PARK16基因多态性与PD相关性研究及初诊PD非运动症状情况
|
摘要
目的:探讨PARK16基因多态性(SNP)与帕金森病(PD)易患性的关系,分析其SNP的基因型和等位基因频率及不同基因型的优势比(Odds Ratios)和其临床特征。
方法:采用病例-对照研究选择PD患者407例和516名健康对照,利用TaqMan荧光定量PCR方法检测中国汉族人群中PARK16基因Rs947211和Rs823128基因多态性,并对不同基因型临床资料进行分析。
结果:
1 PARK16基因的多态性位点Rs947211在PD组基因型频率为:GG 35.4%(144/407)、AG 45.7%(186/407)、AA 18.9%(77/226),对照组分别为26.4%(136/516)、53.3%(275/516)、20.3%(105/516),2组基因型频率差异具有统计学意义(基因型X~2=8.97,P=0.011;等位基因X~2=5.03,P=0.027)。采用Logistic回归校正性别、年龄后,以野生型GG为参照,其PD组AG OR值=0.63,95% CI:0.47-0.85,P=0.002;AA OR=0.68,95% CI:0.47-0.99,P=0.046。暴露于A等位基因型(AA+AG)的OR=0.64(95% CI: 0.48-0.85,P=0.002)。将PD组进一步按照家族史分层分析发现,散发性PD PARK16 rs947211基因型与对照组有统计学差异(OR(MH)=0.66, 95%CI: 0.50-0.86,X~2=8.85,P=0.003)。
2 Rs823128在PD组基因型频率分布为AA 71.6% (280/391),AG 25.1%(98/391),GG 3.3% (13/391),等位基因频率:A 84.1%,G 15.9%,对照组为:AA 75.2% (312/415),AG 22.2% (92/415),GG 2.7% (11/415),等位基因频率:A 86.3%,G 13.7%,两组基因型和等位基因频率均无统计学意义(基因型X~2=1.37,P=0.503;等位基因X~2=1.44,P=0.233)。
3 PD组PARK16 rs947211和rs8231283三种基因型在性别、年龄、发病年龄、病程、有无家族史、主要特征、帕金森病统一评分量表Ⅲ(UPDRSⅢ)、哈密顿抑郁量表(HAMD)、哈密顿焦虑量表(HAMA)、抑郁自评量表(SDS)、焦虑自评量表(SAS)、帕金森病睡眠量表(PDSS)、帕金森病非运动症状量表(PDNMS)、蒙特利尔认知量表(MOCA)、简易精神状态检查量表(MMSE)临床方面均无统计学意义(P>0.05)。
结论:中国汉族人群中PARK16基因与PD易患性相关。
目的:探讨初诊帕金森病(PD)患者非运动症状量表(NMSQuest)细项和NMS症状群(NMSQ-D)的发生和分布情况及与PD的临床基本资料和各个量表的关系。
方法:收集首次就诊的PD患者61例,在未服用抗PD药物的前提下进行PD基本信息登记和相关量表评估,并与89名正常对照组的NMS相比较。
结果: PD组96.72%的患者存在NMS,PD组NMS平均发生数(9.1±5.2)、PD轻度组(7.2±3.7)和PD中度组(12.2±4.6)与正常对照组(2.9±2.5)相比有显著差异(P<0.01)。PD组中以近记忆力下降(62.3%,38例)、注意力下降(57.4%,35例)、便秘(49.2%,30例)为最常见,与健康对照组均有显著差异(P<0.01)。PD轻度组以近记忆力下降(64.3%,27例)、注意力下降(52.4%,22例)、便秘(42.9%,18例)和入睡难或易醒(42.9%,18例)为最常见,除入睡难或易醒,其余均与对照组有显著差异(P<0.01)。PD中度组以注意力下降(64.7%,11例)、近记忆力下降(58.8%,10例)、便秘(58.8%,10例)和夜梦增多(58.8%,10例)为最常见,除近记忆力下降外,其余均与健康对照组均有显著差异(P<0.01)。NMS症状群(NMSQ-D)经Kruskal-Wallis检验发现与之关系最密切的是H-Y分期,其次是病程、UPDRS-Ⅲ,与年龄、发病年龄无差异。NMSQuest与H-Y分期(r=0.339,P<0.01)、SDS(r=0.724,P<0.01)、SAS(r=0.700,P<0.01)成正相关;与PDSS (r=-0.578,P<0.01)负相关;与年龄、发病年龄、性别、病程、UPDRS-Ⅲ评分、MOCA无关。
结论: PD初诊患者非运动症状复杂多样,发生率明显高于正常人,故需重视初诊患者的非运动症状,在早期就加以干预和治疗。
Objective: To investigate the association between PARK16 gene polymorphism and Parkinson’s disease (PD) susceptibility in Chinese Han population, and to analyze its SNP genotypes, frequencies and odds ratios(OR) of different genotypes.
Methods: The association between two SNP loci in PARK16 gene (Rs947211, Rs823128) and PD susceptibility was investigated by TaqMan quantitative polymerase chain reaction (PCR) in 407 PD patients and 516 healthy controls. Clinical data was also analyzed. Results:
1 In PD group, three genotypes of Rs947211 (GG, AG and AA) accounted for 35.4%, 45.7%, 18.9%, Control group 26.4%, 53.3%, 20.3% respectively, two groups were significant differences (P<0.05). GG genotype as the reference, after adjusting age and gender, OR value of AG of PD group was 0.63 (95% CI: 0.47-0.85, P=0.002) and OR of AA genotype was 0.68 (95% CI: 0.47-0.99, P=0.046). Exposure to the A allele (AA+AG), and its OR was 0.64 (95% CI: 0.48-0.85, P=0.002). Subsequently, it could be concluded that there was a lower risk factor in sporadic PD than familiar PD (OR (MH) =0.66, 95% CI: 0.50-0.86, X~2=8.85, P=0.003).
2 The frequencies of genotypes and Allele of Rs823128 in PD group were no significantly different with control group(X~2=1.37, P=0.503; X~2=1.44, P=0.233).
3 Clinical features of the Rs947211 and Rs823128 in three genotypes were further analyzed, and there were no differences between the clinical characteristics in the patients in the three genotypes for genders, ages, age-at-onset, disease durations, family histories, cardinal features (resting tremor, rigidity and mixed symptoms), scores of Hoehn-Yahr stage, UPDRSⅢscores (on-stage), HAMD scores, HAMA scores, SDS scores, SAS scores, PDSS scores, PDNMS scores, MOCA scores and MMSE scores.
Conclusion: PARK16 is associated with PD patients in Chinese Han population.
Objective: To investigate the incidence, distribution of non-motor symptoms (NMS) and NMSQuest-Details (NMSQ-D) in patients with newly diagnosed PD, and its relationship with clinical features and various scales.
Methods: 61 PD patients without taking any drugs and 89 normal controls were collected in outpatient visits, and their clinic information and related scales were also evaluated.
Results: 96.7% PD total patients presented with NMS, decreased recent memory (62.3%, n=38), decreased attention (57.4%, n =35), and constipation (49.2%, n=30) were the most common in PD group, there were significantly different between PD group and Normal group (P <0.01), so did the moderate and mild groups of PD. NMSQuest average score of the PD group (9.1±5.2), PD moderate disease group of NMS (12.2±4.6) and mild group (7.2±3.7) were significantly higher than the control group (2.9±2.5) (P <0.01). We also found that NMSQust Details (NMSQ-D) were most closely with the HY stage by Kruskal Wallis test, the followed were the course of disease and UPDRS-Ⅲ, no difference was found between age and age of onset. NMSQuest and HY stage (r = 0.339, P <0.01), SDS (r = 0.724, P <0.01), SAS (r = 0.700, P <0.01) were Positive correlation; And PDSS (r =- 0.578, P <0.01) was negative correlation; age, age at onset, gender, duration, UPDRS-Ⅲscore and MOCA had nothing to do with NMSQuest.
Conclusion: Non-motor symptoms in patients with newly diagnosed PD were complex and diverse, which were significantly higher than normal, and people are susceptible to ignore them, so we need to pay attention to them and treating at the early-stage PD diseases.
方法:采用病例-对照研究选择PD患者407例和516名健康对照,利用TaqMan荧光定量PCR方法检测中国汉族人群中PARK16基因Rs947211和Rs823128基因多态性,并对不同基因型临床资料进行分析。
结果:
1 PARK16基因的多态性位点Rs947211在PD组基因型频率为:GG 35.4%(144/407)、AG 45.7%(186/407)、AA 18.9%(77/226),对照组分别为26.4%(136/516)、53.3%(275/516)、20.3%(105/516),2组基因型频率差异具有统计学意义(基因型X~2=8.97,P=0.011;等位基因X~2=5.03,P=0.027)。采用Logistic回归校正性别、年龄后,以野生型GG为参照,其PD组AG OR值=0.63,95% CI:0.47-0.85,P=0.002;AA OR=0.68,95% CI:0.47-0.99,P=0.046。暴露于A等位基因型(AA+AG)的OR=0.64(95% CI: 0.48-0.85,P=0.002)。将PD组进一步按照家族史分层分析发现,散发性PD PARK16 rs947211基因型与对照组有统计学差异(OR(MH)=0.66, 95%CI: 0.50-0.86,X~2=8.85,P=0.003)。
2 Rs823128在PD组基因型频率分布为AA 71.6% (280/391),AG 25.1%(98/391),GG 3.3% (13/391),等位基因频率:A 84.1%,G 15.9%,对照组为:AA 75.2% (312/415),AG 22.2% (92/415),GG 2.7% (11/415),等位基因频率:A 86.3%,G 13.7%,两组基因型和等位基因频率均无统计学意义(基因型X~2=1.37,P=0.503;等位基因X~2=1.44,P=0.233)。
3 PD组PARK16 rs947211和rs8231283三种基因型在性别、年龄、发病年龄、病程、有无家族史、主要特征、帕金森病统一评分量表Ⅲ(UPDRSⅢ)、哈密顿抑郁量表(HAMD)、哈密顿焦虑量表(HAMA)、抑郁自评量表(SDS)、焦虑自评量表(SAS)、帕金森病睡眠量表(PDSS)、帕金森病非运动症状量表(PDNMS)、蒙特利尔认知量表(MOCA)、简易精神状态检查量表(MMSE)临床方面均无统计学意义(P>0.05)。
结论:中国汉族人群中PARK16基因与PD易患性相关。
目的:探讨初诊帕金森病(PD)患者非运动症状量表(NMSQuest)细项和NMS症状群(NMSQ-D)的发生和分布情况及与PD的临床基本资料和各个量表的关系。
方法:收集首次就诊的PD患者61例,在未服用抗PD药物的前提下进行PD基本信息登记和相关量表评估,并与89名正常对照组的NMS相比较。
结果: PD组96.72%的患者存在NMS,PD组NMS平均发生数(9.1±5.2)、PD轻度组(7.2±3.7)和PD中度组(12.2±4.6)与正常对照组(2.9±2.5)相比有显著差异(P<0.01)。PD组中以近记忆力下降(62.3%,38例)、注意力下降(57.4%,35例)、便秘(49.2%,30例)为最常见,与健康对照组均有显著差异(P<0.01)。PD轻度组以近记忆力下降(64.3%,27例)、注意力下降(52.4%,22例)、便秘(42.9%,18例)和入睡难或易醒(42.9%,18例)为最常见,除入睡难或易醒,其余均与对照组有显著差异(P<0.01)。PD中度组以注意力下降(64.7%,11例)、近记忆力下降(58.8%,10例)、便秘(58.8%,10例)和夜梦增多(58.8%,10例)为最常见,除近记忆力下降外,其余均与健康对照组均有显著差异(P<0.01)。NMS症状群(NMSQ-D)经Kruskal-Wallis检验发现与之关系最密切的是H-Y分期,其次是病程、UPDRS-Ⅲ,与年龄、发病年龄无差异。NMSQuest与H-Y分期(r=0.339,P<0.01)、SDS(r=0.724,P<0.01)、SAS(r=0.700,P<0.01)成正相关;与PDSS (r=-0.578,P<0.01)负相关;与年龄、发病年龄、性别、病程、UPDRS-Ⅲ评分、MOCA无关。
结论: PD初诊患者非运动症状复杂多样,发生率明显高于正常人,故需重视初诊患者的非运动症状,在早期就加以干预和治疗。
Objective: To investigate the association between PARK16 gene polymorphism and Parkinson’s disease (PD) susceptibility in Chinese Han population, and to analyze its SNP genotypes, frequencies and odds ratios(OR) of different genotypes.
