Dynamic hyperpolarized 129Xe gas exchange spectroscopy

Abstract

The invention relates to a dynamic hyperpolarization 129Xe gas exchange spectrometry. The present invention relates to a method and apparatus for generating dynamic spectral parameters from hyperpolarized 129Xe dynamic NMR free induction decay signals of lungs by fitting including one or more non-Lorentz line shapes, such as a Voigt line shape for fitting a barrier resonance signal, and further signal processing to identify parameters of cardiac oscillations and for assessing a disease state using these parameters, methods and systems for use in drug discovery or monitoring of disease states.

Description

[0001] Related Applications

[0002] This application claims the benefit of and priority to U.S. Patent Application Serial No. 16 / 406,630, filed May 8, 2019, and U.S. Provisional Application Serial No. 62 / 673,175, filed May 18, 2018, the contents of which are hereby incorporated by reference as if set forth in their entirety herein.

[0003] Government funding

[0004] This invention was made with government support under Grant Nos. NHLB1 R01HL105643 and NHLBI R01HL126771 awarded by the National Institutes of Health and Grant No. HHSN268201700001C awarded by the Department of Health and Human Services. The U.S. Government has certain rights in this invention.

[0005] Copyright reserved

[0006] A portion of the disclosure of this patent document contains material that is claimed for copyright protection. The copyright owner has no objection to the facsimile reproduction or reproduction by anyone of the patent document or the patent disclosure, as it appears in the Patent and Trademark Office patent files or records, but otherwise reserves all other rights whatsoever. Technical Field

[0007] The present invention relates to medical assessment using in vivo NMR spectroscopy. Background Art

[0008] Hyperpolarization (HP) 129 Xe MRI is emerging as a valuable tool for imaging lung structure and function. See Kruger et al., Functional imaging of the lungs with gas agents, Journal of Magnetic Resonance Imaging, 2016; 43(2):295-315; Matin et al., Chronic obstructive pulmonary disease: lobar analysis with hyperpolarized 129 Xe MRimaging (Chronic Obstructive Pulmonary Disease: Using Hyperpolarization 129Xe MR imaging for lung lobe analysis, Radiology, 2016;282(3):857-868. Arguably, its most notable feature as a probe of lung function is related to its solubility in blood and biological tissues, combined with a unique in vivo chemical shift that reflects the local environment. See Cherubini et al. Hyperpolarisedxenoninbiology, Progress in Nuclear Magnetic Resonance Spectroscopy, 2003;42(1):1-30. Dissolved in human blood 129 Xe exhibits different resonances for red blood cells (RBC) and plasma, separated by approximately 22 ppm. See Norquay et al. 129 Xe chemical shift in human blood and pulmonary blood oxygenation measurement in humans using hyperpolarized 129Xe NMR 129 Xe chemical shift and human pulmonary blood oxygenation measurement), Magnetic resonance in medicine, 2017; 77(4): 1399-1408; Wolber et al. Hyperpolarized 129 Xe NMR as a probe for blood oxygenation 129 XeNMR as a probe of blood oxygenation), Magnetic Resonance in Medicine, 2000; 43(4): 491-496. Relative to the gas phase resonance at 0 ppm, obtained in human lung 129 The Xe spectrum also shows a unique RBC peak at 217 ppm, as well as the peaks of RBCs dissolved in both plasma and parenchyma. 129Xe composition resonance. See Kaushik et al., Measuring diffusion limitation with aperfusion-limited gas—hyperpolarized 129Xe gas-transfer spectroscopy in patients with idiopathic pulmonary fibrosis, Journal of Applied Physiology, 2014; 117(6); 577-585. Because these environments also form diffusion 129 Xe or O 2 The resonance is transferred to the barrier of the RBC, so it is often called barrier resonance. See Cleveland et al. 3D MRI of impaired hyperpolarized 129 Xe uptake in a rat model of pulmonary fibrosis 129 3D MRI of Xe absorption), NMR in Biomedicine, 2014; 27(12): 1502-1514. Although recent high-resolution spectroscopy suggests that the barrier resonance may contain additional structure, it is generally believed to be shifted in frequency by about 198 ppm. See 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 129 Xe resonance: quantifying spectral features in healthy subjects and patients with idiopathic pulmonary fibrosis), Magnetic Resonance in Medicine, 2017;78(4):1306-1315. The contents of the cited documents are hereby incorporated by reference as if fully set forth herein.

[0009] Recently, it has been used 129These unique spectral properties of Xe can be used to generate 3D images of gas exchange in the lungs. See Qing et al., Regional mapping of gas uptake by blood and tissue in the human lung using hyperpolarized xenon-129 MRI, Journal of Magnetic Resonance Imaging, 2014;39(2):346-359. This imaging shows impaired gas exchange in various diseases that affect the cardiopulmonary system. For example, in patients with idiopathic pulmonary fibrosis (IPF), the barrier in the lungs is impaired throughout most of the lungs. 129 Xe uptake was significantly increased, while its transfer to RBCs was focally impaired. See Wang et al. Using hyperpolarized 129 Xe MRI to quantify regional gas transfer in idiopathic pulmonary fibrosis (using hyperpolarized 129 Xe MRI Quantification of Regional Gas Shifts in Idiopathic Pulmonary Fibrosis), Thorax, 2017:thoraxjnl-2017-210070. In contrast, in the case of COPD with emphysema, both barrier absorption and RBC shifts are reduced. See Wang et al. Quantitative Analysis of Hyperpolarized 129 XeGas TransferMRI (Hyperpolarized 129 Xe gas transfer MRI quantitative analysis), Medical Physics, 2017. In addition, 129 Xe gas exchange MRI has recently demonstrated impaired RBC transfer in pulmonary vascular disease. See Dahhan et al., Abnormalities in hyperpolarized 129Xe magnetic resonance imaging and spectroscopy in two patients with pulmonary vascular disease, Pulmonary circulation, 2016; 6(1): 126-131. The contents of the references cited in the background art are hereby incorporated by reference as if recorded in full herein.

[0010] Patients may present with multiple comorbidities such as asthma-COPD overlap syndrome (ACOS), combined fibrosis and emphysema (CPFE), or secondary pulmonary hypertension (PH), and it may be important to distinguish the underlying pathophysiology responsible for the impaired gas exchange.

[0011] Pulmonary vascular disease (PVD), such as pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease (PVOD), leads to obstruction of blood flow through the pulmonary vasculature, which causes right heart failure. Even with current therapies, PVD is still associated with great morbidity and mortality, with a 5-year survival of only ~50%. However, the management of PVD is greatly limited by its diagnostic criteria and non-invasive methods for monitoring the disease. The most common PVD, PAH, can only be diagnosed by invasive right heart catheterization (RHC). In addition, it requires meeting specific hemodynamic and clinical criteria: pulmonary hypertension (PH), defined as mean pulmonary artery pressure (mPAP) ≥ 25 mmHg and pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg in the absence of obvious cardiac, pulmonary or specific systemic diseases. Other PVDs are diagnosed by pathology or exclusion. These strict criteria may exclude patients who actually suffer from pathological lesions of PVD, who may benefit from treatment with pulmonary vasodilators. For example, patients with diastolic heart failure or lung disease may develop significant precapillary PH associated with high pulmonary vascular resistance (PVR). Unfortunately, secondary causes of this increased resistance often prevent invasive catheterization from definitively diagnosing PVD. However, in an aging population, this situation of suspected PVD in patients with concomitant diseases is becoming increasingly common.

[0012] Therefore, there is a need for non-invasive techniques that can aid in the diagnosis and / or monitoring of pulmonary hypertension and interstitial lung disease, including PVD, especially for the many patients who may benefit from PAH-specific therapies but would otherwise likely remain untreated. Summary of the invention

[0013] Embodiments of the present invention provide non-invasive systems and methods to generate three different 129 Xe resonance—— 129 Xe gas resonance, 129 Xe barrier resonance and 129 Xe red blood cells ("RBCs" or "RBC") resonances are associated with multiple dynamic spectroscopic parameters of the gas exchange region of the lung.

[0014] Embodiments of the present invention may provide non-invasive methods and systems to aid in the diagnosis and / or monitoring of pulmonary hypertension and interstitial lung disease, including PAH.

[0015] Embodiments of the present invention may be used with129 Dynamic spectroscopy of Xe correlates with markers to differentiate between precapillary (ie, pulmonary hypertension) and postcapillary vasculature diseases.

[0016] Embodiments of the present invention provide disease specific signature patterns including peak-to-peak height values ​​and / or oscillation shapes of one or more of RBC amplitude, chemical shift, and phase.

[0017] The oscillations may be associated with one or more of the inspiration, breath-hold, and / or expiration time periods.

[0018] Embodiments of the present invention provide a library of disease signature patterns that may be useful for: diagnosing lung disease or injury, studying or evaluating interstitial lung disease or injury and / or its progression or remission, and / or evaluating the effectiveness of targeted therapies, side effects or unintentional negative effects of therapy or drug treatment and / or drug discovery.

[0019] Embodiments of the present invention may be used 129 Xe MRI gas exchange ventilation, barrier and RBC images together with dynamic spectroscopy to differentiate between pre-capillary and post-capillary vasculature conditions or diseases and / or for example can determine how much of the capillary bed is compromised or injured.

[0020] Embodiments of the present invention may correct and / or adjust RBC oscillation amplitude via stroke volume and lung exchange volume.

[0021] Embodiments of the present invention relate to methods for generating dynamic spectral parameters. The method comprises: obtaining free induction decay (FID) of a gas exchange region of one or more lungs of a subject during a breathing maneuver including one or more of inhalation / inspiration, breath holding, and exhalation / exhalation 129 Xe NMR signal 129 Xe spectrum; the obtained spectrum of FID is fitted using the curve fitting function 129 Xe spectrum; and generate multiple dynamic 129 Xe spectral parameters. Using one or more non-Lorentzian line shapes 129 The Xe spectrum is modeled, and multiple dynamic 129 The Xe spectral parameters include a time plot of at least one of the following: (i) barrier amplitude, barrier chemical shift (ppm), one or more barrier full width at half maximum (FWHM) (ppm) parameters; (ii) gas amplitude, gas chemical shift (ppm), gas FWHM (ppm) and gas phase (degrees); and (iii) red blood cell (RBC) amplitude, RBC chemical shift (ppm), RBC FWHM (ppm) and RBC phase (degrees).

[0022] The method may include, prior to the fitting and generating steps, extracting 129 Temporal variation of XeRBC resonance.

[0023] This fit can be modeled as a Voigt line shape using 129 Xe barrier resonances and their respective Lorentz lineshape modeling 129 XeRBC and 129 The Xe gas phase resonance is carried out. The barrier resonance can be expressed by the Lorentz FWHM parameter and the Gaussian FWHM (FWHM G )(ppm) parameters are used to characterize the two.

[0024] The method may further include adjusting the amplitude "A" of the RBC amplitude graph by multiplying (V_stroke_ref / V_stroke)*(PEV / PEV_ref). RBC ”. V_stroke_ref is the reference stroke volume, such as 94 ml or 95 ml (adult), V_stroke is the subject’s actual stroke volume, PEV_ref is the reference pulmonary exchange volume, and PEV is the subject’s measured pulmonary exchange volume.

[0025] The method may further include correcting the RBC amplitude "A" by dividing the calculated apparent T1 decay constant (T1app) 129 The magnitude of the RBC amplitude plot of the Xe spectral parameters for magnetization decay caused by T1 and RF-induced depolarization during the breath-hold period of the respiratory maneuver can be obtained by fitting the RBC amplitude within time "t" as To quantify T1app.

[0026] The method may further include 129 The amplitudes of the Xe spectral parameters were detrended and the peak-to-peak changes over time were then calculated.

[0027] The method may further include calculating the temporal change in signal amplitude of the RBC amplitude (A) as a percentage change relative to the baseline: (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 (seconds).

[0028] The method may further include calculating the temporal change in the signal amplitude of the RBC amplitude (A) using a peak-to-peak analysis of the difference between maximum and minimum values ​​in the oscillating signal of the RBC amplitude.

[0029] The method may further include high pass filtering each of the RBC amplitude, RBC chemical shift, RBC phase, and RBCFWHM at a 0.5 Hz cutoff frequency to thereby remove residual baseline variations and provide a filtered parameter graph of the RBC spectral parameters.

[0030] The method may further include fitting the filtered parameter graph to a sinusoidal curve with a phase offset:

[0031]

[0032] Among them A pk-pk is the peak-to-peak amplitude, f c is the heart rate, t is the time in seconds, and is the phase shift, and where f c is the heart frequency derived from the subject's RBC amplitude oscillations.

[0033] f c It can be used for time fitting of all other RBC spectral parameters (chemical shift, line width and phase).

[0034] The method may further include normalizing the RBC amplitude spectrum parameter, the barrier amplitude spectrum parameter, and the gas amplitude spectrum parameter to the barrier phase or the gas phase. 129 Xe signal.

[0035] The method may further comprise, prior to the fitting and generating steps, pre-processing the raw FID by Fourier transforming the raw data along the indirect time domain relative to the breath-holding period of the respiratory action, retaining only coefficients exceeding a defined threshold, and then Fourier transforming back along the indirect frequency domain to provide a FID with an increased SNR relative to the raw FID for fitting, thereby filtering out non-dominant frequencies from the indirect time domain to smooth out temporal changes between different FIDs while leaving the spectral-frequency domain intact.

[0036] The method may further include using a sliding rectangular window filter on the FID and averaging a plurality of time-domain filtered FIDs to provide a FID with increased SNR for fitting.

[0037] The acquisition may be responsive, at least in part, to a pulse sequence having a TR in the range of 20 ms-300 ms and a flip angle of approximately 20-90 degrees to thereby provide increased sensitivity to cardiogenic oscillations.

[0038] The obtaining may be responsive, at least in part, to a pulse sequence having a TR in the range of 200-300 ms and a flip angle in the range of 20-90 degrees.

[0039] The method may further include providing different pulmonary hypertension and interstitial lung disease-related 129 Multiple definitions of Xe spectral parameters identify distinct disease patterns.

[0040] The method may further include electronically evaluating the generated 129 Xe spectral parameters to identify whether the subject has one or more of the different disease pattern identification features defined.

[0041] One or more of the defined different disease patterns may include oscillations in one or more of the RBC spectral parameters exceeding a defined peak-to-peak threshold.

[0042] One or more of the defined different disease patterns may include oscillations in one or more of the RBC spectral parameters below a defined peak-to-peak threshold.

[0043] One or more of the different disease patterns defined may be based on 129 The shape of the oscillations of one or more of the Xe spectral parameters.

[0044] At least one interstitial lung disease may have a disease pattern signature with an RBC frequency shift that decreases during a breath hold of the breathing effort relative to the inspiratory and / or expiratory portions of the breathing effort.

[0045] The different disease patterns defined can differentiate precapillary vessel obstruction by reduced RBC amplitude oscillations relative to defined criteria.

[0046] The different disease patterns defined can distinguish post-capillary vascular disease from pre-capillary vascular disease by increased RBC amplitude oscillations relative to defined criteria.

[0047] One or more of the different disease patterns defined may optionally identify combined pre-capillary and post-capillary vascular disease through the shape of the RBC amplitude oscillations.

[0048] The method may further include comparing RBC amplitude oscillations of one or more RBC plots before and after administration of the agent, and identifying vascular reactivity and / or changes based on changes in the RBC amplitude oscillations.

[0049] The agent may be a vasodilator, optionally the vasodilator is an inhaled vasodilator.

[0050] The agent may include a prostacyclin.

[0051] The method may further comprise comparing the gas exchange of the subject 129Xe MRI images to detect pulmonary hypertension associated with reduced RBC mobilization that affects a portion of the lung that is disproportionately larger than can be explained by the portion with abnormal barrier absorption.

[0052] During the breathing maneuver, the acquired data may be acquired between every 20 ms and every 300 ms. The breathing maneuver may include a breath hold, a full inhalation, and a full exhalation over a period of 10 to 30 seconds.

[0053] It can be obtained by using four spectral parameters: amplitude (a), frequency (f), phase The fitting is performed for each resonance characterized by the Lorentzian linewidth (FWHM), and for the barrier resonance, a fifth parameter, the Gaussian linewidth (FWHM G ), where the fit is made for the barrier resonance initialized with equal Lorentzian and Gaussian linewidths, and where the fit is made using the following equation:

[0054]

[0055] The method may further include identifying whether the subject has IPF, wherein IPF can be characterized by a disease signature pattern having RBC amplitude oscillations that are significantly larger (at least about 1.25 times or 1.5 times larger) than those of a healthy population, and RBC frequency (chemical shift / ppm) and phase oscillations that are at least 1.5 times, typically at least 2 times, that of a healthy population.

[0056] RBC amplitude variations can be at least 1.5 times that of healthy people (optionally, 16.8±5.2% vs. 9.7±2.9%; P=0.008), chemical shift oscillations are more than 5 times that of healthy people (optionally, 0.43±0.33ppm vs. 0.083±0.05ppm; P<0.001), and RBC phase oscillations are more than 5 times that of healthy people (optionally, 7.7±5.6° vs. 1.4±0.8°; P<0.001).

[0057] The method may further include transmitting the acquired data from the imaging site to a remote server using the MR scanner. The remote server may perform the fitting and generating actions. The remote server may include data related to pulmonary hypertension and interstitial lung disease. 129 A database of or communication with defined signatures of different disease patterns using Xe spectral parameters.

[0058] The method may further comprise obtaining a plurality of 129 Xe imaging parameters, including at least two of RBC defect percentage, ventilation defect percentage, and barrier defect percentage; and based on the obtained129 Xe imaging parameters and multiple dynamic 129 At least two of the Xe spectral parameters identify whether the patient suffers from cardiopulmonary disease.

[0059] IPF can be characterized by a characteristic pattern of disease signatures including RBC chemical shifts (ppm) below 217 ppm.

