Clinical Manifestations and Mechanisms of Autoimmune Disease-Related Multiple Cerebral Infarcts.

It is important to investigate the clinical characteristics and identify the stroke mechanisms of patients with autoimmune disease-related stroke, which are necessary for early etiology diagnosis, accurate treatment and preventive strategies. In this article we retrospectively studied eight cases of acute ischemic stroke associated with autoimmune diseases, and without competing conventional stroke etiologies. The characteristics of stroke (clinical and radiological features), the laboratory tests especially serum D-dimer levels (as a marker of hypercoagulable state), and embolic signals on transcranial Doppler were evaluated for all eight patients. High-resolution magnetic resonance imaging (HRMRI), which can help to evaluate vasculitis was performed in four patients. The possible underlying mechanisms of these cases were discussed based on these manifestations. As a result, autoimmune diseases in our study included systemic lupus erythematosus (n=5), mixed connective tissue disease (n=1), central nervous system vasculitis (n=1), and Takayasu arteritis (n=1). All eight patients presented with acute infarction lesions in ≥2 vascular territories. Most patients presented with numerous small and medium infarction lesions located in the cortical and subcortical areas. Multiple stroke mechanisms were involved in these cases, including hypercoagulability (n=4), cardiac embolism (n=1) and vasculitis (n=3). Embolic signals could be detected on transcranial Doppler in all three stroke mechanisms. In conclusion, our study revealed the characteristics of autoimmune disease-related stroke. For patients with multiple acute cerebral infarcts within non-single arterial territories, autoimmune disease is an important etiology not to be neglected. Multiple stroke mechanisms were involved in these cases.

Plaque Distribution of Basilar Artery Fenestration by 3D High-Resolution MR Vessel Wall Imaging.

The association between fenestrations and neurovascular pathology is not well defined. The morphology of vessel wall plays an important role in the development of neurovascular pathology. We sought to explore the plaque distribution around basilar artery fenestration (BAF) by three-dimensional high-resolution MR vessel wall imaging (3D HRMRI). Patients with BAF on 3D HRMRI images were enrolled. All cross-sectional slices of basilar arteries were assessed and categorized based on the location of fenestration as proximal segment, in-bifurcation segment, and distal segment. Furthermore, plaques in the in-bifurcation segment were classified according to their orientation being centered on the lateral, interior, dorsal, or ventral wall of the vessel. In all, 12 cases with BAF involving 661 cross-sectional image slices in entire basilar arteries were included. Plaques were found in 190 image slices, with the distribution of 41 slices in the proximal segment, 144 slices in the in-bifurcation segment and 67 slices in the distal segment. Plaques were found more frequently in the proximal and in-bifurcation segments than in the distal segment (P < 0.001), but there was no statistical difference between the proximal and in-bifurcation segment (P = 0.11). In the in-bifurcation segment, plaques were more frequently located at the lateral (50.0%) than other interior (16.0%), dorsal (21.0%), and ventral (13.0%) wall (P < 0.001).Plaques of BAF tend to locate in the proximal and in-bifurcation segments, especially at the lateral wall of the in-bifurcation segment.

High resolution magnetic resonance imaging in pathogenesis diagnosis of single lenticulostriate infarction with nonstenotic middle cerebral artery, a retrospective study.

BACKGROUND: It is usually difficult to identify stroke pathogenesis for single lenticulostriate infarction with nonstenotic middle cerebral artery (MCA). Our aim is to differentiate the two pathogeneses, non-branch atheromatous small vessel disease and branch atheromatous disease (BAD) by high-resolution magnetic resonance imaging (HR-MRI). METHODS: Thirty-two single lenticulostriate infarction patients with nonstenotic MCA admitted to the China-Japan Friendship Hospital from December 2014 to August 2017 were enrolled for retrospective analysis. National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), atherosclerotic risk factors, imaging features, and the characteristic of MCA vessel wall in HR-MRI were evaluated. RESULTS: MCA plaques were detected in 15(46.9%) patients which implied BAD and 8 of 15 (53.3%) patients had plaques location in upper dorsal side of the vessel wall. Patients with HR-MRI identified plaques had a significantly larger infarction lesion length (1.95 ± 0.86 cm versus 1.38 ± 0.55 cm; P = 0.031) and larger lesion volume (2.95 ± 3.94 cm3 versus 0.90 ± 0.94 cm3; P = 0.027) than patients without plaques. Patients with HR-MRI identified plaques had a significant higher percentage of proximal lesions than patients without plaques (P = 0.055). However, according to the location of MCA plaques, there were no significant differences in terms of imaging features, NIHSS and mRS. CONCLUSION: We demonstrated high frequency of MCA atheromatous plaques visualized in single lenticulostriate infarction patients with nonstenotic MCA by using HR-MRI. Patients with HR-MRI identified plaque presented larger infarction lesions and more proximal lesions than patients without plaque, which were consistent with imaging features of BAD. HR-MRI is an important and effective tool for identifying stroke etiology in patients with nonstenotic MCA.

