@phdthesis{Beaucamp2021, author = {Beaucamp, Marcel}, title = {Pr{\"a}diktion des Verschlusses großer intrakranieller Arterien anhand pr{\"a}klinischer Schlaganfallscores}, doi = {10.25972/OPUS-21511}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-215117}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {2015 konnte in mehreren Studien ESCAPE, EXTENDED IA, MR CLEAN, REVASCAT, SWIFT-PRIME eine signifikante {\"U}berlegenheit der mechanischen Thrombektomie verglichen mit der alleinigen i. v. Lysetherapie mit rtPA bezogen auf Revaskularisierung bei Patienten mit einer LVO (large vessel occlusion) nachgewiesen werden. Diese neue Therapiem{\"o}glichkeit erforderte eine Aufteilung der Patienten die von einer Thrombektomie profitieren (LVO) und der Patienten, die keiner Thrombektomie zugef{\"u}hrt werden k{\"o}nnen (nLVO). Die zentrale Fragestellung der Studie ist: Kann ein symptomorientierter Schlaganfallscore die Wahrscheinlichkeit eines großen intrakraniellen Gef{\"a}ßverschlusses mit hinreichender Pr{\"a}zision vorhersagen und kann auf Basis dieser Vorhersage ein Patient direkt in ein {\"u}bergeordnetes Schlagfanfallzentrum gebracht werden, obwohl sich dadurch eine Bridging Lysetherapie verz{\"o}gern w{\"u}rde? Um diesen Fragen auf den Grund zu gehen f{\"u}hrten wir eine monozentrische Querschnittstudie durch, in deren Rahmen 215 Patienten rekrutiert wurden. Die Rekrutierung erfolgte mittels eines aus Subitems bereits etablierter Schlafanfallscores (FAST, CPSS, LAPSS, 3ISS, RACE), zusammengesetzten Fragebogens. Die ausgef{\"u}llten Frageb{\"o}gen wurde in Excel digitalisiert und mittels SPSS, Signifikanz und Odds Ratio berechnet. Anschließend wurde aus den signifikanten Subitems mit der h{\"o}chsten Odds Ratio ein neuer einfach anzuwendender Schlaganfallscore, bestehend aus den pr{\"a}klinisch erhobenen Daten gebildet (W{\"u}rzburg Score of Large Vessel Occlusions, WOLVE- Score). Weiter wurden Signifikanz, Odds Ratio, Sensitivit{\"a}t und Spezifit{\"a}t des WOLVE-Score mit denen der oben genannten etablieren Scores verglichen.}, subject = {Schlaganfall}, language = {de} } @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} } @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} } @phdthesis{KuettnergebWeber2021, author = {K{\"u}ttner [geb. Weber], Sarah-Lucia}, title = {Der Optikusnervenscheidendurchmesser als Instrument zur Prognoseeinsch{\"a}tzung bei Patienten mit hypoxischer Enzephalopathie nach erfolgreicher Reanimation}, doi = {10.25972/OPUS-23766}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237669}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Eine Prognoseeinsch{\"a}tzung bei Patienten mit hypoxischer Enzephalopathie (HIE) nach Reanimation wird fr{\"u}hestens 72 Stunden nach Reanimation empfohlen. Bis zu diesem Zeitpunkt besteht eine f{\"u}r {\"A}rzte und Angeh{\"o}rige belastende prognostische L{\"u}cke. Und auch nach 72 Stunden bestehen nur ungenaue Angaben zum weiteren Vorgehen, sodass eine fundierte Prognoseeinsch{\"a}tzung aktuell eine deutliche Herausforderung im Alltag klinisch t{\"a}tiger {\"A}rzte darstellt. Der Nervus opticus ist als Bestandteil des zentralen Nervensystems mit dem Liquorsystem verbunden. Intrazerebrale Druckerh{\"o}hungen wirken sich daher unmittelbar auf die ihn ummantelnde Nervenscheide und deren Durchmesser aus, sodass sich die Bestimmung des Optikusnervenscheidendurchmessers (ONSD) mittels transorbitaler Sonographie in der Diagnostik unterschiedlicher intrakranieller Erkrankungen bereits bew{\"a}hrt hat. Das Krankheitsbild der HIE wurde als weiteres m{\"o}gliches Einsatzgebiet des ONSD jedoch bisher nicht untersucht. 
Ziel dieser Dissertation war es daher, den ONSD grunds{\"a}tzlich auf seine Verl{\"a}sslichkeit als Prognoseparameter bei HIE nach Reanimation zu {\"u}berpr{\"u}fen. Besonderes Augenmerk lag hierbei auf der Erm{\"o}glichung einer fr{\"u}hzeitigen Prognoseeinsch{\"a}tzung innerhalb von 24 Stunden sowie auf der Definition eines prognostischen Cut-Off-Wertes als klare Entscheidungshilfe f{\"u}r weitere therapeutische Strategien. 24, 48 und 72 Stunden nach Reanimation werden signifikant unterschiedliche ONSD unter {\"u}berlebenden und verstorbenen Patienten nachgewiesen. Letztere weisen dabei im Vergleich sowohl h{\"o}here als auch im zeitlichen Verlauf signifikant ansteigende ONSD-Werte auf. Als prognostischer Cut-Off-Wert konnte eine Grenze bei 5,75mm festgelegt werden. Zusammenfassend stellt die sonographische Bestimmung des ONSD eine sinnvolle Zusatzdiagnostik in der Prognoseeinsch{\"a}tzung bei Patienten mit HIE nach Reanimation dar.}, subject = {Wiederbelebung}, language = {de} } @phdthesis{Auchter2021, author = {Auchter, Antonia}, title = {Schlafassoziierte Ver{\"a}nderung der lokalen Feldpotential Aktivit{\"a}t im Nucleus subthalamicus bei Patienten mit Morbus Parkinson}, doi = {10.25972/OPUS-23782}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237822}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Die tiefe Hirnstimulation ist eine etablierte und hocheffiziente operative Behandlungsmethode f{\"u}r Patienten mit idiopathischem Parkinson- Syndrom (IPS). Als Zielgebiet dient in den meisten F{\"a}llen der Nucleus subthalamicus. Die Indikationen zur Implantation einer tiefen Hirnstimulation (THS) sind medikament{\"o}s nicht behandelbare motorische Fluktuationen und Dyskinesien oder ein medikament{\"o}s nicht kontrollierbarer Tremor. Bislang erfolgt eine kontinuierliche Stimulation. Little et al. konnten jedoch bereits in ihrer 2013 ver{\"o}ffentlichen Studie zeigen, dass eine adaptive Stimulation, gemessen am UPDRS, um 27 \% effektiver war und entsprechend die Stimulationszeit um 56 \% gesenkt werden konnte. Voraussetzung f{\"u}r die Anwendbarkeit einer adaptiven Stimulation im klinischen Alltag ist der Nachweis eines oder mehrerer Physiomarker, welche als R{\"u}ckkopplungssignal f{\"u}r den Stimulationsbeginn dienen. Diese Marker m{\"u}ssen verl{\"a}sslich mit dem Auftreten und der Auspr{\"a}gung der Bewegungsst{\"o}rungen korrelieren. Die Systeme m{\"u}ssen die Signale auslesen und entsprechend darauf reagieren k{\"o}nnen, damit ein sogenanntes Closed- loop- Verfahren entstehen kann. Bei diesen Markern handelt es sich um sogenannte lokale Feldpotenzialaktivit{\"a}ten, das heißt niederfrequente Potential{\"a}nderungen von Zellen in subkortikalen Arealen des Gehirns, welche {\"u}ber Elektroden der THS abgeleitet werden k{\"o}nnen. Der Stimulator Activa PC+S (Medtronic) erm{\"o}glicht es erstmalig Aufzeichnungen von LFP- Daten, außerhalb eines experimentellen Laboraufbaus, mittels dauerhaft implantiertem Ger{\"a}t vorzunehmen und damit auch Langzeitanalysen durchzuf{\"u}hren. Erkenntnisse vergangener Studien ergaben, dass die synchronisierte, pathologisch gesteigerte oszillatorische Aktivit{\"a}t im Beta-Frequenzband (13- 35 Hz) eine bedeutende Rolle im Bezug auf die Pathophysiologie des IPS spielt und als krankheitsspezifische Aktivit{\"a}t gilt. Es konnte bereits belegt werden, dass die Verbesserung der motorischen Symptome (Bradykinese und Rigor) mit dem Ausmaß der Suppression der Betaband- Aktivit{\"a}t korreliert. Die Betabandaktivit{\"a}t als lokale Feldpotentialaktivit{\"a}t kann als Physiomarker einer adaptiven Stimulation dienen. Unser Hauptaugenmerk galt daher der Analyse der Betabandaktivit{\"a}t oder anderer Frequenzbereiche w{\"a}hrend des Schlafes um hier die THS bedarfsgerecht einzusetzen. Hierf{\"u}r wurden n{\"a}chtliche subkortikale LFP- Aufzeichnungen parallel zur Schlaf- Polysomnographie durchgef{\"u}hrt. Zudem erfolgte in der vorliegenden Arbeit sowohl in unserem Vorversuch als auch in unserem Hauptversuch die Anwendung des UPDRS Teil III zur Erfassung der motorischen Symptome, sowie die Durchf{\"u}hrung von Frageb{\"o}gen zur Erfassung der nicht- motorischen Symptome, insbesondere des Schlafes vor und nach Implantation der tiefen Hirnstimulation. Wir konnten belegen, dass es nach Implantation der THS zu einer Erh{\"o}hung der Schlafeffizienz und zu einer Erh{\"o}hung des Anteils der Schlafstadien II und III und damit einhergehend zu einer Steigerung der Schlafqualit{\"a}t kommt. {\"U}bereinstimmend mit anderen Studien konnten wir zeigen, dass sich die Motorik unter Stimulation deutlich verbessert. Im Vorversuch reduzierte sich der mittlere pr{\"a}operative MDS- UPDRS III im MedsOFF verglichen mit dem mittleren postoperativ MDS- UPDRS III im MedsOFF/StimON um 37 \%. In der PC+S- Studie imponierte eine Reduktion um 67\%. Zudem zeigte sich eine Reduktion der nicht- motorischen Symptome durch die THS, insbesondere in der Kategorie Schlaf. Die Ergebnisse der vorliegenden Arbeit ergaben außerdem, dass die Betabandaktivität im Schlafstadium II und vor allem im Schlafstadium III am geringsten ist. Im Schlafstadium I und REM ist die Betabandaktivit{\"a}t höher als im Schlafstadium II und III. Hierbei war entscheidend, dass die Patienten eine klar abgrenzbare Betabandaktivit{\"a}t im Wachstadium aufwiesen und die Elektrodenkontakte im dorsolateralen Kerngebiet des STN lokalisiert waren. Gegenl{\"a}ufig dazu verh{\"a}lt sich die Deltaaktivität. Sie ist im Schlafstadium II und besonders im Stadium III am h{\"o}chsten. Stadium I ist mit durchschnittlich um 7,3 \% niedriger als im Wachstadium. Am geringsten ist sie jedoch im REM-Schlafstadium. Indem wir mit der Betabandaktivit{\"a}t und Deltaaktivit{\"a}t in den einzelnen Schlafstadien einen stabilen und reproduzierbaren Physiomarker finden konnten, sind wir unserem Ziel der adaptiven THS ein St{\"u}ck n{\"a}her gekommen.}, subject = {Parkinson}, language = {de} } @phdthesis{Koeberle2021, author = {K{\"o}berle, Philipp}, title = {High-resolution ultrasound for the identification of pathological patterns in patients with polyneuropathies and amyotrophic lateral sclerosis}, doi = {10.25972/OPUS-24580}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245800}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Neuropathies are a group of potentially treatable diseases with an often disabling and restricting course. Amyotrophic lateral sclerosis (ALS) is a lethal disease without causal treatment possibilities. The objective of this study was to examine the diagnostic utility of HRUS for the differentiation of subtypes of axonal and demyelinating neuropathies and to investigate its utility for the sonological differentiation of ALS. The hypothetical statement that neuropathy causes enlargement of peripheral nerves compared to healthy controls proved to be right, but the adjunctive assumption that ALS does not cause enlargement of peripheral nerves proved to be wrong - in patients with ALS slight enlargement of peripheral nerves was visible as well. The statement that nerve enlargement can be detected by measurement of the cross-sectional area (CSA) and the longitudinal diameter (LD) with comparable results proved to be right, but the enlargement was slightly less present by measurement of the LD. The statement that axonal and demyelinating neuropathies show distinct patterns of nerve enlargement must be answered differentiated: The comparison between axonal and demyelinating neuropathies showed a stronger nerve enlargement in patients with demyelinating neuropathies than in patients with axonal neuropathies at proximal nerve segments of upper extremities. In the comparison of diagnose-defined subgroups of inflammatory demyelinating neuropathies a respective specific pattern of nerve enlargement was visible. However, remarkable in this context was the strong nerve enlargement found in patients with NSVN, which is classified as an axonal neuropathy. Stratification for specific findings in nerve biopsy did not lead to constructive differences in comparison between the different groups. To sum up, HRUS showed to provide a useful contribution in the diagnostic process of neuropathies and ALS but needs to be integrated in a multimodal diagnostic approach.