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Background: Cognitive reserve may protect against the effects of brain pathology, but few studies have looked at whether cognitive reserve modifies the adverse effects of vascular brain pathology. Objective: We determined if cognitive reserve attenuates the associations of vascular brain lesions with worse cognition in persons with subjective concerns or mild impairment. Methods: We analyzed 200 participants aged 50–90 years from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study. Cognition was measured using the Montreal Cognitive Assessment and a neuropsychological test battery. High vascular lesion burden was defined as two or more supratentorial infarcts or beginning confluent or confluent white matter hyperintensity. Cognitive reserve proxies included education, occupational attainment, marital status, social activities, physical activity, household income, and multilingualism. Results: Mean age was 72.8 years and 48% were female; 73.5% had mild cognitive impairment and 26.5% had subjective concerns. Professional/managerial occupations, annual household income≥$60,000 per year, not being married/common law, and high physical activity were independently associated with higher cognition. Higher vascular lesion burden was associated with lower executive function, but the association was not modified by cognitive reserve. Conclusion: Markers of cognitive reserve are associated with higher cognition. Vascular lesion burden is associated with lower executive function. However, cognitive reserve does not mitigate the effects of vascular lesion burden on executive function. Public health efforts should focus on preventing vascular brain injury as well as promoting lifestyle factors related to cognitive reserve, as cognitive reserve alone may not mitigate the effects of vascular brain injury.

Background The relationship between duration of transient neurological events and presence of diffusion‐weighted lesions by symptom type is unclear. Methods and Results This was a substudy of SpecTRA (Spectrometry for Transient Ischemic Attack Rapid Assessment), a multicenter prospective cohort of patients with minor ischemic cerebrovascular events or stroke mimics at academic emergency departments in Canada. For this study we included patients with resolved symptoms and determined the presence of diffusion‐weighted imaging (DWI) lesion on magnetic resonance imaging within 7 days. Using logistic regression, we evaluated the association between symptom duration and DWI lesion, assessing for interaction with symptom type (focal only versus nonfocal/mixed), and adjusting for age, sex, education, comorbidities, and systolic blood pressure. Of 658 patients included, a DWI lesion was present in 232 (35.1%). There was a significant interaction between symptom duration and symptom type. For those with focal‐only symptoms, there was a continuous increase in DWI probability up to 24 hours in duration (ranging from ≈40% to 80% probability). In stratified analyses, the increase in probability of DWI lesion with increased duration of focal symptoms was seen in women but not men. For those with nonfocal or mixed symptoms, predicted probability of DWI lesion was ≈35% and was greater in men, but did not increase with longer duration. Conclusions Increased duration of neurological deficits is associated with greater probability of DWI lesion in those with focal symptoms only. For individuals with nonfocal or mixed symptoms, about one‐third had DWI lesions, but the probability did not increase with duration. These results may be important to improve risk stratification of transient neurological events.

Rationale Following endovascular treatment, poor clinical outcomes are more frequent if the initial infarct core or volume of irreversible brain damage is large. Clinical outcomes may be improved using neuroprotective agents that reduce stroke volume and improve recovery. Aim The aim of the REPERFUSE NA1 was to replicate the preclinical neuroprotection study that significantly reduced infarct volume in a primate model of ischemia reperfusion. Specifically, REPERFUSE NA1 will determine if administration of the neuroprotectant NA1 prior to endovascular therapy can significantly reduce early (Day 2 subtract Day 1 diffusion-weighted imaging volume) and delayed secondary infarct (90-day whole brain atrophy plus FLAIR volume—Day 1 diffusion-weighted imaging volume) growth, as measured by magnetic resonance imaging. Methods and design REPERFUSE-NA1 is a magnetic resonance imaging observational substudy of ESCAPE-NA1 (ClinicalTrialGov NCT02930018). A total of 150 acute stroke patients will be recruited (including 20% attrition) that have been randomized to either NA1 or placebo in the ESCAPE-NA1 trial. Study outcomes Primary—Early infarct growth measured using diffusion-weighted imaging will be at least 30% smaller in patients receiving NA1 compared to placebo. Secondary—Delayed secondary stroke injury at 90 days will be significantly reduced in patients receiving NA1 compared to placebo, as well as delayed secondary growth at 90 days. Conclusion REPERFUSE-NA1 will demonstrate the effect of NA1 neuroprotection on reducing the early and delayed stroke injury after reperfusion treatment.

Objectives: The impact of lung cancer screening on smoking is unclear, especially in deprived populations who are underrepresented in screening trials. The aim of this observational cohort study was to investigate whether a community-based lung cancer screening programme influenced smoking behaviour and smoking attitude in socio-economically deprived populations. Material and Methods: Ever-smokers, age 55–74, registered at participating General Practices were invited to a community-based Lung Health Check (LHC). This included an assessment of respiratory symptoms, lung cancer risk (PLCOm2012), spirometry and signposting to stop smoking services. Those at high risk (PLCOM2012≥1.51%) were offered annual low-dose CT screening over two rounds. Self-reported smoking status and behaviour were recorded at the LHC and again 12 months later, when attitudes to smoking were also assessed. Results: 919 participants (51% women) were included in the analysis (77% of attendees); median deprivation rank in the lowest decile for England. At baseline 50.3% were current smokers. One-year quit rate was 10.2%, quitting was associated with increased baseline symptoms (adjOR 2.62, 95% CI 1.07–6.41; p = 0.035) but not demographics or screening results. 55% attributed quitting to the LHC. In current smokers, 44% reported the LHC had made them consider stopping, 29% it made them try to stop and 25% made them smoke less whilst only 1.7% and 0.7% said it made them worry less about smoking or think it acceptable to smoke. Conclusions: Our data suggest a community-based lung cancer screening programme in deprived areas positively impacts smoking behaviour, with no evidence of a ‘licence to smoke’ in those screened.

