Professor Neil Spratt

© 2018 Elsevier B.V. Triheptanoin, the medium-chain triglyceride of heptanoate, has been shown to be anticonvulsant and neuroprotective in several neurological disorders. In the gastrointestinal tract, triheptanoin is cleaved to heptanoate, which is then taken up by the blood and most tissues, including liver, heart and brain. Here we evaluated the neuroprotective effects of heptanoate and its effects on mitochondrial oxygen consumption in vitro. We also investigated the neuroprotective effects of triheptanoin compared to long-chain triglycerides when administered after stroke onset in rats. Heptanoate pre-treatment protected cultured neurons against cell death induced by oxygen glucose deprivation and N-methyl-D-aspartate. Incubation of cultured astrocytes with heptanoate for 2 h increased mitochondrial proton leak and also enhanced basal respiration and ATP turnover, suggesting that heptanoate protects against oxidative stress and is used as fuel. However, continuous 72 h infusion of triheptanoin initiated 1 h after middle cerebral artery occlusion in rats did not alter stroke volume at 3 days or neurological deficit at 1 and 3 days relative to long-chain triglyceride control treatment.

© 2017 - IOS Press and the authors. The already established and widely used intravenous application of recombinant tissue plasminogen activator as a re-opening strategy for acute vessel occlusion in ischemic stroke was recently added by mechanical thrombectomy, representing a fundamental progress in evidence-based medicine to improve the patient's outcome. This has been paralleled by a swift increase in our understanding of pathomechanisms underlying many neurovascular diseases and most prevalent forms of dementia. Taken together, these current advances offer the potential to overcome almost two decades of marginally successful translational research on stroke and dementia, thereby spurring the entire field of translational neuroscience. Moreover, they may also pave the way for the renaissance of classical neuroprotective paradigms. This review reports and summarizes some of the most interesting and promising recent achievements in neurovascular and dementia research. It highlights sessions from the 9th International Symposium on Neuroprotection and Neurorepair that have been discussed from April 19th to 22nd in Leipzig, Germany. To acknowledge the emerging culture of interdisciplinary collaboration and research, special emphasis is given on translational stories ranging from fundamental research on neurode- and -regeneration to late stage translational or early stage clinical investigations.

© 2017 Elsevier Ltd Ischaemia/excitotoxicity produces persistent activation of CaMKII (Ca2+-calmodulin stimulated protein kinase II) that initiates cell death. This study investigated the involvement of CaMKII phosphorylation at T286 and T253 in producing this persistent activation. In T286A-aCaMKII transgenic mice that lack the ability to phosphorylate aCaMKII at T286, transient occlusion of the middle cerebral artery for 90¿min resulted in no significant difference in infarct size compared to normal littermate controls. Overexpression of the phospho-mimic mutant T286D-aCaMKII in differentiated neuroblastoma cell lines did not enhance excitotoxicity-induced cell death compared to overexpression of wild type aCaMKII. By contrast, overexpression of the phospho-mimic mutant T253D-aCaMKII significantly enhanced excitotoxicity-induced cell death whereas overexpression of the phospho-null mutant T253V-aCaMKII produced no enhancement. These results indicate that T286 phosphorylation does not play a significant role in ischaemia/excitotoxicity induced CaMKII-mediated cell death and suggest that T253 phosphorylation is required to produce the persistent activation of CaMKII involved in ischaemia/excitotoxicity induced cell death.

© 2016 Telestroke services have been shown to increase stroke therapy access in rural areas. The implementation of advanced CT imaging for patient assessment may improve patient selection and detection of stroke mimics in conjunction with telestroke. We implemented a telestroke service supported by multimodal CT imaging in a rural hospital in Australia. Over 21¿months we conducted an evaluation of service activation, thrombolysis rates and use of multimodal imaging to assess the feasibility of the service. Rates of symptomatic intracranial haemorrhage and 90-day modified Rankin Score were used as safety outcomes. Fifty-eight patients were assessed using telestroke, of which 41 were regarded to be acute ischemic strokes and 17 to be stroke mimics on clinical grounds. Of the 41 acute stroke patients, 22 patients were deemed eligible for thrombolysis. Using multimodal CT imaging, 8 more patients were excluded from treatment because of lack of treatment target. Multimodal imaging failed to be obtained in one patient. For the 14 treated patients, median door-imaging time was 38¿min. Median door-treatment time was 91¿min. A 90-day mRS ¿2 was achieved in 40% of treated patients. We conclude that a telestroke service using advanced CT imaging for therapy decision assistance can be successfully implemented in regional Australia and can be used to guide acute stroke treatment decision-making and improve access to thrombolytic therapy. Efficiency and safety is comparable to established telestroke services.

© 2017 Informa UK Limited, trading as Taylor & Francis Group Purpose: Boredom may impede engagement in inpatient rehabilitation following an acquired brain injury. This review aimed to: (1) describe the experience and (2) quantify the incidence of boredom; (3) identify measurement tools used to quantify boredom; (4) summarize factors contributing to boredom, and (5) outline evidence-based interventions shown to reduce boredom during inpatient rehabilitation. Methods: Two researchers independently screened publications retrieved from electronic database searches. Publications presenting patient, carer or staff data relating to boredom in inpatients with acquired brain injuries were included. Results: Two thousand four hundred and ninety-nine references were retrieved, 88 full texts were reviewed, with 24 studies included. The majority of studies reported qualitative data indicating boredom to be a common experience of patients with acquired brain injuries (n¿=¿14 studies +1 review). The incidence of boredom post acquired brain injury is unknown. Personal and organizational factors and the physical environment may contribute to boredom (n¿=¿11 studies +2 reviews). Qualitative work (n¿=¿9 studies) indicates that use of the creative-arts or exposure to environmental enrichment may help alleviate boredom in patients with acquired brain injuries during inpatient rehabilitation. Conclusion: Further mixed-methods research is required to establish the incidence of and contributing factors to boredom in patients with acquired brain injuries undergoing rehabilitation. Understanding this will help inform future research aimed at improving patient engagement in inpatient rehabilitation.Implications for rehabilitationBoredom is commonly reported by hospitalised patients with ABI to negatively affect their rehabilitation yet the scope of the problem has not been measured.Boredom is a complex phenomenon, likely influenced by a number of personal and environmental factors that are not fully understood in this population.Through a better understanding of boredom, interventions may be developed to improve patient engagement in inpatient rehabilitation programs.

