@phdthesis{Kerscher2018,
  author    = {Kerscher, Susanne Regina},
  title     = {Die Rolle von Makrophagen an der motorischen Endplatte bei der Pathogenese neuromuskul{\"a}rer Erkrankungen am Beispiel von Tiermodellen peripherer Neuropathien vom Charcot-Marie-Tooth-Typ},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-169412},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2018},
  abstract  = {Bei den Charcot-Marie-Tooth (CMT) Neuropathien handelt es sich um erbliche Erkrankungen des peripheren Nervensystems, die progredient zu motorischen und sensorischen Defiziten f{\"u}hren und f{\"u}r die bislang keine kausalen Therapieoptionen existieren. In verschiedenen Studien konnte gezeigt werden, dass Entz{\"u}ndungsreaktionen, insbesondere durch Lymphozyten und Makrophagen vermittelt, eine bedeutende Rolle bei der Pathogenese dieser Erkrankung spielen. Neben neuronaler und axonaler Sch{\"a}digung, sowie Demyelinisierung ist in untersuchten Myelin Mutanten auch eine erh{\"o}hte Anzahl an denervierten neuromuskul{\"a}rer Endplatten zu erkennen. Eine genetische Blockade der Makrophagen-Aktivierung konnte in den Studien eine Verbesserung s{\"a}mtlicher neuropathologischer Merkmale bei gleichzeitig reduzierter Makrophagenanzahl zeigen. Ob und welche Rolle Makrophagen bei der Denervation neuromuskul{\"a}rer Endplatten spielen, blieb bislang ungekl{\"a}rt. In dieser Studie konnte in allen untersuchten Myelin Mutanten im Vergleich zum Wildtyp eine Zunahme an neuromuskul{\"a}ren Synapsen beobachtet werden, die mit Makrophagen r{\"a}umlich assoziiert waren. Daneben zeigten entsprechende Myelin Mutanten eine Zunahme denervierter und partiell denervierter Endplatten und zwar interessanterweise direkt proportional zur Anzahl an Synapsen in Assoziation mit Makrophagen. Das bedeutet, dass die Anzahl an Endplatten in Assoziation mit Makrophagen verh{\"a}ltnism{\"a}ßig parallel zur Anzahl an denervierten Endplatten zunahm, w{\"a}hrend die Anzahl an Makrophagen im gesamten Muskel nahezu unver{\"a}ndert blieb. Dies deutet eine m{\"o}gliche Rolle der r{\"a}umlich mit Endplatten assoziierten Makrophagen an deren Denervation an. Dabei waren alle Synapsen in Assoziation mit Makrophagen innerviert und damit morphologisch intakt. Bei doppel-mutanten M{\"a}usen mit genetischer Blockade der Makrophagen-Aktivierung waren die beschriebenen pathologischen Merkmale an der neuromuskul{\"a}ren Synapse deutlich reduziert bei gleichzeitig signifikanter Abnahme an Makrophagen in Assoziation mit Endplatten. {\"A}hnliche pathologische Auff{\"a}lligkeiten wie bei Myelin Mutanten fanden sich in geringerer Auspr{\"a}gung auch im Wildtyp im Rahmen des Alterungsprozesses sowie auch bei M{\"a}usen mit Defizienz des neurotrophen Faktors CNTF. Zusammenfassend deuten die Ergebnisse darauf hin, dass sowohl in der Pathogenese der CMT Neuropathie wie auch im Rahmen altersbedingter Neurodegeneration ein Makrophagen-vermittelter Schaden an der neuromuskul{\"a}ren Endplatte entsteht. Wesentliche Mediatoren scheinen hierbei das von Fibroblasten und vermutlich auch perisynaptischen Fibroblasten exprimierte CSF-1 zu sein, sowie MCP-1, das durch Schwann Zellen und m{\"o}glicherweise auch von terminalen Schwann Zellen freigesetzt wird. Auch eine Defizienz des neurotrophen Faktors CNTF bewirkt zumindest in geringem Ausmaß eine Zunahme der pathologischen Merkmale Denervation und Makrophagen-Endplatten-Assoziation im Vergleich zum Wildtyp. Diese Ergebnisse erweitern insbesondere das Wissen um Pathomechanismen an der neuromuskul{\"a}ren Endplatte und er{\"o}ffnen neue M{\"o}glichkeiten der Behandlung f{\"u}r CMT und weitere neuromuskul{\"a}re Erkrankungen.},
  subject      = {CMT},
  language  = {de}
}
@phdthesis{KuscheTekin2019,
  author    = {Kusche-Tekin, Burak Baris},
  title     = {Entwicklung einer fokalen Dystonie durch periphere Nervensch{\"a}digung bei \(Tor1a\) +/- M{\"a}usen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175161},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {Focal dystonia manifests in Tor1a+/- mice via a striatal dopaminergic dysregulation triggered by peripheral nerve injury Chi Wang Ip, Ioannis U. Isaias, Burak B. Kusche - Tekin, Dennis Klein, Janos Groh, Aet O'Leary, Susanne Knorr, Takahiro Higuchi, James B. Koprich, Jonathan M. Brotchie, Klaus V. Toyka, Andreas Reif, Jens Volkmann Abstract Isolated generalized dystonia is a central motor network disorder characterized by twisted movements or postures. The most frequent genetic cause is a GAG deletion in the Tor1a (DYT1) gene encoding torsinA with a reduced penetrance of 30-40 \% suggesting additional genetic or environmental modifiers. Development of dystonia-like movements after a standardized peripheral nerve crush lesion in wild type (wt) and Tor1a+/- mice, that express 50 \% torsinA only, was assessed by scoring of hindlimb movements during tail suspension, by rotarod testing and by computer-assisted gait analysis. Western blot analysis was performed for dopamine transporter (DAT), D1 and D2 receptors from striatal and quantitative RT-PCR analysis for DAT from midbrain dissections. Autoradiography was used to assess the functional DAT binding in striatum. Striatal dopamine and its metabolites were analyzed by high performance liquid chromatography. After nerve crush injury, we found abnormal posturing in the lesioned hindlimb of both mutant and wt mice indicating the profound influence of the nerve lesion (15x vs. 12x relative to control) resembling human peripheral pseudodystonia. In mutant mice the phenotypic abnormalities were increased by about 40 \% (p < 0.05). This was accompanied by complex alterations of striatal dopamine homeostasis. Pharmacological blockade of dopamine synthesis reduced severity of dystonia-like movements, whereas treatment with L-Dopa aggravated these but only in mutant mice suggesting a DYT1 related central component relevant to the development of abnormal involuntary movements. Our findings suggest that upon peripheral nerve injury reduced torsinA concentration and environmental stressors may act in concert in causing the central motor network dysfunction of DYT1 dystonia.},