Background: Early infarct growth after endovascular therapy (EVT) may lead to unfavorable outcomes despite successful reperfusion. The REPERFUSE-NA1 study replicated the preclinical NA1 experiment by investigating the effect of NA1 on early DWI infarct growth in acute ischemic stroke patients receiving EVT. Methods: REPERFUSE-NA1 was a sub-study of the randomized controlled trial ESCAPE-NA1 (ClinicalTrialGov NCT02930018). Patients received MRI within 5 hours and 24 hours of EVT. The primary outcome was early diffusion weighted (DWI) infarct growth. The secondary outcome was region-specific DWI infarct growth in the white matter, cortical grey matter and basal ganglia. Results: A total of 71 patients was included, of whom 67 had sufficient MR imaging at 5h and 24h post-EVT. For patients who received NA1 compared to placebo, the median age (68.8 v 67.5), baseline NIHSS (15.5 v 16), time from symptom onset to reperfusion (161 v 167 minutes) and mTICI 2b-3 (94.4% v 94.3%) were statistically not different. Median DWI volumes post-EVT (5h) were 13.0 mL (IQR, 5.9-28.1) in NA1 and 13.3 mL (IQR, 3.1-27.0) in placebo. At 24h median DWI volumes increased to 22.6 mL (IQR, 11.2-63.4) in the NA1 group and 22.4 mL (IQR, 7.4-52.3) in the placebo group, equating to a 48.4% DWI volume growth in the NA1 group and a 66.0% growth in the placebo group. Median DWI volume growth was 55.1% for NA1 patients who received alteplase compared to 41.3% for NA1 patients who did not receive alteplase (p=0.65). In terms of region-specific infarct volumes, absolute growth was 2.27mL (IQR, 0.70-6.19) in the white matter, 3.93 mL (IQR, 0.18-12.40) in cortical grey matter, and 1.20 mL (IQR, 0.31-2.62) in basal ganglia in the overall cohort. Between the NA1 and the placebo groups, lesion growth in the white matter (1.96 mL v 2.77mL), cortical gray matter (3.93 mL v 4.07 mL) and basal ganglia (1.62 mL v 0.89 mL) did not differ significantly. Conclusion: There was substantial infarct growth early after EVT, with the largest absolute growth in cortical grey matter. No significant effect of NA1 on early infarct growth was observed.

Background: Toxic amyloid-β (Aβ) peptides aggregate into higher molecular weight assemblies and accumulate not only in the extracellular space, but also in the walls of blood vessels in the brain, increasing their permeability, and promoting immune cell migration and activation. Given the prominent role of the immune system, phagocytic blood cells may contact pathological brain materials. Objective: To develop a novel method for early Alzheimer’s disease (AD) detection, we used blood leukocytes, that could act as “sentinels” after trafficking through the brain microvasculature, to detect pathological amyloid by labelling with a conformationally-sensitive fluorescent amyloid probe and imaging with confocal spectral microscopy. Methods: Formalin-fixed peripheral blood mononuclear cells (PBMCs) from cognitively healthy control (HC) subjects, mild cognitive impairment (MCI) and AD patients were stained with the fluorescent amyloid probe K114, and imaged. Results were validated against cerebrospinal fluid (CSF) biomarkers and clinical diagnosis. Results: K114-labeled leukocytes exhibited distinctive fluorescent spectral signatures in MCI/AD subjects. Comparing subjects with single CSF biomarker-positive AD/MCI to negative controls, our technique yielded modest AUCs, which improved to the 0.90 range when only MCI subjects were included in order to measure performance in an early disease state. Combining CSF Aβ42 and t-Tau metrics further improved the AUC to 0.93. Conclusion: Our method holds promise for sensitive detection of AD-related protein misfolding in circulating leukocytes, particularly in the early stages of disease.

Background Determining mechanisms of secondary stroke injury related to cerebral blood flow and the severity of microvascular injury contributing to edema and blood-brain barrier breakdown will be critical for the development of adjuvant therapies for revascularization treatment. Aim To characterize the heterogeneity of the ischemic lesion using quantitative T2 imaging along with diffusion-weighted magnetic resonance imaging (DWI) within five hours of treatment. Methods Quantitative T2 magnetic resonance imaging was acquired within 5 h (baseline) and at 24 h (follow-up) of stroke treatment in 29 patients. Dynamic contrast enhanced permeability imaging was performed at baseline in a subgroup of patients. Absolute volume change and lesion percent change was determined for the quantitative T2, DWI, and absolute volume change sequences. A Gaussian process with RRELIEFF feature selection algorithm was used for prediction of relative quantitative T2 and DWI lesion growth, baseline and follow-up quantitative T2/DWI lesion ratios, and also NIHSS at 24 h and change in NIHSS from admission to 24 h. Results In n = 27 patients, median (interquartile range) lesion percent change was 114.8% (48.9%, 259.1%) for quantitative T2, 48.2% (−12.6%, 179.6%) for absolute volume change, and 62.7% (26.3%, 230.9%) for DWI, respectively. Our model, consisting of baseline NIHSS, CT ASPECTS, and systolic blood pressure, showed a strong correlation with quantitative T2 percent change (cross correlation R2 = 0.80). There was a strong predictive ability for quantitative T2/DWI lesion ratio at 24 h using baseline NIHSS and last seen normal to 24 h magnetic resonance imaging time (cross correlation R2 = 0.93). Baseline dynamic contrast enhanced permeability was moderately correlated to the baseline quantitative T2 values (rho = 0.38). Conclusion Quantitative T2 imaging provides critical information for development of therapeutic approaches that could ameliorate microvascular damage during ischemia reperfusion.

