MMP-9 as a Biomarker for Predicting Hemorrhagic Strokes in Moyamoya Disease.
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SUBMITTER: Lu J
PROVIDER: S-EPMC8438170 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Objective: To evaluate clinical and radiological outcomes after revascularization of hemorrhagic moyamoya disease (MMD). Materials and Methods: We retrospectively collected patients with hemorrhagic MMD who received revascularization from January 2011 to June 2018 at a high-volume stroke center. Rebleeding, ischemic stroke, modified Rankin Scale (mRS) and death after revascularization were used to evaluate long-term clinical outcome. Poor neurological outcome was defined as a mRS>2. The changes of original and revascularization collaterals were used to evaluate radiological outcome. The clinical and radiological outcomes between patients with different surgical revascularization were compared. Results: A total of 312 patients (319 hemispheres) were recruited, including 133 hemispheres (41.7%) with indirect revascularization and 186 hemispheres (58.3%) with direct revascularization. In 308 hemispheres with clinical follow-up data, Postoperative rebleeding, ischemic stroke, poor neurological outcome and death occurred in 13.0% (40/308), 2.6% (8/308), 12.0% (37/308), and 6.2% (19/308) of the hemispheres, respectively. The rates of postoperative rebleeding (8.5 vs. 19.1%, P = 0.006) and poor neurological outcome (8.5 vs. 16.8%, P = 0.026) were lower in hemispheres with direct revascularization than those with indirect revascularization. However, there was no statistically significant difference in the rates of postoperative ischemic stroke (1.1 vs. 4.6%, P = 0.129) and death (4.5 vs. 8.4%, P = 0.162) between the two groups. Multivariate logistic regression analysis indicated that the risk of postoperative rebleeding was higher in those with untreated aneurysms, repetitive bleeding episodes, normal perfusion status, and indirect revascularization (P < 0.05). In 78 hemispheres with radiological follow-up data, the regression of moyamoya vessels, anterior choroidal artery (AchA), posterior communicating artery (PcomA) and aneurysms were present in 44.9, 47.4, 25.6, and 11.5% of the hemispheres, respectively. The regression of original collaterals and establishment of revascularization collaterals were more significant in hemispheres with direct revascularization than those with indirect revascularization (P < 0.05). Conclusion: Direct revascularization may be superior to indirect revascularization for prevention of rebleeding and poor neurological outcome in adults with hemorrhagic MMD. The risk of postoperative rebleeding was higher in those with untreated aneurysms, repetitive bleeding episodes, normal perfusion status, and indirect revascularization. The regression of original collaterals and establishment of revascularization collaterals after revascularization were more significant in hemispheres with direct revascularization than those with indirect revascularization.
| S-EPMC7221061 | biostudies-literature
Project description:Objective: To explore the cerebral hemodynamic changes after revascularization in patients with hemorrhagic moyamoya disease (MMD). Materials and Methods: We retrospectively included 57 hemorrhagic MMD patients in a high-volume stroke center from January 2016 to December 2018. All subjects were evaluated with whole-brain CT perfusion (CTP) before and after surgical revascularization. Absolute and relative CTP values in the regions of cortical middle cerebral artery territory (CMT) and deep brain area (DBA) of hemorrhagic hemispheres were measured. Differences between pre- and post-operative CTP values were assessed comprehensively. The patients were categorized into subgroups based on revascularization subtypes and postoperative CTP intervals. Results: The relative cerebral blood volume (rCBV) in DBA and CMT significantly reduced in postoperative CTP (P < 0.05). The median and interquartile range of the proportion of rCBV decrease (rCBVc%) were 7.2% (2.3-13.2%). The rCBV reduction retained statistical significant in patients who received subtypes of revascularization, and in patients with variable intervals of follow-up (P < 0.05). There was no significant difference of rCBVc% between patients who received different revascularization and among patients with different postoperative CTP intervals (P > 0.05). The relative mean transit time (rMTT) and relative time to peak (rTTP) also showed downward trends, but without retainable statistical significance in stratified analysis. There was no significant change in relative cerebral blood flow (rCBF) (P > 0.05). Conclusion: In patients with hemorrhagic MMD, the CBV appeared to decrease and be relatively stable in the chronic phase after revascularization, with varying degrees of MTT and TTP shortening. However, there was no significant change in CBF.
