TY - THES A1 - Brunder, Anna-Michelle T1 - Nodale und paranodale Autoantikörper bei inflammatorischen Polyneuropathien: Nachweis, Charakterisierung und Assoziation zu klinischen Verlaufsformen T1 - Nodal and paranodal autoantibodies in chronic inflammatoric polyneuropathies: Detection, characterization and assoziation with clinical course N2 - In den letzten Jahren gewann das Konzept der Paranodopathien als eigene Krankheitsentität der inflammatorischen Polyneuropathien zunehmend an Bedeutung. Die Forschung konzentrierte sich dabei überwiegend auf die chronisch inflammatorische Polyradikuloneuropathie (CIDP). In dieser Arbeit werden (para-)nodale Antikörper gegen Neurofascin-155, panNeurofascin, Contactin-1 und Caspr-1 in einer großen Kohorte von Patienten mit Guillain-Barré-Syndrom (GBS) und CIDP nachgewiesen. Patienten mit Anti-panNeurofascin-Antikörpern zeigten besonders schwere Verlaufsformen. Patienten mit anderen (para-)nodalen Antikörpern zeigten je nach IgG-Subklasse der Antikörper spezifische klinische Merkmale und ein unterschiedliches Ansprechen auf die Therapie. Die Arbeit zeigt, dass die Bestimmung (para-)nodaler Antikörper bei Patienten mit GBS und CIDP im klinischen Alltag zur Einordung der Prognose und Therapieplanung sinnvoll sein kann. N2 - In the last years the concept of paranodopathy as an own disease entity has gained more relevance. So far, most studies focused on chronic inflammatory polyneuropathy (CIDP). In this study, autoantibodies against neurofascin-155, pan-neurofascin, contactin-1, and capsr-1 in a cohort of Guillain-Barré-syndrome (GBS) and CIDP were detected. All patients with anti-pan-neurofascin-antibodies suffered from a very severe course of disease. Patients with other (para-)nodal autoantibodies showed common clinical features and therapeutic response depending on the autoantibody and their IgG-subclasses. This study shows that (para-)nodal autoantibodies should be determined in GBS and CIDP to estimate clinical course and therapeutic response. KW - Polyneuropathie KW - Guillain-Barré-Syndrom KW - Autoantikörper KW - Neurofascin KW - Contactin KW - Caspr KW - (Para-)nodale Autoantikörper Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-282185 ER - TY - THES A1 - Leinfelder, Teresa T1 - Untersuchung von Trainingseffekten bei der Verwendung einer auditorischen P300-basierten EEG Gehirn-Computer Schnittstelle mittels fMRI Analyse T1 - Investigation of training effects of a P300-based EEG brain-computer interface using fMRI analysis N2 - In dieser Dissertation untersuchten wir die neuronalen Korrelate des Training-Effektes einer auditorischen P300 Gehirn-Computer Schnittstelle mittels fMRI Analyse in einem prä-post Design mit zehn gesunden Testpersonen. Wir wiesen in drei Trainings-sitzungen einen Trainingseffekt in der EEG-Analyse der P300 Welle nach und fanden entsprechende Kontraste in einer prä-post Analyse von fMRI Daten, wobei in allen fünf Sitzungen das gleiche Paradigma verwendet wurde. In der fMRI Analyse fanden wir fol-gende Ergebnisse: in einem Target-/ Nichttarget Kontrast zeigte sich verstärkte Aktivie-rung in Generatorregionen der P300 Welle (temporale und inferiore frontale Regionen) und interessanterweise auch in motorassoziierten Arealen, was höhere kognitiver Pro-zesse wie Aufmerksamkeitslenkung und Arbeitsspeicher widerspiegeln könnte. Der Kon-trast des Trainingseffektes zeigte nach dem Training einen stärkeren Rebound Effekt im Sinne einer verstärkten Aktivierung in Generatorregionen der P300 Welle, was eine ver-besserte Erkennung und Prozessierung von Target-Stimuli reflektieren könnte. Eine Ab-nahme von Aktivierung in frontalen Arealen in diesem Kontrast könnte durch effizientere Abläufe kognitiver Prozesse und des Arbeitsgedächtnis erklärt werden. N2 - In this dissertation we investigated the neuronal correlates of the training effect of an auditory P300-based brain-computer interface using fMRI analysis in a prae-post de-sign in a group of ten healthy probands. We showed a training effect during three training sessions with EEG analysis of the P300 wave and found corresponding contrasts in a prae-post analysis of fMRI data, while using the same paradigma in all sessions. In the fMRI analysis we found the following results: in a target / nontarget contrast we found enhancement of activation in generator regions of the P300 wave such as temporal and inferior frontal areas and interestingly also in motor associated areas which could reflect higher cognitive processes such as attention and working memory. In the contrast of the effects of training we found a stronger rebound effect as a correlate of stronger activation after training in generator regions of P300, possibly reflecting better discrimination and processing of stimuli. The decrease of activation in frontal areas in this contrast could be explained by increased efficiency of cognitive processing and working memory through training. KW - Gehirn-Computer-Schnittstelle KW - Neurofeedback KW - Ereigniskorreliertes Potenzial KW - Funktionelle Kernspintomografie KW - auditorisches Neurofeedback Training KW - P300 Welle KW - EEG KW - BCI KW - ALS KW - auditory KW - fMRI Analyse KW - prä-post Design Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290683 ER - TY - THES A1 - Nguyen, Ngoc Bich T1 - Vitamin D bei Patienten mit idiopathischen Parkinson-Syndrom T1 - Vitamin D in patients with idiopathic Parkinson's disease N2 - In einer Vielzahl von epidemiologischen Studien zeigten Patienten, die an einem idiopathischen Parkinson-Syndrom (IPS) erkrankt waren, erniedrigte Vitamin D-Serumspiegel (25-(OH)-Vit D). Die Rolle von Vitamin D im Knochenstoffwechsel ist weitgehend bekannt, allerdings konnten Assoziationen zwischen Vitamin D und chronischen Erkrankungen, die das Nervensystem sowie das kardiovaskuläre und immunologische System betreffen, nachgewiesen werden. In Tiermodellen konnten anti-oxidative Effekte von Vitamin D im Nervensystem gezeigt werden. In den letzten Jahren häuften sich allerdings Studien, die gegen einen direkten Zusammenhang zwischen IPS und Vitamin D sprechen. Demnach stellt sich die Frage, ob dem gehäuften Auftreten eines Vitamin D-Mangels bei IPS-Patienten eine krankheitsspezifische Ursache zugrunde liegt oder ob diese lediglich ein unspezifisches krankheitsbegleitendes Phänomen darstellt. In der vorliegenden Arbeit wurden in einer retrospektiven Analyse Parkinson-Patienten aus der neurogerontopsychiatrischen Tagesklinik sowie der neurogeriatrischen Frührehastation der Neurologischen Klinik der Universitätsklinik Würzburg hinsichtlich ihres 25-(OH)-Vit D-Serumspiegel mit zwei Kontrollgruppen bestehend aus Patienten mit psychiatrischer bzw. anderweitig neurologischer Erkrankung, die keiner Parkinson-Erkrankung entsprach, verglichen. Im Anschluss wurde auf mögliche Konfounder sowie der Zusammenhang zwischen IPS-Risiko bzw. Krankheitsschwere und 25-(OH)-Vit D-Serumspiegel untersucht. Der mittlere 25-(OH)-Vit D-Serumspiegel der Neurologie-Gruppe war im Vergleich zur Psychiatrie-Gruppe signifikant niedriger. Der Unterschied zwischen IPS-Gruppe und Psychiatrie- bzw. Neurologie-Gruppe war nicht signifikant. Bei Hinzunahme von weiteren rekrutierten Parametern (Body-Mass-Index, Frailty, Sturzanamnese, Gehhilfe, CHA2DS2-VASc-Score, C-reaktives Protein, Hämoglobin) konnte kein signifikanter Unterschied zwischen der Neurologie- und Psychiatrie-Gruppe mehr gefunden werden. Das Risiko sowie die Krankheitsschwere einer Parkinson-Erkrankung, gemessen am Hoehn-Yahr-Stadium und den erreichten