}, subject = {Polyneuropathie}, language = {en} } @phdthesis{Christ2021, author = {Christ, Nicolas}, title = {Die Auswirkung zerebraler Mikroblutungen auf die kognitive Leistungsf{\"a}higkeit nach isch{\"a}mischem Schlaganfall}, doi = {10.25972/OPUS-24367}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-243679}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {In der vorliegenden Studie wurde untersucht, ob zerebrale Mikroblutungen (CMB) bereits im fr{\"u}hen Verlauf nach isch{\"a}mischem Schlaganfall (IS) oder Transitorisch-Isch{\"a}mischer Attacke (TIA) mit kognitivem Abbau assoziiert sind und ob spezifische kognitive Dom{\"a}nen besonders betroffen sind. Der Vergleich zweier Probandengruppen mit IS/TIA und CMB bzw. IS/TIA ohne CMB hinsichtlich ihrer Ergebnisse in der neuropsychologischen Testbatterie CERAD ergab, dass CMB bereits sechs Monate nach dem zerebrovaskul{\"a}ren Ereignis mit einem kognitiven Abbau assoziiert sind. Multilokul{\"a}re CMB zeigen eine st{\"a}rkere Auswirkung auf die Kognition als solche CMB, die in einer einzigen Hirnregion gefunden wurden. Zudem wurde eine signifikante Korrelation zwischen dem Grad der kognitiven Einschr{\"a}nkung und der Anzahl der CMB errechnet. Die separate Betrachtung derjenigen Testungen, welche das episodische Ged{\"a}chtnis erfassen, zeigte eine Beeintr{\"a}chtigung der Testpersonen beim Wiedererkennen von zuvor gelernten W{\"o}rtern. Bei der Untersuchung des semantischen Ged{\"a}chtnisses der ProbandInnen fiel eine signifikant eingeschr{\"a}nkte phonematische Wortfl{\"u}ssigkeit auf, die semantische Fl{\"u}ssigkeit und das Benennen jedoch waren weniger betroffen. Die Dom{\"a}ne „Visuokonstruktive F{\"a}higkeiten" wurde ebenfalls in drei Untertests beurteilt. Hierbei zeigten sich keine Defizite der Testgruppe beim Abzeichnen der dargebotenen Figuren, die Reproduktion hingegen war signifikant gest{\"o}rt. Es zeigte sich keine CMB-bedingte Einschr{\"a}nkung der exekutiven Funktionen.}, subject = {Hirnblutung}, language = {de} } @phdthesis{Klaus2021, author = {Klaus, Laura-Christin}, title = {Generierung und Charakterisierung eines neuen Mausmodells des Morbus Parkinson durch AAV1/2 vermittelte {\"U}berexpression von humanem mutiertem A53T-α-Synuclein in der Substantia nigra}, doi = {10.25972/OPUS-23921}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239217}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Auch wenn die {\"A}tiopathogenese von Morbus Parkinson bis heute nicht vollst{\"a}ndig gekl{\"a}rt ist, scheint α-Synuclein (α-Syn) eine zentrale Rolle zu spielen. Die Entdeckung als genetische Ursache der Erkrankung, als Hauptbestandteil der Lewy-K{\"o}rper (LK) und seine Assoziation mit verschiedenen anderen potenziellen {\"a}tiologischen Faktoren verdeutlichen dies. Bei Ratten und Affen f{\"u}hrte eine AAV1/2-vermittelte {\"U}berexpression von A53T-α-Syn zu einer Degeneration dopaminerger Neurone in der Substantia nigra (SN), einem striatalen dopaminergen Defizit sowie Verhaltensauff{\"a}lligkeiten. In Anbetracht bestimmter Vorteile der Mausspezies, war es das Ziel dieser Dissertation - die im Rahmen eines kollaborativen Projektes mit dem Toronto Western Research Institut in Ontario, Kanada entstanden ist - dieses auf AAV1/2-A53T-α-Syn basierende Parkinson-Modell auf M{\"a}use zu {\"u}bertragen. Dazu wurde AAV1/2-A53T-α-Syn oder leerer AAV1/2-Vektor in einer Dosis von 1,5 µl mit einer Konzentration von 5,16 x 10^12 gp/ml stereotaktisch einseitig in die rechte SN von C57BL/6-wt-M{\"a}usen injiziert. {\"U}ber einen Zeitraum von 11 Wochen wurden verschiedene Verhaltensexperimente durchgef{\"u}hrt und die beiden Versuchstiergruppen miteinander verglichen. Post-mortem erfolgten verschiedene immunhistochemische Untersuchungen. Es konnte gezeigt werden, dass die einseitige Injektion von AAV1/2-A53T-α-Syn in die SN bei M{\"a}usen eine weit verbreitete {\"U}berexpression von A53T-α-Syn in dopaminergen Neuronen der SN induzierte, die innerhalb von 10 Wochen zu signifikanten fr{\"u}hen und persistierenden motorischen Verhaltensauff{\"a}lligkeiten, nigrostriataler Degeneration und Entwicklung einer Lewy-{\"a}hnlichen Pathologie f{\"u}hrte. Durch die Generierung und Charakterisierung dieses neuen Parkinson-Mausmodells, das klinische und histopathologische Merkmale der menschlichen Erkrankung widerspiegelt, besteht nun die M{\"o}glichkeit es weiterzuentwickeln und z.B. auf transgene M{\"a}use zu {\"u}bertragen, um u.a. molekulare Mechanismen der Parkinson-Krankheit zu entschl{\"u}sseln und pr{\"a}klinische Tests von krankheitsmodifizierenden Therapien durchzuf{\"u}hren.}, subject = {Parkinson-Krankheit}, language = {de} } @phdthesis{Waldmann2021, author = {Waldmann, Amelie Friederike}, title = {K{\"o}rperselbstgef{\"u}hl und Puppenhandillusion bei Patienten mit Morbus Parkinson im medikament{\"o}sen ON und OFF}, doi = {10.25972/OPUS-23200}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232009}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {In der vorliegenden Studie untersuchten wir das K{\"o}rperselbstgef{\"u}hl von Patienten mit Morbus Parkinson und altersgematchten gesunden Teilnehmern mithilfe der Puppenhandillusion. Bei diesem Paradigma wird dadurch, dass die verdeckte Hand der Testperson zeitgleich mit einer sichtbaren Puppenhand bestrichen wird, das Gef{\"u}hl hervorgerufen, die Kunsthand sei die eigene (gemessen mittels Fragebogen zur Illusion und propriozeptivem Drift). Eine zeitlich versetzte (asynchrone) Stimulation dient als Kontrollbedingung. Innerhalb der Parkinsonpatienten wurde dar{\"u}ber hinaus eine Untergruppe zus{\"a}tzlich im medikament{\"o}sen OFF-Zustand untersucht. Die Annahme, dass die Parkinsonerkrankung mit einer gest{\"o}rten K{\"o}rperselbstwahrnehmung einhergeht, spiegelt sich in den Ergebnissen wider: Bei den Patienten mit Parkinsonerkrankung trat unabh{\"a}ngig vom Stimulationsmodus ein h{\"o}herer propriozeptiver Drift als bei den Gesunden ein. Wurden die Patienten anschließend nach dem Erleben der Illusion befragt, fielen die Antworten allerdings nur w{\"a}hrend der asynchronen Durchf{\"u}hrung positiver als bei der Kontrollgruppe aus. Die Untersuchungen des Drifts und Fragebogens im ON- gegen{\"u}ber OFF-Zustand lieferten keinen Unterschied. Die vorliegende Studie liefert Hinweise darauf, dass die gemessenen Unterschiede bei Parkinsonpatienten gegen{\"u}ber Gesunden auf ein internes Rauschen eingehender sensorischer Signale beim Morbus Parkinson sowie auf die Beteiligung nicht-dopaminerger Systeme zur{\"u}ckzuf{\"u}hren sein k{\"o}nnten. Die zunehmende Aufmerksamkeit gegen{\"u}ber einer ver{\"a}nderten K{\"o}rperwahrnehmung bei Parkinsonpatienten und deren Grundlagen im Bereich der multisensorischen Integration k{\"o}nnte k{\"u}nftig neue M{\"o}glichkeiten in der ganzheitlichen Therapie liefern mit dem Ziel, die Lebensqualit{\"a}t der Patienten zu steigern.}, subject = {Parkinson-Krankheit}, language = {de} } @article{EgenolfAltenschildescheKressetal.2021, author = {Egenolf, Nadine and Altenschildesche, Caren Meyer zu and Kreß, Luisa and Eggermann, Katja and Namer, Barbara and Gross, Franziska and Klitsch, Alexander and Malzacher, Tobias and Kampik, Daniel and Malik, Rayaz A. and Kurth, Ingo and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan}, title = {Diagnosing small fiber neuropathy in clinical practice: a deep phenotyping study}, series = {Therapeutic Advances in Neurological Disorders}, volume = {14}, journal = {Therapeutic Advances in Neurological Disorders}, issn = {1756-2864}, doi = {10.1177/17562864211004318}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232019}, year = {2021}, abstract = {Background and aims: Small fiber neuropathy (SFN) is increasingly suspected in patients with pain of uncertain origin, and making the diagnosis remains a challenge lacking a diagnostic gold standard. Methods: In this case-control study, we prospectively recruited 86 patients with a medical history and clinical phenotype suggestive of SFN. Patients underwent neurological examination, quantitative sensory testing (QST), and distal and proximal skin punch biopsy, and were tested for pain-associated gene loci. Fifty-five of these patients additionally underwent pain-related evoked potentials (PREP), corneal confocal microscopy (CCM), and a quantitative sudomotor axon reflex test (QSART). Results: Abnormal distal intraepidermal nerve fiber density (IENFD) (60/86, 70\%) and neurological examination (53/86, 62\%) most frequently reflected small fiber disease. Adding CCM and/or PREP further increased the number of patients with small fiber impairment to 47/55 (85\%). Genetic testing revealed potentially pathogenic gene variants in 14/86 (16\%) index patients. QST, QSART, and proximal IENFD were of lower impact. Conclusion: We propose to diagnose SFN primarily based on the results of neurological examination and distal IENFD, with more detailed phenotyping in specialized centers.}, language = {en} } @phdthesis{Hornburger2021, author = {Hornburger, Hannah}, title = {Die Rolle des prim{\"a}ren somatosensiblen Kortex f{\"u}r die multisensorische Integration bei der Puppenhandillusion - eine tDCS-Studie}, doi = {10.25972/OPUS-23232}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232323}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {In der Puppenhandillusion (PHI) wird durch die synchrone Ber{\"u}hrung der nicht-sichtbaren Hand des Probanden und einer sichtbaren Puppenhand ein illusio-n{\"a}res K{\"o}rperzugeh{\"o}rigkeitsgef{\"u}hl induziert. Dieses Paradigma erlaubt es zu untersuchen, wie das Gehirn widerspr{\"u}chliche multisensorische Informationen w{\"a}hrend einer perzeptiven Inferenz aufl{\"o}st. Vorausgehende Studien weisen darauf hin, dass der Konflikt zwischen visueller und propriozeptiver Information vor der PHI durch eine Abschw{\"a}chung des so-matosensiblen Inputs behoben wird. Um herauszufinden, ob eine Exzitabilit{\"a}ts-Minderung des prim{\"a}ren somatosensiblen Kortex die PHI verst{\"a}rken kann, kam die kathodale transkranielle Gleichstromstimulation (c-tDCS) zum Einsatz. An dreißig gesunden Probanden wurde die PHI ohne (=baseline) und w{\"a}hrend tDCS untersucht. Jeder Proband erhielt kathodale, anodale und sham-Stimulation an drei unterschiedlichen Tagen im Abstand von je einer Woche. Das PHI-Paradigma wurde in sechs Distanzen (von 17,5 bis 67,5 cm) zwischen der eigenen Hand und der Puppenhand durchgef{\"u}hrt. Das Auftreten der PHI wurde anhand eines Fragebogens (Illusionsscore, IS) und der Abweichung der gef{\"u}hlten Handposition in Bezug zur realen Position (relativer Drift, RD) evalu-iert. Die kathodale Stimulation war mit einem signifikanten Anstieg des IS im Vergleich zur anodalen Stimulation assoziiert, wohingegen die RD-Werte {\"u}ber alle Stimulationsarten hinweg vergleichbar waren. Die fehlende Signifikanz zwischen Verum und Sham-Stimulation wurde auf die geringe Effektst{\"a}rke bei vergleichsweise kleinem Probandenkollektiv bezogen. Die Ergebnisse dieser Studie zeigen jedoch eine verst{\"a}rkte Wahrnehmung der PHI unabh{\"a}ngig von demographischen Faktoren, wenn kathodale tDCS {\"u}ber dem kontralateralen prim{\"a}ren somatosensiblen Kortex appliziert wurde. Dies unterst{\"u}tzt unsere Hypothese, dass eine Abschw{\"a}chung der somatosensiblen Pr{\"a}zision den Weg f{\"u}r eine erleichterte Integration eines fremden K{\"o}rperteils in das eigene K{\"o}rperschema ebnet.}, subject = {tDCS}, language = {de} } @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{Klitsch2021, author = {Klitsch, Alexander}, title = {Corneal and cutaneous factors contributing to small fiber pathology in fibromyalgia syndrome}, doi = {10.25972/OPUS-22439}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224398}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {We examined 143 patients suffering from FMS, a syndrome characterized by chronic widespread pain, sleep disturbances, and fatigue. Etiology and pathophysiology of FMS are scarcely understood. In recent years abnormalities of small Aδ- and C-nerve fibers have been found in subgroups of FMS patients. It is yet unclear how such SFP is caused in FMS patients and how it contributes to FMS symptoms. We used CCM to analyze corneal small nerve fibers and associated LC, comparing FMS patients' results to those from 65 healthy controls and 41 disease controls suffering from SFN. We, further, assessed expression levels of mRNA and miRNA in keratinocytes taken from skin punch biopsies of FMS patients and healthy controls kept as monocellular cell cultures. A screening was performed using NGS in a small cohort of 12 FMS patients and 5 healthy controls. Results were validated in larger cohorts by qRT-PCR. As in previous studies IENFD and CNFD were reduced in a subgroup of FMS patients. We found identical LC densities in FMS patients, healthy controls, and SFN patients. The subpopulation of dLCfiber contact in FMS and SFN patients was lower than in healthy controls. Our RNA expression analysis revealed one mRNA that was expressed higher in FMS patients than in controls: PRSS21. We conclude that reduced neurotrophic signaling of LC may contribute to SFP in the cornea. Epidermal PRSS21 expression and dLCfiber contact density are promising biomarker candidates for FMS diagnosis.