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 - THES A1 - Nuth, Linda T1 - Niederfrequente, Tiefe Hirnstimulation bei Parkinson-Patienten mit ON-Freezing. Identifikation von Respondern anhand kinematischer Gangparameter T1 - Predictive factors for Improvement of Gait by Low-frequency subthalamic deep brain stimulation in Parkinson patients with ON-Freezing N2 - Das ON-Freezing ist ein seltenes, aber generell extrem schwer zu therapierendes Phänomen. Es betrifft Parkinson-Patienten mit und ohne THS. Die derzeitige Literaturlage spiegelt wider, dass es unterschiedliche Strategien gibt, diesem Phänomen zu begegnen. Ein allgemeingültiges Therapiekonzept existiert dabei nicht. Für einige Patienten mit STN-THS konnte durch eine Reduktion der Stimulationsfrequenz eine Besserung der Gangstörung erzielt werden. Andere profitierten vom Einsatz sogenannter Interleaving-Protokolle mit gleichzeitiger Stimulation der Substantia nigra (Sn). Im Vergleich zu anderen Arbeiten, die keine vorhersagbaren Parameter gefunden oder sich auf Symptome, Ausprägung der Subtypen und Erkrankungsdauer oder den Zeitpunkt der Erkrankung konzentriert haben, verfolgten wir die Absicht, die Effekte der LF-Stim des STN auf Parkinson-Patienten mit Gangstörung und Freezing-Phänomen zu untersuchen und herauszufinden, ob man Gangparameter identifizieren kann, an Hand derer man das Ansprechen auf eine LF-Stim vorhersagen kann. Unter der Einschränkung, dass die Zahl der Probanden unserer Studie sehr gering ist, haben wir herausgefunden, dass diejenigen Patienten besser auf eine LF-Stim ansprechen, die unter der Standard-HF-Stim eine signifikant höhere Ganggeschwindigkeit und eine größere Schrittlänge aufzeigen und nur ein intermittierendes Freezing haben. Darüber hinaus zeigte sich ein besseres Ansprechen der LF-Stim bei Parkinson-Patienten mit akinetisch-rigidem Parkinson-Phänotyp. Unsere Ergebnisse bestätigen die Annahme, dass sich L-Dopa additiv zur Stimulationstherapie bei manchen Parkinson-Patienten zusätzlich positiv auf die motorischen PD-Symptome auswirken kann. In Bezug auf die Verbesserung der Gangparameter zeigte sich in unseren Ergebnissen allerdings, dass L-Dopa eher eine untergeordnete Rolle spielt. Aufgrund der niedrigen Anzahl von Respondern in unserer Studie lässt sich daher sicherlich noch keine allgemeingültige Regel ableiten. Es bedarf letztlich weiterer Studien mit größeren Untersuchungszahlen, um unsere Thesen zu stützen und abzusichern. In jedem Fall wird aber das ON-Freezing auch weiterhin eine therapeutische Herausforderung bleiben. N2 - Patients with Parkinson's Disease (PD) and subthalamic nucleus deep brain stimulation (STN-DBS) often demonstrate continues severe gait disturbances including freezing of gait (FOG). Individual cases report an improvement of kinematic gait parameters as well as a reduction of freezing episodes. To determine, if a change in STN-DBS frequency to 80 Hz improves gait disturbances and reduces freezing episodes and to identify characteristics of responders, a multitask protocol was carried out in 6 patients with PD, STN-DBS and severe gait disorders involving an analysis if linear walking at different velocities. KW - Parkinson KW - Niederfrequenzstimulation KW - tiefe Hirnstimulation KW - ON-Freezing Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150317 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 - THES A1 - Purrer, Veronika T1 - Nicht-motorische Begleitsymptome bei Patienten mit Essentiellen Tremor T1 - Non-motor symptoms in patients with essential tremor N2 - Der essentielle Tremor (ET) ist eine der häufigsten Bewegungsstörungen, welcher lange Zeit als rein motorische Störung angesehen wurde. Aufgrund zunehmender Belege über nicht-motorisch Begleitsymptome wandelte sich dieses Bild jedoch in den letzten Jahren zunehmend. In der vorliegenden Arbeit untersuchten wir 113 Probanden aus der Allgemeinbevölkerung mit klinisch definitiven oder wahrscheinlichen ET anhand einer breiten Batterie neuro-psychologischer Testverfahren. Es gelang hierbei signifikante Unterschiede im Vergleich zu gesunden Eichstichproben im Hinblick auf neuro-psychologische Charakteristika, wie Apathie, Ängstlichkeit und exekutive Dysfunktion, sowie deren negativen Einfluss auf die Lebensqualität der Probanden darzustellen. Bisher werden im klinischen Alltag nicht-motorische Begleitphänomene beim ET nicht regelhaft erfasst; aufgrund unserer Ergebnisse und der Relevanz vor allem im Hinblick auf die Lebensqualität des Einzelnen halten wir jedoch die Erfassung und gegebenenfalls Behandlung dieser Symptome für ebenso relevant. N2 - Essential tremor (ET) is one of the most common movement disorders, which was previously considered a purely motor disorder. Due to increasing evidence of non-motor symptoms, however, this picture has changed recently. In the present study we investigated 113 subjects from the general population with clinically definite or probable ET using a broad battery of neuro-psychological screening tools. Thereby, significant differences in neuro-psychological characteristics, such as apathy, anxiety and executive dysfunction, as well as their negative impact on the quality of life of the subjects could be demonstrated in comparison to healthy samples. Up to now, non-motor symptoms in ET are generally not been recorded in the clinical routine; however, based on our findings and the relevance to the individual's quality of life in particular, we consider the assessment and, where appropriate, treatment of these symptoms to be equally relevant. KW - Essentieller Tremor KW - Nicht-motorische Begleitsymptome KW - ET Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193665 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 - 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 - 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 - BOOK A1 - Reiners, Karlheinz T1 - Neuropathie und Motorik N2 - No abstract available KW - Nervenregeneration ; Periphere Nervenverletzung ; Neuromuskuläre Krankheit ; Axonverletzung ; Entmarkung Y1 - 1990 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-33843 ER - TY - JOUR A1 - Isaias, Ioannis U. A1 - Trujillo, Paula A1 - Summers, Paul A1 - Marotta, Giorgio A1 - Mainardi, Luca A1 - Pezzoli, Gianni A1 - Zecca, Luigi A1 - Costa, Antonella T1 - Neuromelanin Imaging and Dopaminergic Loss in Parkinson's Disease JF - Frontiers in Aging Neuroscience N2 - Parkinson's disease (PD) is a progressive neurodegenerative disorder in which the major pathologic substrate is a loss of dopaminergic neurons from the substantia nigra. Our main objective was to determine the correspondence between changes in the substantia nigra, evident in neuromelanin and iron sensitive magnetic resonance imaging (MRI), and dopaminergic striatal innervation loss in patients with PD. Eighteen patients and 18 healthy control subjects were included in the study. Using neuromelanin-MRI, we measured the volume of the substantia nigra and the contrast-to-noise-ratio between substantia nigra and a background region. The apparent transverse relaxation rate and magnetic susceptibility of the substantia nigra were calculated from dual-echo MRI. Striatal dopaminergic innervation was measured as density of dopamine transporter (DAT) by means of single-photon emission computed tomography and [123I] N-ω-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) tropane. Patients showed a reduced volume of the substantia nigra and contrast-to-noise-ratio and both positively correlated with the corresponding striatal DAT density. The apparent transverse relaxation rate and magnetic susceptibility values of the substantia nigra did not differ between patients and healthy controls. The best predictor of DAT reduction was the volume of the substantia nigra. Clinical and imaging correlations were also investigated for the locus coeruleus. Our results suggest that neuromelanin-MRI can be used for quantifying substantia nigra pathology in PD where it closely correlates with dopaminergic striatal innervation loss. Longitudinal studies should further explore the role of Neuromelanin-MRI as an imaging biomarker of PD, especially for subjects at risk of developing the disease. KW - MRI KW - neuromelanin KW - dopamine KW - Parkinson's disease KW - FP-CIT SPECT Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164046 VL - 8 IS - 196 ER - TY - JOUR A1 - Sulzer, David A1 - Cassidy, Clifford A1 - Horga, Guillermo A1 - Kang, Un Jung A1 - Fahn, Stanley A1 - Casella, Luigi A1 - Pezzoli, Gianni A1 - Langley, Jason A1 - Hu, Xiaoping P. A1 - Zucca, Fabio A. A1 - Isaias, Ioannis U. A1 - Zecca, Luigi T1 - Neuromelanin detection by magnetic resonance imaging (MRI) and its promise as a biomarker for Parkinson’s disease JF - npj Parkinson's Disease N2 - The diagnosis of Parkinson’s disease (PD) occurs after pathogenesis is advanced and many substantia nigra (SN) dopamine neurons have already died. Now that therapies to block this neuronal loss are under development, it is imperative that the disease be diagnosed at earlier stages and that the response to therapies is monitored. Recent studies suggest this can be accomplished by magnetic resonance imaging (MRI) detection of neuromelanin (NM), the characteristic pigment of SN dopaminergic, and locus coeruleus (LC) noradrenergic neurons. NM is an autophagic product synthesized via oxidation of catecholamines and subsequent reactions, and in the SN and LC it increases linearly during normal aging. In PD, however, the pigment is lost when SN and LC neurons die. As shown nearly 25 years ago by Zecca and colleagues, NM’s avid binding of iron provides a paramagnetic source to enable electron and nuclear magnetic resonance detection, and thus a means for safe and noninvasive measure in living human brain. Recent technical improvements now provide a means for MRI to differentiate between PD patients and age-matched healthy controls, and should be able to identify changes in SN NM with age in individuals. We discuss how MRI detects NM and how this approach might be improved. We suggest that MRI of NM can be used to confirm PD diagnosis and monitor disease progression. We recommend that for subjects at risk for PD, and perhaps generally for older people, that MRI sequences performed at regular intervals can provide a pre-clinical means to detect presymptomatic PD. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240207 VL - 4 ER - TY - JOUR A1 - Martini, Rudolf A1 - Willison, Hugh T1 - Neuroinflammation in the peripheral nerve: cause, modulator, or bystander in peripheral neuropathies? JF - GLIA N2 - The role of innate and adaptive inflammation as a primary driver or modifier of neuropathy in premorbidly normal nerves, and as a critical player in amplifying neuropathies of other known causes (e.g., genetic, metabolic) is incompletely understood and under-researched, despite unmet clinical need. Also, cellular and humoral components of the adaptive and innate immune system are substantial disease modifying agents in the context of neuropathies and, at least in some neuropathies, there is an identified tight interrelationship between both compartments of the immune system. Additionally, the quadruple relationship between Schwann cell, axon, macrophage, and endoneurial fibroblast, with their diverse membrane bound and soluble signalling systems, forms a distinct focus for investigation in nerve diseases with inflammation secondary to Schwann cell mutations and possibly others. Identification of key immunological effector pathways that amplify neuropathic features and associated clinical symptomatology including pain should lead to realistic and timely possibilities for translatable therapeutic interventions using existing immunomodulators, alongside the development of novel therapeutic targets. KW - Charcot-Marie-Tooth KW - Guillain-Barré-Syndrom KW - familial amyloidotic polyneuropathy KW - motor axonal neuropathy KW - Schwann cell dedifferentiation KW - glycation end products KW - innate immune system KW - adaptive immune system KW - macrophage KW - fibroblast KW - lymphocytes KW - nodes of Ranvier Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189696 VL - 64 IS - 4 ER - TY - JOUR A1 - Grotemeyer, Alexander A1 - McFleder, Rhonda Leah A1 - Wu, Jingjing A1 - Wischhusen, Jörg A1 - Ip, Chi Wang T1 - Neuroinflammation in Parkinson’s disease – putative pathomechanisms and targets for disease-modification JF - Frontiers in Immunology N2 - Parkinson’s disease (PD) is a progressive and debilitating chronic disease that affects more than six million people worldwide, with rising prevalence. The hallmarks of PD are motor deficits, the spreading of pathological α-synuclein clusters in the central nervous system, and neuroinflammatory processes. PD is treated symptomatically, as no causally-acting drug or procedure has been successfully established for clinical use. Various pathways contributing to dopaminergic neuron loss in PD have been investigated and described to interact with the innate and adaptive immune system. We discuss the possible contribution of interconnected pathways related to the immune response, focusing on the pathophysiology and neurodegeneration of PD. In addition, we provide an overview of clinical trials targeting neuroinflammation in PD. KW - Parkinson’s disease KW - neuroinflammation KW - T cells KW - microglia KW - neurodegeneration KW - animal models KW - inflammatory cascades Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-274665 SN - 1664-3224 VL - 13 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 - Karikari, Akua A. A1 - McFleder, Rhonda L. A1 - Ribechini, Eliana A1 - Blum, Robert A1 - Bruttel, Valentin A1 - Knorr, Susanne A1 - Gehmeyr, Mona A1 - Volkmann, Jens A1 - Brotchie, Jonathan M. A1 - Ahsan, Fadhil A1 - Haack, Beatrice A1 - Monoranu, Camelia-Maria A1 - Keber, Ursula A1 - Yeghiazaryan, Rima A1 - Pagenstecher, Axel A1 - Heckel, Tobias A1 - Bischler, Thorsten A1 - Wischhusen, Jörg A1 - Koprich, James B. A1 - Lutz, Manfred B. A1 - Ip, Chi Wang T1 - Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson’s disease mice JF - Brain, Behavior, and Immunity N2 - Background Antigen-specific neuroinflammation and neurodegeneration are characteristic for neuroimmunological diseases. In Parkinson’s disease (PD) pathogenesis, α-synuclein is a known culprit. Evidence for α-synuclein-specific T cell responses was recently obtained in PD. Still, a causative link between these α-synuclein responses and dopaminergic neurodegeneration had been lacking. We thus addressed the functional relevance of α-synuclein-specific immune responses in PD in a mouse model. Methods We utilized a mouse model of PD in which an Adeno-associated Vector 1/2 serotype (AAV1/2) expressing human mutated A53T-α-Synuclein was stereotactically injected into the substantia nigra (SN) of either wildtype C57BL/6 or Recombination-activating gene 1 (RAG1)\(^{-/-}\) mice. Brain, spleen, and lymph node tissues from different time points following injection were then analyzed via FACS, cytokine bead assay, immunohistochemistry and RNA-sequencing to determine the role of T cells and inflammation in this model. Bone marrow transfer from either CD4\(^{+}\)/CD8\(^{-}\), CD4\(^{-}\)/CD8\(^{+}\), or CD4\(^{+}\)/CD8\(^{+}\) (JHD\(^{-/-}\)) mice into the RAG-1\(^{-/-}\) mice was also employed. In addition to the in vivo studies, a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay was utilized. Results AAV-based overexpression of pathogenic human A53T-α-synuclein in dopaminergic neurons of the SN stimulated T cell infiltration. RNA-sequencing of immune cells from PD mouse brains confirmed a pro-inflammatory gene profile. T cell responses were directed against A53T-α-synuclein-peptides in the vicinity of position 53 (68–78) and surrounding the pathogenically relevant S129 (120–134). T cells were required for α-synuclein-induced neurodegeneration in vivo and in vitro, while B cell deficiency did not protect from dopaminergic