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Outcomes following endovascular thrombectomy (EVT) for large vessel occlusion stroke remain variable. Clinical predictors include presenting NIHSS and age, surrogate metrics of stroke severity and pre-stroke brain health, respectively. Imaging biomarkers can also predict outcome, but prognostic models typically only include biomarkers of acute stroke severity. This study aimed at exploring how incorporating both imaging biomarkers of stroke severity and brain frailty, automatically derived from routine imaging, impacts outcome prediction following successful EVT. In this single-center retrospective study of 215 patients presenting with anterior circulation stroke, we evaluated prognostic significance of automated analysis outputs from e-Stroke. Acute ischemic volume (AIV) and e-ASPECTS were used to define stroke severity. Cerebral atrophy was used as a marker of brain frailty. Models incorporating imaging biomarkers, clinical features, procedural factors, and combinations of these were evaluated using multivariate regression models predicting mRS 0-2 at 30 and 90-days, NIHSS improvement, mortality and sICH. Incorporation of brain atrophy into models negated the effect of age on patient outcome. The interaction of stroke severity with age was similar to that of infarct volume and brain atrophy. Models incorporating age, presenting NIHSS, AIV, atrophy, reperfusion status and time to recanalization outperformed clinical models at predicting NIHSS improvement (ROC AUC 0.81 and 0.57, respectively) and 90-day mRS. Combinations of imaging and clinical features were superior for predicting any outcome compared with clinical or imaging features in isolation. Models incorporating automated image analysis of acute infarct volume and atrophy outperform models based solely on clinical characteristics for predicting short- and long-term outcome following EVT. Atrophy as a marker of brain frailty is associated with poorer long-term outcomes and negates the effect of age in multivariate models. AIV tempers the effect of intervention on early neurological improvement. Better understanding the relationship between stroke severity and baseline health status may improve patient selection strategies for reperfusion therapies.

Amide proton transfer (APT) magnetic resonance imaging (MRI) is a pH-sensitive imaging technique that can potentially complement existing clinical imaging protocol for the assessment of ischemic stroke. This review aims to summarize the developments in the clinical research of APT imaging of ischemic stroke after 17 years of progress since its first preclinical study in 2003. Three electronic databases: PubMed, Scopus, and Cochrane Library were systematically searched for articles reporting clinical studies on APT imaging of ischemic stroke. Only articles in English published between 2003 to 2020 that involved patients presenting ischemic stroke-like symptoms that underwent APT MRI were included. Of 1,093 articles screened, 14 articles met the inclusion criteria with a total of 282 patients that had been scanned using APT imaging. Generally, the clinical studies agreed APT effect to be hypointense in ischemic tissue compared to healthy tissue, allowing for the detection of ischemic stroke. Other uses of APT imaging have also been investigated in the studies, including penumbra identification, predicting long term clinical outcome, and serving as a biomarker for supportive treatment monitoring. The published results demonstrated the potential of APT imaging in these applications, but further investigations and larger trials are needed for conclusive evidence. Future studies are recommended to report the result of asymmetry analysis at 3.5 ppm along with the findings of the study to reduce this contribution to the heterogeneity of experimental methods observed and to facilitate effective comparison of results between studies and centers. In addition, it is important to focus on the development of fast 3D imaging for full volumetric ischemic tissue assessment for clinical translation.

Amide proton transfer (APT) imaging, a variant of chemical exchange saturation transfer (CEST) MRI, has shown promise in detecting ischemic tissue acidosis following impaired aerobic metabolism in animal models and in human stroke patients due to the sensitivity of the amide proton exchange rate to changes in pH within the physiological range. Recent studies have demonstrated the possibility of using APT-MRI to detect acidosis of the ischemic penumbra enabling the assessment of stroke severity and risk of progression, monitoring of treatment progress, and prognostication of clinical outcome. This paper reviews current APT imaging methods actively used in ischemic stroke research and explores the clinical aspects of ischemic stroke and future applications for these methods.

Frailty is a distinctive health state in which the ability of older people to cope with acute stressors is compromised by an increased vulnerability brought by age-associated declines in physiological reserve and function across multiple organ systems. Although closely associated with age, multimorbidity, and disability, frailty is a discrete syndrome that is associated with poorer outcomes across a range of medical conditions. However, its role in cerebrovascular disease and stroke has received limited attention. The estimated rise in the prevalence of frailty associated with changing demographics over the coming decades makes it an important issue for stroke practitioners, cerebrovascular research, clinical service provision, and stroke survivors alike. This review will consider the concept and models of frailty, how frailty is common in cerebrovascular disease, the impact of frailty on stroke risk factors, acute treatments, and rehabilitation, and considerations for future applications in both cerebrovascular clinical and research settings.

