Acute Ischemic Tissue Research Articles

Abstract TMP69: Random Rater Sampling For Deep Learning Algorithm To Segment Acute Ischemic Stroke On Non-contrast Computed Tomography

Introduction: The delineation of volume and location of acute ischemic brain tissue (AIBT) on Non-Contrast CT (NCCT) increases the efficiency of endovascular treatment decisions. However, the manual segmentation of the AIBT on NCCT is a challenging task and suffers from low inter-expert agreement. Whether supervised deep convolutional neural networks (CNN) are more accurate than expert raters remain to be determined, and the optimal ground truth segmentation of AIBT is unclear given the low inter-expert agreement. We hypothesized that randomly sampling ground truth segmentations of expert raters would enable the CNN to better approximate an accurate ground truth and increase performance. Methods: The data set consisted of 200 NCCT images (Figure 1a)) of acute ischemic stroke patients presenting within 6-16h and consenting to the DEFUSE3 trial. Three experienced neuroradiologists manually segmented the AIBT (Figure 1b)1.-3.). The aggregated validation sets of 5-fold-cross-validation were used to compare the (i) average inter-expert agreement, the average performance of (ii) three individual CNNs trained on each rater and (iii) one CNN trained with random rater sampling. Results: (iii) Random rater sampling (Figure 1c)) lead to a CNN performance superior to (ii) the average performance of individually trained CNNs. The reliability of a CNN goes beyond the human inter-expert agreement (i) (Surface Dice at Tolerance 5mm: 0.88 versus 0.68 and 0.67, respectively; Table 1). Conclusions: The volume and location of AIBT on NCCT can reliably be segmented by a CNN. The agreement between a randomly chosen rater and the CNN predictions surpasses the inter-expert agreement (Table 1).

Reader Response: Race-Ethnic Disparities in Rates of Declination of Thrombolysis for Stroke

Using the Get With the Guidelines-Stroke registry, Mendelson et al.1 showed that 3.7% of patients with acute ischemic stroke decline intravenous tissue plasminogen activator (tPA), despite being eligible. The authors found significant racial differences in the tPA declination rates. Compared with non-Hispanic White patients, non-Hispanic Black patients were 21% more likely to decline tPA and Asian patients were 28% less likely.

Accuracy of Automated Computer-Aided Diagnosis for Stroke Imaging: A Critical Evaluation of Current Evidence.

There is increasing interest in computer applications, using artificial intelligence methodologies, to perform health care tasks previously performed by humans, particularly in medical imaging for diagnosis. In stroke, there are now commercial artificial intelligence software for use with computed tomography or MR imaging to identify acute ischemic brain tissue pathology, arterial obstruction on computed tomography angiography or as hyperattenuated arteries on computed tomography, brain hemorrhage, or size of perfusion defects. A rapid, accurate diagnosis may aid treatment decisions for individual patients and could improve outcome if it leads to effective and safe treatment; or conversely, to disaster if a delayed or incorrect diagnosis results in inappropriate treatment. Despite this potential clinical impact, diagnostic tools including artificial intelligence methods are not subjected to the same clinical evaluation standards as are mandatory for drugs. Here, we provide an evidence-based review of the pros and cons of commercially available automated methods for medical imaging diagnosis, including those based on artificial intelligence, to diagnose acute brain pathology on computed tomography or magnetic resonance imaging in patients with stroke.

Characterization of tissue and functional deficits in a clinically translational pig model of acute ischemic stroke

The acute stroke phase is a critical time frame used to evaluate stroke severity, therapeutic options, and prognosis while also serving as a major tool for the development of diagnostics. To further understand stroke pathophysiology and to enhance the development of treatments, our group developed a translational pig ischemic stroke model. In this study, the evolution of acute ischemic tissue damage, immune responses, and functional deficits were further characterized. Stroke was induced by middle cerebral artery occlusion in Landrace pigs. At 24 h post-stroke, magnetic resonance imaging revealed a decrease in ipsilateral diffusivity, an increase in hemispheric swelling resulting in notable midline shift, and intracerebral hemorrhage. Stroke negatively impacted white matter integrity with decreased fractional anisotropy values in the internal capsule. Like patients, pigs showed a reduction in circulating lymphocytes and a surge in neutrophils and band cells. Functional responses corresponded with structural changes through reductions in open field exploration and impairments in spatiotemporal gait parameters. Characterization of acute ischemic stroke in pigs provided important insights into tissue and functional-level assessments that could be used to identify potential biomarkers and improve preclinical testing of novel therapeutics.

