鼻咽癌患者放疗前后脑白质微观结构的动态改变与其神经认知功能的相关性：DTI-TBSS研究
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摘要
第一部分鼻咽癌患者放疗前后认知功能与正常人对照研究
目的：
采用简易精神状态检查(mini mental status examination, MMSE)量表对鼻咽癌患者接受放射治疗前及放射治疗后不同时间点进行整体认知功能的动态评价,探讨放疗对鼻咽癌患者神经认知功能的影响及变化趋势。
材料与方法：
1.研究对象
本研究共纳入128例被试,其中鼻咽癌患者组100例,正常对照组28例。100例鼻咽癌患者中,男72例,女28例,平均年龄43.73±9.88岁(19-65)岁,受教育程度10.27±3.24年(6-16)年。所有患者均由病理活检证实,肿瘤分期为T1N0M0～T4N2Mo期(UICC第七版)。放疗后磁共振随访时间从放疗完成后1周至12年不等,中位随访时间为7.5个月。根据国内外研究,我们将患者组按放疗前和放疗完成后行DTI检查的不同时间将其分为4组：第1组为放疗前组(pre-RT),25例；第2组为放疗后0-6个月组(post-RT0-6m)(放疗后平均3.02个月),25例；第3组为放疗后>6-12个月组(post-RT>6-12m)(放疗后平均8.14个月),25例：第4组为放疗后>12个月组(post-RT>12m)(放疗后平均31.19个月),25例。鼻咽癌患者组的纳入标准包括：(1)均为病理证实后放疗前或首次接受放射治疗的患者；(2)鼻咽癌治疗方案接近,均施行三维适形调强放射治疗(总剂量/分割剂量/分割次数,66-74GY/1.8～2.0GY/30-35次)。所有患者在放疗期间至放疗后均联合应用多药化疗,主要化疗药物有5-氟尿嘧啶、顺铂和紫杉类等；(3)均为汉族,右利手；(4)无颅内侵犯及脑内转移；(5)颅内无脑血管病变及脑肿瘤病变；(6)无头颅外伤史及颅内手术史；(7)无高血压、心脏病、糖尿病、高血脂、代谢性疾病及精神疾病；(8)常规MR平扫及增强扫描颅内未发现明显异常信号改变。
正常对照组28例(年龄、性别、受教育程度、利手与鼻咽癌患者组相匹配的健康人),男20例,女8例,平均年龄43.57±11.75岁(24～62)岁,受教育程度10.29±3.63年(6～16)年。所有纳入的研究对象均在试验前被详细告知试验目的、方法和注意事项,并签署知情同意书正式同意参加试验。
2.神经心理学测试
采用简易精神状态检查(mini mental status examination, MMSE)量表对所有128例被试的整体认知功能进行评价。
3.统计学分析
利用SPSS13.0软件,采用单因素方差分析(one-way ANOVA)评价鼻咽癌患者放疗前、放疗后不同时间组及对照组之间年龄、受教育程度的差异,采用卡方检验评价上述各组之间性别构成的差异。采用多个独立样本比较的Kruskal-Wallis H检验比较各组间MMSE评分的差异,组间有差异者进一步多重比较,采用Bonferroni法调整P值。检验水准α取0.05,P<0.05认为差异有统计学意义。
结果：
1.鼻咽癌患者放疗前组、放疗后不同时间组以及正常对照组之间年龄(F=0.908,P=0.462)、性别(χ2=1.191,P=0.880)及受教育程度(F=0.253,P=0.907)差异无统计学意义(P>0.05)；所有被试均为右利手,分组均衡性尚好。
2.鼻咽癌患者放疗前组、放疗后不同时间组及正常对照组之间MMSE评分的差异无统计学意义(χ2=5.429,P=0.246)。
结论：
1、鼻咽癌患者局部三维适形调强放疗后的MMSE评分与放疗前及正常对照组相比,随着时间的推移,在统计学上没有显著性降低。
2、鼻咽癌三维适形调强放疗后患者的认知功能具有动态变化的趋势,放疗后6个月内MMSE评分出现一过性的轻度降低,之后逐渐升高,1年后恢复至放疗前水平。
3、采用局部三维适形调强放射治疗的现代技术,常规分割剂量(≤2Gy),常用的总剂量(66～74Gy),分割次数为30～35次,治疗鼻咽癌是安全的,对常规头颅MRI阴性患者的整体认知功能无显著影响。
第二部分鼻咽癌患者放疗前后脑白质微观结构改变：DTI-TBSS研究
目的：
1、利用磁共振扩散张量成像技术(DTI)和基于纤维束示踪的空间统计(tract based spatial statistic, TBSS)的后处理技术,与放疗前基线水平及正常对照组比较,评价鼻咽癌患者放疗后不同时期脑白质微观结构的动态改变情况。
2、探讨鼻咽癌患者放疗前后不同时期脑白质微观结构改变与其整体认知功能评分之间的关系。
材料与方法：
1.研究对象
107例被试被纳入本研究：鼻咽癌患者组81例,平均年龄为44.26±9.91岁(19-65岁),男60例,女21例,受教育程度10.27±3.30年(6～16年)。所有患者均由病理活检证实,肿瘤分期为T4N2Mo期(UICC第七版)。放疗后磁共振随访时间从放疗完成后1周至4年7个月不等,中位随访时间为7.5个月。根据国内外研究,我们将患者组按放疗前和放疗完成后行DTI检查的不同时间将其分为4组：第1组为放疗前组(pre-RT),23例；第2组为放疗后0-6个月组(post-RT0-6m)(放疗后平均3.14个月),21例；第3组为放疗后>6-12个月组(post-RT>6-12m)(放疗后平均8.13个月),20例；第4组为放疗后>12个月组(post-RT>12m)(放疗后平均23.89个月),17例。鼻咽癌患者组的纳入标准同第一部分。
正常对照组26例(年龄、性别、受教育程度、利手与鼻咽癌患者组相匹配的健康人),平均年龄为43.73±11.67岁(24～62岁),男18例,女8例,受教育程度10.23±3.49年(6-16年)。所有纳入的研究对象均在试验前被详细告知试验目的、方法和注意事项,并签署知情同意书正式同意参加试验。
2.神经心理学测试
采用简易精神状态检查(mini mental status examination, MMSE)量表对所有被试的整体认知功能进行评价(同第一部分)。
3.扫描设备与序列
所有被试均采用美国GE SIGNA EXCITE3.0T磁共振成像仪扫描进行静息态下脑功能数据采集,使用标准八通道头颅线圈接收核磁共振信号。DTI数据采集之前均进行常规的全脑轴位T1WI、T2WI及FLAIR序列扫描,以排除脑部疾患。DTI数据采集采用单次激发平面回波(single-shot echo-planar imaging, SS-EPI)序列以及并行采集技术(array spatial sensitivity encoding technique, ASSET),平行于大脑前后联合连线平面,得到覆盖全脑的轴位扩散加权图像。具体参数如下：扩散敏感梯度方向为25个,扩散敏感系数b值为1000s/mmz和0s/mmm2,重复时间(TR)=12000ms,回波时间(TE)=75.5ms,视野(FOV)=24cm×24cm,矩阵(matrix size)=128×128,层厚(thickness)=3.Omm,层间距(slice gap)=0mm,激励次数(NEX)=1,翻转角(flip angle)=90°。
4.图像后处理