Structural brain changes indicative of dementia occur up to 20 years before the onset of clinical symptoms. Efforts to modify the disease process after the onset of cognitive symptoms have been unsuccessful in recent years. Thus, future trials must begin during the preclinical phases of the disease before symptom onset. Age related cognitive decline is often the result of two coexisting brain pathologies: Alzheimer's disease (amyloid, tau, and neurodegeneration) and vascular disease. This review article highlights some of the common neuroimaging techniques used to visualize the accumulation of neurodegenerative and vascular pathologies during the preclinical stages of dementia such as structural magnetic resonance imaging, positron emission tomography, and white matter hyperintensities. We also describe some emerging neuroimaging techniques such as arterial spin labeling, diffusion tensor imaging, and quantitative susceptibility mapping. Recent literature suggests that structural imaging may be the most sensitive and cost-effective marker to detect cognitive decline, while molecular positron emission tomography is primarily useful for detecting disease specific pathology later in the disease process. Currently, the presence of vascular disease on magnetic resonance imaging provides a potential target for optimizing vascular risk reduction strategies, and the presence of vascular disease may be useful when combined with molecular and metabolic markers of neurodegeneration for identifying the risk of cognitive impairment.

Introduction: Transient ischemic attack (TIA) and minor ischemic stroke (IS) is associated with a increased risk of late life dementia. In this study we aim to study the extent to which the rates of hippocampal atrophy in TIA/IS differ from healthy controls, and how they are correlated to neuropsychological measurements. Methods: TIA or minor stroke patients were tested with a neuropsychological battery including tests of executive function, and verbal and non-verbal memory at three time points out to 3 years. Annualized rates of hippocampal atrophy in TIA/IS patients were compared to controls. A linear-mixed regression model was used to assess the difference in rates of hippocampal atrophy after adjusting for time and demographic characteristics. Results: TIA/IS patients demonstrated a higher hippocampal atrophy rate than healthy controls over a 3-year interval: the annual percentage change of the left hippocampal volume was 2.5% (78 mm3 per year (SD 60)) for TIA/IS patients compared to 0.9% (29 mm3 per year (SD 32)) for controls (p

Hippocampus atrophy is an early structural feature that can be measured from magnetic resonance imaging (MRI) to improve the diagnosis of neurological diseases. An accurate and robust standardized hippocampus segmentation method is required for reliable atrophy assessment. The aim of this work was to develop and evaluate an automatic segmentation tool (DeepHarp) for hippocampus delineation according to the ADNI harmonized hippocampal protocol (HarP). DeepHarp utilizes a two-step process. First, the approximate location of the hippocampus is identified in T1-weighted MRI datasets using an atlas-based approach, which is used to crop the images to a region-of-interest (ROI) containing the hippocampus. In the second step, a convolutional neural network trained using datasets with corresponding manual hippocampus annotations is used to segment the hippocampus from the cropped ROI. The proposed method was developed and validated using 107 datasets with manually segmented hippocampi according to the ADNI-HarP standard as well as 114 multi-center datasets of patients with Alzheimer’s disease, mild cognitive impairment, cerebrovascular disease, and healthy controls. Twenty-three independent datasets manually segmented according to the ADNI-HarP protocol were used for testing to assess the accuracy, while an independent test-retest dataset was used to assess precision. The proposed DeepHarp method achieved a mean Dice similarity score of 0.88, which was significantly better than four other established hippocampus segmentation methods used for comparison. At the same time, the proposed method also achieved a high test-retest precision (mean Dice score: 0.95). In conclusion, DeepHarp can automatically segment the hippocampus from T1-weighted MRI datasets according to the ADNI-HarP protocol with high accuracy and robustness, which can aid atrophy measurements in a variety of pathologies.

Introduction Vascular disease is a common cause of dementia, and often coexists with other brain pathologies such as Alzheimer's disease to cause mixed dementia. Many of the risk factors for vascular disease are treatable. Our objective was to review evidence for diagnosis and treatment of vascular cognitive impairment (VCI) to issue recommendations to clinicians. Methods A subcommittee of the Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD) reviewed areas of emerging evidence. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used to assign the quality of the evidence and strength of the recommendations. Results Using standardized diagnostic criteria, managing hypertension to conventional blood pressure targets, and reducing risk for stroke are strongly recommended. Intensive blood pressure lowering in middle‐aged adults with vascular risk factors, using acetylsalicylic acid in persons with VCI and covert brain infarctions but not if only white matter lesions are present, and using cholinesterase inhibitors are weakly recommended. Conclusions The CCCDTD has provided evidence‐based recommendations for diagnosis and management of VCI for use nationally in Canada, that may also be of use worldwide.

