A mathematical model for temporal cerebral blood flow response to acetazolamide evaluated in patients with Moyamoya disease.

BACKGROUND: Paired cerebral blood flow (CBF) measurement is usually acquired before and after vasoactive stimulus to estimate cerebrovascular reserve (CVR). However, CVR may be confounded because of variations in time-to-maximum CBF response (tmax) following acetazolamide injection. With a mathematical model, CVR can be calculated insensitive to variations in tmax, and a model offers the possibility to calculate additional model-derived parameters. A model that describes the temporal CBF response following a vasodilating acetazolamide injection is proposed and evaluated. METHODS: A bi-exponential model was adopted and fitted to four CBF measurements acquired using arterial spin labelling before and initialised at 5, 15 and 25 min after acetazolamide injection in a total of fifteen patients with Moyamoya disease. Curve fitting was performed using a non-linear least squares method with a priori constraints based on simulations. RESULTS: Goodness of fit (mean absolute error) varied between 0.30 and 0.62 ml·100 g-1·min-1. Model-derived CVR was significantly higher compared to static CVR measures. Maximum CBF increase occurred earlier in healthy- compared to diseased vascular regions. CONCLUSIONS: The proposed mathematical model offers the possibility to calculate CVR insensitive to variations in time to maximum CBF response which gives a more detailed characterisation of CVR compared to static CVR measures. Although the mathematical model adapts generally well to this dataset of patients with MMD it should be considered as experimental; hence, further studies in healthy populations and other patient cohorts are warranted.

Moyamoya disease presenting with symptomatic ischemic stroke during new-generation tyrosine kinase inhibitor treatment: two illustrative cases.

Tyrosine kinase inhibitors (TKIs) have been widely used to treat chronic myeloid leukemia. Nilotinib and ponatinib, which are second- and third-generation TKIs, have been reported to cause cerebrovascular arterial complications. Here, we present two cases of moyamoya disease presenting with symptomatic ischemic stroke during new-generation TKI treatment. We judged that new-generation TKI treatment was a factor in symptomatic ischemic stroke of unknown moyamoya disease in both cases. Noninvasive examinations using magnetic resonance imaging or carotid ultrasonography should be performed before and during new-generation TKI treatment in order to prevent symptomatic ischemic stroke.

Cilostazol for the management of moyamoya disease: a systematic review of the early evidence, efficacy, safety, and future directions.

Surgical revascularization remains the standard treatment for symptomatic moyamoya disease (MMD). As with any major surgical treatment, revascularization is associated with risks and limitations, denoting the need for noninvasive treatments to improve ischemic symptoms and prevent strokes. Cilostazol is a selective phosphodiesterase III inhibitor with antiplatelet, antithrombotic, and vasodilatory effects commonly used in peripheral vascular disease. Clinical studies assessing the efficacy of cilostazol in the management of stroke and MMD were recently reported, although a comprehensive assessment of the overall evidence is lacking. A systematic scoping review was conducted to assess the early evidence on cilostazol administration in patients with MMD. The inclusion criteria encompassed original human studies primarily focused on cilostazol's safety, efficacy, or utilization in managing MMD patients. A search of the PubMed database was conducted in June 2023, yielding 5 peer-reviewed publications that satisfied the inclusion criteria and were subjected to narrative synthesis. Risk of bias assessment was not applicable due to the scoping nature of this review. East Asian studies demonstrate increasing rates of cilostazol prescriptions for patients with MMD. In a large population-based study, cilostazol was compared to other antiplatelet medications and yielded the largest decrease in mortality among patients with newly diagnosed MMD. Other studies reported significant improvements in cerebral blood flow and cognitive function, which were deemed to be independent of one another. There are limited data on the safety profile of cilostazol in the MMD population, although the evidence derived from various studies performed in the general stroke population can likely provide insights into its potential utility in MMD patients. Cilostazol targets several critical pathways involved in the pathophysiology of MMD. The evidence corroborates the potential benefits of cilostazol for the management of MMD, although these findings should be interpreted with caution due to the small number of studies and lack of randomized trials. Subgroups of patients need to be identified who can safely undergo medical management in lieu of revascularization surgery or to improve surgical outcomes. Additional studies are needed to assess the efficacy and safety of cilostazol therapy, especially in Western populations.

Antiplatelet therapy may improve the prognosis of patients with moyamoya disease: a 12-year retrospective study.

