@phdthesis{Feierabend2006, author = {Feierabend, Stefanie}, title = {Informationsgehalt und Akzeptanz zweier K{\"o}rperschemata bei Patienten mit orofazialen Schmerzen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-20970}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2006}, abstract = {Ziel dieser prospektiven multizentrischen Studie war der Vergleich 2 verschiedener Schemata zur Schmerzzeichnung bei Patienten mit orofazialen Schmerzen. 204 Patienten, die wegen orofazialer Schmerzen einen (Zahn)arzt aufsuchten, erhielten randomisiert 2 unterschiedliche K{\"o}rperschemata zur Schmerzzeichnung und einen Fragebogen zu deren Beurteilung. Ein Schema war dem Deutschen Schmerzfragebogen entnommen (Bogen A), das andere war mit der Intention entwickelt worden, den K{\"o}rper symmetrisch darzustellen und eine computergest{\"u}tzte Auswertung zu erm{\"o}glichen (Bogen B). Diese Zeichnung war großformatiger und enthielt ein vergr{\"o}ßertes Kopfschema. Die Antworten wurden bzgl. Pr{\"a}ferenz, Anzahl und Verteilung der Schmerzgebiete und {\"U}bereinstimmung zwischen den Schemata ausgewertet sowie mit Patientendaten korreliert. Die Daten von 183 Patienten waren auswertbar. Von 100/183 Patienten wurde Bogen B bevorzugt, von 57/183 Bogen A, unabh{\"a}ngig von Geschlecht, Alter und Erkrankungsdauer. Fast alle Patienten gaben mehr als ein Schmerzgebiet an, nur 43/183 Patienten Schmerzen ausschließlich in der Gesichts- und Kopfregion. Anzahl und Lokalisation der Schmerzgebiete waren zwischen den Schemata nicht unterschiedlich. Detaillierte Kopf- und K{\"o}rperschemata k{\"o}nnen ohne {\"U}berforderung der Patienten sinnvoll in die Diagnostik orofazialer Schmerzen eingesetzt werden und sind n{\"u}tzlich, um Komorbidit{\"a}ten zu erkennen.}, language = {de} } @article{SchischlevskijCordtsGuentheretal.2021, author = {Schischlevskij, Pavel and Cordts, Isabell and G{\"u}nther, Ren{\´e} and Stolte, Benjamin and Zeller, Daniel and Schr{\"o}ter, Carsten and Weyen, Ute and Regensburger, Martin and Wolf, Joachim and Schneider, Ilka and Hermann, Andreas and Metelmann, Moritz and Kohl, Zacharias and Linker, Ralf A. and Koch, Jan Christoph and Stendel, Claudia and M{\"u}schen, Lars H. and Osmanovic, Alma and Binz, Camilla and Klopstock, Thomas and Dorst, Johannes and Ludolph, Albert C. and Boentert, Matthias and Hagenacker, Tim and Deschauer, Marcus and Lingor, Paul and Petri, Susanne and Schreiber-Katz, Olivia}, title = {Informal caregiving in amyotrophic lateral sclerosis (ALS): a high caregiver burden and drastic consequences on caregivers' lives}, series = {Brain Sciences}, volume = {11}, journal = {Brain Sciences}, number = {6}, issn = {2076-3425}, doi = {10.3390/brainsci11060748}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240981}, year = {2021}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients' informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers' burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients' CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients' functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King's Stages for ALS. The caregivers' burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers' burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients' functional status (r\(_p\) = -0.555, p < 0.001, n = 242). It was influenced by the CGs' own mental health issues due to caregiving (+11.36, 95\% CI [6.84; 15.87], p < 0.001), patients' wheelchair dependency (+9.30, 95\% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs' depression (r\(_p\) = 0.627, p < 0.001, n = 234), anxiety (r\(_p\) = 0.550, p < 0.001, n = 234), and poorer physical condition (r\(_p\) = -0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients' impairment in daily routine (r\(_s\) = -0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs' lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs' work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required.}, language = {en} } @article{KreisslStoutWongetal.2011, author = {Kreissl, Michael C. and Stout, David B. and Wong, Koon-Pong and Wu, Hsiao-Ming and Caglayan, Evren and Ladno, Waldemar and Zhang, Xiaoli and Prior, John and Reiners, Christoph and Huang, Sung-Cheng and Schelbert, Heinrich R.}, title = {Influence of Dietary Interventions and Insulin on Myocardial, Skeletal Muscle and Brain [18F]-Fluorodeoxyglucose Kinetics in Mice}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68775}, year = {2011}, abstract = {Background: We evaluated the effect of insulin stimulation and dietary changes on myocardial, skeletal muscle and brain [18F]-fluorodeoxyglucose (FDG) kinetics and uptake in vivo in intact mice. Methods: Mice were anesthetized with isoflurane and imaged under different conditions: non-fasted (n = 7; "controls"), non-fasted with insulin (2 IU/kg body weight) injected subcutaneously immediately prior to FDG (n = 6), fasted (n = 5), and fasted with insulin injection (n = 5). A 60-min small-animal PET with serial blood sampling and kinetic modeling was performed. Results: We found comparable FDG standardized uptake values (SUVs) in myocardium in the non-fasted controls and non-fasted-insulin injected group (SUV 45-60 min, 9.58 ± 1.62 vs. 9.98 ± 2.44; p = 0.74), a lower myocardial SUV was noted in the fasted group (3.48 ± 1.73; p < 0.001). In contrast, the FDG uptake rate constant (Ki) for myocardium increased significantly by 47\% in non-fasted mice by insulin (13.4 ± 3.9 ml/min/100 g vs. 19.8 ± 3.3 ml/min/100 g; p = 0.030); in fasted mice, a lower myocardial Ki as compared to controls was observed (3.3 ± 1.9 ml/min/100 g; p < 0.001). Skeletal muscle SUVs and Ki values were increased by insulin independent of dietary state, whereas in the brain, those parameters were not influenced by fasting or administration of insulin. Fasting led to a reduction in glucose metabolic rate in the myocardium (19.41 ± 5.39 vs. 3.26 ± 1.97 mg/min/100 g; p < 0.001), the skeletal muscle (1.06 ± 0.34 vs. 0.34 ± 0.08 mg/min/100 g; p = 0.001) but not the brain (3.21 ± 0.53 vs. 2.85 ± 0.25 mg/min/100 g; p = 0.19). Conclusions: Changes in organ SUVs, uptake rate constants and metabolic rates induced by fasting and insulin administration as observed in intact mice by small-animal PET imaging are consistent with those observed in isolated heart/muscle preparations and, more importantly, in vivo studies in larger animals and in humans. When assessing the effect of insulin on the myocardial glucose metabolism of non-fasted mice, it is not sufficient to just calculate the SUV - dynamic imaging with kinetic modeling is necessary.}, subject = {Insulin}, language = {en} } @article{BaumToykaBlueheretal.2021, author = {Baum, Petra and Toyka, Klaus V. and Bl{\"u}her, Matthias and Kosacka, Joanna and Nowicki, Marcin}, title = {Inflammatory mechanisms in the pathophysiology of diabetic peripheral neuropathy (DN) — new aspects}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {19}, issn = {1422-0067}, doi = {10.3390/ijms221910835}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284556}, year = {2021}, abstract = {The pathogenesis of diabetic neuropathy is complex, and various pathogenic pathways have been proposed. A better understanding of the pathophysiology is warranted for developing novel therapeutic strategies. Here, we summarize recent evidence from experiments using animal models of type 1 and type 2 diabetes showing that low-grade intraneural inflammation is a facet of diabetic neuropathy. Our experimental data suggest that these mild inflammatory processes are a likely common terminal pathway in diabetic neuropathy associated with the degeneration of intraepidermal nerve fibers. In contrast to earlier reports claiming toxic effects of high-iron content, we found the opposite, i.e., nutritional iron deficiency caused low-grade inflammation and fiber degeneration while in normal or high non-heme iron nutrition no or only extremely mild inflammatory signs were identified in nerve tissue. Obesity and dyslipidemia also appear to trigger mild inflammation of peripheral nerves, associated with neuropathy even in the absence of overt diabetes mellitus. Our finding may be the experimental analog of recent observations identifying systemic proinflammatory activity in human sensorimotor diabetic neuropathy. In a rat model of type 1 diabetes, a mild neuropathy with inflammatory components could be induced by insulin treatment causing an abrupt reduction in HbA1c. This is in line with observations in patients with severe diabetes developing a small fiber neuropathy upon treatment-induced rapid HbA1c reduction. If the inflammatory pathogenesis could be further substantiated by data from human tissues and intervention studies, anti-inflammatory compounds with different modes of action may become candidates for the treatment or prevention of diabetic neuropathy.}, language = {en} } @article{GrotemeyerFischerKoprichetal.2023, author = {Grotemeyer, Alexander and Fischer, Judith F. and Koprich, James B. and Brotchie, Jonathan M. and Blum, Robert and Volkmann, Jens and Ip, Chi Wang}, title = {Inflammasome inhibition protects dopaminergic neurons from α-synuclein pathology in a model of progressive Parkinson's disease}, series = {Journal of Neuroinflammation}, volume = {20}, journal = {Journal of Neuroinflammation}, doi = {10.1186/s12974-023-02759-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357652}, year = {2023}, abstract = {Neuroinflammation has been suggested as a pathogenetic mechanism contributing to Parkinson's disease (PD). However, anti-inflammatory treatment strategies have not yet been established as a therapeutic option for PD patients. We have used a human α-synuclein mouse model of progressive PD to examine the anti-inflammatory and neuroprotective effects of inflammasome inhibition on dopaminergic (DA) neurons in the substantia nigra (SN). As the NLRP3 (NOD-, LRR- and pyrin domain-containing 3)-inflammasome is a core interface for both adaptive and innate inflammation and is also highly druggable, we investigated the implications of its inhibition. Repeat administration of MCC950, an inhibitor of NLRP3, in a PD model with ongoing pathology reduced CD4\(^+\) and CD8\(^+\) T cell infiltration into the SN. Furthermore, the anti-inflammasome treatment mitigated microglial activation and modified the aggregation of α-synuclein protein in DA neurons. MCC950-treated mice showed significantly less neurodegeneration of DA neurons and a reduction in PD-related motor behavior. In summary, early inflammasome inhibition can reduce neuroinflammation and prevent DA cell death in an α-synuclein mouse model for progressive PD.}, language = {en} } @article{GoebVollZimmermannetal.2021, author = {G{\"o}b, Vanessa and Voll, Maximilian G. and Zimmermann, Lena and Hemmen, Katharina and Stoll, Guido and Nieswandt, Bernhard and Schuhmann, Michael K. and Heinze, Katrin G. and Stegner, David}, title = {Infarct growth precedes cerebral thrombosis following experimental stroke in mice}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-021-02360-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265791}, year = {2021}, abstract = {Ischemic stroke is among the leading causes of disability and death worldwide. In acute ischemic stroke, successful recanalization of occluded vessels is the primary therapeutic aim, but even if it is achieved, not all patients benefit. Although blockade of platelet aggregation did not prevent infarct progression, cerebral thrombosis as cause of secondary infarct growth has remained a matter of debate. As cerebral thrombi are frequently observed after experimental stroke, a thrombus-induced impairment of the brain microcirculation is considered to contribute to tissue damage. Here, we combine the model of transient middle cerebral artery occlusion (tMCAO) with light sheet fluorescence microscopy and immunohistochemistry of brain slices to investigate the kinetics of thrombus formation and infarct progression. Our data reveal that tissue damage already peaks after 8 h of reperfusion following 60 min MCAO, while cerebral thrombi are only observed at later time points. Thus, cerebral thrombosis is not causative for secondary infarct growth during ischemic stroke.}, language = {en} } @article{OdorferHomolaReichetal.2019, author = {Odorfer, Thorsten M. and Homola, Gy{\"o}rgy A. and Reich, Martin M. and Volkmann, Jens and Zeller, Daniel}, title = {Increased finger-tapping related cerebellar activation in cervical dystonia, enhanced by transcranial stimulation: an indicator of compensation?}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, number = {231}, issn = {1664-2295}, doi = {10.3389/fneur.2019.00231}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196249}, year = {2019}, abstract = {Background: Cervical dystonia is a movement disorder causing abnormal postures and movements of the head. While the exact pathophysiology of cervical dystonia has not yet been fully elucidated, a growing body of evidence points to the cerebellum as an important node. Methods: Here, we examined the impact of cerebellar interference by transcranial magnetic stimulation on finger-tapping related brain activation and neurophysiological measures of cortical excitability and inhibition in cervical dystonia and controls. Bilateral continuous theta-burst stimulation was used to modulate cerebellar cortical excitability in 16 patients and matched healthy controls. In a functional magnetic resonance imaging arm, data were acquired during simple finger tapping before and after cerebellar stimulation. In a neurophysiological arm, assessment comprised motor-evoked potentials amplitude and cortical silent period duration. Theta-burst stimulation over the dorsal premotor cortex and sham stimulation (neurophysiological arm only) served as control conditions. Results: At baseline, finger tapping was associated with increased activation in the ipsilateral cerebellum in patients compared to controls. Following cerebellar theta-burst stimulation, this pattern was even more pronounced, along with an additional movement-related activation in the contralateral somatosensory region and angular gyrus. Baseline motor-evoked potential amplitudes were higher and cortical silent period duration shorter in patients compared to controls. After cerebellar theta-burst stimulation, cortical silent period duration increased significantly in dystonia patients. Conclusion: We conclude that in cervical dystonia, finger movements—though clinically non-dystonic—are associated with increased activation of the lateral cerebellum, possibly pointing to general motor disorganization, which remains subclinical in most body regions. Enhancement of this activation together with an increase of silent period duration by cerebellar continuous theta-burst stimulation may indicate predominant disinhibitory effects on Purkinje cells, eventually resulting in an inhibition of cerebello-thalamocortical circuits.}, language = {en} } @article{UeceylerKewenigKittelSchneideretal.2015, author = {{\"U}{\c{c}}eyler, Nurcan and Kewenig, Susanne and Kittel-Schneider, Sarah and Fallgatter, Andreas J. and Sommer, Claudia}, title = {Increased cortical activation upon painful stimulation in fibromyalgia syndrome}, series = {BMC Neurology}, volume = {15}, journal = {BMC Neurology}, number = {210}, doi = {10.1186/s12883-015-0472-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125230}, year = {2015}, abstract = {Background Fibromyalgia syndrome (FMS) is a chronic condition characterized by widespread pain and associated symptoms. We investigated cerebral activation in FMS patients by functional near-infrared spectroscopy (fNIRS). Methods Two stimulation paradigms were applied: a) painful pressure stimulation at the dorsal forearm; b) verbal fluency test (VFT). We prospectively recruited 25 FMS patients, ten patients with unipolar major depression (MD) without pain, and 35 healthy controls. All patients underwent neurological examination and all subjects were investigated with questionnaires (pain, depression, FMS, empathy). Results FMS patients had lower pressure pain thresholds than patients with MD and controls (p < 0.001) and reported higher pain intensity (p < 0.001). Upon unilateral pressure pain stimulation fNIRS recordings revealed increased bilateral cortical activation in FMS patients compared to controls (p < 0.05). FMS patients also displayed a stronger contralateral activity over the dorsolateral prefrontal cortex in direct comparison to patients with MD (p < 0.05). While all three groups performed equally well in the VFT, a frontal deficit in cortical activation was only found in patients with depression (p < 0.05). Performance and cortical activation correlated negatively in FMS patients (p < 0.05) and positively in patients with MD (p < 0.05). Conclusion Our data give further evidence for altered central nervous processing in patients with FMS and the distinction between FMS and MD.}, language = {en} } @article{UeceylerHomolaGonzalezetal.2014, author = {{\"U}{\c{c}}eyler, Nurcan and Homola, Gy{\"o}rgy A. and Gonz{\´a}lez, Hans Guerrero and Kramer, Daniela and Wanner, Christoph and Weidemann, Frank and Solymosi, L{\´a}szl{\´o} and Sommer, Claudia}, title = {Increased Arterial Diameters in the Posterior Cerebral Circulation in Men with Fabry Disease}, doi = {10.1371/journal.pone.0087054}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112614}, year = {2014}, abstract = {A high load of white matter lesions and enlarged basilar arteries have been shown in selected patients with Fabry disease, a disorder associated with an increased stroke risk. We studied a large cohort of patients with Fabry disease to differentially investigate white matter lesion load and cerebral artery diameters. We retrospectively analyzed cranial magnetic resonance imaging scans of 87 consecutive Fabry patients, 20 patients with ischemic stroke, and 36 controls. We determined the white matter lesion load applying the Fazekas score on fluid-attenuated inversion recovery sequences and measured the diameters of cerebral arteries on 3D-reconstructions of the time-of-flight-MR-angiography scans. Data of different Fabry patient subgroups (males - females; normal - impaired renal function) were compared with data of patients with stroke and controls. A history of stroke or transient ischemic attacks was present in 4/30 males (13\%) and 5/57 (9\%) females with Fabry disease, all in the anterior circulation. Only one man with Fabry disease showed confluent cerebral white matter lesions in the Fazekas score assessment (1\%). Male Fabry patients had a larger basilar artery (p<0.01) and posterior cerebral artery diameter (p<0.05) compared to male controls. This was independent of disease severity as measured by renal function and did not lead to changes in arterial blood flow properties. A basilar artery diameter of >3.2 mm distinguished between men with Fabry disease and controls (sensitivity: 87\%, specificity: 86\%, p<0.001), but not from stroke patients. Enlarged arterial diameters of the posterior circulation are present only in men with Fabry disease independent of disease severity.}, language = {en} } @article{WeiseBasseLuesebrinkKleinschnitzetal.2011, author = {Weise, Gesa and Basse-L{\"u}sebrink, Thomas C. and Kleinschnitz, Christoph and Kampf, Thomas and Jakob, Peter M. and Stoll, Guido}, title = {In Vivo Imaging of Stepwise Vessel Occlusion in Cerebral Photothrombosis of Mice by \(^{19}\)F MRI}, series = {PLoS One}, volume = {6}, journal = {PLoS One}, number = {12}, doi = {10.1371/journal.pone.0028143}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137792}, pages = {e28143}, year = {2011}, abstract = {Background \(^{19}\)F magnetic resonance imaging (MRI) was recently introduced as a promising technique for in vivo cell tracking. In the present study we compared \(^{19}\)F MRI with iron-enhanced MRI in mice with photothrombosis (PT) at 7 Tesla. PT represents a model of focal cerebral ischemia exhibiting acute vessel occlusion and delayed neuroinflammation. Methods/Principal Findings Perfluorocarbons (PFC) or superparamagnetic iron oxide particles (SPIO) were injected intravenously at different time points after photothrombotic infarction. While administration of PFC directly after PT induction led to a strong \(^{19}\)F signal throughout the entire lesion, two hours delayed application resulted in a rim-like \(^{19}\)F signal at the outer edge of the lesion. These findings closely resembled the distribution of signal loss on T2-weighted MRI seen after SPIO injection reflecting intravascular accumulation of iron particles trapped in vessel thrombi as confirmed histologically. By sequential administration of two chemically shifted PFC compounds 0 and 2 hours after illumination the different spatial distribution of the \(^{19}\)F markers (infarct core/rim) could be visualized in the same animal. When PFC were applied at day 6 the fluorine marker was only detected after long acquisition times ex vivo. SPIO-enhanced MRI showed slight signal loss in vivo which was much more prominent ex vivo indicative for neuroinflammation at this late lesion stage. Conclusion Our study shows that vessel occlusion can be followed in vivo by \(^{19}\)F and SPIO-enhanced high-field MRI while in vivo imaging of neuroinflammation remains challenging. The timing of contrast agent application was the major determinant of the underlying processes depicted by both imaging techniques. Importantly, sequential application of different PFC compounds allowed depiction of ongoing vessel occlusion from the core to the margin of the ischemic lesions in a single MRI measurement.}, language = {en} } @article{HussHalbgebauerOeckletal.2016, author = {Huss, Andr{\´e} M. and Halbgebauer, Steffen and {\"O}ckl, Patrick and Trebst, Corinna and Spreer, Annette and Borisow, Nadja and Harrer, Andrea and Brecht, Isabel and Balint, Bettina and Stich, Oliver and Schlegel, Sabine and Retzlaff, Nele and Winkelmann, Alexander and Roesler, Romy and Lauda, Florian and Yildiz, {\"O}zlem and Voß, Elke and Muche, Rainer and Rauer, Sebastian and Bergh, Florian Then and Otto, Markus and Paul, Friedemann and Wildemann, Brigitte and Kraus, J{\"o}rg and Ruprecht, Klemens and Stangel, Martin and Buttmann, Mathias and Zettl, Uwe K. and Tumani, Hayrettin}, title = {Importance of cerebrospinal fluid analysis in the era of McDonald 2010 criteria: a German-Austrian retrospective multicenter study in patients with a clinically isolated syndrome}, series = {Journal of Neurology}, volume = {263}, journal = {Journal of Neurology}, number = {12}, doi = {10.1007/s00415-016-8302-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186619}, pages = {2499-2504}, year = {2016}, abstract = {The majority of patients presenting with a first clinical symptom suggestive of multiple sclerosis (MS) do not fulfill the MRI criteria for dissemination in space and time according to the 2010 revision of the McDonald diagnostic criteria for MS and are thus classified as clinically isolated syndrome (CIS). To re-evaluate the utility of cerebrospinal fluid (CSF) analysis in the context of the revised McDonald criteria from 2010, we conducted a retrospective multicenter study aimed at determining the prevalence and predictive value of oligoclonal IgG bands (OCBs) in patients with CIS. Patients were recruited from ten specialized MS centers in Germany and Austria. We collected data from 406 patients; at disease onset, 44/406 (11 \%) fulfilled the McDonald 2010 criteria for MS. Intrathecal IgG OCBs were detected in 310/362 (86 \%) of CIS patients. Those patients were twice as likely to convert to MS according to McDonald 2010 criteria as OCB-negative individuals (hazard ratio = 2.1, p = 0.0014) and in a shorter time period of 25 months (95 \% CI 21-34) compared to 47 months in OCB-negative individuals (95 \% CI 36-85). In patients without brain lesions at first attack and presence of intrathecal OCBs (30/44), conversion rate to MS was 60 \% (18/30), whereas it was only 21 \% (3/14) in those without OCBs. Our data confirm that in patients with CIS the risk of conversion to MS substantially increases if OCBs are present at onset. CSF analysis definitely helps to evaluate the prognosis in patients who do not have MS according to the revised McDonald criteria.}, language = {en} } @article{UeceylerKahnKrameretal.2013, author = {{\"U}{\c{c}}eyler, Nurcan and Kahn, Ann-Kathrin and Kramer, Daniela and Zeller, Daniel and Casanova-Molla, Jordi and Wanner, Christoph and Weidemann, Frank and Katsarava, Zaza and Sommer, Claudia}, title = {Impaired small fiber conduction in patients with Fabry disease: a neurophysiological case-control study}, series = {BMC Neurology}, journal = {BMC Neurology}, doi = {10.1186/1471-2377-13-47}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96527}, year = {2013}, abstract = {Background Fabry disease is an inborn lysosomal storage disorder which is associated with small fiber neuropathy. We set out to investigate small fiber conduction in Fabry patients using pain-related evoked potentials (PREP). Methods In this case-control study we prospectively studied 76 consecutive Fabry patients for electrical small fiber conduction in correlation with small fiber function and morphology. Data were compared with healthy controls using non-parametric statistical tests. All patients underwent neurological examination and were investigated with pain and depression questionnaires. Small fiber function (quantitative sensory testing, QST), morphology (skin punch biopsy), and electrical conduction (PREP) were assessed and correlated. Patients were stratified for gender and disease severity as reflected by renal function. Results All Fabry patients (31 men, 45 women) had small fiber neuropathy. Men with Fabry disease showed impaired cold (p < 0.01) and warm perception (p < 0.05), while women did not differ from controls. Intraepidermal nerve fiber density (IENFD) was reduced at the lower leg (p < 0.001) and the back (p < 0.05) mainly of men with impaired renal function. When investigating A-delta fiber conduction with PREP, men but not women with Fabry disease had lower amplitudes upon stimulation at face (p < 0.01), hands (p < 0.05), and feet (p < 0.01) compared to controls. PREP amplitudes further decreased with advance in disease severity. PREP amplitudes and warm (p < 0.05) and cold detection thresholds (p < 0.01) at the feet correlated positively in male patients. Conclusion Small fiber conduction is impaired in men with Fabry disease and worsens with advanced disease severity. PREP are well-suited to measure A-delta fiber conduction.}, language = {en} } @article{StengelVulinovicMeieretal.2020, author = {Stengel, Felix and Vulinovic, Franca and Meier, Britta and Gr{\"u}tz, Karen and Klein, Christine and Capetian, Philipp}, title = {Impaired differentiation of human induced neural stem cells by TOR1A overexpression}, series = {Molecular Biology Reports}, volume = {47}, journal = {Molecular Biology Reports}, doi = {10.25972/OPUS-24117}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241177}, pages = {3993-4001}, year = {2020}, abstract = {DYT-TOR1A is the most common inherited dystonia caused by a three nucleotide (GAG) deletion (dE) in the TOR1A gene. Death early after birth and cortical anomalies of the full knockout in rodents underscore its developmental importance. We therefore explored the timed effects of TOR1A-wt and TOR1A-dE during differentiation in a human neural in vitro model. We used lentiviral tet-ON expression of TOR1A-wt and -dE in induced neural stem cells derived from healthy donors. Overexpression was induced during proliferation of neural precursors, during differentiation and after differentiation into mature neurons. Overexpression of both wildtype and mutated protein had no effect on the viability and cell number of neural precursors as well as mature neurons when initiated before or after differentiation. However, if induced during differentiation, overexpression of TOR1A-wt and -dE led to a pronounced reduction of mature neurons in a dose dependent manner. Our data underscores the importance of physiological expression levels of TOR1A as crucial for proper neuronal differentiation. We did not find evidence for a specific impact of the mutated TOR1A on neuronal maturation.