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Background: Intracranial occlusion site, contrast permeability, and clot burden are thrombus characteristics that influence alteplase-associated reperfusion. In this study, we assessed the reperfusion efficacy of tenecteplase and alteplase in subgroups based on these characteristics in a pooled analysis of the EXTEND-IA TNK trial (Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke)., Methods: Patients with large vessel occlusion were randomized to treatment with tenecteplase (0.25 or 0.4 mg/kg) or alteplase before thrombectomy in hospitals across Australia and New Zealand (2015-2019). The primary outcome, early reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion on first-pass angiogram. We compared the effect of tenecteplase versus alteplase overall, and in subgroups, based on the following measured with computed tomography angiography: intracranial occlusion site, contrast permeability (measured via residual flow grades), and clot burden (measured via clot burden scores). We adjusted for covariates using mixed effects logistic regression models., Results: Tenecteplase was associated with higher odds of early reperfusion (75/369 [20%] versus alteplase: 9/96 [9%], adjusted odds ratio [aOR], 2.18 [95% CI, 1.03-4.63]). The difference between thrombolytics was notable in occlusions with low clot burden (tenecteplase: 66/261 [25%] versus alteplase: 5/67 [7%], aOR, 3.93 [95% CI, 1.50-10.33]) when compared to high clot burden lesions (tenecteplase: 9/108 [8%] versus alteplase: 4/29 [14%], aOR, 0.58 [95% CI, 0.16-2.06]; P interaction =0.01). We did not observe an association between contrast permeability and tenecteplase treatment effect (permeability present: aOR, 2.83 [95% CI, 1.00-8.05] versus absent: aOR, 1.98 [95% CI, 0.65-6.03]; P interaction =0.62). Tenecteplase treatment effect was superior with distal M1 or M2 occlusions (53/176 [30%] versus alteplase: 4/42 [10%], aOR, 3.73 [95% CI, 1.25-11.11]), but both thrombolytics had limited efficacy with internal carotid artery occlusions (tenecteplase 1/73 [1%] versus alteplase 1/19 [5%], aOR, 0.22 [95% CI, 0.01-3.83]; P interaction =0.16)., Conclusions: Tenecteplase demonstrates superior early reperfusion versus alteplase in lesions with low clot burden. Reperfusion efficacy remains limited in internal carotid artery occlusions and lesions with high clot burden. Further innovation in thrombolytic therapies are required.

Background: Insomnia is one of the most common sleep disorders yet its relationship to the biology of Alzheimer's disease remains equivocal., Objective: We investigated the cross-sectional relationship between insomnia symptom severity and cerebrospinal fluid (CSF) concentrations of Alzheimer's disease biomarkers in a cognitively unimpaired middle-aged community sample., Methods: A total of 63 participants from the Healthy Brain Project (age = 59±7 years; 67% women) completed a lumbar puncture and two weeks of actigraphy to measure two of insomnia's core features: difficulty initiating sleep (prolonged sleep onset latency) and difficulty maintaining sleep (wake after sleep onset [WASO] and number of awakenings). Additionally, the Insomnia Severity Index (ISI) was completed by 58 participants. Linear and Tobit regression were used to estimate the associations between each insomnia variable and CSF Aβ42, phosphorylated tau 181 (p-tau181), total-tau, and neurofilament light chain protein (NfL), adjusting for age, sex, and APOEɛ4 genotype., Results: Higher ISI score was associated with greater average levels of CSF Aβ42 (per point: 30.7 pg/mL, 95% CI: 4.17-57.3, p = 0.023), as was higher WASO (per 10 min: 136 pg/mL, 95% CI: 48-223, p = 0.002) and more awakenings (per 5:123 pg/mL, 95% CI = 55-192, p < 0.001). Difficulty initiating sleep was not associated with CSF Aβ42, nor were insomnia features associated with p-tau181, total-tau, or NfL levels., Conclusion: Insomnia symptoms were associated with higher CSF Aβ42 levels in this relatively young, cognitively unimpaired sample. These findings may reflect increased amyloid production due to acute sleep disruption.

Introduction: Many patients with cognitive and neuropsychiatric symptoms face diagnostic delay and misdiagnosis. We investigated whether cerebrospinal fluid (CSF) neurofilament light (NfL) and total-tau (t-tau) could assist in the clinical scenario of differentiating neurodegenerative (ND) from psychiatric disorders (PSY), and rapidly progressive disorders., Methods: Biomarkers were examined in patients from specialist services (ND and PSY) and a national Creutzfeldt-Jakob registry (Creutzfeldt-Jakob disease [CJD] and rapidly progressive dementias/atypically rapid variants of common ND, RapidND)., Results: A total of 498 participants were included: 197 ND, 67 PSY, 161 CJD, 48 RapidND, and 20 controls. NfL was elevated in ND compared to PSY and controls, with highest levels in CJD and RapidND. NfL distinguished ND from PSY with 95%/78% positive/negative predictive value, 92%/87% sensitivity/specificity, 91% accuracy. NfL outperformed t-tau in most real-life clinical diagnostic dilemma scenarios, except distinguishing CJD from RapidND., Discussion: We demonstrated strong generalizable evidence for the diagnostic utility of CSF NfL in differentiating ND from psychiatric disorders, with high accuracy., (© 2022 the Alzheimer's Association.)

Background: Cerebral edema after large hemispheric infarction is associated with poor functional outcome and mortality. Net water uptake (NWU) quantifies the degree of hypoattenuation on unenhanced-computed tomography (CT) and is increasingly used to measure cerebral edema in stroke research. Hemorrhagic transformation and parenchymal contrast staining after thrombectomy may confound NWU measurements. We investigated the correlation of NWU measured postthrombectomy with volumetric markers of cerebral edema and association with functional outcomes., Methods: In a pooled individual patient level analysis of patients presenting with anterior circulation large hemispheric infarction (core 80-300 mL or Alberta Stroke Program Early CT Score ≤5) in the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke trials) data set, cerebral edema was defined as the volumetric expansion of the ischemic hemisphere expressed as a ratio to the contralateral hemisphere(rHV). NWU and midline-shift were compared with rHV as the reference standard on 24-hour follow-up CT, adjusted for hemorrhagic transformation and the use of thrombectomy. Association between edema markers and day 90 functional outcomes (modified Rankin Scale) was assessed using ordinal logistic regression., Results: Overall (n=144), there was no correlation between NWU and rHV (r s =0.055, P =0.51). In sub-group analyses, a weak correlation between NWU with rHV was observed after excluding patients with any degree of hemorrhagic transformation (r s =0.211, P =0.015), which further improved after excluding thrombectomy patients (r s =0.453, P =0.001). Midline-shift correlated strongly with rHV in all sub-group analyses (r s >0.753, P =0.001). Functional outcome at 90 days was negatively associated with rHV (adjusted common odds ratio, 0.46 [95% CI, 0.32-0.65]; P <0.001) and midline-shift (adjusted common odds ratio, 0.85 [95% CI, 0.78-0.92]; P <0.001) but not NWU (adjusted common odds ratio, 1.00 [95% CI, 0.97-1.03]; P =0.84), adjusted for age, baseline National Institutes of Health Stroke Scale, and thrombectomy. Prognostic performance of NWU improved after excluding patients with hemorrhagic transformation and thrombectomy (adjusted odds ratio, 0.90 [95% CI, 0.80-1.02]; P =0.10)., Conclusions: NWU correlated poorly with conventional markers of cerebral edema and was not associated with clinical outcome in the presence of hemorrhagic transformation and thrombectomy. Measuring NWU postthrombectomy requires validation before implementation into clinical research. At present, the use of NWU should be limited to baseline CT, or follow-up CT only in patients without hemorrhagic transformation or treatment with thrombectomy.

Background: Recent reports raise the possibility of cerebral amyloid angiopathy (CAA) leading to intracerebral hemorrhage in young adults following childhood neurosurgery, suggesting transmission of amyloid-β (Aβ) through neurosurgical procedures including dura mater grafting. Parenchymal Aβ deposition, and to a lesser extent tau aggregation, similar to that seen in Alzheimer disease, have also been described., Methods: We conducted a database review of 634 consecutive intracerebral hemorrhage patients aged <65 years at a tertiary stroke center over 20 years to identify such patients., Results: We identified 3 patients aged in their thirties who presented with spontaneous lobar intracerebral hemorrhage, with imaging or neuropathology consistent with CAA, and a history of childhood neurosurgery. Two of these patients had undergone a dural repair using cadaveric dura mater (Lyodura). In addition to CAA, both patients had neuropathologically confirmed parenchymal Aβ and tau deposits, characteristic of Alzheimer disease., Conclusions: Our findings support the concept of neurosurgical Aβ transmission but suggest that such cases are rare in standard clinical practice.