OBJECTIVES: The clinical value of antiplatelet therapy (APT) for moyamoya disease (MMD) remains controversial. Our study attempts to clarify the value of APT in this disease. METHODS: We collected basic information, treatment strategies, and prognostic information on patients with MMD from 2010 to 2022 at our center. The data were divided into two groups, depending on whether APT was used or not, and compared by Pearson Chi-Square, Fisher's exact test, or Wilcoxon rank-sum test. We used propensity scores or inverse probability of treatment weighting to balance the covariates. Following this, we performed a meta-analysis of APT use in MMD. RESULTS: 177 patients were enrolled, with a median follow-up of 41.1 months. APT did not affect the prognosis of patients with perioperative MMD, ischemic MMD, or asymptomatic MMD (P > 0.05), without increasing cerebral hemorrhagic risk. In contrast, APT was found to reduce mortality among patients with hemorrhagic MMD (P = 0.019), without affecting functional status, increasing stroke risk, or causing intracerebral hemorrhage (P > 0.05). But the small group cannot show the effect of APT. Our meta-analysis included nine articles involving 28,925 patients with MMD. It showed that APT could reduce stroke risk (odds ratio, OR = 0.57, 95% CI 0.49 to 0.65) and the Modified Rankin Scale (mRS) (weighted mean difference, WMD = - 0.07, 95% CI 0.14-0.00) during follow-up. The cohort study has limited weight (1.97% and 19.29%) in the meta-analysis. CONCLUSION: Although the limited number of included documents, APT could be beneficial to the prognosis of MMD.

Association between statin therapy and the risk of stroke in patients with moyamoya disease: a nationwide cohort study.

BACKGROUND AND OBJECTIVE: Knowledge regarding the pharmacological treatment for moyamoya disease (MMD), a chronic and progressive cerebrovascular disease conferring greater stroke risk, is limited. In the present study, whether statin therapy is associated with a reduced risk of stroke in patients with MMD was investigated. METHODS: This was a retrospective cohort study in which the occurrence of stroke in patients with newly diagnosed MMD was investigated using the nationwide health insurance database in Korea from January 2007 to March 2021. A multivariable Cox proportional hazards regression model was constructed for stroke, in which statin therapy after MMD diagnosis was treated as a time-dependent variable. Adjustment was done for sex, age, presence of comorbidities, concurrent stroke, revascularisation surgery and treatment with antiplatelets. RESULTS: The present study included 13 373 newly diagnosed patients with MMD; 40.8% had a concurrent stroke at the time of MMD diagnosis. During the mean follow-up of 5.1±3.3 years, 631 patients (4.7%) suffered a stroke event (haemorrhagic stroke: 458 patients, ischaemic stroke: 173 patients). Statin therapy after MMD diagnosis was significantly associated with a reduced risk of stroke (adjusted HR 0.74; 95% CI 0.60 to 0.91, p=0.004). In the secondary outcome analysis, the risk of haemorrhagic stroke (adjusted HR 0.74; 95% CI 0.58 to 0.95, p=0.018) and ischaemic stroke (adjusted HR 0.75; 95% CI 0.52 to 1.08, p=0.124) were reduced with the statin treatment. Taking statins was also associated with a lower risk of all-cause mortality (adjusted HR 0.47; 95% CI 0.33 to 0.67, p<0.001). CONCLUSION: In patients with MMD, statin therapy was associated with a reduced risk of subsequent stroke. The findings indicate statin treatment may be beneficial for patients with MMD, however the results should be confirmed in randomised controlled trials.

Microembolic signals and antiplatelet therapy in Moyamoya angiopathy.

BACKGROUND: Embolism as a cause of stroke is widely neglected in Moyamoya angiopathy (MMA), and recommendations for use of antiplatelet therapy (APT) vary. We examined the presence of microembolic signals (MES) during transcranial Doppler (TCD) monitoring and assessed the effects of APT on the occurrence of MES in MMA. PATIENTS AND METHODS: We retrospectively analysed patients with MMA treated at our centre between 2011 and 2021. TCD was performed at first presentation and at most visits, while number of visits varied between individual patients. TCD was performed for 30 min bilaterally. Patient demographics, vascular risk factors, and antiplatelet treatment were collected from each clinic visit and ischemic and haemorrhagic episodes were captured as recorded during follow-up visits. RESULTS: 209 patients were included in the analysis (mean age 38.7 ± 15.3, 28% male). 21 patients with 27 MES-positive TCD examinations were identified (10%). Patient characteristics were similar in MES-positive and MES-negative groups. However, recent ischemic events were detected at a significantly higher rate in MES-positive patients (42.9% vs 4.8%, p < 0.001). After MES detection, change of antiplatelet drug regime was performed, leading to loss of MES in all cases. Dual APT was preferably used in the MES-positive group (p < 0.001) but no significant difference of haemorrhage during follow-up-visits was observed. Reduction of APT before bypass-surgery triggered MES in four patients. CONCLUSION: APT is required in patients with MMA. MES monitoring may help to identify risk patients in need of intensified APT.