DTI数据分析采用FSL (FMRIB Software Library, www.fmrib.ox.ac.uk/fsl, version4.1.9)提供的工具包。具体步骤包括：(1)使用FSL软件FDT套件中的eddy correct函式对原始DTI数据进行头动和涡流校正。(2)利用FSL软件中BET套件以每个被试者的B0图像作为依据,产生各自的脑mask。(3)通过FDT套件中的dtifit函式,进行扩散张量的计算。输出的结果包括：部分各向异性(fractional anisotropy, FA)、平均扩散率(mean diffusivity, MD)、三个本征值(λ1、λ2、λ3)及相对应的三个特征向量(V1、V2、V3)等,再通过FSL函式计算出λ#(λ#=λ1)和λ⊥[λ⊥=(λ2+λ3)/2]。然后按照TBSS流程进行分析：tbss_1_preproc, tbss_2_reg,tbss_3_postreg,tbss_4_prestats。接着利用FSL软件中的randomise函式分别对鼻咽癌患者放疗前、放疗后不同时间组及正常对照组的FA值、MD值、λ#值和λ⊥值进行基于纤维束示踪的全脑显著性差异统计分析,参考TFCE (threshold-free cluster enhancement)的演算法,在统计方法上通过permutation的方法,从而有效地控制并校正在多重比较时寻找被试者间FA图数值差异时可能发生的FWE(family-wise error)概率。
5.统计学分析
FA值、MD值、λ#值及λ⊥值图组间基于体素的比较,采用randomize工具进行的非参数统计阈值分析的统计方法,置换测试次数为5000,多重比较校正采用以簇为基础的校正方法,P<0.05且簇>50个体素(体素大小：1×1×lmm3)认为有统计学意义。采用偏相关分析方法(以年龄和受教育程度为协变量),评价鼻咽癌患者放疗前、放疗后TBSS的相关指标(包括组间差异区域的平均FA值、MD值、λ#值及λ⊥值)与其MMSE评分之间的相关关系。P<0.05认为相关性有统计学意义。
结果：
TBSS结果：
1.平均FA值
右侧额叶、顶叶及枕叶白质的FA值在放疗后0-6月组(G2)较放疗前(G1)明显下降(P<0.05,多重比较校正),之后逐渐恢复,其中右侧额叶及右侧顶叶白质的FA值在放疗后一年以上组(G4)仍未恢复至放疗前水平,明显低于放疗前水平；右侧枕叶白质的FA值在放疗后一年以上组(G4)恢复至接近放疗前水平,未见明显差别。右侧小脑及左侧顶叶白质的FA值在放疗后0-6月组(G2)较放疗前(G1)明显升高(P<0.05,多重比较校正),之后逐渐减低,其中右侧小脑的FA值在放疗后一年以上组(G4)仍未恢复至放疗前水平,明显高于放疗前水平；左侧顶叶白质的FA值在放疗后一年以上组(G4)接近放疗前水平,未见明显差别。
2.平均λ#值
双侧枕叶、双侧颞叶及双侧顶叶白质多个脑区的λ#值在放疗后六个月内(G2)较放疗前(G1)明显升高(P<0.05,多重比较校正),之后逐渐下降,其中双侧颞叶、左侧枕叶、部分双侧顶叶白质的¨值在放疗后一年以上组(G4)仍明显高于放疗前水平；右侧枕叶及余双侧顶叶白质的λ#值在放疗后一年以上组(G4)接近放疗前水平,未见明显差别。
3.平均λ⊥值
右侧枕叶、左侧额-顶交界区、左侧顶叶白质多个脑区的λ⊥值在放疗后六个月内(G2)较放疗前(G1)明显升高(P<0.05,多重比较校正),之后逐渐下降,其中左侧顶叶白质的λ⊥值在放疗后一年以上组(G4)仍明显高于放疗前水平；右侧枕叶及左侧额-顶交界区白质的λ⊥值在放疗后一年以上组(G4)接近放疗前水平,未见明显差别。右侧小脑及左侧半卵圆中心的λ⊥值在放疗后六个月内(G2)较放疗前(G1)明显减低(P<0.05,多重比较校正),之后逐渐升高,在放疗后一年以上组(G4)仍未恢复至放疗前水平,较放疗前仍明显减低。
4.平均MD值
双侧颞叶、右侧枕叶、左侧顶叶、右侧枕-颞交界区、左侧半卵圆中心、左侧额-顶交界区白质多个脑区的MD值在放疗后六个月内(G2)较放疗前(G1)明显升高(P<0.05,多重比较校正),之后逐渐下降,大部分脑区的MD值在放疗后一年以上组(G4)恢复至接近放疗前水平,未见明显差别；而右侧枕叶白质的MD值在放疗后一年以上组(G4)仍明显高于放疗前水平。
相关性分析结果：
鼻咽癌患者放疗后0-6个月(G2)与放疗前(G1)组间比较有显著性差异脑区的DTI各指标与MMSE评分的相关性分析结果如下：右侧枕叶白质(r=0.483,P=0.027)、左侧顶叶白质(r=0.445,P=0.034)的FA值与其MMSE评分呈正相关；右侧顶叶白质的λ#值与其MMSE评分呈正相关(r=0.498,P=0.025)；左侧额-顶交界区白质的λ⊥值与其MMSE评分呈负相关(r=-0.482,P=0.027)；左侧额-顶交界区白质的MD值与其MMSE评分呈负相关(r=-0.487,P=0.025),左侧顶叶白质的MD值与其MMSE评分呈正相关(r=0.514,P=0.035)。其余组间差异脑区的FA值、λ#值、λ⊥值和MD值与MMSE评分之间的相关性无显著统计学意义。
结论：
1.作为目前唯一能在活体上对水分子运动进行测量与成像的无创性方法,DTI能够在常规头颅MRI发现异常之前,灵敏、动态地监测鼻咽癌放疗后脑白质微观结构的损伤。
2.放射治疗对鼻咽癌患者可产生较广泛的、累及多个脑区的脑白质微观结构的损伤,而不仅仅局限于颞叶；并且脑白质微观结构的异常是复杂的、动态的、暂时性的改变,在放疗后6个月内损伤最严重,随后脑组织损伤会逐渐修复,一年之后较放疗前有不同程度的恢复。
3.鼻咽癌患者放疗后6个月内多个脑区的FA值降低、λ⊥值和MD值升高以及λ#值升高,提示这些区域的脑白质微观结构的损伤主要以脑水肿、脱髓鞘改变为主,可能伴有轻度的轴索退变。
4.鼻咽癌患者组间差异脑区中,右侧枕叶白质、左侧顶叶白质的FA值与其MMSE评分呈正相关；右侧订叶白质的λ#值与其MMSE评分呈正相关；左侧额-顶交界区白质的λ⊥值与其MMSE评分呈负相关；左侧额-顶交界区白质的MD值与其MMSE评分呈负相关,左侧顶叶白质的MD值与其MMSE评分呈正相关。表明鼻咽癌放疗后广泛的脑白质微观结构损伤影响了患者的认知功能,DTI活体测量脑白质微观结构的变化有可能为早期评价放射性脑损伤以及认知功能障碍提供更敏感的生物学标记物。
Part one:A comparative study of neurocognitive function between patients with nasopharyngeal carcinoma before and after radiotherapy and healthy subjects
Objective
To evaluate dynamically the overall cognitive function of the patients with nasopharyngeal carcinoma (NPC) before and after radiotherapy (RT) at different time points by using the mini mental state examination (MMSE) scale, and to investigate the effects of RT on the neurocognitive status of the NPC patients and the change trend with time.