Methods: The association between two SNP loci in PARK16 gene (Rs947211, Rs823128) and PD susceptibility was investigated by TaqMan quantitative polymerase chain reaction (PCR) in 407 PD patients and 516 healthy controls. Clinical data was also analyzed. Results:
1 In PD group, three genotypes of Rs947211 (GG, AG and AA) accounted for 35.4%, 45.7%, 18.9%, Control group 26.4%, 53.3%, 20.3% respectively, two groups were significant differences (P<0.05). GG genotype as the reference, after adjusting age and gender, OR value of AG of PD group was 0.63 (95% CI: 0.47-0.85, P=0.002) and OR of AA genotype was 0.68 (95% CI: 0.47-0.99, P=0.046). Exposure to the A allele (AA+AG), and its OR was 0.64 (95% CI: 0.48-0.85, P=0.002). Subsequently, it could be concluded that there was a lower risk factor in sporadic PD than familiar PD (OR (MH) =0.66, 95% CI: 0.50-0.86, X~2=8.85, P=0.003).
2 The frequencies of genotypes and Allele of Rs823128 in PD group were no significantly different with control group(X~2=1.37, P=0.503; X~2=1.44, P=0.233).
3 Clinical features of the Rs947211 and Rs823128 in three genotypes were further analyzed, and there were no differences between the clinical characteristics in the patients in the three genotypes for genders, ages, age-at-onset, disease durations, family histories, cardinal features (resting tremor, rigidity and mixed symptoms), scores of Hoehn-Yahr stage, UPDRSⅢscores (on-stage), HAMD scores, HAMA scores, SDS scores, SAS scores, PDSS scores, PDNMS scores, MOCA scores and MMSE scores.
Conclusion: PARK16 is associated with PD patients in Chinese Han population.
Objective: To investigate the incidence, distribution of non-motor symptoms (NMS) and NMSQuest-Details (NMSQ-D) in patients with newly diagnosed PD, and its relationship with clinical features and various scales.
Methods: 61 PD patients without taking any drugs and 89 normal controls were collected in outpatient visits, and their clinic information and related scales were also evaluated.
Results: 96.7% PD total patients presented with NMS, decreased recent memory (62.3%, n=38), decreased attention (57.4%, n =35), and constipation (49.2%, n=30) were the most common in PD group, there were significantly different between PD group and Normal group (P <0.01), so did the moderate and mild groups of PD. NMSQuest average score of the PD group (9.1±5.2), PD moderate disease group of NMS (12.2±4.6) and mild group (7.2±3.7) were significantly higher than the control group (2.9±2.5) (P <0.01). We also found that NMSQust Details (NMSQ-D) were most closely with the HY stage by Kruskal Wallis test, the followed were the course of disease and UPDRS-Ⅲ, no difference was found between age and age of onset. NMSQuest and HY stage (r = 0.339, P <0.01), SDS (r = 0.724, P <0.01), SAS (r = 0.700, P <0.01) were Positive correlation; And PDSS (r =- 0.578, P <0.01) was negative correlation; age, age at onset, gender, duration, UPDRS-Ⅲscore and MOCA had nothing to do with NMSQuest.
Conclusion: Non-motor symptoms in patients with newly diagnosed PD were complex and diverse, which were significantly higher than normal, and people are susceptible to ignore them, so we need to pay attention to them and treating at the early-stage PD diseases.
引文
[1] K Chaudhuri, M Buxton-Thomas, V Dhawan, R Peng, C Meilak, D Brooks. Long duration asymmetrical postural tremor is likely to predict development of Parkinson’s disease and not essential tremor: clinical follow up study of 13 cases. Neurol Neurosurgery Psychiatry, 2005, 76(1) :115-117
[2] Rocca W.A. Prevalence of Parkinson's disease in China.Lancet Neurol, 2005,4 (6): 328-329
[3] Yoshikuni Mizuno, Nobutaka Hattori, Shin-ichiro Kubo, Shigeto Sato, Kenya Nishioka, Taku Hatano, Hiroyuki Tomiyama, Manabu Funayama, Yutaka Machida, Hideki Mochizuki. Progress in the pathogenesis and genetics of Parkinson's disease. Philos Trans R Soc Lond B Biol Sci, 2008, 363 (1500): 2215-2227
[4] Nuytemans K, Theuns J, Cruts M, Van Broeckhoven C. Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Hum Mutat, 2010, 31 (7): 763-780
[5] Keyser RJ, Lesage S, Brice A, Carr J, Bardien S. Assessing the prevalence of PINK1 genetic variants in South African patients diagnosed with early- and late-onset Parkinson's disease. Biochem Biophys Res Commun, 2010, 398(1): 125-129
[6] Qing H, Wong W, McGeer EG, McGeer PL. Lrrk2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications. Biochem Biophys Res Commun, 2009, 387(1): 149-152
[7] Kabuta T, Wada K. Insights into links between familial and sporadic Parkinson's disease: physical relationship between UCH-L1 variants and chaperone-mediated autophagy. Autophagy, 2008, 4 (6): 827-829
[8] Guzman JN, Sanchez-Padilla J, Wokosin D, Kondapalli J, Ilijic E, Schumacker PT, Surmeier DJ. Oxidant stress evoked by pacemaking indopaminergic neurons is attenuated by DJ-1. Nature, 2010, 468(7324): 696-700.