Clinical and Radiological Features of Wallerian Degeneration of the Middle Cerebellar Peduncles Secondary to Pontine Infarction.

BACKGROUND: Wallerian degeneration (WD) of bilateral middle cerebellar peduncles (MCPs) can occur following pontine infarction, but its characteristics have not yet been clarified because of the low incidence. Thus, the present study discussed the clinical and radiological features to improve the awareness of this disease. METHODS: Clinical and radiological information from consecutive individuals diagnosed with WD of bilateral MCPs following pontine infarction in three hospitals over the past 4 years between October 2012 and October 2016 were retrospectively investigated and compared with a control group (patients with pontine infarction had no secondary WD). RESULTS:: This study involved 30 patients with WD of MCPs, with a detection rate of only 4.9%. The primary infarctions (χ2 =24.791, P = 0.001, vs. control group) were located in the paramedian pons in 21 cases (70.0%), and ventrolateral pons in nine cases (30.0%). WD of the MCPs was detected 8-24 weeks after pons infarction using conventional magnetic resonance imaging (MRI); all secondary WDs were asymptomatic and detected incidentally. All WD lesions exhibited bilateral, symmetrical, and boundary blurring on MRI. The signal features were hypointense on T1-weighted imaging, hyperintense on T2-weighted imaging and fluid-attenuated inversion recovery, and slightly hyperintense or isointense on diffusion-weighted imaging and apparent diffusion coefficient maps. Secondary brainstem atrophy was found in six (20.0%) cases. A Modified Rankin Scale score 0-2 was found in 10 (33.3%) cases and score >2 in 20 (66.7%) cases at 90 days after discharge, and the short-term prognosis was worse than that in control group (χ2 =12.814, P = 0.001). CONCLUSIONS: Despite the rarity of bilateral and symmetrical lesions of MCPs, secondary WD should be highly suspected if these lesions occur within 6 months after pontine infarction, particularly paramedian pons. Conventional MRI appears to be a relatively sensitive method for detecting WD of MCPs, which might affect the short-term prognosis.

Dural arteriovenous fistula disguised as cerebral venous sinus thrombosis.

Dural arteriovenous fistulas (DAVFs) are direct communications between the intracranial arterial and venous systems without an intervening nidus. Clinicians sometimes fail to give a correct diagnosis of DAVF. Given the similarity of their clinical and magnetic resonance imaging (MRI) manifestations, diagnostic confusion may arise between DAVF and cerebral venous sinus thrombosis (CVST) (Simon et al., 2009). The clinical management of DAVFs differs from that of CVST (Ma et al., 2015; Yang et al., 2015). Anticoagulation therapy is restricted in some cases of DAVFs, especially when they are associated with retrograde venous flow, due to the increased risk of hemorrhage. Here we present a case of a DAVF patient who had been initially misdiagnosed as CVST. We summarize the reasons for misdiagnosis and give some recommendations to address this problem.

Current Status and Future Perspective of Stenting for Symptomatic Intracranial Atherosclerotic Disease: A Meta-Analysis.

The aim of this study was to evaluate the safety and effectiveness of percutaneous transluminal angioplasty and stenting (PTAS) for intracranial atherosclerotic disease (ICAD) by conducting a meta-analysis. Two independent observers searched PubMed, EMBASE, and Cochrane Library for relevant studies up to 31 December 2016. A meta-analysis was conducted using Review Manager 5.3. Three studies involving 581 cases were included. The meta-analysis indicated that any stroke (RR = 3.13; 95% CI: 1.80-5.42), ischemic stroke (RR = 2.15; 95% CI: 1.19-3.89), and intracranial hemorrhage (RR = 14.71; 95% CI: 1.96-110.48) within 30 days in medical therapy alone were lower compared with PTAS plus medical therapy, but there were no significant differences in any stroke and ischemic stroke beyond 30 days between the two groups. There were also no significant differences in any death and myocardial infarction between the two groups. This meta-analysis demonstrated that, compared with medical therapy alone, PTAS for ICAD had a high risk of complication, but most complications in PTAS group occurred within 30 days after the operation, and beyond 30 days the PTAS was not inferior compared with medical therapy alone. Further studies are needed to reduce the periprocedural complications and reappraise the PTAS.

