TY - JOUR A1 - Traub, Jan A1 - Otto, Markus A1 - Sell, Roxane A1 - Homola, György A. A1 - Steinacker, Petra A1 - Oeckl, Patrick A1 - Morbach, Caroline A1 - Frantz, Stefan A1 - Pham, Mirko A1 - Störk, Stefan A1 - Stoll, Guido A1 - Frey, Anna T1 - Serum glial fibrillary acidic protein indicates memory impairment in patients with chronic heart failure JF - ESC Heart Failure N2 - Aims Cognitive dysfunction occurs frequently in patients with heart failure (HF), but early detection remains challenging. Serum glial fibrillary acidic protein (GFAP) is an emerging biomarker of cognitive decline in disorders of primary neurodegeneration such as Alzheimer's disease. We evaluated the utility of serum GFAP as a biomarker for cognitive dysfunction and structural brain damage in patients with stable chronic HF. Methods and results Using bead-based single molecule immunoassays, we quantified serum levels of GFAP in patients with HF participating in the prospective Cognition.Matters-HF study. Participants were extensively phenotyped, including cognitive testing of five separate domains and magnetic resonance imaging (MRI) of the brain. Univariable and multivariable models, also accounting for multiple testing, were run. One hundred and forty-six chronic HF patients with a mean age of 63.8 ± 10.8 years were included (15.1% women). Serum GFAP levels (median 246 pg/mL, quartiles 165, 384 pg/mL; range 66 to 1512 pg/mL) did not differ between sexes. In the multivariable adjusted model, independent predictors of GFAP levels were age (T = 5.5; P < 0.001), smoking (T = 3.2; P = 0.002), estimated glomerular filtration rate (T = −4.7; P < 0.001), alanine aminotransferase (T = −2.1; P = 0.036), and the left atrial end-systolic volume index (T = 3.4; P = 0.004). NT-proBNP but not serum GFAP explained global cerebral atrophy beyond ageing. However, serum GFAP levels were associated with the cognitive domain visual/verbal memory (T = −3.0; P = 0.003) along with focal hippocampal atrophy (T = 2.3; P = 0.025). Conclusions Serum GFAP levels are affected by age, smoking, and surrogates of the severity of HF. The association of GFAP with memory dysfunction suggests that astroglial pathologies, which evade detection by conventional MRI, may contribute to memory loss beyond ageing in patients with chronic HF. KW - Glial fibrillary acidic protein KW - GFAP KW - Chronic heart failure KW - Cognitive decline KW - Memory dysfunction KW - Brain atrophy Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312736 VL - 9 IS - 4 ER - TY - THES A1 - Schramm, Axel T1 - Sensomotorische Integration bei zervikalen Dystonien T1 - Sensorimotor integration in cervical dystonia N2 - Zervikale Dystonien gehören zu den häufigsten Formen fokaler Dystonien. Diese sind durch anhaltende, unwillkürliche Muskelkontraktionen gekennzeichnet, welche zu verdrehenden oder repetitiven Bewegungen oder abnormalen Haltungen des Kopfes führen. Ein seit über 100 Jahren beobachtetes Phänomen stellt hierbei die Möglichkeit dar, mittels sogenannter "sensibler Trickmanöver", welche meistens in einer leichten Berührung von Arealen im Kopfbereich bestehen, die pathologische Muskelaktivität zu reduzieren und damit die Kopfposition zu normalisieren. Ziel der vorliegenden Arbeit war es, eine breite und vor allem erstmalig quantitative Charakterisierung von wirksamen Trickmanövern vorzunehmen und so verschiedene Einflußgrößen auf die Wirksamkeit solcher Tricks zu untersuchen. Hierzu wurden die Muskelaktivitäten der vier wichtigsten den Kopf drehenden Muskeln mittels Oberflächen-EMG abgeleitet und die Veränderungen bei Trickapplikation unterschiedlicher Lokalisation, Modalität und bei verschiedenen Ausgangspositionen ermittelt. 1) Hinsichtlich der Lokalisation ergaben sich über alle Patienten gemittelt keine signifikante Seitendifferenz, und auch bei individuellem Vergleich zeigten sich bei rund 50% der Patienten keine signifikanten Unterschiede zwischen kontralateraler und ipsilateraler Trickapplikation. Unter den getesteten Applikationsorten grenzte sich das Areal "Wange" mit durchschnittlich 33%iger Reduktion der gesamten EMG-Aktivität signifikant gegen die Areale "Kinn" (-23%) und "Hals" (-23%) ab und war bei 79% der Patienten am besten wirksam. 2) Bei weiterer Untersuchung verschiedener Trickmodalitäten auf dem für jeden Patienten individuell wirksamsten Areal waren neben dem klassischen Trickmanöver (-42%) auch die Verwendung eines Plastikstabes durch den Patienten (-43%) oder Untersucher (-32%), sowie nicht-sensible Manöver wie das Heben des Armes ohne eigentliche Berührung (-18%) und die bloße Vorstellung einer Trickapplikation (-20%) hochsignifikant wirksam. Allerdings korrelierten sensible und (wie die beiden letztgenannten) nicht-sensible Tricks nicht miteinander, was auf einen prinzipiell unterschiedlichen Wirkmechanismus hinweisen könnte. Visuelle Rückkopplung über einen Spiegel hatte im Gegensatz dazu keine Wirkung. 3) Bezüglich der Bedeutung der Kopfposition für Muskelaktivität und Trickwirksamkeit zeigte sich bereits bei willkürlicher Einnahme einer Neutralposition ohne Trickanwendung eine signifikante Reduktion agonistischer Muskelaktivität (-30%), die allerdings von einer leichten antagonistischen Aktivierung begleitet war (+2,4%). Überraschenderweise war die Applikation eines Tricks um so wirksamer, je weiter der Kopf zu Beginn auf die zur dystonen Drehrichtung kontralateralen Seite gedreht war. Demgegenüber ließ sich bei Trickapplikation in dystoner Maximalposition kaum mehr eine Wirkung nachweisen (-12%). Die vorliegenden Ergebnisse sprechen aufgrund der unspezifischen Wirkung verschiedenster Trickmanöver (2) und Lokalisationen (1) für die Einbeziehung höherer sensomotorischer Integrationszentren wie z. B. des Parietalcortex in den Wirkmechanismus. Sensible Trickmanöver könnten bei auf die pathologische Kopfposition adaptierten sensiblen Afferenzen Zusatzinformationen über die Kopfposition im Vergleich zum Rumpf liefern. Möglicherweise sind diese umso wirksamer, je weiter sich der Kopf noch auf der kontralateralen Seite befindet (3), da in dieser Situation die dystone Muskelaktivität noch gering und das sensible Mismatch, über welches sensible Stimuli modulierend einwirken könnten, maximal ist. Nach den vorgelegten Ergebnissen läßt sich erstmals ein zweiphasiger Ablauf der Trickwirkung postulieren: Der in einer ersten Phase teils willkürlich in eine günstige Ausgangsposition gebrachte Kopf kann durch die Anwendung sensibler Stimuli oder Imagination in einer zweiten Phase mit geringerer Anstrengung und unter Ausnutzung kortikaler sensomotorischer Servomechanismen stabilisiert werden. Im Rahmen der vorgelegten Studie konnte das Verständnis für therapeutisch nutzbare sensible Trickmanöver verbessert und somit Patienten unterschiedliche Trickstrategien an die Hand gegeben werden. Die Identifikation der zentralen Rolle höherer integrativer Zentren wie dem Parietalcortex im Rahmen des Wirkmechanismus, könnte dabei Ausgangspunkt für neue Therapieansätze in Form einer gezielten Beeinflussung solcher Areale sein. N2 - Sensory tricks in cervical dystonia frequently lead to a marked reduction of dystonic muscle activity, a fact that has been described as „geste antagonistique“ more than a century ago. In order to evaluate the impact of the degree of head rotation as well as mode and location on the efficacy of such sensory tricks, agonistic and antagonistic muscle activities in 26 patients with predominantly rotational torticollis have been systematically analyzed using a 4-channel surface EMG. In the subgroup of 19 patients with a clinically effective trick, touching the neck, chin or cheek on the ipsi- and contralateral side of head rotation all led to a significant (p<0.002) reduction of agonistic and antagonistic EMG activity. Patients without a clinically effective trick showed no significant change in EMG-activity. There was a strong correlation between the efficacy of a trick manoeuvre and the head position. No significant reduction during trick application was seen at the maximum dystonic head position while trick application in a neutral or even contralateral position led to a highly reduction of EMG-activity. Besides typical trick manoeuvres such as manually touching the sensitive area, other stimuli also led to significant reduction of EMG activity: use of a plastic stick instead of the finger by the patient (p<0.001) or by the investigator (p<0.001), elevating the arm and holding the finger close to the respective skin area without touching it (p<0,002), as well as mere thinking of performing the trick manoeuvre (p<0.002). As conclusion trigger mechanisms for tricks in cervical dystonia seem to be rather unspecific involving higher centres of sensorimotor integration. Based on these findings a 2-phase-model is proposed: In a first step normalization of head posture by stronger counterpressure or volitional antagonistic muscle activity might partly reduce dystonic activity, so that in a second step stabilisation of this head position applying a sensory trick manoeuvre is possible. Challenging the central adaption on distorted sensorimotor information in the nearby neutral head position seems to be the critical mechanism. KW - Dystonie KW - Torticollis KW - Trick KW - Geste KW - sensomotorisch KW - dystonia KW - torticollis KW - sensory KW - trick KW - geste Y1 - 2002 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-4722 ER - TY - THES A1 - Nehring, Claudia T1 - Sensitivität elektrophysiologischer Parameter bei der chronischen inflammatorischen demyelinisierenden Polyneuropathie (CIDP) in der Beurteilung des Langzeitverlaufes T1 - Sensitivity of electrophysiologic parameters of CIDP in the judgement of the long term course N2 - Die Chronische Inflammatorische Demyelinisierende Polyneuropathie (CIDP) ist eine seltene autoimmune Erkrankung des peripheren Nervensystems. In der vorliegenden Dissertation wurden die Akten von 23 CIDP – Patienten der Neurologischen Klinik der Universität Würzburg aus dem Zeitraum von 1990 bis 1999 ausgewertet und die elektrophysiologischen Parameter sowohl mit den klinischen Befunden als auch mit den Biopsiebefunden in Beziehung gestellt. Folgende Schlussfolgerungen konnten gezogen werden : - In dem untersuchten Patientenkollektiv war die sensomotorische Form der CIDP mit überwiegend motorischen Symptomen die häufigste Ausprägungsform. Hingegen treten rein motorische und rein sensible Formen sehr selten auf. - Die Krankheit manifestierte sich überwiegend an den distalen Extremitäten. - Die oberen Extremitäten waren selten und in keinem Fall isoliert betroffen. - Die systematische Auswertung des klinischen Schwergrades erfolgte anhand des Modifizierten Rankin Scores, der sowohl motorische als auch sensible Symptome berücksichtigt. Zusätzlich erfolgte der Entwurf eines sensiblen Scores, bei dem die sensiblen Symptome der Patienten in Zahlenwerten ausgedrückt sind. - Der Vergleich des klinischen Schweregrades mit den neurophysiologischen Befunden ergab vier unterschiedliche Korrelationstypen, die von sehr enger Korrelation bis hin zu nur geringen Übereinstimmungen reichten. - Der Schwergrad der Beeinträchtigung der Patienten war im Langzeitverlauf mit dem axonalen Verlust korreliert. Es fand sich eine gute Korrelation der Muskelsummenaktionspotentiale (CMAP) des Nervus medianus und des Nervus tibialis sowie der sensiblen Nervenaktionspotentiale (SNAP) des Nervus suralis mit dem Score. - Es ergab sich ein signifikanter Zusammenhang zwischen der Amplitude des Nervus suralis NAP`s und dem Ausmaß des Axonverlustes, wohingegen zwischen der Nervenleitungsgeschwindigkeit des Nervus suralis und dem Axonverlust nur eine geringe Abhängigkeit besteht. - Der Grad der Demyelinisierung korrelierte mit der Anzahl der endoneuralen Makrophagen. - Zwischen der Nervenleitgeschwindigkeit des Nervus suralis und dem Grad der Demyelinisierung im Biopsat konnte keine eindeutige Abhängigkeit nachgewiesen werden. - Es besteht ein Zusammenhang zwischen der Spontanaktivität im EMG und im Verlauf abnehmenden Nervenleitgeschwindigkeiten des Nervus medianus, der aber statistisch nicht signifikant ist. - Insbesondere ist die NLG- Abnahme in den ersten Wochen ein prognostisch ungünstiges Zeichen. - Eine Analogie zwischen einer durch das EMG nachgewiesenen Spontanaktivität und der Amplitude des Nervus suralis besteht. - Zwischen den Amplituden der motorischen Summenaktionspotentiale des Nervus tibialis oder den Amplituden der sensiblen Nervenaktionspotentiale des Nervus suralis auf der einen Seite und dem Ausmaß der Spontanaktivität im EMG auf der anderen Seite bestehen erkennbare Korrelationen. N2 - The CIDP is a rare autoimmune disease of the peripheral nervous system. In this dissertation there have been evaluated charts of patients of the neurological clinic of the university of Würzburg in the period from 1990 to 1999. From them were analyzed the electrophysiological parameters, the clinical items and the nerve biopsy results and compared with each other. The following conclusions have been found: - In this collective of patients the sensomotor form of CIDP with mainly motor symptoms was the most frequent one. Purely motor or sensible forms were rare. - The disease was manifesting itself predominantly on the distal extremities. - The upper extremities were rare and in no case isolate disabled. - For the systematic utilization of the clinical disability grade was made in use of the Modified Rankin Score, which took into consideration both the motor as well as the sensible symptoms. In addition there was developed a Sensible Score, with whom sensible symptoms are expressed in numbers. - The comparison of the clinical disability grade showed four different correlation types, which ranked from very narrow correlation to only small agreements. - The disability grade of the patients was in the long term course correlated with the axonal loss. There was a good correlation between the compound muscle action potential (CMAP) of the nervus medianus and the nervus tibialis and the nerve action potential (SNAP) of the nervus suralis with the score. - The degree of demyelination correlated with the number of endoneural macrophages. - No unequivocal dependence could be proven between the nerve conduction velocity of the nervus suralis and the degree of demyelination in the biopsy. - There was found a connection between the spontaneous activity (a diagnostic parameter of the EMG) and nerve conduction velocities of the nervus medianus, which were droped off in the course of the illness. The coherence was not statistically significant. - The removal of nerve conduction velocity in the first weeks is a prognostic unfavourable sign. - There exists an analogy between the spontaneous activity, found with the EMG, and the amplitude of the nervus suralis. - Between the amplitudes of the sensible nerve action potential of the nervus tibialis or the amplitudes of the sensible nerve action potentials of the nervus suralis on one hand and the amount of spontaneous activity on the other there were found correlations. KW - CIDP KW - PNP KW - EMG KW - NLG KW - Nervenbiopsie KW - CIDP KW - PNP KW - EMG KW - nerve conduction studies KW - nerve biopsy Y1 - 2003 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-7659 ER - TY - JOUR A1 - Magg, Barbara A1 - Riegler, Christoph A1 - Wiedmann, Silke A1 - Heuschmann, Peter A1 - Sommer, Claudia A1 - Üçeyler, Nurcan T1 - Self-administered version of the Fabry-associated pain questionnaire for adult patients JF - Orphanet Journal of Rare Diseases N2 - Background Fabry-associated pain may be the first symptom of Fabry disease (FD) and presents with a unique phenotype including mostly acral burning triggerable pain attacks, evoked pain, pain crises, and permanent pain. We recently developed and validated the first Fabry Pain Questionnaire (FPQ) for adult patients. Here we report on the validation of the self-administered version of the FPQ that no longer requires a face-to-face interview but can be filled in by the patients themselves allowing more flexible data collection. Methods At our Würzburg Fabry Center for Interdisciplinary Treatment, Germany, we have developed the self-administered version of the FPQ by adapting the questionnaire to a self-report version. To do this, consecutive Fabry patients with current or past pain history (n = 56) were first interviewed face-to-face. Two weeks later patients’ self-reported questionnaire results were collected by mail (n = 55). We validated the self-administered version of the FPQ by assessing the inter-rater reliability agreement of scores obtained by supervised administration and self-administration of the FPQ. Results The FPQ contains 15 questions on the different pain phenotypes, on pain development during life with and without therapy, and on impairment due to pain. Statistical analysis showed that the majority of questions were answered in high agreement in both sessions with a mean AC1-statistic of 0.857 for 55 nominal-scaled items and a mean ICC of 0.587 for 9 scores. Conclusions This self-administered version of the first pain questionnaire for adult Fabry patients is a useful tool to assess Fabry-associated pain without a time-consuming face-to-face interview but via a self-reporting survey allowing more flexible usage. KW - Fabry disease KW - Fabry-associated pain KW - pain questionnaire Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145294 VL - 10 IS - 113 ER - TY - JOUR A1 - Ben-Kraiem, Adel A1 - Sauer, Reine-Solange A1 - Norwig, Carla A1 - Popp, Maria A1 - Bettenhausen, Anna-Lena A1 - Atalla, Mariam Sobhy A1 - Brack, Alexander A1 - Blum, Robert A1 - Doppler, Kathrin A1 - Rittner, Heike Lydia T1 - Selective blood-nerve barrier leakiness with claudin-1 and vessel-associated macrophage loss in diabetic polyneuropathy JF - Journal of Molecular Medicine N2 - Diabetic polyneuropathy (DPN) is the most common complication in diabetes and can be painful in up to 26% of all diabetic patients. Peripheral nerves are shielded by the blood-nerve barrier (BNB) consisting of the perineurium and endoneurial vessels. So far, there are conflicting results regarding the role and function of the BNB in the pathophysiology of DPN. In this study, we analyzed the spatiotemporal tight junction protein profile, barrier permeability, and vessel-associated macrophages in Wistar rats with streptozotocin-induced DPN. In these rats, mechanical hypersensitivity developed after 2 weeks and loss of motor function after 8 weeks, while the BNB and the blood-DRG barrier were leakier for small, but not for large molecules after 8 weeks only. The blood-spinal cord barrier remained sealed throughout the observation period. No gross changes in tight junction protein or cytokine expression were observed in all barriers to blood. However, expression of Cldn1 mRNA in perineurium was specifically downregulated in conjunction with weaker vessel-associated macrophage shielding of the BNB. Our results underline the role of specific tight junction proteins and BNB breakdown in DPN maintenance and differentiate DPN from traumatic nerve injury. Targeting claudins and sealing the BNB could stabilize pain and prevent further nerve damage. KW - macrophages KW - neuropathy KW - barrier KW - pain Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265237 VL - 99 IS - 9 ER - TY - JOUR A1 - Volkmann, Jens A1 - Albanese, Alberto A1 - Antonini, Angelo A1 - Chaudhuri, K. Ray A1 - Clarke, Karl E. A1 - de Bie, Rob M. A. A1 - Deuschl, Günther A1 - Eggert, Karla A1 - Houeto, Jean-Luc A1 - Kulisevsky, Jaime A1 - Nyholm, Dag A1 - Odin, Per A1 - Ostergaard, Karen A1 - Poewe, Werner A1 - Pollak, Pierre A1 - Rabey, Jose Martin A1 - Rascol, Olivier A1 - Ruzicka, Evzen A1 - Samuel, Michael A1 - Speelman, Hans A1 - Sydow, Olof A1 - Valldeoriola, Francesc A1 - van der Linden, Chris A1 - Oertel, Wolfgang T1 - Selecting deep brain stimulation or infusion therapies in advanced Parkinson’s disease: an evidence-based review JF - Journal of Neurology N2 - Motor complications in Parkinson’s disease (PD) result from the short half-life and irregular plasma fluctuations of oral levodopa. When strategies of providing more continuous dopaminergic stimulation by adjusting oral medication fail, patients may be candidates for one of three device-aided therapies: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, or continuous duodenal/jejunal levodopa/carbidopa pump infusion (DLI). These therapies differ in their invasiveness, side-effect profile, and the need for nursing care. So far, very few comparative studies have evaluated the efficacy of the three device-aided therapies for specific motor problems in advanced PD. As a result, neurologists currently lack guidance as to which therapy could be most appropriate for a particular PD patient. A group of experts knowledgeable in all three therapies reviewed the currently available literature for each treatment and identified variables of clinical relevance for choosing one of the three options such as type of motor problems, age, and cognitive and psychiatric status. For each scenario, pragmatic and (if available) evidence-based recommendations are provided as to which patients could be candidates for either DBS, DLI, or subcutaneous apomorphine. KW - Parkinson’s disease KW - apomorphine KW - deep brain stimulation KW - duodenal levodopa infusion Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132373 VL - 260 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 - Rauschenberger, Lisa A1 - Knorr, Susanne A1 - Pisani, Antonio A1 - Hallett, Mark A1 - Volkmann, Jens A1 - Ip, Chi Wang T1 - Second hit hypothesis in dystonia: Dysfunctional cross talk between neuroplasticity and environment? JF - Neurobiology of Disease N2 - One of the great mysteries in dystonia pathophysiology is the role of environmental factors in disease onset and development. Progress has been made in defining the genetic components of dystonic syndromes, still the mechanisms behind the discrepant relationship between dystonic genotype and phenotype remain largely unclear. Within this review, the preclinical and clinical evidence for environmental stressors as disease modifiers in dystonia pathogenesis are summarized and critically evaluated. The potential role of extragenetic factors is discussed in monogenic as well as adult-onset isolated dystonia. The available clinical evidence for a "second hit" is analyzed in light of the reduced penetrance of monogenic dystonic syndromes and put into context with evidence from animal and cellular models. The contradictory studies on adult-onset dystonia are discussed in detail and backed up by evidence from animal models. Taken together, there is clear evidence of a gene-environment interaction in dystonia, which should be considered in the continued quest to unravel dystonia pathophysiology. KW - dystonia KW - second hit KW - pathophysiology KW - gene-environment interaction Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265028 VL - 159 ER - TY - THES A1 - Teuteberg, Philipp Wilhelm Friedemann T1 - Schmerzhafte Mononeuropathie an C57BL/6 Mäusen: Studien mit neutralisierenden Antikörpern gegen Tumor-Nekrose-Faktor Alpha an zwei verschiedenen Läsionsmodellen T1 - XX N2 - Die vorliegende Arbeit befaßt sich mit zwei Modellen einer schmerzhaften Mononeuropathie an der C57BL/6-Maus sowie deren Beeinflussung durch neutralisierende AK gegen TNF. Dafür wurden die Nn. ischiadici der Mäuse operativ manipuliert, zum einen in Form der CCI durch drei den Nerven einschnürende Ligaturen und zum anderen in Form der PST durch Heraustrennen eines Drittels des Nervendurchmessers. Beide Operationsmodelle lösten bei den Mäusen eine schmerzhafte Neuropathie aus. Es wurde untersucht, inwieweit zum Zeitpunkt der jeweiligen Operation oder am 4. postoperativen Tag applizierte TNF-AK das Schmerz-assoziierte Verhalten beeinflussen konnten und ob diese Behandlung einen Einfluß auf die Zytokinexpression im Endoneurium, auf den Makrophageneinstrom und auf die Nervenregeneration hatte. Hierzu wurden Verhaltenstests sowie immunhistochemische und morphometrische Methoden verwendet. Aus den vorliegenden Ergebnissen kann geschlossen werden, daß der bei CCI vermutete Einfluß der epineuralen Entzündung auf das Schmerz-assoziierte Verhalten kleiner ist als ursprünglich angenommen. Die Tatsache, daß zumindest auf einen Parameter (Hitzehyperalgesie) nicht nur die präventive sondern auch die therapeutische TNF-Hemmung wirksam war, läßt auf einen Einsatz von TNF-Hemmern bei bestimmten Formen des neuropathischen Schmerzes zur Therapieergänzung hoffen. Obwohl die TNF-Hemmung in den hier verwendeten Dosen und Applikationsweisen keinen Einfluß auf die endoneurale Zytokinexpression, Makrophagendichte und Regeneration hatte, sollten zukünftige Studien diese Parameter unter variierten Applikationsbedingungen genauer untersuchen. KW - Mononeuropathie KW - Tumor-Nekrose-Faktor KW - Allodynie KW - Hyperalgesie KW - Neuropathic Pain KW - Chronic Constriction Injury KW - Partial Sciatic Transection Y1 - 2003 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-5346 ER - TY - THES A1 - Papagianni, Aikaterini T1 - Schmerz-assoziierte elektrisch evozierte Potentiale (PREP) bei Patienten mit neuropathischen Schmerzsyndromen T1 - Pain-related evoked potentials (PREP) in patients with neuropathic pain N2 - In der vorliegenden Studie wurden 32 Patienten (19 Frauen, 13 Männer, medianes Alter 50 Jahren, Spanne: 26-83 Jahre) mit einem klinisch akralen neuropathischen Schmerzsyndrom unterschiedlicher Genese mittels QST, PREP und Hautbiopsie untersucht. Unser Patientenkollektiv bestand aus drei Subgruppen: sechsen Patienten erfüllten die Kriterien einer SFN, acht Patienten hatten eine Neuropathie der großkalibrigen Nervenfasern mit zusätzlicher Beeinträchtigung der kleinkalibrigen Nervenfasern und weitere acht Patienten hatten ein akrales Schmerzsyndrom mit neuropathischen Charakteristika, ohne vorbekannte Diagnose einer Neuropathie der groß- oder kleinkalibrigen Nervenfasern. Die Patienten wurden mittels klinischer neurologischer Untersuchung, elektrophysiologischer Tests, QST, PREP und Hautbiopsie untersucht. Die Patientendaten wurden jeweils mit Daten großer Kontrollgruppen verglichen, die wir in unserer Klinik unter Angehörigen und Freunden unserer Patienten mit deren Einwilligung rekrutiert hatten. QST und die Hautbiopsie waren bei Patienten mit SFN und PNP jeweils auffällig, bei akralem Schmerzsyndrom unklarer Ätiologie hingegen unauffällig. Nach elektrischer kutaner Stimulation aller drei Körperregionen zeigte sich eine Amplitudenminderung der PREP-Reizantwort in allen Patientensubgruppen (7,5 µV in der SFN-Gruppe, 3,8 µV in der PNP-Gruppe, und 11,3 µV bei den Patienten mit akralem Schmerzsyndrom). Somit konnten wir zeigen, dass eine Kleinfaserpathologie in der Studienpopulation von Patienten mit neuropathischem Schmerzsyndrom besteht. Nur die Amplitudenminderung der PREP bildet diese Pathologie ab. Diese Daten erlauben uns die eingangs aufgestellte Hypothese, dass PREP zur Diagnostik bei Frage nach Kleinfaserbeteiligung geeignet ist, positiv zu belegen. PREP ist eine nicht-invasive Methode für die Evaluation der Funktion v.a. der Aδ-Faser mit standardisiertem Ablaufprotokoll zur Erhebung von reproduzierbaren Daten. Sie kann bei Patienten mit der Anamnese eines akralen neuropathischen Schmerzsyndroms einen objektiven Hinweis auf eine Dysfunktion der kleinkalibrigen Nervenfasern, auch wenn bereits etablierte Methoden (QST und Hautbiopsie) unauffällig bleiben, erbringen. Entsprechend können die PREP eine wertvolle Ergänzung der klinischen Untersuchungsbatterie für die Evaluation der Funktion der kleinkalibrigen Nervenfasern sein. N2 - 32 adult patients (19 female, 13 male, median age 50 years, range 26-83) suffering from acral neuropathic pain were examined with QST, PREP and skin punch biopsy. Applying current diagnostic criteria and the results of the neurophysiological studies, 16/32 (50%) patients were classified as having idiopathic SFN (Devigili et al., 2008), 8/32 (25%) patients had a mixed fiber neuropathy (MFN, i.e. large and small fiber neuropathy), and 8/32 (25%) patients had neuropathic pain without signs of a large fiber neuropathy or SFN. Patients with SFN and mixed fiber neuropathy were having pathological findings in the skin punch biopsy (reduction of the intraepidermal nerve fiber density-IENFD), while normal findings were seen in patients with acral neuropathic pain Pain related evoked potentials after electrical skin stimulation at three body regions (face, hand, foot) revealed reduction of the peak-to-peak amplitude (PPA) in all patient-groups. Therefore, PREP was the only test providing findings of a small fiber impairment in patients with acral neuropathic pain even when QST and skin punch biopsy remained normal. PREP, as non-invasive method for the evaluation of the Aδ-pathways can be proposed as a valuable additional test for the evaluation of small fiber dysfunction in patients with neuropathic pain syndromes. KW - PREP KW - neuropathischer Schmerz KW - small-fiber-Neuropathie KW - pain related evoked potentials KW - small fiber neuropathy KW - neuropathic pain KW - Schmerz-assoziierte elektrisch evozierte Potentiale Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159728 ER - TY - THES A1 - Auchter, Antonia T1 - Schlafassoziierte Veränderung der lokalen Feldpotential Aktivität im Nucleus subthalamicus bei Patienten mit Morbus Parkinson T1 - Sleep-associated changes in local field potential activity in the nucleus subthalamicus in patients with Parkinson's disease N2 - Die tiefe Hirnstimulation ist eine etablierte und hocheffiziente operative Behandlungsmethode für Patienten mit idiopathischem Parkinson- Syndrom (IPS). Als Zielgebiet dient in den meisten Fällen der Nucleus subthalamicus. Die Indikationen zur Implantation einer tiefen Hirnstimulation (THS) sind medikamentös nicht behandelbare motorische Fluktuationen und Dyskinesien oder ein medikamentös nicht kontrollierbarer Tremor. Bislang erfolgt eine kontinuierliche Stimulation. Little et al. konnten jedoch bereits in ihrer 2013 veröffentlichen Studie zeigen, dass eine adaptive Stimulation, gemessen am UPDRS, um 27 % effektiver war und entsprechend die Stimulationszeit um 56 % gesenkt werden konnte. Voraussetzung für die Anwendbarkeit einer adaptiven Stimulation im klinischen Alltag ist der Nachweis eines oder mehrerer Physiomarker, welche als Rückkopplungssignal für den Stimulationsbeginn dienen. Diese Marker müssen verlässlich mit dem Auftreten und der Ausprägung der Bewegungsstörungen korrelieren. Die Systeme müssen die Signale auslesen und entsprechend darauf reagieren können, damit ein sogenanntes Closed- loop- Verfahren entstehen kann. Bei diesen Markern handelt es sich um sogenannte lokale Feldpotenzialaktivitäten, das heißt niederfrequente Potentialänderungen von Zellen in subkortikalen Arealen des Gehirns, welche über Elektroden der THS abgeleitet werden können. Der Stimulator Activa PC+S (Medtronic) ermöglicht es erstmalig Aufzeichnungen von LFP- Daten, außerhalb eines experimentellen Laboraufbaus, mittels dauerhaft implantiertem Gerät vorzunehmen und damit auch Langzeitanalysen durchzuführen. Erkenntnisse vergangener Studien ergaben, dass die synchronisierte, pathologisch gesteigerte oszillatorische Aktivität im Beta-Frequenzband (13- 35 Hz) eine bedeutende Rolle im Bezug auf die Pathophysiologie des IPS spielt und als krankheitsspezifische Aktivität gilt. Es konnte bereits belegt werden, dass die Verbesserung der motorischen Symptome (Bradykinese und Rigor) mit dem Ausmaß der Suppression der Betaband- Aktivität korreliert. Die Betabandaktivität als lokale Feldpotentialaktivität kann als Physiomarker einer adaptiven Stimulation dienen. Unser Hauptaugenmerk galt daher der Analyse der Betabandaktivität oder anderer Frequenzbereiche während des Schlafes um hier die THS bedarfsgerecht einzusetzen. Hierfür wurden nächtliche subkortikale LFP- Aufzeichnungen parallel zur Schlaf- Polysomnographie durchgeführt. Zudem erfolgte in der vorliegenden Arbeit sowohl in unserem Vorversuch als auch in unserem Hauptversuch die Anwendung des UPDRS Teil III zur Erfassung der motorischen Symptome, sowie die Durchführung von Fragebögen zur Erfassung der nicht- motorischen Symptome, insbesondere des Schlafes vor und nach Implantation der tiefen Hirnstimulation. Wir konnten belegen, dass es nach Implantation der THS zu einer Erhöhung der Schlafeffizienz und zu einer Erhöhung des Anteils der Schlafstadien II und III und damit einhergehend zu einer Steigerung der Schlafqualität kommt. Übereinstimmend mit anderen Studien konnten wir zeigen, dass sich die Motorik unter Stimulation deutlich verbessert. Im Vorversuch reduzierte sich der mittlere präoperative MDS- UPDRS III im MedsOFF verglichen mit dem mittleren postoperativ MDS- UPDRS III im MedsOFF/StimON um 37 %. In der PC+S- Studie imponierte eine Reduktion um 67%. Zudem zeigte sich eine Reduktion der nicht- motorischen Symptome durch die THS, insbesondere in der Kategorie Schlaf. Die Ergebnisse der vorliegenden Arbeit ergaben außerdem, dass die Betabandaktivität im Schlafstadium II und vor allem im Schlafstadium III am geringsten ist. Im Schlafstadium I und REM ist die Betabandaktivität höher als im Schlafstadium II und III. Hierbei war entscheidend, dass die Patienten eine klar abgrenzbare Betabandaktivität im Wachstadium aufwiesen und die Elektrodenkontakte im dorsolateralen Kerngebiet des STN lokalisiert waren. Gegenläufig dazu verhält sich die Deltaaktivität. Sie ist im Schlafstadium II und besonders im Stadium III am höchsten. Stadium I ist mit durchschnittlich um 7,3 % niedriger als im Wachstadium. Am geringsten ist sie jedoch im REM-Schlafstadium. Indem wir mit der Betabandaktivität und Deltaaktivität in den einzelnen Schlafstadien einen stabilen und reproduzierbaren Physiomarker finden konnten, sind wir unserem Ziel der adaptiven THS ein Stück näher gekommen. N2 - Deep brain stimulation is an established and highly efficient surgical treatment modality for patients with idiopathic Parkinson's syndrome (IPS). The target area in most cases is the subthalamic nucleus. The indications for implantation of deep brain stimulation (THS) are motor fluctuations and dyskinesias that cannot be treated with medication or tremor that cannot be controlled with medication. To date, continuous stimulation has been used. However, Little et al. were already able to show in their study published in 2013 that adaptive stimulation was 27% more effective, as measured by UPDRS, and that the stimulation time could be reduced by 56% accordingly. A prerequisite for the applicability of adaptive stimulation in clinical practice is the detection of one or more physiomarkers that serve as feedback signals for the onset of stimulation. These markers must correlate reliably with the occurrence and severity of movement disorders. The systems must be able to read out the signals and react to them accordingly, so that a so-called closed-loop procedure can be created. These markers are so-called local field potential activities, i.e. low-frequency potential changes of cells in subcortical areas of the brain, which can be derived via electrodes of the THS. The Activa PC+S stimulator (Medtronic) makes it possible for the first time to record LFP data outside of an experimental laboratory setup using a permanently implanted device and thus also to perform long-term analyses. Findings of past studies revealed that synchronized, pathologically enhanced oscillatory activity in the beta frequency band (13- 35 Hz) plays a significant role in relation to the pathophysiology of IPS and is considered disease-specific activity. It has already been demonstrated that the improvement of motor symptoms (bradykinesia and rigor) correlates with the extent of suppression of beta-band activity. Beta-band activity as local field potential activity may serve as a physiomarker of adaptive stimulation. Therefore, our main focus was on the analysis of beta-band activity or other frequency ranges during sleep in order to apply THS as needed. For this purpose, nocturnal subcortical LFP recordings were performed in parallel to sleep polysomnography. In addition, the UPDRS Part III was used to record motor symptoms in our preliminary trial as well as in our main trial, and questionnaires were administered to record nonmotor symptoms, especially sleep before and after implantation of deep brain stimulation. We were able to prove that after implantation of THS there is an increase in sleep efficiency and an increase in the proportion of sleep stages II and III and thus an associated increase in sleep quality. Consistent with other studies, we demonstrated that motor function improves significantly under stimulation. In the preliminary trial, the mean preoperative MDS- UPDRS III in MedsOFF was reduced by 37% compared with the mean postoperative MDS- UPDRS III in MedsOFF/StimON. In the PC+S- study, a reduction of 67% was impressive. In addition, THS showed a reduction in non-motor symptoms, especially in the sleep category. The results of the present work also revealed that beta-band activity is lowest in sleep stage II and especially in sleep stage III. In sleep stage I and REM, beta-band activity is higher than in sleep stage II and III. Here, it was crucial that the patients showed a clearly delineable beta-band activity in the waking stage and that the electrode contacts were localized in the dorsolateral nucleus area of the STN. Opposite to this is the delta activity. It is highest in sleep stage II and especially in stage III. Stage I is lower than in the waking stage, with an average of 7.3%. However, it is lowest in the REM sleep stage. By finding a stable and reproducible physiomarker with beta band activity and delta activity in the individual sleep stages, we have come a step closer to our goal of adaptive THS. KW - Parkinson KW - Lokale Feldpotentialaktivität KW - Nucleus subthalamicus Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237822 ER - TY - JOUR A1 - Steinhardt, Maximilian J. A1 - Cejka, Vladimir A1 - Chen, Mengmeng A1 - Bäuerlein, Sabrina A1 - Schäfer, Julia A1 - Adrah, Ali A1 - Ihne-Schubert, Sandra M. A1 - Papagianni, Aikaterini A1 - Kortüm, K. Martin A1 - Morbach, Caroline A1 - Störk, Stefan T1 - Safety and tolerability of SGLT2 inhibitors in cardiac amyloidosis — a clinical feasibility study JF - Journal of Clinical Medicine N2 - Sodium-glucose transport protein 2 inhibitors (SGLT2i) slow the progression of renal dysfunction and improve the prognosis of patients with heart failure. Amyloidosis constitutes an important subgroup for which evidence is lacking. Amyloidotic fibrils originating from misfolded transthyretin and light chains are the causal agents in ATTR and AL amyloidosis. In these most frequent subtypes, cardiac involvement is the most common organ manifestation. Because cardiac and renal function frequently deteriorate over time, even under best available treatment, SGLT2i emerge as a promising treatment option due to their reno- and cardioprotective properties. We retrospectively analyzed patients with cardiac amyloidosis, who received either dapagliflozin or empagliflozin. Out of 79 patients, 5.1% had urinary tract infections; 2 stopped SGLT2i therapy; and 2.5% died unrelated to the intake of SGLT2i. No genital mycotic infections were observed. As expected, a slight drop in the glomerular filtration rate was noted, while the NYHA functional status, cardiac and hepatic function, as well as the 6 min walk distance remained stable over time. These data provide a rationale for the use of SGLT2i in patients with amyloidosis and concomitant cardiac or renal dysfunction. Prospective randomized data are desired to confirm safety and to prove efficacy in this increasingly important group of patients. KW - heart failure KW - chronic kidney disease KW - amyloidosis KW - SGLT2 inhibitors Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-356024 SN - 2077-0383 VL - 13 IS - 1 ER - TY - JOUR A1 - Vogt, Marius L. A1 - Kollikowski, Alexander M. A1 - Weidner, Franziska A1 - Strinitz, Marc A1 - Feick, Jörn A1 - Essig, Fabian A1 - Neugebauer, Herrmann A1 - Haeusler, Karl Georg A1 - Pham, Mirko A1 - Maerz, Alexander T1 - Safety and Effectiveness of the New Generation APERIO® Hybrid Stent-retriever Device in Large Vessel Occlusion Stroke JF - Clinical Neuroradiology N2 - Background It is unknown whether technological advancement of stent-retriever devices influences typical observational indicators of safety or effectiveness. Methods Observational retrospective study of APERIO® (AP) vs. new generation APERIO® Hybrid (APH) (Acandis®, Pforzheim, Germany) stent-retriever device (01/2019–09/2020) for mechanical thrombectomy (MT) in large vessel occlusion (LVO) stroke. Primary effectiveness endpoint was successful recanalization eTICI (expanded Thrombolysis In Cerebral Ischemia) ≥ 2b67, primary safety endpoint was occurrence of hemorrhagic complications after MT. Secondary outcome measures were time from groin puncture to first pass and successful reperfusion, and the total number of passes needed to achieve the final recanalization result. Results A total of 298 patients with LVO stroke who were treated by MT matched the inclusion criteria: 148 patients (49.7%) treated with AP vs. 150 patients (50.3%) treated with new generation APH. Successful recanalization was not statistically different between both groups: 75.7% for AP vs. 79.3% for APH; p = 0.450. Postinterventional hemorrhagic complications and particularly subarachnoid hemorrhage as the entity possibly associated with stent-retriever device type was significantly less frequent in the group treated with the APH: 29.7% for AP and 16.0% for APH; p = 0.005; however, rates of symptomatic hemorrhage with clinical deterioration and in domo mortality were not statistically different. Neither the median number of stent-retriever passages needed to achieve final recanalization, time from groin puncture to first pass, time from groin puncture to final recanalization nor the number of cases in which successful recanalization could only be achieved by using a different stent-retriever as bail-out device differed between both groups. Conclusion In the specific example of the APERIO® stent-retriever device, we observed that further technological developments of the new generation device were not associated with disadvantages with respect to typical observational indicators of safety or effectiveness. KW - APERIO Hybrid KW - mechanical thrombectomy KW - stent-retriever device KW - stroke KW - APERIO Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-264817 VL - 32 IS - 1 ER - TY - JOUR A1 - Tony, Hans-Peter A1 - Burmester, Gerd A1 - Schulze-Koops, Hendrik A1 - Grunke, Mathias A1 - Henes, Joerg A1 - Kötter, Ina A1 - Haas, Judith A1 - Unger, Leonore A1 - Lovric, Svjetlana A1 - Haubitz, Marion A1 - Fischer-Betz, Rebecca A1 - Chehab, Gamal A1 - Rubbert-Roth, Andrea A1 - Specker, Christof A1 - Weinerth, Jutta A1 - Holle, Julia A1 - Müller-Ladner, Ulf A1 - König, Ramona A1 - Fiehn, Christoph A1 - Burgwinkel, Philip A1 - Budde, Klemens A1 - Sörensen, Helmut A1 - Meurer, Michael A1 - Aringer, Martin A1 - Kieseier, Bernd A1 - Erfurt-Berge, Cornelia A1 - Sticherling, Michael A1 - Veelken, Roland A1 - Ziemann, Ulf A1 - Strutz, Frank A1 - von Wussow, Praxis A1 - Meier, Florian MP A1 - Hunzelmann, Nico A1 - Schmidt, Enno A1 - Bergner, Raoul A1 - Schwarting, Andreas A1 - Eming, Rüdiger A1 - Schwarz-Eywill, Michael A1 - Wassenberg, Siegfried A1 - Fleck, Martin A1 - Metzler, Claudia A1 - Zettl, Uwe A1 - Westphal, Jens A1 - Heitmann, Stefan A1 - Herzog, Anna L. A1 - Wiendl, Heinz A1 - Jakob, Waltraud A1 - Schmidt, Elvira A1 - Freivogel, Klaus A1 - Dörner, Thomas A1 - Hertl, Michael A1 - Stadler, Rudolf T1 - Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID) JF - Arthritis Research & Therapy N2 - Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin’s lymphoma in a real-life clinical setting. Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators. Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician’s visual analogue scale; mean improvement from baseline of 12.1 mm) KW - GRAID Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-142856 VL - 13 IS - R75 ER - TY - JOUR A1 - Wurmb, Thomas Erik A1 - Schlereth, Stefan A1 - Kredel, Markus A1 - Muellenbach, Ralf M. A1 - Wunder, Christian A1 - Brederlau, Jörg A1 - Roewer, Norbert A1 - Kenn, Werner A1 - Kunze, Ekkehard T1 - Routine Follow-Up Cranial Computed Tomography for Deeply Sedated, Intubated, and Ventilated Multiple Trauma Patients with Suspected Severe Head Injury JF - BioMed Research International N2 - Background. Missed or delayed detection of progressive neuronal damage after traumatic brain injury (TBI) may have negative impact on the outcome. We investigated whether routine follow-up CT is beneficial in sedated and mechanically ventilated trauma patients. Methods. The study design is a retrospective chart review. A routine follow-up cCT was performed 6 hours after the admission scan. We defined 2 groups of patients, group I: patients with equal or recurrent pathologies and group II: patients with new findings or progression of known pathologies. Results. A progression of intracranial injury was found in 63 patients (42%) and 18 patients (12%) had new findings in cCT 2 (group II). In group II a change in therapy was found in 44 out of 81 patients (54%). 55 patients with progression or new findings on the second cCT had no clinical signs of neurological deterioration. Of those 24 patients (44%) had therapeutic consequences due to the results of the follow-up cCT. Conclusion. We found new diagnosis or progression of intracranial pathology in 54% of the patients. In 54% of patients with new findings and progression of pathology, therapy was changed due to the results of follow-up cCT. In trauma patients who are sedated and ventilated for different reasons a routine follow-up CT is beneficial. KW - Computertomographie Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120084 IS - 361949 ER - TY - JOUR A1 - Albert-Weissenberger, Christiane A1 - Mencl, Stine A1 - Hopp, Sarah A1 - Kleinschnitz, Christoph A1 - Siren, Anna-Leena T1 - Role of the kallikrein-kinin system in traumatic brain injury JF - Frontiers in Cellular Neuroscience N2 - Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Despite improvements in acute intensive care, there are currently no specific therapies to ameliorate the effects of TBI. Successful therapeutic strategies for TBI should target multiple pathophysiologic mechanisms that occur at different stages of brain injury. The kallikrein-kinin system is a promising therapeutic target for TBI as it mediates key pathologic events of traumatic brain damage, such as edema formation, inflammation, and thrombosis. Selective and specific kinin receptor antagonists and inhibitors of plasma kallikrein and coagulation factor XII have been developed, and have already shown therapeutic efficacy in animal models of stroke and TBI. However, conflicting preclinical evaluation, as well as limited and inconclusive data from clinical trials in TBI, suggests that caution should be taken before transferring observations made in animals to humans. This review summarizes current evidence on the pathologic significance of the kallikrein-kinin system during TBI in animal models and, where available, the experimental findings are compared with human data. KW - bradykinin KW - factor XII KW - kallikrein–kinin system KW - kinin receptor KW - traumatic brain injury Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118226 SN - 1662-5102 VL - 8 ER - TY - THES A1 - Subramanian, Narayan T1 - Role of NaV1.9 in activity dependent axon growth in embryonic cultured motoneurons T1 - Die Rolle der NaV1.9 in Aktivität abhängig Axonwachstum in embryonalen kultivierten Motoneuronen N2 - Spontaneous neural activity has been shown to regulate crucial events in neurite growth including axonal branching and path finding. In animal models of spinal muscular atrophy (SMA) cultured embryonic mouse motoneurons show distinct defect in axon elongation and neural activity. This defect is governed by abnormal clustering of Ca2+ channels in the axonal regions and the protruding growth cone area. The mechanisms that regulate the opening of calcium channels in developing motoneurons are not yet clear. The question was addressed by blocking neural activity in embryonic cultured motoneurons by pharmacological inhibition of voltage-gated sodium channels (VGSC) by saxitoxin (STX) and tetrodotoxin (TTX). Low dosages of STX resulted in significant reduction of axon growth and neural activity in cultured motoneurons. This pharmacological treatment did not affect survival of motoneurons in comparison to control motoneurons that was grown in the presence of survival neurotrophic factors BDNF and CNTF. It was also found that STX was 10 times more potent than TTX a common inhibitor of VGSC with a reduced activity on the TTX-insensitive sodium channels NaV1.5, NaV1.8 and NaV1.9. Reverse Transcriptase-PCR experiments revealed the presence of NaV1.9 as the likely candidate that begins to express from embryonic stage sixteen in the mouse spinal cord. Immunolabelling experiments showed that the channel is expressed in the axonal compartments and axonal growth cones in cultured motoneurons. Suppression of NaV1.9 in cultured motoneurons by lentivirus mediated short hairpin-RNA (shRNA) resulted in shorter axon length in comparison with uninfected and scrambled constructs. Further, embryonic motoneurons cultured from NaV1.9 knockout mice also showed a significant reduction in neural activity and axon growth. The findings of this work highlight the role of NaV1.9 as an important contender in regulating activity dependent axon growth in embryonic cultured motoneurons. NaV1.9 could therefore be considered as a prospective molecule that could play an important role in regulating axon growth in motoneuron disease models like spinal muscular atrophy (SMA). N2 - Spontane neuronale Aktivität reguliert essentielle Ereignisse im Neuritenwachstum, wie beispielsweise die axonale Verzweigung und die Erkennung des Wachstumspfades. Motoneurone, die aus Tiermodellen der Spinalen Muskelatrophie (SMA) gewonnen werden, zeigen einen auffälligen Defekt im Streckenwachstum von Axonen und in der neuronalen Aktivität. Dieser Defekt wird von anormaler Clusterbildung von Ca2+ Kanälen in axonalen Regionen und in Wachstumskegeln begleitet. Die Mechanismen, die das Öffnen von Kalziumkanälen in embryonalen Motoneuronen in der Entwicklung regulieren, und die für das aktivitätsabhängige Axonwachstum benötigt werden, sind nicht bekannt. Diese Frage wurde in dieser Studie bearbeitet, indem neuronale Aktivität in embryonalen Motoneuronen durch pharmakologische Inhibition von spannungsabhängigen Natriumkanälen durch Saxitoxin (STX) und Tetrodotoxin blockiert wurde. Geringe Dosen von Saxitoxin bewirkten eine deutliche Reduktion des Axonwachstums und der neuronalen Aktivität in kultivierten Motoneuronen. Diese pharmakologische Behandlung beeinflusste nicht das Überleben von Motoneuronen im Vergleich zu Kontroll-Motoneuronen, die in der Anwesenheit der neurotrophen Faktoren BDNF und CNTF kultiviert wurden. Saxitoxin war etwa 5-10-mal potenter als TTX, ein üblicher Blocker spannungsabhängiger Natriumkanäle mit einer verminderte Aktivität auf die TTX-insensitiven Natriumkanäle NaV1.5, NaV1.8, und NaV1.9. Reverse-Transkriptase-PCR Experimente bestätigten die Anwesenheit von NaV1.9 am Tag E16 (embryonaler Tag 16) im Rückenmark der Maus. NaV1.9 ist ein einzigartiger Typus von einem Natriumkanal welcher in der Lage ist neuronale Erregbarkeit in der Nähe des Ruhemembranpotentials zu steuern. Deshalb war NaV1.9 ein guter Kandidat für einen Kanal, der spontane Erregung in Motoneuronen vermittelt. Immunofärbungen zeigten, dass NaV1.9 in axonalen Kompartimenten und axonalen Wachstumskegeln von kultivierten Motoneuronen exprimiert ist. Die Unterdrückung von NaV1.9 in kultivierten Motoneuronen durch lentiviralexprimierte short hairpin-RNA (shRNA) resultierte in kürzerer Axonlänge, im Vergleich zu nicht-infizierten Motoneuronen oder Motoneuronen, die eine sinnlose Kontroll-shRNA Sequenz exprimierten. Embryonale, kultivierte Motoneurone von NaV1.9 knockout Mäusen zeigten eine signifikante Verringerung der neuronalen Aktivität und verkürzte Axone. Diese Ergebnisse weisen auf eine Bedeutung von NaV1.9 im aktivitätsabhängigen Axonwachstum hin KW - Axon KW - Embryonalentwicklung KW - Motoneuron KW - Natriumkanal KW - Motoneuronen KW - NaV1.9 KW - motoneuron KW - Nav1.9 KW - axon growth Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-57536 ER - TY - THES A1 - Kroner-Milsch, Antje T1 - Role of immune cells in hereditary myelinopathies T1 - Rolle von Immunzellen in hereditären Myelinopathien N2 - Myelin mutations in the central and peripheral nervous system lead to severely disabling, currently untreatable diseases. In this study, we used transgenic PLP overexpressing mice (PLPtg) as a model for central inherited myelinopathies, such as leukodystrophies, and heterozygously P0 deficient (P0+/-) mice as models for peripheral hereditary polyneuropathies. Both models are characterized by low grade nervous tissue inflammation. Macrophages and CD8+ T- lymphocytes contribute to the myelin pathology as shown by crossbreeding experiments with immunodeficient mice. Having shown the relevance of CD8+ T- lymphocytes in PLPtg mice, we investigated the influence of one major cytotoxic molecule (granzyme B) on neural damage. By generation of granzyme B deficient PLPtg bone marrow chimeras, we could demonstrate a reduction of myelin pathology and oligodendrocyte death. Taken together, granzyme B is at least partly responsible for the cytotoxicity induced neural damage in PLPtg mice. To further explore the role of immune modulation, we focussed on the influence of the coinhibitory molecule PD-1, a CD28-related receptor expressed on activated T- and B-lymphocytes. By investigating myelin mutants of the CNS and PNS (PLPtg and P0+/-) with an additional PD-1 deficiency, induced by crossbreeding or bone marrow chimerization, we found a significant increase of CD8+ T- lymphocytes and massive increase of the myelin pathology in both the CNS and PNS model. In PLPtg mice, absence of PD-1 increased oligodendrocyte apoptosis, clonal expansions and a higher propensity of CNS but not peripheral CD8+ T- cells to secrete proinflammatory cytokines. In P0+/- mice, absence of PD-1 lead to moderate motor and sensory disturbances, confirming the important role of PD-1 in immune homeostasis. Taken together, we identified granzyme B as an important effector agent of cytotoxic T-lymphocytes in PLPtg mice and PD-1 as a crucial player in regulating the effector cells in our models of central and peripheral myelinopathy. Alterations of this regulatory pathway lead to overt neuroinflammation of high pathogenetic impact. These results might help to understand mechanisms responsible for high clinical variability of polygenic or even monogenic disorders of the nervous system. N2 - Myelinmutationen des zentralen und peripheren Nervensystems verursachen erheblich behindernde und bislang nicht heilbare Erkrankungen. In dieser Arbeit verwendeten wir transgene PLP überexprimierende Mäuse (PLPtg) als Modell für zentrale Myelinopathien und heterozygot P0 defiziente (P0+/-) Mäuse als Modell für hereditäre Neuropathien des peripheren Nervensystems. Beide Modelle zeigen eine niedriggradige Inflammation des Nervengewebes. Durch Verpaarung mit immundefizienten Mausstämmen konnten wir die Relevanz von Makrophagen und T- Lymphozyten in der Entstehung der Myelinpathologie zeigen. Nachdem wir beweisen konnten, dass CD8+ T- Lymphozyten maßgeblich zur Pathologie in PLPtg Mäusen beitragen untersuchten wir den Einfluss eines wichtigen zytotoxischen Moleküls, Granzym B, auf den neuralen Schaden. Durch Generierung von Granzym B defizienten PLPtg Knochenmarkschimären konnten wir eine deutliche Reduktion des glialen Schadens und der Oligodendrozytenapoptose nachweisen. Granzym B ist also zumindest teilweise verantwortlich für die Schädigung, die durch T- Lymphozyten hervorgerufen wird. Um die zusätzliche Informationen über die Rolle der Immunmodulation in unseren Modellen zu gewinnen, untersuchten wir das koinhibitorische Molekül PD-1, einen CD-28 verwandten Rezeptor, der auf B- und T- Lymphozyten exprimiert wird. Bei der Untersuchung von Myelinmutanten des ZNS und PNS (PLPtg und P0+/-), die zusätzlich PD-1 defizient waren, konnten wir einen signifikanten Anstieg von CD8+ T- Lymphozyten und eine deutliche Verschlechterung des glialen Schadens beobachten. In PLPtg Mäusen induzierte die Abwesenheit von PD-1 verstärkte Oligodendrozytenapoptose und klonale Expansion. Außerdem neigen ZNS- Lymphozyten aber nicht periphere CD8+ T- Zellen zur verstärkten Sekretion von proinflammatorischen Zytokinen. In P0+/- Mäusen führt Abwesenheit von PD-1 zu moderaten motorischen und sensorischen Störungen, was die wichtige Rolle von PD-1 in immunologischen Regulationsmechanismen unterstreicht. Zusammenfassend kann man festhalten, daß Granzym B ein wichtiges Effektormolekül zytotoxischer T- Zellen in PLPtg Mäusen ist. PD-1 spielt eine wichtige Rolle in der Regulation von Effektorzellen in unseren Modellen für zentrale und periphere Myelinopathien. Veränderungen dieser Regulation können deutliche Neuroinflammation mit starker Myelinpathologie hervorrufen. Diese Ergebnisse können dazu beitragen, die starke klinische Variabilität von polygenen und sogar monogenen neurologischen Erkrankungen zu erklären. KW - Myelinopathie KW - T- Lymphozyt KW - Multiple Sklerose KW - Neuropathie KW - PD-1 KW - Myelinopathy KW - neuropathy KW - T-lymphocyte KW - multiple sclerosis Y1 - 2008 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-28976 ER - TY - JOUR A1 - Häuser, Winfried A1 - Walitt, Brian A1 - Fitzcharles, Mary-Ann A1 - Sommer, Claudia T1 - Review of pharmacological therapies in fibromyalgia syndrome JF - Arthritis Research & Therapy N2 - This review addresses the current status of drug therapy for the management of fibromyalgia syndrome (FMS) and is based on interdisciplinary FMS management guidelines, meta-analyses of drug trial data, and observational studies. In the absence of a single gold-standard medication, patients are treated with a variety of drugs from different categories, often with limited evidence. Drug therapy is not mandatory for the management of FMS. Pregabalin, duloxetine, milnacipran, and amitriptyline are the current first-line prescribed agents but have had a mostly modest effect. With only a minority of patients expected to experience substantial benefit, most will discontinue therapy because of either a lack of efficacy or tolerability problems. Many drug treatments have undergone limited study and have had negative results. It is unlikely that these failed pilot trials will undergo future study. However, medications, though imperfect, will continue to be a component of treatment strategy for these patients. Both the potential for medication therapy to relieve symptoms and the potential to cause harm should be carefully considered in their administration. Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121598 SN - 1465-9913 VL - 16 IS - 201 ER - TY - JOUR A1 - Aster, Hans-Christoph A1 - Romanos, Marcel A1 - Walitza, Susanne A1 - Gerlach, Manfred A1 - Mühlberger, Andreas A1 - Rizzo, Albert A1 - Andreatta, Marta A1 - Hasenauer, Natalie A1 - Hartrampf, Philipp E. A1 - Nerlich, Kai A1 - Reiners, Christoph A1 - Lorenz, Reinhard A1 - Buck, Andreas K. A1 - Deserno, Lorenz T1 - Responsivity of the striatal dopamine system to methylphenidate — A within-subject I-123-β-CIT-SPECT study in male children and adolescents with attention-deficit/hyperactivity disorder JF - Frontiers in Psychiatry N2 - Background: Methylphenidate (MPH) is the first-line pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD). MPH binds to the dopamine (DA) transporter (DAT), which has high density in the striatum. Assessments of the striatal dopamine transporter by single positron emission computed tomography (SPECT) in childhood and adolescent patients are rare but can provide insight on how the effects of MPH affect DAT availability. The aim of our within-subject study was to investigate the effect of MPH on DAT availability and how responsivity to MPH in DAT availability is linked to clinical symptoms and cognitive functioning. Methods Thirteen adolescent male patients (9–16 years) with a diagnosis of ADHD according to the DSM-IV and long-term stimulant medication (for at least 6 months) with MPH were assessed twice within 7 days using SPECT after application of I-123-β-CIT to examine DAT binding potential (DAT BP). SPECT measures took place in an on- and off-MPH status balanced for order across participants. A virtual reality continuous performance test was performed at each time point. Further clinical symptoms were assessed for baseline off-MPH. Results On-MPH status was associated with a highly significant change (−29.9%) of striatal DAT BP as compared to off-MPH (t = −4.12, p = 0.002). A more pronounced change in striatal DAT BP was associated with higher off-MPH attentional and externalizing symptom ratings (Pearson r = 0.68, p = 0.01). Striatal DAT BP off-MPH, but not on-MPH, was associated with higher symptom ratings (Pearson r = 0.56, p = 0.04). Conclusion Our findings corroborate previous reports from mainly adult samples that MPH changes striatal DAT BP availability and suggest higher off-MPH DAT BP, likely reflecting low baseline DA levels, as a marker of symptom severity. KW - methylphenidate KW - attention deficit/hyperactivity disorder (ADHD) KW - striatum KW - single photon emission computed tomography (SPECT) KW - responsivity KW - caudate nucleus KW - dopamine transporter (DAT) Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270862 SN - 1664-0640 VL - 13 ER - TY - JOUR A1 - Korn, Thomas A1 - Kleinschnitz, Christoph A1 - Magnus, Tim A1 - Meuth, Sven G. A1 - Linker, Ralf A. T1 - Report on the 7th scientific meeting of the Association for the Advancement of Young Academics in Neurology (NEUROWIND e.V.) held in Motzen, Germany, October 30–November 1, 2015 JF - Experimental and Translational Stroke Medicine N2 - From October 30–November 1, 2015, the 7th NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Seventy doctoral students and postdocs from over 25 different groups working in German and Swiss University Hospitals or Research Institutes attended the meeting to discuss their latest experiments and findings in the fields of neuroimmunology, neurodegeneration and neurovascular research. This meeting report summarizes the many diverse presentations and the new preclinical to clinical neurology research data that were shared by the participants at the meeting. KW - NEUROWIND Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146595 VL - 8 IS - 3 ER - TY - JOUR A1 - Kleinschnitz, Christoph A1 - Linker, Ralf A. A1 - Magnus, Tim A1 - Korn, Thomas A1 - Meuth, Sven G. T1 - Report on the 6th scientific meeting of the “Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie” (NEUROWIND e.V.) held in Motzen, Germany, Oct. 31th – Nov. 2nd, 2014 JF - Experimental & Translational Stroke Medicine N2 - From October 31th – November 2nd, 2014, the 6th NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. 70 doctoral students and postdocs from over 25 different groups working in German and Swiss university hospitals or research institutes attended the meeting to discuss their latest experiments and findings in the fields of neuroimmunology, neurodegeneration and neurovascular research. The meeting was regarded as a very well organized platform to support research of young investigators in Germany and all participants enjoyed the stimulating environment for lively in depth discussions. According to the major aim of NEUROWIND e.V. to support younger researchers in Germany the 4th NEUROWIND YOUNG SCIENTIST AWARD for experimental neurology was awarded to Michael Breckwoldt on his work in the group of Thomas Misgeld (Institute of Neuronal Cell Biology, Technische Universität München, Germany). The successful project was published in Nature Medicine entitled “Multiparametric optical analysis of mitochondrial redox signals during neuronal physiology and pathology in vivo”. This outstanding paper deals with a molecular imaging approach in living mice to optically analyze the role of mitochondrial redox signals in axons in health and disease. The award is endowed with 20.000 Euro sponsored by Merck Serono GmbH, Darmstadt, Germany (unrestricted educational grant). This year’s keynote lecture was given by Bernhard Hemmer, Head of the Department of Neurology at the Klinikum rechts der Isar, Technische Universität München. Dr. Hemmer highlighted the particular role of B cells and (auto)antibodies in multiple sclerosis (MS). As a new highlight Dr. Urbahns, head of global discovery technologies at Merck research laboratories, gave insights from research practice in the pharmaceutical industry and introduced a shift in the view on present-day drug discovery paradigms. Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125049 VL - 7 IS - 1 ER - TY - JOUR A1 - Linker, Ralf A. A1 - Magnus, Tim A1 - Korn, Thomas A1 - Kleinschnitz, Christoph A1 - Meuth, Sven G. T1 - Report on the 5‘th scientific meeting of the “Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie” (NEUROWIND e.V.) held in Motzen, Germany, Oct. 25th – Oct. 27th, 2013 JF - Experimental & Translational Stroke Medicine N2 - From october 25th - 27th 2013, the 5th NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. This year more than 60 doctoral students and postdocs from over 25 different groups working in German university hospitals or research institutes attended the meeting to discuss their latest findings in the fields of neuroimmunology, neurodegeneration and neurovascular research. All participants appreciated the stimulating environment in Motzen, Brandenburg, and people took the opportunity for scientific exchange, discussion about ongoing projects and already started further collaborations. Like in the previous years, the symposium was regarded as a very well organized platform to support research of young investigators in Germany. According to the major aim of NEUROWIND e.V. to support younger researchers in Germany the 3rd NEUROWIND YOUNG SCIENTIST AWARD for experimental neurology was awarded to Ruth Stassart working in the group of Klaus Armin Nave and Wolfgang Brück (MPI Göttingen and Department of Neuropathology, Göttingen Germany). The successful work was published in Nature Neuroscience entitled “A role for Swann cell-derived neuregulin-1 in remyelination”. This outstanding paper deals with the function of Schwann cell neuregulin as an endogenous factor for myelin repair. The award is endowed with 20.000 Euro sponsored by Merck Serono GmbH, Darmstadt, Germany (unrestricted educational grant). This year’s keynote lecture was given by Albert Ludolph, Head of the Department of Neurology at the University Clinic of Ulm. Dr. Ludolph highlighted the particular role of individual scientists for the development of research concepts in Alzheimer´s disease (AD) and frontotemporal dementia (FTD). KW - NEUROWIND Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129230 VL - 5 IS - 15 ER - TY - RPRT A1 - Linker, Ralf, A. A1 - Meuth, Sven G. A1 - Magnus, Tim A1 - Korn, Thomas A1 - Kleinschnitz, Christoph T1 - Report on the 4'th scientific meeting of the "Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Nov. 2'nd - Nov. 4'th, 2012 [meeting report] N2 - From November 2nd - 4th 2012, the 4th NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Again more than 60 participants, predominantly at the doctoral student or postdoc level, gathered to share their latest findings in the fields of neurovascular research, neurodegeneration and neuroinflammation. Like in the previous years, the symposium provided an excellent platform for scientific exchange and the presentation of innovative projects in the stimulating surroundings of the Brandenburg outback. This year’s keynote lecture on the pathophysiological relevance of neuronal networks was given by Christian Gerloff, Head of the Department of Neurology at the University Clinic of Hamburg-Eppendorf. Another highlight of the meeting was the awarding of the NEUROWIND e.V. prize for young scientists working in the field of experimental neurology. The award is donated by the Merck Serono GmbH, Darmstadt, Germany and is endowed with 20.000 Euro. This year the jury decided unanimously to adjudge the award to Michael Gliem from the Department of Neurology at the University Clinic of Düsseldorf (group of Sebastian Jander), Germany, for his outstanding work on different macrophage subsets in the pathogenesis of ischemic stroke published in the Annals of Neurology in 2012. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76407 ER - TY - JOUR A1 - Kleinschnitz, Christph A1 - Meuth, Sven G. A1 - Magnus, Tim A1 - Korn, Thomas A1 - Linker, Ralf A. T1 - Report on the 3'rd scientific meeting of the "Verein zur Förderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Nov. 4'th - Nov. 6'th, 2011 N2 - From November 4th- 6th 2011, the 3rd NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Like in the previous years, the meeting provided an excellent platform for scientific exchange and the presentation of innovative projects for young colleagues in the fields of neurovascular research, neuroinflammation and neurodegeneration. As kick-off to the scientific sessions, Reinhard Hohlfeld, Head of the Institute for Clinical Neuroimmunology in Munich, gave an illustrious overview on the many fascinations of neuroimmunologic research. A particular highlight on the second day of the meeting was the award of the 1’st NEUROWIND e.V. prize for young academics in the field of experimental neurology. This award is posted for young colleagues under the age of 35 with a significant achievement in the field of neurovascular research, neuroinflammation or neurodegeneration and comprises an amount of 20.000 Euro, founded by Merck Serono GmbH, Darmstadt. Germany. The first prize was awarded to Ivana Nikic from Martin Kerschensteiner’s group in Munich for her brilliant work on a reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis, published in Nature Medicine in 2011. This first prize award ceremony was a great incentive for the next call for proposals now upcoming in 2012. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75388 ER - TY - RPRT A1 - Magnus, Tim A1 - Linker, Ralf A. A1 - Meuth, Sven G. A1 - Kleinschnitz, Christoph A1 - Korn, Thomas T1 - Report on the 2nd scientific meeting of the "Verein zur Foerderung des Wissenschaftlichen Nachwuchses in der Neurologie" (NEUROWIND e.V.) held in Motzen, Germany, Oct. 29'th - Oct. 31'st, 2010 N2 - Summary of the scientific contributions to the NEUROWIND meeting 2010: Contributions in the fields of neuroimmunology and neurodegeneration KW - Wissenschaftlicher Nachwuchs KW - Neurologie Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68789 ER - TY - JOUR A1 - Braun, Alexandra A1 - Evdokimov, Dimitar A1 - Frank, Johanna A1 - Pauli, Paul A1 - Wabel, Thomas A1 - Üçeyler, Nurcan A1 - Sommer, Claudia T1 - Relevance of Religiosity for Coping Strategies and Disability in Patients with Fibromyalgia Syndrome JF - Journal of Religion and Health N2 - Coping strategies are essential for the outcome of chronic pain. This study evaluated religiosity in a cohort of patients with fibromyalgia syndrome (FMS), its effect on pain and other symptoms, on coping and FMS-related disability. A total of 102 FMS patients were recruited who filled in questionnaires, a subgroup of 42 patients participated in a face-to-face interview, and data were evaluated by correlation and regression analyses. Few patients were traditionally religious, but the majority believed in a higher existence and described their spirituality as "transcendence conviction". The coping strategy "praying-hoping" and the ASP dimension "religious orientation" (r = 0.5, P < 0.05) showed a significant relationship independent of the grade of religiosity (P < 0.05). A high grade of belief in a higher existence was negatively associated with the choice of ignoring as coping strategy (r = - 0.4, P < 0.05). Mood and affect-related variables had the highest impact on disability (b = 0.5, P < 0.05). In this cohort, the grade of religiosity played a role in the choice of coping strategies, but had no effects on health and mood outcome. KW - Fibromyalgia syndrome KW - religiosity KW - coping KW - disability Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-269135 SN - 1573-6571 VL - 61 IS - 1 ER - TY - JOUR A1 - Elhfnawy, Ahmed Mohamed A1 - Abd El‐Raouf, Mervat A1 - Volkmann, Jens A1 - Fluri, Felix A1 - Elsalamawy, Doaa T1 - Relation of infarction location and volume to vertigo in vertebrobasilar stroke JF - Brain and Behavior N2 - Objective Vertigo is a common presentation of vertebrobasilar stroke. Anecdotal reports have shown that vertigo occurs more often in multiple than in single brainstem or cerebellar infarctions. We examined the relation between the location and volume of infarction and vertigo in patients with vertebrobasilar stroke. Methods Consecutive patients with vertebrobasilar stroke were prospectively recruited. The infarction location and volume were assessed in the diffusion‐weighted magnetic resonance imaging. Results Fifty‐nine patients were included, 32 (54.2%) with vertigo and 27 (45.8%) without vertigo. The infarction volume did not correlate with National Institute of Health Stroke Scale (NIHSS) score on admission (Spearman ρ = .077, p = .56) but correlated with modified Rankin Scale (ρ = .37, p = .004) on discharge. In the vertigo group, the proportion of men was lower (53.1% vs. 77.8%, p = .049), fewer patients had focal neurological deficits (65.6% vs. 96.3%, p = .004), patients tended to present later (median [IQR] was 7.5 [4–46] vs. 4 [2–12] hours, p = .052), numerically fewer patients received intravenous thrombolysis (15.6% vs. 37%, p = .06), and the total infarction volume was larger (5.6 vs. 0.42 cm3, p = .008) than in nonvertigo group. In multivariate logistic regression, infarction location either in the cerebellum or in the dorsal brainstem (odds ratio [OR] 16.97, 95% CI 3.1–92.95, p = .001) and a total infarction volume of >0.48 cm3 (OR 4.4, 95% CI 1.05–18.58, p = .043) were related to vertigo. In another multivariate logistic regression, after adjusting for age, sex, intravenous thrombolysis, serum level of white blood cells, and atrial fibrillation, vertigo independently predicted a total infarction volume of >0.48 cm3 (OR 5.75, 95% CI 1.43–23.08, p = .01). Conclusion Infarction location in the cerebellum and/or dorsal brainstem is an independent predictor of vertigo. Furthermore, larger infarction volume in these structures is associated with vertigo. A considerable proportion of patients with vascular vertigo present without focal neurological deficits posing a diagnostic challenge. National Institute of Health Stroke Scale is not sensitive for vertebrobasilar stroke. KW - brain stem KW - cerebellum KW - infarction volume KW - stroke KW - vertebrobasilar insufficiency KW - vertigo Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218047 VL - 10 IS - 3 ER - TY - THES A1 - Elhfnawy, Ahmed T1 - Relation between the length of the internal carotid stenotic segment and ischemic cerebrovascular events as well as white matter lesion load T1 - Zusammenhang zwischen der Stenoselänge der Arteria carotis interna und ischämischen zerebrovaskulären Ereignissen sowie der Läsionslast der weißen Substanz N2 - Background and Purpose: Internal carotid artery stenosis ≥70% is a leading cause of ischemic cerebrovascular events. However, a considerable percentage of stroke survivors with symptomatic internal carotid artery stenosis have <70% stenosis with a vulnerable plaque. Whether the length of internal carotid artery stenosis is associated with high risk of ischemic cerebrovascular events or with white matter lesions is poorly investigated. Our main aim was to investigate the relation between the length of internal carotid artery stenosis and the development of ischemic cerebrovascular events as well as ipsi-, contralateral as well as mean white matter lesion load. Methods: In a retrospective cross-sectional study, 168 patients with 208 internal carotid artery stenosis were identified. The degree and length of internal carotid artery stenosis as well as plaque morphology (hypoechoic, mixed or echogenic) were assessed on ultrasound scans. The white matter lesions were assessed in 4 areas separately, (periventricular and deep white matter lesions on each hemisphere), using the Fazekas scale. The mean white matter lesions load was calculated as the mean of these four values. Results: A statistically significant inverse correlation between the ultrasound-measured length and degree of internal carotid artery stenosis was detected for symptomatic