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基础研究
EC-T化疗后乳腺癌患者大脑自发神经活动异常的静息态功能磁共振成像研究
冯伟 刘同辉 李朋 王雪原 陈瑞 张华文 宁龙

Cite this article as: Feng W, Liu TH, Li P, et al. Abnormal spontaneous brain activities in breast cancer patients after EC-T chemotherapy: A resting-state functional magnetic resonance imaging study[J]. Chin J Magn Reson Imaging, 2022, 13(6): 56-60.本文引用格式:冯伟, 刘同辉, 李朋, 等. EC-T化疗后乳腺癌患者大脑自发神经活动异常的静息态功能磁共振成像研究[J]. 磁共振成像, 2022, 13(6): 56-60. DOI:10.12015/issn.1674-8034.2022.06.011.


[摘要] 目的 采用静息态功能磁共振成像(resting-state functional MRI,rs-fMRI)及低频振幅(amplitude of low frequency fluctuation,ALFF)算法探讨EC-T (E:表柔比星,C:环磷酰胺,T:紫杉醇)化疗后乳腺癌患者认知功能障碍相关的自发脑活动异常。材料与方法 纳入29例经病理证实为乳腺浸润性导管癌的女性患者(病例组),所有患者均接受标准的EC-T序贯化学治疗。同期选择30例年龄及受教育程度相匹配的女性健康志愿者(对照组)。所有受试者首先行蒙特利尔认知评估量表(Montreal Cognitive Assessment,MoCA)及听觉词语测试-华山版(Auditory Verbal Learning Test-Huashan version,AVLT-H),然后行3D脑容积成像及rs-fMRI扫描。最后采用DPARSF软件包对静息态图像进行处理,使用SPSS 19.0软件包对临床资料及量表得分进行统计学分析。结果 病例组MoCA评分低于对照组,差异有统计学意义(P=0.002),两组间AVLT-H各子项得分差异均无统计学意义(P>0.05);病例组左侧背外侧额上回(Frontal_Sup_L) ALFF值高于对照组,差异有统计学意义(P<0.001),小脑蚓_6 (Vermis_6)、左侧前扣带回(Cingulum_Ant_L) ALFF值低于对照组,差异有统计学意义(P<0.001)。Pearson相关分析显示左侧前扣带回ALFF值与MoCA评分呈显著正相关(r=0.789,P<0.001)。结论 接受EC-T化疗后的乳腺浸润性导管癌患者存在整体认知功能障碍,关键脑区出现自发神经活动异常并与整体认知功能损伤密切相关,这些脑区的自发神经活动异常有望成为EC-T化疗后乳腺癌患者认知功能障碍监测及治疗的影像学标记。
[Abstract] Objective Using resting-state functional magnetic imaging (rs-fMRI) and amplitude of low frequency fluctuation (ALFF) algorithm to investigate the abnormal spontaneous brain activities and related cognitive dysfunction in breast cancer patients after chemotherapy.Materials and Methods We selected twenty-nine patients with invasive ductal carcinoma of the breast (patients group) confirmed by pathology. All patients were female and all received standard EC-T (E: Epirubicin; C: Cyclophosphamide; T: Paclitaxel) sequential chemotherapy. Thirty age- and education level matched female healthy volunteers (controls group) were selected during the same period. All subjects first underwent Montreal Cognitive Assessment (MoCA) and Auditory Verbal Learning Test-Huashan version (AVLT-H), 3D brain volume imaging and rs-fMRI scans. Finally, the DPARSF software package was used for processing and statistical analysis. The SPSS 19.0 software package was used for statistical analysis of clinical data and scales.Results The MoCA scores of the patients group were lower than controls group (P=0.002). There was no significant difference in the scores of each sub-item of AVLT-H between-group (P>0.05). The ALFF values of left dorsolateral superior frontal gyrus (Frontal_Sup_L) in the Patients group were higher than controls group (P<0.001), whereas the ALFF values of cerebellar vermis_6 (Vermis_6) and left lateral cingulate gyrus (Cingulum_Ant_L) were lower than the controls group (P<0.001). Pearson correlation analysis showed that the ALFF values of the left lateral cingulate gyrus were significantly positive correlated with the MoCA score (r=0.789, P<0.001).Conclusions Patients with breast invasive ductal carcinoma after EC-T chemotherapy have global cognitive dysfunction. Spontaneous neural activity abnormalities in key brain regions are closely related to the overall cognitive impairment. Spontaneous brain activity abnormalities in these regions are expected to become imaging markers for monitoring and treatment of breast cancer patients' cognitive dysfunction after EC-T chemotherapy.
[关键词] 乳腺癌;认知功能障碍;化疗;低频振幅;静息态功能磁共振成像
[Keywords] breast cancer;cognitive dysfunction;chemotherapy;amplitude of low frequency fluctuation;resting-state functional magnetic resonance imaging

