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1.  Distinctive distribution of lymphocytes in unruptured and previously untreated brain arteriovenous malformation 
To test the hypothesis that lymphocyte infiltration in brain arteriovenous malformation (bAVM) is not associated with iron deposition (indicator of microhemorrhage).
Sections of unruptured, previously untreated bAVM specimens (n=19) were stained immunohistochemically for T-lymphocytes (CD3+), B-lymphocytes (CD20+), plasma cells (CD138+) and macrophages (CD68+). Iron deposition was assessed by hematoxylin and eosin and Prussian blue stains. Superficial temporal arteries (STA) were used as control.
Both T lymphocytes and macrophages were present in unruptured, previously untreated bAVM specimens, whereas few B cells and plasma cells were detected. Iron deposition was detected in 8 specimens (42%; 95% confidence interval =20–67%). The samples with iron deposition tended to have more macrophages than those without (666±313 vs 478±174 cells/mm2; P=0.11). T-cells were clustered on the luminal side of the endothelial surface, on the vessel-wall, and in the perivascular regions. There was no correlation between T lymphocyte load and iron deposition (P=0.88). No macrophages and lymphocytes were detected in STA controls.
T-lymphocytes were present in bAVM specimens. Unlike macrophages, the load and location of T-lymphocytes were not associated with iron deposition, suggesting the possibility of an independent cell-mediated immunological mechanism in bAVM pathogenesis.
PMCID: PMC4283567  PMID: 25568888
B-lymphocyte; human brain arteriovenous malformation; inflammatory cells; microhemorrhage; T-lymphocyte
2.  Analysis of Changes in Hepatic Gene Expression in a Murine Model of Tolerance to Acetaminophen Hepatotoxicity (Autoprotection) 
Toxicology and applied pharmacology  2013;274(1):156-167.
Pretreatment of mice with a low hepatotoxic dose of acetaminophen (APAP) results in resistance to a subsequent, higher dose of APAP. This mouse model, termed APAP autoprotection was used here to identify differentially expressed genes and cellular pathways that could contribute to this development of resistance to hepatotoxicity. Male C57BL/6J mice were pretreated with APAP (400 mg/kg) and then challenged 48 hr later with 600 mg APAP/kg. Livers were obtained 4 or 24 hr later and total hepatic RNA was isolated and hybridized to Affymetrix Mouse Genome MU430_2 GeneChip. Statistically significant genes were determined and gene expression changes were also interrogated using the Causal Reasoning Engine (CRE). Extensive literature review narrowed our focus to methionine adenosyl transferase-1 alpha (MAT1A), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), flavin-containing monooxygenase 3 (Fmo3) and galectin-3 (Lgals3). Down-regulation of MAT1A could lead to decreases in S-adenosylmethionine (SAMe), which is known to protect against APAP toxicity. Nrf2 activation is expected to play a role in protective adaptation. Up-regulation of Lgals3, one of the genes supporting the Nrf2 hypothesis, can lead to suppression of apoptosis and reduced mitochondrial dysfunction. Fmo3 induction suggests the involvement of an enzyme not known to metabolize APAP in the development of tolerance to APAP toxicity. Subsequent quantitative RT-PCR and immunochemical analysis confirmed the differential expression of some of these genes in the APAP autoprotection model. In conclusion, our genomics strategy identified cellular pathways that might further explain the molecular basis for APAP autoprotection.
PMCID: PMC3901410  PMID: 24126418
acetaminophen; liver; autoprotection; gene array; hepatotoxicity
3.  Temporal lobe arteriovenous malformations: anatomical subtypes, surgical strategy, and outcomes 
Journal of neurosurgery  2013;119(3):616-628.
Descriptions of temporal lobe arteriovenous malformations (AVMs) are inconsistent. To standardize reporting, the authors blended existing descriptions in the literature into an intuitive classification with 5 anatomical subtypes: lateral, medial, basal, sylvian, and ventricular. The authors’ surgical experience with temporal lobe AVMs was reviewed according to these subtypes.
Eighty-eight patients with temporal lobe AVMs were treated surgically.
Lateral temporal lobe AVMs were the most common (58 AVMs, 66%). Thirteen AVMs (15%) were medial, 9 (10%) were basal, and 5 (6%) were sylvian. Ventricular AVMs were least common (3 AVMs, 3%). A temporal craniotomy based over the ear was used in 64%. Complete AVM resection was achieved in 82 patients (93%). Four patients (5%) died in the perioperative period (6 in all were lost to follow-up); 71 (87%) of the remaining 82 patients had good outcomes (modified Rankin Scale scores 0–2); and 68 (83%) were unchanged or improved after surgery.
Categorization of temporal AVMs into subtypes can assist with surgical planning and also standardize reporting. Lateral AVMs are the easiest to expose surgically, with circumferential access to feeding arteries and draining veins at the AVM margins. Basal AVMs require a subtemporal approach, often with some transcortical dissection through the inferior temporal gyrus. Medial AVMs are exposed tangentially with an orbitozygomatic craniotomy and transsylvian dissection of anterior choroidal artery and posterior cerebral artery feeders in the medial cisterns. Medial AVMs posterior to the cerebral peduncle require transcortical approaches through the temporooccipi tal gyrus. Sylvian AVMs require a wide sylvian fissure split and differentiation of normal arteries, terminal feeding arteries, and transit arteries. Ventricular AVMs require a transcortical approach through the inferior temporal gyrus that avoids the Meyer loop. Surgical results with temporal lobe AVMs are generally good, and classifying them does not offer any prediction of surgical risk.
