@phdthesis{Palm2008, author = {Palm, Florian}, title = {{\"U}ber die Wirkung von Serotonin in einem chronisch entz{\"u}ndlichen Schmerzmodell mit komplettem Freund´schen Adjuvans an M{\"a}usen mit einer genetischen Defizienz f{\"u}r den Serotonintransporter.}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-30508}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2008}, abstract = {In der Behandlung neuropathischer und anderer chronischer Schmerzen werden trizyklische Antidepressiva bereits mit Erfolg eingesetzt, die nebenwirkungs{\"a}rmeren SSRI zeigen jedoch nur einen m{\"a}ßigen Erfolg. In dieser Studie gingen wir der Frage nach, inwieweit 5-HTT -/- M{\"a}use, die als Modell einer lebenslangen Behandlung mit SSRI gelten, in einem chronisch entz{\"u}ndlichen Schmerzmodell ein anderes Schmerzverhalten zeigen als Wild-typen und ob sich auf neuronaler Ebene durch das Ausschalten des 5-HT Transporters Ursachen f{\"u}r ein ge{\"a}ndertes Schmerzverhalten finden lassen. Von besonderem Interesse war dabei auch, welche Rolle 5-HT in der peripheren Schmerzvermittlung zukommt. Mit standardisierten Testverfahren wurden die 5-HTT -/- M{\"a}use und Wildtypm{\"a}use nach i.pl. Injektion von CFA auf zwei Schmerzqualit{\"a}ten hin untersucht. Die Schmerzschwelle f{\"u}r taktile Reize wurde mit von Frey Haaren bestimmt, zur Testung der Hitzehyperalgesie wurde eine Infrarotw{\"a}rmequelle benutzt. Anschließend wurden an dem Gewebe immunhistochemische Analysen durchgef{\"u}hrt und mittels HPLC der Gehalt an 5-HT in verschiedenen Gewebeproben bestimmt. Es konnte gezeigt werden, dass M{\"a}use mit dem Genotyp 5-HTT -/- gegen{\"u}ber dem Wildtyp von einer durch CFA-Injektion induzierten Hitzehyperalgesie weitgehend unbeeintr{\"a}chtigt bleiben. Gleichzeitig bestand bei den KO-M{\"a}usen im Vergleich zu den Wildtypen eine deutlichere Abnahme der Hautinnervation sowie eine st{\"a}rker ausgepr{\"a}gte Verletzung von DRG-Neuronen, entsprechend einer erh{\"o}hten neuronalen Vulnerabilit{\"a}t gegen{\"u}ber CFA. Im Gewebe der KO-M{\"a}use fand sich durchweg weniger 5-HT als bei Wildtypen, in DRG-Neuronen der KO-M{\"a}use war weiterhin weniger BDNF detektierbar. Wir postulieren, dass f{\"u}r die reduzierte Hitzehyperalgesie bei den KO-M{\"a}usen unter anderem der geringere Gewebespiegel von 5-HT und damit folglich in einer Art Ursachen-Wirkungskette auch die geringeren Gewebespiegel von BDNF und 5-HIAA mit ihren entsprechenden Auswirkungen verantwortlich sind. 5-HTT -/- M{\"a}use als Modell f{\"u}r eine lebenslange Behandlung mit SSRI sind also nicht nur wie k{\"u}rzlich beschrieben im neuropathischen Schmerzmodell, sondern auch in einem chronisch entz{\"u}ndlichen Schmerzmodell weitgehend vor einer Hitzehyperalgesie gesch{\"u}tzt. Unter der Ber{\"u}cksichtigung dieser Daten sollte daher der Einsatz von SSRI in der Behandlung chronischer Schmerzen erneut {\"u}berpr{\"u}ft werden.}, subject = {Serotonin}, language = {de} } @phdthesis{Bohr2022, author = {Bohr, Arne}, title = {{\"U}ber den Einfluss einer kontinuierlichen tiefen Hirnstimulation des pedunkulopontinen tegmentalen Nucleus auf motorische Defizite in einem Ratten-Schlaganfallmodell}, publisher = {Current Neurovascular Research}, doi = {10.25972/OPUS-27187}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-271876}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Bei einem isch{\"a}mischen Schlaganfall bestehen neben dem Verlust von neuronalen Zellen auch dysfunktionale Signale, die sich pathologisch auf die tieferen motorischen Zentren des zentralen Nervensystems auswirken k{\"o}nnen. Mittels tiefer Hirnstimulation kann die Weiterleitung pathologischer Signale im Bereich des neuronalen Netzwerks unterbrochen werden. In dieser Arbeit wurde ein Tiermodell verwendet, in welchem bei insgesamt 18 Ratten ein photothrombotischer Schlaganfall des rechten sensomotorischen Kortex induziert wurde. Nachdem bei jedem Tier eine Mikroelektrode in den Bereich des pedunkulopontinen tegmentalen Nucleus implantiert worden war, wurde eine kontinuierliche tiefe Hirnstimulation {\"u}ber 10 Tage durchgef{\"u}hrt. Die Gegen{\"u}berstellung der Fall- und Kontrollgruppe im Beam-Walking- und Ladder-Rung-Walking-Test ergab hierbei keine Verbesserung der motorischen Defizite durch die Intervention. Das Ergebnis l{\"a}sst sich vor dem Hintergrund neuerer Erkenntnisse einordnen, nach welchen der pedunkulopontine tegmentale Nucleus nicht f{\"u}r die Bewegungsinitiierung verantwortlich ist.}, subject = {Schlaganfall}, language = {de} } @phdthesis{Hullin2016, author = {Hullin, Marcus}, title = {Zusammenhang zwischen Raumwahrnehmung, K{\"o}rperselbstgef{\"u}hl und Puppenhandillusion bei gesunden {\"A}lteren und Patienten mit kortikobasalem Syndrom}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134291}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Das K{\"o}rperselbstgef{\"u}hl (KSG) bezeichnet das Gef{\"u}hl, einen bestimmten K{\"o}r-perteil als dem eigenen K{\"o}rper zugeh{\"o}rig zu empfinden. Es erscheint stabil und nicht st{\"o}rbar, l{\"a}sst sich jedoch bei den meisten Menschen experimentell beein-flussen. Ein Beispiel hierf{\"u}r ist die Puppenhandillusion (PHI), bei der die nicht sichtbare eigene Hand des Probanden und eine sichtbare Plastikhand in glei-cher Stellung an den gleichen Fingerstellen synchron mit zwei Pinseln bestri-chen wird, wodurch die Wahrnehmung entsteht, die Plastikhand sei die eigene. Ver{\"a}nderungen des KSG k{\"o}nnen jedoch auch im Rahmen neurodegenerativer Erkrankungen vorkommen. So nimmt beim kortikobasalen Syndrom (CBS) etwa die H{\"a}lfte der Patienten im Krankheitsverlauf einen Arm und seine Bewegungen als fremd war ("Alien-limb"-Ph{\"a}nomen). Das CBS beginnt oft einseitig und ist durch eine rasch fortschreitende, akinetisch-rigide Parkinson-Symptomatik, aber auch durch kortikale Funktionsst{\"o}rungen gekennzeichnet, so dass es ne-ben einer St{\"o}rung des KSG auch zu einer St{\"o}rung der r{\"a}umlichen Aufmerk-samkeit (Hemineglect) kommt. Bislang wurde der Zusammenhang zwischen Raumwahrnehmung, KSG und PHI bei gesunden {\"a}lteren Menschen noch nicht systematisch untersucht. Ebenso wenig war bisher bekannt, inwieweit das KSG bei CBS-Patienten durch die PHI modulierbar ist. Wir untersuchten 65 gesunde {\"a}ltere Probanden (60 - 90 Jahre) ohne neurologi-sche Vorerkrankungen sowie zehn Patienten zwischen 59 und 77 Jahren mit wahrscheinlichem oder m{\"o}glichem CBS. Den kognitiven und orientierend seeli-schen Zustand eruierten wir mit Hilfe des PANDA- und des Uhrentests, die Raumwahrnehmung testeten wir mittels des Milner-Landmark-Tests sowie des Letter-Cancellation-Tests, das spontane K{\"o}rperselbstgef{\"u}hl wurde mittels eines Fragebogens erfasst. Der PHI-Versuch wurde mit synchroner sowie asynchro-ner taktiler Stimulation durchgef{\"u}hrt, das Auftreten eines Selbstgef{\"u}hls f{\"u}r die Plastikhand wurde subjektiv {\"u}ber spontane {\"A}ußerungen und einen etablierten Fragebogen, objektiv {\"u}ber den sog. propriozeptiven Drift der stimulierten Hand erfasst. Unter den Kontrollprobanden fanden sich 12\% mit einer wahrscheinlichen De-menz, wohingegen dies bei 80\% der CBS-Patienten der Fall war. Im Milner-Landmark-Test zeigte sich bei den Kontrollprobanden eine {\"U}bersch{\"a}tzung des rechten Segmentes einer mittig geteilten Linie, entsprechend einem milden Hemineglect, bei den CBS-Patienten konnte keine einheitliche Tendenz festge-stellt werden. Das spontane K{\"o}rperselbstgef{\"u}hl stellte sich bei nahezu allen Probanden als intakt dar, w{\"a}hrend sich bei vier Patienten mit CBS Hinweise auf aktuelle oder intermittierende St{\"o}rungen desselben ergaben. Die Puppenhandil-lusion war in der Gruppe gesunder {\"A}lterer bei synchroner Stimulation ausl{\"o}s-bar, nicht jedoch bei asynchroner Stimulation. Eine Lateralisierungstendenz zeigte sich nicht. Dar{\"u}ber hinaus konnte bei den Probanden eine positive Korre-lation zwischen dem propriozeptiven Drift der linken Hand nach synchroner Stimulation und dem Hemineglect nach links gefunden werden. Bei den CBS-Patienten fand sich unabh{\"a}ngig von der Stimulationsart (synchron oder asyn-chron) eine erh{\"o}hte Bereitschaft, die linke Puppenhand ins eigene K{\"o}rperbild zu integrieren. Das Auftreten der PHI bei gesunden {\"a}lteren Probanden ist vergleichbar mit den Daten j{\"u}ngerer Probandengruppen. Hinweise auf eine hemisph{\"a}rische Laterali-sierungstendenz der PHI ergaben sich nicht, jedoch scheint der in dieser Grup-pe festgestellte leichtgradige Hemineglect nach links den multisensorischen Prozess zu beeinflussen, eine k{\"u}nstliche Hand in das eigene K{\"o}rperschema zu integrieren. Bei den CBS-Patienten war die PHI unabh{\"a}ngig vom Stimulations-modus links besser ausl{\"o}sbar als rechts, was mit vorwiegend rechtshemisph{\"a}-rischen krankheitsbedingten Ver{\"a}nderungen des multisensorischen Integrati-onsprozesses vereinbar ist.}, subject = {Raumwahrnehmung}, language = {de} } @phdthesis{Bellinger2020, author = {Bellinger, Daniel}, title = {Zeitwahrnehmung in der Musik bei Morbus Parkinson - eine psychophysische Studie}, doi = {10.25972/OPUS-19876}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-198766}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Parkinson Patienten sind im Gegensatz zu gesunden Probanden in der kognitiven Verarbeitung zeitlicher Parameter, im Sinne einer Diskriminierungsf{\"a}higkeit f{\"u}r zeitliche Fehler innerhalb der Musikwahrnehmung beeintr{\"a}chtigt. Dies betrifft lediglich die Zeiterkennung in h{\"o}heren Intervallbereichen (> 600ms) und ist am ehesten durch Fluktuationen der Aufmerksamkeit, des Ged{\"a}chtnisses, aber auch im Vergleich zu anderen Studien durch methodische Ans{\"a}tze zu erkl{\"a}ren. Durch die Koppelung des Audiostimulus an klare Rhythmusstrukturen weist diese Studie jedoch darauf hin, dass {\"U}berschneidungen zu anderen neuronalen Netzwerken existieren, die zur Kompensationsstrategie rekrutiert und nutzbar gemacht werden k{\"o}nnen. Dazu geh{\"o}ren etwa die Verarbeitung zeitlicher (Cerebellum) und musikperzeptiver Leistungen, wie etwa die Verarbeitung musikalischer Syntax (BA 6, 22, 44). Etwaige Wahrnehmungsdefizite k{\"o}nnen durch Mechanismen musiksyntaktischer Verarbeitung kompensiert werden, da zeitliche und syntaktische Strukturen in der Musik auf ihre Kongruenz hin abgeglichen und somit multineuronal mediiert werden (Paradigma der Zeit-Syntax-Kongruenz in der Musikwahrnehmung). Weiterhin sind vermutlich top-down-bottom-up-Prozesse als multimodale Interaktionen an diesem Kompensationsmechanismus beteiligt. Außerdem ist festzuhalten, dass das Krankheitsstadium nicht zwangsl{\"a}ufig mit einem st{\"a}rkeren Wahrnehmungsdefizit f{\"u}r zeitliche Strukturen einhergehen muss, obwohl - wenn auch noch tolerabel - mit Progression der Erkrankung dieses Kompensationsmodell {\"u}ber Prinzipien der Gestaltwahrnehmung zusammenbricht und es hier zu schlechteren perzeptiven Leistungen kommen kann. Die Ergebnisse der OFF-Testungen und jener unter DBS-Therapie lassen weiterhin aufgrund der kleinen Stichprobe keine klare Aussage zu und machen weitere Untersuchungen notwendig. Das physiologische Alter korreliert außerdem mit der sensorischen Leistung, die allerdings starken, individuellen Unterschieden ausgesetzt ist und von multifaktoriellen Voraussetzungen abh{\"a}ngt. Auch zeigt die Studie, dass Menschen mit einem hohen Musikverst{\"a}ndnis und einer musikalischen Ausbildung ein feineres Diskriminierungsverm{\"o}gen in der zeitlichen Verarbeitung besitzen, welches v.a. im zeitlich niedrigen Intervallbereich (< 500ms) evident wird.}, subject = {Parkinson}, language = {de} } @article{WagenhaeuserRickertSommeretal.2022, author = {Wagenh{\"a}user, Laura and Rickert, Vanessa and Sommer, Claudia and Wanner, Christoph and Nordbeck, Peter and Rost, Simone and {\"U}{\c{c}}eyler, Nurcan}, title = {X-chromosomal inactivation patterns in women with Fabry disease}, series = {Molecular Genetics \& Genomic Medicine}, volume = {10}, journal = {Molecular Genetics \& Genomic Medicine}, number = {9}, doi = {10.1002/mgg3.2029}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312795}, year = {2022}, abstract = {Background Although Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene (GLA), women may develop severe symptoms. We investigated X-chromosomal inactivation patterns (XCI) as a potential determinant of symptom severity in FD women. Patients and Methods We included 95 women with mutations in GLA (n = 18 with variants of unknown pathogenicity) and 50 related men, and collected mouth epithelial cells, venous blood, and skin fibroblasts for XCI analysis using the methylation status of the androgen receptor gene. The mutated X-chromosome was identified by comparison of samples from relatives. Patients underwent genotype categorization and deep clinical phenotyping of symptom severity. Results 43/95 (45\%) women carried mutations categorized as classic. The XCI pattern was skewed (i.e., ≥75:25\% distribution) in 6/87 (7\%) mouth epithelial cell samples, 31/88 (35\%) blood samples, and 9/27 (33\%) skin fibroblast samples. Clinical phenotype, α-galactosidase A (GAL) activity, and lyso-Gb3 levels did not show intergroup differences when stratified for X-chromosomal skewing and activity status of the mutated X-chromosome. Conclusions X-inactivation patterns alone do not reliably reflect the clinical phenotype of women with FD when investigated in biomaterial not directly affected by FD. However, while XCI patterns may vary between tissues, blood frequently shows skewing of XCI patterns.}, language = {en} } @phdthesis{Tschakarjan2008, author = {Tschakarjan, Senop}, title = {Wirksamkeit und Vertr{\"a}glichkeit von Cyclophosphamid bei Multipler Sklerose: Eine retrospektive Analyse}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-29005}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2008}, abstract = {Cyclophosphamid (Endoxan\&\#63720;) ist ein zytostatisches Medikament, welches wegen seiner immunsuppressiven Wirkung eine breite Anwendung in der Therapie systemischer Autoimmunerkrankungen findet. Es wird als Medikation bei schwerer chronisch-progressiver Multipler Sklerose empfohlen, um die weitere Progredienz einzuschr{\"a}nken oder zu verhindern. Bisherige klinische Studien {\"u}ber den Wert dieses therapeutischen Einsatzes liefern aber kontroverse Ergebnisse. Aus diesem Grund erschien es sinnvoll, die {\"u}ber einen l{\"a}ngeren Zeitraum an der Neurologischen Universit{\"a}tsklinik W{\"u}rzburg mit der Cyclophosphamid-Therapie bei MS-Patienten gesammelten Erfahrungen in einer retrospektiven Analyse darzustellen. Patienten und Methoden: Zwischen 1983 und 2000 wurden 118 MS Patienten (75 Frauen, 43 M{\"a}nner, durchschnittliches Alter zu Beginn der Therapie 46,6 ± 8,5 Jahre, durchschnittliche Krankheitsdauer zu Beginn der Therapie 9,7 ± 5,1 Jahre) mit Cyclophosphamid behandelt. 103 Patienten (87\%) litten an chronisch progressiver MS (69 SPMS, 25 PPMS, 5 CP, 4 CP mit RR) und 2 an einem schubf{\"o}rmigen Verlauf. Bei den meisten Patienten war eine rapide Verschlechterung (Mittlerer EDSS-Wert 6,5), mit Gefahr des Gehverlustes, Grund f{\"u}r den Therapiebeginn. Die Induktionstherapie wurde mit 350 mg/m2 K{\"o}rperoberfl{\"a}che Cyclophosphamid, zumeist in Kombination mit 1000mg Methylprednisolon, {\"u}ber 3 - 5 Tage eingeleitet und mit 600 - 1000 mg/m2 in 4 - 12-w{\"o}chigen Abst{\"a}nden beibehalten. Die EDSS-Werte wurden zu Beginn, j{\"a}hrlich und nach Beendigung der Therapie erfasst. Der Progressions-Index wurde als Quotient aus EDSS-Wert und Krankheitsdauer definiert. Ergebnisse: 63 Patienten erhielten Cyclophosphamid l{\"a}nger als ein Jahr und wurden eingehender untersucht. Die vorherrschenden Gr{\"u}nde f{\"u}r einen vorzeitigen Therapieabbruch waren weitere Progression (n=18) oder nicht tolerable Nebenwirkungen (n=9). Zwei Patienten nahmen die Therapie nach einer Pause wieder auf. Die l{\"a}nger als ein Jahr behandelten Patienten vertrugen die Therapie gut. Nebenwirkungen wurden von 82 \% berichtet, wobei die meisten als mild bezeichnet wurden (WHO Grad 1). Bei 9 \% waren sie schwerwiegend (WHO Grad 2), bei weiteren 10 \% f{\"u}hrten sie zum Therapieabbruch (WHO Grad 3). Die durchschnittliche Behandlungsdauer betrug 28,8 +/- 12,3 Monate, mit einer durchschnittlichen kumulativen Dosis von 12,3 ± 7,4 g. Der durchschnittliche Nachbeobachtungszeitraum betrug 39,3 ± 28,7 Monate. Der mittlere EDSS-Wert stieg signifikant von 5,0 auf 6,25 in den zwei Jahren vor Therapiebeginn, blieb stabil w{\"a}hrend der Behandlung und stieg nach Beendigung der Therapie weiter auf 7,0. Parallel dazu war der Progressions-Index am h{\"o}chsten bei Therapiebeginn mit 0,64, fiel zum Ende der Therapie auf 0,50 und sank weiter auf 0,44 w{\"a}hrend des Follow-Ups. 71\% blieben stabil w{\"a}hrend der Behandlung, 13\% verbesserten sich, und 16\% verschlechterten sich. Schlussfolgerung: Die Daten dieser retrospektiven Analyse zeigen, dass bei Versagen der Standardtherapie einer schweren chronisch-progredienten Multiplen Sklerose Cyclophosphamid in Form einer Induktionstherapie mit Auffrischzyklen alle 4-12 Wochen im Rahmen einer Eskalationstherapie effektiv und vertretbaren NW eingesetzt werden kann.}, subject = {Multiple Sclerosis Society of Canada}, language = {de} } @article{KraftDrechslerGunrebenetal.2014, author = {Kraft, Peter and Drechsler, Christiane and Gunreben, Ignaz and Nieswandt, Bernhard and Stoll, Guido and Heuschmann, Peter Ulrich and Kleinschnitz, Christoph}, title = {Von Willebrand Factor Regulation in Patients with Acute and Chronic Cerebrovascular Disease: A Pilot, Case-Control Study}, series = {PLoS ONE}, volume = {9}, journal = {PLoS ONE}, number = {6}, issn = {1932-6203}, doi = {10.1371/journal.pone.0099851}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119588}, pages = {e99851}, year = {2014}, abstract = {Background and Purpose In animal models, von Willebrand factor (VWF) is involved in thrombus formation and propagation of ischemic stroke. However, the pathophysiological relevance of this molecule in humans, and its potential use as a biomarker for the risk and severity of ischemic stroke remains unclear. This study had two aims: to identify predictors of altered VWF levels and to examine whether VWF levels differ between acute cerebrovascular events and chronic cerebrovascular disease (CCD). Methods A case-control study was undertaken between 2010 and 2013 at our University clinic. In total, 116 patients with acute ischemic stroke (AIS) or transitory ischemic attack (TIA), 117 patients with CCD, and 104 healthy volunteers (HV) were included. Blood was taken at days 0, 1, and 3 in patients with AIS or TIA, and once in CCD patients and HV. VWF serum levels were measured and correlated with demographic and clinical parameters by multivariate linear regression and ANOVA. Results Patients with CCD (158±46\%) had significantly higher VWF levels than HV (113±36\%, P<0.001), but lower levels than AIS/TIA patients (200±95\%, P<0.001). Age, sex, and stroke severity influenced VWF levels (P<0.05). Conclusions VWF levels differed across disease subtypes and patient characteristics. Our study confirms increased VWF levels as a risk factor for cerebrovascular disease and, moreover, suggests that it may represent a potential biomarker for stroke severity, warranting further investigation.}, language = {en} } @phdthesis{Nguyen2021, author = {Nguyen, Ngoc Bich}, title = {Vitamin D bei Patienten mit idiopathischen Parkinson-Syndrom}, doi = {10.25972/OPUS-22302}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223026}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {In einer Vielzahl von epidemiologischen Studien zeigten Patienten, die an einem idiopathischen Parkinson-Syndrom (IPS) erkrankt waren, erniedrigte Vitamin D-Serumspiegel (25-(OH)-Vit D). Die Rolle von Vitamin D im Knochenstoffwechsel ist weitgehend bekannt, allerdings konnten Assoziationen zwischen Vitamin D und chronischen Erkrankungen, die das Nervensystem sowie das kardiovaskul{\"a}re und immunologische System betreffen, nachgewiesen werden. In Tiermodellen konnten anti-oxidative Effekte von Vitamin D im Nervensystem gezeigt werden. In den letzten Jahren h{\"a}uften sich allerdings Studien, die gegen einen direkten Zusammenhang zwischen IPS und Vitamin D sprechen. Demnach stellt sich die Frage, ob dem geh{\"a}uften Auftreten eines Vitamin D-Mangels bei IPS-Patienten eine krankheitsspezifische Ursache zugrunde liegt oder ob diese lediglich ein unspezifisches krankheitsbegleitendes Ph{\"a}nomen darstellt. In der vorliegenden Arbeit wurden in einer retrospektiven Analyse Parkinson-Patienten aus der neurogerontopsychiatrischen Tagesklinik sowie der neurogeriatrischen Fr{\"u}hrehastation der Neurologischen Klinik der Universit{\"a}tsklinik W{\"u}rzburg hinsichtlich ihres 25-(OH)-Vit D-Serumspiegel mit zwei Kontrollgruppen bestehend aus Patienten mit psychiatrischer bzw. anderweitig neurologischer Erkrankung, die keiner Parkinson-Erkrankung entsprach, verglichen. Im Anschluss wurde auf m{\"o}gliche Konfounder sowie der Zusammenhang zwischen IPS-Risiko bzw. Krankheitsschwere und 25-(OH)-Vit D-Serumspiegel untersucht. Der mittlere 25-(OH)-Vit D-Serumspiegel der Neurologie-Gruppe war im Vergleich zur Psychiatrie-Gruppe signifikant niedriger. Der Unterschied zwischen IPS-Gruppe und Psychiatrie- bzw. Neurologie-Gruppe war nicht signifikant. Bei Hinzunahme von weiteren rekrutierten Parametern (Body-Mass-Index, Frailty, Sturzanamnese, Gehhilfe, CHA2DS2-VASc-Score, C-reaktives Protein, H{\"a}moglobin) konnte kein signifikanter Unterschied zwischen der Neurologie- und Psychiatrie-Gruppe mehr gefunden werden. Das Risiko sowie die Krankheitsschwere einer Parkinson-Erkrankung, gemessen am Hoehn-Yahr-Stadium und den erreichten Werten im MDS UPDRS III, korrelierten mit dem Vitamin D-Serumspiegel. Allerdings war auch hier nach Hinzunahme von Kovariaten wie Alter, Geschlecht und Krankheitsdauer der Effekt nicht mehr signifikant. Die Ergebnisse unterst{\"u}tzen die Annahme, dass die vorgefundenen niedrigen 25-(OH)-Vit D-Serumspiegel bei Parkinson-Patienten ein krankheitsbegleitendes Ph{\"a}nomen ist, das wom{\"o}glich durch die eingeschr{\"a}nkten motorischen F{\"a}higkeiten mit resultierend niedriger Sonnenexposition bedingt ist und durch zunehmende Kranheitsdauer und damit Krankheitsschwere verst{\"a}rkt wird. Da es sich jedoch beim IPS um eine Krankheit handelt, die zum Einen mit motorischen Einschr{\"a}nkungen und resultierend erh{\"o}htem Sturzrisiko einhergeht und zum Anderen vorwiegend Menschen h{\"o}heren Alters betrifft, besteht ein erh{\"o}htes Osteoporose- und sturzbedingtes Frakturrisiko, sodass ein Monitoring des Vitamin D-Serumspiegels sowie eine gegebenenfalls notwendige Vitamin D-Supplementierung weiterhin eine Rolle in der Behandlung von Parkinson-Patienten spielen.}, subject = {Vitamin D-Mangel}, language = {de} } @article{CapetianMuellerVolkmannetal.2020, author = {Capetian, Philipp and M{\"u}ller, Lorenz and Volkmann, Jens and Heckmann, Manfred and Erg{\"u}n, S{\"u}leyman and Wagner, Nicole}, title = {Visualizing the synaptic and cellular ultrastructure in neurons differentiated from human induced neural stem cells - an optimized protocol}, series = {International Journal of Molecular Sciences}, volume = {21}, journal = {International Journal of Molecular Sciences}, number = {5}, issn = {1422-0067}, doi = {10.3390/ijms21051708}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236053}, year = {2020}, abstract = {The size of the synaptic subcomponents falls below the limits of visible light microscopy. Despite new developments in advanced microscopy techniques, the resolution of transmission electron microscopy (TEM) remains unsurpassed. The requirements of tissue preservation are very high, and human post mortem material often does not offer adequate quality. However, new reprogramming techniques that generate human neurons in vitro provide samples that can easily fulfill these requirements. The objective of this study was to identify the culture technique with the best ultrastructural preservation in combination with the best embedding and contrasting technique for visualizing neuronal elements. Two induced neural stem cell lines derived from healthy control subjects underwent differentiation either adherent on glass coverslips, embedded in a droplet of highly concentrated Matrigel, or as a compact neurosphere. Afterward, they were fixed using a combination of glutaraldehyde (GA) and paraformaldehyde (PFA) followed by three approaches (standard stain, Ruthenium red stain, high contrast en-bloc stain) using different combinations of membrane enhancing and contrasting steps before ultrathin sectioning and imaging by TEM. The compact free-floating neurospheres exhibited the best ultrastructural preservation. High-contrast en-bloc stain offered particularly sharp staining of membrane structures and the highest quality visualization of neuronal structures. In conclusion, compact neurospheres growing under free-floating conditions in combination with a high contrast en-bloc staining protocol, offer the optimal preservation and contrast with a particular focus on visualizing membrane structures as required for analyzing synaptic structures.}, language = {en} } @phdthesis{Frank2021, author = {Frank, Franziska}, title = {Ver{\"a}nderung der Ranvier'schen Schn{\"u}rringarchitektur bei Patienten mit diabetischer Neuropathie}, doi = {10.25972/OPUS-21966}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219668}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {In der Krankheitsentstehung der diabetischen Neuropathie wird die paranodale Demyelinisierung als ein m{\"o}glicher Pathomechanismus diskutiert, wobei Studien mit Gewebeproben von Patienten aufgrund der Invasivit{\"a}t limitiert sind. In der vorliegenden Studie wurden periphere Nervenfasern in Hautbiopsien von Patienten mit diabetischer Neuropathie und in Patienten mit Diabetes mellitus ohne Neuropathie untersucht. Ziel war es, nodale und paranodale Ver{\"a}nderungen, wie eine Dispersion der paranodalen Proteine Caspr und Neurofascin oder der nodalen Na-Kan{\"a}le, zu detektieren und die Proben auf verl{\"a}ngerte Ranvier`sche Schn{\"u}rringe zu untersuchen. Es wurde die Hypothese {\"u}berpr{\"u}ft, dass paranodale Demyelinisierungen bei Patienten mit diabetischer Neuropathie in Hautbiopsien, als minimal-invasive Methode, nachweisbar sind. Hautproben von Patienten mit Diabetes mellitus ohne Neuropathie sollten zudem in einem fr{\"u}hen Krankheitsstadium untersucht werden. F{\"u}r die Untersuchung konnten 35 Patienten mit einer diabetischen Neuropathie, 17 Patienten mit Diabetes mellitus und 31 Kontrollen eingeschlossen werden. Immunfluoreszenzf{\"a}rbungen mit Antik{\"o}rpern gegen Caspr, Neurofascin und Natrium-Kan{\"a}len wurden zur Analyse der Ranvier`schen Schn{\"u}rringarchitektur durchgef{\"u}hrt und ausgewertet. Eine erh{\"o}hte Anzahl an verl{\"a}ngerten Schn{\"u}rringen, als Zeichen einer segmentalen Demyelinisierung, konnte in den Patienten mit diabetischer Neuropathie aber auch in Patienten mit Diabetes mellitus nachgewiesen werden. Weiterhin waren vermehrt Ver{\"a}nderungen der paranodalen Proteine, wie eine Dispersion von Caspr und Neurofascin in den Proben des Fingers der Patienten mit diabetischer Neuropathie sowie eine Dispersion von Neurofascin im Unterschenkel in beiden Patientengruppen nachweisbar. Interessanterweise waren einzelne Ver{\"a}nderungen auch in den gesunden Kontrollen auffindbar. Ver{\"a}nderungen der Schn{\"u}rringarchitektur lassen sich mithilfe der Hautbiopsie nachweisen und quantifizieren. Nodale und paranodale Ver{\"a}nderungen weisen auf demyelinisierende Prozesse in Patienten mit diabetischer Neuropathie hin und finden sich auch bereits in einem fr{\"u}hen Krankheitsstadium.}, subject = {Ranvier-Schn{\"u}rring}, language = {de} } @article{IpWischhusen2023, author = {Ip, Chi Wang and Wischhusen, J{\"o}rg}, title = {Versatile guardians: regenerative regulatory T cells in Parkinson's disease rodent models}, series = {Signal Transduction and Targeted Therapy}, volume = {8}, journal = {Signal Transduction and Targeted Therapy}, doi = {10.1038/s41392-023-01681-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357674}, year = {2023}, abstract = {No abstract available.