冯伟    刘同辉    李朋    王雪原    陈瑞    张华文    宁龙 *  

陕西省核工业二一五医院医学影像科,咸阳 712001

宁龙,E-mail:254431957@qq.com

作者利益冲突声明:全部作者均声明无利益冲突。


基金项目: 陕西省科技攻关计划 2019SF-209
收稿日期:2021-10-20
接受日期:2022-04-13
中图分类号:R445.2  R737.9  R749.2 
文献标识码:A
DOI: 10.12015/issn.1674-8034.2022.06.011
本文引用格式:冯伟, 刘同辉, 李朋, 等. EC-T化疗后乳腺癌患者大脑自发神经活动异常的静息态功能磁共振成像研究[J]. 磁共振成像, 2022, 13(6): 56-60. DOI:10.12015/issn.1674-8034.2022.06.011.

       乳腺癌是女性最常见癌症,在全球女性癌症相关死亡原因中位居第二,在我国女性所患恶性肿瘤中乳腺癌患病率居于首位[1]。化疗已经成为治疗癌症最成功的治疗策略之一,但大多数接受化疗的乳腺癌患者会出现不同程度的认知功能障碍,如记忆力、注意力、学习能力、推理能力、执行能力及空间感的能力等的下降,被称为化疗相关认知障碍(chemotherapy-induced cognitive impairment,CICI),又称为化疗脑[2]。静息态功能磁共振成像(resting-state functional MRI,rs-fMRI)被广泛应用于认知功能障碍的研究[3],已有研究者通过rs-fMRI及低频振幅(amplitude of low frequency fluctuation,ALFF)算法探究乳腺癌患者的化疗相关认知功能障碍[4],但由于纳入患者化疗方案的多样性,不能表征特定化疗方案的特异性脑功能损伤特征。本研究旨在采用rs-fMRI研究接受标准EC-T (E:表柔比星,C:环磷酰胺,T:紫杉醇)化疗方案的乳腺浸润性导管癌患者大脑局部自发神经活动异常以及相关的特异性认知损伤,进一步阐述乳腺癌患者认知功能障碍的机制,探寻认知障碍相关的影像学标记,为早发现、早治疗化疗后乳腺癌患者脑功能改变提供客观影像学依据。

1 材料与方法

1.1 研究对象

       本研究得到陕西省核工业二一五医院伦理委员会批准(批准文号:2019015),所有受试者均提前签署知情同意书。纳入29例陕西省核工业二一五医院肿瘤内科2018年11月至2020年7月之间收治的经病理证实为单侧乳腺浸润性导管癌的女性患者(病例组),年龄(45.31±7.03)岁。纳入标准:(1)单侧乳腺浸润性导管癌的女性患者(病理证实);(2)已完成标准的EC-T序贯化学治疗;(3)年龄<60周岁;(4)未绝经。排除标准:(1)脑血管病、脑肿瘤、脑外伤等颅脑器质性病变;(2)严重的语言障碍、视力模糊、听觉丧失和其他临床相关疾病症状,无法配合完成神经心理学评估;(3)幽闭恐惧症等MRI检查禁忌证。同期公开招募30例健康志愿者作为对照组,年龄(43.77±5.58)岁,纳入标准:(1)与病例组年龄、性别及教育程度相匹配;(2)近期体检结果提示健康状况良好;(3)神经心理学评估及头颅MRI检查配合良好;(4)头颅MRI正常。

