【作者】 陈蕾；

【导师】 张本恕；

【作者基本信息】 天津医科大学 ， 神经病学， 2009， 博士

【摘要】 研究目的:探讨常见帕金森叠加征的临床特点和鉴别要点;探讨原发性帕金森病(idiopathic Parkinson’s disease,IPD)和帕金森叠加征在常规MRI、SMI成像技术和18F-FDG PET扫描中的影像学表现;并对帕金森叠加征中部分突触核蛋白病[多系统萎缩(multiple system atrophy, MSA)和路易小体痴呆(dementia with Lewy bodies, DLB)]患者进行SNCA基因的A30P和A53T突变筛查,探讨这两种突变是否与MSA和DLB的发病有关。研究方法:选取2004年1月～2009年4月间在天津医科大学总医院神经内科椎体外系门诊就诊的原发性帕金森病IPD患者73例、MSA患者68例、DLB患者10例、进行性核上性麻痹(progressive supranulcear palsy,PSP)患者15例和皮质基底节变性(corticobasal degeration,CBD)患者6例。对所有入组患者进行详细的病史问卷调查、体格检查、MMSE认知功能筛查和头CT/MRI检查,对部分研究对象采用了MR的磁敏感加权成像(susceptibility weightedimaging, SWI)技术和脑18F-FDG PET扫描。对2007年3月～2008年5月间入组的MSA和DLB这两种α-突触核蛋白病患者抽取静脉血,进行SNCA基因的A30P和A53T突变检测。数据应用SPSS11.0统计软件分析,计量资料比较采用单因素方差分析(ANOVA),计数资料的比较采用x~2检验。研究结果:1、临床资料:各组患者主要临床特点(包括发病年龄、单侧发病、体位性低血压、小便障碍、睡眠障碍、小脑体征、认知功能障碍、静止性震颤、姿势性震颤、强直、运动迟缓、姿势异常、肌张力障碍、异己肢、幻觉、眼动异常、人格改变、跌倒和LD治疗反应)除姿势异常,均呈现组间差异,且这些差异的显著性很高(P≤0.001)。其中发病年龄,以MSA组最小(57. 75±7. 652岁),DLB组和PSP组最大(69.40±5. 337岁和68. 33±7. 306岁)。单侧发病,PD组和CBD均为单侧发病,DLB组和PSP组均为双侧同时发病,而MSA组只有很少部分单侧发病(2.9%)。直立性低血压在MSA组发生率最高(50.0%),而DLB组和CBD组未见体位性低血压。小便障碍以MSA组发生率最高(67. 6%), PSP组和CBD组各为26. 7%和16. 7%, DLB组未见小便障碍。可疑REM睡眠障碍各组发生率均很高,其中以PSP组最高(93. 3%), PD组最低(41. 1%)。小脑体征MSA组发生率最高(61. 8%),而PD组、DLB组和CBD组未见。认知功能障碍见于所有DLB患者,PSP组和CDB组发生率也很高(66. 7%和83.3%), MSA组未见认知功能障碍。静止性震颤见于所有PD患者,部分DLB患者也可见静止性震颤(20.0%), PSP和CBD患者未见静止性震颤。而姿势性震颤见于全部DLB患者,MSA组发生率也很高(86. 8%),PSP组最低(6. 7%)。强直见于所有PD、DLB和PSP患者,MSA组和CBD组的发生率接近(69. 1%和66. 7%)。运动迟缓也见于所有PD、DLB和PSP患者,MSA组和CBD组的发生率也很接近(67. 6%和66. 7%)。肌张力障碍和异己肢仅见于CBD患者,且发生率很高(66.7%)。幻觉见于全部DLB患者,见于少数PSP患者(13. 3%),未见于PD、MSA和CBD患者。眼动异常见于多数PSP患者(66.7%),见于少数CBD患者(16.7%)。人格改变见于全部CBD患者,绝大多数DLB和PSP患者(90. 0%和93. 3%),见于极少数PD和MSA患者(13. 7%和14.7%)。跌倒以PSP组最多见(93.3%), PD组最少见(9.6%)。LD治疗反应以PD组最好(100. 0%) , DLB组次之(70. 0%) , PSP组最差(6.7%)。2、头MR检查:59例MSA患者接受头MRI检查,其中MRI显示橄榄桥脑小脑萎缩48例(81.4%), T2加权像上的壳核低信号4例(6. 8%),桥脑“十字面包征”30例(50.8%)。15例PSP患者中3例(20.0%)头MRI正中矢壮位显示中脑特征性“蜂鸟样”改变。全部6例CBD患者( 100.0%)头MRI检查显示不对称的皮质特别是额顶区萎缩,1例(16. 7%)显示T2加权像上壳核低信号。3、SWI序列成像:25例IPD患者的SWI序列校正相位图对细小灰质核团的显示黑质、苍白球、壳核、尾状核和丘脑均存在不同程度的铁沉积。4、脑18F-FDG PET扫描:17例患者接受了18F-FDG PET扫描的MSA患者中,MSA-P组显示皮质下神经核团如基底节示踪剂摄取减少;MSA-C组显示小脑皮质示踪剂摄取减少。DLB患者双侧枕叶及顶叶后部等脑区示踪剂摄取减少。PSP患者显示双侧额叶皮质、皮质下结构如纹状体、中脑示踪剂摄取减少。CBD患者显示额、顶叶皮质示踪剂摄取不对称性减少,以患肢对侧大脑皮层为著,皮质下核团如丘脑、壳核呈不对称性示踪剂代谢减少,也以患肢对侧为著。5、SNCA基因的A30P和A53T突变检测:未在MSA和DLB患者中发现SNCA基因的A30P和A53T突变。结论:1、各帕金森叠加征均有其特异性临床特点,这些临床特点有助于将它们与原发性帕金森病相鉴别,也有助于它们之间的彼此鉴别。2、头MRI检查、SWI序列成像技术和脑18F-FDG PET扫描可辅助IPD和帕金森叠加征的诊断和鉴别。3、未在DLB和MSA患者中发现SNCA基因A53T和A30P突变,人种因素、MSA和DLB与IPD不同的病因和病理改变,可能造成了这一阴性结果。。更多还原

【Abstract】 Objective:Several neurodegenerative disorders share with idiopathicParkinson’s disease (IPD)the features of bradykinesia,rigidity,hypokinetic speech,and unsteady gait.As these disorders bear clinical similarity to IPD,they have beentermed Parkinson-plus syndromes.These disorders have clinical and neuropathologicfeatures that are different from those of IPD.Furthermore,some Parkinson-plussyndromes are classified into alpha-synucleinopathy and tauopathy according to themain pathologic changes.The predominant pathologic change