}, language = {en} } @phdthesis{Pracher2004, author = {Pracher, Florian}, title = {Verhalten von C-Fasern der Maus w{\"a}hrend repetitiver elektrischer Stimulation : Bedeutung f{\"u}r die Fasererregbarkeit und die Rolle von Ih und Nav1.8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-7933}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2004}, abstract = {Die Axone im peripheren Nerven unterliegen w{\"a}hrend elektrischer Erregung kontinuierlichen dynamischen {\"A}nderungen ihrer Membraneigenschaften. Auf ein Aktionspotential folgt zun{\"a}chst die absolute und die relative Refrakt{\"a}rperiode, dann eine Periode der {\"U}bererregbarkeit („superexcitability") und schliesslich die Zeit der sp{\"a}ten Untererregbarkeit („delayed subexcitability"). Stimuliert man unmyelinisierte Nervenfasern {\"u}ber einen l{\"a}ngeren Zeitraum, so kommt es zu einer kontinuierlichen Erh{\"o}hung der Reizschwelle und damit einhergehend zu einer Zunahme der Latenz (="activity dependent slowing"). Dabei bestehen Unterschiede zwischen den einzelnen funktionellen Faserklassen. In dieser Arbeit konnte erstmals bei Ableitung von C-Fasern in C57BL/6 M{\"a}usen in vitro gezeigt werden, dass hitzeunempfindliche CM- und CMC-Fasern w{\"a}hrend elektrischer Stimulation eine geringere Latenzzunahme erfuhren als hitzesensible CMH- und CMHC-Fasern, auch in der Fasererholung bestanden Unterschiede zwischen beiden Gruppen. Dass in diesem Porozess Ih-Kan{\"a}le die Latenzzunahme v.a. bei den hitzeunempfindlichen Fasern limitieren, konnte in Experimenten mit den Ih-Kanal-Blockern CsCl (5mM) und ZD 7288 (1-50µM) gezeigt werden. In Ableitungen von C-Fasern in M{\"a}usen mit Inaktivierung des Gens von Nav1.8 kam es vor allem bei den hitzeempfindlichen Fasern h{\"a}ufiger zu Leitungsblocks, die Latenz{\"a}nderungen waren geringer als bei den Wildtyp-Tieren. Str{\"o}me durch diesen Kanal scheinen einerseits f{\"u}r die Leitungssicherheit der Fasern eine Rolle zu spielen, andererseits scheinen sie auch {\"u}ber einen erh{\"o}hten Natriumeinstrom w{\"a}hrend des Aktionspotentials und damit einer st{\"a}rkeren Aktivierung der Na+/K+-ATPase die Dauer der Refrakt{\"a}rperiode zu beeinflussen. Beide Mechanismen beeinflussen somit die Reizschwelle und damit die Erregbarkeit einer Faser. Sowohl die Kinetik von Ih als auch die von Nav1.8 wird durch Entz{\"u}ndungsmediatoren beeinflusst, damit werden sie zu interessanten Kandidaten bei der Sensibilisierung von Fasern im Rahmen von inflammatorischen und neuropathischen Schmerzen.}, language = {de} } @phdthesis{Schubert2011, author = {Schubert, Andrea Julia}, title = {Vergleich der Ergebnisse von Karotis-Stenting und -TEA an der Universit{\"a}tsklinik W{\"u}rzburg}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-67130}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2011}, abstract = {Der Vergleich der Verfahren Karotisstenting und Karotis-TEA an der Universit{\"a}tsklinik W{\"u}rzburg zeigt, dass bei richtiger Indikationsstellung sowie ausreichender Erfahrung der Neuroradiologen, CAS eine ernstzunehmende Alternative zu CEA darstellt. Besonderes Augenmerk lag dabei auf periprozeduale Komplikationen sowie Langzeitergebnisse bez{\"u}glich Tod,Insult und Restenose.}, subject = {Carotis}, language = {de} } @article{KrajkaNaujockPaulyetal.2021, author = {Krajka, Victor and Naujock, Maximilian and Pauly, Martje G. and Stengel, Felix and Meier, Britta and Stanslowsky, Nancy and Klein, Christine and Seibler, Philip and Wegner, Florian and Capetian, Philipp}, title = {Ventral Telencephalic Patterning Protocols for Induced Pluripotent Stem Cells}, series = {Frontiers in Cell and Developmental Biology}, volume = {9}, journal = {Frontiers in Cell and Developmental Biology}, issn = {2296-634X}, doi = {10.3389/fcell.2021.716249}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244607}, year = {2021}, abstract = {The differentiation of human induced pluripotent stem cells (hiPSCs) into specific cell types for disease modeling and restorative therapies is a key research agenda and offers the possibility to obtain patient-specific cells of interest for a wide range of diseases. Basal forebrain cholinergic neurons (BFCNs) play a particular role in the pathophysiology of Alzheimer's dementia and isolated dystonias. In this work, various directed differentiation protocols based on monolayer neural induction were tested for their effectiveness in promoting a ventral telencephalic phenotype and generating BFCN. Ventralizing factors [i.e., purmorphamine and Sonic hedgehog (SHH)] were applied at different time points, time intervals, and concentrations. In addition, caudal identity was prevented by the use of a small molecule XAV-939 that inhibits the Wnt-pathway. After patterning, gene expression profiles were analyzed by quantitative PCR (qPCR). Rostro-ventral patterning is most effective when initiated simultaneously with neural induction. The most promising combination of patterning factors was 0.5 μM of purmorphamine and 1 μM of XAV-939, which induces the highest expression of transcription factors specific for the medial ganglionic eminence, the source of GABAergic inter- and cholinergic neurons in the telencephalon. Upon maturation of cells, the immune phenotype, as well as electrophysiological properties were investigated showing the presence of marker proteins specific for BFCN (choline acetyltransferase, ISL1, p75, and NKX2.1) and GABAergic neurons. Moreover, a considerable fraction of measured cells displayed mature electrophysiological properties. Synaptic boutons containing the vesicular acetylcholine transporter (VACHT) could be observed in the vicinity of the cells. This work will help to generate basal forebrain interneurons from hiPSCs, providing a promising platform for modeling neurological diseases, such as Alzheimer's disease or Dystonia.}, language = {en} } @article{HaarmannVollmuthKollikowskietal.2023, author = {Haarmann, Axel and Vollmuth, Christoph and Kollikowski, Alexander M. and Heuschmann, Peter U. and Pham, Mirko and Stoll, Guido and Neugebauer, Hermann and Schuhmann, Michael K.}, title = {Vasoactive soluble endoglin: a novel biomarker indicative of reperfusion after cerebral large-vessel occlusion}, series = {Cells}, volume = {12}, journal = {Cells}, number = {2}, issn = {2073-4409}, doi = {10.3390/cells12020288}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304995}, year = {2023}, abstract = {Now that mechanical thrombectomy has substantially improved outcomes after large-vessel occlusion stroke in up to every second patient, futile reperfusion wherein successful recanalization is not followed by a favorable outcome is moving into focus. Unfortunately, blood-based biomarkers, which identify critical stages of hemodynamically compromised yet reperfused tissue, are lacking. We recently reported that hypoxia induces the expression of endoglin, a TGF-β co-receptor, in human brain endothelium in vitro. Subsequent reoxygenation resulted in shedding. Our cell model suggests that soluble endoglin compromises the brain endothelial barrier function. To evaluate soluble endoglin as a potential biomarker of reperfusion (-injury) we analyzed its concentration in 148 blood samples of patients with acute stroke due to large-vessel occlusion. In line with our in vitro data, systemic soluble endoglin concentrations were significantly higher in patients with successful recanalization, whereas hypoxia alone did not induce local endoglin shedding, as analyzed by intra-arterial samples from hypoxic vasculature. In patients with reperfusion, higher concentrations of soluble endoglin additionally indicated larger infarct volumes at admission. In summary, we give translational evidence that the sequence of hypoxia and subsequent reoxygenation triggers the release of vasoactive soluble endoglin in large-vessel occlusion stroke and can serve as a biomarker for severe ischemia with ensuing recanalization/reperfusion.}, language = {en} } @article{KunzePhamRaslanetal.2012, author = {Kunze, Ekkehard and Pham, Mirko and Raslan, Furat and Stetter, Christian and Lee, Jin-Yul and Solymosi, Laszlo and Ernestus, Ralf-Ingo and Hamilton Vince, Giles and Westermaier, Thomas}, title = {Value of Perfusion CT, Transcranial Doppler Sonography and Neurological Examination to detect delayed Vasospasm after aneurysmal Subarachnoid Hemorrhage [Research Article]}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76241}, year = {2012}, abstract = {Background If detected in time, delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) may be treated by balloon angioplasty or chemical vasospasmolysis in order to enhance cerebral blood flow (CBF) and protect the brain from ischemic damage. This study was conceived to compare the diagnostic accuracy of detailed neurological examination, Transcranial Doppler Sonography (TCD), and Perfusion-CT (PCT) to detect angiographic vasospasm. Methods The sensitivity, specificity, positive and negative predictive values of delayed ischemic neurological deterioration (DIND), pathological findings on PCT- maps, and accelerations of the mean flow velocity (MVF) were calculated. Results The accuracy of DIND to predict angiographic vasospasm was 0.88. An acceleration of MFV in TCD (>140 cm/s) had an accuracy of 0.64, positive PCT-findings of 0.69 with a higher sensitivity, and negative predictive value than TCD. Interpretation Neurological assessment at close intervals is the most sensitive and specific parameter for cerebral vasospasm. PCT has a higher accuracy, sensitivity and negative predictive value than TCD. If detailed neurological evaluation is possible, it should be the leading parameter in the management and treatment decisions. If patients are not amenable to detailed neurological examination, PCT at regular intervals is a helpful tool to diagnose secondary vasospasm after aneurysmal SAH.}, subject = {Medizin}, language = {en} } @article{FrankeBieberStolletal.2021, author = {Franke, Maximilian and Bieber, Michael and Stoll, Guido and Schuhmann, Michael Klaus}, title = {Validity and Efficacy of Methods to Define Blood Brain Barrier Integrity in Experimental Ischemic Strokes: A Comparison of Albumin Western Blot, IgG Western Blot and Albumin Immunofluorescence}, series = {Methods and Protocols}, volume = {4}, journal = {Methods and Protocols}, number = {1}, issn = {2409-9279}, doi = {10.3390/mps4010023}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234214}, year = {2021}, abstract = {The clinical and preclinical research of ischemic strokes (IS) is becoming increasingly comprehensive, especially with the emerging evidence of complex thrombotic and inflammatory interactions. Within these, the blood brain barrier (BBB) plays an important role in regulating the cellular interactions at the vascular interface and is therefore the object of many IS-related questions. Consequently, valid, economic and responsible methods to define BBB integrity are necessary. Therefore, we compared the three ex-vivo setups albumin Western blot (WB), IgG WB and albumin intensity measurement (AIM) with regard to validity as well as temporal and economic efficacy. While the informative value of the three methods correlated significantly, the efficacy of the IgG WB dominated.}, language = {en} } @article{SilwedelHuettenSpeeretal.2023, author = {Silwedel, Christine and H{\"u}tten, Matthias C. and Speer, Christian P. and H{\"a}rtel, Christoph and Haarmann, Axel and Henrich, Birgit and Tijssen, Maud P. M. and Alnakhli, Abdullah Ahmed and Spiller, Owen B. and Schlegel, Nicolas and Seidenspinner, Silvia and Kramer, Boris W. and Glaser, Kirsten}, title = {Ureaplasma-driven neonatal neuroinflammation: novel insights from an ovine model}, series = {Cellular and Molecular Neurobiology}, volume = {43}, journal = {Cellular and Molecular Neurobiology}, number = {2}, doi = {10.1007/s10571-022-01213-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324285}, pages = {785-795}, year = {2023}, abstract = {Ureaplasma species (spp.) are considered commensals of the adult genitourinary tract, but have been associated with chorioamnionitis, preterm birth, and invasive infections in neonates, including meningitis. Data on mechanisms involved in Ureaplasma-driven neuroinflammation are scarce. The present study addressed brain inflammatory responses in preterm lambs exposed to Ureaplasma parvum (UP) in utero. 7 days after intra-amniotic injection of UP (n = 10) or saline (n = 11), lambs were surgically delivered at gestational day 128-129. Expression of inflammatory markers was assessed in different brain regions using qRT-PCR and in cerebrospinal fluid (CSF) by multiplex immunoassay. CSF was analyzed for UP presence using ureB-based real-time PCR, and MRI scans documented cerebral white matter area and cortical folding. Cerebral tissue levels of atypical chemokine receptor (ACKR) 3, caspases 1-like, 2, 7, and C-X-C chemokine receptor (CXCR) 4 mRNA, as well as CSF interleukin-8 protein concentrations were significantly increased in UP-exposed lambs. UP presence in CSF was confirmed in one animal. Cortical folding and white matter area did not differ among groups. The present study confirms a role of caspases and the transmembrane receptors ACKR3 and CXCR4 in Ureaplasma-driven neuroinflammation. Enhanced caspase 1-like, 2, and 7 expression may reflect cell death. Increased ACKR3 and CXCR4 expression has been associated with inflammatory central nervous system (CNS) diseases and impaired blood-brain barrier function. According to these data and previous in vitro findings from our group, we speculate that Ureaplasma-induced caspase and receptor responses affect CNS barrier properties and thus facilitate neuroinflammation.}, language = {en} } @article{SilwedelSpeerHaarmannetal.2019, author = {Silwedel, Christine and Speer, Christian P. and Haarmann, Axel and Fehrholz, Markus and Claus, Heike and Schlegel, Nicolas and Glaser, Kirsten}, title = {Ureaplasma species modulate cytokine and chemokine responses in human brain microvascular endothelial cells}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {14}, issn = {1422-0067}, doi = {10.3390/ijms20143583}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201848}, year = {2019}, abstract = {Ureaplasma species are common colonizers of the adult genitourinary tract and often considered as low-virulence commensals. Intraamniotic Ureaplasma infections, however, facilitate chorioamnionitis and preterm birth, and cases of Ureaplasma-induced neonatal sepsis, pneumonia, and meningitis raise a growing awareness of their clinical relevance. In vitro studies are scarce but demonstrate distinct Ureaplasma-driven impacts on immune mechanisms. The current study addressed cytokine and chemokine responses upon exposure of native or lipopolysaccharide (LPS) co-stimulated human brain microvascular endothelial cells (HBMEC) to Ureaplasma urealyticum or U. parvum, using qRT-PCR, RNA sequencing, multi-analyte immunoassay, and flow cytometry. Ureaplasma exposure in native HBMEC reduced monocyte chemoattractant protein (MCP)-3 mRNA expression (p < 0.01, vs. broth). In co-stimulated HBMEC, Ureaplasma spp. attenuated LPS-evoked mRNA responses for C-X-C chemokine ligand 5, MCP-1, and MCP-3 (p < 0.05, vs. LPS) and mitigated LPS-driven interleukin (IL)-1α protein secretion, as well as IL-8 mRNA and protein responses (p < 0.05). Furthermore, Ureaplasma isolates increased C-X-C chemokine receptor 4 mRNA levels in native and LPS co-stimulated HBMEC (p < 0.05). The presented results may imply immunomodulatory capacities of Ureaplasma spp. which may ultimately promote chronic colonization and long-term neuroinflammation.}, language = {en} } @phdthesis{Schroeder2002, author = {Schr{\"o}der, Barbara Christiane}, title = {Untersuchungen zur pharmakologischen Hemmung der Zytokin-induzierbaren NO-Synthase in kultivierten Mikroglia-Zellen und Makrophagen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-6837}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2002}, abstract = {Mikrogliazellen fungieren als Makrophagen im ZNS, wo sie verschiedene Abwehrfunktionen gegen Mikroorganismen {\"u}bernehmen, Zellreste beseitigen und eine wichtige Rolle bei Autoimmunerkrankungen des ZNS spielen. Mikrogliazellen exprimieren unter anderem eine NO-Synthase, die durch Zytokine induzierbar ist. Da NO f{\"u}r Neurone und Oligodendrozyten toxisch sein kann, waren wir daran interessiert, Substanzen zu identifizieren, die eine hemmende Wirkung auf die zytokin-induzierbare NO-Synthase in Makrophagen und Mikrogliazellen haben. Unter den getesteten Zytokinen, Wachstumsfaktoren, Neuropeptiden, Chemokinen und Tyrosinkinase-Hemmern war lediglich der Tyrosinkinaseinhibitor Methyl-2,5-Dihydroxycinnamat als NO-Synthase-Hemmstoff erfolgreich. Da die NO-Produktion eine Rolle in der Pathogenese der Experimentellen Autoimmunen Enzephalomyelitis (EAE) und der Experimentellen Autoimmunen Neuritis (EAN) spielt, war auch die M{\"o}glichkeit eines therapeutischen Einsatzes des NO-Synthase-Inhibitors von Interesse. Dieser scheint jedoch im Falle von Methyl-2,5-Dihydroxycinnamat aufgrund seiner Toxizit{\"a}t in h{\"o}herer Konzentration und des daraus resultierenden engen Therapeutischen Dosisfensters sehr eingeschr{\"a}nkt.}, language = {de} } @phdthesis{HoppKraemer2016, author = {Hopp-Kr{\"a}mer, Sarah}, title = {Untersuchungen zur Pathophysiologie und therapeutischer Relevanz des Blutgerinnungsfaktors XII nach experimentellem Sch{\"a}del-Hirn-Trauma}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144421}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Das Sch{\"a}del-Hirn-Trauma (SHT) entsteht durch {\"a}ußere Gewalteinwirkung auf den Kopf und verursacht mechanisch eine Sch{\"a}digung des Hirngewebes. Zus{\"a}tzlich tragen sekund{\"a}re Pathomechanismen, wie Entz{\"u}ndungsprozesse und die Sch{\"a}digung der Blut-Hirn-Schranke (BHS), dazu bei, dass sich das initial gesch{\"a}digte L{\"a}sionsareal im Laufe der Zeit vergr{\"o}ßert. Vor allem bei jungen Erwachsenen ist das SHT eine der h{\"a}ufigsten Ursachen f{\"u}r bleibende Behinderungen und Todesf{\"a}lle. Aufgrund der schweren Auswirkungen des SHT und der bislang fehlenden Therapieoptionen ist die Identifizierung neuer Zielstrukturen f{\"u}r eine kausale Therapie von gr{\"o}ßter Bedeutung. Ausgehend von tierexperimentellen Studien ist das Kallikrein-Kinin-System (KKS) ein besonders erfolgversprechender Angriffspunkt zur Behandlung des SHT. Die Aktivierung des KKS {\"u}ber den Gerinnungsfaktor XII (FXII) und die darauf folgende Bildung von Bradykinin sind mit dem Entstehen von Hirn{\"o}demen und Entz{\"u}ndungsreaktionen assoziiert. Vorangegangene Studien haben weiterhin die Frage aufgeworfen, ob und in welchem Maße thrombotische Prozesse einen Einfluss auf die Pathophysiologie und die sekund{\"a}ren Hirnsch{\"a}digungen nach SHT haben. Da FXII sowohl das KKS als auch die intrinsische plasmatische Gerinnungskaskade initiiert und somit zur Fibrinbildung beitr{\"a}gt, stand FXII im Mittelpunkt der Untersuchungen dieser Dissertation. Die vorliegende Arbeit besch{\"a}ftigt sich mit den Fragen, (I) inwiefern FXII eine Rolle bei der sekund{\"a}ren Hirnsch{\"a}digung nach Trauma spielt und (II) ob thrombotische Prozesse ein pathophysiologisches Merkmal nach Trauma darstellen. In zwei unterschiedlichen Trauma-Modellen wurden FXII-defiziente Tiere und mit einem spezifischen Inhibitor des aktivierten FXII (FXIIa) behandelte Tiere gegen Kontrolltiere nach SHT verglichen. Die Analyse der funktionellen Ausfallerscheinungen und des Ausmaßes an neuronaler Degeneration zeigte, dass FXII-Defizienz und FXIIa-Inhibition vor den Auswirkungen eines SHT sch{\"u}tzen. Als zugrundeliegende Mechanismen wurden die Reduktion von thrombotisch verschlossenen Gef{\"a}ßen in der Mikrovaskulatur des Gehirns sowie der Schutz vor BHS-St{\"o}rungen und verringerte inflammatorische Prozesse identifiziert. Weiterhin wurde festgestellt, dass eine Blockade der intrinsischen Gerinnungskaskade {\"u}ber FXII keine intrazerebralen Blutungen ausl{\"o}st. In Gewebeproben von Patienten mit SHT wurde gezeigt, dass Thrombozytenaggregate auch im klinischen Verlauf auftreten und sich somit die tierexperimentellen Befunde auf die humane Situation {\"u}bertragen lassen. Insgesamt tragen die Ergebnisse dazu bei, die komplexen und vielf{\"a}ltigen Pathomechanismen nach SHT besser zu verstehen und vor allem die Relevanz thrombo-inflammatorischer Prozesse nach SHT aufzuzeigen. Die gezielte Blockade des FXII(a) k{\"o}nnte als therapeutisches Prinzip zur Abschw{\"a}chung der Sekund{\"a}rschaden nach SHT geeignet sein.}, subject = {Sch{\"a}del-Hirn-Trauma}, language = {de} } @phdthesis{Leinweber2022, author = {Leinweber, Jonas}, title = {Untersuchung zur pathophysiologischen Rolle und therapeutischen Relevanz der neuen Inhibitoren der plasmatischen Blutgerinnung Agaphelin und Ixolaris im experimentellen Schlaganfallmodell der Maus}, doi = {10.25972/OPUS-25292}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252921}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Beim isch{\"a}mischen Schlaganfall f{\"u}hrt ein thrombotischer Verschluss von gehirnversorgenden Arterien zu einer akuten Durchblutungsst{\"o}rung, mit der Folge von neurologischen Defiziten. Prim{\"a}res Therapieziel ist es, diese Blutgerinnsel aufzul{\"o}sen, um die Sauerstoffversorgung des Gehirns wiederherzustellen und den isch{\"a}mischen Hirnschaden zu begrenzen. Dazu stehen die intraven{\"o}sen Thrombolyse mit rt-PA (rekombinanter Gewebe-Plasminogen-Aktivator) sowie die endovaskul{\"a}re mechanische Thrombektomie zur Verf{\"u}gung. H{\"a}ufig kann ein Schlaganfall, trotz erfolgreicher Rekanalisation der Gef{\"a}ße, zu einer weiteren Gr{\"o}ßenzunahme des Infarktes und neurologischen Defiziten bei den Patienten f{\"u}hren. Diese Gr{\"o}ßenzunahme beruht zum einen auf einem sich entwickelnden Hirn{\"o}dem und zum anderen auf entz{\"u}ndlichen Prozessen. Zahlreiche Hinweise deuten darauf hin, dass der Schlaganfall ein Zusammenspiel aus thrombotischen und entz{\"u}ndlichen Ereignissen ist, ein Ph{\"a}nomen, das als Thromboinflammation bezeichnet wird. Aufgrund der begrenzten Behandlungsm{\"o}glichkeiten ist die Entwicklung neuer Therapieans{\"a}tze f{\"u}r den isch{\"a}mischen Schlaganfall besonders wichtig. Agaphelin und Ixolaris sind Proteine aus den Speicheldr{\"u}sen von H{\"a}matophagen, f{\"u}r welche in fr{\"u}heren Studien eine starke antithrombotische Wirkung bei gleichzeitig geringem Blutungsrisiko nachgewiesen wurde. Diese m{\"o}glichen antithrombotischen Effekte wurden in dieser Studie im Hinblick auf ihre Wirksamkeit und Sicherheit im Mausmodell der zerebralen Isch{\"a}mie untersucht. Die Behandlung der M{\"a}use mit Agaphelin 1 Stunde nach transienter Okklusion der Arteria cerebri media (tMCAO) f{\"u}hrte zu kleineren Schlaganfallvolumina und geringeren neurologischen Defiziten an Tag 1 nach dem Schlaganfall. Die Mortalit{\"a}t der M{\"a}use war bis Tag 7 deutlich gesunken. Aus klinischer Sicht ist ebenfalls relevant, dass der starke antithrombotische Effekt von Agaphelin im Mausmodell nicht mit einem erh{\"o}hten Risiko f{\"u}r intrazerebrale Blutungen einherging. Diesem protektiven Effekt von Agaphelin lagen eine verminderte intrazerebrale Thrombusbildung, eine abgeschw{\"a}chte Entz{\"u}ndungsantwort und eine Stabilisierung der Blut-Hirn-Schranke sowie eine Reduzierung der Apoptose zugrunde. Nach der Gabe von Ixolaris 1 Stunde nach tMCAO waren zwar signifikant geringere Infarktgr{\"o}ßen messbar, diese f{\"u}hrten allerdings nicht zu einer Verbesserung der neurologischen Defizite. Zudem verursachte die Gabe von Ixolaris schon 24 Stunden nach tMCAO erhebliche intrazerebrale Blutungen und auch die Mortalit{\"a}t der M{\"a}use war zu diesem Zeitpunkt bereits erh{\"o}ht. Aufgrund dieser massiven Nebenwirkungen scheint Ixolaris kein geeigneter Kandidat f{\"u}r eine humane Anwendung zu sein. Bei Agaphelin hingegen k{\"o}nnte es sich um einen vielversprechenden Kandidaten f{\"u}r die Behandlung des isch{\"a}mischen Schlaganfalls handeln. Vor einer m{\"o}glichen Testung von Agaphelin in klinischen Studien, sind weitere translationale Untersuchungen notwendig, um ein noch pr{\"a}ziseres Verst{\"a}ndnis f{\"u}r die Wirksamkeit und Sicherheit von Agaphelin zu gewinnen. Insgesamt stellt die Hemmung thromboinflammatorischer Prozesse, ohne eine Erh{\"o}hung der Blutungskomplikationen, eine vielversprechende Option zur Behandlung des isch{\"a}mischen Schlaganfalls dar.}, subject = {Schlaganfall}, language = {de} } @phdthesis{Wilhelmi2024, author = {Wilhelmi, Kai Alexander}, title = {Untersuchung von Ver{\"a}nderungen der myelinisierten Nervenfasern durch Entmarkung in Haut- und Nervenbiopsien von Patienten mit Polyneuropathie}, doi = {10.25972/OPUS-36004}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-360046}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {In dieser Arbeit wurde durch das immunhistochemische Anf{\"a}rben von nodalen (Natriumkan{\"a}le, NF), paranodalen (Caspr, NF) und internodalen (MBP) Proteinen der in Fingerhautbiopsien vorhanden Nervenfasern untersucht, ob eine Ver{\"a}nderung der typischen Verteilungsmuster dieser Proteine, eine demyelinisierende Polyneuropathie anzeigen kann. Dazu wurden am Universit{\"a}tsklinikum W{\"u}rzburg prospektiv 93 Polyneuropathie-Patienten und 25 Kontrollpersonen rekrutiert. Bei allen Patienten wurden Hautstanzbiospien am Zeigefinger durchgef{\"u}hrt. Bei 35 Patienten mit schweren oder unklaren Verl{\"a}ufen, wurden konsiliarisch Nervus suralis Biopsien durchgef{\"u}hrt. Aus einem Abschnitt von 27 dieser Biopsien, konnten im Rahmen dieser Arbeit Zupfnervenpr{\"a}parate angefertigt und analog zu den Hautbiopsien ausgewertet werden. Aus der Routinediagnostik der Klinik flossen weiterhin die Ergebnisse der elektrophysiologischen Routinediagnostik und der Histologiebefund der Nervus suralis Biopsien in die Auswertung ein. Zusammenfassend kamen ver{\"a}nderte Natriumkanalbanden in Fingerhautbiopsien signifikant h{\"a}ufiger bei Patienten mit elektrophysiologisch als demyelinisierend befundeten Polyneuropathien, als bei Patienten mit elektrophysiologisch als axonal befundeten Polyneuropathien vor. Vielfach fanden sich ver{\"a}nderte Natriumkanalbanden inmitten para- und internodal unauff{\"a}lliger Schn{\"u}rringe und umgekehrt. Diese Beobachtung st{\"u}tzt die bereits in Vorarbeiten vorgeschlagene und in der aktuellen Leitlinie zur Diagnostik f{\"u}r Polyneuropathien aufgegriffene Entit{\"a}t der Paranodopathien (Uncini, Susuki, \& Yuki, 2013). M{\"o}glich w{\"a}re, dass eine ver{\"a}nderte Verteilung der Natriumkan{\"a}le die schnelle Leitf{\"a}higkeit beeintr{\"a}chtigen und somit trotz intakter Bemarkung, elektrophysiologisch das Bild einer demyelinisierenden Neuropathie vermittelt. Ein direkter Zusammenhang zwischen dem Auftreten von doppelten und verl{\"a}ngerten Natriumkanalbanden und einzelnen Messwerten (z.B. Amplituden und Latenzzeiten) fand sich nicht. Auch in den Zupfnervenpr{\"a}paraten der Nervus suralis Biopsien, konnten o.g. Verteilungsmuster untersucht werden. Deren Vorkommen zeigte sich als unabh{\"a}ngig vom elektrophysiologischen und histologischen Befund, von der {\"A}tiologie der PNP und von den gefundenen Ver{\"a}nderungen in den Hautbiopsien des betreffenden Patienten.}, subject = {Polyneuropathie}, language = {de} } @phdthesis{Leinfelder2022, author = {Leinfelder, Teresa}, title = {Untersuchung von Trainingseffekten bei der Verwendung einer auditorischen P300-basierten EEG Gehirn-Computer Schnittstelle mittels fMRI Analyse}, doi = {10.25972/OPUS-29068}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290683}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {In dieser Dissertation untersuchten wir die neuronalen Korrelate des Training-Effektes einer auditorischen P300 Gehirn-Computer Schnittstelle mittels fMRI Analyse in einem pr{\"a}-post Design mit zehn gesunden Testpersonen. Wir wiesen in drei Trainings-sitzungen einen Trainingseffekt in der EEG-Analyse der P300 Welle nach und fanden entsprechende Kontraste in einer pr{\"a}-post Analyse von fMRI Daten, wobei in allen f{\"u}nf Sitzungen das gleiche Paradigma verwendet wurde. In der fMRI Analyse fanden wir fol-gende Ergebnisse: in einem Target-/ Nichttarget Kontrast zeigte sich verst{\"a}rkte Aktivie-rung in Generatorregionen der P300 Welle (temporale und inferiore frontale Regionen) und interessanterweise auch in motorassoziierten Arealen, was h{\"o}here kognitiver Pro-zesse wie Aufmerksamkeitslenkung und Arbeitsspeicher widerspiegeln k{\"o}nnte. Der Kon-trast des Trainingseffektes zeigte nach dem Training einen st{\"a}rkeren Rebound Effekt im Sinne einer verst{\"a}rkten Aktivierung in Generatorregionen der P300 Welle, was eine ver-besserte Erkennung und Prozessierung von Target-Stimuli reflektieren k{\"o}nnte. Eine Ab-nahme von Aktivierung in frontalen Arealen in diesem Kontrast k{\"o}nnte durch effizientere Abl{\"a}ufe kognitiver Prozesse und des Arbeitsged{\"a}chtnis erkl{\"a}rt werden.}, subject = {Gehirn-Computer-Schnittstelle}, language = {de} } @phdthesis{Schubert2017, author = {Schubert, Anna-Lena}, title = {Untersuchung potenzieller Biomarker in Haut- und Nervenbiopsaten von Patienten mit schmerzhaften und schmerzlosen Polyneuropathien}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-153254}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Polyneuropathien sind eine {\"a}tiologisch heterogene Erkrankung des peripheren Nervensystems. In bis zu 30\% der F{\"a}lle ist eine Zuordnung zu einem bestimmten PNP Subtyp auch nach aufw{\"a}ndiger und zum Teil invasiver Diagnostik nicht m{\"o}glich. Bislang fehlt ein diagnostischer Biomarker bei PNP, der z.B. bei der Unterscheidung zwischen einzelnen diagnostischen Subgruppen oder entz{\"u}ndlichen und nicht-entz{\"u}ndlichen Erkrankungsformen helfen k{\"o}nnte. In einer prospektiven Studie mit insgesamt 97 Patienten mit Neuropathien verschiedenster {\"A}tiologie und 17 gesunden Kontrollpersonen erstellten wir Genexpressionsprofile von inflammatorischen Markern und Markern der Regeneration peripherer Nerven in Haut- und N. suralis-Biopsaten. Es wurden Inflammationsmarker (TAC1, CRMP2, AIF1, IL-6) und Marker, die in die Regeneration peripherer Nerven involviert sind (SCD, Netrin-1, DCC, UNC5H2, NEO1, Netrin-G1, Netrin-G2), mittels qRT-PCR untersucht. Alle Patienten erhielten eine N. suralis-Biopsie und/oder eine Hautbiopsie von Ober- beziehungsweise Unterschenkel. Weder in den Haut- noch in den N. suralis-Biopsaten konnten Unterschiede in der Genexpression dieser Marker zwischen einzelnen diagnostischen Subgruppen gefunden werden. Der Inflammationsmarker AIF1 war jedoch in Patienten-Hautproben sowohl proximal als auch distal h{\"o}her exprimiert als bei gesunden Kontrollpersonen (p < 0,05 bzw. p < 0,01). Zudem fand sich in den Hautproben von PNP-Patienten eine deutlich reduzierte Genexpression von Regenerationsmarkern aus der Netrin-Familie verglichen mit den Hautproben gesunder Probanden (Netrin-1, DCC, UNC5H2, NEO1 sowie Netrin-G1 und G2; p < 0,05 bis p < 0,001). Ferner wies Netrin-1 in distalen Hautproben bei Patienten mit einer entz{\"u}ndlichen PNP eine niedrigere Genexpression auf, als bei Patienten mit einer nicht-entz{\"u}ndlichen Erkrankungsform (p < 0,05). Die Genexpression von NEO1 in distalen Hautproben war bei schmerzloser PNP und gesunden Kontrollpersonen h{\"o}her als bei schmerzhafter PNP (p < 0,05). Sowohl eine Erh{\"o}hung bestimmter Inflammationsmarker als auch eine Verminderung von Regenerationsmarkern peripherer Nerven k{\"o}nnen bei der Pathophysiologie von Polyneuropathien involviert sein. Insbesondere Mitglieder der Netrin-Familie scheinen eine komplexe Rolle f{\"u}r das Axonwachstum, jedoch auch f{\"u}r entz{\"u}ndliche Prozesse zu spielen.