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1.  Selective neuronal loss in ischemic stroke and cerebrovascular disease 
As a sequel of brain ischemia, selective neuronal loss (SNL)—as opposed to pannecrosis (i.e. infarction)—is attracting growing interest, particularly because it is now detectable in vivo. In acute stroke, SNL may affect the salvaged penumbra and hamper functional recovery following reperfusion. Rodent occlusion models can generate SNL predominantly in the striatum or cortex, showing that it can affect behavior for weeks despite normal magnetic resonance imaging. In humans, SNL in the salvaged penumbra has been documented in vivo mainly using positron emission tomography and 11C-flumazenil, a neuronal tracer validated against immunohistochemistry in rodent stroke models. Cortical SNL has also been documented using this approach in chronic carotid disease in association with misery perfusion and behavioral deficits, suggesting that it can result from chronic or unstable hemodynamic compromise. Given these consequences, SNL may constitute a novel therapeutic target. Selective neuronal loss may also develop at sites remote from infarcts, representing secondary ‘exofocal' phenomena akin to degeneration, potentially related to poststroke behavioral or mood impairments again amenable to therapy. Further work should aim to better characterize the time course, behavioral consequences—including the impact on neurological recovery and contribution to vascular cognitive impairment—association with possible causal processes such as microglial activation, and preventability of SNL.
doi:10.1038/jcbfm.2013.188
PMCID: PMC3887360  PMID: 24192635
carotid disease; cerebral ischemia; 11C-flumazenil; neuronal death; PET; vascular cognitive impairment
2.  Clinical and Radiological Spectrum of Posterior Reversible Encephalopathy Syndrome: Does Age Make a Difference? – A Retrospective Comparison between Adult and Pediatric Patients 
PLoS ONE  2014;9(12):e115073.
Background
Posterior reversible encephalopathy syndrome (PRES) is a serious and increasingly recognized disorder, but data from observational studies on clinicoradiological differences between etiologies and age groups are limited. In this study, we aimed to investigate the clinical and imaging characteristics of PRES in children compared to adults in a large cohort.
Methods
We retrospectively reviewed the radiological report data bases between January 1999 and August 2012 for patients with PRES (total of 110 patients). Patients fulfilling the criteria for PRES after detailed investigation of clinical charts and imaging studies were separated into children (<18years) and adults (≥18years). Various imaging features at onset of symptoms and on follow-up as well as clinical and paraclinical data were analyzed.
Results
A total of 19 pediatric and 91 adult patients with PRES were included into the study. In pediatric PRES patients, seizures were significantly more frequent as initial PRES-related symptom (p = 0.01). In addition, in children the superior frontal sulcus topographic lesion pattern occurred as frequent as the parieto-occipital one and was significantly more prevalent than in adults (p = 0.02). In contrast, in adults visual disturbances tended to occur more frequently than in children (p = 0.05). Also, severity of edema tended to be greater in adults than in children (p = 0.07).
Conclusion
In our PRES cohort, we found relevant clinicoradiological differences between pediatric and adult PRES patients. However, prospective studies are warranted to establish factors that are specifically associated with pediatric PRES.
doi:10.1371/journal.pone.0115073
PMCID: PMC4267732  PMID: 25514795
3.  Influence of Pigment Epithelium-Derived Factor on Outcome after Striatal Cerebral Ischemia in the Mouse 
PLoS ONE  2014;9(12):e114595.
We here suggest that pigment epithelium-derived factor (PEDF) does not have an effect on lesion size, behavioral outcome, cell proliferation, or cell death after striatal ischemia in the mouse. PEDF is a neurotrophic factor with neuroprotective, antiangiogenic, and antipermeability effects. It influences self-renewal of neural stem cells and proliferation of microglia. We investigated whether intraventricular infusion of PEDF reduces infarct size and cell death, ameliorates behavioral outcome, and influences cell proliferation in the one-hour middle cerebral artery occlusion (MCAO) mouse model of focal cerebral ischemia. C57Bl6/N mice were implanted with PEDF or artificial cerebrospinal fluid (control) osmotic pumps and subjected to 60-minute MCAO 48 hours after pump implantation. They received daily BrdU injections for 7 days after MCAO in order to investigate cell proliferation. Infarct volumes were determined 24 hours after reperfusion using magnetic resonance imaging. We removed the pumps on day 5 and performed behavioral testing between day 7 and 21. Immunohistochemical staining was performed to determine the effect of PEDF on cell proliferation and cell death. Our model produced an ischemic injury confined solely to striatal damage. We detected no reduction in infarct sizes and cell death in PEDF- vs. CSF-infused MCAO mice. Behavioral outcome and cell proliferation did not differ between the groups. However, we cannot exclude that PEDF might work under different conditions in stroke. Further studies will elucidate the effect of PEDF treatment on cell proliferation and behavioral outcome in moderate to severe ischemic injury in the brain.
doi:10.1371/journal.pone.0114595
PMCID: PMC4255036  PMID: 25470280
4.  High prevalence of NMDA receptor IgA/IgM antibodies in different dementia types 
Objective
To retrospectively determine the frequency of N-Methyl-D-Aspartate (NMDA) receptor (NMDAR) autoantibodies in patients with different forms of dementia.
