" (block 310).

[0141] The stroke volume is the amount of blood that the right side of the heart pumps out with each beat. The nominal (adult) value is generally reported as 94 or 95 ml. All else being equal, a larger stroke volume would be expected to generate a larger RBC amplitude oscillation. The stroke volume can be determined invasively from a right heart catheterization, which measures ventricular volume from an echocardiogram, or non-invasively from certain time-resolved proton cardiac MRI acquisitions. See "Normal human left and right ventricular dimensions for MRI as assessed by turbo gradient echo and steady-state free precession imaging sequences" by Alfakih, Khaled, et al., Journal of Magnetic Resonance Imaging 17.3 (2003): 323-329. In the absence of such data, it can be estimated from the principle of relative growth rates. See "Stroke volume and cardiac output in normotensive children and adults: assessment of relations with body size and impact of overweight" by de Simone, Giovanni, et al., Circulation 95.7 (1997): 1837-1843. The entire contents of which are hereby incorporated by reference as if fully set forth herein.

[0142] Information from the shape of the RBC oscillation amplitude is potentially used to help distinguish pure precapillary disease from postcapillary disease and complex precapillary and postcapillary pulmonary hypertension (Cpc-PH).

[0143] "Pulmonary exchange volume" is a criterion for the lung volume that receives blood due to the stroke volume. For a given stroke volume, when the pulmonary exchange volume is large, the RBC amplitude oscillation decays.

[0144] The pulmonary exchange volume ("PEV") is 129 derivable from Xe gas exchange MRI. It can be modeled as the thoracic volume minus the volume that constitutes ventilation disorders and minus the volume not involved in RBC transport.

[0145] Mathematically, PEV = TCV * (1 - VDP - RDP) Equation 3 where TCV = thoracic volume, VDP = ventilation disorder rate, and RDP = RBC transport disorder rate. VDP and RDP can be calculated from Xe MRI images (see FIGS. 7A, 7B) (block 315). 129 For example, a subject with a thoracic cavity of 4 liters and 10% VDP + 10% RDP has a pulmonary exchange volume of 80% × 4 liters = 3.2 liters.

[0146] In an embodiment of the present invention, it is assumed that the pulmonary exchange volume is multiplied by the dynamic spectroscopy RBC amplitude oscillation and divided by the cardiac output.

[0147] The cardiac output can also be measured by the ventricular volume from an echocardiogram. Alternatively, a published level value of 94 or 95 mL, or other defined level values based on relative growth rates, can be used. For example, the stroke volume is calculated by dividing the cardiac output by the heart rate. The cardiac output is increased or decreased up to 3 / 4 of the output with body weight, and the heart rate is increased or decreased up to -1 / 4 of the output. Therefore, it is expected that the stroke volume increases or decreases linearly with body weight.

[0148] Naturally, when the blood volume is large, the RBC amplitude oscillation decreases, but when the cardiac output is large, the RBC amplitude oscillation increases. This suggests that in IPF patients, who often have a very small and narrow chest, high RBC oscillation results in a natural decrease in the exchangeable blood volume.

[0149] When the blood volume is large, naturally, the RBC amplitude oscillation decreases, but when the cardiac output is large, the RBC amplitude oscillation increases. This suggests that in IPF patients, who often have a very small and narrow chest, high RBC oscillation results in a natural decrease in the exchangeable blood volume.

[0150] The "adjusted" RBC amplitude oscillation is (V_stroke_ref / V_stroke)*(PEV / PEV_ref) Equation 4 by which the obtained (i.e., initially measured) RBC amplitude oscillation A RBC can be multiplied, where V_stroke_ref is a reference stroke volume such as 94 ml or 95 ml (for adults), V_stroke is the actual stroke volume of the patient, PEV_ref is the reference exchange volume, and PEV is the measured exchange volume of the patient (block 320).

[0151] Referring again to FIG. 3, for example, a subject can be determined to have IPF characterized by RBC amplitude oscillations that are significantly larger (i.e., about 1.5 to 2 times larger) than those of healthy volunteer subjects. In IPF patients, the RBC frequency (chemical shift / ppm) and phase oscillation are also significantly larger than those of the healthy cohort, generally at least 2-fold, 3-fold, 4-fold, or 5-fold larger than those of the healthy cohort. In the IPF and healthy cohorts, the RBC amplitude variation is approximately twice as high (16.8 ± 5.2% and 9.7 ± 2.9%; P = 0.008), the chemical shift oscillation is more than 5-fold higher (0.43 ± 0.33 ppm and 0.083 ± 0.05 ppm; P < 0.001), and the RBC phase oscillation was more than 5-fold higher (7.7 ± 5.6° and 1.4 ± 0.8°; P < 0.001).

[0152] In IPF, since the pulmonary exchange volume PEV is very small, the RBC amplitude oscillation is considered large. When the RBC oscillation is corrected for PEV, it is assumed to potentially decrease significantly. Thus, the more specific diagnostic features of dynamic spectroscopy in IPF patients are chemical shift and phase oscillation, which do not require correction for PEV. So far, such oscillations have been seen only in patients with IPF.

[0153] It is assumed that the increase in RBC amplitude oscillation is the result of either post-capillary occlusion caused by fibrosis or the delivery of cardiac output to a significantly reduced capillary blood volume. Importantly, RBC frequency and phase oscillation are predicted to be caused by delayed oxygenation associated with interstitial lung disease. This is due to the 129 sensitivity of Xe-RBC resonance, enabling unique detection. The observation of oscillation at this frequency in the IPF cohort serves as a criterion for interstitial hypertrophy that causes delayed oxygen diffusion.

[0154] The PAH cohort is characterized by significantly smaller RBC oscillations compared to the normal cohort (Figure 3). Also, in Group 1 PH, no significant differences in RBC chemical shift or phase oscillation from normal values are observed.

[0155] Since patients with pre-existing conditions (i.e., IPF, PAH, LHF) are under drug treatment and are relatively well managed compared to pre-diagnosis patients, these findings in the small patient population used to create dynamic spectroscopic parameters for such patients are particularly noteworthy.

[0156] While not wishing to be bound by any particular theory, small RBC amplitude oscillations are explained by high impedance in the pulmonary artery and small arteries, which helps attenuate changes in capillary volume occurring during diastole.

[0157] Large RBC amplitude oscillations are seen in PH, but RBC frequency / phase oscillations are small or absent. High RBC amplitude oscillations are considered a marker of post-capillary occlusion.

[0158] RBC frequency / phase oscillation appears to have an inherent association with delayed oxygenation occurring in interstitial lung disease, particularly IPF.

[0159] Whether RBC frequency / phase oscillation is associated with idiopathic interstitial pneumonia remains unclear, but this form of pneumonia can be distinguished from IPF based on the 129 Xe spectral parameters, dynamic, static, dynamic and static 129 Xe spectral parameters. It is assumed that it can be distinguished from IPF.

[0160] In some specific embodiments, it is assumed that due to fluctuations above and below the healthy cohort or population level, various defined disease patterns can distinguish post-capillary diseases from pre-capillary diseases.

[0161] In embodiments of the present invention, PAH can be pointed out using the peak-to-peak RBC amplitude oscillation reduced relative to a defined level.

[0162] In embodiments of the present invention, the shape of the RBC amplitude oscillation can be evaluated to point out complex pre- and post-capillary pathological conditions.

[0163] Low RBC amplitude oscillation seems to be a signature specific to pre-capillary, arterial diseases, and patients for whom PAH drug treatment is considered beneficial.

[0164] High RBC amplitude oscillation is expected to be a signature of post-capillary diseases, and these patients will likely experience adverse effects by receiving PAH drug treatment.

[0165] It is assumed that there are several potential methods to obtain dynamic spectroscopic data that improve during standard acquisition.

[0166] Embodiments of the present invention enable the detection of potentially treatable pre-capillary PH in patients with previous lung diseases (such as COPD, IPF, etc.) based on gas exchange MRI. That is, poor barrier conditions (low barrier in COPD or high barrier in IPF) and gas exchange 129Patients with RBC transport disorders affecting a proportion of the lungs that is more imbalanced than can be accounted for by Xe MRI may be used to identify additional and prominent features.

[0167] In embodiments of the present invention, gas exchange MRI and / or dynamic spectroscopy can be performed before and after administration of pharmaceuticals such as vasodilators, hyperoxia therapeutics, diuretics, or prostacyclin. 129 Comparison of oscillatory changes in the spectral parameters of Xe dynamic spectroscopy can be detected, for example, to determine the effect of a drug on function. For example, administration of inhaled nitric oxide or inhaled prostacyclin can reveal areas of the gas exchange image of the lungs that are susceptible to vasodilation indicative of recovery of RBC transport. Similarly, dynamic spectroscopy can show increased / elevated RBC oscillation amplitudes relative to before such administration.

[0168] From the problems of hyperoxia, similar improvements in local RBC transport and recovery of RBC oscillation amplitude are also revealed.

[0169] In several COPD patients, even after correction of a relatively large exchangeable capillary volume, a large reduction in RBC amplitude oscillation is present. This may indicate pre-capillary pulmonary hypertension.

[0170] Now referring to FIG. 9, an example of a medical system 1100 is shown. The medical system 1100 may include at least one server 1150. The at least one server 1150 may be configured to comprise a dynamic 129 Xe spectroscopy module 1124, and / or 129 may be configured to comprise a database 1126 of Xe disease signature patterns.

[0171] At least one server 1150 can generally communicate with the imaging location 1110 and / or the clinician location 1210 via at least one respective digital processor 1110p, 1210p. The imaging location 1110 can be a hospital or other facility (mobile or permanent) equipped with an MRI scanner 1125. The clinician location 1210 is either remote from or at the imaging location 1110. The server 1150 is remote from both the imaging location 1110 and the clinician location 1210. Alternatively, the server 1150 can be on-site at either the clinician location or the imaging location 1210, 1110.

[0172] The server 1150 can be integrated into a single server or distributed among one or more servers or other circuits and databases at a single physical location or spatially separated locations. Similarly, the dynamic 129 The Xe spectroscopy module 1124 can be distributed among a number of processors or databases or integrated into one. 129 The Xe dynamic spectrum can be electronically transmitted to the 1150 server using a DICOM system for automated image analysis.

[0173] The server 1150 can be embodied as a stand-alone server or stored as part of another computing infrastructure. The server 1150 can be stand-alone or embodied as one or more enterprise, application, personal, pervasive, and / or embedded computer systems interconnected by a wireless network including public and / or private, real and / or virtual, wired and / or Internet and including various types of tangible non-transitory computer-readable media. The server 1150 can also communicate with a computer network via a wired or wireless connection and include various types of tangible non-transitory computer-readable media.

[0174] The server 1150 can be provided using cloud computing including on-demand provision of computing resources via a computer network including appropriate firewalls 1160 and privacy protocols to comply with HIPPA or other legal regulations. The resources can be embodied as applications, databases, file services, e-mails, etc., along with various infrastructure services (e.g., computing, storage, etc.). In the traditional computing model, both data and software are generally stored entirely on the user's computer. In cloud computing, the user's computer may store little software or data (perhaps just the operating system and / or web browser) and can function as merely a display terminal for processes occurring on a network of external computers. Cloud computing services (or an aggregation of multiple cloud resources) are generally referred to as the "cloud". Cloud storage can include a model of network computer data storage where data is stored on a number of virtual servers rather than residing on one or more dedicated servers.

[0175] The plurality of imaging sites 1110 can be in communication with the server 1150 and one or more clinician sites 1210. The server 1150 can receive and analyze NMR data of each patient from various sites 1110 at any time. The server 1150 can analyze and generate patient reports in a FIFO (first-in first-out) manner, optionally with urgent or prioritized review. Multiple analyses can be performed simultaneously or sequentially on the server 1150 or other devices in communication with the server 1150, and associated reports can be generated and sent to one or more devices 1211 of clinician users.

[0176] The imaging location 1110 and / or the clinician location 1210 can communicate with the server 1150 via one or more computer networks such as a local area network (LAN), a wide area network (WAN), and may include a private intranet and / or the public Internet (also known as the World Wide Web or the "Web" or the "Internet").

[0177] The server 1150 can be configured to send analysis reports or suspect test or evaluation data to one or more clinician devices 1211 such as a computer, a tablet, or a smartphone (shown as being at the imaging location but one or more may be remote from the imaging location).

[0178] FIG. 10 is a schematic diagram of an MRI scanner 1125 including a superconducting magnet 1140, a gradient system 1165, and an RF coil 1170 that communicates with an RF amplifier (not shown) associated with an MRI scanner well known in the art. Signals from the RF coil 1170 can be transmitted to a receiver 1205 via a cable (commonly a BNC cable). The MRI scanner 1125 also includes a controller 1105 and a frequency adjustment circuit 1102 that can generate a desired RF excitation frequency for exciting hyperpolarized 129 Xe. The MRI scanner 1125 also includes a display 1130. The display 1130 can be local or remote and can be provided as part of a clinician workstation. The display 1130 can be configured to display images of RBCs and barriers 129 substantially simultaneously with a plot of the oscillation of Xe to provide clinical data of the gas exchange region of the lung.

[0179] According to some embodiments of the invention, the MRI scanner 1125 also includes or is in communication with a dynamic spectroscopy module 1224 that can electronically (automatically) switch the operating mode, frequency, and phase in accordance with a program and communicate with the frequency adjustment circuit 1102 and the receiver 1205, and / or electronically instruct the excitation and acquisition of appropriate signals to create cardiopulmonary spectroscopy parameters. Alternatively, NMR signal data for each subject can be collected and transmitted to the server 1150 for post-acquisition processing. The NMR signal data can be transmitted from the PACS (Picture Archiving and Communication System) 1224 to the server 1150.

