1、 帕金森病伴认知障碍的多模态MR研究进展 Advance of multi modality MR in Parkinsons disease with cognitive impairment概念流行病学病因发病机制神经病理临床表现药物治疗多模态MR在认知障碍中的应用 目录Content 概念Conception帕金森病（Parkinsons disease，PD），又称震颤麻痹（Paralysis agitans），由英国医师James Parkinson（1817年）首先描述，是一种中老年人常见的中枢神经系统变性疾病，以中脑黑质多巴胺能神经元大量变性丢失和路易小体（Lewy body）形
2、成为病理特点，以静止性震颤、肌强直、运动迟缓和慌张步态及非运动症状为临床特征。认知障碍：指定向力、记忆力、计算力及智力下降，通过简易智能精神状态检查量表（MMSE）协助诊断。分类：帕金森病合并轻度认知损害（PD-MCI）和帕金森病痴呆（PDD）。流行病学Epidemiology国外文献报道，60岁以上的人发病率为约2%。1 随着年龄的增加帕金森病的发病率逐渐上升。据国外流行病学调查，PD患者中40会伴发认知功能障碍。2全球不同地区间帕金森病发病率无明显差异：欧洲全人群发病率为922/10万人年、北美洲全人群发病率为1113/10万人年、亚洲全人群发病率为1.5 17.0/10万人年。3病因Et
3、iologic factors年龄老化环境因素遗传易患性家族遗传性发病机制Pathogenesis帕金森病是一种中老年人常见的中枢神经系统变性疾病，发病机制尚未明确。目前较认可的有遗传因素、环境因素、蛋白质表达异常、氧化应激、铁代谢异常、泛素-蛋白酶体系统及自噬等相关。PD患者的认知功能损害在病理表现上主要与边缘系统包括（海马、内嗅皮质、扣带回、杏仁核、前核、丘脑、乳头体、隔区)神经变性密切相关。记忆损害与海马萎缩有关，注意力不能保持则与额回萎缩有关。NeuropathologyDauer W,et al.Neuron,2003,39(6):889-909.(A)It is composed
4、of dopaminergic neurons whose cell bodies are located in the substantia nigra pars compacta(SNpc;see arrows).These neurons project(thick solid red lines)to the basal ganglia and synapse in the striatum.(B)In Parkinsons disease,the nigrostriatal pathway degenerates.There is a marked loss of dopaminer
5、gic neurons that project to the putamen(dashed line)and a much more modest loss of those that project to the caudate(thin red solid line).(C)Immunohistochemical labeling ofintraneuronal inclusions,termed Lewy bodies,in a SNpc dopaminergic neuron.4 临床表现Clinical features运动症状：静止性震颤、肌强直、运动迟缓、慌张步态等。非运动症状
6、：认知障碍、抑郁、幻觉、睡眠紊乱等精神方面症状。药物治疗Drug Therapy左旋多巴替代治疗DR激动剂金刚烷胺单胺氧化酶B（MAO-B）抑制剂儿茶酚-氧位-甲基转移酶（COMT）抑制剂Drug TherapyLuigi Albert.Wikipedia,July,2014.Treatment in the initial state aims to attain an optimal trade off between good management of symptoms and side effects resulting from enhancement of dopaminergi
7、c function.The start of L-DOPA treatment may be delayed by using other medications such as MAO-B inhibitors and dopamine agonists,in the hope of causing the onset of dyskinesias to be retarded.多模态磁共振成像Multi Modality Magnetic Resonance Imaging 磁共振成像最主要的一个优点就是它具有多种成像模态，釆用多模态磁共振成像已经成为多个研究领域特别是神经、精神性疾病领
8、域的一个重要研究手段。多模态MR在认知障碍中的应用Application of multi modality MR in cognitive impairment磁敏感加权成像（susceptibility weighted imaging，SWI）质子磁共振波谱分析(Proton magnetic resonance spectroscopy，1H-MRS）弥散张量成像（diffusion tensor imaging，DTI）基于体素的形态学分析（voxel based morphometric，VBM）基于纤维的空间统计方法（tract based spatial statistics，