[9] Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, Kawaguchi T, Tsunoda T, Watanabe M, Takeda A, Tomiyama H, Nakashima K, Hasegawa K, Obata F, Yoshikawa T, Kawakami H, Sakoda S, Yamamoto M, Hattori N, Murata M, Nakamura Y, Toda T. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nature Genetics, 2009, 41 (12): 1303-1307
[10] Simón-Sánchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, Paisan-Ruiz C, Lichtner P, Scholz SW, Hernandez DG, Krüger R, Federoff M, Klein C, Goate A, Perlmutter J, Bonin M, Nalls MA, Illig T, Gieger C, Houlden H, Steffens M, Okun MS, Racette BA, Cookson MR, Foote KD, Fernandez HH, Traynor BJ, Schreiber S, Arepalli S, Zonozi R, Gwinn K, van der Brug M, Lopez G, Chanock SJ, Schatzkin A, Park Y, Hollenbeck A, Gao J, Huang X, Wood NW, Lorenz D, Deuschl G, Chen H, Riess O, Hardy JA, Singleton AB, Gasser T. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nature Genetics, 2009, 41 (12): 1308-1312
[11] Kolisek M, Launay P, Beck A, Sponder G, Serafini N, Brenkus M, Froschauer EM, Martens H, Fleig A, Schweigel M. SLC41Al is a novel mammalian Mg2+ carrier. J Biol Chem, 2008, 283(23): 16235-16247
[12] HeliP-Wooley A, Thoene JG. Sucrose-induced vacuolation results in increased expression of cholesterol biosynthesis and lysosomal genes.Exp Cell Res, 2004, 292(1): 89-100
[13] Wi?niewski JR, Zougman A, Krüger S, Zió?kowski P, Pude?ko M, Bebenek M, Mann M. Constitutive and dynamic phosphorylation and acetylation sites on NUCKS, a hypermodified nuclear protein, studied by quantitative proteomics. Proteins, 2008 Nov 15; 73(3): 710-718
[14] National Collaborating Centre for Chronic Conditions (UK), Parkinson’s disease: National clinical guideline for diagnosis and management inprimary and secondary care. London: Royal College of Physicians (UK), 2006
[15] Kalendar R, Lee D, Schulman AH. Invited Review:FastPCR Software for PCR Primer and Probe Design and Repeat Search.Genes Genomes and Genomics, 2009, 3: l-14
[16] Takahashi R, Kawamata J, Takeuchi H. Pathogenesis of sporadic Parkinson’s disease: contribution of genetic and environmental risk factors. Rinsho Shinkeigaku, 2009, 49(1): 885-887
[17] Arianna Tucci, Mike A Nalls, Henry Houlden, Tamas Revesz, Andrew B Singleton, Nicholas W Wood, John Hardy, Coro Paisán-Ruiz. Genetic variability at the PARK16 locus. Eur J Hum Genet, 2010, 18(12): 1356-1359
[18] Mata IF, Yearout D, Alvarez V, Coto E, de Mena L, Ribacoba R, Lorenzo-Betancor O, Samaranch L, Pastor P, Cervantes S, Infante J, Garcia-Gorostiaga I, Sierra M, Combarros O, Snapinn KW, Edwards KL, Zabetian CP. Replication of MAPT and SNCA, but not PARK16-18, as Susceptibility Genes for Parkinson’s Disease. Mov Disord, 2011, 26(5): 819-823
[19] Tan EK, Kwok HH, Tan LC, Zhao WT, Prakash KM, Au WL, Pavanni R, Ng YY, Satake W, Zhao Y, Toda T, Liu JJ. Analysis of GWAS-linked loci in Parkinson disease reaffirms PARK16 as a susceptibility locus. Neurology, 2010,75 (6): 508-512
[20] Ramirez A, Ziegler A, Winkler S, Kottwitz J, Giesen R, Díaz-Grez F, Miranda M, Venegas P, Godoy OT, Avello R, Behrens MI, Klein C, Segura-Aguilar J, Lohmann K. Association of Parkinson disease to PARK16 in a Chilean Sample. Parkinsonism Relat Disord, 2011, 17(1): 70-71
[21] Vilari?o-Güell C, Ross OA, Aasly JO, White LR, Rajput A, Rajput AH, Lynch T, Krygowska-Wajs A, Jasinska-Myga B, Opala G, Barcikowska M, Lee MC, Hentati F, Uitti RJ, Wszolek ZK, Farrer MJ, Wu RM. Anindependent replication of PARK16 in Asian samples. Neurology, 2010, 75(24): 2248-2249
[22] Li DH, Wang J, Mao CJ, Hu WD, Xiao L, Yang YP, Qin ZH, Liu CF. Association of PARK 16 polymorphisms with Parkinson's disease in Han population of Suzhou area. Zhonghua Yi Xue Za Zhi, 2011, 91(5): 296-300
[23] Chang XL, Mao XY, Li HH, Zhang JH, Li NN, Burgunder JM, Peng R, Tan EK. Association of GWAS loci with PD in China. Am J Med Genet B Neuropsychiatr Genet, 2011,156 B (3): 334-339
[1] National Collaborating Centre for Chronic Conditions (UK). Parkinson’s disease: National clinical guideline for diagnosis and management in primary and secondary care. London: Royal College of Physicians (UK), 2006
[2] Chaudhuri KR, Martinez-Martin P, SchaPira AH, Stocchi F, Sethi K, Odin P, Brown RG, Koller W, Barone P, MacPhee G, Kelly L, Rabey M, MacMahon D, Thomas S, Ondo W, Rye D, Forbes A, Tluk S, Dhawan V, Bowron A, Williams AJ, Olanow CW. International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson's disease: the NMSQuest study. Movement Disorders, 2006, 21(7):916-923
[3] Chaudhuri KR, Martinez-Martin P, Brown RG, Sethi K, Stocchi F, Odin P, Ondo W, Abe K, Macphee G, Macmahon D, Barone P, Rabey M, Forbes A, Breen K, Tluk S, Naidu Y, Olanow W, Williams AJ, Thomas S, Rye D, Tsuboi Y, Hand A, Schapira AH. The metric properties of a novel non-motor symptoms scale for Parkinson's disease: Results from an international pilot study. Mov Disord, 2007, 22(13):1901-1911
[4]干静,刘振国,周明珠,周桢源,应黎,陈伟.帕金森病患者非运动症状的研究.中华老年医学杂志,2008,27(6): 409-412
[5]张宁,刘卫国,叶民,张颖冬.帕金森病非运动症状的特征研究,中华行为医学与脑科学杂志. 2010, 19(4):331-333
[6] Martinez-martin P, SchaPira AH, Stocchi F, Sethi K, Odin P, MacPhee G, Brown RG, Naidu Y, Clayton L, Abe K, Tsuboi Y, MacMahon D, Barone P, Rabey M, Bonuccelli U, Forbes A, Breen K, Tluk S, Olanow CW, Thomas S, Rye D, Hand A, Williams AJ, Ondo W, Chaudhuri KR. Prevalence of Nonmotor Symptoms in Parkinson’s disease in an International Setting: Study Using Nonmotor Symptoms Questionnaire in 545 Patients. Mov Disord, 2007, 22(11):1623-1629
[7] Chaudhuri KR, Prieto-Jurcynska C, Naidu Y, Mitra T, Frades-Payo B, Tluk S, Ruessmann A, Odin P, Macphee G, Stocchi F, Ondo W, Sethi K, Schapira AH, Martinez Castrillo JC, Martinez-Martin P. The Nondeclaration of Nonmotor Symptoms of Parkinson’s Disease to Health Care Professionals: An International Study Using the Nonmotor Symptoms Questionnaire. Movement Disordment, 2010, 25(6):697-701
[8] Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson's disease-related Pathology. Cell Tissue Res, 2004, 318 (1):121-134
[9] Kim HJ, Park SY, Cho YJ, Hong KS, Cho JY, Seo SY, Lee DH, Jeon BS. Nonmotor symptoms in de novo Parkinson disease before and after dopaminergic treatment. Journal of the Neurological Sciences, 2009, 287(1-2):200–204
[10] Hely MA, Reid WG, Adena MA, et al. The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord, 2008, 23(6):837-844
[11] Sakakibara R, Shinotoh H, Uchiyama T, Sakuma M, Kashiwado M, Yoshiyama M, Hattori T. Questionnaire based assessment of Pelvic organ dysfunction in Parkinson's disease. Auton Neurosci, 2001, 92(1-2):76-85
[12] Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD, Grandinetti A, Blanchette PL, Popper JS, Ross GW. Frequency of bowel movements and the future risk of Parkinson's disease. Neurology, 2001, 57(3): 456-462
[13]赵康仁,吴颉言,朱朝阳,韩泰然,马震祥,俞俊洪.帕金森病患者的抑郁及其相关因素.临床神经病学杂志, 2001, 14(1): 33-34
[14] Shulman LM, Taback RL, Rabinstein AA, Weiner WJ. Non-recognition of depression and other non-motor symptoms in Parkinson’s diseases. Parkinsonism Relat Disord, 2002, 8(3):193-197
[15] Ziemssen T, Reichmann H. Non-motor dysfunction in Parkinson's disease. Parkinsonism Relat Disord, 2007, 13(6):323-332
[16] Winge K, Fowler CJ. Bladder dysfunction in Parkinsonism: mechanisms, prevalence, symptoms, and management. MovDisord, 2006, 21(6): 737–745
[17] Chaudhuri KR. Nocturnal symptom complex in PD and its management. Neurology, 2003, 61(Supp 3):S17-S23
[18] Kumar S, Bhatia M, Behari M. Sleep disorders in Parkinson’s disease. Movement Disorders, 2002, 17(4):775-781
[19]毛成洁,戴永萍,刘春风.早期帕金森患者睡眠障碍的相关分析.江苏医学,2007,33(9):897-899
[20]何远宏,朱迎慧,刘柳,王鹏.帕金森病患者睡眠障碍临床分析.中国实用神经疾病杂志,2008,11(10):29-30
[21] Mathias CJ. Cardiovascular autonomic function in Parkinsonian patients . Clin Neurosci,1998, 5 :153-166
[22] Haehnet A, Boesveldt s, Berendse HW, Mackay-Sim A, Fleischmann J, Silburn PA, Johnston AN, Mellick GD, Herting B, Reichmann H, Hummel T. Prevalence of smell loss in Parkinson’s disease: a multicenter study. Parkinsonism Relat Disord, 2009, 15(7):490-494
[23] Scherder J, Sergeant, Swaab DF. Pain processing in dementia and its relation to neuropathology. Lancet, 2003, 2(11): 677-686
[1] K Chaudhuri, M Buxton-Thomas, V Dhawan, R Peng, C Meilak, D Brooks. Long duration asymmetrical postural tremor is likely to predict development of Parkinson’s disease and not essential tremor: clinical follow up study of 13 cases. Neurol Neurosurgery Psychiatry, 2005, 76(1):115-117
[2] Polymeropoulos MH, Lavedan C, Leroy E, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science, 1997, 276(5321):2045-2047
