Temperature measurement method and device based on phosphocreatine chemical exchange saturation transfer imaging

Abstract

The invention relates to a temperature measurement method and device based on phosphocreatine chemical exchange saturation transfer imaging. The method comprises the following steps: (1) carrying out chemical exchange saturation transfer imaging on creatine phosphate phantom at different temperatures, and calculating apparent chemical shift of creatine phosphate in the creatine phosphate phantom at different temperatures; (2) fitting the mathematical relationship between the apparent chemical shift of the creatine phosphate and the temperature of the creatine phosphate phantom; and (3) carrying out in-vivo phosphocreatine chemical exchange saturation transfer imaging on the individual to be detected, calculating the apparent chemical shift of phosphocreatine in the individual to be detected, and generating a temperature map of the biological tissue of the individual to be detected according to the mathematical relationship. The absolute temperature imaging technology based on the CEST effect of endogenous phosphocreatine and the temperature dependence of the endogenous phosphocreatine is developed, and the method has the advantages of being high in spatial resolution, high in sensitivity, non-invasive, capable of being repeated for multiple times and the like, and has good clinical conversion application and popularization prospects.

Description

Technical Field

[0001] This invention belongs to the field of magnetic resonance imaging technology and relates to a temperature measurement method and device based on phosphocreatine chemical exchange saturation transfer imaging. Background Technology

[0002] Temperature is a crucial physiological indicator for biological tissues, comprehensively characterizing their metabolic processes and blood perfusion, thus maintaining homeostasis. Biochemical reactions and drug release processes within the body are temperature-sensitive, and disease states (such as infection, trauma, tumors, and degenerative changes) are often accompanied by temperature imbalances. Therefore, non-invasive absolute temperature detection technology is of great significance for studying the physiological and pathological mechanisms of biological tissues.

[0003] Current temperature imaging technologies include imaging techniques based on physical phenomena such as the relaxation characteristics of hydrogen protons in biological tissues, X-ray absorption characteristics, and acoustic characteristics. These technologies have drawbacks such as low specificity, ionizing radiation damage, and low resolution. Among them, magnetic resonance thermometry is mainly based on the temperature dependence of magnetic resonance parameters such as proton density, T1 and T2 relaxation times, dispersion coefficient, proton resonance frequency, and magnetization transfer. Currently, the most widely used techniques for measuring absolute temperature include: (1) the proton resonance frequency method (PRF), which utilizes water hydrogen protons. 1The resonance frequency of H is temperature dependent, while the chemical shift of some macromolecules is not easily affected by temperature, such as acetyl-aspartic acid (NAA). Magnetic resonance spectroscopy (MRS) imaging technology is used to measure the chemical shift of water hydrogen protons relative to a reference macromolecule at different temperatures. By fitting, a mathematical relationship between chemical shift and temperature is established, thereby achieving non-invasive temperature measurement. However, the resolution of this method is currently low, and its temperature measurement is easily affected by motion and magnetic field drift; (2) Based on the relationship between the free diffusion coefficient of water molecules and temperature, the absolute temperature of tissues such as cerebrospinal fluid is measured. However, this technique is only suitable for estimating the temperature of liquid components in biological tissues and cannot be used for tissues where water molecule diffusion is restricted; (3) By injecting paramagnetic chelates as exogenous reference substances, and utilizing the chemical exchange saturation transfer (CEST) effect of chelates, imaging technology is used to measure the chemical shift of chelates at different temperatures in biological tissues, and a mathematical relationship between it and temperature is obtained by fitting. Although the paramagnetic CEST effect of chelates is highly sensitive to temperature, the biosafety of paramagnetic chelates is a major barrier limiting their application, preventing repeated injections for temperature measurement and hindering their widespread use in human imaging. Furthermore, due to the blood-brain barrier, exogenous reference materials cannot effectively cross the blood-brain barrier to reach the brain, making the feasibility of using paramagnetic chelates for brain temperature measurement unclear. These chelating agents still have issues with biosafety and biostability, and are currently only used for drug development and animal testing.