Methods
Clinical characterization of 660 patients with dementia, neurodegenerative disease without dementia, other neurological disorders and age-matched healthy controls combined with retrospective analysis of serum or cerebrospinal fluid (CSF) for the presence of NMDAR antibodies. Antibody binding to receptor mutants and the effect of immunotherapy were determined in a subgroup of patients.
Results
Serum NMDAR antibodies of IgM, IgA, or IgG subtypes were detected in 16.1% of 286 dementia patients (9.5% IgM, 4.9% IgA, and 1.7% IgG) and in 2.8% of 217 cognitively healthy controls (1.9% IgM and 0.9% IgA). Antibodies were rarely found in CSF. The highest prevalence of serum antibodies was detected in patients with “unclassified dementia” followed by progressive supranuclear palsy, corticobasal syndrome, Parkinson’s disease-related dementia, and primary progressive aphasia. Among the unclassified dementia group, 60% of 20 patients had NMDAR antibodies, accompanied by higher frequency of CSF abnormalities, and subacute or fluctuating disease progression. Immunotherapy in selected prospective cases resulted in clinical stabilization, loss of antibodies, and improvement of functional imaging parameters. Epitope mapping showed varied determinants in patients with NMDAR IgA-associated cognitive decline.
Interpretation
Serum IgA/IgM NMDAR antibodies occur in a significant number of patients with dementia. Whether these antibodies result from or contribute to the neurodegenerative disorder remains unknown, but our findings reveal a subgroup of patients with high antibody levels who can potentially benefit from immunotherapy.
doi:10.1002/acn3.120
PMCID: PMC4241809  PMID: 25493273
5.  Prehospital stroke care 
Neurology  2013;81(5):501-508.
Brain cells die rapidly after stroke and any effective treatment must start as early as possible. In clinical routine, the tight time–outcome relationship continues to be the major limitation of therapeutic approaches: thrombolysis rates remain low across many countries, with most patients being treated at the late end of the therapeutic window. In addition, there is no neuroprotective therapy available, but some maintain that this concept may be valid if administered very early after stroke. Recent innovations have opened new perspectives for stroke diagnosis and treatment before the patient arrives at the hospital. These include stroke recognition by dispatchers and paramedics, mobile telemedicine for remote clinical examination and imaging, and integration of CT scanners and point-of-care laboratories in ambulances. Several clinical trials are now being performed in the prehospital setting testing prehospital delivery of neuroprotective, antihypertensive, and thrombolytic therapy. We hypothesize that these new approaches in prehospital stroke care will not only shorten time to treatment and improve outcome but will also facilitate hyperacute stroke research by increasing the number of study participants within an ultra-early time window. The potentials, pitfalls, and promises of advanced prehospital stroke care and research are discussed in this review.
doi:10.1212/WNL.0b013e31829e0fdd
PMCID: PMC3776535  PMID: 23897876
6.  Automated real-time text messaging as a means for rapidly identifying acute stroke patients for clinical trials 
Trials  2014;15(1):304.
Background
Recruiting stroke patients into acute treatment trials is challenging because of the urgency of clinical diagnosis, treatment, and trial inclusion. Automated alerts that identify emergency patients promptly may improve trial performance. The main purposes of this project were to develop an automated real-time text messaging system to immediately inform physicians of patients with suspected stroke and to test its feasibility in the emergency setting.
Methods
An electronic standardized stroke algorithm (SSA) was implemented in the clinical information system (CIS) and linked to a remote data capture system. Within 10 minutes following the documentation and storage of basic information to CIS, a text message was triggered for patients with suspected stroke and sent to a dedicated trial physician. Each text message provided anonymized information on the exact department and unit, date and time of admission, age, sex, and National Institute of Health Stroke Scale (NIHSS) of the patient. All necessary information needed to generate a text message was already available – routine processes in the emergency department were not affected by the automated real-time text messaging system. The system was tested for three 4-week periods. Feasibility was analyzed based on the number of patients correctly identified by the SSA and the door-to-message time.
Results
In total, 513 text messages were generated for patients with suspected stroke (median age 74 years (19–106); 50.3% female; median NIHSS 4 (0–41)), representing 96.6% of all cases. For 48.3% of these text messages, basic documentation was completed within less than 1 hour and a text message was sent within 60 minutes after patient admission.
Conclusions
The system proved to be stable in generating text messages using IT-based CIS to identify acute stroke trial patients. The system operated on information which is documented routinely and did not result in a higher workload. Delays between patient admission and the text message were caused by delayed completion of basic documentation. To use the automated real-time text messaging system to immediately identify emergency patients suitable for acute stroke trials, further development needs to focus on eliminating delays in documentation for the SSA in the emergency department.
doi:10.1186/1745-6215-15-304
PMCID: PMC4133070  PMID: 25073719
Acute trials; CIS; IT-based; Notification tool; Patient identification; Recruitment; Selection criteria; Stroke
7.  Histone Acetylation and CREB Binding Protein Are Required for Neuronal Resistance against Ischemic Injury 
PLoS ONE  2014;9(4):e95465.
