@article{WohnradeVellingMixetal.2023, author = {Wohnrade, Camilla and Velling, Ann-Kathrin and Mix, Lucas and Wurster, Claudia D. and Cordts, Isabell and Stolte, Benjamin and Zeller, Daniel and Uzelac, Zeljko and Platen, Sophia and Hagenacker, Tim and Deschauer, Marcus and Lingor, Paul and Ludolph, Albert C. and Lul{\´e}, Doroth{\´e}e and Petri, Susanne and Osmanovic, Alma and Schreiber-Katz, Olivia}, title = {Health-related quality of life in spinal muscular atrophy patients and their caregivers — a prospective, cross-sectional, multi-center analysis}, series = {Brain Sciences}, volume = {13}, journal = {Brain Sciences}, number = {1}, issn = {2076-3425}, doi = {10.3390/brainsci13010110}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-305048}, year = {2023}, abstract = {Spinal muscular atrophy (SMA) is a disabling disease that affects not only the patient's health-related quality of life (HRQoL), but also causes a high caregiver burden (CGB). The aim of this study was to evaluate HRQoL, CGB, and their predictors in SMA. In two prospective, cross-sectional, and multi-center studies, SMA patients (n = 39) and SMA patient/caregiver couples (n = 49) filled in the EuroQoL Five Dimension Five Level Scale (EQ-5D-5L) and the Short Form Health Survey 36 (SF-36). Caregivers (CGs) additionally answered the Zarit Burden Interview (ZBI) and the Hospital Anxiety and Depression Scale (HADS). Patients were clustered into two groups with either low or high HRQoL (EQ-5D-5L index value <0.259 or >0.679). The latter group was mostly composed of ambulatory type III patients with higher motor/functional scores. More severely affected patients reported low physical functioning but good mental health and vitality. The CGB (mean ZBI = 22/88) correlated negatively with patients' motor/functional scores and age. Higher CGB was associated with a lower HRQoL, higher depression and anxiety, and more health impairments of the CGs. We conclude that patient and CG well-being levels interact closely, which highlights the need to consider the health of both parties while evaluating novel treatments.}, language = {en} } @article{WiesslerTalucciPiroetal.2024, author = {Wiessler, Anna-Lena and Talucci, Ivan and Piro, Inken and Seefried, Sabine and H{\"o}rlin, Verena and Baykan, Bet{\"u}l B. and T{\"u}z{\"u}n, Erdem and Schaefer, Natascha and Maric, Hans M. and Sommer, Claudia and Villmann, Carmen}, title = {Glycine receptor β-targeting autoantibodies contribute to the pathology of autoimmune diseases}, series = {Neurology: Neuroimmunology \& Neuroinflammation}, volume = {11}, journal = {Neurology: Neuroimmunology \& Neuroinflammation}, number = {2}, doi = {10.1212/NXI.0000000000200187}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349958}, year = {2024}, abstract = {Background and Objectives Stiff-person syndrome (SPS) and progressive encephalomyelitis with rigidity and myoclonus (PERM) are rare neurologic disorders of the CNS. Until now, exclusive GlyRα subunit-binding autoantibodies with subsequent changes in function and surface numbers were reported. GlyR autoantibodies have also been described in patients with focal epilepsy. Autoimmune reactivity against the GlyRβ subunits has not yet been shown. Autoantibodies against GlyRα1 target the large extracellular N-terminal domain. This domain shares a high degree of sequence homology with GlyRβ making it not unlikely that GlyRβ-specific autoantibody (aAb) exist and contribute to the disease pathology. Methods In this study, we investigated serum samples from 58 patients for aAb specifically detecting GlyRβ. Studies in microarray format, cell-based assays, and primary spinal cord neurons and spinal cord tissue immunohistochemistry were performed to determine specific GlyRβ binding and define aAb binding to distinct protein regions. Preadsorption approaches of aAbs using living cells and the purified extracellular receptor domain were further used. Finally, functional consequences for inhibitory neurotransmission upon GlyRβ aAb binding were resolved by whole-cell patch-clamp recordings. Results Among 58 samples investigated, cell-based assays, tissue analysis, and preadsorption approaches revealed 2 patients with high specificity for GlyRβ aAb. Quantitative protein cluster analysis demonstrated aAb binding to synaptic GlyRβ colocalized with the scaffold protein gephyrin independent of the presence of GlyRα1. At the functional level, binding of GlyRβ aAb from both patients to its target impair glycine efficacy. Discussion Our study establishes GlyRβ as novel target of aAb in patients with SPS/PERM. In contrast to exclusively GlyRα1-positive sera, which alter glycine potency, aAbs against GlyRβ impair receptor efficacy for the neurotransmitter glycine. Imaging and functional analyses showed that GlyRβ aAbs antagonize inhibitory neurotransmission by affecting receptor function rather than localization.}, language = {en} } @article{RauschenbergerPiroKasaragodetal.2023, author = {Rauschenberger, Vera and Piro, Inken and Kasaragod, Vikram Babu and H{\"o}rlin, Verena and Eckes, Anna-Lena and Kluck, Christoph J. and Schindelin, Hermann and Meinck, Hans-Michael and Wickel, Jonathan and Geis, Christian and T{\"u}z{\"u}n, Erdem and Doppler, Kathrin and Sommer, Claudia and Villmann, Carmen}, title = {Glycine receptor autoantibody binding to the extracellular domain is independent from receptor glycosylation}, series = {Frontiers in Molecular Neuroscience}, volume = {16}, journal = {Frontiers in Molecular Neuroscience}, doi = {10.3389/fnmol.2023.1089101}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304206}, year = {2023}, abstract = {Glycine receptor (GlyR) autoantibodies are associated with stiff-person syndrome and the life-threatening progressive encephalomyelitis with rigidity and myoclonus in children and adults. Patient histories show variability in symptoms and responses to therapeutic treatments. A better understanding of the autoantibody pathology is required to develop improved therapeutic strategies. So far, the underlying molecular pathomechanisms include enhanced receptor internalization and direct receptor blocking altering GlyR function. A common epitope of autoantibodies against the GlyRα1 has been previously defined to residues 1A-33G at the N-terminus of the mature GlyR extracellular domain. However, if other autoantibody binding sites exist or additional GlyR residues are involved in autoantibody binding is yet unknown. The present study investigates the importance of receptor glycosylation for binding of anti-GlyR autoantibodies. The glycine receptor α1 harbors only one glycosylation site at the amino acid residue asparagine 38 localized in close vicinity to the identified common autoantibody epitope. First, non-glycosylated GlyRs were characterized using protein biochemical approaches as well as electrophysiological recordings and molecular modeling. Molecular modeling of non-glycosylated GlyRα1 did not show major structural alterations. Moreover, non-glycosylation of the GlyRα1N38Q did not prevent the receptor from surface expression. At the functional level, the non-glycosylated GlyR demonstrated reduced glycine potency, but patient GlyR autoantibodies still bound to the surface-expressed non-glycosylated receptor protein in living cells. Efficient adsorption of GlyR autoantibodies from patient samples was possible by binding to native glycosylated and non-glycosylated GlyRα1 expressed in living not fixed transfected HEK293 cells. Binding of patient-derived GlyR autoantibodies to the non-glycosylated GlyRα1 offered the possibility to use purified non-glycosylated GlyR extracellular domain constructs coated on ELISA plates and use them as a fast screening readout for the presence of GlyR autoantibodies in patient serum samples. Following successful adsorption of patient autoantibodies by GlyR ECDs, binding to primary motoneurons and transfected cells was absent. Our results indicate that the glycine receptor autoantibody binding is independent of the receptor's glycosylation state. Purified non-glycosylated receptor domains harbouring the autoantibody epitope thus provide, an additional reliable experimental tool besides binding to native receptors in cell-based assays for detection of autoantibody presence in patient sera.}, language = {en} } @article{RauschenbergervonWardenburgSchaeferetal.2020, author = {Rauschenberger, Vera and von Wardenburg, Niels and Schaefer, Natascha and Ogino, Kazutoyo and Hirata, Hiromi and Lillesaar, Christina and Kluck, Christoph J. and Meinck, Hans-Michael and Borrmann, Marc and Weishaupt, Andreas and Doppler, Kathrin and Wickel, Jonathan and Geis, Christian and Sommer, Claudia and Villmann, Carmen}, title = {Glycine Receptor Autoantibodies Impair Receptor Function and Induce Motor Dysfunction}, series = {Annals of Neurology}, volume = {88}, journal = {Annals of Neurology}, number = {3}, doi = {10.1002/ana.25832}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-216005}, pages = {544 -- 561}, year = {2020}, abstract = {Objective Impairment of glycinergic neurotransmission leads to complex movement and behavioral disorders. Patients harboring glycine receptor autoantibodies suffer from stiff-person syndrome or its severe variant progressive encephalomyelitis with rigidity and myoclonus. Enhanced receptor internalization was proposed as the common molecular mechanism upon autoantibody binding. Although functional impairment of glycine receptors following autoantibody binding has recently been investigated, it is still incompletely understood. Methods A cell-based assay was used for positive sample evaluation. Glycine receptor function was assessed by electrophysiological recordings and radioligand binding assays. The in vivo passive transfer of patient autoantibodies was done using the zebrafish animal model. Results Glycine receptor function as assessed by glycine dose-response curves showed significantly decreased glycine potency in the presence of patient sera. Upon binding of autoantibodies from 2 patients, a decreased fraction of desensitized receptors was observed, whereas closing of the ion channel remained fast. The glycine receptor N-terminal residues \(^{29}\)A to \(^{62}\)G were mapped as a common epitope of glycine receptor autoantibodies. An in vivo transfer into the zebrafish animal model generated a phenotype with disturbed escape behavior accompanied by a reduced number of glycine receptor clusters in the spinal cord of affected animals. Interpretation Autoantibodies against the extracellular domain mediate alterations of glycine receptor physiology. Moreover, our in vivo data demonstrate that the autoantibodies are a direct cause of the disease, because the transfer of human glycine receptor autoantibodies to zebrafish larvae generated impaired escape behavior in the animal model compatible with abnormal startle response in stiff-person syndrome or progressive encephalitis with rigidity and myoclonus patients.}, language = {en} } @article{KleinschnitzGoebelMeuthetal.2014, author = {Kleinschnitz, Christoph and G{\"o}bel, Kerstin and Meuth, Sven G. and Kraft, Peter}, title = {Glatiramer acetate does not protect from acute ischemic stroke in mice}, doi = {10.1186/2040-7378-6-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110528}, year = {2014}, abstract = {Background The role of the immune system in the pathophysiology of acute ischemic stroke is increasingly recognized. However, targeted treatment strategies to modulate immunological pathways in stroke are still lacking. Glatiramer acetate is a multifaceted immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. Experimental studies suggest that glatiramer acetate might also work in other neuroinflammatory or neurodegenerative diseases apart from multiple sclerosis. Findings We evaluated the efficacy of glatiramer acetate in a mouse model of brain ischemia/reperfusion injury. 60 min of transient middle cerebral artery occlusion was induced in male C57Bl/6 mice. Pretreatment with glatiramer acetate (3.5 mg/kg bodyweight) 30 min before the induction of stroke did not reduce lesion volumes or improve functional outcome on day 1. Conclusions Glatiramer acetate failed to protect from acute ischemic stroke in our hands. Further studies are needed to assess the true therapeutic potential of glatiramer acetate and related immunomodulators in brain ischemia.}, 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} } @phdthesis{MeyerzuAltenschildesche2022, author = {Meyer zu Altenschildesche, Caren}, title = {Genetische Variationen bei Patienten mit idiopathischer Small fiber Neuropathie}, doi = {10.25972/OPUS-28274}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-282742}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Die Literatur beschreibt unter Patienten mit idiopathischer Small fiber Neuro-pathie (SFN) einen Anteil von etwa ein F{\"u}nftel bis Drittel mit Variationen unkla-rer pathogenetischer Relevanz in Schmerz-assoziierten Genen. Dies best{\"a}tig-te sich im Rahmen unserer klinischen Studie: {\"U}ber die Zeit von Mai 2015 bis Januar 2020 konnten bei 13 von 66 (21\%) eingeschlossenen Patienten mit klinischem Verdacht auf SFN genetische Variationen in Schmerz-assoziierten Genen detektiert werden. Solche Ver{\"a}nderungen k{\"o}nnen {\"u}ber Gain- oder Loss-of-Function-Mechanismen die Funktion codierter nozizeptiver Signalpro-teine modulieren und so potentiell zur SFN-Symptomatik f{\"u}hren. Im Rahmen der Studie erfolgte neben der genetischen Diagnostik eine umfangreiche Un-tersuchung der Teilnehmer. In der Diagnostik stachen die potentiell geneti-schen SFN-Patienten nicht heraus und auch klinisch fielen nur dezente Unter-schiede zu den {\"u}brigen Patienten auf: Wir zeigten, dass die Betroffenen h{\"a}ufi-ger von {\"a}ußeren Einflussfaktoren getriggerte Schmerzattacken erleiden und eine tendenziell weitl{\"a}ufigere Symptommanifestation aufwiesen. Dies {\"a}hnelt der Klinik anderer heredit{\"a}rer neuropathischer Schmerzsyndrome wie der pa-roxysmalen extremen Schmerzst{\"o}rung (PEPD) oder den famili{\"a}ren episodi-schen Schmerzsyndromen (FEPS). Die potentiell genetische Grundlage f{\"u}hrte bei unseren Patienten zu einer st{\"a}rkeren Limitation im t{\"a}glichen und berufli-chen Alltag und minderte die Lebensqualit{\"a}t der Betroffenen deutlich. M{\"o}gli-che Ursache hierf{\"u}r war auch die herausfordernde Therapie der Patienten mit Genvariationen: F{\"u}r den gleichen Behandlungserfolg mussten die Patienten mit potentiell genetischer SFN deutlich mehr Wirkstoffe einnehmen und {\"u}ber-haupt versuchen. Obwohl nur minimale klinische Hinweise eine potentiell ge-netische Genese andeuten, sollten diese fr{\"u}hzeitig durch eine strukturierte Anamnese erkannt werden. Die Sammlung von Daten zu betroffenen Familien kann die pathogenetische Relevanz der Variationen erh{\"a}rten. Auch wird im Feld der genetischen Schmerzforschung rasant an zielgerichteten Analgetika gearbeitet, die fehlregulierte Rezeptoren blockieren sollen. Damit k{\"o}nnte Be-troffenen k{\"u}nftig gezielt geholfen werden. Wir empfehlen auf Grundlage unse-rer Studie bei Vorliegen genannter hinweisender Charakteristika eine geneti-sche Testung und Beratung zus{\"a}tzlich zur weiteren {\"a}tiologischen Diagnostik. Das zu untersuchende Panel sollte m{\"o}glichst viele Schmerz-assoziierte Gene umfassen - vorrangig die Gene codierend f{\"u}r die spannungsabh{\"a}ngigen Nat-riumkan{\"a}le SCN9A, -10A und 11A und die TRP-Kanalproteine TRPA1, TRPV1 und -3.}, subject = {Neuropathie}, language = {de} } @article{QuartaVoglConstantinetal.2011, author = {Quarta, Serena and Vogl, Christian and Constantin, Cristina E. and {\"U}{\c{c}}eyler, Nurcan and Sommer, Claudia and Kress, Michaela}, title = {Genetic evidence for an essential role of neuronally expressed IL-6 signal transducer gp130 in the induction and maintenance of experimentally induced mechanical hypersensitivity \(in\) \(vivo\) and \(in\) \(vitro\)}, series = {Molecular Pain}, volume = {7,73}, journal = {Molecular Pain}, doi = {10.1186/1744-8069-7-73}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140380}, pages = {1-9}, year = {2011}, abstract = {Tenderness and mechanical allodynia are key symptoms of malignant tumor, inflammation and neuropathy. The proinflammatory cytokine interleukin-6 (IL-6) is causally involved in all three pathologies. IL-6 not only regulates innate immunity and inflammation but also causes nociceptor sensitization and hyperalgesia. In general and in most cell types including immune cells and sensory neurons, IL-6 binds soluble mu receptor subunits which heteromerizes with membrane bound IL-6 signal transducer gp130. In the present study, we used a conditional knock-out strategy to investigate the importance of signal transducer gp130 expressed in C nociceptors for the generation and maintenance of mechanical hypersensitivity. Nociceptors were sensitized to mechanical stimuli by experimental tumor and this nociceptor sensitization was preserved at later stages of the pathology in control mice. However, in mice with a conditional deletion of gp130 in Nav1.8 expressing nociceptors mechanical hypersensitivity by experimental tumor, nerve injury or inflammation recovery was not preserved in the maintenance phase and nociceptors exhibited normal mechanical thresholds comparable to untreated mice. Together, the results argue for IL-6 signal transducer gp130 as an essential prerequisite in nociceptors for long-term mechanical hypersensitivity associated with cancer, inflammation and nerve injury.}, language = {en} } @phdthesis{Klaus2021, author = {Klaus, Laura-Christin}, title = {Generierung und Charakterisierung eines neuen Mausmodells des Morbus Parkinson durch AAV1/2 vermittelte {\"U}berexpression von humanem mutiertem A53T-α-Synuclein in der Substantia nigra}, doi = {10.25972/OPUS-23921}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239217}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Auch wenn die {\"A}tiopathogenese von Morbus Parkinson bis heute nicht vollst{\"a}ndig gekl{\"a}rt ist, scheint α-Synuclein (α-Syn) eine zentrale Rolle zu spielen. Die Entdeckung als genetische Ursache der Erkrankung, als Hauptbestandteil der Lewy-K{\"o}rper (LK) und seine Assoziation mit verschiedenen anderen potenziellen {\"a}tiologischen Faktoren verdeutlichen dies. Bei Ratten und Affen f{\"u}hrte eine AAV1/2-vermittelte {\"U}berexpression von A53T-α-Syn zu einer Degeneration dopaminerger Neurone in der Substantia nigra (SN), einem striatalen dopaminergen Defizit sowie Verhaltensauff{\"a}lligkeiten. In Anbetracht bestimmter Vorteile der Mausspezies, war es das Ziel dieser Dissertation - die im Rahmen eines kollaborativen Projektes mit dem Toronto Western Research Institut in Ontario, Kanada entstanden ist - dieses auf AAV1/2-A53T-α-Syn basierende Parkinson-Modell auf M{\"a}use zu {\"u}bertragen. Dazu wurde AAV1/2-A53T-α-Syn oder leerer AAV1/2-Vektor in einer Dosis von 1,5 µl mit einer Konzentration von 5,16 x 10^12 gp/ml stereotaktisch einseitig in die rechte SN von C57BL/6-wt-M{\"a}usen injiziert. {\"U}ber einen Zeitraum von 11 Wochen wurden verschiedene Verhaltensexperimente durchgef{\"u}hrt und die beiden Versuchstiergruppen miteinander verglichen. Post-mortem erfolgten verschiedene immunhistochemische Untersuchungen. Es konnte gezeigt werden, dass die einseitige Injektion von AAV1/2-A53T-α-Syn in die SN bei M{\"a}usen eine weit verbreitete {\"U}berexpression von A53T-α-Syn in dopaminergen Neuronen der SN induzierte, die innerhalb von 10 Wochen zu signifikanten fr{\"u}hen und persistierenden motorischen Verhaltensauff{\"a}lligkeiten, nigrostriataler Degeneration und Entwicklung einer Lewy-{\"a}hnlichen Pathologie f{\"u}hrte. Durch die Generierung und Charakterisierung dieses neuen Parkinson-Mausmodells, das klinische und histopathologische Merkmale der menschlichen Erkrankung widerspiegelt, besteht nun die M{\"o}glichkeit es weiterzuentwickeln und z.B. auf transgene M{\"a}use zu {\"u}bertragen, um u.a. molekulare Mechanismen der Parkinson-Krankheit zu entschl{\"u}sseln und pr{\"a}klinische Tests von krankheitsmodifizierenden Therapien durchzuf{\"u}hren.}, subject = {Parkinson-Krankheit}, language = {de} } @article{LauUeceylerCairnsetal.2022, author = {Lau, Kolja and {\"U}{\c{c}}eyler, Nurcan and Cairns, Tereza and Lorenz, Lora and Sommer, Claudia and Schindeh{\"u}tte, Magnus and Amann, Kerstin and Wanner, Christoph and Nordbeck, Peter}, title = {Gene variants of unknown significance in Fabry disease: Clinical characteristics of c.376AG (p.Ser126Gly)}, series = {Molecular Genetics \& Genomic Medicine}, volume = {10}, journal = {Molecular Genetics \& Genomic Medicine}, number = {5}, doi = {10.1002/mgg3.1912}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312817}, year = {2022}, abstract = {Background Anderson-Fabry disease (FD) is an X-linked lysosomal storage disorder with varying organ involvement and symptoms, depending on the underlying mutation in the alpha-galactosidase A gene (HGNC: GLA). With genetic testing becoming more readily available, it is crucial to precisely evaluate pathogenicity of each genetic variant, in order to determine whether there is or might be not a need for FD-specific therapy in affected patients and relatives at the time point of presentation or in the future. Methods This case series investigates the clinical impact of the specific GLA gene variant c.376A>G (p.Ser126Gly) in five (one heterozygous and one homozygous female, three males) individuals from different families, who visited our center between 2009 and 2021. Comprehensive neurological, nephrological and cardiac examinations were performed in all cases. One patient received a follow-up examination after 12 years. Results Index events leading to suspicion of FD were mainly unspecific neurological symptoms. However, FD-specific biomarkers, imaging examinations (i.e., brain MRI, heart MRI), and tissue-specific diagnostics, including kidney and skin biopsies, did not reveal evidence for FD-specific symptoms or organ involvement but showed normal results in all cases. This includes findings from 12-year follow-up in one patient with renal biopsy. Conclusion These findings suggest that p.Ser126Gly represents a benign GLA gene variant which per se does not cause FD. Precise clinical evaluation in individuals diagnosed with genetic variations of unknown significance should be performed to distinguish common symptoms broadly prevalent in the general population from those secondary to FD.}, language = {en} } @article{PalmisanoBrandtVissanietal.2020, author = {Palmisano, Chiara and Brandt, Gregor and Vissani, Matteo and Pozzi, Nicol{\´o} G. and Canessa, Andrea and Brumberg, Joachim and Marotta, Giorgio and Volkmann, Jens and Mazzoni, Alberto and Pezzoli, Gianni and Frigo, Carlo A. and Isaias, Ioannis U.}, title = {Gait Initiation in Parkinson's Disease: Impact of Dopamine Depletion and Initial Stance Condition}, series = {Frontiers in Bioengineering and Biotechnology}, volume = {8}, journal = {Frontiers in Bioengineering and Biotechnology}, issn = {2296-4185}, doi = {10.3389/fbioe.2020.00137}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200801}, year = {2020}, abstract = {Postural instability, in particular at gait initiation (GI), and resulting falls are a major determinant of poor quality of life in subjects with Parkinson's disease (PD). Still, the contribution of the basal ganglia and dopamine on the feedforward postural control associated with this motor task is poorly known. In addition, the influence of anthropometric measures (AM) and initial stance condition on GI has never been consistently assessed. The biomechanical resultants of anticipatory postural adjustments contributing to GI [imbalance (IMB), unloading (UNL), and stepping phase) were studied in 26 unmedicated subjects with idiopathic PD and in 27 healthy subjects. A subset of 13 patients was analyzed under standardized medication conditions and the striatal dopaminergic innervation was studied in 22 patients using FP-CIT and SPECT. People with PD showed a significant reduction in center of pressure (CoP) displacement and velocity during the IMB phase, reduced first step length and velocity, and decreased velocity and acceleration of the center of mass (CoM) at toe off of the stance foot. All these measurements correlated with the dopaminergic innervation of the putamen and substantially improved with levodopa. These results were not influenced by anthropometric parameters or by the initial stance condition. In contrast, most of the measurements of the UNL phase were influenced by the foot placement and did not correlate with putaminal dopaminergic innervation. Our results suggest a significant role of dopamine and the putamen particularly in the elaboration of the IMB phase of anticipatory postural adjustments and in the execution of the first step. The basal ganglia circuitry may contribute to defining the optimal referent body configuration for a proper initiation of gait and possibly gait adaptation to the environment.}, language = {en} } @phdthesis{Brandt2020, author = {Brandt, Gregor A.}, title = {Gait Initiation in Parkinson's Disease: The Interplay of Dopamine and Postural Control}, doi = {10.25972/OPUS-21463}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214636}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Deterioration of gait and alterations of physiological gait initiation contribute significantly to the burden of disease in Parkinson's disease. This paper systematically investigates disease-specific alterations during the postural phases of gait initiation and demonstrates the influence of dopaminergic networks by assessing levodopa mediated improvements in motor performance and correlation of motor behavior with loss of striatal and cortical dopaminergic neurons. Particular attention is given to known confounders such as initial stance and anthropometrics.}, subject = {Parkinson-Krankheit}, language = {en} } @article{IsaiasDipaolaMichietal.2014, author = {Isaias, Ioannis Ugo and Dipaola, Mariangela and Michi, Marlies and Marzegan, Alberto and Volkmann, Jens and Rodocanachi Roidi, Mariana L. and Frigo, Carlo Albino and Cavallari, Paolo}, title = {Gait Initiation in Children with Rett Syndrome}, series = {PLoS ONE}, volume = {9}, journal = {PLoS ONE}, number = {4}, issn = {1932-6203}, doi = {10.1371/journal.pone.0092736}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119789}, pages = {e92736}, year = {2014}, abstract = {Rett syndrome is an X-linked neurodevelopmental condition mainly characterized by loss of spoken language and a regression of purposeful hand use, with the development of distinctive hand stereotypies, and gait abnormalities. Gait initiation is the transition from quiet stance to steady-state condition of walking. The associated motor program seems to be centrally mediated and includes preparatory adjustments prior to any apparent voluntary movement of the lower limbs. Anticipatory postural adjustments contribute to postural stability and to create the propulsive forces necessary to reach steady-state gait at a predefined velocity and may be indicative of the effectiveness of the feedforward control of gait. In this study, we examined anticipatory postural adjustments associated with gait initiation in eleven girls with Rett syndrome and ten healthy subjects. Muscle activity (tibialis anterior and soleus muscles), ground reaction forces and body kinematic were recorded. Children with Rett syndrome showed a distinctive impairment in temporal organization of all phases of the anticipatory postural adjustments. The lack of appropriate temporal scaling resulted in a diminished impulse to move forward, documented by an impairment in several parameters describing the efficiency of gait start: length and velocity of the first step, magnitude and orientation of centre of pressure-centre of mass vector at the instant of (swing-)toe off. These findings were related to an abnormal muscular activation pattern mainly characterized by a disruption of the synergistic activity of antagonistic pairs of postural muscles. This study showed that girls with Rett syndrome lack accurate tuning of feedforward control of gait.