Advances in moyamoya disease: pathogenesis, diagnosis, and therapeutic interventions

Abstract

Moyamoya disease (MMD) is a type of cerebrovascular disease characterized by occlusion of the distal end of the internal carotid artery and the formation of collateral blood vessels. Over the past 20 years, the landscape of research on MMD has significantly transformed. In this review, we provide insights into the pathogenesis, diagnosis, and therapeutic interventions in MMD. The development of high-throughput sequencing technology has expanded our understanding of genetic susceptibility, identifying MMD-related genes beyond RNF213, such as ACTA2, DIAPH1, HLA, and others. The genetic susceptibility of MMD to its pathological mechanism was summarized and discussed. Based on the second-hit theory, the influences of inflammation, immunity, and environmental factors on MMD were also appropriately summarized. Despite these advancements, revascularization surgery remains the primary treatment for MMD largely because of the lack of effective in vivo and in vitro models. In this study, 16 imaging diagnostic methods for MMD were summarized. Regarding therapeutic intervention, the influences of drugs, endovascular procedures, and revascularization surgeries on patients with MMD were discussed. Future research on the central MMD vascular abnormalities and peripheral circulating factors will provide a more comprehensive understanding of the pathogenic mechanisms of MMD.

Keywords

genetic susceptibility / immunity / moyamoya disease / pathogenesis / pathological angiogenesis

References

[1] Scott R, Smith ER. Moyamoya disease and moyamoya syndrome. N Engl J Med. 2009; 360(12): 1226-1237.

[2] Sato Y, Kazumata K, Nakatani E, Houkin K, Kanatani Y. Characteristics of moyamoya disease based on national registry data in Japan. Stroke. 2019; 50(8): 1973-1980.

[3] Kuriyama S, Kusaka Y, Fujimura M, et al. Prevalence and clinicoepidemiological features of moyamoya disease in Japan. Stroke. 2008; 39(1): 42-47.

[4] Wakai K, Tamakoshi A, Ikezaki K, et al. Epidemiological features of moyamoya disease in Japan: findings from a nationwide survey. Clin Neurol Neurosurg. 1997; 99(2): S1-S5.

[5] Bao X-Y, Wang Q-N, Zhang Y, et al. Epidemiology of moyamoya disease in China: single-center, population-based study. World Neurosurg. 2019; 122: e917-e923.

[6] Starke RM, Crowley RW, Maltenfort M, et al. Moyamoya disorder in the United States. Neurosurgery. 2012; 71(1): 93-99.

[7] Kainth D, Chaudhry SA, Kainth H, Suri FK, Qureshi AI. Epidemiological and clinical features of moyamoya disease in the USA. Neuroepidemiology. 2013; 40(4): 282-287.

[8] Ihara M, Yamamoto Y, Hattori Y, et al. Moyamoya disease: diagnosis and interventions. Lancet Neurol. 2022; 21(8): 747-758.

[9] Gonzalez NR, Amin-Hanjani S, Bang OY, et al. Adult moyamoya disease and syndrome: current perspectives and future directions: a scientific statement from the American Heart Association/American Stroke Association. Stroke. 2023; 54(10): e465-e479.

[10] Tokairin K, Hamauchi S, Ito M, et al. Vascular smooth muscle cell derived from IPS cell of moyamoya disease—comparative characterization with endothelial cell transcriptome. J Stroke Cerebrovasc Dis. 2020; 29(12): 105305.

[11] Blecharz KG, Frey D, Schenkel T, et al. Autocrine release of angiopoietin-2 mediates cerebrovascular disintegration in moyamoya disease. J Cereb Blood Flow Metab. 2017; 37(4): 1527-1539.

[12] Kuroda S, Fujimura M, Takahashi J, et al. Diagnostic criteria for moyamoya disease -2021 revised version. Neurol Med Chir (Tokyo). 2022; 62(7): 307-312.

[13] Fujimura M, Tominaga T, Kuroda S, et al. 2021 Japanese guidelines for the management of moyamoya disease: guidelines from the research committee on moyamoya disease and Japan Stroke Society. Neurol Med Chir. 2022; 62(4): 165-170.

[14] Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis; Health Labour Sciences Research Grant for Research on Measures for Infractable Diseases. Guidelines for diagnosis and treatment of moyamoya disease (spontaneous occlusion of the circle of Willis). Neurol Med Chir. 2012; 52(5): 245-266.

[15] Mukerji N, Cook DJ, Steinberg GK. Is local hypoperfusion the reason for transient neurological deficits after STA-MCA bypass for moyamoya disease?. J Neurosurg. 2015; 122(1): 90-94.

[16] Fujimura M, Mugikura S, Kaneta T, Shimizu H, Tominaga T. Incidence and risk factors for symptomatic cerebral hyperperfusion after superficial temporal artery-middle cerebral artery anastomosis in patients with moyamoya disease. Surg Neurol. 2009; 71(4): 442-447.

[17] Kaku Y, Iihara K, Nakajima N, et al. Cerebral blood flow and metabolism of hyperperfusion after cerebral revascularization in patients with moyamoya disease. J Cereb Blood Flow Metab. 2012; 32(11): 2066-2075.

[18] Lee SU, Oh CW, Kwon OK, et al. Surgical treatment of adult moyamoya disease. Curr Treat Options Neurol. 2018; 20(7): 20.

[19] Takekawa Y, Umezawa T, Ueno Y, Sawada T, Kobayashi M. Pathological and immunohistochemical findings of an autopsy case of adult moyamoya disease. Neuropathology. 2004; 24(3): 236-242. JNojotJSoN.

[20] Takagi Y, Kikuta K, Nozaki K. Hashimoto NJNm-c. Histological features of middle cerebral arteries from patients treated for moyamoya disease. Neurol Med Chir (Tokyo). 2007; 47(1): 1-4.

[21] Kuroda S, Houkin K. Moyamoya disease: current concepts and future perspectives. Lancet Neurol. 2008; 7(11): 1056-1066.

[22] Takagi Y, Hermanto Y, Takahashi JC, et al. Histopathological characteristics of distal middle cerebral artery in adult and pediatric patients with moyamoya disease. Neurol Med Chir (Tokyo). 2016; 56(6): 345-349.

[23] Takagi Y, Kikuta K, Sadamasa N, Nozaki K, Hashimoto NJN. Caspase-3-dependent apoptosis in middle cerebral arteries in patients with moyamoya disease. Neurosurgery. 2006; 59(4): 894-900. discussion 900–1.

[24] Lim M, Cheshier S, Steinberg GK. New vessel formation in the central nervous system during tumor growth, vascular malformations, and moyamoya. Curr Neurovasc Res. 2006; 3(3): 237-245.

[25] Oka K, Yamashita M, Sadoshima S, Tanaka K. Pathological anatomy, histology. Cerebral haemorrhage in moyamoya disease at autopsy. Virchows Arch A Pathol Anat Histol. 1981; 392(3): 247-261.

[26] Yamashita M, Tanaka K, Matsuo T, Yokoyama K, Fujii T, Sakamoto H. Cerebral dissecting aneurysms in patients with moyamoya disease. Report of two cases. J Neurosurg. 1983; 58(1): 120-125.

[27] Li B, Wang C-C, Zhao Z-Z, et al. A histological, ultrastructural and immunohistochemical study of superficial temporal arteries and middle meningeal arteries in moyamoya disease. Acta Pathol Japon. 1991; 41(7): 521-530.

[28] Dei Cas M, Carrozzini T, Pollaci G, et al. Plasma lipid profiling contributes to untangle the complexity of moyamoya arteriopathy. Int J Mol Sci. 2021; 22(24): 13410.

[29] Lu J, Wang J, Lin Z, et al. MMP-9 as a biomarker for predicting hemorrhagic strokes in moyamoya disease. Front Neurol. 2021; 12: 721118.

[30] He S, Zhang J, Liu Z, et al. Upregulated cytoskeletal proteins promote pathological angiogenesis in moyamoya disease. Stroke. 2023; 54(12): 3153-3164.

[31] Wang Z, Ji C, Han Q, Wang Z, Huang Y. Data-independent acquisition-based serum proteomic profiling of adult moyamoya disease patients reveals the potential pathogenesis of vascular changes. J Mol Neurosci. 2022; 72(12): 2473-2485.

[32] Kim S, Yoo J, Cho B, et al. Elevation of CRABP-I in the cerebrospinal fluid of patients with moyamoya disease. Stroke. 2003; 34(12): 2835-2841.