[0004] In conclusion, developing accurate and non-invasive in vivo tissue temperature measurement technology remains one of the urgent problems to be solved. Summary of the Invention

[0005] To address the current lack of non-invasive, sensitive, and high spatial resolution in vivo biological tissue temperature measurement technology, this invention provides a temperature measurement method and device based on phosphocreatine chemical exchange saturation transfer imaging, aiming to provide an accurate and non-invasive in vivo tissue temperature measurement technology.

[0006] To achieve this objective, the present invention adopts the following technical solution:

[0007] In a first aspect, the present invention provides the application of creatine phosphate in chemical exchange saturation transfer imaging thermometry, wherein creatine phosphate is used as an internal reference to construct temperature relationship curves.

[0008] In this invention, phosphocreatine (PCr, molecular formula C4H) is analyzed in detail. 10The response of N3O5P (Chemical exchange saturation transfer, CEST) to absolute temperature was studied, revealing a strong mathematical correlation between the apparent chemical shift of the amino hydrogen proton of creatine phosphate and temperature. This allows creatine phosphate to be used as an endogenous reference for CEST temperature imaging, enabling the development of an absolute temperature imaging technique based on the CEST effect and temperature dependence of endogenous creatine phosphate. This technique offers advantages such as high spatial resolution, high sensitivity, non-invasiveness, and repeatability, and shows promising prospects for clinical translation and widespread application.

[0009] Secondly, the present invention provides a temperature measurement method based on phosphocreatine chemical exchange saturation transfer imaging, the method comprising the following steps:

[0010] (1) Perform chemical exchange saturation transfer imaging on phosphocreatine phantoms at different temperatures and calculate the apparent chemical shift of phosphocreatine in the phosphocreatine phantoms at different temperatures.

[0011] (2) Fit the mathematical relationship between the apparent chemical shift of phosphocreatine and the temperature of the phosphocreatine phantom;

[0012] (3) Perform chemical exchange saturation transfer imaging on phosphocreatine in the sample to be tested, calculate the apparent chemical shift of phosphocreatine in the sample to be tested, and calculate the temperature of the sample to be tested based on the mathematical relationship between the apparent chemical shift of phosphocreatine and the temperature of the creatine phantom fitted in step (3).

[0013] This invention designs an in vivo, absolute temperature measurement method based on the endogenous creatine phosphate CEST effect, which can be used not only for clinical applications, but also for basic research for non-disease diagnosis purposes, such as the spatiotemporal distribution of brain temperature, homeostasis mechanisms, and physiological significance.

[0014] It is understandable that the sample to be tested can be tissue containing creatine phosphate, such as muscle or brain.

[0015] Specifically, the method includes (1) performing chemical exchange saturation transfer imaging on phosphocreatine phantoms at different temperatures and calculating the apparent chemical shift of phosphocreatine in the phosphocreatine phantoms at different temperatures; (2) fitting the mathematical relationship between the apparent chemical shift of phosphocreatine and the temperature of the phosphocreatine phantoms; (3) performing in vivo chemical exchange saturation transfer imaging on the individual to be tested, calculating the apparent chemical shift of phosphocreatine in the individual to be tested, and generating a temperature map of the biological tissue of the individual to be tested based on the mathematical relationship between the apparent chemical shift of phosphocreatine and the temperature of the phosphocreatine phantoms fitted in step (2).

[0016] Preferably, the raw materials for preparing the phosphocreatine mummy include phosphocreatine, phosphate buffer, and water.

[0017] Preferably, the concentration of creatine phosphate in the creatine phosphate mummy is 5 to 80 mmol / L, including but not limited to 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 65, 70, 75, 76, 77, 78 or 79 mmol / L.

[0018] Preferably, the pH of the phosphocreatine methane is 6.7 to 7.3, including but not limited to 6.8, 6.9, 7, 7.0, 7.1 or 7.2.

[0019] Preferably, the different temperatures mentioned in step (1) are 10 to 45°C, including but not limited to 11, 12, 13, 15, 16, 18, 20, 22, 24, 26, 28, 30, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 or 44°C.

[0020] Preferably, the method further includes the step of preparing creatine phosphate biomimetic.

[0021] Preferably, the method for preparing the creatine phosphate malignant includes:

[0022] Phosphocreatine, phosphate buffer, and deionized water were mixed and the pH was adjusted to obtain the phosphocreatine mummy.