}, language = {en} } @article{PalmisanoBeccariaHaufeetal.2022, author = {Palmisano, Chiara and Beccaria, Laura and Haufe, Stefan and Volkmann, Jens and Pezzoli, Gianni and Isaias, Ioannis U.}, title = {Gait initiation impairment in patients with Parkinson's disease and freezing of gait}, series = {Bioengineering}, volume = {9}, journal = {Bioengineering}, number = {11}, issn = {2306-5354}, doi = {10.3390/bioengineering9110639}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297579}, year = {2022}, abstract = {Freezing of gait (FOG) is a sudden episodic inability to produce effective stepping despite the intention to walk. It typically occurs during gait initiation (GI) or modulation and may lead to falls. We studied the anticipatory postural adjustments (imbalance, unloading, and stepping phase) at GI in 23 patients with Parkinson's disease (PD) and FOG (PDF), 20 patients with PD and no previous history of FOG (PDNF), and 23 healthy controls (HCs). Patients performed the task when off dopaminergic medications. The center of pressure (CoP) displacement and velocity during imbalance showed significant impairment in both PDNF and PDF, more prominent in the latter patients. Several measurements were specifically impaired in PDF patients, especially the CoP displacement along the anteroposterior axis during unloading. The pattern of segmental center of mass (SCoM) movements did not show differences between groups. The standing postural profile preceding GI did not correlate with outcome measurements. We have shown impaired motor programming at GI in Parkinsonian patients. The more prominent deterioration of unloading in PDF patients might suggest impaired processing and integration of somatosensory information subserving GI. The unaltered temporal movement sequencing of SCoM might indicate some compensatory cerebellar mechanisms triggering time-locked models of body mechanics in PD.}, language = {en} } @article{HaufeIsaiasPellegrinietal.2023, author = {Haufe, Stefan and Isaias, Ioannis U. and Pellegrini, Franziska and Palmisano, Chiara}, title = {Gait event prediction using surface electromyography in parkinsonian patients}, series = {Bioengineering}, volume = {10}, journal = {Bioengineering}, number = {2}, issn = {2306-5354}, doi = {10.3390/bioengineering10020212}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304380}, year = {2023}, abstract = {Gait disturbances are common manifestations of Parkinson's disease (PD), with unmet therapeutic needs. Inertial measurement units (IMUs) are capable of monitoring gait, but they lack neurophysiological information that may be crucial for studying gait disturbances in these patients. Here, we present a machine learning approach to approximate IMU angular velocity profiles and subsequently gait events using electromyographic (EMG) channels during overground walking in patients with PD. We recorded six parkinsonian patients while they walked for at least three minutes. Patient-agnostic regression models were trained on temporally embedded EMG time series of different combinations of up to five leg muscles bilaterally (i.e., tibialis anterior, soleus, gastrocnemius medialis, gastrocnemius lateralis, and vastus lateralis). Gait events could be detected with high temporal precision (median displacement of <50 ms), low numbers of missed events (<2\%), and next to no false-positive event detections (<0.1\%). Swing and stance phases could thus be determined with high fidelity (median F1-score of ~0.9). Interestingly, the best performance was obtained using as few as two EMG probes placed on the left and right vastus lateralis. Our results demonstrate the practical utility of the proposed EMG-based system for gait event prediction, which allows the simultaneous acquisition of an electromyographic signal to be performed. This gait analysis approach has the potential to make additional measurement devices such as IMUs and force plates less essential, thereby reducing financial and preparation overheads and discomfort factors in gait studies.}, language = {en} } @phdthesis{Dang2011, author = {Dang, Su-Yin Judith}, title = {Funktionelle Bedeutung der Neuroplastizit{\"a}t bei Multipler Sklerose}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-73817}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2011}, abstract = {Die Multiple Sklerose ist eine chronische neurologische Erkrankung, welche in der industrialisierten Welt einen der h{\"a}ufigsten Gr{\"u}nde f{\"u}r eine bleibende Behinderung bei jungen Erwachsenen darstellt. Obwohl die ZNS-Sch{\"a}digung, charakterisiert durch Demyelinisierung und axonale Sch{\"a}digung im Rahmen entz{\"u}ndlicher Vorg{\"a}nge, durch verschiedene Reparaturmechanismen reduziert wird, akkumuliert die L{\"a}sionslast im zentralen Nervensystem mit der Zeit. T2-gewichtete MRT-Studien zeigen, dass die dargestellten Pathologien nur m{\"a}ßig mit den motorischen Defiziten korrelieren. Diese Diskrepanz wird unter anderem auf Vorg{\"a}nge der Neuroplastizit{\"a}t zur{\"u}ckgef{\"u}hrt, als deren Basismechanismen Langzeitpotenzierung (LTP) und -depression (LTD) gelten. In verschiedenen fMRT-Studien haben sich Hinweise ergeben, dass diese adaptiven Ver{\"a}nderungen zur Reorganisation kortikaler Repr{\"a}sentationmuster f{\"u}hren k{\"o}nnen, so dass bei MS-Patienten eine ausgedehntere Aktivierung ipsilateraler sensomotorischer Areale bei motorischen Aufgaben zu beobachten ist. Die transkranielle Magnetstimulation (TMS) bietet die M{\"o}glichkeit, mittels virtueller L{\"a}sionstechniken eine direkte Aussage {\"u}ber die kausale Beziehung zwischen Struktur und Funktion zu liefern. Die funktionelle Rolle ipsilateraler Motorareale wurde an 26 MS-Patienten, in Relation zu ihrer motorischen Beeintr{\"a}chtigung und ZNS-Sch{\"a}digung, und an nach Alter, Geschlecht und H{\"a}ndigkeit zugeordneten Kontrollprobanden, untersucht. Die motorische Leistungsf{\"a}higkeit wurde durch verschiedene Tests zur Handfunktion erhoben. Die ZNS-Sch{\"a}digung wurde mittels MR-Spektroskopie als NAA/Cr Quotient sowie durch die CML erhoben. Die Aufgabe zur einfachen Reaktionszeit (SRT) bestand aus einer isometrischen Abduktionsbewegung des rechten Daumens gegen einen Kraftaufnehmer auf ein akustisches Go-Signal. Mit TMS-Einzelreizen wurde mit Hilfe einer Neuronavigation eine reversible virtuelle L{\"a}sion {\"u}ber bestimmten Gehirnarealen, kontralateraler M1, ipsilateraler M1 und ipsilateraler PMd, erzeugt. Es wurde eine Kontrollstimulation {\"u}ber MO durchgef{\"u}hrt. Die TMS-Einzelreize wurden 100ms nach dem Go-Signal appliziert. Als SRT wurde der Zeitraum zwischen dem Go-Signal und EMG-Beginn im APB definiert. Die signifikanten SRT-Verl{\"a}ngerungen bei TMS {\"u}ber dem ipsilateralen M1 und dem ipsilateralen PMd zeigen, dass diese Regionen eine Rolle bei der motorischen Funktion bei MS spielen. Die fehlenden Korrelationen zwischen motorischen Funktionstest und NAA/Cr-Verh{\"a}ltnis sowie die inverse Korrelation zur kortikomuskul{\"a}ren Latenz sind durch strukturell von der krankheitsbedingten Pathologie betroffenen kompensierenden Gehirnregionen erkl{\"a}rbar. Bei dem Theta Burst Experiments (TBS) wurde ein virtueller L{\"a}sionseffekt durch eine repetitive TMS-Intervention {\"u}ber dem ipsilateralen M1 induziert. Die Ergebnisse zeigen {\"a}hnliche Ver{\"a}nderungen der Exzitabilit{\"a}t bei MS-Patienten und gesunden Kontrollprobanden, was schließen l{\"a}sst, dass die LTD bei mild bis moderat betroffenen MS-Patienten weitestgehend unbeeintr{\"a}chtigt ist. MS-Patienten zeigen im Vergleich zu den Kontrollen eine {\"a}hnliche Minderung der Verhaltensleistung, Trefferquote in ein Kraftfenster, der MS-Patienten im Kontrollvergleich. Die Ergebnisse zeigen, dass ipsilaterale motorische Areale in der Lage sind den prim{\"a}r motorischen Kortex soweit zu kompensieren, jedoch die F{\"a}higkeit zur Kompensation in fortgeschrittenen Krankheitsstadien eingeschr{\"a}nkt ist. Abschließend kann man zusammenfassen, dass die funktionelle Rekrutierung von ipsilateralen Motorarealen eine adaptive Antwort auf chronische Gehirnsch{\"a}digung bei MS-Patienten sein kann, allerdings mit Einschr{\"a}nkung der Kapazit{\"a}t in fortgeschrittenen Krankheitsstadien. Nachdem die synaptische Plastizit{\"a}t weitestgehend intakt scheint, sollte man besonders Mechanismen der sp{\"a}ten Phase der Plastizit{\"a}t f{\"o}rdern, welche auf eine langfristige kortikale Plastizit{\"a}t abzielen. Weitere Studien in diesem Forschungszweig k{\"o}nnten einen Beitrag zur Entwicklung therapeutischer Konzepte der Neurorehabilitation bei Multipler Sklerose leisten.}, subject = {Neuronale Plastizit{\"a}t}, language = {de} } @article{HaarmannNehenDeissetal.2015, author = {Haarmann, Axel and Nehen, Mathias and Deiß, Annika and Buttmann, Mathias}, title = {Fumaric acid esters do not reduce inflammatory NF-\(\kappa\)B/p65 nuclear translocation, ICAM-1 expression and T-cell adhesiveness of human brain microvascular endothelial cells}, series = {International Journal of Molecular Sciences}, volume = {16}, journal = {International Journal of Molecular Sciences}, doi = {10.3390/ijms160819086}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148295}, pages = {19086-19095}, year = {2015}, abstract = {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 \(\mu\)M blocked the IL-1\(\beta\)-induced nuclear translocation of NF-\(\kappa\)B/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-1\(\beta\)-stimulated activation of p38 MAPK in brain endothelium. Furthermore, neither DMF nor MMF reduced the basal or IL-1\(\beta\)-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.}, language = {en} } @article{SchurigHaeuslerGrittneretal.2019, author = {Schurig, Johannes and Haeusler, Karl Georg and Grittner, Ulrike and Nolte, Christian H. and Fiebach, Jochen B. and Audebert, Heinrich J. and Endres, Matthias and Rocco, Andrea}, title = {Frequency of Hemorrhage on Follow Up Imaging in Stroke Patients Treated With rt-PA Depending on Clinical Course}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, doi = {10.3389/fneur.2019.00368}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234947}, year = {2019}, abstract = {Background: According to current guidelines, stroke patients treated with rt-PA should undergo brain imaging to exclude intracerebral bleeding 24 h after thrombolysis, before the start of medical secondary prevention. However, the usefulness of routine follow-up imaging with regard to changes in therapeutic management in patients without neurological deterioration is unclear. We hypothesized that follow up brain imaging solely to exclude bleeding in patients who clinically improved after rt-PA application may not be necessary. Methods: Retrospective single-center analysis including stroke patients treated with rt-PA. Records were reviewed for hemorrhagic transformation one day after systemic thrombolysis and brain imaging-based changes in therapeutic management. Twenty-four hour after thrombolysis patients were divided into four groups: (1) increased NIHSS score; (2) unchanged NIHSS score; (3) improved NIHSS score and; (4) NIHSS score = 0. Results: Out of 188 patients (mean age 73 years, 100 female) receiving rt-PA, 32 (17\%) had imaging-proven hemorrhagic transformation including 11 (6\%) patients with parenchymal hemorrhage. Patients in group (1, 2) more often had hypertension (p = 0.015) and more often had parenchymal hemorrhage (9 vs. 4\%; p < 0.206) compared to group (3, 4) and imaging-based changes in therapeutic management were more frequent (19\% vs. 6\%; p = 0.007). Patients of group (3, 4) had no changes in therapeutic management in 94\% of the cases. Patients in group (4) had no hemorrhagic transformation in routine follow-up brain imaging. Conclusions: Frequency of hemorrhagic transformation in Routine follow-up brain imaging and consecutive changes in therapeutic management were different depending on clinical course measured by NHISS score.}, language = {en} } @article{MeyerzuHoersteCordesMausbergetal.2014, author = {Meyer zu H{\"o}rste, Gerd and Cordes, Steffen and Mausberg, Anne K. and Zozulya, Alla L. and Wessig, Carsten and Sparwasser, Tim and Mathys, Christian and Wiendl, Heinz and Hartung, Hans-Peter and Kieseier, Bernd C.}, title = {FoxP3+Regulatory T Cells Determine Disease Severity in Rodent Models of Inflammatory Neuropathies}, series = {PLOS ONE}, volume = {9}, journal = {PLOS ONE}, number = {10}, doi = {10.1371/journal.pone.0108756}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115239}, pages = {e108756}, year = {2014}, abstract = {Inflammatory neuropathies represent disabling human autoimmune disorders with considerable disease variability. Animal models provide insights into defined aspects of their disease pathogenesis. Forkhead box P3 (FoxP3)+ regulatory T lymphocytes (Treg) are anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. Dysfunction or a reduced frequency of Tregs have been associated with different human autoimmune disorders. We here analyzed the functional relevance of Tregs in determining disease manifestation and severity in murine models of autoimmune neuropathies. We took advantage of the DEREG mouse system allowing depletion of Treg with high specificity as well as anti-CD25 directed antibodies to deplete Tregs in mice in actively induced experimental autoimmune neuritis (EAN). Furthermore antibody-depletion was performed in an adoptive transfer model of chronic neuritis. Early Treg depletion increased clinical EAN severity both in active and adoptive transfer chronic neuritis. This was accompanied by increased proliferation of myelin specific T cells and histological signs of peripheral nerve inflammation. Late stage Treg depletion after initial disease manifestation however did not exacerbate inflammatory neuropathy symptoms further. We conclude that Tregs determine disease severity in experimental autoimmune neuropathies during the initial priming phase, but have no major disease modifying function after disease manifestation. Potential future therapeutic approaches targeting Tregs should thus be performed early in inflammatory neuropathies.}, language = {en} } @article{SchuhmannBittnerMeuthetal.2015, author = {Schuhmann, Michael K. and Bittner, Stefan and Meuth, Sven G. and Kleinschnitz, Christoph and Fluri, Felix}, title = {Fingolimod (FTY720-P) does not stabilize the blood-brain barrier under inflammatory conditions in an in vitro model}, series = {International Journal of Molecular Sciences}, volume = {16}, journal = {International Journal of Molecular Sciences}, doi = {10.3390/ijms161226177}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145047}, pages = {29454-29466}, year = {2015}, abstract = {Breakdown of the blood-brain barrier (BBB) is an early hallmark of multiple sclerosis (MS), a progressive inflammatory disease of the central nervous system. Cell adhesion in the BBB is modulated by sphingosine-1-phosphate (S1P), a signaling protein, via S1P receptors (S1P\(_1\)). Fingolimod phosphate (FTY720-P) a functional S1P\(_1\) antagonist has been shown to improve the relapse rate in relapsing-remitting MS by preventing the egress of lymphocytes from lymph nodes. However, its role in modulating BBB permeabilityin particular, on the tight junction proteins occludin, claudin 5 and ZO-1has not been well elucidated to date. In the present study, FTY720-P did not change the transendothelial electrical resistance in a rat brain microvascular endothelial cell (RBMEC) culture exposed to inflammatory conditions and thus did not decrease endothelial barrier permeability. In contrast, occludin was reduced in RBMEC culture after adding FTY720-P. Additionally, FTY720-P did not alter the amount of endothelial matrix metalloproteinase (MMP)-9 and MMP-2 in RBMEC cultures. Taken together, our observations support the assumption that S1P\(_1\) plays a dual role in vascular permeability, depending on its ligand. Thus, S1P\(_1\) provides a mechanistic basis for FTY720-P-associated disruption of endothelial barrierssuch as the blood-retinal barrierwhich might result in macular edema.}, language = {en} } @article{CanesiGiordanoLazzarietal.2016, author = {Canesi, Margherita and Giordano, Rosaria and Lazzari, Lorenza and Isalberti, Maurizio and Isaias, Ioannis Ugo and Benti, Riccardo and Rampini, Paolo and Marotta, Giorgio and Colombo, Aurora and Cereda, Emanuele and Dipaola, Mariangela and Montemurro, Tiziana and Vigano, Mariele and Budelli, Silvia and Montelatici, Elisa and Lavazza, Cristiana and Cortelezzi, Agostino and Pezzoli, Gianni}, title = {Finding a new therapeutic approach for no-option Parkinsonisms: mesenchymal stromal cells for progressive supranuclear palsy}, series = {Journal of Translational Medicine}, volume = {14}, journal = {Journal of Translational Medicine}, number = {127}, doi = {10.1186/s12967-016-0880-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165725}, pages = {1-11}, year = {2016}, abstract = {Background: The trophic, anti-apoptotic and regenerative effects of bone marrow mesenchymal stromal cells (MSC) may reduce neuronal cell loss in neurodegenerative disorders. Methods: We used MSC as a novel candidate therapeutic tool in a pilot phase-I study for patients affected by progressive supranuclear palsy (PSP), a rare, severe and no-option form of Parkinsonism. Five patients received the cells by infusion into the cerebral arteries. Effects were assessed using the best available motor function rating scales (UPDRS, Hoehn and Yahr, PSP rating scale), as well as neuropsychological assessments, gait analysis and brain imaging before and after cell administration. Results: One year after cell infusion, all treated patients were alive, except one, who died 9 months after the infusion for reasons not related to cell administration or to disease progression (accidental fall). In all treated patients motor function rating scales remained stable for at least six-months during the one-year follow-up. Conclusions: We have demonstrated for the first time that MSC administration is feasible in subjects with PSP. In these patients, in whom deterioration of motor function is invariably rapid, we recorded clinical stabilization for at least 6 months. These encouraging results pave the way to the next randomized, placebo-controlled phase-II study that will definitively provide information on the efficacy of this innovative approach.}, language = {en} } @article{BinderLangePozzietal.2023, author = {Binder, Tobias and Lange, Florian and Pozzi, Nicol{\`o} and Musacchio, Thomas and Daniels, Christine and Odorfer, Thorsten and Fricke, Patrick and Matthies, Cordula and Volkmann, Jens and Capetian, Philipp}, title = {Feasibility of local field potential-guided programming for deep brain stimulation in Parkinson's disease: a comparison with clinical and neuro-imaging guided approaches in a randomized, controlled pilot trial}, series = {Brain Stimulation}, volume = {16}, journal = {Brain Stimulation}, number = {5}, doi = {10.1016/j.brs.2023.08.017}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350280}, pages = {1243-1251}, year = {2023}, abstract = {Highlights • Beta-Guided programming is an innovative approach that may streamline the programming process for PD patients with STN DBS. • While preliminary findings from our study suggest that Beta Titration may potentially mitigate STN overstimulation and enhance symptom control, • Our results demonstrate that beta-guided programming significantly reduces programming time, suggesting it could be efficiently integrated into routine clinical practice using a commercially available patient programmer. Background Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced Parkinson's disease (PD). Clinical outcomes after DBS can be limited by poor programming, which remains a clinically driven, lengthy and iterative process. Electrophysiological recordings in PD patients undergoing STN-DBS have shown an association between STN spectral power in the beta frequency band (beta power) and the severity of clinical symptoms. New commercially-available DBS devices now enable the recording of STN beta oscillations in chronically-implanted PD patients, thereby allowing investigation into the use of beta power as a biomarker for DBS programming. Objective To determine the potential advantages of beta-guided DBS programming over clinically and image-guided programming in terms of clinical efficacy and programming time. Methods We conducted a randomized, blinded, three-arm, crossover clinical trial in eight Parkinson's patients with STN-DBS who were evaluated three months after DBS surgery. We compared clinical efficacy and time required for each DBS programming paradigm, as well as DBS parameters and total energy delivered between the three strategies (beta-, clinically- and image-guided). Results All three programming methods showed similar clinical efficacy, but the time needed for programming was significantly shorter for beta- and image-guided programming compared to clinically-guided programming (p < 0.001). Conclusion Beta-guided programming may be a useful and more efficient approach to DBS programming in Parkinson's patients with STN-DBS. It takes significantly less time to program than traditional clinically-based programming, while providing similar symptom control. In addition, it is readily available within the clinical DBS programmer, making it a valuable tool for improving current clinical practice.}, language = {en} } @article{KraftFleischerWiedmannetal.2017, author = {Kraft, Peter and Fleischer, Anna and Wiedmann, Silke and R{\"u}cker, Viktoria and Mackenrodt, Daniel and Morbach, Caroline and Malzahn, Uwe and Kleinschnitz, Christoph and St{\"o}rk, Stefan and Heuschmann, Peter U.}, title = {Feasibility and diagnostic accuracy of point-of-care handheld echocardiography in acute ischemic stroke patients - a pilot study}, series = {BMC Neurology}, volume = {17}, journal = {BMC Neurology}, number = {159}, doi = {10.1186/s12883-017-0937-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158081}, year = {2017}, abstract = {Background: Standard echocardiography (SE) is an essential part of the routine diagnostic work-up after ischemic stroke (IS) and also serves for research purposes. However, access to SE is often limited. We aimed to assess feasibility and accuracy of point-of-care (POC) echocardiography in a stroke unit (SU) setting. Methods: IS patients were recruited on the SU of the University Hospital W{\"u}rzburg, Germany. Two SU team members were trained in POC echocardiography for a three-month period to assess a set of predefined cardiac parameters including left ventricular ejection fraction (LVEF). Diagnostic agreement was assessed by comparing POC with SE executed by an expert sonographer, and intraclass correlation coefficient (ICC) or kappa (κ) with 95\% confidence intervals (95\% CI) were calculated. Results: In the 78 patients receiving both POC and SE agreement for cardiac parameters was good, with ICC varying from 0.82 (95\% CI 0.71-0.89) to 0.93 (95\% CI 0.87-0.96), and κ from 0.39 (-95\% CI 0.14-0.92) to 0.79 (95\% CI 0.67-0.91). Detection of systolic dysfunction with POC echocardiography compared to SE was very good, with an area under the curve of 0.99 (0.96-1.00). Interrater agreement for LVEF measured by POC echocardiography was good with κ 0.63 (95\% CI 0.40-0.85). Conclusions: POC echocardiography in a SU setting is feasible enabling reliable quantification of LVEF and preliminary assessment of selected cardiac parameters that might be used for research purposes. Its potential clinical utility in triaging stroke patients who should undergo or do not necessarily require SE needs to be investigated in larger prospective diagnostic studies.}, language = {en} } @article{GolombeckWessigMonoranuetal.2013, author = {Golombeck, Stefanie Kristin and Wessig, Carsten and Monoranu, Camelia-Maria and Sch{\"u}tz, Ansgar and Solymosi, Laszlo and Melzer, Nico and Kleinschnitz, Christoph}, title = {Fatal atypical reversible posterior leukoencephalopathy syndrome: a case report}, series = {Journal of Medical Case Reports}, volume = {7}, journal = {Journal of Medical Case Reports}, number = {14}, doi = {10.1186/1752-1947-7-14}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135517}, year = {2013}, abstract = {Introduction: Reversible posterior leukoencephalopathy syndrome - a reversible subacute global encephalopathy clinically presenting with headache, altered mental status, visual symptoms such as hemianopsia or cortical blindness, motor symptoms, and focal or generalized seizures - is characterized by a subcortical vasogenic edema symmetrically affecting posterior brain regions. Complete reversibility of both clinical signs and magnetic resonance imaging lesions is regarded as a defining feature of reversible posterior leukoencephalopathy syndrome. Reversible posterior leukoencephalopathy syndrome is almost exclusively seen in the setting of a predisposing clinical condition, such as pre-eclampsia, systemic infections, sepsis and shock, certain autoimmune diseases, various malignancies and cytotoxic chemotherapy, transplantation and concomitant immunosuppression (especially with calcineurin inhibitors) as well as episodes of abrupt hypertension. We describe for the first time clinical, radiological and histological findings in a case of reversible posterior leukoencephalopathy syndrome with an irreversible and fatal outcome occurring in the absence of any of the known predisposing clinical conditions except for a hypertensive episode. Case presentation: A 58-year-old Caucasian woman presented with a two-week history of subacute and progressive occipital headache, blurred vision and imbalance of gait and with no evidence for raised arterial blood pressure during the two weeks previous to admission. Her past medical history was unremarkable except for controlled arterial hypertension. Cerebral magnetic resonance imaging demonstrated cortical and subcortical lesions with combined vasogenic and cytotoxic edema atypical for both venous congestion and arterial infarction. Routine laboratory and cerebrospinal fluid parameters were normal. The diagnosis of reversible posterior leukoencephalopathy syndrome was established. Within hours after admission the patient showed a rapidly decreasing level of consciousness, extension and flexion synergisms, bilaterally extensor plantar responses and rapid cardiopulmonary decompensation requiring ventilatory and cardiocirculatory support. Follow-up cerebral imaging demonstrated widespread and confluent cytotoxic edematous lesions in different arterial territories, global cerebral swelling, and subsequent upper and lower brainstem herniation. Four days after admission, the patient was declared dead because of brain death. Conclusion: This case demonstrates that fulminant and fatal reversible posterior leukoencephalopathy syndrome may occur spontaneously, that is, in the absence of any of the known predisposing systemic conditions.