[0060] A method for identifying a cardiopulmonary disease in a patient comprises: obtaining a plurality of 129 Xe imaging parameters include red blood cell (RBC) defect percentage, ventilation defect percentage, and barrier defect percentage; multiple parameters including RBC displacement oscillation and RBC amplitude oscillation are obtained 129 Xe dynamic spectrum parameters; and based on the obtained 129 Xe imaging parameters and 129 Xe dynamic spectrum parameters indicate whether the patient has cardiopulmonary disease.

[0061] The method may further include: 129 Xe imaging parameters and 129 Xe dynamic spectral parameters are used to generate graphic identification features of the patient's cardiopulmonary health or disease status, and then based on the generated graphic identification features, it is identified whether the patient has cardiopulmonary disease.

[0062] The method may further include comparing the generated graphic identification feature to a graphic identification feature library, the graphic identification feature library including a unique graphic identification feature for each of the following: chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), left heart failure (LHF), and pulmonary arterial hypertension (PAH).

[0063] The method may further include providing a diagnostic model that defines the likelihood of different diseases based on different thresholds of the peak of the RBC oscillation and the peak of the chemical shift (ppm) oscillation. Identification may be performed using the provided diagnostic model.

[0064] Still other embodiments are directed to an MRI scanner system comprising: an MRI scanner including an MRI receiver; and at least one processor in communication with the MRI scanner and configured to perform any of the methods of the present invention.

[0065] Other embodiments are directed to a medical assessment system comprising a server in communication with at least one MRI scanner and having at least one processor for performing any of the methods of the present invention.

[0066] Although described herein with respect to method aspects of the present invention, it will be understood that the present invention may also be embodied as a system and computer program product.

[0067] When reading the following drawings and detailed description, other systems, methods and / or computer program products according to embodiments of the present invention will be or will become apparent to those skilled in the art. It is intended that all such additional systems, methods and / or computer program products be included in this description, be within the scope of the present invention and be protected by the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] The patent or application file contains at least one drawing executed in color. Copies of the patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0069] Features of the present invention will be more readily understood from the following detailed description of exemplary embodiments of the present invention when read in conjunction with the accompanying drawings.

[0070] Figure 1 is a representative healthy subject during inhalation, breath holding and exhalation according to an embodiment of the present invention 129 Graphs / diagrams of spectral parameters of Xe gas (left graph), barrier (middle graph) and RBC (right graph) resonances (normalized) over time.

[0071] Figure 2 is a representative sample of a subject with IPF during inhalation, breath holding, and exhalation according to an embodiment of the present invention. 129 Graphs / diagrams of spectral parameters of Xe gas (left graph), barrier (middle graph) and RBC (right graph) resonances (normalized) over time.

[0072] Figure 3 is a graph / plot of normalized and detrended RBC spectral parameters over time (“dynamic”) during breath holding in a healthy subject (left graph), two subjects with IPF, two subjects with PAH, and two subjects with LHF according to an embodiment of the present invention.

[0073] 4A-4D are graphs / diagrams comparing peak-to-peak cardiogenic oscillations in RBC spectral parameters in healthy subjects versus IPF subjects during breath-hold according to embodiments of the present invention. FIG. 4A compares peak-to-peak RBC amplitude oscillations (percent). FIG. 4B compares peak-to-peak RBC FWHM oscillations (ppm). FIG. 4C compares peak-to-peak RBC chemical shift oscillations (ppm). Figure 4D Compare peak-to-peak RBC phase (degrees) oscillations.

[0074] 5A-5D are graphs / diagrams comparing oscillations of RBC spectral parameters for healthy vs. IPF and PAH populations / subjects according to embodiments of the present invention. FIG. 5A compares peak-to-peak RBC amplitude oscillations (percent). FIG. 5B compares peak-to-peak RBCFWHM oscillations (ppm). FIG. 5C compares peak-to-peak RBC chemical shift oscillations (ppm). Figure 5D Compare peak-to-peak RBC phase (degrees) oscillations.

[0075] Fig. 6A is a plot of the dissolution phase fit with large FID average and minimum residual error for the 3-Lorentz model (left) and the barrier Voigt model (left), according to an embodiment of the present invention.

[0076] Figure 6B is a graph illustrating dynamically acquired spectra for healthy volunteers that return a poor fit of the barrier resonances in the 3-Lorentz model (left and middle set of panels) that is overcome by the barrier Voight model (rightmost panel) in accordance with an embodiment of the present invention.

[0077] Fig. 7A is a color-coded image of a COPD patient with severe ventilation defect (top two rows of ventilation images), but in which barrier absorption (middle two rows) and RBC absorption (bottom two rows) are relatively well matched, according to an embodiment of the present invention. 129 A collection of Xe MRI images.

[0078] Figure 7B is a color coding for COPD patients according to an embodiment of the present invention 129 Xe MRI images (top two rows of ventilation images) with barrier uptake (middle two rows) and RBC uptake (bottom two rows) showing that the RBC transfer defect is disproportionately worse than the barrier uptake, suggesting possible precapillary pulmonary hypertension.

[0079] Fig. 8A is a flow chart of actions that can be used to perform embodiments of the present invention.

[0080] Figure 8B is a flow chart of actions that can be used to perform embodiments of the present invention.

[0081] Figure 8C is a flow chart of actions that can be used to perform embodiments of the present invention.

[0082] Fig.8D is a flow chart of actions that may be performed to adjust an RBC amplitude oscillation value in accordance with an embodiment of the present invention.

[0083] Fig. 9is a block diagram of a data processing system that may be used to use multiple oscillations associated with RBCs and / or barrier curve diagrams according to some embodiments of the present invention. 129 Defined signatures of Xe spectral parameters are used to identify different disease states.

[0084] Fig.10 is a schematic illustration of a medical assessment system in communication with an MRI imaging system according to an embodiment of the present invention.

[0085] Fig.11 is a block diagram of a data processing system according to an embodiment of the present invention.

[0086] Figures 12A-12D is a graph comparing static parameters for healthy and IPF subjects during the first second of a breath hold with the RBC phase set to zero degrees according to an embodiment of the present invention. Fig. 12A (Left panel) RBC chemical shift (ppm), FWHM (ppm), FWHM G (ppm) and phase (degrees). Fig. 12B Barrier chemical shift (ppm), FWHM (ppm), FWHM G (ppm) and phase (degrees). Fig. 12C Graph showing derived metrics for the RBC:Barrier ratio. Fig.12D Illustrated is a derived metric of the RBC-barrier frequency difference (ie, the difference in chemical shift between the RBC and barrier peaks) for chemical shift (ppm) according to an embodiment of the present invention.

[0087] Fig.13 is the normalized and detrended RBC spectral parameter dynamics during breath holding from a representative healthy volunteer (left panel) and 5 subjects with IPF according to an embodiment of the present invention. The solid line represents the sinusoidal fit.

[0088] Fig.14 is a table of subject demographics, pulmonary function test (PFT) results, and RBC oscillation information according to an embodiment of the present invention.

[0089] Fig.15 is a table of demographic and clinical characteristics stratified by condition according to an embodiment of the present invention.

[0090] Fig.16 is a color-coded representation of a representative subject from each population (healthy, COPD, IPF, LHF, and PAH) according to an embodiment of the present invention. 129 Collection of Xe MRI images (maps) with ventilation plots in the top row, barriers in the middle row and RBC uptake / transfer in the bottom row.

[0091] 17A is a graph of ventilation defect percentages for healthy and different disease populations in accordance with an embodiment of the present invention.

[0092] 17B is a graph of the percentage of RBC defects in healthy and different disease populations according to an embodiment of the present invention.

[0093] 17C is a graph of barrier defect percentages for healthy and different disease populations according to an embodiment of the present invention.

[0094] Fig.17D is a graph of barrier high percentages for healthy and different disease populations according to an embodiment of the present invention.

[0095] 18A is a graph of RBC delta amplitude (%) over time (s) for healthy and different disease populations according to an embodiment of the present invention.

[0096] Fig.18B is a graph of RBC delta displacement (ppm) over time (s) for healthy and different diseased populations according to an embodiment of the present invention.

[0097] 19A is a graph of RBC amplitude oscillation (%) with respect to healthy and different disease populations in accordance with an embodiment of the present invention.

[0098] Fig.19B is a graph of RBC displacement oscillation (ppm) with respect to healthy and different disease populations according to an embodiment of the present invention.

[0099] Fig. 20 is an illustration of a conceptual model depicting disease phenotypes and biomarker parameters at the alveolar-capillary interface according to an embodiment of the present invention.

[0100] Fig.21 is a set of radar graphs according to an embodiment of the present invention, which is based on 129 Xe imaging and spectroscopy parameters / markers illustrate the clinical course of patients with COPD, IPF, LHF, and PAH 129 Xe disease state and health marker features.

[0101] 22 represents ventilation, barrier, and RBC images of a healthy lung and associated amplitude and chemical shift spectra in accordance with an embodiment of the present invention.

[0102] 23 represents ventilation, barrier, and RBC images and associated amplitude and chemical shift spectra of a subject with PAH, in accordance with an embodiment of the present invention.

[0103] Fig.24 Ventilation, barrier, and RBC images and associated amplitude and chemical shift spectra represent a subject with ILD according to an embodiment of the present invention.

[0104] Fig.25 is a graph of RBC amplitude oscillation (%) for healthy and different lung disease state(s) according to an embodiment of the present invention.

[0105] Fig.26 is a graph of true positive rate versus false positive rate of a ROC curve using RBC amplitude oscillations according to an embodiment of the present invention.

[0106] Fig. 27 is a collection of 3D images (ventilation, barrier and RBC) illustrating the metrics healthy and different disease populations that can further differentiate different disease populations according to an embodiment of the present invention.

[0107] Fig.28 is a schematic illustration of a diagnostic analysis protocol that may be used to identify defined parameters of a disease state in accordance with an embodiment of the present invention.

[0108] Fig.29 is an example application of image and spectral metric parameters of Subject A that may be used for a diagnostic analysis protocol according to an embodiment of the present invention.

[0109] Fig.30 The diagram illustrates a diagnostic analysis of metric parameters applied to subject A according to an embodiment of the present invention.

[0110] Fig.31 is an example application of image and spectral metric parameters of subject B that may be used for a diagnostic analysis protocol according to an embodiment of the present invention.

[0111] Fig.32 Illustrated is a diagnostic analysis of metric parameters applied to subject B according to an embodiment of the present invention. DETAILED DESCRIPTION

[0112] Although the present invention can be completed in modified and alternative forms, its specific embodiments are shown in the drawings by way of example and will be described in detail. However, it should be understood that it is not intended to limit the present invention to the specific forms disclosed, but on the contrary, the present invention will cover all modifications, equivalents and alternatives that fall within the spirit and scope of the present invention. Throughout the description of the figures, the same reference numerals represent the same elements.

[0113] In the drawings, the thickness of some lines, layers, components, elements or features may be exaggerated for clarity. Unless otherwise specified, dashed lines illustrate optional features or operations. Unless otherwise specifically noted, the order of operations (or steps) is not limited to the order presented in the claims or drawings.

[0114] The terms used herein are only used to describe the purpose of a particular embodiment, and are not intended to limit the present invention. Unless the context clearly indicates otherwise, as used herein, the singular form "one", "an", "the" is intended to also include plural forms. It will be further understood that when used in the specification, the term "include" (singular form) and / or "include" (participle form) specifies the presence of the feature, integer, step, operation, element and / or part, but does not exclude the presence or increase of one or more other features, integers, steps, operations, elements, parts and / or its group. As used herein, the term "and / or" includes any and all combinations of one or more associated listed items. As used herein, phrases such as "between X and Y" and "between about X and Y" should be interpreted as including X and Y. As used herein, phrases such as "between about X and Y" mean "between about X and about Y". As used herein, phrases such as "from about X to Y" mean "from about X to about Y".

[0115] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as those commonly understood by those of ordinary skill in the art to which the present invention belongs. It will be further understood that terms such as those defined in commonly used dictionaries should be interpreted as having meanings consistent with their meanings in the context of the specification and in the relevant art, and should not be interpreted in an idealized or too formal sense unless explicitly defined in this document. For the sake of brevity and / or clarity, well-known functions or configurations may not be described in detail.

[0116] It will be understood that although the terms first, second, etc. can be used in this article to describe various elements, components, regions, layers and / or sections, these elements, components, regions, layers and / or sections should not be limited by these terms. These terms are only used to distinguish an element, component, region, layer or section from another region, layer or section. Therefore, the first element, component, region, layer or section discussed below can be referred to as the second element, component, region, layer or section without departing from the teachings of the present invention.

[0117] 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-field magnet (typically between about .1T and about .5T), a medium or high-field superconducting magnet, an RF pulse excitation system, and a gradient field system. MRI scanners are well known to those skilled in the art. Examples of commercially available clinical MRI scanners include, for example, those provided by General Electric Medical Systems, Siemens, Philips, Varian, Bruker, Marconi, Hitachi, and Toshiba. An MRI system can have any appropriate magnetic field strength, such as, for example, about 1.5T, and can be a system of higher fields between about 2.0T-10.0T.

[0118] The term "high field strength" refers to magnetic field strengths above 1.0 T, typically above 1.5 T, such as 2.0 T or 3.0 T. However, the invention is not limited to these field strengths and may be adapted for use with higher field strength magnets, such as, for example, 3.0 T or even higher.

[0119] The term "hyperpolarization" 129 Xe refers to a substance with an increased polarization above its natural or equilibrium level. 129 Xe. As known to those skilled in the art, it can be induced by spin exchange with optically pumped alkali metal vapor. See U.S. Pat. No. 5,545,396 to Albert et al.; and U.S. Pat. No. 5,642,625 and U.S. Pat. No. 5,809,801 to Cates et al. These references are hereby incorporated by reference as if fully set forth herein. Suitable for generating hyperpolarized 129 One polarizer for Xe is the 9800, 9810, or 9820 polarizer model manufactured by Polarean, Imaging plc of Durham, N.C. Thus, as used herein, the terms "hyperpolarized," "polarized," and the like mean artificially enhancing the polarization of certain noble gas nuclei above natural or equilibrium levels.

[0120] The term "automatically" means that the operation is capable of being performed substantially and typically entirely without human or manual input, and is typically directed or performed programmatically. The term "electronically" includes both wireless and wired connections between components. The term "programmatically" means under the direction of a computer program that communicates with electronic circuitry and other hardware and / or software.

[0121] The term "3-D image" refers to a visualization in 2-D that uses volume data that can represent features with different visual properties (such as different intensities, opacities, colors, textures, etc.) so that the visualization appears to be a 3-D image. For example, a 3-D image of the lungs can be generated to illustrate differences in barrier thickness using color or opacity differences across the image volume. Therefore, the term "3-D" in relation to an image does not require actual 3-D visibility (such as with 3-D glasses), but only the appearance of 3-D in a 2-D viewing space such as a display. A 3-D image includes multiple 2-D slices. The 3-D image can be a volume rendering and / or a series of 2-D slices that are familiar to those skilled in the art, which can be visually flipped through.

[0122] The term "detrended" and its derivatives mean adjusting the amplitude signal that decays during breath holding by correcting for the apparent T1 relaxation caused by a combination of true oxygen-induced relaxation and relaxation caused by the applied RF pulses. This flattens the amplitude signal relative to the non-detrended amplitude signal so that oscillations can be more easily identified and / or quantified.

[0123] Regarding the oscillations of the RBC spectrum of different spectral parameters, the term "normalization" and its derivatives mean 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), which can often be performed as a normalization before detrending to show the dynamics of RBC, barrier and gas.

[0124] The actual RBC oscillation amplitude can also be "normalized" for a specific patient / subject by adjusting for the individual patient's stroke volume and / or available capillary exchange.

[0125] The terms "raw data", "raw FID" and "raw NMR signal" refer to the complex NMR signal acquired in the time domain prior to Fourier transformation.

[0126] 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 number can vary by + / -20%. The term "about" with respect to resonance frequency means 2-5 ppm (RBC chemical shift varies from about 214.5-219).

[0127] As is known, the basic NMR spectral line shape has amplitude, chemical shift (sometimes called frequency), line width (s), and phase (degrees). The FID is a time domain signal (a decaying oscillation). Frequency and chemical shift are identical. Chemical shift is the frequency referenced to some standard frequency, and is usually quoted in ppm rather than Hz. Likewise, FWHM / line width can be given in either Hz or ppm. Conversion of FWHM / line width from Hz to ppm is done by dividing by 129 Xe Larmor frequency.

[0128] Embodiments of the present invention may be particularly suitable for use with human patients, but may also be used with animals or other mammalian subjects.

[0129] In summary, embodiments of the present invention obtain and quantify hyperpolarization exchanged in gas exchange regions of the lungs during a breathing maneuver (ie, protocol) associated with one or all of inspiration, breath hold, and expiration. 129 The gas exchange area of ​​the lung includes the airspace, interstitial barrier and red blood cells (RBC) that are sensitive to lung pathophysiology. 129 Xe gas exchange. The embodiments of the present invention obtain and evaluate 129 The dynamics of Xe spectroscopy have been particularly focused on quantifying cardiogenic oscillations in RBC resonance.

[0130] As discussed in the background, 129 The spectroscopic properties of Xe have been well characterized both in vitro and in vivo. 129 The extraordinary sensitivity of Xe diffusion barrier uptake and RBC transfer to multiple pathologies is promising, even if it presents new challenges. 129 In addition to the static parameters of Xe gas transfer spectra, their temporal dynamics offer the opportunity to gain insights that may have additional clinical significance. To this end, previous work reported interesting observations on cardiac pulsation in terms of RBC resonance amplitude. See Norquay et al. 129 Xe chemical shift in human blood and pulmonary bloodoxygenation measurement in humans using hyperpolarized 129 Xe NMR (using hyperpolarized 129 Xe NMR of human blood 129Xe chemical shift and measurement of pulmonary blood oxygenation in humans, Magnetic Resonance in Medicine, 2017;77(4):1399-1408; and Ruppert et al., Detecting pulmonary capillary blood pulsations using hyperpolarized xenon-129 chemical shift saturation recovery (CSSR) MR spectroscopy, Magnetic Resonance in Medicine, 2015. The contents of these references are hereby incorporated by reference. However, this work focuses primarily on characterizing the saturation of alveolar blood in the alveolar septum unit on a time scale of 0-100 ms via the chemical shift saturation recovery (CSSR) method. 129 Xe absorption. See Qing et al., Assessment of lung function in asthma and COPD using hyperpolarized 129Xe chemical shift saturation recovery spectroscopy and dissolved-phase MRI, NMR in Biomedicine, 2014a;27(12):1490-1501; and Stewart et al., Experimental validation of the hyperpolarized 129Xe chemical shift saturation recovery technique in healthy volunteers and subjects with interstitial lung disease, Magnetic Resonance in Medicine, 2015;74(1):196-207. As such, 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.

