【作者】 周福庆；

【导师】 龚洪翰； Chi-Shing Zee；

【作者基本信息】 南昌大学 ， 外科学， 2010， 博士

【摘要】 目的：(1)回顾性评估多发性硬化(Multiple Sclerosis, MS)T1高信号病灶定量弥散张量(Diffusion Tensor Imaging,DTI)值改变,研究其与脑组织损害参数(脑萎缩)之间的关系；(2)探讨多发性硬化早期表现正常胼胝体的定量DTI改变,并探讨表现正常胼胝体经Hofer’s新分区方案FA值的定量改变；(3)探讨MS患者表现正常的脑干区域、边缘系统、联络纤维、投射纤维定量DTI的改变；(4)评估多发性硬化患者表现正常的皮层灰质(CGM)和深部灰质(DGM)定量DTI值和标化T2-信号强度(nT2-SI)的改变。方法：2008年1月至2009年8月经University of Southern California(USC)医学中心临床确诊的MS患者总共100例,40例健康志愿者作为对照组。下列情况被排除：(a)MS图像质量较差者,(b)其他严重神经系统或系统性疾病,或(c)年龄超过60岁者(避免在MRI上区分年龄相关和高信号病灶或脑萎缩)。所有受试者扫描采用3.0 T Signa Echo-speed磁共振系统(General Electric, Milwaukee, USA)。所有受试者接受常规横断位自旋回波(spin echo)T2加权成像(TR 3000 ms, TE 30/122ms; matrix size 256×256; FOV 240 mm;层厚5mm)和T2 T2-FLAIR(TR 8800 ms, TE 30/158 ms; matrix size 256×256; FOV240mm),T1加权成像(TR=600 ms,TE=10ms,axial slices 5 mm)及T1增强扫描(0.1mmol/kg Gd-DTPA).横断位的弥散张量成像使用脉冲梯度、自旋回波、回波平面成像(TR/TE,2000/74; matrix,256×256; FOV,240×240 mm;层厚5 mm; b=1000 s/mm2),弥散加权使用15个非共线方向。依据不同的研究目的放置感兴趣区,比较两组上述不同区域定量DTI参数改变,包括平均弥散系数(Mean Diffusion, MD)和各向异性分数(Fractional anisotropy, FA)值的改变,并分析其与nT2-SI值和脑实质分数(brain parenchymal fraction, BPF)/T2病灶容积(lesion volumes, LV)等参数之间的相关性。MS患者和健康对照组的FA值和MD值之间的比较采用协方差分析法,MD、FA和FA之间的相关性分析使用Spearman秩相关检验。T1高信号病灶DTI参数和年龄、疾病进程、和脑萎缩参数(BPF和第三脑室宽度)的相关性使用Pearson相关性检验。所有统计使用SPSS13.0(SPSS Inc, Chicago, IL)分析。结果：(1)在16个患者中发现T1高信号病灶(至少1处),总共28个病灶。T1高信号病灶较T1其他信号病灶MD值低但高于正常白质(F=3.931,p=0.0009844),T1高信号病灶FA值(F=3.24,p=0.0001743)和容积比(Volume Ratio, VR)(F=1.664, P=0.000442)高于T1低/等信号病灶但低于表现正常白质(normal-appearing white matter, NAWM)和正常白质。在T1高信号病灶中FA值和MD值之间呈负相关(r=-0.437,P<0.02),MD值和VR值之间呈负相关(r=-0.423,P=0.025),T1高信号病灶在FA值和VR值之间存在相关性(r=0.678；P<0.001)。T1高信号病灶FA值(r=-0.111,P=0.018)、VR值(r=-0.142,P=0.003)分别和第三脑室宽度呈显著负相关,T1高信号MD值和第三脑室宽度具有显著的相关性(r=0.379,P<0.001)。T1高信号病灶的MD值和脑实质分数(BrainParenchymal Fraction, BPF) (r=-0.304, P<0.001)之间存在显著的负相关,T1高信号病灶VR值和BPF(r=0.096,P=0.042)之间存在显著的相关性,但T1高信号病灶FA值和BPF之间并无显著相关性。(2)早期MS患者的表现正常胼胝体(normal-appearing corpus callosum, NACC)与正常对照组比较FA值下降(P<0.001)、MD值增加(P<0.001),但早期MS患者额、枕区的NAWM和正常对照比较其FA值(P=0.216)/MD值(P=0.673)差异并无统计学意义。NACC的平均MD值和反映脑实质中央性萎缩的Evans指数间存在相关性(r=0.648,P=0.043)。(3)在健康志愿者中,Hofer’s新分区方案FA值组内比较差异具有统计学意义(P<0.001),FA(区Ⅴ)>FA(区Ⅰ)>FA(区Ⅳ)>FA(区Ⅱ)>FA(区Ⅲ),在RRMS患者中同样观察到这些区域的FA值具有不均一性：FA(区Ⅴ)>FA(区Ⅰ)>FA(区Ⅱ)>FA(区Ⅲ)>FA(区Ⅳ)；RRMS患者区Ⅱ(F=4.159,P=0.046)、区Ⅲ(F=9.257,P=0.004)、区Ⅳ(F=12.234,P=0.001)的FA值较健康对照组明显降低；胼胝体的区Ⅴ的FA值同样出现降低趋势,但无统计学意义(P=0.179)；胼胝体的区工的FA值未见明显改变(P=0.787)。在Hofer’s新分区方案中,胼胝体组内FA值和BPF之间(P值范围：0.086-0.969)、FA值和T2病灶容积之间(P值范围：0.127-0.658)均无相关性。(4)经ANCOVA协方差分析,RRMS组患者皮质脊髓束/皮质脑桥束(L：P=0.03；R：P=0.02)、小脑下脚(L：P=0.03；R：P=0.037)、小脑上脚(L：P=0.036；R：P=0.041)、内侧丘系(L：P=0.014；R：P=0.035)的FA值较对照组明显降低。RRMS组患者皮质脊髓束/皮质脑桥束(L：P=0.004；R：P=0.046)、小脑下脚(L：P=0.047；R：P=0.011)、小脑上脚(L：P=0.021；R：P=0.011)、内侧丘系(L：P=0.002；R：P=0.044)的MD值较对照组明显增高。小脑中脚的MD值及FA值两组间差异均无统计学意义(P>0.05)。RRMS患者表现正常脑干白质纤维束的MD值及FA值与BPF/T2病灶容积之间均无相关性。(5) RRMS组患者穹窿束(F=15.605,P=0.000135)、右侧穹窿/终纹束(F=15.772,P=0.000127)、左侧穹窿/终纹束(F=8.53,P=0.004)的FA值较健康对照组明显降低；RRMS组患者穹窿束(F=13.28,P=0.0004)、右侧终纹束(F=10.943,P=0.002)、右侧穹窿/终纹束(F=7.326,P=0.008)的MD值较健康对照组明显增高；RRMS组患者左/右侧的前、后扣带束、右侧终纹束、左侧终纹束的FA和对照组比较差异无统计学意义；RRMS组患者左/右侧的前、后扣带束、左侧终纹束、左侧穹窿／终纹束的MD值较健康对照比较差异均无统计学意义。