| S-EPMC7026453 | biostudies-literature
Project description:Background and purposeThe pathogenesis of moyamoya disease (MMD) remains poorly understood, and no reliable molecular biomarkers for MMD have been identified to date. The present study aimed to identify epigenetic biomarkers for use in the diagnosis of MMD.MethodsWe performed integrated analyses of gene expression profiles and DNA methylation profiles in endothelial colony forming cells (ECFCs) from three patients with MMD and two healthy individuals. Candidate gene mRNA expression and DNA methylation status were further validated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and pyrosequencing analysis of an expanded ECFC sample set from nine patients with MMD and ten controls. We evaluated the diagnostic accuracy of the potential biomarkers identified here using receiver operating characteristic curve analyses and further measured major angiogenic factor expression levels using a tube formation assay and RT-qPCR.ResultsFive candidate genes were selected via integrated analysis; all five were upregulated by hypomethylation of specific promoter CpG sites. After further validation in an expanded sample set, we identified a candidate biomarker gene, sortilin 1 (SORT1). DNA methylation status at a specific SORT1 promoter CpG site in ECFCs readily distinguished patients with MMD from the normal controls with high accuracy (area under the curve 0.98, sensitivity 83.33%, specificity 100%). Furthermore, SORT1 overexpression suppressed endothelial cell tube formation and modulated major angiogenic factor and matrix metalloproteinase-9 expression, implying SORT1 involvement in MMD pathogenesis.Conclusions Our findings suggest that DNA methylation status at the SORT1 promoter CpG site may be a potential biomarker for MMD.
| S-EPMC6186926 | biostudies-literature
Project description:ObjectiveMoyamoya disease (MMD) is a unique cerebrovascular occlusive disease characterized by progressive steno-occlusion within the terminal segment of the internal carotid artery. However, good collaterals from an external carotid artery are essential to compensate for the ischemia in moyamoya disease. This study aimed to investigate the transforming growth factor-beta 1 (TGFβ1) in plasma as a potential biomarker for predicting collateral formation in ischemic MMD.MethodsThe transcriptome profile downloaded from Gene Expression Omnibus (GEO) was used to analyze the differential expression of genes between the ischemic MMD and the control groups. We prospectively recruited 23 consecutive patients with ischemic MMD that was diagnosed via digital subtraction angiography (DSA). Nine patients with intracranial aneurysms and four healthy people served as controls. The collaterals from the external carotid artery were examined using DSA. We evaluated whether the collateral formation was associated with TGFβ1 in patients with ischemic MMD. Western blot, RT-qPCR, ELISA, and tube formation assay were used to explore the relationship between TGFβ1 and angiogenesis, as well as the potential mechanisms.ResultsThe mRNA levels of TGFβ1 were upregulated in the patients with ischemic MMD. The plasma TGFβ1 levels were higher in the patients with ischemic MMD than in the aneurysm and healthy patients (p < 0.05). The collateral formation group has higher levels of serum TGFβ1 than the non-collateral formation group (p < 0.05). The levels of vascular endothelial growth factor (VEGF) are positively correlated with TGFβ1 levels in the plasma (R 2 = 0.6115; p < 0.0001). TGFβ1 regulates VEGF expression via the activation of the TGFβ pathway within HUVEC cells, as well as TGFβ1 stimulating HUVEC cells to secrete VEGF into the cell culture media. An in vitro assay revealed that TGFβ1 promotes angiogenesis within the endothelial cells.ConclusionOur findings suggest that TGFβ1 plays a vital role in promoting collateral formation by upregulating VEGF expression in ischemic MMD.
| S-EPMC9301205 | biostudies-literature
Project description: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.