}, subject = {Biomarker}, language = {de} } @phdthesis{Kilgue2019, author = {Kilgu{\´e}, Alexander Pina}, title = {Untersuchung der Schn{\"u}rringarchitektur in Hautbiopsien von Patienten mit Polyneuropathien}, doi = {10.25972/OPUS-17690}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176900}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {Polyneuropathien (PNP) k{\"o}nnen zu einer Reorganisation der nodalen und paranodalen Membranproteine mit in der Folge fehlerhafter Axon-Schwann-Zell-Interaktionen f{\"u}hren. Im Rahmen der Basisdiagnostik einer Polyneuropathie haben sich Hautbiopsien als weniger invasive Erg{\"a}nzung zur Suralisbiopsie mit einem geringen Nebenwirkungsrisiko entwickelt. Die Morphologie dermaler Nervenfasern l{\"a}sst sich mittels Immunohistochemie in der Haut gezielt untersuchen. In der vorliegenden Studie wurde die Hypothese {\"u}berpr{\"u}ft, ob pathologisch auff{\"a}llige Ranvier-Schn{\"u}rringe Hinweise auf Unterschiede bei PNP-Subgruppen und Sch{\"a}digungsmuster liefern. Daneben wurden die Hypothesen {\"u}berpr{\"u}ft, ob Entz{\"u}ndungszellen an myelinisierten Nervenfasern kolokalisiert nachweisbar sind und ob Hautbiopsien einen zus{\"a}tzlichen Nutzen zur PNP-Basisdiagnostik liefern. Von 92 Patienten wurden Hautbiopsien von Finger, Ober-und Unterschenkel wurden entnommen, daraus gewonnene myelinisierte Nervenfasern der Haut wurden mittels immunohistochemischer Antik{\"o}rper-Doppelf{\"a}rbungen analysiert. Neuropathische Sch{\"a}digungsformen vom axonalen und demyelinisierenden Typ zeigten keine signifikante Korrelation mit dem Auftreten von verl{\"a}ngerten Ranvier-Schn{\"u}rringen und der Dispersion charakteristischer paranodaler und nodaler Membranproteine (Neurofascin, Caspr, Pan-Natrium-Kan{\"a}le). Kolokalisierte Entz{\"u}ndungszellen an myelinisierten Nervenfasern bei entz{\"u}ndlichen PNP ließen sich nicht nachweisen. PNP-Subgruppen zeigten keine signifikanten Unterschiede in Hinblick auf eine pathologische nodale oder paranodale Organisation. Der Zusatznutzen von Hautbiopsien in der PNP-Basisdiagnostik kann in Bezug auf die vorliegende Arbeit nur eingeschr{\"a}nkt best{\"a}tigt werden. Da Fingerbiopsien im Vergleich zu Proben aus Ober- und Unterschenkel eine signifikant h{\"o}here Dichte myelinisierter Nervenb{\"u}ndel pro Fl{\"a}che Dermis aufweisen, w{\"a}re es durchaus denkbar, zuk{\"u}nftig prim{\"a}r Fingerbiopsien zu entnehmen um diese auf etwaige pathologische Ver{\"a}nderungen infolge neuropathischer Erkrankungen zu untersuchen. Anamnese, Basisdiagnostik und klinischer Befund erbringen nach wie vor den wichtigsten Beitrag zur PNP-Diagnostik.}, subject = {Polyneuropathie}, language = {de} } @phdthesis{Frank2019, author = {Frank, Johanna}, title = {Untersuchung der Kleinfaserpathologie beim Fibromyalgie-Syndrom}, publisher = {Annals of Neurology, The Journal of Rheumatology}, doi = {10.25972/OPUS-19265}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-192653}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {Die Studienergebnisse st{\"u}tzen das Konzept, dass das periphere Nervensystem zu Schmerzen beim Fibromyalgie-Syndrom (FMS) beitr{\"a}gt. An der Neurologischen Universit{\"a}tsklinik W{\"u}rzburg wurden 53 FMS Patientinnen und 35 gesunde Kontrollen rekrutiert, ausf{\"u}hrlich anamnestiziert inklusive spezieller Schmerzfrageb{\"o}gen, neurologisch und mittels spezieller Tests auf eine St{\"o}rung der kleinkalibrigen A-delta- und C-Nervenfasern untersucht. Hierzu geh{\"o}rte eine quantitative sensorische Testung mit Pleasant touch Untersuchung und die schmerz-assoziierten elektrisch-evoziierten Potentiale f{\"u}r die Kleinfaserfunktion und die corneale confocale Mikroskopie, sowie die Analyse von Hautstanbiopsien f{\"u}r die Kleinfasermorphologie. Im Unterschied zu gesunden Kontrollen wiesen die FMS Patientinnen eine Reduktion, als auch eine Funktions{\"a}nderung der kleinkalibrigen Nervenfasern auf. Des Weiteren konnten wir aus der heterogenen Patientenpopulation anhand von unterschiedlichen Nervenfaserdichten der Haut eine Subgruppe mit generalisierter Reduktion der Hautinnervation identifizieren, die besonders schwer betroffen ist. Diese Subgruppenanalysen k{\"o}nnen k{\"u}nftig von großer Bedeutung f{\"u}r die Therapiewahl sein.}, subject = {Fibromyalgie}, language = {de} } @phdthesis{Oezkent2022, author = {{\"O}zkent, Helena}, title = {Untersuchung der Beteiligung der kleinen Nervenfasern bei Patient/-innen mit Antik{\"o}rper-assoziierten Neuropathien}, doi = {10.25972/OPUS-26929}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-269293}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {In der vorliegenden Studie wurden QST, QSART, Hautbiopsien und Frageb{\"o}gen genutzt, um die Beteiligung kleiner Nervenfasern bei verschiedenen Formen der Immunneuropathien zu untersuchen. Wir konnten hierbei eine signifikante Beeintr{\"a}chtigung der thermischen Reizleitung bei CIDP- und MADSAM-Patient/-innen nachweisen sowie eine signifikant reduzierte Schweißproduktion am distalen Unterschenkel bei MADSAM-Patient/-innen. Diese Ergebnisse belegen in allen drei Untergruppen der immunvermittelten Neuropathien eine Beteiligung kleiner auch unmyelinisierter Nervenfasertypen. MADSAM- und CIDP-Patient/-innen wiesen in der QST ein {\"a}hnliches Sch{\"a}digungsmuster auf. Dagegen unterschieden sie sich signifikant in der QSART. Diese Ergebnisse k{\"o}nnen als weiterer Hinweis auf unterschiedliche zugrundeliegende Pathomechanismen verstanden werden. MMN-Patient/-innen wiesen insgesamt die geringste Small-Fiber-Beteiligung in den quantitativen Testungen auf. Auch lagen bei MMN-Patient/-innen durchschnittlich die geringsten Schmerz-Scores und autonomen Symptome vor. Es zeigten sich wenig signifikante Unterschiede zwischen seropositiven und seronegativen Neuropathie-Patient/-innen. Diese jedoch best{\"a}tigten unsere Hypothese einer etwas geringeren Small-Fiber-Beteiligung bei seropositiven Patient/-innen. Bei der Vielzahl an unterschiedlichen Pathomechanismen innerhalb der immunvermittelten Neuropathien erscheinen weitere Subklassifizierungen f{\"u}r eine optimale Diagnosestellung und Therapie unabdingbar. Diese Arbeit konnte mit den oben genannten Untersuchungen einen weiteren Beitrag zur Identifikation von klinischen und quantitativen Unterschieden innerhalb dieser großen Erkrankungsgruppe leisten. K{\"u}nftige, gr{\"o}ßere Studien dieser Art k{\"o}nnen m{\"o}glicherweise hier nur als Tendenzen gesehene Erkenntnisse belegen und sollten durch zus{\"a}tzliche Informationen wie Korrelation zu Krankheitsdauer, Therapie, Laborchemie und elektrophysiologischen Untersuchen weitere interessante Erkenntnisse liefern.}, subject = {Polyneuropathie}, language = {de} } @phdthesis{Karus2022, author = {Karus, Christine}, title = {Untersuchung der Architektur von Proteinstrukturen des Ranvier-Schn{\"u}rrings mittels der super-hochaufl{\"o}senden Mikroskopiemethode dSTORM}, doi = {10.25972/OPUS-27456}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-274568}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Ranvier-Schn{\"u}rringe spielen eine entscheidende Rolle bei der schnellen Weiterleitung von elektrischen Impulsen in Nervenzellen. Bei bestimmten neurologischen Erkrankungen, den Neuropathien, kann es zu St{\"o}rungen in der ultrastrukturellen Organisation verschiedener Schn{\"u}rring-Proteine kommen (Doppler et al., 2018, Doppler et al., 2016). Eine detailliertere Kenntnis der genauen Anordnung dieser Schn{\"u}rring-Proteine und eventueller Abweichungen von dieser Anordnung im Krankheitsfall, k{\"o}nnte der Schl{\"u}ssel zu einer vereinfachten Diagnostik von bestimmten Neuropathie- Formen sein. Ziel meiner Arbeit war es daher, die Untersuchung der ultrastrukturellen Architektur der (para-)nodalen Adh{\"a}sionsproteine Neurofascin-155 und Caspr1 unter Verwendung der super-hochaufl{\"o}senden Mikroskopiemethode dSTORM (direct Stochastic Optical Reconstruction Microscopy) an murinen Zupfnervenpr{\"a}paraten zu etablieren. Nach erster Optimierung der Probenpr{\"a}paration f{\"u}r die 2-Farben-dSTORM sowie der korrelationsbasierten Bildanalyse, konnte ich mittels modellbasierter Simulation die zugrundeliegende Molek{\"u}lorganisation identifizieren und mit Hilfe der Ergebnisse aus fr{\"u}heren Untersuchungen validieren. In einem translationalen Ansatz habe ich anschließend humane Zupfnervenpr{\"a}parate von 14 Probanden mit unterschiedlichen Formen einer Neuropathie mikroskopiert und ausgewertet, um die Anwendbarkeit dieses Ansatzes in der Diagnostik zu testen. Obgleich keine signifikanten Unterschiede zwischen physiologischem und pathologischem neurologischem Gewebe hinsichtlich Neurofascin-155 und Caspr1 festgestellt werden konnten, scheint der Ansatz grunds{\"a}tzlich dennoch vielversprechend zu sein, bedarf jedoch noch weiteren Anstrengungen hinsichtlich Probenpr{\"a}paration, Auswertungs- und Versuchsprotokollen und einer gr{\"o}ßeren Anzahl an humanen Biopsien mit homogenerem Krankheitsbild.}, language = {de} } @phdthesis{Stallforth2007, author = {Stallforth, Sabine}, title = {Unterschiedliche Wirkungen der TNF-alpha-Rezeptoren auf De- und Regeneration peripherer NervenEine Studie an TNF-alpha-Rezeptor-Knockoutm{\"a}usen in zwei verschiedenen Tiermodellen f{\"u}r Nervenl{\"a}sionen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-24808}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2007}, abstract = {Noch immer ist die Behandlung von Neuropathien mit den g{\"a}ngigen therapeutischen Mitteln f{\"u}r viele Patienten sehr unbefriedigend. Als erfolgsversprechender therapeutischer Ansatz werden zur Zeit Wege erforscht, welche direkt in die molekularen Entstehungsmechanismen pathologischer Ver{\"a}nderungen und regenerationsf{\"o}rdernder Mechanismen eingreifen, um dadurch eine Heilung von Nervensch{\"a}den zu erm{\"o}glichen. Bisher sind die Erkenntnisse {\"u}ber diese Mechanismen nicht vollst{\"a}ndig genug, um daraus eine sichere Behandlungsm{\"o}glichkeit abzuleiten. Wegweisende Erkenntnisse deuten sich allerdings durch Studien von unterschiedlichen Vertretern des Zytokinnetzwerkes an - darunter auch TNF-alpha - welche als molekulare Ursache neuropathischer Ver{\"a}nderungen diskutiert werden. In dieser Studie wurde an Knockoutm{\"a}usen der Einfluss des jeweiligen TNF-alpha-Rezeptors auf morphologische Ver{\"a}nderungen nach CCI (Chronic constriction injury) und Crush-Verletzung des N. ischiadicus untersucht. Nach 3,7,15 und 36 Tagen (CCI) bzw. 3,7 und 28 Tagen (Crush) wurden in Methylenblau gef{\"a}rbten Semid{\"u}nnschnitten intakte und degenerierte Nervenfasern, Makrophagen, Angioproliferation, {\"O}dembildung udn Ver{\"a}nderung des Anteils nicht neuronaler Zellen lichtmikroskopisch beurteilt. Zus{\"a}tzlich wurden Mac-1+ Makrophagen immunzytochemisch erfasst. Die Ergebnisse zeigten in beiden Modellen und bei beiden Knockouttypen eine starke axonale Sch{\"a}digung, die von einer großen endoneuroalen Makrophagenansammlung begleitet war. Bei TNF-R1-/- M{\"a}usen war eine st{\"a}rkere und verl{\"a}ngerte Degeneration mit entsprechend h{\"o}heren Makrophagenzahlen sichtbar. In den Immunzytochemischen F{\"a}rbungen wiesen die TNF-R1-/- M{\"a}use hingegen den geringsten Makropahgenanteil auf.Trotz der starken Sch{\"a}digung war die anschließende Regeneration im Gegensatz zu WT und TNF-R2-/- M{\"a}usen besser. Die {\"O}dembildung war bei den TNF-R2-/- nach CCI besonders stark ausgepr{\"a}gt und von einer schlechten Regeneration gefolgt. W{\"a}hrend die gefundenen Daten auf eine Beteiligung beider Rezeptoren w{\"a}hrend degenerativer Prozesse hindeuten, scheint insbesondere TNF-R2 regenerationsf{\"o}rdernde Effekte zu vermitteln.}, subject = {peripheral nerve}, language = {de} } @article{ContarinoSmitvandenDooletal.2016, author = {Contarino, Maria Fiorella and Smit, Marenka and van den Dool, Joost and Volkmann, Jens and Tijssen, Marina A. J.}, title = {Unmet Needs in the Management of Cervical Dystonia}, series = {Frontiers in Neurology}, volume = {7}, journal = {Frontiers in Neurology}, number = {165}, doi = {10.3389/fneur.2016.00165}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165225}, year = {2016}, abstract = {Cervical dystonia (CD) is a movement disorder which affects daily living of many patients. In clinical practice, several unmet treatment needs remain open. This article focuses on the four main aspects of treatment. We describe existing and emerging treatment approaches for CD, including botulinum toxin injections, surgical therapy, management of non-motor symptoms, and rehabilitation strategies. The unsolved issues regarding each of these treatments are identified and discussed, and possible future approaches and research lines are proposed.}, language = {en} } @article{GabrielJirůHillmannKraftetal.2020, author = {Gabriel, Katharina M. A. and J{\´i}rů-Hillmann, Steffi and Kraft, Peter and Selig, Udo and R{\"u}cker, Victoria and M{\"u}hler, Johannes and D{\"o}tter, Klaus and Keidel, Matthias and Soda, Hassan and Rascher, Alexandra and Schneider, Rolf and Pfau, Mathias and Hoffmann, Roy and Stenzel, Joachim and Benghebrid, Mohamed and Goebel, Tobias and Doerck, Sebastian and Kramer, Daniela and Haeusler, Karl Georg and Volkmann, Jens and Heuschmann, Peter U. and Fluri, Felix}, title = {Two years' experience of implementing a comprehensive telemedical stroke network comprising in mainly rural region: the Transregional Network for Stroke Intervention with Telemedicine (TRANSIT-Stroke)}, series = {BMC Neurology}, volume = {20}, journal = {BMC Neurology}, doi = {10.1186/s12883-020-01676-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229214}, year = {2020}, abstract = {Background Telemedicine improves the quality of acute stroke care in rural regions with limited access to specialized stroke care. We report the first 2 years' experience of implementing a comprehensive telemedical stroke network comprising all levels of stroke care in a defined region. Methods The TRANSIT-Stroke network covers a mainly rural region in north-western Bavaria (Germany). All hospitals providing acute stroke care in this region participate in TRANSIT-Stroke, including four hospitals with a supra-regional certified stroke unit (SU) care (level III), three of those providing teleconsultation to two hospitals with a regional certified SU (level II) and five hospitals without specialized SU care (level I). For a two-year-period (01/2015 to 12/2016), data of eight of these hospitals were available; 13 evidence-based quality indicators (QIs) related to processes during hospitalisation were evaluated quarterly and compared according to predefined target values between level-I- and level-II/III-hospitals. Results Overall, 7881 patients were included (mean age 74.6 years +/- 12.8; 48.4\% female). In level-II/III-hospitals adherence of all QIs to predefined targets was high ab initio. In level-I-hospitals, three patterns of QI-development were observed: a) high adherence ab initio (31\%), mainly in secondary stroke prevention; b) improvement over time (44\%), predominantly related to stroke specific diagnosis and in-hospital organization; c) no clear time trends (25\%). Overall, 10 out of 13 QIs reached predefined target values of quality of care at the end of the observation period. Conclusion The implementation of the comprehensive TRANSIT-Stroke network resulted in an improvement of quality of care in level-I-hospitals.}, language = {en} } @article{EhlingBittnerBobaketal.2010, author = {Ehling, P. and Bittner, S. and Bobak, N. and Schwarz, T. and Wiendl, H. and Budde, T. and Kleinschnitz, Christoph and Meuth, S. G.}, title = {Two pore domain potassium channels in cerebral ischemia: a focus on K2p9.1 (TASK3, KCNK9)}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68129}, year = {2010}, abstract = {BACKGROUND: Recently, members of the two-pore domain potassium channel family (K2P channels) could be shown to be involved in mechanisms contributing to neuronal damage after cerebral ischemia. K2P3.1-/- animals showed larger infarct volumes and a worse functional outcome following experimentally induced ischemic stroke. Here, we question the role of the closely related K2P channel K2P9.1. METHODS: We combine electrophysiological recordings in brain-slice preparations of wildtype and K2P9.1-/- mice with an in vivo model of cerebral ischemia (transient middle cerebral artery occlusion (tMCAO)) to depict a functional impact of K2P9.1 in stroke formation. RESULTS: Patch-clamp recordings reveal that currents mediated through K2P9.1 can be obtained in slice preparations of the dorsal lateral geniculate nucleus (dLGN) as a model of central nervous relay neurons. Current characteristics are indicative of K2P9.1 as they display an increase upon removal of extracellular divalent cations, an outward rectification and a reversal potential close to the potassium equilibrium potential. Lowering extracellular pH values from 7.35 to 6.0 showed comparable current reductions in neurons from wildtype and K2P9.1-/- mice (68.31 +/- 9.80\% and 69.92 +/- 11.65\%, respectively). These results could be translated in an in vivo model of cerebral ischemia where infarct volumes and functional outcomes showed a none significant tendency towards smaller infarct volumes in K2P9.1-/- animals compared to wildtype mice 24 hours after 60 min of tMCAO induction (60.50 +/- 17.31 mm3 and 47.10 +/- 19.26 mm3, respectively). CONCLUSIONS: Together with findings from earlier studies on K2P2.1-/- and K2P3.1-/- mice, the results of the present study on K2P9.1-/- mice indicate a differential contribution of K2P channel subtypes to the diverse and complex in vivo effects in rodent models of cerebral ischemia.}, subject = {Kaliumkanal}, language = {en} } @phdthesis{Leffler2003, author = {Leffler, Andreas}, title = {TRPV1 ist ein polymodaler Rezeptor von nozizeptiven Spinalganglienzellen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-10748}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2003}, abstract = {In der vorliegenden Arbeit wurde mittels der Whole-Cell Patch-Clamp Methode sensible Neurone von transgenen M{\"a}usen untersucht, bei denen das Gen f{\"u}r TRPV1 (transient receptor potential V1) deletiert wurde. Das Ergebniss wurde mit den Daten von Wildtyp M{\"a}usen verglichen. TRPV1 (fr{\"u}her VR1; vanilloid receptor 1) wird nahezu selektiv in sensiblen Neuronen exprimiert und wird im heterologen Expressionssystem durch Vanilloide, Hitze (> 43°C) und Protonen aktiviert. Durch diese Eigenschaften scheint TRPV1 f{\"u}r die rezeptiven Eigenschaften polymodaler Nozizeptoren von großer Bedeutung zu sein. Als ein Model des peripheren afferenten Neurons wurde die Aktivierbarkeit kultivierter Spinalganglienzellen durch Vanilloide, Protonen und Hitze elektrophysiologisch untersucht. W{\"a}hrend etwa 35\% der Wildtyp-Zellen Vanilloid-sensibel waren, fehlte in Zellen der TRPV1-knockout Maus jegliche Vanilloid-Sensibilit{\"a}t. Auch bei der Protonen-Sensibilit{\"a}t wurde eine signifikante Reduktion in TRPV1-knockout Zellen beobachtet. In Wildtyp-Zellen wurde eine hohe Protonen-Sensibilit{\"a}t fast ausschliesslich in Vanilloid-sensiblen Zellen beobachtet. Hitze-induzierte Einw{\"a}rtsstr{\"o}me mit einer Aktivierungsschwelle bei 43°C wurden ausschliesslich in Vanilloid-sensiblen Zellen der Wildtyp-Maus beobachtet. Dagegen wurden Hitze-induzierte Einw{\"a}rtsstr{\"o}me mit einer Aktivierungsschwelle {\"u}ber 53°C in sowohl Wildtyp- als auch in TRPV1-knockout Zellen beobachtet. Im Bezug auf die Bedetung von TRPV1, wurde die Funktionalit{\"a}t zwei distinkter Populationen von Spinalganglienzellen, NGF- bzw. GDNF-abh{\"a}ngigen Neuronen, durch eine Lebendf{\"a}rbung mit IB4-FITC untersucht. Hinsichtlich Vanilloid-, Protonen-, Hitze-Sensibilit{\"o}t wurden jedoch keine Unterschiede zwischen IB4-negative und IB4-positive Neuronen beobachtet. Die vorliegende Studie zeigt damit, dass TRPV1 f{\"u}r Vanilliod-Sensibilit{\"a}t sensibler Neurone essentiell ist. Weiterhin konnte gezeigt werden, dass TRPV1 ein wichtiges Transduktionselement f{\"u}r sowohl die Protonen-Sensibilit{\"a}t als auch f{\"u}r die Hitze-Sensibilit{\"a}t in Spinalganglienzellen darstellt. Die Daten dieser zellul{\"a}ren Untersuchungen konnten in weiteren in vitro und in vivo Untersuchungen best{\"a}tigt werden (Caterina et al., 2000).}, language = {de} } @article{PozziPalmisanoReichetal.2022, author = {Pozzi, Nicol{\´o} G. and Palmisano, Chiara and Reich, Martin M. and Capetian, Philip and Pacchetti, Claudio and Volkmann, Jens and Isaias, Ioannis U.}, title = {Troubleshooting gait disturbances in Parkinson's disease with deep brain stimulation}, series = {Frontiers in Human Neuroscience}, volume = {16}, journal = {Frontiers in Human Neuroscience}, issn = {1662-5161}, doi = {10.3389/fnhum.2022.806513}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-274007}, year = {2022}, abstract = {Deep brain stimulation (DBS) of the subthalamic nucleus or the globus pallidus is an established treatment for Parkinson's disease (PD) that yields a marked and lasting improvement of motor symptoms. Yet, DBS benefit on gait disturbances in PD is still debated and can be a source of dissatisfaction and poor quality of life. Gait disturbances in PD encompass a variety of clinical manifestations and rely on different pathophysiological bases. While gait disturbances arising years after DBS surgery can be related to disease progression, early impairment of gait may be secondary to treatable causes and benefits from DBS reprogramming. In this review, we tackle the issue of gait disturbances in PD patients with DBS by discussing their neurophysiological basis, providing a detailed clinical characterization, and proposing a pragmatic programming approach to support their management.}, language = {en} } @article{CruccuPennisiAntoninietal.2014, author = {Cruccu, Giorgio and Pennisi, Elena M. and Antonini, Giovanni and Biasiotta, Antonella and Di Stefano, Giulia and La Cesa, Silvia and Leone, Caterina and Raffa, Salvatore and Sommer, Claudia and Truini, Andrea}, title = {Trigeminal isolated sensory neuropathy (TISN) and FOSMN syndrome: despite a dissimilar disease course do they share common pathophysiological mechanisms?}, series = {BMC Neurology}, volume = {14}, journal = {BMC Neurology}, issn = {1471-2377}, doi = {10.1186/s12883-014-0248-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114249}, year = {2014}, abstract = {Background: Patients presenting with bilateral trigeminal hypoesthesia may go on to have trigeminal isolated sensory neuropathy, a benign, purely trigeminal neuropathy, or facial-onset sensory motor neuronopathy (FOSMN), a malignant life-threatening condition. No diagnostic criteria can yet differentiate the two conditions at their onset. Nor is it clear whether the two diseases are distinct entities or share common pathophysiological mechanisms. Methods: Seeking pathophysiological and diagnostic information to distinguish these two conditions at their onset, in this neurophysiological and morphometric study we neurophysiologically assessed function in myelinated and unmyelinated fibres and histologically examined supraorbital nerve biopsy specimens with optic and electron microscopy in 13 consecutive patients with recent onset trigeminal hypoesthesia and pain. Results: The disease course distinctly differed in the 13 patients. During a mean 10 year follow-up whereas in eight patients the disease remained relatively stable, in the other five it progressed to possibly life-threatening motor disturbances and extra-trigeminal spread. From two to six years elapsed between the first sensory symptoms and the onset of motor disorders. In patients with trigeminal isolated sensory neuropathy (TISN) and in those with FOSMN neurophysiological and histological examination documented a neuronopathy manifesting with trigeminal nerve damage selectively affecting myelinated fibres, but sparing the Ia-fibre-mediated proprioceptive reflex. Conclusions: Although no clinical diagnostic criteria can distinguish the two conditions at onset, neurophysiological and nerve-biopsy findings specify that in both disorders trigeminal nerve damage manifests as a dissociated neuronopathy affecting myelinated and sparing unmyelinated fibres, thus suggesting similar pathophysiological mechanisms.}, language = {en} } @article{GesslerLehmannBoeseletal.2021, author = {Gessler, Florian and Lehmann, Felix and B{\"o}sel, Julian and Fuhrer, Hannah and Neugebauer, Hermann and Wartenberg, Katja E. and Wolf, Stefan and Bernstock, Joshua D. and Niesen, Wolf-Dirk and Schuss, Patrick}, title = {Triage and Allocation of Neurocritical Care Resources During the COVID 19 Pandemic - A National Survey}, series = {Frontiers in Neurology}, volume = {11}, journal = {Frontiers in Neurology}, issn = {1664-2295}, doi = {10.3389/fneur.2020.609227}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221593}, year = {2021}, abstract = {Objective: In light of the ongoing COVID-19 pandemic and the associated hospitalization of an overwhelming number of ventilator-dependent patients, medical and/or ethical patient triage paradigms have become essential. While guidelines on the allocation of scarce resources do exist, such work within the subdisciplines of intensive care (e.g., neurocritical care) remains limited. Methods: A 16-item questionnaire was developed that sought to explore/quantify the expert opinions of German neurointensivists with regard to triage decisions. The anonymous survey was conducted via a web-based platform and in total, 96 members of the Initiative of German Neurointensive Trial Engagement (IGNITE)-study group were contacted via e-mail. The IGNITE consortium consists of an interdisciplinary panel of specialists with expertise in neuro-critical care (i.e., anesthetists, neurologists and neurosurgeons). Results: Fifty members of the IGNITE consortium responded to the questionnaire; in total the respondents were in charge of more than 500 Neuro ICU beds throughout Germany. Common determinants reported which affected triage decisions included known patient wishes (98\%), the state of health before admission (96\%), SOFA-score (85\%) and patient age (69\%). Interestingly, other principles of allocation, such as a treatment of "youngest first" (61\%) and members of the healthcare sector (50\%) were also noted. While these were the most accepted parameters affecting the triage of patients, a "first-come, first-served" principle appeared to be more accepted than a lottery for the allocation of ICU beds which contradicts much of what has been reported within the literature. The respondents also felt that at least one neurointensivist should serve on any interdisciplinary triage team. Conclusions: The data gathered in the context of this survey reveal the estimation/perception of triage algorithms among neurointensive care specialists facing COVID-19. Further, it is apparent that German neurointensivists strongly feel that they should be involved in any triage decisions at an institutional level given the unique resources needed to treat patients within the Neuro ICU.