早发性及晚发性帕金森病的多模态磁共振研究

发布时间：2018-05-09 13:57

本文选题：早发性帕金森病 + 晚发性帕金森病　；参考：《浙江大学》2017年博士论文

【摘要】：研究背景原发性帕金森病(idiopathic Parkinson's disease,简称帕金森病)是一种常见的中枢神经系统退行性疾病,其主要表现为运动功能的损害,以静止性震颤、肌强直、运动迟缓、姿势步态异常为其四大运动主征,同时还可能伴有认知功能损害、抑郁等非运动症状。通常帕金森病患者的发病年龄为55-60岁,在40岁(部分文献定义为50岁)以前就出现首个帕金森症状的被称为早发性帕金森病(Early-onset Parkinson's disease,EOPD)。EOPD患者的临床表现与晚发性帕金森病(Late-onset Parkinson's disease,LOPD)大体相似,但该类患者仍具有其特殊的临床表现及疾病进展特征。例如,EOPD患者对多巴制剂疗效反应较好,疾病进展较LOPD缓慢,但更多更早的出现运动困难、肌张力障碍、运动波动等运动并发症。不仅如此,在非运动症状上也存在差异,例如EOPD患者认知障碍发生率小于LOPD患者,但抑郁症状发生率却明显高于LOPD患者。尽管对EOPD与LOPD这些临床差异的研究结果比较明确,但造成这种差异的原因目前仍不清楚。近年来神经影像学技术被越来越多的运用于EOPD与LOPD患者的研究。采用核素成像技术通过对两类患者黑质纹状体区域突触层面进行多巴胺能示踪的研究结果较为矛盾,却仍然为这两类患者的疾病异质性提供了脑内线索。但核素成像技术具有放射性,且研究多局限于黑质或纹状体核团的成像,忽略了患者脑内其他部位结构功能改变对疾病的影响。磁共振成像技术弥补了这些缺陷,目前已有部分文献应用该技术对EOPD与LOPD患者展开研究。研究发现伴有左旋多巴引起的异动症的EOPD与LOPD患者大脑灰质体积增加区域不同。而通过测量组织弛豫速率发现EOPD及LOPD患者在基底节核团及黑质的脑铁变化不同,近年的两项fMRI研究发现该两类患者脑功能还存在差异。这些研究提示了 EOPD与LOPD两类患者脑内结构、功能、代谢可能存在差异,且这种差异可能并不仅存在于中脑及基底节核团,还可能广泛的存在于皮层组织,而磁共振成像技术是检测这些差异的有效手段。研究发现小脑不仅和震颤、多巴制剂引起的异动症等运动症状及认知功能损害等非运动症状的产生有关,可能还对基底节区的多巴胺能损伤起补偿作用。因此小脑可能在帕金森病中同时起病理及代偿的双重作用,近年来已经成为研究帕金森病的又一重要靶点。综上,本研究将采用多模态磁共振技术对EOPD与LOPD患者的脑铁代谢、脑结构尤其是小脑结构,以及静息状态下的脑网络功能连接展开研究,探索两类患者脑内代谢、结构、功能的差异及其与临床特征的相关性。方法实验一:以发病年龄50岁为分界点,我们将纳入的帕金森病患者分为EOPD(35人)与LOPD(33人)组,并同时纳入分别与之相对应的对照组(年轻对照24人,年老对照22人),进行临床评估及ESWAN序列扫描。将获得的相位图采用定量磁敏感图技术进行重建并获得磁化率图。选取两侧苍白球、壳核、尾状核头部、黑质致密部(SNc)、黑质网状部(SNr)以及红核为感兴趣区,采用手绘感兴趣区方式进行磁化率测量,获得每个感兴趣的定量脑铁含量信息。分析患者与对应正常对照之间的脑铁含量差异及其与临床信息的关系。实验二:分别纳入EOPD(28人)、LOPD(37人)及与之相对应的对照组各23人,进行临床评估并采集3D结构像。受试者图像采用基于体素的形态学分析(VBM)技术进行全脑结构分析,其中配准技术采用DARTEL算法,采用6mm全宽半高高斯核进行平滑。平滑后的图像控制年龄、性别后在SPM8软件上进行统计分析获得患者与其相应对照的全脑结构改变信息,并进行后期临床相关分析。实验三:纳入EOPD(31人)、LOPD(39人)及与之相对应的对照组各23人,进行临床评估并采集3D结构像。图像预处理在SPM8软件上进行,所有受试者图像沿前后联合进行手工原点重定位,采用SUIT工具包将T1加权图像进行分割,得到仅包括幕下组织的图像,分割后的灰质图像空间标准化至SUIT模板,然后进行空间重采样,最后采用6mm的全宽半高高斯核进行平滑。在进行平滑步骤前,对每个受试者小脑总体积进行计算。患者与其相对应的对照组预处理后的图像以年龄、性别及小脑总体积为协变量进行两样本t检验,获得小脑结构改变信息,并进行临床相关分析。实验四:纳入EOPD(29人)、LOPD(33人)及与之相对应的对照组(年轻对照22人,年老对照23人),进行临床评估并进行静息态功能磁共振扫描,使用DPARSF软件包对采集的静息态功能磁共振图像进行标准化的图像数据预处理,其中每个受试者的前10个时间点的脑图像被舍弃,图像平滑采用6mm的全宽半高高斯核进行平滑。使用Group ICA/IVA of fMRI Toolbox(GIFT)软件工具平台对平滑后的数据进行数据驱动的独立成分分析,设置成分数为24,根据Smith等学者研究报道选取最为匹配的DMN与DAN网络。以年龄、性别为协变量对比患者与其相对应的对照组间DAN与DMN网络内功能连接情况,并进行临床相关分析。结果实验一:与YC组对比,EOPD患者在SNc(P =0.004)以及SNr(P =0.009)磁化率增高,表明EOPD患者在该两个核团脑铁含量增高。而在LOPD组,不仅SNc(P =0.002)、SNr(P =0.032)两个部位磁化率增高,壳核(P =0.020)的磁化率也出现增高。LOPD患者SNc的磁化率值与HY分级、UPDRS第二部分评分呈正相关;而SNr的磁化率值与UPDRS第二部分评分呈正相关;而壳核的磁化率值与UPDRS第二部分评分Ⅱ,UPDRS第三部分评分呈正相关。EOPD患者中未发现脑铁含量增高与临床信息的相关性。实验二:与YC组相比,EOPD患者在左侧壳核、额下回及岛叶以及脑干的灰质密度减低,在右侧枕叶与两侧小脑后叶灰质密度增加。而与OC组相比,LOPD患者在左侧小脑后叶、左侧枕叶、脑干及右侧辅助运动区灰质密度减低,而在左侧颞中回灰质密度增加。两组患者具有组间差异的脑区灰质密度未发现与临床信息有统计学相关,但是在EOPD患者组,增加的右侧小脑灰质密度与减低的脑干灰质密度相关(P=0.029,r=-0.428)。实验三:以PFDR0.05为统计学上有显著性差异。LOPD与其对应的OC组之间未发现有显著性差异的脑区。而EOPD组与其对应的YC相比,在两侧齿状核灰质体积减少,而在两侧半球的Ⅶb、Ⅶa、CrusⅡ灰质体积增加。在EOPD患者组中,右侧半球外侧的Ⅶb与Ⅷa区域灰质体积分别与患者病程(Ⅶb:P=0.045,r=0.381;Ⅷa:P=0.046,r=0.381)、UPDRS 评分(Ⅶb:P=0.024,r=0.425;Ⅷa:P=0.020,r=0.437)及 HAMD 评分(Ⅶb:P=0.018,r=0.442;Ⅷa:P=0.010,r=0.478)呈正相关。实验四:与相应的正常对照相比,EOPD与LOPD患者DAN网络都出现主要节点的功能连接减低,但EOPD患者DAN网络功能连接降低区域位于左侧顶叶(顶上小叶/楔前叶),而LOPD患者DAN网络功能连接降低区域位于右侧额叶视区及左侧小脑后叶。同样与相应的正常对照相比,EOPD患者DM[N的两侧楔前叶/后扣带回皮层功能连接降低,LOPD患者DMN两侧背内侧前额叶皮层功能连接降低。两组患者DAN、DMN功能连接降低区域在本研究中未发现与两类患者临床评分存在统计学相关关系。但是在EOPD患者中DAN减低区域的功能连接与DMN减低区域的功能连接呈正相关(P=0.030,r=0.434)。结论综上所述,我们的研究显示:(1)EOPD与LOPD患者具有发病年龄相关的不同脑铁沉积模式。(2)EOPD患者与LOPD患者脑内灰质密度改变模式存在不同。尤其小脑部位,在两类患者中所起的作用可能不同:在两类患者中不仅起病理作用,在EOPD患者中可能起重要的代偿作用,从而减缓了 EOPD患者疾病的进展,但同时也可能导致了其运动并发症的发生率增高。(3)EOPD与LOPD患者都存在DMN、DAN网络节点功能连接降低现象,但EOPD患者功能连接降低都位于网络的关键节点,提示该类患者这两个网络功能损害可能更甚于LOPD患者。同时在EOPD患者中,DAN与DMN关键节点功能连接减低呈正相关,我们推测可能反应了该类患者静息状态下大脑整体功能水平出现减低,但该推测目前仍需进一步研究证实。