  language  = {de}
}
@phdthesis{Schreiber2019,
  author    = {Schreiber, David Lukas},
  title     = {CSF-1-Rezeptor Inhibitor als Therapieansatz in Mausmodellen f{\"u}r Charcot-Marie-Tooth Neuropathien Typ 1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-174931},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {Charcot-Marie-Tooth Neuropathien sind die h{\"a}ufigsten heredit{\"a}ren Erkrankungen des peripheren Nervensystems und dennoch bis heute nicht therapierbar. Die Lebensqualit{\"a}t der Patienten ist durch motorische und sensorische Defizite der Extremit{\"a}ten h{\"a}ufig stark eingeschr{\"a}nkt. Ursache k{\"o}nnen unter anderem Mutationen in Schwann-Zellen sein, die zu dem typischen Bild von Demyelinisierung und axonalem Schaden f{\"u}hren. In den letzten Jahren konnte in Mausmodellen das Immunsystem als wichtiger Mediator in der Pathogenese der CMT 1 Subtypen A, B und X identifiziert werden. Insbesondere Makrophagen spielen eine tragende Rolle bei dem Verlust der axonalen Integrit{\"a}t, bei der Sch{\"a}digung der Myelinscheiden, sowie bei der Dedifferenzierung von Schwann-Zellen. Entscheidender Faktor f{\"u}r Proliferation und Aktivierung der Makrophagen ist hierbei das Zytokin CSF-1, dessen korrespondierender Rezeptor auf Makrophagen exprimiert wird. Der CSF-1/CSF1R Signalweg bietet somit einen vielversprechenden Angriffspunkt. In der vorliegenden Arbeit wurden Mausmodelle der CMT 1 Subtypen A, B und X mit einem niedermolekularen CSF-1-Rezeptor Inhibitor behandelt. Anschließend erfolgte eine funktionelle und strukturelle Auswertung der peripheren Nerven. Das beste Ansprechen auf die Therapie zeigten Cx32def Mutanten. Strukturell fielen ein verringerter axonaler Schaden und eine verbesserte axonale Regenerationsf{\"a}higkeit sowie erhaltene neuromuskul{\"a}re Synapsen auf. Funktionell {\"a}ußerte sich dies in verbesserten elektrophysiologischen Parametern und einem Krafterhalt, welcher als klinischer Parameter die gr{\"o}ßte Relevanz f{\"u}r betroffene Patienten hat und somit besonders hervorzuheben ist. Auch P0het Mutanten zeigten Verbesserungen nach der CSF1RI Behandlung. Anders als bei Cx32def Tieren zeigte sich hier jedoch vor allem ein Erhalt der Myelinintegrit{\"a}t. Weiterhin wirkte sich die Therapie positiv auf elektrophysiologische Parameter und Krafttests aus. Vor allem besonders stark betroffene Individuen schienen hierbei von der CSF1RI Behandlung zu profitieren. Bei PMP22tg Mutanten hingegen konnten keine positiven Effekte der CSF1RI Behandlung nachgewiesen werden. Strukturelle und funktionelle Parameter behandelter Tiere unterschieden sich nicht von unbehandelten. Diese Ergebnisse unterstreichen die Relevanz der sekund{\"a}ren Entz{\"u}ndungsreaktion in CMT 1 Neuropathien als wichtigen Mediator in der Pathogenese. Weiterhin konnte gezeigt werden, dass eine Intervention im CSF-1/CSF1R Signalweg einen vielversprechenden m{\"o}glichen Ansatz f{\"u}r die Therapie der bisher nicht behandelbaren CMT 1 Subypen X und B darstellt. Unausweichlich ist hierbei ein m{\"o}glichst fr{\"u}her Therapiestart vor Auspr{\"a}gung der ersten molekularen und histologischen Ver{\"a}nderungen. Im Hinblick auf die nicht die Lebenserwartung reduzierende Erkrankung muss ferner eine Minimierung der Nebenwirkungen der Therapie gew{\"a}hrleistet sein. Besonders hervorzuheben ist hier die Verwendung eines Inhibitors, welcher nicht in das zentrale Nervensystem vordringen kann und somit die Funktion der Mikroglia nicht beeintr{\"a}chtigt.},
  subject      = {CSF-1},
  language  = {de}
}
@article{AsterEvdokimovBraunetal.2022,
  author    = {Aster, Hans-Christoph and Evdokimov, Dimitar and Braun, Alexandra and {\"U}{\c{c}}eyler, Nurcan and Kampf, Thomas and Pham, Mirko and Homola, Gy{\"o}rgy A. and Sommer, Claudia},
  title     = {CNS imaging characteristics in fibromyalgia patients with and without peripheral nerve involvement},
  series = {Scientific Reports},
  volume    = {12},
  journal   = {Scientific Reports},
  number    = {1},
  doi       = {10.1038/s41598-022-10489-1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300562},
  year      = {2022},
  abstract  = {We tested the hypothesis that reduced skin innervation in fibromyalgia syndrome is associated with specific CNS changes. This prospective case-control study included 43 women diagnosed with fibromyalgia syndrome and 40 healthy controls. We further compared the fibromyalgia subgroups with reduced (n = 21) and normal (n = 22) skin innervation. Brains were analysed for cortical volume, for white matter integrity, and for functional connectivity. Compared to controls, cortical thickness was decreased in regions of the frontal, temporal and parietal cortex in the fibromyalgia group as a whole, and decreased in the bilateral pericalcarine cortices in the fibromyalgia subgroup with reduced skin innervation. Diffusion tensor imaging revealed a significant increase in fractional anisotropy in the corona radiata, the corpus callosum, cingulum and fornix in patients with fibromyalgia compared to healthy controls and decreased FA in parts of the internal capsule and thalamic radiation in the subgroup with reduced skin innervation. Using resting-state fMRI, the fibromyalgia group as a whole showed functional hypoconnectivity between the right midfrontal gyrus and the posterior cerebellum and the right crus cerebellum, respectively. The subgroup with reduced skin innervation showed hyperconnectivity between the inferior frontal gyrus, the angular gyrus and the posterior parietal gyrus. Our results suggest that the subgroup of fibromyalgia patients with pronounced pathology in the peripheral nervous system shows alterations in morphology, structural and functional connectivity also at the level of the encephalon. We propose considering these subgroups when conducting clinical trials.},
  language  = {en}
}
@article{PritchardFalkLarssonetal.2016,
