吳仁華

磁共振氨基質(zhì)子轉(zhuǎn)移成像技術(shù)原理和應(yīng)用

吳仁華*

本文概述了氨基質(zhì)子轉(zhuǎn)移(amide proton transfer, APT)技術(shù)與化學(xué)交換飽和轉(zhuǎn)移(chem ical exchange saturation transfer, CEST)技術(shù)的關(guān)系、APT技術(shù)的原理、影響APT技術(shù)的諸多因素，特別是在體APT成像需研究核奧氏效應(yīng)(nuc lear Overhauser effect, NOE)的重要性。闡述了APT技術(shù)的應(yīng)用，主要有pH成像、溫度成像、APT加權(quán)像在各器官組織的臨床應(yīng)用。

氨基質(zhì)子轉(zhuǎn)移；化學(xué)交換飽和轉(zhuǎn)移；核奧氏效應(yīng)；酸堿度成像；溫度成像

Received 17 Feb 2016, Accepted 3 Apr 2016

ACKNOW LEDGM ENTSThis work was part of National Natural Science Foundation of China (No. 81471730).

磁共振氨基質(zhì)子轉(zhuǎn)移(am ide proton transfer, APT)成像[1-4]是化學(xué)交換飽和轉(zhuǎn)移(chem ical exchange saturation transfer, CEST)技術(shù)[5-6]的一種，CEST技術(shù)與磁化傳遞技術(shù)[7-8]密切相關(guān)，從某種意義來說，CEST技術(shù)是特異性預(yù)飽和的磁化傳遞技術(shù)，而臨床上應(yīng)用的磁化傳遞成像是非特異性飽和的磁化傳遞技術(shù)。盡管CEST成像目前還有許多問題尚待解決，特別是在體CEST成像主要會(huì)有直接水飽和(溢出效應(yīng))、大分子交換池(磁化傳遞)和核奧氏效應(yīng)(nuclear overhauser effect, NOE)等的影響[9-10]，由于CEST成像具有高空間和時(shí)間分辨率的優(yōu)點(diǎn)[11-13]，可檢測蛋白和代謝物中的可交換質(zhì)子，用于無創(chuàng)傷的酸堿度(pH值)成像[1, 4]、內(nèi)源性蛋白分子成像[14-15]、代謝物成像[16-17]、細(xì)胞標(biāo)記[18-19]、報(bào)告基因的研究[20]等，目前是磁共振成像研究的熱點(diǎn)。

CEST技術(shù)中的APT成像在模型、動(dòng)物和人體層面上有過非常多的研究[9, 11, 14, 16, 21]，學(xué)術(shù)界有過廣泛的討論，目前認(rèn)為在優(yōu)化技術(shù)的前提下，在人體層面上可以獲得APT加權(quán)像[22]，APT加權(quán)像具有重要的臨床應(yīng)用價(jià)值，特別是應(yīng)用于腦腫瘤的診斷和鑒別診斷[3, 23-25]、腦卒中的早期診斷[26-27]、神經(jīng)變性疾病的定性[28-29]、肝糖原檢測[30]等，本文主要綜述APT成像的技術(shù)原理和臨床應(yīng)用價(jià)值。

1 氨基質(zhì)子轉(zhuǎn)移成像技術(shù)原理

1.1 氨基質(zhì)子的預(yù)飽和頻率

APT成像的技術(shù)原理也基于CEST技術(shù)的原理，只是APT成像的預(yù)飽和脈沖頻率是特異性飽和氨基質(zhì)子。Forsen等[31]在1963年利用雙共振方法開創(chuàng)性地研究了快速化學(xué)反應(yīng)現(xiàn)象。Guivel-Scharen等[32]在1998年研究小分子溶液的磁化傳遞現(xiàn)象時(shí)最早觀察到靠近水共振頻率Z譜的不對(duì)稱性，為了與既往的磁化傳遞名詞相區(qū)分，將這一磁共振現(xiàn)象命名為 CEST。這些學(xué)者發(fā)現(xiàn)水的氫質(zhì)子(4.7 ppm)與內(nèi)源的游離蛋白質(zhì)和多肽上的酰胺基(-NH)質(zhì)子(8.3 ppm)存在一個(gè)快速的化學(xué)交換(氫交換)的過程，而且此過程與環(huán)境的pH值相互依賴，這一磁共振現(xiàn)象隨之被命名為氨基質(zhì)子轉(zhuǎn)移[13, 33-35]。

1.2 CEST技術(shù)原理的二池、三池模型

對(duì)CEST技術(shù)原理最經(jīng)典的解釋是二池模型(圖1)[13, 27, 36]，假設(shè)人體內(nèi)環(huán)境中有如下兩池(A、B池)，A池代表體內(nèi)水質(zhì)子信號(hào)，B池代表體內(nèi)某游離大分子的某個(gè)(或幾個(gè))質(zhì)子信號(hào)，在主磁場中(B0)二者會(huì)有著不同的共振進(jìn)動(dòng)頻率，通過施加選擇性的脈沖(預(yù)飽和脈沖B1)飽和B池信號(hào)，在適當(dāng)?shù)臈l件下(適宜的溫度、pH范圍)，這些質(zhì)子會(huì)和周圍的水質(zhì)子發(fā)生化學(xué)交換，進(jìn)而將部分飽和傳遞到A池，通過特定磁共振技術(shù)采集到的A池信號(hào)可以反映出該CEST效應(yīng)的強(qiáng)弱效果[13, 33-35]。