}, language = {en} } @article{EssigKollikowskiPhametal.2020, author = {Essig, Fabian and Kollikowski, Alexander M. and Pham, Mirko and Solymosi, L{\´a}szl{\´o} and Stoll, Guido and Haeusler, Karl Georg and Kraft, Peter and Schuhmann, Michael K.}, title = {Immunohistological analysis of neutrophils and neutrophil extracellular traps in human thrombemboli causing acute ischemic stroke}, series = {International Journal of Molecular Sciences}, volume = {21}, journal = {International Journal of Molecular Sciences}, number = {19}, issn = {1422-0067}, doi = {10.3390/ijms21197387}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236192}, year = {2020}, abstract = {Ischemic stroke caused by thromboembolic occlusion of large cerebral arteries, such as the internal carotid (ICA) and/or the middle cerebral artery (MCA), is treated by mechanical thrombectomy (MT). MT allows salvage of the vessel-occluding thrombemboli, which most frequently originate from the left atrium or the left ventricle of the heart or from sites of plaque rupture within large arteries above the heart. Clot composition may influence the efficacy of (intravenous) thrombolysis and MT, respectively. We analyzed 37 human thrombemboli obtained from acute ischemic stroke patients during MT with special emphasis on histological staining of neutrophils and neutrophil extracellular traps (NETs). We found neutrophils as the main cellular component of cerebral thrombemboli but encountered considerable morphological heterogeneity. Neutrophils accumulated in the border region of fibrin-rich structures indicating possible interaction of neutrophils with distinct structural thrombembolus components. Web-like NETs were found in 35 of 37 thrombemboli in varying amounts. NETs were almost exclusively found within fibrin-rich areas. Importantly, stroke etiology, age and present oral anticoagulation was associated with morphological patterns and the amount of neutrophils. Correlation of histological data and imaging data revealed that relative Hounsfield units of cerebral thrombemboli positively correlated with the amount of red blood cells. In summary, our results demonstrate that neutrophils and NETs are substantial constituents of cerebral thrombemboli and contribute to their structural complexity.}, language = {en} } @article{SchuhmannGunrebenKleinschnitzetal.2016, author = {Schuhmann, Michael K. and Gunreben, Ignaz and Kleinschnitz, Christoph and Kraft, Peter}, title = {Immunohistochemical Analysis of Cerebral Thrombi Retrieved by Mechanical Thrombectomy from Patients with Acute Ischemic Stroke}, series = {International Journal of Molecular Sciences}, volume = {17}, journal = {International Journal of Molecular Sciences}, number = {3}, doi = {10.3390/ijms17030298}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166206}, pages = {298}, year = {2016}, abstract = {Mechanical thrombectomy is a novel treatment option for patients with acute ischemic stroke (AIS). Only a few studies have previously suggested strategies to categorize retrieved clots according to their histologic composition. However, these reports did not analyze potential biomarkers that are of importance in stroke-related inflammation. We therefore histopathologically investigated 37 intracerebral thrombi mechanically retrieved from patients with AIS, and focused on the composition of immune cells and platelets. We also conducted correlation analyses of distinctive morphologic patterns (erythrocytic, serpentine, layered, red, white, mixed appearance) with clinical parameters. Most T cells and monocytes were detected in erythrocytic and red clots, in which the distribution of these cells was random. In contrast, von Willebrand factor (vWF)-positive areas co-localized with regions of fibrin and collagen. While clots with huge amounts of vWF seem to be associated with a high National Institute of Health Stroke Scale score at admission, histologic findings could not predict the clinical outcome at discharge. In summary, we provide the first histologic description of mechanically retrieved intracerebral thrombi regarding biomarkers relevant for inflammation in ischemic stroke.}, language = {en} } @article{GrohBerveMartini2021, author = {Groh, Janos and Berve, Kristina and Martini, Rudolf}, title = {Immune modulation attenuates infantile neuronal ceroid lipofuscinosis in mice before and after disease onset}, series = {Brain Communications}, volume = {3}, journal = {Brain Communications}, number = {2}, doi = {10.1093/braincomms/fcab047}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260167}, year = {2021}, abstract = {Targeting neuroinflammation in models for infantile and juvenile forms of neuronal ceroid lipofuscinosis (NCL, CLN disease) with the clinically established immunomodulators fingolimod and teriflunomide significantly attenuates the neurodegenerative phenotype when applied preventively, i.e. before the development of substantial neural damage and clinical symptoms. Here, we show that in a mouse model for the early onset and rapidly progressing CLN1 form, more complex clinical phenotypes like disturbed motor coordination and impaired visual acuity are also ameliorated by immunomodulation. Moreover, we show that the disease outcome can be attenuated even when fingolimod and teriflunomide treatment starts after disease onset, i.e. when neurodegeneration is ongoing and clinical symptoms are detectable. In detail, treatment with either drug led to a reduction in T-cell numbers and microgliosis in the CNS, although not to the same extent as upon preventive treatment. Pharmacological immunomodulation was accompanied by a reduction of axonal damage, neuron loss and astrogliosis in the retinotectal system and by reduced brain atrophy. Accordingly, the frequency of myoclonic jerks and disturbed motor coordination were attenuated. Overall, disease alleviation was remarkably substantial upon therapeutic treatment with both drugs, although less robust than upon preventive treatment. To test the relevance of putative immune-independent mechanisms of action in this model, we treated CLN1 mice lacking mature T- and B-lymphocytes. Immunodeficient CLN1 mice showed, as previously reported, an improved neurological phenotype in comparison with genuine CLN1 mice which could not be further alleviated by either of the drugs, reflecting a predominantly immune-related therapeutic mechanism of action. The present study supports and strengthens our previous view that repurposing clinically approved immunomodulators may alleviate the course of CLN1 disease in human patients, even though diagnosis usually occurs when symptoms have already emerged.}, language = {en} } @article{StrinitzPhamMaerzetal.2021, author = {Strinitz, Marc and Pham, Mirko and M{\"a}rz, Alexander G. and Feick, J{\"o}rn and Weidner, Franziska and Vogt, Marius L. and Essig, Fabian and Neugebauer, Hermann and Stoll, Guido and Schuhmann, Michael K. and Kollikowski, Alexander M.}, title = {Immune cells invade the collateral circulation during human stroke: prospective replication and extension}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {17}, issn = {1422-0067}, doi = {10.3390/ijms22179161}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284281}, year = {2021}, abstract = {It remains unclear if principal components of the local cerebral stroke immune response can be reliably and reproducibly observed in patients with acute large-vessel-occlusion (LVO) stroke. We prospectively studied a large independent cohort of n = 318 consecutive LVO stroke patients undergoing mechanical thrombectomy during which cerebral blood samples from within the occluded anterior circulation and systemic control samples from the ipsilateral cervical internal carotid artery were obtained. An extensive protocol was applied to homogenize the patient cohort and to standardize the procedural steps of endovascular sample collection, sample processing, and laboratory analyses. N = 58 patients met all inclusion criteria. (1) Mean total leukocyte counts were significantly higher within the occluded ischemic cerebral vasculature (I) vs. intraindividual systemic controls (S): +9.6\%, I: 8114/µL ± 529 vs. S: 7406/µL ± 468, p = 0.0125. (2) This increase was driven by neutrophils: +12.1\%, I: 7197/µL ± 510 vs. S: 6420/µL ± 438, p = 0.0022. Leukocyte influx was associated with (3) reduced retrograde collateral flow (R\(^2\) = 0.09696, p = 0.0373) and (4) greater infarct extent (R\(^2\) = 0.08382, p = 0.032). Despite LVO, leukocytes invade the occluded territory via retrograde collateral pathways early during ischemia, likely compromising cerebral hemodynamics and tissue integrity. This inflammatory response can be reliably observed in human stroke by harvesting immune cells from the occluded cerebral vascular compartment.}, language = {en} } @article{UeceylerTopuzoğluSchiesseretal.2011, author = {{\"U}{\c{c}}eyler, Nurcan and Topuzoğlu, Teng{\"u} and Schießer, Peter and Hahnenkamp, Saskia and Sommer, Claudia}, title = {IL-4 Deficiency Is Associated with Mechanical Hypersensitivity in Mice}, series = {PLoS One}, volume = {6}, journal = {PLoS One}, number = {12}, doi = {10.1371/journal.pone.0028205}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137924}, pages = {e28205}, year = {2011}, abstract = {Interleukin-4 (IL-4) is an anti-inflammatory and analgesic cytokine that induces opioid receptor transcription. We investigated IL-4 knockout (ko) mice to characterize their pain behavior before and after chronic constriction injury (CCI) of the sciatic nerve as a model for neuropathic pain. We investigated opioid responsivity and measured cytokine and opioid receptor gene expression in the peripheral and central nervous system (PNS, CNS) of IL-4 ko mice in comparison with wildtype (wt) mice. Na{\"i}ve IL-4 ko mice displayed tactile allodynia (wt: 0.45 g; ko: 0.18 g; p<0.001), while responses to heat and cold stimuli and to muscle pressure were not different. No compensatory changes in the gene expression of tumor necrosis factor-alpha (TNF), IL-1β, IL-10, and IL-13 were found in the PNS and CNS of na{\"i}ve IL-4 ko mice. However, IL-1β gene expression was stronger in the sciatic nerve of IL-4 ko mice (p<0.001) 28 days after CCI and only IL-4 ko mice had elevated IL-10 gene expression (p = 0.014). Remarkably, CCI induced TNF (p<0.01), IL-1β (p<0.05), IL-10 (p<0.05), and IL-13 (p<0.001) gene expression exclusively in the ipsilateral spinal cord of IL-4 ko mice. The compensatory overexpression of the anti-inflammatory and analgesic cytokines IL-10 and IL-13 in the spinal cord of IL-4 ko mice may explain the lack of genotype differences for pain behavior after CCI. Additionally, CCI induced gene expression of μ, κ, and δ opioid receptors in the contralateral cortex and thalamus of IL-4 ko mice, paralleled by fast onset of morphine analgesia, but not in wt mice. We conclude that a lack of IL-4 leads to mechanical sensitivity; the compensatory hyperexpression of analgesic cytokines and opioid receptors after CCI, in turn, protects IL-4 ko mice from enhanced pain behavior after nerve lesion.}, language = {en} } @article{PuschmannSommer2011, author = {Puschmann, Anne-Katrin and Sommer, Claudia}, title = {Hypervigilance or avoidance of trigger related cues in migraineurs? - A case-control study using the emotional stroop task}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69103}, year = {2011}, abstract = {Background: "Negative affect" is one of the major migraine triggers. The aim of the study was to assess attentional biases for negative affective stimuli that might be related to migraine triggers in migraine patients with either few or frequent migraine and healthy controls. Methods: Thirty-three subjects with frequent migraine (FM) or with less frequent episodic migraine, and 20 healthy controls conducted two emotional Stroop tasks in the interictal period. In task 1, general affective words and in task 2, pictures of affective faces (angry, neutral, happy) were used. For each task we calculated two emotional Stroop indices. Groups were compared using one-way ANOVAs. Results: The expected attentional bias in migraine patients was not found. However, in task 2 the controls showed a significant attentional bias to negative faces, whereas the FM group showed indices near zero. Thus, the FM group responded faster to negative than to positive stimuli. The difference between the groups was statistically significant. Conclusions: The findings in the FM group may reflect a learned avoidance mechanism away from affective migraine triggers.}, subject = {Migr{\"a}ne}, language = {en} } @article{PuschmannSommer2011, author = {Puschmann, Anne-Katrin and Sommer, Claudia}, title = {Hypervigilance or avoidance of trigger related cues in migraineurs? - A case-control study using the emotional stroop task}, series = {BMC Neurology}, volume = {11}, journal = {BMC Neurology}, number = {141}, doi = {10.1186/1471-2377-11-141}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137750}, year = {2011}, abstract = {Background "Negative affect" is one of the major migraine triggers. The aim of the study was to assess attentional biases for negative affective stimuli that might be related to migraine triggers in migraine patients with either few or frequent migraine and healthy controls. Methods Thirty-three subjects with frequent migraine (FM) or with less frequent episodic migraine, and 20 healthy controls conducted two emotional Stroop tasks in the interictal period. In task 1, general affective words and in task 2, pictures of affective faces (angry, neutral, happy) were used. For each task we calculated two emotional Stroop indices. Groups were compared using one-way ANOVAs. Results The expected attentional bias in migraine patients was not found. However, in task 2 the controls showed a significant attentional bias to negative faces, whereas the FM group showed indices near zero. Thus, the FM group responded faster to negative than to positive stimuli. The difference between the groups was statistically significant. Conclusions The findings in the FM group may reflect a learned avoidance mechanism away from affective migraine triggers.}, language = {en} } @article{KraftSchuhmannGarzetal.2017, author = {Kraft, Peter and Schuhmann, Michael K. and Garz, Cornelia and Jandke, Solveig and Urlaub, Daniela and Mencl, Stine and Zernecke, Alma and Heinze, Hans-Jochen and Carare, Roxana O. and Kleinschnitz, Christoph and Schreiber, Stefanie}, title = {Hypercholesterolemia induced cerebral small vessel disease}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {8}, doi = {10.1371/journal.pone.0182822}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170493}, pages = {e0182822}, year = {2017}, abstract = {Background While hypercholesterolemia plays a causative role for the development of ischemic stroke in large vessels, its significance for cerebral small vessel disease (CSVD) remains unclear. We thus aimed to understand the detailed relationship between hypercholesterolemia and CSVD using the well described Ldlr\(^{-/-}\) mouse model. Methods We used Ldlr\(^{-/-}\) mice (n = 16) and wild-type (WT) mice (n = 15) at the age of 6 and 12 months. Ldlr\(^{-/-}\) mice develop high plasma cholesterol levels following a high fat diet. We analyzed cerebral capillaries and arterioles for intravascular erythrocyte accumulations, thrombotic vessel occlusions, blood-brain barrier (BBB) dysfunction and microbleeds. Results We found a significant increase in the number of erythrocyte stases in 6 months old Ldlr\(^{-/-}\) mice compared to all other groups (P < 0.05). Ldlr\(^{-/-}\) animals aged 12 months showed the highest number of thrombotic occlusions while in WT animals hardly any occlusions could be observed (P < 0.001). Compared to WT mice, Ldlr\(^{-/-}\) mice did not display significant gray matter BBB breakdown. Microhemorrhages were observed in one Ldlr\(^{-/-}\) mouse that was 6 months old. Results did not differ when considering subcortical and cortical regions. Conclusions In Ldlr\(^{-/-}\) mice, hypercholesterolemia is related to a thrombotic CSVD phenotype, which is different from hypertension-related CSVD that associates with a hemorrhagic CSVD phenotype. Our data demonstrate a relationship between hypercholesterolemia and the development of CSVD. Ldlr\(^{-/-}\) mice appear to be an adequate animal model for research into CSVD.}, language = {en} } @article{HansenSeilerRumpfetal.2012, author = {Hansen, Niels and Seiler, Carola and Rumpf, Julian and Kraft, Peter and Dlaske, Henry and Abele-Horn, Marianne and Muellges, Wolfgang}, title = {Human Tuberculous Meningitis Caused by \(Mycobacterium\) \(caprae\)}, series = {Case Reports in Neurology}, volume = {4}, journal = {Case Reports in Neurology}, number = {1}, doi = {10.1159/000337299}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123425}, pages = {54-60}, year = {2012}, abstract = {INTRODUCTION: Tuberculous meningitis (TM) causes substantial morbidity and mortality in humans. Human TM has been known to be induced by bacteria from the Mycobacterium tuberculosis complex (MTBC), such as M. tuberculosis and M. bovis. CASE PRESENTATION: We describe a case of meningitis treated with fosfomycin, which showed partial effectiveness in an 80-year-old patient. After a lethal myocardial infarction, M. caprae (MC) was identified in cerebrospinal fluid culture. This isolated acid-fast organism was first identified as MTBC by MTBC-specific PCR (16S rDNA-PCR). Furthermore, species-specific identification of the isolate was done by gyrB PCR-restriction fragment length polymorphism analysis of a part of gyrB DNA. Colony morphology of the isolated MC strain showed dysgonic growth on Lowenstein-Jensen medium. The strain was susceptible to pyrazinamide (PZA). CONCLUSION: This isolated strain was convincingly identified as MC according to the phenotypic and genotypic characteristics and PZA sensitivity. This is the first report of MC causing TM.}, language = {en} } @article{GeisWeishauptGruenewaldetal.2011, author = {Geis, Christian and Weishaupt, Andreas and Gr{\"u}newald, Benedikt and Wultsch, Thomas and Reif, Andreas and Gerlach, Manfred and Dirkx, Ron and Solimena, Michele and Toyka, Klaus V and Folli, Franco and Perani, Daniela and Heckmann, Manfred and Sommer, Claudia}, title = {Human Stiff-Person Syndrome IgG Induces Anxious Behavior in Rats}, series = {Plos One}, volume = {6}, journal = {Plos One}, number = {2}, doi = {10.1371/journal.pone.0016775}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140506}, pages = {e16775}, year = {2011}, abstract = {Background: Anxiety is a heterogeneous behavioral domain playing a role in a variety of neuropsychiatric diseases. While anxiety is the cardinal symptom in disorders such as panic disorder, co-morbid anxious behavior can occur in a variety of diseases. Stiff person syndrome (SPS) is a CNS disorder characterized by increased muscle tone and prominent agoraphobia and anxiety. Most patients have high-titer antibodies against glutamate decarboxylase (GAD) 65. The pathogenic role of these autoantibodies is unclear. Methodology/Principal Findings: We re-investigated a 53 year old woman with SPS and profound anxiety for GABA-A receptor binding in the amygdala with (11) C-flumazenil PET scan and studied the potential pathogenic role of purified IgG from her plasma filtrates containing high-titer antibodies against GAD 65. We passively transferred the IgG fraction intrathecally into rats and analyzed the effects using behavioral and in vivo electrophysiological methods. In cell culture, we measured the effect of patient IgG on GABA release from hippocampal neurons. Repetitive intrathecal application of purified patient IgG in rats resulted in an anxious phenotype resembling the core symptoms of the patient. Patient IgG selectively bound to rat amygdala, hippocampus, and frontal cortical areas. In cultured rat hippocampal neurons, patient IgG inhibited GABA release. In line with these experimental results, the GABA-A receptor binding potential was reduced in the patient's amygdala/hippocampus complex. No motor abnormalities were found in recipient rats. Conclusion/Significance: The observations in rats after passive transfer lead us to propose that anxiety-like behavior can be induced in rats by passive transfer of IgG from a SPS patient positive for anti-GAD 65 antibodies. Anxiety, in this case, thus may be an antibody-mediated phenomenon with consecutive disturbance of GABAergic signaling in the amygdala region.}, language = {en} } @article{GeisWeishauptGruenewaldetal.2011, author = {Geis, Christian and Weishaupt, Andreas and Gr{\"u}newald, Benedikt and Wultsch, Thomas and Reif, Andreas and Gerlach, Manfred and Dirkx, Ron and Solimena, Michele and Perani, Daniela and Heckmann, Manfred and Toyka, Klaus V. and Folli, Franco and Sommer, Claudia}, title = {Human Stiff-Person Syndrome IgG Induces Anxious Behavior in Rats}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-74757}, year = {2011}, abstract = {Background: Anxiety is a heterogeneous behavioral domain playing a role in a variety of neuropsychiatric diseases. While anxiety is the cardinal symptom in disorders such as panic disorder, co-morbid anxious behavior can occur in a variety of diseases. Stiff person syndrome (SPS) is a CNS disorder characterized by increased muscle tone and prominent agoraphobia and anxiety. Most patients have high-titer antibodies against glutamate decarboxylase (GAD) 65. The pathogenic role of these autoantibodies is unclear. Methodology/Principal Findings: We re-investigated a 53 year old woman with SPS and profound anxiety for GABA-A receptor binding in the amygdala with (11)C-flumazenil PET scan and studied the potential pathogenic role of purified IgG from her plasma filtrates containing high-titer antibodies against GAD 65. We passively transferred the IgG fraction intrathecally into rats and analyzed the effects using behavioral and in vivo electrophysiological methods. In cell culture, we measured the effect of patient IgG on GABA release from hippocampal neurons. Repetitive intrathecal application of purified patient IgG in rats resulted in an anxious phenotype resembling the core symptoms of the patient. Patient IgG selectively bound to rat amygdala, hippocampus, and frontal cortical areas. In cultured rat hippocampal neurons, patient IgG inhibited GABA release. In line with these experimental results, the GABA-A receptor binding potential was reduced in the patient's amygdala/hippocampus complex. No motor abnormalities were found in recipient rats. Conclusion/Significance: The observations in rats after passive transfer lead us to propose that anxiety-like behavior can be induced in rats by passive transfer of IgG from a SPS patient positive for anti-GAD 65 antibodies. Anxiety, in this case, thus may be an antibody-mediated phenomenon with consecutive disturbance of GABAergic signaling in the amygdala region.}, subject = {Medizin}, language = {en} } @article{HaarmannSchuhmannSilwedeletal.2019, author = {Haarmann, Axel and Schuhmann, Michael K. and Silwedel, Christine and Monoranu, Camelia-Maria and Stoll, Guido and Buttmann, Mathias}, title = {Human brain endothelial CXCR2 is inflammation-inducible and mediates CXCL5- and CXCL8-triggered paraendothelial barrier breakdown}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {3}, issn = {1422-0067}, doi = {10.3390/ijms20030602}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201297}, year = {2019}, abstract = {Chemokines (C-X-C) motif ligand (CXCL) 5 and 8 are overexpressed in patients with multiple sclerosis, where CXCL5 serum levels were shown to correlate with blood-brain barrier dysfunction as evidenced by gadolinium-enhanced magnetic resonance imaging. Here, we studied the potential role of CXCL5/CXCL8 receptor 2 (CXCR2) as a regulator of paraendothelial brain barrier function, using the well-characterized human cerebral microvascular endothelial cell line hCMEC/D3. Low basal CXCR2 mRNA and protein expression levels in hCMEC/D3 were found to strongly increase under inflammatory conditions. Correspondingly, immunohistochemistry of brain biopsies from two patients with active multiple sclerosis revealed upregulation of endothelial CXCR2 compared to healthy control tissue. Recombinant CXCL5 or CXCL8 rapidly and transiently activated Akt/protein kinase B in hCMEC/D3. This was followed by a redistribution of tight junction-associated protein zonula occludens-1 (ZO-1) and by the formation of actin stress fibers. Functionally, these morphological changes corresponded to a decrease of paracellular barrier function, as measured by a real-time electrical impedance-sensing system. Importantly, preincubation with the selective CXCR2 antagonist SB332235 partially prevented chemokine-induced disturbance of both tight junction morphology and function. We conclude that human brain endothelial CXCR2 may contribute to blood-brain barrier disturbance under inflammatory conditions with increased CXCL5 and CXCL8 expression, where CXCR2 may also represent a novel pharmacological target for blood-brain barrier stabilization.}, language = {en} } @article{SchreglmannBhatia2022, author = {Schreglmann, Sebastian R. and Bhatia, Kailash P.}, title = {HOPS-Associated Neurological Disorders: Lysosomal Dysfunction as an Emerging Concept Underlying Dystonia}, series = {Movement Disorders Clinical Practice}, volume = {9}, journal = {Movement Disorders Clinical Practice}, number = {4}, doi = {10.1002/mdc3.13405}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318736}, pages = {452 -- 453}, year = {2022}, language = {en} } @phdthesis{Koeberle2021, author = {K{\"o}berle, Philipp}, title = {High-resolution ultrasound for the identification of pathological patterns in patients with polyneuropathies and amyotrophic lateral sclerosis}, doi = {10.25972/OPUS-24580}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245800}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Neuropathies are a group of potentially treatable diseases with an often disabling and restricting course. Amyotrophic lateral sclerosis (ALS) is a lethal disease without causal treatment possibilities. The objective of this study was to examine the diagnostic utility of HRUS for the differentiation of subtypes of axonal and demyelinating neuropathies and to investigate its utility for the sonological differentiation of ALS. The hypothetical statement that neuropathy causes enlargement of peripheral nerves compared to healthy controls proved to be right, but the adjunctive assumption that ALS does not cause enlargement of peripheral nerves proved to be wrong - in patients with ALS slight enlargement of peripheral nerves was visible as well. The statement that nerve enlargement can be detected by measurement of the cross-sectional area (CSA) and the longitudinal diameter (LD) with comparable results proved to be right, but the enlargement was slightly less present by measurement of the LD. The statement that axonal and demyelinating neuropathies show distinct patterns of nerve enlargement must be answered differentiated: The comparison between axonal and demyelinating neuropathies showed a stronger nerve enlargement in patients with demyelinating neuropathies than in patients with axonal neuropathies at proximal nerve segments of upper extremities. In the comparison of diagnose-defined subgroups of inflammatory demyelinating neuropathies a respective specific pattern of nerve enlargement was visible. However, remarkable in this context was the strong nerve enlargement found in patients with NSVN, which is classified as an axonal neuropathy. Stratification for specific findings in nerve biopsy did not lead to constructive differences in comparison between the different groups. To sum up, HRUS showed to provide a useful contribution in the diagnostic process of neuropathies and ALS but needs to be integrated in a multimodal diagnostic approach.