}, subject = {Fibromyalgie}, language = {en} } @phdthesis{Peterka2021, author = {Peterka, Manuel}, title = {Propriozeptive St{\"o}rungen bei Morbus Parkinson - Explorative Untersuchungen zu Art, Ausmaß und potenzieller Rekalibrierung mithilfe der LSVT-BIG-Therapie}, doi = {10.25972/OPUS-22612}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226129}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Beim idiopathischen Parkinson Syndrom (IPS) gewinnen nicht-motorische Symptome in Forschung und Klinik zunehmend an Bedeutung. So findet sich in der Literatur vermehrt Evidenz, dass die Propriozeption bei Patienten mit IPS (PmIPS) gest{\"o}rt ist. Verschiedene klinische und neuroanatomische Studien weisen darauf hin, dass es beim IPS zu einer fehlerhaften sensomotorischen Integration von propriozeptiven Informationen in den Basalganglien kommt. Zudem gibt es Hinweise, dass die passiv-sensible Wahrnehmung von Propriozeption pathologisch ver{\"a}ndert ist. Außerdem wird vermutet, dass durch propriozeptives Training eine Verbesserung der Parkinsonsymptomatik erreicht werden kann. Ein spezielles Trainingsprogramm, die LSVT-BIG-Therapie, bei der gezielt trainiert wird, Bewegungen mit einer großen Amplitude durchzuf{\"u}hren, konnte motorische Symptome und Mobilit{\"a}t beim IPS effektiv verbessern. In der vorliegenden Arbeit stellten wir folgende Hypothesen auf: Das IPS geht mit einer fehlerhaften sensomotorischen Integration von Propriozeption einher. Die afferente propriozeptive Wahrnehmung ist ebenfalls pathologisch ver{\"a}ndert. Eine propriozeptive Rekalibrierung ist mithilfe der LSVT-BIG-Therapie m{\"o}glich. F{\"u}r die {\"U}berpr{\"u}fung dieser Hypothesen schlossen wir 30 PmIPS und 15 gesunde Probanden in unsere Fall-Kontroll-Studie ein und f{\"u}hrten eine Eingangsuntersuchung durch. 11 PmIPS absolvierten anschließend eine vierw{\"o}chige LSVT-BIG-Therapie. Die Folgeuntersuchungen fanden 4 und 8 Wochen nach der Eingangsuntersuchung statt. 78 Diese beinhalteten neuropsychologische Testungen, außerdem die Bestimmung der Lebensqualit{\"a}t, die Erhebung des motorischen Teils der Movement Disorder Society Unified Parkinson´s Disease Rating Scale (MDS-UPDRS III), Untersuchungen zur Feinmotorik, die Durchf{\"u}hrung einer diagnostischen Transkraniellen Magnetstimulation (TMS) sowie Testverfahren zur Propriozeption, darunter sowohl Zeigeversuche, als auch die Bestimmung der Position einer Extremit{\"a}t, ohne visuelle Kontrolle. Die Ergebnisse zeigten, dass die IPS-Gruppe gegen{\"u}ber der gesunden Kontrollgruppe signifikant gr{\"o}ßere Zeigefehler machte, wohingegen die Bestimmung der Position einer Extremit{\"a}t in beiden Gruppen vergleichbar pr{\"a}zise m{\"o}glich war. Zus{\"a}tzlich zeigte eine von sieben Messungen der Feinmotorik einen signifikanten Unterschied zwischen PmIPS und Kontrollen. Die Messungen der TMS erbrachten hingegen keine signifikant messbaren Unterschiede zwischen den Gruppen. In den Folgeuntersuchungen nach therapeutischer Intervention ergaben die Zeige{\"u}bungen eine signifikante Verbesserung der BIG-Gruppe im Zeitverlauf. Die Untersuchungen zu Feinmotorik und MDS-UPDRS III ergaben zwar eine tendenzielle Verbesserung durch die LSVT-BIG-Therapie, waren jedoch statistisch nicht signifikant. Die Lebensqualit{\"a}t der PmIPS in der BIG-Gruppe verbesserte sich signifikant nach Intervention. Die Ergebnisse sprechen f{\"u}r die Hypothese der fehlerhaften propriozeptiven Integration beim Morbus Parkinson. Dies zeigte sich f{\"u}r aktive sensomotorische Tasks, nicht hingegen in der passiv-sensiblen propriozeptiven Testung. Auch wenn weitere Studien mit gr{\"o}ßeren Kohorten ben{\"o}tigt werden, legt unsere Studie nahe, dass die LSVT-BIG-Therapie mit einer propriozeptiven Rekalibrierung einhergeht. Damit erkl{\"a}rt sich m{\"o}glicherweise der nachhaltige Erfolg der Therapie.}, subject = {Propriozeption}, language = {de} } @article{EssigBabilonVollmuthetal.2021, author = {Essig, Fabian and Babilon, Lilith and Vollmuth, Christoph and Kollikowski, Alexander M. and Pham, Mirko and Solymosi, L{\´a}szl{\´o} and Haeusler, Karl Georg and Kraft, Peter and Stoll, Guido and Schuhmann, Michael K.}, title = {High mobility group box 1 protein in cerebral thromboemboli}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {20}, issn = {1422-0067}, doi = {10.3390/ijms222011276}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265568}, year = {2021}, abstract = {High-mobility group box 1 protein (HMGB1) is a damage-associated molecular pattern (DAMP) involved in neutrophil extracellular trap (NET) formation and thrombosis. NETs are regularly found in cerebral thromboemboli. We here analyzed associated HMGB1 expression in human thromboemboli retrieved via mechanical thrombectomy from 37 stroke patients with large vessel occlusion. HMGB1 was detected in all thromboemboli, accounting for 1.7\% (IQR 0.6-6.2\%) of the total thromboemboli area and was found to be colocalized with neutrophils and NETs and in spatial proximity to platelets. Correlation analysis revealed that the detection of HMGB1 was strongly related to the number of neutrophils (r = 0.58, p = 0.0002) and platelets (r = 0.51, p = 0.001). Our results demonstrate that HMGB1 is a substantial constituent of thromboemboli causing large vessel occlusion stroke.}, language = {en} } @article{SchuhmannPappStolletal.2021, author = {Schuhmann, Michael K. and Papp, Lena and Stoll, Guido and Blum, Robert and Volkmann, Jens and Fluri, Felix}, title = {Mesencephalic electrical stimulation reduces neuroinflammation after photothrombotic stroke in rats by targeting the cholinergic anti-inflammatory pathway}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {3}, issn = {1422-0067}, doi = {10.3390/ijms22031254}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259099}, year = {2021}, abstract = {Inflammation is crucial in the pathophysiology of stroke and thus a promising therapeutic target. High-frequency stimulation (HFS) of the mesencephalic locomotor region (MLR) reduces perilesional inflammation after photothrombotic stroke (PTS). However, the underlying mechanism is not completely understood. Since distinct neural and immune cells respond to electrical stimulation by releasing acetylcholine, we hypothesize that HFS might trigger the cholinergic anti-inflammatory pathway via activation of the α7 nicotinic acetylcholine receptor (α7nAchR). To test this hypothesis, rats underwent PTS and implantation of a microelectrode into the MLR. Three hours after intervention, either HFS or sham-stimulation of the MLR was applied for 24 h. IFN-γ, TNF-α, and IL-1α were quantified by cytometric bead array. Choline acetyltransferase (ChAT)\(^+\) CD4\(^+\)-cells and α7nAchR\(^+\)-cells were quantified visually using immunohistochemistry. Phosphorylation of NFĸB, ERK1/2, Akt, and Stat3 was determined by Western blot analyses. IFN-γ, TNF-α, and IL-1α were decreased in the perilesional area of stimulated rats compared to controls. The number of ChAT\(^+\) CD4\(^+\)-cells increased after MLR-HFS, whereas the amount of α7nAchR\(^+\)-cells was similar in both groups. Phospho-ERK1/2 was reduced significantly in stimulated rats. The present study suggests that MLR-HFS may trigger anti-inflammatory processes within the perilesional area by modulating the cholinergic system, probably via activation of the α7nAchR.}, 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{KuzkinaBargarSchmittetal.2021, author = {Kuzkina, Anastasia and Bargar, Connor and Schmitt, Daniela and R{\"o}ßle, Jonas and Wang, Wen and Schubert, Anna-Lena and Tatsuoka, Curtis and Gunzler, Steven A. and Zou, Wen-Quan and Volkmann, Jens and Sommer, Claudia and Doppler, Kathrin and Chen, Shu G.}, title = {Diagnostic value of skin RT-QuIC in Parkinson's disease: a two-laboratory study}, series = {NPJ Parkinson's Disease}, volume = {7}, journal = {NPJ Parkinson's Disease}, number = {1}, doi = {10.1038/s41531-021-00242-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260451}, year = {2021}, abstract = {Skin alpha-synuclein deposition is considered a potential biomarker for Parkinson's disease (PD). Real-time quaking-induced conversion (RT-QuIC) is a novel, ultrasensitive, and efficient seeding assay that enables the detection of minute amounts of alpha-synuclein aggregates. We aimed to determine the diagnostic accuracy, reliability, and reproducibility of alpha-synuclein RT-QuIC assay of skin biopsy for diagnosing PD and to explore its correlation with clinical markers of PD in a two-center inter-laboratory comparison study. Patients with clinically diagnosed PD (n = 34), as well as control subjects (n = 30), underwent skin punch biopsy at multiple sites (neck, lower back, thigh, and lower leg). The skin biopsy samples (198 in total) were divided in half to be analyzed by RT-QuIC assay in two independent laboratories. The a-synuclein RT-QuIC assay of multiple skin biopsies supported the clinical diagnosis of PD with a diagnostic accuracy of 88.9\% and showed a high degree of inter-rater agreement between the two laboratories (92.2\%). Higher alpha-synuclein seeding activity in RT-QuIC was shown in patients with longer disease duration and more advanced disease stage and correlated with the presence of REM sleep behavior disorder, cognitive impairment, and constipation. The alpha-synuclein RT-QuIC assay of minimally invasive skin punch biopsy is a reliable and reproducible biomarker for Parkinson's disease. Moreover, alpha-synuclein RT-QuIC seeding activity in the skin may serve as a potential indicator of progression as it correlates with the disease stage and certain non-motor symptoms.}, language = {en} } @article{StetterLopezCaperuchipiHoppKraemeretal.2021, author = {Stetter, Christian and Lopez-Caperuchipi, Simon and Hopp-Kr{\"a}mer, Sarah and Bieber, Michael and Kleinschnitz, Christoph and Sir{\´e}n, Anna-Leena and Albert-Weißenberger, Christiane}, title = {Amelioration of cognitive and behavioral deficits after traumatic brain injury in coagulation factor XII deficient mice}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {9}, issn = {1422-0067}, doi = {10.3390/ijms22094855}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284959}, year = {2021}, abstract = {Based on recent findings that show that depletion of factor XII (FXII) leads to better posttraumatic neurological recovery, we studied the effect of FXII-deficiency on post-traumatic cognitive and behavioral outcomes in female and male mice. In agreement with our previous findings, neurological deficits on day 7 after weight-drop traumatic brain injury (TBI) were significantly reduced in FXII\(^{-/-}\) mice compared to wild type (WT) mice. Also, glycoprotein Ib (GPIb)-positive platelet aggregates were more frequent in brain microvasculature of WT than FXII\(^{-/-}\) mice 3 months after TBI. Six weeks after TBI, memory for novel object was significantly reduced in both female and male WT but not in FXII\(^{-/-}\) mice compared to sham-operated mice. In the setting of automated home-cage monitoring of socially housed mice in IntelliCages, female WT mice but not FXII\(^{-/-}\) mice showed decreased exploration and reacted negatively to reward extinction one month after TBI. Since neuroendocrine stress after TBI might contribute to trauma-induced cognitive dysfunction and negative emotional contrast reactions, we measured peripheral corticosterone levels and the ration of heart, lung, and spleen weight to bodyweight. Three months after TBI, plasma corticosterone levels were significantly suppressed in both female and male WT but not in FXII\(^{-/-}\) mice, while the relative heart weight increased in males but not in females of both phenotypes when compared to sham-operated mice. Our results indicate that FXII deficiency is associated with efficient post-traumatic behavioral and neuroendocrine recovery.