Angiopoietin-2 associates with poor prognosis in Moyamoya angiopathy.

OBJECTIVE: Moyamoya angiopathy (MA) is a rare cerebrovascular disorder characterized by recurrent ischemic/hemorrhagic strokes due to progressive occlusion of the intracranial carotid arteries. The lack of reliable disease severity biomarkers led us to investigate molecular features of a Caucasian cohort of MA patients. METHODS: The participants consisted of 30 MA patients and 40 controls. We measured cerebrospinal fluid (CSF) levels of angiogenic/inflammatory factors (ELISA). We then applied quantitative real-time PCR on cerebral artery specimens for expression analyses of angiogenic factors. By an immunoassay based on microfluidic technology, we examined the potential correlations between plasma protein expression and MA clinical progression. A RNA interference approach toward Ring Finger Protein 213 (RNF213) and a tube formation assay were applied in cellular model. RESULTS: We detected a statistically significant (p < 0.000001) up-regulation of Angiopoietin-2 (Ang-2) in CSF and stenotic middle cerebral arteries (RQ >2) of MA patients compared to controls. A high Ang-2 plasma concentration (p = 0.018) was associated with unfavorable outcome in a subset of MA patients. ROC curve analyses indicated Ang-2 as diagnostic CSF biomarker (>3741 pg/mL) and prognostic plasma biomarker (>1162 pg/mL), to distinguish stable-from-progressive MA. Consistently, MA cellular model showed a significant up-regulation (RQ >2) of Ang-2 in RNF213 silenced condition. INTERPRETATION: Our results pointed out Ang-2 as a reliable biomarker mirroring arterial steno-occlusion and vascular instability of MA in CSF and blood, providing a candidate factor for patient stratification. This pilot study may pave the way to the validation of a biomarker to identify progressive MA patients deserving a specific treatment path.

SDF-1/CXCR4 axis participants in the pathophysiology of adult patients with moyamoya disease.

BACKGROUND: Moyamoya disease (MMD) is characterized by an abundance of moyamoya vessels; however, the precise mechanism driving the spontaneous angiogenesis of these compensatory vessels remains unclear. Previous research has established a link between the stromal cell-derived factor-1 (SDF-1)/ CXC receptor 4 (CXCR4) axis and angiogenesis under hypoxic conditions. Nevertheless, the alterations in this axis within the cerebrospinal fluid, arachnoid membranes and vascular tissue of MMD patients have not been fully investigated. METHODS: Our study enrolled 66 adult MMD patients and 61 patients with atherosclerotic vascular disease (ACVD). We investigated the SDF-1 concentration in cerebrospinal fluid (CSF) and CXCR4 expression level on the arachnoid membranes and vascular tissue. We utilized enzyme-linked immunosorbent assay and immunohistochemistr. Additionally, we cultured and stimulated human brain microvascular endothelial cells (HBMECs) and smooth muscle cells (SMCs) under oxygen and glucose deprivation (OGD) conditions followed by reoxygenation, to examine any changes in the SDF-1/CXCR4 axis. RESULTS: The results demonstrated an elevation in the level of SDF-1 in CSF among MMD patients compared to those with ACVD. Moreover, the expression of CXCR4 in arachnoid membranes and vascular tissue showed a similar trend. Furthermore, the content of CXCR4 in HBMECs and SMCs increased with the duration of ischemia and hypoxia. However, it was observed that the expression of CXCR4 decreased at OGD/R 24h compared to OGD 24h. The temporal pattern of SDF-1 expression in HBMECs and SMCs mirrored that of CXCR4 expression. CONCLUSION: These findings indicate a critical role for the SDF-1/CXCR4 axis in the angiogenesis of moyamoya disease.

Use of a panel of four microRNAs in CSF as a predicted biomarker for postoperative neoangiogenesis in moyamoya disease.