| S-EPMC6306562 | biostudies-literature
Project description:The pathogenesis and development of Moyamoya disease are still unclear. This study aimed to investigate the effect of desmoglein-2 (DSG2) on Moyamoya disease and determine the inhibitory effect of DSG2 in vascular remodeling in Moyamoya disease.RNA sequencing, immunohistochemistry (IHC), and western blotting were used to detect the expression of DSG2 in the superficial temporal artery (STA) tissues of Moyamoya disease. The association between DSG2 and endothelial cells' biological activities was investigated by cell counting kit-8 (CCK-8), migration assay, tube formation assay, flow cytometry with Annexin V-FITC/PI staining, and TUNEL apoptotic cell detection kit. Pathways affected by overexpression or knockdown of DSG2 were identified in endothelial cells.The expression of DSG2 in the STA tissues of Moyamoya disease was lower than that in normal controls. Overexpression of DSG2 inhibits the proliferation and migration but promotes apoptosis in endothelial cells, and low DSG2 levels result in impaired angiogenesis. In addition, there was an interaction between DSG2 and MMP-9, and DSG2 acted through the PI3K signaling in endothelial cells.Our results indicate that DSG2 affects PI3K signaling in vascular endothelial cells, and MMP-9 is involved in DSG2-mediated vascular changes in Moyamoya disease.
| S-EPMC11339177 | biostudies-literature
Project description:We aimed to investigate whether mitochondrial dysfunction in extracellular cerebrospinal fluid (CSF), which is associated with autophagy and mitophagy, might be involved in neurological outcomes in adult patients with hemorrhagic moyamoya disease (MMD) whose pathogenesis related to poor outcomes is not well-known. CSF samples were collected from 43 adult MMD patients and analyzed according to outcomes at 3 months. Fluorescence-activated cell sorter analysis (FACS) and the JC-1 red/green ratio were used to assess mitochondrial cells and intact mitochondrial membrane potential (MMP). We performed quantitative real-time polymerase chain reaction and Western blotting analyses of autophagy and mitophagy-related markers, including HIF1α, ATG5, pBECN1, BECN1, BAX, BNIP3L, DAPK1, and PINK1. Finally, FACS analysis with specific fluorescence-conjugated antibodies was performed to evaluate the potential cellular origin of CSF mitochondrial cells. Twenty-seven females (62.8%) with a mean age of 47.4 ± 9.7 years were included in the study. Among 43 patients with hemorrhagic MMD, 23 (53.5%) had poor outcomes. The difference in MMP was evident between the two groups (2.4 ± 0.2 in patients with poor outcome vs. 3.5 ± 0.4 in patients with good outcome; p = 0.02). A significantly higher expression (2-ΔCt) of HIF1α, ATG5, DAPK1 followed by BAX and BNIP3L mRNA and protein was also observed in poor-outcome patients compared to those with good outcomes. Higher percentage of vWF-positive mitochondria, suggesting endothelial cell origins, was observed in patients with good outcome compared with those with poor outcome (25.0 ± 1.4% in patients with good outcome vs. 17.5 ± 1.5% in those with poor outcome; p < 0.01). We observed the association between increased mitochondrial dysfunction concomitant with autophagy and mitophagy in CSF cells and neurological outcomes in adult patients with hemorrhagic MMD. Further prospective multicenter studies are needed to determine whether it has a diagnostic value for risk prediction.
| S-EPMC10447448 | biostudies-literature
Project description:Background and purposeAlthough low glomerular filtration rate (GFR) and albuminuria are associated with increased risk of stroke, few studies compared their contribution to risk of ischemic versus hemorrhagic stroke separately. We contrasted the association of these kidney measures with ischemic versus hemorrhagic stroke.MethodsWe pooled individual participant data from 4 community-based cohorts: 3 from the United States and 1 from The Netherlands. GFR was estimated using both creatinine and cystatin C, and albuminuria was quantified by urinary albumin-to-creatinine ratio (ACR). Associations of estimated GFR and ACR were compared for each stroke type (ischemic versus intraparenchymal hemorrhagic) using study-stratified Cox regression.ResultsAmong 29,595 participants (mean age, 61 [SD 12.5] years; 46% men; 17% black), 1261 developed stroke (12% hemorrhagic) during 280,549 person-years. Low estimated GFR was significantly associated with increased risk of ischemic stroke, but not hemorrhagic stroke, whereas high ACR was associated with both stroke types. Adjusted hazard ratios for ischemic and hemorrhagic stroke at estimated GFR of 45 (versus 95) mL/min per 1.73 m2 were 1.30 (95% confidence interval, 1.01-1.68) and 0.92 (0.47-1.81), respectively. In contrast, the corresponding hazard ratios for ACR of 300 (versus 5) mg/g were 1.62 (1.27-2.07) for ischemic and 2.57 (1.37-4.83) for hemorrhagic stroke, with significantly stronger association with hemorrhagic stroke (P=0.04). For hemorrhagic stroke, the association of elevated ACR was of similar magnitude as that of elevated systolic blood pressure.ConclusionsWhereas albuminuria showed significant association with both stroke types, the association of decreased estimated GFR was only significant for ischemic stroke. The strong association of albuminuria with both stroke types warrants clinical attention and further investigations.