Background: Emerging data suggest tissue within the infarct lesion is not homogenously damaged following ischemic stroke but has a gradient of injury. Using blood-brain-barrier (BBB) disruption as a marker of tissue injury, we tested whether therapeutic reperfusion improves clinical outcome by reducing the severity of tissue injury within the infarct in patients with ischemic stroke., Methods: In a pooled analysis of patients treated for anterior circulation large vessel occlusion in the EXTEND-IA TNK (Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke) and EXTEND-IA part-2 (Determining the Optimal Dose of Tenecteplase Before Endovascular Therapy for Ischaemic Stroke) trials, post-treatment BBB permeability at 24 hours was calculated based on the extent of T1-brightening by extravascular gadolinium on T2* perfusion-weighted imaging and measured within the diffusion-weighted-imaging lesion. First, to determine the clinical significance of BBB disruption as a marker of severity of tissue injury, we examined the association between post-treatment BBB permeability and functional outcome. Second, we performed an exploratory (reperfusion, BBB permeability, functional outcome) mediation analysis to estimate the proportion of the reperfusion-outcome relationship that is mediated by change in BBB permeability., Results: In the 238 patients analyzed, an increased BBB permeability measured within the infarct at 24 hours was associated with a reduced likelihood of favorable outcome (90-day modified Rankin Scale score of ≤2) after adjusting for age, baseline National Institutes of Health Stroke Scale, premorbid modified Rankin Scale, infarct topography, laterality, thrombolytic agent, sex, parenchymal hematoma, and follow-up infarct volume (adjusted odds ratio, 0.86 [95% CI, 0.75-0.98]; P =0.023). Mediation analysis suggested reducing the severity of tissue injury (as estimated by BBB permeability) accounts for 18.2% of the association between reperfusion and favorable outcome, as indicated by a reduction in the regression coefficient of reperfusion after addition of BBB permeability as a covariate., Conclusions: In patients with ischemic stroke, reduced severity of tissue injury within the infarct, as determined by assessing the integrity of the BBB, is independently associated with improved functional outcome. In addition to reducing diffusion-weighted imaging-defined infarct volume, reperfusion may also improve clinical outcome by reducing tissue injury severity within the infarct.

Rationale: Haematoma growth is common early after intracerebral haemorrhage (ICH), and is a key determinant of outcome. Tranexamic acid, a widely available antifibrinolytic agent with an excellent safety profile, may reduce haematoma growth., Methods and Design: Stopping intracerebral haemorrhage with tranexamic acid for hyperacute onset presentation including mobile stroke units (STOP-MSU) is a phase II double-blind, randomised, placebo-controlled, multicentre, international investigator-led clinical trial, conducted within the estimand statistical framework., Hypothesis: In patients with spontaneous ICH, treatment with tranexamic acid within 2 hours of onset will reduce haematoma expansion compared with placebo., Sample Size Estimates: A sample size of 180 patients (90 in each arm) would be required to detect an absolute difference in the primary outcome of 20% (placebo 39% vs treatment 19%) under a two-tailed significance level of 0.05. An adaptive sample size re-estimation based on the outcomes of 144 patients will allow a possible increase to a prespecified maximum of 326 patients., Intervention: Participants will receive 1 g intravenous tranexamic acid over 10 min, followed by 1 g intravenous tranexamic acid over 8 hours; or matching placebo., Primary Efficacy Measure: The primary efficacy measure is the proportion of patients with haematoma growth by 24±6 hours, defined as either ≥33% relative increase or ≥6 mL absolute increase in haematoma volume between baseline and follow-up CT scan., Discussion: We describe the rationale and protocol of STOP-MSU, a phase II trial of tranexamic acid in patients with ICH within 2 hours from onset, based in participating mobile stroke units and emergency departments., Competing Interests: Competing interests: Henry Zhao has received grant funding from the Medical Research Future Fund (Commonwealth Government of Australia). Leonid Churilov is co-chairperson of the Australasian Stroke Trials Network (unpaid). Andrew Cheung has received honoraria for lectures/presentations from Medtronic and Stryker and support for attending meetings and/or travel from Stryker. Rohan Grimley is a member of the Clinical Council, Stroke Foundation (Australia). Chung Hsu has received grants from the Ministry of Health and Welfare in Taiwan. Peter Mitchell has received institutional research grants from Stryker and Medtronic, travel support for attendance of international conferences and honoraria for speaking at symposia from Stryker, and is an executive member and immediate past president of the Australian and New Zealand Society of Neuroradiology (ANZSNR)., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: Detailed study of tenecteplase (TNK) in patients older than 80 years is limited. The objective of our study was to assess the safety and efficacy of TNK at 0.25 and 0.40 mg/kg doses in patients older than 80 years with large vessel occlusion., Methods: We performed a pooled analysis of the EXTEND-IA TNK randomized controlled trials (n = 502). Patients were adults presenting with ischemic stroke due to occlusion of the intracranial internal carotid, middle cerebral, or basilar artery presenting within 4.5 hours of symptom onset. We compared the treatment effect of TNK 0.25 mg/kg, TNK 0.40 mg/kg, and alteplase 0.90 mg/kg, stratifying for patient age (>80 years). Outcomes evaluated include 90-day modified Rankin Scale (mRS) score, all-cause mortality, and symptomatic ICH. Treatment effect was adjusted for baseline NIH Stroke Score, age, and time from symptom onset to puncture via mixed effects proportional odds and logistic regression models., Results: In patients >80 years (n = 137), TNK 0.25 mg/kg was associated with improved 90-day mRS (median 3 vs 4, adjusted common odds ratio (acOR) 2.70, 95% CI 1.23-5.94) and reduced mortality (acOR 0.34, 95% CI 0.13-0.91) vs 0.40 mg/kg. TNK 0.25 mg/kg was associated with improved 90-day mRS (median 3 vs 4, acOR 2.28, 95% CI 1.03-5.05) vs alteplase. No difference in 90-day mRS or mortality was detected between alteplase and TNK 0.40 mg/kg. Symptomatic ICH was observed in 4 patients treated with TNK 0.40 mg/kg, 1 patient treated with alteplase, and 0 patients treated with TNK 0.25 mg/kg. In patients ≤80 years, no differences in 90-day mRS, mortality, or symptomatic ICH were observed among TNK 0.25 mg/kg, alteplase, and TNK 0.40 mg/kg., Discussion: TNK 0.25 mg/kg was associated with improved 90-day mRS and lower mortality in patients older than 80 years. No differences among the doses were observed in younger patients., Trial Registration Information: NCT02388061, NCT03340493., Classification of Evidence: This study provides Class II evidence that tenecteplase 0.25 mg/kg given before endovascular therapy in patients >80 years old with large vessel occlusion stroke is associated with better functional outcomes at 90 days and reduced mortality when compared to tenecteplase 0.40 mg/kg or alteplase 0.90 mg/kg., (© 2022 American Academy of Neurology.)

Background and Objectives: The relevance of impaired microvascular tissue-level reperfusion despite complete upstream macrovascular angiographic reperfusion (no-reflow) in human stroke remains controversial. We investigated the prevalence and clinical-radiologic features of this phenomenon and its associations with outcomes in 3 international randomized controlled thrombectomy trials with prespecified follow-up perfusion imaging., Methods: In a pooled analysis of the Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-Arterial (EXTEND-IA; ClinicalTrials.gov NCT01492725), Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke (EXTEND-IA TNK; NCT02388061), and Determining the Optimal Dose of Tenecteplase Before Endovascular Therapy for Ischaemic Stroke (EXTEND-IA TNK Part 2; NCT03340493) trials, patients undergoing thrombectomy with final angiographic expanded Treatment in Cerebral Infarction score of 2c to 3 score for anterior circulation large vessel occlusion and 24-hour follow-up CT or MRI perfusion imaging were included. No-reflow was defined as regions of visually demonstrable persistent hypoperfusion on relative cerebral blood volume or flow maps within the infarct and verified quantitatively by >15% asymmetry compared to a mirror homolog in the absence of carotid stenosis or reocclusion., Results: Regions of no-reflow were identified in 33 of 130 patients (25.3%), encompassed a median of 60.2% (interquartile range 47.8%-70.7%) of the infarct volume, and involved both subcortical (n = 26 of 33, 78.8%) and cortical (n = 10 of 33, 30.3%) regions. Patients with no-reflow had a median 25.2% (interquartile range 16.4%-32.2%, p < 0.00001) relative cerebral blood volume interside reduction and 19.1% (interquartile range 3.9%-28.3%, p = 0.00011) relative cerebral blood flow reduction but similar mean transit time (median -3.3%, interquartile range -11.9% to 24.4%, p = 0.24) within the infarcted region. Baseline characteristics were similar between patients with and those without no-reflow. The presence of no-reflow was associated with hemorrhagic transformation (adjusted odds ratio [aOR] 1.79, 95% confidence interval [CI] 2.32-15.57, p = 0.0002), greater infarct growth (β = 11.00, 95% CI 5.22-16.78, p = 0.00027), reduced NIH Stroke Scale score improvement at 24 hours (β = -4.06, 95% CI 6.78-1.34, p = 0.004) and being dependent or dead at 90 days as assessed by the modified Rankin Scale (aOR 3.72, 95% CI 1.35-10.20, p = 0.011) in multivariable analysis., Discussion: Cerebral no-reflow in humans is common, can be detected by its characteristic perfusion imaging profile using readily available sequences in the clinical setting, and is associated with posttreatment complications and being dependent or dead. Further studies evaluating the role of no-reflow in secondary injury after angiographic reperfusion are warranted., Classification of Evidence: This study provides Class II evidence that cerebral no-reflow on CT/MRI perfusion imaging at 24 hours is associated with posttreatment complications and poor 3-month functional outcome., (© 2021 American Academy of Neurology.)

