TY - JOUR A1 - Frerichs, K. A1 - Sirèn, Anna-Leena A1 - Feuerstein, G. A1 - Hallenbeck, JM T1 - The onset of postischemic hypoperfusion in rats is precipitous and may be controlled by local neurons N2 - Background and Purpose: Reperfusion following transient global cerebral ischemia is characterized by an initial hyperemic phase, which precedes hypo perfusion. The pathogenesis of these flow derangements remains obscure. Our study investigates the dynamics of postischemic cerebral blood flow changes, with particular attention to the role of local neurons. Metho(Js: We assessed local cortical blood flow continuously by laser Doppler flowmetry to permit observation of any rapid flow changes after forebrain ischemia induced by four-vessel occlusion for 20 minutes in rats. To investigate the role of local cortical neurons in the regulation of any blood flow fluctuations, five rats received intracortical microinjections of a neurotoxin (10 p,g ibotenic acid in 1 p,1; 1.5-mm-depth parietal cortex) 24 hours before ischemia to induce selective and localized neuronal depletion in an area corresponding to the sampie volume of the laser Doppler probe (1 mm3 ). Local cerebral blood flow was measured within the injection site and at an adjacent control site. Results: Ischemia was followed by marked hyperemia (235 ±23% of control, n =7), followed by secondary hypoperfusion (45±3% of control, n=7). The transition from hyperemia to hypoperfusioo occurred not gradually but precipitously (maximal slope of flow decay: 66±6%/min; n=7). In ibotenic acid-injected rats, hyperemia was preserved at the injection site, but the sudden decline of blood flow was abolished (maximal slope of flow decay: 5±3%/min compared with 53±8%/min at the control site; n=5, p=40y) and 2/13 (<40y) respectively. Conclusions: Neuropathic pain and sensory deficits of the distal extremities are common in patients with Fabry’s disease. QST and IENFD analysis are important for early diagnosis of nerve involvement in Fabry’s disease. Small fiber function may improve under ERT in patients without severe renal impairment. KW - Fabry’s disease KW - neuropathic pain KW - QST KW - IENFD KW - ERT KW - Fabry’s disease KW - neuropathic pain KW - QST KW - IENFD KW - ERT Y1 - 2009 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-32844 ER - TY - THES A1 - Yu-Hwa, Huang T1 - The Role of HLA-G-expressing Regulatory T cells in Multiple Sclerosis: A Perspective of Beneficial Inflammation in the Central Nervous System Inflammation T1 - Die Rolle HLA-G-exprimierender regulatorischer T-Zellen in multipler Sklerose: Möglichkeit einer hilfreichen Entzündung bei Entzündungserkrankung des zentralen Nervensystems N2 - Die Regulation von Effektor-T-Zellen ist ein wichtiger Mechanismus zur Kontrolle organspezifischer Entzündungen. Dabei sind regulatorische T-Zellen (Treg) maßgeblich an der Aufrechterhaltung peripherer Immuntoleranz und parenchymaler Immunhomöostase beteiligt. Eine neue Population von humanen, natürlich vorkommenden Treg Zellen wurde durch ihre konstitutive Expression des immuntolerogenen Moleküls HLA-G identifiziert. Im ersten Teil dieser Arbeit wurden die Mechanismen, durch die CD4+ HLA-Gpos Treg Zellen ihre Zielzellen (autologe HLA-Gneg T-Zellen) modulieren, aufgeklärt. Unter Verwendung eines Suppressionsansatzes in Abwesenheit von antigenpräsentierenden Zellen (APC) wurden T-T-Zell-Interaktionen, die die Proliferation von HLA-Gneg T-Zellen hemmen, demonstriert. Diese Suppression, die durch die Stimulierung des T-Zell-Rezeptors auf HLA-Gpos Treg Zellen verstärkt wurde, war unabhängig vom Zell-Zell-Kontakt. Die HLA-Gneg T-Zellen erlangten nach Entfernung der HLA-Gpos Treg Zellen und einer erneuten Stimulierung ihrer T-Zell- Rezeptoren ihre Fähigkeit zur Proliferation wieder. Dies wies auf die Umkehrbarkeit dieser Suppression hin. Darüber hinaus war die HLA-Gpos Treg-vermittelte Suppression entscheidend von der IL-10- Sekretion, nicht jedoch von TGF-β abhängig. Zusammengefasst beschreibt dieser Teil der Arbeit eine detaillierte Charakterisierung der Mechanismen, wie HLA-Gpos Treg HLA-Gneg TZellen supprimieren. Das tiefere Verständnis der Wirkmechanismen von HLA-Gpos Treg könnte in therapeutischen Strategien verwendet werden, in denen die regulatorische Funktion der T-Zell-Suppression verstärkt oder moduliert werden soll. Im zweiten Teil dieser Arbeit wurde die potenzielle Rolle von HLA-Gpos Treg bei der Multiplen Sklerose (MS) untersucht, einer klassischen Autoimmunerkrankung des Zentralnervensystems (ZNS). Im Gegensatz zu Vergleichspatienten mit nicht-entzündlichen Erkrankungen konnte im Liquor von MS Patienten eine erhöhte Anzahl von HLA-Gpos Treg gefunden werden. Diese aus dem Liquor isolierten HLA-Gpos Treg wiesen phänotypische Merkmale von zentralen Gedächtnis-T-Zellen (CD45RA- CD27+) auf, exprimierten den Aktivierungsmarker ICOS sowie deutlich höhere Level des Chemokinrezeptors (CCR) CCR5 und agierten als starke Suppressoren der autologen CD4+ T-Zellproliferation. Durch Verwendung eines in vitro Modells der humanen Bluthirnschranke konnte demonstriert werden, dass HLA-Gpos Treg eine starke Neigung zur Migration haben, die durch die CCR5- Liganden MIP1α und RANTES, nicht jedoch durch MIP3β (Ligand von CCR7) unterstützt wird. Diese Chemokin-induzierte Migration von HLA-Gpos Treg war auch mit einer Steigerung der suppressiven Kapazität nach Zelltransmigration assoziiert. Im Gegensatz zu CD4+CD25+, FoxP3-exprimierenden Treg zeigten HLA-Gpos Treg von MS-Patienten keine beeinträchtigte Funktionalität. Dies deutet auf eine selektive Rekrutierung von HLA-Gpos Treg zu Entzündungsherden im ZNS und ihre Beteiligung an der Bekämpfung der destruktiven Entzündung hin. Die Ergebnisse dieser Studien tragen zum weitergehenden Verständnis der Rolle und Funktion HLA-Gpos Treg Zellen bei und stellen somit ein wichtiges pathophysiologisches Beispiel „gutartiger“ T-Zell-Entzündung während der ZNS Autoimmunität dar, das sowohl aus pathophysiologischer als auch therapeutischer Sicht interessant ist. N2 - Regulation of effector T cells is an important mechanism to control organ-specific inflammation. Thereby regulatory T cells (Treg cells) are essential for maintaining peripheral immune tolerance and for establishing parenchyma immune homeostasis. A novel population of natural human Treg characterized by the constitutive expression of the immune-tolerogenic human HLA-G molecule has been identified. In the first part of the study, we elucidated the mechanism(s) by which CD4+ HLA-Gpos Treg modulates their cellular targets namely autologous HLA-G negative responder T cells (HLAGneg Tresp). Using a suppression system free of antigen-presenting cells (APC), we demonstrate a T-T cell interaction resulting in suppression of HLA-Gneg Tresp. We could also show that this suppression was independent of cell-cell contact. Importantly, stimulus of T cell receptor (TCR) on HLA-Gpos Treg facilitated their suppressive capacity. We also observed that removal of HLA-Gpos Treg from the established co-cultures could restore the ability of HLA-Gneg Tresp to proliferate upon TCR re-stimulation, indicating that the suppression was reversible. Further, HLA-Gpos Treg–mediated suppression was critically depending on the secretion of IL-10 but not TGF-β. Taken together, this part of the work provides an in-depth characterization of the mechanisms of how HLA-Gpos Treg suppresses T responder cells in direct T-T interactions. Understanding the suppressive mechanism used by HLA-Gpos Treg may help to develop therapeutic strategies to modulate regulatory arms of T-cell suppression. In the second part of this study, the potential role of HLA-Gpos Treg in the pathophysiological process of Multiple Sclerosis (MS), a prototypic autoimmune inflammatory central nervous system (CNS), has been investigated. We found that HLA-Gpos Treg are enriched in the cerebrospinal fluid (CSF) from MS patients, but not in non-inflammatory controls. CSFderived HLA-Gpos Treg showed predominance of central memory (CD45RA-CD27+) phenotype, exhibited markers of activation (ICOS), and had significantly higher expression of the inflammatory chemokine receptor CCR5. Importantly, these cells demonstrated as potent suppressors to autologous CD4+ T-cell proliferation. Using an in vitro model of human blood brain barrier, we showed that HLA-Gpos Treg have a strong propensity to migrate, which could be facilitated by MIP1α and RANTES (ligands of CCR5) but not MIP3β (a ligand of CCR7). The HLA-Gpos Treg migration triggered by chemokines was also associated with a gain of suppressive capacity upon cellular transmigration. In contrast to CD4+CD25+ naturally occurring FoxP3-expressing Treg, HLA-Gpos Treg from patients with MS did not exhibit impaired function, suggesting that HLA-Gpos Treg are selectively recruited to the sites of CNS inflammation in an effort to combat destructive inflammation during MS. Our results contribute to the understanding of the role and function of HLA-Gpos Treg and provide an important example of “beneficial” T-cell inflammation in CNS autoimmunity- interesting both from a patho/-physiological and a therapeutically point of view. KW - Regulatorische T-Zellen KW - Multiplen Sklerose KW - HLA-G KW - Zentralnervensystems KW - Chemokinrezeptors KW - Regulatory T cells KW - Multiple Sclerosis KW - HLA-G KW - Central Nervous System KW - Chemokine Receptor Y1 - 2009 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-39957 ER - TY - JOUR A1 - Ueceyler, Nurcan A1 - Biko, Lydia A1 - Sommer, Claudia T1 - MDL-28170 Has No Analgesic Effect on CCI Induced Neuropathic Pain in Mice N2 - The calpain inhibitor MDL-28710 blocks the early local pro-inflammatory cytokine gene expression in mice after chronic constriction nerve injury (CCI). Onehundred- thirteen wild type mice of C57Bl/6J background received CCI of the right sciatic nerve. Mechanical paw withdrawal thresholds and thermal withdrawal latencies were investigated at baseline and at 1, 3, and 7 days after CCI. Three application regimens were used for MDL-28170: a) single injection 40 min before CCI; b) serial injections of MDL- 28170 40 min before and up to day three after CCI; c) sustained application via intraperitoneal osmotic pumps. The control animals received the vehicle DMSO/PEG 400. The tolerable dose of MDL-28170 for mice was 30 mg/kg body weight, higher doses were lethal within the first hours after application. Mechanical withdrawal thresholds and thermal withdrawal latencies were reduced after CCI and did not normalize after single or serial injections, nor with application of MDL-28170 via osmotic pumps. Although the calpain inhibitor MDL-28170 inhibits the early local cytokine upregulation in the sciatic nerve after CCI, pain behavior is not altered. This finding implies that local cytokine upregulation after nerve injury alone is only one factor in the induction and maintenance of neuropathic pain. KW - Medizin KW - calpain KW - neuropathic pain KW - MDL-28170 KW - chronic constriction nerve injury (CCI) Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68359 ER - TY - JOUR A1 - Braeuninger, Stefan A1 - Kleinschnitz, C. A1 - Stoll, G. T1 - Interleukin-18 does not influence infarct volume or functional outcome in the early stage after transient focal brain ischemia in mice N2 - Interleukin-18 (IL-18) is a proinflammatory cytokine of the interleukin-1 family which is upregulated after cerebral ischemia. The functional role of IL-18 in cerebral ischemia is unknown. In the present study, we compared infarct size in IL-18 knock-out and wild-type mice 24 hours and 48 hours after 1-hour transient middle cerebral artery occlusion (tMCAO). Moreover, the functional outcome was evaluated in a modified Bederson score, foot fault test and grip test. There were no significant differences in infarct size or functional outcome tests between wild-type and IL-18 knock-out mice. These data indicate that the early inflammatory response to cerebral ischemia does not involve IL-18, in contrast to other interleukin-1 family members such as interleukin-1. KW - Interleukin-18 Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68141 ER - TY - JOUR A1 - Chen, Yong A1 - Boettger, Michael K. A1 - Reif, Andreas A1 - Schmitt, Angelika A1 - Ueceyler, Nurcan A1 - Sommer, Claudia T1 - Nitric oxide synthase modulates CFA-induced thermal hyperalgesia through cytokine regulation in mice N2 - Background: Although it has been largely demonstrated that nitric oxide synthase (NOS), a key enzyme for nitric oxide (NO) production, modulates inflammatory pain, the molecular mechanisms underlying these effects remain to be clarified. Here we asked whether cytokines, which have well-described roles in inflammatory pain, are downstream targets of NO in inflammatory pain and which of the isoforms of NOS are involved in this process. Results: Intraperitoneal (i.p.) pretreatment with 7-nitroindazole sodium salt (7-NINA, a selective neuronal NOS inhibitor), aminoguanidine hydrochloride (AG, a selective inducible NOS inhibitor), L-N(G)-nitroarginine methyl ester (L-NAME, a non-selective NOS inhibitor), but not L-N(5)-(1-iminoethyl)-ornithine (L-NIO, a selective endothelial NOS inhibitor), significantly attenuated thermal hyperalgesia induced by intraplantar (i.pl.) injection of complete Freund’s adjuvant (CFA). Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed a significant increase of nNOS, iNOS, and eNOS gene expression, as well as tumor necrosis factor-alpha (TNF), interleukin-1 beta (IL-1b), and interleukin-10 (IL-10) gene expression in plantar skin, following CFA. Pretreatment with the NOS inhibitors prevented the CFA-induced increase of the pro-inflammatory cytokines TNF and IL-1b. The increase of the antiinflammatory cytokine IL-10 was augmented in mice pretreated with 7-NINA or L-NAME, but reduced in mice receiving AG or L-NIO. NNOS-, iNOS- or eNOS-knockout (KO) mice had lower gene expression of TNF, IL-1b, and IL-10 following CFA, overall corroborating the inhibitor data. Conclusion: These findings lead us to propose that inhibition of NOS modulates inflammatory thermal hyperalgesia by regulating cytokine expression. KW - Medizin Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68349 ER - TY - JOUR A1 - Kraft, P. A1 - Schwarz, T. A1 - Pochet, L. A1 - Stoll, G. A1 - Kleinschnitz, Christoph T1 - COU254, a specific 3-carboxamide-coumarin inhibitor of coagulation factor XII, does not protect mice from acute ischemic stroke N2 - Background: Anticoagulation is an important means to prevent from acute ischemic stroke but is associated with a significant risk of severe hemorrhages. Previous studies have shown that blood coagulation factor XII (FXII)- deficient mice are protected from pathological thrombus formation during cerebral ischemia without bearing an increased bleeding tendency. Hence, pharmacological blockade of FXII might be a promising and safe approach to prevent acute ischemic stroke and possibly other thromboembolic disorders but pharmacological inhibitors selective over FXII are still lacking. In the present study we investigated the efficacy of COU254, a novel nonpeptidic 3-carboxamide-coumarin that selectively blocks FXII activity, on stroke development and post stroke functional outcome in mice. Methods: C57Bl/6 mice were treated with COU254 (40 mg/kg i.p.) or vehicle and subjected to 60 min transient middle cerebral artery occlusion (tMCAO) using the intraluminal filament method. After 24 h infarct volumes were determined from 2,3,5-Triphenyltetrazoliumchloride(TTC)-stained brain sections and functional scores were assessed. Hematoxylin and eosin (H&E) staining was used to estimate the extent of neuronal cell damage. Thrombus formation within the infarcted brain areas was analyzed by immunoblot. Results: Infarct volumes and functional outcomes on day 1 after tMCAO did not significantly differ between COU254 pre-treated mice or untreated controls (p > 0.05). Histology revealed extensive ischemic neuronal damage regularly including the cortex and the basal ganglia in both groups. COU254 treatment did not prevent intracerebral fibrin(ogen) formation. Conclusions: COU254 at the given concentration of 40 mg/kg failed to demonstrate efficacy in acute ischemic stroke in this preliminary study. Further preclinical evaluation of 3-carboxamide-coumarins is needed before the antithrombotic potential of this novel class of FXII inhibitors can be finally judged. KW - Schlaganfall KW - Maus KW - COU254 Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68103 ER - TY - JOUR A1 - Pham, Mirko A1 - Helluy, X. A1 - Braeuninger, S. A1 - Jakob, P. A1 - Stoll, G. A1 - Kleinschnitz, Christoph A1 - Bendszus, M. T1 - Outcome of experimental stroke in C57Bl/6 and Sv/129 mice assessed by multimodal ultra-high field MRI N2 - Transgenic mice bred on C57Bl/6 or Sv/129 genetic background are frequently used in stroke research. It is well established that variations in cerebrovascular anatomy and hemodynamics can influence stroke outcome in different inbred mouse lines. We compared stroke development in C57Bl/6 and Sv/129 mice in the widely used model of transient middle cerebral artery occlusion (tMCAO) by multimodal ultra-high field magnetic resonance imaging (MRI). C57Bl/6 and Sv/129 mice underwent 60 min of tMCAO and were analyzed by MRI 2 h and 24 h afterwards. Structural and functional images were registered to a standard anatomical template. Probability maps of infarction were rendered by automated segmentation from quantitative T2-relaxometric images. Whole-brain segmentation of infarction was accomplished manually on high-resolution T2-weighted (T2-w) RARE images. Cerebral perfusion (cerebral blood flow, CBF) was measured quantitatively by modified continuous arterial-spin-labeling (CASL) and apparent diffusion coefficients (ADC) by spin-echo diffusion-weighted imaging (DWI). Probabilities of cortical (95.1% ± 3.1 vs. 92.1% ± 2.5; p > 0.05) and subcortical (100% vs. 100%; p > 0.05) infarctions at 24 h were similar in both groups as was the whole-brain volumetric extent of cerebral infarction. In addition, CBF and ADC values did not differ between C57Bl/6 and Sv/129 mice at any time point or region of interest. The C57Bl/6 and Sv/129 genetic background is no major confounding factor of infarct size and cerebral perfusion in the tMCAO model. KW - NMR-Tomographie Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68115 ER - TY - JOUR A1 - Ehling, P. A1 - Bittner, S. A1 - Bobak, N. A1 - Schwarz, T. A1 - Wiendl, H. A1 - Budde, T. A1 - Kleinschnitz, Christoph A1 - Meuth, S. G. T1 - Two pore domain potassium channels in cerebral ischemia: a focus on K2p9.1 (TASK3, KCNK9) N2 - BACKGROUND: Recently, members of the two-pore domain potassium channel family (K2P channels) could be shown to be involved in mechanisms contributing to neuronal damage after cerebral ischemia. K2P3.1-/- animals showed larger infarct volumes and a worse functional outcome following experimentally induced ischemic stroke. Here, we question the role of the closely related K2P channel K2P9.1. METHODS: We combine electrophysiological recordings in brain-slice preparations of wildtype and K2P9.1-/- mice with an in vivo model of cerebral ischemia (transient middle cerebral artery occlusion (tMCAO)) to depict a functional impact of K2P9.1 in stroke formation. RESULTS: Patch-clamp recordings reveal that currents mediated through K2P9.1 can be obtained in slice preparations of the dorsal lateral geniculate nucleus (dLGN) as a model of central nervous relay neurons. Current characteristics are indicative of K2P9.1 as they display an increase upon removal of extracellular divalent cations, an outward rectification and a reversal potential close to the potassium equilibrium potential. Lowering extracellular pH values from 7.35 to 6.0 showed comparable current reductions in neurons from wildtype and K2P9.1-/- mice (68.31 +/- 9.80% and 69.92 +/- 11.65%, respectively). These results could be translated in an in vivo model of cerebral ischemia where infarct volumes and functional outcomes showed a none significant tendency towards smaller infarct volumes in K2P9.1-/- animals compared to wildtype mice 24 hours after 60 min of tMCAO induction (60.50 +/- 17.31 mm3 and 47.10 +/- 19.26 mm3, respectively). CONCLUSIONS: Together with findings from earlier studies on K2P2.1-/- and K2P3.1-/- mice, the results of the present study on K2P9.1-/- mice indicate a differential contribution of K2P channel subtypes to the diverse and complex in vivo effects in rodent models of cerebral ischemia. KW - Kaliumkanal KW - Ischemia Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68129 ER - TY - JOUR A1 - Haarmann, Axel A1 - Deiss, Annika A1 - Prochaska, Juergen A1 - Foerch, Christian A1 - Weksler, Babette A1 - Romero, Ignacio A1 - Couraud, Pierre-Olivier A1 - Stoll, Guido A1 - Rieckmann, Peter A1 - Buttmann, Mathias T1 - Evaluation of Soluble Junctional Adhesion Molecule-A as a Biomarker of Human Brain Endothelial Barrier Breakdown N2 - Background: An inducible release of soluble junctional adhesion molecule-A (sJAM-A) under pro-inflammatory conditions was described in cultured non-CNS endothelial cells (EC) and increased sJAM-A serum levels were found to indicate inflammation in non-CNS vascular beds. Here we studied the regulation of JAM-A expression in cultured brain EC and evaluated sJAM-A as a serum biomarker of blood-brain barrier (BBB) function. Methodology/Principal Findings: As previously reported in non-CNS EC types, pro-inflammatory stimulation of primary or immortalized (hCMEC/D3) human brain microvascular EC (HBMEC) induced a redistribution of cell-bound JAM-A on the cell surface away from tight junctions, along with a dissociation from the cytoskeleton. This was paralleled by reduced immunocytochemical staining of occludin and zonula occludens-1 as well as by increased paracellular permeability for dextran 3000. Both a self-developed ELISA test and Western blot analysis detected a constitutive sJAM-A release by HBMEC into culture supernatants, which importantly was unaffected by pro-inflammatory