烟雾病易感因素研究进展
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摘要
烟雾病是一种进行性脑血管病,具有种族易感性、家族聚集性特征。烟雾血管表现出内膜增厚,中膜变薄,内弹力板迂曲,伴有淋巴细胞浸润等特征性病理表现,其病因及发病机制尚未完全阐明,目前认为该病与内皮细胞、平滑肌细胞、细胞外基质的异常代谢和炎性反应相关。作者从遗传因素、机体内环境因素、免疫因素3个层面,阐述内皮细胞易感基因环指蛋白213、平滑肌细胞易感基因、细胞外基质代谢相关基因、血管生成相关因子以及免疫易感基因在烟雾病的发生、发展中所起的作用。
Moyamoya disease( MMD) is a progressive cerebrovascular disease with characteristics of ethnic susceptibility and familial aggregation. The pathological changes of stenosed vessels in MMD include intima thickening,tunica media thinning,irregular undulation of the internal elastic laminae and lymphocytic infiltration. The etiology and pathogenesis are not completely clarified. It is presently thought that this disease is related to endothelial cells,smooth muscle cells,abnormal metabolism of extracellular matrix and inflammatory responses. This review will discuss,from genetic,cellular environmental and immunological perspectives,the specific roles of several genes in the development of MMD,including endothelial cell susceptibility gene ring finger protein 213,smooth muscle cell susceptibility genes,extracellular matrix genes,angiogenesis factors and immune-related genes.
Moyamoya disease( MMD) is a progressive cerebrovascular disease with characteristics of ethnic susceptibility and familial aggregation. The pathological changes of stenosed vessels in MMD include intima thickening,tunica media thinning,irregular undulation of the internal elastic laminae and lymphocytic infiltration. The etiology and pathogenesis are not completely clarified. It is presently thought that this disease is related to endothelial cells,smooth muscle cells,abnormal metabolism of extracellular matrix and inflammatory responses. This review will discuss,from genetic,cellular environmental and immunological perspectives,the specific roles of several genes in the development of MMD,including endothelial cell susceptibility gene ring finger protein 213,smooth muscle cell susceptibility genes,extracellular matrix genes,angiogenesis factors and immune-related genes.
引文
[1]Kim JS.Moyamoya disease:epidemiology,clinical features,and diagnosis[J].J Stroke,2016,18(1):2-11.
[2]Krischek B,Kasuya H,Khan N,et al.Genetic and clinical characteristics of Moyamoya disease in Europeans[J].Acta Neurochir Suppl,2011,112:31-34.
[3]Rao M,Zhang H,Liu Q,et al.Clinical and experimental pathology of Moyamoya disease[J].Chin Med J(Engl),2003,116(12):1845-1849.
[4]Yamauchi T,Tada M,Houkin K,et al.Linkage of familial Moyamoya disease(spontaneous occlusion of the circle of Willis)to chromosome 17q25[J].Stroke,2000,31(4):930-935.
[5]Nanba R,Tada M,Kuroda S,et al.Sequence analysis and bioinformatics analysis of chromosome 17q25 in familial Moyamoya disease[J].Childs Nerv Syst,2005,21(1):62-68.
[6]Mineharu Y,Takenaka K,Yamakawa H,et al.Inheritance pattern of familial Moyamoya disease:autosomal dominant mode and genomic imprinting[J].J Neurol Neurosurg Psychiatry,2006,77(9):1025-1029.
[7]Mineharu Y,Liu W,Inoue K,et al.Autosomal dominant Moyamoya disease maps to chromosome 17q25.3.[J].Neurology,2008,70(24 Pt 2):2357-2363.
[8]Liu W,Hashikata H,Inoue K,et al.A rare Asian founder polymorphism of Raptor may explain the high prevalence of Moyamoya disease among East Asians and its low prevalence among Caucasians[J].Environ Health Prev Med,2010,15(2):94-104.
[9]Liu W,Morito D,Takashima S,et al.Identification of RNF213 as a susceptibility gene for Moyamoya disease and its possible role in vascular development[J].PLo SOne,2011,6(7):e22542.
[10]Liu W,Hitomi T,Kobayashi H,et al.Distribution of M oyam oya d isease su scep tib ility p olym orp h ism p.R4 8 1 0 K in RNF213 in East and Southeast Asian populations[J].Neurol Med Chir(Tokyo),2012,52(5):299-303.