1.2 化疗方案

       本研究所有乳腺浸润性导管癌患者均接受标准EC-T序贯化学治疗(E:表柔比星;C:环磷酰胺;T:紫杉醇),具体化疗方案为:表柔比星(60 mg/m2)+环磷酰胺(600 mg/m2)化疗4周期后再进行紫杉醇(100 mg/m2)化疗4周期,每个化疗周期为7 d,时间间隔为14 d,总时长为6个月;所有患者从化疗结束至纳入研究间隔时间6~12 (9.41±1.74)个月。

1.3 认知评估

       我们分别采用听觉言语学习测试-华山版(Auditory Verbal Learning Test-Huashan version,AVLT-H)和蒙特利尔认知评估量表(Montreal Cognitive Assessment,MoCA)评估每一位受试者的记忆功能和整体认知功能。AVLT-H是公认的测试受试者在不同工作记忆阶段记忆能力的可靠方法,主要包括即时记忆、短期延迟记忆、长期延迟记忆和再认[5, 6]。MoCA广泛应用于轻度认知障碍患者的整体认知评估,主要测试受试者的视空间、执行、命名、记忆、注意、语言、抽象和定向等方面的能力[7, 8]

1.4 数据采集

       扫描设备:美国GE Discovery 750 3.0 T超导MR扫描仪,8通道头颈联合线圈。扫描时受试者仰卧位,头先进,用海绵垫从双侧固定头部防止移动,用耳塞减少噪音干扰,嘱咐患者在扫描过程中保持闭眼、清醒,避免思考活动,定位线平行于前后联合线,从颅顶扫描至颅底。首先行常规T1WI、T2WI、T2-液体衰减反转恢复(fluid-attenuated inversion recovery,FLAIR)序列扫描筛查颅脑器质性病变。用3D脑容积成像(3D brain volume imaging,3D-BRAVO)序列采集所有受试者的全脑高分辨结构像,扫描参数:TE=3.2 ms,TR=8.2 ms;层间隔=0,层厚=1 mm,翻转角=15°,视野=240 mm×240 mm,矩阵=256×256,扫描次数=160。rs-fMRI采集使用单次激发SE-EPI序列,扫描参数:TE=50 ms,TR=2000 ms;层间隔=0,层厚=4.0 mm;翻转角=90°,视野=240 mm×240 mm,矩阵=64×64;体素大小=3 mm×3 mm×3 mm,扫描时间为6 min 10 s,包含185个脑容积。

1.5 MRI数据处理

       采用基于MATLAB R2012b平台处理静息态血氧水平依赖功能磁共振成像(blood oxygen level-dependent functional magnetic resonance imaging,BOLD-fMRI)数据,采用DPARSF软件包(Data Processing Assistant for Resting-State fMRI,DPARSF) V2.1 Advance Edition软件(http://www.restmri.net/forum/DPARSF)分析EPI采集的原始数据。处理步骤:(1)将所有受试者的颅脑MRI数据由DICOM格式转换为NIFTI格式;(2)去除每个受试者前10个时间点的fMRI数据;(3)以每次扫描的中心层(第31层)为参考层对每个受试者的数据进行时间序列校正;(4)排除水平移位>3 mm或旋转移位>3°的受试者;(5)将功能像与自身结构像相配准,采用加拿大蒙特利尔神经病学研究所(Montreal Neurological Institute,MNI)标准头部解剖模版为模版,并投射在标准MNI模板,以体素大小3 mm×3 mm×3 mm对数据进行重采样;(6)去除线性漂移,以减少低频线性漂移影响;(7)去除全脑平均信号、头动参数、脑脊液及白质信号的影响;(8)计算每个体素在0.01~0.1 Hz频段的ALFF。