[0180] Now referring to FIG. 11, a data processing system 1316 is shown that can be used to provide a [ 129 Xe (providing Xe for NMR signal decomposition in the dissolved phase of gas exchange) 129 Xe dynamic spectroscopy module 1124 and a curve approximation module 1327. Thus, according to some embodiments of the present invention, the system 1316 includes a memory 1336 that communicates with a processor 1300. The data processing system 1316 may further include input / output (I / O) circuits and / or data ports 1346 that also communicate with the processor 1300. The system 1316 may include virtual storage such as a RAMDISK, along with removable and / or fixed media such as floppy disks, ZIP drives, hard disks, and the like. The input / output data port 1346 can be used to transfer information between the data processing system 1316 and another computer system or network (e.g., the Internet). These components are conventional components such as those used in many conventional computing devices, and their functionality regarding conventional operations is generally well known to those skilled in the art.

[0181] FIG. 11 shows a processor 1300 and a memory 1336 that can be used in an embodiment of a system according to some embodiments of the present invention. The processor 1300 communicates with the memory 1336 via an address / data bus 1348. The processor 1300 can be, for example, a commercially available or custom microprocessor. The memory 1336 represents one or more memory devices that store software and data used to provide 129 Xe MRI image data or 129 Xe NMR spectral data. The memory 1336 can include, but is not limited to, devices of the following types: cache, ROM, PROM, EPROM, EEPROM, flash, SRAM, and DRAM.

[0182] As shown in FIG. 11, the memory 1336 can store up to two or more categories of software and / or data, namely an operating system 1352, an input / output device driver 1358, data 1356, and an application program 1354. FIG. 11 shows that the data 1356 can include patient NMR spectral data 1326.

[0183] As is recognized by those skilled in the art, the operating system 1352 can be an operating system based on IBM (registered trademark), OS / 2 (registered trademark), AIX (registered trademark), zOS (registered trademark) operating system, or Microsoft (registered trademark) Windows (registered trademark) (e.g., Windows XP, Windows NT, Windows 10, Windows Server 2016) or Unix or Linux (registered trademark) TMIt can be any operating system suitable for use with a data processing system. IBM, OS / 2, AIX, zOS are trademarks of IBM (International Business Machines Corporation) in the United States or other countries or both, while Linux is a trademark of Linus Torvalds in the United States or other countries or both. Microsoft and Windows are trademarks of Microsoft Corporation in the United States or other countries or both. A virtualization platform that supports one or more operating systems may also be used (i.e., VMWARE). The input / output device driver 1358 generally includes software routines accessed through the operating system 1352 by the application program 1354 to communicate with devices such as components of the input / output circuit 1346 and certain memory 1336. The application program 1354 is an example of a program that implements various features of the circuits and modules according to some embodiments of the present invention. Finally, the data 1356 represents static or dynamic data used by the application program 1354, the operating system 1352, the input / output device driver 1358, and other software programs that may reside in the memory 1336.

[0184] As will be appreciated by those skilled in the art, although the present invention is illustrated in FIG. 11 with respect to application program 1354 including modules 1124, 1327, other configurations are also within the scope of the present invention. For example, instead of application program 1354, these circuits and modules can also be incorporated into operating system 1352 or other such logical portions of the data processing system. Further, as will be appreciated by those skilled in the art, although application program 1354 is illustrated in a single data processing system, such functionality can be distributed, for example, across one or more data processing systems in a client / server arrangement of the type described above. Accordingly, the present invention should not be construed as limited to the illustrated configuration, but can be provided by other arrangements and / or divisions of functionality among data processing systems. For example, although FIG. 11 is illustrated as having various modules, one or more of these modules can be combined or separated without departing from the scope of the present invention.

[0185] FIG. 11 illustrates an exemplary hardware / software architecture that can be used, but it will be understood that the present invention is not limited to such a configuration and is intended to encompass configurations capable of performing the above operations. Also, according to various embodiments of the present invention, the functionality of the data processing system and the hardware / software architecture can be embodied as a single processor system, a multiprocessor system, or a network of stand-alone computer systems.

[0186] The computer program code for performing the operations of the data processing system described above with respect to the figures can be written in high-level programming languages such as PYTHON, Java, C, and / or C++ for development convenience. Additionally, the computer program code for performing the operations of the embodiments of the present invention may be written in other programming languages such as, but not limited to, interpreted languages. Some modules or routines may also be written in assembly language or microcode to improve performance and / or memory usage. It will further be appreciated that the functionality of any or all of the program modules may be implemented using individual hardware components, one or more application-specific integrated circuits (ASICs), or a programmed digital signal processor or microprocessor.

[0187] The present invention is described with reference to flowchart illustrations and / or block diagrams of methods, systems, and computer program products according to exemplary embodiments of the invention. These flowchart illustrations and / or block diagrams further illustrate exemplary operations for managing and / or providing calendar-based time-limited passcodes according to some embodiments of the present invention. It will be understood that each block of the flowchart illustrations and / or block diagrams, and combinations of blocks in the flowchart illustrations and / or block diagrams, can be implemented by computer program instructions and / or hardware operations. These computer program instructions can be provided to the processor of a general purpose computer, a special purpose computer, or other programmable data processing apparatus for producing a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, are means and / or circuitry for implementing the functions specified in the singular or plural blocks of the flowchart illustrations and / or block diagrams.

[0188] These computer program instructions can also be stored in a computer-usable or computer-readable non-transitory memory that can direct a computer or other programmable data processing apparatus to function in a particular manner, so that a product is produced that includes instructions for implementing the functions specified in one or more blocks of a flowchart and / or block diagram by instructions stored in the computer-usable or computer-readable memory.

[0189] The computer program instructions may also be loaded onto a computer or other programmable data processing apparatus to cause a series of operational steps to be performed on the computer or other programmable apparatus and to implement a computer-implemented process for providing steps for instructions being executed on the computer or other programmable apparatus to implement the functions specified in one or more blocks of a flowchart and / or block diagram.

[0190] Flowcharts and block diagrams illustrate the architecture, functionality, and operation of some embodiments of a method, system, and computer program product. In this regard, each block represents a module, segment, or portion of code that includes one or more executable instructions for implementing the specified logical function. It should also be noted that in other implementations, the functions noted in the blocks may occur out of the order described. For example, two blocks shown in succession may, depending on the related functionality, actually be executed substantially simultaneously, or the blocks may sometimes be executed in the reverse order.

[0191] The present invention may be embodied as a system, method, and / or computer program product. Accordingly, the present invention may be embodied in hardware and / or in software (including firmware, resident software, microcode, etc.). Further, the present invention may take the form of a computer program product embodied in a computer-usable or computer-readable storage medium having computer-usable or computer-readable program code, for use by or in connection with an instruction execution system. In the context of this document, a computer-usable or computer-readable medium may be any non-transitory medium that can store, store, communicate, propagate, or transport a program for use by or in connection with an instruction execution system, apparatus, or device.

[0192] A computer-usable or computer-readable medium may be, for example, an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system, apparatus, device, or propagation medium. More specific examples (a non-exhaustive list) of the computer-readable medium would include the following: an electrical connection having one or more wires, a portable computer diskette, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or Flash memory), an optical fiber, and a portable compact disc read-only memory (CD-ROM).

[0193] Furthermore, the user's computer, a remote computer (i.e., a server), or both may be integrated with or communicate with other systems, such as, for example, the control cabinet of an MRI scanner system, a hospital PACS (Picture Archiving and Communication System), and / or a clinician workstation.

[0194] Non-limiting examples are described below.

[0195] Example Example 1 Subject Recruitment This study was approved by the Duke University Institutional Review Board, and written informed consent was obtained from all subjects prior to participation. Dynamic 129 Xe spectra were acquired from 8 healthy volunteer subjects (7 men and 1 woman; 26.4 ± 4.9 years old) and 9 IPF subjects (7 men and 2 women; 66.1 ± 5.6 years old). Healthy volunteer subjects had no history of prior lung disease, cardiac arrhythmia, or smoking. IPF subjects were diagnosed according to the ATS criteria that confirm a UIP pattern from CT or surgical lung biopsy. See "An official ATS / ERS / JRS / ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management" by Raghu et al., American journal of respiratory and critical care medicine 2011;183(6):788-824.

[0196] Xenon polarization and administration Using a commercial polarizer (Model 9810, Polarean, Inc., Durham, North Carolina, USA), 300 mL of isotope-enriched 129 Xe (85%) was hyperpolarized to approximately 20% via rubidium vapor spin-exchange optical pumping. The hyperpolarized 129 Xe was stored at cryogenic temperatures and thawed in a 1 L Tedlar bag (Jensen Nitrogen Products, Coral Springs, Florida). In this way, an equivalent of 51 mL dose-equivalent of hyperpolarized 129 Xe (spectrum, enrichment, product of xenon amount) was obtained. See "Hyperpolarized 129Dose and pulse sequence considerations for hyperpolarized Xe ventilation MRI 129 See "Xe ventilation MRI" Magnetic Resonance Imaging 2015;33(7):877-885, the contents of which are incorporated herein by reference as if fully set forth. The bag volume was inflated to 1 L using ultrapure N2.

[0197] After two warm-up breaths, the subject will 129 Xe is inhaled and held for 8 seconds, then slowly exhaled. Kaushik et al., "Measurement of Diffusion Limitation with Perfusion-Limiting Gases - Hyperpolarization in Patients with Idiopathic Pulmonary Fibrosis," 129 Xe gas transport spectroscopy (Measuring diffusion limitation with a perfusion-limited gas - hyperpolarized 129 See "Xe gas-transfer spectroscopy in patients with idiopathic pulmonary fibrosis," Journal of Applied Physiology 2014;117(6):577-585, the contents of which are incorporated herein by reference as if set forth in full. Data acquisition began during inhalation before the subject initiated a respiratory pause. During MRI, each subject's heart rate and oxygen saturation were monitored using an MR-compatible monitoring system (Expression Model 865214; Invivo Corporation, Orlando, FL).

[0198] 129 Xe spectroscopy Dissolution-phase spectra were acquired using a 1.5T GE scanner operating on the 15M4EXCITE platform (GE Healthcare, Waukesha, WI). Subjects were equipped with a quadrature body coil (Clinical MR Solution, Brookfield, WI) tuned to 17.66 MHz. Dissolution-phase Xe was selectively excited using a 1.2 ms two-lobe sinusoidal pulse applied at a frequency 3.832 Hz (217 ppm) above the gas phase. 129 Spectra were acquired at a transmit frequency adjusted to selectively excite Xe. Over the course of a 16-second respiratory cycle, 802 free induction decays (FIDs) were acquired at 512 samples per FID, with an echo time (TE) = 0.932 ms, a repetition time (TR) = 20 ms, a dwell time per point = 32 μs, and a flip angle ≈20°.

[0199] However, it is assumed that the temporal resolution can be decreased from 20 ms to approximately 300 ms. Assuming a maximum heart rate of 100 beats per minute (BPM) is expected to be encountered, samples would need to be taken at twice this frequency, i.e., 3.33 Hz, to satisfy the Nyquist criterion. This means that signals can be acquired approximately every 300 ms. A decrease in temporal resolution (increase in TR) provides several advantages. For example, spectral resolution can be increased by sampling the FID over a longer period (increasing the sampling rate). When the temporal resolution decreases, there is an opportunity to decrease the bandwidth (or increase the dwell time) to increase the SNR.

[0200] Alternatively, spectra can be acquired with a large flip angle (i.e., approximately 90° and approximately 20°C). This increases the signal-to-noise ratio and results in a more reliable spectral analysis. Also, by using a 90° pulse, all dissolution-phase magnetization is dephased after each readout. Therefore, the signal is sensitive to newly diffused magnetization and is expected to increase sensitivity to delayed oxygenation in interstitial lung disease.

[0201] Spectral processing Prior to spectral approximation, two filtering steps were applied to improve the spectral SNR while minimizing the need to sacrifice the temporal resolution required to capture cardiopulmonary dynamics. First, the raw FID was processed using the Spectral Improvement by Fourier Thresholding (SIFT) method. This involves Fourier transforming the raw data in the indirect time dimension (time with respect to breath-hold) and retaining only the coefficients that exceed a predetermined threshold. The data is then inverse Fourier transformed in the indirect frequency dimension to undergo spectral curve approximation. Thus, this preprocessing filters out non-dominant frequencies from the indirect time dimension, smoothing the temporal variations between FIDs while leaving the spectral frequency region unchanged. The time-domain SIFT-filtered FIDs are then averaged using a 5-FID sliding boxcar window filter and subsequently undergo complex approximation in the time domain using a custom MATLAB® toolkit. See "Uncovering a third dissolved-phase 129 Xe resonance in the human lung: Quantifying spectroscopic features in healthy subjects and patients with idiopathic pulmonary fibrosis" by Robertson et al., Magnetic resonance in medicine 2017;78(4):1306-1315. The entire content is hereby incorporated by reference as if fully set forth herein. 129 Most prior literature has treated the dissolved-phase

[0202] Xe spectrum as consisting of two simple Lorentzian RBC and barrier resonances, but recent studies have shown that the barrier resonance is more structured. "Uncovering a third dissolved-phase 129 Xe resonance in the human lung: Quantifying spectroscopic features in healthy subjects and patients with idiopathic pulmonary fibrosis" by Robertson et al. 129Xe Resonance: Quantifying Spectroscopic Features in Healthy Subjects and Patients with Idiopathic Pulmonary Fibrosis (Uncovering a third dissolved-phase 129 Xe resonance in the human lung: Quantifying spectroscopic features in healthy subjects and patients with idiopathic pulmonary fibrosis)”. See Magnetic resonance in medicine 2017;78(4):1306-1315. The entire content is incorporated herein by reference as if fully set forth. This was addressed by Robertson et al. by making the barrier consist of two independent resonances. However, this required an approximation with four additional degrees of freedom, which was not supported by the SNR and spectral resolution of the dynamic acquisition data. This was demonstrated by the presence of a poor-condition approximation for the dynamic acquisition spectrum. Instead, a Voigt model was approximated to allow for a special non-Lorentzian structure for the barrier resonance. This linearity represents the convolution of Lorentzian peaks including a Gaussian distribution and requires only one additional degree of freedom for approximation. Specifically, two individual linewidth parameters, namely the Lorentzian linewidth (FWHM) and the Gaussian linewidth (FWHM G ) are seen. See Use of voigt lineshape for quantification of in vivo 1H spectra by Marshall I, Higinbotham J, Bruce S, Freise A. Magnetic resonance in medicine 1997;37(5):651-657. The entire content is incorporated herein by reference as if fully set forth.