Introduction: Engagement in cognitively stimulating work and activities may slow cognitive decline and dementia. We examined the individual and combined associations of four cognitive engagement indices (educational attainment, occupational complexity, social engagement, and cognitively stimulating leisure activities) with objective and subjective cognition., Methods: Middle-aged adults (n = 1864) enrolled in the Healthy Brain Project completed the Cogstate Brief Battery, the Cognitive Function Instrument, and self-report questionnaires of cognitive engagement., Results: Educational attainment and leisure activity engagement were individually associated with memory performance. Participants were classified based on whether they rated highly in zero to four cognitive engagement indices. Compared to participants with no indices, participants with two or more indices performed moderately better on memory., Discussion: Results suggest that greater variety of cognitive engagement across different areas of life is related to better memory in midlife. Possible explanation for this relationship may be increased opportunity for enhancing cognitive reserve, but further investigations are required., Competing Interests: P. Maruff is a full‐time employee of Cogstate Ltd., the company that provides the Cogstate Brief Battery. All other investigators have no relevant disclosures to report., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

The coronavirus disease 2019 (COVID-19) pandemic has presented unique challenges to stroke care and research internationally. In particular, clinical trials in stroke are vulnerable to the impacts of the pandemic at multiple stages, including design, recruitment, intervention, follow-up, and interpretation of outcomes. A carefully considered approach is required to ensure the appropriate conduct of stroke trials during the pandemic and to maintain patient and participant safety. This has been recently addressed by the International Council for Harmonisation which, in November 2019, released an addendum to the Statistical Principles for Clinical Trials guidelines entitled Estimands and Sensitivity Analysis in Clinical Trials. In this article, we present the International Council for Harmonisation estimand framework for the design and conduct of clinical trials, with a specific focus on its application to stroke clinical trials. This framework aims to align the clinical and scientific objectives of a trial with its design and end points. It also encourages the prospective consideration of potential postrandomization intercurrent events which may occur during a trial and either impact the ability to measure an end point or its interpretation. We describe the different categories of such events and the proposed strategies for dealing with them, specifically focusing on the COVID-19 pandemic as a source of intercurrent events. We also describe potential practical impacts posed by the COVID-19 pandemic on trials, health systems, study groups, and participants, all of which should be carefully reviewed by investigators to ensure an adequate practical and statistical strategy is in place to protect trial integrity. We provide examples of the implementation of the estimand framework within hypothetical stroke trials in intracerebral hemorrhage and stroke recovery. While the focus of this article is on COVID-19 impacts, the strategies and principles proposed are well suited for other potential events or issues, which may impact clinical trials in the field of stroke.

Background and Purpose: Whether reperfusion into infarcted tissue exacerbates cerebral edema has treatment implications in patients presenting with extensive irreversible injury. We investigated the effects of endovascular thrombectomy and reperfusion on cerebral edema in patients presenting with radiological evidence of large hemispheric infarction at baseline., Methods: In a systematic review and individual patient-level meta-analysis of 7 randomized controlled trials comparing thrombectomy versus medical therapy in anterior circulation ischemic stroke published between January 1, 2010, and May 31, 2017 (Highly Effective Reperfusion Using Multiple Endovascular Devices collaboration), we analyzed the association between thrombectomy and reperfusion with maximal midline shift (MLS) on follow-up imaging as a measure of the space-occupying effect of cerebral edema in patients with large hemispheric infarction on pretreatment imaging, defined as diffusion-magnetic resonance imaging or computed tomography (CT)-perfusion ischemic core 80 to 300 mL or noncontrast CT-Alberta Stroke Program Early CT Score ≤5. Risk of bias was assessed using the Cochrane tool., Results: Among 1764 patients, 177 presented with large hemispheric infarction. Thrombectomy and reperfusion were associated with functional improvement (thrombectomy common odds ratio =2.30 [95% CI, 1.32–4.00]; reperfusion common odds ratio =4.73 [95% CI, 1.66–13.52]) but not MLS (thrombectomy β=−0.27 [95% CI, −1.52 to 0.98]; reperfusion β=−0.78 [95% CI, −3.07 to 1.50]) when adjusting for age, National Institutes of Health Stroke Score, glucose, and time-to-follow-up imaging. In an exploratory analysis of patients presenting with core volume >130 mL or CT-Alberta Stroke Program Early CT Score ≤3 (n=76), thrombectomy was associated with greater MLS after adjusting for age and National Institutes of Health Stroke Score (β=2.76 [95% CI, 0.33–5.20]) but not functional improvement (odds ratio, 1.71 [95% CI, 0.24–12.08])., Conclusions: In patients presenting with large hemispheric infarction, thrombectomy and reperfusion were not associated with MLS, except in the subgroup with very large core volume (>130 mL) in whom thrombectomy was associated with increased MLS due to space-occupying ischemic edema. Mitigating cerebral edema-mediated secondary injury in patients with very large infarcts may further improve outcomes after reperfusion therapies.

Background and Purpose: Mobile stroke units (MSUs) improve reperfusion therapy times in acute ischemic stroke (AIS). However, prehospital management options for intracerebral hemorrhage (ICH) are less established. We describe the initial Melbourne MSU experience in ICH., Methods: Consecutive patients with ICH and AIS treated by the Melbourne MSU were included. We describe demographics, proportions of patients receiving specific therapies, and bypass to comprehensive/neurosurgical centers. We also compare operational time metrics between patients with MSU-ICH and MSU-AIS., Results: During a 2-year period, the Melbourne MSU managed 49 patients with ICH, mean (SD) age 74 (12) years, median (interquartile range) National Institutes of Health Stroke Scale 17 (12–20). Intravenous antihypertensives were the commonest treatment provided (46.9%). Bypass of a primary center to a comprehensive center with neurosurgical expertise occurred in 32.7% of patients with MSU-ICH compared with 20.5% of patients with MSU-AIS. Compared with patients with MSU-AIS, patients with MSU-ICH had faster onset-to-emergency-call, and onset-to-scene-arrival times at the median and 75th percentiles., Conclusions: MSUs can facilitate ultra-early ICH diagnosis, management, and triage.

Objective: To investigate the efficacy of tenecteplase (TNK), a genetically modified variant of alteplase with greater fibrin specificity and longer half-life than alteplase, prior to endovascular thrombectomy (EVT) in patients with basilar artery occlusion (BAO)., Methods: To determine whether TNK is associated with better reperfusion rates than alteplase prior to EVT in BAO, clinical and procedural data of consecutive patients with BAO from the Basilar Artery Treatment and Management (BATMAN) registry and the Tenecteplase vs Alteplase before Endovascular Therapy for Ischemic Stroke (EXTEND-IA TNK) trial were retrospectively analyzed. Reperfusion >50% or absence of retrievable thrombus at the time of the initial angiogram was evaluated., Results: We included 110 patients with BAO treated with IV thrombolysis prior to EVT (mean age 69 [SD 14] years; median NIH Stroke Scale score 16 [interquartile range (IQR) 7-32]). Nineteen patients were thrombolysed with TNK (0.25 mg/kg or 0.40 mg/kg) and 91 with alteplase (0.9 mg/kg). Reperfusion >50% occurred in 26% (n = 5/19) of patients thrombolysed with TNK vs 7% (n = 6/91) thrombolysed with alteplase (risk ratio 4.0, 95% confidence interval 1.3-12; p = 0.02), despite shorter thrombolysis to arterial puncture time in the TNK-treated patients (48 [IQR 40-71] minutes) vs alteplase-treated patients (110 [IQR 51-185] minutes; p = 0.004). No difference in symptomatic intracranial hemorrhage was observed (0/19 [0%] TNK, 1/91 [1%] alteplase; p = 0.9)., Conclusions: TNK may be associated with an increased rate of reperfusion in comparison with alteplase before EVT in BAO. Randomized controlled trials to compare TNK with alteplase in patients with BAO are warranted., Clinicaltrialsgov Identifiers: NCT02388061 and NCT03340493., Classification of Evidence: This study provides Class III evidence that TNK leads to higher reperfusion rates in comparison with alteplase prior to EVT in patients with BAO., (© 2021 American Academy of Neurology.)