1.6 统计学分析

       使用SPSS 19.0软件包对临床资料及量表进行统计学分析。采用两样本t检验比较年龄、受教育年限、AVLT-H评分、MOCA评分差异,提取病例组与对照组差异性脑区的ALFF值,并与AVLT-H及MoCA评分进行Pearson相关分析,以P<0.05为差异有统计学意义。

2 结果

2.1 一般资料

       两组受试者受教育年限、年龄差异均无统计学意义(P>0.05),见表1。病例组MoCA评分低于健康志愿者,差异有统计学意义(P<0.05),AVLT-H量表各子项得分差异无统计学意义(P>0.05),见表1

表1  人口统计学资料及神经心理学量表(x¯±s)
Tab. 1  Demographic data and neuropsychological scale (x¯±s)

2.2 ALFF差异有统计学意义脑区组间比较

       病例组左侧背外侧额上回(Frontal_Sup_L) ALFF值高于对照组,差异有统计学意义(P<0.05,AlphaSim校正),小脑蚓_6 (Vermis_6)、左侧前扣带回(Cingulum_Ant_L) ALFF值低于对照组,差异有统计学意义(P<0.05,AlphaSim校正),见表2图1

图1  组间低频振幅差异有统计学意义脑区图。红色区域表示病例组较对照组低频振幅值增高区域,位于左侧背外侧额上回;蓝色区域表示患者组较对照组低频振幅值减低区域,位于小脑蚓、左侧前扣带回。
Fig. 1  Brain area diagram of significant difference in amplitude of low frequency fluctuation (ALFF) between groups. The red area indicates the area with higher ALFF value in the case group than tht in the control group, which is located in the left dorsolateral superior frontal gyrus.The blue area indicates the area where the ALFF value of the patient group is lower than that of the control group, which is located in the cerebellar vermis and the left anterior cingulate gyrus.
表2  组间ALFF差异的脑区
Tab. 2  Brain regions of ALFF differences between groups

2.3 病例组差异脑区的ALFF值与MoCA评分的相关性分析

       Pearson相关分析显示病例组左侧前扣带回ALFF值与MoCA评分呈显著正相关(r=0.789,P<0.001),见图2

图2  病例组左侧前扣带回ALFF值与MoCA评分呈显著正相关(r=0.789,P<0.001)。注:MoCA:蒙特利尔认知评估量表;ALFF:低频振幅。
Fig. 2  ALFF value of left anterior cingulate gyrus in case group was significantly positively correlated with MoCA score (r=0.789, P<0.001). Note: MoCA: Montreal Cognitive Assessment; ALFF: amplitude of low frequency fluctuation.

3 讨论

       本研究发现接受EC-T化疗方案的乳腺浸润性导管癌患者出现多区域自发脑活动异常,主要位于左侧背外侧额上回、小脑蚓及左侧前扣带回,同时发现乳腺癌患者存在整体认知功能障碍,Pearson相关分析显示左侧前扣带回自发脑活动减低与整体认知损伤评分呈显著正相关,这可为临床工作中针对乳腺癌患者认知功能障碍的诊断及治疗提供有效的监测指标。