PMCID: PMC4159961  PMID: 23848823
arteriovenous malformation; temporal lobe; anatomical subtype; microsurgical resection; vascular disorders
4.  Deep Arteriovenous Malformations in the Basal Ganglia, Thalamus, and Insula: Microsurgical Management, Techniques, and Results 
Neurosurgery  2013;73(3):417-429.
Arteriovenous malformations (AVMs) in the basal ganglia, thalamus, and insula are considered inoperable given their depth, eloquence, and limited surgical exposure. While many neurosurgeons opt for radiosurgery or observation, others have challenged the belief that deep AVMs are inoperable. Further discussion of patient selection, technique, and multimodality management is needed.
To describe and discuss the technical considerations of microsurgical resection for deep-seated AVMs.
Patients with deep AVMs who underwent surgery during a 14-year period were reviewed using a prospective AVM registry.
Microsurgery was performed in 48 patients with AVMs in the basal ganglia (n=10), thalamus (n=13), or insula (n=25). The most common Spetzler-Martin grade was III- (68%). Surgical approaches included transsylvian (67%), transcallosal (19%), and transcortical (15%). Complete resection was achieved in 34 patients (71%), and patients with incomplete resection were treated with radiosurgery. Forty-five patients (94%) were improved or unchanged (mean follow-up 1.6 years).
This experience advances the notion that select deep AVMs may be operable lesions. Patients were highly selected for small size, hemorrhagic presentation, young age, and compactness – factors embodied in the Spetzler-Martin and Supplementary grading systems. Overall, 10 different approaches were used, exploiting direct, transcortical corridors created by hemorrhage or maximizing anatomical corridors through subarachnoid spaces and ventricles that minimize brain transgression. The same cautious attitude exercised in selecting patients for surgery was also exercised in deciding extent of resection, opting for incomplete resection and radiosurgery more than with other AVMs to prioritize neurological outcomes.
PMCID: PMC4123817  PMID: 23728451
Arteriovenous malformation; Basal ganglia; Insula; Microsurgery; Thalamus
5.  Perioperative Management of Coagulation in Nontraumatic Intracerebral Hemorrhage 
Anesthesiology  2013;119(1):10.1097/ALN.0b013e318297c18a.
PMCID: PMC3815673  PMID: 23695175
6.  Cerebellar Arteriovenous Malformations: Anatomical Subtypes, Surgical Results, and Increased Predictive Accuracy of the Supplementary Grading System 
Neurosurgery  2012;71(6):1111-1124.
Anatomical diversity amongst cerebellar AVMs calls for a classification that is intuitive and surgically informative. Selection tools like the Spetzler-Martin grading system are designed to work best with cerebral AVMs, but have shortcomings with cerebellar AVMs.
To define subtypes of cerebellar AVMs that clarify anatomy and surgical management, determine results according to subtypes, and compare predictive accuracies of Spetzler-Martin and supplementary systems.
From a consecutive surgical series of 500 patients, 60 had cerebellar AVMs, 39 had brain stem AVMs and were excluded, and 401 had cerebral AVMs.
Cerebellar AVM subtypes were: 18 vermian, 13 suboccipital, 12 tentorial, 12 petrosal, and 5 tonsillar. Patients with tonsillar and tentorial AVMs fared best. Cerebellar AVMs presented with hemorrhage more than cerebral AVMs (p<0.001). Cerebellar AVMs were more likely to drain deep (p=0.036) and less likely eloquent (p<0.001). The predictive accuracy of supplementary grade was better than that of Spetzler-Martin grade with cerebellar AVMs (areas under the ROC curve 0.74 and 0.59, respectively). The predictive accuracy of the supplementary system was consistent for cerebral and cerebellar AVMs, whereas that of the Spetzler-Martin system was greater with cerebral AVMs.
Patients with cerebellar AVMs present with hemorrhage more than patients with cerebral AVMs, justifying an aggressive treatment posture. The supplementary system is better than the Spetzler-Martin system at predicting outcomes after cerebellar AVM resection. Key components of the Spetzler-Martin system, like venous drainage and eloquence, are distorted by cerebellar anatomy in ways that components of the supplementary system are not.
PMCID: PMC3923506  PMID: 22986595
arteriovenous malformation; cerebellum; microsurgical resection; Spetzler Martin grading scale; supplementary grading scale
7.  Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain 
Vessels in brain arteriovenous malformations (bAVM) are prone to rupture. The underlying pathogenesis is not clear. Hereditary hemorrhagic telangiectasia type 2 (HHT2) patients with activin receptor-like kinase 1 (Alk1) mutation have a higher incidence of bAVM than the general population. We tested the hypothesis that vascular endothelial growth factor (VEGF) impairs vascular integrity in the Alk1-deficient brain through reduction of mural cell-coverage.