neurodegeneration. Conclusions Using T cell and/or B cell deficient mice and a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay, we confirmed in vivo and in vitro that pathogenic α-synuclein peptide-specific T cell responses can cause dopaminergic neurodegeneration and thereby contribute to PD-like pathology. KW - Parkinson’s disease KW - α-synuclein-specific T cells KW - neurodegeneration Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300600 VL - 101 SP - 194 EP - 210 ER - TY - JOUR A1 - Sommer, Claudia A1 - Carroll, Antonia S. A1 - Koike, Haruki A1 - Katsuno, Masahisa A1 - Ort, Nora A1 - Sobue, Gen A1 - Vucic, Steve A1 - Spies, Judith M. A1 - Doppler, Kathrin A1 - Kiernan, Matthew C. T1 - Nerve biopsy in acquired neuropathies JF - Journal of the Peripheral Nervous System N2 - A diagnosis of neuropathy can typically be determined through clinical assessment and focused investigation. With technological advances, including significant progress in genomics, the role of nerve biopsy has receded over recent years. However, making a specific and, in some cases, tissue-based diagnosis is essential across a wide array of potentially treatable acquired peripheral neuropathies. When laboratory investigations do not suggest a definitive diagnosis, nerve biopsy remains the final step to ascertain the etiology of the disease. The present review highlights the utility of nerve biopsy in confirming a diagnosis, while further illustrating the importance of a tissue-based diagnosis in relation to treatment strategies, particularly when linked to long-term immunosuppressive therapies, KW - inflammatory neuropathy KW - nerve biopsy KW - nerve tumor KW - neuroleukemiosis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259555 VL - 26 IS - S2 ER - TY - JOUR A1 - Rolfes, Leoni A1 - Ruck, Tobias A1 - David, Christina A1 - Mencl, Stine A1 - Bock, Stefanie A1 - Schmidt, Mariella A1 - Strecker, Jan-Kolja A1 - Pfeuffer, Steffen A1 - Mecklenbeck, Andreas-Schulte A1 - Gross, Catharina A1 - Gliem, Michael A1 - Minnerup, Jens A1 - Schuhmann, Michael K. A1 - Kleinschnitz, Christoph A1 - Meuth, Sven G. T1 - Natural Killer Cells Are Present in Rag1\(^{−/−}\) Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke JF - Translational Stroke Research N2 - Rag1\(^{−/−}\) mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1\(^{−/−}\) mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1\(^{null}\)IL2rg\(^{null}\) (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1\(^{−/−}\) and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1\(^{−/−}\) NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1\(^{−/−}\) were comparable in number and function to those in WT mice. Rag1\(^{−/−}\) mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1−/− controls. Our results indicate that NK cells from Rag1−/− mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke. KW - infarction KW - middle cerebral artery occlusion KW - animal model KW - inflammation KW - natural killer cells Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-308924 SN - 1868-4483 SN - 1868-601X VL - 13 IS - 1 ER - TY - JOUR A1 - Sommer, Claudia T1 - Natural course of Guillain-Barré syndrome JF - European Journal of Neurology KW - Guillain-Barré syndrome KW - intravenous immunoglobulin KW - immunomodulation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318757 VL - 29 IS - 10 SP - 2881 EP - 2882 ER - TY - THES A1 - Schneider, Katharina T1 - Nachweis und Analyse von Phospho-Alpha-Synuclein-Ablagerungen in Hautnerven von Patienten mit Morbus Parkinson oder Multisystematrophie T1 - Proof and analysis of phospho-alpha-synuclein in the skin of patients with Parkinsons' disease or multiple system atrophy N2 - Zielsetzung der Studie war es, Ablagerungen des phosphorylierten Alpha-Synucleins in der Haut von Patienten mit Morbus Parkinson und atypischen Parkinson-Syndromen zu untersuchen und deren Auswirkungen auf das periphere Nervensystem zu erforschen. Dazu wurden Hautbiopsien von 92 Patienten mit Morbus Parkinson, 12 Patienten mit MSA und 13 Patienten mit einer Tauopathie sowie 83 gesunden Kontrollpersonen immunhisto-chemisch gefärbt und unter dem Mikroskop untersucht. Mit einer Sensitivität von 52 % für den Morbus Parkinson und 67 % für die MSA bei hoher Spezifität stellt der Nachweis von Phospho-Alpha-Synuclein in den kleinen Nervenfasern der Haut einen geeigneten Biomarker dar. Während die Ablagerungen des phosphorylierten Alpha-Synucleins bei Patienten mit Morbus Parkinson eher in autonomen Strukturen nachweisbar waren, fanden sie sich bei Patienten mit MSA eher in sub- und intraepidermal gelegenen Nervenfasern. Phospho-Alpha-Synuclein konnte in allen untersuchten Nervenfasersubtypen nachgewiesen werden, also in CGRP-, SP-, TH- und VIP-positiven Fasern. Bei den in der vorliegenden Studie untersuchten Parkinson-Patienten waren keine Veränderungen in der sensiblen Neurographie des Nervus suralis erkennbar. Die intraepidermale Nervenfaserdichte sowie die Innervation der Schweißdrüsen waren jedoch teilweise vermindert und auch in der QST zeigten sich Auffälligkeiten. Ein Zusammenhang zu dem Vorhandensein von Phospho-Alpha-Synuclein-Ablagerungen konnte jedoch nur für die Innervation der Musculi arrectores pilorum hergestellt werden. Bei der Untersuchung der pathophysiologischen Hintergründe, durch die Phospho-Alpha-Synuclein-Ablagerungen zu Nervenfaserschädigungen führen, konnten die Hinweise auf eine Beteiligung von axonalen Transportproteinen, Mikrotubuli oder Mitochondrien nicht erhärtet werden. N2 - The aim of this study was to examine dermal phospho-alpha-synuclein deposits of patients with Parkinson's disease or multiple system atrophy. KW - Synuclein KW - Parkinson-Krankheit KW - Alpha-Synuclein Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-169694 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 - Bittner, Stefan A1 - Bobak, Nicole A1 - Hofmann, Majella-Sophie A1 - Schuhmann, Michael K. A1 - Ruck, Tobias A1 - Göbel, Kerstin A1 - Brück, Wolfgang A1 - Wiendl, Heinz A1 - Meuth, Sven G. T1 - Murine K\(_{2P}\)5.1 Deficiency Has No Impact on Autoimmune Neuroinflammation due to Compensatory K\(_{2P}\)3.1-and K\(_{V}\)1.3-Dependent Mechanisms JF - International Journal of Molecular Sciences N2 - Lymphocytes express potassium channels that regulate physiological cell functions, such as activation, proliferation and migration. Expression levels of K\(_{2P}\)5.1(TASK2; KCNK5) channels belonging to the family of two-pore domain potassium channels have previously been correlated to the activity of autoreactive T lymphocytes in patients with multiple sclerosis and rheumatoid arthritis. In humans, K\(_{2P}\)5.1 channels are upregulated upon T cell stimulation and influence T cell effector functions. However, a further clinical translation of targeting K\(_{2P}\)5.1 is currently hampered by a lack of highly selective inhibitors, making it necessary to evaluate the impact of KCNK5 in established preclinical animal disease models. We here demonstrate that K\(_{2P}\)5.1 knockout (K\(_{2P}\)5.1\(^{-/-}\) mice display no significant alterations concerning T cell cytokine production, proliferation rates, surface marker molecules or signaling pathways. In an experimental model of autoimmune neuroinflammation, K\(_{2P}\)5.1\(^{-/-}\) mice show a comparable disease course to wild-type animals and no major changes in the peripheral immune system or CNS compartment. A compensatory upregulation of the potassium channels K\(_{2P}\)3.1 and K\(_{V}\)1.3 seems to counterbalance the deletion of K\(_{2P}\)5.1. As an alternative model mimicking autoimmune neuroinflammation, experimental autoimmune encephalomyelitis in the common marmoset has been proposed, especially for testing the efficacy of new potential drugs. Initial experiments show that K\(_{2P}\)5.1 is functionally expressed on marmoset T lymphocytes, opening up the possibility for assessing future K\(_{2P}\)5.1-targeting drugs. KW - domain potassium channels KW - volume regulation KW - multiple-sclerosis KW - potassium channels KW - multiple sclerosis KW - ion channels KW - K+ channel KW - T lymphocytes KW - up-regulation KW - TASK2 KW - K2P channels KW - B cells KW - ph KW - K\(_{2P}\)5.1 KW - KCNK5 KW - autoimmune neuroinflammation KW - EAE Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151454 VL - 16 SP - 16880 EP - 16896 ER - TY - THES A1 - Egenolf, Nadine T1 - Multidimensionale morphologische und elektrophysiologische Analyse von Patienten mit Small Fiber Neuropathie T1 - Multidimensional morphological and electrophysiological analysis of patients with small fiber neuropathy N2 - Die Small Fiber Neuropathie (SFN) bildet eine Untergruppe der sensiblen Neuropathien, bei der die Aδ- und C-Fasern betroffen sind. Die Patienten berichten v.a. von brennenden Schmerzen und Dysästhesien, seltener auch von autonomen Funktionsstörungen. Bei fehlendem Goldstandard und normalen Nervenleitungsstudien ist die Diagnostik erschwert, da selbst nach Spezialuntersuchungen wie Hautstanzbiopsie und quantitativer sensorischer Testung (QST) viele Patienten trotz typischer Anamnese der Diagnosestellung entgehen. Wir rekrutierten 55 Patienten und 31 gesunde Kontrollen. Nach neurologischer Untersuchung und Ausschluss einer Polyneuropathie mittels Elektroneurographie wurden bei allen Studienteilnehmern Hautstanzbiopsien am Ober- und Unterschenkel zur Ermittlung der intraepidermalen Nervenfaserdichte (IENFD) entnommen sowie eine QST zur Funktionsprüfung der kleinen Nervenfasern durchgeführt. Die Studienteilnehmer wurden zudem mit cornealer confocaler Mikroskopie (CCM) und der Ableitung Schmerz-assoziierter evozierter Potentiale (PREP) untersucht. Zur autonomen Testung erfolgte die Messung der Schweißproduktion mittels quantitativem sudomotorischem Axonreflextest (QSART). Die neurologische Untersuchung zeigte in 55% der Patienten Hinweise auf eine Kleinfaserpathologie. Die distale IENFD war bei 62% der Patienten reduziert, die QST bei 22% der Patienten auffällig. Die PREP Latenzen waren in der Patientengruppe länger als bei den Kontrollen, die Amplituden niedriger. Bei der cornealen Innervation zeigte sich eine Reduktion der Nervenfaserdichte, Nervenfaserlänge und Nervenastdichte. Die in QSART gemessenen Parameter zeigten sich zu 86% unauffällig. Während nach klinischer Untersuchung, Hautbiopsie und QST in 53% der Fälle in 2 von 3 Untersuchungen eine Pathologie der kleinen Fasern festgestellt werden konnte, stieg die Rate bei zusätzlicher Anwendung von PREP und CCM auf 80% (ohne Berücksichtigung von QST). Zusammenfassend sollten die klinische Untersuchung und die Hautstanzbiopsie bei allen Patienten mit Verdacht auf SFN erfolgen. PREP und CCM sind unter den verfügbaren zusätzlichen Untersuchungen diagnostisch am wertvollsten. Wichtig ist allerdings, dass bei fehlendem Goldstandard eine SFN auch bei unauffälligen Tests nicht ausgeschlossen werden kann. Zusätzlich können die Mikroneurographie und die genetische Analyse wertvolle Hinweise auf eine Kleinfaserfunktionsstörung und deren Pathophysiologie geben. N2 - Small fiber neuropathy (SFN) forms a subgroup of sensory neuropathies, in which the Aδ- and C-fibers are impaired. Patients mainly report burning pain and dysesthesia, less frequently also autonomic dysfunctions. In absence of a diagnostic gold standard and under normal nerve conduction studies, the diagnosis is difficult. Even after special examinations such as skin punch biopsy and quantitative sensory testing (QST), many patients are not diagnosed despite a typical pain history. We prospectively recruited 55 patients and 31 healthy controls in our study. After neurological examination and exclusion of a polyneuropathy by means of neurological examination and electroneurography, skin punch biopsies were taken from the upper and lower leg of all study participants to determine the intraepidermal nerve fiber density (IENFD). QST was performed to investigate the function of the small nerve fibers. Study participants were also examined with corneal confocal microscopy (CCM) and derivation of pain-related evoked potentials (PREP). For autonomous testing, the sweat production was measured using quantitative sudomotor axon reflex testing (QSART). Neurological examination showed hints for small fiber pathology in 55% of patients. The distal IENFD was reduced in 62% of patients, while QST was abnormal in 22% of patients. The PREP latencies were longer in the patient group than in the controls, the amplitudes were smaller. Corneal innervation showed a reduction of nerve fiber density, nerve fiber length, and nerve branch density in patients compared to controls. The parameters measured in QSART were 86% unremarkable. While after clinical examination, skin biopsy, and QST a pathology of the small fibers could be detected in 53% of the cases in 2 of 3 examinations, the rate increased to 80% with additional application of PREP and CCM (without consideration of QST). In summary, neurological examination should be performed together with skin biopsy in all patients with suspected SFN. PREP and CCM are diagnostically most valuable among the available additional examinations. However, it is important to note that in the absence of a gold standard, SFN cannot be excluded even with normal test results. In addition, microneurography and genetic analysis can provide valuable information about a small fiber dysfunction and its pathophysiology. KW - Neuropathischer Schmerz KW - Nervenfaser KW - Evoziertes Potenzial KW - Konfokale Mikroskopie KW - Sensorik KW - Small Fiber Neuropathie KW - Hautstanzbiopsie KW - Quantitative sensorische Testung KW - Mikroneurographie KW - Schmerz-assoziierte evozierte Potenziale KW - Genetik KW - Quantitativer sudomotorischer Axonreflextest KW - Corneale confocale Mikroskopie KW - Intraepidermale Nervenfaserdichte KW - small fiber neuropathy Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202938 ER - TY - JOUR A1 - Lenders, Malte A1 - Hennermann, Julia B. A1 - Kurschat, Christine A1 - Rolfs, Arndt A1 - Canaan-Kühl, Sima A1 - Sommer, Claudia A1 - Üçeyler, Nurcan A1 - Kampmann, Christoph A1 - Karabul, Nesrin A1 - Giese, Anne-Katrin A1 - Duning, Thomas A1 - Stypmann, Jörg A1 - Krämer, Johannes A1 - Weidemann, Frank A1 - Brand, Stefan-Martin A1 - Wanner, Christoph A1 - Brand, Eva T1 - Multicenter Female Fabry Study (MFFS) - clinical survey on current treatment of females with Fabry disease JF - Orphanet Journal of Rare Diseases N2 - Background The aim of the present study was to assess manifestations of and applied treatment concepts for females with Fabry disease (FD) according to the current European Fabry Guidelines. Methods Between 10/2008 and 12/2014, data from the most recent visit of 261 adult female FD patients from six German Fabry centers were retrospectively analyzed. Clinical presentation and laboratory data, including plasma lyso-Gb3 levels were assessed. Results Fifty-five percent of females were on enzyme replacement therapy (ERT), according to recent European FD guidelines. Thirty-three percent of females were untreated although criteria for ERT initiation were fulfilled. In general, the presence of left ventricular hypertrophy (LVH) seemed to impact more on ERT initiation than impaired renal function. In ERT-naïve females RAAS blockers were more often prescribed if LVH was present rather than albuminuria. Affected females with missense mutations showed a similar disease burden compared to females with nonsense mutations. Elevated plasma lyso-Gb3 levels in ERT-naïve females seem to be a marker of disease burden, since patients showed comparable incidences of organ manifestations even if they were ~8 years younger than females with normal lyso-Gb3 levels. Conclusion The treatment of the majority of females with FD in Germany is in line with the current European FD guidelines. However, a relevant number of females remain untreated despite organ involvement, necessitating a careful reevaluation of these females. KW - Fabry disease