3.1 乳腺癌患者多区域自发脑活动异常

       ALFF是通过使用0.01~0.08 Hz这一低频段内所有频率点上振幅值的平均值来反映一个体素的自发性活动强弱,从能量角度反映神经元静息状态下自发活动水平,ALFF的改变提示该脑区神经元自发活动存在异常[9, 10, 11]。本研究发现接受EC-T化疗方案的浸润性导管癌患者组左侧背外侧额上回ALFF值增高,小脑蚓、左侧前扣带回ALFF值降低。左侧背外侧额上回及左侧扣带和扣带旁脑回是默认网络(default mode network,DMN)的重要构成脑区。DMN是在静息状态下处于激活状态的大脑功能网络,主要包概括内侧前额叶皮质、双侧顶下小叶、前扣带回、后扣带回、楔前叶及双侧海马等脑区[12, 13],且DMN 的活动与人脑的记忆、情感、认知等功能密切相关,DMN活动异常可见于多种疾病患者[14, 15, 16]。背外侧额上回与情绪调节、认知过程和自我意识等密切相关[17],小脑蚓部可影响感觉运动功能、工作记忆等认知功能[18, 19],扣带回对记忆、情感及动作等认知功能有重要作用[20]。刘伟等[21]纵向研究化疗对乳腺癌患者静息态局部脑活动和认知功能的影响发现化疗引起双侧楔前叶、颞中回神经元自发活动增强,Chen等[22]研究发现接受化疗的老年乳腺癌患者双侧胼胝体下回和右前扣带回神经元自发活动增强,左侧楔前叶神经元自发活动减弱,它们均属于DMN的构成脑区,但与我们研究发现神经元自发活动异常的脑区不同,这可能与患者年龄、乳腺癌的病理类型以及所接受的化疗方案的差异有关。既往研究已经证实烷化剂、蒽环类以及紫杉烷类化疗药物可以靶向作用于DNA修复和细胞分裂的各个方面,从而引起细胞凋亡,进一步导致脑结构和功能的改变,紫杉醇已被证实具有抗血管生成作用,表柔比星亦被证实与血管毒性相关[23, 24, 25]。DMN对药物毒性尤其易感,化疗引起炎症反应和氧化应激的增加被认为增加了对DMN的毒性作用[26]。由此推测EC-T化疗可能导致了乳腺癌患者大脑DMN的网络异常,出现了部分脑区神经元活动改变,从而影响患者的认知功能。

3.2 乳腺浸润性导管癌患者左侧前扣带回自发神经活动减低与整体认知障碍密切相关

       在临床实践中,大多数接受化疗的患者存在不同程度的以注意力、记忆力及意识运动功能减退为主要表现的认知功能障碍[27]。迄今为止,乳腺癌化疗相关认知功能障碍可能是多种因素共同作用的结果,其发病机制尚未完全清楚,但已有研究证实化疗药物的直接或间接神经毒性作用、氧化应激反应、炎症反应以及激素水平的变化等是其可能的致病因素[28, 29]。我们的研究发现MoCA评分差异有统计学意义,而AVLT-H评分差异无统计学意义,提示接受EC-T化疗方案的浸润性导管癌患者存在整体认知功能障碍,无明显记忆功能障碍。Pearson相关分析发现,左侧前扣带回ALFF值与MoCA评分呈正相关,提示接受EC-T化疗方案的浸润性导管癌患者存在整体认知损伤及局部脑区的自发活动异常,进一步证实扣带回可能是化疗后乳腺癌患者认知功能障碍相关的关键损伤脑区,可能为临床工作中针对化疗后乳腺癌患者认知功能障碍的诊断、监测及干预提供有效的影像学监测指标。总之,本研究选择同一病理类型(浸润性导管癌)、特定化疗方案(EC-T)的乳腺癌患者,通过rs-fMRI证实左侧前扣带回自发神经活动异常可能是化疗后认知功能障碍的潜在机制。

3.3 不足与展望

       本研究为横断面研究,样本量相对较少,无法纵向观察化疗后乳腺浸润性导管癌患者大脑局部自发神经活动异常以及相关的特异性认知损伤在整个疾病过程中的动态变化。此外,本研究未全面考虑乳腺癌疾病本身及内分泌治疗等其他部分治疗对患者的影响,也未评估患者的焦虑、抑郁等情绪状态。在今后的研究中应当长期跟踪随访乳腺癌患者,进一步增加样本量,系统地运用MRI多模态成像技术,全面阐述乳腺癌患者认知功能障碍的机制,为早发现、早治疗化疗后乳腺癌患者脑功能改变提供客观影像学依据。

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