  author    = {Pritchard, Rory A. and Falk, Lovissa and Larsson, Mathilda and Leinders, Mathias and Sorkin, Linda S.},
  title     = {Different phosphoinositide 3-kinase isoforms mediate carrageenan nociception and inflammation},
  series = {Pain},
  volume    = {157},
  journal   = {Pain},
  number    = {1},
  doi       = {10.1097/j.pain.0000000000000341},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-150248},
  pages     = {137-146},
  year      = {2016},
  abstract  = {Phosphoinositide 3-kinases (PI3Ks) participate in signal transduction cascades that can directly activate and sensitize nociceptors and enhance pain transmission. They also play essential roles in chemotaxis and immune cell infiltration leading to inflammation. We wished to determine which PI3K isoforms were involved in each of these processes. Lightly anesthetized rats (isoflurane) were injected subcutaneously with carrageenan in their hind paws. This was preceded by a local injection of 1\% DMSO vehicle or an isoform-specific antagonist to PI3K-α (compound 15-e), -β (TGX221), -δ (Cal-101), or -γ (AS252424). We measured changes in the mechanical pain threshold and spinal c-Fos expression (4 hours after injection) as indices of nociception. Paw volume, plasma extravasation (Evans blue, 0.3 hours after injection), and neutrophil (myeloperoxidase; 1 hour after injection) and macrophage (CD11b+; 4 hour after injection) infiltration into paw tissue were the measured inflammation endpoints. Only PI3K-γ antagonist before treatment reduced the carrageenan-induced pain behavior and spinal expression of c-Fos (P ≤ 0.01). In contrast, pretreatment with PI3K-α, -δ, and-γ antagonists reduced early indices of inflammation. Plasma extravasation PI3K-α (P ≤ 0.05), -δ (P ≤ 0.05), and -γ (P ≤ 0.01), early (0-2 hour) edema -α (P ≤ 0.05), -δ (P ≤ 0.001), and -γ (P ≤ 0.05), and neutrophil infiltration (all P ≤ 0.001) were all reduced compared to vehicle pretreatment. Later (2-4 hour), edema and macrophage infiltration (P ≤ 0.05) were reduced by only the PI3K-δ and -γ isoform antagonists, with the PI3K-δ antagonist having a greater effect on edema. PI3K-β antagonism was ineffective in all paradigms. These data indicate that pain and clinical inflammation are pharmacologically separable and may help to explain clinical conditions in which inflammation naturally wanes or goes into remission, but pain continues unabated.},
  language  = {en}
}
@article{GabrielJirůHillmannKraftetal.2020,
  author    = {Gabriel, Katharina M. A. and J{\´i}rů-Hillmann, Steffi and Kraft, Peter and Selig, Udo and R{\"u}cker, Victoria and M{\"u}hler, Johannes and D{\"o}tter, Klaus and Keidel, Matthias and Soda, Hassan and Rascher, Alexandra and Schneider, Rolf and Pfau, Mathias and Hoffmann, Roy and Stenzel, Joachim and Benghebrid, Mohamed and Goebel, Tobias and Doerck, Sebastian and Kramer, Daniela and Haeusler, Karl Georg and Volkmann, Jens and Heuschmann, Peter U. and Fluri, Felix},
  title     = {Two years' experience of implementing a comprehensive telemedical stroke network comprising in mainly rural region: the Transregional Network for Stroke Intervention with Telemedicine (TRANSIT-Stroke)},
  series = {BMC Neurology},
  volume    = {20},
  journal   = {BMC Neurology},
  doi       = {10.1186/s12883-020-01676-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229214},
  year      = {2020},
  abstract  = {Background Telemedicine improves the quality of acute stroke care in rural regions with limited access to specialized stroke care. We report the first 2 years' experience of implementing a comprehensive telemedical stroke network comprising all levels of stroke care in a defined region. Methods The TRANSIT-Stroke network covers a mainly rural region in north-western Bavaria (Germany). All hospitals providing acute stroke care in this region participate in TRANSIT-Stroke, including four hospitals with a supra-regional certified stroke unit (SU) care (level III), three of those providing teleconsultation to two hospitals with a regional certified SU (level II) and five hospitals without specialized SU care (level I). For a two-year-period (01/2015 to 12/2016), data of eight of these hospitals were available; 13 evidence-based quality indicators (QIs) related to processes during hospitalisation were evaluated quarterly and compared according to predefined target values between level-I- and level-II/III-hospitals. Results Overall, 7881 patients were included (mean age 74.6 years +/- 12.8; 48.4\% female). In level-II/III-hospitals adherence of all QIs to predefined targets was high ab initio. In level-I-hospitals, three patterns of QI-development were observed: a) high adherence ab initio (31\%), mainly in secondary stroke prevention; b) improvement over time (44\%), predominantly related to stroke specific diagnosis and in-hospital organization; c) no clear time trends (25\%). Overall, 10 out of 13 QIs reached predefined target values of quality of care at the end of the observation period. Conclusion The implementation of the comprehensive TRANSIT-Stroke network resulted in an improvement of quality of care in level-I-hospitals.},
  language  = {en}
}
@article{DauerneeJoppeTatenhorstCaldiGomesetal.2021,
  author    = {Dauer n{\´e}e Joppe, Karina and Tatenhorst, Lars and Caldi Gomes, Lucas and Zhang, Shuyu and Parvaz, Mojan and Carboni, Eleonora and Roser, Anna-Elisa and El DeBakey, Hazem and B{\"a}hr, Mathias and Vogel-Mikuš, Katarina and Wang Ip, Chi and Becker, Stefan and Zweckstetter, Markus and Lingor, Paul},
  title     = {Brain iron enrichment attenuates α-synuclein spreading after injection of preformed fibrils},
  series = {Journal of Neurochemistry},
  volume    = {159},
  journal   = {Journal of Neurochemistry},
  number    = {3},
  doi       = {10.1111/jnc.15461},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262544},
  pages     = {554 -- 573},
  year      = {2021},
