TY - JOUR A1 - Hohnmann, Christopher A1 - Milles, Bianca A1 - Schinke, Michael A1 - Schroeter, Michael A1 - Ulzheimer, Jochen A1 - Kraft, Peter A1 - Kleinschnitz, Christoph A1 - Lehmann, Paul V. A1 - Kuerten, Stefanie T1 - Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood JF - Acta Neuropathologica Communications N2 - Introduction B cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients. Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) directly ex vivo and after 96 h of polyclonal stimulation. Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS). Results Nine patients displayed B cells in the blood producing brain-specific antibodies directly ex vivo. Six patients were classified as B cell positive donors only after polyclonal B cell stimulation. In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorized MS relapses into three different patterns. Patients who displayed brain-reactive B cell responses both directly ex vivo and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; p = 0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse. The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40%) with a pattern II and three of 14 patients (21.4%) with a pattern III response (p = 0.0005; hazard ratio 6.08 (95% confidence interval 1.87-19.77). Conclusions Our data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients. KW - predictive value KW - MS KW - ELISPOT KW - B cells KW - relapse Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126124 VL - 2 IS - 138 ER - TY - JOUR A1 - Hohmann, Christopher A1 - Milles, Bianca A1 - Schinke, Michael A1 - Schroeter, Michael A1 - Ulzheimer, Jochen A1 - Kraft, Peter A1 - Kleinschnitz, Christoph A1 - Lehmann, Paul V. A1 - Kuerten, Stefanie T1 - Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood JF - Acta Neuropathologica Communications N2 - INTRODUCTION: B cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients. Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) directly ex vivo and after 96 h of polyclonal stimulation. Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS). RESULTS: Nine patients displayed B cells in the blood producing brain-specific antibodies directly ex vivo. Six patients were classified as B cell positive donors only after polyclonal B cell stimulation. In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorized MS relapses into three different patterns. Patients who displayed brain-reactive B cell responses both directly ex vivo and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; p = 0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse. The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40%) with a pattern II and three of 14 patients (21.4%) with a pattern III response (p = 0.0005; hazard ratio 6.08 (95% confidence interval 1.87-19.77). CONCLUSIONS: Our data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients. KW - ELISPOT KW - MS KW - predictive value KW - relapse KW - B cells Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120580 SN - 2051-5960 VL - 2 IS - 138 ER - TY - JOUR A1 - Kraft, Peter A1 - Drechsler, Christiane A1 - Gunreben, Ignaz A1 - Heuschmann, Peter Ulrich A1 - Kleinschnitz, Christoph T1 - Case-control study of platelet glycoprotein receptor Ib and IIb/IIIa expression in patients with acute and chronic cerebrovascular disease JF - PLoS ONE N2 - Background Animal models have been instrumental in defining thrombus formation, including the role of platelet surface glycoprotein (GP) receptors, in acute ischemic stroke (AIS). However, the involvement of GP receptors in human ischemic stroke pathophysiology and their utility as biomarkers for ischemic stroke risk and severity requires elucidation. Aims To determine whether platelet GPIb and GPIIb/IIIa receptors are differentially expressed in patients with AIS and chronic cerebrovascular disease (CCD) compared with healthy volunteers (HV) and to identify predictors of GPIb and GPIIb/IIIa expression. Methods This was a case-control study of 116 patients with AIS or transient ischemic attack (TIA), 117 patients with CCD, and 104 HV who were enrolled at our University hospital from 2010 to 2013. Blood sampling was performed once in the CCD and HV groups, and at several time points in patients with AIS or TIA. Linear regression and analysis of variance were used to analyze correlations between platelet GPIb and GPIIb/IIIa receptor numbers and demographic and clinical parameters. Results GPIb and GPIIb/IIIa receptor numbers did not significantly differ between the AIS, CCD, and HV groups. GPIb receptor expression level correlated significantly with the magnitude of GPIIb/IIIa receptor expression and the neutrophil count. In contrast, GPIIb/IIIa receptor numbers were not associated with peripheral immune-cell sub-population counts. Creactive protein was an independent predictor of GPIIb/IIIa (not GPIb) receptor numbers. Conclusions Platelet GPIb and GPIIb/IIIa receptor numbers did not distinguish between patient or control groups in this study, negating their potential use as a biomarker for predicting stroke risk. KW - von Willebrand factor KW - cardiovascular disease KW - increased risk KW - mice impact KW - polymorphisms inflammation KW - blood coagulability KW - atherosclerosis KW - acute ischemic stroke Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148806 VL - 10 IS - 3 ER - TY - JOUR A1 - Zeller, Daniel A1 - Heidemeier, Anke A1 - Grigoleit, Götz Ulrich A1 - Müllges, Wolfgang T1 - Case report: subacute tetraplegia in an immunocompromised patient JF - BMC Neurology N2 - Background: Clinical reasoning in Neurology is based on general associations which help to deduce the site of the lesion. However, even “golden principles” may occasionally be deceptive. Here, we describe the case of subacute flaccid tetraparesis due to motor cortical lesions. To our knowledge, this is the first report to include an impressive illustration of nearly symmetric motor cortical involvement of encephalitis on brain MRI. Case presentation: A 51 year old immunocompromized man developed a high-grade pure motor flaccid tetraparesis over few days. Based on clinical presentation, critical illness polyneuromyopathy was suspected. However, brain MRI revealed symmetrical hyperintensities strictly limited to the subcortical precentral gyrus. An encephalitis, possibly due to CMV infection, turned out to be the most likely cause. Conclusion: While recognition of basic clinical patterns is indispensable in neurological reasoning, awareness of central conditions mimicking peripheral nervous disease may be crucial to detect unsuspected, potentially treatable conditions. KW - tetraparesis KW - motor cortex KW - CMV KW - encephalitis KW - case report Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157576 VL - 17 IS - 31 ER - TY - JOUR A1 - Montellano, Felipe A. A1 - Kluter, Elisabeth J. A1 - Rücker, Viktoria A1 - Ungethüm, Kathrin A1 - Mackenrodt, Daniel A1 - Wiedmann, Silke A1 - Dege, Tassilo A1 - Quilitzsch, Anika A1 - Morbach, Caroline A1 - Frantz, Stefan A1 - Störk, Stefan A1 - Haeusler, Karl Georg A1 - Kleinschnitz, Christoph A1 - Heuschmann, Peter U. T1 - Cardiac dysfunction and high-sensitive C-reactive protein are associated with troponin T elevation in ischemic stroke: insights from the SICFAIL study JF - BMC Neurology N2 - Background Troponin elevation is common in ischemic stroke (IS) patients. The pathomechanisms involved are incompletely understood and comprise coronary and non-coronary causes, e.g. autonomic dysfunction. We investigated determinants of troponin elevation in acute IS patients including markers of autonomic dysfunction, assessed by heart rate variability (HRV) time domain variables. Methods Data were collected within the Stroke Induced Cardiac FAILure (SICFAIL) cohort study. IS patients admitted to the Department of Neurology, Würzburg University Hospital, underwent baseline investigation including cardiac history, physical examination, echocardiography, and blood sampling. Four HRV time domain variables were calculated in patients undergoing electrocardiographic Holter monitoring. Multivariable logistic regression with corresponding odds ratios (OR) and 95% confidence intervals (CI) was used to investigate the determinants of high-sensitive troponin T (hs-TnT) levels ≥14 ng/L. Results We report results from 543 IS patients recruited between 01/2014–02/2017. Of those, 203 (37%) had hs-TnT ≥14 ng/L, which was independently associated with older age (OR per year 1.05; 95% CI 1.02–1.08), male sex (OR 2.65; 95% CI 1.54–4.58), decreasing estimated glomerular filtration rate (OR per 10 mL/min/1.73 m2 0.71; 95% CI 0.61–0.84), systolic dysfunction (OR 2.79; 95% CI 1.22–6.37), diastolic dysfunction (OR 2.29; 95% CI 1.29–4.02), atrial fibrillation (OR 2.30; 95% CI 1.25–4.23), and increasing levels of C-reactive protein (OR 1.48 per log unit; 95% CI 1.22–1.79). We did not identify an independent association of troponin elevation with the investigated HRV variables. Conclusion Cardiac dysfunction and elevated C-reactive protein, but not a reduced HRV as surrogate of autonomic dysfunction, were associated with increased hs-TnT levels in IS patients independent of established cardiovascular risk factors. KW - echocardiography KW - ischemic stroke KW - troponin KW - heart failure KW - biomarkers Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300119 VL - 22 IS - 1 ER - TY - JOUR A1 - Albert-Weissenberger, Christiane A1 - Mencl, Stine A1 - Schuhmann, Michael K. A1 - Salur, Irmak A1 - Göb, Eva A1 - Langhauser, Friederike A1 - Hopp, Sarah A1 - Hennig, Nelli A1 - Meuth, Sven G. A1 - Nolte, Marc W. A1 - Sirén, Anna-Leena A1 - Kleinschnitz, Christoph T1 - C1-Inhibitor protects from focal brain trauma in a cortical cryolesion mice model by reducing thrombo-inflammation JF - Frontiers in Cellular Neuroscience N2 - Traumatic brain injury (TBI) induces a strong inflammatory response which includes blood-brain barrier damage, edema formation and infiltration of different immune cell subsets. More recently, microvascular thrombosis has been identified as another pathophysiological feature of TBI. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is activated in different neurological diseases. C1-Inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-Inhibitor in a model of TBI. Male and female C57BL/6 mice were subjected to cortical cryolesion and treated with C1-Inhibitor after 1 h. Lesion volumes were assessed between day 1 and day 5 and blood-brain barrier damage, thrombus formation as well as the local inflammatory response were determined post TBI. Treatment of male mice with 15.0 IU C1-Inhibitor, but not 7.5 IU, 1 h after cryolesion reduced lesion volumes by ~75% on day 1. This protective effect was preserved in female mice and at later stages of trauma. Mechanistically, C1-Inhibitor stabilized the blood-brain barrier and decreased the invasion of immune cells into the brain parenchyma. Moreover, C1-Inhibitor had strong antithrombotic effects. C1-Inhibitor represents a multifaceted anti-inflammatory and antithrombotic compound that prevents traumatic neurodegeneration in clinically meaningful settings. KW - thrombosis KW - traumatic brain injury KW - C1-inhibitor KW - blood-brain barrier KW - contact-kinin system KW - edema KW - inflammation Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119263 SN - 1662-5102 VL - 8 ER - TY - JOUR A1 - Gunkel, Sarah A1 - Schötzau, Andreas A1 - Fluri, Felix T1 - Burden of cerebral small vessel disease and changes of diastolic blood pressure affect clinical outcome after acute ischemic stroke JF - Scientific Reports N2 - Elevated and low blood pressure (BP) may lead to poor functional outcome after ischemic stroke, which is conflicting. Hence, there must be another factor—such as cerebral small vessel disease (cSVD) -interacting with BP and thus, affecting outcome. Here, we investigate the relationship between BP and cSVD regarding outcome after stroke. Data of 423/503 stroke patients were prospectively analyzed. Diastolic (DBP) and systolic BP (SBP) were collected on hospital admission (BP\(_{ad}\)) and over the first 72 h (BP\(_{72h}\)). cSVD-burden was determined on MR-scans. Good functional outcome was defined as a modified Rankin Scale score ≤ 2 at hospital discharge and 12 months thereafter. cSVD was a predictor of poor outcome (OR 2.8; p < 0.001). SBPad, DBP\(_{ad}\) and SBP\(_{72h}\) were not significantly associated with outcome at any time. A significant relationship was found between DBP\(_{72h}\), (p < 0.01), cSVD (p = 0.013) and outcome at discharge. At 12 months, we found a relationship between outcome and DBP\(_{72h}\) (p = 0.018) and a statistical tendency regarding cSVD (p = 0.08). Changes in DBP72h were significantly related with outcome. There was a U-shaped relationship between DBP\(_{72h}\) and outcome at discharge. Our results suggest an individualized stroke care by either lowering or elevating DBP depending on cSVD-burden in order to influence functional outcome. KW - cerebrovascular disorders KW - neurological disorders KW - stroke KW - white matter disease Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357669 VL - 13 ER - TY - JOUR A1 - McFleder, Rhonda L. A1 - Makhotkina, Anastasiia A1 - Groh, Janos A1 - Keber, Ursula A1 - Imdahl, Fabian A1 - Peña Mosca, Josefina A1 - Peteranderl, Alina A1 - Wu, Jingjing A1 - Tabuchi, Sawako A1 - Hoffmann, Jan A1 - Karl, Ann-Kathrin A1 - Pagenstecher, Axel A1 - Vogel, Jörg A1 - Beilhack, Andreas A1 - Koprich, James B. A1 - Brotchie, Jonathan M. A1 - Saliba, Antoine-Emmanuel A1 - Volkmann, Jens A1 - Ip, Chi Wang T1 - Brain-to-gut trafficking of alpha-synuclein by CD11c\(^+\) cells in a mouse model of Parkinson’s disease JF - Nature Communications N2 - Inflammation in the brain and gut is a critical component of several neurological diseases, such as Parkinson’s disease (PD). One trigger of the immune system in PD is aggregation of the pre-synaptic protein, α-synuclein (αSyn). Understanding the mechanism of propagation of αSyn aggregates is essential to developing disease-modifying therapeutics. Using a brain-first mouse model of PD, we demonstrate αSyn trafficking from the brain to the ileum of male mice. Immunohistochemistry revealed that the ileal αSyn aggregations are contained within CD11c+ cells. Using single-cell RNA sequencing, we demonstrate that ileal CD11c\(^+\) cells are microglia-like and the same subtype of cells is activated