[Abstract]:Background primary Parkinson's disease (idiopathic Parkinson's disease, referred to as Parkinson's disease) is a common degenerative disease of the central nervous system, which is mainly manifested in motor function damage, with static tremor, myotonic, slow motion, and postural gait abnormalities as its four major motor signs, and may also be accompanied by cognitive impairment. Non motor symptoms, such as injury, depression, and so on. Usually the onset age of patients with Parkinson's disease is 55-60 years old, and the first Parkinson symptom (Early-onset Parkinson's disease, EOPD).EOPD patients with the first Parkinson symptom before the age of 50 years old (Late-onset Parkinson's DI) Sease, LOPD) are generally similar, but these patients still have special clinical manifestations and characteristics of disease progression. For example, EOPD patients respond better to DOPA preparation, disease progression is slower than LOPD, but more early symptoms of motor complications such as dyskinesia, dystonia, movement fluctuations, and not only so, but also in non motor symptoms. Differences, for example, the incidence of cognitive impairment in EOPD patients is less than that of LOPD patients, but the incidence of depressive symptoms is significantly higher than that of LOPD patients. Although the results of these differences between EOPD and LOPD are more clear, the reasons for this difference are still unclear. In recent years, neuroimaging techniques have been used more and more in EOPD and LOPD The results of radionuclide imaging of two groups of patients with dopamine tracers at the synaptic layer in the substantia nigra region are relatively contradictory, but still provide intracerebral clues for the heterogeneity of the two types of patients. However, the radionuclide imaging technology is radioactive, and the research is limited to the formation of the substantia nigra or the striatum. Like, neglecting the effects of structural changes in other parts of the brain on the disease. Magnetic resonance imaging technology has made up for these defects. Currently, some literature has been used to study EOPD and LOPD patients. The study found that EOPD and LOPD patients with levodopa induced dyskinesia have different areas of gray matter volume in the brain. The changes in the basal ganglia and substantia nigra of the EOPD and LOPD patients were detected by measuring the tissue relaxation rate. In recent years, two fMRI studies found differences in the brain function of the two types of patients. These studies suggest that there may be differences in the structure, function, and metabolism of the brain in the EOPD and LOPD two patients, and this difference may not only exist. Magnetic resonance imaging is an effective means to detect these differences in the mesencephalon and basal ganglia nuclei, and magnetic resonance imaging is an effective means to detect these differences. It is found that the cerebellum is not only associated with the onset of motor symptoms, such as dyskinesia caused by dopa preparations, and impairment of cognitive function, but also the dopamine in the basal ganglia region. The cerebellum may play a compensatory role. Therefore, the cerebellum may play a double role of pathology and compensation in Parkinson's disease. In recent years, it has become another important target for the study of Parkinson's disease. To sum up, this study will use multimodal magnetic resonance (MRI) technique for the brain iron metabolism, the structure of the brain, especially the cerebellar structure, and resting state in the patients with EOPD and LOPD. Study on brain network functional connection to explore the difference in brain metabolism, structure, function and its correlation with clinical characteristics in two types of patients. Method Experiment 1: We divided the patients with Parkinson's disease into EOPD (35) and LOPD (33 people) with the age of onset at the age of 50, and included the corresponding control group (young). The clinical evaluation and ESWAN sequence scan were performed in 24 people, aged 22 people. The obtained