Intravenous thrombolysis and endovascular thrombectomy for acute ischaemic stroke in patients with Moyamoya disease - a systematic review and meta-summary of case reports.

BACKGROUND AND AIMS: Patients with Moyamoya disease (MMD) can present with ischaemic or haemorrhagic stroke. There is no good evidence for treatment strategies in MMD-associated acute ischaemic stroke (AIS), particularly for treatments like intravenous thrombolysis (IVT) and endovascular thrombectomy (ET). As the intracranial vessels are friable in MMD, and the risk of bleeding is high, the use of IVT and ET is controversial. To clarify the safety and efficacy of IVT/ET in the treatment of MMD-associated AIS, we performed a systematic review and meta-summary to examine this issue. METHODS: A systematic search was performed from four electronic databases: PubMed (MEDLINE), Cochrane Library, EMBASE and Scopus, profiling data from inception till 21 November 2021, as well as, manually on Google Scholar. RESULTS: Ten case reports detailing 10 MMD patients presenting with AIS and undergoing IVT or ET, or both, were included in the analysis. The median National Institute of Health Stroke Scale score at presentation was 10 (Interquartile Range [IQR] = 6.0-16.5). IVT alone was instituted in 6 patients, primary ET was attempted in 2, and 2 had received bridging IVT with ET. Of the 4 patients who underwent ET, 2 patients achieved successful reperfusion (modified Thrombolysis In Cerebral Infarction scale [mTICI] ≥ 2b). In terms of functional outcomes, One patient achieved complete recovery (modified Rankin Scale 0), 4 patients attained improvement in neurological status, and 4 had no improvement, whilst functional outcome was unreported in 1 patient. No patient experienced symptomatic intracranial haemorrhage. CONCLUSIONS: In this systematic review and meta-summary, the utility of IVT and ET in MMD-associated AIS appears feasible in selected cases. Further larger cohort studies are required to evaluate these treatment approaches. HIGHLIGHTS: · AIS in MMD was typically managed with bypass surgery but not via thrombolysis or thrombectomy. · In this meta-summary, all patients treated with thrombolysis and/or thrombectomy survived and some experienced symptomatic and/or functional improvement. · Further larger cohort studies are necessary for investigating the role of thrombolysis and/or thrombectomy as treatment of AIS in MMD.

Benefits and risks of antiplatelet medication in hemodynamically stable adult moyamoya disease.

Revascularization surgery is considered a standard treatment for preventing additional stroke in symptomatic moyamoya disease (MMD). In hemodynamically stable, and asymptomatic or mildly symptomatic patients, however, the treatment strategy is controversial because of the obscure natural course of them. The authors analyzed the benefits and risks of antiplatelet medication in those patients. Medical data were retrospectively reviewed in 439 hemispheres of 243 patients with stable hemodynamic status. Overall, 121 patients (49.8%) with 222 studied hemispheres (50.6%) took antiplatelet medication. Symptomatic cerebral infarction and hemorrhage occurred in 10 (2.3%) and 30 (6.8%) hemispheres, over a mean follow-up of 62.0 ± 43.4 months (range 6-218 months). The use of antiplatelet agents was statistically insignificant in terms of symptomatic infarction, hemorrhage and improvement of ischemic symptoms. In subgroup analyses within the antiplatelet group according to drug potency and duration of medication, a longer duration of antiplatelet medication significantly improved ischemic symptoms (adjusted OR 1.02; 95% CI 1.01-1.03; p = 0.006). Antiplatelet medication failed to prevent symptomatic cerebral infarction or improve ischemic symptoms. However, antiplatelet therapy did not increase the risk of cerebral hemorrhage.

Association of Antiplatelet Therapy, Including Cilostazol, With Improved Survival in Patients With Moyamoya Disease in a Nationwide Study.