INTRODUCTION AND AIMS: At present, the treatment for moyamoya disease (MMD) primarily consists of combined direct and indirect bypass surgery. Nevertheless, more than half of indirect bypass surgeries fail to develop good collaterals from the dura and temporal muscle. This study aimed to investigate whether microRNAs (miRNAs) in cerebrospinal fluid (CSF) could serve as biomarkers for the prediction of postoperative collateral formation. METHODS: Moyamoya disease patients with indirect bypass surgery were divided into angiogenesis and non-angiogenesis groups, CSF was obtained, and miRNA sequencing was performed using the CSF. Candidate miRNAs were filtered and subsequently verified through qRT-PCR. The diagnostic utility of these differential miRNAs was investigated by using receiver operating characteristic (ROC) curve analysis. Finally, the potential biological processes and signaling pathways associated with candidate miRNAs were analyzed using R software. RESULTS: The expression levels of four miRNAs (miR-92a-3p, miR-486-3p, miR-25-3p, and miR-155-5p) were significantly increased in the angiogenesis group. By combining these four miRNAs (area under the curve [AUC] =0.970), we established an accurate predictive model of collateral circulation after indirect bypass surgery in MMD patients. GO and KEGG analyses demonstrated a high correlation with biological processes and signaling pathways related to angiogenesis. CONCLUSION: The 4-miRNA signature is a good model to predict angiogenesis after indirect bypass surgery and help the surgeon to select a appreciate bypass strategy.

Choroid plexus perfusion and intracranial cerebrospinal fluid changes after angiogenesis.

Recent studies have provided evidence that cortical brain ischemia may influence choroid plexus function, and such communication may be mediated by either traditional CSF circulation pathways and/or a possible glymphatic pathway. Here we investigated the hypothesis that improvements in arterial health following neoangiogenesis alter (i) intracranial CSF volume and (ii) choroid plexus perfusion in humans. CSF and tissue volume measurements were obtained from T1-weighted MRI, and cortical and choroid plexus perfusion were obtained from perfusion-weighted arterial spin labeling MRI, in patients with non-atherosclerotic intracranial stenosis (e.g. Moyamoya). Measurements were repeated after indirect surgical revascularization, which elicits cortical neoangiogenesis near the revascularization site (n = 23; age = 41.8 ± 13.4 years), or in a cohort of participants at two time points without interval surgeries (n = 10; age = 41.7 ± 10.7 years). Regression analyses were used to evaluate dependence of perfusion and volume on state (time 1 vs. 2). Post-surgery, neither CSF nor tissue volumes changed significantly. In surgical patients, cortical perfusion increased and choroid plexus perfusion decreased after surgery; in participants without surgeries, cortical perfusion reduced and choroid plexus perfusion increased between time points. Findings are discussed in the context of a homeostatic mechanism, whereby arterial health, paravascular flow, and/or ischemia can affect choroid plexus perfusion.

Elevation of Proenkephalin 143-183 in Cerebrospinal Fluid in Moyamoya Disease.

BACKGROUND: In moyamoya disease (MMD), the causes of differences in clinical features between children and adults and of the dramatic temporal changes in moyamoya vessels are poorly understood. We previously discovered elevated levels of m/z 4588 and m/z 4473 peptides in cerebrospinal fluid (CSF) in patients with MMD. This study examined the amino acid sequences of these peptides and quantified in specimens. METHODS: The m/z 4588 and m/z 4473 peptides in CSF from patients with MMD were purified and concentrated by high-performance liquid chromatography and ultrafiltration. Liquid chromatography coupled with tandem mass spectrometry analysis was performed to identify the amino acid sequences of these peptides. We quantified these peptides in samples using sandwich enzyme-linked immunosorbent assay, and concentrations in CSF were compared between MMD (n = 40, 19 male; median age, 37 years) and non-MMD intracranial disease (n = 40, 19 male; median age, 39 years) as controls. RESULTS: These peptides were identified as proenkephalin 143-183 (PENK 143-183). The concentration of PENK 143-183 was significantly greater in patients with MMD (median, 8,270 pmol/L) than control patients (median, 3,760 pmol/L; P < 0.001) and decreased in an age-dependent manner in MMD (r = -0.57; P < 0.001). The area under the receiver operating characteristic curve in children (age <18 years) was 0.885 (95% confidence interval 0.741-1). The correlation between proenkephalin concentration and temporal changes in moyamoya vessels was suggested. CONCLUSIONS: Proenkephalin 143-183 in CSF may offer a helpful diagnostic biomarker in pediatric MMD. The effect of enkephalin peptides through opioid growth factor receptor or delta opioid receptor might be associated with the pathophysiology of MMD.