}, language = {en} } @article{DauerneeJoppeTatenhorstCaldiGomesetal.2021, author = {Dauer n{\´e}e Joppe, Karina and Tatenhorst, Lars and Caldi Gomes, Lucas and Zhang, Shuyu and Parvaz, Mojan and Carboni, Eleonora and Roser, Anna-Elisa and El DeBakey, Hazem and B{\"a}hr, Mathias and Vogel-Mikuš, Katarina and Wang Ip, Chi and Becker, Stefan and Zweckstetter, Markus and Lingor, Paul}, title = {Brain iron enrichment attenuates α-synuclein spreading after injection of preformed fibrils}, series = {Journal of Neurochemistry}, volume = {159}, journal = {Journal of Neurochemistry}, number = {3}, doi = {10.1111/jnc.15461}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262544}, pages = {554 -- 573}, year = {2021}, abstract = {Regional iron accumulation and α-synuclein (α-syn) spreading pathology within the central nervous system are common pathological findings in Parkinson's disease (PD). Whereas iron is known to bind to α-syn, facilitating its aggregation and regulating α-syn expression, it remains unclear if and how iron also modulates α-syn spreading. To elucidate the influence of iron on the propagation of α-syn pathology, we investigated α-syn spreading after stereotactic injection of α-syn preformed fibrils (PFFs) into the striatum of mouse brains after neonatal brain iron enrichment. C57Bl/6J mouse pups received oral gavage with 60, 120, or 240 mg/kg carbonyl iron or vehicle between postnatal days 10 and 17. At 12 weeks of age, intrastriatal injections of 5-µg PFFs were performed to induce seeding of α-syn aggregates. At 90 days post-injection, PFFs-injected mice displayed long-term memory deficits, without affection of motor behavior. Interestingly, quantification of α-syn phosphorylated at S129 showed reduced α-syn pathology and attenuated spreading to connectome-specific brain regions after brain iron enrichment. Furthermore, PFFs injection caused intrastriatal microglia accumulation, which was alleviated by iron in a dose-dependent way. In primary cortical neurons in a microfluidic chamber model in vitro, iron application did not alter trans-synaptic α-syn propagation, possibly indicating an involvement of non-neuronal cells in this process. Our study suggests that α-syn PFFs may induce cognitive deficits in mice independent of iron. However, a redistribution of α-syn aggregate pathology and reduction of striatal microglia accumulation in the mouse brain may be mediated via iron-induced alterations of the brain connectome.}, language = {en} } @article{BaumToykaBlueheretal.2021, author = {Baum, Petra and Toyka, Klaus V. and Bl{\"u}her, Matthias and Kosacka, Joanna and Nowicki, Marcin}, title = {Inflammatory mechanisms in the pathophysiology of diabetic peripheral neuropathy (DN) — new aspects}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {19}, issn = {1422-0067}, doi = {10.3390/ijms221910835}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284556}, year = {2021}, abstract = {The pathogenesis of diabetic neuropathy is complex, and various pathogenic pathways have been proposed. A better understanding of the pathophysiology is warranted for developing novel therapeutic strategies. Here, we summarize recent evidence from experiments using animal models of type 1 and type 2 diabetes showing that low-grade intraneural inflammation is a facet of diabetic neuropathy. Our experimental data suggest that these mild inflammatory processes are a likely common terminal pathway in diabetic neuropathy associated with the degeneration of intraepidermal nerve fibers. In contrast to earlier reports claiming toxic effects of high-iron content, we found the opposite, i.e., nutritional iron deficiency caused low-grade inflammation and fiber degeneration while in normal or high non-heme iron nutrition no or only extremely mild inflammatory signs were identified in nerve tissue. Obesity and dyslipidemia also appear to trigger mild inflammation of peripheral nerves, associated with neuropathy even in the absence of overt diabetes mellitus. Our finding may be the experimental analog of recent observations identifying systemic proinflammatory activity in human sensorimotor diabetic neuropathy. In a rat model of type 1 diabetes, a mild neuropathy with inflammatory components could be induced by insulin treatment causing an abrupt reduction in HbA1c. This is in line with observations in patients with severe diabetes developing a small fiber neuropathy upon treatment-induced rapid HbA1c reduction. If the inflammatory pathogenesis could be further substantiated by data from human tissues and intervention studies, anti-inflammatory compounds with different modes of action may become candidates for the treatment or prevention of diabetic neuropathy.}, language = {en} } @article{WieseDennstaedtHollmannetal.2021, author = {Wiese, Teresa and Dennst{\"a}dt, Fabio and Hollmann, Claudia and Stonawski, Saskia and Wurst, Catherina and Fink, Julian and Gorte, Erika and Mandasari, Putri and Domschke, Katharina and Hommers, Leif and Vanhove, Bernard and Schumacher, Fabian and Kleuser, Burkard and Seibel, J{\"u}rgen and Rohr, Jan and Buttmann, Mathias and Menke, Andreas and Schneider-Schaulies, J{\"u}rgen and Beyersdorf, Niklas}, title = {Inhibition of acid sphingomyelinase increases regulatory T cells in humans}, series = {Brain Communications}, volume = {3}, journal = {Brain Communications}, number = {2}, doi = {10.1093/braincomms/fcab020}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259868}, year = {2021}, abstract = {Genetic deficiency for acid sphingomyelinase or its pharmacological inhibition has been shown to increase Foxp3\(^+\) regulatory T-cell frequencies among CD4\(^+\) T cells in mice. We now investigated whether pharmacological targeting of the acid sphingomyelinase, which catalyzes the cleavage of sphingomyelin to ceramide and phosphorylcholine, also allows to manipulate relative CD4\(^+\) Foxp3\(^+\) regulatory T-cell frequencies in humans. Pharmacological acid sphingomyelinase inhibition with antidepressants like sertraline, but not those without an inhibitory effect on acid sphingomyelinase activity like citalopram, increased the frequency of Foxp3\(^+\) regulatory T cell among human CD4\(^+\) T cells in vitro. In an observational prospective clinical study with patients suffering from major depression, we observed that acid sphingomyelinase-inhibiting antidepressants induced a stronger relative increase in the frequency of CD4\(^+\) Foxp3\(^+\) regulatory T cells in peripheral blood than acid sphingomyelinase-non- or weakly inhibiting antidepressants. This was particularly true for CD45RA\(^-\) CD25\(^{high}\) effector CD4\(^+\) Foxp3\(^+\) regulatory T cells. Mechanistically, our data indicate that the positive effect of acid sphingomyelinase inhibition on CD4\(^+\) Foxp3\(^+\) regulatory T cells required CD28 co-stimulation, suggesting that enhanced CD28 co-stimulation was the driver of the observed increase in the frequency of Foxp3+ regulatory T cells among human CD4\(^+\) T cells. In summary, the widely induced pharmacological inhibition of acid sphingomyelinase activity in patients leads to an increase in Foxp3+ regulatory T-cell frequencies among CD4\(^+\) T cells in humans both in vivo and in vitro.}, 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} } @phdthesis{Andreska2021, author = {Andreska, Thomas}, title = {Effects of dopamine on BDNF / TrkB mediated signaling and plasticity on cortico-striatal synapses}, doi = {10.25972/OPUS-17431}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-174317}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Progressive loss of voluntary movement control is the central symptom of Parkinson's disease (PD). Even today, we are not yet able to cure PD. This is mainly due to a lack of understanding the mechanisms of movement control, network activity and plasticity in motor circuits, in particular between the cerebral cortex and the striatum. Brain-derived neurotrophic factor (BDNF) has emerged as one of the most important factors for the development and survival of neurons, as well as for synaptic plasticity. It is thus an important target for the development of new therapeutic strategies against neurodegenerative diseases. Together with its receptor, the Tropomyosin receptor kinase B (TrkB), it is critically involved in development and function of the striatum. Nevertheless, little is known about the localization of BDNF within presynaptic terminals in the striatum, as well as the types of neurons that produce BDNF in the cerebral cortex. Furthermore, the influence of midbrain derived dopamine on the control of BDNF / TrkB interaction in striatal medium spiny neurons (MSNs) remains elusive so far. Dopamine, however, appears to play an important role, as its absence leads to drastic changes in striatal synaptic plasticity. This suggests that dopamine could regulate synaptic activity in the striatum via modulation of BDNF / TrkB function. To answer these questions, we have developed a sensitive and reliable protocol for the immunohistochemical detection of endogenous BDNF. We find that the majority of striatal BDNF is provided by glutamatergic, cortex derived afferents and not dopaminergic inputs from the midbrain. In fact, we found BDNF in cell bodies of neurons in layers II-III and V of the primary and secondary motor cortex as well as layer V of the somatosensory cortex. These are the brain areas that send dense projections to the dorsolateral striatum for control of voluntary movement. Furthermore, we could show that these projection neurons significantly downregulate the expression of BDNF during the juvenile development of mice between 3 and 12 weeks. In parallel, we found a modulatory effect of dopamine on the translocation of TrkB to the cell surface in postsynaptic striatal Medium Spiny Neurons (MSNs). In MSNs of the direct pathway (dMSNs), which express dopamine receptor 1 (DRD1), we observed the formation of TrkB aggregates in the 6-hydroxydopamine (6-OHDA) model of PD. This suggests that DRD1 activity controls TrkB surface expression in these neurons. In contrast, we found that DRD2 activation has opposite effects in MSNs of the indirect pathway (iMSNs). Activation of DRD2 promotes a rapid decrease in TrkB surface expression which was reversible and depended on cAMP. In parallel, stimulation of DRD2 led to induction of phospho-TrkB (pTrkB). This effect was significantly slower than the effect on TrkB surface expression and indicates that TrkB is transactivated by DRD2. Together, our data provide evidence that dopamine triggers dual modes of plasticity on striatal MSNs by acting on TrkB surface expression in DRD1 and DRD2 expressing MSNs. This surface expression of the receptor is crucial for the binding of BDNF, which is released from corticostriatal afferents. This leads to the induction of TrkB-mediated downstream signal transduction cascades and long-term potentiation (LTP). Therefore, the dopamine-mediated translocation of TrkB could be a mediator that modulates the balance between dopaminergic and glutamatergic signaling to allow synaptic plasticity in a spatiotemporal manner. This information and the fact that TrkB is segregated to persistent aggregates in PD could help to improve our understanding of voluntary movement control and to develop new therapeutic strategies beyond those focusing on dopaminergic supply.}, subject = {Brain-derived neurotrophic factor}, language = {en} } @article{SchischlevskijCordtsGuentheretal.2021, author = {Schischlevskij, Pavel and Cordts, Isabell and G{\"u}nther, Ren{\´e} and Stolte, Benjamin and Zeller, Daniel and Schr{\"o}ter, Carsten and Weyen, Ute and Regensburger, Martin and Wolf, Joachim and Schneider, Ilka and Hermann, Andreas and Metelmann, Moritz and Kohl, Zacharias and Linker, Ralf A. and Koch, Jan Christoph and Stendel, Claudia and M{\"u}schen, Lars H. and Osmanovic, Alma and Binz, Camilla and Klopstock, Thomas and Dorst, Johannes and Ludolph, Albert C. and Boentert, Matthias and Hagenacker, Tim and Deschauer, Marcus and Lingor, Paul and Petri, Susanne and Schreiber-Katz, Olivia}, title = {Informal caregiving in amyotrophic lateral sclerosis (ALS): a high caregiver burden and drastic consequences on caregivers' lives}, series = {Brain Sciences}, volume = {11}, journal = {Brain Sciences}, number = {6}, issn = {2076-3425}, doi = {10.3390/brainsci11060748}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240981}, year = {2021}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients' informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers' burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients' CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients' functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King's Stages for ALS. The caregivers' burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers' burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients' functional status (r\(_p\) = -0.555, p < 0.001, n = 242). It was influenced by the CGs' own mental health issues due to caregiving (+11.36, 95\% CI [6.84; 15.87], p < 0.001), patients' wheelchair dependency (+9.30, 95\% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs' depression (r\(_p\) = 0.627, p < 0.001, n = 234), anxiety (r\(_p\) = 0.550, p < 0.001, n = 234), and poorer physical condition (r\(_p\) = -0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients' impairment in daily routine (r\(_s\) = -0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs' lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs' work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required.