Materials and Methods
1. Subjects
One hundred and twenty-eight subjects were investigated in this study, including100NPC patients and28healthy subjects matched for age, gender, and education.100patients [72males,28females, mean age43.73±9.88years (range19-65years), years of education10.27±3.24(range6-16years)] with pathologically confirmed NPC were included in the study, with staging from TIN0M0to T4N2M0(Union for International Cancer Control, seventh edition,2009). MRI follow-up time after RT ranged from1week to12years after completion of RT, and the median follow-up time was7.5months. All patients underwent a fractionated radiation therapy with three-dimensional conformal and intensity-modulated techniques (total dose/fraction dose/exposures,66-74Gy/1.8-2.0Gy/30-35times) for the first time. In every patient the same fractionation schedule was followed:one fraction per day, five fractions per week. All of the patients received two to four courses of concomitant chemotherapy during and after RT with one or more agents, such as cisplatin, fluorouracil and gemcitabine, depending on the clinical stage. Excluded from this study were patients with intracranial invasion, intracranial primary tumors or metastases, vascular lesions of the brain, head trauma and intracranial surgery, hypertension, heart disease, diabetes, hyperlipidemia, metabolic diseases, major psychiatric or neurological illness and other underlying disease that could possibly result in cognitive impairment. According to the international and domestic staging systems for classifying radiation-induced brain injury, we divided the NPC patients on the basis of the time before and after completion of RT into four subgroups:group1(pre-RT, or baseline, n=25); group2(0-6months post-RT, n=25); group3(>6-12months post-RT, n=25); group4(>12months post-RT, n=25). Control group included28healthy subjects,20males,8females, mean age43.57±11.75years (range24-62years), years of education10.29±3.63(range6-16years), who had no history of intracranial lesions, brain injury or neurocognitive deficits. All subjects were right-handed, native Chinese speakers. Each participant was fully informed about the purpose, methods, and precautions of the project, and formally agreed to participate and signed the informed consent form.
2. Neuropsychological tests
For all eligible participants, the Chinese version of the the Mini-Mental State Examination (MMSE) was used to assess their cognitive state in this study. MMSE was administered by a physician during the same period with the MRI examinations.
3. Statistic analysis
Data were analyzed by using the Statistical Package for Social Sciences (SPSS for Windows, Version13.0, Chicago, IL, USA). One-way analysis of variance (ANOVA) was performed to compare the differences in the age and years of education among different groups. Chi-square test was performed to assess the differences of gender among different groups. Cognitive performance was evaluated as a change in scores over time. The Kruskal-Wallis H test with multiple comparisons using Bonferroni post hoc test was used to determine the statistical differences of the MMSE scores across the different groups. A two-side P value<0.05was considered to be statistically significant.
Results
1. There was no significant difference in the age (F=0.908, P=0.462), years of education (F=0.253, P=0.907) and gender (χ2=1.191, P=0.880) among the groups before and after RT at different time points in NPC patients and control group.
2. There was no significant significantly difference in the MMSE scores (χ2=5.429, P=0.246) among the different groups.
Conclusion
1. No statistically significant decrease in MMSE scores over the period of follow-up was found after RT with three-dimensional conformal and intensity-modulated techniques compared with pre-RT in NPC patients and control group.
2. The neurocognitive function after three-dimensional conformal intensity modulated radiotherapy for NPC patients showed dynamic change. The MMSE scores temporary decline occurred within6months after RT, but then will recover gradually, and will recovered to the level of the pre-RT after12month.
3. Our results supports the safety of focal RT using three-dimensional conformal and intensity-modulated techniques in conventional fractionation (≤2Gy), commonly prescribed total doses (66-74Gy) and exposures (30-35times) for treatment of nasopharyngeal carcinoma. The modern techniques may have no significant impact on overall neurocognitive performance of normal-appearing WM in NPC patients.
Part two:White matter microstructural changes before and after radiotherapy in patients with nasopharyngeal carcinoma:a DTI-TBSS study
Objective
1. To noninvasively investigate white matter (WM) microstructural dynamic changes before and after radiotherapy (RT) at different times by using diffusion tensor imaging (DTI) and tract based spatial statistic (TBSS) in comparison to the baseline and healthy subjects in nasopharyngeal carcinoma (NPC) patients.
2. To explore whether white matter (WM) microstructural changes before and after RT at different times associate with neurocognitive outcome of NPC patients monitored using the Mini-Mental State Examination (MMSE).
Materials and Methods
1. Subjects
One hundred and seven subjects were investigated in this study, including81NPC patients and26healthy subjects matched for age, gender, and education.81patients [60males,21females, mean age44.26±9.91years (range19-65years), years of education10.27±3.30(range6-16years)] with pathologically confirmed NPC were included in the study, with staging from T1N0M0to T4N2M0(Union for International Cancer Control, seventh edition,2009). MRI follow-up time after radiotherapy ranged from1week to4years and7months after completion of radiotherapy, and the median follow-up time was7.5months. All patients underwent a fractionated radiation therapy with three-dimensional conformal and intensity-modulated techniques (total dose/fraction dose/exposures,66-74Gy/1.8-2.0Gy/30-35times) for the first time. In every patient the same fractionation schedule was followed:one fraction per day, five fractions per week. All of the patients received two to four courses of concomitant chemotherapy during and after RT with one or more agents, such as cisplatin, fluorouracil and gemcitabine, depending on the clinical stage. Excluded from this study were patients with intracranial invasion, intracranial primary tumors or metastases, vascular lesions of the brain, head trauma and intracranial surgery, hypertension, heart disease, diabetes, hyperlipidemia, metabolic diseases, major psychiatric or neurological illness and other underlying disease that could possibly result in cognitive impairment. According to the international and domestic staging systems for classifying radiation-induced brain injury, we divided the NPC patients on the basis of the time before and after completion of RT into four subgroups:group1(pre-RT, or baseline, n=23); group2(0-6months post-RT, n=21); group3(>6-12months post-RT, n=20); group4(>12months post-RT, n=17). Control group included26healthy subjects,18males,8females, mean age43.73±11.67years (range24-62years), years of education10.23±3.49(range6-16years), who had no history of intracranial lesions, brain injury or neurocognitive deficits. All subjects were right-handed, native Chinese speakers. Each participant was fully informed about the purpose, methods, and precautions of the project, and formally agreed to participate and signed the informed consent form.