Werten im MDS UPDRS III, korrelierten mit dem Vitamin D-Serumspiegel. Allerdings war auch hier nach Hinzunahme von Kovariaten wie Alter, Geschlecht und Krankheitsdauer der Effekt nicht mehr signifikant. Die Ergebnisse unterstützen die Annahme, dass die vorgefundenen niedrigen 25-(OH)-Vit D-Serumspiegel bei Parkinson-Patienten ein krankheitsbegleitendes Phänomen ist, das womöglich durch die eingeschränkten motorischen Fähigkeiten mit resultierend niedriger Sonnenexposition bedingt ist und durch zunehmende Kranheitsdauer und damit Krankheitsschwere verstärkt wird. Da es sich jedoch beim IPS um eine Krankheit handelt, die zum Einen mit motorischen Einschränkungen und resultierend erhöhtem Sturzrisiko einhergeht und zum Anderen vorwiegend Menschen höheren Alters betrifft, besteht ein erhöhtes Osteoporose- und sturzbedingtes Frakturrisiko, sodass ein Monitoring des Vitamin D-Serumspiegels sowie eine gegebenenfalls notwendige Vitamin D-Supplementierung weiterhin eine Rolle in der Behandlung von Parkinson-Patienten spielen. N2 - A large number of primarily epidemiologic studies revealed low serum vitamin D in patients with idiopathic Parkinson’s disease (PD). The role of vitamin D in bone health is well-known, but there is also increasing evidence suggesting an association between vitamin D and chronic diseases affecting nervous, cardiovascular and immune system. Animal studies demonstrated antioxidative effects of pretreatment with vitamin D in central nervous system after exposure to neurotoxic substances. However, results of recent studies are inconsistent with prior findings as they could not show low vitamin D levels in PD. The objective of this study was to further evaluate the correlation between vitamin D and PD as there is the possibility of reverse causality: Either low vitamin D level as an independent factor is involved in the pathogenesis of PD or impaired physical mobility caused by the disease itself results in less sun exposure and therefore low vitamin D levels. This retrospective study examined serum vitamin D level of three patient cohorts affected by either PD, a psychiatric or neurologic disease other than PD. All groups were recruited from either the neurogerontopsychiatric day hospital or the early neurorehabilitation unit of the University Hospital Würzburg. Potential confounding variables were identified and vitamin D levels and risk as well as severity of PD using Part III of the Unified Parkinson’s Disease Rating Scale and Hoehn & Yahr Stage were examined. The prevalence of vitamin D insufficiency was higher in the neurologic cohort than in the PD and psychiatric cohort. After adjusting for potential confounding variables (Body mass index, frailty, history of falls, mobility devices, CHA2DS2-VASc-Score, C-reactive protein, hemoglobin) no statistically significant difference could be seen. In regard to PD risk and disease severity a correlation with vitamin D levels was also demonstrated but not significant after adjusting for confounders. The results of this study support the hypothesis that vitamin D level in patients with Parkinson’s disease is low because of disease- and frailty-mediated impaired mobility and consecutive reduced sun exposure. Therefore a disease progression with worsened motor symptoms can lower serum levels. In addition to the motor symptoms Parkinson’s disease occurs mostly in people of older age; thus, risk for fractures are higher in patients with PD compared to healthy controls. In summary, monitoring serum vitamin D levels and if required supplementation of vitamin D is still a necessary part in the treatment of Parkinson’s disease. KW - Vitamin D-Mangel KW - Parkinson-Krankheit KW - Vitamin D KW - Idiopathisches Parkinson-Syndrom KW - Neurogeriatrie Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223026 ER - TY - THES A1 - Stengel, Helena Maria T1 - Paranodale und nodale Autoantikörper: Charakterisierung der Anti-Neurofascin-Autoantikörper-assoziierten Neuropathie und Untersuchung des Effektes von Anti-Contactin-1-Autoantikörpern im Zellkulturmodell T1 - Paranodal and nodal autoantibodies: Characterization of the anti-neurofascin autoantibody-associated neuropathy and examination of the effect of anti-contactin-1 autoantibodies in a cell culture model N2 - Die (Para-)nodopathie ist neben der primär axonalen und der primär demyelinisierenden Polyneuropathie eine neue Krankheitsentität, die sich durch eine Schädigung der Funktion des Ranvierschen Schnürringes auszeichnet. Die Forschung zu (para-)nodalen Autoantikörpern fokussierte sich bislang hauptsächlich auf Neurofascin-155- und Contactin-1-Autoantikörper der Subklasse IgG4. In dieser Studie wurden die Seren von insgesamt 264 PatientInnen mit CIDP, GBS oder anderen Formen von Polyneuropathien mittels Bindungsassays an murinen Ischiadicuszupfnerven und gegebenenfalls ELISA auf (para-)nodale Autoantikörper gescrennt. Positive Autoantikörperbefunde wurden bei IgG-Autoantikörpern mittels Bindungsassays an transfizierten HEK-293-Zellen und bei IgM-Autoantikörpern mittels Western Blot bestätigt. ELISA Untersuchungen dienten zur näheren Spezifizierung. Weiterhin wurde die zeitabhängige Wirkung von Contactin-1-Autoantikörpern im Zellkulturmodell untersucht. Die im folgenden dargestellten Ergebnisse zeigen, dass die (Para-)nodopathie nicht auf die bisher am häufigsten beschriebene Erkrankung mit IgG4-Autoantikörpern beschränkt werden sollte. Bei dem extrem schwer betroffenen IgG-Patient 1 konnte ein Pan-Neurofascin-IgG3-Autoantikörper nachgewiesen werden. Als charakteristische Symptome für diese Autoantikörper konnten in Übereinstimmung mit weiteren Fallberichten Tetraplegie, Beatmungspflichtigkeit sowie eine schwere Hirnnervenbeteiligung bis zur Locked-In-Symptomatik identifiziert werden. Diese Patienten heben sich deutlich von den PatientInnen mit den bisher hauptsächlich beschriebenen Neurofascin-155-IgG4-Autoantikörpern ab, die wie IgG-Patient 2 charakteristischerweise in jungem Alter an einer CIDP mit Tremor ohne Besserung unter IVIG-Therapie leiden. Es wurden fünf PatientInnen mit Neurofascin-155-IgM-Autoantikörpern identifiziert, die eine akut beginnende Erkrankung mit Tetraparese, Tremor und neuropathischen Schmerzen zeigten. Ob sich dieser Phänotyp als charakteristisch für eine Neurofascin-155-IgM-(Para-)nodopathie bestätigt, sollte in weiteren Studien untersucht werden. Im murinen Zellkulturmodell an cerebellären Neuronen und Spinalganglienneuronen zeigte sich nach Inkubation mit Contactin-1-IgG-Patientenantikörpern eine zeitabhängige, rasch reversible Verminderung der Contactin-1-Protein-Expression in immunhistochemischen Färbungen sowie Western Blots, die durch eine Internalisierung des Contactin-1-Proteins erklärbar wäre. Der Angriff von Autoantikörpern an Spinalganglienneuronen und cerebellären Neurone sollte in weitere pathophysiologische Überlegungen miteinbezogen werden, da hierdurch typische Symptome der (Para-)nodopathie wie eine sensible Ataxie oder ein cerebellärer Tremor erklärt werden könnten. N2 - (Para-)nodopathy is besides primary axonal and primary demyelinating polyneuropathy a new disease entity characterized by damage to the function of the node of ranvier. Research on (para)nodal autoantibodies has up to now mainly focused on neurofascin-155 and contactin-1 autoantibodies of IgG4 subclass. In this study sera from 264 patients with CIDP, GBS, or other forms of polyneuropathies were screened for the presence of (para-)nodal autoantibodies by binding assays on murine sciatic nerve and