Abstract WP291: Diabetes Impairs Long-term Functional Recovery in an Embolic Stroke Model in Sex Independent Manner

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Weiguo Li ◽  
Sherif Hafez ◽  
John Paul Valenzuela ◽  
Rebecca Ward ◽  
Guangkuo Dong ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Hemorrhagic Transformation ◽  
Cognitive Outcome ◽  
Embolic Stroke ◽  
Neurological Deficits ◽  
Independent Manner ◽  
Male And Female ◽  
The Impact

Ischemic stroke is a leading cause of death and disability. Diabetes not only increases the risk of stroke, it also worsens the outcomes, increases the risk of hemorrhagic transformation (HT) and impairs recovery after stroke. It is well established that young females are more protected and show better outcomes than males after stroke. However, the impact of diabetes on long term recovery after stroke in both sexes was not clear. Accordingly, this study tested the hypothesis that diabetes impairs long term functional recovery after ischemic stroke in a sex independent manner. Methods: Diabetes was induced in male and female Wistar rats using high fat diet and low dose streptozotocin (30 mg/Kg). After 8 weeks of diabetes, animals were subjected to embolic stroke. Male and female Wistar normoglycemic age matched rats were used as controls. Motor (composite score: 14 best outcome and adhesive removal-ART) and cognitive (novel object recognition, NOR) deficits were assessed at day1, 3, 7 and 14. Results: Female control animals had better outcomes compared to the males. Mortality was higher in diabetic animals, especially in males. The neurological deficits were greater in diabetic animals with no difference between males and females. Conclusion: Diabetes impaired functional and cognitive outcome and recovery after ischemic stroke in a sex independent manner.

Abstract WMP81: Low Dose tPA Worsens The Short Term Outcomes After Thromboembolic Stroke In Both Male And Female Diabetic Animals

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Weiguo Li ◽  
John Paul Valenzuela ◽  
Guangkuo Dong ◽  
Rebecca Ward ◽  
Susan C Fagan ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Infarct Size ◽  
Functional Outcome ◽  
Low Dose ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Diabetic Rats ◽  
Embolic Stroke ◽  
Neurological Deficits ◽  
Male And Female

Diabetes worsens stroke outcome and increases the risk of hemorrhagic transformation (HT) after ischemic stroke, especially with tPA treatment. We previously showed that low dose tPA decreased infarct size and improved functional outcome in both male and female control rats with embolic stroke. In the current study, we hypothesized that low dose tPA will also improve the functional recovery after the embolic stroke in both male and female animals with diabetes. Diabetes was induced in age matched male and female Wistar rats with high fat diet and low dose streptozotocin (30 mg/kg, i.p.). Embolic stroke was induced with middle cerebral artery occlusion. The animals were treated with or without tPA (1 mg/kg, i.v.) at 90 min after surgery. Neurological deficits (composite score and adhesive removal test-ART), infarct size, edema ratio, and HT index were assessed 3 days after surgery. The blood flow has increased in the tPA treated animals in the first 1 to 1.5 hr after treatment. The infarct size and edema was not significantly different in untreated animals, but HT was greater in female diabetic rats. The tPA treatment worsened HT in both genders with no change in infarct size. Decline in ART was worsened with tPA treatment in both sexes. Our data suggest that the low dose tPA after ischemic stroke has detrimental effects on the cerebrovascular recovery and functional outcome in both male and female animals with diabetes.

scholarly journals Impact of Post-Stroke Recanalization on General and Upper Limb Functioning: A Prospective, Observational Study

2021 ◽  
Vol 13 (1) ◽  
pp. 46-58
Author(s):  
João Paulo Branco ◽  
Filipa Rocha ◽  
João Sargento-Freitas ◽  
Gustavo C. Santo ◽  
António Freire ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Observational Study ◽  
Acute Ischemic Stroke ◽  
Upper Limb ◽  
Functional Recovery ◽  
Prospective Observational Study ◽  
Positive Impact ◽  
Rehabilitation Program ◽  
Patient Functioning ◽  
The Impact