  abstract  = {Regional iron accumulation and α-synuclein (α-syn) spreading pathology within the central nervous system are common pathological findings in Parkinson's disease (PD). Whereas iron is known to bind to α-syn, facilitating its aggregation and regulating α-syn expression, it remains unclear if and how iron also modulates α-syn spreading. To elucidate the influence of iron on the propagation of α-syn pathology, we investigated α-syn spreading after stereotactic injection of α-syn preformed fibrils (PFFs) into the striatum of mouse brains after neonatal brain iron enrichment. C57Bl/6J mouse pups received oral gavage with 60, 120, or 240 mg/kg carbonyl iron or vehicle between postnatal days 10 and 17. At 12 weeks of age, intrastriatal injections of 5-µg PFFs were performed to induce seeding of α-syn aggregates. At 90 days post-injection, PFFs-injected mice displayed long-term memory deficits, without affection of motor behavior. Interestingly, quantification of α-syn phosphorylated at S129 showed reduced α-syn pathology and attenuated spreading to connectome-specific brain regions after brain iron enrichment. Furthermore, PFFs injection caused intrastriatal microglia accumulation, which was alleviated by iron in a dose-dependent way. In primary cortical neurons in a microfluidic chamber model in vitro, iron application did not alter trans-synaptic α-syn propagation, possibly indicating an involvement of non-neuronal cells in this process. Our study suggests that α-syn PFFs may induce cognitive deficits in mice independent of iron. However, a redistribution of α-syn aggregate pathology and reduction of striatal microglia accumulation in the mouse brain may be mediated via iron-induced alterations of the brain connectome.},
  language  = {en}
}
@article{WangIpKlausKarikarietal.2017,
  author    = {Wang Ip, Chi and Klaus, Laura-Christin and Karikari, Akua A. and Visanji, Naomi P. and Brotchie, Jonathan M. and Lang, Anthony E. and Volkmann, Jens and Koprich, James B.},
  title     = {AAV1/2-induced overexpression of A53T-α-synuclein in the substantia nigra results in degeneration of the nigrostriatal system with Lewy-like pathology and motor impairment: a new mouse model for Parkinson's disease},
  series = {Acta Neuropathologica Communications},
  volume    = {5},
  journal   = {Acta Neuropathologica Communications},
  number    = {11},
  doi       = {10.1186/s40478-017-0416-x},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159429},
  year      = {2017},
  abstract  = {α-Synuclein is a protein implicated in the etiopathogenesis of Parkinson's disease (PD). AAV1/2-driven overexpression of human mutated A53T-α-synuclein in rat and monkey substantia nigra (SN) induces degeneration of nigral dopaminergic neurons and decreases striatal dopamine and tyrosine hydroxylase (TH). Given certain advantages of the mouse, especially it being amendable to genetic manipulation, translating the AAV1/2-A53T α-synuclein model to mice would be of significant value. AAV1/2-A53T α-synuclein or AAV1/2 empty vector (EV) at a concentration of 5.16 x 10\(^{12}\) gp/ml were unilaterally injected into the right SN of male adult C57BL/6 mice. Post-mortem examinations included immunohistochemistry to analyze nigral α-synuclein, Ser129 phosphorylated α-synuclein and TH expression, striatal dopamine transporter (DAT) levels by autoradiography and dopamine levels by high performance liquid chromatography. At 10 weeks, in AAV1/2-A53T α-synuclein mice there was a 33\% reduction in TH+ dopaminergic nigral neurons (P < 0.001), 29\% deficit in striatal DAT binding (P < 0.05), 38\% and 33\% reductions in dopamine (P < 0.001) and DOPAC (P < 0.01) levels and a 60\% increase in dopamine turnover (homovanilic acid/dopamine ratio; P < 0.001). Immunofluorescence showed that the AAV1/2-A53T α-synuclein injected mice had widespread nigral and striatal expression of vector-delivered A53T-α-synuclein. Concurrent staining with human PD SN samples using gold standard histological methodology for Lewy pathology detection by proteinase K digestion and application of specific antibody raised against human Lewy body α-synuclein (LB509) and Ser129 phosphorylated α-synuclein (81A) revealed insoluble α-synuclein aggregates in AAV1/2-A53T α-synuclein mice resembling Lewy-like neurites and bodies. In the cylinder test, we observed significant paw use asymmetry in the AAV1/2-A53T α-synuclein group when compared to EV controls at 5 and 9 weeks post injection (P < 0.001; P < 0.05). These data show that unilateral injection of AAV1/2-A53T α-synuclein into the mouse SN leads to persistent motor deficits, neurodegeneration of the nigrostriatal dopaminergic system and development of Lewy-like pathology, thereby reflecting clinical and pathological hallmarks of human PD.},
  language  = {en}
}
@article{JariusKleiterRuprechtetal.2016,
  author    = {Jarius, Sven and Kleiter, Ingo and Ruprecht, Klemens and Asgari, Nasrin and Pitarokoili, Kalliopi and Borisow, Nadja and H{\"u}mmert, Martin W. and Trebst, Corinna and Pache, Florence and Winkelmann, Alexander and Beume, Lena-Alexandra and Ringelstein, Marius and Stich, Oliver and Aktas, Orhan and Korporal-Kuhnke, Mirjam and Schwarz, Alexander and Lukas, Carsten and Haas, J{\"u}rgen and Fechner, Kai and Buttmann, Mathias and Bellmann-Strobl, Judith and Zimmermann, Hanna and Brandt, Alexander U. and Franciotta, Diego and Schanda, Kathrin and Paul, Friedemann and Reindl, Markus and Wildemann, Brigitte},
  title     = {MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: Brainstem involvement - frequency, presentation and outcome},
  series = {Journal of Neuroinflammation},
  volume    = {13},
  journal   = {Journal of Neuroinflammation},
  number    = {281},
  doi       = {10.1186/s12974-016-0719-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165543},
  pages     = {1-23},
  year      = {2016},
  abstract  = {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.},
  language  = {en}
}
@article{SadovnickTraboulseeBernalesetal.2016,