or hypoxia/reoxygenation challenge. Accordingly, serum levels of sJAM-A were unaltered in 14 patients with clinically active multiple sclerosis compared to 45 stable patients and remained unchanged in 13 patients with acute ischemic non-small vessel stroke over time. Conclusion: Soluble JAM-A was not suited as a biomarker of BBB breakdown in our hands. The unexpected non-inducibility of sJAM-A release at the human BBB might contribute to a particular resistance of brain EC to inflammatory stimuli, protecting the CNS compartment. KW - Biomarker KW - Gehirn Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68468 ER - TY - JOUR A1 - Doerck, Sebastian A1 - Goebel, Kerstin A1 - Weise, Gesa A1 - Schneider-Hohendorf, Tilman A1 - Reinhardt, Michael A1 - Hauff, Peter A1 - Schwab, Nicholas A1 - Linker, Ralf A1 - Maeurer, Mathias A1 - Meuth, Sven G. A1 - Wiendl, Heinz T1 - Temporal Pattern of ICAM-I Mediated Regulatory T Cell Recruitment to Sites of Inflammation in Adoptive Transfer Model of Multiple Sclerosis N2 - Migration of immune cells to the target organ plays a key role in autoimmune disorders like multiple sclerosis (MS). However, the exact underlying mechanisms of this active process during autoimmune lesion pathogenesis remain elusive. To test if pro-inflammatory and regulatory T cells migrate via a similar molecular mechanism, we analyzed the expression of different adhesion molecules, as well as the composition of infiltrating T cells in an in vivo model of MS, adoptive transfer experimental autoimmune encephalomyelitis in rats. We found that the upregulation of ICAM-I and VCAM-I parallels the development of clinical disease onset, but persists on elevated levels also in the phase of clinical remission. However, the composition of infiltrating T cells found in the developing versus resolving lesion phase changed over time, containing increased numbers of regulatory T cells (FoxP3) only in the phase of clinical remission. In order to test the relevance of the expression of cell adhesion molecules, animals were treated with purified antibodies to ICAM-I and VCAM-I either in the phase of active disease or in early remission. Treatment with a blocking ICAM-I antibody in the phase of disease progression led to a milder disease course. However, administration during early clinical remission aggravates clinical symptoms. Treatment with anti-VCAM-I at different timepoints had no significant effect on the disease course. In summary, our results indicate that adhesion molecules are not only important for capture and migration of pro-inflammatory T cells into the central nervous system, but also permit access of anti-inflammatory cells, such as regulatory T cells. Therefore it is likely to assume that intervention at the blood brain barrier is time dependent and could result in different therapeutic outcomes depending on the phase of CNS lesion development. KW - Multiple Sklerose Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68565 ER - TY - JOUR A1 - Kraft, Peter A1 - Schwarz, Tobias A1 - Meijers, Joost C. M. A1 - Stoll, Guido A1 - Kleinschnitz, Christoph T1 - Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Deficient Mice Are Susceptible to Intracerebral Thrombosis and Ischemic Stroke N2 - Background: Thrombus formation is a key step in the pathophysiology of acute ischemic stroke and results from the activation of the coagulation cascade. Thrombin plays a central role in this coagulation system and contributes to thrombus stability via activation of thrombin-activatable fibrinolysis inhibitor (TAFIa). TAFIa counteracts endogenous fibrinolysis at different stages and elevated TAFI levels are a risk factor for thrombotic events including ischemic stroke. Although substantial in vitro data on the influence of TAFI on the coagulation-fibrinolysis-system exist, investigations on the consequences of TAFI inhibition in animal models of cerebral ischemia are still lacking. In the present study we analyzed stroke development and post stroke functional outcome in TAFI-/- mice. Methodology/Principal Findings: TAFI-/- mice and wild-type controls were subjected to 60 min transient middle cerebral artery occlusion (tMCAO) using the intraluminal filament method. After 24 hours, functional outcome scores were assessed and infarct volumes weremeasured from 2,3,5-Triphenyltetrazoliumchloride (TTC)-stained brain slices. Hematoxylin and eosin (H&E) staining was used to estimate the extent of neuronal cell damage. Thrombus formation within the infarcted brain areas was analyzed by immunoblot. Infarct volumes and functional outcomes did not significantly differ between TAFI-/- mice and controls (p.0.05). Histology revealed extensive ischemic neuronal damage regularly including the cortex and the basal ganglia in both groups. TAFI deficiency also had no influence on intracerebral fibrin(ogen) formation after tMCAO. Conclusion: Our study shows that TAFI does not play a major role for thrombus formation and neuronal degeneration after ischemic brain challenge. KW - Thrombus Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68519 ER - TY - JOUR A1 - Kraft, Peter A1 - Benz, Peter Michael A1 - Austinat, Madeleine A1 - Brede, Marc Elmar A1 - Schuh, Kai A1 - Walter, Ulrich A1 - Stoll, Guido A1 - Kleinschnitz, Christoph T1 - Deficiency of Vasodilator-Stimulated Phosphoprotein (VASP) Increases Blood-Brain-Barrier Damage and Edema Formation after Ischemic Stroke in Mice N2 - Background: Stroke-induced brain edema formation is a frequent cause of secondary infarct growth and deterioration of neurological function. The molecular mechanisms underlying edema formation after stroke are largely unknown. Vasodilator-stimulated phosphoprotein (VASP) is an important regulator of actin dynamics and stabilizes endothelial barriers through interaction with cell-cell contacts and focal adhesion sites. Hypoxia has been shown to foster vascular leakage by downregulation of VASP in vitro but the significance of VASP for regulating vascular permeability in the hypoxic brain in vivo awaits clarification. Methodology/Principal Findings: Focal cerebral ischemia was induced in Vasp2/2 mice and wild-type (WT) littermates by transient middle cerebral artery occlusion (tMCAO). Evan’s Blue tracer was applied to visualize the extent of blood-brainbarrier (BBB) damage. Brain edema formation and infarct volumes were calculated from 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain slices. Both mouse groups were carefully controlled for anatomical and physiological parameters relevant for edema formation and stroke outcome. BBB damage (p,0.05) and edema volumes (1.7 mm360.5 mm3 versus 0.8 mm360.4 mm3; p,0.0001) were significantly enhanced in Vasp2/2 mice compared to controls on day 1 after tMCAO. This was accompanied by a significant increase in infarct size (56.1 mm3617.3 mm3 versus 39.3 mm3610.7 mm3, respectively; p,0.01) and a non significant trend (p.0.05) towards worse neurological outcomes. Conclusion: Our study identifies VASP as critical regulator of BBB maintenance during acute ischemic stroke. Therapeutic modulation of VASP or VASP-dependent signalling pathways could become a novel strategy to combat excessive edema formation in ischemic brain damage. KW - Vasodilatator-stimuliertes Phosphoprotein KW - Vasodilator-Stimulated Phosphoprotein Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68522 ER - TY - JOUR A1 - Kleinschnitz, Christoph A1 - Grund, Henrike A1 - Wingler, Kirstin A1 - Armitage, Melanie E. A1 - Jones, Emma A1 - Mittal, Manish A1 - Barit, David A1 - Schwarz, Tobias A1 - Geis, Christian A1 - Kraft, Peter A1 - Barthel, Konstanze A1 - Schuhmann, Michael K. A1 - Herrmann, Alexander M. A1 - Meuth, Sven G. A1 - Stoll, Guido A1 - Meurer, Sabine A1 - Schrewe, Anja A1 - Becker, Lore A1 - Gailus-Durner, Valerie A1 - Fuchs, Helmut A1 - Klopstock, Thomas A1 - de Angelis, Martin Hrabe A1 - Jandeleit-Dahm, Karin A1 - Shah, Ajay M. A1 - Weissmann, Norbert A1 - Schmidt, Harald H. H. W. T1 - Post-Stroke Inhibition of Induced NADPH Oxidase Type 4 Prevents Oxidative Stress and Neurodegeneration N2 - Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox42/2) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox42/2 mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy. KW - Schlaganfall Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68416 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 - 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 - 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 - 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 - TY - JOUR A1 - Puschmann, Anne-Katrin A1 - Sommer, Claudia T1 - Hypervigilance or avoidance of trigger related cues in migraineurs? - A case-control study using the emotional stroop task N2 - Background: “Negative affect” is one of the major migraine triggers. The aim of the study was to assess attentional biases for negative affective stimuli that might be related to migraine triggers in migraine patients with either few or frequent migraine and healthy controls. Methods: Thirty-three subjects with frequent migraine (FM) or with less frequent episodic migraine, and 20 healthy controls conducted two emotional Stroop tasks in the interictal period. In task 1, general affective words and in task 2, pictures of affective faces (angry, neutral, happy) were used. For each task we calculated two emotional Stroop indices. Groups were compared using one-way ANOVAs. Results: The expected attentional bias in migraine patients was not found. However, in task 2 the controls showed a significant attentional bias to negative faces, whereas the FM group showed indices near zero. Thus, the FM group responded faster to negative than to positive stimuli. The difference between the groups was statistically significant. Conclusions: The findings in the FM group may reflect a learned avoidance mechanism away from affective migraine triggers. KW - Migräne Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-69103 ER - TY - THES A1 - Subramanian, Narayan T1 - Role of NaV1.9 in activity dependent axon growth in embryonic cultured motoneurons T1 - Die Rolle der NaV1.9 in Aktivität abhängig Axonwachstum in embryonalen kultivierten Motoneuronen N2 - Spontaneous neural activity has been shown to regulate crucial events in neurite growth including axonal branching and path finding. In animal models of spinal muscular atrophy (SMA) cultured embryonic mouse motoneurons show distinct defect in axon elongation and neural activity. This defect is governed by abnormal clustering of Ca2+ channels in the axonal regions and the protruding growth cone area. The mechanisms that regulate the opening of calcium channels in developing motoneurons are not yet clear. The question was addressed by blocking neural activity in embryonic cultured motoneurons by pharmacological inhibition of voltage-gated sodium channels (VGSC) by saxitoxin (STX) and tetrodotoxin (TTX). Low dosages of STX resulted in significant reduction of axon growth and neural activity in cultured motoneurons. This pharmacological treatment did not affect survival of motoneurons in comparison to control motoneurons that was grown in the presence of survival neurotrophic factors BDNF and CNTF. It was also found that STX was 10 times more potent than TTX a common inhibitor of VGSC with a reduced activity on the TTX-insensitive sodium channels NaV1.5, NaV1.8 and NaV1.9. Reverse Transcriptase-PCR experiments revealed the presence of NaV1.9 as the likely candidate that begins to express from embryonic stage sixteen in the mouse spinal cord. Immunolabelling experiments showed that the channel is expressed in the axonal compartments and axonal growth cones in cultured motoneurons. Suppression of NaV1.9 in cultured motoneurons by lentivirus mediated short hairpin-RNA (shRNA) resulted in shorter axon length in comparison with uninfected and scrambled constructs. Further, embryonic motoneurons cultured from NaV1.9 knockout mice also showed a significant reduction in neural activity and axon growth. The findings of this work highlight the role of NaV1.9 as an important contender in regulating activity dependent axon growth in embryonic cultured motoneurons. NaV1.9 could therefore be considered as a prospective molecule that could play an important role in regulating axon growth in motoneuron disease models like spinal muscular atrophy (SMA). N2 - Spontane neuronale Aktivität reguliert essentielle Ereignisse im Neuritenwachstum, wie beispielsweise die axonale Verzweigung und die Erkennung des Wachstumspfades. Motoneurone, die aus Tiermodellen der Spinalen Muskelatrophie (SMA) gewonnen werden, zeigen einen auffälligen Defekt im Streckenwachstum von Axonen und in der neuronalen Aktivität. Dieser Defekt wird von anormaler Clusterbildung von Ca2+ Kanälen in axonalen Regionen und in Wachstumskegeln begleitet. Die Mechanismen, die das Öffnen von Kalziumkanälen in embryonalen Motoneuronen in der Entwicklung regulieren, und die für das aktivitätsabhängige Axonwachstum benötigt werden, sind nicht bekannt. Diese Frage wurde in dieser Studie bearbeitet, indem neuronale Aktivität in embryonalen Motoneuronen durch pharmakologische Inhibition von spannungsabhängigen Natriumkanälen durch Saxitoxin (STX) und Tetrodotoxin blockiert wurde. Geringe Dosen von Saxitoxin bewirkten eine deutliche Reduktion des Axonwachstums und der neuronalen Aktivität in kultivierten Motoneuronen. Diese pharmakologische Behandlung beeinflusste nicht das Überleben von Motoneuronen im Vergleich zu Kontroll-Motoneuronen, die in der Anwesenheit der neurotrophen Faktoren BDNF und CNTF kultiviert wurden. Saxitoxin war etwa 5-10-mal potenter als TTX, ein üblicher Blocker spannungsabhängiger Natriumkanäle mit einer verminderte Aktivität auf die TTX-insensitiven Natriumkanäle NaV1.5, NaV1.8, und NaV1.9. Reverse-Transkriptase-PCR Experimente bestätigten die Anwesenheit von NaV1.9 am Tag E16 (embryonaler Tag 16) im Rückenmark der Maus. NaV1.9 ist ein einzigartiger Typus von einem Natriumkanal welcher in der Lage ist neuronale Erregbarkeit in der Nähe des Ruhemembranpotentials zu steuern. Deshalb war NaV1.9 ein guter Kandidat für einen Kanal, der spontane Erregung in Motoneuronen vermittelt. Immunofärbungen zeigten, dass NaV1.9 in axonalen Kompartimenten und axonalen Wachstumskegeln von kultivierten Motoneuronen exprimiert ist. Die Unterdrückung von NaV1.9 in kultivierten Motoneuronen durch lentiviralexprimierte short hairpin-RNA (shRNA) resultierte in kürzerer Axonlänge, im Vergleich zu nicht-infizierten Motoneuronen oder Motoneuronen, die eine sinnlose Kontroll-shRNA Sequenz exprimierten. Embryonale, kultivierte Motoneurone von NaV1.9 knockout Mäusen zeigten eine signifikante Verringerung der neuronalen Aktivität und verkürzte Axone. Diese Ergebnisse weisen auf eine Bedeutung von NaV1.9 im aktivitätsabhängigen Axonwachstum hin KW - Axon KW - Embryonalentwicklung KW - Motoneuron KW - Natriumkanal KW - Motoneuronen KW - NaV1.9 KW - motoneuron KW - Nav1.9 KW - axon growth Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-57536 ER - TY - RPRT A1 - Magnus, Tim A1 - Linker, Ralf A. A1 - Meuth, Sven G. A1 - Kleinschnitz, Christoph A1 - Korn, Thomas T1 - Report on the 2nd scientific meeting of the "Verein zur Foerderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Oct. 29'th - Oct. 31'st, 2010 N2 - Summary of the scientific contributions to the NEUROWIND meeting 2010: Contributions in the fields of neuroimmunology and neurodegeneration KW - Wissenschaftlicher Nachwuchs KW - Neurologie Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68789 ER - TY - JOUR A1 - Bittner, Stefan A1 - Bobak, Nicole A1 - Feuchtenberger, Martin A1 - Herrmann, Alexander M A1 - Göbel, Kerstin A1 - Kinne, Raimund W A1 - Hansen, Anker J A1 - Budde, Thomas A1 - Kleinschnitz, Christoph A1 - Frey, Oliver A1 - Tony, Hans-Peter A1 - Wiendl, Heinz A1 - Meuth, Sven G T1 - Expression of K\(_2\)\(_P\)5.1 potassium channels on CD4\(^+\)T lymphocytes correlates with disease activity in rheumatoid arthritis patients JF - Arthritis Research & Therapy N2 - Introduction CD4+ T cells express K2P5.1 (TWIK-related acid-sensitive potassium channel 2 (TASK2); KCNK5), a member of the two-pore domain potassium channel family, which has been shown to influence T cell effector functions. Recently, it was shown that K2P5.1 is upregulated upon (autoimmune) T cell stimulation. The aim of this study was to correlate expression levels of K2P5.1 on T cells from patients with rheumatoid arthritis (RA) to disease activity in these patients. Methods Expression levels of K2P5.1 were measured by RT-PCR in the peripheral blood of 58 patients with RA and correlated with disease activity parameters (C-reactive protein levels, erythrocyte sedimentation rates, disease activity score (DAS28) scores). Twenty patients undergoing therapy change were followed-up for six months. Additionally, synovial fluid and synovial biopsies were investigated for T lymphocytes expressing K2P5.1. Results K2P5.1 expression levels in CD4+ T cells show a strong correlation to DAS28 scores in RA patients. Similar correlations were found for serological inflammatory parameters (erythrocyte sedimentation rate, C-reactive protein). In addition, K2P5.1 expression levels of synovial fluid-derived T cells are higher compared to peripheral blood T cells. Prospective data in individual patients show a parallel behaviour of K2P5.1 expression to disease activity parameters during a longitudinal follow-up for six months. Conclusions Disease activity in RA patients correlates strongly with K2P5.1 expression levels in CD4+ T lymphocytes in the peripheral blood in cross-sectional as well as in longitudinal observations. Further studies are needed to investigate the exact pathophysiological mechanisms and to evaluate the possible use of K2P5.1 as a potential biomarker for disease activity and differential diagnosis. KW - neurology Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-139334 VL - 13 IS - R21 ER - TY - JOUR A1 - Puschmann, Anne-Katrin A1 - Sommer, Claudia T1 - Hypervigilance or avoidance of trigger related cues in migraineurs? - A case-control study using the emotional stroop task JF - BMC Neurology N2 - Background "Negative affect" is one of the major migraine triggers. The aim of the study was to assess attentional biases for negative affective stimuli that might be related to migraine triggers in migraine patients with either few or frequent migraine and healthy controls. Methods Thirty-three subjects with frequent migraine (FM) or with less frequent episodic migraine, and 20 healthy controls conducted two emotional Stroop tasks in the interictal period. In task 1, general affective words and in task 2, pictures of affective faces (angry, neutral, happy) were used. For each task we calculated two emotional Stroop indices. Groups were compared using one-way ANOVAs. Results The expected attentional bias in migraine patients was not found. However, in task 2 the controls showed a significant attentional bias to negative faces, whereas the FM group showed indices near zero. Thus, the FM group responded faster to negative than to positive stimuli. The difference between the groups was statistically significant. Conclusions The findings in the FM group may reflect a learned avoidance mechanism away from affective migraine triggers. KW - migraineur KW - cue Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137750 VL - 11 IS - 141 ER - TY - JOUR A1 - Weise, Gesa A1 - Basse-Lüsebrink, Thomas C. A1 - Kleinschnitz, Christoph A1 - Kampf, Thomas A1 - Jakob, Peter M. A1 - Stoll, Guido T1 - In Vivo Imaging of Stepwise Vessel Occlusion in Cerebral Photothrombosis of Mice by \(^{19}\)F MRI JF - PLoS One N2 - Background \(^{19}\)F magnetic resonance imaging (MRI) was recently introduced as a promising technique for in vivo cell tracking. In the present study we compared \(^{19}\)F MRI with iron-enhanced MRI in mice with photothrombosis (PT) at 7 Tesla. PT represents a model of focal cerebral ischemia exhibiting acute vessel occlusion and delayed neuroinflammation. Methods/Principal Findings Perfluorocarbons (PFC) or superparamagnetic iron oxide particles (SPIO) were injected intravenously at different time points after photothrombotic infarction. While administration of PFC directly after PT induction led to a strong \(^{19}\)F signal throughout the entire lesion, two hours delayed application resulted in a rim-like \(^{19}\)F signal at the outer edge of the lesion. These findings closely resembled the distribution of signal loss on T2-weighted MRI seen after SPIO injection reflecting intravascular accumulation of iron particles trapped in vessel thrombi as confirmed histologically. By sequential administration of two chemically shifted PFC compounds 0 and 2 hours after illumination the different spatial distribution of the \(^{19}\)F markers (infarct core/rim) could be visualized in the same animal. When PFC were applied at day 6 the fluorine marker was only detected after long acquisition times ex vivo. SPIO-enhanced MRI showed slight signal loss in vivo which was much more prominent ex vivo indicative for neuroinflammation at this late lesion stage. Conclusion Our study shows that vessel occlusion can be followed in vivo by \(^{19}\)F and SPIO-enhanced high-field MRI while in vivo imaging of neuroinflammation remains challenging. The timing of contrast agent application was the major determinant of the underlying processes depicted by both imaging techniques. Importantly, sequential application of different PFC compounds allowed depiction of ongoing vessel occlusion from the core to the margin of the ischemic lesions in a single MRI measurement. KW - in vivo imaging KW - magnetic resonance imaging KW - macrophages KW - emulsions KW - infarction KW - fluorine KW - prefrontal cortex KW - developmental signaling Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137792 VL - 6 IS - 12 ER - TY - JOUR A1 - Üçeyler, Nurcan A1 - Topuzoğlu, Tengü A1 - Schießer, Peter A1 - Hahnenkamp, Saskia A1 - Sommer, Claudia T1 - IL-4 Deficiency Is Associated with Mechanical