Downregulation of Apolipoprotein-E and Apolipoprotein-J in Moyamoya Disease-A Proteome Analysis of Cerebrospinal Fluid.

BACKGROUND AND PURPOSE: Genetic factors are closely involved in the etiology of moyamoya disease (MMD). However, its postgenomic mechanisms are still unknown. This study was aimed to identify specific biomarkers in the cerebrospinal fluid (CSF) of patients with MMD, using quantitative proteome technique. METHODS: This study included 10 patients with MMD and 4 controls. The CSF was collected without blood contamination during surgery. A comparative 2-dimensional gel electrophoresis study (2D-PAGE) was performed. Protein spots that showed significant differences between moyamoya patients and controls were selected for further analysis by mass spectrometry. RESULTS: On 2D-PAGE, 2 proteins were significantly upregulated, and 2 other proteins were downregulated in the CSF of MMD. Further mass spectrometry analysis revealed that haptoglobin and α-1-B-glycoprotein (A1BG) were upregulated. On the other hand, apolipoprotein-E (apoE), apoE precursor, and apolipoprotein-J (apoJ) were significantly downregulated in the CSF of MMD. The observed probability-based MOWSE score was 72 for haptoglobin (P <.05), 521 for A1BG (P <.05), 62 for apoE (P <.05), 72 for apoE precursor (P <.05), and 112 for apoJ (P <.05). CONCLUSION: Although the role of A1BG in the central nervous system is still unknown, the overexpressed haptoglobin may indicate the inflammation and/or angiogenesis in MMD. The downregulation of apoE and apoJ strongly suggests a critical role of lipid metabolism in the development and progression of MMD. These proteins may be novel biomarkers in shedding light on the pathogenesis of MMD, although further studies would be warranted.

1H-NMR-based metabolomic analysis of cerebrospinal fluid from adult bilateral moyamoya disease: comparison with unilateral moyamoya disease and atherosclerotic stenosis.

Although metabolomics has been increasingly used to observe metabolic pattern and disease-specific metabolic markers, metabolite profiling for moyamoya disease (MMD) has not yet been done in adults. This study investigated cerebrospinal fluid (CSF) metabolites specific to bilateral MMD (B-MMD) and compared them to those of unilateral MMD (U-MMD) or atherosclerotic stenosis with hydrogen-1 nuclear magnetic resonance spectroscopy to identify metabolic biomarkers associated with MMD in adults.CSF samples of B-MMD (n = 29), U-MMD (n = 11), and atherosclerotic cerebrovascular disease (ACVD) (n = 8) were recruited. Principal component analysis, partial least square discriminant analysis, and orthogonal projections to latent structure discriminant analysis (OPLS-DA) were done for the comparisons. Diagnostic performance was acquired by prediction of 1 left-out sample from the distinction model constructed with the rest of the samples.B-MMD showed an increase in glutamine (P < 0.001) and taurine (P = 0.004), and a decrease in glucose (P < 0.001), citrate (P = 0.002), and myo-inositol (P = 0.006) than those in ACVD. U-MMD showed a higher level of glutamine (P = 0.005) and taurine (P = 0.034), and a lower level of glutamate (P < 0.004) than those in ACVD. No difference at the metabolite level was observed between B-MMD and U-MMD. Cross-validation with the OPLS-DA model showed a high accuracy for the prediction of MMD.The results of the study suggest that a metabolomics approach may be helpful in confirming MMD and providing a better understanding of MMD pathogenesis. Elevated glutamine in the CSF may be associated with MMD pathogenesis, which was different from ACVD.

Biomarker research for moyamoya disease in cerebrospinal fluid using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry.