2. Neuropsychological tests
For all eligible participants, the Chinese version of the the Mini-Mental State Examination (MMSE) was used to assess their cognitive state in this study (the same as the first part). MMSE was administered by a physician during the same period with the MRI examinations.
3. DTI data acquisition
All MR imaging data were acquired using a3.0T GE clinical scanner (SIGNA EXCITE GE Medical Systems, Milwaukee, WI, USA) with an eight-channel head coil. The routine MRI brain protocol including axial T1-weighted images (TR/TE, 600/15ms), T2-weighted images (TR/TE,5200/140ms), and T2-weighted fluid attenuated inversion recovery (TR/TE/IR,9000/120/2100ms) was obtained for every subject to detect intracranial lesions. DTI scans were performed employing a single-shot echo-planar imaging sequence and array spatial sensitivity encoding technique with the following parameters:repetition time (TR)12000ms, echo time (TE)75.5ms, field of view (FOV)24×24cm, matrix128R128, slice thickness3mm with no interslice gap, NEX=1, flip angle90°. Images were collected along25non-collinear diffusion gradient directions with a b-value of1000sec/mm2, and one set of null images with b=0sec/mm2was acquired.
4. DTI data processing and TBSS analysis
DTI data was analyzed by using FSL (FMRIB Software Library, www.fmrib.ox.ac.uk/fsl, version4.19) tools. The procedure of DTI data processing included:First, diffusion tensor images were corrected for head movement and eddy current distortion by using FDT tool of the FSL software. Second, mask image for each brain was created by using each subject' B0image with BET tool of the FSL software. Then, the diffusion tensor was calculated on a voxel-by-voxel basis by using dtifit. Maps of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ‖=λ1) and radial diffusivity [λ⊥=(λ2+λ3)/2] were obtained. And then follow the tract based spatial statistic (TBSS) processes, first running the next steps: tbss_1_preproc, tbss_2_reg, tbss_3_postreg, tbss_4_prestats. Subsequently, threshold-free cluster enhancement (TFCE) in randomise was used to perform the multisubject analysis of FA, MD, λ‖and λ⊥respectively, permutation-based correction for multiple comparisons at P<0.05.
5. Statistic analysis
Patial correlation analysis with age and years of education as covariates was performed to investigate the underlying relationship between the patients'MMSE scors and the mean FA, MD, λ‖and λ⊥values in significantly different areas that revealed by pre-RT vs0-6months post-RT in NPC patients. A two-side P value less than0.05was considered as significant correlation.
Results
TBSS results
1. FA values
Compared with pre-RT group, the mean FA values in the right frontal lobe, right parietal lobe and right occipital lobe white matter reduced significantly in post-RT0-6m group (P<0.05), then increased gradually. Until one year after RT (group4), the FA level in the right frontal lobe and right parietal lobe white matter had remained significantly lower than that in the pre-RT group, while the FA level in the right occipital lobe white matter was slightly lower than pre-RT, but was not significantly different.
Compared with pre-RT group, the mean FA values in the right cerebellum and left parietal lobe white matter increased significantly in post-RT0-6m group (P<0.05), then reduced gradually. Until one year after RT (group4), the FA level in the right cerebellum had remained significantly higher than that in the pre-RT group, while the FA level in the left parietal lobe white matter had been restored and was not significantly different from that in the pre-RT group.
2.λ‖values
Compared with pre-RT group, the λ‖values in significantly different areas in the bilateral occipital lobe, temporal lobe and parietal lobe white matter increased significantly in post-RT0-6m group (P<0.05), then reduced gradually. Until one year after RT (group4), the λ‖level in the bilateral temporal lobe, left occipital lobe, part of the bilateral parietal lobe white matter was still significantly higher than that in the pre-RT group; while the λ‖level in the right occipital lobe and rest of the bilateral parietal lobe white matter was close to the values in the pre-RT group and there was no significant difference.
3.λ⊥values
Compared with pre-RT group, the mean λ⊥values in the right occipital lobe, left frontal-parietal junction area and left parietal lobe white matter increased significantly in post-RT0-6m group (P<0.05), then reduced gradually. Until one year after RT (group4), the λ⊥level in the left parietal lobe white matter had remained significantly higher than that in the pre-RT group; while the λ⊥level in the right occipital lobe and left frontal-parietal junction area white matter was close to the values in the pre-RT group and was not significantly different.
Compared with pre-RT group, the mean λ⊥values in the right cerebellum and left centrum semiovale reduced significantly in post-RT0-6m group (P<0.05), then increased gradually. Until one year after RT (group4), the λ⊥level in the above brain areas had remained significantly lower than that in the pre-RT group.
4. MD values
Compared with pre-RT group, the MD values in significantly different areas in the right occipital lobe, bilateral temporal lobe, the right occipital-temporal junction area, the left parietal lobe, the left centrum semiovale, the left frontal-parietal junction area white matter increased significantly in post-RT0-6m group (P<0.05), then reduced gradually. Until one year after RT (group4), the MD level in the right occipital lobe white matter was still significantly higher than that in the pre-RT group; while the MD level in the rest brain areas mentioned above was close to the values in the pre-RT group and there was no significant difference.
Correlation results
FA value in the right occipital (r=0.483, P=0.027), and left parietal (r=0.445, P=0.034) white matter that revealed by groups comparison between pre-RT vs post-RT0-6m correlated positively with MMSE score of NPC patients. λ‖value in the right parietal white matter (r=0.498, P=0.025) correlated positively with MMSE score of NPC patients. λ‖value in the left frontal-parietal junction area white matter (r=-0.482, P=0.027) correlated negatively with MMSE score of NPC patients. MD value in the left frontal-parietal junction area (r=-0.487, P=0.025) correlated negatively with MMSE score of NPC patients. MD value in the left parietal (r=0.514, P=0.035) correlated positively with MMSE score of NPC patients.
Conclusion
1. As the only noninvasive method for characterizing changes in tissue microstructural organization and diffusivity of water changes in brain tissue in vivo, DTI may be used in sensitive discovering and dynamical monitoring the subtle abnormalities of the radiation-induced WM microstructure, earlier than conventional cranial MRI, following RT for NPC patients.
2. For NPC patients, radiotherapy may produce extensive white matter microstructure damage, involving multiple brain regions and not just limited to the temporal lobe. Furthermore, WM microstructure abnormalities are complex, dynamic and temporary, brain tissue injury is most serious within6months after radiotherapy, then will repair gradually, and will be close to the level of the pre-RT after12month.
3. The FA value decreased significantly, and λ⊥, MD,λ‖value increased significantly in multiple WM regions within6months after RT compared with pre-RT in NPC patients, suggesting that WM microstructural damage in these regions may be caused mainly by brain edema and demyelination, and may be accompanied by mild axonal degeneration.
4. The mean FA, MD, λ‖and λ⊥values in significantly different areas that revealed by pre-RT vs0-6months post-RT in NPC patients were correlated significantly with their MMSE score. It indicates that extensive WM microstructure damage after radiotherapy affects the patient's cognitive function, and DTI in vivo measurement of WM microstructure changes may provide sensitive imaging biomarkers for early evaluation of radiation-induced brain injury and cognitive dysfunction.