internal carotid artery stenosis ≥70% (Spearman correlation coefficient ρ = –0.57, p < 0.001, n = 51) but neither for symptomatic internal carotid artery stenosis <70% (ρ = 0.15, p = 0.45, n = 27) nor for asymptomatic internal carotid artery stenosis (ρ = 0.07, p = 0.64, n = 54). The median (IQR) length for symptomatic internal carotid artery stenosis <70% and ≥70% was 17 (15–20) and 15 (12–19) mm (p = 0.06), respectively, while that for symptomatic internal carotid artery stenosis <90% and symptomatic internal carotid artery stenosis 90% was 18 (15–21) and 13 (10–16) mm, respectively (p < 0.001). Among patients with internal carotid artery stenosis <70%, a cut-off length of ≥16 mm was found for symptomatic internal carotid artery stenosis rather than asymptomatic internal carotid artery stenosis with a sensitivity and specificity of 74.1% and 51.1%, respectively. Irrespective of the stenotic degree, plaques of the symptomatic internal carotid artery stenosis compared to asymptomatic internal carotid artery stenosis were significantly more often echolucent (43.2 vs. 24.6%, p = 0.02). The length but not the degree of internal carotid artery stenosis showed a very slight trend toward association with ipsilateral white matter lesions and with mean white matter lesions load. Conclusion: We found a statistically insignificant tendency for the ultrasound-measured length of symptomatic internal carotid artery stenosis <70% to be longer than that of symptomatic internal carotid artery stenosis ≥70%. Moreover, the ultrasound-measured length of symptomatic internal carotid artery stenosis <90% was significantly longer than that of symptomatic internal carotid artery stenosis 90%. Among patients with symptomatic internal carotid artery stenosis ≥70%, the degree and length of stenosis were inversely correlated. Furthermore, we have shown that a slight correlation exists between the length of stenosis and the presence of ipsilateral white matter lesions which might be due to microembolisation originating from the carotid plaque. Larger studies are needed before a clinical implication can be drawn from these results. N2 - Hintergrund: Stenose der A. carotis interna ≥70% ist eine der führenden Ursachen für ischämische zerebrovaskuläre Ereignisse. Ein beträchtlicher Prozentsatz der Schlaganfall-Überlebenden mit symptomatischer Stenose der A. carotis interna weist jedoch eine Stenose <70% mit einer „vulnerable Plaque“ auf. Ob die Länge der Stenose der A. carotis interna mit einem hohen Risiko für ischämische zerebrovaskuläre Ereignisse oder mit Läsionen der weißen Substanz verbunden ist, wird nur unzureichend untersucht. Unser Hauptziel war es, den Zusammenhang zwischen der Länge der Stenose der Aerteria carotis interna und der Entwicklung von ischämischen zerebrovaskulären Ereignissen sowie der ipsi-, kontralateralen und mittleren Läsionslast der weißen Substanz zu untersuchen. Methode: In einer retrospektiven Querschnittsstudie wurden 168 Patienten mit 208 Stenosen der A. carotis interna identifiziert. Der Stenosegrad und die Stenoselänge sowie die Plaquemorphologie (echoarm, gemischt oder echogen) wurden mittels Ultraschall untersucht. Die Läsionen der weißen Substanz wurden in 4 Bereichen (periventrikuläre und subkortilae Läsionen der weißen Substanz, jeweils auf jeder Hemisphäre) mittels Fazekas-Skala bewertet. Der mittlere dieser vier Werte wurde ebenso berechnet. Ergebnisse: Eine statistisch signifikante inverse Korrelation zwischen der mit Ultraschall gemessenen Länge und dem Stenosegrad der A. carotis interna wurde für eine symptomatische Stenose der A. carotis interna von ≥ 70% festgestellt (Spearman-Korrelationskoeffizient ρ = –0,57, p <0,001, n = 51), jedoch keine bei symptomatischer Stenose der A. carotis interna <70% (ρ = 0,15, p = 0,45, n = 27) und bei asymptomatischer Stenose der A. carotis interna (ρ = 0,07, p = 0,64, n = 54). Die mediane Länge (IQR) für symptomatische Stenosen der A. carotis interna <70% und ≥ 70% betrug 17 (15–20) bzw. 15 (12–19) mm (p = 0,06), die für symptomatische Stenosen der A. carotis interna <90% und symptomatische Stenose der A. carotis interna 90% betrugen 18 (15–21) bzw. 13 (10–16) mm (p <0,001). Bei Patienten mit einer Stenose der A. carotis interna <70% wurde für eine symptomatische Stenose der A. carotis interna einen Grenzwert von ≥ 16 mm gefunden, und nicht für eine asymptomatische Stenose der A. carotis interna mit einer Sensitivität und Spezifität von 74,1% bzw. 51,1%. Unabhängig vom stenotischen Grad waren Plaques der symptomatischen Stenose der A. carotis interna im Vergleich zur asymptomatischen Stenose der A. carotis interna signifikant häufiger echoarm (43,2 vs. 24,6%, p = 0,02). Die Stenoselänge, aber nicht der Stenosegrad der A. carotis interna zeigte einen sehr geringen Trend zur Assoziation mit ipsilateralen Läsionen der weißen Substanz und mit der mittleren Läsionslast der weißen Substanz. Schlussfolgerung: Es wurde eine statistisch nicht signifikante Tendenz gefunden, dass die ultraschallgemessene Länge der symptomatischen Stenose der A. carotis interna <70% länger ist als die der symptomatischen Stenose der A. carotis interna ≥ 70%. Darüber hinaus war die durch Ultraschall gemessene Länge der symptomatischen Stenose der A. carotis interna <90% signifikant länger als die der symptomatischen Stenose der A. carotis interna 90%. Bei Patienten mit symptomatischer Stenose der A. carotis interna ≥ 70% waren Stenosegrad und Stenoselänge invers korreliert. Darüber hinaus haben wir gezeigt, dass eine leichte Korrelation zwischen der Stenoselänge und der ipsilateralen Läsionen der weißen Substanz besteht, die möglicherweise auf eine Mikroembolisation zurückzuführen sind, die vom Carotis-Plaque herrührt. Größere Studien sind erforderlich, bevor aus diesen Ergebnissen eine klinische Implikation abgeleitet werden kann. KW - Carotisstenose KW - Schlaganfall KW - White matter lesions KW - Stenosis length KW - Stenosis degree Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191616 ER - TY - THES A1 - Schmid, Benedikt T1 - Relation between cerebral arterio-venous transit time and neuropsychological performance in patients with vascular dementia T1 - Beziehung zwischen zerebraler arterio-venöser Transitzeit und neuropsychologischer Testleistung bei Patienten mit vaskulärer Demenz N2 - Dementia, or any form of degenerative cognitive decline, is one of the major problems in present, and even more will be in future medicine. With Alzheimer's disease (AD) being the most prevalent, Vascular Dementia is the second most entity of dementing processes in the elderly. As diagnostic criteria are still imprecise and in many cases do not embrace early stages of the disease, recent studies have proposed more detailed classifications of the newly created condition Vascular Cognitive Impairment (VCI). Of all conditions subsumed under this term, subcortical small-vessel alterations are the most common cause for cognitive decline. The diagnosis of dementia / cognitive impairment is presently often made in late stages of the disease, when therapeutical options are poor. Thus, early detection of changes of the subcortical small vessels is desirable, when there is still time to identify and aggressively treat risk factors and underlying conditions like diabetes, hyper- or hypotension, and hyperlipidemia. This study aimed to evaluate whether cTT correlates to cognitive dysfunction, i.e. if cTT is fit as an early diagnostic tool for VCI. The study cohort included 38 patients from the Neurological Clinic of the Würzburg University hospital admitted due to diagnoses other than dementia or stroke. As a result of this study it turned out that cTT is certainly capable of fulfilling the task to easily and effectively detect and evaluate possible microvascular lesions of the brain with respect to the actual clinical relevance for the patient. When compared to the other proposed diagnostic tools, neuropsychological testing and MRI, the advantages of cTT are obvious: its measurement is a low-cost and quick procedure which would spare both patients and examiners a long neuropsychological exam or complement it. cTT is safe to assess as the only possible risks derive from the use of the contrast agent, which are rare and easily manageable. It has also proven to be more accurate in showing the extent of cognitive impairment than MRI. Finally, it is widely available. The only prerequisite is an ultrasound machine capable of transcranial color-coded duplex sonography. No cost-intensive procedures like MRI are needed. So, with neuropsychological testing remaining the gold standard, cTT here proved to be a reliable alternative which is more time- and cost-effective than MRI. N2 - Demenzen und alle anderen Formen kongnitiver Leistungseinschränkungen gehören heute zu den bedeutendsten medizinischen Herausforderungen und werden in der Zukunft noch weiter an Bedeutung gewinnen. Die häufigste der Demenzerkrankungen bei älteren Patienten ist die Alzheimer-Krankheit, gefolgt von den vaskulären Demenzen. Da die Diagnosekriterien in vielen Fällen noch unpräzise sind und vor allem frühe Stadien der Erkrankung nicht erfassen, wurden in der neueren Literatur detailliertere Untergruppen der neu eingeführten Entität „vaskuläre kognitive Funktionsstörung“ (vascular cognitive impairment, VCI) etabliert. Subkortikale Veränderungen an den kleinsten Gefäßen stellen unter allen Pathologien, die unter diesem Begriff subsumiert sind, die häufigste Ursache für kognitive Leistungseinschränkungen dar. Die Diagnose Demenz bzw. VCI wird oft erst in späten Stadien der Krankheit gestellt, wenn die therapeutischen Mittel bereits stark begrenzt sind. Deshalb wäre eine Möglichkeit zur frühen Entdeckung subkortikaler Gefäßveränderungen wünschenswert in einem Stadium der Krankheit, in dem es noch möglich ist, Risikofaktoren wie Diabetes mellitus, arterielle Hyper- und Hypotonie und Fettstoffwechselstörungen auszumachen und konseqeuent zu behandeln. Das Ziel dieser Studie war es zu untersuchen, ob cTT mit dem Ausmaß kognitiver Dysfunktion korreliert, ob also cTT als frühes diagnostisches Verfahren für vaskuläre demenzielle Prozesse geeignet ist. Die Studienpopulation umfasste 38 Patienten aus der Klinik und Poliklinik für Neurologie der Universität Würzburg. Ein Ergebnis dieser Studie ist, dass die cTT sicherlich in der Lage ist, einfach und zuverlässig mögliche mikrovaskuläre Schädigungen des Gehirns auch im Hinblick auf ihre tatsächliche klinische Relevanz zu entdecken. Im Vergleich mit anderen Diagnoseverfahren (Testpsychologie und MRT) sind die Vorteile der cTT offensichtlich: die Messung ist ein kostengünstiges und schnelles Verfahren, das sowohl Patienten als auch Untersuchern eine langwierige neuropsychologische Untersuchung erspart. Die Messung der cTT ist ein sicheres Verfahren, da die wenigen aus der Anwendung des Kontrastmittels sich ergebenden Risiken selten und gegebenenfalls leicht behandelbar sind. Zudem erwies sich die cTT als präziser bei der Aufgabe, das Ausmaß kognitiver Dysfunktion zu messen, als es die MRT vermochte. Zuletzt ist die cTT auch flächendeckend verfügbar. Die einzige Voraussetzung ist ein Duplex-fähiges Ultraschallgerät. Kostenintesive Untersuchungen wie die MRT können vermieden werden. Wenn auch die Testpsychologie der Goldstandard bleiben wird, erwies sich die cTT als zuverlässige Alternative die im Vergleich zur MRT sowohl Zeit als auch Kosten spart. KW - Demenz KW - Psychologische Diagnostik KW - Neuropsychologie KW - Ultraschall KW - Ultraschalldiagnostik KW - dementia KW - neuropsychology KW - ultrasound Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-71234 ER - TY - THES A1 - Schanz, Stefan T1 - Rehabilitation des Schlaganfalls – Evaluation eines interdisziplinären Behandlungskonzepts auf einer spezialisierten Station T1 - Stroke rehabilitation – evaluation of an interdisciplinary treatment concept on a specialized ward N2 - Die Rehabilitation von Schlaganfallpatienten erfordert ein interdisziplinäres Vorgehen. Dies ist im klinischen Alltag oft nur schwer umsetzbar. Im Jahr 2011 wurde daher im Neurologischen Rehabilitationszentrum Quellenhof in Bad Wildbad ein spezielles Behandlungskonzept für Schlaganfallpatienten entwickelt. Mit dieser Studie sollte die Wirksamkeit dieses neuen Konzepts untersucht werden. Dabei wurde die Behandlung im Schlaganfallkonzept mit der bisher üblichen Behandlung verglichen. Zielparameter waren der Barthel-Index und die modifizierte Rankin-Skala bei Aufnahme und bei Entlassung. Die Ergebnisse zeigen, dass sowohl die bisherige Behandlung als auch die Behandlung im Schlaganfallkonzept effektiv sind. Im Schlaganfallkonzept konnte jedoch ein größerer Zugewinn an alltagsrelevanten Fähigkeiten erzielt werden; zudem berichteten Pflegekräfte und Therapeuten eine verbesserte Zusammenarbeit. Somit steigert das Schlaganfallkonzept nicht nur die Alltagskompetenz der Patienten, sondern auch den Wissenstransfer zwischen den Berufsgruppen und die Interdisziplinarität. N2 - Rehabilitation of patients with stroke requires an interdisciplinary approach that is difficult to implement in everyday clinical life. Therefore, in 2011 the Neurological Rehabilitation Center Quellenhof in Bad Wildbad established a unique therapy concept. This study investigated the efficacy of this newly developed concept by comparing it to usual treatment. Main outcome parameters were the Barthel-Index and the modified Rankin-Scale at admission and discharge. The results show that the therapy in the usual treatment group as well as in the newly developed concept group is effective. However, therapy in the newly developed concept group leads to more progress in the activities of daily living of patients and also improved knowledge and cooperation within the rehabilitation team. KW - Schlaganfall KW - Rehabilitation KW - Barthel-Index modifizierte Rankin-Skala KW - stroke KW - rehabilitation KW - Barthel-Index modified Rankin-Scale Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260011 ER - TY - JOUR A1 - Kraft, Peter A1 - Drechsler, Christiane A1 - Gunreben, Ignaz A1 - Heuschmann, Peter Ulrich A1 - Kleinschnitz, Christoph T1 - Regulation of Blood Coagulation Factors XI and XII in Patients with Acute and Chronic Cerebrovascular Disease: A Case-Control Study JF - Cerebrovascular Diseases N2 - Background: Animal models have implicated an integral role for coagulation factors XI (FXI) and XII (FXII) in thrombus formation and propagation of ischemic stroke (IS). However, it is unknown if these molecules contribute to IS pathophysiology in humans, and might be of use as biomarkers for IS risk and severity. This study aimed to identify predictors of altered FXI and FXII levels and to determine whether there are differences in the levels of these coagulation factors between acute cerebrovascular events and chronic cerebrovascular disease (CCD). Methods: In this case-control study, 116 patients with acute ischemic stroke (AIS) or transitory ischemic attack (TIA), 117 patients with CCD, and 104 healthy volunteers (HVs) were enrolled between 2010 and 2013 at our University hospital. Blood sampling was undertaken once in the CCD and HV groups and on days 0, 1, and 3 after stroke onset in patients with AIS or TIA. Correlations between serum FXI and FXII levels and demographic and clinical parameters were tested by linear regression and analysis of variance. Results: The mean age of AIS/TIA patients was 70 ± 12. Baseline clinical severity measured with NIHSS and Barthel Index was 4.8 ± 6.0 and 74 ± 30, respectively. More than half of the patients had an AIS (58%). FXI levels were significantly correlated with different leukocyte subsets (p < 0.05). In contrast, FXII serum levels showed no significant correlation (p > 0.1). Neither FXI nor FXII levels correlated with CRP (p > 0.2). FXII levels were significantly higher in patients with CCD compared with those with AIS/TIA (mean ± SD 106 ± 26% vs. 97 ± 24%; univariate analysis: p < 0.05); these differences did not reach significance in multivariate analysis adjusted for sex and age. FXI levels did not differ significantly between study groups. Sex and age were significantly associated with FXI and/or FXII levels in patients with AIS/TIA (p < 0.05). In contrast, no statistical significant influence was found for treatment modality (thrombolysis or not), pre-treatment with platelet inhibitors, and severity of stroke. Conclusions: In this study, there was no differential regulation of FXI and FXII levels between disease subtypes but biomarker levels were associated with patient and clinical characteristics. FXI and FXII levels might be no valid biomarker for predicting stroke risk. KW - biomarker KW - factor XI KW - factor XII KW - ischemic stroke KW - chronic cerebrovascular disease Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199076 SN - 1015-9770 SN - 1421-9786 N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively. VL - 38 IS - 5 ER - TY - THES A1 - Klein, Oliver T1 - Regulation der Chemokinexpression in humanen zerebralen Endothelzellen T1 - regulation of chemokinexpression in human cerebral endothelial cells N2 - Humane zerebrale Endothelzellen sind in vitro in der Lage nach Stimulation mit proinflammatorischen Zytokinen Chemokine zu produzieren. Diese sind von Bedeutung in der Entwicklung von entzündlichen ZNS-Erkrankungen. So scheinen zerebrale Endothelzellen neben Astrozyten und Mikroglia als Produzenten dieser Schlüsselmoleküle zu fungieren. N2 - Human cerebral endothelial cells are able to produce chemokines after stimulation with proinflammatory cytokines. Chemokines have a pivotal role in inflammatory cns disorders. So cerebral endothelial cells seems to be another cell typ besides astrocytes and microglia, that synthesize these important molecules. KW - Blut-Hirn-Schranke KW - zerebrale Endothelzellen KW - Chemokine KW - blood-brain-barrier KW - cerebral endothelial cells KW - chemokines Y1 - 2004 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-11567 ER - TY - THES A1 - Gößler, Ulrich T1 - Regulation der Capsaicin-Sensitivität von murinen Spinalganglienzellen durch neurotrophe Faktoren T1 - Regulation of Capsaicin-Sensitivity in murine dorsal root ganglia by neurotrophic factors N2 - In der vorliegenden Arbeit konnte anhand von Zellkulturen von Spinalganglienzellen herausgearbeitet werden, dass die Regulation der Capsaicin-Sensitivität in der Maus von vielen Faktoren abhängig ist: Es ließ sich ein komplexes System der Regulation von Capsaicin-induziertem Cobalt-Uptake als Surrogat-Marker für nozizeptive Neurone herausarbeiten: Zum einen konnte gezeigt werden, dass NGF dosisabhängig Einfluss auf die peptiderge Neuronenpopulation nimmt und über den niederaffinen NGF-Rezeptor p75NTR Capsaicin-Empfindlichkeit, CGRP-Expression und VR1-Expression reguliert. Dieser Rezeptor hat dabei keine Bedeutung für den konstitutiven Cobalt-Uptake, jedoch für die Aufrechterhaltung des Cobalt-Uptakes in der Zellkultur. Zum anderen konnte gezeigt werden, dass GDNF dosisabhängig den Anteil der Neurone mit Capsaicin-induziertem Cobalt-Uptake reguliert und dosisabhängig parallel in zwei Gruppen von Spinalganglienzellen den Cobalt-Uptake induziert: einerseits über den GDNF-Rezeptor GFRa2 und die Rezeptortyrosinkinase c-RET in der IB4-Population, andererseits über GFRa1 und SRC-Kinasen in der GFRa1-Population. In der vorliegenden Arbeit konnte gezeigt werden, dass Spinalganglienzellen die Sensibilität gegenüber noxischen Reizen selbständig komplex regulieren und damit auf äußere Einflüsse reagieren können. Möglicherweise ergeben sich in Zukunft neue Ansatzpunkte der Therapie dadurch, dass die Neurone direkt beeinflusst werden können. N2 - NGF is required for the survival of nociceptive sensory neurons during development and it continues to regulate the phenotype of nociceptors in the adult. Here we asked whether the NGF-mediated modulation of capsaicin-sensitivity, CGRP- and VR1-expression depends on the presence of the low affinity neurotrophin receptor p75 (p75NTR). DRG-neurons of adult Balb/C mice or mice lacking p75NTR were cultured in the presence or absence of NGF (50 ng/ml) for 6 hours or 6 days. Sensitivity to capsaicin (1µM) was assessed histochemically by the method of cobalt uptake. Six hours after dissociation there was no difference of the mean (±SEM) percentage of capsaicin induced cobalt uptake, CGRP- and VR1-expression in wildtype mice or mice lacking p75NTR. When neurons of wildtype mice were cultured for 6 days in the absence of NGF, cobalt uptake, CGRP- and VR1-expreeion decreased significantly to 12 ± 1 %. This decline of capsaicin sensitivity could dose-dependently been prevented by NGF, but the normalisation was absent when function blocking antibodies against p75NTR were added. Likewise animals lacking p75NTR showed the same decline of cobalt uptake, CGRP- and VR1expression as wildtype mice, but addition of NGF failed to rescue capsaicin-sensitivity. We conclude that p75NTR is not important for the development and maintenance of constitutive capsaicin-sensitivity, CGRP- and VR1-expression in adult mice, but is required for the NGF-mediated rescue of capsaicin sensitivity, CGRP- and VR1expression in cell culture. KW - Capsaicin KW - Neurotrophe Faktoren KW - Capsaicin KW - Neurotrophic Factors Y1 - 2003 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-8500 ER - TY - JOUR A1 - Haarmann, Axel A1 - Zimmermann, Lena A1 - Bieber, Michael A1 - Silwedel, Christine A1 - Stoll, Guido A1 - Schuhmann, Michael K. T1 - Regulation and release of vasoactive endoglin by brain endothelium in response to hypoxia/reoxygenation in stroke JF - International Journal of Molecular Sciences N2 - In large vessel occlusion stroke, recanalization to restore cerebral perfusion is essential but not necessarily sufficient for a favorable outcome. Paradoxically, in some patients, reperfusion carries the risk of increased tissue damage and cerebral hemorrhage. Experimental and clinical data suggest that endothelial cells, representing the interface for detrimental platelet and leukocyte responses, likely play a crucial role in the phenomenon referred to as ischemia/reperfusion (I/R)-injury, but the mechanisms are unknown. We aimed to determine the role of endoglin in cerebral I/R-injury; endoglin is a membrane-bound protein abundantly expressed by endothelial cells that has previously been shown to be involved in the maintenance of vascular homeostasis. We investigated the expression of membranous endoglin (using Western blotting and RT-PCR) and the generation of soluble endoglin (using an enzyme-linked immunosorbent assay of cell culture supernatants) after hypoxia and subsequent reoxygenation in human non-immortalized brain endothelial cells. To validate these in vitro data, we additionally examined endoglin expression in an intraluminal monofilament model of permanent and transient middle cerebral artery occlusion in mice. Subsequently, the effects of recombinant human soluble endoglin were assessed by label-free impedance-based measurement of endothelial monolayer integrity (using the xCELLigence DP system) and immunocytochemistry. Endoglin expression is highly inducible by hypoxia in human brain endothelial monolayers in vitro, and subsequent reoxygenation induced its shedding. These findings were corroborated in mice during MCAO; an upregulation of endoglin was displayed in the infarcted hemispheres under occlusion, whereas endoglin expression was significantly diminished after transient MCAO, which is indicative of shedding. Of note is the finding that soluble endoglin induced an inflammatory phenotype in endothelial monolayers. The treatment of HBMEC with endoglin resulted in a decrease in transendothelial resistance and the downregulation of VE-cadherin. Our data establish a novel mechanism in which hypoxia triggers the initial endothelial upregulation of endoglin and subsequent reoxygenation triggers its release as a vasoactive mediator that, when rinsed into adjacent vascular beds after recanalization, can contribute to cerebral reperfusion injury. KW - endoglin KW - soluble endoglin KW - CD105 KW - human brain endothelium KW - HBMEC KW - hypoxia KW - reoxygenation KW - ischemia/reperfusion injury KW - vascular homeostasis KW - middle cerebral artery occlusion KW - stroke Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284361 SN - 1422-0067 VL - 23 IS - 13 ER - TY - THES A1 - Fischer, Stefan Martin T1 - Regulation and functional consequences of MCP-1 expression in a model of Charcot-Marie-Tooth 1B disease T1 - Regulation und funktionelle Relevanz von MCP-1 in einem Model der Charcot-Marie-Tooth 1B Erkrankung N2 - Charcot-Marie-Tooth 1B (CMT1B) is a progressive inherited demyelinating disease of human peripheral nervous system leading to sensory and/or motor function disability and is caused by mutations in the P0 gene. Mice heterozygously deficient for P0 (P0+/-) are an adequate model of this human disorder showing myelin degeneration, formation of onion bulbs, remyelination and a reduced motor conduction velocity of around 30m/s similar to patients. Previously, it had been shown that T-lymphocytes and macrophages play a crucial role during pathogenesis in peripheral nerves of P0+/- mice. Both, T-lymphocytes and macrophages increase in number in the endoneurium and deletion of T-lymphocytes or deletion of a macrophage-directed cytokine ameliorates the disease. In this study the monocyte chemoattractant protein-1 (MCP-1) was identified as an early regulated cytokine before onset of disease is visible at the age of six months. MCP-1 mRNA and protein expression could be detected in femoral quadriceps and sciatic nerves of P0+/- mice already at the age of one month but not in cutaneous saphenous nerves which are never affected by the disease. MCP-1 was shown to be expressed by Schwann cells and to mediate the immigration of immune cells into peripheral nerves. Deletion of MCP-1 in P0+/- mice accomplished by crossbreeding P0 and MCP-1 deficient mice revealed a substantial reduction of immune cells in peripheral nerves of P0+/-/MCP-1+/- and P0+/-/MCP-1-/- mice at the age of six months. In twelve months old mice reduction of immune cells in peripheral nerves is accompanied by amelioration of demyelinating disease in P0+/-/MCP-1+/- and aggravation of demyelinating disease in lumbar ventral roots of P0+/ /MCP-1-/- mice in comparison to P0+/ /MCP 1+/+ mice. Furthermore, activation of the MEK1/2-ERK1/2 signalling cascade could be demonstrated to take place in Schwann cells of affected peripheral nerves of P0+/- mice overlapping temporarily and spatially with MCP-1 expression. An animal experiment using a MEK1/2-inhibitor in vivo, CI-1040, revealed that upon reduction of ERK1/2 phosphorylation MCP-1 mRNA expression is diminished suggesting that the activation of the MEK1/2-ERK1/2 signalling cascade is necessary for MCP-1 expression. Additionally, peripheral nerves of P0+/- mice showing reduced ERK1/2 phosphorylation and MCP-1 mRNA expression also show reduced numbers of macrophages in the endoneurium. This study shows a molecular link between a Schwann cell based mutation and immune cell function. Inhibition of the identified signalling cascade might be a putative target for therapeutic approaches. N2 - Die humane Erkrankung Charcot-Marie-Tooth 1B (CMT1B) ist eine erbliche, chronisch fortschreitende Erkrankung des peripheren Nervensystems die durch Mutation des P0-Gens verursacht wird und zu motorischen und/oder sensorischen Defiziten führt. Sehr ähnlich der humanen Erkrankung weist das Mausmodell, eine für das Myelinprotein P0 heterozygot-defiziente Maus (P0+/-), Degeneration peripheren Myelins, aufeinanderfolgende Zyklen von De- und Remyelinisierung als auch reduzierte Nervenleitgeschwindigkeiten auf. Wissenschaftliche Untersuchungen am Mausmodell ergaben eine Beteiligung von T-Lymphozyten und Makrophagen an der Pathogenese. In dieser Studie wurde das Chemokin „Monocyte Chemoattractant Protein-1“ (MCP-1) als pathogen-relevant in P0+/- Mäusen identifiziert. MCP-1 mRNA und Protein wurden sowohl im Alter von sechs und zwölf Monaten nachgewiesen, Stadien, in denen morphologische Veränderungen peripherer Nerven von P0+/- Mäusen zu erkennen sind, aber auch im Alter von einen und drei Monaten, ein Alter bei dem pathologischen Veränderungen nicht zu finden sind. Mit Hilfe von MCP-1 defizienten Mäusen (MCP-1-/-) und Verpaarung mit P0-defizienten Mäusen konnten weiterführende Untersuchungen zur Rolle von MCP-1 im peripheren Nerv der Maus durchgeführt werden. So zeigte es sich mittels Transplantation von GFP-positivem Knochenmark, dass MCP 1 die Infiltration von Makrophagen aus dem Blut in periphere Nerven vermittelt. Weiterhin konnte gezeigt werden, dass periphere Nerven von sechs Monate alten P0+/-/MCP-1+/- und P0+/-/MCP-1-/- Mäusen trotz signifikant niedrigerer Anzahl von Immunzellen keine Milderung der Demyelinisierung zeigen. Hingegen weisen periphere Nerven von zwölf Monate alten P0+/ /MCP-1+/- Mäusen sowohl weniger Makrophagen und T-Lymphozyten als auch wesentlich weniger pathologische Veränderungen auf. Periphere Nerven von P0+/-/MCP-1-/- Tieren dagegen zeigen nur eine nicht signifikante Reduktion von Immunzellen und sogar eine Verschlechterung des Phänotyps im Vergleich zu ventralen Spinalwurzeln von P0+/-/MCP-1+/+ Mäusen. Weiterführende Untersuchungen ergaben, dass eine Aktivierung der MEK1/2-ERK1/2 Signalkaskade sowohl in peripheren Nerven von drei und sechs Monate alten P0+/- Mäusen zu finden ist, allerdings, ähnlich der Expression von MCP-1, nur in peripheren Nerven, die von der Demyelinisierung betroffen sein können. Unter Verwendung eines Inhibitors der Kinasen MEK1 und 2 konnte in vivo gezeigt werden, dass Phosphorylierung von ERK1/2 für die erhöhte MCP-1 Expression in peripheren Nerven von P0+/- Mäusen notwendig ist. Darüber hinaus wurde durch Verminderung der ERK1/2-Phosphorylierung eine Reduktion von Makrophagen im Endoneurium von P0+/- Tieren erzielt. KW - Schwann-Zelle KW - Peripheres Nervensystem KW - Charcot-Marie-Syndrom KW - Makrophage KW - Entmarkung KW - Myelin KW - Chemokine KW - Schwann cell KW - Peripheral nervous system KW - Charcot-Marie-Tooth syndrom KW - Macrophage KW - Demyelination KW - Myelin KW - Chemokine Y1 - 2008 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-29189 ER - TY - JOUR A1 - Evdokimov, Dimitar A1 - Frank, Johanna A1 - Klitsch, Alexander A1 - Unterecker, Stefan A1 - Warrings, Bodo A1 - Serra, Jordi A1 - Papagianni, Aikaterini A1 - Saffer, Nadine A1 - Meyer zu Altenschildesche, Caren A1 - Kampik, Daniel A1 - Malik, Rayaz A. A1 - Sommer, Claudia A1 - Üceyler, Nurcan T1 - Reduction of skin innervation is associated with a severe fibromyalgia phenotype JF - Annals of Neurology N2 - Objective: To assess patterns and impact of small nerve fiber dysfunction and pathology in patients with fibromyalgia syndrome (FMS). Methods: One hundred seventeen women with FMS underwent neurological examination, questionnaire assessment, neurophysiology assessment, and small fiber tests: skin punch biopsy, corneal confocal microscopy, microneurography, quantitative sensory testing including C-tactile afferents, and pain-related evoked potentials. Data were compared with those of women with major depressive disorder and chronic widespread pain (MD-P) and healthy women. Results: Intraepidermal nerve fiber density (IENFD) was reduced at different biopsy sites in 63% of FMS patients (MDP: 10%, controls: 18%; p < 0.001 for each). We found 4 patterns of skin innervation in FMS: normal, distally reduced, proximally reduced, and both distally and proximally reduced (p < 0.01 for each compared to controls). Microneurography revealed initial activity-dependent acceleration of conduction velocity upon low frequencies of stimulation in 1A fibers, besides 1B fiber spontaneous activity and mechanical sensitization in FMS patients. FMS patients had elevated warm detection thresholds (p < 0.01), impaired C-tactile afferents (p < 0.05), and reduced amplitudes (p < 0.001) of pain-related evoked potentials compared to controls. Compared to FMS patients with normal skin innervation, those with generalized IENFD reduction had higher pain intensity and impairment due to pain, higher disease burden, more stabbing pain and paresthesias, and more anxiety (p < 0.05 for each). FMS patients with generalized IENFD reduction also had lower corneal nerve fiber density (p < 0.01) and length (p < 0.05). Interpretation: The extent of small fiber pathology is related to symptom severity in FMS. This knowledge may have implications for the diagnostic classification and treatment of patients with FMS. KW - fibromyalgia Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206168 VL - 86 IS - 4 ER - TY - JOUR A1 - Lange, Florian A1 - Steigerwald, Frank A1 - Malzacher, Tobias A1 - Brandt, Gregor Alexander A1 - Odorfer, Thorsten Michael A1 - Roothans, Jonas A1 - Reich, Martin M. A1 - Fricke, Patrick A1 - Volkmann, Jens A1 - Matthies, Cordula A1 - Capetian, Philipp D. T1 - Reduced Programming Time and Strong Symptom Control Even in Chronic Course Through Imaging-Based DBS Programming JF - Frontiers in Neurology N2 - Objectives: Deep brain stimulation (DBS) programming is based on clinical response testing. Our clinical pilot trial assessed the feasibility of image-guided programing using software depicting the lead location in a patient-specific anatomical model. Methods: Parkinson's disease patients with subthalamic nucleus-DBS were randomly assigned to standard clinical-based programming (CBP) or anatomical-based (imaging-guided) programming (ABP) in an 8-week crossover trial. Programming characteristics and clinical outcomes were evaluated. Results: In 10 patients, both programs led to similar motor symptom control (MDS-UPDRS III) after 4 weeks (medicationOFF/stimulationON; CPB: 18.27 ± 9.23; ABP: 18.37 ± 6.66). Stimulation settings were not significantly different, apart from higher frequency in the baseline program than CBP (p = 0.01) or ABP (p = 0.003). Time spent in a program was not significantly different (CBP: 86.1 ± 29.82%, ABP: 88.6 ± 29.0%). Programing time was significantly shorter (p = 0.039) with ABP (19.78 ± 5.86 min) than CBP (45.22 ± 18.32). Conclusion: Image-guided DBS programming in PD patients drastically reduces programming time without compromising symptom control and patient satisfaction in this small feasibility trial. KW - directional deep brain stimulation KW - image-guided programming KW - subthalamic nucleus KW - chronic stimulation KW - randomized controlled double-blind study KW - Parkinson's disease Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-249634 SN - 1664-2295 VL - 12 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 - Klitsch, Alexander A1 - Evdokimov, Dimitar A1 - Frank, Johanna A1 - Thomas, Dominique A1 - Saffer, Nadine A1 - Meyer zu Altenschildesche, Caren A1 - Sisignano, Marco A1 - Kampik, Daniel A1 - Malik, Rayaz A. A1 - Sommer, Claudia A1 - Üçeyler, Nurcan T1 - Reduced association between dendritic cells and corneal sub‐basal nerve fibers in patients with fibromyalgia syndrome JF - Journal of the Peripheral Nervous System N2 - In our study, we aimed at investigating corneal langerhans cells (LC) in patients with fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) as potential contributors to corneal small fiber pathology. We enrolled women with FMS (n = 134) and SFN (n = 41) who underwent neurological examination, neurophysiology, prostaglandin analysis in tear fluid, and corneal confocal microscopy (CCM). Data were compared with those of 60 age‐matched female controls. After screening for dry eye disease, corneal LC were counted and sub‐classified as dendritic (dLC) and non‐dendritic (ndLC) cells with or without nerve fiber association. We further analyzed corneal nerve fiber density (CNFD), length (CNFL), and branch density (CNBD). Neurological examination indicated deficits of small fiber function in patients with SFN. Nerve conduction studies were normal in all participants. Dry eye disease was more prevalent in FMS (17%) and SFN (28%) patients than in controls (5%). Tear fluid prostaglandin levels did not differ between FMS patients and controls. While corneal LC density in FMS and SFN patients was not different from controls, there were fewer dLC in association with nerve fibers in FMS and SFN patients than in controls (P < .01 each). Compared to controls, CNFL was lower in FMS and SFN patients (P < .05 each), CNFD was lower only in FMS patients (P < .05), and CNBD was lower only in SFN patients (P < .001). There was no difference in any CCM parameter between patients with and without dry eyes. Our data indicate changes in corneal innervation and LC distribution in FMS and SFN, potentially based on altered LC signaling. KW - corneal confocal microscopy KW - fibromyalgia syndrome KW - Langerhans cells KW - pain KW - small fiber neuropathy Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214150 VL - 25 IS - 1 ER - TY - JOUR A1 - Elhfnawy, Ahmed Mohamed A1 - Elsalamawy, Doaa A1 - Abdelraouf, Mervat A1 - Schliesser, Mira A1 - Volkmann, Jens A1 - Fluri, Felix T1 - Red flags for a concomitant giant cell arteritis in patients with vertebrobasilar stroke: a cross-sectional study and systematic review JF - Acta Neurologica Belgica N2 - Giant cell arteritis (GCA) may affect the brain-supplying arteries, resulting in ischemic stroke, whereby the vertebrobasilar territory is most often involved. Since etiology is unknown in 25% of stroke patients and GCA is hardly considered as a cause, we examined in a pilot study, whether screening for GCA after vertebrobasilar stroke might unmask an otherwise missed disease. Consecutive patients with vertebrobasilar stroke were prospectively screened for GCA using erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hemoglobin, and halo sign of the temporal and vertebral artery on ultrasound. Furthermore, we conducted a systematic literature review for relevant studies. Sixty-five patients were included, and two patients (3.1%) were diagnosed with GCA. Patients with GCA were older in age (median 85 versus 69 years, p = 0.02). ESR and CRP were significantly increased and hemoglobin was significantly lower in GCA patients compared to non-GCA patients (median, 75 versus 11 mm in 1 h, p = 0.001; 3.84 versus 0.25 mg/dl, p = 0.01, 10.4 versus 14.6 mg/dl, p = 0.003, respectively). Multiple stenoses/occlusions in the vertebrobasilar territory affected our two GCA patients (100%), but only five (7.9%) non-GCA patients (p = 0.01). Our literature review identified 13 articles with 136 stroke patients with concomitant GCA. Those