Epigenetic transcriptional regulation by histone acetylation depends on the balance between histone acetyltransferase (HAT) and deacetylase activities (HDAC). Inhibition of HDAC activity provides neuroprotection, indicating that the outcome of cerebral ischemia depends crucially on the acetylation status of histones. In the present study, we characterized the changes in histone acetylation levels in ischemia models of focal cerebral ischemia and identified cAMP-response element binding protein (CREB)–binding protein (CBP) as a crucial factor in the susceptibility of neurons to ischemic stress. Both neuron-specific RNA interference and neurons derived from CBP heterozygous knockout mice showed increased damage after oxygen-glucose deprivation (OGD) in vitro. Furthermore, we demonstrated that ischemic preconditioning by a short (5 min) subthreshold occlusion of the middle cerebral artery (MCA), followed 24 h afterwards by a 30 min occlusion of the MCA, increased histone acetylation levels in vivo. Ischemic preconditioning enhanced CBP recruitment and histone acetylation at the promoter of the neuroprotective gene gelsolin leading to increased gelsolin expression in neurons. Inhibition of CBP's HAT activity attenuated neuronal ischemic preconditioning. Taken together, our findings suggest that the levels of CBP and histone acetylation determine stroke outcome and are crucially associated with the induction of an ischemia-resistant state in neurons.
doi:10.1371/journal.pone.0095465
PMCID: PMC3991684  PMID: 24748101
8.  Thyroid-Stimulating Hormone, White Matter Hyperintensities, and Functional Outcome in Acute Ischemic Stroke Patients 
Background
Thyroid-stimulating hormone (TSH) concentrations are frequently altered in acute ischemic stroke patients. It is becoming increasingly apparent that various hormones in the hypothalamus-pituitary-thyroid axis may be associated with functional stroke outcome. We have previously shown that white matter hyperintensities (WMH) of presumed vascular origin are strong indicators of functional outcome. It is unclear whether an association exists between WMH and TSH. We therefore sought to determine whether TSH levels, measured in acute ischemic stroke patients, are associated with WMH and functional outcome.
Methods
We analyzed all first ischemic stroke patients who participated in the Berlin ‘Cream & Sugar’ Study (NCT 01378468) and completed a 1-year follow-up assessment from January 2009 to March 2013. Patients were stratified into 3 groups: (1) low TSH (0.1-0.44 μU/ml); (2) normal TSH (0.44-2.5 μU/ml), and (3) high TSH (2.5-20 μU/ml). WMH were assessed using the Fazekas and Wahlund visual rating scales. Functional outcome was assessed using the modified Rankin Scale and was performed via telephone at 1 year by a certified rater.
Results
183 patients were included [median age 66, interquartile range (IQR) 54-75; 33% females; median National Institute of Health Stroke Scale 3, IQR 1-4, range 0-24]. Venous samples were collected a median of 4 days (IQR 3-5) following initial symptom onset between 8 and 9 a.m. following a 10-hour fast. Patients with normal TSH levels (n = 132; 72%) had significantly higher rates of prestroke diabetes than patients with high TSH levels (normal TSH 17%; high TSH 1%; p = 0.03). Additionally, patients with normal TSH levels tended to have higher estimated glomerular filtration rates than patients with high and low TSH concentrations (normal TSH median estimated glomerular filtration rates: 83 ml/min/1.73 m2; high TSH median estimated glomerular filtration rates: 76 ml/min/1.73 m2; low TSH median: 78 ml/min/1.73 m2; p = 0.068). Logistical regression analysis force-adjusted for age (quartiles), NIHSS (quartiles), prestroke diabetes status, and stroke subtype revealed significant associations between WMH and TSH [Wahlund scores: odds ratio 2.547, 95% confidence interval (CI) 1.159-5.598, p = 0.020; Fazekas scores: odds ratio 2.530, 95% CI 1.115-5.741, p = 0.003]. Functional outcome was not significantly associated with TSH levels in univariate or multivariate models.
Conclusion
TSH levels are independently associated with WMH in acute ischemic stroke patients. Based on our findings, we cannot recommend assessing TSH to estimate the 1-year functional outcome following ischemic stroke.
doi:10.1159/000360217
PMCID: PMC3995386  PMID: 24803914
Stroke; Ischemia; Hyperthyroidism; Hypothyroidism; Thyrotropin; White matter hyperintensities; Leukoaraiosis

9.  Assessing post-stroke behavior in mouse models of focal ischemia 
Experimental treatment strategies and neuroprotective drugs that showed therapeutic promise in animal models of stroke have failed to produce beneficial effects in human stroke patients. The difficulty in translating preclinical findings to humans represents a major challenge in cerebrovascular research. The reasons behind this translational road block might be explained by a number of factors, including poor quality control in various stages of the research process, the validity of experimental stroke models, and differences in drug administration and pharmacokinetics. Another major difference between animal studies and clinical trials is the choice of end point or outcome measures. Here, we discuss the necessity of poststroke behavioral testing to bridge the gap between clinical and experimental end points. We review established sensory-motor tests for outcome determination after focal ischemia based on the published literature as well as our own personal experience. Selected tests are described in more detail and good laboratory practice standards for behavioral testing are discussed. This review is intended for stroke researchers planning to use behavioral testing in mice.
doi:10.1038/jcbfm.2012.185
PMCID: PMC3587814  PMID: 23232947
behavior; focal ischemia; functional outcome; sensory-motor tests; stroke
10.  Biomarkers and perfusion – training-induced changes after stroke (BAPTISe): protocol of an observational study accompanying a randomized controlled trial 
BMC Neurology  2013;13:197.
