TY - JOUR A1 - Zeller, Daniel A1 - Dang, Su-Yin A1 - Weise, David A1 - Rieckmann, Peter A1 - Toyka, Klaus V. A1 - Classen, Joseph T1 - Excitability decreasing central motor plasticity is retained in multiple sclerosis patients N2 - Background: Compensation of brain injury in multiple sclerosis (MS) may in part work through mechanisms involving neuronal plasticity on local and interregional scales. Mechanisms limiting excessive neuronal activity may have special significance for retention and (re-)acquisition of lost motor skills in brain injury. However, previous neurophysiological studies of plasticity in MS have investigated only excitability enhancing plasticity and results from neuroimaging are ambiguous. Thus, the aim of this study was to probe long-term depression-like central motor plasticity utilizing continuous theta-burst stimulation (cTBS), a non-invasive brain stimulation protocol. Because cTBS also may trigger behavioral effects through local interference with neuronal circuits, this approach also permitted investigating the functional role of the primary motor cortex (M1) in force control in patients with MS. Methods: We used cTBS and force recordings to examine long-term depression-like central motor plasticity and behavioral consequences of a M1 lesion in 14 patients with stable mild-to-moderate MS (median EDSS 1.5, range 0 to 3.5) and 14 age-matched healthy controls. cTBS consisted of bursts (50 Hz) of three subthreshold biphasic magnetic stimuli repeated at 5 Hz for 40 s over the hand area of the left M1. Corticospinal excitability was probed via motor-evoked potentials (MEP) in the abductor pollicis brevis muscle over M1 before and after cTBS. Force production performance was assessed in an isometric right thumb abduction task by recording the number of hits into a predefined force window. Results: cTBS reduced MEP amplitudes in the contralateral abductor pollicis brevis muscle to a comparable extent in control subjects (69 ± 22% of baseline amplitude, p < 0.001) and in MS patients (69 ± 18%, p < 0.001). In contrast, postcTBS force production performance was only impaired in controls (2.2 ± 2.8, p = 0.011), but not in MS patients (2.0 ± 4.4, p = 0.108). The decline in force production performance following cTBS correlated with corticomuscular latencies (CML) in MS patients, but did not correlate with MEP amplitude reduction in patients or controls. Conclusions: Long-term depression-like plasticity remains largely intact in mild-to-moderate MS. Increasing brain injury may render the neuronal networks less responsive toward lesion-induction by cTBS. KW - Medizin KW - Multiple sclerosis KW - LTD KW - Motor plasticity KW - TMS KW - Motor cortex Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76333 ER - TY - THES A1 - Schmid, Benedikt T1 - Relation between cerebral arterio-venous transit time and neuropsychological performance in patients with vascular dementia T1 - Beziehung zwischen zerebraler arterio-venöser Transitzeit und neuropsychologischer Testleistung bei Patienten mit vaskulärer Demenz N2 - Dementia, or any form of degenerative cognitive decline, is one of the major problems in present, and even more will be in future medicine. With Alzheimer's disease (AD) being the most prevalent, Vascular Dementia is the second most entity of dementing processes in the elderly. As diagnostic criteria are still imprecise and in many cases do not embrace early stages of the disease, recent studies have proposed more detailed classifications of the newly created condition Vascular Cognitive Impairment (VCI). Of all conditions subsumed under this term, subcortical small-vessel alterations are the most common cause for cognitive decline. The diagnosis of dementia / cognitive impairment is presently often made in late stages of the disease, when therapeutical options are poor. Thus, early detection of changes of the subcortical small vessels is desirable, when there is still time to identify and aggressively treat risk factors and underlying conditions like diabetes, hyper- or hypotension, and hyperlipidemia. This study aimed to evaluate whether cTT correlates to cognitive dysfunction, i.e. if cTT is fit as an early diagnostic tool for VCI. The study cohort included 38 patients from the Neurological Clinic of the Würzburg University hospital admitted due to diagnoses other than dementia or stroke. As a result of this study it turned out that cTT is certainly capable of fulfilling the task to easily and effectively detect and evaluate possible microvascular lesions of the brain with respect to the actual clinical relevance for the patient. When compared to the other proposed diagnostic tools, neuropsychological testing and MRI, the advantages of cTT are obvious: its measurement is a low-cost and quick procedure which would spare both patients and examiners a long neuropsychological exam or complement it. cTT is safe to assess as the only possible risks derive from the use of the contrast agent, which are rare and easily manageable. It has also proven to be more accurate in showing the extent of cognitive impairment than MRI. Finally, it is widely available. The only prerequisite is an ultrasound machine capable of transcranial color-coded duplex sonography. No cost-intensive procedures like MRI are needed. So, with neuropsychological testing remaining the gold standard, cTT here proved to be a reliable alternative which is more time- and cost-effective than MRI. N2 - Demenzen und alle anderen Formen kongnitiver Leistungseinschränkungen gehören heute zu den bedeutendsten medizinischen Herausforderungen und werden in der Zukunft noch weiter an Bedeutung gewinnen. Die häufigste der Demenzerkrankungen bei älteren Patienten ist die Alzheimer-Krankheit, gefolgt von den vaskulären Demenzen. Da die Diagnosekriterien in vielen Fällen noch unpräzise sind und vor allem frühe Stadien der Erkrankung nicht erfassen, wurden in der neueren Literatur detailliertere Untergruppen der neu eingeführten Entität „vaskuläre kognitive Funktionsstörung“ (vascular cognitive impairment, VCI) etabliert. Subkortikale Veränderungen an den kleinsten Gefäßen stellen unter allen Pathologien, die unter diesem Begriff subsumiert sind, die häufigste Ursache für kognitive Leistungseinschränkungen dar. Die Diagnose Demenz bzw. VCI wird oft erst in späten Stadien der Krankheit gestellt, wenn die therapeutischen Mittel bereits stark begrenzt sind. Deshalb wäre eine Möglichkeit zur frühen Entdeckung subkortikaler Gefäßveränderungen wünschenswert in einem Stadium der Krankheit, in dem es noch möglich ist, Risikofaktoren wie Diabetes mellitus, arterielle Hyper- und Hypotonie und Fettstoffwechselstörungen auszumachen und konseqeuent zu behandeln. Das Ziel dieser Studie war es zu untersuchen, ob cTT mit dem Ausmaß kognitiver Dysfunktion korreliert, ob also cTT als frühes diagnostisches Verfahren für vaskuläre demenzielle Prozesse geeignet ist. Die Studienpopulation umfasste 38 Patienten aus der Klinik und Poliklinik für Neurologie der Universität Würzburg. Ein Ergebnis dieser Studie ist, dass die cTT sicherlich in der Lage ist, einfach und zuverlässig mögliche mikrovaskuläre Schädigungen des Gehirns auch im Hinblick auf ihre tatsächliche klinische Relevanz zu entdecken. Im Vergleich mit anderen Diagnoseverfahren (Testpsychologie und MRT) sind die Vorteile der cTT offensichtlich: die Messung ist ein kostengünstiges und schnelles Verfahren, das sowohl Patienten als auch Untersuchern eine langwierige neuropsychologische Untersuchung erspart. Die Messung der cTT ist ein sicheres Verfahren, da die wenigen aus der Anwendung des Kontrastmittels sich ergebenden Risiken selten und gegebenenfalls leicht behandelbar sind. Zudem erwies sich die cTT als präziser bei der Aufgabe, das Ausmaß kognitiver Dysfunktion zu messen, als es die MRT vermochte. Zuletzt ist die cTT auch flächendeckend verfügbar. Die einzige Voraussetzung ist ein Duplex-fähiges Ultraschallgerät. Kostenintesive Untersuchungen wie die MRT können vermieden werden. Wenn auch die Testpsychologie der Goldstandard bleiben wird, erwies sich die cTT als zuverlässige Alternative die im Vergleich zur MRT sowohl Zeit als auch Kosten spart. KW - Demenz KW - Psychologische