Methods and Results
Adult Alk11f/2f mice (loxP sites flanking exons 4-6) and wild-type (WT) mice were injected with 2×107 PFU Ad-Cre and 2×109 genome copies of AAV-VEGF to induce focal homozygous Alk1 deletion (in Alk11f/2f mice) and angiogenesis. Brain vessels were analyzed eight weeks later. Compared to WT mice, the Alk1-deficient brain had more fibrin (99±30×103 pixels/mm2 vs. 40±13×103, P=0.001), iron deposition (508±506 pixels/mm2 vs. 6 ±49, P=0.04), and Iba1+ microglia/macrophage infiltration (888±420 Iba1+ cells/mm2 vs. 240±104 Iba1+, P=0.001) after VEGF stimulation. In the angiogenic foci, the Alk1-deficient brain had more α-SMA- vessels (52±9% vs. 12±7%, P<0.001), fewer vascular associated pericytes (503±179/mm2 vs. 931±115, P<0.001), and reduced PDGFR-β expression (26±9%, P<0.001).
Reduction of mural cell coverage in response to VEGF stimulation is a potential mechanism for the impairment of vessel wall integrity in HHT2-associated bAVM.
PMCID: PMC3569037  PMID: 23241407
brain arteriovenous malformation; activin receptor-like kinase 1; pericyte; iron deposition; PDGFR-β
8.  G Protein-Coupled Receptor 124 (GPR124) Gene Polymorphisms and Risk of Brain Arteriovenous Malformation 
Translational stroke research  2012;3(4):418-427.
Abnormal endothelial proliferation and angiogenesis may contribute to brain arteriovenous malformation (BAVM) formation. G protein-coupled receptor 124 (GPR124) mediates embryonic CNS angiogenesis; thus we investigated the association of single nucleotide polymorphisms (SNPs) and haplotypes in GPR124 with risk of BAVM. Ten tagging SNPs spanning 39 kb of GPR124 were genotyped in 195 Caucasian BAVM patients and 243 Caucasian controls. SNP and haplotype association with risk of BAVM was screened using χ2 analysis. Associated variants were further evaluated using multivariable logistic regression, adjusting for age and sex. The minor alleles of 3 GPR124 SNPs adjacent to exon 2 and localized to a 16 kb region of high linkage disequilibrium were associated with reduced risk of BAVM (rs7015566 A, P=0.001; rs7823249 T, P=0.014; rs12676965 C, P=0.007). SNP rs7015566 (intron 1) remained associated after permutation testing (additive model P=0.033). Haplotype analysis revealed a significant overall association (χ2=12.55, 4 df, P=0.014); 2 haplotypes (ATCC, P=0.006 and GGCT, P=0.008) were associated with risk of BAVM. We genotyped a known synonymous SNP (rs16887051) in exon 2, however genotype frequency did not differ between cases and controls. Sequencing of conserved GPR124 regions revealed a novel indel polymorphism in intron 2. Immunohistochemistry confirmed GPR124 expression in the endothelium with no qualitative difference in expression between BAVM cases and controls. SNP rs7015566 mapping to intron 1 of GPR124 was associated with BAVM susceptibility among Caucasians. Future work is focused on investigating this gene region.
PMCID: PMC3544200  PMID: 23329986
Angiogenesis; Genetics; Intracerebral hemorrhage; Risk factor; Vascular malformation
9.  A Genome-Wide Investigation of Copy Number Variation in Patients with Sporadic Brain Arteriovenous Malformation 
PLoS ONE  2013;8(10):e71434.
Brain arteriovenous malformations (BAVM) are clusters of abnormal blood vessels, with shunting of blood from the arterial to venous circulation and a high risk of rupture and intracranial hemorrhage. Most BAVMs are sporadic, but also occur in patients with Hereditary Hemorrhagic Telangiectasia, a Mendelian disorder caused by mutations in genes in the transforming growth factor beta (TGFβ) signaling pathway.
To investigate whether copy number variations (CNVs) contribute to risk of sporadic BAVM, we performed a genome-wide association study in 371 sporadic BAVM cases and 563 healthy controls, all Caucasian. Cases and controls were genotyped using the Affymetrix 6.0 array. CNVs were called using the PennCNV and Birdsuite algorithms and analyzed via segment-based and gene-based approaches. Common and rare CNVs were evaluated for association with BAVM.
A CNV region on 1p36.13, containing the neuroblastoma breakpoint family, member 1 gene (NBPF1), was significantly enriched with duplications in BAVM cases compared to controls (P = 2.2×10−9); NBPF1 was also significantly associated with BAVM in gene-based analysis using both PennCNV and Birdsuite. We experimentally validated the 1p36.13 duplication; however, the association did not replicate in an independent cohort of 184 sporadic BAVM cases and 182 controls (OR = 0.81, P = 0.8). Rare CNV analysis did not identify genes significantly associated with BAVM.
We did not identify common CNVs associated with sporadic BAVM that replicated in an independent cohort. Replication in larger cohorts is required to elucidate the possible role of common or rare CNVs in BAVM pathogenesis.
PMCID: PMC3789669  PMID: 24098321
10.  Minocycline and tetracycline-class antibiotics are protective against partial seizures in vivo 
Epilepsy & behavior : E&B  2012;24(3):314-318.
Increasing evidence suggests the role of inflammation in enhancing neuronal excitability and contributing to epileptogenesis. Tetracycline-class antibiotics minocycline, doxycycline, and tetracycline have been shown to have anti-apoptotic and anti-inflammatory effects.