[0203] The full approximation signal can be calculated using Equation 1. Each resonance is characterized by four spectral parameters, namely amplitude (a), frequency (f), phase (φ), and Lorentz linewidth. For barrier resonances, a fifth parameter, the Gaussian linewidth (FWHM G ) was also extracted. The approximation of the barrier resonance was started with equal Lorentz and Gaussian linewidths.

Number

[0204] All frequencies (Hz) were reported as chemical shifts (ppm) above the frequency of the gaseous 129 Xe resonance.

[0205] Normalization and quantification of cardiogenic spectral changes in RBC resonance A number of quantitative parameters were analyzed and extracted from three resonances during three respiratory cycles, but we paid particular attention to the characterization of the time variation of the 129 Xe RBC resonance occurring at the cardiac frequency (~1 Hz). To extract these parameters, the amplitude of the RBC peak was first corrected for the magnetization decay caused by T1 and RF-induced depolarization during breath-hold. The apparent T1 decay constant T1 -t / T1app was quantified by approximating the RBC amplitude during breath-hold to Ae app and these were incorporated into it. The mean value T1 app for all subjects was 13.6 ± 2.7 s. This was then used to correct the RBC signal, and the remaining time variation of the signal amplitude was expressed as the rate of change from the baseline. Each of the RBC spectral parameters was further high-pass filtered at a cut-off frequency of 0.5 Hz to remove residual baseline fluctuations. Then the parameter plots after correction and filtering were approximated to a sine curve including the phase offset.

Number

[0206] Statistical analysis Statistical analysis was performed using MATLAB. The Mann-Whitney-Wilcox U test was used to determine whether the difference between normal healthy subjects and IPF subjects was statistically significant (P < 0.05).

[0207] Results of Example 1 For each subject, age, gender, pulmonary function test results, and the scale of the oscillation of the RBC spectral parameters are summarized in Table 1 (Figure 14).

[0208] Quantification of static spectral parameters 129 Prior to the analysis of Xe spectral dynamics, static parameters averaged over the first second of breath-hold were determined. In Figures 12A - 12D, the resulting RBC and barrier approximation parameters are compared between healthy subjects and the IPF cohort along with the associated derived ratios. The mean RBC:barrier amplitude ratio (Figure 12C) for healthy volunteer subjects was 0.58 ± 0.12, and this decreased significantly to 0.18 ± 0.07 (P < 0.001) in IPF patients. The RBC frequency (Figure 12A) was 1.5 ppm lower in the IPF cohort (P = 0.004), and its Lorentz line width was 1.7 ppm narrower (P = 0.001). The barrier frequency (Figure 12B) was also 0.5 ppm lower in IPF (P = 0.0025), and the Lorentz component of its line width was 0.9 ppm smaller (P = 0.006). The Gaussian line width did not differ between the healthy subject cohort (P = 0.2). These differences contributing to the phase difference between the resonance of barrier Figure 12B and RBC (Figure 12A) were 17.0° smaller compared to the healthy subject cohort (P = 0.006).

[0209] During the breathing motion 129Xe spectrum change Figure 1 shows three results for a typical healthy volunteer (subject 6). 129 The spectral dynamics of all Xe resonances are displayed. Respiratory activity is reflected in each of the fitted parameters, facilitating discrimination between inhalation, respiratory pauses, and exhalation. When the subject exhales, the gas resonance frequency shifts negatively by 0.11 ppm and the linewidth broadens by 0.1 ppm. In contrast, exhalation shifts the barrier resonance positively by 0.06 ppm and narrows the Lorentzian linewidth by 0.29 ppm. The RBC resonance appears to be affected by both inhalation and exhalation primarily in its linewidth, which, like the barrier, narrows slightly (0.37 ppm) during exhalation. The RBC amplitude also exhibits a significant periodicity at a frequency of 58 cycles per minute, consistent with the subject's heart rate (61 and 65 bpm, respectively) recorded by pulse oximetry immediately before and after acquisition. These dynamics are also present, albeit subtle, when the RBC chemical shift and phase are at the same frequency.

[0210] Figure 2 displays the same spectral dynamics shown for a subject with IPF (Subject 13). As in the healthy volunteer, the gas-phase parameters reflect both inhalation and exhalation dynamics, and this is also evident in the barrier resonances through an increase in chemical shift and narrowing of both linewidth parameters during exhalation. The RBC resonances slightly indicate inspiration, while an increase in chemical shift and Lorentzian linewidth, coupled with a decrease in phase, clearly distinguishes exhalation. In this IPF patient, the RBC amplitude is also periodic at a frequency close to the subject's heart rate before and after the scan (71 cycles per minute compared to 70 and 72 bpm, respectively). Interestingly, this cardiac periodicity is also evident in both RBC chemical shift and phase.

[0211] These cardiac dynamics that affect RBC spectral parameters can be more appreciable in plots after normalization and trend removal, as shown in Fig. 13 for representative healthy volunteers and several IPF patients. In healthy volunteers, the RBC amplitude varied by 9.1% peak-to-peak (pk-pk), while the oscillations in RBC chemical shift and phase remained less than 0.05 ppm and 1.5°, respectively. In contrast, in the first IPF subject (IPF13), not only was there a more than two-fold larger RBC amplitude variation (19.9% pk-pk), but also an oscillation in RBC chemical shift that was nearly six-fold larger at 0.29 ppm, while the phase varied by nearly four-fold more at 5.8°. Such oscillations in RBC amplitude, frequency, and phase were also prominent in the other IPF subjects shown.

[0212] Variation in Oscillation Amplitude between IPF and Healthy Subjects Fig. 4 compares the magnitude of cardiogenic oscillations in RBC spectral parameters between healthy volunteers and IPF patients. In the IPF and healthy cohorts, the RBC amplitude variation was nearly two-fold higher (16.8 ± 5.2% and 9.7 ± 2.9%; P = 0.008), the chemical shift oscillation was more than five-fold higher (0.43 ± 0.33 ppm and 0.083 ± 0.05 ppm; P < 0.001), and the RBC phase oscillation was more than five-fold higher (7.7 ± 5.6° and 1.4 ± 0.8°; P < 0.001). Only the RBC linewidth was statistically different between the two cohorts (0.3 ± 0.2 ppm and 0.2 ± 0.1 ppm; P = 0.1).

[0213] Discussion Advantages of Using Barrier Forkts The fork linear model was found to approximate the Xe barrier resonance dynamics more robustly than the "3-Lorentz" approximation (one for RBC and two for barriers). In the 3-Lorentz model, a lower residual error occurs than with barrier forkts when approximating high-resolution, high-SNR spectra, but dynamically 129 it was found that the fork linear model approximates the Xe barrier resonance dynamics more robustly than the "3-Lorentz" approximation (one for RBC and two for barriers). In the 3-Lorentz model, a lower residual error occurs than with barrier forkts when approximating high-resolution, high-SNR spectra, but dynamically 129It is not very suitable for the low SNR and spectral resolution present in Xe acquisition. Refer to "Uncovering a third dissolved-phase Xe resonance in the human lung: Quantifying spectroscopic features in healthy subjects and patients with idiopathic pulmonary fibrosis" by Robertson et al., Magnetic resonance in medicine 2017;78(4):1306 - 1315, which is demonstrated by a highly variable approximation for the two barrier resonances seen in Figure 6B. In contrast, the barrier fork model was able to capture the additional structure of the barrier resonance while maintaining stability during the acquisition process. This is expected to result from the fact that it requires only one additional degree of freedom instead of four required to approximate the barrier with two Lorentzian resonances. Also, the two-component dissolved-phase approximation of RBCs to Lorentzian and the barrier to the fork model leaves unchanged the current three-compartment model for gas exchange that underlies the gas exchange imaging method and CSSR analysis. Refer to "YV MOXE: a model of gas exchange for hyperpolarized Xe magnetic resonance of the lung" by Chang, Magnetic resonance in medicine 2013;69(3):884 - 890. 129 Xe resonance in the human lung: Quantifying spectroscopic features in healthy subjects and patients with idiopathic pulmonary fibrosis 129 Refer to "Uncovering a third dissolved-phase Xe resonance in the human lung: Quantifying spectroscopic features in healthy subjects and patients with idiopathic pulmonary fibrosis" by Robertson et al., Magnetic resonance in medicine 2017;78(4):1306 - 1315, which is demonstrated by a highly variable approximation for the two barrier resonances seen in Figure 6B. In contrast, the barrier fork model was able to capture the additional structure of the barrier resonance while maintaining stability during the acquisition process. This is expected to result from the fact that it requires only one additional degree of freedom instead of four required to approximate the barrier with two Lorentzian resonances. Also, the two-component dissolved-phase approximation of RBCs to Lorentzian and the barrier to the fork model leaves unchanged the current three-compartment model for gas exchange that underlies the gas exchange imaging method and CSSR analysis. Refer to "YV MOXE: a model of gas exchange for hyperpolarized Xe magnetic resonance of the lung" by Chang, Magnetic resonance in medicine 2013;69(3):884 - 890. 129 Xe magnetic resonance of the lung 129 Refer to "YV MOXE: a model of gas exchange for hyperpolarized Xe magnetic resonance of the lung" by Chang, Magnetic resonance in medicine 2013;69(3):884 - 890.

[0214] Importantly, it was found that similar RBC parameters to the three-Lorentz approximation were obtained in the barrier fork model when comparing the approximation of the large average of the data. In the barrier fork model, an RBC:barrier ratio of 0.59±0.11 for healthy volunteer subjects with reasonable consistency was obtained for the previous two- and three-peak Lorentz approximations for the lysis resonance, which were 0.55±0.13 and 0.44±0.07 respectively, and a significant decrease in this ratio was accurately captured in the IPF subjects. By Kaushik et al., "Measuring diffusion limitation with a perfusion-limited gas―hyperpolarized 129 Xe gas-transfer spectroscopy in patients with idiopathic pulmonary fibrosis)", Journal of Applied Physiology 2014;117(6):557 - 585, and by Robertson et al., "Uncovering a third dissolved-phase 129 Xe resonance in the human lung: Quantifying spectroscopic features in healthy subjects and patients with idiopathic pulmonary fibrosis)", Magnetic resonance in medicine 2017;78(4):1306 - 1315. See also 129 Xe resonance in the human lung: Quantifying spectroscopic features in healthy subjects and patients with idiopathic pulmonary fibrosis)」Magnetic resonance in medicine 2017;78(4):1306 - 1315. 129 Refer to "Measuring diffusion limitation with a perfusion-limited gas―hyperpolarized

[0215] Origin of temporal dynamics 129The temporal changes in the Xe spectrum are directly reported in the physiology dynamics of gas exchange in the lung and pulmonary capillaries. The finding that almost all spectral parameters reflect the dynamics related to the respiratory motion is impressive. This is particularly clear during exhalation, accompanied by an increase in the gas-phase linewidth combined with a narrowing of the correspondence of both dissolved-phase peaks. This narrowing, which is inversely proportional to the apparent transverse relaxation time T2*, suggests an improvement in the local magnetic field inhomogeneity determined by the volume magnetic susceptibility of Δχ ≒ 9 ppm between air and tissue in the lung. See "Spatially resolved measurements of hyperpolarized gas properties in the lung in vivo Part I: Diffusion coefficient" by Chen et al., Magnetic resonance in medicine 1999;42(4):721-728. During exhalation, the passive compression of the lung moves air from the alveolar sacs and reduces the total alveolar ventilation. See "Morphometric changes in the human pulmonary acinus during inflation" by Hajari et al., Journal of Applied Physiology 2012;112(6):937-943. And this increases the tissue volume fraction relative to air while the mean capillary diameter increases with the mean alveolar wall thickness.See Glazier et al., "Measurements of capillary dimensions and blood volume in rapidly frozen lungs," Journal of Applied Physiology 1969;26(1):65-76, and Tsunoda et al., "Lung volume, thickness of alveolar walls, and microscopic anisotropy of expansion," Respiration physiology 1974;22(3):285-296. Thus, during exhalation, there is little dissolved-phase xenon atoms located near the air-tissue boundary, narrowing the RBC and barrier line widths. In contrast, gas-phase xenon atoms are expected to be located near the tissue interface, hence increasing the gas-phase line width.

