Cohort profile: Chinese moyamoya disease cohort study

Cohort profile: Chinese moyamoya disease cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Cohort profile: Chinese moyamoya disease cohort study Fangbin Hao, Cong Han, Gan Gao, Simeng Liu, MinJie Wang, Rimiao Yang, and 25 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2799246/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background : The etiology and natural course of moyamoya disease (MMD) remain unknown. This study evaluated the natural course and etiology of MMD using data from the Chinese MMD (C-MMD) cohort study. Methods : The C-MMD cohort consisted of 6,167 patients with MMD treated at our center over the past 20 years. We analyzed the medical history and laboratory and imaging examination results of the patients at different stages of the disease to identify common features of MMD. Results : The median age for symptom onset was 32 years. The age distribution was bimodal; the highest peak was between ages 35 and 45 years, with a smaller peak between ages 3 and 9 years. The female-to-male ratio was 1:1. The disease occurred mainly in the Han people and was rarely observed in minority nationalities. In our cohort, a transient ischemic attack was the most common initial clinical manifestation (46.3%); others included infarction (25.0%), hemorrhage (15.1%), and headache (7.9%). Conclusions: The C-MMD cohort is currently one of the largest single-center MMD cohorts in the world. This study provides baseline data for future research on the etiology and natural course of MMD. Clinical Trial Registration: This study has been registered in the Chinese Clinical trial registry (registration number: ChiCTR2200064160) on September 28, 2022. moyamoya disease transient ischemic attack magnetic resonance angiography digital subtraction angiography Figures Figure 1 Figure 2 Figure 3 1 Introduction Moyamoya disease (MMD) is a primary chronic cerebrovascular disorder characterized by gradual stenosis and occlusion of the bilateral distal internal carotid arteries and the proximal portion of the anterior or middle cerebral arteries. [ 1 , 2 ] MMD is the most common pediatric cerebrovascular disease and the leading cause of stroke in children and young adults in Japan, Korea, and China. [ 3 – 5 ] Furthermore, MMD can manifest as ischemic or hemorrhagic strokes, seizures, and cognitive impairment, resulting in a high prevalence of disability and death. [ 6 ] The high disability rate of MMD also burdens the patients’ families and society. MMD is more prevalent in East Asian populations, such as Japan, Korea, and China, than in Europe, America, and Africa. [ 4 , 7 – 12 ] Furthermore, the incidence of MMD has been increasing for the last few years owing to increased numbers of evaluations and thus disease recognition. For example, the MMD incidence rate in Japan was 1.13/100,000 people in 2012, showing a nearly two-fold increase from 2003. [ 5 , 13 ] This trend has also been observed in Korea, with an incidence rate of 18.1/100,000 people in 2013 versus 4.3/100,000 in 2005, a nearly three-fold increase. [ 4 ] China has the largest population in the world, and recent epidemiological data reported an annual increase in MMD from 2016 to 2018, from 0.88 to 1.47/100,00 people. [ 7 ] The MMD incidence has also increased in the United States from 1988 to 2004; 2,247 patients with MMD were admitted to the hospital, but 7,473 patients were hospitalized from 2005 to 2008. Thus, the incidence rate increased from 0.086/100,000 people in 2005 to 0.57/100,000 in 2012. [ 14 – 17 ] MMD is a serious disease with a poor prognosis; thus, the social burden increases with the number of MMD cases. However, the etiology, pathogenesis, and clinical course of MMD are unclear. [ 18 ] Consequently, suitable animal models have not been established, and basic research has not progressed beyond the molecular and cellular levels. [ 19 ] MMD susceptibility genes have been identified, such as ring finger protein 213-coding gene RNF213 ; however, no apparent causative etiology factor has been found. [ 15 , 16 , 20 ] Moreover, the clinical manifestations of MMD vary greatly, with considerable differences in the onset time, progression rate, disease severity, and therapeutic effect among patients. In addition, the genetic background of patients with MMD in China is complex; therefore, MMD subtypes may exist. [ 7 , 21 ] Finally, few large-scale studies have been conducted on MMD. Thus, little is known about the clinical course. Clarifying the natural course of the disease and its etiology is an urgent issue. Over the last 20 years, our institution has collected clinical information on patients with MMD treated at our center, establishing the Chinese MMD (C-MMD) cohort. Therefore, this study assessed the C-MMD cohort to elucidate the clinical course and the etiology of MMD. 2 Methods 2.1 Study population The C-MMD cohort study is a Chinese nationwide observational study comprising patients registered at PLA General Hospital and then followed up in a real-world setting. The inclusion criteria were based on the 2021 Guidelines for the diagnosis of MMD. [ 22 ] The inclusion criteria were: (1) The presence of stenosis or occlusion of the intracranial internal carotid artery or proximal portions of the anterior or middle cerebral arteries on digital subtraction angiography (DSA) or magnetic resonance angiography (MRA); (2) observation of abnormal vascular networks during the arterial phase of the disease near occlusive or stenotic lesions on DSA or abnormal vascular networks in the basal ganglia on MRA; and (3) bilaterality of findings (1) and (2). The exclusion criteria were (1) incomplete medical records and (2) moyamoya syndrome caused by atherosclerosis, autoimmune diseases, meningitis, brain tumor, Down syndrome, neurofibromatosis, head trauma, cerebrovascular injury due to head radiation irradiation, and other clearly defined causes. 2.2 Data collection Clinical data and biological samples were collected. Clinical data included patients' medical history, imaging examination, laboratory results, and cognitive function results. Table 1 presents the specific assessment contents. 2.2.1 Clinical data 2.2.1.1 Medical history data We collected demographic and clinical data, including age, sex, place of birth, time of admission, marital status, occupation, first symptoms, co-existing diseases, past medical history, familial history, cerebrovascular events, surgery, and drug therapy. The first symptom type, onset time, and attack frequency were also recorded. Cerebrovascular events were determined based on the clinical history and an imaging examination. Modified Rankin Scale and National Institute of Health Stroke Scale scores were used for evaluating survival status and scored by professionally trained neurologists. 2.2.1.2 Imaging data A dedicated individual gathered C-MMD imaging data systematically starting in 2002. All images were stored in a dedicated radiology film library and backed up electronically. The C-MMD study collected patients' DSA, magnetic resonance imaging, MRA, perfusion-weighted imaging, contrast-enhanced high-resolution magnetic wall imaging, computerized tomography, emission computerized tomography, positron emission tomography-computed tomography, and transcranial Doppler ultrasound images. The DSA Suzuki grade, [ 23 ] post-operative Matsushima grade, [ 24 ] and MMD collateral grading score [ 25 ] were also analyzed. 2.2.1.3 Cognitive function Systematic cognitive function assessments were conducted. Cognitive data were collected by a qualified and trained specialist (Hou-Di Zhang). Nine cognitive assessment scales were used, including the Montreal Cognitive Assessment, [ 26 , 27 ] the Mini-Mental State Examination, [ 28 ] Activity of Daily Living Scale, [ 29 , 30 ] the 17-item Hamilton Rating Scale for Depression, [ 31 ] clock drawing test, [ 32 ] the Chinese auditory verbal learning test, [ 28 , 33 ] Trail Making Test A and B, [ 34 ] and Boston Naming Test. [ 35 ] 2.2.1.4 Laboratory examination Patients were routinely tested on the second day of each admission for routine blood tests, blood biochemical tests, and immune tests. 2.2.2 Biological sample collection Biological samples were retained for further investigation to assess the etiology of MMD and identify biomarkers that reflect disease progression. A written informed consent form approved by the Ethics Committee of PLA General Hospital was signed by the patient or their guardian before biological sample collection. Blood samples (4 mL EDTA tube and 4 mL SST tube) and urine samples (10 mL) were collected and stored in four parts in a -80°C freezer. 