鄭陽，王曉明

磁化傳遞成像和酰胺質子轉移成像聯合評價新生兒腦損傷的初步研究

鄭陽，王曉明*

目的應用酰胺質子轉移成像(amide proton transfer，APT)聯合磁化傳遞(magnetization transfer，MT)成像對新生兒從腦內環(huán)境角度評估新生兒腦損傷。材料與方法新生兒共38名，腦損傷13例，為病例組；常規(guī)MRI檢查腦內無異常25例為對照組。常規(guī)MRI檢查后補充APT-MT成像掃描。測量所有新生兒雙側額葉深部白質、基底節(jié)區(qū)、枕葉深部白質的APT值以及磁化傳遞率(magnetization transfer ratio，MTR)值（以下用APT/MTR表示），以及病例組病灶區(qū)及其對側的APT/MTR值。采用SPSS 19.0軟件進行統(tǒng)計分析。結果(1)對照組中，額葉深部白質、基底節(jié)及枕葉深部白質APT/MTR值均有顯著性差異(P＜0.05)。(2)對照組中，APT/MTR值隨孕齡增長而逐漸升高。(3)病例組病灶內APT/ MTR值低于對側(P＜0.05)。結論圍產期缺氧缺血是全腦代謝變化，APT-MT成像可從內環(huán)境及分子水平評估新生兒腦損傷。

磁共振成像；新生兒；腦；酰胺質子轉移成像；磁化傳遞成像

Key wordsMagnetic resonance imaging; Neonatal; Brain; Amide proton transfer; Magnetization transfer imaging

缺氧缺血腦損傷是圍產期多種原因引起的腦組織病變，是一種全腦的缺氧缺血(hypoxic ischemic，HI)后再灌注性腦損傷。目前再灌注損傷在HIE發(fā)病中的作用日益受到重視，當腦組織由低灌注轉移到再灌注時，會出現一系列病理生理改變。當腦內HI時，有氧能量代謝過程障礙[1-3]，有氧代謝轉為無氧代謝，無氧代謝過程產生乳酸，腦組織內乳酸增多，堆積的乳酸可以使糖代謝受到抑制，使ATP耗竭，從而使細胞內酸中毒加重[4-5]。

新生兒圍產期各種原因造成的腦損傷，會引起腦組織內環(huán)境的改變。有研究表明，HI后腦組織酸中毒，哺乳動物腦組織細胞內pH值約在7.2～7.3左右，細胞外pH值約在7.3～7.4左右[6-8]。腦內pH的調節(jié)至關重要，對于腦內蛋白質的結構及酶的作用尤為明顯，因此及時了解及調控細胞內pH值對腦組織改善是非常重要的。能否應用磁共振技術反映這種腦組織內環(huán)境的變化是一個新的課題，近年來一種新的磁共振內對比技術即酰胺質子轉移(amide proton transfer，APT)成像[9]，可以通過水的信號變化來反映蛋白質及體內酸堿度的變化。APT成像信號取決于酰胺質子和自由水質子的交換速率[10]，而這種交換速率依賴于體內的酸堿度及蛋白質濃度[11-13]。APT技術正是基于上述原理利用水的信號產生內對比。目前，該技術已經在多方面進行應用研究[14-19]。

磁化傳遞(magnetization transfer，MT)成像是通過測量生物組織內大分子中的質子和自由水質子的相互作用來實現的[20]，大分子中的質子包括與蛋白質、其他大分子、膜結合的質子。不同組織的磁化傳遞量是不同的，對組織的磁化傳遞進行定量分析，可以了解組織的特征，最常用的定量指標是磁化傳遞率(magnetization transfer ratio，MTR)，MTR代表生物大分子完全或部分飽和所導致的信號百分比。本研究通過APT聯合MT成像對新生兒腦損傷進行評估，從腦內環(huán)境角度評估新生兒腦損傷的病理生理變化。

