scholarly journals Neural Stem Cell Extracellular Vesicles Disrupt Midline Shift Predictive Outcomes in Porcine Ischemic Stroke Model

2019 ◽  
Vol 11 (4) ◽  
pp. 776-788 ◽  
Author(s):  
Samantha E. Spellicy ◽  
Erin E. Kaiser ◽  
Michael M. Bowler ◽  
Brian J. Jurgielewicz ◽  
Robin L. Webb ◽  
...  
Keyword(s):  
Stem Cell ◽  
Ischemic Stroke ◽  
Functional Outcome ◽  
Neural Stem Cell ◽  
Functional Outcomes ◽  
Extracellular Vesicle ◽  
Stroke Model ◽  
Midline Shift ◽  
Post Stroke ◽  
Non Invasive

AbstractMagnetic resonance imaging (MRI) is a clinically relevant non-invasive imaging tool commonly utilized to assess stroke progression in real time. This study investigated the utility of MRI as a predictive measure of clinical and functional outcomes when a stroke intervention is withheld or provided, in order to identify biomarkers for stroke functional outcome under these conditions. Fifteen MRI and ninety functional parameters were measured in a middle cerebral artery occlusion (MCAO) porcine ischemic stroke model. Multiparametric analysis of correlations between MRI measurements and functional outcome was conducted. Acute axial and coronal midline shift (MLS) at 24 h post-stroke were associated with decreased survival and recovery measured by modified Rankin scale (mRS) and were significantly correlated with 52 measured acute (day 1 post) and chronic (day 84 post) gait and behavior impairments in non-treated stroked animals. These results suggest that MLS may be an important non-invasive biomarker that can be used to predict patient outcomes and prognosis as well as guide therapeutic intervention and rehabilitation in non-treated animals and potentially human patients that do not receive interventional treatments. Neural stem cell–derived extracellular vesicle (NSC EV) was a disruptive therapy because NSC EV administration post-stroke disrupted MLS correlations observed in non-treated stroked animals. MLS was not associated with survival and functional outcomes in NSC EV–treated animals. In contrast to untreated animals, NSC EVs improved stroked animal outcomes regardless of MLS severity.

Abstract TP107: Midline Shift Predicts Functional Outcomes in Porcine Ischemic Stroke Model

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Samantha Spellicy ◽  
Erin Kaiser ◽  
Michael Bowler ◽  
Brian Jurgielewicz ◽  
Robin Webb ◽  
...  
Keyword(s):  
Animal Model ◽  
Ischemic Stroke ◽  
Functional Outcomes ◽  
Randomized Study ◽  
Large Animal Model ◽  
Control Group ◽  
Large Animal ◽  
Midline Shift ◽  
Post Stroke ◽  
Significant Difference

In this study, we sought to identify acute MRI parameters which are predictive of long-term functional outcomes as well as assess the effects of a neural stem cell extracellular vesicle (NSC EV) therapeutic in a large animal model of ischemic stroke. In this randomized study, stroke was induced through a permanent right-sided middle cerebral artery occlusion (MCAO) on 16 male landrace pigs, which were divided into either treatment or control group. NSC EVs or PBS was administered at 2, 14, and 24 hours, and MRI was conducted at day 1 and 84 post-stroke. Data on 65 gait and 25 behavior parameters were collected pre-stroke and at multiple timepoints over 84 days following MCAO. Of all 15 measured MRI parameters, axial and coronal midline shift (MLS), at day 1 post stroke, had the highest total number of significant correlations (52 parameters at p<0.05) to acute and chronic functional measurements in control animals such as step time in the left front limb (p=0.0322) and cycle time in the right hind limb (p=0.0011) respectively. This suggests MLS is the best overall predictor of specific functional deficits at both acute and chronic timepoints, which to our knowledge has never been shown in an animal model. Additionally, the parameters found to be correlated to MLS in control animals were not correlated in NSC EV-treated animals, suggesting NSC EV treatment disrupts this natural correlation between degree of MLS and functional outcomes. NSC EVs and control pigs were binned into either high or low MLS groups and their survival and recovery was assessed by the modified Rankin Scale (mRS). While there was a significant difference in mRS scores of control animals with high and low MLS at day 6 post-MCAO (p=0.0008), there was not in NSC EV-treated animals (p=0.6754). Further, there was a significant difference in survival of control animals with high and low axial MLS (p=0.0401), but not in the NSC EV group (p=0.4142). Additionally, mRNA expression of GFAP was significantly correlated with increasing MLS in non-treated but not NSC EV-treated animals. These findings show although NSC EV treatment does not significantly alter the degree of MLS 1-day post-MCAO, it does alter gene expression, increase survival, and improve functional recovery following large MLS alterations.