[11]Kamada F,Aoki Y,Narisawa A,et al.A genome-wide association study identifies RNF213 as the first Moyamoya disease gene[J].J Hum Genet,2011,56(1):34-40.
[12]Wu Z,Jiang H,Zhang L,et al.Molecular analysis of RNF213 gene for Moyamoya disease in the Chinese Han population[J].PLo S One,2012,7(10):e48179.
[13]Akagawa H,Mukawa M,Nariai T,et al.Novel and recurrent RNF213 variants in Japanese pediatric patients with Moyamoya disease[J].Hum Genome Var,2018,5:17060.
[14]Kobayashi H,Brozman M,KyselováK,et al.RNF213 rare variants in Slovakian and Czech Moyamoya disease patients[J].PLo S One,2016,11(10):e0164759.
[15]Morito D,Nishikawa K,Hoseki J,et al.Moyamoya disease-associated protein mysterin/RNF213 is a novel AAA+ATPase,which dynamically changes its oligomeric state[J].Sci Rep,2014,4:4442.
[16]Kobayashi H,Matsuda Y,Hitomi T,et al.Biochemical and functional characterization of RNF213(mysterin)R4810K,a susceptibility mutation of Moyamoya disease,in angiogenesis in vitro and in vivo[J].J Am Heart Assoc,2015,4:e002146.
[17]Hamauchi S,Shichinohe H,Uchino H,et al.Cellular functions and gene and protein expression profiles in endothelial cells derived from Moyamoya disease-specific i PS cells[J].PLo S One,2016,11(9):e0163561.
[18]Ohkubo K,Sakai Y,Inoue H,et al.Moyamoya disease susceptibility gene RNF2 1 3 links inflammatory and angiogenic signals in endothelial cells[J].Sci Rep,2015,5:13191.
[19]Hitomi T,Habu T,Kobayashi H,et al.The Moyamoya disease susceptibility variant RNF213 R4810K(rs112735431)induces genomic instability by mitotic abnormality[J].Biochem Biophys Res Commun,2013,439(4):419-426.
[20]Bang OY,Chung JW,Kim SJ,et al.Caveolin-1,ring finger protein 2 1 3,and endothelial function in Moyamoya disease[J].Int J Stroke.2016,11(9):999-1008.
[21]Bang OY,Fujimura M,Kim SK,et al.The pathophysiology of Moyamoya disease:an update[J].J Stroke,2016,18(1):12-20.
[22]Liu J,Wang XB,Park DS,et al.Caveolin-1 expression enhances endothelial capillary tubule formation[J].J Biol Chem,2002,277(12):10661-10668.
[23]Miyatake S,Touho H,Miyake N,et al.Sibling cases of Moyamoya disease having homozygous and heterozygous c.14576G>A variant in RNF213 showed varying clinical course and severity[J].J Hum Genet,2012,57(12):804-806.
[24]Koizumi A,Kobayashi H,Hitomi T,et al.A new horizon of Moyamoya disease and associated health risks explored through RNF213[J].Environ Health Prev Med,2016,21(2):55-70.
[25]Ma YG,Zhang Q,Yu LB,et al.Role of ring finger protein213 in Moyamoya disease[J].Chin Med J(Engl),2016,129(20):2497-2501.
[26]Kanoke A,Fujimura M,Niizuma K,et al.Temporal profile of the vascular anatomy evaluated by 9.4-tesla magnetic resonance angiography and histological analysis in mice with the R4859K mutation of RNF213,the susceptibility gene for moyamoya disease[J].Brain Res,2015,1624:497-505.
[27]Ito A,Fujimura M,Niizuma K,et al.Enhanced post-ischemic angiogenesis in mice lacking RNF213;a susceptibility gene for moyamoya disease[J].Brain Res,2015,1594:310-320.
[28]Sato-Maeda M,Fujimura M,Kanoke A,et al.Transient middle cerebral artery occlusion in mice induces neuronal expression of RNF213,a susceptibility gene for moyamoya disease[J].Brain Res,2015,1630:50-55.
[29]Morimoto T,Enmi JI,Hattori Y,et al.Dysregulation of RNF213 promotes cerebral hypoperfusion[J].Sci Rep,2018,8(1):3607.