[0216] 129 The high-frequency dynamics of Xe-RBC transport provide an interesting means of how the cardiac cycle affects gas exchange. The RBC signals in these acquisitions interact with the RBCs in the pulmonary capillary bed 129 and mainly originate from the Xe nuclei. This strong localization occurs from the use of a relatively large flip angle (~20°) in combination with a short repetition time (TR = 20 ms) relative to the RBC transit time (~750 ms). Therefore, the magnetization of the dissolved-phase 129 Xe atoms rapidly decays by the RF pulse and can only be replenished through continuous diffusive gas transport in space. However, 129 when the Xe atoms move past the gas exchange unit into the large container, such replenishment no longer occurs and the residual magnetization rapidly decays by RF pulsing. Therefore, from the variations detected in the RBC resonance, evidence is obtained that the 129 Xe-RBC transport is temporally dependent on the capillary pressure and the blood volume oscillations driven by the cardiac cycle.

[0217] The oscillation of the RBC signal amplitude reflects the periodic change in the number of Xe atoms. This observation is expected to be caused by the cardiogenic fluctuation of the capillary volume. The pulmonary capillaries are subject to a slightly higher blood pressure during systole and an accompanying decrease during diastole. See "Pulmonary venous flow velocities recorded by transthoracic Doppler ultrasound: relation to left ventricular diastolic pressures" by Rossvoll et al., Journal of the American College of Cardiology 1993;21(7);1687 - 1696. Such pressure changes are expected to affect the capillary blood volume, as recently demonstrated by synchrotron imaging during the respiratory cycle. See "Synchrotron Imaging Shows Effect of Ventilator Settings of Intra-breath Cyclic Changes in Pulmonary Blood Volume" by Porra et al., American Journal of Respiratory Cell and Molecular Biology 2017 (ja). Here, it has been found that the relative RBC amplitude fluctuations are approximately twice as large in the subjects with IPF, suggesting that the relative change in the capillary blood volume during the cardiac cycle is greater in these patients than in healthy volunteer controls. This is expected to be the result of these patients having large areas of capillary destruction where RBC transport is absent. "Hyperpolarization to Quantify Local Gas Transport in Idiopathic Pulmonary Fibrosis" by Wang et al. 129 ​129 Using hyperpolarized 129 Xe MRI to quantify regional gas transfer in idiopathic pulmonary fibrosis), see "Thorax" 2017 Thorax Journal (thoraxjnl)-2017-210070. The content is incorporated by reference as if it were set forth above. Therefore, the additional capillary blood volume during systole is distributed to the effective capillary volume, which is relatively small.

[0218] Assuming that in vivo studies have shown that the RBC frequency depends non-linearly on the blood oxygenation level sO2, the observation of cardiogenic oscillations in the RBC chemical shift in IPF patients is of particular interest. By Norquay et al., "Hyperpolarized 129 Xe NMR in human blood 129 Xe chemical shift and pulmonary blood oxygenation measurement 129 Xe chemical shift in human blood and pulmonary blood oxygenation measurement in humans using hyperpolarized 129 Xe NMR)", Magnetic Resonance in Medicine 2017;77(4):1399-1408, and by Wolber et al., "Hyperpolarized 129 Xe NMR as a probe for blood oxygenation (Hyperpolarized 129See "Xe NMR as a probe for blood oxygenation", Magnetic resonance in medicine 2000;43(4):491-496. Over the physiologically relevant range of sO2 = 0.6 - 0.98, the RBC chemical shift increases sigmoidally by over 4 ppm. This suggests that, assuming a maximum sO2 of 0.95, the pulsation observed at an RBC chemical shift of 0.43 ppm reflects an overall sO2 change of about 0.07 in the pulmonary capillaries. The fact that RBC frequency pulsations are seen in IPF but not in healthy subjects suggests that this is a potentially unique signature for delays in oxygen diffusion transport across the alveolar-capillary barrier. That is, when deoxygenated blood enters the capillary bed during systole, oxygenation is delayed in patients with severe interstitial hypertrophy. In normal volunteers who are healthy, capillary RBCs reach full oxygenation in about 250 milliseconds, i.e., one-third of the total capillary transit time. See "Respiratory physiology: the essentials" by West et al., Lippincott Williams & Wilkins 2012. Therefore, in healthy volunteer subjects 129 the mean sO2 of RBCs receiving 129 Xe is biased towards full oxygenation. In contrast, the thick interstitial barrier tissue present in IPF patients delays gas diffusion, resulting in a more widely distributed sO2 level across the pulmonary capillary bed. Thus, healthy volunteer subjects and IPF subjects may have the same distal O2 saturation level, but

[0219] from a technical perspective, the heartbeat is 129 even more prominent in the phase of the 129 Xe-RBC resonance. This metric, which is proportional to the chemical shift, provides a relatively clean signal that has been found to be more robust. 129Observation of pulsation in terms of Xe RBC frequency and phase has ultimately proven useful in distinguishing the cause of dyspnea due to interstitial disease from other causes of gas exchange dysfunction such as pulmonary vascular disease. See "Abnormalities in hyperpolarized 129 Xe magnetic resonance imaging and spectroscopy in two patients with pulmonary vascular disease" by Dahhan et al., Pulmonary Circulation 2016;6(1):126-131. The entire content is hereby incorporated by reference as if fully set forth herein. 129 The conclusions of Example 1

[0220] In this study, a series of novel parameters that can be used to further characterize gas exchange were obtained, and a method for acquiring, processing, and analyzing Xe spectra over a simple 16-second spectroscopic acquisition and respiratory motion was successfully identified. The collected FIDs were approximated to a Lorentzian for RBC and gas resonances and to a Voigt line shape for barrier resonances. This was done while restricting the degrees of freedom so that the approximation algorithm also converged for the low SNR and spectral resolution of dynamic acquisitions, adapting to the additional structure of the barrier resonances. The spectroscopic approximation parameters for each Xe resonance were determined with a temporal resolution of 20 milliseconds. Analysis of the static spectral parameters revealed features that distinguish the IPF and healthy control cohorts, generally consistent with previous studies. Their dynamics showed that all three resonances were sensitive to respiratory motion, with clear changes seen in the RBC and gas linewidths. Most notably, oscillations were found in the RBC amplitude, chemical shift, and phase at the cardiac frequency. These oscillations were significantly larger in IPF patients than in healthy controls. Thus, static and dynamic 129 Xe spectra can be used to distinguish IPF patients from healthy controls. 129 spectra can be used to distinguish IPF patients from healthy controls. 129Careful analysis of one or both of the Xe spectra can potentially provide a wide range of additional information useful for further discriminating the diverse underlying causes of gas exchange dysfunction.

[0221] Example 2 As the number of patients with heart and lung complications increases, one increasingly faces the limitations of standard diagnostic criteria. In this Example 2, non-invasive 129 Xenon MR imaging spectroscopy is used to determine the local gas transport dysfunction and blood flow patterns specific to chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), left heart failure (LHF), and pulmonary arterial hypertension (PAH).

[0222] 129 Xe imaging provides useful quantification of local functional workloads, but more detailed characterization of the whole-lung 129 Xe spectral index is thought to provide additional metrics useful for further discriminating underlying lesions. This plethoric 129 number of non-invasive imaging and spectroscopic markers of lung gas transport and blood flow derived from hyperpolarized

[0223] In this Example 2, a comprehensive panel of non-invasive 129 Xe MR imaging and spectroscopy is applied to a cohort of patients with pre-existing heart and lung diseases. Hyperpolarized 129 Xe freely diffuses from the space to RBCs up to the interstitial barrier tissue. In these compartments, individual frequency shifts of 0 ppm, 198 ppm, and 217 ppm are 129 seen in the 129 Xe atoms. These properties can be utilized to create maps of the 3D imaging and quantification of the 129The Xe spectrum is acquired dynamically, for example, every about 20 milliseconds, to reveal cardiogenic oscillations in RBC amplitude (%) and frequency shift (ppm).

[0224] In this Example 2, healthy volunteers (n = 23) and patients with COPD (n = 8), IPF (n = 12), LHF (n = 6), and PAH (n = 10) 129 underwent Xe gas transport imaging and dynamic spectroscopy. For each patient, 3D maps showing ventilation, barrier uptake, and red blood cell (RBC) transport were created. Dynamic 129 Xe spectroscopy was used to quantify cardiogenic oscillations in RBC signal amplitude and frequency shift.

[0225] Compared to healthy volunteers, all patient groups showed decreased ventilation and RBC transport (p ≤ 0.01, p ≤ 0.01). COPD patients showed more ventilation and barrier impairment compared to all other groups (p ≤ 0.02, p ≤ 0.02). In contrast, IPF patients showed high barrier uptake compared to all other groups (p ≤ 0.007) and high RBC amplitude and shift oscillations compared to healthy volunteers (p = 0.007, p ≤ 0.01). Both COPD and PAH patients showed lower RBC amplitude oscillations compared to healthy volunteers (p = 0.02, p =.005). LHF was distinguishable from PAH by high RBC amplitude oscillations (p = 0.01).

[0226] Each of COPD, IPF, LHF, and PAH has a unique 129 XeMR imaging and dynamic spectroscopy "signature". Each of the signatures can be described as a combination of various 129 Xe imaging and 129 Xe spectroscopy parameters, generally shown as at least two unique indicators or graphic markers each using six such parameters. These indicators are useful for the diagnostic challenges of cardiopulmonary diseases and enhance the understanding of local lung function and hemodynamics at the alveolar-capillary level.

[0227] Figure 15 shows a table of demographic and clinical characteristics stratified by the conditions of IPF = idiopathic pulmonary fibrosis, COPD = chronic obstructive pulmonary disease, PAH = pulmonary arterial hypertension, 6MWD = six-minute walk distance, PFT = pulmonary function test, PCWP = pulmonary capillary wedge pressure, and PVR = pulmonary vascular resistance, RVSP = right ventricular systolic pressure. Continuous variables are presented as median (IQR), and categorical variables are presented as frequency (proportion).

[0228] Recruitment of Subjects The protocol was approved by the Institutional Review Board of Duke University Medical Center. Healthy volunteers and patients with either COPD, IPF, LHF, or PAH were recruited, and all provided written informed consent. None of the healthy volunteers had a smoking history or previous respiratory symptoms. COPD was diagnosed using spirometry with a post-bronchodilator forced expiratory volume in 1 second (FEV1) / forced vital capacity (FVC) ≤ 70% predicted. See Celli et al., "Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS / ERS position paper," Eur Respir J. 2004;23(6):932-46. The diagnosis of IPF was established according to the ATS / ERS criteria from either the confirmation pattern of a usual interstitial pneumonia (UIP) pattern on CT or surgical lung biopsy. See Raghu et al., "An official ATS / ERS / JRS / ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management," Am J Respir Crit Care Med. 2011;183(6):788-824. LHF was confirmed by echocardiogram.Refer to "Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging" by Lang et al. (Journal of the American Society of Echocardiography, Vol. 28, Page 1, 2015), 2016, 29(6): 521 - 521. PAH was defined according to World Health Organization criteria and diagnosed by right heart catheterization, with mean pulmonary artery pressure (mPAP) ≥ 25 mmHg and pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg at rest. Refer to "Updated Clinical Classification of Pulmonary Hypertension" by Simonneau et al. (Journal of the American College of Cardiology, 2009, 54(1): S43 - S54). All clinical examinations were conducted as part of routine care. Pulmonary function tests (PFT) were performed on all patients and 83% of healthy volunteers to evaluate baseline lung function.

[0229] MRI acquisition 129Xe imaging spectroscopy was acquired on either a 1.5T (GE 15M4 EXCITE) or 3T (SIEMENS MAGNETOM Trio) scanner. For each subject, 3D images of gas and dissolved-phase data were acquired using interleaved radial acquisition during a 15-second breath-hold. See “Probing the regional distribution of pulmonary gas exchange through single-breath gas- and dissolved-phase Xe-129 MR imaging” by Kaushik, S.S. et al., Journal of Applied Physiology 2013;115(6):850-860. The content is hereby incorporated by reference as if fully set forth herein. Data were acquired at an echo time that resolved two dissolved-phase compartments using the one-point Dixon method. See “Single-breath clinical imaging of hyperpolarized (129)Xe in the airspaces, barrier, and red blood cells using an interleaved 3D radial 1-point Dixon acquisition” by Kaushik et al., Magn Reson Med 2016;75(4):1434-43. The content is hereby incorporated by reference as if fully set forth herein. Thus, 3D images of the gas, barrier, and RBC components were created with 2.8 mm isotropic voxels. Subjects were imaged during breath-hold 129 for hyperpolarized Xe. 129Dynamic spectroscopy is also performed, in which Xe free induction decay (FID) is collected every 20 milliseconds (TE = 0.932 milliseconds, flip angle ≈ 20°, dwell time = 32 μs, 512 / 1024 points). See "A protocol for quantifying cardiogenic oscillations in dynamic (129)Xe gas exchange spectroscopy: The effects of idiopathic pulmonary fibrosis" by Bier et al., NMR Biomed 2018:e4029. The content is incorporated by reference as if fully set forth above.