Background: Despite intracerebral haemorrhage causing 5% of deaths worldwide, few evidence-based therapeutic strategies other than stroke unit care exist. Tranexamic acid decreases haemorrhage in conditions such as acute trauma and menorrhoea. We aimed to assess whether tranexamic acid reduces intracerebral haemorrhage growth in patients with acute intracerebral haemorrhage., Methods: We did a prospective, double-blind, randomised, placebo-controlled, investigator-led, phase 2 trial at 13 stroke centres in Australia, Finland, and Taiwan. Patients were eligible if they were aged 18 years or older, had an acute intracerebral haemorrhage fulfilling clinical criteria (eg, Glasgow Coma Scale score of >7, intracerebral haemorrhage volume <70 mL, no identified or suspected secondary cause of intracerebral haemorrhage, no thrombotic events within the previous 12 months, no planned surgery in the next 24 h, and no use of anticoagulation), had contrast extravasation on CT angiography (the so-called spot sign), and were treatable within 4·5 h of symptom onset and within 1 h of CT angiography. Patients were randomly assigned (1:1) to receive either 1 g of intravenous tranexamic acid over 10 min followed by 1 g over 8 h or matching placebo, started within 4·5 h of symptom onset. Randomisation was done using a centralised web-based procedure with randomly permuted blocks of varying size. All patients, investigators, and staff involved in patient management were masked to treatment. The primary outcome was intracerebral haemorrhage growth (>33% relative or >6 mL absolute) at 24 h. The primary and safety analyses were done in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT01702636)., Findings: Between March 1, 2013, and Aug 13, 2019, we enrolled and randomly assigned 100 participants to the tranexamic acid group (n=50) or the placebo group (n=50). Median age was 71 years (IQR 57-79) and median intracerebral haemorrhage volume was 14·6 mL (7·9-32·7) at baseline. The primary outcome was not different between the two groups: 26 (52%) patients in the placebo group and 22 (44%) in the tranexamic acid group had intracerebral haemorrhage growth (odds ratio [OR] 0·72 [95% CI 0·32-1·59], p=0·41). There was no evidence of a difference in the proportions of patients who died or had thromboembolic complications between the groups: eight (16%) in the placebo group vs 13 (26%) in the tranexamic acid group died and two (4%) vs one (2%) had thromboembolic complications. None of the deaths was considered related to study medication., Interpretation: Our study does not provide evidence that tranexamic acid prevents intracerebral haemorrhage growth, although the treatment was safe with no increase in thromboembolic complications. Larger trials of tranexamic acid, with simpler recruitment methods and an earlier treatment window, are justified., Funding: National Health and Medical Research Council, Royal Melbourne Hospital Foundation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Alzheimer's disease neuropathologies (amyloid-β and tau) frequently co-exist to varying degrees in Lewy body dementias (LBD), which include dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD)., Objectives: To investigate the prevalence of tau in DLB and PDD, and its associations with clinical outcomes., Methods: We searched the major electronic databases using the search term: ("dementia with Lewy bodies" OR "diffuse Lewy body disease" OR "Lewy body variant of Alzheimer's disease") AND ("tau protein" OR "tauopathy" OR "neurofibrillary tangle"), for relevant studies which evaluated tau in LBD. Forty-nine articles met the inclusion criteria for data extraction. Where appropriate, a random-effect meta-analysis was performed to obtain pooled estimates for prevalence and risk ratios (RR) or standardized mean differences (SMD) for clinical features, diagnostic accuracy and cognition., Results: Braak neurofibrillary tangle stage ≥ III was observed in 66% (n = 1511, 95%CI 60%-73%) of DLB and 52% (n = 433, 95%CI 27%-76%) of PDD at autopsy. Abnormal CSF phosphorylated-tau levels were present in 28% (n = 925, 95%CI 25%-31%) of DLB and 15% (n = 172, 95%CI 5%-24%) of PDD cases. Higher tau burden in DLB was associated with reduced likelihood of manifesting visual hallucinations (RR 0.56; 95%CI 0.40-0.77) and motor parkinsonism (RR 0.62; 95%CI 0.40-0.98), lower diagnostic accuracy of DLB during life (RR 0.49; 95%CI 0.38-0.64) and worse cognition prior to death (SMD 0.63; 95%CI 0.46-0.81)., Conclusions: Tau is common in LBD and may reduce clinical diagnostic accuracy in people with DLB. Prospective longitudinal studies are needed to understand the roles of co-morbid neuropathologies in Lewy body dementias., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background and Purpose: The novel severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), now named coronavirus disease 2019 (COVID-19), may change the risk of stroke through an enhanced systemic inflammatory response, hypercoagulable state, and endothelial damage in the cerebrovascular system. Moreover, due to the current pandemic, some countries have prioritized health resources towards COVID-19 management, making it more challenging to appropriately care for other potentially disabling and fatal diseases such as stroke. The aim of this study is to identify and describe changes in stroke epidemiological trends before, during, and after the COVID-19 pandemic., Methods: This is an international, multicenter, hospital-based study on stroke incidence and outcomes during the COVID-19 pandemic. We will describe patterns in stroke management, stroke hospitalization rate, and stroke severity, subtype (ischemic/hemorrhagic), and outcomes (including in-hospital mortality) in 2020 during COVID-19 pandemic, comparing them with the corresponding data from 2018 and 2019, and subsequently 2021. We will also use an interrupted time series (ITS) analysis to assess the change in stroke hospitalization rates before, during, and after COVID-19, in each participating center., Conclusion: The proposed study will potentially enable us to better understand the changes in stroke care protocols, differential hospitalization rate, and severity of stroke, as it pertains to the COVID-19 pandemic. Ultimately, this will help guide clinical-based policies surrounding COVID-19 and other similar global pandemics to ensure that management of cerebrovascular comorbidity is appropriately prioritized during the global crisis. It will also guide public health guidelines for at-risk populations to reduce risks of complications from such comorbidities., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Web-based platforms are used increasingly to assess cognitive function in unsupervised settings. The utility of cognitive data arising from unsupervised assessments remains unclear. We examined the acceptability, usability, and validity of unsupervised cognitive testing in middle-aged adults enrolled in the Healthy Brain Project., Methods: A total of 1594 participants completed unsupervised assessments of the Cogstate Brief Battery. Acceptability was defined by the amount of missing data, and usability by examining error of test performance and the time taken to read task instructions and complete tests (learnability)., Results: Overall, we observed high acceptability (98% complete data) and high usability (95% met criteria for low error rates and high learnability). Test validity was confirmed by observation of expected inverse relationships between performance and increasing test difficulty and age., Conclusion: Consideration of test design paired with acceptability and usability criteria can provide valid indices of cognition in the unsupervised settings used to develop registries of individuals at risk for Alzheimer's disease., Competing Interests: S Perin, RF Buckley, MP Pase, N Yassi, and YY Lim report no disclosures. A Schembri and P Maruff are full‐time employees of Cogstate Ltd., (© 2020 the Alzheimer's Association.)

Introduction: Superior cognitive performance in older adults may reflect underlying resistance to age-associated neurodegeneration. While elevated amyloid β (Aβ) deposition (Aβ+) has been associated with increased cortical atrophy, it remains unknown whether "SuperAgers" may be protected from Aβ-associated neurodegeneration., Methods: Neuropsychologically defined SuperAgers (n = 172) and cognitively normal for age (n = 172) older adults from the Australian Imaging, Biomarkers and Lifestyle study were case matched. Rates of cortical atrophy over 8 years were examined by SuperAger classification and Aβ status., Results: Of the case-matched SuperAgers and cognitively normal for age older adults, 40.7% and 40.1%, respectively, were Aβ+. Rates of age- and Aβ-associated atrophy did not differ between the groups on any measure. Aβ- individuals displayed the slowest rates of atrophy., Discussion: Maintenance of superior memory in late life does not reflect resistance to age- or Aβ-associated atrophy. However, those individuals who reached old age without cognitive impairment nor elevated Aβ deposition (i.e. Aβ-) displayed reduced rates of cortical atrophy., (© 2019 The Authors.)

Background: Characterizing the earliest demonstrable cognitive decline in middle-aged adults at risk of Alzheimer's disease (AD) will allow for the better understanding of the early disease trajectory, and the provision of therapies prior to clinical symptom onset. We developed an online platform- healthybrainproject.org.au (Healthy Brain Project; HBP)- to recruit, assess, and monitor at-risk middle-aged adults., Objective: Describe the HBP methodology and report baseline characteristics and adherence indices of participants., Methods: Between February 2017 and August 2018, 4,000 community-based middle-aged Australian adults with a first or second-degree family history of dementia enrolled at our website (healthybrainproject.org.au). Participants were directed to complete five modules: "Basics", "Health History", "How You Feel", "How You Live", and "How You Think". Of these, 1,816 participants have received a saliva sampling kit for genetic analysis., Results: Participants had a mean (SD) age of 55.5 (6.8) years, 11.8 (3.4) years of education, and annual personal income of AUD$68,830 ($35,044). Participants took 26.4 (49.7) days after enrolment to complete questionnaires and cognitive tests. Most participants were from Victoria (63%), followed by New South Wales (14%). Most participants (74%) were female and 76% identified as Caucasian. Approximately 36% of participants completed all modules (n = 1,450), and 56% (n = 2,221) completed 4 out of 5 modules. Most saliva kits (89%) had been returned., Conclusion: The HBP joins a handful of online registries worldwide that assess and monitor a large cohort of individuals at risk of AD. Our study extends on these efforts by focusing on midlife, where the earliest signs of cognitive and pathological changes will manifest.