IntroductionCerebral small vessel disease (cSVD) accounts for 20%–25% of strokes and is the most common cause of vascular cognitive impairment (VCI). In an animal VCI model, inducing brief periods of limb ischaemia-reperfusion reduces subsequent ischaemic brain injury with remote and local protective effects, with hindlimb remote ischaemic conditioning (RIC) improving cerebral blood flow, decreasing white-matter injury and improving cognition. Small human trials suggest RIC is safe and may prevent recurrent strokes. It remains unclear what doses of chronic daily RIC are tolerable and safe, whether effects persist after treatment cessation, and what parameters are optimal for treatment response.Methods and analysisThis prospective, open-label, randomised controlled trial (RCT) with blinded end point assessment and run-in period, will recruit 24 participants, randomised to one of two RIC intensity groups: one arm treated once daily or one arm twice daily for 30 consecutive days. RIC will consistent of 4 cycles of blood pressure cuff inflation to 200 mm Hg for 5 min followed by 5 min deflation (total 35 min). Selection criteria include: age 60–85 years, evidence of cSVD on brain CT/MRI, Montreal Cognitive Assessment (MoCA) score 13–24 and preserved basic activities of living. Outcomes will be assessed at 30 days and 90 days (60 days after ceasing treatment). The primary outcome is adherence (completing ≥80% of sessions). Secondary safety/tolerability outcomes include the per cent of sessions completed and pain/discomfort scores from patient diaries. Efficacy outcomes include changes in cerebral blood flow (per arterial spin-label MRI), white-matter hyperintensity volume, diffusion tensor imaging, MoCA and Trail-Making tests.Ethics and disseminationResearch Ethics Board approval has been obtained. The results will provide information on feasibility, dose, adherence, tolerability and outcome measures that will help design a phase IIb RCT of RIC, with the potential to prevent VCI. Results will be disseminated through peer-reviewed publications, organisations and meetings.Trial registration numberNCT04109963.

Objectives Cerebral blood flow (CBF) measurements after endovascular therapy (EVT) for acute ischemic stroke are important to distinguish early secondary injury related to persisting ischemia from that related to reperfusion when considering clinical response and infarct growth. Methods We compare reperfusion quantified by the modified Thrombolysis in Cerebral Infarction Score (mTICI) with perfusion measured by MRI dynamic contrast-enhanced perfusion within 5 h of EVT anterior circulation stroke. MR perfusion (rCBF, rCBV, rTmax, rT0) and mTICI scores were included in a predictive model for change in NIHSS at 24 h and diffusion-weighted imaging (DWI) lesion growth (acute to 24 h MRI) using a machine learning RRELIEFF feature selection coupled with a support vector regression. Results For all perfusion parameters, mean values within the acute infarct for the TICI-2b group (considered clinically good reperfusion) were not significantly different from those in the mTICI Conclusion MR perfusion following EVT provides accurate physiological approach to understanding the relationship of CBF, clinical outcome, and DWI growth. Advances in knowledge MR perfusion CBF acquired is a robust, objective reperfusion measurement providing following recanalization of the target occlusion which is critical to distinguish potential therapeutic harm from the failed technical success of EVT as well as improve the responsiveness of clinical trial outcomes to disease modification.

Background and purposePatients with transient ischemic attack (TIA) show evidence of cognitive impairment but the reason is not clear. Measurement of microstructural changes in white matter (WM) using diffusion tensor imaging (DTI) may be a useful outcome measure. We report WM changes using DTI and the relationship with neuropsychological performance in a cohort of transient ischemic attack (TIA) and non-TIA subjects.MethodsNinety-five TIA subjects and 51 non-TIA subjects were assessed using DTI and neuropsychological batteries. Fractional anisotropy (FA) and mean diffusivity (MD) maps were generated and measurements were collected from WM tracts. Adjusted mixed effects regression modelled the relationship between groups and DTI metrics.ResultsTransient ischemic attack subjects had a mean age of 67.9 ± 9.4 years, and non-TIA subjects had a mean age 64.9 ± 9.9 years. The TIA group exhibited higher MD values in the fornix (0.36 units, P < 0.001) and lower FA in the superior longitudinal fasciculus (SLF) (-0.29 units, P = 0.001), genu (-0.22 units, P = 0.016), and uncinate fasciculus (UF) (-0.26 units, P = 0.004). Compared to non-TIA subjects, subjects with TIA scored lower on the Addenbrooke's Cognitive Assessment-Revised (median score 95 vs 91, P = 0.01) but showed no differences in scores on the Montreal Cognitive Assessment (median 27 vs 26) or the Mini-Mental State Examination (median 30). TIA subjects had lower scores in memory (median 44 vs 52, P < 0.01) and processing speed (median 45 vs 62, P < 0.01) but not executive function, when compared to non-TIA subjects. Lower FA and higher MD in the fornix, SLF, and UF were associated with poorer performance on tests of visual memory and executive function but not verbal memory. Lower FA in the UF and fornix were related to higher timed scores on the TMT-B (P < 0.01), and higher SLF MD was related to higher scores on TMT-B (P < 0.01), confirming worse executive performance in the TIA group.ConclusionsDTI scans may be useful for detecting microstructural disease in TIA subjects before cognitive symptoms develop. DTI parameters, white matter hyperintensities, and vascular risk factors underly some of the altered neuropsychological measures in TIA subjects.