[0230] Quantitative processing and analysis 3D images of each compartment are represented in a quantitative map and assigned to color clusters using thresholds derived from a healthy subject reference cohort. See "Quantitative analysis of hyperpolarized 129 Xe gas transfer MRI" by Wang, Z, et al., Med Phys 2017;44(6):2415 - 2428, and "Using Hyperpolarized 129 Xe MRI to Quantify the Pulmonary Ventilation Distribution" by He, M., et al., Acad Radiol 2016;23(12):1521 - 1531. The content of both is incorporated herein by reference as if fully set forth. The resulting binned map contains 129 Xe MRI 129 in which the 129Xe ventilation, barrier tissue uptake, and RBC transport are depicted. Each of these maps was quantified by calculating the percentage of the lung in which signal impairment and hyperintensity were seen. Wang, Z., et al., "Quantitative analysis of hyperpolarized 129 Xe gas transport MRI 129See "Dynamic acquisition FID for gas, barrier, and RBC spectral parameter determination approximated in the time domain" in Med Phys 2017;44(6):2415-2428, the contents of which are hereby incorporated by reference as if fully set forth herein. The dynamic acquisition FID was approximated in the time domain to determine gas, barrier, and RBC spectral parameters. See "A protocol for quantifying cardiogenic oscillations in dynamic (129)Xe gas exchange spectroscopy: The effects of idiopathic pulmonary fibrosis" by Bier, E.A., et al. in NMR Biomed 2018;e4029, the contents of which are hereby incorporated by reference as if fully set forth herein. The time-dependent RBC signal was detrended and cardiogenic oscillations in amplitude and frequency shift were quantified by peak-to-peak values relative to the mean. Again, see "A protocol for quantifying cardiogenic oscillations in dynamic (129)Xe gas exchange spectroscopy: The effects of idiopathic pulmonary fibrosis" by Bier, E.A., et al. in NMR Biomed 2018:e4029. Imaging and spectroscopic findings were compared across all cohorts.

[0231] Statistical methods Imaging and spectroscopic features were compared between cohorts. All calculations were performed using JMP 14 (SAS Institute Inc., Cary, NC). First, a one-way analysis of variance was performed using the non-parametric Kruskal-Wallis test. When significant differences were detected, the Mann-Whitney U test was used for pairwise analysis. Statistical significance was claimed for p < 0.05.

[0232] Study cohort This study included 23 healthy volunteer subjects, 8 COPD patients, 12 IPF patients, 6 LHF patients, and 10 PAH patients. The subject demographics and PFT results are summarized in Figure 15.

[0233] In the gas, barrier, RBC compartments 129 3D isotropic images of Xe were acquired in 19 healthy volunteer subjects and all patients. Dynamic spectroscopy was acquired in 13 healthy volunteer subjects, 6 COPD patients, 8 IPF patients, 5 LHF patients, and 10 PAH patients. Subjects were excluded from either imaging or spectral analysis if the acquisitions did not reach an appropriate SNR necessary for reliable quantification.

[0234] Determination of disease-specific imaging-derived metrics Representative ventilation and gas transport maps from subjects in each group are shown in Figure 16 along with the derived quantitative metrics. For each map, the percentage of voxels included in bins of impairment, low values, and high values is reported. In healthy volunteer subjects, all three compartments 129Most of the Xe signal is included within ±1 standard deviation from the mean of the reference distribution and thus in the "normal" green bins. In contrast, in the COPD subjects, significant impairments were seen in all three compartments shown in the red bins - ventilation, barrier, RBC. Relatively normal ventilation was seen in the IPF subjects, but significant high-barrier uptake areas were associated with impairment of RBC transport in the lower lobes. Both LHF and PAH patients had some ventilation impairment and relatively normal barriers, but more significant deficiencies in RBC transport. Ventilation, barrier uptake, and RBC transport maps of representative subjects from each cohort. Color bins represent signal intensity, with red being the lowest, blue / violet being the highest, and green representing voxels within the healthy reference range. Each map is quantified by the impairment (D), low (L), and high (H) rates calculated as the voxel fraction of the lowest value, second lowest value, and two bins of the highest value of each map, respectively.

[0235] Figures 17A - 17D quantitatively evaluate these imaging features across the cohorts and compare the rates of ventilation impairment, RBC impairment, barrier defects, and high barriers. Ventilation impairment (Figure 17A), RBC impairment (Figure 17B), barrier impairment (Figure 17C), comparison of barrier high rates for all cohorts (Figure 17D). Asterisks represent values that are significantly higher (red - R) or lower (green - G) compared to all other cohorts. Compared to healthy subjects, all disease cohorts showed high ventilation impairment (p ≤ 0.01) and RBC impairment (p ≤ 0.01). COPD was characterized by significantly high rates of ventilation impairment (p ≤ 0.02) and barrier impairment (p ≤ 0.02). In IPF, unique low barrier defects (p ≤ 0.02) and high high-barrier rates (p ≤ 0.007) were seen. Slightly high ventilation impairment and moderately high RBC impairment were seen in PAH and LHF. High rates of impairment in ventilation (p ≤ 0.01 for all comparisons) and RBC transport (p ≤ 0.01 for all comparisons) were seen in all patient groups compared to healthy subjects. The COPD cohort stood out with the highest rate of ventilation impairment (41.5 ± 22.6%, p ≤ 0.02 for all comparisons) and was the only one showing impairment of barrier uptake (10.4 ± 7.1%, ≤ 0.02 for all comparisons). In contrast, IPF patients were distinguishable from other groups by the highest voxel rate and had 129Xe uptake was high (39.8%, p ≤ 0.007 for all comparisons). Moderate ventilation impairment (11.5 ± 6.7%, p = 0.0003 vs. healthy subjects) was only seen in IPF subjects, while RBC impairment (11.3 ± 6.7%, p = 0.0001 vs. healthy subjects) was quite significant. Slightly higher ventilation impairment (LHF: 11.7 ± 6.2%, p = 0.01 vs. healthy subjects; PAH: 8.4 ± 4.7%, p = 0.01 vs. healthy subjects) and high RBC transport impairment (LFH: 13.3 ± 10.2%, p = 0.01 vs. healthy subjects; PAH: 14.5 ± 9.3%, p = 0.002 vs. healthy subjects) were seen in LHF and PAH patients, with similar imaging features.

[0236] Disease-specific spectroscopy-derived indices Figures 18A and 18B show the RBC signal amplitude and shift oscillation after trend removal for representative subjects from each group showing cardiogenic oscillation. Separately, for the RBC signal amplitude of each patient (Figure 18A), oscillation occurs at the same frequency as that person's heart rate. Such cardiogenic oscillation is mainly seen as RBC frequency shift in IPF patients. High RBC amplitude oscillation is seen in both IPF and LHF patients. In contrast, RBC signal oscillation is decreased in both PAH and COPD patients. Oscillation at RBC shift is only seen in IPF patients (Figure 18B).

[0237] Figures 19A and 19B show the comparison of cardiogenic RBC amplitude and shift indices in group units. In healthy subjects, RBC amplitude (Figure 19A) oscillates with a peak-to-peak height of 10.0 ± 2.6%, and RBC shift oscillation is very small (0.07 ± 0.05 ppm). RBC shift (Figure 19B) shows significant oscillation only in the IPF cohort (0.46 ± 0.33 ppm, p ≤ 0.01 for all comparisons). In IPF patients, larger RBC amplitude oscillations (16.7 ± 5.5%, p = 0.007) are seen compared to healthy volunteer controls. RBC amplitude oscillations are decreased in both COPD and PAH compared to healthy volunteer controls (COPD: 5.5 ± 4.7%, p = 0.02; PAH: 6.0 ± 3.6%, p = 0.005). In subjects with LHF, RBC amplitude oscillations were larger than in healthy volunteer controls, but this did not reach statistical significance (13.0 ± 5.1%, p = 0.2). However, these oscillations were significantly higher compared to subjects with PAH (p = 0.01). Thus, Figures 19A and 19B show the oscillations of RBC amplitude and frequency shift compared across the entire cohort, respectively. Gray (G) asterisks represent significant differences between cohorts, and red (R) asterisks represent higher values compared to all other cohorts. Lower RBC amplitude oscillations are seen in COPD (p = 0.02) and PAH (p = 0.005) compared to healthy subjects, but higher in IPF (p = 0.007). Also, in LHF and RBC, amplitude oscillations are significantly higher compared to PAH (p = 0.01). Significantly higher RBC shift oscillations are seen in IPF patients compared to all other cohorts (p ≤ 0.01).

[0238] Discussion 129 Discrimination of Diverse Disease Phenotypes by Xe Biomarkers In this study, specific to patients with COPD, IPF, PAH, and LHF 129The Xe MR imaging spectroscopic signature was determined. COPD was characterized by low RBC amplitude oscillation, with significantly higher ventilation and barrier impairment rates compared to all other diseases. However, in COPD, consistent with the heterogeneity of the disease, the ventilation impairment rate varies widely within the cohort. See Pike et al., "Regional Heterogeneity of Chronic Obstructive Pulmonary Disease Phenotypes: Pulmonary He-3 Magnetic Resonance Imaging and Computed Tomography," COPD - Journal of Chronic Obstructive Pulmonary Disease, 2016, 13(5): 601 - 609, the entire contents of which are incorporated herein by reference as if fully set forth. In contrast, IPF was characterized primarily by high barrier uptake, virtually non - existent barrier impairment rate, high RBC amplitude oscillation, and prominent oscillation of RBC shift. PAH and LHF showed similar imaging features (slightly higher ventilation, barrier, RBC impairment rates compared to healthy volunteer controls). However, PAH was distinguishable from LHF by lower RBC amplitude oscillation compared to healthy subjects, while such oscillation was high in LHF. All four disease cohorts showed significant RBC transport impairment.

[0239] These imaging findings are consistent with previous studies that have determined high ventilation impairment in COPD patients. See Wang et al., "Hyperpolarized (129)Xe gas transfer MRI: the transition from 1.5T to 3T," Magn Reson Med, 2018, and Qing et al., "Hyperpolarized 129Assessment of lung function in asthma and COPD using hyperpolarized 129 Xe chemical shift saturation recovery spectroscopy and dissolved-phase MRI」 by NMR in Biomedicine 2014, 27(12): 1490-1501, and "Quantitative analysis of hyperpolarized 129 Xe ventilation imaging in healthy volunteers and subjects with chronic obstructive pulmonary disease" by Virgincar et al in NMR in Biomedicine 2013, 26(4): 424-435. The entire contents of which are hereby incorporated by reference as if fully set forth herein. 129 See "Assessment of lung function in asthma and COPD using hyperpolarized

[0240] The observation that barrier uptake is also decreased in COPD is a new finding that is expected to reflect emphysematous lung destruction and loss of the surface area for gas exchange. This loss further leads to a decrease in RBC transport. In IPF, the disease is characterized by increased barrier uptake, mainly at the lung bases, associated with impaired RBC transport. By Kaushik et al., "Single-breath clinical imaging of hyperpolarized (129)Xe in the airspaces, barrier, and red blood cells using an interleaved 3D radial 1-point Dixon acquisition", Magnetic Resonance in Medicine (Magn Reson Med), 2016, 75(4): 1434-1443, and by Kaushik et al., "Measuring diffusion limitation with a perfusion-limited gas - hyperpolarized 129 Xe transport spectroscopy in patients with idiopathic pulmonary fibrosis 129"Xe gas-transfer spectroscopy in patients with idiopathic pulmonary fibrosis)", Journal of Applied Physiology 2014; 117(6): 577-85, and "Hyperpolarized (129)Xe gas transfer MRI: the transition from 1.5T to 3T" by Wang et al., Magn reson Med 2018, and "Using hyperpolarized (129)Xe MRI to quantify regional gas transfer in idiopathic pulmonary fibrosis" by Wang et al., Thorax 2018.73(1): 21-28, and "Probing the regional distribution of pulmonary gas exchange through single-breath gas- and dissolved-phase Xe-129 MR imaging" by Kaushik et al., Journal of Applied Physiology 2013.115(6): 850-860. The entire content is hereby incorporated by reference as if fully set forth herein. Further, this study 129 provides important context for prior studies showing that cardiogenic oscillations in Xe RBC amplitude and shift are significantly increased in IPF patients compared to healthy controls. "Estimation of diffusion limitation by perfusion-limited gas - hyperpolarized 129Xe gas transport spectroscopy (Measuring diffusion limitation with a perfusion-limited gas―hyperpolarized 129 Xe gas-transfer spectroscopy in patients with idiopathic pulmonary fibrosis)」 in the Journal of Applied Physiology (J Appl Physiol), 2014, 117(6): 577 - 85, and "A protocol for quantifying cardiogenic oscillations in dynamic (129)Xe gas exchange spectroscopy: The effects of idiopathic pulmonary fibrosis" by Bier et al. in NMR in Biomedicine (NMR Biomed), 2018: e4029. The entire content is incorporated herein by reference as if fully set forth. Now, obtaining such data in this extensive cohort suggests that RBC shift oscillations have so far been unique to IPF and are not observed in COPD, LHF, or PAH. Also, the high RBC amplitude oscillations seen in IPF are only additionally seen in LHF, suggesting that this is a marker of post-capillary PH.