}, language = {en} } @article{BaumKojKloetingetal.2021, author = {Baum, Petra and Koj, Severin and Kl{\"o}ting, Nora and Bl{\"u}her, Matthias and Classen, Joseph and Paeschke, Sabine and Gericke, Martin and Toyka, Klaus V. and Nowicki, Marcin and Kosacka, Joanna}, title = {Treatment-induced neuropathy in diabetes (TIND) — Developing a disease model in type 1 diabetic rats}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {4}, issn = {1422-0067}, doi = {10.3390/ijms22041571}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285793}, year = {2021}, abstract = {Treatment-induced neuropathy in diabetes (TIND) is defined by the occurrence of an acute neuropathy within 8 weeks of an abrupt decrease in glycated hemoglobin-A1c (HbA1c). The underlying pathogenic mechanisms are still incompletely understood with only one mouse model being explored to date. The aim of this study was to further explore the hypothesis that an abrupt insulin-induced fall in HbA1c may be the prime causal factor of developing TIND. BB/OKL (bio breeding/OKL, Ottawa Karlsburg Leipzig) diabetic rats were randomized in three groups, receiving insulin treatment by implanted subcutaneous osmotic insulin pumps for 3 months, as follows: Group one received 2 units per day; group two 1 unit per day: and group three 1 unit per day in the first month, followed by 2 units per day in the last two months. We serially examined blood glucose and HbA1c levels, motor- and sensory/mixed afferent conduction velocities (mNCV and csNCV) and peripheral nerve morphology, including intraepidermal nerve fiber density and numbers of Iba-1 (ionized calcium binding adaptor molecule 1) positive macrophages in the sciatic nerve. Only in BB/OKL rats of group three, with a rapid decrease in HbA1c of more than 2\%, did we find a significant decrease in mNCV in sciatic nerves (81\% of initial values) after three months of treatment as compared to those group three rats with a less marked decrease in HbA1c <2\% (mNCV 106\% of initial values, p ≤ 0.01). A similar trend was observed for sensory/mixed afferent nerve conduction velocities: csNCV were reduced in BB/OKL rats with a rapid decrease in HbA1c >2\% (csNCV 90\% of initial values), compared to those rats with a mild decrease <2\% (csNCV 112\% of initial values, p ≤ 0.01). Moreover, BB/OKL rats of group three with a decrease in HbA1c >2\% showed significantly greater infiltration of macrophages by about 50\% (p ≤ 0.01) and a decreased amount of calcitonin gene related peptide (CGRP) positive nerve fibers as compared to the animals with a milder decrease in HbA1c. We conclude that a mild acute neuropathy with inflammatory components was induced in BB/OKL rats as a consequence of an abrupt decrease in HbA1c caused by high-dose insulin treatment. This experimentally induced neuropathy shares some features with TIND in humans and may be further explored in studies into the pathogenesis and treatment of TIND.}, language = {en} } @article{BieberFoersterHaefelietal.2021, author = {Bieber, Michael and Foerster, Kathrin I. and Haefeli, Walter E. and Pham, Mirko and Schuhmann, Michael K. and Kraft, Peter}, title = {Treatment with edoxaban attenuates acute stroke severity in mice by reducing blood-brain barrier damage and inflammation}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {18}, issn = {1422-0067}, doi = {10.3390/ijms22189893}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284481}, year = {2021}, abstract = {Patients with atrial fibrillation and previous ischemic stroke (IS) are at increased risk of cerebrovascular events despite anticoagulation. In these patients, treatment with non-vitamin K oral anticoagulants (NOAC) such as edoxaban reduced the probability and severity of further IS without increasing the risk of major bleeding. However, the detailed protective mechanism of edoxaban has not yet been investigated in a model of ischemia/reperfusion injury. Therefore, in the current study we aimed to assess in a clinically relevant setting whether treatment with edoxaban attenuates stroke severity, and whether edoxaban has an impact on the local cerebral inflammatory response and blood-brain barrier (BBB) function after experimental IS in mice. Focal cerebral ischemia was induced by transient middle cerebral artery occlusion in male mice receiving edoxaban, phenprocoumon or vehicle. Infarct volumes, functional outcome and the occurrence of intracerebral hemorrhage were assessed. BBB damage and the extent of local inflammatory response were determined. Treatment with edoxaban significantly reduced infarct volumes and improved neurological outcome and BBB function on day 1 and attenuated brain tissue inflammation. In summary, our study provides evidence that edoxaban might exert its protective effect in human IS by modulating different key steps of IS pathophysiology, but further studies are warranted.}, language = {en} } @article{AblinFitzcharlesBuskilaetal.2013, author = {Ablin, Jacob and Fitzcharles, Mary-Ann and Buskila, Dan and Shir, Yoram and Sommer, Claudia and H{\"a}user, Winfried}, title = {Treatment of Fibromyalgia Syndrome: Recommendations of Recent Evidence-Based Interdisciplinary Guidelines with Special Emphasis on Complementary and Alternative Therapies}, series = {Evidence-Bayed Complementary and Alternative Medicine}, journal = {Evidence-Bayed Complementary and Alternative Medicine}, issn = {1741-427X}, doi = {10.1155/2013/485272}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122235}, pages = {485272}, year = {2013}, abstract = {Objective. Current evidence indicates that there is no single ideal treatment for fibromyalgia syndrome (FMS). First choice treatment options remain debatable, especially concerning the importance of complementary and alternative medicine (CAM) treatments. Methods. Three evidence-based interdisciplinary guidelines on FMS in Canada, Germany, and Israel were compared for their first choice and CAM-recommendations. Results. All three guidelines emphasized a patient-tailored approach according to the key symptoms. Aerobic exercise, cognitive behavioral therapy, and multicomponent therapy were first choice treatments. The guidelines differed in the grade of recommendation for drug treatment. Anticonvulsants (gabapentin, pregabalin) and serotonin noradrenaline reuptake inhibitors (duloxetine, milnacipran) were strongly recommended by the Canadian and the Israeli guidelines. These drugs received only a weak recommendation by the German guideline. In consideration of CAM-treatments, acupuncture, hypnosis/guided imagery, and Tai Chi were recommended by the German and Israeli guidelines. The Canadian guidelines did not recommend any CAM therapy. Discussion. Recent evidence-based interdisciplinary guidelines concur on the importance of treatment tailored to the individual patient and further emphasize the need of self-management strategies (exercise, and psychological techniques).}, language = {en} } @article{WalterReilichThieleetal.2013, author = {Walter, Maggie C. and Reilich, Peter and Thiele, Simone and Schessl, Joachim and Schreiber, Herbert and Reiners, Karlheinz and Kress, Wolfram and M{\"u}ller-Reible, Clemens and Vorgerd, Matthias and Urban, Peter and Schrank, Bertold and Deschauer, Marcus and Schlotter-Weigel, Beate and Kohnen, Ralf and Lochm{\"u}ller, Hans}, title = {Treatment of dysferlinopathy with deflazacort: a double-blind, placebo-controlled clinical trial}, series = {Orphanet Journal of Rare Diseases}, volume = {8}, journal = {Orphanet Journal of Rare Diseases}, number = {26}, issn = {1750-1172}, doi = {10.1186/1750-1172-8-26}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125663}, year = {2013}, abstract = {Background: Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B). Methods: We assessed the one-year-natural course of dysferlinopathy, and the safety and efficacy of deflazacort treatment in a double-blind, placebo-controlled cross-over trial. After one year of natural course without intervention, 25 patients with genetically defined dysferlinopathy were randomized to receive deflazacort and placebo for six months each (1 mg/kg/day in month one, 1 mg/kg every 2nd day during months two to six) in one of two treatment sequences. Results: During one year of natural course, muscle strength declined about 2\% as measured by CIDD (Clinical Investigation of Duchenne Dystrophy) score, and 76 Newton as measured by hand-held dynamometry. Deflazacort did not improve muscle strength. In contrast, there is a trend of worsening muscle strength under deflazacort treatment, which recovers after discontinuation of the study drug. During deflazacort treatment, patients showed a broad spectrum of steroid side effects. Conclusion: Deflazacort is not an effective therapy for dysferlinopathies, and off-label use is not warranted. This is an important finding, since steroid treatment should not be administered in patients with dysferlinopathy, who may be often misdiagnosed as polymyositis.}, language = {en} } @article{LehriederZapantisPhametal.2023, author = {Lehrieder, Dominik and Zapantis, Nikolaos and Pham, Mirko and Schuhmann, Michael Klaus and Haarmann, Axel}, title = {Treating seronegative neuromyelitis optica spectrum disorder with inebilizumab: a case report}, series = {Frontiers in Neurology}, volume = {14}, journal = {Frontiers in Neurology}, doi = {10.3389/fneur.2023.1297341}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-354031}, year = {2023}, abstract = {Background Neuromyelitis optica spectrum disorder (NMOSD) is a devastating inflammatory disease of the central nervous system that is often severely disabling from the outset. The lack of pathognomonic aquaporin 4 (AQP4) antibodies in seronegative NMOSD not only hinders early diagnosis, but also limits therapeutic options, in contrast to AQP4 antibody-positive NMOSD, where the therapeutic landscape has recently evolved massively. Case presentation We report a 56-year-old woman with bilateral optic neuritis and longitudinally extensive myelitis as the index events of a seronegative NMOSD, who was successfully treated with inebilizumab. Conclusion Treatment with inebilizumab may be considered in aggressive seronegative NMOSD. Whether broader CD19-directed B cell depletion is more effective than treatment with rituximab remains elusive.}, language = {en} } @article{BinderMayBaronetal.2011, author = {Binder, Andreas and May, Denisa and Baron, Ralf and Maier, Christoph and T{\"o}lle, Thomas R. and Treede, Rolf-Detlef and Berthele, Achim and Faltraco, Frank and Flor, Herta and Gierthm{\"u}hlen, Janne and Haenisch, Sierk and Huge, Volker and Magerl, Walter and Maih{\"o}fner, Christian and Richter, Helmut and Rolke, Roman and Scherens, Andrea and {\"U}{\c{c}}eyler, Nurcan and Ufer, Mike and Wasner, Gunnar and Zhu, Jihong and Cascorbi, Ingolf}, title = {Transient Receptor Potential Channel Polymorphisms Are Associated with the Somatosensory Function in Neuropathic Pain Patients}, series = {PLoS ONE}, volume = {6}, journal = {PLoS ONE}, number = {3}, doi = {10.1371/journal.pone.0017387}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142782}, pages = {e17387}, year = {2011}, abstract = {Transient receptor potential channels are important mediators of thermal and mechanical stimuli and play an important role in neuropathic pain. The contribution of hereditary variants in the genes of transient receptor potential channels to neuropathic pain is unknown. We investigated the frequency of transient receptor potential ankyrin 1, transient receptor potential melastin 8 and transient receptor potential vanilloid 1 single nucleotide polymorphisms and their impact on somatosensory abnormalities in neuropathic pain patients. Within the German Research Network on Neuropathic Pain (Deutscher Forscbungsverbund Neuropathischer Schmerz) 371 neuropathic pain patients were phenotypically characterized using standardized quantitative sensory testing. Pyrosequencing was employed to determine a total of eleven single nucleotide polymorphisms in transient receptor potential channel genes of the neuropathic pain patients and a cohort of 253 German healthy volunteers. Associations of quantitative sensory testing parameters and single nucleotide polymorphisms between and within groups and subgroups, based on sensory phenotypes, were analyzed. Single nucleotide polymorphisms frequencies did not differ between both the cohorts. However, in neuropathic pain patients transient receptor potential ankyrin 1 710G>A (rs920829, E179K) was associated with the presence of paradoxical heat sensation (p=0.03), and transient receptor potential vanilloid 1 1911A>G (rs8065080, I585V) with cold hypoalgesia (p=0.0035). Two main subgroups characterized by preserved (1) and impaired (2) sensory function were identified. In subgroup 1 transient receptor potential vanilloid 1 1911A>G led to significantly less heat hyperalgesia, pinprick hyperalgesia and mechanical hypaesthesia (p=0.006, p=0.005 and p<0.001) and transient receptor potential vanilloid 1 1103C>G (rs222747, M315I) to cold hypaesthesia (p=0.002), but there was absence of associations in subgroup 2. In this study we found no evidence that genetic variants of transient receptor potential channels are involved in the expression of neuropathic pain, but transient receptor potential channel polymorphisms contributed significantly to the somatosensory abnormalities of neuropathic pain patients.}, language = {en} } @article{HartmannsbergerScribaGuidolinetal.2024, author = {Hartmannsberger, Beate and Scriba, Sabrina and Guidolin, Carolina and Becker, Juliane and Mehling, Katharina and Doppler, Kathrin and Sommer, Claudia and Rittner, Heike L.}, title = {Transient immune activation without loss of intraepidermal innervation and associated Schwann cells in patients with complex regional pain syndrome}, series = {Journal of Neuroinflammation}, volume = {21}, journal = {Journal of Neuroinflammation}, doi = {10.1186/s12974-023-02969-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357164}, year = {2024}, abstract = {Background Complex regional pain syndrome (CRPS) develops after injury and is characterized by disproportionate pain, oedema, and functional loss. CRPS has clinical signs of neuropathy as well as neurogenic inflammation. Here, we asked whether skin biopsies could be used to differentiate the contribution of these two systems to ultimately guide therapy. To this end, the cutaneous sensory system including nerve fibres and the recently described nociceptive Schwann cells as well as the cutaneous immune system were analysed. Methods We systematically deep-phenotyped CRPS patients and immunolabelled glabrous skin biopsies from the affected ipsilateral and non-affected contralateral finger of 19 acute (< 12 months) and 6 chronic (> 12 months after trauma) CRPS patients as well as 25 sex- and age-matched healthy controls (HC). Murine foot pads harvested one week after sham or chronic constriction injury were immunolabelled to assess intraepidermal Schwann cells. Results Intraepidermal Schwann cells were detected in human skin of the finger—but their density was much lower compared to mice. Acute and chronic CRPS patients suffered from moderate to severe CRPS symptoms and corresponding pain. Most patients had CRPS type I in the warm category. Their cutaneous neuroglial complex was completely unaffected despite sensory plus signs, e.g. allodynia and hyperalgesia. Cutaneous innate sentinel immune cells, e.g. mast cells and Langerhans cells, infiltrated or proliferated ipsilaterally independently of each other—but only in acute CRPS. No additional adaptive immune cells, e.g. T cells and plasma cells, infiltrated the skin. Conclusions Diagnostic skin punch biopsies could be used to diagnose individual pathophysiology in a very heterogenous disease like acute CRPS to guide tailored treatment in the future. Since numbers of inflammatory cells and pain did not necessarily correlate, more in-depth analysis of individual patients is necessary.}, language = {en} } @article{IpIsaiasKuscheTekinetal.2016, author = {Ip, Chi Wang and Isaias, Ioannis U. and Kusche-Tekin, Burak B. and Klein, Dennis and Groh, Janos and O´Leary, Aet and Knorr, Susanne and Higuchi, Takahiro and Koprich, James B. and Brotchie, Jonathan M. and Toyka, Klaus V. and Reif, Andreas and Volkmann, Jens}, title = {Tor1a+/- mice develop dystonia-like movements via a striatal dopaminergic dysregulation triggered by peripheral nerve injury}, series = {Acta Neuropathologica Communications}, volume = {4}, journal = {Acta Neuropathologica Communications}, number = {108}, doi = {10.1186/s40478-016-0375-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147839}, year = {2016}, abstract = {Isolated generalized dystonia is a central motor network disorder characterized by twisted movements or postures. The most frequent genetic cause is a GAG deletion in the Tor1a (DYT1) gene encoding torsinA with a reduced penetrance of 30-40 \% suggesting additional genetic or environmental modifiers. Development of dystonia-like movements after a standardized peripheral nerve crush lesion in wild type (wt) and Tor1a+/- mice, that express 50 \% torsinA only, was assessed by scoring of hindlimb movements during tail suspension, by rotarod testing and by computer-assisted gait analysis. Western blot analysis was performed for dopamine transporter (DAT), D1 and D2 receptors from striatal and quantitative RT-PCR analysis for DAT from midbrain dissections. Autoradiography was used to assess the functional DAT binding in striatum. Striatal dopamine and its metabolites were analyzed by high performance liquid chromatography. After nerve crush injury, we found abnormal posturing in the lesioned hindlimb of both mutant and wt mice indicating the profound influence of the nerve lesion (15x vs. 12x relative to control) resembling human peripheral pseudodystonia. In mutant mice the phenotypic abnormalities were increased by about 40 \% (p < 0.05). This was accompanied by complex alterations of striatal dopamine homeostasis. Pharmacological blockade of dopamine synthesis reduced severity of dystonia-like movements, whereas treatment with L-Dopa aggravated these but only in mutant mice suggesting a DYT1 related central component relevant to the development of abnormal involuntary movements. Our findings suggest that upon peripheral nerve injury reduced torsinA concentration and environmental stressors may act in concert in causing the central motor network dysfunction of DYT1 dystonia.}, language = {en} } @article{OdorferYabeHiewetal.2023, author = {Odorfer, Thorsten M. and Yabe, Marie and Hiew, Shawn and Volkmann, Jens and Zeller, Daniel}, title = {Topological differences and confounders of mental rotation in cervical dystonia and blepharospasm}, series = {Scientific Reports}, volume = {13}, journal = {Scientific Reports}, doi = {10.1038/s41598-023-33262-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357713}, year = {2023}, abstract = {Mental rotation (mR) bases on imagination of actual movements. It remains unclear whether there is a specific pattern of mR impairment in focal dystonia. We aimed to investigate mR in patients with cervical dystonia (CD) and blepharospasm (BS) and to assess potential confounders. 23 CD patients and 23 healthy controls (HC) as well as 21 BS and 19 hemifacial spasm (HS) patients were matched for sex, age, and education level. Handedness, finger dexterity, general reaction time, and cognitive status were assessed. Disease severity was evaluated by clinical scales. During mR, photographs of body parts (head, hand, or foot) and a non-corporal object (car) were displayed at different angles rotated within their plane. Subjects were asked to judge laterality of the presented image by keystroke. Both speed and correctness were evaluated. Compared to HC, CD and HS patients performed worse in mR of hands, whereas BS group showed comparable performance. There was a significant association of prolonged mR reaction time (RT) with reduced MoCA scores and with increased RT in an unspecific reaction speed task. After exclusion of cognitively impaired patients, increased RT in the mR of hands was confined to CD group, but not HS. While the question of whether specific patterns of mR impairment reliably define a dystonic endophenotype remains elusive, our findings point to mR as a useful tool, when used carefully with control measures and tasks, which may be capable of identifying specific deficits that distinguish between subtypes of dystonia.}, language = {en} } @article{LanghauserHeilerGrudzenskietal.2012, author = {Langhauser, Friederike L. and Heiler, Patrick M. and Grudzenski, Saskia and Lemke, Andreas and Alonso, Angelika and Schad, Lothar R. and Hennerici, Michael G. and Meairs, Stephen and Fata, Marc}, title = {Thromboembolic stroke in C57BL/6 mice monitored by 9.4 T MRI using a 1H cryo probe}, series = {Experimental and Translational Stroke Medicine}, volume = {4}, journal = {Experimental and Translational Stroke Medicine}, number = {18}, doi = {10.1186/2040-7378-4-18}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124218}, year = {2012}, abstract = {Background A new thromboembolic animal model showed beneficial effects of t-PA with an infarct volume reduction of 36.8\% in swiss mice. Because knock-out animal experiments for stroke frequently used C57BL76 mice we evaluated t-PA effects in this mouse strain and measured infarct volume and vascular recanalisation in-vivo by using high-field 9.4 T MRI and a 1H surface cryo coil. Methods Clot formation was triggered by microinjection of murine thrombin into the right middle cerebral artery (MCA). Animals (n = 28) were treated with 10 mg/kg, 5 mg/kg or no tissue plasminogen activator (t-PA) 40 min after MCA occlusion. For MR-imaging a Bruker 9.4 T animal system with a 1H surface cryo probe was used and a T2-weighted RARE sequence, a diffusion weighted multishot EPI sequence and a 3D flow-compensated gradient echo TOF angiography were performed. Results The infarct volume in animals treated with t-PA was significantly reduced (0.67 ± 1.38 mm3 for 10 mg/kg and 10.9 ± 8.79 mm3 for 5 mg/kg vs. 19.76 ± 2.72 mm3 ; p < 0.001) compared to untreated mice. An additional group was reperfused with t-PA inside the MRI. Already ten minutes after beginning of t-PA treatment, reperfusion flow was re-established in the right MCA. However, signal intensity was lower than in the contralateral MCA. This reduction in cerebral blood flow was attenuated during the first 60 minutes after reperfusion. 24 h after MCA occlusion and reperfusion, no difference in signal intensity of the contralateral and ipsilateral MCAs was observed. Conclusions We confirm a t-Pa effect using this stroke model in the C57BL76 mouse strain and demonstrate a chronological sequence MRI imaging after t-PA using a 1H surface cryo coil in a 9.4 T MRI. This setting will allow testing of new thrombolytic strategies for stroke treatment in-vivo in C57BL76 knock-out mice.}, language = {en} } @article{KraftSchwarzMeijersetal.2010, author = {Kraft, Peter and Schwarz, Tobias and Meijers, Joost C. M. and Stoll, Guido and Kleinschnitz, Christoph}, title = {Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Deficient Mice Are Susceptible to Intracerebral Thrombosis and Ischemic Stroke}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68519}, year = {2010}, abstract = {Background: Thrombus formation is a key step in the pathophysiology of acute ischemic stroke and results from the activation of the coagulation cascade. Thrombin plays a central role in this coagulation system and contributes to thrombus stability via activation of thrombin-activatable fibrinolysis inhibitor (TAFIa). TAFIa counteracts endogenous fibrinolysis at different stages and elevated TAFI levels are a risk factor for thrombotic events including ischemic stroke. Although substantial in vitro data on the influence of TAFI on the coagulation-fibrinolysis-system exist, investigations on the consequences of TAFI inhibition in animal models of cerebral ischemia are still lacking. In the present study we analyzed stroke development and post stroke functional outcome in TAFI-/- mice. Methodology/Principal Findings: TAFI-/- mice and wild-type controls were subjected to 60 min transient middle cerebral artery occlusion (tMCAO) using the intraluminal filament method. After 24 hours, functional outcome scores were assessed and infarct volumes weremeasured from 2,3,5-Triphenyltetrazoliumchloride (TTC)-stained brain slices. Hematoxylin and eosin (H\&E) staining was used to estimate the extent of neuronal cell damage. Thrombus formation within the infarcted brain areas was analyzed by immunoblot. Infarct volumes and functional outcomes did not significantly differ between TAFI-/- mice and controls (p.0.05). Histology revealed extensive ischemic neuronal damage regularly including the cortex and the basal ganglia in both groups. TAFI deficiency also had no influence on intracerebral fibrin(ogen) formation after tMCAO. Conclusion: Our study shows that TAFI does not play a major role for thrombus formation and neuronal degeneration after ischemic brain challenge.}, subject = {Thrombus}, language = {en} } @phdthesis{Toeppner2020, author = {T{\"o}ppner, Verena}, title = {Therapie und Outcome von Patienten mit aneurysmatischer Subarachnoidalblutung am Universit{\"a}tsklinikum W{\"u}rzburg}, doi = {10.25972/OPUS-20912}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-209129}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Die aneurysmatische SAB ist trotz etablierter Therapieverfahren (Coiling und Clipping) weiterhin ein Krankheitsbild mit hoher Mortalit{\"a}t. In unserer Arbeit haben wir retrospektiv die Patientenakten der Patienten, die mit der Diagnose aneurysmatische SAB am Universit{\"a}tsklinikum W{\"u}rzburg zwischen dem 01.01.1999 und dem 31.12.2009 aufgenommen wurden, ausgewertet. Es konnte dargestellt werden das als Hauptrisikofaktoren f{\"u}r ein schlechtes Therapieergebnis ein schlechter Aufnahmestatus des Patienten und das Auftreten von Komplikationen im Verlauf verantwortlich sind.}, subject = {Subarachnoidalblutung}, language = {de} } @phdthesis{Ramthor2007, author = {Ramthor, Mathias}, title = {Therapeutischer Einfluß von zwei Antidepressiva auf das Schmerzverhalten von Ratten mit einer chronischen Konstriktionsl{\"a}sion des N. ischiadicus}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-23739}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2007}, abstract = {In dieser Arbeit sollte an weiblichen Sprague Dawley Ratten untersucht werden, ob sich durch die Antidepressiva Amitriptylin und Venlafaxin Schmerzverhalten nach Nervenl{\"a}sion verringern l{\"a}ßt und wenn ja, welche Mechanismen dieser Wirkung zugrunde liegen. Den Tieren wurde einseitig der N. ischiadicus nach dem Nervenl{\"a}sionsmodell der Chronic-Constriction-Injury (CCI) operiert. Das Schmerzverhalten der mit Antidepressiva behandelten Tiere wurde {\"u}ber zwei bis drei Wochen verblindet im Vergleich mit plazebobehandelten Tieren untersucht. Das Ausmaß von Hitzehyperalgesie und taktiler Allodynie wurde durch die Anwendung etablierter Testverfahren quantifiziert. Amitriptylin hatte in der Dosis von zweimal t{\"a}glich 10 mg/kg KG i.p. keinen relevanten Effekt auf das Schmerzverhalten der Tiere. Eine akute Gabe von Amitriptylin bei Tieren, die zuvor {\"u}ber 19 Tage chronisch mit Amitriptylin behandelt worden waren, reduzierte die taktile Allodynie geringgradig und hatte keinen Einfluß auf die Hitzehyperalgesie. Venlafaxin in der Dosis von zweimal t{\"a}glich 25 mg/kg KG p.o. reduzierte in einigen Teilversuchen m{\"a}ßiggradig die Hitzehyperalgesie und die taktile Allodynie nach CCI. Auf diesen Ergebnissen aufbauend wurde versucht, die Wirkung der chronischen Venlafaxin-Medikation durch Kombination mit zus{\"a}tzlich akut verabreichten alpha-adrenergen- bzw. µ-Opiat-Rezeptor-agonistischen Substanzen zu verst{\"a}rken. Die Kombination von Venlafaxin mit dem alpha-2A-Rezeptoragonisten Clonidin ergab eine Wirkungsverst{\"a}rkung in Bezug auf die Reduktion der Hitzehyperalgesie, wobei sich zus{\"a}tzlich eine Eigenwirkung von Clonidin nachweisen ließ. Der µ-Opiat-Rezeptor-Agonist Morphin f{\"u}hrte hingegen zu keiner signifikanten Wirkungsverst{\"a}rkung in Kombination mit Venlafaxin. Im Anschluß an die jeweilige Testreihe wurde den Tieren Nervengewebe entnommen, welches nach immunhistochemischer F{\"a}rbung f{\"u}r alpha-2A- und µ-Rezeptoren morphometrisch evaluiert wurde. Dies diente der Untersuchung der Hypothese, daß den o.g. Wirkungen eine Vermehrung der entsprechenden Rezeptoren bei Venlafaxin-behandelten Tieren zugrunde lag. Die chronische postoperative Gabe von Venlafaxin hatte keinen Einfluß auf die Anzahl von alpha-2A-Rezeptor-immunreaktiven Neuronen im Spinalganglion CCI-operierter Ratten. Allerdings ließ sich unter der Medikation die Immunreaktivit{\"a}t f{\"u}r alpha-2A-Rezeptoren vermehrt in großkalibrigen Spinalganglienneuronen nachweisen. Die chronische postoperative Gabe von Venlafaxin f{\"u}hrte zudem zu einer Zunahme von µ-Opiat-Rezeptoren im ipsilateralen N. ischiadicus CCI-operierter Ratten. Im Spinalganglion ergab sich nach Venlafaxinbehandlung keine Ver{\"a}nderung der Anzahl der µ-Rezeptor-immunreaktiven Neurone. Allerdings konnte durch chronische Venlafaxin-Medikation eine Ph{\"a}notyp-Verschiebung mit Auftreten von µ-Rezeptor-Immunreaktivit{\"a}t in großkalibrigen Neuronen, wie sie nach CCI ohne Venlafaxinbehandlung auftrat, verhindert werden. Die Ergebnisse der Arbeit zeigen, daß die chronische, zweimal t{\"a}gliche Anwendung der Antidepressiva Amitriptylin und Venlafaxin das Schmerz-assoziierte Verhalten von Ratten nach einer peripheren Nervenl{\"a}sion inkonstant und nur in unzureichendem Ausmaß beeinflussen. Unabh{\"a}ngig davon wurden in den immunhistochemischen Untersuchungen Ver{\"a}nderungen in der Verteilung µ- und alpha-adrenerger Rezeptoren in Spinalganglionzellen und Ischiasnerv beobachtet, die auf eine kontinuierliche Venlafaxin-Medikation zur{\"u}ckzuf{\"u}hren zu sein scheinen. Ber{\"u}cksichtigt man vor diesem Hintergrund die Tatsache, daß sich die Venlafaxinwirkung durch den alpha-2A-Agonisten Clonidin verst{\"a}rken ließ, so bieten diese Zusammenh{\"a}nge eine m{\"o}gliche Erkl{\"a}rung f{\"u}r die zugrundeliegenden Mechanismen der Wirkungsvermittlung von Antidepressiva in der Behandlung einer schmerzhaften Mononeuropathie.