in the brain and ileum of PD mice. Moreover, by utilizing mice expressing the photo-convertible protein, Dendra2, we show that CD11c\(^+\) cells traffic from the brain to the ileum. Together these data provide a mechanism of αSyn trafficking between the brain and gut. KW - antigen-presenting cells KW - neuroimmunology KW - Parkinson's disease Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357696 VL - 14 ER - TY - JOUR A1 - Pozzi, Nicoló Gabriele A1 - Bolzoni, Francesco A1 - Biella, Gabriele Eliseo Mario A1 - Pezzoli, Gianni A1 - Ip, Chi Wang A1 - Volkmann, Jens A1 - Cavallari, Paolo A1 - Asan, Esther A1 - Isaias, Ioannis Ugo T1 - Brain noradrenergic innervation supports the development of Parkinson’s tremor: a study in a reserpinized rat model JF - Cells N2 - The pathophysiology of tremor in Parkinson’s disease (PD) is evolving towards a complex alteration to monoaminergic innervation, and increasing evidence suggests a key role of the locus coeruleus noradrenergic system (LC-NA). However, the difficulties in imaging LC-NA in patients challenge its direct investigation. To this end, we studied the development of tremor in a reserpinized rat model of PD, with or without a selective lesioning of LC-NA innervation with the neurotoxin DSP-4. Eight male rats (Sprague Dawley) received DSP-4 (50 mg/kg) two weeks prior to reserpine injection (10 mg/kg) (DR-group), while seven male animals received only reserpine treatment (R-group). Tremor, rigidity, hypokinesia, postural flexion and postural immobility were scored before and after 20, 40, 60, 80, 120 and 180 min of reserpine injection. Tremor was assessed visually and with accelerometers. The injection of DSP-4 induced a severe reduction in LC-NA terminal axons (DR-group: 0.024 ± 0.01 vs. R-group: 0.27 ± 0.04 axons/um\(^2\), p < 0.001) and was associated with significantly less tremor, as compared to the R-group (peak tremor score, DR-group: 0.5 ± 0.8 vs. R-group: 1.6 ± 0.5; p < 0.01). Kinematic measurement confirmed the clinical data (tremor consistency (% of tremor during 180 s recording), DR-group: 37.9 ± 35.8 vs. R-group: 69.3 ± 29.6; p < 0.05). Akinetic–rigid symptoms did not differ between the DR- and R-groups. Our results provide preliminary causal evidence for a critical role of LC-NA innervation in the development of PD tremor and foster the development of targeted therapies for PD patients. KW - Parkinson’s disease KW - tremor KW - locus coeruleus KW - noradrenaline KW - reserpinized rat model Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357721 SN - 2073-4409 VL - 12 IS - 21 ER - TY - JOUR A1 - Isaias, Ioannis U. A1 - Brumberg, Joachim A1 - Pozzi, Nicoló G. A1 - Palmisano, Chiara A1 - Canessa, Andrea A1 - Marotta, Giogio A1 - Volkmann, Jens A1 - Pezzoli, Gianni T1 - Brain metabolic alterations herald falls in patients with Parkinson's disease JF - Annals of Clinical and Translational Neurology N2 - Pathophysiological understanding of gait and balance disorders in Parkinson’s disease is insufficient and late recognition of fall risk limits efficacious followup to prevent or delay falls. We show a distinctive reduction of glucose metabolism in the left posterior parietal cortex, with increased metabolic activity in the cerebellum, in parkinsonian patients 6–8 months before their first fall episode. Falls in Parkinson’s disease may arise from altered cortical processing of body spatial orientation, possibly predicted by abnormal cortical metabolism. KW - Parkionson's disease KW - brain metabolic alterations Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235982 VL - 7 IS - 4 ER - TY - JOUR A1 - Dauer née Joppe, Karina A1 - Tatenhorst, Lars A1 - Caldi Gomes, Lucas A1 - Zhang, Shuyu A1 - Parvaz, Mojan A1 - Carboni, Eleonora A1 - Roser, Anna‐Elisa A1 - El DeBakey, Hazem A1 - Bähr, Mathias A1 - Vogel‐Mikuš, Katarina A1 - Wang Ip, Chi A1 - Becker, Stefan A1 - Zweckstetter, Markus A1 - Lingor, Paul T1 - Brain iron enrichment attenuates α‐synuclein spreading after injection of preformed fibrils JF - Journal of Neurochemistry N2 - Regional iron accumulation and α‐synuclein (α‐syn) spreading pathology within the central nervous system are common pathological findings in Parkinson's disease (PD). Whereas iron is known to bind to α‐syn, facilitating its aggregation and regulating α‐syn expression, it remains unclear if and how iron also modulates α‐syn spreading. To elucidate the influence of iron on the propagation of α‐syn pathology, we investigated α‐syn spreading after stereotactic injection of α‐syn preformed fibrils (PFFs) into the striatum of mouse brains after neonatal brain iron enrichment. C57Bl/6J mouse pups received oral gavage with 60, 120, or 240 mg/kg carbonyl iron or vehicle between postnatal days 10 and 17. At 12 weeks of age, intrastriatal injections of 5‐µg PFFs were performed to induce seeding of α‐syn aggregates. At 90 days post‐injection, PFFs‐injected mice displayed long‐term memory deficits, without affection of motor behavior. Interestingly, quantification of α‐syn phosphorylated at S129 showed reduced α‐syn pathology and attenuated spreading to connectome‐specific brain regions after brain iron enrichment. Furthermore, PFFs injection caused intrastriatal microglia accumulation, which was alleviated by iron in a dose‐dependent way. In primary cortical neurons in a microfluidic chamber model in vitro, iron application did not alter trans‐synaptic α‐syn propagation, possibly indicating an involvement of non‐neuronal cells in this process. Our study suggests that α‐syn PFFs may induce cognitive deficits in mice independent of iron. However, a redistribution of α‐syn aggregate pathology and reduction of striatal microglia accumulation in the mouse brain may be mediated via iron‐induced alterations of the brain connectome. KW - alpha‐synuclein KW - alpha‐synuclein propagation KW - alpha‐synuclein seeding KW - iron dyshomeostasis KW - Parkinson's disease Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262544 VL - 159 IS - 3 SP - 554 EP - 573 ER - TY - JOUR A1 - Westermaier, Thomas A1 - Stetter, Christian A1 - Raslan, Furat A1 - Vinc, Giles Hamilton A1 - Ernestus, Ralf-Ingo T1 - Brain edema formation correlates with perfusion deficit during the first six hours after experimental subarachnoid hemorrhage in rats N2 - Background: Severe brain edema is observed in a number of patients suffering from subarachnoid hemorrhage (SAH). Little is known about its pathogenesis and time-course in the first hours after SAH. This study was performed to investigate the development of brain edema and its correlation with brain perfusion after experimental SAH. Methods: Male Sprague–Dawley rats, randomly assigned to one of six groups (n = 8), were subjected to SAH using the endovascular filament model or underwent a sham operation. Animals were sacrificed 15, 30, 60, 180 or 360 minutes after SAH. Intracranial pressure (ICP), mean arterial blood pressure (MABP), cerebral perfusion pressure (CPP) and bilateral local cerebral blood flow (LCBF) were continuously measured. Brain water content (BWC) was determined by the wet/dry-weight method. Results: After SAH, CPP and LCBF rapidly decreased. The decline of LCBF markedly exceeded the decline of CPP and persisted until the end of the observation period. BWC continuously increased. A significant correlation was observed between the BWC and the extent of the perfusion deficit in animals sacrificed after 180 and 360 minutes. Conclusions: The significant correlation with the perfusion deficit after SAH suggests that the development of brain edema is related to the extent of ischemia and acute vasoconstriction in the first hours after SAH. KW - Medizin KW - Subarachnoid hemorrhage KW - Cerebral blood flow KW - Brain ischemia KW - Brain edema KW - Animal models Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75765 ER - TY - THES A1 - Neukirchen, Sebastian T1 - Borrelienneuropathie - eine histologische und immunhistochemische Charakterisierung T1 - Borrelianeuropathy - a histologic and immunhistochemical characterization N2 - Die Pathomechanismen der Neuropathie bei Neuroborreliose sind noch immer unklar. In der vorliegenden Studie untersuchten wir 22 Patienten mit einer Neuropathie bei Neuroborreliose (BN) (3 Patienten in Stadium 2, 19 Patienten in Stadium 3) und verglichen diese mit 9 Patienten einer vaskulitischen Neuropathie (VN) und 14 Patienten einer idiopathisch axonalen Neuropathie (AN). Histologische und immunhistochemische Färbungen wurden mit Antikörpern gegen Leu4, CD68, 27E10 (frühzeitig aktivierte Makrophagen) und 25F9 (späte Makrophagen), Membrane-Attack-Komplex C5b-9, Adhäsionsmolekül ICAM sowie inflammatorische Zytokine Tumor Nekrose-Faktor-alpha (TNF-alpha), Interleukin-1ß (IL-1ß) und Interleukin-6 (IL-6), als auch Metalloproteinase MMP-9 durchgeführt, ferner mit Antikörpern gegen das membranassoziierte Glykoprotein HLA-DR3. Zusätzlich wurden Semi-Dünn-Schnitte angefertigt. Klinisch wiesen die meisten BN Patienten eine distal symmetrische sensomotorische Neuropathie auf, nur 6/22 Patienten waren schmerzfrei. Die Mehrzahl (18/22) der BN Neuropathien waren primär axonal mit perivaskulären (6/22), in 8 Fällen vaskulitischen Infiltraten. Das Perineurium war schwerpunktmäßig im Rahmen einer Borrelien-assoziierten Neuropathie betroffen. Das lies sich aus dem gegenüber den Kontrollgruppen signifikant verdickten Perineurium, der vermehrten Vaskularisation des Perineuriums und der starken IR für das Zytokin TNF-α schliessen, in geringerem Ausmaß für IL-1β, und für die terminale Komplementkomponente C5b9. Perivaskuläre und vaskuläre Infiltrate sowie die betont perineurale Expression bestimmter inflammatorischer Zytokine und Adhäsionsmoleküle erschienen charakteristisch für eine Neuropathie bei Neuroborreliose. Autoimmune Reaktionen mit Angriff am Perineurium können für die Pathogenese der Neuropathie bei Neuroborreliose bedeutsam sein. N2 - The pathologic mechanisms in Lyme Borreliosis are still unknown. In this study we examinated 22 patients with neuropathy in Neuroborreliosis (3 patients in stadium 2, 19 patients in stadium 3) and compared them to 9 patients with vasculitic neuropathy (VN) and to 14 patients with idiopathic axonal neuropathy (AN). Histologic and immunohistochemical stainings on sural nerve biopsies with antibodies against Leu4, CD68, 27E10 (early macrophages) and 25F9 (late macrophages), membrane-attack-complex C5b9, adhesionmolecule ICAM and inflammatoric cytokines tumor-necrosis-factor-alpha (TNF-alpha), interleukin-1β (IL-1β) and interleukin-6 (IL-6), metalloproteinases-9 (MMP-9) and membrane-associated glykoprotein HLA-DR3 were obtained. Additional semi thin sections were performed. Clinically, most of the patients had distal, symmetric, sensomotoric neuropathy, only 6 (of 22) did not feel any pain. Most of the BN-patients showed a primary axonal neuropathy, in 6 cases (of 22) with pervasculitic and in 8 cases with vasculitic infiltrates. Perineurial tissues play an extraodinary important role for the pathogenesis of neuroborreliosis. This can be claimed because of the significant thickened perineurium, the increased perineurial vascularisation and the intense IR for cytokine TNF alpha. Perivascular and vascular infiltrates as well as the definite perineurial expression of certain inflammatory cytokines and adhesion molecules seemed to be distinguishing for neuropathy in context of Neuroborreliosis. Autoimmune reactions followed by affection of the perineurium may play a role in the pathogenesis of a neuroborreliosis. KW - Borrelien KW - Neuropathie KW - Suralisbiopsien KW - Lyme-Krankheit KW - ECM KW - Borreliosis KW - neuropathy KW - sural nerve KW - Lyme-disease KW - ECM Y1 - 2005 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-16147 ER - TY - JOUR A1 - Göbel, Kerstin A1 - Pankratz, Susann A1 - Asaridou, Chloi-Magdalini A1 - Herrmann, Alexander M. A1 - Bittner, Stefan A1 - Merker, Monika A1 - Ruck, Tobias A1 - Glumm, Sarah A1 - Langhauser, Friederike A1 - Kraft, Peter A1 - Krug, Thorsten F. A1 - Breuer, Johanna A1 - Herold, Martin A1 - Gross, Catharina C. A1 - Beckmann, Denise A1 - Korb-Pap, Adelheid A1 - Schuhmann, Michael K. A1 - Kuerten, Stefanie A1 - Mitroulis, Ioannis A1 - Ruppert, Clemens A1 - Nolte, Marc W. A1 - Panousis, Con A1 - Klotz, Luisa A1 - Kehrel, Beate A1 - Korn, Thomas A1 - Langer, Harald F. A1 - Pap, Thomas A1 - Nieswandt, Bernhard A1 - Wiendl, Heinz A1 - Chavakis, Triantafyllos A1 - Kleinschnitz, Christoph A1 - Meuth, Sven G. T1 - Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells JF - Nature Communications N2 - Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein–kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders. KW - blood coagulation KW - factor XII KW - neuroinflammation KW - dendric cells Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165503 VL - 7 IS - 11626 ER - TY - JOUR A1 - Schuhmann, Michael K. A1 - Guthmann, Josua A1 - Stoll, Guido A1 - Nieswandt, Bernhard A1 - Kraft, Peter A1 - Kleinschnitz, Christoph T1 - Blocking of platelet glycoprotein receptor Ib reduces “thrombo-inflammation” in mice with acute ischemic stroke JF - Journal of Neuroinflammation N2 - Background: Ischemic stroke causes a strong inflammatory response that includes T cells, monocytes/macrophages, and neutrophils. Interaction of these immune cells with platelets and endothelial cells facilitates microvascular dysfunction and leads to secondary infarct growth. We recently showed that blocking of platelet glycoprotein (GP) receptor Ib improves stroke outcome without increasing the risk of intracerebral hemorrhage. Until now, it has been unclear whether GPIb only mediates thrombus formation or also contributes to the pathophysiology of local inflammation. Methods: Focal cerebral ischemia was induced in C57BL/6 mice by a 60-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with antigen-binding fragments (Fab) against the platelet surface molecules GPIb (p0p/B Fab). Rat immunoglobulin G (IgG) Fab was used as control treatment. Stroke outcome, including infarct size and functional deficits as well as the local inflammatory response, was assessed on day 1 after tMCAO. Results: Blocking of GPIb reduced stroke size and improved functional outcome on day 1 after tMCAO without increasing the risk of intracerebral hemorrhage. As expected, disruption of GPIb-mediated pathways in platelets significantly reduced thrombus burden in the cerebral