ELISA. Positive autoantibody findings were confirmed by binding assays on transfected HEK-293 cells for IgG autoantibodies and by western blot for IgM autoantibodies. ELISA assays were used for further specification. Furthermore the time-dependent effect of contactin-1 autoantibodies was investigated in a cell culture model. The results, presented in the following, show that (para-)nodopathy should not be limited to the up to now most commonly described disease with IgG4 autoantibodies. In the extremely severely affected IgG patient 1 pan-neurofascin IgG3 autoantibodies were detected. In accordance with other case reports tetraplegia, the need for artificial ventilation and severe cranial nerve involvement up to locked-in syndrome could be identified as characteristic symptoms for these autoantibodies. These patients clearly differ from the patients with neurofascin-155 IgG4 autoantibodies, which have been mainly described so far and who, like IgG patient 2, characteristically suffer from CIDP with tremor, have a younger age of onset and do not show improvement under IVIG therapy. Five patients with neurofascin-155 IgM autoantibodies were identified, who showed acute onset disease with tetraparesis, tremor, and neuropathic pain. Whether this phenotype is confirmed to be characteristic of neurofascin-155 IgM (para-)nodopathy should be investigated in further studies. In the murine cell culture model of cerebellar granule neurons and dorsal root ganglion neurons, incubation with contactin-1 IgG patient antibodies showed a time-dependent, rapidly reversible decrease in contactin-1 protein expression in immunohistochemical staining as well as western blots, which could be explained by internalization of contactin-1 protein. The effect of autoantibodies on dorsal root ganglion neurons and cerebellar granule neurons should be considered in further pathophysiological considerations, as this could explain typical symptoms of (para-)nodopathy such as sensory ataxia or cerebellar tremor. KW - Ranvier-Schnürring KW - Polyneuropathie KW - Guillain-Barré-Syndrom KW - Autoantikörper KW - Zellkultur KW - Paranodale und nodale Autoantikörper KW - Anti-Neurofascin-Autoantikörper-assoziierten Neuropathie KW - Pan-Neurofascin-IgG3 KW - Neurofascin-155-IgG4-(Para-)nodopathie KW - Neurofascin-155-IgM KW - Effekte von Contactin-1-IgG-Patientenantikörpern im Zellkulturmodell Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-254662 ER - TY - THES A1 - Weigl, Anna T1 - Korrelation zwischen subjektiver Fatigue und objektiven physischen und kognitiven Einschränkungen bei Multipler Sklerose: eine Querschnittsstudie T1 - Correlation between subjective fatigue and objective physical and cognitive impairment in multiple sclerosis: a cross-sectional study N2 - Fatigue als ein „überwältigendes Gefühl von Müdigkeit, Energielosigkeit und Erschöpfung” stellt bei Patienten mit MS ein häufig auftretendes und oft im Alltag beeinträchtigendes Symptom dar, das sowohl mit körperlichen als auch mit kognitiven Erschöpfungssymptomen einhergeht. Die objektive Erfassung des Schweregrades der Fatigue beim einzelnen Patienten stellt ein Problem dar, da bisher keine objektiven Messverfahren zur Erfassung der Fatigue existieren. Im klinischen Alltag kommen meist Fragebögen zum Einsatz, die das Ausmaß der subjektiven Beeinträchtigung durch Fatigue im Alltag quantifizieren sollen. Ziel dieser Arbeit war es, zu untersuchen, inwieweit bestimmte im klinischen Alltag erhobene Parameter Rückschlüsse auf die subjektive Fatigue bei Patienten mit MS erlauben, auch im Hinblick darauf, ob sich einzelne Parameter besonders zur Einschätzung der körperlichen bzw. kognitiven Fatigue eignen. Zudem sollte untersucht werden, ob die untersuchten klinischen Parameter bei bestimmten Patientengruppen besser als bei anderen Rückschlüsse auf die subjektive Fatigue erlauben. Erfasst wurde die subjektive Fatigue durch das Würzburger Erschöpfungsinventar bei Multipler Sklerose (WEIMuS), einer Serie von Fragen, die zwischen körperlicher und kognitiver Fatigue unterscheiden. Dazu wurden Korrelationsanalysen zwischen der WEIMuS-Gesamtskala bzw. deren Subskalen für körperliche und kognitive Fatigue und EDSS-Wert, MSFC Z-Score einschließlich dessen Subscores und der Zeit des 50-Meter-Gehversuchs durchgeführt. Bezüglich der körperlichen Fatigue ergaben sich zwischen der WEIMuS-Subskala für körperliche Fatigue und dem EDSS sowie der Zeit des 50-Meter-Gehversuchs im Vergleich die stärksten, absolut gesehen als mittelstark zu wertende, Korrelationen. Bezüglich der kognitiven Fatigue ergab sich die stärkste Korrelation zwischen der WEIMuS-Subskala für kognitive Fatigue und dem PASAT3, die allerdings trotzdem als gering zu werten ist. Mit EDSS und 50-Meter-Gehversuch scheinen also zwei objektive klinische Parameter zu existieren, die in einem gewissen Maß auf die subjektive Fatigue rückschließen lassen. Ziel weiterer Untersuchungen wird es sein müssen, einen geeigneten klinischen Parameter zu finden, der bessere Rückschlüsse auf die subjektive kognitive Fatigue erlaubt als der PASAT3. Zwischen der WEIMuS-Gesamtskala bzw. deren Subskalen für körperliche und kognitive Fatigue und Alter, Geschlecht und Erkrankungsdauer fanden sich bestenfalls geringe Korrelationen, weshalb diese Parameter ungeeignet erscheinen, Aussagen über die subjektive Fatigue zu machen. Durch die Einteilung der Patienten nach Alter und Geschlecht konnte untersucht werden, inwieweit diese Parameter Einfluss auf die untersuchten Zusammenhänge zwischen klinischen Parametern und subjektiver Fatigue haben. Die Korrelationen zwischen den WEIMuS-Subskalen für körperliche und kognitive Fatigue mit den untersuchten klinischen Parametern waren für junge Patienten überwiegend stärker als für ältere Patienten, insbesondere ältere Männer. Somit scheinen die untersuchten klinischen Parameter bei jüngeren Patienten besser geeignet, Aussagen über die subjektive Fatigue zu machen als bei älteren. Insgesamt ist festzuhalten, dass EDSS und 50-Meter-Gehversuch insbesondere bei jungen Patienten zu einer besseren objektiven Beurteilbarkeit vor allem der körperlichen Fatigue im klinischen Alltag beitragen können. N2 - Fatigue as an "overwhelming feeling of tiredness, lack of energy and exhaustion" is a common and often disabling symptom in patients with MS, which is associated with both physical and cognitive symptoms of exhaustion. The objective assessment of the severity of fatigue in the individual patient is a problem, because so far no objective measurement methods exist for the assessment of fatigue. In clinical practice, questionnaires are usually used to quantify the extent of subjective impairment caused by fatigue in everyday life. The aim of this study was to investigate the extent to which certain parameters collected in everyday clinical practice allow conclusions to be drawn about subjective fatigue in patients with MS, also with regard to whether individual parameters are particularly suitable for assessing physical or cognitive fatigue. In addition, it should be investigated whether the examined clinical parameters allow better conclusions about the subjective fatigue in certain patient groups than in others. Subjective fatigue was assessed by the Würzburger Erschöpfungsinventar bei Multipler Sklerose (WEIMuS), a series of questions that distinguish between physical and cognitive fatigue. For this purpose, correlation analyses were performed between the WEIMuS total scale or its subscales for physical and cognitive fatigue and EDSS