[3] Kruger R,Kuhn W, Muller T, Woitalla D, Graeber M, K?sel S, Przuntek H, Epplen JT, Sch?ls L, Riess O. Ala30Pro mutation in the gene encoding alpha—synuclein in Parkinson’s disease. Nat Genet, 1998, 18(2): 106-108
[4] Zarranz TJ, Alergre J, Go’mez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atarés B, Llorens V, Gomez Tortosa E, del Ser T, Mu?oz DG, de Yebenes JG. New mutation, E46K, ofα-synuclein causes Parkinson and Lewy body dementia. Ann Neurol, 2004, 55(2): 164-173
[5] Polymeropoulos MH, Higgins JJ, Golbe LI, Johnson WG, Ide SE, Di IG, Sanges G, Stenroos ES, Pho LT, Schaffer AA, Lazzarini AM, Nussbaum RL, Duvoisin RC. Mapping of a gene for Parkinson’s disease to chromosome 4q21–q23. Science, 1996, 274(5290):1197-1199
[6] Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di IG, Golbe LI, Nussbaum RL. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science, 1997, 276(5321): 2045-2047
[7] Miller DW, Hague SM, Clarimon J, Baptista M, Gwinn-Hardy K, Cookson MR, Singleton AB.α-synuclein in b1ood and brain from familial Parkinson’s disease with SNCA locus triplication. Neurology, 2004, 62(10): 1835-1838
[8] Williams-Gray CH,Goris A,Foltynie T, Brown J, Maranian M, Walton A, Compston DA, Sawcer SJ, Barker RA. No alterations inα-synuclein gene dosage observed in sporadic Parkinson’s disease. Mov Disord, 2006, 21(5): 731-732
[9] Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, Kawaguchi T, Tsunoda T, Watanabe M, Takeda A, Tomiyama H, Nakashima K, Hasegawa K, Obata F, Yoshikawa T, Kawakami H, Sakoda S, Yamamoto M, Hattori N, Murata M, Nakamura Y, Toda T. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease, Nat Genet, 2009 ,41(12):1303-1307
[10] Wang M, Hattori N, Matsumine H, Kobayashi T, Yoshino H, Morioka A, Kitada T, Asakawa S, Minoshima S, Shimizu N, Mizuno Y. Polymorphism in the parkin gene in sporadic Parkinson’s diseases. Ann Neurol, 1999, 45(5):655-658
[11] Kitada T,Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature, 1998, 392(6676): 605-608
[12] Lucking CB, Durr A, Bonifati V, Vaughan J, De Michele G, Gasser T, Harhangi BS, Meco G, Denèfle P, Wood NW, Agid Y, Brice A. Association between early-onset Parkinson's disease and mutations in the parkin gene. N Engl J Med 2000; 342(21):1560-1567
[13] Periquet M, Latouche M, Lohmann E, Rawal N, De Michele G, Ricard S, Teive H, Fraix V, Vidailhet M, Nicholl D, Barone P, Wood NW, Raskin S, Deleuze JF, Agid Y, Dürr A, Brice A. Parkin mutations are frequent inpatients with isolated early-onset parkinsonism. Brain, 2003, 126(pt 6):1271–1278
[14] Mata IF, Lockhart PJ, Farrer MJ. Parkin genetics: one model for Parkinson's disease. Hum Mol Genet, 2004, 13(spec no 1):R12-R133
[15] Farrer MJ. Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet, 2006, 7(4): 306-318
[16]宁玉萍,徐严明,王玉凯,刘焯霖. Parkin基因R/W366及V/L380多态性与散发性帕金森病.中国神经精神疾病杂志, 2002, 28(1):17-19
[17]宁玉萍,刘焯霖,徐严明,王玉凯.Parkin基因S/N167多态性与散发性帕金森病关联研究.中华医学遗传学杂志, 2002, 19(6):513-514
[18] Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, Harta G, Brownstein MJ, Jonnalagada S, Chernova T, Dehejia A, Lavedan C, Gasser T, Steinbach PJ, Wilkinson KD, Polymeropoulos MH. The ubiquitin pathway in Parkinson’s disease. Nature, 1998, 395(6701): 451-452
[19] Carmine A, Westerlund M, Bergman O, Nissbrandt H, Lind C, Sydow O, Galter D. S18Y in ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) associated with decreased risk of Parkinson’s diseases in Sweden. Parkinsonism Relat Disord, 2007, 13(5):295-298
[20] Shi Q, Tao E. An Ile93 Met substitution in the UCH-L1 gene is not a diseases-causing mutation for idiopathic Parkinson’s diseases. Chinese Med J, 2003, 116(2): 312-313
[21] Zhang J, Hattori N, Giladi N, Mizuno Y. Failure to find mutations in ubiquitin carboxy-terminal hydrolase L1gene in familial Parkinson’s diseases. Parkinsonism Relat Disord, 2000, 6(4):199-200
[22] Lincoln S, Vaughan J, Wood N, Baker M, Adamson J, Gwinn-Hardy K, Lynch T, Hardy J, Farrer M. Low frequency of pathogenic mutations in the ubiquitin carboxyterminal hydrolase gene in familial Parkinson’s diseases. Neuroreport, 1999, 10(2):427-429
[23] Levecque C, Destee A, Mouroux V, Becquet E, Defebvre L, Amouyel P, Chartier-Harlin MC. No genetic association of the ubiquitincarboxy-terminal hydrolase-L1 gene S18Y polymorphism with familial Parkinson’s diseases. J Neural Transm, 2001, 108(8-9):979-984
[24]郭纪锋,唐北沙,张玉虎,夏昆,蔡芳,潘乾,沈璐,江泓,赵国华,严新翔,曹立.常染色体隐性遗传性早发型帕金森综合征DJ-1基因突变研究.中华医学遗传学杂志, 2005, 22(6):641-643
[25] Valente EM, Bentivoglio AR,Dixon PH, Ferraris A, Ialongo T, Frontali M, Albanese A, Wood NW. Localization of a novel Iocus for autosomal recessive early-onset parkinsonism, PARK6,on human chromosome lp35-p36.Am J Hum Genet,200l,68(4):895-900
[26] Valente EM, Abou-sleiman PM,CaputoV, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW. Hereditary early-onset Parkinson’s disease eaused by mutations in PINKI. Science, 2004, 304(5674):1158-1160
[27]王枫,陈彪,冯秀丽,邹海强,马敬红,董秀敏,李勇杰. PINKI基因多态位点IVS5-5G>A可能增加中国人晚发性帕金森病的发病风险.中华医学遗传学杂志, 2007, 2(3):305-309
[28]张玉虎,唐北沙,郭纪锋,夏昆,许波,蔡芳,邓汉湘,严新翔,陈涛,曹立,潘乾,龙志高.常染色体隐性遗传早发性帕金森综合征6型PINKI基因的突变分析,中华医学杂志, 2005, 85(22):1538-1541
[29] Alcalay RN, Mejia-Santana H, Tang MX, Rosado L, Verbitsky M, Kisselev S, Ross BM, Louis ED, Comella CL, Colcher A, Jennings D, Nance MA, Bressman S, Scott WK, Tanner C, Mickel SF, Andrews HF, Waters CH, Fahn S, Cote LJ, Frucht SJ, Ford B, Rezak M, Novak K, Friedman JH, Pfeiffer R, Marsh L, Hiner B, Siderowf A, Caccappolo E, Ottman R, Clark LN, Marder KS. Motor phenotype of LRRK2 G2019S carriers in early-onset Parkinson disease. Arch Neurol, 2009, 66(12): 1517-1522
[30] Chan DK, Ng PW, Mok V, Yeung J, Fang ZM, Clarke R, Leung E, Wong L. LRRK2 Gly2385Arg mutation and clinical features in a Chinese population with early-onset Parkinson's disease compared to late-onset patients. J Neural Transm, 2008, 115(9):1275-7
[31] Yu L, Hu F, Zou X, Jiang Y, Liu Y, He X, Xi J, Liu L, Liu Z, He L, Xu Y. LRRK2 R1628P contributes to Parkinson's disease susceptibility in Chinese Han populations from mainland China. Brain Res, 2009, 1296:113-116
[32] Ross OA, Wu YR, Lee MC, Funayama M, Chen ML, Soto AI, Mata IF, Lee-Chen GJ, Chen CM, Tang M, Zhao Y, Hattori N, Farrer MJ, Tan EK, Wu RM. Analysis of Lrrk2 R1628P as 8 risk factor for Parkinsen’s diseases.Ann Neurol,2008, 64(1): 88 - 92
[33] Lu CS, Wu-Chou YH, Van Doeselaar M, Simons EJ, Chang HC, Breedveld GJ, Di Fonzo A, Chen RS, Weng YH, Lai SC, Oostra BA, Bonifati V.The LRRK2 Arg1628Pro variant is a risk factor for Parkimon’s diseases in the Chinese population. Neurogenetics, 2008, 9(4): 27l-276
[34] Simón-Sánchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, Paisan-Ruiz C, Lichtner P, Scholz SW, Hernandez DG, Krüger R, Federoff M, Klein C, Goate A, Perlmutter J, Bonin M, Nalls MA, Illig T, Gieger C, Houlden H, Steffens M, Okun MS, Racette BA, Cookson MR, Foote KD, Fernandez HH, Traynor BJ, Schreiber S, Arepalli S, Zonozi R, Gwinn K, van der Brug M, Lopez G, Chanock SJ, Schatzkin A, Park Y, Hollenbeck A, Gao J, Huang X, Wood NW, Lorenz D, Deuschl G, Chen H, Riess O, Hardy JA, Singleton AB, Gasser T. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nature Genetics, 2009, 41 (12): 1308-1312
[35] Kolisek M, Launay P, Beck A, Sponder G, Serafini N, Brenkus M, Froschauer EM, Martens H, Fleig A, Schweigel M. SLC41Al is a novel mammalian Mg2+ carrier. J Biol Chem, 2008, 283(23):16235-16247
[36] Hermosura MC, Nayakanti H, Domvkov MV, Calderon FR, Ryazanov AG, Haymer DS, Garruto RM. A TRPM7 variant shows altered sensitivity tomagnesium that may contribute to the pathogenesis of two Guamanian neurodegenerative disorders. Proc Natl Acad sci USA, 2005, 102(32): 11510-11515
[37] HeliP-Wooley A, Thoene JG. Sucrose-induced vacuolation results in increased expression of cholesterol biosynthesis and lysosomal genes.Exp Cell Res, 2004, 292(1):89-100
[38] Arianna Tucci, Mike A Nalls, Henry Houlden, Tamas Revesz, Andrew B Singleton, Nicholas W Wood, John Hardy, Coro Paisán-Ruiz.Genetic variability at the PARK16 locus. Eur J Hum Genet, 2010 18(12): 1356-1359
[39] Mata IF, Yearout D, Alvarez V, Coto E, de Mena L, Ribacoba R, Lorenzo-Betancor O, Samaranch L, Pastor P, Cervantes S, Infante J, Garcia-Gorostiaga I, Sierra M, Combarros O, Snapinn KW, Edwards KL, Zabetian CP. Replication of MAPT and SNCA, but not PARK16-18, as Susceptibility Genes for Parkinson’s Disease. Mov Disord, 2011, 26(5): 819-823
[40] Chang XL, Mao XY, Li HH, Zhang JH, Li NN, Burgunder JM, Peng R, Tan EK. Association of GWAS loci with PD in China. Am J Med Genet B Neuropsychiatr Genet, 2011, 156B (3):334-339
[1] Welsh M. Parkinson's disease and quality of life: issues and challenges beyond motor symptoms. Neurol Clin, 2004, 22(3 Suppl):S141-148