microvasculature. In addition, inhibition of GPIb limited the local inflammatory response in the ischemic brain as indicated by lower numbers of infiltrating T cells and macrophages and lower expression levels of inflammatory cytokines compared with rat IgG Fab-treated controls. Conclusion: In acute ischemic stroke, thrombus formation and inflammation are closely intertwined (“thrombo-inflammation”). Blocking of platelet GPIb can ameliorate thrombo-inflammation. KW - ischemic stroke KW - occlusion KW - transient middle cerebral artery KW - glycoprotein receptor Ib KW - thrombo-inflammation Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157582 VL - 14 IS - 18 ER - TY - JOUR A1 - Albert-Weissenberger, Christiane A1 - Stetter, Christian A1 - Meuth, Sven G. A1 - Göbel, Kerstin A1 - Bader, Michael A1 - Sirén, Anna-Leena A1 - Kleinschnitz, Christoph T1 - Blocking of Bradykinin Receptor B1 Protects from Focal Closed Head Injury in Mice by Reducing Axonal Damage and Astroglia Activation JF - Journal of Cerebral Blood Flow and Metabolism N2 - The two bradykinin receptors B1R and B2R are central components of the kallikrein–kinin system with different expression kinetics and binding characteristics. Activation of these receptors by kinins triggers inflammatory responses in the target organ and in most situations enhances tissue damage. We could recently show that blocking of B1R, but not B2R, protects from cortical cryolesion by reducing inflammation and edema formation. In the present study, we investigated the role of B1R and B2R in a closed head model of focal traumatic brain injury (TBI; weight drop). Increased expression of B1R in the injured hemispheres of wild-type mice was restricted to the later stages after brain trauma, i.e. day 7 (P<0.05), whereas no significant induction could be observed for the B2R (P>0.05). Mice lacking the B1R, but not the B2R, showed less functional deficits on day 3 (P<0.001) and day 7 (P<0.001) compared with controls. Pharmacological blocking of B1R in wild-type mice had similar effects. Reduced axonal injury and astroglia activation could be identified as underlying mechanisms, while inhibition of B1R had only little influence on the local inflammatory response in this model. Inhibition of B1R may become a novel strategy to counteract trauma-induced neurodegeneration. KW - R-715 KW - kinin receptors KW - closed head injury KW - β-APP KW - astrocytes KW - TNF-α Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125903 VL - 32 IS - 9 ER - TY - JOUR A1 - Bieber, Michael A1 - Schuhmann, Michael K. A1 - Bellut, Maximilian A1 - Stegner, David A1 - Heinze, Katrin G. A1 - Pham, Mirko A1 - Nieswandt, Bernhard A1 - Stoll, Guido T1 - Blockade of platelet glycoprotein Ibα augments neuroprotection in Orai2-deficient mice during middle cerebral artery occlusion JF - International Journal of Molecular Sciences N2 - During ischemic stroke, infarct growth before recanalization diminishes functional outcome. Hence, adjunct treatment options to protect the ischemic penumbra before recanalization are eagerly awaited. In experimental stroke targeting two different pathways conferred protection from penumbral tissue loss: (1) enhancement of hypoxic tolerance of neurons by deletion of the calcium channel subunit Orai2 and (2) blocking of detrimental lymphocyte–platelet responses. However, until now, no preclinical stroke study has assessed the potential of combining neuroprotective with anti-thrombo-inflammatory interventions to augment therapeutic effects. We induced focal cerebral ischemia in Orai2-deficient (Orai2\(^{-/-}\)) mice by middle cerebral artery occlusion (MCAO). Animals were treated with anti-glycoprotein Ib alpha (GPIbα) Fab fragments (p0p/B Fab) blocking GPIbα–von Willebrand factor (vWF) interactions. Rat immunoglobulin G (IgG) Fab was used as the control treatment. The extent of infarct growth before recanalization was assessed at 4 h after MCAO. Moreover, infarct volumes were determined 6 h after recanalization (occlusion time: 4 h). Orai2 deficiency significantly halted cerebral infarct progression under occlusion. Inhibition of platelet GPIbα further reduced primary infarct growth in Orai2\(^{-/-}\) mice. During ischemia–reperfusion, upon recanalization, mice were likewise protected. All in all, we show that neuroprotection in Orai2\(^{-/-}\) mice can be augmented by targeting thrombo-inflammation. This supports the clinical development of combined neuroprotective/anti-platelet strategies in hyper-acute stroke. KW - ischemic penumbra KW - Orai2 KW - glycoprotein receptor Ibα KW - ischemic stroke KW - thrombo-inflammation KW - middle cerebral artery occlusion Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286038 SN - 1422-0067 VL - 23 IS - 16 ER - TY - THES A1 - Wagemann, Esther T1 - Biopsiediagnostik von entzündlichen Polyneuropathien T1 - Biopsy diagnostics of inflammatory polyneuropathies N2 - Polyneuropathien sind Erkrankungen des peripheren Nervensystems. Die Erkrankung kommt gehäuft als Zweiterkrankungen bei anderen Primärerkrankungen vor, daher ist es schwierig, epidemiologische Angaben zu machen. Ätiologisch lassen sich Polyneuropathien in fünf große Gruppen einteilen: Hereditäre Polyneuropathien, entzündliche Polyneuropathien, vaskulär bedingte Polyneuropathien, exotoxische Polyneuropathien und endotoxisch-metabolische Polyneuropathien. Die Differentialdiagnose der Polyneuropathie richtet sich nach dem zeitlichen Verlauf der Krankheit, dem betroffenen System und danach, ob primär die Axone oder die Markscheiden betroffen sind. Für die Diagnosestellung einer Polyneuropathie werden Anamnese und klinischer Befund, elektrophysiologische Untersuchungen, Laboruntersuchungen, genetische Untersuchungen und die histopathologische Untersuchung herangezogen. Entscheidend für die Therapie ist es, die behandelbaren Polyneuropathien zu erkennen, hierunter u.a. die entzündlichen Formen. Die hierfür entnommene Suralisbiopsie ist wegen ihrer invasiven Natur erst dann indiziert, wenn die Differentialdiagnose mit nicht-invasiven Maßnahmen nicht geklärt werden kann, sich aber eine Behandlungskonsequenz erwarten lässt. Die exakte Diagnose setzt bei einigen Polyneuropathien eine neuropathologische Diagnostik voraus. Die Nervenbiopsie muss optimal aufbereitet und ausgewertet werden. Hierfür stehen verschiedene Färbe- und Aufbereitungsmethoden zur Verfügung. In dieser Arbeit wurde untersucht, ob anhand eines Schnellschnittes (d.h. Gefrier-Querschnitt des biopsierten Nerven mit Hämatoxylin-Eosin gefärbt) bereits Hinweise auf entzündliche Infiltrate als Zeichen einer Neuritis und damit einer therapiebedürftigen und aber auch therapierbaren Neuropathie gefunden werden können. Anhand eines vordefinierten Schemas wurden die Biopsate in verblindeter Weise von einem Laien und einem erfahrenem Untersucher histologisch begutachtet und den entzündlichen/nicht entzündlichen Diagnosegruppen zugeordnet. Es wurde untersucht, ob die entzündlichen Veränderungen im Hämatoxylin-Eosin-Gefrierschnitt so deutlich sind, dass auch ein Laienauswerter diese erkennen kann. Ebenso wurden die Untersuchungsergebnisse mittels Hämatoxylin-Eosin- Färbung an Gefrier- und Paraffinschnitten mit den Untersuchungsergebnissen mittels immunhistochemischer Färbemethoden verglichen. Des weiteren wurde untersucht, ob bei histologisch gesicherter Entzündung klinische Einflussfaktoren ermittelt werden können, die auf die neuropathologische Diagnostik Auswirkung haben. Die Ergebnisse der Studie zeigen, dass sich die Hämatoxylin-Eosin-Färbung für eine erste und schnelle Diagnostik von entzündlichen Polyneuropathien als wertvoll erwies. Dies gilt für den erfahrenen und unerfahrenen Untersucher. Es zeigen sich keine klinischen Einflussfaktoren für die histopathologische Diagnosestellung. Die Ergebnisse der Studie zeigen, dass schon eine einfache Färbemethode wie die Hämatoxylin-Eosin-Färbung an Gefrier-und Paraffinschnitten bei Polyneuropathie unklarer Genese hilfreich bei einer differenzierten Diagnosefindung sein kann. N2 - Polyneuropathies are diseases of the peripheral nervous system. The disease is more common as secondary diseases in other primary diseases, so it is difficult to provide epidemiological data. Etiologically, polyneuropathies can be divided into five large groups: hereditary polyneuropathies, inflammatory polyneuropathies, vascularly caused polyneuropathies, exotoxic polyneuropathies and endotoxic-metabolic polyneuropathies. The differential diagnosis of polyneuropathy depends on the temporal course of the disease, the affected system and whether the axons or myelin sheaths are primarily affected. The diagnosis of polyneuropathy is based on anamnesis and clinical findings, electrophysiological examinations, laboratory tests, genetic tests and histopathological examinations. It is crucial for therapy to recognise the treatable polyneuropathies, including the inflammatory forms. Due to its invasive nature, the suralis biopsy taken for this purpose is only indicated if the differential diagnosis cannot be clarified with non-invasive measures, but a treatment consequence can be expected. The precise diagnosis of some polyneuropathies requires neuropathological diagnostics. The nerve biopsy must be optimally prepared and evaluated. Various staining and preparation methods are available for this purpose. In this work, it was investigated whether a rapid section (i. e. freezing cross-section of the biopsy nerve with hematoxyline eosin stained) can already be used to find indications of inflammatory infiltrates as signs of neuritis and thus of neuropathy requiring therapy and which can also be treated. On the basis of a predefined scheme, the biopsy specimens were examined histologically by a layman and an experienced examiner in a blinded manner and assigned to the inflammatory/non-inflammatory diagnostic groups. It was investigated whether the inflammatory changes in the haematoxylin-eosin frozen section are so clear that even a lay person can detect them. The results of the tests were also compared with the results of immunohistochemical staining methods using haematoxyline-eosin staining on frozen and paraffin sections. Furthermore, it was investigated whether histologically confirmed inflammation can be used to determine clinical influencing factors that have an effect on neuropathological diagnostics. The results of the study show that hematoxyline eosin staining proved to be valuable for the initial and rapid diagnosis of inflammatory polyneuropathies. This applies to the experienced and inexperienced examiner. There are no clinical influencing factors for histopathological diagnosis. The results of the study show that even a simple staining method such as the haematoxylin-eosin staining of frozen and paraffin sections can be helpful in the diagnosis of polyneuropathy with unclear genesis. KW - Biopsiediagnostik von entzündlichen Polyneuropathien Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-155031 ER - TY - THES A1 - Gossger, Nicoletta Philippine T1 - Bildgebende Verfahren in der Diagnostik von Myopathien T1 - Imaging techniques in myopathies N2 - Ziel dieser Arbeit war es, die Aussagefähigkeit der Kernspintomographie mit der der Histologie und der Sonographie im Hinblick auf Umbauvorgänge im Muskel in einem Patientenkollektiv mit Myopathien verschiedener Ätiologie zu vergleichen. Weiterhin sollte überprüft werden, ob die MRT-Untersuchung mittels fettsupprimierter TIRM-Sequenz und T1-gewichteter Sequenz nach Kontrastmittelgabe eine zusätzliche Hilfe bei der Diagnosefindung darstellt. Hierzu wurden über den Zeitraum von zwei Jahren 26 Patienten, die in der Neurologischen Universitätsklinik Würzburg mit einer Myopathie aufgenommen wurden, nach einem standardisierten Protokoll klinisch, laborchemisch, sonographisch (n=16) sowie kernspintomographisch untersucht. Außerdem erfolgte zur histologischen Diagnostik nach Aufklärung des Patienten eine Muskelbiopsie. Die kernspintomographische Untersuchung umfasste eine konventionelle T1-gewichtete Sequenz, eine fettunterdrückte TIRM-Sequenz und eine T1-gewichtete Sequenz nach der Gabe von Gadolinium-DTPA. Das Patientenkollektiv wurde für die statistische Auswertung in drei klinische Diagnosegruppen aufgeteilt: nicht-entzündliche, degenerative Myopathien (Gruppe A1), nicht-entzündliche, nicht-degenerative Myopathien (Gruppe A2) und entzündliche Myopathien (Gruppe B). Die T1-gewichtete Spinechosequenz zeigte sich in diesen Untersuchungen wie in vorangegangenen Arbeiten im Bezug auf fett- und bindegewebigen Umbauvorgänge des Muskelparenchyms am sensitivsten. Muskuläre Veränderungen in der T1-gewichteten Sequenz korrelieren mit der Schwere des Muskelumbaus in der Histologie und dem MRC-Kraftgrad als funktionellen Parameter. Pathologische Befunde in der ödemsensitiven TIRM-Sequenz fanden sich bei entzündlichen und nicht-entzündlichen Myopathien etwa gleich häufig. Unsere Ergebnisse legen also nahe, dass eine Ödementstehung nicht zwangsläufig an eine entzündliche Genese gebunden ist. Eine Korrelation des histologischen Entzündungsscores mit der TIRM-Sequenz konnte in keiner der Diagnosegruppen nachgewiesen werden. Hieraus ist abzuleiten, dass zur genauen Lokalisation der Muskelbiopsie eine MRT-Diagnostik vor allem bei entzündlichen Myopathien sehr zu empfehlen ist. In dieser Arbeit fanden sich in der Patientengruppe mit einer degenerativen Myopathie häufiger als bisher beschrieben pathologische Auffälligkeiten (46 % der Patienten) in der T1-Sequenz nach Kontrastmittelgabe. Die Kontrastmittelanreicherung entspricht nicht in jedem Fall einer in der TIRM-Sequenz festgestellten Ödemausbreitung. Bei den entzündlichen Myopathien zeigte sich eine Korrelation der CK-Aktivität mit der T1-gewichteten Sequenz nach Kontrastmittelgabe, jedoch nicht mit den beiden anderen MRT-Sequenzen. An Hand der vorliegenden Befunde lässt sich vermuten, dass Kontrastmittelanreicherung ein Ausdruck aktiver muskulärer Umbauprozesse im Rahmen entzündlicher und degenerativer Myopathien ist. Damit scheint unter dem Aspekt der Erfassung der Aktivität einer Myopathie eine Kontrastmittelgabe bei der MRT-Diagnostik auch bei degenerativen neuromuskulären Erkrankungen sinnvoll. Die Befunde der Sonographie korrelieren mit den Befunden aus der T1-gewichteten MRT- Sequenz, mit der Schwere des Muskelumbaus in der Histologie und dem MRC-Kraftgrad. Diese Ergebnisse zeigen die gute Nachweisrate von muskulären Veränderungen durch die Sonographie. Alle drei zu vergleichenden Untersuchungsmethoden eignen sich für die Diagnostik von Myopathien. Eine spezifische Diagnose der Muskelerkrankungen auf Grund der MRT allein, ist, auch bei der hier untersuchten Anwendung von zusätzlicher Kontrastmittelgabe, noch nicht möglich. Die Diagnosestellung erfolgt letztendlich aus der Anamnese und der Gesamtheit aller Befunde. Welche apparativen und bildgebenden Verfahren hierbei zum Einsatz kommen, muss individuell entschieden werden, da die Untersuchungsverfahren unterschiedliche Aspekte der Erkrankung beleuchten. Die vorliegenden Ergebnisse könnten hierbei eine Entscheidungshilfe sein. N2 - Aim of this study was to asses and compare three techniques of imaging in myopathies of different origin. 