}, subject = {Polyneuropathie}, language = {en} } @article{UeceylerSommer2014, author = {{\"U}{\c{c}}eyler, Nurcan and Sommer, Claudia}, title = {High-Dose Capsaicin for the Treatment of Neuropathic Pain: What We Know and What We Need to Know}, series = {Pain and Therapy}, volume = {3}, journal = {Pain and Therapy}, number = {2}, issn = {2193-651X}, doi = {10.1007/s40122-014-0027-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120669}, pages = {73-84}, year = {2014}, abstract = {Neuropathic pain is a frequent and disabling condition with diverse underlying etiologies and is often difficult to treat. Systemic drug treatment is often limited in efficacy. Furthermore, adverse effects may be a limiting factor when trying to reach the necessary dose. Analgesics that can be applied topically have the potential to largely overcome this problem. They may be of particular advantage in localized neuropathic pain syndromes such as postherpetic neuralgia or small fiber neuropathy. Capsaicin, the pungent component of chili peppers, is a natural ligand of the transient receptor potential vanilloid 1 channel and has long been used as topically applicable cream with concentrations of 0.025 to 0.075\%. In 2009, a high-concentration transdermal capsaicin 8\% patch (Qutenza ; Acorda Therapeutics, Inc., Ardsley, NY, USA; Astellas Pharma Europe Ltd., Chertsey, Surrey, UK) was introduced for the treatment of peripheral neuropathic pain syndromes other than of diabetic origin in adults. It has since been widely used in diverse neuropathic pain disorders. In this review article, we summarize current knowledge on Qutenza, its advantages and problems, and expose unmet needs.}, language = {en} } @article{EssigBabilonVollmuthetal.2021, author = {Essig, Fabian and Babilon, Lilith and Vollmuth, Christoph and Kollikowski, Alexander M. and Pham, Mirko and Solymosi, L{\´a}szl{\´o} and Haeusler, Karl Georg and Kraft, Peter and Stoll, Guido and Schuhmann, Michael K.}, title = {High mobility group box 1 protein in cerebral thromboemboli}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {20}, issn = {1422-0067}, doi = {10.3390/ijms222011276}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265568}, year = {2021}, abstract = {High-mobility group box 1 protein (HMGB1) is a damage-associated molecular pattern (DAMP) involved in neutrophil extracellular trap (NET) formation and thrombosis. NETs are regularly found in cerebral thromboemboli. We here analyzed associated HMGB1 expression in human thromboemboli retrieved via mechanical thrombectomy from 37 stroke patients with large vessel occlusion. HMGB1 was detected in all thromboemboli, accounting for 1.7\% (IQR 0.6-6.2\%) of the total thromboemboli area and was found to be colocalized with neutrophils and NETs and in spatial proximity to platelets. Correlation analysis revealed that the detection of HMGB1 was strongly related to the number of neutrophils (r = 0.58, p = 0.0002) and platelets (r = 0.51, p = 0.001). Our results demonstrate that HMGB1 is a substantial constituent of thromboemboli causing large vessel occlusion stroke.}, language = {en} } @article{BeyerJadaszSamperAgreloetal.2020, author = {Beyer, Felix and Jadasz, Janusz and Samper Agrelo, Iria and Schira-Heinen, Jessica and Groh, Janos and Manousi, Anastasia and B{\"u}termann, Christine and Estrada, Veronica and Reiche, Laura and Cantone, Martina and Vera, Julio and Vigan{\`o}, Francesca and Dimou, Leda and M{\"u}ller, Hans Werner and Hartung, Hans-Peter and K{\"u}ry, Patrick}, title = {Heterogeneous fate choice of genetically modulated adult neural stem cells in gray and white matter of the central nervous system}, series = {Glia}, volume = {68}, journal = {Glia}, number = {2}, doi = {10.1002/glia.23724}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218566}, pages = {393 -- 406}, year = {2020}, abstract = {Apart from dedicated oligodendroglial progenitor cells, adult neural stem cells (aNSCs) can also give rise to new oligodendrocytes in the adult central nervous system (CNS). This process mainly confers myelinating glial cell replacement in pathological situations and can hence contribute to glial heterogeneity. Our previous studies demonstrated that the p57kip2 gene encodes an intrinsic regulator of glial fate acquisition and we here investigated to what degree its modulation can affect stem cell-dependent oligodendrogenesis in different CNS environments. We therefore transplanted p57kip2 knockdown aNSCs into white and gray matter (WM and GM) regions of the mouse brain, into uninjured spinal cords as well as in the vicinity of spinal cord injuries and evaluated integration and differentiation in vivo. Our experiments revealed that under healthy conditions intrinsic suppression of p57kip2 as well as WM localization promote differentiation toward myelinating oligodendrocytes at the expense of astrocyte generation. Moreover, p57kip2 knockdown conferred a strong benefit on cell survival augmenting net oligodendrocyte generation. In the vicinity of hemisectioned spinal cords, the gene knockdown led to a similar induction of oligodendroglial features; however, newly generated oligodendrocytes appeared to suffer more from the hostile environment. This study contributes to our understanding of mechanisms of adult oligodendrogenesis and glial heterogeneity and further reveals critical factors when considering aNSC mediated cell replacement in injury and disease.}, language = {en} } @article{WohnradeVellingMixetal.2023, author = {Wohnrade, Camilla and Velling, Ann-Kathrin and Mix, Lucas and Wurster, Claudia D. and Cordts, Isabell and Stolte, Benjamin and Zeller, Daniel and Uzelac, Zeljko and Platen, Sophia and Hagenacker, Tim and Deschauer, Marcus and Lingor, Paul and Ludolph, Albert C. and Lul{\´e}, Doroth{\´e}e and Petri, Susanne and Osmanovic, Alma and Schreiber-Katz, Olivia}, title = {Health-related quality of life in spinal muscular atrophy patients and their caregivers — a prospective, cross-sectional, multi-center analysis}, series = {Brain Sciences}, volume = {13}, journal = {Brain Sciences}, number = {1}, issn = {2076-3425}, doi = {10.3390/brainsci13010110}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-305048}, year = {2023}, abstract = {Spinal muscular atrophy (SMA) is a disabling disease that affects not only the patient's health-related quality of life (HRQoL), but also causes a high caregiver burden (CGB). The aim of this study was to evaluate HRQoL, CGB, and their predictors in SMA. In two prospective, cross-sectional, and multi-center studies, SMA patients (n = 39) and SMA patient/caregiver couples (n = 49) filled in the EuroQoL Five Dimension Five Level Scale (EQ-5D-5L) and the Short Form Health Survey 36 (SF-36). Caregivers (CGs) additionally answered the Zarit Burden Interview (ZBI) and the Hospital Anxiety and Depression Scale (HADS). Patients were clustered into two groups with either low or high HRQoL (EQ-5D-5L index value <0.259 or >0.679). The latter group was mostly composed of ambulatory type III patients with higher motor/functional scores. More severely affected patients reported low physical functioning but good mental health and vitality. The CGB (mean ZBI = 22/88) correlated negatively with patients' motor/functional scores and age. Higher CGB was associated with a lower HRQoL, higher depression and anxiety, and more health impairments of the CGs. We conclude that patient and CG well-being levels interact closely, which highlights the need to consider the health of both parties while evaluating novel treatments.}, language = {en} } @article{WiesslerTalucciPiroetal.2024, author = {Wiessler, Anna-Lena and Talucci, Ivan and Piro, Inken and Seefried, Sabine and H{\"o}rlin, Verena and Baykan, Bet{\"u}l B. and T{\"u}z{\"u}n, Erdem and Schaefer, Natascha and Maric, Hans M. and Sommer, Claudia and Villmann, Carmen}, title = {Glycine receptor β-targeting autoantibodies contribute to the pathology of autoimmune diseases}, series = {Neurology: Neuroimmunology \& Neuroinflammation}, volume = {11}, journal = {Neurology: Neuroimmunology \& Neuroinflammation}, number = {2}, doi = {10.1212/NXI.0000000000200187}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349958}, year = {2024}, abstract = {Background and Objectives Stiff-person syndrome (SPS) and progressive encephalomyelitis with rigidity and myoclonus (PERM) are rare neurologic disorders of the CNS. Until now, exclusive GlyRα subunit-binding autoantibodies with subsequent changes in function and surface numbers were reported. GlyR autoantibodies have also been described in patients with focal epilepsy. Autoimmune reactivity against the GlyRβ subunits has not yet been shown. Autoantibodies against GlyRα1 target the large extracellular N-terminal domain. This domain shares a high degree of sequence homology with GlyRβ making it not unlikely that GlyRβ-specific autoantibody (aAb) exist and contribute to the disease pathology. Methods In this study, we investigated serum samples from 58 patients for aAb specifically detecting GlyRβ. Studies in microarray format, cell-based assays, and primary spinal cord neurons and spinal cord tissue immunohistochemistry were performed to determine specific GlyRβ binding and define aAb binding to distinct protein regions. Preadsorption approaches of aAbs using living cells and the purified extracellular receptor domain were further used. Finally, functional consequences for inhibitory neurotransmission upon GlyRβ aAb binding were resolved by whole-cell patch-clamp recordings. Results Among 58 samples investigated, cell-based assays, tissue analysis, and preadsorption approaches revealed 2 patients with high specificity for GlyRβ aAb. Quantitative protein cluster analysis demonstrated aAb binding to synaptic GlyRβ colocalized with the scaffold protein gephyrin independent of the presence of GlyRα1. At the functional level, binding of GlyRβ aAb from both patients to its target impair glycine efficacy. Discussion Our study establishes GlyRβ as novel target of aAb in patients with SPS/PERM. In contrast to exclusively GlyRα1-positive sera, which alter glycine potency, aAbs against GlyRβ impair receptor efficacy for the neurotransmitter glycine. Imaging and functional analyses showed that GlyRβ aAbs antagonize inhibitory neurotransmission by affecting receptor function rather than localization.}, language = {en} } @article{RauschenbergerPiroKasaragodetal.2023, author = {Rauschenberger, Vera and Piro, Inken and Kasaragod, Vikram Babu and H{\"o}rlin, Verena and Eckes, Anna-Lena and Kluck, Christoph J. and Schindelin, Hermann and Meinck, Hans-Michael and Wickel, Jonathan and Geis, Christian and T{\"u}z{\"u}n, Erdem and Doppler, Kathrin and Sommer, Claudia and Villmann, Carmen}, title = {Glycine receptor autoantibody binding to the extracellular domain is independent from receptor glycosylation}, series = {Frontiers in Molecular Neuroscience}, volume = {16}, journal = {Frontiers in Molecular Neuroscience}, doi = {10.3389/fnmol.2023.1089101}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304206}, year = {2023}, abstract = {Glycine receptor (GlyR) autoantibodies are associated with stiff-person syndrome and the life-threatening progressive encephalomyelitis with rigidity and myoclonus in children and adults. Patient histories show variability in symptoms and responses to therapeutic treatments. A better understanding of the autoantibody pathology is required to develop improved therapeutic strategies. So far, the underlying molecular pathomechanisms include enhanced receptor internalization and direct receptor blocking altering GlyR function. A common epitope of autoantibodies against the GlyRα1 has been previously defined to residues 1A-33G at the N-terminus of the mature GlyR extracellular domain. However, if other autoantibody binding sites exist or additional GlyR residues are involved in autoantibody binding is yet unknown. The present study investigates the importance of receptor glycosylation for binding of anti-GlyR autoantibodies. The glycine receptor α1 harbors only one glycosylation site at the amino acid residue asparagine 38 localized in close vicinity to the identified common autoantibody epitope. First, non-glycosylated GlyRs were characterized using protein biochemical approaches as well as electrophysiological recordings and molecular modeling. Molecular modeling of non-glycosylated GlyRα1 did not show major structural alterations. Moreover, non-glycosylation of the GlyRα1N38Q did not prevent the receptor from surface expression. At the functional level, the non-glycosylated GlyR demonstrated reduced glycine potency, but patient GlyR autoantibodies still bound to the surface-expressed non-glycosylated receptor protein in living cells. Efficient adsorption of GlyR autoantibodies from patient samples was possible by binding to native glycosylated and non-glycosylated GlyRα1 expressed in living not fixed transfected HEK293 cells. Binding of patient-derived GlyR autoantibodies to the non-glycosylated GlyRα1 offered the possibility to use purified non-glycosylated GlyR extracellular domain constructs coated on ELISA plates and use them as a fast screening readout for the presence of GlyR autoantibodies in patient serum samples. Following successful adsorption of patient autoantibodies by GlyR ECDs, binding to primary motoneurons and transfected cells was absent. Our results indicate that the glycine receptor autoantibody binding is independent of the receptor's glycosylation state. Purified non-glycosylated receptor domains harbouring the autoantibody epitope thus provide, an additional reliable experimental tool besides binding to native receptors in cell-based assays for detection of autoantibody presence in patient sera.}, language = {en} } @article{RauschenbergervonWardenburgSchaeferetal.2020, author = {Rauschenberger, Vera and von Wardenburg, Niels and Schaefer, Natascha and Ogino, Kazutoyo and Hirata, Hiromi and Lillesaar, Christina and Kluck, Christoph J. and Meinck, Hans-Michael and Borrmann, Marc and Weishaupt, Andreas and Doppler, Kathrin and Wickel, Jonathan and Geis, Christian and Sommer, Claudia and Villmann, Carmen}, title = {Glycine Receptor Autoantibodies Impair Receptor Function and Induce Motor Dysfunction}, series = {Annals of Neurology}, volume = {88}, journal = {Annals of Neurology}, number = {3}, doi = {10.1002/ana.25832}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-216005}, pages = {544 -- 561}, year = {2020}, abstract = {Objective Impairment of glycinergic neurotransmission leads to complex movement and behavioral disorders. Patients harboring glycine receptor autoantibodies suffer from stiff-person syndrome or its severe variant progressive encephalomyelitis with rigidity and myoclonus. Enhanced receptor internalization was proposed as the common molecular mechanism upon autoantibody binding. Although functional impairment of glycine receptors following autoantibody binding has recently been investigated, it is still incompletely understood. Methods A cell-based assay was used for positive sample evaluation. Glycine receptor function was assessed by electrophysiological recordings and radioligand binding assays. The in vivo passive transfer of patient autoantibodies was done using the zebrafish animal model. Results Glycine receptor function as assessed by glycine dose-response curves showed significantly decreased glycine potency in the presence of patient sera. Upon binding of autoantibodies from 2 patients, a decreased fraction of desensitized receptors was observed, whereas closing of the ion channel remained fast. The glycine receptor N-terminal residues \(^{29}\)A to \(^{62}\)G were mapped as a common epitope of glycine receptor autoantibodies. An in vivo transfer into the zebrafish animal model generated a phenotype with disturbed escape behavior accompanied by a reduced number of glycine receptor clusters in the spinal cord of affected animals. Interpretation Autoantibodies against the extracellular domain mediate alterations of glycine receptor physiology. Moreover, our in vivo data demonstrate that the autoantibodies are a direct cause of the disease, because the transfer of human glycine receptor autoantibodies to zebrafish larvae generated impaired escape behavior in the animal model compatible with abnormal startle response in stiff-person syndrome or progressive encephalitis with rigidity and myoclonus patients.}, language = {en} } @article{KleinschnitzGoebelMeuthetal.2014, author = {Kleinschnitz, Christoph and G{\"o}bel, Kerstin and Meuth, Sven G. and Kraft, Peter}, title = {Glatiramer acetate does not protect from acute ischemic stroke in mice}, doi = {10.1186/2040-7378-6-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110528}, year = {2014}, abstract = {Background The role of the immune system in the pathophysiology of acute ischemic stroke is increasingly recognized. However, targeted treatment strategies to modulate immunological pathways in stroke are still lacking. Glatiramer acetate is a multifaceted immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. Experimental studies suggest that glatiramer acetate might also work in other neuroinflammatory or neurodegenerative diseases apart from multiple sclerosis. Findings We evaluated the efficacy of glatiramer acetate in a mouse model of brain ischemia/reperfusion injury. 60 min of transient middle cerebral artery occlusion was induced in male C57Bl/6 mice. Pretreatment with glatiramer acetate (3.5 mg/kg bodyweight) 30 min before the induction of stroke did not reduce lesion volumes or improve functional outcome on day 1. Conclusions Glatiramer acetate failed to protect from acute ischemic stroke in our hands. Further studies are needed to assess the true therapeutic potential of glatiramer acetate and related immunomodulators in brain ischemia.}, language = {en} } @article{MuellerGirardHopfneretal.2016, author = {M{\"u}ller, Stefanie H. and Girard, Simon L. and Hopfner, Franziska and Merner, Nancy D. and Bourassa, Cynthia V. and Lorenz, Delia and Clark, Lorraine N. and Tittmann, Lukas and Soto-Ortolaza, Alexandra I. and Klebe, Stephan and Hallett, Mark and Schneider, Susanne A. and Hodgkinson, Colin A. and Lieb, Wolfgang and Wszolek, Zbigniew K. and Pendziwiat, Manuela and Lorenzo-Betancor, Oswaldo and Poewe, Werner and Ortega-Cubero, Sara and Seppi, Klaus and Rajput, Alex and Hussl, Anna and Rajput, Ali H. and Berg, Daniela and Dion, Patrick A. and Wurster, Isabel and Shulman, Joshua M. and Srulijes, Karin and Haubenberger, Dietrich and Pastor, Pau and Vilari{\~n}o-G{\"u}ell, Carles and Postuma, Ronald B. and Bernard, Genevi{\`e}ve and Ladwig, Karl-Heinz and Dupr{\´e}, Nicolas and Jankovic, Joseph and Strauch, Konstantin and Panisset, Michel and Winkelmann, Juliane and Testa, Claudia M. and Reischl, Eva and Zeuner, Kirsten E. and Ross, Owen A. and Arzberger, Thomas and Chouinard, Sylvain and Deuschl, G{\"u}nther and Louis, Elan D. and Kuhlenb{\"a}umer, Gregor and Rouleau, Guy A.}, title = {Genome-wide association study in essential tremor identifies three new loci}, series = {Brain}, volume = {139}, journal = {Brain}, doi = {10.1093/brain/aww242}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186541}, pages = {3163-3169}, year = {2016}, abstract = {We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.}, language = {en} } @phdthesis{MeyerzuAltenschildesche2022, author = {Meyer zu Altenschildesche, Caren}, title = {Genetische Variationen bei Patienten mit idiopathischer Small fiber Neuropathie}, doi = {10.25972/OPUS-28274}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-282742}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Die Literatur beschreibt unter Patienten mit idiopathischer Small fiber Neuro-pathie (SFN) einen Anteil von etwa ein F{\"u}nftel bis Drittel mit Variationen unkla-rer pathogenetischer Relevanz in Schmerz-assoziierten Genen. Dies best{\"a}tig-te sich im Rahmen unserer klinischen Studie: {\"U}ber die Zeit von Mai 2015 bis Januar 2020 konnten bei 13 von 66 (21\%) eingeschlossenen Patienten mit klinischem Verdacht auf SFN genetische Variationen in Schmerz-assoziierten Genen detektiert werden. Solche Ver{\"a}nderungen k{\"o}nnen {\"u}ber Gain- oder Loss-of-Function-Mechanismen die Funktion codierter nozizeptiver Signalpro-teine modulieren und so potentiell zur SFN-Symptomatik f{\"u}hren. Im Rahmen der Studie erfolgte neben der genetischen Diagnostik eine umfangreiche Un-tersuchung der Teilnehmer. In der Diagnostik stachen die potentiell geneti-schen SFN-Patienten nicht heraus und auch klinisch fielen nur dezente Unter-schiede zu den {\"u}brigen Patienten auf: Wir zeigten, dass die Betroffenen h{\"a}ufi-ger von {\"a}ußeren Einflussfaktoren getriggerte Schmerzattacken erleiden und eine tendenziell weitl{\"a}ufigere Symptommanifestation aufwiesen. Dies {\"a}hnelt der Klinik anderer heredit{\"a}rer neuropathischer Schmerzsyndrome wie der pa-roxysmalen extremen Schmerzst{\"o}rung (PEPD) oder den famili{\"a}ren episodi-schen Schmerzsyndromen (FEPS). Die potentiell genetische Grundlage f{\"u}hrte bei unseren Patienten zu einer st{\"a}rkeren Limitation im t{\"a}glichen und berufli-chen Alltag und minderte die Lebensqualit{\"a}t der Betroffenen deutlich. M{\"o}gli-che Ursache hierf{\"u}r war auch die herausfordernde Therapie der Patienten mit Genvariationen: F{\"u}r den gleichen Behandlungserfolg mussten die Patienten mit potentiell genetischer SFN deutlich mehr Wirkstoffe einnehmen und {\"u}ber-haupt versuchen. Obwohl nur minimale klinische Hinweise eine potentiell ge-netische Genese andeuten, sollten diese fr{\"u}hzeitig durch eine strukturierte Anamnese erkannt werden. Die Sammlung von Daten zu betroffenen Familien kann die pathogenetische Relevanz der Variationen erh{\"a}rten. Auch wird im Feld der genetischen Schmerzforschung rasant an zielgerichteten Analgetika gearbeitet, die fehlregulierte Rezeptoren blockieren sollen. Damit k{\"o}nnte Be-troffenen k{\"u}nftig gezielt geholfen werden. Wir empfehlen auf Grundlage unse-rer Studie bei Vorliegen genannter hinweisender Charakteristika eine geneti-sche Testung und Beratung zus{\"a}tzlich zur weiteren {\"a}tiologischen Diagnostik. Das zu untersuchende Panel sollte m{\"o}glichst viele Schmerz-assoziierte Gene umfassen - vorrangig die Gene codierend f{\"u}r die spannungsabh{\"a}ngigen Nat-riumkan{\"a}le SCN9A, -10A und 11A und die TRP-Kanalproteine TRPA1, TRPV1 und -3.}, subject = {Neuropathie}, language = {de} } @article{QuartaVoglConstantinetal.2011, author = {Quarta, Serena and Vogl, Christian and Constantin, Cristina E. and {\"U}{\c{c}}eyler, Nurcan and Sommer, Claudia and Kress, Michaela}, title = {Genetic evidence for an essential role of neuronally expressed IL-6 signal transducer gp130 in the induction and maintenance of experimentally induced mechanical hypersensitivity \(in\) \(vivo\) and \(in\) \(vitro\)}, series = {Molecular Pain}, volume = {7,73}, journal = {Molecular Pain}, doi = {10.1186/1744-8069-7-73}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140380}, pages = {1-9}, year = {2011}, abstract = {Tenderness and mechanical allodynia are key symptoms of malignant tumor, inflammation and neuropathy. The proinflammatory cytokine interleukin-6 (IL-6) is causally involved in all three pathologies. IL-6 not only regulates innate immunity and inflammation but also causes nociceptor sensitization and hyperalgesia. In general and in most cell types including immune cells and sensory neurons, IL-6 binds soluble mu receptor subunits which heteromerizes with membrane bound IL-6 signal transducer gp130. In the present study, we used a conditional knock-out strategy to investigate the importance of signal transducer gp130 expressed in C nociceptors for the generation and maintenance of mechanical hypersensitivity. Nociceptors were sensitized to mechanical stimuli by experimental tumor and this nociceptor sensitization was preserved at later stages of the pathology in control mice. However, in mice with a conditional deletion of gp130 in Nav1.8 expressing nociceptors mechanical hypersensitivity by experimental tumor, nerve injury or inflammation recovery was not preserved in the maintenance phase and nociceptors exhibited normal mechanical thresholds comparable to untreated mice. Together, the results argue for IL-6 signal transducer gp130 as an essential prerequisite in nociceptors for long-term mechanical hypersensitivity associated with cancer, inflammation and nerve injury.}, language = {en} } @phdthesis{Klaus2021, author = {Klaus, Laura-Christin}, title = {Generierung und Charakterisierung eines neuen Mausmodells des Morbus Parkinson durch AAV1/2 vermittelte {\"U}berexpression von humanem mutiertem A53T-α-Synuclein in der Substantia nigra}, doi = {10.25972/OPUS-23921}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239217}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Auch wenn die {\"A}tiopathogenese von Morbus Parkinson bis heute nicht vollst{\"a}ndig gekl{\"a}rt ist, scheint α-Synuclein (α-Syn) eine zentrale Rolle zu spielen. Die Entdeckung als genetische Ursache der Erkrankung, als Hauptbestandteil der Lewy-K{\"o}rper (LK) und seine Assoziation mit verschiedenen anderen potenziellen {\"a}tiologischen Faktoren verdeutlichen dies. Bei Ratten und Affen f{\"u}hrte eine AAV1/2-vermittelte {\"U}berexpression von A53T-α-Syn zu einer Degeneration dopaminerger Neurone in der Substantia nigra (SN), einem striatalen dopaminergen Defizit sowie Verhaltensauff{\"a}lligkeiten. In Anbetracht bestimmter Vorteile der Mausspezies, war es das Ziel dieser Dissertation - die im Rahmen eines kollaborativen Projektes mit dem Toronto Western Research Institut in Ontario, Kanada entstanden ist - dieses auf AAV1/2-A53T-α-Syn basierende Parkinson-Modell auf M{\"a}use zu {\"u}bertragen. Dazu wurde AAV1/2-A53T-α-Syn oder leerer AAV1/2-Vektor in einer Dosis von 1,5 µl mit einer Konzentration von 5,16 x 10^12 gp/ml stereotaktisch einseitig in die rechte SN von C57BL/6-wt-M{\"a}usen injiziert. {\"U}ber einen Zeitraum von 11 Wochen wurden verschiedene Verhaltensexperimente durchgef{\"u}hrt und die beiden Versuchstiergruppen miteinander verglichen. Post-mortem erfolgten verschiedene immunhistochemische Untersuchungen. Es konnte gezeigt werden, dass die einseitige Injektion von AAV1/2-A53T-α-Syn in die SN bei M{\"a}usen eine weit verbreitete {\"U}berexpression von A53T-α-Syn in dopaminergen Neuronen der SN induzierte, die innerhalb von 10 Wochen zu signifikanten fr{\"u}hen und persistierenden motorischen Verhaltensauff{\"a}lligkeiten, nigrostriataler Degeneration und Entwicklung einer Lewy-{\"a}hnlichen Pathologie f{\"u}hrte. Durch die Generierung und Charakterisierung dieses neuen Parkinson-Mausmodells, das klinische und histopathologische Merkmale der menschlichen Erkrankung widerspiegelt, besteht nun die M{\"o}glichkeit es weiterzuentwickeln und z.B. auf transgene M{\"a}use zu {\"u}bertragen, um u.a. molekulare Mechanismen der Parkinson-Krankheit zu entschl{\"u}sseln und pr{\"a}klinische Tests von krankheitsmodifizierenden Therapien durchzuf{\"u}hren.}, subject = {Parkinson-Krankheit}, language = {de} } @article{LauUeceylerCairnsetal.2022, author = {Lau, Kolja and {\"U}{\c{c}}eyler, Nurcan and Cairns, Tereza and Lorenz, Lora and Sommer, Claudia and Schindeh{\"u}tte, Magnus and Amann, Kerstin and Wanner, Christoph and Nordbeck, Peter}, title = {Gene variants of unknown significance in Fabry disease: Clinical characteristics of c.376AG (p.Ser126Gly)}, series = {Molecular Genetics \& Genomic Medicine}, volume = {10}, journal = {Molecular Genetics \& Genomic Medicine}, number = {5}, doi = {10.1002/mgg3.1912}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312817}, year = {2022}, abstract = {Background Anderson-Fabry disease (FD) is an X-linked lysosomal storage disorder with varying organ involvement and symptoms, depending on the underlying mutation in the alpha-galactosidase A gene (HGNC: GLA). With genetic testing becoming more readily available, it is crucial to precisely evaluate pathogenicity of each genetic variant, in order to determine whether there is or might be not a need for FD-specific therapy in affected patients and relatives at the time point of presentation or in the future. Methods This case series investigates the clinical impact of the specific GLA gene variant c.376A>G (p.Ser126Gly) in five (one heterozygous and one homozygous female, three males) individuals from different families, who visited our center between 2009 and 2021. Comprehensive neurological, nephrological and cardiac examinations were performed in all cases. One patient received a follow-up examination after 12 years. Results Index events leading to suspicion of FD were mainly unspecific neurological symptoms. However, FD-specific biomarkers, imaging examinations (i.e., brain MRI, heart MRI), and tissue-specific diagnostics, including kidney and skin biopsies, did not reveal evidence for FD-specific symptoms or organ involvement but showed normal results in all cases. This includes findings from 12-year follow-up in one patient with renal biopsy. Conclusion These findings suggest that p.Ser126Gly represents a benign GLA gene variant which per se does not cause FD. Precise clinical evaluation in individuals diagnosed with genetic variations of unknown significance should be performed to distinguish common symptoms broadly prevalent in the general population from those secondary to FD.