[33] Maruwaka M, Yoshikawa K, Okamoto S, et al. Biomarker research for moyamoya disease in cerebrospinal fluid using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. J Stroke Cerebrovasc Dis. 2015; 24(1): 104-111.

[34] He S, Liang J, Xue G, et al. RNA profiling of sEV (small extracellular vesicles)/exosomes reveals biomarkers and vascular endothelial dysplasia with moyamoya disease. J Cereb Blood Flow Metab. 2023; 43(7): 1194-1205.

[35] Wang X, Han C, Jia Y, Wang J, Ge W, Duan L. Proteomic profiling of exosomes from hemorrhagic moyamoya disease and dysfunction of mitochondria in endothelial cells. Stroke. 2021; 52(10): 3351-3361.

[36] Jeon JP, Yun T, Jin X, et al. 1H-NMR-based metabolomic analysis of cerebrospinal fluid from adult bilateral moyamoya disease: comparison with unilateral moyamoya disease and atherosclerotic stenosis. Medicine (Baltimore). 2015; 94(17): e629.

[37] Geng C, Cui C, Guo Y, et al. Metabolomic profiling revealed potential biomarkers in patients with moyamoya disease. Front Neurosci. 2020; 14: 308.

[38] He S, Wang Y, Liu Z, et al. Metabolomic signatures associated with pathological angiogenesis in moyamoya disease. Clin Transl Med. 2023; 13(12): e1492.

[39] Liu X, Jin F, Wang C, et al. Targeted metabolomics analysis of serum amino acid profiles in patients with moyamoya disease. Amino Acids. 2022; 54(1): 137-146.

[40] 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. PLoS One. 2011; 6(7): e22542.

[41] Hitomi T, Habu T, Kobayashi H, et al. Downregulation of securin by the variant RNF213 R4810K (rs112735431, G>A) reduces angiogenic activity of induced pluripotent stem cell-derived vascular endothelial cells from moyamoya patients. Biochem Biophys Res Commun. 2013; 438(1): 13-19.

[42] Hitomi T, Habu T, Kobayashi H, et al. The moyamoya disease susceptibility variant RNF213 R4810K (rs112735431) induces genomic instability by mitotic abnormality. Biochem Biophys Res Commun. 2013; 439(4): 419-426.

[43] 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 Am Heart Assoc. 2015; 4(7): e002146.

[44] Pollaci G, Gorla G, Potenza A, et al. Novel multifaceted roles for RNF213 protein. Int J Mol Sci. 2022; 23(9): 4492.

[45] Ohkubo K, Sakai Y, Inoue H, et al. Moyamoya disease susceptibility gene RNF213 links inflammatory and angiogenic signals in endothelial cells. Sci Rep. 2015; 5: 13191.

[46] Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell. 2019; 176(6): 1248-1264.

[47] Sakamoto S, Kiura Y, Yamasaki F, et al. Expression of vascular endothelial growth factor in dura mater of patients with moyamoya disease. Neurosurg Rev. 2008; 31(1): 77-81. discussion 81.

[48] Park YS, Jeon YJ, Kim HS, et al. The role of VEGF and KDR polymorphisms in moyamoya disease and collateral revascularization. PLoS One. 2012; 7(10): e47158.

[49] Kang HS, Kim JH, Phi JH, et al. Plasma matrix metalloproteinases, cytokines and angiogenic factors in moyamoya disease. J Neurol Neurosurg Psychiatry. 2010; 81(6): 673-678.

[50] Marushima A, Nieminen M, Kremenetskaia I, et al. Balanced single-vector co-delivery of VEGF/PDGF-BB improves functional collateralization in chronic cerebral ischemia. J Cereb Blood Flow Metab. 2020; 40(2): 404-419.

[51] Hiramatsu M, Hishikawa T, Tokunaga K, et al. Combined gene therapy with vascular endothelial growth factor plus apelin in a chronic cerebral hypoperfusion model in rats. J Neurosurg. 2017; 127(3): 679-686.

[52] Wu MY, Hill CS. TGF-beta superfamily signaling in embryonic development and homeostasis. Dev Cell. 2009; 16(3): 329-343.

[53] Hojo M, Hoshimaru M, Miyamoto S, et al. Role of transforming growth factor-beta1 in the pathogenesis of moyamoya disease. J Neurosurg. 1998; 89(4): 623-629.

[54] Chen Y, Tang M, Li H, Liu H, Wang J, Huang J. TGFbeta1 as a predictive biomarker for collateral formation within ischemic moyamoya disease. Front Neurol. 2022; 13: 899470.

[55] Wang C, Sun C, Zhao Y, et al. RNF213 gene silencing upregulates transforming growth factor beta1 expression in bone marrow-derived mesenchymal stem cells and is involved in the onset of moyamoya disease. Exp Ther Med. 2021; 22(3): 1024.

[56] Yamamoto M, Aoyagi M, Tajima S, et al. Increase in elastin gene expression and protein synthesis in arterial smooth muscle cells derived from patients with moyamoya disease. Stroke. 1997; 28(9): 1733-1738.

[57] Hellström M, Gerhardt H, Kalén M, et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol. 2001; 153(3): 543-553.

[58] Aoyagi M, Fukai N, Matsushima Y, Yamamoto M, Yamamoto K. Kinetics of 125I-PDGF binding and down-regulation of PDGF receptor in arterial smooth muscle cells derived from patients with moyamoya disease. J Cell Physiol. 1993; 154(2): 281-288.

[59] Yamamoto M, Aoyagi M, Fukai N, Matsushima Y, Yamamoto KJS. Differences in cellular responses to mitogens in arterial smooth muscle cells derived from patients with moyamoya disease. Stroke. 1998; 29(6): 1188-1193.

[60] Hayashi T, Yamamoto S, Hamashima T, Mori H, Sasahara M, Kuroda S. Critical role of platelet-derived growth factor-alpha in angiogenesis after indirect bypass in a murine moyamoya disease model. J Neurosurg. 2020; 134(5): 1535-1543.

[61] Wang LS, Wang H, Zhang QL, Yang ZJ, Kong FX, Wu CT. Hepatocyte growth factor gene therapy for ischemic diseases. Hum Gene Ther. 2018; 29(4): 413-423.

[62] Nanba R, Kuroda S, Ishikawa T, Houkin K, Iwasaki YJS. Increased expression of hepatocyte growth factor in cerebrospinal fluid and intracranial artery in moyamoya disease. Stroke. 2004; 35(12): 2837-2842.

[63] Abhinav K, Lee AG, Pendharkar AV, et al. Comprehensive profiling of secreted factors in the cerebrospinal fluid of moyamoya disease patients. Transl Stroke Res. 2023; 15(2): 399-408.

[64] Reuss B, von Bohlen und Halbach O. Fibroblast growth factors and their receptors in the central nervous system. Cell Tissue Res. 2003; 313(2): 139-157.

[65] Malek A, Connors S, Robertson R, Folkman J, Scott R. Elevation of cerebrospinal fluid levels of basic fibroblast growth factor in moyamoya and central nervous system disorders. Pediatr Neurosurg. 1997; 27(4): 182-189.

[66] Bedini G, Blecharz K, Nava S, et al. Vasculogenic and angiogenic pathways in moyamoya disease. Curr Med Chem. 2016; 23(4): 315-345.

[67] Mertens R, Graupera M, Gerhardt H, et al. The genetic basis of moyamoya disease. Transl Stroke Res. 2022; 13(1): 25-45.

[68] Baba T, Houkin K, Kuroda S. Novel epidemiological features of moyamoya disease. J Neurol Neurosurg Psychiatry. 2008; 79(8): 900-904.

[69] Mineharu Y, Takenaka K, Yamakawa H, et al. Inheritance pattern of familial moyamoya disease: autosomal dominant mode and genomic imprinting. J Neurol Neurosurg Psychiatry. 2006; 77(9): 1025-1029.

[70] Nanba R, Kuroda S, Tada M, Ishikawa T, Houkin K, Iwasaki Y. Clinical features of familial moyamoya disease. Child’s Nerv Syst: ChNS. 2006; 22(3): 258-262.

[71] Kang HS, Kim SK, Cho BK, Kim YY, Hwang YS, Wang KC. Single nucleotide polymorphisms of tissue inhibitor of metalloproteinase genes in familial moyamoya disease. Neurosurgery. 2006; 58(6): 1074-1080. discussion 1074–80.