Introduction: Selection criteria for endovascular thrombectomy (EVT) for emergent large-vessel occlusion (ELVO) stroke increasingly rely on CT perfusion (CTP) findings at presentation. While perfusion imaging is used to estimate the likelihood of deriving long-term functional benefit from EVT, there is comparatively little data on how perfusion deficits relate to domains of neurological function. Here, we investigated region-specific hypoperfusion as a driver of neurological dysfunction through correspondence between NIHSS items and CTP. Methods: We included 169 patients with ELVO presenting to Mayo Clinic Rochester or Jacksonville, who had baseline CTP and itemised NIHSS data. Perfusion was quantified as mean transit time using e-CTP (Brainomix Ltd., Oxford, UK) and thresholded to ≥5 s for lesion masking. Voxel-wise lesion-symptom mapping (VLSM) was performed using sparse canonical correlations analysis (Lesymap package, R). Results: Total NIHSS was most strongly predicted by left MCA territory hypoperfusion, corresponding to language-eloquent cortical areas and dominant hemisphere motor tracts (figure 1). Contralateral limb motor deficits (NIHSS 5 and 6) were mainly associated with subcortical and white matter hypoperfusion; there was an additional strong signal for left frontal cortex in language function (NIHSS 9). The remaining NIHSS items were less well localised. Conclusions: Expanding on previous pilot data, our results provide further evidence for the feasibility of hypoperfusion-to-symptom mapping in ELVO. This could allow for more nuanced clinical-imaging mismatch determination, and selection of patients based on specific neurological deficits that may be reversible.

Background Computed tomography (CT) angiography collateral score (CTA-CS) is an important clinical outcome predictor following mechanical thrombectomy for ischemic stroke with large vessel occlusion (LVO). The present multireader study aimed to evaluate the performance of e-CTA software for automated assistance in CTA-CS scoring. Materials and Methods Brain CTA images of 56 patients with anterior LVO were retrospectively processed. Twelve readers of various clinical training, including junior neuroradiologists, senior neuroradiologists, and neurologists graded collateral flow using visual CTA-CS scale in two sessions separated by a washout period. Reference standard was the consensus of three expert readers. Duration of reading time, inter-rater reliability, and statistical comparison of readers’ performance metrics were analyzed between the e-CTA assisted and unassisted sessions. Results e-CTA assistance resulted in significant increase in mean accuracy (58.6% to 67.5%, p = 0.003), mean F1 score (0.574 to 0.676, p = 0.002), mean precision (58.8% to 68%, p = 0.007), and mean recall (58.7% to 69.9%, p = 0.002), especially with slight filling deficit (CTA-CS 2 and 3). Mean reading time was reduced across all readers (103.4 to 59.7 s, p = 0.001), and inter-rater agreement in CTA-CS assessment was increased (Krippendorff's alpha 0.366 to 0.676). Optimized occlusion laterality detection was also noted with mean accuracy (92.9% to 96.8%, p = 0.009). Conclusion Automated assistance for CTA-CS using e-CTA software provided helpful decision support for readers in terms of improving scoring accuracy and reading efficiency for physicians with a range of experience and training backgrounds and leading to significant improvements in inter-rater agreement.

