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Current stroke therapy is focused on recanalizing strategies, but neuroprotective co-treatments are still lacking. Modern concepts of the ischemia-affected neurovascular unit (NVU) and surrounding penumbra emphasize the complexity during the transition from initial damaging to regenerative processes. While early treatment with neurotrophic factors was shown to result in lesion size reduction and blood-brain barrier (BBB) stabilization, cellular consequences from these treatments are poorly understood. This study explored delayed cellular responses not only to ischemic stroke, but also to an early treatment with neurotrophic factors. Rats underwent 60 minutes of focal cerebral ischemia. Fluorescence labeling was applied to sections from brains perfused 7 days after ischemia. Analyses focused on NVU constituents including the vasculature, astrocytes and microglia in the ischemic striatum, the border zone and the contralateral hemisphere. In addition to histochemical signs of BBB breakdown, a strong up-regulation of collagen IV and microglia activation occurred within the ischemic core with simultaneous degradation of astrocytes and their endfeet. Activated astroglia were mainly depicted at the border zone in terms of a glial scar formation. Early treatment with pigment epithelium-derived factor (PEDF) resulted in an attenuation of the usually up-regulated collagen IV-immunoreactivity. However, glial activation was not influenced by treatment with PEDF or the epidermal growth factor (EGF). In conclusion, these data on ischemia-induced cellular reactions within the NVU might help to develop treatments addressing the transition from injury towards regeneration. Thereby, the integrity of the vasculature in close relation to neighboring structures like astrocytes appears as a promising target.

Intracranial hemorrhages are associated with high rates of disability and mortality. Telemedicine in general provides clinical healthcare at a distance by using videotelephony and teleradiology and is used particularly in acute stroke care medicine (TeleStroke). TeleStroke considerably improves quality of stroke care (for instance, by increasing thrombolysis) and may be valuable for the management of intracranial hemorrhages in rural hospitals and hospitals lacking neurosurgical departments, given that surgical/interventional therapy is only recommended for a subgroup of patients. The aim of this study was to analyze the frequency, anatomical locations of intracranial hemorrhage, risk factors, and the proportion of patients transferred to specialized hospitals. We evaluated teleconsultations conducted between 2008 and 2010 in a large cohort of patients consecutively enrolled in the Telemedical Project for Integrated Stroke Care (TEMPiS) network. In cases in which intracranial hemorrhage was detected, all images were re-examined and analyzed with a focus on frequency, location, risk factors, and further management. Overall, 6187 patients presented with stroke-like symptoms. Intracranial hemorrhages were identified in 631 patients (10.2%). Of these, intracerebral hemorrhages were found in 423 cases (67.0%), including 174 (41.1%) in atypical locations and 227 (53.7%) in typical sites among other locations. After 14 days of hospitalization in community facilities, the mortality rate in patients with intracranial hemorrhages was 15.1% (95/631). Two hundred and twenty-three patients (35.3%) were transferred to neurological/neurosurgical hospitals for diagnostic workup or additional treatment. Community hospitals are confronted with patients with intracranial hemorrhage, whose management requires specific neurosurgical and hematological expertise with respect to hemorrhage subtype and clinical presentation. TeleStroke networks help select patients who need advanced neurological and/or neurosurgical care. The relatively low proportion of interhospital transfers shown in this study reflects a differentiated decision process on the basis of both guidelines and standard operating procedures.

Transcranial B-mode sonography is an easy to use bedside imaging modality to monitor significant changes of the brain parenchyma such as in malignant middle cerebral infarction or intracerebral hemorrhage. The elevation of intracranial pressure can be followed with various neurosonographical techniques: Measurements of the ventricular width, midline shift, arterial resistance, and optic nerve sheath diameter. They should be viewed as complementary to each other and to other imaging modalities. Repeated cCT and MRI may be avoided in unstable patients by bedside neurosonography in the hands of an experienced physician. Monitoring of evolving hydrocephalus using serial measurements of the third and lateral ventricles can be used to guide therapeutic decisions such as the removal of a ventricular drainage. The cessation of cerebral blood flow in the case of intracranial pressure exceeding systemic arterial pressure is an important part of brain death diagnostics. Early demonstration of a sufficient temporal bone window is needed in patients in whom brain death may be expected. Cerebrovascular autoregulation is an integer component of the brain's blood supply and is compromised in a variety of neurological diseases. In neurological/neurosurgical patients in the intensive care unit, its assessment allows for extended neuromonitoring and control of therapeutic procedures.