[0131] Although 3D gas exchange MRI provides an important method for characterizing the spatial distribution of gas exchange impairment, it alone may not be sufficient to determine the underlying cause. For example, dyspnea can result from interstitial lung disease or underlying cardiac or pulmonary vascular disease. Even within PVD, it can be difficult to determine whether the obstruction is pre- or post-capillary, and this becomes even more difficult in the context of other lung diseases. Furthermore, existing methods for evaluating PVD require invasive right heart catheterization. By combining 3D 129 Xe gas exchange MRI and assessment 129 The cardiopulmonary dynamics of Xe spectroscopy uniquely addresses these issues non-invasively.

[0132] However, it was not until 2017 that Bier et al., Proc. Intl. Soc. Mag. Reson. Med. 25 (2017) 2152 reported RBC chemical shifts that were physically impossible given the in vitro RBC chemical shift values. That is, anything below 214.5 was generally considered physically impossible. For example, the 2017 work showed RBC frequencies as low as 212 ppm. Embodiments of the present invention provide a robust acquisition and processing framework to provide quantified dissolved phases with improved spectral parameters 129 Clinically relevant RBC spectral parameters of Xe. For example, using the improved processing method and system according to the present invention, the RBC chemical shift in seven healthy volunteers changed from 213.8 ± 0.5 ppm to 217.6 ± 0.6 ppm, and in IPF subjects, it changed from 213.7 ± 1.3 ppm to 216.3 ± 0.9 ppm.

[0133] The inventors have found that to develop robust quantization methods and algorithms, one must face the challenges presented by 129 Complex underlying spectral structure of the Xe-barrier resonance and / or relatively low spectral resolution of the dissolved phase 129 The inventors also found that in addition to the changes in RBC amplitude, there are other dynamic 129 Xe spectral parameters (4-5 per resonance) which can be analyzed to provide insights into the underlying conditions and / or to differentiate between different conditions.

[0134] Comparison with one or more healthy people (i.e., population standards) can be used to provide insights into the interpretation of patients with pulmonary vascular disease. Thus, embodiments of the present invention can provide: a) acquisition of pulmonary vascular disease with sufficient temporal and spectral resolution; 129The goal is to develop a strategy to characterize the temporal dynamics of Xe transfer, thereby allowing clinically useful and / or statistically reliable results, b) a robust analytical framework to quantify dynamics such as cardiogenic oscillations and c) representative data from healthy populations and patients with disease to facilitate clinical interpretation.

[0135] Population standards may be established using one or more healthy subjects (ie, humans), and may be provided based on age and sex, or age only, or sex only.

[0136] Embodiments of the present invention continuously acquire information about every 5-400 ms, more typically about every 20 ms to about every 300 ms, of the respiratory action. 129 Xe Free Induction Decay (FID) is used to fully characterize the dynamics of each resonance (gas, barrier and RBC). This provides "dynamic spectroscopy", i.e., the dynamics of each resonance over a period of time associated with a breathing maneuver including at least one of inspiration / breath-hold and exhalation. 129 Xe NMR signal parameters. Embodiments of the present invention may then apply sophisticated time-domain curve fitting methods and / or algorithms that can robustly quantify each Xe NMR signal by its amplitude, chemical shift(s), line width, and phase. 129 Xe resonance (gas, barrier and RBC).

[0137] In some specific embodiments, a signal acquisition and processing algorithm and / or method may be used that accommodates the lower signal-to-noise ratio (SNR) and spectral resolution of such dynamically acquired data in two ways. First, it may incorporate one or more tailored (defined) preprocessing steps to remove high frequency noise outside of a physiologically plausible range. Second, it may use curve fitting using one or more non-Lorentzian line shape modeling to provide for the detection of the low signal-to-noise ratio (SNR) and spectral resolution of such dynamically acquired data. 129 Innovative treatment of the Xe spectrum, the modeling preferably requires no more than one or two additional fitting degrees of freedom (relative to the Lorentzian only) to preserve temporal and / or spectral resolution.

[0138] In some presently preferred embodiments, the barrier resonance lineshape is fit using a Voigt spectral profile to incorporate its known complexity while requiring only one additional degree of freedom for the fit. The terms "Voigt spectral profile" and "Voight lineshape" are interchangeably described herein as "Voigt curve fit function".

[0139] Embodiments of the present invention may generate spectral parameters sensitive to gas exchange in the lungs by acquiring NMR raw signal data during a breathing maneuver, which may include each of inhalation / inhalation, breath holding, and exhalation / exhalation.

[0140] Figure 1Figure 2 shows the breathing patterns of a representative healthy subject during inspiration, breath-hold (grey bars / middle part of the graph), and exhalation. 129 Temporal changes of spectral parameters of Xe gas, barrier and RBC resonance. In this graph / diagram, all amplitudes are normalized to maxima / maximum 129 Xe barrier signal amplitude. For example, if the maximum barrier amplitude = 10, and the maximum RBC amplitude = 5, then the RBC graph will show a maximum signal of 0.5, while the maximum signal of the barrier will show a maximum amplitude of 1. This can be performed by first determining the value of the maximum barrier signal, and then dividing the gas, barrier, and RBC signal amplitudes by this value. As another example, the maximum raw barrier signal may be approximately 3.0×10 3 Alternatively, the RBC amplitude can be divided by the barrier amplitude at each time point to generate a time-dependent RBC:barrier ratio that indicates overall gas exchange efficiency. Figure 1 Arrows in the figure highlight / point to some spectral changes associated with breathing action and the lines above the RBC amplitude ( Figure 1 , Figure 2 Emphasize / highlight cardiogenic oscillations).

[0141] Note that other normalization factors can be used, such as normalization to 129 Xe gas amplitude or 129 The Xe gas resonance signal value (ie, maximum, minimum, median or mean gas amplitude) or normalized to any of these values ​​for the barrier resonance.

[0142] Yet another method of normalizing the amplitudes of the different spectral parameters may be to use the barrier / gas phase with respect to time (ie, normalize on a per time point basis). This would result in a plot of RBC:barrier ratio or RBC:gas ratio with respect to time.

[0143] Figure 1 Figure 2 shows the skeletal muscle mass of a subject with IPF (Subject 13) during inhalation, breath-hold (grey bars), and exhalation. 129 Temporal changes of spectral parameters of Xe gas, barrier and RBC resonances. Again, all amplitudes are normalized to the maximum 129 Xe signal. Unlike healthy volunteers, the RBC resonance exhibits clear oscillations with heart rate not only in amplitude but also in chemical shift and phase, as indicated by the black bars.

[0144] Figure 2Figure 2 shows the normalized and detrended RBC spectral parameter dynamics during breath holding in one representative healthy volunteer and two subjects with IPF, as well as two subjects with PAH and one subject with left heart failure (LHF). The solid lines represent the sinusoidal fit. Note the larger RBC amplitude oscillations in IPF, accompanied by larger RBC frequency / phase oscillations. In contrast, PAH patients exhibited smaller RBC oscillations. Patients with left heart failure (LHF) exhibited larger RBC amplitude oscillations, but decreased and / or no significant frequency (displacement / ppm) and phase oscillations.

[0145] Figure 3-4D Figure 1 shows the peak-to-peak cardiogenic oscillations of RBC spectral parameters during breath holding in healthy subjects versus IPF subjects. The oscillations of RBC amplitude, chemical shift, and phase were significantly greater in IPF subjects (red / dashed line and right side of the graph) than in healthy volunteers (P=0.008, P=0.001, and P=0.002). *Statistical difference between the two groups (P<0.05).

[0146] 5A-5D compare the oscillations of RBC amplitude, chemical shift and phase between healthy (green and left data of each graph), IPF (red and middle data of each graph) and PAH (magenta and right data of each graph). IPF is distinguished by the amplitude, frequency and phase oscillations of RBCs that are significantly greater than those of the normal population. PAH is distinguished by the RBC amplitude oscillations that are significantly less than those of the normal population.

[0147] Fig. 6A is a set of dissolution phase fits for a large FID average that exhibit the smallest residual errors for both the 3-Lorentzian fit (left graph) and the barrier Voigt model fit (right panel). Figure 6B is a graph of dynamically acquired spectra of a set of healthy subjects that return an ill-conditioned fit to the barrier resonance in the 3-Lorentz model (left and middle panels), but which is overcome by the barrier Voigt model (right panel). The FWHM (ppm) panel of the barrier using the Voigt model has the FWHM G Lines and Lorentz lines (at FWHM G Lorentzian shown as a solid line above the line), which provides a more reliable RBC fit (e.g. Figure 1 and Figure 2 ).

[0148] In the past, Robertson et al. proposed managing the complexity of the barrier resonance by using two Lorentz resonances instead of one. See Robertson et al. Uncovering a third dissolved-phase 129Xeresonance in the human lung: Quantifying spectroscopic features in healthy subjects and patients with idiopathic pulmonary fibrosis 129 Xe resonance: quantification of spectral features in healthy subjects and patients with idiopathic pulmonary fibrosis), Magnetic Resonance in Medicine 2017;78(4):1306-1315, the contents of which are hereby incorporated by reference as if set forth in their entirety herein. However, this approach produces a poorly conditioned fit of the dynamic spectrum because it requires more degrees of freedom for fitting. The lineshape of the Voigt profile represents the convolution of the Lorentzian peak with a Gaussian distribution and requires only one additional degree of freedom for fitting. Specifically, it returns two different linewidth parameters - the Lorentzian and Gaussian parameters. See Marshall et al. Use of Voigt lineshape for quantification of in vivo 1 H spectra (Quantification of in vivo 1H spectra using Voigt lineshapes), Magnet Resonance in Medicine 1997; 37(5): 651-657, the contents of which are hereby incorporated by reference as if fully set forth herein.

[0149] In other embodiments, other curve fitting functions that provide sufficient temporal and spectral resolution to produce accurate barrier resonance data may be used, i.e., one or more non-Lorentzian line shapes or a mixture of one or more non-Lorentzian and Lorentzian line shapes may be used to fit the barrier resonance data. 129 Xe spectrum modeling.

[0150] Fig. 7A is a collection of color-coded images (Ventilation, Barrier:Gas, RBC:Gas) of a COPD patient with severe ventilatory defect, but with relatively good matching of barrier and RBC absorption. Figure 7B is a collection of corresponding color-coded images of a COPD patient in which the RBC transfer defect is disproportionately worse than barrier absorption, indicating possible precapillary pulmonary hypertension.

[0151] Fig. 8A is an example flow chart of a signal processing action that can be used to generate dynamic spectral parameters according to an embodiment of the present invention. Data is obtained within a frequency range. The data includes a dissolved phase and a gas phase 129Xe resonances (gas, barrier and RBC resonances) are obtained over the entire range to perform curve fitting and determine the frequency / chemical shift of each resonance over a time period associated with a breathing maneuver including one or more of inhalation, breath holding and exhalation (block 100). The obtained free induction decay (FID) curve of the NMR signal over the time period is fit to a function that models the RBC and gas peaks as Lorentzian curves with amplitude, frequency, FWHM and phase, and models the barrier resonance as a Voigt profile with an additional Gaussian FWHM (block 110). That is, the Voigt line shape can be used to model (or fit) 129 The Xe barrier resonates and can be modeled (fitted) using (only) the corresponding Lorentzian lineshape 129 Xe-RBC and 129 Xe-Gas Phase Resonance. The barrier resonance has only one frequency, and fitting it to a Voigt function allows it to have both Lorentzian and Gaussian FWHMs, but only one amplitude, frequency, and phase. Separate Lorentzian and Gaussian curves are not required; the barrier signal fits only a single lineshape with two linewidth parameters. This accommodates the complexity of the barrier lineshape while limiting the additional required fitting degrees of freedom. Curve fitting can be performed in a way that minimizes the error between the model function and the data to identify the barrier versus RBC versus gas signal.

[0152] 129 Xe gas, barrier and RBC spectral parameters are generated based on curve fitting: gas, barrier and RBC spectral parameters each include amplitude, chemical shift (ppm), FWHM (ppm) and phase (degrees), and the barrier spectral parameters also include FWHM in the time period G (Frame 120).

[0153] Estimates of amplitude, frequency, FWHM, and phase and at least frequency and FWHM may be provided based on median or average values ​​for one or more healthy subjects and used as initial inputs to curve fitting (block 102).

[0154] The FID may include an average of a selected subset of raw data dynamic FIDs that are averaged together at corresponding different time points to create a first high SNR FID for initial curve fitting (block 112). For example, 3-10 FIDs (such as 3, 4, 5, 6, 7, 8, 9, or 10 FIDs) are averaged together at corresponding time points during the breathing maneuver to improve the SNR.

[0155] The amplitude can be normalized to the (maximum) barrier amplitude and / or gas amplitude 129 Xe signal (block 122).

[0156] 129The Xe gas phase frequency may be defined as a 0 ppm reference frequency (block 114 ).

[0157] The resonant frequency can be converted to chemical shift (ppm) units by using the gas phase frequency as a reference frequency and using the MRI scanner's 129 Xe Larmor frequency or 129 The center frequency of Xe converts the FWHM from Hz to ppm (box 115). For example, if the scanner transmitter frequency is 34 MHz, and the gas phase signal is detected at 0 Hz, and the RBC signal is detected at 7.378 kHz, then the RBC chemical shift is 7.378 kHz / 34 MHz or 217 ppm.

[0158] The curve fitting results can be electronically evaluated to determine whether the RBC chemical shift is ≥214.5ppm and whether the barrier chemical shift is ≥196.0ppm (box 116). If this condition is not met, the original estimate or input can be updated and / or a larger number of FIDs can be used to provide an average FID for the revised first high SNRFID, and then a second curve fit can be performed (box 117). If yes, the curve fit is acceptable and no iterative changes or further curve fits or adjustments are required. If not, the initial estimate can be updated / revised. In addition, the RBC frequency can be evaluated to confirm that it is within the range of 215-220ppm, and the barrier frequency can be evaluated to confirm that it is within the range of 195-198ppm, and the FWHM can be evaluated to confirm that they are less than 20 (box 118).

[0159] For accuracy, the frequency (chemical shift) of the gas phase reference may also be electronically evaluated to ensure that it is not artificially identified based on a poor fit due to poor signal acquisition and / or low signal-to-noise ratio (block 119).

[0160] Can be based on dynamic 129 The Xe spectral parameters are correlated with relevant disease identifying characteristic patterns to identify a cardiopulmonary or pulmonary disease state or condition (block 124).

[0161] The likelihood of the presence or absence of PAH, LHF, IPF can be identified based on an identification characteristic pattern that does not include significant, increased or decreased oscillations and / or statistically validated peak-to-peak variations relative to population standards (normal population) in one or more of the following: amplitude oscillations, phase oscillations, FWHM(s) oscillations, and chemical shift oscillations (ppm) of one or more of the RBC, gas, and barrier spectral parameters (box 126).

[0162] The amplitudes of the spectral parameters associated with breath-hold time periods between 1-30 seconds may be normalized and detrended, and then optionally, a sinusoidal fit may be applied to at least some of the RBC spectral parameters (block 128).

[0163] A disease state or condition may be identified based at least in part on the shape of the RBC amplitude oscillations (block 129). Embodiments of the present application contemplate that the actual shape of the RBC oscillations may reveal information about an underlying disease state or condition. RBC oscillations are not (always) purely sinusoidal, and the way the oscillations rise and fall may provide information about an underlying disease condition.

[0164] The time-dependent amplitude may be detrended over the breath-hold period to flatten the amplitude signal to account for signal decay and increase signal oscillation relative to the non-detrended amplitude signal (block 130). That is, the RBC spectral parameters may be normalized and detrended or detrended and normalized. The breath-hold period may be between 1 and 30 seconds. Optionally, a sinusoidal curve fit may be applied to at least some of the (adjusted) RBC spectral parameters.

[0165] Figure 8B is another example flow chart according to an embodiment of the present invention. The raw data is read in (obtained) (box 150). The SIFT technique can be applied to noise reduction (box 155). See Doyle et al., SIFT, a postprocessing method that increases the signal-to-noise ratio of spectra which vary in time, Journal of Magnetic Resonance, Series B, 1994; 103(2): 128-133; and Rowland et al., AP, Spectral improvement by fourier thresholding of in vivo dynamic spectroscopy data, Magnetic Resonance in Medicine, 2015, the contents of which are hereby incorporated by reference as if recorded in full herein.

[0166] Optionally, the middle third of the FIDs of the raw data can be averaged together to create a high SN RFID (block 160). Provide / define Amplitude, Frequency, FWHM, FWHM GAn initial estimate (guess) of the and phase (block 163). An initial guess / estimate of the high SNRFID may be provided as a first curve fitting iteration, and the results of that fit used to provide an updated guess for a smaller average block that incorporates the dynamics.

[0167] Frequency and FWHM and FWHM G The estimate can be based on the average (or median) value of a healthy population (box 163). The high SNR RFID can be fit using a barrier Voigt model (box 165). The gas phase frequency can be defined as the 0 ppm reference frequency (box 167). The results of the high SNR fit can be converted to ppm units (box 170).