Summary Background Oral anticoagulation reduces the rate of systemic embolism for patients with atrial fibrillation by two-thirds, but its benefits for patients with previous intracranial haemorrhage are uncertain. In the Start or STop Anticoagulants Randomised Trial (SoSTART), we aimed to establish whether starting is non-inferior to avoiding oral anticoagulation for survivors of intracranial haemorrhage who have atrial fibrillation. Methods SoSTART was a prospective, randomised, open-label, assessor-masked, parallel-group, pilot phase trial done at 67 hospitals in the UK. We recruited adults (aged ≥18 years) who had survived at least 24 h after symptomatic spontaneous intracranial haemorrhage, had atrial fibrillation, and had a CHA2DS2-VASc score of at least 2. Web-based computerised randomisation incorporating a minimisation algorithm allocated participants (1:1) to start or avoid long-term (≥1 year) full treatment dose open-label oral anticoagulation. The participants assigned to start oral anticoagulation received either a direct oral anticoagulant or vitamin K antagonist, and the group assigned to avoid oral anticoagulation received standard clinical practice (antiplatelet agent or no antithrombotic agent). The primary outcome was recurrent symptomatic spontaneous intracranial haemorrhage, and was adjudicated by an individual masked to treatment allocation. All outcomes were ascertained for at least 1 year after randomisation and assessed in the intention-to-treat population of all randomly assigned participants, using Cox proportional hazards regression adjusted for minimisation covariates. We planned a sample size of 190 participants (one-sided p=0·025, power 90%, allowing for non-adherence) based on a non-inferiority margin of 12% (or adjusted hazard ratio [HR] of 3·2). This trial is registered with ClinicalTrials.gov (NCT03153150) and is complete. Findings Between March 29, 2018, and Feb 27, 2020, consent was obtained at 61 sites for 218 participants, of whom 203 were randomly assigned at a median of 115 days (IQR 49–265) after intracranial haemorrhage onset. 101 were assigned to start and 102 to avoid oral anticoagulation. Participants were followed up for median of 1·2 years (IQR 0·97–1·95; completeness 97·2%). Starting oral anticoagulation was not non-inferior to avoiding oral anticoagulation: eight (8%) of 101 in the start group versus four (4%) of 102 in the avoid group had intracranial haemorrhage recurrences (adjusted HR 2·42 [95% CI 0·72–8·09]; p=0·152). Serious adverse events occurred in 17 (17%) participants in the start group and 15 (15%) in the avoid group. 22 (22%) patients in the start group and 11 (11%) patients in the avoid group died during the study. Interpretation Whether starting oral anticoagulation was non-inferior to avoiding it for people with atrial fibrillation after intracranial haemorrhage was inconclusive, although rates of recurrent intracranial haemorrhage were lower than expected. In view of weak evidence from analyses of three composite secondary outcomes, the possibility that oral anticoagulation might be superior for preventing symptomatic major vascular events should be investigated in adequately powered randomised trials. Funding British Heart Foundation, Medical Research Council, Chest Heart & Stroke Scotland.

Background and objective:In hyperacute ischaemic stroke, T2 of cerebral water increases with time. Quantifying this change may be informative of the extent of tissue damage and onset time. Our objective was to develop a user-unbiased method to measure the effect of cerebral ischaemia on T2 to study stroke onset time-dependency in human acute stroke lesions. Methods:Six rats were subjected to permanent middle cerebral occlusion to induce focal ischaemia, and a consecutive cohort of acute stroke patients (n=38) were recruited within 9 hours from symptom onset. T1-weighted structural, T2 relaxometry, and diffusion MRI for apparent diffusion coefficient (ADC) were acquired. Ischaemic lesions were defined as regions of lowered ADC. The median T2 difference (ΔT2) between lesion and contralateral non-ischaemic control region was determined by the newly-developed spherical reference method, and data compared to that obtained by the mirror reference method. Linear regressions and receiver operating characteristics (ROC) were compared between the two methods. Results:ΔT2 increases linearly in rat brain ischaemia by 1.9 ± 0.8 ms/h during the first 6 hours, as determined by the spherical reference method. In patients, ΔT2 linearly increases by 1.6 ± 1.4 and 1.9 ± 0.9 ms/h in the lesion, as determined by the mirror reference and spherical reference method, respectively. ROC analyses produced areas under the curve of 0.83 and 0.71 for the spherical and mirror reference methods, respectively. Conclusions:Data from the spherical reference method showed that the median T2 increase in the ischaemic lesion is correlated with stroke onset time in a rat as well as in a human patient cohort, opening the possibility of using the approach as a timing tool in clinics.

Computed tomography angiography (CTA) collateral scoring can identify patients most likely to benefit from mechanical thrombectomy and those more likely to have good outcomes and ranges from 0 (no collaterals) to 3 (complete collaterals). In this study, we used a machine learning approach to categorise the degree of collateral flow in 98 patients who were eligible for mechanical thrombectomy and generate an e-CTA collateral score (CTA-CS) for each patient (e-STROKE SUITE, Brainomix Ltd., Oxford, UK). Three experienced neuroradiologists (NRs) independently estimated the CTA-CS, first without and then with knowledge of the e-CTA output, before finally agreeing on a consensus score. Addition of the e-CTA improved the intraclass correlation coefficient (ICC) between NRs from 0.58 (0.46–0.67) to 0.77 (0.66–0.85, p = 0.003). Automated e-CTA, without NR input, agreed with the consensus score in 90% of scans with the remaining 10% within 1 point of the consensus (ICC 0.93, 0.90–0.95). Sensitivity and specificity for identifying favourable collateral flow (collateral score 2–3) were 0.99 (0.93–1.00) and 0.94 (0.70–1.00), respectively. e-CTA correlated with the Alberta Stroke Programme Early CT Score (Spearman correlation 0.46, p < 0.001) highlighting the value of good collateral flow in maintaining tissue viability prior to reperfusion. In conclusion, ­e-CTA provides a real-time and fully automated approach to collateral scoring with the potential to improve consistency of image interpretation and to independently quantify collateral scores even without expert rater input.