The objective of this study is to assess the impact of recanalization (spontaneous and therapeutic) on upper limb functioning and general patient functioning after stroke. This is a prospective, observational study of patients hospitalized due to acute ischemic stroke in the territory of the middle cerebral artery (n = 98). Patients completed a comprehensive rehabilitation program and were followed-up for 24 weeks. The impact of recanalization on patient functioning was evaluated using the modified Rankin Scale (mRS) and Stroke Upper Limb Capacity Scale (SULCS). General and upper limb functioning improved markedly in the first three weeks after stroke. Age, gender, and National Institutes of Health Stroke Scale (NIHSS) score at admission were associated with general and upper limb functioning at 12 weeks. Successful recanalization was associated with better functioning. Among patients who underwent therapeutic recanalization, NIHSS scores ≥16.5 indicate lower general functioning at 12 weeks (sensibility = 72.4%; specificity = 78.6%) and NIHSS scores ≥13.5 indicate no hand functioning at 12 weeks (sensibility = 83.8%; specificity = 76.5%). Recanalization, either spontaneous or therapeutic, has a positive impact on patient functioning after acute ischemic stroke. Functional recovery occurs mostly within the first 12 weeks after stroke, with greater functional gains among patients with successful recanalization. Higher NIHSS scores at admission are associated with worse functional recovery.

Abstract 90: Diabetes Impairs Post-stroke Cerebrovascular Plasticity And Long-term Functional Recovery.

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Roshini Prakash ◽  
Weiguo Li ◽  
Zhi Qu ◽  
Susan C Fagan ◽  
Adviye Ergul
Keyword(s):  
Cognitive Decline ◽  
Reperfusion Injury ◽  
Functional Recovery ◽  
Diabetic Rats ◽  
Neurological Deficits ◽  
Ischemic Reperfusion Injury ◽  
Post Stroke ◽  
Ischemic Reperfusion ◽  
Sensorimotor Recovery ◽  
The Impact

Background: Stroke associated with pre-existing diabetes worsens ischemic injury and impairs recovery. We have previously shown that type-2-diabetic rats subjected to cerebral ischemic reperfusion injury develop hemorrhagic transformation (HT) and greater neurological deficits. These diabetic rats also exhibit enhanced dysfunctional cerebral neovascularization that increases the risk of bleeding post-stroke. However, our knowledge of vascular and functional plasticity during the recovery phase of diabetic stroke is limited. This study tested the hypothesis that post-stroke neovascularization is impaired in diabetes and this is associated with poor sensorimotor and cognitive outcomes. Methods: Reparative neovascularization was assessed in the lesional and non-lesional areas in diabetic rats after 14 days of ischemic reperfusion injury. 3-dimensional reconstruction of the FITC stained vasculature were obtained by confocal microscopy and stereological parameters including vascular volume and surface area were measured. Astrogliosis was also determined by GFAP staining. The relative rates of sensorimotor recovery, cognitive decline and spontaneous activity were assessed. Results: Diabetes impairs reparative neovascularization in the lesional areas compared to control rats. Astroglial swelling and reactivity was pronounced in diabetic stroke compared to control stroke. Rate of sensorimotor recovery was significantly slower in diabetic stroke compared to the controls. Diabetes also exacerbated anxiety-like symptoms and cognitive decline post-stroke relative to control. Conclusion: Diabetes impairs post-stroke reparative neovascularization and impedes functional recovery. The impact of glycemic control on poor recovery in this critical period needs to be tested. N=6-8 * p≤ 0.05, ** p≤ 0.005

scholarly journals Long-term decreased cannabinoid type-1 receptor activity restores specific neurological phenotypes in the Ts65Dn mouse model of Down syndrome