scholarly journals Long term Post-Stroke Functional Outcomes: a comparison of diabetics and non-diabetics

2021 ◽  
Author(s):  
Deidre Anne de Silva ◽  
Kaavya Narasimhalu ◽  
Ian Wang Huang ◽  
Fung Peng Woon ◽  
John C. Allen ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Outcome ◽  
Functional Outcomes ◽  
Age Group ◽  
Stroke Patients ◽  
Poor Functional Outcome ◽  
Post Stroke ◽  
The Impact

Introduction: Diabetes mellitus (DM) is known to influence outcomes in the short-term following stroke. However, the impact of DM on long-term functional outcomes after stroke is unclear. We compared functional outcomes periodically over 7 years between diabetic and non-diabetic ischemic stroke patients and investigated the impact of DM on the long-term trajectory of post-stroke functional outcomes. We also studied the influence of age on the diabetes-functional outcome association. Methods: This is a longitudinal observational cohort study of 802 acute ischemic stroke patients admitted to the Singapore General Hospital from 2005 to 2007. Functional outcomes were assessed using the modified Rankin Scale (mRS) with poor functional outcome defined as mRS≥3. Follow-up data was determined at 6 months and at median follow-up durations of 29 and 86 months. Results: Among the 802 ischemic stroke patients studied (mean age 64 ± 12 years, male 63%), 42% had DM. In regression analyses adjusting for covariates, diabetic patients were more likely to have poor functional outcomes at 6 months (OR=2.12, 95% CI: 1.23–3.67) and at median follow-up durations of 29 months (OR=1.96, 95% CI: 1.37–2.81) and 86 months (OR=2.27, 95% CI: 1.58–3.25). In addition, age modulated the effect of DM, with younger stroke patients (≤65 years) more likely to have long term poor functional outcome at the 29-month (p=0.0179) and 86-month (p=0.0144) time points. Conclusions: DM was associated with poor functional outcomes following ischemic stroke in the long term with the effect remaining consistent throughout the 7-year follow-up period. Age modified the effect of DM in the long term, with an observed increase in risk in the ≤65 age group but not in the >65 age group.

Abstract WP7: Leukoaraiosis And Outcomes After Intra-arterial Therapy In Acute Ischemic Stroke

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Dan-Victor V Giurgiutiu ◽  
Albert J Yoo ◽  
Kaitlin Fitzpatrick ◽  
Zeshan Chaudhry ◽  
Lee H Schwamm ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Artery Occlusion ◽  
Post Stroke ◽  
Good Functional Outcome ◽  
Grade 3 ◽  
Risk Of Hemorrhage

Background: Selecting patients most likely to benefit (MLTB) from intra-arterial therapy (IAT) is essential to assure favorable outcomes after intervention for acute ischemic stroke (AIS). Leukoaraiosis (LA) has been linked to infarct growth, risk of hemorrhage after IV rt-PA, and poor post-stroke outcomes. We investigated whether LA severity is associated with AIS outcomes after IAT. Methods: We analyzed consecutive AIS subjects from our institutional GWTG-Stroke database enrolled between 01/01/2007-06/30/2009, who met our pre-specified criteria for MLTB: CTA and MRI within 6 hours from last known well, NIHSS score ≥8, baseline DWI volume (DWIv) ≤ 100 cc, and proximal artery occlusion and were treated with IAT. LA volume (LAv) was assessed on FLAIR using validated, semi-automated protocols. We analyzed CTA to assess collateral grade; post-IAT angiogram for recanalization status (TICI score ≥2B); and the 24-hour CT for symptomatic ICH (sICH). Logistic regression was used to determine independent predictors of good functional outcome (mRS≤ 2) and mortality at 90 days post-stroke. Results: There were 48 AIS subjects in this analysis (mean age 69.2, SD±13.8; 55% male; median LAv 4cc, IQR 2.2-8.8cc; median NIHSS 15, IQR 13-19; median DWIv 15.4cc, IQR 9.2-20.3cc). Of these, 34 (72%) received IV rt-PA; 3 (6%) had sICH; 21 (44.7%) recanalized; and 23 (50%) had collateral grade ≥3. At 90 days, 15/48 (36.6%) were deceased and 15/48 had mRS≤ 2. In univariate analysis, recanalization (OR 6.2, 95%CI 1.5-25.5), NIHSS (OR 0.8 per point, 95%CI 0.64-0.95), age (OR 0.95 per yr, 95%CI 0.89-0.99) were associated with good outcome, whereas age (OR 1.1, 95%CI 1.01-1.14) and HTN (OR 5.6, 95%CI 1.04-29.8) were associated with mortality. In multivariable analysis including age, NIHSS, recanalization, collateral grade, and LAv, only recanalization independently predicted good functional outcome (OR 21.3, 95%CI 2.3-199.9) and reduced mortality (OR 0.15, 95%CI 0.02-1.12) after IAT. Conclusions: LA severity is not associated with poor outcome in patients selected MLTB for IAT. Among AIS patients considered likely to benefit from IAT, only recanalization independently predicted good functional outcome and decreased mortality.