}, language = {de} } @phdthesis{Karl2017, author = {Karl, Franziska}, title = {The role of miR-21 in the pathophysiology of neuropathic pain using the model of B7-H1 knockout mice}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-156004}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {The impact of microRNA (miRNA) as key players in the regulation of immune and neuronal gene expression and their role as master switches in the pathophysiology of neuropathic pain is increasingly recognized. miR-21 is a promising candidate that could be linked to the immune and the nociceptive system. To further investigate the pathophysiological role of miR-21 in neuropathic pain, we assesed mice deficient of B7 homolog 1 (B7-H1 ko), a protein with suppressive effect on inflammatory responses. B7-H1 ko mice and wildtype littermates (WT) of three different age-groups, young (8 weeks), middle-aged (6 months), and old (12 months) received a spared nerve injury (SNI). Thermal withdrawal latencies and mechanical withdrawal thresholds were determined. Further, we investigated anxiety-, depression-like and cognitive behavior. Quantitative real time PCR was used to determine miR-21 relative expression in peripheral nerves, dorsal root ganglia and white blood cells (WBC) at distinct time points after SNI. Na{\"i}ve B7-H1 ko mice showed mechanical hyposensitivity with increasing age. Young and middle-aged B7-H1 ko mice displayed lower mechanical withdrawal thresholds compared to WT mice. From day three after SNI both genotypes developed mechanical and heat hypersensitivity, without intergroup differences. As supported by the results of three behavioral tests, no relevant differences were found for anxiety-like behavior after SNI in B7-H1 ko and WT mice. Also, there was no indication of depression-like behavior after SNI or any effect of SNI on cognition in both genotypes. The injured nerves of B7-H1 ko and WT mice showed higher miR-21 expression and invasion of macrophages and T cells 7 days after SNI without intergroup differences. Perineurial miR-21 inhibitor injection reversed SNI-induced mechanical and heat hypersensitivity in old B7-H1 ko and WT mice. This study reveals that reduced mechanical thresholds and heat withdrawal latencies are associated with miR-21 induction in the tibial and common peroneal nerve after SNI, which can be reversed by perineurial injection of a miR-21 inhibitor. Contrary to expectations, miR-21 expression levels were not higher in B7-H1 ko compared to WT mice. Thus, the B7-H1 ko mouse may be of minor importance for the study of miR-21 related pain. However, these results spot the contribution of miR-21 in the pathophysiology of neuropathic pain and emphasize the crucial role of miRNA in the regulation of neuronal and immune circuits that contribute to neuropathic pain.}, subject = {neuropathic pain}, language = {en} } @article{DingSeusingNasseroleslamietal.2023, author = {Ding, Hao and Seusing, Nelly and Nasseroleslami, Bahman and Anwar, Abdul Rauf and Strauss, Sebastian and Lotze, Martin and Grothe, Matthias and Groppa, Sergiu and Muthuraman, Muthuraman}, title = {The role of ipsilateral motor network in upper limb movement}, series = {Frontiers in Physiology}, volume = {14}, journal = {Frontiers in Physiology}, issn = {1664-042X}, doi = {10.3389/fphys.2023.1199338}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321805}, year = {2023}, abstract = {The execution of voluntary movements is primarily governed by the cerebral hemisphere contralateral to the moving limb. Previous research indicates that the ipsilateral motor network, comprising the primary motor cortex (M1), supplementary motor area (SMA), and premotor cortex (PM), plays a crucial role in the planning and execution of limb movements. However, the precise functions of this network and its interplay in different task contexts have yet to be fully understood. Twenty healthy right-handed participants (10 females, mean age 26.1 ± 4.6 years) underwent functional MRI scans while performing biceps brachii representations such as bilateral, unilateral flexion, and bilateral flexion-extension. Ipsilateral motor evoked potentials (iMEPs) were obtained from the identical set of participants in a prior study using transcranial magnetic stimulation (TMS) targeting M1 while employing the same motor tasks. The voxel time series was extracted based on the region of interest (M1, SMA, ventral PM and dorsal PM). Directed functinal connectivity was derived from the extracted time series using time-resolved partial directed coherence. We found increased connectivity from left-PMv to both sides M1, as well as right-PMv to both sides SMA, in unilateral flexion compared to bilateral flexion. Connectivity from left M1 to left-PMv, and left-SMA to right-PMd, also increased in both unilateral flexion and bilateral flexion-extension compared to bilateral flexion. However, connectivity between PMv and right-M1 to left-PMd decreased during bilateral flexion-extension compared to unilateral flexion. Additionally, during bilateral flexion-extension, the connectivity from right-M1 to right-SMA had a negative relationship with the area ratio of iMEP in the dominant side. Our results provide corroborating evidence for prior research suggesting that the ipsilateral motor network is implicated in the voluntary movements and underscores its involvement in cognitive processes such as movement planning and coordination. Moreover, ipsilateral connectivity from M1 to SMA on the dominant side can modulate the degree of ipsilateral M1 activation during bilateral antagonistic contraction.}, language = {en} } @phdthesis{Hoerner2024, author = {H{\"o}rner, Michaela}, title = {The role of inflammation in hereditary spastic paraplegia type 11}, doi = {10.25972/OPUS-30336}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303368}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Hereditary spastic paraplegias (HSPs) are genetically-determined, neurodegenerative disorders characterized by progressive weakness and spasticity of the lower limbs. Spastic paraplegia type 11 (SPG11) is a complicated form of HSP, which is caused by mutations in the SPG11 gene encoding spatacsin, a protein possibly involved in lysosomal reformation. Based on our previous studies demonstrating that secondary neuroinflammation can be a robust amplifier of various genetically-mediated diseases of both the central and peripheral nervous system, we here test the possibility that neuroinflammation may modify the disease outcome also in a mouse model for SPG11. Spg11-knockout (Spg11-/-) mice develop early walking pattern and behavioral abnormalities, at least partially reflecting motor, and behavioral changes typical for patients. Furthermore, we detected a progressive increase in axonal damage and axonal spheroid formation in the white and grey matter compartments of the central nervous system of Spg11-/- mice. This was accompanied by a concomitant substantial increase of secondary inflammation by cytotoxic CD8+ and CD4+ T-lymphocytes. We here provide evidence that disease-related changes can be ameliorated/delayed by the genetic deletion of the adaptive immune system. Accordingly, we provide evidence that repurposing clinically approved immunomodulators (fingolimod/FTY720 or teriflunomide), that are in use for treatment of multiple sclerosis (MS), also improve disease symptoms in mice, when administered in an early (before neural damage) or late (after/during neural damage) treatment regime. This work provides strong evidence that immunomodulation can be a therapeutic option for the still untreatable SPG11, including its typical neuropsychological features. This poses the question if inflammation is not only a disease amplifier in SPG11 but can act as a unifying factor also for other genetically mediated disorders of the CNS. If true, this may pave the way to therapeutic options in a wide range of still untreatable, primarily genetic, neurological disorders by repurposing approved immunomodulators.}, subject = {Entz{\"u}ndung}, language = {en} } @phdthesis{YuHwa2009, author = {Yu-Hwa, Huang}, title = {The Role of HLA-G-expressing Regulatory T cells in Multiple Sclerosis: A Perspective of Beneficial Inflammation in the Central Nervous System Inflammation}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-39957}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2009}, abstract = {Die Regulation von Effektor-T-Zellen ist ein wichtiger Mechanismus zur Kontrolle organspezifischer Entz{\"u}ndungen. Dabei sind regulatorische T-Zellen (Treg) maßgeblich an der Aufrechterhaltung peripherer Immuntoleranz und parenchymaler Immunhom{\"o}ostase beteiligt. Eine neue Population von humanen, nat{\"u}rlich vorkommenden Treg Zellen wurde durch ihre konstitutive Expression des immuntolerogenen Molek{\"u}ls HLA-G identifiziert. Im ersten Teil dieser Arbeit wurden die Mechanismen, durch die CD4+ HLA-Gpos Treg Zellen ihre Zielzellen (autologe HLA-Gneg T-Zellen) modulieren, aufgekl{\"a}rt. Unter Verwendung eines Suppressionsansatzes in Abwesenheit von antigenpr{\"a}sentierenden Zellen (APC) wurden T-T-Zell-Interaktionen, die die Proliferation von HLA-Gneg T-Zellen hemmen, demonstriert. Diese Suppression, die durch die Stimulierung des T-Zell-Rezeptors auf HLA-Gpos Treg Zellen verst{\"a}rkt wurde, war unabh{\"a}ngig vom Zell-Zell-Kontakt. Die HLA-Gneg T-Zellen erlangten nach Entfernung der HLA-Gpos Treg Zellen und einer erneuten Stimulierung ihrer T-Zell- Rezeptoren ihre F{\"a}higkeit zur Proliferation wieder. Dies wies auf die Umkehrbarkeit dieser Suppression hin. Dar{\"u}ber hinaus war die HLA-Gpos Treg-vermittelte Suppression entscheidend von der IL-10- Sekretion, nicht jedoch von TGF-\&\#946; abh{\"a}ngig. Zusammengefasst beschreibt dieser Teil der Arbeit eine detaillierte Charakterisierung der Mechanismen, wie HLA-Gpos Treg HLA-Gneg TZellen supprimieren. Das tiefere Verst{\"a}ndnis der Wirkmechanismen von HLA-Gpos Treg k{\"o}nnte in therapeutischen Strategien verwendet werden, in denen die regulatorische Funktion der T-Zell-Suppression verst{\"a}rkt oder moduliert werden soll. Im zweiten Teil dieser Arbeit wurde die potenzielle Rolle von HLA-Gpos Treg bei der Multiplen Sklerose (MS) untersucht, einer klassischen Autoimmunerkrankung des Zentralnervensystems (ZNS). Im Gegensatz zu Vergleichspatienten mit nicht-entz{\"u}ndlichen Erkrankungen konnte im Liquor von MS Patienten eine erh{\"o}hte Anzahl von HLA-Gpos Treg gefunden werden. Diese aus dem Liquor isolierten HLA-Gpos Treg wiesen ph{\"a}notypische Merkmale von zentralen Ged{\"a}chtnis-T-Zellen (CD45RA- CD27+) auf, exprimierten den Aktivierungsmarker ICOS sowie deutlich h{\"o}here Level des Chemokinrezeptors (CCR) CCR5 und agierten als starke Suppressoren der autologen CD4+ T-Zellproliferation. Durch Verwendung eines in vitro Modells der humanen Bluthirnschranke konnte demonstriert werden, dass HLA-Gpos Treg eine starke Neigung zur Migration haben, die durch die CCR5- Liganden MIP1\&\#945; und RANTES, nicht jedoch durch MIP3\&\#946; (Ligand von CCR7) unterst{\"u}tzt wird. Diese Chemokin-induzierte Migration von HLA-Gpos Treg war auch mit einer Steigerung der suppressiven Kapazit{\"a}t nach Zelltransmigration assoziiert. Im Gegensatz zu CD4+CD25+, FoxP3-exprimierenden Treg zeigten HLA-Gpos Treg von MS-Patienten keine beeintr{\"a}chtigte Funktionalit{\"a}t. Dies deutet auf eine selektive Rekrutierung von HLA-Gpos Treg zu Entz{\"u}ndungsherden im ZNS und ihre Beteiligung an der Bek{\"a}mpfung der destruktiven Entz{\"u}ndung hin. Die Ergebnisse dieser Studien tragen zum weitergehenden Verst{\"a}ndnis der Rolle und Funktion HLA-Gpos Treg Zellen bei und stellen somit ein wichtiges pathophysiologisches Beispiel „gutartiger" T-Zell-Entz{\"u}ndung w{\"a}hrend der ZNS Autoimmunit{\"a}t dar, das sowohl aus pathophysiologischer als auch therapeutischer Sicht interessant ist.}, subject = {Regulatorische T-Zellen}, language = {en} } @article{GomezFernandezLopezdeLapuentePortillaAstobizaetal.2020, author = {G{\´o}mez-Fern{\´a}ndez, Paloma and Lopez de Lapuente Portilla, Aitzkoa and Astobiza, Ianire and Mena, Jorge and Urtasun, Andoni and Altmann, Vivian and Matesanz, Fuencisla and Otaegui, David and Urcelay, Elena and Antig{\"u}edad, Alfredo and Malhotra, Sunny and Montalban, Xavier and Castillo-Trivi{\~n}o, Tamara and Espino-Pais{\´a}n, Laura and Aktas, Orhan and Buttmann, Mathias and Chan, Andrew and Fontaine, Bertrand and Gourraud, Pierre-Antoine and Hecker, Michael and Hoffjan, Sabine and Kubisch, Christian and K{\"u}mpfel, Tania and Luessi, Felix and Zettl, Uwe K. and Zipp, Frauke and Alloza, Iraide and Comabella, Manuel and Lill, Christina M. and Vandenbroeck, Koen}, title = {The rare IL22RA2 signal peptide coding variant rs28385692 decreases secretion of IL-22BP isoform-1, -2 and -3 and is associated with risk for multiple sclerosis}, series = {Cells}, volume = {9}, journal = {Cells}, number = {1}, issn = {2073-4409}, doi = {10.3390/cells9010175}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200769}, year = {2020}, abstract = {The IL22RA2 locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly (p = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by IL22RA2 (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset (p = 3.17 × 10\(^{-4}\)). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50\%-60\% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS.}, language = {en} } @phdthesis{Dreykluft2013, author = {Dreykluft, Angela}, title = {The PD-1/B7-H1 Pathway in a Transgenic Mouse Model for Spontaneous Autoimmune Neuroinflammation: Immunological Studies on Devic B7-H1-/- Mice}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-83288}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2013}, abstract = {Multiple sclerosis is an autoimmune disease of the central nervous system characterized by inflammatory, demyelinating lesions and neuronal death. Formerly regarded as a variant of MS, neuromyelitis optica (NMO)/Devic's disease is now recognized as a distinct neurological disorder exhibiting characteristic inflammatory and demyelinated foci in the optic nerves and the spinal cord sparing the brain. With the introduction of the double-transgenic "Devic mouse" model featuring spontaneous, adjuvant-free incidence of autoimmune neuroinflammation due to the interaction of transgenic MOG-specific T and B cells, a promising tool was found for the analysis of factors triggering or preventing autoimmunity. The co-inhibitory molecule B7-H1 has been proposed to contribute to the maintenance of peripheral tolerance and to confine autoimmune inflammatory damage via the PD-1/B7-H1 pathway. Compared to Devic B7-H1+/+ mice, Devic B7-H1-/- mice developed clinical symptoms with a remarkably higher incidence rate and faster kinetics emphasized by deteriorated disease courses and a nearly quadrupled mortality rate. Remarkably enlarged immune-cell accumulation in the CNS of Devic B7-H1-/- mice, in particular of activated MOG-specific CD4+ T cells, correlated with the more severe clinical features. Our studies showed that the CNS not only was the major site of myelin-specific CD4+ T-cell activation but also that B7-H1 expression within the target organ significantly influenced T-cell activation and differentiation levels. Analysis at disease maximum revealed augmented accumulation of MOG-specific CD4+ T cells in the peripheral lymphoid organs of Devic B7-H1-/- mice partly due to increased T-cell proliferation rates. Transgenic MOG-specific B cells of Devic B7-H1-/- mice activated MOG-specific CD4+ T cells more efficiently than B cells of Devic B7-H1+/+ mice. This observation indicated a relevant immune-modulating role of B7-H1 on APCs (antigen-presenting cells) in this mouse model. We also assumed altered thymic selection processes to be involved in increased peripheral CD4+ T-cell numbers of Devic B7-H1-/- mice as we found more thymocytes expressing the transgenic MOG-specific T-cell receptor (TCR). Moreover, preliminary in vitro experiments hinted on an enhanced survival of TCRMOG-transgenic CD4+ T cells of Devic B7-H1-/- mice; a mechanism that might as well have led to higher peripheral T-cell accumulation. Elevated levels of MOG-specific CD4+ T cells in the periphery of Devic B7-H1-/- mice could have entailed the higher quantities in the CNS. However, mechanisms such as CNS-specific proliferation and/or apoptosis/survival could also have contributed. This should be addressed in future investigations. Judging from in vitro migration assays and adoptive transfer experiments on RAG-1-/- recipient mice, migratory behavior of MOG-specific CD4+ T cells of Devic B7-H1+/+ and Devic B7-H1-/- mice seemed not to differ. However, enhanced expression of the transmigration-relevant integrin LFA-1 on CD4+ T cells in young symptom-free Devic B7-H1-/- mice might hint on temporally differently pronounced transmigration capacities during the disease course. Moreover, we attributed the earlier conversion of CD4+ T cells into Th1 effector cells in Devic B7-H1-/- mice during the initiation phase to the lack of co-inhibitory signaling via PD-1/B7-H1 possibly leading to an accelerated disease onset. Full blown autoimmune inflammatory processes could have masked these slight effects of B7-H1 in the clinical phase. Accordingly, at peak of the disease, Th1 and Th17 effector functions of peripheral CD4+ T cells were comparable in both mouse groups. Moreover, judging from titers of MOG-specific IgG1 and IgM antibodies, alterations in humoral immunity were not detected. Therefore, clinical differences could not be explained by altered T-cell or B-cell effector functions at disease maximum. B7-H1 rather seemed to take inhibitory effect in the periphery during the initiation phase only and consistently within the target organ by parenchymal expression. Our observations indicate that B7-H1 plays a relevant role in the regulation of T-cell responses in this mouse model for spontaneous CNS autoimmunity. By exerting immune-modulating effects in the preclinical as well as the clinical phase of the disease, B7-H1 contributed to the confinement of the immunopathological tissue damage in Devic B7-H1+/+ mice mirrored by later disease onsets and lower disease scores. As a model for spontaneous autoimmunity featuring a close to 100 \% incidence rate, the Devic B7-H1-/- mouse may prove instrumental in clarifying disease-triggering and -limiting factors and in validating novel therapeutic approaches in the field of autoimmune neuroinflammation, in particular the human Devic's disease.}, subject = {Autoimmunit{\"a}t}, language = {en} } @phdthesis{Klein2015, author = {Klein, Dennis}, title = {The pathogenic role of endogenous antibodies in a mouse model for Charcot-Marie-Tooth 1B neuropathy}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121941}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Charcot-Marie-Tooth (CMT) type 1 neuropathies are a genetically heterogeneous group of non-treatable inherited disorders affecting the peripheral nervous system that lead to sensory and motor dysfunction. Secondary low grade inflammation, implicating the innate and adaptive immune system, could previously be identified as a substantial disease modifier in two mouse models for CMT1, CMT1B and 1X, respectively. However, the exact mechanism how the adaptive immune system contributes to disease pathogenesis is not completely understood. Based on observations that the accumulation of endogenous antibodies to myelin components is important for rapid myelin clearance after nerve injury during Wallerian degeneration, a possibly similar mechanism was considered for endogenous antibodies as disease amplifier in mice heterozygously deficient for P0 (P0het), mimicking some typical features of CMT1B. In this study an increased antibody deposition was detected in the affected peripheral nerves of P0het myelin mutant mice. By crossbreeding P0het mutants with mice specifically lacking B-lymphocytes, and therefore antibodies (JHD-/-), a decline of endoneurial macrophages together with a substantially ameliorated demyelination could be demonstrated in 6-month-old mutant mice. Moreover, reconstitution with murine IgGs reverted the neuropathic phenotype, substantiating that endogenous antibodies are potentially pathogenic at this early stage of disease. Unexpectedly, in 12-months-old P0het mutants, JHD deficiency resulted in disease aggravation accompanied by an increased inflammatory reaction and M2-polarized macrophage response. These observations suggest that in a mouse model for CMT1B, the lack of endogenous antibodies has a dichotomous effect: ameliorating early macrophage-mediated demyelination, as opposed to increasing inflammatory reactions leading to disease aggravation at older ages.}, subject = {Maus}, language = {en} } @article{FrerichsSirenFeuersteinetal.1992, author = {Frerichs, K. and Sir{\`e}n, Anna-Leena and Feuerstein, G. and Hallenbeck, JM}, title = {The onset of postischemic hypoperfusion in rats is precipitous and may be controlled by local neurons}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-47980}, year = {1992}, abstract = {Background and Purpose: Reperfusion following transient global cerebral ischemia is characterized by an initial hyperemic phase, which precedes hypo perfusion. The pathogenesis of these flow derangements remains obscure. Our study investigates the dynamics of postischemic cerebral blood flow changes, with particular attention to the role of local neurons. Metho(Js: We assessed local cortical blood flow continuously by laser Doppler flowmetry to permit observation of any rapid flow changes after forebrain ischemia induced by four-vessel occlusion for 20 minutes in rats. To investigate the role of local cortical neurons in the regulation of any blood flow fluctuations, five rats received intracortical microinjections of a neurotoxin (10 p,g ibotenic acid in 1 p,1; 1.5-mm-depth parietal cortex) 24 hours before ischemia to induce selective and localized neuronal depletion in an area corresponding to the sampie volume of the laser Doppler probe (1 mm3 ). Local cerebral blood flow was measured within the injection site and at an adjacent control site. Results: Ischemia was followed by marked hyperemia (235 ±23\% of control, n =7), followed by secondary hypoperfusion (45±3\% of control, n=7). The transition from hyperemia to hypoperfusioo occurred not gradually but precipitously (maximal slope of flow decay: 66±6\%/min; n=7). In ibotenic acid-injected rats, hyperemia was preserved at the injection site, but the sudden decline of blood flow was abolished (maximal slope of flow decay: 5±3\%/min compared with 53±8\%/min at the control site; n=5, p47\%. A significant correlation was described between the asymmetry indices of the swinging of the two arms and dopaminergic striatal innervation. When arm ROM was reduced, we found a positive correlation between upper-lower limb phase shift modulation ( at different gait velocities) and striatal dopaminergic innervation. These findings are preliminary evidence that dopaminergic striatal tone plays a modulatory role in upper-limb locomotor synergies and upper-lower limb coupling while walking at different velocities.}, language = {en} } @phdthesis{Schwab2009, author = {Schwab, Nicholas}, title = {The importance of CD8\(^+\) T cells and antigen-presenting cells in the immune reaction of primary inflammatory versus degenerative diseases}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-37330}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2009}, abstract = {The bidirectional influence of parenchymal cells and cells of the immune system, especially of antigen-presenting and CD8\(^+\) T cells, in situations of putative auto- immune pathogenicity and degeneration was the main topic of this thesis. In the first part, the influence of human muscle cells on antigen-presenting cells was investigated. In inflammatory myopathies prominent infiltrates of immune cells containing T cells and antigen-presenting cells like macrophages and dendritic cells are present. The hypothesis was that human myoblasts have an inhibiting influence on these antigen-presenting cells under homeostatic conditions. A dysfunction or impairment under inflammatory circumstances might contribute to the development of myopathic conditions. The surface analysis of dendritic cells cocultured with myoblasts showed that immature dendritic cells could be driven into a reversible semi- mature state with significantly elevated levels of CD80. These dendritic cells were additionally characterized by their inhibiting function on T-cell proliferation. It was also shown that the lysates of healthy myoblasts could strongly enhance the phagocytic ability of macrophages, which could help with muscle regeneration and which might be disturbed in myositis patients. The second part of this thesis was about the clonal specificity of CD8\(^+\) T cells in a mouse model with genetically induced over-expression of PLP in oligodendrocytes. Here, we could show that the cytotoxic T lymphocytes, which had previously been shown to be pathogenic, were clonally expanded in the CNS of the transgenic mice. The amino acid sequences of the corresponding receptor chains were not identical, yet showed some similarities, which could mean that these clones recognize similar antigens (or epitopes of the same antigen). The knockout of PD-1 in this setting allowed for an analysis of the importance of tissue immune regulation. It became evident that the absence of PD-1 induced a larger number of clonal expansions in the CNS, hinting towards a reduced threshold for clonal disturbance and activation in these T cells. The expansions were, however, not pathogenic by themselves. Only in the presence of tissue damage and an antigenic stimulus (in our case the overexpression of PLP), the PD-1 limitation exacerbated the immune pathogenicity. Therefore, only in the presence of a "tissue damage signal", the dyshomeostasis of T cells lacking PD-1 achieved high pathogenetic relevance. Finally, we investigated the pathogenetic role of CD8 T cells in Rasmussen encephalitis, a rare and chronic neurological disease mainly affecting children. The analysis of the T-cell receptor repertoire in Rasmussen encephalitis patients in the peripheral CD4\(^+\) and CD8\(^+\) T-cell compartments as well as the brain revealed the involvement of T cells in the pathogenicity of this disease. Many clonal expansions in the brain matched CD8\(^+\) T-cell expansions in the periphery on the sequence level. These putatively pathogenic clones could be visualized by immunohistochemistry in the brain and were found in close proximity to astrocytes and neurons. Additionally, the expanded clones could be found in the periphery of patients for at least one year.}, subject = {T-Lymphozyt}, language = {en} } @phdthesis{Spitzel2023, author = {Spitzel, Marlene}, title = {The impact of inflammation, hypoxia, and vasculopathy on pain development in the α-galactosidase A mouse model of Morbus Fabry}, doi = {10.25972/OPUS-34579}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-345794}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Fabry disease (FD), an X-linked lysosomal storage disorder, is caused by variants in the gene α-galactosidase A (GLA). As a consequence, the encoded homonymous enzyme GLA is not produced in sufficient amount or does not function properly. Subsequently, globotriaosylceradmide (Gb3), the target substrate of GLA, starts accumulating in several cell types, especially neurons and endothelial cells. FD patients suffer from multiorgan symptoms including cardiomyopathy, nephropathy, stroke, and acral burning pain. It is suggested that the impact of pathological Gb3 accumulation, inflammatory and hypoxic processes, and vasculopathy are contributing to the specific FD pain phenotype. Thus, we investigated the role of inflammation, hypoxia, and vasculopathy on molecular level in dorsal root ganglia (DRG) of the GLA knockout (KO) mouse model. Further, we investigated pain-like characteristics of GLA KO mice at baseline (BS), after capsaicin administration, and after repeated enzyme replacement therapy (ERT) administration for a period of 1.5 years. Acquired data showed disturbances in immune response markers represented by downregulated inflammation-associated genes and lower numbers of CD206+ macrophages in DRG of GLA KO mice. Hypoxic mechanisms were active in DRG of GLA KO mice reflected by increased gene expression of hypoxia- and DNA damage-associated targets, higher numbers of hypoxia-inducible factor 1α-positive (HIF1α+) and carbonic anhydrase 9-positive (CA9+) neurons in DRG of GLA KO mice, and DRG neuronal HIF1α cytosolic-nuclear translocation in GLA KO mice. Vascularization in DRG of GLA KO mice was reduced including lower numbers of blood vessel branches and reduced total blood vessel length. Pain-like behavior of the GLA KO mouse model revealed no mechanical hypersensitivity at BS but age-dependent heat hyposensitivity, which developed also age-matched wild type (WT) mice. Capsaicin administration under isoflurane anesthesia did not elicit the development of nocifensive behavior in GLA KO mice after mechanical or heat stimulation. Repeated ERT administration did not show a clear effect in GLA KO mice in terms of restored heat hyposensitivity to BS paw withdrawal latencies. In summary, we demonstrated the impact of disturbed immune response markers, active hypoxic mechanisms, and reduced vascularization on molecular FD pathophysiology.