Background Although antiplatelet agents are frequently prescribed in moyamoya disease in routine clinical practice, there are no large-scale epidemiologic trials or randomized trial evidence to support their use in patients with moyamoya disease. Methods and Results Using the Korean National Health Insurance Service database, patients diagnosed with moyamoya disease between 2002 and 2016 were followed up for up to 14 years to assess, using time-dependent Cox regression in all patients and in a propensity score-matched cohort, the association of antiplatelet therapy and individual antiplatelet agents with survival. Among 25 978 patients with newly diagnosed moyamoya disease, mean age was 37.6±19.9 years, 61.6% were women, and total follow-up was 163 347 person-years. Among 9154 patients who were prescribed antiplatelet agents at least once during the follow-up period, the proportion prescribed cilostazol gradually increased from 5.5% in 2002 to 56.0% in 2016. Any antiplatelet use was associated with reduced risk of death (hazard ratio, 0.77; 95% CI, 0.70-0.84) in a multivariate model. Among individual antiplatelet agents, cilostazol was associated with greater reduction in mortality than the 5 other antiplatelet regimens. Subgroup analysis, according to the age group and history of ischemic stroke, and sensitivity analysis, using propensity score-matched analysis, revealed consistent results. Conclusions Antiplatelet therapy is associated with substantial improvement in survival in patients with moyamoya disease, and cilostazol is associated with greater survival benefit compared with other antiplatelet regimens. These results provisionally support the use of antiplatelet therapy in patients with moyamoya disease and the conduct of confirmatory randomized controlled trials.

Effects of aspirin and heparin treatment on perioperative outcomes in patients with Moyamoya disease.

BACKGROUND: When superficial temporal artery-middle cerebral artery bypass is combined with indirect methods (e.g., revascularization surgery) to treat Moyamoya disease (MMD), antiplatelet treatment can impact bypass patency, infarction, or hemorrhage complications. Recently, heparin has been proposed as an anticoagulant treatment against white thrombus at the anastomosis site. The study aims to evaluate the effect of aspirin on the perioperative outcomes and investigate the results of heparin treatment for white thrombus. METHODS: This retrospective study included 74 procedures of combined revascularization surgery for MMD patients who either received or did not receive aspirin. Perioperative outcomes were compared between the two groups. In addition, the effects of heparin treatment for white thrombus were evaluated. RESULTS: The rate of white thrombus at the anastomosis site was significantly higher in the non-aspirin medication group (univariate: p = 0.032, multivariate: p = 0.044) and, accordingly, initial bypass patency was lower in the non-aspirin medication group (p = 0.049). Of the 17 patients with white thrombus development, five received heparin injections, and all white thrombi disappeared; however, there was one case of epidural hematoma and another of subdural hematoma. The risk of hemorrhagic complications was significantly higher in the surgical procedures that received heparin injections (p = 0.021). CONCLUSIONS: In MMD patients who received combined revascularization surgery, aspirin medication lowered the occurrence of white thrombus. Heparin injections help to treat white thrombus but can enhance the risk of hemorrhagic complications.

Study on Novel Nanoparticle Slow-Release Drugs for Moyamoya Disease.

Spontaneous basilar artery occlusive disease is a disease characterized by thickening of the intima of the bilateral internal carotid artery and the anterior and middle cerebral arteries, gradually narrowing the arterial diameter, and compensatory dilatation of the perforating artery at the base of the brain. Aspirin (acetylsalicylic acid), as a classic non-steroidal anti-inflammatory drug, has been proven to have antiplatelet, anti-inflammatory, and immune-regulating effects. But how to achieve long-term sustained release of aspirin and achieve anti-platelet aggregation remains to be studied. This study intends to build a microsphere sustained-release system to achieve long-term stable and slow release of aspirin drug, thereby achieving a more ideal anti-platelet aggregation effect. The therapeutic effects of three groups of nanoparticle sustained-release drug regimens on platelet aggregation were compared. The results showed that the platelet inhibition rate and NIHSS scores before treatment were compared between the three groups; compared with the other groups, the PLGA group had higher AA and ADP pathway-induced platelet inhibition rates after treatment and lower plasma Lp-PLA2 and NIHSS scores. This shows that aspirin nanoparticle slow-release drugs can effectively increase platelet inhibition rate and improve the antiplatelet ability of patients with spontaneous basilar artery occlusive disease, which is beneficial to promoting prognosis recovery.

Construction and Comprehensive Analysis of Dysregulated Long Noncoding RNA-Associated Competing Endogenous RNA Network in Moyamoya Disease.