Abstract 11: Comparison Of Various Methods Of Assessment Of Intracranial Collaterals On The Pretreatment Ct-angiograms To Predict Outcomes In Acute Anterior Circulation Ischemic Stroke

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
leonard L yeo ◽  
benjamin wakerley ◽  
Aftab Ahmad ◽  
prakash Paliwal ◽  
kay ng ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Outcome ◽  
Functional Outcomes ◽  
Treatment Time ◽  
Scoring Systems ◽  
Anterior Circulation ◽  
Unaffected Side ◽  
Computed Tomographic ◽  
Pre Treatment ◽  
Iv Tpa

Background: The presence of effective collateral blood flow patterns may influence response to intravenously administered tissue plasminogen activator (IV-tPA) in acute ischemic stroke (AIS). We compared various existing methods of scoring collaterals on the pre-treatment computed tomographic angiogram (CTA) of the brain for a reliable prediction of functional outcome in AIS patients. Methods: Consecutive AIS patients treated with IV-tPA within 4.5 hours of symptom-onset during 2007-2011 were included. Data were collected for demographics, vascular risk factors, National Institute of Health Stroke Scale (NIHSS) scores and stroke subtypes. Intracranial collaterals were evaluated by 2 independent blinded neuroradiologists via 4 predefined criteria- Miteff’s system that grades middle cerebral artery (MCA) collateral branches with respect to the sylvian fissure; Maas system that compares collaterals on the affected hemisphere against the unaffected side; modified Tan’s scale where collaterals in 50% or more of the MCA territory are classified as good; and a 20-point collateral grading scale in regions corresponding to Alberta Stroke Program Early CT score (ASPECTS) methodology. Good functional outcomes at 3-months were determined by modified Rankin scale (mRS) scores of 0-1. Results: CTA was performed in 115 patients with anterior circulation AIS before IV-tPA bolus. Median age 66yrs (range 35-92), 42% males, median NIHSS 19 points (range 3-30) and median onset-to-treatment time 155 minutes. Overall, 52 (45.2%) patients achieved good functional outcome at 3-months. Univariable analysis revealed younger age, absence of diabetes, lower pre-tPA NIHSS scores and good collaterals according to ASPECTS methodology as significantly associated with good functional outcomes. On multivariable logistic regression, only lower NIHSS (OR 1.111 per NIHSS point; 95% CI 1.023-1.206, p=0.013) and good collaterals by ASPECTS methodology (OR 1.117 per point; 95%CI 1.006-1.241, p=0.039) were found as independent predictors of good outcomes. Conclusion: Of the existing intracranial collaterals scoring systems, only the ASPECTS methodology serves as a reliable predictor of favorable outcomes at 3-months in patients with anterior circulation AIS.

A Review on Preclinical Models of Ischemic Stroke: Insights Into the Pathomechanisms and New Treatment Strategies

2021 ◽  
Vol 19 ◽  
Author(s):  
Aditya A Singh ◽  
Akash Kharwar ◽  
Manoj P. Dandekar
Keyword(s):  
Stem Cell ◽  
Ischemic Stroke ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Neurotrophic Factors ◽  
Treatment Strategies ◽  
Experimental Models ◽  
Cerebral Stroke ◽  
Post Stroke ◽  
Stroke Models