}, language = {en} } @article{PalmisanoBrandtVissanietal.2020, author = {Palmisano, Chiara and Brandt, Gregor and Vissani, Matteo and Pozzi, Nicol{\´o} G. and Canessa, Andrea and Brumberg, Joachim and Marotta, Giorgio and Volkmann, Jens and Mazzoni, Alberto and Pezzoli, Gianni and Frigo, Carlo A. and Isaias, Ioannis U.}, title = {Gait Initiation in Parkinson's Disease: Impact of Dopamine Depletion and Initial Stance Condition}, series = {Frontiers in Bioengineering and Biotechnology}, volume = {8}, journal = {Frontiers in Bioengineering and Biotechnology}, issn = {2296-4185}, doi = {10.3389/fbioe.2020.00137}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200801}, year = {2020}, abstract = {Postural instability, in particular at gait initiation (GI), and resulting falls are a major determinant of poor quality of life in subjects with Parkinson's disease (PD). Still, the contribution of the basal ganglia and dopamine on the feedforward postural control associated with this motor task is poorly known. In addition, the influence of anthropometric measures (AM) and initial stance condition on GI has never been consistently assessed. The biomechanical resultants of anticipatory postural adjustments contributing to GI [imbalance (IMB), unloading (UNL), and stepping phase) were studied in 26 unmedicated subjects with idiopathic PD and in 27 healthy subjects. A subset of 13 patients was analyzed under standardized medication conditions and the striatal dopaminergic innervation was studied in 22 patients using FP-CIT and SPECT. People with PD showed a significant reduction in center of pressure (CoP) displacement and velocity during the IMB phase, reduced first step length and velocity, and decreased velocity and acceleration of the center of mass (CoM) at toe off of the stance foot. All these measurements correlated with the dopaminergic innervation of the putamen and substantially improved with levodopa. These results were not influenced by anthropometric parameters or by the initial stance condition. In contrast, most of the measurements of the UNL phase were influenced by the foot placement and did not correlate with putaminal dopaminergic innervation. Our results suggest a significant role of dopamine and the putamen particularly in the elaboration of the IMB phase of anticipatory postural adjustments and in the execution of the first step. The basal ganglia circuitry may contribute to defining the optimal referent body configuration for a proper initiation of gait and possibly gait adaptation to the environment.}, language = {en} } @phdthesis{Brandt2020, author = {Brandt, Gregor A.}, title = {Gait Initiation in Parkinson's Disease: The Interplay of Dopamine and Postural Control}, doi = {10.25972/OPUS-21463}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214636}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Deterioration of gait and alterations of physiological gait initiation contribute significantly to the burden of disease in Parkinson's disease. This paper systematically investigates disease-specific alterations during the postural phases of gait initiation and demonstrates the influence of dopaminergic networks by assessing levodopa mediated improvements in motor performance and correlation of motor behavior with loss of striatal and cortical dopaminergic neurons. Particular attention is given to known confounders such as initial stance and anthropometrics.}, subject = {Parkinson-Krankheit}, language = {en} } @article{IsaiasDipaolaMichietal.2014, author = {Isaias, Ioannis Ugo and Dipaola, Mariangela and Michi, Marlies and Marzegan, Alberto and Volkmann, Jens and Rodocanachi Roidi, Mariana L. and Frigo, Carlo Albino and Cavallari, Paolo}, title = {Gait Initiation in Children with Rett Syndrome}, series = {PLoS ONE}, volume = {9}, journal = {PLoS ONE}, number = {4}, issn = {1932-6203}, doi = {10.1371/journal.pone.0092736}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119789}, pages = {e92736}, year = {2014}, abstract = {Rett syndrome is an X-linked neurodevelopmental condition mainly characterized by loss of spoken language and a regression of purposeful hand use, with the development of distinctive hand stereotypies, and gait abnormalities. Gait initiation is the transition from quiet stance to steady-state condition of walking. The associated motor program seems to be centrally mediated and includes preparatory adjustments prior to any apparent voluntary movement of the lower limbs. Anticipatory postural adjustments contribute to postural stability and to create the propulsive forces necessary to reach steady-state gait at a predefined velocity and may be indicative of the effectiveness of the feedforward control of gait. In this study, we examined anticipatory postural adjustments associated with gait initiation in eleven girls with Rett syndrome and ten healthy subjects. Muscle activity (tibialis anterior and soleus muscles), ground reaction forces and body kinematic were recorded. Children with Rett syndrome showed a distinctive impairment in temporal organization of all phases of the anticipatory postural adjustments. The lack of appropriate temporal scaling resulted in a diminished impulse to move forward, documented by an impairment in several parameters describing the efficiency of gait start: length and velocity of the first step, magnitude and orientation of centre of pressure-centre of mass vector at the instant of (swing-)toe off. These findings were related to an abnormal muscular activation pattern mainly characterized by a disruption of the synergistic activity of antagonistic pairs of postural muscles. This study showed that girls with Rett syndrome lack accurate tuning of feedforward control of gait.}, language = {en} } @article{PalmisanoBeccariaHaufeetal.2022, author = {Palmisano, Chiara and Beccaria, Laura and Haufe, Stefan and Volkmann, Jens and Pezzoli, Gianni and Isaias, Ioannis U.}, title = {Gait initiation impairment in patients with Parkinson's disease and freezing of gait}, series = {Bioengineering}, volume = {9}, journal = {Bioengineering}, number = {11}, issn = {2306-5354}, doi = {10.3390/bioengineering9110639}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297579}, year = {2022}, abstract = {Freezing of gait (FOG) is a sudden episodic inability to produce effective stepping despite the intention to walk. It typically occurs during gait initiation (GI) or modulation and may lead to falls. We studied the anticipatory postural adjustments (imbalance, unloading, and stepping phase) at GI in 23 patients with Parkinson's disease (PD) and FOG (PDF), 20 patients with PD and no previous history of FOG (PDNF), and 23 healthy controls (HCs). Patients performed the task when off dopaminergic medications. The center of pressure (CoP) displacement and velocity during imbalance showed significant impairment in both PDNF and PDF, more prominent in the latter patients. Several measurements were specifically impaired in PDF patients, especially the CoP displacement along the anteroposterior axis during unloading. The pattern of segmental center of mass (SCoM) movements did not show differences between groups. The standing postural profile preceding GI did not correlate with outcome measurements. We have shown impaired motor programming at GI in Parkinsonian patients. The more prominent deterioration of unloading in PDF patients might suggest impaired processing and integration of somatosensory information subserving GI. The unaltered temporal movement sequencing of SCoM might indicate some compensatory cerebellar mechanisms triggering time-locked models of body mechanics in PD.}, language = {en} } @article{HaufeIsaiasPellegrinietal.2023, author = {Haufe, Stefan and Isaias, Ioannis U. and Pellegrini, Franziska and Palmisano, Chiara}, title = {Gait event prediction using surface electromyography in parkinsonian patients}, series = {Bioengineering}, volume = {10}, journal = {Bioengineering}, number = {2}, issn = {2306-5354}, doi = {10.3390/bioengineering10020212}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304380}, year = {2023}, abstract = {Gait disturbances are common manifestations of Parkinson's disease (PD), with unmet therapeutic needs. Inertial measurement units (IMUs) are capable of monitoring gait, but they lack neurophysiological information that may be crucial for studying gait disturbances in these patients. Here, we present a machine learning approach to approximate IMU angular velocity profiles and subsequently gait events using electromyographic (EMG) channels during overground walking in patients with PD. We recorded six parkinsonian patients while they walked for at least three minutes. Patient-agnostic regression models were trained on temporally embedded EMG time series of different combinations of up to five leg muscles bilaterally (i.e., tibialis anterior, soleus, gastrocnemius medialis, gastrocnemius lateralis, and vastus lateralis). Gait events could be detected with high temporal precision (median displacement of <50 ms), low numbers of missed events (<2\%), and next to no false-positive event detections (<0.1\%). Swing and stance phases could thus be determined with high fidelity (median F1-score of ~0.9). Interestingly, the best performance was obtained using as few as two EMG probes placed on the left and right vastus lateralis. Our results demonstrate the practical utility of the proposed EMG-based system for gait event prediction, which allows the simultaneous acquisition of an electromyographic signal to be performed. This gait analysis approach has the potential to make additional measurement devices such as IMUs and force plates less essential, thereby reducing financial and preparation overheads and discomfort factors in gait studies.}, language = {en} } @phdthesis{Dang2011, author = {Dang, Su-Yin Judith}, title = {Funktionelle Bedeutung der Neuroplastizit{\"a}t bei Multipler Sklerose}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-73817}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2011}, abstract = {Die Multiple Sklerose ist eine chronische neurologische Erkrankung, welche in der industrialisierten Welt einen der h{\"a}ufigsten Gr{\"u}nde f{\"u}r eine bleibende Behinderung bei jungen Erwachsenen darstellt. Obwohl die ZNS-Sch{\"a}digung, charakterisiert durch Demyelinisierung und axonale Sch{\"a}digung im Rahmen entz{\"u}ndlicher Vorg{\"a}nge, durch verschiedene Reparaturmechanismen reduziert wird, akkumuliert die L{\"a}sionslast im zentralen Nervensystem mit der Zeit. T2-gewichtete MRT-Studien zeigen, dass die dargestellten Pathologien nur m{\"a}ßig mit den motorischen Defiziten korrelieren. Diese Diskrepanz wird unter anderem auf Vorg{\"a}nge der Neuroplastizit{\"a}t zur{\"u}ckgef{\"u}hrt, als deren Basismechanismen Langzeitpotenzierung (LTP) und -depression (LTD) gelten. In verschiedenen fMRT-Studien haben sich Hinweise ergeben, dass diese adaptiven Ver{\"a}nderungen zur Reorganisation kortikaler Repr{\"a}sentationmuster f{\"u}hren k{\"o}nnen, so dass bei MS-Patienten eine ausgedehntere Aktivierung ipsilateraler sensomotorischer Areale bei motorischen Aufgaben zu beobachten ist. Die transkranielle Magnetstimulation (TMS) bietet die M{\"o}glichkeit, mittels virtueller L{\"a}sionstechniken eine direkte Aussage {\"u}ber die kausale Beziehung zwischen Struktur und Funktion zu liefern. Die funktionelle Rolle ipsilateraler Motorareale wurde an 26 MS-Patienten, in Relation zu ihrer motorischen Beeintr{\"a}chtigung und ZNS-Sch{\"a}digung, und an nach Alter, Geschlecht und H{\"a}ndigkeit zugeordneten Kontrollprobanden, untersucht. Die motorische Leistungsf{\"a}higkeit wurde durch verschiedene Tests zur Handfunktion erhoben. Die ZNS-Sch{\"a}digung wurde mittels MR-Spektroskopie als NAA/Cr Quotient sowie durch die CML erhoben. Die Aufgabe zur einfachen Reaktionszeit (SRT) bestand aus einer isometrischen Abduktionsbewegung des rechten Daumens gegen einen Kraftaufnehmer auf ein akustisches Go-Signal. Mit TMS-Einzelreizen wurde mit Hilfe einer Neuronavigation eine reversible virtuelle L{\"a}sion {\"u}ber bestimmten Gehirnarealen, kontralateraler M1, ipsilateraler M1 und ipsilateraler PMd, erzeugt. Es wurde eine Kontrollstimulation {\"u}ber MO durchgef{\"u}hrt. Die TMS-Einzelreize wurden 100ms nach dem Go-Signal appliziert. Als SRT wurde der Zeitraum zwischen dem Go-Signal und EMG-Beginn im APB definiert. Die signifikanten SRT-Verl{\"a}ngerungen bei TMS {\"u}ber dem ipsilateralen M1 und dem ipsilateralen PMd zeigen, dass diese Regionen eine Rolle bei der motorischen Funktion bei MS spielen. Die fehlenden Korrelationen zwischen motorischen Funktionstest und NAA/Cr-Verh{\"a}ltnis sowie die inverse Korrelation zur kortikomuskul{\"a}ren Latenz sind durch strukturell von der krankheitsbedingten Pathologie betroffenen kompensierenden Gehirnregionen erkl{\"a}rbar. Bei dem Theta Burst Experiments (TBS) wurde ein virtueller L{\"a}sionseffekt durch eine repetitive TMS-Intervention {\"u}ber dem ipsilateralen M1 induziert. Die Ergebnisse zeigen {\"a}hnliche Ver{\"a}nderungen der Exzitabilit{\"a}t bei MS-Patienten und gesunden Kontrollprobanden, was schließen l{\"a}sst, dass die LTD bei mild bis moderat betroffenen MS-Patienten weitestgehend unbeeintr{\"a}chtigt ist. MS-Patienten zeigen im Vergleich zu den Kontrollen eine {\"a}hnliche Minderung der Verhaltensleistung, Trefferquote in ein Kraftfenster, der MS-Patienten im Kontrollvergleich. Die Ergebnisse zeigen, dass ipsilaterale motorische Areale in der Lage sind den prim{\"a}r motorischen Kortex soweit zu kompensieren, jedoch die F{\"a}higkeit zur Kompensation in fortgeschrittenen Krankheitsstadien eingeschr{\"a}nkt ist. Abschließend kann man zusammenfassen, dass die funktionelle Rekrutierung von ipsilateralen Motorarealen eine adaptive Antwort auf chronische Gehirnsch{\"a}digung bei MS-Patienten sein kann, allerdings mit Einschr{\"a}nkung der Kapazit{\"a}t in fortgeschrittenen Krankheitsstadien. Nachdem die synaptische Plastizit{\"a}t weitestgehend intakt scheint, sollte man besonders Mechanismen der sp{\"a}ten Phase der Plastizit{\"a}t f{\"o}rdern, welche auf eine langfristige kortikale Plastizit{\"a}t abzielen. Weitere Studien in diesem Forschungszweig k{\"o}nnten einen Beitrag zur Entwicklung therapeutischer Konzepte der Neurorehabilitation bei Multipler Sklerose leisten.}, subject = {Neuronale Plastizit{\"a}t}, language = {de} } @article{HaarmannNehenDeissetal.2015, author = {Haarmann, Axel and Nehen, Mathias and Deiß, Annika and Buttmann, Mathias}, title = {Fumaric acid esters do not reduce inflammatory NF-\(\kappa\)B/p65 nuclear translocation, ICAM-1 expression and T-cell adhesiveness of human brain microvascular endothelial cells}, series = {International Journal of Molecular Sciences}, volume = {16}, journal = {International Journal of Molecular Sciences}, doi = {10.3390/ijms160819086}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148295}, pages = {19086-19095}, year = {2015}, abstract = {Dimethyl fumarate (DMF) is approved for disease-modifying treatment of patients with relapsing-remitting multiple sclerosis. Animal experiments suggested that part of its therapeutic effect is due to a reduction of T-cell infiltration of the central nervous system (CNS) by uncertain mechanisms. Here we evaluated whether DMF and its primary metabolite monomethyl fumarate (MMF) modulate pro-inflammatory intracellular signaling and T-cell adhesiveness of nonimmortalized single donor human brain microvascular endothelial cells at low passages. Neither DMF nor MMF at concentrations of 10 or 50 \(\mu\)M blocked the IL-1\(\beta\)-induced nuclear translocation of NF-\(\kappa\)B/p65, whereas the higher concentration of DMF inhibited the nuclear entry of p65 in human umbilical vein endothelium cultured in parallel. DMF and MMF also did not alter the IL-1\(\beta\)-stimulated activation of p38 MAPK in brain endothelium. Furthermore, neither DMF nor MMF reduced the basal or IL-1\(\beta\)-inducible expression of ICAM-1. In accordance, both fumaric acid esters did not reduce the adhesion of activated Jurkat T cells to brain endothelium under basal or inflammatory conditions. Therefore, brain endothelial cells probably do not directly mediate a potential blocking effect of fumaric acid esters on the inflammatory infiltration of the CNS by T cells.}, language = {en} } @article{SchurigHaeuslerGrittneretal.2019, author = {Schurig, Johannes and Haeusler, Karl Georg and Grittner, Ulrike and Nolte, Christian H. and Fiebach, Jochen B. and Audebert, Heinrich J. and Endres, Matthias and Rocco, Andrea}, title = {Frequency of Hemorrhage on Follow Up Imaging in Stroke Patients Treated With rt-PA Depending on Clinical Course}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, doi = {10.3389/fneur.2019.00368}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234947}, year = {2019}, abstract = {Background: According to current guidelines, stroke patients treated with rt-PA should undergo brain imaging to exclude intracerebral bleeding 24 h after thrombolysis, before the start of medical secondary prevention. However, the usefulness of routine follow-up imaging with regard to changes in therapeutic management in patients without neurological deterioration is unclear. We hypothesized that follow up brain imaging solely to exclude bleeding in patients who clinically improved after rt-PA application may not be necessary. Methods: Retrospective single-center analysis including stroke patients treated with rt-PA. Records were reviewed for hemorrhagic transformation one day after systemic thrombolysis and brain imaging-based changes in therapeutic management. Twenty-four hour after thrombolysis patients were divided into four groups: (1) increased NIHSS score; (2) unchanged NIHSS score; (3) improved NIHSS score and; (4) NIHSS score = 0. Results: Out of 188 patients (mean age 73 years, 100 female) receiving rt-PA, 32 (17\%) had imaging-proven hemorrhagic transformation including 11 (6\%) patients with parenchymal hemorrhage. Patients in group (1, 2) more often had hypertension (p = 0.015) and more often had parenchymal hemorrhage (9 vs. 4\%; p < 0.206) compared to group (3, 4) and imaging-based changes in therapeutic management were more frequent (19\% vs. 6\%; p = 0.007). Patients of group (3, 4) had no changes in therapeutic management in 94\% of the cases. Patients in group (4) had no hemorrhagic transformation in routine follow-up brain imaging. Conclusions: Frequency of hemorrhagic transformation in Routine follow-up brain imaging and consecutive changes in therapeutic management were different depending on clinical course measured by NHISS score.}, language = {en} } @article{MeyerzuHoersteCordesMausbergetal.2014, author = {Meyer zu H{\"o}rste, Gerd and Cordes, Steffen and Mausberg, Anne K. and Zozulya, Alla L. and Wessig, Carsten and Sparwasser, Tim and Mathys, Christian and Wiendl, Heinz and Hartung, Hans-Peter and Kieseier, Bernd C.}, title = {FoxP3+Regulatory T Cells Determine Disease Severity in Rodent Models of Inflammatory Neuropathies}, series = {PLOS ONE}, volume = {9}, journal = {PLOS ONE}, number = {10}, doi = {10.1371/journal.pone.0108756}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115239}, pages = {e108756}, year = {2014}, abstract = {Inflammatory neuropathies represent disabling human autoimmune disorders with considerable disease variability. Animal models provide insights into defined aspects of their disease pathogenesis. Forkhead box P3 (FoxP3)+ regulatory T lymphocytes (Treg) are anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. Dysfunction or a reduced frequency of Tregs have been associated with different human autoimmune disorders. We here analyzed the functional relevance of Tregs in determining disease manifestation and severity in murine models of autoimmune neuropathies. We took advantage of the DEREG mouse system allowing depletion of Treg with high specificity as well as anti-CD25 directed antibodies to deplete Tregs in mice in actively induced experimental autoimmune neuritis (EAN). Furthermore antibody-depletion was performed in an adoptive transfer model of chronic neuritis. Early Treg depletion increased clinical EAN severity both in active and adoptive transfer chronic neuritis. This was accompanied by increased proliferation of myelin specific T cells and histological signs of peripheral nerve inflammation. Late stage Treg depletion after initial disease manifestation however did not exacerbate inflammatory neuropathy symptoms further. We conclude that Tregs determine disease severity in experimental autoimmune neuropathies during the initial priming phase, but have no major disease modifying function after disease manifestation. Potential future therapeutic approaches targeting Tregs should thus be performed early in inflammatory neuropathies.}, language = {en} } @article{SchuhmannBittnerMeuthetal.2015, author = {Schuhmann, Michael K. and Bittner, Stefan and Meuth, Sven G. and Kleinschnitz, Christoph and Fluri, Felix}, title = {Fingolimod (FTY720-P) does not stabilize the blood-brain barrier under inflammatory conditions in an in vitro model}, series = {International Journal of Molecular Sciences}, volume = {16}, journal = {International Journal of Molecular Sciences}, doi = {10.3390/ijms161226177}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145047}, pages = {29454-29466}, year = {2015}, abstract = {Breakdown of the blood-brain barrier (BBB) is an early hallmark of multiple sclerosis (MS), a progressive inflammatory disease of the central nervous system. Cell adhesion in the BBB is modulated by sphingosine-1-phosphate (S1P), a signaling protein, via S1P receptors (S1P\(_1\)). Fingolimod phosphate (FTY720-P) a functional S1P\(_1\) antagonist has been shown to improve the relapse rate in relapsing-remitting MS by preventing the egress of lymphocytes from lymph nodes. However, its role in modulating BBB permeabilityin particular, on the tight junction proteins occludin, claudin 5 and ZO-1has not been well elucidated to date. In the present study, FTY720-P did not change the transendothelial electrical resistance in a rat brain microvascular endothelial cell (RBMEC) culture exposed to inflammatory conditions and thus did not decrease endothelial barrier permeability. In contrast, occludin was reduced in RBMEC culture after adding FTY720-P. Additionally, FTY720-P did not alter the amount of endothelial matrix metalloproteinase (MMP)-9 and MMP-2 in RBMEC cultures. Taken together, our observations support the assumption that S1P\(_1\) plays a dual role in vascular permeability, depending on its ligand. Thus, S1P\(_1\) provides a mechanistic basis for FTY720-P-associated disruption of endothelial barrierssuch as the blood-retinal barrierwhich might result in macular edema.}, language = {en} } @article{CanesiGiordanoLazzarietal.2016, author = {Canesi, Margherita and Giordano, Rosaria and Lazzari, Lorenza and Isalberti, Maurizio and Isaias, Ioannis Ugo and Benti, Riccardo and Rampini, Paolo and Marotta, Giorgio and Colombo, Aurora and Cereda, Emanuele and Dipaola, Mariangela and Montemurro, Tiziana and Vigano, Mariele and Budelli, Silvia and Montelatici, Elisa and Lavazza, Cristiana and Cortelezzi, Agostino and Pezzoli, Gianni}, title = {Finding a new therapeutic approach for no-option Parkinsonisms: mesenchymal stromal cells for progressive supranuclear palsy}, series = {Journal of Translational Medicine}, volume = {14}, journal = {Journal of Translational Medicine}, number = {127}, doi = {10.1186/s12967-016-0880-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165725}, pages = {1-11}, year = {2016}, abstract = {Background: The trophic, anti-apoptotic and regenerative effects of bone marrow mesenchymal stromal cells (MSC) may reduce neuronal cell loss in neurodegenerative disorders. Methods: We used MSC as a novel candidate therapeutic tool in a pilot phase-I study for patients affected by progressive supranuclear palsy (PSP), a rare, severe and no-option form of Parkinsonism. Five patients received the cells by infusion into the cerebral arteries. Effects were assessed using the best available motor function rating scales (UPDRS, Hoehn and Yahr, PSP rating scale), as well as neuropsychological assessments, gait analysis and brain imaging before and after cell administration. Results: One year after cell infusion, all treated patients were alive, except one, who died 9 months after the infusion for reasons not related to cell administration or to disease progression (accidental fall). In all treated patients motor function rating scales remained stable for at least six-months during the one-year follow-up. Conclusions: We have demonstrated for the first time that MSC administration is feasible in subjects with PSP. In these patients, in whom deterioration of motor function is invariably rapid, we recorded clinical stabilization for at least 6 months. These encouraging results pave the way to the next randomized, placebo-controlled phase-II study that will definitively provide information on the efficacy of this innovative approach.}, language = {en} } @article{BinderLangePozzietal.2023, author = {Binder, Tobias and Lange, Florian and Pozzi, Nicol{\`o} and Musacchio, Thomas and Daniels, Christine and Odorfer, Thorsten and Fricke, Patrick and Matthies, Cordula and Volkmann, Jens and Capetian, Philipp}, title = {Feasibility of local field potential-guided programming for deep brain stimulation in Parkinson's disease: a comparison with clinical and neuro-imaging guided approaches in a randomized, controlled pilot trial}, series = {Brain Stimulation}, volume = {16}, journal = {Brain Stimulation}, number = {5}, doi = {10.1016/j.brs.2023.08.017}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350280}, pages = {1243-1251}, year = {2023}, abstract = {Highlights • Beta-Guided programming is an innovative approach that may streamline the programming process for PD patients with STN DBS. • While preliminary findings from our study suggest that Beta Titration may potentially mitigate STN overstimulation and enhance symptom control, • Our results demonstrate that beta-guided programming significantly reduces programming time, suggesting it could be efficiently integrated into routine clinical practice using a commercially available patient programmer. Background Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced Parkinson's disease (PD). Clinical outcomes after DBS can be limited by poor programming, which remains a clinically driven, lengthy and iterative process. Electrophysiological recordings in PD patients undergoing STN-DBS have shown an association between STN spectral power in the beta frequency band (beta power) and the severity of clinical symptoms. New commercially-available DBS devices now enable the recording of STN beta oscillations in chronically-implanted PD patients, thereby allowing investigation into the use of beta power as a biomarker for DBS programming. Objective To determine the potential advantages of beta-guided DBS programming over clinically and image-guided programming in terms of clinical efficacy and programming time. Methods We conducted a randomized, blinded, three-arm, crossover clinical trial in eight Parkinson's patients with STN-DBS who were evaluated three months after DBS surgery. We compared clinical efficacy and time required for each DBS programming paradigm, as well as DBS parameters and total energy delivered between the three strategies (beta-, clinically- and image-guided). Results All three programming methods showed similar clinical efficacy, but the time needed for programming was significantly shorter for beta- and image-guided programming compared to clinically-guided programming (p < 0.001). Conclusion Beta-guided programming may be a useful and more efficient approach to DBS programming in Parkinson's patients with STN-DBS. It takes significantly less time to program than traditional clinically-based programming, while providing similar symptom control. In addition, it is readily available within the clinical DBS programmer, making it a valuable tool for improving current clinical practice.