}, language = {en} } @article{GolombeckWessigMonoranuetal.2013, author = {Golombeck, Stefanie Kristin and Wessig, Carsten and Monoranu, Camelia-Maria and Sch{\"u}tz, Ansgar and Solymosi, Laszlo and Melzer, Niko and Kleinschnitz, Christoph}, title = {Fatal atypical reversible posterior leukoencephalopathy syndrome: a case report}, series = {Journal of Medical Case Reports}, volume = {7}, journal = {Journal of Medical Case Reports}, number = {14}, doi = {10.1186/1752-1947-7-14}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129456}, year = {2013}, abstract = {Introduction: Reversible posterior leukoencephalopathy syndrome - a reversible subacute global encephalopathy clinically presenting with headache, altered mental status, visual symptoms such as hemianopsia or cortical blindness, motor symptoms, and focal or generalized seizures - is characterized by a subcortical vasogenic edema symmetrically affecting posterior brain regions. Complete reversibility of both clinical signs and magnetic resonance imaging lesions is regarded as a defining feature of reversible posterior leukoencephalopathy syndrome. Reversible posterior leukoencephalopathy syndrome is almost exclusively seen in the setting of a predisposing clinical condition, such as pre-eclampsia, systemic infections, sepsis and shock, certain autoimmune diseases, various malignancies and cytotoxic chemotherapy, transplantation and concomitant immunosuppression (especially with calcineurin inhibitors) as well as episodes of abrupt hypertension. We describe for the first time clinical, radiological and histological findings in a case of reversible posterior leukoencephalopathy syndrome with an irreversible and fatal outcome occurring in the absence of any of the known predisposing clinical conditions except for a hypertensive episode. Case presentation: A 58-year-old Caucasian woman presented with a two-week history of subacute and progressive occipital headache, blurred vision and imbalance of gait and with no evidence for raised arterial blood pressure during the two weeks previous to admission. Her past medical history was unremarkable except for controlled arterial hypertension. Cerebral magnetic resonance imaging demonstrated cortical and subcortical lesions with combined vasogenic and cytotoxic edema atypical for both venous congestion and arterial infarction. Routine laboratory and cerebrospinal fluid parameters were normal. The diagnosis of reversible posterior leukoencephalopathy syndrome was established. Within hours after admission the patient showed a rapidly decreasing level of consciousness, extension and flexion synergisms, bilaterally extensor plantar responses and rapid cardiopulmonary decompensation requiring ventilatory and cardiocirculatory support. Follow-up cerebral imaging demonstrated widespread and confluent cytotoxic edematous lesions in different arterial territories, global cerebral swelling, and subsequent upper and lower brainstem herniation. Four days after admission, the patient was declared dead because of brain death. Conclusion: This case demonstrates that fulminant and fatal reversible posterior leukoencephalopathy syndrome may occur spontaneously, that is, in the absence of any of the known predisposing systemic conditions.}, language = {en} } @phdthesis{Nowak2013, author = {Nowak, Eva}, title = {Expression und Funktion von Integrin α-4 in humanen zerebralen Endothelzellen - Analysen unter Zuhilfenahme des therapeutisch eingesetzten Antik{\"o}rpers Natalizumab}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-99300}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Natalizumab ist ein humanisierter monoklonaler Antik{\"o}rper gegen das Oberfl{\"a}chenadh{\"a}sionsmolek{\"u}l Integrin α-4, der zur Therapie von schweren Verlaufsformen der Multiplen Sklerose (MS) zugelassen ist. Integrin α-4/β-1 wird durch Leukozyten exprimiert und steuert deren Extravasation {\"u}ber die Bindung an VCAM-1 (vascular cell adhesion molecule-1) auf Endothelzellen. Natalizumab wirkt {\"u}ber eine Blockade der Leukozytenadh{\"a}sion. In einigen Publikationen konnte dar{\"u}ber hinaus gezeigt werden, dass Integrin α-4 auch auf zerebralen Endothelzellen von M{\"a}usen und Ratten exprimiert wird. In der vorliegenden Arbeit wurde die Expression und Funktion von Integrin α-4 in kultivierten prim{\"a}ren humanen zerebralen Endothelzellen untersucht. Die im Rahmen dieser Arbeit an verschiedenen Einzelspenderpr{\"a}parationen durchgef{\"u}hrten FACS-Analysen zeigten, dass Integrin α-4 in unterschiedlicher Auspr{\"a}gung auf prim{\"a}ren zerebralen Endothelzellisolationen nachzuweisen war. Mit Hilfe immunzytochemischer F{\"a}rbungen konnte ein spezifisches Verteilungsmuster des Integrin α-4 in Form eines feinen, granul{\"a}ren Musters im Bereich des Zellleibes dokumentiert werden. In Adh{\"a}sionsversuchen zeigten Integrin α-4-exprimierende Endothelzellen nach Zugabe von Natalizumab in niedriger Konzentration eine verminderte F{\"a}higkeit zur Haftung an Fibronectin, einem Bindungspartner in der extrazellul{\"a}ren Matrix. In hohen Konzentrationen dominierte im eingesetzten experimentellen System ein unspezifischer Blockadeeffekt, der auch mit Kontrollantik{\"o}rpern zu beobachten war. In MS-L{\"a}sionen findet sich auch die l{\"o}sliche Form des VCAM-1 (sVCAM-1), die m{\"o}glicherweise mit endothelialem Integrin α-4 interagiert. Daher wurde mit Hilfe von Western-Blot-Untersuchungen die intrazellul{\"a}re Signaltransduktion unter Stimulation mit sVCAM-1 untersucht. Es zeigte sich wie in anderen Endothelarten vorbeschrieben eine Aktivierung des p38-MAP-Kinase-Signalweges. Zusammenfassend wurde demonstriert, dass prim{\"a}re humane zerebrale Endothelzellen Integrin α-4 exprimieren und dass dieses wahrscheinlich nicht nur f{\"u}r die mechanische Verankerung in der Extrazellul{\"a}rmatrix eine Bedeutung besitzt, sondern auch als Induktor intrazellul{\"a}rer Signaltransduktion fungiert, welche die Schrankeneigenschaften zerebraler Endothelzellen beeinflussen k{\"o}nnte.}, subject = {Integrin}, language = {de} } @article{BittnerBobakFeuchtenbergeretal.2011, author = {Bittner, Stefan and Bobak, Nicole and Feuchtenberger, Martin and Herrmann, Alexander M and G{\"o}bel, Kerstin and Kinne, Raimund W and Hansen, Anker J and Budde, Thomas and Kleinschnitz, Christoph and Frey, Oliver and Tony, Hans-Peter and Wiendl, Heinz and Meuth, Sven G}, title = {Expression of K\(_2\)\(_P\)5.1 potassium channels on CD4\(^+\)T lymphocytes correlates with disease activity in rheumatoid arthritis patients}, series = {Arthritis Research \& Therapy}, volume = {13}, journal = {Arthritis Research \& Therapy}, number = {R21}, doi = {10.1186/ar3245}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-139334}, year = {2011}, abstract = {Introduction CD4+ T cells express K2P5.1 (TWIK-related acid-sensitive potassium channel 2 (TASK2); KCNK5), a member of the two-pore domain potassium channel family, which has been shown to influence T cell effector functions. Recently, it was shown that K2P5.1 is upregulated upon (autoimmune) T cell stimulation. The aim of this study was to correlate expression levels of K2P5.1 on T cells from patients with rheumatoid arthritis (RA) to disease activity in these patients. Methods Expression levels of K2P5.1 were measured by RT-PCR in the peripheral blood of 58 patients with RA and correlated with disease activity parameters (C-reactive protein levels, erythrocyte sedimentation rates, disease activity score (DAS28) scores). Twenty patients undergoing therapy change were followed-up for six months. Additionally, synovial fluid and synovial biopsies were investigated for T lymphocytes expressing K2P5.1. Results K2P5.1 expression levels in CD4+ T cells show a strong correlation to DAS28 scores in RA patients. Similar correlations were found for serological inflammatory parameters (erythrocyte sedimentation rate, C-reactive protein). In addition, K2P5.1 expression levels of synovial fluid-derived T cells are higher compared to peripheral blood T cells. Prospective data in individual patients show a parallel behaviour of K2P5.1 expression to disease activity parameters during a longitudinal follow-up for six months. Conclusions Disease activity in RA patients correlates strongly with K2P5.1 expression levels in CD4+ T lymphocytes in the peripheral blood in cross-sectional as well as in longitudinal observations. Further studies are needed to investigate the exact pathophysiological mechanisms and to evaluate the possible use of K2P5.1 as a potential biomarker for disease activity and differential diagnosis.}, language = {en} } @article{FeldheimKesslerSchmittetal.2018, author = {Feldheim, Jonas and Kessler, Almuth F and Schmitt, Dominik and Wilczek, Lara and Linsenmann, Thomas and Dahlmann, Mathias and Monoranu, Camelia M and Ernestus, Ralf-Ingo and Hagemann, Carsten and L{\"o}hr, Mario}, title = {Expression of activating transcription factor 5 (ATF5) is increased in astrocytomas of different WHO grades and correlates with survival of glioblastoma patients}, series = {OncoTargets and Therapy}, volume = {11}, journal = {OncoTargets and Therapy}, doi = {10.2147/OTT.S176549}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177541}, pages = {8673-8684}, year = {2018}, abstract = {Background: ATF5 suppresses differentiation of neuroprogenitor cells and is overexpressed in glioblastoma (GBM). A reduction of its expression leads to apoptotic GBM cell death. Data on ATF5 expression in astrocytoma WHO grade II (low-grade astrocytoma [LGA]) are scarce and lacking on recurrent GBM. Patients and methods: ATF5 mRNA was extracted from frozen samples of patients' GBM (n=79), LGA (n=40), and normal brain (NB, n=10), quantified by duplex qPCR and correlated with retrospectively collected clinical data. ATF5 protein expression was evaluated by measuring staining intensity on immunohistochemistry. Results: ATF5 mRNA was overexpressed in LGA (sevenfold, P<0.001) and GBM (tenfold, P<0.001) compared to NB, which was confirmed on protein level. Although ATF5 mRNA expression in GBM showed a considerable fluctuation range, groups of varying biological behavior, that is, local/multifocal growth or primary tumor/relapse and the tumor localization at diagnosis, were not significantly different. ATF5 mRNA correlated with the patients' age (r=0.339, P=0.028) and inversely with Ki67-staining (r=-0.421, P=0.007). GBM patients were allocated to a low and a high ATF5 expression group by the median ATF5 overexpression compared to NB. Kaplan-Meier analysis and Cox regression indicated that ATF5 mRNA expression significantly correlated with short-term survival (t<12 months, median survival 18 vs 13 months, P=0.022, HR 2.827) and progression-free survival (PFS) (12 vs 6 months, P=0.024). This advantage vanished after 24 months (P=0.084). Conclusion: ATF5 mRNA expression could be identified as an additional, though not independent factor correlating with overall survival and PFS. Since its inhibition might lead to the selective death of glioma cells, it might serve as a potential ubiquitous therapeutic target in astrocytic tumors.}, language = {en} } @phdthesis{Fischer2009, author = {Fischer, Cindy Erika Elisabeth}, title = {Expression des fetalen Acetylcholinrezeptors im Muskel bei experimenteller Nervenl{\"a}sion der Ratte und bei Neuropathien des Menschen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-36619}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2009}, abstract = {No abstract available}, subject = {Acetylcholinrezeptor}, language = {de} } @article{SchnabelCamenKnebeletal.2021, author = {Schnabel, Renate B. and Camen, Stephan and Knebel, Fabian and Hagendorff, Andreas and Bavendiek, Udo and B{\"o}hm, Michael and Doehner, Wolfram and Endres, Matthias and Gr{\"o}schel, Klaus and Goette, Andreas and Huttner, Hagen B. and Jensen, Christoph and Kirchhof, Paulus and Korosoglou, Grigorius and Laufs, Ulrich and Liman, Jan and Morbach, Caroline and Navabi, Darius G{\"u}nther and Neumann-Haefelin, Tobias and Pfeilschifter, Waltraut and Poli, Sven and Rizos, Timolaos and Rolf, Andreas and R{\"o}ther, Joachim and Sch{\"a}bitz, Wolf R{\"u}diger and Steiner, Thorsten and Thomalla, G{\"o}tz and Wachter, Rolf and Haeusler, Karl Georg}, title = {Expert opinion paper on cardiac imaging after ischemic stroke}, series = {Clinical Research in Cardiology}, volume = {110}, journal = {Clinical Research in Cardiology}, number = {7}, issn = {1861-0692}, doi = {10.1007/s00392-021-01834-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266662}, pages = {938-958}, year = {2021}, abstract = {This expert opinion paper on cardiac imaging after acute ischemic stroke or transient ischemic attack (TIA) includes a statement of the "Heart and Brain" consortium of the German Cardiac Society and the German Stroke Society. The Stroke Unit-Commission of the German Stroke Society and the German Atrial Fibrillation NETwork (AFNET) endorsed this paper. Cardiac imaging is a key component of etiological work-up after stroke. Enhanced echocardiographic tools, constantly improving cardiac computer tomography (CT) as well as cardiac magnetic resonance imaging (MRI) offer comprehensive non- or less-invasive cardiac evaluation at the expense of increased costs and/or radiation exposure. Certain imaging findings usually lead to a change in medical secondary stroke prevention or may influence medical treatment. However, there is no proof from a randomized controlled trial (RCT) that the choice of the imaging method influences the prognosis of stroke patients. Summarizing present knowledge, the German Heart and Brain consortium proposes an interdisciplinary, staged standard diagnostic scheme for the detection of risk factors of cardio-embolic stroke. This expert opinion paper aims to give practical advice to physicians who are involved in stroke care. In line with the nature of an expert opinion paper, labeling of classes of recommendations is not provided, since many statements are based on expert opinion, reported case series, and clinical experience.}, language = {en} } @phdthesis{Rott2005, author = {Rott, Evelyn}, title = {Experimentelle autoimmune Enzephalomyelitis in beta2 Mikroglobulin knock-out M{\"a}usen : axonaler Schaden entsteht unabh{\"a}ngig von MHC-I Expression}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-19500}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2005}, abstract = {CD4 T-Zellen wurden lange als die vor allem pathogen wirkenden Immunzellen bei chronisch entz{\"u}ndlichen ZNS-Erkrankungen angesehen. Wir untersuchten die Wirkung von CD8 T-Zellen in der EAE (exp. autoimmunen Enzephalomyelitis = Tiermodell der Multiplen Sklerose) anhand von beta2-Mikroglobulin knock-out M{\"a}usen (fehlende CD8 T-Zellen). Ergebnis: im Vergleich zu den Wildtyptieren zeigten die Knock-outs eine signifikant st{\"a}rker ausgepr{\"a}gte Erkrankung bei der mit verschiedenen Antigenen (MOG, MBP) induzierten EAE mit erh{\"o}hter Mortalit{\"a}t. Histologisch fnad sich eine vermehrte Infiltration von Makrophagen und Mikroglia. Die Demyelinisierung war bei den Knock-outs st{\"a}rker ausgepr{\"a}gt, ebenso auch der axonale Schaden. Das Fehlen von funktionellen CD8 T-Zellen f{\"u}hrte demnach zu einer Verst{\"a}rkung der autoimmunen Gewebssch{\"a}digung im ZNS.}, language = {de} } @article{JirůHillmannGabrielSchuleretal.2022, author = {J{\´i}rů-Hillmann, Steffi and Gabriel, Katharina M. A. and Schuler, Michael and Wiedmann, Silke and M{\"u}hler, Johannes and D{\"o}tter, Klaus and Soda, Hassan and Rascher, Alexandra and Benesch, Sonka and Kraft, Peter and Pfau, Mathias and Stenzel, Joachim and von Nippold, Karin and Benghebrid, Mohamed and Schulte, Kerstin and Meinck, Ralf and Volkmann, Jens and Haeusler, Karl Georg and Heuschmann, Peter U.}, title = {Experiences of family caregivers 3-months after stroke: results of the prospective trans-regional network for stroke intervention with telemedicine registry (TRANSIT-Stroke)}, series = {BMC Geriatrics}, volume = {22}, journal = {BMC Geriatrics}, doi = {10.1186/s12877-022-02919-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313330}, year = {2022}, abstract = {Background Long-term support of stroke patients living at home is often delivered by family caregivers (FC). We identified characteristics of stroke patients being associated with receiving care by a FC 3-months (3 M) after stroke, assessed positive and negative experiences and individual burden of FC caring for stroke patients and determined factors associated with caregiving experiences and burden of FC 3 M after stroke. Methods Data were collected within TRANSIT-Stroke, a regional telemedical stroke-network comprising 12 hospitals in Germany. Patients with stroke/TIA providing informed consent were followed up 3 M after the index event. The postal patient-questionnaire was accompanied by an anonymous questionnaire for FC comprising information on positive and negative experiences of FC as well as on burden of caregiving operationalized by the Caregiver Reaction Assessment and a self-rated burden-scale, respectively. Multivariable logistic and linear regression analyses were performed. Results Between 01/2016 and 06/2019, 3532 patients provided baseline and 3 M-follow-up- data and 1044 FC responded to questionnaires regarding positive and negative caregiving experiences and caregiving burden. 74.4\% of FC were older than 55 years, 70.1\% were women and 67.5\% were spouses. Older age, diabetes and lower Barthel-Index in patients were significantly associated with a higher probability of receiving care by a FC at 3 M. Positive experiences of FC comprised the importance (81.5\%) and the privilege (70.0\%) of caring for their relative; negative experiences of FC included financial difficulties associated with caregiving (20.4\%). Median overall self-rated burden was 30 (IQR: 0-50; range 0-100). Older age of stroke patients was associated with a lower caregiver burden, whereas younger age of FC led to higher burden. More than half of the stroke patients in whom a FC questionnaire was completed did self-report that they are not being cared by a FC. This stroke patient group tended to be younger, more often male with less severe stroke and less comorbidities who lived more often with a partner. Conclusions The majority of caregivers wanted to care for their relatives but experienced burden at the same time. Elderly patients, patients with a lower Barthel Index at discharge and diabetes are at higher risk of needing care by a family caregiver. Trial registration The study was registered at "German Clinical Trial Register": DRKS00011696. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML\&TRIAL_ID=DRKS00011696}, language = {en} } @article{BadrMcFlederWuetal.2022, author = {Badr, Mohammad and McFleder, Rhonda L. and Wu, Jingjing and Knorr, Susanne and Koprich, James B. and H{\"u}nig, Thomas and Brotchie, Jonathan M. and Volkmann, Jens and Lutz, Manfred B. and Ip, Chi Wang}, title = {Expansion of regulatory T cells by CD28 superagonistic antibodies attenuates neurodegeneration in A53T-α-synuclein Parkinson's disease mice}, series = {Journal of Neuroinflammation}, volume = {19}, journal = {Journal of Neuroinflammation}, doi = {10.1186/s12974-022-02685-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300580}, year = {2022}, abstract = {Background Regulatory CD4\(^+\)CD25\(^+\)FoxP3\(^+\) T cells (Treg) are a subgroup of T lymphocytes involved in maintaining immune balance. Disturbance of Treg number and impaired suppressive function of Treg correlate with Parkinson's disease severity. Superagonistic anti-CD28 monoclonal antibodies (CD28SA) activate Treg and cause their expansion to create an anti-inflammatory environment. Methods Using the AAV1/2-A53T-α-synuclein Parkinson's disease mouse model that overexpresses the pathogenic human A53T-α-synuclein (hαSyn) variant in dopaminergic neurons of the substantia nigra, we assessed the neuroprotective and disease-modifying efficacy of a single intraperitoneal dose of CD28SA given at an early disease stage. Results CD28SA led to Treg expansion 3 days after delivery in hαSyn Parkinson's disease mice. At this timepoint, an early pro-inflammation was observed in vehicle-treated hαSyn Parkinson's disease mice with elevated percentages of CD8\(^+\)CD69\(^+\) T cells in brain and increased levels of interleukin-2 (IL-2) in the cervical lymph nodes and spleen. These immune responses were suppressed in CD28SA-treated hαSyn Parkinson's disease mice. Early treatment with CD28SA attenuated dopaminergic neurodegeneration in the SN of hαSyn Parkinson's disease mice accompanied with reduced brain numbers of activated CD4\(^+\), CD8\(^+\) T cells and CD11b\(^+\) microglia observed at the late disease-stage 10 weeks after AAV injection. In contrast, a later treatment 4 weeks after AAV delivery failed to reduce dopaminergic neurodegeneration. Conclusions Our data indicate that immune modulation by Treg expansion at a timepoint of overt inflammation is effective for treatment of hαSyn Parkinson's disease mice and suggest that the concept of early immune therapy could pose a disease-modifying option for Parkinson's disease patients.}, language = {en} } @article{ZellerDangWeiseetal.2012, author = {Zeller, Daniel and Dang, Su-Yin and Weise, David and Rieckmann, Peter and Toyka, Klaus V. and Classen, Joseph}, title = {Excitability decreasing central motor plasticity is retained in multiple sclerosis patients}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76333}, year = {2012}, abstract = {Background: Compensation of brain injury in multiple sclerosis (MS) may in part work through mechanisms involving neuronal plasticity on local and interregional scales. Mechanisms limiting excessive neuronal activity may have special significance for retention and (re-)acquisition of lost motor skills in brain injury. However, previous neurophysiological studies of plasticity in MS have investigated only excitability enhancing plasticity and results from neuroimaging are ambiguous. Thus, the aim of this study was to probe long-term depression-like central motor plasticity utilizing continuous theta-burst stimulation (cTBS), a non-invasive brain stimulation protocol. Because cTBS also may trigger behavioral effects through local interference with neuronal circuits, this approach also permitted investigating the functional role of the primary motor cortex (M1) in force control in patients with MS. Methods: We used cTBS and force recordings to examine long-term depression-like central motor plasticity and behavioral consequences of a M1 lesion in 14 patients with stable mild-to-moderate MS (median EDSS 1.5, range 0 to 3.5) and 14 age-matched healthy controls. cTBS consisted of bursts (50 Hz) of three subthreshold biphasic magnetic stimuli repeated at 5 Hz for 40 s over the hand area of the left M1. Corticospinal excitability was probed via motor-evoked potentials (MEP) in the abductor pollicis brevis muscle over M1 before and after cTBS. Force production performance was assessed in an isometric right thumb abduction task by recording the number of hits into a predefined force window. Results: cTBS reduced MEP amplitudes in the contralateral abductor pollicis brevis muscle to a comparable extent in control subjects (69 ± 22\% of baseline amplitude, p < 0.001) and in MS patients (69 ± 18\%, p < 0.001). In contrast, postcTBS force production performance was only impaired in controls (2.2 ± 2.8, p = 0.011), but not in MS patients (2.0 ± 4.4, p = 0.108). The decline in force production performance following cTBS correlated with corticomuscular latencies (CML) in MS patients, but did not correlate with MEP amplitude reduction in patients or controls. Conclusions: Long-term depression-like plasticity remains largely intact in mild-to-moderate MS. Increasing brain injury may render the neuronal networks less responsive toward lesion-induction by cTBS.}, subject = {Medizin}, language = {en} } @phdthesis{Haehnel2022, author = {H{\"a}hnel, Luzia Maria}, title = {Evaluation von Beta-2-Mikroglobulin, Laktat und Angiotensin-Converting Enzyme im Liquor als Biomarker der Multiplen Sklerose}, doi = {10.25972/OPUS-25850}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258503}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {This study investigates the suitability of beta-2-microglobulin (β2-microglobulin), lactate and angiotensin-converting enzyme (ACE) as biomarkers, given the good availability of these parameters in routine diagnostics but lack of data in this regard. For this purpose, 6,310 CSF samples obtained at the Neurological Clinic of the University Hospital of W{\"u}rzburg were analyzed. Closer analysis was carried out of 276 cases with non-inflammatory neurological diseases (NIND; control group) and 438 MS cases not taking an immunotherapy treatment (study group). In the MS cases, the form of progression of the disease and the disease activity (clinical relapses, progression index) were recorded. A clear correlation could be seen between age and CSF levels of β2-microglobulin, lactate and ACE in both the MS and control groups, whereby a correction was required for the subsequent comparison studies; this could also at least partly explain the contradictory data obtained in other studies to date. The MS cases showed elevated β2-microglobulin and lactate levels and decreased ACE levels in CSF compared to the controls. In both groups, there was a positive correlation between β2-microglobulin and ACE levels. In the separate analysis of the forms of progression of MS, cases with clinically-isolated syndrome (CIS) and relapsing-remitting MS (RRMS) revealed elevated β2-microglobulin levels, whilst cases with secondary-progressive or primary-progressive MS (SPMS or PPMS) did not. Lactate levels were only increased in cases of CIS. Cases with a relapsing course showed reduced ACE levels. The disease activity could not reliably be mapped by the parameters. Lactate levels tended to be elevated during a relapse, but this result was no longer significant after correction. Lactate levels also showed a positive correlation with the progression index. Our findings in this study provide evidence that the examined analysis parameters cannot be used in isolation to assess progression, disease activity and duration of disease. However, the significant differences between relapsing and chronic-progressive courses support the hypothesis of different underlying mechanisms of pathogenesis, and could serve as a starting basis for further studies.}, subject = {Multiple Sklerose}, language = {de} } @article{HaarmannDeissProchaskaetal.2010, author = {Haarmann, Axel and Deiss, Annika and Prochaska, Juergen and Foerch, Christian and Weksler, Babette and Romero, Ignacio and Couraud, Pierre-Olivier and Stoll, Guido and Rieckmann, Peter and Buttmann, Mathias}, title = {Evaluation of Soluble Junctional Adhesion Molecule-A as a Biomarker of Human Brain Endothelial Barrier Breakdown}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68468}, year = {2010}, abstract = {Background: An inducible release of soluble junctional adhesion molecule-A (sJAM-A) under pro-inflammatory conditions was described in cultured non-CNS endothelial cells (EC) and increased sJAM-A serum levels were found to indicate inflammation in non-CNS vascular beds. Here we studied the regulation of JAM-A expression in cultured brain EC and evaluated sJAM-A as a serum biomarker of blood-brain barrier (BBB) function. Methodology/Principal Findings: As previously reported in non-CNS EC types, pro-inflammatory stimulation of primary or immortalized (hCMEC/D3) human brain microvascular EC (HBMEC) induced a redistribution of cell-bound JAM-A on the cell surface away from tight junctions, along with a dissociation from the cytoskeleton. This was paralleled by reduced immunocytochemical staining of occludin and zonula occludens-1 as well as by increased paracellular permeability for dextran 3000. Both a self-developed ELISA test and Western blot analysis detected a constitutive sJAM-A release by HBMEC into culture supernatants, which importantly was unaffected by pro-inflammatory or hypoxia/reoxygenation challenge. Accordingly, serum levels of sJAM-A were unaltered in 14 patients with clinically active multiple sclerosis compared to 45 stable patients and remained unchanged in 13 patients with acute ischemic non-small vessel stroke over time. Conclusion: Soluble JAM-A was not suited as a biomarker of BBB breakdown in our hands. The unexpected non-inducibility of sJAM-A release at the human BBB might contribute to a particular resistance of brain EC to inflammatory stimuli, protecting the CNS compartment.}, subject = {Biomarker}, language = {en} } @phdthesis{Bischofs2005, author = {Bischofs, Stefan}, title = {Evaluation der antihyperalgetischen und neuroregenerativen Wirkung von Topiramat nach tierexperimenteller peripherer Nervenl{\"a}sion}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-18352}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2005}, abstract = {Evaluation der antihyperalgetischen wie neuroregenerativen Potenz von Topiramat nach peripherer Nervenl{\"a}sion. Untersuchung im Tiermodell nach CCI / Crush-Nervenl{\"a}sion. Verhaltenstestungen, morphometrisch histologische Analysen, Immunhistochemische F{\"a}rbungen, elektrophysiologische Studien sowie RT-PCR. Topiramat zeigte hierbei - modulierende Wirkung auf die Entwicklung einer mechanischen Hyperalgesie wie K{\"a}lteallodynie nach CCI, auf Hitzehyperalgesie wie K{\"a}lteallodynia nach Crush - keine neuroprotektive oder pro-regenerative Wirkung in den von uns verwendeten L{\"a}sionsmodellen - eine ausgepr{\"a}gte Modulation des zellul{\"a}ren Zytokinmilieus distal der Nervenl{\"a}sion im Sinne einer Hochregulation proinflammatorischer Zytokine.