inalpha-synucleinopathies isα-synuclein(AS)abnormal aggregation in central nervoussystem.In the present study,detailed clinical investigations and neuroimagingexaminations were performed to explore the clinical features of Parkisnon PlusSyndromes.As the AS plays a key role in pathogenesis of alpha-synucleinopathies,the most common pathogenic mutations in AS gene-A30P and A53T mutations weredetected in the patients with MSA and DLB to determine whether genetic factorscould contribute to mechanism of sporadic alpha-synucleinopathes.Methods:73 IPD patients,68 MSA patients,10 DLB patients,15 PSP patientsand 6 CBD patients from neurology department of Tianjin general hospital wereincruited between January 1,2004 and April 30,2009.All patients were given detailedinvestigation,physical examination,mini-mental status examination and brainCT/MRI examination.Iron deposition in central nervous system was evaluatedamong 21 PD patients with SWI technique.41 patients were performed the 18F-FDGPET imaging.MSA and DLB patients who recruited from March 1 st,2007 to May31 st,2008 were extracted peripheral blood to detect the A30P and A53T mutations inSNCA gene with using polymerase chain reation-restriction fragment lengthpolymorphism(PCR-RFLP).Statistical analysis was performed with SPSS 11.0software.ANOVA was used to compare the measurement data.x~2 test was used tocompare the enumeration data.Results:l.Clinical features:The main clinical features including onset age,unilateral onset,orthostatic hypotension,bladder dysfunction,sleep dysfunction, cerebellar symptoms,cognitive impairment,rest tremor,postural tremor,rigidity,bradykinesia,postural instability,dystonia,alien limb phenomena,hallucination,eyemovement dysfunction,personality change,fall and levodopa response differedsignificantly among the groups(p(?)0.001).The onset age in MSA group waslowest(57.75±7.652 years),while was highest in DLB group(69.40±5.337 years).Allthe patients with PD and CBD were unilateral onset.All the patients with DLB andPSP were bilateral onset on the contrary.The patients with MSA rarely wereunilateral onset(2.9%).The incidence of orthostatic hypotension was highest in MSAgroup(50.0%).The patients with DLB and CBD had no orthostatic hypotension.The incidence of bladder dysfunction was highest in MSA group(67.6%),which was26.7% and 16.7% in PSP and CBD groups respectively.The patients with DLB hadno bladder dysfunction.The incidence of possible REM sleep disorder were high ineach group with the highest incidence in PSP group(93.3%)and the lowest incidencein PD group(41.1%).The incidence of cerebellar symptoms was highest in MSAgroup(61.8%)compared to PD,DLB and CBD groups in which there was no casewith cerebellar symptoms.All the DLB patients had cognitive impairment.Theincidence of cognitive impairment was high in PSP and CBD group either(66.7% and83.3% respectively).The patients with MSA had no cognitive impairment.All the PDpatients had rest tremor.20.0% DLB patients had rest tremor.The patients with PSPand CBD had