Hypersensitivity in Mice JF - PLoS One N2 - Interleukin-4 (IL-4) is an anti-inflammatory and analgesic cytokine that induces opioid receptor transcription. We investigated IL-4 knockout (ko) mice to characterize their pain behavior before and after chronic constriction injury (CCI) of the sciatic nerve as a model for neuropathic pain. We investigated opioid responsivity and measured cytokine and opioid receptor gene expression in the peripheral and central nervous system (PNS, CNS) of IL-4 ko mice in comparison with wildtype (wt) mice. Naïve IL-4 ko mice displayed tactile allodynia (wt: 0.45 g; ko: 0.18 g; p<0.001), while responses to heat and cold stimuli and to muscle pressure were not different. No compensatory changes in the gene expression of tumor necrosis factor-alpha (TNF), IL-1β, IL-10, and IL-13 were found in the PNS and CNS of naïve IL-4 ko mice. However, IL-1β gene expression was stronger in the sciatic nerve of IL-4 ko mice (p<0.001) 28 days after CCI and only IL-4 ko mice had elevated IL-10 gene expression (p = 0.014). Remarkably, CCI induced TNF (p<0.01), IL-1β (p<0.05), IL-10 (p<0.05), and IL-13 (p<0.001) gene expression exclusively in the ipsilateral spinal cord of IL-4 ko mice. The compensatory overexpression of the anti-inflammatory and analgesic 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. Additionally, CCI induced gene expression of μ, κ, and δ opioid receptors in the contralateral cortex and thalamus of IL-4 ko mice, paralleled by fast onset of morphine analgesia, but not in wt mice. We conclude that a lack of IL-4 leads to mechanical sensitivity; the compensatory hyperexpression of analgesic cytokines and opioid receptors after CCI, in turn, protects IL-4 ko mice from enhanced pain behavior after nerve lesion. KW - mouse models KW - animal behavior KW - sciatic nerves KW - spinal cord KW - opioids KW - cytokines KW - gene expression KW - mice Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137924 VL - 6 IS - 12 ER - TY - JOUR A1 - Burlina, Alessandro P. A1 - Sims, Katherine B. A1 - Politei, Juan M. A1 - Bennett, Gary J. A1 - Baron, Ralf A1 - Sommer, Claudia A1 - Moller, Anette Torvin A1 - Hilz, Max J. T1 - Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel JF - BMC Neurology N2 - Background: Fabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of lipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fibers are particularly affected and small fiber peripheral neuropathy often clinically manifests at young age. Peripheral pain can be chronic and/or occur as provoked attacks of excruciating pain. Manifestations of dysfunction of small autonomic fibers may include, among others, impaired sweating, gastrointestinal dysmotility, and abnormal pain perception. Patients with Fabry disease often remain undiagnosed until severe complications involving the kidney, heart, peripheral nerves and/or brain have arisen. Methods: An international expert panel convened with the goal to provide guidance to clinicians who may encounter unrecognized patients with Fabry disease on how to diagnose these patients early using simple diagnostic tests. A further aim was to offer recommendations to control neuropathic pain. Results: We describe the neuropathy in Fabry disease, focusing on peripheral small fiber dysfunction - the hallmark of early neurologic involvement in this disorder. The clinical course of peripheral pain is summarized, and the importance of medical history-taking, including family history, is highlighted. A thorough physical examination (e. g., angiokeratoma, corneal opacities) and simple non-invasive sensory perception tests could provide clues to the diagnosis of Fabry disease. Reported early clinical benefits of enzyme replacement therapy include reduction of neuropathic pain, and adequate management of residual pain to a tolerable and functional level can substantially improve the quality of life for patients. Conclusions: Our recommendations can assist in diagnosing Fabry small fiber neuropathy early, and offer clinicians guidance in controlling peripheral pain. This is particularly important since management of pain in young patients with Fabry disease appears to be inadequate. KW - Enzyme replacement therapy KW - Quality of life KW - Small-fiber neuropathy KW - Rochester diabetic neuropathy KW - Randomized controlled trial KW - Agalsidase beta therapy KW - Outcome survey KW - Pharmacological management KW - Clinical manifestations KW - Alpha galactosidase KW - Diagnosis KW - Fabry KW - Disease KW - Neuropathy KW - Pain KW - Treatment Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135309 VL - 11 IS - 61 ER - TY - JOUR A1 - Weise, Gesa A1 - Stoll, Guido T1 - Magnetic resonance imaging of blood brain/nerve barrier dysfunction and leukocyte infiltration: closely related or discordant? JF - Frontiers in Neurology N2 - Unlike other organs the nervous system is secluded from the rest of the organism by the blood brain barrier (BBB) or blood nerve barrier (BNB) preventing passive influx of fluids from the circulation. Similarly, leukocyte entry to the nervous system is tightly controlled. Breakdown of these barriers and cellular inflammation are hallmarks of inflammatory as well as ischemic neurological diseases and thus represent potential therapeutic targets. The spatiotemporal relationship between BBB/BNB disruption and leukocyte infiltration has been a matter of debate. We here review contrast-enhanced magnetic resonance imaging (MRI) as a non-invasive tool to depict barrier dysfunction and its relation to macrophage infiltration in the central and peripheral nervous system under pathological conditions. Novel experimental contrast agents like Gadofluorine M (Gf) allow more sensitive assessment of BBB dysfunction than conventional Gadolinium (Gd)-DTPA enhanced MRI. In addition, Gf facilitates visualization of functional and transient alterations of the BBB remote from lesions. Cellular contrast agents such as superparamagnetic iron oxide particles (SPIO) and perfluorocarbons enable assessment of leukocyte (mainly macrophage) infiltration by MR technology. Combined use of these MR contrast agents disclosed that leukocytes can enter the nervous system independent from a disturbance of the BBB, and vice versa, a dysfunctional BBB/BNB by itself is not sufficient to attract inflammatory cells from the circulation. We will illustrate these basic imaging findings in animal models of multiple sclerosis, cerebral ischemia, and traumatic nerve injury and review corresponding findings in patients. KW - contrast-enhanced MRI KW - neuroinflammation KW - gadolinium-DTPA KW - gadofluorine KW - iron oxide nanoparticles KW - blood brain barrier Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123359 VL - 3 IS - 178 ER - TY - JOUR A1 - Hansen, Niels A1 - Seiler, Carola A1 - Rumpf, Julian A1 - Kraft, Peter A1 - Dlaske, Henry A1 - Abele-Horn, Marianne A1 - Muellges, Wolfgang T1 - Human Tuberculous Meningitis Caused by \(Mycobacterium\) \(caprae\) JF - Case Reports in Neurology N2 - INTRODUCTION: Tuberculous meningitis (TM) causes substantial morbidity and mortality in humans. Human TM has been known to be induced by bacteria from the Mycobacterium tuberculosis complex (MTBC), such as M. tuberculosis and M. bovis. CASE PRESENTATION: We describe a case of meningitis treated with fosfomycin, which showed partial effectiveness in an 80-year-old patient. After a lethal myocardial infarction, M. caprae (MC) was identified in cerebrospinal fluid culture. This isolated acid-fast organism was first identified as MTBC by MTBC-specific PCR (16S rDNA-PCR). Furthermore, species-specific identification of the isolate was done by gyrB PCR-restriction fragment length polymorphism analysis of a part of gyrB DNA. Colony morphology of the isolated MC strain showed dysgonic growth on Lowenstein-Jensen medium. The strain was susceptible to pyrazinamide (PZA). CONCLUSION: This isolated strain was convincingly identified as MC according to the phenotypic and genotypic characteristics and PZA sensitivity. This is the first report of MC causing TM. KW - Mycobacterium caprae KW - Mycobacterium caprae KW - fosfomycin KW - Tuberkulose KW - Mycobacterium tuberculosis complex KW - tuberculous meningitis KW - cerebrospinal fluid culture Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123425 VL - 4 IS - 1 ER - TY - JOUR A1 - Boltze, Johannes A1 - Kleinschnitz, Christoph A1 - Reymann, Klaus G. A1 - Reiser, Georg A1 - Wagner, Daniel-Christoph A1 - Kranz, Alexander A1 - Michalski, Dominik T1 - Neurovascular pathophysiology in cerebral ischemia, dementia and the ageing brain – current trends in basic, translational and clinical research JF - Experimental & Translational Stroke Medicine N2 - The 7th International Symposium on Neuroprotection and Neurorepair was held from May 2nd to May 5th, 2012 in Potsdam, Germany. The symposium, which directly continues the successful Magdeburg meeting series, attracted over 330 colleagues from 29 countries to discuss recent findings and advances in the field. The focus of the 2012 symposium was widened from stroke and traumatic brain injury to neurodegenerative diseases, notably dementia, and more generally the ageing brain. Thereby, emphasis was given on neurovascular aspects of neurodegeneration and stroke including the blood–brain barrier, recent findings regarding the pathomechanism of Alzheimer’s disease, and brain imaging approaches. In addition, neurobiochemical aspects of neuroprotection, the role of astrogliosis, the clinical progress of cell-based approaches as well as translational hurdles and opportunities were discussed in-depth. This review summarizes some of the most stimulating discussions and reports from the meeting. KW - translational research KW - small vessel disease KW - Alzheimer’s disease KW - cerebral ischemia KW - neurorepair KW - neuroprotection KW - vascular dementia KW - mitochondria KW - astrogliosis KW - in vivo imaging Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126679 VL - 4 IS - 14 ER - TY - JOUR A1 - Kraft, Peter A1 - De Meyer, Simon F. A1 - Kleinschnitz, Christoph T1 - Next-Generation Antithrombotics in Ischemic Stroke: Preclinical Perspective on ‘Bleeding-Free Antithrombosis’ JF - Journal of Cerebral Blood Flow and Metabolism N2 - The present antithrombotic drugs used to treat or prevent ischemic stroke have significant limitations: either they show only moderate efficacy (platelet inhibitors), or they significantly increase the risk for hemorrhages (thrombolytics, anticoagulants). Although most strokes are caused by thrombotic or embolic vessel occlusions, the pathophysiological role of platelets and coagulation is largely unclear. The introduction of novel transgenic mouse models and specific coagulation inhibitors facilitated a detailed analysis of molecular pathways mediating thrombus formation in models of acute ischemic stroke. Prevention of early platelet adhesion to the damaged vessel wall by blocking platelet surface receptors glycoprotein Ib alpha (GPIbα) or glycoprotein VI (GPVI) protects from stroke without provoking bleeding complications. In addition, downstream signaling of GPIbα and GPVI has a key role in platelet calcium homeostasis and activation. Finally, the intrinsic coagulation cascade, activated by coagulation factor XII (FXII), has only recently been identified as another important mediator of thrombosis in cerebrovascular disease, thereby disproving established concepts. This review summarizes the latest insights into the pathophysiology of thrombus formation in the ischemic brain. Potential clinical merits of novel platelet inhibitors and anticoagulants as powerful and safe tools to combat ischemic stroke are discussed. KW - von Willebrand factor KW - platelets KW - glycoprotein Ib KW - FXII KW - coagulation KW - Stim Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126538 VL - 32 IS - 10 ER - TY - JOUR A1 - Langhauser, Friederike L. A1 - Heiler, Patrick M. A1 - Grudzenski, Saskia A1 - Lemke, Andreas A1 - Alonso, Angelika A1 - Schad, Lothar R. A1 - Hennerici, Michael G. A1 - Meairs, Stephen A1 - Fata, Marc T1 - Thromboembolic stroke in C57BL/6 mice monitored by 9.4 T MRI using a 1H cryo probe JF - Experimental and Translational Stroke Medicine N2 - Background A new thromboembolic animal model showed beneficial effects of t-PA with an infarct volume reduction of 36.8% in swiss mice. Because knock-out animal experiments for stroke frequently used C57BL76 mice we evaluated t-PA effects in this mouse strain and measured infarct volume and vascular recanalisation in-vivo by using high-field 9.4 T MRI and a 1H surface cryo coil. Methods Clot formation was triggered by microinjection of murine thrombin into the right middle cerebral artery (MCA). Animals (n = 28) were treated with 10 mg/kg, 5 mg/kg or no tissue plasminogen activator (t-PA) 40 min after MCA occlusion. For MR-imaging a Bruker 9.4 T animal system with a 1H surface cryo probe was used and a T2-weighted RARE sequence, a diffusion weighted multishot EPI sequence and a 3D flow-compensated gradient echo TOF angiography were performed. Results The infarct volume in animals treated with t-PA was significantly reduced (0.67 ± 1.38 mm3 for 10 mg/kg and 10.9 ± 8.79 mm3 for 5 mg/kg vs. 19.76 ± 2.72 mm3 ; p < 0.001) compared to untreated mice. An additional group was reperfused with t-PA inside the MRI. Already ten minutes after beginning of t-PA treatment, reperfusion flow was re-established in the right MCA. However, signal intensity was lower than in the contralateral MCA. This reduction in cerebral blood flow was attenuated during the first 60 minutes after reperfusion. 24 h after MCA occlusion and reperfusion, no difference in signal intensity of the contralateral and ipsilateral MCAs was observed. Conclusions We confirm a t-Pa effect using this stroke model in the C57BL76 mouse strain and demonstrate a chronological sequence MRI imaging after t-PA using a 1H surface cryo coil in a 9.4 T MRI. This setting will allow testing of new thrombolytic strategies for stroke treatment in-vivo in C57BL76 knock-out mice. KW - animal models KW - MRI KW - experimental KW - embolic stroke KW - T-PA Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124218 VL - 4 IS - 18 ER - TY - JOUR A1 - Horn, Michael A1 - Baumann, Reto A1 - Pereira, Jorge A. A1 - Sidiropoulos, Páris N. M. A1 - Somandin, Christian A1 - Welzl, Hans A1 - Stendel, Claudia A1 - Lühmann, Tessa A1 - Wessig, Carsten A1 - Toyka, Klaus V. A1 - Relvas, João B. A1 - Senderek, Jan A1 - Suter, Ueli T1 - Myelin is dependent on the Charcot–Marie–Tooth Type 4H disease culprit protein FRABIN/FGD4 in Schwann cells JF - Brain N2 - Studying the function and malfunction of genes and proteins associated with inherited forms of peripheral neuropathies has provided multiple clues to our understanding of myelinated nerves in health and disease. Here, we have generated a mouse model for the peripheral neuropathy Charcot–Marie–Tooth disease type 4H by constitutively disrupting the mouse orthologue of the suspected culprit gene FGD4 that encodes the small RhoGTPase Cdc42-guanine nucleotide exchange factor Frabin. Lack of Frabin/Fgd4 causes dysmyelination in mice in early peripheral nerve development, followed by profound myelin abnormalities and demyelination at later stages. At the age of 60 weeks, this was accompanied by electrophysiological deficits. By crossing mice carrying alleles of Frabin/Fgd4 flanked by loxP sequences with animals expressing Cre recombinase in a cell type-specific manner, we show that Schwann cell-autonomous Frabin/Fgd4 function is essential for proper myelination without detectable primary contributions from neurons. Deletion of Frabin/Fgd4 in Schwann cells of fully myelinated nerve fibres revealed that this protein is not only required for correct nerve development but also for accurate myelin maintenance. Moreover, we established that correct activation of Cdc42 is dependent on Frabin/Fgd4 function in healthy peripheral nerves. Genetic disruption of Cdc42 in Schwann cells of adult myelinated nerves resulted in myelin alterations similar to those observed in Frabin/Fgd4-deficient mice, indicating that Cdc42 and the Frabin/Fgd4–Cdc42 axis are critical for myelin homeostasis. In line with known regulatory roles of Cdc42, we found that Frabin/Fgd4 regulates Schwann cell endocytosis, a process that is increasingly recognized as a relevant mechanism in peripheral nerve pathophysiology. Taken together, our results indicate that regulation of Cdc42 by Frabin/Fgd4 in Schwann cells is critical for the structure and function of the peripheral nervous system. In particular, this regulatory link is continuously required in adult fully myelinated nerve fibres. Thus, mechanisms regulated by Frabin/Fgd4–Cdc42 are promising targets that can help to identify additional regulators of myelin development and homeostasis, which may crucially contribute also to malfunctions in different types of peripheral neuropathies. KW - Frabin/Fgd4 KW - myelination KW - hereditary motor and sensory neuropathy KW - Charcot–Marie–Tooth disease KW - Rho-GTPase Cdc42 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125390 VL - 135 ER - TY - JOUR A1 - Albert-Weissenberger, Christiane A1 - Stetter, Christian A1 - Meuth, Sven G. A1 - Göbel, Kerstin A1 - Bader, Michael A1 - Sirén, Anna-Leena A1 - Kleinschnitz, Christoph T1 - Blocking of Bradykinin Receptor B1 Protects from Focal Closed Head Injury in Mice by Reducing Axonal Damage and Astroglia Activation JF - Journal of Cerebral Blood Flow and Metabolism N2 - The two bradykinin receptors B1R and B2R are central components of the kallikrein–kinin system with different expression kinetics and binding characteristics. Activation of these receptors by kinins triggers inflammatory responses in the target organ and in most situations enhances tissue damage. We could recently show that blocking of B1R, but not B2R, protects from cortical cryolesion by reducing inflammation and edema formation. In the present study, we investigated the role of B1R and B2R in a closed head model of focal traumatic brain injury (TBI; weight drop). Increased expression of B1R in the injured hemispheres of wild-type mice was restricted to the later stages after brain trauma, i.e. day 7 (P<0.05), whereas no significant induction could be observed for the B2R (P>0.05). Mice lacking the B1R, but not the B2R, showed less functional deficits on day 3 (P<0.001) and day 7 (P<0.001) compared with controls. Pharmacological blocking of B1R in wild-type mice had similar effects. Reduced axonal injury and astroglia activation could be identified as underlying mechanisms, while inhibition of B1R had only little influence on the local inflammatory response in this model. Inhibition of B1R may become a novel strategy to counteract trauma-induced neurodegeneration. KW - R-715 KW - kinin receptors KW - closed head injury KW - β-APP KW - astrocytes KW - TNF-α Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125903 VL - 32 IS - 9 ER - TY - JOUR A1 - Minnerup, Jens A1 - Sutherland, Brad A. A1 - Buchan, Alastair M. A1 - Kleinschnitz, Christoph T1 - Neuroprotection for Stroke: Current Status and Future Perspectives JF - International Journal of Molecular Science N2 - Neuroprotection aims to prevent salvageable neurons from dying. Despite showing efficacy in experimental stroke studies, the concept of neuroprotection has failed in clinical trials. Reasons for the translational difficulties include a lack of methodological agreement between preclinical and clinical studies and the heterogeneity of stroke in humans compared to homogeneous strokes in animal models. Even when the international recommendations for preclinical stroke research, the Stroke Academic Industry Roundtable (STAIR) criteria, were followed, we have still seen limited success in the clinic, examples being NXY-059 and haematopoietic growth factors which fulfilled nearly all the STAIR criteria. However, there are a number of neuroprotective treatments under investigation in clinical trials such as hypothermia and ebselen. Moreover, promising neuroprotective treatments based on a deeper understanding of the complex pathophysiology of ischemic stroke such as inhibitors of NADPH oxidases and PSD-95 are currently evaluated in preclinical studies. Further concepts to improve translation include the investigation of neuroprotectants in multicenter preclinical Phase III-type studies, improved animal models, and close alignment between clinical trial and preclinical methodologies. Future successful translation will require both new concepts for preclinical testing and innovative approaches based on mechanistic insights into the ischemic cascade. KW - free radical scavenger KW - ischemic cascade KW - acute ischemic stroke KW - trial KW - focal cerebral-ischemia KW - interleukin-1 receptor antagonist KW - colony-stimulating factor KW - tissue-plasminogen activator KW - traumatic brain injury KW - placebo-controlled KW - alias pilot trial KW - damage cool aid KW - neuroprotection KW - ischemic stroke KW - translation KW - STAIR Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134730 VL - 13 IS - 9 ER - TY - JOUR A1 - Isaias, Ioannis U. A1 - Marzegan, Alberto A1 - Pezzoli, Gianni A1 - Marotta, Giorgio A1 - Canesi, Margherita A1 - Biella, Gabriele E. M. A1 - Volkmann, Jens A1 - Cavallari, Paolo T1 - A role for locus coeruleus in Parkinson tremor JF - Frontiers in Human Neuroscience N2 - We analyzed rest tremor, one of the etiologically most elusive hallmarks of Parkinson disease(PD), in 12 consecutive PD patients during a specific task activating the locus coeruleus (LC) to investigate a putative role of noradrenaline (NA) in tremor generation and suppression. Clinical diagnosis was confirmed in all subjects by reduced dopamine reuptake transporter (DAT) binding values investigated by single photon computed tomography imaging (SPECT) with [\(^{123}\)I] N-\(\omega\)-fluoropropyl-2 \(\beta\)-carbomethoxy-3 \(\beta\)-(4-iodophenyl) tropane (FP-CIT). The intensity of tremor (i.e., the power of Electromyography [EMG] signals), but not its frequency, significantly increased during the task. In six subjects, tremor appeared selectively during the task. In a second part of the study, we retrospectively reviewed SPECT with FP-CIT data and confirmed the lack of correlation between dopaminergic loss and tremor by comparing DAT binding values of 82 PD subjects with bilateral tremor (n = 27), unilateral tremor (n = 22), and no tremor (n = 33). This study suggests a role of the LC in Parkinson tremor. KW - locus coeruleus KW - disease KW - basal ganglia KW - resting tremor KW - functional neuroanatomy KW - dopamine KW - norepinephrine KW - progression KW - binding KW - rat KW - noradrenalin KW - parkinson disease KW - tremor Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133955 VL - 5 IS - 179 ER - TY - JOUR A1 - Isaias, Ioannis U. A1 - Volkmann, Jens A1 - Marzegan, Alberto A1 - Marotta, Giorgio A1 - Cavallari, Paolo A1 - Pezzoli, Gianni T1 - The Influence of Dopaminergic Striatal Innervation on Upper Limb Locomotor Synergies JF - PLoS One N2 - To determine the role of striatal dopaminergic innervation on upper limb synergies during walking, we measured arm kinematics in 13 subjects with Parkinson disease. Patients were recruited according to several inclusion criteria to represent the best possible in vivo model of dopaminergic denervation. Of relevance, we included only subjects with normal spatio-temporal parameters of the stride and gait speed to avoid an impairment of upper limbs locomotor synergies as a consequence of gait impairment per se. Dopaminergic innervation of the striatum was measured by FP-CIT and SPECT. All patients showed a reduction of gait-associated arms movement. No linear correlation was found between arm ROM reduction and contralateral dopaminergic putaminal innervation loss. Still, a partition analysis revealed a 80% chance of reduced arm ROM when putaminal dopamine content loss was >47%. A significant correlation was described between the asymmetry indices of the swinging of the two arms and dopaminergic striatal innervation. When arm ROM was reduced, we found a positive correlation between upper-lower limb phase shift modulation ( at different gait velocities) and striatal dopaminergic innervation. These findings are preliminary evidence that dopaminergic striatal tone plays a modulatory role in upper-limb locomotor synergies and upper-lower limb coupling while walking at different velocities. KW - pet KW - Parkinsons disease KW - basal ganglia KW - spinal-cord KW - walking KW - gait KW - arm KW - coordination KW - movements Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133976 VL - 7 IS - 12 ER - TY - JOUR A1 - Brandt, Alexander U. A1 - Zimmermann, Hanna A1 - Kaufhold, Falko A1 - Promesberger, Julia A1 - Schippling, Sven A1 - Finis, David A1 - Aktas, Orhan A1 - Geis, Christian A1 - Ringelstein, Marius A1 - Ringelstein, E. Bernd A1 - Hartung, Hans-Peter A1 - Paul, Friedemann A1 - Kleffner, Ilka A1 - Dörr, Jan T1 - Patterns of Retinal Damage Facilitate Differential Diagnosis between Susac Syndrome and MS JF - PLoS One N2 - Susac syndrome, a rare but probably underdiagnosed combination of encephalopathy, hearing loss, and visual deficits due to branch retinal artery occlusion of unknown aetiology has to be considered as differential diagnosis in various conditions. Particularly, differentiation from multiple sclerosis is often challenging since both clinical presentation and diagnostic findings may overlap. Optical coherence tomography is a powerful and easy to perform diagnostic tool to analyse the morphological integrity of retinal structures and is increasingly established to depict characteristic patterns of retinal pathology in multiple sclerosis. Against this background we hypothesised that differential patterns of retinal pathology facilitate a reliable differentiation between Susac syndrome and multiple sclerosis. In this multicenter cross-sectional observational study optical coherence tomography was performed in nine patients with a definite diagnosis of Susac syndrome. Data were compared with age-, sex-, and disease duration-matched relapsing remitting multiple sclerosis patients with and without a history of optic neuritis, and with healthy controls. Using generalised estimating equation models, Susac patients showed a significant reduction in either or both retinal nerve fibre layer thickness and total macular volume in comparison to both healthy controls and relapsing remitting multiple sclerosis patients. However, in contrast to the multiple sclerosis patients this reduction was not distributed over the entire scanning area but showed a distinct sectorial loss especially in the macular measurements. We therefore conclude that patients with Susac syndrome show distinct abnormalities in optical coherence tomography in comparison to multiple sclerosis patients. These findings recommend optical coherence tomography as a promising tool for differentiating Susac syndrome from MS. KW - optical coherence tomography KW - vasculopathy KW - artery occlusion KW - hearing loss KW - microangiopathy KW - brain KW - endotheliopathy KW - antibodies KW - multiple-sclerosis KW - retinocochleocerebral Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134013 VL - 7 IS - 6 ER - TY - JOUR A1 - Jarius, Sven A1 - Ruprecht, Klemens A1 - Wildemann, Brigitte A1 - Kuempfel, Tania A1 - Ringelstein, Marius A1 - Geis, Christian A1 - Kleiter, Ingo A1 - Kleinschnitz, Christoph A1 - Berthele, Achim A1 - Brettschneider, Johannes A1 - Hellwig, Kerstin A1 - Hemmer, Bernhard A1 - Linker, Ralf A. A1 - Lauda, Florian A1 - Hayrettin, Christoph A. A1 - Tumani, Hayrettin A1 - Melms, Arthur A1 - Trebst, Corinna A1 - Stangel, Martin A1 - Marziniak, Martin A1 - Hoffmann, Frank A1 - Schippling, Sven A1 - Faiss, Jürgen H. A1 - Neuhaus, Oliver A1 - Ettrich, Barbara A1 - Zentner, Christian A1 - Guthke, Kersten A1 - Hofstadt-van Oy, Ulrich A1 - Reuss, Reinhard A1 - Pellkofer, Hannah A1 - Ziemann, Ulf A1 - Kern, Peter A1 - Wandinger, Klaus P. A1 - Bergh, Florian Then A1 - Boettcher, Tobias A1 - Langel, Stefan A1 - Liebetrau, Martin A1 - Rommer, Paulus S. A1 - Niehaus, Sabine A1 - Münch, Christoph A1 - Winkelmann, Alexander A1 - Zettl, Uwe K A1 - Metz, Imke A1 - Veauthier, Christian A1 - Sieb, Jörn P. A1 - Wilke, Christian A1 - Hartung, Hans P. A1 - Aktas, Orhan A1 - Paul, Friedemann T1 - Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients JF - Journal of Neuroinflammation N2 - Background: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. Objective: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. Methods: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%). Results: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of <= 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades <= 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions >= 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome. KW - cerebrospinal-fluid KW - intractable hiccup KW - extensiv transverse myelitis KW - multiple sclerosis KW - anti-aquaporin-4 antibody KW - NMO-IGG KW - aquaporin-4 autoantibodies KW - immune-response KW - myasthenia gravis KW - immunoglobulin-G Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133636 VL - 9 IS - 14 ER - TY - JOUR A1 - Brecht, Isabel A1 - Weissbrich, Benedikt A1 - Braun, Julia A1 - Toyka, Klaus Viktor A1 - Weishaupt, Andreas A1 - Buttmann, Mathias T1 - Intrathecal, Polyspecific Antiviral Immune Response in Oligoclonal Band Negative Multiple Sclerosis JF - PLoS One N2 - Background: Oligoclonal bands (OCB) are detected in the cerebrospinal fluid (CSF) in more than 95% of patients with multiple sclerosis (MS) in the Western hemisphere. Here we evaluated the intrathecal, polyspecific antiviral immune response as a potential diagnostic CSF marker for OCB-negative MS patients. Methodology/Principal Findings: We tested 46 OCB-negative German patients with paraclinically well defined, definite MS. Sixteen OCB-negative patients with a clear diagnosis of other autoimmune CNS disorders and 37 neurological patients without evidence for autoimmune CNS inflammation served as control groups. Antibodies against measles, rubella, varicella zoster and herpes simplex virus in paired serum and CSF samples were determined by ELISA, and virus-specific immunoglobulin G antibody indices were calculated. An intrathecal antibody synthesis against at least one neurotropic virus was detected in 8 of 26 (31%) patients with relapsing-remitting MS, 8 of 12 (67%) with secondary progressive MS and 5 of 8 (63%) with primary progressive MS, in 3 of 16 (19%) CNS autoimmune and 3 of 37 (8%) non-autoimmune control patients. Antibody synthesis against two or more viruses was found in 11 of 46 (24%) MS patients but in neither of the two control groups. On average, MS patients with a positive antiviral immune response were older and had a longer disease duration than those without. Conclusion: Determination of the intrathecal, polyspecific antiviral immune response may allow to establish a CSF-supported diagnosis of MS in OCB-negative patients when two or more of the four virus antibody indices are elevated. KW - MS KW - cerebrospinal fluid KW - differential diagnosis KW - nervous-system KW - criteria KW - serum Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134426 VL - 7 IS - 7 ER - TY - JOUR A1 - Ip, Chi Wang A1 - Kroner, Antje A1 - Groh, Janos A1 - Huber, Marianne A1 - Klein, Dennis A1 - Spahn, Irene A1 - Diem, Ricarda A1 - Williams, Sarah K. A1 - Nave, Klaus-Armin A1 - Edgar, Julia M. A1 - Martini, Rudolf T1 - Neuroinflammation by Cytotoxic T-Lymphocytes Impairs Retrograde Axonal Transport in an Oligodendrocyte Mutant Mouse JF - PLoS One N2 - Mice overexpressing proteolipid protein (PLP) develop a leukodystrophy-like disease involving cytotoxic, CD8+ T-lymphocytes. Here we show that these cytotoxic T-lymphocytes perturb retrograde axonal transport. Using fluorogold stereotactically injected into the colliculus superior, we found that PLP overexpression in oligodendrocytes led to significantly reduced retrograde axonal transport in retina ganglion cell axons. We also observed an accumulation of mitochondria in the juxtaparanodal axonal swellings, indicative for a disturbed axonal transport. PLP overexpression in the absence of T-lymphocytes rescued retrograde axonal transport defects and abolished axonal swellings. Bone marrow transfer from wildtype mice, but not from perforin- or granzyme B-deficient mutants, into lymphocyte-deficient PLP mutant mice led again to impaired axonal transport and the formation of axonal swellings, which are predominantly located at the juxtaparanodal region. This demonstrates that the adaptive immune system, including cytotoxic T-lymphocytes which release perforin and granzyme B, are necessary to perturb axonal integrity in the PLP-transgenic disease model. Based on our observations, so far not attended molecular and cellular players belonging to the immune system should be considered to understand pathogenesis in inherited myelin disorders with progressive axonal damage. KW - myelin KW - experimental autoimmune encephalomyelitis KW - degeneration KW - axonopathic changes KW - neural apoptosis KW - nervous system KW - motor function KW - proteolipid protein gene KW - retinal ganglion cells KW - granzyme B KW - multiple sclerosis Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134982 VL - 7 IS - 8 ER - TY - JOUR A1 - Dupuis, Luc A1 - Dengler, Reinhard A1 - Heneka, Michael T. A1 - Meyer, Thomas A1 - Zierz, Stephan A1 - Kassubek, Jan A1 - Fischer, Wilhelm A1 - Steiner, Franziska A1 - Lindauer, Eva A1 - Otto, Markus A1 - Dreyhaupt, Jens A1 - Grehl, Torsten A1 - Hermann, Andreas A1 - Winkler, Andrea S. A1 - Bogdahn, Ulrich A1 - Benecke, Reiner A1 - Schrank, Bertold A1 - Wessig, Carsten A1 - Grosskreutz, Julian A1 - Ludolph, Albert C. T1 - A Randomized, Double Blind, Placebo-Controlled Trial of Pioglitazone in Combination with Riluzole in Amyotrophic Lateral Sclerosis JF - PLoS One N2 - Background: Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS). Methods/Principal Findings: We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95% CI: 0.71-2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated. Conclusion/Significance: Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole. KW - ALS KW - transgenic mouse model KW - central nervous system KW - nonalcoholic steatohepatitis KW - PPAR-gamme KW - hexanucleotide repeat KW - disease progression KW - delays progression KW - SOD1 mutations KW - monocycline Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130255 VL - 7 IS - 6 ER - TY - JOUR A1 - Raslan, Furat A1 - Albert-Weißenberger, Christiane A1 - Westermaier, Thomas A1 - Saker, Saker A1 - Kleinschmitz, Christoph A1 - Lee, Jin-Yul T1 - A modified double injection model of cisterna magna for the study of delayed cerebral vasospasm following subarachnoid hemorrhage in rats N2 - Delayed cerebral vasospasm following subarachnoid hemorrhage (SAH) is a serious medical complication, characterized by constriction of cerebral arteries leading to varying degrees of cerebral ischemia. Numerous clinical and experimental studies have been performed in the last decades; however, the pathophysiologic mechanism of cerebral vasospasm after SAH still remains unclear. Among a variety of experimental SAH models, the double hemorrhage rat model involving direct injection of autologous arterial blood into the cisterna magna has been used most frequently for the study of delayed cerebral vasospasm following SAH in last years. Despite the simplicity of the technique, the second blood injection into the cisterna magna may result in brainstem injury leading to high mortality. Therefore, a modified double hemorrhage model of cisterna magna has been developed in rat recently. We describe here step by step the surgical technique to induce double SAH and compare the degree of vasospasm with other cisterna magna rat models using histological assessment of the diameter and cross-sectional area of the basilar artery KW - Medizin KW - Cerebral vasospasm KW - Cisterna magna KW - Double hemorrhage model KW - Rat KW - Subarachnoid Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76038 ER - TY - JOUR A1 - Kunze, Ekkehard A1 - Pham, Mirko A1 - Raslan, Furat A1 - Stetter, Christian A1 - Lee, Jin-Yul A1 - Solymosi, Laszlo A1 - Ernestus, Ralf-Ingo A1 - Hamilton Vince, Giles A1 - Westermaier, Thomas T1 - Value of Perfusion CT, Transcranial Doppler Sonography and Neurological Examination to detect delayed Vasospasm after aneurysmal Subarachnoid Hemorrhage [Research Article] N2 - Background If detected in time, delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) may be treated by balloon angioplasty or chemical vasospasmolysis in order to enhance cerebral blood flow (CBF) and protect the brain from ischemic damage. This study was conceived to compare the diagnostic accuracy of detailed neurological examination, Transcranial Doppler Sonography (TCD), and Perfusion-CT (PCT) to detect angiographic vasospasm. Methods The sensitivity, specificity, positive and negative predictive values of delayed ischemic neurological deterioration (DIND), pathological findings on PCT- maps, and accelerations of the mean flow velocity (MVF) were calculated. Results The accuracy of DIND to predict angiographic vasospasm was 0.88. An acceleration of MFV in TCD (>140 cm/s) had an accuracy of 0.64, positive PCT-findings of 0.69 with a higher sensitivity, and negative predictive value than TCD. Interpretation Neurological assessment at close intervals is the most sensitive and specific parameter for cerebral vasospasm. PCT has a higher accuracy, sensitivity and negative predictive value than TCD. If detailed neurological evaluation is possible, it should be the leading parameter in the management and treatment decisions. If patients are not amenable to detailed neurological examination, PCT at regular intervals is a helpful tool to diagnose secondary vasospasm after aneurysmal SAH. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76241 ER - TY - JOUR A1 - Westermaier, Thomas A1 - Stetter, Christian A1 - Raslan, Furat A1 - Vinc, Giles Hamilton A1 - Ernestus, Ralf-Ingo T1 - Brain edema formation correlates with perfusion deficit during the first six hours after experimental subarachnoid hemorrhage in rats N2 - Background: Severe brain edema is observed in a number of patients suffering from subarachnoid hemorrhage (SAH). Little is known about its pathogenesis and time-course in the first hours after SAH. This study was performed to investigate the development of brain edema and its correlation with brain perfusion after experimental SAH. Methods: Male Sprague–Dawley rats, randomly assigned to one of six groups (n = 8), were subjected to SAH using the endovascular filament model or underwent a sham operation. Animals were sacrificed 15, 30, 60, 180 or 360 minutes after SAH. Intracranial pressure (ICP), mean arterial blood pressure (MABP), cerebral perfusion pressure (CPP) and bilateral local cerebral blood flow (LCBF) were continuously measured. Brain water content (BWC) was determined by the wet/dry-weight method. Results: After SAH, CPP and LCBF rapidly decreased. The decline of LCBF markedly exceeded the decline of CPP and persisted until the end of the observation period. BWC continuously increased. A significant correlation was observed between the BWC and the extent of the perfusion deficit in animals sacrificed after 180 and 360 minutes. Conclusions: The significant correlation with the perfusion deficit after SAH suggests that the development of brain edema is related to the extent of ischemia and acute vasoconstriction in the first hours after SAH. KW - Medizin KW - Subarachnoid hemorrhage KW - Cerebral blood flow KW - Brain ischemia KW - Brain edema KW - Animal models Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75765 ER - TY - RPRT A1 - Linker, Ralf, A. A1 - Meuth, Sven G. A1 - Magnus, Tim A1 - Korn, Thomas A1 - Kleinschnitz, Christoph T1 - Report on the 4'th scientific meeting of the "Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Nov. 2'nd - Nov. 4'th, 2012 [meeting report] N2 - From November 2nd - 4th 2012, the 4th NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Again more than 60 participants, predominantly at the doctoral student or postdoc level, gathered to share their latest findings in the fields of neurovascular research, neurodegeneration and neuroinflammation. Like in the previous years, the symposium provided an excellent platform for scientific exchange and the presentation of innovative projects in the stimulating surroundings of the Brandenburg outback. This year’s keynote lecture on the pathophysiological relevance of neuronal networks was given by Christian Gerloff, Head of the Department of Neurology at the University Clinic of Hamburg-Eppendorf. Another highlight of the meeting was the awarding of the NEUROWIND e.V. prize for young scientists working in the field of experimental neurology. The award is donated by the Merck Serono GmbH, Darmstadt, Germany and is endowed with 20.000 Euro. This year the jury decided unanimously to adjudge the award to Michael Gliem from the Department of Neurology at the University Clinic of Düsseldorf (group of Sebastian Jander), Germany, for his outstanding work on different macrophage subsets in the pathogenesis of ischemic stroke published in the Annals of Neurology in 2012. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76407 ER - 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 - 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 - Kress, Michaela A1 - Hüttenhofer, Alexander A1 - Landry, Marc A1 - Kuner, Rohini A1 - Favereaux, Alexandre A1 - Greenberg, David A1 - Bednarik, Josef A1 - Heppenstall, Paul A1 - Kronenberg, Florian A1 - Malcangio, Marzia A1 - Rittner, Heike A1 - Üçeyler, Nurcan A1 - Trajanoski, Zlatko A1 - Mouritzen, Peter A1 - Birklein, Frank A1 - Sommer, Claudia A1 - Soreq, Hermona T1 - microRNAs in nociceptive circuits as predictors of future clinical applications JF - Frontiers in Molecular Neuroscience N2 - Neuro-immune alterations in the peripheral and central nervous system play a role in the pathophysiology of chronic pain, and non-coding RNAs – and microRNAs (miRNAs) in particular – regulate both immune and neuronal processes. Specifically, miRNAs control macromolecular complexes in neurons, glia and immune cells and regulate signals used for neuro-immune communication in the pain pathway. Therefore, miRNAs may be hypothesized as critically important master switches modulating chronic pain. In particular, understanding the concerted function of miRNA in the regulation of nociception and endogenous analgesia and defining the importance of miRNAs in the circuitries and cognitive, emotional and behavioral components involved in pain is expected to shed new light on the enigmatic pathophysiology of neuropathic pain, migraine and complex regional pain syndrome. Specific miRNAs may evolve as new druggable molecular targets for pain prevention and relief. Furthermore, predisposing miRNA expression patterns and inter-individual variations and polymorphisms in miRNAs and/or their binding sites may serve as biomarkers for pain and help to predict individual risks for certain types of pain and responsiveness to analgesic drugs. miRNA-based diagnostics are expected to develop into hands-on tools that allow better patient stratification, improved mechanism-based treatment, and targeted prevention strategies for high risk individuals. KW - chronic pain KW - biomarker KW - polymorphism KW - miRNA-based diagnostics KW - miRNA expression patterns KW - miRNA polymorphisms KW - antagomir KW - miRNA-based analgesic Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154597 VL - 6 IS - 33 ER - TY - JOUR A1 - Ablin, Jacob A1 - Fitzcharles, Mary-Ann A1 - Buskila, Dan A1 - Shir, Yoram A1 - Sommer, Claudia A1 - Häuser, Winfried T1 - Treatment of Fibromyalgia Syndrome: Recommendations of Recent Evidence-Based Interdisciplinary Guidelines with Special Emphasis on Complementary and Alternative Therapies JF - Evidence-Bayed Complementary and Alternative Medicine N2 - Objective. Current evidence indicates that there is no single ideal treatment for fibromyalgia syndrome (FMS). First choice treatment options remain debatable, especially concerning the importance of complementary and alternative medicine (CAM) treatments. Methods. Three evidence-based interdisciplinary guidelines on FMS in Canada, Germany, and Israel were compared for their first choice and CAM-recommendations. Results. All three guidelines emphasized a patient-tailored approach according to the key symptoms. Aerobic exercise, cognitive behavioral therapy, and multicomponent therapy were first choice treatments. The guidelines differed in the grade of recommendation for drug treatment. Anticonvulsants (gabapentin, pregabalin) and serotonin noradrenaline reuptake inhibitors (duloxetine, milnacipran) were strongly recommended by the Canadian and the Israeli guidelines. These drugs received only a weak recommendation by the German guideline. In consideration of CAM-treatments, acupuncture, hypnosis/guided imagery, and Tai Chi were recommended by the German and Israeli guidelines. The Canadian guidelines did not recommend any CAM therapy. Discussion. Recent evidence-based interdisciplinary guidelines concur on the importance of treatment tailored to the individual patient and further emphasize the need of self-management strategies (exercise, and psychological techniques). KW - metaanalysis KW - management KW - care Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-122235 SN - 1741-427X ER - TY - JOUR A1 - Walter, Maggie C. A1 - Reilich, Peter A1 - Thiele, Simone A1 - Schessl, Joachim A1 - Schreiber, Herbert A1 - Reiners, Karlheinz A1 - Kress, Wolfram A1 - Müller-Reible, Clemens A1 - Vorgerd, Matthias A1 - Urban, Peter A1 - Schrank, Bertold A1 - Deschauer, Marcus A1 - Schlotter-Weigel, Beate A1 - Kohnen, Ralf A1 - Lochmüller, Hans T1 - Treatment of dysferlinopathy with deflazacort: a double-blind, placebo-controlled clinical trial JF - Orphanet Journal of Rare Diseases N2 - Background: Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B). Methods: We assessed the one-year-natural course of dysferlinopathy, and the safety and efficacy of deflazacort treatment in a double-blind, placebo-controlled cross-over trial. After one year of natural course without intervention, 25 patients with genetically defined dysferlinopathy were randomized to receive deflazacort and placebo for six months each (1 mg/kg/day in month one, 1 mg/kg every 2nd day during months two to six) in one of two treatment sequences. Results: During one year of natural course, muscle strength declined about 2% as measured by CIDD (Clinical Investigation of Duchenne Dystrophy) score, and 76 Newton as measured by hand-held dynamometry. Deflazacort did not improve muscle strength. In contrast, there is a trend of worsening muscle strength under deflazacort treatment, which recovers after discontinuation of the study drug. During deflazacort treatment, patients showed a broad spectrum of steroid side effects. Conclusion: Deflazacort is not an effective therapy for dysferlinopathies, and off-label use is not warranted. This is an important finding, since steroid treatment should not be administered in patients with dysferlinopathy, who may be often misdiagnosed as polymyositis. KW - Deflazacort KW - muscle strength KW - gridle muscular-dystrophy KW - Duchenne dystrphy KW - Miyoshi myopathy KW - mutation KW - prednisone KW - gene KW - 2B KW - children KW - design KW - steroids KW - therapy KW - dysferlinopathy KW - Limb girdle muscular dystrophy (LGMD) Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125663 SN - 1750-1172 VL - 8 IS - 26 ER - TY - JOUR A1 - Karle, Kathrin N. A1 - Schüle, Rebecca A1 - Klebe, Stephan A1 - Otto, Susanne A1 - Frischholz, Christian A1 - Liepelt-Scarfone, Inga A1 - Schöls, Ludger T1 - Electrophysiological characterisation of motor and sensory tracts in patients with hereditary spastic paraplegia (HSP) JF - Orphanet Journal of Rare Diseases N2 - Background: Hereditary spastic paraplegias (HSPs) are characterised by lower limb spasticity due to degeneration of the corticospinal tract. We set out for an electrophysiological characterisation of motor and sensory tracts in patients with HSP. Methods: We clinically and electrophysiologically examined a cohort of 128 patients with genetically confirmed or clinically probable HSP. Motor evoked potentials (MEPs) to arms and legs, somato-sensory evoked potentials of median and tibial nerves, and nerve conduction studies of tibial, ulnar, sural, and radial nerves were assessed. Results: Whereas all patients showed clinical signs of spastic paraparesis, MEPs were normal in 27% of patients and revealed a broad spectrum with axonal or demyelinating features in the others. This heterogeneity can at least in part be explained by different underlying genotypes, hinting for distinct pathomechanisms in HSP subtypes. In the largest subgroup, SPG4, an axonal type of damage was evident. Comprehensive electrophysiological testing disclosed a more widespread affection of long fibre tracts involving peripheral nerves and the sensory system in 40%, respectively. Electrophysiological abnormalities correlated with the severity of clinical symptoms. Conclusions: Whereas HSP is primarily considered as an upper motoneuron disorder, our data suggest a more widespread affection of motor and sensory tracts in the central and peripheral nervous system as a common finding in HSP. The distribution patterns of electrophysiological abnormalities were associated with distinct HSP genotypes and could reflect different underlying pathomechanisms. Electrophysiological measures are independent of symptomatic treatment and may therefore serve as a reliable biomarker in upcoming HSP trials. KW - motor evoked potential (MEP) KW - amyotrophic-lateral-sclerosis KW - somatosensory-evoked-potentials KW - Silver-syndrome KW - gene mutations KW - SPG4 KW - mouse model KW - ALSIN gene KW - neuropathy KW - paraparesis KW - protein KW - electrophysiology KW - hereditary spastic paraplegia (HSP) Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124763 SN - 1750-1172 VL - 8 IS - 158 ER - TY - JOUR A1 - Golombeck, Stefanie Kristin A1 - Wessig, Carsten A1 - Monoranu, Camelia-Maria A1 - Schütz, Ansgar A1 - Solymosi, Laszlo A1 - Melzer, Nico A1 - Kleinschnitz, Christoph T1 - Fatal atypical reversible posterior leukoencephalopathy syndrome: a case report JF - Journal of Medical Case Reports N2 - Introduction: Reversible posterior leukoencephalopathy syndrome – a reversible subacute global encephalopathy clinically presenting with headache, altered mental status, visual symptoms such as hemianopsia or cortical blindness, motor symptoms, and focal or generalized seizures – is characterized by a subcortical vasogenic edema symmetrically affecting posterior brain regions. Complete reversibility of both clinical signs and magnetic resonance imaging lesions is regarded as a defining feature of reversible posterior leukoencephalopathy syndrome. Reversible posterior leukoencephalopathy syndrome is almost exclusively seen in the setting of a predisposing clinical condition, such as pre-eclampsia, systemic infections, sepsis and shock, certain autoimmune diseases, various malignancies and cytotoxic chemotherapy, transplantation and concomitant immunosuppression (especially with calcineurin inhibitors) as well as episodes of abrupt hypertension. We describe for the first time clinical, radiological and histological findings in a case of reversible posterior leukoencephalopathy syndrome with an irreversible and fatal outcome occurring in the absence of any of the known predisposing clinical conditions except for a hypertensive episode. Case presentation: A 58-year-old Caucasian woman presented with a two-week history of subacute and progressive occipital headache, blurred vision and imbalance of gait and with no evidence for raised arterial blood pressure during the two weeks previous to admission. Her past medical history was unremarkable except for controlled arterial hypertension. Cerebral magnetic resonance imaging demonstrated cortical and subcortical lesions with combined vasogenic and cytotoxic edema atypical for both venous congestion and arterial infarction. Routine laboratory and cerebrospinal fluid parameters were normal. The diagnosis of reversible posterior leukoencephalopathy syndrome was established. Within hours after admission the patient showed a rapidly decreasing level of consciousness, extension and flexion synergisms, bilaterally extensor plantar responses and rapid cardiopulmonary decompensation requiring ventilatory and cardiocirculatory support. Follow-up cerebral imaging demonstrated widespread and confluent cytotoxic edematous lesions in different arterial territories, global cerebral swelling, and subsequent upper and lower brainstem herniation. Four days after admission, the patient was declared dead because of brain death. Conclusion: This case demonstrates that fulminant and fatal reversible posterior leukoencephalopathy syndrome may occur spontaneously, that is, in the absence of any of the known predisposing systemic conditions. KW - reversible posterior leukoencephalopathy syndrome KW - generalized cerebral edema KW - cerebral autoregulation KW - blood pressure Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135517 VL - 7 IS - 14 ER - TY - JOUR A1 - Volkmann, Jens A1 - Albanese, Alberto A1 - Antonini, Angelo A1 - Chaudhuri, K. Ray A1 - Clarke, Karl E. A1 - de Bie, Rob M. A. A1 - Deuschl, Günther A1 - Eggert, Karla A1 - Houeto, Jean-Luc A1 - Kulisevsky, Jaime A1 - Nyholm, Dag A1 - Odin, Per A1 - Ostergaard, Karen A1 - Poewe, Werner A1 - Pollak, Pierre A1 - Rabey, Jose Martin A1 - Rascol, Olivier A1 - Ruzicka, Evzen A1 - Samuel, Michael A1 - Speelman, Hans A1 - Sydow, Olof A1 - Valldeoriola, Francesc A1 - van der Linden, Chris A1 - Oertel, Wolfgang T1 - Selecting deep brain stimulation or infusion therapies in advanced Parkinson’s disease: an evidence-based review JF - Journal of Neurology N2 - Motor complications in Parkinson’s disease (PD) result from the short half-life and irregular plasma fluctuations of oral levodopa. When strategies of providing more continuous dopaminergic stimulation by adjusting oral medication fail, patients may be candidates for one of three device-aided therapies: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, or continuous duodenal/jejunal levodopa/carbidopa pump infusion (DLI). These therapies differ in their invasiveness, side-effect profile, and the need for nursing care. So far, very few comparative studies have evaluated the efficacy of the three device-aided therapies for specific motor problems in advanced PD. As a result, neurologists currently lack guidance as to which therapy could be most appropriate for a particular PD patient. A group of experts knowledgeable in all three therapies reviewed the currently available literature for each treatment and identified variables of clinical relevance for choosing one of the three options such as type of motor problems, age, and cognitive and psychiatric status. For each scenario, pragmatic and (if available) evidence-based recommendations are provided as to which patients could be candidates for either DBS, DLI, or subcutaneous apomorphine. KW - Parkinson’s disease KW - apomorphine KW - deep brain stimulation KW - duodenal levodopa infusion Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132373 VL - 260 ER - TY - JOUR A1 - Ehling, Petra A1 - Göb, Eva A1 - Bittner, Stefan A1 - Budde, Thomas A1 - Ludwig, Andreas A1 - Kleinschnitz, Christoph A1 - Meuth, Sven G. T1 - Ischemia-induced cell depolarization: does the hyperpolarization-activated cation channel HCN2 affect the outcome after stroke in mice? JF - Experimental & Translational Stroke Medicine N2 - Background Brain ischemia is known to include neuronal cell death and persisting neurological deficits. A lack of oxygen and glucose are considered to be key mediators of ischemic neurodegeneration while the exact mechanisms are yet unclear. In former studies the expression of two different two-pore domain potassium \((K_{2P})\) channels (TASK1, TREK1) were shown to ameliorate neuronal damage due to cerebral ischemia. In neurons, TASK channels carrying hyperpolarizing \(K^+\) leak currents, and the pacemaker channel HCN2, carrying depolarizing \(I_h\), stabilize the membrane potential by a mutual functional interaction. It is assumed that this ionic interplay between TASK and HCN2 channels enhances the resistance of neurons to insults accompanied by extracellular pH shifts. Methods In C57Bl/6 (wildtype, WT), \(hcn2^{+/+}\) and \(hcn2^{-/-}\) mice we used an in vivo model of cerebral ischemia (transient middle cerebral artery occlusion (tMCAO)) to depict a functional impact of HCN2 in stroke formation. Subsequent analyses comprise behavioural tests and hcn2 gene expression assays. Results After 60 min of tMCAO induction in WT mice, we collected tissue samples at 6, 12, and 24 h after reperfusion. In the infarcted neocortex, hcn2 expression analyses revealed a nominal peak of hcn2 expression 6 h after reperfusion with a tendency towards lower expression levels with longer reperfusion times. Hcn2 gene expression levels in infarcted basal ganglia did not change after 6 h and 12 h. Only at 24 h after reperfusion, hcn2 expression significantly decreases by ~55%. However, 30 min of tMCAO in hcn2-/- as well as hcn2+/+ littermates induced similar infarct volumes. Behavioural tests for global neurological function (Bederson score) and motor function/coordination (grip test) were performed at day 1 after surgery. Again, we found no differences between the groups. Conclusions Here, we hypothesized that the absence of HCN2, an important functional counter player of TASK channels, affects neuronal survival during stroke-induced tissue damage. However, together with a former study on TASK3 these results implicate that both TASK3 and HCN2 which were supposed to be neuroprotective due to their pH-dependency, do not influence ischemic neurodegeneration during stroke in the tMCAO model. KW - ischemia Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131887 VL - 5 IS - 16 ER - TY - JOUR A1 - Golombeck, Stefanie Kristin A1 - Wessig, Carsten A1 - Monoranu, Camelia-Maria A1 - Schütz, Ansgar A1 - Solymosi, Laszlo A1 - Melzer, Niko A1 - Kleinschnitz, Christoph T1 - Fatal atypical reversible posterior leukoencephalopathy syndrome: a case report JF - Journal of Medical Case Reports N2 - Introduction: Reversible posterior leukoencephalopathy syndrome – a reversible subacute global encephalopathy clinically presenting with headache, altered mental status, visual symptoms such as hemianopsia or cortical blindness, motor symptoms, and focal or generalized seizures – is characterized by a subcortical vasogenic edema symmetrically affecting posterior brain regions. Complete reversibility of both clinical signs and magnetic resonance imaging lesions is regarded as a defining feature of reversible posterior leukoencephalopathy syndrome. Reversible posterior leukoencephalopathy syndrome is almost exclusively seen in the setting of a predisposing clinical condition, such as pre-eclampsia, systemic infections, sepsis and shock, certain autoimmune diseases, various malignancies and cytotoxic chemotherapy, transplantation and concomitant immunosuppression (especially with calcineurin inhibitors) as well as episodes of abrupt hypertension. We describe for the first time clinical, radiological and histological findings in a case of reversible posterior leukoencephalopathy syndrome with an irreversible and fatal outcome occurring in the absence of any of the known predisposing clinical conditions except for a hypertensive episode. Case presentation: A 58-year-old Caucasian woman presented with a two-week history of subacute and progressive occipital headache, blurred vision and imbalance of gait and with no evidence for raised arterial blood pressure during the two weeks previous to admission. Her past medical history was unremarkable except for controlled arterial hypertension. Cerebral magnetic resonance imaging demonstrated cortical and subcortical lesions with combined vasogenic and cytotoxic edema atypical for both venous congestion and arterial infarction. Routine laboratory and cerebrospinal fluid parameters were normal. The diagnosis of reversible posterior leukoencephalopathy syndrome was established. Within hours after admission the patient showed a rapidly decreasing level of consciousness, extension and flexion synergisms, bilaterally extensor plantar responses and rapid cardiopulmonary decompensation requiring ventilatory and cardiocirculatory support. Follow-up cerebral imaging demonstrated widespread and confluent cytotoxic edematous lesions in different arterial territories, global cerebral swelling, and subsequent upper and lower brainstem herniation. Four days after admission, the patient was declared dead because of brain death. Conclusion: This case demonstrates that fulminant and fatal reversible posterior leukoencephalopathy syndrome may occur spontaneously, that is, in the absence of any of the known predisposing systemic conditions. KW - reversible posterior leukoencephalopathy syndrome KW - generalized cerebral edema KW - cerebral autoregulation KW - blood pressure Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129456 VL - 7 IS - 14 ER - TY - JOUR A1 - Fluri, Felix A1 - Heinen, Florian A1 - Kleinschnitz, Christoph T1 - Intravenous Thrombolysis in a Stroke Patient Receiving Rivaroxaban JF - Cerebrovascular Disease Extra N2 - No abstract available. KW - anticoagulants KW - intravenous thrombolysis KW - acute ischemic stroke Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128816 VL - 2013 IS - 3 ER - TY - JOUR A1 - Linker, Ralf A. A1 - Magnus, Tim A1 - Korn, Thomas A1 - Kleinschnitz, Christoph A1 - Meuth, Sven G. T1 - Report on the 5‘th scientific meeting of the “Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie” (NEUROWIND e.V.) held in Motzen, Germany, Oct. 25th – Oct. 27th, 2013 JF - Experimental & Translational Stroke Medicine N2 - From october 25th - 27th 2013, the 5th NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. This year more than 60 doctoral students and postdocs from over 25 different groups working in German university hospitals or research institutes attended the meeting to discuss their latest findings in the fields of neuroimmunology, neurodegeneration and neurovascular research. All participants appreciated the stimulating environment in Motzen, Brandenburg, and people took the opportunity for scientific exchange, discussion about ongoing projects and already started further collaborations. Like in the previous years, the symposium was regarded as a very well organized platform to support research of young investigators in Germany. According to the major aim of NEUROWIND e.V. to support younger researchers in Germany the 3rd NEUROWIND YOUNG SCIENTIST AWARD for experimental neurology was awarded to Ruth Stassart working in the group of Klaus Armin Nave and Wolfgang Brück (MPI Göttingen and Department of Neuropathology, Göttingen Germany). The successful work was published in Nature Neuroscience entitled “A role for Swann cell-derived neuregulin-1 in remyelination”. This outstanding paper deals with the function of Schwann cell neuregulin as an endogenous factor for myelin repair. The award is endowed with 20.000 Euro sponsored by Merck Serono GmbH, Darmstadt, Germany (unrestricted educational grant). This year’s keynote lecture was given by Albert Ludolph, Head of the Department of Neurology at the University Clinic of Ulm. Dr. Ludolph highlighted the particular role of individual scientists for the development of research concepts in Alzheimer´s disease (AD) and frontotemporal dementia (FTD). KW - NEUROWIND Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129230 VL - 5 IS - 15 ER - TY - JOUR A1 - Ehling, Petra A1 - Göb, Eva A1 - Bittner, Stefan A1 - Budde, Thomas A1 - Ludwig, Andreas A1 - Kleinschnitz, Christoph A1 - Meuth, Sven G. T1 - Ischemia-induced cell depolarization: does the hyperpolarization-activated cation channel HCN2 affect the outcome after stroke in mice? JF - Experimental & Translational Stroke Medicine N2 - Background Brain ischemia is known to include neuronal cell death and persisting neurological deficits. A lack of oxygen and glucose are considered to be key mediators of ischemic neurodegeneration while the exact mechanisms are yet unclear. In former studies the expression of two different two-pore domain potassium \((K_{2P})\) channels (TASK1, TREK1) were shown to ameliorate neuronal damage due to cerebral ischemia. In neurons, TASK channels carrying hyperpolarizing \(K^+\) leak currents, and the pacemaker channel HCN2, carrying depolarizing Ih, stabilize the membrane potential by a mutual functional interaction. It is assumed that this ionic interplay between TASK and HCN2 channels enhances the resistance of neurons to insults accompanied by extracellular pH shifts. Methods In C57Bl/6 (wildtype, WT), \(hcn2^{+/+}\) and \(hcn2^{-/-}\) mice we used an in vivo model of cerebral ischemia (transient middle cerebral artery occlusion (tMCAO)) to depict a functional impact of HCN2 in stroke formation. Subsequent analyses comprise behavioural tests and hcn2 gene expression assays. Results After 60 min of tMCAO induction in WT mice, we collected tissue samples at 6, 12, and 24 h after reperfusion. In the infarcted neocortex, hcn2 expression analyses revealed a nominal peak of hcn2 expression 6 h after reperfusion with a tendency towards lower expression levels with longer reperfusion times. Hcn2 gene expression levels in infarcted basal ganglia did not change after 6 h and 12 h. Only at 24 h after reperfusion, hcn2 expression significantly decreases by ~55%. However, 30 min of tMCAO in hcn2-/- as well as hcn2+/+ littermates induced similar infarct volumes. Behavioural tests for