Background: Patient selection for reperfusion therapies requires significant expertise in neuroimaging. Increasingly, machine learning-based analysis is used for faster and standardized patient selection. However, there is little information on how such software influences real-world patient management. Aims: We evaluated changes in thrombolysis and thrombectomy delivery following implementation of automated analysis at a high volume primary stroke centre. Methods: We retrospectively collected data on consecutive stroke patients admitted to a large university stroke centre from two identical 7-month periods in 2017 and 2018 between which the e-Stroke Suite (Brainomix, Oxford, UK) was implemented to analyse non-contrast CT and CT angiography results. Delivery of stroke care was otherwise unchanged. Patients were transferred to a hub for thrombectomy. We collected the number of patients receiving intravenous thrombolysis and/or thrombectomy, the time to treatment; and outcome at 90 days for thrombectomy. Results: 399 patients from 2017 and 398 from 2018 were included in the study. From 2017 to 2018, thrombolysis rates increased from 11.5% to 18.1% with a similar trend for thrombectomy (2.8–4.8%). There was a trend towards shorter door-to-needle times (44–42 min) and CT-to-groin puncture times (174–145 min). There was a non-significant trend towards improved outcomes with thrombectomy. Qualitatively, physician feedback suggested that e-Stroke Suite increased decision-making confidence and improved patient flow. Conclusions: Use of artificial intelligence decision support in a hyperacute stroke pathway facilitates decision-making and can improve rate and time of reperfusion therapies in a hub-and-spoke system of care.

Introduction: Patient selection for acute stroke revascularisation therapies is commonly based on clinical-imaging mismatch paradigms. Anatomical scores or total volumes of brain affected are assumed to correlate with clinical deficit without reference to the functional eloquence of the regions involved. In this study we used the relationship between presenting hypoperfusion abnormality and the corresponding NIHSS to generate functionally weighted atlases from patients with acute ischaemic stroke. Methods: Patients with acute large vessel occlusion (LVO) of the anterior circulation and with CTP at the time of presentation were included in this study. CTP was analysed with e-CTP (Brainomix Ltd., Oxford, UK) and hypoperfusion maps defined (Tmax >6s). Voxelwise lesion to symptom mapping was used to generate probability maps associating regions of hypoperfusion with clinical deficit at presentation. Results: 58 patients with itemised NIHSS and CTP were included. Discrete patterns of deficit were associated with each NIHSS domain. Total NIHSS correlated most strongly with left MCA involvement, consistent with the weighting towards language in this clinical scale. Regions associated with upper and lower limb deficits identified the respective motor cortex regions and descending motor tracts. Example mapping is presented in the Figure (A: total NIHSS, B: left arm paresis, C: left leg paresis). Data from a larger cohort will be presented at the meeting. Conclusions: Functional mapping using associations between presenting NIHSS and hypoperfusion lesion can be used to create eloquence-weighted atlases. Such atlases from stroke patients may be helpful to develop tools to predict clinical deficit associated with a presenting ischemic core lesion defined on non-contrast CT or CTP. This approach could refine clinical-imaging mismatch concepts, expanding endovascular treatment to a wider group of patients who would not currently be treated.

Introduction: Final infarct volume (FIV) is a commonly used imaging endpoint in stroke trials. The aim of this study was to investigate the potential of an automated masking pipeline (Brain Intensity AbNormality Classification Algorithm - BIANCA) on detecting ischemic stroke lesions of follow-up imaging on patients with acute ischemic stroke. Methods: Patients were retrospectively selected from a prospectively acquired mechanical thrombectomy (MT) database from January to July 2019, and were included if they had a follow-up magnetic resonance imaging DWI within 72h from procedure available. Masks were generated on B1000 imaging by clinical research stroke personnel and then compared with volumes delineated by a fully automated supervised method for lesion detection, based on a k-nearest neighbor (k-NN) algorithm. Results: Seventy patients were included. Human FIV measurements mean was comparable with BIANCA [67.7±73.2 vs 71.8±67 (p Conclusion: The automated masking pipeline measurement showed to behighlysimilar to a standardized protocol of FIV estimation at a busy neuroendovascular center and could be used in trials with large numbers of patients.