[30]Kotani Y,Morito D,Sakata K,et al.Alternative exon skipping biases substrate preference of the deubiquitylase USP15 for mysterin RNF213,the Moyamoya disease susceptibility factor[J].Sci Rep,2017,7:44293.
[31]Guo DC,Papke CL,Tran-Fadulu V,et al.Mutations in smooth muscle alpha-actin(ACTA2)cause coronary artery disease,stroke,and Moyamoya disease,along with thoracic aortic disease[J].Am J Hum Genet,2009,84(5):617-627.
[32]Richer J,Milewicz DM,Gow R,et al.R179H mutation in ACTA2 expanding the phenotype to include prune‐belly sequence and skin manifestations[J].Am J Med Genet A,2012,158A(3):664-668.
[33]Hu FY,Zheng HB,Xu YM,et al.ACTA2 is not a major genetic risk gene for Chinese patients with moyamoya disease[J].Int J Stroke,2013,8(7):E43.
[34]Cunningham KS,Gotlieb AI.The role of shear stress in the pathogenesis of atherosclerosis[J].Lab Invest,2005,85(1):9-23.
[35]Wallace S,Guo DC,Regalado E,et al.Disrupted nitric oxide signaling due to GUCY1 A3 mutations increases risk for Moyamoya disease,achalasia and hypertension[J].Clin Genet,2016,90(4):351-360.
[36]Herve D,Philippi A,Belbouab R,et al.Loss ofα1β1soluble guanylate cyclase,the major nitric oxide receptor,leads to Moyamoya and achalasia[J].Am J Hum Genet,2014,94(3):385-394.
[37]Seeger F,Quintyn R,Tanimoto A,et al.Interfacial residues promote an optimal alignment of the catalytic center in human soluble guanylate cyclase:heterodimerization is required but not sufficient for activity[J].Biochemistry,2014,53(13):2153-2165.
[38]Li H,Zhang ZS,Liu W,et al.Association of a functional polymorphism in the MMP-3 gene with moyamoya disease in the Chinese Han population[J].Cerebrovasc Dis,2010,30(6):618-625.
[39]Park YS,Jeon YJ,Kim HS,et al.The GC+CC genotype at position-418 in TIMP-2 promoter and the-157 5GA/-1306 CC genotype in MMP-2 is genetic predisposing factors for prevalence of Moyamoya disease[J].BMCNeurol,2014,14:180.
[40]Kang HS,Kim JH,Phi JH,et al.Plasma matrix metalloproteinases,cytokines and angiogenic factors in moyamoya disease[J].J Neurol Neurosurg Psychiatry,2010,81:673-678.
[41]Ma J,You C.Association between matrix metalloproteinase-3gene polymorphism and Moyamoya disease[J].J Clin Neurosci,2015,22(3):479-482.
[42]汤荡,汪成,徐蔚,等.基质金属蛋白酶-3基因单核苷酸多态性与中国汉族人群烟雾病的关系[J].广东医学,2015,36(11):1698-1700.
[43]张皆德.烟雾病患者血清中MMP-9及TIMP-1的表达及与颅内出血间关系研究[D].广西医科大学,2014.
[44]Bedini G,Blecharz KG,Nava S,et al.Vasculogenic and angiogenic pathways in Moyamoya disease[J].Curr Med Chem,2016,23(4):315-345.
[45]Huang S,Guo ZN,Shi M,et al.Etiology and pathogenesis of Moyamoya disease:an update on disease prevalence[J].Int J Stroke,2017,12(3):246-253.
[46]Patel-Hett S,D'Amore PA.Signal transduction in vasculogenesis and developmental angiogenesis[J].Int JDev Biol,2011,55(4/5):353-363.
[47]Yoshimoto T,Houkin K,Takahashi A,et al.Angiogenic factors in Moyamoya disease[J].Stroke,1996,27(12):2160-2165.
[48]Zou D,Zhao J,Zhang D,et al.Enhancement expression of b FGF in Chinense patients with Moyamoya disease[J].Biomed.Environ Sci,2011,24(1):74-80.
[49]Chanakira A,Dutta R,Charboneau R,et al.Hypoxia differentially regulates arterial and venous smooth muscle cell proliferation via PDGFR-βand VEGFR-2 expression[J].Am J Physiol Heart Circ Physiol,2012,302(5):H1173-H1184.
