Tenecteplase versus standard of care for minor ischaemic stroke with proven occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial.

BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality. METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual. FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059). INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis. FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.

Quantitative detection of grey and white matter amyloid pathology using a combination of K114 and CRANAD-3 fluorescence.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that exacts a huge toll on the patient, the healthcare system and society in general. Abundance and morphology of protein aggregates such as amyloid ß plaques and tau tangles, along with cortical atrophy and gliosis are used as measures to assess the changes in the brain induced by the disease. Not all of these parameters have a direct correlation with cognitive decline. Studies have shown that only particular protein conformers can be the main drivers of disease progression, and conventional approaches are unable to distinguish different conformations of disease-relevant proteins. METHODS AND RESULTS: Using the fluorescent amyloid probes K114 and CRANAD-3 and spectral confocal microscopy, we examined formalin-fixed paraffin-embedded brain samples from different control and AD cases. Based on the emission spectra of the probes used in this study, we found that certain spectral signatures can be correlated with different aggregates formed by different proteins. The combination of spectral imaging and advanced image analysis tools allowed us to detect variability of protein deposits across the samples. CONCLUSION: Our proposed method offers a quicker and easier neuropathological assessment of tissue samples, as well as introducing an additional parameter by which protein aggregates can be discriminated.

Dementia risk and prevention by targeting modifiable vascular risk factors.

The incidence of dementia is expected to double in the next 20 years and will contribute to heavy social and economic burden. Dementia is caused by neuronal loss that leads to brain atrophy years before symptoms manifest. Currently, no cure exists and extensive efforts are being made to mitigate cognitive impairment in late life in order to reduce the burden on patients, caregivers, and society. The most common type of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) often co-exists in the brain and shares common, modifiable risk factors, which are targeted in numerous secondary prevention trials. There is a growing need for non-pharmacological interventions and infrastructural support from governments to encourage psychosocial and behavioral interventions. Secondary prevention trials need to be redesigned based on the risk profile of individual subjects, which require the use of validated and standardized clinical, biological, and neuroimaging biomarkers. Multi-domain approaches have been proposed in high-risk populations that target optimal treatment; clinical trials need to recruit individuals at the highest risk of dementia before symptoms develop, thereby identifying an enriched disease group to test preventative and disease modifying strategies. The underlying aim should be to reduce microscopic brain tissue loss by modifying vascular and lifestyle risk factors over a relatively short period of time, thus optimizing the opportunity for preventing dementia in the future. Collaboration between international research groups is of key importance to the optimal use and allocation of existing resources, and the development of new techniques in preventing dementia. This article is part of the Special Issue "Vascular Dementia".

Randomized assessment of rapid endovascular treatment of ischemic stroke.

BACKGROUND: Among patients with a proximal vessel occlusion in the anterior circulation, 60 to 80% of patients die within 90 days after stroke onset or do not regain functional independence despite alteplase treatment. We evaluated rapid endovascular treatment in addition to standard care in patients with acute ischemic stroke with a small infarct core, a proximal intracranial arterial occlusion, and moderate-to-good collateral circulation. METHODS: We randomly assigned participants to receive standard care (control group) or standard care plus endovascular treatment with the use of available thrombectomy devices (intervention group). Patients with a proximal intracranial occlusion in the anterior circulation were included up to 12 hours after symptom onset. Patients with a large infarct core or poor collateral circulation on computed tomography (CT) and CT angiography were excluded. Workflow times were measured against predetermined targets. The primary outcome was the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. A proportional odds model was used to calculate the common odds ratio as a measure of the likelihood that the intervention would lead to lower scores on the modified Rankin scale than would control care (shift analysis). RESULTS: The trial was stopped early because of efficacy. At 22 centers worldwide, 316 participants were enrolled, of whom 238 received intravenous alteplase (120 in the intervention group and 118 in the control group). In the intervention group, the median time from study CT of the head to first reperfusion was 84 minutes. The rate of functional independence (90-day modified Rankin score of 0 to 2) was increased with the intervention (53.0%, vs. 29.3% in the control group; P<0.001). The primary outcome favored the intervention (common odds ratio, 2.6; 95% confidence interval, 1.7 to 3.8; P<0.001), and the intervention was associated with reduced mortality (10.4%, vs. 19.0% in the control group; P=0.04). Symptomatic intracerebral hemorrhage occurred in 3.6% of participants in intervention group and 2.7% of participants in control group (P=0.75). CONCLUSIONS: Among patients with acute ischemic stroke with a proximal vessel occlusion, a small infarct core, and moderate-to-good collateral circulation, rapid endovascular treatment improved functional outcomes and reduced mortality. (Funded by Covidien and others; ESCAPE ClinicalTrials.gov number, NCT01778335.).