26 Patients, who where admitted to the ward of the neurological clinic of the University of Wuerzburg underwent MRI scans, muscular ultrasound and -with their consent- muscular biopsy. MR Imaging included T1-weighted sequenzes, fatsupressed TIRM-sequenzes and T1-weighted sequenzes after application of contrast medium. Patients with dystrophic myopathies were found to show enhanced signal intensity in sequences after application of contrast medium more often then described before. The enhancement in some cases does not correspond to the expansion of the edema determined in the TIRM-sequenzes. The resultes of the study suggest that enhancement of contrast medium is an expression for the activity of muscular conversion and destruction in scope of inflammatory or dystrophic myopathies. All three compared methodes are suitable to diagnose myopathies. However a specific diagnosis by MRI only is not jet possible. Which imaging techniques are to be used has to be decided for each individual case, fore they illuminate different aspects of the illnes. KW - Bildgebung KW - MRT KW - Sonographie KW - Myopathie KW - Kontrastmittel KW - Imaging KW - myopathy KW - ultrasound KW - MRI KW - contrastmedium Y1 - 2005 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-14712 ER - TY - THES A1 - Kafke, Waldemar T1 - Bestimmung von Zytokinexpressionsprofilen aus humanen Blut- und Hautproben bei Patienten mit small fiber Neuropathie T1 - Analysis of cytokine expression patterns in affected skin amd blood samples in patients with small fiber neuropathy N2 - Zusammenfassend konnte durch unsere Daten die eingangs gestellte Hypothese, dass Patienten mit SFN eine lokal und systemisch erhöhte Expression pro-inflammatorischer und algetischer Zytokine haben, auf lokaler Ebene bei der Untergruppe mit LD-SFN bestätigt werden. Bei der Untergruppe mit NLD-SFN waren keine Unterschiede bei den Zytokinexpressionen zwischen proximalen und distalen Hautbiopsien im Vergleich zu Kontrollprobanden nachweisbar. Zudem zeigten sich deutliche Unterschiede bei den Quotienten der IENFD zwischen beiden Untergruppen. Dies legt die Vermutung nahe, dass die Unterteilung in LD-SFN und NLD-SFN klinisch bedeutsam und ein möglicher Grundstein für das Verständnis der pathophysiologischen Mechanismen der SFN sein könnte. Hieraus könnten sich Fortschritte in der Diagnostik ergeben und gezielte symptomatische und vielleicht sogar kausale Therapien auf lokaler Ebene bei der SFN entwickeln. N2 - A subgroup of patients with small fiber neuropahties with a lenght-dependent distribution pattern concerning the reduction of intraepidermal nerve fibers (LD-SFN) have a higher cytokine gene expression of pro-inflammatory cytokines in affected skin. KW - Small fiber Neuropathie KW - Zytokine KW - Small fiber Neuropathie KW - Zytokine KW - Small fiber neuropathy KW - Cytokines Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-71132 ER - TY - THES A1 - Karina, Karina T1 - Beschreibung der Maßnahmen zur Beschleunigung und Verbesserung der Notfallversorgung von Patienten mit akutem Schlaganfall in einer ländlichen Neurologischen Klinik und sequentielle Messung relevanter Qualitätsindikatoren T1 - Report of measures taken to accelerate and improve emergency care for patients with acute stroke in a rural neurological hospital and sequential measurement of relevant quality indicators N2 - Die hohe Mortalität und hohe Rate an Langzeitbehinderungen nach einem erlittenen Schlaganfall verdeutlichen die Relevanz bestmöglicher Akutversorgung bei Schlaganfallpatienten. Daher ist es unentbehrlich, dass die Akuttherapie bei Schlaganfall stets überprüft und bei Bedarf optimiert wird. Der Großteil der Studien, die sich mit Verbesserungsmaßnahmen in der akuten Schlaganfallversorgung befassen, wird in großen städtischen Krankenhäusern bzw. Universitätsklinika durchgeführt. Studien zu diesem Sachverhalt, die in ländlichen Kliniken durchgeführt wurden, sind noch begrenzt vorhanden. Mit dieser Studie evaluieren wir, ob sich durch die Implementierung neuer Optimierungsmaßnahmen Verbesserungen in den relevanten Qualitätsindikatoren ergeben. Die Ergebnisse sind daher von besonderer Bedeutung, da es für nicht-universitäre Kliniken nur eine begrenzte Anzahl an Studien gibt, die sich mit dieser Thematik beschäftigen. N2 - The high mortality and high rate of long-term disabilities after a stroke illustrate the relevance of the best possible acute care for stroke patients. Therefore, it is essential that the acute therapy for stroke is constantly reviewed and enhanced if necessary. The majority of studies dealing with improvement measures in acute stroke care are carried out in large city hospitals or university hospitals. Studies on this issue conducted in rural clinics are still limited. With this study, we evaluate whether the initiation of some new optimization measures results in improvements in the relevant quality indicators. As a consequence, the results are particularly significant, as there are only a limited number of studies dealing with this topic for non-university hospitals. KW - Verbesserung KW - Improvement KW - stroke care KW - Schlaganfall KW - Ländliche Klinik KW - rural clinics Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-291749 ER - TY - JOUR A1 - Schuhmann, Michael K. A1 - Langhauser, Friederike A1 - Kraft, Peter A1 - Kleinschnitz, Christoph T1 - B cells do not have a major pathophysiologic role in acute ischemic stroke in mice JF - Journal of Neuroinflammation N2 - Background Lymphocytes have been shown to play an important role in the pathophysiology of acute ischemic stroke, but the properties of B cells remain controversial. The aim of this study was to unravel the role of B cells during acute cerebral ischemia using pharmacologic B cell depletion, B cell transgenic mice, and adoptive B cell transfer experiments. Methods Transient middle cerebral artery occlusion (60 min) was induced in wild-type mice treated with an anti-CD20 antibody 24 h before stroke onset, JHD\(^{−/−}\) mice and Rag1\(^{−/−}\) mice 24 h after adoptive B cell transfer. Stroke outcome was assessed at days 1 and 3. Infarct volumes were calculated from 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain sections, and neurological scores were evaluated. The local inflammatory response was determined by real-time PCR and immunohistochemistry. Apoptosis was analyzed by TUNEL staining, and astrocyte activation was revealed using immunohistochemistry and Western blot. Results Pharmacologic depletion of B cells did not influence infarct volumes and functional outcome at day 1 after stroke. Additionally, lack of circulating B cells in JHD\(^{−/−}\) mice also failed to influence stroke outcome at days 1 and 3. Furthermore, reconstitution of Rag1\(^{−/−}\) mice with B cells had no influence on infarct volumes. Conclusion Targeting B cells in experimental stroke did not influence lesion volume and functional outcome during the acute phase. Our findings argue against a major pathophysiologic role of B cells during acute ischemic stroke. KW - ischemic stroke KW - transient middle cerebral artery occlusion KW - B cells Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158155 VL - 14 IS - 112 ER - TY - JOUR A1 - Giordano, Rosaria A1 - Canesi, Margherita A1 - Isalberti, Maurizio A1 - Isaias, Ioannis Ugo A1 - Montemurro, Tiziana A1 - Viganò, Mariele A1 - Montelatici, Elisa A1 - Boldrin, Valentina A1 - Benti, Riccardo A1 - Cortelezzi, Agostino A1 - Fracchiolla, Nicola A1 - Lazzari, Lorenza A1 - Pezzoli, Gianni T1 - Autologous mesenchymal stem cell therapy for progressive supranuclear palsy: translation into a phase I controlled, randomized clinical study JF - Journal of Translational Medicine N2 - Background: Progressive Supranuclear Palsy (PSP) is a sporadic and progressive neurodegenerative disease which belongs to the family of tauopathies and involves both cortical and subcortical structures. No effective therapy is to date available. Methods/design: Autologous bone marrow (BM) mesenchymal stem cells (MSC) from patients affected by different type of parkinsonisms have shown their ability to improve the dopaminergic function in preclinical and clinical models. It is also possible to isolate and expand MSC from the BM of PSP patients with the same proliferation rate and immuphenotypic profile as MSC from healthy donors. BM MSC can be efficiently delivered to the affected brain regions of PSP patients where they can exert their beneficial effects through different mechanisms including the secretion of neurotrophic factors. Here we propose a randomized, placebo-controlled, double-blind phase I clinical trial in patients affected by PSP with MSC delivered via intra-arterial injection. Discussion: To our knowledge, this is the first clinical trial to be applied in a no-option parkinsonism that aims to test the safety and to exploit the properties of autologous mesenchymal stem cells in reducing disease progression. The study has been designed to test the safety of this " first-in-man" approach and to preliminarily explore its efficacy by excluding the placebo effect. Trial registration: NCT01824121 KW - Parkinson's disease KW - cellular therapy KW - deep brain-stimulation KW - bone-marrow KW - transplantation KW - receptor tyrosine kinase KW - Richardson-Olszewski-Syndrome KW - multiple system atrophy KW - advanced therapy medicinal products KW - mesenchymal stem and stromal cells KW - progressive supranuclear palsy KW - treatment options KW - adrenal medulla KW - stromal cells Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117594 VL - 12 IS - 14 ER - TY - THES A1 - Buchwald, Sina T1 - Autoimmune Enzephalitiden am Universitätsklinikum Würzburg von 2006-2016 T1 - Cases of autoimmune encephalitis at the Universitätsklinikum Würzburg from 2006-2016 N2 - In den Jahren von 2006 bis 2016 sind am Universitätsklinikum Würzburg insgesamt 26 Patienten mit der Diagnose einer Autoimmunen Enzephalitis behandelt worden. Diese Arbeit zeigt ihre Krankheitsverläufe, Outcome, die gefundenen Antikörper und die Therapien der jeweiligen Patienten. Im zweiten Schritt wurden die Daten mit den in der Literatur bereits beschrieben Fällen verglichen, um Gemeinsamkeiten, aber auch Unterschiede aufzeigen zu können. N2 - In the time from 2006 to 2016, 26 patients with the diagnosis "autoimmune encephalitis” were treated at the Universitätsklinikum in Würzburg. This paper shows their data, antibody findings, treatments and outcomes. In a second step, this data was compared with cases that have already been described in literature to show similarities and differences. KW - Enzephalitis KW - Autoimmun KW - Encephalitis KW - autoimmune Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-207202 ER - TY - JOUR A1 - Vural, Atay A1 - Doppler, Kathrin A1 - Meinl, Edgar T1 - Autoantibodies Against the Node of Ranvier in Seropositive Chronic Inflammatory Demyelinating Polyneuropathy: Diagnostic, Pathogenic, and Therapeutic Relevance JF - Frontiers in Immunology N2 - Discovery of disease-associated autoantibodies has transformed the clinical management of a variety of neurological disorders. Detection of autoantibodies aids diagnosis and allows patient stratification resulting in treatment optimization. In the last years, a set of autoantibodies against proteins located at the node of Ranvier has been identified in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). These antibodies target neurofascin, contactin1, or contactin-associated protein 1, and we propose to name CIDP patients with these antibodies collectively as seropositive. They have unique clinical characteristics that differ from seronegative CIDP. Moreover, there is compelling evidence that autoantibodies are relevant for the pathogenesis. In this article, we review the current knowledge on the characteristics of autoantibodies against the node of Ranvier proteins and their clinical relevance in CIDP. We start with a description of the structure of the node of Ranvier followed by a summary of assays used to identify seropositive patients; and then, we describe clinical features and characteristics linked to seropositivity. We review knowledge on the role of these autoantibodies for the pathogenesis with relevance for the emerging concept of nodopathy/paranodopathy and summarize the treatment implications. KW - autoantibody KW - seropositive KW - chronic inflammatory demyelinating polyneuropathy KW - node of Ranvier KW - paranode KW - neurofascin KW - contactin KW - contactin-associated protein 1 Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233279 VL - 9 ER - TY - THES A1 - Stößel, Anna T1 - Auswirkungen zerebellärer Gleichstromstimulation auf das motorische Lernen bei gesunden älteren Probanden T1 - Effects of cerebellar anodal transcranial direct current stimulation on motor learning in healthy older adults N2 - Sowohl neurologische Erkrankungen als auch der natürliche Alterungsprozess gehen regelhaft mit einem Untergang von Neuronen einher und bedingen neurologische Funktionsverluste. Diese mit Hilfe nicht-invasiver Techniken, beispielsweise tDCS, zu reduzieren, stellt ein wichtiges Ziel der neurowissenschaftlichen Forschung dar. Neben Arbeiten, die tDCS-Effekte auf das motorische Lernen bei Stimulation des motorischen Kortex nachweisen konnten, gibt es auch Hinweise für solche Effekte bei Stimulation des Kleinhirns. Allerdings besteht derzeit noch eine hohe Variabilität und damit einhergehend eine schlechte Vergleichbarkeit der Studien bezüglich ihrer Stimulationsbedingungen. Das Ansprechen unterschiedlicher Altersgruppen bleibt unklar. In der vorliegenden Arbeit wurden die Effekte zerebellärer a-tDCS auf das