Background: Stroke is a serious neurovascular problem and the leading cause of disability and death worldwide. The disrupted demand to supply ratio of blood and glucose during cerebral ischemia develops hypoxic shock, and subsequently necrotic neuronal death in the affected regions. Multiple causal factors like age, sex, race, genetics, diet, and lifestyle play an important role in the occurrence as well as progression of post-stroke deleterious events. These biological and environmental factors may be contributed to vasculature variable architecture and abnormal neuronal activity. Since recombinant tissue plasminogen activator is the only clinically effective clot bursting drug, there is a huge unmet medical need for newer therapies for the treatment of stroke. Innumerous therapeutic interventions have shown promise in the experimental models of stroke but failed to translate it into clinical counterparts. Methods: Original publications regarding pathophysiology, preclinical experimental models, new targets and therapies targeting ischemic stroke have been reviewed since the 1970s. Results: We highlighted the critical underlying pathophysiological mechanisms of cerebral stroke and preclinical stroke models. We discuss the strengths and caveats of widely used ischemic stroke models, and commented on the potential translational problems. We also describe the new emerging treatment strategies, including stem cell therapy, neurotrophic factors and gut microbiome-based therapy for the management of post-stroke consequences. Results : We highlighted the critical underlying pathophysiological mechanisms of cerebral stroke and preclinical stroke models. We discuss the strengths and caveats of widely used ischemic stroke models, and commented on the potential translational problems. We also describe the new emerging treatment strategies, including stem cell therapy, neurotrophic factors and gut microbiome-based therapy for the management of post-stroke consequences. Conclusion: There are still many inter-linked pathophysiological alterations with regards to stroke, animal models need not necessarily mimic the same conditions of stroke pathology and newer targets and therapies are the need of the hour in stroke research.

Abstract W P29: Tissue Plasminogen Activator Mediated Reperfusion, and Subsequent Improvement in Resting State Connectivity Correlates with Functional Outcome in Acute Ischemic Stroke Patients

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Souvik Sen ◽  
Johann Fridriksson ◽  
Taylor Hanayik ◽  
Christopher Rorden ◽  
Isabel Hubbard ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Connectivity ◽  
Functional Outcome ◽  
Resting State ◽  
Network Connectivity ◽  
Stroke Patients ◽  
Post Stroke ◽  
Resting State Network ◽  
Tissue Plasminogen

Background: Intravenous Tissue Plasminogen Activator (TPA) is the only FDA approved medical therapy for acute ischemic stroke (AIS). Prior study suggests that early recanalization is associated with better stroke outcome. Our aim was to correlate task-negative and task-positive (TN/TP) resting state network activity with tissue perfusion and functional outcome, in stroke patients who received TPA. Method: AIS patients were consented and underwent NIH stroke scale (NIHSS) assessment and magnetic resonance imaging (MRI) scans during TPA infusion (baseline) and six hours post stroke. The MRI sequences include contrast-enhanced perfusion weighted image (PWI) and resting state Blood Oxygen Level-Dependent or BOLD (RSB) images acquired using a Siemens Treo 3T MRI scanner. Additionally, the RSB scan and the NIHSS were obtained at a 30-day follow up visit. Results: Fourteen patients (mean age ± SD=63 ±14, 50% male, 50% white, 43% black and 7% others) who qualified for TPA completed the study at baseline and 6 hours post stroke. Of these, 6 patients had valid follow up data at 30 days. Three patients without cerebral ischemia were excluded. A paired samples t-test comparing baseline and 6h post stroke showed a significantly improved TP network t(10)= -4.24 p< 0.05. The resting network connectivity improved from 6 hours post stroke to 30-days follow up, t(5)= -5.35 p< 0.01. Similarly, NIHSS, at 6h post stroke t(10)= 3.62 p< 0.01 and at 30-days follow up t(5)= -3.4 p< 0.01 were significantly better than the NIHSS at baseline. The 6-hours post-stroke perfusion correlated with the resting network connectivity in both the damaged (r=-0.56 p= 0.07) and intact hemispheres (r= -0.57 p= 0.06). Differences in functional connectivity and NIHSS scores from baseline to 6 h were positively correlated (r= 0.56 p=0.07). Conclusion: In this pilot study we found that TPA led to changes in MRI based resting state networks and associated functional outcome. Correlations were found between perfusion, functional connectivity and NIHSS. This suggests that the improvement of resting state network means improved efficiency of brain activity indicated by functional outcome and may be a potential predictive MRI biomarker for TPA response. A larger study is needed to verify this finding.