Background
Physical activity is believed to exert a beneficial effect on functional and cognitive rehabilitation of patients with stroke. Although studies have addressed the impact of physical exercise in cerebrovascular prevention and rehabilitation, the underlying mechanisms leading to improvement are poorly understood. Training-induced increase of cerebral perfusion is a possible mediating mechanism. Our exploratory study aims to investigate training-induced changes in blood biomarker levels and magnetic resonance imaging in patients with subacute ischemic stroke.
Methods/design
This biomarker-driven study uses an observational design to examine a subgroup of patients in the randomized, controlled PHYS-STROKE trial. In PHYS-STROKE, 215 patients with subacute stroke (hemorrhagic and ischemic) receive either 4 weeks of physical training (aerobic training, 5 times a week, for 50 minutes) or 4 weeks of relaxation sessions (5 times a week, for 50 minutes). A convenience sample of 100 of these patients with ischemic stroke will be included in BAPTISe and will receive magnetic resonance imaging (MRI) scans and an additional blood draw before and after the PHYS-STROKE intervention. Imaging scans will address parameters of cerebral perfusion, vessel size imaging, and microvessel density (the Q factor) to estimate the degree of neovascularization in the brain. Blood tests will determine several parameters of immunity, inflammation, endothelial function, and lipometabolism. Primary objective of this study is to evaluate differential changes in MRI and blood-derived biomarkers between groups. Other endpoints are next cerebrovascular events and functional status of the patient after the intervention and after 3 months assessed by functional scores, in particular walking speed and Barthel index (co-primary endpoints of PHYS-STROKE). Additionally, we will assess the association between functional outcomes and biomarkers including imaging results. For all endpoints we will compare changes between patients who received physical fitness training and patients who had relaxation sessions.
Discussion
This exploratory study will be the first to investigate the effects of physical fitness training in patients with ischemic stroke on MRI-based cerebral perfusion, pertinent blood biomarker levels, and functional outcome. The study may have an impact on current patient rehabilitation strategies and reveal important information about the roles of MRI and blood-derived biomarkers in ischemic stroke.
Trial registration
NCT01954797.
doi:10.1186/1471-2377-13-197
PMCID: PMC3870989  PMID: 24330706
Physical training; Exercise; Subacute stroke; Ischemic stroke; Cerebral perfusion; Biomarkers; Vessel size imaging; Neovascularization; MRI; Rehabilitation
11.  Prehospital Thrombolysis: A Manual from Berlin 
In acute ischemic stroke, time from symptom onset to intervention is a decisive prognostic factor. In order to reduce this time, prehospital thrombolysis at the emergency site would be preferable. However, apart from neurological expertise and laboratory investigations a computed tomography (CT) scan is necessary to exclude hemorrhagic stroke prior to thrombolysis. Therefore, a specialized ambulance equipped with a CT scanner and point-of-care laboratory was designed and constructed. Further, a new stroke identifying interview algorithm was developed and implemented in the Berlin emergency medical services. Since February 2011 the identification of suspected stroke in the dispatch center of the Berlin Fire Brigade prompts the deployment of this ambulance, a stroke emergency mobile (STEMO). On arrival, a neurologist, experienced in stroke care and with additional training in emergency medicine, takes a neurological examination. If stroke is suspected a CT scan excludes intracranial hemorrhage. The CT-scans are telemetrically transmitted to the neuroradiologist on-call. If coagulation status of the patient is normal and patient's medical history reveals no contraindication, prehospital thrombolysis is applied according to current guidelines (intravenous recombinant tissue plasminogen activator, iv rtPA, alteplase, Actilyse).
Thereafter patients are transported to the nearest hospital with a certified stroke unit for further treatment and assessment of strokeaetiology. After a pilot-phase, weeks were randomized into blocks either with or without STEMO care. Primary end-point of this study is time from alarm to the initiation of thrombolysis. We hypothesized that alarm-to-treatment time can be reduced by at least 20 min compared to regular care.
doi:10.3791/50534
PMCID: PMC4112646  PMID: 24300505
Medicine; Issue 81; Telemedicine; Emergency Medical Services; Stroke; Tomography; X-Ray Computed; Emergency Treatment; [stroke; thrombolysis; prehospital; emergency medical services; ambulance
12.  Assessment of Paclitaxel Induced Sensory Polyneuropathy with “Catwalk” Automated Gait Analysis in Mice 
PLoS ONE  2013;8(10):e76772.
Neuropathic pain as a symptom of sensory nerve damage is a frequent side effect of chemotherapy. The most common behavioral observation in animal models of chemotherapy induced polyneuropathy is the development of mechanical allodynia, which is quantified with von Frey filaments. The data from one study, however, cannot be easily compared with other studies owing to influences of environmental factors, inter-rater variability and differences in test paradigms. To overcome these limitations, automated quantitative gait analysis was proposed as an alternative, but its usefulness for assessing animals suffering from polyneuropathy has remained unclear. In the present study, we used a novel mouse model of paclitaxel induced polyneuropathy to compare results from electrophysiology and the von Frey method to gait alterations measured with the Catwalk test. To mimic recently improved clinical treatment strategies of gynecological malignancies, we established a mouse model of dose-dense paclitaxel therapy on the common C57Bl/6 background. In this model paclitaxel treated animals developed mechanical allodynia as well as reduced caudal sensory nerve action potential amplitudes indicative of a sensory polyneuropathy. Gait analysis with the Catwalk method detected distinct alterations of gait parameters in animals suffering from sensory neuropathy, revealing a minimized contact of the hind paws with the floor. Treatment of mechanical allodynia with gabapentin improved altered dynamic gait parameters. This study establishes a novel mouse model for investigating the side effects of dose-dense paclitaxel therapy and underlines the usefulness of automated gait analysis as an additional easy-to-use objective test for evaluating painful sensory polyneuropathy.
