Acute Stage Of Stroke Research Articles

Perspective of SGLT2 Inhibition in Treatment of Conditions Connected to Neuronal Loss: Focus on Alzheimer's Disease and Ischemia-Related Brain Injury.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are oral anti-hyperglycemic agents approved for the treatment of type 2 diabetes mellitus. Some reports suggest their presence in the central nervous system and possible neuroprotective properties. SGLT2 inhibition by empagliflozin has shown to reduce amyloid burden in cortical regions of APP/PS1xd/db mice. The same effect was noticed regarding tau pathology and brain atrophy volume. Empagliflozin presented beneficial effect on cognitive function, which may be connected to an increase in cerebral brain-derived neurotrophic factor. Canagliflozin and dapagliflozin may possess acetylcholinesterase inhibiting activity, resembling in this matter Alzheimer’s disease-registered therapies. SGLT2 inhibitors may prove to impact risk factors of atherosclerosis and pathways participating both in acute and late stage of stroke. Their mechanism of action can be related to induction in hepatocyte nuclear factor-1α, vascular endothelial growth factor-A, and proinflammatory factors limitation. Empagliflozin may have a positive effect on preservation of neurovascular unit in diabetic mice, preventing its aberrant remodeling. Canagliflozin seems to present some cytostatic properties by limiting both human and mice endothelial cells proliferation. The paper presents potential mechanisms of SGLT-2 inhibitors in conditions connected with neuronal damage, with special emphasis on Alzheimer’s disease and cerebral ischemia.

Early detection of small volume stroke and thromboembolic sources with computed tomography: Rationale and design of the ENCLOSE study.

BackgroundComputed tomography is the most frequently used imaging modality in acute stroke imaging protocols. Detection of small volume infarcts in the brain and cardioembolic sources of stroke is difficult with current computed tomography protocols. Furthermore, the role of computed tomography findings to predict recurrent ischemic stroke is unclear. With ENCLOSE, we aim to improve (1) the detection of small volume infarcts with thin slice computed tomography perfusion (CTP) images and thromboembolic source with cardiac computed tomography techniques in the acute stage of ischemic stroke and (2) prediction of recurrent ischemic stroke with computed tomography-derived predictors.Methods/design: ENCLOSE is a prospective multicenter observational cohort study, which will be conducted in three Dutch stroke centers (ClinicalTrials.gov Identifier: NCT04019483). Patients (≥18 years) with suspected acute ischemic stroke who undergo computed tomography imaging within 9 h after symptom onset are eligible. Computed tomography imaging includes non-contrast CT, CTP, and computed tomography angiography (CTA) from base of the heart to the top of the brain. Dual-energy CT data will be acquired when possible, and thin-slice CTP reconstructions will be obtained in addition to standard 5 mm CTP data. CTP data will be processed with commercially available software and locally developed model-based methods. The post-processed thin-slice CTP images will be compared to the standard CTP images and to magnetic resonance diffusion-weighted imaging performed within 48 h after admission. Detection of cardioembolic sources of stroke will be evaluated on the CTA images. Recurrence will be evaluated 90 days and two years after the index event. The added value of imaging findings to prognostic models for recurrent ischemic stroke will be evaluated.ConclusionThe aim of ENCLOSE is to improve early detection of small volume stroke and thromboembolic sources and to improve prediction of recurrence in patients with acute ischemic stroke.

Comparison of Anti-oncotic Effect of TRPM4 Blocking Antibody in Neuron, Astrocyte and Vascular Endothelial Cell Under Hypoxia.

