Tobias Engelhorn

Small interfering RNA-mediated xCT silencing in gliomas inhibits neurodegeneration and alleviates brain edema

Neurodegeneration and brain edema are hallmarks of human malignant brain tumors. Here we show that genetic or pharmacological inhibition of the glutamate transporter xCT (Xc− system, encoded by SLC7a11) in vivo leads to abrogated neurodegeneration, attenuated perifocal edema and prolonged survival. These results show a crucial role for xCT in glioma-induced neurodegeneration and brain edema, corroborating the concept that edema formation may be in part a consequence of peritumoral cell death.

The angiotensin II type 1-receptor blocker candesartan increases cerebral blood flow, reduces infarct size, and improves neurologic outcome after transient cerebral ischemia in rats

The goal of the present study was to test the impact of administration time of the angiotensin II type 1–receptor blocker candesartan on cerebral blood flow (CBF), infarct size, and neuroscore in transient cerebral ischemia. Therefore, 1-hour middle cerebral artery occlusion (MCAO) was followed by reperfusion. Rats received 0.5-mg/kg candesartan intravenously 2 hours before MCAO (pretreatment), 24 hours after MCAO, every 24 hours after MCAO, or 2 hours before and every 24 hours after MCAO. Infarct size (mm3) and a neuroscore at day 7 were compared with controls. CBF was quantified by radiolabeled microspheres and laser-Doppler flowmetry. Compared with controls (95 ± 8), infarct size in candesartan-treated groups was smaller (59 ± 5, 68 ± 10, 28 ± 3, and 15 ± 3, respectively; P < 0.05). Although there was no difference in neuroscore between pretreatment and controls (1.55 ± 0.18, 1.80 ± 0.13), other treatment regimens resulted in improved neuroscores (1.33 ± 0.16, 1.11 ± 0.11, 0.73 ± 0.15; P < 0.05). CBF in pretreated animals at 0.5 hours after MCAO was significantly higher than in controls (0.58 ± 0.09 mL · g−1 ·· min−1 and 44% ± 7% of baseline compared with 0.49 ± 0.06 mL · g−1 ·· min−1 and 37% ± 6%, microspheres and laser-Doppler flowmetry; P < 0.05). Thus, candesartan reduces infarct size even if administered only during reperfusion. Apart from pretreatment, other treatment regimens result in significantly improved neuroscores. In the acute phase of cerebral ischemia, candesartan increases CBF.

Efficient drug-delivery using magnetic nanoparticles — biodistribution and therapeutic effects in tumour bearing rabbits

UNLABELLED To treat tumours efficiently and spare normal tissues, targeted drug delivery is a promising alternative to conventional, systemic administered chemotherapy. Drug-carrying magnetic nanoparticles can be concentrated in tumours by external magnetic fields, preventing the nanomaterial from being cleared by metabolic burden before reaching the tumour. Therefore in Magnetic Drug Targeting (MDT) the favoured mode of application is believed to be intra-arterial. Here, we show that a simple yet versatile magnetic carrier-system (hydrodynamic particles diameter <200nm) accumulates the chemotherapeutic drug mitoxantrone efficiently in tumours. With MDT we observed the following drug accumulations relative to the recovery from all investigated tissues: tumour region: 57.2%, liver: 14.4%, kidneys: 15.2%. Systemic intra-venous application revealed different results: tumour region: 0.7%, liver: 14.4 % and kidneys: 77.8%. The therapeutic outcome was demonstrated by complete tumour remissions and a survival probability of 26.7% (P=0.0075). These results are confirming former pilot experiments and implying a milestone towards clinical studies. FROM THE CLINICAL EDITOR This team of investigators studied drug carrying nanoparticles for magnetic drug targeting (MDT), demonstrating the importance of intra-arterial administration resulting in improved clinical outcomes in the studied animal model compared with intra-venous.

Flat Detector CT in the Evaluation of Brain Parenchyma, Intracranial Vasculature, and Cerebral Blood Volume: A Pilot Study in Patients with Acute Symptoms of Cerebral Ischemia

BACKGROUND AND PURPOSE: The viability of both brain parenchyma and vascular anatomy is important in estimating the risk and potential benefit of revascularization in patients with acute cerebral ischemia. We tested the hypothesis that when used in conjunction with IV contrast, FD-CT imaging would provide both anatomic and physiologic information that would correlate well with that obtained by using standard multisection CT techniques. MATERIALS AND METHODS: Imaging of brain parenchyma (FD-CT), cerebral vasculature (FD-CTA), and cerebral blood volume (FD-CBV) was performed in 10 patients. All patients also underwent conventional multisection CT, CTA, CTP (including CBV, CTP-CBV), and conventional catheter angiography. Correlation of the corresponding images was performed by 2 experienced neuroradiologists. RESULTS: There was good correlation of the CBV color maps and absolute values between FD-CBV and CTP-CBV (correlation coefficient, 0.72; P < .001). The Bland-Altman test showed a mean difference of CBV values between FD-CT and CTP-CBV of 0.04 ± 0.55 mL/100 mL. All vascular lesions identified with standard CTA were also visualized with FD-CTA. Visualization of brain parenchyma by using FD-CT was poor compared with that obtained by using standard CT. CONCLUSIONS: Both imaging of the cerebral vasculature and measurements of CBV by using FD-CT are feasible. The resulting vascular images and CBV measurements compared well with ones made by using standard CT techniques. The ability to measure CBV and also visualize cerebral vasculature in the angiography suite may offer significant advantages in the management of patients. FD-CT is not yet equivalent to CT for imaging of brain parenchyma.