KW - females KW - lyso-Gb3 KW - enzyme replacement therapy KW - guidelines Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166543 VL - 11 IS - 88 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 - Herm, Juliane A1 - Schurig, Johannes A1 - Martinek, Martin R. A1 - Höltgen, Reinhard A1 - Schirdewan, Alexander A1 - Kirchhof, Paulus A1 - Wieczorek, Marcus A1 - Pürerfellner, Helmut A1 - Heuschmann, Peter U. A1 - Fiebach, Jochen B. A1 - Haeusler, Karl Georg T1 - MRI-detected brain lesions in AF patients without further stroke risk factors undergoing ablation - a retrospective analysis of prospective studies JF - BMC Cardiovascular Disorders N2 - Background Atrial fibrillation (AF) without other stroke risk factors is assumed to have a low annual stroke risk comparable to patients without AF. Therefore, current clinical guidelines do not recommend oral anticoagulation for stroke prevention of AF in patients without stroke risk factors. We analyzed brain magnetic resonance imaging (MRI) imaging to estimate the rate of clinically inapparent (“silent”) ischemic brain lesions in these patients. Methods We pooled individual patient-level data from three prospective studies comprising stroke-free patients with symptomatic AF. All study patients underwent brain MRI within 24–48 h before planned left atrial catheter ablation. MRIs were analyzed by a neuroradiologist blinded to clinical data. Results In total, 175 patients (median age 60 (IQR 54–67) years, 32% female, median CHA\(_2\)DS\(_2\)-VASc = 1 (IQR 0–2), 33% persistent AF) were included. In AF patients without or with at least one stroke risk factor, at least one silent ischemic brain lesion was observed in 4 (8%) out of 48 and 10 (8%) out of 127 patients, respectively (p > 0.99). Presence of silent ischemic brain lesions was related to age (p = 0.03) but not to AF pattern (p = 0.77). At least one cerebral microbleed was detected in 5 (13%) out of 30 AF patients without stroke risk factors and 25 (25%) out of 108 AF patients with stroke risk factors (p = 0.2). Presence of cerebral microbleeds was related to male sex (p = 0.04) or peripheral artery occlusive disease (p = 0.03). Conclusion In patients with symptomatic AF scheduled for ablation, brain MRI detected silent ischemic brain lesions in approximately one in 12 patients, and microbleeds in one in 5 patients. The prevalence of silent ischemic brain lesions did not differ in AF patients with or without further stroke risk factors. KW - Clinically silent stroke KW - atrial fibrillation KW - magnetic resonance imaging KW - cerebral microbleeds Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201226 VL - 19 ER - TY - THES A1 - Hillerer, Claudia T1 - MR-Protonen-Spektroskopie des Linsenkerns bei idiopathischen Handdystonien T1 - H Magnetic Resonance Spectroscopy of the Lentiform Nucleus in Idiopathic Focal Hand Dystonia N2 - Die Pathogenese der idiopathischen Handdystonie ist bis heute nicht abschließend geklärt. Verschiedene Befunde sprechen für eine Läsion der Basalganglien, insbesondere des Linsenkerns. Insbesondere bildgebende Verfahren wie MRT, Sonographie, PET oder SPECT, und Untersuchungen bei sekundären Dystonieformen weisen in diese Richtung. Trotz vielfacher Anstrengungen, den zugrunde liegenden Pathomechanismus aufzudecken, ist es bis heute noch nicht gelungen, ein einheitliches anatomisches oder biochemisches Korrelat für die Störung verantwortlich zu machen: So bieten einige pathoanatomische Studien Hinweise auf Zellverlust und Gliose im Striatum, andere zeigten Veränderungen in der Konzentration verschiedener Neurotransmitter. Jüngere Untersuchungen lassen einen gestörten Komplex I der mitochondrialen Atmungskette vermuten. Da die Ätiologie der Dystonien bisher letztlich nicht geklärt ist, bietet die Protonenspektroskopie die Möglichkeit, Stoffwechselveränderungen sowie Änderungen der Gewebszusammensetzung und der Konzentrationen darin enthaltener Stoffe zu untersuchen und so Hypothesen zur Genese der idiopathischen Dystonie herauszuarbeiten. Wir untersuchten 14 Patienten mit idiopathischem Schreibkrampf und 11 gesunde, altersentsprechende Probanden, die nachweislich an keiner zentral-neurologischen Erkrankung litten. Zur Messung wurde eine Standard-Kopfspule ( 1,5 T Ganzkörper MR-Tomograph, Siemens Magnetom Vision, Erlangen) verwendet. Die Spektrenerhebung erfolgte mit Hilfe einer PRESS-Sequenz (TR= 1365 ms, TE= 135 ms), das Voxel war auf das Gebiet des Linsenkerns zentriert. Die anhand der Spektren ermittelten Metabolitenverhältnisse von NAA:Cho, NAA:Crea, Cho:Crea und Lac:Crea ergaben keine statistisch signifikante Seitendifferenz innerhalb der Patientengruppe, auch ein Vergleich zwischen Patienten- und Kontrollgruppe blieb ohne statistische Differenz (p>0,05). Somit konnten durch die Protonenspektroskopie keine Veränderungen der Metabolitenkonzentrationen bei der idiopathischen Handdystonie festgestellt werden. Es ergibt sich damit kein Hinweis darauf, daß idiopathischen Dystonien ein meßbarer Verlust von Neuronen, eine damit einhergehende sekundäre Gliose oder eine meßbare Störung des Energiehaushalts, sei es durch erhöhte Umsatzraten oder eine fehlerhafte oxidative Phosphorylierung, zugrunde liegt. Eine mögliche Erklärung dieser unauffälligen Befunde bei Dystoniepatienten könnte die Annahme einer Störung des Stoffwechsels in nur wenigen Neuronen bieten, was sich der Sensitivität der Methode entziehen kann. Denkbar sind auch Konzentrationsänderungen von Neurotransmittern, Einlagerungen von Schwermetallen (z.B.Kupfer), Veränderungen der oxidativen Phosphorylierung oder Änderungen der Rezeptordichte. Generalisierte Dystonien müßten eine eventuell vorhandene Pathologie am deutlichsten aufweisen und wären deshalb ebenfalls ein interessantes Krankheitsbild. Die spektroskopische Untersuchung gestaltet sich aber wegen des bei dieser Form zu erwartenden erhöhten Auftretens von Bewegungsartefakten schwierig. Auch das Verwenden veränderter Meßparameter (TE, TR) oder einer höheren Tesla-Zahl bei einem größeren Patientenkollektiv wäre zur weiteren Abklärung anzustreben. Insbesondere sollten Schreibkrampf-Patienten mit Hilfe der funktionellen MR-Spektroskopie während des Auftretens dystoner Verkrampfungen oder auch während der Durchführung willkürlicher Fingerbewegungen untersucht werden. Bisher latente Veränderungen könnten sich dann, unter der so erzeugten motorischen Aktivierung, manifestieren. N2 - The pathogenesis of primary focal hand dystonia is still unknown. Several radiologic findings and also findings by studies in patients with secondary dystonia point toward the basal ganglia, especially the lentiform nucleus as a possible site of the lesion. There are also abnormalities in histopathologic and biochemical examinations: cell loss and gliosis in the striatum are described as well as an imbalance of neurotransmitters or defects of the complex I of the respiratory chain. But all these results are inconsistent, so the question is open as to whether neurodegeneration occurs in basal ganglia of primary dystonia. H-magnetic resonance spectroscopy (MRS) in vivo is a non-invasive technique for the examination of brain metabolites. It has proved helpful to assess neuronal degeneration and loss or changes in the tissue composition in various basal ganglia disorders, but data of dystonia patients is lacking so far. We have examinated 14 patients with primary focal hand dystonia and 11 healthy control subjects. For the examination a standard quadrature head coil was used (1.5-T MR whole body imager, Siemens AG, Erlangen, Germany). Single volume spectra were obtained using a PRESS sequenz (TR=1365ms, TE=135ms). The voxels (3.375 or 8.0 cm³) were centered on the lentiform nucleus. No statistically significant difference of the measured metabolite ratios of N-acetylaspartate (NAA)/creatine, NAA/choline, choline/creatine or lactate/creatine were found, neither by the intraindividual comparison between the left and right sided lentiform nucleus of the patient group nor by the comparison between patient and control group. So we found no evidence that primary focal dystonia is associated with a conspicuous loss of neurons with secondary gliosis or a marked disturbance of the energy metabolism caused by defects of the respiratory chain or an increased turnover. A possible reason for the normal findings is the limited sensitivity of the method, so minor abnormalities cannot be excluded. For future investigations it will be interesting to examinate patients with generalised dystonia or patients with focal dystonia at the time of a dystonic contraction or active finger movement, because if there are just small changes in the metabolite ratios, it should be recognizable in this cases first. Also changes in the study protocol (p.e. other TE or TR) or examinations with a 3-T imager could bring a benefit. KW - Dystonie KW - Protonenspektroskopie KW - Basalganglien KW - Dystonia KW - Proton Magnetic Resonance Spectroscopy KW - Basal ganglia Y1 - 2001 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-1182401 ER - TY - JOUR A1 - Pötter-Nerger, Monika A1 - Reese, Rene A1 - Steigerwald, Frank A1 - Heiden, Jan Arne A1 - Herzog, Jan A1 - Moll, Christian K. E. A1 - Hamel, Wolfgang A1 - Ramirez-Pasos, Uri A1 - Falk, Daniela A1 - Mehdorn, Maximilian A1 - Gerloff, Christian A1 - Deuschl, Günther A1 - Volkmann, Jens T1 - Movement-Related Activity of Human Subthalamic Neurons during a Reach-to-Grasp Task JF - Frontiers in Human Neuroscience N2 - The aim of the study was to record movement-related single unit activity (SUA) in the human subthalamic nucleus (STN) during a standardized motor task of the upper limb. We performed microrecordings from the motor region of the human STN and registered kinematic data in 12 patients with Parkinson’s disease (PD) undergoing deep brain stimulation surgery (seven women, mean age 62.0 ± 4.7 years) while they intraoperatively performed visually cued reach-to-grasp movements using a grip device. SUA was analyzed offline in relation to different aspects of the movement (attention, start of the movement, movement velocity, button press) in terms of firing frequency, firing pattern, and oscillation. During the reach-to-grasp movement, 75/114 isolated subthalamic neurons exhibited movement-related activity changes. The largest proportion of single units showed modulation of firing frequency during several phases of the reach and grasp (polymodal neurons, 45/114), particularly an increase of firing rate during the reaching phase of the movement, which often correlated with movement velocity. The firing pattern (bursting, irregular, or tonic) remained unchanged during movement compared to rest. Oscillatory single unit firing activity (predominantly in the theta and beta frequency) decreased with movement onset, irrespective of oscillation frequency. This study shows for the first time specific, task-related, SUA changes during the reach-to-grasp movement in humans. KW - subthalamic nucleus KW - deep brain stimulation KW - Parkinson’s disease KW - neurophysiology KW - beta oscillation KW - reach-to-grasp movement Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170361 VL - 11 IS - 436 ER - TY - JOUR A1 - Meziane, Hadj Boumediene A1 - Moisello, Clara A1 - Perfetti, Bernardo A1 - Kvint, Svetlana A1 - Isaias, Ioannis Ugo A1 - Quartarone, Angelo A1 - Di Rocco, Alessandro A1 - Ghilardi, Maria Felice T1 - Movement preparation and bilateral modulation of beta activity in aging and Parkinson's disease JF - PLoS ONE N2 - In previous studies of young subjects performing a reaction-time reaching task, we found that faster reaction times are associated with increased suppression of beta power over primary sensorimotor areas just before target presentation. Here we ascertain whether such beta decrease similarly occurs in normally aging subjects and also in patients with Parkinson's disease (PD), where deficits in movement execution and abnormalities of beta power are usually present. We found that in both groups, beta power decreased during the motor task in the electrodes over the two primary sensorimotor areas. However, before target presentation, beta decreases in PD were significantly smaller over the right than over the left areas, while they were symmetrical in controls. In both groups, functional connectivity between the two regions, measured with imaginary coherence, increased before the target appearance; however, in PD, it decreased immediately after, while in controls, it remained elevated throughout motor planning. As in previous studies with young subjects, the degree of beta power before target appearance correlated with reaction time. The values of coherence during motor planning, instead, correlated with movement time, peak velocity and acceleration. We conclude that planning of prompt and fast movements partially depends on coordinated beta activity of both sensorimotor areas, already at the time of target presentation. The delayed onset of beta decreases over the right region observed in PD is possibly related to a decreased functional connectivity between the two areas, and this might account for deficits in force programming, movement duration and velocity modulation. KW - event-related desynchronization KW - reaction-time tasks KW - brain dynamics KW - coherence KW - bradykinesia KW - activation KW - cortical oscillatory activity KW - voluntary movement KW - EEG data KW - L-DOPA Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144147 VL - 10 IS - 1 ER - TY - THES A1 - Kißner [geb. Stenger], Stefanie Martina T1 - Morphologische Untersuchungen an Myoblasten von Patienten, die an facioscapulohumeraler Muskeldystrophie (FSHD) leiden T1 - Morphological studies on myoblasts of patients with facioscapulohumeral muscular dystrophy N2 - Die autosomal-dominant vererbte facioscapulohumerale Muskeldystrophie (FSHD) ist mit einer Prävalenz von etwa 1:20.000 die dritthäufigste Form der hereditären Myopathien. Erste Beschwerden werden meist in der zweiten Lebensdekade beobachtet. Betroffen sind vor allem die Muskulatur von Gesicht, Schultern, Oberarmen, die Fußhebermuskulatur und die Muskeln des Hüftgürtels. FSHD wird durch einen Gendefekt ausgelöst, der den langen Arm des Chromosoms vier (4q35) betrifft, wobei es zur teilweisen Deletion des polymorphen Abschnitts D4Z4, der für das Protein DUX4 codiert, kommt. Dabei treten unter anderem Störungen in der DUX4-Expression, Veränderungen der myogenen Genexpression, eine Unterdrückung der Muskelzelldifferenzierung und eine Inhibition der Muskelbildung auf. FSHD und eine andere Form der Muskeldystrophie, die Emery-Dreifuss-Muskeldystrophie (EDMD), zeigen trotz unterschiedlicher genetischer Ursachen phänotypisch Ähnlichkeiten in der Ausprägung der Erkrankungen. In früheren Studien zeigte die Kernhülle von EDMD-Myoblasten morphologische Auffälligkeiten. In anderen Untersuchungen waren morphologische Veränderungen der Mitochondrien von FSHD-Patienten festzustellen. Daher wurden elektronenmikroskopische Untersuchungen der Kernhülle und der Mitochondrien von FSHD-Myoblasten durchgeführt und mit der entsprechenden Kontrolle verglichen. Hierfür wurden drei verschiedene Zelllinien-Paare in unterschiedlichen Passagen, das heißt unterschiedlicher Anzahl an Subkultivierungen, eingesetzt, wobei in den höheren Passagen vermehrt morphologische Atypien beobachtet werden konnten. Die eingesetzten Zelllinien differenzieren sich durch verschiedene Parameter wie beispielsweise Alter und Geschlecht der Patienten. Dabei zeigten sich sowohl zwischen den Kontrollzellen als auch zwischen den FSHD-Myoblasten Unterschiede. Im Rahmen der Probenvorbereitung für die Elektronenmikroskopie kamen zwei verschiedene Fixierungsmethoden zum Einsatz: die konventionelle chemische Fixierung, Entwässerung und Flacheinbettung von Kulturzellen und die Hochdruckgefrierung mit anschließender Gefriersubstitution. In Bezug auf die Qualität des Strukturerhalts, die beim Hochdruckgefrieren erreicht wird, wird dieser