score, MSFC Z-score including its subscores, and the time of the 50-meter walk test. Regarding physical fatigue, the WEIMuS physical fatigue subscale and the EDSS and the time of the 50-meter walk test showed the strongest correlations in comparison, which could be considered medium in absolute terms. Regarding cognitive fatigue, the strongest correlation was found between the WEIMuS cognitive fatigue subscale and the PASAT3, which, however, should still be considered low. Thus, with EDSS and 50-meter walk test, two objective clinical parameters seem to exist that can be used to infer subjective fatigue to a certain extent. The aim of further investigations will have to be to find a suitable clinical parameter that allows better conclusions about subjective cognitive fatigue than the PASAT3. Between the WEIMuS total scale or its subscales for physical and cognitive fatigue and age, gender and duration of illness, at best only low correlations were found, which is why these parameters appear unsuitable for making statements about subjective fatigue. By classifying patients according to age and gender, it was possible to investigate the extent to which these parameters influence the correlations investigated between clinical parameters and subjective fatigue. The correlations between the WEIMuS physical and cognitive fatigue subscales with the clinical parameters studied were predominantly stronger for young patients than for older patients, especially older men. Thus, the clinical parameters studied appear to be better at providing information about subjective fatigue in younger patients than in older patients. Overall, it can be concluded that EDSS and 50-meter-walk test can contribute to a better objective assessability especially of physical fatigue in clinical practice, especially in young patients. KW - Multiple Sklerose KW - Fatigue Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218960 ER - TY - JOUR A1 - Schuhmann, Michael K. A1 - Bieber, Michael A1 - Franke, Maximilian A1 - Kollikowski, Alexander M. A1 - Stegner, David A1 - Heinze, Katrin G. A1 - Nieswandt, Bernhard A1 - Pham, Mirko A1 - Stoll, Guido T1 - Platelets and lymphocytes drive progressive penumbral tissue loss during middle cerebral artery occlusion in mice JF - Journal of Neuroinflammation N2 - Background In acute ischemic stroke, cessation of blood flow causes immediate tissue necrosis within the center of the ischemic brain region accompanied by functional failure in the surrounding brain tissue designated the penumbra. The penumbra can be salvaged by timely thrombolysis/thrombectomy, the only available acute stroke treatment to date, but is progressively destroyed by the expansion of infarction. The underlying mechanisms of progressive infarction are not fully understood. Methods To address mechanisms, mice underwent filament occlusion of the middle cerebral artery (MCAO) for up to 4 h. Infarct development was compared between mice treated with antigen-binding fragments (Fab) against the platelet surface molecules GPIb (p0p/B Fab) or rat immunoglobulin G (IgG) Fab as control treatment. Moreover, Rag1\(^{−/−}\) mice lacking T-cells underwent the same procedures. Infarct volumes as well as the local inflammatory response were determined during vessel occlusion. Results We show that blocking of the platelet adhesion receptor, glycoprotein (GP) Ibα in mice, delays cerebral infarct progression already during occlusion and thus before recanalization/reperfusion. This therapeutic effect was accompanied by decreased T-cell infiltration, particularly at the infarct border zone, which during occlusion is supplied by collateral blood flow. Accordingly, mice lacking T-cells were likewise protected from infarct progression under occlusion. Conclusions Progressive brain infarction can be delayed by blocking detrimental lymphocyte/platelet responses already during occlusion paving the way for ultra-early treatment strategies in hyper-acute stroke before recanalization. KW - ischemic penumbra KW - glycoprotein receptor Ib KW - T-cells KW - ischemic stroke KW - thrombo-inflammation KW - middle cerebral artery occlusion Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259172 VL - 18 IS - 1 ER - TY - JOUR A1 - Piroth, Tobias A1 - Boelmans, Kai A1 - Amtage, Florian A1 - Rijntjes, Michel A1 - Wierciochin, Anna A1 - Musacchio, Thomas A1 - Weiller, Cornelius A1 - Volkmann, Jens A1 - Klebe, Stephan T1 - Adult-Onset Niemann-Pick Disease Type C: Rapid Treatment Initiation Advised but Early Diagnosis Remains Difficult JF - Frontiers in Neurology N2 - Niemann–Pick type C disease (NP-C) presents with heterogeneous neurological and psychiatric symptoms. Adult onset is rare and possibly underdiagnosed due to frequent lack of specific and obvious key symptoms. For both early and adolescent/adult onset, the available data from studies and case reports describe a positive effect of Miglustat (symptom relief or stabilization). However, due to the low frequency of NP-C, experience with this therapy is still limited. We describe two adult-onset cases of NP-C. In both cases, vertical supranuclear gaze palsy was not recognized at symptom onset. Correct diagnosis was delayed from onset of symptoms by more than 10 years. The video demonstrates the broad spectrum of symptoms in later stages of the disease. Compared with published data, the treatment outcome observed in our cases after delayed initiation of Miglustat therapy was disappointing, with continuing disease progression in both cases. Thus, early treatment initiation could be necessary to achieve a good symptomatic effect. Hence, early biochemical testing for NP-C should be considered in patients suffering from atypical neurological/neuropsychological and psychiatric symptoms, even in cases of uncertainty. KW - Niemann–Pick disease type C KW - adult-onset KW - NPC1 gene KW - NPC2 gene KW - plasma oxysterols Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171001 VL - 8 IS - 108 ER - TY - JOUR A1 - Üçeyler, Nurcan A1 - Schließer, Mira A1 - Evdokimov, Dimitar A1 - Radziwon, Jakub A1 - Feulner, Betty A1 - Unterecker, Stefan A1 - Rimmele, Florian A1 - Walter, Uwe T1 - Reduced midbrain raphe echogenicity in patients with fibromyalgia syndrome JF - PloS One N2 - Objectives The pathogenesis of fibromyalgia syndrome (FMS) is unclear. Transcranial ultrasonography revealed anechoic alteration of midbrain raphe in depression and anxiety disorders, suggesting affection of the central serotonergic system. Here, we assessed midbrain raphe echogenicity in FMS. Methods Sixty-six patients underwent transcranial sonography, of whom 53 were patients with FMS (27 women, 26 men), 13 patients with major depression and physical pain (all women), and 14 healthy controls (11 women, 3 men). Raphe echogenicity was graded visually as normal or hypoechogenic, and quantified by digitized image analysis, each by investigators blinded to the clinical diagnosis. Results Quantitative midbrain raphe echogenicity was lower in patients with FMS compared to healthy controls (p<0.05), but not different from that of patients with depression and accompanying physical pain. Pain and FMS symptom burden did not correlate with midbrain raphe echogenicity as well as the presence and severity of depressive symptoms. Conclusion We found reduced echogenicity of the midbrain raphe area in patients with FMS and in patients with depression and physical pain, independent of the presence or severity of pain, FMS, and depressive symptoms. Further exploration of