也有學(xué)者提出磁共振CEST技術(shù)原理的三池模型及其它模型，所謂三池模型即是將組織中的質(zhì)子分為三個(gè)池。第一個(gè)池為自由水池，為磁共振成像提供大量信號(hào)。第二個(gè)池為結(jié)合池，包含與蛋白質(zhì)、其他大分子或者細(xì)胞膜束縛的氫質(zhì)子，主要是人體中的半固態(tài)組織，這些氫質(zhì)子的信號(hào)在常規(guī)磁共振成像技術(shù)中是無法被檢測的。第三池為特定分子池，系游離大分子(某些內(nèi)源游離大分子或CEST對(duì)比劑)上的氫質(zhì)子(包括某些羥基、胺基、酰胺基及亞胺基等)為可交換的質(zhì)子。CEST技術(shù)主要研究的是第三池與自由水池的交換效應(yīng)，但結(jié)合池的影響不可忽視[27, 33-37]。

1.3 外源性化合物的研究

APT成像主要依賴內(nèi)源性的氨基質(zhì)子，當(dāng)應(yīng)用某些外源性化合物時(shí)，如鑭系螯合物[38]、CT掃描的對(duì)比劑[39]等，氨基質(zhì)子的交換會(huì)發(fā)生變化，這對(duì)于酸堿度的研究有一定意義。

1.4 核奧氏效應(yīng)(NOE)

應(yīng)用化合物模型對(duì)APT成像進(jìn)行研究時(shí)，可以得到非常規(guī)整的CEST譜(Z譜)和效果非常好的APT圖，但在體研究時(shí)，特別是人體研究時(shí)，Z譜不可能規(guī)整，其中主要是受到NOE的影響，因而目前認(rèn)為在人體層面上獲得的是APT加權(quán)像[22]。NOE的定義可以這樣表述：當(dāng)某一自旋的核磁共振(nuclear magnetic resonance, NMR)吸收得到飽和時(shí)，另一自旋的NMR吸收強(qiáng)度積分值的改變[40]。在分析Z譜時(shí)，認(rèn)為氨基質(zhì)子對(duì)側(cè)的譜線為NOE效應(yīng)[41-43]。要深入研究APT成像，必須研究NOE的影響及其NOE成像。

2 氨基質(zhì)子轉(zhuǎn)移成像技術(shù)的應(yīng)用

2.1 在體器官組織的pH測定

APT成像技術(shù)已有很廣泛的應(yīng)用，其中一個(gè)主要方向是在體器官組織的pH測定[1, 4, 44-46]。相對(duì)于磁共振譜方法的pH成像，APT成像方法具有高空間和時(shí)間分辨率。正常的人體機(jī)能有賴于正常的穩(wěn)定的內(nèi)環(huán)境，組織pH的改變是提示許多病理變化的指標(biāo)。腫瘤細(xì)胞內(nèi)pH(pH i)及細(xì)胞外pH (pHe)存在梯度差。與正常組織相比，pHe通常較低，而pHi可以較高或基本無變化。因此，通過檢測pH的變化可評(píng)估腫瘤病人的預(yù)后及治療反應(yīng)[45]。APT成像的pH研究大部分在3 T以上場強(qiáng)磁共振機(jī)器上進(jìn)行，筆者研究在臨床1.5 T機(jī)器上也可以實(shí)現(xiàn)pH的檢測[4](圖2)。

對(duì)于pH的測定，目前的研究方向是全面考慮影響pH測定的各種因素[47]，進(jìn)而精準(zhǔn)無損傷地在體量化器官組織的pH值[48]，不僅量化細(xì)胞內(nèi)pH (pHi)，結(jié)合外源性對(duì)比劑[39, 49]，也量化細(xì)胞外pH (pHe)值，有助于良性腫瘤與惡性腫瘤的鑒別，也有助于腫瘤異質(zhì)性的判定，觀察一些疾病的治療效果。

2.2 在體器官組織的溫度測定

結(jié)合外源性對(duì)比劑[50]，應(yīng)用氨基質(zhì)子轉(zhuǎn)移技術(shù)可以在體測定pH值的同時(shí)，測定組織的溫度差異。結(jié)合水交換譜(w ater exchange spectrum, WEX)，不應(yīng)用外源性對(duì)比劑也可以獲得相似的pH和溫度信息，該技術(shù)也有在體應(yīng)用的潛力[51]，無損傷的在體器官組織磁共振溫度測定相對(duì)于紅外線溫度測定，其內(nèi)部結(jié)構(gòu)更清楚，有望應(yīng)用于腫瘤射頻治療的溫度監(jiān)測。