were old in age. Headache, increased inflammatory markers, and anemia were frequently reported. Multiple stenoses/occlusions in the vertebrobasilar territory affected around 70% of stroke patients with GCA. Increased inflammatory markers, older age, anemia, and multiple stenoses/occlusions in the vertebrobasilar territory may be regarded as red flags for GCA among patients with vertebrobasilar stroke. KW - giant cell arteritis KW - vertebrobasilar stroke KW - blood sedimentation KW - C-reactive protein KW - hemoglobin KW - stenosis Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-315610 SN - 0300-9009 SN - 2240-2993 VL - 120 IS - 6 ER - TY - JOUR A1 - Biegstraaten, Marieke A1 - Arngrímsson, Reynir A1 - Barbey, Frederic A1 - Boks, Lut A1 - Cecchi, Franco A1 - Deegan, Patrick B A1 - Feldt-Rasmussen, Ulla A1 - Geberhiwot, Tarekegn A1 - Germain, Dominique P A1 - Hendriksz, Chris A1 - Hughes, Derralynn A A1 - Kantola, Ilkka A1 - Karabul, Nesrin A1 - Lavery, Christine A1 - Linthorst, Gabor E A1 - Mehta, Atul A1 - van de Mheen, Erica A1 - Oliveira, João P A1 - Parini, Rossella A1 - Ramaswami, Uma A1 - Rudnicki, Michael A1 - Serra, Andreas A1 - Sommer, Claudia A1 - Sunder-Plassmann, Gere A1 - Svarstad, Einar A1 - Sweeb, Annelies A1 - Terryn, Wim A1 - Tylki-Szymanska, Anna A1 - Tøndel, Camilla A1 - Vujkovac, Bojan A1 - Weidemann, Frank A1 - Wijburg, Frits A A1 - Woolfson, Peter A1 - Hollak, Carla EM T1 - Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document JF - Orphanet Journal of Rare Diseases N2 - Introduction: Fabry disease (FD) is a lysosomal storage disorder resulting in progressive nervous system, kidney and heart disease. Enzyme replacement therapy (ERT) may halt or attenuate disease progression. Since administration is burdensome and expensive, appropriate use is mandatory. We aimed to define European consensus recommendations for the initiation and cessation of ERT in patients with FD. Methods: A Delphi procedure was conducted with an online survey (n = 28) and a meeting (n = 15). Patient organization representatives were present at the meeting to give their views. Recommendations were accepted with ≥75% agreement and no disagreement. Results: For classically affected males, consensus was achieved that ERT is recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but may be considered in patients of ≥16 years in the absence of clinical signs or symptoms of organ involvement. Classically affected females and males with non-classical FD should be treated as soon as there are early clinical signs of kidney, heart or brain involvement, while treatment may be considered in females with non-classical FD with early clinical signs that are considered to be due to FD. Consensus was achieved that treatment should not be withheld from patients with severe renal insufficiency (GFR < 45 ml/min/1.73 m\(^{2}\)) and from those on dialysis or with cognitive decline, but carefully considered on an individual basis. Stopping ERT may be considered in patients with end stage FD or other co-morbidities, leading to a life expectancy of <1 year. In those with cognitive decline of any cause, or lack of response for 1 year when the sole indication for ERT is neuropathic pain, stopping ERT may be considered. Also, in patients with end stage renal disease, without an option for renal transplantation, in combination with advanced heart failure (NYHA class IV), cessation of ERT should be considered. ERT in patients who are non-compliant or fail to attend regularly at visits should be stopped. Conclusion: The recommendations can be used as a benchmark for initiation and cessation of ERT, although final decisions should be made on an individual basis. Future collaborative efforts are needed for optimization of these recommendations. KW - Fabry disease KW - enzyme replacement therapy KW - recommendations KW - Delphi procedure Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175374 VL - 10 IS - 36 ER - TY - JOUR A1 - Friedrich, Maximilian A1 - Hartig, Johannes A1 - Prüss, Harald A1 - Ip, Wang Chi A1 - Volkmann, Jens T1 - Rapidly progressive dementia: Extending the spectrum of GFAP-astrocytopathies? JF - Annals of Clinical and Translational Neurology N2 - Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is a steroid-responsive meningoencephalomyelitis, sometimes presenting with atypical clinical signs such as movement disorders or psychiatric and autonomic features. Beyond clinical presentation and imaging, diagnosis relies on detection of GFAP-antibodies (AB) in CSF. Using quantitative behavioral, serologic, and immunohistochemical analyses, we characterize two patients longitudinally over 18–24 months who presented with rapidly progressive neurocognitive deterioration in the context of GFAP-AB in CSF and unremarkable cranial MRI studies. Intensified immunotherapy was associated with clinical stabilization. The value of GFAP-AB screening in selected cases of rapidly progressive dementias is discussed. KW - GFAP-astrocytopathies KW - dementia Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312957 VL - 9 IS - 3 ER - TY - THES A1 - Scheytt, Sarah T1 - Quantifizierung von GAP 43 positiven intraepidermalen Nervenfasern bei Patienten mit Polyneuropathie und gesunden Kontrollen T1 - Quantification of GAP 43 positive intraepidermal nerve fibers in patients with neuropathy and healthy controls N2 - Polyneuropathien (PNP) sind mit einer Prävalenz von bis zu 7% in der Gesamtbevölkerung eine häufige Diagnose. Bei der Ursachenabklärung der PNP hat sich in den letzten Jahren die immunhistochemische Bestimmung der intraepidermalen Nervenfaserdichte aus Hautstanzbiopsien mittels einer axonalen PGP 9.5 Färbung etabliert. Ein zusätzlicher Marker ist GAP 43 - ein axonales Protein, das von regenerierenden Nervenfasern exprimiert wird. In der vorliegenden Studie wurde die Dichte von PGP 9.5 und GAP 43 positiven Nervenfasern anhand immunhistochemischer Färbungen an Hautstanzbiopsien vom lateralen Unter- und Oberschenkel von Patienten mit PNP unterschiedlicher Genese und von gesunden Kontrollen quantifiziert. Wir konnten zeigen, dass PNP Patienten im Vergleich zu Kontrollpersonen deutlich weniger GAP 43 positive Nervenfasern in ihren Hautbiopsien aufweisen. Obwohl sich bei PNP Patienten absolut gesehen weniger GAP 43 positive Nervenfasern fanden, war der Anteil an GAP 43 positiven Nervenfasern im Vergleich zur Kontrollgruppe höher, was mit einer gesteigerten regenerativen Aktivität in geschädigten Nervenfasern zusammenhängen kann. In der Patienten- und Kontrollgruppe fanden sich mehr PGP 9.5 und GAP 43 positive Nervenfasern am Ober- als am Unterschenkel, was durch die grundsätzlich dichtere Innervation proximaler Hautareale bedingt ist und bei PNP Patienten durch den im Krankheitsverslauf typischerweise längenabhängigen Verlust der peripheren kutanen Innervation noch verstärkt wird. Die Analyse potentieller Einflussfaktoren ergab beim Unterschenkel für beide Färbungen eine negative Korrelation zwischen Alter und Nervenfaserdichte. Das Geschlecht und das Vorhandensein von Schmerzen hatten keinen Einfluss auf die Hautinnervation. Die Arbeit zeigt anhand des bisher größten Patienten- und Kontrollkollektivs, dass regenerierende intraepidermale Nervenfasern mittels einer Immunhistochemie für GAP 43 zuverlässig quantifizierbar sind. Bei künftigen longitudinalen Studien kann nun ein möglicher Zusammenhang zwischen der Dichte GAP 43 positiver Nervenfasern und der Prognose bzw. dem Ansprechen auf Therapien untersucht werden. N2 - Polyneuropathies (NP) are a common neurological disease with a prevalence of 7%. In the diagnosis of NPs the determination of intraepidermal nerve fiber density in skin punch biopsies with an immunhistochemical staining for PGP 9.5 is an established procedure. An additional marker is GAP 43 - an axonal protein, that is expressed by regenerating nerve fibers. In this study we determined the densitiy of PGP 9.5 and GAP 43 positive nerve fibers with immunhistochemical staining on skin punch biopsies of the lateral lower leg an thigh from patients with NP and healthy controls. We showed, that NP patients had less GAP 43 positive nerve fibers in skin biopsies compared to healthy controls. Although NP patients had in absolute terms less GAP 43 positive nerve fibers, they had proportionately more GAP 43 positive nerve fibers compared to healthy controls. This may be due to a higher regenerating activity in damaged nerve fibers. In the patient- and controlgroup there were more PGP 9.5 and GAP 43 positive nerve fibers on the thigh compared to the lower leg due to a generally higher innervation of proximal skin areas. This is intensified in NP patients by the for the disease typical length dependent loss of peripheral skin innervation. The analysis of potential influencing factors showed in the lower leg a negative correlation between age and nerve fiber density. Gender and the existence of pain showed no influence on skin innervation. This study shows with the to date biggest patient- and controlcollective, that regenerating intraepidermal nerve fibers are reliably quantifiable with an immunhistochemical staining for GAP 43. For future longitudinal studies there should be analysed, if there is a possible relationship between the densitiy of GAP 43 nerve fibers and the prognosis or the treatment response of NP. KW - Polyneuropathie KW - Hautbiopsie KW - GAP 43 KW - skin biopsy KW - Neuropathy Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-94782 ER - TY - THES A1 - Braun, Alexandra T1 - Psychosocial and somatic resilience factors of patients with fibromyalgia syndrome (FMS) T1 - Psychosoziale und somatische Resilienzfaktoren bei Patienten mit dem Fibromyalgie Syndrom (FMS) N2 - Background: In recent years, health care has increasingly become the focus of public interest, politics, health insurance companies, and research. This includes the development of therapeutic concepts that can respond individually to patients' resources in order to improve coping with chronic diseases. Research into psychosocial and biological resilience factors is very important and the basic objective of the present work. I studied patients with fibromyalgia syndrome (FMS), who suffer among others from chronic pain, fatigue, sleep and gastrointestinal problems. This patient cohort is characterized by a pronounced heterogeneity in terms of clinical outcome, degree in disability and coping. FMS has a prevalence of 3 – 8 % in the Western population and has a significant socio-economic impact. Validated psychosocial resilience factors include optimism, humor, coherence, self-efficacy, awareness with one's own resources and the ability to apply them profitably (coping), and a healthy social environment with positive relationships. Studies in patients with cancer revealed religiosity as positive and negative factor on the health outcome, but there is little data on religious aspects of pain resilience. Various genetic polymorphisms and anti-inflammatory cytokines are known as biological resilience factors. Various microRNA (miRNA) were detected to contribute to resilience in the context of stress and psychiatric disorders. Objective: The underlying research question of this work is to understand the factors that make some FMS patients resilient and others not, even though they suffer from the same disease. The long-term aim was to understand mechanisms and influencing factors of resilience to design preventive and resource-oriented therapies for FMS patients. Material and Methods: Three studies examined religious, physiological, biological, and psychosocial factors which may contribute to resilience in FMS patients. Study one combined data of questionnaires, a psychosocial interview, and regression analyses to investigate the relevance of religiosity for coping and resilience. Study two examined variance explaining factors and defined clusters among FMS patients by their differences in coping, pain phenotype and disability. The factor analysis used variables derived from questionnaires and qPCR of cytokines in white blood samples (WBC) of patients and healthy controls. Study three assessed cluster-wise miRNA signatures which may underly differences in behaviour, emotional and physiological disability, and resilience among patient clusters. A cluster-specific speculative model of a miRNA-mediated regulatory cycle was proposed and its potential targets verified by an online tool. Results: The data from the first study revealed a not very religious patient cohort, which was rather ambivalent towards the institution church, but described itself as a believer. The degree of religiosity played a role in the choice of coping strategy but had no effect on psychological parameters or health outcomes. The coping strategy "reinterpretation", which is closely related iv to the religious coping "reappraisal", had the highest influence on FMS related disability. Cognitive active coping strategies such as reappraisal which belongs to religious coping had the highest effect on FMS related disability (resilience) and could be trained by a therapist. Results from the second study showed high variances of all measured cytokines within the patient group and no difference between patient and control group. The high dispersion indicated cluster among patients. Factor analysis extracted four variance-explaining factors named as affective load, coping, pain, and pro-inflammatory cytokines. Psychological factors such as depression were the most decisive factors of everyday stress in life and represented the greatest influence on the variance of the data. Study two identified four clusters with respective differences in the factors and characterized them as poorly adapted (maladaptive), well adapted (adaptive), vulnerable and resilient. Their naming was based on characteristics of both resilience concepts, indicated by patients who were less stress-sensitive and impaired as a personal characteristic and by patients who emerged as more resilient from a learning and adaptive process. The data from the variance analysis suggests that problem- and emotion-focused coping strategies and a more anti-inflammatory cytokine pattern are associated with low impairment and contribute to resilience. Additional favorable factors include low anxiety, acceptance, and persistence. Some cluster-specific intervention proposals were created that combine existing concepts of behavioral and mindfulness therapies with alternative therapies such as vitamin D supplementation and a healthy intestinal flora. The results of the third study revealed lower relative gene expression of miR103a-3p, miR107, and miR130a-3p in the FMS cohort compared to the healthy controls with a large effect size. The adaptive cluster had the highest gene expression of miR103a-3p and tendentially of miR107, which was correlated with the subscale score "physical abuse" of the trauma questionnaire. Further correlations were found in particular with pain catastrophizing and FMS-related disability. MiR103a-3p and miR107 form a miRNA-family. Based on this, we proposed a miR103a/107 regulated model of an adaptive process to stress, inflammation and pain by targeting genetic factors which are included in different anti-inflammatory and stress-regulating pathways. Conclusion: All three studies provide new insights into resilience in FMS patients. Cognitive coping (reappraisal/reinterpretation) plays a central role and thus offers therapeutic targets (reframing in the context of behavioral therapy). Religosity as a resilience factor was only partially valid for our patient cohort. Basically, the use of resource-oriented therapy in large institutions still requires research and interdisciplinary cooperation to create a consensus between the humanities, natural sciences and humanism. N2 - Hintergrund: Die Gesunderhaltung ist in den letzten Jahren mehr und mehr in den Fokus des Interesses der Öffentlichkeit, Politik, Krankenkassen und Forschung gerückt. Dazu zählt auch die Entwicklung von Therapiekonzepten, die individuell auf die Bedürfnisse und Ressourcen der Patienten zugeschnitten sind, um den Umgang mit insbesondere chronischen Erkrankungen zu verbessern. Die Erforschung von psychosozialen und biologischen Resilienzfaktoren ist hierfür sehr wichtig, und das grundlegende Ziel der vorliegenden Arbeit. Zielgruppe sind Patienten mit Fibromyalgiesyndrom (FMS). Symptome des FMS sind u.a. chronischer Schmerz, Erschöpfung, Schlaf und Magen-, Darmprobleme. Die Patientengruppe erscheint in der Klinik als sehr heterogene mit unterschiedlichen Beeinträchtigungsgraden und verschiedenen Strategien, mit den Auswirkungen der Erkrankung umzugehen. Die Prävalenz des FMS liegt bei 3 – 8% in der westlichen Bevölkerung und ist somit von erheblicher gesellschaftlicher und sozioökonomischer Bedeutung. Validierte psychosoziale Resilienzfaktoren sind u.a. Optimismus, Humor, Kohärenzgefühl, Selbstwirksamkeit, Bewusstsein der eigenen Ressourcen und die Fähigkeit diese gewinnbringend anzuwenden (Coping) und ein gesundes soziales Umfeld mit positiven Beziehungen. Studien an Krebspatienten ergaben unterschiedliche Effekte von Religiosität als Copingstrategie und Resilienzfaktor. Im Allgemeinen liegen wenige Daten vor zum Thema Religiosität / als Schutzfaktor bei Schmerzpatienten. Als biologische Resilienzfaktoren sind verschiedene genetische Polymophismen, anti-inflammatorische Zytokine und microRNA (miRNA) bekannt, die zur Resilienz bei chronischem Stress und psychiatrischen Krankheitsbildern beitragen. Ziel: Die zugrundeliegende Forschungsfrage dieser vorliegenden Arbeit ist, welche Faktoren dazu beitragen, dass manche Patienten resilienter sind als andere, obwohl sie unter derselben Erkrankung leiden. Das langfristige Ziel dieser Forschung ist es, Mechanismen und Einflussfaktoren der Resilienz zu verstehen, um präventive und gezielte Ressourcen-orientierte Therapien für FMS Patienten zu entwickeln. Material und Methoden: Insgesamt drei Studien untersuchten explorativ eine Reihe von religiösen, physiologischen, biologischen und psychosozialen Faktoren und ihre Rolle als Schutzfaktor bei Patienten mit FMS. Studie 1 kombinierte Daten von Fragebögen, einem psychologischen Interview und Regressionsanalysen, um die Relevanz von Religiosität für das Coping und Resilienz zu untersuchen. Studie 2 versuchte mit einer explorativen Faktorenanalyse Einflussfaktoren zu ermitteln, die für die heterogene Datenlage der Patienten verantwortlich sind. Mithilfe einer Clusteranalyse wurden Subgruppen anhand ihrer Unterschiede in mentaler Gesundheit, Coping, Schmerzphänotyp und Beeinträchtigung definiert. Die Faktorenanalyse verwendete Daten der Fragebögen und Genexpressionsanalysen ausgewählter Zytokine aus Blutproben der Patienten und einer gesunden Kontrollgruppe. Zuletzt wurden Cluster-spezifische Therapievorschläge auf der Basis bereits bekannter Therapien zusammengestellt. Studie 3 bestimmte Cluster-charakteristische miRNA Signaturen, die verantwortlich für die Cluster-spezifischen Unterschiede in Verhalten (coping), emotionaler und körperlicher Beeinträchtigung, und Resilienz sein können. Die Ergebnisse wurden in einem Regulationsschema zusammengefasst und schlagen einen möglichen miRNA-regulierten Mechanismus von adaptivem Verhalten vor. Die potentiellen genetischen Targets wurden mittels eines online Tools „Target Scan Human“ verifiziert. Ergebnisse: Die Daten der ersten Studie zeigten eine wenig religiöse Patientenkohorte, die der Institution Kirche eher ambivalent gegenüberstand, sich jedoch dennoch als gläubig beschrieb. Der Grad der Religiosität spielte eine Rolle bei der Wahl der Copingstrategie, hatte jedoch keinen Einfluss auf psychologische Parameter oder die Gesundheit. Die Copingstrategie „Reinterpretation“, welche auch nah verwandt mit dem religiösen Coping „reappraisal“ ist, hatte einen signifikanten Einfluss auf die Beeinträchtigung, und könnte innerhalb einer Verhaltenstherapie erlernt werden. Ergebnisse der zweiten Studie zeigen hohe Varianzen aller gemessenen Zytokine innerhalb der Patientengruppe und keinen signifikanten Unterschied zwischen Patienten- und Kontrollgruppe. Die hohe Streuung deutete auf Subgruppen innerhalb der FMS Kohorte hin. Mittels einer Faktorenanalyse wurden vier Faktoren ermittelt, die dieser Varianz zugrunde liegen, welche absteigend als affektive Belastung, Coping, Schmerz und pro-inflammatorische Zytokine benannt wurden. Interessant ist, dass psychische Faktoren wie Depression den höchsten Einfluss auf die Belastung im Alltag darstellten und auch den größten Einfluss auf die Varianz der Daten abbildete. Studie 2 konnte vier Subgruppen mit jeweiligen Unterschieden in den charakterisierten Faktoren ermitteln und diese als schlecht angepasst (maladaptive), gut angepasst (adaptive), vulnerabel und resilient charakterisieren. Ihre Benennung basierte auf Charakteristika beider Resilienzkonzepte. Es gab Anzeichen für Patienten, die weniger stresssensibel und beeinträchtigt waren aufgrund von Persönlichkeitsstrukturen sowie Patienten, die aus einem Lern- und Anpassungsprozess nun resilienter hervorgingen. Die Daten der Varianzanalyse legten nahe, dass problem- und emotionsfokussierte Copingstrategien und ein eher antiinflammatorisches Zytokinmuster mit einer niedrigen Beeinträchtigung assoziiert sind und eher zur Resilienz beitragen. Zusätzliche begünstigende Faktoren sind niedrige Angstwerte, Akzeptanz und Durchhaltevermögen. Basierend auf diesen Erkenntnissen wurden einige Subgruppen-spezifische Interventionsvorschläge vorgestellt, welche bereits existierende Konzepte der Verhaltens- und Achtsamkeitstherapien mit alternativen Therapien wie Supplementierung von Vitamin D und eine gesunde Darmflora miteinander kombinieren. Die Ergebnisse der dritten Studie zeigten eine niedrigere relative Genexpression von miR103a-3p, miR107 und miR130a-3p in der FMS Kohorte verglichen mit der gesunden Kontrollkohorte mit einer großen Effektstärke. Die höchste relative Genexpression zeigte miR103a im adaptiven Cluster, das Cluster mit der niedrigsten Beeinträchtigung. MiR107 tendierte zu einer leicht erhöhten relativen Expression im adaptiven Cluster und war mit dem Subskalenscore „körperlicher Missbrauch“ des Traumafragebogens korreliert. Weitere Korrelationen fanden sich insbesondere mit den Variablen psychologischer Fragebögen zu Schmerz Katastrophisieren und FMS-bezogene Beeinträchtigung. MiR103a-3p und miR107 bilden zuammen eine miRNA Familie mit gleichen physiologischen Funktionen. Basierend auf diesen Erkenntnissen, schlugen wir ein Model der miR103a/107 regulierten Anpassung an Stress, Entzündung und Schmerz unter Einbezug verifizierter Gene, vor. Schlussfolgerung: Zusammenfassend geben alle drei Studien neue Einblicke in die Resilienzfaktoren von FMS Patienten. Dabei kommt dem kognitiven Coping (reappraisal / reinterpretation) eine zentrale Rolle zu, was therapeutische Ansatzpunkte (reframing innerhalb einer Verhaltenstherapie) bietet. Religiosität konnte sich in der hier untersuchten Kohorte als Schutzfaktor nur bedingt validieren. Grundsätzlich benötigt der Einsatz von ressourcenorientierter Therapie innerhalb großer Kliniken noch einiges an Forschung und interdisziplinärer Zusammenarbeit, die einen Konsens zwischen Geisteswissenschaften, Naturwissenschaften und Humanismus schafft. KW - Resilienz KW - resilience KW - Fibromyalgia KW - somatic resilience KW - psychosocial resilience Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242809 ER - TY - THES A1 - Ostertag, Viktoria Charlotte Caroline T1 - Präventive und therapeutische Behandlung mit einem CSF-1-Rezeptorinhibitor bei verschiedenen Charcot-Marie-Tooth Mausmodellen T1 - Preventive and therapeutic treatment with a CSF-receptor-inhibitor in various Charcot-Marie-Tooth mouse models N2 - Die Charcot-Marie-Tooth-Neuropathie umfasst eine heterogene Gruppe von erblichen unter anderem demyelinisierenden Erkrankungen des peripheren Nervensystems. Trotz ihrer hohen Prävalenz von 1:2.500 gibt es bis dato keine kausalen Therapiemöglichkeiten. Durch den progressiven Krankheitsverlauf wird die Lebensqualität der Patienten stetig gemindert; der fortschreitende Verlust der Muskelkraft und Störungen des Gangbildes sind besonders belastend. Ursächlich für die CMT1-Neuropathie sind unter anderem Mutationen in Genen, die für Moleküle des Myelins von Schwannzellen codieren. Diese Mutationen führen zu einer verminderten Stabilität und Funktion des Myelins und so letzten Endes zu einer Demyelinisierung und axonalen Schädigung der peripheren Nerven. Weitere Studien in CMT1-Mausmodellen zeigten jedoch, dass nicht nur die verringerte Myelinstabilität sondern auch eine durch das Immunsystem vermittelte geringgradige Entzündungsreaktion für die Symptome ursächlich sein könnte. Hier spielen vor allem Makrophagen eine zentrale Rolle. Das Zytokin CSF-1 aktiviert die Makrophagen und verursacht so eine Demyelinisierung der peripheren Nerven. In P0het und Cx32def Mausmodellen konnte nachgewiesen werden, dass eine medikamentöse Inhibition des CSF-1-Rezeptors an Makrophagen zu einem verbesserten Nervphänotypen und einer deutlichen Abmilderung des Krankheitsbildes führte. In dieser Arbeit wurden in P0het und Cx32def Mausmodellen weiterführende Behandlungsstudien mit einem CSF-1-RI durchgeführt, die untersuchen, zu welchem Zeitpunkt innerhalb des Krankheitsverlaufs (therapeutisch oder präventiv) eine erfolgreiche Therapie noch möglich ist und ob bei einem früheren Beginn eine noch bessere Wirkung erzielt werden kann. Abhängig von den verschiedenen Start- und Endpunkten waren unterschiedliche Ergebnisse zu beobachten: Hinsichtlich der klinischen Parameter wie der Greifkraft und der Anzahl an abnormal innervierten Synapsen zeigten die Tiere im präventiven Behandlungszweig in beiden Mausmodellen das beste Ergebnis im Vergleich zu den Kontrolltieren. Diese substantielle Verbesserung ließ sich unabhängig von einem Makrophagen-Reflux sogar noch 6 Monate nach Behandlungsabbruch nachweisen. Bezüglich der endoneuralen Makrophagendepletion war sowohl in den P0het als auch den Cx32def Tieren im präventiven sowie im therapeutischen Behandlungszweig eine signifikante Verbesserung zu beobachten. Diese Ergebnisse heben ein weiteres Mal die Bedeutung der Makrophagen als Teil einer Entzündungsreaktion in der Pathogenese der CMT1-Neuropathie hervor. Des Weiteren konnte die These gefestigt werden, dass eine Inhibition des CSF-1-Rezeptors zu verbesserten histopathologischen sowie funktionellen Parametern führt. Um ein gutes Ansprechen auf die Therapie zu erzielen, müssen ein möglichst früher Therapiebeginn sowie eine nachhaltige Behandlungsdauer gewährleistet sein. N2 - "Macrophage-mediated inflamma3on is a potent driver of disease progression in mouse models of Charcot-Marie-Tooth (CMT) 1 diseases. This leads to the possibility to consider these cells as therapeu3c targets to dampen disease outcome in the so far non-treatable neuropathies. As a pharmacological proof-of-principle study, long-term targe3ng of nerve macrophages with the orally applied CSF-1 receptor specific kinase (c-FMS) inhibitor PLX5622 showed a substan3al allevia3on of the neuropathy in dis3nct CMT1 mouse models. However, regarding transla3onal op3ons, clinically relevant ques3ons emerged regarding treatment onset, dura3on and termina3on. Corrobora3ng previous data, we here show that in a model for CMT1B, peripheral neuropathy was substan3ally alleviated aQer early con3nuous PLX5622 treatment in CMT1B mice, leading to preserved motor func3on. However, late-onset treatment failed to mi3gate histopathological and clinical features, despite a similar reduc3on in the number of macrophages. Surprisingly, in CMT1B mice, termina3ng early PLX5622 treatment at six months was s3ll sufficient to preserve motor func3on at 12 months of age, sugges3ng a long-las3ng, therapeu3c effect of early macrophage deple3on. This novel and unexpected finding may have important transla3onal implica3ons, since we here show that con3nuous macrophage targe3ng appears not to be necessary for disease allevia3on, provided that the treatment starts within an early, cri3cal 3me window.” (Ostertag et al., Experimental Neurology, 2022) KW - Charcot-Marie-Syndrom KW - Neuropathie KW - Charcot-Marie-Tooth KW - CSF-1-Rezeptor-Inhibitor Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-308528 ER - TY - THES A1 - Pausch, Jonas Franz T1 - Präferentielle Lokalisation von Makrophagen im räumlichen Umfeld von Ranvier'schen Schnürringen - Morphologische Analysen zur räumlichen Verteilung von Makrophagen in Mausmodellen für erbliche Neuropathien T1 - Preferential localisation of macrophages near nodes of Ranvier - morpholocgical analyses in mose models for ihertited peripheral neuropathie N2 - Die Charcot-Marie-Tooth Typ 1 Erkrankungen sind eine genetisch heterogene Gruppe, aktuell nicht kurativ therapierbarer, erblicher Neuropathien des Peripheren Nervensystems. Klinische Manifestationen reichen von Sensibilitäts-störungen, verminderten Muskeleigenreflexen, sowie fortschreitenden Lähmungen, bis hin zu Muskelatrophie und bedeuten für die betroffenen Patienten eine starke Einschränkung der Lebensqualität. Anhand früherer Studien wurde Makrophagen, als Teil des angeborenen Immunsystems, eine entscheidende Rolle in der Pathogenese dreier CMT1-Unterformen zugeschrieben. Abgesehen von den morphologischen Manifestationen der demyelinisierenden CMT1-Erkrankungen, wie simultanes Auftreten von Dedifferenzierung, sowie Hypo-, und Demyelinisierung erkrankter Schwann-Zellen, sind pathologische Veränderungen der Domänengliederung der Ranvier’schen Schnürringe betroffener Nervenfasern ebenfalls von der Aktivierung pathogener Makrophagen abhängig. Auf der Basis verschiedener veröffentlichter Studien, welche sowohl demyelinisierende Erkrankungen des ZNS, aber auch primär durch axonale Schäden gekennzeichnete Erkrankungen des PNS beinhalten, besteht ein möglicher räumlicher Zusammenhang zwischen Architekturstörungen der RS und aktivierten pathogenen Mikrogliazellen bzw. Makrophagen. In dieser Studie konnte, anhand morphologischer Analysen von peripherem Nervengewebe, in Wt-Mäusen erstmals eine unerwartete präferentielle Lokalisation von Makrophagen im räumlichen Umfeld von RS beobachtet werden. Hierbei scheint, trotz des Fehlens einer direkten Zell-Zell-Interaktion zwischen Makrophagen und RS, vor allem im Hinblick auf die ebenfalls im räumlichen Umfeld von RS nachweisbare EZM und Fibroblasten, eine funktionelle Relevanz der assoziierten Makrophagen für die Aufrechterhaltung der Domänengliederung bzw. elektrophysiologischen Eigenschaften myelinisierter peripherer Nervenfasern denkbar. Im Gegensatz dazu wurde trotz der signifikanten Zunahme der Makrophagenanzahlen in den drei untersuchten CMT1-Mausmodellen keine erhöhte räumliche Assoziation mit den RS der mutierten Schwann-Zellen beobachtet. Vielmehr konnten anhand des Vergleiches mit wildtypischen Kontrollmäusen signifikant erniedrigte Assoziationsraten beider Strukturen in den CMT1-Modelltieren festgestellt werden. Folglich scheint die von der Einwanderung und Aktivierung pathogener Makrophagen abhängige Störung der Domänengliederung der RS der mutierten Schwann-Zellen, nicht durch eine direkte Interaktion bzw. räumliche Assoziation von Makrophagen mit RS ausgelöst zu werden. N2 - The Charcot-Marie-Tooth neuropathies are a heterogenous group of inherited neuropathies oft he peripheral nervous system currenly incurable. Clinical symptoms vary from sensory loss, reduced tendon reflexes, muscular atrophy to progressive disability. According to different studies macrophages, as a part oft he innate immune system, play a crucial role in the pathogenesis of three different CMT-1 subtypes. Apart from morphological changes like dedifferentiation as well as hypo- and demyelination of diseased Schwann-cells, pathological alterations of nodes of Ranvier are also driven by activated marophages. As already described for demyelinating disoders oft he CNS, as well as neruodegenerative disorders oft he PNS, we investigated the spatial association of macrophages with diseased nodes of Ranvier. According to morphological analysis of peripheral nerve tissue this study is the first to describe an unexpected preferential spatial localization of macrophages near nodes of Ranvier in healthy nerves. Despite direct cell-cell interactions macrohages might play a functional role regarding the turnover of ECM and fibroblasts surrounding nodes of Ranvier, as well as the maintenance oft he architecture and electrophysiological features of peripheral nerve fibers. KW - Makrophagen KW - Erbliche Neuropathien KW - Charcot-Marie-Tooth KW - Ranvier'sche Schnürringe KW - CMT KW - Ranvier'sche Schnürringe Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143801 ER - TY - THES A1 - Beaucamp, Marcel T1 - Prädiktion des Verschlusses großer intrakranieller Arterien anhand präklinischer Schlaganfallscores T1 - Prediction of large vessel oclusions by using preclinical stroke scores N2 - 2015 konnte in mehreren Studien ESCAPE, EXTENDED IA, MR CLEAN, REVASCAT, SWIFT-PRIME eine signifikante Überlegenheit der mechanischen Thrombektomie verglichen mit der alleinigen i. v. Lysetherapie mit rtPA bezogen auf Revaskularisierung bei Patienten mit einer LVO (large vessel occlusion) nachgewiesen werden. Diese neue Therapiemöglichkeit erforderte eine Aufteilung der Patienten die von einer Thrombektomie profitieren (LVO) und der Patienten, die keiner Thrombektomie zugeführt werden können (nLVO). Die zentrale Fragestellung der Studie ist: Kann ein symptomorientierter Schlaganfallscore die Wahrscheinlichkeit eines großen intrakraniellen Gefäßverschlusses mit hinreichender Präzision vorhersagen und kann auf Basis dieser Vorhersage ein Patient direkt in ein übergeordnetes Schlagfanfallzentrum gebracht werden, obwohl sich dadurch eine Bridging Lysetherapie verzögern würde? Um diesen Fragen auf den Grund zu gehen führten wir eine monozentrische Querschnittstudie durch, in deren Rahmen 215 Patienten rekrutiert wurden. Die Rekrutierung erfolgte mittels eines aus Subitems bereits etablierter Schlafanfallscores (FAST, CPSS, LAPSS, 3ISS, RACE), zusammengesetzten Fragebogens. Die ausgefüllten Fragebögen wurde in Excel digitalisiert und mittels SPSS, Signifikanz und Odds Ratio berechnet. Anschließend wurde aus den signifikanten Subitems mit der höchsten Odds Ratio ein neuer einfach anzuwendender Schlaganfallscore, bestehend aus den präklinisch erhobenen Daten gebildet (Würzburg Score of Large Vessel Occlusions, WOLVE- Score). Weiter wurden Signifikanz, Odds Ratio, Sensitivität und Spezifität des WOLVE-Score mit denen der oben genannten etablieren Scores verglichen. N2 - 2015 several publications ESCAPE, EXTENDED IA, MR CLEAN, REVASCAT, SWIFT-PRIME proofed a significant superiority of the mechanical thrombectomy in Patients suffering from a LVO (large vessel occlusion) concerning revascularization rates compared to i. v. thrombolysis with rtPA, alone. This newly discovered therapy required a new distribution of patients who could profit from a thrombectomy (LVO) and those who would not profit from a thrombectomy (nLVO). The key question is: Can a symptom related stroke score predict the probability of a large vessel occlusion with a sufficient precision and is it possible to admit a patient to a comprehensive stroke center based on this prediction, even though an early bridging thrombolysis is delayed. To answer this question we performed a cross-sectional study in which 215 patients were recruited by using a composite questionnaire consisting of subitems from established stroke scores (FAST, CPSS, LAPSS, 3ISS, RACE). The questionnaire was digitalized in Ecxel. Statistical calculations of the significancy and the odds ratio were conducted in SPSS. The significant subitems with the highest odds ratio were used to construct a new simple stroke score for LVO recognition in the field (Würzburg Score of Large Vessel Occlusions, WOLVE- Score). Eventually the significancy, odds ratio sensitivity and specificity of the WOLVE-Score were calculated and compared to the ones of the established scores. KW - Schlaganfall KW - Gefäßverschluss KW - Score KW - Thrombektomie KW - Revaskularisierung KW - Stroke KW - Score KW - LVO Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215117 ER - TY - THES A1 - Mönter, Boris T1 - Protonenempfindlichkeit von Spinalganglienneuronen bei Wildtypmäusen und Mausmutanten mit einem Mangel an TRPV 1 oder ASIC 3 T1 - Proton-sensibility of spinal root ganglion neurons in wildtype-mice and mutants with a lack of TRPV 1 or ASIC 3 N2 - In den letzten Jahren wurden große Fortschritte in der Aufklärung von Mechanismen der Protonensensibilität auf molekularer Ebene gemacht, die ein wesentliches Element der Nozizeption darstellt. In dieser Arbeit wurde der Einfluss von den in diesem Zusammenhang entdeckten Kanälen TRPV1 und ASIC3 auf die Protonensensitivität von nativen Spinalganglienneuronen, sowie Unterschiede zwischen der IB4-positiven und der IB4-negativen Population untersucht. Hierzu wurden Patch-Clamp-Studien an isolierten Neuronen von TRPV1-defizienten und ASIC3-defizienten Mäusen durchgeführt. Die Ergebnisse dieser Experimente bestätigen dabei die wesentliche Rolle von TRPV1 für die Protonensensibilität. Insbesondere für nicht desensibilisierende Komponenten von protoneninduzierten Strömen, die für die Transduktion extrazelluärer azidotischer Schmerzzustände in eine anhaltende Erregung des nozizeptiven Systems verantwortlich sind, ist TRPV1 von großer Bedeutung. Diese sind in den TRPV1-defizienten Neuronen stark reduziert. Der Einfluss von ASIC3 auf diese Komponenten ist hingegen gering, auch wenn es Hinweise auf eine Beteiligung dieses Rezeptors an diesen Komponenten gibt. Größere Bedeutung hat ASIC3 für schnell desensibilisierende Komponenten der Reaktion dieser Neurone auf Protonen, die von ASIC3-defizienten seltener als von Wildtyp-Neuronen gezeigt werden. Die Bedeutung dieser transienten Komponenten ist nicht geklärt, wahrscheinlich erfüllen sie eine modulatorische Funktion, nicht nur im nozizeptiven System. Noch wenig ist über die funktionellen Unterschiede der zwei verschiedenen Subpopulationen nozizeptiver Neurone bekannt, die durch die Bindung des Isolektins B4 differenziert werden können. Diese Arbeit gibt Hinweise darauf, dass sich diese auch in ihrer Protonensensitivität unterscheiden. Das könnte Ausdruck dafür sei, dass diese an der Wahrnehmung unterschiedlicher Schmerzzustände beteiligt sind. Die Charakterisierung der Mechanismen des komplexen nozizeptiven Systems auf zellulärer und molekularer Ebene ist Vorraussetzung zur Entwicklung von gezielt wirkenden, analgetischen Pharmaka. Die schon lange bekannte Wirksamkeit von Capsaicin – dem wohl bekanntesten Agonisten von TRPV1 – bei verschiedenen schmerzhaften Zuständen und fortschreitende Erkenntnisse über die Bedeutung dieses und der ASIC-Rezeptoren bei der Wahrnehmung von schmerzassoziierter Gewebsazidose, zeigt Wege auf, über die solche Medikamente ihre Wirkung entfalten könnten. N2 - Big advantages were made in the last years to enlight the mechanisms of protonsensibility on the molecular level, which is a major element of nociception. The influence of the ion-channels TRPV 1 and ASIC 3 on protonsensitivity, which were discovered in this context and differences between IB4-positive and IB4-negative neuron-populations are investigated in this work. Patch-clamp-studies in isolated neurons of TRPV 1-deficient and ASIC 3-deficient mice were conducted for that purpose. The results of this experiments affirm the essential role of TRPV 1 for protonsensitivity. TRPV 1 is important especially for non-desensitising components of proton-induced currents, which are responsible for the transduction of extracellular acidotic painful states. These are strongly reduced in TRPV 1-deficient mice. The influence of ASIC 3 is small, although there is evidence of a participation of this receptor for this components. ASIC 3 is more important for quickly desensitising components of the reaction to protons of such neurons, which occur less often in AISC 3-deficient than in wildtype-mice. The function of these transient components are not entirely clear, they probably have a modulatory effect, not only within the nociceptive system. Still not much is known about the functional differences of two subpopulations of nociceptive neurons, which can be differentiated by the binding of the Isolectin B4. This work shows, that they differ in their protonsensitivity. This shows that they might be involved in the reception of different painful states. The characterisation of the mechanisms of the complex nociceptive system on cellular and molecular level is required to develop efficient analgetic drugs. The efficiency of capsaicin, probably the best known agonist for TRPV 1, for different painful states and better knowledge about the function of this receptor and those of the ASIC-family for the reception of pain-associated tissue-acidosis shows, how new analgetic drugs might be able to work. KW - TRPV 1 KW - ASIC 3 KW - Protonen KW - Spinalganglienneuron KW - Schmerz KW - TRPV 1 KW - ASIC 3 KW - protons KW - dorsal root ganglion neuron KW - pain Y1 - 2004 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-10271 ER - TY - THES A1 - Peterka, Manuel T1 - Propriozeptive Störungen bei Morbus Parkinson – Explorative Untersuchungen zu Art, Ausmaß und potenzieller Rekalibrierung mithilfe der LSVT-BIG-Therapie T1 - Propriozeptive disorders in Parkinon’s disease - Explorative assessment of character, extent and possible recalibration through LSVT-BIG-Therapy N2 - Beim idiopathischen Parkinson Syndrom (IPS) gewinnen nicht-motorische Symptome in Forschung und Klinik zunehmend an Bedeutung. So findet sich in der Literatur vermehrt Evidenz, dass die Propriozeption bei Patienten mit IPS (PmIPS) gestört ist. Verschiedene klinische und neuroanatomische Studien weisen darauf hin, dass es beim IPS zu einer fehlerhaften sensomotorischen Integration von propriozeptiven Informationen in den Basalganglien kommt. Zudem gibt es Hinweise, dass die passiv-sensible Wahrnehmung von Propriozeption pathologisch verändert ist. Außerdem wird vermutet, dass durch propriozeptives Training eine Verbesserung der Parkinsonsymptomatik erreicht werden kann. Ein spezielles Trainingsprogramm, die LSVT-BIG-Therapie, bei der gezielt trainiert wird, Bewegungen mit einer großen Amplitude durchzuführen, konnte motorische Symptome und Mobilität beim IPS effektiv verbessern. In der vorliegenden Arbeit stellten wir folgende Hypothesen auf: Das IPS geht mit einer fehlerhaften sensomotorischen Integration von Propriozeption einher. Die afferente propriozeptive Wahrnehmung ist ebenfalls pathologisch verändert. Eine propriozeptive Rekalibrierung ist mithilfe der LSVT-BIG-Therapie möglich. Für die Überprüfung dieser Hypothesen schlossen wir 30 PmIPS und 15 gesunde Probanden in unsere Fall-Kontroll-Studie ein und führten eine Eingangsuntersuchung durch. 