1 材料與方法

1.1 研究對象及分組

以本院新生兒病房申請MR掃描者為研究對象，患者住院原因主要有呼吸道感染、腹瀉、發(fā)熱、皮膚黃染等，臨床醫(yī)師懷疑腦部有病變者，申請MRI檢查。排除腦內占位，發(fā)育遲緩，先天畸形以及腦內代謝疾病等，其中常規(guī)MRI發(fā)現不同程度腦白質損傷和(或)腦梗死，作為病例組；與病例組孕齡相匹配(校正孕齡天數相差±2 d)，且常規(guī)MRI未發(fā)現神經系統(tǒng)異常者，作為對照組。以上診斷均由2名及以上有經驗的影像醫(yī)師共同完成。以上研究設計獲得本院倫理委員會批準(倫理編號：2016PS280K)。在獲得患兒監(jiān)護人知情同意并經過臨床醫(yī)生對新生兒狀態(tài)評估得到允許的前提下，完成常規(guī)MRI檢查后立即行APT-MT 成像掃描。所有新生兒在常規(guī)檢查前 30 min給予5 %的水合氯醛(50 mg/kg)灌腸，檢查時注意保暖及舒適。

1.2 常規(guī)MR掃描設備及參數

所有新生兒采用Philips 3.0 T MR儀(Achieva 3.0 T TX；Philips Healthcare Systems，Best，the Netherlands)進行掃描，筆形束，二階勻場。體線圈發(fā)射，八通道頭線圈(SENSE)接收。常規(guī)MR掃描方案：T1WI、T2WI、DWI。常規(guī)MRI序列參數如下：T1WI采用FFE序列：TR 200 ms，TE 2.3 ms，FOV 188 mm×155 mm，矩陣256×180，層厚5 mm，掃描時間36.8 s ；T2WI采用TSE序列：TR 200 ms，TE 4.6 ms，FOV 180 mm×161 mm，矩陣224×162，層厚5 mm，掃描時間42.8 s。

1.3 APT-MT序列及圖像后處理

APT-MT序列：APT-MT掃描一次采集，后處理過程中分別得出APT及MT的圖像及數據。所有新生兒采用橫斷位T1WI定位，定位于基底節(jié)層面。病例組增加顯示病灶最大層面。 APT-MT采用多次偏置射頻脈沖采集方法[21]，連續(xù)頻率飽和脈沖500 ms。APT-MT圖像采集和Z譜采集相結合同時采集。在距離水的共振頻率不同位置處(0，±0.25，±0.5，±0.75，±1，±1.5，±2，±2.5，±3 (2)，±3.25(4)，±3.5 (8)，±3.75 (4)，±4 (2)，±4.5，±5，±6 ppm和15.6 ppm；括號里的數字代表采集的次數，沒有括號標記的表示采集一次(采集多個頻率飽和射頻脈沖，未施加射頻激勵的圖像作為標準化圖像。這種采集方法能夠校正B0場的不均勻性，得出的APT圖像有較好的信噪比，并且使掃描時間能夠更加接近于臨床應用，單層掃描時間4 min16 s。APT-MT掃描參數如下：TR 4000 ms；TE 8.1 ms；矩陣108×71，FOV 170 mm×145 mm，層厚5 mm。將 APT-MT 原始數據導入交互式數據分析語言中的程序(IDL；Research Systems，Inc.，Boulder，CO，USA)進行分析測值并重建出偽彩圖。首先，獲得基于體素的Z譜(標準化的信號強度，Ssat/S0是31個偏置脈沖的函數，Ssat是施加飽和脈沖后的信號強度，S0是未施加飽和脈沖的信號強度)。通過一個12階的多項式擬合，獲得Z譜最低點的位置，得到B0場的不均勻分布，從而對Z譜進行場校正。在經過校正后的Z譜取左右對稱的±3.5 ppm (APT)及15.6 ppm (MT)數據點，進行非均勻性分析[MTRasym(3.5 ppm)=Ssat(－3.5 ppm)/S0－Ssat(3.5 ppm)/ S0]、MTR=1－Ssat/S0最終獲得APT及MT權重磁共振成像，APT及MTR值用百分比表示。