Protective effect of tetrahydroxy stilbene glucoside on learning and memory by regulating synaptic plasticity.

Damage to synaptic plasticity induced by neurotoxicity of amyloid-beta is regarded to be one of the pathological mechanisms of learning and memory disabilities in Alzheimer's disease patients. This study assumed that the damage of amyloid-beta to learning and memory abilities was strongly associated with the changes in the Fyn/N-methyl-D-aspartate receptor 2B (NR2B) expression. An APP695V7171 transgenic mouse model of Alzheimer's disease was used and treatment with tetrahydroxy-stilbene glucoside was administered intragastrically. Results showed that intragastric administration of tetrahydroxy-stilbene glucoside improved the learning and memory abilities of the transgenic mice through increasing NR2B receptors and Fyn expression. It also reversed parameters for synaptic interface structure of gray type I. These findings indicate that tetrahydroxy stilbene glucoside has protective effects on the brain, and has prospects for its clinical application to improve the learning and memory abilities and treat Alzheimer's disease.

Curcumin Attenuates Beta-Amyloid-Induced Neuroinflammation via Activation of Peroxisome Proliferator-Activated Receptor-Gamma Function in a Rat Model of Alzheimer's Disease.

Neuroinflammation is known to have a pivotal role in the pathogenesis of Alzheimer's disease (AD), and curcumin has been reported to have therapeutical effects on AD because of its anti-inflammatory effects. Curcumin is not only a potent PPARγ agonist, but also has neuroprotective effects on cerebral ischemic injury. However, whether PPARγ activated by curcumin is responsible for the anti-neuroinflammation and neuroprotection on AD remains unclear, and needs to be further investigated. Here, using both APP/PS1 transgenic mice and beta-amyloid-induced neuroinflammation in mixed neuronal/glial cultures, we showed that curcumin significantly alleviated spatial memory deficits in APP/PS1 mice and promoted cholinergic neuronal function in vivo and in vitro. Curcumin also reduced the activation of microglia and astrocytes, as well as cytokine production and inhibited nuclear factor kappa B (NF-κB) signaling pathway, suggesting the beneficial effects of curcumin on AD are attributable to the suppression of neuroinflammation. Attenuation of these beneficial effects occurred when co-administrated with PPARγ antagonist GW9662 or silence of PPARγ gene expression, indicating that PPARγ might be involved in anti-inflammatory effects. Circular dichroism and co-immunoprecipitation analysis showed that curcumin directly bound to PPARγ and increased the transcriptional activity and protein levels of PPARγ. Taking together, these data suggested that PPARγ might be a potential target of curcumin, acting to alleviate neuroinflammation and improve neuronal function in AD.

STAT3 signal that mediates the neural plasticity is involved in willed-movement training in focal ischemic rats.

Willed-movement training has been demonstrated to be a promising approach to increase motor performance and neural plasticity in ischemic rats. However, little is known regarding the molecular signals that are involved in neural plasticity following willed-movement training. To investigate the potential signals related to neural plasticity following willed-movement training, littermate rats were randomly assigned into three groups: middle cerebral artery occlusion, environmental modification, and willed-movement training. The infarct volume was measured 18 d after occlusion of the right middle cerebral artery. Reverse transcription-polymerase chain reaction (PCR) and immunofluorescence staining were used to detect the changes in the signal transducer and activator of transcription 3 (STAT3) mRNA and protein, respectively. A chromatin immunoprecipitation was used to investigate whether STAT3 bound to plasticity-related genes, such as brain-derived neurotrophic factor (BDNF), synaptophysin, and protein interacting with C kinase 1 (PICK1). In this study, we demonstrated that STAT3 mRNA and protein were markedly increased following 15-d willed-movement training in the ischemic hemispheres of the treated rats. STAT3 bound to BDNF, PICK1, and synaptophysin promoters in the neocortical cells of rats. These data suggest that the increased STAT3 levels after willed-movement training might play critical roles in the neural plasticity by directly regulating plasticity-related genes.

High-resolution Magnetic Resonance Vessel Wall Imaging for Intracranial Arterial Stenosis.