In stroke and other neurological diseases, Transient Receptor Potential Melastatin 4 (TRPM4) has been reported to cause oncotic cell death which is due to an excessive influx of sodium ions. Following stroke, hypoxia condition activates TRPM4 channel, and the sodium influx via TRPM4 is further enhanced by an increased TRPM4 expression. However, the effect of TRPM4 inhibition on oncotic cell death, particularly during the acute stage, remains largely unknown. Recently, we have developed a polyclonal antibody M4P that specifically inhibits TRPM4 channel. M4P blocks the channel via binding to a region close to the channel pore from extracellular space. Using M4P, we evaluated the acute effect of blocking TRPM4 in neurons, astrocytes, and vascular endothelial cells. In a rat stroke model, M4P co-localized with neuronal marker NeuN and endothelial marker vWF, whereas few GFAP positive astrocytes were stained by M4P in the ipsilateral hemisphere. When ATP was acutely depleted in cultured cortical neurons and microvascular endothelial cells, cell swelling was induced. Application of M4P significantly blocked TRPM4 current and attenuated oncosis. TUNEL assay, PI staining and western blot on cleaved Caspase-3 revealed that M4P could ameliorate apoptosis after 24 h hypoxia exposure. In contrast, acute ATP depletion in cultured astrocytes failed to demonstrate an increase of cell volume, and application of M4P or control IgG had no effect on cell volume change. When TRPM4 was overexpressed in astrocytes, acute ATP depletion successfully induced oncosis which could be suppressed by M4P treatment. Our results demonstrate that comparing to astrocytes, neurons, and vascular endothelial cells are more vulnerable to hypoxic injury. During the acute stage of stroke, blocking TRPM4 channel could protect neurons and vascular endothelial cells from oncotic cell death.

Mir363-3p Treatment Attenuates Long-Term Cognitive Deficits Precipitated by an Ischemic Stroke in Middle-Aged Female Rats.

Cognitive impairment and memory loss are commonly seen after stroke and a third of patients will develop signs of dementia a year after stroke. Despite a large number of studies on the beneficial effects of neuroprotectants, few studies have examined the effects of these compounds/interventions on long-term cognitive impairment. Our previous work showed that the microRNA mir363-3p reduced infarct volume and sensory-motor impairment in the acute stage of stroke in middle-aged females but not males. Thus, the present study determined the impact of mir363-3p treatment on stroke-induced cognitive impairment in middle-aged females. Sprague–Dawley female rats (12 months of age) were subjected to middle cerebral artery occlusion (MCAo; or sham surgery) and injected (iv) with mir363-3p mimic (MCAo + mir363-3p) or scrambled oligos (MCAo + scrambled) 4 h later. Sensory-motor performance was assessed in the acute phase (2–5 days after stroke), while all other behaviors were tested 6 months after MCAo (18 months of age). Cognitive function was assessed by the novel object recognition test (declarative memory) and the Barnes maze (spatial memory). The MCAo + scrambled group showed reduced preference for a novel object after the stroke and poor learning in the spatial memory task. In contrast, mir363-3p treated animals were similar to either their baseline performance or to the sham group. Histological analysis showed significant deterioration of specific white matter tracts due to stroke, which was attenuated in mir363-3p treated animals. The present data builds on our previous finding to show that a neuroprotectant can abrogate the long-term effects of stroke.

Tactics of surgical treatment of acute brain ischemia caused by atherosclerotic damage of the brachiocephalic arteries

The study objective is to test tactics of surgical treatment of patients with brachiocephalic artery pathology in the acute stage of ischemic stroke.Materials and methods. In the period between 01.07.2014 and 31.12.2017 at the Neurosurgery Division of the N.V. Sklifosovsky Research Institute of Emergency Medicine and the Neurosurgery Division of the N.A. Semashko Republican Clinical Hospital (Simferopol), 125 surgeries were performed in patients with occlusion and stenosis of the precerebral arteries in the acute stage of ischemic stroke. Carotid endarterectomy was performed in 69 cases, among them 54 were performed by eversion technique, 15 traditionally, in 4 cases sympathectomy of the internal carotid artery (ICA) was performed, in 4 – endarterectomy from the external carotid artery, in 3 – redirection of the ICA, in 2 – ICA prosthesis, in 9 – thrombointimectomy. Extracranial-intracranial bypass anastomosis was performed in patients with acute ICA thrombosis (n = 16) and symptomatic ICA occlusion (n = 22).Results. Good and moderate results (4–5 points per the Glasgow Outcome Scale) were achieved in 119 (95.2 %) observations. Level of consciousness impairment, evaluations per the NIHSS, Rankin, Rivermead scales, brain ischemia volume, presence of brain hypoperfusion prior to surgery, timetable of surgical intervention, postoperative characteristics of the volumetric blood flow and brain reperfusion characteristics significantly affected treatment results. Total rate of complications and deaths was 4.8 %. In 3 cases, death was caused by myocardial infarction, malignant hyperperfusion with hemorrhagic transformation of the ischemic lesion and repeat stroke.Conclusion. Surgical treatment of patients with transient ischemic attacks, acute small or completed stroke should be performed as soon as possible: this tactic decreases the risk of repeat ischemic attacks and improves functional outcomes of treatment. In case of crescendo of a transient ischemic attack or progressing stroke, surgical treatment should be postponed and performed 24 hours after stabilization of the patient’s neurological status.