Purpose: Transcranial perfusion sonography (TPS) is an emerging noninvasive bedside method for evaluating brain perfusion. The purpose was to assess the feasibility of a low MI/almost real-time frame rate approach and to test its intra-/interobserver variability., Materials and Methods: 10 healthy volunteers were investigated 3 times with TPS at a low MI (1.0) and a high frame rate (8.3 Hz). Investigations were performed by 2 sonographers in a cross-over design: 1.) twofold measurements each with 5 volunteers (intraobserver test), and 2.) single measurements of the other 5 volunteers (interobserver test). From 8 established regions of interest (ROI), time-intensity curves (TIC) with the following parameters were calculated: peak intensity (PI), time-to-PI (TTP), area-under-curve (AUC), and cerebral transit time (CTT). The TIC quality was described by the coefficient of determination. TIC parameters were presented descriptively. Intra- and interobserver variability was tested by Spearman's correlation., Results: The overall quality of the TIC was very good (mean r(2) = 0.92, 0.87 - 0.97). TTP (25.7 - 28.1 sec; mean 26.8 sec) and CTT (8.2 - 10.7 sec; mean 9.9 sec) were the most robust parameters. The intraobserver variability was lower with the more experienced sonographer (r = 0.70 vs. r = 0.29). The interobserver reliability was r = 0.34 (p < 0.05)., Conclusion: Low MI TPS allows for nearly real-time imaging facilitating probe control. Sound sonographer experience allows for a high reliability and makes TPS an interesting tool for the diagnosis and follow-up of perfusion changes, e. g. in stroke or anti-angiogenic brain tumor therapy., (© Georg Thieme Verlag KG Stuttgart · New York.)

Many chronic neurologic diseases do not respond to small molecule therapeutics, and have no effective long-term therapy. Gene therapy offers the promise of an effective cure for both genetic and acquired brain disease. However, the limiting problem in brain gene therapy is delivery to brain followed by regulation of the expression of the transgene. Present day gene vectors do not cross the blood-brain barrier (BBB). Consequently, brain gene therapy requires craniotomy and the local injection of a viral gene vector. However, there are few brain disorders that can be effectively treated with local injection. Most applications of gene therapy require global expression in the brain of the exogenous gene, and this can only be achieved with a noninvasive delivery through the BBB--the trans-vascular route to brain. An additional consideration is the potential toxicity of all viral and nonviral approaches, which may either integrate into the host genome and cause insertional mutagenesis or cause inflammation in the brain. Nonviral, noninvasive gene therapy of the brain is now possible with the development of a new approach to targeting therapeutic genes to the brain following an IV administration. This approach utilizes genetically engineered molecular Trojan horses, which ferry the gene across the BBB and into neurons. Global and reversible expression of therapeutic genes in the human brain without surgery and without viral vectors is now possible.

P-glycoprotein (P-gp) and caveolin-1alpha are both involved in membrane transport, and studies in rodent brain show that these proteins are specifically localized at the microvascular endothelium, which forms the blood-brain barrier (BBB). In humans, P-gp is also expressed in astrocytes, especially in pathological tissue. The present study examines the cellular expression of P-gp and caveolin-1alpha in fresh-frozen brain from healthy rhesus monkey using confocal microscopy and polyclonal antibodies against either P-gp or caveolin-1alpha co-labeled for astrocytes or microvascular endothelium. P-gp and caveolin-1alpha are expressed in both astrocytes and endothelium of healthy primate brain. These findings suggest that P-gp and caveolin-1alpha share a broad spectrum of cellular expression and may play a role in drug transport within the brain in addition to the BBB.

Expression plasmids encoding either luciferase or beta-galactosidase were encapsulated in the interior of an "artificial virus" comprised of an 85 nm pegylated immunoliposome, which was targeted to the rhesus monkey brain in vivo with a monoclonal antibody (MAb) to the human insulin receptor (HIR). The HIRMAb enables the liposome carrying the exogenous gene to undergo transcytosis across the blood-brain barrier and endocytosis across the neuronal plasma membrane following intravenous injection. The level of luciferase gene expression in the brain was 50-fold higher in the rhesus monkey as compared to the rat. Widespread neuronal expression of the beta-galactosidase gene in primate brain was demonstrated by both histochemistry and confocal microscopy. This approach makes feasible reversible adult transgenics in 24 hours.