无明显肝性脑病的乙肝肝硬化患者脑静息态下多模态MRI研究
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摘要
第一部分无明显肝性脑病的乙肝肝硬化患者认知功能与正常人对照研究
目的：
1、采用正常被试初步建立肝性脑病心理测试积分(psychometric hepatic encephalopathy score,PHES)量表预期值计算公式。
2、采用PHES量表探讨无明显肝性脑病(overt hepatic encephalopathy, OHE)的乙肝肝硬化患者与正常人认知功能之间差异。
3、探讨无OHE的乙肝肝硬化患者神经认知改变与其肝功能损害严重程度之间的关系。
材料与方法：
本研究共纳入133名正常被试及34名无OHE的乙肝肝硬化患者,所有被试共分为三组：乙肝肝硬化组34例,男29例,女5例,平均年龄为45.09±9.88岁(27～67岁),受教育程度10.18±3.51年(6-19年)；正常标准组133例,男81例,女52例,平均年龄为45.06±10.79岁(22～65岁),受教育程度10.51±3.70年(6-19年)；从正常标准组中选取34例与乙肝肝硬化组性别严格匹配、年龄及教育程度相差≤3年的正常被试作为正常对照组,其中男29例,女5例,平均年龄为44.62±9.70岁(28～63岁),受教育程度11.56±3.09年(6-16年)。
对纳入研究的所有乙肝肝硬化患者均进行了血生化检查,并行Child-pugh评分以评价肝功能损害程度。所有167例被试均行神经心理测试。神经心理测试采用PHES试验组,包括数字连接试验A (number connection test A, NCT-A)、数字连接试验B (number connection test B, NCT-B)、数字符号试验(digit symbol test, DST)、系列打点试验(serial dotting test, SDT)、线追踪试验(line tracing test, LTT)5项心理智能测试,并记录试验完成的时间(s)或个数(n)。
统计学分析软件均通过SPSS13.0统计软件包完成。PHES量表的5项心理智能测试结果均以Mean±SD (1±SD)形式表示。分别以正常对照组的5项神经心理测试结果为因变量,将年龄(岁)、性别(男=1；女=2)及教育程度(年)引入回归模型,对正常标准组5项心理智能测试结果分别进行多元线性回归分析以获得每项测试的回归方程。按照5个一般回归方程产生的预期值计算公式分别计算出每个被试每项心理智能测试的预期值,再计算Z值(预期值与实际值之差),Z值大于或等于1SD记为+1分,Z值在-1SD、-2SDs、-3SDs以下分别记为-1、-2、-3分,PHES值为5项心理智能测试积分之和。采用两独立样本t检验分别比较乙肝肝硬化组与正常对照组之间NCT-A (s)、NCT-B (s)、 DST (n)、SDT(s)、LTT(s+n)各项原始值之间的差异；采用非参数秩和检验中的两独立样本Mann-Whitney U检验比较两组间PHES差异是否有统计学意义；采用Spearman相关性分析研究乙肝肝硬化组PHES与Child-pugh评分之间的相关性。P<0.05认为差异有统计学意义。
结果：
1、年龄及受教育程度均作为影响因素被引入5个一般线性回归模型,并分别得出PHES的5项心理智能测试的预期值计算公式。
2、与正常对照组比较,乙肝肝硬化组5项神经心理测试NCT-A、 NCT-B、 SDT、 LTT所需时间均增加(P<0.01)、DST完成的个数减少(P<0.007)、PHES值下降(P<0.001)。
3、乙肝肝硬化组PHES值与Child-pugh评分呈负相关(rs=-0.367,P=0.033)
结论：
1、 PHES量表较全面评价无OHE的乙肝肝硬化患者的认知功能改变,但仍存在一定的影响因素。
2、无OHE的乙肝肝硬化患者NCT-A、NCT-B、 DST、 SDT、 LTT5项心理智能测试完成能力及PHES值均显著低于正常人,表明这些患者存在运动、视觉、精神集中度及注意力、记忆能力方面的不同程度的认知损害。
3、无OHE的乙肝肝硬化患者肝功能越差,其认知功能损害就趋于严重。
第二部分无明显肝性脑病的乙肝肝硬化患者静息态脑功能局部一致性研究
目的：
1、利用脑静息态血氧水平依赖功能磁共振成像技术及局部一致性(regional homogeneity, ReHo)算法探讨无OHE的乙肝肝硬化患者静息态下局部脑区神经元活动的改变情况。
2、探讨无OHE乙肝肝硬化患者ReHo的改变与其认知功能改变、肝功能损害程度之间的关系。
材料与方法：
64例被试被纳入本研究：乙肝肝硬化组(无OHE)32例,男27例,女5例,平均年龄为44.69±9.86岁(27～67岁),受教育程度10.34±3.62年(6-19年)。正常对照组包括34例与乙肝肝硬化患者性别严格匹配、年龄及教育程度相差≤3年的正常被试,男27例,女5例,平均年龄为44.22±9.67岁(28-63岁),受教育程度11.84±3.20年(6-16年)。对所有乙肝肝硬化患者行Child-pugh评分以评价其肝功能损害程度,行PHES测试评价其认知功能(同第一部分)。
采用飞利浦1.5T双梯度磁共振成像扫描仪行静息态下脑功能数据采集,16通道神经血管线圈进行信号接收。采用GRE-EPI技术行覆盖全脑的静息态脑功能扫描,参数如下：TR/TE=3000/50ms,翻转角=90。,层厚／层间距=4.5/0mm,矩阵=64×64,视野=230×230mm,采集160个时相。
图像预处理基于Matlab7.11分析软件平台的DPARSF软件对静息态脑功能磁共振数据进行预处理,具体处理步骤包括：1、剔除前10个时相的采集图像,以防止磁场达到稳态前的一过性信号改变；2、时间差异校正；3、头动校正,估计扫描期间的头动参数,三维平移超过1.5mm、三维旋转超过1.5。的被试从本研究中剔除；4、空间标准化,将头动校正后的数据标准化到MNI模板；5、去线性漂移；6、低频滤波,采用0.01-0.08Hz带宽对所得信号进行低频滤波,去除低频线性漂移及高频生理性噪声的干扰。ReHo计算采用REST软件,通过计算每个给定体素的肯德尔和谐系数(Kendall's coefficient concordance,KCC)值,可获得每个被试的KCC图,通过每一体素的KCC值除以全脑平均KCC值生成标准化的ReHo图。对所有产生的数据结果使用8mm半高带宽的平滑核对图像进行空间平滑。
采用SPM8及REST软件对两组被试的ReHo统计图进行两独立样本t检验(以年龄、教育程度、呼吸频率及心率为协变量),结果多重比较校正(AlphaSim校正,P<0.01且簇>74个体素)后的P<0.05认为差异有统计学意义。采用Spearman相关分析评价乙肝肝硬化患者组间显著差异脑区平均ReHo值与其PHES值、Child-pugh评分之间的关系,P<0.05认为相关性有统计学意义。
结果：
1、与正常组比较,乙肝肝硬化组双侧额下回／额中回ReHo值显著升高,左侧舌回、双侧楔前叶／楔叶、右侧枕中回、左侧颞中回、双侧中央前回及旁中央小叶ReHo值显著减低(P<0.05;AlphaSim校正：P<0.01且簇>74个体素)。
2、无OHE的乙肝肝硬化患者左侧舌回(rs=0.369,P=0.037)、双侧楔前叶／楔叶(rs=0.468,P=0.007)、右侧枕中回(rs=0.438,P=0.012)、左侧中央前回(rs=0.442,P=0.011)、右侧中央前回(rs=0.575,P=0.001)及双侧旁中央小叶(rs=0.475,P=0.006)平均ReHo值与其PHES呈正相关性。
3、无OHE的乙肝肝硬化患者Chlid-pugh评分与所有组间差异脑区ReHo值之间
相关性均无统计学意义(P>0.05)。
结论：
1、无OHE的乙肝肝硬化患者存在多个脑区ReHo的异常,主要表现在视觉处理相关皮层(左侧舌回及颞中回、右侧枕中回)、运动相关皮层(双侧中央前回及旁中央小叶)、默认网络区域(双侧楔前叶／楔叶)ReHo显著减低,而双侧额下回／额中回ReHo显著增高,提示这些脑区局部神经元自发活动同步性的异常。
2、无OHE的乙肝肝硬化患者视觉相关区域、运动相关区域、默认网络脑区平均ReHo值与其PHES值呈正相关性,这表明这些区域ReHo异常可能是其认知功能受损的神经病理基础,且提示ReHo值可以作为这些患者潜在认知损害的客观评价指标。
3、无OHE的乙肝肝硬化患者肝功能损害程度与其脑ReHo改变之间无显著相关性。