Motor imagery for gait rehabilitation after stroke.

Motor imagery (MI) is defined as a mentally rehearsed task in which movement is imagined but is not performed. The approach includes repetitive imagined body movements or rehearsing imagined acts to improve motor performance. To assess the treatment effects of MI for enhancing ability to walk among people following stroke. We searched the Cochrane Stroke Group registry, CENTRAL, MEDLINE, Embase and seven other databases. We also searched trial registries and reference lists. The last searches were conducted on 24 February 2020. Randomized controlled trials (RCTs) using MI alone or associated with action observation or physical practice to improve gait in individuals after stroke. The critical outcome was the ability to walk, assessed using either a continuous variable (walking speed) or a dichotomous variable (dependence on personal assistance). Important outcomes included walking endurance, motor function, functional mobility, and adverse events. Two review authors independently selected the trials according to pre-defined inclusion criteria, extracted the data, assessed the risk of bias, and applied the GRADE approach to evaluate the certainty of the evidence. The review authors contacted the study authors for clarification and missing data. We included 21 studies, involving a total of 762 participants. Participants were in the acute, subacute, or chronic stages of stroke, and had a mean age ranging from 50 to 78 years. All participants presented at least some gait deficit. All studies compared MI training versus other therapies. Most of the included studies used MI associated with physical practice in the experimental groups. The treatment time for the experimental groups ranged from two to eight weeks. There was a high risk of bias for at least one assessed domain in 20 of the 21 included studies. Regarding our critical outcome, there was very low-certainty evidence that MI was more beneficial for improving gait (walking speed) compared to other therapies at the end of the treatment (pooled standardized mean difference (SMD) 0.44; 95% confidence interval (CI) 0.06 to 0.81; P = 0.02; six studies; 191 participants; I² = 38%). We did not include the outcome of dependence on personal assistance in the meta-analysis, because only one study provided information regarding the number of participants that became dependent or independent after interventions. For our important outcomes, there was very low-certainty evidence that MI was no more beneficial than other interventions for improving motor function (pooled mean difference (MD) 2.24, 95% CI -1.20 to 5.69; P = 0.20; three studies; 130 participants; I² = 87%) and functional mobility at the end of the treatment (pooled SMD 0.55, 95% CI -0.45 to 1.56; P = 0.09; four studies; 116 participants; I² = 64.2%). No adverse events were observed in those studies that reported this outcome (seven studies). We were unable to pool data regarding walking endurance and all other outcomes at follow-up. We found very low-certainty evidence regarding the short-term benefits of MI on walking speed in individuals who have had a stroke, compared to other therapies. Evidence was insufficient to estimate the effect of MI on the dependence on personal assistance and walking endurance. Compared with other therapies, the evidence indicates that MI does not improve motor function and functional mobility after stroke (very low-certainty evidence). Evidence was also insufficient to estimate the effect of MI on gait, motor function, and functional mobility after stroke compared to placebo or no intervention. Motor Imagery and other therapies used for gait rehabilitation after stroke do not appear to cause significant adverse events.

Involvement of Matrix Metalloproteinase 9 in Vertebral Arterial Dissection With Posterior Circulation Ischemic Stroke.