}, language = {en} } @article{KraftFleischerWiedmannetal.2017, author = {Kraft, Peter and Fleischer, Anna and Wiedmann, Silke and R{\"u}cker, Viktoria and Mackenrodt, Daniel and Morbach, Caroline and Malzahn, Uwe and Kleinschnitz, Christoph and St{\"o}rk, Stefan and Heuschmann, Peter U.}, title = {Feasibility and diagnostic accuracy of point-of-care handheld echocardiography in acute ischemic stroke patients - a pilot study}, series = {BMC Neurology}, volume = {17}, journal = {BMC Neurology}, number = {159}, doi = {10.1186/s12883-017-0937-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158081}, year = {2017}, abstract = {Background: Standard echocardiography (SE) is an essential part of the routine diagnostic work-up after ischemic stroke (IS) and also serves for research purposes. However, access to SE is often limited. We aimed to assess feasibility and accuracy of point-of-care (POC) echocardiography in a stroke unit (SU) setting. Methods: IS patients were recruited on the SU of the University Hospital W{\"u}rzburg, Germany. Two SU team members were trained in POC echocardiography for a three-month period to assess a set of predefined cardiac parameters including left ventricular ejection fraction (LVEF). Diagnostic agreement was assessed by comparing POC with SE executed by an expert sonographer, and intraclass correlation coefficient (ICC) or kappa (κ) with 95\% confidence intervals (95\% CI) were calculated. Results: In the 78 patients receiving both POC and SE agreement for cardiac parameters was good, with ICC varying from 0.82 (95\% CI 0.71-0.89) to 0.93 (95\% CI 0.87-0.96), and κ from 0.39 (-95\% CI 0.14-0.92) to 0.79 (95\% CI 0.67-0.91). Detection of systolic dysfunction with POC echocardiography compared to SE was very good, with an area under the curve of 0.99 (0.96-1.00). Interrater agreement for LVEF measured by POC echocardiography was good with κ 0.63 (95\% CI 0.40-0.85). Conclusions: POC echocardiography in a SU setting is feasible enabling reliable quantification of LVEF and preliminary assessment of selected cardiac parameters that might be used for research purposes. Its potential clinical utility in triaging stroke patients who should undergo or do not necessarily require SE needs to be investigated in larger prospective diagnostic studies.}, language = {en} } @article{GolombeckWessigMonoranuetal.2013, author = {Golombeck, Stefanie Kristin and Wessig, Carsten and Monoranu, Camelia-Maria and Sch{\"u}tz, Ansgar and Solymosi, Laszlo and Melzer, Nico and Kleinschnitz, Christoph}, title = {Fatal atypical reversible posterior leukoencephalopathy syndrome: a case report}, series = {Journal of Medical Case Reports}, volume = {7}, journal = {Journal of Medical Case Reports}, number = {14}, doi = {10.1186/1752-1947-7-14}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135517}, year = {2013}, abstract = {Introduction: Reversible posterior leukoencephalopathy syndrome - a reversible subacute global encephalopathy clinically presenting with headache, altered mental status, visual symptoms such as hemianopsia or cortical blindness, motor symptoms, and focal or generalized seizures - is characterized by a subcortical vasogenic edema symmetrically affecting posterior brain regions. Complete reversibility of both clinical signs and magnetic resonance imaging lesions is regarded as a defining feature of reversible posterior leukoencephalopathy syndrome. Reversible posterior leukoencephalopathy syndrome is almost exclusively seen in the setting of a predisposing clinical condition, such as pre-eclampsia, systemic infections, sepsis and shock, certain autoimmune diseases, various malignancies and cytotoxic chemotherapy, transplantation and concomitant immunosuppression (especially with calcineurin inhibitors) as well as episodes of abrupt hypertension. We describe for the first time clinical, radiological and histological findings in a case of reversible posterior leukoencephalopathy syndrome with an irreversible and fatal outcome occurring in the absence of any of the known predisposing clinical conditions except for a hypertensive episode. Case presentation: A 58-year-old Caucasian woman presented with a two-week history of subacute and progressive occipital headache, blurred vision and imbalance of gait and with no evidence for raised arterial blood pressure during the two weeks previous to admission. Her past medical history was unremarkable except for controlled arterial hypertension. Cerebral magnetic resonance imaging demonstrated cortical and subcortical lesions with combined vasogenic and cytotoxic edema atypical for both venous congestion and arterial infarction. Routine laboratory and cerebrospinal fluid parameters were normal. The diagnosis of reversible posterior leukoencephalopathy syndrome was established. Within hours after admission the patient showed a rapidly decreasing level of consciousness, extension and flexion synergisms, bilaterally extensor plantar responses and rapid cardiopulmonary decompensation requiring ventilatory and cardiocirculatory support. Follow-up cerebral imaging demonstrated widespread and confluent cytotoxic edematous lesions in different arterial territories, global cerebral swelling, and subsequent upper and lower brainstem herniation. Four days after admission, the patient was declared dead because of brain death. Conclusion: This case demonstrates that fulminant and fatal reversible posterior leukoencephalopathy syndrome may occur spontaneously, that is, in the absence of any of the known predisposing systemic conditions.}, language = {en} } @article{GolombeckWessigMonoranuetal.2013, author = {Golombeck, Stefanie Kristin and Wessig, Carsten and Monoranu, Camelia-Maria and Sch{\"u}tz, Ansgar and Solymosi, Laszlo and Melzer, Niko and Kleinschnitz, Christoph}, title = {Fatal atypical reversible posterior leukoencephalopathy syndrome: a case report}, series = {Journal of Medical Case Reports}, volume = {7}, journal = {Journal of Medical Case Reports}, number = {14}, doi = {10.1186/1752-1947-7-14}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129456}, year = {2013}, abstract = {Introduction: Reversible posterior leukoencephalopathy syndrome - a reversible subacute global encephalopathy clinically presenting with headache, altered mental status, visual symptoms such as hemianopsia or cortical blindness, motor symptoms, and focal or generalized seizures - is characterized by a subcortical vasogenic edema symmetrically affecting posterior brain regions. Complete reversibility of both clinical signs and magnetic resonance imaging lesions is regarded as a defining feature of reversible posterior leukoencephalopathy syndrome. Reversible posterior leukoencephalopathy syndrome is almost exclusively seen in the setting of a predisposing clinical condition, such as pre-eclampsia, systemic infections, sepsis and shock, certain autoimmune diseases, various malignancies and cytotoxic chemotherapy, transplantation and concomitant immunosuppression (especially with calcineurin inhibitors) as well as episodes of abrupt hypertension. We describe for the first time clinical, radiological and histological findings in a case of reversible posterior leukoencephalopathy syndrome with an irreversible and fatal outcome occurring in the absence of any of the known predisposing clinical conditions except for a hypertensive episode. Case presentation: A 58-year-old Caucasian woman presented with a two-week history of subacute and progressive occipital headache, blurred vision and imbalance of gait and with no evidence for raised arterial blood pressure during the two weeks previous to admission. Her past medical history was unremarkable except for controlled arterial hypertension. Cerebral magnetic resonance imaging demonstrated cortical and subcortical lesions with combined vasogenic and cytotoxic edema atypical for both venous congestion and arterial infarction. Routine laboratory and cerebrospinal fluid parameters were normal. The diagnosis of reversible posterior leukoencephalopathy syndrome was established. Within hours after admission the patient showed a rapidly decreasing level of consciousness, extension and flexion synergisms, bilaterally extensor plantar responses and rapid cardiopulmonary decompensation requiring ventilatory and cardiocirculatory support. Follow-up cerebral imaging demonstrated widespread and confluent cytotoxic edematous lesions in different arterial territories, global cerebral swelling, and subsequent upper and lower brainstem herniation. Four days after admission, the patient was declared dead because of brain death. Conclusion: This case demonstrates that fulminant and fatal reversible posterior leukoencephalopathy syndrome may occur spontaneously, that is, in the absence of any of the known predisposing systemic conditions.}, language = {en} } @phdthesis{Nowak2013, author = {Nowak, Eva}, title = {Expression und Funktion von Integrin α-4 in humanen zerebralen Endothelzellen - Analysen unter Zuhilfenahme des therapeutisch eingesetzten Antik{\"o}rpers Natalizumab}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-99300}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Natalizumab ist ein humanisierter monoklonaler Antik{\"o}rper gegen das Oberfl{\"a}chenadh{\"a}sionsmolek{\"u}l Integrin α-4, der zur Therapie von schweren Verlaufsformen der Multiplen Sklerose (MS) zugelassen ist. Integrin α-4/β-1 wird durch Leukozyten exprimiert und steuert deren Extravasation {\"u}ber die Bindung an VCAM-1 (vascular cell adhesion molecule-1) auf Endothelzellen. Natalizumab wirkt {\"u}ber eine Blockade der Leukozytenadh{\"a}sion. In einigen Publikationen konnte dar{\"u}ber hinaus gezeigt werden, dass Integrin α-4 auch auf zerebralen Endothelzellen von M{\"a}usen und Ratten exprimiert wird. In der vorliegenden Arbeit wurde die Expression und Funktion von Integrin α-4 in kultivierten prim{\"a}ren humanen zerebralen Endothelzellen untersucht. Die im Rahmen dieser Arbeit an verschiedenen Einzelspenderpr{\"a}parationen durchgef{\"u}hrten FACS-Analysen zeigten, dass Integrin α-4 in unterschiedlicher Auspr{\"a}gung auf prim{\"a}ren zerebralen Endothelzellisolationen nachzuweisen war. Mit Hilfe immunzytochemischer F{\"a}rbungen konnte ein spezifisches Verteilungsmuster des Integrin α-4 in Form eines feinen, granul{\"a}ren Musters im Bereich des Zellleibes dokumentiert werden. In Adh{\"a}sionsversuchen zeigten Integrin α-4-exprimierende Endothelzellen nach Zugabe von Natalizumab in niedriger Konzentration eine verminderte F{\"a}higkeit zur Haftung an Fibronectin, einem Bindungspartner in der extrazellul{\"a}ren Matrix. In hohen Konzentrationen dominierte im eingesetzten experimentellen System ein unspezifischer Blockadeeffekt, der auch mit Kontrollantik{\"o}rpern zu beobachten war. In MS-L{\"a}sionen findet sich auch die l{\"o}sliche Form des VCAM-1 (sVCAM-1), die m{\"o}glicherweise mit endothelialem Integrin α-4 interagiert. Daher wurde mit Hilfe von Western-Blot-Untersuchungen die intrazellul{\"a}re Signaltransduktion unter Stimulation mit sVCAM-1 untersucht. Es zeigte sich wie in anderen Endothelarten vorbeschrieben eine Aktivierung des p38-MAP-Kinase-Signalweges. Zusammenfassend wurde demonstriert, dass prim{\"a}re humane zerebrale Endothelzellen Integrin α-4 exprimieren und dass dieses wahrscheinlich nicht nur f{\"u}r die mechanische Verankerung in der Extrazellul{\"a}rmatrix eine Bedeutung besitzt, sondern auch als Induktor intrazellul{\"a}rer Signaltransduktion fungiert, welche die Schrankeneigenschaften zerebraler Endothelzellen beeinflussen k{\"o}nnte.}, subject = {Integrin}, language = {de} } @article{BittnerBobakFeuchtenbergeretal.2011, author = {Bittner, Stefan and Bobak, Nicole and Feuchtenberger, Martin and Herrmann, Alexander M and G{\"o}bel, Kerstin and Kinne, Raimund W and Hansen, Anker J and Budde, Thomas and Kleinschnitz, Christoph and Frey, Oliver and Tony, Hans-Peter and Wiendl, Heinz and Meuth, Sven G}, title = {Expression of K\(_2\)\(_P\)5.1 potassium channels on CD4\(^+\)T lymphocytes correlates with disease activity in rheumatoid arthritis patients}, series = {Arthritis Research \& Therapy}, volume = {13}, journal = {Arthritis Research \& Therapy}, number = {R21}, doi = {10.1186/ar3245}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-139334}, year = {2011}, abstract = {Introduction CD4+ T cells express K2P5.1 (TWIK-related acid-sensitive potassium channel 2 (TASK2); KCNK5), a member of the two-pore domain potassium channel family, which has been shown to influence T cell effector functions. Recently, it was shown that K2P5.1 is upregulated upon (autoimmune) T cell stimulation. The aim of this study was to correlate expression levels of K2P5.1 on T cells from patients with rheumatoid arthritis (RA) to disease activity in these patients. Methods Expression levels of K2P5.1 were measured by RT-PCR in the peripheral blood of 58 patients with RA and correlated with disease activity parameters (C-reactive protein levels, erythrocyte sedimentation rates, disease activity score (DAS28) scores). Twenty patients undergoing therapy change were followed-up for six months. Additionally, synovial fluid and synovial biopsies were investigated for T lymphocytes expressing K2P5.1. Results K2P5.1 expression levels in CD4+ T cells show a strong correlation to DAS28 scores in RA patients. Similar correlations were found for serological inflammatory parameters (erythrocyte sedimentation rate, C-reactive protein). In addition, K2P5.1 expression levels of synovial fluid-derived T cells are higher compared to peripheral blood T cells. Prospective data in individual patients show a parallel behaviour of K2P5.1 expression to disease activity parameters during a longitudinal follow-up for six months. Conclusions Disease activity in RA patients correlates strongly with K2P5.1 expression levels in CD4+ T lymphocytes in the peripheral blood in cross-sectional as well as in longitudinal observations. Further studies are needed to investigate the exact pathophysiological mechanisms and to evaluate the possible use of K2P5.1 as a potential biomarker for disease activity and differential diagnosis.}, language = {en} } @article{FeldheimKesslerSchmittetal.2018, author = {Feldheim, Jonas and Kessler, Almuth F and Schmitt, Dominik and Wilczek, Lara and Linsenmann, Thomas and Dahlmann, Mathias and Monoranu, Camelia M and Ernestus, Ralf-Ingo and Hagemann, Carsten and L{\"o}hr, Mario}, title = {Expression of activating transcription factor 5 (ATF5) is increased in astrocytomas of different WHO grades and correlates with survival of glioblastoma patients}, series = {OncoTargets and Therapy}, volume = {11}, journal = {OncoTargets and Therapy}, doi = {10.2147/OTT.S176549}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177541}, pages = {8673-8684}, year = {2018}, abstract = {Background: ATF5 suppresses differentiation of neuroprogenitor cells and is overexpressed in glioblastoma (GBM). A reduction of its expression leads to apoptotic GBM cell death. Data on ATF5 expression in astrocytoma WHO grade II (low-grade astrocytoma [LGA]) are scarce and lacking on recurrent GBM. Patients and methods: ATF5 mRNA was extracted from frozen samples of patients' GBM (n=79), LGA (n=40), and normal brain (NB, n=10), quantified by duplex qPCR and correlated with retrospectively collected clinical data. ATF5 protein expression was evaluated by measuring staining intensity on immunohistochemistry. Results: ATF5 mRNA was overexpressed in LGA (sevenfold, P<0.001) and GBM (tenfold, P<0.001) compared to NB, which was confirmed on protein level. Although ATF5 mRNA expression in GBM showed a considerable fluctuation range, groups of varying biological behavior, that is, local/multifocal growth or primary tumor/relapse and the tumor localization at diagnosis, were not significantly different. ATF5 mRNA correlated with the patients' age (r=0.339, P=0.028) and inversely with Ki67-staining (r=-0.421, P=0.007). GBM patients were allocated to a low and a high ATF5 expression group by the median ATF5 overexpression compared to NB. Kaplan-Meier analysis and Cox regression indicated that ATF5 mRNA expression significantly correlated with short-term survival (t<12 months, median survival 18 vs 13 months, P=0.022, HR 2.827) and progression-free survival (PFS) (12 vs 6 months, P=0.024). This advantage vanished after 24 months (P=0.084). Conclusion: ATF5 mRNA expression could be identified as an additional, though not independent factor correlating with overall survival and PFS. Since its inhibition might lead to the selective death of glioma cells, it might serve as a potential ubiquitous therapeutic target in astrocytic tumors.}, language = {en} } @phdthesis{Fischer2009, author = {Fischer, Cindy Erika Elisabeth}, title = {Expression des fetalen Acetylcholinrezeptors im Muskel bei experimenteller Nervenl{\"a}sion der Ratte und bei Neuropathien des Menschen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-36619}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2009}, abstract = {No abstract available}, subject = {Acetylcholinrezeptor}, language = {de} } @article{SchnabelCamenKnebeletal.2021, author = {Schnabel, Renate B. and Camen, Stephan and Knebel, Fabian and Hagendorff, Andreas and Bavendiek, Udo and B{\"o}hm, Michael and Doehner, Wolfram and Endres, Matthias and Gr{\"o}schel, Klaus and Goette, Andreas and Huttner, Hagen B. and Jensen, Christoph and Kirchhof, Paulus and Korosoglou, Grigorius and Laufs, Ulrich and Liman, Jan and Morbach, Caroline and Navabi, Darius G{\"u}nther and Neumann-Haefelin, Tobias and Pfeilschifter, Waltraut and Poli, Sven and Rizos, Timolaos and Rolf, Andreas and R{\"o}ther, Joachim and Sch{\"a}bitz, Wolf R{\"u}diger and Steiner, Thorsten and Thomalla, G{\"o}tz and Wachter, Rolf and Haeusler, Karl Georg}, title = {Expert opinion paper on cardiac imaging after ischemic stroke}, series = {Clinical Research in Cardiology}, volume = {110}, journal = {Clinical Research in Cardiology}, number = {7}, issn = {1861-0692}, doi = {10.1007/s00392-021-01834-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266662}, pages = {938-958}, year = {2021}, abstract = {This expert opinion paper on cardiac imaging after acute ischemic stroke or transient ischemic attack (TIA) includes a statement of the "Heart and Brain" consortium of the German Cardiac Society and the German Stroke Society. The Stroke Unit-Commission of the German Stroke Society and the German Atrial Fibrillation NETwork (AFNET) endorsed this paper. Cardiac imaging is a key component of etiological work-up after stroke. Enhanced echocardiographic tools, constantly improving cardiac computer tomography (CT) as well as cardiac magnetic resonance imaging (MRI) offer comprehensive non- or less-invasive cardiac evaluation at the expense of increased costs and/or radiation exposure. Certain imaging findings usually lead to a change in medical secondary stroke prevention or may influence medical treatment. However, there is no proof from a randomized controlled trial (RCT) that the choice of the imaging method influences the prognosis of stroke patients. Summarizing present knowledge, the German Heart and Brain consortium proposes an interdisciplinary, staged standard diagnostic scheme for the detection of risk factors of cardio-embolic stroke. This expert opinion paper aims to give practical advice to physicians who are involved in stroke care. In line with the nature of an expert opinion paper, labeling of classes of recommendations is not provided, since many statements are based on expert opinion, reported case series, and clinical experience.}, language = {en} } @phdthesis{Rott2005, author = {Rott, Evelyn}, title = {Experimentelle autoimmune Enzephalomyelitis in beta2 Mikroglobulin knock-out M{\"a}usen : axonaler Schaden entsteht unabh{\"a}ngig von MHC-I Expression}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-19500}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2005}, abstract = {CD4 T-Zellen wurden lange als die vor allem pathogen wirkenden Immunzellen bei chronisch entz{\"u}ndlichen ZNS-Erkrankungen angesehen. Wir untersuchten die Wirkung von CD8 T-Zellen in der EAE (exp. autoimmunen Enzephalomyelitis = Tiermodell der Multiplen Sklerose) anhand von beta2-Mikroglobulin knock-out M{\"a}usen (fehlende CD8 T-Zellen). Ergebnis: im Vergleich zu den Wildtyptieren zeigten die Knock-outs eine signifikant st{\"a}rker ausgepr{\"a}gte Erkrankung bei der mit verschiedenen Antigenen (MOG, MBP) induzierten EAE mit erh{\"o}hter Mortalit{\"a}t. Histologisch fnad sich eine vermehrte Infiltration von Makrophagen und Mikroglia. Die Demyelinisierung war bei den Knock-outs st{\"a}rker ausgepr{\"a}gt, ebenso auch der axonale Schaden. Das Fehlen von funktionellen CD8 T-Zellen f{\"u}hrte demnach zu einer Verst{\"a}rkung der autoimmunen Gewebssch{\"a}digung im ZNS.}, language = {de} } @article{JirůHillmannGabrielSchuleretal.2022, author = {J{\´i}rů-Hillmann, Steffi and Gabriel, Katharina M. A. and Schuler, Michael and Wiedmann, Silke and M{\"u}hler, Johannes and D{\"o}tter, Klaus and Soda, Hassan and Rascher, Alexandra and Benesch, Sonka and Kraft, Peter and Pfau, Mathias and Stenzel, Joachim and von Nippold, Karin and Benghebrid, Mohamed and Schulte, Kerstin and Meinck, Ralf and Volkmann, Jens and Haeusler, Karl Georg and Heuschmann, Peter U.}, title = {Experiences of family caregivers 3-months after stroke: results of the prospective trans-regional network for stroke intervention with telemedicine registry (TRANSIT-Stroke)}, series = {BMC Geriatrics}, volume = {22}, journal = {BMC Geriatrics}, doi = {10.1186/s12877-022-02919-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313330}, year = {2022}, abstract = {Background Long-term support of stroke patients living at home is often delivered by family caregivers (FC). We identified characteristics of stroke patients being associated with receiving care by a FC 3-months (3 M) after stroke, assessed positive and negative experiences and individual burden of FC caring for stroke patients and determined factors associated with caregiving experiences and burden of FC 3 M after stroke. Methods Data were collected within TRANSIT-Stroke, a regional telemedical stroke-network comprising 12 hospitals in Germany. Patients with stroke/TIA providing informed consent were followed up 3 M after the index event. The postal patient-questionnaire was accompanied by an anonymous questionnaire for FC comprising information on positive and negative experiences of FC as well as on burden of caregiving operationalized by the Caregiver Reaction Assessment and a self-rated burden-scale, respectively. Multivariable logistic and linear regression analyses were performed. Results Between 01/2016 and 06/2019, 3532 patients provided baseline and 3 M-follow-up- data and 1044 FC responded to questionnaires regarding positive and negative caregiving experiences and caregiving burden. 74.4\% of FC were older than 55 years, 70.1\% were women and 67.5\% were spouses. Older age, diabetes and lower Barthel-Index in patients were significantly associated with a higher probability of receiving care by a FC at 3 M. Positive experiences of FC comprised the importance (81.5\%) and the privilege (70.0\%) of caring for their relative; negative experiences of FC included financial difficulties associated with caregiving (20.4\%). Median overall self-rated burden was 30 (IQR: 0-50; range 0-100). Older age of stroke patients was associated with a lower caregiver burden, whereas younger age of FC led to higher burden. More than half of the stroke patients in whom a FC questionnaire was completed did self-report that they are not being cared by a FC. This stroke patient group tended to be younger, more often male with less severe stroke and less comorbidities who lived more often with a partner. Conclusions The majority of caregivers wanted to care for their relatives but experienced burden at the same time. Elderly patients, patients with a lower Barthel Index at discharge and diabetes are at higher risk of needing care by a family caregiver. Trial registration The study was registered at "German Clinical Trial Register": DRKS00011696. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML\&TRIAL_ID=DRKS00011696}, language = {en} } @article{BadrMcFlederWuetal.2022, author = {Badr, Mohammad and McFleder, Rhonda L. and Wu, Jingjing and Knorr, Susanne and Koprich, James B. and H{\"u}nig, Thomas and Brotchie, Jonathan M. and Volkmann, Jens and Lutz, Manfred B. and Ip, Chi Wang}, title = {Expansion of regulatory T cells by CD28 superagonistic antibodies attenuates neurodegeneration in A53T-α-synuclein Parkinson's disease mice}, series = {Journal of Neuroinflammation}, volume = {19}, journal = {Journal of Neuroinflammation}, doi = {10.1186/s12974-022-02685-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300580}, year = {2022}, abstract = {Background Regulatory CD4\(^+\)CD25\(^+\)FoxP3\(^+\) T cells (Treg) are a subgroup of T lymphocytes involved in maintaining immune balance. Disturbance of Treg number and impaired suppressive function of Treg correlate with Parkinson's disease severity. Superagonistic anti-CD28 monoclonal antibodies (CD28SA) activate Treg and cause their expansion to create an anti-inflammatory environment. Methods Using the AAV1/2-A53T-α-synuclein Parkinson's disease mouse model that overexpresses the pathogenic human A53T-α-synuclein (hαSyn) variant in dopaminergic neurons of the substantia nigra, we assessed the neuroprotective and disease-modifying efficacy of a single intraperitoneal dose of CD28SA given at an early disease stage. Results CD28SA led to Treg expansion 3 days after delivery in hαSyn Parkinson's disease mice. At this timepoint, an early pro-inflammation was observed in vehicle-treated hαSyn Parkinson's disease mice with elevated percentages of CD8\(^+\)CD69\(^+\) T cells in brain and increased levels of interleukin-2 (IL-2) in the cervical lymph nodes and spleen. These immune responses were suppressed in CD28SA-treated hαSyn Parkinson's disease mice. Early treatment with CD28SA attenuated dopaminergic neurodegeneration in the SN of hαSyn Parkinson's disease mice accompanied with reduced brain numbers of activated CD4\(^+\), CD8\(^+\) T cells and CD11b\(^+\) microglia observed at the late disease-stage 10 weeks after AAV injection. In contrast, a later treatment 4 weeks after AAV delivery failed to reduce dopaminergic neurodegeneration. Conclusions Our data indicate that immune modulation by Treg expansion at a timepoint of overt inflammation is effective for treatment of hαSyn Parkinson's disease mice and suggest that the concept of early immune therapy could pose a disease-modifying option for Parkinson's disease patients.}, language = {en} } @article{ZellerDangWeiseetal.2012, author = {Zeller, Daniel and Dang, Su-Yin and Weise, David and Rieckmann, Peter and Toyka, Klaus V. and Classen, Joseph}, title = {Excitability decreasing central motor plasticity is retained in multiple sclerosis patients}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76333}, year = {2012}, abstract = {Background: Compensation of brain injury in multiple sclerosis (MS) may in part work through mechanisms involving neuronal plasticity on local and interregional scales. Mechanisms limiting excessive neuronal activity may have special significance for retention and (re-)acquisition of lost motor skills in brain injury. However, previous neurophysiological studies of plasticity in MS have investigated only excitability enhancing plasticity and results from neuroimaging are ambiguous. Thus, the aim of this study was to probe long-term depression-like central motor plasticity utilizing continuous theta-burst stimulation (cTBS), a non-invasive brain stimulation protocol. Because cTBS also may trigger behavioral effects through local interference with neuronal circuits, this approach also permitted investigating the functional role of the primary motor cortex (M1) in force control in patients with MS. Methods: We used cTBS and force recordings to examine long-term depression-like central motor plasticity and behavioral consequences of a M1 lesion in 14 patients with stable mild-to-moderate MS (median EDSS 1.5, range 0 to 3.5) and 14 age-matched healthy controls. cTBS consisted of bursts (50 Hz) of three subthreshold biphasic magnetic stimuli repeated at 5 Hz for 40 s over the hand area of the left M1. Corticospinal excitability was probed via motor-evoked potentials (MEP) in the abductor pollicis brevis muscle over M1 before and after cTBS. Force production performance was assessed in an isometric right thumb abduction task by recording the number of hits into a predefined force window. Results: cTBS reduced MEP amplitudes in the contralateral abductor pollicis brevis muscle to a comparable extent in control subjects (69 ± 22\% of baseline amplitude, p < 0.001) and in MS patients (69 ± 18\%, p < 0.001). In contrast, postcTBS force production performance was only impaired in controls (2.2 ± 2.8, p = 0.011), but not in MS patients (2.0 ± 4.4, p = 0.108). The decline in force production performance following cTBS correlated with corticomuscular latencies (CML) in MS patients, but did not correlate with MEP amplitude reduction in patients or controls. Conclusions: Long-term depression-like plasticity remains largely intact in mild-to-moderate MS. Increasing brain injury may render the neuronal networks less responsive toward lesion-induction by cTBS.