doi:10.1371/journal.pone.0076772
PMCID: PMC3797113  PMID: 24143194
13.  Fasting Versus Post-Challenge Triglycerides and Pre-Existing Cavitating Lacunes: A Berlin “Cream & Sugar” Substudy 
Background and Purpose: Although the presence of cavitating lacunes on brain imaging may have prognostic implications, the modifiable risk factors underlying these frequently observed lesions are not completely understood. We sought to determine if fasting and post-challenge triglycerides associate with cavitating lacunes.
Methods: All first ischemic stroke patients who completed a novel combined oral triglyceride and glucose tolerance test and MRI between January 2009 and June 2012 were included. Fluid-attenuated inversion recovery or T2 MRI sequences were used to visualize cavitating lacunes and white matter hyperintensities, which were graded using the Wahlund visual scale.
Results: One hundred and ninety patients were included (median age 66, IQR 52–73; 33% female; median National Institute of Health Stroke Scale 2, IQR 1–4). A forward stepwise binary logistical regression analysis applying the Hosmer–Lemeshow goodness of fit test adjusted for parameters significant in univariate analyses (at the p < 0.10 level) revealed that Wahlund scores (Wahlund 0–4: reference; Wahlund 5–10: adjusted odds ratio, 5.1; 95% confidence interval, 1.3–20.0, p = 0.019; Wahlund>10: adjusted odds ratio 9.6; 95% CI, 1.55–59.35; p = 0.015) and the highest quartile of post-challenge triglycerides (>295 mg/dL; adjusted odds ratio, 7.36; 95% confidence interval 1.24–43.70; p = 0.028) independently associated with the presence of cavitating lacunes.
Conclusion: Post-challenge serum triglycerides are independently associated with the presence of cavitating lacunes.
doi:10.3389/fneur.2013.00092
PMCID: PMC3706746  PMID: 23847590
ischemia; cerebral lacunes; leukoaraiosis; white matter disease; triglycerides; glucose
14.  Essential role of interleukin-6 in post-stroke angiogenesis 
Brain  2012;135(6):1964-1980.
Ambivalent effects of interleukin-6 on the pathogenesis of ischaemic stroke have been reported. However, to date, the long-term actions of interleukin-6 after stroke have not been investigated. Here, we subjected interleukin-6 knockout (IL-6−/−) and wild-type control mice to mild brain ischaemia by 30-min filamentous middle cerebral artery occlusion/reperfusion. While ischaemic tissue damage was comparable at early time points, IL-6−/− mice showed significantly increased chronic lesion volumes as well as worse long-term functional outcome. In particular, IL-6−/− mice displayed an impaired angiogenic response to brain ischaemia with reduced numbers of newly generated endothelial cells and decreased density of perfused microvessels along with lower absolute regional cerebral blood flow and reduced vessel responsivity in ischaemic striatum at 4 weeks. Similarly, the early genomic activation of angiogenesis-related gene networks was strongly reduced and the ischaemia-induced signal transducer and activator of transcription 3 activation observed in wild-type mice was almost absent in IL-6−/− mice. In addition, systemic neoangiogenesis was impaired in IL-6−/− mice. Transplantation of interleukin-6 competent bone marrow into IL-6−/− mice (IL-6chi) did not rescue interleukin-6 messenger RNA expression or the early transcriptional activation of angiogenesis after stroke. Accordingly, chronic stroke outcome in IL-6chi mice recapitulated the major effects of interleukin-6 deficiency on post-stroke regeneration with significantly enhanced lesion volumes and reduced vessel densities. Additional in vitro experiments yielded complementary evidence, which showed that after stroke resident brain cells serve as the major source of interleukin-6 in a self-amplifying network. Treatment of primary cortical neurons, mixed glial cultures or immortalized brain endothelia with interleukin 6-induced robust interleukin-6 messenger RNA transcription in each case, whereas oxygen–glucose deprivation did not. However, oxygen–glucose deprivation of organotypic brain slices resulted in strong upregulation of interleukin-6 messenger RNA along with increased transcription of key angiogenesis-associated genes. In conclusion, interleukin-6 produced locally by resident brain cells promotes post-stroke angiogenesis and thereby affords long-term histological and functional protection.