Background and Purpose: The e-Stroke Suite software (Brainomix, Oxford, United Kingdom) is a tool designed for the automated quantification of The Alberta Stroke Program Early CT Score and ischemic core volumes on noncontrast computed tomography (NCCT). We sought to compare the prediction of postreperfusion infarct volumes and the clinical outcomes across NCCT e-Stroke software versus RAPID (IschemaView, Menlo Park, CA) computed tomography perfusion measurements. Methods: All consecutive patients with anterior circulation large vessel occlusion stroke presenting at a tertiary care center between September 2010 and November 2018 who had available baseline infarct volumes on both NCCT e-Stroke Suite software and RAPID CTP as well as final infarct volume (FIV) measurements and achieved complete reperfusion (modified Thrombolysis in Cerebral Infarction scale 2c-3) post-thrombectomy were included. The associations between estimated baseline ischemic core volumes and FIV as well as 90-day functional outcomes were assessed. Results: Four hundred seventy-nine patients met inclusion criteria. Median age was 64 years (55–75), median e-Stroke and computed tomography perfusion ischemic core volumes were 38.4 (21.8–58) and 5 (0–17.7) mL, respectively, whereas median FIV was 22.2 (9.1–56.2) mL. The correlation between e-Stroke and CTP ischemic core volumes was moderate (R=0.44; P P P 6 hours) treatment windows. Multivariate analysis showed that both e-Stroke software NCCT baseline ischemic core volume (adjusted odds ratio, 0.98 [95% CI, 0.97–0.99]) and RAPID CTP ischemic core volume (adjusted odds ratio, 0.98 [95% CI, 0.97–0.99]) were independently and comparably associated with good outcome (modified Rankin Scale score of 0–2) at 90 days. Conclusions: NCCT e-Stroke Suite software performed similarly to RAPID CTP in assessing postreperfusion FIV and functional outcomes for both early- and late-presenting patients. NCCT e-Stroke volumes seems to represent a viable alternative in centers where access to advanced imaging is limited. Moreover, the future development of fusion maps of NCCT and CTP ischemic core estimates may improve upon the current performance of these tools as applied in isolation.

Background: Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy.Methods: RESTART was a prospective, randomised, open-label, blinded-endpoint, parallel-group trial at 122 hospitals in the UK that assessed whether starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. For this prespecified subgroup analysis, consultant neuroradiologists masked to treatment allocation reviewed brain CT or MRI scans performed before randomisation to confirm participant eligibility and rate features of the intracerebral haemorrhage and surrounding brain. We followed participants for primary (recurrent symptomatic intracerebral haemorrhage) and secondary (ischaemic stroke) outcomes for up to 5 years (reported elsewhere). For this report, we analysed eligible participants with intracerebral haemorrhage according to their treatment allocation in primary subgroup analyses of cerebral microbleeds on MRI and in exploratory subgroup analyses of other features on CT or MRI. The trial is registered with the ISRCTN registry, number ISRCTN71907627.Findings: Between May 22, 2013, and May 31, 2018, 537 participants were enrolled, of whom 525 (98%) had intracerebral haemorrhage: 507 (97%) were diagnosed on CT (252 assigned to start antiplatelet therapy and 255 assigned to avoid antiplatelet therapy, of whom one withdrew and was not analysed) and 254 (48%) underwent the required brain MRI protocol (122 in the start antiplatelet therapy group and 132 in the avoid antiplatelet therapy group). There were no clinically or statistically significant hazards of antiplatelet therapy on recurrent intracerebral haemorrhage in primary subgroup analyses of cerebral microbleed presence (2 or more) versus absence (0 or 1) (adjusted hazard ratio [HR] 0·30 [95% CI 0·08–1·13] vs 0·77 [0·13–4·61]; pinteraction=0·41), cerebral microbleed number 0–1 versus 2–4 versus 5 or more (HR 0·77 [0·13–4·62] vs 0·32 [0·03–3·66] vs 0·33 [0·07–1·60]; pinteraction=0·75), or cerebral microbleed strictly lobar versus other location (HR 0·52 [0·004–6·79] vs 0·37 [0·09–1·28]; pinteraction=0·85). There was no evidence of heterogeneity in the effects of antiplatelet therapy in any exploratory subgroup analyses (all pinteraction>0·05).Interpretation: Our findings exclude all but a very modest harmful effect of antiplatelet therapy on recurrent intracerebral haemorrhage in the presence of cerebral microbleeds. Further randomised trials are needed to replicate these findings and investigate them with greater precision.Funding: British Heart Foundation.