}, language = {de} } @phdthesis{Magg2017, author = {Magg, Barbara}, title = {Etablierung und Validierung des W{\"u}rzburger Fabry Schmerzfragebogens f{\"u}r erwachsene Patienten}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154928}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Der M. Fabry ist eine X-chromosomal vererbte lysosomale Speicherkankheit, die zu einem Multiorganversagen f{\"u}hrt. Ein fr{\"u}hes Symptom sind Schmerzen, die meist schon in der fr{\"u}hen Kindheit einsetzen. Das Besondere an diesen Schmerzen ist, dass sie sich sehr unterschiedlich u.a. bez{\"u}glich ihres Verlaufs, ihrer Dauer und ihrer Lokalisation pr{\"a}sentieren k{\"o}nnen. Diese Fabry-assoziierten Schmerzen sind meist brennend und akral betont, k{\"o}nnen aber auch andere Qualit{\"a}ten aufweisen und sehr variable K{\"o}rperpartien erfassen, was ihre diagnostische Einordnung erschwert. Bisher verf{\"u}gbare validierte Schmerzfrageb{\"o}gen k{\"o}nnen das Spektrum der Fabry-assoziierten Schmerzen nicht erfassen. In dieser Arbeit wird der erste M. Fabry spezifische Schmerzfragebogen f{\"u}r Erwachsene in zwei Versionen pr{\"a}sentiert. Die erste Version ist eine Interview Version (iFPQ), bei der der Arzt in einem pers{\"o}nlichen Gespr{\"a}ch mit dem Patienten mit Hilfe des Fragbogens alle wesentlichen Aspekte der Fabry-assoziierten Schmerzen erfragen kann. Die zweite Version kann eigenst{\"a}ndig vom Patienten ausgef{\"u}llt werden (saFPQ). Zur Etablierung der Frageb{\"o}gen wurde in einer Pilotstudie zun{\"a}chst mit 20 Patienten eine erste Version des iFPQ entwickelt. Nach Verbesserungen wurde die Interview Version mit Hilfe von 42 Studienteilnehmern validiert, die jeweils an einem Erst- und Zweitgespr{\"a}ch im Abstand von zwei Wochen teilnahmen. Hierbei wurde auch der NPSI als vergleichender Fragebogen ausgef{\"u}llt. Bei der ersten statistischen Analyse ergab sich eine gute Reliabilit{\"a}t mit ICC-Werten von 0,896 bis 0,999 aber eine unzureichende Validit{\"a}t zwischen iFPQ und NPSI mit K-Werten von 0,257 bis 0,566. Nach der ersten statistischen Analyse wurde der Fragebogen erneut {\"u}berarbeitet und mit Hilfe von 20 Studienteilnehmern erneut validiert. Anschließend zeigte sich eine gute Validit{\"a}t mit K-Werten von 0,634 bis 1,0. Der saFPQ wurde im Anschluss an die finale iFPQ Version entwickelt. Bei 40 Patienten erfolgte ein Erstgespr{\"a}ch, bei dem die Patienten die valide Version des iFPQ ausf{\"u}llten. Im Abstand von zwei Wochen schickten die Patienten dann die selbst{\"a}ndig ausgef{\"u}llte Version des saFPQ postalisch zur{\"u}ck. Die postalische Version erweitert die Flexibilit{\"a}t dieses Fragebogens. Sie ist f{\"u}r den klinischen Alltag sehr relevant. Die Resonanz der Patienten hinsichtlich beider Frageb{\"o}gen war sehr positiv. Perspektivisch ist die Entwicklung einer englischen Version geplant.}, subject = {M.Fabry}, language = {de} } @article{SchanbacherBieberReindersetal.2022, author = {Schanbacher, Constanze and Bieber, Michael and Reinders, Yvonne and Cherpokova, Deya and Teichert, Christina and Nieswandt, Bernhard and Sickmann, Albert and Kleinschnitz, Christoph and Langhauser, Friederike and Lorenz, Kristina}, title = {ERK1/2 activity is critical for the outcome of ischemic stroke}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {2}, issn = {1422-0067}, doi = {10.3390/ijms23020706}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-283991}, year = {2022}, abstract = {Ischemic disorders are the leading cause of death worldwide. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are thought to affect the outcome of ischemic stroke. However, it is under debate whether activation or inhibition of ERK1/2 is beneficial. In this study, we report that the ubiquitous overexpression of wild-type ERK2 in mice (ERK2\(^{wt}\)) is detrimental after transient occlusion of the middle cerebral artery (tMCAO), as it led to a massive increase in infarct volume and neurological deficits by increasing blood-brain barrier (BBB) leakiness, inflammation, and the number of apoptotic neurons. To compare ERK1/2 activation and inhibition side-by-side, we also used mice with ubiquitous overexpression of the Raf-kinase inhibitor protein (RKIP\(^{wt}\)) and its phosphorylation-deficient mutant RKIP\(^{S153A}\), known inhibitors of the ERK1/2 signaling cascade. RKIP\(^{wt}\) and RKIP\(^{S153A}\) attenuated ischemia-induced damages, in particular via anti-inflammatory signaling. Taken together, our data suggest that stimulation of the Raf/MEK/ERK1/2-cascade is severely detrimental and its inhibition is rather protective. Thus, a tight control of the ERK1/2 signaling is essential for the outcome in response to ischemic stroke.}, language = {en} } @phdthesis{Moetzing2002, author = {M{\"o}tzing, Sandra}, title = {Entwicklung von Merkelzellen in der Haut von P0-defizienten M{\"a}usen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-578}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2002}, abstract = {Heredit{\"a}re periphere Neuropathien sind chronische Erkrankungen des peripheren Nervensystems, einhergehend mit Muskelschw{\"a}che und sensorischer Dysfunktion. Die Merkelzelle als Mechanorezeptor der Haut wird von einer myelinisierten langsam adaptierenden Afferenz (Aß) innerviert. Deshalb wurde in der vorliegenden Arbeit als sekund{\"a}rer Indikator f{\"u}r die distale Innervation in P0-defizienten M{\"a}usen, ein Tiermodell der heredit{\"a}ren motorisch-sensorischen D{\´e}j{\´e}rine-Sottas-Neuropathie, die Merkelzellzahl in der Haut dieser Tiere untersucht. Zus{\"a}tzlich wurde untersucht, ob durch den Gendefekt das unmyelinisierte Nervenfasersystem der Haut und das Vorkommen von Neurotrophinen (NT-3, NGF) in den P0-defizienten M{\"a}usen beeinflußt wird. Zur Anwendung kamen 6 Wochen, 4 Monate und 6 Monate alte Wildtyp- und P0-defiziente M{\"a}use. Unter Zuhilfenahme immunhistochemischer F{\"a}rbemethoden, computergest{\"u}tzter und lichtmikroskopischer Auswerteverfahren konnte ein Verlust von Merkelzellen in behaarter als auch in unbehaarter Haut mit fortschreitenden Alter der Tiere gezeigt werden. Die Bestimmung des NT-3- und NGF-Gehaltes mittels enzymgekoppelten Assays ergab keine signifikante Reduktion des Vorkommens dieser Neurotrophine. Neben dem betr{\"a}chtlichen Verlust an Merkelzellen konnte man keinen Effekt auf unmyelinisierte intraepidermale Nervenfasern nachweisen. Im Gegensatz dazu stellte eine parallel durchgef{\"u}hrte Studie an Nervus femoralis und Nervus ischiadicus in 6 Monate alten P0-defizienten Tieren eine 70 Prozent Reduktion myelinisierter Axone fest, so daß wir daraus eine Abh{\"a}ngigkeit der Merkelzelle von ihrer assoziierten myelinisierten SAI-Afferenz sowohl in behaarter als auch in unbehaarter Haut in den P0-defizienten Tieren schlußfolgerten. Der Verlust an Merkelzellen und die Beeintr{\"a}chtigung von myelinisierten Nervenfasern in den P0-defizienten Tieren kann nicht als sekund{\"a}re Wirkung eines ver{\"a}nderten trophischen Gehaltes an NT-3 oder NGF angesehen werden, sondern ist vielmehr durch den axonalen Verlust erkl{\"a}rbar. Die intraepidermalen unmyelinisierten Nervenfasern bleiben durch den Gendefekt unbeeinflußt, so daß die Mutation im P0-Gen eine Spezifit{\"a}t f{\"u}r das myelinisierte Nervenfasersystem zeigt. Wichtige Ergebnisse dieser Arbeit wurden bereits ver{\"o}ffentlicht.}, 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} } @article{JovanovicKlassenHeuschmannetal.2020, author = {Jovanovic, Ana and Klassen, Philipp and Heuschmann, Peter and Sommer, Claudia and Roberts, Mark and {\"U}{\c{c}}eyler, Nurcan}, title = {English version of the self-administered Fabry Pain Questionnaire for adult patients}, series = {Orphanet Journal of Rare Diseases}, volume = {15}, journal = {Orphanet Journal of Rare Diseases}, doi = {10.1186/s13023-020-01580-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230298}, year = {2020}, abstract = {Background Pain is an early symptom of Fabry disease (FD) and is characterized by a unique phenotype with mainly episodic acral and triggerable burning pain. Recently, we designed and validated the first pain questionnaire for adult FD patients in an interview and a self-administered version in German: the Wurzburg Fabry Pain Questionnaire (FPQ). We now report the validation of the English version of the self-administered FPQ (enFPQ). Methods After two forward-backward translations of the FPQ by native German and native English speakers, the enFPQ was applied at The Mark Holland Metabolic Unit, Manchester, UK for validation. Consecutive patients with genetically ascertained FD and current or previous FD pain underwent a face-to-face interview using the enFPQ. Two weeks later, patients filled in the self-administered enFPQ at home. The agreement between entries collected by supervised administration and self-administration of the enFPQ was assessed via Gwet's AC1-statistics (AC1) for nominal-scaled scores and intraclass correlation coefficient (ICC) for interval-scaled elements. Results Eighty-three FD patients underwent the face-to-face interview and 54 patients sent back a completed self-administered version of the enFPQ 2 weeks later. We found high agreement with a mean AC1-statistics of 0.725 for 55 items, and very high agreement with a mean ICC of 0.811 for 9 items. Conclusions We provide the validated English version of the FPQ for self-administration in adult FD patients. The enFPQ collects detailed information on the individual FD pain phenotype and thus builds a solid basis for better pain classification and treatment in patients with FD.}, language = {en} } @article{KleinGrohWeishauptetal.2015, author = {Klein, Dennis and Groh, Janos and Weishaupt, Andreas and Martini, Rudolf}, title = {Endogenous antibodies contribute to macrophage-mediated demyelination in a mouse model for CMT1B}, series = {Journal of Neuroinflammation}, volume = {12}, journal = {Journal of Neuroinflammation}, number = {49}, doi = {10.1186/s12974-015-0267-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125036}, year = {2015}, abstract = {Background We could previously identify components of both the innate and the adaptive immune system as disease modifiers in the pathogenesis of models for Charcot-Marie-Tooth (CMT) neuropathies type 1B and 1X. As part of the adaptive immune system, here we investigated the role of antibodies in a model for CMT1B. Methods Antibodies were localized and characterized in peripheral nerves of the CMT1B model by immunohistochemistry and Western blot analysis. Experimental ablation of antibodies was performed by cross breeding the CMT1B models with mutants deficient in B-lymphocytes (JHD-/- mutants). Ameliorated demyelination by antibody deficiency was reverted by intravenous injection of mouse IgG fractions. Histopathological analysis was performed by immunocytochemistry and light and quantitative electron microscopy. Results We demonstrate that in peripheral nerves of a mouse model for CMT1B, endogenous antibodies strongly decorate endoneurial tubes of peripheral nerves. These antibodies comprise IgG and IgM subtypes and are preferentially, but not exclusively, associated with nerve fiber aspects nearby the nodes of Ranvier. In the absence of antibodies, the early demyelinating phenotype is substantially ameliorated. Reverting the neuropathy by reconstitution with murine IgG fractions identified accumulating antibodies as potentially pathogenic at this early stage of disease. Conclusions Our study demonstrates that in a mouse model for CMT1B, endogenous antibodies contribute to early macrophage-mediated demyelination and disease progression. Thus, both the innate and adaptive immune system are mutually interconnected in a genetic model for demyelination. Since in Wallerian degeneration antibodies have also been shown to be involved in myelin phagocytosis, our study supports our view that inherited demyelination and Wallerian degeneration share common mechanisms, which are detrimental when activated under nonlesion conditions.}, language = {en} } @phdthesis{Siedler2018, author = {Siedler, Gabriela Anja}, title = {Elektrisch evozierte Schmerz-assoziierte Potentiale bei Patienten mit small - und large fiber Neuropathien}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167186}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2018}, abstract = {In dieser Studie wurden 108 Patienten mit PNP, 60 Patienten mit M. Fabry und 58 gesunde Kontrollpersonen mittels PREP auf eine small fiber-Pathologie untersucht. Zudem erfolgte eine PREP-Untersuchung bei 5 gesunden Probanden und 3 Patienten nach Anwendung von lokalem Capsaicin. Zur Charakterisierung der small fibers erfolgten zudem Anamnese, klinische Untersuchung, die Frageb{\"o}gen NPSI, GCPS und ADS, QST und eine Hautbiopsie. In der Gruppe der Patienten mit PNP waren sowohl Patienten mit LFN, MFN und SFN unterschiedlicher {\"A}tiologie vertreten. Patienten mit einer MFN und Patienten mit einer zu einer Mitbeteiligung der small fibers passenden Anamnese (MFN und SFN) wiesen eine verl{\"a}ngerte N1-Latenz nach Stimulation am Fuß auf. Bei einer reduzierten IENFD in der proximalen Hautbiopsie zeigte sich die PPA nach Stimulation im Gesicht reduziert, beide Werte korrelierten positiv miteinander. Bei Patienten mit einer demyelinisierenden PNP war die N1-Latenz nach Stimulation an der Hand verl{\"a}ngert, zudem war bei Patienten mit CIDP die PPA nach Stimulation an Gesicht und Hand reduziert. M. Fabry ist eine X-chromosomal vererbte lysosomale Speicherkrankheit, welche mit einer SFN einhergehen kann. Weibliche Patienten mit M. Fabry und einer subjektiven Hypohidrose als klinische Pr{\"a}sentation einer small fiber Pathologie wiesen eine reduzierte PPA nach Stimulation an Gesicht, Hand und Fuß auf. {\"U}ber die gesamte Patientengruppe hinweg zeigte sich eine negative Korrelation der PPA nach Stimulation am Fuß mit der klinischen Schmerzpr{\"a}sentation im NPSI (Summenscore, Subscores evozierte Schmerzen und Schmerzattacken), sowie bei weiblichen Patienten mit der CDT, WDT und TSL in der QST als Marker f{\"u}r die small fiber Funktion. Patienten mit einer l{\"a}ngenunabh{\"a}ngigen Reduktion der IENFD wiesen eine niedrigere PPA nach Stimulation am Fuß auf. Ein nicht-auswertbares PREP-Potential spricht nach Ausschluss messtechnischer Artefakte f{\"u}r eine fortgeschrittene Nervenfasersch{\"a}digung. Probanden und Patienten zeigten nach Applikation von topischem Capsaicin eine Reduktion der PPA. PREP ist eine einfache, komplikationslos durchzuf{\"u}hrende und objektive Methode zur Untersuchung der small fibers. Sie stellt eine sinnvolle Erg{\"a}nzung zu den bereits etablierten Methoden QST und Hautbiopsie dar und bietet insbesondere f{\"u}r die Evaluation von Medikamenteneffekten wie z.B. von topischem Capsaicin eine vielversprechende Untersuchungsm{\"o}glichkeit.}, subject = {Fabry-Krankheit}, language = {de} } @article{KarleSchueleKlebeetal.2013, author = {Karle, Kathrin N. and Sch{\"u}le, Rebecca and Klebe, Stephan and Otto, Susanne and Frischholz, Christian and Liepelt-Scarfone, Inga and Sch{\"o}ls, Ludger}, title = {Electrophysiological characterisation of motor and sensory tracts in patients with hereditary spastic paraplegia (HSP)}, series = {Orphanet Journal of Rare Diseases}, volume = {8}, journal = {Orphanet Journal of Rare Diseases}, number = {158}, issn = {1750-1172}, doi = {10.1186/1750-1172-8-158}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124763}, year = {2013}, abstract = {Background: Hereditary spastic paraplegias (HSPs) are characterised by lower limb spasticity due to degeneration of the corticospinal tract. We set out for an electrophysiological characterisation of motor and sensory tracts in patients with HSP. Methods: We clinically and electrophysiologically examined a cohort of 128 patients with genetically confirmed or clinically probable HSP. Motor evoked potentials (MEPs) to arms and legs, somato-sensory evoked potentials of median and tibial nerves, and nerve conduction studies of tibial, ulnar, sural, and radial nerves were assessed. Results: Whereas all patients showed clinical signs of spastic paraparesis, MEPs were normal in 27\% of patients and revealed a broad spectrum with axonal or demyelinating features in the others. This heterogeneity can at least in part be explained by different underlying genotypes, hinting for distinct pathomechanisms in HSP subtypes. In the largest subgroup, SPG4, an axonal type of damage was evident. Comprehensive electrophysiological testing disclosed a more widespread affection of long fibre tracts involving peripheral nerves and the sensory system in 40\%, respectively. Electrophysiological abnormalities correlated with the severity of clinical symptoms. Conclusions: Whereas HSP is primarily considered as an upper motoneuron disorder, our data suggest a more widespread affection of motor and sensory tracts in the central and peripheral nervous system as a common finding in HSP. The distribution patterns of electrophysiological abnormalities were associated with distinct HSP genotypes and could reflect different underlying pathomechanisms. Electrophysiological measures are independent of symptomatic treatment and may therefore serve as a reliable biomarker in upcoming HSP trials.}, language = {en} } @article{SchuhmannStollPappetal.2019, author = {Schuhmann, Michael K. and Stoll, Guido and Papp, Lena and Bohr, Arne and Volkmann, Jens and Fluri, Felix}, title = {Electrical stimulation of the mesencephalic locomotor region has no impact on blood-brain barrier alterations after cerebral photothrombosis in rats}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {16}, issn = {1422-0067}, doi = {10.3390/ijms20164036}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201284}, year = {2019}, abstract = {Blood-brain barrier (BBB) disruption is a critical event after ischemic stroke, which results in edema formation and hemorrhagic transformation of infarcted tissue. BBB dysfunction following stroke is partly mediated by proinflammatory agents. We recently have shown that high frequency stimulation of the mesencephalic locomotor region (MLR-HFS) exerts an antiapoptotic and anti-inflammatory effect in the border zone of cerebral photothrombotic stroke in rats. Whether MLR-HFS also has an impact on BBB dysfunction in the early stage of stroke is unknown. In this study, rats were subjected to photothrombotic stroke of the sensorimotor cortex and implantation of a stimulating microelectrode into the ipsilesional MLR. Thereafter, either HFS or sham stimulation of the MLR was applied for 24 h. After scarifying the rats, BBB disruption was assessed by determining albumin extravasation and tight junction integrity (claudin 3, claudin 5, and occludin) using Western blot analyses and immunohistochemistry. In addition, by applying zymography, expression of pro-metalloproteinase-9 (pro-MMP-9) was analyzed. No differences were found regarding infarct size and BBB dysfunction between stimulated and unstimulated animals 24 h after induction of stroke. Our results indicate that MLR-HFS neither improves nor worsens the damaged BBB after stroke. Attenuating cytokines/chemokines in the perilesional area, as mediated by MLR-HFS, tend to play a less significant role in preventing the BBB integrity.}, language = {en} } @article{SchuhmannStollBohretal.2019, author = {Schuhmann, Michael K. and Stoll, Guido and Bohr, Arne and Volkmann, Jens and Fluri, Felix}, title = {Electrical stimulation of the mesencephalic locomotor region attenuates neuronal loss and cytokine expression in the perifocal region of photothrombotic stroke in rats}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {9}, issn = {1422-0067}, doi = {10.3390/ijms20092341}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201355}, year = {2019}, abstract = {Deep brain stimulation of the mesencephalic locomotor region (MLR) improves the motor symptoms in Parkinson's disease and experimental stroke by intervening in the motor cerebral network. Whether high-frequency stimulation (HFS) of the MLR is involved in non-motor processes, such as neuroprotection and inflammation in the area surrounding the photothrombotic lesion, has not been elucidated. This study evaluates whether MLR-HFS exerts an anti-apoptotic and anti-inflammatory effect on the border zone of cerebral photothrombotic stroke. Rats underwent photothrombotic stroke of the right sensorimotor cortex and the implantation of a microelectrode into the ipsilesional MLR. After intervention, either HFS or sham stimulation of the MLR was applied for 24 h. The infarct volumes were calculated from consecutive brain sections. Neuronal apoptosis was analyzed by TUNEL staining. Flow cytometry and immunohistochemistry determined the perilesional inflammatory response. Neuronal apoptosis was significantly reduced in the ischemic penumbra after MLR-HFS, whereas the infarct volumes did not differ between the groups. MLR-HFS significantly reduced the release of cytokines and chemokines within the ischemic penumbra. MLR-HFS is neuroprotective and it reduces pro-inflammatory mediators in the area that surrounds the photothrombotic stroke without changing the number of immune cells, which indicates that MLR-HFS enables the function of inflammatory cells to be altered on a molecular level.}, language = {en} } @phdthesis{Sturn2006, author = {Sturn, Anja}, title = {Einfluss von niedrigdosierter Heparinbehandlung auf den Verlauf von Stammganglienblutungen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-19113}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2006}, abstract = {ZIEL: An m{\"o}glichst großer Fallzahl und vergleichbarem Patientenkollektiv zu {\"u}berpr{\"u}fen, ob eine niedrigdosierte Heparintherapie f{\"u}r Patienten mit intracerebralen Blutungen sch{\"a}dliche oder n{\"u}tzliche Auswirkungen hat. METHODEN: retrospektive Analyse von 238 Patienten mit Stammganglienblutungen hinsichtlich Heparinbehandlung sowie operativer vs. konservativer Behandlung und folgende Auswirkung auf Blutungskomplikation, thrombembolische Ereignisse, Mortalit{\"a}t und funktionellem Outcome nach dem GOS. ERGEBNIS: kein Nachblutungsrisiko, durchweg g{\"u}nstigere Prognose f{\"u}r heparinbehandelte Patienten (86\% im Kollektiv), bei tendenziell positiver Patientenselektion, weitere prospektive Studien gerechtfertigt und w{\"u}nschenswert; operative Therapieindikation streng zu stellen}, language = {de} } @phdthesis{Weiss2024, author = {Weiß, Eva Maria}, title = {Einfluss von Makrophagen auf autophagische Vorg{\"a}nge in Schwann´schen Zellen unter den Bedingungen von Nervenl{\"a}sion und genetisch bedingter Neuropathie}, doi = {10.25972/OPUS-36967}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369674}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Charcot-Marie-Tooth (CMT) Neuropathien stellen als h{\"a}ufigste erblich bedingte neurologische Erkrankungen eine Gruppe genetisch heterogener, chronisch progredienter peripherer Polyneuropathien dar. Die Lebensqualit{\"a}t der Patienten ist bei fehlender kurativer Therapieoption vor allem durch motorische und sensorische Defizite deutlich eingeschr{\"a}nkt. In verschiedenen Studien konnte die pathophysiologische Relevanz einer sekund{\"a}ren Entz{\"u}ndungsreaktion, insbesondere durch Makrophagen und Lymphozyten vermittelt, in Mausmodellen dreier CMT1 Subtypen (CMT1A, CMT1B, CMT1X) aufgezeigt werden. Auch in Folge einer L{\"a}sion peripherer Nerven ist eine akute Entz{\"u}ndungsreaktion von entscheidender Bedeutung, wobei sich bereits Gemeinsamkeiten zwischen der postl{\"a}sionalen Waller´schen Degeneration (WD) und CMT1 Neuropathien identifizieren ließen. W{\"a}hrend die aktive Beteiligung der Autophagie Schwann´scher Zellen (hier kurz SZ Autophagie genannt) an der Myelindegradation im Falle einer WD jedoch vielfach beschrieben wurde, ist {\"A}hnliches in CMT1 Neuropathien bisher nur unzureichend untersucht. Da in einer Studie in Cx32def Mausmodellen der CMT1X Erkrankung auch nach Reduktion endoneuraler Makrophagen anhaltende Demyelinisierung beobachtet werden konnte, sollte das Vorkommen von SZ Autophagie sowie deren m{\"o}gliche Beeinflussung durch Makrophagen in diesen Myelinmutanten untersucht werden. In der vorliegenden Arbeit wurden sowohl Wildtyp (Wt) M{\"a}use in ex vivo und in vivo Modellen einer WD als auch Cx32def Myelinmutanten zweier Altersstufen (4 und 12 Monate) mit einem niedermolekularen CSF1-Rezeptor-Inhibitor (CSF1RI) zur Reduktion endoneuraler Makrophagen behandelt, wobei sich vergleichende histochemische bzw. immunhistochemische Analysen peripherer Nerven behandelter und unbehandelter Tiere anschlossen. Im Rahmen der Etablierung immunhistochemischer Methodik zeigte sich hierbei unter den kontrollierten Bedingungen einer ex vivo Ischiasnervenkultur eine vermehrte Aktivierung der SZ Autophagie in behandelten Wt M{\"a}usen. Auch 4 Monate alte behandelte Cx32def Tiere wiesen, verglichen mit unbehandelten Myelinmutanten bzw. Wt M{\"a}usen derselben Altersstufe, eine vermehrte autophagische Aktivit{\"a}t in SZ auf. Diese scheint sich jedoch im weiteren Verlauf der Erkrankung zu reduzieren, da im Falle der 12 Monate alten Cx32def Modelltiere weniger autophagisch aktive SZ Profile bzw. kaum Unterschiede zwischen behandelten und unbehandelten Tieren beobachtet werden konnten. Die Ergebnisse lassen somit eine m{\"o}gliche aktive Beteiligung von SZ Autophagie insbesondere in der Pathophysiologie der fr{\"u}hen Phase einer CMT1X Erkrankung sowie deren Beeinflussung durch endoneurale Makrophagen vermuten. Dies sollte vornehmlich in der Entwicklung von Therapiestrategien der CMT1X bedacht werden, da sich eine fr{\"u}he Reduktion pathophysiologisch relevanter endoneuraler Makrophagen somit auch nachteilig auf die Myelinintegrit{\"a}t auswirken k{\"o}nnte.}, subject = {Schwann-Zelle}, language = {de} } @phdthesis{Wind2020, author = {Wind, Teresa Elisabeth}, title = {Einfluss von Alter und Polyneuropathie auf zeitliche Wahrnehmungsschwellen somatosensorischer und kin{\"a}sthetischer Stimuli und propriozeptive Leistungsf{\"a}higkeit}, doi = {10.25972/OPUS-20804}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-208047}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Zeitliche Diskrimination somatosensorischer und kin{\"a}sthetischer Stimuli wurde als neurophysiologisches Korrelat f{\"u}r propriozeptive Pr{\"a}zision postuliert und bei verschiedenen Bewegungsst{\"o}rungen als pathologisch beschrieben. Ziel der Untersuchung war es, den Einfluss von Alter und Polyneuropathie auf die kin{\"a}sthetische (TDMT) und taktile (STDT) zeitliche Wahrnehmungsschwelle sowie die propriozeptive Genauigkeit bei Zeigeversuchen systematisch zu untersuchen. Hierf{\"u}r wurden 54 gesunde Probanden und 25 Polyneuropathie-Patienten im Alter zwischen 30 und 76 Jahren untersucht. Die STDT-Messung erfolgte mit Oberfl{\"a}chenelektroden, die an der Zeigefingerspitze bzw. am Großzehengrundgelenk angebracht wurden. Die TDMT-Werte wurden mit Hilfe einer sterilen Nadelelektrode erfasst, welche in den Musculus flexor carpi radialis bzw. Musculus tibialis anterior inseriert wurde. Die Daten zur Propriozeption wurden mit Hilfe eines Goniometers erhoben und beinhalteten dabei aktive Zeigeaufgaben (Zeigen auf eine LED, Nachahmung einer Bewegung anhand einer auf einem Computerbildschirm dargebotenen PFEIL-Darstellung unterschiedlicher L{\"a}nge) und die Einsch{\"a}tzung der Position der jeweiligen Extremit{\"a}t nach passiver Bewegung (PASSIV). Die Messungen erfolgten jeweils ohne visuelle R{\"u}ckmeldung. Die Zeigefehler (Abweichung von der Zielposition) bzw. Sch{\"a}tzfehler (Abweichung der gesch{\"a}tzten von der tats{\"a}chlichen Position nach passiver Auslenkung) wurden als Maß der propriozeptiven Pr{\"a}zision verwendet. Die Ergebnisse der gesunden Probandengruppe zeigten, dass h{\"o}heres Alter mit h{\"o}heren STDT- und TDMT-Werten korrelierte. Die Polyneuropathie-Patienten erzielten in allen Bereichen (Diskriminationsschwellen und Propriozeptionsaufgaben) signifikant schlechtere Ergebnisse als die gesunde Kontrollgruppe. Zus{\"a}tzlich konnte eine statistisch signifikante positive Korrelation zwischen der propriozeptiven Pr{\"a}zision bei den aktiven Zeige-Aufgaben (LED und PFEIL) und den zeitlichen Diskriminationsschwellen (STDT und TDMT) gezeigt werden. In Anbetracht dieser Ergebnisse sollten das Patienten-Alter und m{\"o}gliche St{\"o}rungen der peripheren Nervenleitung ber{\"u}cksichtigt werden, wenn STDT-und TDMT-Bestimmungen bei Patienten mit Bewegungsst{\"o}rungen angewendet werden. Die Korrelation zwischen den Diskriminationsschwellen und der Performance bei aktiven Zeigeversuchen (PFEIL- und LED-Aufgabe) legt nahe, dass STDT und TDMT Indikatoren der propriozeptiven Funktion sein k{\"o}nnten. Es ist weitere Forschungsarbeit notwendig, um diese Beziehung exakt zu beleuchten. Im Falle einer Best{\"a}tigung der Befunde auch bei Patienten mit Bewegungsst{\"o}rungen erscheint denkbar, dass sich STDT und TDMT als vergleichsweise leicht messbare und gut quantifizierbare Parameter der Propriozeption herausstellen mit Potenzial zur differenzialdiagnostischen Anwendung, m{\"o}glicherweise aber auch als Surrogatparameter einer gezielten rehabilitativen Behandlung.