motorische Lernen bei gesunden älteren Probanden untersucht. Im Cross-over-Design wurde zu unterschiedlichen Zeitpunkten (vor bzw. nach der motorischen Aufgabe) stimuliert und im 24-Stunden-Verlauf die Langzeitwirkung evaluiert. Gruppe A erhielt vor einer motorischen Übungsaufgabe eine zerebelläre Stimulation, entweder als a-tDCS oder Scheinstimulation, Gruppe B nach der Übungsaufgabe. Zur Überprüfung der Effekte auf das Sequenzlernen diente der Finger-Tapping-Task. Der Lernerfolg wurde anhand der Genauigkeit, der Sequenzdauer und des Skill-Index gemessen. Die Ergebnisse deuten darauf hin, dass eine zerebelläre a-tDCS vor einer Übungsaufgabe zu einer Verbesserung der Konsolidierung der Fähigkeit, eine Zahlenfolge möglichst schnell und gleichzeitig genau einzutippen, führt, während die Stimulation nach einer Übungsaufgabe das motorische Lernen nicht zu beeinflussen scheint. Insgesamt stützen die Ergebnisse zum Teil die bisherigen Hinweise, dass eine zerebellär applizierte a-tDCS das motorische Lernen verbessern kann. Aufgrund einiger Limitationen, besonders der geringen Gruppengröße, verbleibt dieses Ergebnis jedoch vorläufig und bedarf einer Bestätigung in größeren Probandengruppen. Es bleibt von hohem Interesse, die optimalen Bedingungen für die Anwendung von tDCS am Kleinhirn zu definieren, um motorische Lernprozesse positiv zu beeinflussen. Dies ist die Voraussetzung dafür, zerebelläre tDCS mittelfristig auch zu therapeutischen Zwecken anwenden zu können. N2 - Neurological diseases as well as the natural aging process are regularly accompanied by a loss of neurons resulting into a loss of neurological function. Reducing these impactswith the help of non-invasive techniques, such as transcranial direct current stiumulation (tDCS), is an important goal of neuroscientific research. In addition to studies successfully providing evidence that tDCS is impacting motor learning when stimulating the motor cortex, indication of similar effects exist when stimulating the cerebellum. Unfortunately studies today only provide poor comparability given the underlying inconsistency in stimulation conditions and consequentially yielded results. The response of different age groups remains unclear. The following study explores the effects of cerebellar anodal transranial direct current simulation (a-tDSC) on healthy elderly subjects. Using a crossover design, patience were stimulated at different times (before or after the motor task) and long-term effects were evaluated over a 24-hour period. Group A received cerebellar stimulation prior to a motor exercise in form of an actual a-tDCS or sham stimulation, Group B received treatment after the exercise. The finger tapping task was used to verify the effects on sequence learning. Learning success was measured by accuracy, sequence duration, and skill index. The results indicate that cerebellar a-tDCS prior to the exercise task leads to enhanced consolidation of the ability to type a sequence of numbers quickly and accurately at the same time, whereas stimulation after the exercise task does not seem to affect motor learning. Overall, the results partially support previous evidence that cerebellar applied a-tDCS can improve motor learning. Due to some limitations, in particular the small sample size, results are preliminary and require confirmation across a larger population. Defining the optimal conditions for the application of tDCS to the cerebellum to positively influence motor learning processes remains of high interest. It is the prerequisite to enable application of cerebellar tDCS for therapeutic purposes in the medium term. KW - Motorisches Lernen KW - Kleinhirn KW - transkranielle Gleichstromstimulation (tDCS) KW - finger-tapping task (FTT) KW - zerebelläre Gleichstromstimulation KW - motor learning KW - tDCS Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-317930 ER - TY - JOUR A1 - Huss, André A1 - Abdelhak, Ahmed A1 - Mayer, Benjamin A1 - Tumani, Hayrettin A1 - Müller, Hans-Peter A1 - Althaus, Katharina A1 - Kassubek, Jan A1 - Otto, Markus A1 - Ludolph, Albert C. A1 - Yilmazer-Hanke, Deniz A1 - Neugebauer, Hermann T1 - Association of serum GFAP with functional and neurocognitive outcome in sporadic small vessel disease JF - Biomedicines N2 - Cerebrospinal fluid (CSF) and serum biomarkers are critical for clinical decision making in neurological diseases. In cerebral small vessel disease (CSVD), white matter hyperintensities (WMH) are an important neuroimaging biomarker, but more blood-based biomarkers capturing different aspects of CSVD pathology are needed. In 42 sporadic CSVD patients, we prospectively analysed WMH on magnetic resonance imaging (MRI) and the biomarkers neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), chitinase3-like protein 1 (CHI3L1), Tau and Aβ1-42 in CSF and NfL and GFAP in serum. GFAP and CHI3L1 expression was studied in post-mortem brain tissue in additional cases. CSVD cases with higher serum NfL and GFAP levels had a higher modified Rankin Scale (mRS) and NIHSS score and lower CSF Aβ1-42 levels, whereas the CSF NfL and CHI3L1 levels were positively correlated with the WMH load. Moreover, the serum GFAP levels significantly correlated with the neurocognitive functions. Pathological analyses in CSVD revealed a high density of GFAP-immunoreactive fibrillary astrocytic processes in the periventricular white matter and clusters of CHI3L1-immunoreactive astrocytes in the basal ganglia and thalamus. Thus, besides NfL, serum GFAP is a highly promising fluid biomarker of sporadic CSVD, because it does not only correlate with the clinical severity but also correlates with the cognitive function in patients. KW - chitinase-3-like protein 1 KW - GFAP KW - neurofilaments KW - white matter hyperintensities KW - biomarker KW - CSVD Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285973 SN - 2227-9059 VL - 10 IS - 8 ER - TY - JOUR A1 - Elhfnawy, Ahmed Mohamed A1 - Volkmann, Jens A1 - Schliesser, Mira A1 - Fluri, Felix T1 - Are cerebral white matter lesions related to the presence of bilateral internal carotid artery stenosis or to the length of stenosis among patients with ischemic cerebrovascular events? JF - Frontiers in Neurology N2 - Background and purpose: Previous studies delivered contradicting results regarding the relation between the presence of an internal carotid artery stenosis (ICAS) and the occurence of white matter lesions (WMLs). We hypothesize that special characteristics related to the ICAS might be related to the WMLs. We examined the relation between the presence of bilateral ICAS, the degree and length of stenosis and ipsi-, contralateral as well as mean white matter lesion load (MWMLL). Methods: In a retrospective cohort, patients with ischemic stroke or transient ischemic attack (TIA) as well as ipsi- and/or contralateral ICAS were identified. The length and degree of ICAS, as well as plaque morphology (hypoechoic, mixed or echogenic), were assessed on ultrasound scans and, if available, the length was also measured on magnetic resonance angiography (MRA) scans, and/or digital subtraction angiography (DSA). The WMLs were assessed in 4 areas separately, (periventricular and deep WMLs on each hemispherer), using the Fazekas scale. The MWMLL was calculated as the mean of these four values. Results: 136 patients with 177 ICAS were identified. A significant correlation between age and MWMLL was observed (Spearman correlation coefficient, ρ = 0.41, p < 0.001). Before adjusting for other risk factors, a significantly positive relation was found between the presence of bilateral ICAS and MWMLL (p = 0.039). The length but not the degree of ICAS showed a very slight trend toward association with ipsilateral WMLs and with MWMLL. In an age-adjusted multivariate logistic regression with MWMLL ≥2 as the outcome measure, atrial fibrillation (OR 3.54, 95% CI 1.12–11.18, p = 0.03), female sex (OR 3.11, 95% CI 1.19–8.11, p = 0.02) and diabetes mellitus (OR 2.76, 95% CI 1.16–6.53, p = 0.02) were significantly related to WMLs, whereas the presence of bilateral stenosis showed a trend toward significance (OR 2.25, 95% CI 0.93–5.45, p = 0.074). No relation was found between plaque morphology and MWMLL, periventricular, or deep WMLs. Conclusion: We have shown a slight correlation between the length of stenosis and the presence of WMLs which might be due to microembolisation originating from the carotid plaque. However, the presence of bilateral ICAS seems also to be related to WMLs which may point to common underlying vascular risk factors contributing to the occurrence of WML. KW - stroke KW - transient ischemic attack KW - white matter lesions KW - internal carotid artery stenosis KW - bilateral internal carotid artery stenosis KW - degree of stenosis KW - length of stenosis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201241 VL - 10 IS - 919 ER - TY - THES A1 - Preisshofen, Tobias T1 - Apoptosemessungen bei Thymompatienten mit und ohne Myasthenia Gravis T1 - patient with thymoma N2 - Thmyome komen sehr selten mit und ohne Myasthenia Gravis vor und sind ein gutes Beispiel für Autoimmunerkrankungen N2 - Thymoma are very rare KW - Thymom KW - Mysthenia Gravis KW - thymoma Y1 - 2005 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-15973 ER - TY - JOUR A1 - Stengel, Helena A1 - Vural, Atay A1 - Brunder, Anna-Michelle A1 - Heinius, Annika A1 - Appeltshauser, Luise A1 - Fiebig, Bianca A1 - Giese, Florian A1 - Dresel, Christian A1 - Papagianni, Aikaterini A1 - Birklein, Frank A1 - Weis, Joachim A1 - Huchtemann, Tessa A1 - Schmidt, Christian A1 - Körtvelyessy, Peter A1 - Villmann, Carmen A1 - Meinl, Edgar A1 - Sommer, Claudia A1 - Leypoldt, Frank A1 - Doppler, Kathrin T1 - Anti–pan-neurofascin IgG3 as a marker of fulminant autoimmune neuropathy JF - Neurology: Neuroimmunology & Neuroinflammation N2 - Objective To identify and characterize patients with autoantibodies against different neurofascin (NF) isoforms. Methods Screening of a large cohort of patient sera for anti-NF autoantibodies by ELISA and further characterization by cell-based assays, epitope mapping, and complement binding assays. Results Two different clinical phenotypes became apparent in this study: The well-known clinical picture of subacute-onset severe sensorimotor neuropathy with tremor that is known to be associated with IgG4 autoantibodies against the paranodal isoform NF-155 was found in 2 patients. The second phenotype with a dramatic course of disease with tetraplegia and almost locked-in syndrome was associated with IgG3 autoantibodies against nodal and paranodal isoforms of NF in 3 patients. The epitope against which these autoantibodies were directed in this second phenotype was the common Ig domain found in all 3 NF isoforms. In contrast, anti–NF-155 IgG4 were directed against the NF-155–specific Fn3Fn4 domain. The description of a second phenotype of anti–NF-associated neuropathy is in line with some case reports of similar patients that were published in the last year. Conclusions Our results indicate that anti–pan-NF-associated neuropathy differs from anti–NF-155-associated neuropathy, and epitope and subclass play a major role in the pathogenesis and severity of anti–NF-associated neuropathy and should be determined to correctly classify patients, also in respect to possible differences in therapeutic response. KW - neurology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202462 VL - 6 IS - 5 ER - TY - JOUR A1 - Appeltshauser, Luise A1 - Brunder, Anna-Michelle A1 - Heinius, Annika A1 - Körtvélyessy, Peter A1 - Wandinger, Klaus-Peter A1 - Junker, Ralf A1 - Villmann, Carmen A1 - Sommer, Claudia A1 - Leypoldt, Frank A1 - Doppler, Kathrin T1 - Antiparanodal antibodies and IgG subclasses in acute autoimmune neuropathy JF - Neurology: Neuroimmunology & Neuroinflammation N2 - Objective To determine whether IgG subclasses of antiparanodal autoantibodies are related to disease course and treatment response in acute- to subacute-onset neuropathies, we retrospectively screened 161 baseline serum/CSF samples and 66 follow-up serum/CSF samples. Methods We used ELISA and immunofluorescence assays to detect antiparanodal IgG and their subclasses and titers in serum/CSF of patients with Guillain-Barre syndrome (GBS), recurrent GBS (R-GBS), Miller-Fisher syndrome, and acute- to subacute-onset chronic inflammatory demyelinating polyradiculoneuropathy (A-CIDP). We evaluated clinical data retrospectively. Results We detected antiparanodal autoantibodies with a prevalence of 4.3% (7/161), more often in A-CIDP (4/23, 17.4%) compared with GBS (3/114, 2.6%). Longitudinal subclass analysis in the patients with GBS revealed IgG2/3 autoantibodies against Caspr-1 and against anti-contactin-1/Caspr-1, which disappeared at remission. At disease onset, patients with A-CIDP had IgG2/3 anti-Caspr-1 and anti-contactin-1/Caspr-1 or IgG4 anti-contactin-1 antibodies, IgG3 being associated with good response to IV immunoglobulins (IVIg). In the chronic phase of disease, IgG subclass of one patient with A-CIDP switched from IgG3 to IgG4. Conclusion Our data (1) confirm and extend previous observations that antiparanodal IgG2/3 but not IgG4 antibodies can occur in acute-onset neuropathies manifesting as monophasic GBS, (2) suggest association of IgG3 to a favorable response to IVIg, and (3) lend support to the hypothesis that in some patients, an IgG subclass switch from IgG3 to IgG4 may be the correlate of a secondary progressive or relapsing course following a GBS-like onset. KW - Guillain-Barre-Syndrome KW - inflammatory demyelinating polyradiculoneuropathy KW - musk myasthenia gravis KW - periperal nerve KW - neurofascin KW - autoantibodies KW - ontactin 1 KW - biopsies KW - binding KW - switch Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230079 VL - 7 IS - 5 ER - TY - JOUR A1 - Doppler, Kathrin A1 - Schuster, Yasmin A1 - Appeltshauser, Luise A1 - Biko, Lydia A1 - Villmann, Carmen A1 - Weishaupt, Andreas A1 - Werner, Christian A1 - Sommer, Claudia T1 - Anti-CNTN1 IgG3 induces acute conduction block and motor deficits in a passive transfer rat model JF - Journal of Neuroinflammation N2 - Background: Autoantibodies against the paranodal protein contactin-1 have recently been described in patients with severe acute-onset autoimmune neuropathies and mainly belong to the IgG4 subclass that does not activate complement. IgG3 anti-contactin-1 autoantibodies are rare, but