Art der Fixierung eine Überlegenheit gegenüber allen anderen Verfahren zugeschrieben. Diese allgemeine Aussage kann nicht vollständig auf die Untersuchungen an den Myoblasten übertragen werden. Für die Untersuchung der Kernmembranen sind beide Methoden geeignet, wobei der Abstand zwischen innerer und äußerer Kernmembran nach der HPF-Fixierung schärfer abgebildet wurde. Bei der Darstellung der Mitochondrien zeigten die elektronenmikroskopischen Aufnahmen nach dem Hochdruckgefrieren bessere und schärfere Ergebnisse. Die Kernporen waren bei beiden Fixierungsmethoden gut erkennbar. Beim Vergleich der gesunden und erkrankten Myoblasten wiesen die Kontrollzellen deutlich weniger Auffälligkeiten auf als die Myoblasten von FSHD-Patienten. Innere und äußere Kernmembran verliefen bei den Kontrollzellen meist parallel und die Mitochondrien zeigten in den meisten Fällen eine typische wurmartige, längliche Form mit Cristae. Dies traf sowohl für die konventionelle Fixierung als auch für das Hochdruckgefrieren zu. Die erkrankten Myoblasten wiesen im Vergleich zur Kontrolle bei beiden Fixierungsmethoden deutliche Auffälligkeiten in der Mitochondrien-Morphologie auf. Neben einer oft großen Variationsbreite hinsichtlich Form und Länge war auch das teilweise Fehlen der Cristae festzustellen. Bei Betrachtung der Kernhülle fielen jedoch deutliche Unterschiede zwischen konventioneller und HPF-Fixierung auf. Die äußere Kernmembran der konventionell fixierten FSHD-Myoblasten verlief unregelmäßig und gewellt. Im Gegensatz dazu wies die Kernhülle der HPF-fixierten erkrankten Myoblasten einen erstaunlich parallelen Verlauf auf. Da bei EDMD in vorangegangenen Untersuchungen auch fluoreszenzmikroskopisch Veränderungen der erkrankten Zellen auffällig waren, wurde neben den Methoden der Elektronenmikroskopie das Vorliegen und die Verteilung verschiedener Proteine in FSHD-Myoblasten mittels indirekter Immunfluoreszenz untersucht und mit den Kontrollzellen verglichen. Zur Beurteilung der Kernhülle wurden Antikörper gegen Lamin A/C und Nukleoporine eingesetzt. Die Mitochondrien wurden mithilfe des Antikörpers ANT1/2, der an den Adenin-Nukleotid-Translokator der inneren Mitochondrienmembran bindet, untersucht. Im Gegensatz zu den Untersuchungen an EDMD-Myoblasten waren die Lamine A und C sowie die Kernporen sowohl bei den Myoblasten der FSHD-Patienten als auch bei den Kontrollzellen nachweisbar und gleichmäßig verteilt. Bei der indirekten Immunfluoreszenz mit ANT1/2 zeigten sich Unterschiede zwischen den untersuchten Myoblasten-Paaren. Durch die vorliegenden Ergebnisse ist darauf zu schließen, dass die Myoblasten von FSHD-Patienten Veränderungen Mitochondrien aufweisen. Die Untersuchungen der Kernhülle liefern abhängig von der Fixierungsmethode unterschiedliche Ergebnisse. N2 - The autosomal dominant facioscapulohumeral muscular dystrophy (FSHD), with a prevalence of about 1:20,000, is the third most common form of hereditary myopathy. First complaints are usually observed in the second decade of life. Most affected are the muscles of the face, shoulders, upper arms, lower legs and girdle. FSHD is triggered by a gene defect affecting the long arm of chromosome four (4q35), resulting in the partial deletion of polymorphic portion D4Z4 encoding the protein DUX4. This leads to disorders in DUX4 expression, changes in myogenic gene expression, suppression of muscle cell differentiation and inhibition of muscle formation. FSHD and another form of muscular dystrophy, the Emery-Dreifuss muscular dystrophy (EDMD), show phenotypic similarities in the severity of the disease, despite different genetic causes. In previous studies, the nuclear envelope of EDMD myoblasts showed morphological abnormalities. Other studies revealed morphological changes in the mitochondria of FSHD patients. Therefore, electron micrographs of the nuclear envelope and mitochondria of FSHD myoblasts were performed and compared to the corresponding control. For this purpose, three different pairs of myoblasts were used in different passages, that is, different numbers of subcultures, with increased morphological atypia being observed in the higher passages. The cell lines used differentiate by several parameters such as age and sex of the patients. There were differences between the control cells as well as between the FSHD myoblasts. Two different fixation methods were used in sample preparation for electron microscopy: conventional chemical fixation, drainage and flat embedding of cultured cells and high-pressure freezing with subsequent freeze substitution. In terms of the quality of structure preservation achieved in high pressure freezing, this type of fixation is attributed superiority over all other methods. This general statement cannot be completely applied to the investigations on the myoblasts. For the investigation of the nuclear membranes both methods are suitable, whereby the distance between inner and outer nuclear membrane after the HPF fixation was more sharply mapped. In the representation of mitochondria, the electron micrographs after high pressure freezing showed better and sharper results. The nuclear pores were easily recognizable in both fixation methods. When comparing the healthy and diseased myoblasts, the control cells showed significantly less abnormalities than the myoblasts of FSHD patients. The inner and outer nuclear membrane were mostly parallel in the control cells, and the mitochondria in most cases showed a typical worm-like elongated form with cristae. This was true for both conventional fixation and high pressure freezing. FSHD myoblasts exhibited marked abnormalities in mitochondrial morphology compared to controls in both fixation methods. In addition to an often wide range of variation in shape and length there was also noted the partial absence of cristae. When looking at the nuclear envelope, however, there were clear differences between conventional and HPF fixation. The outer nuclear membrane of the conventionally fixed FSHD myoblasts was irregular and wavy. In contrast, the nuclear envelope of HPF fixed diseased myoblasts showed an astonishingly parallel course. Since in EDMD changes in the diseased cells were also noticeable by fluorescence microscopy, in addition to the methods of electron microscopy, the presence and distribution of various proteins in FSHD myoblasts was examined by indirect immunofluorescence and compared with the control cells. To assess the nuclear envelope, antibodies against lamin A/C and nucleoporins were used. The mitochondria were examined using the antibody ANT1 / 2, which binds to the adenine nucleotide translocator of the inner mitochondrial membrane. In contrast to the studies on EDMD myoblasts, the lamins A and C as well as the nuclear pores were detectable and evenly distributed both in the myoblasts of the FSHD patients and in the control cells. Indirect immunofluorescence with ANT1 / 2 showed differences between the investigated myoblasts. The present results suggest that the myoblasts of FSHD patients have changes in mitochondria. The investigations of the nuclear envelope provide different results depending on the fixation method. KW - Landouzy-Déjerine-Atrophie KW - Facioscapulohumeral muscular dystrophy KW - Myoblast KW - Morphologie KW - FSHD KW - myoblast KW - Myoblasten KW - HPF KW - morphology Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-156676 ER - TY - JOUR A1 - Silwedel, Christine A1 - Haarmann, Axel A1 - Fehrholz, Markus A1 - Claus, Heike A1 - Speer, Christian P. A1 - Glaser, Kirsten T1 - More than just inflammation: Ureaplasma species induce apoptosis in human brain microvascular endothelial cells JF - Journal of Neuroinflammation N2 - Background Ureaplasma species (spp.) are commonly regarded as low-virulent commensals but may cause invasive diseases in immunocompromised adults and in neonates, including neonatal meningitis. The interactions of Ureaplasma spp. with host defense mechanisms are poorly understood. This study addressed Ureaplasma-driven cell death, concentrating on apoptosis as well as inflammatory cell death. Methods Human brain microvascular endothelial cells (HBMEC) were exposed to Ureaplasma (U.) urealyticum serovar 8 (Uu8) and U. parvum serovar 3 (Up3). Resulting numbers of dead cells as well as mRNA levels and enzyme activity of key agents in programmed cell death were assessed by flow cytometry, RNA sequencing, and qRT-PCR, respectively. xCELLigence data were used for real-time monitoring of changes in cell adhesion properties. Results Both Ureaplasma isolates induced cell death (p < 0.05, vs. broth). Furthermore, Ureaplasma spp. enhanced mRNA levels for genes in apoptosis, including caspase 3 (Up3 p < 0.05, vs. broth), caspase 7 (p < 0.01), and caspase 9 (Up3 p < 0.01). Caspase 3 activity was increased upon Uu8 exposure (p < 0.01). Vice versa, Ureaplasma isolates downregulated mRNA levels for proteins involved in inflammatory cell death, namely caspase 1 (Uu8 p < 0.01, Up3 p < 0.001), caspase 4 (Uu8 p < 0.05, Up3 p < 0.01), NOD-like receptor pyrin domain-containing 3 (Uu8 p < 0.05), and receptor-interacting protein kinase 3 (p < 0.05). Conclusions By inducing apoptosis in HBMEC as main constituents of the blood-brain barrier, Ureaplasma spp. may provoke barrier breakdown. Simultaneous suppression of inflammatory cell death may additionally attenuate host defense strategies. Ultimate consequence could be invasive and long-term CNS infections by Ureaplasma spp. KW - Ureaplasma urealyticum KW - Ureaplasma parvum KW - Neuroinflammation KW - Meningitis KW - Caspase KW - Apoptosis KW - HBMEC Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200711 VL - 16 ER - TY - JOUR A1 - Jarius, Sven A1 - Kleiter, Ingo A1 - Ruprecht, Klemens A1 - Asgari, Nasrin A1 - Pitarokoili, Kalliopi A1 - Borisow, Nadja A1 - Hümmert, Martin W. A1 - Trebst, Corinna A1 - Pache, Florence A1 - Winkelmann, Alexander A1 - Beume, Lena-Alexandra A1 - Ringelstein, Marius A1 - Stich, Oliver A1 - Aktas, Orhan A1 - Korporal-Kuhnke, Mirjam A1 - Schwarz, Alexander A1 - Lukas, Carsten A1 - Haas, Jürgen A1 - Fechner, Kai A1 - Buttmann, Mathias A1 - Bellmann-Strobl, Judith A1 - Zimmermann, Hanna A1 - Brandt, Alexander U. A1 - Franciotta, Diego A1 - Schanda, Kathrin A1 - Paul, Friedemann A1 - Reindl, Markus A1 - Wildemann, Brigitte T1 - MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: Brainstem involvement - frequency, presentation and outcome JF - Journal of Neuroinflammation N2 - Background Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) are present in a subset of aquaporin-4 (AQP4)-IgG-negative patients with optic neuritis (ON) and/or myelitis. Little is known so far about brainstem involvement in MOG-IgG-positive patients. Objective To investigate the frequency, clinical and paraclinical features, course, outcome, and prognostic implications of brainstem involvement in MOG-IgG-positive ON and/or myelitis. Methods Retrospective case study. Results Among 50 patients with MOG-IgG-positive ON and/or myelitis, 15 (30 %) with a history of brainstem encephalitis were identified. All were negative for AQP4-IgG. Symptoms included respiratory insufficiency, intractable nausea and vomiting (INV), dysarthria, dysphagia, impaired cough reflex, oculomotor nerve palsy and diplopia, nystagmus, internuclear ophthalmoplegia (INO), facial nerve paresis, trigeminal hypesthesia/dysesthesia, vertigo, hearing loss, balance difficulties, and gait and limb ataxia; brainstem involvement was asymptomatic in three cases. Brainstem inflammation was already present at or very shortly after disease onset in 7/15 (47 %) patients. 16/21 (76.2 %) brainstem attacks were accompanied by acute myelitis and/or ON. Lesions were located in the pons (11/13), medulla oblongata (8/14), mesencephalon (cerebral peduncles; 2/14), and cerebellar peduncles (5/14), were adjacent to the fourth ventricle in 2/12, and periaqueductal in 1/12; some had concomitant diencephalic (2/13) or cerebellar lesions (1/14). MRI or laboratory signs of blood-brain barrier damage were present in 5/12. Cerebrospinal fluid pleocytosis was found in 11/14 cases, with neutrophils in 7/11 (3-34 % of all CSF white blood cells), and oligoclonal bands in 4/14. Attacks were preceded by acute infection or vaccination in 5/15 (33.3 %). A history of teratoma was noted in one case. The disease followed a relapsing course in 13/15 (87 %); the brainstem was involved more than once in 6. Immunosuppression was not always effective in preventing relapses. Interferon-beta was followed by new attacks in two patients. While one patient died from central hypoventilation, partial or complete recovery was achieved in the remainder following treatment with high-dose steroids and/or plasma exchange. Brainstem involvement was associated with a more aggressive general disease course (higher relapse rate, more myelitis attacks, more frequently supratentorial brain lesions, worse EDSS at last follow-up). Conclusions Brainstem involvement is present in around one third of MOG-IgG-positive patients with ON and/or myelitis. Clinical manifestations are diverse and may include symptoms typically seen in AQP4-IgG-positive neuromyelitis optica, such as INV and respiratory insufficiency, or in multiple sclerosis, such as INO. As MOG-IgG-positive brainstem encephalitis may take a serious or even fatal course, particular attention should be paid to signs or symptoms of additional brainstem involvement in patients presenting with MOG-IgG-positive ON and/or myelitis. KW - Myelin oligodendrocyte glycoprotein (MOG) antibodies KW - MOG-IgG KW - Neuromyelitis optica spectrum disorders (NMOSD) KW - Brainstem encephalitis KW - Rhombencephalitis KW - Optic neuritis KW - Myelitis KW - Longitudinally extensive transverse myelitis (LETM) KW - Cerebellitis KW - Ataxia KW - Respiratory insufficiency KW - Intractable nausea and vomiting KW - Facial nerve palsy KW - Diplopia Internuclear ophthalmoplegia (INO) KW - Hearing loss KW - Aquaporin-4 antibodies (AQP4-Ig, NMO-IgG)G Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165543 VL - 13 IS - 281 ER - TY - JOUR A1 - Jarius, Sven A1 - Ruprecht, Klemens A1 - Kleiter, Ingo A1 - Borisow, Nadja A1 - Asgari, Nasrin A1 - Pitarokoili, Kalliopi A1 - Pache, Florence A1 - Stich, Oliver A1 - Beume, Lena-Alexandra A1 - Hümmert, Martin W. A1 - Ringelstein, Marius A1 - Trebst, Corinna A1 - Winkelmann, Alexander A1 - Schwarz, Alexander A1 - Buttmann, Mathias A1 - Zimmermann, Hanna A1 - Kuchling, Joseph A1 - Franciotta, Diego A1 - Capobianco, Marco A1 - Siebert, Eberhard A1 - Lukas, Carsten A1 - Korporal-Kuhnke, Mirjam A1 - Haas, Jürgen A1 - Fechner, Kai A1 - Brandt, Alexander U. A1 - Schanda, Kathrin A1 - Aktas, Orhan A1 - Paul, Friedemann A1 - Reindl, Markus A1 - Wildemann, Brigitte T1 - MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome JF - Journal of Neuroinflammation N2 - Background A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG). Objective To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes. Methods Retrospective multicenter study. Results The sex ratio was 1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease followed a multiphasic course in 80% (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40% (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36%) and markedly impaired ambulation due to paresis or ataxia (25%) as the most common long-term sequelae. Functional blindness in one or both eyes was noted during at least one ON attack in around 70%. Perioptic enhancement was present in several patients. Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70%). Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44%. Fourty-one percent had a history of simultaneous ON and myelitis. Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50%; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one). CSF pleocytosis (partly neutrophilic) was present in 70%, oligoclonal bands in only 13%, and blood-CSF-barrier dysfunction in 32%. Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal. Full recovery was achieved by plasma exchange in some cases, including after IVMP failure. Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was associated with ongoing or increasing disease activity. Rituximab and ofatumumab were effective in some patients. However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion. Coexisting autoimmunity was rare (9%). Wingerchuk’s 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28%, 32%, 15%, 33%, respectively; MS had been suspected in 36%. Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases. Conclusion Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD. The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis. KW - Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) KW - Aquaporin-4 antibodies (AQP4-IgG, NMO-IgG) KW - Optic neuritis KW - Transverse myelitis KW - Longitudinally extensive transverse myelitis KW - Magnetic resonance imaging KW - Autoantibodies KW - Neuromyelitis optica spectrum disorders (NMOSD) KW - Cerebrospinal fluid KW - Oligoclonal bands KW - Electrophysiology KW - Evoked potentials KW - Treatment KW - Therapy KW - Methotrexate KW - Azathioprine KW - Rituximab KW - Ofatumumab KW - Interferon beta KW - Glatiramer acetate KW - Natalizumab KW - Outcome KW - Pregnancy KW - Infections KW - Vaccination KW - Multiple sclerosis KW - Barkhof criteria KW - McDonald criteria KW - Wingerchuk criteria 2006 and 2015 KW - IPND criteria KW - International consensus diagnostic criteria for neuromyelitis optica spectrum disorders Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165570 VL - 13 IS - 280 ER - TY - JOUR A1 - Jarius, Sven A1 - Ruprecht, Klemens A1 - Kleiter, Ingo A1 - Borisow, Nadja A1 - Asgari, Nasrin A1 - Pitarokoili, Kalliopi A1 - Pache, Florence A1 - Stich, Oliver A1 - Beume, Lena-Alexandra A1 - Hümmert, Martin W. A1 - Trebst, Corinna A1 - Ringelstein, Marius A1 - Aktas, Orhan A1 - Winkelmann, Alexander A1 - Buttmann, Mathias A1 - Schwarz, Alexander A1 - Zimmermann, Hanna A1 - Brandt, Alexander U. A1 - Franciotta, Diego A1 - Capobianco, Marco A1 - Kuchling, Joseph A1 - Haas, Jürgen A1 - Korporal-Kuhnke, Mirjam A1 - Lillevang, Soeren Thue A1 - Fechner, Kai A1 - Schanda, Kathrin A1 - Paul, Friedemann A1 - Wildemann, Brigitte A1 - Reindl, Markus T1 - MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin JF - Journal of Neuroinflammation N2 - Background Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been suggested to play a role in a subset of patients with neuromyelitis optica and related disorders. Objective To assess (i) the frequency of MOG-IgG in a large and predominantly Caucasian cohort of patients with optic neuritis (ON) and/or myelitis; (ii) the frequency of MOG-IgG among AQP4-IgG-positive patients and vice versa; (iii) the origin and frequency of MOG-IgG in the cerebrospinal fluid (CSF); (iv) the presence of MOG-IgG at disease onset; and (v) the influence of disease activity and treatment status on MOG-IgG titers. Methods 614 serum samples from patients with ON and/or myelitis and from controls, including 92 follow-up samples from 55 subjects, and 18 CSF samples were tested for MOG-IgG using a live cell-based assay (CBA) employing full-length human MOG-transfected HEK293A cells. Results MOG-IgG was detected in 95 sera from 50 patients with ON and/or myelitis, including 22/54 (40.7%) patients with a history of both ON and myelitis, 22/103 (21.4%) with a history of ON but no myelitis and 6/45 (13.3%) with a history of longitudinally extensive transverse myelitis but no ON, and in 1 control patient with encephalitis and a connective tissue disorder, all of whom were negative for AQP4-IgG. MOG-IgG was absent in 221 further controls, including 83 patients with AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and 85 with multiple sclerosis (MS). MOG-IgG was found in 12/18 (67%) CSF samples from MOG-IgG-seropositive patients; the MOG-IgG-specific antibody index was negative in all cases, indicating a predominantly peripheral origin of CSF MOG-IgG. Serum and CSF MOG-IgG belonged to the complement-activating IgG1 subclass. MOG-IgG was present already at disease onset. The antibodies remained detectable in 40/45 (89%) follow-up samples obtained over a median period of 16.5 months (range 0–123). Serum titers were higher during attacks than during remission (p < 0.0001), highest during attacks of simultaneous myelitis and ON, lowest during acute isolated ON, and declined following treatment. Conclusions To date, this is the largest cohort studied for IgG to human full-length MOG by means of an up-to-date CBA. MOG-IgG is present in a substantial subset of patients with ON and/or myelitis, but not in classical MS. Co-existence of MOG-IgG and AQP4-IgG is highly uncommon. CSF MOG-IgG is of extrathecal origin. Serum MOG-IgG is present already at disease onset and remains detectable in the long-term course. Serum titers depend on disease activity and treatment status. KW - Neuromyelitis optica (NMO) KW - Devic’s syndrome KW - Optic neuritis KW - Transverse Myelitis KW - Longitudinally extensive transverse myelitis (LETM) KW - Neuromyelitis optica spectrum disorders (NMOSD) KW - Multiple sclerosis KW - Autoantibodies KW - Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) KW - Neuromyelitis optica antibodies (NMO-IgG) KW - Aquaporin-4 antibodies (AQP4-IgG) KW - Cell-based assays KW - Cerebrospinal fluid KW - Antibody index Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165659 VL - 13 IS - 279 ER - TY - THES A1 - Merzyn, Cornelia T1 - Modulation systemischer Chemokinspiegel durch rekombinantes Interferon-beta bei Patienten mit multipler Sklerose T1 - Modulation of systemic chemokine levels by recombinant interferon-beta in patients with multiple sclerosis N2 - Multiple Sklerose (MS) ist eine chronisch-entzündliche Erkrankung des Zentralen Nervensystems mit deutlich ausgeprägten Autoimmunphänomenen. Das derzeit meistverwendete Therapeutikum zur Sekundärprophylaxe von Krankheitsschüben ist rekombinantes Interferon-β (IFN-β). Wirk- und Nebenwirkungsmechanismen des Medikaments werden bisher nur partiell verstanden. In der Pathogenese der MS spielt eine Familie chemotaktisch wirksamer Zytokine, der Chemokine, eine entscheidende Rolle. Ziel dieser Studie war zu untersuchen, ob IFN-β die systemischen Konzentrationen der Pathogenese-relevanten Chemokine CXCL10, CCL2 und außerdem des endogenen Pyrogens IL-6 verändert, und ob diese Veränderungen mit dem Auftreten grippeartiger Nebenwirkungen korrelieren. Zu diesem Zweck wurden bei 37 Patienten mit schubförmiger MS zu drei Zeitpunkten – vor sowie 6 und 24 Stunden nach der Applikation von IFN-β – die genannten Botenstoffe im Blut bestimmt. Parallel wurden subjektiv empfundene grippeartige Nebenwirkungen mit Hilfe eines standardisierten Fragebogens abgefragt, und die Körperkerntemperatur wurde gemessen. Als Kontrollen dienten gesunde Probanden, derzeit nicht immunmodulatorisch behandelte MS-Patienten und MS-Patienten unter Therapie mit Glatirameracetat. Nur bei den mit IFN-β behandelten Patienten zeigte sich nach 6 Stunden ein signifikanter transienter Anstieg der Konzentrationen von CXCL10, CCL2. Der Anstieg der Chemokinkonzentrationen korrelierte mit einem transienten IL-6-Anstieg und dem Auftreten grippeartiger Nebenwirkungen. Chemokine, unter denen sich zahlreiche starke endogene Pyrogene befinden, könnten somit für die häufig zu beobachtenden grippeartigen Nebenwirkungen mit verantwortlich sein. Die Ergebnisse werfen die weiterführende Frage auf, ob die beobachtete Chemokininduktion auch relevant für den therapeutischen Effekt von IFN- ist. Ob Chemokine sich erfolgreich als Biomarker zur Prädiktion des Therapieerfolgs einsetzen lassen, wird derzeit in einem weiterführenden Projekt untersucht. N2 - Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with clear autoimmune phenomena. Recombinant Interferon-β (IFN-β) is currently the most widely used treatment to prevent relapses. The mechanisms and side effects of the drug are only partially understood. A family of chemotactical active cytokines, the chemokines, play a decisive role in the pathogenesis of MS. The aim of this study was to examine if IFN-β alters the systemic concentrations of CXCL10 and CCL2, two chemokines that are relevant in the pathogenesis, and of IL-6, an endogenous pyrogen. A further aim was to discover whether these concentrations correlate with the appearance of flu-like symptoms, a common adverse effect of IFN-β. 37 patients with relapsing-remitting MS were tested three times to measure the chemokine concentrations in their blood – prior to IFN-β application, and again 6 and 24 hours after application. Concurrently, the occurrence of flu-like symptoms was recorded with the help of a standardized questionnaire and through body temperature measurements. The control groups consisted of healthy subjects, MS patients not receiving any treatment, and MS patients treated with glatiramer acetate. After 6 hours, only the MS patients treated with IFN-β showed a significant transient elevation in the concentrations of CXCL10 and CCL2. This elevation correlated with a transient increase in the IL-6 concentration and the appearance of flu-like symptoms. Among the chemokines there are many strong endogenous pyrogens, which might be responsible for the commonly observed, flu-like side effects of IFN-β. The results raise the question of whether the observed induction of chemokines is also relevant for the therapeutic effect of IFN-β. Whether chemokines can be used as biomarkers to predict therapeutic success is currently being explored in ongoing work built upon this study. KW - Multiple Sklerose KW - Interferon KW - Chemokine KW - CCL2 KW - CXCL10 KW - CCL2 KW - CXCL10 Y1 - 2008 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-35828 ER - TY - THES A1 - Nehen, Mathias Julius T1 - Modulation der Schrankenfunktion primärer humaner zerebraler Endothelzellen durch Fumarsäureester unter inflammatorischen und nicht-inflammatorischen Bedingungen T1 - Fumaracids modulation on the barrier of primary human cerebral endothelia cells in inflammatory and non-imflammatory conditions N2 - Die Multiple Sklerose ist eine bisher nicht heilbare, chronisch-inflammatorische demyelinisierende Erkrankung des zentralen Nervensystems. Trotz intensiver Forschungsbemühungen ist der exakte Pathomechanismus nicht vollkommen verstanden. Klar ist jedoch, dass der Blut-Hirn-Schranke eine entscheidende Rolle bei der Pathogenese zukommt. Seit Februar 2014 ist mit Dimethylfumarat ein neues orales Medikament für die schubförmige Multiple Sklerose zugelassen. Die Wirkungen von Fumarsäureestern auf humane zerebrale Endothelzellen als Grundsteine der Blut-Hirn-Schranke sind allerdings nur unzureichend untersucht. Mehrere Forschungsgruppen demonstrierten an humanem Nabelschnurvenenendothel einen hemmenden Effekt von Fumarsäureestern auf die Adhäsion von Leukozyten und beschrieben eine Inhibition der Aktivierung des proinflammatorischen Transkriptionsfaktors NFB in den Endothelzellen. Aufgrund der charakteristischen Eigenschaften zerebralen Endothels ist eine Übertragung dieser Beobachtungen auf die Blut-Hirn-Schranke allerdings nicht ohne weiteres möglich. Daher galt es potentielle Effekte von Fumarsäureestern auf primäre humane zerebrale Endothelzellen als in vitro Modell der Blut-Hirn-Schranke zu überprüfen. Dabei wurden die Zellen nicht nur unter ruhenden Bedingungen, sondern auch unter inflammatorischer Stimulation mit TNF-α, IL-1 und IFN untersucht, einem Milieu, wie es in inflammatorischen MS Läsionen zu finden ist. In Leukozyten-Adhäsionsassays konnte durch Inkubation mit Monomethylfumarat und Dimethylfumarat keine funktionale Beeinflussung der Adhäsion von T-Lymphozyten an den verwendeten zerebralen Endothelzellen verzeichnet werden. Kongruent dazu fand sich in durchflusszytometrischen Analysen keine Hemmung der inflammatorisch vermittelten Expression des Adhäsionsmoleküls ICAM-1, welches eine tragende Rolle bei der Leukozytenmigration spielt. Inflammatorische intrazelluläre Signalwege, wie die NFB-Kerntranslokation oder die Phosphorylierung von p38 wurden in HECE im Gegensatz zu HUVEC durch Fumarsäureester ebenso wenig beeinflusst. Diese in sich konsistenten Ergebnisse führen zu der Schlussfolgerung, dass im Gegensatz zu anderen Gefäßbetten weder Dimethylfumarat noch Monomethylfumarat direkt am zerebralen Endothel anti-inflammatorisch wirken. N2 - Dimethyl fumarate (DMF) is approved for disease-modifying treatment of patients with relapsing-remitting multiple sclerosis. Animal experiments suggested that part of its therapeutic effect is due to a reduction of T-cell infiltration of the central nervous system (CNS) by uncertain mechanisms. Here we evaluated whether DMF and its primary metabolite monomethyl fumarate (MMF) modulate pro-inflammatory intracellular signaling and T-cell adhesiveness of nonimmortalized single donor human brain microvascular endothelial cells at low passages. Neither DMF nor MMF at concentrations of 10 or 50 μM blocked the IL-1β-induced nuclear translocation of NF-κB/p65, whereas the higher concentration of DMF inhibited the nuclear entry of p65 in human umbilical vein endothelium cultured in parallel. DMF and MMF also did not alter the IL-1β-stimulated activation of p38 MAPK in brain endothelium. Furthermore, neither DMF nor MMF reduced the basal or IL-1β-inducible expression of ICAM-1. In accordance, both fumaric acid esters did not reduce the adhesion of activated Jurkat T cells to brain endothelium under basal or inflammatory conditions. Therefore, brain endothelial cells probably do not directly mediate a potential blocking effect of fumaric acid esters on the inflammatory infiltration of the CNS by T cells. KW - Multiple Sklerose KW - Blut-Hirn-Schranke KW - Dimethylfumarat Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240925 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 - THES A1 - Leinders, Mathias T1 - microRNAs in chronic pain T1 - microRNAs bei chronischen Schmerzen N2 - Chronic pain is a common problem in clinical practice, not well understood clinically, and frequently tough to satisfactorily diagnose. Because the pathophysiology is so complex, finding effective treatments for people with chronic pain has been overall less than successful and typically reduced to an unsatisfactory trial-and-error process, all of which translates into a significant burden to society. Knowledge of the mechanisms underlying the development of chronic pain, and moreover why some patients experience pain and others not, may aid in developing specific treatment regimens. Although nerve injuries are major contributors to pain chronification, they cannot explain the entire phenomenon. Considerable research has underscored the importance of the immune system for the development and maintenance of chronic pain, albeit the exact factors regulating inflammatory reactions remain unclear. Understanding the putative molecular and cellular regulator switches of inflammatory reactions will open novel opportunities for immune modulatory analgesics with putatively higher specificity and less adverse effects. It has become clear that small, non- coding RNA molecules known as microRNAs are in fact potent regulators of many thousands of genes and possibly cross-communicate between cellular pathways in multiple systems acting as so-called “master-switches”. Aberrant expression of miRNAs is now implicated in numerous disorders, including nerve injuries as well as in inflammatory processes. Moreover, compelling evidence supports the idea that miRNAs also regulate pain, and in analogy to the oncology field aid in the differential diagnosis of disease subtypes. In fact, first reports describing characteristic miRNA expression profiles in blood or cerebrospinal fluid of patients with distinct pain conditions are starting to emerge, however evidence linking specific miRNA expression profiles to specific pain disorders is