© 2017 American Academy of Neurology. Objective: To test whether patients with complete vessel occlusion show greater recanalization at 24 hours and have improved clinical outcomes at 24 hours and 90 days when treated with tenecteplase compared to alteplase. Methods: Pooled clinical and imaging data from 2 phase 2 randomized trials comparing tenecteplase with alteplase allowed CT angiography (CTA) scans to be assessed centrally for occlusion status at baseline and at 24 hours post thrombolysis using the modified thrombolysis in cerebral infarction (TICI) scale. Twenty-four-hour poststroke NIH Stroke Scale (NIHSS) and 90-day modified Rankin Scale (mRS) scores were also compared between treatment groups using linear regression to generate odds ratios (ORs). Results: From 146 pooled patients, 69 had a TICI 0/1 occlusion overall at baseline. Tenecteplase-treated patients with a complete vessel occlusion had greater complete recanalization rates at 24 hours (71% for tenecteplase vs 43% for alteplase, p < 0.001). Patients with a TICI 0/1 occlusion who were treated with tenecteplase also showed greater early clinical improvement (median NIHSS change with tenecteplase was 9, interquartile range [IQR] 6, alteplase 1, IQR 1, p = 0.001) and higher rates of favorable 90-day outcomes (mRS 0-1 of tenecteplase compared with alteplase, OR 4.82, 95% confidence interval 1.02-7.84, p = 0.05). Conclusions: Tenecteplase may offer greater recanalization efficacy compared to alteplase, possibly exaggerated in patients with complete vessel occlusions on baseline CTA.

© Cambridge University Press 2017. Background Survival into adult life in patients with aortic coarctation is typical following surgical and catheter-based techniques to relieve obstruction. Late sequelae are recognised, including stroke, hypertension, and intracerebral aneurysm formation, with the underlying mechanisms being unclear. We hypothesised that patients with a history of aortic coarctation may have abnormalities of cerebral blood flow compared with controls. Methods Patients with a history of aortic coarctation underwent assessment of cerebral vascular function. Vascular responsiveness of intracranial vessels to hypercapnia and degree of cerebral artery stiffness using Doppler-derived pulsatility indices were used. Response to photic stimuli was used to assess neurovascular coupling, which reflects endothelial function in response to neuronal activation. Patient results were compared with age- and sex-matched controls. Results A total of 13 adult patients (males=10; 77%) along with 13 controls underwent evaluation. The mean age was 36.1±3.7 years in the patient group. Patients with a background of aortic coarctation were noted to have increased pulse pressure on blood pressure assessment at baseline with increased intracranial artery stiffness compared with controls. Patients with a history of aortic coarctation had less reactive cerebral vasculature to hypercapnic stimuli and impaired neurovascular coupling compared with controls. Results Adult patients with aortic coarctation had increased intracranial artery stiffness compared with controls, in addition to cerebral vasculature showing less responsiveness to hypercapnic and photic stimuli. Further studies are required to assess the aetiology and consequences of these documented abnormalities in cerebral blood flow in terms of stroke risk, cerebral aneurysm formation, and cognitive dysfunction.

© 2017 American Heart Association, Inc. Background and Purpose - Advanced imaging to identify tissue pathophysiology may provide more accurate prognostication than the clinical measures used currently in stroke. This study aimed to derive and validate a predictive model for functional outcome based on acute clinical and advanced imaging measures. Methods - A database of prospectively collected sub-4.5 hour patients with ischemic stroke being assessed for thrombolysis from 5 centers who had computed tomographic perfusion and computed tomographic angiography before a treatment decision was assessed. Individual variable cut points were derived from a classification and regression tree analysis. The optimal cut points for each assessment variable were then used in a backward logic regression to predict modified Rankin scale (MRS) score of 0 to 1 and 5 to 6. The variables remaining in the models were then assessed using a receiver operating characteristic curve analysis. Results - Overall, 1519 patients were included in the study, 635 in the derivation cohort and 884 in the validation cohort. The model was highly accurate at predicting MRS score of 0 to 1 in all patients considered for thrombolysis therapy (area under the curve [AUC] 0.91), those who were treated (AUC 0.88) and those with recanalization (AUC 0.89). Next, the model was highly accurate at predicting MRS score of 5 to 6 in all patients considered for thrombolysis therapy (AUC 0.91), those who were treated (0.89) and those with recanalization (AUC 0.91). The odds ratio of thrombolysed patients who met the model criteria achieving MRS score of 0 to 1 was 17.89 (4.59-36.35, P<0.001) and for MRS score of 5 to 6 was 8.23 (2.57-26.97, P<0.001). Conclusions - This study has derived and validated a highly accurate model at predicting patient outcome after ischemic stroke.

© 2017 National Stroke Association Background Patients with acute ischemic stroke and large vessel occlusion (LVO) may benefit from prehospital identification and transfer to a center offering endovascular therapy. Aims We aimed to assess the accuracy of an existing 8-item stroke scale (National Institutes of Health Stroke Scale-8 [NIHSS-8]) for identification of patients with acute stroke with LVO. Methods We retrospectively calculated NIHSS-8 scores in a population of consecutive patients with presumed acute stroke assessed by emergency medical services (EMS). LVO was identified on admission computed tomography angiography. Accuracy to identify LVO was calculated using receiver operating characteristics analysis. We used weighted Cohen's kappa statistics to assess inter-rater reliability for the NIHSS-8 score between the EMS and the hospital stroke team on a prospectively evaluated subgroup. Results Of the 551 included patients, 381 had a confirmed ischemic stroke and 136 patients had an LVO. NIHSS scores were significantly higher in patients with LVO (median 18; interquartile range 14-22). The NIHSS-8 score reliably predicted the presence of LVO (area under the receiver operating characteristic curve.82). The optimum NIHSS-8 cutoff of 8 or more had a sensitivity of.81, specificity of.75, and Youden index of.56 for prediction of LVO. The EMS and the stroke team reached substantial agreement (¿ =.69). Conclusions Accuracy of the NIHSS-8 to identify LVO in a population of patients with suspected acute stroke is comparable to existing prehospital stroke scales. The scale can be performed by EMS with reasonable reliability. Further validation in the field is needed to assess accuracy of the scale to identify patients with LVO eligible for endovascular treatment in a prehospital setting.