have been detected during the acute onset of disease in some cases. There is evidence that anti-contactin-1 prevents adhesive interaction, and chronic exposure to anti-contactin-1 IgG4 leads to structural changes at the nodes accompanied by neuropathic symptoms. However, the pathomechanism of acute onset of disease and the pathogenic role of IgG3 anti-contactin-1 is largely unknown. Methods: In the present study, we aimed to model acute autoantibody exposure by intraneural injection of IgG of patients with anti-contacin-1 autoantibodies to Lewis rats. Patient IgG obtained during acute onset of disease (IgG3 predominant) and IgG from the chronic phase of disease (IgG4 predominant) were studied in comparison. Results: Conduction blocks were measured in rats injected with the “acute” IgG more often than after injection of “chronic” IgG (83.3% versus 35%) and proved to be reversible within a week after injection. Impaired nerve conduction was accompanied by motor deficits in rats after injection of the “acute” IgG but only minor structural changes of the nodes. Paranodal complement deposition was detected after injection of the “acute IgG”. We did not detect any inflammatory infiltrates, arguing against an inflammatory cascade as cause of damage to the nerve. We also did not observe dispersion of paranodal proteins or sodium channels to the juxtaparanodes as seen in patients after chronic exposure to anti-contactin-1. Conclusions: Our data suggest that anti-contactin-1 IgG3 induces an acute conduction block that is most probably mediated by autoantibody binding and subsequent complement deposition and may account for acute onset of disease in these patients. This supports the notion of anti-contactin-1-associated neuropathy as a paranodopathy with the nodes of Ranvier as the site of pathogenesis. KW - complement deposition KW - paranodopathy KW - anti-contactin-1 KW - CIDP KW - passive transfer KW - autoantibody Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200476 VL - 16 IS - 73 ER - TY - JOUR A1 - Simon, Micha A1 - Ipek, Rojda A1 - Homola, György A. A1 - Rovituso, Damiano M. A1 - Schampel, Andrea A1 - Kleinschnitz, Christoph A1 - Kuerten, Stefanie T1 - Anti-CD52 antibody treatment depletes B cell aggregates in the central nervous system in a mouse model of multiple sclerosis JF - Journal of Neuroinflammation N2 - Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) for which several new treatment options were recently introduced. Among them is the monoclonal anti-CD52 antibody alemtuzumab that depletes mainly B cells and T cells in the immune periphery. Considering the ongoing controversy about the involvement of B cells and in particular the formation of B cell aggregates in the brains of progressive MS patients, an in-depth understanding of the effects of anti-CD52 antibody treatment on the B cell compartment in the CNS itself is desirable. Methods: We used myelin basic protein (MBP)-proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 (B6) mice as B cell-dependent model of MS. Mice were treated intraperitoneally either at the peak of EAE or at 60 days after onset with 200 μg murine anti-CD52 vs. IgG2a isotype control antibody for five consecutive days. Disease was subsequently monitored for 10 days. The antigen-specific B cell/antibody response was measured by ELISPOT and ELISA. Effects on CNS infiltration and B cell aggregation were determined by immunohistochemistry. Neurodegeneration was evaluated by Luxol Fast Blue, SMI-32, and Olig2/APC staining as well as by electron microscopy and phosphorylated heavy neurofilament serum ELISA. Results: Treatment with anti-CD52 antibody attenuated EAE only when administered at the peak of disease. While there was no effect on the production of MP4-specific IgG, the treatment almost completely depleted CNS infiltrates and B cell aggregates even when given as late as 60 days after onset. On the ultrastructural level, we observed significantly less axonal damage in the spinal cord and cerebellum in chronic EAE after anti-CD52 treatment. Conclusion: Anti-CD52 treatment abrogated B cell infiltration and disrupted existing B cell aggregates in the CNS. KW - Alemtuzumab KW - B cells KW - CD52 KW - CNS KW - EAE KW - MS Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176120 VL - 15 IS - 225 ER - TY - JOUR A1 - Fluri, Felix A1 - Schuhmann, Michael K A1 - Kleinschnitz, Christoph T1 - Animal models of ischemic stroke and their application in clinical research JF - Drug Design, Development and Therapy N2 - This review outlines the most frequently used rodent stroke models and discusses their strengths and shortcomings. Mimicking all aspects of human stroke in one animal model is not feasible because ischemic stroke in humans is a heterogeneous disorder with a complex pathophysiology. The transient or permanent middle cerebral artery occlusion (MCAo) model is one of the models that most closely simulate human ischemic stroke. Furthermore, this model is characterized by reliable and well-reproducible infarcts. Therefore, the MCAo model has been involved in the majority of studies that address pathophysiological processes or neuroprotective agents. Another model uses thromboembolic clots and thus is more convenient for investigating thrombolytic agents and pathophysiological processes after thrombolysis. However, for many reasons, preclinical stroke research has a low translational success rate. One factor might be the choice of stroke model. Whereas the therapeutic responsiveness of permanent focal stroke in humans declines significantly within 3 hours after stroke onset, the therapeutic window in animal models with prompt reperfusion is up to 12 hours, resulting in a much longer action time of the investigated agent. Another major problem of animal stroke models is that studies are mostly conducted in young animals without any comorbidity. These models differ from human stroke, which particularly affects elderly people who have various cerebrovascular risk factors. Choosing the most appropriate stroke model and optimizing the study design of preclinical trials might increase the translational potential of animal stroke models. KW - permanent and transient middle cerebral artery occlusion KW - thromboembolic clot model KW - mouse KW - rat KW - microsphere/macrosphere KW - endothelin-1 KW - photothrombosis KW - thromboembolic stroke Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149157 VL - 9 ER - TY - JOUR A1 - Sadovnick, A. Dessa A1 - Traboulsee, Anthony L. A1 - Bernales, Cecily Q. A1 - Ross, Jay P. A1 - Forwell, Amanda L. A1 - Yee, Irene M. A1 - Guillot-Noel, Lena A1 - Fontaine, Bertrand A1 - Cournu-Rebeix, Isabelle A1 - Alcina, Antonio A1 - Fedetz, Maria A1 - Izquierdo, Guillermo A1 - Matesanz, Fuencisla A1 - Hilven, Kelly A1 - Dubois, Bénédicte A1 - Goris, An A1 - Astobiza, Ianire A1 - Alloza, Iraide A1 - Antigüedad, Alfredo A1 - Vandenbroeck, Koen A1 - Akkad, Denis A. A1 - Aktas, Orhan A1 - Blaschke, Paul A1 - Buttmann, Mathias A1 - Chan, Andrew A1 - Epplen, Joerg T. A1 - Gerdes, Lisa-Ann A1 - Kroner, Antje A1 - Kubisch, Christian A1 - Kümpfel, Tania A1 - Lohse, Peter A1 - Rieckmann, Peter A1 - Zettl, Uwe K. A1 - Zipp, Frauke A1 - Bertram, Lars A1 - Lill, Christina M. A1 - Fernandez, Oscar A1 - Urbaneja, Patricia A1 - Leyva, Laura A1 - Alvarez-Cermeño, Jose Carlos A1 - Arroyo, Rafael A1 - Garagorri, Aroa M. A1 - García-Martínez, Angel A1 - Villar, Luisa M. A1 - Urcelay, Elena A1 - Malhotra, Sunny A1 - Montalban, Xavier A1 - Comabella, Manuel A1 - Berger, Thomas A1 - Fazekas, Franz A1 - Reindl, Markus A1 - Schmied, Mascha C. A1 - Zimprich, Alexander A1 - Vilariño-Güell, Carles T1 - Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients JF - G3: Genes Genomes Genetics N2 - Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93–1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility. KW - multiple sclerosis KW - genetics KW - linkage KW - association KW - plasminogen Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165405 VL - 6 IS - 7 ER - TY - JOUR A1 - Aster, H-C A1 - Evdokimov, D. A1 - Braun, A. A1 - Üçeyler, N. A1 - Sommer, C. T1 - Analgesic Medication in Fibromyalgia Patients: A Cross-Sectional Study JF - Pain Research and Management N2 - There is no approved drug for fibromyalgia syndrome (FMS) in Europe. In the German S3 guideline, amitriptyline, duloxetine, and pregabalin are recommended for temporary use. The aim of this study was to cross-sectionally investigate the current practice of medication in FMS patients in Germany. We systematically interviewed 156 patients with FMS, while they were participating in a larger study. The patients had been stratified into subgroups with and without a decrease in intraepidermal nerve fiber density. The drugs most commonly used to treat FMS pain were nonsteroidal anti-inflammatory drugs (NSAIDs) (41.0% of all patients), metamizole (22.4%), and amitriptyline (12.8%). The most frequent analgesic treatment regimen was “on demand” (53.9%), during pain attacks, while 35.1% of the drugs were administered daily and the remaining in other regimens. Median pain relief as self-rated by the patients on a numerical rating scale (0–10) was 2 points for NSAIDS, 2 for metamizole, and 1 for amitriptyline. Drugs that were discontinued due to lack of efficacy rather than side effects were acetaminophen, flupirtine, and selective serotonin reuptake inhibitors. Reduction in pain severity was best achieved by NSAIDs and metamizole. Our hypothesis that a decrease in intraepidermal nerve fiber density might represent a neuropathic subtype of FMS, which would be associated with better effectiveness of drugs targeting neuropathic pain, could not be confirmed in this cohort. Many FMS patients take “on-demand” medication that is not in line with current guidelines. More randomized clinical trials are needed to assess drug effects in FMS subgroups. KW - Fibromyalgia KW - analgesic medication KW - study Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300578 VL - 2022 ER - TY - JOUR A1 - Kline, Rachel A. A1 - Lößlein, Lena A1 - Kurian, Dominic A1 - Aguilar Martí, Judit A1 - Eaton, Samantha L. A1 - Court, Felipe A. A1 - Gillingwater, Thomas H. A1 - Wishart, Thomas M. T1 - An optimized comparative proteomic approach as a tool in neurodegenerative disease research JF - Cells N2 - Recent advances in proteomic technologies now allow unparalleled assessment of the molecular composition of a wide range of sample types. However, the application of such technologies and techniques should not be undertaken lightly. Here, we describe why the design of a proteomics experiment itself is only the first step in yielding high-quality, translatable results. Indeed, the effectiveness and/or impact of the majority of contemporary proteomics screens are hindered not by commonly considered technical limitations such as low proteome coverage but rather by insufficient analyses. Proteomic experimentation requires a careful methodological selection to account for variables from sample collection, through to database searches for peptide identification to standardised post-mass spectrometry options directed analysis workflow, which should be adjusted for each study, from determining when and how to filter proteomic data to choosing holistic versus trend-wise analyses for biologically relevant patterns. Finally, we highlight and discuss the difficulties inherent in the modelling and study of the majority of progressive neurodegenerative conditions. We provide evidence (in the context of neurodegenerative research) for the benefit of undertaking a comparative approach through the application of the above considerations in the alignment of publicly available pre-existing data sets to identify potential novel regulators of neuronal stability. KW - proteomics KW - systems biology KW - experimental design KW - neurodegeneration KW - pathway analysis KW - data filtering Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285912 SN - 2073-4409 VL - 11 IS - 17 ER - TY - JOUR A1 - Albert-Weißenberger, Christiane A1 - Várrallyay, Csanád A1 - Raslan, Furat A1 - Kleinschnitz, Christoph A1 - Sirén, Anna-Leena T1 - An experimental protocol for mimicking pathomechanisms of traumatic brain injury in mice N2 - Traumatic brain injury (TBI) is a result of an outside force causing immediate mechanical disruption of brain tissue and delayed pathogenic events. In order to examine injury processes associated with TBI, a number of rodent models to induce brain trauma have been described. However, none of these models covers the entire spectrum of events that might occur in TBI. Here we provide a thorough methodological description of a straightforward closed head weight drop mouse model to assess brain injuries close to the clinical conditions of human TBI. KW - Medizin KW - closed head injury KW - traumatic brain injury KW - neurobehavioural deficits KW - astrocyte KW - microglia KW - neurons Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75368 ER - TY - JOUR A1 - Hansen, Niels A1 - Kahn, Ann-Kathrin A1 - Zeller, Daniel A1 - Katsarava, Zaza A1 - Sommer, Claudia A1 - Üçeyler, Nurcan T1 - Amplitudes of pain-related evoked potentials are useful to detect small fiber involvement in painful mixed fiber neuropathies in addition to quantitative sensory testing – an electrophysiological study JF - Frontiers in Neurology N2 - To investigate the usefulness of pain-related evoked potentials (PREP) elicited by electrical stimulation for the identification of small fiber involvement in patients with mixed fiber neuropathy (MFN). Eleven MFN patients with clinical signs of large fiber impairment and neuropathic pain and ten healthy controls underwent clinical and electrophysiological evaluation. Small fiber function, electrical conductivity and morphology were examined by quantitative sensory testing (QST), PREP, and skin punch biopsy. MFN was diagnosed following clinical and electrophysiological examination (chronic inflammatory demyelinating neuropathy: n = 6; vasculitic neuropathy: n = 3; chronic axonal ­neuropathy: n = 2). The majority of patients with MFN characterized their pain by descriptors that mainly represent C-fiber-mediated pain. In QST, patients displayed elevated cold, warm, mechanical, and vibration detection thresholds and cold pain thresholds indicative of MFN. PREP amplitudes in patients correlated with cold (p < 0.05) and warm detection thresholds (p < 0.05). Burning