  author    = {Sadovnick, A. Dessa and Traboulsee, Anthony L. and Bernales, Cecily Q. and Ross, Jay P. and Forwell, Amanda L. and Yee, Irene M. and Guillot-Noel, Lena and Fontaine, Bertrand and Cournu-Rebeix, Isabelle and Alcina, Antonio and Fedetz, Maria and Izquierdo, Guillermo and Matesanz, Fuencisla and Hilven, Kelly and Dubois, B{\´e}n{\´e}dicte and Goris, An and Astobiza, Ianire and Alloza, Iraide and Antig{\"u}edad, Alfredo and Vandenbroeck, Koen and Akkad, Denis A. and Aktas, Orhan and Blaschke, Paul and Buttmann, Mathias and Chan, Andrew and Epplen, Joerg T. and Gerdes, Lisa-Ann and Kroner, Antje and Kubisch, Christian and K{\"u}mpfel, Tania and Lohse, Peter and Rieckmann, Peter and Zettl, Uwe K. and Zipp, Frauke and Bertram, Lars and Lill, Christina M. and Fernandez, Oscar and Urbaneja, Patricia and Leyva, Laura and Alvarez-Cerme{\~n}o, Jose Carlos and Arroyo, Rafael and Garagorri, Aroa M. and Garc{\´i}a-Mart{\´i}nez, Angel and Villar, Luisa M. and Urcelay, Elena and Malhotra, Sunny and Montalban, Xavier and Comabella, Manuel and Berger, Thomas and Fazekas, Franz and Reindl, Markus and Schmied, Mascha C. and Zimprich, Alexander and Vilari{\~n}o-G{\"u}ell, Carles},
  title     = {Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients},
  series = {G3: Genes Genomes Genetics},
  volume    = {6},
  journal   = {G3: Genes Genomes Genetics},
  number    = {7},
  doi       = {10.1534/g3.116.030841},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165405},
  pages     = {2073-2079},
  year      = {2016},
  abstract  = {Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95\% CI = 0.93-1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.},
  language  = {en}
}
@article{Gonzalez‐EscamillaMuthuramanReichetal.2019,
  author    = {Gonzalez-Escamilla, Gabriel and Muthuraman, Muthuraman and Reich, Martin M. and Koirala, Nabin and Riedel, Christian and Glaser, Martin and Lange, Florian and Deuschl, G{\"u}nther and Volkmann, Jens and Groppa, Sergiu},
  title     = {Cortical network fingerprints predict deep brain stimulation outcome in dystonia},
  series = {Movement Disorders},
  volume    = {34},
  journal   = {Movement Disorders},
  number    = {10},
  doi       = {10.1002/mds.27808},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213532},
  pages     = {1536 -- 1545},
  year      = {2019},
  abstract  = {Background Deep brain stimulation (DBS) is an effective evidence-based therapy for dystonia. However, no unequivocal predictors of therapy responses exist. We investigated whether patients optimally responding to DBS present distinct brain network organization and structural patterns. Methods From a German multicenter cohort of 82 dystonia patients with segmental and generalized dystonia who received DBS implantation in the globus pallidus internus, we classified patients based on the clinical response 3 years after DBS. Patients were assigned to the superior-outcome group or moderate-outcome group, depending on whether they had above or below 70\% motor improvement, respectively. Fifty-one patients met MRI-quality and treatment response requirements (mean age, 51.3 ± 13.2 years; 25 female) and were included in further analysis. From preoperative MRI we assessed cortical thickness and structural covariance, which were then fed into network analysis using graph theory. We designed a support vector machine to classify subjects for the clinical response based on individual gray-matter fingerprints. Results The moderate-outcome group showed cortical atrophy mainly in the sensorimotor and visuomotor areas and disturbed network topology in these regions. The structural integrity of the cortical mantle explained about 45\% of the DBS stimulation amplitude for optimal response in individual subjects. Classification analyses achieved up to 88\% of accuracy using individual gray-matter atrophy patterns to predict DBS outcomes. Conclusions The analysis of cortical integrity, informed by group-level network properties, could be developed into independent predictors to identify dystonia patients who benefit from DBS.},
  language  = {en}
}
@article{UeceylerSchroeterKafkeetal.2016,
  author    = {{\"U}{\c{c}}eyler, Nurcan and Schr{\"o}ter, Nils and Kafke, Waldemar and Kramer, Daniela and Wanner, Christoph and Weidemann, Frank and Sommer, Claudia},
  title     = {Skin Globotriaosylceramide 3 Load Is Increased in Men with Advanced Fabry Disease},
  series = {PLoS ONE},
  volume    = {11},
  journal   = {PLoS ONE},
  number    = {11},
  doi       = {10.1371/journal.pone.0166484},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-178856},
  year      = {2016},
  abstract  = {Background The X-chromosomally linked life-limiting Fabry disease (FD) is associated with deposits of the sphingolipid globotriaosylceramide 3 (Gb3) in various tissues. Skin is easily accessible and may be used as an additional diagnostic and follow-up medium. Our aims were to visualize skin Gb3 deposits in FD patients applying immunofluorescence and to determine if cutaneous Gb3 load correlates with disease severity. Methods At our Fabry Center for Interdisciplinary Therapy we enrolled 84 patients with FD and 27 healthy controls. All subjects underwent 5-mm skin punch biopsy at the lateral lower leg and the back. Skin samples were processed for immunohistochemistry using antibodies against CD77 (i.e. Gb3). Cutaneous Gb3 deposition was quantified in a blinded manner and correlated to clinical data. Results We found that Gb3 load was higher in distal skin of male FD patients compared to healthy controls (p<0.05). Men (p<0.01) and women (p<0.05) with a classic FD phenotype had higher distal skin Gb3 load than healthy controls. Men with advanced disease as reflected by impaired renal function, and men and women with small fiber neuropathy had more Gb3 deposits in distal skin samples than males with normal renal function (p<0.05) and without small fiber neuropathy. Gb3 deposits were not different between patients with and without enzyme replacement therapy. Conclusions Immunofluorescence on minimally invasive skin punch biopsies may be useful as a tool for assessment and follow-up in FD patients.},