[2] Tolosa E, Compta Y, Gaig C. The premotor phase of Parkinson's disease. Parkinsonism Relat Disord, 2007, 13(Suppl): S2-7
[3] Chaudhuri KR. Nocturnal symptom complex in PD and its management. Neurology, 2003, 61(Supp 3):S17-S23
[4] Kumar S, Bhatia M, Behari M. Sleep disorders in Parkinson’s disease. Movement Disorders, 2002, 17(4):775-781
[5]毛成洁,戴永萍,刘春风.早期帕金森患者睡眠障碍的相关分析.江苏医学,2007,33(9):897-899
[6]何远宏,朱迎慧,刘柳,王鹏.帕金森病患者睡眠障碍临床分析.中国实用神经疾病杂志,2008,11(10):29-30
[7] Mondragon-Rezola E, Arratibel-Echarren I, Ruiz-Martinez J, Martí-MassóJF. Sleep disorders in Parkinson’s disease: insomnia and sleep fragmentation. daytime hypersomnia, alterations to the circadian rhythm and sleep apnea syndrome. Rev Neurol, 2010, 50(Suppl 2): S21-26
[8] Meral H, Aydemir T, Ozer F, Ozturk O, Ozben S, Erol C, Cetin S, Hanoglu L, Ozkayran T, Yilsen M. Relationship between visual hallucinations and REM sleep behavior disorder in patients with Porkinson’s disease. Clinical Neurology and Neurosurgery, 2007, 109(10):862-867
[9] Abbott RD, Ross GW, White LR, Tanner CM, Masaki KH, Nelson JS, Curb JD, Petrovitch H. Excessive daytime sleepiness and subsequent development of Parkinson disease. Neurology, 2005, 65(9):1442-1446
[10] Ondo WG,Perkins T,Swick T, Hull KL Jr, Jimenez JE, Garris TS, Pardi D. Sodium oxybate for excessive daytime sleepiness in Parkinson disease:a open—label polysomnorgraphic stydy.Arch Neurol,2008,65:1337-1340
[11] Happe S, Pirker W, Kloseh G, Sauter C, Zeitlhofer J. Periodic leg movements in patients with Parkinson’s disease are associated with reduced striatal dopamine transporter binding. J Neurol, 2003, 250 (1):83-86
[12]中华医学会神经病学分会帕金森病及运动障碍学组.不宁腿综合症的诊断标准及治疗指南.中华神经科杂志,2009,42(10):709-711
[13] Ferreira JJ, Galitzky M, Montastruc JL, Rascol O. Sleep attacks and Parkimon’s disease treatment. Lancet, 2000, 355(9212): 1333-1334
[14] Hirayama M, Nakflmura T, Hori N, Koike Y, Sobue G. The video images of sleep attacks in Parkinson’s disease. Mov Disorder, 2008, 23(2):288-290
[15] Chaudhuri KR, Yates L, Martinez-Martin P. The non-motor symptom complex of Parkinson’s disease: a comprehensive assessment is essential. Curt Neural Neurosci Rep, 2005, 5(4): 275-283
[16] Chaudhuri KR, Healy DG, Sehapira AH. Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol, 2006, 5(3): 235-245
[17] Shulman LM, Taback RL, Rabinstein AA, Weiner WJ. Non-recognition of depression and other non-motor symptoms in Parkinson’s diseases. Parkinsonism Relat Disord, 2002, 8(3):193-197
[18] Ziemssen T, Reichmann H. Non-motor dysfunction in Parkinson's disease. Parkinsonism Relat Disord, 2007, 13(6):323-332
[19] Fleminger S. Left-sided Parkinson's disease is associated with greater anxiety and depression. Psychol Med, 1991, 21(3): 629-638
[20]赵康仁,吴颉言,朱朝阳,韩泰然,马震祥,俞俊洪.帕金森病患者的抑郁及其相关因素.临床神经病学杂志, 2001, 14(1): 33-34
[21] Aarland D, Larsen JP, Goek Lim N, Janvin C, Karlsen K, Tandberg E, Cummings JL. Range of neuropsychiatric disturbances in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry, 1999, 67(4):492-496
[22] Kitsch-Darrow L, Fernandes HF, Marsiske M, Okun MS, Bowers D. Dissociatingapathy and depression in Parkinson disease. Neurology, 2006, 67(7): 33-38
[23] Padala PR, Petty F, Bhatia SC. Methylphenidate may treat apathy independent of depression. Ann Pharmacother, 2005, 39(11): 1947-1949
[24] Aarsland D, Br?nnick K, Larsen JP, Tysnes OB, Alves G. Cognitive impairment in incident, untreated Parkinson disease: the Norwegian ParkWest study. Neurology, 2009, 72(13):1121-1126
[25] Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG. The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord, 2008, 23(6):837-844
[26] Barnes J, David AS.Visual hallucinations in Parkinson’s disease;a review and henomenological survey. Neurol Neurosurg Psychmt, 2001, 70(6): 727-733
[27] Mathias CJ. Cardiovascular autonomic function in Parkinsonian patients . Clin Neurosci,1998, 5 :153-166
[28] Singer W, Opfer-Gejrking TL, Mcphee BR, Hilz MJ, Bharucha AE, Low PA. Acetylcholinesterase Inhibition: a novel approach in the treatment of neurogenic orthostatic Hypotension. J Ncorosurg Psychiatry, 2003,74(9): 1294-1298
[29] Wood LD, Neumiller JJ, Setter SM, Dobbins EK. Clinical review of treatment options for select nonmotor symptoms of Parkinson's disease. Am J Geriatr Pharmacother, 2010, 8(4):294-315
[30] Sakakibara R, Shinotoh H, Uchiyama T, Sakuma M, Kashiwado M, Yoshiyama M, Hattori T. Questionnaire based assessment of Pelvic organ dysfunction in Parkinson's disease. Auton Neurosci, 2001, 92(1-2):76-85
[31] Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD, Grandinetti A, Blanchette PL, Popper JS, Ross GW. Frequency of bowel movements and the future risk of Parkinson's disease. Neurology, 2001, 57(3): 456-462
[32] Zangaglia R, Martignoni E, Glorioso M, Ossola M, Riboldazzi G, Calandrella D, Brunetti G, Pacchetti C. Macrogol for the treatment ofconstipation in Parkinson’s disease. A randomized placebo-controlled study, Mov Disord, 2007, 22(9):1239-1244
[33] Winge K, Fowler CJ. Bladder dysfunction in Parkinsonism: mechanisms, prevalence, symptoms, and management. MovDisord, 2006, 21(6): 737–745
[34] Pfeiffer RF. Gastrointestinal, Urological, and Sexual Dysfunctionin Parkinson’s disease. Mov Disord, 2010, 25(Suppl 1):S94-97
[35] Kulaksizoglu H, Parman Y. Use of botulinim toxin-A for the treatment of overactive bladder symptoms in patients with Parkinsons's disease. Parkinsonism Relat Disord, 2010, 16(8):531-4
[36] Wermuth L, Stenager E. Sexual problems in young patients with Parkinson’s disease. Acta Neurol Scand, 1995, 91(6): 453-455
[37] Vázquez-Sáánchez F, Rodríguez-Martínez E, Arés-Luque A. Urinary disorders, sexual dysfunction and hypersexuality in Parkinson's disease, Rev Neurol, 2010, 50(Suppl 2):S27-31
[38] [Safarinejad MR, Taghva A, Shekarchi B, Safarinejad Sh. Safety and efficacy of sildenafil citrate in the treatment of Parkinson-emergent erectile dysfunction: a double-blind, placebo-controlled, randomized study. Int J Impot Res, 2010, 22(5):325-35
[39] Haehnet A, Boesveldt s, Berendse HW, Mackay-Sim A, Fleischmann J, Silburn PA, Johnston AN, Mellick GD, Herting B, Reichmann H, Hummel T. Prevalence of smell loss in Parkinson’s disease: a multicenter study. Parkinsonism Relat Disord, 2009, 15(7):490-494
[40] Ponsen MM, Stoffers D, Booij J, van Eck-Smit BL, Wolters ECh, Berendse HW. Idiopathic hyposmia as a preclinical Sign of Parkinson’s disease. Ann Neurol, 2004, 56(2):173-181
[41] Baba T, Takeda A, Kikuchi A, Nishio Y, Hosokai Y, Hirayama K, Hasegawa T, Sugeno N, Suzuki K, Mori E, Takahashi S, Fukuda H, Itoyama Y. Association of olfactory dysfunction and brain Metabolism in Parkinson's disease. Mov Disord, 2011, 26(4):621-8
[42] Djaldetti R, Shifrin A, Rogowski Z, Sprecher E, Melamed E, Yarnitsky D. Quantitative measurement of pain sensation in patients with Parkinson disease. Neurology, 2004, 62(12): 2171-2175
[43] Scherder J, Sergeant, Swaab DF. Pain processing in dementia and its relation to neuropathology. Lancet, 2003, 2(11): 677-686
[44] Chang Jing-Yu. Brain stimulation for neurologicaland psychiatric disorders, current status and future direction. Journal of Pharmacology & Experimental Therapeutics, 2004, 309(1): 1-7
[2] Rocca W.A. Prevalence of Parkinson's disease in China.Lancet Neurol, 2005,4 (6): 328-329
[3] Yoshikuni Mizuno, Nobutaka Hattori, Shin-ichiro Kubo, Shigeto Sato, Kenya Nishioka, Taku Hatano, Hiroyuki Tomiyama, Manabu Funayama, Yutaka Machida, Hideki Mochizuki. Progress in the pathogenesis and genetics of Parkinson's disease. Philos Trans R Soc Lond B Biol Sci, 2008, 363 (1500): 2215-2227
[4] Nuytemans K, Theuns J, Cruts M, Van Broeckhoven C. Genetic etiology of Parkinson disease associated with mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 genes: a mutation update. Hum Mutat, 2010, 31 (7): 763-780
[5] Keyser RJ, Lesage S, Brice A, Carr J, Bardien S. Assessing the prevalence of PINK1 genetic variants in South African patients diagnosed with early- and late-onset Parkinson's disease. Biochem Biophys Res Commun, 2010, 398(1): 125-129
[6] Qing H, Wong W, McGeer EG, McGeer PL. Lrrk2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications. Biochem Biophys Res Commun, 2009, 387(1): 149-152
[7] Kabuta T, Wada K. Insights into links between familial and sporadic Parkinson's disease: physical relationship between UCH-L1 variants and chaperone-mediated autophagy. Autophagy, 2008, 4 (6): 827-829
[8] Guzman JN, Sanchez-Padilla J, Wokosin D, Kondapalli J, Ilijic E, Schumacker PT, Surmeier DJ. Oxidant stress evoked by pacemaking indopaminergic neurons is attenuated by DJ-1. Nature, 2010, 468(7324): 696-700.