doi:10.1093/brain/aws075
PMCID: PMC3359750  PMID: 22492561
cerebral ischaemia; interleukin-6; inflammation; angiogenesis; regeneration
15.  Certain types of iron oxide nanoparticles are not suited to passively target inflammatory cells that infiltrate the brain in response to stroke 
Intravenous administration of iron oxide nanoparticles during the acute stage of experimental stroke can produce signal intensity changes in the ischemic region. This has been attributed, albeit controversially, to the infiltration of iron-laden blood-borne macrophages. The properties of nanoparticles that render them most suitable for phagocytosis is a matter of debate, as is the most relevant timepoint for administration. Both of these questions are examined in the present study. Imaging experiments were performed in mice with 30 minutes of middle cerebral artery occlusion (MCAO). Iron oxide nanoparticles with different charges and sizes were used, and mice received 300 μmol Fe/kg intravenously: either superparamagnetic iron oxide nanoparticles (SPIOs), ultrasmall SPIOs, or very small SPIOs. The particles were administered 7 days before MCAO, at the time of reperfusion, or 72 hours after MCAO. Interestingly, there was no observable signal change in the ischemic brains that could be attributed to iron. Furthermore, no Prussian blue-positive cells were found in the brains or blood leukocytes, despite intense staining in the livers and spleens. This implies that the nanoparticles selected for this study are not phagocytosed by blood-borne leukocytes and do not enter the ischemic mouse brain.
doi:10.1038/jcbfm.2013.22
PMCID: PMC3652690  PMID: 23443176
inflammation; iron oxide nanoparticles; magnetic resonance imaging; stroke
16.  The neurovascular unit as a selective barrier to polymorphonuclear granulocyte (PMN) infiltration into the brain after ischemic injury 
Acta Neuropathologica  2012;125(3):395-412.
The migration of polymorphonuclear granulocytes (PMN) into the brain parenchyma and release of their abundant proteases are considered the main causes of neuronal cell death and reperfusion injury following ischemia. Yet, therapies targeting PMN egress have been largely ineffective. To address this discrepancy we investigated the temporo-spatial localization of PMNs early after transient ischemia in a murine transient middle cerebral artery occlusion (tMCAO) model and human stroke specimens. Using specific markers that distinguish PMN (Ly6G) from monocytes/macrophages (Ly6C) and that define the cellular and basement membrane boundaries of the neurovascular unit (NVU), histology and confocal microscopy revealed that virtually no PMNs entered the infarcted CNS parenchyma. Regardless of tMCAO duration, PMNs were mainly restricted to luminal surfaces or perivascular spaces of cerebral vessels. Vascular PMN accumulation showed no spatial correlation with increased vessel permeability, enhanced expression of endothelial cell adhesion molecules, platelet aggregation or release of neutrophil extracellular traps. Live cell imaging studies confirmed that oxygen and glucose deprivation followed by reoxygenation fail to induce PMN migration across a brain endothelial monolayer under flow conditions in vitro. The absence of PMN infiltration in infarcted brain tissues was corroborated in 25 human stroke specimens collected at early time points after infarction. Our observations identify the NVU rather than the brain parenchyma as the site of PMN action after CNS ischemia and suggest reappraisal of targets for therapies to reduce reperfusion injury after stroke.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-012-1076-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s00401-012-1076-3
PMCID: PMC3578720  PMID: 23269317
Neurovascular unit; Polymorphonuclear granulocyte; Migration; Human; Mouse
17.  Rate of cardiac arrhythmias and silent brain lesions in experienced marathon runners: rationale, design and baseline data of the Berlin Beat of Running study 
Background
Regular exercise is beneficial for cardiovascular health but a recent meta-analysis indicated a relationship between extensive endurance sport and a higher risk of atrial fibrillation, an independent risk factor for stroke. However, data on the frequency of cardiac arrhythmias or (clinically silent) brain lesions during and after marathon running are missing.
Methods/ Design
In the prospective observational “Berlin Beat of Running” study experienced endurance athletes underwent clinical examination (CE), 3 Tesla brain magnetic resonance imaging (MRI), carotid ultrasound imaging (CUI) and serial blood sampling (BS) within 2-3 days prior (CE, MRI, CUI, BS), directly after (CE, BS) and within 2 days after (CE, MRI, BS) the 38th BMW BERLIN-MARATHON 2011. All participants wore a portable electrocardiogram (ECG)-recorder throughout the 4 to 5 days baseline study period. Participants with pathological MRI findings after the marathon, troponin elevations or detected cardiac arrhythmias will be asked to undergo cardiac MRI to rule out structural abnormalities. A follow-up is scheduled after one year.
Results
Here we report the baseline data of the enrolled 110 athletes aged 36-61 years. Their mean age was 48.8 ± 6.0 years, 24.5% were female, 8.2% had hypertension and 2.7% had hyperlipidaemia. Participants have attended a mean of 7.5 ± 6.6 marathon races within the last 5 years and a mean of 16 ± 36 marathon races in total. Their weekly running distance prior to the 38th BMW BERLIN-MARATHON was 65 ± 17 km. Finally, 108 (98.2%) Berlin Beat-Study participants successfully completed the 38th BMW BERLIN-MARATHON 2011.
Discussion
Findings from the “Berlin Beats of Running” study will help to balance the benefits and risks of extensive endurance sport. ECG-recording during the marathon might contribute to identify athletes at risk for cardiovascular events. MRI results will give new insights into the link between physical stress and brain damage.
Trial registration
clinicaltrials.gov NCT01428778
doi:10.1186/1471-2261-12-69
PMCID: PMC3458995  PMID: 22938148
Marathon running; ECG-recording; Magnetic resonance imaging; Blood sampling; Cardiac arrhythmia
18.  Ultrahigh-Field MRI in Human Ischemic Stroke – a 7 Tesla Study 
PLoS ONE  2012;7(5):e37631.