global neurological function (Bederson score) and motor function/coordination (grip test) were performed at day 1 after surgery. Again, we found no differences between the groups. Conclusions Here, we hypothesized that the absence of HCN2, an important functional counter player of TASK channels, affects neuronal survival during stroke-induced tissue damage. However, together with a former study on TASK3 these results implicate that both TASK3 and HCN2 which were supposed to be neuroprotective due to their pH-dependency, do not influence ischemic neurodegeneration during stroke in the tMCAO model. KW - neurology Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129240 VL - 5 IS - 16 ER - TY - JOUR A1 - Kleinschnitz, Christoph A1 - Mencl, Stine A1 - Garz, Cornelia A1 - Niklass, Solveig A1 - Braun, Holger A1 - Göb, Eva A1 - Homola, György A1 - Heinze, Hans-Jochen A1 - Reymann, Klaus G. A1 - Schreiber, Stefanie T1 - Early microvascular dysfunction in cerebral small vessel disease is not detectable on 3.0 Tesla magnetic resonance imaging: a longitudinal study in spontaneously hypertensive stroke-prone rats JF - Experimental & Translational Stroke Medicine N2 - Background Human cerebral small vessel disease (CSVD) has distinct histopathologic and imaging findings in its advanced stages. In spontaneously hypertensive stroke-prone rats (SHRSP), a well-established animal model of CSVD, we recently demonstrated that cerebral microangiopathy is initiated by early microvascular dysfunction leading to the breakdown of the blood–brain barrier and an activated coagulatory state resulting in capillary and arteriolar erythrocyte accumulations (stases). In the present study, we investigated whether initial microvascular dysfunction and other stages of the pathologic CSVD cascade can be detected by serial magnetic resonance imaging (MRI). Findings Fourteen SHRSP and three control (Wistar) rats (aged 26–44 weeks) were investigated biweekly by 3.0 Tesla (3 T) MRI. After perfusion, brains were stained with hematoxylin–eosin and histology was correlated with MRI data. Three SHRSP developed terminal CSVD stages including cortical, hippocampal, and striatal infarcts and macrohemorrhages, which could be detected consistently by MRI. Corresponding histology showed small vessel thromboses and increased numbers of small perivascular bleeds in the infarcted areas. However, 3 T MRI failed to visualize intravascular erythrocyte accumulations, even in those brain regions with the highest densities of affected vessels and the largest vessels affected by stases, as well as failing to detect small perivascular bleeds. Conclusion Serial MRI at a field strength of 3 T failed to detect the initial microvascular dysfunction and subsequent small perivascular bleeds in SHRSP; only terminal stages of cerebral microangiopathy were reliably detected. Further investigations at higher magnetic field strengths (7 T) using blood- and flow-sensitive sequences are currently underway. KW - Cerebral small vessel disease KW - SHRSP KW - MRI Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97056 UR - http://www.etsmjournal.com/content/5/1/8 ER - TY - JOUR A1 - Üçeyler, Nurcan A1 - Kahn, Ann-Kathrin A1 - Kramer, Daniela A1 - Zeller, Daniel A1 - Casanova-Molla, Jordi A1 - Wanner, Christoph A1 - Weidemann, Frank A1 - Katsarava, Zaza A1 - Sommer, Claudia T1 - Impaired small fiber conduction in patients with Fabry disease: a neurophysiological case–control study JF - BMC Neurology N2 - Background Fabry disease is an inborn lysosomal storage disorder which is associated with small fiber neuropathy. We set out to investigate small fiber conduction in Fabry patients using pain-related evoked potentials (PREP). Methods In this case–control study we prospectively studied 76 consecutive Fabry patients for electrical small fiber conduction in correlation with small fiber function and morphology. Data were compared with healthy controls using non-parametric statistical tests. All patients underwent neurological examination and were investigated with pain and depression questionnaires. Small fiber function (quantitative sensory testing, QST), morphology (skin punch biopsy), and electrical conduction (PREP) were assessed and correlated. Patients were stratified for gender and disease severity as reflected by renal function. Results All Fabry patients (31 men, 45 women) had small fiber neuropathy. Men with Fabry disease showed impaired cold (p < 0.01) and warm perception (p < 0.05), while women did not differ from controls. Intraepidermal nerve fiber density (IENFD) was reduced at the lower leg (p < 0.001) and the back (p < 0.05) mainly of men with impaired renal function. When investigating A-delta fiber conduction with PREP, men but not women with Fabry disease had lower amplitudes upon stimulation at face (p < 0.01), hands (p < 0.05), and feet (p < 0.01) compared to controls. PREP amplitudes further decreased with advance in disease severity. PREP amplitudes and warm (p < 0.05) and cold detection thresholds (p < 0.01) at the feet correlated positively in male patients. Conclusion Small fiber conduction is impaired in men with Fabry disease and worsens with advanced disease severity. PREP are well-suited to measure A-delta fiber conduction. KW - Fabry disease KW - Pain-related evoked potentials KW - Small fiber neuropathy KW - A-delta fibers Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-96527 UR - http://www.biomedcentral.com/1471-2377/13/47 ER - TY - THES A1 - Groh, Janos Michael T1 - Pathogenic impact of immune cells in mouse models of neuronal ceroid lipofuscinosis T1 - Pathogener Einfluss von Immunzellen in Mausmodellen der Neuronalen Ceroid Lipofuszinose N2 - The neuronal ceroid lipofuscinoses (NCLs) are fatal neurodegenerative disorders in which the visual system is affected in early stages of disease. A typical accompanying feature is neuroinflammation, the pathogenic impact of which is presently unknown. In this study, the role of inflammatory cells in the pathogenesis was investigated in Palmitoyl-protein thioesterase 1-deficient (Ppt1-/-) and Ceroidlipofuscinosis, neuronal 3-deficient (Cln3-/-) mice, models of the infantile and juvenile forms of NCL, respectively. Focusing predominantly on the visual system, an infiltration of CD8+ cytotoxic Tlymphocytes and an activation of microglia/macrophage-like cells was observed early in disease. To analyze the pathogenic impact of lymphocytes, Ppt1-/- mice were crossbred with mice lacking lymphocytes (Rag1-/-) and axonal transport, perturbation and neuronal survival were scored. Lack of lymphocytes led to a significant amelioration of neuronal disease and reconstitution experiments revealed a crucial role of CD8+ cytotoxic T-lymphocytes. Lack of lymphocytes also caused an improved clinical phenotype and extended longevity. To investigate the impact of microglia/macrophage-like cells, Ppt1-/- and Cln3-/- mice were crossbred with mice lacking sialoadhesin (Sn-/-), a monocyte lineage-restricted cell adhesion molecule important for interactions between macrophage-like cells and lymphocytes. Similar to the lack of lymphocytes, absence of sialoadhesin significantly ameliorated the disease in Ppt1-/- and Cln3-/- mice. Taken together, both T-lymphocytes and microglia/macrophage-like cells were identified as pathogenic mediators in two distinct forms of fatal inherited neurodegenerative storage disorders. These studies expand the concept of secondary inflammation as a common pathomechanistic feature in some neurological diseases and provide novel insights that may be crucial for developing treatment strategies for different forms of NCL. N2 - Die Neuronalen Ceroid Lipofuszinosen (NCL) sind tödlich verlaufende neurodegenerative Erkrankungen, bei denen das visuelle System frühzeitig im Krankheitsverlauf betroffen ist. Eine typische Begleiterscheinung sind Entzündungsreaktionen, deren pathogenetischer Einfluss bisher ungeklärt ist. In dieser Studie wurde die Rolle von Entzündungszellen bei der Pathogenese in Palmitoyl-protein thioestease 1-defizienten (Ppt1-/-) und Ceroid-lipofuscinosis, neuronal 3-defizienten (Cln3-/-) Mäusen untersucht, den jeweiligen Modellen der Infantilen und Juvenilen Formen der NCL. Mit besonderem Augenmerk auf das visuelle System wurde früh in der Krankheit ein Aufkommen von CD8+ zytotoxischen T-Lymphozyten und eine Aktivierung von Mikroglia/Makrophagen-ähnlichen Zellen beobachtet. Um den pathogenetischen Einfluss der Lymphozyten zu klären, wurden Ppt1-/- Mäuse mit Mäusen verkreuzt, welche keine Lymphozyten besitzen (Rag1-/-). An den generierten Doppelmutanten wurden axonaler Transport, axonale Schädigung und neuronales Überleben bestimmt. Die Abwesenheit von Lymphozyten führte zu einer signifikanten Abmilderung der neuronalen Schädigung und Rekonstitutions-Experimente zeigten, dass CD8+ zytotoxische T-Lymphozyten eine entscheidende Rolle spielen. Die Abwesenheit dieser Lymphozyten führte außerdem zu einem abgemilderten klinischen Phänotyp und einem verlängerten Überleben. Um den Einfluss von Mikroglia/Makrophagen zu untersuchen wurden Ppt1-/- und Cln3-/- Mäuse mit Sialoadhesin-defizienten Mäusen (Sn-/-) verkreuzt. Sn ist ein Monozyten-spezifisches Zelladhäsionsmolekül, das wichtig für Interaktionen zwischen Makrophagen-ähnlichen Zellen und Lymphozyten ist. Ähnlich wie die Abwesenheit von Lymphozyten führte die Abwesenheit von Sialoadhesin zu einer signifikanten Abmilderung der Krankheit in Ppt1-/- und Cln3-/- Mäusen. Zusammengefasst wurden sowohl T-Lymphozyten als auch Mikroglia/Makrophagenähnliche Zellen als pathogenetische Mediatoren in zwei verschiedenen Formen von tödlich verlaufenden erblichen neurodegenerativen Speicherkrankheiten identifiziert. Diese Untersuchungen erweitern das Konzept der sekundären Entzündungsreaktion als verbreitete pathomechanistische Erscheinung in einigen neurologischen Erkrankungen und liefern neue Perspektiven für die Entwicklung von Behandlungsstrategien für verschiedene Formen der NCL. KW - Nervendegeneration KW - Maus KW - Entzündung KW - T-Lymphozyt KW - Neuronale Ceroid Lipofuszinose KW - Neuroinflammation KW - Neurodegeneration KW - axonaler Schaden KW - T-Lymphozyten KW - neuronal ceroid lipofuscinosis KW - neuroinflammation KW - neurodegeneration KW - axonal damage KW - T-lymphocytes Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-77684 ER - TY - THES A1 - Dreykluft, Angela T1 - The PD-1/B7-H1 Pathway in a Transgenic Mouse Model for Spontaneous Autoimmune Neuroinflammation: Immunological Studies on Devic B7-H1-/- Mice T1 - Der PD-1/B7-H1 Signalweg in einem transgenen Mausmodell für spontane autoimmune Neuroinflammation: Immunologische Studien an Devic B7-H1-/- Mäusen N2 - Multiple sclerosis is an autoimmune disease of the central nervous system characterized by inflammatory, demyelinating lesions and neuronal death. Formerly regarded as a variant of MS, neuromyelitis optica (NMO)/Devic’s disease is now recognized as a distinct neurological disorder exhibiting characteristic inflammatory and demyelinated foci in the optic nerves and the spinal cord sparing the brain. With the introduction of the double-transgenic “Devic mouse” model featuring spontaneous, adjuvant-free incidence of autoimmune neuroinflammation due to the interaction of transgenic MOG-specific T and B cells, a promising tool was found for the analysis of factors triggering or preventing autoimmunity. The co-inhibitory molecule B7-H1 has been proposed to contribute to the maintenance of peripheral tolerance and to confine autoimmune inflammatory damage via the PD-1/B7-H1 pathway. Compared to Devic B7-H1+/+ mice, Devic B7-H1-/- mice developed clinical symptoms with a remarkably higher incidence rate and faster kinetics emphasized by deteriorated disease courses and a nearly quadrupled mortality rate. Remarkably enlarged immune-cell accumulation in the CNS of Devic B7-H1-/- mice, in particular of activated MOG-specific CD4+ T cells, correlated with the more severe clinical features. Our studies showed that the CNS not only was the major site of myelin-specific CD4+ T-cell activation but also that B7-H1 expression within the target organ significantly influenced T-cell activation and differentiation levels. Analysis at disease maximum revealed augmented accumulation of MOG-specific CD4+ T cells in the peripheral lymphoid organs of Devic B7-H1-/- mice partly due to increased T-cell proliferation rates. Transgenic MOG-specific B cells of Devic B7-H1-/- mice activated MOG-specific CD4+ T cells more efficiently than B cells of Devic B7-H1+/+ mice. This observation indicated a relevant immune-modulating role of B7-H1 on APCs (antigen-presenting cells) in this mouse model. We also assumed altered thymic selection processes to be involved in increased peripheral CD4+ T-cell numbers of Devic B7-H1-/- mice as we found more thymocytes expressing the transgenic MOG-specific T-cell receptor (TCR). Moreover, preliminary in vitro experiments hinted on an enhanced survival of TCRMOG-transgenic CD4+ T cells of Devic B7-H1-/- mice; a mechanism that might as well have led to higher peripheral T-cell accumulation. Elevated levels of MOG-specific CD4+ T cells in the periphery of Devic B7-H1-/- mice could have entailed the higher quantities in the CNS. However, mechanisms such as CNS-specific proliferation and/or apoptosis/survival could also have contributed. This should be addressed in future investigations. Judging from in vitro migration assays and adoptive transfer experiments on RAG-1-/- recipient mice, migratory behavior of MOG-specific CD4+ T cells of Devic B7-H1+/+ and Devic B7-H1-/- mice seemed not to differ. However, enhanced expression of the transmigration-relevant integrin LFA-1 on CD4+ T cells in young symptom-free Devic B7-H1-/- mice might hint on temporally differently pronounced transmigration capacities during the disease course. Moreover, we attributed the earlier conversion of CD4+ T cells into Th1 effector cells in Devic B7-H1-/- mice during the initiation phase to the lack of co-inhibitory signaling via PD-1/B7-H1 possibly leading to an accelerated disease onset. Full blown autoimmune inflammatory processes could have masked these slight effects of B7-H1 in the clinical phase. Accordingly, at peak of the disease, Th1 and Th17 effector functions of peripheral CD4+ T cells were comparable in both mouse groups. Moreover, judging from titers of MOG-specific IgG1 and IgM antibodies, alterations in humoral immunity were not detected. Therefore, clinical differences could not be explained by altered T-cell or B-cell effector functions at disease maximum. B7-H1 rather seemed to take inhibitory effect in the periphery during the initiation phase only and consistently within the target organ by parenchymal expression. Our observations indicate that B7-H1 plays a relevant role in the regulation of T-cell responses in this mouse model for spontaneous CNS autoimmunity. By exerting immune-modulating effects in the preclinical as well as the clinical phase of the disease, B7-H1 contributed to the confinement of the immunopathological tissue damage in Devic B7-H1+/+ mice mirrored by later disease onsets and lower disease scores. As a model for spontaneous autoimmunity featuring a close to 100 % incidence rate, the Devic B7-H1-/- mouse may prove instrumental in clarifying disease-triggering and -limiting factors and in validating novel therapeutic approaches in the field of autoimmune neuroinflammation, in particular the human Devic’s disease. N2 - Multiple Sklerose ist eine Autoimmunerkrankung des zentralen Nervensystems, die durch entzündliche, demyelinisierende Läsionen und neuronalen Tod gekennzeichnet ist. Einst als Variante der MS betrachtet, gilt die Neuromyelitis optica (NMO) / Devic-Krankheit heute als eigenständige neurologische Erkrankung, bei der charakteristische Läsionen in den Sehnerven und im Rückenmark jedoch nicht im Gehirn auftreten. Mit der Einführung des doppelt-transgenen "Devic Maus"-Modells, bei dem es zur spontanen, Adjuvans-freien Inzidenz von autoimmuner Neuroinflammation durch Expression transgener MOG-spezifischer T- und B-Zellen kommt, wurde ein vielversprechendes Werkzeug für die Analyse von Faktoren gefunden, die Autoimmunität auslösen bzw. hemmen können. Das ko-inhibitorische Molekül B7-H1 trägt über den PD-1/B7-H1 Signalweg vermeintlich zur Aufrechterhaltung peripherer Toleranz bei. Devic B7-H1-/ - Mäuse entwickelten im Vergleich zu Devic B7-H1+/ + Mäusen Symptome, die mit deutlich höherer Inzidenz und schnellerer Kinetik einhergingen, unterstrichen von verstärkten Krankheitsverläufen und einer nahezu vervierfachten Sterblichkeit. Die verstärkte Akkumulierung von Immunzellen im ZNS, insbesondere von aktivierten MOG-spezifischen CD4+ T-Zellen, korrelierte mit den schwerwiegenderen klinischen Merkmalen. Unsere Untersuchungen zeigten nicht nur, dass die Aktivierung von myelin-spezifischen CD4+ T-Zellen hauptsächlich im ZNS stattfand, sondern auch, dass im Zielorgan exprimiertes B7-H1 maßgeblich den T-Zell-Aktivierungs- und -Differenzierungsgrad beeinflusste. Analysen am Krankheitsmaximum zeigten eine verstärkte Akkumulierung von MOG-spezifischen CD4+ T-Zellen in den Lymphorganen von Devic B7-H1-/- Mäusen, die wir teils auf erhöhte T-Zell-Proliferation zurückzuführten. Transgene MOG-spezifische B-Zellen der Devic B7-H1-/- Mäuse aktivierten effizienter als B-Zellen der Devic B7-H1+/+ Mäuse MOG-spezifische CD4+ T-Zellen. Dies deutet auf eine wichtige immunmodulierende Rolle von B7-H1 auf Antigen-präsentierenden Zellen in diesem Mausmodell hin. Veränderte Selektionsprozesse im Thymus trugen wohlmöglich zu den höheren CD4+ T-Zellzahlen in der Peripherie bei. Vorläufige in vitro Experimente deuteten auf ein verbessertes Überleben von TCRMOG-transgenen CD4+ T-Zellen aus Devic B7-H1-/- Mäusen hin. Eine erhöhte Anzahl von peripheren MOG-spezifischen CD4+ T-Zellen könnte zu den größeren Mengen im ZNS von Devic B7-H1-/- Mäusen geführt haben. Jedoch sind zusätzliche Mechanismen wie ZNS-spezifische Proliferation und/oder Apoptose bzw. Überleben denkbar. Dies sollte in zukünftigen Untersuchungen genauer analysiert werden. Anhand von in vitro-Migrationsassays und Adoptiver Transfer-Experimenten in RAG-1-/- Mäusen schlossen wir, dass das Migrationsverhalten von MOG-spezifischen CD4+ T-Zellen von Devic B7-H1-/- Mäusen nicht verändert war. Allerdings deutet die verstärkte Expression des transmigrationsrelevanten Intergins LFA-1 auf CD4+ T-Zellen in jungen, symptomfreien Devic B7-H1-/- Mäusen auf im Krankheitsverlauf zeitlich verschieden ausgeprägte Transmigrationskapazitäten hin. Die frühere Differenzierung von peripheren CD4+ T-Zellen in Th1-Effektorzellen in Devic B7-H1-/- Mäusen während der Initiationsphase schrieben wir der fehlenden inhibierenden Wirkung des PD-1/B7-H1 Signalwegs zu, was den früheren Krankheitsbeginn bedingt haben könnte. Stark ausgeprägte autoimmune Entzündungsreaktionen am Krankheitsmaximum maskierten jedoch wahrscheinlich diese schwachen Effekte von B7-H1. Dies wurde durch die Tatsache untermauert, dass am Krankheitsmaximum Th1- und Th17-Effektorfunktionen von peripheren CD4+ T-Zellen in beiden Mausgruppen vergleichbar ausgeprägt waren. Des Weiteren bestanden am Krankheitsmaximum keine Unterschiede in der humoralen Immunität. Die beobachteten klinischen Unterschiede waren demnach nicht durch veränderte periphere T-Zell- oder B-Zell-Effektorfunktionen in dieser Krankheitsphase erklärbar. Vielmehr scheint B7-H1 in der Peripherie ausschließlich während der Initiationsphase der Krankheit und fortwährend im Zielorgan durch seine parenchymale Expression immuninhibierend zu wirken. Unsere Beobachtungen zeigen, dass B7-H1 eine relevante Rolle bei der Immunregulierung im vorliegenden Mausmodell für spontane ZNS-Autoimmunität spielt. Durch immunmodulierende Effekte in der präklinischen sowie der klinischen Phase der Krankheit trug B7-H1 zu der Begrenzung der immunpathologischen Gewebeschädigung in Devic B7-H1+/+ Mäusen bei, sichtbar an einem späteren Krankheitsbeginn und leichteren -verlauf. Als Tiermodell für spontane ZNS-Autoimmunität mit nahezu 100 %iger Inzidenz könnte sich die Devic B7-H1-/- Maus als hilfreich bei der Klärung krankheitsauslösender und -limitierender Faktoren erweisen sowie bei der Validierung neuer therapeutischer Ansätze im Bereich der autoimmunen Neuroinflammation, insbesondere der Devic-Krankheit im Menschen. KW - Autoimmunität KW - Zentralnervensystem KW - Neuroinflammation KW - B7-H1 KW - Ko-inhibitorischer Signalweg KW - Devic Maus KW - autoimmunity KW - neuroinflammation KW - B7-H1 KW - co-inhibitory signalling KW - Devic mice KW - Maus KW - Entzündung KW - Signaltransduktion Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-83288 ER - TY - JOUR A1 - Gunreben, Ignaz A1 - Geis, Christian A1 - Kleinschnitz, Christoph T1 - Acute tetraparesis secondary to bilateral precentral gyral cerebral ischemia: a case report JF - Journal of Medical Case Reports N2 - Introduction Sudden tetraparesis represents a neurological emergency and is most often caused by traumatic spinal cord injury, spinal epidural bleeding or brainstem ischemia and less frequently by medial disc herniation or spinal ischemia. Case presentation Here we report the rare case of an 82-year-old Caucasian man who developed severe tetraparesis four days after radical cystoprostatectomy. An emergency diagnostic study for spinal cord affection was normal. Brain magnetic resonance imaging revealed acute bilateral ischemic strokes in the precentral gyri as the underlying cause. Conclusions This case report underlines the need to also consider unusual causes of tetraparesis in an emergency situation apart from spinal cord or brain stem injury in order not to leave severe symptomatology unclear and possibly miss therapeutic options. KW - Medizin Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-96179 UR - http://www.jmedicalcasereports.com/content/7/1/61 ER - TY - JOUR A1 - Kraft, Peter A1 - Drechsler, Christiane A1 - Gunreben, Ignaz A1 - Heuschmann, Peter Ulrich A1 - Kleinschnitz, Christoph T1 - Regulation of Blood Coagulation