[0023] Preferably, the chemical exchange saturation transfer imaging method includes using pre-saturated radio frequency combined with sequences such as fast spin echo or gradient echo for signal excitation and acquisition.

[0024] Preferably, the pre-saturated radio frequency is biased relative to the water-hydrogen proton resonance frequency in the range of -5.0ppm to +5.0ppm.

[0025] Preferably, the frequency interval of the signal excitation and acquisition scheme near the creatine phosphate CEST peak is less than or equal to 0.05 ppm.

[0026] Preferably, the apparent chemical shift of creatine phosphate includes the chemical shift of the amino hydrogen proton of creatine phosphate relative to the resonance frequency of the hydrogen proton of water.

[0027] Preferably, the formula for calculating the apparent chemical shift of phosphocreatine is shown in equation (1).

[0028]

[0029] Among them, S sat (Δω) / S0 is the attenuation ratio of the water-hydrogen proton signal under pre-saturated radio frequency with a bias frequency of Δω, where Δω is the frequency shift relative to the water-hydrogen proton resonance frequency, and A i ω i and σi represents the amplitude, resonant frequency shift, and linewidth of the CEST peak of the i-th exchangeable hydrogen proton cell, respectively, and N represents the total number of exchangeable proton cells.

[0030] As a preferred technical solution, the temperature measurement method based on phosphocreatine chemical exchange saturation transfer imaging includes the following steps:

[0031] (1) Mix phosphocreatine, phosphate buffer and deionized water, adjust the pH to 6.7-7.3 and the creatine concentration to 5-80 mmol / L to obtain phosphocreatine mummy;

[0032] (2) Chemical exchange saturation transfer imaging of the phosphocreatine phantom at different temperatures. The specific parameters can be adjusted according to different imaging platforms. For example, the specific parameters of a 5.0T magnetic resonance imaging platform can be: the pre-saturation radio frequency is selected as a continuous wave with a duration of 3000 to 5000 milliseconds and B1 is 0.3 to 0.6 μT. The signal is acquired by combining the fast spin echo sequence. The imaging is performed at intervals within the range of -5ppm to +5ppm offset of the pre-saturation radio frequency relative to the water hydrogen proton resonance frequency. The frequency interval near the phosphocreatine CEST peak is less than or equal to 0.05ppm. The apparent chemical shift of phosphocreatine in the phosphocreatine phantom is calculated based on Equation (1).

[0033] (3) Fit the mathematical relationship between the apparent chemical shift of phosphocreatine and the temperature of the phosphocreatine phantom;

[0034] (4) Perform chemical exchange saturation transfer imaging on phosphocreatine in the sample to be tested, calculate the apparent chemical shift of phosphocreatine in the sample to be tested, and calculate the temperature of the sample to be tested based on the mathematical relationship between the apparent chemical shift of phosphocreatine and the temperature of the phosphocreatine phantom fitted in step (3).

[0035] Thirdly, the present invention provides a temperature measuring device based on phosphocreatine chemical exchange saturation transfer imaging, the temperature measuring device being used to perform the steps of the temperature measuring method based on phosphocreatine chemical exchange saturation transfer imaging described in the second aspect; the temperature measuring device includes a phosphocreatine biomimetic simulation unit, a fitting unit, and an in vivo testing unit.

[0036] The creatine phosphate biomimetic simulation unit is used to perform the following:

[0037] Chemical exchange saturation transfer imaging was performed on phosphocreatine phantoms at different temperatures to calculate the apparent chemical shift of phosphocreatine in the phantoms at different temperatures.

[0038] The fitting unit is used to perform the following:

[0039] The mathematical relationship between the apparent chemical shift of phosphocreatine and the temperature of the phosphocreatine phantom was fitted.

[0040] The in vivo testing unit is used to perform the following:

[0041] In vivo phosphocreatine chemical exchange saturation transfer imaging is performed on the test individual to calculate the apparent chemical shift of phosphocreatine in the biological tissue of the test individual, and a temperature map of the biological tissue of the test individual is generated based on the mathematical relationship between the apparent chemical shift of phosphocreatine and the temperature of the phosphocreatine phantom fitted by the fitting unit.