}, subject = {Propriozeption}, language = {de} } @article{HiewNguemeniZeller2022, author = {Hiew, Shawn and Nguemeni, Carine and Zeller, Daniel}, title = {Efficacy of transcranial direct current stimulation in people with multiple sclerosis: a review}, series = {European Journal of Neurology}, volume = {29}, journal = {European Journal of Neurology}, number = {2}, doi = {10.1111/ene.15163}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259424}, pages = {648-664}, year = {2022}, abstract = {Background and purpose Multiple sclerosis (MS) is a chronic inflammatory disease causing a wide range of symptoms including motor and cognitive impairment, fatigue and pain. Over the last two decades, non-invasive brain stimulation, especially transcranial direct current stimulation (tDCS), has increasingly been used to modulate brain function in various physiological and pathological conditions. However, its experimental applications for people with MS were noted only as recently as 2010 and have been growing since then. The efficacy for use in people with MS remains questionable with the results of existing studies being largely conflicting. Hence, the aim of this review is to paint a picture of the current state of tDCS in MS research grounded on studies applying tDCS that have been done to date. Methods A keyword search was performed to retrieve articles from the earliest article identified until 14 February 2021 using a combination of the groups (1) 'multiple sclerosis', 'MS' and 'encephalomyelitis' and (2) 'tDCS' and 'transcranial direct current stimulation'. Results The analysis of the 30 articles included in this review underlined inconsistent effects of tDCS on the motor symptoms of MS based on small sample sizes. However, tDCS showed promising benefits in ameliorating fatigue, pain and cognitive symptoms. Conclusion Transcranial direct current stimulation is attractive as a non-drug approach in ameliorating MS symptoms, where other treatment options remain limited. The development of protocols tailored to the individual's own neuroanatomy using high definition tDCS and the introduction of network mapping in the experimental designs might help to overcome the variability between studies.}, 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{FlacheneckerBuresGawliketal.2020, author = {Flachenecker, Peter and Bures, Anna Karoline and Gawlik, Angeli and Weiland, Ann-Christin and Kuld, Sarah and Gusowski, Klaus and Streber, Ren{\´e} and Pfeifer, Klaus and Tallner, Alexander}, title = {Efficacy of an internet-based program to promote physical activity and exercise after inpatient rehabilitation in persons with multiple sclerosis: a randomized, single-blind, controlled study}, series = {International Journal of Environmental Research and Public Health}, volume = {17}, journal = {International Journal of Environmental Research and Public Health}, number = {12}, issn = {1660-4601}, doi = {10.3390/ijerph17124544}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-207863}, year = {2020}, abstract = {Background: Multimodal rehabilitation improves fatigue and mobility in persons with multiple sclerosis (PwMS). Effects are transient and may be conserved by internet-based physical activity promotion programs. Objective: Evaluate the effects of internet-based physical activity and exercise promotion on fatigue, quality of life, and gait in PwMS after inpatient rehabilitation. Methods: PwMS (Expanded Disability Status Scale (EDSS) ≤ 6.0, fatigue: W{\"u}rzburg Fatigue Inventory for Multiple Sclerosis (WEIMuS) ≥ 32) were randomized into an intervention group (IG) or a control group (CG). After rehabilitation, IG received 3 months of internet-based physical activity promotion, while CG received no intervention. Primary outcome: self-reported fatigue (WEIMuS). Secondary outcomes: quality of life (Multiple Sclerosis Impact Scale 29, MSIS-29), gait (2min/10m walking test, Tinetti score). Measurements: beginning (T0) and end (T1) of inpatient rehabilitation, 3 (T2) and 6 (T3) months afterwards. Results: 64 of 84 PwMS were analyzed (IG: 34, CG: 30). After rehabilitation, fatigue decreased in both groups. At T2 and T3, fatigue increased again in CG but was improved in IG (p < 0.001). MSIS-29 improved in both groups at T1 but remained improved at T2 and T3 only in IG. Gait improvements were more pronounced in IG at T2. Conclusions: The study provides Class II evidence that the effects of rehabilitation on fatigue, quality of life, and gait can be maintained for 3-6 months with an internet-based physical activity and exercise promotion program.}, language = {en} } @article{SchuhmannFluri2017, author = {Schuhmann, Michael K. and Fluri, Felix}, title = {Effects of fullerenols on mouse brain microvascular endothelial cells}, series = {International Journal of Molecular Sciences}, volume = {18}, journal = {International Journal of Molecular Sciences}, number = {8}, issn = {1422-0067}, doi = {10.3390/ijms18081783}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158072}, year = {2017}, abstract = {Fullerenols, water-soluble C60-fullerene derivatives, have been shown to exert neuroprotective effects in vitro and in vivo, most likely due to their capability to scavenge free radicals. However, little is known about the effects of fullerenols on the blood-brain barrier (BBB), especially on cerebral endothelial cells under inflammatory conditions. Here, we investigated whether the treatment of primary mouse brain microvascular endothelial cells with fullerenols impacts basal and inflammatory blood-brain barrier (BBB) properties in vitro. While fullerenols (1, 10, and 100 µg/mL) did not change transendothelial electrical resistance under basal and inflammatory conditions, 100 µg/mL of fullerenol significantly reduced erk1/2 activation and resulted in an activation of NFκB in an inflammatory milieu. Our findings suggest that fullerenols might counteract oxidative stress via the erk1/2 and NFκB pathways, and thus are able to protect microvascular endothelial cells under inflammatory conditions.}, language = {en} } @phdthesis{Andreska2021, author = {Andreska, Thomas}, title = {Effects of dopamine on BDNF / TrkB mediated signaling and plasticity on cortico-striatal synapses}, doi = {10.25972/OPUS-17431}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-174317}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Progressive loss of voluntary movement control is the central symptom of Parkinson's disease (PD). Even today, we are not yet able to cure PD. This is mainly due to a lack of understanding the mechanisms of movement control, network activity and plasticity in motor circuits, in particular between the cerebral cortex and the striatum. Brain-derived neurotrophic factor (BDNF) has emerged as one of the most important factors for the development and survival of neurons, as well as for synaptic plasticity. It is thus an important target for the development of new therapeutic strategies against neurodegenerative diseases. Together with its receptor, the Tropomyosin receptor kinase B (TrkB), it is critically involved in development and function of the striatum. Nevertheless, little is known about the localization of BDNF within presynaptic terminals in the striatum, as well as the types of neurons that produce BDNF in the cerebral cortex. Furthermore, the influence of midbrain derived dopamine on the control of BDNF / TrkB interaction in striatal medium spiny neurons (MSNs) remains elusive so far. Dopamine, however, appears to play an important role, as its absence leads to drastic changes in striatal synaptic plasticity. This suggests that dopamine could regulate synaptic activity in the striatum via modulation of BDNF / TrkB function. To answer these questions, we have developed a sensitive and reliable protocol for the immunohistochemical detection of endogenous BDNF. We find that the majority of striatal BDNF is provided by glutamatergic, cortex derived afferents and not dopaminergic inputs from the midbrain. In fact, we found BDNF in cell bodies of neurons in layers II-III and V of the primary and secondary motor cortex as well as layer V of the somatosensory cortex. These are the brain areas that send dense projections to the dorsolateral striatum for control of voluntary movement. Furthermore, we could show that these projection neurons significantly downregulate the expression of BDNF during the juvenile development of mice between 3 and 12 weeks. In parallel, we found a modulatory effect of dopamine on the translocation of TrkB to the cell surface in postsynaptic striatal Medium Spiny Neurons (MSNs). In MSNs of the direct pathway (dMSNs), which express dopamine receptor 1 (DRD1), we observed the formation of TrkB aggregates in the 6-hydroxydopamine (6-OHDA) model of PD. This suggests that DRD1 activity controls TrkB surface expression in these neurons. In contrast, we found that DRD2 activation has opposite effects in MSNs of the indirect pathway (iMSNs). Activation of DRD2 promotes a rapid decrease in TrkB surface expression which was reversible and depended on cAMP. In parallel, stimulation of DRD2 led to induction of phospho-TrkB (pTrkB). This effect was significantly slower than the effect on TrkB surface expression and indicates that TrkB is transactivated by DRD2. Together, our data provide evidence that dopamine triggers dual modes of plasticity on striatal MSNs by acting on TrkB surface expression in DRD1 and DRD2 expressing MSNs. This surface expression of the receptor is crucial for the binding of BDNF, which is released from corticostriatal afferents. This leads to the induction of TrkB-mediated downstream signal transduction cascades and long-term potentiation (LTP). Therefore, the dopamine-mediated translocation of TrkB could be a mediator that modulates the balance between dopaminergic and glutamatergic signaling to allow synaptic plasticity in a spatiotemporal manner. This information and the fact that TrkB is segregated to persistent aggregates in PD could help to improve our understanding of voluntary movement control and to develop new therapeutic strategies beyond those focusing on dopaminergic supply.}, subject = {Brain-derived neurotrophic factor}, language = {en} } @article{KleinGrohYuanetal.2022, author = {Klein, Dennis and Groh, Janos and Yuan, Xidi and Berve, Kristina and Stassart, Ruth and Fledrich, Robert and Martini, Rudolf}, title = {Early targeting of endoneurial macrophages alleviates the neuropathy and affects abnormal Schwann cell differentiation in a mouse model of Charcot-Marie-Tooth 1A}, series = {Glia}, volume = {70}, journal = {Glia}, number = {6}, doi = {10.1002/glia.24158}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318714}, pages = {1100 -- 1116}, year = {2022}, abstract = {We have previously shown that targeting endoneurial macrophages with the orally applied CSF-1 receptor specific kinase (c-FMS) inhibitor PLX5622 from the age of 3 months onwards led to a substantial alleviation of the neuropathy in mouse models of Charcot-Marie-Tooth (CMT) 1X and 1B disease, which are genetically-mediated nerve disorders not treatable in humans. The same approach failed in a model of CMT1A (PMP22-overexpressing mice, line C61), representing the most frequent form of CMT. This was unexpected since previous studies identified macrophages contributing to disease severity in the same CMT1A model. Here we re-approached the possibility of alleviating the neuropathy in a model of CMT1A by targeting macrophages at earlier time points. As a proof-of-principle experiment, we genetically inactivated colony-stimulating factor-1 (CSF-1) in CMT1A mice, which resulted in lower endoneurial macrophage numbers and alleviated the neuropathy. Based on these observations, we pharmacologically ablated macrophages in newborn CMT1A mice by feeding their lactating mothers with chow containing PLX5622, followed by treatment of the respective progenies after weaning until the age of 6 months. We found that peripheral neuropathy was substantially alleviated after early postnatal treatment, leading to preserved motor function in CMT1A mice. Moreover, macrophage depletion affected the altered Schwann cell differentiation phenotype. These findings underscore the targetable role of macrophage-mediated inflammation in peripheral nerves of inherited neuropathies, but also emphasize the need for an early treatment start confined to a narrow therapeutic time window in CMT1A models and potentially in respective patients.}, language = {en} } @article{KleinschnitzMenclGarzetal.2013, author = {Kleinschnitz, Christoph and Mencl, Stine and Garz, Cornelia and Niklass, Solveig and Braun, Holger and G{\"o}b, Eva and Homola, Gy{\"o}rgy and Heinze, Hans-Jochen and Reymann, Klaus G. and Schreiber, Stefanie}, title = {Early microvascular dysfunction in cerebral small vessel disease is not detectable on 3.0 Tesla magnetic resonance imaging: a longitudinal study in spontaneously hypertensive stroke-prone rats}, series = {Experimental \& Translational Stroke Medicine}, journal = {Experimental \& Translational Stroke Medicine}, doi = {10.1186/2040-7378-5-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97056}, year = {2013}, abstract = {Background Human cerebral small vessel disease (CSVD) has distinct histopathologic and imaging findings in its advanced stages. In spontaneously hypertensive stroke-prone rats (SHRSP), a well-established animal model of CSVD, we recently demonstrated that cerebral microangiopathy is initiated by early microvascular dysfunction leading to the breakdown of the blood-brain barrier and an activated coagulatory state resulting in capillary and arteriolar erythrocyte accumulations (stases). In the present study, we investigated whether initial microvascular dysfunction and other stages of the pathologic CSVD cascade can be detected by serial magnetic resonance imaging (MRI). Findings Fourteen SHRSP and three control (Wistar) rats (aged 26-44 weeks) were investigated biweekly by 3.0 Tesla (3 T) MRI. After perfusion, brains were stained with hematoxylin-eosin and histology was correlated with MRI data. Three SHRSP developed terminal CSVD stages including cortical, hippocampal, and striatal infarcts and macrohemorrhages, which could be detected consistently by MRI. Corresponding histology showed small vessel thromboses and increased numbers of small perivascular bleeds in the infarcted areas. However, 3 T MRI failed to visualize intravascular erythrocyte accumulations, even in those brain regions with the highest densities of affected vessels and the largest vessels affected by stases, as well as failing to detect small perivascular bleeds. Conclusion Serial MRI at a field strength of 3 T failed to detect the initial microvascular dysfunction and subsequent small perivascular bleeds in SHRSP; only terminal stages of cerebral microangiopathy were reliably detected. Further investigations at higher magnetic field strengths (7 T) using blood- and flow-sensitive sequences are currently underway.}, language = {en} } @article{BurlinaSimsPoliteietal.2011, author = {Burlina, Alessandro P. and Sims, Katherine B. and Politei, Juan M. and Bennett, Gary J. and Baron, Ralf and Sommer, Claudia and Moller, Anette Torvin and Hilz, Max J.}, title = {Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel}, series = {BMC Neurology}, volume = {11}, journal = {BMC Neurology}, number = {61}, doi = {10.1186/1471-2377-11-61}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135309}, pages = {1-11}, year = {2011}, abstract = {Background: Fabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of lipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fibers are particularly affected and small fiber peripheral neuropathy often clinically manifests at young age. Peripheral pain can be chronic and/or occur as provoked attacks of excruciating pain. Manifestations of dysfunction of small autonomic fibers may include, among others, impaired sweating, gastrointestinal dysmotility, and abnormal pain perception. Patients with Fabry disease often remain undiagnosed until severe complications involving the kidney, heart, peripheral nerves and/or brain have arisen. Methods: An international expert panel convened with the goal to provide guidance to clinicians who may encounter unrecognized patients with Fabry disease on how to diagnose these patients early using simple diagnostic tests. A further aim was to offer recommendations to control neuropathic pain. Results: We describe the neuropathy in Fabry disease, focusing on peripheral small fiber dysfunction - the hallmark of early neurologic involvement in this disorder. The clinical course of peripheral pain is summarized, and the importance of medical history-taking, including family history, is highlighted. A thorough physical examination (e. g., angiokeratoma, corneal opacities) and simple non-invasive sensory perception tests could provide clues to the diagnosis of Fabry disease. Reported early clinical benefits of enzyme replacement therapy include reduction of neuropathic pain, and adequate management of residual pain to a tolerable and functional level can substantially improve the quality of life for patients. Conclusions: Our recommendations can assist in diagnosing Fabry small fiber neuropathy early, and offer clinicians guidance in controlling peripheral pain. This is particularly important since management of pain in young patients with Fabry disease appears to be inadequate.}, language = {en} } @article{SpitzelWagnerBreyeretal.2022, author = {Spitzel, Marlene and Wagner, Elise and Breyer, Maximilian and Henniger, Dorothea and Bayin, Mehtap and Hofmann, Lukas and Mauceri, Daniela and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan}, title = {Dysregulation of immune response mediators and pain-related ion channels is associated with pain-like behavior in the GLA KO mouse model of Fabry disease}, series = {Cells}, volume = {11}, journal = {Cells}, number = {11}, issn = {2073-4409}, doi = {10.3390/cells11111730}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-275186}, year = {2022}, abstract = {Fabry disease (FD) is a rare life-threatening disorder caused by deficiency of the alpha-galactosidase A (GLA) enzyme with a characteristic pain phenotype. Impaired GLA production or function leads to the accumulation of the cell membrane compound globotriaosylceramide (Gb3) in the neurons of the dorsal root ganglia (DRG) of FD patients. Applying immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT PCR) analysis on DRG tissue of the GLA knockout (KO) mouse model of FD, we address the question of how Gb3 accumulation may contribute to FD pain and focus on the immune system and pain-associated ion channel gene expression. We show a higher Gb3 load in the DRG of young (<6 months) (p < 0.01) and old (≥12 months) (p < 0.001) GLA KO mice compared to old wildtype (WT) littermates, and an overall suppressed immune response in the DRG of old GLA KO mice, represented by a reduced number of CD206\(^+\) macrophages (p < 0.01) and lower gene expression levels of the inflammation-associated targets interleukin(IL)1b (p < 0.05), IL10 (p < 0.001), glial fibrillary acidic protein (GFAP) (p < 0.05), and leucine rich alpha-2-glycoprotein 1 (LRG1) (p < 0.01) in the DRG of old GLA KO mice compared to old WT. Dysregulation of immune-related genes may be linked to lower gene expression levels of the pain-associated ion channels calcium-activated potassium channel 3.1 (KCa3.1) and transient receptor potential ankyrin 1 channel (TRPA1). Ion channel expression might further be disturbed by impaired sphingolipid recruitment mediated via the lipid raft marker flotillin-1 (FLOT1). This impairment is represented by an increased number of FLOT1\(^+\) DRG neurons with a membranous expression pattern in old GLA KO mice compared to young GLA KO, young WT, and old WT mice (p < 0.001 each). Further, we provide evidence for aberrant behavior of GLA KO mice, which might be linked to dysregulated ion channel gene expression levels and disturbed FLOT1 distribution patterns. Behavioral testing revealed mechanical hypersensitivity in young (p < 0.01) and old (p < 0.001) GLA KO mice compared to WT, heat hypersensitivity in young GLA KO mice (p < 0.001) compared to WT, age-dependent heat hyposensitivity in old GLA KO mice (p < 0.001) compared to young GLA KO mice, and cold hyposensitivity in young (p < 0.001) and old (p < 0.001) GLA KO mice compared to WT, which well reflects the clinical phenotype observed in FD patients.}, language = {en} } @article{SimonRauskolbGunnersenetal.2015, author = {Simon, Christian M. and Rauskolb, Stefanie and Gunnersen, Jennifer M. and Holtmann, Bettina and Drepper, Carsten and Dombert, Benjamin and Braga, Massimiliano and Wiese, Stefan and Jablonka, Sibylle and P{\"u}hringer, Dirk and Zielasek, J{\"u}rgen and Hoeflich, Andreas and Silani, Vincenzo and Wolf, Eckhard and Kneitz, Susanne and Sommer, Claudia and Toyka, Klaus V. and Sendtner, Michael}, title = {Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy}, series = {Acta Neuropathologica}, volume = {130}, journal = {Acta Neuropathologica}, doi = {10.1007/s00401-015-1446-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154569}, pages = {373 -- 387}, year = {2015}, abstract = {Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes.The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor(IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP.}, language = {en} } @article{AndreskaLueningschroerWolfetal.2023, author = {Andreska, Thomas and L{\"u}ningschr{\"o}r, Patrick and Wolf, Daniel and McFleder, Rhonda L. and Ayon-Olivas, Maurilyn and Rattka, Marta and Drechsler, Christine and Perschin, Veronika and Blum, Robert and Aufmkolk, Sarah and Granado, Noelia and Moratalla, Rosario and Sauer, Markus and Monoranu, Camelia and Volkmann, Jens and Ip, Chi Wang and Stigloher, Christian and Sendtner, Michael}, title = {DRD1 signaling modulates TrkB turnover and BDNF sensitivity in direct pathway striatal medium spiny neurons}, series = {Cell Reports}, volume = {42}, journal = {Cell Reports}, number = {6}, doi = {10.1016/j.celrep.2023.112575}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349932}, year = {2023}, abstract = {Highlights • Dopamine receptor-1 activation induces TrkB cell-surface expression in striatal neurons • Dopaminergic deficits cause TrkB accumulation and clustering in the ER • TrkB clusters colocalize with cargo receptor SORCS-2 in direct pathway striatal neurons • Intracellular TrkB clusters fail to fuse with lysosomes after dopamine depletion Summary Disturbed motor control is a hallmark of Parkinson's disease (PD). Cortico-striatal synapses play a central role in motor learning and adaption, and brain-derived neurotrophic factor (BDNF) from cortico-striatal afferents modulates their plasticity via TrkB in striatal medium spiny projection neurons (SPNs). We studied the role of dopamine in modulating the sensitivity of direct pathway SPNs (dSPNs) to BDNF in cultures of fluorescence-activated cell sorting (FACS)-enriched D1-expressing SPNs and 6-hydroxydopamine (6-OHDA)-treated rats. DRD1 activation causes enhanced TrkB translocation to the cell surface and increased sensitivity for BDNF. In contrast, dopamine depletion in cultured dSPN neurons, 6-OHDA-treated rats, and postmortem brain of patients with PD reduces BDNF responsiveness and causes formation of intracellular TrkB clusters. These clusters associate with sortilin related VPS10 domain containing receptor 2 (SORCS-2) in multivesicular-like structures, which apparently protects them from lysosomal degradation. Thus, impaired TrkB processing might contribute to disturbed motor function in PD.}, language = {en} } @article{JaenschEvdokimovEgenolfetal.2024, author = {J{\"a}nsch, Sarah and Evdokimov, Dimitar and Egenolf, Nadine and Meyer zu Altenschildesche, Caren and Kreß, Luisa and {\"U}{\c{c}}eyler, Nurcan}, title = {Distinguishing fibromyalgia syndrome from small fiber neuropathy: a clinical guide}, series = {Pain Reports}, volume = {9}, journal = {Pain Reports}, number = {1}, doi = {10.1097/PR9.0000000000001136}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350306}, year = {2024}, abstract = {Introduction: Fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) are distinct pain conditions that share commonalities and may be challenging as for differential diagnosis. Objective: To comprehensively investigate clinical characteristics of women with FMS and SFN to determine clinically applicable parameters for differentiation. Methods: We retrospectively analyzed medical records of 158 women with FMS and 53 with SFN focusing on pain-specific medical and family history, accompanying symptoms, additional diseases, and treatment. We investigated data obtained using standardized pain, depression, and anxiety questionnaires. We further analyzed test results and findings obtained in standardized small fiber tests. Results: FMS patients were on average ten years younger at symptom onset, described higher pain intensities requiring frequent change of pharmaceutics, and reported generalized pain compared to SFN. Pain in FMS was accompanied by irritable bowel or sleep disturbances, and in SFN by paresthesias, numbness, and impaired glucose metabolism (P < 0.01 each). Family history was informative for chronic pain and affective disorders in FMS (P < 0.001) and for neurological disorders in SFN patients (P < 0.001). Small fiber pathology in terms of skin denervation and/or thermal sensory threshold elevation was present in 110/158 (69.7 \%) FMS patients and 39/53 (73.6 \%) SFN patients. FMS patients mainly showed proximally reduced skin innervation and higher corneal nerve branch densities (p<0.001) whereas SFN patients were characterized by reduced cold detection and prolonged electrical A-delta conduction latencies (P < 0.05). Conclusions: Our data show that FMS and SFN differ substantially. Detailed pain, drug and family history, investigating blood glucose metabolism, and applying differential small fiber tests may help to improve diagnostic differentiation and targeted therapy.