第三部分无明显肝性脑病的乙肝肝硬化患者基于体素的脑灰质形态研究目的：
1、利用高分辨磁共振检查技术及VBM分析方法探讨无OHE的乙肝肝硬化患者脑灰质体积的改变情况。
2、探讨无OHE的乙肝肝硬化患者的灰质体积的改变与其认知功能改变、肝功能损害之间的关系。材料与方法：
54例被试被纳入本研究：乙肝肝硬化组27例,男24例,女3例,平均年龄为45.15±9.53岁(27～67岁),受教育程度10.48±3.72年(6-19年)。正常对照组为与乙肝肝硬化患者性别严格匹配、年龄及教育程度相差≤3岁的正常被试27例,男24例,女3例,平均年龄为45.04±9.56岁(28～63岁),受教育程度12.19±2.99年(6-16年)。对所有乙肝肝硬化患者行Child-pugh评分以评价其肝功能损害程度,行PHES测试评价其认知功能(同第一部分)。
仪器设备同前,采用3D快速场回波序列(FFE)进行高分辨T1加权像采集,参数如下：TR/TE=25/4.1ms,翻转角=30°,层厚／层间距=I/0mm,矩阵=231×231,视野=230×230mm,平行于正中矢状面进行全脑采集。
图像预处理采用安装在SPM8软件下的VBM8工具箱,主要步骤包括：1、空间标准化：将扫描得到的结构图像标准化到DARTEL-MNI模板(已标准化到MNI空间的DARTEL模板)；2、图像分割：采用ICBM模板去除非脑组织。之后,基于最大后验概率(MAP)及部分容积估算(PVE)的分割技术将标准化后的脑组织进行分割为灰质、白质和脑脊液；3、调整：为保持每个个体校正全脑容积后的绝对灰质体积,对灰质图像进行非线性校正；4、平滑：将分割后的灰质图像采用8mm半高带宽的高斯平滑核进行空间平滑。
采用两独立样本t检验的统计方法和SPSS13.0软件包对两组被试全脑容积和全脑灰质容积总量进行比较,P<0.05认为差异有统计学意义。采用一般线性模型和随机场理论对两组被试脑灰质进行基于体素的比较(以年龄、受教育程度为协变量),应用逐个像素单边检验,P<0.001(未校正)且簇>200mm3认为有统计学意义。采用偏相关分析(以年龄及受教育程度为协变量),分别评价乙肝肝硬化患者全脑灰质总容积、组间显著性差异区的脑灰质体积与其PHES之间、Child-pugh评分之间的相关性,P<0.05认为差异有统计学意义。
结果：
1、乙肝肝硬化组与正常对照组间颅内容积无明显差异(P=0.504)。乙肝肝硬化组脑灰质容积总量显著大于正常对照组(P<0.001)。
2、较正常对照组相比,乙肝肝硬化组多个脑区灰质体积增加(P<0.001,未校正,簇>200mm3),主要表现在：双侧小脑半球；双侧梭状回(扩展至双侧丘脑／尾状核／楔前叶／楔叶／枕中回／岛叶／舌回)、双侧眶额叶皮层、双侧额中回、双侧额下回、右侧颞中回、右侧颞下回；双侧中央前回、双侧旁中央小叶、右侧顶下小叶、扣带中回、桥脑。
3、乙肝肝硬化患者PHES与全脑灰质总容积呈负相关(r=-0.631,P=0.001)。乙肝肝硬化患者PHES与大部分差异脑区灰质体积呈负相关,包括：双侧梭状回(r=-0.709,P<0.001)、左侧额中回(r：=-0.546,P=0.005)、双侧额下回(左：r=-0.446,P=0.026；右：r=-0.406,P=0.044)、右侧颞中回(r=-0.736,P<0.001)、右侧颞下回(r=-0.545,P=0.005)；双侧中央前回(左：r==-0.635,P=0.001；右：r=-0.655,P<0.001)、双侧旁中央小叶(r=-0.594,P=0.002)、扣带中回(r=-0.524,P=0.007)、桥脑(r=-0.569,P=0.003)。乙肝肝硬化患者Chlid-pugh分级与灰质总容积与所有差异脑区灰质体积相关性无统计学意义(P值均>0.05)。
结论：
1、无OHE的乙肝肝硬化患者存在脑灰质体积的广泛增加。
2、无OHE的乙肝肝硬化患者随脑灰质体积的增加,其认知功能损害越显著,表明灰质体积的增加可能是肝硬化患者认知功能异常的形态学基础,且提示这些脑区灰质容积的增加可作为其认知功能损害严重程度的形态学指标。
3、无OHE的乙肝肝硬化患者肝功能损害程度与灰质体积的增加之间无显著相关性。
第四部分无明显肝性脑病的乙肝肝硬化患者脑白质改变：DTI-TBSS研究
目的：
1、利用磁共振扩散张量成像技术(DTI)及基于纤维束示踪的空间统计(TBSS)的数据后处理方法评价无OHE的乙肝肝硬化存在的白质改变。
2、探讨无OHE的乙肝肝硬化患者脑白质改变与其认知功能、肝功能损害之间的关系。
材料与方法：
60例被试被纳入本研究：乙肝肝硬化组30例,男25例,女5例,平均年龄为46.43±9.49岁(32～67岁),受教育程度9.97±3.22年(6,--19年)。正常对照组30例(与乙肝肝硬化组性别严格匹配、年龄及教育程度相差≤3岁),男25例,女5例,平均年龄为45.83±8.67岁(32～63岁),受教育程度11.43±3.00年(6-16年)。对所有乙肝肝硬化患者行Child-pugh评分以评价肝功能损害程度,行PHES测试来评价其认知功能损害程度(同第一部分)。
仪器及设备同前,采用SE-EPI序列进行DTI数据采集,参数如下：扩散敏感方向为33个,扩散敏感系数为b=800和0s/mm2, TR/TE=19837/62ms,翻转角=90°,层厚／层间距=2/0mm,平行于前后联合线平面进行覆盖全脑采集。
DTI数据分析采用FSL工具包。首先对原始数据进行头动和涡流校正,接着利用BET套件产生各自的Mask,然后利用FDT套件中的dtifit中生成平均弥散率值(mean diffusivity, MD)、部分各向异性值(fractional anisotropy, FA)。随后按照TBSS流程进行分析：tbss_l_preproc,tbss_2_reg, tbss_3_postreg, tbss_4_prestats。两组间FA值,MD值的比较采用randomise工具进行的非参数统计阈值分析(TFCE)的统计方法。多重比较校正(FWE校正)后,P<0.05认为有统计学意义。
采用两独立样本t检验及SPSS13.0软件包分析两组间全脑平均FA值及MD值、差异脑区的FA值及MD值之间的差异。采用偏相关分析(以年龄及教育程度为协变量)分别评价乙肝肝硬化患者TBSS相关指标(包括全脑平均FA及MD值、组间差异区域平均FA及MD值)与其PHES、Child-pugh评分之间的相关关系。P<0.05认为差异有统计学意义。
结果：
1、两组间比较未见FA值显著减低或增加的脑区。与正常组比较,乙肝肝硬化组右侧额叶、顶叶及颞叶、双侧内囊、外囊、小脑上脚、小脑中脚、小脑蚓部、小脑半球及脑干的MD值显著升高(P<0.05,FWE校正)。
2、两组之间全脑平均FA值无显著差异(P=0.716)。与正常对照组比较,乙肝肝硬化组全脑平均MD值(P=0.044)及组间差异脑区平均MD值(P<0.001)均显著高于正常对照组。
3、乙肝肝硬化患者PHES与其全脑平均FA值(r=0.180,P=0.358)、全脑平均MD值(r=-0.310,P=0.108)及组间差异脑区平均MD值(r=-0.287,P=0.138)之间的相关性无统计学意义。Child-pugh评分与全脑平均FA值之间的相关性无统计学意义(r=-0.197, P=0.315);Child-pugh评分与全脑平均MD值(r=0.686,P<0.001)、组间差异脑区平均MD值之间呈正相关(r=0.620,P<0.001)。
结论：
1、无OHE的乙肝肝硬化患者存在广泛脑白质MD值的明显升高,但不伴有FA值的改变,提示这些区域存在广泛的细胞外间隙脑水肿,而不伴有白质微结构的破坏。
2、MD值升高区域的平均值与Child-pugh评分呈显著正相关,表明无OHE的肝硬化患者肝功能越差,其细胞外间隙脑水肿的程度就越严重。
Part one:A comparative study of cognitive function between patients with HBV-related cirrhosis without overt hepatic encephalopathy and healthy subjects.
Objective:
1. To obtain the5formulas used to calculate predicted values in psychometric hepatic encephalopathy score (PHES) by using PHES normative data from healthy subjects.
