分子影像新技术——氘代谢波谱及成像的综述与展望

目前常用的分子影像技术主要有正电子发射型断层显像（PET）、质子磁共振波谱（¹H MRS）及成像（¹H MRSI）、化学交换饱和转移（CEST）、超极化¹³C MRSI等.近4年来,氘代谢波谱（DMS）及成像（DMI）作为一种新兴的分子影像技术获得了越来越多的关注,其通过采集注射或口服氘代葡萄糖后的目标组织与正常组织间氘代谢产物的磁共振信号进行组织区分.相比于其他分子影像方法,该影像技术具有无辐射、稳定性好、扫描操作相对简单等优点.本文综述了近年来DMS/DMI技术的研究进展及其意义,归纳总结了其临床应用价值,并对该技术未来的发展和改进方向,以及应用前景进行了展望.     

1.5 T磁共振化学交换饱和转移成像的影响因素分析

本文探讨1.5 T磁共振化学交换饱和转移（Chemical Exchange Saturation Transfer,CEST）成像的影响因素.通过试管模型和临床病例,采用GE Signa HDe 1.5 T磁共振成像（Magnetic Resonance Imaging,MRI）扫描仪分别进行不同矩阵、激励次数、翻转角、磁化传递翻转角的CEST成像对比分析,以及不同激励次数、磁化传递翻转角的Z谱分析,并从成像组织、成像设备、成像技术等方面对原始图信号、酰胺质子转移（Amide Proton Transfer,APT）信号及Z谱进行分析研究.实验结果表明1.5 T MRI扫描仪的CEST图像信噪比相对较低,且磁场稳定性及均匀度影响了CEST成像的效果.在其他参数不变的情况下,降低采集矩阵和增加激励次数与翻转角可以增加原始图像信噪比.磁化传递翻转角为105°时,CEST成像效果最好.激励次数为2、磁化传递翻转角为105°时,所得数据符合组织Z谱情况.模型Z谱在磁化传递频率为-294~-194 Hz范围可显示30%谷氨酸（Glu）、碘剂（I₃₂₀）、纯水（H₂O）、肌酸（Cr）的信号差异,与H₂O差异最大处在-244~-214 Hz.原始图像信号30% I₃₂₀明显高于Glu、H₂O、Cr,Cr略低于Glu,APT图Cr略低于Glu.25例脑肿瘤的APT图呈高信号、12例脑梗塞的APT图呈低信号,CEST原始图像均可区分病变区域.有12例因采集时间、患者配合情况、环境及室温等影响导致CEST成像的失败.由此得出1.5 T场强下,CEST技术受到成像组织、设备、技术等因素的影响,需要进行多方面优化.在保证磁场稳定性及均匀度的情况下,优化参数的CEST成像和Z谱成像可以区分代谢物及其浓度.     

内源性蛋白质分子成像的研究进展

酰氨质子转移（amide proton transfer, APT）成像是一种新的分子MRI技术,它可用来测量组织中内源性蛋白质. 理论上,APT-MRI信号强度主要取决于游离蛋白质的酰氨质子浓度以及交换速度,而酰氨质子交换速度与组织pH有关. 因此,APT-MRI技术已经被用于无创性中风pH成像（通常pH降低）和肿瘤蛋白质含量成像（通常蛋白质量提高）. 近期对大鼠的实验表明,APT-MRI技术可用来区分放射性坏死和胶质瘤. 该综述文章简要地介绍了APT成像的基本原理以及它在动物模型与临床中风和肿瘤成像中的应用.     

基于神经网络拟合的腹部化学交换饱和转移成像

磁共振成像（Magnetic Resonance Imaging，MRI）化学交换饱和转移（Chemical Exchange Saturation Transfer，CEST）技术在临床诊断中展现了巨大的潜力，但在腹部成像中受到主磁场偏移量大的挑战，而且利用传统的非对称性分析法得到的酰胺质子转移（Amide Proton Transfer，APT）成像对比度受到核奥氏增强（Nuclear Overhauser Enhancement，NOE）效应的干扰.本文提出了一种基于神经网络拟合的CEST后处理方法，对每个像素采集得到的Z谱特征进行识别，不需要额外序列扫描即可得到背景参考Z谱与主磁场偏移量，用以校正和获得理想的Z谱，并进一步分离得到源自APT效应与NOE效应的信号.鸡蛋清和健康志愿者腹部成像结果显示，本文提出的基于神经网络的CEST后处理方法效果较好.     