1.4 感興趣區(qū)的選擇及數據后處理

感興趣區(qū)(region of interest，ROI)的選擇由有經驗的影像醫(yī)師來完成，所有新生兒選擇雙側額葉深部白質、基底節(jié)及枕葉深部白質(圖1)，病例組增加病灶及病灶對側相同部位的ROI。以T1WI作為參考，小心地在APT及MT偽彩圖中勾畫并測量APT/MTR值。APT-MT偽彩圖中信號由高到低顯示為由紅～藍，相應APT/MTR值為由大到小。ROI選擇注意避開顱骨、腦脊液及腦室。病例組ROI選擇應在病變范圍內，不超過病變邊緣。

1.5 統(tǒng)計學分析

數據統(tǒng)計學處理采用軟件SPSS 19.0軟件處理，計量資料以均數±標準差表示。采用配對樣本t檢驗，分析對照組各部位雙側APT/MTR值是否存在差異，若無差異，雙側APT/MTR值按部位納入各組進行分析；采用ANOVA分析，比較對照組額葉、基底節(jié)及枕葉深部白質之間APT-MT值是否存在顯著性差異。采用兩樣本t檢驗分析病例組病灶及對側APT-MT值是否存在差異。P＜0.05為差異有統(tǒng)計學意義。

圖2 對照組新生兒腦內APT/MTR值隨孕齡(周)的變化。A～C：為對照組腦內額葉深部白質、基底節(jié)及枕葉深部白質APT值隨孕齡變化趨勢；D～F：為對照組腦內額葉深部白質、基底節(jié)及枕葉深部白質MTR值隨孕齡變化趨勢。腦內不同部位APT/MTR值隨孕齡增長而升高Fig. 2 Changes between gestational age (weeks) and APT/MTR values of control group. Changes between gestational age (weeks) and APT values in the deep white matter of the frontal lobe (A), basal ganglia (B), and deep white matter of the occipital lobe (C). Changes between gestational age (weeks) and MTR values in the deep white matter of the frontal lobe (D), basal ganglia (E), and deep white matter of the occipital lobe (F).

2 結果

2.1 研究對象

常規(guī)MRI發(fā)現腦損傷者(新生兒腦白質不同程度損傷9例，左腦半球新發(fā)大面積腦梗死1例，局灶腦梗死3例)共13例，作為病例組。孕齡27～41周，中位年齡為34周+5 d。其中早產兒8例，中位年齡32周+1 d；足月兒5例，中位年齡37周+4 d。

與病例組孕齡匹配(校正孕齡相差≤2 d)，且常規(guī)MRI腦內無異常表現新生兒25名(不包括出生窒息，先天畸形，發(fā)育落后等神經系統(tǒng)疾病)作為對照組，孕齡27～41周，中位年齡為36周+1 d。其中包括早產兒13例，中位年齡為32周+3 d；足月兒12例，中位年齡為37周+5 d。

2.2 對照組新生兒APT/MTR值統(tǒng)計及分析

對照組中，各部位(額葉深部白質、基底節(jié)及枕葉深部白質) APT/MTR值雙側均無顯著性差異(P＞0.05)。因此，各部位雙側APT/MTR值分別納入各部位統(tǒng)計。額葉深部白質、基底節(jié)及枕葉深部白質之間APT/MTR值存在顯著性差異(P＜0.05)，由大到小依次為：基底節(jié)，枕葉深部白質，額葉深部白質。對照組新生兒各部位(雙側額葉深部白質、基底節(jié)及枕葉深部白質) APT/MTR值隨孕齡(周)增加呈升高趨勢(圖2，3)。

圖3 對照組不同修正月齡的新生兒腦MR軸面圖像。a～c列為早產兒腦(修正孕齡28周+1 d、30周+2 d、35周+5)，d列為足月兒腦(40周+3 d)。第一排為T1WI，第二排為相應的T2WI，第三排為APT圖像，第四排為MT圖像。由圖3可見，隨著修正孕齡增長與髓鞘化形成，APT信號逐漸升高(受限于對比度)，MT成像信號也增高(基底節(jié)顯示最為明顯)Fig. 3 Axial MRI Images of neonatal brain at different corrected gestational ages. Columns a—d represent images from neonates with corrected gestational ages of 28 w+1 d、30 w+2 d、35 w+ 5, and 40 w+3 d, respectively. Images from the 4 rows are as follows: row 1=T1WI; row 2=T2WI images; row 3=APT images; and row 4 = MTR images. From Figure 3, we can conclude that with increased growth associated with age, the APT signal appears to gradually increase (signal is somewhat limited by image contrast). The MT signal is increased with gestational ages.