}, subject = {Medizin}, language = {en} } @phdthesis{Haehnel2022, author = {H{\"a}hnel, Luzia Maria}, title = {Evaluation von Beta-2-Mikroglobulin, Laktat und Angiotensin-Converting Enzyme im Liquor als Biomarker der Multiplen Sklerose}, doi = {10.25972/OPUS-25850}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258503}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {This study investigates the suitability of beta-2-microglobulin (β2-microglobulin), lactate and angiotensin-converting enzyme (ACE) as biomarkers, given the good availability of these parameters in routine diagnostics but lack of data in this regard. For this purpose, 6,310 CSF samples obtained at the Neurological Clinic of the University Hospital of W{\"u}rzburg were analyzed. Closer analysis was carried out of 276 cases with non-inflammatory neurological diseases (NIND; control group) and 438 MS cases not taking an immunotherapy treatment (study group). In the MS cases, the form of progression of the disease and the disease activity (clinical relapses, progression index) were recorded. A clear correlation could be seen between age and CSF levels of β2-microglobulin, lactate and ACE in both the MS and control groups, whereby a correction was required for the subsequent comparison studies; this could also at least partly explain the contradictory data obtained in other studies to date. The MS cases showed elevated β2-microglobulin and lactate levels and decreased ACE levels in CSF compared to the controls. In both groups, there was a positive correlation between β2-microglobulin and ACE levels. In the separate analysis of the forms of progression of MS, cases with clinically-isolated syndrome (CIS) and relapsing-remitting MS (RRMS) revealed elevated β2-microglobulin levels, whilst cases with secondary-progressive or primary-progressive MS (SPMS or PPMS) did not. Lactate levels were only increased in cases of CIS. Cases with a relapsing course showed reduced ACE levels. The disease activity could not reliably be mapped by the parameters. Lactate levels tended to be elevated during a relapse, but this result was no longer significant after correction. Lactate levels also showed a positive correlation with the progression index. Our findings in this study provide evidence that the examined analysis parameters cannot be used in isolation to assess progression, disease activity and duration of disease. However, the significant differences between relapsing and chronic-progressive courses support the hypothesis of different underlying mechanisms of pathogenesis, and could serve as a starting basis for further studies.}, subject = {Multiple Sklerose}, language = {de} } @article{HaarmannDeissProchaskaetal.2010, author = {Haarmann, Axel and Deiss, Annika and Prochaska, Juergen and Foerch, Christian and Weksler, Babette and Romero, Ignacio and Couraud, Pierre-Olivier and Stoll, Guido and Rieckmann, Peter and Buttmann, Mathias}, title = {Evaluation of Soluble Junctional Adhesion Molecule-A as a Biomarker of Human Brain Endothelial Barrier Breakdown}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68468}, year = {2010}, abstract = {Background: An inducible release of soluble junctional adhesion molecule-A (sJAM-A) under pro-inflammatory conditions was described in cultured non-CNS endothelial cells (EC) and increased sJAM-A serum levels were found to indicate inflammation in non-CNS vascular beds. Here we studied the regulation of JAM-A expression in cultured brain EC and evaluated sJAM-A as a serum biomarker of blood-brain barrier (BBB) function. Methodology/Principal Findings: As previously reported in non-CNS EC types, pro-inflammatory stimulation of primary or immortalized (hCMEC/D3) human brain microvascular EC (HBMEC) induced a redistribution of cell-bound JAM-A on the cell surface away from tight junctions, along with a dissociation from the cytoskeleton. This was paralleled by reduced immunocytochemical staining of occludin and zonula occludens-1 as well as by increased paracellular permeability for dextran 3000. Both a self-developed ELISA test and Western blot analysis detected a constitutive sJAM-A release by HBMEC into culture supernatants, which importantly was unaffected by pro-inflammatory or hypoxia/reoxygenation challenge. Accordingly, serum levels of sJAM-A were unaltered in 14 patients with clinically active multiple sclerosis compared to 45 stable patients and remained unchanged in 13 patients with acute ischemic non-small vessel stroke over time. Conclusion: Soluble JAM-A was not suited as a biomarker of BBB breakdown in our hands. The unexpected non-inducibility of sJAM-A release at the human BBB might contribute to a particular resistance of brain EC to inflammatory stimuli, protecting the CNS compartment.}, subject = {Biomarker}, language = {en} } @phdthesis{Bischofs2005, author = {Bischofs, Stefan}, title = {Evaluation der antihyperalgetischen und neuroregenerativen Wirkung von Topiramat nach tierexperimenteller peripherer Nervenl{\"a}sion}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-18352}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2005}, abstract = {Evaluation der antihyperalgetischen wie neuroregenerativen Potenz von Topiramat nach peripherer Nervenl{\"a}sion. Untersuchung im Tiermodell nach CCI / Crush-Nervenl{\"a}sion. Verhaltenstestungen, morphometrisch histologische Analysen, Immunhistochemische F{\"a}rbungen, elektrophysiologische Studien sowie RT-PCR. Topiramat zeigte hierbei - modulierende Wirkung auf die Entwicklung einer mechanischen Hyperalgesie wie K{\"a}lteallodynie nach CCI, auf Hitzehyperalgesie wie K{\"a}lteallodynia nach Crush - keine neuroprotektive oder pro-regenerative Wirkung in den von uns verwendeten L{\"a}sionsmodellen - eine ausgepr{\"a}gte Modulation des zellul{\"a}ren Zytokinmilieus distal der Nervenl{\"a}sion im Sinne einer Hochregulation proinflammatorischer Zytokine.}, language = {de} } @phdthesis{Magg2017, author = {Magg, Barbara}, title = {Etablierung und Validierung des W{\"u}rzburger Fabry Schmerzfragebogens f{\"u}r erwachsene Patienten}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154928}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Der M. Fabry ist eine X-chromosomal vererbte lysosomale Speicherkankheit, die zu einem Multiorganversagen f{\"u}hrt. Ein fr{\"u}hes Symptom sind Schmerzen, die meist schon in der fr{\"u}hen Kindheit einsetzen. Das Besondere an diesen Schmerzen ist, dass sie sich sehr unterschiedlich u.a. bez{\"u}glich ihres Verlaufs, ihrer Dauer und ihrer Lokalisation pr{\"a}sentieren k{\"o}nnen. Diese Fabry-assoziierten Schmerzen sind meist brennend und akral betont, k{\"o}nnen aber auch andere Qualit{\"a}ten aufweisen und sehr variable K{\"o}rperpartien erfassen, was ihre diagnostische Einordnung erschwert. Bisher verf{\"u}gbare validierte Schmerzfrageb{\"o}gen k{\"o}nnen das Spektrum der Fabry-assoziierten Schmerzen nicht erfassen. In dieser Arbeit wird der erste M. Fabry spezifische Schmerzfragebogen f{\"u}r Erwachsene in zwei Versionen pr{\"a}sentiert. Die erste Version ist eine Interview Version (iFPQ), bei der der Arzt in einem pers{\"o}nlichen Gespr{\"a}ch mit dem Patienten mit Hilfe des Fragbogens alle wesentlichen Aspekte der Fabry-assoziierten Schmerzen erfragen kann. Die zweite Version kann eigenst{\"a}ndig vom Patienten ausgef{\"u}llt werden (saFPQ). Zur Etablierung der Frageb{\"o}gen wurde in einer Pilotstudie zun{\"a}chst mit 20 Patienten eine erste Version des iFPQ entwickelt. Nach Verbesserungen wurde die Interview Version mit Hilfe von 42 Studienteilnehmern validiert, die jeweils an einem Erst- und Zweitgespr{\"a}ch im Abstand von zwei Wochen teilnahmen. Hierbei wurde auch der NPSI als vergleichender Fragebogen ausgef{\"u}llt. Bei der ersten statistischen Analyse ergab sich eine gute Reliabilit{\"a}t mit ICC-Werten von 0,896 bis 0,999 aber eine unzureichende Validit{\"a}t zwischen iFPQ und NPSI mit K-Werten von 0,257 bis 0,566. Nach der ersten statistischen Analyse wurde der Fragebogen erneut {\"u}berarbeitet und mit Hilfe von 20 Studienteilnehmern erneut validiert. Anschließend zeigte sich eine gute Validit{\"a}t mit K-Werten von 0,634 bis 1,0. Der saFPQ wurde im Anschluss an die finale iFPQ Version entwickelt. Bei 40 Patienten erfolgte ein Erstgespr{\"a}ch, bei dem die Patienten die valide Version des iFPQ ausf{\"u}llten. Im Abstand von zwei Wochen schickten die Patienten dann die selbst{\"a}ndig ausgef{\"u}llte Version des saFPQ postalisch zur{\"u}ck. Die postalische Version erweitert die Flexibilit{\"a}t dieses Fragebogens. Sie ist f{\"u}r den klinischen Alltag sehr relevant. Die Resonanz der Patienten hinsichtlich beider Frageb{\"o}gen war sehr positiv. Perspektivisch ist die Entwicklung einer englischen Version geplant.}, subject = {M.Fabry}, language = {de} } @article{SchanbacherBieberReindersetal.2022, author = {Schanbacher, Constanze and Bieber, Michael and Reinders, Yvonne and Cherpokova, Deya and Teichert, Christina and Nieswandt, Bernhard and Sickmann, Albert and Kleinschnitz, Christoph and Langhauser, Friederike and Lorenz, Kristina}, title = {ERK1/2 activity is critical for the outcome of ischemic stroke}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {2}, issn = {1422-0067}, doi = {10.3390/ijms23020706}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-283991}, year = {2022}, abstract = {Ischemic disorders are the leading cause of death worldwide. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are thought to affect the outcome of ischemic stroke. However, it is under debate whether activation or inhibition of ERK1/2 is beneficial. In this study, we report that the ubiquitous overexpression of wild-type ERK2 in mice (ERK2\(^{wt}\)) is detrimental after transient occlusion of the middle cerebral artery (tMCAO), as it led to a massive increase in infarct volume and neurological deficits by increasing blood-brain barrier (BBB) leakiness, inflammation, and the number of apoptotic neurons. To compare ERK1/2 activation and inhibition side-by-side, we also used mice with ubiquitous overexpression of the Raf-kinase inhibitor protein (RKIP\(^{wt}\)) and its phosphorylation-deficient mutant RKIP\(^{S153A}\), known inhibitors of the ERK1/2 signaling cascade. RKIP\(^{wt}\) and RKIP\(^{S153A}\) attenuated ischemia-induced damages, in particular via anti-inflammatory signaling. Taken together, our data suggest that stimulation of the Raf/MEK/ERK1/2-cascade is severely detrimental and its inhibition is rather protective. Thus, a tight control of the ERK1/2 signaling is essential for the outcome in response to ischemic stroke.}, language = {en} } @phdthesis{Moetzing2002, author = {M{\"o}tzing, Sandra}, title = {Entwicklung von Merkelzellen in der Haut von P0-defizienten M{\"a}usen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-578}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2002}, abstract = {Heredit{\"a}re periphere Neuropathien sind chronische Erkrankungen des peripheren Nervensystems, einhergehend mit Muskelschw{\"a}che und sensorischer Dysfunktion. Die Merkelzelle als Mechanorezeptor der Haut wird von einer myelinisierten langsam adaptierenden Afferenz (Aß) innerviert. Deshalb wurde in der vorliegenden Arbeit als sekund{\"a}rer Indikator f{\"u}r die distale Innervation in P0-defizienten M{\"a}usen, ein Tiermodell der heredit{\"a}ren motorisch-sensorischen D{\´e}j{\´e}rine-Sottas-Neuropathie, die Merkelzellzahl in der Haut dieser Tiere untersucht. Zus{\"a}tzlich wurde untersucht, ob durch den Gendefekt das unmyelinisierte Nervenfasersystem der Haut und das Vorkommen von Neurotrophinen (NT-3, NGF) in den P0-defizienten M{\"a}usen beeinflußt wird. Zur Anwendung kamen 6 Wochen, 4 Monate und 6 Monate alte Wildtyp- und P0-defiziente M{\"a}use. Unter Zuhilfenahme immunhistochemischer F{\"a}rbemethoden, computergest{\"u}tzter und lichtmikroskopischer Auswerteverfahren konnte ein Verlust von Merkelzellen in behaarter als auch in unbehaarter Haut mit fortschreitenden Alter der Tiere gezeigt werden. Die Bestimmung des NT-3- und NGF-Gehaltes mittels enzymgekoppelten Assays ergab keine signifikante Reduktion des Vorkommens dieser Neurotrophine. Neben dem betr{\"a}chtlichen Verlust an Merkelzellen konnte man keinen Effekt auf unmyelinisierte intraepidermale Nervenfasern nachweisen. Im Gegensatz dazu stellte eine parallel durchgef{\"u}hrte Studie an Nervus femoralis und Nervus ischiadicus in 6 Monate alten P0-defizienten Tieren eine 70 Prozent Reduktion myelinisierter Axone fest, so daß wir daraus eine Abh{\"a}ngigkeit der Merkelzelle von ihrer assoziierten myelinisierten SAI-Afferenz sowohl in behaarter als auch in unbehaarter Haut in den P0-defizienten Tieren schlußfolgerten. Der Verlust an Merkelzellen und die Beeintr{\"a}chtigung von myelinisierten Nervenfasern in den P0-defizienten Tieren kann nicht als sekund{\"a}re Wirkung eines ver{\"a}nderten trophischen Gehaltes an NT-3 oder NGF angesehen werden, sondern ist vielmehr durch den axonalen Verlust erkl{\"a}rbar. Die intraepidermalen unmyelinisierten Nervenfasern bleiben durch den Gendefekt unbeeinflußt, so daß die Mutation im P0-Gen eine Spezifit{\"a}t f{\"u}r das myelinisierte Nervenfasersystem zeigt. Wichtige Ergebnisse dieser Arbeit wurden bereits ver{\"o}ffentlicht.}, language = {de} } @phdthesis{KuscheTekin2019, author = {Kusche-Tekin, Burak Baris}, title = {Entwicklung einer fokalen Dystonie durch periphere Nervensch{\"a}digung bei \(Tor1a\) +/- M{\"a}usen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175161}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {Focal dystonia manifests in Tor1a+/- mice via a striatal dopaminergic dysregulation triggered by peripheral nerve injury Chi Wang Ip, Ioannis U. Isaias, Burak B. Kusche - Tekin, Dennis Klein, Janos Groh, Aet O'Leary, Susanne Knorr, Takahiro Higuchi, James B. Koprich, Jonathan M. Brotchie, Klaus V. Toyka, Andreas Reif, Jens Volkmann Abstract Isolated generalized dystonia is a central motor network disorder characterized by twisted movements or postures. The most frequent genetic cause is a GAG deletion in the Tor1a (DYT1) gene encoding torsinA with a reduced penetrance of 30-40 \% suggesting additional genetic or environmental modifiers. Development of dystonia-like movements after a standardized peripheral nerve crush lesion in wild type (wt) and Tor1a+/- mice, that express 50 \% torsinA only, was assessed by scoring of hindlimb movements during tail suspension, by rotarod testing and by computer-assisted gait analysis. Western blot analysis was performed for dopamine transporter (DAT), D1 and D2 receptors from striatal and quantitative RT-PCR analysis for DAT from midbrain dissections. Autoradiography was used to assess the functional DAT binding in striatum. Striatal dopamine and its metabolites were analyzed by high performance liquid chromatography. After nerve crush injury, we found abnormal posturing in the lesioned hindlimb of both mutant and wt mice indicating the profound influence of the nerve lesion (15x vs. 12x relative to control) resembling human peripheral pseudodystonia. In mutant mice the phenotypic abnormalities were increased by about 40 \% (p < 0.05). This was accompanied by complex alterations of striatal dopamine homeostasis. Pharmacological blockade of dopamine synthesis reduced severity of dystonia-like movements, whereas treatment with L-Dopa aggravated these but only in mutant mice suggesting a DYT1 related central component relevant to the development of abnormal involuntary movements. Our findings suggest that upon peripheral nerve injury reduced torsinA concentration and environmental stressors may act in concert in causing the central motor network dysfunction of DYT1 dystonia.}, language = {de} } @article{JovanovicKlassenHeuschmannetal.2020, author = {Jovanovic, Ana and Klassen, Philipp and Heuschmann, Peter and Sommer, Claudia and Roberts, Mark and {\"U}{\c{c}}eyler, Nurcan}, title = {English version of the self-administered Fabry Pain Questionnaire for adult patients}, series = {Orphanet Journal of Rare Diseases}, volume = {15}, journal = {Orphanet Journal of Rare Diseases}, doi = {10.1186/s13023-020-01580-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230298}, year = {2020}, abstract = {Background Pain is an early symptom of Fabry disease (FD) and is characterized by a unique phenotype with mainly episodic acral and triggerable burning pain. Recently, we designed and validated the first pain questionnaire for adult FD patients in an interview and a self-administered version in German: the Wurzburg Fabry Pain Questionnaire (FPQ). We now report the validation of the English version of the self-administered FPQ (enFPQ). Methods After two forward-backward translations of the FPQ by native German and native English speakers, the enFPQ was applied at The Mark Holland Metabolic Unit, Manchester, UK for validation. Consecutive patients with genetically ascertained FD and current or previous FD pain underwent a face-to-face interview using the enFPQ. Two weeks later, patients filled in the self-administered enFPQ at home. The agreement between entries collected by supervised administration and self-administration of the enFPQ was assessed via Gwet's AC1-statistics (AC1) for nominal-scaled scores and intraclass correlation coefficient (ICC) for interval-scaled elements. Results Eighty-three FD patients underwent the face-to-face interview and 54 patients sent back a completed self-administered version of the enFPQ 2 weeks later. We found high agreement with a mean AC1-statistics of 0.725 for 55 items, and very high agreement with a mean ICC of 0.811 for 9 items. Conclusions We provide the validated English version of the FPQ for self-administration in adult FD patients. The enFPQ collects detailed information on the individual FD pain phenotype and thus builds a solid basis for better pain classification and treatment in patients with FD.}, language = {en} } @article{KleinGrohWeishauptetal.2015, author = {Klein, Dennis and Groh, Janos and Weishaupt, Andreas and Martini, Rudolf}, title = {Endogenous antibodies contribute to macrophage-mediated demyelination in a mouse model for CMT1B}, series = {Journal of Neuroinflammation}, volume = {12}, journal = {Journal of Neuroinflammation}, number = {49}, doi = {10.1186/s12974-015-0267-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125036}, year = {2015}, abstract = {Background We could previously identify components of both the innate and the adaptive immune system as disease modifiers in the pathogenesis of models for Charcot-Marie-Tooth (CMT) neuropathies type 1B and 1X. As part of the adaptive immune system, here we investigated the role of antibodies in a model for CMT1B. Methods Antibodies were localized and characterized in peripheral nerves of the CMT1B model by immunohistochemistry and Western blot analysis. Experimental ablation of antibodies was performed by cross breeding the CMT1B models with mutants deficient in B-lymphocytes (JHD-/- mutants). Ameliorated demyelination by antibody deficiency was reverted by intravenous injection of mouse IgG fractions. Histopathological analysis was performed by immunocytochemistry and light and quantitative electron microscopy. Results We demonstrate that in peripheral nerves of a mouse model for CMT1B, endogenous antibodies strongly decorate endoneurial tubes of peripheral nerves. These antibodies comprise IgG and IgM subtypes and are preferentially, but not exclusively, associated with nerve fiber aspects nearby the nodes of Ranvier. In the absence of antibodies, the early demyelinating phenotype is substantially ameliorated. Reverting the neuropathy by reconstitution with murine IgG fractions identified accumulating antibodies as potentially pathogenic at this early stage of disease. Conclusions Our study demonstrates that in a mouse model for CMT1B, endogenous antibodies contribute to early macrophage-mediated demyelination and disease progression. Thus, both the innate and adaptive immune system are mutually interconnected in a genetic model for demyelination. Since in Wallerian degeneration antibodies have also been shown to be involved in myelin phagocytosis, our study supports our view that inherited demyelination and Wallerian degeneration share common mechanisms, which are detrimental when activated under nonlesion conditions.}, language = {en} } @phdthesis{Siedler2018, author = {Siedler, Gabriela Anja}, title = {Elektrisch evozierte Schmerz-assoziierte Potentiale bei Patienten mit small - und large fiber Neuropathien}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167186}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2018}, abstract = {In dieser Studie wurden 108 Patienten mit PNP, 60 Patienten mit M. Fabry und 58 gesunde Kontrollpersonen mittels PREP auf eine small fiber-Pathologie untersucht. Zudem erfolgte eine PREP-Untersuchung bei 5 gesunden Probanden und 3 Patienten nach Anwendung von lokalem Capsaicin. Zur Charakterisierung der small fibers erfolgten zudem Anamnese, klinische Untersuchung, die Frageb{\"o}gen NPSI, GCPS und ADS, QST und eine Hautbiopsie. In der Gruppe der Patienten mit PNP waren sowohl Patienten mit LFN, MFN und SFN unterschiedlicher {\"A}tiologie vertreten. Patienten mit einer MFN und Patienten mit einer zu einer Mitbeteiligung der small fibers passenden Anamnese (MFN und SFN) wiesen eine verl{\"a}ngerte N1-Latenz nach Stimulation am Fuß auf. Bei einer reduzierten IENFD in der proximalen Hautbiopsie zeigte sich die PPA nach Stimulation im Gesicht reduziert, beide Werte korrelierten positiv miteinander. Bei Patienten mit einer demyelinisierenden PNP war die N1-Latenz nach Stimulation an der Hand verl{\"a}ngert, zudem war bei Patienten mit CIDP die PPA nach Stimulation an Gesicht und Hand reduziert. M. Fabry ist eine X-chromosomal vererbte lysosomale Speicherkrankheit, welche mit einer SFN einhergehen kann. Weibliche Patienten mit M. Fabry und einer subjektiven Hypohidrose als klinische Pr{\"a}sentation einer small fiber Pathologie wiesen eine reduzierte PPA nach Stimulation an Gesicht, Hand und Fuß auf. {\"U}ber die gesamte Patientengruppe hinweg zeigte sich eine negative Korrelation der PPA nach Stimulation am Fuß mit der klinischen Schmerzpr{\"a}sentation im NPSI (Summenscore, Subscores evozierte Schmerzen und Schmerzattacken), sowie bei weiblichen Patienten mit der CDT, WDT und TSL in der QST als Marker f{\"u}r die small fiber Funktion. Patienten mit einer l{\"a}ngenunabh{\"a}ngigen Reduktion der IENFD wiesen eine niedrigere PPA nach Stimulation am Fuß auf. Ein nicht-auswertbares PREP-Potential spricht nach Ausschluss messtechnischer Artefakte f{\"u}r eine fortgeschrittene Nervenfasersch{\"a}digung. Probanden und Patienten zeigten nach Applikation von topischem Capsaicin eine Reduktion der PPA. PREP ist eine einfache, komplikationslos durchzuf{\"u}hrende und objektive Methode zur Untersuchung der small fibers. Sie stellt eine sinnvolle Erg{\"a}nzung zu den bereits etablierten Methoden QST und Hautbiopsie dar und bietet insbesondere f{\"u}r die Evaluation von Medikamenteneffekten wie z.B. von topischem Capsaicin eine vielversprechende Untersuchungsm{\"o}glichkeit.}, subject = {Fabry-Krankheit}, language = {de} } @article{KarleSchueleKlebeetal.2013, author = {Karle, Kathrin N. and Sch{\"u}le, Rebecca and Klebe, Stephan and Otto, Susanne and Frischholz, Christian and Liepelt-Scarfone, Inga and Sch{\"o}ls, Ludger}, title = {Electrophysiological characterisation of motor and sensory tracts in patients with hereditary spastic paraplegia (HSP)}, series = {Orphanet Journal of Rare Diseases}, volume = {8}, journal = {Orphanet Journal of Rare Diseases}, number = {158}, issn = {1750-1172}, doi = {10.1186/1750-1172-8-158}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124763}, year = {2013}, abstract = {Background: Hereditary spastic paraplegias (HSPs) are characterised by lower limb spasticity due to degeneration of the corticospinal tract. We set out for an electrophysiological characterisation of motor and sensory tracts in patients with HSP. Methods: We clinically and electrophysiologically examined a cohort of 128 patients with genetically confirmed or clinically probable HSP. Motor evoked potentials (MEPs) to arms and legs, somato-sensory evoked potentials of median and tibial nerves, and nerve conduction studies of tibial, ulnar, sural, and radial nerves were assessed. Results: Whereas all patients showed clinical signs of spastic paraparesis, MEPs were normal in 27\% of patients and revealed a broad spectrum with axonal or demyelinating features in the others. This heterogeneity can at least in part be explained by different underlying genotypes, hinting for distinct pathomechanisms in HSP subtypes. In the largest subgroup, SPG4, an axonal type of damage was evident. Comprehensive electrophysiological testing disclosed a more widespread affection of long fibre tracts involving peripheral nerves and the sensory system in 40\%, respectively. Electrophysiological abnormalities correlated with the severity of clinical symptoms. Conclusions: Whereas HSP is primarily considered as an upper motoneuron disorder, our data suggest a more widespread affection of motor and sensory tracts in the central and peripheral nervous system as a common finding in HSP. The distribution patterns of electrophysiological abnormalities were associated with distinct HSP genotypes and could reflect different underlying pathomechanisms. Electrophysiological measures are independent of symptomatic treatment and may therefore serve as a reliable biomarker in upcoming HSP trials.}, language = {en} } @article{SchuhmannStollPappetal.2019, author = {Schuhmann, Michael K. and Stoll, Guido and Papp, Lena and Bohr, Arne and Volkmann, Jens and Fluri, Felix}, title = {Electrical stimulation of the mesencephalic locomotor region has no impact on blood-brain barrier alterations after cerebral photothrombosis in rats}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {16}, issn = {1422-0067}, doi = {10.3390/ijms20164036}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201284}, year = {2019}, abstract = {Blood-brain barrier (BBB) disruption is a critical event after ischemic stroke, which results in edema formation and hemorrhagic transformation of infarcted tissue. BBB dysfunction following stroke is partly mediated by proinflammatory agents. We recently have shown that high frequency stimulation of the mesencephalic locomotor region (MLR-HFS) exerts an antiapoptotic and anti-inflammatory effect in the border zone of cerebral photothrombotic stroke in rats. Whether MLR-HFS also has an impact on BBB dysfunction in the early stage of stroke is unknown. In this study, rats were subjected to photothrombotic stroke of the sensorimotor cortex and implantation of a stimulating microelectrode into the ipsilesional MLR. Thereafter, either HFS or sham stimulation of the MLR was applied for 24 h. After scarifying the rats, BBB disruption was assessed by determining albumin extravasation and tight junction integrity (claudin 3, claudin 5, and occludin) using Western blot analyses and immunohistochemistry. In addition, by applying zymography, expression of pro-metalloproteinase-9 (pro-MMP-9) was analyzed. No differences were found regarding infarct size and BBB dysfunction between stimulated and unstimulated animals 24 h after induction of stroke. Our results indicate that MLR-HFS neither improves nor worsens the damaged BBB after stroke. Attenuating cytokines/chemokines in the perilesional area, as mediated by MLR-HFS, tend to play a less significant role in preventing the BBB integrity.