9、TBSS）血氧水平依赖磁共振脑功能成像(Blood oxygenation level dependent fMRI，BOLD-fMRI）磁敏感加权成像（SWI）SWI利用磁场中组织局部或内部间磁敏感差异而产生增强磁共振影像对比的一种T2脉冲序列技术，反映的是组织磁化属性。对于显示静脉血管、血液成分、钙化、铁沉积等非常敏感。可用于脑组织铁沉积的生化及定量分析。铁对于中枢神经系统的多种功能活动来说极其重要，在颅内主要位于锥体外系，特别是黑质致密部。SWI 上能够显示早期PD患者黑质铁沉积高于正常人5。Susceptibility Weighted ImagingSWI phase values
10、of substantia nigra of(A)control group(-0.901),(B)early PD group(0.110),and(C)intermediate/advanced PD group(0.130).There were significant differences in phase values of nigra between control individuals and patients with early PD(all p 0.05).all values were significantly(all p 0.05)different in pat
11、ients with intermediate and advanced PD.Wu S F,et al.European Review for Medical&Pharmacological Sciences,2014,18(18):2605-2608.ABC质子磁共振波谱分析(1H-MRS）MRS是利用磁共振显像和化学位移作用，检测活体组织能量代谢、生化改变及化合物定量分析的一种无创性影像技术。N-乙酰天冬氨酸(NAA）是哺乳动物神经系统中普遍存在的化合物之一，NAA在脑内几乎全部位于神经元内，其浓度降低反映了神经元或轴突的破坏和缺失以及功能的异常。Cho是细胞膜磷酯代谢的一个组成成分，C
12、ho含量增加提示有神经胶质细胞增生，肌酸(CR)为能量代谢产物，浓度相对稳定，作为 1H-MRS研究的内参物。通过 H-MRS测定颅内特定部位的NAACR、CHoCR值。运用于帕金森病伴认知障碍的研究中，发现NAACR比值在枕叶减少，CHoCR值在后扣带回增加。(a)VOI within the substantia nigra(A),basal ganglia(B),posterior cingulated(C)a n d o c c i p i t a l l o b e (D).(b)Typical spectra obtained from a healthy adult.Major
13、peaks indicate choline(Cho),creatine(Cr)and Nacetylaspartat(NAA).The ratios of NAA and Cho in relative to Cr were used to minimize the influence of structural tissue atrophy within the VOI on the MRS results.7 Proton Magnetic Resonance SpectroscopyNie K,et al.Parkinsonism&Related Disorders,2012,19(3
14、):329334.Changes of the ratio of Cho/Cr in the posterior cingulate.Note an increase in the Cho/Cr in the posterior cingulate when compared with the healthy control.The data were presented in mean and standard deviation(SD).Magnetic Resonance SpectroscopyNie K,et al.Parkinsonism&Related Disorders,201
15、2,19(3):329334.Changes of the ratio of NAA/Cr in the occipital lobe.A decrease of the NAA/Crratio was shown in PD-MCI patients.The data were presented in mean and standard deviation(SD).弥散张量成像（DTI）DTI 是在DWI 技术基础上发展起来的一种新的磁共振成像技术,DTI 研究近年来发展迅速，该技术能够无创地显示脑白质纤维走行，是目前脑部退行性疾病研究热点。DTI 的各向异性可由几个指标量化，包括FA(f
16、ractional anisotropy)、AI(anisotropy index)，其中FA 最为常用，反映神经纤维的完整性等。通过DTI发现帕金森病患者左侧前扣带束、胼胝体膝部结构FA值下降，提示该区域受损，可能在帕金森病认知功能损害的发生过程中发挥重要作用。Diffusion Tensor ImagingTable the maximum level of the body of the lateral ventricle in different cognitive function groups.Note:the green arrow genu;white arrow in the
17、 splenium of corpus callosum.Cognition of Parkinsons disease.Functional group;mild cognitive impairment in Parkinsons disease;Parkinsons disease dementia group.Deng bin-mei,Southern Medical University,2012.基于体素的形态学分析（VBM）原理：VBM方法引入到DTI 研究中，采用SPM 软件对各向异性指数（fractional anisotropy，FA）图和平均扩散率（mean diffus