2. To explore differences in cognitive function between patients with HBV-related cirrhosis without overt hepatic encephalopathy (OHE) and healthy subjects by using PHES battery of tests.
3. To explore the relationship between impaired cognitive of patients with function HBV-related cirrhosis without OHE and abnormal liver function.
Materials and Methods:
One hundred and thirty-three healthy subjects and34patients with HBV-related cirrhosis without OHE and were investigated in this study. Standard group included133healthy subjects (81male,52female), mean age45.06±10.79years (range22～65), years of education10.51±3.70(range6～19). Cirrhotic group was comprised of34patients (29male,5female), mean age45.09±9.88years (range27～67), years of education10.18±3.51(range6-19); and a total of34matched healthy subjects (age:well matched; sex and education level:within3years) were selected from standard group as a control group (29male,5female), mean age44.62±9.70years (range28～63), years of education11.56±3.09(range6-16).
Biochemical tests were performed in all patients with HBV-related cirrhosis, and the liver function status of each patient was assessed using the Child-Pugh score. All167subjects underwent the PHES battery of tests. This paper-pencil test battery consisted of the number connection test A (NCT-A) and B (NCT-B), the digit symbol test (DST), the serial dotting test (SDT), and the line tracing test (LTT-time and errors). At the same time, the test results were recorded.
Analyses were conducted using software (SPSS, version13.0; Chicago, Ⅲ). Five psychometric test results are expressed as means±SD. In the first step, valid regression models were obtained with Pearson's correlations between the psychometric test results of and age (years), gender (male=l; female=2) and education level (years) in standard group. In the second step, the unstandardized beta coefficients of these analyses were used in the final formulas to correct for these factors. These formulas were then used to predict values (Z values) for cirrhotic patients, and the difference between the predicted and observed results for each test was divided by the corresponding SD for the reference population to obtain the deviation from'normal'as a multiple of the SD. Finally, differences for each test in multiples of the SD were summed as follows:a result≥1SD above the predicted was scored as+1, results-1SD,-2SDs and-3SDs below the predicted were scored as-1,-2and-3, respectively. Two independent sample t-tests were performed to assess the differences in raw results of five psychometric tests between two groups. Mann-Whitney U test was performed to assess the differences in the performance level on the PHES between two groups. A spearman correlation analysis was performed between their performance level on the PHES and Child-pugh score in cirrhotic patients. A two-side P value less than0.05was considered as statistically significant.
Results:
1. In the multivariate analysis using multiple linear regressions, both age and education were found to be independent variables related to all the tests. Five formulas used to calculate predicted values were obtained.
2. Compared with the control subjects, the completion time for NCT-A、NCT-B、 SDT、LTT was increased significantly (P<0.01) and completion numbers for DST (P=0.007) were decreased significantly in cirrhotic patients. Cirrhotic patients had significantly worse performance of PHES (P<0.001) than healthy subjects.
3. A significant negative correlation was observed between the performance of PHES and Child-pugh score in cirrhotic patients (rs=-0.367, P=0.033).
Conclusions:
1. PHES battery of tests can be used to assess comprehensively the alterations of cognitive function in patients with HBV-related cirrhosis without OHE, but it should noted that there still exist factors influencing the results in PHES battery of tests.
2. Patients with HBV-related cirrhosis without OHE had significantly worse performance of all the five psychometric test (NCT-A, NCT-B, DST, SDT, LTT) results and PHES than healthy subjects. Those findings reveal the existence of deficits in motor performance, visual perception visuoconstructive abilities, concentration and attention, and memory in those patients.
3. The poorer the liver function in patients with HBV-related cirrhosis without OHE is, the more serious impaired cognitive function tends to be.
Part two:Regional homogeneity abnormalities in patients with hepatitis B virus-related cirrhosis without OHE:a resting-state fMRI study
Objectives:1.To investigate regional activity abnormalities of patients with HBV-related cirrhosis without OHE by using resting-state fMRI and Regional homogeneity (ReHo) method in the resting state.
2. To investigate whether these ReHo abnormalities of neural activity in patients with HBV-related cirrhosis without OHE can be related to their impaired cognitive function and abnormal liver function.
Materials and Methods:
Sixty-four subjects were investigated in this study. Cirrhotic group was comprised of32patients with HBV-related cirrhosis without OHE (27male,5female), mean age44.69±9.86years (range27～67), years of education10.34±3.62(range6～19). Control group included32matched healthy subjects (age:well matched; sex and education level:within3years),27male and5female, mean age44.22±9.67years (range28～63), years of education11.84±3.20(range6-16). The liver function status of all patients was assessed using the Child-Pugh score. All subjects underwent the PHES battery of tests (the same as the first part).
MR imaging data were obtained with a1.5-T MR imager with a16channel neurovascular coil to receive the signal. A gradient-echo echo-planar (GRE-EPI) sequence was used to acquire functional images. Scan parameters:TR/TE=3,000/50ms, flip angle=90°, thickness/gap=4.5/0mm, matrix=64×64, field of view (FOV)=230×230mm, total volumes=160.
The imaging data were mainly preprocessed with a MATLAB toolbox called DPARSF (http://restfmri.net/forum/DPARSF) for "pipeline" data analysis of resting-state fMRI.1. The first ten time points were discarded to avoid transient signal changes before magnetization reached steady-state.2. Slice timing.3. Realignment:the raw data were corrected for the head motion. Subjects with head motion exceeding1.5mm in any dimension through the resting-state run will be discarded from further analysis.4. Normalization:all data were spatial normalized to the Montreal Neurological Institute (MNI) template.5. Removal of linear trends.6. Temporally filtered (band pass,0.01-0.08Hz):to remove the effects of very low-frequency drift and physiological high frequency respiratory and cardiac noise. REST software was used to calculate the ReHo value of each subject. This is accomplished on a voxel-by-voxel basis by calculating Kendall's coefficient of concordance (KCC) of time series of a given voxel with those of its nearest26neighbors. The KCC value was calculated to every voxel, and an individual KCC map was obtained for each subject. To reduce the influence of individual variations in the KCC value, normalization of ReHo maps was preformed through dividing the KCC among each voxel by averaged KCC of the whole brain. The resulting data were then spatially smoothed with an8-mm full-width at half-maximum (FWHM) Gaussian kernel.
By using SPM8and REST software, a second-level random-effect two-sample t-test was performed on the individual normalized ReHo maps in a voxel-by-voxel manner by taking years of age and education, cardiac rates and respiratory rates as confounding covariates. Significant differences were set at the threshold of a corrected cluster level of P less than0.05(AlphaSim corrected, a combined threshold of P<0.01, and a minimum cluster size of74voxels). Spearman correlation analysis of the mean ReHo values in significant different areas with performance level on the PHES and Child-pugh score in patients were performed, respectively. A two-side P value less than0.05was considered as statistically significant.
Results:
1. Compared with the control group, the cirrhotic patients group showed significant ReHo decreases in the bilateral precuneus/cuneus (PCu/Cu), precentral gyrus (PCG) and paracentral lobule (PCL), left lingual gyrus (LG) and middle temporal gyrus (MTG) and right middle occipital gyrus (MOG). A significant ReHo increase was found in the bilateral inferior/medial frontal gyrus (IFG/MFG)(P<0.05; AlphaSim corrected, a combined threshold of P<0.01, and a minimum cluster size of74voxels).
2. Correlation analysis of the mean ReHo values in significant different brain areas against performance level on the PHES in patients revealed significantly positive correlation in the left LG (rs=0.369; P=0.037), right MOG (rs=0.38; P=0.012) and bilateral PCu/Cu (rs=0.468; P=0.007), PCG (left:rs=0.442, P=0.011; right: rs=0.575, P=0.001), PCL (rs=0.475; P=0.006).
3. Correlation analysis of the mean ReHo values in all significant different brain areas against Child-pugh score in patients revealed no statistical significant correlation (P>0.05).
Conclusions:
1. Patients with HBV-related cirrhosis without OHE showed decreased ReHo most lay in motor cortex (left LG and MTG, and right MOG), visual cortex (bilateral PCG and PCL) and default mode network (bilateral PCu/Cu), while showed increased ReHo in the bilateral IFG/MFG. Those abnormalities reflect the destruction of local synchronization of spontaneous low-frequency BOLD in those regions.
2. The mean ReHo values in the identified regions, mainly including visual (left LG and right MOG), motor (bilateral PCG and PCL) association cortex and default mode network (bilateral PCu/Cu) were significantly positively correlated with the PHES in patients with HBV-related cirrhosis without OHE. These findings shed light on the pathophysiological mechanisms underlying cognitive alterations of cirrhotic patients and demonstrate the feasibility of using ReHo as a research and clinical tool to monitor the progression of cognitive impairment of cirrhotic patients without OHE.
3. There is no significant correlation between ReHo abnormalities in patients with HBV-related cirrhosis without OHE and their abnormal liver function.