Validation of a proteomic biomarker panel to diagnose minor-stroke and transient ischaemic attack: phase 2 of SpecTRA, a large scale translational study.

OBJECTIVE: To validate our previously developed 16 plasma-protein biomarker panel to differentiate between transient ischaemic attack (TIA) and non-cerebrovascular emergency department (ED) patients. METHOD: Two consecutive cohorts of ED patients prospectively enrolled at two urban medical centers into the second phase of SpecTRA study (training, cohort 2A, n = 575; test, cohort 2B, n = 528). Plasma samples were analyzed using liquid chromatography/multiple reaction monitoring-mass spectrometry. Logistic regression models which fit cohort 2A were validated on cohort 2B. RESULTS: Three of the panel proteins failed quality control and were removed from the panel. During validation, panel models did not outperform a simple motor/speech (M/S) deficit variable. Post-hoc analyses suggested the measured behaviour of L-selectin and coagulation factor V contributed to poor model performance. Removal of these proteins increased the external performance of a model containing the panel and the M/S variable. CONCLUSIONS: Univariate analyses suggest insulin-like growth factor-binding protein 3 and serum paraoxonase/lactonase 3 are reliable and reproducible biomarkers for TIA status. Logistic regression models indicated L-selectin, apolipoprotein B-100, coagulation factor IX, and thrombospondin-1 to be significant multivariate predictors of TIA. We discuss multivariate feature subset analyses as an exploratory technique to better understand a panel's full predictive potential.

A longitudinal magnetic resonance imaging study of neurodegenerative and small vessel disease, and clinical cognitive trajectories in non demented patients with transient ischemic attack: the PREVENT study.

BACKGROUND: Late-life cognitive decline, caused by progressive neuronal loss leading to brain atrophy years before symptoms are detected, is expected to double in Canada over the next two decades. Cognitive impairment in late life is attributed to vascular and lifestyle related risk factors in mid-life in a substantial proportion of cases (50%), thereby providing an opportunity for effective prevention of cognitive decline if incipient disease is detected earlier. Patients presenting with transient ischemic attack (TIA) commonly display some degree of cognitive impairment and are at a 4-fold increased risk of dementia. In the Predementia Neuroimaging of Transient Ischemic Attack (PREVENT) study, we will address what disease processes (i.e., Alzheimer's vs. vascular disease) lead to neurodegeneration, brain atrophy, and cognitive decline, and whether imaging measurements of brain iron accumulation using quantitative susceptibility mapping predicts subsequent brain atrophy and cognitive decline. METHODS: A total of 440 subjects will be recruited for this study with 220 healthy subjects and 220 TIA patients. Early Alzheimer's pathology will be determined by cerebrospinal fluid samples (including tau, a marker of neuronal injury, and amyloid ß1-42) and by MR measurements of iron accumulation, a marker for Alzheimer's-related neurodegeneration. Small vessel disease will be identified by changes in white matter lesion volume. Predictors of advanced rates of cerebral and hippocampal atrophy at 1 and 3 years will include in vivo Alzheimer's disease pathology markers, and MRI measurements of brain iron accumulation and small vessel disease. Clinical and cognitive function will be assessed annually post-baseline for a period of 5-years using a clinical questionnaire and a battery of neuropsychological tests, respectively. DISCUSSION: The PREVENT study expects to demonstrate that TIA patients have increased early progressive rates of cerebral brain atrophy after TIA, before cognitive decline can be clinically detected. By developing and optimizing high-level machine learning models based on clinical data, image-based (quantitative susceptibility mapping, regional brain, and white matter lesion volumes) features, and cerebrospinal fluid biomarkers, PREVENT will provide a timely opportunity to identify individuals at greatest risk of late-life cognitive decline early in the course of disease, supporting future therapeutic strategies for the promotion of healthy aging.