© MA Healthcare Ltd. Aims: To determine if community-dwelling stroke survivors can achieve exercise intensities sufficient to improve cardiorespiratory fitness during a single session of circuit training using an interval training approach. Methods: Thirteen independently ambulant participants within 1 year of stroke were included in this observational study (females=54%; median age=65.6 years; interquartile range=23.9). Exercise intensities were assessed throughout an individually tailored circuit of up to seven 5-minute workstations from a selection of nine functional (e.g. walking, stairs, balance) and three ergometer (upright cycle, rower, treadmill) workstations. The interval durations ranged from 5¿60 seconds. Oxygen consumption (VO2) was recorded continuously using a portable metabolic system. The average VO2during each 30-second epoch was determined. VO2=10.5 mL/kg/min was categorised as =moderate intensity. Findings: Participants exercised at VO2=10.5 mL/kg/min for the majority of the time on the workstations [functional: 369/472 epochs (78%), ergometer: 170/204 epochs (83%)]. Most (69%) participants exercised for =30 minutes. No serious adverse events occurred. Conclusions: Applying interval training principles to a circuit of functional and ergometer workstations enabled ambulant participants to exercise at an intensity and for a duration that can improve cardiorespiratory fitness. The training approach appears feasible, safe and a promising way to incorporate both cardiorespiratory fitness and functional training into post-stroke management.

© 2016 Elsevier Ltd. All rights reserved. Although a wide range of strategies have been established to improve intravenous tissue plasminogen activator (IV-tPA) treatment rates, international benchmarking has not been regularly used as a systems improvement tool. We compared acute stroke codes (ASC) between two hospitals in Australia and Japan to study the activation process and potentially improve the implementation of thrombolysis. Consecutive patients who were admitted to each hospital via ASC were prospectively collected. We compared IV-tPA rates, factors contributing to exclusion from IV-tPA, and pre- and in-hospital process of care. IV-tPA treatment rates were significantly higher in the Australian hospital than in the Japanese (41% versus 25% of acute ischaemic stroke patients, p = 0.0016). In both hospitals, reasons for exclusion from IV-tPA treatment were intracerebral haemorrhage, mild symptoms, and stroke mimic. Patients with baseline National Institutes of Health Stroke Scale score =5 were more likely to be excluded from IV-tPA in the Japanese hospital. Of patients treated with IV-tPA, the door-to-needle time (median, 63 versus 54 minutes, p = 0.0355) and imaging-to-needle time (34 versus 27 minutes, p = 0.0220) were longer in the Australian hospital. Through international benchmarking using cohorts captured under ASC, significant differences were noted in rates of IV-tPA treatment and workflow speed. This variation highlights opportunity to improve and areas to focus targeted practice improvement strategies.

© 2016 John Wiley & Sons Ltd. Introduction: Presence of white matter hyperintensity (WMH) on MRI is a marker of cerebral small vessel disease and is associated with increased small vessel stroke and increased risk of hemorrhagic transformation (HT) after thrombolysis. Aim: We sought to determine whether white matter hypoperfusion (WMHP) on perfusion CT (CTP) was related to WMH, and if WMHP predisposed to acute lacunar stroke subtype and HT after thrombolysis. Methods: Acute ischemic stroke patients within 12 h of symptom onset at 2 centers were prospectively recruited between 2011 and 2013 for the International Stroke Perfusion Imaging Registry. Participants routinely underwent baseline CT imaging, including CTP, and follow-up imaging with MRI at 24 h. Results: Of 229 ischemic stroke patients, 108 were Caucasians and 121 Chinese. In the contralateral white matter, patients with acute lacunar stroke had lower cerebral blood flow (CBF) and cerebral blood volume (CBV), compared to those with other stroke subtypes (P = 0.041). There were 46 patients with HT, and WMHP was associated with increased risk of HT (R2= 0.417, P = 0.002). Compared to previously reported predictors of HT, WMHP performed better than infarct core volume (R2= 0.341, P = 0.034), very low CBV volume (R2= 0.249, P = 0.026), and severely delayed perfusion (Tmax>14 second R2= 0.372, P = 0.011). Patients with WMHP also had larger acute infarcts and increased infarct growth compared to those without WMHP (mean 28 mL vs. 13 mL P < 0.001). Conclusion: White matter hypoperfusion remote to the acutely ischemic region on CTP is a marker of small vessel disease and was associated with increased HT, larger acute infarct cores, and greater infarct growth.

© 2016 Schleicher et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background: Early recanalization of large cerebral vessels in ischemic stroke is associated with improved clinical outcome, however persisting hypoperfusion leads to poor clinical recovery despite large vessel recanalization. Limited experimental sonothrombolysis studies have shown that addition of microbubbles during treatment can improve microvascular patency. We aimed to determine the effect of two different microbubble formulations on microvascular patency in a rat stroke model. Methods: We tested BR38 and SonoVue® microbubble-enhanced sonothrombolysis in Wistar rats submitted to 90-minute filament occlusion of the middle cerebral artery. Rats were randomized to treatment (n = 6/group): control, rt-PA, or rt-PA+3-MHz ultrasound insonation with BR38 or SonoVue® at full or 1/3 dose. Treatment duration was 60 minutes, beginning after withdrawal of the filament, and sacrifice was immediately after treatment. Vascular volumes were evaluated with microcomputed tomography. Results: Total vascular volume of the ipsilateral hemisphere was reduced in control and rt-PA groups (p<0.05), but was not significantly different from the contralateral hemisphere in all microbubble-treated groups (p>0.1). Conclusions: Microbubble-enhanced sonothrombolysis improves microvascular patency. This effect is not dose- or microbubble formulation-dependent suggesting a class effect of microbubbles promoting microvascular reopening. This study demonstrates that microbubble-enhanced sonothrombolysis may be a therapeutic strategy for patients with persistent hypoperfusion of the ischemic territory.