Part three:Research on the gray matter volume of patients with hepatitis B virus-related cirrhosis without OHE:a voxel-based morphometry study
Objective:
1. To investigate the gray matter (GM) volume abnormalities in patients with HBV-related cirrhosis without OHE by using high resolution MRI and voxel-based morphometry (VBM) method.
2. To investigate whether these GM volume abnormalities in patients with HBV-related cirrhosis without OHE can be related to their impaired cognitive function and abnormal liver function.
Materials and Methods:
Fifty-four subjects were investigated in this study. Cirrhotic group was comprised of27patients with HBV-related cirrhosis without OHE (24male,3female), mean age45.15±9.53years (range27～67), years of education10.48±3.72(range6～19). Control group included27matched healthy subjects (age:well matched; sex and education level:within3years),24male and3female, mean age45.04±9.56years (range28～63), years of education12.19±2.99(range6～16). The liver function status of patients was assessed using the Child-Pugh score. All subjects underwent the PHES battery of tests (the same as the first part).
MRI data were obtained on a Philips Achieva1.5T Nova Dual MR scanner. A three-dimensional fast field echo (FFE) pulse sequence was used to produce contiguous sagittal images. Scan parameters:TR/TE=25/4.1ms, thickness/gap=1/0mm, matrix=232×231, field of view (FOV)=230×230mm, flip angle=30°.
Images analysis was performed using the VBM8tool, an extension tool of SPM. The main procedures include:1. Spatial normalization: High-dimensional spatial normalization was chosen and the T1images were normalized to an already existing Dartel-template in MNI space.2. Segment: International Consortium for Brain Mapping (ICBM) template was used to remove non-brain tissue from the images. Then, maximum a posterior (MAP) and partial volume estimation (PVE) approaches were used to segment the images into GM, white matter and cerebrospinal fluid.3. Modulation: non-linear was introduced to modulate the resulting GM images so that the voxels'values indicate the absolute amount of tissue corrected for individual brain sizes.4. The resulting images were smoothed with an8-mm full width at half maximum (FWHM) isotropic Gaussian kernel.
By using SPSS soft (version13.0), two independent sample t-tests were performed to assess the differences in the whole brain volume and total GM volume between two groups. A two-side P value less than0.05was considered as statistically significant. A voxel based comparison was used to identify the differences between two groups. Statistical maps were set at a cluster-level threshold of p<0.001, uncorrected with extended threshold of200contiguous voxels. Partial correlation analysis was performed with age and year of education as covariates to assess the relation of total GM volume and the GM volume in significant different brain areas with PHES and Child-pugh score in cirrhotic patients, respectively. A two-side P value less than0.05was considered as statistically significant.
Results:
1. There was no significant difference in the whole brain volume between two groups (P=0.504). Compared with the controls, the total GM volume was significantly increased (P<0.001) in cirrhotic patients.
2. Compared with the controls, GM volume increased significantly in bilateral cerebellar hemisphere, fusiform gyrus (extend to bilatera thalamus/caudate/precuneus/cuneus/middle occipital gyrus/middle temporal gyrus/inferior frontal gyrus/insula/lingual gyrus), bilateral orbitofrontal cortex, bilateral middle frontal gyrus, bilateral inferior frontal gyrus, right middle temporal gyrus, right inferior temporal gyrus, bilateral precentral gyrus, bilateral paracentral lobule, middle cingulate cortex and pons (P<0.001,uncorrected, clusters>200mm3) in cirrhotic patients.
3. Significant negative correlation was observed between the total GM volume and PHES in cirrhotic patients (r=-0.631, P=0.001). Partial correlation analysis of the GM volume in significant different brain areas against PHES in patients revealed significantly negative correlation in bilateral fusiform gyrus (r=-0.709, P<0.001), left middle frontal gyrus (r=-0.546, P=0.005), bilateral inferior frontal gyrus (left: r=-0.446, P=0.026; right:r=-0.406, P=0.044), right middle temporal gyrus (r=-0.736, P<0.001), right inferior temporal gyrus (r=-0.545, P=0.005), bilateral precentral gyrus (left:r=-0.635, P=0.001; right:r=-0.655, P<0.001), bilateral paracentral lobule (r=-0.594, P=0.002), middle cingulate cortex (r=-0.524, P=0.007) and pons (r=-0.569, P=0.003).
4. Correlation analysis of the total GM volume, GM volume in all significant different brain areas against Child-pugh score in patients revealed no statistical significant correlation (P>0.05).
Conclusion:
1. Patients with HBV-related cirrhosis without OHE have increased GM volume in many brain regions.
2. Most of increased GM volume in patients with HBV-related cirrhosis without OHE was negative correlated with the degree of impaired cognitive function. It suggests that the increased GM volume may be underlying basis of impaired cognitive function. It olso demonstrates that the incresed GM volume in those brain regions can be used as a morphology indictor to monitor the progression of cognitive impairment of cirrhotic patients without OHE.
3. There is no significant correlation between GM volume abnormalities in patients with HBV-related cirrhosis without OHE and their abnormal liver function.
Part four:White Matter changes in patients with HBV-related cirrhosis without OHE:A DTI and TBSS study
Objective:
1. To assess the white matter (WM) changes by using diffusion tensor imaging (DTI) and tract based spatial statistic (TBSS) in patients with HBV-related cirrhosis without OHE.
2. To explore the relationship between WM changes in patients with HBV-related cirrhosis without OHE and impaired cognitive function, and abnormal liver function.
Materials and Methods:
Sixty subjects were investigated in this study. Cirrhotic group was comprised of30patients with HBV-related cirrhosis without OHE (25male,5female), mean age46.43±9.49years (range32～67), years of education9.97±3.22(range6～19). Control group included30matched healthy subjects (age:well matched; sex and education level:within3years),25male and5female, mean age45.83±8.67years (range28～63), years of education11.43±3.00(range6-16). The liver function status of patients was assessed using the Child-Pugh score. All subjects underwent the PHES battery of tests (the same as the first part).
MRI data were obtained on a Philips Achieva1.5T Nova Dual MR scanner. A spin-echo echo-planar imaging (SE-EPI) sequence was used to acquire DTI data. Scan parameters:acquired in33noncollinear diffusion gradient directions, b values=800and0s/mm2, T R/TE=19837/62ms, thickness/gap=2/0mm, flip angle=90°.
DTI data was analysis by using FSL tools. First, diffusion-tensor images were corrected for head movements and eddy current distortion. Then, brain extraction tool (BET) was using to delete non-brain tissue from an image of the whole head and output a binary brain mask image. The diffusion tensor was estimated on a voxel-by-voxel basis by using dtifit (a part of the FDT). Maps of mean diffusivity (MD), fractional anisotropy (FA) were obtained. Running TBSS first involves running next steps:tbss_1_preproc, tbss_2_reg, tbss_3_postreg, tbss_4_prestats. Subsequently, using the threshold-free cluster enhancement (TFCE) option in randomise to perform statistics for FA and MD maps between two groups [Permutation-based correction for multiple comparisons (FWE) at P<0.05].
By using SPSS soft (version13.0), two independent sample t-tests were performed to assess the differences in the whole-brain mean FA and MD values, mean FA and MD values of the abnormal regions. Partial correlation analysis was performed with age and year of education as covariates to assess the relation of those indexes in TBSS with PHES and Child-pugh score in cirrhotic patients, respectively. A two-side P value less than0.05was considered as statistically significant.
Results:
1. Compared with controls, MD values of right frontal lobe, parietal lobe, temporal lobe, bilateral internal and external capsule, bilateral superior cerebellar peduncle, middle cerebellar peduncle, Cerebellar Vermis, cerebelar hemisphere and brain stem (P<0.05, FWE corrected). There was no difference in FA values between two groups.
2. There was no difference in whole-brain mean FA between two groups (P=0.716). Compared with the controls, the whole-brain mean MD values (P=0.044) and mean MD values in the abnormal regions (P<0.001) significantly increased in cirrhotic patients.
3. No significant correlation were observed between PHES and the whole-brain mean FA (r=0.180, P=0.358) or MD values (r=-0.310, P=0.108), between PHES and mean MD values (r=-0.287, P=0.138), and between Child-pugh score and the whole-brain mean FA values (r=-0.197, P=0.315) in cirrhotic patients. Significant positive correlation were observed between Child-pugh score and whole-brain mean MD values (r=0.686, P<0.001) and mean MD values in the abnormal regions (r=0.620, P<0.001).
Conclusion:
1. The increased MD values with no concomitant changes in FA in many WM regions in patients with HBV-related cirrhosis without OHE indicates the presence of extracellular brain edema, while without damage of WM microstructure.