Imaging and Baseline Predictors of Cognitive Performance in Minor Ischemic Stroke and Patients With Transient Ischemic Attack at 90 Days.

BACKGROUND AND PURPOSE: Few studies have examined predictors of cognitive impairment after minor ischemic stroke and transient ischemic attack (TIA). We examined clinical and imaging features associated with worse cognitive performance at 90 days. METHODS: TIA or patients with minor stroke underwent neuropsychological testing 90 days post event. Z scores were calculated for cognitive tests, and then grouped into domains of executive function (EF), psychomotor processing speed (PS), and memory. White matter hyperintensity and diffusion-weighted imaging volumes were measured on baseline magnetic resonance imaging. Ninety-day outcomes included modified Rankin Scale (mRS) and Centre for Epidemiological Studies Depression Scale (CES-D) score. RESULTS: Ninety-two patients were included, 76% male, 54% TIA, and mean age 65.1±12.0. Sixty-four percent were diffusion-weighted imaging positive. Median domain z scores were not significantly different from published norms (P>0.05): memory -0.03, EF -0.12, and PS -0.05. Patient performance ≥1 SD below normal was 20% on memory, 16% on PS, and 17% on EF. Cognitive scores did not differ by diagnosis (stroke versus TIA), stroke pathogenesis, presence of obstructive sleep apnea, and diffusion-weighted imaging or white matter hyperintensity volumes. In multivariable analyses, lower EF was associated with previous cortical infarct on magnetic resonance imaging (P=0.03), mRS score of >1; P=0.0003 and depressive symptoms (CES-D ≥16; P=0.03). Lower PS scores were associated with previous cortical infarct (P=0.02), acute bilateral positive diffusion-weighted imaging (P=0.02), mRS score of >1 (P=0.003), and CES-D ≥16 (P=0.03). CONCLUSIONS: Despite average-range cognitive performance in this TIA and population with minor stroke, we found associations of EF and PS with evidence of previous stroke, postevent disability, and depression.

Intra-Arterial Therapy and Post-Treatment Infarct Volumes: Insights From the ESCAPE Randomized Controlled Trial.

BACKGROUND AND PURPOSE: The goal of reperfusion therapy in acute ischemic stroke is to limit brain infarction. The objective of this study was to investigate whether the beneficial effect of endovascular treatment on functional outcome could be explained by a reduction in post-treatment infarct volume. METHODS: The Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial was a multicenter randomized open-label trial with blinded outcome evaluation. Among 315 enrolled subjects (endovascular treatment n=165; control n=150), 314 subject's infarct volumes at 24 to 48 hours on magnetic resonance imaging (n=254) or computed tomography (n=60) were measured. Post-treatment infarct volumes were compared by treatment assignment and recanalization/reperfusion status. Appropriate statistical models were used to assess relationship between baseline clinical and imaging variables, post-treatment infarct volume, and functional status at 90 days (modified Rankin Scale). RESULTS: Median post-treatment infarct volume in all subjects was 21 mL (interquartile range =65 mL), in the intervention arm, 15.5 mL (interquartile range =41.5 mL), and in the control arm, 33.5 mL (interquartile range =84 mL; P<0.01). Baseline National Institute of Health Stroke Scale (P<0.01), site of occlusion (P<0.01), baseline noncontrast computed tomographic scan Alberta Stroke Program Early CT score (ASPECTS) (P<0.01), and recanalization (P<0.01) were independently associated with post-treatment infarct volume, whereas age, sex, treatment type, intravenous alteplase, and time from onset to randomization were not (P>0.05). Post-treatment infarct volume (P<0.01) and delta National Institute of Health Stroke Scale (P<0.01) were independently associated with 90-day modified Rankin Scale, whereas laterality (left versus right) was not. CONCLUSIONS: These results support the primary results of the ESCAPE trial and show that the biological underpinning of the success of endovascular therapy is a reduction in infarct volume. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01778335.