}, language = {en} } @article{SchuhmannStollBohretal.2019, author = {Schuhmann, Michael K. and Stoll, Guido and Bohr, Arne and Volkmann, Jens and Fluri, Felix}, title = {Electrical stimulation of the mesencephalic locomotor region attenuates neuronal loss and cytokine expression in the perifocal region of photothrombotic stroke in rats}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {9}, issn = {1422-0067}, doi = {10.3390/ijms20092341}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201355}, year = {2019}, abstract = {Deep brain stimulation of the mesencephalic locomotor region (MLR) improves the motor symptoms in Parkinson's disease and experimental stroke by intervening in the motor cerebral network. Whether high-frequency stimulation (HFS) of the MLR is involved in non-motor processes, such as neuroprotection and inflammation in the area surrounding the photothrombotic lesion, has not been elucidated. This study evaluates whether MLR-HFS exerts an anti-apoptotic and anti-inflammatory effect on the border zone of cerebral photothrombotic stroke. Rats underwent photothrombotic stroke of the right sensorimotor cortex and the implantation of a microelectrode into the ipsilesional MLR. After intervention, either HFS or sham stimulation of the MLR was applied for 24 h. The infarct volumes were calculated from consecutive brain sections. Neuronal apoptosis was analyzed by TUNEL staining. Flow cytometry and immunohistochemistry determined the perilesional inflammatory response. Neuronal apoptosis was significantly reduced in the ischemic penumbra after MLR-HFS, whereas the infarct volumes did not differ between the groups. MLR-HFS significantly reduced the release of cytokines and chemokines within the ischemic penumbra. MLR-HFS is neuroprotective and it reduces pro-inflammatory mediators in the area that surrounds the photothrombotic stroke without changing the number of immune cells, which indicates that MLR-HFS enables the function of inflammatory cells to be altered on a molecular level.}, language = {en} } @phdthesis{Sturn2006, author = {Sturn, Anja}, title = {Einfluss von niedrigdosierter Heparinbehandlung auf den Verlauf von Stammganglienblutungen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-19113}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2006}, abstract = {ZIEL: An m{\"o}glichst großer Fallzahl und vergleichbarem Patientenkollektiv zu {\"u}berpr{\"u}fen, ob eine niedrigdosierte Heparintherapie f{\"u}r Patienten mit intracerebralen Blutungen sch{\"a}dliche oder n{\"u}tzliche Auswirkungen hat. METHODEN: retrospektive Analyse von 238 Patienten mit Stammganglienblutungen hinsichtlich Heparinbehandlung sowie operativer vs. konservativer Behandlung und folgende Auswirkung auf Blutungskomplikation, thrombembolische Ereignisse, Mortalit{\"a}t und funktionellem Outcome nach dem GOS. ERGEBNIS: kein Nachblutungsrisiko, durchweg g{\"u}nstigere Prognose f{\"u}r heparinbehandelte Patienten (86\% im Kollektiv), bei tendenziell positiver Patientenselektion, weitere prospektive Studien gerechtfertigt und w{\"u}nschenswert; operative Therapieindikation streng zu stellen}, language = {de} } @phdthesis{Weiss2024, author = {Weiß, Eva Maria}, title = {Einfluss von Makrophagen auf autophagische Vorg{\"a}nge in Schwann´schen Zellen unter den Bedingungen von Nervenl{\"a}sion und genetisch bedingter Neuropathie}, doi = {10.25972/OPUS-36967}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369674}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Charcot-Marie-Tooth (CMT) Neuropathien stellen als h{\"a}ufigste erblich bedingte neurologische Erkrankungen eine Gruppe genetisch heterogener, chronisch progredienter peripherer Polyneuropathien dar. Die Lebensqualit{\"a}t der Patienten ist bei fehlender kurativer Therapieoption vor allem durch motorische und sensorische Defizite deutlich eingeschr{\"a}nkt. In verschiedenen Studien konnte die pathophysiologische Relevanz einer sekund{\"a}ren Entz{\"u}ndungsreaktion, insbesondere durch Makrophagen und Lymphozyten vermittelt, in Mausmodellen dreier CMT1 Subtypen (CMT1A, CMT1B, CMT1X) aufgezeigt werden. Auch in Folge einer L{\"a}sion peripherer Nerven ist eine akute Entz{\"u}ndungsreaktion von entscheidender Bedeutung, wobei sich bereits Gemeinsamkeiten zwischen der postl{\"a}sionalen Waller´schen Degeneration (WD) und CMT1 Neuropathien identifizieren ließen. W{\"a}hrend die aktive Beteiligung der Autophagie Schwann´scher Zellen (hier kurz SZ Autophagie genannt) an der Myelindegradation im Falle einer WD jedoch vielfach beschrieben wurde, ist {\"A}hnliches in CMT1 Neuropathien bisher nur unzureichend untersucht. Da in einer Studie in Cx32def Mausmodellen der CMT1X Erkrankung auch nach Reduktion endoneuraler Makrophagen anhaltende Demyelinisierung beobachtet werden konnte, sollte das Vorkommen von SZ Autophagie sowie deren m{\"o}gliche Beeinflussung durch Makrophagen in diesen Myelinmutanten untersucht werden. In der vorliegenden Arbeit wurden sowohl Wildtyp (Wt) M{\"a}use in ex vivo und in vivo Modellen einer WD als auch Cx32def Myelinmutanten zweier Altersstufen (4 und 12 Monate) mit einem niedermolekularen CSF1-Rezeptor-Inhibitor (CSF1RI) zur Reduktion endoneuraler Makrophagen behandelt, wobei sich vergleichende histochemische bzw. immunhistochemische Analysen peripherer Nerven behandelter und unbehandelter Tiere anschlossen. Im Rahmen der Etablierung immunhistochemischer Methodik zeigte sich hierbei unter den kontrollierten Bedingungen einer ex vivo Ischiasnervenkultur eine vermehrte Aktivierung der SZ Autophagie in behandelten Wt M{\"a}usen. Auch 4 Monate alte behandelte Cx32def Tiere wiesen, verglichen mit unbehandelten Myelinmutanten bzw. Wt M{\"a}usen derselben Altersstufe, eine vermehrte autophagische Aktivit{\"a}t in SZ auf. Diese scheint sich jedoch im weiteren Verlauf der Erkrankung zu reduzieren, da im Falle der 12 Monate alten Cx32def Modelltiere weniger autophagisch aktive SZ Profile bzw. kaum Unterschiede zwischen behandelten und unbehandelten Tieren beobachtet werden konnten. Die Ergebnisse lassen somit eine m{\"o}gliche aktive Beteiligung von SZ Autophagie insbesondere in der Pathophysiologie der fr{\"u}hen Phase einer CMT1X Erkrankung sowie deren Beeinflussung durch endoneurale Makrophagen vermuten. Dies sollte vornehmlich in der Entwicklung von Therapiestrategien der CMT1X bedacht werden, da sich eine fr{\"u}he Reduktion pathophysiologisch relevanter endoneuraler Makrophagen somit auch nachteilig auf die Myelinintegrit{\"a}t auswirken k{\"o}nnte.}, subject = {Schwann-Zelle}, language = {de} } @phdthesis{Wind2020, author = {Wind, Teresa Elisabeth}, title = {Einfluss von Alter und Polyneuropathie auf zeitliche Wahrnehmungsschwellen somatosensorischer und kin{\"a}sthetischer Stimuli und propriozeptive Leistungsf{\"a}higkeit}, doi = {10.25972/OPUS-20804}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-208047}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Zeitliche Diskrimination somatosensorischer und kin{\"a}sthetischer Stimuli wurde als neurophysiologisches Korrelat f{\"u}r propriozeptive Pr{\"a}zision postuliert und bei verschiedenen Bewegungsst{\"o}rungen als pathologisch beschrieben. Ziel der Untersuchung war es, den Einfluss von Alter und Polyneuropathie auf die kin{\"a}sthetische (TDMT) und taktile (STDT) zeitliche Wahrnehmungsschwelle sowie die propriozeptive Genauigkeit bei Zeigeversuchen systematisch zu untersuchen. Hierf{\"u}r wurden 54 gesunde Probanden und 25 Polyneuropathie-Patienten im Alter zwischen 30 und 76 Jahren untersucht. Die STDT-Messung erfolgte mit Oberfl{\"a}chenelektroden, die an der Zeigefingerspitze bzw. am Großzehengrundgelenk angebracht wurden. Die TDMT-Werte wurden mit Hilfe einer sterilen Nadelelektrode erfasst, welche in den Musculus flexor carpi radialis bzw. Musculus tibialis anterior inseriert wurde. Die Daten zur Propriozeption wurden mit Hilfe eines Goniometers erhoben und beinhalteten dabei aktive Zeigeaufgaben (Zeigen auf eine LED, Nachahmung einer Bewegung anhand einer auf einem Computerbildschirm dargebotenen PFEIL-Darstellung unterschiedlicher L{\"a}nge) und die Einsch{\"a}tzung der Position der jeweiligen Extremit{\"a}t nach passiver Bewegung (PASSIV). Die Messungen erfolgten jeweils ohne visuelle R{\"u}ckmeldung. Die Zeigefehler (Abweichung von der Zielposition) bzw. Sch{\"a}tzfehler (Abweichung der gesch{\"a}tzten von der tats{\"a}chlichen Position nach passiver Auslenkung) wurden als Maß der propriozeptiven Pr{\"a}zision verwendet. Die Ergebnisse der gesunden Probandengruppe zeigten, dass h{\"o}heres Alter mit h{\"o}heren STDT- und TDMT-Werten korrelierte. Die Polyneuropathie-Patienten erzielten in allen Bereichen (Diskriminationsschwellen und Propriozeptionsaufgaben) signifikant schlechtere Ergebnisse als die gesunde Kontrollgruppe. Zus{\"a}tzlich konnte eine statistisch signifikante positive Korrelation zwischen der propriozeptiven Pr{\"a}zision bei den aktiven Zeige-Aufgaben (LED und PFEIL) und den zeitlichen Diskriminationsschwellen (STDT und TDMT) gezeigt werden. In Anbetracht dieser Ergebnisse sollten das Patienten-Alter und m{\"o}gliche St{\"o}rungen der peripheren Nervenleitung ber{\"u}cksichtigt werden, wenn STDT-und TDMT-Bestimmungen bei Patienten mit Bewegungsst{\"o}rungen angewendet werden. Die Korrelation zwischen den Diskriminationsschwellen und der Performance bei aktiven Zeigeversuchen (PFEIL- und LED-Aufgabe) legt nahe, dass STDT und TDMT Indikatoren der propriozeptiven Funktion sein k{\"o}nnten. Es ist weitere Forschungsarbeit notwendig, um diese Beziehung exakt zu beleuchten. Im Falle einer Best{\"a}tigung der Befunde auch bei Patienten mit Bewegungsst{\"o}rungen erscheint denkbar, dass sich STDT und TDMT als vergleichsweise leicht messbare und gut quantifizierbare Parameter der Propriozeption herausstellen mit Potenzial zur differenzialdiagnostischen Anwendung, m{\"o}glicherweise aber auch als Surrogatparameter einer gezielten rehabilitativen Behandlung.}, subject = {Propriozeption}, language = {de} } @article{HiewNguemeniZeller2022, author = {Hiew, Shawn and Nguemeni, Carine and Zeller, Daniel}, title = {Efficacy of transcranial direct current stimulation in people with multiple sclerosis: a review}, series = {European Journal of Neurology}, volume = {29}, journal = {European Journal of Neurology}, number = {2}, doi = {10.1111/ene.15163}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259424}, pages = {648-664}, year = {2022}, abstract = {Background and purpose Multiple sclerosis (MS) is a chronic inflammatory disease causing a wide range of symptoms including motor and cognitive impairment, fatigue and pain. Over the last two decades, non-invasive brain stimulation, especially transcranial direct current stimulation (tDCS), has increasingly been used to modulate brain function in various physiological and pathological conditions. However, its experimental applications for people with MS were noted only as recently as 2010 and have been growing since then. The efficacy for use in people with MS remains questionable with the results of existing studies being largely conflicting. Hence, the aim of this review is to paint a picture of the current state of tDCS in MS research grounded on studies applying tDCS that have been done to date. Methods A keyword search was performed to retrieve articles from the earliest article identified until 14 February 2021 using a combination of the groups (1) 'multiple sclerosis', 'MS' and 'encephalomyelitis' and (2) 'tDCS' and 'transcranial direct current stimulation'. Results The analysis of the 30 articles included in this review underlined inconsistent effects of tDCS on the motor symptoms of MS based on small sample sizes. However, tDCS showed promising benefits in ameliorating fatigue, pain and cognitive symptoms. Conclusion Transcranial direct current stimulation is attractive as a non-drug approach in ameliorating MS symptoms, where other treatment options remain limited. The development of protocols tailored to the individual's own neuroanatomy using high definition tDCS and the introduction of network mapping in the experimental designs might help to overcome the variability between studies.}, language = {en} } @article{GruenewaldBennettToykaetal.2016, author = {Gr{\"u}newald, Benedikt and Bennett, Jeffrey L. and Toyka, Klaus V. and Sommer, Claudia and Geis, Christian}, title = {Efficacy of Polyvalent Human Immunoglobulins in an Animal Model of Neuromyelitis Optica Evoked by Intrathecal Anti-Aquaporin 4 Antibodies}, series = {International Journal of Molecular Sciences}, volume = {17}, journal = {International Journal of Molecular Sciences}, number = {9}, doi = {10.3390/ijms17091407}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166000}, pages = {1407}, year = {2016}, abstract = {Neuromyelitis Optica Spectrum Disorders (NMOSD) are associated with autoantibodies (ABs) targeting the astrocytic aquaporin-4 water channels (AQP4-ABs). These ABs have a direct pathogenic role by initiating a variety of immunological and inflammatory processes in the course of disease. In a recently-established animal model, chronic intrathecal passive-transfer of immunoglobulin G from NMOSD patients (NMO-IgG), or of recombinant human AQP4-ABs (rAB-AQP4), provided evidence for complementary and immune-cell independent effects of AQP4-ABs. Utilizing this animal model, we here tested the effects of systemically and intrathecally applied pooled human immunoglobulins (IVIg) using a preventive and a therapeutic paradigm. In NMO-IgG animals, prophylactic application of systemic IVIg led to a reduced median disease score of 2.4 on a 0-10 scale, in comparison to 4.1 with sham treatment. Therapeutic IVIg, applied systemically after the 10th intrathecal NMO-IgG injection, significantly reduced the disease score by 0.8. Intrathecal IVIg application induced a beneficial effect in animals with NMO-IgG (median score IVIg 1.6 vs. sham 3.7) or with rAB-AQP4 (median score IVIg 2.0 vs. sham 3.7). We here provide evidence that treatment with IVIg ameliorates disease symptoms in this passive-transfer model, in analogy to former studies investigating passive-transfer animal models of other antibody-mediated disorders.}, language = {en} } @article{FlacheneckerBuresGawliketal.2020, author = {Flachenecker, Peter and Bures, Anna Karoline and Gawlik, Angeli and Weiland, Ann-Christin and Kuld, Sarah and Gusowski, Klaus and Streber, Ren{\´e} and Pfeifer, Klaus and Tallner, Alexander}, title = {Efficacy of an internet-based program to promote physical activity and exercise after inpatient rehabilitation in persons with multiple sclerosis: a randomized, single-blind, controlled study}, series = {International Journal of Environmental Research and Public Health}, volume = {17}, journal = {International Journal of Environmental Research and Public Health}, number = {12}, issn = {1660-4601}, doi = {10.3390/ijerph17124544}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-207863}, year = {2020}, abstract = {Background: Multimodal rehabilitation improves fatigue and mobility in persons with multiple sclerosis (PwMS). Effects are transient and may be conserved by internet-based physical activity promotion programs. Objective: Evaluate the effects of internet-based physical activity and exercise promotion on fatigue, quality of life, and gait in PwMS after inpatient rehabilitation. Methods: PwMS (Expanded Disability Status Scale (EDSS) ≤ 6.0, fatigue: W{\"u}rzburg Fatigue Inventory for Multiple Sclerosis (WEIMuS) ≥ 32) were randomized into an intervention group (IG) or a control group (CG). After rehabilitation, IG received 3 months of internet-based physical activity promotion, while CG received no intervention. Primary outcome: self-reported fatigue (WEIMuS). Secondary outcomes: quality of life (Multiple Sclerosis Impact Scale 29, MSIS-29), gait (2min/10m walking test, Tinetti score). Measurements: beginning (T0) and end (T1) of inpatient rehabilitation, 3 (T2) and 6 (T3) months afterwards. Results: 64 of 84 PwMS were analyzed (IG: 34, CG: 30). After rehabilitation, fatigue decreased in both groups. At T2 and T3, fatigue increased again in CG but was improved in IG (p < 0.001). MSIS-29 improved in both groups at T1 but remained improved at T2 and T3 only in IG. Gait improvements were more pronounced in IG at T2. Conclusions: The study provides Class II evidence that the effects of rehabilitation on fatigue, quality of life, and gait can be maintained for 3-6 months with an internet-based physical activity and exercise promotion program.}, language = {en} } @article{SchuhmannFluri2017, author = {Schuhmann, Michael K. and Fluri, Felix}, title = {Effects of fullerenols on mouse brain microvascular endothelial cells}, series = {International Journal of Molecular Sciences}, volume = {18}, journal = {International Journal of Molecular Sciences}, number = {8}, issn = {1422-0067}, doi = {10.3390/ijms18081783}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158072}, year = {2017}, abstract = {Fullerenols, water-soluble C60-fullerene derivatives, have been shown to exert neuroprotective effects in vitro and in vivo, most likely due to their capability to scavenge free radicals. However, little is known about the effects of fullerenols on the blood-brain barrier (BBB), especially on cerebral endothelial cells under inflammatory conditions. Here, we investigated whether the treatment of primary mouse brain microvascular endothelial cells with fullerenols impacts basal and inflammatory blood-brain barrier (BBB) properties in vitro. While fullerenols (1, 10, and 100 µg/mL) did not change transendothelial electrical resistance under basal and inflammatory conditions, 100 µg/mL of fullerenol significantly reduced erk1/2 activation and resulted in an activation of NFκB in an inflammatory milieu. Our findings suggest that fullerenols might counteract oxidative stress via the erk1/2 and NFκB pathways, and thus are able to protect microvascular endothelial cells under inflammatory conditions.}, language = {en} } @phdthesis{Andreska2021, author = {Andreska, Thomas}, title = {Effects of dopamine on BDNF / TrkB mediated signaling and plasticity on cortico-striatal synapses}, doi = {10.25972/OPUS-17431}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-174317}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Progressive loss of voluntary movement control is the central symptom of Parkinson's disease (PD). Even today, we are not yet able to cure PD. This is mainly due to a lack of understanding the mechanisms of movement control, network activity and plasticity in motor circuits, in particular between the cerebral cortex and the striatum. Brain-derived neurotrophic factor (BDNF) has emerged as one of the most important factors for the development and survival of neurons, as well as for synaptic plasticity. It is thus an important target for the development of new therapeutic strategies against neurodegenerative diseases. Together with its receptor, the Tropomyosin receptor kinase B (TrkB), it is critically involved in development and function of the striatum. Nevertheless, little is known about the localization of BDNF within presynaptic terminals in the striatum, as well as the types of neurons that produce BDNF in the cerebral cortex. Furthermore, the influence of midbrain derived dopamine on the control of BDNF / TrkB interaction in striatal medium spiny neurons (MSNs) remains elusive so far. Dopamine, however, appears to play an important role, as its absence leads to drastic changes in striatal synaptic plasticity. This suggests that dopamine could regulate synaptic activity in the striatum via modulation of BDNF / TrkB function. To answer these questions, we have developed a sensitive and reliable protocol for the immunohistochemical detection of endogenous BDNF. We find that the majority of striatal BDNF is provided by glutamatergic, cortex derived afferents and not dopaminergic inputs from the midbrain. In fact, we found BDNF in cell bodies of neurons in layers II-III and V of the primary and secondary motor cortex as well as layer V of the somatosensory cortex. These are the brain areas that send dense projections to the dorsolateral striatum for control of voluntary movement. Furthermore, we could show that these projection neurons significantly downregulate the expression of BDNF during the juvenile development of mice between 3 and 12 weeks. In parallel, we found a modulatory effect of dopamine on the translocation of TrkB to the cell surface in postsynaptic striatal Medium Spiny Neurons (MSNs). In MSNs of the direct pathway (dMSNs), which express dopamine receptor 1 (DRD1), we observed the formation of TrkB aggregates in the 6-hydroxydopamine (6-OHDA) model of PD. This suggests that DRD1 activity controls TrkB surface expression in these neurons. In contrast, we found that DRD2 activation has opposite effects in MSNs of the indirect pathway (iMSNs). Activation of DRD2 promotes a rapid decrease in TrkB surface expression which was reversible and depended on cAMP. In parallel, stimulation of DRD2 led to induction of phospho-TrkB (pTrkB). This effect was significantly slower than the effect on TrkB surface expression and indicates that TrkB is transactivated by DRD2. Together, our data provide evidence that dopamine triggers dual modes of plasticity on striatal MSNs by acting on TrkB surface expression in DRD1 and DRD2 expressing MSNs. This surface expression of the receptor is crucial for the binding of BDNF, which is released from corticostriatal afferents. This leads to the induction of TrkB-mediated downstream signal transduction cascades and long-term potentiation (LTP). Therefore, the dopamine-mediated translocation of TrkB could be a mediator that modulates the balance between dopaminergic and glutamatergic signaling to allow synaptic plasticity in a spatiotemporal manner. This information and the fact that TrkB is segregated to persistent aggregates in PD could help to improve our understanding of voluntary movement control and to develop new therapeutic strategies beyond those focusing on dopaminergic supply.}, subject = {Brain-derived neurotrophic factor}, language = {en} } @article{KleinGrohYuanetal.2022, author = {Klein, Dennis and Groh, Janos and Yuan, Xidi and Berve, Kristina and Stassart, Ruth and Fledrich, Robert and Martini, Rudolf}, title = {Early targeting of endoneurial macrophages alleviates the neuropathy and affects abnormal Schwann cell differentiation in a mouse model of Charcot-Marie-Tooth 1A}, series = {Glia}, volume = {70}, journal = {Glia}, number = {6}, doi = {10.1002/glia.24158}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318714}, pages = {1100 -- 1116}, year = {2022}, abstract = {We have previously shown that targeting endoneurial macrophages with the orally applied CSF-1 receptor specific kinase (c-FMS) inhibitor PLX5622 from the age of 3 months onwards led to a substantial alleviation of the neuropathy in mouse models of Charcot-Marie-Tooth (CMT) 1X and 1B disease, which are genetically-mediated nerve disorders not treatable in humans. The same approach failed in a model of CMT1A (PMP22-overexpressing mice, line C61), representing the most frequent form of CMT. This was unexpected since previous studies identified macrophages contributing to disease severity in the same CMT1A model. Here we re-approached the possibility of alleviating the neuropathy in a model of CMT1A by targeting macrophages at earlier time points. As a proof-of-principle experiment, we genetically inactivated colony-stimulating factor-1 (CSF-1) in CMT1A mice, which resulted in lower endoneurial macrophage numbers and alleviated the neuropathy. Based on these observations, we pharmacologically ablated macrophages in newborn CMT1A mice by feeding their lactating mothers with chow containing PLX5622, followed by treatment of the respective progenies after weaning until the age of 6 months. We found that peripheral neuropathy was substantially alleviated after early postnatal treatment, leading to preserved motor function in CMT1A mice. Moreover, macrophage depletion affected the altered Schwann cell differentiation phenotype. These findings underscore the targetable role of macrophage-mediated inflammation in peripheral nerves of inherited neuropathies, but also emphasize the need for an early treatment start confined to a narrow therapeutic time window in CMT1A models and potentially in respective patients.}, language = {en} } @article{KleinschnitzMenclGarzetal.2013, author = {Kleinschnitz, Christoph and Mencl, Stine and Garz, Cornelia and Niklass, Solveig and Braun, Holger and G{\"o}b, Eva and Homola, Gy{\"o}rgy and Heinze, Hans-Jochen and Reymann, Klaus G. and Schreiber, Stefanie}, title = {Early microvascular dysfunction in cerebral small vessel disease is not detectable on 3.0 Tesla magnetic resonance imaging: a longitudinal study in spontaneously hypertensive stroke-prone rats}, series = {Experimental \& Translational Stroke Medicine}, journal = {Experimental \& Translational Stroke Medicine}, doi = {10.1186/2040-7378-5-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97056}, year = {2013}, abstract = {Background Human cerebral small vessel disease (CSVD) has distinct histopathologic and imaging findings in its advanced stages. In spontaneously hypertensive stroke-prone rats (SHRSP), a well-established animal model of CSVD, we recently demonstrated that cerebral microangiopathy is initiated by early microvascular dysfunction leading to the breakdown of the blood-brain barrier and an activated coagulatory state resulting in capillary and arteriolar erythrocyte accumulations (stases). In the present study, we investigated whether initial microvascular dysfunction and other stages of the pathologic CSVD cascade can be detected by serial magnetic resonance imaging (MRI). Findings Fourteen SHRSP and three control (Wistar) rats (aged 26-44 weeks) were investigated biweekly by 3.0 Tesla (3 T) MRI. After perfusion, brains were stained with hematoxylin-eosin and histology was correlated with MRI data. Three SHRSP developed terminal CSVD stages including cortical, hippocampal, and striatal infarcts and macrohemorrhages, which could be detected consistently by MRI. Corresponding histology showed small vessel thromboses and increased numbers of small perivascular bleeds in the infarcted areas. However, 3 T MRI failed to visualize intravascular erythrocyte accumulations, even in those brain regions with the highest densities of affected vessels and the largest vessels affected by stases, as well as failing to detect small perivascular bleeds. Conclusion Serial MRI at a field strength of 3 T failed to detect the initial microvascular dysfunction and subsequent small perivascular bleeds in SHRSP; only terminal stages of cerebral microangiopathy were reliably detected. Further investigations at higher magnetic field strengths (7 T) using blood- and flow-sensitive sequences are currently underway.}, language = {en} } @article{BurlinaSimsPoliteietal.2011, author = {Burlina, Alessandro P. and Sims, Katherine B. and Politei, Juan M. and Bennett, Gary J. and Baron, Ralf and Sommer, Claudia and Moller, Anette Torvin and Hilz, Max J.