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by steno-occlusive change in bilateral internal carotid arteries with unknown etiology. To discover biomarker candidates in cerebrospinal fluid from MMD patients, proteome analysis was performed by the surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Three peptides, 4473Da, 4475Da, and 6253Da, were significantly elevated in MMD group. A positive correlation between 4473Da peptide and postoperative angiogenesis was determined. Twenty MMD patients were enrolled in this pilot study, including 11 pediatric cases less than 18 years of age (mean age, 8.67 years) and 9 adult MMD patients (mean age, 38.1 years). This study also includes 17 control cases with the mean age of 27.9 years old. In conclusion, 4473Da peptide is supposed to be a reliable biomarker of MMD. 4473Da peptide showed higher intensity peaks especially in younger MMD patients, and it was proved to be highly related to postoperative angiogenesis. Further study is needed to show how 4473Da peptide is involved with the etiology and the onset of MMD.

The roles of methylenetetrahydrofolate reductase 677C>T and 1298A>C polymorphisms in moyamoya disease patients.

PURPOSE: The methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C polymorphisms, which are associated with hyperhomocysteinemia and nitric oxide (NO) deficiency (which is related to atherothrombosis and cerebral ischemia), have not been studied in moyamoya disease. A case-control study was performed to investigate whether the MTHFR 677C>T and 1298A>C polymorphisms contribute to moyamoya disease (MMD). METHODS: One hundred and seven Korean patients with MMD (mean age, 20.85 ± 15.89 years; 66.4 % female) and 232 healthy control subjects (mean age, 23.99 ± 16.16 years; 56.8 % female) were included. Genotyping for the MTHFR 677C>T and 1298A>C polymorphisms and measurements of homocysteine, folate, vitamin B12, and NO in the cerebrospinal fluid (CSF) were performed. The statistical analysis was performed by multivariate linear regression and logistic regression. RESULT: The MTHFR 677CT+TT genotype frequency was significantly increased with early-onset MMD (<10 years) compared with late-onset MMD (≥10 years) (adjusted odds ratio, 3.392; 95 % confidence interval, 1.294-8.893, P = 0.013). The MTHFR 677C-1298C/677T-1298A diplotype (1.71 ± 1.23 arbitrary units) presented significantly lower NO levels in the CSF compared with the 677C-1298A/677C-1298A diplotype (11.40 ± 12.24 arbitrary units). CONCLUSION: The MTHFR 677C>T and 1298A>C polymorphisms have restricted roles in the Korean MMD population. Therefore, further studies involving larger and more heterogeneous cohorts are needed to extend our understanding of the influence of polymorphisms in MTHFR and other thrombophilic genes on MMD.

Expression of cellular retinoic acid-binding protein-I (CRABP-I) in the cerebrospinal fluid of adult onset moyamoya disease and its association with clinical presentation and postoperative haemodynamic change.

OBJECTIVE: The elevation of cellular retinoic acid-binding protein-I (CRABP-I) has been suggested as a candidate in the pathogenesis of paediatric moyamoya disease (MMD). However, few studies have addressed CRABP-I in adult onset MMD. The aim of this study was to examine the expression of CRABP-I in the cerebrospinal fluid (CSF) of adult onset MMD, and to evaluate its association with clinical presentation and postoperative haemodynamic change. METHODS: This study examined the CSF from 103 patients: bilateral MMD, n=58 (56.3%); unilateral MMD, n=19 (18.4%); atherosclerotic cerebrovascular disease (ACVD), n=21 (20.4%); and control group, n=5 (4.9%). The intensity of CRABP-I was confirmed by western blotting and expressed as the median (25th-75th percentile). The differences in CRABP-I expression according to disease entity (unilateral MMD vs bilateral MMD vs ACVD), initial presenting symptoms (haemorrhage vs ischaemia) and postoperative haemodynamic change (vascular reserve in single photon emission CT and basal collateral vessels in digital subtraction angiography) were analysed. RESULTS: CRABP-I intensities in bilateral MMD (1.45(0.86-2.52)) were significantly higher than in unilateral MMD (0.91(0.78-1.20)) (p=0.044) or ACVD (0.85(0.66-1.11)) (p=0.004). No significant differences were noted based on the initial presenting symptoms (p=0.687). CRABP-I was not associated with improvement in vascular reserve (p=0.327), but with decrease in basal collateral vessels (p=0.023) postoperatively. CONCLUSIONS: Higher CRABP-I in the CSF can be associated with typical bilateral MMD pathogenesis in adults. Additionally, postoperative basal collateral change may be related to the degree of CRABP-I expression.