(6) RRMS组患者联络纤维钩束(unc)(L：F=5.498,P=0.024；R：F=5.158,P=0.029)、下纵束(ilf)(L：F=8.267,P=0.007；R：F=5.108,P=0.03)、胼胝体/下枕—额束(cc/ifo)伴行部分(L：F=5.669,P=0.022；R：F=7.162,P=0.011)、下枕—额束/下纵束(ifo/ilf)伴行部分(L：F=4.521,P=0.04；R：F=5.437,P=0.025)的FA值较健康对照组低,差异有统计学意义；RRMS组患者ilf(L:F=5.012, P=0.031; R:F=5.48, P=0.025)、ifo/ilf伴行部分(L：F=8.318,P=0.006; R:F=12.882, P=0.00094)、cc/ifo伴行部分(L：F=5.426,P=0.025；R：F=5.8,P=0.021)的MD值较健康对照组高,差异有统计学意义；RRMS组患者双侧unc/ilf伴行部分、双侧unc/ifo伴行部分、双侧sfo、双侧上纵束的FA(P：0.065-0.599)值/MD(P：0.075-0.327)值和对照组比较差异均无统计学意义,双侧unc的MD值和对照组比较差异无统计学意义。(7)RRMS组患者投射纤维丘脑后辐射(ptr)(L：F=12.158,P=0.001；R：F=4.401,P=0.043)、皮质桥脑纤维束/丘脑前辐射(cpt/atr)(L:F=6.545,P=0.015；R：F=5.371,P=0.026)、皮质脑桥束/皮质后辐射(cpt/ptr)(L:F=12.141, P=0.001;R:F=4.682, P=0.037)、皮质脑桥束/皮质脊髓束/皮质上辐射(cpt/cst/str)(L：F=8.794,P=0.005：R：F=5.446,P=0.025)的FA值较健康对照组低,差异有统计学意义；RRMS组患者atr(L：F=1.198,P=0.281；R：F=0.641,P=0.428)的FA和对照组比较差异无统计学意义。RRMS组患者cpt/ptr (L:F=7.466, P=0.009;R:F=7.205, P=0.011)、cpt/cst/str(L：F=2.653,P=0.02;R：F=10.36,P=0.0035)的MD值较健康对照组增高,差异有统计学意义；RRMS组患者atr(L:F=1.020, P=0.319; R:F=0.211, P=0.649)、Ⅲptr(L:F=1.636, P=0.209; R:F=1.606, P=0.213). cpt/atr(L:F=1.872, P=0.179;R：F=0.026,P=0.874)的MD值较健康对照比较差异均无统计学意义。(8)MS患者的皮层灰质(CGM)区域较对照组存在较高的MD值和较低的FA值(P<0.05)。然而,在MS患者的深部灰质(DGM)较对照组的MD/FA值的差异并无统计学意义。在MS患者的DGM中,nT2-SI值较对照组显著降低(P<0.05),但在MS患者的CGM中,nT2-SI值较对照组并无显著性的减低。在MS患者CGM中,仅额叶MD值和BPF(R:P=0.009, L:P=0.036)或T2LV(R:P=0.002, L:P=0.047)之间存在(负)显著相关性。在MS患者除左侧丘脑和双侧红核外的所有DGM区域nT2-SI值和BPF之间存在显著的相关性(r=0.282-0.504,P<0.05)。在所有DGM区域的nT2-SI值和MS患者T2 LV之间并无显著相关性。结论：(1)MS患者T1高信号病灶的定量DTI值介于T1等／低信号病灶和NAWM之间；T1高信号病灶的定量FA值和BPF／第三脑室宽度之间具有相关性,但在FA和BPF之间并不具有相关性；轴突的髓鞘再生可能是病灶高信号的原因。(2)MS疾病早期损害优先出现在胼胝体,胼胝体的结构特点可能是其在MS早期较其他白质纤维束易受损害的原因；而在表现正常胼胝体内,部分区域(区Ⅱ、区Ⅲ、区Ⅳ)存在微观病理改变,这些改变可能和胼胝体原发性缺血、局部微病灶等因素有关。(3)在多发性硬化患者表现正常白质中,边缘系统、脑干白质、联络纤维、投射纤维中部分纤维束、部分区域定量DTI改变,表明上述纤维束存在微观病变,定量DTI可以作为反映MS表现正常白质纤维微观病理性改变的敏感工具。(4)在CGM, MS患者定量DTI值的变化和BPF/T2 LV之间的相关性提示在该区域存在由炎症、脱髓鞘或华氏变性的微结构破坏,但CGM的变化并不依赖于BPF和T2病灶的变化；在DGM,MS患者nT2-SI的降低及其与BPF(脑萎缩)之间的相关性,提示存在和慢性破坏有关的铁沉积。本研究表明在CGM和DGM中可能存在不同的病理损害机制。更多还原

【Abstract】 Purpose:(1)To evaluate retrospectively quantitative diffusion tensor imaging (DTI) values of hyperintense lesions on nonenhanced T1-weighted magnetic resonance (MR) images in patients with multiple sclerosis (MS) to elucidate the degree of demyelination or remyelination associated with Tl hyperintense lesions and study their relationship to MR markers of tissue damage (brain atrophy).(2) To investigate the quantitative DTI changes of normal-appearing corpus callosum (NACC) and other normal-appearing white matter (NAWM) in patient with early MS; and elucidating the pathogenesis of the NACC by Hofer’s new scheme in Relapsing-Remitting Multiple Sclerosis (RRMS).(3) The objective of our study was to detect the change of quantitative DTI values in normal-appearing white matter fiber tracts region of brainstem, limbic system, association fibers, projection fibers in the patients with RRMS.