pain and the presence of par-/dysesthesias correlated negatively with PREP amplitudes (p < 0.05). PREP amplitudes correlating with cold and warm detection thresholds, burning pain, and par-/dysesthesias support employing PREP amplitudes as an additional tool in conjunction with QST for detecting small fiber impairment in patients with MFN. KW - burning pain KW - quantitative sensory testing KW - mixed fiber neuropathy KW - pain-related evoked potentials KW - Aδ- and C-fibers KW - neuropathic pain Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124824 VL - 6 ER - TY - JOUR A1 - Stetter, Christian A1 - Lopez-Caperuchipi, Simon A1 - Hopp-Krämer, Sarah A1 - Bieber, Michael A1 - Kleinschnitz, Christoph A1 - Sirén, Anna-Leena A1 - Albert-Weißenberger, Christiane T1 - Amelioration of cognitive and behavioral deficits after traumatic brain injury in coagulation factor XII deficient mice JF - International Journal of Molecular Sciences N2 - Based on recent findings that show that depletion of factor XII (FXII) leads to better posttraumatic neurological recovery, we studied the effect of FXII-deficiency on post-traumatic cognitive and behavioral outcomes in female and male mice. In agreement with our previous findings, neurological deficits on day 7 after weight-drop traumatic brain injury (TBI) were significantly reduced in FXII\(^{−/−}\) mice compared to wild type (WT) mice. Also, glycoprotein Ib (GPIb)-positive platelet aggregates were more frequent in brain microvasculature of WT than FXII\(^{−/−}\) mice 3 months after TBI. Six weeks after TBI, memory for novel object was significantly reduced in both female and male WT but not in FXII\(^{−/−}\) mice compared to sham-operated mice. In the setting of automated home-cage monitoring of socially housed mice in IntelliCages, female WT mice but not FXII\(^{−/−}\) mice showed decreased exploration and reacted negatively to reward extinction one month after TBI. Since neuroendocrine stress after TBI might contribute to trauma-induced cognitive dysfunction and negative emotional contrast reactions, we measured peripheral corticosterone levels and the ration of heart, lung, and spleen weight to bodyweight. Three months after TBI, plasma corticosterone levels were significantly suppressed in both female and male WT but not in FXII\(^{−/−}\) mice, while the relative heart weight increased in males but not in females of both phenotypes when compared to sham-operated mice. Our results indicate that FXII deficiency is associated with efficient post-traumatic behavioral and neuroendocrine recovery. KW - closed head injury KW - contact-kinin system KW - object recognition memory KW - IntelliCage KW - Crespi effect KW - stress Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284959 SN - 1422-0067 VL - 22 IS - 9 ER - TY - JOUR A1 - Capetian, Philipp A1 - Roessner, Veit A1 - Korte, Caroline A1 - Walitza, Susanne A1 - Riederer, Franz A1 - Taurines, Regina A1 - Gerlach, Manfred A1 - Moser, Andreas T1 - Altered urinary tetrahydroisoquinoline derivatives in patients with Tourette syndrome: reflection of dopaminergic hyperactivity? JF - Journal of Neural Transmission N2 - Tetrahydroisoquinolines (TIQs) such as salsolinol (SAL), norsalsolinol (NSAL) and their methylated derivatives N-methyl-norsalsolinol (NMNSAL) and N-methyl-salsolinol (NMSAL), modulate dopaminergic neurotransmission and metabolism in the central nervous system. Dopaminergic neurotransmission is thought to play an important role in the pathophysiology of chronic tic disorders, such as Tourette syndrome (TS). Therefore, the urinary concentrations of these TIQ derivatives were measured in patients with TS and patients with comorbid attention-deficit/hyperactivity disorder (TS + ADHD) compared with controls. Seventeen patients with TS, 12 with TS and ADHD, and 19 age-matched healthy controls with no medication took part in this study. Free levels of NSAL, NMNSAL, SAL, and NMSAL in urine were measured by a two-phase chromatographic approach. Furthermore, individual TIQ concentrations in TS patients were used in receiver-operating characteristics (ROC) curve analysis to examine the diagnostic value. NSAL concentrations were elevated significantly in TS [434.67 ± 55.4 nmol/l (standard error of mean = S.E.M.), two-way ANOVA, p < 0.0001] and TS + ADHD patients [605.18 ± 170.21 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] compared with controls [107.02 ± 33.18 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] and NSAL levels in TS + ADHD patients were elevated significantly in comparison with TS patients (two-way ANOVA, p = 0.017). NSAL demonstrated an AUC of 0.93 ± 0.046 (S.E.M) the highest diagnostic value of all metabolites for the diagnosis of TS. Our results suggest a dopaminergic hyperactivity underlying the pathophysiology of TS and ADHD. In addition, NSAL concentrations in urine may be a potential diagnostic biomarker of TS. KW - Tourette syndrome KW - ADHD KW - tics KW - biomarkers KW - tetrahydroisoquinoline derivates Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235771 SN - 0300-9564 VL - 128 ER - TY - THES A1 - Musacchio, Thomas Giuseppe T1 - ALS und MMN mimics bei Patienten mit BSCL2 Mutationen - eine Erweiterung des klinischen Spektrums der hereditären Spinalparalyse SPG17 T1 - ALS and MMN mimics in patients with BSCL2 mutations - the expanding clinical spectrum of SPG17 hereditary spastic paraplegia N2 - Die hereditäre Spinalparalyse SPG17 ist eine autosomal-dominant vererbte Motoneuronerkrankung, welche durch Mutationen im BSCL2 (Seipin) Gen verursacht wird. Klassischerweise äußert sich die Krankheit durch eine spastische Paraparese der Beine und Amyotrophie der Hände (Silver-Syndrom) oder eine vorwiegend periphere (senso-)motorische Neuropathie. Für die vorliegende Arbeit wurden insgesamt sieben Patienten aus vier verschiedenen Familien, bei denen heterozygote Mutationen im BSCL2 Gen nachgewiesen werden konnten, klinisch sowie elektrophysiologisch und molekulargenetisch untersucht. Es gelang hierbei zwei bisher unbekannte phänotypische Ausprägungen zu beschreiben, welche die Symptomatik und den Verlauf einer Multifokalen Motorischen Neuropathie (MMN) bzw. einer Amyotrophen Lateralsklerose (ALS) imitieren und hiervon nur durch den genetischen Befund zu unterscheiden sind. Anhand dieser Ergebnisse erfolgte dann nach extensiver Literaturrecherche eine Zusammenfassung aller bisher publizierten Fälle der SPG17 und eine Einordnung der hier erstbeschriebenen Phänotypen in einen Vorschlag zur Erweiterung des bisher verwendeten Klassifikationssystems von BSCL 2 Mutationen. N2 - Silver syndrome/SPG17 is a motor Manifestation of mutations in the BSCL2 gene and usually presents as a complicated form of hereditary spastic paraplegia (HSP). This work presents clinical data, follow-up, and genetic results of seven patients with Silver syndrome/SPG17 including of four families and it was possible to describe two unknown new clinical phenotypes for the frist time, which are mimicking an amyotrophic lateral sclerosis (ALS)-like phenotype and multifocal Motor neuropathy (MMN) phenotype and can only be distinguished by the genetic phenotype. On the Basis of These results an extensive literature recherche was performed and all published cases of SPG17 were screened and discussed with the new entities. Furtehrmore a new classicication System was proposed. KW - Hereditäre spastische Spinalparalyse KW - Myatrophische Lateralsklerose KW - SPG17 KW - ALS KW - MMN Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154224 ER - TY - JOUR A1 - Wirsching, Isabelle A1 - Ort, Nora A1 - Üçeyler, Nurcan T1 - ALS or ALS mimic by neuroborreliosis — A case report JF - Clinical Case Reports N2 - Comprehensive investigation in motor neuron disease is vital not to miss a treatable differential diagnosis. Neuroborreliosis should be considered during an ALS work‐up. However, false‐positive CSF results do occur, and thus, results should be interpreted carefully in context of all clinical test results. KW - ALS mimic KW - El Escorial KW - motor neuron disease KW - muscle atrophy KW - neuroborreliosis Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201308 VL - 8 ER - TY - JOUR A1 - Hopp, Sarah A1 - Nolte, Marc W. A1 - Stetter, Christian A1 - Kleinschnitz, Christoph A1 - Sirén, Anna-Leena A1 - Albert-Weissenberger, Christiane T1 - Alleviation of secondary brain injury, posttraumatic inflammation, and brain edema formation by inhibition of factor XIIa JF - Journal of Neuroinflammation N2 - Background: Traumatic brain injury (TBI) is a devastating neurological condition and a frequent cause of permanent disability. Posttraumatic inflammation and brain edema formation, two pathological key events contributing to secondary brain injury, are mediated by the contact-kinin system. Activation of this pathway in the plasma is triggered by activated factor XII. Hence, we set out to study in detail the influence of activated factor XII on the abovementioned pathophysiological features of TBI. Methods: Using a cortical cryogenic lesion model in mice, we investigated the impact of genetic deficiency of factor XII and inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused Infestin-4 on the release of bradykinin, the brain lesion size, and contact-kinin system-dependent pathological events. We determined protein levels of bradykinin, intracellular adhesion molecule-1, CC-chemokine ligand 2, and interleukin-1β by enzyme-linked immunosorbent assays and mRNA levels of genes related to inflammation by quantitative real-time PCR. Brain lesion size was determined by tetrazolium chloride staining. Furthermore, protein levels of the tight junction protein occludin, integrity of the blood-brain barrier, and brain water content were assessed by Western blot analysis, extravasated Evans Blue dye, and the wet weight-dry weight method, respectively. Infiltration of neutrophils and microglia/activated macrophages into the injured brain lesions was quantified by immunohistological stainings. Results: We show that both genetic deficiency of factor XII and inhibition of activated factor XII in mice diminish brain injury-induced bradykinin release by the contact-kinin system and minimize brain lesion size, blood-brain barrier leakage, brain edema formation, and inflammation in our brain injury model. Conclusions: Stimulation of bradykinin release by activated factor XII probably plays a prominent role in expanding secondary brain damage by promoting brain edema formation and inflammation. Pharmacological blocking of activated factor XII could be a useful therapeutic principle in the treatment of TBI-associated pathologic processes by alleviating posttraumatic inflammation and brain edema formation. KW - factor XII KW - focal brain lesion KW - brain edema Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157490 VL - 14 IS - 39 ER - TY - THES A1 - Rost, Anna-Lena T1 - Akute erregerbedingte Meningoenzephalitiden am Universitätsklinikum Würzburg von 2006-2015 T1 - Acute pathogen-induced meningoencephalitides at the University Hospital of Würzburg between 2006-2015 N2 - Am Universitätsklinikum Würzburg wurden zwischen 2006-2015 447 Fälle einer akuten erregerbedingten Meningoenzephalitis in den Kliniken der Neurologie, Kinderklinik, Neurochirurgie und Psychiatrie behandelt. Es konnten sowohl Fälle durch Bakterien als auch Fälle durch Viren, Parasiten und Pilze gesichert werden. Diese Arbeit beschreibt die lokale Epidemiologie akuter erregerbedingter Meningoenzephalitiden. N2 - At the University Hospital of Würzburg, 447 cases of acute pathogen-induced meningoencephalitis were treated in the clinics of neurology, pediatrics, neurosurgery and psychiatry between 2006-2015. Cases due to bacteria as well as cases due to viruses, parasites and fungi were secured. This paper describes the local epidemiology of acute pathogen-induced meningoencephalitides. KW - Meningoenzephalitis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240846 ER - TY - THES A1 - Yuan, Xidi T1 - Aging and inflammation in the peripheral nervous system T1 - Altern und Entzündung im peripheren Nervensystem N2 - Aging is known to be a risk factor for structural abnormalities and functional decline in the nervous system. Characterizing age-related changes is important to identify putative pathways to overcome deleterious effects and improve life quality for the elderly. In this study, the peripheral nervous system of 24-month-old aged C57BL/6 mice has been investigated and compared to 12-month-old adult mice. Aged mice showed pathological alterations in their peripheral nerves similar to nerve biopsies from elderly human individuals, with nerve fibers showing demyelination and axonal damage. Such changes were lacking in nerves of adult 12-month-old mice and adult, non-aged humans. Moreover, neuromuscular junctions of 24-month-old mice showed increased denervation compared to adult mice. These alterations were accompanied by elevated numbers of macrophages in the peripheral nerves of aged mice. The neuroinflammatory conditions were associated with impaired myelin integrity and with a decline of nerve conduction properties and muscle strength in aged mice. To determine the pathological impact of macrophages in the aging mice, macrophage depletion was performed in mice by oral administration of CSF-1R specific kinase (c-FMS) inhibitor PLX5622 (300 mg/kg body weight), which reduced the number of macrophages in the peripheral nerves by 70%. The treated mice showed attenuated demyelination, less muscle denervation and preserved muscle strength. This indicates that macrophage-driven inflammation in the peripheral nerves is partially responsible for the age-related neuropathy in mice. Based on previous observations that systemic inflammation can accelerate disease progression in mouse models of neurodegenerative diseases, it was hypothesized that systemic inflammation can exacerbate the peripheral neuropathy found in aged mice. To investigate this hypothesis, aged C57BL/6 mice were intraperitoneally injected with a single dose of lipopolysaccharide (LPS; 500 μg/kg body weight) to induce systemic inflammation by mimicking bacterial infection, mostly via activation of Toll-like receptors (TLRs). Altered endoneurial macrophage activation, highlighted by Trem2 downregulation, was found in LPS injected aged mice one month after injection. This was accompanied by a so far rarely observed form of