2. Increased MD value in patients with HBV-related cirrhosis without OHE was positive correlated with the degree of impaired liver function. It suggests that the worse the liver function, the more serious the extracellular WM edema will be.
目的：
1、采用正常被试初步建立肝性脑病心理测试积分(psychometric hepatic encephalopathy score,PHES)量表预期值计算公式。
2、采用PHES量表探讨无明显肝性脑病(overt hepatic encephalopathy, OHE)的乙肝肝硬化患者与正常人认知功能之间差异。
3、探讨无OHE的乙肝肝硬化患者神经认知改变与其肝功能损害严重程度之间的关系。
材料与方法：
本研究共纳入133名正常被试及34名无OHE的乙肝肝硬化患者,所有被试共分为三组：乙肝肝硬化组34例,男29例,女5例,平均年龄为45.09±9.88岁(27～67岁),受教育程度10.18±3.51年(6-19年)；正常标准组133例,男81例,女52例,平均年龄为45.06±10.79岁(22～65岁),受教育程度10.51±3.70年(6-19年)；从正常标准组中选取34例与乙肝肝硬化组性别严格匹配、年龄及教育程度相差≤3年的正常被试作为正常对照组,其中男29例,女5例,平均年龄为44.62±9.70岁(28～63岁),受教育程度11.56±3.09年(6-16年)。
对纳入研究的所有乙肝肝硬化患者均进行了血生化检查,并行Child-pugh评分以评价肝功能损害程度。所有167例被试均行神经心理测试。神经心理测试采用PHES试验组,包括数字连接试验A (number connection test A, NCT-A)、数字连接试验B (number connection test B, NCT-B)、数字符号试验(digit symbol test, DST)、系列打点试验(serial dotting test, SDT)、线追踪试验(line tracing test, LTT)5项心理智能测试,并记录试验完成的时间(s)或个数(n)。
统计学分析软件均通过SPSS13.0统计软件包完成。PHES量表的5项心理智能测试结果均以Mean±SD (1±SD)形式表示。分别以正常对照组的5项神经心理测试结果为因变量,将年龄(岁)、性别(男=1；女=2)及教育程度(年)引入回归模型,对正常标准组5项心理智能测试结果分别进行多元线性回归分析以获得每项测试的回归方程。按照5个一般回归方程产生的预期值计算公式分别计算出每个被试每项心理智能测试的预期值,再计算Z值(预期值与实际值之差),Z值大于或等于1SD记为+1分,Z值在-1SD、-2SDs、-3SDs以下分别记为-1、-2、-3分,PHES值为5项心理智能测试积分之和。采用两独立样本t检验分别比较乙肝肝硬化组与正常对照组之间NCT-A (s)、NCT-B (s)、 DST (n)、SDT(s)、LTT(s+n)各项原始值之间的差异；采用非参数秩和检验中的两独立样本Mann-Whitney U检验比较两组间PHES差异是否有统计学意义；采用Spearman相关性分析研究乙肝肝硬化组PHES与Child-pugh评分之间的相关性。P<0.05认为差异有统计学意义。
结果：
1、年龄及受教育程度均作为影响因素被引入5个一般线性回归模型,并分别得出PHES的5项心理智能测试的预期值计算公式。
2、与正常对照组比较,乙肝肝硬化组5项神经心理测试NCT-A、 NCT-B、 SDT、 LTT所需时间均增加(P<0.01)、DST完成的个数减少(P<0.007)、PHES值下降(P<0.001)。
3、乙肝肝硬化组PHES值与Child-pugh评分呈负相关(rs=-0.367,P=0.033)
结论：
1、 PHES量表较全面评价无OHE的乙肝肝硬化患者的认知功能改变,但仍存在一定的影响因素。
2、无OHE的乙肝肝硬化患者NCT-A、NCT-B、 DST、 SDT、 LTT5项心理智能测试完成能力及PHES值均显著低于正常人,表明这些患者存在运动、视觉、精神集中度及注意力、记忆能力方面的不同程度的认知损害。
3、无OHE的乙肝肝硬化患者肝功能越差,其认知功能损害就趋于严重。
第二部分无明显肝性脑病的乙肝肝硬化患者静息态脑功能局部一致性研究
目的：
1、利用脑静息态血氧水平依赖功能磁共振成像技术及局部一致性(regional homogeneity, ReHo)算法探讨无OHE的乙肝肝硬化患者静息态下局部脑区神经元活动的改变情况。
2、探讨无OHE乙肝肝硬化患者ReHo的改变与其认知功能改变、肝功能损害程度之间的关系。
材料与方法：
64例被试被纳入本研究：乙肝肝硬化组(无OHE)32例,男27例,女5例,平均年龄为44.69±9.86岁(27～67岁),受教育程度10.34±3.62年(6-19年)。正常对照组包括34例与乙肝肝硬化患者性别严格匹配、年龄及教育程度相差≤3年的正常被试,男27例,女5例,平均年龄为44.22±9.67岁(28-63岁),受教育程度11.84±3.20年(6-16年)。对所有乙肝肝硬化患者行Child-pugh评分以评价其肝功能损害程度,行PHES测试评价其认知功能(同第一部分)。
采用飞利浦1.5T双梯度磁共振成像扫描仪行静息态下脑功能数据采集,16通道神经血管线圈进行信号接收。采用GRE-EPI技术行覆盖全脑的静息态脑功能扫描,参数如下：TR/TE=3000/50ms,翻转角=90。,层厚／层间距=4.5/0mm,矩阵=64×64,视野=230×230mm,采集160个时相。
图像预处理基于Matlab7.11分析软件平台的DPARSF软件对静息态脑功能磁共振数据进行预处理,具体处理步骤包括：1、剔除前10个时相的采集图像,以防止磁场达到稳态前的一过性信号改变；2、时间差异校正；3、头动校正,估计扫描期间的头动参数,三维平移超过1.5mm、三维旋转超过1.5。的被试从本研究中剔除；4、空间标准化,将头动校正后的数据标准化到MNI模板；5、去线性漂移；6、低频滤波,采用0.01-0.08Hz带宽对所得信号进行低频滤波,去除低频线性漂移及高频生理性噪声的干扰。ReHo计算采用REST软件,通过计算每个给定体素的肯德尔和谐系数(Kendall's coefficient concordance,KCC)值,可获得每个被试的KCC图,通过每一体素的KCC值除以全脑平均KCC值生成标准化的ReHo图。对所有产生的数据结果使用8mm半高带宽的平滑核对图像进行空间平滑。
采用SPM8及REST软件对两组被试的ReHo统计图进行两独立样本t检验(以年龄、教育程度、呼吸频率及心率为协变量),结果多重比较校正(AlphaSim校正,P<0.01且簇>74个体素)后的P<0.05认为差异有统计学意义。采用Spearman相关分析评价乙肝肝硬化患者组间显著差异脑区平均ReHo值与其PHES值、Child-pugh评分之间的关系,P<0.05认为相关性有统计学意义。
结果：
1、与正常组比较,乙肝肝硬化组双侧额下回／额中回ReHo值显著升高,左侧舌回、双侧楔前叶／楔叶、右侧枕中回、左侧颞中回、双侧中央前回及旁中央小叶ReHo值显著减低(P<0.05;AlphaSim校正：P<0.01且簇>74个体素)。
2、无OHE的乙肝肝硬化患者左侧舌回(rs=0.369,P=0.037)、双侧楔前叶／楔叶(rs=0.468,P=0.007)、右侧枕中回(rs=0.438,P=0.012)、左侧中央前回(rs=0.442,P=0.011)、右侧中央前回(rs=0.575,P=0.001)及双侧旁中央小叶(rs=0.475,P=0.006)平均ReHo值与其PHES呈正相关性。
3、无OHE的乙肝肝硬化患者Chlid-pugh评分与所有组间差异脑区ReHo值之间
相关性均无统计学意义(P>0.05)。
结论：
1、无OHE的乙肝肝硬化患者存在多个脑区ReHo的异常,主要表现在视觉处理相关皮层(左侧舌回及颞中回、右侧枕中回)、运动相关皮层(双侧中央前回及旁中央小叶)、默认网络区域(双侧楔前叶／楔叶)ReHo显著减低,而双侧额下回／额中回ReHo显著增高,提示这些脑区局部神经元自发活动同步性的异常。
2、无OHE的乙肝肝硬化患者视觉相关区域、运动相关区域、默认网络脑区平均ReHo值与其PHES值呈正相关性,这表明这些区域ReHo异常可能是其认知功能受损的神经病理基础,且提示ReHo值可以作为这些患者潜在认知损害的客观评价指标。
3、无OHE的乙肝肝硬化患者肝功能损害程度与其脑ReHo改变之间无显著相关性。
第三部分无明显肝性脑病的乙肝肝硬化患者基于体素的脑灰质形态研究目的：