Diagnostik KW - Neuropsychologie KW - Ultraschall KW - Ultraschalldiagnostik KW - dementia KW - neuropsychology KW - ultrasound Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-71234 ER - TY - THES A1 - Topuzoglu, Tengü Gülsüm T1 - Charakterisierung von IL-4 Knockout-Mäusen und ihrer Zytokin- und Opioidrezeptor-Expression im peripheren und zentralen Nervensystem T1 - Characterization of IL-4 knockout-mice and their cytokine- and opioidreceptor gene expression in the peripheral and central nervous system N2 - In der vorliegenden Arbeit wurde der Einfluss eines Mangels des antiinflammatorischen Zytokins Interleukin(IL)-4 am Tiermodell einer experimentellen Mononeuropathie (engl. chronic constriction injury, CCI) untersucht. Zentrale Fragestellung der Studie war, ob IL-4 knockout(ko)-Mäuse im Vergleich zu Wildtyp(wt)-Mäusen mit einem gesteigerten Schmerzverhalten sowie einer veränderten Zytokinantwort und Opioidrezeptor-Expression nach Anwendung eines neuropathischen Schmerzmodells (CCI) reagieren. In mehreren Tierstudien war zuvor eine antiinflammatorische und analgetische Wirkung von IL-4 belegt worden (Vale et al. 2003; Hao et al. 2006) und in klinischen Studien war ein verminderter IL-4-Spiegel bei Patienten mit verschiedenen neuropathischen Schmerzsyndromen mit einer gesteigerten Schmerzempfindung verbunden (Üçeyler et al. 2006; Üçeyler et al. 2007b). Da IL-4 die Transkription von Opioidrezeptoren induziert (Kraus et al. 2001; Börner et al. 2004), wurde zudem das Ansprechen von IL-4 ko-Mäusen auf Morphin und die Genexpression zentraler Opioidrezeptoren untersucht. Vor sowie bis vier Wochen nach Durchführung einer CCI wurden IL-4 ko- sowie wt- Mäuse hinsichtlich ihrer Empfindlichkeit auf mechanische und thermische Stimuli analysiert. Zum Zeitpunkt des Schmerzmaximums nach CCI (Tag 7 bis 9) wurde zudem das Ansprechen beider Genotypen auf Morphin untersucht. Die Genexpression pro- (IL-1 beta, TNF) und antiinflammatorischer Zytokine (IL-10, IL- 13) im peripheren (N. ischiadicus) und zentralen Nervensystem (lumbales und zervikales Rückenmark, Pons, Thalamus, Hypothalamus, Striatum, Kortex) sowie die Genexpression zentraler Opioidrezeptoren (mü-OR, delta-OR, kappa-OR) wurde bei beiden Genotypen vor sowie vier Wochen nach CCI mittels Real-Time-PCR bestimmt. Unbehandelte IL-4 ko-Mäuse zeigten im Vergleich zu wt-Mäusen bereits vor Durchführung einer CCI eine mechanische Überempfindlichkeit (Hyperalgesie), was möglicherweise durch die bei IL-4-Mangel fehlenden zentralen inhibitorischen Mechanismen bedingt ist. Nach CCI entwickelten sowohl IL-4 ko- als auch wt-Mäuse eine gleich ausgeprägte mechanische und thermische Hyperalgesie. Die Tatsache, dass die mechanische Überempfindlichkeit bei IL-4 ko-Mäusen nach Nervenläsion nicht überproportional steigt, kann Ausdruck der nachgewiesenen kompensatorisch stärker ausgeprägten Genexpression proinflammatorischer, aber insbesondere auch antiinflammatorischer Zytokine in diesem Genotyp sein. Nur bei IL-4 ko-Mäusen war vier Wochen nach CCI die Genexpression der anti- inflammatorischen Zytokine im N. ischiadicus (IL-10) und ipsilateralen Rückenmark (IL-10, IL-13), jedoch auch die der proinflammatorischen Zytokine im ipsilateralen Rückenmark (TNF, IL-1 beta) erhöht. Nach CCI sprachen IL-4 ko-Mäuse schneller auf Morphingabe an als wt-Mäuse, was durch den bei diesem Genotyp stärker ausgeprägten Anstieg der Genexpression der Opioidrezeptortypen delta-OR und kappa-OR im kontralateralen Thalamus bedingt sein kann. N2 - In this study the pain behavior of IL-4 knockout (ko) mice was characterized before and after chronic constriction injury (CCI) of the sciatic nerve as an established model for neuropathic pain. The opioid responsivity of IL-4 ko-mice was tested and four weeks after CCI the cytokine and opioid receptor gene expression in the peripheral and central nervous system of IL-4 ko mice was measured compared to wildtype (wt) mice. Before CCI IL-4 ko mice showed tactile allodynia, while responses to heat did not differ in comparison to wt-mice. No compensatory changes in the gene expression of the measured cytokines (tumor necrosis factor-alpha (TNF), IL-1b, IL-10, and IL-13) were found in the PNS and CNS of na ̈ıve IL-4 ko mice. Four weeks after CCI IL-1b gene expression was stronger in the sciatic nerve of IL-4 ko mice (p,0.001) and only IL-4 ko mice had elevated IL-10 gene expression in the sciatic nerve. Only in IL-4 ko-mice there was an upregulated gene expression four weeks after CCI of TNF (p,0.01), IL-1b (p,0.05), IL-10 (p,0.05), and IL-13 (p,0.001) in the ipsilateral spinal cord. The compensatory overexpression of the anti-inflammatory cytokines IL-10 and IL-13 in the spinal cord of IL-4 ko mice may explain the lack of genotype differences for pain behavior after CCI. CCI upregulated gene expression of k, and d opioid receptors in the contralateral thalamus of IL-4 ko mice, in accordance with an observed fast onset of morphine analgesia compared to wt mice. KW - Neuralgie KW - Interleukin-4 KW - Zytokin KW - Opioidrezeptor KW - Genexpression KW - Neuropathischer Schmerz KW - Interleukin-4 KW - cytokine KW - opioidreceptor KW - mRNA expression KW - mice Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-72372 ER - TY - JOUR A1 - Albert-Weißenberger, Christiane A1 - Várrallyay, Csanád A1 - Raslan, Furat A1 - Kleinschnitz, Christoph A1 - Sirén, Anna-Leena T1 - An experimental protocol for mimicking pathomechanisms of traumatic brain injury in mice N2 - Traumatic brain injury (TBI) is a result of an outside force causing immediate mechanical disruption of brain tissue and delayed pathogenic events. In order to examine injury processes associated with TBI, a number of rodent models to induce brain trauma have been described. However, none of these models covers the entire spectrum of events that might occur in TBI. Here we provide a thorough methodological description of a straightforward closed head weight drop mouse model to assess brain injuries close to the clinical conditions of human TBI. KW - Medizin KW - closed head injury KW - traumatic brain injury KW - neurobehavioural deficits KW - astrocyte KW - microglia KW - neurons Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75368 ER - TY - JOUR A1 - Kleinschnitz, Christph A1 - Meuth, Sven G. A1 - Magnus, Tim A1 - Korn, Thomas A1 - Linker, Ralf A. T1 - Report on the 3'rd scientific meeting of the "Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Nov. 4'th - Nov. 6'th, 2011 N2 - From November 4th- 6th 2011, the 3rd NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Like in the previous years, the meeting provided an excellent platform for scientific exchange and the presentation of innovative projects for young colleagues in the fields of neurovascular research, neuroinflammation and neurodegeneration. As kick-off to the scientific sessions, Reinhard Hohlfeld, Head of the Institute for Clinical Neuroimmunology in Munich, gave an illustrious overview on the many fascinations of neuroimmunologic research. A particular highlight on the second day of the meeting was the award of the 1’st NEUROWIND e.V. prize for young academics in the field of experimental neurology. This award is posted for young colleagues under the age of 35 with a significant achievement in the field of neurovascular research, neuroinflammation or neurodegeneration and comprises an amount of 20.000 Euro, founded by Merck Serono GmbH, Darmstadt. Germany. The first prize was awarded to Ivana Nikic from Martin Kerschensteiner’s group in Munich for her brilliant work on a reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis, published in Nature Medicine in 2011. This first prize award ceremony was a great incentive for the next call for proposals now upcoming in 2012. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75388 ER - TY - THES A1 - Patzkó, Ágnes T1 - CSF-1 receptor as a target for the treatment of Charcot-Marie-Tooth disease 1 T1 - CSF-1 Rezeptor als Target für die Behandlung der Charcot-Marie-Tooth Krankheit Typ 1 N2 - Previous studies by our group revealed that chronic low grade inflammation implicating phagocytosing macrophages is a highly relevant mechanism in the pathogenesis of Charcot-Marie-Tooth disease. The lack of CSF-1, the primary regulator of macrophage function and survival, led to a robust and persistent amelioration of the phenotype in two authentic mouse models of CMT. Moreover, a close contact between CSF-1 producing fibroblasts and endoneurial macrophages carrying CSF-1R has been confirmed in nerve biopsies of CMT patients, further supporting the clinical significance of this pathway. In the current study we treated 3 distinct mouse models of CMT1: the PMP22tg mice as a model for CMT1A, the P0+/- mice as a model for CMT1B and the Cx32def mice as a model for CMT1X, with a CSF-1R specific kinase (c-FMS) inhibitor (800-1200 mg PLX5622/ kg chow) according to different treatment regimes mimicking an ideal early onset treatment, a late onset treatment and the withdrawal of the drug. Using the above mentioned doses of PLX5622, we documented a dramatic decrease in macrophage numbers in the PNS of all 3 myelin mutants, except for the quadriceps nerve of Cx32def mice. Fibroblast numbers remained unchanged in treated animals. Surprisingly, in spite of the decrease in the number of detrimental macrophages we could not detect an unequivocal phenotypic improvement. CMAP amplitudes were reduced in both wild type and myelin mutant mice treated with CSF-1R inhibitor in comparison to untreated littermates. Corresponding to the electrophysiological findings, the axon number and the percentage of large diameter axons were reduced in the quadriceps nerve of treated P0+/- and Cx32def mice. By contrast we observed a higher number of fully myelinated axons, in parallel with a decrease in the percentage of demyelinated (and hypermyelinated in PMP22tg mice) fibers in the ventral roots of P0+/- mice treated with CSF-1R inhibitor from 3 months up to 6 months of age and PMP22tg animals treated from 9 months up to 15 months of age. Our results indicate that CSF-1R inhibitor has the potential to improve the demyelinating phenotype of at least two models of CMT1. Nevertheless, further studies are necessary (for example with lower doses of the inhibitor) to minimize or even eliminate the putative neurotoxic effect we observed with high dose treatment conditions. N2 - Vorhergehende Studien unserer Gruppe haben gezeigt, dass eine niedriggradige Entzündung, die von phagozytierenden Makrophagen ausgeht, von ausserordentlicher Bedeutung für die Pathogenese der Charcot-Marie-Tooth Krankheit ist. In Abwesenheit von CSF-1, des primären Regulators für Funktion und Überleben von Makrophagen, trat eine stabile und dauerhafte Verbesserung des Phänotyps in den zwei etablierten CMT Mausmodellen auf. Darüber hinaus konnte ein enger Kontakt zwischen CSF-1-produzierenden Fibroblasten und Makrophagen, die den zugehörigen Rezeptor CSF-1Rexprimieren, in Nervbiopsien von CMT Patienten bestätigt werden, was die klinische Relevanz dieses Mechanismus weiter verdeutlicht. In der aktuellen Studie wurden drei verschiedene CMT1 Mausmodelle, PMP22tg Mäuse als Modell für CMT1A, P0+/- Mäuse als Modell für CMT1B und Cx32-defiziente Mäuse als Modell für CMT1X, mit einem Inhibitor der CSF-1R spezifischen Kinase (c-FMS) (800-1200 mg PLX5622/kg Futter) behandelt. Der Inhibitor wurde gemäß den verschiedenen Behandlungsmethoden eingesetzt, um den Verlauf eineridealerweise frühzeitigen und einer spät-beginnenden Behandlung und des Entzug des Medikaments zu imitieren. Nach der Behandlung mit PLX5622 konnten wir im PNS aller drei Myelin-Mutanten, mit Ausnahme des N. quadriceps von Cx32-defizienten Mäusen, einen drastischen Rückgang der Makrophagenanzahl feststellen. Die Anzahl der Fibroblasten blieb in den behandelten Tieren unverändert. Überraschenderweise konnten wir, trotz des Rückgangs der Anzahl an schädlichen Makrophagen, keine einheitliche Verbesserung des Phänotyps dokumentieren. CMAP Amplituden waren nach CSF-1R Inhibitor Behandlung sowohl in Wild-Typ Mäusenals auch in den Myelin-Mutanten geringer als in unbehandelten Kontrolltieren. Passend zu den elektrophysiologischen Ergebnissen war die Anzahl an Axonen und die Prozentzahl an großkalibrigen Axonen im N. quadriceps von behandelten P0+/- und Cx32-defizienten Mäusen reduziert.Im Gegensatz dazu war eine erhöhte Menge an normalmyelinisierten Axonen, mit einer gleichzeitigen Reduktiondemyelinisierter Fasern (und hypermyelinisierten in PMP22tg Mäusen) in den ventralen Spinalwurzeln von P0+/- Mäusen zu beobachten, die mit dem CSF-1R Inhibitor im Alter von 3 bis 6 Monaten behandelt worden waren sowie bei PMP22tg Mäusen, die im Alter von 9 bis 15 Monaten den Inhibitor erhalten hatten. Unsere Ergebnisse deuten an, dass der CSF-1R Inhibitor das Potential besitzt, zumindest in zwei Modellen von CMT1 den demyelinisierenden Phänotyp zu verbessern. Dennoch müssen weitere Studien durchgeführt werden (z.B. die Verwendung einer niedrigeren Dosis des Inhibitors), um den möglichen neurotoxischen Effekt, der bei oben genannten Behandlungsbedingungen zu beobachten war, zu minimieren oder ganz zu beheben. KW - Makrophage KW - Charcot-Marie-Tooth KW - Charcot-Marie-Tooth disease KW - Myelin KW - CSF-1 Rezeptor KW - Neuropathie KW - macrophage KW - CSF-1 receptor KW - neuropathy KW - myelin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-85325 ER - TY - JOUR A1 - Pham, Mirko A1 - Helluy, Xavier A1 - Kleinschnitz, Christoph A1 - Kraft, Peter A1 - Bartsch, Andreas J. A1 - Jakob, Peter A1 - Nieswandt, Bernhard A1 - Bendszus, Martin A1 - Guido, Stoll T1 - Sustained Reperfusion after Blockade of Glycoprotein-Receptor-Ib in Focal Cerebral Ischemia: An MRI Study at 17.6 Tesla JF - PLoS ONE N2 - Background: Inhibition of early platelet adhesion by blockade of glycoprotein-IB (GPIb) protects mice from ischemic stroke. To elucidate underlying mechanisms in-vivo, infarct development was followed by ultra-high field MRI at 17.6 Tesla. Methods: Cerebral infarction was induced by transient-middle-cerebral-artery-occlusion (tMCAO) for 1 hour in C57/BL6 control mice (N = 10) and mice treated with 100 mg Fab-fragments of the GPIb blocking antibody p0p/B 1 h after tMCAO (N = 10). To control for the effect of reperfusion, additional mice underwent permanent occlusion and received anti-GPIb treatment (N = 6; pMCAO) or remained without treatment (N = 3; pMCAO). MRI 2 h and 24 h after MCAO measured cerebral-blood-flow (CBF) by continuous arterial-spin labelling, the apparent-diffusion-coefficient (ADC), quantitative-T2 and T2-weighted imaging. All images were registered to a standard mouse brain MRI atlas and statistically analysed voxel-wise, and by cortico-subcortical ROI analysis. Results: Anti-GPIb treatment led to a relative increase of postischemic CBF vs. controls in the cortical territory of the MCA (2 h: 44.2 +/- 6.9 ml/100g/min versus 24 h: 60.5 +/- 8.4; p = 0.0012, F((1,18)) = 14.63) after tMCAO. Subcortical CBF 2 h after tMCAO was higher in anti-GPIb treated animals (45.3 +/- 5.9 vs. controls: 33.6 +/- 4.3; p = 0.04). In both regions, CBF findings were clearly related to a lower probability of infarction (Cortex/Subcortex of treated group: 35%/65% vs. controls: 95%/100%) and improved quantitative-T2 and ADC. After pMCAO, anti-GPIb treated mice developed similar infarcts preceded by severe irreversible hypoperfusion as controls after tMCAO indicating dependency of stroke protection on reperfusion. Conclusion: Blockade of platelet adhesion by anti-GPIb-Fab-fragments results in substantially improved CBF early during reperfusion. This finding was in exact spatial correspondence with the prevention of cerebral infarction and indicates in-vivo an increased patency of the microcirculation. Thus, progression of infarction during early ischemia and reperfusion can be mitigated by anti-platelet treatment. KW - Von-Willebrand-factor KW - Experimental stroke KW - Magnetic-resonance KW - Arterial water KW - Brain KW - Perfusion KW - Mice KW - Inflammation KW - Coefficient KW - mechanisms Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-142608 VL - 6 IS - 4 ER - TY - JOUR A1 - Quarta, Serena A1 - Vogl, Christian A1 - Constantin, Cristina E. A1 - Üçeyler, Nurcan A1 - Sommer, Claudia A1 - Kress, Michaela T1 - Genetic evidence for an essential role of neuronally expressed IL-6 signal transducer gp130 in the induction