2.3 Follow up The C-MMD study design was a historical prospective cohort with follow-up from the time of first admission to the hospital. The follow-up methods included in-hospital and out-of-hospital follow-ups. In-hospital follow-ups included in-hospital and out-patient follow-ups. Out-of-hospital follow-ups consisted of email, telephone, WeChat, and electronic medical record follow-ups. Follow-ups were mainly conducted by one trained researcher (Qian Zhang) and performed three and six months after discharge and every year after that. 2.4 Data management and quality control A web-based electronic data capture system was used to capture all clinical data. An independent data safety and monitoring committee was established to supervise the conduct of the C-MMD study, composed of clinicians and statistical experts. Regular meetings occurred to ensure that the study design and data statistics were scientific. The cohort was quality controlled by the professional statistics team of the Department of Statistics and Epidemiology, Graduate School, Chinese PLA General Hospital, and all data were entered by professionally trained medical staff and epidemiology professionals. All information was checked by the C-MMD data safety and monitoring committee. The Ethics Committee of the General Hospital of the Chinese People's Liberation Army approved this study (No. KY-2022-9-69-1). This study has been registered in the Chinese Clinical trial registry (registration number: ChiCTR2200064160). 3 Results 3.1 Demographic data The C-MMD cohort study enrolled 6,167 patients with MMD. All patients were admitted to the Department of Neurosurgery at the Chinese PLA General Hospital between April 2002 and May 2022. Each patient had a unique patient ID number and complete clinical records available in the hospital’s database. The patients were from 32 provinces in China. The primary ethnic group was Han Chinese (98.9%); Mongolian, Manchu, and 11 other minority nationalities accounted for 1.1%. The male-to-female ratio was nearly 1:1 (3,096:3,068). The youngest patient was three months old at the onset time, and the oldest was 75 years old. The mean age at admission was 34.78 years, and the age distribution was bimodal (Fig. 1 ). More women were aged 15 to 24 than men (female-to-male ratio, 3:2 [294:189]). The age distributions of other groups were similar (Figure 2). The primary onset symptom was a transient ischemic attack (TIA). The proportion of patients with TIA was comparable to that of Japanese and South Korean patients but higher than that of European and American populations. Compared to the national hospital MMD survey led by Tiantan Hospital, the proportion of patients with cerebral infarction and cerebral hemorrhage was slightly lower than those with TIA but similar to that of the Japanese epidemiological survey (Figure 3). Most patients in the C-MMD cohort were from the Hebei, Shandong, and Henan provinces. 3.2 Familial occurrence The proportion of patients with a family history was 7.1% (442/6,167). Of the 6,167 patients with MMD, 122 patients had siblings with an MMD diagnosis, 68 had mothers with MMD, and 102 had fathers with MMD. Cerebral or MRA exams were performed on all family members mentioned earlier. 3.3 Follow-up Overall, 61.6% (3801/6167) of the patients underwent in-hospital follow-ups. The rate of overall follow-up using standardized and active out-of-hospital follow-up assessments was 92.6%. The primary follow-up concerns were the changes in symptoms, laboratory results, imaging indicators, and drug use in other hospitals. 4 Discussion MMD was first reported in 1957 [ 2 ] and is highly prevalent among people of Asian descent, especially those of East Asia. Furthermore, as MRA and computed tomography angiography examinations have become more accessible, more cases of MMD have been discovered. For instance, in Japan, approximately 0.07% of individuals in the general population have MMD, with an estimated prevalence of 50.7/100,000 people. [ 36 ] Korea's Ministry of Health and Welfare reported a 15% increase in the prevalence of MMD from 2004 to 2008 (from 5.2/100,000 people to 9.1/100,000), reaching 18.1/100,000 in 2013. [ 4 ] Additionally, recent epidemiological studies in China reported that the number of new MMD cases increased from 0.88/100,000 people in 2016 to 1.47/100,000 in 2018. [ 7 ] European and American countries experience lower rates of MMD than East Asian countries, but their incidence rates have also increased over the past few years. [ 15 ] For example, the U.S. Department of Health Insurance and the National Inpatient System reported 2,247 MMD-related hospitalizations from 1988 to 2004 and 7,473 hospitalizations from 2005 to 2008. [ 14 , 16 ] Japanese and Korean studies have reported two onset age peaks for MMD: first in childhood (average age: 5 to 10 years), then in adulthood (average age: 40 to 50 years). [ 4 , 5 ] In the C-MMD cohort, the onset age varied from 0 to 77 years, with two peaks similar to those reported in the Japanese and South Korean studies. Conversely, an epidemiological MMD study led by Tiantan Hospital that included 47,443 patients admitted to 1,312 hospitals in China between 2016 and 2018 [ 7 ] reported a unimodal age distribution. We propose two explanations for these conflicting results. First, there are no standard MMD symptoms; thus, some children with mild early symptoms may not have been diagnosed and treated at that time. Second, our center treated more children with MMD because we began systematically treating patients with MMD earlier and gave great attention to detecting and treating children with MMD. Asian epidemiological surveys from Japan reported more female patients with MMD than men (female-to-male ratio, from 1.8:1 to 2.2:1), [ 5 , 13 ] as did studies of heterogeneous American populations (2.5:1 and 1.8:1) [ 14 ] and a white European population (4.25:1). [ 37 ] The C-MMD cohort ratio was 1:1, consistent with Chinese epidemiology research. [ 7 ] Hence, Chinese patients with MMD may have a unique genetic background. Patients with MMD can present with various symptoms, mainly classified as cerebral ischemia, cerebral hemorrhages, and others. [ 38 , 39 ] However, improved screening methods have increased the number of patients with MMD without obvious clinical symptoms. [ 36 ] The molecular etiology and natural progression of MMD and the lack of effective animal models necessitate a large cohort study to summarize clinical characteristics and explore possible pathogenic mechanisms. [ 6 ] As a result, our team collected clinical and biological data on 6,167 patients with MMD. The C-MMD study is an ongoing nationwide real-world observational study registered in PLA General Hospital in China. Consequently, the C-MMD study is one of the most extensive MMD cohort studies with some notable strengths. First, this study collected various forms of information, including patients' symptomatology, imaging, laboratory examination, and cognitive function data, resulting in a compressive collection of data that enables disease severity and survival status evaluations from multiple perspectives. Second, the follow-up time was extensive, with a low loss-to-follow-up rate. This study systematically includes patients with MMD starting in 2002, and over the past 20 years, our team has maintained good doctor-patient relationships. Furthermore, many patients were hospitalized for multiple follow-up visits, providing good conditions for monitoring the natural course of MMD. Third, we built a valuable biobank and subsequently identified some MMD susceptibility genes in the Chinese population through large sample genome-wide association studies. At present, 3,952 biological samples have been collected for the C-MMD study, providing good scope for further studies on the etiology of and biomarkers for MMD. 5 Limitations This study also has several limitations. First, the C-MMD study was conducted in Beijing, the capital of China; thus, many patients were referred to our hospital. Therefore, some medical records regarding the first onset were missing. Second, this single-center historically prospective hospital-based study may have selection and information bias. 6 Conclusion MMD is currently one of the largest single-center MMD cohorts in the world. This study provides baseline data for future research on the etiology and natural course of the disease. Declarations Funding This research was supported by the National Natural Science Foundation of China (Grant no: 82171280). Competing Interests The authors have no relevant financial or non-financial interests to disclose. Author Contributions The C-MMD cohort is established and the data collection is conducted by the steering committee with teams (F.H., M.L., C.H., G.G., S.L., M.W., R.Y., Z.Z., D.Y., Q.Z., H.Z., Q.G., X.W., X.S., H.F., J.L., Z.Z., X.B., J.F., B.L., B.R., H.W., Q.W., S.P., B.Z., Z. Z., Y. H., Z. S., M. L., and L.D.). L.D., M.L., C.H., and F.H. designed this study. F.H. supervised the research and drafted the manuscript. M.L. and F.H. organized and analyzed the data. All authors contributed to data analysis, assisted with data interpretation, and critically revised and approved the manuscript. Ethics Approval The Ethics Committee of the General Hospital of the Chinese People's Liberation Army approved this study (No. KY-2022-9-69-1). This study has been registered in the Chinese Clinical trial registry (registration number: ChiCTR2200064160). Consent to Participate A written informed consent form approved by the Ethics Committee of PLA General Hospital was signed by each patient or guardian before biological sample collection. Consent to Publish All authors agree to publish. Acknowledgments We would like to extend our sincere gratitude to all participants in the C-MMD study, as well as all members of the research team. We would like to thank Editage (www.editage.cn) for English language editing. References Kuroda S, Houkin K. Moyamoya disease: current concepts and future perspectives. Lancet Neurol. 