Infarct in a New Territory After Treatment Administration in the ESCAPE Randomized Controlled Trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times).

BACKGROUND AND PURPOSE: Infarct in a new previously unaffected territory (INT) is a potential complication of endovascular treatment. We applied a recently proposed methodology to identify and classify INTs in the ESCAPE randomized controlled trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times). METHODS: The core laboratory identified INTs on 24-hour follow-up imaging, blinded to treatment allocation, after assessing all baseline imaging. INTs were classified into 3 types (I-III) and 2 subtypes (A/B) based on size and if catheter manipulation was likely performed across the vessel territory ostium. Logistic regression was used to understand the effect of multiple a priori identified variables on INT occurrence. Ordinal logistic regression was used to analyze the effect of INTs on modified Rankin Scale shift at 90 days. RESULTS: From 308 patients included, 14 INTs (4.5% overall; 2.8% on follow-up noncontrast computed tomography, 11.7% on follow-up magnetic resonance imaging) were identified (5.0% in endovascular treatment arm versus 4.0% in control arm [P=0.7]). The use of intravenous alteplase was associated with a 68% reduction in the odds of INT occurrence (3.0% with versus 9.1% without; odds ratio, 0.32; 95% confidence interval, 0.11-0.96; adjusted for age, sex, and treatment type). No other variables were associated with INTs. INT occurrence was associated with reduced probability of good clinical outcome (common odds ratio, 0.25; 95% confidence interval, 0.09-0.74; adjusted for age, type of treatment, and follow-up scan). CONCLUSIONS: INTs are uncommon, detected more frequently on follow-up magnetic resonance imaging, and affect clinical outcome. In experienced centers, endovascular treatment is likely not causal, whereas intravenous alteplase may be therapeutic. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01778335.

Recurrent mild cerebral ischemia: enhanced brain injury following acute compared to subacute recurrence in the rat.

BACKGROUND: In the current study, a transient cerebral ischemia producing selective cell death was designated a mild ischemic insult. A comparable insult in humans is a transient ischemic attack (TIA) that is associated with functional recovery but can have imaging evidence of minor ischemic damage including cerebral atrophy. A TIA also predicts a high risk for early recurrence of a stroke or TIA and thus multiple ischemic insults are not uncommon. Not well understood is what the effect of differing recovery times between mild ischemic insults has on their pathophysiology. We investigated whether cumulative brain damage would differ if recurrence of a mild ischemic insult occurred at 1 or 3 days after a first insult. RESULTS: A transient episode of middle cerebral artery occlusion via microclip was produced to elicit mild ischemic changes-predominantly scattered necrosis. This was followed 1 or 3 days later by a repeat of the same insult. Brain damage assessed histologically 7 days later was substantially greater in the 1 day recurrent group than the 3 days recurrent group, with areas of damage consisting predominantly of regions of incomplete infarction and pannecrosis in the 1 day group but predominantly regions of selective necrosis and smaller areas of incomplete infarction in the 3 days group (P < 0.05). Enhanced injury was reflected by greater number of cells staining for macrophages/microglia with ED1 and greater alterations in GFAP staining of reactive astrocytes in the 1 day than 3 days recurrent groups. The differential susceptibility to injury did not correspond to higher levels of injurious factors present at the time of the second insult such as BBB disruption or increased cytokines (tumor necrosis factor). Microglial activation, with potential for some beneficial effects, appeared greater at 3 days than 1 day. Also blood analysis demonstrated changes that included an acute increase in granulocytes and decrease in platelets at 1 day compared to 3 days post transient ischemia. CONCLUSIONS: Dynamic changes in multiple inflammatory responses likely contribute to the time dependence of the extent of damage produced by recurrent mild ischemic insults. The time of mild stroke recurrence is crucial with early recurrence producing greater damage than subacute recurrence and this supports urgency for determining and implementing optimal stroke management directly after a TIA.