and maintenance of experimentally induced mechanical hypersensitivity \(in\) \(vivo\) and \(in\) \(vitro\) JF - Molecular Pain N2 - Tenderness and mechanical allodynia are key symptoms of malignant tumor, inflammation and neuropathy. The proinflammatory cytokine interleukin-6 (IL-6) is causally involved in all three pathologies. IL-6 not only regulates innate immunity and inflammation but also causes nociceptor sensitization and hyperalgesia. In general and in most cell types including immune cells and sensory neurons, IL-6 binds soluble mu receptor subunits which heteromerizes with membrane bound IL-6 signal transducer gp130. In the present study, we used a conditional knock-out strategy to investigate the importance of signal transducer gp130 expressed in C nociceptors for the generation and maintenance of mechanical hypersensitivity. Nociceptors were sensitized to mechanical stimuli by experimental tumor and this nociceptor sensitization was preserved at later stages of the pathology in control mice. However, in mice with a conditional deletion of gp130 in Nav1.8 expressing nociceptors mechanical hypersensitivity by experimental tumor, nerve injury or inflammation recovery was not preserved in the maintenance phase and nociceptors exhibited normal mechanical thresholds comparable to untreated mice. Together, the results argue for IL-6 signal transducer gp130 as an essential prerequisite in nociceptors for long-term mechanical hypersensitivity associated with cancer, inflammation and nerve injury. KW - Leukemia Inhibitory Factor KW - Mediated Inflammatory Hyperalgesia KW - Necrosis-factor-Alpha KW - Oncostatin-M-Receptor KW - Rat Sensory Neurons KW - Rheumatoid-Arthritis KW - Interleukin-6-Deficient mice KW - Peripheral Inflammation KW - Thermal Hyperalgesia KW - Heat Hyperalgesia KW - proinflammatory cytokine KW - Interleukin-6 KW - chronic pain KW - nociceptor sensitization KW - hyperalgesia KW - allodynia Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-140380 VL - 7,73 ER - TY - JOUR A1 - Hopfner, Franziska A1 - Schormair, Barbara A1 - Knauf, Franziska A1 - Berthele, Achim A1 - Tölle, Thomas R. A1 - Baron, Ralf A1 - Maier, Christoph A1 - Treede, Rolf-Detlef A1 - Binder, Andreas A1 - Sommer, Claudia A1 - Maihöfner, Christian A1 - Kunz, Wolfram A1 - Zimprich, Friedrich A1 - Heemann, Uwe A1 - Pfeufer, Arne A1 - Näbauer, Michael A1 - Kääb, Stefan A1 - Nowak, Barbara A1 - Gieger, Christian A1 - Lichtner, Peter A1 - Trenkwalder, Claudia A1 - Oexle, Konrad A1 - Winkelmann, Juliane T1 - Novel SCARB2 mutation in Action Myoclonus-Renal Failure syndrome and evaluation of SCARB2 mutations in isolated AMRF features JF - BMC Neurology N2 - Background: Action myoclonus-renal failure syndrome is a hereditary form of progressive myoclonus epilepsy associated with renal failure. It is considered to be an autosomal-recessive disease related to loss-of-function mutations in SCARB2. We studied a German AMRF family, additionally showing signs of demyelinating polyneuropathy and dilated cardiomyopathy. To test the hypothesis whether isolated appearance of individual AMRF syndrome features could be related to heterozygote SCARB2 mutations, we screened for SCARB2 mutations in unrelated patients showing isolated AMRF features. Methods: In the AMRF family all exons of SCARB2 were analyzed by Sanger sequencing. The mutation screening of unrelated patients with isolated AMRF features affected by either epilepsy (n = 103, progressive myoclonus epilepsy or generalized epilepsy), demyelinating polyneuropathy (n = 103), renal failure (n = 192) or dilated cardiomyopathy (n = 85) was performed as high resolution melting curve analysis of the SCARB2 exons. Results: A novel homozygous 1 bp deletion (c.111delC) in SCARB2 was found by sequencing three affected homozygous siblings of the affected family. A heterozygous sister showed generalized seizures and reduction of nerve conduction velocity in her legs. No mutations were found in the epilepsy, renal failure or dilated cardiomyopathy samples. In the polyneuropathy sample two individuals with demyelinating disease were found to be carriers of a SCARB2 frameshift mutation (c.666delCCTTA). Conclusions: Our findings indicate that demyelinating polyneuropathy and dilated cardiomyopathy are part of the action myoclonus-renal failure syndrome. Moreover, they raise the possibility that in rare cases heterozygous SCARB2 mutations may be associated with PNP features. KW - Demyelinating peripheral neuropathy KW - Beta-glucocerebrosidase KW - Epilepsy KW - LIMP-2 KW - Mice Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141209 VL - 11 IS - 134 ER - TY - JOUR A1 - Binder, Andreas A1 - May, Denisa A1 - Baron, Ralf A1 - Maier, Christoph A1 - Tölle, Thomas R. A1 - Treede, Rolf-Detlef A1 - Berthele, Achim A1 - Faltraco, Frank A1 - Flor, Herta A1 - Gierthmühlen, Janne A1 - Haenisch, Sierk A1 - Huge, Volker A1 - Magerl, Walter A1 - Maihöfner, Christian A1 - Richter, Helmut A1 - Rolke, Roman A1 - Scherens, Andrea A1 - Üçeyler, Nurcan A1 - Ufer, Mike A1 - Wasner, Gunnar A1 - Zhu, Jihong A1 - Cascorbi, Ingolf T1 - Transient Receptor Potential Channel Polymorphisms Are Associated with the Somatosensory Function in Neuropathic Pain Patients JF - PLoS ONE N2 - Transient receptor potential channels are important mediators of thermal and mechanical stimuli and play an important role in neuropathic pain. The contribution of hereditary variants in the genes of transient receptor potential channels to neuropathic pain is unknown. We investigated the frequency of transient receptor potential ankyrin 1, transient receptor potential melastin 8 and transient receptor potential vanilloid 1 single nucleotide polymorphisms and their impact on somatosensory abnormalities in neuropathic pain patients. Within the German Research Network on Neuropathic Pain (Deutscher Forscbungsverbund Neuropathischer Schmerz) 371 neuropathic pain patients were phenotypically characterized using standardized quantitative sensory testing. Pyrosequencing was employed to determine a total of eleven single nucleotide polymorphisms in transient receptor potential channel genes of the neuropathic pain patients and a cohort of 253 German healthy volunteers. Associations of quantitative sensory testing parameters and single nucleotide polymorphisms between and within groups and subgroups, based on sensory phenotypes, were analyzed. Single nucleotide polymorphisms frequencies did not differ between both the cohorts. However, in neuropathic pain patients transient receptor potential ankyrin 1 710G>A (rs920829, E179K) was associated with the presence of paradoxical heat sensation (p=0.03), and transient receptor potential vanilloid 1 1911A>G (rs8065080, I585V) with cold hypoalgesia (p=0.0035). Two main subgroups characterized by preserved (1) and impaired (2) sensory function were identified. In subgroup 1 transient receptor potential vanilloid 1 1911A>G led to significantly less heat hyperalgesia, pinprick hyperalgesia and mechanical hypaesthesia (p=0.006, p=0.005 and p<0.001) and transient receptor potential vanilloid 1 1103C>G (rs222747, M315I) to cold hypaesthesia (p=0.002), but there was absence of associations in subgroup 2. In this study we found no evidence that genetic variants of transient receptor potential channels are involved in the expression of neuropathic pain, but transient receptor potential channel polymorphisms contributed significantly to the somatosensory abnormalities of neuropathic pain patients. KW - Paradoxical heat sensation KW - Neurogenic inflammation KW - Capsaicin receptor KW - TRP Channels KW - Cold KW - Mechanisms KW - Hyperalgesia KW - Sensitivity KW - Expression KW - Stimuli Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-142782 VL - 6 IS - 3 ER - TY - JOUR A1 - Tony, Hans-Peter A1 - Burmester, Gerd A1 - Schulze-Koops, Hendrik A1 - Grunke, Mathias A1 - Henes, Joerg A1 - Kötter, Ina A1 - Haas, Judith A1 - Unger, Leonore A1 - Lovric, Svjetlana A1 - Haubitz, Marion A1 - Fischer-Betz, Rebecca A1 - Chehab, Gamal A1 - Rubbert-Roth, Andrea A1 - Specker, Christof A1 - Weinerth, Jutta A1 - Holle, Julia A1 - Müller-Ladner, Ulf A1 - König, Ramona A1 - Fiehn, Christoph A1 - Burgwinkel, Philip A1 - Budde, Klemens A1 - Sörensen, Helmut A1 - Meurer, Michael A1 - Aringer, Martin A1 - Kieseier, Bernd A1 - Erfurt-Berge, Cornelia A1 - Sticherling, Michael A1 - Veelken, Roland A1 - Ziemann, Ulf A1 - Strutz, Frank A1 - von Wussow, Praxis A1 - Meier, Florian MP A1 - Hunzelmann, Nico A1 - Schmidt, Enno A1 - Bergner, Raoul A1 - Schwarting, Andreas A1 - Eming, Rüdiger A1 - Schwarz-Eywill, Michael A1 - Wassenberg, Siegfried A1 - Fleck, Martin A1 - Metzler, Claudia A1 - Zettl, Uwe A1 - Westphal, Jens A1 - Heitmann, Stefan A1 - Herzog, Anna L. A1 - Wiendl, Heinz A1 - Jakob, Waltraud A1 - Schmidt, Elvira A1 - Freivogel, Klaus A1 - Dörner, Thomas A1 - Hertl, Michael A1 - Stadler, Rudolf T1 - Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID) JF - Arthritis Research & Therapy N2 - Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin’s lymphoma in a real-life clinical setting. Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators. Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician’s visual analogue scale; mean improvement from baseline of 12.1 mm) KW - GRAID Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-142856 VL - 13 IS - R75 ER - TY - JOUR A1 - Geis, Christian A1 - Weishaupt, Andreas A1 - Grünewald, Benedikt A1 - Wultsch, Thomas A1 - Reif, Andreas A1 - Gerlach, Manfred A1 - Dirkx, Ron A1 - Solimena, Michele A1 - Toyka, Klaus V A1 - Folli, Franco A1 - Perani, Daniela A1 - Heckmann, Manfred A1 - Sommer, Claudia T1 - Human Stiff-Person Syndrome IgG Induces Anxious Behavior in Rats JF - Plos One N2 - Background: Anxiety is a heterogeneous behavioral domain playing a role in a variety of neuropsychiatric diseases. While anxiety is the cardinal symptom in disorders such as panic disorder, co-morbid anxious behavior can occur in a variety of diseases. Stiff person syndrome (SPS) is a CNS disorder characterized by increased muscle tone and prominent agoraphobia and anxiety. Most patients have high-titer antibodies against glutamate decarboxylase (GAD) 65. The pathogenic role of these autoantibodies is unclear. Methodology/Principal Findings: We re-investigated a 53 year old woman with SPS and profound anxiety for GABA-A receptor binding in the amygdala with (11) C-flumazenil PET scan and studied the potential pathogenic role of purified IgG from her plasma filtrates containing high-titer antibodies against GAD 65. We passively transferred the IgG fraction intrathecally into rats and analyzed the effects using behavioral and in vivo electrophysiological methods. In cell culture, we measured the effect of patient IgG on GABA release from hippocampal neurons. Repetitive intrathecal application of purified patient IgG in rats resulted in an anxious phenotype resembling the core symptoms of the patient. Patient IgG selectively bound to rat amygdala, hippocampus, and frontal cortical areas. In cultured rat hippocampal neurons, patient IgG inhibited GABA release. In line with these experimental results, the GABA-A receptor binding potential was reduced in the patient's amygdala/hippocampus complex. No motor abnormalities were found in recipient rats. Conclusion/Significance: The observations in rats after passive transfer lead us to propose that anxiety-like behavior can be induced in rats by passive transfer of IgG from a SPS patient positive for anti-GAD 65 antibodies. Anxiety, in this case, thus may be an antibody-mediated phenomenon with consecutive disturbance of GABAergic signaling in the amygdala region. KW - Glutamic-acid decarboxylase anxiety KW - spinal-cord-injury KW - presynaptic inhibition KW - 65-kda isoform KW - fear memory KW - antibodies KW - disorder KW - neurons KW - anxiety KW - autoantibodies Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-140506 VL - 6 IS - 2 ER - TY - JOUR A1 - Geis, Christian A1 - Weishaupt, Andreas A1 - Grünewald, Benedikt A1 - Wultsch, Thomas A1 - Reif, Andreas A1 - Gerlach, Manfred A1 - Dirkx, Ron A1 - Solimena, Michele A1 - Perani, Daniela A1 - Heckmann, Manfred A1 - Toyka, Klaus V. A1 - Folli, Franco A1 - Sommer, Claudia T1 - Human Stiff-Person Syndrome IgG Induces Anxious Behavior in Rats N2 - Background: Anxiety is a heterogeneous behavioral domain playing a role in a variety of neuropsychiatric diseases. While anxiety is the cardinal symptom in disorders such as panic disorder, co-morbid anxious behavior can occur in a variety of diseases. Stiff person syndrome (SPS) is a CNS disorder characterized by increased muscle tone and prominent agoraphobia and anxiety. Most patients have high-titer antibodies against glutamate decarboxylase (GAD) 65. The pathogenic role of these autoantibodies is unclear. Methodology/Principal Findings: We re-investigated a 53 year old woman with SPS and profound anxiety for GABA-A receptor binding in the amygdala with (11)C-flumazenil PET scan and studied the potential pathogenic role of purified IgG from her plasma filtrates containing high-titer antibodies against GAD 65. We passively transferred the IgG fraction intrathecally into rats and analyzed the effects using behavioral and in vivo electrophysiological methods. In cell culture, we measured the effect of patient IgG on GABA release from hippocampal neurons. Repetitive intrathecal application of purified patient IgG in rats resulted in an anxious phenotype resembling the core symptoms of the patient. Patient IgG selectively bound to rat amygdala, hippocampus, and frontal cortical areas. In cultured rat hippocampal neurons, patient IgG inhibited GABA release. In line with these experimental results, the GABA-A receptor binding potential was reduced in the patient’s amygdala/hippocampus complex. No motor abnormalities were found in recipient rats. Conclusion/Significance: The observations in rats after passive transfer lead us to propose that anxiety-like behavior can be induced in rats by passive transfer of IgG from a SPS patient positive for anti-GAD 65 antibodies. Anxiety, in this case, thus may be an antibody-mediated phenomenon with consecutive disturbance of GABAergic signaling in the amygdala region. KW - Medizin Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-74757 ER - TY - THES A1 - Kafke, Waldemar T1 - Bestimmung von Zytokinexpressionsprofilen aus humanen Blut- und Hautproben bei Patienten mit small fiber Neuropathie T1 - Analysis of cytokine expression patterns in affected skin amd blood samples in patients with small fiber neuropathy N2 - Zusammenfassend konnte durch unsere Daten die eingangs gestellte Hypothese, dass Patienten mit SFN eine lokal und systemisch erhöhte Expression pro-inflammatorischer und algetischer Zytokine haben, auf lokaler Ebene bei der Untergruppe mit LD-SFN bestätigt werden. Bei der Untergruppe mit NLD-SFN waren keine Unterschiede bei den Zytokinexpressionen zwischen proximalen und distalen Hautbiopsien im Vergleich zu Kontrollprobanden nachweisbar. Zudem zeigten sich deutliche Unterschiede bei den Quotienten der IENFD zwischen beiden Untergruppen. Dies legt die Vermutung nahe, dass die Unterteilung in LD-SFN und NLD-SFN klinisch bedeutsam und ein möglicher Grundstein für das Verständnis der pathophysiologischen Mechanismen der SFN sein könnte. Hieraus könnten sich Fortschritte in der Diagnostik ergeben und gezielte symptomatische und vielleicht sogar kausale Therapien auf lokaler Ebene bei der SFN entwickeln. N2 - A subgroup of patients with small fiber neuropahties with a lenght-dependent distribution pattern concerning the reduction of intraepidermal nerve fibers (LD-SFN) have a higher cytokine gene expression of pro-inflammatory cytokines in affected skin. KW - Small fiber Neuropathie KW - Zytokine KW - Small fiber Neuropathie KW - Zytokine KW - Small fiber neuropathy KW - Cytokines Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-71132 ER - TY - JOUR A1 - Üceyler, Nurcan A1 - Häuser, Winfried A1 - Sommer, Claudia T1 - Systematic review with meta-analysis: Cytokines in fibromyalgia syndrome N2 - Background: To perform a systematic review and meta-analysis on cytokine levels in patients with fibromyalgia syndrome (FMS). Methods: Through December 2010 we systematically reviewed the databases PubMed, MEDLINE, and PsycINFO and screened the reference lists of 22 review articles for suitable