目的：
采用简易精神状态检查(mini mental status examination, MMSE)量表对鼻咽癌患者接受放射治疗前及放射治疗后不同时间点进行整体认知功能的动态评价,探讨放疗对鼻咽癌患者神经认知功能的影响及变化趋势。
材料与方法：
1.研究对象
本研究共纳入128例被试,其中鼻咽癌患者组100例,正常对照组28例。100例鼻咽癌患者中,男72例,女28例,平均年龄43.73±9.88岁(19-65)岁,受教育程度10.27±3.24年(6-16)年。所有患者均由病理活检证实,肿瘤分期为T1N0M0～T4N2Mo期(UICC第七版)。放疗后磁共振随访时间从放疗完成后1周至12年不等,中位随访时间为7.5个月。根据国内外研究,我们将患者组按放疗前和放疗完成后行DTI检查的不同时间将其分为4组：第1组为放疗前组(pre-RT),25例；第2组为放疗后0-6个月组(post-RT0-6m)(放疗后平均3.02个月),25例；第3组为放疗后>6-12个月组(post-RT>6-12m)(放疗后平均8.14个月),25例：第4组为放疗后>12个月组(post-RT>12m)(放疗后平均31.19个月),25例。鼻咽癌患者组的纳入标准包括：(1)均为病理证实后放疗前或首次接受放射治疗的患者；(2)鼻咽癌治疗方案接近,均施行三维适形调强放射治疗(总剂量/分割剂量/分割次数,66-74GY/1.8～2.0GY/30-35次)。所有患者在放疗期间至放疗后均联合应用多药化疗,主要化疗药物有5-氟尿嘧啶、顺铂和紫杉类等；(3)均为汉族,右利手；(4)无颅内侵犯及脑内转移；(5)颅内无脑血管病变及脑肿瘤病变；(6)无头颅外伤史及颅内手术史；(7)无高血压、心脏病、糖尿病、高血脂、代谢性疾病及精神疾病；(8)常规MR平扫及增强扫描颅内未发现明显异常信号改变。
正常对照组28例(年龄、性别、受教育程度、利手与鼻咽癌患者组相匹配的健康人),男20例,女8例,平均年龄43.57±11.75岁(24～62)岁,受教育程度10.29±3.63年(6～16)年。所有纳入的研究对象均在试验前被详细告知试验目的、方法和注意事项,并签署知情同意书正式同意参加试验。
2.神经心理学测试
采用简易精神状态检查(mini mental status examination, MMSE)量表对所有128例被试的整体认知功能进行评价。
3.统计学分析
利用SPSS13.0软件,采用单因素方差分析(one-way ANOVA)评价鼻咽癌患者放疗前、放疗后不同时间组及对照组之间年龄、受教育程度的差异,采用卡方检验评价上述各组之间性别构成的差异。采用多个独立样本比较的Kruskal-Wallis H检验比较各组间MMSE评分的差异,组间有差异者进一步多重比较,采用Bonferroni法调整P值。检验水准α取0.05,P<0.05认为差异有统计学意义。
结果：
1.鼻咽癌患者放疗前组、放疗后不同时间组以及正常对照组之间年龄(F=0.908,P=0.462)、性别(χ2=1.191,P=0.880)及受教育程度(F=0.253,P=0.907)差异无统计学意义(P>0.05)；所有被试均为右利手,分组均衡性尚好。
2.鼻咽癌患者放疗前组、放疗后不同时间组及正常对照组之间MMSE评分的差异无统计学意义(χ2=5.429,P=0.246)。
结论：
1、鼻咽癌患者局部三维适形调强放疗后的MMSE评分与放疗前及正常对照组相比,随着时间的推移,在统计学上没有显著性降低。
2、鼻咽癌三维适形调强放疗后患者的认知功能具有动态变化的趋势,放疗后6个月内MMSE评分出现一过性的轻度降低,之后逐渐升高,1年后恢复至放疗前水平。
3、采用局部三维适形调强放射治疗的现代技术,常规分割剂量(≤2Gy),常用的总剂量(66～74Gy),分割次数为30～35次,治疗鼻咽癌是安全的,对常规头颅MRI阴性患者的整体认知功能无显著影响。
第二部分鼻咽癌患者放疗前后脑白质微观结构改变：DTI-TBSS研究
目的：
1、利用磁共振扩散张量成像技术(DTI)和基于纤维束示踪的空间统计(tract based spatial statistic, TBSS)的后处理技术,与放疗前基线水平及正常对照组比较,评价鼻咽癌患者放疗后不同时期脑白质微观结构的动态改变情况。
2、探讨鼻咽癌患者放疗前后不同时期脑白质微观结构改变与其整体认知功能评分之间的关系。
材料与方法：
1.研究对象
107例被试被纳入本研究：鼻咽癌患者组81例,平均年龄为44.26±9.91岁(19-65岁),男60例,女21例,受教育程度10.27±3.30年(6～16年)。所有患者均由病理活检证实,肿瘤分期为T4N2Mo期(UICC第七版)。放疗后磁共振随访时间从放疗完成后1周至4年7个月不等,中位随访时间为7.5个月。根据国内外研究,我们将患者组按放疗前和放疗完成后行DTI检查的不同时间将其分为4组：第1组为放疗前组(pre-RT),23例；第2组为放疗后0-6个月组(post-RT0-6m)(放疗后平均3.14个月),21例；第3组为放疗后>6-12个月组(post-RT>6-12m)(放疗后平均8.13个月),20例；第4组为放疗后>12个月组(post-RT>12m)(放疗后平均23.89个月),17例。鼻咽癌患者组的纳入标准同第一部分。
正常对照组26例(年龄、性别、受教育程度、利手与鼻咽癌患者组相匹配的健康人),平均年龄为43.73±11.67岁(24～62岁),男18例,女8例,受教育程度10.23±3.49年(6-16年)。所有纳入的研究对象均在试验前被详细告知试验目的、方法和注意事项,并签署知情同意书正式同意参加试验。
2.神经心理学测试
采用简易精神状态检查(mini mental status examination, MMSE)量表对所有被试的整体认知功能进行评价(同第一部分)。
3.扫描设备与序列
所有被试均采用美国GE SIGNA EXCITE3.0T磁共振成像仪扫描进行静息态下脑功能数据采集,使用标准八通道头颅线圈接收核磁共振信号。DTI数据采集之前均进行常规的全脑轴位T1WI、T2WI及FLAIR序列扫描,以排除脑部疾患。DTI数据采集采用单次激发平面回波(single-shot echo-planar imaging, SS-EPI)序列以及并行采集技术(array spatial sensitivity encoding technique, ASSET),平行于大脑前后联合连线平面,得到覆盖全脑的轴位扩散加权图像。具体参数如下：扩散敏感梯度方向为25个,扩散敏感系数b值为1000s/mmz和0s/mmm2,重复时间(TR)=12000ms,回波时间(TE)=75.5ms,视野(FOV)=24cm×24cm,矩阵(matrix size)=128×128,层厚(thickness)=3.Omm,层间距(slice gap)=0mm,激励次数(NEX)=1,翻转角(flip angle)=90°。
4.图像后处理