The apparent diffusion coefficient (ADC) of cerebral water, as measured by diffusion MRI, rapidly decreases in ischaemia, highlighting a lesion in acute stroke patients. The MRI T 2 relaxation time changes in ischaemic brain such that T 2 in ADC lesions may be informative of the extent of tissue damage, potentially aiding in stratification for treatment. We have developed a novel user-unbiased method of determining the changes in T 2 in ADC lesions as a function of clinical symptom duration based on voxel-wise referencing to a contralateral brain volume. The spherical reference method calculates the most probable pre-ischaemic T 2 on a voxel-wise basis, making use of features of the contralateral hemisphere presumed to be largely unaffected. We studied whether T 2 changes in the two main cerebral tissue types, i.e. in grey matter (GM) and white matter (WM), would differ in stroke. Thirty-eight acute stroke patients were accrued within 9 h of symptom onset and scanned at 3 T for 3D T 1-weighted, multi b-value diffusion and multi-echo spin echo MRI for tissue type segmentation, quantitative ADC and absolute T 2 images, respectively. T 2 changes measured by the spherical reference method were 1.94 ± 0.61, 1.50 ± 0.52 and 1.40 ± 0.54 ms h-1 in the whole, GM, and WM lesions, respectively. Thus, T 2 time courses were comparable between GM and WM independent of brain tissue type involved. We demonstrate that T 2 changes in ADC-delineated lesions can be quantified in the clinical setting in a user unbiased manner and that T 2 change correlated with symptom onset time, opening the possibility of using the approach as a tool to assess severity of tissue damage in the clinical setting.

Harston et al. establish proof of principle for clinical use of pH-weighted MRI in patients with acute ischaemic stroke. Detailed tissue-level analysis reveals that cerebral intracellular pH, a marker of metabolic stress, is associated with eventual tissue outcome, and complements established imaging modalities., The original concept of the ischaemic penumbra suggested imaging of regional cerebral blood flow and metabolism would be required to identify tissue that may benefit from intervention. Amide proton transfer magnetic resonance imaging, a chemical exchange saturation transfer technique, has been used to derive cerebral intracellular pH in preclinical stroke models and has been proposed as a metabolic marker of ischaemic penumbra. In this proof of principle clinical study, we explored the potential of this pH-weighted magnetic resonance imaging technique at tissue-level. Detailed voxel-wise analysis was performed on data from a prospective cohort of 12 patients with acute ischaemic stroke. Voxels within ischaemic core had a more severe intracellular acidosis than hypoperfused tissue recruited to the final infarct (P < 0.0001), which in turn was more acidotic than hypoperfused tissue that survived (P < 0.0001). In addition, when confined to the grey matter perfusion deficit, intracellular pH (P < 0.0001), but not cerebral blood flow (P = 0.31), differed between tissue that infarcted and tissue that survived. Within the presenting apparent diffusion coefficient lesion, intracellular pH differed between tissue with early apparent diffusion lesion pseudonormalization and tissue with true radiographic recovery. These findings support the need for further investigation of pH-weighted imaging in patients with acute ischaemic stroke.

It has been proposed that metabolic markers of baseline brain oxygenation have a role to play in the early identification of the ischemic penumbra. Streamlined-qBOLD is a magnetic resonance imaging technique that does not require exogenous contrast. It is a refinement of the quantitative BOLD methodology that provides a simplified approach to mapping and quantifying baseline brain oxygenation related parameters (reversible transverse relaxation rate (R2′), deoxygenated blood volume (DBV) and deoxyhaemoglobin concentration ([dHb])) in a clinically relevant manner. Streamlined-qBOLD was applied to an exploratory cohort of acute stroke patients in a serial imaging study. Detailed voxel-level analysis was used to quantify the metabolic profile of ischaemic tissue on presentation and investigate these metrics in relation to tissue outcome. Individual patient examples illustrate the appropriate interpretation of R2′, DBV and [dHb] in acute stroke and demonstrate the ability of this method to deliver regional information related to oxygen metabolism in the ischaemic tissue. Regional analysis confirms that R2′, DBV and [dHb] vary between regions of ischaemia with different tissue outcomes.