Time to Wake-Up: Extending the Window for Management of Unknown-Onset Strokes.

The term "Wake-Up Stroke" is applied to a patient who displays no symptoms before sleep, but wakes with neurologic deficits suggestive of stroke. The current guidelines for acute ischemic stroke limit intravenous tissue plasminogen activator use to stroke patients in whom symptom onset or last known well is less than 4.5 hours. Approximately one-third of acute ischemic stroke patients present with unknown time of symptom onset and are often not eligible for intravenous reperfusion therapy in clinical practice. This review provides an overview of several earlier trials that used advanced neuroimaging to determine eligibility for reperfusion therapy in patients with unknown stroke onset. The reassuring results of these earlier trials that led to recent thrombolysis trials specifically targeted at "wake-up stroke" patients are discussed in this review. Ongoing studies aim to expand our knowledge regarding the safety and efficacy of thrombolysis in these patients.

Functionalization of Clinically Approved MRI Contrast Agents for the Delivery of VEGF.

In combining the two clinically approved substances ferumoxytol and VEGF-165 via peptide coupling, we propose a straightforward approach to obtain a potentially ready-to-use theranostic contrast agent for specific cardiovascular diseases. Clinical and preclinical magnetic resonance imaging (MRI) studies have shown that intravenously applied superparamagnetic ferumoxytol nanoparticles accumulate in acute ischemic myocardial tissue. On the other hand, growth factors such as VEGF-165 (vascular endothelial growth factor) play a major role during angiogenesis and vasculogenesis. Promising clinical studies with systemic application of VEGF-165 have been performed in the past. However, following untargeted systemic application, the biological half-life of VEGF-165 was too short to develop its full effect. Therefore, we hypothesized that ferumoxytol particles functionalized with VEGF-165 will accumulate in ischemic myocardial regions and can be detected by MRI, while the prolonged retention of VEGF-165 due to ferumoxytol-coupling will help to prevent adverse tissue remodeling. In addition, strategies such as magnetic targeting can be used to enhance targeted local accumulation. As a precondition for further preclinical research, we confirmed the successful coupling between ferumoxytol and VEGF-165 in detail (TEM, XPS, and IR spectroscopy), characterized the functionalized ferumoxytol particles (DLS, TEM, and MRI) and performed in vitro tests that showed their superior effect on cell growth and survival.

Abstract TP104: Theophylline as an Add-On to Thrombolytic Therapy in Acute Ischemic Stroke: Results of the Randomized Controlled PhaseII TEA-Stroke Trial

Introduction: In acute ischemic stroke, delayed revascularisation increases the risk of enlargement of the ischemic core associated with poor clinical outcome. Neuroprotective agents may immediately protect the penumbra and by that extend the time window for tissue-saving reperfusion. The vasoactive agent theophylline has been shown to reduce brain tissue edema, brain damage and mortality in animal stroke models. However, results from the animal studies, clinical case series and previous randomized clinical trials with theophylline in stroke patients were controversial. In this prospective trial, the primary study objective was to evaluate whether theophylline is safe and efficient in acute ischemic stroke patients as an add-on to thrombolytic therapy. Hypothesis: We hypothesized that treatment with theophylline can improve capillary flow in acute ischemic brain tissue and thus facilitate reperfusion leading to reduced volume of infarct growth and clinical improvement. Methods: The TEA-Stroke Trial is a two-center, proof of concept phase II clinical study with a randomized, double-blinded, placebo-controlled design. Patients with acute ischemic stroke verified by magnetic resonance imaging (MRI) and a National Institute of Health Stroke Scale ≥4 were randomized 1:1 to either theophylline or placebo as an add-on to standard thrombolytic therapy. The dual primary outcome measures included infarct growth assessed by MRI and clinical improvement assessed by the National Institute of Health Stroke scale at the 24-hour follow-up. A sample size of 120 subjects was estimated to detect a 22% difference between the treatment groups (80% power, alpha = 0.05) based on the MRI surrogate marker. Results: The study was stopped early after randomization of 64 patients for futility reasons because of slow recruitment. There were no safety concerns. Detailed blinded data analysis is ongoing and the main results will be presented. Conclusion: The TEA-Stroke Trial is the first study to evaluate whether the addition of theophylline to thrombolytic therapy is safe and efficient in patients with acute ischemic stroke. The main trial results will be discussed. Trial Registration: EudraCT number 2013-001989-42

Rapid Identification of Ischemic Injury in Renal Tissue by Mass-Spectrometry Imaging.