DTI数据分析采用FSL (FMRIB Software Library, www.fmrib.ox.ac.uk/fsl, version4.1.9)提供的工具包。具体步骤包括：(1)使用FSL软件FDT套件中的eddy correct函式对原始DTI数据进行头动和涡流校正。(2)利用FSL软件中BET套件以每个被试者的B0图像作为依据,产生各自的脑mask。(3)通过FDT套件中的dtifit函式,进行扩散张量的计算。输出的结果包括：部分各向异性(fractional anisotropy, FA)、平均扩散率(mean diffusivity, MD)、三个本征值(λ1、λ2、λ3)及相对应的三个特征向量(V1、V2、V3)等,再通过FSL函式计算出λ#(λ#=λ1)和λ⊥[λ⊥=(λ2+λ3)/2]。然后按照TBSS流程进行分析：tbss_1_preproc, tbss_2_reg,tbss_3_postreg,tbss_4_prestats。接着利用FSL软件中的randomise函式分别对鼻咽癌患者放疗前、放疗后不同时间组及正常对照组的FA值、MD值、λ#值和λ⊥值进行基于纤维束示踪的全脑显著性差异统计分析,参考TFCE (threshold-free cluster enhancement)的演算法,在统计方法上通过permutation的方法,从而有效地控制并校正在多重比较时寻找被试者间FA图数值差异时可能发生的FWE(family-wise error)概率。
5.统计学分析
FA值、MD值、λ#值及λ⊥值图组间基于体素的比较,采用randomize工具进行的非参数统计阈值分析的统计方法,置换测试次数为5000,多重比较校正采用以簇为基础的校正方法,P<0.05且簇>50个体素(体素大小：1×1×lmm3)认为有统计学意义。采用偏相关分析方法(以年龄和受教育程度为协变量),评价鼻咽癌患者放疗前、放疗后TBSS的相关指标(包括组间差异区域的平均FA值、MD值、λ#值及λ⊥值)与其MMSE评分之间的相关关系。P<0.05认为相关性有统计学意义。
结果：
TBSS结果：
1.平均FA值
右侧额叶、顶叶及枕叶白质的FA值在放疗后0-6月组(G2)较放疗前(G1)明显下降(P<0.05,多重比较校正),之后逐渐恢复,其中右侧额叶及右侧顶叶白质的FA值在放疗后一年以上组(G4)仍未恢复至放疗前水平,明显低于放疗前水平；右侧枕叶白质的FA值在放疗后一年以上组(G4)恢复至接近放疗前水平,未见明显差别。右侧小脑及左侧顶叶白质的FA值在放疗后0-6月组(G2)较放疗前(G1)明显升高(P<0.05,多重比较校正),之后逐渐减低,其中右侧小脑的FA值在放疗后一年以上组(G4)仍未恢复至放疗前水平,明显高于放疗前水平；左侧顶叶白质的FA值在放疗后一年以上组(G4)接近放疗前水平,未见明显差别。
2.平均λ#值
双侧枕叶、双侧颞叶及双侧顶叶白质多个脑区的λ#值在放疗后六个月内(G2)较放疗前(G1)明显升高(P<0.05,多重比较校正),之后逐渐下降,其中双侧颞叶、左侧枕叶、部分双侧顶叶白质的¨值在放疗后一年以上组(G4)仍明显高于放疗前水平；右侧枕叶及余双侧顶叶白质的λ#值在放疗后一年以上组(G4)接近放疗前水平,未见明显差别。
3.平均λ⊥值
右侧枕叶、左侧额-顶交界区、左侧顶叶白质多个脑区的λ⊥值在放疗后六个月内(G2)较放疗前(G1)明显升高(P<0.05,多重比较校正),之后逐渐下降,其中左侧顶叶白质的λ⊥值在放疗后一年以上组(G4)仍明显高于放疗前水平；右侧枕叶及左侧额-顶交界区白质的λ⊥值在放疗后一年以上组(G4)接近放疗前水平,未见明显差别。右侧小脑及左侧半卵圆中心的λ⊥值在放疗后六个月内(G2)较放疗前(G1)明显减低(P<0.05,多重比较校正),之后逐渐升高,在放疗后一年以上组(G4)仍未恢复至放疗前水平,较放疗前仍明显减低。
4.平均MD值
双侧颞叶、右侧枕叶、左侧顶叶、右侧枕-颞交界区、左侧半卵圆中心、左侧额-顶交界区白质多个脑区的MD值在放疗后六个月内(G2)较放疗前(G1)明显升高(P<0.05,多重比较校正),之后逐渐下降,大部分脑区的MD值在放疗后一年以上组(G4)恢复至接近放疗前水平,未见明显差别；而右侧枕叶白质的MD值在放疗后一年以上组(G4)仍明显高于放疗前水平。
相关性分析结果：
鼻咽癌患者放疗后0-6个月(G2)与放疗前(G1)组间比较有显著性差异脑区的DTI各指标与MMSE评分的相关性分析结果如下：右侧枕叶白质(r=0.483,P=0.027)、左侧顶叶白质(r=0.445,P=0.034)的FA值与其MMSE评分呈正相关；右侧顶叶白质的λ#值与其MMSE评分呈正相关(r=0.498,P=0.025)；左侧额-顶交界区白质的λ⊥值与其MMSE评分呈负相关(r=-0.482,P=0.027)；左侧额-顶交界区白质的MD值与其MMSE评分呈负相关(r=-0.487,P=0.025),左侧顶叶白质的MD值与其MMSE评分呈正相关(r=0.514,P=0.035)。其余组间差异脑区的FA值、λ#值、λ⊥值和MD值与MMSE评分之间的相关性无显著统计学意义。
结论：
1.作为目前唯一能在活体上对水分子运动进行测量与成像的无创性方法,DTI能够在常规头颅MRI发现异常之前,灵敏、动态地监测鼻咽癌放疗后脑白质微观结构的损伤。
2.放射治疗对鼻咽癌患者可产生较广泛的、累及多个脑区的脑白质微观结构的损伤,而不仅仅局限于颞叶；并且脑白质微观结构的异常是复杂的、动态的、暂时性的改变,在放疗后6个月内损伤最严重,随后脑组织损伤会逐渐修复,一年之后较放疗前有不同程度的恢复。
3.鼻咽癌患者放疗后6个月内多个脑区的FA值降低、λ⊥值和MD值升高以及λ#值升高,提示这些区域的脑白质微观结构的损伤主要以脑水肿、脱髓鞘改变为主,可能伴有轻度的轴索退变。
4.鼻咽癌患者组间差异脑区中,右侧枕叶白质、左侧顶叶白质的FA值与其MMSE评分呈正相关；右侧订叶白质的λ#值与其MMSE评分呈正相关；左侧额-顶交界区白质的λ⊥值与其MMSE评分呈负相关；左侧额-顶交界区白质的MD值与其MMSE评分呈负相关,左侧顶叶白质的MD值与其MMSE评分呈正相关。表明鼻咽癌放疗后广泛的脑白质微观结构损伤影响了患者的认知功能,DTI活体测量脑白质微观结构的变化有可能为早期评价放射性脑损伤以及认知功能障碍提供更敏感的生物学标记物。
Part one:A comparative study of neurocognitive function between patients with nasopharyngeal carcinoma before and after radiotherapy and healthy subjects
Objective
To evaluate dynamically the overall cognitive function of the patients with nasopharyngeal carcinoma (NPC) before and after radiotherapy (RT) at different time points by using the mini mental state examination (MMSE) scale, and to investigate the effects of RT on the neurocognitive status of the NPC patients and the change trend with time.