2008;7:1056–66. https://doi.org/10.1016/S1474-4422(08)70240-0 Scott RM, Smith ER. Moyamoya disease and Moyamoya syndrome. N Engl J Med. 2009;360:1226–37. https://doi.org/10.1056/NEJMra0804622 Sun Y, Zhou G, Feng J, Chen L, Liu G, Wang J, et al. Incidence and prevalence of Moyamoya disease in urban China: a nationwide retrospective cohort study. Stroke Vasc Neurol. 2021;6:615–23. https://doi.org/10.1136/svn-2021-000909 Kim T, Lee H, Bang JS, Kwon OK, Hwang G, Oh CW. Epidemiology of Moyamoya disease in Korea: based on National Health Insurance Service data. J Korean Neurosurg Soc. 2015;57:390–5. https://doi.org/10.3340/jkns.2015.57.6.390 Hoshino H, Izawa Y, Suzuki N, Research Committee on Moyamoya Disease. Epidemiological features of Moyamoya disease in Japan. Neurol Med Chir (Tokyo) . 2012;52:295–8. https://doi.org/10.2176/nmc.52.295 Ihara M, Yamamoto Y, Hattori Y, Liu W, Kobayashi H, Ishiyama H, et al. Moyamoya disease: diagnosis and interventions. Lancet Neurol. 2022;21:747–58. https://doi.org/10.1016/S1474-4422(22)00165-X Zhang D, Huang L, Huang Z, Zhou Q, Yang X, Gu H, et al. Epidemiology of Moyamoya disease in China: A nationwide hospital-based study. Lancet Reg Health West Pac. 2022;18:100331. https://doi.org/10.1016/j.lanwpc.2021.100331 Sato Y, Kazumata K, Nakatani E, Houkin K, Kanatani Y. Characteristics of Moyamoya disease based on national registry data in Japan. Stroke . 2019;50:1973–80. https://doi.org/10.1161/STROKEAHA.119.024689 Birkeland P, Lauritsen J. Incidence of Moyamoya disease in Denmark: A population-based register study. Acta Neurochir Suppl. 2018;129:91–3 Gaillard J, Klein J, Duran D, Storey A, Scott RM, Kahle K, et al. Incidence, clinical features, and treatment of familial moyamoya in pediatric patients: a single-institution series. J Neurosurg Pediatr. 2017;19:553–9. https://doi.org/10.3171/2016.12.PEDS16468 Hammond CK, Shapson-Coe A, Govender R, van Toorn R, Ndondo A, Wieselthaler N, et al. Moyamoya syndrome in South African children with HIV-1 infection. J Child Neurol. 2016;31:1010–7. https://doi.org/10.1177/0883073816635747 Kossorotoff M, Hervé D, Toulgoat F, Renaud C, Presles E, Chabriat H, et al. Paediatric moyamoya in mainland France: a comprehensive survey of academic neuropaediatric centres. Cerebrovasc Dis. 2012;33:76–9. https://doi.org/10.1159/000333424 Kuriyama S, Kusaka Y, Fujimura M, Wakai K, Tamakoshi A, Hashimoto S, et al. Prevalence and clinicoepidemiological features of Moyamoya disease in Japan: findings from a nationwi de epidemiological survey. Stroke . 2008;39:42–7. https://doi.org/10.1161/STROKEAHA.107.490714 Kainth D, Chaudhry SA, Kainth H, Suri FK, Qureshi AI. Epidemiological and clinical features of Moyamoya disease in the USA. Neuroepidemiology . 2013;40:282–7. https://doi.org/10.1159/000345957 Starke RM, Crowley RW, Maltenfort M, Jabbour PM, Gonzalez LF, Tjoumakaris SI, et al. Moyamoya disorder in the United States. Neurosurgery . 2012;71:93–9. https://doi.org/10.1227/NEU.0b013e318253ab8e Lee DJ, Liebeskind DS. Characterization of inpatient moyamoya in the United States: 1988–2004. Front Neurol. 2011;2:43. https://doi.org/10.3389/fneur.2011.00043 Uchino K, Johnston SC, Becker KJ, Tirschwell DL. Moyamoya disease in Washington State and California. Neurology . 2005;65:956–8. https://doi.org/10.1212/01.wnl.0000176066.33797.82 Rosi A, Riordan CP, Smith ER, Scott RM, Orbach DB. Clinical status and evolution in moyamoya: which angiographic findings correlate? Brain Commun. 2019;1:fcz029. https://doi.org/10.1093/braincomms/fcz029 Dorschel KB, Wanebo JE. Genetic and proteomic contributions to the pathophysiology of moyamoya angiopathy and related vascular diseases. Appl Clin Genet. 2021;14:145–71. https://doi.org/10.2147/TACG.S252736 Huang S, Guo ZN, Shi M, Yang Y, Rao M. Etiology and pathogenesis of Moyamoya disease: an update on disease prevalence. Int J Stroke . 2017;12:246–53. https://doi.org/10.1177/1747493017694393 Duan L, Wei L, Tian Y, Zhang Z, Hu P, Wei Q, et al. Novel susceptibility loci for Moyamoya disease revealed by a genome-wide association study. Stroke . 2018;49:11–8. https://doi.org/10.1161/STROKEAHA.117.017430 Kuroda S, Fujimura M, Takahashi J, Kataoka H, Ogasawara K, Iwama T, et al.. Diagnostic Criteria for Moyamoya Disease – 2021 Revised Version. Neurol Med Chir (Tokyo). rev. version . 2022;62:307–12. https://doi.org/10.2176/jns-nmc.2022-0072 Suzuki J, Takaku A. Cerebrovascular “moyamoya” disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol. 1969;20:288–99. https://doi.org/10.1001/archneur.1969.00480090076012 Matsushima T, Inoue T, Suzuki SO, Fujii K, Fukui M, Hasuo K. Surgical treatment of Moyamoya disease in pediatric patients--comparison between the results of indir ect and direct revascularization procedures. Neurosurgery . 1992;31:401–5. https://doi.org/10.1227/00006123-199209000-00003 Liu ZW, Han C, Zhao F, Qiao PG, Wang H, Bao XY, et al. Collateral circulation in Moyamoya disease: A new grading system. Stroke . 2019;50:2708–15. https://doi.org/10.1161/STROKEAHA.119.024487 Smith CR, Cavanagh J, Sheridan M, Grosset KA, Cullen B, Grosset DG. Factor structure of the Montreal Cognitive Assessment in Parkinson disease. Int J Geriatr Psychiatry . 2020;35:188–94. https://doi.org/10.1002/gps.5234 Kasten M, Bruggemann N, Schmidt A, Klein C. Validity of the MoCA and MMSE in the detection of MCI and dementia in Parkinson disease. Neurology . 2010;75:478; author reply 478–9. https://doi.org/10.1212/WNL.0b013e3181e7948a Shen XX, Zhang HD, Fu HG, Xu JL, Zhang HT, Hou L, et al. Association of cognitive function and hypoperfusion in Moyamoya disease patients without stroke. J Cereb Blood Flow Metab. 2022:271678X221140349 Lahav O, Katz N. Independent older adult’s IADL and executive function according to cognitive performance. OTJR (Thorofare N J) . 2020;40:183–9. https://doi.org/10.1177/1539449220905813 Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist . 1969;9:179–86. https://doi.org/10.1093/geront/9.3_Part_1.179 Lin CH, Park C, McIntyre RS. Early improvement in HAMD-17 and HAMD-7 scores predict response and remission in depressed patients treated with fluoxetine or electroconvulsive therapy. J Affect Disord. 2019;253:154–61. https://doi.org/10.1016/j.jad.2019.04.082 Yamamoto S, Mogi N, Umegaki H, Suzuki Y, Ando F, Shimokata H, et al. The clock drawing test as a valid screening method for mild cognitive impairment. Dement Geriatr Cogn Disord. 2004;18:172–9. https://doi.org/10.1159/000079198 Leung AW, Cheng SK, Mak AK, Leung KK, Li LS, Lee TM. Functional gain in hemorrhagic stroke patients is predicted by functional level and cognitive abilities measured at hospital admission. NeuroRehabilitation . 2010;27:351–8. https://doi.org/10.3233/NRE-2010-0619 Rossini ED, Karl MA. The Trail Making Test A and B: a technical note on structural nonequivalence. Percept Mot Skills. 1994;78:625–6. https://doi.org/10.2466/pms.1994.78.2.625 Leite KS, Miotto EC, Nitrini R, Yassuda MS, Test BN. Boston Naming Test (BNT) original, Brazilian adapted version and short forms: normative data for illiterate and low-educated older adults. Int Psychogeriatr. 2017;29:825–33. https://doi.org/10.1017/S1041610216001952 Ikeda K, Iwasaki Y, Kashihara H, Hosozawa KI, Anan K, Tamura M, et al. Adult Moyamoya disease in the asymptomatic Japanese population. J Clin Neurosci. 2006;13:334–8. https://doi.org/10.1016/j.jocn.2005.02.026 Acker G, Goerdes S, Schneider UC, Schmiedek P, Czabanka M, Vajkoczy P. Distinct clinical and radiographic characteristics of Moyamoya disease amongst European Caucasians. Eur J Neurol. 2015;22:1012–7. https://doi.org/10.1111/ene.12702 Hirano Y, Miyawaki S, Imai H, Hongo H, Teranishi Y, Dofuku S, et al. Differences in clinical features among different onset patterns in Moyamoya disease. J Clin Med. 2021;10:2815. https://doi.org/10.3390/jcm10132815 Hirano Y, Miyawaki S, Imai H, Hongo H, Ohara K, Dofuku S, et al. Association between the onset pattern of adult Moyamoya disease and risk factors for stroke. Stroke . 