}, language = {en} } @article{ErbacherVaknineMoshitzkyetal.2022, author = {Erbacher, Christoph and Vaknine, Shani and Moshitzky, Gilli and Lobentanzer, Sebastian and Eisenberg, Lina and Evdokimov, Dimitar and Sommer, Claudia and Greenberg, David S. and Soreq, Hermona and {\"U}{\c{c}}eyler, Nurcan}, title = {Distinct CholinomiR blood cell signature as a potential modulator of the cholinergic system in women with fibromyalgia syndrome}, series = {Cells}, volume = {11}, journal = {Cells}, number = {8}, issn = {2073-4409}, doi = {10.3390/cells11081276}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270686}, year = {2022}, abstract = {Fibromyalgia syndrome (FMS) is a heterogeneous chronic pain syndrome characterized by musculoskeletal pain and other key co-morbidities including fatigue and a depressed mood. FMS involves altered functioning of the central and peripheral nervous system (CNS, PNS) and immune system, but the specific molecular pathophysiology remains unclear. Anti-cholinergic treatment is effective in FMS patient subgroups, and cholinergic signaling is a strong modulator of CNS and PNS immune processes. Therefore, we used whole blood small RNA-sequencing of female FMS patients and healthy controls to profile microRNA regulators of cholinergic transcripts (CholinomiRs). We compared microRNA profiles with those from Parkinson's disease (PD) patients with pain as disease controls. We validated the sequencing results with quantitative real-time PCR (qRT-PCR) and identified cholinergic targets. Further, we measured serum cholinesterase activity in FMS patients and healthy controls. Small RNA-sequencing revealed FMS-specific changes in 19 CholinomiRs compared to healthy controls and PD patients. qRT-PCR validated miR-182-5p upregulation, distinguishing FMS patients from healthy controls. mRNA targets of CholinomiRs bone morphogenic protein receptor 2 and interleukin 6 signal transducer were downregulated. Serum acetylcholinesterase levels and cholinesterase activity in FMS patients were unchanged. Our findings identified an FMS-specific CholinomiR signature in whole blood, modulating immune-related gene expression.}, language = {en} } @article{BolzoniEspostiMarcheseetal.2018, author = {Bolzoni, Francesco and Esposti, Roberto and Marchese, Silvia M. and Pozzi, Nicol{\´o} G. and Ramirez-Pasos, Uri E. and Isaias, Ioannis U. and Cavallari, Paolo}, title = {Disrupt of intra-limb APA pattern in parkinsonian patients performing index-finger flexion}, series = {Frontiers in Physiology}, volume = {9}, journal = {Frontiers in Physiology}, issn = {1664-042X}, doi = {10.3389/fphys.2018.01745}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369245}, year = {2018}, abstract = {Voluntary movements induce postural perturbations which are counteracted by anticipatory postural adjustments (APAs). These actions are known to build up long fixation chains toward available support points (inter-limb APAs), so as to grant whole body equilibrium. Moreover, recent studies highlighted that APAs also build-up short fixation chains, within the same limb where a distal segment is moved (intra-limb APAs), aimed at stabilizing the proximal segments. The neural structures generating intra-limb APAs still need investigations; the present study aims to compare focal movement kinematics and intra-limb APA latencies and pattern between healthy subjects and parkinsonian patients, assuming the latter as a model of basal ganglia dysfunction. Intra-limb APAs that stabilize the arm when the index-finger is briskly flexed were recorded in 13 parkinsonian patients and in 10 age-matched healthy subjects. Index-finger movement was smaller in parkinsonian patients vs. healthy subjects (p = 0.01) and more delayed with respect to the onset of the prime mover flexor digitorum superficialis (FDS, p < 0.0001). In agreement with the literature, in all healthy subjects the FDS activation was preceded by an inhibitory intra-limb APA in biceps brachii (BB) and anterior deltoid (AD), and almost simultaneous to an excitatory intra-limb APA in triceps brachii (TB). In parkinsonian patients, no significant differences were found for TB and AD intra-limb APA timings, however only four patients showed an inhibitory intra-limb APA in BB, while other four did not show any BB intra-limb APAs and five actually developed a BB excitation. The frequency of occurrence of normal sign, lacking, and inverted BB APAs was different in healthy vs. parkinsonian participants (p = 0.0016). The observed alterations in index-finger kinematics and intra-limb APA pattern in parkinsonian patients suggest that basal ganglia, in addition to shaping the focal movement, may also contribute to intra-limb APA control.}, language = {en} } @article{SteigerwaldMuellerJohannesetal.2016, author = {Steigerwald, Frank and M{\"u}ller, Lorenz and Johannes, Silvia and Matthies, Cordula and Volkmann, Jens}, title = {Directional deep brain stimulation of the subthalamic nucleus: a pilot study using a novel neurostimulation device}, series = {Movement Disorders}, volume = {31}, journal = {Movement Disorders}, number = {8}, doi = {10.1002/mds.26669}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-187683}, pages = {1240-1243}, year = {2016}, abstract = {Introduction A novel neurostimulation system allows steering current in horizontal directions by combining segmented leads and multiple independent current control. The aim of this study was to evaluate directional DBS effects on parkinsonian motor features and adverse effects of subthalamic neurostimulation. Methods Seven PD patients implanted with the novel directional DBS system for bilateral subthalamic DBS underwent an extended monopolar review session during the first postoperative week, in which current thresholds were determined for rigidity control and stimulation-induced adverse effects using either directional or ring-mode settings. Results Effect or adverse effect thresholds were modified by directional settings for each of the 14 STN leads. Magnitude of change varied markedly between leads, as did orientation of optimal horizontal current steering. Conclusion Directional current steering through chronically implanted segmented electrodes is feasible, alters adverse effect and efficacy thresholds in a highly individual manner, and expands the therapeutic window in a monopolar review as compared to ring-mode DBS.}, language = {en} } @article{SchuhmannLanghauserZimmermannetal.2023, author = {Schuhmann, Michael K. and Langhauser, Friederike and Zimmermann, Lena and Bellut, Maximilian and Kleinschnitz, Christoph and Fluri, Felix}, title = {Dimethyl fumarate attenuates lymphocyte infiltration and reduces infarct size in experimental stroke}, series = {International journal of molecular sciences}, volume = {24}, journal = {International journal of molecular sciences}, number = {21}, doi = {10.3390/ijms242115540}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357731}, year = {2023}, abstract = {Ischemic stroke is associated with exacerbated tissue damage caused by the activation of immune cells and the initiation of other inflammatory processes. Dimethyl fumarate (DMF) is known to modulate the immune response, activate antioxidative pathways, and improve the blood-brain barrier (BBB) after stroke. However, the specific impact of DMF on immune cells after cerebral ischemia remains unclear. In our study, male mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 min and received oral DMF (15 mg/kg) or a vehicle immediately after tMCAO, followed by twice-daily administrations for 7 days. Infarct volume was assessed on T2-weighted magnetic resonance images on days 1 and 7 after tMCAO. Brain-infiltrating immune cells (lymphocytes, monocytes) and microglia were quantified using fluorescence-activated cell sorting. DMF treatment significantly reduced infarct volumes and brain edema. On day 1 after tMCAO, DMF-treated mice showed reduced lymphocyte infiltration compared to controls, which was not observed on day 7. Monocyte and microglial cell counts did not differ between groups on either day. In the acute phase of stroke, DMF administration attenuated lymphocyte infiltration, probably due to its stabilizing effect on the BBB. This highlights the potential of DMF as a therapeutic candidate for mitigating immune cell-driven damage in stroke.}, language = {en} } @article{KarlGriesshammerUeceyleretal.2017, author = {Karl, Franziska and Grießhammer, Anne and {\"U}{\c{c}}eyler, Nurcan and Sommer, Claudia}, title = {Differential Impact of miR-21 on Pain and Associated Affective and Cognitive Behavior after Spared Nerve Injury in B7-H1 ko Mouse}, series = {Frontiers in Molecular Neuroscience}, volume = {10}, journal = {Frontiers in Molecular Neuroscience}, number = {219}, doi = {10.3389/fnmol.2017.00219}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170722}, year = {2017}, abstract = {MicroRNAs (miRNAs) are increasingly recognized as regulators of immune and neuronal gene expression and are potential master switches in neuropathic pain pathophysiology. miR-21 is a promising candidate that may link the immune and the pain system. To investigate the pathophysiological role of miR-21 in neuropathic pain, we assessed mice deficient of B7 homolog 1 (B7-H1), a major inhibitor of inflammatory responses. In previous studies, an upregulation of miR-21 had been shown in mouse lymphocytes. Young (8 weeks), middle-aged (6 months), and old (12 months) B7-H1 ko mice and wildtype littermates (WT) received a spared nerve injury (SNI). We assessed thermal withdrawal latencies and mechanical withdrawal thresholds. Further, we performed tests for anxiety-like and cognitive behavior. Quantitative real time PCR was used to determine miR-21 relative expression in peripheral nerves, and dorsal root ganglia (DRG) at distinct time points after SNI. We found mechanical hyposensitivity with increasing age of na{\"i}ve B7-H1 ko mice. Young and middle-aged B7-H1 ko mice were more sensitive to mechanical stimuli compared to WT mice (young: p < 0.01, middle-aged: p < 0.05). Both genotypes developed mechanical and heat hypersensitivity (p < 0.05) after SNI, without intergroup differences. No relevant differences were found after SNI in three tests for anxiety like behavior in B7-H1 ko and WT mice. Also, SNI had no effect on cognition. B7-H1 ko and WT mice showed a higher miR-21 expression (p < 0.05) and invasion of macrophages and T cells in the injured nerve 7 days after SNI without intergroup differences. Our study reveals that increased miR-21 expression in peripheral nerves after SNI is associated with reduced mechanical and heat withdrawal thresholds. These results point to a role of miR-21 in the pathophysiology of neuropathic pain, while affective behavior and cognition seem to be spared. Contrary to expectations, B7-H1 ko mice did not show higher miR-21 expression than WT mice, thus, a B7-H1 knockout may be of limited relevance for the study of miR-21 related pain.}, language = {en} } @article{BailNotzRovitusoetal.2017, author = {Bail, Kathrin and Notz, Quirin and Rovituso, Damiano M. and Schampel, Andrea and Wunsch, Marie and Koeniger, Tobias and Schropp, Verena and Bharti, Richa and Scholz, Claus-Juergen and Foerstner, Konrad U. and Kleinschnitz, Christoph and Kuerten, Stefanie}, title = {Differential effects of FTY720 on the B cell compartment in a mouse model of multiple sclerosis.}, series = {Journal of Neuroinflammation}, volume = {14}, journal = {Journal of Neuroinflammation}, number = {148}, doi = {10.1186/s12974-017-0924-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157869}, year = {2017}, abstract = {Background: MP4-induced experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS), which enables targeted research on B cells, currently much discussed protagonists in MS pathogenesis. Here, we used this model to study the impact of the S1P1 receptor modulator FTY720 (fingolimod) on the autoreactive B cell and antibody response both in the periphery and the central nervous system (CNS). Methods: MP4-immunized mice were treated orally with FTY720 for 30 days at the peak of disease or 50 days after EAE onset. The subsequent disease course was monitored and the MP4-specific B cell/antibody response was measured by ELISPOT and ELISA. RNA sequencing was performed to determine any effects on B cell-relevant gene expression. S1P\(_{1}\) receptor expression by peripheral T and B cells, B cell subset distribution in the spleen and B cell infiltration into the CNS were studied by flow cytometry. The formation of B cell aggregates and of tertiary lymphoid organs (TLOs) was evaluated by histology and immunohistochemistry. Potential direct effects of FTY720 on B cell aggregation were studied in vitro. Results: FTY720 significantly attenuated clinical EAE when treatment was initiated at the peak of EAE. While there was a significant reduction in the number of T cells in the blood after FTY720 treatment, B cells were only slightly diminished. Yet, there was evidence for the modulation of B cell receptor-mediated signaling upon FTY720 treatment. In addition, we detected a significant increase in the percentage of B220\(^{+}\) B cells in the spleen both in acute and chronic EAE. Whereas acute treatment completely abrogated B cell aggregate formation in the CNS, the numbers of infiltrating B cells and plasma cells were comparable between vehicle- and FTY720-treated mice. In addition, there was no effect on already developed aggregates in chronic EAE. In vitro B cell aggregation assays suggested the absence of a direct effect of FTY720 on B cell aggregation. However, FTY720 impacted the evolution of B cell aggregates into TLOs. Conclusions: The data suggest differential effects of FTY720 on the B cell compartment in MP4-induced EAE.}, 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{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{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-191312}, 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{HeckerGruenerHartmannsbergeretal.2023, author = {Hecker, Katharina and Gr{\"u}ner, Julia and Hartmannsberger, Beate and Appeltshauser, Luise and Villmann, Carmen and Sommer, Claudia and Doppler, Kathrin}, title = {Different binding and pathogenic effect of neurofascin and contactin-1 autoantibodies in autoimmune nodopathies}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1189734}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320395}, year = {2023}, abstract = {Introduction IgG4 autoantibodies against paranodal proteins are known to induce acute-onset and often severe sensorimotor autoimmune neuropathies. How autoantibodies reach their antigens at the paranode in spite of the myelin barrier is still unclear. Methods We performed in vitro incubation experiments with patient sera on unfixed and unpermeabilized nerve fibers and in vivo intraneural and intrathecal passive transfer of patient IgG to rats, to explore the access of IgG autoantibodies directed against neurofascin-155 and contactin-1 to the paranodes and their pathogenic effect. Results We found that in vitro incubation resulted in weak paranodal binding of anti-contactin-1 autoantibodies whereas anti-neurofascin-155 autoantibodies bound to the nodes more than to the paranodes. After short-term intraneural injection, no nodal or paranodal binding was detectable when using anti-neurofascin-155 antibodies. After repeated intrathecal injections, nodal more than paranodal binding could be detected in animals treated with anti-neurofascin-155, accompanied by sensorimotor neuropathy. In contrast, no paranodal binding was visible in rats intrathecally injected with anti-contactin-1 antibodies, and animals remained unaffected. Conclusion These data support the notion of different pathogenic mechanisms of anti-neurofascin-155 and anti-contactin-1 autoantibodies and different accessibility of paranodal and nodal structures.}, language = {en} } @article{PolatWohllebenKosmalaetal.2022, author = {Polat, B{\"u}lent and Wohlleben, Gisela and Kosmala, Rebekka and Lisowski, Dominik and Mantel, Frederick and Lewitzki, Victor and L{\"o}hr, Mario and Blum, Robert and Herud, Petra and Flentje, Michael and Monoranu, Camelia-Maria}, title = {Differences in stem cell marker and osteopontin expression in primary and recurrent glioblastoma}, series = {Cancer Cell International}, volume = {22}, journal = {Cancer Cell International}, issn = {1475-2867}, doi = {10.1186/s12935-022-02510-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301240}, year = {2022}, abstract = {Background Despite of a multimodal approach, recurrences can hardly be prevented in glioblastoma. This may be in part due to so called glioma stem cells. However, there is no established marker to identify these stem cells. Methods Paired samples from glioma patients were analyzed by immunohistochemistry for expression of the following stem cell markers: CD133, Musashi, Nanog, Nestin, octamer-binding transcription factor 4 (Oct4), and sex determining region Y-box 2 (Sox2). In addition, the expression of osteopontin (OPN) was investigated. The relative number of positively stained cells was determined. By means of Kaplan-Meier analysis, a possible association with overall survival by marker expression was investigated. Results Sixty tissue samples from 30 patients (17 male, 13 female) were available for analysis. For Nestin, Musashi and OPN a significant increase was seen. There was also an increase (not significant) for CD133 and Oct4. Patients with mutated Isocitrate Dehydrogenase-1/2 (IDH-1/2) status had a reduced expression for CD133 and Nestin in their recurrent tumors. Significant correlations were seen for CD133 and Nanog between OPN in the primary and recurrent tumor and between CD133 and Nestin in recurrent tumors. By confocal imaging we could demonstrate a co-expression of CD133 and Nestin within recurrent glioma cells. Patients with high CD133 expression had a worse prognosis (22.6 vs 41.1 months, p = 0.013). A similar trend was seen for elevated Nestin levels (24.9 vs 41.1 months, p = 0.08). Conclusions Most of the evaluated markers showed an increased expression in their recurrent tumor. CD133 and Nestin were associated with survival and are candidate markers for further clinical investigation.}, language = {en} } @phdthesis{Schmid2007, author = {Schmid, Harriet}, title = {Die Wirkung des Phosphodiesterase-IV-Inhibitors Mesopram auf Faktoren der Blut-Hirn-Schranke}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-26345}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2007}, abstract = {Multiple Sklerose ist eine chronisch degenerative Erkrankung des ZNS, deren Therapie-m{\"o}glichkeiten noch immer begrenzt sind. In der vorliegenden Arbeit wurde in vitro der selektive PDE-IV-Inhibitor Mesopram untersucht, welcher bereits in einer Phase II Studie bei Patienten mit klinisch gesicherter MS zum Einsatz kommt. Anhand von HBMEC's, die als ein Model der menschlichen BHS gelten, konnten TJ's (ZO-1, Claudin-3, Occludin), Adh{\"a}sionsmolek{\"u}le (ICAM, VCAM, MCAM), Zytokine und Chemokine (AR, Il-6, MCP-1, Il-8) und MMP-2 nachgewiesen werden. Diese Faktoren sind bei der Zerst{\"o}rung der BHS in der Pathologie der MS beteiligt. Die Idee dieser Arbeit war es, durch die spezifische PDE-IV-Inhibition mit Mesopram die untersuchten Faktoren der BHS so zu beeinflussen, dass eine weitere Permeabilit{\"a}tserh{\"o}hung verhindert werden k{\"o}nnte. Da es sich bei MS um eine inflammatorische Erkrankung handelt und TNF\&\#945; in MS-L{\"a}sionen gefunden wird, wurde in dieser Arbeit TNF\&\#945; als inflammatorischer Stimulus verwendet. Unter TNF\&\#945;-Stimulation wurden die meisten der genannten Faktoren vermehrt exprimiert. Keine Ver{\"a}nderung unter TNF\&\#945; zeigten Occludin, ZO-1, VCAM und MMP-2. Die HBMEC's wurden {\"u}ber 24 und 48 h mit TNF\&\#945; und Mesopram stimuliert. Es konnte in den unterschiedlichen Auswertungen (ELISA, FACS, Western Blot, Zymographie) keine regulatorische Modulation der verschiedenen Faktoren unter Mesopram-induzierter cAMP-Erh{\"o}hung nachgewiesen werden.}, subject = {Blut-Hirn-Schranke}, language = {de} } @phdthesis{Lintner2022, author = {Lintner, Hannes}, title = {Die Wertigkeit des Liquorbiomarkers CXCL-13 in der Diagnostik der Neuroborreliose und anderer neuroinflammatorischer Erkrankungen}, doi = {10.25972/OPUS-26047}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260471}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Zu den h{\"a}ufigsten Symptomen der Neuroborreliose z{\"a}hlen Meningopolyradikulitis, lymphozyt{\"a}re Meningitis und eine Beteiligung von Hirnnerven. Die Diagnosestellung erfolgt anhand klinischer Symptomatik, Liquoranalyse und Antik{\"o}rperuntersuchungen von Liquor und Serum. Besonders in der Fr{\"u}hphase der Infektion gestaltet sich die Diagnosesicherung aufgrund der noch fehlenden Antik{\"o}rperreaktion jedoch oftmals sehr schwierig. Die Ergebnisse mehrerer Studien legen nahe, dass CXCL-13 einen wertvollen Beitrag leisten k{\"o}nnte, um diese diagnostische L{\"u}cke zu schließen. Ziel der Studie war es, die Wertigkeit des Liquorbiomarkers CXCL-13 in der Diagnostik der Neuroborreliose und anderer neuroinflammatorischer Erkrankungen anhand eines großen unselektierten Kollektivs zu ermitteln, einen cut-off Wert f{\"u}r die Verwendung im klinischen Alltag zu definieren und die Ergebnisse mit der bestehenden Literatur zu vergleichen. Daf{\"u}r wurden am Klinikum Wels-Grieskirchen {\"u}ber einen Zeitraum von 3 Jahren alle Patienten analysiert, bei denen im Rahmen einer Liquorpunktion die CXCL-13 Konzentration bestimmt wurde. Die Patienten wurden anhand der Hauptdiagnose bei Entlassung in 12 Diagnosegruppen aufgeteilt, f{\"u}r die Einteilung der Neuroborreliose Patienten wurden die Diagnoseleitlinien der DGN herangezogen. Alle Liquorproben wurden routinem{\"a}ßig auf Zellzahl, Gesamteiweiß und Laktat untersucht, die CXCL-13 Konzentration wurde anhand eines enzyme-linked immunsorbent assay (CXCL-13 ELISA, Euroimmun) bestimmt. Unter den 1410 augewerteten Patienten fanden sich 29 F{\"a}lle mit gesicherter Neuroborreliose sowie 9 F{\"a}lle mit wahrscheinlicher/m{\"o}glicher Neuroborreliose. Beide Neuroborreliosegruppen zeigten eine deutlich erh{\"o}hte mediane CXCL-13 Konzentration (554pg/ml bzw. 649pg/ml), in der Gruppe der bakteriellen und Pilzinfektionen (n=6) fand sich ebenfalls ein deutlich erh{\"o}hter Median von 410pg/ml. Alle anderen Gruppen wiesen signifikant niedrigere CXCL-13 Konzentrationen auf (p<0,001), lediglich bei sechs Patienten aus der Gruppe der soliden Tumore, darunter ein kutanes Lymphom und f{\"u}nf hirneigene Tumore, wurden Werte {\"u}ber 500pg/ml gefunden. Anhand einer ROC-Kurve wurde der ideale cut-off f{\"u}r die Diagnose der gesicherten Neuroborreliose errechnet. Dieser lag bei 55,5pg/ml mit einer Sensitivit{\"a}t von 96,6\% (95\% KI 80,4-99,8\%) und einer Spezifit{\"a}t von 94,9\% (95\% KI 93,5-95,9\%). Bei 28 der 29 gesicherten Neuroborreliosef{\"a}lle konnte ein positiver Antik{\"o}rperindex nachgewiesen werden, dies entspricht einer Sensitivit{\"a}t von 96,6\%. Der direkte Erregernachweis mittels PCR wurde bei neun Patienten durchgef{\"u}hrt, er war lediglich in zwei F{\"a}llen positiv, die Sensitivit{\"a}t lag bei 22,2\%. Bei den Patienten mit wahrscheinlicher Neuroborreliose (n=5) war eine Bestimmung des Antik{\"o}rper-Index nicht m{\"o}glich, da entweder nur im Serum oder im Liquor borrelienspezifische Antik{\"o}rper vorlagen. Alle Patienten zeigten eine typische klinische Symptomatik, eine lymphozyt{\"a}re Pleozytose und deutlich erh{\"o}hte CXCL-13 Konzentrationen. Es erfolgte eine antibiotische Therapie mit Ceftriaxon, worauf die Symptomatik rasch r{\"u}ckl{\"a}ufig war. Die Ergebnisse der Studie best{\"a}tigen die hohe Wertigkeit von CXCL-13 f{\"u}r die Diagnose der Neuroborreliose und belegen die {\"U}bertragbarkeit der bisherigen Funde auf ein unselektiertes Patientenkollektiv. Die CXCL-13 Bestimmung ist dem direkten Erregernachweis deutlich {\"u}berlegen, dieser ist aufgrund der niedrigen Sensitivit{\"a}t lediglich als Best{\"a}tigungstest geeignet. Im Vergleich zum borrelienspezifischen Antik{\"o}rper-Index ist CXCL-13 als in etwa ebenb{\"u}rtig anzusehen. Besonders in der Fr{\"u}hphase der Infektion bietet die CXCL-13 Bestimmung aufgrund der Latenzzeit bis zur Nachweisbarkeit von Antik{\"o}rpern jedoch einen deutlichen Vorteil. Zus{\"a}tzlich f{\"a}llt die CXCL-13 Konzentration nach erfolgter Therapie rasch wieder ab, wodurch es sich auch als Verlaufsparameter eignet. Ein positiver Antik{\"o}rper-Index kann {\"u}ber viele Jahre persistieren, weshalb eine Unterscheidung zwischen akuter und abgelaufener Infektion unm{\"o}glich ist. Am sinnvollsten erscheint eine Kombination von CXCL-13 und Antik{\"o}rper-Index, in Verbindung mit der klinischen Pr{\"a}sentation ergibt sich so eine sehr hohe diagnostische Sicherheit in allen Stadien der Erkrankung.}, subject = {Borreliose}, language = {de} } @phdthesis{Seager2022, author = {Seager, Anna}, title = {Die ur{\"a}mische Neuropathie - ein Vitamin-B\(_{12}\)-Mangel?}, doi = {10.25972/OPUS-29109}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-291094}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Eine Vielzahl von Patienten mit fortgeschrittener, beziehungsweise dialysepflichtiger Niereninsuffizienz entwickeln eine Polyneuropathie. Die Pathogenese der ur{\"a}mischen Neuropathie (UN) ist nicht gekl{\"a}rt, sodass auf der Suche nach dem Pathomechanismus auch ein Vitamin-B12-Mangel diskutiert werden muss, da dieser {\"a}hnliche Symptome wie die UN hervorrufen kann. Ziel dieser Studie war es, den Zusammenhang zwischen den Parametern des Vitamin-B12-Stoffwechsels und der UN darzustellen. In einer prospektiven Studie mit insgesamt 54 teilnehmenden Patienten wurden diese vor und nach einer Vitamin-B12-Substitution laborchemisch untersucht. Zudem erhielten die Patienten neben einer klinischen Untersuchung eine elektroneurographische Diagnostik des N. suralis und des N. tibialis, sowie eine QST-Untersuchung.}, subject = {Ur{\"a}mie}, language = {de} } @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{Kobsar2005, author = {Kobsar, Igor V.}, title = {Die Rolle von Immunzellen bei der prim{\"a}r genetisch-vermittelten Demyelinisierung in einem Mausmodell f{\"u}r die Charcot-Marie-Tooth-Neuropathie, Typ 1X}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-17047}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2005}, abstract = {Ziel der vorliegenden Arbeit war, zu untersuchen, ob Immunzellen den Schweregrad einer peripheren Neuropathie im Mausmodell von CMT1X (Cx32def (Cx32-defiziente) Maus) beeinflussen k{\"o}nnen. Mit Hilfe von immunhistochemischen F{\"a}rbemethoden, lichtmikroskopischen, immunelektronenmikroskopischen und computergest{\"u}tzen konventionellen elektronenmikroskopischen Auswertungsverfahren wurde die Anzahl von endoneuralen Makrophagen und CD8+ T-Zellen, sowie die Morphologie von Quadricepsnerven und ventralen Spinalwurzeln analysiert.. Aufgrund der vorliegenden Ergebnissen k{\"o}nnen dabei folgende Aussagen getroffen werden: 1. Makrophagen und CD8+ T-Zellen sind in Quadricepsnerven von Cx32-defizienten M{\"a}usen hochreguliert, wobei die Anzahl der endoneuralen Makrophagen die Anzahl der CD8+ T-Zellen wesentlich {\"u}bersteigt. Die Anzahl war altersabh{\"a}ngig und korrelierte mit dem Schweregrad des pathomorphologischen Bildes der peripheren Neuropathie. 2. Mit Immunelektronenmikroskopie haben wir eindeutig identifizierbare endoneurale Makrophagen innerhalb der endoneuralen R{\"o}hren in engem Kontakt zu demyelinisierten oder in Demyelinisierung begriffenen Axonen nachgewiesen. Endoneurale Makrophagen enthielten h{\"a}ufig Reste von phagozytiertem Myelin. 3. Bei Immun- und konventioneller Elektronenmikroskopie haben wir h{\"a}ufig ausgepr{\"a}gte Kontakte zwischen Makrophagen und Fibroblasten beobachtet. 4. In Cx32def/RAG-1-/- Doppelmutanten, die zus{\"a}tzlich zu der Myelinmutation auch keine reifen Lymphozyten beinhalten, ist eine signifikant geringere Hochregulation der Anzahl von endoneuralen Makrophagen nachweisbar, ebenso eine wesentliche Abmilderung der pathologischen Ver{\"a}nderungen von Quadricepsnerven und ventralen Spinalwurzeln im Vergleich zu Cx32def/ RAG-1+/? Geschwistertieren. Diese Ergebnisse lassen die Schlußfolgerung zu, daß Makrophagen und CD8+ T-Zellen die prim{\"a}r genetisch-bedingte Demyelinisierung im Mausmodell f{\"u}r CMT1X wesentlich verst{\"a}rkend beeinflussen. Aufgrund der {\"a}hnlichen Literaturdaten {\"u}ber das Mausmodell von CMT1B (P0+/- Mutante) k{\"o}nnen wir vermuten, daß die Interaktion zwischen Schwann- und Immunzellen eine wichtige Komponente der peripheren Demyelinisierung in Mausmodellen f{\"u}r CMT1 ist.