1、利用高分辨磁共振检查技术及VBM分析方法探讨无OHE的乙肝肝硬化患者脑灰质体积的改变情况。
2、探讨无OHE的乙肝肝硬化患者的灰质体积的改变与其认知功能改变、肝功能损害之间的关系。材料与方法：
54例被试被纳入本研究：乙肝肝硬化组27例,男24例,女3例,平均年龄为45.15±9.53岁(27～67岁),受教育程度10.48±3.72年(6-19年)。正常对照组为与乙肝肝硬化患者性别严格匹配、年龄及教育程度相差≤3岁的正常被试27例,男24例,女3例,平均年龄为45.04±9.56岁(28～63岁),受教育程度12.19±2.99年(6-16年)。对所有乙肝肝硬化患者行Child-pugh评分以评价其肝功能损害程度,行PHES测试评价其认知功能(同第一部分)。
仪器设备同前,采用3D快速场回波序列(FFE)进行高分辨T1加权像采集,参数如下：TR/TE=25/4.1ms,翻转角=30°,层厚／层间距=I/0mm,矩阵=231×231,视野=230×230mm,平行于正中矢状面进行全脑采集。
图像预处理采用安装在SPM8软件下的VBM8工具箱,主要步骤包括：1、空间标准化：将扫描得到的结构图像标准化到DARTEL-MNI模板(已标准化到MNI空间的DARTEL模板)；2、图像分割：采用ICBM模板去除非脑组织。之后,基于最大后验概率(MAP)及部分容积估算(PVE)的分割技术将标准化后的脑组织进行分割为灰质、白质和脑脊液；3、调整：为保持每个个体校正全脑容积后的绝对灰质体积,对灰质图像进行非线性校正；4、平滑：将分割后的灰质图像采用8mm半高带宽的高斯平滑核进行空间平滑。
采用两独立样本t检验的统计方法和SPSS13.0软件包对两组被试全脑容积和全脑灰质容积总量进行比较,P<0.05认为差异有统计学意义。采用一般线性模型和随机场理论对两组被试脑灰质进行基于体素的比较(以年龄、受教育程度为协变量),应用逐个像素单边检验,P<0.001(未校正)且簇>200mm3认为有统计学意义。采用偏相关分析(以年龄及受教育程度为协变量),分别评价乙肝肝硬化患者全脑灰质总容积、组间显著性差异区的脑灰质体积与其PHES之间、Child-pugh评分之间的相关性,P<0.05认为差异有统计学意义。
结果：
1、乙肝肝硬化组与正常对照组间颅内容积无明显差异(P=0.504)。乙肝肝硬化组脑灰质容积总量显著大于正常对照组(P<0.001)。
2、较正常对照组相比,乙肝肝硬化组多个脑区灰质体积增加(P<0.001,未校正,簇>200mm3),主要表现在：双侧小脑半球；双侧梭状回(扩展至双侧丘脑／尾状核／楔前叶／楔叶／枕中回／岛叶／舌回)、双侧眶额叶皮层、双侧额中回、双侧额下回、右侧颞中回、右侧颞下回；双侧中央前回、双侧旁中央小叶、右侧顶下小叶、扣带中回、桥脑。
3、乙肝肝硬化患者PHES与全脑灰质总容积呈负相关(r=-0.631,P=0.001)。乙肝肝硬化患者PHES与大部分差异脑区灰质体积呈负相关,包括：双侧梭状回(r=-0.709,P<0.001)、左侧额中回(r：=-0.546,P=0.005)、双侧额下回(左：r=-0.446,P=0.026；右：r=-0.406,P=0.044)、右侧颞中回(r=-0.736,P<0.001)、右侧颞下回(r=-0.545,P=0.005)；双侧中央前回(左：r==-0.635,P=0.001；右：r=-0.655,P<0.001)、双侧旁中央小叶(r=-0.594,P=0.002)、扣带中回(r=-0.524,P=0.007)、桥脑(r=-0.569,P=0.003)。乙肝肝硬化患者Chlid-pugh分级与灰质总容积与所有差异脑区灰质体积相关性无统计学意义(P值均>0.05)。
结论：
1、无OHE的乙肝肝硬化患者存在脑灰质体积的广泛增加。
2、无OHE的乙肝肝硬化患者随脑灰质体积的增加,其认知功能损害越显著,表明灰质体积的增加可能是肝硬化患者认知功能异常的形态学基础,且提示这些脑区灰质容积的增加可作为其认知功能损害严重程度的形态学指标。
3、无OHE的乙肝肝硬化患者肝功能损害程度与灰质体积的增加之间无显著相关性。
第四部分无明显肝性脑病的乙肝肝硬化患者脑白质改变：DTI-TBSS研究
目的：
1、利用磁共振扩散张量成像技术(DTI)及基于纤维束示踪的空间统计(TBSS)的数据后处理方法评价无OHE的乙肝肝硬化存在的白质改变。
2、探讨无OHE的乙肝肝硬化患者脑白质改变与其认知功能、肝功能损害之间的关系。
材料与方法：
60例被试被纳入本研究：乙肝肝硬化组30例,男25例,女5例,平均年龄为46.43±9.49岁(32～67岁),受教育程度9.97±3.22年(6,--19年)。正常对照组30例(与乙肝肝硬化组性别严格匹配、年龄及教育程度相差≤3岁),男25例,女5例,平均年龄为45.83±8.67岁(32～63岁),受教育程度11.43±3.00年(6-16年)。对所有乙肝肝硬化患者行Child-pugh评分以评价肝功能损害程度,行PHES测试来评价其认知功能损害程度(同第一部分)。
仪器及设备同前,采用SE-EPI序列进行DTI数据采集,参数如下：扩散敏感方向为33个,扩散敏感系数为b=800和0s/mm2, TR/TE=19837/62ms,翻转角=90°,层厚／层间距=2/0mm,平行于前后联合线平面进行覆盖全脑采集。
DTI数据分析采用FSL工具包。首先对原始数据进行头动和涡流校正,接着利用BET套件产生各自的Mask,然后利用FDT套件中的dtifit中生成平均弥散率值(mean diffusivity, MD)、部分各向异性值(fractional anisotropy, FA)。随后按照TBSS流程进行分析：tbss_l_preproc,tbss_2_reg, tbss_3_postreg, tbss_4_prestats。两组间FA值,MD值的比较采用randomise工具进行的非参数统计阈值分析(TFCE)的统计方法。多重比较校正(FWE校正)后,P<0.05认为有统计学意义。
采用两独立样本t检验及SPSS13.0软件包分析两组间全脑平均FA值及MD值、差异脑区的FA值及MD值之间的差异。采用偏相关分析(以年龄及教育程度为协变量)分别评价乙肝肝硬化患者TBSS相关指标(包括全脑平均FA及MD值、组间差异区域平均FA及MD值)与其PHES、Child-pugh评分之间的相关关系。P<0.05认为差异有统计学意义。
结果：
1、两组间比较未见FA值显著减低或增加的脑区。与正常组比较,乙肝肝硬化组右侧额叶、顶叶及颞叶、双侧内囊、外囊、小脑上脚、小脑中脚、小脑蚓部、小脑半球及脑干的MD值显著升高(P<0.05,FWE校正)。
2、两组之间全脑平均FA值无显著差异(P=0.716)。与正常对照组比较,乙肝肝硬化组全脑平均MD值(P=0.044)及组间差异脑区平均MD值(P<0.001)均显著高于正常对照组。
3、乙肝肝硬化患者PHES与其全脑平均FA值(r=0.180,P=0.358)、全脑平均MD值(r=-0.310,P=0.108)及组间差异脑区平均MD值(r=-0.287,P=0.138)之间的相关性无统计学意义。Child-pugh评分与全脑平均FA值之间的相关性无统计学意义(r=-0.197, P=0.315);Child-pugh评分与全脑平均MD值(r=0.686,P<0.001)、组间差异脑区平均MD值之间呈正相关(r=0.620,P<0.001)。
结论：
1、无OHE的乙肝肝硬化患者存在广泛脑白质MD值的明显升高,但不伴有FA值的改变,提示这些区域存在广泛的细胞外间隙脑水肿,而不伴有白质微结构的破坏。
2、MD值升高区域的平均值与Child-pugh评分呈显著正相关,表明无OHE的肝硬化患者肝功能越差,其细胞外间隙脑水肿的程度就越严重。
Part one:A comparative study of cognitive function between patients with HBV-related cirrhosis without overt hepatic encephalopathy and healthy subjects.
Objective:
1. To obtain the5formulas used to calculate predicted values in psychometric hepatic encephalopathy score (PHES) by using PHES normative data from healthy subjects.
2. To explore differences in cognitive function between patients with HBV-related cirrhosis without overt hepatic encephalopathy (OHE) and healthy subjects by using PHES battery of tests.