Dynamics of cerebral injury, perfusion, and blood-brain barrier changes after temporary and permanent middle cerebral artery occlusion in the rat

By means of magnetic resonance imaging (MRI) we longitudinally monitored the evolution of ischemic injury, changes in cerebral hemodynamics and alterations of the blood-brain barrier (BBB) during permanent or temporary middle cerebral artery occlusion (MCAO) in rats. Using the intraluminal suture occlusion model, male Sprague-Dawley rats were subjected to either permanent MCAO (Group A, n = 6), reperfusion after 1 h (Group B, n = 5), or reperfusion after 3 h (Group C, n = 5). Diffusion- and perfusion-weighted MRI and Gd-DTPA enhanced T1-weighted images were performed at six time points from 0.5 to 6 h post-MCAO. The lesion volume increased progressively in group A, decreased significantly in group B (P<0.01), and only showed a tendency toward reduction in group C. Perfusion-weighted MRI delineated severe perfusion deficits in the ischemic core, confirmed early and late reperfusion, and was able to demonstrate postischemic hyperperfusion in group C. Gd-DTPA extravasation was found in all animals with permanent MCAO and initially became grossly visible between 4.5 and 6 h post-MCAO. While only 2 animals demonstrated contrast enhancement in group B, widespread BBB changes were detected immediately following late reperfusion (Group C). Our results demonstrate that with advanced MRI techniques, alterations of the BBB can be correlated with the hemodynamic and biophysical consequences of reperfusion.

Flat-panel detector volumetric CT for visualization of subarachnoid hemorrhage and ventricles: preliminary results compared to conventional CT

IntroductionThe aim of this study was to compare flat-panel volumetric CT (VCT) to conventional CT (cCT) in the visualization of the extent of subarachnoid hemorrhage (SAH) and the width of the ventricles in patients with acute SAH.MethodsIncluded in the study were 22 patients with an acutely ruptured cerebral aneurysm who received VCT during coil embolization. VCT image quality, the extent of SAH (using a modified Fisher score and total slice number with SAH visible) and the width of the ventricles (Evans index) were evaluated by two experienced neuroradiologists (RAD1 and RAD2) and compared to the findings on cCT. Ten patients undergoing VCT for reasons other than SAH served as negative controls.ResultsInterobserver agreement in rating image quality was excellent for cCT (Kendall W value 0.94) and good for VCT (0.74). SAH was identified by RAD1 and RAD2 on VCT images in all patients. The modified Fisher scores underestimated the extent of SAH on VCT images in comparison with cCT images. Pearson’s correlation coefficient (r) regarding the number of image slices with SAH visible on cCT images compared with the number on VCT images was 0.85 for RAD1 and 0.84 for RAD2. The r value for the degree of interobserver agreement for the number of slices with SAH visible was 0.99 for cCT, and 0.95 for VCT images (n = 19), respectively. The width of the ventricles measured in terms of the Evans Index showed excellent concordance between the modalities (r = 0.81 vs. 0.82).ConclusionOur preliminary results indicate that VCT is helpful in evaluating SAH in the angiography suite. Additionally, reliable evaluation of ventricle width is feasible. However, there are limitations with regard to the visibility of SAH on VCT images in comparison to cCT images.

Flat Panel Detector Angiographic CT for Stent-Assisted Coil Embolization of Broad-Based Cerebral Aneurysms

BACKGROUND AND PURPOSE: The purpose of this work was to evaluate angiographic CT (ACT) in the combined application of a self-expanding neurovascular stent and detachable platinum coils in the management of broad-based and fusiform intracranial aneurysms. MATERIALS AND METHODS: Eleven patients harboring wide-necked intracranial aneurysms were treated with a flexible self-expanding neurovascular stent and subsequent aneurysm embolization with platinum microcoils. ACT was performed after the interventional procedure to analyze stent position and the relationship of coils to the stent. Postprocessing included multiplanar reconstructions (MPRs) and maximum intensity projections (MIPs). ACT volume datasets were postprocessed for soft tissue visualization. RESULTS: Accurate stent placement with subsequent coil occlusion of the aneurysms was feasible in all of the patients. Similar to nonsubtracted digital subtraction angiography (DSA) images, radiopaque platinum stent markers showed excellent visibility in ACT as well. The stent struts themselves, hardly visible in nonsubtracted DSA, were visible in MPRs and MIPs of ACT in all of the patients. In aneurysms larger than 10 mm in diameter, accurate stent assessment at the level of the coils was limited due to beam hardening artifacts. Postprocedural ACT in all of the patients did not reveal any evidence of procedure-related intracranial hemorrhage. CONCLUSION: ACT provides cross-sectional, 3D visualization of endovascular stents otherwise hardly visible with plain fluoroscopy. ACT enables us to accurately determine stent position, which may be helpful in complex stent-assisted aneurysm coiling procedures. However, in aneurysms larger than 10 mm in diameter, beam hardening artifacts caused by the endoaneurysmal coil package impair visibility of the stent. Further data are necessary to evaluate the usefulness of ACT in stent-assisted aneurysm coiling.