original articles. Original articles investigating cytokines in patients with FMS were included. Data were extracted by two independent authors. Differences of the cytokine levels of FMS patients and controls were summarized by standardized mean differences (SMD) using a random effects model. Study quality was assessed applying methodological scores: modified Center of Evidence Based Medicine, Newcastle-Ottawa-Scale, and Würzburg Methodological Quality Score. Results: Twenty-five articles were included investigating 1255 FMS patients and 800 healthy controls. Data of 13/25 studies entered meta-analysis. The overall methodological quality of studies was low. The results of the majority of studies were not comparable because methods, investigated material, and investigated target cytokines differed. Systematic review of the selected 25 articles revealed that FMS patients had higher serum levels of interleukin (IL)-1 receptor antagonist, IL-6, and IL-8, and higher plasma levels of IL-8. Meta-analysis of eligible studies showed that FMS patients had higher plasma IL-6 levels compared to controls (SMD = -0.34 [-0.64, -0.03] 95% CI; p = 0.03). The majority of investigated cytokines were not different between patients and controls. Conclusions: The pathophysiological role of cytokines in FMS is still unclear. Studies of higher quality and with higher numbers of subjects are needed. KW - Fibromyalgie Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-69189 ER - TY - THES A1 - Dang, Su-Yin Judith T1 - Funktionelle Bedeutung der Neuroplastizität bei Multipler Sklerose T1 - The functional relevance of neuronal plasticity in multiple sclerosis N2 - Die Multiple Sklerose ist eine chronische neurologische Erkrankung, welche in der industrialisierten Welt einen der häufigsten Gründe für eine bleibende Behinderung bei jungen Erwachsenen darstellt. Obwohl die ZNS-Schädigung, charakterisiert durch Demyelinisierung und axonale Schädigung im Rahmen entzündlicher Vorgänge, durch verschiedene Reparaturmechanismen reduziert wird, akkumuliert die Läsionslast im zentralen Nervensystem mit der Zeit. T2-gewichtete MRT-Studien zeigen, dass die dargestellten Pathologien nur mäßig mit den motorischen Defiziten korrelieren. Diese Diskrepanz wird unter anderem auf Vorgänge der Neuroplastizität zurückgeführt, als deren Basismechanismen Langzeitpotenzierung (LTP) und -depression (LTD) gelten. In verschiedenen fMRT-Studien haben sich Hinweise ergeben, dass diese adaptiven Veränderungen zur Reorganisation kortikaler Repräsentationmuster führen können, so dass bei MS-Patienten eine ausgedehntere Aktivierung ipsilateraler sensomotorischer Areale bei motorischen Aufgaben zu beobachten ist. Die transkranielle Magnetstimulation (TMS) bietet die Möglichkeit, mittels virtueller Läsionstechniken eine direkte Aussage über die kausale Beziehung zwischen Struktur und Funktion zu liefern. Die funktionelle Rolle ipsilateraler Motorareale wurde an 26 MS-Patienten, in Relation zu ihrer motorischen Beeinträchtigung und ZNS-Schädigung, und an nach Alter, Geschlecht und Händigkeit zugeordneten Kontrollprobanden, untersucht. Die motorische Leistungsfähigkeit wurde durch verschiedene Tests zur Handfunktion erhoben. Die ZNS-Schädigung wurde mittels MR-Spektroskopie als NAA/Cr Quotient sowie durch die CML erhoben. Die Aufgabe zur einfachen Reaktionszeit (SRT) bestand aus einer isometrischen Abduktionsbewegung des rechten Daumens gegen einen Kraftaufnehmer auf ein akustisches Go-Signal. Mit TMS-Einzelreizen wurde mit Hilfe einer Neuronavigation eine reversible virtuelle Läsion über bestimmten Gehirnarealen, kontralateraler M1, ipsilateraler M1 und ipsilateraler PMd, erzeugt. Es wurde eine Kontrollstimulation über MO durchgeführt. Die TMS-Einzelreize wurden 100ms nach dem Go-Signal appliziert. Als SRT wurde der Zeitraum zwischen dem Go-Signal und EMG-Beginn im APB definiert. Die signifikanten SRT-Verlängerungen bei TMS über dem ipsilateralen M1 und dem ipsilateralen PMd zeigen, dass diese Regionen eine Rolle bei der motorischen Funktion bei MS spielen. Die fehlenden Korrelationen zwischen motorischen Funktionstest und NAA/Cr-Verhältnis sowie die inverse Korrelation zur kortikomuskulären Latenz sind durch strukturell von der krankheitsbedingten Pathologie betroffenen kompensierenden Gehirnregionen erklärbar. Bei dem Theta Burst Experiments (TBS) wurde ein virtueller Läsionseffekt durch eine repetitive TMS-Intervention über dem ipsilateralen M1 induziert. Die Ergebnisse zeigen ähnliche Veränderungen der Exzitabilität bei MS-Patienten und gesunden Kontrollprobanden, was schließen lässt, dass die LTD bei mild bis moderat betroffenen MS-Patienten weitestgehend unbeeinträchtigt ist. MS-Patienten zeigen im Vergleich zu den Kontrollen eine ähnliche Minderung der Verhaltensleistung, Trefferquote in ein Kraftfenster, der MS-Patienten im Kontrollvergleich. Die Ergebnisse zeigen, dass ipsilaterale motorische Areale in der Lage sind den primär motorischen Kortex soweit zu kompensieren, jedoch die Fähigkeit zur Kompensation in fortgeschrittenen Krankheitsstadien eingeschränkt ist. Abschließend kann man zusammenfassen, dass die funktionelle Rekrutierung von ipsilateralen Motorarealen eine adaptive Antwort auf chronische Gehirnschädigung bei MS-Patienten sein kann, allerdings mit Einschränkung der Kapazität in fortgeschrittenen Krankheitsstadien. Nachdem die synaptische Plastizität weitestgehend intakt scheint, sollte man besonders Mechanismen der späten Phase der Plastizität fördern, welche auf eine langfristige kortikale Plastizität abzielen. Weitere Studien in diesem Forschungszweig könnten einen Beitrag zur Entwicklung therapeutischer Konzepte der Neurorehabilitation bei Multipler Sklerose leisten. N2 - Multiple Sclerosis is a chronic neurological disease, which is one of the common reasons in the industrial world causing a lasting disablement at young adults. Despite of reduction by several mechanisms the cns injury characterized by demyelinizing and axonal injury in order of inflammatory processes the lesion load of the cns accumulates over the years. T2-weighted MRI studies only show moderate correlations between the represented pathologies and the motoric deficits. This discrepancy is attributed i.a. to procedures of neuroplasticity whose basic mechanisms are considered as Long-term potentiation (LTP) and -depression (LTD). Several fMRI studies suggest a reogranization of cortical representative pattern due to these adaptive changes. Therefore an extended activation of ipilaterale sensomotoric areas is observed in MS patients performing motoric tasks. Transcranial Magnetic Stimulation (TMS) provides via lesional techniques the possibility of a direct conclusion causal link to structure and function. The functional role of ipsilateral motor areas has been examined in 26 MS patients in relation to their motor impairment and cns injury. Healthy controls were matched for age, sex and handedness. The motor performance was assessed by a test battery of hand function. The cns injury was evaluated using magnetic resonance spectroscopy (NAA/Cr Quotient) and TMS (CML). The Simple Reaction Time task (SRT) consisted of a brisk isometric abduction of the right thumb against a force transducer as a respond to an auditorily Go-Signal. With the help of a neuronavigational device a reversible virtual lesion, delivered by TMS single pulses, were applied to specific brain areas, contralateral M1, ipsilateral M1 and ipsilateral PMD. A control stimulation were assessed to MO??. TMS Single pulses were applied 100ms after Go-Signal. SRT were defined as the time between Go-Signal and EMG onset. Significant extention of SRT after TMS to ipsilateral M1 and ipsilateral PMd evidence the role of these regions in motoric function in MS. The missing correlation between motor performance and NAA/Cr Quotient as well as the inverse correlation to CML are explainable by compensation brain regions which are themselves structurally affected by disease pathologies. In the Thetaburs experiments (TBS) a virtual lesion was induced by a repetitive TMS intervention to ipsilateral M1. The results show a similar change of excitability in MS patients and healthy controls which concludes that