Tenecteplase-tissue-type plasminogen activator evaluation for minor ischemic stroke with proven occlusion.

BACKGROUND AND PURPOSE: Minor stroke and transient ischemic attack with an intracranial occlusion are associated with neurological deterioration and disability. Tenecteplase (TNK-tissue-type plasminogen activator) compared with alteplase is easier to administer, has a longer half-life, higher fibrin specificity, possibly a lower rate of intracranial hemorrhage, and may be an ideal thrombolytic agent in this population. METHODS: TNK-Tissue-Type Plasminogen Activator Evaluation for Minor Ischemic Stroke With Proven Occlusion (TEMPO-1) was a multicenter, prospective, uncontrolled, TNK-tissue-type plasminogen activator dose-escalation, safety, and feasibility trial. Patients with a National Institutes of Health Stroke Scale ≤5 within 12 hours of symptom onset, intracranial arterial occlusion on computed tomographic angiography and absence of well-evolved infarction were eligible. Fifty patients were enrolled; 25 patients at a dose of 0.1 mg/kg, and 25 patients at 0.25 mg/kg. Primary outcome was the rate of drug-related serious adverse events. Secondary outcomes included recanalization and 90-day neurological outcome (modified Rankin Scale, 0-1). RESULTS: Median baseline National Institutes of Health Stroke Scale was 2.5 (interquartile range, 1), and median age was 71 (interquartile range, 22) years. There were no drug-related serious adverse events in tier 1. In tier 2, there was 1 symptomatic intracranial hemorrhage (4%; 95% confidence interval, 0.01-20.0). Stroke progression occurred in 6% of cases. Overall, 66% had excellent functional outcome (modified Rankin Scale, 0-1) at 90 days. Recanalization rates were high; 0.1 mg/kg (39% complete and 17% partial), 0.25 mg/kg (52% complete and 9% partial). Complete recanalization was significantly related to excellent functional outcome (modified Rankin Scale, 0-1) at 90 days (relative risk, 1.65; 95% confidence interval, 1.09-2.5; P=0.026). CONCLUSIONS: Administration of TNK-tissue-type plasminogen activator in minor stroke with intracranial occlusion is both feasible and safe. A larger randomized controlled trial is needed to prove that this treatment is efficacious. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01654445.

Historic Stroke Motor Severity Score Predicts Progression in TIA/Minor Stroke.

BACKGROUND: transient ischemic attack (tIA) and minor stroke have a high risk of early neurological deterioration, and patients who experience early improvement are at risk of deterioration. We generated a score for quantifying the worst reported motor and speech deficits and assessed whether this predicted outcome. METHODS: 510 tIA or minor stroke (NIHSS>4) patients were included. the Historical Stroke Severity Score (HSSS) prospectively quantified the patient's description of the worst motor or speech deficits. the HSSS was rated at the time of first assessment with more severe deficits scoring higher. Motor HSSS included assessments of arm and leg motor power (score total 0-5). Speech HSSS assessed severity of dysarthria and aphasia (total 0-3). the association between motor and speech HSSS and symptom progression was assessed during the 90-day follow-up period. RESULTS: the proportion of patients in each category of the motor HSSS was 0: 43% (216/510), 1: 22%(110/510), 2: 17% (89/510), 3: 7% (37/510), 4: 5% (28/510) and 5: 6% (30/510). Motor HSSS was associated with symptom progression (p=0.004) but not recurrent stroke. Speech HSSS was not associated with either progression or recurrent stroke. Motor HSSS predicted disability (p=0.002) and intracranial occlusion (p=0.012). Disability increased with increasing motor HSSS. CONCLUSIONS: taking a detailed history about the severity of motor deficits, but not speech, predicted outcome in tIA and minor stroke patients. A score based on the patient's description of the severity of motor symptoms predicted symptom progression, intracranial occlusion and functional outcome, but not recurrent stroke in a tIA and minor stroke population.Le Historical Stroke Severity Score moteur prédit la progression d'un accès ischémique cérébral transitoire / d'un accident vasculaire cérébral mineur.