2021 ◽  
Author(s):  
Anna Vazquez-Oliver ◽  
Silvia Perez-Garcia ◽  
Nieves Pizarro ◽  
Laura Molina-Porcel ◽  
Rafael de la Torre ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Side Effects ◽  
Mouse Model ◽  
Neurological Deficits ◽  
Wild Type ◽  
Male And Female ◽  
Cannabinoid Type 1 Receptor ◽  
Cognitive Improvement

Intellectual disability is the most prevalent and limiting hallmark of Down syndrome (DS), without any pharmacological treatment available. Neurodegeneration and neuroinflammation are relevant neurological features of DS reaching to early development of Alzheimer s disease. Preclinical evidence suggests that the endocannabinoid system, an important neuromodulator on cognition and neuroinflammation, could act as beneficial target in DS. Indeed, cannabinoid type-1 receptor (CB1R) activity was enhanced in the hippocampus of young-adult trisomic Ts65Dn mice, a well-characterized surrogate model of DS. In previous studies, inhibition of CB1R, was able to restore key neurological deficits in this mouse model. To determine the possible clinical relevance of this target, it is mandatory to evaluate the long-term consequences of attenuated CB1R activity and to minimize the possible side-effects associated to this mechanism. We found that CB1R expression was significantly enhanced in the hippocampus brains of aged DS subjects. Similarly, middle-aged trisomic mice showed enhanced CB1R expression. Long-term oral administration of a low dose of the CB1R specific antagonist rimonabant was administered to male and female Ts65Dn trisomic and wild-type mice from the time of weaning to 10 months, an age when signs of neurodegeneration have been described in the model. CB1R inhibition resulted in significant cognitive improvement in novel object-recognition memory in trisomic male and female mice, reaching a similar performance to that of wild-type littermates. Interestingly, this long-term rimonabant treatment modify locomotor activity, anxiety-like behavior, body weight or survival rates. Brain analysis at 10 months of age revealed noradrenergic and cholinergic neurodegeneration signs in trisomic mice that were not modified by the treatment, although the alterations in hippocampal microglia morphology shown by vehicle-treated trisomic mice was normalized in trisomic mice exposed to rimonabant. Altogether, our results demonstrate a sustained pro-cognitive effect of CB1R inhibition at doses that do not produce major side effects that could be associated to an anti-inflammatory action, suggesting a potential interest in this target of to preserve cognitive functionality in DS.

Abstract WP105: Tissue Plasminogen Activator (tPA) is Essential for Functional Recovery After Stroke by Promoting Axonal Outgrowth

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Shubei Ma
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Functional Recovery ◽  
Stroke Recovery ◽  
White Matter Integrity ◽  
Blue Staining ◽  
Tissue Plasminogen

Objectives: Stroke is the leading cause of long term neurological disability with limited therapeutic options. Human recombinant tissue plasminogen activator (tPA) is currently the only FDA approved drug for the thrombolytic treatment of ischemic stroke. Emerging evidence suggests that the effects of tPA in ischemic brain may extend beyond its thrombolytic activity. In this study, we investigated the role of tPA in long term stroke recovery. Methods: Cortical infarct was induced by distal middle cerebral artery occlusion (dMCAO) in tPA knockout (KO) and wild type (WT) mice. Sensorimotor functions were evaluated at 3-35 days after dMCAO. White matter integrity was assessed by luxol fast blue staining, immunohistochemistry for SMI-32, and diffusion tensor imaging (DTI). The neuronal tracer biotinylated dextran amine (BDA) was used to label the corticorubral tract and the corticospinal tract. For rescue experiment, tPA (2mg/kg) was delivered intranasally to tPA KO mice once a day for 14 days starting 6h after dMCAO. Results: Infarct volume was comparable between tPA KO and WT mice after dMCAO. Sensorimotor deficits after dMCAO were exacerbated in tPA KO mice than WT mice. tPA KO mice also showed more severe demyelination in post-stroke white matter and reduced axonal sprouting at 35 days after dMCAO compared to WT mice. DTI studies revealed deteriorated white matter integrity in tPA KO mice, as manifested by decreased fractional anisotropy. Intranasal delivery of tPA after dMCAO rescued the neurological phenotype shown by tPA KO mice. Conclusion: Endogenous tPA promotes white matter integrity and is essential for functional recovery after ischemic stroke. tPA may be a novel neurorestorative therapy for stroke recovery.