}, language = {en} } @article{SchnabelCamenKnebeletal.2021, author = {Schnabel, Renate B. and Camen, Stephan and Knebel, Fabian and Hagendorff, Andreas and Bavendiek, Udo and B{\"o}hm, Michael and Doehner, Wolfram and Endres, Matthias and Gr{\"o}schel, Klaus and Goette, Andreas and Huttner, Hagen B. and Jensen, Christoph and Kirchhof, Paulus and Korosoglou, Grigorius and Laufs, Ulrich and Liman, Jan and Morbach, Caroline and Navabi, Darius G{\"u}nther and Neumann-Haefelin, Tobias and Pfeilschifter, Waltraut and Poli, Sven and Rizos, Timolaos and Rolf, Andreas and R{\"o}ther, Joachim and Sch{\"a}bitz, Wolf R{\"u}diger and Steiner, Thorsten and Thomalla, G{\"o}tz and Wachter, Rolf and Haeusler, Karl Georg}, title = {Expert opinion paper on cardiac imaging after ischemic stroke}, series = {Clinical Research in Cardiology}, volume = {110}, journal = {Clinical Research in Cardiology}, number = {7}, issn = {1861-0692}, doi = {10.1007/s00392-021-01834-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266662}, pages = {938-958}, year = {2021}, abstract = {This expert opinion paper on cardiac imaging after acute ischemic stroke or transient ischemic attack (TIA) includes a statement of the "Heart and Brain" consortium of the German Cardiac Society and the German Stroke Society. The Stroke Unit-Commission of the German Stroke Society and the German Atrial Fibrillation NETwork (AFNET) endorsed this paper. Cardiac imaging is a key component of etiological work-up after stroke. Enhanced echocardiographic tools, constantly improving cardiac computer tomography (CT) as well as cardiac magnetic resonance imaging (MRI) offer comprehensive non- or less-invasive cardiac evaluation at the expense of increased costs and/or radiation exposure. Certain imaging findings usually lead to a change in medical secondary stroke prevention or may influence medical treatment. However, there is no proof from a randomized controlled trial (RCT) that the choice of the imaging method influences the prognosis of stroke patients. Summarizing present knowledge, the German Heart and Brain consortium proposes an interdisciplinary, staged standard diagnostic scheme for the detection of risk factors of cardio-embolic stroke. This expert opinion paper aims to give practical advice to physicians who are involved in stroke care. In line with the nature of an expert opinion paper, labeling of classes of recommendations is not provided, since many statements are based on expert opinion, reported case series, and clinical experience.}, language = {en} } @phdthesis{Braun2021, author = {Braun, Alexandra}, title = {Psychosocial and somatic resilience factors of patients with fibromyalgia syndrome (FMS)}, doi = {10.25972/OPUS-24280}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242809}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Background: In recent years, health care has increasingly become the focus of public interest, politics, health insurance companies, and research. This includes the development of therapeutic concepts that can respond individually to patients' resources in order to improve coping with chronic diseases. Research into psychosocial and biological resilience factors is very important and the basic objective of the present work. I studied patients with fibromyalgia syndrome (FMS), who suffer among others from chronic pain, fatigue, sleep and gastrointestinal problems. This patient cohort is characterized by a pronounced heterogeneity in terms of clinical outcome, degree in disability and coping. FMS has a prevalence of 3 - 8 \% in the Western population and has a significant socio-economic impact. Validated psychosocial resilience factors include optimism, humor, coherence, self-efficacy, awareness with one's own resources and the ability to apply them profitably (coping), and a healthy social environment with positive relationships. Studies in patients with cancer revealed religiosity as positive and negative factor on the health outcome, but there is little data on religious aspects of pain resilience. Various genetic polymorphisms and anti-inflammatory cytokines are known as biological resilience factors. Various microRNA (miRNA) were detected to contribute to resilience in the context of stress and psychiatric disorders. Objective: The underlying research question of this work is to understand the factors that make some FMS patients resilient and others not, even though they suffer from the same disease. The long-term aim was to understand mechanisms and influencing factors of resilience to design preventive and resource-oriented therapies for FMS patients. Material and Methods: Three studies examined religious, physiological, biological, and psychosocial factors which may contribute to resilience in FMS patients. Study one combined data of questionnaires, a psychosocial interview, and regression analyses to investigate the relevance of religiosity for coping and resilience. Study two examined variance explaining factors and defined clusters among FMS patients by their differences in coping, pain phenotype and disability. The factor analysis used variables derived from questionnaires and qPCR of cytokines in white blood samples (WBC) of patients and healthy controls. Study three assessed cluster-wise miRNA signatures which may underly differences in behaviour, emotional and physiological disability, and resilience among patient clusters. A cluster-specific speculative model of a miRNA-mediated regulatory cycle was proposed and its potential targets verified by an online tool. Results: The data from the first study revealed a not very religious patient cohort, which was rather ambivalent towards the institution church, but described itself as a believer. The degree of religiosity played a role in the choice of coping strategy but had no effect on psychological parameters or health outcomes. The coping strategy "reinterpretation", which is closely related iv to the religious coping "reappraisal", had the highest influence on FMS related disability. Cognitive active coping strategies such as reappraisal which belongs to religious coping had the highest effect on FMS related disability (resilience) and could be trained by a therapist. Results from the second study showed high variances of all measured cytokines within the patient group and no difference between patient and control group. The high dispersion indicated cluster among patients. Factor analysis extracted four variance-explaining factors named as affective load, coping, pain, and pro-inflammatory cytokines. Psychological factors such as depression were the most decisive factors of everyday stress in life and represented the greatest influence on the variance of the data. Study two identified four clusters with respective differences in the factors and characterized them as poorly adapted (maladaptive), well adapted (adaptive), vulnerable and resilient. Their naming was based on characteristics of both resilience concepts, indicated by patients who were less stress-sensitive and impaired as a personal characteristic and by patients who emerged as more resilient from a learning and adaptive process. The data from the variance analysis suggests that problem- and emotion-focused coping strategies and a more anti-inflammatory cytokine pattern are associated with low impairment and contribute to resilience. Additional favorable factors include low anxiety, acceptance, and persistence. Some cluster-specific intervention proposals were created that combine existing concepts of behavioral and mindfulness therapies with alternative therapies such as vitamin D supplementation and a healthy intestinal flora. The results of the third study revealed lower relative gene expression of miR103a-3p, miR107, and miR130a-3p in the FMS cohort compared to the healthy controls with a large effect size. The adaptive cluster had the highest gene expression of miR103a-3p and tendentially of miR107, which was correlated with the subscale score "physical abuse" of the trauma questionnaire. Further correlations were found in particular with pain catastrophizing and FMS-related disability. MiR103a-3p and miR107 form a miRNA-family. Based on this, we proposed a miR103a/107 regulated model of an adaptive process to stress, inflammation and pain by targeting genetic factors which are included in different anti-inflammatory and stress-regulating pathways. Conclusion: All three studies provide new insights into resilience in FMS patients. Cognitive coping (reappraisal/reinterpretation) plays a central role and thus offers therapeutic targets (reframing in the context of behavioral therapy). Religosity as a resilience factor was only partially valid for our patient cohort. Basically, the use of resource-oriented therapy in large institutions still requires research and interdisciplinary cooperation to create a consensus between the humanities, natural sciences and humanism.}, subject = {Resilienz}, language = {en} } @phdthesis{Rost2021, author = {Rost, Anna-Lena}, title = {Akute erregerbedingte Meningoenzephalitiden am Universit{\"a}tsklinikum W{\"u}rzburg von 2006-2015}, doi = {10.25972/OPUS-24084}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240846}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Am Universit{\"a}tsklinikum W{\"u}rzburg wurden zwischen 2006-2015 447 F{\"a}lle einer akuten erregerbedingten Meningoenzephalitis in den Kliniken der Neurologie, Kinderklinik, Neurochirurgie und Psychiatrie behandelt. Es konnten sowohl F{\"a}lle durch Bakterien als auch F{\"a}lle durch Viren, Parasiten und Pilze gesichert werden. Diese Arbeit beschreibt die lokale Epidemiologie akuter erregerbedingter Meningoenzephalitiden.}, subject = {Meningoenzephalitis}, language = {de} } @article{PiroEckesKasaragodetal.2021, author = {Piro, Inken and Eckes, Anna-Lena and Kasaragod, Vikram Babu and Sommer, Claudia and Harvey, Robert J. and Schaefer, Natascha and Villmann, Carmen}, title = {Novel Functional Properties of Missense Mutations in the Glycine Receptor β Subunit in Startle Disease}, series = {Frontiers in Molecular Neuroscience}, volume = {14}, journal = {Frontiers in Molecular Neuroscience}, issn = {1662-5099}, doi = {10.3389/fnmol.2021.745275}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246676}, year = {2021}, abstract = {Startle disease is a rare disorder associated with mutations in GLRA1 and GLRB, encoding glycine receptor (GlyR) α1 and β subunits, which enable fast synaptic inhibitory transmission in the spinal cord and brainstem. The GlyR β subunit is important for synaptic localization via interactions with gephyrin and contributes to agonist binding and ion channel conductance. Here, we have studied three GLRB missense mutations, Y252S, S321F, and A455P, identified in startle disease patients. For Y252S in M1 a disrupted stacking interaction with surrounding aromatic residues in M3 and M4 is suggested which is accompanied by an increased EC\(_{50}\) value. By contrast, S321F in M3 might stabilize stacking interactions with aromatic residues in M1 and M4. No significant differences in glycine potency or efficacy were observed for S321F. The A455P variant was not predicted to impact on subunit folding but surprisingly displayed increased maximal currents which were not accompanied by enhanced surface expression, suggesting that A455P is a gain-of-function mutation. All three GlyR β variants are trafficked effectively with the α1 subunit through intracellular compartments and inserted into the cellular membrane. In vivo, the GlyR β subunit is transported together with α1 and the scaffolding protein gephyrin to synaptic sites. The interaction of these proteins was studied using eGFP-gephyrin, forming cytosolic aggregates in non-neuronal cells. eGFP-gephyrin and β subunit co-expression resulted in the recruitment of both wild-type and mutant GlyR β subunits to gephyrin aggregates. However, a significantly lower number of GlyR β aggregates was observed for Y252S, while for mutants S321F and A455P, the area and the perimeter of GlyR β subunit aggregates was increased in comparison to wild-type β. Transfection of hippocampal neurons confirmed differences in GlyR-gephyrin clustering with Y252S and A455P, leading to a significant reduction in GlyR β-positive synapses. Although none of the mutations studied is directly located within the gephyrin-binding motif in the GlyR β M3-M4 loop, we suggest that structural changes within the GlyR β subunit result in differences in GlyR β-gephyrin interactions. Hence, we conclude that loss- or gain-of-function, or alterations in synaptic GlyR clustering may underlie disease pathology in startle disease patients carrying GLRB mutations.