基于纤维骨架空间统计方法对雷特综合征患儿脑白质结构与疾病严重度和发育水平的病例对照研究

Analysis of the correlations between white matter characteristics,clinical severity and developmental level in children with Rett syndrome based on tract⁃based spatial statistics:A case⁃control study

背景动物模型及细胞学水平研究提出雷特综合征(RTT)存在神经元发育不成熟及连接障碍,但在RTT患儿中大脑白质发育及连接情况不明。目的利用MR弥散张量成像(DTI)探讨RTT患儿白质参数指标异常情况及与疾病严重度和发育水平的相关性。设计病例对照研究。方法以复旦大学附属儿科医院(我院)符合典型RTT诊断,存在MECP2基因突变或缺失,行MR常规扫描、Griffith精神发育量表⁃中文版(GDS⁃C)测评和RTT严重程度评分(RSSS)的2~6岁患儿为RTT组,以与病例组同期在我院儿保科及神经内科因主诉头晕、头痛就诊并行头颅MR平扫未发现局灶性或者弥漫性颅内病变且行中国常模标准化量表丹佛发育筛查(DST)结果为正常的2~6岁女孩为对照组(TD组)。GDS⁃C、RSSS和DST测评均在我院儿童保健科完成,测评时间与MR检查相距≤1个月。统一使用我院MR设备,设定DTI序列行MR扫描并获得DTI的4项参数,利用基于纤维骨架的空间统计学(TBSS)进行统计学分析,获得两组间参数差异及定位脑区。主要结局指标RTT白质异常脑区与RSSS和GDS⁃C各能区的相关性。结果2014年6月至2021年6月RTT组22例、TD组23例进入分析,两组年龄差异无统计学意义。RTT组RSSS测评5.5±1.33,GDS⁃C总发育商(DQ)15.8±6.8,其中运动能区发育商(ADQ)为30.2±10.6、个人⁃社会能区发育商(BDQ)为14.6±9.1、听力⁃语言能区发育商(CDQ)为15±7.7、手眼协调能区发育商(DDQ)为9.9±6.2、表现能区发育商(EDQ)为9.2±3.9。TD组DST测评总DQ为94~118(103±7)。各向异性(FA)值RTT组低于TD组,平均弥散量(MD)值和径向弥散率(DR)值RTT组高于TD组,差异均有统计学意义;轴向弥散率(DA)值2组差异无统计学意义。DTI白质TBSS分析结果(FDR校正,P<0.05):RTT组较TD组FA值减低的纤维束主要位于胼胝体的辐射线额部及压部、双侧上纵束、左侧下纵束、内囊后肢及钩形束;RTT组较TD组MD值增加的纤维束主要位于胼胝体体部;RTT组较TD组DR值增加的纤维束主要位于胼胝体膝部、压部及右侧矢状层;RTT组较TD组DA值增加的纤维束主要位于胼胝体体部和压部。RTT的RSSS得分与胼胝体辐射线额部和左侧上纵束的FA值呈负相关,与胼胝体体部MD值、DR值和DA值呈正相关。内囊后肢FA值与GDS⁃C总DQ、A~E能区的DQ均呈正相关。右侧矢状层DR值与GDS⁃C总DQ、A~E能区的DQ均呈负相关。结论RTT儿童可能存在胼胝体发育不良、大脑广泛性连接障碍及皮层下⁃皮层环路的结构和连接异常。

Background Animal models and cytological studies suggested that Rett syndrome(RTT)had neuronal development and connection deficits,but it still remains unclear how the brain white matter develops and connects in patients.Objective To explore the abnormalities of multiple white matter parameters using diffusion tensor imaging(DTI)in RTT children and its correlation with disease severity and developmental level.Design Case⁃control study.Methods Children aged 2 to 6 years old,diagnosed with typical RTT and confirmed with MECP2 mutation or deletion,were recruited as the RTT group.Routine MRI scan,Griffith Developmental Scale⁃Chinese Version(GDS⁃C)and RTT Severity Score(RSSS)were taken as evaluations.Children aged 2 to 6 years with normal Developmental Screening Test(DST)scores,undergoing MR scan because of paroxysmal dizziness or headache but without recognizable lesions or abnormalities on scans,were recruited as typically developing(TD)controls.GDS⁃C,RSSS and DST were performed in the Health Care Department of Children Hospital of Fudan University.MR was scanned in the same GE 7503T scanner in the Radiology Department of our hospital.All of the GDS⁃C,RSSS,DST and MR scans were completed within one month.Four DTI parameters were collected and tract⁃based spatial statistics(TBSS)were applied to obtain DTI parameter differences and locations between two groups.Main outcome measures Abnormal white matter brain areas in RTT and the correlations with RSSS and developmental domains of GDS⁃C.Results From June 2014 to June 2021,we recruited 22 children as RTT group and 23 children as TD controls.The age difference was not statistically significant.The RSSS score in RTT was 5.5±1.33.The total DQ of GDS⁃C was 15.8±6.8 and as in domains ADQ was 30.2±10.6,BDQ was 14.6±9.1,CDQ was 15±7.7,DDQ was 9.9±6.2,EDQ was 9.2±3.9.DST score in TD group ranged from 94 to 118(103±7).The general FA value in RTT group was lower than that in TD group,MD and DR values in RTT group was higher than that in TD group,and no group difference was found as for DA.DTI⁃TBSS analysis results(FDR corrected,P<0.05)showed the fibers with lower FA values in RTT group were mainly located in the forceps minor,splenium of corpus callosum,bilateral superior longitudinal fasciculus,left inferior longitudinal fasciculus,retrolenticular part of internal capsule and uncinate fasciculus;the fibers with increased MD values in the RTT group were mainly located in the body of corpus callosum;the fibers with increased DR values in the RTT group were mainly located in the genu of corpus callosum;the fibers with increased DA values in the RTT group were mainly located in the body and splenium of corpus callosum.In RTT group,RSSS was negatively correlated with FA values in splenium of corpus callosum and left superior longitudinal fasciculus,and was positively correlated with MD value and DR value in the body of corpus callosum.FA value of retrolenticular part of internal capsule was positively correlated with the total DQ and DQs of each domain from the GDS⁃C.DR value of right sagittal stratum was negatively correlated with the total DQ and DQs of each domain from the GDS⁃C.Conclusion This study applied DTI combined with TBSS method in children with RTT and typical development.Results revealed that corpus callosum dysplasia,pervasive brain connectivity deficit and subcortical⁃cortical circuit structure and connection abnormalities could be found in RTT children.