The increasing analytical speed of mass-spectrometry imaging (MSI) has led to growing interest in the medical field. Acute kidney injury is a severe disease with high morbidity and mortality. No reliable cut-offs are known to estimate the severity of acute kidney injury. Thus, there is a need for new tools to rapidly and accurately assess acute ischemia, which is of clinical importance in intensive care and in kidney transplantation. We investigated the value of MSI to assess acute ischemic kidney tissue in a porcine model. A perfusion model was developed where paired kidneys received warm (severe) or cold (minor) ischemia (n = 8 per group). First, ischemic tissue damage was systematically assessed by two blinded pathologists. Second, MALDI-MSI of kidney tissues was performed to study the spatial distributions and compositions of lipids in the tissues. Histopathological examination revealed no significant difference between kidneys, whereas MALDI-MSI was capable of a detailed discrimination of severe and mild ischemia by differential expression of characteristic lipid-degradation products throughout the tissue within 2 h. In particular, lysolipids, including lysocardiolipins, lysophosphatidylcholines, and lysophosphatidylinositol, were dramatically elevated after severe ischemia. This study demonstrates the significant potential of MSI to differentiate and identify molecular patterns of early ischemic injury in a clinically acceptable time frame. The observed changes highlight the underlying biochemical processes of acute ischemic kidney injury and provide a molecular classification tool that can be deployed in assessment of acute ischemic kidney injury.

A Magnetic Resonance Imaging Protocol for Stroke Onset Time Estimation in Permanent Cerebral Ischemia

MRI provides a sensitive and specific imaging tool to detect acute ischemic stroke by means of a reduced diffusion coefficient of brain water. In a rat model of ischemic stroke, differences in quantitative T1 and T2 MRI relaxation times (qT1 and qT2) between the ischemic lesion (delineated by low diffusion) and the contralateral non-ischemic hemisphere increase with time from stroke onset. The time dependency of MRI relaxation time differences is heuristically described by a linear function and thus provides a simple estimate of stroke onset time. Additionally, the volumes of abnormal qT1 and qT2 within the ischemic lesion increase linearly with time providing a complementary method for stroke timing. A (semi)automated computer routine based on the quantified diffusion coefficient is presented to delineate acute ischemic stroke tissue in rat ischemia. This routine also determines hemispheric differences in qT1 and qT2 relaxation times and the location and volume of abnormal qT1 and qT2 voxels within the lesion. Uncertainties associated with onset time estimates of qT1 and qT2 MRI data vary from ± 25 min to ± 47 min for the first 5 hours of stroke. The most accurate onset time estimates can be obtained by quantifying the volume of overlapping abnormal qT1 and qT2 lesion volumes, termed 'Voverlap' (± 25 min) or by quantifying hemispheric differences in qT2 relaxation times only (± 28 min). Overall, qT2 derived parameters outperform those from qT1. The current MRI protocol is tested in the hyperacute phase of a permanent focal ischemia model, which may not be applicable to transient focal brain ischemia.

A Magnetic Resonance Imaging Protocol for Stroke Onset Time Estimation in Permanent Cerebral Ischemia.