We investigated the anti-seizure effects of tetracycline-class antibiotics minocycline, doxycycline, and tetracycline in vivo by using the maximal electric shock (MES), 6Hz (minimal clonic seizure) test, and subcutaneous Metrazol (scMET) models of epilepsy.
Minocycline, doxycycline, and tetracycline showed anticonvulsant effects in abolishing partial seizures in a mouse model of 6Hz seizure test. A dose-dependent effect was found, with ED50 of 170mg/kg for minocycline, 157 mg/kg for doxycycline, and 255 mg/kg for tetracycline with peak onset at 0.5 hours. At high doses, minocycline (250mg/kg) and doxycycline (150mg/kg) also have toxic effects, from motor impairments to respiratory failure and death. These drugs had no effects on the MES and scMET tests.
In three tests of anti-seizure activity, minocycline, doxycycline, and tetracycline were found to be protective in one: the 6Hz seizure model. Our data suggest that minocycline and other tetracycline-class drugs may offer some degree of anticonvulsant effect in the setting of CNS disease trials.
PMCID: PMC3761078  PMID: 22579030
minocycline; doxycycline; tetracycline; seizure; neuroprotection; antiepileptic drugs; anticonvulsant drugs; epilepsy
11.  Evaluating Performance of the Spetzler-Martin Supplemented Model in Selecting Brain Arteriovenous Malformation Patients for Surgery 
Our recently proposed point scoring model includes the widely-used Spetzler-Martin (SM)-5 variables, along with age, unruptured presentation, and diffuse border (SM-Supp). Here we evaluate the SM-Supp model performance compared to SM-5, SM-3, and Toronto prediction models using net reclassification index (NRI), which quantifies the correct movement in risk reclassification, and validate the model in an independent dataset.
Bad outcome was defined as worsening between preoperative and final postoperative modified Rankin Scale score. Point scores for each model were used as predictors in logistic regression, and predictions evaluated using NRI at varying thresholds (10–30%) and any threshold (continuous NRI>0). Performance was validated in an independent dataset (n=117).
Net gain in risk reclassification was better using the SM-Supp model over a range of threshold values (NRI=9–25%) and significantly improved overall predictions for outcomes in the development dataset, yielding a continuous NRI of 64% versus SM-5, 67% versus SM-3, and 61% versus Toronto (all P<0.001). In the validation dataset, the SM-Supp model again correctly reclassified a greater proportion of patients versus SM-5 (82%), SM-3 (85%), and Toronto models (69%).
The SM-Supp model demonstrated better discrimination and risk reclassification than several existing models and should be considered for clinical practice to estimate surgical risk in BAVM patients.
PMCID: PMC3431204  PMID: 22821608
receiver operator curve; Modified Rankin Scale; net reclassification
12.  BDNF Val66Met Polymorphism Predicts Worse Functional Outcome After Surgery in Unruptured Brain Arteriovenous Malformation Patients 
Background and Purpose
The Val66Met polymorphism of brain-derived neurotrophic factor (BDNF) is associated with decreased BDNF secretion and poor outcome after acute neurological injury. We hypothesized that the Met allele is associated with worsening of functional outcome after brain arteriovenous malformation (BAVM) resection.
341 surgically-treated BAVM patients with outcome data were genotyped for Val66Met. Outcome was change in modified Rankin Scale (mRS) preoperatively versus postoperatively, dichotomized into poor (change>0) or good outcome (change≤0). Likelihood ratio test for interactions and logistic regression analysis were performed.
A significant interaction (p=0.03) of Val66Met genotype and hemorrhagic presentation existed; thus, ruptured and unruptured patients were considered separately. The Met allele was associated with increased risk of poor outcome among patients presenting unruptured (OR=2.15, 95% CI=1.02–4.55, p=0.045) but not ruptured (OR=0.54, 95% CI=0.19–1.53, p=0.25), adjusting for covariates.
The Val66Met polymorphism is associated with worsened surgical outcome in unruptured BAVM patients, a group that currently has no good risk predictors. Further studies replicating these findings are needed.
PMCID: PMC3431194  PMID: 22773554
Brain-derived neurotrophic factor; Genetics; Arteriovenous Malformations; Outcomes; Surgery
13.  Brain arteriovenous malformation multiplicity predicts diagnosis of Hereditary Hemorrhagic Telangiectasia: Quantitative assessment 
To quantitatively estimate the relationship between multiplicity of brain arteriovenous malformations (bAVMs) and the diagnosis of hereditary hemorrhagic telangiectasia (HHT).
We combined databases from two large North American bAVM referral centers, including demographics, clinical presentation and angiographic characteristics, and compared HHT patients with non-HHT patients. Logistic regression analysis was performed to quantify the association between bAVM multiplicity and odds of HHT diagnosis. Sensitivity, specificity, positive and negative predictive value (PPV, NPV), and positive and negative likelihood ratios (LR) were calculated to determine accuracy of bAVM multiplicity for screening HHT.