[0241] Alveolar-capillary interface model depicting disease phenotypes Figure 20 shows for each disease state 129 a schematic conceptual architecture of the alveolar-capillary interface that helps to interpret Xe imaging spectroscopic biomarkers. This figure illustrates alveoli, capillaries, interstitial barrier tissue, RBCs, 129 Xe atoms. For each disease state, 129 the predicted effects on Xe biomarkers (ventilation, barrier, RBC) are shown. These conceptual diagrams, without limitation of the present invention, in the context of gas transport physiology 129Can be useful for interpreting patterns of Xe MRI and spectroscopic signatures. In healthy subjects, 129 Xe atoms freely diffuse into alveoli and the alveolar-capillary interface, yielding images that reflect normal ventilation, barrier uptake, and RBC transport. In COPD, chronic airway inflammation and mild airway obstruction cause ventilation impairment, and the loss of alveolar surface area associated with emphysema results in a decrease in 129 Xe uptake in the interstitial barrier tissue. See "Systematic manifestations and comorbidities of COPD" by Barnes et al., European Respiratory Journal 2009;33(5):1165-1185. The entire content is incorporated herein by reference as if fully set forth. This is related to complications of RBC transport, but in many patients, poor RBC transport reflecting additional loss of the vasculature is seen as an imbalance. See "Cardiopulmonary Coupling in Chronic Obstructive Pulmonary Disease The Role of Imaging" by Rahaghi, F.N., E.J.R. van Beek, G.R. Washko, Journal of Thoracic Imaging 2014;29(2):81-91. The entire content is incorporated herein by reference as if fully set forth. In contrast, in IPF, interstitial fibrosis causes 129Xe uptake increases. See Lederer et al., "Idiopathic Pulmonary Fibrosis," N Engl J Med 2018; 379(8):797 - 798, the contents of which are hereby incorporated by reference as if fully set forth herein. And this causes diffusion limitations that likely function to reduce RBC transport in addition to perfusion deficits. See Wang, J.M., et al., "Using hyperpolarized (129)Xe MRI to quantify regional gas transfer in idiopathic pulmonary fibrosis," Thorax 2018; 73(1):21 - 28, the contents of which are hereby incorporated by reference as if fully set forth herein. When such disruption is accompanied by maintenance of stroke volume, large relative capillary volume oscillations occur between systole and diastole. This appears as large RBC amplitude oscillations. In the setting of pulmonary hypertension (PH), left heart failure (LHF) is characterized by post - capillary impedance (primarily due to pulmonary venous PH). Since the high impedance begins downstream of the capillary bed, it is associated with large capillary volume oscillations during the cardiac cycle and results in large spectral RBC amplitude oscillations once again. It is not entirely clear what impairs RBC transport, but it is well - known that patients with LHF develop gas exchange abnormalities including a decrease in DLCO that is secondary to chronic impairment due to pulmonary venous congestion.See "Impaired Pulmonary Diffusion in Heart Failure With Preserved Ejection Fraction" by Olson et al., Journal of the American College of Cardiology - Heart Failure, 2016, 4(6), pages 490 - 498, and "Alveolar Gas Diffusion Abnormalities in Heart Failure" by Guazzi, M., Journal of Cardiac Failure, 2008, 14(8): pages 695 - 702. The entire content is incorporated herein by reference as if fully set forth. And finally, it is assumed that PAH is characterized by high precapillary impedance resulting from, among other things, pulmonary arteriolar remodeling and occlusion that can result in loss of alveolar membrane diffusing capacity and pulmonary capillary blood volume. See "Loss of alveolar membrane diffusing capacity and pulmonary capillary blood volume in pulmonary arterial hypertension" by Farha et al., Respiratory Research, 2013, 14. The entire content is incorporated herein by reference as if fully set forth. These features of PAH are not predicted to directly affect ventilation or diffusion barrier uptake, but rather result in flow occurring upstream of the capillary bed due to RBC transport impairment and increased impedance. And this results in a decrease in pulmonary capillary blood volume and cardiogenic blood volume oscillations at the capillary bed. It can result in a decrease in RBC signal amplitude oscillations, which at least at present appears to be the most distinctive feature distinguishing precapillary from postcapillary PH.

[0242] Differentiation of Cardiopulmonary Diseases in Clinical Settings In summary, non-invasive129 This combination of Xe MR imaging and spectroscopic parameters enables monitoring of gas transport at the alveolar capillary level, which is thought to be useful not only for characterizing and quantifying disease burden, but also for determining signatures that help distinguish between states or diseases of cardiopulmonary insufficiency. Potential outputs from this approach are shown in Figure 21, which shows a radar plot (chart) of four major imaging features and two major spectroscopic features - ventilation impairment, barrier impairment, high barrier uptake, RBC impairment, RBC amplitude, and shift oscillation. Integrating these features for each disease group yields an initial graphic output that visually and clearly displays these phenotypes. Creating such a plot for individual patients yields a powerful protocol for determining the primary phenotypes to be considered. A radar chart is a graphical method for displaying multivariate Xe data in the form of a two-dimensional chart of three or more quantitative variables, with one or more diverse measurement units such as percentages and ppm represented on axes starting from the same point. Of course, other outputs can be used, such as, but not limited to, parallel coordinate plots with axes arranged radially. 129 Xe data, with one or more diverse measurement units such as percentages and ppm represented on axes starting from the same point. Of course, other outputs can be used, such as, but not limited to, parallel coordinate plots with axes arranged radially.

[0243] In Figure 21, the radar plot shows the primary Xe MR imaging and spectroscopic signatures associated with patients with COPD, IPF, LHF, and PAH. Here, the mean cohort values of the major markers are shown on six radii - ventilation impairment, barrier impairment, barrier height, RBC impairment rate derived from imaging, RBC shift oscillation, and amplitude oscillation from spectroscopy. 129 In addition to distinguishing between various cardiopulmonary symptoms,

[0244] 129 ​Xe MRI may be useful in determining the underlying cause of dyspnea in patients with mixed cardiopulmonary diseases, such as patients with complications. This is a common clinical symptom in the elderly population, and many people may have complications of COPD and LHF that exacerbate ILD or PAH. See "Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry" by Hoeper et al., International Journal of Cardiology (Int J Cardiol), 2013, 168(2): 871-80. The content is incorporated herein by reference as if fully set forth. Furthermore, early diagnosis is being increasingly emphasized in diseases such as ILD and PAH (see "Barriers to timely diagnosis of interstitial lung disease in the real world: the INTENSITY survey" by Cosgrove, G.P., et al., BMC Pulmonary Medicine (BMC Pulm Med), 2018, 18(1): 9, and "Early detection of pulmonary arterial hypertension" by Lau et al., Nature Reviews Cardiology (Nat Rev Cardiol), 2015, 12(3): 143-55). 129A highly sensitive probe for early diagnosis and disease progression is obtained by the Xe spectroscopic index, the content of which is incorporated herein by reference as if fully described. Further, the RBC transport signal indicates the ultimate disease burden for gas transport function and can therefore be used to evaluate disease progression and treatment response. See "New Developments in Imaging Idiopathic Pulmonary Fibrosis With Hyperpolarized Xenon Magnetic Resonance Imaging" by Mammarappallil, J.G., et al., Journal of Thoracic Imaging 2019;34(2):136-150. The content of which is incorporated herein by reference as if fully described. Considering the limitations of current diagnostic tests, 129 The information provided by Xe gas transport imaging and dynamic spectroscopy has the potential to improve patient care.

[0245] Study Comment In cardiopulmonary symptoms 129 When comparing Xe MR imaging and spectroscopic signatures, there are several limitations in the study of Example 2. First, the heterogeneity and comorbidities of patients in each disease cohort 129 Limit the ability to determine the patterns of Xe imaging and spectroscopy and contribute to the variability of each group. For example, all PAH patients have received treatment for PAH and many, recently, have not had a catheterization, which 129It suppresses the severity of PAH at the time of Xe research. Furthermore, this study is attempting to recruit patients with only LHF as a model of post-capillary impedance. Considering the general progression of the disease state from left heart dysfunction to right heart dysfunction over time, several may also have right heart failure. See "Left ventricular heart failure and pulmonary hypertension" by Rosenkranz et al., Eur Heart J 2016;37(12):942-54. The content is hereby incorporated by reference as if fully set forth herein. In fact, from this phenotypic progression, the large variations in RBC amplitude oscillations (maximum: 21.5%, minimum: 8.0%, standard deviation: 5.1%) seen in our LHF cohort are explained. Another limitation is that subject scans were performed on different platforms with two magnetic field strengths. The quantification method using a healthy control group performed with the same acquisition protocol is designed to account for potential factors such as T1 and T2* decay, which can affect gas transport measurements. By Wang et al., "Hyperpolarization" 129See "Quantitative analysis of hyperpolarized 129 Xe gas transfer MRI" in Med Phys 2017;44(6):2415-2428, the content of which is hereby incorporated by reference as if fully set forth herein. However, the above and other factors limited the size of the healthy reference cohort, which was significantly younger than the general patient cohort. Since the lungs of the elderly are reported to undergo physiological changes that can affect gas transport function, future studies may benefit from constructing a healthier population with better age control. See "Physiological changes in respiratory function associated with ageing" by Janssens, J. P., J. C. Pache, L. P. Nicod in Eur Respir J 1999;13(1):197-205, the content of which is hereby incorporated by reference as if fully set forth herein.

[0246] Conclusion In this study of Example 2, we applied hyperpolarized 129 Xe gas transfer imaging spectroscopy to healthy subjects and patients with COPD, IPF, LHF, and PAH. As a non-invasive, non-ionizing tool, hyperpolarized 129 Xe gas transfer MRI provides a fundamentally new approach for directly imaging local function while capturing hemodynamics at the alveolar-capillary level. The unique imaging spectroscopy signatures determined for each of these diseases may help overcome some of the diagnostic challenges faced by clinicians treating patients with cardiorespiratory diseases. 129 Hyperpolarized 129 Xe gas transfer MRI 129 Hyperpolarized 129 Xe gas transfer MRI provides a fundamentally new approach for directly imaging local function while capturing hemodynamics at the alveolar-capillary level. The unique imaging spectroscopy signatures determined for each of these diseases may help overcome some of the diagnostic challenges faced by clinicians treating patients with cardiorespiratory diseases. 129 We are confident that hyperpolarized 129 Xe gas transfer imaging spectroscopy is a promising technology in the characterization of cardiorespiratory disease pathophysiology and may contribute to a comprehensive understanding of the multifactorial etiology of dyspnea and / or the development of individualized treatment approaches with further validation in large-scale studies.

[0247] Example 3 In this Example 3, an experiment was performed to evaluate whether the sources of pre-capillary (PAH) and post-capillary (PHpost) PH could be discriminated while considering lung complications such as ILD or COPD.

[0248] In this study, hyperpolarized 129 Local gas exchange and hemodynamics were obtained by Xe MRI. In this study, single-breath 3D MRI images of ventilation, barrier, and blood (RBC compartment) were obtained to determine the impairment of the gas exchange region of the lung and the single-breath dynamic spectroscopy of RBC peak amplitude and chemical shift (ppm) over time.

[0249] Recruitment of experimental subjects Healthy: 22; ILD: 12; PAH: 10, left heart failure: 6 (substitute for post-capillary PH): COPD: 8

[0250] Method: Obtained for each subject 129 Xe gas exchange imaging and dynamic spectroscopy

[0251] Figure 22 shows the ventilation, barrier, RBC images, and the associated lung amplitude and chemical shift spectra of healthy subjects. The RBC impairment was 2% and the low RBC value was 5%. The peak amplitude was 10.3%, while the frequency oscillation was 0.02 ppm.

[0252] Figure 23 shows the ventilation, barrier, RBC images, and the associated amplitude and chemical shift spectra of PAH subjects. The RBC impairment was 11% and the low RBC value was 33%. The peak amplitude was 4.3%, while the frequency oscillation was 0.06 ppm.

[0253] Figure 24 shows the ventilation, barrier, RBC images, and the associated amplitude and chemical shift spectra of ILD subjects. The RBC impairment was 19% and the low RBC value was 20%. The peak amplitude was 12.8%, while the frequency oscillation was 0.31 ppm.

[0254] RBC amplitude oscillation was used to determine healthy subjects, and pre- and post-capillary PH. Figure 25 is a graph of RBC amplitude oscillation (%) for healthy subjects and various lung conditions including ILD, PAH, PHpost, and COPD. As shown in the supplementary explanation on the right side of the graph, the various lines from the top (highest RBC amplitude oscillation) to the bottom (lowest) indicate prediction of PHpost or ILD, likelihood of PHpost or ILD, exclusion, likelihood of arteriopathy, and prediction of arteriopathy.

[0255] Figure 26 is a graph of true positive rate and false positive rate using the ROC curve of RBC amplitude oscillation to determine the threshold for separating / discriminating healthy subjects, and pre- and post-capillary PH. The ROC curve area is shown with the best threshold: 7.9.

[0256] Figure 27 is a 3D image set (ventilation, barrier, RBC) of healthy subjects and various disease cohorts showing a lung map indicating indicators that can further discriminate various disease cohorts (ILD, PAH, PHpost, COPD).

[0257] Figure 28 is a schematic diagram of a diagnostic analysis protocol (i.e., model) of defined parameters that can be used to determine the disease state by ventilation, barrier, and RBC damage rates from a 3D lung map, along with dynamic spectroscopic parameters of RBC amplitude and frequency oscillation. In this model, 34 out of 40 subjects (85%) with both imaging and spectroscopy data were accurately classified.

[0258] Figure 29 is an application example of the image and spectral index parameters of subject A used in the diagnostic analysis protocol based on ventilation, barrier, and RBC damage rates from a 3D lung map, along with dynamic spectroscopic parameters of RBC amplitude and RBC frequency oscillation.

[0259] Figure 30 illustrates the diagnostic analysis applied to the indicator parameters of subject A, showing various diagnostic decisions made based on RBC amplitude oscillation, RBC damage rate, ventilation, and barrier defect rate.

[0260] Figure 31 is an application example of the image and spectral index parameters of subject B using a diagnostic analysis protocol based on ventilation, barrier, and RBC damage rate from a 3D lung map, along with the dynamic spectral parameters of RBC amplitude and RBC frequency oscillation.

[0261] Figure 32 illustrates the diagnostic analysis applied to the index parameters of subject B, showing various diagnostic decisions made based on RBC amplitude oscillation, RBC damage rate, ventilation, and barrier defect rate.

[0262] Conclusion of Example 3 The diagnostic analysis model shows the prospect of distinguishing the sources of precapillary (PAH) and postcapillary (PHpost) pulmonary hypertension while considering lung complications such as ILD or COPD. Note that all PAH patients have received standard treatment, and PH has not been clearly excluded from the ILD and COPD cohorts. In the future, it would be desirable to conduct an expected test in a large cohort that underwent right heart catheterization on the same day as a criterion for measuring the sensitivity and specificity of the ability of the Xe index. 129 An expected test in a large cohort that underwent right heart catheterization on the same day would be desirable as a criterion for measuring the sensitivity and specificity of the ability of the Xe index.

