WO2022242214A1 - 一种基于肌酸化学交换饱和转移成像的测温方法及装置 - Google Patents

一种基于肌酸化学交换饱和转移成像的测温方法及装置 Download PDF

Info

Publication number
WO2022242214A1
WO2022242214A1 PCT/CN2022/072719 CN2022072719W WO2022242214A1 WO 2022242214 A1 WO2022242214 A1 WO 2022242214A1 CN 2022072719 W CN2022072719 W CN 2022072719W WO 2022242214 A1 WO2022242214 A1 WO 2022242214A1
Authority
WO
WIPO (PCT)
Prior art keywords
creatine
mimic
temperature
water
relative
Prior art date
Application number
PCT/CN2022/072719
Other languages
English (en)
French (fr)
Inventor
张丽娟
邹超
蔡思琦
周诗辉
周洋
郑海荣
刘新
Original Assignee
深圳先进技术研究院
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 深圳先进技术研究院 filed Critical 深圳先进技术研究院
Publication of WO2022242214A1 publication Critical patent/WO2022242214A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/01—Measuring temperature of body parts ; Diagnostic temperature sensing, e.g. for malignant or inflamed tissue
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01K—MEASURING TEMPERATURE; MEASURING QUANTITY OF HEAT; THERMALLY-SENSITIVE ELEMENTS NOT OTHERWISE PROVIDED FOR
    • G01K11/00—Measuring temperature based upon physical or chemical changes not covered by groups G01K3/00, G01K5/00, G01K7/00 or G01K9/00