Background: CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome., Methods: In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1, 2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 μm 2 /s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0-2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered., Findings: We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0·47 [95% CI 0·30-0·72], p=0·0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0·77 [0·69-0·86] per 10 mL, p interaction =0·29; diffusion MRI OR 0·87 [0·81-0·94] per 10 mL, p interaction =0·94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low., Interpretation: Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imaging-to-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions., Funding: Medtronic., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background and Purpose: Degeneration of gray matter and subcortical structures after ischemic stroke has been well described. However, little is known about white matter degeneration after stroke. It is unclear whether white matter degeneration occurs throughout the whole brain, or whether patterns of degeneration occur more in specific brain areas., Methods: We prospectively collected National Institutes of Health Stroke Scale (NIHSS) scores and diffusion tensor imaging (DTI) in patients with acute ischemic stroke within the first week after onset (baseline), and at 1 and 3 months. DTI was processed to produce maps of fractional anisotropy, apparent diffusion coefficients, and axial and radial diffusivity. DTI parameters in specified regions-of-interest corresponding to items on the NIHSS were calculated and changes over time were assessed using linear mixed-effect modeling., Results: Seventeen patients were included in the study. Mean age (SD) was 71 (11.7) years, and median (IQR) baseline NIHSS 9 (5-13.3). Changes over time were observed in both visual cortices, contralesional primary motor cortex, premotor cortex, and superior temporal gyrus (P < .05). Changes in the ipsilesional motor cortex and inferior parietal lobule were only seen in patients with scores on the respective NIHSS-items (P < .05). No significant changes in global white matter diffusivity parameters were identified (P > .05)., Conclusion: White matter changes after stroke may be localized rather than a global phenomenon., (© 2018 by the American Society of Neuroimaging.)

Background and Purpose- The volume of estimated ischemic core using computed tomography perfusion (CTP) imaging can identify ischemic stroke patients who are likely to benefit from reperfusion, particularly beyond standard time windows. We assessed the accuracy of pretreatment CTP estimated ischemic core in patients with successful endovascular reperfusion. Methods- Patients from the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) and EXTEND-IA TNK (Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke) databases who had pretreatment CTP, >50% angiographic reperfusion, and follow-up magnetic resonance imaging at 24 hours were included. Ischemic core volume on baseline CTP data was estimated using relative cerebral blood flow <30% (RAPID, iSchemaView). Follow-up diffusion magnetic resonance imaging was registered to CTP, and the diffusion lesion was outlined using a semiautomated algorithm. Volumetric and spatial agreement (using Dice similarity coefficient, average Hausdorff distance, and precision) was assessed, and expert visual assessment of quality was performed. Results- In 120 patients, median CTP estimated ischemic core volume was 7.8 mL (IQR, 1.8-19.9 mL), and median diffusion lesion volume at 24 hours was 30.8 mL (IQR, 14.9-67.6 mL). Median volumetric difference was 4.4 mL (IQR, 1.2-12.0 mL). Dice similarity coefficient was low (median, 0.24; IQR, 0.15-0.37). The median precision (positive predictive value) of 0.68 (IQR, 0.40-0.88) and average Hausdorff distance (median, 3.1; IQR, 1.8-5.7 mm) indicated reasonable spatial agreement for regions estimated as ischemic core at baseline. Overestimation of total ischemic core volume by CTP was uncommon. Expert visual review revealed overestimation predominantly in white matter regions. Conclusions- CTP estimated ischemic core volumes were substantially smaller than follow-up diffusion-weighted imaging lesions at 24 hours despite endovascular reperfusion within 2 hours of imaging. This may be partly because of infarct growth. Volumetric CTP core overestimation was uncommon and not related to imaging-to-reperfusion time. Core overestimation in white matter should be a focus of future efforts to improve CTP accuracy.

Background: Intravenous infusion of alteplase is used for thrombolysis before endovascular thrombectomy for ischemic stroke. Tenecteplase, which is more fibrin-specific and has longer activity than alteplase, is given as a bolus and may increase the incidence of vascular reperfusion., Methods: We randomly assigned patients with ischemic stroke who had occlusion of the internal carotid, basilar, or middle cerebral artery and who were eligible to undergo thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or alteplase (at a dose of 0.9 mg per kilogram; maximum dose, 90 mg) within 4.5 hours after symptom onset. The primary outcome was reperfusion of greater than 50% of the involved ischemic territory or an absence of retrievable thrombus at the time of the initial angiographic assessment. Noninferiority of tenecteplase was tested, followed by superiority. Secondary outcomes included the modified Rankin scale score (on a scale from 0 [no neurologic deficit] to 6 [death]) at 90 days. Safety outcomes were death and symptomatic intracerebral hemorrhage., Results: Of 202 patients enrolled, 101 were assigned to receive tenecteplase and 101 to receive alteplase. The primary outcome occurred in 22% of the patients treated with tenecteplase versus 10% of those treated with alteplase (incidence difference, 12 percentage points; 95% confidence interval [CI], 2 to 21; incidence ratio, 2.2; 95% CI, 1.1 to 4.4; P=0.002 for noninferiority; P=0.03 for superiority). Tenecteplase resulted in a better 90-day functional outcome than alteplase (median modified Rankin scale score, 2 vs. 3; common odds ratio, 1.7; 95% CI, 1.0 to 2.8; P=0.04). Symptomatic intracerebral hemorrhage occurred in 1% of the patients in each group., Conclusions: Tenecteplase before thrombectomy was associated with a higher incidence of reperfusion and better functional outcome than alteplase among patients with ischemic stroke treated within 4.5 hours after symptom onset. (Funded by the National Health and Medical Research Council of Australia and others; EXTEND-IA TNK ClinicalTrials.gov number, NCT02388061 .).

Background and Purpose: Clinical triage scales for prehospital recognition of large vessel occlusion (LVO) are limited by low specificity when applied by paramedics. We created the 3-step ambulance clinical triage for acute stroke treatment (ACT-FAST) as the first algorithmic LVO identification tool, designed to improve specificity by recognizing only severe clinical syndromes and optimizing paramedic usability and reliability., Methods: The ACT-FAST algorithm consists of (1) unilateral arm drift to stretcher <10 seconds, (2) severe language deficit (if right arm is weak) or gaze deviation/hemineglect assessed by simple shoulder tap test (if left arm is weak), and (3) eligibility and stroke mimic screen. ACT-FAST examination steps were retrospectively validated, and then prospectively validated by paramedics transporting culturally and linguistically diverse patients with suspected stroke in the emergency department, for the identification of internal carotid or proximal middle cerebral artery occlusion. The diagnostic performance of the full ACT-FAST algorithm was then validated for patients accepted for thrombectomy., Results: In retrospective (n=565) and prospective paramedic (n=104) validation, ACT-FAST displayed higher overall accuracy and specificity, when compared with existing LVO triage scales. Agreement of ACT-FAST between paramedics and doctors was excellent (κ=0.91; 95% confidence interval, 0.79-1.0). The full ACT-FAST algorithm (n=60) assessed by paramedics showed high overall accuracy (91.7%), sensitivity (85.7%), specificity (93.5%), and positive predictive value (80%) for recognition of endovascular-eligible LVO., Conclusions: The 3-step ACT-FAST algorithm shows higher specificity and reliability than existing scales for clinical LVO recognition, despite requiring just 2 examination steps. The inclusion of an eligibility step allowed recognition of endovascular-eligible patients with high accuracy. Using a sequential algorithmic approach eliminates scoring confusion and reduces assessment time. Future studies will test whether field application of ACT-FAST by paramedics to bypass suspected patients with LVO directly to endovascular-capable centers can reduce delays to endovascular thrombectomy., (© 2018 American Heart Association, Inc.)

Background and hypothesis Intravenous thrombolysis with alteplase remains standard care prior to thrombectomy for eligible patients within 4.5 h of ischemic stroke onset. However, alteplase only succeeds in reperfusing large vessel arterial occlusion prior to thrombectomy in a minority of patients. We hypothesized that tenecteplase is non-inferior to alteplase in achieving reperfusion at initial angiogram, when administered within 4.5 h of ischemic stroke onset, in patients planned to undergo endovascular therapy. Study design EXTEND-IA TNK is an investigator-initiated, phase II, multicenter, prospective, randomized, open-label, blinded-endpoint non-inferiority study. Eligibility requires a diagnosis of ischemic stroke within 4.5 h of stroke onset, pre-stroke modified Rankin Scale≤3 (no upper age limit), large vessel occlusion (internal carotid, basilar, or middle cerebral artery) on multimodal computed tomography and absence of contraindications to intravenous thrombolysis. Patients are randomized to either IV alteplase (0.9 mg/kg, max 90 mg) or tenecteplase (0.25 mg/kg, max 25 mg) prior to thrombectomy. Study outcomes The primary outcome measure is reperfusion on the initial catheter angiogram, assessed as modified treatment in cerebral infarction 2 b/3 or the absence of retrievable thrombus. Secondary outcomes include modified Rankin Scale at day 90 and favorable clinical response (reduction in National Institutes of Health Stroke Scale by ≥8 points or reaching 0-1) at day 3. Safety outcomes are death and symptomatic intracerebral hemorrhage. Trial registration ClinicalTrials.gov NCT02388061.