[Background] The prevalence of ex vivo ‘high on-treatment platelet reactivity (HTPR)’ and its relationship with recurrent vascular events/outcomes in patients with ischaemic cerebrovascular disease (CVD) is unclear., [Methods] A systematic review and meta-analysis was performed in accordance with the PRISMA statement. MEDLINE, EMBASE and Cochrane Library were searched for completed manuscripts until May 2019 on TIA/ischaemic stroke patients, ≥ 18 years, treated with commonly-prescribed antiplatelet therapy, who had platelet function/reactivity testing and prospective follow-up data on recurrent stroke/TIA, myocardial infarction, vascular death or other cerebrovascular outcomes. Data were pooled using random-effects meta-analysis. Primary outcome was the composite risk of recurrent stroke/TIA, myocardial infarction or vascular death. Secondary outcomes were recurrent stroke/TIA, severe stroke (NIHSS > 16) or disability/impairment (modified Rankin scale ≥ 3) during follow-up., [Results] Antiplatelet–HTPR prevalence was 3–65% with aspirin, 8–56% with clopidogrel and 1.8–35% with aspirin–clopidogrel therapy. Twenty studies (4989 patients) were included in our meta-analysis. There was a higher risk of the composite primary outcome (OR 2.93, 95% CI 1.90–4.51) and recurrent ischaemic stroke/TIA (OR 2.43, 95% CI 1.51–3.91) in patients with vs. those without ‘antiplatelet–HTPR’ on any antiplatelet regimen. These risks were also more than twofold higher in patients with vs. those without ‘aspirin–HTPR’ and ‘dual antiplatelet–HTPR’, respectively. Clopidogrel–HTPR status did not significantly predict outcomes, but the number of eligible studies was small. The risk of severe stroke was higher in those with vs. without antiplatelet–HTPR (OR 2.65, 95% CI 1.00–7.01)., [Discussion] Antiplatelet–HTPR may predict risks of recurrent vascular events/outcomes in CVD patients. Given the heterogeneity between studies, further prospective, multi-centre studies are warranted., Dr. Lim’s research was funded by The Meath Foundation, The Irish Institute of Clinical Neuroscience/Novartis Ireland Fellowship Grant, The Vascular Neurology Research Foundation Ireland, the Irish Heart Foundation Stroke Prevention Bursary programme, and by an unrestricted educational grant from Biogen Idec, Ireland. Dr. Murphy’s research was funded by the Trinity College Dublin Innovation Bursary, The Meath Foundation, Joint Irish Institute of Clinical Neuroscience/Merck Serono Fellowship in Neuroscience Grant, The Vascular Neurology Research Foundation Ireland, and by an unrestricted educational grant from Bayer HealthCare, Ireland and Verum Diagnostica, GmbH. Dr Offiah’s Research is funded by The Meath Foundation and The Vascular Neurology Research Foundation Ireland and by an unrestricted educational grant from SINNOWA Medical Science & Technology Co., China. Prof Thijs’ research is supported by The Florey Institute of Neuroscience and Mental Health, which acknowledges support from the Victorian Government and funding from an Operational Infrastructure Support Grant. Prof Prodan’s research is supported by a United States Department of Veterans Affairs Merit Award (1I01CX000340). Prof Kelly is supported by grants from the Health Research Board Ireland. Prof Barber is supported by grants from the Canadian Institute of Health Research and the Heart and Stroke Foundation of Canada. Prof Werring receives research support from the Stroke Association and the British Heart Foundation. Prof Thijs has received personal fees for lectures and consulting fees from Bayer, Boehringer Ingelheim, BMS/Pfizer and Amgen. Prof. Bath is a Stroke Association Professor of Stroke Medicine and NIHR Senior Investigator, a non-executive Director of ‘Platelet Solutions Ltd.®, and owns 3 shares; he has received personal fees for consulting from DiaMedica, Moleac, Nestle, Sanofi and Phagenesis. Prof Werring has received honoraria for consulting and lectures from Bayer and Portola, and for consulting from Alnylam.

Background A proportion of patients presenting with acute small ischemic strokes have poor functional outcomes, even following rapid recanalization treatment. Aims Infarct growth may occur even after successful recanalization and could represent an appropriate endpoint for future stroke therapy trials. Methods Magnetic resonance diffusion-weighted imaging lesion volumes were obtained at 5 h (initial posttreatment) and 24 h (follow-up) after acute stroke treatment for n = 33 in ischemic stroke patients. Sample sizes per arm (90% power, 30% effect size) for diffusion-weighted imaging lesion growth between initial and 24 h, early change in the National Institutes of Health Stroke Scale between pre- and 24 h, National Institutes of Health Stroke Scale at 24 h, and diffusion-weighted imaging lesion volume at 24 h were estimated to power a placebo-controlled stroke therapy trial. Results For patients with poor recanalization (modified thrombolysis in cerebral infarction Conclusion Despite best efforts to recanalize the ischemic brain, early diffusion-weighted imaging lesion growth still occurs. Treatment trials in stroke should consider early diffusion-weighted imaging lesion growth as a surrogate outcome measure to significantly reduce sample sizes.

Acute stroke treatment requires simple, quick and accurate detection of early ischemic changes to facilitate treatment decisions guided by published selection criteria. The aim of this study was to determine the accuracy and reliability of multiphase computed tomography angiography (mCTA) perfusion hypoattenuation for detecting early severe ischemia.Non-contrast CT (NCCT), mCTA for regional leptomeningeal score (mCTA-rLMC), and mCTA perfusion lesion visibility (mCTA-arterial and mCTA-venous) were assessed blinded to clinical information in patients treated with endovascular therapy (EVT). The extent of early ischemia defined by regions of hypoattenuation was evaluated by the Alberta Stroke Program Early CT Score (ASPECTS). The ASPECTS scores were dichotomized based on the American Heart Association (AHA) guidelines for EVT selection, ASPECTS ≥6 vs.6. The diagnostic accuracy was calculated by comparison to 24-h magnetic resonance imaging (MRI) or CT ASPECTS. Inter-observer reliability of NCCT and mCTA ASPECTS was evaluated. Machine learning models were used to predict the clinical follow-up outcome, e.g. National Institutes of Health Stroke scale (NIHSS) and modified Rankin scale (mRS) from baseline imaging data and patient information.A total of 89 acute stroke patients (68 ± 15 years of age) were analyzed (33 TICI-0, 56 TICI-2b or 3). Median baseline NIHSS was 17. The mCTA-venous had a large effect on accurately identifying early ischemia when dichotomized for ASPECTS ≥6 vs6 (likelihood ratio [LR+] 10 vs. [LR-] 0.29) compared to the moderate effect of NCCT ([LR+] = 6.7; [LR-] = 0.56) and mCTA-rLMC [(LR+ = 8.0; (LR-) = 0.83)]. The inter-observer reliability in mCTA-venous was almost perfect for all ASPECTS regions except the internal capsule. The machine learning support factor regression model identified mCTA-venous as the most important imaging covariate for predicting 24-h NIHSS and 90-day mRS.The assessment of mCTA-venous permits a more accurate detection of early ischemia than NCCT and mCTA-rLMC score and is predictive of clinical outcome. We would recommend the inclusion of mCTA perfusion lesion in future endovascular trials aiming at extending current AHA guidelines for EVT in stroke patients with low ASPECTS.