[50]Weinberg DG,Arnaout OM,Rahme RJ,et al.Moyamoya disease:a review of histopathology,biochemistry,and genetics[J].Neurosurg Focus,2011,30(6):E20.
[51]Rafat N,Beck GCh,Pe1a-Tapia PG,et al.Increased levels of circulating endothelial progenitor cells in patients with Moyamoya disease[J].Stroke,2009,40(2):432-438.
[52]Sigdel TK,Shoemaker LD,Chen R,et al.Immune response profiling identifies autoantibodies specific to Moyamoya patients[J].Orphanet J Rare Dis,2013,8:45.
[53]Hong SH,Wang KC,Kim SK,et al.Association of HLA-DR and-DQ genes with familial Moyamoya disease in Koreans[J].J Korean Neurosurg Soc,2009,46(6):558-563.
[54]陈赞,菅凤增,王伊鹏,等.烟雾病免疫相关基因研究[J].中国脑血管病杂志,2005,2(5):198-201.
[55]申伟,李劲松,李伟,等.免疫相关蛋白在烟雾病患者硬脑膜血管壁中的表达[J].中国脑血管病杂志,2013,10(4):174-177.
[2]Krischek B,Kasuya H,Khan N,et al.Genetic and clinical characteristics of Moyamoya disease in Europeans[J].Acta Neurochir Suppl,2011,112:31-34.
[3]Rao M,Zhang H,Liu Q,et al.Clinical and experimental pathology of Moyamoya disease[J].Chin Med J(Engl),2003,116(12):1845-1849.
[4]Yamauchi T,Tada M,Houkin K,et al.Linkage of familial Moyamoya disease(spontaneous occlusion of the circle of Willis)to chromosome 17q25[J].Stroke,2000,31(4):930-935.
[5]Nanba R,Tada M,Kuroda S,et al.Sequence analysis and bioinformatics analysis of chromosome 17q25 in familial Moyamoya disease[J].Childs Nerv Syst,2005,21(1):62-68.
[6]Mineharu Y,Takenaka K,Yamakawa H,et al.Inheritance pattern of familial Moyamoya disease:autosomal dominant mode and genomic imprinting[J].J Neurol Neurosurg Psychiatry,2006,77(9):1025-1029.
[7]Mineharu Y,Liu W,Inoue K,et al.Autosomal dominant Moyamoya disease maps to chromosome 17q25.3.[J].Neurology,2008,70(24 Pt 2):2357-2363.
[8]Liu W,Hashikata H,Inoue K,et al.A rare Asian founder polymorphism of Raptor may explain the high prevalence of Moyamoya disease among East Asians and its low prevalence among Caucasians[J].Environ Health Prev Med,2010,15(2):94-104.
[9]Liu W,Morito D,Takashima S,et al.Identification of RNF213 as a susceptibility gene for Moyamoya disease and its possible role in vascular development[J].PLo SOne,2011,6(7):e22542.
[10]Liu W,Hitomi T,Kobayashi H,et al.Distribution of M oyam oya d isease su scep tib ility p olym orp h ism p.R4 8 1 0 K in RNF213 in East and Southeast Asian populations[J].Neurol Med Chir(Tokyo),2012,52(5):299-303.
[11]Kamada F,Aoki Y,Narisawa A,et al.A genome-wide association study identifies RNF213 as the first Moyamoya disease gene[J].J Hum Genet,2011,56(1):34-40.
[12]Wu Z,Jiang H,Zhang L,et al.Molecular analysis of RNF213 gene for Moyamoya disease in the Chinese Han population[J].PLo S One,2012,7(10):e48179.
[13]Akagawa H,Mukawa M,Nariai T,et al.Novel and recurrent RNF213 variants in Japanese pediatric patients with Moyamoya disease[J].Hum Genome Var,2018,5:17060.
[14]Kobayashi H,Brozman M,KyselováK,et al.RNF213 rare variants in Slovakian and Czech Moyamoya disease patients[J].PLo S One,2016,11(10):e0164759.
[15]Morito D,Nishikawa K,Hoseki J,et al.Moyamoya disease-associated protein mysterin/RNF213 is a novel AAA+ATPase,which dynamically changes its oligomeric state[J].Sci Rep,2014,4:4442.