Definitions

  • the application belongs to the technical field of non-invasive temperature measurement, and relates to a temperature measurement method and device based on creatine chemical exchange saturation transfer imaging.
  • Brain tissue temperature can fluctuate with neural activity and brain metabolism, and is regulated and affected by body temperature through blood circulation. Most physical and chemical reactions in the process of brain neuron activity are temperature sensitive. Many diseases (such as brain trauma, stroke, tumor, multiple sclerosis and epilepsy, etc.) will destroy the homeostasis of brain temperature, resulting in abnormal local brain temperature, brain temperature The spatial distribution pattern changes, and causes a series of reactions such as abnormal cell metabolism, secondary neuron damage, blood vessel and blood-brain barrier damage. Therefore, non-invasive absolute temperature imaging technology is of great significance for exploring the mechanism of brain temperature regulation under physiological and pathological conditions and in-depth exploration of the complex pathological mechanism of brain injury.
  • the magnetic resonance thermometry method is mainly based on the temperature dependence of magnetic resonance parameters such as proton density, T1 and T2 relaxation time, diffusion coefficient, proton resonance frequency, and magnetization transfer.
  • magnetic resonance spectroscopy Magnetic resonance Spectroscopy (MRS) imaging technology measures the chemical shifts of reference macromolecular substances relative to water hydrogen protons at different temperatures, and establishes the relationship between chemical shifts and temperatures of reference substances by fitting, so as to realize the
  • MRS magnetic resonance spectroscopy
  • the current imaging resolution of this method is low, and temperature measurement is easily affected by motion and magnetic field drift
  • Measure the absolute temperature of tissues such as cerebrospinal fluid based on the relationship between the free diffusion coefficient of water molecules and temperature , but at present, this technology is only applicable to detect the temperature
  • This application provides a temperature measurement method and device based on creatine chemical exchange saturation transfer imaging.
  • the method is based on the relationship between the chemical exchange saturation transfer effect of creatine and temperature, combined with magnetic resonance imaging technology, to achieve high spatial resolution High-rate, highly sensitive, non-invasive absolute temperature measurement.
  • the present application provides a temperature measurement method based on creatine chemical exchange saturation transfer imaging, the method comprising the following steps:
  • step (2) fitting the mathematical relationship between the chemical shift of creatine relative to water and the creatine mimic body temperature; chemical shift, and calculate the sample temperature according to the mathematical relationship between the chemical shift of creatine relative to water and the temperature of creatine analog in step (2).
  • creatine (Cr) as an important energy metabolite, has a stable concentration in the brain, and the creatine chemical exchange saturation transfer effect (Cr-CEST) is insensitive to the influence of non-temperature environmental factors such as pH , and its CEST exchange rate is about 7-8 times that of phosphocreatin (PCr) under physiological temperature and pH conditions. Temperature dependence for high spatial resolution, high sensitivity, non-invasive absolute temperature measurements.
  • thermometry method based on creatine chemical exchange saturation transfer imaging of the present application can be used for non-disease diagnosis or treatment purposes, or for scientific research.
  • the raw materials for the preparation of the creatine mimic include creatine, agar powder, phosphate buffer and deionized water.
  • the addition of agar powder can increase the strength of creatine mimics and avoid artifacts caused by heat conduction during detection.
  • the concentration of creatine in the creatine mimic is 10-120 mmol/L, including but not limited to 11 mmol/L, 12 mmol/L, 13 mmol/L, 15 mmol/L, 20 mmol/L, 30 mmol/L, 40mmol/L, 50mmol/L, 60mmol/L, 70mmol/L, 80mmol/L, 90mmol/L, 100mmol/L, 105mmol/L, 110mmol/L, 112mmol/L, 115mmol/L, 118mmol/L or 119mmol/L L.
  • said creatine has a reagent purity greater than 98%.
  • the pH of the creatine mimic is 6.0-7.2, including but not limited to 6.1, 6.2, 6.3, .6.4, 6.6, 6.7, 6.8, 6.9 or 7.1.
  • the temperature range of the creatine mimic is 10-43°C, including but not limited to 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C , 20°C, 25°C, 30°C, 35°C, 36°C, 37°C, 38°C or 39°C.
  • thermometry based on creatine chemical exchange saturation transfer imaging further includes the step of preparing creatine mimics.
  • the preparation method of the creatine mimic comprises:
  • Creatine, agar powder, phosphate buffer and deionized water are mixed and heated to adjust the pH to obtain the creatine mimic.
  • the creatine, agar powder, phosphate buffer and deionized water are prepared into different concentration of creatine mimic body mixture, and by dropping sodium hydroxide solution or hydrochloric acid solution to adjust the pH value, the prepared mixture is heated until the agar powder is completely dissolved, stirred evenly and placed in a plastic container to cool naturally.
  • step (1) chemical exchange saturation transfer imaging is performed on the creatine mimic, the constant temperature water bath device is set to a specific temperature, and the prepared creatine mimic with different pH values and creatine concentrations is placed in the water bath , and insert an optical fiber temperature probe to monitor and record the real-time temperature of the creatine phantom. After the phantom temperature is stable, start CEST scanning.
  • the saturation effect is through the dynamic exchange of the amino hydrogen protons of creatine and the water hydrogen protons, so that the water hydrogen protons are also saturated, resulting in the water hydrogen protons MRI signal decreased.
  • the pre-saturation excitation pulse frequency is equal to the water-hydrogen proton resonance frequency, all the water-hydrogen protons are saturated, and the signal acquisition tends to zero.
  • the bias frequency increases, the saturated water signal decreases gradually, while the magnetic resonance signal increases gradually.
  • the bias frequency is exactly the excitation frequency of amino hydrogen protons of creatine, the amino hydrogen protons of creatine are saturated and exchanged with water hydrogen protons, and the signal intensity corresponding to this frequency has a downward trend.
  • ⁇ represents the chemical shift (ppm) of creatine amino hydrogen proton relative to water
  • the formula R2 is 0.893
  • the p value is less than 0.001.
  • the z-spectra of water hydrogen protons and amino hydrogen protons of creatine can be fitted according to the method of multi-pool Lorentzian fitting (Multi-pool Lorentzian Fitting), as shown in formula (3), to improve the calculation of creatine amino Accuracy of hydrogen proton chemical shifts.
  • a i , ⁇ i and ⁇ i represent the amplitude, chemical shift and linewidth of the z-spectrum of the i-th proton pool, respectively, and N represents the total number of proton pools.
  • ⁇ represents the chemical shift (ppm) of creatine amino hydrogen proton relative to water
  • the formula R2 is 0.956
  • the p value is less than 0.001
  • the fitting accuracy of this formula is higher.
  • the method of chemical exchange saturation transfer imaging includes using a pre-saturation excitation pulse combined with a spin echo-echo-planar sequence or a gradient echo sequence for signal acquisition, and performing interval imaging.