Introduction
Magnetic resonance imaging (MRI) using field strengths up to 3 Tesla (T) has proven to be a powerful tool for stroke diagnosis. Recently, ultrahigh-field (UHF) MRI at 7 T has shown relevant diagnostic benefits in imaging of neurological diseases, but its value for stroke imaging has not been investigated yet. We present the first evaluation of a clinically feasible stroke imaging protocol at 7 T. For comparison an established stroke imaging protocol was applied at 3 T.
Methods
In a prospective imaging study seven patients with subacute and chronic stroke were included. Imaging at 3 T was immediately followed by 7 T imaging. Both protocols included T1-weighted 3D Magnetization-Prepared Rapid-Acquired Gradient-Echo (3D-MPRAGE), T2-weighted 2D Fluid Attenuated Inversion Recovery (2D-FLAIR), T2-weighted 2D Fluid Attenuated Inversion Recovery (2D-T2-TSE), T2* weighted 2D Fast Low Angle Shot Gradient Echo (2D-HemoFLASH) and 3D Time-of-Flight angiography (3D-TOF).
Results
The diagnostic information relevant for clinical stroke imaging obtained at 3 T was equally available at 7 T. Higher spatial resolution at 7 T revealed more anatomical details precisely depicting ischemic lesions and periinfarct alterations. A clear benefit in anatomical resolution was also demonstrated for vessel imaging at 7 T. RF power deposition constraints induced scan time prolongation and reduced brain coverage for 2D-FLAIR, 2D-T2-TSE and 3D-TOF at 7 T versus 3 T.
Conclusions
The potential of 7 T MRI for human stroke imaging is shown. Our pilot study encourages a further evaluation of the diagnostic benefit of stroke imaging at 7 T in a larger study.
doi:10.1371/journal.pone.0037631
PMCID: PMC3365122  PMID: 22701525
19.  SUMO2/3 conjugation is an endogenous neuroprotective mechanism 
Small ubiquitin-like modifier (SUMO)2/3 but not SUMO1 conjugation is activated after transient cerebral ischemia. To investigate its function, we blocked neuronal SUMO2/3 translation through lentiviral microRNA delivery in primary cortical neurons. Viability was unaffected by SUMO2/3 silencing unless neurons were stressed by transient oxygen–glucose deprivation (OGD). Both 15 and 45 minutes of OGD were tolerated by control microRNA-expressing neurons but damaged >60% of neurons expressing SUMO2/3 microRNA. Damaging OGD (75 minutes) increased neuronal loss to 54% (control microRNA) and to 99% (SUMO2/3 microRNA). This suggests that activation of SUMO2/3 conjugation is an endogenous neuroprotective stress response.
doi:10.1038/jcbfm.2011.112
PMCID: PMC3210338  PMID: 21863037
endogenous neuroprotection; lentiviral microRNA delivery; oxygen–glucose deprivation; SUMO conjugation
20.  Troponin elevation in acute ischemic stroke (TRELAS) - protocol of a prospective observational trial 
BMC Neurology  2011;11:98.
Background
Levels of the cardiac muscle regulatory protein troponin T (cTnT) are frequently elevated in patients with acute ischemic stroke and elevated cTnT predicts poor outcome and mortality. The pathomechanism of troponin release may relate to co-morbid coronary artery disease and myocardial ischemia or, alternatively, to neurogenic cardiac damage due to autonomic activation after acute ischemic stroke. Therefore, there is uncertainty about how acute ischemic stroke patients with increased cTnT levels should be managed regarding diagnostic and therapeutic workup.
Methods/Design
The primary objective of the prospective observational trial TRELAS (TRoponin ELevation in Acute ischemic Stroke) is to investigate the frequency and underlying pathomechanism of cTnT elevation in acute ischemic stroke patients in order to give guidance for clinical practice. All consecutive patients with acute ischemic stroke admitted within 72 hours after symptom onset to the Department of Neurology at the Campus Benjamin Franklin of the University Hospital Charité will be screened for cTnT elevations (i.e. >= 0.05 μg/l) on admission and again on the following day. Patients with increased cTnT will undergo coronary angiography within 72 hours. Diagnostic findings of coronary angiograms will be compared with age- and gender-matched patients presenting with Non-ST-Elevation myocardial infarction to the Department of Cardiology. The primary endpoint of the study will be the occurrence of culprit lesions in the coronary angiogram indicating underlying co-morbid obstructive coronary artery disease. Secondary endpoints will be the localization of stroke in the cerebral imaging and left ventriculographic findings of wall motion abnormalities suggestive of stroke-induced global cardiac dysfunction.
Discussion
TRELAS will prospectively determine the frequency and possible etiology of troponin elevation in a large cohort of ischemic stroke patients. The findings are expected to contribute to clarify pathophysiologic concepts of co-morbid cardiac damage in ischemic stroke patients and also to provide a basis for clinical recommendations for cardiac workup of such patients.
Trial registration
clinicaltrials.gov NCT01263964
doi:10.1186/1471-2377-11-98
PMCID: PMC3166899  PMID: 21824425
21.  Temporal Retinal Nerve Fiber Loss in Patients with Spinocerebellar Ataxia Type 1 
PLoS ONE  2011;6(7):e23024.
Background
Autosomal dominant spinocerebellar ataxia type 1 is an adult onset progressive disorder with well characterized neurodegeneration in the cerebellum and brainstem. Beyond brain atrophy, few data exist concerning retinal and optic nerve involvement.