[72] Paez MT, Yamamoto T. Single nucleotide polymorphisms of tissue inhibitor of metalloproteinase genes in familial moyamoya disease. Neurosurgery. 2007; 60(3): E582. Author reply E582.

[73] Fujimura M, Watanabe M, Narisawa A, Shimizu H, Tominaga T. Increased expression of serum matrix metalloproteinase-9 in patients with moyamoya disease. Surg Neurol. 2009; 72(5): 476-480. discussion 480.

[74] 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. Cerebrovasc Dis (Basel, Switzerland). 2010; 30(6): 618-625.

[75] Roder C, Peters V, Kasuya H, et al. Common genetic polymorphisms in moyamoya and atherosclerotic disease in Europeans. Child’s Nerv Syst: ChNS. 2011; 27(2): 245-252.

[76] Wang X, Zhang Z, Liu W, et al. Impacts and interactions of PDGFRB, MMP-3, TIMP-2, and RNF213 polymorphisms on the risk of moyamoya disease in Han Chinese human subjects. Gene. 2013; 526(2): 437-442.

[77] Ma J, You C. Association between matrix metalloproteinase-3 gene polymorphism and moyamoya disease. J Clin Neurosci. 2015; 22(3): 479-482.

[78] Wang X, Wang Y, Nie F, et al. Association of genetic variants with moyamoya disease in 13 000 individuals: a meta-analysis. Stroke. 2020; 51(6): 1647-1655.

[79] 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. Am J Hum Genet. 2009; 84(5): 617-627.

[80] Roder C, Peters V, Kasuya H, et al. Analysis of ACTA2 in European moyamoya disease patients. Eur J Paediatr Neurol: EJPN. 2011; 15(2): 117-122.

[81] Shimojima K, Yamamoto T. ACTA2 is not a major disease-causing gene for moyamoya disease. J Hum Genet. 2009; 54(11): 687-688.

[82] Hu FY, Zheng HB, Xu YM, Jiang Y, Zhou D. ACTA2 is not a major genetic risk gene for Chinese patients with moyamoya disease. Int J Stroke. 2013; 8(7): E43.

[83] Hojo M, Hoshimaru M, Miyamoto S, et al. Role of transforming growth factor-beta1 in the pathogenesis of moyamoya disease. J Neurosurg. 1998; 89(4): 623-629.

[84] Roder C, Peters V, Kasuya H, et al. Polymorphisms in TGFB1 and PDGFRB are associated with moyamoya disease in European patients. Acta Neurochir. 2010; 152(12): 2153-2160.

[85] Liu C, Roder C, Schulte C, et al. Analysis of TGFB1 in European and Japanese moyamoya disease patients. Eur J Med Genet. 2012; 55(10): 531-534.

[86] He J, Wang R, Zhang D, Zhang Y, Zhang Q, Zhao J. Expression of circulating vascular endothelial growth factor-antagonizing cytokines and vascular stabilizing factors prior to and following bypass surgery in patients with moyamoya disease. Exp Ther Med. 2014; 8(1): 302-308.

[87] Kitahara T, Okumura K, Semba A, Yamaura A, Makino H. Genetic and immunologic analysis on moya-moya. J Neurol Neurosurg Psychiatry. 1982; 45(11): 1048-1052.

[88] Aoyagi M, Ogami K, Matsushima Y, Shikata M, Yamamoto M, Yamamoto K. Human leukocyte antigen in patients with moyamoya disease. Stroke. 1995; 26(3): 415-417.

[89] Inoue TK, Ikezaki K, Sasazuki T, Matsushima T, Fukui M. Analysis of class II genes of human leukocyte antigen in patients with moyamoya disease. Clin Neurol Neurosurg. 1997; 99(suppl 2): S234-S237.

[90] Han H, Pyo CW, Yoo DS, Huh PW, Cho KS, Kim DS. Associations of moyamoya patients with HLA class I and class II alleles in the Korean population. J Korean Med Sci. 2003; 18(6): 876-880.

[91] Hong SH, Wang KC, Kim SK, Cho BK, Park MH. Association of HLA-DR and -DQ genes with familial moyamoya disease in Koreans. J Korean Neurosurg Soc. 2009; 46(6): 558-563.

[92] Kraemer M, Horn PA, Roder C, et al. Analysis of human leucocyte antigen genes in Caucasian patients with idiopathic moyamoya angiopathy. Acta Neurochir. 2012; 154(3): 445-454.

[93] Tashiro R, Niizuma K, Khor SS, et al. Identification of HLA-DRB1*04:10 allele as risk allele for Japanese moyamoya disease and its association with autoimmune thyroid disease: a case-control study. PLoS One. 2019; 14(8): e0220858.

[94] Wan J, Ling W, Zhengshan Z, Xianbo Z, Lian D, Kai W. Association of HLA-DQA2 and HLA-B with moyamoya disease in the Chinese Han population. Neurol Genet. 2021; 7(3): e592.

[95] Park YS, Min KT, Kim TG, et al. Age-specific eNOS polymorphisms in moyamoya disease. Child’s Nerv Syst: ChNS. 2011; 27(11): 1919-1926.

[96] Duan L, Wei L, Tian Y, et al. Novel susceptibility loci for moyamoya disease revealed by a genome-wide association study. Stroke. 2018; 49(1): 11-18.

[97] Park YS, Jeon YJ, Kim HS, et al. The roles of methylenetetrahydrofolate reductase 677C>T and 1298A>C polymorphisms in moyamoya disease patients. Child’s Nerv Syst: ChNS. 2014; 30(10): 1687-1695.

[98] Hervé D, Philippi A, Belbouab R, et al. Loss of α1β1 soluble guanylate cyclase, the major nitric oxide receptor, leads to moyamoya and achalasia. Am J Hum Genet. 2014; 94(3): 385-394.

[99] Wallace S, Guo DC, Regalado E, et al. Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension. Clin Genet. 2016; 90(4): 351-360.

[100] Zhang Q, Liu Y, Zhang D, et al. RNF213 as the major susceptibility gene for Chinese patients with moyamoya disease and its clinical relevance. J Neurosurg. 2017; 126(4): 1106-1113.

[101] Miskinyte S, Butler MG, Hervé D, et al. Loss of BRCC3 deubiquitinating enzyme leads to abnormal angiogenesis and is associated with syndromic moyamoya. Am J Hum Genet. 2011; 88(6): 718-728.

[102] Janczar S, Fogtman A, Koblowska M, et al. Novel severe hemophilia A and moyamoya (SHAM) syndrome caused by Xq28 deletions encompassing F8 and BRCC3 genes. Blood. 2014; 123(25): 4002-4004.

[103] Lavin M, Jenkins PV, Keenan C, et al. X-linked moyamoya syndrome associated with severe haemophilia A. Haemophilia. 2016; 22(1): e51-4.

[104] Tzeravini E, Samara S, Kouramba A, et al. Severe hemophilia A and moyamoya syndrome in a 19-year-old boy caused by Xq28 microdeletion. Case Rep Neurol. 2022; 14(2): 261-267.

[105] Kundishora AJ, Peters ST, Pinard A, et al. DIAPH1 variants in non-East Asian patients with sporadic moyamoya disease. JAMA Neurol. 2021; 78(8): 993-1003.

[106] Kamada F, Aoki Y, Narisawa A, et al. A genome-wide association study identifies RNF213 as the first moyamoya disease gene. J Hum Genet. 2011; 56(1): 34-40.

[107] 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. Sci Rep. 2014; 4: 4442.

[108] Liu W, Hitomi T, Kobayashi H, Harada KH, Koizumi A. Distribution of moyamoya disease susceptibility polymorphism p.R4810K in RNF213 in East and Southeast Asian populations. Neurol Med Chir (Tokyo). 2012; 52(5): 299-303.

[109] Cao Y, Kobayashi H, Morimoto T, Kabata R, Harada KH, Koizumi A. Frequency of RNF213 p.R4810K, a susceptibility variant for moyamoya disease, and health characteristics of carriers in the Japanese population. Environ Health Prevent Med. 2016; 21(5): 387-390.

[110] Kim EH, Yum MS, Ra YS, et al. Importance of RNF213 polymorphism on clinical features and long-term outcome in moyamoya disease. J Neurosurg. 2016; 124(5): 1221-1227.

[111] Lee MJ, Chen YF, Fan PC, et al. Mutation genotypes of RNF213 gene from moyamoya patients in Taiwan. J Neurol Sci. 2015; 353(1–2): 161-165.