2.3 在各器官組織的應(yīng)用

2.3.1 在腦的應(yīng)用

APT技術(shù)早期應(yīng)用于腦梗塞的研究，認(rèn)為APT成像比彌散加權(quán)像在顯示梗死組織方面更有優(yōu)勢[1]，在判斷腦梗死半暗帶方面也有優(yōu)勢[52]，能更精確判斷腦梗死半暗帶的范圍，這對(duì)于是否選擇溶栓治療非常有幫助。APT成像在腦梗死方面的研究一直持續(xù)至今[52-55]，在超急性期腦卒中的動(dòng)物中，可簡便地區(qū)分開出血性腦中和缺血性腦卒中[55]。APT技術(shù)同時(shí)也較多地應(yīng)用于腦腫瘤方面的研究[3, 24, 56]，研究認(rèn)為APT技術(shù)有助于腦腫瘤的診斷、鑒別診斷和治療，應(yīng)用APT技術(shù)顯示膠質(zhì)瘤的內(nèi)部結(jié)構(gòu)，可以與應(yīng)用對(duì)比劑時(shí)才能獲取的信息相媲美，可應(yīng)用于轉(zhuǎn)移瘤和高級(jí)別神經(jīng)上皮腫瘤的鑒別診斷。在神經(jīng)變性疾病方面，APT技術(shù)有助于神經(jīng)變性疾病的早期診斷，可作為帕金森病臨床診斷和病情監(jiān)測的有效工具，為帕金森病的病理生理研究提供重要的信息[29]。

2.3.2 在腎臟的應(yīng)用

結(jié)合外源性對(duì)比劑，APT技術(shù)可應(yīng)用于腎臟pH的測定，目前在小鼠腎臟獲得了較好的pH成像[49]，有望應(yīng)用于腎臟損傷程度的判定、腎臟腫瘤的診斷和鑒別診斷，以及腎移植的效果評(píng)價(jià)等。

2.3.3 在肝臟的應(yīng)用

結(jié)合APT技術(shù)和CEST技術(shù)，肝APT加權(quán)像和肝糖原成像已在動(dòng)物和人體成功獲得。在動(dòng)物實(shí)驗(yàn)中，禁食前后和四氯化碳中毒模型前后肝APT加權(quán)像和肝糖原成像均有明顯的差異。人體肝APT加權(quán)像和肝糖原成像也有好的重復(fù)性。為常規(guī)磁共振肝成像提供了有益的補(bǔ)充，特別是有益于早期肝纖維化的認(rèn)識(shí)，這對(duì)于今后肝臟疾病的處理會(huì)有影響[30]。

2.3.4 在乳腺的應(yīng)用

APT技術(shù)也應(yīng)用到乳腺組織[57-58]。在動(dòng)物乳腺癌模型研究中，結(jié)果表明APT技術(shù)提供癌細(xì)胞在腫瘤組織內(nèi)的分布信息，有望了解腫瘤對(duì)周邊正常組織侵襲的情況[57]。應(yīng)用APT技術(shù)在人乳腺正常纖維腺樣組織成功成像，今后也可應(yīng)用于研究病理組織，有益于乳腺疾病的診斷和預(yù)后判定[58]。

圖1 化學(xué)交換飽和轉(zhuǎn)移的二池模型 圖2 4個(gè)pH值不同的離心試管(a～d)與裝有等量水的試管(e)的磁化傳遞成像，施加了預(yù)報(bào)和脈沖，紅圓圈所標(biāo)定的是感興趣區(qū)，測定結(jié)果a～d各試管信號(hào)強(qiáng)度不同F(xiàn)ig. 1 Model of Two pools for CEST Fig. 2 MT imaging of four centrifuge tubes with different pH values(a—d) and a tube w ith water (e) obtained w ith saturation pulse. The red circles denote regions of interest with different signal intensities for tubes a—d.

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M agnetic resonance am ide p roton transfer (APT) imaging: description of technical principles and potential applications

WU Ren-hua*
Department of M edical Imaging, the 2nd A ffiliated Hospital, Shantou University M edical College, Shantou 515041, China

Am ide proton transfer (APT) imaging is related to chem ical exchange saturation transfer (CEST) technique. This review focuses on description of APT technical principles, factors influencing APT imaging, and relationship between in vivo APT imaging and nuc lear Overhauser effect (NOE). Potential clinical applications of APT technique, such as pH imaging, temperature imaging, as well as APT-weighted imaging for organs and tissues, are discussed.

Am ide proton transfer; Chem ical exchange saturation transfer; Nuclear Overhauser effect; pH imaging; Tem perature imaging

國家自然科學(xué)基金項(xiàng)目(編號(hào)：81471730)

汕頭大學(xué)醫(yī)學(xué)院第二附屬醫(yī)院，汕頭515041

ail: cjr.wurenhua@vip.163.com

2016-02-17

接受日期：2016-04-03

R445.2

A

10.12015/issn.1674-8034.2016.04.003

吳仁華. 磁共振氨基質(zhì)子轉(zhuǎn)移成像技術(shù)原理和應(yīng)用. 磁共振成像, 2016, 7(4): 254–258.

*Correspondence to: Wu RH, E-mail: cjr.wurenhua@vip.163.com