胶束型磁共振成像分子探针的设计与应用

飞速发展的分子影像学在肿瘤的早期诊断及检测中发挥着越来越重要的作用.磁共振成像(MRI)是分子影像学的重要分支，具有其他成像技术不可比拟的优越性和广阔的发展前景.它不需要放射性示踪剂，没有电离辐射，具有高的空间、时间分辨率和组织对比度.近年来，新型磁共振分子探针及成像序列取得了一系列进展，包括环境响应型分子探针、¹⁹F成像、¹²⁹Xe超极化成像以及化学交换饱和转移成像等，进一步拓展了MRI的应用范围.研究和开发靶向性好、弛豫效率高且安全性好的新型多模态MRI造影剂，进一步提高灵敏度是MRI领域的一项重要课题，例如将胶束的特性与一些MRI新方法结合，寻找合适的胶束体系，以提高MRI分子探针的灵敏度；或者引入多模态分子探针，弥补磁共振方法的不足.本文综述了胶束型MRI分子探针核心技术的研究进展与应用，并指出分子影像技术在生物医学工程研究和临床诊断中的重要性.     

糖尿病脑病的磁共振研究

糖尿病是由胰岛素分泌不足（T1DM）或胰岛素抵抗（T2DM）而引发的慢性代谢疾病,严重影响人们的生活质量. 中枢神经系统是糖尿病并发症的易感部位. 临床研究和流行病学调查结果显示,糖尿病会引发脑白质损伤、脑萎缩和认知功能障碍,并会增加脑卒中的风险. 磁共振成像和活体磁共振波谱可提供大脑解剖结构、功能及代谢等多方面的信息. 近年来,随着人们对糖尿病脑病关注度的不断增加和认识的不断加深,磁共振成像和活体波谱开始并越来越多地被应用于该疾病的研究. 该文综述磁共振成像与活体波谱技术在糖尿病脑病研究中的应用及最新进展.     

7 T 下脂肪对基于 NOE 的磁共振对比成像的影响

核 Overhauser 增强(NOE)效应在高场下的化学交换饱和转移中会造成 Z 谱高场位置的负背景信号,有望成为一种新的磁共振成像(MRI)对比机制．然而,研究指出, NOE信号的发生区域与主要的脂肪信号的频率位置有重叠,因此 MRI 中观察到的 NOE 信号有可能混合了脂肪信号．该文通过鸡蛋的模型实验,初步分析了脂肪含量较高的组织内脂肪信号对 NOE 效应的影响,并通过健康大鼠鼠脑及颅内肿瘤大鼠鼠脑实验,分析了脂肪对脑部 NOE 对比成像及基于 NOE 对比成像的疾病诊断的影响．结果表明,脂肪含量较高的组织内脂肪信号会引起伪 NOE 效应,并影响 NOE对比图像的准确性．
     

组织蛋白酶B响应的超极化129Xe MRI探针对肺癌细胞的超灵敏探测

组织蛋白酶B（Cat B）是一种溶酶体半胱氨酸蛋白酶,在细胞代谢中起重要作用.已有研究表明Cat B在肺癌细胞中会过表达.因此,细胞内Cat B水平的检测非常重要.迄今为止,细胞内Cat B的检测方法主要为荧光成像,但该技术受限于渗透性和自发荧光背景干扰.为了解决这些问题,我们设计了一种基于超极化¹²⁹Xe磁共振成像的新型探针.它由一个作为¹²⁹Xe核磁共振（NMR）报告基团的穴番分子笼和一个作为Cat B特异性可裂解基团的酰胺键组成.当探针与Cat B相互作用时,酰胺键的断裂会导致其¹²⁹Xe化学位移发生变化.结合超极化-化学交换饱和转移（Hyper-CEST）技术,可为Cat B提供一种新颖的检测方法.     