Prevalence of HHT was 2.8% in the combined group. bAVM multiplicity was present in 39% of HHT patients and was highly associated with diagnosis of HHT in univariate (OR=83, 95% CI:40–173, P<0.0001) and multivariable (OR=87, 95% CI: 38–195, P<0.001) models, adjusting for age at presentation (P=0.013), non-symptomatic presentation (P=0.029) and cohort site (P=0.021). bAVM multiplicity alone was associated with high specificity (99.2%, 95%CI: 98.7–99.6%) and NPV (98.3%, 95% CI: 97.6–98.8%), and low sensitivity (39.3%, 95% CI: 26.5–53.2%) and PPV (59.5%, 95% CI: 42.1–75.2%). Positive and negative LR was 51 and 0.61, respectively, for diagnosis of HHT. HHT bAVMs were also more often smaller in size (<3 cm), non-eloquent in location and associated with superficial venous drainage, compared to non-HHT bAVMs.
Multiplicity of bAVMs is highly predictive of the diagnosis of HHT. The presence of multiple bAVMs should alert the clinician to the high probability of HHT and lead to comprehensive investigation for this diagnosis.
PMCID: PMC3727386  PMID: 22034007
arteriovenous malformation; hereditary hemorrhagic telangiectasia; brain
14.  Perlecan Domain V is Upregulated in Human Brain Arteriovenous Malformation (BAVM) and could Mediate VEGF Effect in Lesional Tissue 
Neuroreport  2012;23(10):627-630.
Brain arteriovenous malformation (BAVM), a rare but important cause of intracranial hemorrhage, has increased angiogenesis and inflammation as key components of the nidus of abnormal vessels and stroma that form the resected surgical specimen. Accordingly, vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGFβ) have both been implicated in BAVM pathology for their pro-angiogenic and vascular-regulating roles. The c-terminal fragment of the extracellular matrix component perlecan (domain V, DV) has been shown to be increased and to, via the α5β1 integrin, increase VEGF levels in and around areas of cerebral ischemic injury, another pro-angiogenic condition. We sought to determine whether the concentrations of DV, DV’s proangiogenic receptor α5β1 integrin, or DV’s anti-angiogenic receptor α2β1 integrin are elevated in human BAVM tissue. DV levels were increased in BAVM compared to control brain tissue from epileptic resection, as was α5β1 integrin. Additionally, α5β1 integrin was preferentially increased and localized to endothelial cells compared to α2β1 integrin. VEGF and TGFβ levels were also increased in BAVM compared to control tissue. Furthermore, increases in all components were strongly correlated. Excessive generation of pro-angiogenic DV in BAVM suggests that DV may participate in its pathology and may represent a future therapeutic target.
PMCID: PMC3535489  PMID: 22643235
Arteriovenous Malformation; AVM
15.  Ferumoxytol-enhanced MRI to Image Inflammation within Human Brain Arteriovenous Malformations: A Pilot Investigation 
Translational stroke research  2012;3(Supplement 1):166-173.
Inflammation cell infiltration and cytokine expression are seen in the vascular walls and intervening stroma of resected brain arteriovenous malformation (bAVM) specimens, even in unruptured and previously untreated lesions. Macrophages may play a critical role in bAVM progression to rupture, and could serve as a marker for rupture risk. We assessed feasibility of imaging macrophages within the bAVM nidus using ferumoxytol-enhanced MRI in four patients with already diagnosed bAVMs using iron-sensitive imaging (ISI; T2*-GE-MRI sequence). Patients were imaged at baseline and at either 1 day (n=2) or 5 days (n=2) after infusion of 5mg/kg of ferumoxytol. Residual intravascular ferumoxytol obscured evaluation for uptake in bAVM vascular walls and stroma at the 1-day time point. The two cases imaged at 5 days showed less intravascular tracer but had signal loss in the nidal region consistent with ferumoxytol localization. One case underwent surgical resection; there was prominent vascular wall CD68 staining. Ferumoxytol-enhanced-MRI for assessing bAVM inflammatory cell burden appears feasible and has the potential to be developed as a biomarker to study lesional inflammatory events.
PMCID: PMC3445332  PMID: 23002401
Arteriovenous malformations; Inflammation; Magnetic resonance imaging; Ferumoxytol; USPIO
16.  Acetylcholineestarase-Inhibiting Alkaloids from Lycoris radiata Delay Paralysis of Amyloid Beta-Expressing Transgenic C. elegans CL4176 
PLoS ONE  2013;8(5):e63874.
The limited symptom relief and side effects of current Alzheimer’s disease (AD) medications warrant urgent discovery and study of new anti-AD agents. The “cholinergic hypothesis” of AD prompts us to search for plant-derived acetylcholineesterase (AChE) inhibitors such as galanthamine that has been licensed in Europe for AD treatment. We used the unique amyloid β-expressing transgenic C. elegans CL4176, which exhibits paralysis when human Aβ1–42 is induced, to study two natural benzylphenethylamine alkaloids isolated from Lycoris radiata (L’ Her.) Herb, galanthamine and haemanthidine, and their synthetic derivatives 1,2-Di-O-acetyllycorine and 1-O-acetyllycorine for their anti-paralysis effects. Our data indicate that these Lycoris compounds effectively delay the paralysis of CL4176 worms upon temperature up-shift, and prolong the lives of these transgenic worms. Lycoris compounds were shown to significantly inhibit the gene expression of ace-1 and ace-2. Additionally, the Lycoris compounds may modulate inflammatory and stress-related gene expressions to combat the Aβ-toxicity in C. elegans.