Abstract WP88: Volumetric Measures of Hemorrhagic Transformation After Acute Ischemic Stroke Predicts Neurological Deterioration Better Than Radiologic Classification

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Ali Hamzehloo ◽  
Atul Kumar ◽  
Laura Heitsch ◽  
Daniel Strbian ◽  
Agnieszka Slowik ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Neurological Status ◽  
Hemorrhagic Transformation ◽  
Neurological Deterioration ◽  
Receiver Operating Curve ◽  
Early Neurological Deterioration ◽  
Hemorrhage Volume ◽  
The Difference ◽  
The Impact

Introduction: Hemorrhagic transformation (HT) after acute ischemic stroke (AIS) may contribute to neurologic deterioration. The current radiologic classification of HT is qualitative and distinguishes petechial hemorrhagic infarction from parenchymal hematoma (PH-1 and PH-2). However, this grading scheme is subjective and may not accurately reflect the impact of HT on neurological status and outcome. We sought to evaluate whether the volume of hemorrhage was a better marker of deterioration. Methods: We evaluated AIS patients with follow-up CT imaging from a prospective stroke genetics study. HT seen within 36 hours of AI was classified using ECASS criteria. In addition, we outlined all confluent areas of hemorrhage to derive hemorrhage volume (HV). We calculated ΔNIHSS as the difference between baseline and 24-hour NIHSS. Early neurological deterioration (END) was defined as ΔNIHSS of -4 points or more. Association of radiologic HT grade and HV with ΔNIHSS and END were analyzed using linear regression and receiver-operating-curve testing. Results: We analyzed 948 stroke patients with median NIHSS 7 (IQR 4-14), 64% receiving tPA and ΔNIHSS +2 (IQR 0-5). 294 (31%) had HT (146 HI1, 63 HI2, 42 PH1 and 43 PH2). HT was associated with higher baseline NIHSS but not with tPA treatment or ΔNIHSS. END occurred in 113 (12%) including 46 with HT (16%) vs. 67 (10%) without HT (p=0.02). Amongst those with HT, the radiologic grade was not associated with ΔNIHSS or END (20% of PH2, 20% of PH1 vs. 15% of HI1/HI2, p=0.40). However, greater HV was associated with ΔNIHSS (adjusting for baseline NIHSS and tPA, estimate -1.5 point per 10-ml, p=0.0001) and with END (those with END had median HV 7 vs. 3-ml, p=0.001). A cut-off of 12-ml had 45% sensitivity and 90% specificity for END (AUC of 0.72). Conclusion: We demonstrated that while HT was associated with a higher risk of END, the ECASS classification alone did not distinguish those who worsened. It appears that hemorrhage volume may better predict worsening NIHSS and END with moderate sensitivity.

scholarly journals Intracranial Vertebrobasilar Calcification in Patients with Ischemic Stroke Is a Predictor of Recurrent Stroke, Vascular Disease, and Death: A Case-Control Study

2020 ◽  
Vol 17 (6) ◽  
pp. 2013
Author(s):  
Jožef Magdič ◽  
Nino Cmor ◽  
Matevž Kaube ◽  
Tanja Hojs Fabjan ◽  
Larissa Hauer ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Vascular Disease ◽  
Recurrent Stroke ◽  
Case Control ◽  
University Hospital ◽  
Stroke Recurrence ◽  
Vascular Events ◽  
Vertebrobasilar Artery ◽  
The Impact