2020;51:3124–8. https://doi.org/10.1161/STROKEAHA.120.030653 Funaki T, Takahashi JC, Houkin K, Kuroda S, Takeuchi S, Fujimura M, et al. Angiographic features of hemorrhagic Moyamoya disease with high recurrence risk: a supplementary analysis of the Japan Adult moyamoya Trial. J Neurosurg. 2018;128:777–84. https://doi.org/10.3171/2016.11.JNS161650 Bersano A, Bedini G, Nava S, Acerbi F, Sebastiano DR, Binelli S, et al. GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of Moyamoya disease-study protocol and preliminary results. Neurol Sci. 2019;40:561–70. https://doi.org/10.1007/s10072-018-3664-z Table Table 1 is not available with this version. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2799246","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":192678027,"identity":"7fa10401-f0c2-4b3f-bf10-0bb07dc942da","order_by":0,"name":"Fangbin Hao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzElEQVRIiWNgGAWjYBACfv7mA4f/VNjIMbY3EKlFcsaxxAc8Z9KMmXsOEKnFoCHH2IC37XBi+4wEYrUwHDCTkGBjNuad+XjjDYYam2iCWsyZG9IkDHjY5CRnpxVbMBxLy20gpMWy4cAxiQQJHmPD2TlmEowNhwlrMTiQ2CZxwEAicf/NM0RrSWY2bEgwSGycwUOkFmAgMz5mOJBgzNgD9EsCMX7h5+//cJjx339gVB7eeONDjQ1hLSiOlEggRTlEC6k6RsEoGAWjYGQAADytQouPiiDcAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-5607-6926","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Fangbin","middleName":"","lastName":"Hao","suffix":""},{"id":192678028,"identity":"4231137e-51f0-4581-9125-3ca10c87b62b","order_by":1,"name":"Cong Han","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Cong","middleName":"","lastName":"Han","suffix":""},{"id":192678029,"identity":"57e8e247-f17b-4f26-ae65-96761f311674","order_by":2,"name":"Gan Gao","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Gan","middleName":"","lastName":"Gao","suffix":""},{"id":192678030,"identity":"f47fded5-b53d-4406-bde1-b68c532a682e","order_by":3,"name":"Simeng Liu","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Simeng","middleName":"","lastName":"Liu","suffix":""},{"id":192678031,"identity":"fe787bef-a32e-43d9-8b2f-be9dc30c4066","order_by":4,"name":"MinJie Wang","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"MinJie","middleName":"","lastName":"Wang","suffix":""},{"id":192678032,"identity":"0de2de10-bfee-4437-85c2-0cf2671c0bb7","order_by":5,"name":"Rimiao Yang","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rimiao","middleName":"","lastName":"Yang","suffix":""},{"id":192678033,"identity":"0a5bf441-8709-42d2-b937-243c7c8f660f","order_by":6,"name":"Zhengxing Zou","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhengxing","middleName":"","lastName":"Zou","suffix":""},{"id":192678034,"identity":"d97f9be9-52ec-47cf-9321-55e8a08a7097","order_by":7,"name":"Dan Yu","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Dan","middleName":"","lastName":"Yu","suffix":""},{"id":192678035,"identity":"85a5aac9-a74a-431f-a3c9-44d66d2f3e93","order_by":8,"name":"Caihong Sun","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Caihong","middleName":"","lastName":"Sun","suffix":""},{"id":192678036,"identity":"ea12b91b-f1d4-4d34-a00b-6395240c68ad","order_by":9,"name":"Qian Zhang","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Zhang","suffix":""},{"id":192678037,"identity":"360508b6-bfeb-4829-8457-0bacf7801efb","order_by":10,"name":"Houdi Zhang","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Houdi","middleName":"","lastName":"Zhang","suffix":""},{"id":192678038,"identity":"b6c040d0-8440-49e3-ad01-473ba3c7fd4c","order_by":11,"name":"Qing-Bao Guo","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qing-Bao","middleName":"","lastName":"Guo","suffix":""},{"id":192678039,"identity":"a3c35b0a-c468-4fd1-964a-3453bd5a5f45","order_by":12,"name":"Xiaopeng Wang","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaopeng","middleName":"","lastName":"Wang","suffix":""},{"id":192678040,"identity":"efd00867-f9d7-40e1-ad3a-ff2d5abe3ded","order_by":13,"name":"XuXuan Shen","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"XuXuan","middleName":"","lastName":"Shen","suffix":""},{"id":192678041,"identity":"0be9fedb-a28a-45e6-864c-3d6545b6ada8","order_by":14,"name":"Heguan Fu","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Heguan","middleName":"","lastName":"Fu","suffix":""},{"id":192678042,"identity":"d7dbe77a-0402-4b1f-a387-32ed4e257484","order_by":15,"name":"JingJie Li","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"JingJie","middleName":"","lastName":"Li","suffix":""},{"id":192678043,"identity":"35a60a86-1bd3-4659-b784-0a9917307545","order_by":16,"name":"Zhengshan Zhang","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhengshan","middleName":"","lastName":"Zhang","suffix":""},{"id":192678044,"identity":"a04523d9-43a3-4b44-a092-08761893b64c","order_by":17,"name":"Xiangyang Bao","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiangyang","middleName":"","lastName":"Bao","suffix":""},{"id":192678045,"identity":"4013eb2b-f1e7-4426-9a4f-4524e106b853","order_by":18,"name":"Jie Feng","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Feng","suffix":""},{"id":192678046,"identity":"cf9a5d85-c866-4815-b7a8-dd874f7b7627","order_by":19,"name":"Bin Li","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Bin","middleName":"","lastName":"Li","suffix":""},{"id":192678047,"identity":"7d334c6d-deb2-4252-9778-b58d68770c8f","order_by":20,"name":"Bin Ren","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Bin","middleName":"","lastName":"Ren","suffix":""},{"id":192678048,"identity":"80af7a42-6f19-4410-a8dc-bbd9b28a0348","order_by":21,"name":"Hui Wang","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Wang","suffix":""},{"id":192678049,"identity":"d7abe9e4-b1cb-4910-8318-be2dac52f6a7","order_by":22,"name":"Qiannan Wang","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qiannan","middleName":"","lastName":"Wang","suffix":""},{"id":192678050,"identity":"275ebce0-5f50-4c72-ae3e-540eb1e33d6b","order_by":23,"name":"Songtao Pei","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Songtao","middleName":"","lastName":"Pei","suffix":""},{"id":192678051,"identity":"aa440740-97e3-4632-a285-035ae1a3ec1d","order_by":24,"name":"Bo Zhao","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Bo","middleName":"","lastName":"Zhao","suffix":""},{"id":192678052,"identity":"58246bcf-1158-4d78-9da5-aa104d4e6b1b","order_by":25,"name":"Zhenglong Zou","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhenglong","middleName":"","lastName":"Zou","suffix":""},{"id":192678053,"identity":"93ae3345-988e-4f8c-a5d7-8f89906b8b32","order_by":26,"name":"Yiqin Han","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yiqin","middleName":"","lastName":"Han","suffix":""},{"id":192678054,"identity":"a81bb621-a0e6-4c53-9d46-bd5f36511551","order_by":27,"name":"Huaiyu Tong","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Huaiyu","middleName":"","lastName":"Tong","suffix":""},{"id":192678055,"identity":"bfff9a0f-8f11-4742-b840-097471f00219","order_by":28,"name":"Zhenghui Sun","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhenghui","middleName":"","lastName":"Sun","suffix":""},{"id":192678056,"identity":"cebe3a38-2063-4f2e-a7e9-7a217fca023c","order_by":29,"name":"Miao Liu","email":"","orcid":"","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Miao","middleName":"","lastName":"Liu","suffix":""},{"id":192678057,"identity":"d71256bb-df1b-4286-95dc-3880b633db03","order_by":30,"name":"Lian Duan","email":"","orcid":"https://orcid.org/0000-0001-7210-056X","institution":"PLAGH: Chinese PLA General Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lian","middleName":"","lastName":"Duan","suffix":""}],"badges":[],"createdAt":"2023-04-10 15:09:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2799246/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2799246/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":36009930,"identity":"cf152fac-ef02-40b4-9821-6f0b1e4416ab","added_by":"auto","created_at":"2023-04-19 15:09:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":10607,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAge distribution of C-MMD patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eC-MMD: Chinese moyamoya disease\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-2799246/v1/ef35e49e35051ffe4bba8c83.png"},{"id":36009929,"identity":"d12570dd-78cc-4651-8cc9-c77c49d73ada","added_by":"auto","created_at":"2023-04-19 15:09:57","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":12967,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDistribution of male-to-female ratios in C-MMD patients at different ages\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eC-MMD: Chinese moyamoya disease\u003c/p\u003e","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-2799246/v1/b567bcb6ad5a5ac6ca464766.png"},{"id":36009931,"identity":"fe273e78-8611-42fe-942b-7c187006ea6e","added_by":"auto","created_at":"2023-04-19 15:09:57","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":18876,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDistribution of first symptoms in C-MMD patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eC-MMD: Chinese moyamoya disease; TIA: transient ischemic attack\u003c/p\u003e","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-2799246/v1/87d7141a455cad8d9e8f8c35.png"},{"id":40194439,"identity":"9477cac8-0b33-4e6e-b177-7476aef2ac6a","added_by":"auto","created_at":"2023-07-18 13:31:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":485790,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2799246/v1/70b985e2-0246-41d4-bf29-fa6253aac333.pdf"}],"financialInterests":"","formattedTitle":"Cohort profile: Chinese moyamoya disease cohort study","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eMoyamoya disease (MMD) is a primary chronic cerebrovascular disorder characterized by gradual stenosis and occlusion of the bilateral distal internal carotid arteries and the proximal portion of the anterior or middle cerebral arteries. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] MMD is the most common pediatric cerebrovascular disease and the leading cause of stroke in children and young adults in Japan, Korea, and China. [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] Furthermore, MMD can manifest as ischemic or hemorrhagic strokes, seizures, and cognitive impairment, resulting in a high prevalence of disability and death. [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] The high disability rate of MMD also burdens the patients\u0026rsquo; families and society.\u003c/p\u003e \u003cp\u003eMMD is more prevalent in East Asian populations, such as Japan, Korea, and China, than in Europe, America, and Africa. [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] Furthermore, the incidence of MMD has been increasing for the last few years owing to increased numbers of evaluations and thus disease recognition. For example, the MMD incidence rate in Japan was 1.13/100,000 people in 2012, showing a nearly two-fold increase from 2003. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] This trend has also been observed in Korea, with an incidence rate of 18.1/100,000 people in 2013 versus 4.3/100,000 in 2005, a nearly three-fold increase. [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] China has the largest population in the world, and recent epidemiological data reported an annual increase in MMD from 2016 to 2018, from 0.88 to 1.47/100,00 people. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] The MMD incidence has also increased in the United States from 1988 to 2004; 2,247 patients with MMD were admitted to the hospital, but 7,473 patients were hospitalized from 2005 to 2008. Thus, the incidence rate increased from 0.086/100,000 people in 2005 to 0.57/100,000 in 2012. [\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eMMD is a serious disease with a poor prognosis; thus, the social burden increases with the number of MMD cases. However, the etiology, pathogenesis, and clinical course of MMD are unclear. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] Consequently, suitable animal models have not been established, and basic research has not progressed beyond the molecular and cellular levels. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] MMD susceptibility genes have been identified, such as ring finger protein 213-coding gene \u003cem\u003eRNF213\u003c/em\u003e; however, no apparent causative etiology factor has been found. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] Moreover, the clinical manifestations of MMD vary greatly, with considerable differences in the onset time, progression rate, disease severity, and therapeutic effect among patients. In addition, the genetic background of patients with MMD in China is complex; therefore, MMD subtypes may exist. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] Finally, few large-scale studies have been conducted on MMD. Thus, little is known about the clinical course.\u003c/p\u003e \u003cp\u003eClarifying the natural course of the disease and its etiology is an urgent issue. Over the last 20 years, our institution has collected clinical information on patients with MMD treated at our center, establishing the Chinese MMD (C-MMD) cohort. Therefore, this study assessed the C-MMD cohort to elucidate the clinical course and the etiology of MMD.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study population\u003c/h2\u003e \u003cp\u003eThe C-MMD cohort study is a Chinese nationwide observational study comprising patients registered at PLA General Hospital and then followed up in a real-world setting. The inclusion criteria were based on the 2021 Guidelines for the diagnosis of MMD. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe inclusion criteria were: (1) The presence of stenosis or occlusion of the intracranial internal carotid artery or proximal portions of the anterior or middle cerebral arteries on digital subtraction angiography (DSA) or magnetic resonance angiography (MRA); (2) observation of abnormal vascular networks during the arterial phase of the disease near occlusive or stenotic lesions on DSA or abnormal vascular networks in the basal ganglia on MRA; and (3) bilaterality of findings (1) and (2).\u003c/p\u003e \u003cp\u003eThe exclusion criteria were (1) incomplete medical records and (2) moyamoya syndrome caused by atherosclerosis, autoimmune diseases, meningitis, brain tumor, Down syndrome, neurofibromatosis, head trauma, cerebrovascular injury due to head radiation irradiation, and other clearly defined causes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Data collection\u003c/h2\u003e \u003cp\u003eClinical data and biological samples were collected. Clinical data included patients' medical history, imaging examination, laboratory results, and cognitive function results. Table\u0026nbsp;1 presents the specific assessment contents.\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003e2.2.1 Clinical data\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section4\"\u003e \u003ch2\u003e2.2.1.1 Medical history data\u003c/h2\u003e \u003cp\u003eWe collected demographic and clinical data, including age, sex, place of birth, time of admission, marital status, occupation, first symptoms, co-existing diseases, past medical history, familial history, cerebrovascular events, surgery, and drug therapy. The first symptom type, onset time, and attack frequency were also recorded. Cerebrovascular events were determined based on the clinical history and an imaging examination. Modified Rankin Scale and National Institute of Health Stroke Scale scores were used for evaluating survival status and scored by professionally trained neurologists.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section4\"\u003e \u003ch2\u003e2.2.1.2 Imaging data\u003c/h2\u003e \u003cp\u003eA dedicated individual gathered C-MMD imaging data systematically starting in 2002. All images were stored in a dedicated radiology film library and backed up electronically. The C-MMD study collected patients' DSA, magnetic resonance imaging, MRA, perfusion-weighted imaging, contrast-enhanced high-resolution magnetic wall imaging, computerized tomography, emission computerized tomography, positron emission tomography-computed tomography, and transcranial Doppler ultrasound images. The DSA Suzuki grade, [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] post-operative Matsushima grade, [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] and MMD collateral grading score [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] were also analyzed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section4\"\u003e \u003ch2\u003e2.2.1.3 Cognitive function\u003c/h2\u003e \u003cp\u003eSystematic cognitive function assessments were conducted. Cognitive data were collected by a qualified and trained specialist (Hou-Di Zhang). Nine cognitive assessment scales were used, including the Montreal Cognitive Assessment, [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] the Mini-Mental State Examination, [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] Activity of Daily Living Scale, [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] the 17-item Hamilton Rating Scale for Depression, [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] clock drawing test, [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e] the Chinese auditory verbal learning test, [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] Trail Making Test A and B, [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] and Boston Naming Test. [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section4\"\u003e \u003ch2\u003e2.2.1.4 Laboratory examination\u003c/h2\u003e \u003cp\u003ePatients were routinely tested on the second day of each admission for routine blood tests, blood biochemical tests, and immune tests.