PMCID: PMC3652842  PMID: 23675513
17.  Silent Intralesional Microhemorrhage as a Risk Factor for Brain AVM Rupture 
Background and Purpose
We investigated whether brain arteriovenous malformation (bAVM) silent intralesional microhemorrhage (SIM), i.e., asymptomatic bleeding in the nidal compartment, might serve as a marker for increased risk of symptomatic intracranial hemorrhage (ICH). We evaluated two markers to assess the occurrence of SIM: neuroradiological assessment of evidence of old hemorrhage (EOOH)— imaging evidence of bleeding before the outcome events, and hemosiderin positivity in H&E-stained paraffin block sections.
We included cases from a bAVM database with recorded neuroradiological data or available surgical paraffin blocks. Using two endpoints, index ICH and new ICH after diagnosis (censored at treatment, loss to follow-up, or death), we performed logistic or Cox regression to assess EOOH and hemosiderin positivity, adjusting for age, sex, deep-only venous drainage, maximal bAVM size, deep location, and associated arterial aneurysms.
EOOH was present in 6.5% (n=975) of patients and highly predictive of index ICH (p<0.001; OR=3.97; 95% CI, 2.1-7.5), adjusting for other risk factors. In a multivariable model (n=643), EOOH was an independent predictor of new ICH (HR=3.53; 95% CI=1.35-9.23; p=.010). Hemosiderin positivity was found in 36.2% (29.6% in unruptured; 47.8% in ruptured; p=.04), and associated with index ICH in univariate (OR=2.18; 95%CI 1.03-4.61; p=.042; n=127) and multivariable models (OR=3.64; 95% CI=1.11-12.00; p=.034; n=79).
The prevalence of SIM is high and there is evidence for an association with both index and subsequent ICH. Further development of means to detect SIM during bAVM evaluation may present an opportunity to improve risk-stratification, especially for unruptured bAVMs.
PMCID: PMC3335931  PMID: 22308253
brain arteriovenous malformation; hemorrhage; risk factor; survival; brain microbleed; hemosiderin
18.  Transsylvian-Transinsular Approaches to the Insula and Basal Ganglia: Operative Techniques and Results with Vascular Lesions 
Neurosurgery  2012;70(4):824-834.
Lesions in the insula and basal ganglia can be risky to resect due to their depth and proximity to critical structures, particularly in the dominant hemisphere. Transsylvian approaches shorten the surgical distance to these lesions, preserve perisylvian temporal and frontal cortex, and minimize brain transgression.
We report our experience with transsylvian-transinsular approaches to vascular lesions.
The anterior approach opened the sphenoidal and insular portions of the Sylvian fissure and exposed the limen insulae and short gyri, whereas the posterior approach opened the insular and opercular portions of the Sylvian fissure and exposed the circular sulcus and long gyri.
41 patients with vascular lesions (24 arteriovenous malformations (AVM) and 17 cavernous amlformations (CM)) were treated surgically with a transsylvian-transinsular approach. Complete resection was obtained in 87.5% of AVMs and 95% of CMs. Permanent neurologic morbidity related to surgery was observed in 2 AVM patients (5%), with the remaining 39 patients (95%) improved or unchanged postoperatively (modified Rankin Scale scores 0–2 in 83%). There were no new language deficits in patients with dominant hemisphere lesions.
Transsylvian-transinsular approaches safely expose vascular pathology in or deep to the insula while preserving overlying eloquent cortex in the frontal and temporal lobes. The anterior transsylvian-transinsular approach can be differentiated from the posterior approach based on technical differences in splitting the Sylvian fissure and anatomical differences in final exposure. Discriminating patient selection and careful microsurgical technique are essential.
PMCID: PMC3303997  PMID: 21937930
19.  Macrophage Imaging Within Human Cerebral Aneurysms Wall Using Ferumoxytol-Enhanced MRI: a Pilot Study 
Macrophages play a critical role in cerebral aneurysm formation and rupture. The purpose of this study is to demonstrate the feasibility and optimal parameters of imaging macrophages within human cerebral aneurysm wall using ferumoxytol-enhanced-MRI.
Methods and Results
19 unruptured aneurysms in 11 patients were imaged using T2*-GE-MRI sequence. Two protocols were utilized. Protocol A: infusion of 2.5mg/kg of ferumoxytol and imaging at day 0 and 1. Protocol B: infusion of 5mg/kg of ferumoxytol and imaging at day 0 and 3. All images were reviewed independently by two neuroradiologists to assess for ferumoxytol-associated loss of MRI signal intensity within aneurysm wall. Aneurysm tissue was harvested for histologic analysis.
Fifty percent(5/10) of aneurysms in protocol A showed ferumoxytol-associated signal changes in aneurysm walls compared to 78% (7/9) of aneurysms in protocol B. Aneurysm tissue harvested from patients infused with ferumoxytol stained positive for both CD68+, demonstrating macrophage infiltration, and Prussian-Blue, demonstrating uptake of iron particles. Tissue harvested from controls stained positive for CD68 but not Prussian-Blue.
Imaging with T2*-GE-MRI at 72 hours post-infusion of 5mg/kg of ferumoxytol establishes a valid and useful approximation of optimal dose and timing parameters for macrophages imaging within aneurysm wall. Further studies are needed to correlate these imaging findings with risk of intracranial aneurysm rupture.