LTD is not compromised in mild to moderate affected MS patients. MS patients presented in comparison to controlls a similiar discrease of behavioral performance, hit rate in a force range. The results evidence that ipsilateral motor areas have the ability to compensate the primary motor cortex. But the ability for compensation is limited in advanced stages of illness. The concluding summary is that functional recruitment of ipsilateral motor areas are adaptive response to chronic brain injury in MS patients but with limited capacity in advanced stages of illness. As the synaptic plasticity seem intact to the greatest possible extent mechanism of the late stadium of plasticity should be supported which aim at long term cortical plasticity. Further studies in this branch of research could contribute the development of therapeutic concepts of neurorehabilitation in MS. KW - Neuronale Plastizität KW - Multiple Sklerose KW - Transkranielle Magnetstimulation KW - neuronal plasticity KW - multiple sclerosis KW - transcranial magnetic stimulation Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-73817 ER - TY - JOUR A1 - Chen, Y. A1 - Palm, F. A1 - Lesch, K. P. A1 - Gerlach, M. A1 - Moessner, R. A1 - Sommer, C. T1 - 5-hydroxyindolacetic acid (5-HIAA), a main metabolite of serotonin, is responsible for complete Freund's adjuvant-induced thermal hyperalgesia in mice N2 - Background: The role of serotonin (5-hydroxytrptamine, 5-HT) in the modulation of pain has been widely studied. Previous work led to the hypothesis that 5-hydroxyindolacetic acid (5-HIAA), a main metabolite of serotonin, might by itself influence pain thresholds. Results: In the present study, we investigated the role of 5-HIAA in inflammatory pain induced by intraplantar injection of complete Freund’s adjuvant (CFA) into the hind paw of mice. Wild-type mice were compared to mice deficient of the 5-HT transporter (5-HTT-/- mice) using behavioral tests for hyperalgesia and high-performance liquid chromatography (HPLC) to determine tissue levels of 5-HIAA. Wild-type mice reproducibly developed thermal hyperalgesia and paw edema for 5 days after CFA injection. 5-HTT-/- mice treated with CFA had reduced thermal hyperalgesia on day 1 after CFA injection and normal responses to heat hereafter. The 5-HIAA levels in spinal cord and sciatic nerve as measured with HPLC were lower in 5-HTT-/- mice than in wild-type mice after CFA injection. Pretreatment of wild-type mice with intraperitoneal injection of para-chlorophenylalanine (p-CPA), a serotonin synthesis inhibitor, resulted in depletion of the 5-HIAA content in spinal cord and sciatic nerve and decrease in thermal hyperalgesia in CFA injected mice. The application of exogenous 5-HIAA resulted in potentiation of thermal hyperalgesia induced by CFA in 5-HTT-/- mice and in wild-type mice pretreated with p- CPA, but not in wild-type mice without p-CPA pretreatment. Further, methysergide, a broad-spectrum serotonin receptor antagonist, had no effect on 5-HIAA-induced potentiation of thermal hyperalgesia in CFA-treated wildtype mice. Conclusion: Taken together, the present results suggest that 5-HIAA plays an important role in modulating peripheral thermal hyperalgesia in CFA induced inflammation, probably via a non-serotonin receptor mechanism. KW - Medizin Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68858 ER - TY - THES A1 - Stenner, Max-Philipp T1 - Diapedese und immuntolerogene Funktion regulatorischer T Zellen in der schubförmigen Multiplen Sklerose unter Therapie mit Natalizumab T1 - Diapedesis and tolerogenic function of regulatory T cells under natalizumab therapy of relapsing-remitting multiple sclerosis N2 - Die schubförmige Multiple Sklerose (MS) ist eine chronisch-entzündliche, demyelinisierende, multifokale Erkrankung des Zentralnervensystems (ZNS). Autoreaktive immunologische Prozesse, insbesondere der T-Zell vermittelten Immunität, leisten einen entscheidenden Beitrag zur Pathogenese der schubförmigen MS. Ein wesentlicher Schritt in immunpathogenetischen Modellen ist die transendotheliale Migration von Immunzellen über die Blut-Hirn-Schranke. Die Interaktion des very late antigen 4 (VLA-4) mit dem vascular cell adhesion molecule 1 (VCAM-1) und mit Fibronectin leistet einen wesentlichen Beitrag zur Extravasation von T Zellen in das ZNS. Auf dieser Schlüsselfunktion des VLA-4 gründet die Therapie mit Natalizumab, einem monoklonalen Antikörper gegen die α4 Integrinkette. Ziel der vorliegenden Studie war es, die Auswirkungen der Therapie der schubförmigen MS mit Natalizumab auf die transendotheliale Migration von CD4+CD25+FOXP3+ und CD4+HLA-G+ regulatorischen T Zellen (Treg) und auf die antiproliferative Funktion von FOXP3+ Treg zu untersuchen. Zentrale Hypothese war, dass Natalizumab über eine universelle Blockade der Immunzellinvasion in das ZNS hinaus immunmodulatorisch wirkt. Unter Verwendung eines prospektiven, longitudinalen Studiendesigns wurden die T Zellen von RR-MS Patienten unter Therapie mit Natalizumab (n=31) sowie von stabilen RR-MS Patienten ohne Therapie und gesunden Spendern in jeweils zwei in vitro Modellen der Blut-Hirn-Schranke sowie Treg vermittelter Immuntoleranz untersucht. FOXP3+ regulatorische T-Zellen banden weniger Natalizumab und exprimierten weniger VLA-4 als nicht-regulatorische T Helferzellen, bewahrten unter Therapie jedoch einen höheren Anteil ihrer ursprünglichen VLA-4 Expression. FOXP3+ Treg gesunder Spender wiesen in vitro höhere Migrationsraten über mikrovaskuläre humane Hirnendothelzellen als nicht-regulatorische T Helferzellen auf und akkumulierten innerhalb der T-Zell Population nach Migration. Dagegen reicherten sich FOXP3+ Treg von MS Patienten in Folge der Migration nur nach Vorbehandlung des Endothel mit inflammatorischen Zytokinen an, nicht jedoch ohne diese Vorbehandlung. Natalizumab beeinträchtigte die transendotheliale Migration von FOXP3+ Treg und nicht-regulatorischen T Helferzellen von MS Patienten in vergleichbaren Ausmaßen. HLA-G+ Treg zeigten in den Migrationsanalysen ein den FOXP3+ Treg entgegengesetztes Muster und wiesen ausschließlich in der MS, nicht jedoch im Gesunden, eine höhere Migrationsrate auf als HLA-G- T Helferzellen. Diese Akkumulation von HLA-G+ Treg in der migrierten Zellfraktion ließ sich nach Therapiebeginn nicht mehr nachweisen. Eine ergänzende Einzelfallstudie zu Auswirkungen des LFA-1 Antagonisten Efalizumab auf Treg ergab Hinweise auf eine Schlüsselfunktion dieses Integrins für die Migration von FOXP3+ Treg. Die Analyse der FOXP3+ Treg Suppressorfunktion zeigte eine schrittweise Zunahme des suppressiven Einflusses von FOXP3+ Treg auf die Reifung dendritischer Zellen unter Natalizumabtherapie. Zeitlich parallel kam es zu einem Ungleichgewicht in der Expression von LFA-1 auf der Oberfläche von FOXP3+ Treg und nicht-regulatorischen T Helferzellen. Zusammenfassend stützt die Studie die Hypothese immunmodulatorischer Effekte von Natalizumab in der schubförmigen Multiplen Sklerose, insbesondere auf den Antagonismus von regulatorischen und Effektor-T Zellen. Die Arbeit belegt, dass Natalizumab in vivo über die Blockade von VLA-4 hinaus modulatorisch in das Netzwerk von Adhäsionsmolekülen auf T Zellen eingreift. Die Studienergebnisse ergeben ein Überwiegen regulatorischer Einflüsse auf die Reifung dendritischer Zellen unter Therapie. Berichte zum Beitrag von LFA-1 zur Suppressorfunktion von FOXP3+ Treg werden durch Daten der vorliegenden Studie unterstützt und um Hinweise auf eine zusätzliche, spezifische Bedeutung des Integrins zur präferentiellen Diapedese dieser Treg über die Blut-Hirn-Schranke im Gesunden erweitert. Zudem liefert die Arbeit erstmals Hinweise auf einen Defekt der transendothelialen Migration von FOXP3+ Treg über die Blut-Hirn-Schranke in der schubförmigen Multiplen Sklerose, der zur Entstehung neuer Läsionen beitragen könnte. N2 - Relapsing-remitting multiple sclerosis (MS) is a multifocal, chronic, inflammatory, demyelinating disease of the central nervous system (CNS). Autoreactive processes, in particular T-cell mediated immunity, are essential to the pathogenesis of MS. A pivotal step in immunopathogenetic models is the diapedesis of immune cells across the blood-brain