Safety and Outcome after Thrombolysis in Stroke Patients with Mild Symptoms

Background: Thrombolytic therapy is frequently withheld in patients with minor stroke symptoms. However, recent studies demonstrate that a substantial proportion of these patients dies or remains permanently disabled because of underestimation of symptom severity at baseline or secondary deterioration. We aimed to assess the safety and outcome of thrombolysis therapy in patients with minor but disabling stroke symptoms. Methods: 32 patients presenting with mild symptoms were treated with intravenous recombinant tissue-type plasminogen activator between April 2006 and April 2008. Data were extracted from a prospectively collected database. Baseline demographic data, and clinical, laboratory and imaging findings were analyzed. Outcome was assessed using the modified Rankin Scale (mRS) score at 3 months and was dichotomized into favorable (mRS 0–1) versus unfavorable (mRS 2–6). Results: In the majority of patients, the left hemisphere was affected, with aphasia representing the most common symptom leading to treatment decision. The frequency of perfusion lesion (46%) and vessel occlusion (35%) at baseline was high but had no effect on the outcome at 3 months in our series of treated patients. Outcome was favorable in 94% of patients, and 47% recovered without any persisting symptom. Only one asymptomatic and no symptomatic hemorrhage was observed. Conclusion: Our data support current guidelines and international licenses which give no lower National Institutes of Health Stroke Scale (NIHSS) limit for intravenous thrombolysis (IVT). Considering the accumulating evidence that the natural course in patients with mild symptoms is not as favorable as often assumed and taking the low risk of bleeding in those patients into account, patients with mild but disabling symptoms should be treated with IVT regardless of their baseline NIHSS score.

99mTc Annexin V Imaging of Neonatal Hypoxic Brain Injury

Background and Purpose— Delayed cell loss in neonates after cerebral hypoxic-ischemic injury (HII) is believed to be a major cause of cerebral palsy. In this study, we used radiolabeled annexin V, a marker of delayed cell loss (apoptosis), to image neonatal rabbits suffering from HII. Methods Twenty-two neonatal New Zealand White rabbits had ligation of the right common carotid artery with reduction of inspired oxygen concentration to induce HII. Experimental animals (n=17) were exposed to hypoxia until an ipsilateral hemispheric decrease in the average diffusion coefficient occurred. After reversal of hypoxia and normalization of average diffusion coefficient values, experimental animals were injected with 99mTc annexin V. Radionuclide images were recorded 2 hours later. Results Experimental animals showed no MR evidence of blood-brain barrier breakdown or perfusion abnormalities after hypoxia. Annexin images demonstrated multifocal brain uptake in both hemispheres of experimental but not control animals. Histology of the brains from experimental animals demonstrated scattered pyknotic cortical and hippocampal neurons with cytoplasmic vacuolization of glial cells without evidence of apoptotic nuclei by terminal deoxynucleotidyl transferase–mediated dUTP nick end-labeling (TUNEL) staining. Double staining with markers of cell type and exogenous annexin V revealed that annexin V was localized in the cytoplasm of scattered neurons and astrocytes in experimental and, less commonly, control brains in the presence of an intact blood-brain barrier. Conclusions Apoptosis may develop after HII even in brains that appear normal on diffusion-weighted and perfusion MR. These data suggest a role of radiolabeled annexin V screening of neonates at risk for the development of cerebral palsy.

Visualisation of intracerebral haemorrhage with flat-detector CT compared to multislice CT: results in 44 cases

The aim of the study was to test the reliability of intracerebral haemorrhage (ICH) detection with C-arm-mounted flat-detector computed tomography (FD-CT) in the angio suite as compared to multislice CT (MSCT). In this study 44 patients with 45 ICH were included. All patients were investigated with MSCT and FD-CT during angiographic evaluation. As a control group we included 16 patients without ICH. In each haematoma we assessed volumetric data of the ICH and counted the numbers of ICH-positive slices. Using interobserver ratings, we additionally investigated the potential of FD-CT to serve as a diagnostic tool to detect ICH. In FD-CT three haematomas were not detected because of motion and beam-hardening artefacts in the region close to the skull base. The r value for the degree of interobserver agreement for the number of slices was 0.95 for MSCT and 0.94 for FD-CT. Measurements of the area and the calculated volume of the ICH showed high inter- and intraobserver agreement. Our results indicate that FD-CT is a helpful tool in the daily emergency management of ICH patients as detection of ICH was found to be nearly as reliable as in MSCT. Limitations of this technology are motion and beam-hardening artefacts that may mask small haematomas located in the posterior fossa or the skull base.