phase maps were reconstructed with magnetic susceptibility mapping and obtained the magnetic susceptibility map. The two sides of the globus pallidus, the putamen, the caudate nucleus, the dense part of the substantia nigra (SNc), the substantia nigra reticularis (SNr) and the red nucleus were selected as the region of interest, and the hand-painted area of interest was used. Measurement of magnetic susceptibility, obtain each interesting quantitative brain iron content information. Analyze the difference of brain iron content between patients and corresponding normal controls and their relationship with clinical information. Experiment two: EOPD (28 people), LOPD (37 people) and the corresponding control group of 23 people, clinical evaluation and collection of 3D structure. The whole brain structure analysis was performed using the Morphin based morphological analysis (VBM) technique, in which the registration technique used the DARTEL algorithm and the 6mm full width half high Gauss kernel to smooth. The smooth image was used to control the age. After sex, the statistical analysis of the whole brain structure was obtained on the SPM8 software. Clinical correlation analysis. Experiment three: EOPD (31 people), LOPD (39 people) and the corresponding control group of 23 people, clinical evaluation and collection of 3D structure image. Image preprocessing on the SPM8 software, all the subjects image along the joint manual repositioning, using the SUIT toolkit to segment T1 weighted images, get only The image of the sub episodes, the gray matter image space after the segmentation is standardized to the SUIT template, then the space is resampling, and then the full width half of the Gauss kernel of the 6mm is used to smooth. The total volume of the cerebellum is calculated before the smoothing step. Two samples t test was carried out with the total volume of the cerebellum to obtain the information of the changes in the cerebellum structure and to carry out clinical correlation analysis. Experiment four: included in the EOPD (29 people), LOPD (33 people) and the corresponding control group (22 young control, aged 23 people), performed bed assessment and performed resting state functional magnetic resonance scanning, using DPARSF software The packet has standardized image data preprocessing for the collected resting functional magnetic resonance image, in which the brain images of the first 10 time points of each subject are abandoned and the image smoothing is smooth using the full width half of the Gauss kernel of 6mm. The smooth data is processed using the Group ICA/IVA of fMRI Toolbox (GIFT) software tool platform. The independent component analysis, set up as 24, selected the most matched DMN and DAN network according to the Smith and other scholars, compared the functional connection between the DAN and DMN networks between the patients and the corresponding control groups with age, sex and the corresponding control group, and carried out clinical correlation analysis. Results Experiment 1: compared with the YC group, EOPD patients were in SN. The increased magnetic susceptibility of C (P =0.004) and SNr (P =0.009) showed that the content of iron in the two nuclei increased in EOPD patients. In LOPD group, not only SNc (P =0.002), but also the magnetic susceptibility of the two parts of the SNr was increased, and the magnetic susceptibility of the putamen was also higher than that of the second part. The magnetic susceptibility of R was positively correlated with the score of UPDRS second, while the magnetic susceptibility of the putamen was associated with the UPDRS second part score II, and the score of the UPDRS third was positively correlated with the correlation between the increased iron content in the.EOPD patients and the clinical information. Experiment two: compared with the YC