Blood Pressure Variability during Angiography in Patients with Ischemic Stroke and Intracranial Artery Stenosis.

Our aim was to investigate factors predicting blood pressure (BP) variability during diagnostic cerebral angiography and associations between BP variability and clinical outcomes in patients with acute and subacute ischemic stroke and intracranial artery stenosis. 114 patients with ischemic stroke and intracranial artery stenosis (stenosis rate >50%) were recruited. Patients who underwent cerebral angiography within 3 days and 3-14 days of disease onset are referred to be Group A and Group S, respectively. BP variability in Group A was defined as the coefficient of variance (CV) of BP. Univariate and multivariate regression analyses were used to identify predictors of CV of BP and associations between CV of BP and clinical outcomes at discharge. In Group A patients, advanced age was associated with increased CV of SBP and diastolic blood pressure (DBP), and antihypertensive use was associated with lower CV of SBP. Male was associated with lower CV of DBP. In Group S, higher CV of SBP was associated with hypertension and antihypertensive use. Males had lower CV of SBP than females. The calcium channel blocker was associated with lower CV of DBP. Higher scores of the Stroke Scale at admission were significantly associated with poor clinical outcomes for both groups, while BP variability was not. Factors associated with BP variability are significantly different between stroke patients undergoing angiography within 3 days vs. 3-14 days after disease onset. BP variability is not significantly associated with clinical outcomes at discharge.

Cathepsin K Knockout Exacerbates Haemorrhagic Transformation Induced by Recombinant Tissue Plasminogen Activator After Focal Cerebral Ischaemia in Mice.

Severe haemorrhagic transformation (HT), a common complication of recombinant tissue plasminogen activator (rtPA) treatment, predicts poor clinical outcomes in acute ischaemic stroke. The search for agents to mitigate this effect includes investigating biomolecules involved in neovascularization. This study examines the role of Cathepsin K (Ctsk) in rtPA-induced HT after focal cerebral ischaemia in mice. After knockout of Ctsk, the gene encoding Ctsk, the outcomes of Ctsk+/+ and Ctsk-/- mice were compared 24 h after rtPA-treated cerebral ischaemia with respect to HT severity, neurological deficits, brain oedema, infarct volume, number of apoptotic neurons and activated microglia/macrophage, blood-brain barrier integrity, vascular endothelial growth factor (VEGF) expression and Akt-mTOR pathway activation. We observed that haemoglobin levels, brain oedema and infarct volume were significantly greater and resulted in more severe neurological deficits in Ctsk-/- than in Ctsk+/+ mice. Consistent with our hypothesis, the number of NeuN-positive neurons was lower and the number of TUNEL-positive apoptotic neurons and activated microglia/macrophage was higher in Ctsk-/- than in Ctsk+/+ mice. Ctsk knockout mice exhibited more severe blood-brain barrier (BBB) disruption, with microvascular endothelial cells exhibiting greater VEGF expression and lower ratios of phospo-Akt/Akt and phospo-mTOR/mTOR than in Ctsk+/+ mice. This study is the first to provide molecular insights into Ctsk-regulated HT after cerebral ischaemia, suggesting that Ctsk deficiency may disrupt the BBB via Akt/mTOR/VEGF signalling, resulting in neurological deficits and neuron apoptosis. Ctsk administration has the potential as a novel modality for improving the safety of rtPA treatment following stroke.

Comprehensive analysis of differentially expressed profiles of long non-coding RNAs and messenger RNAs in kaolin-induced hydrocephalus.

BACKGROUNDS: The pathophysiology of hydrocephalus induced brain damage remains unclear. Long non-coding RNAs (lncRNAs) have been demonstrated to be implicated in many central nervous system diseases. However, the roles of lncRNAs in hydrocephalus injury are poorly understood. METHODS: The present study depicted the expression profiles of lncRNAs and messenger RNAs (mRNAs) in C57BL/6 mice with kaolin-induced hydrocephalus and saline controls using high-throughput RNA sequencing. Afterward, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to identify potential targets that correlated with hydrocephalus. In addition, co-expression networks and cis- and trans-regulation were predicted using bioinformatics methods. Finally, representative lncRNAs and mRNAs were further validation using quantitative real-time polymerase chain reaction. RESULTS: A total of 1575 lncRNAs and 1168 mRNAs were differentially expressed (DE) in hydrocephalus. GO and KEGG analyses indicated several immune and inflammatory response-associated pathways may be important in the hydrocephalus. Besides, functional enrichment analysis based on co-expression network showed several similar pathways, such as chemokine signaling pathway, phagosome, MAPK signaling pathway and complement and coagulation cascade. Cis-regulation prediction revealed 5 novel lncRNAs might regulate their nearby coding genes, and trans-regulation revealed several lncRNAs participate in pathways regulated by transcription factors, including BPTF, FOXM1, NR5A2, P2RX5, and NR6A1. CONCLUSIONS: In conclusion, our results provide candidate genes involved in hydrocephalus and suggest a new perspective on the modulation of lncRNAs in hydrocephalus.