}, subject = {Fabry-Krankheit}, language = {en} } @article{NiemannHuberWagneretal.2014, author = {Niemann, Axel and Huber, Nina and Wagner, Konstanze M. and Somandin, Christian and Horn, Michael and Lebrun-Julien, Fr{\´e}d{\´e}ric and Angst, Brigitte and Pereira, Jorge A. and Halfter, Hartmut and Welzl, Hans and Feltri, M. Laura and Wrabetz, Lawrence and Young, Peter and Wessig, Carsten and Toyka, Klaus V. and Suter, Ueli}, title = {The Gdap1 knockout mouse mechanistically links redox control to Charcot-Marie-Tooth disease}, series = {Brain}, volume = {137}, journal = {Brain}, number = {3}, doi = {10.1093/brain/awt371}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120731}, pages = {668-82}, year = {2014}, abstract = {The ganglioside-induced differentiation-associated protein 1 (GDAP1) is a mitochondrial fission factor and mutations in GDAP1 cause Charcot-Marie-Tooth disease. We found that Gdap1 knockout mice (\(Gdap1^{-/-}\)), mimicking genetic alterations of patients suffering from severe forms of Charcot-Marie-Tooth disease, develop an age-related, hypomyelinating peripheral neuropathy. Ablation of Gdap1 expression in Schwann cells recapitulates this phenotype. Additionally, intra-axonal mitochondria of peripheral neurons are larger in \(Gdap1^{-/-}\) mice and mitochondrial transport is impaired in cultured sensory neurons of \(Gdap1^{-/-}\) mice compared with controls. These changes in mitochondrial morphology and dynamics also influence mitochondrial biogenesis. We demonstrate that mitochondrial DNA biogenesis and content is increased in the peripheral nervous system but not in the central nervous system of \(Gdap1^{-/-}\) mice compared with control littermates. In search for a molecular mechanism we turned to the paralogue of GDAP1, GDAP1L1, which is mainly expressed in the unaffected central nervous system. GDAP1L1 responds to elevated levels of oxidized glutathione by translocating from the cytosol to mitochondria, where it inserts into the mitochondrial outer membrane. This translocation is necessary to substitute for loss of GDAP1 expression. Accordingly, more GDAP1L1 was associated with mitochondria in the spinal cord of aged \(Gdap1^{-/-}\) mice compared with controls. Our findings demonstrate that Charcot-Marie-Tooth disease caused by mutations in GDAP1 leads to mild, persistent oxidative stress in the peripheral nervous system, which can be compensated by GDAP1L1 in the unaffected central nervous system. We conclude that members of the GDAP1 family are responsive and protective against stress associated with increased levels of oxidized glutathione.}, language = {en} } @article{KrupkaMayWeimeretal.2016, author = {Krupka, Jennifer and May, Frauke and Weimer, Thomas and Pragst, Ingo and Kleinschnitz, Christoph and Stoll, Guido and Panousis, Con and Dickneite, Gerhard and Nolte, Marc W.}, title = {The Coagulation Factor XIIa Inhibitor rHA-Infestin-4 Improves Outcome after Cerebral Ischemia/Reperfusion Injury in Rats}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0146783}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167370}, pages = {e0146783}, year = {2016}, abstract = {Background and Purpose Ischemic stroke provokes severe brain damage and remains a predominant disease in industrialized countries. The coagulation factor XII (FXII)-driven contact activation system plays a central, but not yet fully defined pathogenic role in stroke development. Here, we investigated the efficacy of the FXIIa inhibitor rHA-Infestin-4 in a rat model of ischemic stroke using both a prophylactic and a therapeutic approach. Methods For prophylactic treatment, animals were treated intravenously with 100 mg/kg rHA-Infestin-4 or an equal volume of saline 15 min prior to transient middle cerebral artery occlusion (tMCAO) of 90 min. For therapeutic treatment, 100 mg/kg rHA-Infestin-4, or an equal volume of saline, was administered directly after the start of reperfusion. At 24 h after tMCAO, rats were tested for neurological deficits and blood was drawn for coagulation assays. Finally, brains were removed and analyzed for infarct area and edema formation. Results Within prophylactic rHA-Infestin-4 treatment, infarct areas and brain edema formation were reduced accompanied by better neurological scores and survival compared to controls. Following therapeutic treatment, neurological outcome and survival were still improved although overall effects were less pronounced compared to prophylaxis. Conclusions With regard to the central role of the FXII-driven contact activation system in ischemic stroke, inhibition of FXIIa may represent a new and promising treatment approach to prevent cerebral ischemia/reperfusion injury.}, language = {en} } @article{RovitusoDuffySchroeteretal.2015, author = {Rovituso, Damiano M. and Duffy, Catharina E. and Schroeter, Michael and Kaiser, Claudia C. and Kleinschnitz, Christoph and Bayas, Antonios and Elsner, Rebecca and Kuerten, Stefanie}, title = {The brain antigen-specific B cell response correlates with glatiramer acetate responsiveness in relapsing-remitting multiple sclerosis patients}, series = {Scientific Reports}, volume = {5}, journal = {Scientific Reports}, number = {14265}, doi = {10.1038/srep14265}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148172}, year = {2015}, abstract = {B cells have only recently begun to attract attention in the immunopathology of multiple sclerosis (MS). Suitable markers for the prediction of treatment success with immunomodulatory drugs are still missing. Here we evaluated the B cell response to brain antigens in n = 34 relapsing-remitting MS (RRMS) patients treated with glatiramer acetate (GA) using the enzyme-linked immunospot technique (ELISPOT). Our data demonstrate that patients can be subdivided into responders that show brain-specific B cell reactivity in the blood and patients without this reactivity. Only in patients that classified as B cell responders, there was a significant positive correlation between treatment duration and the time since last relapse in our study. This correlation was GA-specific because it was absent in a control group that consisted of interferon-\(\beta\) (IFN-\(\beta\))-treated RRMS patients (n = 23). These data suggest that GA has an effect on brain-reactive B cells in a subset of patients and that only this subset benefits from treatment. The detection of brain-reactive B cells is likely to be a suitable tool to identify drug responders.}, language = {en} } @article{GrohHoernerMartini2018, author = {Groh, Janos and H{\"o}rner, Michaela and Martini, Rudolf}, title = {Teriflunomide attenuates neuroinflammation-related neural damage in mice carrying human PLP1 mutations}, series = {Journal of Neuroinflammation}, volume = {15}, journal = {Journal of Neuroinflammation}, number = {194}, doi = {10.1186/s12974-018-1228-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176524}, year = {2018}, abstract = {Background: Genetically caused neurological disorders of the central nervous system (CNS) are mostly characterized by poor or even fatal clinical outcome and few or no causative treatments are available. Often, these disorders are associated with low-grade, disease-promoting inflammation, another feature shared by progressive forms of multiple sclerosis (PMS). We previously generated two mouse lines carrying distinct mutations in the oligodendrocytic PLP1 gene that have initially been identified in patients diagnosed with MS. These mutations cause a loss of PLP function leading to a histopathological and clinical phenotype common to both PMS and genetic CNS disorders, like hereditary spastic paraplegias. Importantly, neuroinflammation promotes disease progression in these models, suggesting that pharmacological modulation of inflammation might ameliorate disease outcome. Methods: We applied teriflunomide, an approved medication for relapsing-remitting MS targeting activated T-lymphocytes, in the drinking water (10 mg/kg body weight/day). Experimental long-term treatment of PLP mutant mice was non-invasively monitored by longitudinal optical coherence tomography and by rotarod analysis. Immunomodulatory effects were subsequently analyzed by flow cytometry and immunohistochemistry and treatment effects regarding neural damage, and neurodegeneration were assessed by histology and immunohistochemistry. Results: Preventive treatment with teriflunomide attenuated the increase in number of CD8+ cytotoxic effector T cells and fostered the proliferation of CD8+ CD122+ PD-1+ regulatory T cells in the CNS. This led to an amelioration of axonopathic features and neuron loss in the retinotectal system, also reflected by reduced thinning of the innermost retinal composite layer in longitudinal studies and ameliorated clinical outcome upon preventive long-term treatment. Treatment of immune-incompetent PLP mutants did not provide evidence for a direct, neuroprotective effect of the medication. When treatment was terminated, no rebound of neuroinflammation occurred and histopathological improvement was preserved for at least 75 days without treatment. After disease onset, teriflunomide halted ongoing axonal perturbation and enabled a recovery of dendritic arborization by surviving ganglion cells. However, neither neuron loss nor clinical features were ameliorated, likely due to already advanced neurodegeneration before treatment onset. Conclusions: We identify teriflunomide as a possible medication not only for PMS but also for inflammation-related genetic diseases of the nervous system for which causal treatment options are presently lacking.}, language = {en} } @article{DoerckGoebelWeiseetal.2010, author = {Doerck, Sebastian and Goebel, Kerstin and Weise, Gesa and Schneider-Hohendorf, Tilman and Reinhardt, Michael and Hauff, Peter and Schwab, Nicholas and Linker, Ralf and Maeurer, Mathias and Meuth, Sven G. and Wiendl, Heinz}, title = {Temporal Pattern of ICAM-I Mediated Regulatory T Cell Recruitment to Sites of Inflammation in Adoptive Transfer Model of Multiple Sclerosis}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68565}, year = {2010}, abstract = {Migration of immune cells to the target organ plays a key role in autoimmune disorders like multiple sclerosis (MS). However, the exact underlying mechanisms of this active process during autoimmune lesion pathogenesis remain elusive. To test if pro-inflammatory and regulatory T cells migrate via a similar molecular mechanism, we analyzed the expression of different adhesion molecules, as well as the composition of infiltrating T cells in an in vivo model of MS, adoptive transfer experimental autoimmune encephalomyelitis in rats. We found that the upregulation of ICAM-I and VCAM-I parallels the development of clinical disease onset, but persists on elevated levels also in the phase of clinical remission. However, the composition of infiltrating T cells found in the developing versus resolving lesion phase changed over time, containing increased numbers of regulatory T cells (FoxP3) only in the phase of clinical remission. In order to test the relevance of the expression of cell adhesion molecules, animals were treated with purified antibodies to ICAM-I and VCAM-I either in the phase of active disease or in early remission. Treatment with a blocking ICAM-I antibody in the phase of disease progression led to a milder disease course. However, administration during early clinical remission aggravates clinical symptoms. Treatment with anti-VCAM-I at different timepoints had no significant effect on the disease course. In summary, our results indicate that adhesion molecules are not only important for capture and migration of pro-inflammatory T cells into the central nervous system, but also permit access of anti-inflammatory cells, such as regulatory T cells. Therefore it is likely to assume that intervention at the blood brain barrier is time dependent and could result in different therapeutic outcomes depending on the phase of CNS lesion development.}, subject = {Multiple Sklerose}, language = {en} } @article{OdorferWindZeller2019, author = {Odorfer, Thorsten M. and Wind, Teresa and Zeller, Daniel}, title = {Temporal discrimination thresholds and proprioceptive performance: impact of age and nerve conduction}, series = {Frontiers in Neuroscience}, volume = {13}, journal = {Frontiers in Neuroscience}, number = {1241}, issn = {1662-453X}, doi = {10.3389/fnins.2019.01241}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195648}, year = {2019}, abstract = {Background Increasing attention is payed to the contribution of somatosensory processing in motor control. In particular, temporal somatosensory discrimination has been found to be altered differentially in common movement disorders. To date, there have only been speculations as to how impaired temporal discrimination and clinical motor signs may relate to each other. Prior to disentangling this relationship, potential confounders of temporal discrimination, in particular age and peripheral nerve conduction, should be assessed, and a quantifiable measure of proprioceptive performance should be established. ObjectiveTo assess the influence of age and polyneuropathy (PNP) on somatosensory temporal discrimination threshold (STDT), temporal discrimination movement threshold (TDMT), and behavioral measures of proprioception of upper and lower limbs. Methods STDT and TDMT were assessed in 79 subjects (54 healthy, 25 with PNP; age 30-79 years). STDT was tested with surface electrodes over the thenar or dorsal foot region. TDMT was probed with needle electrodes in flexor carpi radialis (FCR) and tibialis anterior (TA) muscle. Goniometer-based devices were used to assess limb proprioception during (i) active pointing to LED markers, (ii) active movements in response to variable visual cues, and (iii) estimation of limb position following passive movements. Pointing (or estimation) error was taken as a measure of proprioceptive performance. Results In healthy subjects, higher age was associated with higher STDT and TDMT at upper and lower extremities, while age did not correlate with proprioceptive performance. Patients with PNP showed higher STDT and TDMT values and decreased proprioceptive performance in active pointing tasks compared to matched healthy subjects. As an additional finding, there was a significant correlation between performance in active pointing tasks and temporal discrimination thresholds. Conclusion Given their notable impact on measures of temporal discrimination, age and peripheral nerve conduction need to be accounted for if STDT and TDMT are applied in patients with movement disorders. As a side observation, the correlation between measures of proprioception and temporal discrimination may prompt further studies on the presumptive link between these two domains.}, language = {en} } @article{BarlinnWinzerWorthmannetal.2021, author = {Barlinn, J. and Winzer, S. and Worthmann, H. and Urbanek, C. and H{\"a}usler, K. G. and G{\"u}nther, A. and Erdur, H. and G{\"o}rtler, M. and Busetto, L. and Wojciechowski, C. and Schmitt, J. and Shah, Y. and B{\"u}chele, B. and Sokolowski, P. and Kraya, T. and Merkelbach, S. and Rosengarten, B. and Stangenberg-Gliss, K. and Weber, J. and Schlachetzki, F. and Abu-Mugheisib, M. and Petersen, M. and Schwartz, A. and Palm, F. and Jowaed, A. and Volbers, B. and Zickler, P. and Remi, J. and Bardutzky, J. and B{\"o}sel, J. and Audebert, H. J. and Hubert, G. J. and Gumbinger, C.}, title = {Telemedizin in der Schlaganfallversorgung - versorgungsrelevant f{\"u}r Deutschland}, series = {Der Nervenarzt}, volume = {92}, journal = {Der Nervenarzt}, number = {6}, issn = {0028-2804}, doi = {10.1007/s00115-021-01137-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307752}, pages = {593-601}, year = {2021}, abstract = {Hintergrund und Ziel Telemedizinische Schlaganfall-Netzwerke tragen dazu bei, die Schlaganfallversorgung und insbesondere den Zugang zu zeitkritischen Schlaganfalltherapien in vorrangig strukturschwachen, l{\"a}ndlichen Regionen zu gew{\"a}hrleisten. Ziel ist eine Darstellung der Nutzungsfrequenz und regionalen Verteilung dieser Versorgungsstruktur. Methoden Die Kommission „Telemedizinische Schlaganfallversorgung" der Deutschen Schlaganfall-Gesellschaft f{\"u}hrte eine Umfragestudie in allen Schlaganfall-Netzwerken durch. Ergebnisse In Deutschland sind 22 telemedizinische Schlaganfall-Netzwerke aktiv, welche insgesamt 43 Zentren (pro Netzwerk: Median 1,5, Interquartilsabstand [IQA] 1-3) sowie 225 Kooperationskliniken (pro Netzwerk: Median 9, IQA 4-17) umfassen und an einem unmittelbaren Zugang zur Schlaganfallversorgung f{\"u}r 48 Mio. Menschen teilhaben. Im Jahr 2018 wurden 38.211 Telekonsile (pro Netzwerk: Median 1340, IQA 319-2758) durchgef{\"u}hrt. Die Thrombolyserate betrug 14,1 \% (95 \%-Konfidenzintervall 13,6-14,7 \%), eine Verlegung zur Thrombektomie wurde bei 7,9 \% (95 \%-Konfidenzintervall 7,5-8,4 \%) der isch{\"a}mischen Schlaganfallpatienten initiiert. Das Finanzierungssystem ist uneinheitlich mit einem Verg{\"u}tungssystem f{\"u}r die Zentrumsleistungen in nur drei Bundesl{\"a}ndern. Diskussion Etwa jeder 10. Schlaganfallpatient wird telemedizinisch behandelt. Die telemedizinischen Schlaganfall-Netzwerke erreichen vergleichbar hohe Lyseraten und Verlegungen zur Thrombektomie wie neurologische Stroke-Units und tragen zur Sicherstellung einer fl{\"a}chendeckenden Schlaganfallversorgung bei. Eine netzwerk{\"u}bergreifende Sicherstellung der Finanzierung und einheitliche Erhebung von Qualit{\"a}tssicherungsdaten haben das Potenzial diese Versorgungsstruktur zuk{\"u}nftig weiter zu st{\"a}rken.}, language = {de} } @article{SchuhmannKraftBieberetal.2019, author = {Schuhmann, Michael K. and Kraft, Peter and Bieber, Michael and Kollikowski, Alexander M. and Schulze, Harald and Nieswandt, Bernhard and Pham, Mirko and Stegner, David and Stoll, Guido}, title = {Targeting platelet GPVI plus rt-PA administration but not α2β1-mediated collagen binding protects against ischemic brain damage in mice}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {8}, issn = {1422-0067}, doi = {10.3390/ijms20082019}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201700}, year = {2019}, abstract = {Platelet collagen interactions at sites of vascular injuries predominantly involve glycoprotein VI (GPVI) and the integrin α2β1. Both proteins are primarily expressed on platelets and megakaryocytes whereas GPVI expression is also shown on endothelial and integrin α2β1 expression on epithelial cells. We recently showed that depletion of GPVI improves stroke outcome without increasing the risk of cerebral hemorrhage. Genetic variants associated with higher platelet surface integrin α2 (ITGA2) receptor levels have frequently been found to correlate with an increased risk of ischemic stroke in patients. However until now, no preclinical stroke study has addressed whether platelet integrin α2β1 contributes to the pathophysiology of ischemia/reperfusion (I/R) injury. Focal cerebral ischemia was induced in C57BL/6 and Itga2\(^{-/-}\) mice by a 60 min transient middle cerebral artery occlusion (tMCAO). Additionally, wild-type animals were pretreated with anti-GPVI antibody (JAQ1) or Fab fragments of a function blocking antibody against integrin α2β1 (LEN/B). In anti-GPVI treated animals, intravenous (IV) recombinant tissue plasminogen activator (rt-PA) treatment was applied immediately prior to reperfusion. Stroke outcome, including infarct size and neurological scoring was determined on day 1 after tMCAO. We demonstrate that targeting the integrin α2β1 (pharmacologic; genetic) did neither reduce stroke size nor improve functional outcome on day 1 after tMCAO. In contrast, depletion of platelet GPVI prior to stroke was safe and effective, even when combined with rt-PA treatment. Our results underscore that GPVI, but not ITGA2, is a promising and safe target in the setting of ischemic stroke.}, language = {en} } @article{HoppAlbertWeissenbergerMencletal.2016, author = {Hopp, Sarah and Albert-Weissenberger, Christiane and Mencl, Stine and Bieber, Michael and Schuhmann, Michael K. and Stetter, Christian and Nieswandt, Bernhard and Schmidt, Peter M. and Monoranu, Camelia-Maria and Alafuzoff, Irina and Marklund, Niklas and Nolte, Marc W. and Sir{\´e}n, Anna-Leena and Kleinschnitz, Christoph}, title = {Targeting coagulation factor XII as a novel therapeutic option in brain trauma}, series = {Annals of Neurology}, volume = {79}, journal = {Annals of Neurology}, number = {6}, doi = {10.1002/ana.24655}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-188800}, pages = {970-982}, year = {2016}, abstract = {Objective: Traumatic brain injury is a major global public health problem for which specific therapeutic interventions are lacking. There is, therefore, a pressing need to identify innovative pathomechanism-based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury. Methods: We investigated the impact of genetic deficiency of factor XII and acute inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused infestin-4 (rHA-Infestin-4) on trauma-induced microvascular thrombus formation and the subsequent outcome in 2 mouse models of traumatic brain injury. Results: Our study showed that both genetic deficiency of factor XII and an inhibition of activated factor XII in mice minimize trauma-induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human factor XII in factor XII-deficient mice fully restored injury-induced microvascular thrombus formation and brain damage. Interpretation: The robust protective effect of rHA-Infestin-4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies.}, language = {en} } @phdthesis{LangjahrverhHeld2018, author = {Langjahr [verh. Held], Melissa}, title = {Systemische Expression von Zytokinen bei schmerzhaften und schmerzlosen Polyneuropathien}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154445}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2018}, abstract = {Die Pathophysiologie der PNP wie auch die Entstehung der oft assoziierten neuropathischen Schmerzen ist unklar. Gleichzeitig gibt es bislang keine geeigneten Biomarker, die die oft komplizierte Differentialdiagnose vereinfachen k{\"o}nnen. Einige Tiermodelle und klinische Studien lieferten bereits Hinweise auf die entscheidende Rolle pro- und anti-inflammatorischer Zytokine in diesen Prozessen. Ziel unserer Studie war es, die systemische Genexpression pro- und anti-inflammatorischer Zytokine in einer großen Kohorte von Patienten mit PNP verschiedener {\"A}tiologie zu charakterisieren. Insgesamt konnten 111 PNP-Patienten und 38 gesunde Kontrollpersonen prospektiv rekrutiert werden. Nach Isolation von PBMC aus Blutproben von 97 Patienten wurde die Genexpression der pro-inflammatorischen Zytokine TNF, IL1, IL2, IL6, IL8 und der anti-inflammatorischen Zytokine IL4 und IL10 mittels qRT-PCR bestimmt. Bei 47 Patienten und 12 Kontrollen wurde zudem die IL6-, IL-8- und TNF-Zytokinproduktion von PBMC in vitro nach Stimulation durch LPS mittels ELISA untersucht. Hauptbefund war ein pro-inflammatorisches Zytokinprofil der PNP-Patienten mit h{\"o}herer Genexpression von IL1, IL2, IL8 und TNF im Vergleich zu den gesunden Kontrollen. Im Falle der entz{\"u}ndlichen Neuropathien konnte zudem eine niedrigere Genexpression von IL10 im Vergleich zu Gesunden nachgewiesen werden. Sowohl schmerzhafte als auch schmerzlose Verlaufsformen wiesen ein pro-inflammatorisches Zytokingenexpressionsprofil im Vergleich zu Gesunden auf, das bei schmerzhaften PNP deutlich mehr beteiligte pro-inflammatorische Zytokine umfasste; relevante Unterschiede zwischen den PNP-Patienten mit und ohne Schmerz sowie der diagnostischen Subgruppen fanden sich nicht. Eine niedrigere Stimulationsschwelle der PBMC lag bei PNP-Patienten im Vergleich zu Gesunden nicht vor. Insgesamt erscheint die Rolle einzelner Zytokine als systemische Biomarker f{\"u}r die Differenzierung verschiedener PNP-Formen bzw. bez{\"u}glich neuropathischen Schmerzes aufgrund einer niedrigen Spezifit{\"a}t deutlich eingeschr{\"a}nkt. Dennoch sprechen unsere Ergebnisse f{\"u}r eine m{\"o}gliche Rolle eines pro-inflammatorischen Milieus bei der Entstehung bzw. des Verlaufes verschiedener entz{\"u}ndlicher und nicht-entz{\"u}ndlicher Neuropathien und neuropathischen Schmerzes.}, subject = {Polyneuropathie}, language = {de} } @article{GarciaFernandezHoefflinRauschetal.2023, author = {Garc{\´i}a-Fern{\´a}ndez, Patricia and H{\"o}fflin, Klemens and Rausch, Antonia and Strommer, Katharina and Neumann, Astrid and Cebulla, Nadine and Reinhold, Ann-Kristin and Rittner, Heike and {\"U}{\c{c}}eyler, Nurcan and Sommer, Claudia}, title = {Systemic inflammatory markers in patients with polyneuropathies}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1067714}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304217}, year = {2023}, abstract = {Introduction In patients with peripheral neuropathies (PNP), neuropathic pain is present in 50\% of the cases, independent of the etiology. The pathophysiology of pain is poorly understood, and inflammatory processes have been found to be involved in neuro-degeneration, -regeneration and pain. While previous studies have found a local upregulation of inflammatory mediators in patients with PNP, there is a high variability described in the cytokines present systemically in sera and cerebrospinal fluid (CSF). We hypothesized that the development of PNP and neuropathic pain is associated with enhanced systemic inflammation. Methods To test our hypothesis, we performed a comprehensive analysis of the protein, lipid and gene expression of different pro- and anti-inflammatory markers in blood and CSF from patients with PNP and controls. Results While we found differences between PNP and controls in specific cytokines or lipids, such as CCL2 or oleoylcarnitine, PNP patients and controls did not present major differences in systemic inflammatory markers in general. IL-10 and CCL2 levels were related to measures of axonal damage and neuropathic pain. Lastly, we describe a strong interaction between inflammation and neurodegeneration at the nerve roots in a specific subgroup of PNP patients with blood-CSF barrier dysfunction. Conclusion In patients with PNP systemic inflammatory, markers in blood or CSF do not differ from controls in general, but specific cytokines or lipids do. Our findings further highlight the importance of CSF analysis in patients with peripheral neuropathies.}, language = {en} } @article{UeceylerHaeuserSommer2011, author = {{\"U}ceyler, Nurcan and H{\"a}user, Winfried and Sommer, Claudia}, title = {Systematic review with meta-analysis: Cytokines in fibromyalgia syndrome}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69189}, year = {2011}, abstract = {Background: To perform a systematic review and meta-analysis on cytokine levels in patients with fibromyalgia syndrome (FMS). Methods: Through December 2010 we systematically reviewed the databases PubMed, MEDLINE, and PsycINFO and screened the reference lists of 22 review articles for suitable original articles. Original articles investigating cytokines in patients with FMS were included. Data were extracted by two independent authors. Differences of the cytokine levels of FMS patients and controls were summarized by standardized mean differences (SMD) using a random effects model. Study quality was assessed applying methodological scores: modified Center of Evidence Based Medicine, Newcastle-Ottawa-Scale, and W{\"u}rzburg Methodological Quality Score. Results: Twenty-five articles were included investigating 1255 FMS patients and 800 healthy controls. Data of 13/25 studies entered meta-analysis. The overall methodological quality of studies was low. The results of the majority of studies were not comparable because methods, investigated material, and investigated target cytokines differed. Systematic review of the selected 25 articles revealed that FMS patients had higher serum levels of interleukin (IL)-1 receptor antagonist, IL-6, and IL-8, and higher plasma levels of IL-8. Meta-analysis of eligible studies showed that FMS patients had higher plasma IL-6 levels compared to controls (SMD = -0.34 [-0.64, -0.03] 95\% CI; p = 0.03). The majority of investigated cytokines were not different between patients and controls. Conclusions: The pathophysiological role of cytokines in FMS is still unclear. Studies of higher quality and with higher numbers of subjects are needed.}, subject = {Fibromyalgie}, language = {en} } @article{ElhfnawyVolkmannSchliesseretal.2019, author = {Elhfnawy, Ahmed Mohamed and Volkmann, Jens and Schliesser, Mira and Fluri, Felix}, title = {Symptomatic vs. asymptomatic 20-40\% internal carotid artery stenosis: Does the plaque size matter?}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, number = {960}, doi = {10.3389/fneur.2019.00960}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201262}, year = {2019}, abstract = {Background: Around 9-15\% of ischemic strokes are related to internal carotid artery (ICA)-stenosis ≥50\%. However, the extent to which ICA-stenosis <50\% causes ischemic cerebrovascular events is uncertain. We examined the relation between plaque cross-sectional area and length and the risk of ischemic stroke or TIA among patients with ICA-stenosis of 20-40\%. Methods: We retrospectively identified patients admitted to the Department of Neurology, University Hospital of W{\"u}rzburg, from January 2011 until September 2016 with ischemic stroke or TIA and concomitant ICA-stenosis of 20-40\%, either symptomatic or asymptomatic. Plaque length and cross-sectional area were assessed on ultrasound scans. Results: We identified 41 patients with ischemic stroke or TIA and ICA-stenosis of 20-40\%; 14 symptomatic and 27 asymptomatic. The plaque cross-sectional area was significantly larger among symptomatic than asymptomatic ICA-stenosis; median values (IQR) were 0.45 (0.21-0.69) cm2 and 0.27 (0.21-0.38) cm2, p = 0.03, respectively. A plaque cross-sectional area ≥0.36 cm2 had a sensitivity of 71\% and a specificity of 76\% for symptomatic compared with asymptomatic ICA-stenosis. In a sex-adjusted multivariate logistic regression, a plaque cross-sectional area ≥0.36 cm2 and a plaque length ≥1.65 cm were associated with an OR (95\% CI) of 5.54 (1.2-25.6), p = 0.028 and 1.78 (0.36-8.73), p = 0.48, respectively, for symptomatic ICA-stenosis. Conclusion: Large plaques might increase the risk of ischemic stroke or TIA among patients with low-grade ICA-stenosis of 20-40\%. Sufficiently powered prospective longitudinal cohort studies are needed to definitively test the stroke risk stratification value of carotid plaque length and cross-sectional area in the setting of current optimal medical treatment.