BackgroundSpontaneous vertebral arterial dissection (VAD) is an important cause of posterior circulation ischemic stroke (PCS), but its pathogenesis remains elusive. Matrix metalloproteinase 9 (MMP‐9) is a gelatinase involved in inflammation process and several vascular diseases, such as aorta dissection, but its role in VBD is unclear yet. The present study aimed to determine the association between serum MMP‐9 level and VAD‐related PCS.Methods and ResultsWe recruited 149 patients with PCS, of which 30 were VAD and 119 had other determined etiologies (non‐VAD), and 219 non‐stroke individuals. Serum MMP‐9 was measured within 14 days from stroke onset. The age of VAD group was 59.6±15.0 years, which is similar to non‐stroke group (P=0.510) but significantly younger than non‐VAD group (69.9±14.0 years, P<0.001). Males and vascular risk factors were significantly more prevalent in VAD and non‐VAD groups than non‐stroke group (P<0.001). Multivariate logistic regression analysis adjusting potential confounders revealed that every 100 ng/mL of serum MMP‐9 level increment significantly predicted VAD (versus non‐stroke group: odds ratio (OR), 4.572; 95% CI, 2.240–9.333, P<0.001; versus non‐VAD group: OR, 1.819; 95% CI, 1.034–3.200, P=0.038).ConclusionsPatients with VAD‐related PCS had higher levels of serum MMP‐9 at the acute stage of stroke compared with non‐stroke individuals and PCS of other causes, supporting the potential involvement of extracellular matrix‐degrading protease in the mechanism of VAD, which leads to ischemic events.

Effects of trunk exercise with physioball to improve trunk balance among subjects with stroke: a systematic review and meta-analysis.

Poststroke subjects present with difficulties of reduced functional mobility and balance. Trunk impairment is common among stroke subjects which hinder the performance of upper and lower limb. In poststroke rehabilitation limbs are provided much attention than the trunk. Trunk function has been identified as an important early predictor of functional outcome after stroke. Physioball is commonly used among healthy subjects in performing trunk exercises. This systematic review with meta-analysis is conducted to investigate the effect of trunk exercises performed using physioball in improving trunk performance after stroke. Six authors identified relevant articles from the following databases: PubMed, Google Scholar, CINAHL (Cumulative Index and Nursing and Allied Health Literature), PEDro (Physiotherapy Evidence Database). Articles evaluating the effect of physioball exercise for improving trunk stability among stroke subjects were included. Databases were screened from 2009 and up to 2019. Qualitative synthesis of evidence was prepared and meta-analysis was implemented to draw pooled effects of physioball exercise on improving trunk performance and balance among stroke subjects. Eight papers were included, totaling 273 participants. All the articles included in this review demonstrated moderate to good quality. Meta-analysis performed with seven papers demonstrated statistical significance of physioball in improving trunk performance during acute and subacute stages of stroke. Brunnel Balance Assessment outcomes demonstrated statistically significant improvement of balance among overall stroke survivors. Trunk exercise performed over a physioball is effective during the acute and subacute stage. This meta-analysis could not find its significant effect in improving trunk performance in the chronic stages.

Changes of Tissue Factors and Tissue Factor Pathway Inhibitors in the Acute Phase of Cardiogenic Stroke in Patients With Atrial Fibrillation

Abstract Background To investigate changes of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in the acute phase of cardiogenic stroke in patients with atrial fibrillation (AF). Methods A total of 152 patients with nonvalvular persistent AF, 103 cardiogenic stroke patients with nonvalvular persistent AF, and 126 cases with noncardiogenic stroke were enrolled. Non-AF patients (n = 138) without stroke served as controls. The clinical data, biochemical indicators, and plasma levels of von Willebrand factor (vWF), TF, and TFPI were determined. Results Compared with controls, the plasma levels of vWF and TF were significantly higher, while TFPI and TFPI/TF ratio were lower in noncardiogenic stroke patients (all P &amp;lt; 0.05). Compared with cardiogenic stroke patients, noncardiogenic stroke subjects showed significantly higher plasma vWF and TF levels while TFPI levels and TFPI/TF ratio were significantly lower (all P &amp;lt; 0.05). Compared with AF patients, plasma levels of vWF, TF, and TFPI were higher while TFPI/TF ratios were decreased in the cardiogenic ischemic stroke subjects (all P &amp;lt; 0.05). Logistic regression analysis showed that a lower TFPI/TF ratio was an independent predictor of cardiogenic stroke in patients with nonvalvular AF (odds ratio = 3.78, 95% confidence interval: 1.86–7.31). Conclusions During the acute stage of stroke, TFPI/TF ratio is decreased in both cardiogenic and noncardiogenic stroke patients while plasma TFPI levels show divergent changes.

Infarct growth patterns may vary in acute stroke due to large vessel occlusion and recanalization with endovascular therapy.