MRI provides a sensitive and specific imaging tool to detect acute ischemic stroke by means of a reduced diffusion coefficient of brain water. In a rat model of ischemic stroke, differences in quantitative T1 and T2 MRI relaxation times (qT1 and qT2) between the ischemic lesion (delineated by low diffusion) and the contralateral non-ischemic hemisphere increase with time from stroke onset. The time dependency of MRI relaxation time differences is heuristically described by a linear function and thus provides a simple estimate of stroke onset time. Additionally, the volumes of abnormal qT1 and qT2 within the ischemic lesion increase linearly with time providing a complementary method for stroke timing. A (semi)automated computer routine based on the quantified diffusion coefficient is presented to delineate acute ischemic stroke tissue in rat ischemia. This routine also determines hemispheric differences in qT1 and qT2 relaxation times and the location and volume of abnormal qT1 and qT2 voxels within the lesion. Uncertainties associated with onset time estimates of qT1 and qT2 MRI data vary from ± 25 min to ± 47 min for the first 5 hours of stroke. The most accurate onset time estimates can be obtained by quantifying the volume of overlapping abnormal qT1 and qT2 lesion volumes, termed 'Voverlap' (± 25 min) or by quantifying hemispheric differences in qT2 relaxation times only (± 28 min). Overall, qT2 derived parameters outperform those from qT1. The current MRI protocol is tested in the hyperacute phase of a permanent focal ischemia model, which may not be applicable to transient focal brain ischemia.

Investigating potentially salvageable penumbra tissue in an in vivo model of transient ischemic stroke using sodium, diffusion, and perfusion magnetic resonance imaging.

Background Diffusion magnetic resonance imaging (MRI) is the current-state-of-the-art technique to clinically investigate acute (0–24 h) ischemic stroke tissue. However, reduced apparent diffusion coefficient (ADC)—considered a marker of tissue damage—was observed to reverse spontaneously during the subacute stroke phase (24–72 h) which means that low ADC cannot be used to reflect the damaged tissue after 24 h in experimental and clinical studies. One reason for the change in ADC is that ADC values drop with cytotoxic edema (acute phase) and rise when vasogenic edema begins (subacute phase). Recently, combined 1H- and 23Na-MRI was proposed as a more accurate approach to improve delineation between reversible (penumbra) and irreversible ischemic injury (core). The aim of this study was to investigate the effects of reperfusion on the ADC and the sodium MRI signal after experimental ischemic stroke in rats in well-defined areas of different viability levels of the cerebral lesion, i.e. core and penumbra as defined via perfusion and histology. Transient middle cerebral artery occlusion was induced in male rats by using the intraluminal filament technique. MRI sodium, perfusion and diffusion measurement was recorded before reperfusion, shortly after reperfusion and 24 h after reperfusion. The animals were reperfused after 90 min of ischemia.ResultsSodium signal in core did not change before reperfusion, increased after reperfusion while sodium signal in penumbra was significantly reduced before reperfusion, but showed no changes after reperfusion compared to control. The ADC was significantly decreased in core tissue at all three time points compared to contralateral side. This decrease recovered above commonly applied viability thresholds in the core after 24 h.ConclusionsReduced sodium-MRI signal in conjunction with reduced ADC can serve as a viability marker for penumbra detection and complement hydrogen diffusion- and perfusion-MRI in order to facilitate time-independent assessment of tissue fate and cellular bioenergetics failure in stroke patients.

Sensitive mapping of acute ischemic tissue injury with fast diffusion kurtosis imaging

Sensitive mapping of acute ischemic tissue injury with fast diffusion kurtosis imaging

Pharmacologicalmodification of thegabaergicsystem as a potentialvariant of cerebral protection in acute cerebral ischemia