[0168] The RBC chemical shift can be evaluated to confirm that it is ≥214.5ppm, and the barrier chemical shift can be evaluated to confirm that it is ≥196.0ppm (box 172). If these conditions are not met (false), the fitting can stop (box 174). For example, a stop decision can be made based on the number of attempts or a defined SNR threshold. If true, the initial estimate / guess can be updated using the results from a higher SNR fit and / or a higher SNRFID (box 175). A high or higher SNR FID can utilize an updated guess / estimate fit (box 180). Five FIDs can be averaged together at each time point of a high SNRFID (box 182). Although for some embodiments, it is believed that five FIDs provide sufficient resolution, fewer FIDs can be averaged together, such as three or four FIDs, or more than five, such as a range of 6-10.

[0169] Figure 8C is another flow chart that may be used to evaluate actions of a subject according to an embodiment of the present invention. A database of disease-significant characteristic patterns of oscillations of gas, barrier, and RBC 129Xe resonances is provided (block 200).

[0170] Obtaining hyperpolarization of the subject during a breathing maneuver including one or more of inspiration, breath holding, and exhalation 129 Raw (FID) of the NMR signal of Xe (block 210).

[0171] Generate and 129 A graph of the oscillations associated with the Xe barrier, RBC, and gas resonances (block 220).

[0172] Based on the oscillations, RBC chemical shift, and RBC amplitude oscillations, the subject can be identified as having pre- or post-capillary pulmonary vasculature disease (block 230). For example, only patients with pure pre-capillary disease benefit from PH drugs, while patients with any post-capillary obstruction cannot be treated with PH drugs, so correct characterization is important.

[0173] The database may also include disease thresholds for reduced RBC:barrier ratios in IPF subjects relative to population norms (block 202).

[0174] The FID or average FID may be pre-processed to filter non-dominant frequencies (ie, frequencies associated with noise) from the indirect time dimension to smooth out temporal variations between FIDs while keeping the spectral-frequency domain intact (block 212).

[0175] The FID or average FID may be complex fit in the time domain (block 214).

[0176] A model where the RBC and gas peaks are Lorentzian with amplitude, chemical shift, FWHM and phase, and for the barrier resonance the barrier peak is a Gaussian with an additional linewidth (FWHM G )'s Voight profile (block 215).

[0177] The following equation S can be used fit Curve fitting is performed (block 216).

[0178]

[0179] It is possible to extract the pulses occurring at the heart rate (approximately 1 Hz). 129 Temporal variation of the Xe RBC resonance (block 211).

[0180] The amplitude of the RBC peak may be corrected using T1app (block 217).

[0181] The RBC amplitude during the breath-hold period can be fitted to To calculate T1app (block 218).

[0182] In other words, the signal can be divided by exp(-t / T1 app )*exp(-t start / T1 app ) to correct the amplitude "A" of the RBC signal, where the second term is a scaling term used to adjust the amplitude to match the original signal. The signal amplitude is expressed in arbitrary units.

[0183] The RBC amplitude can be calculated as a percent change relative to a baseline (block 222). For example, the RBC signal during a breath hold can be fit to the function of block 216. The value of the function at each time point t can then be calculated and used as a baseline. The RBC baseline can be viewed as a percent change by taking the difference between the measured and calculated values ​​and dividing it by the calculated value. The baseline can be defined as the result of the exponential decay fit in block 218 and is essentially a percent change relative to a grand average of many oscillations:

[0184] (RBC_signal-RBC_fitted) / RBC_fitted Equation 2.

[0185] The action at block 222 may use the corrected amplitude from block 217 .

[0186] The acquired signals may include pre- or post-drug challenge or drug delivery data (block 210).

[0187] Oscillograms can be used to assess gas exchange 129 Xe MRI images to identify disease state or monitor progression (box 232).

[0188] The frequency of the oscillations can be used to determine the subject's heart rate.

[0189] Static values ​​of one or more of the spectral parameters may also be evaluated to obtain information about different disease states and / or conditions, alone or in combination with one or more of the dynamic spectral parameters.

[0190] Fig.8D 300. The following is a flow chart of actions 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 stroke volume and a new parameter called "pulmonary exchange volume" (block 310).

[0191] Stroke volume is the volume of blood pumped by the right side of the heart with each beat. Nominal (adult) values ​​are usually reported as 94 or 95 ml. All things being equal, a larger cardiac stroke volume is likely to generate larger RBC amplitude oscillations. Stroke volume can be determined invasively from right heart catheterization, can be measured by ventricular volumes from echocardiography, or can be determined noninvasively from some types of time-resolved proton cardiac MRI acquisitions. See Alfakih, Khaled, et al., “Normal human left and right ventricular dimensions for MRI as assessedby turbo gradient echo and steady-state free precession imaging sequences,” Journal of Magnetic Resonance Imaging 17.3 (2003): 323-329. If such data are not available, estimates can be made based on the principle of alometric scaling. See de Simone, Giovanni et al., "Stroke volume and cardiac output innormotensive children and adults: assessment of relations with body size and impact of overweight," Circulation 95.7 (1997): 1837-1843. The contents of these articles are hereby incorporated by reference as if fully set forth herein.

[0192] Information from the shape of the RBC oscillation amplitude can be used to potentially help differentiate pure precapillary disease from postcapillary disease versus combined postcapillary and precapillary pulmonary hypertension (Cpc-PH).

[0193] "Pulmonary exchange volume" is a measure of the volume of the lungs that receives blood from the stroke volume. For a given stroke volume, a larger pulmonary exchange volume will attenuate the RBC amplitude oscillations.

[0194] The pulmonary exchange volume (PEV) can be calculated from 129 Xe gas exchange MRI is derived. It can be modeled as the thoracic volume minus the volume composed of ventilation defects minus the volume not involved in RBC transfer.

[0195] In mathematics:

[0196] PEV = TCV*(1-VDP–RDP), Equation 3

[0197] Where TCV = thoracic cavity volume, VDP = ventilation defect percentage, and RDP = RBC transfer defect percentage. 129 VDP and RDP were calculated from Xe MRI images (see Fig. 7A , 7B )(frame 315).

[0198] For example, the lung exchange capacity of a subject with a 4 liter chest cavity and 10% VDP + 10% RDP is 80% x 4 liters = 3.2 liters.

[0199] Embodiments of the present invention contemplate that dynamic spectral RBC amplitude oscillations may be multiplied by the lung exchange volume and divided by the cardiac stroke volume.

[0200] Cardiac stroke volume can also be measured by ventricular volume from echocardiography. Alternatively, a published standard value of 94 or 95 mL or other defined standard values ​​based on an allometric scale can be used. For example, stroke volume is calculated by dividing cardiac output by heart rate. Cardiac output scales to a power of 3 / 4 with body weight, while heart rate scales to a power of -1 / 4. Therefore, it is expected that stroke volume scales linearly with body weight.

[0201] Larger blood volumes will naturally reduce RBC amplitude oscillations, whereas larger cardiac stroke volumes will enhance RBC amplitude oscillations. This suggests that in patients with IPF, who often have very small, restricted thoracic cavities, enhanced RBC oscillations are likely a natural consequence of reduced exchangeable blood volume.

[0202] The "adjusted" RBC amplitude oscillation may be the obtained (ie, initially measured) RBC amplitude oscillation A RBC Multiply by:

[0203] (V_stroke_ref / V_stroke)*(PEV / PEV_ref). Equation 4

[0204] Where V_stroke_ref is a reference stroke volume, such as 94 ml or 95 ml (for adults), V_stroke is the patient's actual stroke volume, PEV_ref is a reference exchange volume, and PEV is the patient's measured exchange volume (block 320).

[0205] Reference again Figure 3For example, a subject may be identified as having IPF, which is characterized by significantly greater (i.e., approximately 1.5-2 times that of healthy volunteers) RBC amplitude oscillations. In IPF patients, RBC frequency (chemical shift / ppm) and phase oscillations are also significantly greater than in healthy people, typically at least 2, 3, 4, or 5 times that of healthy people. In IPF vs. healthy people, RBC amplitude variation is almost twice (16.8±5.2% vs. 9.7±2.9%; P=0.008), chemical shift oscillations are more than 5 times (0.43±0.33ppm vs. 0.083±0.05ppm; P<0.001), and RBC phase oscillations are more than 5 times (7.7±5.6° vs. 1.4±0.8°; P<0.001).

[0206] In IPF, RBC amplitude oscillations are considered large because the lung exchange volume PEV is small. It is expected that when RBC oscillations are corrected for PEV, they may be significantly reduced. Therefore, the more specific diagnostic features of dynamic spectroscopy in patients with IPF are chemical shift and phase oscillations, which do not require correction of PEV. So far, such oscillations have only been seen in patients with IPF.

[0207] The larger RBC amplitude oscillations are expected to be a result of post-capillary obstruction caused by fibrosis or a result of cardiac output being delivered to a significantly smaller capillary blood volume. Importantly, the RBC frequency and phase oscillations are expected to result from the delayed oxygenation associated with interstitial lung disease. 129 The sensitivity of the Xe-RBC resonance to blood oxygenation is uniquely detectable. The observation that this frequency oscillates in the IPF population is a measure of interstitial thickening that results in delayed diffusion of oxygen.

[0208] The PAH population can be characterized as exhibiting significantly less RBC oscillations than the normal population ( Figure 3 ). In addition, Group 1 PH did not show RBC chemical shifts or phase oscillations that were significantly different from normal values.

[0209] These findings are particularly noteworthy in a small population for generating dynamic spectral parameters for patients with the indicated conditions (ie, IPF, PAH, and LHF) because these patients are on medication and are relatively well controlled compared to patients who would present for diagnosis.

[0210] While not wishing to be bound by any particular theory, smaller RBC amplitude oscillations are explained by higher resistance in the pulmonary arteries and arterioles, which serve to attenuate changes in capillary blood volume that occur during diastole.

[0211] PH can exhibit large RBC amplitude oscillations but little or no RBC frequency / phase oscillations. Enhanced RBC amplitude oscillations are considered a marker for post-capillary obstruction.

[0212] RBC frequency / phase oscillations appear to be uniquely associated with the delayed oxygenation that occurs in interstitial lung disease, particularly IPF.

[0213] It is unclear whether RBC frequency / phase oscillations are associated with NSIP, but it is hypothesized that this may be based on the association between patient populations and “healthy populations” or population norms. 129 Xe spectral parameters (dynamic, static, or dynamic and static) distinguish this form of pneumonia from IPF.

[0214] In some specific embodiments, it is contemplated that the different disease patterns defined can distinguish post-capillary vascular disease from pre-capillary vascular disease by variations above or below healthy population or group norms.

[0215] Embodiments of the present invention may use reduced peak-to-peak RBC amplitude oscillations relative to defined standards to indicate PAH.

[0216] Embodiments of the present invention may evaluate the shape of RBC amplitude oscillations to indicate combined pre-capillary and post-capillary vascular disease states.

[0217] Reduced RBC amplitude oscillations appear to be a unique signature of precapillary arterial disease, and patients presenting with these symptoms may benefit from PAH pharmacological treatment.

[0218] Enhanced RBC amplitude oscillations are likely to be a hallmark feature of post-capillary disease, and these patients will be harmed by PAH medication.

[0219] Several potential approaches are envisioned for acquiring dynamic spectral data that would improve upon standard acquisition.

[0220] Embodiments of the present invention may be able to be based on gas exchange MRI (ie, Fig. 7A , 7B ) to detect potentially treatable precapillary PH in patients with existing lung disease (e.g., COPD, IPF, etc.). That is, patients with impaired RBC transfer have a disproportionately greater percentage of the lung affected than could be explained by poor barrier status (low barrier in COPD, or high barrier in IPF), and gas exchange 129 Xe can be used to identify additional characteristic features.

[0221] Embodiments of the present invention can obtain gas exchange MRI and / or dynamic spectroscopy before and after administration of agents such as vasodilators, hyperoxia, diuretics, or prostacyclin. For example, it can be detected 129 Comparison of oscillation changes in spectral parameters of Xe dynamic spectroscopy to determine the effect of an agent on function. For example, delivery of inhaled nitric oxide or inhaled prostacyclin may be able to reveal areas of prone vascular dilation in gas exchange images of the lungs, which would show restored RBC transfer. Similarly, dynamic spectroscopy can show enhanced / increased RBC oscillation amplitude relative to before such administration.

[0222] Hyperoxic challenge may also reveal similar improvements in recovery area RBC transfer and RBC oscillation amplitude.

[0223] In some COPD patients, greatly reduced RBC amplitude oscillations may persist even after correction for the relatively large exchangeable capillary blood volume. This may indicate precapillary pulmonary hypertension.

[0224] Now go to Fig. 9 , shows an example medical system 1100. The medical system 1100 may include at least one server 1150. The at least one server 1150 may be configured with a dynamic 129 Xe spectrum analysis module 1124 and / or configured with 129 Database 1126 of Xe disease signature patterns.

[0225] At least one server 1150 may communicate with an imaging site 1110 and / or a clinician site 1210, typically via at least one respective digital processor 1110p, 1210p. The imaging site 1110 may be a hospital or other facility (mobile or permanent) having an MRI scanner 1125. The clinician site 1210 may be remote from or at the imaging site 1110. The server 1150 may be remote from both the imaging site 1110 and the clinician site 1210, alternatively, the server 1150 may be on-site at the clinician site 1210 or the imaging site 1110, respectively.

[0226] Server 1150 may be integrated into a single server, or may be distributed across one or more servers or other circuits or databases at a single physical site or spatially separated locations. Similarly, dynamic data maintained by one or more servers 1150 may be stored in a separate computer or other storage medium. 129 The Xe spectrum analysis module 1124 can be distributed to multiple processors or databases or integrated into one. 129 The Xe dynamic spectra are electronically transmitted to the 1150 server for automated image analysis.

[0227] Server 1150 may be embodied as a stand-alone server or may be included as part of other computing infrastructure. Server 1150 may be embodied as one or more enterprise, application, personal, distributed and / or embedded computer systems, which may be independent or interconnected through public and / or private, real and / or virtual, wired and / or wireless networks including the Internet, and may include various types of tangible, non-transitory computer-readable media. Server 1150 may also communicate with a computer network via a wired or wireless connection, and may include various types of tangible, non-transitory computer-readable media.

[0228] Server 1150 may be provided using cloud computing, which includes providing computing resources on demand via a computer network with appropriate firewalls 1160 and privacy protocols to comply with HIPPA or other regulatory requirements. Resources may be embodied in various infrastructure services (e.g., computing, storage, etc.) as well as applications, databases, file services, email, etc. In the traditional computing model, both data and software are typically completely contained in the user's computer; in cloud computing, the user's computer may contain very little software or data (perhaps an operating system and / or a web browser) and is used only as a display terminal for processes that appear on an external computer network. Cloud computing services (or a collection of multiple cloud resources) may generally be referred to as a "cloud." Cloud storage may include a model of networked computer data storage in which data is stored on multiple virtual servers rather than hosted on one or more dedicated servers.

[0229] Multiple imaging sites 1110 can communicate with a server 1150 and one or more clinician sites 1210. The server 1150 can receive and analyze NMR data for each patient from different sites 1110 at any one time. It is expected that the server 1150 can analyze and generate patient reports in a FIFO (first in, first out) manner, optionally with rush or ranked priority comments. Multiple analyses can be performed simultaneously or serially 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 the clinician user.

[0230] The imaging site 1110 and / or clinician site 1210 can communicate with the server 1150 via a computer network such as one or more of a local area network (LAN), a wide area network (WAN), and can include a private intranet and / or the public Internet (also known as the "World Wide Web" or "the Net" or "the Internet").

[0231] The server 1150 may be configured to send analysis reports or subject test or assessment data to one or more clinician devices 1211, such as a computer, tablet, or smartphone (shown at the imaging site, but one or more may be remote from the imaging site).

[0232] Fig.10 1 is a schematic diagram of an MRI scanner 1125 having a superconducting magnet 1140, a gradient system 1165, and an RF coil 1170 in communication with an RF amplifier (not shown) associated with the MRI scanner, as is well known to those skilled in the art. Signals from the RF coil 1170 can be transmitted to a receiver 1205 via a cable (typically a BNC cable). The MRI scanner 1125 also includes a controller 1105 that can tune the MRI scanner to generate signals for exciting the hyperpolarized dissolution phase. 129 A frequency regulator circuit 1102 for the desired RF excitation frequency of Xe, and a display 1130, which may be local or remote and may be provided as part of a clinician workstation. The display 1130 may be configured to be substantially the same as 129 Xe's oscillogram displays both RBC and barrier images simultaneously to provide clinical data on the gas exchange regions of the lung.

[0233] According to some embodiments of the present invention, the MRI scanner 1125 may also include or communicate with a dynamic spectroscopy module 1224, which may programmatically communicate with the frequency regulator circuit 1102 and the receiver 1205 to electronically (automatically) switch the operating mode, frequency, phase, and / or electronically guide the excitation and acquisition of appropriate signals and generate cardiopulmonary spectroscopy parameters. Alternatively, the NMR signal data of each subject may be collected and transmitted to the server 1150 for post-acquisition processing. The NMR signal data may be transmitted to the server 1150 from a PACS (Picture Archiving and Communication System) 1224.

[0234] Reference now Fig.11 , shows a data processing system 1316, which can be used to provide 129 Xe dynamic spectroscopy module 1124 (which can provide gas exchange for NMR signal decomposition phase 129Xe) and curve fitting module 1327. Therefore, according to some embodiments of the present invention, system 1316 includes memory 1336 that communicates with processor 1300. Data processing system 1316 may further include input / output (I / O) circuits and / or (multiple) data ports 1346, which also communicate with processor 1300. System 1316 may include removable and / or fixed media, such as floppy disks, ZIP drives, hard disks, etc., and virtual storage devices, such as RAMDISK. The (multiple) I / O data ports 1346 can be used to transfer information between data processing system 1316 and another computer system or network (e.g., the Internet). These components can be conventional components, such as those used in many conventional computing devices, and their functions regarding conventional operations are generally known to those skilled in the art.