  language  = {en}
}
@article{GruenewaldBennettToykaetal.2016,
  author    = {Gr{\"u}newald, Benedikt and Bennett, Jeffrey L. and Toyka, Klaus V. and Sommer, Claudia and Geis, Christian},
  title     = {Efficacy of Polyvalent Human Immunoglobulins in an Animal Model of Neuromyelitis Optica Evoked by Intrathecal Anti-Aquaporin 4 Antibodies},
  series = {International Journal of Molecular Sciences},
  volume    = {17},
  journal   = {International Journal of Molecular Sciences},
  number    = {9},
  doi       = {10.3390/ijms17091407},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166000},
  pages     = {1407},
  year      = {2016},
  abstract  = {Neuromyelitis Optica Spectrum Disorders (NMOSD) are associated with autoantibodies (ABs) targeting the astrocytic aquaporin-4 water channels (AQP4-ABs). These ABs have a direct pathogenic role by initiating a variety of immunological and inflammatory processes in the course of disease. In a recently-established animal model, chronic intrathecal passive-transfer of immunoglobulin G from NMOSD patients (NMO-IgG), or of recombinant human AQP4-ABs (rAB-AQP4), provided evidence for complementary and immune-cell independent effects of AQP4-ABs. Utilizing this animal model, we here tested the effects of systemically and intrathecally applied pooled human immunoglobulins (IVIg) using a preventive and a therapeutic paradigm. In NMO-IgG animals, prophylactic application of systemic IVIg led to a reduced median disease score of 2.4 on a 0-10 scale, in comparison to 4.1 with sham treatment. Therapeutic IVIg, applied systemically after the 10th intrathecal NMO-IgG injection, significantly reduced the disease score by 0.8. Intrathecal IVIg application induced a beneficial effect in animals with NMO-IgG (median score IVIg 1.6 vs. sham 3.7) or with rAB-AQP4 (median score IVIg 2.0 vs. sham 3.7). We here provide evidence that treatment with IVIg ameliorates disease symptoms in this passive-transfer model, in analogy to former studies investigating passive-transfer animal models of other antibody-mediated disorders.},
  language  = {en}
}
@article{MuellerGirardHopfneretal.2016,
  author    = {M{\"u}ller, Stefanie H. and Girard, Simon L. and Hopfner, Franziska and Merner, Nancy D. and Bourassa, Cynthia V. and Lorenz, Delia and Clark, Lorraine N. and Tittmann, Lukas and Soto-Ortolaza, Alexandra I. and Klebe, Stephan and Hallett, Mark and Schneider, Susanne A. and Hodgkinson, Colin A. and Lieb, Wolfgang and Wszolek, Zbigniew K. and Pendziwiat, Manuela and Lorenzo-Betancor, Oswaldo and Poewe, Werner and Ortega-Cubero, Sara and Seppi, Klaus and Rajput, Alex and Hussl, Anna and Rajput, Ali H. and Berg, Daniela and Dion, Patrick A. and Wurster, Isabel and Shulman, Joshua M. and Srulijes, Karin and Haubenberger, Dietrich and Pastor, Pau and Vilari{\~n}o-G{\"u}ell, Carles and Postuma, Ronald B. and Bernard, Genevi{\`e}ve and Ladwig, Karl-Heinz and Dupr{\´e}, Nicolas and Jankovic, Joseph and Strauch, Konstantin and Panisset, Michel and Winkelmann, Juliane and Testa, Claudia M. and Reischl, Eva and Zeuner, Kirsten E. and Ross, Owen A. and Arzberger, Thomas and Chouinard, Sylvain and Deuschl, G{\"u}nther and Louis, Elan D. and Kuhlenb{\"a}umer, Gregor and Rouleau, Guy A.},
  title     = {Genome-wide association study in essential tremor identifies three new loci},
  series = {Brain},
  volume    = {139},
  journal   = {Brain},
  doi       = {10.1093/brain/aww242},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186541},
  pages     = {3163-3169},
  year      = {2016},
  abstract  = {We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.},
  language  = {en}
}
@article{BrumbergSchroeterBlazhenetsetal.2020,
  author    = {Brumberg, Joachim and Schr{\"o}ter, Nils and Blazhenets, Ganna and Frings, Lars and Volkmann, Jens and Lapa, Constantin and Jost, Wolfgang H. and Isaias, Ioannis U. and Meyer, Philipp T.},
  title     = {Differential diagnosis of parkinsonism: a head-to-head comparison of FDG PET and MIBG scintigraphy},
  series = {NPJ Parkinsons Disease},
  volume    = {6},
  journal   = {NPJ Parkinsons Disease},
  doi       = {10.1038/s41531-020-00141-y},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230675},
  year      = {2020},
  abstract  = {[\(^{18}\)F]fluorodeoxyglucose (FDG) PET and [\(^{123}\)I]metaiodobenzylguanidine (MIBG) scintigraphy may contribute to the differential diagnosis of neurodegenerative parkinsonism. To identify the superior method, we retrospectively evaluated 54 patients with suspected neurodegenerative parkinsonism, who were referred for FDG PET and MIBG scintigraphy. Two investigators visually assessed FDG PET scans using an ordinal 6-step score for disease-specific patterns of Lewy body diseases (LBD) or atypical parkinsonism (APS) and assigned the latter to the subgroups multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal syndrome. Regions-of-interest analysis on anterior planar MIBG images served to calculate the heart-to-mediastinum ratio. Movement disorder specialists blinded to imaging results established clinical follow-up diagnosis by means of guideline-derived case vignettes. Clinical follow-up (1.7 +/- 2.3 years) revealed the following diagnoses: n = 19 LBD (n = 17 Parkinson's disease [PD], n = 1 PD dementia, and n = 1 dementia with Lewy bodies), n = 31 APS (n = 28 MSA, n = 3 PSP), n = 3 non-neurodegenerative parkinsonism; n = 1 patient could not be diagnosed and was excluded. Receiver operating characteristic analyses for discriminating LBD vs. non-LBD revealed a larger area under the curve for FDG PET than for MIBG scintigraphy at statistical trend level for consensus rating (0.82 vs. 0.69, p = 0.06; significant for investigator \#1: 0.83 vs. 0.69, p = 0.04). The analysis of PD vs. MSA showed a similar difference (0.82 vs. 0.69, p = 0.11; rater \#1: 0.83 vs. 0.69, p = 0.07). Albeit the notable differences in diagnostic performance did not attain statistical significance, the authors consider this finding clinically relevant and suggest that FDG PET, which also allows for subgrouping of APS, should be preferred.},