Intracranial artery calcification can be detected on nonenhanced brain computer tomography (NECT) and is a predictor of early vascular events. Here, we assessed the impact of vertebrobasilar artery calcification (VBC) on the long-term risk for recurrent stroke and vascular events. We performed a case-control trial of all consecutive stroke patients admitted to the University Hospital of Maribor, Slovenia over a period of 14 months. VBC was defined as presence of a hyperdense area within vertebrobasilar arteries that exceeds > 90 Hounsfield units as seen on NECT. Clinical follow-up information was obtained from the hospital documentation system and mortality registry of the district and included recurrent stroke, subsequent vascular events (myocardial infarction, heart failure, peripheral arterial occlusive disease), and death. We followed a total of 448 patients for a median of 1505 days (interquartile range, IQR 188-2479). Evidence for VBC was present in 243 (54.2%) patients. Median age was 76 years, recurrent stroke occurred in 33 (7.4%), any vascular events in 71 (15.8%), and death in 276 (61.6%). VBC was associated with a higher risk of recurrent stroke (hazard ratio, HR 3.13, 95% confidence interval (CI 1.35–7.20)) and vascular events (HR 2.05, 95% CI 1.21–3.47). Advanced age, male gender, and ischemic stroke involving the entire anterior circulation raised the likelihood for death. We conclude that the presence of VBC in patients with ischemic stroke is a short- and long-term prognostic factor for stroke recurrence and subsequent manifestation of acute vascular disease. Further understanding of the pathophysiology of VBC is warranted.

IM-12 activates the Wnt–β-catenin signaling pathway and attenuates rtPA-induced hemorrhagic transformation in rats after acute ischemic stroke

2019 ◽  
Vol 97 (6) ◽  
pp. 702-708 ◽  
Author(s):  
Ting Wang ◽  
Yu-Mei Duan ◽  
Qiao Fu ◽  
Tao Liu ◽  
Jin-Cheng Yu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Signaling Pathway ◽  
Glycogen Synthase ◽  
Hemorrhagic Transformation ◽  
Neurological Deficits ◽  
Control Group ◽  
High Morbidity ◽  
Sprague Dawley ◽  
Gsk 3Β

Hemorrhagic transformation (HT) is a devastating complication for patients with acute ischemic stroke (AIS) who are treated with tissue plasminogen activator (tPA). HT is associated with high morbidity and mortality, but no effective treatments are currently available to reduce the risk of HT. Therefore, methods to prevent HT are urgently needed. In this study, we used IM-12, an inhibitor of glycogen synthase kinase 3β (GSK-3β), to evaluate the role of the Wnt–β-catenin signaling pathway in recombinant tPA (rtPA)-induced HT. Sprague–Dawley rats were subjected to a middle cerebral artery occlusion (MCAO) model of ischemic stroke, and then were either administered rtPA, rtPA combined with IM-12, or the vehicle at 4 h after stroke was induced. Our results indicate that rats subjected to HT had more severe neurological deficits, brain edema, and blood–brain barrier (BBB) breakdown, and had a greater infarction volume than the control group. Rats treated with IM-12 had improved outcomes compared with those of rats treated with rtPA alone. Moreover, IM-12 increased the protein expression of β-catenin and downstream proteins while suppressing the expression of GSK-3β. These results suggest that IM-12 reduces rtPA-induced HT and attenuates BBB disruption, possibly through activation of the Wnt–β-catenin signaling pathway, and provides a potential therapeutic strategy for preventing tPA-induced HT after AIS.

scholarly journals BMS-986020, a Specific LPA1 Antagonist, Provides Neuroprotection against Ischemic Stroke in Mice

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1097
Author(s):  
Bhakta Prasad Gaire ◽  
Arjun Sapkota ◽  
Ji Woong Choi
Keyword(s):  
Ischemic Stroke ◽  
Survival Rate ◽  
Cell Apoptosis ◽  
Functional Disability ◽  
Brain Infarction ◽  
Tissue Loss ◽  
Neurological Deficits ◽  
Neuroprotective Effects ◽  
Acute Injuries