Identification of novel biomarker candidates by proteomic analysis of cerebrospinal fluid from patients with moyamoya disease using SELDI-TOF-MS.

BACKGROUND: Moyamoya disease (MMD) is an uncommon cerebrovascular condition with unknown etiology characterized by slowly progressive stenosis or occlusion of the bilateral internal carotid arteries associated with an abnormal vascular network. MMD is a major cause of stroke, specifically in the younger population. Diagnosis is based on only radiological features as no other clinical data are available. The purpose of this study was to identify novel biomarker candidate proteins differentially expressed in the cerebrospinal fluid (CSF) of patients with MMD using proteomic analysis. METHODS: For detection of biomarkers, CSF samples were obtained from 20 patients with MMD and 12 control patients. Mass spectral data were generated by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) with an anion exchange chip in three different buffer conditions. After expression difference mapping was undertaken using the obtained protein profiles, a comparative analysis was performed. RESULTS: A statistically significant number of proteins (34) were recognized as single biomarker candidate proteins which were differentially detected in the CSF of patients with MMD, compared to the control patients (p < 0.05). All peak intensity profiles of the biomarker candidates underwent classification and regression tree (CART) analysis to produce prediction models. Two important biomarkers could successfully classify the patients with MMD and control patients. CONCLUSIONS: In this study, several novel biomarker candidate proteins differentially expressed in the CSF of patients with MMD were identified by a recently developed proteomic approach. This is a pilot study of CSF proteomics for MMD using SELDI technology. These biomarker candidates have the potential to shed light on the underlying pathogenesis of MMD.

Primary central nervous system vasculitis and moyamoya disease: similarities and differences.

Primary central nervous system vasculitis (PCNSV) and moyamoya disease (MMD) represent rare and poorly-understood causes of stroke. Both may present with similar clinical and auxiliary findings, but differentiation is extremely important because they require different treatment regimens. Our cohort included 21 white patients with PCNSV and 21 white patients with MMD. Clinical and diagnostic features were obtained by retrospective chart review; follow-up information and outcome were obtained prospectively. Data were compared between patients with PCNSV and MMD using Chi square test or Fisher's exact test for categorical data and Mann-Whitney U test for continuous data. The mean age at symptom onset was 42.48 years in PCNSV and 31.0 years in MMD (p = 0.008). All patients with MMD presented with ischemic events while cerebral ischemia was observed in only 14 of 21 patients (66.7%) with PCNSV (p = 0.004). There was no significant difference regarding the frequency of headaches, which represented an important symptom in both conditions. Conventional cerebral angiography verified correct diagnosis in 13 of 17 patients (76.5%) with PCNSV while angiogram verified correct diagnosis in all patients with MMD (p = 0.032). MRI and cerebrospinal fluid studies were appropriate to differentiate between the inflammatory and the non-inflammatory disease. Three PCNSV patients and two MMD patients died within documented follow-up. Despite important pathophysiological and angiographic differences, PCNSV and MMD may present with similar clinical and auxiliary findings. An intensive workup including MRI, conventional cerebral angiography and CSF studies is required to avoid misdiagnosis.

Detection of a gamma-carboxy-glutamate as novel post-translational modification of human transthyretin.

During analysis of the proteome in the cerebrospinal fluid (CSF) of the Caucasian form of moyamoya disease (MMD), a novel post-translational modification of human transthyretin was observed. Two-dimensional electrophoresis and subsequent peptide sequencing with ESI-MS/MS were performed to discover the gamma-carboxylation of the Glu-42 (Gla-42).

CSF proteome: a protein repository for potential biomarker identification.