Previous chronic symptomatic and asymptomatic cerebral hemorrhage in patients with acute ischemic stroke.

PURPOSE: Identifying previous chronic cerebral hemorrhage (PCH), especially asymptomatic cases in patients with ischemic stroke, is essential for proper antithrombotic management. The study aimed to further clarify the prevalence of PCH and the associated factors in patients with acute ischemic stroke using multi-modal neuroimaging including susceptibility-weighted MR imaging (SWI). METHODS: This was a retrospective cross-sectional study of 382 patients with acute ischemic stroke. All patients underwent 3.0-T MRI for cranial SWI, 1.5-T or 3.0-T conventional cranial MRI, and cranial CT. Patients found with PCH were matched 1:4 with patients without PCH. Clinical manifestation, computed tomography, conventional cranial MRI, and cranial SWI were used to determine PCH. Clinical and neuroimaging findings between the patients with symptomatic vs. asymptomatic PCH were compared. RESULTS: Thirty-six patients (36/382, 9.4%) were determined to have had a PCH. Of these 36 patients, 17 (17/36, 47.2%, or 17/382, 4.5%) had asymptomatic PCH. Multivariable analysis showed that serum total cholesterol (OR = 0.510, 95%CI 0.312-0.832, P = 0.007), cerebral microbleeds (OR = 6.251, 95%CI 2.220-17.601, P = 0.001), and antithrombotic drugs history (OR = 3.213, 95%CI 1.018-10.145, P = 0.047) were independently associated with PCH. Asymptomatic PCH had similar clinical and neuroimaging characteristics with symptomatic PCH. CONCLUSION: PCH is not uncommon in acute ischemic stroke patients. Total serum cholesterol, cerebral microbleeds on SWI, and history of antithrombotic drugs were independently associated with PCH in patients with acute ischemic stroke. Asymptomatic PCH, which is easier to be missed and has similar characteristics with symptomatic PCH, should draw much attention.

Rivaroxaban does not influence hemorrhagic transformation in a diabetes ischemic stroke and endovascular thrombectomy model.

Managing endovascular thrombectomy (ET) in diabetic ischemic stroke (IS) with novel anticoagulants is challenging due to putative risk of intracerebral hemorrhage. The study evaluates increased hemorrhagic transformation (HT) risk in Rivaroxaban-treated diabetic rats post ET. Diabetes was induced in male Sprague-Dawley rats by intraperitoneal injection of 60 mg/kg streptozotocin. After 4-weeks, rats were pretreated orally with 30 mg/kg Rivaroxaban/saline; prothrombin time was monitored. IS and ET was induced after 1 h, by thread-induced transient middle cerebral artery occlusion (tMCAO) that mimicked mechanical ET for proximal MCA occlusion at 60 min. After 24 h reperfusion, infarct volumes, HT, blood-brain barrier (BBB) permeability, tight junction at peri-ischemic lesion and matrix metalloproteinase-9 (MMP-9) activity was measured. Diabetic rats seemed to exhibit increased infarct volume and HT at 24 h after ET than normal rats. Infarct volumes and functional outcomes did not differ between Rivaroxaban and diabetic control groups. A significant increase in HT volumes and BBB permeability under Rivaroxaban treatment was not detected. Compared to diabetic control group, neither the occludin expression was remarkably lower in the Rivaroxaban group nor the MMP-9 activity was higher. Together, Rivaroxaban does not increase HT after ET in diabetic rats with proximal MCA occlusion, since Rivaroxaban has fewer effects on post-ischemic BBB permeability.

The Posterior Insula Shows Disrupted Brain Functional Connectivity in Female Migraineurs Without Aura Based on Brainnetome Atlas.