A Randomized Controlled Trial of Tenecteplase Versus Standard of Care for Minor Ischemic Stroke with Proven Occlusion (TEMPO-2): Rational and design of a multicenter, randomized open-label clinical trial.

BACKGROUND: Almost half of acute ischemic stroke patients present with mild symptoms and there are large practice variations in their treatment globally. Individuals with an intracranial occlusion who present with minor stroke are at an increased risk of early neurological deterioration and poor outcomes. Individual patient data meta-analysis in the subgroup of patients with minor deficits showed benefit of alteplase in improving outcomes; however, this benefit has not been seen with intravenous alteplase in published randomized trials. DESIGN: TEMPO-2 (A Randomized Controlled Trial of Tenecteplase Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion) is a prospective, open label with blinded outcome assessment, randomized controlled trial, designed to test the superiority of intravenous tenecteplase (0.25 mg/kg) over nonthrombolytic standard of care, with an estimated sample size of 1274 patients. Adult patients presenting with acute ischemic stroke with the National Institutes of Health Stroke Scale (NIHSS) ⩽ 5 and visible arterial occlusion or perfusion deficit within 12 h of onset are randomized to receive either tenecteplase (0.25 mg/kg) or standard of care. The primary outcome is return to baseline neurological functioning, measured by the modified Rankin scale (mRS) at 90 days. Safety outcomes include death and symptomatic hemorrhage (intra or extra-cranial). Other secondary outcomes include mRS 0-1, mRS 0-2, ordinal shift analysis of the mRS, partial, and full recanalization on follow-up computed tomography angiogram. CONCLUSION: Results of this trial will aid in determining whether there is benefit of using tenecteplase (0.25 mg/kg) in treating patients presenting with minor stroke who are at high risk of developing poor outcomes due to presence of an intracranial occlusion. DATA ACCESS STATEMENT: Data will be available upon reasonable request.

A dietary polyphenol resveratrol acts to provide neuroprotection in recurrent stroke models by regulating AMPK and SIRT1 signaling, thereby reducing energy requirements during ischemia.

Polyphenol resveratrol (RSV) has been associated with Silent Information Regulator T1 (SIRT1) and AMP-activated protein kinase (AMPK) metabolic stress sensors and probably responds to the intracellular energy status. Our aim here was to investigate the neuroprotective effects of RSV and its association with SIRT1 and AMPK signaling in recurrent ischemia models. In this study, elderly male Wistar rats received a combination of two mild transient middle cerebral artery occlusions (tMCAOs) as an in vivo recurrent ischemic model. Primary cultured cortical neuronal cells subjected to combined oxygen-glucose deprivation (OGD) were used as an in vitro recurrent ischemic model. RSV administration significantly reduced infarct volumes, improved behavioral deficits and protected neuronal cells from cell death in recurrent ischemic stroke models in vivo and in vitro. RSV treatments significantly increased the intracellular NAD(+) /NADH ratio, AMPK and SIRT1 activities, decreased energy assumption and restored cell energy ATP level. SIRT1 and AMPK inhibitors and specific small interfering RNA (siRNA) for SIRT1 and AMPK significantly abrogated the neuroprotection induced by RSV. AMPK-siRNA and inhibitor decreased SIRT1 activities; however, SIRT1-siRNA and inhibitor had no impact on phospho-AMPK (p-AMPK) levels. These results indicated that the neuroprotective effects of RSV increased the intracellular NAD(+) /NADH ratio as well as AMPK and SIRT1 activities, thereby reducing energy ATP requirements during ischemia. SIRT1 is a downstream target of p-AMPK signaling induced by RSV in the recurrent ischemic stroke model.