}, language = {en} } @article{PhamHelluyKleinschnitzetal.2011, author = {Pham, Mirko and Helluy, Xavier and Kleinschnitz, Christoph and Kraft, Peter and Bartsch, Andreas J. and Jakob, Peter and Nieswandt, Bernhard and Bendszus, Martin and Guido, Stoll}, title = {Sustained Reperfusion after Blockade of Glycoprotein-Receptor-Ib in Focal Cerebral Ischemia: An MRI Study at 17.6 Tesla}, series = {PLoS ONE}, volume = {6}, journal = {PLoS ONE}, number = {4}, doi = {10.1371/journal.pone.0018386}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142608}, pages = {e18386}, year = {2011}, abstract = {Background: Inhibition of early platelet adhesion by blockade of glycoprotein-IB (GPIb) protects mice from ischemic stroke. To elucidate underlying mechanisms in-vivo, infarct development was followed by ultra-high field MRI at 17.6 Tesla. Methods: Cerebral infarction was induced by transient-middle-cerebral-artery-occlusion (tMCAO) for 1 hour in C57/BL6 control mice (N = 10) and mice treated with 100 mg Fab-fragments of the GPIb blocking antibody p0p/B 1 h after tMCAO (N = 10). To control for the effect of reperfusion, additional mice underwent permanent occlusion and received anti-GPIb treatment (N = 6; pMCAO) or remained without treatment (N = 3; pMCAO). MRI 2 h and 24 h after MCAO measured cerebral-blood-flow (CBF) by continuous arterial-spin labelling, the apparent-diffusion-coefficient (ADC), quantitative-T2 and T2-weighted imaging. All images were registered to a standard mouse brain MRI atlas and statistically analysed voxel-wise, and by cortico-subcortical ROI analysis. Results: Anti-GPIb treatment led to a relative increase of postischemic CBF vs. controls in the cortical territory of the MCA (2 h: 44.2 +/- 6.9 ml/100g/min versus 24 h: 60.5 +/- 8.4; p = 0.0012, F((1,18)) = 14.63) after tMCAO. Subcortical CBF 2 h after tMCAO was higher in anti-GPIb treated animals (45.3 +/- 5.9 vs. controls: 33.6 +/- 4.3; p = 0.04). In both regions, CBF findings were clearly related to a lower probability of infarction (Cortex/Subcortex of treated group: 35\%/65\% vs. controls: 95\%/100\%) and improved quantitative-T2 and ADC. After pMCAO, anti-GPIb treated mice developed similar infarcts preceded by severe irreversible hypoperfusion as controls after tMCAO indicating dependency of stroke protection on reperfusion. Conclusion: Blockade of platelet adhesion by anti-GPIb-Fab-fragments results in substantially improved CBF early during reperfusion. This finding was in exact spatial correspondence with the prevention of cerebral infarction and indicates in-vivo an increased patency of the microcirculation. Thus, progression of infarction during early ischemia and reperfusion can be mitigated by anti-platelet treatment.}, language = {en} } @article{TraubGrondeyGassenmaieretal.2022, author = {Traub, Jan and Grondey, Katja and Gassenmaier, Tobias and Schmitt, Dominik and Fette, Georg and Frantz, Stefan and Boivin-Jahns, Val{\´e}rie and Jahns, Roland and St{\"o}rk, Stefan and Stoll, Guido and Reiter, Theresa and Hofmann, Ulrich and Weber, Martin S. and Frey, Anna}, title = {Sustained increase in serum glial fibrillary acidic protein after first ST-elevation myocardial infarction}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {18}, issn = {1422-0067}, doi = {10.3390/ijms231810304}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288261}, year = {2022}, abstract = {Acute ischemic cardiac injury predisposes one to cognitive impairment, dementia, and depression. Pathophysiologically, recent positron emission tomography data suggest astroglial activation after experimental myocardial infarction (MI). We analyzed peripheral surrogate markers of glial (and neuronal) damage serially within 12 months after the first ST-elevation MI (STEMI). Serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were quantified using ultra-sensitive molecular immunoassays. Sufficient biomaterial was available from 45 STEMI patients (aged 28 to 78 years, median 56 years, 11\% female). The median (quartiles) of GFAP was 63.8 (47.0, 89.9) pg/mL and of NfL 10.6 (7.2, 14.8) pg/mL at study entry 0-4 days after STEMI. GFAP after STEMI increased in the first 3 months, with a median change of +7.8 (0.4, 19.4) pg/mL (p = 0.007). It remained elevated without further relevant increases after 6 months (+11.7 (0.6, 23.5) pg/mL; p = 0.015), and 12 months (+10.3 (1.5, 22.7) pg/mL; p = 0.010) compared to the baseline. Larger relative infarction size was associated with a higher increase in GFAP (ρ = 0.41; p = 0.009). In contrast, NfL remained unaltered in the course of one year. Our findings support the idea of central nervous system involvement after MI, with GFAP as a potential peripheral biomarker of chronic glial damage as one pathophysiologic pathway.}, language = {en} } @phdthesis{Palmisano2022, author = {Palmisano, Chiara}, title = {Supraspinal Locomotor Network Derangements: A Multimodal Approach}, doi = {10.25972/OPUS-26644}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266442}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Parkinson's Disease (PD) constitutes a major healthcare burden in Europe. Accounting for aging alone, ~700,000 PD cases are predicted by 2040. This represents an approximately 56\% increase in the PD population between 2005 and 2040, with a consequent rise in annual disease-related medical costs. Gait and balance disorders are a major problem for patients with PD and their caregivers, mainly because to their correlation with falls. Falls occur as a result of a complex interaction of risk factors. Among them, Freezing of Gait (FoG) is a peculiar gait derangement characterized by a sudden and episodic inability to produce effective stepping, causing falls, mobility restrictions, poor quality of life, and increased morbidity and mortality. Between 50-70\% of PD patients have FoG and/or falls after a disease duration of 10 years, only partially and inconsistently improved by dopaminergic treatment and Deep Brain Stimulation (DBS). Treatment-induced worsening has been also observed under certain conditions. Effective treatments for gait disturbances in PD are lacking, probably because of the still poor understanding of the supraspinal locomotor network. In my thesis, I wanted to expand our knowledge of the supraspinal locomotor network and in particular the contribution of the basal ganglia to the control of locomotion. I believe this is a key step towards new preventive and personalized therapies for postural and gait problems in patients with PD and related disorders. In addition to patients with PD, my studies also included people affected by Progressive Supranuclear Palsy (PSP). PSP is a rare primary progressive parkinsonism characterized at a very early disease stage by poor balance control and frequent backwards falls, thus providing an in vivo model of dysfunctional locomotor control. I focused my attention on one of the most common motor transitions in daily living, the initiation of gait (GI). GI is an interesting motor task and a relevant paradigm to address balance and gait impairments in patients with movement disorders, as it is associated with FoG and high risk of falls. It combines a preparatory (i.e., the Anticipatory Postural Adjustments [APA]) and execution phase (the stepping) and allows the study of movement scaling and timing as an expression of muscular synergies, which follow precise and online feedback information processing and integration into established feedforward patterns of motor control. By applying a multimodal approach that combines biomechanical assessments and neuroimaging investigations, my work unveiled the fundamental contribution of striatal dopamine to GI in patients with PD. Results in patients with PSP further supported the fundamental role of the striatum in GI execution, revealing correlations between the metabolic intake of the left caudate nucleus with diverse GI measurements. This study also unveiled the interplay of additional brain areas in the motor control of GI, namely the Thalamus, the Supplementary Motor Area (SMA), and the Cingulate cortex. Involvement of cortical areas was also suggested by the analysis of GI in patients with PD and FoG. Indeed, I found major alterations in the preparatory phase of GI in these patients, possibly resulting from FoG-related deficits of the SMA. Alterations of the weight shifting preceding the stepping phase were also particularly important in PD patients with FoG, thus suggesting specific difficulties in the integration of somatosensory information at a cortical level. Of note, all patients with PD showed preserved movement timing of GI, possibly suggesting preserved and compensatory activity of the cerebellum. Postural abnormalities (i.e., increased trunk and thigh flexion) showed no relationship with GI, ruling out an adaptation of the motor pattern to the altered postural condition. In a group of PD patients implanted with DBS, I further explored the pathophysiological functioning of the locomotor network by analysing the timely activity of the Subthalamic Nucleus (STN) during static and dynamic balance control (i.e., standing and walking). For this study, I used novel DBS devices capable of delivering stimulation and simultaneously recording Local Field Potentials (LFP) of the implanted nucleus months and years after surgery. I showed a gait-related frequency shift in the STN activity of PD patients, possibly conveying cortical (feedforward) and cerebellar (feedback) information to mesencephalic locomotor areas. Based on this result, I identified for each patient a Maximally Informative Frequency (MIF) whose power changes can reliably classify standing and walking conditions. The MIF is a promising input signal for new DBS devices that can monitor LFP power modulations to timely adjust the stimulation delivery based on the ongoing motor task (e.g., gait) performed by the patient (adaptive DBS). Altogether my achievements allowed to define the role of different cortical and subcortical brain areas in locomotor control, paving the way for a better understanding of the pathophysiological dynamics of the supraspinal locomotor network and the development of tailored therapies for gait disturbances and falls prevention in PD and related disorders.}, language = {en} } @phdthesis{RamirezPasos2019, author = {Ramirez Pasos, Uri Eduardo}, title = {Subthalamic Nucleus Neural Synchronization and Connectivity during Limbic Processing of Emotional Pictures: Evidence from Invasive Recordings in Patients with Parkinson's Disease}, doi = {10.25972/OPUS-16985}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-169850}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {In addition to bradykinesia and tremor, patients with Parkinson's disease (PD) are known to exhibit non-motor symptoms such as apathy and hypomimia but also impulsivity in response to dopaminergic replacement therapy. Moreover, a plethora of studies observe differences in electrocortical and autonomic responses to both visual and acoustic affective stimuli in PD subjects compared to healthy controls. This suggests that the basal ganglia (BG), as well as the hyperdirect pathway and BG thalamocortical circuits, are involved in affective processing. Recent studies have shown valence and dopamine-dependent changes in synchronization in the subthalamic nucleus (STN) in PD patients during affective tasks. This thesis investigates the role of dopamine, valence, and laterality in STN electrophysiology by analyzing event-related potentials (ERP), synchronization, and inter-hemispheric STN connectivity. STN recordings were obtained from PD patients with chronically implanted electrodes for deep brain stimulation during a passive affective picture presentation task. The STN exhibited valence-dependent ERP latencies and lateralized 'high beta' (28-40 Hz) event-related desynchronization. This thesis also examines the role of dopamine, valence, and laterality on STN functional connectivity with the anterior cingulate cortex (ACC) and the amygdala. The activity of these limbic structures was reconstructed using simultaneously recorded electroencephalographic signals. While the STN was found to establish early coupling with both structures, STN-ACC coupling in the 'alpha' range (7-11 Hz) and uncoupling in the 'low beta' range (14-21 Hz) were lateralized. Lateralization was also observed at the level of synchrony in both reconstructed sources and for ACC ERP amplitude, whereas dopamine modulated ERP latency in the amygdala. These results may deepen our current understanding of the STN as a limbic node within larger emotional-motor networks in the brain.
}, subject = {Nucleus subthalamicus}, language = {en} } @article{OezdağAcarlıKleinEgenolfetal.2022, author = {{\"O}zdağ Acarl{\i}, Ay{\c{s}}e Nur and Klein, Thomas and Egenolf, Nadine and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan}, title = {Subepidermal Schwann cell counts correlate with skin innervation - an exploratory study}, series = {Muscle \& Nerve}, volume = {65}, journal = {Muscle \& Nerve}, number = {4}, doi = {10.1002/mus.27496}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318726}, pages = {471 -- 479}, year = {2022}, abstract = {Introduction/Aims Schwann cell clusters have been described at the murine dermis-epidermis border. We quantified dermal Schwann cells in the skin of patients with small-fiber neuropathy (SFN) compared with healthy controls to correlate with the clinical phenotype. Methods Skin punch biopsies from the lower legs of 28 patients with SFN (11 men, 17 women; median age, 54 [range, 19-73] years) and 9 healthy controls (five men, four women, median age, 34 [range, 25-69] years) were immunoreacted for S100 calcium-binding protein B as a Schwann cell marker, protein-gene product 9.5 as a pan-neuronal marker, and CD207 as a Langerhans cell marker. Intraepidermal nerve fiber density (IENFD) and subepidermal Schwann cell counts were determined. Results Skin samples of patients with SFN showed lower IENFD (P < .05), fewer Schwann cells per millimeter (P < .01), and fewer Schwann cell clusters per millimeter (P < .05) than controls. When comparing SFN patients with reduced (n = 13; median age, 53 [range, 19-73] years) and normal distal (n = 15, median age, 54 [range, 43-68] years) IENFD, the number of solitary Schwann cells per millimeter (p < .01) and subepidermal nerve fibers associated with Schwann cell branches (P < .05) were lower in patients with reduced IENFD. All three parameters correlated positively with distal IENFD (P < .05 to P < .01), whereas no correlation was found between Schwann cell counts and clinical pain characteristics. Discussion Our data raise questions about the mechanisms underlying the interdependence of dermal Schwann cells and skin innervation in SFN. The temporal course and functional impact of Schwann cell presence and kinetics need further investigation.}, language = {en} } @article{WutzlerKrogiasGrauetal.2019, author = {Wutzler, Alexander and Krogias, Christos and Grau, Anna and Veltkamp, Roland and Heuschmann, Peter U. and Haeusler, Karl Georg}, title = {Stroke prevention in patients with acute ischemic stroke and atrial fibrillation in Germany - a cross sectional survey}, series = {BMC Neurology}, volume = {19}, journal = {BMC Neurology}, doi = {10.1186/s12883-019-1249-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201078}, pages = {25}, year = {2019}, abstract = {Background Atrial fibrillation (AF) is present in 15-20\% of patients with acute ischemic stroke. Oral anticoagulation reduces the risk of AF-related recurrent stroke but clinical guideline recommendations are rather vague regarding its use in the acute phase of stroke. We aimed to assess the current clinical practice of medical stroke prevention in AF patients during the acute phase of ischemic stroke. Methods In April 2017, a standardized anonymous questionnaire was sent to clinical leads of all 298 certified stroke units in Germany. Results Overall, 154 stroke unit leads participated (response rate 52\%). Anticoagulation in the acute phase of stroke is considered feasible in more than 90\% of AF patients with ischemic stroke. Clinicians assume that about two thirds of all AF patients (range 20-100\%) are discharged on oral anticoagulation. According to local preferences, acetylsalicylic acid is given orally in the majority of patients with delayed initiation of oral anticoagulation. A non-vitamin K-dependent oral anticoagulant (NOAC) is more often prescribed than a vitamin K-dependent oral anticoagulant (VKA). VKA is more often chosen in patients with previous VKA intake than in VKA naive patients. In the minority of patients, stroke unit leads discuss the prescription of a specific oral anticoagulant with the treating general practitioner. Adherence to medical stroke prevention after hospital discharge is not assessed on a regular basis in any patient by the majority of participating stroke centers. Conclusions Early secondary stroke prevention in AF patients in German stroke units is based on OAC use but prescription modalities vary in clinical practice.}, language = {en} } @article{CanessaPozziArnulfoetal.2016, author = {Canessa, Andrea and Pozzi, Nicol{\`o} G. and Arnulfo, Gabriele and Brumberg, Joachim and Reich, Martin M. and Pezzoli, Gianni and Ghilardi, Maria F. and Matthies, Cordula and Steigerwald, Frank and Volkmann, Jens and Isaias, Ioannis U.}, title = {Striatal Dopaminergic Innervation Regulates Subthalamic Beta-Oscillations and Cortical-Subcortical Coupling during Movements: Preliminary Evidence in Subjects with Parkinson's Disease}, series = {Frontiers in Human Neuroscience}, volume = {10}, journal = {Frontiers in Human Neuroscience}, number = {611}, doi = {10.3389/fnhum.2016.00611}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164061}, year = {2016}, abstract = {Activation of the basal ganglia has been shown during the preparation and execution of movement. However, the functional interaction of cortical and subcortical brain areas during movement and the relative contribution of dopaminergic striatal innervation remains unclear. We recorded local field potential (LFP) activity from the subthalamic nucleus (STN) and high-density electroencephalography (EEG) signals in four patients with Parkinson's disease (PD) off dopaminergic medication during a multi-joint motor task performed with their dominant and non-dominant hand. Recordings were performed by means of a fully-implantable deep brain stimulation (DBS) device at 4 months after surgery. Three patients also performed a single-photon computed tomography (SPECT) with [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (FP-CIT) to assess striatal dopaminergic innervation. Unilateral movement execution led to event-related desynchronization (ERD) followed by a rebound after movement termination event-related synchronization (ERS) of oscillatory beta activity in the STN and primary sensorimotor cortex of both hemispheres. Dopamine deficiency directly influenced movement-related beta-modulation, with greater beta-suppression in the most dopamine-depleted hemisphere for both ipsi- and contralateral hand movements. Cortical-subcortical, but not interhemispheric subcortical coherencies were modulated by movement and influenced by striatal dopaminergic innervation, being stronger in the most dopamine-depleted hemisphere. The data are consistent with a role of dopamine in shielding subcortical structures from an excessive cortical entrapment and cross-hemispheric coupling, thus allowing fine-tuning of movement.}, language = {en} } @article{RickertWagenhaeuserNordbecketal.2020, author = {Rickert, V. and Wagenh{\"a}user, L. and Nordbeck, P. and Wanner, C. and Sommer, C. and Rost, S. and {\"U}{\c{c}}eyler, N.}, title = {Stratification of Fabry mutations in clinical practice: a closer look at α-galactosidase A-3D structure}, series = {Journal of Internal Medicine}, volume = {288}, journal = {Journal of Internal Medicine}, number = {5}, doi = {10.1111/joim.13125}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218125}, pages = {593 -- 604}, year = {2020}, abstract = {Background Fabry disease (FD) is an X-linked lysosomal storage and multi-system disorder due to mutations in the α-galactosidase A (α-GalA) gene. We investigated the impact of individual amino acid exchanges in the α-GalA 3D-structure on the clinical phenotype of FD patients. Patients and methods We enrolled 80 adult FD patients with α-GalA missense mutations and stratified them into three groups based on the amino acid exchange location in the α-GalA 3D-structure: patients with active site mutations, buried mutations and other mutations. Patient subgroups were deep phenotyped for clinical and laboratory parameters and FD-specific treatment. Results Patients with active site or buried mutations showed a severe phenotype with multi-organ involvement and early disease manifestation. Patients with other mutations had a milder phenotype with less organ impairment and later disease onset. α-GalA activity was lower in patients with active site or buried mutations than in those with other mutations (P < 0.01 in men; P < 0.05 in women) whilst lyso-Gb3 levels were higher (P < 0.01 in men; <0.05 in women). Conclusions The type of amino acid exchange location in the α-GalA 3D-structure determines disease severity and temporal course of symptom onset. Patient stratification using this parameter may become a useful tool in the management of FD patients.}, language = {en} } @phdthesis{Cheong2018, author = {Cheong, David}, title = {Stereologische Untersuchung der Gesamtanzahl dopaminerger Neurone in der Substantia Nigra von C57BL/6 M{\"a}usen unter Benutzung des „optical fractionator" und einer Standard-Mikroskopieausr{\"u}stung}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-162753}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2018}, abstract = {In pre-clinical Parkinson's disease research, analysis of the nigrostriatal tract, including quantification of dopaminergic neuron loss within the substantia nigra, is essential. To estimate the total dopaminergic neuron number, unbiased stereology using the optical fractionator method is currently considered the gold standard. Because the theory behind the optical fractionator method is complex and because stereology is difficult to achieve without specialized equipment, several commercially available complete stereology systems that include the necessary software do exist, purely for cell counting reasons. Since purchasing a specialized stereology setup is not always feasible, for many reasons, this report describes a method for the stereological estimation of dopaminergic neuronal cell counts using standard microscopy equipment, including a light microscope, a motorized object table (x, y, z plane) with imaging software, and a computer for analysis. A step-by-step explanation is given on how to perform stereological quantification using the optical fractionator method, and pre-programmed files for the calculation of estimated cell counts are provided. To assess the accuracy of this method, a comparison to data obtained from a commercially available stereology apparatus was performed. Comparable cell numbers were found using this protocol and the stereology device, thus demonstrating the precision of this protocol for unbiased stereology. Source: Ip, C. W., Cheong, D., Volkmann, J. Stereological Estimation of Dopaminergic Neuron Number in the Mouse Substantia Nigra Using the Optical Fractionator and Standard Microscopy Equipment. J. Vis. Exp. (127), e56103, doi:10.3791/56103 (2017)}, subject = {Stereologie}, language = {de} } @article{ElhfnawyHeuschmannPhametal.2019, author = {Elhfnawy, Ahmed Mohamed and Heuschmann, Peter U. and Pham, Mirko and Volkmann, Jens and Fluri, Felix}, title = {Stenosis length and degree interact with the risk of cerebrovascular events related to internal carotid artery stenosis}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, number = {317}, issn = {1664-2295}, doi = {10.3389/fneur.2019.00317}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196225}, year = {2019}, abstract = {Background and Purpose: Internal carotid artery stenosis (ICAS)≥70\% is a leading cause of ischemic cerebrovascular events (ICVEs). However, a considerable percentage of stroke survivors with symptomatic ICAS (sICAS) have <70\% stenosis with a vulnerable plaque. Whether the length of ICAS is associated with high risk of ICVEs is poorly investigated. Our main aim was to investigate the relation between the length of ICAS and the development of ICVEs. Methods: In a retrospective cross-sectional study, we identified 95 arteries with sICAS and another 64 with asymptomatic internal carotid artery stenosis (aICAS) among 121 patients with ICVEs. The degree and length of ICAS as well as plaque echolucency were assessed on ultrasound scans. Results: A statistically significant inverse correlation between the ultrasound-measured length and degree of ICAS was detected for sICAS≥70\% (Spearman correlation coefficient ρ = -0.57, p < 0.001, n = 51) but neither for sICAS<70\% (ρ = 0.15, p = 0.45, n = 27) nor for aICAS (ρ = 0.07, p = 0.64, n = 54). The median (IQR) length for sICAS<70\% and ≥70\% was 17 (15-20) and 15 (12-19) mm (p = 0.06), respectively, while that for sICAS<90\% and sICAS 90\% was 18 (15-21) and 13 (10-16) mm, respectively (p < 0.001). Among patients with ICAS <70\%, a cut-off length of ≥16 mm was found for sICAS rather than aICAS with a sensitivity and specificity of 74.1\% and 51.1\%, respectively. Irrespective of the stenotic degree, plaques of the sICAS compared to aICAS were significantly more often echolucent (43.2 vs. 24.6\%, p = 0.02). Conclusion: We found a statistically insignificant tendency for the ultrasound-measured length of sICAS<70\% to be longer than that of sICAS≥70\%. Moreover, the ultrasound-measured length of sICAS<90\% was significantly longer than that of sICAS 90\%. Among patients with sICAS≥70\%, the degree and length of stenosis were inversely correlated. Larger studies are needed before a clinical implication can be drawn from these results.}, language = {en} } @article{NguemeniHiewKoegleretal.2021, author = {Nguemeni, Carine and Hiew, Shawn and K{\"o}gler, Stefanie and Homola, Gy{\"o}rgy A. and Volkmann, Jens and Zeller, Daniel}, title = {Split-belt training but not cerebellar anodal tDCS improves stability control and reduces risk of fall in patients with multiple sclerosis}, series = {Brain Sciences}, volume = {12}, journal = {Brain Sciences}, number = {1}, issn = {2076-3425}, doi = {10.3390/brainsci12010063}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252179}, year = {2021}, abstract = {The objective of this study was to examine the therapeutic potential of multiple sessions of training on a split-belt treadmill (SBT) combined with cerebellar anodal transcranial direct current stimulation (tDCS) on gait and balance in People with Multiple Sclerosis (PwMS). Twenty-two PwMS received six sessions of anodal (PwMS\(_{real}\), n = 12) or sham (PwMS\(_{sham}\), n = 10) tDCS to the cerebellum prior to performing the locomotor adaptation task on the SBT. To evaluate the effect of the intervention, functional gait assessment (FGA) scores and distance walked in 2 min (2MWT) were measured at the baseline (T0), day 6 (T5), and at the 4-week follow up (T6). Locomotor performance and changes of motor outcomes were similar in PwMS\(_{real}\) and PwMS\(_{sham}\) independently from tDCS mode applied to the cerebellum (anodal vs. sham, on FGA, p = 0.23; and 2MWT, p = 0.49). When the data were pooled across the groups to investigate the effects of multiple sessions of SBT training alone, significant improvement of gait and balance was found on T5 and T6, respectively, relative to baseline (FGA, p < 0.001 for both time points). The FGA change at T6 was significantly higher than at T5 (p = 0.01) underlining a long-lasting improvement. An improvement of the distance walked during the 2MWT was also observed on T5 and T6 relative to T0 (p = 0.002). Multiple sessions of SBT training resulted in a lasting improvement of gait stability and endurance, thus potentially reducing the risk of fall as measured by FGA and 2MWT. Application of cerebellar tDCS during SBT walking had no additional effect on locomotor outcomes.