(4)The objective of our study was to evaluate the changes of quantitative diffusion tensor (DT) metrics and normalized T2-Signal Intensity (nT2-SI) values of normal-appearing cortical gray matter (CGM) and deep gray matter (DGM) in patients with Multiple Sclerosis (MS).Materials and Methods:Institutional review board approval was obtained; informed consent was waived for this HIPAA-compliant study, we retrospectively reviewed a database of clinical and MR imaging data in consecutive patients with clinically definite MS who were referred to University of Southern California(USC) medical center from Jan 1,2008, to Aug.30,2009, including 100 patients with MS and 40 healthy control subjects without evidence of MS clinically or on imaging.. We excluded patients with any of the following:(a) poor-quality MR images, (b) other major neurologic and/or systemic diseases, or (c) age older than 60 years (to avoid confounding with findings related to age-related hyperintense and age-related atrophy on MR images. All scans were performed on a 3.0 T Signa Echo-speed MRI system (General Electric, Milwaukee, USA). All patients had conventional axial spin echo T2 weighted images (TR 3000 ms, TE 30/122ms; matrix size 256×256; FOV 240 mm; slices thickness 5 mm) and T2-FLAIR(TR 8800 ms, TE 30/158 ms; matrix size 256X256; FOV 240 mm; slice thickness 5 mm). Axial T1-weighted MR images (TR=600 ms, TE=10ms, axial slices 5 mm) were also acquired pre-and 20 min post-administration of 0.3 mmol/kg Gd-DTPA. Axial DTI was then performed using pulsed gradient, spin-echo, echo-planar imaging (repetition time [TR]/echo time [TE],2000/74; matrix,256×256; field of view,240×240 mm; slices 5 mm; b=1000 s/mm2). Diffusion weighting was applied along 15 noncollinear axies. Fractional anisotropy (FA)/mean diffusivity (MD) of lesions, NAWM, NAGM were measured and differences between two groups were analyzed, and the relationship between DTI parameters and brain atrophy were investigated in this study. Analysis of variance (ANOVA) was performed for regression analysis when the dependent variable was continuous and the independent variables were nominal or continuous. The FA values of T1 hyperintense lesions was correlated with age, disease duration, and MR measures of brain atrophy (BPF and third ventricular width) by using the Pearson correlation test. All statistical analysis was performed using SPSS version 13.0 (SPSS Inc, Chicago, IL).Results:(1) At least one T1 hyperintense lesion was found in 16 patients (total, 28 lesions). hyperintense lesion on T1-weighted imaging (T1WI) had lower MD than others signal intensity lesion on T1WI but higher than normal white matter (F=3.931, P<0.001); FA (F=3.24,P<0.001) and volume ratio (VR) (F=1.664, P< 0.001) was higher in hyperintense lesion on T1WI than hypointense/isointense on T1WI but was lower than NAWM and normal white matter in controls. There was correlation between FA and VR (r=0.678; P<0.001) and inverse correlation between FA and MD (r=-0.437; P=0.02), MD and VR (r=-0.423; P=0.025) for T1 hyperintense lesion. The MD values of T1 hyperintense lesions(r=-0.304; P<0.001) and the VR values of T1 hyperintense lesions(r=0.096; P=0.042) were significantly (negative) correlated with Brain parenchymal fraction (BPF; higher BPF score); the FA values of T1 hyperintense lesions (r=-0.111; P=0.018), the MD values of T1 hyperintense lesions (r=0.379; P<0.001) and the VR values of T1 hyperintense lesions (r=-0.142; P=0.003) were significantly correlated with third ventricular width (lower width). However, the FA value of T1 hyperintense lesions was not significantly associated with BPF(r=0.083; P=0.08).