[0263] Several embodiments of the present invention are given as examples. Many changes and modifications can be made without substantially departing from the principles of the present invention. Such changes and modifications are intended to be included within the scope of the present invention presented in the following claims. 〔Appendix 1〕 A method for creating dynamic spectroscopic parameters, During a respiratory motion that includes one or more of inhalation / inspiration, apnea, and exhalation / expiration, the free induction decay (FID) of the gas exchange region of one or both lungs of a subject 129 of the Xe NMR signal 129 to obtain a Xe spectrum, the obtained FID of the 129 Xe spectrum is approximated by a curve approximation function, with one or more non-Lorentzian lines in the 129 Xe spectrum being modeled, based on the approximation, a plurality of dynamic 129 Xe spectral parameters are electronically created, the plurality of dynamic 129 Xe spectral parameters being (i) parameters of barrier amplitude, barrier chemical shift (ppm), and one or more barrier full width at half maximum (FWHM) (ppm), (ii) gas amplitude, gas chemical shift (ppm), gas FWHM (ppm), and gas phase (degrees), (iii) red blood cell (RBC) amplitude, RBC chemical shift (ppm), RBC FWHM (ppm), and RBC phase (degrees), including at least one time-course plot of A method comprising. 〔Appendix 2〕 Before the approximation and creation steps, extracting the temporal variation of the 129 Xe RBC resonance occurring at the cardiac frequency, further comprising the method according to Appendix 1. 〔Appendix 3〕 The approximation is performed with a Xe barrier resonance modeled as a Voigt line shape, 129 each of the resonances of the Xe RBC and 129 Xe gas phase is modeled using a Lorentzian line shape, and the barrier resonance is characterized by both a Lorentzian FWHM parameter and a Gaussian FWHM (FWHM 129 )(ppm) parameter, the method according to Appendix 1. G 〔Appendix 4〕 Further comprising adjusting the amplitude “A ” of the RBC amplitude plot by multiplication of (V_stroke_ref / V_stroke)*(PEV / PEV_ref) RBC ​ V_stroke_ref is a reference stroke volume such as 94 ml or 95 ml (for adults), V_stroke is the actual stroke volume of the subject, PEV_ref is the reference pulmonary exchange volume, and PEV is the pulmonary exchange volume of the subject by measurement. The method according to Appendix 1. [Appendix 5] By dividing the RBC amplitude "A" by the calculated apparent T1 decay constant (T1app), for the magnetization decay and RF-induced depolarization caused by T1 during the apnea period of the respiratory motion, the 129 amplitude of the RBC amplitude plot of the Xe spectral parameter is further corrected, and the RBC amplitude at time "t" is approximated by Ae -t / F1app The method according to Appendix 2, wherein T1app is quantified by approximation. [Appendix 6] The 129 The method according to Appendix 1, further including calculating the variation between peaks over time after trend removal of the amplitude of the Xe spectral parameter. [Appendix 7] The method further includes calculating the rate of change of the time variation of the signal amplitude of the RBC amplitude (A) from the baseline as rbc_amp_percent, rbc_amp_percent=(rbc_amp - A*exp(-t / T1 app )) / (A*exp(-t / T1 app )) where T1 app is the T1 decay constant and t is time (seconds). The method according to Appendix 2. [Appendix 8] The method according to Appendix 2, further including calculating the time variation of the signal amplitude of the RBC amplitude (A) using peak-to-peak analysis of the difference between the maximum and minimum values of the oscillation signal of the RBC amplitude. [Appendix 9] The method according to Appendix 1, further including removing residual baseline variation by high-pass filtering each of the RBC amplitude, RBC chemical shift, RBC phase, and RBC FWHM at a 0.5 Hz cut-off frequency to provide a filtered parameter plot of the RBC spectral parameter. [Appendix 10] The method further includes approximating the filtered parameter plot to a sine curve including a phase offset,

Number

Number

Description of Symbols

[0264] 1100 Medical System 1102 Frequency Adjustment Circuit 1105 Receiver 1110 Imaging Location 1110P Digital Processor 1124 Dynamic 129 Xe Spectral Analysis Module 1125 MRI Scanner 1126 129 Xe Disease Signature Pattern Database 1130 Display 1140 Superconducting Magnet 1150 Server 1160 Firewall 1165 Gradient System 1170 RF Coil 1205 Controller 1210 Clinician Location 1210P Digital Processor 1211 Clinician Device 1224 Dynamic Spectroscopy Module / Image Storage and Communication System 1300 Processor 1316 Data Processing System 1326 Patient NMR Spectrum Data 1327 Curve Fitting Module 1336 Memory 1346 Input / Output Circuit / Input / Output Data Port 1348 Address / Data Bus 1352 Operating System 1354 Application Program 1356 Data 1358 Input / Output Device Driver

Claims

1. A method for creating spectroscopic parameters for the medical evaluation of a subject, comprising: During the breathing motion, a series of １２９ acquiring Xe free induction decay (FID) of one or both lungs' gas exchange regions of the subject, Approximating the real and imaginary components of the FID in the time domain using one or more non-Lorentzian curve approximation functions, wherein the curve approximation function １２９ Xe barrier resonance, １２９ resonance of the Xe gas phase, and １２９ resonance of Xe red blood cells (RBCs) are each modeled, and the １２９ Xe barrier resonance is at least partially modeled using the one or more non-Lorentzians, Based on the approximation, a plurality of RBC spectral parameters including RBC amplitude, RBC chemical shift (ppm), RBC full width at half maximum (FWHM) (ppm), and RBC phase (degrees) １２９ is to electronically create Xe spectral parameters, and the plurality of １２９ Xe spectral parameters are (i) parameters of barrier amplitude, barrier chemical shift (ppm), and one or more barrier FWHM (ppm); and (ii) the RBC amplitude, the RBC chemical shift (ppm), the RBC FWHM (ppm), and the RBC phase (degrees); Static and dynamic using at least one plot over time １２９ including Xe spectral parameters, and including; The static and dynamic １２９ The Xe spectral parameters include RBC amplitude oscillation, RBC chemical shift oscillation, RBC FWHM oscillation, and RBC phase oscillation, modifying the peak-to-peak amplitude of the RBC amplitude oscillation based at least in part on the estimated pulmonary exchange volume of the subject; method.

2. Before and / or during the approximation step, Generated at a cardiac frequency １２９ The method according to claim 1, further comprising extracting temporal variations in XeRBC resonance.

3. The approximation is performed using the forked linearity approximated as a forked linearity characterized by both the Lorentz FWHM parameter and the Gaussian FWHM (FWHM Ｇ )(ppm) parameter, the １２９ Xe barrier resonance, and the １２９ Xe RBC resonance approximated using a Lorentzian line shape. When the RBC transport disorder is above a specified threshold and the ventilation disorder and / or the barrier disorder are below the specified threshold, and the peak-to-peak amplitude of the corrected RBC amplitude oscillation is 7.9% or less, the diagnosis is performed so that the subject is highly likely to have precapillary pulmonary hypertension. The RBC transport disorder, the ventilation disorder, and the barrier disorder are in the single lung or both lungs of the subject １２９ electronically automatically calculated from a gas exchange image of Xe magnetic resonance imaging (MRI), and the peak-to-peak amplitude of the corrected RBC amplitude oscillation is performed using the calculated RBC transport disorder, the method according to claim 1.

4. The respiratory motion includes respiratory arrest, and the method further includes modifying the amplitude of the plot of the RBC amplitude for magnetization decay caused by T1 and radio frequency (RF)-induced depolarization during the respiratory arrest period of the respiratory motion by dividing the RBC amplitude "A" by a calculated apparent T1 decay constant (T1app), and approximating the RBC amplitude at time "t" to e －ｔ／Ｔ１ａｐｐ The method according to claim 2, wherein T1app is quantified by approximating to.

5. The foregoing １２９ The method according to claim 1, further comprising calculating the variation between peaks over time after removing the amplitude of the Xe spectral parameter from the trend.

6. further comprising calculating, as a rate of change from a baseline (rbc_amp_percent), a temporal change in the signal amplitude of the RBC amplitude (A) to create the RBC amplitude oscillation; rbc_amp_percent = (rbc_amp - A * exp(-t / T1 ａｐｐ )) / (A * exp(-t / T1 ａｐｐ )) where T1 ａｐｐ is the T1 decay constant and t is time (seconds), The method according to claim 1.

7. The method according to claim 1, further comprising calculating a temporal change in the signal amplitude of the RBC amplitude (A) using a peak-to-peak analysis of the difference between the maximum and minimum values of the RBC amplitude oscillation.

8. A computer system for the electronic medical evaluation of the lungs of a plurality of different subjects, the computer system comprising: During the breathing motion, a series of １２９ Xe free induction decay (FID) is acquired for the gas exchange regions of one or both lungs of each subject, approximating the FID using one or more non-Lorentzian modeled curve approximation functions; Based on the approximation, a plurality of １２９ Xe spectral parameters are electronically created, and the plurality of １２９ Xe spectral parameters are (i) parameters of barrier amplitude, barrier chemical shift (ppm), and one or more barrier full width at half maximum FWHM (ppm); and (ii) RBC spectral parameters including red blood cell (RBC) amplitude, RBC chemical shift (ppm), RBC FWHM (ppm), and RBC phase (degrees); Among them, static and / or dynamic using time-course plots １２９ including Xe spectral parameters, removing residual baseline fluctuations by high-pass filtering each of the RBC amplitude, the RBC chemical shift, the RBC phase, and the RBC FWHM at a 0.5 Hz cutoff frequency to provide a filtered parameter plot of the RBC spectral parameters. Providing the filtered parameter plot of the RBC spectral parameters to an image processing circuit and analyzing the filtered parameter plot of the RBC spectral parameters to determine whether each of the subjects has one or more cardiopulmonary conditions and / or lung disorders or diseases. Comprising at least one processor configured as such. A computer system.

9. The at least one processor is further configured to approximate the filtered parameter plot to a sine curve including a phase offset. 【Number 1】 A ｐｋ－ｐｋ is the peak - to - peak amplitude, f ｃ is the heart rate, t is time (seconds), φ is the phase offset, and f ｃ is the heart rate derived from the RBC amplitude oscillation of the subject, the computer system according to claim 8.

10. f ｃ The computer system according to claim 9, which is used for the temporal approximation of other RBC spectral parameters including RBC chemical shift, line width, and phase.

11. Before and / or after the correction step, normalizing the RBC amplitude oscillation according to a Xe signal in a barrier phase or a gas phase １２９ The method according to claim 1, further comprising normalizing according to a Xe signal.

12. Before the approximation and creation steps, preprocessing the raw FID by Fourier transforming the raw data in the indirect time domain related to the breath-holding time of the respiratory motion of the breathing, retaining only the coefficients exceeding a specified threshold value, and performing an inverse Fourier transform in the indirect time domain to provide an FID with a high SNR for the raw FID for the approximation, further including filtering out non-primary frequencies from the indirect time domain providing the time-domain filtered FID to smooth the temporal variations between different FIDs while keeping the spectral frequency domain unchanged. The method according to claim 1.

13. Using an FID sliding boxcar window filter and averaging a plurality of the time-domain filtered FIDs to provide an FID with a high SNR for the approximation. The method according to claim 12.

14. The acquisition is at least partially responsive to a pulse sequence having a repetition time (TR) in the range of about 20 milliseconds to 300 milliseconds and a flip angle in the range of about 20 to 90 degrees, providing high sensitivity to cardiac oscillations. The method according to claim 1.

15. The acquisition is at least partially responsive to a pulse sequence having a repetition time (TR) in the range of 200 to 300 milliseconds and a flip angle in the range of 20 to 90 degrees. The method according to claim 1.

16. A method implemented by a computer system, a method for assisting in non-invasively screening a subject for one or more cardiopulmonary diseases, comprising: A series of the gas exchange regions of one or both lungs of the subject during a breathing motion １２９ acquiring Xe free induction decay (FID), Approximating the real and imaginary components of the FID in the time domain using one or more non-Lorentzian linearly modeled curve approximation functions, wherein the curve approximation function １２９ Xe barrier resonance, １２９ resonance of the Xe gas phase, and １２９ modeling each of the Xe erythrocyte (RBC) resonances, and the １２９ Xe barrier resonance is at least partially modeled using the one or more non-Lorentzians, Based on the approximation, a plurality of RBC spectral parameters including RBC amplitude, RBC chemical shift (ppm), RBC full width at half maximum (FWHM) (ppm), and RBC phase (degrees) １２９ is to electronically create Xe spectral parameters, and the plurality of １２９ Xe spectral parameters are (i) parameters of a barrier amplitude, a barrier chemical shift (ppm), and one or more barrier FWHMs (ppm); (ii) the RBC amplitude, the RBC chemical shift (ppm), the RBC FWHM (ppm), and the RBC phase (degrees); Static and dynamic using at least one plot over time １２９ including Xe spectral parameters, and including; The static and dynamic １２９ The Xe spectral parameters include RBC amplitude oscillation, RBC chemical shift oscillation, RBC FWHM oscillation, and RBC phase oscillation, of the single lung or both lungs of the subject １２９ acquiring a gas exchange image by Xe magnetic resonance imaging (MRI), from the gas exchange images of the single lung or both lungs of the subject, electronically calculating RBC transport disorders, ventilation disorders, and barrier disorders; １２９ from Xe magnetic resonance imaging (MRI) gas exchange images, electronically calculating RBC transport disorders, ventilation disorders, and barrier disorders; electronically providing a database including a plurality of defined diverse disease patterns, wherein the plurality of defined diverse disease patterns precapillary pulmonary hypertension, at least partially defined by each defined disease pattern including the peak-to-peak amplitude of the RBC amplitude oscillation at 7.9% or less; precapillary pulmonary hypertension, at least partially defined by each defined disease pattern including the peak-to-peak amplitude of the RBC amplitude oscillation greater than 13.85%; and said providing; including; method.