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e2.2.2 Biological sample collection\u003c/h2\u003e \u003cp\u003eBiological samples were retained for further investigation to assess the etiology of MMD and identify biomarkers that reflect disease progression. A written informed consent form approved by the Ethics Committee of PLA General Hospital was signed by the patient or their guardian before biological sample collection. Blood samples (4 mL EDTA tube and 4 mL SST tube) and urine samples (10 mL) were collected and stored in four parts in a -80\u0026deg;C freezer.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Follow up\u003c/h2\u003e \u003cp\u003eThe C-MMD study design was a historical prospective cohort with follow-up from the time of first admission to the hospital. The follow-up methods included in-hospital and out-of-hospital follow-ups. In-hospital follow-ups included in-hospital and out-patient follow-ups. Out-of-hospital follow-ups consisted of email, telephone, WeChat, and electronic medical record follow-ups. Follow-ups were mainly conducted by one trained researcher (Qian Zhang) and performed three and six months after discharge and every year after that.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Data management and quality control\u003c/h2\u003e \u003cp\u003eA web-based electronic data capture system was used to capture all clinical data. An independent data safety and monitoring committee was established to supervise the conduct of the C-MMD study, composed of clinicians and statistical experts. Regular meetings occurred to ensure that the study design and data statistics were scientific. The cohort was quality controlled by the professional statistics team of the Department of Statistics and Epidemiology, Graduate School, Chinese PLA General Hospital, and all data were entered by professionally trained medical staff and epidemiology professionals. All information was checked by the C-MMD data safety and monitoring committee.\u003c/p\u003e \u003cp\u003e The Ethics Committee of the General Hospital of the Chinese People's Liberation Army approved this study (No. KY-2022-9-69-1). This study has been registered in the Chinese Clinical trial registry (registration number: ChiCTR2200064160).\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv class=\"Section2\" id=\"Sec14\"\u003e\n \u003ch2\u003e3.1 Demographic data\u003c/h2\u003e\n \u003cp\u003eThe C-MMD cohort study enrolled 6,167 patients with MMD. All patients were admitted to the Department of Neurosurgery at the Chinese PLA General Hospital between April 2002 and May 2022. Each patient had a unique patient ID number and complete clinical records available in the hospital\u0026rsquo;s database. The patients were from 32 provinces in China. The primary ethnic group was Han Chinese (98.9%); Mongolian, Manchu, and 11 other minority nationalities accounted for 1.1%. The male-to-female ratio was nearly 1:1 (3,096:3,068). The youngest patient was three months old at the onset time, and the oldest was 75 years old. The mean age at admission was 34.78 years, and the age distribution was bimodal (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003eMore women were aged 15 to 24 than men (female-to-male ratio, 3:2 [294:189]). The age distributions of other groups were similar (Figure 2).\u003c/p\u003e\n\u003cp\u003eThe primary onset symptom was a transient ischemic attack (TIA). The proportion of patients with TIA was comparable to that of Japanese and South Korean patients but higher than that of European and American populations. Compared to the national hospital MMD survey led by Tiantan Hospital, the proportion of patients with cerebral infarction and cerebral hemorrhage was slightly lower than those with TIA but similar to that of the Japanese epidemiological survey (Figure 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMost patients in the C-MMD cohort were from the Hebei, Shandong, and Henan provinces.\u003c/p\u003e\n\u003cdiv class=\"Section2\" id=\"Sec15\"\u003e\n \u003ch2\u003e3.2 Familial occurrence\u003c/h2\u003e\n \u003cp\u003eThe proportion of patients with a family history was 7.1% (442/6,167). Of the 6,167 patients with MMD, 122 patients had siblings with an MMD diagnosis, 68 had mothers with MMD, and 102 had fathers with MMD. Cerebral or MRA exams were performed on all family members mentioned earlier.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec16\"\u003e\n \u003ch2\u003e3.3 Follow-up\u003c/h2\u003e\n \u003cp\u003eOverall, 61.6% (3801/6167) of the patients underwent in-hospital follow-ups. The rate of overall follow-up using standardized and active out-of-hospital follow-up assessments was 92.6%. The primary follow-up concerns were the changes in symptoms, laboratory results, imaging indicators, and drug use in other hospitals.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eMMD was first reported in 1957 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] and is highly prevalent among people of Asian descent, especially those of East Asia. Furthermore, as MRA and computed tomography angiography examinations have become more accessible, more cases of MMD have been discovered. For instance, in Japan, approximately 0.07% of individuals in the general population have MMD, with an estimated prevalence of 50.7/100,000 people. [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] Korea's Ministry of Health and Welfare reported a 15% increase in the prevalence of MMD from 2004 to 2008 (from 5.2/100,000 people to 9.1/100,000), reaching 18.1/100,000 in 2013. [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] Additionally, recent epidemiological studies in China reported that the number of new MMD cases increased from 0.88/100,000 people in 2016 to 1.47/100,000 in 2018. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] European and American countries experience lower rates of MMD than East Asian countries, but their incidence rates have also increased over the past few years. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] For example, the U.S. Department of Health Insurance and the National Inpatient System reported 2,247 MMD-related hospitalizations from 1988 to 2004 and 7,473 hospitalizations from 2005 to 2008. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eJapanese and Korean studies have reported two onset age peaks for MMD: first in childhood (average age: 5 to 10 years), then in adulthood (average age: 40 to 50 years). [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] In the C-MMD cohort, the onset age varied from 0 to 77 years, with two peaks similar to those reported in the Japanese and South Korean studies. Conversely, an epidemiological MMD study led by Tiantan Hospital that included 47,443 patients admitted to 1,312 hospitals in China between 2016 and 2018 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] reported a unimodal age distribution. We propose two explanations for these conflicting results. First, there are no standard MMD symptoms; thus, some children with mild early symptoms may not have been diagnosed and treated at that time. Second, our center treated more children with MMD because we began systematically treating patients with MMD earlier and gave great attention to detecting and treating children with MMD.\u003c/p\u003e \u003cp\u003eAsian epidemiological surveys from Japan reported more female patients with MMD than men (female-to-male ratio, from 1.8:1 to 2.2:1), [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] as did studies of heterogeneous American populations (2.5:1 and 1.8:1) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] and a white European population (4.25:1). [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] The C-MMD cohort ratio was 1:1, consistent with Chinese epidemiology research. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Hence, Chinese patients with MMD may have a unique genetic background.