[0042] Preferably, the temperature measuring device further includes a creatine biomimetic preparation unit for performing the following:

[0043] Phosphocreatine, phosphate buffer, and deionized water were mixed and the pH was adjusted to obtain phosphocreatine mummy.

[0044] Preferably, the chemical exchange saturation transfer imaging method includes using pre-saturated radio frequency combined with sequences such as fast spin echo or gradient echo for signal excitation and acquisition.

[0045] Preferably, the pre-saturated radio frequency is biased relative to the water-hydrogen proton resonance frequency in the range of -5.0ppm to +5.0ppm.

[0046] Preferably, the frequency interval of the signal excitation and acquisition scheme near the creatine phosphate CEST peak is less than or equal to 0.05 ppm.

[0047] Preferably, the apparent chemical shift of creatine phosphate includes the chemical shift of the amino hydrogen proton of creatine phosphate relative to the resonance frequency of the hydrogen proton of water.

[0048] Preferably, the chemical shift of phosphocreatine is calculated using the formula (1) shown above.

[0049] Compared with the prior art, the present invention has at least the following beneficial effects:

[0050] This invention deeply analyzes the response of the saturation transfer effect of phosphocreatine chemical exchange to absolute temperature, and discovers that the apparent chemical shift of the amino hydrogen proton of phosphocreatine has a high mathematical correlation with temperature. Therefore, phosphocreatine can be used as an endogenous reference for CEST temperature imaging to develop an absolute temperature imaging technology based on the CEST effect of endogenous phosphocreatine and its temperature dependence. This technology has advantages such as high spatial resolution, high sensitivity, non-invasiveness, and repeatability, as well as good prospects for clinical translation and promotion. Attached Figure Description

[0051] Figure 1 This is a technical roadmap for temperature measurement methods;

[0052] Figure 2 Z-spectrum images of creatine phosphate phantoms obtained by CEST imaging at different temperatures;

[0053] Figure 3 This is a graph showing the mathematical relationship between the apparent chemical shift of phosphocreatine and temperature.

[0054] Figure 4 The temperature map of the generated creatine phosphate biomimetic is based on the temperature response relationship of PCr-CEST.

[0055] Figure 5A A structural image of the lower leg of a healthy subject;

[0056] Figure 5B PCr-CEST apparent chemical shift plot;

[0057] Figure 5C A temperature map of leg muscle tissue generated based on the PCr-CEST temperature response relationship. Detailed Implementation

[0058] The technical solution of the present invention will be further described below with reference to the accompanying drawings and specific embodiments. However, the following examples are merely simplified examples of the present invention and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention is determined by the claims.

[0059] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased from legitimate channels.

[0060] Temperature is a crucial indicator of physiological and pathological changes in organisms. Accurately quantifying the temperature and distribution of biological tissues is of significant scientific importance for inferring metabolic levels, blood flow regulation, and other physiological homeostasis, as well as disease treatment responses. Currently, non-invasive, sensitive, and high spatial resolution in vivo biological tissue thermometry techniques are lacking, especially for the brain, located in the closed bony cranial cavity, where the spatiotemporal distribution, homeostatic mechanisms, and physiological significance of temperature remain poorly understood. This invention analyzes the response of creatine phosphate chemical exchange saturation transfer effect to absolute temperature, and based on this analysis, realizes a non-invasive, absolute temperature mapping technique based on creatine phosphate CEST imaging.

[0061] Specifically, this invention designs an in vivo, absolute temperature measurement method based on the endogenous creatine phosphate CEST effect, combined with magnetic resonance imaging technology, to achieve high-resolution analysis of biological tissue temperature and generate temperature spectra. The technology roadmap is as follows: Figure 1 As shown, it mainly consists of four parts: creatine phosphate phantom preparation, in vitro PCr-CEST imaging, PCr-CEST and temperature relationship fitting, and in vivo PCr-CEST experiment.

[0062] Creatine phosphate mummy preparation: Creatine phosphate mummy at different concentrations was prepared using creatine phosphate, PBS phosphate buffer, and deionized water. The target pH value was set by adding sodium hydroxide solution or hydrochloric acid solution. After stirring evenly, the mixture was placed in a plastic container and allowed to cool naturally.