  • the pre-saturation excitation pulse includes 10 rectangular pulses.
  • the manner of interval imaging includes interval imaging in the range of -3.0ppm to +3.0ppm when the frequency of the pre-saturation excitation pulse is offset relative to the hydrogen proton resonance frequency of water, and the number of intervals is greater than 200 times.
  • thermometry method based on creatine chemical exchange saturation transfer imaging is shown in Figure 1, specifically including the following steps:
  • the CEST sequence consists of a pre-saturation excitation pulse and an image signal acquisition sequence.
  • the range of bias -3.0ppm to +3.0ppm is interval imaging, and the number of intervals is more than 200 times.
  • a sequence of excitation pulses without pre-saturation is used to scan a picture as a reference.
  • the signal intensity is recorded as S 0 , and then a series of different biases are used.
  • a series of images are obtained by scanning the pre-saturation excitation pulse sequence with the frequency ⁇ , the signal intensity is recorded as S sat ( ⁇ ), and the signal ratio S sat ( ⁇ )/S 0 is the pre-saturation excitation pulse with the bias frequency ⁇ .
  • the above process can be repeated using creatine mimics of different concentrations and pH values and the relationship between the chemical shift of creatine relative to water and temperature can be re-fitted to evaluate the reliability of the relationship between the chemical shift of creatine relative to water and temperature. Repeatability and stability not susceptible to other environmental factors; and
  • the present application provides a temperature measuring device based on creatine chemical exchange saturation transfer imaging
  • the temperature measuring device is used in the temperature measurement method based on creatine chemical exchange saturation transfer imaging described in the first aspect
  • the The temperature measuring device includes a creatine mimic test unit, a fitting unit and a sample test unit.
  • the creatine mimic test unit is used to perform chemical exchange saturation transfer imaging on the creatine mimic, and analyze the chemical shift of creatine relative to water in the creatine mimic
  • the fitting unit is used to fit the creatine Relative to the mathematical relationship between the chemical shift of water and the creatine mimic temperature
  • the sample test unit is used for chemical exchange saturation transfer imaging of creatine in the sample, and analyzes the chemical shift of creatine in the sample relative to water, and according to the The sample temperature is calculated from the mathematical relationship between the chemical shift of creatine relative to water fitted by the fitting unit and the creatine mimic temperature.
  • the temperature measuring device further includes a creatine mimic unit.
  • the creatine mimic unit is used to mix and heat creatine, agar powder, phosphate buffer and deionized water to adjust pH to obtain the creatine mimic.
  • the method of chemical exchange saturation transfer imaging in the creatine phantom test unit includes using pre-saturation excitation pulse combined with spin echo-echo-planar sequence or gradient echo sequence for signal acquisition, and performing interval imaging.
  • the pre-saturation excitation pulse includes 10 rectangular pulses.
  • the manner of interval imaging includes interval imaging in the range of -3.0ppm to +3.0ppm when the frequency of the pre-saturation excitation pulse is offset relative to the hydrogen proton resonance frequency of water, and the number of intervals is greater than 200 times.
  • the temperature measurement method based on creatine chemical exchange saturation transfer imaging of the present application uses creatine as an endogenous reference substance, and utilizes the temperature dependence of creatine and water CEST effect to perform high spatial resolution and high sensitivity , Non-invasive absolute temperature measurement, which can be applied to non-invasive and label-free brain temperature measurement;
  • the temperature measurement method based on creatine chemical exchange saturation transfer imaging of the present application has high stability and accuracy, simple operation, no radioactivity, and is conducive to popularization.
  • Figure 1 is a technical roadmap of the present application.
  • Fig. 4 is a graph showing the relationship between the chemical shift of creatine relative to water and the temperature measured based on the resonance frequency spectrum symmetry analysis.
  • Fig. 5 is the z-spectrum (z-spectra) of the CEST effect of creatine in porcine brain samples fitted at 28°C based on the multi-pool Lorentz method.
  • Fig. 6 is a graph showing the relationship between the chemical shift of creatine relative to water and temperature measured based on multi-cell Lorentzian fitting.
  • Embodiment 1 prepares creatine mimic body
  • a mixed solution with a creatine concentration of 100mmol/L heat the solution until the agar powder is completely dissolved, stir it evenly, place it in a plastic test tube and let it cool naturally to obtain a creatine mimic.
  • the CEST sequence consists of two parts: a pre-saturation excitation pulse and a spin echo-echo-planar imaging sequence.
  • Saturation excitation pulse frequency relative to water hydrogen proton resonance frequency offset -3.0ppm to +3.0ppm in the range of 0.03ppm for imaging the number of intervals is 200 times, first scan a picture with a sequence without pre-saturation excitation pulse as a reference , the signal intensity is recorded as S 0 , and then a series of images are obtained by scanning with a series of pre-saturation excitation pulse sequences with different bias frequencies ⁇ , as shown in Figure 2, the signal intensity is recorded as S sat ( ⁇ ), and the signal ratio S sat ( ⁇ )/S 0 is the signal attenuation under the action of a pre-saturation excitation pulse with a bias frequency of ⁇ , defined as the z-spectrum (z-spectra), as shown in Figure 3, the z-spectra is compared to the water hydrogen proton resonance
  • the frequency symmetric data S sat (+ ⁇ ) and S sat (- ⁇ ) are subtracted and divided by S sat (- ⁇ ), the result can character
  • the chemical shifts for water are 1.89ppm, 1.86ppm, 1.89ppm, 1.92ppm, 1.95ppm, 2.01ppm, 2.04ppm and 2.04ppm, respectively.
  • ⁇ represents the chemical shift (ppm) of creatine amino hydrogen proton relative to water
  • the formula R2 is 0.893
  • the p value is less than 0.001.
  • ⁇ represents the chemical shift (ppm) of creatine amino hydrogen proton relative to water
  • the formula R2 is 0.956
  • the p value is less than 0.001
  • the fitting accuracy of this formula is higher.
  • the temperature measurement method based on creatine chemical exchange saturation transfer imaging in this application uses creatine as an endogenous reference substance, and utilizes the temperature dependence of the CEST effect between creatine and water to perform high spatial resolution, high Sensitive, non-invasive absolute temperature measurement.
  • the present application illustrates the detailed method of the present application through the above-mentioned examples, but the present application is not limited to the above-mentioned detailed method, that is, it does not mean that the application must rely on the above-mentioned detailed method to be implemented.
  • Those skilled in the art should understand that any improvement to the present application, the equivalent replacement of each raw material of the product of the present application, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the present application.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Medical Informatics (AREA)
  • Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Pathology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Physics & Mathematics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Magnetic Resonance Imaging Apparatus (AREA)