Materials and Methods
1. Subjects
One hundred and twenty-eight subjects were investigated in this study, including100NPC patients and28healthy subjects matched for age, gender, and education.100patients [72males,28females, mean age43.73±9.88years (range19-65years), years of education10.27±3.24(range6-16years)] with pathologically confirmed NPC were included in the study, with staging from TIN0M0to T4N2M0(Union for International Cancer Control, seventh edition,2009). MRI follow-up time after RT ranged from1week to12years after completion of RT, and the median follow-up time was7.5months. All patients underwent a fractionated radiation therapy with three-dimensional conformal and intensity-modulated techniques (total dose/fraction dose/exposures,66-74Gy/1.8-2.0Gy/30-35times) for the first time. In every patient the same fractionation schedule was followed:one fraction per day, five fractions per week. All of the patients received two to four courses of concomitant chemotherapy during and after RT with one or more agents, such as cisplatin, fluorouracil and gemcitabine, depending on the clinical stage. Excluded from this study were patients with intracranial invasion, intracranial primary tumors or metastases, vascular lesions of the brain, head trauma and intracranial surgery, hypertension, heart disease, diabetes, hyperlipidemia, metabolic diseases, major psychiatric or neurological illness and other underlying disease that could possibly result in cognitive impairment. According to the international and domestic staging systems for classifying radiation-induced brain injury, we divided the NPC patients on the basis of the time before and after completion of RT into four subgroups:group1(pre-RT, or baseline, n=25); group2(0-6months post-RT, n=25); group3(>6-12months post-RT, n=25); group4(>12months post-RT, n=25). Control group included28healthy subjects,20males,8females, mean age43.57±11.75years (range24-62years), years of education10.29±3.63(range6-16years), who had no history of intracranial lesions, brain injury or neurocognitive deficits. All subjects were right-handed, native Chinese speakers. Each participant was fully informed about the purpose, methods, and precautions of the project, and formally agreed to participate and signed the informed consent form.
2. Neuropsychological tests
For all eligible participants, the Chinese version of the the Mini-Mental State Examination (MMSE) was used to assess their cognitive state in this study. MMSE was administered by a physician during the same period with the MRI examinations.
3. Statistic analysis
Data were analyzed by using the Statistical Package for Social Sciences (SPSS for Windows, Version13.0, Chicago, IL, USA). One-way analysis of variance (ANOVA) was performed to compare the differences in the age and years of education among different groups. Chi-square test was performed to assess the differences of gender among different groups. Cognitive performance was evaluated as a change in scores over time. The Kruskal-Wallis H test with multiple comparisons using Bonferroni post hoc test was used to determine the statistical differences of the MMSE scores across the different groups. A two-side P value<0.05was considered to be statistically significant.
Results
1. There was no significant difference in the age (F=0.908, P=0.462), years of education (F=0.253, P=0.907) and gender (χ2=1.191, P=0.880) among the groups before and after RT at different time points in NPC patients and control group.
2. There was no significant significantly difference in the MMSE scores (χ2=5.429, P=0.246) among the different groups.
Conclusion
1. No statistically significant decrease in MMSE scores over the period of follow-up was found after RT with three-dimensional conformal and intensity-modulated techniques compared with pre-RT in NPC patients and control group.
2. The neurocognitive function after three-dimensional conformal intensity modulated radiotherapy for NPC patients showed dynamic change. The MMSE scores temporary decline occurred within6months after RT, but then will recover gradually, and will recovered to the level of the pre-RT after12month.
3. Our results supports the safety of focal RT using three-dimensional conformal and intensity-modulated techniques in conventional fractionation (≤2Gy), commonly prescribed total doses (66-74Gy) and exposures (30-35times) for treatment of nasopharyngeal carcinoma. The modern techniques may have no significant impact on overall neurocognitive performance of normal-appearing WM in NPC patients.
Part two:White matter microstructural changes before and after radiotherapy in patients with nasopharyngeal carcinoma:a DTI-TBSS study
Objective
1. To noninvasively investigate white matter (WM) microstructural dynamic changes before and after radiotherapy (RT) at different times by using diffusion tensor imaging (DTI) and tract based spatial statistic (TBSS) in comparison to the baseline and healthy subjects in nasopharyngeal carcinoma (NPC) patients.
2. To explore whether white matter (WM) microstructural changes before and after RT at different times associate with neurocognitive outcome of NPC patients monitored using the Mini-Mental State Examination (MMSE).
Materials and Methods
1. Subjects
One hundred and seven subjects were investigated in this study, including81NPC patients and26healthy subjects matched for age, gender, and education.81patients [60males,21females, mean age44.26±9.91years (range19-65years), years of education10.27±3.30(range6-16years)] with pathologically confirmed NPC were included in the study, with staging from T1N0M0to T4N2M0(Union for International Cancer Control, seventh edition,2009). MRI follow-up time after radiotherapy ranged from1week to4years and7months after completion of radiotherapy, and the median follow-up time was7.5months. All patients underwent a fractionated radiation therapy with three-dimensional conformal and intensity-modulated techniques (total dose/fraction dose/exposures,66-74Gy/1.8-2.0Gy/30-35times) for the first time. In every patient the same fractionation schedule was followed:one fraction per day, five fractions per week. All of the patients received two to four courses of concomitant chemotherapy during and after RT with one or more agents, such as cisplatin, fluorouracil and gemcitabine, depending on the clinical stage. Excluded from this study were patients with intracranial invasion, intracranial primary tumors or metastases, vascular lesions of the brain, head trauma and intracranial surgery, hypertension, heart disease, diabetes, hyperlipidemia, metabolic diseases, major psychiatric or neurological illness and other underlying disease that could possibly result in cognitive impairment. According to the international and domestic staging systems for classifying radiation-induced brain injury, we divided the NPC patients on the basis of the time before and after completion of RT into four subgroups:group1(pre-RT, or baseline, n=23); group2(0-6months post-RT, n=21); group3(>6-12months post-RT, n=20); group4(>12months post-RT, n=17). Control group included26healthy subjects,18males,8females, mean age43.73±11.67years (range24-62years), years of education10.23±3.49(range6-16years), who had no history of intracranial lesions, brain injury or neurocognitive deficits. All subjects were right-handed, native Chinese speakers. Each participant was fully informed about the purpose, methods, and precautions of the project, and formally agreed to participate and signed the informed consent form.