Introduction: The Acute Stroke Imaging Roadmap III identifies structural distortion due to vasogenic edema and hemorrhage as a research priority for defining final infarction. Non-linear registration (NLR) of a follow up scan to an undistorted presenting scan could correct for distortions due to edema, hemorrhage or atrophy, achieving this goal. In addition, the difference between the volume of infarction following NLR and the volume following a rigid body registration (RBR) reflects the degree of anatomical distortion. In this study we evaluate this technique to correct for subacute edema at different timepoints, and generate a metric to quantify brain swelling at these times. We determine whether early edema at 24 hours predicts edema at 1 week. Methods: Patients with non-lacunar ischemic stroke were recruited into a MRI study. Patients had structural T1-weighted, T2-weighted FLAIR and diffusion-weighted imaging (DWI, b=1000/0) at presentation, 24hrs, 1wk and 1mo. Infarction was defined manually at 24hrs using DWI, and at 1wk and 1mo using FLAIR image by 2 raters. To quantify edema, both NLR warps and RBR matrices were generated between the T1 images at each timepoint to the presenting T1 scan. Infarct masks were transformed to presenting image space using RBR and NLR, and the relative difference in volumes used to quantify the Edema Metric (EM). Results: 34 patients were recruited into the study. NLR corrected for distortions due to edema and hemorrhagic transformation at the 24hr and 1wk timepoints. The EM at 24 hours, 1 week and 1 month were 17.7% (p=0.009), 26.5% (p=0.02), and 7.1% (p=0.05) respectively for the manually defined infarct masks. EM at 24 hours predicted edema at 1 week (r 2 =37%, p=0.009), but not at 1 month (r 2 =3%, p=0.6). Conclusions: NLR provides an opportunity to correct for edema at subacute timepoints and by comparing infarct volumes to those following RBR provides a measure of edema. The EM quantifies the contribution of edema at 24hrs and 1wk, and potentially allows the selection of patients at 24hrs who are likely to develop significant swelling at 1 week. The EM may also be useful in stroke trials to quantify the effect sizes of treatments aimed at minimizing edema in stroke.

Lacunar infarction is traditionally ascribed to lipohyalinosis or microatheroma. We report the case of 40-year-old man, without traditional risk factors for ischemic stroke, who presented to the Emergency Department with recurrent episodes of transient right-sided weakness and paresthesia. Lacunar infarction was confirmed on diffusion-weighted MRI and blood tests showed a marked polycythemia. Quantitative magnetic resonance perfusion imaging demonstrated dramatically abnormal perfusion throughout both cerebral hemispheres, and transcranial Doppler revealed reduced cerebral artery velocities, both consistent with the proposed mechanism of hyperviscosity. His symptoms settled with treatment of the polycythemia and workup did not find another cause of ischemic stroke. We propose that hyperviscosity secondary to steroid-induced polycythemia caused ischemia in this case and not lipohyalinosis or microatheroma, to which lacunar disease is commonly attributed.

Purpose To compare quantification of the amide proton transfer (APT) effect pre- and post-gadolinium contrast agent (Gd) administration in order to establish to what extent Gd alters quantification of the APT effect. Materials and Methods Four patients with internal carotid stenosis were recruited. APT imaging was acquired pre- and post-contrast in two sessions (before and after surgery) to assess the extent of relaxation time, T1, change on APT effect calculated using magnetization transfer ratio asymmetry analysis at offsets of ±3.5 ppm relative to water resonance. Statistical and modeling evaluations were performed on the pre- and post-contrast APT effect to study the sensitivity to contrast administration. Results Before surgery, the post-contrast T1 was estimated to drop

Alteplase is the only drug licensed for acute ischemic stroke, and in this formulation, the thrombolytic agent recombinant tissue plasminogen activator (rtPA) is stabilized in a solution of L-arginine. Improved functional outcomes after alteplase administration have been shown in clinical trials, along with improved histological and behavioral measures in experimental models of embolic stroke. However, in animal models of mechanically induced ischemia, alteplase can exacerbate ischemic damage. We have systematically reviewed the literature of both rtPA and L-arginine administration in mechanical focal ischemia. The rtPA worsens ischemic damage under certain conditions, whereas L-arginine can have both beneficial and deleterious effects dependent on the time of administration. The interaction between rtPA and L-arginine may be leading to the production of nitric oxide, which can cause direct neurotoxicity, altered cerebral blood flow, and disruption of the neurovascular unit. We suggest that alternative formulations of rtPA, in the absence of L-arginine, would provide new insight into rtPA neurotoxicity, and have the potential to offer more efficacious thrombolytic therapy for ischemic stroke patients. © 2010 ISCBFM All rights reserved.

Acknowledgements and Sources of Funding The research was supported by the National Institute for Health Research Oxford Biomedical Research Centre Programme, the Dunhill Medical Trust (grant No. OSRP1/1006) and the Centre of Excellence for Personalized Healthcare funded by the Wellcome Trust and Engineering and Physical Sciences Research Council under grant No. WT 088877/Z/09/Z. We wish to acknowledge the facilities provided by the Oxford Acute Vascular Imaging Centre.