Background: Preclinical Alzheimer's disease (AD) is defined by cerebral amyloid-β positivity (Aβ+) in cognitively normal (CN) older adults., Objective: To estimate the risk of progression to the symptomatic stages of AD due to PET Aβ+ and the extent that progression was influenced by other demographic, genetic, and clinical characteristics in a large prospective study., Methods: Fine-Gray subdistribution modeling was used to examine the risk of progression from CN to MCI/dementia due to Aβ+, APOEɛ4 carriage, and their interaction in the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging CN cohort (n = 599) over 8 years., Results: 17.7% Aβ+ and 8.1% Aβ-progressed over 8 years (OR: 2.43). Risk of progression for Aβ+ was 65-104% greater than Aβ-. Aβ+ APOEɛ4 carriers were at 348% greater risk than all other participants. Significant risk factors of progression in Aβ+ were age (HR: 1.05), PET SUVR (HR: 2.49) and APOE ɛ4 carriage (HR: 2.63); only age was a significant risk factor in Aβ-(HR: 1.09). Aβ-progressors were not near the threshold for Aβ+. These relationships were not moderated by hypertension, diabetes, obesity, or stroke/TIA., Conclusion: Aβ+ is an important prognostic marker for progression from CN to MCI/dementia in older adults and APOEɛ4 carriage provides further predictive value in the presence of Aβ+. These data suggest that Aβ-associated clinical progression is consistent with clinical-pathological models of AD, whereas progression in the absence of elevated Aβ deposition may be the result of neuropathological processes other than AD that accumulate with age.

Background: Endovascular thrombectomy improves functional outcome in large vessel occlusion ischemic stroke. We examined disability, quality of life, survival and acute care costs in the EXTEND-IA trial, which used CT-perfusion imaging selection., Methods: Large vessel ischemic stroke patients with favorable CT-perfusion were randomized to endovascular thrombectomy after alteplase versus alteplase-only. Clinical outcome was prospectively measured using 90-day modified Rankin scale (mRS). Individual patient expected survival and net difference in Disability/Quality-adjusted life years (DALY/QALY) up to 15 years from stroke were modeled using age, sex, 90-day mRS, and utility scores. Level of care within the first 90 days was prospectively measured and used to estimate procedure and inpatient care costs (US$ reference year 2014)., Results: There were 70 patients, 35 in each arm, mean age 69, median NIHSS 15 (IQR 12-19). The median (IQR) disability-weighted utility score at 90 days was 0.65 (0.00-0.91) in the alteplase-only versus 0.91 (0.65-1.00) in the endovascular group ( p  = 0.005). Modeled life expectancy was greater in the endovascular versus alteplase-only group (median 15.6 versus 11.2 years, p  = 0.02). The endovascular thrombectomy group had fewer simulated DALYs lost over 15 years [median (IQR) 5.5 (3.2-8.7) versus 8.9 (4.7-13.8), p  = 0.02] and more QALY gained [median (IQR) 9.3 (4.2-13.1) versus 4.9 (0.3-8.5), p  = 0.03]. Endovascular patients spent less time in hospital [median (IQR) 5 (3-11) days versus 8 (5-14) days, p  = 0.04] and rehabilitation [median (IQR) 0 (0-28) versus 27 (0-65) days, p  = 0.03]. The estimated inpatient costs in the first 90 days were less in the thrombectomy group (average US$15,689 versus US$30,569, p  = 0.008) offsetting the costs of interhospital transport and the thrombectomy procedure (average US$10,515). The average saving per patient treated with thrombectomy was US$4,365., Conclusion: Thrombectomy patients with large vessel occlusion and salvageable tissue on CT-perfusion had reduced length of stay and overall costs to 90 days. There was evidence of clinically relevant improvement in long-term survival and quality of life., Clinical Trial Registration: http://www.ClinicalTrials.gov NCT01492725 (registered 20/11/2011).

Background and Purpose: Simultaneous multiple intracerebral hemorrhages (SMICHs) are uncommon. Few single-center studies have analyzed characteristics and outcome of SMICH. We analyzed clinical characteristics and outcome of SMICH patients from 2 comprehensive stroke centers., Methods: Baseline imaging from consecutive intracerebral hemorrhage (ICH) patients (n=1552) from Helsinki ICH study and Royal Melbourne Hospital ICH study was screened for SMICH. ICH pathogenesis was classified according to the structural lesion, medication, amyloid angiopathy, systemic/other disease, hypertension, undetermined classification system (SMASH-U). ICH caused by trauma, tumor, and aneurysmal rupture was excluded. Baseline clinical and radiological characteristics and 90-day mortality were compared between SMICH and single ICH patients. Association of SMICH with 90-day mortality was assessed in multivariable logistic regression models adjusted for predictors of ICH outcome., Results: Of 1452 patients, 85 (5.9%) were classified as SMICH. SMICH were more often female (58% versus 42%; P =0.004), had lower baseline Glasgow Coma Scale (12 versus 14; P =0.008), and more frequent lobar location (59% versus 34%; P <0.001) compared with single ICH. The SMASH-U pathogenesis of SMICH patients was less often hypertensive (20% versus 37%; P =0.001), more often systemic coagulopathy (12% versus 3%; P <0.001), and trended toward more cerebral amyloid angiopathy (32% versus 23%; P =0.071). SMICH was not associated with 90-day mortality on univariate (37% versus 35%; P =0.610), multivariable (odds ratio, 0.783; 95% confidence interval, 0.401-1.529; P =0.473), or propensity score-matched analyses (odds ratio, 0.760; 95% confidence interval, 0.352-1.638; P =0.484)., Conclusions: SMICH occurs in ≈1 in 20 ICH, more commonly with lobar located hematomas and systemic coagulopathy with less hypertensive angiopathy. The associated mortality is similar to single ICH. Given varied etiologies, SMICH management should target the underlying pathology., (© 2017 American Heart Association, Inc.)

Introduction: Few proven therapies for intracerebral haemorrhage exist. Preliminary observational evidence suggests that sulphonylurea and metformin may be protective in ischaemic stroke. We assessed the association of pre-intracerebral haemorrhage sulphonylurea and metformin use on outcome in diabetic patients., Methods: We merged datasets from the consecutive single-centre Helsinki ICH Study, the intracerebral haemorrhage arm of the Virtual International Stroke Trials Archive (VISTA-ICH) and the Royal Melbourne Hospital ICH Study. Logistic regression adjusting for known predictors of intracerebral haemorrhage outcome (age, sex, baseline Glasgow Coma Scale, National Institutes of Health Stroke Scale, intracerebral haemorrhage volume, infratentorial location, intraventricular extension, and pre-intracerebral haemorrhage warfarin use) estimated the association of metformin and sulphonylurea with all-cause 90-day mortality., Results: From a dataset of 2404 consecutive intracerebral haemorrhage patients, we included 374 (16%) patients with diabetes. Of these, 113 (30%) died by 90 days. Metformin was used in 148 (40%) patients and sulphonylurea in 115 (31%) patients at intracerebral haemorrhage onset. After adjusting for baseline characteristics, metformin use was associated with lower 90-day mortality (OR 0.51; 95% CI 0.26-0.97; p  = 0.041) irrespective of whether the drug was continued or not during the admission, while sulphonylurea use was not associated with mortality (OR 0.96; 95% CI 0.49-1.88; p  = 0.906). Haematoma location or evacuation did not modify the association between metformin and mortality; neither did adding insulin use, baseline glucose and serum creatinine into the model (OR 0.50; 95% CI 0.25-0.99; p  = 0.047)., Conclusion: Pre-intracerebral haemorrhage metformin use was associated with improved outcome in diabetic intracerebral haemorrhage patients. Our results generate hypotheses which after further validation could be tested in clinical trials., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: TT reports receiving grants from Boehringer-Ingelheim, Sanofi Aventis, Brains Gate, Bayer, Pfizer, and personal fees from Bayer and Pfizer, outside the submitted work. SMD has received consulting fees from Boehringer Ingelheim, BMS, Pfizer, Ever Neuropharma and Medtronic. AM reports speaker’s honoraria and travel cost from Siemens and speaker’s honoraria and consulting fees from Stryker and Boehringer Ingelheim outside the submitted work. All other authors report no relevant disclosures.

Cerebral ischaemic and haemorrhagic lesions are commonly visualised on MRI studies in older patients. Although there is evidence for their association with cognitive outcome in large series, the utility of their detection for individual prognostication is limited at this stage. Studies which evaluate these findings as a comprehensive suite, with due attention to alternative pathological conditions, especially Alzheimer disease, may improve the understanding of the precise contribution of cerebrovascular disease towards cognitive impairment and dementia, and the potential interdependence of this contribution on the presence and severity of alternative brain pathology.