}, language = {de} } @phdthesis{Hornburger2021, author = {Hornburger, Hannah}, title = {Die Rolle des prim{\"a}ren somatosensiblen Kortex f{\"u}r die multisensorische Integration bei der Puppenhandillusion - eine tDCS-Studie}, doi = {10.25972/OPUS-23232}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232323}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {In der Puppenhandillusion (PHI) wird durch die synchrone Ber{\"u}hrung der nicht-sichtbaren Hand des Probanden und einer sichtbaren Puppenhand ein illusio-n{\"a}res K{\"o}rperzugeh{\"o}rigkeitsgef{\"u}hl induziert. Dieses Paradigma erlaubt es zu untersuchen, wie das Gehirn widerspr{\"u}chliche multisensorische Informationen w{\"a}hrend einer perzeptiven Inferenz aufl{\"o}st. Vorausgehende Studien weisen darauf hin, dass der Konflikt zwischen visueller und propriozeptiver Information vor der PHI durch eine Abschw{\"a}chung des so-matosensiblen Inputs behoben wird. Um herauszufinden, ob eine Exzitabilit{\"a}ts-Minderung des prim{\"a}ren somatosensiblen Kortex die PHI verst{\"a}rken kann, kam die kathodale transkranielle Gleichstromstimulation (c-tDCS) zum Einsatz. An dreißig gesunden Probanden wurde die PHI ohne (=baseline) und w{\"a}hrend tDCS untersucht. Jeder Proband erhielt kathodale, anodale und sham-Stimulation an drei unterschiedlichen Tagen im Abstand von je einer Woche. Das PHI-Paradigma wurde in sechs Distanzen (von 17,5 bis 67,5 cm) zwischen der eigenen Hand und der Puppenhand durchgef{\"u}hrt. Das Auftreten der PHI wurde anhand eines Fragebogens (Illusionsscore, IS) und der Abweichung der gef{\"u}hlten Handposition in Bezug zur realen Position (relativer Drift, RD) evalu-iert. Die kathodale Stimulation war mit einem signifikanten Anstieg des IS im Vergleich zur anodalen Stimulation assoziiert, wohingegen die RD-Werte {\"u}ber alle Stimulationsarten hinweg vergleichbar waren. Die fehlende Signifikanz zwischen Verum und Sham-Stimulation wurde auf die geringe Effektst{\"a}rke bei vergleichsweise kleinem Probandenkollektiv bezogen. Die Ergebnisse dieser Studie zeigen jedoch eine verst{\"a}rkte Wahrnehmung der PHI unabh{\"a}ngig von demographischen Faktoren, wenn kathodale tDCS {\"u}ber dem kontralateralen prim{\"a}ren somatosensiblen Kortex appliziert wurde. Dies unterst{\"u}tzt unsere Hypothese, dass eine Abschw{\"a}chung der somatosensiblen Pr{\"a}zision den Weg f{\"u}r eine erleichterte Integration eines fremden K{\"o}rperteils in das eigene K{\"o}rperschema ebnet.}, subject = {tDCS}, language = {de} } @phdthesis{Emmerich2020, author = {Emmerich, Christoph}, title = {Die Rolle der clathrin- und dynaminabh{\"a}ngigen Endozytose bei der Internalisation von anti-Amphiphysin-Autoantik{\"o}rpern im Falle des Stiff-Person-Syndroms, untersucht am Zellkulturmodell hippocampaler Neurone}, doi = {10.25972/OPUS-20936}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-209360}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {In dieser Arbeit wurde mit Hilfe von small-molecule Inhibitoren die Rolle von clathrin- und dynaminabh{\"a}ngigen Endozytosemechanismen bei der Aufnahme von anti-Amphiphysin-Autoantik{\"o}rpern am Zellkulturmodell prim{\"a}rer hippocampaler Neurone untersucht. Hierbei konnte eine Beeinflussung der Autoaantik{\"o}rperaufnahme durch die Intervention gezeigt werden. Außerdem erfolgte der Versuch der Etablierung eines siRNA knockdowns unter Zuhilfenahme unterschiedlicher Traansfektionsreaaagenzien.}, subject = {siRNA}, language = {de} } @phdthesis{Zeumer2023, author = {Zeumer, Karolina}, title = {Die Rolle dendritischer Zellen beim isch{\"a}mischen Schlaganfall}, doi = {10.25972/OPUS-30258}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-302580}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Ziel dieser Studie war es, zu untersuchen, ob dendritische Zellen eine Rolle beim isch{\"a}mischen Schlaganfall spielen. Zur Beantwortung dieser Fragestellung wurde ein Mausmodell gew{\"a}hlt, in dem es nach Administration von Diphterietoxin zur selektiven Depletion CD11c positiver Zellen kommt (C.FVB-Tg(Itgax-DTR/EGFP)57Lan/J). Hierbei wird der Diphterietoxinrezeptor unter dem CD11c Promotor (ITGAX) exprimiert. Aufgrund der Wiederherstellung dendritischer Zellen nach ca. 24 Stunden waren wiederholte Applikationen von Diphterietoxin notwendig. Die Zusammensetzung anderer Immunzellen wurde dabei im Wesentlichen nicht ge{\"a}ndert. F{\"u}r eine Schlaganfallinduktion wurde eine tMCAO (transient middle cerebral artery occlusion) durchgef{\"u}hrt. Hierbei wird durch Okklusion der A. cerebri media mittels Verschlussfilament f{\"u}r 30 oder 60 Minuten ein Schlaganfall im Mediastromgebiet induziert. Es wurden unterschiedliche Verschlusszeiten, Zeitpunkte und Depletionsraten untersucht. In keinem der Versuchsans{\"a}tze kam es zu einer signifikanten Ver{\"a}nderung des Schlaganfallvolumens nach Depletion CD11c positiver Zellen. Mittels quantitativer real-time PCR wurde die Expression unterschiedlicher Zytokine nach tMCAO und CD11c-Depletion untersucht. An Tag 1 nach Schlaganfallinduktion und hoher Depletionsrate ergab sich eine Verminderung der Expression von IL-1β und IL-6, w{\"a}hrend an Tag 3 und niedriger Depletionsrate die Expression dieser Zytokine nach CD11c-Depletion zunahm. Grund hierf{\"u}r k{\"o}nnte die Expression dieser Zytokine durch andere Zellen des Immunsystems, wie etwa neutrophile Granulozyten oder Mikroglia/Makrophagen sein, die m{\"o}glicherweise einer regulatorischen Funktion durch die Interaktion von Dendritischen Zellen und regulatorischen T-Zellen unterliegen. Weitere experimentelle Ans{\"a}tze sind notwendig, um diese Fragestellung beantworten zu k{\"o}nnen. TGF-β zeigte durchgehend in allen Versuchsanordnungen eine verminderte Expression nach der Depletion dendritischer Zellen. Es ist naheliegend, dass dieses neuroprotektiv-regulatorische Zytokin direkt einer Produktion durch dendritische Zellen oder von nachfolgend aktivierten T-Zellen unterliegt. In immunhistochemischen Studien konnte des Weiteren keine {\"A}nderung des Immigrationsverhaltens von CD11b+ Zellen ins Gehirn gesehen werden. Diese Studie unterliegt jedoch einigen Limitationen. So stellte sich im Laufe der Experimente heraus, dass die wiederholte Applikation von Diphterietoxin zu einer erh{\"o}hten Mortalit{\"a}t der Versuchstiere f{\"u}hrte. Nach Fertigstellung der Experimente erschien hierzu eine Publikation, welche die wiederholte Administration von DTX und die Entwicklung einer Myokarditis im gew{\"a}hlten Mausmodell in Zusammenhang brachte.}, subject = {Schlaganfall}, language = {de} } @phdthesis{Schaefer2002, author = {Sch{\"a}fer, Sabine}, title = {Die funktionelle Relevanz humoraler und zellul{\"a}rer Immunreaktionen gegen Campylobacter jejuni in der Pathogenese von Immunneuropathien}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-5531}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2002}, abstract = {Verschiedene m{\"o}gliche Pathomechanismen einer Campylobacter jejuni-spezifischen Immunantwort bei der Entstehung akuter Immunneuropathien wurden untersucht. Neben anderen wurden f{\"u}r die Untersuchungen auch C. jejuni-St{\"a}mme eingesetzt, welche von Guillain-Barr{\´e}- (GBS) und Miller-Fisher-syndrome (MFS) Patienten isoliert worden waren. Es wurden Ultraschall-Gesamt-Homogenate der C. jejuni St{\"a}mme sowie von Salmonella typhimurium als Kontrollbakterium hergestellt. Anschließend wurden verschiedene Proteinfraktionen isoliert und die Lipopolysaccharide (LPS) der Bakterien isoliert. Durch Immunisierung von Ratten mit diesen C. jejuni-Pr{\"a}parationen konnten keine Krankheitszeichen der experimentellen autoimmunen Neuritis (EAN) ausgel{\"o}st werden. Trotz Produktion hoher Titer C. jejuni-spezifischer Antik{\"o}rper verlief in diesen Tieren eine anschließend durch P2-spezifische T-Lymphozyten induzierte adoptiv transferierte EAN (AT-EAN) nicht schwerer als in mit komplettem Freund´schen Adjuvans (CFA) kontrollimmunisierten Ratten. Nach Immunisierung mit C. jejuni-Protein wurden C. jejuni-spezifische T-Zellen von Lewis-Ratten gewonnen, die mit allen getesteten C. jejuni-St{\"a}mmen als Antigen reagieren, jedoch zeigten C. jejuni-spezifische Ratten-T-Zellen in vitro keine Kreuzreaktivit{\"a}t mit PNS-Antigenen und induzierten in vivo keine Neuritis. Im Modell der EAN l{\"a}ßt sich durch F{\"u}ttern des Antigens eine nat{\"u}rliche orale Toleranz induzieren, welche die Tiere gegen eine aktiv induzierte EAN resistent macht. Die immunologische Auswirkung der enteralen Gabe von C. jejuni-LPS auf die nat{\"u}rliche Immuntoleranz wurde untersucht. Dabei konnte bei diskrepanten Ergebnissen keine pathogene Bedeutung von enteralen C. jejuni-Antigenen in der Ratte festgestellt werden. Zur Generation und Untersuchung C. jejuni-spezifischer monoklonaler Antik{\"o}rper wurden Balb/c-M{\"a}use mit C. jejuni-LPS-Pr{\"a}parationen in CFA immunisiert und die Milzzellen dieser Tiere mit Maus-Myelomzellen fusioniert. Es konnte eine Vielzahl von monoklonalen Antik{\"o}rpern etabliert werden. Selektive Spezifit{\"a}ten der monoklonalen Antik{\"o}rper f{\"u}r C. jejuni-LPS oder -protein wurden detektiert, die meisten der monoklonalen Antik{\"o}rper als IgM, einige als IgG charakterisiert. Die Antik{\"o}rper reagieren mit allen getesteten C. jejuni-St{\"a}mmen sowohl im ELISA als auch im Western Blot kreuz. Eine Reaktivit{\"a}t der Antik{\"o}rper mit verschiedenen Gangliosiden konnte nicht nachgewiesen werden. Zur Untersuchung eines elektrophysiologisch fassbaren blockierenden Effektes von C. jejuni-spezifischen Antik{\"o}rpern wurden Makro-patch-clamp-Untersuchungen am M{\"a}usezwerchfell mit dialysierten Seren von C. jejuni-immunisierten Ratten durchgef{\"u}hrt. Einige der C. jejuni-Antiseren blockierten die pr{\"a}synaptische Quantenfreisetzung partiell. Dieser Effekt war C. jejuni-spezifisch und durch Salmonella-Antiserum oder Kontrollseren CFA-immunisierter Tiere nicht induzierbar. Ein von uns generierter monoklonaler IgG-Antik{\"o}rper gegen C. jejuni-LPS wurde ebenfalls in Makro-patch-clamp-Untersuchungen getestet und blockierte die Quantenfreisetzung. Weiterhin wurden humane T-Zellen gegen C. jejuni HB 93-13 generiert. Es konnte erstmals gezeigt werden, daß diese Zellen mit anderen C. jejuni-St{\"a}mmen, jedoch nicht mit Salmonellen, kreuzreagieren und ausschließlich Proteine jedoch nicht LPS erkennen. Die generierten Zellen sind alle HLA-DR restringiert und der Ph{\"a}notyp wurde als CD 4+/CD 8-, \&\#61537;/\&\#61538;-TZR+ identifiziert. Einige der C. jejuni-spezifischen T-Zell-Linien zeigten eine starke oder partielle Kreuzreaktivit{\"a}t mit humanem rekombinantem P2-Protein des PNS und mit einzelnen P2-Peptiden. Dieser Befund belegt erstmals, dass durch Konfrontation mit C. jejuni eine zellul{\"a}re Immunantwort angestoßen werden kann, die in autoimmuner Weise mit Myelinprotein des PNS kreuzreagiert.}, subject = {Campylobacter jejuni}, language = {de} } @phdthesis{Gross2010, author = {Groß, Catharina Luise}, title = {Die funktionelle Beteiligung verschiedener Hirnregionen in einer das K{\"o}rperselbstgef{\"u}hl t{\"a}uschenden Illusion: Eine L{\"a}sionsstudie}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-51319}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2010}, abstract = {Das K{\"o}rperselbstgef{\"u}hl stellt einen elementaren, jedoch selten beachteten Bestandteil unserer Wahrnehmung dar, ohne dass wir den Alltag nicht bew{\"a}ltigen k{\"o}nnten. Umso gravierender ist es, wenn dieses Selbstverst{\"a}ndnis f{\"u}r den eigenen K{\"o}rper oder f{\"u}r einen K{\"o}rperteil durch z.B. einen Schlaganfall verloren geht. Die Grundlagen der Entstehung und der St{\"o}rung des K{\"o}rperselbstgef{\"u}hles sind bisher nur teilweise bekannt. Diese Studie hat zwei Aspekte des K{\"o}rperselbstgef{\"u}hles bei Schlaganfallpatienten un-tersucht: die St{\"o}rung der Puppenhandillusion als eine Unf{\"a}higkeit, eine Illusion der Zu-geh{\"o}rigkeit einer Puppenhand zum eigenen K{\"o}rper zu empfinden und Asomatognosie als eine spontane St{\"o}rung des Zugeh{\"o}rigkeitsgef{\"u}hles zur eigenen Hand. Mit der so genannten Puppenhandillusion (PHI) kann auf einfache Weise die Basis der Selbstidentifikation untersucht werden. Innerhalb kurzer Zeit entsteht bei dem Proban-den der Eindruck, eine vor ihm liegende Puppenhand geh{\"o}re zu ihm. Die PHI entsteht, wenn die eigene, f{\"u}r den Probanden verdeckte Hand und eine f{\"u}r den Probanden sicht-bare, direkt {\"u}ber der eigenen Hand platzierte, lebensgroße Puppenhand zeit- und orts-synchron an den Fingern mit Pinseln ber{\"u}hrt und bestrichen werden. Es wurden 120 gesunde Probanden und 70 Schlaganfallpatienten an beiden H{\"a}nden mit der PHI untersucht und das Vorhandensein der PHI durch einen anschließend beantworteten Fragebogen festgestellt. Zus{\"a}tzlich wurden 64 Schlaganfallpatienten auf das Vorhandensein einer Asomatognosie hin untersucht. Eine Analyse der isch{\"a}mischen L{\"a}sionen der Schlaganfallpatienten wurde mit den dif-fusionsgewichteten MRT-Bildern und frei im Internet erh{\"a}ltlicher Software durchge-f{\"u}hrt. Die Isch{\"a}mien wurden manuell als regions of interest (ROI) markiert und in den Standardraum des MNI152-Gehirns transformiert. Rechtshemisph{\"a}rische L{\"a}sionen wurden {\"u}ber die Mittellinie gespiegelt. Es wurden Subtraktionsanalysen und ein voxel-based lesion-symptom mapping (VLSM) zur Feststellung der f{\"u}r die PHI und eine nor-male Somatognosie essentiellen Hirnregionen angewandt. Repetitive transkranielle Magnetstimulation (rTMS) als reversible L{\"a}sionstechnik wurde {\"u}ber dem ventralen pr{\"a}motorischen Kortex bei 8 Probanden durchgef{\"u}hrt. Erstmals wurde eine große Gruppe gesunder Probanden mit der PHI untersucht. Es zeigten sich keine signifikanten Unterschiede im Auftreten der PHI in Bezug auf Alter, Geschlecht, K{\"o}rperseite und H{\"a}ndigkeit. Die PHI konnte bei 86\% der Probanden an beiden H{\"a}nden induziert werden. Bei der rTMS-Untersuchung konnte nach Stimulation des pr{\"a}motorischen Kortex keine signifikante {\"A}nderung des Illusionserlebnisses beobachtet werden. Eine kontral{\"a}sional gest{\"o}rte PHI fand sich bei 11 (16\%), eine bilateral gest{\"o}rte PHI bei zus{\"a}tzlich 7 (10\%) der 70 Schlaganfallpatienten. Wir fanden L{\"a}sionsvoxel innerhalb der subkortikalen weißen Substanz in direkter struk-tureller N{\"a}he zum pr{\"a}motorischen, pr{\"a}frontalen und parietalen Kortex sowie zur Insel-region, welche eine signifikante Assoziation mit kontral{\"a}sionaler bzw. beidseitiger PHI-St{\"o}rung aufweisen. Eine kontral{\"a}sionale Asomatognosie wurde bei 18 (28\%) von 64 Schlaganfallpatienten gefunden. Asomatognosie korrelierte nicht mit einer gest{\"o}rten PHI- weder in der klini-schen Untersuchung noch hinsichtlich der L{\"a}sionslokalisation. Unsere Resultate sind vereinbar mit einer Rolle des pr{\"a}motorischen Kortex und dessen subkortikalen Verbindungen, sowie parietaler Hirnregionen und der Inselregion bei der Entstehung der PHI. Bei Schlaganfallpatienten korrelierte eine St{\"o}rung der PHI und eine Asomatognosie nicht miteinander, folglich gehen wir von zwei unabh{\"a}ngig voneinander bestehenden Mechanismen aus, denen verschiedene neuronale Netzwerke zugrunde liegen.}, subject = {Anosognosie}, language = {de} } @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 }, language = {de} } @phdthesis{Ortler2009, author = {Ortler, Sonja}, title = {Die Bedeutung koinhibitorischer Signale in der ZNS Immunregulation: die Rolle des B7-Homologs B7-H1 (PD-L1)}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-34784}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2009}, abstract = {Das koinhibitorische Molek{\"u}l B7-H1 beeinflusst adaptive Immunantworten und ist vermutlich an den Mechanismen zur Aufrechterhaltung peripherer Toleranz und der Limitierung inflammatorischen Schadens beteiligt. Zus{\"a}tzlich kommt DZ eine entscheidende Bedeutung in der Entwicklung, Aufrechterhaltung und Regulation ZNS-spezifischer Autoimmunit{\"a}t und Inflammationsprozessen zu. Um den B7-H1/PD-1-Signalweg eingehender zu untersuchen, wurden adaptive Immunantworten und die Zielorgan-spezifische Infiltration im Modell der MOG35-55-induzierten EAE analysiert, einem Tiermodell der MS, das durch neurologische Sch{\"a}digungen und progressive Paralyse bedingt durch die inflammatorische Demyelinisierung im ZNS charakterisiert ist. Im Vergleich zu Wildtyptieren zeigten B7-H1-/- M{\"a}use einen beschleunigten Krankheitsbeginn und eine signifikante Steigerung des Schweregrads der EAE. Periphere MOG35-55-spezifische IFNg-/IL-17-Immunzellantworten traten in B7-H1-/- M{\"a}usen verfr{\"u}ht und verst{\"a}rkt auf, klangen allerdings auch schneller ab. Im ZNS persistierte jedoch eine signifikant h{\"o}here Anzahl aktivierter, Neuroantigen-spezifischer T-Zellen w{\"a}hrend allen Phasen der EAE, wobei diese Zellen ebenfalls gr{\"o}ßere Mengen proinflammatorischer Zytokine sezernieren konnten. Experimente mit APZ-assoziiertem B7-H1, die einen direkten inhibitorischen Effekt auf die Aktivierung und Proliferation MOG35-55-spezifischer Effektorzellen zeigten, unterst{\"u}tzen die Hypothese, dass parenchymale Expression von B7-H1 ausschlaggebend f{\"u}r das Schicksal von T-Zellen im Zielorgan ist. B7-H1 stellt damit ein Schl{\"u}sselmolek{\"u}l f{\"u}r die Kontrolle parenchymaler Immunreaktionen dar. Nachdem die Relevanz von B7-H1 auf APZ in vitro bewiesen werden konnte, wurde der Einfluss von B7-H1 auf systemisch oder intrazerebral injizierten DZ mit immunogenem oder tolerogenem Ph{\"a}notyp untersucht. Intraven{\"o}se Applikation von tolerogenen B7-H1-/- DZ resultierte in einer besseren Protektion gegen EAE, und dieser Effekt war von einer gesteigerten Produktion Tr1-/Th2-typischer Zytokine sowie einer verst{\"a}rkten Sekretion von IL-4 und IL-13 durch CD1d-restringierte T-Zellen in der Peripherie begleitet. Die Anzahl Neuroantigen-spezifischer T-Zellen, die proinflammatorische Zytokine sezernierten, war dementsprechend sowohl in der Peripherie als auch im ZNS reduziert. In diesem Zusammenhang konnte f{\"u}r B7-H1 eine wesentliche Beteiligung an der Inhibition der Aktivierung antigen-spezifischer, regulatorischer T-Zellen und CD1d-restringierter T-Zellen gefunden werden. Bei der Injektion intrazerebraler DZ bewirkten tolerogene DZ im Vergleich zu immunogenen DZ eine Reduktion der ZNS-Infiltration mit CD4+ T-Zellen in der fr{\"u}hen Phase der Erkrankung. Außerdem konnte eine Ver{\"a}nderung des intrazerebralen Zytokinmilieus von IFNg/IL-17 exprimierenden enzephalitogenen T-Zellen zu IL-10+ regulatorischen T-Zellen gezeigt werden. B7-H1-Defizienz auf APZ verst{\"a}rkte diesen Effekt und f{\"u}hrte dadurch in den M{\"a}usen zur partiellen Protektion gegen klinische Symptome der EAE. Zus{\"a}tzlich wurde die Beteiligung von B7-H1 an der Rekrutierung und ZNS-lokalisierten Induktion der Proliferation CD8+ regulatorischer T-Zellen durch DZ beschrieben. Unabh{\"a}ngig vom Ph{\"a}notyp der DZ wurde eine bereits in der fr{\"u}hen Phase vorhandene und dauerhaft expandierende Population von CD8+ T-Zellen im ZNS DZ[B7-H1-/-]-injizierter M{\"a}use gefunden. Diese Zellen konnten in vitro die Proliferation MOG35-55-spezifischer CD4+ T-Zellen supprimieren und wirkten so mutmaßlich an der Abmilderung der EAE mit. Zusammengefasst zeigen die Ergebnisse dieser Arbeit die entscheidende Bedeutung von B7 H1 auf DZ als immuninhibitorisches Molek{\"u}l, das sowohl enzephalitogene als auch regulatorische T-Zell-Antworten moduliert und damit zur Limitation von Immunantworten beitr{\"a}gt.}, subject = {Multiple Sklerose}, language = {de} } @phdthesis{Wagenhaeuser2023, author = {Wagenh{\"a}user, Laura Maria}, title = {Die Auswirkungen der X-Inaktivierung auf den klinischen Ph{\"a}notyp bei Patientinnen mit Morbus Fabry}, doi = {10.25972/OPUS-31153}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-311530}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {M. Fabry ist eine X-chromosomal vererbte Stoffwechselerkrankung. Die Mutation im α-Galactosidase A Gen f{\"u}hrt zur reduzierten Aktivit{\"a}t des Enzyms und zur Akkumulation der Stoffwechselprodukte im gesamten K{\"o}rper. Von der daraus resultierenden Multiorganerkrankung sind sowohl M{\"a}nner, als auch Frauen betroffen. Als Grund hierf{\"u}r steht eine verschobene X-Inaktivierung zur Diskussion. In der vorliegenden Arbeit wurden 104 Frauen rekrutiert und die X-Inaktivierungsmuster in Mundschleimhautepithel, Blut und Hautfibroblasten untersucht. Es wurden umfangreiche klinische und laborchemische Untersuchungen durchgef{\"u}hrt, sodass von jeder Patientin ein klinischer Ph{\"a}notyp vorlag, der mit Hilfe eines numerischen Scores klassifiziert wurde. Es zeigte sich, dass Blut ein leicht zu asservierendes Biomaterial mit einer hohen Pr{\"a}valenz an verschobenen X-Inaktivierungsmustern darstellt. Eine signifikante Korrelation mit dem klinischen Ph{\"a}notyp konnte in keinem der drei untersuchten Gewebe nachgewiesen werden.}, subject = {Fabry-Krankheit}, language = {de} } @phdthesis{Christ2021, author = {Christ, Nicolas}, title = {Die Auswirkung zerebraler Mikroblutungen auf die kognitive Leistungsf{\"a}higkeit nach isch{\"a}mischem Schlaganfall}, doi = {10.25972/OPUS-24367}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-243679}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {In der vorliegenden Studie wurde untersucht, ob zerebrale Mikroblutungen (CMB) bereits im fr{\"u}hen Verlauf nach isch{\"a}mischem Schlaganfall (IS) oder Transitorisch-Isch{\"a}mischer Attacke (TIA) mit kognitivem Abbau assoziiert sind und ob spezifische kognitive Dom{\"a}nen besonders betroffen sind. Der Vergleich zweier Probandengruppen mit IS/TIA und CMB bzw. IS/TIA ohne CMB hinsichtlich ihrer Ergebnisse in der neuropsychologischen Testbatterie CERAD ergab, dass CMB bereits sechs Monate nach dem zerebrovaskul{\"a}ren Ereignis mit einem kognitiven Abbau assoziiert sind. Multilokul{\"a}re CMB zeigen eine st{\"a}rkere Auswirkung auf die Kognition als solche CMB, die in einer einzigen Hirnregion gefunden wurden. Zudem wurde eine signifikante Korrelation zwischen dem Grad der kognitiven Einschr{\"a}nkung und der Anzahl der CMB errechnet. Die separate Betrachtung derjenigen Testungen, welche das episodische Ged{\"a}chtnis erfassen, zeigte eine Beeintr{\"a}chtigung der Testpersonen beim Wiedererkennen von zuvor gelernten W{\"o}rtern. Bei der Untersuchung des semantischen Ged{\"a}chtnisses der ProbandInnen fiel eine signifikant eingeschr{\"a}nkte phonematische Wortfl{\"u}ssigkeit auf, die semantische Fl{\"u}ssigkeit und das Benennen jedoch waren weniger betroffen. Die Dom{\"a}ne „Visuokonstruktive F{\"a}higkeiten" wurde ebenfalls in drei Untertests beurteilt. Hierbei zeigten sich keine Defizite der Testgruppe beim Abzeichnen der dargebotenen Figuren, die Reproduktion hingegen war signifikant gest{\"o}rt. Es zeigte sich keine CMB-bedingte Einschr{\"a}nkung der exekutiven Funktionen.}, subject = {Hirnblutung}, language = {de} } @phdthesis{Stenner2011, author = {Stenner, Max-Philipp}, title = {Diapedese und immuntolerogene Funktion regulatorischer T Zellen in der schubf{\"o}rmigen Multiplen Sklerose unter Therapie mit Natalizumab}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-70573}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2011}, abstract = {Die schubf{\"o}rmige Multiple Sklerose (MS) ist eine chronisch-entz{\"u}ndliche, demyelinisierende, multifokale Erkrankung des Zentralnervensystems (ZNS). Autoreaktive immunologische Prozesse, insbesondere der T-Zell vermittelten Immunit{\"a}t, leisten einen entscheidenden Beitrag zur Pathogenese der schubf{\"o}rmigen MS. Ein wesentlicher Schritt in immunpathogenetischen Modellen ist die transendotheliale Migration von Immunzellen {\"u}ber die Blut-Hirn-Schranke. Die Interaktion des very late antigen 4 (VLA-4) mit dem vascular cell adhesion molecule 1 (VCAM-1) und mit Fibronectin leistet einen wesentlichen Beitrag zur Extravasation von T Zellen in das ZNS. Auf dieser Schl{\"u}sselfunktion des VLA-4 gr{\"u}ndet die Therapie mit Natalizumab, einem monoklonalen Antik{\"o}rper gegen die α4 Integrinkette. Ziel der vorliegenden Studie war es, die Auswirkungen der Therapie der schubf{\"o}rmigen MS mit Natalizumab auf die transendotheliale Migration von CD4+CD25+FOXP3+ und CD4+HLA-G+ regulatorischen T Zellen (Treg) und auf die antiproliferative Funktion von FOXP3+ Treg zu untersuchen. Zentrale Hypothese war, dass Natalizumab {\"u}ber eine universelle Blockade der Immunzellinvasion in das ZNS hinaus immunmodulatorisch wirkt. Unter Verwendung eines prospektiven, longitudinalen Studiendesigns wurden die T Zellen von RR-MS Patienten unter Therapie mit Natalizumab (n=31) sowie von stabilen RR-MS Patienten ohne Therapie und gesunden Spendern in jeweils zwei in vitro Modellen der Blut-Hirn-Schranke sowie Treg vermittelter Immuntoleranz untersucht. FOXP3+ regulatorische T-Zellen banden weniger Natalizumab und exprimierten weniger VLA-4 als nicht-regulatorische T Helferzellen, bewahrten unter Therapie jedoch einen h{\"o}heren Anteil ihrer urspr{\"u}nglichen VLA-4 Expression. FOXP3+ Treg gesunder Spender wiesen in vitro h{\"o}here Migrationsraten {\"u}ber mikrovaskul{\"a}re humane Hirnendothelzellen als nicht-regulatorische T Helferzellen auf und akkumulierten innerhalb der T-Zell Population nach Migration. Dagegen reicherten sich FOXP3+ Treg von MS Patienten in Folge der Migration nur nach Vorbehandlung des Endothel mit inflammatorischen Zytokinen an, nicht jedoch ohne diese Vorbehandlung. Natalizumab beeintr{\"a}chtigte die transendotheliale Migration von FOXP3+ Treg und nicht-regulatorischen T Helferzellen von MS Patienten in vergleichbaren Ausmaßen. HLA-G+ Treg zeigten in den Migrationsanalysen ein den FOXP3+ Treg entgegengesetztes Muster und wiesen ausschließlich in der MS, nicht jedoch im Gesunden, eine h{\"o}here Migrationsrate auf als HLA-G- T Helferzellen. Diese Akkumulation von HLA-G+ Treg in der migrierten Zellfraktion ließ sich nach Therapiebeginn nicht mehr nachweisen. Eine erg{\"a}nzende Einzelfallstudie zu Auswirkungen des LFA-1 Antagonisten Efalizumab auf Treg ergab Hinweise auf eine Schl{\"u}sselfunktion dieses Integrins f{\"u}r die Migration von FOXP3+ Treg. Die Analyse der FOXP3+ Treg Suppressorfunktion zeigte eine schrittweise Zunahme des suppressiven Einflusses von FOXP3+ Treg auf die Reifung dendritischer Zellen unter Natalizumabtherapie. Zeitlich parallel kam es zu einem Ungleichgewicht in der Expression von LFA-1 auf der Oberfl{\"a}che von FOXP3+ Treg und nicht-regulatorischen T Helferzellen. Zusammenfassend st{\"u}tzt die Studie die Hypothese immunmodulatorischer Effekte von Natalizumab in der schubf{\"o}rmigen Multiplen Sklerose, insbesondere auf den Antagonismus von regulatorischen und Effektor-T Zellen. Die Arbeit belegt, dass Natalizumab in vivo {\"u}ber die Blockade von VLA-4 hinaus modulatorisch in das Netzwerk von Adh{\"a}sionsmolek{\"u}len auf T Zellen eingreift. Die Studienergebnisse ergeben ein {\"U}berwiegen regulatorischer Einfl{\"u}sse auf die Reifung dendritischer Zellen unter Therapie. Berichte zum Beitrag von LFA-1 zur Suppressorfunktion von FOXP3+ Treg werden durch Daten der vorliegenden Studie unterst{\"u}tzt und um Hinweise auf eine zus{\"a}tzliche, spezifische Bedeutung des Integrins zur pr{\"a}ferentiellen Diapedese dieser Treg {\"u}ber die Blut-Hirn-Schranke im Gesunden erweitert. Zudem liefert die Arbeit erstmals Hinweise auf einen Defekt der transendothelialen Migration von FOXP3+ Treg {\"u}ber die Blut-Hirn-Schranke in der schubf{\"o}rmigen Multiplen Sklerose, der zur Entstehung neuer L{\"a}sionen beitragen k{\"o}nnte.