[9] Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, Kawaguchi T, Tsunoda T, Watanabe M, Takeda A, Tomiyama H, Nakashima K, Hasegawa K, Obata F, Yoshikawa T, Kawakami H, Sakoda S, Yamamoto M, Hattori N, Murata M, Nakamura Y, Toda T. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nature Genetics, 2009, 41 (12): 1303-1307
[10] Simón-Sánchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, Paisan-Ruiz C, Lichtner P, Scholz SW, Hernandez DG, Krüger R, Federoff M, Klein C, Goate A, Perlmutter J, Bonin M, Nalls MA, Illig T, Gieger C, Houlden H, Steffens M, Okun MS, Racette BA, Cookson MR, Foote KD, Fernandez HH, Traynor BJ, Schreiber S, Arepalli S, Zonozi R, Gwinn K, van der Brug M, Lopez G, Chanock SJ, Schatzkin A, Park Y, Hollenbeck A, Gao J, Huang X, Wood NW, Lorenz D, Deuschl G, Chen H, Riess O, Hardy JA, Singleton AB, Gasser T. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nature Genetics, 2009, 41 (12): 1308-1312
[11] Kolisek M, Launay P, Beck A, Sponder G, Serafini N, Brenkus M, Froschauer EM, Martens H, Fleig A, Schweigel M. SLC41Al is a novel mammalian Mg2+ carrier. J Biol Chem, 2008, 283(23): 16235-16247
[12] HeliP-Wooley A, Thoene JG. Sucrose-induced vacuolation results in increased expression of cholesterol biosynthesis and lysosomal genes.Exp Cell Res, 2004, 292(1): 89-100
[13] Wi?niewski JR, Zougman A, Krüger S, Zió?kowski P, Pude?ko M, Bebenek M, Mann M. Constitutive and dynamic phosphorylation and acetylation sites on NUCKS, a hypermodified nuclear protein, studied by quantitative proteomics. Proteins, 2008 Nov 15; 73(3): 710-718
[14] National Collaborating Centre for Chronic Conditions (UK), Parkinson’s disease: National clinical guideline for diagnosis and management inprimary and secondary care. London: Royal College of Physicians (UK), 2006
[15] Kalendar R, Lee D, Schulman AH. Invited Review:FastPCR Software for PCR Primer and Probe Design and Repeat Search.Genes Genomes and Genomics, 2009, 3: l-14
[16] Takahashi R, Kawamata J, Takeuchi H. Pathogenesis of sporadic Parkinson’s disease: contribution of genetic and environmental risk factors. Rinsho Shinkeigaku, 2009, 49(1): 885-887
[17] Arianna Tucci, Mike A Nalls, Henry Houlden, Tamas Revesz, Andrew B Singleton, Nicholas W Wood, John Hardy, Coro Paisán-Ruiz. Genetic variability at the PARK16 locus. Eur J Hum Genet, 2010, 18(12): 1356-1359
[18] Mata IF, Yearout D, Alvarez V, Coto E, de Mena L, Ribacoba R, Lorenzo-Betancor O, Samaranch L, Pastor P, Cervantes S, Infante J, Garcia-Gorostiaga I, Sierra M, Combarros O, Snapinn KW, Edwards KL, Zabetian CP. Replication of MAPT and SNCA, but not PARK16-18, as Susceptibility Genes for Parkinson’s Disease. Mov Disord, 2011, 26(5): 819-823
[19] Tan EK, Kwok HH, Tan LC, Zhao WT, Prakash KM, Au WL, Pavanni R, Ng YY, Satake W, Zhao Y, Toda T, Liu JJ. Analysis of GWAS-linked loci in Parkinson disease reaffirms PARK16 as a susceptibility locus. Neurology, 2010,75 (6): 508-512
[20] Ramirez A, Ziegler A, Winkler S, Kottwitz J, Giesen R, Díaz-Grez F, Miranda M, Venegas P, Godoy OT, Avello R, Behrens MI, Klein C, Segura-Aguilar J, Lohmann K. Association of Parkinson disease to PARK16 in a Chilean Sample. Parkinsonism Relat Disord, 2011, 17(1): 70-71
[21] Vilari?o-Güell C, Ross OA, Aasly JO, White LR, Rajput A, Rajput AH, Lynch T, Krygowska-Wajs A, Jasinska-Myga B, Opala G, Barcikowska M, Lee MC, Hentati F, Uitti RJ, Wszolek ZK, Farrer MJ, Wu RM. Anindependent replication of PARK16 in Asian samples. Neurology, 2010, 75(24): 2248-2249
[22] Li DH, Wang J, Mao CJ, Hu WD, Xiao L, Yang YP, Qin ZH, Liu CF. Association of PARK 16 polymorphisms with Parkinson's disease in Han population of Suzhou area. Zhonghua Yi Xue Za Zhi, 2011, 91(5): 296-300
[23] Chang XL, Mao XY, Li HH, Zhang JH, Li NN, Burgunder JM, Peng R, Tan EK. Association of GWAS loci with PD in China. Am J Med Genet B Neuropsychiatr Genet, 2011,156 B (3): 334-339
[1] National Collaborating Centre for Chronic Conditions (UK). Parkinson’s disease: National clinical guideline for diagnosis and management in primary and secondary care. London: Royal College of Physicians (UK), 2006
[2] Chaudhuri KR, Martinez-Martin P, SchaPira AH, Stocchi F, Sethi K, Odin P, Brown RG, Koller W, Barone P, MacPhee G, Kelly L, Rabey M, MacMahon D, Thomas S, Ondo W, Rye D, Forbes A, Tluk S, Dhawan V, Bowron A, Williams AJ, Olanow CW. International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson's disease: the NMSQuest study. Movement Disorders, 2006, 21(7):916-923
[3] Chaudhuri KR, Martinez-Martin P, Brown RG, Sethi K, Stocchi F, Odin P, Ondo W, Abe K, Macphee G, Macmahon D, Barone P, Rabey M, Forbes A, Breen K, Tluk S, Naidu Y, Olanow W, Williams AJ, Thomas S, Rye D, Tsuboi Y, Hand A, Schapira AH. The metric properties of a novel non-motor symptoms scale for Parkinson's disease: Results from an international pilot study. Mov Disord, 2007, 22(13):1901-1911
[4]干静,刘振国,周明珠,周桢源,应黎,陈伟.帕金森病患者非运动症状的研究.中华老年医学杂志,2008,27(6): 409-412
[5]张宁,刘卫国,叶民,张颖冬.帕金森病非运动症状的特征研究,中华行为医学与脑科学杂志. 2010, 19(4):331-333
[6] Martinez-martin P, SchaPira AH, Stocchi F, Sethi K, Odin P, MacPhee G, Brown RG, Naidu Y, Clayton L, Abe K, Tsuboi Y, MacMahon D, Barone P, Rabey M, Bonuccelli U, Forbes A, Breen K, Tluk S, Olanow CW, Thomas S, Rye D, Hand A, Williams AJ, Ondo W, Chaudhuri KR. Prevalence of Nonmotor Symptoms in Parkinson’s disease in an International Setting: Study Using Nonmotor Symptoms Questionnaire in 545 Patients. Mov Disord, 2007, 22(11):1623-1629
[7] Chaudhuri KR, Prieto-Jurcynska C, Naidu Y, Mitra T, Frades-Payo B, Tluk S, Ruessmann A, Odin P, Macphee G, Stocchi F, Ondo W, Sethi K, Schapira AH, Martinez Castrillo JC, Martinez-Martin P. The Nondeclaration of Nonmotor Symptoms of Parkinson’s Disease to Health Care Professionals: An International Study Using the Nonmotor Symptoms Questionnaire. Movement Disordment, 2010, 25(6):697-701
[8] Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson's disease-related Pathology. Cell Tissue Res, 2004, 318 (1):121-134
[9] Kim HJ, Park SY, Cho YJ, Hong KS, Cho JY, Seo SY, Lee DH, Jeon BS. Nonmotor symptoms in de novo Parkinson disease before and after dopaminergic treatment. Journal of the Neurological Sciences, 2009, 287(1-2):200–204
[10] Hely MA, Reid WG, Adena MA, et al. The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord, 2008, 23(6):837-844
[11] Sakakibara R, Shinotoh H, Uchiyama T, Sakuma M, Kashiwado M, Yoshiyama M, Hattori T. Questionnaire based assessment of Pelvic organ dysfunction in Parkinson's disease. Auton Neurosci, 2001, 92(1-2):76-85
[12] Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD, Grandinetti A, Blanchette PL, Popper JS, Ross GW. Frequency of bowel movements and the future risk of Parkinson's disease. Neurology, 2001, 57(3): 456-462
[13]赵康仁,吴颉言,朱朝阳,韩泰然,马震祥,俞俊洪.帕金森病患者的抑郁及其相关因素.临床神经病学杂志, 2001, 14(1): 33-34
[14] Shulman LM, Taback RL, Rabinstein AA, Weiner WJ. Non-recognition of depression and other non-motor symptoms in Parkinson’s diseases. Parkinsonism Relat Disord, 2002, 8(3):193-197
[15] Ziemssen T, Reichmann H. Non-motor dysfunction in Parkinson's disease. Parkinsonism Relat Disord, 2007, 13(6):323-332
[16] Winge K, Fowler CJ. Bladder dysfunction in Parkinsonism: mechanisms, prevalence, symptoms, and management. MovDisord, 2006, 21(6): 737–745
[17] Chaudhuri KR. Nocturnal symptom complex in PD and its management. Neurology, 2003, 61(Supp 3):S17-S23
[18] Kumar S, Bhatia M, Behari M. Sleep disorders in Parkinson’s disease. Movement Disorders, 2002, 17(4):775-781
[19]毛成洁,戴永萍,刘春风.早期帕金森患者睡眠障碍的相关分析.江苏医学,2007,33(9):897-899
[20]何远宏,朱迎慧,刘柳,王鹏.帕金森病患者睡眠障碍临床分析.中国实用神经疾病杂志,2008,11(10):29-30
[21] Mathias CJ. Cardiovascular autonomic function in Parkinsonian patients . Clin Neurosci,1998, 5 :153-166
[22] Haehnet A, Boesveldt s, Berendse HW, Mackay-Sim A, Fleischmann J, Silburn PA, Johnston AN, Mellick GD, Herting B, Reichmann H, Hummel T. Prevalence of smell loss in Parkinson’s disease: a multicenter study. Parkinsonism Relat Disord, 2009, 15(7):490-494
[23] Scherder J, Sergeant, Swaab DF. Pain processing in dementia and its relation to neuropathology. Lancet, 2003, 2(11): 677-686