}, language = {en} } @article{GoebVollZimmermannetal.2021, author = {G{\"o}b, Vanessa and Voll, Maximilian G. and Zimmermann, Lena and Hemmen, Katharina and Stoll, Guido and Nieswandt, Bernhard and Schuhmann, Michael K. and Heinze, Katrin G. and Stegner, David}, title = {Infarct growth precedes cerebral thrombosis following experimental stroke in mice}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-021-02360-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265791}, year = {2021}, abstract = {Ischemic stroke is among the leading causes of disability and death worldwide. In acute ischemic stroke, successful recanalization of occluded vessels is the primary therapeutic aim, but even if it is achieved, not all patients benefit. Although blockade of platelet aggregation did not prevent infarct progression, cerebral thrombosis as cause of secondary infarct growth has remained a matter of debate. As cerebral thrombi are frequently observed after experimental stroke, a thrombus-induced impairment of the brain microcirculation is considered to contribute to tissue damage. Here, we combine the model of transient middle cerebral artery occlusion (tMCAO) with light sheet fluorescence microscopy and immunohistochemistry of brain slices to investigate the kinetics of thrombus formation and infarct progression. Our data reveal that tissue damage already peaks after 8 h of reperfusion following 60 min MCAO, while cerebral thrombi are only observed at later time points. Thus, cerebral thrombosis is not causative for secondary infarct growth during ischemic stroke.}, language = {en} } @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{SchuhmannBieberFrankeetal.2021, author = {Schuhmann, Michael K. and Bieber, Michael and Franke, Maximilian and Kollikowski, Alexander M. and Stegner, David and Heinze, Katrin G. and Nieswandt, Bernhard and Pham, Mirko and Stoll, Guido}, title = {Platelets and lymphocytes drive progressive penumbral tissue loss during middle cerebral artery occlusion in mice}, series = {Journal of Neuroinflammation}, volume = {18}, journal = {Journal of Neuroinflammation}, number = {1}, doi = {10.1186/s12974-021-02095-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259172}, pages = {46}, year = {2021}, abstract = {Background In acute ischemic stroke, cessation of blood flow causes immediate tissue necrosis within the center of the ischemic brain region accompanied by functional failure in the surrounding brain tissue designated the penumbra. The penumbra can be salvaged by timely thrombolysis/thrombectomy, the only available acute stroke treatment to date, but is progressively destroyed by the expansion of infarction. The underlying mechanisms of progressive infarction are not fully understood. Methods To address mechanisms, mice underwent filament occlusion of the middle cerebral artery (MCAO) for up to 4 h. Infarct development was compared between mice treated with antigen-binding fragments (Fab) against the platelet surface molecules GPIb (p0p/B Fab) or rat immunoglobulin G (IgG) Fab as control treatment. Moreover, Rag1\(^{-/-}\) mice lacking T-cells underwent the same procedures. Infarct volumes as well as the local inflammatory response were determined during vessel occlusion. Results We show that blocking of the platelet adhesion receptor, glycoprotein (GP) Ibα in mice, delays cerebral infarct progression already during occlusion and thus before recanalization/reperfusion. This therapeutic effect was accompanied by decreased T-cell infiltration, particularly at the infarct border zone, which during occlusion is supplied by collateral blood flow. Accordingly, mice lacking T-cells were likewise protected from infarct progression under occlusion. Conclusions Progressive brain infarction can be delayed by blocking detrimental lymphocyte/platelet responses already during occlusion paving the way for ultra-early treatment strategies in hyper-acute stroke before recanalization.}, language = {en} } @article{SommerCarrollKoikeetal.2021, author = {Sommer, Claudia and Carroll, Antonia S. and Koike, Haruki and Katsuno, Masahisa and Ort, Nora and Sobue, Gen and Vucic, Steve and Spies, Judith M. and Doppler, Kathrin and Kiernan, Matthew C.}, title = {Nerve biopsy in acquired neuropathies}, series = {Journal of the Peripheral Nervous System}, volume = {26}, journal = {Journal of the Peripheral Nervous System}, number = {S2}, doi = {10.1111/jns.12464}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259555}, pages = {S21-S41}, year = {2021}, abstract = {A diagnosis of neuropathy can typically be determined through clinical assessment and focused investigation. With technological advances, including significant progress in genomics, the role of nerve biopsy has receded over recent years. However, making a specific and, in some cases, tissue-based diagnosis is essential across a wide array of potentially treatable acquired peripheral neuropathies. When laboratory investigations do not suggest a definitive diagnosis, nerve biopsy remains the final step to ascertain the etiology of the disease. The present review highlights the utility of nerve biopsy in confirming a diagnosis, while further illustrating the importance of a tissue-based diagnosis in relation to treatment strategies, particularly when linked to long-term immunosuppressive therapies,}, language = {en} } @article{PeseschkianCordtsGuentheretal.2021, author = {Peseschkian, Tara and Cordts, Isabell and G{\"u}nther, Ren{\´e} and Stolte, Benjamin and Zeller, Daniel and Schr{\"o}ter, Carsten and Weyen, Ute and Regensburger, Martin and Wolf, Joachim and Schneider, Ilka and Hermann, Andreas and Metelmann, Moritz and Kohl, Zacharias and Linker, Ralf A. and Koch, Jan Christoph and B{\"u}chner, Boriana and Weiland, Ulrike and Sch{\"o}nfelder, Erik and Heinrich, Felix and Osmanovic, Alma and Klopstock, Thomas and Dorst, Johannes and Ludolph, Albert C. and Boentert, Matthias and Hagenacker, Tim and Deschauer, Marcus and Lingor, Paul and Petri, Susanne and Schreiber-Katz, Olivia}, title = {A nation-wide, multi-center study on the quality of life of ALS patients in Germany}, series = {Brain Sciences}, volume = {11}, journal = {Brain Sciences}, number = {3}, issn = {2076-3425}, doi = {10.3390/brainsci11030372}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234147}, year = {2021}, abstract = {Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (β = -1.96 per increase of one point in the ALSFRS-R score, p < 0.001). "Limb-onset" ALS (lALS) was associated with a better QoL than "bulbar-onset" ALS (bALS) (mean ALSAQ-5 total score 55.46 versus 60.99, p = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (β = -7.60, p = 0.001), being tracheostomized (β = -14.80, p = 0.004) and using non-invasive ventilation (β = -5.71, p = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (β = 5.95, p = 0.007), and increasing age (β = 0.18, p = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care.}, language = {en} } @article{KremerPauwelsPozzietal.2021, author = {Kremer, Naomi I. and Pauwels, Rik W. J. and Pozzi, Nicol{\`o} G. and Lange, Florian and Roothans, Jonas and Volkmann, Jens and Reich, Martin M.}, title = {Deep Brain Stimulation for Tremor: Update on Long-Term Outcomes, Target Considerations and Future Directions}, series = {Journal of Clinical Medicine}, volume = {10}, journal = {Journal of Clinical Medicine}, number = {16}, issn = {2077-0383}, doi = {10.3390/jcm10163468}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244982}, year = {2021}, abstract = {Deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus is one of the main advanced neurosurgical treatments for drug-resistant tremor. However, not every patient may be eligible for this procedure. Nowadays, various other functional neurosurgical procedures are available. In particular cases, radiofrequency thalamotomy, focused ultrasound and radiosurgery are proven alternatives to DBS. Besides, other DBS targets, such as the posterior subthalamic area (PSA) or the dentato-rubro-thalamic tract (DRT), may be appraised as well. In this review, the clinical characteristics and pathophysiology of tremor syndromes, as well as long-term outcomes of DBS in different targets, will be summarized. The effectiveness and safety of lesioning procedures will be discussed, and an evidence-based clinical treatment approach for patients with drug-resistant tremor will be presented. Lastly, the future directions in the treatment of severe tremor syndromes will be elaborated.}, language = {en} } @phdthesis{Nehen2021, author = {Nehen, Mathias Julius}, title = {Modulation der Schrankenfunktion prim{\"a}rer humaner zerebraler Endothelzellen durch Fumars{\"a}ureester unter inflammatorischen und nicht-inflammatorischen Bedingungen}, doi = {10.25972/OPUS-24092}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240925}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Die Multiple Sklerose ist eine bisher nicht heilbare, chronisch-inflammatorische demyelinisierende Erkrankung des zentralen Nervensystems. Trotz intensiver Forschungsbem{\"u}hungen ist der exakte Pathomechanismus nicht vollkommen verstanden. Klar ist jedoch, dass der Blut-Hirn-Schranke eine entscheidende Rolle bei der Pathogenese zukommt. Seit Februar 2014 ist mit Dimethylfumarat ein neues orales Medikament f{\"u}r die schubf{\"o}rmige Multiple Sklerose zugelassen. Die Wirkungen von Fumars{\"a}ureestern auf humane zerebrale Endothelzellen als Grundsteine der Blut-Hirn-Schranke sind allerdings nur unzureichend untersucht. Mehrere Forschungsgruppen demonstrierten an humanem Nabelschnurvenenendothel einen hemmenden Effekt von Fumars{\"a}ureestern auf die Adh{\"a}sion von Leukozyten und beschrieben eine Inhibition der Aktivierung des proinflammatorischen Transkriptionsfaktors NFB in den Endothelzellen. Aufgrund der charakteristischen Eigenschaften zerebralen Endothels ist eine {\"U}bertragung dieser Beobachtungen auf die Blut-Hirn-Schranke allerdings nicht ohne weiteres m{\"o}glich. Daher galt es potentielle Effekte von Fumars{\"a}ureestern auf prim{\"a}re humane zerebrale Endothelzellen als in vitro Modell der Blut-Hirn-Schranke zu {\"u}berpr{\"u}fen. Dabei wurden die Zellen nicht nur unter ruhenden Bedingungen, sondern auch unter inflammatorischer Stimulation mit TNF-α, IL-1 und IFN untersucht, einem Milieu, wie es in inflammatorischen MS L{\"a}sionen zu finden ist. In Leukozyten-Adh{\"a}sionsassays konnte durch Inkubation mit Monomethylfumarat und Dimethylfumarat keine funktionale Beeinflussung der Adh{\"a}sion von T-Lymphozyten an den verwendeten zerebralen Endothelzellen verzeichnet werden. Kongruent dazu fand sich in durchflusszytometrischen Analysen keine Hemmung der inflammatorisch vermittelten Expression des Adh{\"a}sionsmolek{\"u}ls ICAM-1, welches eine tragende Rolle bei der Leukozytenmigration spielt. Inflammatorische intrazellul{\"a}re Signalwege, wie die NFB-Kerntranslokation oder die Phosphorylierung von p38 wurden in HECE im Gegensatz zu HUVEC durch Fumars{\"a}ureester ebenso wenig beeinflusst. Diese in sich konsistenten Ergebnisse f{\"u}hren zu der Schlussfolgerung, dass im Gegensatz zu anderen Gef{\"a}ßbetten weder Dimethylfumarat noch Monomethylfumarat direkt am zerebralen Endothel anti-inflammatorisch wirken.