[112] Shoemaker LD, Clark MJ, Patwardhan A, et al. Disease variant landscape of a large multiethnic population of moyamoya patients by exome sequencing. G3 (Bethesda, MD). 2015; 6(1): 41-49.

[113] Cecchi AC, Guo D, Ren Z, et al. RNF213 rare variants in an ethnically diverse population with moyamoya disease. Stroke. 2014; 45(11): 3200-3207.

[114] Okazaki S, Morimoto T, Kamatani Y, et al. Moyamoya disease susceptibility variant RNF213 p.R4810K increases the risk of ischemic stroke attributable to large-artery atherosclerosis. Circulation. 2019; 139(2): 295-298.

[115] Kobayashi H, Brozman M, Kyselová K, et al. RNF213 rare variants in Slovakian and Czech moyamoya disease patients. PLoS One. 2016; 11(10): e0164759.

[116] Koizumi A, Kobayashi H, Hitomi T, Harada KH, Habu T, Youssefian S. A new horizon of moyamoya disease and associated health risks explored through RNF213. Environ Health Prevent Med. 2016; 21(2): 55-70.

[117] Wang Y, Zhang Z, Wei L, et al. Predictive role of heterozygous p.R4810K of RNF213 in the phenotype of Chinese moyamoya disease. Neurology. 2020; 94(7): e678-e686.

[118] 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 Hum Genet. 2012; 57(12): 804-806.

[119] Wang X, Zhang Z, Wang Y, et al. Clinical and genetic risk factors of long-term outcomes after encephaloduroarteriosynangiosis in moyamoya disease in China. J Stroke Cerebrovasc Dis. 2021; 30(7): 105847.

[120] Ge P, Ye X, Liu X, et al. Association between p.R4810K variant and long-term clinical outcome in patients with moyamoya disease. Front Neurol. 2019; 10: 662.

[121] Miyatake S, Miyake N, Touho H, et al. Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease. Neurology. 2012; 78(11): 803-810.

[122] Kim WH, Kim SD, Nam MH, et al. Posterior circulation involvement and collateral flow pattern in moyamoya disease with the RNF213 polymorphism. Child’s Nerv Syst: ChNS. 2019; 35(2): 309-314.

[123] Sonobe S, Fujimura M, Niizuma K, et al. Temporal profile of the vascular anatomy evaluated by 9.4-T magnetic resonance angiography and histopathological analysis in mice lacking RNF213: a susceptibility gene for moyamoya disease. Brain Res. 2014; 1552: 64-71.

[124] Ahel J, Lehner A, Vogel A, et al. Moyamoya disease factor RNF213 is a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism. eLife. 2020; 9: e56185.

[125] He S, Ye X, Duan R, et al. Epigenome-wide association study reveals differential methylation sites and association of gene expression regulation with ischemic moyamoya disease in adults. Oxid Med Cell Longev. 2022; 2022: 7192060.

[126] Wu Z, Jiang H, Zhang L, et al. Molecular analysis of RNF213 gene for moyamoya disease in the Chinese Han population. PLoS One. 2012; 7(10): e48179.

[127] Harel T, Posey JE, Graham BH, et al. Atypical presentation of moyamoya disease in an infant with a de novo RNF213 variant. Am J Med Genet Part A. 2015; 167a(11): 2742-2747.

[128] Guey S, Kraemer M, Hervé D, et al. Rare RNF213 variants in the C-terminal region encompassing the RING-finger domain are associated with moyamoya angiopathy in Caucasians. Eur J Hum Genet: EJHG. 2017; 25(8): 995-1003.

[129] Butler GS, Overall CM. Updated biological roles for matrix metalloproteinases and new “intracellular” substrates revealed by degradomics. Biochemistry. 2009; 48(46): 10830-10845.

[130] Georgescu MM, Pinho Mda C, Richardson TE, et al. The defining pathology of the new clinical and histopathologic entity ACTA2-related cerebrovascular disease. Acta Neuropathol Commun. 2015; 3: 81.

[131] Shimada A, Nyitrai M, Vetter IR, et al. The core FH2 domain of diaphanous-related formins is an elongated actin binding protein that inhibits polymerization. Mol Cell. 2004; 13(4): 511-522.

[132] Goode BL, Eck MJ. Mechanism and function of formins in the control of actin assembly. Annu Rev Biochem. 2007; 76: 593-627.

[133] Pan J, Lordier L, Meyran D, et al. The formin DIAPH1 (mDia1) regulates megakaryocyte proplatelet formation by remodeling the actin and microtubule cytoskeletons. Blood. 2014; 124(26): 3967-3977.

[134] Stritt S, Nurden P, Turro E, et al. A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss. Blood. 2016; 127(23): 2903-2914.

[135] Gaengel K, Genové G, Armulik A, Betsholtz C. Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol. 2009; 29(5): 630-638.

[136] Rafat N, Beck G, Peña-Tapia PG, Schmiedek P, Vajkoczy P. Increased levels of circulating endothelial progenitor cells in patients with moyamoya disease. Stroke. 2009; 40(2): 432-438.

[137] Müller CR, Ehninger G, Goldmann SF. Gene and haplotype frequencies for the loci hLA-A, hLA-B, and hLA-DR based on over 13, 000 German blood donors. Hum Immunol. 2003; 64(1): 137-151.

[138] Shiina T, Hosomichi K, Inoko H, Kulski JK. The HLA genomic loci map: expression, interaction, diversity and disease. J Hum Genet. 2009; 54(1): 15-39.

[139] Moncada S, Higgs A. The L-arginine-nitric oxide pathway. New Engl J Med. 1993; 329(27): 2002-2012.

[140] Moro MA, Cárdenas A, Hurtado O, Leza JC, Lizasoain I. Role of nitric oxide after brain ischaemia. Cell Calcium. 2004; 36(3–4): 265-275.

[141] Loscalzo J. Homocysteine-mediated thrombosis and angiostasis in vascular pathobiology. J Clin Invest. 2009; 119(11): 3203-3205.

[142] Ge P, Zhang Q, Ye X, et al. Modifiable risk factors associated with moyamoya disease: a case-control study. Stroke. 2020; 51(8): 2472-2479.

[143] Ueland PM, Hustad S, Schneede J, Refsum H, Vollset SE. Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci. 2001; 22(4): 195-201.

[144] Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998; 64(3): 169-172.

[145] He Q, Ge P, Ye X, et al. Hyperhomocysteinemia is a predictor for poor postoperative angiogenesis in adult patients with moyamoya disease. Front Neurol. 2022; 13: 902474.

[146] Mineharu Y, Miyamoto S. RNF213 and GUCY1A3 in moyamoya disease: key regulators of metabolism, inflammation, and vascular stability. Front Neurol. 2021; 12: 687088.

[147] Mattei AL, Bailly N, Meissner A. DNA methylation: a historical perspective. Trends Genet. 2022; 38(7): 676-707.

[148] Krishna Smriti M, Trollope Alexandra F, Golledge J. The relevance of epigenetics to occlusive cerebral and peripheral arterial disease. Clin Sci. 2015; 128(9): 537-558.

[149] Smith ZD, Hetzel S, Meissner A. DNA methylation in mammalian development and disease. Nat Rev Genet. 2024; 26(1): 7-30.

[150] Wang Y, Zhang L, Lyu T, et al. Association of DNA methylation/demethylation with the functional outcome of stroke in a hyperinflammatory state. Neural Regen Res. 2024; 19(10): 2229-2239.

[151] Golledge J, Biros E, Bingley J, Iyer V, Krishna SM. Epigenetics and peripheral artery disease. Curr Atheroscler Rep. 2016; 18(4): 15.

[152] Endres M, Meisel A, Biniszkiewicz D, et al. DNA methyltransferase contributes to delayed ischemic brain injury. J Neurosci. 2000; 20(9): 3175-3181.

[153] Xu S, Chen T, Yu J, et al. Insights into the regulatory role of epigenetics in moyamoya disease: current advances and future prospectives. Mol Ther—Nucleic Acids. 2024; 35(3): 102281.

[154] Sung HY, Lee JY, Park AK, et al. Aberrant promoter hypomethylation of Sortilin 1: a moyamoya disease biomarker. J Stroke. 2018; 20(3): 350-361.

[155] He S, Ye X, Duan R, et al. Epigenome-wide association study reveals differential methylation sites and association of gene expression regulation with ischemic moyamoya disease in adults. Oxid Med Cell Longev. 2022; 2022: 1-13.