[1] K Chaudhuri, M Buxton-Thomas, V Dhawan, R Peng, C Meilak, D Brooks. Long duration asymmetrical postural tremor is likely to predict development of Parkinson’s disease and not essential tremor: clinical follow up study of 13 cases. Neurol Neurosurgery Psychiatry, 2005, 76(1):115-117
[2] Polymeropoulos MH, Lavedan C, Leroy E, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science, 1997, 276(5321):2045-2047
[3] Kruger R,Kuhn W, Muller T, Woitalla D, Graeber M, K?sel S, Przuntek H, Epplen JT, Sch?ls L, Riess O. Ala30Pro mutation in the gene encoding alpha—synuclein in Parkinson’s disease. Nat Genet, 1998, 18(2): 106-108
[4] Zarranz TJ, Alergre J, Go’mez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atarés B, Llorens V, Gomez Tortosa E, del Ser T, Mu?oz DG, de Yebenes JG. New mutation, E46K, ofα-synuclein causes Parkinson and Lewy body dementia. Ann Neurol, 2004, 55(2): 164-173
[5] Polymeropoulos MH, Higgins JJ, Golbe LI, Johnson WG, Ide SE, Di IG, Sanges G, Stenroos ES, Pho LT, Schaffer AA, Lazzarini AM, Nussbaum RL, Duvoisin RC. Mapping of a gene for Parkinson’s disease to chromosome 4q21–q23. Science, 1996, 274(5290):1197-1199
[6] Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di IG, Golbe LI, Nussbaum RL. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science, 1997, 276(5321): 2045-2047
[7] Miller DW, Hague SM, Clarimon J, Baptista M, Gwinn-Hardy K, Cookson MR, Singleton AB.α-synuclein in b1ood and brain from familial Parkinson’s disease with SNCA locus triplication. Neurology, 2004, 62(10): 1835-1838
[8] Williams-Gray CH,Goris A,Foltynie T, Brown J, Maranian M, Walton A, Compston DA, Sawcer SJ, Barker RA. No alterations inα-synuclein gene dosage observed in sporadic Parkinson’s disease. Mov Disord, 2006, 21(5): 731-732
[9] Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, Kawaguchi T, Tsunoda T, Watanabe M, Takeda A, Tomiyama H, Nakashima K, Hasegawa K, Obata F, Yoshikawa T, Kawakami H, Sakoda S, Yamamoto M, Hattori N, Murata M, Nakamura Y, Toda T. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease, Nat Genet, 2009 ,41(12):1303-1307
[10] Wang M, Hattori N, Matsumine H, Kobayashi T, Yoshino H, Morioka A, Kitada T, Asakawa S, Minoshima S, Shimizu N, Mizuno Y. Polymorphism in the parkin gene in sporadic Parkinson’s diseases. Ann Neurol, 1999, 45(5):655-658
[11] Kitada T,Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature, 1998, 392(6676): 605-608
[12] Lucking CB, Durr A, Bonifati V, Vaughan J, De Michele G, Gasser T, Harhangi BS, Meco G, Denèfle P, Wood NW, Agid Y, Brice A. Association between early-onset Parkinson's disease and mutations in the parkin gene. N Engl J Med 2000; 342(21):1560-1567
[13] Periquet M, Latouche M, Lohmann E, Rawal N, De Michele G, Ricard S, Teive H, Fraix V, Vidailhet M, Nicholl D, Barone P, Wood NW, Raskin S, Deleuze JF, Agid Y, Dürr A, Brice A. Parkin mutations are frequent inpatients with isolated early-onset parkinsonism. Brain, 2003, 126(pt 6):1271–1278
[14] Mata IF, Lockhart PJ, Farrer MJ. Parkin genetics: one model for Parkinson's disease. Hum Mol Genet, 2004, 13(spec no 1):R12-R133
[15] Farrer MJ. Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet, 2006, 7(4): 306-318
[16]宁玉萍,徐严明,王玉凯,刘焯霖. Parkin基因R/W366及V/L380多态性与散发性帕金森病.中国神经精神疾病杂志, 2002, 28(1):17-19
[17]宁玉萍,刘焯霖,徐严明,王玉凯.Parkin基因S/N167多态性与散发性帕金森病关联研究.中华医学遗传学杂志, 2002, 19(6):513-514
[18] Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, Harta G, Brownstein MJ, Jonnalagada S, Chernova T, Dehejia A, Lavedan C, Gasser T, Steinbach PJ, Wilkinson KD, Polymeropoulos MH. The ubiquitin pathway in Parkinson’s disease. Nature, 1998, 395(6701): 451-452
[19] Carmine A, Westerlund M, Bergman O, Nissbrandt H, Lind C, Sydow O, Galter D. S18Y in ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) associated with decreased risk of Parkinson’s diseases in Sweden. Parkinsonism Relat Disord, 2007, 13(5):295-298
[20] Shi Q, Tao E. An Ile93 Met substitution in the UCH-L1 gene is not a diseases-causing mutation for idiopathic Parkinson’s diseases. Chinese Med J, 2003, 116(2): 312-313
[21] Zhang J, Hattori N, Giladi N, Mizuno Y. Failure to find mutations in ubiquitin carboxy-terminal hydrolase L1gene in familial Parkinson’s diseases. Parkinsonism Relat Disord, 2000, 6(4):199-200
[22] Lincoln S, Vaughan J, Wood N, Baker M, Adamson J, Gwinn-Hardy K, Lynch T, Hardy J, Farrer M. Low frequency of pathogenic mutations in the ubiquitin carboxyterminal hydrolase gene in familial Parkinson’s diseases. Neuroreport, 1999, 10(2):427-429
[23] Levecque C, Destee A, Mouroux V, Becquet E, Defebvre L, Amouyel P, Chartier-Harlin MC. No genetic association of the ubiquitincarboxy-terminal hydrolase-L1 gene S18Y polymorphism with familial Parkinson’s diseases. J Neural Transm, 2001, 108(8-9):979-984
[24]郭纪锋,唐北沙,张玉虎,夏昆,蔡芳,潘乾,沈璐,江泓,赵国华,严新翔,曹立.常染色体隐性遗传性早发型帕金森综合征DJ-1基因突变研究.中华医学遗传学杂志, 2005, 22(6):641-643
[25] Valente EM, Bentivoglio AR,Dixon PH, Ferraris A, Ialongo T, Frontali M, Albanese A, Wood NW. Localization of a novel Iocus for autosomal recessive early-onset parkinsonism, PARK6,on human chromosome lp35-p36.Am J Hum Genet,200l,68(4):895-900
[26] Valente EM, Abou-sleiman PM,CaputoV, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, González-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW. Hereditary early-onset Parkinson’s disease eaused by mutations in PINKI. Science, 2004, 304(5674):1158-1160
[27]王枫,陈彪,冯秀丽,邹海强,马敬红,董秀敏,李勇杰. PINKI基因多态位点IVS5-5G>A可能增加中国人晚发性帕金森病的发病风险.中华医学遗传学杂志, 2007, 2(3):305-309
[28]张玉虎,唐北沙,郭纪锋,夏昆,许波,蔡芳,邓汉湘,严新翔,陈涛,曹立,潘乾,龙志高.常染色体隐性遗传早发性帕金森综合征6型PINKI基因的突变分析,中华医学杂志, 2005, 85(22):1538-1541
[29] Alcalay RN, Mejia-Santana H, Tang MX, Rosado L, Verbitsky M, Kisselev S, Ross BM, Louis ED, Comella CL, Colcher A, Jennings D, Nance MA, Bressman S, Scott WK, Tanner C, Mickel SF, Andrews HF, Waters CH, Fahn S, Cote LJ, Frucht SJ, Ford B, Rezak M, Novak K, Friedman JH, Pfeiffer R, Marsh L, Hiner B, Siderowf A, Caccappolo E, Ottman R, Clark LN, Marder KS. Motor phenotype of LRRK2 G2019S carriers in early-onset Parkinson disease. Arch Neurol, 2009, 66(12): 1517-1522
[30] Chan DK, Ng PW, Mok V, Yeung J, Fang ZM, Clarke R, Leung E, Wong L. LRRK2 Gly2385Arg mutation and clinical features in a Chinese population with early-onset Parkinson's disease compared to late-onset patients. J Neural Transm, 2008, 115(9):1275-7
[31] Yu L, Hu F, Zou X, Jiang Y, Liu Y, He X, Xi J, Liu L, Liu Z, He L, Xu Y. LRRK2 R1628P contributes to Parkinson's disease susceptibility in Chinese Han populations from mainland China. Brain Res, 2009, 1296:113-116
[32] Ross OA, Wu YR, Lee MC, Funayama M, Chen ML, Soto AI, Mata IF, Lee-Chen GJ, Chen CM, Tang M, Zhao Y, Hattori N, Farrer MJ, Tan EK, Wu RM. Analysis of Lrrk2 R1628P as 8 risk factor for Parkinsen’s diseases.Ann Neurol,2008, 64(1): 88 - 92
[33] Lu CS, Wu-Chou YH, Van Doeselaar M, Simons EJ, Chang HC, Breedveld GJ, Di Fonzo A, Chen RS, Weng YH, Lai SC, Oostra BA, Bonifati V.The LRRK2 Arg1628Pro variant is a risk factor for Parkimon’s diseases in the Chinese population. Neurogenetics, 2008, 9(4): 27l-276
[34] Simón-Sánchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, Paisan-Ruiz C, Lichtner P, Scholz SW, Hernandez DG, Krüger R, Federoff M, Klein C, Goate A, Perlmutter J, Bonin M, Nalls MA, Illig T, Gieger C, Houlden H, Steffens M, Okun MS, Racette BA, Cookson MR, Foote KD, Fernandez HH, Traynor BJ, Schreiber S, Arepalli S, Zonozi R, Gwinn K, van der Brug M, Lopez G, Chanock SJ, Schatzkin A, Park Y, Hollenbeck A, Gao J, Huang X, Wood NW, Lorenz D, Deuschl G, Chen H, Riess O, Hardy JA, Singleton AB, Gasser T. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nature Genetics, 2009, 41 (12): 1308-1312
[35] Kolisek M, Launay P, Beck A, Sponder G, Serafini N, Brenkus M, Froschauer EM, Martens H, Fleig A, Schweigel M. SLC41Al is a novel mammalian Mg2+ carrier. J Biol Chem, 2008, 283(23):16235-16247
[36] Hermosura MC, Nayakanti H, Domvkov MV, Calderon FR, Ryazanov AG, Haymer DS, Garruto RM. A TRPM7 variant shows altered sensitivity tomagnesium that may contribute to the pathogenesis of two Guamanian neurodegenerative disorders. Proc Natl Acad sci USA, 2005, 102(32): 11510-11515