}, subject = {Multiple Sklerose}, language = {de} } @phdthesis{Soda2021, author = {Soda, Hassan}, title = {Interdisziplin{\"a}res Schlaganfallmanagement anhand des Stroke Manager Programms - Studiendaten und Perspektiven f{\"u}r die Schlaganfallversorgung}, doi = {10.25972/OPUS-24206}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242061}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Die Schlaganfallnachsorge in Deutschland wird von verschiedenen Leistungserbringern gepr{\"a}gt, die teilweise komplement{\"a}re und komplexe Dienstleistungen erbringen und sektoren{\"u}bergreifend arbeiten. In Bad Neustadt wurde in Kooperation mit der Universit{\"a}t W{\"u}rzburg und dem Zentrum f{\"u}r Telemedizin Bad Kissingen das Stroke Manager Programm entwickelt und evaluiert. Das strukturierte Nachsorgeprogramm Stroke Manager basiert auf einer standardisierten Informations- und Software Unterst{\"u}tzung von der Akutversorgung bis drei Monate nach Entlassung aus der station{\"a}ren Versorgung. Anhand der Ergebnisse des Stroke Manager Programms konnte eine vergleichsweise hohe Persistenz bzgl. der station{\"a}r verordneten medikament{\"o}sen Sekund{\"a}rpr{\"a}vention {\"u}ber einen Zeitraum von drei Monaten festgestellt werden, ebenso konnten wir nachweisen, dass sich das Programm positiv auf die Versorgungsqualit{\"a}t sowie die Patientenzufriedenheit nach Schlaganfall auswirken kann. Die im Stroke Manager-Programm betreuten Schlaganfallpatienten wiesen im Vergleich signifikante Unterschiede bei den Faktoren Rauchverhalten, Schlaganfallschweregrad und subjektive, globale Lebensqualit{\"a}t auf.}, subject = {Stroke Manager}, language = {de} } @article{LangeSteigerwaldMalzacheretal.2021, author = {Lange, Florian and Steigerwald, Frank and Malzacher, Tobias and Brandt, Gregor Alexander and Odorfer, Thorsten Michael and Roothans, Jonas and Reich, Martin M. and Fricke, Patrick and Volkmann, Jens and Matthies, Cordula and Capetian, Philipp D.}, title = {Reduced Programming Time and Strong Symptom Control Even in Chronic Course Through Imaging-Based DBS Programming}, series = {Frontiers in Neurology}, volume = {12}, journal = {Frontiers in Neurology}, issn = {1664-2295}, doi = {10.3389/fneur.2021.785529}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-249634}, year = {2021}, abstract = {Objectives: Deep brain stimulation (DBS) programming is based on clinical response testing. Our clinical pilot trial assessed the feasibility of image-guided programing using software depicting the lead location in a patient-specific anatomical model. Methods: Parkinson's disease patients with subthalamic nucleus-DBS were randomly assigned to standard clinical-based programming (CBP) or anatomical-based (imaging-guided) programming (ABP) in an 8-week crossover trial. Programming characteristics and clinical outcomes were evaluated. Results: In 10 patients, both programs led to similar motor symptom control (MDS-UPDRS III) after 4 weeks (medicationOFF/stimulationON; CPB: 18.27 ± 9.23; ABP: 18.37 ± 6.66). Stimulation settings were not significantly different, apart from higher frequency in the baseline program than CBP (p = 0.01) or ABP (p = 0.003). Time spent in a program was not significantly different (CBP: 86.1 ± 29.82\%, ABP: 88.6 ± 29.0\%). Programing time was significantly shorter (p = 0.039) with ABP (19.78 ± 5.86 min) than CBP (45.22 ± 18.32). Conclusion: Image-guided DBS programming in PD patients drastically reduces programming time without compromising symptom control and patient satisfaction in this small feasibility trial.}, language = {en} } @article{NguemeniStiehlHiewetal.2021, author = {Nguemeni, Carine and Stiehl, Annika and Hiew, Shawn and Zeller, Daniel}, title = {No Impact of Cerebellar Anodal Transcranial Direct Current Stimulation at Three Different Timings on Motor Learning in a Sequential Finger-Tapping Task}, series = {Frontiers in Human Neuroscience}, volume = {15}, journal = {Frontiers in Human Neuroscience}, issn = {1662-5161}, doi = {10.3389/fnhum.2021.631517}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225477}, year = {2021}, abstract = {Background: Recently, attention has grown toward cerebellar neuromodulation in motor learning using transcranial direct current stimulation (tDCS). An important point of discussion regarding this modulation is the optimal timing of tDCS, as this parameter could significantly influence the outcome. Hence, this study aimed to investigate the effects of the timing of cerebellar anodal tDCS (ca-tDCS) on motor learning using a sequential finger-tapping task (FTT). Methods: One hundred and twenty two healthy young, right-handed subjects (96 females) were randomized into four groups (During\(_{sham}\), Before, During\(_{real}\), After). They performed 2 days of FTT with their non-dominant hand on a custom keyboard. The task consisted of 40 s of typing followed by 20 s rest. Each participant received ca-tDCS (2 mA, sponge electrodes of 25 cm\(^{2}\), 20 min) at the appropriate timing and performed 20 trials on the first day (T1, 20 min). On the following day, only 10 trials of FTT were performed without tDCS (T2, 10 min). Motor skill performance and retention were assessed. Results: All participants showed a time-dependent increase in learning. Motor performance was not different between groups at the end of T1 (p = 0.59). ca-tDCS did not facilitate the retention of the motor skill in the FTT at T2 (p = 0.27). Thus, our findings indicate an absence of the effect of ca-tDCS on motor performance or retention of the FTT independently from the timing of stimulation. Conclusion: The present results suggest that the outcome of ca-tDCS is highly dependent on the task and stimulation parameters. Future studies need to establish a clear basis for the successful and reproducible clinical application of ca-tDCS.}, language = {en} } @article{EichnerReisDoresetal.2021, author = {Eichner, Felizitas A. and Reis, Joschua M. and Dores, Joaquim and Pavlovic, Vladimir and Kreß, Luisa and Daneshkhah, Naeimeh and Weinhardt, Renate and Grau, Armin and M{\"u}hler, Johannes and Soda, Hassan and Schwarzbach, Christopher J. and Schuler, Michael and H{\"a}usler, Karl Georg and Heuschmann, Peter U.}, title = {Cross-sectional study on patients' understanding and views of the informed consent procedure of a secondary stroke prevention trial}, series = {European Journal of Neurology}, volume = {28}, journal = {European Journal of Neurology}, number = {8}, doi = {10.1111/ene.14917}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259404}, pages = {2639-2647}, year = {2021}, abstract = {Background and purpose Improving understanding of study contents and procedures might enhance recruitment into studies and retention during follow-up. However, data in stroke patients on understanding of the informed consent (IC) procedure are sparse. Methods We conducted a cross-sectional study among ischemic stroke patients taking part in the IC procedure of an ongoing cluster-randomized secondary prevention trial. All aspects of the IC procedure were assessed in an interview using a standardized 20-item questionnaire. Responses were collected within 72 h after the IC procedure and analyzed quantitatively and qualitatively. Participants were also asked their main reasons for participation. Results A total of 146 stroke patients (65 ± 12 years old, 38\% female) were enrolled. On average, patients recalled 66.4\% (95\% confidence interval = 65.2\%-67.5\%) of the content of the IC procedure. Most patients understood that participation was voluntary (99.3\%) and that they had the right to withdraw consent (97.1\%); 79.1\% of the patients recalled the study duration and 56.1\% the goal. Only 40.3\% could clearly state a benefit of participation, and 28.8\% knew their group allocation. Younger age, higher graduation, and allocation to the intervention group were associated with better understanding. Of all patients, 53\% exclusively stated a personal and 22\% an altruistic reason for participation. Conclusions Whereas understanding of patient rights was high, many patients were unable to recall other important aspects of study content and procedures. Increased attention to older and less educated patients may help to enhance understanding in this patient population. Actual recruitment and retention benefit of an improved IC procedure remains to be tested in a randomized trial.}, language = {en} } @article{StrinitzPhamMaerzetal.2021, author = {Strinitz, Marc and Pham, Mirko and M{\"a}rz, Alexander G. and Feick, J{\"o}rn and Weidner, Franziska and Vogt, Marius L. and Essig, Fabian and Neugebauer, Hermann and Stoll, Guido and Schuhmann, Michael K. and Kollikowski, Alexander M.}, title = {Immune cells invade the collateral circulation during human stroke: prospective replication and extension}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {17}, issn = {1422-0067}, doi = {10.3390/ijms22179161}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284281}, year = {2021}, abstract = {It remains unclear if principal components of the local cerebral stroke immune response can be reliably and reproducibly observed in patients with acute large-vessel-occlusion (LVO) stroke. We prospectively studied a large independent cohort of n = 318 consecutive LVO stroke patients undergoing mechanical thrombectomy during which cerebral blood samples from within the occluded anterior circulation and systemic control samples from the ipsilateral cervical internal carotid artery were obtained. An extensive protocol was applied to homogenize the patient cohort and to standardize the procedural steps of endovascular sample collection, sample processing, and laboratory analyses. N = 58 patients met all inclusion criteria. (1) Mean total leukocyte counts were significantly higher within the occluded ischemic cerebral vasculature (I) vs. intraindividual systemic controls (S): +9.6\%, I: 8114/µL ± 529 vs. S: 7406/µL ± 468, p = 0.0125. (2) This increase was driven by neutrophils: +12.1\%, I: 7197/µL ± 510 vs. S: 6420/µL ± 438, p = 0.0022. Leukocyte influx was associated with (3) reduced retrograde collateral flow (R\(^2\) = 0.09696, p = 0.0373) and (4) greater infarct extent (R\(^2\) = 0.08382, p = 0.032). Despite LVO, leukocytes invade the occluded territory via retrograde collateral pathways early during ischemia, likely compromising cerebral hemodynamics and tissue integrity. This inflammatory response can be reliably observed in human stroke by harvesting immune cells from the occluded cerebral vascular compartment.}, language = {en} } @article{GrohBerveMartini2021, author = {Groh, Janos and Berve, Kristina and Martini, Rudolf}, title = {Immune modulation attenuates infantile neuronal ceroid lipofuscinosis in mice before and after disease onset}, series = {Brain Communications}, volume = {3}, journal = {Brain Communications}, number = {2}, doi = {10.1093/braincomms/fcab047}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260167}, year = {2021}, abstract = {Targeting neuroinflammation in models for infantile and juvenile forms of neuronal ceroid lipofuscinosis (NCL, CLN disease) with the clinically established immunomodulators fingolimod and teriflunomide significantly attenuates the neurodegenerative phenotype when applied preventively, i.e. before the development of substantial neural damage and clinical symptoms. Here, we show that in a mouse model for the early onset and rapidly progressing CLN1 form, more complex clinical phenotypes like disturbed motor coordination and impaired visual acuity are also ameliorated by immunomodulation. Moreover, we show that the disease outcome can be attenuated even when fingolimod and teriflunomide treatment starts after disease onset, i.e. when neurodegeneration is ongoing and clinical symptoms are detectable. In detail, treatment with either drug led to a reduction in T-cell numbers and microgliosis in the CNS, although not to the same extent as upon preventive treatment. Pharmacological immunomodulation was accompanied by a reduction of axonal damage, neuron loss and astrogliosis in the retinotectal system and by reduced brain atrophy. Accordingly, the frequency of myoclonic jerks and disturbed motor coordination were attenuated. Overall, disease alleviation was remarkably substantial upon therapeutic treatment with both drugs, although less robust than upon preventive treatment. To test the relevance of putative immune-independent mechanisms of action in this model, we treated CLN1 mice lacking mature T- and B-lymphocytes. Immunodeficient CLN1 mice showed, as previously reported, an improved neurological phenotype in comparison with genuine CLN1 mice which could not be further alleviated by either of the drugs, reflecting a predominantly immune-related therapeutic mechanism of action. The present study supports and strengthens our previous view that repurposing clinically approved immunomodulators may alleviate the course of CLN1 disease in human patients, even though diagnosis usually occurs when symptoms have already emerged.