Objective
To evaluate retinal changes in SCA1 patients compared to age and gender matched healthy controls.
Methodology/Principal Findings
Nine patients with SCA1 were prospectively recruited from the ataxia clinic and were compared to nine age and gender matched healthy controls. Both cohorts received assessment of visually evoked potentials and eye examination by optical coherence tomography to determine retinal nerve fiber layer thickness and total macular volume. While no differences were found in visually evoked potentials, SCA1 patients showed a significant reduction of mean retinal nerve fiber layer thickness (RNFLT) compared to healthy controls (84±13 µm vs. 97±8 µm, p = 0.004). Temporal areas showed the most prominent RNFLT reduction with high statistical significances (temporal-inferior: p<0.001, temporal: p<0.001, temporal-superior: p = 0.005) whereas RNFLT in nasal areas was in the range of the control group. From six SCA1 patients an additional macular scan was obtained. The comparison to the corresponding healthy control showed a slight but not significant reduction in TMV (8.22±0.68 mm3 vs. 8.61±0.41 mm3, p = 0.15).
Conclusion
In SCA1 patients, we found evidence for degeneration of retinal nerve fibers. The temporal focus of the observed retinal nerve fiber layer reduction suggests an involvement of the papillo-macular bundle which resembles pathology found in toxic or mitochondrial optic nerve disease such as Leber's hereditary optic neuropathy (LHON) or dominant optic atrophy (DOA).
doi:10.1371/journal.pone.0023024
PMCID: PMC3146534  PMID: 21829579
22.  Tension Pneumocephalus with Diplegia and Deterioration of Consciousness 
Case Reports in Neurology  2011;3(1):48-49.
Tension pneumocephalus results from intracranial air under pressure as a rare complication after head injury or craniofacial surgery. A 58-year-old man underwent ethmoid sinus surgery and subsequently developed rapidly progressive global headache, restlessness, diplegia with sensory loss, and deterioration of the conscious level. A head CT demonstrated extensive pneumocephalus with gross compression of the brain. The frontal retention of air caused widening of the interhemispheric fissure leading to a peaked appearance of the frontal poles, referred to as the ‘Mount Fuji sign’. Surgical revision of a dural air leak resulted in rapid improvement and full clinical resolution. Early diagnosis of tension pneumocephalus and emergent surgical treatment are crucial to prevent life-threatening deterioration.
doi:10.1159/000324824
PMCID: PMC3072193  PMID: 21490712
Tension pneumocephalus; Mount Fuji sign; Emergency; Diplegia
23.  Neuronal injury: folate to the rescue? 
The Journal of Clinical Investigation  2010;120(5):1383-1386.
Strong epidemiological evidence indicates that derangement of single-carbon metabolism has detrimental effects for proper CNS functioning. Conversely, a role for folate supplementation in the treatment and prevention of neurodegenerative and neuropsychiatric disorders remains to be established. In this issue of the JCI, in an elegant series of experiments in rodents, Iskandar and colleagues demonstrate a crucial role of folate in the regeneration of afferent spinal neurons after injury. Probing sequential steps in folate metabolism, from cellular entry to DNA methylation, the authors show that axonal regeneration relies upon the integrity of DNA methylation pathways. These findings provide the first demonstration of an epigenetic mechanism contributing to neurorepair and suggest that manipulation of the methylation milieu may offer promising new therapeutic avenues to promote regeneration.
doi:10.1172/JCI40764
PMCID: PMC2860906  PMID: 20424316
25.  The Role of Fasting Versus Non-Fasting Triglycerides in Ischemic Stroke: A Systematic Review 
Objective: To synthesize results from pertinent studies and determine if fasting and/or non-fasting triglycerides are a risk factor for ischemic stroke. Method: We performed two independent systematic literature searches using the PubMed and ScienceDirect databases to identify studies examining the relationship between fasting and non-fasting triglyceride concentrations and ischemic stroke risk. A meta-analysis was performed using ischemic stroke as a primary endpoint. Results: Twenty-five reports were identified, including 13 prospective cohort and 12 case–control studies. Baseline characteristics, study samples, methods, and primary outcomes varied. Of 13 prospective cohort studies, nine assessed triglyceride concentrations in the fasting state. Seven of these identified triglycerides as an independent risk factor for ischemic stroke risk (n = 1624 ischemic cases). Three prospective cohort studies identified a positive association between elevated non-fasting triglyceride concentrations and ischemic stroke risk (n = 2050 ischemic cases). One prospective cohort study that compared fasting and non-fasting triglycerides identified only non-fasting triglycerides as an independent risk factor for ischemic stroke. Of 12 case–control studies identified, five identified a positive relationship between ischemic stroke risk and elevated fasting triglycerides (n = 838 cases). Seven case–control studies were included in the meta-analysis (n = 1996 ischemic stroke cases), revealing an odds ratio of 1.15 (95% CI, 1.08–1.21). Conclusions: The available data are inconsistent. The relationship between triglyceride levels and ischemic stroke needs further investigation under standardized conditions. We recommend a standardized triglyceride tolerance test to further investigate the associations between fasting versus non-fasting triglyceride levels and ischemic stroke.
doi:10.3389/fneur.2010.000133
PMCID: PMC3008919  PMID: 21188262
ischemic stroke; triglycerides; epidemiology

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