  language  = {en}
}
@article{EvdokimovDinkelFranketal.2020,
  author    = {Evdokimov, Dimitar and Dinkel, Philine and Frank, Johanna and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan},
  title     = {Characterization of dermal skin innervation in fibromyalgia syndrome},
  series = {PLoS One},
  volume    = {15},
  journal   = {PLoS One},
  number    = {1},
  doi       = {10.1371/journal.pone.0227674},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229299},
  year      = {2020},
  abstract  = {Introduction We characterized dermal innervation in patients with fibromyalgia syndrome (FMS) as potential contribution to small fiber pathology. Methods Skin biopsies of the calf were collected (86 FMS patients, 35 healthy controls). Skin was immunoreacted with antibodies against protein gene product 9.5, calcitonine gene-related peptide, substance P, CD31, and neurofilament 200 for small fiber subtypes. We assessed two skin sections per patient; on each skin section, two dermal areas (150 x 700 mu m each) were investigated for dermal nerve fiber length (DNFL). Results In FMS patients we found reduced DNFL of fibers with vessel contact compared to healthy controls (p<0.05). There were no differences for the other nerve fiber subtypes. Discussion We found less dermal nerve fibers in contact with blood vessels in FMS patients than in controls. The pathophysiological relevance of this finding is unclear, but we suggest the possibility of a relationship with impaired thermal tolerance commonly reported by FMS patients.},
  language  = {en}
}
@phdthesis{Messinger2023,
  author    = {Messinger, Julia},
  title     = {Die Effekte von IVIG auf die Antik{\"o}rperbindung und Komplementablagerung bei Anti-Neurofascin-positiver Nodo-Paranodopathie},
  doi       = {10.25972/OPUS-32110},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321109},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {Autoantik{\"o}rper gegen nodo-paranodale Proteine des Ranvier'schen Schn{\"u}rrings wie Neurofascin-155 (NF-155), Contactin-1 und Caspr wurden in der Literatur bei Patienten/Patientinnen mit Immunneuropathien beschrieben. Bei zwei bis zehn Prozent der Patienten/Patientinnen mit Immunneuropathien k{\"o}nnen Autoantik{\"o}rper gegen Isoformen des Neurofascin detektiert werden. Patienten/Patientinnen mit Autoantik{\"o}rpern gegen NF-155 weisen gemeinsame klinische Merkmale auf, unter anderem einen schweren Verlauf mit subakutem Beginn, vorwiegend motorischen Defiziten, Tremor und einem schlechten Ansprechen auf eine Therapie mit intraven{\"o}sen Immunglobulinen (IVIG). Ein Grund f{\"u}r Letzteres k{\"o}nnte sein, dass es sich {\"u}berwiegend um Autoantik{\"o}rper der Subklasse IgG4 handelt, die als anti-inflammatorisch gelten und kein Komplement aktivieren. Neben der IgG4-Subklasse k{\"o}nnen bei manchen Erkrankten auch die proinflammatorischen IgG-Subklassen 1 bis 3 nachgewiesen werden. Bei der Anti-Pan-Neurofascin (155/140/186) Polyneuropathie zeigt sich klinisch h{\"a}ufig ein fulminanter Ph{\"a}notyp mit IgG3 Pr{\"a}dominanz. Das Ziel dieser Studie war, die Autoantik{\"o}rper-induzierte Komplementablagerung zu detektieren, sowie die Rolle der IgG Subklasse und die Effekte von IVIG auf Antik{\"o}rperbindung, Komplementaktivierung und Effektorfunktionen zu untersuchen. Hierzu wurde das Serum von 212 Probanden/-innen mit der Verdachtsdiagnose einer entz{\"u}ndlichen Neuropathie auf Autoantik{\"o}rper gegen NF-155 mittels ELISA und Bindungsversuchen an M{\"a}usezupfnerven gescreent. Im Fall eines positiven Ergebnisses dienten zellbasierte Bindungsversuche mit NF-155-transfizierten HEK-293- Zellen als Best{\"a}tigungstest. Die Effekte unterschiedlicher IVIG Konzentrationen auf die Antik{\"o}rperbindung und Komplementablagerung wurden in ELISA, Komplementbindungsassays und zellbasierten Verfahren getestet. Außerdem wurde mithilfe von LDH-Zytotoxizit{\"a}tsmessungen die Komplement-induzierte Zelllyse sowie die Effekte von IVIG untersucht. Klinische Daten wurden retrospektiv ausgewertet. F{\"u}nf Patienten/Patientinnen mit hohen Autoantik{\"o}rpertitern gegen NF-155 und ein Patient mit Anti-Pan-Neurofascin Autoantik{\"o}rpern konnten in der Studie detektiert werden. Der Patient mit Autoantik{\"o}rpern gegen alle drei Isoformen des Neurofascins und IgG3-Pr{\"a}dominanz zeigte die deutlichste Komplementablagerung. Bei drei Patienten/Patientinnen, die IgG1, IgG2 und IgG4 aufwiesen, war eine Aktivierung des Komplementsystems zu beobachten, w{\"a}hrend bei zwei Patienten mit pr{\"a}dominanter IgG4-Antik{\"o}rpersubklasse keine Komplementablagerung nachweisbar war. Bei Letzteren war eine Therapie mit IVIG in der Vorgeschichte erfolglos, w{\"a}hrend es bei zwei der Patienten/Patientinnen mit anderen IgG-Subklassen und Komplementbindung unter IVIG Therapie zu einer m{\"a}ßigen bis deutlichen Symptombesserung in der Akutphase kam. Eine Koinkubation mit IVIG f{\"u}hrte in den ELISA basierten und zellbasierten Versuchen zu keinem Effekt auf die Autoantik{\"o}rperbindung an das Zielantigen, jedoch zu einer deutlichen Reduktion der Antik{\"o}rper-vermittelten Komplementbindung. Diese Reduktion war sowohl bei Koinkuabtion von IVIG mit dem Komplementfaktor C1q als auch bei Pr{\"a}inkubation von IVIG vor C1q Gabe zu sehen. Bei zwei der Patienten/Patientinnen mit hohen Komplementablagerungen konnte eine erh{\"o}hte Zytotoxizit{\"a}t nachgewiesen werden, welche bei Zugabe von IVIG verringert wurde. Schlussfolgernd ist die Autoantik{\"o}rper-induzierte Komplementablagerung abh{\"a}ngig von der pr{\"a}dominanten IgG Subklasse. IVIG f{\"u}hrt zu einer deutlichen, konzentrationsabh{\"a}ngigen Reduktion der Komplementablagerung, sowie m{\"o}glicher zytotoxischer Effektorfunktionen wie die Zytolyse myelinisierter Schwannzellen oder Nervenaxonen. Dar{\"u}ber hinaus k{\"o}nnte die Subklassenanalyse von Erkrankten das Therapieansprechen auf IVIG vorhersagen und sollte daher eine wichtige Rolle in der Diagnostik der Nodo-Paranodopathie spielen. IVIG sowie andere {\"u}ber das Komplementsystem wirkende Therapeutika k{\"o}nnen in der Behandlung der schwer betroffenen Patienten/Patientinnen, insbesondere bei Anti-Pan-Neurofascin positiver Neuropathie, in Betracht gezogen werden.},
