發(fā)布時間：2018-05-09 13:57

  本文選題：早發(fā)性帕金森病 + 晚發(fā)性帕金森病　； 參考：《浙江大學》2017年博士論文

【摘要】：研究背景原發(fā)性帕金森病(idiopathic Parkinson's disease,簡稱帕金森病)是一種常見的中樞神經(jīng)系統(tǒng)退行性疾病,其主要表現(xiàn)為運動功能的損害,以靜止性震顫、肌強直、運動遲緩、姿勢步態(tài)異常為其四大運動主征,同時還可能伴有認知功能損害、抑郁等非運動癥狀。通常帕金森病患者的發(fā)病年齡為55-60歲,在40歲(部分文獻定義為50歲)以前就出現(xiàn)首個帕金森癥狀的被稱為早發(fā)性帕金森病(Early-onset Parkinson's disease,EOPD)。EOPD患者的臨床表現(xiàn)與晚發(fā)性帕金森病(Late-onset Parkinson's disease,LOPD)大體相似,但該類患者仍具有其特殊的臨床表現(xiàn)及疾病進展特征。例如,EOPD患者對多巴制劑療效反應較好,疾病進展較LOPD緩慢,但更多更早的出現(xiàn)運動困難、肌張力障礙、運動波動等運動并發(fā)癥。不僅如此,在非運動癥狀上也存在差異,例如EOPD患者認知障礙發(fā)生率小于LOPD患者,但抑郁癥狀發(fā)生率卻明顯高于LOPD患者。盡管對EOPD與LOPD這些臨床差異的研究結(jié)果比較明確,但造成這種差異的原因目前仍不清楚。近年來神經(jīng)影像學技術(shù)被越來越多的運用于EOPD與LOPD患者的研究。采用核素成像技術(shù)通過對兩類患者黑質(zhì)紋狀體區(qū)域突觸層面進行多巴胺能示蹤的研究結(jié)果較為矛盾,卻仍然為這兩類患者的疾病異質(zhì)性提供了腦內(nèi)線索。但核素成像技術(shù)具有放射性,且研究多局限于黑質(zhì)或紋狀體核團的成像,忽略了患者腦內(nèi)其他部位結(jié)構(gòu)功能改變對疾病的影響。磁共振成像技術(shù)彌補了這些缺陷,目前已有部分文獻應用該技術(shù)對EOPD與LOPD患者展開研究。研究發(fā)現(xiàn)伴有左旋多巴引起的異動癥的EOPD與LOPD患者大腦灰質(zhì)體積增加區(qū)域不同。而通過測量組織弛豫速率發(fā)現(xiàn)EOPD及LOPD患者在基底節(jié)核團及黑質(zhì)的腦鐵變化不同,近年的兩項fMRI研究發(fā)現(xiàn)該兩類患者腦功能還存在差異。這些研究提示了 EOPD與LOPD兩類患者腦內(nèi)結(jié)構(gòu)、功能、代謝可能存在差異,且這種差異可能并不僅存在于中腦及基底節(jié)核團,還可能廣泛的存在于皮層組織,而磁共振成像技術(shù)是檢測這些差異的有效手段。研究發(fā)現(xiàn)小腦不僅和震顫、多巴制劑引起的異動癥等運動癥狀及認知功能損害等非運動癥狀的產(chǎn)生有關(guān),可能還對基底節(jié)區(qū)的多巴胺能損傷起補償作用。因此小腦可能在帕金森病中同時起病理及代償?shù)碾p重作用,近年來已經(jīng)成為研究帕金森病的又一重要靶點。綜上,本研究將采用多模態(tài)磁共振技術(shù)對EOPD與LOPD患者的腦鐵代謝、腦結(jié)構(gòu)尤其是小腦結(jié)構(gòu),以及靜息狀態(tài)下的腦網(wǎng)絡功能連接展開研究,探索兩類患者腦內(nèi)代謝、結(jié)構(gòu)、功能的差異及其與臨床特征的相關(guān)性。方法實驗一:以發(fā)病年齡50歲為分界點,我們將納入的帕金森病患者分為EOPD(35人)與LOPD(33人)組,并同時納入分別與之相對應的對照組(年輕對照24人,年老對照22人),進行臨床評估及ESWAN序列掃描。