[0063] In vitro PCr-CEST imaging: The constant temperature water bath was set to the target temperature. Phantoms with different pH values ​​and creatine phosphate concentrations were placed in the water bath, and a fiber optic temperature probe was inserted to monitor and record the real-time temperature of the phantoms. CEST scanning began after the phantom temperature stabilized. First, without applying pre-saturated radio frequency, a reference CEST image was generated based on a fast spin echo sequence, and the signal intensity of the voxel was denoted as S0. Then, a pre-saturated radio frequency excitation signal with a bias frequency of Δω was used, and the signal was read out using a fast spin echo sequence, with the signal intensity denoted as S. sat (Δω). By changing the bias frequency of the pre-saturated radio frequency, the above process is repeated for multiple imaging operations, ultimately yielding a series of CEST images, S sat (Δω) / S0 represents the attenuation ratio of the water-hydrogen proton signal under pre-saturated radio frequency (RF) with a bias frequency of Δω, defined as the z-spectrum. When the RF frequency equals the resonant frequency of the water-hydrogen protons, all water-hydrogen protons are saturated, and the acquired signal approaches zero. As the bias frequency increases, the saturated water signal gradually decreases, while the imaging signal gradually increases. When the bias frequency is exactly the resonant frequency of the amino hydrogen proton of creatine phosphate, the amino hydrogen proton of creatine phosphate is excited and saturated, undergoing chemical exchange with the water-hydrogen protons. After repeated saturation and exchange processes, the signal intensity of the water-hydrogen protons at this saturation frequency will show a significant decrease.

[0064] The apparent chemical shift of the PCr amino hydrogen proton was calculated based on the Z-spectrum fitted using the multi-pool Lorentz model:

[0065]

[0066] Where Δω is the frequency shift relative to the water hydrogen proton resonance frequency, A i ω i and σ i represents the amplitude, resonant frequency shift, and linewidth of the CEST peak of the i-th exchangeable hydrogen proton cell, respectively, and N represents the total number of exchangeable proton cells.

[0067] Change the temperature of the constant temperature water bath, and repeat the above process after the temperature of the phantom stabilizes. Record the apparent chemical shift of the amino hydrogen proton of creatine phosphate measured at different temperatures.

[0068] PCr-CEST and Temperature Relationship Fitting: Based on the apparent chemical shift of creatine phosphate amino hydrogen protons measured at different temperatures and the actual phantom temperature recorded by the fiber optic temperature probe, a mathematical relationship between the apparent chemical shift of PCr and temperature was fitted. The above process was repeated by changing the concentration of the creatine phosphate phantom and the pH value, and the PCr-CEST and temperature relationship was refitted to evaluate the repeatability and stability of the PCr-CEST and temperature relationship.

[0069] In vivo PCr-CEST experiment: Using a magnetic resonance imaging sequence optimized and tested in vitro PCr-CEST experiments, PCr-CEST imaging scans of the human lower leg were performed. Based on the mathematical relationship between PCr apparent chemical shift and temperature, the PCr-CEST images were converted into temperature images. Human body temperature was measured and recorded during the experiment as the gold standard to verify and correct the accuracy of the PCr-CEST temperature imaging results.

[0070] Example 1

[0071] This embodiment provides a temperature measurement method.

[0072] 1. Creatine phosphate mummy preparation

[0073] The phosphocreatine reagent used (C4H) 10 Prepare a solution with pH 7.0 and creatine phosphate concentration of 80 mmol / L using N3O5P (Sigma Aldrich), PBS phosphate buffer, and deionized water. Stir well and place in a plastic test tube to cool naturally.