11 PmIPS absolvierten anschließend eine vierwöchige LSVT-BIG-Therapie. Die Folgeuntersuchungen fanden 4 und 8 Wochen nach der Eingangsuntersuchung statt. 78 Diese beinhalteten neuropsychologische Testungen, außerdem die Bestimmung der Lebensqualität, die Erhebung des motorischen Teils der Movement Disorder Society Unified Parkinson´s Disease Rating Scale (MDS-UPDRS III), Untersuchungen zur Feinmotorik, die Durchführung einer diagnostischen Transkraniellen Magnetstimulation (TMS) sowie Testverfahren zur Propriozeption, darunter sowohl Zeigeversuche, als auch die Bestimmung der Position einer Extremität, ohne visuelle Kontrolle. Die Ergebnisse zeigten, dass die IPS-Gruppe gegenüber der gesunden Kontrollgruppe signifikant größere Zeigefehler machte, wohingegen die Bestimmung der Position einer Extremität in beiden Gruppen vergleichbar präzise möglich war. Zusätzlich zeigte eine von sieben Messungen der Feinmotorik einen signifikanten Unterschied zwischen PmIPS und Kontrollen. Die Messungen der TMS erbrachten hingegen keine signifikant messbaren Unterschiede zwischen den Gruppen. In den Folgeuntersuchungen nach therapeutischer Intervention ergaben die Zeigeübungen eine signifikante Verbesserung der BIG-Gruppe im Zeitverlauf. Die Untersuchungen zu Feinmotorik und MDS-UPDRS III ergaben zwar eine tendenzielle Verbesserung durch die LSVT-BIG-Therapie, waren jedoch statistisch nicht signifikant. Die Lebensqualität der PmIPS in der BIG-Gruppe verbesserte sich signifikant nach Intervention. Die Ergebnisse sprechen für die Hypothese der fehlerhaften propriozeptiven Integration beim Morbus Parkinson. Dies zeigte sich für aktive sensomotorische Tasks, nicht hingegen in der passiv-sensiblen propriozeptiven Testung. Auch wenn weitere Studien mit größeren Kohorten benötigt werden, legt unsere Studie nahe, dass die LSVT-BIG-Therapie mit einer propriozeptiven Rekalibrierung einhergeht. Damit erklärt sich möglicherweise der nachhaltige Erfolg der Therapie. N2 - There is growing evidence for proprioceptive dysfunction in patients with Parkinson’s disease (PD). Several clinical and neuranatomical studies conclude, that the sensorimotor integration of proprioception is impaired at the level of the basal ganglia. Moreover, passive perception of propriozeptive information has shown to be altered in 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. The aim of our research was to assess proprioceptive impairment in PwPD as compared to matched controls and to probe potential recalibration effects of the LSVT-BIG therapy on proprioception. The following methods were used. Proprioceptive performance, fine motor skills and transcranial magnetic stimulation 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. The results show, that compared to the control group, PwPD produced significantly larger pointing errors. However, PwPD and matched controls did not differ in indicating wrist position. 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. Accordingly, we can conlcude that sensorimotor integration of propriozeption is altered but not passsive perception of propriozeptive information. Furthermore, 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 - Propriozeption KW - Parkinson-Krankheit KW - Physiotherapie Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226129 ER - TY - JOUR A1 - Steinhardt, M. J. A1 - Wiercinska, E. A1 - Pham, M. A1 - Grigoleit, G. U. A1 - Mazzoni, A. A1 - Da-Via, M. A1 - Zhou, X. A1 - Meckel, K. A1 - Nickel, K. A1 - Duell, J. A1 - Krummenast, F. C. A1 - Kraus, S. A1 - Hopkinson, C. A1 - Weissbrich, B. A1 - Müllges, W. A1 - Stoll, G. A1 - Kortüm, K. M. A1 - Einsele, H. A1 - Bonig, H. A1 - Rasche, L. T1 - Progressive multifocal leukoencephalopathy in a patient post allo-HCT successfully treated with JC virus specific donor lymphocytes JF - Journal of Translational Medicine N2 - Background Progressive multifocal leukoencephalopathy is a demyelinating CNS disorder. Reactivation of John Cunningham virus leads to oligodendrocyte infection with lysis and consequent axonal loss due to demyelination. Patients usually present with confusion and seizures. Late diagnosis and lack of adequate therapy options persistently result in permanent impairment of brain functions. Due to profound T cell depletion, impairment of T-cell function and potent immunosuppressive factors, allogeneic hematopoietic cell transplantation recipients are at high risk for JCV reactivation. To date, PML is almost universally fatal when occurring after allo-HCT. Methods To optimize therapy specificity, we enriched JCV specific T-cells out of the donor T-cell repertoire from the HLA-identical, anti-JCV-antibody positive family stem cell donor by unstimulated peripheral apheresis [1]. For this, we selected T cells responsive to five JCV peptide libraries via the Cytokine Capture System technology. It enables the enrichment of JCV specific T cells via identification of stimulus-induced interferon gamma secretion. Results Despite low frequencies of responsive T cells, we succeeded in generating a product containing 20 000 JCV reactive T cells ready for patient infusion. The adoptive cell transfer was performed without complication. Consequently, the clinical course stabilized and the patient slowly went into remission of PML with JCV negative CSF and containment of PML lesion expansion. Conclusion We report for the first time feasibility of generating T cells with possible anti-JCV activity from a seropositive family donor, a variation of virus specific T-cell therapies suitable for the post allo transplant setting. We also present the unusual case for successful treatment of PML after allo-HCT via virus specific T-cell therapy. KW - Myeloma KW - JCV KW - Prodigy KW - CCS KW - PML KW - Donor lymphocytes KW - Adaptive cell transfer Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229307 VL - 18 ER - TY - THES A1 - Yin, Jing T1 - Progressive alterations of pro- and antidegeneration markers in the nigrostriatal tract of the AAV1/2-A53T-α synuclein rat model of Parkinson’s disease T1 - Progressive Veränderungen von Pro- und Antidegenerationsmarkern im Nigrostriataltrakt des AAV1/2-A53T-α-Synuclein-Rattenmodells der Parkinson-Krankheit N2 - Neurodegeneration plays an essential role in Parkinson’s disease (PD). Several crucial neuronal pro-and antidegeneration markers were described to be altered in disease models accompanied by neurodegeneration. In the AAV1/2-A53T-aSyn PD rat model progressive time-dependent motor impairment and neurodegeneration in the nigrostriatal tract starting from 2 weeks after PD model induction could be found. Downregulation of Nrf2 in SN and nigrostriatal axon localization, a trend of Tau downregulation in SN and upregulation in axon localization in the AAV1/2-A53T-aSyn PD rat model were observed, indicating potential therapeutic value of these two molecular targets in PD. No alterations of SARM1 and NMNAT2 could be detected, indicating little relevance of these two molecules with our AAV1/2-A53T-aSyn rat model. N2 - Die Neurodegeneration spielt eine wesentliche Rolle bei der Parkinson-Krankheit (PD). Es wurde beschrieben, dass mehrere entscheidende neuronale Pro- und Antidegenerationsmarker in Krankheitsmodellen, die von Neurodegeneration begleitet werden, verändert sind. Im AAV1/2-A53T-aSyn PD-Rattenmodell konnte eine fortschreitende zeitabhängige motorische Beeinträchtigung und Neurodegeneration im Nigrostriataltrakt ab 2 Wochen nach PD-Modellinduktion gefunden werden. Herunterregulierung von Nrf2 in SN und nigrostriataler Axonlokalisierung, ein Trend der Tau-Herunterregulierung in SN und Hochregulierung in Axonlokalisierung im AAV1/2-A53T-aSyn-PD-Rattenmodell wurden beobachtet, was auf einen potenziellen therapeutischen Wert dieser beiden molekularen Ziele bei PD hinweist. Es konnten keine Veränderungen von SARM1 und NMNAT2 nachgewiesen werden, was auf eine geringe Relevanz dieser beiden Moleküle mit unserem AAV1/2-A53T-aSyn-Rattenmodell hinweist. KW - Parkinson's disease KW - Neurodegeneration Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260645 ER - TY - THES A1 - Pizon, Dorothea T1 - Prognose des raumfordernden Mediainfarktes bei konservativer vs. operativer Therapie am Universitätsklinikum Würzburg 1993-2005 T1 - Prognosis of conservative vs. surgical treatment of the space-occupying middle cerebral artery infarction at the University Hospital Wuerzburg 1993-2005 N2 - In dieser Studie wurden Schlaganfallpatienten untersucht, die einen ausgedehnten Infarkt im Versorgungsgebiet der A.cerebri media erlitten und wegen Bewusstseinstrübung (sog. Maligner Mediainfarkt) auf der Neurologischen Intensivstation des Universitätsklinikums Würzburg im Zeitraum von 1991 bis 2005 behandelt wurde, um herauszufinden, welchen Einfluss eine operative Behandlung auf den kritisch erhöhten Hirnsdrucks zusätzlich zur konservativen Intensivtherapie auf Mortalität sowie langfristige Lebensqualität hatte. Insgesamt konnten die Daten von 292 Patienten ausgewertet werden, wovon 259 konservativ und 33 operativ behandelt worden waren. Es zeigte sich insgesamt, dass eine stillschweigende günstige Selektion für eine Trepanation sprach (jünger, eher keine Aphasie, weniger Komorbiditäten). Die Hemikraniektomie senkte die Mortalität in der Akutphase hochsignifikant (K: 22, 4%, T: 3,0%; p=0,009). Sie hatte erwartungsgemäß auch einen positiven Einfluss auf das Vigilanzniveau: die Quote von wachen Patienten war bei Entlassung der Trepanierten um 66% höher als bei Aufnahme, bei den konservativ Behandelten war sie nur um 33,3 % gestiegen. Das vorherrschende Symptom bei Aufnahme und Entlassung war eine motorische bzw. sensomotorische Hemiparese. Der Anteil der Aphasiker bei den 201 konservativ therapierten Patienten, die den stationären Aufenthalt überlebt haben, ist von bei Aufnahme 56,2% auf bei Entlassung 48,6% gesunken. Bei den 32 trepanierten Patienten ist er dagegen mit 50% gleich geblieben, obwohl 2/3 aller Patienten an der nicht-dominanten Hemisphäre operiert worden waren. Es war und ist auch nicht zu erwarten, dass eine Entlastung von Hirndruck qualitativ die hirninfarktbedingten Symptome beseitigt. Die Nachbefragung der Patienten fand im Schnitt 64,7 Monate nach erlittenem Mediainfarkt statt. Inzwischen waren von den 259 konservativ Behandelten 47,1% verstorben, von den 33 Hemikraniektomierten nur 24,2%. Die poststationäre Mortalität im weiteren Verlauf war anteilsmäßig gering (K: 24%, T: 21,2%). Die Überlebensdauer der Trepanierten war dreimal so lang wie die der nicht operierten (K: 11,6 Monate, T: 34,4 Monate). Diese Unterschiede im Langzeitüberleben sind wahrscheinlicher auf die geringeren Komorbiditäten der Trepanierten zurückzuführen, als auf die stattgehabte Operation an sich. Allerdings ist nicht auszuschließen, dass die durch Trepanation frühzeitiger verbesserte Wachheit sich auch günstig auf lebensverkürzende Folgekomplikationen ausgewirkt haben könnte. In der Nachbefragung zeigte sich, dass bezüglich der erworbenen körperlichen Funktionsdefizite, gemessen am Barthel Index, zwischen den beiden Kollektiven kein signifikanter Unterschied bestand. Die ehemals konservativ behandelten Patienten kamen auf durchschnittlich 75, die trepanierten Patienten auf 60 von 100 Punkten. Im Lebensalltag schlägt sich dieser Unterschied von 15 Punkten relevant nieder, aber insgesamt liegen beide Patientenkollektive im Bereich einer leichten bis nicht vorhandenen Abhängigkeit. Die vergleichbaren Langzeitdaten von Patienten mit Mediainfarkt liegen in einem ähnlichen Bereich. Erstmalig werden hier Langzeitdaten solcher Patienten über die Lebensqualität vorgelegt, gemessen mit dem SF-36. Nachvollziehbar zeigte sich ein deutlicher Unterschied zur Lebensqualität der Durchschnittsbevölkerung, insbesondere im Bereich der körperlichen Belastbarkeit. Für uns unerwartet günstig fielen die Antworten auf der eher psychologischen Ebene aus. Es zeigten sich bei allen Punkten des SF-36 keine signifikanten Unterschiede zwischen dem konservativ behandelten und den hemikraniektomierten Patienten, so dass die Operation als solche keinen eigenständigen Einfluss auf die langfristige Lebensqualität nahm. Zusammengefasst verbesserte die osteoklastische Trepanation des raumfordernden malignen Mediainfarkts die Überlebenschance in der Akutphase signifikant, was mit inzwischen publizierten kontrollierten Studienergebnissen übereinstimmt. Der Langzeitverlauf nach überlebter Akutkrankheit gestaltet sich unabhängig von der Trepanation. Es gibt aufgrund der erworbenen Behinderung eine weiterhin relativ hohe längerfristige Sterblichkeit. Bemerkenswert ist, dass die Selbsteinschätzung der Lebensqualität von Patienten mit einer erheblichen infarktbedingen körperlichen Behinderung psychologisch-emotional nur geringfügig von der Selbstwahrnehmung in der nicht- behinderten Durchschnittsbevölkerung. Dass bedeutet, dass Spekulationen über die zukünftige Lebensqualität keinen Einfluss auf die Operationsindikation nehmen sollten. N2 - In this retrospective study we looked at the sub-group of stroke patients who suffered a large infarction in the area of the middle cerebral artery and were treated in neurological intensive care between 1991 and 2005 due to imminent or already existent decreased conscious level (so called malignant middle cerebral artery infarction) (n=292). The aim was to find out what influence a surgical treatment has on stroke-related increased intracerebral pressure additionally to the usual conservative intesive therapy with regards to acute and longterm survival. In total data from 292 intensiv care patients was evaluated, which consisted of 259 purely conservatively and 33 surgically treated patients. 
Altogether there was a positive selection for surgically treated patients (younger, no aphasia, less comorbidities). Decompressive hemicraniectomy lowered the mortality in the acute phase significantly (c: 22.4%, h: 3.0%; p=0.009). As expected decompressive hemicraniectomy also positively influenced the conscious level: the number of fully alert patients on discharge was 66% higher than on admission. In the group of the conservatively treated patients this number was only 33% higher (on discharge: c: 87% and h: 90.6% fully alert).The mean physical findings on discharge from neurological intensive care showed no significant difference between the conservatively and surgically treated group. The main symptoms were – as on admission – a motor or sensomotor hemiparesis. The prevalence of aphasia dropped in the group of 201 conservatively patients who survived the hospital stay from 56.2% on admission to 48.% on discharge (p= 0.5). In the 32 patients after hemicraniectomy who survived the hospital admission the number of aphasic patients did not change from admission to discharge (50%). It is not expected that a release of intracerebral pressure completely resolves stroke-connected symptoms. During the stay on intensive care physical and neuropsychological function was not systemically assessed using stroke function scales so we cannot comment on how the symptoms changed quantatively after the treatment. There is a possibility that arguments would be pro-hemicraniectomy. On average 64.7 months passed between the stroke and the follow-up examination. In the meantime 47.1% of the 259 conservatively treated patients had died. Of 33 patients after decompressive hemicraniectomy only 24.2% had died (p=0.01). There was a significant difference in the hospital mortality (c: 24%, h: 21.2%). The longterm mortality showed a smaller difference (c: 24%, h: 21.2%). The survival period of the surgically treated patients was three times longer (c: 11.6%, h: 34.4 months). The difference in survival length is most likely due to less comorbidities in the surgically treated patients than to the hemicraniectomy itself. However it can also not be ruled out that due to the earlier achieved improvement of conscious level postoperatively potential future complications could be prevented. With regards to acquired physical functional deficits, measured with the Barthel index, both groups did not reveal any significant difference (p=0.10). The mean Barthel index in the conservatively treated patients was 75 out of 100 and 60 out of 100 in the patients after decompressive hemicraniectomy. That means that patients from both groups were either independent or slightly dependant from other people in their every day life. For the first time we were presenting longterm data on subjective quality of life from patients after middle cerebral artery infarction, measured with the SF-36 health survey [Bullinger et al. 1998]. As expected there was a major difference between our patient group and a comparable average population, especially in areas like “physical function”. The results on a more psychological level like “vitality” and “mental health” were better than expected. They only mildly differed from the average population. The SF-36 health survey did not show any significant difference between the conservatively treated and the surgically treated group. That indicates how the decompressive hemicraniectomy alone did not have an influence on longterm quality of life. In summary the survival rate was inreased significantly by decompressive hemicraniectomy in malignant middle cerebral artery infarction at the University Hospital Wuerzburg between 1991 and 2005, which was also confirmed by other publicated controlled studies [Jüttler et al. 2007; Vahedi et al. 2007; Fandino et al. 2004]. It is remarkable that the subjective quality of life of patients with a considerable disability differs only slightly from the perception of a non-impaired control group. That means that speculations about a future quality of life should not influence a decision for or against decompressive hemicraniectomy. KW - Arteria cerebri media KW - Schlaganfall KW - Arteria carotis interna KW - Carotisstenose KW - Trepanation KW - Infarkt KW - Hirndruck KW - Hirnödem KW - Sekundärprävention KW - Barthel Index KW - Rehabilitation KW - Matched pairs KW - dekompressive Hemikraniektomie KW - maligner Mediainfarkt KW - Dekompressionskraniektomie KW - Middle cerebral artery infarction KW - malignant middle cerebrial artery infarction KW - decompressive hemicraniectomy KW - Barthel Index Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-70232 ER - TY - JOUR A1 - Göpfert, Dennis A1 - Traub, Jan A1 - Sell, Roxane A1 - Homola, György A. A1 - Vogt, Marius A1 - Pham, Mirko A1 - Frantz, Stefan A1 - Störk, Stefan A1 - Stoll, Guido A1 - Frey, Anna T1 - Profiles of cognitive impairment in chronic heart failure—A cluster analytic approach JF - Frontiers in Human Neuroscience N2 - Background Cognitive impairment is a major comorbidity in patients with chronic heart failure (HF) with a wide range of phenotypes. In this study, we aimed to identify and compare different clusters of cognitive deficits. Methods The prospective cohort study “Cognition.Matters-HF” recruited 147 chronic HF patients (aged 64.5 ± 10.8 years; 16.2% female) of any etiology. All patients underwent extensive neuropsychological testing. We performed a hierarchical cluster analysis of the cognitive domains, such as intensity of attention, visual/verbal memory, and executive function. Generated clusters were compared exploratively with respect to the results of cardiological, neurological, and neuroradiological examinations without correction for multiple testing. Results Dendrogram and the scree plot suggested three distinct cognitive profiles: In the first cluster, 42 patients (28.6%) performed without any deficits in all domains. Exclusively, the intensity of attention deficits was seen in the second cluster, including 55 patients (37.4%). A third cluster with 50 patients (34.0%) was characterized by deficits in all cognitive domains. Age (p = 0.163) and typical clinical markers of chronic HF, such as ejection fraction (p = 0.222), 6-min walking test distance (p = 0.138), NT-proBNP (p = 0.364), and New York Heart Association class (p = 0.868) did not differ between clusters. However, we observed that women (p = 0.012) and patients with previous cardiac valve surgery (p = 0.005) prevailed in the “global deficits” cluster and the “no deficits” group had a lower prevalence of underlying arterial hypertension (p = 0.029). Total brain volume (p = 0.017) was smaller in the global deficit cluster, and serum levels of glial fibrillary acidic protein were increased (p = 0.048). Conclusion Apart from cognitively healthy and globally impaired HF patients, we identified a group with deficits only in the intensity of attention. Women and patients with previous cardiac valve surgery are at risk for global cognitive impairment when suffering HF and could benefit from special multimodal treatment addressing the psychosocial condition. KW - chronic heart failure KW - cluster analysis KW - cognitive impairment KW - intensity of attention KW - glial fibrillary acidic protein Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313429 VL - 17 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 - TY - THES A1 - Cholewa, Ute T1 - Procalcitonin in der Frühdiagnose der bakteriellen Meningitis T1 - Procalcitonin in the early diagnosis of bacterial meningitis N2 - Die Prognose einer lebensbedrohlichen Meningitis wird bestimmt durch möglichst erregergerechte und möglichst frühzeitige Therapie. Dabei spielt die Unterscheidung zwischen eitriger Meningitis durch typische oder schwer anzüchtbare Bakterien und abakterieller Meningitis eine Rolle, um die potentiellen Komplikationen unnötiger Polypragmasie zu vermeiden. Daher sind möglichst einfach und rasch zu bestimmende Laborparameter zur Untersuchung wünschenswert. Als relativ neuer Parameter zur Differenzierung bakterieller von nicht bakteriellen Infekten ist Procalcitonin (PCT) eingeführt, dessen Bestimmung jetzt auch am Krankenbett möglich ist. PCT hat bisher seine Nützlichkeit v. a. in der Sepsiserkennung und –therapie gezeigt. Erste Fragestellung dieser retrospektiven Analyse von Meningoencephalitispatienten war, ob bei Erwachsenen durch Messung des PCT-Spiegels eine Differenzierung zwischen bakterieller oder viraler Genese gelingt, und ob der Bedsidetest so zuverlässig ist wie der aufwändigere LUMItest®. Dazu wurden retrospektiv die Daten von 141 Patienten erhoben, die 1992-2001 an der Neurologischen Universitätsklinik Würzburg mit gesicherter Meningitis behandelt wurden, von denen sowohl Akten als auch Liquor- und Serumasservate vorlagen, in denen die PCT-Messungen durchgeführt wurden. In den Untersuchungen von Schwarz et al. [102], Gendrel et al. [100] und Jereb et al. [104] wurde bei einem PCT-Grenzwert von 0,5 ng/ml eine Spezifität von 100 % für die Differenzierung bakterielle verusus abakterielle Meninigitis gefunden. Dagegen wären bei gleicher Messmethodik im hier vorliegendem größeren Patientengut 35 % der gesicherten bakteriellen Meningitiden bei einem „cut-off“ von 0,5 ng/ml nicht als solche erkannt worden. 5 % der nicht-bakteriellen Meningitiden wären mittels PCT-Messung als bakteriell eingestuft worden. Im hier untersuchten Patientenkollektiv hatte PCT als diagnostischer Parameter für diese Fragestellung bei einem Grenzwert von 0,5 ng/ml eine Sensitivität von 65 % und eine Spezifität von 96 %. Eine 100 % Spezifität wäre in unserer Untersuchung bei einem „cut-off“ von 1 ng/ml erreicht worden. Diese Grenze wird jedoch auf dem Schnelltest nicht angegeben. Es stellte sich hier heraus, dass der PCT®-Q Schnelltest im Bereich > 0,5 ng/ml bzw. <0,5 ng/ml dem LUMItest® vergleichbare Ergebnisse lieferte. Das bedeutet zwar, dass alle bakteriellen Meningitiden durch typische Erreger (Meningokokken und Pneumokokken) rasch und sicher bettseitig mittels PCT-Schnelltest hätten identifiziert werden können. Aber ein niedriger PCT-Wert schloss eine bakterielle Meningitis, insbesondere eine durch „atypische Erreger“ wie Listerien und Mycobakterien, nicht sicher aus. Denkbare Störgrößen für das vorliegende Ergebnis sind Antibiotikagabe und Immunschwäche. Ein statistisch auffallender Einfluss einer Antibiotikatherapie auf den PCT-Spiegel konnte in unserem Patientengut nicht festgestellt werden. Für die wenigen Fälle mit anzunehmender verminderter Immunleistung ließ sich keine Regel bezüglich der PCT-Reaktion ableiten. Damit erscheint der Schnelltest im klinischen Alltag für eine 100% spezifische, sichere Unterscheidung bakterielle vs. nicht-bakterielle Meniongoencephalitis nicht geeignet; das bisher größte untersuchte Kollektiv hat den in der Literatur angegebenen „cut-off“ von 0,5 ng/ml für eine sichere Differenzierung nicht bestätigen können. Die zweite Frage ist, ob die Messung des PCT den traditionellen Parametern Liquorzellzahl, Liquoreiweiß, Liquor/Serum-Glucosequotient, BSG, Serumleukozytenzahl oder CRP bezüglich Spezifität und Sensitivität in der Differentialdiagnose überlegen ist. Es zeigte sich, dass CRP bei einem Grenzwert von 5-6 mg/dl mit einer Sensitivität und Spezifität von 95 % und 98 % die sicherste Differenzierung zwischen bakterieller und abakterieller Meningitis bei diesem Patientenkollektiv leistete. Mithin kann die PCT-Bestimmung am Krankenbett in der Akutaufnahmesituation eines Patienten mit Meningoencephalitis bei Werten > 10 ng/ml zwar treffsicher die Diagnose einer Meningokokken- oder Pneumokokken-Infektion stützen. Für jede darüber hinaus gehende Schlussfolgerung erscheint die PCT-Messung aber entbehrlich wegen mangelhafter Spezifität und Sensitivität und v.a. der Unterlegenheit gegenüber traditionell herangezogenen Laborparametern, insbesondere CRP. Folglich erwies sich die Bestimmung des PCT bei akuter Meningoencephalitis als entbehrlich. N2 - Objectives: Can serum-Procalcitonin (PCT) distinguish more exactly bacterial from abacterial meningitis/meningoencephalitis than the common parameters (like cerebrospinal fluid leukocyte count, cerebrospinal fluid protein, serum/cerebrospinal fluid glucose quotient, erythrocyte sedimentation rate, white blood cell count and C-reactive protein)? Design: Retrospective case series Patients: A total of 141 patients (56 woman, 87 men) Intervention: Blood samples Main results: By taking a cut-off-level of 0,5 ng/ml for PCT (as provided by the producer), this parameter shows a sensitivity of 65 % and specificity of 96%. It turned out that CRP did the safest distinction between bacterial and abacterial meningitis by choosing a cut-off-level of 5-6 mg/dl with a sensitivity and specificity of 95% and 98% at this patient collective. Conclusion: In this study PCT proved to be a dispensable parameter for the early diagnosis of the bacterial meningitis. KW - Procalcitonin KW - Meningitis KW - Meningoencephalitis KW - procalcitonin KW - meningitis KW - meningoencephalitis Y1 - 2005 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-16490 ER - TY - JOUR A1 - Saudek, František A1 - Cahová, Monika A1 - Havrdová, Terezie A1 - Zacharovová, Klára A1 - Daňková, Helena A1 - Voska, Luděk A1 - Lánská, Věra A1 - Üçeyler, Nurcan A1 - Sommer, Claudia T1 - Preserved Expression of Skin Neurotrophic Factors in Advanced Diabetic Neuropathy Does Not Lead to Neural Regeneration despite Pancreas and Kidney Transplantation JF - Journal of Diabetes Research N2 - Diabetic peripheral neuropathy (DPN) is a common complication of diabetes with potential severe consequences. Its pathogenesis involves hyperglycemia-linked mechanisms, which may include changes in the expression of neurotrophic growth factors. We analyzed the expression of 29 factors potentially related to nerve degeneration and regeneration in skin biopsies from 13 type 1 diabetic pancreas and kidney recipients with severe DPN including severe depletion of intraepidermal nerve fibers (IENF) in lower limb skin biopsies (group Tx1 1st examination). The investigation was repeated after a median 28-month period of normoglycemia achieved by pancreas transplantation (group Tx1 2nd examination). The same tests were performed in 13 stable normoglycemic pancreas and kidney recipients 6-12 years posttransplantation (group Tx2), in 12 matched healthy controls (group HC), and in 12 type 1 diabetic subjects without severe DPN (group DM). Compared to DM and HC groups, we found a significantly higher (p < 0.05-0.001) expression of NGF (nerve growth factor), NGFR (NGF receptor), NTRK1 (neurotrophic receptor tyrosine kinase 1), GDNF (glial cell-derived neurotrophic factor), GFRA1 (GDNF family receptor alpha 1), and GFAP (glial fibrillary acidic protein) in both transplant groups (Tx1 and Tx2). Enhanced expression of these factors was not normalized following the median 28-month period of normoglycemia (Tx1 2nd examination) and negatively correlated with IENF density and with electrophysiological indices of DPN (vibration perception threshold, electromyography, and autonomic tests). In contrast to our expectation, the expression of most of 29 selected factors related to neural regeneration was comparable in subjects with severe peripheral nerve fiber depletion and healthy controls and the expression of six factors was significantly upregulated. These findings may be important for better understanding the pathophysiology of nerve regeneration and for the development of intervention strategies. KW - Nerve growth-factorcopy KW - Corneal confocal microscopy KW - Factor messenger-RNA KW - Schwann-cells KW - Gene-expression KW - Receptors KW - Identification KW - Innervation KW - Mechanisms KW - Gland Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227469 VL - 2018 IS - 2309108 ER - TY - JOUR A1 - Gulberti, A. A1 - Moll, C.K.E. A1 - Hamel, W. A1 - Buhmann, C. A1 - Koeppen, J.A. A1 - Boelmans, K. A1 - Zittel, S. A1 - Gerloff, C. A1 - Westphal, M. A1 - Schneider, T.R. A1 - Engel, A.K. T1 - Predictive timing functions of cortical beta oscillations are impaired in Parkinson's disease and influenced by L-DOPA and deep brain stimulation of the subthalamic nucleus Impaired beta-band timing functions in PD JF - NeuroImage: Clinical N2 - Cortex-basal ganglia circuits participate in motor timing and temporal perception, and are important for the dynamic configuration of sensorimotor networks in response to exogenous demands. In Parkinson's disease (PD) patients, rhythmic auditory stimulation (RAS) induces motor performance benefits. Hitherto, little is known concerning contributions of the basal ganglia to sensory facilitation and cortical responses to RAS in PD. Therefore, we conducted an EEG study in 12 PD patients before and after surgery for subthalamic nucleus deep brain stimulation (STN-DBS) and in 12 age-matched controls. Here we investigated the effects of levodopa and STN-DBS on resting-state EEG and on the cortical-response profile to slow and fast RAS in a passive-listening paradigm focusing on beta-band oscillations, which are important for auditory–motor coupling. The beta-modulation profile to RAS in healthy participants was characterized by local peaks preceding and following auditory stimuli. In PD patients RAS failed to induce pre-stimulus beta increases. The absence of pre-stimulus beta-band modulation may contribute to impaired rhythm perception in PD. Moreover, post-stimulus beta-band responses were highly abnormal during fast RAS in PD patients. Treatment with levodopa and STN-DBS reinstated a post-stimulus beta-modulation profile similar to controls, while STN-DBS reduced beta-band power in the resting-state. The treatment-sensitivity of beta oscillations suggests that STN-DBS may specifically improve timekeeping functions of cortical beta oscillations during fast auditory pacing. KW - Parkinson's disease KW - interval timing KW - beta oscillations KW - subthalamic nucleus KW - deep brain stimulation Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150049 VL - 9 ER - TY - JOUR A1 - Farinelli, Veronica A1 - Palmisano, Chiara A1 - Marchese, Silvia Maria A1 - Strano, Camilla Mirella Maria A1 - D’Arrigo, Stefano A1 - Pantaleoni, Chiara A1 - Ardissone, Anna A1 - Nardocci, Nardo A1 - Esposti, Roberto A1 - Cavallari, Paolo T1 - Postural control in children with cerebellar ataxia JF - Applied Sciences N2 - Controlling posture, i.e., governing the ensemble of involuntary muscular activities that manage body equilibrium, represents a demanding function in which the cerebellum plays a key role. Postural activities are particularly important during gait initiation when passing from quiet standing to locomotion. Indeed, several studies used such motor task for evaluating pathological conditions, including cerebellar disorders. The linkage between cerebellum maturation and the development of postural control has received less attention. Therefore, we evaluated postural control during quiet standing and gait initiation in children affected by a slow progressive generalized cerebellar atrophy (SlowP) or non-progressive vermian hypoplasia (Joubert syndrome, NonP), compared to that of healthy children (H). Despite the similar clinical evaluation of motor impairments in NonP and SlowP, only SlowP showed a less stable quiet standing and a shorter and slower first step than H. Moreover, a descriptive analysis of lower limb and back muscle activities suggested a more severe timing disruption in SlowP. Such differences might stem from the extent of cerebellar damage. However, literature reports that during childhood, neural plasticity of intact brain areas could compensate for cerebellar agenesis. We thus proposed that the difference might stem from disease progression, which contrasts the consolidation of compensatory strategies. KW - children KW - gait initiation KW - postural control KW - generalized cerebellar atrophy KW - cerebellar vermis hypoplasia KW - progressive ataxia KW - compensatory strategies Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200692 SN - 2076-3417 VL - 10 IS - 5 ER - TY - JOUR A1 - Kleinschnitz, Christoph A1 - Grund, Henrike A1 - Wingler, Kirstin A1 - Armitage, Melanie E. A1 - Jones, Emma A1 - Mittal, Manish A1 - Barit, David A1 - Schwarz, Tobias A1 - Geis, Christian A1 - Kraft, Peter A1 - Barthel, Konstanze A1 - Schuhmann, Michael K. A1 - Herrmann, Alexander M. A1 - Meuth, Sven G. A1 - Stoll, Guido A1 - Meurer, Sabine A1 - Schrewe, Anja A1 - Becker, Lore A1 - Gailus-Durner, Valerie A1 - Fuchs, Helmut A1 - Klopstock, Thomas A1 - de Angelis, Martin Hrabe A1 - Jandeleit-Dahm, Karin A1 - Shah, Ajay M. A1 - Weissmann, Norbert A1 - Schmidt, Harald H. H. W. T1 - Post-Stroke Inhibition of Induced NADPH Oxidase Type 4 Prevents Oxidative Stress and Neurodegeneration N2 - Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox42/2) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox42/2 mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy. KW - Schlaganfall Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68416 ER - TY - THES A1 - Kohl, Bianca Dorothea T1 - PMP22-overexpressing mice as a model for Charcot-Marie-Tooth 1A neuropathy implicate a role of immune-related cells T1 - PMP22-überexprimierende Mäuse als Modell einer Charcot-Marie-Tooth 1A Neuropatie. N2 - Charcot-Marie-Tooth disease (CMT) is a cohort of human hereditary disorders of the peripheral nervous system (PNS) which exhibit symptoms like sensory dysfunction, muscle weakness and gait disturbances. Different mutations are described as causation for this neuropathy, such as a duplication of chromosome 17 comprising the gene for the peripheral myelin protein-22 (PMP22). Based on different animal models former studies identified immune cells, i.e. macrophages and T-lymphocytes, as crucial mediators of pathology in these neuropathies. In this study, PMP22-overexpressing mice (PMP22tg, C61), serving as a model for a specific type of CMT – CMT1A – were crossbred with immune-deficient mutant mice to examine the impact of the immune system on nerve pathology. Crossbreeding of PMP22tg mice with recombination activating gene-1 (RAG-1) deficient mice, lacking mature T- and B-lymphocytes, caused no striking alterations of pathogenesis in peripheral nerves of mutant mice. In contrast, crossbreeding of PMP22tg myelin mutants with mice deficient in the chemokine monocyte chemoattractant protein-1 (MCP-1, CCL2) caused an amelioration of the demyelinating phenotype of peripheral nerves when MCP-1 was either reduced or completely absent. Furthermore, functional investigations, i.e. neurographic recordings and examinations of the grip strength of the extremities, revealed an amelioration in PMP22tg/MCP-1-/- mice in regard to a symptomatic improvement in the compound action muscle potential (CMAP) and stronger grip strength of the hindlimbs. Interestingly, peripheral nerves of PMP22tg mice showed an irregular distribution of potassium channels in presence of MCP-1, whereas the absence of MCP-1 in the myelin mutants rescued the ion channel distribution and resulted in a more wild type-like phenotype. Having shown the impact of MCP-1 as an important mediator of nerve pathology in PMP22/MCP-1 double mutants, the regulation of this chemokine became an important target for potential treatment strategies. We found that the signaling cascade MEK1/2/ERK1/2 was more strongly activated in peripheral nerves of PMP22tg mice compared to nerves of wild type mice. This activation corresponded to an increase in MCP-1 mRNA expression in peripheral nerves at the same age. Furthermore, a MEK1/2-inhibitor was used in vivo to confirm the regulation of MCP-1 by the MEK1/2/ERK1/2 pathway. After a treatment period of three weeks, a clear reduction of ERK1/2-phosphorylation as well as a reduction of MCP-1 mRNA expression was observed, accompanied by a decline in macrophage number in peripheral nerves of PMP22tg mice. These observations suggest that the expression of MCP-1 is crucial for the neuropathological progression in a mouse model for CMT1A. Therefore, this chemokine could provide a basis for a putative treatment strategy of inherited neuropathies. N2 - Die Charcot-Marie-Tooth Erkrankungen (CMT) sind eine Gruppe von humanen, erblichen Erkrankungen des peripheren Nervensystems (PNS), welche Symptome wie sensible Störungen, Muskelschwäche und Gangstörungen verursachen können. Verschiedene Mutationen, z.B. eine Duplikation des Chromosoms 17, welches das Gen für das periphere Myelinprotein-22 (PMP22) enthält, sind als Ursache für diese Neuropathie beschrieben. Anhand verschiedener Tiermodelle wurde in früheren Studien gezeigt, dass Immunzellen, insbesondere Makrophagen und T-Lymphozyten, maßgeblich an der Pathogenese dieser Neuropathien beteiligt sind. In der vorliegenden Studie wurden PMP22-überexprimierende Mäuse (PMP22tg, C61) als Modell einer spezifischen CMT-Form – CMT1A – mit immun-defizienten Mutanten verkreuzt, um die modulierende Rolle des Immunsystems innerhalb der Pathogenese peripherer Nerven untersuchen zu können. Die Verkreuzung von PMP22tg Mäusen mit „recombination activating gene-1“-defizienten Mutanten (RAG-1-/-), die keine reifen T- und B-Lymphozyten besitzen, resultierte in keiner deutlich veränderten Pathologie der peripheren Nerven. Im Gegensatz hierzu führte die Verkreuzung der Myelinmutanten mit Mäusen, defizient für das Chemokin „monocyte chemoattractant protein-1“ (MCP-1), zu einer Abschwächung des demyelinisierenden Phänotyps in peripheren Nerven, wenn MCP-1 reduziert war oder völlig fehlte. Funktionelle Analysen, wie elektrophysiologische Messungen und Untersuchungen der Kraft in den Extremitäten, zeigten zudem in PMP22tg/MCP-1-/- Mäusen eine symptomatische Verbesserung, was sich in einer höheren Amplitude (compound muscle action potential, CMAP) und einer erhöhten Kraft in den Hinterpfoten der Mäuse widerspiegelte. Interessanterweise zeigten periphere Nerven der PMP22tg Mäuse eine abnorme Verteilung von Kalium-Kanälen, wohingegen das Fehlen von MCP-1 in den Myelinmutanten zu einer Verteilung dieser Ionenkanäle führte, die ähnlich zu Wildtyp-Mäusen war. Da MCP-1 in den PMP22/MCP-1 Doppelmutanten einen deutlichen Einfluss auf die Pathogenese aufwies, wurde die Regulation dieses Chemokins im Hinblick auf mögliche Therapie-Ansätze untersucht. Diese Untersuchung zeigte, dass die MEK1/2/ERK1/2-Signalkaskade in peripheren Nerven von PMP22tg Mäusen stärker aktiviert wird als in Nerven von Wildtyp-Tieren. Die Aktivierung dieser Signalkaskade ging dabei mit einer erhöhten MCP-1 mRNA Expression in peripheren Nerven von Tieren des gleichen Alters einher. Ergänzend wurde ein MEK1/2-Inhibitor in vivo verwendet, um die Regulation von MCP-1 durch die MEK1/2/ERK1/2 Kaskade zu bestätigen. Nach einer Behandlungszeit von drei Wochen wurde eine deutliche Reduktion der ERK1/2-Phosphorylierung, sowie eine Reduktion der MCP-1 mRNA Expression und eine geringere Makrophagen-Anzahl in peripheren Nerven von PMP22tg Mäusen detektiert. Diese Untersuchungen zeigen, dass die Expression von MCP-1 entscheidend für den neuropathologischen Verlauf in einem Mausmodell für CMT1A ist. Somit bietet dieses Chemokin eine Basis für die Entwicklung neuer Behandlungsstrategien peripherer Neuropathien. KW - Myelin KW - Makrophage KW - Entmarkung KW - Schwann Zellen KW - PMP22 KW - MCP-1 KW - Immunzellen KW - Periphere Nerven KW - Schwann cells KW - PMP22 KW - MCP-1 KW - immune cells KW - peripheral nerves Y1 - 2009 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-43066 ER - TY - JOUR A1 - Lüningschrör, Patrick A1 - Binotti, Beyenech A1 - Dombert, Benjamin A1 - Heimann, Peter A1 - Perez-Lara, Angel A1 - Slotta, Carsten A1 - Thau-Habermann, Nadine A1 - von Collenberg, Cora R. A1 - Karl, Franziska A1 - Damme, Markus A1 - Horowitz, Arie A1 - Maystadt, Isabelle A1 - Füchtbauer, Annette A1 - Füchtbauer, Ernst-Martin A1 - Jablonka, Sibylle A1 - Blum, Robert A1 - Üçeyler, Nurcan A1 - Petri, Susanne A1 - Kaltschmidt, Barbara A1 - Jahn, Reinhard A1 - Kaltschmidt, Christian A1 - Sendtner, Michael T1 - Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease JF - Nature Communications N2 - Autophagy-mediated degradation of synaptic components maintains synaptic homeostasis but also constitutes a mechanism of neurodegeneration. It is unclear how autophagy of synaptic vesicles and components of presynaptic active zones is regulated. Here, we show that Pleckstrin homology containing family member 5 (Plekhg5) modulates autophagy of synaptic vesicles in axon terminals of motoneurons via its function as a guanine exchange factor for Rab26, a small GTPase that specifically directs synaptic vesicles to preautophagosomal structures. Plekhg5 gene inactivation in mice results in a late-onset motoneuron disease, characterized by degeneration of axon terminals. Plekhg5-depleted cultured motoneurons show defective axon growth and impaired autophagy of synaptic vesicles, which can be rescued by constitutively active Rab26. These findings define a mechanism for regulating autophagy in neurons that specifically targets synaptic vesicles. Disruption of this mechanism may contribute to the pathophysiology of several forms of motoneuron disease. KW - autophagy KW - synaptic vesicles KW - Pleckstrin homology containing family member 5 (Plekhg5) KW - regulation KW - motoneuron disease Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170048 VL - 8 IS - 678 ER - TY - THES A1 - Zimmermann [née Papp], Lena T1 - Platelets as modulators of blood-brain barrier disruption and inflammation in the pathophysiology of ischemic stroke T1 - Thrombozyten als Modulatoren der Blut-Hirn-Schrankenstörung und Inflammation in der Pathophysiologie des ischämischen Schlaganfalls N2 - Ischemia-reperfusion injury (I/R injury) is a common complication in ischemic stroke (IS) treatment, which is characterized by a paradoxical perpetuation of tissue damage despite the successful re-establishment of vascular perfusion. This phenomenon is known to be facilitated by the detrimental interplay of platelets and inflammatory cells at the vascular interface. However, the spatio-temporal and molecular mechanisms underlying these cellular interactions and their contribution to infarct progression are still incompletely understood. Therefore, this study intended to clarify the temporal mechanisms of infarct growth after cerebral vessel recanalization. The data presented here could show that infarct progression is driven by early blood-brain-barrier perturbation and is independent of secondary thrombus formation. Since previous studies unravelled the secretion of platelet granules as a molecular mechanism of how platelets contribute to I/R injury, special emphasis was placed on the role of platelet granule secretion in the process of barrier dysfunction. By combining an in vitro approach with a murine IS model, it could be shown that platelet α-granules exerted endothelial-damaging properties, whereas their absence (NBEAL2-deficiency) translated into improved microvascular integrity. Hence, targeting platelet α-granules might serve as a novel treatment option to reduce vascular integrity loss and diminish infarct growth despite recanalization. Recent evidence revealed that pathomechanisms underlying I/R injury are already instrumental during large vessel occlusion. This indicates that penumbral tissue loss under occlusion and I/R injury during reperfusion share an intertwined relationship. In accordance with this notion, human observational data disclosed the presence of a neutrophil dominated immune response and local platelet activation and secretion, by the detection of the main components of platelet α-granules, within the secluded vasculature of IS patients. These initial observations of immune cells and platelets could be further expanded within this thesis by flow cytometric analysis of local ischemic blood samples. Phenotyping of immune cells disclosed a yet unknown shift in the lymphocyte population towards CD4+ T cells and additionally corroborated the concept of an immediate intravascular immune response that is dominated by granulocytes. Furthermore, this thesis provides first-time evidence for the increased appearance of platelet-leukocyte-aggregates within the secluded human vasculature. Thus, interfering with immune cells and/or platelets already under occlusion might serve as a potential strategy to diminish infarct expansion and ameliorate clinical outcome after IS. N2 - Eine häufig auftretende Komplikation in der Behandlung des ischämischen Schlaganfalls ist der Ischämie/Reperfusion Schaden (I/R Schaden), welcher trotz der erfolgreichen Wiederherstellung der zerebralen Durchblutung durch ein paradoxes Fortschreiten des entstandenen Gewebeschadens charakterisiert ist. Dieses Phänomen wird durch das schädigende Zusammenspiel von Thrombozyten und inflammatorischen Zellen am vaskulären Endothel verursacht. Allerdings sind die räumlich-temporalen und molekularen Mechanismen dieser zellulären Interaktionen und deren Beteiligung am Infarktwachstum noch nicht vollständig verstanden. Daraus folgend, beabsichtigte diese Arbeit eben diese temporalen Mechanismen des fortschreitenden Infarktwachstums nach der zerebralen Gefäßwiedereröffnung aufzuklären. Die hier vorgestellten Daten implizieren, dass das anhaltende Fortschreiten des Gewebeschadens durch die Schädigung der Bluthirnschranke verursacht wird und somit unabhängig vom Auftreten sekundär gebildeter Thromben ist. In vorangegangenen Studien konnte die Freisetzung von thrombozytären Granula als molekularer Mechanismus, mit welchem Thrombozyten zum I/R Schaden beitragen, aufgedeckt werden. Basierend auf diesen Studien wurde in dieser Arbeit ein besonderes Augenmerk auf die Sekretion thrombozytärer Granula im Zusammenhang mit der Beeinträchtigung der endothelialen Barriere gelegt. Durch die Kombination eines in vitro Ansatzes mit einem murinen Model des ischämischen Schlaganfalls konnte gezeigt werden, dass α-Granula endothelialen Schaden verursachen, wohingegen deren Absenz (NBEAL2 Defizienz) zu einer verbesserten mikrovaskulären Integrität führte. Aufgrund dessen könnte das Adressieren der α-Granula als eine neuartige Therapieoption zum Erhalt der vaskulären Integrität und zur Verminderung des Infarktwachstums trotz Rekanalisation genutzt werden. Neuste Erkenntnisse enthüllten, dass die dem I/R Schaden zu Grunde liegenden Pathomechanismen bereits während des Verschlusses eines großen hirnversorgenden Gefäßes zu beobachten sind. Dies deutet darauf hin, dass der Verlust von penumbralem Gewebe unter Okklusion und I/R Schädigung während der Reperfusion im engen Zusammenhang stehen. Im Einklang hiermit konnten humane Daten eine Neutrophilen-dominierte Immunantwort und lokale Thrombozyten Aktivierung und deren Sekretion, anhand der Detektion der α-Granula Hauptkomponenten, im verschlossenen Gefäßsystem von ischämischen Schlaganfall Patienten nachweisen. Diese anfänglichen Beobachtungen konnten im Rahmen dieser Arbeit anhand durchflusszytometrischer Untersuchungen von lokal abgenommenen ischämischen Blutproben erweitert werden. Die Phänotypisierung von Immunzellen enthüllte eine bisher unbekannte Verschiebung der Lymphozyten Population hin zu CD4+ T-Zellen und bekräftigte zusätzlich das Konzept einer unmittelbaren intravaskulären Immunantwort, welche durch Granulozyten dominiert wird. Darüber hinaus konnte in dieser Thesis das erste Mal das erhöhte Auftreten von Thrombozyten-Leukozyten-Aggregaten in dem verschlossenen humanen Gefäßsystem nachgewiesen werden. Demzufolge könnte eine Beeinflussung von Immunzellen und/oder Thrombozyten bereits unter Okklusion als potentiell vielversprechende Strategie genutzt werden, um die Ausweitung des Infarktes einzuschränken und klinische Endpunkte nach einem ischämischen Schlaganfall zu verbessern. KW - Schlaganfall KW - Thrombozyt KW - Entzündung KW - Thrombo-inflammation KW - Ischemic stroke KW - Platelets KW - Inflamamtion KW - Immune cells KW - Vascular system Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-302850 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 - Kollikowski, Alexander M. A1 - Pham, Mirko A1 - März, Alexander G. A1 - Papp, Lena A1 - Nieswandt, Bernhard A1 - Stoll, Guido A1 - Schuhmann, Michael K. T1 - Platelet Activation and Chemokine Release Are Related to Local Neutrophil-Dominant Inflammation During Hyperacute Human Stroke JF - Translational Stroke Research N2 - Experimental evidence has emerged that local platelet activation contributes to inflammation and infarct formation in acute ischemic stroke (AIS) which awaits confirmation in human studies. We conducted a prospective observational study on 258 consecutive patients undergoing mechanical thrombectomy (MT) due to large-vessel-occlusion stroke of the anterior circulation (08/2018-05/2020). Intraprocedural microcatheter aspiration of 1 ml of local (occlusion condition) and systemic arterial blood samples (self-control) was performed according to a prespecified protocol. The samples were analyzed for differential leukocyte counts, platelet counts, and plasma levels of the platelet-derived neutrophil-activating chemokine C-X-C-motif ligand (CXCL) 4 (PF-4), the neutrophil attractant CXCL7 (NAP-2), and myeloperoxidase (MPO). The clinical-biological relevance of these variables was corroborated by specific associations with molecular-cellular, structural-radiological, hemodynamic, and clinical-functional parameters. Seventy consecutive patients fulfilling all predefined criteria entered analysis. Mean local CXCL4 (+ 39%: 571 vs 410 ng/ml, P = .0095) and CXCL7 (+ 9%: 693 vs 636 ng/ml, P = .013) concentrations were higher compared with self-controls. Local platelet counts were lower (- 10%: 347,582 vs 383,284/µl, P = .0052), whereas neutrophil counts were elevated (+ 10%: 6022 vs 5485/µl, P = 0.0027). Correlation analyses revealed associations between local platelet and neutrophil counts (r = 0.27, P = .034), and between CXCL7 and MPO (r = 0.24, P = .048). Local CXCL4 was associated with the angiographic degree of reperfusion following recanalization (r =  - 0.2523, P = .0479). Functional outcome at discharge correlated with local MPO concentrations (r = 0.3832, P = .0014) and platelet counts (r = 0.288, P = .0181). This study provides human evidence of cerebral platelet activation and platelet-neutrophil interactions during AIS and points to the relevance of per-ischemic thrombo-inflammatory mechanisms to impaired reperfusion and worse functional outcome following recanalization. KW - chemokines KW - CXCL4 KW - PF4 KW - CXCL7 KW - NAP-2 KW - ischemic stroke Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270194 SN - 1868-601X VL - 13 IS - 3 ER - TY - JOUR A1 - Gschmack, Eva A1 - Monoranu, Camelia-Maria A1 - Marouf, Hecham A1 - Meyer, Sarah A1 - Lessel, Lena A1 - Idris, Raja A1 - Berg, Daniela A1 - Maetzler, Walter A1 - Steigerwald, Frank A1 - Volkmann, Jens A1 - Gerlach, Manfred A1 - Riederer, Peter A1 - Koutsilieri, Eleni A1 - Scheller, Carsten T1 - Plasma autoantibodies to glial fibrillary acidic protein (GFAP) react with brain areas according to Braak staging of Parkinson’s disease JF - Journal of Neural Transmission N2 - Idiopathic Parkinson’s disease (PD) is characterized by a progredient degeneration of the brain, starting at deep subcortical areas such as the dorsal motor nucleus of the glossopharyngeal and vagal nerves (DM) (stage 1), followed by the coeruleus–subcoeruleus complex; (stage 2), the substantia nigra (SN) (stage 3), the anteromedial temporal mesocortex (MC) (stage 4), high-order sensory association areas and prefrontal fields (HC) (stage 5) and finally first-order sensory association areas, premotor areas, as well as primary sensory and motor field (FC) (stage 6). Autoimmunity might play a role in PD pathogenesis. Here we analyzed whether anti-brain autoantibodies differentially recognize different human brain areas and identified autoantigens that correlate with the above-described dissemination of PD pathology in the brain. Brain tissue was obtained from deceased individuals with no history of neurological or psychiatric disease and no neuropathological abnormalities. Tissue homogenates from different brain regions (DM, SN, MC, HC, FC) were subjected to SDS-PAGE and Western blot. Blots were incubated with plasma samples from 30 PD patients and 30 control subjects and stained with anti-IgG antibodies to detect anti-brain autoantibodies. Signals were quantified. Prominent autoantigens were identified by 2D-gel-coupled mass spectrometry sequencing. Anti-brain autoantibodies are frequent and occur both in healthy controls and individuals with PD. Glial fibrillary acidic protein (GFAP) was identified as a prominent autoantigen recognized in all plasma samples. GFAP immunoreactivity was highest in DM areas and lowest in FC areas with no significant differences in anti-GFAP autoantibody titers between healthy controls and individuals with PD. The anti-GFAP autoimmunoreactivity of different brain areas correlates with the dissemination of histopathological neurodegeneration in PD. We hypothesize that GFAP autoantibodies are physiological but might be involved as a cofactor in PD pathogenesis secondary to a leakage of the blood–brain barrier. KW - Parkinson KW - GFAP KW - autoantibodies KW - Braak Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325161 VL - 129 IS - 5-6 ER - TY - JOUR A1 - Bellinger, Daniel A1 - Altenmüller, Eckart A1 - Volkmann, Jens T1 - Perception of time in music in patients with Parkinson's disease - The processing of musical syntax compensates for rhythmic deficits JF - Frontiers in Neuroscience N2 - Objective: Perception of time as well as rhythm in musical structures rely on complex brain mechanisms and require an extended network of multiple neural sources. They are therefore sensitive to impairment. Several psychophysical studies have shown that patients with Parkinson's disease (PD) have deficits in perceiving time and rhythms due to a malfunction of the basal ganglia (BG) network. Method: In this study we investigated the time perception of PD patients during music perception by assessing their just noticeable difference (JND) in the time perception of a complex musical Gestalt. We applied a temporal discrimination task using a short melody with a clear beat-based rhythm. Among the subjects, 26 patients under L-Dopa administration and 21 age-matched controls had to detect an artificially delayed time interval in the range between 80 and 300 ms in the middle of the musical period. We analyzed the data by (a) calculating the detection threshold directly, (b) by extrapolating the JNDs, (c) relating it to musical expertise. Results: Patients differed from controls in the detection of time-intervals between 220 and 300 ms (*p = 0.0200, n = 47). Furthermore, this deficit depended on the severity of the disease (*p = 0.0452; n = 47). Surprisingly, PD patients did not show any deficit of their JND compared to healthy controls, although the results showed a trend (*p = 0.0565, n = 40). Furthermore, no significant difference of the JND was found according to the severity of the disease. Additionally, musically trained persons seemed to have lower thresholds in detecting deviations in time and syntactic structures of music (*p = 0.0343, n = 39). Conclusion: As an explanation of these results, we would like to propose the hypothesis of a time-syntax-congruency in music perception suggesting that processing of time and rhythm is a Gestalt process and that cortical areas involved in processing of musical syntax may compensate for impaired BG circuits that are responsible for time processing and rhythm perception. This mechanism may emerge more strongly as the deficits in time processing and rhythm perception progress. Furthermore, we presume that top-down-bottom-up-processes interfere additionally and interact in this context of compensation. KW - Parkinson disease KW - psychophysics KW - time perception KW - rhythm perception KW - musical syntax KW - just noticeable difference (JND) Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171805 VL - 11 ER - TY - JOUR A1 - Bieniussa, Linda A1 - Kahraman, Baran A1 - Skornicka, Johannes A1 - Schulte, Annemarie A1 - Voelker, Johannes A1 - Jablonka, Sibylle A1 - Hagen, Rudolf A1 - Rak, Kristen T1 - Pegylated insulin-like growth factor 1 attenuates hair cell loss and promotes presynaptic maintenance of medial olivocochlear cholinergic fibers in the cochlea of the progressive motor neuropathy mouse JF - Frontiers in Neurology N2 - The progressive motor neuropathy (PMN) mouse is a model of an inherited motor neuropathy disease with progressive neurodegeneration. Axon degeneration associates with homozygous mutations of the TBCE gene encoding the tubulin chaperone E protein. TBCE is responsible for the correct dimerization of alpha and beta-tubulin. Strikingly, the PMN mouse also develops a progressive hearing loss after normal hearing onset, characterized by degeneration of the auditory nerve and outer hair cell (OHC) loss. However, the development of this neuronal and cochlear pathology is not fully understood yet. Previous studies with pegylated insulin-like growth factor 1 (peg-IGF-1) treatment in this mouse model have been shown to expand lifespan, weight, muscle strength, and motor coordination. Accordingly, peg-IGF-1 was evaluated for an otoprotective effect. We investigated the effect of peg-IGF-1 on the auditory system by treatment starting at postnatal day 15 (p15). Histological analysis revealed positive effects on OHC synapses of medial olivocochlear (MOC) neuronal fibers and a short-term attenuation of OHC loss. Peg-IGF-1 was able to conditionally restore the disorganization of OHC synapses and maintain the provision of cholinergic acetyltransferase in presynapses. To assess auditory function, frequency-specific auditory brainstem responses and distortion product otoacoustic emissions were recorded in animals on p21 and p28. However, despite the positive effect on MOC fibers and OHC, no restoration of hearing could be achieved. The present work demonstrates that the synaptic pathology of efferent MOC fibers in PMN mice represents a particular form of “efferent auditory neuropathy.” Peg-IGF-1 showed an otoprotective effect by preventing the degeneration of OHCs and efferent synapses. However, enhanced efforts are needed to optimize the treatment to obtain detectable improvements in hearing performances. KW - cochlea KW - microtubules KW - MOC fibers KW - hearing loss KW - pegylated insulin-like growth factor 1 KW - outer hair cell (OHC) KW - motor neuropathy Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-276669 SN - 1664-2295 VL - 13 ER - TY - JOUR A1 - Brandt, Alexander U. A1 - Zimmermann, Hanna A1 - Kaufhold, Falko A1 - Promesberger, Julia A1 - Schippling, Sven A1 - Finis, David A1 - Aktas, Orhan A1 - Geis, Christian A1 - Ringelstein, Marius A1 - Ringelstein, E. Bernd A1 - Hartung, Hans-Peter A1 - Paul, Friedemann A1 - Kleffner, Ilka A1 - Dörr, Jan T1 - Patterns of Retinal Damage Facilitate Differential Diagnosis between Susac Syndrome and MS JF - PLoS One N2 - Susac syndrome, a rare but probably underdiagnosed combination of encephalopathy, hearing loss, and visual deficits due to branch retinal artery occlusion of unknown aetiology has to be considered as differential diagnosis in various conditions. Particularly, differentiation from multiple sclerosis is often challenging since both clinical presentation and diagnostic findings may overlap. Optical coherence tomography is a powerful and easy to perform diagnostic tool to analyse the morphological integrity of retinal structures and is increasingly established to depict characteristic patterns of retinal pathology in multiple sclerosis. Against this background we hypothesised that differential patterns of retinal pathology facilitate a reliable differentiation between Susac syndrome and multiple sclerosis. In this multicenter cross-sectional observational study optical coherence tomography was performed in nine patients with a definite diagnosis of Susac syndrome. Data were compared with age-, sex-, and disease duration-matched relapsing remitting multiple sclerosis patients with and without a history of optic neuritis, and with healthy controls. Using generalised estimating equation models, Susac patients showed a significant reduction in either or both retinal nerve fibre layer thickness and total macular volume in comparison to both healthy controls and relapsing remitting multiple sclerosis patients. However, in contrast to the multiple sclerosis patients this reduction was not distributed over the entire scanning area but showed a distinct sectorial loss especially in the macular measurements. We therefore conclude that patients with Susac syndrome show distinct abnormalities in optical coherence tomography in comparison to multiple sclerosis patients. These findings recommend optical coherence tomography as a promising tool for differentiating Susac syndrome from MS. KW - optical coherence tomography KW - vasculopathy KW - artery occlusion KW - hearing loss KW - microangiopathy KW - brain KW - endotheliopathy KW - antibodies KW - multiple-sclerosis KW - retinocochleocerebral Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134013 VL - 7 IS - 6 ER - TY - JOUR A1 - Karl, Franziska A1 - Wußmann, Maximiliane A1 - Kreß, Luisa A1 - Malzacher, Tobias A1 - Fey, Phillip A1 - Groeber‐Becker, Florian A1 - Üçeyler, Nurcan T1 - Patient‐derived in vitro skin models for investigation of small fiber pathology JF - Annals of Clinical and Translational Neurology N2 - Objective To establish individually expandable primary fibroblast and keratinocyte cultures from 3‐mm skin punch biopsies for patient‐derived in vitro skin models to investigate of small fiber pathology. Methods We obtained 6‐mm skin punch biopsies from the calf of two patients with small fiber neuropathy (SFN) and two healthy controls. One half (3 mm) was used for diagnostic intraepidermal nerve fiber density (IENFD). From the second half, we isolated and cultured fibroblasts and keratinocytes. Cells were used to generate patient‐derived full‐thickness three‐dimensional (3D) skin models containing a dermal and epidermal component. Cells and skin models were characterized morphologically, immunocyto‐ and ‐histochemically (vimentin, cytokeratin (CK)‐10, CK 14, ki67, collagen1, and procollagen), and by electrical impedance. Results Distal IENFD was reduced in the SFN patients (2 fibers/mm each), while IENFD was normal in the controls (8 fibers/mm, 7 fibers/mm). Two‐dimensional (2D) cultured skin cells showed normal morphology, adequate viability, and proliferation, and expressed cell‐specific markers without relevant difference between SFN patient and healthy control. Using 2D cultured fibroblasts and keratinocytes, we obtained subject‐derived 3D skin models. Morphology of the 3D model was analogous to the respective skin biopsy specimens. Both, the dermal and the epidermal layer carried cell‐specific markers and showed a homogenous expression of extracellular matrix proteins. Interpretation Our protocol allows the generation of disease‐specific 2D and 3D skin models, which can be used to investigate the cross‐talk between skin cells and sensory neurons in small fiber pathology. KW - neurology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201649 VL - 6 IS - 9 ER - TY - THES A1 - Knorr, Susanne T1 - Pathophysiology of early-onset isolated dystonia in a DYT-TOR1A rat model with trauma-induced dystonia-like movements T1 - Pathophysiologie der früh beginnenden, isolierten Dystonie in einem DYT-TOR1A Rattenmodell mit Trauma-induzierten Dystonie-ähnlichen Bewegungen N2 - Early-onset torsion dystonia (DYT-TOR1A, DYT1) is an inherited hyperkinetic movement disorder caused by a mutation of the TOR1A gene encoding the torsinA protein. DYT-TOR1A is characterized as a network disorder of the central nervous system (CNS), including predominantly the cortico-basal ganglia-thalamo-cortical loop resulting in a severe generalized dystonic phenotype. The pathophysiology of DYTTOR1A is not fully understood. Molecular levels up to large-scale network levels of the CNS are suggested to be affected in the pathophysiology of DYT-TOR1A. The reduced penetrance of 30% - 40% indicates a gene-environmental interaction, hypothesized as “second hit”. The lack of appropriate and phenotypic DYT-TOR1A animal models encouraged us to verify the “second hit” hypothesis through a unilateral peripheral nerve trauma of the sciatic nerve in a transgenic asymptomatic DYT-TOR1A rat model (∆ETorA), overexpressing the human mutated torsinA protein. In a multiscale approach, this animal model was characterized phenotypically and pathophysiologically. Nerve-injured ∆ETorA rats revealed dystonia-like movements (DLM) with a partially generalized phenotype. A physiomarker of human dystonia, describing increased theta oscillation in the globus pallidus internus (GPi), was found in the entopeduncular nucleus (EP), the rodent equivalent to the human GPi, of nerve-injured ∆ETorA rats. Altered oscillation patterns were also observed in the primary motor cortex. Highfrequency stimulation (HFS) of the EP reduced DLM and modulated altered oscillatory activity in the EP and primary motor cortex in nerve-injured ∆ETorA rats. Moreover, the dopaminergic system in ∆ETorA rats demonstrated a significant increased striatal dopamine release and dopamine turnover. Whole transcriptome analysis revealed differentially expressed genes of the circadian clock and the energy metabolism, thereby pointing towards novel, putative pathways in the pathophysiology of DYTTOR1A dystonia. In summary, peripheral nerve trauma can trigger DLM in genetically predisposed asymptomatic ΔETorA rats leading to neurobiological alteration in the central motor network on multiple levels and thereby supporting the “second hit” hypothesis. This novel symptomatic DYT-TOR1A rat model, based on a DYT-TOR1A genetic background, may prove as a valuable chance for DYT-TOR1A dystonia, to further investigate the pathomechanism in more detail and to establish new treatment strategies. N2 - Früh beginnende Torsionsdystonie (DYT-TOR1A, DYT1) ist eine genetisch bedingte hyperkinetische Bewegungsstörung, die aufgrund einer Mutation im TOR1A Gen verursacht wird, welches für das TorsinA-Protein codiert. DYT-TOR1A wird als zentrale Netzwerkstörung bezeichnet und betrifft hauptsächlich die kortiko-striatothalamo-kortikale Funktionsschleife, welches schließlich zu einem schweren generalisierten dystonen Phänotyp führt. Die Pathophysiologie von DYT-TOR1A ist nicht vollständig verstanden, man geht jedoch davon aus, dass Ebenen im Zentralnervensystem von molekularer Basis bis hin zu ganzen Netzwerken betroffen sind. Die reduzierte Penetranz von nur 30% bis 40% deutet auf eine Gen-UmweltInteraktion hin, im Sinne einer „2-Treffer-Hypothese“. Auch das Fehlen eines adäquaten DYT-TOR1A Tiermodelles hat uns dazu veranlasst, die „2-TrefferHypothese“ zu verifizieren, indem eine unilaterale periphere Quetschläsion des Nervus ischiadicus in einem transgenen, asymptomatischen DYT-TOR1A Rattenmodell (∆ETorA) durchgeführt wurde, welches das humane mutierte TorsinA-Protein überexprimiert. Das Tiermodell wurde phänotypisch und pathophysiologisch auf verschiedenen Analysenebenen charakterisiert. ∆ETorA Ratten mit Quetschläsion entwickelten Dystonie-ähnliche Bewegungen (DLM) mit teilweise generalisiertem Phänotyp. Erhöhte Theta-Oszillationen im Globus pallidus internus (GPi) sind bezeichnend für die humane Dystonie, welche auch im Nucleus entopeduncularis (EP), dem Äquivalent zum humanen GPi, von ∆ETorA Ratten mit Quetschläsion nachgewiesen wurden. Veränderte oszillatorische Muster wurden auch im primären Motorkortex gefunden. Hochfrequenz-Stimulation (HFS) des EP konnte das klinische Erscheinungsbild verbessern und hatte zudem auch einen modulatorischen Effekt auf die veränderte oszillatorische Aktivität des EP und des primären Motorcortex von ∆ETorA Ratten mit Quetschläsion. Auch das veränderte dopaminerge System erwies sich als ein pathologisches Merkmal in ∆ETorA Ratten. Es fand sich eine erhöhte striatale Ausschüttung von Dopamin und ein erhöhter Dopaminumsatz. In der Transkriptomanalyse kamen die zirkadiane Uhr und der Energiemetabolismus als weitere potentielle Signalwege in der Pathophysiologie der DYT-TOR1A Dystonie zum Vorschein. Zusammengefasst konnten DLM in genetisch prädisponierten, asymptomatischen ΔETorA Ratten mittels peripheren Nerventraumas ausgelöst werden, welches zu neurobiologischen Veränderungen in verschiedenen Ebenen des zentralen motorischen Netzwerk führte. Somit konnte die „2-Treffer-Hypothese“ bestätigt werden. Dieses neue symptomatische DYT-TOR1A Rattenmodell, fundiert auf der genetischen Grundlage von DYT-TOR1A, kann sich als wertvolle Möglichkeit für die DYT-TOR1A Dystonie erweisen, um Pathomechanismen genauer zu untersuchen und neue Behandlungsstrategien zu entwickeln. KW - Dystonie KW - Trauma KW - Ratte KW - Zentralnervensystem KW - DYT-TOR1A KW - early-onset isolated dystonia KW - gene-environmental interaction KW - peripheral nerve trauma KW - striatum KW - dopamine KW - deep brain stimulation Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206096 ER - TY - THES A1 - Reymann, Stephan Andreas T1 - Pathophysiologische Rolle und therapeutische Relevanz von Plasmakallikrein beim experimentellen Schlaganfall T1 - Pathophysiological role and therapeutic relevance of plasma kallikrein in experimental stroke N2 - Die Rolle thromboinflammatorischer Vorgänge in der Pathogenese des ischämischen Schlaganfalls ist in den letzten Jahren immer mehr in den wissenschaftlichen Fokus gerückt. Plasmakallikrein (PK) spaltet von hochmolekularem Kininogen (KNG) Bradykinin (BK) ab und ist dadurch Ausgangspunkt des proinflammatorischen Kallikrein-Kinin-Systems (KKS). Zum anderen kann es den Gerinnungsfaktor XII (FXII) aktivieren, den Ausgangspunkt der intrinsischen Gerinnungskaskade. Es initiiert also sowohl inflammatorische als auch thrombotische Vorgänge. Daher wurde in dieser Arbeit der Effekt einer Blockade PKs in einem Mausmodell der fokalen zerebralen Ischämie untersucht – und zwar sowohl durch genetische Depletion als auch durch pharmakologische Blockade. Beide Ansätze brachten einen nachhaltigen protektiven Effekt in Bezug auf Infarktgrößen und funktionelles Outcome, ohne die Blutungsgefahr zu erhöhen. N2 - Recent scientific evidence raises the question whether ischemic stroke is a thromboinflammatory disease. Plasma kallikrein (PK) cleaves high–molecular-weight kininogen to release bradykinin (BK) and is a key constituent of the proinflammatory contact-kinin system. In addition, PK can activate coagulation factor XII, the origin of the intrinsic coagulation cascade. Thus, PK triggers 2 important pathological pathways of stroke formation, thrombosis and inflammation. Therefore we investigated the consequences of both genetic and pharmacological PK inhibition in a model of ischemic stroke and found out that PK-inhibition leads to significantly smaller brain infarctions and less severe neurological deficits compared with controls without an increase in infarct-associated hemorrhage. KW - Plasmakallikrein KW - Schlaganfall KW - Plasmakallikrein ischämischer Schlaganfall Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135834 ER - TY - THES A1 - Ritter, Christian T1 - Pathomechanismen von Antikörpern gegen Aquaporin 4 in einem Tiermodell für die Neuromyelitis Optica T1 - Pathomechanism of antibodies against aquaporin 4 in an animal model for neuromyelitis opitca N2 - Die Neuromyelitis Optica (NMO) ist eine schwerwiegende autoimmune Erkrankung des zentralen Nervensystems (ZNS), die mit rezidivierenden Optikusneuritiden und Querschnittsmyelitiden einhergeht. Als serologischer Biomarker wurden Autoantikörper gegen Aquaporin 4 (anti-AQP4-AK) identifiziert. Mit Hilfe eines passiv-Transfer Rattenmodelles mit implantierten intrathekalen Kathetern wurden aufgereinigte IgG Fraktionen (NMO-IgG) von Plasmapheresematerial anti-AQP4-AK positiver NMO Patienten verabreicht. Zum Nachweis der Antigen-Spezifität wurden in weiteren Versuchsgruppen rekombinante IgG-AK gegen AQP4 appliziert. Die repetitive Injektion von NMO-IgG oder anti-AQP4-AK führte zu einer signifikanten klinischen Verschlechterung und einer reduzierten motorischen Leistungsfähigkeit der Versuchstiere im Vergleich zu Kontrollen. Mittels Magnetresonanztomographie konnten exemplarisch Kontrastmittel-aufnehmende Läsionsareale im Rückenmark der Versuchstiere im Bereich der Katheterspitze detektiert werden. Histopathologisch zeigte sich in diesen Läsionsbereichen eine Anreicherung von intrathekal applizierten humanen IgG, ein Verlust der Expression von AQP4 und des Glutamattransporters EAAT2. Im Gegensatz zu der bisher bekannten, Komplement-induzierten Gewebedestruktion bei NMO-Patienten mit entzündlichen Läsionen wurde hier keine Depletion von Astrozyten oder Komplementaktivierung beobachtet. Stattdessen kam es in den hier beschriebenen Arealen mit IgG-Ablagerung zu einer Hypertrophie und Vermehrung der GFAP-positiven Astrozyten. Die Ergebnisse lassen auf eine pathophysiologisch relevante, intrinsische und komplement-unabhängige Wirkung von anti-AQP4-AK schließen. N2 - Neuromyelitis optica (NMO) is a severe autoimmune disease of the central nervous system (CNS). As a biomarker autoantibodies against AQP4 (anti-AQP4-Abs) have been identified. Via passiv-transfer animal model with intrathecally implanted catheters, purified IgG fractions (NMO-IgG) from anti-AQP4-Abs positive patients have been applicated. Repetitive injection of NMO-IgG led to a significant clinical disease induction along with reduced motor function. Via MRI-scan lesions in the spinal cord could be identified. Histopathological analysis revealed a loss of AQP4 and glutamat transporter EAAT2. Complement induced tissue inflammation hasn't been observed. These results reveal a pathophysiological relevant, intrinsic and complement independent effect of anti-AQP4-Abs. KW - Autoantikörper KW - Aquaporin4 KW - Neuromyelitis Optica KW - Autoantikörper KW - Aquaporin4 KW - Neuromyelitis Optica KW - Autoantibodies KW - Aquaporin4 Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-85526 ER - TY - THES A1 - Groh, Janos Michael T1 - Pathogenic impact of immune cells in mouse models of neuronal ceroid lipofuscinosis T1 - Pathogener Einfluss von Immunzellen in Mausmodellen der Neuronalen Ceroid Lipofuszinose N2 - The neuronal ceroid lipofuscinoses (NCLs) are fatal neurodegenerative disorders in which the visual system is affected in early stages of disease. A typical accompanying feature is neuroinflammation, the pathogenic impact of which is presently unknown. In this study, the role of inflammatory cells in the pathogenesis was investigated in Palmitoyl-protein thioesterase 1-deficient (Ppt1-/-) and Ceroidlipofuscinosis, neuronal 3-deficient (Cln3-/-) mice, models of the infantile and juvenile forms of NCL, respectively. Focusing predominantly on the visual system, an infiltration of CD8+ cytotoxic Tlymphocytes and an activation of microglia/macrophage-like cells was observed early in disease. To analyze the pathogenic impact of lymphocytes, Ppt1-/- mice were crossbred with mice lacking lymphocytes (Rag1-/-) and axonal transport, perturbation and neuronal survival were scored. Lack of lymphocytes led to a significant amelioration of neuronal disease and reconstitution experiments revealed a crucial role of CD8+ cytotoxic T-lymphocytes. Lack of lymphocytes also caused an improved clinical phenotype and extended longevity. To investigate the impact of microglia/macrophage-like cells, Ppt1-/- and Cln3-/- mice were crossbred with mice lacking sialoadhesin (Sn-/-), a monocyte lineage-restricted cell adhesion molecule important for interactions between macrophage-like cells and lymphocytes. Similar to the lack of lymphocytes, absence of sialoadhesin significantly ameliorated the disease in Ppt1-/- and Cln3-/- mice. Taken together, both T-lymphocytes and microglia/macrophage-like cells were identified as pathogenic mediators in two distinct forms of fatal inherited neurodegenerative storage disorders. These studies expand the concept of secondary inflammation as a common pathomechanistic feature in some neurological diseases and provide novel insights that may be crucial for developing treatment strategies for different forms of NCL. N2 - Die Neuronalen Ceroid Lipofuszinosen (NCL) sind tödlich verlaufende neurodegenerative Erkrankungen, bei denen das visuelle System frühzeitig im Krankheitsverlauf betroffen ist. Eine typische Begleiterscheinung sind Entzündungsreaktionen, deren pathogenetischer Einfluss bisher ungeklärt ist. In dieser Studie wurde die Rolle von Entzündungszellen bei der Pathogenese in Palmitoyl-protein thioestease 1-defizienten (Ppt1-/-) und Ceroid-lipofuscinosis, neuronal 3-defizienten (Cln3-/-) Mäusen untersucht, den jeweiligen Modellen der Infantilen und Juvenilen Formen der NCL. Mit besonderem Augenmerk auf das visuelle System wurde früh in der Krankheit ein Aufkommen von CD8+ zytotoxischen T-Lymphozyten und eine Aktivierung von Mikroglia/Makrophagen-ähnlichen Zellen beobachtet. Um den pathogenetischen Einfluss der Lymphozyten zu klären, wurden Ppt1-/- Mäuse mit Mäusen verkreuzt, welche keine Lymphozyten besitzen (Rag1-/-). An den generierten Doppelmutanten wurden axonaler Transport, axonale Schädigung und neuronales Überleben bestimmt. Die Abwesenheit von Lymphozyten führte zu einer signifikanten Abmilderung der neuronalen Schädigung und Rekonstitutions-Experimente zeigten, dass CD8+ zytotoxische T-Lymphozyten eine entscheidende Rolle spielen. Die Abwesenheit dieser Lymphozyten führte außerdem zu einem abgemilderten klinischen Phänotyp und einem verlängerten Überleben. Um den Einfluss von Mikroglia/Makrophagen zu untersuchen wurden Ppt1-/- und Cln3-/- Mäuse mit Sialoadhesin-defizienten Mäusen (Sn-/-) verkreuzt. Sn ist ein Monozyten-spezifisches Zelladhäsionsmolekül, das wichtig für Interaktionen zwischen Makrophagen-ähnlichen Zellen und Lymphozyten ist. Ähnlich wie die Abwesenheit von Lymphozyten führte die Abwesenheit von Sialoadhesin zu einer signifikanten Abmilderung der Krankheit in Ppt1-/- und Cln3-/- Mäusen. Zusammengefasst wurden sowohl T-Lymphozyten als auch Mikroglia/Makrophagenähnliche Zellen als pathogenetische Mediatoren in zwei verschiedenen Formen von tödlich verlaufenden erblichen neurodegenerativen Speicherkrankheiten identifiziert. Diese Untersuchungen erweitern das Konzept der sekundären Entzündungsreaktion als verbreitete pathomechanistische Erscheinung in einigen neurologischen Erkrankungen und liefern neue Perspektiven für die Entwicklung von Behandlungsstrategien für verschiedene Formen der NCL. KW - Nervendegeneration KW - Maus KW - Entzündung KW - T-Lymphozyt KW - Neuronale Ceroid Lipofuszinose KW - Neuroinflammation KW - Neurodegeneration KW - axonaler Schaden KW - T-Lymphozyten KW - neuronal ceroid lipofuscinosis KW - neuroinflammation KW - neurodegeneration KW - axonal damage KW - T-lymphocytes Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-77684 ER - TY - JOUR A1 - Wolf, Karen A1 - Braun, Attila A1 - Haining, Elizabeth J. A1 - Tseng, Yu-Lun A1 - Kraft, Peter A1 - Schuhmann, Michael K. A1 - Gotru, Sanjeev K. A1 - Chen, Wenchun A1 - Hermanns, Heike M. A1 - Stoll, Guido A1 - Lesch, Klaus-Peter A1 - Nieswandt, Bernhard T1 - Partially Defective Store Operated Calcium Entry and Hem(ITAM) Signaling in Platelets of Serotonin Transporter Deficient Mice JF - PLoS One N2 - Background Serotonin (5-hydroxytryptamin, 5-HT) is an indolamine platelet agonist, biochemically derived from tryptophan. 5-HT is secreted from the enterochromaffin cells into the gastrointestinal tract and blood. Blood 5-HT has been proposed to regulate hemostasis by acting as a vasoconstrictor and by triggering platelet signaling through 5-HT receptor 2A (5HTR2A). Although platelets do not synthetize 5-HT, they take 5-HT up from the blood and store it in their dense granules which are secreted upon platelet activation. Objective To identify the molecular composite of the 5-HT uptake system in platelets and elucidate the role of platelet released 5-HT in thrombosis and ischemic stroke. Methods: 5-HT transporter knockout mice (5Htt\(^{-/-}\)) were analyzed in different in vitro and in vivo assays and in a model of ischemic stroke. Results In 5Htt\(^{-/-}\) platelets, 5-HT uptake from the blood was completely abolished and agonist-induced Ca2+ influx through store operated Ca\(^{2+}\) entry (SOCE), integrin activation, degranulation and aggregation responses to glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) were reduced. These observed in vitro defects in 5Htt\(^{-/-}\) platelets could be normalized by the addition of exogenous 5-HT. Moreover, reduced 5-HT levels in the plasma, an increased bleeding time and the formation of unstable thrombi were observed ex vivo under flow and in vivo in the abdominal aorta and carotid artery of 5Htt\(^{-/-}\) mice. Surprisingly, in the transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke 5Htt\(^{-/-}\) mice showed nearly normal infarct volume and the neurological outcome was comparable to control mice. Conclusion Although secreted platelet 5-HT does not appear to play a crucial role in the development of reperfusion injury after stroke, it is essential to amplify the second phase of platelet activation through SOCE and plays an important role in thrombus stabilization. KW - platelets KW - serotonin KW - integrins KW - blood flow KW - collagens KW - platelet activation KW - platelet aggregation KW - ischemic stroke Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146399 VL - 11 IS - 1 ER - TY - THES A1 - Pozzi, Nicoló Gabriele T1 - Parkinson’s disease revisited: multiple circuitopathies T1 - Neuinterpretation des Morbus Parkinson als multiple Netzwerkerkrankung N2 - Parkinson’s disease (PD) is among the most common neurodegenerative conditions, and it is characterized by the progressive loss of dopaminergic neurons and a great variability in clinical expression. Despite several effective medications, it still causes disability as all patients show treatment-resistant symptoms and complications. A possible reason for this therapeutic-burden and great clinical variability lies in a probable misconception about its pathophysiology, one that focuses on neurodegeneration, while largely neglecting its functional consequences and the related compensatory changes. In this thesis, I expand on the hypothesis that some PD symptoms have a dysfunctional origin and reflect derangements of neural network dynamics, the means by which brain coordination supports any motor behaviour. In particular, I have investigated resting tremor and freezing of gait, two common symptoms with an enigmatic mechanism and suboptimal management. In the case of tremor, I predicted a pathological change in response to dopamine loss, which included the activation of noradrenergic (NA) neurons of the locus coeruleus (LC) projecting to the cerebellum. This compensatory LC activation that supports dopaminergic neurons might indeed come at the expense of tremor development. To assess the role of LC-NA in tremor development, I recorded tremor occurrence in the reserpinized rat model of PD, one of very few showing tremor, after selective lesioning (with the neurotoxin DSP-4) of the LC-NA terminal axons. DSP-4 induced a severe reduction of LC-NA terminal axons in the cerebellar cortex and this was associated with a significant reduction in tremor development. Unlike its development, tremor frequency and the akinetic rigid signs did not differ between the groups, thus suggesting a dopaminergic dependency. These findings suggest that the LC-NA innervation of the cerebellum has a critical role for PD tremor, possibly by exerting a network effect, which gates the cerebello-thalamic-cortical circuit into pathological oscillations upon a dopaminergic loss in the basal ganglia. In contrast, for the study of freezing of gait, I worked with human PD subjects and deep brain stimulation, a therapeutic neuromodulation device that in some prototypes also allows the recording of neural activity in freely-moving subjects. Gait freezing is a disabling PD symptom that suddenly impairs effective stepping, thus causing falls and disability. Also in this study, I hypothesized that the underlying pathophysiology may be represented by dysfunctional neural network dynamics that abruptly impair locomotor control by affecting the communication in the supraspinal locomotor network. To test this hypothesis, I investigated the coupling between the cortex and the subthalamic nucleus, two main nodes of the supraspinal locomotor network, in freely-moving subjects PD patients and also performed molecular brain imaging of striatal dopamine receptor density and kinematic measurements. I found that in PD patients, walking is associated with cortical-subthalamic stable coupling in a low-frequency band (i.e. θ-α rhythms). In contrast, these structures decoupled when gait freezing occurred in the brain hemisphere with less dopaminergic innervation. These findings suggest that freezing of gait is a “circuitopathy”, with dysfunctional cortical-subcortical communication. Altogether the results of my experiments support the hypothesis that the pathophysiology of PD goes beyond neurodegenerative (loss-of-function) processes and that derangement of neural network dynamics coincides with some disabling PD symptoms, thus suggesting that PD can be interpreted as the combination of multiple circuitopathies. N2 - Die Parkinson-Krankheit ist eine neurodegenerative Erkrankung mit einem progressiven Verlust dopaminerger Neurone, die trotz wirksamer Medikamente zur Einschränkung in der Lebensqualität führen kann. Eine mögliche Ursache für diese unzureichende Behandlung der Symptome liegt in einem möglichen Missverständnis über die Pathophysiologie der Krankheit, die sich auf die Neurodegeneration konzentriert. Bei der Parkinson-Krankheit können jedoch funktionelle Veränderungen aufgrund der Neurodegeneration sowie die damit verbundenen kompensatorischen Modifikationen sehr wichtig sein. Der Fokus meiner Dissertation liegt in der Bearbeitung der Hypothese, dass einige Symptome der Parkinson-Krankheit einen dysfunktionellen Ursprung haben können. Insbesodere habe ich den Ruhetremor und das Freezing-Phänomen, das eine Blockade des Gehens bedeutet, untersucht, um zu erklären, ob ein Störung der neuronalen Netzwerkdynamik diese Symptome verursachen kann. In dieser Arbeit wurde zuerst die Entwicklung des Ruhetremors bei der Parkinson-Krankheit untersucht. Meine Hypothese war, dass eine Aktivierung von projizierenden noradrenergen Fasern des Locus-Coeruleus zum Cerebellum das Auftreten des Tremors verursachen kann, welches durch den Verlust dopaminerger Neurone verursacht wird. Da die Aktivität des Locus-Coeruleus bei Patienten mit Parkisnon-Krankheit nicht messbar ist, wurde dies in einem Parkinson-Rattenmodell untersucht. Die Ratten wurden etweder mit Reserpin oder mit Reserpine plus eine Neurotoxin gegen noradrenerger Neuronen (DSP-4) behandelt. Diese Behandlung mit DSP-4 führte zur Degeneration noradrenerger Terminalen im Locus-Coeruleus. Das Auftreten von Tremor zwischen die beiden Gruppen von Ratten war unterschiedlich. Insbesondere entwickelten DSP-4 behandelte Ratten einen niedrigen Ruhetremor. Dieses Ergebnis deutet darauf hin, dass die noradrenerge Innervation des Cerebellums vom Locus-Ceruleus für das Auftreten des Ruhetremors eine große Rolle spielt. In der Frequenz des Tremors sowie in den akinetischen Symptomen konnte kein Unterschied zwischen den Gruppen festgestellt werden. Das zeigt, dass diese akinetischen Symptome vom Dopaminverlust abhängig sind. Die Kombination von Tremor und akinetischen Symptomen kann aufgrund eines patologischen Netzwerkeffekts entstehen, welche vom Verlust dopaminerger Neurone in den Basalganglien im Zusammenspiel mit der kompensatorischen Aktivierung noradrenerger Neurone des Locus-Coeruleus verursacht werden kann. Des Weiteren wurde der Ursprung des Freezing-Phänomens bei Patienten, die an der Parkinson-Krankheit leiden und eine therapeutische Behandlung mittels Tiefer Hirnstimulation (THS) bekommen haben, untersucht. Insbesodere konnten mittels neuer THS-Prototypen Messungen neuronaler Aktivität von Bewegungen durchgeführt werden. In dieser Studie stellte ich die Hypothese auf, dass die Pathophysiologie des Freezings durch eine fehlerhafte neuronale Dynamik der Bewegungsnetzwerke erklärt werden kann. Um dies zu testen, wurde die Kommunikation zwischen den zwei Hauptknoten des Bewegungsnetzwerkes, dem Kortex und dem Nucleus Subthalamicus, bei THS behandelten Parkinson-Patienten während des Gehens und den Freezing-Episoden untersucht. Zudem wurde bei diesen Patienten eine molekulare Darstellung der dopaminergen Rezeptoren in den Basalganglien durchgeführt. Zusätzlich wurden kinematischen Messungen der Bewegungen vorgenommen, die eine präzise Beschreibung des Freezings ermöglichen. Es konnte gezeigt werden, dass bei Patienten mit der Parkinson-Krankheit ein Zusammenhang von stabiler Kommunikation zwischen dem Kortex und dem Nucleus Subthalamicus bei einer bestimten Frequenz (d.h. θ-α-Rhythmen) beim Gehen besteht. Beim Auftreten des Freezing-Phänomens konnte diese Kommunikation in der Gehirnhemisphäre mit weniger dopaminerger Innervation nicht mehr nachgewiesen werden. Diese Ergebnisse deuten darauf hin, dass das Freezing-Phänomen eine „Circuitopathie“ ist, in der eine fehlerhafte Kommunikation zwischen kortikalen und subkortikalen Arealen zur Bewegungsblockade führen kann. Insgesamt stützen die Ergebnisse meiner Experimente die Hypothese, dass die Pathophysiologie der Parkinson-Krankheit sowohl über neurodegenerative Prozesse (Zellverlust) als auch über Störungen der neuronalen Netzwerkdynamik (Funktionsverlust) hinausgeht. Das deutet darauf hin, dass die Parkison-Krankheit als „Circuitopathie“ interpretiert werden kann. KW - Parkinson-Krankheit KW - freezing of gait KW - resting tremor KW - circuitopathies Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-216715 ER - TY - JOUR A1 - Mencacci, Niccoló E. A1 - Isaias, Ioannis U. A1 - Reich, Martin M. A1 - Ganos, Christos A1 - Plagnol, Vincent A1 - Polke, James M. A1 - Bras, Jose A1 - Hersheson, Joshua A1 - Stamelou, Maria A1 - Pittman, Alan M. A1 - Noyce, Alastair J. A1 - Mok, Kin Y. A1 - Opladen, Thomas A1 - Kunstmann, Erdmute A1 - Hodecker, Sybille A1 - Münchau, Alexander A1 - Volkmann, Jens A1 - Samnick, Samuel A1 - Sidle, Katie A1 - Nanji, Tina A1 - Sweeney, Mary G. A1 - Houlden, Henry A1 - Batla, Amit A1 - Zecchinelli, Anna L. A1 - Pezzoli, Gianni A1 - Marotta, Giorgio A1 - Lees, Andrew A1 - Alegria, Paulo A1 - Krack, Paul A1 - Cormier-Dequaire, Florence A1 - Lesage, Suzanne A1 - Brice, Alexis A1 - Heutink, Peter A1 - Gasser, Thomas A1 - Lubbe, Steven J. A1 - Morris, Huw R. A1 - Taba, Pille A1 - Koks, Sulev A1 - Majounie, Elisa A1 - Gibbs, J. Raphael A1 - Singleton, Andrew A1 - Hardy, John A1 - Klebe, Stephan A1 - Bhatia, Kailash P. A1 - Wood, Nicholas W. T1 - Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers JF - Brain N2 - GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease. KW - DOPA-responsive-dystonia KW - GCH1 KW - Parkinson's disease KW - dopamine KW - exome sequencing Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121268 VL - 137 IS - 9 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 - JOUR A1 - Del Vecchio, Jasmin A1 - Hanafi, Ibrahem A1 - Pozzi, Nicoló Gabriele A1 - Capetian, Philipp A1 - Isaias, Ioannis U. A1 - Haufe, Stefan A1 - Palmisano, Chiara T1 - Pallidal recordings in chronically implanted dystonic patients: mitigation of tremor-related artifacts JF - Bioengineering N2 - Low-frequency oscillatory patterns of pallidal local field potentials (LFPs) have been proposed as a physiomarker for dystonia and hold the promise for personalized adaptive deep brain stimulation. Head tremor, a low-frequency involuntary rhythmic movement typical of cervical dystonia, may cause movement artifacts in LFP signals, compromising the reliability of low-frequency oscillations as biomarkers for adaptive neurostimulation. We investigated chronic pallidal LFPs with the Percept\(^{TM}\) PC (Medtronic PLC) device in eight subjects with dystonia (five with head tremors). We applied a multiple regression approach to pallidal LFPs in patients with head tremors using kinematic information measured with an inertial measurement unit (IMU) and an electromyographic signal (EMG). With IMU regression, we found tremor contamination in all subjects, whereas EMG regression identified it in only three out of five. IMU regression was also superior to EMG regression in removing tremor-related artifacts and resulted in a significant power reduction, especially in the theta-alpha band. Pallido-muscular coherence was affected by a head tremor and disappeared after IMU regression. Our results show that the Percept PC can record low-frequency oscillations but also reveal spectral contamination due to movement artifacts. IMU regression can identify such artifact contamination and be a suitable tool for its removal. KW - dystonia KW - tremor KW - local field potentials KW - globus pallidus KW - deep brain stimulation Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313498 SN - 2306-5354 VL - 10 IS - 4 ER - TY - JOUR A1 - Politei, Juan M. A1 - Bouhassira, Didier A1 - Germain, Dominique P. A1 - Goizet, Cyril A1 - Guerrero-Sola, Antonio A1 - Hilz, Max J. A1 - Hutton, Elspeth J. A1 - Karaa, Amel A1 - Liuori, Rocco A1 - Üceyler, Nurcan A1 - Zeltzer, Lonnie K. A1 - Burlina, Alessandro T1 - Pain in fabry disease: practical recommendations for diagnosis and treatment JF - CNS Neuroscience & Therapeutics N2 - Aims: Patients with Fabry disease (FD) characteristically develop peripheral neuropathy at an early age, with pain being a crucial symptom of underlying pathology. However, the diagnosis of pain is challenging due to the heterogeneous and nonspecific symptoms. Practical guidance on the diagnosis and management of pain in FD is needed. Methods: In 2014, experts met to discuss recent advances on this topic and update clinical guidance. Results: Emerging disease-specific tools, including FabryScan, Fabry-specific Pediatric Health and Pain Questionnaire, and Wurzburg Fabry Pain Questionnaire, and more general tools like the Total Symptom Score can aid diagnosis, characterization, and monitoring of pain in patients with FD. These tools can be complemented by more objective and quantifiable sensory testing. In male and female patients of any age, pain related to FD can be an early indication to start disease-specific enzyme replacement therapy before potentially irreversible organ damage to the kidneys, heart, or brain occurs. Conclusion: To improve treatment outcomes, pain should be diagnosed early in unrecognized or newly identified FD patients. Treatment should include: (a) enzyme replacement therapy controlling the progression of underlying pathology; (b) adjunctive, symptomatic pain management with analgesics for chronic neuropathic and acute nociceptive, and inflammatory or mixed pain; and (c) lifestyle modifications. KW - Enzyme replacement therapy KW - Small fiber dysfunction KW - System involvement KW - Outcome survey KW - Fabry disease KW - Randomized controlled-trial KW - Chronic neuropathic pain KW - Agalsidase beta KW - Screening questionnaire KW - Dose reduction KW - Adult patients KW - Diagnosis KW - Pain KW - Peripheral nervous system Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188127 VL - 22 IS - 7 ER - TY - THES A1 - Visan, Ion Lucian T1 - P0 specific T-cell repertoire in wild-type and P0 deficient mice N2 - Zusammenfassung Das Myelinprotein P0 stellt eine zentrale Komponente für die Stabilität und Funktionalität der Myelinscheiden des peripheren Nervensystems dar. Mutationen des P0-Proteins führen zu verschiedenen, schwer behindernden peripheren Neuropathien wie der Charcot-Marie-Tooth- oder der Dejerine-Sotas-Erkrankung. Wir haben das Tiermodell der P0-Knock-Out-Mäuse verwendet, um im Vergleich zu den C57BL/6-Wildtyp-Tieren Selektionsmechanismen des P0-spezifischen T-Zell-Repertoires zu untersuchen. Dazu wurde eine Reihe von überlappenden 20-mer-Peptiden benutzt, die die gesamte Aminosäuresequenz von P0 abdeckten. Mit Hilfe dieser Peptide wurde ein sog. „Epitop-Mapping“ der H2-Ab-restringierten T-Zell-Antwort durchgeführt. Auf diese Weise konnte das P0-Peptid 5 (Aminosäure 41-60) in der extrazellulären P0-Domäne als immunogene Determinante identifiziert werden. Dieses immunogene Peptid wurde dann für Untersuchungen der Toleranzmechanismen verwendet und zeigte, dass in P0-Knock-Out-Mäusen ein hochreaktives P0-spezifisches T-Zell-Repertoire vorliegt, während es in Wildtyp-Tieren inaktiviert ist und so Selbsttoleranz erzeugt wird. Die Toleranzerzeugung in Wildtyp- und heterozygoten P0 +/- Mäusen hängt nicht von der Gen-Dosis ab. P0 ist ein gewebespezifisches Antigen, dessen Expression normalerweise auf myelinisierende Schwann-Zellen beschränkt ist. Die klassischen Vorstellungen zu Toleranzmechanismen gegenüber gewebsspezifischen Antigenen schrieben diese vor allem peripheren Immunmechanismen zu. Durch den erstmaligen Nachweis von intrathymischer Expression gewebsspezifischer Antigene wie P0 konnten wir bestätigen, dass für P0 offensichtlich die Expression deutlich weiter verbreitet ist, insbesondere auch auf Thymus-Stroma-Zellen. Unter Verwendung von Knochenmarkschimären haben wir weitere Untersuchungen durchgeführt, wie Knochenmarks-abstammende Zellen im Vergleich zu nicht-hämatopoetischen Zellen Toleranz gegenüber P0 erzeugen können. Unsere Befunde zeigen, dass Knochenmarks-abhängige Zellen nicht ausreichen, um völlige Toleranz zu erzeugen. Zusätzlich wurde eine P0-Expression auf anderen Geweben wie dem Thymus benötigt, um komplette Toleranz zu erhalten. Wir identifizierten ein kryptisches P0-Peptid 8 und zwei subdominante P0-Peptide 1 und 3. Während das Peptid 8 sowohl in Wildtyp- als auch Knock-Out-Mäusen erkannt wurde, wurden die Peptide 1 und 3 in Wildtyp-Mäusen nicht als Immunogen erkannt. Die genannten Peptide wurden verwendet, um eine experimentelle autoimmune Neuritis (EAN) zu erzeugen. Mit keinem der experimentellen Ansätze konnten wir klinische Zeichen einer EAN generieren, allerdings mit dem Peptid 3 doch Entzündung im peripheren Nerven beobachten. Es werden zukünftig weitere Untersuchungen benötigt, um P0-spezifische T-Zell-Linien zu etablieren und so mit höherer Effizienz eine EAN zu erzeugen. Unsere Untersuchungen sprechen dafür, dass bei gentherapeutischen Ansätzen bei erblichen Neuropathien vorsichtig und schrittweise vorgegangen werden muss, da mit sekundärer Autoimmunität und damit Inflammation im peripheren Nerven zu rechnen ist. N2 - Summary Myelin protein zero (P0) is a key myelin component in maintaining the integrity and functionality of the peripheral nervous system. Mutated variants are the cause for several disabilitating peripheral neuropathies such as Charcot-Marie-Tooth disease or Dejerine –Sotas syndrome. Using P0 knockout mice - a mouse model for these diseases - together with their wt counterparts on C57BL/6 background we studied the shaping of the T-cell repertoire specific for P0 in the presence and in the absence of this protein during the ontogeny of T-cells. Our approach was to use a series of overlapping 20-mer peptides covering the entire amino acid sequence of P0. This series of P0 peptides was employed for epitope mapping of the H2-Ab restricted T cell response. Thus, P0 peptide 5 (P0 41-60) in the extracellular domain of P0 was identified as the main immunogenic peptide. The immunogenic peptide containing the core immunodominant determinant in the P0 sequence was employed in studies of tolerance, revealing a highly reactive P0 specific T-cell repertoire in P0 ko mice while in wt mice the high avidity repertoire was inactivated in order to ensure self tolerance. In wild type and heterozygous P0 mice tolerance is not dependent on gene dosage. P0 is a tissue specific antigen whose expression is limited to myelinating Schwann cells. The classical view on tolerance to tissue specific antigens attributed this role to peripheral mechanisms. Driven by the finding that intrathymic expression of tissue-specific antigens is a common occurrence, we confirmed that “promiscuous” expression on thymic stroma holds true also for myelin P0. In addition, using bone marrow chimeras we investigated the capacity of bone marrow derived cells versus nonhematopoietic cells to induce tolerance towards P0. Our findings show that bone marrow derived cells although tolerogenic to some degree are not sufficient to mediate complete tolerance. P0 expression on cells with origin other than bone marrow showed to be sufficient and necessary to induce sound tolerance. We identified one cryptic (P0 peptide 8) and two subdominant epitopes (P0 petides 1, and 3). P0 peptide 8 was reactive in both wt and P0 ko mice. Peptides 1 and 3 were immunogenic in P0 ko but not in wt mice. Several P0 peptides including the immunogenic peptide 5 were involved in direct and adoptive transfer EAN studies. None of them induced clinical signs of EAN. Immunization with P0 peptide 3 did induce inflammation of the peripheral nerves reflected by the infiltration of macrophages and CD3 positive cells. More studies involving highly P0 specific T-cell lines are needed to characterize the P0 induced EAN. Our findings may have direct implications for secondary autoimmunity and inflammation in peripheral nerves developing after correcting the P0 genetic defect by gene therapy in aforementioned diseases. KW - Myelin KW - Genmutation KW - T-Lymphozyt KW - autoimmunität KW - T-zell epitope KW - T-zell repertoir KW - toleranz KW - MPZ (P0) KW - autoimmunity KW - T-cell epitope KW - T-cell repertoire KW - tolerance KW - MPZ (P0) Y1 - 2003 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-5734 ER - TY - JOUR A1 - Pham, Mirko A1 - Helluy, X. A1 - Braeuninger, S. A1 - Jakob, P. A1 - Stoll, G. A1 - Kleinschnitz, Christoph A1 - Bendszus, M. T1 - Outcome of experimental stroke in C57Bl/6 and Sv/129 mice assessed by multimodal ultra-high field MRI N2 - Transgenic mice bred on C57Bl/6 or Sv/129 genetic background are frequently used in stroke research. It is well established that variations in cerebrovascular anatomy and hemodynamics can influence stroke outcome in different inbred mouse lines. We compared stroke development in C57Bl/6 and Sv/129 mice in the widely used model of transient middle cerebral artery occlusion (tMCAO) by multimodal ultra-high field magnetic resonance imaging (MRI). C57Bl/6 and Sv/129 mice underwent 60 min of tMCAO and were analyzed by MRI 2 h and 24 h afterwards. Structural and functional images were registered to a standard anatomical template. Probability maps of infarction were rendered by automated segmentation from quantitative T2-relaxometric images. Whole-brain segmentation of infarction was accomplished manually on high-resolution T2-weighted (T2-w) RARE images. Cerebral perfusion (cerebral blood flow, CBF) was measured quantitatively by modified continuous arterial-spin-labeling (CASL) and apparent diffusion coefficients (ADC) by spin-echo diffusion-weighted imaging (DWI). Probabilities of cortical (95.1% ± 3.1 vs. 92.1% ± 2.5; p > 0.05) and subcortical (100% vs. 100%; p > 0.05) infarctions at 24 h were similar in both groups as was the whole-brain volumetric extent of cerebral infarction. In addition, CBF and ADC values did not differ between C57Bl/6 and Sv/129 mice at any time point or region of interest. The C57Bl/6 and Sv/129 genetic background is no major confounding factor of infarct size and cerebral perfusion in the tMCAO model. KW - NMR-Tomographie Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68115 ER - TY - JOUR A1 - Oder, Daniel A1 - Üceyler, Nurcan A1 - Liu, Dan A1 - Hu, Kai A1 - Petritsch, Bernhard A1 - Sommer, Claudia A1 - Ertl, Georg A1 - Wanner, Christoph A1 - Nordbeck, Peter T1 - Organ manifestations and long-term outcome of Fabry disease in patients with the GLA haplotype D313Y JF - BMJ Open N2 - Objectives: The severity of Fabry disease is dependent on the type of mutation in the α-galactosidase A (AgalA) encoding gene (GLA). This study focused on the impact of the GLA haplotype D313Y on long-term organ involvement and function. Setting and participants: In this monocentric study, all participants presenting with the D313Y haplotype between 2001 and 2015 were comprehensively clinically investigated at baseline and during a 4-year follow-up if available. Five females and one male were included. Primary and secondary outcome measures: Cardiac, nephrological, neurological, laboratory and quality of life data. Results: AgalA enzyme activity in leucocytes (0.3±0.9 nmol/min/mg protein (mean±SD)) and serum lyso-Gb3 (0.6±0.3 ng/mL at baseline) were in normal range in all patients. Cardiac morphology and function were normal (left-ventricular (LV) ejection fraction 66±8%; interventricular septum 7.7±1.4 mm; LV posterior wall 7.5±1.4 mm; normalised LV mass in MRI 52±9 g/m2; LV global longitudinal strain −21.6±1.9%) and there were no signs of myocardial fibrosis in cardiac MRI. Cardiospecific biomarkers were also in normal range. Renal function was not impaired (estimated glomerular filtration rate MDRD 103±15 mL/min; serum-creatinine 0.75±0.07 mg/dL; cystatin-c 0.71±0.12 mg/L). One female patient (also carrying a Factor V Leiden mutation) had a transitory ischaemic attack. One patient showed white matter lesions in brain MRI, but none had Fabry-associated pain attacks, pain crises, evoked pain or permanent pain. Health-related quality of life analysis revealed a reduction in individual well-being. At long-term follow-up after 4 years, no significant change was seen in any parameter. Conclusions: The results of the current study suggest that the D313Y genotype does not lead to severe organ manifestations as seen in genotypes known to be causal for classical FD." KW - inherited metabolic disorders KW - Anderson-Fabry Disease KW - D313Y genotype KW - Fabry cardiomyopathy KW - Fabry nephropathy KW - Fabry-associated pain Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161210 VL - 6 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 - Petzke, Frank A1 - Klose, Petra A1 - Welsch, Patrick A1 - Sommer, Claudia A1 - Häuser, Winfried T1 - Opioids for chronic low back pain: An updated systematic review and meta‐analysis of efficacy, tolerability and safety in randomized placebo‐controlled studies of at least 4 weeks of double‐blind 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 non‐malignant chronic low back pain. Databases and Data Treatment Clinicaltrials.gov, CENTRAL, MEDLINE and PsycINFO were searched from October 2013 to May 2019. Randomized controlled trials comparing opioids with placebo and at least 4 weeks of 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 or standardized mean differences. We added nine new studies with 2,980 participants for a total of 21 studies with 7,650 participants. Study duration ranged between 4 and 15 weeks. Studies with a parallel and cross‐over design: Based on very low to low‐quality evidence, opioids provided no clinically relevant pain relief of 50% or greater, but a clinically relevant reduction of disability compared to placebo. Enriched enrolment randomized withdrawal (EERW) design: Based on very low to low‐quality evidence, opioids provided a clinically relevant pain relief of 50% or greater, but not a clinically relevant reduction of disability compared to placebo. There was no clinically relevant harm with regard to serious adverse events by opioids compared to placebo in studies with parallel/cross‐over and EERW design. There was a relevant harm with regard to drop out rates due to adverse events in studies with parallel/cross‐over, but not in studies with EERW design. Conclusions Opioids may provide a safe and clinically relevant pain relief for 4–15 weeks in highly selected patients. Significance Within the context of randomized controlled trials of 4–15 weeks, opioids provided a clinically relevant pain relief of 30% or greater and a clinically relevant reduction of disability compared to placebo in non‐malignant chronic low back pain. Number needed to treat for an additional drop out due to side effects was 11 (95% confidence interval: 6–33). Assessment of abuse and addiction was incomplete. The frequency of serious adverse events including deaths did not differ from placebo. KW - opioids KW - back pain KW - systematic review Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218498 VL - 24 IS - 3 SP - 497 EP - 517 ER - TY - JOUR A1 - Tütüncü, Serdar A1 - Olma, Manuel A1 - Kunze, Claudia A1 - Dietzel, Joanna A1 - Schurig, Johannes A1 - Fiessler, Cornelia A1 - Malsch, Carolin A1 - Haas, Tobias Eberhard A1 - Dimitrijeski, Boris A1 - Doehner, Wolfram A1 - Hagemann, Georg A1 - Hamilton, Frank A1 - Honermann, Martin A1 - Jungehulsing, Gerhard Jan A1 - Kauert, Andreas A1 - Koennecke, Hans-Christian A1 - Mackert, Bruno-Marcel A1 - Nabavi, Darius A1 - Nolte, Christian H. A1 - Reis, Joschua Mirko A1 - Schmehl, Ingo A1 - Sparenberg, Paul A1 - Stingele, Robert A1 - Völzke, Enrico A1 - Waldschmidt, Carolin A1 - Zeise-Wehry, Daniel A1 - Heuschmann, Peter U. A1 - Endress, Matthias A1 - Haeusler, Karl Georg T1 - Off-label-dosing of non-vitamin K-dependent oral antagonists in AF patients before and after stroke: results of the prospective multicenter Berlin Atrial Fibrillation Registry JF - Journal of Neurology N2 - Aims We aimed to analyze prevalence and predictors of NOAC off-label under-dosing in AF patients before and after the index stroke. Methods The post hoc analysis