[156] Tokairin K, Ito M, Lee AG, et al. Genome-wide DNA methylation profiling reveals low methylation variability in moyamoya disease. Transl Stroke Res. 2024; 2024.

[157] Asselman C, Hemelsoet D, Eggermont D, Dermaut B, Impens F. Moyamoya disease emerging as an immune-related angiopathy. Trends Mol Med. 2022; 28(11): 939-950.

[158] Masuda J, Ogata J, Yutani C. Smooth muscle cell proliferation and localization of macrophages and T cells in the occlusive intracranial major arteries in moyamoya disease. Stroke. 1993; 24(12): 1960-1967.

[159] Lin R, Xie Z, Zhang J, et al. Clinical and immunopathological features of moyamoya disease. PLoS One. 2012; 7(4): e36386.

[160] Sigdel TK, Shoemaker LD, Chen R, et al. Immune response profiling identifies autoantibodies specific to moyamoya patients. Orphanet J Rare Dis. 2013; 8: 45.

[161] Fujimura M, Fujimura T, Kakizaki A, et al. Increased serum production of soluble CD163 and CXCL5 in patients with moyamoya disease: involvement of intrinsic immune reaction in its pathogenesis. Brain Res. 2018; 1679: 39-44.

[162] Guo L, Akahori H, Harari E, et al. CD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis. J Clin Investig. 2018; 128(3): 1106-1124.

[163] Peng W, Xie Y, Liu Y, et al. Targeted delivery of CD163+ macrophage-derived small extracellular vesicles via RGD peptides promote vascular regeneration and stabilization after spinal cord injury. J Control Release. 2023; 361: 750-765.

[164] Ni G, Liu W, Huang X, et al. Increased levels of circulating SDF-1α and CD34+ CXCR4+ cells in patients with moyamoya disease. Eur J Neurol. 2011; 18(11): 1304-1309.

[165] Yoshihara T, Taguchi A, Matsuyama T, et al. Increase in circulating CD34-positive cells in patients with angiographic evidence of moyamoya-like vessels. J Cereb Blood Flow Metab. 2008; 28(6): 1086-1089.

[166] Weng L, Cao X, Han L, et al. Association of increased Treg and Th17 with pathogenesis of moyamoya disease. Sci Rep. 2017; 7(1): 3071.

[167] Kanoke A, Fujimura M, Niizuma K, et al. Temporal profile of magnetic resonance angiography and decreased ratio of regulatory T cells after immunological adjuvant administration to mice lacking RNF213, a susceptibility gene for moyamoya disease. Brain Res. 2016; 1642: 1-9.

[168] Lužnik Z, Anchouche S, Dana R, Yin J. Regulatory T cells in angiogenesis. J Immunol. 2020; 205(10): 2557-2565.

[169] Mejia-Munne JC, Ellis JA, Feldstein NA, Meyers PM, Connolly ES. Moyamoya and inflammation. World Neurosurg. 2017; 100: 575-578.

[170] Mikami T, Suzuki H, Komatsu K, Mikuni N. Influence of inflammatory disease on the pathophysiology of moyamoya disease and quasi-moyamoya disease. Neurol Med Chir (Tokyo). 2019; 59(10): 361-370.

[171] Shirozu N, Ohgidani M, Hata N, et al. Angiogenic and inflammatory responses in human induced microglia-like (iMG) cells from patients with moyamoya disease. Sci Rep. 2023; 13(1): 14842.

[172] Peruzzotti-Jametti L, Willis CM, Krzak G, et al. Mitochondrial complex I activity in microglia sustains neuroinflammation. Nature. 2024; 628(8006): 195-203.

[173] Huang D, Qi H, Yang H, Chen M. Plasma exosomal microRNAs are non-invasive biomarkers of moyamoya disease: a pilot study. Clinics (Sao Paulo). 2023; 78: 100247.

[174] Sudhir BJ, Keelara AG, Venkat EH, Kazumata K, Sundararaman A. The mechanobiological theory: a unifying hypothesis on the pathogenesis of moyamoya disease based on a systematic review. Neurosurg Focus. 2021; 51(3): E6.

[175] Kang K, Shen Y, Zhang Q, et al. MicroRNA expression in circulating leukocytes and bioinformatic analysis of patients with moyamoya disease. Front Genet. 2022; 13: 816919.

[176] Blaj LA, Cucu AI, Tamba BI, Turliuc MD. The role of the NF-kB pathway in intracranial aneurysms. Brain Sci. 2023; 13(12): 1660.

[177] Yuan S, Liu H, Yuan D, et al. PNPLA3 I148M mediates the regulatory effect of NF-kB on inflammation in PA-treated HepG2 cells. J Cell Mol Med. 2020; 24(2): 1541-1552.

[178] Baeriswyl DC, Prionisti I, Peach T, et al. Disturbed flow induces a sustained, stochastic NF-kappaB activation which may support intracranial aneurysm growth in vivo. Sci Rep. 2019; 9(1): 4738.

[179] Takeda M, Tezuka T, Kim M, et al. Moyamoya disease patient mutations in the RING domain of RNF213 reduce its ubiquitin ligase activity and enhance NFkappaB activation and apoptosis in an AAA+ domain-dependent manner. Biochem Biophys Res Commun. 2020; 525(3): 668-674.

[180] Xu Y, Chen B, Guo Z, et al. Identification of diagnostic markers for moyamoya disease by combining bulk RNA-sequencing analysis and machine learning. Sci Rep. 2024; 14(1): 5931.

[181] Xin P, Xu X, Deng C, et al. The role of JAK/STAT signaling pathway and its inhibitors in diseases. Int Immunopharmacol. 2020; 80: 106210.

[182] Murphy ES, Xie H, Merchant TE, Yu JS, Chao ST, Suh JH. Review of cranial radiotherapy-induced vasculopathy. J Neurooncol. 2015; 122(3): 421-429.

[183] Desai SS, Paulino AC, Mai WY, Teh BS. Radiation-induced moyamoya syndrome. Int J Radiat Oncol Biol Phys. 2006; 65(4): 1222-1227.

[184] Coderre JA, Morris GM, Micca PL, et al. Late effects of radiation on the central nervous system: role of vascular endothelial damage and glial stem cell survival. Radiat Res. 2006; 166(3): 495-503.

[185] Reinhold HSCW, Hopewell JW, van der Berg AP. Development of blood vessel-related radiation damage in the fimbria of the central nervous system. Int J Radiat Oncol Biol Phys. 1990; 18(1): 37-42.

[186] Manion B, Sung WS. Radiation-induced moyamoya disease after childhood astrocytoma. J Clin Neurosci. 2011; 18(10): 1403-1405.

[187] Scala M, Fiaschi P, Cama A, et al. Radiation-induced moyamoya syndrome in children with brain tumors: case series and literature review. World Neurosurg. 2020; 135: 118-129.

[188] Mehmood Qadri H, Bashir RA, Amir A, et al. Post-infectious moyamoya syndrome: a review of existing scientific literature from 2000 to 2023. Cureus. 2024; 16(7): e63643.

[189] Arficho KT, Gumma C, Chakko MN. Post cryptococcal moyamoya syndrome in adult human immunodeficiency virus patient with anterior and posterior circulation involvement: case report. Cureus. 2023; 15(8): e44052.

[190] Yamada H, Deguchi K, Tanigawara T, et al. The relationship between moyamoya disease and bacterial infection. Clin Neurol Neurosurg. 1997; 99(suppl 2): S221-S224.

[191] Mineharu Y, Takagi Y, Koizumi A, et al. Genetic and nongenetic factors for contralateral progression of unilateral moyamoya disease: the first report from the SUPRA Japan Study Group. J Neurosurg. 2022; 136(4): 1005-1014.

[192] Ohya Y, Matsuo R, Sato N, et al. Causes of ischemic stroke in young adults versus non-young adults: a multicenter hospital-based observational study. PLoS One. 2022; 17(7): e0268481.

[193] McCarty JL, Leung LY, Peterson RB, et al. Ischemic infarction in young adults: a review for radiologists. Radiographics. 2019; 39(6): 1629-1648.

[194] Yu X, Ge P, Zhai Y, et al. Gut microbiota in adults with moyamoya disease: characteristics and biomarker identification. Front Cell Infect Microbiol. 2023; 13: 1252681.

[195] Vandereyken K, Sifrim A, Thienpont B, Voet T. Methods and applications for single-cell and spatial multi-omics. Nat Rev Genet. 2023; 24(8): 494-515.