this sonographic finding is necessary before this objective technique may enter diagnostic algorithms in FMS and depression. KW - midbrain KW - fibromyalgia KW - depression KW - pain KW - ultrasound imaging KW - neuropathic pain KW - diagnostic medicine KW - migraine Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300639 VL - 17 IS - 11 ER - TY - JOUR A1 - Sommer, Claudia A1 - Carroll, Antonia S. A1 - Koike, Haruki A1 - Katsuno, Masahisa A1 - Ort, Nora A1 - Sobue, Gen A1 - Vucic, Steve A1 - Spies, Judith M. A1 - Doppler, Kathrin A1 - Kiernan, Matthew C. T1 - Nerve biopsy in acquired neuropathies JF - Journal of the Peripheral Nervous System N2 - A diagnosis of neuropathy can typically be determined through clinical assessment and focused investigation. With technological advances, including significant progress in genomics, the role of nerve biopsy has receded over recent years. However, making a specific and, in some cases, tissue-based diagnosis is essential across a wide array of potentially treatable acquired peripheral neuropathies. When laboratory investigations do not suggest a definitive diagnosis, nerve biopsy remains the final step to ascertain the etiology of the disease. The present review highlights the utility of nerve biopsy in confirming a diagnosis, while further illustrating the importance of a tissue-based diagnosis in relation to treatment strategies, particularly when linked to long-term immunosuppressive therapies, KW - inflammatory neuropathy KW - nerve biopsy KW - nerve tumor KW - neuroleukemiosis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259555 VL - 26 IS - S2 ER - TY - JOUR A1 - Karikari, Akua A. A1 - McFleder, Rhonda L. A1 - Ribechini, Eliana A1 - Blum, Robert A1 - Bruttel, Valentin A1 - Knorr, Susanne A1 - Gehmeyr, Mona A1 - Volkmann, Jens A1 - Brotchie, Jonathan M. A1 - Ahsan, Fadhil A1 - Haack, Beatrice A1 - Monoranu, Camelia-Maria A1 - Keber, Ursula A1 - Yeghiazaryan, Rima A1 - Pagenstecher, Axel A1 - Heckel, Tobias A1 - Bischler, Thorsten A1 - Wischhusen, Jörg A1 - Koprich, James B. A1 - Lutz, Manfred B. A1 - Ip, Chi Wang T1 - Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson’s disease mice JF - Brain, Behavior, and Immunity N2 - Background Antigen-specific neuroinflammation and neurodegeneration are characteristic for neuroimmunological diseases. In Parkinson’s disease (PD) pathogenesis, α-synuclein is a known culprit. Evidence for α-synuclein-specific T cell responses was recently obtained in PD. Still, a causative link between these α-synuclein responses and dopaminergic neurodegeneration had been lacking. We thus addressed the functional relevance of α-synuclein-specific immune responses in PD in a mouse model. Methods We utilized a mouse model of PD in which an Adeno-associated Vector 1/2 serotype (AAV1/2) expressing human mutated A53T-α-Synuclein was stereotactically injected into the substantia nigra (SN) of either wildtype C57BL/6 or Recombination-activating gene 1 (RAG1)\(^{-/-}\) mice. Brain, spleen, and lymph node tissues from different time points following injection were then analyzed via FACS, cytokine bead assay, immunohistochemistry and RNA-sequencing to determine the role of T cells and inflammation in this model. Bone marrow transfer from either CD4\(^{+}\)/CD8\(^{-}\), CD4\(^{-}\)/CD8\(^{+}\), or CD4\(^{+}\)/CD8\(^{+}\) (JHD\(^{-/-}\)) mice into the RAG-1\(^{-/-}\) mice was also employed. In addition to the in vivo studies, a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay was utilized. Results AAV-based overexpression of pathogenic human A53T-α-synuclein in dopaminergic neurons of the SN stimulated T cell infiltration. RNA-sequencing of immune cells from PD mouse brains confirmed a pro-inflammatory gene profile. T cell responses were directed against A53T-α-synuclein-peptides in the vicinity of position 53 (68–78) and surrounding the pathogenically relevant S129 (120–134). T cells were required for α-synuclein-induced neurodegeneration in vivo and in vitro, while B cell deficiency did not protect from dopaminergic neurodegeneration. Conclusions Using T cell and/or B cell deficient mice and a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay, we confirmed in vivo and in vitro that pathogenic α-synuclein peptide-specific T cell responses can cause dopaminergic neurodegeneration and thereby contribute to PD-like pathology. KW - Parkinson’s disease KW - α-synuclein-specific T cells KW - neurodegeneration Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300600 VL - 101 SP - 194 EP - 210 ER - TY - JOUR A1 - Peseschkian, Tara A1 - Cordts, Isabell A1 - Günther, René A1 - Stolte, Benjamin A1 - Zeller, Daniel A1 - Schröter, Carsten A1 - Weyen, Ute A1 - Regensburger, Martin A1 - Wolf, Joachim A1 - Schneider, Ilka A1 - Hermann, Andreas A1 - Metelmann, Moritz A1 - Kohl, Zacharias A1 - Linker, Ralf A. A1 - Koch, Jan Christoph A1 - Büchner, Boriana A1 - Weiland, Ulrike A1 - Schönfelder, Erik A1 - Heinrich, Felix A1 - Osmanovic, Alma A1 - Klopstock, Thomas A1 - Dorst, Johannes A1 - Ludolph, Albert C. A1 - Boentert, Matthias A1 - Hagenacker, Tim A1 - Deschauer, Marcus A1 - Lingor, Paul A1 - Petri, Susanne A1 - Schreiber-Katz, Olivia T1 - A nation-wide, multi-center study on the quality of life of ALS patients in Germany JF - Brain Sciences N2 - Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (β = −1.96 per increase of one point in the ALSFRS-R score, p < 0.001). “Limb-onset” ALS (lALS) was associated with a better QoL than “bulbar-onset” ALS (bALS) (mean ALSAQ-5 total score 55.46 versus 60.99, p = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (β = −7.60, p = 0.001), being tracheostomized (β = −14.80, p = 0.004) and using non-invasive ventilation (β = −5.71, p = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (β = 5.95, p = 0.007), and increasing age (β = 0.18, p = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care. KW - Amyotrophic Lateral Sclerosis (ALS) KW - Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) KW - ALS treatment KW - “bulbar-onset” ALS (bALS) KW - “limb-onset” ALS (lALS) KW - EuroQol Five Dimension Five Level Scale (EQ-5D-5L) KW - health-related quality of life (HRQoL) KW - quality of life (QoL) KW - symptom-specific treatment KW - assistive devices Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234147 SN - 2076-3425 VL - 11 IS - 3 ER - TY - JOUR A1 - Kremer, Naomi I. A1 - Pauwels, Rik W. J. A1 - Pozzi, Nicolò G. A1 - Lange, Florian A1 - Roothans, Jonas A1 - Volkmann, Jens A1 - Reich, Martin M. T1 - Deep Brain Stimulation for Tremor: Update on Long-Term Outcomes, Target Considerations and Future Directions JF - Journal of Clinical Medicine N2 - Deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus is one of the main advanced neurosurgical treatments for drug-resistant tremor. However, not every patient may be eligible for this procedure. Nowadays, various other functional neurosurgical procedures are available. In particular cases, radiofrequency thalamotomy, focused ultrasound and radiosurgery are proven alternatives to DBS. Besides, other DBS targets, such as the posterior subthalamic area (PSA) or the dentato-rubro-thalamic tract (DRT), may be appraised as well. In this review, the clinical characteristics and pathophysiology of tremor syndromes, as well as long-term outcomes of DBS in different targets, will be summarized. The effectiveness and safety of lesioning procedures will be discussed, and an evidence-based clinical treatment approach for patients with drug-resistant tremor will