}, language = {en} } @article{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{RauschenbergerKnorrPisanietal.2021, author = {Rauschenberger, Lisa and Knorr, Susanne and Pisani, Antonio and Hallett, Mark and Volkmann, Jens and Ip, Chi Wang}, title = {Second hit hypothesis in dystonia: Dysfunctional cross talk between neuroplasticity and environment?}, series = {Neurobiology of Disease}, volume = {159}, journal = {Neurobiology of Disease}, doi = {10.1016/j.nbd.2021.105511}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265028}, year = {2021}, abstract = {One of the great mysteries in dystonia pathophysiology is the role of environmental factors in disease onset and development. Progress has been made in defining the genetic components of dystonic syndromes, still the mechanisms behind the discrepant relationship between dystonic genotype and phenotype remain largely unclear. Within this review, the preclinical and clinical evidence for environmental stressors as disease modifiers in dystonia pathogenesis are summarized and critically evaluated. The potential role of extragenetic factors is discussed in monogenic as well as adult-onset isolated dystonia. The available clinical evidence for a "second hit" is analyzed in light of the reduced penetrance of monogenic dystonic syndromes and put into context with evidence from animal and cellular models. The contradictory studies on adult-onset dystonia are discussed in detail and backed up by evidence from animal models. Taken together, there is clear evidence of a gene-environment interaction in dystonia, which should be considered in the continued quest to unravel dystonia pathophysiology.}, language = {en} } @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{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{BenKraiemSauerNorwigetal.2021, author = {Ben-Kraiem, Adel and Sauer, Reine-Solange and Norwig, Carla and Popp, Maria and Bettenhausen, Anna-Lena and Atalla, Mariam Sobhy and Brack, Alexander and Blum, Robert and Doppler, Kathrin and Rittner, Heike Lydia}, title = {Selective blood-nerve barrier leakiness with claudin-1 and vessel-associated macrophage loss in diabetic polyneuropathy}, series = {Journal of Molecular Medicine}, volume = {99}, journal = {Journal of Molecular Medicine}, number = {9}, doi = {10.1007/s00109-021-02091-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265237}, pages = {1237-1250}, year = {2021}, abstract = {Diabetic polyneuropathy (DPN) is the most common complication in diabetes and can be painful in up to 26\% of all diabetic patients. Peripheral nerves are shielded by the blood-nerve barrier (BNB) consisting of the perineurium and endoneurial vessels. So far, there are conflicting results regarding the role and function of the BNB in the pathophysiology of DPN. In this study, we analyzed the spatiotemporal tight junction protein profile, barrier permeability, and vessel-associated macrophages in Wistar rats with streptozotocin-induced DPN. In these rats, mechanical hypersensitivity developed after 2 weeks and loss of motor function after 8 weeks, while the BNB and the blood-DRG barrier were leakier for small, but not for large molecules after 8 weeks only. The blood-spinal cord barrier remained sealed throughout the observation period. No gross changes in tight junction protein or cytokine expression were observed in all barriers to blood. However, expression of Cldn1 mRNA in perineurium was specifically downregulated in conjunction with weaker vessel-associated macrophage shielding of the BNB. Our results underline the role of specific tight junction proteins and BNB breakdown in DPN maintenance and differentiate DPN from traumatic nerve injury. Targeting claudins and sealing the BNB could stabilize pain and prevent further nerve damage.}, language = {en} } @article{BrumbergKuzkinaLapaetal.2021, author = {Brumberg, Joachim and Kuzkina, Anastasia and Lapa, Constantin and Mammadova, Sona and Buck, Andreas and Volkmann, Jens and Sommer, Claudia and Isaias, Ioannis U. and Doppler, Kathrin}, title = {Dermal and cardiac autonomic fiber involvement in Parkinson's disease and multiple system atrophy}, series = {Neurobiology of Disease}, volume = {153}, journal = {Neurobiology of Disease}, doi = {10.1016/j.nbd.2021.105332}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260061}, pages = {105332}, year = {2021}, abstract = {Pathological aggregates of alpha-synuclein in peripheral dermal nerve fibers can be detected in patients with idiopathic Parkinson's disease and multiple system atrophy. This study combines skin biopsy staining for p-alpha-synuclein depositions and radionuclide imaging of the heart with [\(^{123}\)I]-metaiodobenzylguanidine to explore peripheral denervation in both diseases. To this purpose, 42 patients with a clinical diagnosis of Parkinson's disease or multiple system atrophy were enrolled. All patients underwent a standardized clinical workup including neurological evaluation, neurography, and blood samples. Skin biopsies were obtained from the distal and proximal leg, back, and neck for immunofluorescence double labeling with anti-p-alpha-synuclein and anti-PGP9.5. All patients underwent myocardial [\(^{123}\)I]-metaiodobenzylguanidine scintigraphy. Dermal p-alpha-synuclein was observed in 47.6\% of Parkinson's disease patients and was mainly found in autonomic structures. 81.0\% of multiple system atrophy patients had deposits with most of cases in somatosensory fibers. The [\(^{123}\)I]-metaiodobenzylguanidine heart-to-mediastinum ratio was lower in Parkinson's disease than in multiple system atrophy patients (1.94 +/- 0.63 vs. 2.91 +/- 0.96; p < 0.0001). Irrespective of the diagnosis, uptake was lower in patients with than without p-alpha-synuclein in autonomic structures (1.42 +/- 0.51 vs. 2.74 +/- 0.83; p < 0.0001). Rare cases of Parkinson's disease with p-alpha-synuclein in somatosensory fibers and multiple system atrophy patients with deposits in autonomic structures or both fiber types presented with clinically overlapping features. In conclusion, this study suggests that alpha-synuclein contributes to peripheral neurodegeneration and mediates the impairment of cardiac sympathetic neurons in patients with synucleinopathies. Furthermore, it indicates that Parkinson's disease and multiple system atrophy share pathophysiologic mechanisms of peripheral nervous system dysfunction with a clinical overlap.}, language = {en} } @article{CapetianRoessnerKorteetal.2021, author = {Capetian, Philipp and Roessner, Veit and Korte, Caroline and Walitza, Susanne and Riederer, Franz and Taurines, Regina and Gerlach, Manfred and Moser, Andreas}, title = {Altered urinary tetrahydroisoquinoline derivatives in patients with Tourette syndrome: reflection of dopaminergic hyperactivity?}, series = {Journal of Neural Transmission}, volume = {128}, journal = {Journal of Neural Transmission}, issn = {0300-9564}, doi = {10.1007/s00702-020-02289-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235771}, pages = {115-121}, year = {2021}, abstract = {Tetrahydroisoquinolines (TIQs) such as salsolinol (SAL), norsalsolinol (NSAL) and their methylated derivatives N-methyl-norsalsolinol (NMNSAL) and N-methyl-salsolinol (NMSAL), modulate dopaminergic neurotransmission and metabolism in the central nervous system. Dopaminergic neurotransmission is thought to play an important role in the pathophysiology of chronic tic disorders, such as Tourette syndrome (TS). Therefore, the urinary concentrations of these TIQ derivatives were measured in patients with TS and patients with comorbid attention-deficit/hyperactivity disorder (TS + ADHD) compared with controls. Seventeen patients with TS, 12 with TS and ADHD, and 19 age-matched healthy controls with no medication took part in this study. Free levels of NSAL, NMNSAL, SAL, and NMSAL in urine were measured by a two-phase chromatographic approach. Furthermore, individual TIQ concentrations in TS patients were used in receiver-operating characteristics (ROC) curve analysis to examine the diagnostic value. NSAL concentrations were elevated significantly in TS [434.67 ± 55.4 nmol/l (standard error of mean = S.E.M.), two-way ANOVA, p < 0.0001] and TS + ADHD patients [605.18 ± 170.21 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] compared with controls [107.02 ± 33.18 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] and NSAL levels in TS + ADHD patients were elevated significantly in comparison with TS patients (two-way ANOVA, p = 0.017). NSAL demonstrated an AUC of 0.93 ± 0.046 (S.E.M) the highest diagnostic value of all metabolites for the diagnosis of TS. Our results suggest a dopaminergic hyperactivity underlying the pathophysiology of TS and ADHD. In addition, NSAL concentrations in urine may be a potential diagnostic biomarker of TS.}, 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{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{HornKristLiebetal.2021, author = {Horn, A. and Krist, L. and Lieb, W. and Montellano, F. A. and Kohls, M. and Haas, K. and Gelbrich, G. and Bolay-Gehrig, S. J. and Morbach, C. and Reese, J. P. and St{\"o}rk, S. and Fricke, J. and Zoller, T. and Schmidt, S. and Triller, P. and Kretzler, L. and R{\"o}nnefarth, M. and Von Kalle, C. and Willich, S. N. and Kurth, F. and Steinbeis, F. and Witzenrath, M. and Bahmer, T. and Hermes, A. and Krawczak, M. and Reinke, L. and Maetzler, C. and Franzenburg, J. and Enderle, J. and Flinspach, A. and Vehreschild, J. and Schons, M. and Illig, T. and Anton, G. and Ungeth{\"u}m, K. and Finkenberg, B. C. and Gehrig, M. T. and Savaskan, N. and Heuschmann, P. U. and Keil, T. and Schreiber, S.}, title = {Long-term health sequelae and quality of life at least 6 months after infection with SARS-CoV-2: design and rationale of the COVIDOM-study as part of the NAPKON population-based cohort platform (POP)}, series = {Infection}, volume = {49}, journal = {Infection}, number = {6}, issn = {0300-8126}, doi = {10.1007/s15010-021-01707-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308960}, pages = {1277-1287}, year = {2021}, abstract = {Purpose Over the course of COVID-19 pandemic, evidence has accumulated that SARS-CoV-2 infections may affect multiple organs and have serious clinical sequelae, but on-site clinical examinations with non-hospitalized samples are rare. We, therefore, aimed to systematically assess the long-term health status of samples of hospitalized and non-hospitalized SARS-CoV-2 infected individuals from three regions in Germany. Methods The present paper describes the COVIDOM-study within the population-based cohort platform (POP) which has been established under the auspices of the NAPKON infrastructure (German National Pandemic Cohort Network) of the national Network University Medicine (NUM). Comprehensive health assessments among SARS-CoV-2 infected individuals are conducted at least 6 months after the acute infection at the study sites Kiel, W{\"u}rzburg and Berlin. Potential participants were identified and contacted via the local public health authorities, irrespective of the severity of the initial infection. A harmonized examination protocol has been implemented, consisting of detailed assessments of medical history, physical examinations, and the collection of multiple biosamples (e.g., serum, plasma, saliva, urine) for future analyses. In addition, patient-reported perception of the impact of local pandemic-related measures and infection on quality-of-life are obtained. Results As of July 2021, in total 6813 individuals infected in 2020 have been invited into the COVIDOM-study. Of these, about 36\% wished to participate and 1295 have already been examined at least once. Conclusion NAPKON-POP COVIDOM-study complements other Long COVID studies assessing the long-term consequences of an infection with SARS-CoV-2 by providing detailed health data of population-based samples, including individuals with various degrees of disease severity. Trial registration Registered at the German registry for clinical studies (DRKS00023742).}, language = {en} }