[0074] 2. In vitro PCr-CEST experiment

[0075] A constant-temperature water bath was used to set the temperature to 38℃ (close to the temperature of the human brain). The prepared creatine phosphate phantom was placed in the water bath, and after the temperature stabilized, CEST imaging was performed (United Imaging Jupiter 5.0T, 48-channel head and neck combined coil). The CEST sequence consists of two parts: a pre-saturated radio frequency module and a fast spin echo image acquisition module. Continuous wave was used as the pre-saturation method, with a saturation time of 4000 ms and B1 set to 0.6 μT. The main parameters of the fast spin echo image acquisition sequence were: TR / TE of 5000 / 7.12 ms, echo train length of 30, voxel size of 1.4 mm × 1.4 mm, slice thickness of 8.0 mm, and FA of 110°. Signal excitation and acquisition were performed within the range of -5.0 ppm to +5.0 ppm offset from the water-hydrogen proton resonance frequency of the pre-saturated radio frequency, with a frequency interval of 0.05 ppm. PCr-CEST imaging was performed at three temperatures: 19.8℃, 34.5℃, and 37.9℃.

[0076] First, without applying pre-saturated radio frequency (RF), a reference CEST image is generated based on a fast spin echo sequence scan, with the signal intensity denoted as S0. Then, a pre-saturated RF excitation signal with a bias frequency of Δω is used, and the signal is read out using a fast spin echo sequence, with the signal intensity denoted as S. sat (Δω). By changing the bias frequency of the pre-saturated radio frequency and repeating the above process, a series of CEST images are finally obtained, with the signal ratio S. sat (Δω) / S0 is the signal attenuation ratio under pre-saturated radio frequency with a bias frequency of Δω. After correction for main magnetic field inhomogeneity, the Z-spectrum is generated. Figure 2 The apparent chemical shift of the amino hydrogen proton of creatine phosphate at this temperature was calculated by fitting the Z-spectrum using a multi-pool Lorentz model.

[0077]

[0078] The constant temperature water bath was adjusted to 19.8℃, 34.5℃, and 37.9℃ in sequence. The apparent chemical shifts of the amino protons of creatine phosphate at the three temperatures were calculated to be 2.53 ppm, 2.60 ppm, and 2.62 ppm, respectively.

[0079] 3. Fitting the relationship between PCr-CEST and temperature

[0080] The apparent chemical shift of the amino proton of creatine phosphate, as measured above, was linearly fitted with temperature using SPSS 19.0. Figure 3 The mathematical relationship is:

[0081] T(℃)=196.08×Δω-475.78(R 2 =0.99, p<0.001)

[0082] Where Δω represents the chemical shift (ppm) of the amino proton of phosphocreatine relative to the hydrogen proton of water.

[0083] Figure 4 Based on the temperature response relationship of the above-mentioned creatine phosphate CEST effect, temperature maps of creatine phosphate phantoms at different temperatures were generated, and the fitted temperatures are close to the actual experimental temperatures.

[0084] Similar results can be obtained by preparing phosphocreatine biomimetics with different concentrations and pH values ​​(5 mmol / L (pH 7.0), 20 mmol / L (pH 6.7), 40 mmol / L (pH 7.3), and 60 mmol / L (pH 7.0)) using the same method described above.

[0085] The above phosphocreatine phantom experiment established the correlation between PCr-CEST and temperature, confirming the feasibility of PCr-CEST temperature measurement.

[0086] Example 2

[0087] This embodiment conducts an in vivo PCr-CEST experiment.

[0088] PCr-CEST imaging (United Imaging Jupiter 5.0T, 24-channel transceiver knee coil) was performed on the lower legs of healthy volunteers. T2-weighted structural images of the lower legs are shown below. Figure 5A As shown, the volunteer's leg surface temperature was measured to be 36.1℃ using a forehead thermometer. The CEST sequence consists of two parts: a pre-saturated radio frequency module and a fast spin echo image acquisition module. Continuous wave was used as the pre-saturation method, with a saturation time of 2000 ms and B1 set to 0.6 μT. The main parameters of the fast spin echo image acquisition sequence were: TR / TE of 5000 / 6.96 ms, echo train length of 30, voxel size of 1.6 mm × 1.6 mm, slice thickness of 10.0 mm, and FA of 110°. Signal excitation and acquisition were performed within the range of -5.0 ppm to +5.0 ppm offset from the water-hydrogen proton resonance frequency of the pre-saturated radio frequency, with a frequency interval set to 0.05 ppm.