(2) In comparison with controls, the patient with early MS had significantly lower FA (P<0.001) and higher MD (P<0.001) for normal-appearing corpus callosum(NACC) regions, but FA values(P=0.216) and MD values(P=0.673) in frontal and occipital regions did not show any significant difference between two group. The change of FA/MD in the entire NACC regions was correlated with the values of Evans (r=0.648, P=0.043) in patients.(3) This study indicates that 1) there was FA heterogeneity in the corpus callosum(CC) subdivisions of Hofer’s new scheme in healthy volunteers and RRMS patients:FA(regionsⅤ)> FA(regionsⅠ)> FA(regionsⅣ)> FA(regionsⅡ)> FA(regionsⅢ), FA(regionsⅤ)>FA(regionsⅠ)>FA(regionsⅡ)>FA(regionsⅢ)> FA(regionsⅣ), respectively; 2) FA in the RRMS group was significantly decreased in the regionsⅡ(F=4.159,P=0.046), regionsⅢ(F=9.257,P=0.004) and regionsⅣ(F=12.234,P=0.001) of Hofer’s new scheme; and 3) the FA of the regionsⅠwas relatively intact in the MS patients compared to the healthy age-matched controls (P=0.787), while the regionsⅤshowed an insignificant trend of reduced FA values (P=0.179). The decrease in FA in every of the NACC subdivisions did not correlate with BPF (P:0.086-0.969) or T2 lesion volume (P:0.127-0.658).(4) In comparison with controls, decreasing FA values in cpt/cst (L:P=0.03; R: P=0.02), icp (L:P=0.03; R:P=0.037), scp (L:P=0.036; R:P=0.041) and ml (L P=0.014; R:P=0.035), as well as increasing MD values in cpt/cst (L:P=0.004; R: P=0.046), icp (L:P=0.047; R:P=0.011), scp (L:P=0.021; R:P=0.011) and ml (L: P=0.002; R:P=0.044) were found in patients with RRMS. No significant difference of FA and MD values was found in mcp between patients with RRMS and controls (P>0.05). None of the MD or FA values in fiber tracts of the brainstem in patients with RRMS was correlated with brain parenchymal fraction (BPF) or T2 lesion volume.(5) In comparison with controls, the RRMS patients had diminished FA values in fornix bundle (F=15.605, P=0.000135), right fornix/stria terminalis bundle (F=15.772, P=0.000127) and left fornix/stria terminalis bundle(F=8.53, P=0.004); the RRMS patients had increased MD values in fornix bundle (F=13.28, P=0.0004), right fornix/stria terminalis bundle (F=7.326, P=0.008) and right stria terminalis bundle (F=10.943, P=0.002). FA and MD values in other regions of limbic system fiber bundle did not show any significant differences between two groups.(6) In comparison with controls, the RRMS patients had diminished FA values in unc(L:F=5.498, P=0.024; R:F=5.158, P=0.029)、ilf(L:F=8.267, P=0.007; R:F=5.108, P=0.03), cc/ifo(L:F=5.669, P=0.022; R:F=7.162, P=0.011)、ifo/ilf (L:F=4.521, P=0.04; R:F=5.437, P=0.025); the RRMS patients had diminished MD values in ilf(L:F=5.012, P=0.031; R:F=5.48, P=0.025)、ifo/ilf(L:F=8.318, P=0.006; R:F=12.882, P=0.00094)、cc/ifo(L:F=5.426, P=0.025; R:F=5.8, P=0.021). FA and MD values in other regions of association fiber bundle did not show any significant differences between two groups.