PMCID: PMC3557844  PMID: 22328774
Intracranial Aneurysm; Inflammation; Magnetic Resonance Imaging; Ferumoxytol; USPIO
20.  Giant Intracranial Aneurysms: Evolution of Management in a Contemporary Surgical Series 
Neurosurgery  2011;69(6):1261-1271.
Many significant microsurgical series of patients with giant aneurysms predate changes in practice during the endovascular era.
A contemporary surgical experience is presented to examine changes in management relative to earlier reports, to establish the role of open microsurgery in the management strategy, and to quantify results for comparison with evolving endovascular therapies.
During a 13-year period, 140 patients with 141 giant aneurysms were treated surgically. 100 aneurysms (71%) were located in the anterior circulation, and 41 aneurysms were located in the posterior circulation.
108 aneurysms (77%) were completely occluded, 14 aneurysms (10%) had minimal residual aneurysm, and 16 aneurysms (11%) were incompletely occluded with reversed or diminished flow. 3 patients with calcified aneurysms were coiled after unsuccessful clipping attempts. 18 patients died in the perioperative period (surgical mortality, 13%). Bypass-related complications resulted from bypass occlusion (7 patients), aneurysm hemorrhage due to incomplete aneurysm occlusion (4 patients), or aneurysm thrombosis with perforator or branch artery occlusion (4 patients). 13 patients were worse at late follow-up (permanent neurological morbidity, 9%; mean length of follow-up, 23±1.9 months). Overall, good outcomes (GOS 5 or 4) were observed in 114 patients (81%) and 109 patients (78%) were improved or unchanged after therapy.
A heavy reliance on bypass techniques plus indirect giant aneurysm occlusion distinguishes this contemporary surgical experience from earlier ones, and obviates the need for hypothermic circulatory arrest. Experienced neurosurgeons can achieve excellent results with surgery as the “first-line” management approach and endovascular techniques as adjuncts to surgery.
PMCID: PMC3529163  PMID: 21734614
bypass; direct clipping; giant aneurysm; indirect aneurysm occlusion; microsurgery
21.  Gene expression profiling of blood in brain arteriovenous malformation patients 
Translational stroke research  2011;2(4):575-587.
Brain arteriovenous malformations (BAVMs) are an important cause of intracranial hemorrhage (ICH) in young adults. Gene expression profiling of blood has led to the identification of stroke biomarkers, and may help identify BAVM biomarkers and illuminate BAVM pathogenesis. It is unknown whether blood gene expression profiles differ between 1) BAVM patients and healthy controls, or 2) unruptured and ruptured BAVM patients at presentation. We characterized blood transcriptional profiles in 60 subjects (20 unruptured BAVM, 20 ruptured BAVM, and 20 healthy controls) using Affymetrix whole genome expression arrays. Expression differences between groups were tested by ANOVA, adjusting for potential confounders. Genes with absolute fold change ≥ 1.2 (false discovery rate corrected p ≤ 0.1) were selected as differentially expressed and evaluated for over-representation in KEGG biological pathways (p ≤ 0.05). Twenty-nine genes were differentially expressed between unruptured BAVM patients and controls, including 13 which may be predictive of BAVM. Patients with ruptured BAVM compared to unruptured BAVM differed in expression of 1490 genes, with over-representation of genes in 8 pathways including MAPK, VEGF, Wnt signaling and several inflammatory pathways. These results suggest clues to the pathogenesis of BAVM and/or BAVM rupture and point to potential biomarkers or new treatment targets.
PMCID: PMC3241209  PMID: 22184505
arteriovenous malformation; blood; gene expression; intracranial hemorrhage; microarray analysis
22.  Elevated BNP is Associated with Vasospasm-Independent Cerebral Infarction Following Aneurysmal Subarachnoid Hemorrhage 
Neurocritical care  2011;15(1):13-18.
Elevated levels of B-type natriuretic peptide (BNP) have been associated with cardiac dysfunction and adverse neurological outcomes after subarachnoid hemorrhage (SAH). We sought to determine whether elevated levels of BNP are independently associated with radiographic cerebral infarction after SAH.
Plasma BNP levels were measured after admission, a mean of 5.5 ± 3.0 days after SAH onset. Cerebral infarction was determined by retrospective review of computerized tomography (CT) scans. Cerebral vasospasm was confirmed by the presence of vascular narrowing on cerebral angiogram. The association between BNP and cerebral infarction was quantified using multivariable logistic regression and reverse stepwise elimination of clinical covariates. A stratified analysis was performed to quantify the association between BNP levels and infarction in patients with and without angiographic vasospasm.
BNP levels were measured from 119 subjects. The median BNP level was 105 pg/ml (interquartile range 37–275 pg/ml). In our multivariable model, the top quartile of BNP levels (≥276 pg/ml) were associated with an increased odds of cerebral infarction (OR 4.2, P = 0.009). The stratified analysis showed that the association between BNP and infarction was strongest in patients without angiographic vasospasm (OR 7.8, P = 0.006).
Elevated levels of BNP are strongly and independently associated with cerebral infarction, and the association is most pronounced in patients without angiographic vasospasm. These results provide further evidence that other mechanisms can contribute to infarction, and BNP may be a useful biomarker in detecting patients at risk for adverse outcomes without large vessel vasospasm.