[0089] First, without applying pre-saturated radio frequency (RF), a reference CEST image is generated based on a fast spin echo sequence scan, with the signal intensity denoted as S0. Then, a pre-saturated RF excitation signal with a bias frequency of Δω is used, and the signal is read out using a fast spin echo sequence, with the signal intensity denoted as S. sat (Δω). By changing the bias frequency of the pre-saturated radio frequency and repeating the above process, a series of CEST images are finally obtained, with the signal ratio S. sat (Δω) / S0 represents the signal attenuation ratio under pre-saturated radio frequency with a bias frequency of Δω. After correction for main magnetic field inhomogeneity, the Z-spectrum is fitted using a multi-cell Lorentz model to calculate the apparent chemical shift map of phosphocreatine amino hydrogen protons in leg muscle tissue. Figure 5B Finally, based on the linear relationship between the apparent chemical shift of the amino hydrogen proton of creatine phosphate obtained in Example 1 and temperature, a temperature map of the leg muscles of healthy volunteers was generated. Figure 5C The calf temperature map measured by PCr-CEST is close to the actual body temperature and has a reasonable distribution.

[0090] In summary, this invention provides an in-depth analysis of the response of the saturation transfer effect of phosphocreatine chemical exchange to absolute temperature. It reveals a highly correlated mathematical relationship between the apparent chemical shift of the amino hydrogen proton of phosphocreatine and temperature. Consequently, phosphocreatine can be used as an endogenous reference for CEST temperature imaging. This allows for the development of an absolute temperature imaging technique based on the CEST effect of endogenous phosphocreatine and its temperature dependence. This technique offers advantages such as high spatial resolution, high sensitivity, non-invasiveness, and repeatability, and has promising prospects for clinical translation and widespread application.

[0091] The applicant declares that the above description is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention fall within the protection and disclosure scope of the present invention.

Claims

1. The application of creatine phosphate in chemical exchange saturation transfer imaging thermometry, characterized in that, The phosphocreatine was used as an internal reference to construct temperature relationship curves.

2. A temperature measurement method based on phosphocreatine chemical exchange saturation transfer imaging, characterized in that, The method includes the following steps: (1) Perform chemical exchange saturation transfer imaging on phosphocreatine phantoms at different temperatures and calculate the apparent chemical shift of phosphocreatine in the phosphocreatine phantoms at different temperatures. (2) Fit the mathematical relationship between the apparent chemical shift of phosphocreatine and the temperature of the phosphocreatine phantom; (3) Perform chemical exchange saturation transfer imaging on phosphocreatine in the sample to be tested, calculate the apparent chemical shift of phosphocreatine in the sample to be tested, and calculate the temperature of the sample to be tested based on the mathematical relationship between the apparent chemical shift of phosphocreatine and the temperature of the phosphocreatine phantom fitted in step (2).

3. The temperature measurement method based on phosphocreatine chemical exchange saturation transfer imaging according to claim 2, characterized in that, The raw materials for preparing the phosphocreatine mummy include phosphocreatine, phosphate buffer, and water. Preferably, the concentration of creatine phosphate in the creatine phosphate mummy is 5–80 mmol / L; Preferably, the pH of the phosphocreatine mimic is 6.7–7.3; Preferably, the different temperatures in step (1) are 10 to 45°C.

4. The temperature measurement method based on phosphocreatine chemical exchange saturation transfer imaging according to claim 2 or 3, characterized in that, The method also includes the step of preparing creatine phosphate biomimetic; Preferably, the method for preparing the creatine phosphate malignant includes: Phosphocreatine, phosphate buffer, and deionized water were mixed and the pH was adjusted to obtain the phosphocreatine mummy.

5. The temperature measurement method based on phosphocreatine chemical exchange saturation transfer imaging according to any one of claims 2-4, characterized in that, The chemical exchange saturation transfer imaging method includes using pre-saturated radio frequency combined with sequences such as fast spin echo or gradient echo for signal excitation and acquisition. Preferably, the pre-saturated radio frequency is biased relative to the water-hydrogen proton resonance frequency in the range of -5.0 ppm to +5.0 ppm; Preferably, the frequency interval of the signal excitation and acquisition scheme near the creatine phosphate CEST peak is less than or equal to 0.05 ppm; Preferably, the apparent chemical shift of creatine phosphate includes the chemical shift of the amino hydrogen proton of creatine phosphate relative to the resonance frequency of the hydrogen proton of water. Preferably, the formula for calculating the apparent chemical shift of phosphocreatine is shown in equation (1); Among them, S sat (Δω) / S0 is the attenuation ratio of the water-hydrogen proton signal under pre-saturated radio frequency with a bias frequency of Δω, where Δω is the frequency shift relative to the water-hydrogen proton resonance frequency, and A i ω i and σ i represents the amplitude, resonant frequency shift, and linewidth of the chemical exchange saturation transfer imaging peak of the i-th exchangeable hydrogen proton cell, respectively, and N represents the total number of exchangeable proton cells.