be presented. Lastly, the future directions in the treatment of severe tremor syndromes will be elaborated. KW - deep brain stimulation KW - tremor KW - essential tremor KW - Parkinson’s disease KW - outcomes KW - clinical approach KW - target considerations KW - future directions Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244982 SN - 2077-0383 VL - 10 IS - 16 ER - TY - JOUR A1 - Samper Agrelo, Iria A1 - Schira-Heinen, Jessica A1 - Beyer, Felix A1 - Groh, Janos A1 - Bütermann, Christine A1 - Estrada, Veronica A1 - Poschmann, Gereon A1 - Bribian, Ana A1 - Jadasz, Janusz J. A1 - Lopez-Mascaraque, Laura A1 - Kremer, David A1 - Martini, Rudolf A1 - Müller, Hans Werner A1 - Hartung, Hans Peter A1 - Adjaye, James A1 - Stühler, Kai A1 - Küry, Patrick T1 - Secretome analysis of mesenchymal stem cell factors fostering oligodendroglial differentiation of neural stem cells in vivo JF - International Journal of Molecular Sciences N2 - Mesenchymal stem cell (MSC)-secreted factors have been shown to significantly promote oligodendrogenesis from cultured primary adult neural stem cells (aNSCs) and oligodendroglial precursor cells (OPCs). Revealing underlying mechanisms of how aNSCs can be fostered to differentiate into a specific cell lineage could provide important insights for the establishment of novel neuroregenerative treatment approaches aiming at myelin repair. However, the nature of MSC-derived differentiation and maturation factors acting on the oligodendroglial lineage has not been identified thus far. In addition to missing information on active ingredients, the degree to which MSC-dependent lineage instruction is functional in vivo also remains to be established. We here demonstrate that MSC-derived factors can indeed stimulate oligodendrogenesis and myelin sheath generation of aNSCs transplanted into different rodent central nervous system (CNS) regions, and furthermore, we provide insights into the underlying mechanism on the basis of a comparative mass spectrometry secretome analysis. We identified a number of secreted proteins known to act on oligodendroglia lineage differentiation. Among them, the tissue inhibitor of metalloproteinase type 1 (TIMP-1) was revealed to be an active component of the MSC-conditioned medium, thus validating our chosen secretome approach. KW - neural stem cells KW - mesenchymal stem cells KW - transplantation KW - oligodendroglia KW - glial fate modulation KW - myelin KW - spinal cord KW - secretome KW - TIMP-1 Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285465 SN - 1422-0067 VL - 21 IS - 12 ER - TY - JOUR A1 - Peterka, Manuel A1 - Odorfer, Thorsten A1 - Schwab, Michael A1 - Volkmann, Jens A1 - Zeller, Daniel T1 - LSVT-BIG therapy in Parkinson's disease: physiological evidence for proprioceptive recalibration JF - BMC Neurology N2 - Background There is growing evidence for proprioceptive dysfunction in patients with Parkinson's disease (PD). The Lee Silvermann Voice Treatment-BIG therapy (LSVT-BIG), a special training program aiming at an increase of movement amplitudes in persons with PD (PwPD), has shown to be effective on motor symptoms. LSVT-BIG is conceptionally based on improving bradykinesia, in particular the decrement of repetitive movements, by proprioceptive recalibration. Objective To assess proprioceptive impairment in PwPD as compared to matched controls and to probe potential recalibration effects of the LSVT-BIG therapy on proprioception. Methods Proprioceptive performance and fine motor skills were assessed in 30 PwPD and 15 matched controls. Measurements with significant impairment in PwPD were chosen as outcome parameters for a standardized 4 weeks amplitude-based training intervention (LSVT-BIG) in 11 PwPD. Proprioceptive performance served as primary outcome measure. Secondary outcome measures included the motor part of the MDS-UPDRS, the nine-hole-peg test, and a questionnaire on quality of life. Post-interventional assessments were conducted at weeks 4 and 8. Results Compared to the control group, PwPD showed significantly larger pointing errors. After 4 weeks of LSVT-BIG therapy and even more so after an additional 4 weeks of continued training, proprioceptive performance improved significantly. In addition, quality of life improved as indicated by a questionnaire. Conclusion LSVT-BIG training may achieve a recalibration of proprioceptive processing in PwPD. Our data indicates a probable physiological mechanism of a symptom-specific, amplitude-based behavioral intervention in PwPD. KW - Proprioception KW - Amplitude KW - Training KW - Pointing error KW - LSVT-big therapy Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230084 VL - 20 ER - TY - THES A1 - Stößel, Anna T1 - Auswirkungen zerebellärer Gleichstromstimulation auf das motorische Lernen bei gesunden älteren Probanden T1 - Effects of cerebellar anodal transcranial direct current stimulation on motor learning in healthy older adults N2 - Sowohl neurologische Erkrankungen als auch der natürliche Alterungsprozess gehen regelhaft mit einem Untergang von Neuronen einher und bedingen neurologische Funktionsverluste. Diese mit Hilfe nicht-invasiver Techniken, beispielsweise tDCS, zu reduzieren, stellt ein wichtiges Ziel der neurowissenschaftlichen Forschung dar. Neben Arbeiten, die tDCS-Effekte auf das motorische Lernen bei Stimulation des motorischen Kortex nachweisen konnten, gibt es auch Hinweise für solche Effekte bei Stimulation des Kleinhirns. Allerdings besteht derzeit noch eine hohe Variabilität und damit einhergehend eine schlechte Vergleichbarkeit der Studien bezüglich ihrer Stimulationsbedingungen. Das Ansprechen unterschiedlicher Altersgruppen bleibt unklar. In der vorliegenden Arbeit wurden die Effekte zerebellärer a-tDCS auf das motorische Lernen bei gesunden älteren Probanden untersucht. Im Cross-over-Design wurde zu unterschiedlichen Zeitpunkten (vor bzw. nach der motorischen Aufgabe) stimuliert und im 24-Stunden-Verlauf die Langzeitwirkung evaluiert. Gruppe A erhielt vor einer motorischen Übungsaufgabe eine zerebelläre Stimulation, entweder als a-tDCS oder Scheinstimulation, Gruppe B nach der Übungsaufgabe. Zur Überprüfung der Effekte auf das Sequenzlernen diente der Finger-Tapping-Task. Der Lernerfolg wurde anhand der Genauigkeit, der Sequenzdauer und des Skill-Index gemessen. Die Ergebnisse deuten darauf hin, dass eine zerebelläre a-tDCS vor einer Übungsaufgabe zu einer Verbesserung der Konsolidierung der Fähigkeit, eine Zahlenfolge möglichst schnell und gleichzeitig genau einzutippen, führt, während die Stimulation nach einer Übungsaufgabe das motorische Lernen nicht zu beeinflussen scheint. Insgesamt stützen die Ergebnisse zum Teil die bisherigen Hinweise, dass eine zerebellär applizierte a-tDCS das motorische Lernen verbessern kann. Aufgrund einiger Limitationen, besonders der geringen Gruppengröße, verbleibt dieses Ergebnis jedoch vorläufig und bedarf einer Bestätigung in größeren Probandengruppen. Es bleibt von hohem Interesse, die optimalen Bedingungen für die Anwendung von tDCS am Kleinhirn zu definieren, um motorische Lernprozesse positiv zu beeinflussen. Dies ist die Voraussetzung dafür, zerebelläre tDCS mittelfristig auch zu therapeutischen Zwecken anwenden zu können. N2 - Neurological diseases as well as the natural aging process are regularly accompanied by a loss of neurons resulting into a loss of neurological function. Reducing these impactswith the help of non-invasive techniques, such as transcranial direct current stiumulation (tDCS), is an important