still insufficient. The present thesis aimed at first, identifying specific miRNA signatures in two distinct chronic pain conditions, namely peripheral neuropathies of different etiologies and fibromyalgia syndrome. Second, it aimed at identifying miRNA profiles to better understand potential factors that differentiate painful from painless neuropathies and third, study the mechanistic role of miRNAs in the pathophysiology of pain, to pave the way for new druggable targets. Three studies were conducted in order to identify miRNA expression signatures that are characteristic for the given chronic pain disorder. The first study measured expression of miR-21, miR-146a and miR-155 in white blood cells, skin and nerve biopsies of patients with peripheral neuropathies. It shows that peripheral neuropathies of different etiologies are associated with increased peripheral miR-21 and miR-146a, but decreased miR-155 expression. More importantly, it was shown that painful neuropathies have increased sural nerve miR-21 and miR-155 expression, but reduced miR-146a and miR-155 expression in distal skin of painful neuropathies. These results point towards the potential use of miRNAs profiles to stratify painful neuropathies. The seconds study extends these findings and first analyzed the role of miR-132-3p in patients and subsequently in an animal model of neuropathic pain. Interestingly, miR-132-3p was upregulated in white blood cells and sural nerve biopsies of patients with painful neuropathies and in animals after spared nerve injury. Pharmacologically modulating the expression of miR-132-3p dose-dependently reversed pain behavior and pain aversion, indicating the pro-nociceptive effect of miR-132-3p in chronic pain. This study thus demonstrates the potential analgesic impact by modulating miRNA expression. Fibromyalgia is associated with chronic widespread pain and, at least in a subgroup, impairment in small nerve fiber morphology and function. Interestingly, the disease probably comprises subgroups with different underlying pathomechanisms. In accordance with this notion, the third study shows that fibromyalgia is associated with both aberrant white blood cell and cutaneous miRNA expression. Being the first of its kind, this study identified miR-let-7d and its downstream target IGF-1R as potential culprit for impaired small nerve fiber homeostasis in a subset of patients with decreased intra-epidermal nerve fiber density. The work presented in this thesis is a substantial contribution towards the goal of better characterizing chronic pain based on miRNA expression signatures and thus pave the way for new druggable targets. N2 - Chronische Schmerzen sind in der klinischen Praxis ein häufiges Problem, die Ätiologie und Pathogenese jedoch oftmals unklar. Aufgrund der Komplexität des pathophysiologischen Ursprunges chronischer Schmerzen, ist bei einem Teil der Patienten Schmerzfreiheit oder Schmerzreduktion mit gängigen Analgetika nur insuffizient zu erreichen. Dies führt zu einer enormen sozio-ökonomischen Belastung für die Gesellschaft. Daher können Kenntnisse über die Mechanismen, die der Entwicklung von chronischen Schmerzen zugrunde liegen, und darüber hinaus, warum einige Patienten Schmerzen entwickeln und andere nicht, bei der Entwicklung spezifischer und individueller Behandlungsschemata helfen. Eine Vielzahl an Studien belegen die Bedeutung des Immunsystems für die Entwicklung und Aufrechterhaltung chronischer Schmerzen, wenngleich die genauen Faktoren, die entzündliche Reaktionen regulieren, noch unklar bleiben. Rezente Entdeckungen der hochkonservierten, nicht-kodierenden RNA-Moleküle, sogenannten microRNAs, lassen in der Tat darauf schließen, dass diese eine wichtige Rolle im Netzwerk der Genregulation spielen. microRNAs regulieren die hochspezifische „cross-communication“ mehrerer simultaner Signaltransduktionsvorgänge zellulärer Prozesse, und werden daher auch "master-switches" genannt. Interessanterweise, wurden aberrante Expressionen spezifischer miRNAs in zahlreichen Krankheiten, einschließlich Nervenverletzungen, sowie in entzündlichen Prozessen nachgewiesen. Darüber hinaus belegen stichhaltige Beweise nicht nur die Idee, dass miRNAs auch bei der Regulierung von Schmerzen eine wichtige Rolle spielen, sondern auch hilfreich bei der Differentialdiagnose von Krankheits- Subtypen sein können. Dies wurde bei rezenten onkologischen Studien deutlich. Tatsächlich weisen erste Berichte auf ein charakteristisches miRNA- Expressionsprofil in Blut oder Zerebrospinalflüssigkeit von Patienten mit verschiedenen Schmerztypen hin. Jedoch ist die Assoziation spezifischer miRNA-Expressionsprofile mit spezifischen Schmerzstörungen noch unzureichend. Die Zielvorgabe der vorliegenden Arbeit war daher zunächst, spezifische miRNA-Signaturen in zwei verschiedenen chronischen Schmerzzuständen zu identifizieren, nämlich peripheren Neuropathien verschiedener Ätiologien und dem Fibromyalgie-Syndrom. Zweitens wurden die erarbeiteten Ergebnisse dazu verwendet, bestimmte miRNA-Profile zu identifizieren, die schmerzhafte von schmerzlosen Neuropathien unterscheiden lassen und einen Hinweis auf die Pathologie der kleinkalibrigen Fasern bei der Fibromyalgie geben. Darüber hinaus wurde die mechanistische Rolle von miRNAs in der Pathophysiologie von Schmerzen Tierexperimentell untersucht, um künftig neuartige Therapien entwickeln zu können. Die erste Studie untersuchte die Expression von miR-21, miR-146a und miR-155 in weißen Blutkörperchen, Haut- und Nervenbiopsien bei Patienten mit peripheren Neuropathien. Sie zeigt, dass periphere Neuropathien verschiedener Ätiologien mit erhöhten peripheren miR-21 und miR-146a und verminderter miR- 155 Expression assoziiert sind. Wichtiger jedoch, dass Patienten mit schmerzhaften Neuropathien erhöhte miR-21 und miR-155-Expression im Suralis und verminderte miR-146a- und miR-155-Expression in distalen im Vergleich zu proximalen Hautbiopsien aufweisen. Diese Ergebnisse weisen auf die potenzielle Verwendung von miRNA-Profilen zur Stratifizierung schmerzhafter Neuropathien hin. Die zweite Studie baut dieses Ergebnis aus und untersuchte zunächst die Rolle von miR-132-3p im humanen und anschließend bei tierexperimentellen neuropathischen Schmerzen. Interessanterweise war miR-132-3p sowohl in weißen Blutkörperchen und Suralis-Nervenbiopsien von Patienten mit schmerzhaften Neuropathien als auch bei Tieren nach Läsion eines peripheren Nervens hochreguliert. Nach pharmakologischer Intervention gab es eine dosisabhängige Schmerzreduktion und Schmerzaversion, was somit auf den pro- nozizeptiven Effekt von miR-132-3p hinweist. Diese Studie zeigt somit die potenzielle analgetische Wirksamkeit microRNA-gerichteter pharmakologischer Interventionen. Das Fibromyalgie Syndrome ist eine chronische Erkrankung, die von einem multilokulären Schmerzbild und Beeinträchtigungen in kleinen Nervenfasern dominiert wird. Es wird angenommen, dass die Erkrankung wahrscheinlich aus Subgruppen mit unterschiedlichen zugrunde liegenden Pathomechanismen besteht. Die hierzu durchgeführte Studie zeigt, dass Fibromyalgie-Patienten veränderte microRNA Expression sowohl in weißen Blutkörperchen als auch in der Haut aufweisen. Erstmals identifiziert diese Studie miR-let-7d und ihr „downstream-target“ IGF-1R als potentiellen Schädigungsmechanismus kleiner Nervenfaserfunktionen, in einer Subgruppe von Patienten mit verminderter intra-epidermalen Nervenfaserdichte. Die Ergebnisse, die in dieser Arbeit vorgestellt werden, liefern einen wesentlichen Beitrag, die Pathophysiologie chronischer Schmerzen, aufgrund von miRNA-Expressions-Signaturen zu charakterisieren. KW - chronic pain KW - microRNA KW - miRNS KW - Chronischer Schmerz Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144395 ER - TY - THES A1 - Hirschmann, Anna T1 - microRNA-Genexpressionsprofile in Blut-, Haut- und Nervenproben von Patienten mit Polyneuropathien T1 - microRNA gene expression profiles in blood, skin and nerve samples of patients with polyneuropathy N2 - Die Polyneuropathie (PNP) ist die häufigste Störung des peripheren Nervensystems bei Erwachsenen. Die Suche nach der Ursache bleibt in vielen Fällen erfolglos, ist aber unverzichtbar, da die Therapiewahl von der Ätiologie der Erkrankung abhängt. Geeignete Biomarker könnten die Differentialdiagnose unter Umständen erleichtern. microRNAs (miRNAs) sind in dieser Hinsicht vielversprechend, da in vielen Studien bei Nervende- und regenerationsprozessen sowie in neuropathischen Schmerzmodellen eine Dysregulation beschrieben wurde. In dieser Studie wurde die Expression zweier miRNAs, miR-103a und miR-let-7d, sowie eines Zielmoleküls der miR-103a, des Kalziumkanals Cav1,2, in einer großen Kohorte von PNP-Patienten unterschiedlicher Ätiologie in Blut, Haut- und Nervenbiopsien untersucht. Insgesamt wurden 116 Patienten und 22 Kontroll-probanden in die Studie eingeschlossen. Nach der Isolation von RNA aus weißen Blutzellen (WBC), Haut- und Nervenbiopsien folgte die Expressionsbestimmung mittels qRT-PCR. Während sich jeweils Unterschiede zwischen PNP-Patienten und Kontrollen und zwischen Patienten mit entzündlicher und solchen mit nicht-entzündlicher PNP zeigten, wurden keine Unterschiede in der Expression zwischen den ätiologischen Subgruppen oder zwischen Patienten mit schmerzhafter und schmerzloser PNP festgestellt. In den Nervenbiopsien der Patientenkohorte ergab sich eine inverse Korrelation der miR-103a und ihrem Zielgen Cacna1c, die darauf hinweisen könnte, dass Cacna1c von der miR-103a negativ reguliert wird. Da in unserer Patientenkohorte keine Unterschiede zwischen den PNP-Subgruppen auftraten, scheint der Einsatz der miR-103a und miR-let-7d als diagnostische Biomarker zur ätiologischen Einordnung einer PNP nicht gerechtfertigt. Dennoch deuten unsere Ergebnisse auf eine mögliche Rolle der untersuchten miRNAs bei Entstehung und Verlauf von PNP hin. Für ein tieferes pathophysiologisches Verständnis der miRNAs vor allem bei entzündlichen Neuropathien, könnte die Untersuchung von weiteren miRNAs und Zielgenen Aufschluss geben. N2 - Polyneuropathies (PNP) are the most frequent disorder of the peripheral nervous system in adults. Since the choice of therapy depends on it, the etiological diagnostic is essential but often remains without results so far. The differential diagnosis could be facilitated by a suitable biomarker. In this respect, microRNA (miRNA) are promising because their dysregulation has been described in processes of nerve degeneration and regeneration as well as in neuropathic pain models. This study investigated the expression of two miRNA, miR-103a and miR-let-7d, and the calcium channel Cav1.2, a target of miR-103a, in a large cohort of PNP patients with different etiology in blood, skin and nerve samples. Altogether, 116 patients and 22 controls have been included in the study. Expressional analysis via qRT-PCR succeeded the isolation of RNA out of white blood cells (WBC), skin and nerve biopsies. Differences have been found between PNP patients and controls and between patients with inflammatory and non-inflammatory PNP. No differences have been recorded between the etiological subgroups or between painful and painless PNP. miR-103a and its target Cacna1c correlated inversely in nerve which could be an indication for Cacna1c being negatively regulated by miR-103a. miR-103a and miR-let-7d do not seem to be appropriate diagnostic biomarkers for the etiological classification of PNP as there have not been found any differences between the PNP subgroups. Nevertheless, our results suggest that miRNA may play a part in the development and the progression of PNP. The investigation of further miRNA and targets could provide insight into a deeper pathophysiological understanding of miRNA, especially in inflammatory neuropathies. KW - miRNS KW - Polyneuropathie KW - Genexpression KW - microRNA KW - miRNA KW - PNP KW - Neuropathischer Schmerz KW - neuropathic pain KW - gene expression Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-217010 ER - TY - JOUR A1 - Reinhold, Ann Kristin A1 - Krug, Susanne M. A1 - Salvador, Ellaine A1 - Sauer, Reine S. A1 - Karl-Schöller, Franziska A1 - Malcangio, Marzia A1 - Sommer, Claudia A1 - Rittner, Heike L. T1 - MicroRNA-21-5p functions via RECK/MMP9 as a proalgesic regulator of the blood nerve barrier in nerve injury JF - Annals of the New York Academy of Sciences N2 - Both nerve injury and complex regional pain syndrome (CRPS) can result in chronic pain. In traumatic neuropathy, the blood nerve barrier (BNB) shielding the nerve is impaired—partly due to dysregulated microRNAs (miRNAs). Upregulation of microRNA-21-5p (miR-21) has previously been documented in neuropathic pain, predominantly due to its proinflammatory features. However, little is known about other functions. Here, we characterized miR-21 in neuropathic pain and its impact on the BNB in a human-murine back translational approach. MiR-21 expression was elevated in plasma of patients with CRPS as well as in nerves of mice after transient and persistent nerve injury. Mice presented with BNB leakage, as well as loss of claudin-1 in both injured and spared nerves. Moreover, the putative miR-21 target RECK was decreased and downstream Mmp9 upregulated, as was Tgfb. In vitro experiments in human epithelial cells confirmed a downregulation of CLDN1 by miR-21 mimics via inhibition of the RECK/MMP9 pathway but not TGFB. Perineurial miR-21 mimic application in mice elicited mechanical hypersensitivity, while local inhibition of miR-21 after nerve injury reversed it. In summary, the data support a novel role for miR-21, independent of prior inflammation, in elicitation of pain and impairment of the BNB via RECK/MMP9. KW - claudin-1 KW - RECK KW - MMP9 KW - CRPS KW - microRNA KW - neuropathic pain KW - blood nerve barrier Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318226 VL - 1515 IS - 1 SP - 184 EP - 195 ER - TY - JOUR A1 - Groh, Janos A1 - Abdelwahab, Tassnim A1 - Kattimani, Yogita A1 - Hörner, Michaela A1 - Loserth, Silke A1 - Gudi, Viktoria A1 - Adalbert, Robert A1 - Imdahl, Fabian A1 - Saliba, Antoine-Emmanuel A1 - Coleman, Michael A1 - Stangel, Martin A1 - Simons, Mikael A1 - Martini, Rudolf T1 - Microglia-mediated demyelination protects against CD8\(^+\) T cell-driven axon degeneration in mice carrying PLP defects JF - Nature Communications N2 - Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes. We show that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8\(^+\) T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce cytoskeletal alterations within myelinating glia and aberrant actomyosin constriction of axons at paranodal domains. Our study identifies detrimental axon-glia-immune interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation. KW - diseases of the nervous system KW - myelin biology and repair KW - neuroimmunology Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357641 VL - 14 ER - TY - THES A1 - Kewenig, Susanne Katharina T1 - Messung der zerebralen Aktivierung mittels funktioneller Nah-Infrarot-Spektroskopie bei Patienten mit Fibromyalgie-Syndrom T1 - Cerebral activation of patients with fibromyalgia syndrome measured by near infrared spectroscopy N2 - Wir untersuchten die zerebrale Aktivierung von Patienten mit Fibromyalgie-Syndrom (FMS) mittels funktioneller Nah-Infrarot-Spektroskopie (fNIRS). Das FMS ist ein Symptomenkomplex aus Schmerzen in mehreren Körperregionen sowie weiteren körperlichen und seelischen Beschwerden, wie Schlafstörungen, kognitiven Defiziten und Depressionen. Die fNIRS ist eine neue, nicht-invasive Technik, die eine indirekte Messung der regionalen kortikalen Hirnaktivierung erlaubt. Es wurden 25 FMS-Patienten, 10 MD-Patienten ohne Schmerzen und 35 gesunde Kontrollen in die Studie eingeschlossen. Alle Patienten wurden klinisch-neurologisch untersucht. Darüber hinaus füllten alle Teilnehmer Fragebögen zu Schmerzen (GCPS, NPSI), FMS-Symptomen (FIQ), Depressionen (BDI II, ADS) und