}, subject = {Neuroimmunologie}, language = {de} } @phdthesis{Schroeter2018, author = {Schr{\"o}ter, Nils}, title = {Diagnostische Wertigkeit von Gb3-Ablagerungen in der Haut von Patienten mit M. Fabry}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-160552}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2018}, abstract = {In der vorliegenden Arbeit wurde gepr{\"u}ft, ob Gb3 in Hautstanzbiopsien von Patienten mit M. Fabry nachweisbar ist, die Ablagerungen quantifizierbar sind, mit der Krankheitsschwere korrelieren, und ob eine Unterscheidung von Patienten und gesunden Kontrollen anhand der dermalen Gb3-Ablagerungen m{\"o}glich ist. Es wurden 84 Patienten mit M. Fabry {\"u}ber das FAZiT sowie 27 gesunde Kontrollen zwischen 2008 und 2013 prospektiv rekrutiert und jeweils eine proximale und eine distale Hautbiopsie entnommen. Zus{\"a}tzlich erfolgten eine Anamnese, eine klinische Untersuchung, eine QST, das Ausf{\"u}llen von Frageb{\"o}gen mit der Fragestellung nach Schmerz und Depression sowie eine Blutentnahme und kardiale Diagnostik. Die Immunfluoreszenz erfolgte mit Antik{\"o}rpern gegen CD77, einem Marker f{\"u}r Gb3. Es erfolgte die verblindete, semiautomatische Quantifizierung der Gb3 Ablagerungen. Hierzu wurden pro Biopsie drei ROI ausgew{\"a}hlt und die Fl{\"a}che der ROIs mit Gb3-Ablagerungen in Relation zu der Gesamtfl{\"a}che der ROIs gesetzt. F{\"u}r die Auswertung wurden die Patienten sowohl nach Geschlecht als auch nach Krankheitsschwere und einzelnen Symptomen stratifiziert Die Gb3 Ablagerungen ließen sich bevorzugt in Schweißdr{\"u}sen und Endothel nachweisen. Es fanden sich jedoch auch gr{\"o}ßere Mengen an Gb3-Ablagerungen ohne ersichtliches anatomischer Korrelat. Die Gb3-Ablagerungen wurden semiautomatisch quantifiziert. Es konnte nachgewiesen werden, dass m{\"a}nnliche Fabry-Patienten eine deutlich gr{\"o}ßere Menge an Gb3 in den distalen Hautbiopsien zeigen als gesunde Kontrollen, Patienten mit einer eingeschr{\"a}nkten Nierenfunktion hatten eine gr{\"o}ßere Menge an Gb3-Ablagerungen in der Haut als Patienten mit einer uneingeschr{\"a}nkten Nierenfunktion. Bei Patienten mit einer SFN waren erh{\"o}hte dermale Gb3 Mengen vorhanden im Vergleich zu gesunden Kontrollen, bei Patienten ohne eine SFN fand sich dieser Unterschied nicht. Patienten mit einem niedrigen SNAP zeigten im Vergleich zu gesunden Kontrollen eine gr{\"o}ßere Menge an Gb3 in ihrer distalen Haut, bei Patienten mit einem h{\"o}heren SNAP fand sich dies nicht. Aus diesen Ergebnissen ergeben sich ein m{\"o}gliches weiteres Werkzeug sowohl f{\"u}r die Diagnosestellung als auch f{\"u}r das Monitoring der Erkrankung, sowie weiterf{\"u}hrend auch ein m{\"o}glicher Indikator f{\"u}r den Therapieerfolg der ERT.}, subject = {Fabry-Krankheit}, language = {de} } @article{KuzkinaBargarSchmittetal.2021, author = {Kuzkina, Anastasia and Bargar, Connor and Schmitt, Daniela and R{\"o}ßle, Jonas and Wang, Wen and Schubert, Anna-Lena and Tatsuoka, Curtis and Gunzler, Steven A. and Zou, Wen-Quan and Volkmann, Jens and Sommer, Claudia and Doppler, Kathrin and Chen, Shu G.}, title = {Diagnostic value of skin RT-QuIC in Parkinson's disease: a two-laboratory study}, series = {NPJ Parkinson's Disease}, volume = {7}, journal = {NPJ Parkinson's Disease}, number = {1}, doi = {10.1038/s41531-021-00242-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260451}, year = {2021}, abstract = {Skin alpha-synuclein deposition is considered a potential biomarker for Parkinson's disease (PD). Real-time quaking-induced conversion (RT-QuIC) is a novel, ultrasensitive, and efficient seeding assay that enables the detection of minute amounts of alpha-synuclein aggregates. We aimed to determine the diagnostic accuracy, reliability, and reproducibility of alpha-synuclein RT-QuIC assay of skin biopsy for diagnosing PD and to explore its correlation with clinical markers of PD in a two-center inter-laboratory comparison study. Patients with clinically diagnosed PD (n = 34), as well as control subjects (n = 30), underwent skin punch biopsy at multiple sites (neck, lower back, thigh, and lower leg). The skin biopsy samples (198 in total) were divided in half to be analyzed by RT-QuIC assay in two independent laboratories. The a-synuclein RT-QuIC assay of multiple skin biopsies supported the clinical diagnosis of PD with a diagnostic accuracy of 88.9\% and showed a high degree of inter-rater agreement between the two laboratories (92.2\%). Higher alpha-synuclein seeding activity in RT-QuIC was shown in patients with longer disease duration and more advanced disease stage and correlated with the presence of REM sleep behavior disorder, cognitive impairment, and constipation. The alpha-synuclein RT-QuIC assay of minimally invasive skin punch biopsy is a reliable and reproducible biomarker for Parkinson's disease. Moreover, alpha-synuclein RT-QuIC seeding activity in the skin may serve as a potential indicator of progression as it correlates with the disease stage and certain non-motor symptoms.}, language = {en} } @article{EgenolfAltenschildescheKressetal.2021, author = {Egenolf, Nadine and Altenschildesche, Caren Meyer zu and Kreß, Luisa and Eggermann, Katja and Namer, Barbara and Gross, Franziska and Klitsch, Alexander and Malzacher, Tobias and Kampik, Daniel and Malik, Rayaz A. and Kurth, Ingo and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan}, title = {Diagnosing small fiber neuropathy in clinical practice: a deep phenotyping study}, series = {Therapeutic Advances in Neurological Disorders}, volume = {14}, journal = {Therapeutic Advances in Neurological Disorders}, issn = {1756-2864}, doi = {10.1177/17562864211004318}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232019}, year = {2021}, abstract = {Background and aims: Small fiber neuropathy (SFN) is increasingly suspected in patients with pain of uncertain origin, and making the diagnosis remains a challenge lacking a diagnostic gold standard. Methods: In this case-control study, we prospectively recruited 86 patients with a medical history and clinical phenotype suggestive of SFN. Patients underwent neurological examination, quantitative sensory testing (QST), and distal and proximal skin punch biopsy, and were tested for pain-associated gene loci. Fifty-five of these patients additionally underwent pain-related evoked potentials (PREP), corneal confocal microscopy (CCM), and a quantitative sudomotor axon reflex test (QSART). Results: Abnormal distal intraepidermal nerve fiber density (IENFD) (60/86, 70\%) and neurological examination (53/86, 62\%) most frequently reflected small fiber disease. Adding CCM and/or PREP further increased the number of patients with small fiber impairment to 47/55 (85\%). Genetic testing revealed potentially pathogenic gene variants in 14/86 (16\%) index patients. QST, QSART, and proximal IENFD were of lower impact. Conclusion: We propose to diagnose SFN primarily based on the results of neurological examination and distal IENFD, with more detailed phenotyping in specialized centers.}, language = {en} } @article{AppeltshauserMessingerStarzetal.2022, author = {Appeltshauser, Luise and Messinger, Julia and Starz, Katharina and Heinrich, David and Brunder, Anna-Michelle and Stengel, Helena and Fiebig, Bianca and Ayzenberg, Ilya and Birklein, Frank and Dresel, Christian and Dorst, Johannes and Dvorak, Florian and Grimm, Alexander and Joerk, Alexander and Leypoldt, Frank and M{\"a}urer, Mathias and Merl, Patrick and Michels, Sebastian and Pitarokoili, Kalliopi and Rosenfeldt, Mathias and Sperfeld, Anne-Dorte and Weihrauch, Marc and Welte, Gabriel Simon and Sommer, Claudia and Doppler, Kathrin}, title = {Diabetes Mellitus Is a Possible Risk Factor for Nodo-paranodopathy With Antiparanodal Autoantibodies}, series = {Neurology: Neuroimmunology \& Neuroinflammation}, volume = {9}, journal = {Neurology: Neuroimmunology \& Neuroinflammation}, number = {3}, doi = {10.1212/NXI.0000000000001163}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300551}, year = {2022}, abstract = {Background and Objectives Nodo-paranodopathies are peripheral neuropathies with dysfunction of the node of Ranvier. Affected patients who are seropositive for antibodies against adhesion molecules like contactin-1 and neurofascin show distinct clinical features and a disruption of the paranodal complex. An axoglial dysjunction is also a characteristic finding of diabetic neuropathy. Here, we aim to investigate a possible association of antibody-mediated nodo-paranodopathy and diabetes mellitus (DM). Methods We retrospectively analyzed clinical data of 227 patients with chronic inflammatory demyelinating polyradiculoneuropathy and Guillain-Barr{\´e} syndrome from multiple centers in Germany who had undergone diagnostic testing for antiparanodal antibodies targeting neurofascin-155, pan-neurofascin, contactin-1-associated protein 1, and contactin-1. To study possible direct pathogenic effects of antiparanodal antibodies, we performed immunofluorescence binding assays on human pancreatic tissue sections. Results The frequency of DM was 33.3\% in seropositive patients and thus higher compared with seronegative patients (14.1\%, OR = 3.04, 95\% CI = 1.31-6.80). The relative risk of DM in seropositive patients was 3.4-fold higher compared with the general German population. Seropositive patients with DM most frequently harbored anti-contactin-1 antibodies and had higher antibody titers than seropositive patients without DM. The diagnosis of DM preceded the onset of neuropathy in seropositive patients. No immunoreactivity of antiparanodal antibodies against pancreatic tissue was detected. Discussion We report an association of nodo-paranodopathy and DM. Our results suggest that DM may be a potential risk factor for predisposing to developing nodo-paranodopathy and argue against DM being induced by the autoantibodies. Our findings set the basis for further research investigating underlying immunopathogenetic connections.}, language = {en} } @phdthesis{Behne2024, author = {Behne, Robert Stefan Friedrich}, title = {Development Of A Human iPSC-Derived Cortical Neuron Model Of Adaptor- Protein-Complex-4-Deficiency}, doi = {10.25972/OPUS-35139}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-351390}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Adaptor-protein-4-deficiency (AP-4-deficiency) is an autosomal-recessive childhood- onset form of complicated hereditary spastic paraplegia (HSP) caused by bi-allelic loss- of-function mutations in one of the four subunits of the AP-4-complex. These four conditions are named SPG47 (AP4B1, OMIM \#614066), SPG50 (AP4M1, OMIM \#612936), SPG51 (AP4E1, OMIM \#613744) and SPG52 (AP4S1, OMIM \#614067), respectively and all present with global developmental delay, progressive spasticity and seizures. Imaging features include a thinning of the corpus callosum, ventriculomegaly and white matter changes. AP-4 is a highly conserved heterotetrameric complex, which is responsible for polarized sorting of transmembrane cargo including the autophagy- related protein 9 A (ATG9A). Loss of any of the four subunits leads to an instable complex and defective sorting of AP-4-cargo. ATG9A is implicated in autophagosome formation and neurite outgrowth. It is missorted in AP-4-deficient cells and CNS-specific knockout of Atg9a in mice results in a phenotype reminiscent of AP-4-deficiency. However, the AP-4-related cellular phenotypes including ATG9A missorting have not been investigated in human neurons. Thus, the aim of this study is to provide the first human induced pluripotent stem cell- derived (iPSC) cortical neuron model of AP-4-deficiency to explore AP-4-related phenotypes in preparation for a high-content screening. Under the hypothesis that AP-4- deficiency leads to ATG9A missorting, elevated ATG9A levels, impaired autophagy and neurite outgrowth in human iPSC-derived cortical neurons, in vitro biochemical and imaging assays including automated high-content imaging and analysis were applied. First, these phenotypes were investigated in fibroblasts from three patients with compound heterozygous mutations in the AP4B1 gene and their sex-matched parental controls. The same cell lines were used to generate iPSCs and differentiate them into human excitatory cortical neurons. This work shows that ATG9A is accumulating in the trans-Golgi-network in AP-4- deficient human fibroblasts and that ATG9A levels are increased compared to parental controls and wild type cells suggesting a compensatory mechanism. Protein levels of the AP4E1-subunit were used as a surrogate marker for the AP-4-complex and were decreased in AP-4-deficient fibroblasts with co-immunoprecipitation confirming the instability of the complex. Lentiviral re-expression of the AP4B1-subunit rescues this corroborating the fact that a stable AP-4-complex is needed for ATG9A trafficking. Surprisingly, autophagic flux was present in AP-4-deficient fibroblasts under nutrient- rich and starvation conditions. These phenotypic markers were evaluated in iPSC-derived cortical neurons and here, a robust accumulation of ATG9A in the juxtanuclear area was seen together with elevated ATG9A protein levels. Strikingly, assessment of autophagy markers under nutrient-rich conditions showed alterations in AP-4-deficient iPSC- derived cortical neurons indicating dysfunctional autophagosome formation. These findings point towards a neuron-specific impairment of autophagy and need further investigation. Adding to the range of AP-4-related phenotypes, neurite outgrowth and branching are impaired in AP-4-deficient iPSC-derived cortical neurons as early as 24h after plating and together with recent studies point towards a distinct role of ATG9A in neurodevelopment independent of autophagy. Together, this work provides the first patient-derived neuron model of AP-4-deficiency and shows that ATG9A is sorted in an AP-4-dependent manner. It establishes ATG9A- related phenotypes and impaired neurite outgrowth as robust markers for a high-content screening. This disease model holds the promise of providing a platform to further study AP-4-deficiency and to search for novel therapeutic targets.}, subject = {Adaptorproteine}, language = {en} } @phdthesis{Kress2020, author = {Kreß, Luisa Sophia}, title = {Determination of cytokine and axon guidance molecule profiles in patients with small fiber neuropathy}, doi = {10.25972/OPUS-20911}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-209113}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {The pathophysiological mechanisms of pain in small fiber neuropathy (SFN) are unclear. Based on experimental and clinical studies, sensitized nociceptors in the skin are reported to be involved in pain development. These nociceptors may be sensitized by cutaneous and systemic pain mediators e.g. pro- and anti-inflammatory cytokines. The aim of our study was, to measure the systemic and local gene expression of pro- and anti-inflammatory cytokines in white blood cells (WBC) as well as in primary fibroblasts and keratinocytes obtained from human skin of patients with SFN. Furthermore, gene expression levels of axon guidance molecules and their receptors, as potential regulators of the intraepidermal nerve fiber density (IENFD), were investigated. 55 patients and 31 healthy controls were prospectively recruited. Participants underwent extensive clinical phenotyping and blood sampling, 6-mm skin punch biopsies were taken from the right lateral calf and the upper thigh. Systemic relative gene expression levels (ΔG) of the interleukin (IL)-1β, IL-2, IL-6, IL-8, and tumor necrosis factor (TNF) was measured in WBC. Skin punch biopsies were taken to determine the IENFD and to obtain primary fibroblast and keratinocyte cell cultures. Skin cells were then used for investigation of ΔG in axon guidance molecules netrin 1 (NTN1) and ephrin A4 (EPHA4) as well as their receptors Unc5b receptor, and ephrin A4 (EFNA4) as well as cytokines IL-1β, IL-4, IL-6, IL-8, IL-10, TNF, and transforming growth factor (TGF). Systemically, gene expression of IL-2, IL-8, and TNF was higher in SFN patients compared to healthy controls. In keratinocytes, higher expression levels of NTN1 and TGF were found when comparing the SFN patients to the controls. In fibroblasts higher gene expression was shown in NTN1, Unc5b, IL-6, and IL-8 when comparing patients to healthy controls. The systemically and local elevated levels of pro-inflammatory, algesic cytokines in SFN patients compared to healthy controls, confirms a potential pathophysiological role in the development of neuropathic pain. Data also indicate fibroblasts and keratinocytes to influence subepidermal and intraepidermal nerve fiber growth through the expression of NTN1 and Unc5b. Thus, skin cells may contribute to the development of neuropathic pain through local denervation.}, subject = {Neuropathischer Schmerz}, language = {en} } @phdthesis{Hemprich2022, author = {Hemprich, Antonia}, title = {Detektion von Autoantik{\"o}rpern gegen Cortactin und Agrin im Serum von Patient*innen mit Myasthenia gravis}, doi = {10.25972/OPUS-28692}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286920}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Myasthenia gravis ist eine Autoimmunerkrankung, die durch St{\"o}rung der Erregungs{\"u}bertragung an der neuromuskul{\"a}ren Endplatte zu einer Schw{\"a}che der Muskulatur f{\"u}hrt. In dieser Arbeit wird die Rolle von Cortactin und Agrin als potentielle neue Antigene von Autoantik{\"o}rpern bei Myasthenia gravis untersucht. Die detektierten Antik{\"o}rper werden charakterisiert und die klinischen Merkmale der Patient*innen ausgewertet.}, subject = {Myasthenia gravis}, language = {de} } @article{BrumbergKuzkinaLapaetal.2021, author = {Brumberg, Joachim and Kuzkina, Anastasia and Lapa, Constantin and Mammadova, Sona and Buck, Andreas and Volkmann, Jens and Sommer, Claudia and Isaias, Ioannis U. and Doppler, Kathrin}, title = {Dermal and cardiac autonomic fiber involvement in Parkinson's disease and multiple system atrophy}, series = {Neurobiology of Disease}, volume = {153}, journal = {Neurobiology of Disease}, doi = {10.1016/j.nbd.2021.105332}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260061}, pages = {105332}, year = {2021}, abstract = {Pathological aggregates of alpha-synuclein in peripheral dermal nerve fibers can be detected in patients with idiopathic Parkinson's disease and multiple system atrophy. This study combines skin biopsy staining for p-alpha-synuclein depositions and radionuclide imaging of the heart with [\(^{123}\)I]-metaiodobenzylguanidine to explore peripheral denervation in both diseases. To this purpose, 42 patients with a clinical diagnosis of Parkinson's disease or multiple system atrophy were enrolled. All patients underwent a standardized clinical workup including neurological evaluation, neurography, and blood samples. Skin biopsies were obtained from the distal and proximal leg, back, and neck for immunofluorescence double labeling with anti-p-alpha-synuclein and anti-PGP9.5. All patients underwent myocardial [\(^{123}\)I]-metaiodobenzylguanidine scintigraphy. Dermal p-alpha-synuclein was observed in 47.6\% of Parkinson's disease patients and was mainly found in autonomic structures. 81.0\% of multiple system atrophy patients had deposits with most of cases in somatosensory fibers. The [\(^{123}\)I]-metaiodobenzylguanidine heart-to-mediastinum ratio was lower in Parkinson's disease than in multiple system atrophy patients (1.94 +/- 0.63 vs. 2.91 +/- 0.96; p < 0.0001). Irrespective of the diagnosis, uptake was lower in patients with than without p-alpha-synuclein in autonomic structures (1.42 +/- 0.51 vs. 2.74 +/- 0.83; p < 0.0001). Rare cases of Parkinson's disease with p-alpha-synuclein in somatosensory fibers and multiple system atrophy patients with deposits in autonomic structures or both fiber types presented with clinically overlapping features. In conclusion, this study suggests that alpha-synuclein contributes to peripheral neurodegeneration and mediates the impairment of cardiac sympathetic neurons in patients with synucleinopathies. Furthermore, it indicates that Parkinson's disease and multiple system atrophy share pathophysiologic mechanisms of peripheral nervous system dysfunction with a clinical overlap.}, language = {en} } @phdthesis{Kuzkina2020, author = {Kuzkina, Anastasia}, title = {Dermal α-synuclein oligomers and aggregates in Parkinson's disease}, doi = {10.25972/OPUS-20436}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204369}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson's disease (PD). These depositions in the brain mostly consist of aggregated α-synuclein (α-syn) phosphorylated at Ser129. A number of studies reported detection of phosphorylated α-syn (p-α-syn) in the dermal nerve fibers in Parkinson's disease. The objective of this study was to investigate whether pathological α-syn accumulations detected in the skin represent aggregated protein. A number of methods aimed at detecting α-syn oligomers and aggregates were first tested and optimized on the brain samples in PD and normal control. These methods included proximity ligation assay (PLA), PET-blot, immunohistochemical (IHC) stains with α-syn aggregate (5G4) or oligomer specific (ASyO5) antibodies and a stain against native α-syn (syn211) after proteinase K (PK) digestion. Subsequently, the most specific methods (stains with 5G4, ASyO5 and syn211 after PK digestion) were studied in two separate patient and control cohorts. Anti-p-α-syn stain was performed in parallel. Single sections from at least 2 biopsy sites from 44 patients and 22 controls (cohort 1) as well as serial sections of 4 biopsy sites from 27 patients and 5 controls (cohort 2) were systematically studied for presence of aggregated and oligomeric α-syn. In total, 5G4 positive deposits were found in 24\% (cohort 1) and 37\% (cohort 2), ASyO5 positive lesions in 17,7\% (cohort 1) and 33\% (cohort 2), syn211 positive lesions after PK digestion in 38,7\% (cohort 1) and 48\% (cohort 2) of cases. There was a major overlap among positivity for a particular staining on the patient level and in most cases, the same nerve fiber was found to be positive for all 4 markers in neighboring sections. Among the skin biopsies which contained p-α-syn accumulation, 59\% were also PK resistant, 41\% were 5G4 positive and 45\% were ASyO5 positive. The samples belonging to normal controls did not show any positive signal in either of the newly established stainings or in the anti-p-α-syn staining. Using 3 distinct IHC methods, α-syn oligomers and aggregates were detectable in the majority of p-α-syn positive skin biopsies. This finding supports the hypothesis that α-syn aggregation occurs in the peripheral (i.e. dermal) nerves and can be specifically detected using skin biopsy.}, subject = {Parkinson-Krankheit}, language = {en} } @article{DopplerBrockmannSedghietal.2018, author = {Doppler, Kathrin and Brockmann, Kathrin and Sedghi, Annahita and Wurster, Isabel and Volkmann, Jens and Oertel, Wolfgang H. and Sommer, Claudia}, title = {Dermal phospho-alpha-synuclein deposition in patients with Parkinson's disease and mutation of the glucocerebrosidase gene}, series = {Frontiers in Neurology}, volume = {9}, journal = {Frontiers in Neurology}, doi = {10.3389/fneur.2018.01094}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222828}, year = {2018}, abstract = {Heterozygous mutations in the glucocerebrosidase gene (GBA1) represent the most common genetic risk factor for Parkinson's disease (PD) and are histopathologically associated with a widespread load of alpha-synuclein in the brain. Therefore, PD patients with GBA1 mutations are a cohort of high interest for clinical trials on disease-modifying therapies targeting alpha-synuclein. There is evidence that detection of phospho-alpha-synuclein (p-syn) in dermal nerve fibers might be a biomarker for the histopathological identification of PD patients even at premotor or very early stages of disease. It is so far unknown whether dermal p-syn deposition can also be found in PD patients with GBA1 mutations and may serve as a biomarker for PD in these patients. Skin biopsies of 10 PD patients with different GBA1 mutations (six N3705, three E326K, one L444P) were analyzed by double-immunofluorescence labeling with anti-p-syn and anti-protein gene product 9.5 (PGP9.5, axonal marker) to detect intraaxonal p-syn deposition. Four biopsy sites (distal, proximal leg, paravertebral Th10, and C7) per patient were studied. P-syn was found in six patients (three N370S, three E326K). P-syn deposition was mainly detected in autonomic nerve fibers, but also in somatosensory fibers and was not restricted to a certain GBA1 mutation. In summary, dermal p-syn in PD patients with GBA1 mutations seems to offer a similar distribution and frequency as observed in patients without a known mutation. Skin biopsy may be suitable to study p-syn deposition in these patients or even to identify premotor patients with GBA1 mutations.}, language = {en} } @phdthesis{KuettnergebWeber2021, author = {K{\"u}ttner [geb. Weber], Sarah-Lucia}, title = {Der Optikusnervenscheidendurchmesser als Instrument zur Prognoseeinsch{\"a}tzung bei Patienten mit hypoxischer Enzephalopathie nach erfolgreicher Reanimation}, doi = {10.25972/OPUS-23766}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237669}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Eine Prognoseeinsch{\"a}tzung bei Patienten mit hypoxischer Enzephalopathie (HIE) nach Reanimation wird fr{\"u}hestens 72 Stunden nach Reanimation empfohlen. Bis zu diesem Zeitpunkt besteht eine f{\"u}r {\"A}rzte und Angeh{\"o}rige belastende prognostische L{\"u}cke. Und auch nach 72 Stunden bestehen nur ungenaue Angaben zum weiteren Vorgehen, sodass eine fundierte Prognoseeinsch{\"a}tzung aktuell eine deutliche Herausforderung im Alltag klinisch t{\"a}tiger {\"A}rzte darstellt. Der Nervus opticus ist als Bestandteil des zentralen Nervensystems mit dem Liquorsystem verbunden. Intrazerebrale Druckerh{\"o}hungen wirken sich daher unmittelbar auf die ihn ummantelnde Nervenscheide und deren Durchmesser aus, sodass sich die Bestimmung des Optikusnervenscheidendurchmessers (ONSD) mittels transorbitaler Sonographie in der Diagnostik unterschiedlicher intrakranieller Erkrankungen bereits bew{\"a}hrt hat. Das Krankheitsbild der HIE wurde als weiteres m{\"o}gliches Einsatzgebiet des ONSD jedoch bisher nicht untersucht. 
Ziel dieser Dissertation war es daher, den ONSD grunds{\"a}tzlich auf seine Verl{\"a}sslichkeit als Prognoseparameter bei HIE nach Reanimation zu {\"u}berpr{\"u}fen. Besonderes Augenmerk lag hierbei auf der Erm{\"o}glichung einer fr{\"u}hzeitigen Prognoseeinsch{\"a}tzung innerhalb von 24 Stunden sowie auf der Definition eines prognostischen Cut-Off-Wertes als klare Entscheidungshilfe f{\"u}r weitere therapeutische Strategien. 24, 48 und 72 Stunden nach Reanimation werden signifikant unterschiedliche ONSD unter {\"u}berlebenden und verstorbenen Patienten nachgewiesen. Letztere weisen dabei im Vergleich sowohl h{\"o}here als auch im zeitlichen Verlauf signifikant ansteigende ONSD-Werte auf. Als prognostischer Cut-Off-Wert konnte eine Grenze bei 5,75mm festgelegt werden. Zusammenfassend stellt die sonographische Bestimmung des ONSD eine sinnvolle Zusatzdiagnostik in der Prognoseeinsch{\"a}tzung bei Patienten mit HIE nach Reanimation dar.}, subject = {Wiederbelebung}, language = {de} } @phdthesis{Rosen2005, author = {Rosen, Sandra}, title = {Der Einsatz von Abciximab (ReoPro®) in der Akutbehandlung von isch{\"a}mischen Hirninfarkten mit und ohne vorangehende Thrombolysebehandlung mit rt-PA}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-17514}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2005}, abstract = {Abciximab wurde, in Phase II-Studien, in der Behandlung der akuten cerebralen Isch{\"a}mie erprobt und es erscheint bisher sicher und effektiv. Obwohl die Effektivit{\"a}t in der Abciximab in Acute Ischemic Stroke Studie nicht prospektiv untersucht wurde, ist jedoch ein Trend zu einem verbessertem Outcome zu beobachten. In unserer Untersuchung wurden 65 Patienten mit cerebralen Isch{\"a}mien in verschiedenen Gef{\"a}ßterritorien mit Abciximab behandelt. Die Patienten zeigten entweder Zeichen und Symptome einer Crescendo-TIA, eines progressive stroke außerhalb des "3-Stunden-Zeitfensters" f{\"u}r eine Thrombolyse oder eine erneute Verschlechterung nach zun{\"a}chst erfolgreicher Thrombolyse. Alle Patienten wurden anhand der modified Rankin Scale (mRS) zum Zeitpunkt des Eintreffens in der Klinik und am Tag der Entlassung von der Stroke Unit untersucht. Ergebnisse: 88\% der Patienten (57/65) verbesserten sich um im Mittel 2,3 Punkte bezogen auf die mRS. 71\% der Patienten (46/65) erreichten eine mRS von 0-2. Es wurden keine fatalen oder symptomatischen intracerebralen Blutungen beobachtet. Fazit: In dieser nicht-randomisierten Untersuchung {\"u}ber die Akuttherapie der cerebralen Isch{\"a}mie, zeigte die Behandlung mit Abciximab alleine oder in Kombination mit Thrombolyse eine klinische Verbesserung in 88\% der Patienten. Blutungskomplikationen waren selten und nie schwerwiegend. Diese Ergebnisse unterst{\"u}tzen die Forderung nach weiteren placebokontrollierten, randomisierten Studien von Abciximab in der Akutbehandlung der cerebralen Isch{\"a}mie.}, language = {de} }