Long-term headache attacks may cause human brain network reorganization in patients with migraine. In the current study, we calculated the topologic properties of functional networks based on the Brainnetome atlas using graph theory analysis in 29 female migraineurs without aura (MWoA) and in 29 female age-matched healthy controls. Compared with controls, female MWoA exhibited that the network properties altered, and the nodal centralities decreased/increased in some brain areas. In particular, the right posterior insula and the left medial superior occipital gyrus of patients exhibited significantly decreased nodal centrality compared with healthy controls. Furthermore, female MWoA exhibited a disrupted functional network, and notably, the two sub-regions of the right posterior insula exhibited decreased functional connectivity with many other brain regions. The topological metrics of functional networks in female MWoA included alterations in the nodal centrality of brain regions and disrupted connections between pair regions primarily involved in the discrimination of sensory features of pain, pain modulation or processing and sensory integration processing. In addition, the posterior insula decreased the nodal centrality, and exhibited disrupted connectivity with many other brain areas in female migraineurs, which suggests that the posterior insula plays an important role in female migraine pathology.

Relationship between intracranial internal carotid artery calcification and enlarged cerebral perivascular space.

PURPOSE: The association between intracranial internal carotid artery (IICA) calcification and lacunes, white matter hyperintensity (WMH), and cerebral microbleeds (CMBs) has been well researched. However, enlarged cerebral perivascular space (PVS) has not yet been reported to correlate with intracranial internal carotid artery calcification. Therefore, the primary aim of this study was to investigate the relationship between IICA calcification and enlarged PVS. METHODS: A total of 189 patients with ischemic stroke in the middle cerebral artery territory who presented within 7 days of ictus from 2012 to 2015 were enrolled respectively. All patients were required to have undergone head computed tomography, magnetic resonance imaging, susceptibility-weighted magnetic resonance imaging, magnetic resonance angiography, or computed tomography angiography. Clinical characteristics were recorded. IICA calcification and enlarged PVS were semi-quantitatively evaluated, and the presence of lacunes, WMH, and CMBs was recorded. RESULTS: Of the 189 patients, 63.5% were male. Mean age of the patients was 68.6 ± 12.2 years. There were 104 patients with IICA calcification. Age, diabetes mellitus, lacunes, and white matter hyperintensity were significantly associated with IICA calcification (P < 0.05). Multivariate logistic regression analysis showed that age, diabetes mellitus, and lacunes were independent predictors of IICA calcification (P < 0.05). A lower risk of IICA calcification was found in patients with a higher enlarged PVS score (P = 0.004). CONCLUSION: Higher enlarged PVS scores were associated with a lesser degree of IICA calcification. There appears to be a relationship between reduced risk of IICA calcification and enlarged PVS.

The sensorimotor network dysfunction in migraineurs without aura: a resting-state fMRI study.

Migraine is a common recurrent neurological disorder combining nausea, vomiting, and hypersensitivities to visual, auditory, olfactory and somatosensory stimuli. However, the dysfunction of the sensorimotor network in migraineurs has not been well clarified. In the present study, we evaluated the dysfunction of the sensorimotor network in 30 migraineurs without aura and in 31 controls by combining regional homogeneity (ReHo), amplitudes of low-frequency fluctuation (ALFF) and degree centrality (DC) analysis methods based on resting-state fMRI. A seed-based functional connectivity (FC) analysis was used to investigate whether the dysfunctional areas within the sensorimotor network exhibited abnormal FC with other brain areas. Compared to the controls, the migraineurs without aura exhibited significantly smaller ReHo, ALFF and DC values in the primary somatosensory cortex (S1) and right premotor cortex (PMC). The migraineurs showed weaker FC between the S1 and brain areas within the pain intensity and spatial discrimination pathways and trigemino-thalamo-cortical nociceptive pathway. We proposed that the dysfunction of the S1 and PMC and the decreased FC between the S1 and brain areas in migraineurs without aura may disrupt the discrimination of sensory features of pain and affect nociception pathways, and would be involved in the dysfunctional mechanism in migraine.

Increased default mode network connectivity and increased regional homogeneity in migraineurs without aura.

BACKGROUND: The precuneus/posterior cingulate cortex, which has been associated with pain sensitivity, plays a pivotal role in the default mode network. However, information regarding migraine-related alterations in resting-state brain functional connectivity in the default mode network and in local regional spontaneous neuronal activity is not adequate. METHODS: This study used functional magnetic resonance imaging to acquire resting-state scans in 22 migraineurs without aura and in 22 healthy matched controls. Independent component analysis, a data-driven method, was used to calculate the resting-state functional connectivity of the default mode network in the patient and healthy control groups. Regional homogeneity (ReHo) was used to analyse the local features of spontaneous resting-state brain activity in the migraineurs without aura. RESULTS: Compared with the healthy controls, migraineurs without aura showed increased functional connectivity in the left precuneus/posterior cingulate cortex within the default mode network and significant increase in ReHo values in the bilateral precuneus/posterior cingulate cortex, left pons and trigeminal nerve entry zone. In addition, functional connectivity was decreased between the areas with abnormal ReHo (using the peaks in the precuneus/posterior cingulate cortex) and other brain areas. CONCLUSIONS: The abnormalities in the precuneus/posterior cingulate cortex suggest that migraineurs without aura may exhibit information transfer and multimodal integration dysfunction and that pain sensitivity and pian processing may also be affected.