(7) In comparison with controls, the RRMS patients had diminished FA values in ptr(L:F=12.158, P=0.001;R:F=4.401, P=0.043), cpt/atr(L:F=6.545, P=0.015;R:F=5.371, P=0.026), cpt/ptr(L:F=12.141, P=0.001;R:F=4.682, P=0.037), cpt/cst/str(L:F=8.794,P=0.005;R:F=5.446,P=0.025); the RRMS patients had diminished MD values in cpt/ptr(L:F=7.466, P=0.009;R:F=7.205, P=0.011), cpt/cst/str(L:F=2.653,P=0.02;R:F=10.36,P=0.0035). FA and MD values in other regions of Projection Fibers bundle did not show any significant differences between two groups.(8) MS patients showed larger MD/smaller FA values in CGM region compared with controls (P<0.05). However, MD/FA values were not statistical significance in the DGM between MS and healthy control group. In DGM of MS patients, a significant decrease of nT2-SI values were observed when compared to controls (P<0.05), but nT2-SI values in CGM of MS patients showed no significant decrease. In CGM, only MD values of frontal lobes in MS patients were significantly (negatively) correlated with BPF(R:P=0.009, L:P=0.036) or T2 LV (R: P=0.002, L:P=0.047). nT2-SI values in all DGM regions of MS patients were significantly correlated with BPF (r=0.282 to 0.504, P<0.05) except for the left thalamus, bilateral red nucleus. There was no correlation between nT2-SI in all DGM regions and T2 LV of MS patients.Conclusion:(1) The quantitative DTI values of T1 hyperintense MS plaques were between hypo-/isointense lesions and NAWM or normal white matter, and correlated with BPF and third ventricular width. Our results supports the notion that axonal remyelination may be the reason for T1 hyperintense lesions.(2) The quantitative DTI values (FA and MD) changes indicate that in early phase of MS there is a preferential occult injury of CC, which is likely due to the corpus callosum construction features; FA values in CC subdivisions of Hofer’s new scheme may represent a rewarding strategy for understanding the subtle clinical deficits of patients with RRMS.(3) The results suggest that there may be pathology change in part of normal-appearing white matter fiber tracts region of limbic system, brainstem, association fibers, projection fibers in RRMS patients. The change of quantitative DTI values detected can help to determine the neural fiber bundle of projection fibers micro pathology change in RRMS patients sensitively.(4) In CGM, the change of quantitative DT metrics of MS patients and the association with BPF and T2 LV, suggest the existence of microstructural destruction corresponding to inflammation, demyelination, or Wallerian degeneration, but the changes of CGM were independent of the concomitant changes of BPF and T2 lesion. In DGM, a decrease of nT2-SI in MS patients and the correlation of nT2-SI values with BPF (brain atrophy), suggest excessive iron deposition related to chronic destruction. Our investigation indicates the possibility of different mechanism of pathological change in CGM and DGM.更多还原