2.3 病例組APT/MTR值統(tǒng)計及比較

病例組13名腦損傷新生兒，病灶側APT/ MTR值與對側相對正常區(qū)域進行比較，結果顯示，病灶側APT/ MTR值與對側存在顯著差異(P＜0.05)：病灶APT=0.45%±0.15%，病灶對側APT=0.95%±病灶MTR=12.68%± 2.03%，病灶對MTR= 17.52%±2.12%(圖4)。病變區(qū)APT/MTR信號較對側減低(圖5)。

4 討論

新生兒腦正常狀態(tài)下內環(huán)境的成分及理化性質在一定范圍內保持穩(wěn)態(tài)，穩(wěn)態(tài)的維持對于腦細胞的生存及腦發(fā)育十分重要[6]。若發(fā)育過程中某種原因導致代謝障礙或供能不足，腦組織缺氧導致局部乳酸等代謝物堆積，腦內環(huán)境也將改變[22]。腦內MTR值的高低主要與組織中的大分子(腦內主要為髓鞘內的膽固醇、脂類)的含量有關[23]，通過 MTR可以間接得到組織的內部組成，提供組織特征。早產兒與足月兒腦發(fā)育程度不同，腦內蛋白含量及髓鞘化程度不同。APT值與蛋白質濃度及pH值均呈正相關，APT-MT值越大表示蛋白質含量及半固態(tài)大分子含量的增加。APT是建立在MT技術基礎之上的，基于蛋白質及多肽中的酰胺質子與水質子之間的交換，反映游離的蛋白質氨基質子濃度的變化。由于APT技術對組織內酸堿度敏感[24]，在急性HI時，假定酰胺質子濃度和溫度保持在恒定，APT值的變化主要反映pH的變化。

圖4 病灶側與病灶對側APT/MTR值分布及比較。病灶內APT/MTR值明顯低于病灶對側Fig. 4 Distribution and comparison of lesion and contralateral region APT/MTR values. The APT/MTR values within lesion are lower than that of contralateral region.

圖5 病例組新生兒腦MR軸面圖像。a、b、c分別是T1WI、T2WI及DWI序列，d、e分別為APT及MT偽彩圖。第1行：女，38周新生兒。左腦半球新發(fā)大面積腦梗死；左腦半球呈大片長T1、長T2信號；DWI呈高信號，累及左顳、枕部及胼胝體壓部；圖d、e顯示位于左腦半球的梗死病灶較右側顯示為低信號(黑色箭頭所示，由于APT圖像分辨率有限，病灶顯示不如MT圖像明顯)。病灶及病灶對側APT/MTR值分別為：APT：0.48%，1.50%；MTR：12.86%，18.43%。第2行：女，足月。左顳葉近期新發(fā)梗死；左顳葉DWI序列呈高信號，APT及MTR偽彩圖中顯示病灶(黑色箭頭所示)信號減低。病灶及病灶對側APT/MTR值分別為：APT：0.44%，0.93%；MTR：13.43%，16.76%。第3行：男，36周+5 d。右顳葉軟化灶形成；右顳葉病灶DWI序列顯示為低信號，d、e顯示病灶(黑色箭所示)信號減低(由于軟化灶形成，腦組織部分蛋白水解，病灶處水含量增多，APT圖像中病灶中出現較多偽影)。病灶及病灶對側APT/MTR值分別為：APT：0.29%，0.91%；MTR：10.25%，16.31%Fig. 5 Axial MRI Images of neonatal brain of case group. a, b and c respectively represent T1WI, T2WI and DWI sequence, figure d, e respectively represent APT and MT images. Row 1: Female, newborn, 38 weeks. Left hemisphere emerging massive cerebral infarction. Left brain hemisphere displayed as long T1 and long T2. DWI showed hyperintensity, involving left temporal, and occipital lobes and the corpus callosum. APT-MT pseudo color, with left brain hemisphere of infarction lesions (black arrow, APT=0.48%, MTR=12.86%) showing a lower signal than the right hemisphere (APT=1.50%, MTR=18.43%). Row 2: Female, full-term infant. Left temporal new cerebral infarction. Left brain hemisphere displayed as DWI hyperintensity. APT-MT pseudo color, with left temporal of infarction lesions (black arrow, APT=0.44%, MTR=13.43%) showing a lower signal than the right hemisphere (APT=0.93%, MTR=16.76%). Row 3: Male, 36 w+5 d, right temporal infarction. Right temporal displayed as DWI hyperintensity. APT-MT pseudo color, with right temporal of infarction lesions (black arrow, APT=0.29%, MTR=10.25%) showing a lower signal than the right hemisphere (APT=0.91%, MTR=16.31%). Due to the formation of softening foci, partial proteolysis of brain tissue, water content in lesions increased, some artifacts appear in APT images in the lesions.