barrier. Transendothalial migration of encephalitogenic T cells across the blood-brain barrier depends critically on the interaction between very late antigen 4 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) as well as fibronectin. The therapeutic rationale for natalizumab, a monoclonal antibody against the α4 chain of VLA-4, is based on this pivotal role of VLA-4 for T-cell diapedesis. This study aimed to examine transendothelial migration of CD4+CD25+FOXP3+ and CD4+HLA-G+ regulatory T cells (Treg) as well as the suppressive capacity of FOXP3+ Treg in relapsing-remitting multiple sclerosis under natalizumab therapy. The study tested the hypothesis that natalizumab exerts immunmodulatory effects beyond a universal blockade of immune cell invasion into the CNS. T cells from MS patients under natalizumab therapy (n=31) were compared to T cells from stable MS patients without treatment and from healthy controls according to a prospective, longitudinal study design. Two in vitro models of the blood-brain barrier and two models of Treg-mediated tolerance were employed. FOXP3+ regulatory T cells exhibited reduced natalizumab binding and VLA-4 expression when compared to non-regulatory T helper cells but preserved a greater proportion of their initial VLA-4 expression under natalizumab therapy. FOXP3+ Treg from healthy controls showed enhanced migration across human brain microvascular endothelial cells when compared to non-regulatory T cells in vitro and accumulated within the T-cell population after migration. FOXP3+ Treg from MS patients, in contrast, accumulated only after pre-treatment of the endothelium with inflammatory cytokines. Natalizumab inhibited transendothelial migration of FOXP3+ Treg and non-regulatory T cells to a similar extent. HLA-G+ Treg showed a reverse pattern in these migration assays: HLA-G+ Treg from MS patients, but not from healthy controls, exhibited enhanced migratory rates when compared to non-regulatory, HLA-G- TH cells. This accumulation of HLA-G+ Treg within the fraction of migrated cells could no longer be detected any more after initiation of natalizumab therapy. The results of a supplementary single case study on the effects of the LFA-1 antagonist efalizumab on Treg pointed towards a pivotal role of this integrin for the preferential migration of FOXP3+ Treg. Suppression of the maturation of dendritic cells by FOXP3+ Treg gradually increased under natalizumab therapy. A growing imbalance in the surface distribution of LFA-1 among FOXP3+ Treg and non-regulatory TH cells parallelled this recovery of MS Treg suppression. In summary, this study supports the hypothesis of immunomodulatory effects of natalizumab in relapsing-remitting multiple sclerosis, particularly on the antagonism between regulatory and effector T cells. The study documents interference of natalizumab with the network of adhesion molecules on T cells in vivo that extends beyond its blockade of VLA-4. Furthermore, it demonstrates a dominance of Treg-mediated suppression on the maturation of dendritic cells under therapy. It supports recent reports on a pivotal role of LFA-1 for suppressive mechanisms of FOXP3+ Treg and points towards a similar relevance for preferential Treg migration across the blood-brain barrier. Lastly, the study provides the first evidence for deficient transendothelial migration of FOXP3+ Treg in multiple sclerosis, which could contribute to early lesion formation. KW - Neuroimmunologie KW - Multiple Sklerose KW - Natalizumab KW - regulatorische T Zellen KW - FOXP3 KW - HLA-G KW - Diapedese KW - natalizumab KW - regulatory T cells KW - FOXP3 KW - HLA-G KW - diapedesis Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-70573 ER - TY - JOUR A1 - Sommer, Claudia A1 - Richter, Helmut A1 - Rogausch, Jan P. A1 - Frettloh, Jule A1 - Lungenhausen, Margitta A1 - Maier, Christoph T1 - A modified score to identify and discriminate neuropathic pain: a study on the German version of the neuropathic pain symptom inventory (NPSI) N2 - Background: Neuropathic pain must be correctly diagnosed for optimal treatment. The questionnaire named Neuropathic Pain Symptom Inventory (NPSI) was developed in its original French version to evaluate the different symptoms of neuropathic pain. We hypothesized that the NPSI might also be used to differentiate neuropathic from non-neuropathic pain. Methods: We translated the NPSI into German using a standard forward-backward translation and administered it in a case-control design to patients with neuropathic (n = 68) and non-neuropathic pain (headache and osteoarthritis, n = 169) to validate it and to analyze its discriminant properties, its sensitivity to change, and to detect neuropathic pain subgroups with distinct profiles. Results: Using a sum score (the NPSI-G score), we found sensitivity to change (r between 0.37 and 0.5 for pain items of the graded chronic pain scale) and could distinguish between neuropathic and other pain on a group basis, but not for individual patients. Post hoc development of a discriminant score with optimized diagnostic properties to distinguish neuropathic pain from non-neuropathic pain resulted in an instrument with high sensitivity (91%) and acceptable specificity (70%). We detected six different pain profiles in the patient group with neuropathic pain; three profiles were found to be distinct. Conclusions: The NPSI-G potentially combines the properties of a diagnostic tool and an instrument to identify subtypes of neuropathic pain. KW - Neuralgie KW - NPSI Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68716 ER - TY - JOUR A1 - Kreissl, Michael C. A1 - Stout, David B. A1 - Wong, Koon-Pong A1 - Wu, Hsiao-Ming A1 - Caglayan, Evren A1 - Ladno, Waldemar A1 - Zhang, Xiaoli A1 - Prior, John A1 - Reiners, Christoph A1 - Huang, Sung-Cheng A1 - Schelbert, Heinrich R. T1 - Influence of Dietary Interventions and Insulin on Myocardial, Skeletal Muscle and Brain [18F]-Fluorodeoxyglucose Kinetics in Mice N2 - Background: We evaluated the effect of insulin stimulation and dietary changes on myocardial, skeletal muscle and brain [18F]-fluorodeoxyglucose (FDG) kinetics and uptake in vivo in intact mice. Methods: Mice were anesthetized with isoflurane and imaged under different conditions: non-fasted (n = 7; "controls"), non-fasted with insulin (2 IU/kg body weight) injected subcutaneously immediately prior to FDG (n = 6), fasted (n = 5), and fasted with insulin injection (n = 5). A 60-min small-animal PET with serial blood sampling and kinetic modeling was performed. Results: We found comparable FDG standardized uptake values (SUVs) in myocardium in the non-fasted controls and non-fasted-insulin injected group (SUV 45-60 min, 9.58 ± 1.62 vs. 9.98 ± 2.44; p = 0.74), a lower myocardial SUV was noted in the fasted group (3.48 ± 1.73; p < 0.001). In contrast, the FDG uptake rate constant (Ki) for myocardium increased significantly by 47% in non-fasted mice by insulin (13.4 ± 3.9 ml/min/100 g vs. 19.8 ± 3.3 ml/min/100 g; p = 0.030); in fasted mice, a lower myocardial Ki as compared to controls was observed (3.3 ± 1.9 ml/min/100 g; p < 0.001). Skeletal muscle SUVs and Ki values were increased by insulin independent of dietary state, whereas in the brain, those parameters were not influenced by fasting or administration of insulin. Fasting led to a reduction in glucose metabolic rate in the myocardium (19.41 ± 5.39 vs. 3.26 ± 1.97 mg/min/100 g; p < 0.001), the skeletal muscle (1.06 ± 0.34 vs. 0.34 ± 0.08 mg/min/100 g; p = 0.001) but not the brain (3.21 ± 0.53 vs. 2.85 ± 0.25 mg/min/100 g; p = 0.19). Conclusions: Changes in organ SUVs, uptake rate constants and metabolic rates induced by fasting and insulin administration as observed in intact mice by small-animal PET imaging are consistent with those observed in isolated heart/muscle preparations and, more importantly, in vivo studies in larger animals and in humans. When assessing the effect of insulin on the myocardial glucose metabolism of non-fasted mice, it is not sufficient to just calculate the SUV - dynamic imaging with kinetic modeling is necessary. KW - Insulin KW - Gehirn KW - Skelettmuskel KW - Maus Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68775 ER -