axonal perturbation, i.e., the occurrence of “dark axons” characterized by a damaged cytoskeleton and an increased overall electron density of the axoplasm. At the same time, however, LPS injection reduced demyelination and muscle denervation in aged mice. Interestingly, TREM2 deficiency in aged mice led to similar changes to LPS injection. This suggests that LPS injection likely mitigates aging-related demyelination and muscle denervation via Trem2 downregulation. Taken together, this study reveals the role of macrophage-driven inflammation as a pathogenic mediator in age-related peripheral neuropathy, and that targeting macrophages might be an option to mitigate peripheral neuropathies in aging individuals. Furthermore, this study shows that systemic inflammation may be an ambivalent modifier of age-related nerve damage, leading to a distinct type of axonal perturbation, but in addition to functionally counteracting, dampened demyelination and muscle denervation. Translationally, it is plausible to assume that tipping the balance of macrophage polarization to one direction or the other may determine the functional outcome in the aging peripheral nervous system of the elderly. N2 - Es ist bekannt, dass das Altern ein Risikofaktor für strukturelle Veränderungen und Funktionsstörungen des Nervensystems ist. Die Charakterisierung altersbedingter Veränderungen ist wichtig, um mögliche Wege zu identifizieren, um schädliche Auswirkungen zu überwinden und die Lebensqualität älterer Menschen zu verbessern. In dieser Studie wurde das periphere Nervensystem von 24 Monate alten gealterten C57BL/6-Mäusen untersucht und mit 12 Monate alten adulten Mäusen verglichen. Gealterte Mäuse zeigten ähnliche pathologische Veränderungen in ihren peripheren Nerven wie Nervenbiopsien älterer Menschen, wobei die Nervenfasern eine Demyelinisierung und axonale Schädigung zeigten. Bei den Nerven von adulten 12 Monate alten Mäusen und nicht gealterten Menschen fehlten solche Veränderungen. Darüber hinaus wiesen die neuromuskulären Endplatten von 24 Monate alten Mäusen im Vergleich zu adulten Mäusen eine erhöhte Denervation auf. Diese Veränderungen wurden von einer erhöhten Anzahl von Makrophagen in den peripheren Nerven gealterter Mäuse begleitet. Die neuroinflammatorischen Bedingungen waren mit einer Beeinträchtigung der Myelinintegrität, einer Abnahme der Nervenleitungseigenschaften und der Muskelkraft bei gealterten Mäusen verbunden. Um den pathologischen Einfluss von Makrophagen bei alternden Mäusen zu bestimmen, wurde die Makrophagen-Depletion bei Mäusen durch orale Verabreichung des CSF-1R-spezifischen Kinase-Inhibitors (c-FMS) PLX5622 (300 mg/kg Körpergewicht) durchgeführt, welche die Anzahl der Makrophagen in den peripheren Nerven um 70% reduzierte. Die behandelten Mäuse zeigten eine verminderte Demyelinisierung, eine reduzierte Muskeldenervation und einen Erhalt der Muskelkraft. Dies deutet darauf hin, dass die durch Makrophagen verursachte Entzündung in den peripheren Nerven teilweise für die altersbedingte Neuropathie bei Mäusen verantwortlich ist. Auf der Grundlage früherer Beobachtungen, dass systemische Entzündungen das Fortschreiten der Krankheit in Mausmodellen neurodegenerativer Erkrankungen beschleunigen können, wurde die Hypothese aufgestellt, dass systemische Entzündungen die periphere Neuropathie in gealterten Mäusen verschlimmern können. Um diese Hypothese zu untersuchen, wurde gealterten C57BL/6-Mäusen eine Einzeldosis Lipopolysaccharid (LPS; 500 μg/kg Körpergewicht) intraperitonal injiziert, um eine systemische Entzündung durch Nachahmung einer bakteriellen Infektion, meist über die Aktivierung von Toll-like-Rezeptoren (TLRs), zu induzieren. Eine veränderte endoneuriale Makrophagenaktivierung, die durch eine reduzierte Trem2-Expression hervorgehoben wird, konnte bei LPS-injizierten gealterten Mäusen einen Monat nach der Injektion gefunden werden. Dies ging einher mit einer bisher selten beobachteten Form der axonalen Perturbation, d.h. dem Auftreten von "dunklen Axonen", die sich durch ein geschädigtes Zytoskelett und eine erhöhte Gesamtelektronendichte des Axoplasmas auszeichnen. Gleichzeitig verringerte die LPS-Injektion jedoch die Demyelinisierung und Muskeldenervation bei gealterten Mäusen. Interessanterweise führte die TREM2 Defizienz bei gealterten Mäusen zu vergleichbaren Veränderungen wie die LPS-Injektion. Dies deutet darauf hin, dass die LPS-Injektion die alterungsbedingte Demyelinisierung und Muskeldenervierung über die Trem2 Herunterregulation abschwächt. Zusammenfassend zeigt diese Studie die Rolle der Makrophagen-getriebenen Entzündung als pathogener Mediator bei der altersbedingten peripheren Neuropathie. Zusätzlich deuten die Ergebnisse darauf hin, dass die gezielte Behandlung von Makrophagen eine Option zur Linderung peripherer Neuropathien bei alternden Menschen sein könnte. Darüber hinaus zeigt diese Studie, dass die systemische Entzündung ein ambivalenter Modifikator der altersbedingten Nervenschädigung sein kann, der zu einer bestimmten Art von axonaler Perturbation führt, aber zusätzlich zu einer funktionell entgegenwirkenden, weniger schweren Demyelinisierung und Muskeldenervation. Translatorisch ist es plausibel anzunehmen, dass eine Veränderung des Gleichgewichts der Makrophagenpolarisation in die eine oder andere Richtung das funktionelle Ergebnis im alternden peripheren Nervensystem der älteren Menschen bestimmen kann. KW - Maus KW - Peripheres Nervensystem KW - Altern KW - Immunsystem KW - macrophages KW - peripheral nervous system KW - aging KW - neuroinflammation KW - Trem2 KW - systemic inflammation Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237378 ER - TY - JOUR A1 - Rauschenberger, Lisa A1 - Behnke, Jennifer A1 - Grotemeyer, Alexander A1 - Knorr, Susanne A1 - Volkmann, Jens A1 - Ip, Chi Wang T1 - Age-dependent neurodegeneration and neuroinflammation in a genetic A30P/A53T double-mutated α-synuclein mouse model of Parkinson’s disease JF - Neurobiology of Disease N2 - The pathogenesis of Parkinson's disease (PD) is closely interwoven with the process of aging. Moreover, increasing evidence from human postmortem studies and from animal models for PD point towards inflammation as an additional factor in disease development. We here assessed the impact of aging and inflammation on dopaminergic neurodegeneration in the hm\(^{2}\)α-SYN-39 mouse model of PD that carries the human, A30P/A53T double-mutated α-synuclein gene. At 2–3 months of age, no significant differences were observed comparing dopaminergic neuron numbers of the substantia nigra (SN) pars compacta of hm\(^{2}\)α-SYN-39 mice with wildtype controls. At an age of 16–17 months, however, hm\(^{2}\)α-SYN-39 mice revealed a significant loss of dopaminergic SN neurons, of dopaminergic terminals in the striatum as well as a reduction of striatal dopamine levels compared to young, 2–3 months transgenic mice and compared to 16–17 months old wildtype littermates. A significant age-related correlation of infiltrating CD4+ and CD8\(^{+}\) T cell numbers with dopaminergic terminal loss of the striatum was found in hm\(^{2}\)α-SYN-39 mice, but not in wildtype controls. In the striatum of 16–17 months old wildtype mice a slightly elevated CD8\(^{+}\) T cell count and CD11b\(^{+}\) microglia cell count was observed compared to younger aged mice. Additional analyses of neuroinflammation in the nigrostriatal tract of wildtype mice did not yield any significant age-dependent changes of CD4\(^{+}\), CD8\(^{+}\) T cell and B220\(^{+}\) B cell numbers, respectively. In contrast, a significant age-dependent increase of CD8\(^{+}\) T cells, GFAP\(^{+}\) astrocytes as well as a pronounced increase of CD11b+ microglia numbers were observed in the SN of hm\(^{2}\)α-SYN-39 mice pointing towards a neuroinflammatory processes in this genetic mouse model for PD. The findings in the hm\(^{2}\)α-SYN-39 mouse model strengthen the evidence that T cell and glial cell responses are involved in the age-related neurodegeneration in PD. The slow and age-dependent progression of neurodegeneration and neuroinflammation in the hm\(^{2}\)α-SYN-39 PD rodent model underlines its translational value and makes it suitable for studying anti-inflammatory therapies. KW - Parkinson's disease KW - neuroinflammation KW - neurodegeneration Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300629 VL - 171 ER - TY - JOUR A1 - Karl, Franziska A1 - Nandini Colaço, Maria B. A1 - Schulte, Annemarie A1 - Sommer, Claudia A1 - Üçeyler, Nurcan T1 - Affective and cognitive behavior is not altered by chronic constriction injury in B7-H1 deficient and wildtype mice JF - BMC Neuroscience N2 - Background Chronic neuropathic pain is often associated with anxiety, depressive symptoms, and cognitive impairment with relevant impact on patients` health related quality of life. To investigate the influence of a pro-inflammatory phenotype on affective and cognitive behavior under neuropathic pain conditions, we assessed mice deficient of the B7 homolog 1 (B7-H1), a major inhibitor of inflammatory response. Results Adult B7-H1 ko mice and wildtype littermates (WT) received a chronic constriction injury (CCI) of the sciatic nerve, and we assessed mechanical and thermal sensitivity at selected time points. Both genotypes developed mechanical (p < 0.001) and heat hypersensitivity (p < 0.01) 7, 14, and 20 days after surgery. We performed three tests for anxiety-like behavior: the light–dark box, the elevated plus maze, and the open field. As supported by the results of these tests for anxiety-like behavior, no relevant differences were found between genotypes after CCI. Depression-like behavior was assessed using the forced swim test. Also, CCI had no effect on depression like behavior. For cognitive behavior, we applied the Morris water maze for spatial learning and memory and the novel object recognition test for object recognition, long-, and short-term memory. Learning and memory did not differ in B7-H1 ko and WT mice after CCI. Conclusions Our study reveals that the impact of B7-H1 on affective-, depression-like- and learning-behavior, and memory performance might play a subordinate role in mice after nerve lesion. KW - B7-H1 KW - Immune system KW - CCI KW - Anxiety KW - Cognitive behavior Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200540 VL - 20 ER - TY - JOUR A1 - Hofmann, Lukas A1 - Karl, Franziska A1 - Sommer, Claudia A1 - Üçeyler, Nurcan T1 - Affective and cognitive behavior in the alpha-galactosidase A deficient mouse model of Fabry disease JF - PLoS ONE N2 - Fabry disease is an X-linked inherited lysosomal storage disorder with intracellular accumulation of globotriaosylceramide (Gb3) due to α-galactosidase A (α-Gal A) deficiency. Fabry patients frequently report of anxiety, depression, and impaired cognitive function. We characterized affective and cognitive phenotype of male mice with α-Gal A deficiency (Fabry KO) and compared results with those of age-matched male wildtype (WT) littermates. Young (3 months) and old (≥ 18 months) mice were tested in the naïve state and after i.pl. injection of complete Freund`s adjuvant (CFA) as an inflammatory pain model. We used the elevated plus maze (EPM), the light-dark box (LDB) and the open field test (OF) to investigate anxiety-like behavior. The forced swim test (FST) and Morris water maze (MWM) were applied to assess depressive-like and learning behavior. The EPM test revealed no intergroup difference for anxiety-like behavior in naïve young and old Fabry KO mice compared to WT littermates, except for longer time spent in open arms of the EPM for young WT mice compared to young Fabry KO mice (p<0.05). After CFA injection, young Fabry KO mice showed increased anxiety-like behavior compared to young WT littermates (p<0.05) and naïve young Fabry KO mice (p<0.05) in the EPM as reflected by shorter time spent in EPM open arms. There were no relevant differences in the LDB and the OF test, except for longer time spent in the center zone of the OF by young WT mice compared to young Fabry KO mice (p<0.05). Complementary to this, depression-like and learning behavior were not different between genotypes and age-groups, except for the expectedly lower memory performance in older age-groups compared to young mice. Our results indicate that genetic influences on affective and cognitive symptoms in FD may be of subordinate relevance, drawing attention to potential influences of environmental and epigenetic factors. KW - cognitive impairment KW - mouse models KW - depression KW - swimming KW - learning KW - Fabry disease KW - genetics Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170745 VL - 12 IS - 6 ER - TY - JOUR A1 - Piroth, Tobias A1 - Boelmans, Kai A1 - Amtage, Florian A1 - Rijntjes, Michel A1 - Wierciochin, Anna A1 - Musacchio, Thomas A1 - Weiller, Cornelius A1 - Volkmann, Jens A1 - Klebe, Stephan T1 - Adult-Onset Niemann-Pick Disease Type C: Rapid Treatment Initiation Advised but Early Diagnosis Remains Difficult JF - Frontiers in Neurology N2 - Niemann–Pick type C disease (NP-C) presents with heterogeneous neurological and psychiatric symptoms. Adult onset is rare and possibly underdiagnosed due to frequent lack of specific and obvious key symptoms. For both early and adolescent/adult onset, the available data from studies and case reports describe a positive effect of Miglustat (symptom relief or stabilization). However, due to the low frequency of NP-C, experience with this therapy is still limited. We describe two adult-onset cases of NP-C. In both cases, vertical supranuclear gaze palsy was not recognized at symptom onset. Correct diagnosis was delayed from onset of symptoms by more than 10 years. The video demonstrates the broad spectrum of symptoms in later stages of the disease. Compared with published data, the treatment outcome observed in our cases after delayed initiation of Miglustat therapy was disappointing, with continuing disease progression in both cases. Thus, early treatment initiation could be necessary to achieve a good symptomatic effect. Hence, early biochemical testing for NP-C should be considered in patients suffering from atypical neurological/neuropsychological and psychiatric symptoms, even in cases of uncertainty. KW - Niemann–Pick disease type C KW - adult-onset KW - NPC1 gene KW - NPC2 gene KW - plasma oxysterols Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171001 VL - 8 IS - 108 ER -