PMCID: PMC3133817  PMID: 21479679
Subarachnoid hemorrhage; Cerebral infarction; Cerebral vasospasm; B-type natriuretic peptide
23.  Temporal Stability of Dysmorphic, Fusiform Aneurysms of the Intra-cranial Internal Carotid Artery 
Estimation of the stability of dysmorphic fusiform aneurysms of the intra-cranial internal carotid artery requires precise monitoring of their volumes. In this report we apply a method using MRI and 3D post-processing to study the evolution of these aneurysms on a prospective cohort of patients not immediately suitable for surgery or endovascular treatment.
Materials and Methods
Ten patients with fusiform aneurysms of the intra-cranial internal carotid artery underwent serial MRI studies. Five patients were studied at two time points and the remainder at multiple time points (mean delay between studies: 12.6 +/− 3.8 months). For each patient, studies from all time points were co-registered. Volumes of each vessel component were calculated.
Mean aneurysm volume was 833 +/− 878 mm3. Mean annual rate of volume progression was 1.37 +/− 2.09 % per year. All the aneurysms were thrombus-free.
This study indicates that, given the relatively low rate of progression of these dysplastic fusiform aneurysms and the complexity of their shape, 3D quantitative volumetric methods can be helpful in monitoring whether any growth has occurred.
PMCID: PMC3125409  PMID: 21419648
24.  Arteriovenous Malformation in the Adult Mouse Brain Resembling the Human Disease 
Annals of neurology  2011;69(6):954-962.
Brain arteriovenous malformations (bAVM) are an important cause of hemorrhagic stroke. The underlying mechanisms are not clear. No animal model for adult bAVM is available for mechanistic exploration. Patients with Hereditary Hemorrhagic Telangiectasia Type2 (HHT2) with activin receptor-like kinase 1 (ALK1; ACVRL1) mutations have a higher incidence of bAVM than the general population. We tested the hypothesis that VEGF stimulation with regional homozygous deletion of Alk1 induces severe dysplasia in the adult mouse brain, akin to human bAVM.
Alk12f/2f (exons 4–6 flanked by loxP sites) and wild-type (WT) mice (8–10 weeks old) were injected with Ad-Cre (2×107 PFU, adenoviral vector expressing Cre recombinase) and AAV-VEGF (2×109 genome copies, adeno-associated viral vectors expressing VEGF) into the basal ganglia. At 8 weeks, blood vessels were analyzed.
Gross vascular irregularities were seen in Alk1 2f/2f mouse brain injected with Ad-Cre and AAV-VEGF. The vessels were markedly enlarged with abnormal patterning resembling aspects of the human bAVM phenotype, displayed altered expression of the arterial and venous markers (EphB4 and Jagged-1), and showed evidence of arteriovenous shunting. Vascular irregularities were not seen in similarly treated WT mice.
Our data indicate that post-natal, adult formation of the human disease bAVM is possible, and that both genetic mutation and angiogenic stimulation are necessary for lesion development. Our work not only provides a testable adult mouse bAVM model for the first time, but also suggests that specific medical therapy can be developed to slow bAVM growth and potentially stabilize the rupture-prone abnormal vasculature.
PMCID: PMC3117949  PMID: 21437931
25.  Angiopoietin-Like 4 (ANGPTL4) Gene Polymorphisms and Risk of Brain Arteriovenous Malformations 
Brain arteriovenous malformations (BAVM) are high-flow vascular lesions prone to intracranial hemorrhage (ICH). Abnormal angiogenesis is a key characteristic of BAVM tissue. Angiopoietin-like 4 (ANGPTL4), a secreted glycoprotein, is thought to be involved in angiogenesis and required for proper postnatal blood vessel partitioning. We investigated whether common single nucleotide polymorphisms (SNPs) in ANGPTL4 were associated with risk of BAVM or ICH.
Methods and Results
We conducted a case-control study of 216 Caucasian BAVM cases and 246 healthy controls, and a secondary case-only analysis, comparing 83 ruptured (ICH) with 133 unruptured BAVM cases at presentation. Four tagSNPs in ANGPTL4 captured variation over a 10-kb region (rs2278236, rs1044250, rs11672433, and rs1808536) and were tested for association with BAVM or ICH. The minor allele (A) of rs11672433 (exon 6, Pro389Pro) was associated with an increased risk of BAVM (p = 0.006), which persisted after adjusting for multiple comparisons (p = 0.03). After adjustments for age and sex, carriers of the minor allele (A) remained at higher risk for BAVM compared to noncarriers (odds ratio, OR = 1.56; 95% confidence interval, CI = 1.01–2.41; p = 0.046) and risk of BAVM was increased with increasing copy of the minor A allele (OR = 1.49, 95% CI = 1.03–2.15; ptrend = 0.03). Five common haplotypes (frequency >1%) were inferred; overall haplotype distribution differed between BAVM cases and controls (χ2 = 12.2, d.f. = 4, p = 0.02). Neither SNPs (p > 0.05) nor haplotype distribution (χ2 = 1.1, d.f. = 4, p = 0.89) were associated with risk of ICH among BAVM cases.
A synonymous SNP in ANGPTL4 and haplotypes carrying it are associated with risk of BAVM but not with ICH presentation in BAVM cases.
PMCID: PMC3030504  PMID: 21212665
Arteriovenous malformations; Cerebrovascular disorders; Epidemiology; Genetics; Intracranial hemorrhage

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