2. Neuropsychological tests
For all eligible participants, the Chinese version of the the Mini-Mental State Examination (MMSE) was used to assess their cognitive state in this study (the same as the first part). MMSE was administered by a physician during the same period with the MRI examinations.
3. DTI data acquisition
All MR imaging data were acquired using a3.0T GE clinical scanner (SIGNA EXCITE GE Medical Systems, Milwaukee, WI, USA) with an eight-channel head coil. The routine MRI brain protocol including axial T1-weighted images (TR/TE, 600/15ms), T2-weighted images (TR/TE,5200/140ms), and T2-weighted fluid attenuated inversion recovery (TR/TE/IR,9000/120/2100ms) was obtained for every subject to detect intracranial lesions. DTI scans were performed employing a single-shot echo-planar imaging sequence and array spatial sensitivity encoding technique with the following parameters:repetition time (TR)12000ms, echo time (TE)75.5ms, field of view (FOV)24×24cm, matrix128R128, slice thickness3mm with no interslice gap, NEX=1, flip angle90°. Images were collected along25non-collinear diffusion gradient directions with a b-value of1000sec/mm2, and one set of null images with b=0sec/mm2was acquired.
4. DTI data processing and TBSS analysis
DTI data was analyzed by using FSL (FMRIB Software Library, www.fmrib.ox.ac.uk/fsl, version4.19) tools. The procedure of DTI data processing included:First, diffusion tensor images were corrected for head movement and eddy current distortion by using FDT tool of the FSL software. Second, mask image for each brain was created by using each subject' B0image with BET tool of the FSL software. Then, the diffusion tensor was calculated on a voxel-by-voxel basis by using dtifit. Maps of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ‖=λ1) and radial diffusivity [λ⊥=(λ2+λ3)/2] were obtained. And then follow the tract based spatial statistic (TBSS) processes, first running the next steps: tbss_1_preproc, tbss_2_reg, tbss_3_postreg, tbss_4_prestats. Subsequently, threshold-free cluster enhancement (TFCE) in randomise was used to perform the multisubject analysis of FA, MD, λ‖and λ⊥respectively, permutation-based correction for multiple comparisons at P<0.05.
5. Statistic analysis
Patial correlation analysis with age and years of education as covariates was performed to investigate the underlying relationship between the patients'MMSE scors and the mean FA, MD, λ‖and λ⊥values in significantly different areas that revealed by pre-RT vs0-6months post-RT in NPC patients. A two-side P value less than0.05was considered as significant correlation.
Results
TBSS results
1. FA values
Compared with pre-RT group, the mean FA values in the right frontal lobe, right parietal lobe and right occipital lobe white matter reduced significantly in post-RT0-6m group (P<0.05), then increased gradually. Until one year after RT (group4), the FA level in the right frontal lobe and right parietal lobe white matter had remained significantly lower than that in the pre-RT group, while the FA level in the right occipital lobe white matter was slightly lower than pre-RT, but was not significantly different.
Compared with pre-RT group, the mean FA values in the right cerebellum and left parietal lobe white matter increased significantly in post-RT0-6m group (P<0.05), then reduced gradually. Until one year after RT (group4), the FA level in the right cerebellum had remained significantly higher than that in the pre-RT group, while the FA level in the left parietal lobe white matter had been restored and was not significantly different from that in the pre-RT group.
2.λ‖values
Compared with pre-RT group, the λ‖values in significantly different areas in the bilateral occipital lobe, temporal lobe and parietal lobe white matter increased significantly in post-RT0-6m group (P<0.05), then reduced gradually. Until one year after RT (group4), the λ‖level in the bilateral temporal lobe, left occipital lobe, part of the bilateral parietal lobe white matter was still significantly higher than that in the pre-RT group; while the λ‖level in the right occipital lobe and rest of the bilateral parietal lobe white matter was close to the values in the pre-RT group and there was no significant difference.
3.λ⊥values
Compared with pre-RT group, the mean λ⊥values in the right occipital lobe, left frontal-parietal junction area and left parietal lobe white matter increased significantly in post-RT0-6m group (P<0.05), then reduced gradually. Until one year after RT (group4), the λ⊥level in the left parietal lobe white matter had remained significantly higher than that in the pre-RT group; while the λ⊥level in the right occipital lobe and left frontal-parietal junction area white matter was close to the values in the pre-RT group and was not significantly different.
Compared with pre-RT group, the mean λ⊥values in the right cerebellum and left centrum semiovale reduced significantly in post-RT0-6m group (P<0.05), then increased gradually. Until one year after RT (group4), the λ⊥level in the above brain areas had remained significantly lower than that in the pre-RT group.
4. MD values
Compared with pre-RT group, the MD values in significantly different areas in the right occipital lobe, bilateral temporal lobe, the right occipital-temporal junction area, the left parietal lobe, the left centrum semiovale, the left frontal-parietal junction area white matter increased significantly in post-RT0-6m group (P<0.05), then reduced gradually. Until one year after RT (group4), the MD level in the right occipital lobe white matter was still significantly higher than that in the pre-RT group; while the MD level in the rest brain areas mentioned above was close to the values in the pre-RT group and there was no significant difference.
Correlation results
FA value in the right occipital (r=0.483, P=0.027), and left parietal (r=0.445, P=0.034) white matter that revealed by groups comparison between pre-RT vs post-RT0-6m correlated positively with MMSE score of NPC patients. λ‖value in the right parietal white matter (r=0.498, P=0.025) correlated positively with MMSE score of NPC patients. λ‖value in the left frontal-parietal junction area white matter (r=-0.482, P=0.027) correlated negatively with MMSE score of NPC patients. MD value in the left frontal-parietal junction area (r=-0.487, P=0.025) correlated negatively with MMSE score of NPC patients. MD value in the left parietal (r=0.514, P=0.035) correlated positively with MMSE score of NPC patients.
Conclusion
1. As the only noninvasive method for characterizing changes in tissue microstructural organization and diffusivity of water changes in brain tissue in vivo, DTI may be used in sensitive discovering and dynamical monitoring the subtle abnormalities of the radiation-induced WM microstructure, earlier than conventional cranial MRI, following RT for NPC patients.
2. For NPC patients, radiotherapy may produce extensive white matter microstructure damage, involving multiple brain regions and not just limited to the temporal lobe. Furthermore, WM microstructure abnormalities are complex, dynamic and temporary, brain tissue injury is most serious within6months after radiotherapy, then will repair gradually, and will be close to the level of the pre-RT after12month.
3. The FA value decreased significantly, and λ⊥, MD,λ‖value increased significantly in multiple WM regions within6months after RT compared with pre-RT in NPC patients, suggesting that WM microstructural damage in these regions may be caused mainly by brain edema and demyelination, and may be accompanied by mild axonal degeneration.
4. The mean FA, MD, λ‖and λ⊥values in significantly different areas that revealed by pre-RT vs0-6months post-RT in NPC patients were correlated significantly with their MMSE score. It indicates that extensive WM microstructure damage after radiotherapy affects the patient's cognitive function, and DTI in vivo measurement of WM microstructure changes may provide sensitive imaging biomarkers for early evaluation of radiation-induced brain injury and cognitive dysfunction.
引文
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