本研究結果顯示，對照組中早產兒與足月兒腦內各部位APT/MTR值不同，這是由于在不同孕齡時期，腦內發(fā)育的程度不同，腦內蛋白質濃度不同所致，而APT/MTR值技術對于蛋白質濃度敏感，能夠探測到早產兒與足月兒之間的這種改變。而各部位的APT/MTR值不同，結果顯示APT/ MTR值由大到小依次為：基底節(jié)區(qū)、枕葉深部白質、額葉深部白質，這與髓鞘化順序從下至上，先中央后周圍，由背側向腹側相一致[25-26]，這正符合腦發(fā)育的順序。當由于某種原因，如早產造成血管發(fā)育不良或腦細胞缺氧缺血時，有氧代謝過程受到障礙，能量來源轉為依靠糖無氧酵解，無氧酵解產生乳酸，使細胞發(fā)生酸中毒，此時酸中毒進一步導致糖代謝受到抑制，代謝率及ATP產生率下降，從而使細胞內酸中毒惡性循環(huán)加重[27]。并且，由于無氧代謝能量不足，細胞膜無法維持正常的離子泵功能，Na+-H+、K+-H+離子交換紊亂，導致H+潴留在細胞內，造成腦組織內乳酸堆積[1，3，28]，導致代謝性酸中毒，病變組織的pH值較其他正常組織低，同時，缺氧也會導致少突膠質細胞損傷[29-30]，會導致發(fā)育障礙，蛋白質合成受到影響，也會導致APT/MTR值的降低。

對于缺氧缺血帶來的內環(huán)境中酸堿度發(fā)生的改變，MRI常規(guī)序列是無法通過水的信號探測到的，而APT-MT技術正是一種通過組織內蛋白質濃度和酸堿度產生內對比的新技術[31]。APT成像中，酰胺質子與水的交換速率是關鍵因素[32-33]，而這種交換速率取決于蛋白質濃度及pH值。Zhou等[10]的小鼠實驗結果顯示，交換速率對于體內酸堿度非常敏感，pH值每改變0.5個單位，交換速率就會發(fā)生50%～70%的改變，這種敏感性使APT技術能夠應用于新生兒腦損傷的評估。

圖4患兒1～3病灶處DWI序列分別為高信號、低信號，表明患兒1、2為近期新發(fā)梗死，患兒3為梗死慢性期或軟化灶形成期?；純?、2 APT/MTR值減低不如患兒3明顯，即DWI序列高信號的病灶中，APT/MTR值較DWI低信號病灶高，分析其主要原因可能是新發(fā)病灶處于細胞毒性水腫期[34]，腦組織蛋白質變化不如梗死慢性期或軟化灶明顯。梗死慢性期或軟化灶內腦組織蛋白質水解，蛋白濃度減低，APT/MTR值進一步降低，故本研究觀察到陳舊梗死灶APT/MTR值較新發(fā)梗死值更低。因此筆者推測，APT-MT成像能夠反映病灶損傷的時期，為梗死發(fā)生的時間提供信息。具體反映梗死急性期及慢性期的APT/MTR臨界值需要進一步研究。