Stroke is a leading cause of death. Stroke survivors often suffer from long-term functional disability. This study demonstrated neuroprotective effects of BMS-986020 (BMS), a selective lysophosphatidic acid receptor 1 (LPA1) antagonist under clinical trials for lung fibrosis and psoriasis, against both acute and sub-acute injuries after ischemic stroke by employing a mouse model with transient middle cerebral artery occlusion (tMCAO). BMS administration immediately after reperfusion significantly attenuated acute brain injuries including brain infarction, neurological deficits, and cell apoptosis at day 1 after tMCAO. Neuroprotective effects of BMS were preserved even when administered at 3 h after reperfusion. Neuroprotection by BMS against acute injuries was associated with attenuation of microglial activation and lipid peroxidation in post-ischemic brains. Notably, repeated BMS administration daily for 14 days after tMCAO exerted long-term neuroprotection in tMCAO-challenged mice, as evidenced by significantly attenuated neurological deficits and improved survival rate. It also attenuated brain tissue loss and cell apoptosis in post-ischemic brains. Mechanistically, it significantly enhanced neurogenesis and angiogenesis in injured brains. A single administration of BMS provided similar long-term neuroprotection except survival rate. Collectively, BMS provided neuroprotection against both acute and sub-acute injuries of ischemic stroke, indicating that BMS might be an appealing therapeutic agent to treat ischemic stroke.

Influence of tumor site on cognitive deficits in children with cerebellar tumors at diagnosis

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 9045-9045
Author(s):  
R. Riccardi ◽  
L. Peruzzi ◽  
L. Iuvone ◽  
C. Colosimo ◽  
G. Tamburrini ◽  
...  
Keyword(s):  
Executive Functions ◽  
Language Processing ◽  
Neurological Examination ◽  
Cognitive Deficits ◽  
Negative Impact ◽  
Cognitive Outcome ◽  
Neurological Deficits ◽  
Cerebellar Hemisphere ◽  
Cerebellar Tumor ◽  
The Impact

9045 Background: Children with cerebellar tumor are at risk for cognitive deficits (CD) depending on surgery and radiotherapy. Only few studies analyze the role of tumor itself in mental functioning (Ellenberg et al., ‘87). Data about neuropsychological organization before any treatment are essential to understand the effect of tumor and have a baseline for analyzing the negative impact of the different treatments in the CD. Aim of this study is to prospectively analyze cognitive functions before treatment in patients (pts) with cerebellar tumors. Methods: Twenty-five pts with cerebellar tumor were assessed at diagnosis.Children with previous and severe neurological disturbances neurological were excluded. Intelligence quotient (IQ) and sectorial cognitive abilities (memory, attention, language, visuospatial and executive functions) were evaluated. Neurological examination (BUSPAR) and magnetic resonance imaging (MRI) were performed in the same period of cognitive assessment. Neurological deficits were classified as major, mild or absent in relation with the results of BUSPAR. Results: Twenty pts were selected; males/females: 12/8; age: 7.6 years (range: 18 m-14.8 y); histhology: pilocytic astrocytoma (9 pts), medulloblastoma (9), ependymoma (1) and atypical teratoid-rabdoid (1); tumor location: right cerebellar hemisphere (4), left (4), vermal (12); neurological examination: major neurological signs (2 pts), mild (10), absent (6); hydrocephalus: 50% of pts. Three pts had IQ values below the average level, although mean IQ values were normal (mean: 99.6; range: 78–118). Sixteen/20 pts had selective CD mainly involving working memory, executive functions, attention, and visual motor integration. Language processing was defective in 6 pts (2/4 right-sides lesions, 4/12 vermal lesion). Conclusions: Sectorial CD are present before treatment in about 80% of pts, mainly related to the location of tumor. Preliminar data suggest a correlation between specific sites inside cerebellum and selective CD, with language problems mainly in right hemispheric tumor. Complex cognitive impairment was present in 15% of pts before treatment. These data will represent the baseline for further analysis about the impact of treatment on cognitive outcome. No significant financial relationships to disclose.

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