[37] HeliP-Wooley A, Thoene JG. Sucrose-induced vacuolation results in increased expression of cholesterol biosynthesis and lysosomal genes.Exp Cell Res, 2004, 292(1):89-100
[38] Arianna Tucci, Mike A Nalls, Henry Houlden, Tamas Revesz, Andrew B Singleton, Nicholas W Wood, John Hardy, Coro Paisán-Ruiz.Genetic variability at the PARK16 locus. Eur J Hum Genet, 2010 18(12): 1356-1359
[39] Mata IF, Yearout D, Alvarez V, Coto E, de Mena L, Ribacoba R, Lorenzo-Betancor O, Samaranch L, Pastor P, Cervantes S, Infante J, Garcia-Gorostiaga I, Sierra M, Combarros O, Snapinn KW, Edwards KL, Zabetian CP. Replication of MAPT and SNCA, but not PARK16-18, as Susceptibility Genes for Parkinson’s Disease. Mov Disord, 2011, 26(5): 819-823
[40] Chang XL, Mao XY, Li HH, Zhang JH, Li NN, Burgunder JM, Peng R, Tan EK. Association of GWAS loci with PD in China. Am J Med Genet B Neuropsychiatr Genet, 2011, 156B (3):334-339
[1] Welsh M. Parkinson's disease and quality of life: issues and challenges beyond motor symptoms. Neurol Clin, 2004, 22(3 Suppl):S141-148
[2] Tolosa E, Compta Y, Gaig C. The premotor phase of Parkinson's disease. Parkinsonism Relat Disord, 2007, 13(Suppl): S2-7
[3] Chaudhuri KR. Nocturnal symptom complex in PD and its management. Neurology, 2003, 61(Supp 3):S17-S23
[4] Kumar S, Bhatia M, Behari M. Sleep disorders in Parkinson’s disease. Movement Disorders, 2002, 17(4):775-781
[5]毛成洁,戴永萍,刘春风.早期帕金森患者睡眠障碍的相关分析.江苏医学,2007,33(9):897-899
[6]何远宏,朱迎慧,刘柳,王鹏.帕金森病患者睡眠障碍临床分析.中国实用神经疾病杂志,2008,11(10):29-30
[7] Mondragon-Rezola E, Arratibel-Echarren I, Ruiz-Martinez J, Martí-MassóJF. Sleep disorders in Parkinson’s disease: insomnia and sleep fragmentation. daytime hypersomnia, alterations to the circadian rhythm and sleep apnea syndrome. Rev Neurol, 2010, 50(Suppl 2): S21-26
[8] Meral H, Aydemir T, Ozer F, Ozturk O, Ozben S, Erol C, Cetin S, Hanoglu L, Ozkayran T, Yilsen M. Relationship between visual hallucinations and REM sleep behavior disorder in patients with Porkinson’s disease. Clinical Neurology and Neurosurgery, 2007, 109(10):862-867
[9] Abbott RD, Ross GW, White LR, Tanner CM, Masaki KH, Nelson JS, Curb JD, Petrovitch H. Excessive daytime sleepiness and subsequent development of Parkinson disease. Neurology, 2005, 65(9):1442-1446
[10] Ondo WG,Perkins T,Swick T, Hull KL Jr, Jimenez JE, Garris TS, Pardi D. Sodium oxybate for excessive daytime sleepiness in Parkinson disease:a open—label polysomnorgraphic stydy.Arch Neurol,2008,65:1337-1340
[11] Happe S, Pirker W, Kloseh G, Sauter C, Zeitlhofer J. Periodic leg movements in patients with Parkinson’s disease are associated with reduced striatal dopamine transporter binding. J Neurol, 2003, 250 (1):83-86
[12]中华医学会神经病学分会帕金森病及运动障碍学组.不宁腿综合症的诊断标准及治疗指南.中华神经科杂志,2009,42(10):709-711
[13] Ferreira JJ, Galitzky M, Montastruc JL, Rascol O. Sleep attacks and Parkimon’s disease treatment. Lancet, 2000, 355(9212): 1333-1334
[14] Hirayama M, Nakflmura T, Hori N, Koike Y, Sobue G. The video images of sleep attacks in Parkinson’s disease. Mov Disorder, 2008, 23(2):288-290
[15] Chaudhuri KR, Yates L, Martinez-Martin P. The non-motor symptom complex of Parkinson’s disease: a comprehensive assessment is essential. Curt Neural Neurosci Rep, 2005, 5(4): 275-283
[16] Chaudhuri KR, Healy DG, Sehapira AH. Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol, 2006, 5(3): 235-245
[17] Shulman LM, Taback RL, Rabinstein AA, Weiner WJ. Non-recognition of depression and other non-motor symptoms in Parkinson’s diseases. Parkinsonism Relat Disord, 2002, 8(3):193-197
[18] Ziemssen T, Reichmann H. Non-motor dysfunction in Parkinson's disease. Parkinsonism Relat Disord, 2007, 13(6):323-332
[19] Fleminger S. Left-sided Parkinson's disease is associated with greater anxiety and depression. Psychol Med, 1991, 21(3): 629-638
[20]赵康仁,吴颉言,朱朝阳,韩泰然,马震祥,俞俊洪.帕金森病患者的抑郁及其相关因素.临床神经病学杂志, 2001, 14(1): 33-34
[21] Aarland D, Larsen JP, Goek Lim N, Janvin C, Karlsen K, Tandberg E, Cummings JL. Range of neuropsychiatric disturbances in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry, 1999, 67(4):492-496
[22] Kitsch-Darrow L, Fernandes HF, Marsiske M, Okun MS, Bowers D. Dissociatingapathy and depression in Parkinson disease. Neurology, 2006, 67(7): 33-38
[23] Padala PR, Petty F, Bhatia SC. Methylphenidate may treat apathy independent of depression. Ann Pharmacother, 2005, 39(11): 1947-1949
[24] Aarsland D, Br?nnick K, Larsen JP, Tysnes OB, Alves G. Cognitive impairment in incident, untreated Parkinson disease: the Norwegian ParkWest study. Neurology, 2009, 72(13):1121-1126
[25] Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG. The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord, 2008, 23(6):837-844
[26] Barnes J, David AS.Visual hallucinations in Parkinson’s disease;a review and henomenological survey. Neurol Neurosurg Psychmt, 2001, 70(6): 727-733
[27] Mathias CJ. Cardiovascular autonomic function in Parkinsonian patients . Clin Neurosci,1998, 5 :153-166
[28] Singer W, Opfer-Gejrking TL, Mcphee BR, Hilz MJ, Bharucha AE, Low PA. Acetylcholinesterase Inhibition: a novel approach in the treatment of neurogenic orthostatic Hypotension. J Ncorosurg Psychiatry, 2003,74(9): 1294-1298
[29] Wood LD, Neumiller JJ, Setter SM, Dobbins EK. Clinical review of treatment options for select nonmotor symptoms of Parkinson's disease. Am J Geriatr Pharmacother, 2010, 8(4):294-315
[30] Sakakibara R, Shinotoh H, Uchiyama T, Sakuma M, Kashiwado M, Yoshiyama M, Hattori T. Questionnaire based assessment of Pelvic organ dysfunction in Parkinson's disease. Auton Neurosci, 2001, 92(1-2):76-85
[31] Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD, Grandinetti A, Blanchette PL, Popper JS, Ross GW. Frequency of bowel movements and the future risk of Parkinson's disease. Neurology, 2001, 57(3): 456-462
[32] Zangaglia R, Martignoni E, Glorioso M, Ossola M, Riboldazzi G, Calandrella D, Brunetti G, Pacchetti C. Macrogol for the treatment ofconstipation in Parkinson’s disease. A randomized placebo-controlled study, Mov Disord, 2007, 22(9):1239-1244
[33] Winge K, Fowler CJ. Bladder dysfunction in Parkinsonism: mechanisms, prevalence, symptoms, and management. MovDisord, 2006, 21(6): 737–745
[34] Pfeiffer RF. Gastrointestinal, Urological, and Sexual Dysfunctionin Parkinson’s disease. Mov Disord, 2010, 25(Suppl 1):S94-97
[35] Kulaksizoglu H, Parman Y. Use of botulinim toxin-A for the treatment of overactive bladder symptoms in patients with Parkinsons's disease. Parkinsonism Relat Disord, 2010, 16(8):531-4
[36] Wermuth L, Stenager E. Sexual problems in young patients with Parkinson’s disease. Acta Neurol Scand, 1995, 91(6): 453-455
[37] Vázquez-Sáánchez F, Rodríguez-Martínez E, Arés-Luque A. Urinary disorders, sexual dysfunction and hypersexuality in Parkinson's disease, Rev Neurol, 2010, 50(Suppl 2):S27-31
[38] [Safarinejad MR, Taghva A, Shekarchi B, Safarinejad Sh. Safety and efficacy of sildenafil citrate in the treatment of Parkinson-emergent erectile dysfunction: a double-blind, placebo-controlled, randomized study. Int J Impot Res, 2010, 22(5):325-35
[39] Haehnet A, Boesveldt s, Berendse HW, Mackay-Sim A, Fleischmann J, Silburn PA, Johnston AN, Mellick GD, Herting B, Reichmann H, Hummel T. Prevalence of smell loss in Parkinson’s disease: a multicenter study. Parkinsonism Relat Disord, 2009, 15(7):490-494
[40] Ponsen MM, Stoffers D, Booij J, van Eck-Smit BL, Wolters ECh, Berendse HW. Idiopathic hyposmia as a preclinical Sign of Parkinson’s disease. Ann Neurol, 2004, 56(2):173-181
[41] Baba T, Takeda A, Kikuchi A, Nishio Y, Hosokai Y, Hirayama K, Hasegawa T, Sugeno N, Suzuki K, Mori E, Takahashi S, Fukuda H, Itoyama Y. Association of olfactory dysfunction and brain Metabolism in Parkinson's disease. Mov Disord, 2011, 26(4):621-8
[42] Djaldetti R, Shifrin A, Rogowski Z, Sprecher E, Melamed E, Yarnitsky D. Quantitative measurement of pain sensation in patients with Parkinson disease. Neurology, 2004, 62(12): 2171-2175
[43] Scherder J, Sergeant, Swaab DF. Pain processing in dementia and its relation to neuropathology. Lancet, 2003, 2(11): 677-686
[44] Chang Jing-Yu. Brain stimulation for neurologicaland psychiatric disorders, current status and future direction. Journal of Pharmacology & Experimental Therapeutics, 2004, 309(1): 1-7