Abstract 3275: Early Neurological Improvement After Intravenous Thrombolysis in Acute Stroke Predicts Long-Term Functional Outcome

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Leonard L Yeo ◽  
Liang Shen ◽  
Ben Wakerley ◽  
Aftab Ahmad ◽  
Kay W Ng ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Functional Outcome ◽  
Symptom Onset ◽  
Functional Outcomes ◽  
Treatment Time ◽  
Favorable Outcome ◽  
Stroke Patients ◽  
Neurological Improvement ◽  
Iv Tpa

Background: Intravenously administered tissue plasminogen activator (IV-TPA) remains the only approved therapeutic agent for arterial recanalization in acute ischemic stroke (AIS). Wide variations in the rates and timing of neurological recovery are observed in thrombolyzed patients. While all IV-TPA treated patients are routinely evaluated for neurological recovery at 24-hours, considerable improvement occurs in some cases within 2-hours of treatment initiation. We evaluated whether early neurological improvement at 2-hours after IV-TPA bolus (ENI-2) can predict functional outcomes in thrombolyzed AIS patients at 3-months. Methods: Data for consecutive stroke patients treated with IV-TPA within 4.5 hours of symptom-onset during 2007-2010 were prospectively entered in the thrombolyzed registry maintained at our tertiary care center. Data were collected for demographic characteristics, vascular risk factors, stroke subtypes and blood pressure levels before IV-TPA bolus. National Institute of Health Stroke Scale (NIHSS) scores were obtained before IV-TPA bolus and at 2-hours. ENI-2 was defined as a reduction in NIHSS score by more than 10-points from baseline score or an absolute score of 4-points or less at 2-hours after IV-TPA bolus. Functional outcomes at 3-months were determined by modified Rankin scale (mRS). Data were analyzed by SPSS 19.0. Results: Of the 2238 AIS patients admitted during the study period, 240 (11%) received IV-TPA within 4.5-hours of symptom-onset. Median age was 65yrs (range 19-92), 63% males, median NIHSS 17points (range 3-35) and median onset-to-treatment time 149 minutes. Overall, 122 (50.8%) patients achieved favorable functional outcome (mRS 0-1) at 3-months. Factors associated with favorable outcome at 3-months on univariable analysis were younger age, female gender, presence of atrial fibrillation, baseline NIHSS, onset-to-treatment time (OTT) and ENI-2. However, multivariable analysis demonstrated NIHSS at onset (OR per 1-point increase 0.907, 95%CI 0.848-0.969) and ENI-2 (OR 4.926 95%CI 1.66-15.15) as independent predictors of favorable outcome at 3-months. Conclusion: Early Neurological improvement at 2-hours after IV-TPA bolus is a strong predictor of the functional outcome at 3-months in acute ischemic stroke patients.

Abstract WMP42: Neuro and Gliogenesis in a Nonhuman Primate Model of Ischemic Stroke with Impaired Dexterous Movements

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Gourav Choudhury ◽  
Marcel Daadi
Keyword(s):  
Stem Cell ◽  
Ischemic Stroke ◽  
Upper Extremity ◽  
Neural Stem Cell ◽  
Ischemia Reperfusion ◽  
Stroke Recovery ◽  
Fine Motor ◽  
Retrieval Task ◽  
Cell Compartment ◽  
Stem Cell Compartment

Ischemic stroke is the leading cause of upper extremity motor impairments. Well-characterized experimental stroke models for upper extremity motor impairment remain underdeveloped. Cortical representation of dexterous movements in nonhuman primates (NHP) is functionally and topographically similar to that in humans. We recently reported the characterization of an NHP model of focal ischemia reperfusion with a defined syndrome, impaired arm function and finger dexterity. In this study, we investigated the cellular changes in the neural stem cell compartment and glial cell populations in this NHP model. NHPs were subjected to transient cerebral ischemia by temporarily occluding the M3 segment of the left side middle cerebral artery (MCA). Motor and cognitive functions following the stroke were evaluated using the object retrieval task with barrier-detour. Postmortem analysis included magnetic resonance imaging (MRI) and immunohistopathology to map the infarct and characterize the neurogenic and gliogenic changes. The MCA occlusion produced significant loss of fine motor function characterized by impaired dexterity. Immunocytochemical analysis revealed significant increase of Sox2+ neural stem cells in the subventricular zone, and of GFAP+ astrocytes (P<0.0001) and Iba-1+ microglia (P<0.0001) in the infarct region. In addition, there was a 42% increase in doublecortin positive cells (P<0.0001) compared to non-ischemic hemisphere. This study describes the cellular composition of the endogenous changes in the neural stem cell compartment and in the stroke region. These data may help reveal the cellular identity mediating neural plasticity and the cellular mechanisms mediating behavioral deficits and post-stroke recovery.

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