Infarct lesion segmentation has been problematic as there are a wide range of relative and absolute diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) thresholds that have been used for this purpose. We examined differences of stroke lesion volume and evolution evaluated by magnetic resonance imaging (MRI) during the immediate post-treatment phase (

Background:Mild behavioral impairment (MBI) describes later life acquired, sustained neuropsychiatric symptoms (NPS) in cognitively normal individuals or those with mild cognitive impairment (MCI), as an at-risk state for incident cognitive decline and dementia. We developed an operational definition of MBI and tested whether the presence of MBI was related to caregiver burden in patients with subjective cognitive decline (SCD) or MCI assessed at a memory clinic.Methods:MBI was assessed in 282 consecutive memory clinic patients with SCD (n = 119) or MCI (n = 163) in accordance with the International Society to Advance Alzheimer's Research and Treatment – Alzheimer's Association (ISTAART–AA) research diagnostic criteria. We operationalized a definition of MBI using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Caregiver burden was assessed using the Zarit caregiver burden scale. Generalized linear regression was used to model the effect of MBI domains on caregiver burden.Results:While MBI was more prevalent in MCI (85.3%) than in SCD (76.5%), this difference was not statistically significant (p = 0.06). Prevalence estimates across MBI domains were affective dysregulation (77.8%); impulse control (64.4%); decreased motivation (51.7%); social inappropriateness (27.8%); and abnormal perception or thought content (8.7%). Affective dysregulation (p = 0.03) and decreased motivation (p=0.01) were more prevalent in MCI than SCD patients. Caregiver burden was 3.35 times higher when MBI was present after controlling for age, education, sex, and MCI (p < 0.0001).Conclusions:MBI was common in memory clinic patients without dementia and was associated with greater caregiver burden. These data show that MBI is a common and clinically relevant syndrome.

Patients with transient ischemic attack (TIA) have a 4-fold increase in developing late-life dementia. Cerebral blood flow has shown to be reduced approximately 30% in patients with Alzheimer’s disease (AD). Vascular abnormalities may initiate and aggravate AD pathology prior to the development of clinical symptoms. We hypothesize that middle-aged patients with a history of TIA will have lower cerebral blood flow (CBF) in the hippocampus, thalamus, white matter and grey matter compared to healthy controls. Additionally, we hypothesize that individuals with lower cerebral blood flow in our regions of interest will have lower cognitive scores. Participants between the ages of 45-85 years old without dementia were subject to a clinical brain MRI arterial-spin-labelling CBF sequence accompanied by a cognitive battery. The cognitive battery included the Montreal Cognitive Assessment (MOCA) and a composite memory score created with the Addenbrooke’s Cognitive Examination, the Brief Visuospatial Memory Test Revised, and the Rey Auditory Verbal Learning Test. TIA patients had their assessments within 14-days of ictus. Atlas-based imaging analysis was performed using FSL. Sixty-three (63) healthy controls (63 + 10 years of age) and 51 TIA (69 + 9 years of age) participants were analyzed. In an independent one-tailed t-test, TIA patients had significantly (p2 =[0.1701-0.2013], p2 =[0.2429-0.2864], p, TIA patients have significantly lower CBF values in regions of interest compared to healthy control subjects and decreased CBF values in all participants are associated with poorer cognitive scores. By investigating neuroimaging biomarkers associated with cognition in mid-life, we may begin to understand why TIA patients have a higher risk of developing AD in late-life.

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.