This study aimed to investigate infarct growth patterns in stroke patients with large vessel occlusion (LVO) and successful recanalization by endovascular therapy (EVT). A total of 135 patients with LVO of the internal carotid artery or proximal segment of the middle cerebral artery admitted within 12h after onset, having baseline National Institute of Health Stroke Scale score ≥ 5 points, and successfully recanalized by EVT were enrolled. Infarct growth pattern models were developed based on infarct volumes on diffusion-weighted imaging before and after reperfusion. Single pattern models of linear, logarithmic, and exponential shapes were initially tested. Their appropriateness was predetermined. If none of these patterns was suitable, the best pattern model, which was the most suitable pattern among the three shapes selected for each individual, was tested. Clinical correlates were explored. Each single pattern model was tested for their suitability. However, none of the single pattern models successfully represented infarct growth curves: Of all subjects, only 63.7%, 62.2%, and 54.1% of patients were explained by the logarithmic, linear, and exponential model, respectively. Compared with the single pattern models, the best pattern model explained 80.7% of the subjects. The linear shape fit best in 40 patients, the logarithmic in 51, and the exponential in 44. Those fit best for the logarithmic pattern showed more favorable outcomes at discharge (31.4%) than did the others (linear, 10.0%; exponential, 9.1%; p = 0.01). Infarct growth patterns may vary among individual patients with acute stroke due to LVO and successful treatment with EVT. • Infarct growth during the acute stage of stroke is highly dynamic and the exact shape remains unknown. • Infarct growth pattern models were developed based on infarct volumes on diffusion-weighted imaging before and after reperfusion. • Infarct growth patterns may not be singular, rather various among individual patients with acute stroke due to LVO and successful treatment with EVT.

Sustained Increases in Immune Transcripts and Immune Cell Trafficking During the Recovery of Experimental Brain Ischemia.

Stroke is a major cause of chronic neurological disability. There is considerable interest in understanding how acute transcriptome changes evolve into subacute and chronic patterns that facilitate or limit spontaneous recovery. Here we mapped longitudinal changes in gene expression at multiple time points after stroke in mice out to 6 months. Adult C57BL/6 mice were subjected to transient middle cerebral artery occlusion. Longitudinal transcriptome levels were measured at 10 time points after stroke from acute to recovery phases of ischemic stroke. Localization and the number of mononuclear phagocytes were determined in the postischemic brain. Whole-mount brain imaging was performed in asplenic mice receiving GFP+ (green fluorescent protein)-tagged splenocytes. Sustained stroke-induced mRNA abundance changes were observed in both hemispheres with 2989 ipsilateral and 822 contralateral genes significantly perturbed. In the hemisphere ipsilateral to the infarct, genes associated with immune functions were strongly affected, including temporally overlapping innate and adaptive immunity and macrophage M1 and M2 phenotype-related genes. The strong immune gene activation was accompanied by the sustained infiltration of peripheral immune cells at acute, subacute, and recovery stages of stroke. The infiltrated immune cells were found in the infarcted area but also in remote regions at 2 months after stroke. The study identifies that immune components are the predominant molecular signatures and they may propagate or continuously respond to brain injury in the subacute to chronic phase after central nervous system injury. The study suggests a potential immune-based strategy to modify injury progression and tissue remodeling in ischemic stroke, even months after the initiating event.

Relationship between blood pressure and outcome changes over time in acute ischemic stroke.

To evaluate whether the relationship between systolic blood pressure (SBP) and stroke outcome varies during the acute stage of ischemic stroke as a function of the elapsed time after stroke onset. Patients who were hospitalized due to ischemic stroke within 6 hours of onset were retrospectively analyzed. SBP data were collected at 8 time points (1, 2, 4, 8, 16, 24, 48, and 72 hours after onset). The primary functional outcome measure was a poor outcome, defined as a modified Rankin Scale score of >2 at 3 months after stroke. Linear and quadratic models were constructed at each time point to assess relationships between SBP and outcome. Of the 2,546 patients, 728 (28.6%) had a poor outcome. SBP, as either a linear or quadratic term, had a significant effect on functional outcome, except at 4 hours after onset. For the initial 2 hours after onset, SBP had nonlinear U-shaped relationships with functional outcome, and patients with SBP of approximately 165 mm Hg were the least likely to have a poor outcome. Quadratic models exhibited a significantly better model fit. For 8-24 hours postonset, SBP exhibited linear relationships with functional outcome. For 48-72 hours postonset, SBP exhibited a J-shaped relationship with functional outcome, and the predicted probability of poor outcome was the lowest in patients with SBP of approximately 125 mm Hg. These relationships were relatively consistent across various sensitivity analyses. This study revealed that the relationship between SBP and functional outcome may depend on elapsed time from stroke onset.