The aim is to study the possible impact of some derivatives of gamma-aminobutyric acid (GABA), piracetam, picamilon and Krebs cycle intermediates - succinate (as sodium salt) on the pathobiochemical changes in the central nervous system, that occur under experimental playing of acute ischemic tissue damage of the cerebrum.Research methods: The study was conducted in 96 rats Wistar, who were on a standardized vivarium diet. Cerebral ischemia was caused by bond of the unilateral common carotid artery. All drugs were administered intraperitoneally once daily for 4 days after modeling of an acute cerebral ischemia after which animals were withdrawn from experiment. In the brain tissues concentrations of pyruvic, izocitric, dairy and apple acids were determined. The activity of antioxidant enzymes: catalase and superoxide dysmutaza. In addition, the brain tissues the contents of lipid peroxidation products were evaluated – diene conjugates and malonic dialdehyde. Level of brain energy production was judged by the content of the adenylic nucleotide and also phosphocreatine . The degree of destruction of the brain cells was assessed by activity of the enzyme lactate dehydrogenase in the blood and brain fraction of the creatine phosphokinase.Research results: As a result of studies, on the 4th day of ischemia a significant carbohydrate metabolism is detected, which is reflected in the sharp strengthening of anaerobic glycolysis and reduced activity of the Krebs cycle reactions, as evidenced by a significant increase in quantity of lactate and decrease in quantity of malate, isocitrate and pyruvate.A sharp strengthening of anaerobic glycolysis results in the accumulation of oxidized products and intermediates especially the latter product – lactic acid. Metabolic acidosis develops against the background of energy failure, which leads to activation of lipid peroxidation reactions. Courses appointment of the cyclic derivatives of GABA piracetam, especially Picamilon, resulted in significantly greater improvement in metabolic parameters compared with sodium succinate may to some extent explained by the higher bioavailability of these agents cells. The impact of these drugs on the nodal points of disturbed metabolism was almost equal and different in antioxidant activity. As to normalization of lipid peroxidation reactions Picamilon was most active.Conclusions: Thus, as a result of the research the following conclusions may be done.1. Bilateral bond of the common carotid artery, accompanied by severe biochemical changes in the brain tissues, that is largely similar to clinical manifestations of acute ischemic stroke.2. Course appointment of GABA derivatives in the acute period of ischemic lesions of the tissues in varyious degrees improves metabolic status of the ischemic brain and detect different degrees of manifestation of cerebral protective action.3. The activity of various GABA derivatives in respect to the different links of pathogenesis of ischemic stroke is not the same, that leads to insufficient sustainable improvement of impaired metabolism when used alone, in the long run may be justification for finding effective combinations of cerebral protective means with different mechanism of action.4. Among the studied drugs, the most active and balanced action was presented by Picamilon drug

Intralesional Patterns of MRI ADC Maps Predict Outcome in Experimental Stroke

Background: After acute ischemia, the tissue that is at risk of infarction can be detected by perfusion-weighted imaging/diffusion-weighted imaging (PWI/DWI) mismatch but the time that is needed to process PWI limits its use. As DWI is highly sensitive to acute ischemic tissue damage, we hypothesized that different ADC patterns represent areas with a different potential for recovery. Methods: In a model of permanent middle cerebral artery occlusion (pMCAO), Sprague-Dawley rats were randomly distributed to sham surgery and pMCAO. We further separated the pMCAO group according to intralesional ADC pattern (homogeneous or heterogeneous). At 24 h after ischemia induction, we analyzed lesion size, functional outcome, cell death expression, and brain protection markers including ROS enzyme NOX-4. MRI included DWI (ADC maps), DTI (tractography), and PWI (CBF, CBV and MTT). Results: The lesion size was similar in pMCAO rats. Animals with a heterogeneous pattern in ADC maps showed better functional outcome in Rotarod test (p = 0.032), less expression of cell death (p = 0.014) and NOX-4 (p = 0.0063), higher intralesional CBF (p = 0.0026) and larger PWI/DWI mismatch (p = 0.007). Conclusions: In a rodent model for ischemic stroke, intralesional heterogeneity in ADC maps was related to better functional outcome in lesions of similar size and interval after pMCAO. DWI ADC maps may assist in the early identification of ischemic tissue with an increased potential for recovery as higher expression of acute protection markers, lower expression of cell death, increased PWI/DWI mismatch, and higher intralesional CBF were present in animals with a heterogeneous ADC pattern.

Phase-based metamorphosis of diffusion lesion in relation to perfusion values in acute ischemic stroke.

Examining the dynamics of stroke ischemia is limited by the standard use of 2D-volume or voxel-based analysis techniques. Recently developed spatiotemporal models such as the 4D metamorphosis model showed promise for capturing ischemia dynamics. We used a 4D metamorphosis model to evaluate acute ischemic stroke lesion morphology from the acute diffusion-weighted imaging (DWI) to final T2-weighted imaging (T2-w). In 20 representative patients, we metamorphosed the acute lesion to subacute lesion to final infarct. From the DWI lesion deformation maps we identified dynamic lesion areas and examined their association with perfusion values inside and around the lesion edges, blinded to reperfusion status. We then tested the model in ten independent patients from the STroke Imaging Repository (STIR). Perfusion values varied widely between and within patients, and were similar in contracting and expanding DWI areas in many patients in both datasets. In 25% of patients, the perfusion values were higher in DWI-contracting than DWI-expanding areas. A similar wide range of perfusion values and ongoing expansion and contraction of the DWI lesion were seen subacutely. There was more DWI contraction and less expansion in patients who received thrombolysis, although with widely ranging perfusion values that did not differ. 4D metamorphosis modeling shows promise as a method to improve use of multimodal imaging to understand the evolution of acute ischemic tissue towards its fate.