Proof of concept study: relating infarct location to stroke disability in the NINDS rt-PA trial.

BACKGROUND: The summed Alberta Stroke Program Early CT Score (ASPECTS) for noncontrast head CT scan represents the extent of early brain ischemia and has been shown to be useful for predicting stroke outcome. The ASPECTS template contains information on anatomical location which so far has not been used in analysis. This may not have been done because adjacent brain regions have related functions and share vascular territory. The task of relating neurological deficit to infarct localization requires brain imaging analysis tools which deal with this issue of relatedness or collinearity. We have previously used partial least squares with penalized logistic regression (PLR) to handle this problem of collinearity. A disadvantage of this method is that it cannot be performed at the bedside and requires processing and analysis in the imaging laboratory. PLR is a simpler analytic tool compared to partial least squares with PLR for dealing with this issue of relatedness (collinearity). It provides results in terms of ß coefficients related to specific infarct locations in a manner that is intuitively understood by clinicians. In this exploratory analysis, we hypothesized that infarct location as represented by the individual ASPECTS region may be independently related to disability. METHODS: ASPECTS from CT scans of patients in the National Institute of Neurological Disorders and Stroke (NINDS) recombinant tissue plasminogen activator (rt-PA) Study were obtained. Due to the collinearity between the ASPECTS regions, we used PLR to determine the independent associations of exposures (rt-PA), demographic variables (age and sex), and imaging (ASPECTS location) with poor outcome as defined by a modified Rankin Scale score of >2. RESULTS: In 607/624 subjects with ASPECTS readings, variables significantly associated with poor outcome included: interactions between ASPECTS M6 region (primary motor cortex/parietal lobe) and age (p = 0.004), lentiform nucleus and age (p = 0.007), and blood sugar level and age (p = 0.01). The model suggested that older age or involvement of either M6 or lentiform nucleus slightly increased the odds of disability. However, the predominant effect was driven by rt-PA which reduced the odds of poor disability (OR 0.597, 95% CI 0.425-0.838, p = 0.003). This may potentially explain why certain patients have smaller gains from rt-PA treatments. CONCLUSION: At an older age, specific infarct locations may be associated with a poorer outcome in this exploratory re-analysis of the NINDS rt-PA Study.

Tissue Window in Stroke Thrombolysis study (TWIST): a safety study.

BACKGROUND: Stroke thrombolysis is limited by the "last-seen well" principle, which defines stroke onset time. A significant minority of stroke patients (~15%) awake with their symptoms and are by definition ineligible for thrombolysis because they were "last-seen well" at the time they went to bed implying an interval that is most often greater than three hours. METHODS: A single-centre prospective, safety study was designed to thrombolyse 20 subjects with stroke-on-awakening. Patients were eligible for inclusion if they were last seen well less than 12 hours previously, specifically including those who awoke from sleep with their stroke deficits. They had a baseline computed tomogram (CT) scan with an ASPECTS score greater than 5, no evidence of well-evolved infarction and a CT angiogram / Trans-cranial Doppler ultrasound study demonstrating an intracranial arterial occlusion. Patients fulfilled all other standard criteria for stroke thrombolysis. The primary outcome was safety defined by symptomatic ICH or death. RESULTS: Among 89 screened patients, 20 were treated with thrombolysis. Two patients (10%) died due to massive carotid territory stroke and two patients (10%) died of stroke complications. Two patients (10%) showed asymptomatic intracerebral hemorrhage (ICH) (petechial hemorrhage) and none symptomatic ICH. Reasons for exclusion were: (a) ASPECTS ≤ 5 (29); (b) well-evolved infarcts on CT (19); (c) historical mRS > 2 (17); (d) no demonstrable arterial occlusion or were too mild to warrant treatment (10). CONCLUSIONS: Patients who awake with their deficits can be safely treated with thrombolysis based upon a tissue window defined by NCCT and CTA/TCD.