Abstract

一种基于肌酸化学交换饱和转移成像的测温方法及装置，其中，该方法包括以下步骤：(1)对肌酸仿体进行肌酸化学交换饱和转移成像，分析肌酸仿体中肌酸相对于水的化学位移；(2)拟合该肌酸相对于水的化学位移和温度的数学关系；(3)对样本中肌酸进行化学交换饱和转移成像，并依据步骤(2)拟合的肌酸相对于水的化学位移和温度的数学关系计算温度。该测温方法以肌酸作为内源性参照物，利用Cr与水CEST效应的温度依赖性可实现高空间分辨率、高敏感性、无创的绝对温度测量。

Description

一种基于肌酸化学交换饱和转移成像的测温方法及装置 技术领域
本申请属于无创测温技术领域，涉及一种基于肌酸化学交换饱和转移成像的测温方法及装置。
背景技术
脑组织温度可随神经活动、脑代谢而发生波动，并通过血流循环受到体温的调节与影响，是表征物质代谢、组织灌注以及血管自我调节能力等组织生理特征的综合指征。大脑神经元活动过程中多数物理化学反应都具有温度敏感性，很多疾病(如脑创伤、中风、肿瘤、多发性硬化和癫痫等)都会破坏脑温内稳态，导致局部脑温异常、脑温空间分布模式改变，并引起细胞代谢异常、继发神经元损伤、血管及血脑屏障损伤等一系列反应。因此，无创绝对温度成像技术对探究生理及病理状态下的脑温调节机制以及深入探究脑损伤复杂病理机制具有重要意义。
磁共振测温方法主要基于质子密度、T1和T2弛豫时间、弥散系数、质子共振频率以及磁化转移等磁共振参数的温度依赖性，目前应用较为广泛的基于磁共振测量绝对温度的技术主要有：(1)利用水氢质子 1H的共振频率具有温度依赖性，而某些大分子物质的化学位移不易受到温度影响，例如乙酰-天门冬氨酸(NAA)，使用磁共振波谱(Magnetic resonance spectroscopy，MRS)成像技术测量不同温度下参考性大分子物质相对于水氢质子的化学位移，并拟合建立参考物质化学位移与温度的关系，从而实现基于质子共振频率(Proton resonance frequency，PRF)的无创测温，但是，目前该方法成像分辨率较低，且温度测量易受到运动以及磁场漂移的影响；(2)基于水分子自由扩散系数与温度之间的关系测量脑脊液等组织的绝对温度，但目前该技术仅可适用于检测纯水组织的温度，无法应用于水分子扩散受限的组织；(3)有研究通过注射顺磁性螯合物作为外源性参照物质，基于化学交换饱和转移(Chemical exchange saturation transfer，CEST)成像技术测量动物体内不同温度下螯合物的化学位移，并拟合得出其与温度的线性关系(参见：Zhang S,Malloy C R,AD Sherry.MRI thermometry based on PARACEST agents[J].Journal of the American Chemical  Society,2005,127(50):17572.)，但顺磁性螯合物的生物安全性有待考量，无法多次反复注射测温，不利于临床推广。
综上所述，提供一种准确且无创的脑部测温方法，对探究生理及病理状态下的脑温调节机制具有重要意义。
发明内容
本申请提供了一种基于肌酸化学交换饱和转移成像的测温方法及装置，所述方法基于肌酸的化学交换饱和传递效应与温度的关系，并结合磁共振成像技术，实现了高空间分辨率、高敏感性、无创的绝对温度测量。
第一方面，本申请提供一种基于肌酸化学交换饱和转移成像的测温方法，所述方法包括以下步骤：
(1)对肌酸仿体进行化学交换饱和转移成像，分析肌酸仿体中肌酸相对于水的化学位移；
(2)拟合所述肌酸相对于水的化学位移和肌酸仿体温度的数学关系；以及(3)对样本中肌酸进行化学交换饱和转移成像，分析样本中肌酸相对于水的化学位移，并依据步骤(2)拟合的肌酸相对于水的化学位移和肌酸仿体温度的数学关系计算样本温度。
本申请中，肌酸(Creatine，Cr)，作为重要能量代谢物，其在脑内浓度稳定，且肌酸化学交换饱和转移效应(Cr-CEST)对pH等非温度的环境因素的影响不敏感，而且在生理温度和pH条件下其CEST交换速率约为磷酸激酸(Phosphocreatin，PCr)的7-8倍，因此本申请以肌酸作为内源性参照物，利用肌酸与水CEST效应的温度依赖性，进行高空间分辨率、高敏感性、无创的绝对温度测量。
本申请的基于肌酸化学交换饱和转移成像的测温方法可用于非疾病诊断或治疗目的，或用于科学研究。
优选地，所述肌酸仿体的制备原料包括肌酸、琼脂粉、磷酸盐缓冲液和去离子水。
本申请中，琼脂粉的加入可提高肌酸仿体强度，避免检测中因热传导而引起伪影。
优选地，所述肌酸仿体中肌酸的浓度为10～120mmol/L，包括但不限于11 mmol/L、12mmol/L、13mmol/L、15mmol/L、20mmol/L、30mmol/L、40mmol/L、50mmol/L、60mmol/L、70mmol/L、80mmol/L、90mmol/L、100mmol/L、105mmol/L、110mmol/L、112mmol/L、115mmol/L、118mmol/L或119mmol/L。
优选地，所述肌酸的试剂纯度大于98％。
优选地，所述肌酸仿体的pH为6.0～7.2，包括但不限于6.1、6.2、6.3、.6.4、6.6、6.7、6.8、6.9或7.1。
优选地，所述肌酸仿体的测温温度范围为10～43℃，包括但不限于11℃、12℃、13℃、14℃、15℃、16℃、17℃、18℃、19℃、20℃、25℃、30℃、35℃、36℃、37℃、38℃或39℃。
优选地，所述基于肌酸化学交换饱和转移成像的测温还包括配制肌酸仿体的步骤。
优选地，所述肌酸仿体的配制方法包括：
将肌酸、琼脂粉、磷酸盐缓冲液和去离子水混合并加热，调节pH，得到所述肌酸仿体，具体为将肌酸、琼脂粉、磷酸盐缓冲液和去离子水配制为不同浓度的肌酸仿体混合液，并通过滴入氢氧化钠溶液或盐酸溶液，调节pH值，将配制好的混合液加热直至琼脂粉完全溶解，搅拌均匀后放置入塑料容器中自然冷却。