CEST成像不同量化方式在急性帕金森氏病小鼠模型研究中的应用比较

本文通过比较7 T场强下化学交换饱和转移（chemical exchange saturation transfer,CEST）成像技术不同量化方式在急性帕金森氏病小鼠模型研究中的应用效果,探讨了客观无创的帕金森氏病研究方案.使用Bruker PharmaScan 7 T小动物磁共振成像（Magnetic Resonance Imaging,MRI）扫描仪,对经1-甲基-4-苯基-1,2,3,6-四氢吡啶（1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,MPTP）急性造模前及造模后第3、10天的小鼠黑质、皮层及海马进行扫描,计算弛豫时间T₁、T₂、MTR_asym（magnetization transfer ratio based on asymmetry analysis）、MTR_rex（magnetization transfer ratio yielding Rex）、AREX（apparent exchange-dependent relaxation）及5池拟合后的胺峰面积Area_amine、酰胺峰面积Area_amide.结果显示仅黑质中融合了倒Z谱分析和5池洛仑兹拟合所得的量化指标MTR_rex、AREX及Area_amine在造模后显著减小,与黑质免疫组化结果一致,而T₁、T₂以及基于Z谱非对称性分析的MTR_asym未见统计学差异,这表明此量化方式消除了直接饱和效应及磁化转移效应的影响,准确性上要优于Z谱非对称分析法,更能正确地提示帕金森氏病黑质的变化.     

组织凝固性坏死对基于纵向弛豫时间的磁共振测温的影响

高强度聚焦超声（High Intensity Focused Ultrasound,HIFU）治疗肿瘤时,为了保证治疗的安全性和有效性,需要对组织温度分布进行实时监测.磁共振成像（Magnetic Resonance Imaging,MRI）具有对温度敏感的成像参数,可以无创检测组织温度.本文结合组织相变对测温的影响,探讨了磁共振测温（Magnetic Resonance Thermometry,MRT）技术能否用于实时监控HIFU治疗.利用两态快速交换模型,提出在组织凝固性坏死的相变前后,MRI的纵向弛豫时间（T₁）参数与组织温度之间具有不同关系.并通过实验验证了上述假设.相对于传统的磁共振测温方法模型,本文考虑了HIFU治疗过程中组织相变对检测温度的影响,对利用磁共振测温引导HIFU治疗具有重要的参考价值.     

A new class of contrast agents for MRI based on proton chemical exchange dependent saturation transfer (CEST)

It has been previously shown that intrinsic metabolites can be imaged based on their water proton exchange rates using saturation transfer techniques. The goal of this study was to identify an appropriate chemical exchange site that could be developed for use as an exogenous chemical exchange dependent saturation transfer (CEST) contrast agent under physiological conditions. These agents would function by reducing the water proton signal through a chemical exchange site on the agent via saturation transfer. The ideal chemical exchange site would have a large chemical shift from water. This permits a high exchange rate without approaching the fast exchange limit at physiological pH (6.5-7.6) and temperature (37 degrees C), as well as minimizing problems associated with magnetic field susceptibility. Numerous candidate chemicals (amino acids, sugars, nucleotides, heterocyclic ring chemicals) were evaluated in this preliminary study. Of these, barbituric acid and 5, 6-dihydrouracil were more fully characterized with regard to pH, temperature, and concentration CEST effects. The best chemical exchange site found was the 5.33-ppm indole ring -NH site of 5-hydroxytryptophan. These data demonstrate that a CEST-based exogenous contrast agent for MRI is feasible.     

Quantitative and qualitative assessment of articular cartilage in the goat knee with magnetization transfer imaging