Hypoxia-inducible factor 1-α in chronic gastrointestinal ischemia

Chronic gastrointestinal ischemia (CGI) is the result of decreased mucosal perfusion. Typical histological characteristics are lacking which hamper its early diagnosis. Hypoxia-inducible factor-1α (HIF-1α) is expressed under acute hypoxia. We investigated HIF-1α expression in chronic ischemic and inflammatory conditions of the human gastrointestinal (GI) tract. Immunohistochemical expression of HIF-1α was analyzed in 61 patients, including patients with CGI, Helicobacter pylori gastritis, ischemic colitis (IC), infectious colitis, and inflammatory bowel disease (IBD), and 22 controls. HIF-1α expression in >10 % of the cells was regarded as positive staining, and expression <10 % of the cells was considered as negative staining. In the upper GI tract, HIF-1α expression was found in 5/20 CGI patients, but not in controls (p = 0.08). The sensitivity and specificity of HIF-1α expression for diagnosing CGI were 25 and 84%, respectively. In the lower GI tract, HIF-1α was expressed in all patients with IC and infectious colitis and in a majority of IBD patients as well as in 7/12 controls. The sensitivity and specificity of HIF-1α for diagnosing IC were 100 and 51%, respectively. HIF-1α expression was more often (p = 0.02) observed in patients with histological signs of inflammation in the lower GI tract. HIF-1α is expressed in acute and chronic ischemic tissue, but also in normal colon tissue and inflammatory disorders.

Defining acute ischemic stroke tissue pathophysiology with whole brain CT perfusion

This study aimed to identify and validate whole brain perfusion computed tomography (CTP) thresholds for ischemic core and salvageable penumbra in acute stroke patients and develop a probability based model to increase the accuracy of tissue pathophysiology measurements. One hundred and eighty-three patients underwent multimodal stroke CT using a 320-slice scanner within 6hours of acute stroke onset, followed by 24hour MRI that included diffusion weighted imaging (DWI) and dynamic susceptibility weighted perfusion imaging (PWI). Coregistered acute CTP and 24hour DWI was used to identify the optimum single perfusion parameter thresholds to define penumbra (in patients without reperfusion), and ischemic core (in patients with reperfusion), using a pixel based receiver operator curve analysis. Then, these results were used to develop a sigma curve fitted probability based model incorporating multiple perfusion parameter thresholds. For single perfusion thresholds, a time to peak (TTP) of +5seconds best defined the penumbra (area under the curve, AUC 0.79 CI 0.74-0.83) while a cerebral blood flow (CBF) of <50% best defined the acute ischemic core (AUC 0.73, CI 0.69-0.77). The probability model was more accurate at detecting the ischemic core (AUC 0.80 SD 0.75-0.83) and penumbra (0.85 SD 0.83-0.87) and was significantly closer in volume to the corresponding reference DWI (P=0.031). Whole brain CTP can accurately identify penumbra and ischemic core using similar thresholds to previously validated 16 or 64slice CTP. Additionally, a novel probability based model was closer to defining the ischemic core and penumbra than single thresholds.