优选地，步骤(1)中对肌酸仿体进行化学交换饱和转移成像，将恒温水浴装置设定至特定温度，将配制好的不同pH值、不同肌酸浓度的肌酸仿体放入水浴中，并插入光纤测温探头监测记录肌酸仿体实时温度，待仿体温度稳定后，开始CEST扫描，首先用无预饱和激发脉冲的序列扫描一幅图作为参照，信号强度记为S 0，随后使用一系列不同的偏置频率Δω的预饱和激发脉冲序列扫描得到一系列图像，信号强度记为S sat(Δω)，信号比例S sat(Δω)/S 0即为偏置频率为Δω的预饱和激发脉冲作用下的信号衰减，定义为z谱(z-spectra)。当肌酸仿体受到频率为Δω的预饱和脉冲激发并被饱和时，该饱和效应通过肌酸的氨基氢质子与水氢质子的动态交换，使水氢质子也被饱和，导致水氢质子的磁共振信号有所下降。当预饱和激发脉冲频率等于水氢质子共振频率时，全部水氢质子被饱和，信号采集趋于零。随着偏置频率增大，被饱和的水信号逐渐减少，磁共振信号则逐渐提高。当偏置频率恰好为肌酸的氨基氢质子激发频率时，肌酸的氨基氢质子被饱和并与水氢质子交换，该频率对应的信号强度有一个下降趋势。
将z-spectra相对于水氢质子共振频率对称的数据S sat(+Δω)和S sat(-Δω)相减并除以S sat(-Δω)，如式(1)所示，结果可表征质子共振频率谱曲线的各点的非对称性，记作CEST asym，CEST asym最大值对应的偏置频率则为肌酸的氨基氢质子的化学位移。
Figure PCTCN2022072719-appb-000001
改变恒温水浴温度，待肌酸仿体温度稳定后重复上述过程，记录不同温度下测得的肌酸氨基氢质子的化学位移。
优选地，拟合所述肌酸相对于水的化学位移和肌酸仿体温度的数学关系，得到数学关系如式(2)所示：
T(℃)＝126.821×Δω-220.811      (2)，
其中Δω表示肌酸氨基氢质子相对于水的化学位移(ppm)，该式R 2为0.893，p值小于0.001。
另可以根据多池洛伦兹模型拟合的方法(Multi-pool Lorentzian Fitting)拟合出水氢质子以及肌酸的氨基氢质子的z-spectra，如式(3)所示，提升计算肌酸氨基氢质子化学位移的精度。
Figure PCTCN2022072719-appb-000002
其中，A i，ω i和σ i分别代表第i个质子池的z谱的幅度、化学位移和线宽，N表示质子池的总数。
根据式(3)计算结果拟合所述肌酸相对于水的化学位移和肌酸仿体温度的数学关系，得到数学关系如式(4)所示：
T(℃)＝169.519×Δω-302.907     (4)，
其中Δω表示肌酸氨基氢质子相对于水的化学位移(ppm)，该式R 2为0.956，p值小于0.001，该式拟合精确度更高。
本申请中，所述化学交换饱和转移成像的方式包括利用预饱和激发脉冲结合自旋回波-平面回波序列或者梯度回波序列进行信号采集，并进行间隔成像。
优选地，所述预饱和激发脉冲包括10个矩形脉冲。
优选地，所述矩形脉冲的持续时间为90～110毫秒(例如可以是91毫秒、92毫秒、93毫秒、95毫秒、98毫秒、100毫秒、105毫秒、106毫秒、108毫 秒或109毫秒)，B1＝0.1～0.3μT。
优选地，所述间隔成像的方式包括在预饱和激发脉冲的频率相对于水氢质子共振频率偏置-3.0ppm到+3.0ppm的范围内间隔成像，间隔次数大于200次。
作为优选的技术方案，所述基于肌酸化学交换饱和转移成像的测温方法的技术路线如图1所示，具体包括以下步骤：
(1)将肌酸、琼脂粉、磷酸盐缓冲液和去离子水混合并加热，调节pH为6.0～7.2，肌酸浓度为10～120mmol/L，得到所述肌酸仿体；
(2)对所述肌酸仿体进行化学交换饱和转移成像，CEST序列由预饱和激发脉冲与图像信号采集序列两部分组成，3.0T磁共振系统中，预饱和激发脉冲由十个矩形脉冲构成，每个矩形脉冲持续时间90～110毫秒，B1＝0.1～0.3μT，结合自旋回波-平面回波序列或者梯度回波序列进行信号采集，在预饱和激发脉冲频率相对于水氢质子共振频率偏置-3.0ppm到+3.0ppm的范围间隔成像，间隔次数大于200次，首先用无预饱和激发脉冲的序列扫描一幅图作为参照，信号强度记为S 0，随后使用一系列不同的偏置频率Δω的预饱和激发脉冲序列扫描得到一系列图像，信号强度记为S sat(Δω)，信号比例S sat(Δω)/S 0即为偏置频率为Δω的预饱和激发脉冲作用下的信号衰减，定义为z谱(z-spectra)，将z-spectra相对于水氢质子共振频率对称的数据S sat(+Δω)和S sat(-Δω)相减并除以S sat(-Δω)，结果可表征质子共振频率谱曲线的各点的非对称性，记作CEST asym，CEST asym最大值对应的偏置频率则为肌酸氨基氢质子相对于水的化学位移，此外，可通过多池洛伦兹模型拟合多个质子池的z谱，从而得到肌酸氨基氢质子相对于水的化学位移；
(3)拟合所述肌酸相对于水的化学位移和肌酸仿体温度的数学关系，根据不同温度下测得的肌酸氨基氢质子相对于水的的化学位移以及光纤测温探头实际记录的肌酸仿体温度，拟合肌酸相对于水的化学位移与肌酸仿体温度的关系；
可使用不同浓度以及pH值的肌酸仿体重复上述过程并重新拟合肌酸相对于水的化学位移与温度的关系，评估肌酸相对于水的化学位移与温度的关系的可靠性、可重复性以及不易受其他环境因素影响的稳定性；以及
(4)对样本中肌酸进行化学交换饱和转移成像，分析样本中肌酸相对于水的化学位移，并依据步骤(3)拟合的肌酸相对于水的化学位移和肌酸仿体温度的数学关系计算样本温度。
第二方面，本申请提供一种基于肌酸化学交换饱和转移成像的测温装置，所述测温装置用于第一方面所述的基于肌酸化学交换饱和转移成像的测温方法中，所述测温装置包括肌酸仿体测试单元、拟合单元和样本测试单元。
所述肌酸仿体测试单元用于对肌酸仿体进行化学交换饱和转移成像，分析肌酸仿体中肌酸相对于水的化学位移，所述拟合单元用于拟合所述肌酸相对于水的化学位移和肌酸仿体温度的数学关系，所述样本测试单元用于对样本中肌酸进行化学交换饱和转移成像，分析样本中肌酸相对于水的化学位移，并依据所述拟合单元拟合的肌酸相对于水的化学位移和肌酸仿体温度的数学关系计算样本温度。
优选地，所述测温装置还包括配制肌酸仿体单元。
所述配制肌酸仿体单元用于将肌酸、琼脂粉、磷酸盐缓冲液和去离子水混合并加热，调节pH，得到所述肌酸仿体。
优选地，所述肌酸仿体测试单元中化学交换饱和转移成像的方式包括利用预饱和激发脉冲结合自旋回波-平面回波序列或者梯度回波序列进行信号采集，并进行间隔成像。
优选地，所述预饱和激发脉冲包括10个矩形脉冲。
优选地，所述矩形脉冲的持续时间为90～110毫秒，B1＝0.1～0.3μT。
优选地，所述间隔成像的方式包括在预饱和激发脉冲的频率相对于水氢质子共振频率偏置-3.0ppm到+3.0ppm的范围内间隔成像，间隔次数大于200次。
与现有技术相比，本申请具有以下有益效果：