[16]Kobayashi H,Matsuda Y,Hitomi T,et al.Biochemical and functional characterization of RNF213(mysterin)R4810K,a susceptibility mutation of Moyamoya disease,in angiogenesis in vitro and in vivo[J].J Am Heart Assoc,2015,4:e002146.
[17]Hamauchi S,Shichinohe H,Uchino H,et al.Cellular functions and gene and protein expression profiles in endothelial cells derived from Moyamoya disease-specific i PS cells[J].PLo S One,2016,11(9):e0163561.
[18]Ohkubo K,Sakai Y,Inoue H,et al.Moyamoya disease susceptibility gene RNF2 1 3 links inflammatory and angiogenic signals in endothelial cells[J].Sci Rep,2015,5:13191.
[19]Hitomi T,Habu T,Kobayashi H,et al.The Moyamoya disease susceptibility variant RNF213 R4810K(rs112735431)induces genomic instability by mitotic abnormality[J].Biochem Biophys Res Commun,2013,439(4):419-426.
[20]Bang OY,Chung JW,Kim SJ,et al.Caveolin-1,ring finger protein 2 1 3,and endothelial function in Moyamoya disease[J].Int J Stroke.2016,11(9):999-1008.
[21]Bang OY,Fujimura M,Kim SK,et al.The pathophysiology of Moyamoya disease:an update[J].J Stroke,2016,18(1):12-20.
[22]Liu J,Wang XB,Park DS,et al.Caveolin-1 expression enhances endothelial capillary tubule formation[J].J Biol Chem,2002,277(12):10661-10668.
[23]Miyatake S,Touho H,Miyake N,et al.Sibling cases of Moyamoya disease having homozygous and heterozygous c.14576G>A variant in RNF213 showed varying clinical course and severity[J].J Hum Genet,2012,57(12):804-806.
[24]Koizumi A,Kobayashi H,Hitomi T,et al.A new horizon of Moyamoya disease and associated health risks explored through RNF213[J].Environ Health Prev Med,2016,21(2):55-70.
[25]Ma YG,Zhang Q,Yu LB,et al.Role of ring finger protein213 in Moyamoya disease[J].Chin Med J(Engl),2016,129(20):2497-2501.
[26]Kanoke A,Fujimura M,Niizuma K,et al.Temporal profile of the vascular anatomy evaluated by 9.4-tesla magnetic resonance angiography and histological analysis in mice with the R4859K mutation of RNF213,the susceptibility gene for moyamoya disease[J].Brain Res,2015,1624:497-505.
[27]Ito A,Fujimura M,Niizuma K,et al.Enhanced post-ischemic angiogenesis in mice lacking RNF213;a susceptibility gene for moyamoya disease[J].Brain Res,2015,1594:310-320.
[28]Sato-Maeda M,Fujimura M,Kanoke A,et al.Transient middle cerebral artery occlusion in mice induces neuronal expression of RNF213,a susceptibility gene for moyamoya disease[J].Brain Res,2015,1630:50-55.
[29]Morimoto T,Enmi JI,Hattori Y,et al.Dysregulation of RNF213 promotes cerebral hypoperfusion[J].Sci Rep,2018,8(1):3607.
[30]Kotani Y,Morito D,Sakata K,et al.Alternative exon skipping biases substrate preference of the deubiquitylase USP15 for mysterin RNF213,the Moyamoya disease susceptibility factor[J].Sci Rep,2017,7:44293.
[31]Guo DC,Papke CL,Tran-Fadulu V,et al.Mutations in smooth muscle alpha-actin(ACTA2)cause coronary artery disease,stroke,and Moyamoya disease,along with thoracic aortic disease[J].Am J Hum Genet,2009,84(5):617-627.
[32]Richer J,Milewicz DM,Gow R,et al.R179H mutation in ACTA2 expanding the phenotype to include prune‐belly sequence and skin manifestations[J].Am J Med Genet A,2012,158A(3):664-668.
[33]Hu FY,Zheng HB,Xu YM,et al.ACTA2 is not a major genetic risk gene for Chinese patients with moyamoya disease[J].Int J Stroke,2013,8(7):E43.
[34]Cunningham KS,Gotlieb AI.The role of shear stress in the pathogenesis of atherosclerosis[J].Lab Invest,2005,85(1):9-23.