Introduction: Haematoma and oedema size determines outcome after intracerebral haemorrhage (ICH), with each added 10 % volume increasing mortality by 5 %. We assessed the reliability of semi-automated computed tomography planimetry using Analyze and Osirix softwares., Methods: We randomly selected 100 scans from 1329 ICH patients from two centres. We used Hounsfield Unit thresholds of 5-33 for oedema and 44-100 for ICH. Three raters segmented all scans using both softwares and 20 scans repeated for intra-rater reliability and segmentation timing. Volumes reported by Analyze and Osirix were compared to volume estimates calculated using the best practice method, taking effective individual slice thickness, i.e. voxel depth, into account., Results: There was excellent overall inter-rater, intra-rater and inter-software reliability, all intraclass correlation coefficients >0.918. Analyze and Osirix produced similar haematoma (mean difference: Analyze - Osirix = 1.5 ± 5.2 mL, 6 %, p ≤ 0.001) and oedema volumes (-0.6 ± 12.6 mL, -3 %, p = 0.377). Compared to a best practice approach to volume calculation, the automated haematoma volume output was 2.6 mL (-11 %) too small with Analyze and 4.0 mL (-18 %) too small with Osirix, whilst the oedema volumes were 2.5 mL (-12 %) and 5.5 mL (-25 %) too small, correspondingly. In scans with variable slice thickness, the volume underestimations were larger, -29%/-36 % for ICH and -29 %/-41 % for oedema. Mean segmentation times were 6:53 ± 4:02 min with Analyze and 9:06 ± 5:24 min with Osirix (p < 0.001)., Conclusion: Our results demonstrate that the method used to determine voxel depth can influence the final volume output markedly. Results of clinical and collaborative studies need to be considered in the context of these methodological differences.

The value of CT perfusion (CTP) in detecting acute lacunar infarcts (LACI) has not been well established. We tested the sensitivity of CTP for LACI. CTP maps of consecutive stroke patients from 2009-2013 were examined. MRI diffusion imaging was used to identify those with LACI. Two stroke neurologists independently evaluated the CTP maps for evidence of a perfusion lesion in a deep perforating artery territory. Cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT) and time to maximum (Tmax) maps were first examined in isolation and then in combination. Inter-observer agreement was measured using Cohen's κ. The lesions identified were later confirmed against the diffusion MRI reference and the sensitivity and specificity of CTP maps calculated. A total of 63 patient scans were analysed. There were 32 patients with MRI-confirmed LACI within the coverage of CTP; 18 in the striatum, 10 thalamic, and four in the corona radiata. Another 31 patients had normal MRI. Inter-rater agreement was good (κ=0.83). Sensitivity (blinded consensus) was highest for MTT (56.2%) compared to Tmax (25%, p<0.001), CBV (9.3%, p=0.021) and CBF (43.7%, p<0.001). MTT maps enable detection of a significant proportion of LACI using CTP., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Only 37 cases of stroke during or soon after long-haul flights have been published to our knowledge. In this retrospective observational study, we searched the Royal Melbourne Hospital prospective stroke database and all discharge summaries from 1 September 2003 to 30 September 2014 for flight-related strokes, defined as patients presenting with stroke within 14days of air travel. We hypothesised that a patent foramen ovale (PFO) is an important, but not the only mechanism, of flight-related stroke. We describe the patient, stroke, and flight characteristics. Over the study period, 131 million passengers arrived at Melbourne airport. Our centre admitted 5727 stroke patients, of whom 42 (0.73%) had flight-related strokes. Flight-related stroke patients were younger (median age 65 versus 73, p<0.001), had similar stroke severity, and received intravenous thrombolysis more often than non-flight-related stroke patients. Seven patients had flight-related intracerebral haemorrhage. The aetiology of the ischaemic strokes was cardioembolic in 14/35 (40%), including seven patients with confirmed PFO, one with atrial septal defect, four with atrial fibrillation, one with endocarditis, and one with aortic arch atheroma. Paradoxical embolism was confirmed in six patients. Stroke related to air travel is a rare occurrence, less than one in a million. Although 20% of patients had a PFO, distribution of stroke aetiologies was diverse and was not limited to PFO and paradoxical embolism., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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 (r (2) = 0.167, p = 0.017). Higher total creatine was associated with better neurological outcome at 24 h (r (2) = 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.

High-fidelity intracranial electrode arrays for recording and stimulating brain activity have facilitated major advances in the treatment of neurological conditions over the past decade. Traditional arrays require direct implantation into the brain via open craniotomy, which can lead to inflammatory tissue responses, necessitating development of minimally invasive approaches that avoid brain trauma. Here we demonstrate the feasibility of chronically recording brain activity from within a vein using a passive stent-electrode recording array (stentrode). We achieved implantation into a superficial cortical vein overlying the motor cortex via catheter angiography and demonstrate neural recordings in freely moving sheep for up to 190 d. Spectral content and bandwidth of vascular electrocorticography were comparable to those of recordings from epidural surface arrays. Venous internal lumen patency was maintained for the duration of implantation. Stentrodes may have wide ranging applications as a neural interface for treatment of a range of neurological conditions.

Introduction: Cerebral atrophy after stroke is associated with poor functional outcome. The prediction and prevention of post-stroke brain atrophy could therefore represent a target for neurorestorative therapies. We investigated the associations between peri-infarct metabolite concentrations measured by quantitative MRS and brain volume change in the infarct hemisphere after stroke., Methods: Twenty patients with ischemic stroke were enrolled. Patients underwent 3T-MRI within 1 week of onset, and at 1 and 3 months. At the baseline scan, an MRS voxel was placed manually in the peri-infarct area and another in the corresponding contralateral region. Volumetric analysis of T1 images was performed using two automated processing packages. Changes in gray and white matter volume were assessed as percentage change between 1 and 3 months., Results: Mean concentrations (institutional units) of N-acetylaspartic acid (NAA) (6.1 vs 7.0, p = 0.039), total creatine (Cr+PCr) (5.4 vs 5.8, p = 0.043), and inositol (4.5 vs 5.0, p = 0.014), were significantly lower in the peri-infarct region compared with the contralateral hemisphere. There was a significant correlation between baseline peri-infarct NAA and white matter volume change in the infarct hemisphere between 1 and 3 months, with lower NAA being associated with subsequent white matter atrophy (Spearman's rho = 0.66, p = 0.010). The baseline concentration of Cr+PCr was also significantly correlated with white matter atrophy in the infarct hemisphere (Spearman's rho = 0.59, p = 0.027). Both of these associations were significant after adjustment for the false discovery rate and were validated using the secondary volumetric method., Conclusion: MRS may be useful in the prediction of white matter atrophy post-stroke and in the testing of novel neurorestorative therapies.

Background: Infarct location has a critical effect on patient outcome after ischemic stroke, but the study of its role independent of overall lesion volume is challenging. We performed a retrospective, hypothesis-generating study of the effect of infarct location on three-month functional outcome in a pooled analysis of the EPITHET and DEFUSE studies., Methods: Posttreatment MRI diffusion lesions were manually segmented and transformed into standard-space. A novel composite brain atlas derived from three standard brain atlases and encompassing 132 cortical and sub-cortical structures was used to segment the transformed lesion into different brain regions, and calculate the percentage of each region infarcted. Classification and Regression Tree (CART) analysis was performed to determine the important regions in each hemisphere associated with nonfavorable outcome at day 90 (modified Rankin score [mRS] > 1)., Results: Overall, 152 patients (82 left hemisphere) were included. Median diffusion lesion volume was 37·0 ml, and median baseline National Institutes of Health Stroke Score was 13. In the left hemisphere, the strongest determinants of nonfavorable outcome were infarction of the uncinate fasciculus, followed by precuneus, angular gyrus and total diffusion lesion volume. In the right hemisphere, the strongest determinants of nonfavorable outcome were infarction of the parietal lobe followed by the putamen., Conclusions: Assessment of infarct location using CART demonstrates regional characteristics associated with poor outcome. Prognostically important locations include limbic, default-mode and language areas in the left hemisphere, and visuospatial and motor regions in the right hemisphere., (© 2015 World Stroke Organization.)

Introduction: Longitudinal brain volume changes have been investigated in a number of cerebral disorders as a surrogate marker of clinical outcome. In stroke, unique methodological challenges are posed by dynamic structural changes occurring after onset, particularly those relating to the infarct lesion. We aimed to evaluate agreement between different analysis methods for the measurement of post-stroke brain volume change, and to explore technical challenges inherent to these methods., Methods: Fifteen patients with anterior circulation stroke underwent magnetic resonance imaging within 1 week of onset and at 1 and 3 months. Whole-brain as well as grey- and white-matter volume were estimated separately using both an intensity-based and a surface watershed-based algorithm. In the case of the intensity-based algorithm, the analysis was also performed with and without exclusion of the infarct lesion. Due to the effects of peri-infarct edema at the baseline scan, longitudinal volume change was measured as percentage change between the 1 and 3-month scans. Intra-class and concordance correlation coefficients were used to assess agreement between the different analysis methods. Reduced major axis regression was used to inspect the nature of bias between measurements., Results: Overall agreement between methods was modest with strong disagreement between some techniques. Measurements were variably impacted by procedures performed to account for infarct lesions., Conclusions: Improvements in volumetric methods and consensus between methodologies employed in different studies are necessary in order to increase the validity of conclusions derived from post-stroke cerebral volumetric studies. Readers should be aware of the potential impact of different methods on study conclusions.