\u003c/p\u003e \u003cp\u003ePatients with MMD can present with various symptoms, mainly classified as cerebral ischemia, cerebral hemorrhages, and others. [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] However, improved screening methods have increased the number of patients with MMD without obvious clinical symptoms. [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe molecular etiology and natural progression of MMD and the lack of effective animal models necessitate a large cohort study to summarize clinical characteristics and explore possible pathogenic mechanisms. [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] As a result, our team collected clinical and biological data on 6,167 patients with MMD. The C-MMD study is an ongoing nationwide real-world observational study registered in PLA General Hospital in China. Consequently, the C-MMD study is one of the most extensive MMD cohort studies with some notable strengths. First, this study collected various forms of information, including patients' symptomatology, imaging, laboratory examination, and cognitive function data, resulting in a compressive collection of data that enables disease severity and survival status evaluations from multiple perspectives. Second, the follow-up time was extensive, with a low loss-to-follow-up rate. This study systematically includes patients with MMD starting in 2002, and over the past 20 years, our team has maintained good doctor-patient relationships. Furthermore, many patients were hospitalized for multiple follow-up visits, providing good conditions for monitoring the natural course of MMD. Third, we built a valuable biobank and subsequently identified some MMD susceptibility genes in the Chinese population through large sample genome-wide association studies. At present, 3,952 biological samples have been collected for the C-MMD study, providing good scope for further studies on the etiology of and biomarkers for MMD.\u003c/p\u003e"},{"header":"5 Limitations","content":"\u003cp\u003eThis study also has several limitations. First, the C-MMD study was conducted in Beijing, the capital of China; thus, many patients were referred to our hospital. Therefore, some medical records regarding the first onset were missing. Second, this single-center historically prospective hospital-based study may have selection and information bias.\u003c/p\u003e"},{"header":"6 Conclusion","content":"\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eMMD is currently one of the largest single-center MMD cohorts in the world. This study provides baseline data for future research on the etiology and natural course of the disease.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003cbr\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eThis research was supported by the National Natural Science Foundation of China (Grant no: 82171280).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting Interests\u003cbr\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthor Contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe C-MMD cohort is established and the data collection is conducted by the steering committee with teams (F.H., M.L., C.H., G.G., S.L., M.W., R.Y., Z.Z., D.Y., Q.Z., H.Z., Q.G., X.W., X.S., H.F., J.L., Z.Z., X.B., J.F., B.L., B.R., H.W., Q.W., S.P., B.Z., Z. Z.,\u0026nbsp;Y.\u0026nbsp;H.,\u0026nbsp;Z.\u0026nbsp;S.,\u0026nbsp;M. L.,\u0026nbsp;and L.D.). L.D., M.L., C.H., and F.H. designed this study. F.H. supervised the research and drafted the manuscript. M.L. and F.H. organized and analyzed the data. All authors contributed to data analysis, assisted with data interpretation, and critically revised and approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics Approval\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eThe Ethics Committee of the General Hospital of the Chinese People\u0026apos;s Liberation Army approved this study (No. KY-2022-9-69-1). This study has been registered in the Chinese Clinical trial registry (registration number: ChiCTR2200064160).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent to Participate\u003cbr\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eA written informed consent form approved by the Ethics Committee of PLA General Hospital was signed by each patient or guardian before biological sample collection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent to Publish\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors agree to publish.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eAcknowledgments\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to extend our sincere gratitude to all participants in the C-MMD study, as well as all members of the research team. We would like to thank Editage (www.editage.cn) for English language editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKuroda S, Houkin K. Moyamoya disease: current concepts and future perspectives. Lancet Neurol. 2008;7:1056\u0026ndash;66. https://doi.org/10.1016/S1474-4422(08)70240-0\u003c/li\u003e\n\u003cli\u003eScott RM, Smith ER. Moyamoya disease and Moyamoya syndrome. N Engl J Med. 2009;360:1226\u0026ndash;37. https://doi.org/10.1056/NEJMra0804622\u003c/li\u003e\n\u003cli\u003eSun Y, Zhou G, Feng J, Chen L, Liu G, Wang J, et al. Incidence and prevalence of Moyamoya disease in urban China: a nationwide retrospective cohort study. Stroke Vasc Neurol. 2021;6:615\u0026ndash;23. https://doi.org/10.1136/svn-2021-000909\u003c/li\u003e\n\u003cli\u003eKim T, Lee H, Bang JS, Kwon OK, Hwang G, Oh CW. Epidemiology of Moyamoya disease in Korea: based on National Health Insurance Service data. J Korean Neurosurg Soc. 2015;57:390\u0026ndash;5. https://doi.org/10.3340/jkns.2015.57.6.390\u003c/li\u003e\n\u003cli\u003eHoshino H, Izawa Y, Suzuki N, Research Committee on Moyamoya Disease. Epidemiological features of Moyamoya disease in Japan. Neurol Med Chir (Tokyo)\u003cem\u003e.\u003c/em\u003e 2012;52:295\u0026ndash;8. https://doi.org/10.2176/nmc.52.295\u003c/li\u003e\n\u003cli\u003eIhara M, Yamamoto Y, Hattori Y, Liu W, Kobayashi H, Ishiyama H, et al. Moyamoya disease: diagnosis and interventions. Lancet Neurol. 2022;21:747\u0026ndash;58. https://doi.org/10.1016/S1474-4422(22)00165-X\u003c/li\u003e\n\u003cli\u003eZhang D, Huang L, Huang Z, Zhou Q, Yang X, Gu H, et al. Epidemiology of Moyamoya disease in China: A nationwide hospital-based study. Lancet Reg Health West Pac. 2022;18:100331. https://doi.org/10.1016/j.lanwpc.2021.100331\u003c/li\u003e\n\u003cli\u003eSato Y, Kazumata K, Nakatani E, Houkin K, Kanatani Y. Characteristics of Moyamoya disease based on national registry data in Japan. Stroke\u003cem\u003e.\u003c/em\u003e 2019;50:1973\u0026ndash;80. https://doi.org/10.1161/STROKEAHA.119.024689\u003c/li\u003e\n\u003cli\u003eBirkeland P, Lauritsen J. Incidence of Moyamoya disease in Denmark: A population-based register study. Acta Neurochir Suppl. 2018;129:91\u0026ndash;3\u003c/li\u003e\n\u003cli\u003eGaillard J, Klein J, Duran D, Storey A, Scott RM, Kahle K, et al. Incidence, clinical features, and treatment of familial moyamoya in pediatric patients: a single-institution series. J Neurosurg Pediatr. 2017;19:553\u0026ndash;9. https://doi.org/10.3171/2016.12.PEDS16468\u003c/li\u003e\n\u003cli\u003eHammond CK, Shapson-Coe A, Govender R, van Toorn R, Ndondo A, Wieselthaler N, et al. Moyamoya syndrome in South African children with HIV-1 infection. J Child Neurol. 2016;31:1010\u0026ndash;7. https://doi.org/10.1177/0883073816635747\u003c/li\u003e\n\u003cli\u003eKossorotoff M, Herv\u0026eacute; D, Toulgoat F, Renaud C, Presles E, Chabriat H, et al. Paediatric moyamoya in mainland France: a comprehensive survey of academic neuropaediatric centres. Cerebrovasc Dis. 2012;33:76\u0026ndash;9. https://doi.org/10.1159/000333424\u003c/li\u003e\n\u003cli\u003eKuriyama S, Kusaka Y, Fujimura M, Wakai K, Tamakoshi A, Hashimoto S, et al. Prevalence and clinicoepidemiological features of Moyamoya disease in Japan: findings from a nationwi de epidemiological survey. Stroke\u003cem\u003e.\u003c/em\u003e 2008;39:42\u0026ndash;7. https://doi.org/10.1161/STROKEAHA.107.490714\u003c/li\u003e\n\u003cli\u003eKainth D, Chaudhry SA, Kainth H, Suri FK, Qureshi AI. Epidemiological and clinical features of Moyamoya disease in the USA. Neuroepidemiology\u003cem\u003e.\u003c/em\u003e 2013;40:282\u0026ndash;7. https://doi.org/10.1159/000345957\u003c/li\u003e\n\u003cli\u003eStarke RM, Crowley RW, Maltenfort M, Jabbour PM, Gonzalez LF, Tjoumakaris SI, et al. Moyamoya disorder in the United States. Neurosurgery\u003cem\u003e.\u003c/em\u003e 2012;71:93\u0026ndash;9. https://doi.org/10.1227/NEU.0b013e318253ab8e\u003c/li\u003e\n\u003cli\u003eLee DJ, Liebeskind DS. Characterization of inpatient moyamoya in the United States: 1988\u0026ndash;2004. Front Neurol. 2011;2:43. https://doi.org/10.3389/fneur.2011.00043\u003c/li\u003e\n\u003cli\u003eUchino K, Johnston SC, Becker KJ, Tirschwell DL. Moyamoya disease in Washington State and California. Neurology\u003cem\u003e.\u003c/em\u003e 2005;65:956\u0026ndash;8. https://doi.org/10.1212/01.wnl.0000176066.33797.82\u003c/li\u003e\n\u003cli\u003eRosi A, Riordan CP, Smith ER, Scott RM, Orbach DB. Clinical status and evolution in moyamoya: which angiographic findings correlate? Brain Commun. 