[35]Wallace S,Guo DC,Regalado E,et al.Disrupted nitric oxide signaling due to GUCY1 A3 mutations increases risk for Moyamoya disease,achalasia and hypertension[J].Clin Genet,2016,90(4):351-360.
[36]Herve D,Philippi A,Belbouab R,et al.Loss ofα1β1soluble guanylate cyclase,the major nitric oxide receptor,leads to Moyamoya and achalasia[J].Am J Hum Genet,2014,94(3):385-394.
[37]Seeger F,Quintyn R,Tanimoto A,et al.Interfacial residues promote an optimal alignment of the catalytic center in human soluble guanylate cyclase:heterodimerization is required but not sufficient for activity[J].Biochemistry,2014,53(13):2153-2165.
[38]Li H,Zhang ZS,Liu W,et al.Association of a functional polymorphism in the MMP-3 gene with moyamoya disease in the Chinese Han population[J].Cerebrovasc Dis,2010,30(6):618-625.
[39]Park YS,Jeon YJ,Kim HS,et al.The GC+CC genotype at position-418 in TIMP-2 promoter and the-157 5GA/-1306 CC genotype in MMP-2 is genetic predisposing factors for prevalence of Moyamoya disease[J].BMCNeurol,2014,14:180.
[40]Kang HS,Kim JH,Phi JH,et al.Plasma matrix metalloproteinases,cytokines and angiogenic factors in moyamoya disease[J].J Neurol Neurosurg Psychiatry,2010,81:673-678.
[41]Ma J,You C.Association between matrix metalloproteinase-3gene polymorphism and Moyamoya disease[J].J Clin Neurosci,2015,22(3):479-482.
[42]汤荡,汪成,徐蔚,等.基质金属蛋白酶-3基因单核苷酸多态性与中国汉族人群烟雾病的关系[J].广东医学,2015,36(11):1698-1700.
[43]张皆德.烟雾病患者血清中MMP-9及TIMP-1的表达及与颅内出血间关系研究[D].广西医科大学,2014.
[44]Bedini G,Blecharz KG,Nava S,et al.Vasculogenic and angiogenic pathways in Moyamoya disease[J].Curr Med Chem,2016,23(4):315-345.
[45]Huang S,Guo ZN,Shi M,et al.Etiology and pathogenesis of Moyamoya disease:an update on disease prevalence[J].Int J Stroke,2017,12(3):246-253.
[46]Patel-Hett S,D'Amore PA.Signal transduction in vasculogenesis and developmental angiogenesis[J].Int JDev Biol,2011,55(4/5):353-363.
[47]Yoshimoto T,Houkin K,Takahashi A,et al.Angiogenic factors in Moyamoya disease[J].Stroke,1996,27(12):2160-2165.
[48]Zou D,Zhao J,Zhang D,et al.Enhancement expression of b FGF in Chinense patients with Moyamoya disease[J].Biomed.Environ Sci,2011,24(1):74-80.
[49]Chanakira A,Dutta R,Charboneau R,et al.Hypoxia differentially regulates arterial and venous smooth muscle cell proliferation via PDGFR-βand VEGFR-2 expression[J].Am J Physiol Heart Circ Physiol,2012,302(5):H1173-H1184.
[50]Weinberg DG,Arnaout OM,Rahme RJ,et al.Moyamoya disease:a review of histopathology,biochemistry,and genetics[J].Neurosurg Focus,2011,30(6):E20.
[51]Rafat N,Beck GCh,Pe1a-Tapia PG,et al.Increased levels of circulating endothelial progenitor cells in patients with Moyamoya disease[J].Stroke,2009,40(2):432-438.
[52]Sigdel TK,Shoemaker LD,Chen R,et al.Immune response profiling identifies autoantibodies specific to Moyamoya patients[J].Orphanet J Rare Dis,2013,8:45.
[53]Hong SH,Wang KC,Kim SK,et al.Association of HLA-DR and-DQ genes with familial Moyamoya disease in Koreans[J].J Korean Neurosurg Soc,2009,46(6):558-563.
[54]陈赞,菅凤增,王伊鹏,等.烟雾病免疫相关基因研究[J].中国脑血管病杂志,2005,2(5):198-201.
[55]申伟,李劲松,李伟,等.免疫相关蛋白在烟雾病患者硬脑膜血管壁中的表达[J].中国脑血管病杂志,2013,10(4):174-177.