We investigated the role of collagen in the magnetization transfer (MT) effect in contrast to other macromolecules. By means of phantoms made of collagen, chondroitin sulfate (CS) and albumin, MR parameters have been optimized in order to reduce the acquisition time and improve the sensitivity, as well as to minimize the contributions from CS and albumin to the MT induced signal attenuation. The same method was used to study cartilage ex vivo (bovine articular and nasal cartilage plugs) and in vivo (goat knee femoral chondyle). In phantom samples, the MT signal attenuation depended on the collagen concentration while contributions from the other macromolecules were found to be minimal. In average, analysis of MT images revealed a 25%, 35% and 30% signal attenuation in 10% w/v type I collagen gels, cartilage plugs, and cartilage from the weight-bearing areas of the goat knee, respectively. Biochemical data revealed that treatment of cartilage plugs with bacterial collagenase led to collagen depletion and correspondingly to a decrease of the MT response. In contrast, trypsin-induced proteoglycan loss in cartilage plugs did not alter the MT effect. A significant correlation was observed between the collagen content in these plugs and their respective MT ratios and the rate constant k for the exchange process bound versus free water. Finally, data obtained from in vivo MT measurement of the goat knee demonstrated that intra-articular injection of papain might not only cause degradation of proteoglycans but also a change in collagen integrity in a dose-dependent manner. We conclude that in vivo measurement of MT ratios gives quantitative and qualitative information on the collagen status and may be applied for the routine evaluation of normal and abnormal articular cartilage.     

一种示踪干细胞的磁共振-荧光双模成像探针

本文设计并合成了Gd基磁共振-荧光双模成像探针——Gd-DOTA-PEG-GA,通过电穿孔的方式标记人源间充质干细胞（hMSCs）.电穿孔标记诱导细胞将探针组装成团簇状纳米粒子进入细胞质,显著延长其与细胞结合的时间,并呈现出明显的T₂信号减弱效应,且信号减弱效应可以持续7天以上.在水溶液中,该探针的发射带集中在498 nm,并且荧光强度在一周内无明显衰减.该探针标记的细胞在荧光倒置显微镜下呈现绿色荧光.这些结果表明该探针可以作为磁共振-荧光双模成像探针用于干细胞示踪.     

Measurement of regional cerebral glucose uptake by magnetic resonance spin-lock imaging

Purpose

The regional uptake of glucose in rat brain in vivo was measured at high resolution using spin-lock magnetic resonance imaging after infusion of the glucose analogue 2-deoxy-d-glucose (2DG). Previous studies of glucose metabolism have used ¹³C-labeled 2DG and NMR spectroscopy, ¹⁸F-labeled fluorodeoxyglucose (FDG) and PET, or chemical exchange saturation transfer (CEST) MRI, all of which have practical limitations. Our goal was to explore the ability of spin-lock sequences to detect specific chemically-exchanging species in vivo and to compare the effects of 2DG in brain tissue on CEST images.

Methods

Numerical simulations of R_1p and CEST contrasts for a variety of sample parameters were performed to evaluate the potential specificity of each method for detecting the exchange contributions of 2DG. Experimental measurements were made in tissue phantoms and in rat brain in vivo which demonstrated the ability of spin-lock sequences for detecting 2DG.

Results

R_1p contrast acquired with appropriate spin-lock sequences can isolate the contribution of exchanging protons in 2DG in vivo and appears to have better sensitivity and more specificity to 2DG–water exchange effects than CEST.

Conclusion

Spin-lock imaging provides a novel approach to the detection and measurement of glucose uptake in brain in vivo.     

Simultaneous determination of labile proton concentration and exchange rate utilizing optimal RF power: Radio frequency power (RFP) dependence of chemical exchange saturation transfer (CEST) MRI

Chemical exchange saturation transfer (CEST) MRI is increasingly used to probe mobile proteins and microenvironment properties, and shows great promise for tumor and stroke diagnosis. However, CEST MRI contrast mechanism is complex, depending not only on the CEST agent concentration, exchange and relaxation properties, but also varying with experimental conditions such as magnetic field strength and RF power. Hence, it remains somewhat difficult to quantify apparent CEST MRI contrast for properties such as pH, temperature and protein content. In particular, CEST MRI is susceptible to RF spillover effects in that RF irradiation may directly saturate the bulk water MR signal, leading to an optimal RF power at which the CEST contrast is maximal. Whereas RF spillover is generally considered an adverse effect, it is noted here that the optimal RF power strongly varies with exchange rate, although with negligible dependence on labile proton concentration. An empirical solution suggested that optimal RF power may serve as a sensitive parameter for simultaneously determining the labile proton content and exchange rate, hence, allowing improved characterization of the CEST system. The empirical solution was confirmed by numerical simulation, and experimental validation is needed to further evaluate the proposed technique.