Magnetic resonance imaging of ischemia viability thresholds and the neurovascular unit.

Neuroimaging has improved our understanding of the evolution of stroke at discreet time points helping to identify irreversibly damaged and potentially reversible ischemic brain. Neuroimaging has also contributed considerably to the basic premise of acute stroke therapy which is to salvage some portion of the ischemic region from evolving into infarction, and by doing so, maintaining brain function and improving outcome. The term neurovascular unit (NVU) broadens the concept of the ischemic penumbra by linking the microcirculation with neuronal-glial interactions during ischemia reperfusion. Strategies that attempt to preserve the individual components (endothelium, glia and neurons) of the NVU are unlikely to be helpful if blood flow is not fully restored to the microcirculation. Magnetic resonance imaging (MRI) is the foremost imaging technology able to bridge both basic science and the clinic via non-invasive real time high-resolution anatomical delineation of disease manifestations at the molecular and ionic level. Current MRI based technologies have focused on the mismatch between perfusion-weighted imaging (PWI) and diffusion weighted imaging (DWI) signals to estimate the tissue that could be saved if reperfusion was achieved. Future directions of MRI may focus on the discordance of recanalization and reperfusion, providing complimentary pathophysiological information to current compartmental paradigms of infarct core (DWI) and penumbra (PWI) with imaging information related to cerebral blood flow, BBB permeability, inflammation, and oedema formation in the early acute phase. In this review we outline advances in our understanding of stroke pathophysiology with imaging, transcending animal stroke models to human stroke, and describing the potential translation of MRI to image important interactions relevant to acute stroke at the interface of the neurovascular unit.

Visualization of atrophy of medial temporal lobes and the septal nuclei in patients with transient ischaemic attack and controls.

Introduction: Transient ischaemic attack (TIA) is associated with increased risk of cognitive decline and dementia as early as one-year post-event. Regional brain atrophy measurements may predict future cognitive decline. Aims: 1) To determine whether Medial Temporal Atrophy (MTA) scores and interseptal distance (ISD) measurements are greater in patients with TIA compared to controls; and 2) To determine whether MTA and ISD predicts cognitive change one year after TIA. Methods: Baseline demographic, vascular risk factors, structural imaging and cognitive tests scores were compared between 103 Patients with TIA and 103 age-and-sex-matched controls from the Predementia Neuroimaging of Transient Ischaemic Attack (PREVENT) Study. MTA was assessed using the Schelten's Scale, and ISD was calculated as the distance between the septal nucleus of each hemisphere. Multiple linear regression models were used to evaluate how MTA and ISD related to cognitive change after adjusting for covariates. Results: Patients with TIA had larger ISD measurements (1.4 mm [SD=1.2] vs. 0.9 mm [SD=1.0]); p < 0.001) and higher right/left MTA scores (both p < 0.05) compared to controls. At baseline, controls performed significantly better on the RAVLT (total recall), BVMT (total and delayed recall) and the Trail Making Task (A and B) compared to patients with TIA. However, at one-year follow-up there was no evidence of decline in the patients with TIA compared with controls. Higher MTA and ISD scores were not associated with cognitive decline. Conclusions: Patients with TIA had higher MTA scores and ISD measurements than controls, but neither were predictors of cognitive decline at one year. Future studies with longer follow-up periods will be required to determine whether higher MTA scores and ISD predict risk of cognitive decline in patients with TIA.