Empathiefähigkeit (SPF) aus. Die kortikale Aktivierung wurde unter drei Stimulations-Bedingungen mittels fNIRS gemessen: 1.) Anwendung mechanischer (Druck-) Schmerzreize auf den dorsalen Unterarm; 2.) Anwendung visuell-emotionaler Reize in Form von neutralen, negativen und Schmerz-assoziierten Bildern; 3.) Wortflüssigkeitstest. Ergänzend wurden die unter 2.) präsentierten Bilder bewertet sowie ein Zahlenverbindungstest durchgeführt. FMS-Patienten hatten in den Schmerzfragebögen und im FIQ-Fragebogen deutlich höhere Werte als MD-Patienten und Kontrollen (p < 0,001). In den Depressionsfragebögen erreichten FMS-Patienten ähnlich hohe Werte wie MD-Patienten. Die Empathiefähigkeit war bei FMS-Patienten tendenziell stärker ausgeprägt als bei MD-Patienten und Kontrollen. FMS-Patienten zeigten niedrigere Druckschmerzschwellen bei gleicher Schmerzintensität als MD-Patienten und Kontrollen (p < 0,001). Auf einen unilateralen schmerzhaften Druckreiz reagierten FMS-Patienten mit einer verstärkten bilateralen kortikalen Aktivierung, die sich im Vergleich zu Kontrollen insbesondere im rechten präfrontalen Kortex (p < 0,05) sowie zu MD-Patienten bilateral im Frontalkortex unterschied (p < 0,05). Auf einen Druckreiz der gleichen Stärke, der für FMS-Patienten schmerzhaft, aber für Zusatzkontrollen schmerzfrei war, zeigten FMS-Patienten im Vergleich zu diesen eine verstärkte Aktivierung im linken dorsolateralen präfrontalen Kortex (p < 0,05). Der kortikale Aktivierungsunterschied bei Schmerz-assoziierten versus neutralen Bildern war bei FMS-Patienten im linken präfrontalen Kortex wesentlich ausgeprägter als bei Kontrollen (p < 0,05), während die Schmerz-assoziierten Bilder von FMS-Patienten weniger unangenehm bewertet wurden als von Kontrollen. Der Aktivierungsunterschied bei negativen versus neutralen Bildern war bei MD-Patienten im linken Frontalkortex wesentlich geringer ausgeprägt als bei FMS-Patienten und Kontrollen (p < 0,05). Im Wortflüssigkeitstest und im Zahlenverbindungstest konnten keine kognitiven Defizite bzw. Aktivierungsunterschiede zwischen FMS-Patienten und Kontrollen gefunden werden. Allerdings zeigten MD-Patienten in beiden Bedingungen des Wortflüssigkeitstests eine geringere frontale Aktivierung als FMS-Patienten und Kontrollen (p < 0,05). Diese Studie belegt die veränderte zentrale Schmerzverarbeitung bei FMS-Patienten und zeigt, dass diese mittels fNIRS messbar ist. FMS-Patienten zeigten stärkere Aktivierungen Schmerz-assoziierter Hirnareale während mechanischer und visueller Schmerzstimuli im Vergleich zu gesunden Kontrollen. Zudem bestätigt diese Studie die Unterscheidung zwischen FMS und Depression. N2 - We investigated cerebral activation in Fibromyalgia syndrome (FMS) patients by functional near-infrared spectroscopy (fNIRS). FMS is a chronic condition characterized by widespread pain and associated symptoms. fNIRS is a new, non-invasive technique that allows an indirect measurement of the regional cortical brain activation. We prospectively recruited 25 FMS patients, ten patients with unipolar major depression (MD) without pain, and 35 healthy controls. All patients underwent neurological examination and all subjects were investigated with questionnaires referring to pain (GCPS, NPSI), FMS-Symptoms (FIQ), depression (BDI II, ADS) and empathy (SPF). Cortical activation was measured by fNIRS applying three stimulation paradigms: 1.) painful pressure stimulation at the dorsal forearm; 2.) visual emotional stimulation with neutral, negative and pain associated pictures; 3.) verbal fluency test. Additionally, the pictures presented at point 2.) were rated and a Zahlenverbindungstest was made. In the pain questionnaires and the FIQ FMS patients had much higher scores than MD patients and controls (p<0,001). In the depression questionnaires FMS patients reached similar high scores as MD patients. FMS patients tended to have higher empathy scores than MD patients and controls. FMS patients had lower pressure pain thresholds than patients with MD and controls (p<0.001) and reported similar pain intensity. Upon unilateral pressure pain stimulation fNIRS recordings revealed increased bilateral cortical activation in FMS patients, showing differences in the right prefrontal cortex compared to controls (p<0.05) and bilaterally in the frontal cortex compared to MD patients (p<0,05). Upon a pressure stimulation of the same magnitude that was painful for FMS patients, but painless for additional controls, FMS patients showed a higher activation in the left dorsolateral prefrontal cortex compared to the additional controls (p<0,05). The cortical activation difference during the presentation of pain associated versus neutral pictures was more pronounced in the left prefrontal cortex of FMS patients compared to controls (p<0,05), whereas the pain associated pictures were rated as less unpleasant by FMS patients compared to controls. The cortical activation difference during the presentation of negative versus neutral pictures was much smaller in the left frontal cortex of MD patients compared to FMS patients and controls (p<0,05). In the verbal fluency test and the Zahlenverbindungstest all three groups performed equally well, a frontal deficit in cortical activation was only found in MD patients (p<0,05). Our data give further evidence for altered central nervous processing in patients with FMS and the distinction between FMS and MD. KW - Fibromyalgie KW - Infrarotspektroskopie KW - Fibromyalgie KW - Nahinfrarot-Spektroskopie KW - fibromyalgia KW - near infrared spectroscopy Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-107515 ER - TY - JOUR A1 - Schuhmann, Michael K. A1 - Papp, Lena A1 - Stoll, Guido A1 - Blum, Robert A1 - Volkmann, Jens A1 - Fluri, Felix T1 - Mesencephalic electrical stimulation reduces neuroinflammation after photothrombotic stroke in rats by targeting the cholinergic anti-inflammatory pathway JF - International Journal of Molecular Sciences N2 - Inflammation is crucial in the pathophysiology of stroke and thus a promising therapeutic target. High-frequency stimulation (HFS) of the mesencephalic locomotor region (MLR) reduces perilesional inflammation after photothrombotic stroke (PTS). However, the underlying mechanism is not completely understood. Since distinct neural and immune cells respond to electrical stimulation by releasing acetylcholine, we hypothesize that HFS might trigger the cholinergic anti-inflammatory pathway via activation of the α7 nicotinic acetylcholine receptor (α7nAchR). To test this hypothesis, rats underwent PTS and implantation of a microelectrode into the MLR. Three hours after intervention, either HFS or sham-stimulation of the MLR was applied for 24 h. IFN-γ, TNF-α, and IL-1α were quantified by cytometric bead array. Choline acetyltransferase (ChAT)\(^+\) CD4\(^+\)-cells and α7nAchR\(^+\)-cells were quantified visually using immunohistochemistry. Phosphorylation of NFĸB, ERK1/2, Akt, and Stat3 was determined by Western blot analyses. IFN-γ, TNF-α, and IL-1α were decreased in the perilesional area of stimulated rats compared to controls. The number of ChAT\(^+\) CD4\(^+\)-cells increased after MLR-HFS, whereas the amount of α7nAchR\(^+\)-cells was similar in both groups. Phospho-ERK1/2 was reduced significantly in stimulated rats. The present study suggests that MLR-HFS may trigger anti-inflammatory processes within the perilesional area by modulating the cholinergic system, probably via activation of the α7nAchR. KW - photothrombotic stroke KW - deep brain stimulation KW - mesencephalic locomotor region KW - neuroinflammation KW - choline acetyltransferase KW - alpha-7 nicotinic acetylcholine receptor Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259099 SN - 1422-0067 VL - 22 IS - 3 ER - TY - THES A1 - Greeske, Juliane T1 - Mechanismen der Makrophagen-Aktivierung in Connexin32-defizienten Mäusen T1 - Mechanisms of Macrphage Activation in Connexin32 deficient mice N2 - Connexin32- defiziente Mäuse stellen ein Mausmodell für eine Form der hereditären peripheren Neuropahtie dar. Es konnte gezeigt werden, dass Makrophagen, möglicherweise aktiviert durch MCP-1, die Demyelinisierung in Connexin32-defizienten Mäusen vermitteln. Diese Arbeit untersucht mögliche Signaltransduktionswege, die in den peripheren Nerven Connexin32- defizienter Mäuse aktiviert sein könnten und damit in Zusammenhang mit der Genexpression von MCP-1 und/oder Makrophagen-Aktivierung stehen könnten. N2 - Connexin32 deficient mice are a well established mouse model for the hereditary neuropathy known as Charcot-Marie-Tooth disease. Recently it was shown that macrophages function as the mediators of demyelination in peripheral nerves. Additionally there was found an icreased gene expression of MCP-1 in peripheral nerves of these animals. This study tries to identify un activated signal transduction pathway in peripheral nerves of Connexin32 deficient mice that may lead to the increased gene expression of MCP-1 and increased number of macrophages in peripheral nerves of Connexin32 deficient mice. KW - Makrophage KW - Immunoblot KW - Peripheres Nervensystem KW - Connexin32-defiziente Maus KW - hereditäre periphere Neuropathie KW - MCP-1 KW - Sigaltransduktionsweg KW - Connexin32 deficient mice KW - hereditary neuropathy KW - MCP-1 KW - signal transduction pathway Y1 - 2008 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-27491 ER - TY - JOUR A1 - Dipaola, Mariangela A1 - Pavan, Esteban E. A1 - Cattaneo, Andrea A1 - Frazzitta, Giuseppe A1 - Pezzoli, Gianni A1 - Cavallari, Paolo A1 - Frigo, Carlo A. A1 - Isaias, Ioannis U. T1 - Mechanical Energy Recovery during Walking in Patients with Parkinson Disease JF - PLoS ONE N2 - The mechanisms of mechanical energy recovery during gait have been thoroughly investigated in healthy subjects, but never described in patients with Parkinson disease (PD). The aim of this study was to investigate whether such mechanisms are preserved in PD patients despite an altered pattern of locomotion. We consecutively enrolled 23 PD patients (mean age 64±9 years) with bilateral symptoms (H&Y ≥II) if able to walk unassisted in medication-off condition (overnight suspension of all dopaminergic drugs). Ten healthy subjects (mean age 62±3 years) walked both at their ‘preferred’ and ‘slow’ speeds, to match the whole range of PD velocities. Kinematic data were recorded by means of an optoelectronic motion analyzer. For each stride we computed spatio-temporal parameters, time-course and range of motion (ROM) of hip, knee and ankle joint angles. We also measured kinetic (Wk), potential (W\(_{p}\)), total (W\(_{totCM}\)) energy variations and the energy recovery index (ER). Along with PD progression, we found a significant correlation of W\(_{totCM}\) and W\(_{p}\) with knee ROM and in particular with knee extension in terminal stance phase. W\(_{k}\) and ER were instead mainly related to gait velocity. In PD subjects, the reduction of knee ROM significantly diminished both W\(_{p}\) and W\(_{totCM}\). Rehabilitation treatments should possibly integrate passive and active mobilization of knee to prevent a reduction of gait-related energetic components. KW - Parkinson disease KW - mechanical energy KW - kinematics KW - velocity KW - hip KW - gait analysis KW - walking KW - knees Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-179739 VL - 11 IS - 6 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 - THES A1 - Karch, Katharina T1 - Mapping and Neutralization of Antibodies against Neurofascin, Contactin 1, Contactin associated protein 1 and Cortactin T1 - Kartierung und Neutralisation von Antikörpern gegen Neurofascin, Contactin 1, Contactin assoziiertes Protein 1 und Cortactin N2 - Immune-mediated polyneuropathies like chronic inflammatory demyelinating polyradiculoneuropathy or Guillain-Barré syndrome are rare diseases of the peripheral nervous system. A subgroup of patients harbors autoantibodies against nodal or paranodal antigens, associated with a distinct phenotype and treatment response. In a part of patients with pathologic paranodal or nodal immunoreactivity the autoantigens remain difficult or impossible to determine owing to limitations of the used detection approach - usually ELISAs (enzyme-linked-immunosorbent-assays) - and incomplete knowledge of the possible autoantigens. Due to their high-throughput, low sample consumption and high sensitivity as well as the possibility to display many putative nodal and paranodal autoantigens simultaneously, peptide microarray-based approaches are prime candidates for the discovery of novel autoantigens, point-of-care diagnostics and, in addition, monitoring of pathologic autoimmune response. Current applications of peptide microarrays are however limited by high false-positive rates and the associated need for detailed follow-up studies and validation. Here, robust peptide microarray-based detection of antibodies and the efficient validation of binding signals by on-chip neutralization is demonstrated. First, autoantigens were displayed as overlapping peptide libraries in microarray format. Copies of the biochips were used for the fine mapping of antibody epitopes. Next, binding signals were validated by antibody neutralization in solution. Since neutralizing peptides are obtained in the process of microarray fabrications, neither throughput nor costs are significantly altered. Similar in-situ validation approaches could contribute to future autoantibody characterization and detection methods as well as to therapeutic research. Areas of application could be expanded to any autoimmune-mediated neurological disease as a long-term vision. N2 - Immunvermittelte Polyneuropathien wie die chronisch-inflammatorische demyelinisierende Polyradikuloneuropathie oder das Guillain-Barré-Syndrom sind seltene Erkrankungen des peripheren Nervensystems. Bei einem Teil dieser Patienten lassen sich Autoantikörper gegen nodale oder paranodale Antigene nachweisen, was mit einem bestimmten Phänotyp und Therapienansprechen assoziiert ist. Aufgrund der Einschränkungen verwendeter Detektionsansätze – üblicherweise ELISAs (Enzyme-linked Immunosorbent Assays) – sowie der unvollständigen Kenntnis potenzieller Autoantigene bleibt es bisher zum Teil schwierig bis unmöglich bei nachgewiesener pathologischer paranodaler bzw. nodaler Immunreaktivität die entsprechenden Autoantigene zu identifizieren. Die hohe Durchsatzleistung, der geringe Verbrauch an Probenmaterial, die hohe Sensitivität sowie die Möglichkeit zahlreiche mutmaßliche nodale und paranodale Autoantigene zeitgleich darzustellen machen Peptid-Microarray-basierte Ansätze zu wesentlichen Kandidaten für die Entdeckung neuer Autoantigene, für Point-of-Care-Diagnostik und darüber hinaus für das Monitoring pathologischer Autoimmunantworten. Durch die hohe Rate falsch positiver Ergebnisse sowie die damit verbundene Notwendigkeit detaillierter Folgestudien und Validierungen sind die gegenwärtigen Anwendungen von Peptid-Microarrays jedoch limitiert. In dieser Arbeit wird eine robuste, Peptid-Microarray-basierte Detektion von Antikörpern sowie eine effiziente Validierung der Bindungssignale mittels On-chip Neutralisation demonstriert. Zuerst wurden die Autoantigene als überlappende Peptidbüchereien im Microarray-Format dargestellt. Kopien der Biochips wurden für die Feinkartierung der Antikörper-Epitope verwendet. Mittels Antikörperneutralisation in Lösung wurden die Bindungssignale anschließend validiert. Da die neutralisierenden Peptide im Microarray- Herstellungsprozess gewonnen werden, ergeben sich weder beim Durchsatz noch bei den Kosten signifikante Änderungen. Vergleichbare In-situ-Validierungsansätze könnten zu künftigen Autoantikörper Charakterisierungen, Detektionsmethoden sowie zu therapeutischen Forschungsansätzen beitragen. Als langfristige Vision könnten die Anwendungsgebiete auf jede beliebige autoimmun-vermittelte neurologische Krankheit ausgeweitet werden. KW - Microarray KW - Antikörper KW - Autoantigen KW - Epitop KW - Neutralisation KW - antibody KW - autoantigen KW - epitope KW - neutralization KW - fine-mapping KW - Neurofascin KW - Contactin 1 KW - Caspr1 KW - Cortactin Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-280223 ER - TY - JOUR A1 - Poh, Eugenia Z. A1 - Green, Courtney A1 - Agostinelli, Luca A1 - Penrose-Menz, Marissa A1 - Karl, Ann-Kathrin A1 - Harvey, Alan R. A1 - Rodger, Jennifer T1 - Manipulating the level of sensorimotor stimulation during LI-rTMS can improve visual circuit reorganisation in adult ephrin-A2A5\(^{-/-}\) Mice JF - International Journal of Molecular Sciences N2 - Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has the potential to treat a variety of neurologic and psychiatric disorders. The extent of rTMS-induced neuroplasticity may be dependent on a subject’s brain state at the time of stimulation. Chronic low intensity rTMS (LI-rTMS) has previously been shown to induce beneficial structural and functional reorganisation within the abnormal visual circuits of ephrin-A2A5\(^{-/-}\) mice in ambient lighting. Here, we administered chronic LI-rTMS in adult ephrin-A2A5\(^{-/-}\) mice either in a dark environment or concurrently with voluntary locomotion. One day after the last stimulation session, optokinetic responses were assessed and fluorescent tracers were injected to map corticotectal and geniculocortical projections. We found that LI-rTMS in either treatment condition refined the geniculocortical map. Corticotectal projections were improved in locomotion+LI-rTMS subjects, but not in dark + LI-rTMS and sham groups. Visuomotor behaviour was not improved in any condition. Our results suggest that the beneficial reorganisation of abnormal visual circuits by rTMS can be significantly influenced by simultaneous, ambient visual input and is enhanced by concomitant physical exercise. Furthermore, the observed pathway-specific effects suggest that regional molecular changes and/or the relative proximity of terminals to the induced electric fields influence the outcomes of LI-rTMS on abnormal circuitry. KW - LI-rTMS KW - neuroplasticity KW - visual pathways KW - topography KW - visual activity KW - locomotion KW - brain state Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284090 SN - 1422-0067 VL - 23 IS - 5 ER - TY - THES A1 - Weise, David Thomas T1 - Maladaptive Plastizität bei Schreibkrampf-Patienten T1 - Maladaptive Plasticity in patients with focal hand dystonia N2 - Der Schreibkrampf ist eine Form der fokalen Handdystonie, die durch anhaltende, unwillkürliche Verkrampfung der Hand beim Schreiben gekennzeichnet ist und zu unnatürlicher, zum Teil statischer und schmerzhafter Handhaltung führt. Bei prädisponierten Personen kann dieser nach exzessiver Wiederholung von stereotypen Bewegungen auftreten. Bewegungen und sensible Stimulation führen durch Mechanismen neuronaler Plastizität zu dynamischer Modulation sensibler und motorischer kortikaler Repräsentationen. Wird neuronale Plastizität nicht in natürlichen Grenzen gehalten, kann es zu veränderten, entdifferenzierten neuronalen Repräsentationen wie sie bei fokaler Handdystonie gefunden werden, führen. Zelluläre Kandidatenmechanismen für die Bildung neuronaler Engramme sind die Langzeitpotenzierung und –depression (LTP / LTD) neuronaler Synapsen. Wir verwendeten die als ein Modell für assoziative LTP und LTD beim Menschen entwickelte assoziative Paarstimulation (PAS). Mit dieser Methode untersuchten wir die zeitlichen und räumlichen Eigenschaften neuronaler Plastizität des Motorkortex bei Schreibkrampf-Patienten. Eine niederfrequente elektrische Stimulation eines peripheren Nerven (N. medianus (MN) oder N. ulnaris (UN)) wurde wiederholt (0,1Hz, 180 Reizpaare) mit einer transkraniellen Magnetstimulation (TMS) über dem homotopen kontralateralen Motorkortex mit einem Zeitintervall von 21,5ms (MN-PAS21.5; UN-PAS21.5) oder 10ms (MN-PAS10) kombiniert. Bei MN-PAS21.5 und MN-PAS10 wurde die optimale Spulenposition so gewählt, dass das magnetisch evozierte motorische Potential (MEP) im kontralateralen M. abductor pollicis brevis (APB) eine maximale Größe annahm, für UN-PAS21.5 wurde die Spule über dem "Hotspot" des M. abductor digiti minimi (ADM) platziert. Zehn Schreibkrampf-Patienten (Alter 39±9 Jahre; Mittelwert±Standardabweichung) und 10 gesunde bezüglich Alter und Geschlecht angepasste Probanden wurden untersucht. Veränderungen der Exzitabilität wurden mittels TMS bis zu 85 min nach der jeweiligen Intervention gemessen. Nach MN-PAS21.5 oder UN-PAS21.5 stieg die Amplitude der MEPs bei den gesunden Probanden nur in den Muskeln, die homotope externe PAS Stimulation erhalten hatten (APB Zielmuskel für MN; ADM für UN), nicht aber in Muskeln, die nicht homotop stimuliert worden waren. Im Gegensatz dazu stiegen bei Schreibkrampf-Patienten nach MN-PAS21.5 oder UN-PAS21.5 die Amplituden der APB und ADM-MEPs unabhängig von dem Ort der peripheren oder zentralen Stimulation. Bei Schreibkrampf-Patienten war eine frühere, stärkere und längere Zunahme der kortikalen Exzitabilität im Vergleich zu den Kontrollen zu verzeichnen. Qualitativ ähnliche Beobachtungen konnten in umgekehrtem Sinne (frühere und längere Abnahme der Exzitabilität im homo- und heterotopen Muskel) nach MN-PAS10 gemacht werden. LTP- und LTD-ähnliche Plastizität ist bei Schreibkrampf-Patienten demnach gesteigert und die normale strenge topographische Spezifität PAS-induzierter Plastizität aufgehoben. Diese maladaptive Plastizität könnte ein Bindeglied zwischen repetitiven Bewegungen und gestörter sensomotorischer Repräsentation darstellen, damit zu einem besseren Verständnis der Pathophysiologie der Dystonie beitragen und letztendlich mögliche therapeutische Konsequenzen implizieren. N2 - Neuronal plasticity is to be kept within operational limits to serve its purpose as a safe memory system that shapes and focuses sensory and motor representations. Temporal and spatial properties of motor cortical plasticity were assessed in patients with writer's cramp (WC) using a model of long-term potentiation (LTP) and long-term-depression (LTD) of synaptic efficacy. Paired associative stimulation (PAS) combined repetitive electric stimulation of the median or ulnar nerve with subsequent transcranial magnetic stimulation of the contralateral dominant motor cortex at 21.5ms (MN-PAS21.5; UN-PAS21.5) or 10ms (MN-PAS10). Motor evoked potentials were recorded from abductor pollicis brevis (APB) muscle and abductor digiti minimi (ADM) muscles in 10 WC patients and 10 matched healthy control subjects. Following MN-PAS21.5 or UN-PAS21.5 in non-dystonic subjects, motor responses increased if the afferent PAS-component came from a homologous peripheral region and remained stable with a non-homologous input. In contrast, following either MN-PAS21.5 or UN-PAS21.5, both APB- and ADM-amplitudes increased in WC-patients. Compared to controls, this increase started earlier, its magnitude was larger and its duration longer. Following MN-PAS10 in controls, APB-amplitudes decreased, while ADM-amplitudes increased. In WC, the decrease of APB-amplitudes started earlier and lasted longer. Of note, ADM-amplitudes were decreased, too. In WC, LTP-like as well as LTD-like plasticity are abnormal with respect to both gain and spatial organization. Findings may help to develop a pathophysiological model explaining core features of focal dystonia. KW - Neuronale Plastizität KW - Dystonie KW - Schreibkrampf KW - Transkranielle magnetische Stimulation KW - Langzeitdepression KW - Langzeitpotenzierung KW - assoziative Paarstimulation KW - plasticity KW - dystonia KW - transcranial magnetic stimulation KW - paired associative stimulation Y1 - 2006 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-26734 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 - Kunze, Ekkehard A1 - Lilla, Nadine A1 - Stetter, Christian A1 - Ernestus, Ralf-Ingo A1 - Westermaier, Thomas T1 - Magnesium protects in episodes of critical perfusion after aneurysmal SAH JF - Translational Neuroscience N2 - Background: To analyze whether magnesium has a neuroprotective effect during episodes that indicate a critical brain perfusion after aneurysmal subarachnoid hemorrhage (SAH). Methods: 107 patients with aSAH were randomized to continuously receive intravenous magnesium sulfate with target serum levels of 2.0 – 2.5 mmol/l (n = 54) or isotonic saline (n = 53). Neurological examination and transcranial Doppler sonography (TCD) were performed daily, Perfusion-CT (PCT) was acquired in 3-day intervals, angiography in case of suspected vasospasm. The primary endpoint was the development of secondary infarction following episodes of delayed ischemic neurological deficit (DIND), elevated mean flow velocity (MFV) in TCD or pathological findings in PCT. Results: In the magnesium group, 9 episodes of DIND were registered, none was followed by secondary infarction. In the control group, 23 episodes of DIND were registered, 9 were followed by secondary infarction (p < 0.05). In the magnesium group, 114 TCD-measurements showed an elevated MFV(> 140 cm/s). 7 were followed by new infarction. In control patients, 135 measurements showed elevated MFV, 32 were followed by new infarction (p < 0.05). 10 of 117 abnormal PCT-findings were followed by new infarction, compared to 30 of 122 in the control-group (p < 0.05). Conclusion: DIND, elevated MFV in TCD and abnormal PCT are findings which are associated with an increased risk to develop delayed secondary infarction. The results of this analysis suggest that magnesium-treatment may reduce the risk to develop infarction in a state of critical brain perfusion. KW - subarachnoid hemorrhage KW - magnesium KW - neuroprotection KW - delayed cerebral infarction Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177078 VL - 9 IS - 1 ER - TY - THES A1 - Schäfer, Kristina T1 - Lässt sich eine Vaskulitische Polyneuropathie mittels B-Bild-Sonographie der Beinnerven identifizieren? T1 - Is it possible to identify a vasculitic polyneuropathy by sonography of the nerves of the lower extremities? N2 - Über die Nervensonographie wurde bereits in den 1980er Jahren erstmals berichtet. Die rasche Weiterentwicklung der Technik hat dazu geführt, dass es inzwischen zahlreiche Fallberichte und einige Studien gibt, die sich mit der Darstellung peripherer Nerven durch Ultraschall als Mittel zur Diagnose verschiedener Nervpathologien beschäftigen. Besonders bei der Diagnostik des epidemiologisch häufigen Karpaltunnelsyndroms ist die sonographische Beurteilung des N. medianus in dieser Lokalisation vielerorts bereits etablierter Bestandteil der Diagnostik. In der hier vorgelegten Studie sollte der Stellenwert der B-Bild-Sonographie peripherer Nerven am Unterschenkel für die Diagnose einer Vaskulitischen Neuropathie geprüft werden. Dazu musste zunächst die Ultraschalluntersuchung spezieller Nerven am Unterschenkel etabliert werden. Diese ist technisch deutlich anspruchsvoller als die Darstellung von Karpaltunnelsyndrom oder Armplexus. Durch die fünfmalige Untersuchung zehn junger Personen wurden ultraschalltechnisch leicht reproduzierbar anatomisch auffindbare und Anisotropie-vermeidende Abschnitte von N. suralis, N. peroneus communis, profundus, superfcialis und N. tibialis definiert und als Messpunkte der Studie zu Grunde gelegt. In die von der Ethikkommission der Medizinischen Fakultät positiv beschiedene Studie wurden 26 Patienten/-innen, die klinisch und elektrophysiologisch nachgewiesen eine Polyneuropathie hatten und bei denen zur Ursachendiagnostik eine Biopsie und histologische Aufarbeitung des N. suralis durchgeführt wurde (Abteilung für Neuropathologie des Pathologischen Instituts der Universität sowie Histologielabor der Neurologischen Universitätsklinik), sowie 26 Kontrollpersonen ohne klinischen Hinweis auf eine Polyneuropathie nach informiertem Einverständnis aufgenommen. Für jede/-n Patienten/-in wurde ein/-e Proband/-in gleichen Geschlechts mit einem Altersunterschied von höchstens fünf Jahren in die Kontrollgruppe aufgenommen. Alle 52 Untersuchten mussten erwachsen und 160 – 180 cm groß sein. Bei allen Patienten/-innen und Kontrollpersonen wurden jeweils der GD, der KD, der LD und die QSF des N. suralis am unteren Drittel der Wade und distal im Bereich des Außenknöchels, des N. tibialis nahe des Innenknöchels, des N. peroneus communis im Bereich des Fibulaköpfchens, des N. peroneus profundus am Fußrücken und nahe der Großzehen und des N. peroneus superficialis im Bereich des distalen Schienbeins bestimmt. Alle gesuchten Nerven waren bei allen Versuchspersonen eindeutig identifizierbar. Die Untersuchungen wurden durch eine Untersucherin mit demselben Gerät, geblindet für das Ergebnis der Histologie, durchgeführt. Das gewährleistete eine Konstanz in der schwierigen und mit Unsicherheiten behafteten Messung der Nervenstrukturen, was ausführlich diskutiert wird. Ein statistisch signifikanter Unterschied zwischen den sonographisch erhobenen Messdaten der PNP-Gruppe und der Kontrollgruppe konnte bei 20 der 28 Parameter gezeigt werden. Bei 11 der 28 Parameter konnte zwischen Vaskulitis-Patienten/-innen und allen anderen, also PNP-Patienten/-innen und der Kontrollgruppe, ein statistisch signifikanter Unterschied festgestellt werden. Außerdem ergab die statistische Analyse bei drei der 28 Messgrößen einen statistisch signifikanten Unterschied zwischen Patienten/-innen mit und ohne Demyelinisierung des N. suralis in der feingeweblichen Untersuchung. Die sonographischen Ergebnisse der Vakulitis-Patienten/-innen unterschieden sich nicht von denen der PNP-Patienten/-innen mit anderer Ätiologie. Es wurde auch kein statistisch signifikanter Unterschied zwischen den Werten der PNP-Patienten/-innen mit und ohne histologisch gesicherte entzündliche Komponente beobachtet. Gemäß der histologischen Untersuchung der Biopsate wurde bei sechs Patienten/-innen eine Vaskulitis diagnostiziert. Bei fünf dieser Patienten/-innen fielen teilweise Kalibersprünge im Sinne einer Zunahme der QSF oder Abflachung im Verlauf des N. suralis, N. peroneus superficialis und N. peroneus communis auf. Aber auch bei Patienten/-innen mit einer anderen Form der Polyneuropathie und einigen Kontrollpersonen waren Besonderheiten im sonographischen Bild einzelner Nerven zu beobachten. Mit der vorgelegten Untersuchung konnte zwar nicht gezeigt werden, dass die Nervensonographie einen Beitrag zur differentialdiagnostischen Abgrenzung Vaskulitischer Polyneuropathien leisten kann, der den Goldstandard invasiver Nervenbiopse entbehrlich machen könnte. Das war bei der histologischen Unterschiedlichkeit der beschädigten Nervenanatomie bei Vaskulitis aber auch nicht ernsthaft zu erwarten. Die vorgelegte Arbeit zeigt aber auch, dass kranke periphere Nerven von gesunden Nerven im Ultraschall unterscheidbar sind, wenn man wie hier systematisch mit 28 Parametern an sieben Messpunkten untersucht. Dies allerdings dauert auch für einen Geübten 40 bis 60 Minuten, so dass die Polyneuropathiediagnostik oder gar Differentialdiagnostik mittels Ultraschall aktuell noch als Forschungsinstrument an großen Fallzahlen anzusehen ist. Dabei wird es künftig für die Gruppenbildung der sonographisch Untersuchten neben ätiologischer und histologischer Gruppenbildung darauf ankommen, das Krankheitsbild besser zu definieren, d.h. Ausmaß von Demyelinisierung, Remyelinisierung und axonalem Untergang in geeignete Skalen zu fassen. Auch die Magnetresonanztomographie stellt eine Option als diagnostischer Baustein bei Vaskulitischer Polyneuropathie dar. Dieses bildgebende Verfahren kann bereits zur Diagnostik von traumatischen Nervverletzungen, Kompressionensyndromen, Raumforderungen im Bereich der Nerven und Plexusneuritis eingesetzt werden. N2 - Is it possible to identify a vasculitic polyneuropathy by sonography of the nerves of the lower extremities? KW - Ultraschalldiagnostik KW - Nervensonographie KW - Vaskulitische Polyneuropathie Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-104712 ER -