Absence of an infarct on MRI is not uncommon after clinical diagnosis of ischemic stroke

IntroductionAn infarct on brain MRI is often seen as gold standard when diagnosing ischemic stroke. Although MRI has high sensitivity in detecting a lesion shortly after ischemic stroke, this rapidly declines when time progresses. We assessed the occurrence of a negative MRI 4–6 weeks after a discharge diagnosis of ischemic stroke, and compared the clinical characteristics of patients with a positive or negative MRI. Patients and methodsThe first 125 patients from a prospective longitudinal study of cognitive recovery after ischemic stroke were included in this study. Clinical characteristics were collected during admission. Per protocol, 4–6 weeks after stroke a brain MRI was performed. We operationalized different levels of certainty of the clinical diagnosis of ischemic stroke of a panel of 3 expert vascular neurologists. ResultsThirty patients (24%) were MRI negative. Patients that were MRI negative had lower stroke severity at admission, shorter duration of hospital-stay, and better functional status at discharge. The panel judged that 18/30 (60%) MRI negative patients and 27/30 (90%) MRI positive patients had a likely diagnosis of ischemic stroke. Compared to MRI negative patients with a less likely diagnosis, those with a likely diagnosis had higher admission stroke severity and more often received an acute intervention. Discussion and conclusionAbsence of an infarct on MRI is not uncommon 4–6 weeks after a clinical diagnosis of ischemic stroke. The relatively high proportion of MRI negative strokes with a likely clinical diagnosis of ischemic stroke indicates that neurologists should be cautious ruling out the diagnosis based on MRI beyond the acute stroke stage.

Methyltransferase 3 Mediated miRNA m6A Methylation Promotes Stress Granule Formation in the Early Stage of Acute Ischemic Stroke.

The modification of methyltransferase-like (METTL) enzymes plays important roles in various cellular responses by regulating microRNA expression. However, how m6A modification is involved in stress granule (SG) formation in the early stage of acute ischemic stroke by affecting the biogenesis processing of microRNAs remains unclear. Here, we established a middle cerebral artery occlusion (MCAO) model in rats and an oxygen-glucose deprivation/reperfusion (OGD/R) model in primary cortical neurons and PC12 cells to explore the potential mechanism between m6A modification and SG formation. The in vivo results showed that the level of infarction and apoptosis increased while SG formation decreased significantly within the ischemic cortex with improved reperfusion time after 2 h of ischemia. Consistent with the in vivo data, an inverse association between the apoptosis level and SG formation was observed in PC12 cells during the reperfusion period after 6 h of OGD stimulation. Both in vivo and in vitro results showed that the expression of METTL3 protein, m6A and miR-335 was significantly decreased with the reperfusion period. Overexpression of the METTL3 and METTL3 gene-knockdown in PC12 cells were achieved via plasmid transfection and CRISPR-Cas9 technology, respectively. Overexpression or knockdown of METTL3 in oxygen-glucose deprivation of PC12 cells resulted in functional maturation of miR-335, SG formation and apoptosis levels. In addition, we found that miR-335 enhanced SG formation through degradation of the mRNA of the eukaryotic translation termination factor (Erf1). In conclusion, we found that METTL3-mediated m6A methylation increases the maturation of miR-335, which promotes SG formation and reduces the apoptosis level of injury neurons and cells, and provides a potential therapeutic strategy for AIS.