17. the created １２９ The method according to claim 16, further comprising electronically evaluating the Xe spectrum parameters to determine whether the subject has one or more of the specified various disease patterns.

18. The method according to claim 16, wherein one or more of the defined diverse disease patterns include an oscillation of the RBC amplitude oscillation, the RBC chemical shift oscillation, the RBC FWHM oscillation, or the RBC phase oscillation that exceeds a defined peak-to-peak threshold.

19. The method according to claim 16, wherein one or more of the defined diverse disease patterns include at least one feature of the RBC amplitude oscillation and the RBC chemical shift oscillation having a peak-to-peak variation below a defined peak-to-peak threshold.

20. The method according to claim 16, wherein one or more of the defined diverse disease patterns are based on the shape of at least one oscillation of the RBC amplitude oscillation, the RBC chemical shift oscillation, the RBC FWHM oscillation, and the RBC phase oscillation.

21. The method according to claim 16, wherein at least one of the defined disease patterns has a disease pattern including an RBC frequency shift obtained during the first second of apnea of the respiratory movement lower than a defined level.

22. The method according to claim 16, wherein one or more of the defined diverse disease patterns determine a complex pre- and post-capillary disease.

23. electronically comparing one or more of the RBC amplitude oscillations, the RBC chemical shift oscillations, the RBC FWHM oscillations, and the RBC phase oscillations before and after administration of the pharmaceutical; and further comprising determining vascular reactivity and / or changes based on changes in the corresponding RBC amplitude oscillations, the method of claim 1.

24. The method of claim 23, wherein the pharmaceutical is a vasodilator.

25. The method of claim 24, wherein the vasodilator is an inhaled vasodilator.

26. The method of claim 23, wherein the pharmaceutical comprises prostacyclin.

27. for gas exchange in the single lung or both lungs of the subject １２９ acquiring Xe magnetic resonance imaging (MRI) images of the gas exchange, and １２９ electronically calculating an RBC transport disorder rate, a ventilation disorder rate, a barrier disorder rate, and a high barrier uptake rate from the Xe MRI images When the corrected RBC amplitude oscillation is 7.9% or less, the subject is highly likely to be diagnosed with precapillary pulmonary hypertension, When the corrected RBC amplitude oscillation is at least 1.5 times greater than that of a healthy subject cohort and / or the high-barrier uptake rate is 20% or more, the subject is highly likely to be diagnosed with idiopathic pulmonary fibrosis (IPF), the method of claim 1.

28. The obtained series of １２９ The method according to claim 1, wherein the data from the XeFID is obtained during the breathing motion at intervals of from 20 milliseconds to 300 milliseconds per breath, and the breathing motion includes a breath hold over a period of about 10 to 30 seconds.

29. The approximation is performed by the four spectral parameters, namely amplitude (a), frequency (f), phase (φ), and Lorentz linewidth (FWHM), of the １２９ Xe barrier resonance, the １２９ resonance of the Xe gas phase, and the １２９ Xe erythrocyte (RBC) resonance, and for the barrier resonance, the Gaussian linewidth (FWHMG), which is the fifth parameter, is also extracted, and the approximation is performed with the barrier resonance initialized with the respective initial Lorentz and Gaussian linewidths, and the approximation is performed using the following equation: 【Number 2】 The method of claim 1.

30. A method of creating spectroscopic parameters for medical evaluation of a subject, comprising: During the breathing motion, a series of １２９ acquiring Xe free induction decay (FID) of one or both lungs' gas exchange regions of the subject, and Approximating the real and imaginary components of the FID in the time domain using one or more non-Lorentzian linearly modeled curve approximation functions, wherein the curve approximation functions are １２９ Xe barrier resonance, １２９ resonance of the Xe gas phase, and １２９ each of the Xe red blood cell (RBC) resonances, and the １２９ Xe barrier resonance is at least partially modeled using the one or more non-Lorentzians Based on the approximation, a plurality of RBC spectral parameters including RBC amplitude, RBC chemical shift (ppm), RBC full width at half maximum (FWHM) (ppm), and RBC phase (degrees) １２９ is to electronically create Xe spectral parameters, and the plurality of １２９ Xe spectral parameters are (i) parameters of barrier amplitude, barrier chemical shift (ppm), and one or more barrier FWHMs (ppm); and (ii) the RBC amplitude, the RBC chemical shift (ppm), the RBC FWHM (ppm), and the RBC phase (degrees); Static and dynamic using at least one plot over time １２９ including Xe spectral parameters, and comprising The static and dynamic １２９ The Xe spectral parameters include RBC amplitude oscillation, RBC chemical shift oscillation, RBC FWHM oscillation, and RBC phase oscillation, Correlating with various pulmonary hypertension and / or interstitial lung diseases １２９ Electronically providing a database including a plurality of defined diverse disease patterns of Xe spectrum parameters, at least some of the plurality of defined diverse disease patterns including a defined set of one or more features of at least two of the RBC amplitude oscillation, the RBC chemical shift oscillation, the RBC FWHM oscillation, and the RBC phase oscillation; and the providing One of the various disease patterns is idiopathic pulmonary fibrosis (IPF) that correlates with the case where the RBC phase oscillation is at least 1.5 times greater than that of a healthy subject cohort and the case where the RBC (chemical shift) oscillation and the RBC phase oscillation are at least 2 times greater than that of a healthy subject cohort. method

31. A method of creating spectroscopic parameters for medical evaluation of a subject, comprising: During the breathing motion, a series of the gas exchange regions of one or both lungs of the subject １２９ is acquired by obtaining Xe free induction decay (FID), Approximating the real and imaginary components of the FID in the time domain using one or more non-Lorentzian modeled curve approximation functions, the curve approximation functions being １２９ Xe barrier resonance,[[]] １２９ resonance in the Xe gas phase, and １２９ modeling each of the Xe red blood cell (RBC) resonances, the １２９ Xe barrier resonance being modeled using at least in part the one or more non-Lorentzians Based on the approximation, a plurality of RBC spectral parameters including RBC amplitude, RBC chemical shift (ppm), RBC full width at half maximum (FWHM) (ppm), and RBC phase (degrees) １２９ is to electronically create Xe spectral parameters, and the plurality of １２９ Xe spectral parameters are (i) parameters of barrier amplitude, barrier chemical shift (ppm), and one or more barrier FWHMs (ppm); and (ii) the RBC amplitude, the RBC chemical shift (ppm), the RBC FWHM (ppm), and the RBC phase (degrees); Static and dynamic using at least one plot over time １２９ Including Xe spectral parameters, and comprising The static and dynamic １２９ The Xe spectral parameters include RBC amplitude oscillation, RBC chemical shift oscillation, RBC FWHM oscillation, and RBC phase oscillation, Correlating with various pulmonary hypertension and / or interstitial lung diseases １２９ Electronically providing a database including a plurality of defined disease patterns of Xe spectrum parameters, at least some of the plurality of defined disease patterns including a defined set of one or more features of at least two of the RBC amplitude oscillation, the RBC chemical shift oscillation, the RBC FWHM oscillation, and the RBC phase oscillation, and said providing One of the various disease patterns described above is idiopathic pulmonary fibrosis (IPF), which correlates with cases where the RBC chemical shift oscillation is more than five times higher than that of the healthy cohort and where the RBC phase oscillation is more than five times higher than that of the healthy cohort. Method.

32. The obtained series of １２９ Further includes transmitting data of Xe free induction decay (FID) from an imaging location to a remote server by a magnetic resonance imaging (MRI) scanner, the remote server performing approximation and creation operations, and the remote server including or being in communication with a database of data of various disease pattern signatures of the １２９ Xe spectral parameter defined, the method according to claim 1.

33. One of the disease patterns of the above-described disease patterns related to idiopathic pulmonary fibrosis (IPF) is at least partially characterized by an RBC chemical shift (ppm) of less than the specified ppm. The method according to claim 16.

34. Furthermore, a plurality of the single lung or the both lungs of the subject including an RBC impairment rate, a ventilation impairment rate, a barrier impairment rate, and a high barrier intake rate １２９ electronically obtaining Xe imaging parameters creating at least one radar plot indicating the disease state of the subject, the radar plot including a plurality of １２９ Xe imaging parameters and １２９ based on Xe spectrum parameters, including a ventilation disorder rate, a barrier disorder rate, an RBC disorder rate, a high barrier uptake rate, the RBC phase oscillation, and an RBC chemical shift oscillation; and the creating; the method according to claim 1.

35. A magnetic resonance imaging (MRI) scanner, At least one processor in communication with the MRI scanner and configured to execute the method according to claim 1. An MRI scanner system comprising.

36. A medical evaluation system comprising a server in communication with at least one magnetic resonance imaging (MRI) scanner and having at least one processor configured to execute the method according to claim 1.

37. Before the acquisition step, the method further includes overpolarization of the gas phase １２９ The method according to claim 1, further comprising providing Xe to the subject.

38. To evaluate one or more diverse disease states and / or symptoms, said dynamic １２９ in combination with one or more of said static Xe spectrum parameters １２９ further comprising electronically evaluating one or more values of said static Xe spectrum parameters, said static １２９ The method according to claim 1, wherein one or more of said static Xe spectrum parameters are derived from a spectrum obtained only over the first part of the breath hold of said respiratory movement.

39. The complex pre- and post-capillary vascular disease correlates with each of the specified disease patterns defined by at least one of the magnitudes, shapes, or frequencies of the RBC amplitude oscillation, the RBC chemical shift oscillation, the RBC FWHM oscillation, or the RBC phase oscillation. The method according to claim 16.

40. １２９ A system for determining whether a patient has one or more defined medical conditions using Xe spectral parameters, comprising: During a respiratory motion, a series of the gas exchange regions of one or both lungs of a patient are １２９ acquired with Xe free induction decay (FID), Using one or more non-Lorentzian linearly modeled curve approximation functions to approximate the FID in the time domain, the curve approximation function modeling each of the resonance of the disorder, the resonance of the red blood cell (RBC), and the resonance of the gas phase. Based on the approximation of a plurality of RBC spectral parameters including RBC amplitude, RBC chemical shift (ppm), RBC full width at half maximum (FWHM) (ppm), and RBC phase (degrees), a plurality of static and dynamic １２９ Xe spectral parameters are created, and the dynamic １２９ Xe spectral parameters are the dynamic １２９ Include oscillations of the plurality of RBC spectral parameters as at least part of the dynamic Xe spectral parameters, Evaluating at least two of the specified shapes, patterns, peak sizes, and / or frequencies of the oscillations of the RBC amplitude, the RBC chemical shift (ppm), the RBC FWHM (ppm), the RBC phase (degrees). from the said single lung or both lungs of the said patient １２９ using data from gas exchange images of Xe magnetic resonance imaging (MRI), calculate the RBC transport disorder rate, ventilation disorder rate, barrier disorder rate, and high barrier uptake rate, and Comprising at least one processor configured to determine whether the patient has one or more specified medical conditions based on the electronic evaluation. The precapillary pulmonary hypertension is determined as one of the above-described specified medical conditions based at least in part on the peak-to-peak amplitude of the oscillation of the RBC amplitude being 7.9% or less, and the patient is determined to be likely to have precapillary pulmonary hypertension. Idiopathic pulmonary fibrosis (IPF) is determined as the one or more specified medical conditions based at least in part on when the peak-to-peak amplitude of the oscillation of the RBC amplitude exceeds 10.2% and / or when the high-barrier uptake rate is 20% or more. System. Claim 41 The static and dynamic １２９ The Xe spectral parameters are barriers using plots over time of barrier amplitude, barrier chemical shift (ppm), and one or more barrier FWHM (ppm). １２９ The system of claim 40, further comprising Xe spectral parameters. Claim 42 said static and dynamic １２９ The Xe spectral parameters include the gas-phase amplitude, the gas-phase chemical shift (ppm), the gas FWHM (ppm), and the gas-phase １２９ The system according to claim 41, further comprising Xe spectral parameters. Claim 43 said plurality of static and dynamic １２９ The Xe spectral parameter includes the RBC chemical shift and the oscillation of the RBC phase, the system according to claim 40. Claim 44 The static １２９ The Xe spectral parameter is derived from a spectrum obtained only for the first approximately one second of apnea of the respiratory motion, the system according to claim 40. Claim 45 the static and dynamic １２９ The Xe spectral parameter includes (i) an RBC / barrier ratio and (ii) a value of an RBC chemical shift calculated based on an average of signals only for an initial approximately 1 second of apnea of the respiratory motion, the system of claim 40. Claim 46 Static １２９ The system according to claim 1, wherein the Xe spectral parameter is an RBC / barrier ratio and is an average value of 0.58 ± 0.12 for healthy subjects. Claim 47 The processor is further configured to use the ventilation disorder rate and / or the RBC transport disorder rate to correct the peak-to-peak amplitude of the oscillation of the RBC amplitude based on the calculated pulmonary exchange volume of the patient, and pulmonary capillary hypertension is determined as the one or more medical conditions when the peak-to-peak amplitude of the oscillation of the corrected RBC amplitude is 7.9% or less. The system according to claim 40.

Images