Factors XI and XII in Patients with Acute and Chronic Cerebrovascular Disease: A Case-Control Study JF - Cerebrovascular Diseases N2 - Background: Animal models have implicated an integral role for coagulation factors XI (FXI) and XII (FXII) in thrombus formation and propagation of ischemic stroke (IS). However, it is unknown if these molecules contribute to IS pathophysiology in humans, and might be of use as biomarkers for IS risk and severity. This study aimed to identify predictors of altered FXI and FXII levels and to determine whether there are differences in the levels of these coagulation factors between acute cerebrovascular events and chronic cerebrovascular disease (CCD). Methods: In this case-control study, 116 patients with acute ischemic stroke (AIS) or transitory ischemic attack (TIA), 117 patients with CCD, and 104 healthy volunteers (HVs) were enrolled between 2010 and 2013 at our University hospital. Blood sampling was undertaken once in the CCD and HV groups and on days 0, 1, and 3 after stroke onset in patients with AIS or TIA. Correlations between serum FXI and FXII levels and demographic and clinical parameters were tested by linear regression and analysis of variance. Results: The mean age of AIS/TIA patients was 70 ± 12. Baseline clinical severity measured with NIHSS and Barthel Index was 4.8 ± 6.0 and 74 ± 30, respectively. More than half of the patients had an AIS (58%). FXI levels were significantly correlated with different leukocyte subsets (p < 0.05). In contrast, FXII serum levels showed no significant correlation (p > 0.1). Neither FXI nor FXII levels correlated with CRP (p > 0.2). FXII levels were significantly higher in patients with CCD compared with those with AIS/TIA (mean ± SD 106 ± 26% vs. 97 ± 24%; univariate analysis: p < 0.05); these differences did not reach significance in multivariate analysis adjusted for sex and age. FXI levels did not differ significantly between study groups. Sex and age were significantly associated with FXI and/or FXII levels in patients with AIS/TIA (p < 0.05). In contrast, no statistical significant influence was found for treatment modality (thrombolysis or not), pre-treatment with platelet inhibitors, and severity of stroke. Conclusions: In this study, there was no differential regulation of FXI and FXII levels between disease subtypes but biomarker levels were associated with patient and clinical characteristics. FXI and FXII levels might be no valid biomarker for predicting stroke risk. KW - biomarker KW - factor XI KW - factor XII KW - ischemic stroke KW - chronic cerebrovascular disease Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199076 SN - 1015-9770 SN - 1421-9786 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 38 IS - 5 ER - TY - JOUR A1 - Häuser, Winfried A1 - Walitt, Brian A1 - Fitzcharles, Mary-Ann A1 - Sommer, Claudia T1 - Review of pharmacological therapies in fibromyalgia syndrome JF - Arthritis Research & Therapy N2 - This review addresses the current status of drug therapy for the management of fibromyalgia syndrome (FMS) and is based on interdisciplinary FMS management guidelines, meta-analyses of drug trial data, and observational studies. In the absence of a single gold-standard medication, patients are treated with a variety of drugs from different categories, often with limited evidence. Drug therapy is not mandatory for the management of FMS. Pregabalin, duloxetine, milnacipran, and amitriptyline are the current first-line prescribed agents but have had a mostly modest effect. With only a minority of patients expected to experience substantial benefit, most will discontinue therapy because of either a lack of efficacy or tolerability problems. Many drug treatments have undergone limited study and have had negative results. It is unlikely that these failed pilot trials will undergo future study. However, medications, though imperfect, will continue to be a component of treatment strategy for these patients. Both the potential for medication therapy to relieve symptoms and the potential to cause harm should be carefully considered in their administration. Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121598 SN - 1465-9913 VL - 16 IS - 201 ER - TY - JOUR A1 - Üçeyler, Nurcan A1 - Homola, György A. A1 - González, Hans Guerrero A1 - Kramer, Daniela A1 - Wanner, Christoph A1 - Weidemann, Frank A1 - Solymosi, László A1 - Sommer, Claudia T1 - Increased Arterial Diameters in the Posterior Cerebral Circulation in Men with Fabry Disease N2 - A high load of white matter lesions and enlarged basilar arteries have been shown in selected patients with Fabry disease, a disorder associated with an increased stroke risk. We studied a large cohort of patients with Fabry disease to differentially investigate white matter lesion load and cerebral artery diameters. We retrospectively analyzed cranial magnetic resonance imaging scans of 87 consecutive Fabry patients, 20 patients with ischemic stroke, and 36 controls. We determined the white matter lesion load applying the Fazekas score on fluid-attenuated inversion recovery sequences and measured the diameters of cerebral arteries on 3D-reconstructions of the time-of-flight-MR-angiography scans. Data of different Fabry patient subgroups (males – females; normal – impaired renal function) were compared with data of patients with stroke and controls. A history of stroke or transient ischemic attacks was present in 4/30 males (13%) and 5/57 (9%) females with Fabry disease, all in the anterior circulation. Only one man with Fabry disease showed confluent cerebral white matter lesions in the Fazekas score assessment (1%). Male Fabry patients had a larger basilar artery (p<0.01) and posterior cerebral artery diameter (p<0.05) compared to male controls. This was independent of disease severity as measured by renal function and did not lead to changes in arterial blood flow properties. A basilar artery diameter of >3.2 mm distinguished between men with Fabry disease and controls (sensitivity: 87%, specificity: 86%, p<0.001), but not from stroke patients. Enlarged arterial diameters of the posterior circulation are present only in men with Fabry disease independent of disease severity. KW - Arterial Diameters KW - ischemic stroke KW - magnetic resonance imaging KW - stroke KW - cerebral arteries KW - renal system KW - central nervous system KW - blood flow KW - lesions Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-112614 ER - TY - JOUR A1 - Üçeyler, Nurcan A1 - Sommer, Claudia T1 - High-Dose Capsaicin for the Treatment of Neuropathic Pain: What We Know and What We Need to Know JF - Pain and Therapy N2 - Neuropathic pain is a frequent and disabling condition with diverse underlying etiologies and is often difficult to treat. Systemic drug treatment is often limited in efficacy. Furthermore, adverse effects may be a limiting factor when trying to reach the necessary dose. Analgesics that can be applied topically have the potential to largely overcome this problem. They may be of particular advantage in localized neuropathic pain syndromes such as postherpetic neuralgia or small fiber neuropathy. Capsaicin, the pungent component of chili peppers, is a natural ligand of the transient receptor potential vanilloid 1 channel and has long been used as topically applicable cream with concentrations of 0.025 to 0.075%. In 2009, a high-concentration transdermal capsaicin 8% patch (Qutenza ; Acorda Therapeutics, Inc., Ardsley, NY, USA; Astellas Pharma Europe Ltd., Chertsey, Surrey, UK) was introduced for the treatment of peripheral neuropathic pain syndromes other than of diabetic origin in adults. It has since been widely used in diverse neuropathic pain disorders. In this review article, we summarize current knowledge on Qutenza, its advantages and problems, and expose unmet needs. KW - transient receptor potential vanilloid 1 (TRPV1) KW - analgesia KW - capsaicin KW - neuropathic pain KW - qutenza Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120669 SN - 2193-651X VL - 3 IS - 2 ER - TY - JOUR A1 - Niemann, Axel A1 - Huber, Nina A1 - Wagner, Konstanze M. A1 - Somandin, Christian A1 - Horn, Michael A1 - Lebrun-Julien, Frédéric A1 - Angst, Brigitte A1 - Pereira, Jorge A. A1 - Halfter, Hartmut A1 - Welzl, Hans A1 - Feltri, M. Laura A1 - Wrabetz, Lawrence A1 - Young, Peter A1 - Wessig, Carsten A1 - Toyka, Klaus V. A1 - Suter, Ueli T1 - The Gdap1 knockout mouse mechanistically links redox control to Charcot–Marie–Tooth disease JF - Brain N2 - The ganglioside-induced differentiation-associated protein 1 (GDAP1) is a mitochondrial fission factor and mutations in GDAP1 cause Charcot–Marie–Tooth disease. We found that Gdap1 knockout mice (\(Gdap1^{−/−}\)), mimicking genetic alterations of patients suffering from severe forms of Charcot–Marie–Tooth disease, develop an age-related, hypomyelinating peripheral neuropathy. Ablation of Gdap1 expression in Schwann cells recapitulates this phenotype. Additionally, intra-axonal mitochondria of peripheral neurons are larger in \(Gdap1^{−/−}\) mice and mitochondrial transport is impaired in cultured sensory neurons of \(Gdap1^{−/−}\) mice compared with controls. These changes in mitochondrial morphology and dynamics also influence mitochondrial biogenesis. We demonstrate that mitochondrial DNA biogenesis and content is increased in the peripheral nervous system but not in the central nervous system of \(Gdap1^{−/−}\) mice compared with control littermates. In search for a molecular mechanism we turned to the paralogue of GDAP1, GDAP1L1, which is mainly expressed in the unaffected central nervous system. GDAP1L1 responds to elevated levels of oxidized glutathione by translocating from the cytosol to mitochondria, where it inserts into the mitochondrial outer membrane. This translocation is necessary to substitute for loss of GDAP1 expression. Accordingly, more GDAP1L1 was associated with mitochondria in the spinal cord of aged \(Gdap1^{−/−}\) mice compared with controls. Our findings demonstrate that Charcot–Marie–Tooth disease caused by mutations in GDAP1 leads to mild, persistent oxidative stress in the peripheral nervous system, which can be compensated by GDAP1L1 in the unaffected central nervous system. We conclude that members of the GDAP1 family are responsive and protective against stress associated with increased levels of oxidized glutathione. KW - animal models KW - Charcot-Marie-Tooth disease KW - mitochondria KW - axonal transport KW - demyelinating disease Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120731 VL - 137 IS - 3 ER - TY - JOUR A1 - Albert-Weissenberger, Christiane A1 - Mencl, Stine A1 - Schuhmann, Michael K. A1 - Salur, Irmak A1 - Göb, Eva A1 - Langhauser, Friederike A1 - Hopp, Sarah A1 - Hennig, Nelli A1 - Meuth, Sven G. A1 - Nolte, Marc W. A1 - Sirén, Anna-Leena A1 - Kleinschnitz, Christoph T1 - C1-Inhibitor protects from focal brain trauma in a cortical cryolesion mice model by reducing thrombo-inflammation JF - Frontiers in Cellular Neuroscience N2 - Traumatic brain injury (TBI) induces a strong inflammatory response which includes blood-brain barrier damage, edema formation and infiltration of different immune cell subsets. More recently, microvascular thrombosis has been identified as another pathophysiological feature of TBI. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is activated in different neurological diseases. C1-Inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-Inhibitor in a model of TBI. Male and female C57BL/6 mice were subjected to cortical cryolesion and treated with C1-Inhibitor after 1 h. Lesion volumes were assessed between day 1 and day 5 and blood-brain barrier damage, thrombus formation as well as the local inflammatory response were determined post TBI. Treatment of male mice with 15.0 IU C1-Inhibitor, but not 7.5 IU, 1 h after cryolesion reduced lesion volumes by ~75% on day 1. This protective effect was preserved in female mice and at later stages of trauma. Mechanistically, C1-Inhibitor stabilized the blood-brain barrier and decreased the invasion of immune cells into the brain parenchyma. Moreover, C1-Inhibitor had strong antithrombotic effects. C1-Inhibitor represents a multifaceted anti-inflammatory and antithrombotic compound that prevents traumatic neurodegeneration in clinically meaningful settings. KW - thrombosis KW - traumatic brain injury KW - C1-inhibitor KW - blood-brain barrier KW - contact-kinin system KW - edema KW - inflammation Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119263 SN - 1662-5102 VL - 8 ER - TY - JOUR A1 - Mencacci, Niccoló E. A1 - Isaias, Ioannis U. A1 - Reich, Martin M. A1 - Ganos, Christos A1 - Plagnol, Vincent A1 - Polke, James M. A1 - Bras, Jose A1 - Hersheson, Joshua A1 - Stamelou, Maria A1 - Pittman, Alan M. A1 - Noyce, Alastair J. A1 - Mok, Kin Y. A1 - Opladen, Thomas A1 - Kunstmann, Erdmute A1 - Hodecker, Sybille A1 - Münchau, Alexander A1 - Volkmann, Jens A1 - Samnick, Samuel A1 - Sidle, Katie A1 - Nanji, Tina A1 - Sweeney, Mary G. A1 - Houlden, Henry A1 - Batla, Amit A1 - Zecchinelli, Anna L. A1 - Pezzoli, Gianni A1 - Marotta, Giorgio A1 - Lees, Andrew A1 - Alegria, Paulo A1 - Krack, Paul A1 - Cormier-Dequaire, Florence A1 - Lesage, Suzanne A1 - Brice, Alexis A1 - Heutink, Peter A1 - Gasser, Thomas A1 - Lubbe, Steven J. A1 - Morris, Huw R. A1 - Taba, Pille A1 - Koks, Sulev A1 - Majounie, Elisa A1 - Gibbs, J. Raphael A1 - Singleton, Andrew A1 - Hardy, John A1 - Klebe, Stephan A1 - Bhatia, Kailash P. A1 - Wood, Nicholas W. T1 - Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers JF - Brain N2 - GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease. KW - DOPA-responsive-dystonia KW - GCH1 KW - Parkinson's disease KW - dopamine KW - exome sequencing Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121268 VL - 137 IS - 9 ER - TY - JOUR A1 - Hohnmann, Christopher A1 - Milles, Bianca A1 - Schinke, Michael A1 - Schroeter, Michael A1 - Ulzheimer, Jochen A1 - Kraft, Peter A1 - Kleinschnitz, Christoph A1 - Lehmann, Paul V. A1 - Kuerten, Stefanie T1 - Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood JF - Acta Neuropathologica Communications N2 - Introduction B cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients. Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) directly ex vivo and after 96 h of polyclonal stimulation. Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS). Results Nine patients displayed B cells in the blood producing brain-specific antibodies directly ex vivo. Six patients were classified as B cell positive donors only after polyclonal B cell stimulation. In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorized MS relapses into three different patterns. Patients who displayed brain-reactive B cell responses both directly ex vivo and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; p = 0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse. The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40%) with a pattern II and three of 14 patients (21.4%) with a pattern III response (p = 0.0005; hazard ratio 6.08 (95% confidence interval 1.87-19.77). Conclusions Our data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients. KW - predictive value KW - MS KW - ELISPOT KW - B cells KW - relapse Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126124 VL - 2 IS - 138 ER - TY - JOUR A1 - Isaias, Ioannis Ugo A1 - Spiegel, Jörg A1 - Brumberg, Joachim A1 - Cosgrove, Kelly P. A1 - Marotta, Giorgio A1 - Oishi, Naoya A1 - Higuchi, Takahiro A1 - Küsters, Sebastian A1 - Schiller, Markus A1 - Dillmann, Ulrich A1 - van Dyck, Christopher H. A1 - Buck, Andreas A1 - Herrmann, Ken A1 - Schloegl, Susanne A1 - Volkmann, Jens A1 - Lassmann, Michael A1 - Fassbender, Klaus A1 - Lorenz, Reinhard A1 - Samnick, Samuel T1 - Nicotinic acetylcholine receptor density in cognitively intact subjects at an early stage of Parkinson's disease JF - Frontiers in Aging Neuroscience N2 - We investigated in vivo brain nicotinic acetylcholine receptor (nAChR) distribution in cognitively intact subjects with Parkinson's disease (PD) at an early stage of the disease. Fourteen patients and 13 healthy subjects were imaged with single photon emission computed tomography and the radiotracer 5-[(123)I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine ([(123)I]5IA). Patients were selected according to several criteria, including short duration of motor signs (<7 years) and normal scores at an extensive neuropsychological evaluation. In PD patients, nAChR density was significantly higher in the putamen, the insular cortex and the supplementary motor area and lower in the caudate nucleus, the orbitofrontal cortex, and the middle temporal gyrus. Disease duration positively correlated with nAChR density in the putamen ipsilateral (ρ = 0.56, p < 0.05) but not contralateral (ρ = 0.49, p = 0.07) to the clinically most affected hemibody. We observed, for the first time in vivo, higher nAChR density in brain regions of the motor and limbic basal ganglia circuits of subjects with PD. Our findings support the notion of an up-regulated cholinergic activity at the striatal and possibly cortical level in cognitively intact PD patients at an early stage of disease. KW - nicotinic receptors KW - Parkinson disease KW - 5IA-SPECT KW - dopamine acetylcholine KW - cognitive decline Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119351 VL - 6 ER - TY - JOUR A1 - Albert-Weissenberger, Christiane A1 - Mencl, Stine A1 - Hopp, Sarah A1 - Kleinschnitz, Christoph A1 - Siren, Anna-Leena T1 - Role of the kallikrein-kinin system in traumatic brain injury JF - Frontiers in Cellular Neuroscience N2 - Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Despite improvements in acute intensive care, there are currently no specific therapies to ameliorate the effects of TBI. Successful therapeutic strategies for TBI should target multiple pathophysiologic mechanisms that occur at different stages of brain injury. The kallikrein-kinin system is a promising therapeutic target for TBI as it mediates key pathologic events of traumatic brain damage, such as edema formation, inflammation, and thrombosis. Selective and specific kinin receptor antagonists and inhibitors of plasma kallikrein and coagulation factor XII have been developed, and have already shown therapeutic efficacy in animal models of stroke and TBI. However, conflicting preclinical evaluation, as well as limited and inconclusive data from clinical trials in TBI, suggests that caution should be taken before transferring observations made in animals to humans. This review summarizes current evidence on the pathologic significance of the kallikrein-kinin system during TBI in animal models and, where available, the experimental findings are compared with human data. KW - bradykinin KW - factor XII KW - kallikrein–kinin system KW - kinin receptor KW - traumatic brain injury Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118226 SN - 1662-5102 VL - 8 ER - TY - JOUR A1 - Hohmann, Christopher A1 - Milles, Bianca A1 - Schinke, Michael A1 - Schroeter, Michael A1 - Ulzheimer, Jochen A1 - Kraft, Peter A1 - Kleinschnitz, Christoph A1 - Lehmann, Paul V. A1 - Kuerten, Stefanie T1 - Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood JF - Acta Neuropathologica Communications N2 - INTRODUCTION: B cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients. Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) directly ex vivo and after 96 h of polyclonal stimulation. Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS). RESULTS: Nine patients displayed B cells in the blood producing brain-specific antibodies directly ex vivo. Six patients were classified as B cell positive donors only after polyclonal B cell stimulation. In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorized MS relapses into three different patterns. Patients who displayed brain-reactive B cell responses both directly ex vivo and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; p = 0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse. The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40%) with a pattern II and three of 14 patients (21.4%) with a pattern III response (p = 0.0005; hazard ratio 6.08 (95% confidence interval 1.87-19.77). CONCLUSIONS: Our data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients. KW - ELISPOT KW - MS KW - predictive value KW - relapse KW - B cells Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120580 SN - 2051-5960 VL - 2 IS - 138 ER - TY - JOUR A1 - Isaias, Ioannis Ugo A1 - Dipaola, Mariangela A1 - Michi, Marlies A1 - Marzegan, Alberto A1 - Volkmann, Jens A1 - Rodocanachi Roidi, Mariana L. A1 - Frigo, Carlo Albino A1 - Cavallari, Paolo T1 - Gait Initiation in Children with Rett Syndrome JF - PLoS ONE N2 - Rett syndrome is an X-linked neurodevelopmental condition mainly characterized by loss of spoken language and a regression of purposeful hand use, with the development of distinctive hand stereotypies, and gait abnormalities. Gait initiation is the transition from quiet stance to steady-state condition of walking. The associated motor program seems to be centrally mediated and includes preparatory adjustments prior to any apparent voluntary movement of the lower limbs. Anticipatory postural adjustments contribute to postural stability and to create the propulsive forces necessary to reach steady-state gait at a predefined velocity and may be indicative of the effectiveness of the feedforward control of gait. In this study, we examined anticipatory postural adjustments associated with gait initiation in eleven girls with Rett syndrome and ten healthy subjects. Muscle activity (tibialis anterior and soleus muscles), ground reaction forces and body kinematic were recorded. Children with Rett syndrome showed a distinctive impairment in temporal organization of all phases of the anticipatory postural adjustments. The lack of appropriate temporal scaling resulted in a diminished impulse to move forward, documented by an impairment in several parameters describing the efficiency of gait start: length and velocity of the first step, magnitude and orientation of centre of pressure-centre of mass vector at the instant of (swing-)toe off. These findings were related to an abnormal muscular activation pattern mainly characterized by a disruption of the synergistic activity of antagonistic pairs of postural muscles. This study showed that girls with Rett syndrome lack accurate tuning of feedforward control of gait. KW - syndrome KW - ankles   KW - biological locomotion KW - kinematics KW - rett KW - soleus muscles KW - walking KW - velocity KW - children Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119789 SN - 1932-6203 VL - 9 IS - 4 ER - TY - JOUR A1 - Kraft, Peter A1 - Drechsler, Christiane A1 - Gunreben, Ignaz A1 - Nieswandt, Bernhard A1 - Stoll, Guido A1 - Heuschmann, Peter Ulrich A1 - Kleinschnitz, Christoph T1 - Von Willebrand Factor Regulation in Patients with Acute and Chronic Cerebrovascular Disease: A Pilot, Case-Control Study JF - PLoS ONE N2 - Background and Purpose In animal models, von Willebrand factor (VWF) is involved in thrombus formation and propagation of ischemic stroke. However, the pathophysiological relevance of this molecule in humans, and its potential use as a biomarker for the risk and severity of ischemic stroke remains unclear. This study had two aims: to identify predictors of altered VWF levels and to examine whether VWF levels differ between acute cerebrovascular events and chronic cerebrovascular disease (CCD). Methods A case–control study was undertaken between 2010 and 2013 at our University clinic. In total, 116 patients with acute ischemic stroke (AIS) or transitory ischemic attack (TIA), 117 patients with CCD, and 104 healthy volunteers (HV) were included. Blood was taken at days 0, 1, and 3 in patients with AIS or TIA, and once in CCD patients and HV. VWF serum levels were measured and correlated with demographic and clinical parameters by multivariate linear regression and ANOVA. Results Patients with CCD (158±46%) had significantly higher VWF levels than HV (113±36%, P<0.001), but lower levels than AIS/TIA patients (200±95%, P<0.001). Age, sex, and stroke severity influenced VWF levels (P<0.05). Conclusions VWF levels differed across disease subtypes and patient characteristics. Our study confirms increased VWF levels as a risk factor for cerebrovascular disease and, moreover, suggests that it may represent a potential biomarker for stroke severity, warranting further investigation. KW - cerebrovascular diseases KW - sex addiction KW - biomarkers KW - ischemic stroke KW - blood KW - stroke KW - platelets KW - demography Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119588 SN - 1932-6203 VL - 9 IS - 6 ER - TY - JOUR A1 - Wurmb, Thomas Erik A1 - Schlereth, Stefan A1 - Kredel, Markus A1 - Muellenbach, Ralf M. A1 - Wunder, Christian A1 - Brederlau, Jörg A1 - Roewer, Norbert A1 - Kenn, Werner A1 - Kunze, Ekkehard T1 - Routine Follow-Up Cranial Computed Tomography for Deeply Sedated, Intubated, and Ventilated Multiple Trauma Patients with Suspected Severe Head Injury JF - BioMed Research International N2 - Background. Missed or delayed detection of progressive neuronal damage after traumatic brain injury (TBI) may have negative impact on the outcome. We investigated whether routine follow-up CT is beneficial in sedated and mechanically ventilated trauma patients. Methods. The study design is a retrospective chart review. A routine follow-up cCT was performed 6 hours after the admission scan. We defined 2 groups of patients, group I: patients with equal or recurrent pathologies and group II: patients with new findings or progression of known pathologies. Results. A progression of intracranial injury was found in 63 patients (42%) and 18 patients (12%) had new findings in cCT 2 (group II). In group II a change in therapy was found in 44 out of 81 patients (54%). 55 patients with progression or new findings on the second cCT had no clinical signs of neurological deterioration. Of those 24 patients (44%) had therapeutic consequences due to the results of the follow-up cCT. Conclusion. We found new diagnosis or progression of intracranial pathology in 54% of the patients. In 54% of patients with new findings and progression of pathology, therapy was changed due to the results of follow-up cCT. In trauma patients who are sedated and ventilated for different reasons a routine follow-up CT is beneficial. KW - Computertomographie Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120084 IS - 361949 ER - TY - JOUR A1 - Giordano, Rosaria A1 - Canesi, Margherita A1 - Isalberti, Maurizio A1 - Isaias, Ioannis Ugo A1 - Montemurro, Tiziana A1 - Viganò, Mariele A1 - Montelatici, Elisa A1 - Boldrin, Valentina A1 - Benti, Riccardo A1 - Cortelezzi, Agostino A1 - Fracchiolla, Nicola A1 - Lazzari, Lorenza A1 - Pezzoli, Gianni T1 - Autologous mesenchymal stem cell therapy for progressive supranuclear palsy: translation into a phase I controlled, randomized clinical study JF - Journal of Translational Medicine N2 - Background: Progressive Supranuclear Palsy (PSP) is a sporadic and progressive neurodegenerative disease which belongs to the family of tauopathies and involves both cortical and subcortical structures. No effective therapy is to date available. Methods/design: Autologous bone marrow (BM) mesenchymal stem cells (MSC) from patients affected by different type of parkinsonisms have shown their ability to improve the dopaminergic function in preclinical and clinical models. It is also possible to isolate and expand MSC from the BM of PSP patients with the same proliferation rate and immuphenotypic profile as MSC from healthy donors. BM MSC can be efficiently delivered to the affected brain regions of PSP patients where they can exert their beneficial effects through different mechanisms including the secretion of neurotrophic factors. Here we propose a randomized, placebo-controlled, double-blind phase I clinical trial in patients affected by PSP with MSC delivered via intra-arterial injection. Discussion: To our knowledge, this is the first clinical trial to be applied in a no-option parkinsonism that aims to test the safety and to exploit the properties of autologous mesenchymal stem cells in reducing disease progression. The study has been designed to test the safety of this " first-in-man" approach and to preliminarily explore its efficacy by excluding the placebo effect. Trial registration: NCT01824121 KW - Parkinson's disease KW - cellular therapy KW - deep brain-stimulation KW - bone-marrow KW - transplantation KW - receptor tyrosine kinase KW - Richardson-Olszewski-Syndrome KW - multiple system atrophy KW - advanced therapy medicinal products KW - mesenchymal stem and stromal cells KW - progressive supranuclear palsy KW - treatment options KW - adrenal medulla KW - stromal cells Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117594 VL - 12 IS - 14 ER - TY - JOUR A1 - Norrmen, Camilla A1 - Figlia, Gianluca A1 - Lebrun-Julien, Frederic A1 - Pereira, Jorge A. A1 - Trötzmüller, Martin A1 - Köfeler, Harald C. A1 - Rantanen, Ville A1 - Wessig, Carsten A1 - van Deijk, Anne-Lieke F. A1 - Smit, August B. A1 - Verheijen, Mark H. G. A1 - Rüegg, Markus A. A1 - Hall, Michael N. A1 - Suter, Ueli T1 - mTORC1 Controls PNS Myelination along the mTORC1-RXR gamma-SREBP-Lipid Biosynthesis Axis in Schwann Cells JF - Cell Reports N2 - Myelin formation during peripheral nervous system (PNS) development, and reformation after injury and in disease, requires multiple intrinsic and extrinsic signals. Akt/mTOR signaling has emerged as a major player involved, but the molecular mechanisms and downstream effectors are virtually unknown. Here, we have used Schwann-cell-specific conditional gene ablation of raptor and rictor, which encode essential components of the mTOR complexes 1 (mTORC1) and 2 (mTORC2), respectively, to demonstrate that mTORC1 controls PNS myelination during development. In this process, mTORC1 regulates lipid biosynthesis via sterol regulatory element-binding proteins (SREBPs). This course of action is mediated by the nuclear receptor RXRg, which transcriptionally regulates SREBP1c downstream of mTORC1. Absence of mTORC1 causes delayed myelination initiation as well as hypomyelination, together with abnormal lipid composition and decreased nerve conduction velocity. Thus, we have identified the mTORC1-RXR gamma-SREBP axis controlling lipid biosynthesis as a major contributor to proper peripheral nerve function. KW - axonal integrity KW - peripheral nervous-system KW - COMPLEX 1 KW - rat hepatocytes KW - SREBP KW - mice KW - growth KW - protein KW - element KW - CNS Myelination Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114847 SN - 2211-1247 VL - 9 IS - 2 ER - TY - JOUR A1 - Cruccu, Giorgio A1 - Pennisi, Elena M. A1 - Antonini, Giovanni A1 - Biasiotta, Antonella A1 - Di Stefano, Giulia A1 - La Cesa, Silvia A1 - Leone, Caterina A1 - Raffa, Salvatore A1 - Sommer, Claudia A1 - Truini, Andrea T1 - Trigeminal isolated sensory neuropathy (TISN) and FOSMN syndrome: despite a dissimilar disease course do they share common pathophysiological mechanisms? JF - BMC Neurology N2 - Background: Patients presenting with bilateral trigeminal hypoesthesia may go on to have trigeminal isolated sensory neuropathy, a benign, purely trigeminal neuropathy, or facial-onset sensory motor neuronopathy (FOSMN), a malignant life-threatening condition. No diagnostic criteria can yet differentiate the two conditions at their onset. Nor is it clear whether the two diseases are distinct entities or share common pathophysiological mechanisms. Methods: Seeking pathophysiological and diagnostic information to distinguish these two conditions at their onset, in this neurophysiological and morphometric study we neurophysiologically assessed function in myelinated and unmyelinated fibres and histologically examined supraorbital nerve biopsy specimens with optic and electron microscopy in 13 consecutive patients with recent onset trigeminal hypoesthesia and pain. Results: The disease course distinctly differed in the 13 patients. During a mean 10 year follow-up whereas in eight patients the disease remained relatively stable, in the other five it progressed to possibly life-threatening motor disturbances and extra-trigeminal spread. From two to six years elapsed between the first sensory symptoms and the onset of motor disorders. In patients with trigeminal isolated sensory neuropathy (TISN) and in those with FOSMN neurophysiological and histological examination documented a neuronopathy manifesting with trigeminal nerve damage selectively affecting myelinated fibres, but sparing the Ia-fibre-mediated proprioceptive reflex. Conclusions: Although no clinical diagnostic criteria can distinguish the two conditions at onset, neurophysiological and nerve-biopsy findings specify that in both disorders trigeminal nerve damage manifests as a dissociated neuronopathy affecting myelinated and sparing unmyelinated fibres, thus suggesting similar pathophysiological mechanisms. KW - amyotrophic-lateral-sclerosis KW - atrophy Kennedys-disease KW - trigeminal nerve KW - neuronopathy KW - trigeminal neuropathy KW - FOSMN KW - facial pain KW - Sjorgens-syndrome KW - reflex KW - afferents KW - neuralgia KW - pathways KW - humans KW - fibers Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114249 SN - 1471-2377 VL - 14 ER - TY - JOUR A1 - Bischoff, Joakim M. A1 - Ringsted, Thomas K. A1 - Petersen, Marian A1 - Sommer, Claudia A1 - Üçeyler, Nurcan A1 - Werner, Mads U. T1 - A Capsaicin (8%) Patch in the Treatment of Severe Persistent Inguinal Postherniorrhaphy Pain: A Randomized, Double-Blind, Placebo-Controlled Trial JF - PLOS ONE N2 - Background: Persistent pain after inguinal herniorrhaphy is a disabling condition with a lack of evidence-based pharmacological treatment options. This randomized placebo-controlled trial investigated the efficacy of a capsaicin 8% cutaneous patch in the treatment of severe persistent inguinal postherniorrhaphy pain. Methods: Forty-six patients with persistent inguinal postherniorrhaphy pain were randomized to receive either a capsaicin 8% patch or a placebo patch. Pain intensity (Numerical Rating Scale [NRS 0-10]) was evaluated under standardized conditions (at rest, during movement, and during pressure) at baseline and at 1, 2 and 3 months after patch application. Skin punch biopsies for intraepidermal nerve fiber density (IENFD) measurements were taken at baseline and 1 month after patch application. Quantitative sensory testing was performed at baseline and at 1, 2, and 3 months after patch application. The primary outcome was comparisons of summed pain intensity differences (SPIDs) between capsaicin and placebo treatments at 1, 2 and 3 months after patch application (significance level P<0.01). Results: The maximum difference in SPID, between capsaicin and placebo treatments, was observed at 1 month after patch application, but the pain reduction was not significant (NRS, mean difference [95% CI]: 5.0 [0.09 to 9.9]; P=0.046). No differences in SPID between treatments were observed at 2 and 3 months after patch application. Changes in IENFD on the pain side, from baseline to 1 month after patch application, did not differ between capsaicin and placebo treatment: 1.9 [-0.1 to 3.9] and 0.6 [-1.2 to 2.5] fibers/mm, respectively (P=0.32). No significant changes in sensory function, sleep quality or psychological factors were associated with capsaicin patch treatment. Conclusions: The study did not demonstrate significant differences in pain relief between capsaicin and placebo treatment, although a trend toward pain improvement in capsaicin treated patients was observed 1 month after patch application. KW - postherpetic neuralgia KW - long-term pain KW - crossover trial KW - neuropathic pain KW - risk factors KW - cutaneous patch KW - scale KW - hernia repair KW - interference KW - validation Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115198 SN - 1932-6203 VL - 9 IS - 10 ER - TY - JOUR A1 - Meyer zu Hörste, Gerd A1 - Cordes, Steffen A1 - Mausberg, Anne K. A1 - Zozulya, Alla L. A1 - Wessig, Carsten A1 - Sparwasser, Tim A1 - Mathys, Christian A1 - Wiendl, Heinz A1 - Hartung, Hans-Peter A1 - Kieseier, Bernd C. T1 - FoxP3+Regulatory T Cells Determine Disease Severity in Rodent Models of Inflammatory Neuropathies JF - PLOS ONE N2 - Inflammatory neuropathies represent disabling human autoimmune disorders with considerable disease variability. Animal models provide insights into defined aspects of their disease pathogenesis. Forkhead box P3 (FoxP3)+ regulatory T lymphocytes (Treg) are anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. Dysfunction or a reduced frequency of Tregs have been associated with different human autoimmune disorders. We here analyzed the functional relevance of Tregs in determining disease manifestation and severity in murine models of autoimmune neuropathies. We took advantage of the DEREG mouse system allowing depletion of Treg with high specificity as well as anti-CD25 directed antibodies to deplete Tregs in mice in actively induced experimental autoimmune neuritis (EAN). Furthermore antibody-depletion was performed in an adoptive transfer model of chronic neuritis. Early Treg depletion increased clinical EAN severity both in active and adoptive transfer chronic neuritis. This was accompanied by increased proliferation of myelin specific T cells and histological signs of peripheral nerve inflammation. Late stage Treg depletion after initial disease manifestation however did not exacerbate inflammatory neuropathy symptoms further. We conclude that Tregs determine disease severity in experimental autoimmune neuropathies during the initial priming phase, but have no major disease modifying function after disease manifestation. Potential future therapeutic approaches targeting Tregs should thus be performed early in inflammatory neuropathies. KW - Guillain-Barre-Syndrome KW - regulatory cells KW - C57BL/6 mice KW - demyelinating polyradiculoneuropathy KW - cytokines KW - pathogenesis KW - polyneuropathy KW - enteropathy KW - peptide KW - experimental autoimmune neuritis Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115239 VL - 9 IS - 10 ER - TY - JOUR A1 - Üçeyler, Nurcan A1 - Valet, Michael A1 - Kafke, Waldemar A1 - Tölle, Thomas R. A1 - Sommer, Claudia T1 - Local and Systemic Cytokine Expression in Patients with Postherpetic Neuralgia N2 - Background Postherpetic neuralgia (PHN) is the painful complication of a varicella zoster virus reactivation. We investigated the systemic and local gene expression of pro- and anti-inflammatory cytokine expression in patients with PHN. Methods Thirteen patients with PHN at the torso (Th4-S1) were recruited. Skin punch biopsies were obtained from the painful and the contralateral painless body area for intraepidermal nerve fiber density (IENFD) and cytokine profiling. Additionally, blood was withdrawn for systemic cytokine expression and compared to blood values of healthy controls. We analyzed the gene expression of selected pro- and anti-inflammatory cytokines (tumor necrosis factor-alpha [TNF] and interleukins [IL]-1β, IL-2, and IL-8). Results IENFD was lower in affected skin compared to unaffected skin (p<0.05), while local gene expression of pro- and anti-inflammatory cytokines did not differ except for two patients who had 7fold higher IL-6 and 10fold higher IL-10 gene expression in the affected skin compared to the contralateral unaffected skin sample. Also, the systemic expression of cytokines in patients with PHN and in healthy controls was similar. Conclusion While the systemic and local expression of the investigated pro- and anti-inflammatory cytokines was not different from controls, this may have been influenced by study limitations like the low number of patients and different disease durations. Furthermore, other cytokines or pain mediators need to be considered. KW - neuropathic pain KW - cytokines KW - pain sensation KW - gene expression KW - nerve fibres KW - RNA extraction KW - shingles KW - skin tumors Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-113041 ER - TY - JOUR A1 - Kleinschnitz, Christoph A1 - Göbel, Kerstin A1 - Meuth, Sven G. A1 - Kraft, Peter T1 - Glatiramer acetate does not protect from acute ischemic stroke in mice N2 - Background The role of the immune system in the pathophysiology of acute ischemic stroke is increasingly recognized. However, targeted treatment strategies to modulate immunological pathways in stroke are still lacking. Glatiramer acetate is a multifaceted immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. Experimental studies suggest that glatiramer acetate might also work in other neuroinflammatory or neurodegenerative diseases apart from multiple sclerosis. Findings We evaluated the efficacy of glatiramer acetate in a mouse model of brain ischemia/reperfusion injury. 60 min of transient middle cerebral artery occlusion was induced in male C57Bl/6 mice. Pretreatment with glatiramer acetate (3.5 mg/kg bodyweight) 30 min before the induction of stroke did not reduce lesion volumes or improve functional outcome on day 1. Conclusions Glatiramer acetate failed to protect from acute ischemic stroke in our hands. Further studies are needed to assess the true therapeutic potential of glatiramer acetate and related immunomodulators in brain ischemia. KW - Glatiramer acetate KW - Stroke KW - Inflammation KW - Neurodegeneration Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-110528 ER - TY - JOUR A1 - Groh, Janos A1 - Stadler, David A1 - Buttmann, Mathias A1 - Martini, Rudolf T1 - Non-invasive assessment of retinal alterations in mouse models of infantile and juvenile neuronal ceroid lipofuscinosis by spectral domain optical coherence tomography N2 - Introduction The neuronal ceroid lipofuscinoses constitute a group of fatal inherited lysosomal storage diseases that manifest in profound neurodegeneration in the CNS. Visual impairment usually is an early symptom and selective degeneration of retinal neurons has been described in patients suffering from distinct disease subtypes. We have previously demonstrated that palmitoyl protein thioesterase 1 deficient (Ppt1-/-) mice, a model of the infantile disease subtype, exhibit progressive axonal degeneration in the optic nerve and loss of retinal ganglion cells, faithfully reflecting disease severity in the CNS. Here we performed spectral domain optical coherence tomography (OCT) in Ppt1-/- and ceroid lipofuscinosis neuronal 3 deficient (Cln3-/-) mice, which are models of infantile and juvenile neuronal ceroid lipofuscinosis, respectively, in order to establish a non-invasive method to assess retinal alterations and monitor disease severity in vivo. Results Blue laser autofluorescence imaging revealed increased accumulation of autofluorescent storage material in the inner retinae of 7-month-old Ppt1-/- and of 16-month-old Cln3-/- mice in comparison with age-matched control littermates. Additionally, optical coherence tomography demonstrated reduced thickness of retinae in knockout mice in comparison with age-matched control littermates. High resolution scans and manual measurements allowed for separation of different retinal composite layers and revealed a thinning of layers in the inner retinae of both mouse models at distinct ages. OCT measurements correlated well with subsequent histological analysis of the same retinae. Conclusions These results demonstrate the feasibility of OCT to assess neurodegenerative disease severity in mouse models of neuronal ceroid lipofuscinosis and might have important implications for diagnostic evaluation of disease progression and therapeutic efficacy in patients. Moreover, the non-invasive method allows for longitudinal studies in experimental models, reducing the number of animals used for research. KW - Optical coherence tomography KW - Neuronal ceroid lipofuscinosis KW - Neurodegeneration KW - Retinal degeneration KW - Lysosomal storage disease Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-110566 ER -