Introduction: Ischemic injury on MRI is defined acutely by measuring the diffusion of water alone. Chemical exchange saturation transfer imaging (CEST) allows measurement of intracellular pH, and changes in protein structure and mobility using Nuclear Overhauser Enhancement (NOE). When identifying treatment targets, changes to protein integrity have the potential to complement diffusion-weighted imaging (DWI) in distinguishing irreversible from reversible intracellular processes that are amenable to therapeutic intervention. Methods: Patients with non-lacunar ischemic stroke underwent serial MRI over 1 month. The imaging protocol included single slice CEST imaging. NOE was quantified using a 3-pool exchange model relative to the contralateral hemisphere (rNOE*). DWI, ASL perfusion imaging, T1-weighted and FLAIR imaging were used to define the tissue outcome: ischemic core, infarct growth, and oligemic tissue that survived. Infarct growth was classified as early or late (before or after 24 hours). Images and masks were registered to CEST native image space for voxelwise and patient-level serial analyses. Results: 30 patients were included in the analysis. Within 6 hours rNOE* in early infarct growth was significantly lower than ischemic core and late infarct growth (p Conclusion: rNOE* showed a discrete temporal profile in tissue that infarcted by 24 hours in contrast to that which survived or infarcted later. This is additive information to that provided by routine acute stroke MRI at presentation, and demonstrates that the imaging of intracellular protein structure and mobility may have a role alongside DWI in helping to predict tissue fate. Further work is required to understand the potential of NOE as a modifiable imaging biomarker.

Desert locusts ( Schistocerca gregaria ) can transform reversibly between the swarming gregarious phase and a solitarious phase, which avoids other locusts. This transformation entails dramatic changes in morphology, physiology, and behavior. We have used the lobula giant movement detector (LGMD) and its postsynaptic target, the descending contralateral movement detector (DCMD), which are visual interneurons that detect looming objects, to analyze how differences in the visual ecology of the two phases are served by altered neuronal function. Solitarious locusts had larger eyes and a greater degree of binocular overlap than those of gregarious locusts. The receptive field to looming stimuli had a large central region of nearly equal response spanning 120° × 60° in both phases. The DCMDs of gregarious locusts responded more strongly than solitarious locusts and had a small caudolateral focus of even further sensitivity. More peripherally, the response was reduced in both phases, particularly ventrally, with gregarious locusts showing greater proportional decrease. Gregarious locusts showed less habituation to repeated looming stimuli along the eye equator than did solitarious locusts. By contrast, in other parts of the receptive field the degree of habituation was similar in both phases. The receptive field organization to looming stimuli contrasts strongly with the receptive field organization of the same neurons to nonlooming local-motion stimuli, which show much more pronounced regional variation. The DCMDs of both gregarious and solitarious locusts are able to detect approaching objects from across a wide expanse of visual space, but phase-specific changes in the spatiotemporal receptive field are linked to lifestyle changes.

BACKGROUND AND PURPOSE: Imaging biomarkers are increasingly used to provide a better understanding of the pathophysiology of acute ischemic stroke. However, this approach of routinely using imaging biomarkers to inform treatment decisions has yet to be translated into successful randomized trials. The aim of this study was to systematically review the use of imaging biomarkers in randomized controlled trials in patients with acute ischemic stroke, exploring the purposes for which the imaging biomarkers were used. MATERIALS AND METHODS: We performed a systematic review of imaging biomarkers used in randomized controlled trials of acute ischemic stroke, in which a therapeutic intervention was trialed within 48 hours of symptom onset. Data bases searched included MEDLINE, EMBASE, strokecenter.org, and the Virtual International Stroke Trials Archive (1995–2014). RESULTS: Eighty-four studies met the criteria, of which 49 used imaging to select patients; 31, for subgroup analysis; and 49, as an outcome measure. Imaging biomarkers were broadly used for 8 purposes. There was marked heterogeneity in the definitions and uses of imaging biomarkers and significant publication bias among post hoc analyses. CONCLUSIONS: Imaging biomarkers offer the opportunity to refine the trial cohort by minimizing participant variation, to decrease sample size, and to personalize treatment approaches for those who stand to benefit most. However, within imaging modalities, there has been little consistency between stroke trials. Greater effort to prospectively use consistent imaging biomarkers should help improve the development of novel treatment strategies in acute stroke and improve comparison between studies.