© 2016 National Stroke Association Background The cardiorespiratory fitness of stroke survivors is low. Center-based exercise programs that include an aerobic component have been shown to improve poststroke cardiorespiratory fitness. This pilot study aims to determine the feasibility, safety, and preliminary efficacy of an individually tailored home- and community-based exercise program to improve cardiorespiratory fitness and walking capacity in stroke survivors. Methods Independently ambulant, community-dwelling stroke survivors were recruited. The control (n¿=¿10) and intervention (n¿=¿10) groups both received usual care. In addition the intervention group undertook a 12-week, individually tailored, home- and community-based exercise program, including once-weekly telephone or e-mail support. Assessments were conducted at baseline and at 12 weeks. Feasibility was determined by retention and program participation, and safety by adverse events. Efficacy measures included change in cardiorespiratory fitness (peak oxygen consumption [VO2peak]) and distance walked during the Six-Minute Walk Test (6MWT). Analysis of covariance was used for data analysis. Results All participants completed the study with no adverse events. All intervention participants reported undertaking their prescribed program. VO2peakimproved more in the intervention group (1.17¿±¿.29¿L/min to 1.35¿±¿.33¿L/min) than the control group (1.24¿±¿.23¿L/min to 1.24¿±¿.33¿L/min, between-group difference¿=¿.18¿L/min, 95% confidence interval [CI]:.01-.36). Distance walked improved more in the intervention group (427¿±¿123¿m to 494¿±¿67m) compared to the control group (456¿±¿101m to 470¿±¿106m, between-group difference¿=¿45¿m, 95% CI:.3-90). Conclusions Our individually tailored approach with once-weekly telephone or e-mail support was feasible and effective in selected stroke survivors. The 16% greater improvement in VO2peakduring the 6MWT achieved in the intervention versus control group is comparable to improvements attained in supervised, center-based programs.

© 2016 The Authors. Background: The kidney-brain interaction has been a topic of growing interest. Past studies of the effect of kidney function on intracerebral hemorrhage (ICH) outcomes have yielded inconsistent findings. Although the second, main phase of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2) suggests the effectiveness of early intensive blood pressure (BP) lowering in improving functional recovery after ICH, the balance of potential benefits and harms of this treatment in those with decreased kidney function remains uncertain. Study Design: Secondary analysis of INTERACT2, which randomly assigned patients with ICH with elevated systolic BP (SBP) to intensive (target SBP < 140 mm Hg) or contemporaneous guideline-based (target SBP < 180 mm Hg) BP management. Setting & Participants: 2,823 patients from 144 clinical hospitals in 21 countries. Predictors Admission estimated glomerular filtration rates (eGFRs) of patients were categorized into 3 groups based on the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation: normal or high, mildly decreased, and moderately to severely decreased (>90, 60-90, and <60 mL/min/1.73 m2, respectively). Outcomes: The effect of admission eGFR on the primary outcome of death or major disability at 90 days (defined as modified Rankin Scale scores of 3-6) was analyzed using a multivariable logistic regression model. Potential effect modification of intensive BP lowering treatment by admission eGFR was assessed by interaction terms. Results: Of 2,623 included participants, 912 (35%) and 280 (11%) had mildly and moderately/severely decreased eGFRs, respectively. Patients with moderately/severely decreased eGFRs had the greatest risk for death or major disability at 90 days (adjusted OR, 1.82; 95% CI, 1.28-2.61). Effects of early intensive BP lowering were consistent across different eGFRs (P = 0.5 for homogeneity). Limitations: Generalizability issues arising from a clinical trial population. Conclusions: Decreased eGFR predicts poor outcome in acute ICH. Early intensive BP lowering provides similar treatment effects in patients with ICH with decreased eGFRs.

© 2015 American Heart Association, Inc. Background and Purpose-Collateral circulation is recognized to influence the life expectancy of the ischemic penumbra in acute ischemic stroke. The best method to quantify collateral status on acute imaging is uncertain. We aimed to determine the relationship between visual collateral status, quantitative collateral assessments, baseline computed tomographic perfusion measures, and tissue outcomes on follow-up imaging. Methods-Sixty-six consecutive patients with acute ischemic stroke clinically eligible for recanalization therapy and with M1 or M2 middle cerebral artery occlusion were evaluated. We compared the visual collateral scoring with measures of contrast peak time delay and contrast peak density. We also compared these measures for their ability to predict perfusion lesion and infarct core volumes, final infarct, and infarct growth. Results-Shorter contrast peak time delay (P=0.041) and higher contrast peak density (P=0.002) were associated with good collateral status. Shorter contrast peak time delay correlated with higher contrast peak density (ß=-4.413; P=0.037). In logistic regression analysis after adjustment for age, sex, onset-computed tomographic time, and occlusion site, higher contrast peak density was independently associated with good collateral status (P=0.009). Multiple regression analysis showed that higher contrast peak density was an independent predictor of smaller perfusion lesion volume (P=0.029), smaller ischemic core volume (P=0.044), smaller follow-up infarct volume (P=0.005), and smaller infarct growth volume (P=0.010). Conclusions-Visual collateral status, contrast peak density, and contrast peak time delay were inter-related, and good collateral status was strongly associated with contrast peak density. Contrast peak density in collateral vessel may be an important factor in tissue fate in acute ischemic stroke.