}, title = {Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel}, series = {BMC Neurology}, volume = {11}, journal = {BMC Neurology}, number = {61}, doi = {10.1186/1471-2377-11-61}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135309}, pages = {1-11}, year = {2011}, abstract = {Background: Fabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of lipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fibers are particularly affected and small fiber peripheral neuropathy often clinically manifests at young age. Peripheral pain can be chronic and/or occur as provoked attacks of excruciating pain. Manifestations of dysfunction of small autonomic fibers may include, among others, impaired sweating, gastrointestinal dysmotility, and abnormal pain perception. Patients with Fabry disease often remain undiagnosed until severe complications involving the kidney, heart, peripheral nerves and/or brain have arisen. Methods: An international expert panel convened with the goal to provide guidance to clinicians who may encounter unrecognized patients with Fabry disease on how to diagnose these patients early using simple diagnostic tests. A further aim was to offer recommendations to control neuropathic pain. Results: We describe the neuropathy in Fabry disease, focusing on peripheral small fiber dysfunction - the hallmark of early neurologic involvement in this disorder. The clinical course of peripheral pain is summarized, and the importance of medical history-taking, including family history, is highlighted. A thorough physical examination (e. g., angiokeratoma, corneal opacities) and simple non-invasive sensory perception tests could provide clues to the diagnosis of Fabry disease. Reported early clinical benefits of enzyme replacement therapy include reduction of neuropathic pain, and adequate management of residual pain to a tolerable and functional level can substantially improve the quality of life for patients. Conclusions: Our recommendations can assist in diagnosing Fabry small fiber neuropathy early, and offer clinicians guidance in controlling peripheral pain. This is particularly important since management of pain in young patients with Fabry disease appears to be inadequate.}, language = {en} } @article{SpitzelWagnerBreyeretal.2022, author = {Spitzel, Marlene and Wagner, Elise and Breyer, Maximilian and Henniger, Dorothea and Bayin, Mehtap and Hofmann, Lukas and Mauceri, Daniela and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan}, title = {Dysregulation of immune response mediators and pain-related ion channels is associated with pain-like behavior in the GLA KO mouse model of Fabry disease}, series = {Cells}, volume = {11}, journal = {Cells}, number = {11}, issn = {2073-4409}, doi = {10.3390/cells11111730}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-275186}, year = {2022}, abstract = {Fabry disease (FD) is a rare life-threatening disorder caused by deficiency of the alpha-galactosidase A (GLA) enzyme with a characteristic pain phenotype. Impaired GLA production or function leads to the accumulation of the cell membrane compound globotriaosylceramide (Gb3) in the neurons of the dorsal root ganglia (DRG) of FD patients. Applying immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT PCR) analysis on DRG tissue of the GLA knockout (KO) mouse model of FD, we address the question of how Gb3 accumulation may contribute to FD pain and focus on the immune system and pain-associated ion channel gene expression. We show a higher Gb3 load in the DRG of young (<6 months) (p < 0.01) and old (≥12 months) (p < 0.001) GLA KO mice compared to old wildtype (WT) littermates, and an overall suppressed immune response in the DRG of old GLA KO mice, represented by a reduced number of CD206\(^+\) macrophages (p < 0.01) and lower gene expression levels of the inflammation-associated targets interleukin(IL)1b (p < 0.05), IL10 (p < 0.001), glial fibrillary acidic protein (GFAP) (p < 0.05), and leucine rich alpha-2-glycoprotein 1 (LRG1) (p < 0.01) in the DRG of old GLA KO mice compared to old WT. Dysregulation of immune-related genes may be linked to lower gene expression levels of the pain-associated ion channels calcium-activated potassium channel 3.1 (KCa3.1) and transient receptor potential ankyrin 1 channel (TRPA1). Ion channel expression might further be disturbed by impaired sphingolipid recruitment mediated via the lipid raft marker flotillin-1 (FLOT1). This impairment is represented by an increased number of FLOT1\(^+\) DRG neurons with a membranous expression pattern in old GLA KO mice compared to young GLA KO, young WT, and old WT mice (p < 0.001 each). Further, we provide evidence for aberrant behavior of GLA KO mice, which might be linked to dysregulated ion channel gene expression levels and disturbed FLOT1 distribution patterns. Behavioral testing revealed mechanical hypersensitivity in young (p < 0.01) and old (p < 0.001) GLA KO mice compared to WT, heat hypersensitivity in young GLA KO mice (p < 0.001) compared to WT, age-dependent heat hyposensitivity in old GLA KO mice (p < 0.001) compared to young GLA KO mice, and cold hyposensitivity in young (p < 0.001) and old (p < 0.001) GLA KO mice compared to WT, which well reflects the clinical phenotype observed in FD patients.}, language = {en} } @article{SimonRauskolbGunnersenetal.2015, author = {Simon, Christian M. and Rauskolb, Stefanie and Gunnersen, Jennifer M. and Holtmann, Bettina and Drepper, Carsten and Dombert, Benjamin and Braga, Massimiliano and Wiese, Stefan and Jablonka, Sibylle and P{\"u}hringer, Dirk and Zielasek, J{\"u}rgen and Hoeflich, Andreas and Silani, Vincenzo and Wolf, Eckhard and Kneitz, Susanne and Sommer, Claudia and Toyka, Klaus V. and Sendtner, Michael}, title = {Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy}, series = {Acta Neuropathologica}, volume = {130}, journal = {Acta Neuropathologica}, doi = {10.1007/s00401-015-1446-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154569}, pages = {373 -- 387}, year = {2015}, abstract = {Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes.The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor(IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP.}, language = {en} } @article{AndreskaLueningschroerWolfetal.2023, author = {Andreska, Thomas and L{\"u}ningschr{\"o}r, Patrick and Wolf, Daniel and McFleder, Rhonda L. and Ayon-Olivas, Maurilyn and Rattka, Marta and Drechsler, Christine and Perschin, Veronika and Blum, Robert and Aufmkolk, Sarah and Granado, Noelia and Moratalla, Rosario and Sauer, Markus and Monoranu, Camelia and Volkmann, Jens and Ip, Chi Wang and Stigloher, Christian and Sendtner, Michael}, title = {DRD1 signaling modulates TrkB turnover and BDNF sensitivity in direct pathway striatal medium spiny neurons}, series = {Cell Reports}, volume = {42}, journal = {Cell Reports}, number = {6}, doi = {10.1016/j.celrep.2023.112575}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349932}, year = {2023}, abstract = {Highlights • Dopamine receptor-1 activation induces TrkB cell-surface expression in striatal neurons • Dopaminergic deficits cause TrkB accumulation and clustering in the ER • TrkB clusters colocalize with cargo receptor SORCS-2 in direct pathway striatal neurons • Intracellular TrkB clusters fail to fuse with lysosomes after dopamine depletion Summary Disturbed motor control is a hallmark of Parkinson's disease (PD). Cortico-striatal synapses play a central role in motor learning and adaption, and brain-derived neurotrophic factor (BDNF) from cortico-striatal afferents modulates their plasticity via TrkB in striatal medium spiny projection neurons (SPNs). We studied the role of dopamine in modulating the sensitivity of direct pathway SPNs (dSPNs) to BDNF in cultures of fluorescence-activated cell sorting (FACS)-enriched D1-expressing SPNs and 6-hydroxydopamine (6-OHDA)-treated rats. DRD1 activation causes enhanced TrkB translocation to the cell surface and increased sensitivity for BDNF. In contrast, dopamine depletion in cultured dSPN neurons, 6-OHDA-treated rats, and postmortem brain of patients with PD reduces BDNF responsiveness and causes formation of intracellular TrkB clusters. These clusters associate with sortilin related VPS10 domain containing receptor 2 (SORCS-2) in multivesicular-like structures, which apparently protects them from lysosomal degradation. Thus, impaired TrkB processing might contribute to disturbed motor function in PD.}, language = {en} } @article{JaenschEvdokimovEgenolfetal.2024, author = {J{\"a}nsch, Sarah and Evdokimov, Dimitar and Egenolf, Nadine and Meyer zu Altenschildesche, Caren and Kreß, Luisa and {\"U}{\c{c}}eyler, Nurcan}, title = {Distinguishing fibromyalgia syndrome from small fiber neuropathy: a clinical guide}, series = {Pain Reports}, volume = {9}, journal = {Pain Reports}, number = {1}, doi = {10.1097/PR9.0000000000001136}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350306}, year = {2024}, abstract = {Introduction: Fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) are distinct pain conditions that share commonalities and may be challenging as for differential diagnosis. Objective: To comprehensively investigate clinical characteristics of women with FMS and SFN to determine clinically applicable parameters for differentiation. Methods: We retrospectively analyzed medical records of 158 women with FMS and 53 with SFN focusing on pain-specific medical and family history, accompanying symptoms, additional diseases, and treatment. We investigated data obtained using standardized pain, depression, and anxiety questionnaires. We further analyzed test results and findings obtained in standardized small fiber tests. Results: FMS patients were on average ten years younger at symptom onset, described higher pain intensities requiring frequent change of pharmaceutics, and reported generalized pain compared to SFN. Pain in FMS was accompanied by irritable bowel or sleep disturbances, and in SFN by paresthesias, numbness, and impaired glucose metabolism (P < 0.01 each). Family history was informative for chronic pain and affective disorders in FMS (P < 0.001) and for neurological disorders in SFN patients (P < 0.001). Small fiber pathology in terms of skin denervation and/or thermal sensory threshold elevation was present in 110/158 (69.7 \%) FMS patients and 39/53 (73.6 \%) SFN patients. FMS patients mainly showed proximally reduced skin innervation and higher corneal nerve branch densities (p<0.001) whereas SFN patients were characterized by reduced cold detection and prolonged electrical A-delta conduction latencies (P < 0.05). Conclusions: Our data show that FMS and SFN differ substantially. Detailed pain, drug and family history, investigating blood glucose metabolism, and applying differential small fiber tests may help to improve diagnostic differentiation and targeted therapy.}, language = {en} } @article{ErbacherVaknineMoshitzkyetal.2022, author = {Erbacher, Christoph and Vaknine, Shani and Moshitzky, Gilli and Lobentanzer, Sebastian and Eisenberg, Lina and Evdokimov, Dimitar and Sommer, Claudia and Greenberg, David S. and Soreq, Hermona and {\"U}{\c{c}}eyler, Nurcan}, title = {Distinct CholinomiR blood cell signature as a potential modulator of the cholinergic system in women with fibromyalgia syndrome}, series = {Cells}, volume = {11}, journal = {Cells}, number = {8}, issn = {2073-4409}, doi = {10.3390/cells11081276}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270686}, year = {2022}, abstract = {Fibromyalgia syndrome (FMS) is a heterogeneous chronic pain syndrome characterized by musculoskeletal pain and other key co-morbidities including fatigue and a depressed mood. FMS involves altered functioning of the central and peripheral nervous system (CNS, PNS) and immune system, but the specific molecular pathophysiology remains unclear. Anti-cholinergic treatment is effective in FMS patient subgroups, and cholinergic signaling is a strong modulator of CNS and PNS immune processes. Therefore, we used whole blood small RNA-sequencing of female FMS patients and healthy controls to profile microRNA regulators of cholinergic transcripts (CholinomiRs). We compared microRNA profiles with those from Parkinson's disease (PD) patients with pain as disease controls. We validated the sequencing results with quantitative real-time PCR (qRT-PCR) and identified cholinergic targets. Further, we measured serum cholinesterase activity in FMS patients and healthy controls. Small RNA-sequencing revealed FMS-specific changes in 19 CholinomiRs compared to healthy controls and PD patients. qRT-PCR validated miR-182-5p upregulation, distinguishing FMS patients from healthy controls. mRNA targets of CholinomiRs bone morphogenic protein receptor 2 and interleukin 6 signal transducer were downregulated. Serum acetylcholinesterase levels and cholinesterase activity in FMS patients were unchanged. Our findings identified an FMS-specific CholinomiR signature in whole blood, modulating immune-related gene expression.}, language = {en} } @article{BolzoniEspostiMarcheseetal.2018, author = {Bolzoni, Francesco and Esposti, Roberto and Marchese, Silvia M. and Pozzi, Nicol{\´o} G. and Ramirez-Pasos, Uri E. and Isaias, Ioannis U. and Cavallari, Paolo}, title = {Disrupt of intra-limb APA pattern in parkinsonian patients performing index-finger flexion}, series = {Frontiers in Physiology}, volume = {9}, journal = {Frontiers in Physiology}, issn = {1664-042X}, doi = {10.3389/fphys.2018.01745}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369245}, year = {2018}, abstract = {Voluntary movements induce postural perturbations which are counteracted by anticipatory postural adjustments (APAs). These actions are known to build up long fixation chains toward available support points (inter-limb APAs), so as to grant whole body equilibrium. Moreover, recent studies highlighted that APAs also build-up short fixation chains, within the same limb where a distal segment is moved (intra-limb APAs), aimed at stabilizing the proximal segments. The neural structures generating intra-limb APAs still need investigations; the present study aims to compare focal movement kinematics and intra-limb APA latencies and pattern between healthy subjects and parkinsonian patients, assuming the latter as a model of basal ganglia dysfunction. Intra-limb APAs that stabilize the arm when the index-finger is briskly flexed were recorded in 13 parkinsonian patients and in 10 age-matched healthy subjects. Index-finger movement was smaller in parkinsonian patients vs. healthy subjects (p = 0.01) and more delayed with respect to the onset of the prime mover flexor digitorum superficialis (FDS, p < 0.0001). In agreement with the literature, in all healthy subjects the FDS activation was preceded by an inhibitory intra-limb APA in biceps brachii (BB) and anterior deltoid (AD), and almost simultaneous to an excitatory intra-limb APA in triceps brachii (TB). In parkinsonian patients, no significant differences were found for TB and AD intra-limb APA timings, however only four patients showed an inhibitory intra-limb APA in BB, while other four did not show any BB intra-limb APAs and five actually developed a BB excitation. The frequency of occurrence of normal sign, lacking, and inverted BB APAs was different in healthy vs. parkinsonian participants (p = 0.0016). The observed alterations in index-finger kinematics and intra-limb APA pattern in parkinsonian patients suggest that basal ganglia, in addition to shaping the focal movement, may also contribute to intra-limb APA control.}, language = {en} } @article{SteigerwaldMuellerJohannesetal.2016, author = {Steigerwald, Frank and M{\"u}ller, Lorenz and Johannes, Silvia and Matthies, Cordula and Volkmann, Jens}, title = {Directional deep brain stimulation of the subthalamic nucleus: a pilot study using a novel neurostimulation device}, series = {Movement Disorders}, volume = {31}, journal = {Movement Disorders}, number = {8}, doi = {10.1002/mds.26669}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-187683}, pages = {1240-1243}, year = {2016}, abstract = {Introduction A novel neurostimulation system allows steering current in horizontal directions by combining segmented leads and multiple independent current control. The aim of this study was to evaluate directional DBS effects on parkinsonian motor features and adverse effects of subthalamic neurostimulation. Methods Seven PD patients implanted with the novel directional DBS system for bilateral subthalamic DBS underwent an extended monopolar review session during the first postoperative week, in which current thresholds were determined for rigidity control and stimulation-induced adverse effects using either directional or ring-mode settings. Results Effect or adverse effect thresholds were modified by directional settings for each of the 14 STN leads. Magnitude of change varied markedly between leads, as did orientation of optimal horizontal current steering. Conclusion Directional current steering through chronically implanted segmented electrodes is feasible, alters adverse effect and efficacy thresholds in a highly individual manner, and expands the therapeutic window in a monopolar review as compared to ring-mode DBS.}, language = {en} } @article{SchuhmannLanghauserZimmermannetal.2023, author = {Schuhmann, Michael K. and Langhauser, Friederike and Zimmermann, Lena and Bellut, Maximilian and Kleinschnitz, Christoph and Fluri, Felix}, title = {Dimethyl fumarate attenuates lymphocyte infiltration and reduces infarct size in experimental stroke}, series = {International journal of molecular sciences}, volume = {24}, journal = {International journal of molecular sciences}, number = {21}, doi = {10.3390/ijms242115540}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357731}, year = {2023}, abstract = {Ischemic stroke is associated with exacerbated tissue damage caused by the activation of immune cells and the initiation of other inflammatory processes. Dimethyl fumarate (DMF) is known to modulate the immune response, activate antioxidative pathways, and improve the blood-brain barrier (BBB) after stroke. However, the specific impact of DMF on immune cells after cerebral ischemia remains unclear. In our study, male mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 min and received oral DMF (15 mg/kg) or a vehicle immediately after tMCAO, followed by twice-daily administrations for 7 days. Infarct volume was assessed on T2-weighted magnetic resonance images on days 1 and 7 after tMCAO. Brain-infiltrating immune cells (lymphocytes, monocytes) and microglia were quantified using fluorescence-activated cell sorting. DMF treatment significantly reduced infarct volumes and brain edema. On day 1 after tMCAO, DMF-treated mice showed reduced lymphocyte infiltration compared to controls, which was not observed on day 7. Monocyte and microglial cell counts did not differ between groups on either day. In the acute phase of stroke, DMF administration attenuated lymphocyte infiltration, probably due to its stabilizing effect on the BBB. This highlights the potential of DMF as a therapeutic candidate for mitigating immune cell-driven damage in stroke.}, language = {en} } @article{KarlGriesshammerUeceyleretal.2017, author = {Karl, Franziska and Grießhammer, Anne and {\"U}{\c{c}}eyler, Nurcan and Sommer, Claudia}, title = {Differential Impact of miR-21 on Pain and Associated Affective and Cognitive Behavior after Spared Nerve Injury in B7-H1 ko Mouse}, series = {Frontiers in Molecular Neuroscience}, volume = {10}, journal = {Frontiers in Molecular Neuroscience}, number = {219}, doi = {10.3389/fnmol.2017.00219}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170722}, year = {2017}, abstract = {MicroRNAs (miRNAs) are increasingly recognized as regulators of immune and neuronal gene expression and are potential master switches in neuropathic pain pathophysiology. miR-21 is a promising candidate that may link the immune and the pain system. To investigate the pathophysiological role of miR-21 in neuropathic pain, we assessed mice deficient of B7 homolog 1 (B7-H1), a major inhibitor of inflammatory responses. In previous studies, an upregulation of miR-21 had been shown in mouse lymphocytes. Young (8 weeks), middle-aged (6 months), and old (12 months) B7-H1 ko mice and wildtype littermates (WT) received a spared nerve injury (SNI). We assessed thermal withdrawal latencies and mechanical withdrawal thresholds. Further, we performed tests for anxiety-like and cognitive behavior. Quantitative real time PCR was used to determine miR-21 relative expression in peripheral nerves, and dorsal root ganglia (DRG) at distinct time points after SNI. We found mechanical hyposensitivity with increasing age of na{\"i}ve B7-H1 ko mice. Young and middle-aged B7-H1 ko mice were more sensitive to mechanical stimuli compared to WT mice (young: p < 0.01, middle-aged: p < 0.05). Both genotypes developed mechanical and heat hypersensitivity (p < 0.05) after SNI, without intergroup differences. No relevant differences were found after SNI in three tests for anxiety like behavior in B7-H1 ko and WT mice. Also, SNI had no effect on cognition. B7-H1 ko and WT mice showed a higher miR-21 expression (p < 0.05) and invasion of macrophages and T cells in the injured nerve 7 days after SNI without intergroup differences. Our study reveals that increased miR-21 expression in peripheral nerves after SNI is associated with reduced mechanical and heat withdrawal thresholds. These results point to a role of miR-21 in the pathophysiology of neuropathic pain, while affective behavior and cognition seem to be spared. Contrary to expectations, B7-H1 ko mice did not show higher miR-21 expression than WT mice, thus, a B7-H1 knockout may be of limited relevance for the study of miR-21 related pain.}, language = {en} } @article{BailNotzRovitusoetal.2017, author = {Bail, Kathrin and Notz, Quirin and Rovituso, Damiano M. and Schampel, Andrea and Wunsch, Marie and Koeniger, Tobias and Schropp, Verena and Bharti, Richa and Scholz, Claus-Juergen and Foerstner, Konrad U. and Kleinschnitz, Christoph and Kuerten, Stefanie}, title = {Differential effects of FTY720 on the B cell compartment in a mouse model of multiple sclerosis.}, series = {Journal of Neuroinflammation}, volume = {14}, journal = {Journal of Neuroinflammation}, number = {148}, doi = {10.1186/s12974-017-0924-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157869}, year = {2017}, abstract = {Background: MP4-induced experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS), which enables targeted research on B cells, currently much discussed protagonists in MS pathogenesis. Here, we used this model to study the impact of the S1P1 receptor modulator FTY720 (fingolimod) on the autoreactive B cell and antibody response both in the periphery and the central nervous system (CNS). Methods: MP4-immunized mice were treated orally with FTY720 for 30 days at the peak of disease or 50 days after EAE onset. The subsequent disease course was monitored and the MP4-specific B cell/antibody response was measured by ELISPOT and ELISA. RNA sequencing was performed to determine any effects on B cell-relevant gene expression. S1P\(_{1}\) receptor expression by peripheral T and B cells, B cell subset distribution in the spleen and B cell infiltration into the CNS were studied by flow cytometry. The formation of B cell aggregates and of tertiary lymphoid organs (TLOs) was evaluated by histology and immunohistochemistry. Potential direct effects of FTY720 on B cell aggregation were studied in vitro. Results: FTY720 significantly attenuated clinical EAE when treatment was initiated at the peak of EAE. While there was a significant reduction in the number of T cells in the blood after FTY720 treatment, B cells were only slightly diminished. Yet, there was evidence for the modulation of B cell receptor-mediated signaling upon FTY720 treatment. In addition, we detected a significant increase in the percentage of B220\(^{+}\) B cells in the spleen both in acute and chronic EAE. Whereas acute treatment completely abrogated B cell aggregate formation in the CNS, the numbers of infiltrating B cells and plasma cells were comparable between vehicle- and FTY720-treated mice. In addition, there was no effect on already developed aggregates in chronic EAE. In vitro B cell aggregation assays suggested the absence of a direct effect of FTY720 on B cell aggregation. However, FTY720 impacted the evolution of B cell aggregates into TLOs. Conclusions: The data suggest differential effects of FTY720 on the B cell compartment in MP4-induced EAE.}, language = {en} } @article{BrumbergSchroeterBlazhenetsetal.2020, author = {Brumberg, Joachim and Schr{\"o}ter, Nils and Blazhenets, Ganna and Frings, Lars and Volkmann, Jens and Lapa, Constantin and Jost, Wolfgang H. and Isaias, Ioannis U. and Meyer, Philipp T.}, title = {Differential diagnosis of parkinsonism: a head-to-head comparison of FDG PET and MIBG scintigraphy}, series = {NPJ Parkinsons Disease}, volume = {6}, journal = {NPJ Parkinsons Disease}, doi = {10.1038/s41531-020-00141-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230675}, year = {2020}, abstract = {[\(^{18}\)F]fluorodeoxyglucose (FDG) PET and [\(^{123}\)I]metaiodobenzylguanidine (MIBG) scintigraphy may contribute to the differential diagnosis of neurodegenerative parkinsonism. To identify the superior method, we retrospectively evaluated 54 patients with suspected neurodegenerative parkinsonism, who were referred for FDG PET and MIBG scintigraphy. Two investigators visually assessed FDG PET scans using an ordinal 6-step score for disease-specific patterns of Lewy body diseases (LBD) or atypical parkinsonism (APS) and assigned the latter to the subgroups multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal syndrome. Regions-of-interest analysis on anterior planar MIBG images served to calculate the heart-to-mediastinum ratio. Movement disorder specialists blinded to imaging results established clinical follow-up diagnosis by means of guideline-derived case vignettes. Clinical follow-up (1.7 +/- 2.3 years) revealed the following diagnoses: n = 19 LBD (n = 17 Parkinson's disease [PD], n = 1 PD dementia, and n = 1 dementia with Lewy bodies), n = 31 APS (n = 28 MSA, n = 3 PSP), n = 3 non-neurodegenerative parkinsonism; n = 1 patient could not be diagnosed and was excluded. Receiver operating characteristic analyses for discriminating LBD vs. non-LBD revealed a larger area under the curve for FDG PET than for MIBG scintigraphy at statistical trend level for consensus rating (0.82 vs. 0.69, p = 0.06; significant for investigator \#1: 0.83 vs. 0.69, p = 0.04). The analysis of PD vs. MSA showed a similar difference (0.82 vs. 0.69, p = 0.11; rater \#1: 0.83 vs. 0.69, p = 0.07). Albeit the notable differences in diagnostic performance did not attain statistical significance, the authors consider this finding clinically relevant and suggest that FDG PET, which also allows for subgrouping of APS, should be preferred.}, language = {en} } @article{PritchardFalkLarssonetal.2016, author = {Pritchard, Rory A. and Falk, Lovissa and Larsson, Mathilda and Leinders, Mathias and Sorkin, Linda S.}, title = {Different phosphoinositide 3-kinase isoforms mediate carrageenan nociception and inflammation}, series = {Pain}, volume = {157}, journal = {Pain}, number = {1}, doi = {10.1097/j.pain.0000000000000341}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-150248}, pages = {137-146}, year = {2016}, abstract = {Phosphoinositide 3-kinases (PI3Ks) participate in signal transduction cascades that can directly activate and sensitize nociceptors and enhance pain transmission. They also play essential roles in chemotaxis and immune cell infiltration leading to inflammation. We wished to determine which PI3K isoforms were involved in each of these processes. Lightly anesthetized rats (isoflurane) were injected subcutaneously with carrageenan in their hind paws. This was preceded by a local injection of 1\% DMSO vehicle or an isoform-specific antagonist to PI3K-α (compound 15-e), -β (TGX221), -δ (Cal-101), or -γ (AS252424). We measured changes in the mechanical pain threshold and spinal c-Fos expression (4 hours after injection) as indices of nociception. Paw volume, plasma extravasation (Evans blue, 0.3 hours after injection), and neutrophil (myeloperoxidase; 1 hour after injection) and macrophage (CD11b+; 4 hour after injection) infiltration into paw tissue were the measured inflammation endpoints. Only PI3K-γ antagonist before treatment reduced the carrageenan-induced pain behavior and spinal expression of c-Fos (P ≤ 0.01). In contrast, pretreatment with PI3K-α, -δ, and-γ antagonists reduced early indices of inflammation. Plasma extravasation PI3K-α (P ≤ 0.05), -δ (P ≤ 0.05), and -γ (P ≤ 0.01), early (0-2 hour) edema -α (P ≤ 0.05), -δ (P ≤ 0.001), and -γ (P ≤ 0.05), and neutrophil infiltration (all P ≤ 0.001) were all reduced compared to vehicle pretreatment. Later (2-4 hour), edema and macrophage infiltration (P ≤ 0.05) were reduced by only the PI3K-δ and -γ isoform antagonists, with the PI3K-δ antagonist having a greater effect on edema. PI3K-β antagonism was ineffective in all paradigms. These data indicate that pain and clinical inflammation are pharmacologically separable and may help to explain clinical conditions in which inflammation naturally wanes or goes into remission, but pain continues unabated.}, language = {en} }