[0235] Fig.11 13. The processor 1300 and memory 1336 are shown, which may be used in embodiments of systems 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 may be, for example, a commercially available or custom microprocessor. The memory 1336 represents one or more storage devices that contain information used to provide the system according to some embodiments of the present invention. 129 Xe MRI image data or 129 Software and data for XeNMR spectral data.Memory 1336 may include, but is not limited to, the following types of devices: cache, ROM, PROM, EPROM, EEPROM, Flash, SRAM, and DRAM.

[0236] like Fig.11 As shown, memory 1336 may contain up to two or more categories of software and / or data: operating system 1352 , I / O device drivers 1358 , data 1356 , and applications 1354 . Fig.11 Graph data 1356 may include patient NMR spectroscopy data 1326 .

[0237] As will be appreciated by those skilled in the art, operating system 1352 may be any operating system suitable for use with a data processing system, such as or Operating system or Windows-based operating systems (e.g., Windows XP, Windows NT, Windows 10, Windows Server 2016) or Unix or Linux TM. IBM, OS / 2, AIX, and zOS are trademarks of International Business Machines Corporation in the United States, other countries, or both, and Linux is a trademark of Linus Torvalds in the United States, other countries, or both. Microsoft and Windows are trademarks of Microsoft Corporation in the United States, other countries, or both. A virtual platform (i.e., VMWARE) supporting one or more operating systems may also be used. Input / output device drivers 1358 typically include software routines accessed by application programs 1354 through operating system 1352 to communicate with components such as input / output circuits 1346 and certain memory 1336. Application programs 1354 illustrate programs that implement various features of the circuits and modules according to some embodiments of the present invention. Finally, data 1356 represents static and dynamic data used by application programs 1354, operating system 1352, input / output device drivers 1358, and other software programs that may reside in memory 1336.

[0238] Although in Fig.11 The present invention is illustrated with reference to application 1354 and modules 1124 and 1327, but as will be appreciated by those skilled in the art, other configurations also fall within the scope of the present invention. For example, these circuits and modules, other than being application 1354, may also be incorporated into an operating system 1352 or other such logical division of a data processing system. In addition, although (multiple) application(s) 1354 are illustrated in a single data processing system, as will be appreciated by those skilled in the art, such functionality may be distributed across one or more data processing systems in a client / server arrangement of the type described above. Therefore, the present invention should not be construed as limited to the illustrated configuration, but may be provided by other arrangements and / or functional divisions between data processing systems. For example, although Fig.11 The illustration is shown as having various modules, but one or more of these modules may be combined or separated without departing from the scope of the invention.

[0239] although Fig.11 An exemplary hardware / software architecture that may be used is illustrated, but it will be understood that the invention is not limited to such a configuration, but is intended to encompass any configuration capable of performing the operations described herein. In addition, according to various embodiments of the invention, the functionality and hardware / software architecture of the data processing system may be implemented as a single processor system, a multi-processor system, or even a network of independent computer systems.

[0240] For development convenience, the computer program code for performing the operation of the data processing system discussed above about the figure can be written in a high-level programming language, such as PYTHON, Java, C and / or C++. In addition, the computer program code for performing the operation of an embodiment of the present invention can also be written in other programming languages, such as but not limited to interpreted languages. Some modules or routines can be written in assembly language or even microcode to enhance performance and / or memory use. It will be further appreciated that the functionality of any or all program modules can also be implemented using discrete hardware components, one or more application specific integrated circuits (ASICs) or a digital signal processor or a microcontroller for programming.

[0241] The present invention is described herein with reference to the flowchart and / or block diagram of method, system and computer program product according to exemplary embodiments of the present invention.These flowcharts and / or block diagrams further illustrate exemplary operations for implementing and / or providing a time-limited password (passcode) based on calendar according to some embodiments of the present invention.It will be understood that each frame of flowchart and / or block diagram, and the combination of frames in flowchart and / or block diagram can be implemented by computer program instructions and / or hardware operations.These computer program instructions can be provided to the processor of general-purpose computer, special-purpose computer or other programmable data processing equipment to produce machine, so that the instruction executed via the processor of computer or other programmable data processing device creates the device and / or circuit for implementing the function specified in the frame or multiple frames of flowchart and / or block diagram.

[0242] These computer program instructions may also be stored in a computer-usable or computer-readable non-transitory memory, which may direct a computer or other programmable data processing device to function in a specific manner so that the instructions stored in the computer-usable or computer-readable memory produce an article of manufacture including instructions for implementing the functions specified in a block or multiple blocks of the flowchart and / or block diagram.

[0243] 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 to produce a computer-implemented process, such that the instructions executed on the computer or other programmable apparatus provide steps for implementing the functions specified in a block or blocks of the flowchart and / or block diagram.

[0244] Flowchart and block diagram illustrate the framework, functionality and operation of some embodiments of method, system and computer program product.In this respect, each frame represents the module, fragment or part of code, and it comprises one or more executable instructions for implementing (multiple) specified logical functions.It should also be noted that in other embodiments, (multiple) functions pointed out in the frame may occur in an order different from the pointed order.For example, in fact, two frames shown continuously can be performed substantially simultaneously or these frames can sometimes be performed in reverse order, which depends on the functionality involved.

[0245] 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 software (including firmware, resident software, microcode, etc.). In addition, the present invention may take the form of a computer program product on a computer-usable or computer-readable storage medium, which has a computer-usable or computer-readable program code embodied in the medium for use by an instruction execution system or in combination with the instruction execution system. In the context of this document, a computer-usable or computer-readable medium may be any non-transitory medium capable of containing, storing, conveying, propagating, or transmitting the program for use by an instruction execution system, device or apparatus or in combination with the instruction execution system, device or apparatus.

[0246] The 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 (non-exhaustive list) of computer readable media would include the following: an electrical connection having one or more conductors, a portable computer disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or flash memory), optical fiber, and a portable compact disk read-only memory (CD-ROM).

[0247] In addition, for example, the user's computer, the remote computer (i.e., server), or both can be integrated into or communicate with other systems, such as a control cabinet of an MRI scanner system, a hospital PACS (picture archiving and communication system), and / or a clinician workstation.

[0248] Non-limiting examples are discussed below.

[0249] Example

[0250] Example 1

[0251] Subject recruitment

[0252] This study was approved by the Duke University Institutional Review Board, and all subjects provided written informed consent prior to participation. 129Xe spectra were acquired in 8 healthy volunteers (7 males and 1 female; 26.4 ± 4.9 years) and 9 subjects with IPF (7 males and 2 females; 66.1 ± 5.6 years). The healthy volunteers had no known pulmonary disorders, no arrhythmias, and no history of smoking. Subjects with IPF were diagnosed according to ATS criteria with confirmation of the UIP pattern on CT or from surgical lung biopsy. See Raghu et al., An official ATS / ERS / JRS / ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management, American journal of respiratory and critical care medicine, 2011;183(6):788-824.

[0253] Xenon polarization and delivery

[0254] 300 mL of isotopically enriched MgSO was pumped via rubidium vapor spin exchange optical pumping using a commercially available polarizer (Model 9810, Polaean, Durham, NC, USA). 129 Xe (85%) is hyperpolarized to approximately 20%. 129 Xe was cryoaccumulated and thawed into 1L Tedlar bags (JensenInert Products, Coral Springs, FL). This provided hyperpolarization 129 51 mL dose equivalent of Xe (product of polarization, enrichment, and xenon volume). See He et al. Dose and pulse sequence considerations for hyperpolarized 129 Xeventilation MRI 129 Dose and pulse sequence considerations for Xe ventilation MRI), Magnetic Resonance Imaging, 2015; 33(7): 877-885; the contents of which are hereby incorporated by reference as if fully set forth herein. 2 Expand bag volume to 1L.

[0255] After two warm-up breaths, the subject inhaled from the functional residual capacity (FRC) 129Xe, then hold their breath for 8 seconds and then exhale slowly. See Kaushik et al. Measuring diffusion limitation with aperfusion-limited gas—hyperpolarized 129 Xe gas-transfer spectroscopy in patients with idiopathic pulmonary fibrosis 129 Xe gas transfer spectroscopy to measure diffusion limitation), Journal of Applied Physiology, 2014; 117(6):577-585; the contents of which are hereby incorporated by reference as if fully set forth herein. Data acquisition began during the inhalation period before the subjects began their breath hold. During MRI, each subject's heart rate and blood oxygen saturation were monitored using an MR-compatible monitoring system (Description Model 865214; Invivo, Orlando, FL).

[0256] 129 Xe spectrum

[0257] Dissolution phase spectra were acquired using a 1.5TGE scanner running a 15M4 EXCITE platform (GE Healthcare, Waukesha, WI). Subjects were fitted with a quadrature vest coil tuned to 17.66 MHz (Clinical MR Solutions, Brookfield, WI). Spectra were acquired using the following: The transmit frequency was tuned to selectively excite the dissolution phase using a 1.2 ms 2-lobed sinusoidal pulse applied at 3,832 Hz (217 ppm) above the gas phase. 129 During the 16-second breathing maneuver, 802 free induction decays (FIDs) were acquired, where each FID had 512 samples, echo time (TE) = 0.932 ms, repetition time (TR) = 20 ms, dwell time at each point = 32 μs, and flip angle ≈ 20°.

[0258] However, imagine that the time resolution could be reduced from 20ms to about 300ms. Assuming that the highest heart rate I am likely to encounter is 100 beats per minute (BPM), I would need to collect samples at twice this rate, or 3.33Hz, to meet the Nyquist criterion. This means that the signal can be acquired approximately every 300ms. Reducing the time resolution (increasing the TR) may provide several advantages. For example, the spectral resolution can be increased by sampling the FID for a longer period of time (increasing the sampling rate). With reduced time resolution, there is an opportunity to reduce the bandwidth (or increase the dwell time), which will increase the SNR.

[0259] Additionally, or alternatively, spectra can be acquired at larger flip angles (i.e., about 90 degrees versus about 20 degrees). This can improve the signal-to-noise ratio, making the spectral analysis more realistic. Also, by using a 90 degree pulse, all dissolved phase magnetization will be destroyed after each readout. Thus, the signal will be sensitive to newly diffused magnetization and may enhance sensitivity to delayed oxygenation in interstitial lung disease.

[0260] Spectral processing

[0261] Prior to fitting the spectra, 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 FIDs were processed using the Fourier Threshold Spectral Improvement (SIFT) method. This involves Fourier transforming the raw data along the indirect time dimension (relative to the time of the breath hold) and retaining only coefficients that exceed a predetermined threshold. The data were then Fourier transformed back along the indirect frequency dimension to undergo spectral curve fitting. This preprocessing therefore filters out non-dominant frequencies from the indirect time dimension to smooth out the temporal changes between FIDs while keeping the spectral-frequency domain intact. The time-domain SIFT-filtered FIDs were then averaged using a 5FID sliding boxcarwindow filter and subsequently subjected to complex fitting in the time domain using a custom MATLAB toolkit. See 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 129Xe resonance: quantifying spectral features in healthy subjects and patients with idiopathic pulmonary fibrosis), Magnetic Resonance in Medicine, 2017;78(4):1306-1315; the contents of which are hereby incorporated by reference as if fully set forth herein.

[0262] Although many existing literatures have already considered the dissolved phase 129 The Xe spectrum was considered to consist of two simple Lorentz RBC and barrier resonances, but recent work has shown that the barrier resonance is more structured. See 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 129 Xe resonances: quantifying spectral features in healthy subjects and patients with idiopathic pulmonary fibrosis), Magnetic Resonance in Medicine, 2017;78(4):1306-1315; the contents of which are hereby incorporated by reference as if set forth in full herein. Robertson et al. addressed this problem by allowing the barrier to consist of two independent resonances. However, this requires fitting with 4 additional degrees of freedom, which are not supported by the SNR and spectral resolution of the dynamically acquired data. This is demonstrated by the method returning an ill-conditioned fit for the dynamically acquired spectrum. Instead, to allow for the additional non-Lorentzian structure of the barrier resonance, it is fitted to a Voigt model. This lineshape represents the convolution of a Lorentzian peak with a Gaussian distribution and requires only one additional degree of freedom for fitting. Specifically, it returns 2 different linewidth parameters - the Lorentzian linewidth (FWHM) and the Gaussian linewidth (FWHM G See Marshall I, Higinbotham J, Bruce S, Freise A, Use of voigt lineshape for quantification of in vivo 1H spectra, Magnetic Resonance in Medicine, 1997; 37(5): 651-657, the contents of which are hereby incorporated by reference as if fully set forth herein.

[0263] The entire fitting signal can be calculated using Equation 1. Each resonance consists of four spectral parameters: amplitude (a), frequency (f), phase For the barrier resonance, a fifth parameter is also extracted, namely the Gaussian linewidth (FWHM G ). Initialize the fit of the barrier resonance with equal Lorentzian and Gaussian linewidths.

[0264]

[0265] All frequencies (Hz) reported are above the gas phase 129 Chemical shift of the Xe resonance frequency in ppm.

[0266] Normalizing and quantifying cardiogenic spectral changes in RBC resonance

[0267] Although a number of quantitative parameters can be analyzed and extracted from the three resonances during the three phases of the respiratory maneuver, we focus on characterizing the The following occurs 129 Temporal variation of the Xe RBC resonance. To extract these parameters, the amplitude of the RBC peak was first corrected for the magnetization decay caused by T1 as well as the RF-induced depolarization during the breath hold. These were incorporated into the apparent T1 decay constant, T1 app In this paper, the RBC amplitude is fitted during the breath-hold period as The mean T1 of all subjects app The RBC signal was then corrected for the time change in the signal amplitude and the remaining time change was expressed as a percentage change relative to the baseline. Each of the RBC spectral parameters was high-pass filtered with a cutoff frequency of 0.5 Hz to remove any residual baseline variation. The corrected and filtered parameter graph was then fitted to a sinusoidal curve with a phase shift:

[0268]

[0269] Among them A pk-pk is the peak-to-peak amplitude, f c is the heart rate, t is the time in seconds, and is the phase shift. Heart frequency f c The RBC amplitude oscillations were obtained for each subject and used for the temporal fitting of all other RBC spectral parameters (chemical shift, line width and phase).

[0270] Statistical analysis

[0271] Statistical analysis was performed in MATLAB. The Mann-Whitney-Wilcox U-test was used to determine whether the differences between healthy normal subjects and IPF subjects were statistically significant (P<0.05).

[0272] Example 1 Results

[0273] For each subject, in Table 1 ( Fig.14 ) summarizes age, sex, lung function test results, and the amplitude of oscillations in RBC spectral parameters.

[0274] Quantifying static spectral parameters

[0275] In the analysis 129 Before the dynamics of the Xe spectrum, the static parameters averaged over the first second of the breath hold were determined. Figures 12A-12D The RBC and barrier fit parameters and the associated ratios obtained were compared between the healthy and IPF populations. The average RBC:barrier amplitude ratios ( Fig. 12C ) was 0.58±0.12, which was significantly reduced to 0.18±0.07 in IPF patients (P<0.001). Fig. 12A ) is 1.5 ppm lower (P = 0.004), and its Lorentz line width is 1.7 ppm narrower (P = 0.001). In IPF, the barrier frequency ( Fig. 12B ) was also 0.5 ppm lower (P = 0.0025), and its Lorentzian component of line width was 0.9 ppm lower (P = 0.006); the Gaussian line width was not different from that of healthy subjects (P = 0.2). These differences contribute to the following: Fig. 12B The barrier resonance of RBC( Fig. 12A ) The phase difference between the resonances was 17.0° smaller than that in the healthy population (P = 0.006).

[0276] During breathing 129 Xe spectrum changes

[0277] exist Figure 1 All three are shown in Figure 2 for a representative healthy volunteer (subject 6). 129 Spectral dynamics of the Xe resonance. The breathing action is reflected in each fitting parameter, easily unstandardizing the inhalation, breath-hold, and exhalation periods. As the subject exhales, the gas resonance frequency shifts negatively by 0.11ppm, and its linewidth widens by 0.1ppm. In contrast, exhalation causes the barrier resonance to shift positively by 0.06ppm, and its Lorentzian linewidth narrows by 0.29ppm. The RBC resonance appears to be affected by both inhalation and exhalation, primarily by its linewidth, which, like the barrier, narrows slightly during exhalation (0.37ppm). The RBC amplitude also exhibits significant periodicity at a frequency of 58 cycles per minute, which is consistent with the subject's heart rate, recorded by pulse oximetry immediately before and after acquisition (61 and 65bpm, respectively). These dynamics are also present in the RBC chemical shift and phase at the same frequencies, although more weakly.

[0278] Figure 2 The same spectral dynamics drawn for a subject with IPF (subject 13) are shown. Like healthy volunteers, the gas phase parameters reflect both the dynamics of inhalation and exhalation, which is also clearly seen in the barrier resonance, which is achieved by increasing the chemical shift when exhaling but narrowing the two line width parameters. The RBC resonance cleverly shows the inhalation, while the exhaled breath is well unstandardized by its increased chemical shift and Lorentz line width increase accompanied by reducing the phase. In this IPF patient, the RBC amplitude is also periodic near the subject's heart rate before and after the scan (compared to 70 and 72bpm, 71 cycles per minute, respectively). Interestingly, this cardiac periodicity is also prominent in both the red blood cell chemical shift and the phase.

[0279] In such Fig.13 These cardiac dynamics that affect RBC spectral parameters are better understood in the normalized and detrended graphs shown for representative healthy volunteers and several IPF patients. In healthy volunteers, the peak-to-peak (pk-pk) variation of RBC amplitude was 9.1%, while the oscillations of RBC chemical shift and phase remained below 0.05ppm and 1.5°, respectively. In contrast, the first subject with IPF (IPF-13) not only showed more than 2 times greater RBC amplitude variation (19.9% ​​pk-pk), but also showed oscillations of RBC chemical shift, which was almost 6 times at 0.29ppm, and the phase changed nearly 4 times at 5.8°. In other IPF subjects depicted, this oscillation of RBC amplitude, frequency and phase is also noteworthy.