group, the EOPD patients were in the left putamen, the lower frontal gyrus and insula, and the brain stem. Gray matter density increased in the right occipital and posterior cerebellar leaves. Compared with the OC group, the gray matter density in the left posterior cerebellar, left occipital lobe, brain stem and right auxiliary motor area decreased in the left left cerebellar, while the gray matter density in the left temporal lobe was increased in the left temporal region. The gray matter density in the two groups was not found in the two groups. There was a statistically significant correlation, but in the EOPD group, the increased right cerebellar gray matter density was associated with the reduced density of the brainstem gray matter (P=0.029, r=-0.428). Experiment three: there was no significant difference between the.LOPD and the corresponding OC group with the significant difference between the PFDR0.05 and the corresponding OC group, while the EOPD group was on both sides compared with the corresponding YC. The volume of gray matter in the dentate nucleus was reduced, while the Volume VII B, VII a, and Crus II gray matter increased in both hemispheres. In the EOPD patients group, the volume of gray matter in the lateral side of the right hemisphere was respectively with the patient's course of disease (VII b:P=0.045, r=0.381; VIII a:P=0.046, r=0.381), and UPDRS score (VII b:P=0.024, VIII. .018, r=0.442, VIII, r=0.478) were positively correlated. Experiment four: compared with the corresponding normal controls, the DAN network of the EOPD and LOPD patients had the functional connection of the main nodes, but the DAN network functional connection in EOPD patients was located in the left parietal lobe (upper lobule / anterior wedge), while LOPD patients were located in the DAN network function connection area. In the right frontal lobes and the left posterior cerebellar lobe, the functional connection between the two sides of the EOPD patient's DM[N and the posterior cingulate cortex of the posterior cingulate cortex of the EOPD patients was lower than that of the corresponding normal control. The function connection of the medial prefrontal cortex in the DMN side of the two sides of the LOPD patients was reduced. The two groups of patients were not found in this study with the two types of patients in this study. There was a statistically significant correlation in the score, but the functional connection of the DAN reduction region in the EOPD patients was positively correlated with the functional connectivity of the DMN reduction region (P=0.030, r=0.434). Conclusion in conclusion, our study showed that (1) EOPD and LOPD patients have different age related age related cerebral iron deposition patterns. (2) EOPD patients and LOPD patients in the brain ash The pattern of mass density change is different, especially in the cerebellum, which may play a different role in the two types of patients: not only in the two type of patients, but also in the EOPD patients, which may play an important compensatory role, thus slowing the progression of the disease in EOPD patients, but also may lead to the increase in the incidence of sports complications. (3) EOPD In patients with LOPD, there are DMN, DAN network node dysfunction, but the function connection reduction of EOPD patients is located at the key node of the network, suggesting that these two network functions may be more impaired than those of LOPD patients. In EOPD patients, DAN and DMN key nodes have a positive correlation with the reduction of energy connections. We speculate possible responses. The overall functional level of the brain in these patients decreased at rest, but this prediction still needs further study.

【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R742.5;R445.2

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