Proteomic analysis is not limited to the analysis of serum or tissues. Synovial, peritoneal, pericardial and cerebrospinal fluid represent unique proteomes for disease diagnosis and prognosis. In particular, cerebrospinal fluid serves as a rich source of putative biomarkers that are not solely limited to neurologic disorders. Peptides, proteolytic fragments and antibodies are capable of crossing the blood-brain barrier, thus providing a repository of pathologic information. Proteomic technologies such as immunoblotting, isoelectric focusing, 2D gel electrophoresis and mass spectrometry have proven useful for deciphering this unique proteome. Cerebrospinal fluid proteins are generally less abundant than their corresponding serum counterparts, necessitating the development and use of sensitive analytical techniques. This review highlights some of the promising areas of cerebrospinal fluid proteomic research and their clinical applications.

Increased expression of hepatocyte growth factor in cerebrospinal fluid and intracranial artery in moyamoya disease.

BACKGROUND AND PURPOSE: The etiology of moyamoya disease still remains unknown. This study was aimed to explore the role of hepatocyte growth factor (HGF), a strong inducer of angiogenesis, in development of moyamoya disease. METHODS: We studied cerebrospinal fluid (CSF) from 39 patients with moyamoya disease (24 children and 15 adults), 6 control patients with cervical spondylosis, and 7 control patients with internal carotid artery occlusion. CSF level of HGF was determined by enzyme-linked immunosorbent assay technique. We also evaluated the distribution of HGF and its cellular receptor c-Met in the carotid fork obtained from 2 patients with moyamoya disease and 2 control patients. RESULTS: CSF level of HGF was 408.2+/-201.6 pg/mL and 443.2+/-193.5 pg/mL in patients with cervical spondylosis and internal carotid artery occlusion, respectively (mean+/-SD). On the other hand, CSF level of HGF was 820.3+/-319.0 pg/mL in patients with moyamoya disease, being significantly higher than those in 2 control groups (P<0.01). Both HGF and c-Met were widely distributed in the media and thickened intima of the carotid fork in patients with moyamoya disease but not in control patients. CONCLUSIONS: This study revealed that HGF is densely found in the carotid fork, and its CSF level is markedly elevated in moyamoya disease, suggesting that HGF may be a key protein for pathogenesis of moyamoya disease.

SEREX identification of the autoantibodies that are prevalent in the cerebrospinal fluid of patients with moyamoya disease.

We performed SEREX (serological analysis of recombinant cDNA expression library) to identify autoantibodies that are prevalent in the cerebrospinal fluid of patients with moyamoya disease. These autoantibodies include PC326 (of unknown function), SRY (sex determining region Y), and peroxisomal D3,D2-enoyl-CoA isomerase.

Elevation of CRABP-I in the cerebrospinal fluid of patients with Moyamoya disease.

BACKGROUND AND PURPOSE: The etiology of moyamoya disease (MMD) remains obscure. This study was undertaken to identify specific proteins associated with the pathogenesis of MMD. METHODS: We studied cerebrospinal fluid (CSF) from 20 patients with angiographically confirmed MMD (4 boys and 16 girls; age range, 3 to 13 years; mean, 7.5 years) and 4 control patients with cerebral palsy who underwent selective dorsal rhizotomy (2 boys and 2 girls; age range, 5 to 10 years; mean, 7.3 years). CSF proteins were analyzed by 2-dimensional polyacrylamide gel electrophoresis, and protein identification was performed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The presence of specific CSF protein in patients with MMD was confirmed by Western blotting. In addition, cerebral CSF was also tested in 7 patients who had other brain diseases but no MMD (2 boys and 5 girls; age range, 1 to 12 years; mean, 6.9 years). RESULTS: We identified 1 polypeptide spot (Mr of 13 to 15 kDa and isoelectric point of 5 to 5.5) that was differentially expressed in the CSF samples of MMD patients (mean optical density intensity, 0.36+/-0.24; range, 0.05 to 0.92) and control spinal CSF samples (mean, 0.03+/-0.04; range, 0 to 0.08; P=0.002). This polypeptide was identified as cellular retinoic acid-binding protein (CRABP)-I. High levels of expression of CRABP-I in the CSF from 17 MMD children were confirmed by Western blotting. CONCLUSIONS: The analysis of the CSF of MMD patients reveals high CRABP-I expression. The present study suggests that the elevation of CRABP-I in CSF may be a candidate for pathogenesis of MMD.