| S-EPMC4517673 | biostudies-literature
Project description:ImportanceWhether recent changes in demographic characteristics and therapeutic technologies have altered stroke outcomes remains unknown.ObjectiveTo determine secular changes in initial neurological severity and short-term functional outcomes of patients with acute stroke by sex using a large population.Design, setting, and participantsThis nationwide, hospital-based, multicenter, prospective registry cohort study used the Japan Stroke Data Bank and included patients who developed acute stroke from January 2000 through December 2019. Patients with stroke, including ischemic and hemorrhagic strokes, who registered within 7 days after symptom onset were studied. Modified Rankin Scale scores were assessed at hospital discharge for all patients.ExposureTime.Main outcomes and measuresInitial severity was assessed by the National Institutes of Health Stroke Scale for ischemic stroke and intracerebral hemorrhage and by the World Federation of Neurological Surgeons grading for subarachnoid hemorrhage. Outcomes were judged as favorable if the modified Rankin Scale score was 0 to 2 and unfavorable if 5 to 6.ResultsOf 183 080 patients, 135 266 (53 800 women [39.8%]; median [IQR] age, 74 [66-82] years) developed ischemic stroke, 36 014 (15 365 women [42.7%]; median [IQR] age, 70 [59-79] years) developed intracerebral hemorrhage, and 11 800 (7924 women [67.2%]; median [IQR] age, 64 [53-75] years) developed subarachnoid hemorrhage. In all 3 stroke types, median ages at onset increased, and the National Institutes of Health Stroke Scale and World Federation of Neurological Surgeons scores decreased throughout the 20-year period on multivariable analysis. In ischemic stroke, the proportion of favorable outcomes showed an increase over time after age adjustment (odds ratio [OR], 1.020; 95% CI, 1.015-1.024 for women vs OR, 1.015; 95% CI, 1.011-1.018 for men) but then stagnated, or even decreased in men, on multivariate adjustment including reperfusion therapy (OR, 0.997; 95% CI, 0.991-1.003 for women vs OR, 0.990; 95% CI, 0.985-0.994 for men). Unfavorable outcomes and in-hospital deaths decreased in both sexes. In intracerebral hemorrhage, favorable outcomes decreased in both sexes, and unfavorable outcomes and deaths decreased only in women. In subarachnoid hemorrhage, the proportion of favorable outcomes was unchanged, and that of unfavorable outcomes and deaths decreased in both sexes.Conclusions and relevanceIn this study, functional outcomes improved in patients with ischemic stroke during the past 20 years in both sexes presumably partly owing to the development of acute reperfusion therapy. The outcomes of patients with hemorrhagic stroke did not clearly improve in the same period.
| S-EPMC8649912 | biostudies-literature
Project description:Cerebral amyloid angiopathy (CAA) is one of the main causes of intracerebral hemorrhage (ICH) in the elderly. Matrix metalloproteinases (MMPs) have been implicated in blood-brain barrier disruption and ICH pathogenesis. In this study, we determined the levels MMP-2 and MMP-9 in plasma and their brain expression in CAA-associated hemorrhagic stroke. Although MMP-2 and MMP-9 plasma levels did not differ among patients and controls, their brain expression was increased in perihematoma areas of CAA-related hemorrhagic strokes compared with contralateral areas and nonhemorrhagic brains. In addition, MMP-2 reactivity was found in β-amyloid (Aβ)-damaged vessels located far from the acute ICH and in chronic microbleeds. MMP-2 expression was associated to endothelial cells, histiocytes and reactive astrocytes, whereas MMP-9 expression was restricted to inflammatory cells. In summary, MMP-2 expression within and around Aβ-compromised vessels might contribute to the vasculature fatal fate, triggering an eventual bleeding.
| S-EPMC8029059 | biostudies-literature