Predictive role of CHADS2 and CHA2DS2-VASc scores on stroke and thromboembolism in patients without atrial fibrillation: a meta-analysis.

OBJECTIVE: CHA2DS2-VASc is the extension of the CHADS2 score developed by Birmingham 2009. This risk stratification schema is often used in clinical setting when considering additional risk factors for developing stroke in AF patients. However, its role in the non-AF population is unknown. This study was designed to evaluate the accuracy of the CHADS2 and the CHA2DS2-VASc scoring systems. METHODS: Studies designed for CHADS2 and CHA2DS2-VASc score in stratifying the risks for stroke development in non-AF patients were included. RESULTS: Among the 114 studies identified, six trials were chosen finally and included for meta-analysis. The pooled diagnostic odds ratio (DOR) for CHADS2 and CHA2DS2-VASc was 2.86 (95% CI =1.83-4.28) and 2.80 (95% CI =1.83-4.28), respectively. CHA2DS2-VASc score was of better sensitivity than CHADS2 score (0.920 vs. 0.768). However, both scores were showed to have inherent heterogeneity and poor specificity. CONCLUSIONS: Though having good diagnostic accuracy, the clinical application of the CHADS2 and CHA2DS2-VASc scores in predicting risk of stroke development in non-AF patients still needs further validation. Key message The overall diagnostic accuracy of CHADS2 and CHA2DS2-VASc in stroke-risk stratification was good in patients with non-atrial fibrillation.

Pulse pressure as an independent predictor of stroke: a systematic review and a meta-analysis.

BACKGROUND: Recent evidence suggests that pulse pressure (PP) is a strong cardiovascular diseases' risk factor. We systematically evaluated all relevant studies to determine whether PP can be used as an independent predictor of stroke and mortality. METHODS AND RESULTS: A meta-analysis was performed by searching the published literature using MEDLINE, Cochrane and Google Scholar databases up to December 15, 2015. We measured the effect size expressed by hazard ratio (HR) and 95 % confidence interval (95 % CI). Eleven publications were included in the analysis. Pooled results demonstrated that 10 mmHg increase in PP was associated with increased risk of stroke occurrence (pooled HR 1.046, 95 % CI 1.025-1.068, P < 0.001). Additionally, systolic blood pressure (SBP) (pooled HR 1.053, 95 % CI 1.033-1.073, P < 0.001) and diastolic blood pressure (DPB) (pooled HR 1.056, 95 % CI 1.038-1.074, P < 0.001) were found to be significant predictors for stroke. We did not find a significant association between PP and all-cause mortality (pooled HR 1.022, 95 % CI 0.983-1.063, P = 0.270). We found SBP (pooled HR 1.008, 95 % CI 1.002-1.014, P = 0.012), but not DBP (pooled HR 1.023, 95 % CI 0.964-1.085, P = 0.451) to be significantly associated with all-cause mortality. CONCLUSIONS: Current data confirms that PP is an independent risk factor for stroke but is not a predictor of mortality.

Repeated Transient Wallenberg's Syndrome: Probable Association with Ipsilateral Vertebral Artery Hypoplasia and Aortic Valve Disease.

BACKGROUND: Here we report a rare case of repeated transient Wallenberg's syndrome and discuss its mechanism. METHODS: Case report and literature review. RESULTS: A 57-year-old man was admitted for 1.5-month repeated transient Wallenberg's syndrome, including right-sided Horner's syndrome, lower limb weakness, and paresthesia on the right side of the body and face. His symptom appeared mostly during physical activity. Symptoms occurred nearly everyday and lasted from 5 minutes to 30 minutes. His cranial magnetic resonance imaging (MRI) including diffusion-weighted MRI imaging was normal, and his cervical contrast-enhanced magnetic resonance angiography reflected right vertebral artery hypoplasia. Twenty-four-hour electrocardiogram and electroencephalography showed no abnormalities. Echocardiography showed aortic valve calcification with moderate aortic stenosis, moderate aortic insufficiency, and dilated aorta. Dual-antiplatelets or warfarin (international normalized ratio reached 2.07) were not effective to reduce the attacks. CONCLUSIONS: Hemodynamic instability due to valve disease combined with right vertebral artery hypoplasia could lead to transient Wallenberg's syndrome. Antithrombotics are often ineffective for this kind of patients and the best therapy for them could be to cure their valve disease. Repeated transient Wallenberg's syndrome is rare and that caused by ipsilateral vertebral artery hypoplasia and severe valve disease has not been reported up till now to our knowledge, so it will widen the knowledge on etiologies of transient ischemic attacks and provide information and reference to cardiologists and neurologists in diagnosis and treatment for patients with similar clinical manifestations.