Background Patients with proximal arterial M2-segment of the Middle Cerebral Artery (M2-MCA) occlusions were largely excluded from endovascular stroke trials. Current American Stroke guidelines are conservative in recommending thrombectomy for such patients. We sought to assess the natural history of medically- treated M2-MCA occlusion patients. Methods This is a prospective multi-central international cohort study of all acute ischemic stroke patients with intracranial occlusions on baseline imaging. Patients with M2-MCA occlusions were identified on baseline CT angiography and non-endovascular-treated patients were included. The M2-MCA segment was defined as the first-order branch of the proximal MCA, excluding the anterior temporal artery. The M2-MCA was further classified according to its visually-assessed diameter relative to the M1-MCA into: M1-equivalent (>90% of the diameter of the M1-MCA), Major (50%–90%), Minor ( Results Out of 575 patients in the entire study, there were a total of 184 M2-MCA occlusions seen. Of those, 104 patients were NOT treated with endovascular therapy: 90 patients (86.5%) received IV TPA and 14 (23.5%) patients conservative management. Among those, 23.1% (24/104) M1-equivalent, 66.4% (69/104) major, and 9.6% (10/104) minor M2-MCA. The median age was 76 years (interquartile range 19 years). The median (IQR) baseline NIHSS score of the cohort was 9 (9): M1-equivalent 12(10), major 9 (9), minor 7 (8). The median baseline ASPECTS was 9 overall and in all M2 groups. Successful recanalization was observed in 44.2% (46/104) of the medical M2 occlusion cohort overall. TPA group was 47.8% (43/90) and conservative group 21.4% (3/14). With IV TPA successful recanalization occurred in 30% (6/20) of M1-equivalent, 50% (31/62) of major, and 75% (6/8) of minor M2-MCA occlusions. In conservative management group successful recanalization occurred in 25% (1/4) of M1-equivalent, 14.3% (1/7) of major, and 50% (1/2) of minor M2-MCA occlusions. Good functional outcome (mRS 0–2) at 90 day was observed in 62.1% (64/104) of the cohort overall. Among those with successful recanalization, 76.1% (35/46) achieved good outcome. With IV TPA, the proportion of patients achieving independent functional outcome was 45% (9/20) with M1-equivalent, 70.5% (43/61) of major, and 62.5% (5/8) of minor M2-MCA occlusions. In the conservative management group, the proportion of patients achieving independent functional outcome at 90 day was 25% (1/4) with M1-equivalent, 71.4% (5/7) of major, and 50% (1/2) of minor M2-MCA occlusions. In logistic regression analyses, successful recanalization predicted independent functional outcome (OR 2.9, 95% CI 1.02 to 8.1, p 0.046). Age (OR 0.89, 95% CI 0.84 to 0.94, p Conclusion While over one half of medically-treated patients with M2-MCA segment occlusions achieve independent outcome, a subset of patients suffers poor functional outcomes at 90 days. Successful recanalization are associated with higher odds of independent functional outcome. Disclosures B. Menon: None. M. Najm: None. F. Al-Ajlan: None. M. Almekhlafi: None. J. Puig: None. M. Castellanos: None. D. Dowlatshahi: None. A. Calleja: None. S. Sohn: None. S. Ahn: None. A. Poppe: None. R. Mikulik: None. N. Asdaghi: None. T. Field: None. A. Jin: None. T. Asil:None. J. Boulanger: None. E. Smith: None. S. Coutts: None. P. Barber: None. S. Bal: None. S. Subramanian: None. S. Mishra: None. A. Trivedi: None. S. Dey: None. M. Eesa: None. T. Sajobi: None. M. Goyal: None. M. Hill: None. A. Demchuk: None.

BACKGROUND Reliable pathologic sampling methods are pivotal in the management of lung cancer patients who have undergone either curative intent or palliative treatment previously. Early diagnosis of localized disease recurrence may facilitate further curative treatment and rebiopsy at the point of disease progression during palliative treatment can inform further management. This study assessed the performance of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) lymph node sampling in a cohort of such patients. METHODS A retrospective analysis of a prospectively maintained database of EBUS-TBNA procedures at the University Hospital of South Manchester from August 2010 to August 2013. All patients with previously treated lung cancer and suspected nodal metastases (defined as nodal enlargement on CT>10 mm in the short axis or abnormal FDG avidity on PET-CT) were included. RESULTS The sensitivity of EBUS-TBNA, on a per patient and per lymph node basis, was 91.4% and 91.8%, respectively (CI, 80.8%-96.5%). The corresponding NPV was 87.5% and 89.7%, respectively (CI, 76.4%-95.9%). There were no major complications and 3 (5.4%) minor complications. From the malignant EBUS-TBNA samples, the NSCLC-NOS rate was 3.2% and adequate tissue for molecular testing was provided in 100% of the cases (16/16). CONCLUSIONS EBUS-TBNA is a safe and highly effective diagnostic procedure in suspected nodal metastases after previous treatment for lung cancer. The sensitivity and NPV are equivalent to EBUS-TBNA in the diagnosis of "new" lung cancer.

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

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 β1–42) 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.

Dementia is a large and growing health problem in developed and developing countries, with total costs approaching 1% of global gross domestic product, threatening the sustainability of healthcare systems.1 There are currently no disease‐modifying treatments for the most common cause of dementia, Alzheimer disease (AD). The second most common contributor to dementia risk is cerebrovascular disease.2 In contrast to AD, there is greater hope that vascular contributions to cognitive impairment can be prevented and treated. Recent evidence that the incidence of dementia is declining has prompted speculation, not yet confirmed, that this decline may be partly attributable to improved vascular care.3, 4 In this article, we review trial design and drug development for vascular cognitive impairment (VCI), focusing on symptomatic patients with vascular mild cognitive impairment (MCI) or dementia. First, we review axes along which vascular components of cognitive impairment can be addressed, including choice of trial population, trial intervention, and type of outcome. Second, we briefly review the pathophysiology of VCI, introducing the concept that trials may focus on disease modification, improving resilience, or enhancing cognition. Third, we systematically review prior drug trials for VCI patients according to drug class and trial size. Finally, we offer suggestions for methodological improvements for future trials.

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 protected by copyright. All rights reserved.

Introduction: Transient ischemic attack (TIA) greatly increases the risk of developing dementia later in life. Measurement of microstructural changes in white matter (WM) using diffusion tensor imaging (DTI) tractography has potential for identifying those at greatest risk of cognitive decline. We hypothesized that patients presenting with TIA have abnormal DTI measures in major WM tracts. Our objective was to determine changes in DTI measures for fractional anisotropy (FA) and medial diffusivity (MD) in frontoparietal (Superior Longitudinal Fasciculus; SF) and medial temporal (Uncinate Fasciculus; UF) WM tracts for TIA patients and healthy controls. Methods: Patients presenting with symptoms of high risk TIA but free of dementia, and healthy volunteer controls were recruited acutely. Structural MRI, inclusive of DTI sequences (31 directions b1000) was performed. FA and MD values were collected in the left and right SLF and UF. Multiple linear regression was performed to determine predictors of DTI values (FA and MD), adjusted for age. Subject’s cognition was screened using Montreal Cognitive Assessment (MoCA). Results: Data from 60 TIA patients (mean age = 68.75 years, SD = 9.39, 45% female) and 33 healthy controls (mean age = 64.97 years, SD = 10.45, 67% female) was analyzed. Linear regression identified that TIA patients have higher FA values in left SLF, F(2, 90) = 9.210, p < .001, R 2 = .170); right SLF, F(2, 90) = 7.154, p = .001, R 2 = .137; and left UF, F(2, 90) = 3.513, p = .034, R 2 = .072, compared to healthy controls. No group changes in MD were observed when corrected for age. TIA patients (median score 24, (interquartile range (IQR) = 5) performed worse than healthy controls (median score = 27, IQR = 4) on the MoCA while controlling for age, F(1, 90) = 7.689, p < .007. Conclusion: TIA patients showed changes in FA of WM tracts related to language and memory function when compared to healthy controls, supporting the presence of incipient microstructural disease. Our results show that measures of microstructural changes using DTI may help identify TIA patients at a greater risk of developing cognitive impairment. Future work aims to identify deterioration of DTI measures over time and their relation to potential vascular and neurodegenerative etiologies.