同時，病例組結果可以得出，針對組織內pH值敏感的APT技術能夠從內環(huán)境水平向發(fā)病原因更進一步進行探測及無創(chuàng)評估腦損傷，這在將來應用于體內無創(chuàng)探測組織內生化環(huán)境有很大前景。值得注意的是，APT技術是在一定條件下應用的：在急性缺氧缺血時[35]，假定酰胺質子濃度基本不變，HI導致的腦組織酸中毒是APT值變化的主要原因。同時，小范圍的溫度波動對于交換速率的影響是忽略不計的。APT技術在臨床應用之前，需要解決的問題有很多[35-37]，如直接水飽和效應、磁化傳遞及提高信噪比，如何提供更好的圖像，以及合適的掃描時間、偏置射頻脈沖的能量及翻轉角度等需要研究。總之，APT技術利用內源性蛋白質及酸堿度無創(chuàng)地成像，可以對新生兒腦損傷進行評估，對深入理解腦發(fā)育過程及理解腦損傷機制有幫助。

新生兒圍產期缺氧缺血存在著內環(huán)境酸堿度的變化，APT-MT技術可以通過內環(huán)境中蛋白質濃度和酸堿度的變化來評估腦損傷，為深入理解新生兒腦損傷提供了新的思路。

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Evaluation of brain injury in neonates by magnetization transfer imaging combined amide proton transfer imaging: a preliminary study

ZHENG Yang, WANG Xiao-ming*
Department of Radiology, Shengjing Hospital of China Medical University, Shenyang 110004, China
*Correspondence to: Wang XM, E-mail: wangxm024@163.com

Objective:To evaluate neonatal brain injury at the internal environmental level with the application of amide proton transfer (APT) imaging and magnetization transfer (MT) imaging by measuring the APT and MTR values of the brain.Materials and Methods:A total of 38 neonatal patients who underwent MRI examination were enrolled in the study. Among them, there were 25 newborns with no abnormalities and 13 cases with brain injury who underwent conventional MRI (T1WI, T2WI, DWI) examination. After obtaining informed consent and permission of clinicians, routine MRI was followed by additional APT-MT scan. APT-MT imaging is single slice scanning, performed at the basal ganglia level in all neonates, and in the case group, with increased localization at the level of lesion, and with the contralateral relatively normal area as self-control. The APT/MTR values of bilateral frontal subcortical white matter, basal ganglia and occipital subcortical white matter were measured for all neonates, as well as the APT/MTR values of the lesion and contralateral areas. Several statistical methods were used for statistical analysis.Results:In the control group, bilateral frontal subcortical white matter, basal ganglia and occipital subcortical white matter had no signif i cant difference in APT/MTR values (P＞0.05). Between the different parts of the brain, the differences among the APT/ MTR of the frontal lobes, basal ganglia, and occipital lobes were signif i cant,P＜0.05. In addition, the APT/MTR values of the above brain regions were found to have a positive correlation with gestational age. In the case group, there were significant differences in APT values between the lesion side and contralateral area, being significantly lower in lesion side than the contralateral side (P＜0.05).Conclusions:From changes in the pH level in the neonatal brain, APT-MT imaging can help to understand neonatal brain injury.

國家自然科學基金(編號：30570541、30770632、81271631)

中國醫(yī)科大學附屬盛京醫(yī)院放射科，沈陽 110004

王曉明，E-mail：wangxm024@163. com

2016-12-19

接受日期：2017-01-10

R445.2；R737.9

A

10.12015/issn.1674-8034.2017.03.006

鄭陽, 王曉明. 磁化傳遞成像和酰胺質子轉移成像聯合評價新生兒腦損傷的初步研究. 磁共振成像, 2017, 8(3): 189-195.

Received 19 Dec 2016, Accepted 10 Jan 2017

ACKNOWLEDGMENTSThis study was supported by National Natural Science Foundation of China (NO. 30570541, 30770632, 81271631).