[0280] Changes in oscillation amplitude between IPF and healthy subjects

[0281] The amplitude of cardiogenic oscillations in RBC spectral parameters between healthy volunteers and IPF patients is compared in Figure 4. In IPF vs. healthy people, RBC amplitude variation is almost twice (16.8 ± 5.2% vs. 9.7 ± 2.9%; P = 0.008), chemical shift oscillations are more than 5 times (0.43 ± 0.33 ppm vs. 0.083 ± 0.05) ppm; P < 0.001) and RBC phase oscillations are more than 5 times (7.7 ± 5.6 ° vs. 1.4 ± 0.8 °; P < 0.001). Only RBC line width is not statistically different between the two populations (0.3 ± 0.2 ppm vs. 0.2 ± 0.1 ppm, P = 0.1).

[0282] discuss

[0283] Benefits of using barrier Voigt

[0284] The Voigt linear model was found to be a more robust fit than the “3-Lorentz” fit (one RBC, two barriers) 129 Xe barrier resonance dynamics. Although, in fitting high-resolution, high-SNR spectra 8 The 3-Lorentz model returns a residual error smaller than the barrier Voigt when , but it is not applicable to dynamic 129 Lower SNR and spectral resolution in Xe acquisition. See 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 129 Xe resonance: quantifying spectral features in healthy subjects and patients with idiopathic pulmonary fibrosis), Magnetic Resonance in Medicine, 2017;78(4):1306-1315. Figure 6B This is demonstrated by the highly variable fits of the two barrier resonances seen in . In contrast, the barrier-Voigt model is able to capture the additional structure of the barrier resonances while remaining stable during acquisition. This is likely due to the fact that it requires only one additional degree of freedom, rather than the four required to fit the barrier to the two Lorentz resonances. Furthermore, the 2-component dissolution phase fits of the RBC to the Lorentz and the barrier to the Voigt model leave intact the current 3-compartment gas exchange model that forms the basis of gas exchange imaging methods and CSSR analysis. See Chang, Y.V. MOXE: a model of gas exchange for hyperpolarized 129 Xe magnetic resonance of the lung (YV MOXE: Lung hyperpolarization 129 Xe magnetic resonance gas exchange model), Magnetic Resonance in Medicine, 2013;69(3):884-890.

[0285] Importantly, comparing the fits to the data for a large number of averages, the barrier-Voigt model was found to return RBC parameters similar to the 3-Lorentz fit. The barrier-Voigt model returned an RBC:barrier ratio of 0.59 ± 0.11 for healthy volunteers, which is reasonably consistent with previous 2-peak and 3-peak Lorentz fits to the dissolution resonance (which were 0.55 ± 0.13 and 0.44 ± 0.07, respectively), and correctly captures the significant reduction in this ratio in subjects with IPF. See Kaushik et al., Measuring diffusion limitation with a perfusion-limited gas—hyperpolarized 129Xe gas-transfer spectroscopy in patients with idiopathic pulmonary fibrosis, J. Appl. Physiol., 2014; 117(6):577-585; 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 129 Xe resonance: quantifying spectral features in healthy subjects and patients with idiopathic pulmonary fibrosis), Magnetic Resonance in Medicine, 2017;78(4):1306-1315.

[0286] The origin of temporal dynamics

[0287] 129 Temporal changes in the Xe spectrum directly report on the physiological dynamics of gas exchange in the lungs and pulmonary capillaries. It was surprisingly found that almost all spectral parameters reflect the dynamics associated with the breathing maneuvers. This is particularly well defined during exhalation, which is accompanied by an increased gas phase linewidth combined with a corresponding narrowing of the two solution phase peaks. This narrowing, which is related to the apparent transverse relaxation time Inversely proportional, possibly suggesting improved local field inhomogeneity, which in the lungs is composed of air and tissue 22The body sensitivity difference of Δχ≈9 ppm between the two is dominated by that of Δχ≈9 ppm. See Chen et al., Spatially resolved measurements of hyperpolarized gas properties in the lung in vivo. Part I: diffusion coefficient. Magnetic Resonance in Medicine, 1999;42(4):721-728. During exhalation, passive compression of the lungs displaces air from the alveolar sacs and reduces the total alveolar volume. See Hajari et al., Morphometric changes in the human pulmonary acinus during inflation. Journal of Applied Physiology, 2012;112(6):937-943. This in turn increases the volume fraction of tissue 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; Tsunoda et al., Lung volume, thickness of alveolar walls, and microscopic anisotropy of expansion, Respiration physiology, 1974; 22(3): 285-296. Thus, during exhalation, less dissolved phase xenon atoms reside near the air-tissue boundary, resulting in a narrowing of the RBC and barrier linewidths. In contrast, gas phase xenon atoms are now more likely to reside near the tissue interface, and the gas phase linewidth therefore increases.

[0288] 129 The high-frequency dynamics of Xe-RBC transfer provide an interesting window into how the cardiac cycle affects gas exchange. The RBC signal in these acquisitions is primarily derived from interactions with RBCs in the pulmonary capillary bed. 129 Xe nuclei appear. This strong localization results from using a relatively large flip angle Plus about RBC transit time The short repetition time (TR = 20 ms) of the dissolution phase129 The magnetization of the Xe atoms is rapidly destroyed by the RF pulse and can only be reversed by 26 However, once 129 If the Xe atoms move to a larger container outside the gas exchange cell, this replenishment no longer occurs, and any remaining magnetization is rapidly destroyed by the RF pulsations. Thus, the fluctuations detected in the RBC resonance provide evidence for the presence of a magnetostriction at the alveolar-capillary interface. 129 Xe-RBC transfer is temporally dependent on capillary pressure and blood volume oscillations driven by the cardiac cycle.

[0289] Oscillations in RBC signal amplitude reflect polarization of interactions with RBCs during the cardiac cycle 129Cyclic variation in the number of Xe atoms. This observation is most likely due to cardiogenic fluctuations in capillary blood volume. The pulmonary capillaries experience slightly elevated blood pressure during systole, with a concomitant decrease during diastole. See Rossvoll et al., Pulmonary venous flow velocities recorded by transthoracic Doppler ultrasound: relation to left ventricular diastolic pressures, Journal of the American College of Cardiology, 1993; 21(7): 1687-1696. Such pressure changes are likely to affect capillary blood volume, as recently demonstrated by synchrotron imaging during the respiratory cycle. See Porra et al., Synchrotron Imaging Shows Effect of Ventilator Settings on Intra-breath Cyclic Changes in Pulmonary Blood Volume, American Journal of Respiratory Cell and Molecular Biology, 2017 (ja). Here, relative RBC amplitude fluctuations were found to be nearly twofold in subjects with IPF, suggesting that relative changes in capillary blood volume during the cardiac cycle are greater in these patients than in healthy volunteers. This is most likely a result of these patients having areas of marked capillary damage in which there is no RBC transfer. See Wang et al., Using hyperpolarized 129 Xe MRI to quantify regional gas transfer in idiopathic pulmonary fibrosis (using hyperpolarized 129 Xe MRI quantifies regional gas shifts in idiopathic pulmonary fibrosis), Thorax, 2017:thoraxjnl-2017-210070; the contents of which are hereby incorporated by reference as if fully set forth herein. Therefore, the additional capillary blood volume during systole is distributed to the relatively small effective capillary volume.

[0290] Given that in vitro studies have shown that RBC frequency depends nonlinearly on blood oxygenation level sO 2 , so the observation of cardiogenic oscillations in RBC chemical shift in patients with IPF is particularly interesting. See Norquay et al. 129 Xe chemicalshift in human blood and pulmonary blood oxygenation measurement in humans using hyperpolarized 129Xe NMR 129 Xe chemical shift and measurement of blood oxygenation in the human lung), Magnetic Resonance in Medicine, 2017;77(4):1399-1408; Wolber et al. Hyperpolarized 129Xe NMR as a probe for blood oxygenation, Magnetic Resonance in Medicine, 2000;43(4):491-496. 2 = 0.6–0.98, the RBC chemical shift increased by more than 4 ppm in a sigmoidal manner. This would indicate that, assuming a maximum sO 2 =0.95, the observed pulsation in the RBC chemical shift of 0.43 ppm reflects the overall sO in the pulmonary capillaries. 2 The change was of the order of 0.07. The fact that RBC frequency pulsation is seen in IPF but not in healthy subjects suggests that this is a potentially unique signature of hindered diffusion transfer of oxygen across the alveolar-capillary barrier. That is, as deoxygenated blood enters the capillary bed during systole, oxygenation is slower in patients with significant interstitial thickening. In healthy normal volunteers, capillary RBCs achieve full oxygenation in approximately 250ms (or one-third of the total capillary transit time). See West et al., Respiratory physiology: the essentials. Lippincott Williams & Wilkins; 2012. Thus, in healthy volunteers, 129 The average sO in RBCs experienced by Xe 2 In contrast, the thicker interstitial barrier tissue present in patients with IPF slows the diffusion of gases and, as a result, the sO in the pulmonary capillary bed 2 Therefore, although healthy volunteers and subjects with IPF may have the same distal O 2 Saturation, but 129Xe spectroscopy detects capillary SO by probing the alveolar-capillary interface 2 The difference of change.

[0291] From a technical point of view, 129 During the Xe-RBC resonance phase, the heart pulsation is even more prominent. This measure, which is linearly related to the chemical shift, provides a relatively pure signal that may prove more robust. 129 The observation of pulsations in Xe RBC frequency and phase may ultimately prove helpful in distinguishing causes of dyspnea attributed to interstitial disease from causes of other gas exchange impairments, such as pulmonary vascular disease. See Dahhan et al., Abnormalities in hyperpolarized 129Xe magnetic resonance imaging and spectroscopy in two patients with pulmonary vascular disease, Pulmonary Circulation, 2016; 6(1): 126-131; the contents of which are hereby incorporated by reference as if set forth in their entirety herein.

[0292] Example 1 Conclusion

[0293] In this study, a simple 16-second spectral acquisition and breathing maneuver was used to collect, process, and analyze 129 The method for Xe spectroscopy was successfully identified, which yields a series of novel parameters that can be used to further characterize gas exchange. The collected FID was fitted to Lorentzian for the RBC and gas resonances, and to Voigt lineshapes for the barrier resonance. This accommodates the additional structure of the barrier resonance while restricting the degrees of freedom so that the fitting algorithm can converge even for the lower SNR and spectral resolution of the dynamic acquisition. Each 129 Spectral fitting parameters of the Xe resonances. Analysis of the static spectral parameters revealed features that distinguished IPF from healthy subjects, which was largely consistent with previous studies. Their dynamics showed that all three resonances were sensitive to respiratory maneuvers, with significant changes in both RBC and gas linewidths. Most notably, the RBC amplitude, chemical shift, and phase were found to oscillate at the cardiac frequency. These oscillations were significantly larger in patients with IPF than in healthy controls. Thus, the static and dynamic 129 Careful analysis of either or both Xe spectra could potentially provide a wide variety of additional information that could help further identify different underlying causes of gas exchange impairment.

[0294] Example 2

[0295] As more patients present with concomitant cardiac and pulmonary disease, the limitations of standard diagnostic criteria are more frequently encountered. In this example 2, noninvasive 129 Xenon MR imaging and spectroscopy are used to identify regional gas transfer impairment and hemodynamic patterns uniquely associated with chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), left heart failure (LHF), and pulmonary arterial hypertension (PAH).

[0296] Although 129 Xe imaging provides useful quantification of regional functional load, but it is believed that more detailed whole lung 129 Xe spectral index characterization provides additional metrics that can help further differentiate the underlying pathology. 129 This non-invasive imaging and spectroscopic markers of pulmonary gas transfer and hemodynamics derived from Xe can provide a comprehensive and non-invasive phenotype of the cardiopulmonary physiology of an individual patient.

[0297] In this example 2, a comprehensive set of non-invasive 129 Xe MR imaging and spectroscopy were applied to a population of patients with known heart and lung disease in order to identify signature features that could differentiate between COPD, IPF, left heart failure (LHF), or pulmonary arterial hypertension (PAH). 129 Xe diffuses freely from the airspace to the interstitial barrier tissue to the RBC. In these compartments, 129 Xe atoms exhibit distinct frequency shifts of 0 ppm, 198 ppm, and 217 ppm, respectively. These properties can be exploited to allow 3D imaging and quantification 129 The distribution of Xe in the airspace (ventilation), its barrier uptake and RBC transport are used to generate maps. These maps can be color-coded to represent different signal intensity levels, with the central (green) bin representing voxels within the normal reference range. 129 Xe spectra, such as approximately every 20 ms, reveal cardiogenic oscillations of RBC amplitude (%) and frequency shift (ppm).

[0298] In this example 2, healthy volunteers (n=23) and patients with COPD (n=8), IPF (n=12), LHF (n=6), and PAH (n=10) experienced 129 Xe gas transfer imaging and dynamic spectroscopy. For each patient, a 3D map was generated to depict ventilation, barrier absorption, and red blood cell (RBC) transfer. Dynamic 129 Xe spectroscopy was used to quantify cardiogenic oscillations in RBC signal amplitude and frequency shift.

[0299] All patient groups demonstrated reduced ventilation and RBC transfer compared to healthy volunteers (p≤0.01, p≤0.01). Patients with COPD were shown to have more ventilation and barrier defects compared to all other groups (p≤0.02, p≤0.02). In contrast, IPF patients were shown to have elevated barrier absorption compared to all other groups (p≤0.007), as well as increased RBC amplitude and displacement oscillations compared to healthy volunteers (p=0.007, p≤0.01). Patients with COPD and PAH both demonstrated reduced RBC amplitude oscillations compared to healthy volunteers (p=0.02, p=.005). LHF was distinguishable from PAH by enhanced RBC amplitude oscillations (p=0.01).

[0300] COPD, IPF, LHF, and PAH each present with unique 129 Xe MR imaging and dynamic spectroscopy "signatures". Each signature can be described as a different 129 Xe imaging and 129 Unique metrics or graphical markers of combinations of Xe spectral parameters, typically at least two per identifying feature, as shown using six such parameters. These metrics may aid in the diagnostic challenges of cardiopulmonary disease and increase the understanding of regional lung function and hemodynamics at the alveolar-capillary level.

[0301] Fig.15 Tables of demographic and clinical characteristics stratified by condition are provided: IPF = idiopathic pulmonary fibrosis; COPD = chronic obstructive pulmonary disease; PAH = pulmonary arterial hypertension; 6MWD = 6-minute walk distance; PFT = pulmonary function test; PCWP = pulmonary capillary wedge pressure; PVR = pulmonary vascular resistance; RVSP = right ventricular systolic pressure. Continuous variables are expressed as median (IQR); categorical variables are expressed as frequency (proportion).

[0302] Subject recruitment

[0303] The protocol was approved by the Institutional Review Board of Duke University Medical Center. Healthy volunteers and patients with COPD, IPF, LHF, or PAH were recruited and provided written informed consent. All healthy volunteers had no history of smoking or known respiratory status. COPD was diagnosed using spirometry, in which the forced expiratory volume after bronchodilator in one second (FEV 1) / forced vital capacity (FVC) ≤70%. 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):p.932-46. The diagnosis of IPF is established according to ATS / ERS criteria from a confirmed pattern of usual interstitial pneumonia (UIP) pattern on CT or from a 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):p.788-824. LHF is confirmed by echocardiography. See Lang, Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging (2015, Vol. 28, p. 1), Journal of the American Society of Echocardiography, 2016; 29(6): p. 521-521. PAH was defined according to the World Health Organization criteria and diagnosed by right heart catheterization with a resting mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg and a pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg.See Simonneau et al., Updated Clinical Classification of Pulmonary Hypertension, Journal of the American College of Cardiology, 2009;54(1):p.S43-S54. All clinical tests were performed as part of routine care. Pulmonary function tests (PFTs) were performed on all patients and 83% of healthy volunteers to assess baseline lung function.

[0304] MRI acquisition

[0305] Acquired on a 1.5T (GE 15M4 EXCITE) or 3T (SIEMENS MAGNETOM Trio) scanner 129Xe imaging and spectroscopy. For each subject, 3D images were acquired using interleaved radial acquisition of gas phase and dissolved phase data during a 15 second breath hold. See Kaushik, SS et al., Probing the regional distribution of pulmonary gas exchange through single-breath gas-and dissolved-phase Xe-129 MR imaging, Journal of Applied Physiology, 2013; 115(6): p850-860, the contents of which are hereby incorporated by reference as if fully described herein. Data were acquired at the echo time, which allowed the decomposition of the two dissolved phase compartments using the 1-point Dixon method. See 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. Magn Reson Med, 2016;75(4):p1434-43, the contents of which are hereby incorporated by reference as if fully set forth herein. This generates 3D images of the gas, barrier, and RBC components using 2.8 mm isotropic voxels. Subjects also underwent dynamic spectroscopy during which 100 μm of the sample were collected every 20 ms (TE = 0.932 ms, flip angle ≈ 20°, dwell time = 32 μs, 512 / 1024 points). 129 Xe free induction decay (FID). See Bier et al., A protocol for quantifying cardiogenic oscillations in dynamic (129)Xe gas exchange spectroscopy: The effects of idiopathic pulmonary fibrosis. NMR Biomed, 2018: p. e4029, the contents of which are hereby incorporated by reference as if fully set forth herein.