(1)本申请的基于肌酸化学交换饱和转移成像的测温方法，以肌酸作为内源性参照物，利用肌酸和水CEST效应的温度依赖性，进行高空间分辨率、高敏感性、无创的绝对温度测量，能够应用于无创、无标记的脑温测量；
(2)本申请的基于肌酸化学交换饱和转移成像的测温方法，具备高稳定性和准确性，操作简单，无放射性，利于推广。
附图说明
图1为本申请技术路线图。
图2为38℃下肌酸仿体(pH＝6.0，100mmol/L)扫描图像。
图3为38℃下肌酸仿体(pH＝6.0，100mmol/L)的z谱(z-spectra)。
图4为基于共振频率谱对称性分析测得的肌酸相对于水的化学位移与温度的关系图。
图5为基于多池洛伦兹方法拟合28℃下猪脑样品肌酸CEST效应的z谱(z-spectra)。
图6为基于多池洛伦兹拟合测得的肌酸相对于水的化学位移与温度的关系图。
具体实施方式
为进一步阐述本申请所采取的技术手段及其效果，以下结合实施例和附图对本申请作进一步地说明。可以理解的是，此处所描述的具体实施方式仅仅用于解释本申请，而非对本申请的限定。
实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可通过正规渠道商购获得的常规产品。
实施例1配制肌酸仿体
使用纯度>98％的肌酸一水试剂(C 4H 11N 3O 3)(1.4915g)、琼脂粉末(1.5g)、磷酸盐缓冲液(10mL)和去离子水(90mL)配制pH＝6.0、肌酸浓度为100mmol/L的混合液100mL，将溶液加热直至琼脂粉末全部溶解，搅拌均匀后放置入塑料试管中自然冷却，得到肌酸仿体。
实施例2Cr-CEST实验
使用恒温水浴装置并将温度设置为38℃(与人体大脑温度相近)，将所述肌酸仿体放入水浴中，并用光纤温度计监测仿体的实时温度，待温度稳定后，进行CEST成像(联影uMR 790，3.0T，32通道头颈线圈)，CEST序列由预饱和激发脉冲与自旋回波-平面回波成像序列两部分组成，预饱和激发脉冲由十个矩形脉冲构成，每个矩形脉冲持续时间100毫秒，B1＝0.1/0.15μT，自旋回波-平面回波图像采集序列TR/TE＝4000/38.6毫秒，成像视野FOV＝80mm，层厚为8.0mm，FA为160度，在预饱和激发脉冲频率相对于水氢质子共振频率偏置-3.0ppm到+3.0ppm的范围内以0.03ppm为间隔成像，间隔次数200次，首先用无预饱和激发脉冲的序列扫描一幅图作为参照，信号强度记为S 0，随后使用一系列不同的偏置频率Δω的预饱和激发脉冲序列扫描得到一系列图像，如图2所示，信 号强度记为S sat(Δω)，信号比例S sat(Δω)/S 0即为偏置频率为Δω的预饱和激发脉冲作用下的信号衰减，定义为z谱(z-spectra)，如图3所示，将z-spectra相对于水氢质子共振频率对称的数据S sat(+Δω)和S sat(-Δω)相减并除以S sat(-Δω)，结果可表征质子共振频率谱曲线的各点的非对称性，记作CEST asym，将CEST asym最大值对应的偏置频率2.01ppm记为该温度下肌酸氨基氢质子相对于水的化学位移。
调整恒温水浴温度，根据对z-spectra的对称性分析，依次测得15.1℃、15.3℃、16.3℃、24.5℃、32.0℃、33.5℃、34.5℃和38.9℃温度下的肌酸氨基氢质子相对于水的化学位移分别为1.89ppm、1.86ppm、1.89ppm、1.92ppm、1.95ppm、2.01ppm、2.04ppm和2.04ppm。此外，根据多池洛伦兹拟合方法依次测得13.8℃、16.30℃、18.30℃、20.30℃、23.56℃、24.50℃、29.30℃、32.00℃、32.07℃、33.50℃、34.50℃、35.68℃、38.10℃、38.9℃温度下肌酸氨基氢质子相对于水的化学位移分别为1.8770ppm、1.8928ppm、1.9016ppm、1.8946ppm、1.9127ppm、1.9421ppm、1.9615ppm、1.9795ppm、1.9615ppm、1.9804ppm、1.9832ppm、2.0051ppm、2.0263ppm、2.0032ppm。
实施例3Cr-CEST与温度关系拟合
使用SPSS 19.0分别对上述基于z-spectra的对称性分析以及多池洛伦兹拟合方法计算所得的肌酸氨基氢质子相对于水的化学位移与温度进行线性拟合，如图5所示，得到数学关系分别如式(2)和(4)所示：
T(℃)＝126.821×Δω-220.811     (2)，
其中Δω表示肌酸氨基氢质子相对于水的化学位移(ppm)，该式R 2为0.893，p值小于0.001。
T(℃)＝169.519×Δω-302.907     (4)，
其中Δω表示肌酸氨基氢质子相对于水的化学位移(ppm)，该式R 2为0.956，p值小于0.001，该式拟合精确度更高。
实施例4生物样本基于Cr-CEST的温度测量
制备猪脑组织匀浆样本，在28.0℃温度下进行CEST扫描(Bruker Biospec，9.4T)，B1＝0.23μT，在预饱和激发脉冲频率相对于水氢质子共振频率偏置-5.0ppm到+5.0ppm的范围内以0.05ppm为间隔成像，扫描次数201次。依据多池 洛伦兹拟合方法(五池模型：水氢质子池、肌酸氨基氢质子池、酰胺质子转移池、核奥氏效应池、磁化转移池)测得该温度下肌酸氨基氢质子相对于水的化学位移为1.9423ppm(图6)，将计算所得的化学位移代入式(2)得到计算温度25.51℃，代入式(4)得到计算温度26.35℃，均接近标定温度28℃。
因实施例中肌酸仿体CEST成像次数有限，数据量较少，且实验条件较为单一，可能影响肌酸化学位移与温度之间的关系拟合，进而影响温度预测的准确性。在实际应用中，可通过增加仿体实验次数、设置多种实验条件、优化z谱拟合策略、增加CEST扫描精度等方法提升Cr-CEST与温度之间数学关系的准确度。
综上所述，本申请的基于肌酸化学交换饱和转移成像的测温方法，以肌酸作为内源性参照物，利用肌酸与水CEST效应的温度依赖性，进行高空间分辨率、高敏感性、无创的绝对温度测量。
申请人声明，本申请通过上述实施例来说明本申请的详细方法，但本申请并不局限于上述详细方法，即不意味着本申请必须依赖上述详细方法才能实施。所属技术领域的技术人员应该明了，对本申请的任何改进，对本申请产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本申请的保护范围和公开范围之内。