goal of neuroscientific research. In addition to studies successfully providing evidence that tDCS is impacting motor learning when stimulating the motor cortex, indication of similar effects exist when stimulating the cerebellum. Unfortunately studies today only provide poor comparability given the underlying inconsistency in stimulation conditions and consequentially yielded results. The response of different age groups remains unclear. The following study explores the effects of cerebellar anodal transranial direct current simulation (a-tDSC) on healthy elderly subjects. Using a crossover design, patience were stimulated at different times (before or after the motor task) and long-term effects were evaluated over a 24-hour period. Group A received cerebellar stimulation prior to a motor exercise in form of an actual a-tDCS or sham stimulation, Group B received treatment after the exercise. The finger tapping task was used to verify the effects on sequence learning. Learning success was measured by accuracy, sequence duration, and skill index. The results indicate that cerebellar a-tDCS prior to the exercise task leads to enhanced consolidation of the ability to type a sequence of numbers quickly and accurately at the same time, whereas stimulation after the exercise task does not seem to affect motor learning. Overall, the results partially support previous evidence that cerebellar applied a-tDCS can improve motor learning. Due to some limitations, in particular the small sample size, results are preliminary and require confirmation across a larger population. Defining the optimal conditions for the application of tDCS to the cerebellum to positively influence motor learning processes remains of high interest. It is the prerequisite to enable application of cerebellar tDCS for therapeutic purposes in the medium term. KW - Motorisches Lernen KW - Kleinhirn KW - transkranielle Gleichstromstimulation (tDCS) KW - finger-tapping task (FTT) KW - zerebelläre Gleichstromstimulation KW - motor learning KW - tDCS Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-317930 ER - TY - THES A1 - Nehen, Mathias Julius T1 - Modulation der Schrankenfunktion primärer humaner zerebraler Endothelzellen durch Fumarsäureester unter inflammatorischen und nicht-inflammatorischen Bedingungen T1 - Fumaracids modulation on the barrier of primary human cerebral endothelia cells in inflammatory and non-imflammatory conditions N2 - Die Multiple Sklerose ist eine bisher nicht heilbare, chronisch-inflammatorische demyelinisierende Erkrankung des zentralen Nervensystems. Trotz intensiver Forschungsbemühungen ist der exakte Pathomechanismus nicht vollkommen verstanden. Klar ist jedoch, dass der Blut-Hirn-Schranke eine entscheidende Rolle bei der Pathogenese zukommt. Seit Februar 2014 ist mit Dimethylfumarat ein neues orales Medikament für die schubförmige Multiple Sklerose zugelassen. Die Wirkungen von Fumarsäureestern auf humane zerebrale Endothelzellen als Grundsteine der Blut-Hirn-Schranke sind allerdings nur unzureichend untersucht. Mehrere Forschungsgruppen demonstrierten an humanem Nabelschnurvenenendothel einen hemmenden Effekt von Fumarsäureestern auf die Adhäsion von Leukozyten und beschrieben eine Inhibition der Aktivierung des proinflammatorischen Transkriptionsfaktors NFB in den Endothelzellen. Aufgrund der charakteristischen Eigenschaften zerebralen Endothels ist eine Übertragung dieser Beobachtungen auf die Blut-Hirn-Schranke allerdings nicht ohne weiteres möglich. Daher galt es potentielle Effekte von Fumarsäureestern auf primäre humane zerebrale Endothelzellen als in vitro Modell der Blut-Hirn-Schranke zu überprüfen. Dabei wurden die Zellen nicht nur unter ruhenden Bedingungen, sondern auch unter inflammatorischer Stimulation mit TNF-α, IL-1 und IFN untersucht, einem Milieu, wie es in inflammatorischen MS Läsionen zu finden ist. In Leukozyten-Adhäsionsassays konnte durch Inkubation mit Monomethylfumarat und Dimethylfumarat keine funktionale Beeinflussung der Adhäsion von T-Lymphozyten an den verwendeten zerebralen Endothelzellen verzeichnet werden. Kongruent dazu fand sich in durchflusszytometrischen Analysen keine Hemmung der inflammatorisch vermittelten Expression des Adhäsionsmoleküls ICAM-1, welches eine tragende Rolle bei der Leukozytenmigration spielt. Inflammatorische intrazelluläre Signalwege, wie die NFB-Kerntranslokation oder die Phosphorylierung von p38 wurden in HECE im Gegensatz zu HUVEC durch Fumarsäureester ebenso wenig beeinflusst. Diese in sich konsistenten Ergebnisse führen zu der Schlussfolgerung, dass im Gegensatz zu anderen Gefäßbetten weder Dimethylfumarat noch Monomethylfumarat direkt am zerebralen Endothel anti-inflammatorisch wirken. N2 - Dimethyl fumarate (DMF) is approved for disease-modifying treatment of patients with relapsing-remitting multiple sclerosis. Animal experiments suggested that part of its therapeutic effect is due to a reduction of T-cell infiltration of the central nervous system (CNS) by uncertain mechanisms. Here we evaluated whether DMF and its primary metabolite monomethyl fumarate (MMF) modulate pro-inflammatory intracellular signaling and T-cell adhesiveness of nonimmortalized single donor human brain microvascular endothelial cells at low passages. Neither DMF nor MMF at concentrations of 10 or 50 μM blocked the IL-1β-induced nuclear translocation of NF-κB/p65, whereas the higher concentration of DMF inhibited the nuclear entry of p65 in human umbilical vein endothelium cultured in parallel. DMF and MMF also did not alter the IL-1β-stimulated activation of p38 MAPK in brain endothelium. Furthermore, neither DMF nor MMF reduced the basal or IL-1β-inducible expression of ICAM-1. In accordance, both fumaric acid esters did not reduce the adhesion of activated Jurkat T cells to brain endothelium under basal or inflammatory conditions. Therefore, brain endothelial cells probably do not directly mediate a potential blocking effect of fumaric acid esters on the inflammatory infiltration of the CNS by T cells. KW - Multiple Sklerose KW - Blut-Hirn-Schranke KW - Dimethylfumarat Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240925 ER - TY - THES A1 - Soda, Hassan T1 - Interdisziplinäres Schlaganfallmanagement anhand des Stroke Manager Programms – Studiendaten und Perspektiven für die Schlaganfallversorgung T1 - Interdisciplinary stroke management using the Stroke Manager program – study data and perspectives for stroke care N2 - Die Schlaganfallnachsorge in Deutschland wird von verschiedenen Leistungserbringern geprägt, die teilweise komplementäre und komplexe Dienstleistungen erbringen und sektorenübergreifend arbeiten. In Bad Neustadt wurde in Kooperation mit der Universität Würzburg und dem Zentrum für Telemedizin Bad Kissingen das Stroke Manager Programm entwickelt und evaluiert. Das strukturierte Nachsorgeprogramm Stroke Manager basiert auf einer standardisierten Informations- und Software Unterstützung von der Akutversorgung bis drei Monate nach Entlassung aus der stationären Versorgung. Anhand der Ergebnisse des Stroke Manager Programms konnte eine vergleichsweise hohe Persistenz bzgl. der stationär verordneten medikamentösen Sekundärprävention über einen Zeitraum von drei Monaten festgestellt werden, ebenso konnten wir nachweisen, dass sich das Programm positiv auf die Versorgungsqualität sowie die Patientenzufriedenheit nach Schlaganfall auswirken kann. Die im Stroke Manager-Programm betreuten Schlaganfallpatienten wiesen im Vergleich signifikante Unterschiede bei den