[196] He S, Zhang J, Liu Z, et al. Upregulated cytoskeletal proteins promote pathological angiogenesis in moyamoya disease. Stroke. 2023; 54(12): 3153-3164.

[197] He S, Wang Y, Liu Z, et al. Metabolomic signatures associated with pathological angiogenesis in moyamoya disease. Clin Transl Med. 2023; 13(12): e1492.

[198] Nakamura Y, Mineharu Y, Kamata T, et al. Lack of association between seropositivity of vasculopathy-related viruses and moyamoya disease. J Stroke Cerebrovasc Dis. 2022; 31(7): 106509.

[199] Li H, Cao X, Gu X, et al. GM-CSF promotes the development of dysfunctional vascular networks in moyamoya disease. Neurosci Bull. 2023; 40(4): 451-465.

[200] Kaku Y, Morioka M, Ohmori Y, et al. Outer-diameter narrowing of the internal carotid and middle cerebral arteries in moyamoya disease detected on 3D constructive interference in steady-state MR image: is arterial constrictive remodeling a major pathogenesis?. Acta Neurochir (Wien). 2012; 154(12): 2151-2157.

[201] Sonobe S, Fujimura M, Niizuma K, et al. Temporal profile of the vascular anatomy evaluated by 9.4-T magnetic resonance angiography and histopathological analysis in mice lacking RNF213: a susceptibility gene for moyamoya disease. Brain Res. 2014; 1552: 64-71.

[202] Meisel A, Liu W, Morito D, et al. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One. 2011; 6(7): e22542.

[203] Kamata I, Terai Y, Ohmoto T. Attempt to establish an experimental animal model of moyamoya disease using immuno-embolic material–histological changes of the arterial wall resulting from immunological reaction in cats. Acta Med Okayama. 2003; 57(3): 143-150.

[204] Tokairin K, Hamauchi S, Ito M, et al. Vascular smooth muscle cell derived from IPS cell of moyamoya disease—comparative characterization with endothelial cell transcriptome. J Stroke Cerebrovasc Dis. 2020; 29(12): 105305.

[205] Blecharz KG, Frey D, Schenkel T, et al. Autocrine release of angiopoietin-2 mediates cerebrovascular disintegration in moyamoya disease. J Cereb Blood Flow Metab. 2016; 37(4): 1527-1539.

[206] Wimmer RA, Leopoldi A, Aichinger M, et al. Human blood vessel organoids as a model of diabetic vasculopathy. Nature. 2019; 565(7740): 505-510.

[207] He S, Zhang J, Wang X, et al. Organoid modeling and single-cell profiling uncover the migration mechanism of smooth muscle cells in moyamoya disease. bioRxiv. 2024.

[208] Fukui M. Guidelines for the diagnosis and treatment of spontaneous occlusion of the circle of Willis (‘moyamoya’ disease). Research Committee on Spontaneous Occlusion of the Circle of Willis (Moyamoya Disease) of the Ministry of Health and Welfare, Japan. Clin Neurol Neurosurg. 1997; 99(suppl 2): S238-S240.

[209] Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis; Health Labour Sciences Research Grant for Research on Measures for Infractable Diseases. Guidelines for diagnosis and treatment of moyamoya disease (spontaneous occlusion of the circle of Willis). Neurol Med Chir. 2012; 52(5): 245-266.

[210] Suzuki J, Takaku A. Cerebrovascular moyamoya disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol. 1969; 20(3): 288-299.

[211] Yamada I, Matsushima Y, Suzuki S. Moyamoya disease: diagnosis with three-dimensional time-of-flight MR angiography. Radiology. 1992; 184(3): 773-778.

[212] Houkin K, Tanaka N, Takahashi A, Kamiyama H, Abe H, Kajii N. Familial occurrence of moyamoya disease. Magnetic resonance angiography as a screening test for high-risk subjects. Childs Nerv Syst. 1994; 10(7): 421-425.

[213] Houkin K, Aoki T, Takahashi A, Abe H. Diagnosis of moyamoya disease with magnetic resonance angiography. Stroke. 1994; 25(11): 2159-2164.

[214] Houkin K, Nakayama N, Kuroda S, Nonaka T, Shonai T, Yoshimoto T. Novel magnetic resonance angiography stage grading for moyamoya disease. Cerebrovasc Dis. 2005; 20(5): 347-354.

[215] Fujiwara H, Momoshima S, Kuribayashi S. Leptomeningeal high signal intensity (ivy sign) on fluid-attenuated inversion-recovery (FLAIR) MR images in moyamoya disease. Eur J Radiol. 2005; 55(2): 224-230.

[216] Ryoo S, Cha J, Kim SJ, et al. High-resolution magnetic resonance wall imaging findings of moyamoya disease. Stroke. 2014; 45(8): 2457-2460.

[217] Oh BH, Moon HC, Baek HM, et al. Comparison of 7T and 3T MRI in patients with moyamoya disease. Magn Reson Imaging. 2017; 37: 134-138.

[218] Togao O, Hiwatashi A, Obara M, et al. 4D ASL-based MR angiography for visualization of distal arteries and leptomeningeal collateral vessels in moyamoya disease: a comparison of techniques. Eur Radiol. 2018; 28(11): 4871-4881.

[219] Funaki T, Takahashi JC, Yoshida K, et al. Periventricular anastomosis in moyamoya disease: detecting fragile collateral vessels with MR angiography. J Neurosurg. 2016; 124(6): 1766-1772.

[220] Funaki T, Takahashi JC, Houkin K, et al. High rebleeding risk associated with choroidal collateral vessels in hemorrhagic moyamoya disease: analysis of a nonsurgical cohort in the Japan Adult Moyamoya Trial. J Neurosurg. 2019; 130(2): 525-530.

[221] Schmiedek P, Piepgras A, Leinsinger G, Kirsch CM, Einhüpl K. Improvement of cerebrovascular reserve capacity by EC-IC arterial bypass surgery in patients with ICA occlusion and hemodynamic cerebral ischemia. J Neurosurg. 1994; 81(2): 236-244.

[222] Yonas H, Smith HA, Durham SR, Pentheny SL, Johnson DW. Increased stroke risk predicted by compromised cerebral blood flow reactivity. J Neurosurg. 1993; 79(4): 483-489.

[223] Gupta A, Chazen JL, Hartman M, et al. Cerebrovascular reserve and stroke risk in patients with carotid stenosis or occlusion: a systematic review and meta-analysis. Stroke. 2012; 43(11): 2884-2891.

[224] Czabanka M, Peña-Tapia P, Schubert GA, et al. Proposal for a new grading of moyamoya disease in adult patients. Cerebrovasc Dis (Basel, Switzerland). 2011; 32(1): 41-50.

[225] Ikezaki K, Matsushima T, Kuwabara Y, Suzuki SO, Nomura T, Fukui M. Cerebral circulation and oxygen metabolism in childhood moyamoya disease: a perioperative positron emission tomography study. J Neurosurg. 1994; 81(6): 843-850.

[226] Nariai T, Matsushima Y, Imae S, et al. Severe haemodynamic stress in selected subtypes of patients with moyamoya disease: a positron emission tomography study. J Neurol Neurosurg Psychiatry. 2005; 76(5): 663-669.

[227] Hara S, Kudo T, Hayashi S, et al. Improvement in cognitive decline after indirect bypass surgery in adult moyamoya disease: implication of (15)O-gas positron emission tomography. Ann Nucl Med. 2020; 34(7): 467-475.

[228] Roder C, Haas P, Fudali M, et al. Neuropsychological impairment in adults with moyamoya angiopathy: preoperative assessment and correlation to MRI and H(2)(15)O PET. Neurosurg Rev. 2020; 43(6): 1615-1622.

[229] Touho H, Karasawa J, Ohnishi H. Preoperative and postoperative evaluation of cerebral perfusion and vasodilatory capacity with 99mTc-HMPAO SPECT and acetazolamide in childhood moyamoya disease. Stroke. 1996; 27(2): 282-289.

[230] Saito N, Nakagawara J, Nakamura H, Teramoto A. Assessment of cerebral hemodynamics in childhood moyamoya disease using a quantitative and a semiquantitative IMP-SPECT study. Ann Nucl Med. 2004; 18(4): 323-331.

[231] So Y, Lee H-Y, Kim S-K, et al. Prediction of the clinical outcome of pediatric moyamoya disease with postoperative basal/acetazolamide stress brain perfusion SPECT after revascularization surgery. Stroke. 2005; 36(7): 1485-1489.