Relaxation Along a Fictitious Field (RAFF) and Z-spectroscopy using Alternating-Phase Irradiation (ZAPI) in Permanent Focal Cerebral Ischemia in Rat

Cerebral ischemia alters the molecular dynamics and content of water in brain tissue, which is reflected in NMR relaxation, diffusion and magnetization transfer (MT) parameters. In this study, the behavior of two new MRI contrasts, Relaxation Along a Fictitious Field (RAFF) and Z-spectroscopy using Alternating-Phase Irradiation (ZAPI), were quantified together with conventional relaxation parameters (T1, T2 and T1ρ) and MT ratios in acute cerebral ischemia in rat. The right middle cerebral artery was permanently occluded and quantitative MRI data was acquired sequentially for the above parameters for up to 6 hours. The following conclusions were drawn: 1) Time-dependent changes in RAFF and T1ρ relaxation are not coupled to those in MT. 2) RAFF relaxation evolves more like transverse, rather than longitudinal relaxation. 3) MT measured with ZAPI is less sensitive to ischemia than conventional MT. 4) ZAPI data suggest alterations in the T2 distribution of macromolecules in acute cerebral ischemia. It was shown that both RAFF and ZAPI provide complementary MRI information from acute ischemic brain tissue. The presented multiparametric MRI data may aid in the assessment of brain tissue status early in ischemic stroke.

Early Identification of Potentially Salvageable Tissue with MRI-Based Predictive Algorithms after Experimental Ischemic Stroke

Individualized stroke treatment decisions can be improved by accurate identification of the extent of salvageable tissue. Magnetic resonance imaging (MRI)-based approaches, including measurement of a 'perfusion-diffusion mismatch' and calculation of infarction probability, allow assessment of tissue-at-risk; however, the ability to explicitly depict potentially salvageable tissue remains uncertain. In this study, five predictive algorithms (generalized linear model (GLM), generalized additive model, support vector machine, adaptive boosting, and random forest) were tested in their potency to depict acute cerebral ischemic tissue that can recover after reperfusion. Acute T2-, diffusion-, and perfusion-weighted MRI, and follow-up T2 maps were collected from rats subjected to right-sided middle cerebral artery occlusion without subsequent reperfusion, for training of algorithms (Group I), and with spontaneous (Group II) or thrombolysis-induced reperfusion (Group III), to determine infarction probability-based viability thresholds and prediction accuracies. The infarction probability difference between irreversible-i.e., infarcted after reperfusion-and salvageable tissue injury-i.e., noninfarcted after reperfusion-was largest for GLM (20±7%) with highest accuracy of risk-based identification of acutely ischemic tissue that could recover on subsequent reperfusion (Dice's similarity index=0.79±0.14). Our study shows that assessment of the heterogeneity of infarction probability with MRI-based algorithms enables estimation of the extent of potentially salvageable tissue after acute ischemic stroke.

Adenosine signaling in normal and sickle erythrocytes and beyond

Sickle cell disease (SCD) is a debilitating hemolytic genetic disorder with high morbidity and mortality affecting millions of individuals worldwide. Although SCD was discovered more than a century ago, no effective mechanism-based prevention and treatment are available due to poorly understood molecular basis of sickling, the fundamental pathogenic process of the disease. SCD patients constantly face hypoxia. One of the best-known signaling molecules to be induced under hypoxic conditions is adenosine. Recent studies demonstrate that hypoxia-mediated elevated adenosine signaling plays an important role in normal erythrocyte physiology. In contrast, elevated adenosine signaling contributes to sickling and multiple life threatening complications including tissue damage, pulmonary dysfunction and priapism. Here, we summarize recent research on the role of adenosine signaling in normal and sickle erythrocytes, progression of the disease and therapeutic implications.In normal erythrocytes, both genetic and pharmacological studies demonstrate that adenosine can enhance 2,3-bisphosphoglycerate (2,3-BPG) production via A2B receptor (ADORA2B) activation, suggesting that elevated adenosine has an unrecognized role in normal erythrocytes to promote O2 release and prevent acute ischemic tissue injury. However, in sickle erythrocytes, the beneficial role of excessive adenosine-mediated 2,3-BPG induction becomes detrimental by promoting deoxygenation, polymerization of sickle hemoglobin and subsequent sickling. Additionally, adenosine signaling via the A2A receptor (ADORA2A) on invariant natural killer T (iNKT) cells inhibits iNKT cell activation and attenuates pulmonary dysfunction in SCD mice. Finally, elevated adenosine coupled with ADORA2BR activation is responsible for priapism, a dangerous complication seen in SCD.Overall, the research reviewed here reveals a differential role of elevated adenosine in normal erythrocytes, sickle erythrocytes, iNK cells and progression of disease. Thus, adenosine signaling represents a potentially important therapeutic target for the treatment and prevention of disease.