Levels of soluble adhesion molecules are elevated in the cerebrospinal fluid of children with moyamoya syndrome.

OBJECTIVE: The pathogenesis of moyamoya syndrome is unknown; however, previous studies suggested an inflammatory component. Because adhesion molecules mediate inflammation during cerebral ischemia, we measured the levels of soluble isoforms of the endothelial adhesion molecules vascular cell adhesion molecule Type 1, intercellular adhesion molecule Type 1, and E-selectin in serum and cerebrospinal fluid (CSF) samples from children with moyamoya syndrome. METHODS: Serum and CSF samples were obtained from children with moyamoya syndrome (n = 20) and patients with congenital spinal deformities (n = 20). Soluble vascular cell adhesion molecule Type 1, intercellular adhesion molecule Type 1, and E-selectin levels were measured in enzyme-linked immunoassays. The correlation between the levels of soluble adhesion molecules and the Suzuki angiographic classification was analyzed. CSF/serum albumin index values were also measured, to determine the integrity of the blood-brain barrier. RESULTS: Compared with the control group, children with moyamoya syndrome exhibited significantly elevated CSF levels of soluble vascular cell adhesion molecule Type 1, intercellular adhesion molecule Type 1, and E-selectin. The albumin index for the moyamoya group was 9, which was significantly higher than that for the control group. However, there were no differences in the serum levels of the three soluble adhesion molecules and no correlations between age, Suzuki classification, and serum and CSF levels of adhesion molecules. CONCLUSION: Our study demonstrates increased CSF levels of soluble endothelial adhesion molecules, suggesting that children with moyamoya syndrome have ongoing central nervous system inflammation, with slight impairment of the blood-brain barrier. These soluble adhesion molecules may be clinically useful as indicators of this inflammatory process and may provide some insight into this enigmatic disease process.

Role of nitric oxide in the control of cerebral microcirculation under physiological and pathological conditions.

Effect of nitric oxide (NO) on vasomotor tone of cerebral parenchymal arterioles was studied in rats. Then, the role of NO was clinically investigated in the pathogenesis of progressive cerebral vascular occlusive disease, moyamoya disease. In rat, the cerebral arterioles, about 30-60 microm in diameter, were dilated by L-arginine, a precursor of NO, at concentrations as low as 0.1 micromol with maximal dilation of 14% at 100 micromol. The arterioles were constricted by N(G)-monomethyl-L-arginine (L-NMMA), a NO synthesis inhibitor. Superoxide dismutase, which seems to protect NO from inactivation, increased sensitivity of L-arginine. Compared with control specimens of cerebral spinal fluid (CSF) obtained from 16 patients, concentrations NO metabolites in the CSF of 23 patients with moyamoya disease were significantly higher. NO metabolites concentrations obtained during initial surgery decreased during a second, contralateral procedure. NO plays an important role in the regulation of basal tone of cerebral parenchymal arterioles and contributes to the increase in collateral circulation in cerebral occlusive disease like moyamoya disease. Vascular bypass surgery can reduce NO metabolites together with abnormal collateral circulation.

A cerebrospinal fluid protein associated with moyamoya disease: report of three cases.

OBJECTIVE: The pathogenesis of moyamoya disease is unknown. The purpose of this study was to detect proteins associated with the pathogenesis of moyamoya disease. CLINICAL PRESENTATION: Cerebrospinal fluid (CSF) samples from three patients with moyamoya disease and four control patients who had cervical lesions but no intracranial lesion were studied. INTERVENTION: CSF proteins separated by two-dimensional polyacrylamide gel electrophoresis were analyzed with the SWISS-2DPAGE and SWISS-PROT databases. In the CSF samples from all three patients with moyamoya disease, a polypeptide spot (Mr = 12,000, pI = 5.35) was observed. This spot was not evident in samples from the four control patients and has not been reported in the SWISS-2DPAGE and SWISS-PROT databases. CONCLUSION: A CSF protein, which is possibly novel and associated with moyamoya disease, has been detected. The analysis of CSF by two-dimensional polyacrylamide gel electrophoresis may reveal a clue by which the molecular mechanism of moyamoya disease may be elucidated.