© 2016, Springer-Verlag Berlin Heidelberg. Introduction: We aimed to assess metabolite profiles in peri-infarct tissue with magnetic resonance spectroscopy (MRS) and correlate these with early and late clinical recovery. Methods: One hundred ten anterior circulation ischemic stroke patients presenting to hospital within 4.5¿h of symptom onset and treated with intravenous thrombolysis were studied. Patients underwent computer tomography perfusion (CTP) scanning and subsequently 3-T magnetic resonance imaging (MRI) 24¿h after stroke onset, including single-voxel, short-echo-time (30¿ms) MRS, and diffusion- and perfusion-weighted imaging (DWI and PWI). MRS voxels were placed in the peri-infarct region in reperfused penumbral tissue. A control voxel was placed in the contralateral homologous area. Results: The concentrations of total creatine (5.39 vs 5.85¿mM, p = 0.044) and N-acetylaspartic acid (NAA, 6.34 vs 7.13¿mM ± 1.57, p < 0.001) were reduced in peri-infarct tissue compared to the matching contralateral region. Baseline National Institutes of Health Stroke Score was correlated with glutamate concentration in the reperfused penumbra at 24¿h (r2= 0.167, p = 0.017). Higher total creatine was associated with better neurological outcome at 24¿h (r2= 0.242, p = 0.004). Lower peri-infarct glutamate was a stronger predictor of worse 3-month clinical outcome (area under the curve (AUC) 0.89, p < 0.001) than DWI volume (AUC = 0.79, p < 0.001). Conclusion: Decreased glutamate, creatine, and NAA concentrations are associated with poor neurological outcome at 24¿h and greater disability at 3¿months. The significant metabolic variation in salvaged tissue may potentially explain some of the variability seen in stroke recovery despite apparently successful reperfusion.

© 2015 ISCBFM All rights reserved. In both the human and animal literature, it has largely been assumed that edema is the primary cause of intracranial pressure (ICP) elevation after stroke and that more edema equates to higher ICP. We recently demonstrated a dramatic ICP elevation 24 hours after small ischemic strokes in rats, with minimal edema. This ICP elevation was completely prevented by short-duration moderate hypothermia soon after stroke. Here, our aims were to determine the importance of edema in ICP elevation after stroke and whether mild hypothermia could prevent the ICP rise. Experimental stroke was performed in rats. ICP was monitored and short-duration mild (35 °C) or moderate (32.5 °C) hypothermia, or normothermia (37 °C) was induced after stroke onset. Edema was measured in three studies, using wet-dry weight calculations, T 2-weighted magnetic resonance imaging, or histology. ICP increased 24 hours after stroke onset in all normothermic animals. Short-duration mild or moderate hypothermia prevented this rise. No correlation was seen between ¿ICP and edema or infarct volumes. Calculated rates of edema growth were orders of magnitude less than normal cerebrospinal fluid production rates. These data challenge current concepts and suggest that factors other than cerebral edema are the primary cause of the ICP elevation 24 hours after stroke onset.

Copyright © 2015 Massachusetts Medical Society. Background: Trials of endovascular therapy for ischemic stroke have produced variable results. We conducted this study to test whether more advanced imaging selection, recently developed devices, and earlier intervention improve outcomes. Methods: We randomly assigned patients with ischemic stroke who were receiving 0.9 mg of alteplase per kilogram of body weight less than 4.5 hours after the onset of ischemic stroke either to undergo endovascular thrombectomy with the Solitaire FR (Flow Restoration) stent retriever or to continue receiving alteplase alone. All the patients had occlusion of the internal carotid or middle cerebral artery and evidence of salvageable brain tissue and ischemic core of less than 70 ml on computed tomographic (CT) perfusion imaging. The coprimary outcomes were reperfusion at 24 hours and early neurologic improvement (.8-point reduction on the National Institutes of Health Stroke Scale or a score of 0 or 1 at day 3). Secondary outcomes included the functional score on the modified Rankin scale at 90 days. Results: The trial was stopped early because of efficacy after 70 patients had undergone randomization (35 patients in each group). The percentage of ischemic territory that had undergone reperfusion at 24 hours was greater in the endovascular-therapy group than in the alteplase-only group (median, 100% vs. 37%; P<0.001). Endovascular therapy, initiated at a median of 210 minutes after the onset of stroke, increased early neurologic improvement at 3 days (80% vs. 37%, P = 0.002) and improved the functional outcome at 90 days, with more patients achieving functional independence (score of 0 to 2 on the modified Rankin scale, 71% vs. 40%; P = 0.01). There were no significant differences in rates of death or symptomatic intracerebral hemorrhage. Conclusions: In patients with ischemic stroke with a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging, early thrombectomy with the Solitaire FR stent retriever, as compared with alteplase alone, improved reperfusion, early neurologic recovery, and functional outcome. (Funded by the Australian National Health and Medical Research Council and others; EXTEND-IA ClinicalTrials.gov number, NCT01492725, and Australian New Zealand Clinical Trials Registry number, ACTRN12611000969965.)

© 2015 ISCBFM. Recent human imaging studies indicate that reduced blood flow through pial collateral vessels ('collateral failure') is associated with late infarct expansion despite stable arterial occlusion. The cause for 'collateral failure' is unknown. We recently showed that intracranial pressure (ICP) rises dramatically but transiently 24 hours after even minor experimental stroke. We hypothesized that ICP elevation would reduce collateral blood flow. First, we investigated the regulation of flow through collateral vessels and the penetrating arterioles arising from them during stroke reperfusion. Wistar rats were subjected to intraluminal middle cerebral artery (MCA) occlusion (MCAo). Individual pial collateral and associated penetrating arteriole blood flow was quantified using fluorescent microspheres. Baseline bidirectional flow changed to MCA-directed flow and increased by >450% immediately after MCAo. Collateral diameter changed minimally. Second, we determined the effect of ICP elevation on collateral and watershed penetrating arteriole flow. Intracranial pressure was artificially raised in stepwise increments during MCAo. The ICP increase was strongly correlated with collateral and penetrating arteriole flow reductions. Changes in collateral flow post-stroke appear to be primarily driven by the pressure drop across the collateral vessel, not vessel diameter. The ICP elevation reduces cerebral perfusion pressure and collateral flow, and is the possible explanation for 'collateral failure' in stroke-in-progression.