[232] Horowitz M, Yonas H, Albright AL. Evaluation of cerebral blood flow and hemodynamic reserve in symptomatic moyamoya disease using stable xenon-CT blood flow. Surg Neurol. 1995; 44(3): 251-261. discussion 262.

[233] Nambu K, Suzuki R, Hirakawa K. Cerebral blood flow: measurement with xenon-enhanced dynamic helical CT. Radiology. 1995; 195(1): 53-57.

[234] Suzuki R, Nariai T, Matsushima Y, Hirakawa K. Xe-CT in cerebrovascular disease and moyamoya disease. Acta Neurol Scand Suppl. 1996; 166: 69-71.

[235] McAuley DJ, Poskitt K, Steinbok P. Predicting stroke risk in pediatric moyamoya disease with xenon-enhanced computed tomography. Neurosurgery. 2004; 55(2): 327-332. discussion 332–333.

[236] Sakamoto S, Ohba S, Shibukawa M, Kiura Y, Arita K, Kurisu K. CT perfusion imaging for childhood moyamoya disease before and after surgical revascularization. Acta Neurochir (Wien). 2006; 148(1): 77-81. discussion 81.

[237] Kang KH, Kim HS, Kim SY. Quantitative cerebrovascular reserve measured by acetazolamide-challenged dynamic CT perfusion in ischemic adult moyamoya disease: initial experience with angiographic correlation. AJNR Am J Neuroradiol. 2008; 29(8): 1487-1493.

[238] Rim NJ, Kim HS, Shin YS, Kim SY. Which CT perfusion parameter best reflects cerebrovascular reserve?: correlation of acetazolamide-challenged CT perfusion with single-photon emission CT in moyamoya patients. AJNR Am J Neuroradiol. 2008; 29(9): 1658-1663.

[239] Ishii Y, Nariai T, Tanaka Y, et al. Practical clinical use of dynamic susceptibility contrast magnetic resonance imaging for the surgical treatment of moyamoya disease. Neurosurgery. 2014; 74(3): 302-309.

[240] Ishii Y, Tanaka Y, Momose T, et al. Chronologic evaluation of cerebral hemodynamics by dynamic susceptibility contrast magnetic resonance imaging after indirect bypass surgery for moyamoya disease. World Neurosurg. 2017; 108: 427-435.

[241] Wolf RL, Detre JA. Clinical neuroimaging using arterial spin-labeled perfusion magnetic resonance imaging. Neurotherapeutics. 2007; 4(3): 346-359.

[242] Yun TJ, Sohn C-H, Han MH, et al. Effect of delayed transit time on arterial spin labeling: correlation with dynamic susceptibility contrast perfusion magnetic resonance in moyamoya disease. Investig Radiol. 2013; 48(11): 795-802.

[243] Blauwblomme T, Lemaitre H, Naggara O, et al. Cerebral blood flow improvement after indirect revascularization for pediatric moyamoya disease: a statistical analysis of arterial spin-labeling MRI. AJNR Am J Neuroradiol. 2016; 37(4): 706-712.

[244] Ha JY, Choi YH, Lee S, et al. Arterial spin labeling MRI for quantitative assessment of cerebral perfusion before and after cerebral revascularization in children with moyamoya disease. Korean J Radiol. 2019; 20(6): 985-996.

[245] Quon JL, Kim LH, Lober RM, Maleki M, Steinberg GK, Yeom KW. Arterial spin-labeling cerebral perfusion changes after revascularization surgery in pediatric moyamoya disease and syndrome. J Neurosurg Pediatr. 2019; 23(4): 486-492.

[246] Agarwal V, Singh P, Ahuja CK, Gupta SK, Aggarwal A, Narayanan R. Non-invasive assessment of cerebral microvascular changes for predicting postoperative cerebral hyperperfusion after surgical revascularisation for moyamoya disease: an arterial spin labelling MRI study. Neuroradiology. 2021; 63(4): 563-572.

[247] Muttaqin Z, Ohba S, Arita K, et al. Cerebral circulation in moyamoya disease: a clinical study using transcranial Doppler sonography. Surg Neurol. 1993; 40(4): 306-313.

[248] Laborde G, Harders A, Klimek L, Hardenack M. Correlation between clinical, angiographic and transcranial Doppler sonographic findings in patients with moyamoya disease. Neurol Res. 1993; 15(2): 87-92.

[249] Lee Y-S, Jung K-H, Roh J-K. Diagnosis of moyamoya disease with transcranial Doppler sonography: correlation study with magnetic resonance angiography. J Neuroimag. 2004; 14(4): 319-323.

[250] Ju K, Zhong L, Ni X, Cao H, Cheng G, Ding L. Cerebral vasomotor reactivity predicts the development of acute stroke in patients with internal carotid artery stenosis. Neurol Neurochir Pol. 2018; 52(3): 374-378.

[251] Yeh S-J, Tang S-C, Tsai L-K, et al. Ultrasonographic changes after indirect revascularization surgery in pediatric patients with moyamoya disease. Ultrasound Med Biol. 2016; 42(12): 2844-2851.

[252] Yeh S-J, Tang S-C, Tsai L-K, et al. Greater ultrasonographic changes in pediatric moyamoya patients compared with adults after indirect revascularization surgeries. J Neurosurg Pediatr. 2018; 22(6): 663-671.

[253] Adla T, Adlova R. Multimodality imaging of carotid stenosis. Int J Angiol. 2015; 24(3): 179-184.

[254] Du L, Jiang H, Li J, Duan T, Zhou C, Yan F. Imaging methods for surgical revascularization in patients with moyamoya disease: an updated review. Neurosurg Rev. 2022; 45(1): 343-356.

[255] Sam K, Poublanc J, Sobczyk O, et al. Assessing the effect of unilateral cerebral revascularisation on the vascular reactivity of the non-intervened hemisphere: a retrospective observational study. BMJ Open. 2015; 5(2): e006014.

[256] Rosen C, McKetton L, Russell J, et al. Long-term changes in cerebrovascular reactivity following EC-IC bypass for intracranial steno-occlusive disease. J Clin Neurosci. 2018; 54: 77-82.

[257] Dlamini N, Shah-Basak P, Leung J, et al. Breath-hold blood oxygen level-dependent MRI: a tool for the assessment of cerebrovascular reserve in children with moyamoya disease. AJNR A J Neuroradiol. 2018; 39(9): 1717-1723.

[258] Hauser T-K, Seeger A, Bender B, et al. Hypercapnic BOLD MRI compared to H(2)(15)O PET/CT for the hemodynamic evaluation of patients with moyamoya disease. Neuroimage Clin. 2019; 22: 101713.

[259] Liu P, Li Y, Pinho M, Park DC, Welch BG, Lu H. Cerebrovascular reactivity mapping without gas challenges. NeuroImage. 2017; 146: 320-326.

[260] Liu P, Liu G, Pinho MC, et al. Cerebrovascular reactivity mapping using resting-state BOLD functional MRI in healthy adults and patients with moyamoya disease. Radiology. 2021; 299(2): 419-425.

[261] Lee M, Guzman R, Bell-Stephens T, Steinberg GK. Intraoperative blood flow analysis of direct revascularization procedures in patients with moyamoya disease. J Cereb Blood Flow Metab. 2011; 31(1): 262-274.

[262] Yu Z, Xe Shi, Brohi SR, Qian H, Liu F, Yang Y. Measurement of blood flow in an intracranial artery bypass from the internal maxillary artery by intraoperative duplex sonography. J Ultrasound Med. 2017; 36(2): 439-447.

[263] Yu Z, Yang Y, Xe Shi, Qian H, Liu F. A comparison of haemodynamics between subcranial-intracranial bypass and the traditional extracranial-intracranial bypass. Br J Neurosurg. 2017; 31(6): 668-671.

[264] Morisawa H, Kawamata T, Kawashima A, et al. Hemodynamics and changes after STA-MCA anastomosis in moyamoya disease and atherosclerotic cerebrovascular disease measured by micro-Doppler ultrasonography. Neurosurg Rev. 2013; 36(3): 411-419.

[265] Nomura M, Tamase A, Kamide T, et al. Pin-point selection of recipient MCA at M4 for STA-MCA bypass using micro-Doppler ultrasonography. J Neurosurg Sci. 2017; 61(4): 446-449.

[266] Ye X, Liu X-J, Ma L, et al. Clinical values of intraoperative indocyanine green fluorescence video angiography with Flow 800 software in cerebrovascular surgery. Chin Med J. 2013; 126(22): 4232-4237.