BACKGROUND: Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by chronic progressive stenosis or occlusion of the bilateral internal carotid artery (ICA), the anterior cerebral artery (ACA), and the middle cerebral artery (MCA). MMD is secondary to the formation of an abnormal vascular network at the base of the skull. However, the etiology and pathogenesis of MMD remain poorly understood. METHODS: A competing endogenous RNA (ceRNA) network was constructed by analyzing sample-matched messenger RNA (mRNA), long non-coding RNA (lncRNA), and microRNA (miRNA) expression profiles from MMD patients and control samples. Then, a protein-protein interaction (PPI) network was constructed to identify crucial genes associated with MMD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were employed with the DAVID database to investigate the underlying functions of differentially expressed mRNAs (DEmRNAs) involved in the ceRNA network. CMap was used to identify potential small drug molecules. RESULTS: A total of 94 miRNAs, 3649 lncRNAs, and 2294 mRNAs were differentially expressed between MMD patients and control samples. A synergistic ceRNA lncRNA-miRNA-mRNA regulatory network was constructed. Core regulatory miRNAs (miR-107 and miR-423-5p) and key mRNAs (STAT5B, FOSL2, CEBPB, and CXCL16) involved in the ceRNA network were identified. GO and KEGG analyses indicated that the DEmRNAs were involved in the regulation of the immune system and inflammation in MMD. Finally, two potential small molecule drugs, CAY-10415 and indirubin, were identified by CMap as candidate drugs for treating MMD. CONCLUSIONS: The present study used bioinformatics analysis of candidate RNAs to identify a series of clearly altered miRNAs, lncRNAs, and mRNAs involved in MMD. Furthermore, a ceRNA lncRNA-miRNA-mRNA regulatory network was constructed, which provides insights into the novel molecular pathogenesis of MMD, thus giving promising clues for clinical therapy.

Postintravenous immunoglobulin stroke in a toddler with Down syndrome: a diagnostic challenge.

Children with Down syndrome have a higher risk of stroke. Similarly, intravenous immunoglobulin (IV Ig) is also known to cause a stroke. We reported a 3-year-old boy with Down syndrome who presented with severe pneumonia and received IV Ig. He developed right hemiparesis 60 hours after the infusion. Blood investigations, echocardiography and carotid Doppler did not suggest vasculitis, thrombophilia or extracranial dissection. Brain computerised tomography (CT) showed acute left frontal and parietal infarcts. Initial magnetic resonance angiography (MRA) of cerebral vessels showed short segment attenuations of both proximal middle cerebral arteries and reduction in the calibre of bilateral supraclinoid internal carotid arteries. The boy was treated with enoxaparin and aspirin. He only had partial recovery of the hemiparesis on follow-up. A repeat MRA 13 months later showed parenchymal collateral vessels suggestive of moyamoya disease. We recommend imaging the cerebral vessels in children with a high risk of moyamoya before giving IV Ig.

Combined structural and diffusion tensor imaging detection of ischemic injury in moyamoya disease: relation to disease advancement and cerebral hypoperfusion.

OBJECTIVE: The microstructural integrity of gray and white matter is decreased in adult moyamoya disease, suggesting covert ischemic injury as a mechanism of cognitive dysfunction. Establishing a microstructural brain imaging marker is critical for monitoring cognitive outcomes following surgical interventions. The authors of the present study determined the pathophysiological basis of altered microstructural brain injury in relation to advanced arterial occlusion, cerebral hypoperfusion, and cognitive function. METHODS: The authors examined 58 patients without apparent brain lesions and 30 healthy controls by using structural MRI, as well as diffusion tensor imaging (DTI). Arterial occlusion in each hemisphere was classified as early or advanced stage based on MRA and posterior cerebral artery (PCA) involvement. Regional cerebral blood flow (rCBF) was measured with N-isopropyl-p-[123I]-iodoamphetamine SPECT. Furthermore, cognitive performance was examined using the Wechsler Adult Intelligence Scale, Third Edition and the Trail Making Test (TMT). Both voxel- and region of interest-based analyses were performed for groupwise comparisons, as well as correlation analysis, using parameters such as cognitive test scores; gray matter volume; fractional anisotropy (FA) of association fiber tracts, including the inferior frontooccipital fasciculus (IFOF) and superior longitudinal fasciculus (SLF); PCA involvement; and rCBF. RESULTS: Compared to the early stages, advanced stages of arterial occlusion in the left hemisphere were associated with a lower Performance IQ (p = 0.031), decreased anterior cingulate volumes (p = 0.0001, uncorrected), and lower FA in the IFOF, cingulum, and forceps major (all p < 0.01, all uncorrected). There was no significant difference in rCBF between the early and the advanced stage. In patients with an advanced stage, PCA involvement was correlated with a significantly lower Full Scale IQ (p = 0.036), cingulate volume (p < 0.01, uncorrected), and FA of the left SLF (p = 0.0002, uncorrected) compared to those with an intact PCA. The rCBF was positively correlated with FA of the SLF, IFOF, and forceps major (r > 0.34, p < 0.05). Global gray matter volumes were moderately correlated with TMT part A (r = 0.40, p = 0.003). FA values in the left SLF were moderately associated with processing speed (r = 0.40, p = 0.002). CONCLUSIONS: Although hemodynamic compensation may mask cerebral ischemia in advanced stages of adult moyamoya disease, the disease progression is detrimental to gray and white matter microstructure as well as cognition. In particular, additional PCA involvement in advanced disease stages may impair key neural substrates such as the cingulum and SLF. Thus, combined structural MRI and DTI are potentially useful for tracking the neural integrity of key neural substrates associated with cognitive function and detecting subtle anatomical changes associated with persistent ischemia, as well as disease progression.