included 1080 patients of the investigator-initiated, multicenter prospective Berlin Atrial Fibrillation Registry, designed to analyze medical stroke prevention in AF patients after acute ischemic stroke. Results At stroke onset, an off-label daily dose was prescribed in 61 (25.5%) of 239 NOAC patients with known AF and CHA2DS2-VASc score ≥ 1, of which 52 (21.8%) patients were under-dosed. Under-dosing was associated with age ≥ 80 years in patients on rivaroxaban [OR 2.90, 95% CI 1.05-7.9, P = 0.04; n = 29] or apixaban [OR 3.24, 95% CI 1.04-10.1, P = 0.04; n = 22]. At hospital discharge after the index stroke, NOAC off-label dose on admission was continued in 30 (49.2%) of 61 patients. Overall, 79 (13.7%) of 708 patients prescribed a NOAC at hospital discharge received an off-label dose, of whom 75 (10.6%) patients were under-dosed. Rivaroxaban under-dosing at discharge was associated with age ≥ 80 years [OR 3.49, 95% CI 1.24-9.84, P = 0.02; n = 19]; apixaban under-dosing with body weight ≤ 60 kg [OR 0.06, 95% CI 0.01-0.47, P < 0.01; n = 56], CHA2DS2-VASc score [OR per point 1.47, 95% CI 1.08-2.00, P = 0.01], and HAS-BLED score [OR per point 1.91, 95% CI 1.28-2.84, P < 0.01]. Conclusion At stroke onset, off-label dosing was present in one out of four, and under-dosing in one out of five NOAC patients. Under-dosing of rivaroxaban or apixaban was related to old age. In-hospital treatment after stroke reduced off-label NOAC dosing, but one out of ten NOAC patients was under-dosed at discharge. KW - NOAC KW - ischemic stroke KW - atrial fibrillation KW - under-dosing Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266969 SN - 1432-1459 VL - 269 IS - 1 ER - TY - THES A1 - Hochheimer, Vanessa Christine T1 - Of cells and enzymes: How dermal fibroblasts can impact pain in Fabry Disease and Why looking at the 3D-structure of α-Galactosidase A may be worthwhile for clinical management of Fabry patients T1 - Über Zellen und Enzyme: Wie Hautfibroblasten Schmerz bei Morbus Fabry beeinflussen können und Warum sich die Betrachtung der 3D-Struktur der α-Galaktosidase A für die klinische Versorgung von Fabry Patienten lohnt N2 - Fabry Disease (FD) is a genetic lysosomal storage disorder based on mutations in the gene encoding α-Galactosidase A (α-GalA) leading to accumulation of globotriaosylceramide (Gb3). Missense mutations induce an amino acid exchange (AAE) in the α-GalA. Pain is a predominant symptom in FD and the pathophysiology is unclear. Skin punch biopsies were obtained from 40 adult FD patients and ten healthy controls and dermal fibroblast cultures were generated for cell culture experiments to investigate Gb3 load, gene and protein expression patterns and ion channel activity. The 3D-structure of α-GalA was downloaded into Pymol Graphics System and the AAE was depicted and located in order to investigate the correlation between the AAE location type in the α-GalA and the clinical FD phenotype. FD dermal fibroblasts showed high Gb3 load depending on treatment interval and expressed Kca1.1 channels. Activity was reduced in FD cells at baseline, but increased over-proportionately upon Gb3-cleavage by enzyme replacement therapy. Gene and protein expression of Kca1.1 was increased in FD cells. FD dermal fibroblasts showed higher gene expression of Notch1 and several cytokines. Further, it was shown that three different AAE location types can be differentiated: mutations in the active site (‘active site’), those buried in the core of α-GalA (‘buried’) and those at another location, mostly on the protein surface (‘other’). FD patients carrying active site or buried mutations showed a severe clinical phenotype with multi-organ manifestation and early disease onset. Patients with other mutations were less severely affected with oligo-organ manifestation sparing the nervous system and later disease onset. These results show that dermal fibroblasts may be involved in FD-associated pain and that stratification of FD patients carrying missense mutations by AAE location type may be an advantageous parameter that can help in the management of FD patients. N2 - M. Fabry ist eine genetisch bedingte lysosomale Speichererkrankung aufgrund von Mutationen im Gen der α-Galaktosidase A (α-GalA) mit Ablagerung von Globotriaosylceramid (Gb3). Missense-Mutationen führen zum Austausch einer Aminosäure (ASA) in der α-GalA. Schmerz ist ein häufiges Symptom, dessen Pathophysiologie unklar ist. Bei 40 Patient*innen mit M. Fabry sowie zehn Kontrollprobanden wurde eine Hautstanzbiopsie durchgeführt und zur Kultivierung von dermalen Fibroblasten verwendet, um den Gb3-Gehalt, Gen- und Proteinexpressionsmuster und Ionenkanalaktivität zu untersuchen. Zudem wurde die 3D-Struktur der α-GalA in Pymol Graphics System geladen und der Ort des ASA dargestellt, um den Zusammenhang zwischen dem ASA in der α-GalA und dem klinischen Phänotypen zu untersuchen. Es zeigte sich, dass Fabry-Fibroblasten erhöhte Gb3-Ablagerungen beinhalten, abhängig von der Zeit zwischen Enzymersatztherapie (ERT) und Biospieentnahme, sowie Kca1.1 Kanäle, deren Funktion in Patientenzellen unter Normalbedingungen reduziert war, der jedoch eine überproportionale Aktivitätszunahme nach Gb3-Abbau mittels ERT zeigte. Die Gen- und Proteinexpression des Kanals war in Fabry-Zellen erhöht. Fabry-Zellen wiesen eine erhöhte Genexpression von Notch1 sowie mehrerer Zytokine auf. Zudem zeigte sich, dass es drei verschiedene ASA Gruppen gab: Mutationen im aktiven Zentrum („active site“), in der Tiefe des Enzyms („buried“) und an anderen Orten, meist an der Oberfläche („other“). Patient*innen mit active site- oder buried-Mutationen zeigten einen schweren Phänotypen mit Multi-Organbeteiligung und frühem Krankheitsbeginn. Patient*innen mit other-Mutationen zeigten eine Beteiligung von wenigen Organen ohne Nervensystem und späteren Krankheitsbeginn. Es zeigt sich, dass dermale Fibroblasten zu Schmerz bei M. Fabry beitragen können und die Einteilung von Patient*innen mit M. Fabry-Missense Mutationen anhand des Ortes des ASA ein lohnender Parameter bei der Betreuung der Patient*innen sein kann. KW - Fabry-Krankheit KW - Hautzelle KW - Schmerz KW - Fabry KW - Fibroblasten KW - 3D-Struktur KW - Fabry disease KW - Pain KW - Fibroblasts KW - 3D structure Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-296607 ER - TY - THES A1 - Weisensee, Tim André T1 - Nutzen von Stroke-Unit-Behandlung für die geriatrische Rehabilitationsprognose T1 - Profit of stroke unit- treatment for the pronostic of geriatric rehabilitation N2 - Die vorliegende Arbeit überprüft an einem nach Alter, Geschlecht, Barthel-Index und Mini-Mental-State-Test gematchten geriatrischen Patientenkollektiv mit erstmaligem Schlaganfall die Wirksamkeit einer vorausgegangenen Akutbehandlung an einer Stroke Unit (n=59) gegenüber einer allgemeinen (internistischen oder neurologischen) stationären Akutbehandlung (n=59) für die Prognose im Laufe einer nachfolgenden geriatrischen Rehabilitationsbehandlung. Hintergrund dieser Frage ist der erhöhte ökonomische Druck im Gesundheitswesen, der eine Effizienzprüfung einer personell, technisch und logistisch aufwändigeren und damit teureren Behandlung auf einer Spezialstation verlangt. Bei Anwendung zahlreicher funktioneller Skalen und Erhebung einiger sozioökonomischer Faktoren zeigte sich auf Signifikanzniveau, dass die auf Stroke Unit Vorbehandelten bei Aufnahme in die Rehabilitation motorisch schwerer beeinträchtigt waren (timed up and go-Test p=0,044, Lachs-Test p=0,34) und sich dann ausgeprägter (Transferleistung p=0,024) auf ein bei Rehabilitationsende schließlich vergleichbares Leistungsniveau verbesserten. Die ursprünglich geplante Langzeiteffizienzbetrachtung im Gruppenvergleich scheiterte an Datenschutzbedenken. Gesundheitsökonomisch relevant ist, dass die Vorverweildauer im Akutkrankenhaus bei Stroke Unit-Patienten sechs Tage kürzer war, die Rehabilitationsdauer allerdings vier Tage länger. Weitergehende Kostenbetrachtungen scheiterten am Unwillen zur Leistungsoffenlegung verschiedener Beteiligter im Gesundheitssystem. Eine plausible Erklärung für diese positive motorische Leistungsweiterentwicklung nach Stroke Unit-Vorbehandlung kann in einer frühzeitigeren und effektiveren Anstrengung durch Krankengymnastik, Ergotherapie, Logopädie, aktivierende Pflege, „enriched environment“ gesucht werden, die sich positiv auf die Plastizität im Gehirn als wesentliche Bedingung zur Funktionswiedergewinnung auswirken könnte, was aber noch umstritten ist und Ziel weiterer Untersuchungen sein muss. N2 - This dissertation compares 2 groups of geriatric patients during their stay in a rehabilitation clinic after they suffered a first apoplexy. The first group is a group a 59 patients who have been admitted in the hospital on a general ward after their stroke. In the second group (n=59), the patients have been admitted in a special stroke unit after the apoplexy. In order to study the profit of the stroke unit pre-treatment, the 2 groups have been compared under the following criteria: age, sex, barthel-index and mini-mental-state examination. A long term comparison of efficiency was impossible because of data protection. The stroke unit patients stayed 6 day shorter in the acute hospital but they had to stay 4 days longer during the rehabilitation treatment before leaving the clinic of rehabilitation. Le travail suivant examine l’efficacité d’un traitement d’urgence dans un service de stroke unit par rapport à un traitement d’urgence dans un service général stationnaire (médecine interne ou neurologie) sur le pronostique lors du traitement de rééducation gériatrique à venir. Afin de pouvoir établir une comparaison, un groupe de patients gériatriques ayant subi un premier AVC a été choisi et couplé selon les critères de l’âge, du sexe, de l’index de Barthel et du test « mini-metal-state ». L’intérêt de cette question est la forte pression économique dans le secteur de la santé qui exige l’examen de l’efficacité d’un traitement dans un service spécialisé dont les moyens personnels, techniques et logistiques sont plus élévés et plus chers. L’utilisation de nombreuses échelles fonctionnelles et le relevé de quelques facteurs socio-économiques ont permis de mettre en évidence de facon significative que les patients traités dans un service stroke unit étaient plus gênés sur le plan motorique lors de l’admission mais qu’à la fin de la rééducation, ils s’étaient améliorés de facon nette, atteignant finalement un niveau de performance comparable. L’observation de l’efficacité à long terme dans le groupe de comparaison initialement prévue, a finalement échoué en raison de doutes quant à la protection des données. En ce qui concerne l’aspect éco-sanitaire, il est flagrant que le séjour à l’hôpital avant la rééducation a duré 6 jours de moins chez les patients du groupe stroke unit, mais la durée de rééducation 4 jours de plus. Il a été impossible d’examiner les coûts plus en détail en raison du refus de différents acteurs du système sanitaire à mettre leurs données à disposition. Cette évolution positive de la performance motorique suite au pré-traitement stroke unit peut s’expliquer par les efforts très précoces fournis en matière de physiothérapie, d’ergothérapie, de logopédie et de soins de rééducation active (enriched environment) qui ont une influence positive sur la plasticité du cerveau, laquelle est une condition indispensable au regain de fonctions. Ceci est encore controversé et devra faire l’objet d’autres études. KW - Geriatrie KW - Stroke unit KW - Prognose KW - Rehabilitation KW - Schlaganfall KW - Geriatrics KW - stroke unit KW - rehabilitation KW - apoplexy KW - prognosis Y1 - 2007 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-24937 ER - TY - JOUR A1 - Hopfner, Franziska A1 - Schormair, Barbara A1 - Knauf, Franziska A1 - Berthele, Achim A1 - Tölle, Thomas R. A1 - Baron, Ralf A1 - Maier, Christoph A1 - Treede, Rolf-Detlef A1 - Binder, Andreas A1 - Sommer, Claudia A1 - Maihöfner, Christian A1 - Kunz, Wolfram A1 - Zimprich, Friedrich A1 - Heemann, Uwe A1 - Pfeufer, Arne A1 - Näbauer, Michael A1 - Kääb, Stefan A1 - Nowak, Barbara A1 - Gieger, Christian A1 - Lichtner, Peter A1 - Trenkwalder, Claudia A1 - Oexle, Konrad A1 - Winkelmann, Juliane T1 - Novel SCARB2 mutation in Action Myoclonus-Renal Failure syndrome and evaluation of SCARB2 mutations in isolated AMRF features JF - BMC Neurology N2 - Background: Action myoclonus-renal failure syndrome is a hereditary form of progressive myoclonus epilepsy associated with renal failure. It is considered to be an autosomal-recessive disease related to loss-of-function mutations in SCARB2. We studied a German AMRF family, additionally showing signs of demyelinating polyneuropathy and dilated cardiomyopathy. To test the hypothesis whether isolated appearance of individual AMRF syndrome features could be related to heterozygote SCARB2 mutations, we screened for SCARB2 mutations in unrelated patients showing isolated AMRF features. Methods: In the AMRF family all exons of SCARB2 were analyzed by Sanger sequencing. The mutation screening of unrelated patients with isolated AMRF features affected by either epilepsy (n = 103, progressive myoclonus epilepsy or generalized epilepsy), demyelinating polyneuropathy (n = 103), renal failure (n = 192) or dilated cardiomyopathy (n = 85) was performed as high resolution melting curve analysis of the SCARB2 exons. Results: A novel homozygous 1 bp deletion (c.111delC) in SCARB2 was found by sequencing three affected homozygous siblings of the affected family. A heterozygous sister showed generalized seizures and reduction of nerve conduction velocity in her legs. No mutations were found in the epilepsy, renal failure or dilated cardiomyopathy samples. In the polyneuropathy sample two individuals with demyelinating disease were found to be carriers of a SCARB2 frameshift mutation (c.666delCCTTA). Conclusions: Our findings indicate that demyelinating polyneuropathy and dilated cardiomyopathy are part of the action myoclonus-renal failure syndrome. Moreover, they raise the possibility that in rare cases heterozygous SCARB2 mutations may be associated with PNP features. KW - Demyelinating peripheral neuropathy KW - Beta-glucocerebrosidase KW - Epilepsy KW - LIMP-2 KW - Mice Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141209 VL - 11 IS - 134 ER - TY - JOUR A1 - Silwedel, Christine A1 - Speer, Christian P. A1 - Haarmann, Axel A1 - Fehrholz, Markus A1 - Claus, Heike A1 - Buttmann, Mathias A1 - Glaser, Kirsten T1 - Novel insights into neuroinflammation: bacterial lipopolysaccharide, tumor necrosis factor α, and Ureaplasma species differentially modulate atypical chemokine receptor 3 responses in human brain microvascular endothelial cells JF - Journal of Neuroinflammation N2 - Background: Atypical chemokine receptor 3 (ACKR3, synonym CXCR7) is increasingly considered relevant in neuroinflammatory conditions, in which its upregulation contributes to compromised endothelial barrier function and may ultimately allow inflammatory brain injury. While an impact of ACKR3 has been recognized in several neurological autoimmune diseases, neuroinflammation may also result from infectious agents, including Ureaplasma species (spp.). Although commonly regarded as commensals of the adult urogenital tract, Ureaplasma spp. may cause invasive infections in immunocompromised adults as well as in neonates and appear to be relevant pathogens in neonatal meningitis. Nonetheless, clinical and in vitro data on Ureaplasma-induced inflammation are scarce. Methods: We established a cell culture model of Ureaplasma meningitis, aiming to analyze ACKR3 variances as a possible pathomechanism in Ureaplasma-associated neuroinflammation. Non-immortalized human brain microvascular endothelial cells (HBMEC) were exposed to bacterial lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α), and native as well as LPS-primed HBMEC were cultured with Ureaplasma urealyticum serovar 8 (Uu8) and U. parvum serovar 3 (Up3). ACKR3 responses were assessed via qRT-PCR, RNA sequencing, flow cytometry, and immunocytochemistry. Results: LPS, TNF-α, and Ureaplasma spp. influenced ACKR3 expression in HBMEC. LPS and TNF-α significantly induced ACKR3 mRNA expression (p < 0.001, vs. control), whereas Ureaplasma spp. enhanced ACKR3 protein expression in HBMEC (p < 0.01, vs. broth control). Co-stimulation with LPS and either Ureaplasma isolate intensified ACKR3 responses (p < 0.05, vs. LPS). Furthermore, stimulation wielded a differential influence on the receptor’s ligands. Conclusions: We introduce an in vitro model of Ureaplasma meningitis. We are able to demonstrate a pro-inflammatory capacity of Ureaplasma spp. in native and, even more so, in LPS-primed HBMEC, underlining their clinical relevance particularly in a setting of co-infection. Furthermore, our data may indicate a novel role for ACKR3, with an impact not limited to auto-inflammatory diseases, but extending to infection-related neuroinflammation as well. AKCR3-induced blood-brain barrier breakdown might constitute a potential common pathomechanism. KW - atypical chemokine receptor 3 KW - human brain microvascular endothelial cells KW - meningitis KW - neuroinflammation KW - Ureaplasma species Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175952 VL - 15 IS - 156 ER - TY - JOUR A1 - Piro, Inken A1 - Eckes, Anna-Lena A1 - Kasaragod, Vikram Babu A1 - Sommer, Claudia A1 - Harvey, Robert J. A1 - Schaefer, Natascha A1 - Villmann, Carmen T1 - Novel Functional Properties of Missense Mutations in the Glycine Receptor β Subunit in Startle Disease JF - Frontiers in Molecular Neuroscience N2 - Startle disease is a rare disorder associated with mutations in GLRA1 and GLRB, encoding glycine receptor (GlyR) α1 and β subunits, which enable fast synaptic inhibitory transmission in the spinal cord and brainstem. The GlyR β subunit is important for synaptic localization via interactions with gephyrin and contributes to agonist binding and ion channel conductance. Here, we have studied three GLRB missense mutations, Y252S, S321F, and A455P, identified in startle disease patients. For Y252S in M1 a disrupted stacking interaction with surrounding aromatic residues in M3 and M4 is suggested which is accompanied by an increased EC\(_{50}\) value. By contrast, S321F in M3 might stabilize stacking interactions with aromatic residues in M1 and M4. No significant differences in glycine potency or efficacy were observed for S321F. The A455P variant was not predicted to impact on subunit folding but surprisingly displayed increased maximal currents which were not accompanied by enhanced surface expression, suggesting that A455P is a gain-of-function mutation. All three GlyR β variants are trafficked effectively with the α1 subunit through intracellular compartments and inserted into the cellular membrane. In vivo, the GlyR β subunit is transported together with α1 and the scaffolding protein gephyrin to synaptic sites. The interaction of these proteins was studied using eGFP-gephyrin, forming cytosolic aggregates in non-neuronal cells. eGFP-gephyrin and β subunit co-expression resulted in the recruitment of both wild-type and mutant GlyR β subunits to gephyrin aggregates. However, a significantly lower number of GlyR β aggregates was observed for Y252S, while for mutants S321F and A455P, the area and the perimeter of GlyR β subunit aggregates was increased in comparison to wild-type β. Transfection of hippocampal neurons confirmed differences in GlyR-gephyrin clustering with Y252S and A455P, leading to a significant reduction in GlyR β-positive synapses. Although none of the mutations studied is directly located within the gephyrin-binding motif in the GlyR β M3-M4 loop, we suggest that structural changes within the GlyR β subunit result in differences in GlyR β-gephyrin interactions. Hence, we conclude that loss- or gain-of-function, or alterations in synaptic GlyR clustering may underlie disease pathology in startle disease patients carrying GLRB mutations. KW - glycine receptor KW - hyperekplexia KW - startle disease KW - gephyrin Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246676 SN - 1662-5099 VL - 14 ER - TY - JOUR A1 - Groh, Janos A1 - Stadler, David A1 - Buttmann, Mathias A1 - Martini, Rudolf T1 - Non-invasive assessment of retinal alterations in mouse models of infantile and juvenile neuronal ceroid lipofuscinosis by spectral domain optical coherence tomography N2 - Introduction The neuronal ceroid lipofuscinoses constitute a group of fatal inherited lysosomal storage diseases that manifest in profound neurodegeneration in the CNS. Visual impairment usually is an early symptom and selective degeneration of retinal neurons has been described in patients suffering from distinct disease subtypes. We have previously demonstrated that palmitoyl protein thioesterase 1 deficient (Ppt1-/-) mice, a model of the infantile disease subtype, exhibit progressive axonal degeneration in the optic nerve and loss of retinal ganglion cells, faithfully reflecting disease severity in the CNS. Here we performed spectral domain optical coherence tomography (OCT) in Ppt1-/- and ceroid lipofuscinosis neuronal 3 deficient (Cln3-/-) mice, which are models of infantile and juvenile neuronal ceroid lipofuscinosis, respectively, in order to establish a non-invasive method to assess retinal alterations and monitor disease severity in vivo. Results Blue laser autofluorescence imaging revealed increased accumulation of autofluorescent storage material in the inner retinae of 7-month-old Ppt1-/- and of 16-month-old Cln3-/- mice in comparison with age-matched control littermates. Additionally, optical coherence tomography demonstrated reduced thickness of retinae in knockout mice in comparison with age-matched control littermates. High resolution scans and manual measurements allowed for separation of different retinal composite layers and revealed a thinning of layers in the inner retinae of both mouse models at distinct ages. OCT measurements correlated well with subsequent histological analysis of the same retinae. Conclusions These results demonstrate the feasibility of OCT to assess neurodegenerative disease severity in mouse models of neuronal ceroid lipofuscinosis and might have important implications for diagnostic evaluation of disease progression and therapeutic efficacy in patients. Moreover, the non-invasive method allows for longitudinal studies in experimental models, reducing the number of animals used for research. KW - Optical coherence tomography KW - Neuronal ceroid lipofuscinosis KW - Neurodegeneration KW - Retinal degeneration KW - Lysosomal storage disease Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-110566 ER - 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 - JOUR A1 - Nguemeni, Carine A1 - Stiehl, Annika A1 - Hiew, Shawn A1 - Zeller, Daniel T1 - No Impact of Cerebellar Anodal Transcranial Direct Current Stimulation at Three Different Timings on Motor Learning in a Sequential Finger-Tapping Task JF - Frontiers in Human Neuroscience N2 - Background: Recently, attention has grown toward cerebellar neuromodulation in motor learning using transcranial direct current stimulation (tDCS). An important point of discussion regarding this modulation is the optimal timing of tDCS, as this parameter could significantly influence the outcome. Hence, this study aimed to investigate the effects of the timing of cerebellar anodal tDCS (ca-tDCS) on motor learning using a sequential finger-tapping task (FTT). Methods: One hundred and twenty two healthy young, right-handed subjects (96 females) were randomized into four groups (During\(_{sham}\), Before, During\(_{real}\), After). They performed 2 days of FTT with their non-dominant hand on a custom keyboard. The task consisted of 40 s of typing followed by 20 s rest. Each participant received ca-tDCS (2 mA, sponge electrodes of 25 cm\(^{2}\), 20 min) at the appropriate timing and performed 20 trials on the first day (T1, 20 min). On the following day, only 10 trials of FTT were performed without tDCS (T2, 10 min). Motor skill performance and retention were assessed. Results: All participants showed a time-dependent increase in learning. Motor performance was not different between groups at the end of T1 (p = 0.59). ca-tDCS did not facilitate the retention of the motor skill in the FTT at T2 (p = 0.27). Thus, our findings indicate an absence of the effect of ca-tDCS on motor performance or retention of the FTT independently from the timing of stimulation. Conclusion: The present results suggest that the outcome of ca-tDCS is highly dependent on the task and stimulation parameters. Future studies need to establish a clear basis for the successful and reproducible clinical application of ca-tDCS. KW - cerebellar tDCS KW - finger-tapping task KW - timing KW - motor learning KW - task retention Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225477 SN - 1662-5161 VL - 15 ER - TY - JOUR A1 - Bellut, Maximilian A1 - Raimondi, Anthony T. A1 - Haarmann, Axel A1 - Zimmermann, Lena A1 - Stoll, Guido A1 - Schuhmann, Michael K. T1 - NLRP3 inhibition reduces rt-PA induced endothelial dysfunction under ischemic conditions JF - Biomedicines N2 - Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is a mainstay of acute ischemic stroke treatment but is associated with bleeding complications, especially after prolonged large vessel occlusion. Recently, inhibition of the NLRP3 inflammasome led to preserved blood–brain barrier (BBB) integrity in experimental stroke in vivo. To further address the potential of NLRP3 inflammasome inhibition as adjunct stroke treatment we used immortalized brain derived endothelial cells (bEnd5) as an in vitro model of the BBB. We treated bEnd5 with rt-PA in combination with the NLRP3 specific inhibitor MCC950 or vehicle under normoxic as well as ischemic (OGD) conditions. We found that rt-PA exerted a cytotoxic effect on bEnd5 cells under OGD confirming that rt-PA is harmful to the BBB. This detrimental effect could be significantly reduced by MCC950 treatment. Moreover, under ischemic conditions, the Cell Index — a sensible indicator for a patent BBB — and the protein expression of Zonula occludens 1 stabilized after MCC950 treatment. At the same time, the extent of endothelial cell death and NLRP3 expression decreased. In conclusion, NLRP3 inhibition can protect the BBB from rt-PA-induced damage and thereby potentially increase the narrow time window for safe thrombolysis in stroke. KW - NLRP3 KW - inflammasome KW - MCC950 KW - rt-PA KW - blood–brain barrier KW - Cell Index KW - ASC KW - ischemic stroke KW - i.v. thrombolysis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267261 SN - 2227-9059 VL - 10 IS - 4 ER - TY - JOUR A1 - Bellut, Maximilian A1 - Papp, Lena A1 - Bieber, Michael A1 - Kraft, Peter A1 - Stoll, Guido A1 - Schuhmann, Michael K. T1 - NLPR3 inflammasome inhibition alleviates hypoxic endothelial cell death in-vitro and protects blood-brain barrier integrity in murine stroke JF - Cell Death & Disease N2 - In ischemic stroke (IS) impairment of the blood-brain barrier (BBB) has an important role in the secondary deterioration of neurological function. BBB disruption is associated with ischemia-induced inflammation, brain edema formation, and hemorrhagic infarct transformation, but the underlying mechanisms are incompletely understood. Dysfunction of endothelial cells (EC) may play a central role in this process. Although neuronal NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome upregulation is an established trigger of inflammation in IS, the contribution of its expression in EC is unclear. We here used brain EC, exposed them to oxygen and glucose deprivation (OGD) in vitro, and analyzed their survival depending on inflammasome inhibition with the NLRP3-specific drug MCC950. During OGD, EC death could significantly be reduced when targeting NLRP3, concomitant with diminished endothelial NLRP3 expression. Furthermore, MCC950 led to reduced levels of Caspase 1 (p20) and activated Gasdermin D as markers for pyroptosis. Moreover, inflammasome inhibition reduced the secretion of pro-inflammatory chemokines, cytokines, and matrix metalloproteinase-9 (MMP9) in EC. In a translational approach, IS was induced in C57Bl/6 mice by 60 mins transient middle cerebral artery occlusion and 23 hours of reperfusion. Stroke volume, functional outcome, the BBB integrity, and-in good agreement with the in vitro results-MMP9 secretion as well as EC survival improved significantly in MCC950-treated mice. In conclusion, our results establish the NLRP3 inflammasome as a critical pathogenic effector of stroke-induced BBB disruption by activating inflammatory signaling cascades and pyroptosis in brain EC. KW - inflammasome KW - preclinical research KW - stroke Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265693 VL - 13 ER - TY - JOUR A1 - Chen, Yong A1 - Boettger, Michael K. A1 - Reif, Andreas A1 - Schmitt, Angelika A1 - Ueceyler, Nurcan A1 - Sommer, Claudia T1 - Nitric oxide synthase modulates CFA-induced thermal hyperalgesia through cytokine regulation in mice N2 - Background: Although it has been largely demonstrated that nitric oxide synthase (NOS), a key enzyme for nitric oxide (NO) production, modulates inflammatory pain, the molecular mechanisms underlying these effects remain to be clarified. Here we asked whether cytokines, which have well-described roles in inflammatory pain, are downstream targets of NO in inflammatory pain and which of the isoforms of NOS are involved in this process. Results: Intraperitoneal (i.p.) pretreatment with 7-nitroindazole sodium salt (7-NINA, a selective neuronal NOS inhibitor), aminoguanidine hydrochloride (AG, a selective inducible NOS inhibitor), L-N(G)-nitroarginine methyl ester (L-NAME, a non-selective NOS inhibitor), but not L-N(5)-(1-iminoethyl)-ornithine (L-NIO, a selective endothelial NOS inhibitor), significantly attenuated thermal hyperalgesia induced by intraplantar (i.pl.) injection of complete Freund’s adjuvant (CFA). Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed a significant increase of nNOS, iNOS, and eNOS gene expression, as well as tumor necrosis factor-alpha (TNF), interleukin-1 beta (IL-1b), and interleukin-10 (IL-10) gene expression in plantar skin, following CFA. Pretreatment with the NOS inhibitors prevented the CFA-induced increase of the pro-inflammatory cytokines TNF and IL-1b. The increase of the antiinflammatory cytokine IL-10 was augmented in mice pretreated with 7-NINA or L-NAME, but reduced in mice receiving AG or L-NIO. NNOS-, iNOS- or eNOS-knockout (KO) mice had lower gene expression of TNF, IL-1b, and IL-10 following CFA, overall corroborating the inhibitor data. Conclusion: These findings lead us to propose that inhibition of NOS modulates inflammatory thermal hyperalgesia by regulating cytokine expression. KW - Medizin Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68349 ER - TY - THES A1 - Nuth, Linda T1 - Niederfrequente, Tiefe Hirnstimulation bei Parkinson-Patienten mit ON-Freezing. Identifikation von Respondern anhand kinematischer Gangparameter T1 - Predictive factors for Improvement of Gait by Low-frequency subthalamic deep brain stimulation in Parkinson patients with ON-Freezing N2 - Das ON-Freezing ist ein seltenes, aber generell extrem schwer zu therapierendes Phänomen. Es betrifft Parkinson-Patienten mit und ohne THS. Die derzeitige Literaturlage spiegelt wider, dass es unterschiedliche Strategien gibt, diesem Phänomen zu begegnen. Ein allgemeingültiges Therapiekonzept existiert dabei nicht. Für einige Patienten mit STN-THS konnte durch eine Reduktion der Stimulationsfrequenz eine Besserung der Gangstörung erzielt werden. Andere profitierten vom Einsatz sogenannter Interleaving-Protokolle mit gleichzeitiger Stimulation der Substantia nigra (Sn). Im Vergleich zu anderen Arbeiten, die keine vorhersagbaren Parameter gefunden oder sich auf Symptome, Ausprägung der Subtypen und Erkrankungsdauer oder den Zeitpunkt der Erkrankung konzentriert haben, verfolgten wir die Absicht, die Effekte der LF-Stim des STN auf Parkinson-Patienten mit Gangstörung und Freezing-Phänomen zu untersuchen und herauszufinden, ob man Gangparameter identifizieren kann, an Hand derer man das Ansprechen auf eine LF-Stim vorhersagen kann. Unter der Einschränkung, dass die Zahl der Probanden unserer Studie sehr gering ist, haben wir herausgefunden, dass diejenigen Patienten besser auf eine LF-Stim ansprechen, die unter der Standard-HF-Stim eine signifikant höhere Ganggeschwindigkeit und eine größere Schrittlänge aufzeigen und nur ein intermittierendes Freezing haben. Darüber hinaus zeigte sich ein besseres Ansprechen der LF-Stim bei Parkinson-Patienten mit akinetisch-rigidem Parkinson-Phänotyp. Unsere Ergebnisse bestätigen die Annahme, dass sich L-Dopa additiv zur Stimulationstherapie bei manchen Parkinson-Patienten zusätzlich positiv auf die motorischen PD-Symptome auswirken kann. In Bezug auf die Verbesserung der Gangparameter zeigte sich in unseren Ergebnissen allerdings, dass L-Dopa eher eine untergeordnete Rolle spielt. Aufgrund der niedrigen Anzahl von Respondern in unserer Studie lässt sich daher sicherlich noch keine allgemeingültige Regel ableiten. Es bedarf letztlich weiterer Studien mit größeren Untersuchungszahlen, um unsere Thesen zu stützen und abzusichern. In jedem Fall wird aber das ON-Freezing auch weiterhin eine therapeutische Herausforderung bleiben. N2 - Patients with Parkinson's Disease (PD) and subthalamic nucleus deep brain stimulation (STN-DBS) often demonstrate continues severe gait disturbances including freezing of gait (FOG). Individual cases report an improvement of kinematic gait parameters as well as a reduction of freezing episodes. To determine, if a change in STN-DBS frequency to 80 Hz improves gait disturbances and reduces freezing episodes and to identify characteristics of responders, a multitask protocol was carried out in 6 patients with PD, STN-DBS and severe gait disorders involving an analysis if linear walking at different velocities. KW - Parkinson KW - Niederfrequenzstimulation KW - tiefe Hirnstimulation KW - ON-Freezing Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150317 ER - TY - JOUR A1 - Isaias, Ioannis Ugo A1 - Spiegel, Jörg A1 - Brumberg, Joachim A1 - Cosgrove, Kelly P. A1 - Marotta, Giorgio A1 - Oishi, Naoya A1 - Higuchi, Takahiro A1 - Küsters, Sebastian A1 - Schiller, Markus A1 - Dillmann, Ulrich A1 - van Dyck, Christopher H. A1 - Buck, Andreas A1 - Herrmann, Ken A1 - Schloegl, Susanne A1 - Volkmann, Jens A1 - Lassmann, Michael A1 - Fassbender, Klaus A1 - Lorenz, Reinhard A1 - Samnick, Samuel T1 - Nicotinic acetylcholine receptor density in cognitively intact subjects at an early stage of Parkinson's disease JF - Frontiers in Aging Neuroscience N2 - We investigated in vivo brain nicotinic acetylcholine receptor (nAChR) distribution in cognitively intact subjects with Parkinson's disease (PD) at an early stage of the disease. Fourteen patients and 13 healthy subjects were imaged with single photon emission computed tomography and the radiotracer 5-[(123)I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine ([(123)I]5IA). Patients were selected according to several criteria, including short duration of motor signs (<7 years) and normal scores at an extensive neuropsychological evaluation. In PD patients, nAChR density was significantly higher in the putamen, the insular cortex and the supplementary motor area and lower in the caudate nucleus, the orbitofrontal cortex, and the middle temporal gyrus. Disease duration positively correlated with nAChR density in the putamen ipsilateral (ρ = 0.56, p < 0.05) but not contralateral (ρ = 0.49, p = 0.07) to the clinically most affected hemibody. We observed, for the first time in vivo, higher nAChR density in brain regions of the motor and limbic basal ganglia circuits of subjects with PD. Our findings support the notion of an up-regulated cholinergic activity at the striatal and possibly cortical level in cognitively intact PD patients at an early stage of disease. KW - nicotinic receptors KW - Parkinson disease KW - 5IA-SPECT KW - dopamine acetylcholine KW - cognitive decline Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119351 VL - 6 ER - TY - THES A1 - Purrer, Veronika T1 - Nicht-motorische Begleitsymptome bei Patienten mit Essentiellen Tremor T1 - Non-motor symptoms in patients with essential tremor N2 - Der essentielle Tremor (ET) ist eine der häufigsten Bewegungsstörungen, welcher lange Zeit als rein motorische Störung angesehen wurde. Aufgrund zunehmender Belege über nicht-motorisch Begleitsymptome wandelte sich dieses Bild jedoch in den letzten Jahren zunehmend. In der vorliegenden Arbeit untersuchten wir 113 Probanden aus der Allgemeinbevölkerung mit klinisch definitiven oder wahrscheinlichen ET anhand einer breiten Batterie neuro-psychologischer Testverfahren. Es gelang hierbei signifikante Unterschiede im Vergleich zu gesunden Eichstichproben im Hinblick auf neuro-psychologische Charakteristika, wie Apathie, Ängstlichkeit und exekutive Dysfunktion, sowie deren negativen Einfluss auf die Lebensqualität der Probanden darzustellen. Bisher werden im klinischen Alltag nicht-motorische Begleitphänomene beim ET nicht regelhaft erfasst; aufgrund unserer Ergebnisse und der Relevanz vor allem im Hinblick auf die Lebensqualität des Einzelnen halten wir jedoch die Erfassung und gegebenenfalls Behandlung dieser Symptome für ebenso relevant. N2 - Essential tremor (ET) is one of the most common movement disorders, which was previously considered a purely motor disorder. Due to increasing evidence of non-motor symptoms, however, this picture has changed recently. In the present study we investigated 113 subjects from the general population with clinically definite or probable ET using a broad battery of neuro-psychological screening tools. Thereby, significant differences in neuro-psychological characteristics, such as apathy, anxiety and executive dysfunction, as well as their negative impact on the quality of life of the subjects could be demonstrated in comparison to healthy samples. Up to now, non-motor symptoms in ET are generally not been recorded in the clinical routine; however, based on our findings and the relevance to the individual's quality of life in particular, we consider the assessment and, where appropriate, treatment of these symptoms to be equally relevant. KW - Essentieller Tremor KW - Nicht-motorische Begleitsymptome KW - ET Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193665 ER -