將獲得的相位圖采用定量磁敏感圖技術(shù)進行重建并獲得磁化率圖。選取兩側(cè)蒼白球、殼核、尾狀核頭部、黑質(zhì)致密部(SNc)、黑質(zhì)網(wǎng)狀部(SNr)以及紅核為感興趣區(qū),采用手繪感興趣區(qū)方式進行磁化率測量,獲得每個感興趣的定量腦鐵含量信息。分析患者與對應正常對照之間的腦鐵含量差異及其與臨床信息的關(guān)系。實驗二:分別納入EOPD(28人)、LOPD(37人)及與之相對應的對照組各23人,進行臨床評估并采集3D結(jié)構(gòu)像。受試者圖像采用基于體素的形態(tài)學分析(VBM)技術(shù)進行全腦結(jié)構(gòu)分析,其中配準技術(shù)采用DARTEL算法,采用6mm全寬半高高斯核進行平滑。平滑后的圖像控制年齡、性別后在SPM8軟件上進行統(tǒng)計分析獲得患者與其相應對照的全腦結(jié)構(gòu)改變信息,并進行后期臨床相關(guān)分析。實驗三:納入EOPD(31人)、LOPD(39人)及與之相對應的對照組各23人,進行臨床評估并采集3D結(jié)構(gòu)像。圖像預處理在SPM8軟件上進行,所有受試者圖像沿前后聯(lián)合進行手工原點重定位,采用SUIT工具包將T1加權(quán)圖像進行分割,得到僅包括幕下組織的圖像,分割后的灰質(zhì)圖像空間標準化至SUIT模板,然后進行空間重采樣,最后采用6mm的全寬半高高斯核進行平滑。在進行平滑步驟前,對每個受試者小腦總體積進行計算。患者與其相對應的對照組預處理后的圖像以年齡、性別及小腦總體積為協(xié)變量進行兩樣本t檢驗,獲得小腦結(jié)構(gòu)改變信息,并進行臨床相關(guān)分析。實驗四:納入EOPD(29人)、LOPD(33人)及與之相對應的對照組(年輕對照22人,年老對照23人),進行臨床評估并進行靜息態(tài)功能磁共振掃描,使用DPARSF軟件包對采集的靜息態(tài)功能磁共振圖像進行標準化的圖像數(shù)據(jù)預處理,其中每個受試者的前10個時間點的腦圖像被舍棄,圖像平滑采用6mm的全寬半高高斯核進行平滑。使用Group ICA/IVA of fMRI Toolbox(GIFT)軟件工具平臺對平滑后的數(shù)據(jù)進行數(shù)據(jù)驅(qū)動的獨立成分分析,設置成分數(shù)為24,根據(jù)Smith等學者研究報道選取最為匹配的DMN與DAN網(wǎng)絡。以年齡、性別為協(xié)變量對比患者與其相對應的對照組間DAN與DMN網(wǎng)絡內(nèi)功能連接情況,并進行臨床相關(guān)分析。結(jié)果實驗一:與YC組對比,EOPD患者在SNc(P =0.004)以及SNr(P =0.009)磁化率增高,表明EOPD患者在該兩個核團腦鐵含量增高。而在LOPD組,不僅SNc(P =0.002)、SNr(P =0.032)兩個部位磁化率增高,殼核(P =0.020)的磁化率也出現(xiàn)增高。LOPD患者SNc的磁化率值與HY分級、UPDRS第二部分評分呈正相關(guān);而SNr的磁化率值與UPDRS第二部分評分呈正相關(guān);而殼核的磁化率值與UPDRS第二部分評分Ⅱ,UPDRS第三部分評分呈正相關(guān)。EOPD患者中未發(fā)現(xiàn)腦鐵含量增高與臨床信息的相關(guān)性。實驗二:與YC組相比,EOPD患者在左側(cè)殼核、額下回及島葉以及腦干的灰質(zhì)密度減低,在右側(cè)枕葉與兩側(cè)小腦后葉灰質(zhì)密度增加。