4047 EEG as a Predictor of Post-Stroke Recovery: A Systematic Review and Meta-Analysis

OBJECTIVES/GOALS: The objective of this study is to perform a systematic review and meta-analysis on the prognostic utility of electroencephalography (EEG) in stroke recovery. METHODS/STUDY POPULATION: A literature search was conducted using three electronic databases, including PubMed, Scopus, and CINAHL. Key search terms were “EEG,” “stroke,” and “rehabilitation”. Only peer-reviewed journal articles published in English that examined the relationship between EEG and a standardized clinical outcome measure(s) at a later time in stroke patients were included. Two independent raters completed data extraction and assessed methodological quality of the studies with the Downs and Black form. A linear meta-regression was performed across subsets of individual studies that utilized a common clinical outcome measure to determine the association between EEG and clinical outcome while adjusting for sample size and study quality. RESULTS/ANTICIPATED RESULTS: 56 papers met the inclusion criteria and were included in the systematic review. The prognostic value of EEG was evidenced at both the acute and chronic stages of stroke. The addition of EEG enhanced prognostic accuracy more than initial clinical assessment scores and/or lesion volume alone. In the meta-analysis, a subset of 10 papers that utilized the National Institutes of Health Stroke Scale (NIHSS) and a subset of 7 papers that utilized the Modified Rankin Scale (MRS) were included. Analysis demonstrated an association between EEG and the subsequent clinical outcome measures. DISCUSSION/SIGNIFICANCE OF IMPACT: Currently, prognosis is largely based on initial behavioral impairment level. However, post-stroke recovery outcomes are heterogeneous despite similar initial clinical presentations. Uncertain prognosis makes it difficult for clinicians to develop personalized treatment plans for patients. Improved prognosis for recovery may guide clinical management for stroke survivors by helping clinicians determine the maximally efficient course of treatment and care. This study suggests that prognostic accuracy may be enhanced using EEG.

MicroRNA-4443 regulates monocyte activation by targeting tumor necrosis factor receptor associated factor 4 in stroke-induced immunosuppression.

MicroRNAs (miRNAs) have been demonstrated to play crucial roles in the early stage of acute ischaemic stroke (AIS). The purpose of this study was to investigate the expression patterns of miRNAs in peripheral blood mononuclear cells (PBMCs) from AIS patients and further explore related molecular mechanisms in stroke-induced immunodeficiency syndrome (SIDS). The miRNA expression patterns of PBMCs were detected by miRNA microarray and validated by quantitative real-time polymerase chain reaction (qRT-PCR) in AIS patients and healthy controls. Bioinformatics methods and luciferase reporter assays were used to detect the downstream target genes. Following stimulation with lipopolysaccharide and interleukin-4, the expression of miR-4443, tumor necrosis factor receptor associated factor 4 (TRAF4) and the nuclear factor kappa B (NF-κB) pathway were evaluated. Furthermore, transfection with miR-4443 mimic or inhibitor in the monocytes was carried out to gain insight into the mechanisms in SIDS. Interleukin-10 in AIS patients was significantly higher than that of healthy controls. The miRNA microarray analysis and qRTPCR validation showed that only miR-4443 was upregulated expressed in PBMCs from AIS patients, especially in monocytes. miR-4443 was shown to directly interact with the 3' untranslated regions of TRAF4, resulting in suppression of TRAF4 protein expression. Furthermore, the expression of miR-4443 and TRAF4 was regulated by stimulation with lipopolysaccharide or interleukin-4. Additionally, overexpression of miR-4443 suppressed the TRAF4/Iκα/NF-κB signaling pathway to activate the expression of anti-inflammatory cytokines in monocytes. The increased expression of miR-4443 induced monocyte dysfunction by targeting TRAF4, which may function as a crucial mediator in SIDS.

Neuro-Clinical Signatures of Language Impairments after Acute Stroke: A VBQ Analysis of Quantitative Native CT Scans