6. The temperature measurement method based on phosphocreatine chemical exchange saturation transfer imaging according to any one of claims 2-5, characterized in that, The method includes the following steps: (1) Mix phosphocreatine, phosphate buffer and deionized water, adjust the pH to 6.7-7.3 and the creatine concentration to 5-80 mmol / L to obtain phosphocreatine mummy; (2) Chemical exchange saturation transfer imaging of the phosphocreatine phantom at different temperatures is performed. Signal excitation and acquisition are performed using pre-saturated radio frequency combined with fast spin echo or gradient echo sequences. The imaging is performed at intervals within the range of -5ppm to +5ppm offset of the pre-saturated radio frequency relative to the water hydrogen proton resonance frequency. The frequency interval near the phosphocreatine CEST peak is less than or equal to 0.05ppm. The apparent chemical shift of phosphocreatine in the phosphocreatine phantom is calculated based on Equation (1). (3) Fit the mathematical relationship between the apparent chemical shift of phosphocreatine and the temperature of the phosphocreatine phantom; (4) Perform chemical exchange saturation transfer imaging on phosphocreatine in the sample to be tested, calculate the apparent chemical shift of phosphocreatine in the sample to be tested, and calculate the temperature of the sample to be tested based on the mathematical relationship between the apparent chemical shift of phosphocreatine and the temperature of the phosphocreatine phantom fitted in step (3).

7. A temperature measuring device based on phosphocreatine chemical exchange saturation transfer imaging, characterized in that, The temperature measuring device is used to perform the steps of the temperature measuring method based on phosphocreatine chemical exchange saturation transfer imaging as described in any one of claims 2-6; The temperature measuring device includes a creatine phosphate biomimetic simulation unit, a fitting unit, and an in vivo testing unit. The creatine phosphate biomimetic simulation unit is used to perform the following: Chemical exchange saturation transfer imaging was performed on phosphocreatine phantoms at different temperatures to calculate the apparent chemical shift of phosphocreatine in the phantoms at different temperatures. The fitting unit is used to perform the following: The mathematical relationship between the apparent chemical shift of phosphocreatine and the temperature of the phosphocreatine phantom was fitted. The in vivo testing unit is used to perform the following: In vivo phosphocreatine chemical exchange saturation transfer imaging is performed on the individual to be tested. The apparent chemical shift of phosphocreatine in the individual's biological tissue is calculated. Based on the mathematical relationship between the apparent chemical shift of phosphocreatine and the temperature of the phosphocreatine phantom fitted by the fitting unit, a temperature map of the biological tissue of the individual to be tested is generated.

8. The temperature measuring device according to claim 7, characterized in that, The temperature measuring device also includes a creatine biomimetic preparation unit for performing the following: Phosphocreatine, phosphate buffer, and deionized water were mixed and the pH was adjusted to obtain phosphocreatine mummy.

9. The temperature measuring device according to claim 7 or 8, characterized in that, The chemical exchange saturation transfer imaging method includes using pre-saturated radio frequency combined with fast spin echo or gradient echo sequences for signal excitation and acquisition. Preferably, the pre-saturated radio frequency is biased relative to the water-hydrogen proton resonance frequency in the range of -5.0 ppm to +5.0 ppm; Preferably, the frequency interval of the signal excitation and acquisition scheme near the creatine phosphate CEST peak is less than or equal to 0.05 ppm.

10. The temperature measuring device according to any one of claims 7-9, characterized in that, The apparent chemical shift of creatine phosphate includes the chemical shift of the amino hydrogen proton of creatine phosphate relative to the resonance frequency of the hydrogen proton of water.

Images