Claims (11)

  1. 一种基于肌酸化学交换饱和转移成像的测温方法，其包括以下步骤：
    (1)对肌酸仿体进行化学交换饱和转移成像，分析肌酸仿体中肌酸相对于水的化学位移；
    (2)拟合所述肌酸相对于水的化学位移和肌酸仿体温度的数学关系；以及
    (3)对样本中肌酸进行化学交换饱和转移成像，分析样本中肌酸相对于水的化学位移，并依据步骤(2)拟合的肌酸相对于水的化学位移和肌酸仿体温度的数学关系计算样本温度。
  2. 根据权利要求1所述的基于肌酸化学交换饱和转移成像的测温方法，其中，所述肌酸仿体的制备原料包括肌酸、琼脂粉、磷酸盐缓冲液。
  3. 根据权利要求1或2所述的基于肌酸化学交换饱和转移成像的测温方法，其中，所述肌酸仿体中肌酸的浓度为10～120mmol/L；
    优选地，所述肌酸的试剂纯度大于98％；
    优选地，所述肌酸仿体的pH为6.0～7.2；
    优选地，所述肌酸仿体的测温温度范围为10～43℃。
  4. 根据权利要求1-3任一项所述的基于肌酸化学交换饱和转移成像的测温方法，其中，所述方法还包括配制肌酸仿体的步骤；
    优选地，所述肌酸仿体的配制方法包括：
    将肌酸、琼脂粉、磷酸盐缓冲液和去离子水混合并加热，调节pH，得到所述肌酸仿体。
  5. 根据权利要求1-4任一项所述的基于肌酸化学交换饱和转移成像的测温方法，其中，所述化学交换饱和转移成像的方式包括利用预饱和激发脉冲结合自旋回波-平面回波序列或者梯度回波序列进行信号采集，并进行间隔成像；
    优选地，所述预饱和激发脉冲包括10个矩形脉冲；
    优选地，所述矩形脉冲的持续时间为90～110毫秒，B1＝0.1～0.3μT；
    优选地，所述间隔成像的方式包括在预饱和激发脉冲频率相对于水氢质子共振频率偏置-3.0ppm到+3.0ppm的范围内间隔成像，间隔次数大于200次。
  6. 根据权利要求1-5任一项所述的基于肌酸化学交换饱和转移成像的测温方法，其中，所述方法包括以下步骤：
    (1)将肌酸、琼脂粉、磷酸盐缓冲液和去离子水混合并加热，调节pH为6.0～7.2，肌酸浓度为10～120mmol/L，得到所述肌酸仿体；
    (2)对所述肌酸仿体进行化学交换饱和转移成像，预饱和激发脉冲中每个矩形脉冲持续90～110毫秒，B1＝0.1～0.3μT，结合自旋回波-平面回波序列或者梯度回波序列进行信号采集，在预饱和激发脉冲的频率相对于水氢质子共振频率偏置-3.0ppm到+3.0ppm的范围内间隔成像，间隔次数大于200次，分析肌酸仿体中肌酸相对于水的化学位移；
    (3)拟合所述肌酸相对于水的化学位移和肌酸仿体温度的数学关系；以及
    (4)对样本中肌酸进行化学交换饱和转移成像，分析样本中肌酸相对于水的化学位移，并依据步骤(3)拟合的肌酸相对于水的化学位移和肌酸仿体温度的数学关系计算样本温度。
  7. 一种基于肌酸化学交换饱和转移成像的测温装置，其用于权利要求1-6任一项所述的基于肌酸化学交换饱和转移成像的测温方法中；
    所述测温装置包括肌酸仿体测试单元、拟合单元和样本测试单元；
    所述肌酸仿体测试单元用于对肌酸仿体进行化学交换饱和转移成像，分析肌酸仿体中肌酸相对于水的化学位移；
    所述拟合单元用于拟合所述肌酸相对于水的化学位移和肌酸仿体温度的数学关系；并且
    所述样本测试单元用于对样本中肌酸进行化学交换饱和转移成像，并依据所述拟合单元拟合的肌酸相对于水的化学位移和肌酸仿体温度的数学关系计算样本温度。
  8. 根据权利要求7所述的测温装置，其中，所述测温装置还包括配制肌酸仿体单元；
    所述配制肌酸仿体单元用于将肌酸、琼脂粉、磷酸盐缓冲液和去离子水混合并加热，调节pH，得到所述肌酸仿体。
  9. 根据权利要求7或8所述的测温装置，其中，所述肌酸仿体测试单元中化学交换饱和转移成像的方式包括利用预饱和激发脉冲结合自旋回波-平面回波序列或者梯度回波序列进行信号采集，并进行间隔成像。
  10. 根据权利要求9所述的测温装置，其中，所述预饱和激发脉冲包括10个矩形脉冲；
    优选地，所述矩形脉冲的持续时间为90～110毫秒，B1＝0.1～0.3μT。
  11. 根据权利要求9所述的测温装置，其特征在于，所述间隔成像的方式 包括在预饱和激发脉冲的频率相对于水氢质子共振频率偏置-3.0ppm到+3.0ppm的范围内间隔成像，间隔次数大于200次。
PCT/CN2022/072719 2021-05-18 2022-01-19 一种基于肌酸化学交换饱和转移成像的测温方法及装置 WO2022242214A1 (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202110540092 2021-05-18
CN202110540092.2 2021-05-18
CN202210022362.5 2022-01-10
CN202210022362.5A CN115371835A (zh) 2021-05-18 2022-01-10 一种基于肌酸化学交换饱和转移成像的测温方法及装置