Ischemic stroke affects language production and/or comprehension and leads to devastating long-term consequences for patients and their families. Previous studies have shown that neuroimaging can increase our knowledge of the basic mechanisms of language recovery. Currently, models for predicting patients' outcomes have limited use in the clinic for the evaluation and optimization of rehabilitative strategies mostly because that are often based on high-resolution magnetic resonance imaging (MRI) data, which are not always possible to carry out in the clinical routine. Here, we investigate the use of Voxel-Based Morphometry (VBM), multivariate modelling and native Computed Tomography (nCT) scans routinely acquired in the acute stage of stroke for identifying biological signatures that explicate the relationships between brain anatomy and types of impairments. 80 stroke patients and 30 controls were included. nCT-scans were acquired in the acute ischemia stage and bedside clinical assessment from board-certified neurologist based on the NIH stroke scale. We use a multivariate Principal Component Analyses (PCA) to identify the brain signatures group the patients according to the presence or absence of impairment and identify the association between local Grey Matter (GM) and White Matter (WM) nCT values with the presence or absence of the impairment. Individual patient's nCT scans were compared to a group of controls' with no radiological signs of stroke to provide an automated delineation of the lesion. Consistently across the whole group the regions that presented significant difference GM and WM values overlap with known areas that support language processing. In summary, the method applied to nCT scans performed in the acute stage of stroke provided robust and accurate information about brain lesions' location and size, as well as quantitative values. We found that nCT and VBQ analyses are effective for identifying neural signatures of concomitant language impairments at the individual level, and neuroanatomical maps of aphasia at the population level. The signatures explicate the neurophysiological mechanisms underlying aetiology of the stroke. Ultimately, similar analyses with larger cohorts could lead to a more integrated multimodal model of behaviour and brain anatomy in the early stage of ischemic stroke.

Effects of virtual reality immersive training with computerized cognitive training on cognitive function and activities of daily living performance in patients with acute stage stroke: A preliminary randomized controlled trial: Retraction.

Effects of virtual reality immersive training with computerized cognitive training on cognitive function and activities of daily living performance in patients with acute stage stroke: A preliminary randomized controlled trial: Retraction.

Untargeted metabolomics predicts the functional outcome of ischemic stroke

Metabolites in blood have been found associated with the occurrence of vascular diseases, but its role in the functional recovery of stroke is unclear. The aim of this study is to investigate whether the untargeted metabolomics at the acute stage of ischemic stroke is able to predict functional recovery. One hundred and fifty patients with acute ischemic stroke were recruited and followed up for 3 months. Fasting blood samples within 7 days of stroke were obtained, liquid chromatography and mass spectrometry were applied to identify outcome-associated metabolites. The patients' clinical characteristics and identified metabolites were included for constructing the outcome prediction model using machine learning approaches. By using multivariate analysis, 220 differentially expressed metabolites (DEMs) were discovered between patients with favorable outcomes (modified Rankin Scale, mRS≤2at 3 months, n=77) and unfavorable outcomes (mRS≥3at 3 months, n=73). After feature selection, 63 DEMs were chosen for constructing the outcome prediction model. The predictive accuracy was below 0.65 when including patients' clinical characteristics, and could reach 0.80 when including patients' clinical characteristics and 63 selected DEMs. The functional enrichment analysis identified platelet activating factor (PAF) as the strongest outcome-associated metabolite, which involved in proinflammatory mediators release, arachidonic acid metabolism, eosinophil degranulation, and production of reactive oxygen species. Metabolomics is a potential method to explore the blood biomarkers of acute ischemic stroke. The patients with unfavorable outcomes had a lower PAF level compared to those with favorable outcomes.

Pro-inflammatory cytokines are associated with the development of post-stroke depression in the acute stage of stroke: A meta-analysis

ABSTRACT Background: Pro-inflammatory cytokines may be associated with post-stroke depression (PSD); however, results from different studies are inconsistent. Objectives: To investigate whether pro-inflammatory cytokines are associated with the development of PSD in acute stroke. Methods: PubMed, Embase, and Web of science were searched for relevant literature. Meta-analyzes were performed to determine whether the baseline blood concentrations of pro-inflammatory cytokines differed between acute stroke patients with and without depression. Sensitivity analyzes and regression analyzes were conducted to explore sources of heterogeneity. Results: We included 889 acute stroke patients from eight original studies, 312 of whom developed PSD and 577 did not. The serum concentrations of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were higher in the PSD group, compared with the non-PSD group (IL-6: SMD = 1.26, 95% CI = [0.55, 1.97], P < 0.001; TNF-α: SMD = 0.61, 95% CI = [0.13, 1.10], P = 0.010). Conclusions: This study indicates IL-6 and TNF-α as potential biomarkers of PSD in the acute stage of stroke and provides theoretical support for the early prevention and treatment of PSD.