© 2014 Informa UK Ltd. All rights reserved. Background: Data highlight the importance of undertaking intense and frequent repetition of activities within stroke rehabilitation to maximise recovery. An enriched environment (EE) provides a medium in which these activities can be performed and enhanced recovery achieved. An EE has been shown to promote neuroplasticity in animal models of stroke, facilitating enhanced recovery of motor and cognitive function. However, the benefit of enriching the environment of stroke survivors remains unknown. Aim: To qualitatively explore stroke survivors' experience of implementation of exposure to an EE within a typical stroke rehabilitation setting, in order to identify facilitators and barriers to participation. Methods: Semi-structured interviews with 10 stroke survivors (7 females and 3 males, mean age of 70.5 years) exposed to an EE for a 2-week period following exposure to routine rehabilitation within a stroke rehabilitation ward. An inductive thematic approach was utilised to collect and analyse data. Results: Qualitative themes emerged concerning the environmental enrichment paradigm including: (1) "It got me moving"-perceived benefits of participation in an EE; (2) "You can be bored or you can be busy."-Attenuating factors influencing participation in an EE; (3) "I don't like to make the staff busier"-limitations to use of the EE. Conclusions: This study provides preliminary support for the implementation of an EE within a typical stroke rehabilitation setting from a patient perspective. Reported benefits included (1) increased motor, cognitive and sensory stimulation, (2) increased social interaction, (3) alleviation of degree of boredom and (4) increased feelings of personal control. However, participants also identified a number of barriers affecting implementation of the EE. We have previously published findings on perceptions of nursing staff working with stroke survivors in this enriched rehabilitation environment who identified that patients benefited from having better access to physical, cognitive and social activities. Together, results contribute to valuable evidence for future implementation of an EE in stroke rehabilitation settings.Implications for RehabilitationStroke survivor access to an enriched environment (EE):Results identified that participation in both individual and communal forms of environment enrichment within the stroke rehabilitation ward resulted in increased access to activities providing increased opportunities for enhanced motor, cognitive and sensory stimulation.Increased access to and participation in activities of the environmental enrichment (individual and communal) interrupted the ongoing cycle of boredom and inactivity experienced by many participants.This study provides preliminary support for the implementation of an EE within a typical stroke rehabilitation setting from a patient perspective.

© 2015 The Author. The use of perfusion imaging to guide selection of patients for stroke thrombolysis remains controversial because of lack of supportive phase three clinical trial evidence. We aimed to measure the outcomes for patients treated with intravenous recombinant tissue plasminogen activator (rtPA) at a comprehensive stroke care facility where perfusion computed tomography was routinely used for thrombolysis eligibility decision assistance. Our overall hypothesis was that patients with 'target' mismatch on perfusion computed tomography would have improved outcomes with rtPA. This was a prospective cohort study of consecutive ischaemic stroke patients who fulfilled standard clinical/non-contrast computed tomography eligibility criteria for treatment with intravenous rtPA, but for whom perfusion computed tomography was used to guide the final treatment decision. The 'real-time' perfusion computed tomography assessments were qualitative; a large perfusion computed tomography ischaemic core, or lack of significant perfusion lesion-core mismatch were considered relative exclusion criteria for thrombolysis. Specific volumetric perfusion computed tomography criteria were not used for the treatment decision. The primary analysis compared 3-month modified Rankin Scale in treated versus untreated patients after 'off-line' (post-treatment) quantitative volumetric perfusion computed tomography eligibility assessment based on presence or absence of 'target' perfusion lesion-core mismatch (mismatch ratio >1.8 and volume >15 ml, core <70 ml). In a second analysis, we compared outcomes of the perfusion computed tomography-selected rtPA-treated patients to an Australian historical cohort of non-contrast computed tomography-selected rtPA-treated patients. Of 635 patients with acute ischaemic stroke eligible for rtPA by standard criteria, thrombolysis was given to 366 patients, with 269 excluded based on visual real-time perfusion computed tomography assessment. After off-line quantitative perfusion computed tomography classification: 253 treated patients and 83 untreated patients had 'target' mismatch, 56 treated and 31 untreated patients had a large ischaemic core, and 57 treated and 155 untreated patients had no target mismatch. In the primary analysis, only in the target mismatch subgroup did rtPA-treated patients have significantly better outcomes (odds ratio for 3-month, modified Rankin Scale 0-2 = 13.8, P < 0.001). With respect to the perfusion computed tomography selected rtPA-treated patients (n = 366) versus the clinical/non-contrast computed tomography selected rtPA-treated patients (n = 396), the perfusion computed tomography selected group had higher adjusted odds of excellent outcome (modified Rankin Scale 0-1 odds ratio 1.59, P = 0.009) and lower mortality (odds ratio 0.56, P = 0.021). Although based on observational data sets, our analyses provide support for the hypothesis that perfusion computed tomography improves the identification of patients likely to respond to thrombolysis, and also those in whom natural history may be difficult to modify with treatment.

© 2013 World Stroke Organization. Background: Perfusion computed tomography is becoming more widely used as a clinical imaging tool to predict potentially salvageable tissue (ischemic penumbra) after ischemic stroke and guide reperfusion therapies. Aims: The study aims to determine whether there are important changes in perfusion computed tomography thresholds defining ischemic penumbra and infarct core over time following stroke. Methods: Permanent middle cerebral artery occlusion was performed in adult outbred Wistar rats (n=6) and serial perfusion computed tomography scans were taken every 30 mins for 2h. To define infarction thresholds at 1h and 2h post-stroke, separate groups of rats underwent 1h (n=6) and 2h (n=6) of middle cerebral artery occlusion followed by reperfusion. Infarct volumes were defined by histology at 24h. Co-registration with perfusion computed tomography maps (cerebral blood flow, cerebral blood volume, and mean transit time) permitted pixel-based analysis of thresholds defining infarction, using receiver operating characteristic curves. Results: Relative cerebral blood flow was the perfusion computed tomography parameter that most accurately predicted penumbra (area under the curve=0·698) and also infarct core (area under the curve=0·750). A relative cerebral blood flow threshold of <75% of mean contralateral cerebral blood flow most accurately predicted penumbral tissue at 0·5h (area under the curve=0·660), 1h (area under the curve=0·659), 1·5h (area under the curve=0·636), and 2h (area under the curve=0·664) after stroke onset. A relative cerebral blood flow threshold of <55% of mean contralateral most accurately predicted infarct core at 1h (area under the curve=0·765) and at 2h (area under the curve=0·689) after middle cerebral artery occlusion. Conclusions: The data provide perfusion computed tomography defined relative cerebral blood flow thresholds for infarct core and ischemic penumbra within the first two hours after experimental stroke in rats. These thresholds were shown to be stable to define the volume of infarct core and penumbra within this time window.