Blood Pressure Reduction in the Acute Phase of an Ischemic Stroke Does Not Improve Short- or Long-Term Dependency or Mortality: A Meta-Analysis of Current Literature.

The purpose of this study was to perform a meta-analysis of current literature to determine whether lowering blood pressure (BP) during the acute phase of an ischemic stroke improves short- and long-term outcomes. PubMed, Cochrane, and Embase were searched until September 5, 2014 using combinations of the search terms: blood pressure reduction, reduced blood pressure, lowering blood pressure, ischemic stroke, acute stroke, and intra-cerebral hemorrhage. Inclusion criteria were randomized controlled trial and patients with acute stroke (ischemic or hemorrhagic) treated with an antihypertensive agent or placebo. Outcome measures were change in systolic and diastolic BP (SBP, DBP) after treatment, and short- and long-term dependency and mortality rates. A total of 459 studies were identified, and ultimately 22 studies were included in the meta-analysis. The total number of participants in the treatment groups was 5672 (range, 6-2308), and in the control groups was 5416 (range, 6-2033). In most studies, more than 50% of the participants were males and the mean age was more than 60 years. The mean follow-up time ranged from 5 days to 12 months. As expected, treatment groups had a greater decrease in BP than control groups, and this effect was seen with different classes of antihypertensive drugs. Short-term and long-term dependency rates were similar between treatment and control groups (short-term dependency: pooled odds ratio [OR] = 1.041, 95% confidence interval [CI]: 0.936-1.159, P = 0.457; long-term dependency: pooled OR = 1.013, 95% CI: 0.915-1.120, P = 0.806). Short-term or long-term mortality was similar between the treatment and control groups (short-term mortality: pooled OR = 1.020, 95% CI: 0.749-1.388, P = .902; long-term mortality: pooled OR = 1.039, 95% CI: 0.883-1.222, P = 0.644). Antihypertensive agents effectively reduce BP during the acute phase of an ischemic stroke, but provide no benefit with respect to short- and long-term dependency and mortality.

Does novel oral anticoagulant improve anticoagulation for non-valvular atrial fibrillation associated stroke: An inpatient registration study in Shanghai.

OBJECTIVE: To summarize the use rate, safety, efficacy of antithrombotics in stroke/transient ischemic attack (TIA) prevention, and reasons for not using dabigatran etexilate (DE) in Shanghai, China. METHODS: Non-valvular atrial fibrillation (NVAF)-associated stroke patients were prospectively registered as an electronic database. Use rate of antithrombotics and reasons for not using DE were extracted during follow-up. Patients' baseline characteristics, recurrent ischemic stroke/TIA events and bleeding complications were analyzed. PATIENTS: From April 2012 to August 2014, 110 inpatients with NVAF-associated stroke were studied in our hospital. NVAF was diagnosed by 12-lead electrocardiogram, 24 h Holter and echocardiography. RESULTS: Before introduction of DE (April 2013), use rates of warfarin and antiplatelets were 28.9% (11/38) and 60.5% (23/38) respectively; after that, use rates of warfarin, DE, and antiplatelets were 20.8% (15/72), 12.5% (9/72), and 43.1% (31/72). The DE did not improve use of anticoagulants (P = 0.639). There were 19 (17.3%) recurrent ischemic stroke events up to October 2015; two (9.5%) in the non-user group, 10 (18.5%) in the antiplatelet group, and seven (20.0%) in the anticoagulants group (P = 0.570). Furthermore, recurrence rates were similar between the DE group (20.0%) and the Warfarin group (20.0%, P = 1.000). The most common reason for not using DE was financial concerns (61.0%), followed by inconvenience to purchase (14.0%) and hemorrhage concerns (11.0%). Two patients using warfarin found fecal occult blood so they stopped warfarin and began to use antiplatelet drugs. No bleeding event occurred in the other groups. Only one patient had side effects (dyspepsia and gastroesophageal reflux) from DE. CONCLUSION: The use rate of either DE or warfarin in Shanghai was low; DE had not improved anticoagulation therapy for NVAF patients in Shanghai mainly because DE had not been covered by health insurance.