3. To explore the relationship between impaired cognitive of patients with function HBV-related cirrhosis without OHE and abnormal liver function.
Materials and Methods:
One hundred and thirty-three healthy subjects and34patients with HBV-related cirrhosis without OHE and were investigated in this study. Standard group included133healthy subjects (81male,52female), mean age45.06±10.79years (range22～65), years of education10.51±3.70(range6～19). Cirrhotic group was comprised of34patients (29male,5female), mean age45.09±9.88years (range27～67), years of education10.18±3.51(range6-19); and a total of34matched healthy subjects (age:well matched; sex and education level:within3years) were selected from standard group as a control group (29male,5female), mean age44.62±9.70years (range28～63), years of education11.56±3.09(range6-16).
Biochemical tests were performed in all patients with HBV-related cirrhosis, and the liver function status of each patient was assessed using the Child-Pugh score. All167subjects underwent the PHES battery of tests. This paper-pencil test battery consisted of the number connection test A (NCT-A) and B (NCT-B), the digit symbol test (DST), the serial dotting test (SDT), and the line tracing test (LTT-time and errors). At the same time, the test results were recorded.
Analyses were conducted using software (SPSS, version13.0; Chicago, Ⅲ). Five psychometric test results are expressed as means±SD. In the first step, valid regression models were obtained with Pearson's correlations between the psychometric test results of and age (years), gender (male=l; female=2) and education level (years) in standard group. In the second step, the unstandardized beta coefficients of these analyses were used in the final formulas to correct for these factors. These formulas were then used to predict values (Z values) for cirrhotic patients, and the difference between the predicted and observed results for each test was divided by the corresponding SD for the reference population to obtain the deviation from'normal'as a multiple of the SD. Finally, differences for each test in multiples of the SD were summed as follows:a result≥1SD above the predicted was scored as+1, results-1SD,-2SDs and-3SDs below the predicted were scored as-1,-2and-3, respectively. Two independent sample t-tests were performed to assess the differences in raw results of five psychometric tests between two groups. Mann-Whitney U test was performed to assess the differences in the performance level on the PHES between two groups. A spearman correlation analysis was performed between their performance level on the PHES and Child-pugh score in cirrhotic patients. A two-side P value less than0.05was considered as statistically significant.
Results:
1. In the multivariate analysis using multiple linear regressions, both age and education were found to be independent variables related to all the tests. Five formulas used to calculate predicted values were obtained.
2. Compared with the control subjects, the completion time for NCT-A、NCT-B、 SDT、LTT was increased significantly (P<0.01) and completion numbers for DST (P=0.007) were decreased significantly in cirrhotic patients. Cirrhotic patients had significantly worse performance of PHES (P<0.001) than healthy subjects.
3. A significant negative correlation was observed between the performance of PHES and Child-pugh score in cirrhotic patients (rs=-0.367, P=0.033).
Conclusions:
1. PHES battery of tests can be used to assess comprehensively the alterations of cognitive function in patients with HBV-related cirrhosis without OHE, but it should noted that there still exist factors influencing the results in PHES battery of tests.
2. Patients with HBV-related cirrhosis without OHE had significantly worse performance of all the five psychometric test (NCT-A, NCT-B, DST, SDT, LTT) results and PHES than healthy subjects. Those findings reveal the existence of deficits in motor performance, visual perception visuoconstructive abilities, concentration and attention, and memory in those patients.
3. The poorer the liver function in patients with HBV-related cirrhosis without OHE is, the more serious impaired cognitive function tends to be.
Part two:Regional homogeneity abnormalities in patients with hepatitis B virus-related cirrhosis without OHE:a resting-state fMRI study
Objectives:1.To investigate regional activity abnormalities of patients with HBV-related cirrhosis without OHE by using resting-state fMRI and Regional homogeneity (ReHo) method in the resting state.
2. To investigate whether these ReHo abnormalities of neural activity in patients with HBV-related cirrhosis without OHE can be related to their impaired cognitive function and abnormal liver function.
Materials and Methods:
Sixty-four subjects were investigated in this study. Cirrhotic group was comprised of32patients with HBV-related cirrhosis without OHE (27male,5female), mean age44.69±9.86years (range27～67), years of education10.34±3.62(range6～19). Control group included32matched healthy subjects (age:well matched; sex and education level:within3years),27male and5female, mean age44.22±9.67years (range28～63), years of education11.84±3.20(range6-16). The liver function status of all patients was assessed using the Child-Pugh score. All subjects underwent the PHES battery of tests (the same as the first part).
MR imaging data were obtained with a1.5-T MR imager with a16channel neurovascular coil to receive the signal. A gradient-echo echo-planar (GRE-EPI) sequence was used to acquire functional images. Scan parameters:TR/TE=3,000/50ms, flip angle=90°, thickness/gap=4.5/0mm, matrix=64×64, field of view (FOV)=230×230mm, total volumes=160.
The imaging data were mainly preprocessed with a MATLAB toolbox called DPARSF (http://restfmri.net/forum/DPARSF) for "pipeline" data analysis of resting-state fMRI.1. The first ten time points were discarded to avoid transient signal changes before magnetization reached steady-state.2. Slice timing.3. Realignment:the raw data were corrected for the head motion. Subjects with head motion exceeding1.5mm in any dimension through the resting-state run will be discarded from further analysis.4. Normalization:all data were spatial normalized to the Montreal Neurological Institute (MNI) template.5. Removal of linear trends.6. Temporally filtered (band pass,0.01-0.08Hz):to remove the effects of very low-frequency drift and physiological high frequency respiratory and cardiac noise. REST software was used to calculate the ReHo value of each subject. This is accomplished on a voxel-by-voxel basis by calculating Kendall's coefficient of concordance (KCC) of time series of a given voxel with those of its nearest26neighbors. The KCC value was calculated to every voxel, and an individual KCC map was obtained for each subject. To reduce the influence of individual variations in the KCC value, normalization of ReHo maps was preformed through dividing the KCC among each voxel by averaged KCC of the whole brain. The resulting data were then spatially smoothed with an8-mm full-width at half-maximum (FWHM) Gaussian kernel.
By using SPM8and REST software, a second-level random-effect two-sample t-test was performed on the individual normalized ReHo maps in a voxel-by-voxel manner by taking years of age and education, cardiac rates and respiratory rates as confounding covariates. Significant differences were set at the threshold of a corrected cluster level of P less than0.05(AlphaSim corrected, a combined threshold of P<0.01, and a minimum cluster size of74voxels). Spearman correlation analysis of the mean ReHo values in significant different areas with performance level on the PHES and Child-pugh score in patients were performed, respectively. A two-side P value less than0.05was considered as statistically significant.
Results:
1. Compared with the control group, the cirrhotic patients group showed significant ReHo decreases in the bilateral precuneus/cuneus (PCu/Cu), precentral gyrus (PCG) and paracentral lobule (PCL), left lingual gyrus (LG) and middle temporal gyrus (MTG) and right middle occipital gyrus (MOG). A significant ReHo increase was found in the bilateral inferior/medial frontal gyrus (IFG/MFG)(P<0.05; AlphaSim corrected, a combined threshold of P<0.01, and a minimum cluster size of74voxels).
2. Correlation analysis of the mean ReHo values in significant different brain areas against performance level on the PHES in patients revealed significantly positive correlation in the left LG (rs=0.369; P=0.037), right MOG (rs=0.38; P=0.012) and bilateral PCu/Cu (rs=0.468; P=0.007), PCG (left:rs=0.442, P=0.011; right: rs=0.575, P=0.001), PCL (rs=0.475; P=0.006).
3. Correlation analysis of the mean ReHo values in all significant different brain areas against Child-pugh score in patients revealed no statistical significant correlation (P>0.05).
Conclusions:
1. Patients with HBV-related cirrhosis without OHE showed decreased ReHo most lay in motor cortex (left LG and MTG, and right MOG), visual cortex (bilateral PCG and PCL) and default mode network (bilateral PCu/Cu), while showed increased ReHo in the bilateral IFG/MFG. Those abnormalities reflect the destruction of local synchronization of spontaneous low-frequency BOLD in those regions.
2. The mean ReHo values in the identified regions, mainly including visual (left LG and right MOG), motor (bilateral PCG and PCL) association cortex and default mode network (bilateral PCu/Cu) were significantly positively correlated with the PHES in patients with HBV-related cirrhosis without OHE. These findings shed light on the pathophysiological mechanisms underlying cognitive alterations of cirrhotic patients and demonstrate the feasibility of using ReHo as a research and clinical tool to monitor the progression of cognitive impairment of cirrhotic patients without OHE.
3. There is no significant correlation between ReHo abnormalities in patients with HBV-related cirrhosis without OHE and their abnormal liver function.