18、ion，MD）图进行体素水平的统计分析，最后得到全脑的差异图，也有研究者将此称为基于体素的分析（voxel based analysis，VBA）。主要用于测量脑灰质密度，发现 PD-MCI患者右颞叶、楔叶、楔前叶，眶额叶皮质密度降低。Voxel Based MorphometricZhang J,et al.International Journal of Clinical&Experimental Medicine,2015,8(9):15383-15392.Gray matter comparison between patients with Parkinson disease wit
19、h and without mild cognitive impairment(PD-MCI versus PD-nMCI).In PD-MCI group,gray matter reductions were more widespread,including right temporal lobe,precuneus,cuneus,lingual gyrus,fusiform gyrus,orbitofrontal cortex.Structural gray matter differences in the two groups showed MCI and nMCI were th
20、e two stages during the progress of the PD.9 基于纤维的空间统计方法（TBSS）TBSS 方法首先需构建一组图像的平均FA 骨架图，骨架图代表被试者较大的白质纤维束中心，然后将所有被试的FA 值投射到平均FA 骨架图上，以确保骨架图上每一个体素的FA 值均来自于最邻近的白质纤维束中心。应用：测量脑白质纤维束，PD-MCI 病人出现双侧大脑半球和胼胝体的脑白质纤维素分布异常，推测PD 病人轻度认知功能低下脑白质联络纤维异常具有相关性。Tract Based Spatial StatisticsTract-based spatial statistics
21、 results in PD-MCI patients compared with healthy controls and PD-Cu patients.Voxelwise group differences are shown in red(decreased FA).Results are overlaid on the WM skeleton(light green)and displayed on the sagittal,coronal,and axial sections of the MNI standard brain in neurological convention(r
22、ight is right)at P 0.05 FWE-corrected.Abbreviations:FA,fractional anisotropy;FWE,familywise error;PD-Cu,cognitively unimpaired PD patients;PD-MCI,PD patients with mild cognitive impairment.10 Agosta F,et al.Human Brain Mapping,2014,35(5):1921-1929.PD 患者的脑功能通路（如中脑缘-纹状体、皮质-纹状体通路）较正常人活跃性减低，并且中脑缘-纹状体通路中
23、的功能缺陷可能与PD 伴非运动症状的潜在病理相关。BOLD-fMRI根据人脑功能区被信号激活时血红蛋白和脱氧血红蛋白两者之间比例发生改变,随之产生局部磁共振信号的改变而进行工作的，应用BOLD-fMRI进行激活研究，探测的BOLD信号可以作为脑功能区活性的直接标志。血氧水平依赖磁共振脑功能成像(BOLD-fMRI)Differences in the connectivity patterns of striatum in patients with Parkinsons disease.Functional connectivity of anterior putamen(PA)was si
24、gnificantly reduced in mesocortex and contralateral putamen.Functional connectivity of posterior putamen(PP)was significantly reduced in mesocortex,contralateral putamen,and sensorimotor cortex.The significance threshold was set at p 0.001 at voxel level and p 0.05 corrected by family-wise error cor
25、rection at cluster level.Abbreviations:L,left;R,right.11 Blood Oxygenation Level Dependent fMRILuo C,et al.Neurobiology of Aging,2014,35(2):431-441.总结ConclusionSWI 上能够显示早期PD患者黑质铁沉积高于正常人。(1H-MRS）运用于帕金森病伴认知障碍的研究中，发现NAACR比值在枕叶减少，CHo CR值在后扣带回增加。DTI发现帕金森病患者左侧前扣带束、胼胝体膝部结构FA值下降。VBM用于测量脑灰质密度，发现 PD-MCI患者右颞叶、楔叶、楔前叶，眶额叶皮质密度降 低。TBSS发现PD-MCI 患者出现双侧大脑半球和胼胝体的脑白质纤维素分布异常。BOLD-fMRI探测的脑缘-纹状体、皮质-纹状体通路BOLD信号降低，标志着该脑功能区活 性降低。