© 2015 Tomkins et al. Background: Early recanalization of occluded vessels in stroke is closely associated with improved clinical outcome. Microbubble-enhanced sonothrombolysis is a promising therapy to improve recanalization rates and reduce the time to recanalization. Testing any thrombolytic therapy requires a model of thromboembolic stroke, but to date these models have been highly variable with regards to clot stability. Here, we developed a model of thromboembolic stroke in rats with site-specific delivery of platelet-rich clots (PRC) to the main stem of the middle cerebral artery (MCA). This model was used in a subsequent study to test microbubble-enhanced sonothrombolysis. Methods: In Study 1 we investigated spontaneous recanalization rates of PRC in vivo over 4 hours and measured infarct volumes at 24 hours. In Study 2 we investigated tPA-mediated thrombolysis and microbubble-enhanced sonothrombolysis in this model. Results: Study 1 demonstrated stable occlusion out to 4 hours in 5 of 7 rats. Two rats spontaneously recanalized at 40 and 70 minutes post-embolism. Infarct volumes were not significantly different in recanalized rats, 43.93 ± 15.44% of the ischemic hemisphere, compared to 48.93 ± 3.9% in non-recanalized animals (p = 0.7). In Study 2, recanalization was not observed in any of the groups post-treatment. Conclusions: Site specific delivery of platelet rich clots to the MCA origin resulted in high rates of MCA occlusion, low rates of spontaneous clot lysis and large infarction. These platelet rich clots were highly resistant to tPA with or without microbubble-enhanced sonothrombolysis. This resistance of platelet rich clots to enhanced thrombolysis may explain recanalization failures clinically and should be an impetus to better clot-type identification and alternative recanalization methods.

Rationale: No evidence-based acute therapies exist for intracerebral hemorrhage. Intracerebral hemorrhage growth is an important determinant of patient outcome. Tranexamic acid is known to reduce hemorrhage in other conditions. Aim: The study aims to test the hypothesis that intracerebral hemorrhage patients selected with computed tomography angiography contrast extravasation 'spot sign' will have lower rates of hematoma growth when treated with intravenous tranexamic acid within 4·5-hours of stroke onset compared with placebo. Design: The Spot sign and Tranexamic acid On Preventing ICH growth - AUStralasia Trial is a multicenter, prospective, 1:1 randomized, double-blind, placebo-controlled, investigator-initiated, academic Phase II trial. Intracerebral hemorrhage patients fulfilling clinical criteria (e.g. Glasgow Coma Scale >7, intracerebral hemorrhage volume <70ml, no identified secondary cause of intracerebral hemorrhage, no thrombotic events within the previous 12 months, no planned surgery) and demonstrating contrast extravasation on computed tomography angiography will receive either intravenous tranexamic acid 1g 10-min bolus followed by 1g eight-hour infusion or placebo. A second computed tomography will be performed at 24 ± 3 hours to evaluate intracerebral hemorrhage growth and patients followed up for three-months. Study outcomes: The primary outcome measure is presence of intracerebral hemorrhage growth by 24 ± 3 hours, defined as either >33% or >6ml increase from baseline, and will be adjusted for baseline intracerebral hemorrhage volume. Secondary outcome measures include growth as a continuous measure, thromboembolic events, and the three-month modified Rankin Scale score. Discussion: This is the first trial to evaluate the efficacy of tranexamic acid in intracerebral hemorrhage patients selected based on an imaging biomarker of high likelihood of hematoma growth. The trial is registered as NCT01702636. © 2013 World Stroke Organization.

Objective: To determine physical, cognitive and social activity levels of stroke patients undergoing rehabilitation, and whether these changed over time. Design: Observational study using behavioural mapping techniques to record patient activity over 12 hours on one weekday and one weekend day at baseline (week 1) and again two weeks later (week 2). Setting: A 20-bed mixed rehabilitation unit. Subjects: Fourteen stroke patients. Interventions: None. Main measures: Percentage of day spent in any activity or physical, cognitive and social activities. Level of independence using the Functional Independence Measure (FIM) and mood using the Patient Health Questionniare-9 (PHQ-9). Results: The stroke patients performed any activity for 49%, social activity for 32%, physical activity for 23% and cognitive activity for 4% of the day. Two weeks later, physical activity levels had increased by 4% (95% confidence interval (CI) 1 to 8), but levels of any activity or social and cognitive activities had not changed significantly. There was a significant: (i) positive correlation between change in physical activity and change in FIM score (r = 0.80), and (ii) negative correlation between change in social activity and change in PHQ-9 score (r = -0.72). The majority of activity was performed by the bedside (37%), and most physical (47%) and cognitive (54%) activities performed when alone. Patients undertook 5% (95% CI 2 to 9) less physical activity on the weekends compared with the weekdays. Conclusions: Levels of physical, cognitive and social activity of stroke patients were low and remained so even though level of independence and mood improved. These findings suggest the need to explore strategies to stimulate activity within rehabilitation environments. © The Author(s) 2013.

© The Author(s) 2014. Background. Regular exercise reduces the risk of a first-ever stroke and is associated with smaller infarcts. Although evidence has suggested that therapeutic exercise following stroke is beneficial, we do not yet know whether exercise reduces stroke severity and improves functional recovery. The mechanisms underlying any benefit remain unclear.Objective. To conduct a systematic review and meta-analysis of studies testing exercise in animal models of ischemic stroke where outcomes were measured as infarct volume, neurobehavioral score, neurogenesis, or a combination of these. We also sought evidence of publication bias.Methods. We searched 3 online databases for publications reporting the use of exercise in focal cerebral ischemia. We used DerSimonian and Laird normalized random-effects meta-analysis and meta-regression to determine the impact of study quality and design on the efficacy of exercise.Results. Overall, exercise reduced infarct volume by 25.2% (95% confidence interval [CI] = 19.0%-31.3%; 65 experiments and 986 animals) and improved neurobehavioral score by 38.2% (95% CI = 29.1%-47.3%; 42 experiments; n = 771). For both outcomes, larger effects were seen when exercise preceded ischemia rather than came after it. For neurobehavioral scores, we found evidence of publication bias. Reported study quality was moderate (median score 5/10). Both model-specific (eg, type of ischemia) and exercise-specific characteristics influenced reported outcome.Conclusion. Exercise, either before or after ischemia, reduced infarct volume and improved neurobehavioral score. However, overall estimates of efficacy were higher in studies at risk of bias, and for neurobehavioral outcomes, there was evidence of a substantial publication bias.