2019;1:fcz029. https://doi.org/10.1093/braincomms/fcz029\u003c/li\u003e\n\u003cli\u003eDorschel KB, Wanebo JE. Genetic and proteomic contributions to the pathophysiology of moyamoya angiopathy and related vascular diseases. Appl Clin Genet. 2021;14:145\u0026ndash;71. https://doi.org/10.2147/TACG.S252736\u003c/li\u003e\n\u003cli\u003eHuang S, Guo ZN, Shi M, Yang Y, Rao M. Etiology and pathogenesis of Moyamoya disease: an update on disease prevalence. Int J Stroke\u003cem\u003e.\u003c/em\u003e 2017;12:246\u0026ndash;53. https://doi.org/10.1177/1747493017694393\u003c/li\u003e\n\u003cli\u003eDuan L, Wei L, Tian Y, Zhang Z, Hu P, Wei Q, et al. Novel susceptibility loci for Moyamoya disease revealed by a genome-wide association study. Stroke\u003cem\u003e.\u003c/em\u003e 2018;49:11\u0026ndash;8. https://doi.org/10.1161/STROKEAHA.117.017430\u003c/li\u003e\n\u003cli\u003eKuroda S, Fujimura M, Takahashi J, Kataoka H, Ogasawara K, Iwama T, et al.. Diagnostic Criteria for Moyamoya Disease \u0026ndash; 2021 Revised Version. Neurol Med Chir (Tokyo). rev. version\u003cem\u003e.\u003c/em\u003e 2022;62:307\u0026ndash;12. https://doi.org/10.2176/jns-nmc.2022-0072\u003c/li\u003e\n\u003cli\u003eSuzuki J, Takaku A. Cerebrovascular \u0026ldquo;moyamoya\u0026rdquo; disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol. 1969;20:288\u0026ndash;99. https://doi.org/10.1001/archneur.1969.00480090076012\u003c/li\u003e\n\u003cli\u003eMatsushima T, Inoue T, Suzuki SO, Fujii K, Fukui M, Hasuo K. Surgical treatment of Moyamoya disease in pediatric patients--comparison between the results of indir ect and direct revascularization procedures. Neurosurgery\u003cem\u003e.\u003c/em\u003e 1992;31:401\u0026ndash;5. https://doi.org/10.1227/00006123-199209000-00003\u003c/li\u003e\n\u003cli\u003eLiu ZW, Han C, Zhao F, Qiao PG, Wang H, Bao XY, et al. Collateral circulation in Moyamoya disease: A new grading system. Stroke\u003cem\u003e.\u003c/em\u003e 2019;50:2708\u0026ndash;15. https://doi.org/10.1161/STROKEAHA.119.024487\u003c/li\u003e\n\u003cli\u003eSmith CR, Cavanagh J, Sheridan M, Grosset KA, Cullen B, Grosset DG. Factor structure of the Montreal Cognitive Assessment in Parkinson disease. Int J Geriatr Psychiatry\u003cem\u003e.\u003c/em\u003e 2020;35:188\u0026ndash;94. https://doi.org/10.1002/gps.5234\u003c/li\u003e\n\u003cli\u003eKasten M, Bruggemann N, Schmidt A, Klein C. Validity of the MoCA and MMSE in the detection of MCI and dementia in Parkinson disease. Neurology\u003cem\u003e.\u003c/em\u003e 2010;75:478; author reply 478\u0026ndash;9. https://doi.org/10.1212/WNL.0b013e3181e7948a\u003c/li\u003e\n\u003cli\u003eShen XX, Zhang HD, Fu HG, Xu JL, Zhang HT, Hou L, et al. Association of cognitive function and hypoperfusion in Moyamoya disease patients without stroke. J Cereb Blood Flow Metab. 2022:271678X221140349\u003c/li\u003e\n\u003cli\u003eLahav O, Katz N. Independent older adult\u0026rsquo;s IADL and executive function according to cognitive performance. OTJR (Thorofare N J)\u003cem\u003e.\u003c/em\u003e 2020;40:183\u0026ndash;9. https://doi.org/10.1177/1539449220905813\u003c/li\u003e\n\u003cli\u003eLawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist\u003cem\u003e.\u003c/em\u003e 1969;9:179\u0026ndash;86. https://doi.org/10.1093/geront/9.3_Part_1.179\u003c/li\u003e\n\u003cli\u003eLin CH, Park C, McIntyre RS. Early improvement in HAMD-17 and HAMD-7 scores predict response and remission in depressed patients treated with fluoxetine or electroconvulsive therapy. J Affect Disord. 2019;253:154\u0026ndash;61. https://doi.org/10.1016/j.jad.2019.04.082\u003c/li\u003e\n\u003cli\u003eYamamoto S, Mogi N, Umegaki H, Suzuki Y, Ando F, Shimokata H, et al. The clock drawing test as a valid screening method for mild cognitive impairment. Dement Geriatr Cogn Disord. 2004;18:172\u0026ndash;9. https://doi.org/10.1159/000079198\u003c/li\u003e\n\u003cli\u003eLeung AW, Cheng SK, Mak AK, Leung KK, Li LS, Lee TM. Functional gain in hemorrhagic stroke patients is predicted by functional level and cognitive abilities measured at hospital admission. NeuroRehabilitation\u003cem\u003e.\u003c/em\u003e 2010;27:351\u0026ndash;8. https://doi.org/10.3233/NRE-2010-0619\u003c/li\u003e\n\u003cli\u003eRossini ED, Karl MA. The Trail Making Test A and B: a technical note on structural nonequivalence. Percept Mot Skills. 1994;78:625\u0026ndash;6. https://doi.org/10.2466/pms.1994.78.2.625\u003c/li\u003e\n\u003cli\u003eLeite KS, Miotto EC, Nitrini R, Yassuda MS, Test BN. Boston Naming Test (BNT) original, Brazilian adapted version and short forms: normative data for illiterate and low-educated older adults. Int Psychogeriatr. 2017;29:825\u0026ndash;33. https://doi.org/10.1017/S1041610216001952\u003c/li\u003e\n\u003cli\u003eIkeda K, Iwasaki Y, Kashihara H, Hosozawa KI, Anan K, Tamura M, et al. Adult Moyamoya disease in the asymptomatic Japanese population. J Clin Neurosci. 2006;13:334\u0026ndash;8. https://doi.org/10.1016/j.jocn.2005.02.026\u003c/li\u003e\n\u003cli\u003eAcker G, Goerdes S, Schneider UC, Schmiedek P, Czabanka M, Vajkoczy P. Distinct clinical and radiographic characteristics of Moyamoya disease amongst European Caucasians. Eur J Neurol. 2015;22:1012\u0026ndash;7. https://doi.org/10.1111/ene.12702\u003c/li\u003e\n\u003cli\u003eHirano Y, Miyawaki S, Imai H, Hongo H, Teranishi Y, Dofuku S, et al. Differences in clinical features among different onset patterns in Moyamoya disease. J Clin Med. 2021;10:2815. https://doi.org/10.3390/jcm10132815\u003c/li\u003e\n\u003cli\u003eHirano Y, Miyawaki S, Imai H, Hongo H, Ohara K, Dofuku S, et al. Association between the onset pattern of adult Moyamoya disease and risk factors for stroke. Stroke\u003cem\u003e.\u003c/em\u003e 2020;51:3124\u0026ndash;8. https://doi.org/10.1161/STROKEAHA.120.030653\u003c/li\u003e\n\u003cli\u003eFunaki T, Takahashi JC, Houkin K, Kuroda S, Takeuchi S, Fujimura M, et al. Angiographic features of hemorrhagic Moyamoya disease with high recurrence risk: a supplementary analysis of the Japan Adult moyamoya Trial. J Neurosurg. 2018;128:777\u0026ndash;84. https://doi.org/10.3171/2016.11.JNS161650\u003c/li\u003e\n\u003cli\u003eBersano A, Bedini G, Nava S, Acerbi F, Sebastiano DR, Binelli S, et al. GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of Moyamoya disease-study protocol and preliminary results. Neurol Sci. 2019;40:561\u0026ndash;70. https://doi.org/10.1007/s10072-018-3664-z\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is not available with this version.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"moyamoya disease, transient ischemic attack, magnetic resonance angiography, digital subtraction angiography","lastPublishedDoi":"10.21203/rs.3.rs-2799246/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2799246/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: The etiology and natural course of moyamoya disease (MMD) remain unknown. This study evaluated the natural course and etiology of MMD using data from the Chinese MMD (C-MMD) cohort study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: The C-MMD cohort consisted of 6,167 patients with MMD treated at our center over the past 20 years. We analyzed the medical history and laboratory and imaging examination results of the patients at different stages of the disease to identify common features of MMD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: The median age for symptom onset was 32 years. The age distribution was bimodal; the highest peak was between ages 35 and 45 years, with a smaller peak between ages 3 and 9 years. The female-to-male ratio was 1:1. The disease occurred mainly in the Han people and was rarely observed in minority nationalities. In our cohort, a transient ischemic attack was the most common initial clinical manifestation (46.3%); others included infarction (25.0%), hemorrhage (15.1%), and headache (7.9%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eThe C-MMD cohort is currently one of the largest single-center MMD cohorts in the world. This study provides baseline data for future research on the etiology and natural course of MMD.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Registration:\u003c/strong\u003e This study has been registered in the Chinese Clinical trial registry (registration number: ChiCTR2200064160) on September 28, 2022.\u003c/p\u003e","manuscriptTitle":"Cohort profile: Chinese moyamoya disease cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-04-19 15:09:52","doi":"10.21203/rs.3.rs-2799246/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ecc27b29-a115-4996-80d4-0b5da26f5405","owner":[],"postedDate":"April 19th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-07-18T13:31:19+00:00","versionOfRecord":[],"versionCreatedAt":"2023-04-19 15:09:52","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2799246","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2799246","identity":"rs-2799246","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}