[0306] Quantitative processing and analysis

[0307] The 3D images of each compartment were rendered as quantitative maps using thresholds derived from a healthy reference population and mapped as color clusters. See Wang, Z. et al., Quantitative analysis of hyperpolarized 129Xe gastransfer MRI. MedPhys, 2017; 44(6): p.2415-2428; He, M. et al., Using Hyperpolarized 129Xe MRI to Quantify the PulmonaryVentilation Distribution. Acad Radiol, 2016; 23(12): p.1521-1531, the contents of which are hereby incorporated by reference as if fully set forth herein. The resulting binned maps depict 129Xe ventilation, barrier tissue absorption, and RBC transfer. Each of these maps is quantified by calculating the percentage of lungs that exhibit signal defects and high signals. See Wang, Z. et al. Quantitative analysis of hyperpolarized 129Xe gas transfer MRI. MedPhys, 2017; 44(6): p.2415-2428, the contents of which are hereby incorporated by reference as if recorded in full herein. Dynamically acquired FIDs are fitted in the time domain to determine gas, barrier, and RBC spectral parameters. See Bier, EA et al. A protocol for quantifying cardiogenic oscillations in dynamic (129)Xe gas exchange spectroscopy: The effects of idiopathic pulmonary fibrosis. NMR Biomedicine, 2018: p. e4029, the contents of which are hereby incorporated by reference as if fully set forth herein. The time-dependent RBC signal was detrended, and the cardiogenic oscillations of its amplitude and frequency excursion were quantified by their peak-to-peak values ​​relative to the mean. See again Bier, EA et al., A protocol for quantifying cardiogenic oscillations in dynamic (129) Xe gas exchange spectroscopy: The effects of idiopathic pulmonary fibrosis. NMR Biomedicine, 2018: p. e4029. Imaging and spectroscopic findings were compared across all populations.

[0308] Statistical methods

[0309] Imaging and spectral features were compared between populations. All calculations were performed using JMP 14 (SAS Institute, Cary, NC). First, one-way analysis of variance was performed using the nonparametric Kruskal-Wallis. When significant differences were detected, pairwise analysis was further performed using the Mann Whitney U test. p < 0.05 was claimed to be statistically significant.

[0310] Study population

[0311] This study included 23 healthy volunteers, 8 patients with COPD, 12 patients with IPF, 6 patients with LHF, and 10 patients with PAH. Subject demographics and PFT results are summarized in Fig.15 middle.

[0312] The gas, barrier and RBC compartments were obtained in 19 healthy volunteers and all patients. 129 3D isotropic images of Xe. Dynamic spectra were acquired on 13 healthy volunteers, 6 patients with COPD, 8 patients with IPF, 5 patients with LHF, and 10 patients with PAH. Subjects were excluded from imaging or spectral analysis if the acquisition could not achieve sufficient SNR required for reliable quantification.

[0313] Identify disease-specific imaging-derived metrics

[0314] Representative ventilation and gas transfer maps from subjects in each group are presented together with the resulting quantitative metrics. Fig.16 For each map, the percentage of voxels falling into the defect, low, and high bins is reported. In healthy volunteers, the majority of all three compartments 129 Xe signals all fall within ± 1 standard deviation of the mean of the reference distribution, and are therefore located in the "normal" green color box. In contrast, COPD subjects all show obvious defects in all three compartments (ventilation, barrier and RBC), indicated by red color boxes. IPF subjects show relatively normal ventilation, but areas of obvious high barrier absorption, accompanied by defects in RBC transfer in the lower lobe. Both LHF and PAH subjects show slight ventilation defects, relatively normal barriers, but more obvious losses of RBC transfer. Ventilation, barrier absorption and RBC transfer maps from representative subjects of each population. Color boxes represent signal intensity, wherein red represents the lowest signal intensity, and blue / purple represents the highest signal intensity, and green represents voxels within the healthy reference range. Each map is quantified by defect (D), low (L) and high (H) percentages, calculated as the voxel scores of the lowest, second lowest and highest two boxes of each map, respectively.

[0315] Figures 17A-17D quantitatively evaluate these imaging features across populations, comparing the percentage of ventilation defects, RBC defects, barrier defects, and high barriers. Comparison of ventilation defects (Figure 17A), RBC defects (Figure 17B), barrier defects (Figure 17C), and high barrier percentages for all populations ( Fig.17D). Asterisks mask values ​​that were significantly increased (red R) or decreased (green G) compared to all other populations. All disease populations showed increased ventilation defects (p≤0.01) and RBC defects (p≤0.01) compared to healthy subjects. COPD was characterized by significantly elevated percentages of ventilation defects (p≤0.02) and barrier defects (p≤0.02). IPF uniquely exhibited reduced barrier defects (p≤0.02), but elevated percentages of high barriers (p≤0.007). PAH and LHF exhibited slightly elevated ventilation defects and moderately elevated RBC defects. All patient groups exhibited greater percentages of defects in ventilation (p≤0.01 for all comparisons) and RBC transfer (p≤0.01 for all comparisons) compared to healthy subjects. The COPD population stood out for the greatest percentage of ventilation defects (41.5 ± 22.6% for all comparisons, p ≤ 0.02) and was the only population to show a barrier absorption defect (10.4 ± 7.1% for all comparisons, p ≤ 0.02). In contrast, IPF patients were distinguished from the other groups by having high 129 The maximum percentage of voxels with Xe uptake was 39.8% for all comparisons, p≤0.007. IPF subjects showed only modest ventilation defects (11.5±6.7%, p=0.0003 vs. healthy), but substantial RBC defects (11.3±6.7%, p=0.0001 vs. healthy). LHF and PAH patients presented similar imaging characteristics with modestly elevated ventilation defects (LHF: 11.7±6.2%, p=0.01 vs. healthy; PAH: 8.4±4.7%, p=0.01 vs. healthy) and increased RBC transfer defects (LFH: 13.3±10.2%, p=0.01 vs. healthy; PAH: 14.5±9.3%, p=0.002 vs. healthy).

[0316] Disease-specific spectra derived metrics

[0317] Figures 18A and 18B show that the detrended RBC signal amplitude and displacement oscillations for representative subjects from each group demonstrate cardiogenic oscillations. It is worth noting that the RBC signal amplitude (Figure 18A) of each patient oscillates at the same frequency as his / her heart rate. IPF patients also clearly show such cardiogenic oscillations in RBC frequency shifts. Both IPF and LHF patients show enhanced RBC amplitude oscillations. In contrast, RBC signal oscillations are reduced in both PAH and COPD patients. Only IPF patients show oscillations in RBC displacement ( Fig.18B ).

[0318] Figures 19A and 19B show a group-by-group comparison of cardiac RBC amplitude and displacement metrics. In healthy subjects, RBC amplitude (Figure 19A) oscillates with a peak-to-peak height of 10.0 ± 2.6%, accompanied by very small RBC displacement oscillations (0.07 ± 0.05 ppm). RBC displacement ( Fig.19B ) oscillated significantly only in the IPF population (0.46±0.33ppm, p≤0.01 for all comparisons). IPF patients also exhibited greater RBC amplitude oscillations compared to healthy volunteers (16.7±5.5%, p=0.007). RBC amplitude oscillations were reduced in both COPD and PAH compared to healthy volunteers (COPD: 5.5±4.7%, p=0.02; PAH: 6.0±3.6%, p=0.005). In subjects with LHF, RBC amplitude oscillations were greater than in healthy volunteers, but 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). Therefore, Figures 19A and 19B show RBC amplitude and frequency shift oscillations compared across populations, respectively. Gray (G) asterisks mark significant differences between populations, and red (R) asterisks mark increased values ​​compared to all other similar populations. Compared to healthy subjects, COPD (p=0.02) and PAH (p=0.005) showed reduced RBC amplitude oscillations, while they were increased in IPF (p=0.007). In addition, in LHF, RBC amplitude oscillations were significantly increased compared to PAH (p=0.01). IPF patients showed significantly increased RBC displacement oscillations compared to all other populations (p≤0.01).

[0319] discuss

[0320] 129 Xe biomarkers distinguish different disease phenotypes

[0321] In this study, unique characteristics of patients with COPD, IPF, PAH, and LHF were identified. 129Xe MR imaging and spectral signatures. COPD is characterized by significantly elevated percentages of ventilation and barrier defects and reduced RBC amplitude oscillations compared to all other disorders. However, in COPD, the percentage of ventilation defects varies greatly among populations, consistent with the heterogeneity of the disease. 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): p.601-609, the contents of which are hereby incorporated by reference as if recorded in full herein. In contrast, IPF is characterized primarily by elevated barrier absorption, almost nonexistent percentage of barrier defects, elevated RBC amplitude oscillations, and significant oscillations in RBC displacement. PAH and LHF presented similar imaging characteristics (slightly elevated ventilation, barrier, and percentage of RBC defects compared to healthy volunteers). However, PAH differed from LHF in that RBC amplitude oscillations were lower than in healthy subjects, whereas in LHF, such oscillations were enhanced. All four disease populations showed significant RBC transfer defects.

[0322] These imaging findings are consistent with previous studies that have identified increased ventilatory defects in patients with COPD. See Wang et al. Hyperpolarized (129)Xe gas transfer MRI: the transition from 1.5T to 3T. Magn Reson Med, 2018; Qing et al. Assessment of lung function in asthma and COPD using hyperpolarized 129Xe chemical shift saturation recovery spectroscopy and dissolved-phase MRI. NMR Biomed, 2014; 27(12): p.1490-501; and Virgincar et al., Quantitative analysis of hyperpolarized 129Xe ventilation imaging in healthy volunteers and subjects with chronic obstructive pulmonary disease. NMR Biomed, 2013; 26(4): p.424-35, the contents of which are hereby incorporated by reference as if fully set forth herein.

[0323] The observation that barrier absorption is also reduced in COPD is a novel finding, most likely reflecting emphysematous lung destruction and loss of surface area for gas exchange. This loss further leads to reduced RBC transfer. In IPF, the disease is characterized by increased barrier absorption and RBC transfer defects, primarily in the lung base. See 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. Magn Reson Med, 2016;75(4):p.1434-43; Kaushik et al., Measuring diffusion limitation with aperfusion-limited gas—hyperpolarized129Xe gas-transfer spectroscopy in patients with idiopathic pulmonary fibrosis. Journal of Applied Physiology, 2014;117(6):577-85; Wang et al., Hyperpolarized (129)Xe gas transfer MRI: the transition from 1.5T to 3T.Magn Reson Med, 2018; Wang et al., Using hyperpolarized (129) Xe MRI to quantify regional gas transfer in idiopathic pulmonary fibrosis, Chest, 2018; 73(1): p. 21-28; and Kaushik et al., Probing the regional distribution of pulmonary gas exchange through single-breath gas-and dissolved-phase Xe-129 MR imaging, Journal of Applied Physiology, 2013; 115(6): p. 850-860, the contents of which are hereby incorporated by reference as if set forth in their entirety herein. In addition, this study provides important context for previous work showing that patients with IPF have a 129Cardiogenic oscillations of Xe RBC amplitude and displacement were significantly enhanced relative to healthy controls. See Kaushik et al., Measuring diffusion limitation with a perfusion-limited gas—hyperpolarized 129Xe gas-transfer spectroscopy in patients with idiopathic pulmonary fibrosis, Journal of Applied Physiology, 2014; 117(6):577-85; and Bier et al., A protocol for quantifying cardiogenic oscillations in dynamic (129)Xe gas exchange spectroscopy: The effects of idiopathic pulmonary fibrosis. NMR Biomed, 2018: p. e4029, the contents of which are hereby incorporated by reference as if fully set forth herein. Now that such data have been obtained in this wider population, it shows that, until now, RBC displacement oscillations are unique to IPF and have not been observed for COPD, LHF, and PAH. Furthermore, the enhanced RBC amplitude oscillations seen in IPF were only additionally seen in LHF, suggesting that this is a marker for post-capillary PH.

[0324] A model of the alveolar-capillary interface to characterize disease phenotypes

[0325] Fig. 20 A conceptual framework illustrating a diagram of the alveolar-capillary interface to help explain the relationship between alveolar and capillary vasculature across disease states. 129 Xe imaging and spectral biomarkers. This image shows the alveoli, capillaries, interstitial barrier tissue, RBCs, and 129 For each disease state, the 129 Expected impact of Xe biomarkers (ventilation, barrier, and RBC). These concept diagrams can help explain each disease in the context of gas transfer physiology. 129 Xe MRI and spectroscopy identify patterns of features, without limitation to the present invention. In a healthy subject, 129Xe atoms diffuse freely into the alveoli and alveolar-capillary interface, translating into images that reflect normal ranges of ventilation, barrier absorption, and RBC transfer. In COPD, chronic airway inflammation and small airway obstruction create ventilation defects, while the loss of alveolar surface area associated with emphysema leads to loss of alveolar surface area in the interstitial barrier tissue. 129 Reduced uptake of Xe. See Barnes et al., Systemic manifestations and comorbidities of COPD, European Respiratory Journal, 2009; 33(5): p. 1165-1185, the contents of which are hereby incorporated by reference as if fully set forth herein. Although many patients exhibit disproportionately greater RBC mobilization, which may reflect additional losses of the vasculature, this is associated with a concomitant reduction in RBC mobilization. See Rahaghi, FN, EJR van Beek, and GR Washko, Cardiopulmonary Coupling in Chronic Obstructive Pulmonary Disease The Role of Imaging, Journal of Thoracic Imaging, 2014; 29(2): p. 80-91, the contents of which are hereby incorporated by reference as if fully set forth herein. In contrast, in IPF, interstitial fibrosis leads to 129Xe uptake is increased. See Lederer et al., Idiopathic Pulmonary Fibrosis. N Engl J Med, 2018;379(8):p.797-798, the contents of which are hereby incorporated by reference as if fully set forth herein. This in turn causes diffusion restriction, which, in addition to the likely perfusion deficit, also serves to reduce RBC transfer. See Wang, JM et al., Using hyperpolarized(129)Xe MRI to quantify regional gastransfer in idiopathic pulmonary fibrosis, Chest 2018;73(1):p.21-28, the contents of which are hereby incorporated by reference as if fully set forth herein. When this disruption is accompanied by preserved stroke volume, it will produce larger relative capillary blood volume oscillations between systole and diastole; this may manifest as larger RBC amplitude oscillations. In the setting of pulmonary hypertension (PH), left heart failure (LHF) is characterized by post-capillary resistance (primarily derived from pulmonary venous PH). Because the high resistance originates downstream from the capillary bed, it is associated with greater capillary blood volume oscillations during the cardiac cycle, again resulting in greater spectral RBC amplitude oscillations. It is less clear what causes the defect in RBC transfer, but patients with LHF are known to experience gas exchange abnormalities, including decreased DLCO, which is thought to be secondary to chronic damage caused by pulmonary venous congestion. See Olson et al., Impaired Pulmonary Diffusion in Heart Failure With Preserved Ejection Fraction, Jacc-Heart Failure, 2016; 4(6): p. 490-498; and Guazzi, M., Alveolar Gas Diffusion Abnormalities in Heart Failure, Journal of Cardiac Failure, 2008; 14(8): p. 695-702, the contents of which are hereby incorporated by reference as if fully set forth herein. And finally, PAH is expected to be characterized by increased precapillary resistance, particularly due to remodeling and occlusion of pulmonary arterioles, which results in loss of alveolar membrane diffusion capacity and pulmonary capillary blood volume.See Farha et al., Loss of alveolar membrane diffusion capacity and pulmonary capillary blood volume in pulmonary arterial hypertension, Respiratory Research, 2013; 14, the contents of which are hereby incorporated by reference as if recorded in full herein. Although these features in PAH may not be expected to directly affect ventilation or diffusion barrier absorption, they may lead to RBC transfer defects and increase resistance to flow occurring upstream of the capillary bed. This in turn can reduce pulmonary capillary blood volume and cardiogenic blood volume oscillations in the capillary bed. This can result in reduced RBC signal amplitude oscillations, which, at least for now, appears to be the feature that most strongly distinguishes pre-capillary PH from post-capillary PH.

[0326] Differentiating cardiopulmonary disease in the clinical setting

[0327] In summary, this non-invasive 129 The combination of Xe MR imaging and spectroscopic parameters allows interrogation of gas transfer at the alveolar capillary level, which appears to be useful not only for characterizing and quantifying disease burden, but also for identifying signatures that may help distinguish cardiopulmonary disorders, states, or diseases. Potential outputs of this approach are Fig.21 It is shown in Fig.21 Radar plots (charts) are shown for 4 key imaging features and 2 key spectral features - ventilation defects, barrier defects, high barrier absorption, RBC defects, and RBC amplitude and displacement oscillations. Integrating these features for each disease group can provide an initial graphical output that displays these phenotypes in a visually distinct manner. Generating such plots for individual patients can provide a powerful protocol to identify the main phenotypes that should be considered. Radar plots are a graphical method that displays multivariate phenotypes in the form of two-dimensional plots of three or more quantitative variables. 129 Xe data, the variables having one or more different units of measurement, such as percentage and ppm, expressed on axes starting from the same point. Of course, other outputs may be used, such as but not limited to parallel coordinate plots, where the axes are arranged radially.

[0328] exist Fig.21 Radar graphs showing the main health risks associated with patients with COPD, IPF, LHF, and PAH 129Xe MR imaging and spectroscopy signatures. Here, mean population values ​​for key markers are plotted on one of six radial lines - ventilation defect, barrier defect, barrier height, percent RBC defect from imaging, and RBC displacement oscillation and amplitude oscillation from spectroscopy.

[0329] In addition to distinguishing various cardiopulmonary conditions, 129 Xe MRI may be useful in determining the underlying cause of dyspnea in patients with mixed cardiopulmonary disease, such as those with comorbidities. This is a common clinical situation in an aging population, many of whom may have concomitant COPD and LHF, which complicates ILD or PAH. See Hoeper et al. Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry. Int J Cardiol, 2013; 168(2): p.871-80, the contents of which are hereby incorporated by reference as if recorded in full herein. Furthermore, as early diagnosis becomes increasingly important in disorders such as ILD and PAH (see Cosgrove, GP, et al. Barriers to timely diagnosis of interstitial lung disease in the real world: the INTENSITY survey. BMC Pulm Med, 2018;18(1):p.9; and Lau et al. Early detection of pulmonary arterial hypertension. Nat Rev Cardiol, 2015;12(3):p.143-55), 129Xe spectral indices can provide sensitive probes for early diagnosis and disease progression, the contents of which are hereby incorporated by reference as if fully set forth herein. In addition, the RBC transfer signal depicts the ultimate disease burden of gas transfer function and can therefore be used to assess disease progression and treatment response. See Mammarappallil, JG et al., New Developments in Imaging Idiopathic Pulmonary Fibrosis With Hyperpolarized Xenon Magnetic Resonance Imaging, Journal of Thoracic Imaging, 2019; 34(2): p.136-150, the contents of which are hereby incorporated by reference as if fully set forth herein. Given the limitations of current diagnostic tests, 129 Xe gas transfer imaging and dynamic spectroscopy provide information with the potential to improve patient care.

