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.

OBJECTIVE: The effect of indirect revascularization to improve cerebral perfusion for moyamoya disease (MMD) is based on ingrowth of new vessels into the cortical brain. Preoperative indicators for neoangiogenesis would be helpful to the selection of appropriate procedures for MMD patients but have not yet been investigated. Our study aimed to identify potential predictors for neovascularization after indirect bypass surgery.METHODS: The authors reviewed consecutive cases with complete clinical and radiological documentation of patients who had undergone surgery between December 2010 and January 2018. Patients who were treated with indirect bypass surgery were included. Cerebrovascular characteristics were evaluated by catheter angiography. Neoangiogenesis after indirect bypass was determined as “good” or “poor” based on the Matsushima standard. Univariate and multivariate analyses were performed to identify predictors for neoangiogenesis after indirect bypass. Subgroup analyses by onset type and surgical type were carried out to identify specific predictors for different populations.RESULTS: In total, 231 hemispheres of 209 patients (mean ± SD age 23.06 ± 15.09 years, range 3–61 years) were retrospectively included. In 146 (63.2%) hemispheres, good neoangiogenesis was observed after indirect revascularization. Multivariate analysis showed that the status of ICA moyamoya vessels (p < 0.001, OR [95% CI] 3.242 [2.007–5.236]) is a predictor of favorable neoangiogenesis after indirect bypass surgery, whereas hemorrhagic onset (p < 0.001, OR [95% CI] 0.138 [0.054–0.353]) is a risk factor for poor neoangiogenesis. In addition, younger age was significantly associated with good neovascularization in patients with hemorrhagic onset (p = 0.027, OR [95% CI] 0.893 [0.808–0.987]), whereas age was not a significant predictor for neovascularization in non–hemorrhagic-onset patients (p = 0.955). Hemispheres with good revascularization had lower incidence of rebleeding, lower modified Rankin Scale scores, and more improvement of symptoms during long-term follow-up (p = 0.026, 0.006, and 0.013, respectively).CONCLUSIONS: Hemorrhagic onset predicts poor neovascularization after indirect bypass surgery for MMD patients. Abundant ICA moyamoya vessels indicate good neoangiogenesis after indirect bypass and vice versa, whereas absent ICA moyamoya vessels predict poor revascularization. Good neovascularization was associated with better long-term outcome. Future studies are needed to further address this issue and clarify the underlying pathophysiological mechanisms.

Objective: Extracranial-intracranial bypass is currently recognized as the optimal treatment for hemorrhagic-type moyamoya disease (MMD) which reduces incidence of rebleeding. Recent studies have reported the advantage of combined bypass over direct bypass for the general MMD patients. However, the effect of direct bypass and combined bypass surgery specifically for hemorrhagic-type MMD had not been investigated yet. Methods: Hemorrhagic-type MMD patients who underwent direct and combined bypass surgery with complete clinical and radiological documentation from a multicenter cohort between 2009 and 2017 were retrospectively included. Surgical methods included superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis (direct bypass), combined STA-MCA bypass with encephalodurosynangiosis (EDS), and combined STA-MCA bypass with encephaloduroarteriosynangiosis (EDAS). Matsushima standard on follow-up catheter angiography was used to assess surgical outcome. Modified Rankin Scale, incidence of rebleeding and ischemia during follow-up were recorded. Rebleeding-free survival rates between direct and combined bypass were compared by Kaplan-Meier analysis. Results: Sixty eight hemorrhagic-onset MMD patients were included in this study, among which 71 hemispheres were treated with surgery (direct bypass: 17; bypass+EDS: 24; bypass+EDAS: 30). Forty six (64.8%) hemispheres had satisfactory revascularization (Matsushima level 2–3) and 26 (36.6%) had poor neoangiogenesis. Matsushima level was not significantly different between surgical groups (P = 0.258). Good neoangiogenesis from dural grafts was achieved in 26 (36.6%) hemispheres, and good neoangiogenesis from STA grafts was only seen in 4 (out of 30, 12.5%) hemispheres. Multivariate analysis showed bypass patency [P < 0.001, OR (95%CI): 13.41 (3.28–54.80)] and dural neoangiogenesis [P < 0.001, OR (95%CI): 13.18 (3.26–53.36)] both independently contributed to good angiographic outcome. During follow-up, incidences of rebleeding or ischemic events, and re-bleeding free survival rate were not significantly different between surgical groups (P = 0.433, P = 0.559, and P = 0.997). However, patients who underwent combined bypass surgery had significantly lower mRS at follow-up comparing to patients who underwent direct bypass (P = 0.006). Conclusion: Combined bypass surgery and direct bypass surgery offered similar revascularization for hemorrhagic MMD. Bypass patency and dural angiogenesis both contributed to revascularization independently. The potential of indirect bypass to grow new vessels in hemorrhagic-MMD patients was generally limited, but dural leaflets offered better neoangiogenesis than STA grafts and was therefore recommended for surgical revascularization of hemorrhagic MMD.

BACKGROUND: Moyamoya disease (MMD) is a rare progressive vascular disease that leads to intracranial internal carotid artery stenosis and eventual occlusion. However, its pathogenesis remains unclear. The purpose of this study is to explore the role of abnormally expressed proteins in the pathogenesis of MMD. METHODS: Data-independent acquisition mass spectrometry identifies the differentially expressed proteins in MMD serum by detecting the serum from 60 patients with MMD and 20 health controls. The differentially expressed proteins were validated using enzyme linked immunosorbent assays. Immunofluorescence for superficial temporal artery and middle cerebral artery specimens was used to explore the morphological changes of vascular wall in MMD. In vitro experiments were used to explore the changes and mechanisms of differentially expressed proteins on endothelial cells. RESULTS: Proteomic analysis showed that a total of 14 726 peptides and 1555 proteins were quantified by mass spectrometry data. FLNA (filamin A) and ZYX (zyxin) proteins were significantly higher in MMD serum compared with those in health controls (Log ₂ FC >2.9 and >2.8, respectively). Immunofluorescence revealed an intimal hyperplasia in superficial temporal artery and middle cerebral artery specimens of MMD. FLNA and ZYX proteins increased the proportion of endothelial cells in S phase and promoted their proliferation, angiogenesis, and cytoskeleton enlargement. Mechanistic studies revealed that AKT (serine/threonine kinase)/GSK-3β (glycogen synthase kinase 3β)/β-catenin signaling pathway plays a major role in these FLNA- and ZYX-induced changes in endothelial cells. CONCLUSIONS: This study provides proteomic data on a large sample size of MMD. The differential expression of FLNA and ZYX in patient with MMD and following in vitro experiments suggest that these upregulated proteins are related to the pathology of cerebrovascular intimal hyperplasia in MMD and are involved in MMD pathogenesis, with diagnostic and therapeutic ramifications.