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.).

Background: Advanced imaging may refine patient selection for ischemic stroke treatment but delays to acquire and process the imaging have limited implementation., Aims: We examined the feasibility of imaging selection in clinical practice using fully automated software in the EXTEND trial program., Methods: CTP and perfusion-diffusion MRI data were processed using fully-automated software to generate a yes/no 'mismatch' classification that determined eligibility for trial therapies. The technical failure/mismatch classification error rate and time to image and treat with CT vs. MR-based selection were examined., Results: In a consecutive series of 776 patients from five sites over six-months the technical failure rate of CTP acquisition/processing (uninterpretable maps) was 3·4% (26/776, 95%CI 2·2-4·9%). Mismatch classification was overruled by expert review in an additional 9·0% (70/776, 95%CI 7·1-11·3%) due to artifactual 'perfusion lesion'. In 154 consecutive patients at one site, median additional time to acquire CTP after non-contrast CT was 6·5 min. Subsequent RAPID processing time varied from 3-10 min across 20 trial centers (median 5 min 20 s). In the EXTEND trial, door-to-needle times in patients randomized on the basis of CTP (n = 47) were median 78 min shorter than MRI-selected (n = 16) patients (P < 0·001)., Conclusions: Automated CTP-based mismatch selection is rapid, robust in clinical practice, and associated with faster treatment decisions than MRI. This technological advance has the potential to improve the standardization and reproducibility of interpretation of advanced imaging and extend use to practice settings beyond highly specialized academic centers., (© 2014 World Stroke Organization.)

Background: Remote structural and functional changes have been previously described after stroke and may have an impact on clinical outcome. We aimed to use multimodal MRI to investigate contralesional subcortical structural and functional changes 3 months after anterior circulation ischemic stroke., Methods: Fifteen patients with acute ischemic stroke had multimodal MRI imaging (including high resolution structural T1-MPRAGE and resting state fMRI) within 1 week of onset and at 1 and 3 months. Seven healthy controls of similar age group were also imaged at a single time point. Contralesional subcortical structural volume was assessed using an automated segmentation algorithm in FMRIB's Integrated Registration and Segmentation Tool (FIRST). Functional connectivity changes were assessed using the intrinsic connectivity contrast (ICC), which was calculated using the functional connectivity toolbox for correlated and anticorrelated networks (Conn)., Results: Contralesional thalamic volume in the stroke patients was significantly reduced at 3 months compared to baseline (median change -2.1%, interquartile range [IQR] -3.4-0.4, p = 0.047), with the predominant areas demonstrating atrophy geometrically appearing to be the superior and inferior surface. The difference in volume between the contralesional thalamus at baseline (mean 6.41 ml, standard deviation [SD] 0.6 ml) and the mean volume of the 2 thalami in controls (mean 7.22 ml, SD 1.1 ml) was not statistically significant. The degree of longitudinal thalamic atrophy in patients was correlated with baseline stroke severity with more severe strokes being associated with a greater degree of atrophy (Spearman's rho -0.54, p = 0.037). There was no significant difference between baseline contralesional thalamic ICC in patients and control thalamic ICC. However, in patients, there was a significant linear reduction in the mean ICC of the contralesional thalamus over the imaging time points (p = 0.041), indicating reduced connectivity to the remainder of the brain., Conclusions: These findings highlight the importance of remote brain areas, such as the contralesional thalamus, in stroke recovery. Similar methods have the potential to be used in the prediction of stroke outcome or as imaging biomarkers of stroke recovery., (© 2015 S. Karger AG, Basel.)

The aim of acute stroke treatment is to reperfuse the penumbra. However, not all posttreatment reperfusion is associated with a good outcome. Recent arterial spin labeling (ASL) studies suggest that patients with hyperperfusion after treatment have a better clinical recovery. This study aimed to determine whether there was a distinctive magnetic resonance spectroscopy (MRS) metabolite profile in hyperperfused tissue after stroke reperfusion therapy. We studied 77 ischemic stroke patients 24 hours after treatment using MRS (single voxel spectroscopy, point resolved spectroscopy, echo time 30 ms), ASL, and diffusion-weighted imaging (DWI). Magnetic resonance spectroscopy voxels were placed in cortical tissue that was penumbral on baseline perfusion imaging but had reperfused at 24 hours (and did not progress to infarction). Additionally, 20 healthy age matched controls underwent MRS. In all, 24 patients had hyperperfusion; 36 had reperfused penumbra without hyperperfusion, and 17 were excluded due to no reperfusion. Hyperperfusion was significantly related to better 3-month clinical outcome compared with patients without hyperperfusion (P=0.007). Patients with hyperperfusion showed increased glutamate (P<0.001), increased N-Acetylaspartate (NAA) (P=0.038), and increased lactate (P<0.002) in reperfused tissue compared with contralateral tissue and healthy controls. Hyperperfused tissue has a characteristic metabolite signature, suggesting that it is more metabolically active and perhaps more capable of later neuroplasticity.

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 <70 ml, 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 1 g 10-min bolus followed by 1 g 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 >6 ml 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 The Authors. International Journal of Stroke © 2013 World Stroke Organization.)

A 57-year-old male patient with hereditary hemorrhagic telangiectasia presented with an acute right middle cerebral artery ischemic stroke. Investigations revealed a right middle cerebral artery M2 occlusion, hypoxemia, and a large pulmonary arteriovenous malformation and right lower limb deep venous thrombosis. Closure of the pulmonary arteriovenous malformation was successfully performed with an Amplatzer device. Catheter closure of pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia is a recognized treatment modality to prevent recurrent ischemic stroke and other embolic and hemorrhagic complications., (Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Intracerebral hemorrhage is a serious potential complication of stroke thrombolysis. We investigated the optimal computed tomography perfusion (CTP) parameter to predict cerebral parenchymal hematoma (PH) in acute ischemic stroke., Methods: Patients with hyperacute ischemic stroke had whole-brain CTP and follow-up computed tomography/MRI to identify hemorrhagic transformation. The association of the 3 parameters relative cerebral blood flow, relative cerebral blood volume, and time to maximum (Tmax) with PH was examined using receiver operating characteristic analysis and multivariate logistic regression., Results: Of 132 patients, 70 were treated with thrombolysis, and 14 (10.6%) developed PH on follow-up imaging. Baseline National Institutes of Health Stroke Scale score (P=0.033) and thrombolysis (P=0.003) were both predictive of PH. Receiver operating characteristic analysis revealed that Tmax>14 s (area under the curve=0.748; P=0.002) and relative cerebral blood flow <30% of contralateral mean (area under the curve=0.689, P=0.021) were the optimal thresholds, and the Bayesian information criterion (+2.6) indicated that Tmax was more strongly associated with PH than relative cerebral blood flow. Tmax >14 s volumes of >5 mL allowed prediction of PH with sensitivity of 79%, specificity of 68%, and negative likelihood ratio of 3.16. Tmax>14 s volume and thrombolysis were both independently predictive of PH in a multivariate logistic regression model (P<0.05)., Conclusions: Tmax >14 s was the CTP parameter most strongly associated with PH. This outperformed relative cerebral blood flow <30%, which closely equates to CTP estimates of ischemic core volume. Although ischemic core volume on CTP is useful in the pretreatment prediction of PH, severe hypoperfusion on Tmax is more strongly associated and may allow better prediction of the likely anatomic location of hemorrhage.

Objective: To test the transferability of the Helsinki stroke thrombolysis model that achieved a median 20-minute door-to-needle time (DNT) to an Australian health care setting., Methods: The existing "code stroke" model at the Royal Melbourne Hospital was evaluated and restructured to include key components of the Helsinki model: 1) ambulance prenotification with patient details alerting the stroke team to meet the patient on arrival; 2) patients transferred directly from triage onto the CT table on the ambulance stretcher; and 3) tissue plasminogen activator (tPA) delivered in CT immediately after imaging. We analyzed our prospective, consecutive tPA registry for effects of these protocol changes on our DNT after implementation during business hours (8 am to 5 pm Monday-Friday) from May 2012., Results: There were 48 patients treated with tPA in the 8 months after the protocol change. Compared with 85 patients treated in 2011, the median (interquartile range) DNT was reduced from 61 (43-75) minutes to 46 (24-79) minutes (p = 0.040). All of the effect came from the change in the in-hours DNT, down from 43 (33-59) to 25 (19-48) minutes (p = 0.009), whereas the out-of-hours delays remain unchanged, from 67 (55-82) to 62 (44-95) minutes (p = 0.835)., Conclusion: We demonstrated rapid transferability of an optimized tPA protocol to a different health care setting. With the cooperation of ambulance, emergency, and stroke teams, we succeeded in the absence of a dedicated neurologic emergency department or electronic patient records, which are features of the Finnish system. The next challenge is providing the same service out-of-hours.