no rest tremor.All the DLB patients had postural tremor which wascommon in MSA group(86.8%)and rare in PSP group.Rigidity was seen in all PD,DLB and PSP patients.The incidence of rigidity was close between MSA group andCBD group(69.1% and 66.7% respectively).Bradykinesia was seen in all PD,DLBand PSP patients.The incidence of bradykinesia was close between MSA group andCBD group either(67.6% and 66.7% respectively).Dystonia and alien limbphenomena were only seen in CBD patients which incidence was both 66.7%.Hallucination was seen in all DLB patients and rare PSP patients(13.3%),whilewasn’t seen in PD,MSA and CBD patients.Eye movement dysfunction was seen inmajority of PSP patients(66.7%)and minority of CBD patients(16.7%).All the CBDpatients had personality change,while majority of the DLB and PSP patients(90.0%and 93.3% respectively)and minority of the PD and MSA patients(13.7% and 14.7% respectively)had.Fall was most prominent in PSP group(93.3%)and rarest in PDgroup(9.6%).The response to levodopa was best in PD group(100.0%),good in DLBgroup(70.0%)and worst in PSP group(6.7%).2.Brain MRI examination:59 MSApatients were given brain MRI examination.Olivopontocerebellar atrophy was seenin 48 patients(81.4%),putaminal hypointensities on T2-weighted images were seen in4 patients(6.8%)and the“hot cross bun”signal in pons was seen in 30patients(50.8%).Hummingbird-like change was seen in midsagittal view of MRI inthree PSP patients (20.0%).All six CBD patients presented asymmetric corticalatrophy especially in frontoparietal areas,and one of them also presented putaminalhypointensities on T2-weighted image.3.Decreased signal intensities were detectedin substantia nigra and basal ganglia areas in IPD patients’ SWI.4.Brain 18F-FDGPET imaging:Among 17 MSA patients who were performed 18F-FDG PET imaging,MSA-P patients usually presented low 18F-FDG intake in the subcortical nuclei suchas basal ganglia,while MSA-C patients usually presented low 18F-FDG intake in thecerebellar cortex,low 18F-FDG intake in bilateral occipital lobes and posteriorparietal areas was seen in DLB patients.The PSP patients presented low 18F-FDGintake in bilateral frontal lobes,subcortical structures such as striatum and midbrain.CBD patients presented asymmetric low 18F-FDG intake in frontoparietal area andsubcortical nuclei such as thalamus and putamen,which was more prominent in thecontralateral side to the involved limb.4.Detection of A30P and A53T mutations inSNCA gene:A30P and A53T mutations weren’t detected in SNCA gene among thepatients with MSA and DLB.Conclusion:1.Each Parkinsonism plus syndrome has its specific clinical featureswhich attribute to rule it out from either IPD or other Parkinsonism plus syndromes.2.Brain cMRI examination,SWI technique and 18F-PET scan can help to diagnoseand differentiate Parkinsonism plus syndromes.3.A30P and A53T mutations weren’tdetected among Chinese DLB and MSA patients.Race and different etiology andpathogenesis among DLB,MSA and IPD contribute to this negative outcome.更多还原