The hemodynamic complexities underlying transient ischemic attacks in early-stage Moyamoya disease: an exploratory CFD study.

Moyamoya disease (MMD) is a rare cerebro-occlusive disease with unknown etiology that can cause both ischemic and hemorrhagic stroke. MMD is characterized by progressive stenosis of the terminal internal carotid artery (ICA) and development of basal brain collaterals. Early-stage MMD is known to cause hemodynamic insufficiency despite mild or moderate stenosis of the intracranial arteries, but the exact mechanism underlying this pathophysiological condition is undetermined. We used high-resolution Large Eddy Simulations to investigate multiple complex hemodynamic phenomena that led to cerebral ischemia in five patients with early-stage MMD. The effects of transitional flow, coherent flow structures and blood shear-thinning properties through regions of tortuous and stenosed arteries were explored and linked to symptomatology. It is evidently shown that in some cases complex vortex structures, such as Rankine-type vortices, redirects blood flow away from some arteries causing significant reduction in blood flow. Moreover, partial blood hammer (PBH) phenomenon was detected in some cases and led to significant hemodynamic insufficiency. PBH events were attributed to the interaction between shear-thinning properties, transitional flow structures and loss of upstream pressure-velocity phase lag. We clearly show that the hemodynamic complexities in early-stage MMD could induce ischemia and explain the non-responsiveness to antiplatelet therapy.

Cranial burr hole with erythropoietin administration induces reverse arteriogenesis from the enriched extracranium.

It is challenging to revitalize ischemic penumbra after an acute stroke with intracranial perfusion insufficiency. To evaluate whether cranial burr hole and erythropoietin (EPO) generate effective revascularization, we investigated the efficacy of the augmentation method for reverse arteriogenesis from the healthy extracranial milieu. An intracranial perfusion insufficiency was created through bilateral internal carotid artery ligation (bICAL) in Sprague-Dawley rats. We administered recombinant human EPO (5000 U/kg) or saline intraperitoneally for 3 days after bICAL. Mechanical barrier disruption (MBD) was performed through a cranial burr hole with small dural cracks in the right hemisphere. The ipsilateral hemisphere with MBD grossly showed vascular networks between the extra- and intra-cranial spaces 2 weeks after the MBD procedure. It also showed significantly increased vessels in the intracranial vasculature adjacent to the MBD region (p = 0.0006). The levels of pro-angiogenic and inflammatory factors with prominent markers of vessel permeability were also significantly increased (MBD-only vs. control; Tnf-α, p = 0.0007; Vegf, p = 0.0206). In the EPO-administered group, such elevations in inflammation were significantly mitigated (combined vs. MBD-only; Tnf-α, p = 0.0008). The ipsilateral hemisphere with MBD-EPO (vs. MBD-only) showed significantly increased vessels (RECA-1, p = 0.0182) and their maturation (RECA-1/α-SMA, p = 0.0046), with upregulation of tumor growth factor-ß1 (Tgf-ß1, p = 0.037) and matrix metalloproteinase-2 (Mmp-2, p = 0.0488). These findings were completely blocked by minocycline (MIC) administration during in vivo (Tgf-ß1, p = 0.0009; Mmp-2, p < 0.0001) and in vitro experiments (tube formation, p < 0.0001). Our data suggest that the MBD procedure (for angiogenic routes) and EPO administration (for an arteriogenic booster) are complimentary and can facilitate successfully "reverse arteriogenesis" in subjects with intracranial perfusion insufficiency.