}, language = {en} } @phdthesis{Graulich2011, author = {Graulich, Michael}, title = {Spinale Effekte von TNF-α am Modell des tumorinduzierten Knochenschmerzes der Maus}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-54439}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2011}, abstract = {Am Modell des tumorinduzierten Schmerzes der Maus wurden sowohl das Schmerzverhalten der Tiere als auch spezifische morphologische Ver{\"a}nderungen im Hinterhorn des R{\"u}ckenmarks (Aktivierung von Astrozyten) und im tumorbefallenen Knochen analysiert. Durch Analyse von M{\"a}usen mit Defizienz f{\"u}r TNF-Rezeptor 1, TNF-Rezeptor 2 oder f{\"u}r beide Rezeptoren konnte die Rolle von TNF-α seiner Rezeptoren bei der Entstehung von tumorinduziertem Schmerz untersucht werden. Im Unterschied zu neuropathischen Schmerzmodellen konnte gezeigt werden, dass beide TNF-Rezeptoren ausgeschaltet werden m{\"u}ssen, um eine signifikante Schmerzreduktion zu erzielen. Die systemische Behandlung mit dem TNF-neutralisierenden Fusionsprotein Etanercept konnte die im genetischen Modell gezeigte Reduktion der mechanischen Allodynie teilweise, aber nicht vollst{\"a}ndig reproduzieren. Eine Hemmung der Mikrogliaaktivierung mittels Minocyclin erbrachte im Tumor-schmerzmodell keinen Effekt auf das Schmerzverhalten der Tiere. Die histologische Analyse der tumoraffizierten Knochen zeigte eine signifikante Zunahme der Osteoklastenaktivit{\"a}t in tumortragenden Tieren. Die Behandlung mit Minocyclin war ohne erkennbaren Effekt auf die Differenzierung und die Aktivit{\"a}t der Osteoklasten. Es ergaben sich jedoch Hinweise, dass TNF-α einen hemmenden Einfluss auf die Osteoklastenaktivit{\"a}t im Knochentumormodell hat, da sowohl in den TNFR-KO-Tieren als auch unter Gabe von Etanercept eine Steigerung der Osteoklastenaktivit{\"a}t nachgewiesen werden konnte. Die Ergebnisse dieser Arbeit zeigen, dass TNF-α eine wichtige Rolle, sowohl in der Entstehung, als auch in der Aufrechterhaltung von tumorinduziertem Schmerz spielt. Hier liegt der Ansatzpunkt f{\"u}r weitere Studien mit dem Ziel, eine spezifische Pharmakotherapie zu entwickeln mit wirksamer TNF-α Blockade auch bei Patienten mit Tumorschmerzen. Nach den Erkenntnissen dieser Arbeit mit Etanercept sollte ein spezielles Augenmerk auf die ZNS-G{\"a}ngigkeit dieser Substanzen gelegt werden und die Gefahr der M{\"o}glichkeit eines vermehrten Tumorwachstum bedacht werden.}, subject = {Neuralgie}, language = {de} } @article{FriedrichSchneiderBuerkleinetal.2023, author = {Friedrich, Maximilian U. and Schneider, Erich and Buerklein, Miriam and Taeger, Johannes and Hartig, Johannes and Volkmann, Jens and Peach, Robert and Zeller, Daniel}, title = {Smartphone video nystagmography using convolutional neural networks: ConVNG}, series = {Journal of Neurology}, volume = {270}, journal = {Journal of Neurology}, number = {5}, doi = {10.1007/s00415-022-11493-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324526}, pages = {2518-2530}, year = {2023}, abstract = {Background Eye movement abnormalities are commonplace in neurological disorders. However, unaided eye movement assessments lack granularity. Although videooculography (VOG) improves diagnostic accuracy, resource intensiveness precludes its broad use. To bridge this care gap, we here validate a framework for smartphone video-based nystagmography capitalizing on recent computer vision advances. Methods A convolutional neural network was fine-tuned for pupil tracking using > 550 annotated frames: ConVNG. In a cross-sectional approach, slow-phase velocity of optokinetic nystagmus was calculated in 10 subjects using ConVNG and VOG. Equivalence of accuracy and precision was assessed using the "two one-sample t-test" (TOST) and Bayesian interval-null approaches. ConVNG was systematically compared to OpenFace and MediaPipe as computer vision (CV) benchmarks for gaze estimation. Results ConVNG tracking accuracy reached 9-15\% of an average pupil diameter. In a fully independent clinical video dataset, ConVNG robustly detected pupil keypoints (median prediction confidence 0.85). SPV measurement accuracy was equivalent to VOG (TOST p < 0.017; Bayes factors (BF) > 24). ConVNG, but not MediaPipe, achieved equivalence to VOG in all SPV calculations. Median precision was 0.30°/s for ConVNG, 0.7°/s for MediaPipe and 0.12°/s for VOG. ConVNG precision was significantly higher than MediaPipe in vertical planes, but both algorithms' precision was inferior to VOG. Conclusions ConVNG enables offline smartphone video nystagmography with an accuracy comparable to VOG and significantly higher precision than MediaPipe, a benchmark computer vision application for gaze estimation. This serves as a blueprint for highly accessible tools with potential to accelerate progress toward precise and personalized Medicine.}, language = {en} } @phdthesis{Ebert2015, author = {Ebert, S{\"o}nke}, title = {Small- und Large-fiber-Beteiligung bei Morbus Parkinson}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124647}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2015}, abstract = {Die hier vorliegende Forschungsarbeit {\"u}berpr{\"u}fte eine m{\"o}gliche Beteiligung des peripheren Nervensystems bei M. Parkinson und den atypischen Parkinson-Syndromen. 31 Patienten mit einem idiopathischen Parkinson-Syndrom (IPD-Patienten) und neun Patienten mit einem atypischen Parkinson-Syndrom (APD-Patienten) sowie 35 altersentsprechende Kontrollprobanden wurden zwischen 2011 und 2012 f{\"u}r diese Studie rekrutiert. Neben der Eigenanamnese und der neurologischen Untersuchung erhielten die Patienten eine Suralisneurographie zur {\"U}berpr{\"u}fung der large fibers und eine Quantitative sensorische Testung (QST) zur Detektion einer m{\"o}glichen Small-fiber-Dysfunktion. Die Vitamin-Bestimmung diente der Untersuchung m{\"o}glicher Zusammenh{\"a}nge zwischen der Levodopa-Therapie, eventuell daraus resultierenden Vitamin-Mangelzust{\"a}nden und einer reduzierten intraepidermalen Nervenfaser-Dichte (IENF-Dichte) beim M. Parkinson. F{\"u}r die histologische Auswertung der IENF-Dichte und der dermalen, myelinisierten Nervenfaserb{\"u}ndel (PGP 9.5- / MBP- Doppelf{\"a}rbung) sowie f{\"u}r die immunohistochemische Untersuchung der Nervenfasersubtypen (anti-alpha-CGRP- und anti-Substanz P-Antik{\"o}rper) wurden bei jedem Probanden vier Hautbiopsien von den Extremit{\"a}ten und dem K{\"o}rperstamm entnommen. Sieben IPD-Patienten und ein Proband mit einem atypischen Parkinson-Syndrom wiesen ein vermindertes sensorisches Nervenaktionspotenzial (SNAP) in der Suralisneurographie auf. Dagegen war eine pathologisch reduzierte Nervenleitgeschwindigkeit nur bei einem IPD-Patienten nachweisbar. Auff{\"a}llig war zudem eine negative Korrelation zwischen der Erkrankungsdauer und dem SNAP (Korrelationskoeffizient -0,367, p<0,03). In der Auswertung der Hautbiopsien konnte eine statistisch signifikante Reduktion der myelinisierten B{\"u}ndel am Unterschenkel der IPD-Patienten festgestellt werden. Bei zehn von 30 IPD-Patienten, jedoch bei keinem der Probanden mit einem atypischen Parkinson-Syndrom, konnte eine verminderte IENF-Dichte nachgewiesen werden. In der statistischen {\"U}berpr{\"u}fung wurde außerdem am Unterschenkel ein signifikanter Unterschied zwischen den IPD-Patienten und der Kontrollkohorte sowie eine negative Korrelation zwischen der Krankheitsdauer und der IENF-Dichte (Korrelationskoeffizient -0,320, p<0,05) festgestellt. Die QST konnte dagegen keinen statistisch signifikanten Unterschied zwischen den einzelnen Kohorten aufzeigen. Im Kontrast dazu fand sich eine l{\"a}ngenunabh{\"a}ngige Reduktion der CGRP-positiven und der Substanz P-positiven IENF-Dichte bei den Patienten mit einem idiopathischen Parkinson-Syndrom. Bemerkenswert war zudem eine signifikante Verminderung der Substanz P-positiven intraepidermalen Nervenfasern am Oberschenkel und R{\"u}cken bei den APD-Patienten. Eine statistisch signifikante Abweichung der CGRP- und Substanz P-positiven B{\"u}ndel konnte dagegen nicht festgestellt werden. In der laborchemischen Untersuchung war ein Zusammenhang zwischen den bestimmten Vitamin-Spiegeln und der kumulativen Levodopa-Dosis sowie zwischen den Vitaminen und der IENF-Dichte lediglich bei dem Vitamin B6 nachweisbar. Zusammengefasst erscheint eine Beteiligung des peripheren Nervensystems beim idiopathischen Parkinson als wahrscheinlich, wohingegen bei den atypischen Parkinson-Syndromen vor allem von einer zentralen Genese ausgegangen werden kann. Basierend auf den Ergebnissen der Suralisneurographie und der Bestimmung der myelinisierten B{\"u}ndel erscheint eine krankheitsbedingte Large-fiber-Beeintr{\"a}chtigung beim M.Parkinson m{\"o}glich. Die nachgewiesene l{\"a}ngenabh{\"a}ngige Small-fiber-Reduktion bei IPD-Patienten wird vermutlich durch eine axonale Transportst{\"o}rung verursacht. Einen krankheitsbedingten Erkl{\"a}rungsansatz f{\"u}r die l{\"a}ngenunabh{\"a}ngige Reduktion der CGRP-positiven und der Substanz P-positiven IENF-Dichte bei IPD-Patienten liefert der Nachweis von neurotoxischem α-Synuclein in den sensiblen Spinatganglien mit einem daraus resultierenden Untergang von sensorischen Nervenfasern. Aufgrund der geringen Anzahl an Parkinson-Patienten mit sensiblen Symptomen und dem fehlenden Nachweis eines statistisch signifikanten Unterschiedes in der QST liegt der Verdacht nahe, dass die ermittelte intraepidermale Nervenfaserreduktion der IPD-Patienten nicht stark genug ausgepr{\"a}gt ist, um eine signifikante Abweichung der QST-Ergebnisse zu verursachen. Weiterhin konnte kein Zusammenhang zwischen der kumulativen Levodopa-Menge, den Vitaminen B12, Methylmalons{\"a}ure sowie Homocystein und dem Auftreten einer Nervenfaserverminderung nachgewiesen werden, was gegen eine iatrogene Beteiligung des peripheren Nervensystems als Nebenwirkung der Levodopa-Therapie spricht. Das idiopathische Parkinson-Syndrom geht mit einer Reduktion der kleinen Nervenfasern einher, welche vermutlich auf die Grunderkrankung selbst zur{\"u}ckzuf{\"u}hren ist. Die Untersuchung der Haut erscheint somit vielversprechend f{\"u}r die Erforschung der Pathogenese und f{\"u}r die Differentialdiagnostik des M. Parkinson.}, subject = {Parkinson-Krankheit}, language = {de} } @phdthesis{He2009, author = {He, Lan}, title = {Small fiber involvement in Fabry's disease}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-32844}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2009}, abstract = {Aim of Investigation: The neurological manifestations of Fabry's disease, a rare, X-linked, multisystem disorder caused by alpha-galactosidase A deficiency and globotriosylceramide (Gb3) accumulation, include both peripheral and central nervous system symptoms. Here we evaluated a prospectively recruited cohort of patients with Fabry's disease for pain, small nerve fiber function, and skin innervation. Methods: 66 patients (31 male and 35 female) were enrolled\&\#65292;31 patients were on ERT. All patients underwent quantitative sensory testing (QST), electrophysiological examination, and extra- and transcranial Doppler sonography. For pain and mood assessment standardized questionnaires were used. Skin biopsies were performed at the left distal leg in 38 patients for intraepidermal nerve fiber density (IENFD) assessment. Results: Age at examination did not differ significantly between women (40.2+/-16.2 years) and men (38.9+/-13.8; n.s.). 29/31 male and 19/35 female patients complained of acroparesthesias or neuropathic pain. QST abnormalities indicative of small fiber impairment were found in 26/31 male and 28/35 female patients. Electrophysiological examination of large fibers and autonomic fibers revealed pathological findings in 11/31 male and 3/35 female patients. All patients had normal Doppler sonography results. Indicators for depression were present in 14/31 male and 10/35 female patients. 20/31 male and 18/35 female patients had a skin biopsy, the IENFD was significantly reduced in male (2.0+/-2.8 fibers/mm) compared with female patients (6.7 +/- 4.4 fibers/mm). In 10 patients free from neurological symptoms, QST and IENFD abnormalities were still detected. Follow up examination after one year in 12 patients under ERT (2.1+/-1.7 years) showed improvement in some symptoms and in QST and neurophysiology in six patients with normal renal function. 20/35 female patients older than 40 y had concomitant diseases, while none of the 18 younger female patients did. The corresponding radio in male patients was 5/19 (>=40y) and 2/13 (<40y) respectively. Conclusions: Neuropathic pain and sensory deficits of the distal extremities are common in patients with Fabry's disease. QST and IENFD analysis are important for early diagnosis of nerve involvement in Fabry's disease. Small fiber function may improve under ERT in patients without severe renal impairment.}, subject = {Fabry's disease}, language = {en} } @article{UeceylerSchroeterKafkeetal.2016, author = {{\"U}{\c{c}}eyler, Nurcan and Schr{\"o}ter, Nils and Kafke, Waldemar and Kramer, Daniela and Wanner, Christoph and Weidemann, Frank and Sommer, Claudia}, title = {Skin Globotriaosylceramide 3 Load Is Increased in Men with Advanced Fabry Disease}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {11}, doi = {10.1371/journal.pone.0166484}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-178856}, year = {2016}, abstract = {Background The X-chromosomally linked life-limiting Fabry disease (FD) is associated with deposits of the sphingolipid globotriaosylceramide 3 (Gb3) in various tissues. Skin is easily accessible and may be used as an additional diagnostic and follow-up medium. Our aims were to visualize skin Gb3 deposits in FD patients applying immunofluorescence and to determine if cutaneous Gb3 load correlates with disease severity. Methods At our Fabry Center for Interdisciplinary Therapy we enrolled 84 patients with FD and 27 healthy controls. All subjects underwent 5-mm skin punch biopsy at the lateral lower leg and the back. Skin samples were processed for immunohistochemistry using antibodies against CD77 (i.e. Gb3). Cutaneous Gb3 deposition was quantified in a blinded manner and correlated to clinical data. Results We found that Gb3 load was higher in distal skin of male FD patients compared to healthy controls (p<0.05). Men (p<0.01) and women (p<0.05) with a classic FD phenotype had higher distal skin Gb3 load than healthy controls. Men with advanced disease as reflected by impaired renal function, and men and women with small fiber neuropathy had more Gb3 deposits in distal skin samples than males with normal renal function (p<0.05) and without small fiber neuropathy. Gb3 deposits were not different between patients with and without enzyme replacement therapy. Conclusions Immunofluorescence on minimally invasive skin punch biopsies may be useful as a tool for assessment and follow-up in FD patients.}, language = {en} } @article{UeceylerKewenigKafkeetal.2014, author = {{\"U}{\c{c}}eyler, Nurcan and Kewenig, Susanne and Kafke, Waldemar and Kittel-Schneider, Sarah and Sommer, Claudia}, title = {Skin cytokine expression in patients with fibromyalgia syndrome is not different from controls}, doi = {10.1186/s12883-014-0185-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110624}, year = {2014}, abstract = {Background Fibromyalgia syndrome (FMS) is a chronic pain syndrome of unknown etiology. There is increasing evidence for small nerve fiber impairment in a subgroup of patients with FMS. We investigated whether skin cytokine and delta opioid receptor (DOR) gene expression in FMS patients differs from controls as one potential contributor to small nerve fiber sensitization. Methods We investigated skin punch biopsies of 25 FMS patients, ten patients with monopolar depression but no pain, and 35 healthy controls. Biopsies were obtained from the lateral upper thigh and lower calf. Gene expression of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF), interleukin (IL)-6, and IL-8 and of the anti-inflammatory cytokine IL-10 was analyzed using quantitative real-time PCR and normalizing data to 18sRNA as housekeeping gene. Additionally, we assessed DOR gene expression. Results All cytokines and DOR were detectable in skin samples of FMS patients, patients with depression, and healthy controls without intergroup difference. Also, gene expression was not different in skin of the upper and lower leg within and between the groups and in FMS patient subgroups. Conclusions Skin cytokine and DOR gene expression does not differ between patients with FMS and controls. Our results do not support a role of the investigated cytokines in sensitization of peripheral nerve fibers as a potential mechanism of small fiber pathology in FMS.}, language = {en} } @phdthesis{Raban2021, author = {Raban, Rebecca Emmi Hildegard}, title = {Sicherheit und Wirksamkeit von intrathekalem Triamcinolon bei Patienten mit chronisch-progredienter Multipler Sklerose : eine retrospektive Longitudinalstudie}, doi = {10.25972/OPUS-22047}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220478}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Im Zeitraum von 2004 bis 2016 erhielten an der Neurologischen Universit{\"a}tsklinik W{\"u}rzburg Patienten mit einer chronisch progredienten Multiplen Sklerose insgesamt 595 Injektionen von intrathekalem Triamcinolonacetonid. Diese Arbeit befasst sich mit Sicherheit, Nebenwirkungen und Wirksamkeit der intrathekalen Therapieform.}, subject = {Intrathekale Applikation}, language = {de} } @article{SchulteBlum2022, author = {Schulte, Annemarie and Blum, Robert}, title = {Shaped by leaky ER: Homeostatic Ca\(^{2+}\) fluxes}, series = {Frontiers in Physiology}, volume = {13}, journal = {Frontiers in Physiology}, issn = {1664-042X}, doi = {10.3389/fphys.2022.972104}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-287102}, year = {2022}, abstract = {At any moment in time, cells coordinate and balance their calcium ion (Ca\(^{2+}\)) fluxes. The term 'Ca\(^{2+}\) homeostasis' suggests that balancing resting Ca2+ levels is a rather static process. However, direct ER Ca\(^{2+}\) imaging shows that resting Ca\(^{2+}\) levels are maintained by surprisingly dynamic Ca\(^{2+}\) fluxes between the ER Ca\(^{2+}\) store, the cytosol, and the extracellular space. The data show that the ER Ca\(^{2+}\) leak, continuously fed by the high-energy consuming SERCA, is a fundamental driver of resting Ca\(^{2+}\) dynamics. Based on simplistic Ca\(^{2+}\) toolkit models, we discuss how the ER Ca\(^{2+}\) leak could contribute to evolutionarily conserved Ca\(^{2+}\) phenomena such as Ca\(^{2+}\) entry, ER Ca\(^{2+}\) release, and Ca\(^{2+}\) oscillations.}, language = {en} } @article{BerveWestMartinietal.2020, author = {Berve, Kristina and West, Brian L. and Martini, Rudolf and Groh, Janos}, title = {Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice}, series = {Journal of Neuroinflammation}, volume = {17}, journal = {Journal of Neuroinflammation}, doi = {10.1186/s12974-020-01996-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230234}, year = {2020}, abstract = {Background The neuronal ceroid lipofuscinoses (CLN diseases) are fatal lysosomal storage diseases causing neurodegeneration in the CNS. We have previously shown that neuroinflammation comprising innate and adaptive immune reactions drives axonal damage and neuron loss in the CNS of palmitoyl protein thioesterase 1-deficient (Ppt1\(^{-/-}\)) mice, a model of the infantile form of the diseases (CLN1). Therefore, we here explore whether pharmacological targeting of innate immune cells modifies disease outcome in CLN1 mice. Methods We applied treatment with PLX3397 (150 ppm in the chow), a potent inhibitor of the colony stimulating factor-1 receptor (CSF-1R) to target innate immune cells in CLN1 mice. Experimental long-term treatment was non-invasively monitored by longitudinal optical coherence tomography and rotarod analysis, as well as analysis of visual acuity, myoclonic jerks, and survival. Treatment effects regarding neuroinflammation, neural damage, and neurodegeneration were subsequently analyzed by histology and immunohistochemistry. Results We show that PLX3397 treatment attenuates neuroinflammation in CLN1 mice by depleting pro-inflammatory microglia/macrophages. This leads to a reduction of T lymphocyte recruitment, an amelioration of axon damage and neuron loss in the retinotectal system, as well as reduced thinning of the inner retina and total brain atrophy. Accordingly, long-term treatment with the inhibitor also ameliorates clinical outcomes in CLN1 mice, such as impaired motor coordination, visual acuity, and myoclonic jerks. However, we detected a sex- and region-biased efficacy of CSF-1R inhibition, with male microglia/macrophages showing higher responsiveness toward depletion, especially in the gray matter of the CNS. This results in a better treatment outcome in male Ppt1\(^{-/-}\) mice regarding some histopathological and clinical readouts and reflects heterogeneity of innate immune reactions in the diseased CNS. Conclusions Our results demonstrate a detrimental impact of innate immune reactions in the CNS of CLN1 mice. These findings provide insights into CLN pathogenesis and may guide in the design of immunomodulatory treatment strategies.}, language = {en} } @article{NotzLotzHerrmannetal.2021, author = {Notz, Quirin and Lotz, Christopher and Herrmann, Johannes and Vogt, Marius and Schlesinger, Tobias and Kredel, Markus and Muellges, Wolfgang and Weismann, Dirk and Westermaier, Thomas and Meybohm, Patrick and Kranke, Peter}, title = {Severe neurological complications in critically ill COVID‑19 patients}, series = {Journal of Neurology}, journal = {Journal of Neurology}, issn = {0340-5354}, doi = {10.1007/s00415-020-10152-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232429}, pages = {1576-1579}, year = {2021}, abstract = {No abstract available.}, language = {en} } @article{TraubOttoSelletal.2022, author = {Traub, Jan and Otto, Markus and Sell, Roxane and G{\"o}pfert, Dennis and Homola, Gy{\"o}rgy and Steinacker, Petra and Oeckl, Patrick and Morbach, Caroline and Frantz, Stefan and Pham, Mirko and St{\"o}rk, Stefan and Stoll, Guido and Frey, Anna}, title = {Serum phosphorylated tau protein 181 and neurofilament light chain in cognitively impaired heart failure patients}, series = {Alzheimer's Research \& Therapy}, volume = {14}, journal = {Alzheimer's Research \& Therapy}, doi = {10.1186/s13195-022-01087-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300515}, year = {2022}, abstract = {Background Chronic heart failure (HF) is known to increase the risk of developing Alzheimer's dementia significantly. Thus, detecting and preventing mild cognitive impairment, which is common in patients with HF, is of great importance. Serum biomarkers are increasingly used in neurological disorders for diagnostics, monitoring, and prognostication of disease course. It remains unclear if neuronal biomarkers may help detect cognitive impairment in this high-risk population. Also, the influence of chronic HF and concomitant renal dysfunction on these biomarkers is not well understood. Methods Within the monocentric Cognition.Matters-HF study, we quantified the serum levels of phosphorylated tau protein 181 (pTau) and neurofilament light chain (NfL) of 146 extensively phenotyped chronic heart failure patients (aged 32 to 85 years; 15.1\% women) using ultrasensitive bead-based single-molecule immunoassays. The clinical work-up included advanced cognitive testing and cerebral magnetic resonance imaging (MRI). Results Serum concentrations of NfL ranged from 5.4 to 215.0 pg/ml (median 26.4 pg/ml) and of pTau from 0.51 to 9.22 pg/ml (median 1.57 pg/ml). We detected mild cognitive impairment (i.e., T-score < 40 in at least one cognitive domain) in 60\% of heart failure patients. pTau (p = 0.014), but not NfL, was elevated in this group. Both NfL (ρ = - 0.21; p = 0.013) and pTau (ρ = - 0.25; p = 0.002) related to the cognitive domain visual/verbal memory, as well as white matter hyperintensity volume and cerebral and hippocampal atrophy. In multivariable analysis, both biomarkers were independently influenced by age (T = 4.6 for pTau; T = 5.9 for NfL) and glomerular filtration rate (T = - 2.4 for pTau; T = - 3.4 for NfL). Markers of chronic heart failure, left atrial volume index (T = 4.6) and NT-proBNP (T = 2.8), were further cardiological determinants of pTau and NfL, respectively. In addition, pTau was also strongly affected by serum creatine kinase levels (T = 6.5) and ferritin (T = - 3.1). Conclusions pTau and NfL serum levels are strongly influenced by age-dependent renal and cardiac dysfunction. These findings point towards the need for longitudinal examinations and consideration of frequent comorbidities when using neuronal serum biomarkers.}, language = {en} } @article{TraubOttoSelletal.2022, author = {Traub, Jan and Otto, Markus and Sell, Roxane and Homola, Gy{\"o}rgy A. and Steinacker, Petra and Oeckl, Patrick and Morbach, Caroline and Frantz, Stefan and Pham, Mirko and St{\"o}rk, Stefan and Stoll, Guido and Frey, Anna}, title = {Serum glial fibrillary acidic protein indicates memory impairment in patients with chronic heart failure}, series = {ESC Heart Failure}, volume = {9}, journal = {ESC Heart Failure}, number = {4}, doi = {10.1002/ehf2.13986}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312736}, pages = {2626-2634}, year = {2022}, abstract = {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.}, language = {en} } @phdthesis{Schramm2002, author = {Schramm, Axel}, title = {Sensomotorische Integration bei zervikalen Dystonien}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-4722}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2002}, abstract = {Zervikale Dystonien geh{\"o}ren zu den h{\"a}ufigsten Formen fokaler Dystonien. Diese sind durch anhaltende, unwillk{\"u}rliche Muskelkontraktionen gekennzeichnet, welche zu verdrehenden oder repetitiven Bewegungen oder abnormalen Haltungen des Kopfes f{\"u}hren. Ein seit {\"u}ber 100 Jahren beobachtetes Ph{\"a}nomen stellt hierbei die M{\"o}glichkeit dar, mittels sogenannter "sensibler Trickman{\"o}ver", welche meistens in einer leichten Ber{\"u}hrung von Arealen im Kopfbereich bestehen, die pathologische Muskelaktivit{\"a}t zu reduzieren und damit die Kopfposition zu normalisieren. Ziel der vorliegenden Arbeit war es, eine breite und vor allem erstmalig quantitative Charakterisierung von wirksamen Trickman{\"o}vern vorzunehmen und so verschiedene Einflußgr{\"o}ßen auf die Wirksamkeit solcher Tricks zu untersuchen. Hierzu wurden die Muskelaktivit{\"a}ten der vier wichtigsten den Kopf drehenden Muskeln mittels Oberfl{\"a}chen-EMG abgeleitet und die Ver{\"a}nderungen bei Trickapplikation unterschiedlicher Lokalisation, Modalit{\"a}t und bei verschiedenen Ausgangspositionen ermittelt. 1) Hinsichtlich der Lokalisation ergaben sich {\"u}ber 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-Aktivit{\"a}t signifikant gegen die Areale "Kinn" (-23\%) und "Hals" (-23\%) ab und war bei 79\% der Patienten am besten wirksam. 2) Bei weiterer Untersuchung verschiedener Trickmodalit{\"a}ten auf dem f{\"u}r jeden Patienten individuell wirksamsten Areal waren neben dem klassischen Trickman{\"o}ver (-42\%) auch die Verwendung eines Plastikstabes durch den Patienten (-43\%) oder Untersucher (-32\%), sowie nicht-sensible Man{\"o}ver wie das Heben des Armes ohne eigentliche Ber{\"u}hrung (-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 k{\"o}nnte. Visuelle R{\"u}ckkopplung {\"u}ber einen Spiegel hatte im Gegensatz dazu keine Wirkung. 3) Bez{\"u}glich der Bedeutung der Kopfposition f{\"u}r Muskelaktivit{\"a}t und Trickwirksamkeit zeigte sich bereits bei willk{\"u}rlicher Einnahme einer Neutralposition ohne Trickanwendung eine signifikante Reduktion agonistischer Muskelaktivit{\"a}t (-30\%), die allerdings von einer leichten antagonistischen Aktivierung begleitet war (+2,4\%). {\"U}berraschenderweise war die Applikation eines Tricks um so wirksamer, je weiter der Kopf zu Beginn auf die zur dystonen Drehrichtung kontralateralen Seite gedreht war. Demgegen{\"u}ber ließ sich bei Trickapplikation in dystoner Maximalposition kaum mehr eine Wirkung nachweisen (-12\%). Die vorliegenden Ergebnisse sprechen aufgrund der unspezifischen Wirkung verschiedenster Trickman{\"o}ver (2) und Lokalisationen (1) f{\"u}r die Einbeziehung h{\"o}herer sensomotorischer Integrationszentren wie z. B. des Parietalcortex in den Wirkmechanismus. Sensible Trickman{\"o}ver k{\"o}nnten bei auf die pathologische Kopfposition adaptierten sensiblen Afferenzen Zusatzinformationen {\"u}ber die Kopfposition im Vergleich zum Rumpf liefern. M{\"o}glicherweise sind diese umso wirksamer, je weiter sich der Kopf noch auf der kontralateralen Seite befindet (3), da in dieser Situation die dystone Muskelaktivit{\"a}t noch gering und das sensible Mismatch, {\"u}ber welches sensible Stimuli modulierend einwirken k{\"o}nnten, maximal ist. Nach den vorgelegten Ergebnissen l{\"a}ßt sich erstmals ein zweiphasiger Ablauf der Trickwirkung postulieren: Der in einer ersten Phase teils willk{\"u}rlich in eine g{\"u}nstige 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 Verst{\"a}ndnis f{\"u}r therapeutisch nutzbare sensible Trickman{\"o}ver verbessert und somit Patienten unterschiedliche Trickstrategien an die Hand gegeben werden. Die Identifikation der zentralen Rolle h{\"o}herer integrativer Zentren wie dem Parietalcortex im Rahmen des Wirkmechanismus, k{\"o}nnte dabei Ausgangspunkt f{\"u}r neue Therapieans{\"a}tze in Form einer gezielten Beeinflussung solcher Areale sein.}, language = {de} }