OBJECTIVE: To discuss the feasibility and clinical value of high-resolution magnetic resonance vessel wall imaging (HRMR VWI) for intracranial arterial stenosis. DATE SOURCES: We retrieved information from PubMed database up to December 2015, using various search terms including vessel wall imaging (VWI), high-resolution magnetic resonance imaging, intracranial arterial stenosis, black blood, and intracranial atherosclerosis. STUDY SELECTION: We reviewed peer-reviewed articles printed in English on imaging technique of VWI and characteristic findings of various intracranial vasculopathies on VWI. We organized this data to explain the value of VWI in clinical application. RESULTS: VWI with black blood technique could provide high-quality images with submillimeter voxel size, and display both the vessel wall and lumen of intracranial artery simultaneously. Various intracranial vasculopathies (atherosclerotic or nonatherosclerotic) had differentiating features including pattern of wall thickening, enhancement, and vessel remodeling on VWI. This technique could be used for determining causes of stenosis, identification of stroke mechanism, risk-stratifying patients, and directing therapeutic management in clinical practice. In addition, a new morphological classification based on VWI could be established for predicting the efficacy of endovascular therapy. CONCLUSIONS: This review highlights the value of HRMR VWI for discrimination of different intracranial vasculopathies and directing therapeutic management.

Wall Imaging for Unilateral Intracranial Vertebral Artery Hypoplasia with Three-dimensional High-isotropic Resolution Magnetic Resonance Images.

BACKGROUND: There are few studies for evaluating wall characteristics of intracranial vertebral artery hypoplasia (VAH). The aim of this study was to determine wall characteristics of VAH with three-dimensional volumetric isotropic turbo spin echo acquisition (3D VISTA) images and differentiate between acquired atherosclerotic stenosis and VAH. METHODS: Thirty patients with suspicious VAH by luminograms were retrospectively enrolled between January 2014 and February 2015. The patients were classified as "acquired atherosclerotic stenosis" or "VAH" based on 3D VISTA images. The wall characteristics of VAH were assessed to determine the presence of atherosclerotic lesions, and the patients were classified into two subgroups (VAH with atherosclerosis and VAH with normal wall). Wall characteristics of basilar arteries and vertebral arteries were also assessed. The clinical and wall characteristics were compared between the two groups. RESULTS: Five of 30 patients with suspicious VAH were finally diagnosed as acquired atherosclerotic stenosis by 3D VISTA images. 25 patients were finally diagnosed as VAH including 16 (64.00%) patients with atherosclerosis and 9 (36.00%) patients with normal wall. In the 16 patients with atherosclerosis, plaque was found in 9 patients, slight wall thickening in 6 patients, and thrombus and wall thickening in 1 patient. Compared with VAH patients with normal wall, VAH patients with atherosclerosis showed atherosclerotic basilar arteries and dominant vertebral arteries more frequently (P = 0.000). CONCLUSIONS: Three-dimensional VISTA images enable differentiation between the acquired atherosclerotic stenosis and VAH. VAH was also prone to atherosclerotic processes.

Plaques of Nonstenotic Basilar Arteries with Isolated Pontine Infarction on Three-dimensional High Isotropic Resolution Magnetic Resonance Imaging.

BACKGROUND: There are few studies for evaluating plaque characteristics of nonstenotic basilar arteries (BA). Our aim was to determine entire BA plaques with a three-dimensional volumetric isotropic turbo spin-echo acquisition (VISTA) and investigate the differences between the patients with and without isolated pontine infarction (IPI). METHODS: Twenty-four consecutive symptomatic patients with nonstenotic BA on time of flight magnetic resonance angiography (TOF MRA) were enrolled from China-Japan Friendship Hospital between January 2014 and December 2014. BA was classified as "normal" or "irregular" based on TOF MRA, and "normal wall", "slight wall-thickening", and "plaque" based on three-dimensional VISTA images. Outcomes from MRA and VISTA were compared. Patients were categorized as IPI and non-IPI groups based on the diffusion-weighted imaging. Clinical and plaque characteristics were compared between the two groups. RESULTS: A total of 1024 image slices including 311 (30.37%) plaque slices, 427 (41.70%) slight wall-thickening slices, and 286 (27.93%) normal wall slices for the entire BA from 23 patients were finally included for analysis. VISTA images detected plaques in all the 9 (100%) irregular MRA patients and 7 of 14 (50%) normal MRA patients. IPI was found in 11 (47.83%) patients. Compared to non-IPI group, the IPI group had a higher percentage of plaque slices (P = 0.001) and lower percentage of normal wall slices (P = 0.014) than non-IPI group. CONCLUSIONS: Three-dimensional VISTA images enable detection of BA plaques not visualized by MRA. BA plaques could be found in both the IPI and non-IPI group. However, IPI group showed plaques more extensively in BA than the non-IPI group.

Neuroinflammation and neuronal autophagic death were suppressed via Rosiglitazone treatment: New evidence on neuroprotection in a rat model of global cerebral ischemia.