Faktoren Rauchverhalten, Schlaganfallschweregrad und subjektive, globale Lebensqualität auf. N2 - Stroke aftercare in Germany is shaped by different service providers, some of whom provide complementary and complex services and work across sectors. In Bad Neustadt, the Stroke Manager Program was developed and evaluated in cooperation with the University of Würzburg and the Centre for Telemedicine Bad Kissingen. The structured aftercare program Stroke Manager is based on standardized information and software support from acute care up to three months after discharge from inpatient care. Based on the results of the Stroke Manager program, a comparatively high persistence of inpatient secondary drug prevention was observed over a period of three months, and we were able to demonstrate that the program can have a positive impact on the quality of care and patient satisfaction after stroke. The stroke patients treated in the Stroke Manager program showed significant differences in smoking behaviour, stroke severity and subjective, global quality of life. KW - Stroke Manager KW - medikamentöse Sekundärprävention bei stroke KW - Lebensqualität nach stroke Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242061 ER - TY - JOUR A1 - Schulte, Annemarie A1 - Blum, Robert T1 - Shaped by leaky ER: Homeostatic Ca\(^{2+}\) fluxes JF - Frontiers in Physiology N2 - At any moment in time, cells coordinate and balance their calcium ion (Ca\(^{2+}\)) fluxes. The term ‘Ca\(^{2+}\) homeostasis’ suggests that balancing resting Ca2+ levels is a rather static process. However, direct ER Ca\(^{2+}\) imaging shows that resting Ca\(^{2+}\) levels are maintained by surprisingly dynamic Ca\(^{2+}\) fluxes between the ER Ca\(^{2+}\) store, the cytosol, and the extracellular space. The data show that the ER Ca\(^{2+}\) leak, continuously fed by the high-energy consuming SERCA, is a fundamental driver of resting Ca\(^{2+}\) dynamics. Based on simplistic Ca\(^{2+}\) toolkit models, we discuss how the ER Ca\(^{2+}\) leak could contribute to evolutionarily conserved Ca\(^{2+}\) phenomena such as Ca\(^{2+}\) entry, ER Ca\(^{2+}\) release, and Ca\(^{2+}\) oscillations. KW - Ca2+ homeostasis KW - Ca2+ ion analysis KW - ER Ca2+ store KW - ER Ca2+ imaging KW - SERCA KW - store-operated Ca2+ entry KW - Ca2+ leak KW - Ca2+ oscillation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-287102 SN - 1664-042X VL - 13 ER - TY - JOUR A1 - Sommer, Claudia A1 - Klose, Petra A1 - Welsch, Patrick A1 - Petzke, Frank A1 - Häuser, Winfried T1 - Opioids for chronic non‐cancer neuropathic pain. An updated systematic review and meta‐analysis of efficacy, tolerability and safety in randomized placebo‐controlled studies of at least 4 weeks duration JF - European Journal of Pain N2 - Background and Objective This updated systematic review evaluated the efficacy, tolerability and safety of opioids compared to placebo in chronic non‐cancer neuropathic pain. Databases and Data Treatment Clinicaltrials.gov, CENTRAL, PubMed and PsycINFO were searched from October 2013 to June 2019. Randomized controlled trials comparing opioids with placebo and at least 4 weeks double‐blinded duration were analysed. Primary outcomes were pain relief of 50% or greater, disability, tolerability and safety. Effects were summarized by a random effects model using risk differences (RD) or standardized mean differences (SMD). We added four new studies with 662 participants for a total of 16 included studies with 2,199 participants. Study duration ranged between 4 and 12 weeks. Studies with a parallel and cross‐over design: Based on low to moderate quality evidence, opioids (buprenorphine, hydromorphone, morphine, oxycodone, tramadol) provided a clinically relevant pain relief of 50% or greater and reduction of disability compared to placebo. There was no clinically relevant harm with regards to the drop out rate due to adverse and serious adverse events by opioids compared to placebo. Enriched enrolment randomized withdrawal design: Based on low to moderate quality evidence, tapentadol provided a clinically relevant pain relief of 50% or greater and reduction of disability compared to placebo in diabetic polyneuropathy. There was no clinically relevant harm with regards to the drop out rate due to adverse and serious adverse events by tapentadol compared to placebo. Conclusions Some opioids provided a short‐term substantial pain relief in highly selected patients in some neuropathic pain syndromes. Significance Some opioids (buprenorphine, morphine, oxycodone, tramadol, tapentadol) provide substantial pain relief compared to placebo in postherpetic neuralgia and peripheral neuropathies of different aetiologies for 4–12 weeks. There is insufficient evidence to support or refute the suggestion that these drugs are effective in other neuropathic pain conditions. The safety of opioids with regards to abuse and deaths in the studies analysed cannot be extrapolated to routine clinical care. Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218487 VL - 24 IS - 1 SP - 3 EP - 18 ER - TY - JOUR A1 - Deeb, Wissam A1 - Giordano, James J. A1 - Rossi, Peter J. A1 - Mogilner, Alon Y. A1 - Gunduz, Aysegul A1 - Judy, Jack W. A1 - Klassen, Bryan T. A1 - Butson, Christopher R. A1 - Van Horne, Craig A1 - Deny, Damiaan A1 - Dougherty, Darin D. A1 - Rowell, David A1 - Gerhardt, Greg A. A1 - Smith, Gwenn S. A1 - Ponce, Francisco A. A1 - Walker, Harrison C. A1 - Bronte-Stewart, Helen M. A1 - Mayberg, Helen S. A1 - Chizeck, Howard J. A1 - Langevin, Jean-Philippe A1 - Volkmann, Jens A1 - Ostrem, Jill L. A1 - Shute, Jonathan B. A1 - Jimenez-Shahed, Joohi A1 - Foote, Kelly D. A1 - Wagle Shukla, Aparna A1 - Rossi, Marvin A. A1 - Oh, Michael A1 - Pourfar, Michael A1 - Rosenberg, Paul B. A1 - Silburn, Peter A. A1 - de Hemptine, Coralie A1 - Starr, Philip A. A1 - Denison, Timothy A1 - Akbar, Umer A1 - Grill, Warren M. A1 - Okun, Michael S. T1 - Proceedings of the Fourth Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies JF - Frontiers in Integrative Neuroscience N2 - This paper provides an overview of current progress in the technological advances and the use of deep brain stimulation (DBS) to treat neurological and neuropsychiatric disorders, as presented by participants of the Fourth Annual DBS Think Tank, which was convened in March 2016 in conjunction with the Center for Movement Disorders and Neurorestoration at the University of Florida, Gainesveille FL, USA. The Think Tank discussions first focused on policy and advocacy in DBS research and clinical practice, formation of registries, and issues involving the use of DBS in the treatment of Tourette Syndrome. Next, advances in the use of neuroimaging and electrochemical markers to enhance DBS specificity were addressed. Updates on ongoing use and developments of DBS for the treatment of Parkinson's disease, essential tremor, Alzheimer's disease, depression, post-traumatic stress disorder, obesity, addiction were presented, and progress toward innovation(s) in closed-loop applications were discussed. Each section of these proceedings provides updates and highlights of new information as presented at this year's international Think Tank, with a view toward current and near future advancement of the field. KW - deep brain stimulation KW - Parkinson’s disease KW - Alzheimer’s disease KW - closed-loop KW - depression KW - post-traumatic stress disorder KW - Tourette syndrome KW - DARPA Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168493 VL - 10 IS - 38 ER -