而與OC組相比,LOPD患者在左側(cè)小腦后葉、左側(cè)枕葉、腦干及右側(cè)輔助運動區(qū)灰質(zhì)密度減低,而在左側(cè)顳中回灰質(zhì)密度增加。兩組患者具有組間差異的腦區(qū)灰質(zhì)密度未發(fā)現(xiàn)與臨床信息有統(tǒng)計學相關(guān),但是在EOPD患者組,增加的右側(cè)小腦灰質(zhì)密度與減低的腦干灰質(zhì)密度相關(guān)(P=0.029,r=-0.428)。實驗三:以PFDR0.05為統(tǒng)計學上有顯著性差異。LOPD與其對應的OC組之間未發(fā)現(xiàn)有顯著性差異的腦區(qū)。而EOPD組與其對應的YC相比,在兩側(cè)齒狀核灰質(zhì)體積減少,而在兩側(cè)半球的Ⅶb、Ⅶa、CrusⅡ灰質(zhì)體積增加。在EOPD患者組中,右側(cè)半球外側(cè)的Ⅶb與Ⅷa區(qū)域灰質(zhì)體積分別與患者病程(Ⅶb:P=0.045,r=0.381;Ⅷa:P=0.046,r=0.381)、UPDRS 評分(Ⅶb:P=0.024,r=0.425;Ⅷa:P=0.020,r=0.437)及 HAMD 評分(Ⅶb:P=0.018,r=0.442;Ⅷa:P=0.010,r=0.478)呈正相關(guān)。實驗四:與相應的正常對照相比,EOPD與LOPD患者DAN網(wǎng)絡都出現(xiàn)主要節(jié)點的功能連接減低,但EOPD患者DAN網(wǎng)絡功能連接降低區(qū)域位于左側(cè)頂葉(頂上小葉/楔前葉),而LOPD患者DAN網(wǎng)絡功能連接降低區(qū)域位于右側(cè)額葉視區(qū)及左側(cè)小腦后葉。同樣與相應的正常對照相比,EOPD患者DM[N的兩側(cè)楔前葉/后扣帶回皮層功能連接降低,LOPD患者DMN兩側(cè)背內(nèi)側(cè)前額葉皮層功能連接降低。兩組患者DAN、DMN功能連接降低區(qū)域在本研究中未發(fā)現(xiàn)與兩類患者臨床評分存在統(tǒng)計學相關(guān)關(guān)系。但是在EOPD患者中DAN減低區(qū)域的功能連接與DMN減低區(qū)域的功能連接呈正相關(guān)(P=0.030,r=0.434)。結(jié)論綜上所述,我們的研究顯示:(1)EOPD與LOPD患者具有發(fā)病年齡相關(guān)的不同腦鐵沉積模式。(2)EOPD患者與LOPD患者腦內(nèi)灰質(zhì)密度改變模式存在不同。尤其小腦部位,在兩類患者中所起的作用可能不同:在兩類患者中不僅起病理作用,在EOPD患者中可能起重要的代償作用,從而減緩了 EOPD患者疾病的進展,但同時也可能導致了其運動并發(fā)癥的發(fā)生率增高。(3)EOPD與LOPD患者都存在DMN、DAN網(wǎng)絡節(jié)點功能連接降低現(xiàn)象,但EOPD患者功能連接降低都位于網(wǎng)絡的關(guān)鍵節(jié)點,提示該類患者這兩個網(wǎng)絡功能損害可能更甚于LOPD患者。同時在EOPD患者中,DAN與DMN關(guān)鍵節(jié)點功能連接減低呈正相關(guān),我們推測可能反應了該類患者靜息狀態(tài)下大腦整體功能水平出現(xiàn)減低,但該推測目前仍需進一步研究證實。
[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.

【學位授予單位】：浙江大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R742.5;R445.2

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