Part three:Research on the gray matter volume of patients with hepatitis B virus-related cirrhosis without OHE:a voxel-based morphometry study
Objective:
1. To investigate the gray matter (GM) volume abnormalities in patients with HBV-related cirrhosis without OHE by using high resolution MRI and voxel-based morphometry (VBM) method.
2. To investigate whether these GM volume abnormalities in patients with HBV-related cirrhosis without OHE can be related to their impaired cognitive function and abnormal liver function.
Materials and Methods:
Fifty-four subjects were investigated in this study. Cirrhotic group was comprised of27patients with HBV-related cirrhosis without OHE (24male,3female), mean age45.15±9.53years (range27～67), years of education10.48±3.72(range6～19). Control group included27matched healthy subjects (age:well matched; sex and education level:within3years),24male and3female, mean age45.04±9.56years (range28～63), years of education12.19±2.99(range6～16). The liver function status of patients was assessed using the Child-Pugh score. All subjects underwent the PHES battery of tests (the same as the first part).
MRI data were obtained on a Philips Achieva1.5T Nova Dual MR scanner. A three-dimensional fast field echo (FFE) pulse sequence was used to produce contiguous sagittal images. Scan parameters:TR/TE=25/4.1ms, thickness/gap=1/0mm, matrix=232×231, field of view (FOV)=230×230mm, flip angle=30°.
Images analysis was performed using the VBM8tool, an extension tool of SPM. The main procedures include:1. Spatial normalization: High-dimensional spatial normalization was chosen and the T1images were normalized to an already existing Dartel-template in MNI space.2. Segment: International Consortium for Brain Mapping (ICBM) template was used to remove non-brain tissue from the images. Then, maximum a posterior (MAP) and partial volume estimation (PVE) approaches were used to segment the images into GM, white matter and cerebrospinal fluid.3. Modulation: non-linear was introduced to modulate the resulting GM images so that the voxels'values indicate the absolute amount of tissue corrected for individual brain sizes.4. The resulting images were smoothed with an8-mm full width at half maximum (FWHM) isotropic Gaussian kernel.
By using SPSS soft (version13.0), two independent sample t-tests were performed to assess the differences in the whole brain volume and total GM volume between two groups. A two-side P value less than0.05was considered as statistically significant. A voxel based comparison was used to identify the differences between two groups. Statistical maps were set at a cluster-level threshold of p<0.001, uncorrected with extended threshold of200contiguous voxels. Partial correlation analysis was performed with age and year of education as covariates to assess the relation of total GM volume and the GM volume in significant different brain areas with PHES and Child-pugh score in cirrhotic patients, respectively. A two-side P value less than0.05was considered as statistically significant.
Results:
1. There was no significant difference in the whole brain volume between two groups (P=0.504). Compared with the controls, the total GM volume was significantly increased (P<0.001) in cirrhotic patients.
2. Compared with the controls, GM volume increased significantly in bilateral cerebellar hemisphere, fusiform gyrus (extend to bilatera thalamus/caudate/precuneus/cuneus/middle occipital gyrus/middle temporal gyrus/inferior frontal gyrus/insula/lingual gyrus), bilateral orbitofrontal cortex, bilateral middle frontal gyrus, bilateral inferior frontal gyrus, right middle temporal gyrus, right inferior temporal gyrus, bilateral precentral gyrus, bilateral paracentral lobule, middle cingulate cortex and pons (P<0.001,uncorrected, clusters>200mm3) in cirrhotic patients.
3. Significant negative correlation was observed between the total GM volume and PHES in cirrhotic patients (r=-0.631, P=0.001). Partial correlation analysis of the GM volume in significant different brain areas against PHES in patients revealed significantly negative correlation in bilateral fusiform gyrus (r=-0.709, P<0.001), left middle frontal gyrus (r=-0.546, P=0.005), bilateral inferior frontal gyrus (left: r=-0.446, P=0.026; right:r=-0.406, P=0.044), right middle temporal gyrus (r=-0.736, P<0.001), right inferior temporal gyrus (r=-0.545, P=0.005), bilateral precentral gyrus (left:r=-0.635, P=0.001; right:r=-0.655, P<0.001), bilateral paracentral lobule (r=-0.594, P=0.002), middle cingulate cortex (r=-0.524, P=0.007) and pons (r=-0.569, P=0.003).
4. Correlation analysis of the total GM volume, GM volume in all significant different brain areas against Child-pugh score in patients revealed no statistical significant correlation (P>0.05).
Conclusion:
1. Patients with HBV-related cirrhosis without OHE have increased GM volume in many brain regions.
2. Most of increased GM volume in patients with HBV-related cirrhosis without OHE was negative correlated with the degree of impaired cognitive function. It suggests that the increased GM volume may be underlying basis of impaired cognitive function. It olso demonstrates that the incresed GM volume in those brain regions can be used as a morphology indictor to monitor the progression of cognitive impairment of cirrhotic patients without OHE.
3. There is no significant correlation between GM volume abnormalities in patients with HBV-related cirrhosis without OHE and their abnormal liver function.
Part four:White Matter changes in patients with HBV-related cirrhosis without OHE:A DTI and TBSS study
Objective:
1. To assess the white matter (WM) changes by using diffusion tensor imaging (DTI) and tract based spatial statistic (TBSS) in patients with HBV-related cirrhosis without OHE.
2. To explore the relationship between WM changes in patients with HBV-related cirrhosis without OHE and impaired cognitive function, and abnormal liver function.
Materials and Methods:
Sixty subjects were investigated in this study. Cirrhotic group was comprised of30patients with HBV-related cirrhosis without OHE (25male,5female), mean age46.43±9.49years (range32～67), years of education9.97±3.22(range6～19). Control group included30matched healthy subjects (age:well matched; sex and education level:within3years),25male and5female, mean age45.83±8.67years (range28～63), years of education11.43±3.00(range6-16). The liver function status of patients was assessed using the Child-Pugh score. All subjects underwent the PHES battery of tests (the same as the first part).
MRI data were obtained on a Philips Achieva1.5T Nova Dual MR scanner. A spin-echo echo-planar imaging (SE-EPI) sequence was used to acquire DTI data. Scan parameters:acquired in33noncollinear diffusion gradient directions, b values=800and0s/mm2, T R/TE=19837/62ms, thickness/gap=2/0mm, flip angle=90°.
DTI data was analysis by using FSL tools. First, diffusion-tensor images were corrected for head movements and eddy current distortion. Then, brain extraction tool (BET) was using to delete non-brain tissue from an image of the whole head and output a binary brain mask image. The diffusion tensor was estimated on a voxel-by-voxel basis by using dtifit (a part of the FDT). Maps of mean diffusivity (MD), fractional anisotropy (FA) were obtained. Running TBSS first involves running next steps:tbss_1_preproc, tbss_2_reg, tbss_3_postreg, tbss_4_prestats. Subsequently, using the threshold-free cluster enhancement (TFCE) option in randomise to perform statistics for FA and MD maps between two groups [Permutation-based correction for multiple comparisons (FWE) at P<0.05].
By using SPSS soft (version13.0), two independent sample t-tests were performed to assess the differences in the whole-brain mean FA and MD values, mean FA and MD values of the abnormal regions. Partial correlation analysis was performed with age and year of education as covariates to assess the relation of those indexes in TBSS with PHES and Child-pugh score in cirrhotic patients, respectively. A two-side P value less than0.05was considered as statistically significant.
Results:
1. Compared with controls, MD values of right frontal lobe, parietal lobe, temporal lobe, bilateral internal and external capsule, bilateral superior cerebellar peduncle, middle cerebellar peduncle, Cerebellar Vermis, cerebelar hemisphere and brain stem (P<0.05, FWE corrected). There was no difference in FA values between two groups.
2. There was no difference in whole-brain mean FA between two groups (P=0.716). Compared with the controls, the whole-brain mean MD values (P=0.044) and mean MD values in the abnormal regions (P<0.001) significantly increased in cirrhotic patients.
3. No significant correlation were observed between PHES and the whole-brain mean FA (r=0.180, P=0.358) or MD values (r=-0.310, P=0.108), between PHES and mean MD values (r=-0.287, P=0.138), and between Child-pugh score and the whole-brain mean FA values (r=-0.197, P=0.315) in cirrhotic patients. Significant positive correlation were observed between Child-pugh score and whole-brain mean MD values (r=0.686, P<0.001) and mean MD values in the abnormal regions (r=0.620, P<0.001).
Conclusion:
1. The increased MD values with no concomitant changes in FA in many WM regions in patients with HBV-related cirrhosis without OHE indicates the presence of extracellular brain edema, while without damage of WM microstructure.
2. Increased MD value in patients with HBV-related cirrhosis without OHE was positive correlated with the degree of impaired liver function. It suggests that the worse the liver function, the more serious the extracellular WM edema will be.
引文
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