Patients with burn wounds are susceptible to wound infection and sepsis. This research introduces a novel burn wound dressing that contains silver nanoparticles (SNPs) to treat infection in a 2-acrylamido-2-methylpropane sulfonic acid sodium salt (AMPS-Na(+) ) hydrogel. Silver nitrate was dissolved in AMPS-Na(+) solution and then exposed to gamma irradiation to form SNP-infused hydrogels. The gamma irradiation results in a cross-linked polymeric network of sterile hydrogel dressing and a reduction of silver ions to form SNPs infused in the hydrogel in a one-step process. About 80% of the total silver was released from the hydrogels after 72 h immersion in simulated body fluid solution; therefore, they could be used on wounds for up to 3 days. All the hydrogels were found to be nontoxic to normal human dermal fibroblast cells. The silver-loaded hydrogels had good inhibitory action against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. Results from a pilot study on a porcine burn model showed that the 5-mM silver hydrogel was efficient at preventing bacterial colonization of wounds, and the results were comparable to the commercially available silver dressings (Acticoat(TM) , PolyMem Silver(®) ). These results support its use as a potential burn wound dressing.

Background:Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) enables minimally invasive lymph node sampling during bronchoscopy under conscious sedation. The primary purpose of this study was to investigate the safety profile of EBUS-TBNA in an elderly population. The secondary aim was to assess the efficacy of EBUS-TBNA for nodal staging and pathological diagnosis in elderly patients with primary lung cancer.Methods:This was a prospective cohort study of patients undergoing EBUS-TBNA, between March 2010 and August 2012, at a single U.K. hospital site. Procedure and outcome data including 6-month follow-up were collected prospectively. Patients were divided into less than 70 (

Correction to: Clin Neuroradiol 2018 https://doi.org/10.1007/s00062-018-0717-x Unfortunately, the author list of the original version of this article contains a mistake. The middle name of the author “Rani Gupta Sah” was erroneously tagged as part of the surname in the article’s metadata. This mistake

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.

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 β 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.

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.

Background and Purpose— Within different brain regions, we determine the comparative value of multiphase computed tomographic angiography (mCTA) and computed tomographic perfusion (CTP) in predicting follow-up infarction. Methods— Patients with M1-middle cerebral artery occlusions were prospectively included in this multicenter study. Regional analysis was performed for each patient within Alberta Stroke Program Early CT Score regions M2 to M6. Regional pial vessel filling was assessed on mCTA in 3 ways: (1) Washout of contrast within pial vessels; (2) Extent of maximal pial vessel enhancement compared with contralateral hemisphere; (3) Delay in maximal pial vessel enhancement compared with contralateral hemisphere. Cerebral blood flow, cerebral blood volume, and Tmax data were extracted within these Alberta Stroke Program Early CT Score regions. Twenty-four- to 36-hour magnetic resonance imaging/CT was assessed for infarct in each Alberta Stroke Program Early CT Score region (defined as >20% infarction within that region). Mixed effects logistic regression models were used to compare mCTA and CTP parameters when predicting brain infarction. Area under the receiver operating characteristics was used to assess discriminative value of statistical models. Results— Seventy-seven patients were included. mCTA parameter washout and CTP parameter Tmax were significantly associated with follow-up infarction in all models ( P P >0.05). Mean Tmax and cerebral blood volume values were significantly different between each washout score ( P P P Conclusions— Similar to CTP, multiphase CTA can be used to predict tissue fate regionally in acute ischemic stroke patients.

Background and Purpose— Only a small percentage of stroke patients are treated with thrombolytic therapy. We sought to determine whether vessel occlusion in mild strokes represented a new target population for interventional therapy. Methods— We imaged 106 acute stroke patients with MRI. Patients were identified with evidence of middle cerebral artery (MCA) occlusion and mild or no stroke signs (National Institutes of Health Stroke Scale [NIHSS] ≤3). They were compared with patients with signs of stroke, NIHSS >3, and MCA occlusion. Results— We identified 5 patients with absent flow on MRA in the MCA and mild or no stroke signs (NIHSS ≤3). All 5 were functionally independent at 3 months. Conclusions— Caution should be exercised in considering thrombolytic therapy in these patients. Quantification of perfusion imaging is required to identify “at risk” mild stroke populations.

Transient or permanent focal brain injury following acute thromboembolic occlusion develops from a complex cascade of pathophysiological events. The processes of excitotoxicity, peri-infarct depolarisation, inflammation, and apoptosis within the ischemic penumbra are proposed. While the translation of therapeutic agents from the animal models to human clinical trials have been disappointing, there remains an atmosphere of optimism as a result of the development of new diagnostic and therapeutic approaches, which include physiological, as opposed to pharmacological, intervention. This article provides an insight into the understanding of cerebral ischemia, together with current and future treatment strategies.Key words: cerebral ischemia, stroke, pathophysiology.