Ischemic stroke is one of the leading causes of mortality and disability with documented high incidence and relapse rate. Accumulating evidence indicates that autophagy participated in neuronal cell death and functional loss induced following ischemia/reperfusion (I/R) injury. The peroxisome proliferating activating receptor-γ (PPAR-γ) agonist, Rosiglitazone (RSG), is known for its anti-inflammatory actions. Previous studies have demonstrated that RSG can exert neuroprotection in animal models of both chronic brain injuries and acute brain insults. However, whether RSG treatment is involved in the autophagic neuronal death following I/R injury remains totally unclear. The present study aimed to hypothesize that treatment of RSG could induce neuroprotective properties in a rat model of global cerebral ischemia (GCI), and thereby to investigate the underline mechanisms. We found that a single injection of RSG immediately following GCI significantly reduced cerebral infarct volume and brain edema, as well as increased neuron survival rate and function recovery. These effects correlate with a decrease of inflammatory cytokines and autophagy-associated proteins expression in the hippocampus region. Our results provide in vivo evidence that RSG significantly protected rats against I/R injury induced brain injury, and the mechanism might associate with inhibiting the processes of neuroinflammation and thereby attenuated of neuronal autophagic death. All data suggest that RSG can be further developed as a clinical neuroprotective candidate in ischemic stroke.

Influence of two common polymorphisms in the EPHX1 gene on warfarin maintenance dosage: a meta-analysis.

We conducted a meta-analysis to investigate the influence of two common single nucleotide polymorphisms (SNPs) (rs2292566 G>A and rs4653436 A>G) in the EPHX1 gene on warfarin maintenance dosages. Relevant literatures were searched using the PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, CBM, and CNKI databases without any language restrictions. STATA Version 12.0 software (Stata Corporation, College Station, TX, USA) was used for this meta-analysis. Standard mean difference and its corresponding 95% confidence interval (95% CI) were calculated. Seven studies met the inclusion criteria, including 2,063 warfarin-treated patients. Meta-analysis results illustrated that EPHX1 rs2292566 G>A polymorphism might be strongly correlated with a higher maintenance dose of warfarin. However, no interaction of EPHX1 rs4653436 A>G polymorphism with warfarin maintenance dosage was detected. A further subgroup analysis based on stratification by ethnicity indicated that EPHX1 rs2292566 G>A polymorphism was positively correlated with warfarin maintenance dosage among Caucasians, but not Asians. No associations were observed between EPHX1 rs4653436 A>G polymorphism warfarin maintenance dosage among both Caucasians and Asians. Our meta-analysis provides robust and unambiguous evidence that EPHX1 rs2292566 polymorphism may affect the maintenance dose of warfarin in Caucasians.

Curcumin protects neurons against oxygen-glucose deprivation/reoxygenation-induced injury through activation of peroxisome proliferator-activated receptor-γ function.

The turmeric derivative curcumin protects against cerebral ischemic injury. We previously demonstrated that curcumin activates peroxisome proliferator-activated receptor-γ (PPARγ), a ligand-activated transcription factor involved in both neuroprotective and anti-inflammatory signaling pathways. This study tested whether the neuroprotective effects of curcumin against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury of rat cortical neurons are mediated (at least in part) by PPARγ. Curcumin (10 µM) potently enhanced PPARγ expression and transcriptional activity following OGD/R. In addition, curcumin markedly increased neuronal viability, as evidenced by decreased lactate dehydrogenase release and reduced nitric oxide production, caspase-3 activity, and apoptosis. These protective effects were suppressed by coadministration of the PPARγ antagonist 2-chloro-5-nitrobenzanilide (GW9662) and by prior transfection of a small-interfering RNA (siRNA) targeting PPARγ, treatments that had no toxic effects on healthy neurons. Curcumin reduced OGD/R-induced accumulation of reactive oxygen species and inhibited the mitochondrial apoptosis pathway, as indicated by reduced release of cytochrome c and apoptosis-inducing factor and maintenance of both the mitochondrial membrane potential and the Bax/Bcl-2 ratio. Again, GW9662 or PPARγ siRNA transfection mitigated the protective effects of curcumin on mitochondrial function. Curcumin suppressed IκB kinase phosphorylation and IκB degradation, thereby inhibiting nuclear factor-κ B (NF-κB) nuclear translocation, effects also blocked by GW9662 or PPARγ siRNA. Immunoprecipitation experiments revealed that PPARγ interacted with NF-κB p65 and inhibited NF-κB activation. The present study provides strong evidence that at least some of the neuroprotective effects of curcumin against OGD/R are mediated by PPARγ activation.