[0330] Research Reviews

[0331] When comparing across cardiopulmonary status 129 There are some limitations to the study of Example 2 when using Xe MR imaging and spectroscopy to identify features. First, the heterogeneity of patients within each disease population and possible comorbidities may limit the ability to 129 The ability to identify patterns in Xe imaging and spectroscopy facilitated the changes in each group. For example, all PAH patients underwent PAH-targeted therapy, and many had not had a recent right heart catheterization, which was 129The severity of PAH in the Xe study may have been limited. In addition, although this study was designed to recruit patients with isolated LHF as a model of postcapillary resistance, some individuals may have also developed right heart failure over time, given the common evolution of pathogens from left to right heart dysfunction. See Rosenkranz et al., Left ventricular heart failure and pulmonary hypertension, Eur Heart J, 2016;37(12):p.942-54, the contents of which are hereby incorporated by reference as if set forth in full herein. Indeed, this phenotypic evolution may partly explain the large variation in RBC amplitude oscillations exhibited by our LHF population (maximum: 21.5%, minimum: 8.0%, SD: 5.1%). Another limitation is that subject scans were performed on different platforms with two field strengths. Quantification methods using a healthy reference group constructed under the same acquisition protocol were designed to incorporate potential factors such as T. 1 and T 2 * attenuation, which may affect gas transfer measurements. See Wang et al., Quantitative analysis of hyperpolarized 129Xe gas transfer MRI, MedPhys, 2017; 44(6): p.2415-2428, the contents of which are hereby incorporated by reference as if fully set forth herein. However, these and other factors limited the size of the healthy reference population, which was also significantly younger than the typical patient in this population. It is reported that because the aging lung is undergoing physiological changes that may affect gas transfer function, future studies would benefit from constructing a larger and age-controlled healthy population. See Janssens, JP, JC Pache and LP Nicod, Physiological changes in respiratory function associated with ageing, Eur Respir J, 1999; 13(1): p. 197-205, the contents of which are hereby incorporated by reference as if fully set forth herein.

[0332] in conclusion

[0333] In this Example 2 study, we applied129 Xe gas transfer imaging and spectroscopy. As a non-invasive and non-ionizing tool, hyperpolarization 129 Xe gas transfer MRI provides a fundamentally new approach to directly image regional function while also capturing hemodynamics at the alveolar-capillary level. The unique imaging and spectral signatures identified for each of these diseases may help overcome some of the diagnostic challenges facing clinicians treating patients with cardiopulmonary disease. 129 Xe gas transfer imaging and spectroscopy is a promising technique for characterizing the pathophysiology of cardiopulmonary diseases and, with further validation in larger studies, it is believed that this could contribute to a comprehensive understanding of the multifactorial pathogenesis of dyspnea and / or the development of personalized treatments.

[0334] Example 3

[0335] In this Example 3, experiments were performed to evaluate whether the pre-capillary (PAH) versus post-capillary (PHpost) origin of PH could be distinguished when taking into account concomitant lung disease such as ILD or COPD.

[0336] In this study, the hyperpolarization 129 Regional Gas Exchange and Hemodynamics with Xe MRI. The study acquired single-breath 3D MRI images of ventilation, barrier, and blood (RBC compartment), which identified defects in lung gas exchange regions, and single-breath dynamic spectra of RBC peak amplitude and chemical shift (ppm) over time.

[0337] Recruitment of experimental subjects

[0338] Healthy: 22; ILD: 12; PAH: 10; left heart failure: 6 (post-capillary PH); COPD: 8.

[0339] Methods: For each subject, 129 Xe gas exchange imaging and dynamic spectroscopy.

[0340] Figure 22 is a representative ventilation, barrier and RBC image of a healthy lung and associated amplitude and chemical shift spectra. RBC deficiency is 2%, RBC low: 5%. Peak amplitude is 10.3% and frequency oscillation is 0.02ppm.

[0341] Figure 23 represents ventilation, barrier and RBC images and associated amplitude and chemical shift spectra of a subject with PAH. RBC deficiency is 11%, RBC low: 33%. Peak amplitude is 4.3% and frequency oscillation is 0.06ppm.

[0342] Fig.24Ventilation, barrier and RBC images and associated amplitude and chemical shift spectra of a representative subject with ILD. RBC defective 19%, RBC low: 20%. Peak amplitude is 12.8% and frequency oscillation is 0.31 ppm.

[0343] RBC amplitude oscillations are used to identify healthy pre- and post-capillary pH. Fig.25 It is a graph of RBC amplitude oscillations (%) for healthy and different disease states of (multiple) lungs including ILD, PAH, PHpost and COPD. As shown in the additional text on the right side of the figure, the various lines from top (highest RBC amplitude oscillations) to bottom (lowest) indicate very likely PHpost or ILD, possible PHpost or ILD, ruled out, possible arterial disease and very likely arterial disease.

[0344] Fig.26 is a plot of the true positive rate versus false positive rate using the ROC curve of RBC amplitude oscillation to determine the threshold for separating / differentiating healthy, pre-capillary, and post-capillary PH. The ROC curve area is shown with the optimal threshold: 7.9.

[0345] Fig. 27 is a set of 3D images (ventilation, barrier and RBC) of healthy and different disease populations illustrating a lung map showing metrics that can further differentiate between different disease populations (ILD, PAH, PHpost, COPD).

[0346] Fig.28 is a schematic illustration of a diagnostic analysis protocol (i.e., model) of defined parameters that can be used to identify disease states with respect to ventilation, barrier, and percentage of RBC defects from a 3-D lung map along with dynamic spectral parameters of RBC amplitude and frequency oscillations. The model correctly classified 34 of 40 subjects (85%) with both imaging and spectral data.

[0347] Fig.29 is an example application of images and spectral metric parameters of subject A, which were used for a diagnostic analysis protocol, with ventilation, barrier, and RBC defect percentages from a 3-D lung map along with dynamic spectral parameters of RBC amplitude and RBC frequency oscillations.

[0348] Fig.30 Diagnostic analysis of metric parameters applied to Subject A is illustrated, illustrating various diagnostic decisions made based on RBC amplitude oscillations, RBC defect percentages, and ventilation and barrier defect percentages.

[0349] Fig.31is an example application of image and spectral metric parameters for subject B using a diagnostic analysis protocol with ventilation, barrier, and RBC defect percentages from a 3-D lung map along with dynamic spectral parameters of RBC amplitude and RBC frequency oscillations.

[0350] Fig.32 The diagnostic analysis of the metric parameters applied to Subject B illustrates various diagnostic decisions made based on RBC amplitude oscillation, RBC defect percentage, and ventilation and barrier defect percentage.

[0351] Conclusion, Example 3

[0352] The diagnostic analysis model shows promise for differentiating pre-capillary (PAH) versus post-capillary (PHpost) origins of PH while taking into account concomitant lung disease, such as ILD or COPD. Of note, all PAH patients received standard care, and PH was not explicitly excluded from the ILD and COPD populations. In the future, it may be desirable to prospectively test a larger population undergoing same-day right heart catheterization as a measure of 129 Xe is the gold standard for measuring the sensitivity and specificity of the ability to detect PAH.

[0353] Some embodiments of the present invention are described herein by way of example. Many changes and modifications may be made to the embodiments without departing substantially from the principles of the present invention. All such changes and modifications are intended to be included herein within the scope of the present invention as set forth in the appended claims.

Claims

1. A computer system comprising a memory, a processor and a computer program stored in the memory, characterized in that: The processor executes the computer program to implement the steps of a method for determining whether a patient suffers from a cardiopulmonary disease, the method comprising: Obtain multiple 129 Xe imaging parameters, including red blood cell (RBC) defect percentage, ventilation defect percentage, and barrier defect percentage; Obtain multiple 129 Xe spectral parameters, including RBC amplitude oscillations; and Based on the obtained 129 Xe imaging parameters and 129 Xe dynamic spectral parameters are used to generate graphic identification features of the patient's cardiopulmonary health or disease status, and the generated graphic identification features identify whether the patient suffers from cardiopulmonary disease.

2. The computer system according to claim 1, wherein: The processor is further configured to compare the generated graphic identification feature to a database comprising a library of graphic identification features, the library of graphic identification features comprising a unique graphic identification feature for each of: Chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), left heart failure (LHF) and pulmonary arterial hypertension (PAH).

3. The computer system of claim 1, wherein the processor is further configured to provide a diagnostic model that defines the likelihood of different diseases based on corresponding different thresholds of peaks of RBC amplitude oscillations.

4. An MRI scanner system, comprising: MRI scanner; and A computer system according to any one of claims 1-3 in communication with an MRI scanner.

5. A medical evaluation system comprising a server in communication with at least one MRI scanner and having the computer system according to any one of claims 1 to 3.

6. The computer system of claim 1, wherein the obtained multiple 129 The Xe imaging parameters also include a high barrier absorption percentage, wherein the processor is further configured to: At least one radar graph showing a disease state of the patient is generated, wherein the at least one radar graph includes ventilation defect percentage, barrier defect percentage, RBC defect percentage, high barrier absorption percentage, and RBC amplitude oscillation.

7. The computer system according to claim 1, wherein: The processor is also configured to electronically compare oscillations of the RBC amplitude oscillations before and after administration of the medicament and identify vascular reactivity and / or changes based on changes in the RBC amplitude oscillations.

8. The computer system of claim 7, wherein the agent is a vasodilator.

9. The computer system according to claim 7, wherein: The vasodilator is an inhaled vasodilator.

10. The computer system of claim 7, wherein the agent comprises prostacyclin.

11. The computer system according to claim 1, wherein: The processor is configured to perform the obtaining step, prior to which, while the patient is in an MRI scanner, at least one large dose of inhalable hyperpolarized 129 Xe gas.

12. The computer system according to claim 1, wherein: Before the obtaining step, the processor is further configured to: A series of gas exchange regions of at least one lung of a patient is obtained during a breathing maneuver. 129 Xe free induction decay (FID); and The real and imaginary components of the FID are fitted in the time domain using a curve fitting function modeled using one or more non-Lorentzian line shapes, wherein the curve fitting function is 129 Xe barrier resonance, 129 Xe gas phase resonance and 129 Each of the Xe red blood cell (RBC) resonances is modeled at least in part using the one or more non-Lorentzian line shapes 129 The Xe barrier resonance is modeled to obtain 129 Xe spectral parameters.

13. A computer system comprising a memory, a processor and a computer program stored in the memory, characterized in that: The processor executes a computer program to implement the steps of a method of generating spectral parameters for medical assessment of a subject, the method comprising: A series of gas exchange regions of one or more lungs of a subject is obtained during a breathing maneuver. 129 Xe free induction decay (FID); The real and imaginary components of the FID are fitted in the time domain using a curve fitting function modeled using one or more non-Lorentzian line shapes, wherein the curve fitting function is 129 Xe barrier resonance, 129 Xe gas phase resonance and 129 Each of the Xe red blood cell (RBC) resonances is modeled where the 129 The Xe barrier resonance is modeled at least in part using the one or more non-Lorentzian lineshapes; and Based on the fitting, a plurality of 129 Xe spectral parameters, RBC spectral parameters including RBC amplitude, The static and dynamic 129 Xe spectral parameters include RBC amplitude oscillation, and The peak-to-peak amplitude of the RBC amplitude oscillations is corrected based at least in part on an estimated lung exchange volume of the subject.

14. A computer system for electronic medical assessment of the lungs of a plurality of different subjects, the computer system comprising at least one processor configured to: A series of gas exchange regions of one or more lungs of a respective subject is obtained during a breathing maneuver. 129 Xe free induction decay (FID); fitting the FID using a curve fitting function modeled using one or more non-Lorentzian line shapes; Based on the curve fitting, a plurality of 129 Xe spectral parameters, wherein the plurality 129 Xe spectrum parameters include static and / or dynamic 129 Xe spectral parameters using plots of red blood cell (RBC) spectral parameters over time including RBC amplitude; high pass filtering the RBC spectral parameters with a cutoff frequency of 0.5 Hz to remove residual baseline variations and provide a filtered parameter graph of the RBC spectral parameters; and The filtered parameter graph of the RBC spectral parameters is provided to an image processing circuit configured to analyze the filtered parameter graph of the RBC spectral parameters to determine whether the corresponding subject suffers from one or more cardiopulmonary conditions and / or lung injury or disease.

15. The computer system of claim 14, wherein: The at least one processor is further configured to fit the filtered parametric profile to a sinusoidal curve having a phase offset: Among them A pk-pk is the peak-to-peak amplitude, f c is the heart rate, t is the time in seconds, and is the phase shift, and where f c is the heart frequency derived from the subject's RBC amplitude oscillations.

16. The computer system of claim 15, wherein f c Used in the temporal fitting of other RBC spectral parameters, including RBC chemical shift, line width and phase.

17. A computer system comprising a memory, a processor and a computer program stored in the memory, characterized in that: The processor executes the computer program to implement the steps of a method for non-invasively screening a subject for one or more cardiopulmonary conditions, the method comprising: A series of gas exchange regions of one or more lungs of a subject is obtained during a breathing maneuver. 129 Xe free induction decay (FID); The real and imaginary components of the FID are fitted in the time domain using a curve fitting function modeled using one or more non-Lorentzian line shapes, wherein the curve fitting function is 129 Xe barrier resonance, 129 Xe gas phase resonance and 129 Each of the Xe red blood cell (RBC) resonances is modeled where the 129 The Xe barrier resonance is modeled at least in part using the one or more non-Lorentzian line shapes; Electronically generate multiple RBC amplitude oscillations 129 Xe spectrum parameters; Obtaining one or more lungs of a subject 129 Xe magnetic resonance imaging (MRI) gas exchange images; from one or more lungs of a subject 129 Xe magnetic resonance imaging (MRI) gas exchange images electronically calculate RBC transport defects, ventilation defects, and barrier defects; and A database comprising a plurality of defined different disease patterns is electronically provided, wherein the plurality of defined disease patterns comprises: Precapillary pulmonary hypertension defined at least in part by a correspondingly defined disease pattern including a peak-to-peak amplitude of RBC amplitude oscillations of 7.9% or less, and A post-capillary vascular disease defined at least in part by a correspondingly defined disease pattern comprising a peak-to-peak amplitude of RBC amplitude oscillations greater than 13.85%.

18. The computer system of claim 17, wherein one or more of the plurality of defined different disease patterns comprises oscillations in RBC amplitude exceeding a defined peak-to-peak threshold.

19. The computer system of claim 17, wherein one or more of the plurality of defined different disease patterns comprises at least one characteristic of the RBC amplitude oscillations having a peak-to-peak variation below a defined peak-to-peak threshold.

20. The computer system of claim 17, wherein one or more of the plurality of defined different disease patterns is based on a shape of oscillations of the RBC amplitude oscillations.

21. The computer system of claim 17, wherein at least one of the plurality of defined different disease patterns has a disease pattern comprising an RBC frequency excursion below a defined standard obtained during a first second of a breath hold of the breathing maneuver.

22. The computer system of claim 1 or claim 17, wherein one or more of the plurality of defined distinct disease patterns identifies combined pre-capillary and post-capillary vascular disease.

23. The computer system of claim 13 or 17, wherein the processor is further configured to electronically compare oscillations of RBC amplitude before and after administration of a medicament and identify vascular reactivity and / or changes based on changes in corresponding RBC oscillations.

24. The computer system of claim 23, wherein: The drug is a vasodilator.

25. The computer system of claim 24, wherein: The vasodilator is an inhaled vasodilator.

26. The computer system of claim 17, wherein a disease pattern among the plurality of defined different disease patterns associated with idiopathic pulmonary fibrosis (IPF) is characterized at least in part by an RBC chemical shift (ppm) below a defined ppm.

27. The computer system of claim 17, wherein: One of the plurality of defined different disease patterns is associated with combined pre-capillary and post-capillary vascular disease and is defined by a corresponding defined disease pattern, the disease pattern comprising one or more of a size, a shape, or a frequency of RBC amplitude oscillations.

28. A computer system comprising a memory, a processor and a computer program stored in the memory, characterized in that: The processor executes the computer program to implement the 129 The steps of a method for identifying whether a patient suffers from one or more defined medical conditions using Xe spectral parameters, the method comprising: Obtain a series of gas exchange regions of one or more lungs of a patient during a breathing maneuver 129 Xe free induction decay (FID); fitting the FIDs in the time domain using a curve fitting function modeled using one or more non-Lorentzian line shapes, wherein the curve fitting function models each of a barrier resonance, a red blood cell (RBC) resonance, and a gas phase resonance; Based on the fitting of multiple RBC spectral parameters including RBC amplitude, multiple static and dynamic 129 Xe spectral parameters, including dynamic 129 Xe spectral parameters include oscillations of RBC amplitude; electronically evaluating one or more of a defined shape, pattern, peak magnitude, and / or frequency of oscillation of the RBC amplitude; and Using blood from one or more lungs of the patient 129 Data from Xe magnetic resonance imaging (MRI) gas exchange images, electronically calculate the RBC transfer defect percentage, ventilation defect percentage, barrier defect percentage, and high barrier absorption percentage, wherein the patient is identified as likely to have precapillary pulmonary hypertension based at least in part on when the peak-to-peak amplitude of the oscillations of the RBC amplitude is 7.9% or less, and Wherein the patient is identified as likely to have idiopathic pulmonary fibrosis (IPF) based at least in part on when the peak to peak amplitude of the oscillations of the RBC amplitude is greater than 10.2% and / or when the high barrier absorption percentage is at or above 20%.

29. The computer system of claim 28, wherein the static and dynamic 129 Xe spectral parameters also include barrier amplitude, barrier chemical shift (ppm) and one or more barrier FWHM (ppm) plots over time. 129 Xe spectral parameters.

Images