[267] Yang T, Higashino Y, Kataoka H, et al. Correlation between reduction in microvascular transit time after superficial temporal artery-middle cerebral artery bypass surgery for moyamoya disease and the development of postoperative hyperperfusion syndrome. J Neurosurg. 2018; 128(5): 1304-1310.

[268] Uda K, Araki Y, Muraoka S, et al. Intraoperative evaluation of local cerebral hemodynamic change by indocyanine green videoangiography: prediction of incidence and duration of postoperative transient neurological events in patients with moyamoya disease. J Neurosurg. 2018(4): 1-9.

[269] Horie N, Fukuda Y, Izumo T, Hayashi K, Suyama K, Nagata I. Indocyanine green videoangiography for assessment of postoperative hyperperfusion in moyamoya disease. Acta Neurochir. 2014; 156(5): 919-926.

[270] Machida T, Ono J, Nomura R, Fujikawa A, Nagano O, Higuchi Y. Venous reddening as a possible sign of hyperperfusion after superficial temporal artery-middle cerebral artery anastomosis for moyamoya disease: case report. Neurol Med Chir (Tokyo). 2014; 54(10): 827-831.

[271] Machida T, Higuchi Y, Nakano S, et al. Cortical venous redness represents tissue circulation status in patients with moyamoya disease. Stroke. 2017; 48(6): 1665-1667.

[272] Kearns KN, Sokolowski JD, Chadwell K, et al. The role of contrast-enhanced ultrasound in neurosurgical disease. Neurosurg Focus. 2019; 47(6): E8.

[273] Knieling F, Rüffer A, Cesnjevar R, et al. Transfontanellar contrast-enhanced ultrasound for monitoring brain perfusion during neonatal heart surgery. Circ Cardiovasc Imaging. 2020; 13(3): e010073.

[274] Premilovac D, Blackwood SJ, Ramsay CJ, Keske MA, Howells DW, Sutherland BA. Transcranial contrast-enhanced ultrasound in the rat brain reveals substantial hyperperfusion acutely post-stroke. J Cereb Blood Flow Metab. 2020; 40(5): 939-953.

[275] Pang CH, Cho WS, Kang HS, Kim JE. Benefits and risks of antiplatelet medication in hemodynamically stable adult moyamoya disease. Sci Rep. 2021; 11(1): 19367.

[276] Yamada S, Oki K, Itoh Y, et al. Effects of surgery and antiplatelet therapy in ten-year follow-up from the registry study of research committee on moyamoya disease in Japan. J Stroke Cerebrovasc Dis. 2016; 25(2): 340-349.

[277] Zhao Y, Zhang Q, Zhang D, Zhao Y. Effect of aspirin in postoperative management of adult ischemic moyamoya disease. World Neurosurg. 2017; 105: 728-731.

[278] Seo WK, Kim JY, Choi EH, et al. Association of antiplatelet therapy, including cilostazol, with improved survival in patients with moyamoya disease in a nationwide study. J Am Heart Assoc. 2021; 10(5): e017701.

[279] Onozuka D, Hagihara A, Nishimura K, et al. Prehospital antiplatelet use and functional status on admission of patients with non-haemorrhagic moyamoya disease: a nationwide retrospective cohort study (J-ASPECT study). BMJ Open. 2016; 6(3): e009942.

[280] Chiba T, Setta K, Shimada Y, et al. Comparison of effects between clopidogrel and cilostazol on cerebral perfusion in nonsurgical adult patients with symptomatically ischemic moyamoya disease: subanalysis of a prospective cohort. J Stroke Cerebrovasc Dis. 2018; 27(11): 3373-3379.

[281] Aihara Y, Kashiwase S, Chiba K, et al. Aspirin use and platelet aggregation in ischemic onset-type pediatric moyamoya patients with intractable headaches (moya-ache). Child’s Nerv Syst: ChNS. 2021; 37(5): 1649-1657.

[282] Yeon JY, Kim JS, Hong SC. Incidental major artery aneurysms in patients with non-hemorrhagic moyamoya disease. Acta Neurochir. 2011; 153(6): 1263-1270.

[283] Kawaguchi S, Sakaki T, Morimoto T, Kakizaki T, Kamada K. Characteristics of intracranial aneurysms associated with moyamoya disease. A review of 111 cases. Acta Neurochir. 1996; 138(11): 1287-1294.

[284] Yu JL, Wang HL, Xu K, Li Y, Luo Q. Endovascular treatment of intracranial aneurysms associated with moyamoya disease or moyamoya syndrome. Interv Neuroradiol. 2010; 16(3): 240-248.

[285] Cho WS, Kim JE, Kim CH, et al. Long-term outcomes after combined revascularization surgery in adult moyamoya disease. Stroke. 2014; 45(10): 3025-3031.

[286] Miyamoto S, Yoshimoto T, Hashimoto N, et al. Effects of extracranial–intracranial bypass for patients with hemorrhagic moyamoya disease. Stroke. 2014; 45(5): 1415-1421.

[287] Karasawa J, Kikuchi H, Furuse S, Kawamura J, Sakaki T. Treatment of moyamoya disease with STA-MCA anastomosis. J Neurosurg. 1978; 49(5): 679-688.

[288] Nielsen TH, Abhinav K, Sussman ES, et al. Direct versus indirect bypass procedure for the treatment of ischemic moyamoya disease: results of an individualized selection strategy. J Neurosurg. 2020; 134(5): 1578-1589.

[289] Houkin K, Kuroda S, Ishikawa T, Abe H. Neovascularization (angiogenesis) after revascularization in moyamoya disease. Which technique is most useful for moyamoya disease?. Acta Neurochir. 2000; 142(3): 269-276.

[290] Czabanka M, Pena-Tapia P, Scharf J, et al. Characterization of direct and indirect cerebral revascularization for the treatment of European patients with moyamoya disease. Cerebrovasc Dis (Basel, Switzerland). 2011; 32(4): 361-369.

[291] Deng X, Gao F, Zhang D, et al. Direct versus indirect bypasses for adult ischemic-type moyamoya disease: a propensity score-matched analysis. J Neurosurg. 2018; 128(6): 1785-1791.

[292] Ding JY, Shang SL, Sun ZS, et al. Remote ischemic conditioning for the treatment of ischemic moyamoya disease. CNS Neurosci Ther. 2020; 26(5): 549-557.

[293] Kuroda S, Group AS. Asymptomatic moyamoya disease: literature review and ongoing AMORE study. Neurol Med Chir (Tokyo). 2015; 55(3): 194-198.

[294] Gross BA, Thomas AJ, Frerichs KU. Endovascular treatment of symptomatic moyamoya. Neurosurg Rev. 2014; 37(4): 579-583.

[295] Nagamine Y, Takahashi S, Sonobe M. Multiple intracranial aneurysms associated with moyamoya disease. Case report. J Neurosurg. 1981; 54(5): 673-676.

[296] Iwama T, Todaka T, Hashimoto N. Direct surgery for major artery aneurysm associated with moyamoya disease. Clin Neurol Neurosurg. 1997; 99(suppl 2): S191-S193.

[297] Peltier J, Vinchon M, Soto-Ares G, Dhellemmes P. Disappearance of a middle cerebral artery aneurysm associated with moyamoya syndrome after revascularization in a child: case report. Child’s Nerv Syst: ChNS. 2008; 24(12): 1483-1487.

[298] Satoh T, Yamamoto Y, Asari S, Sakurai M, Suzuki K. Disappearance and development of cerebral aneurysms in moyamoya disease. Case report. J Neurosurg. 1983; 58(6): 949-953.

[299] Smith ER, Scott RM. Surgical management of moyamoya syndrome. Skull Base. 2005; 15(1): 15-26.

[300] Miyamoto S, Yoshimoto T, Hashimoto N, et al. Effects of extracranial-intracranial bypass for patients with hemorrhagic moyamoya disease: results of the Japan Adult Moyamoya Trial. Stroke. 2014; 45(5): 1415-1421.

[301] Noshiro S, Mikami T, Komatsu K, et al. Neuromodulatory role of revascularization surgery in moyamoya disease. World Neurosurg. 2016; 91: 473-482.

[302] Qian C, Yu X, Li J, Chen J, Wang L, Chen G. The efficacy of surgical treatment for the secondary prevention of stroke in symptomatic moyamoya disease: a meta-analysis. Medicine (Baltimore). 2015; 94(49): e2218.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.