Publications (1)

Publication Number Publication Date
WO2022242214A1 true WO2022242214A1 (zh) 2022-11-24

Family

ID=84060421

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/072719 WO2022242214A1 (zh) 2021-05-18 2022-01-19 一种基于肌酸化学交换饱和转移成像的测温方法及装置

Country Status (2)

Country Link
CN (1) CN115371835A (zh)
WO (1) WO2022242214A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116879338A (zh) * 2023-06-12 2023-10-13 汕头大学医学院第二附属医院 一种vdmp-cest结合非线性拟合检测gaba的方法及系统

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5908864A (en) * 1998-05-28 1999-06-01 Dymatize Enterprises Creatine gel
US20090043223A1 (en) * 2007-08-08 2009-02-12 Siemens Medical Solutions Usa, Inc. Non-Invasive Temperature Scanning and Analysis for Cardiac Ischemia Characterization
CN101507603A (zh) * 2008-10-14 2009-08-19 清华大学 一种磁共振测温的方法和装置
CN104997511A (zh) * 2015-06-01 2015-10-28 中国科学院深圳先进技术研究院 用于磁共振化学交换饱和转移成像的cestr测量方法和系统

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5908864A (en) * 1998-05-28 1999-06-01 Dymatize Enterprises Creatine gel
US20090043223A1 (en) * 2007-08-08 2009-02-12 Siemens Medical Solutions Usa, Inc. Non-Invasive Temperature Scanning and Analysis for Cardiac Ischemia Characterization
CN101507603A (zh) * 2008-10-14 2009-08-19 清华大学 一种磁共振测温的方法和装置
CN104997511A (zh) * 2015-06-01 2015-10-28 中国科学院深圳先进技术研究院 用于磁共振化学交换饱和转移成像的cestr测量方法和系统

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEN, JING ET AL.: "Application Advances of Chemical Exchange Saturation Transfer in Central Nervous System", INTERNATIONAL JOURNAL OF MEDICAL RADIOLOGY, vol. 42, no. 5, 30 September 2019 (2019-09-30), ISSN: 1674-1897 *
ZHANG SHANRONG, MALLOY CRAIG R., SHERRY A. DEAN: "MRI Thermometry Based on PARACEST Agents", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, vol. 127, no. 50, 1 December 2005 (2005-12-01), pages 17572 - 17573, XP093005768, ISSN: 0002-7863, DOI: 10.1021/ja053799t *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116879338A (zh) * 2023-06-12 2023-10-13 汕头大学医学院第二附属医院 一种vdmp-cest结合非线性拟合检测gaba的方法及系统

Also Published As

Publication number Publication date
CN115371835A (zh) 2022-11-22

Similar Documents

Publication Publication Date Title
Haris et al. Exchange rates of creatine kinase metabolites: feasibility of imaging creatine by chemical exchange saturation transfer MRI
Sati et al. In vivo quantification of T2⁎ anisotropy in white matter fibers in marmoset monkeys
US9157976B2 (en) CEST MRI methods for imaging glutaminolysis in cancer
Zu et al. Chemical exchange rotation transfer imaging of intermediate‐exchanging amines at 2 ppm
US20080197840A1 (en) Non-Invasive Mri Measurement of Tissue Glycogen
Hüppi et al. Regional metabolic assessment of human brain during development by proton magnetic resonance spectroscopy in vivo and by high-performance liquid chromatography/gas chromatography in autopsy tissue
Pagani et al. Basic concepts of advanced MRI techniques
Chen et al. Pyruvate to lactate metabolic changes during neurodevelopment measured dynamically using hyperpolarized 13C imaging in juvenile murine brain
WO2022242214A1 (zh) 一种基于肌酸化学交换饱和转移成像的测温方法及装置
Ferland et al. Longitudinal assessment of 1 H-MRS (GABA and Glx) and TMS measures of cortical inhibition and facilitation in the sensorimotor cortex
Lanz et al. Magnetic resonance spectroscopy in the rodent brain: experts' consensus recommendations
Okada et al. Repeatability of proton magnetic resonance spectroscopy of the brain at 7 T: effect of scan time on semi-localized by adiabatic selective refocusing and short-echo time stimulated echo acquisition mode scans and their comparison
Dietrich et al. Fast oxygen‐enhanced multislice imaging of the lung using parallel acquisition techniques
Crémillieux et al. Online quantification of lactate concentration in microdialysate during cerebral activation using 1H-MRS and sensitive NMR microcoil
Mueller et al. On the interference from agar in chemical exchange saturation transfer MRI parameter optimization in model solutions
Reid et al. Reproducibility of 7‐T brain spectroscopy using an ultrashort echo time STimulated Echo Acquisition Mode sequence and automated voxel repositioning
Valette et al. Optimized diffusion‐weighted spectroscopy for measuring brain glutamate apparent diffusion coefficient on a whole‐body MR system
US5479924A (en) Method of measuring the 17 O content and distribution in a body
CN113040744B (zh) 一种用于活体的化学交换饱和转移效应的定量方法
Soher et al. Automated whole‐brain N‐acetylaspartate proton MRS quantification
Hoge et al. Quantitative measurement using fMRI
Jírů et al. The role of relaxation time corrections for the evaluation of long and short echo time 1 H MR spectra of the hippocampus by NUMARIS and LCModel techniques
Yang et al. Increased oxygen consumption in the somatosensory cortex of α-chloralose anesthetized rats during forepaw stimulation determined using MRS at 11.7 Tesla
Mumcu A Simple and Feasible Quantification of Metabolites in the Human Follicular Fluid Using 1H HR-MAS NMR Spectroscopy
CN111521629B (zh) 一种pH定量测量的饱和能量非均匀分布磁共振成像方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22803548

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22803548

Country of ref document: EP

Kind code of ref document: A1