  subject      = {Komplement <Immunologie>},
  language  = {de}
}
@phdthesis{Knorr2024,
  author    = {Knorr, Susanne},
  title     = {Pathophysiology of early-onset isolated dystonia in a DYT-TOR1A rat model with trauma-induced dystonia-like movements},
  doi       = {10.25972/OPUS-20609},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206096},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2024},
  abstract  = {Early-onset torsion dystonia (DYT-TOR1A, DYT1) is an inherited hyperkinetic movement disorder caused by a mutation of the TOR1A gene encoding the torsinA protein. DYT-TOR1A is characterized as a network disorder of the central nervous system (CNS), including predominantly the cortico-basal ganglia-thalamo-cortical loop resulting in a severe generalized dystonic phenotype. The pathophysiology of DYTTOR1A is not fully understood. Molecular levels up to large-scale network levels of the CNS are suggested to be affected in the pathophysiology of DYT-TOR1A. The reduced penetrance of 30\% - 40\% indicates a gene-environmental interaction, hypothesized as "second hit". The lack of appropriate and phenotypic DYT-TOR1A animal models encouraged us to verify the "second hit" hypothesis through a unilateral peripheral nerve trauma of the sciatic nerve in a transgenic asymptomatic DYT-TOR1A rat model (∆ETorA), overexpressing the human mutated torsinA protein. In a multiscale approach, this animal model was characterized phenotypically and pathophysiologically. Nerve-injured ∆ETorA rats revealed dystonia-like movements (DLM) with a partially generalized phenotype. A physiomarker of human dystonia, describing increased theta oscillation in the globus pallidus internus (GPi), was found in the entopeduncular nucleus (EP), the rodent equivalent to the human GPi, of nerve-injured ∆ETorA rats. Altered oscillation patterns were also observed in the primary motor cortex. Highfrequency stimulation (HFS) of the EP reduced DLM and modulated altered oscillatory activity in the EP and primary motor cortex in nerve-injured ∆ETorA rats. Moreover, the dopaminergic system in ∆ETorA rats demonstrated a significant increased striatal dopamine release and dopamine turnover. Whole transcriptome analysis revealed differentially expressed genes of the circadian clock and the energy metabolism, thereby pointing towards novel, putative pathways in the pathophysiology of DYTTOR1A dystonia. In summary, peripheral nerve trauma can trigger DLM in genetically predisposed asymptomatic ΔETorA rats leading to neurobiological alteration in the central motor network on multiple levels and thereby supporting the "second hit" hypothesis. This novel symptomatic DYT-TOR1A rat model, based on a DYT-TOR1A genetic background, may prove as a valuable chance for DYT-TOR1A dystonia, to further investigate the pathomechanism in more detail and to establish new treatment strategies.},
  subject      = {Dystonie},
  language  = {en}
}
@article{EstradaKrebbersVossetal.2018,
  author    = {Estrada, Veronica and Krebbers, Julia and Voss, Christian and Brazda, Nicole and Blazyca, Heinrich and Illgen, Jennifer and Seide, Klaus and J{\"u}rgens, Christian and M{\"u}ller, J{\"o}rg and Martini, Rudolf and Trieu, Hoc Khiem and M{\"u}ller, Hans Werner},
  title     = {Low-pressure micro-mechanical re-adaptation device sustainably and effectively improves locomotor recovery from complete spinal cord injury},
  series = {Communications Biology},
  volume    = {1},
  journal   = {Communications Biology},
  doi       = {10.1038/s42003-018-0210-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227357},
  year      = {2018},
  abstract  = {Traumatic spinal cord injuries result in impairment or even complete loss of motor, sensory and autonomic functions. Recovery after complete spinal cord injury is very limited even in animal models receiving elaborate combinatorial treatments. Recently, we described an implantable microsystem (microconnector) for low-pressure re-adaption of severed spinal stumps in rat. Here we investigate the long-term structural and functional outcome following microconnector implantation after complete spinal cord transection. Re-adaptation of spinal stumps supports formation of a tissue bridge, glial and vascular cell invasion, motor axon regeneration and myelination, resulting in partial recovery of motor-evoked potentials and a thus far unmet improvement of locomotor behaviour. The recovery lasts for at least 5 months. Despite a late partial decline, motor recovery remains significantly superior to controls. Our findings demonstrate that microsystem technology can foster long-lasting functional improvement after complete spinal injury, providing a new and effective tool for combinatorial therapies.},
  language  = {en}
}
@article{RolfesRuckDavidetal.2022,
  author    = {Rolfes, Leoni and Ruck, Tobias and David, Christina and Mencl, Stine and Bock, Stefanie and Schmidt, Mariella and Strecker, Jan-Kolja and Pfeuffer, Steffen and Mecklenbeck, Andreas-Schulte and Gross, Catharina and Gliem, Michael and Minnerup, Jens and Schuhmann, Michael K. and Kleinschnitz, Christoph and Meuth, Sven G.},
  title     = {Natural Killer Cells Are Present in Rag1\(^{-/-}\) Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke},
  series = {Translational Stroke Research},
  volume    = {13},
  journal   = {Translational Stroke Research},
  number    = {1},
  issn      = {1868-4483},
  doi       = {10.1007/s12975-021-00923-3},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308924},
  pages     = {197-211},
  year      = {2022},
  abstract  = {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.},
  language  = {en}
}