Background: Intracranial pressure elevation, peaking three to seven post-stroke is well recognized following large strokes. Data following small-moderate stroke are limited. Therapeutic hypothermia improves outcome after cardiac arrest, is strongly neuroprotective in experimental stroke, and is under clinical trial in stroke. Hypothermia lowers elevated intracranial pressure; however, rebound intracranial pressure elevation and neurological deterioration may occur during rewarming. Hypotheses: (1) Intracranial pressure increases 24h after moderate and small strokes. (2) Short-duration hypothermia-rewarming, instituted before intracranial pressure elevation, prevents this 24h intracranial pressure elevation. Methods: Long-Evans rats with two hour middle cerebral artery occlusion or outbred Wistar rats with three hour middle cerebral artery occlusion had intracranial pressure measured at baseline and 24h. Wistars were randomized to 2·5h hypothermia (32·5°C) or normothermia, commencing 1h after stroke. Results: In Long-Evans rats (n=5), intracranial pressure increased from 10·9±4·6mmHg at baseline to 32·4±11·4mmHg at 24h, infarct volume was 84·3±15·9mm3. In normothermic Wistars (n=10), intracranial pressure increased from 6·7±2·3mmHg to 31·6±9·3mmHg, infarct volume was 31·3±18·4mm3. In hypothermia-treated Wistars (n=10), 24h intracranial pressure did not increase (7·0±2·8mmHg, P<0·001 vs. normothermia), and infarct volume was smaller (15·4±11·8mm3, P<0·05). Conclusions: We saw major intracranial pressure elevation 24h after stroke in two rat strains, even after small strokes. Short-duration hypothermia prevented the intracranial pressure rise, an effect sustained for at least 18h after rewarming. The findings have potentially important implications for design of future clinical trials. © 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization.

Background: Many aspects of CSF dynamics are poorly understood due to the difficulties involved in quantification and visualization. In particular, there is debate surrounding the route of CSF drainage. Our aim was to quantify CSF flow, volume, and drainage route dynamics in vivo in young and aged spontaneously hypertensive rats (SHR) using a novel contrast-enhanced computed tomography (CT) method.Methods: ICP was recorded in young (2-5 months) and aged (16 months) SHR. Contrast was administered into the lateral ventricles bilaterally and sequential CT imaging was used to visualize the entire intracranial CSF system and CSF drainage routes. A customized contrast decay software module was used to quantify CSF flow at multiple locations.Results: ICP was significantly higher in aged rats than in young rats (11.52 ± 2.36 mmHg, versus 7.04 ± 2.89 mmHg, p = 0.03). Contrast was observed throughout the entire intracranial CSF system and was seen to enter the spinal canal and cross the cribriform plate into the olfactory mucosa within 9.1 ± 6.1 and 22.2 ± 7.1 minutes, respectively. No contrast was observed adjacent to the sagittal sinus. There were no significant differences between young and aged rats in either contrast distribution times or CSF flow rates. Mean flow rates (combined young and aged) were 3.0 ± 1.5 µL/min at the cerebral aqueduct; 3.5 ± 1.4 µL/min at the 3rd ventric= and 2.8 ± 0.9 µL/min at the 4th ventricle. Intracranial CSF volumes (and as percentage total brain volume) were 204 ± 97 µL (8.8 ± 4.3%) in the young and 275 ± 35 µL (10.8 ± 1.9%) in the aged animals (NS).Conclusions: We have demonstrated a contrast-enhanced CT technique for measuring and visualising CSF dynamics in vivo. These results indicate substantial drainage of CSF via spinal and olfactory routes, but there was little evidence of drainage via sagittal sinus arachnoid granulations in either young or aged animals. The data suggests that spinal and olfactory routes are the primary routes of CSF drainage and that sagittal sinus arachnoid granulations play a minor role, even in aged rats with higher ICP. © 2014 Murtha et al.; licensee BioMed Central Ltd.

Background: Transient ischemic attacks and minor stroke entail considerable risk of completed stroke but this risk is reduced by prompt assessment and treatment. Risk can be stratified according to the ABCD2 prediction score. Current guidelines suggest specialist assessment and treatment within 24h for high-risk event (ABCD2 score 4-7) and seven-days for low-risk event (ABCD2 score =3). Aims: The study aims to establish paths to care and outcomes for patients referred by general practitioners and emergency departments to an Australian acute access transient ischemic attack service. Methods: This is a prospective audit. Primary outcomes were time from event to referral, from referral to clinic appointment, and from event to appointment. ABCD2 score was calculated for each event. Time from event was modeled using Cox proportional hazards regression. Results: There were 231 clinic attendees (general practitioner: 127; emergency department: 104). Mean time from event to referral was 9·2 days (SD 23·7, median 2), from referral to being seen in the clinic was 13·6 days (SD 19·0, median 7), and from event to being seen in the clinic was 17·2 days (SD 27·1, median 10). Of low-risk patients, 38·5% were seen within seven-days of event. Of high-risk patients, 36·7% were seen within one-day. ABCD2 score was not a significant predictor of any time interval from event to clinic attendance. There were no completed strokes prior to clinic attendance. Conclusions: Times from event to clinic assessment were in excess of current recommendations and risk stratification was suboptimal, though short-term outcomes were good. Improvements in referral mechanisms may enhance risk-stratification and triage. © 2013 World Stroke Organization.