@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{SommerKloseWelschetal.2020, author = {Sommer, Claudia and Klose, Petra and Welsch, Patrick and Petzke, Frank and H{\"a}user, Winfried}, title = {Opioids for chronic non-cancer neuropathic pain. An updated systematic review and meta-analysis of efficacy, tolerability and safety in randomized placebo-controlled studies of at least 4 weeks duration}, series = {European Journal of Pain}, volume = {24}, journal = {European Journal of Pain}, number = {1}, doi = {10.1002/ejp.1494}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218487}, pages = {3 -- 18}, year = {2020}, abstract = {Background and Objective This updated systematic review evaluated the efficacy, tolerability and safety of opioids compared to placebo in chronic non-cancer neuropathic pain. Databases and Data Treatment Clinicaltrials.gov, CENTRAL, PubMed and PsycINFO were searched from October 2013 to June 2019. Randomized controlled trials comparing opioids with placebo and at least 4 weeks double-blinded duration were analysed. Primary outcomes were pain relief of 50\% or greater, disability, tolerability and safety. Effects were summarized by a random effects model using risk differences (RD) or standardized mean differences (SMD). We added four new studies with 662 participants for a total of 16 included studies with 2,199 participants. Study duration ranged between 4 and 12 weeks. Studies with a parallel and cross-over design: Based on low to moderate quality evidence, opioids (buprenorphine, hydromorphone, morphine, oxycodone, tramadol) provided a clinically relevant pain relief of 50\% or greater and reduction of disability compared to placebo. There was no clinically relevant harm with regards to the drop out rate due to adverse and serious adverse events by opioids compared to placebo. Enriched enrolment randomized withdrawal design: Based on low to moderate quality evidence, tapentadol provided a clinically relevant pain relief of 50\% or greater and reduction of disability compared to placebo in diabetic polyneuropathy. There was no clinically relevant harm with regards to the drop out rate due to adverse and serious adverse events by tapentadol compared to placebo. Conclusions Some opioids provided a short-term substantial pain relief in highly selected patients in some neuropathic pain syndromes. Significance Some opioids (buprenorphine, morphine, oxycodone, tramadol, tapentadol) provide substantial pain relief compared to placebo in postherpetic neuralgia and peripheral neuropathies of different aetiologies for 4-12 weeks. There is insufficient evidence to support or refute the suggestion that these drugs are effective in other neuropathic pain conditions. The safety of opioids with regards to abuse and deaths in the studies analysed cannot be extrapolated to routine clinical care.}, language = {en} } @article{RauschenbergervonWardenburgSchaeferetal.2020, author = {Rauschenberger, Vera and von Wardenburg, Niels and Schaefer, Natascha and Ogino, Kazutoyo and Hirata, Hiromi and Lillesaar, Christina and Kluck, Christoph J. and Meinck, Hans-Michael and Borrmann, Marc and Weishaupt, Andreas and Doppler, Kathrin and Wickel, Jonathan and Geis, Christian and Sommer, Claudia and Villmann, Carmen}, title = {Glycine Receptor Autoantibodies Impair Receptor Function and Induce Motor Dysfunction}, series = {Annals of Neurology}, volume = {88}, journal = {Annals of Neurology}, number = {3}, doi = {10.1002/ana.25832}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-216005}, pages = {544 -- 561}, year = {2020}, abstract = {Objective Impairment of glycinergic neurotransmission leads to complex movement and behavioral disorders. Patients harboring glycine receptor autoantibodies suffer from stiff-person syndrome or its severe variant progressive encephalomyelitis with rigidity and myoclonus. Enhanced receptor internalization was proposed as the common molecular mechanism upon autoantibody binding. Although functional impairment of glycine receptors following autoantibody binding has recently been investigated, it is still incompletely understood. Methods A cell-based assay was used for positive sample evaluation. Glycine receptor function was assessed by electrophysiological recordings and radioligand binding assays. The in vivo passive transfer of patient autoantibodies was done using the zebrafish animal model. Results Glycine receptor function as assessed by glycine dose-response curves showed significantly decreased glycine potency in the presence of patient sera. Upon binding of autoantibodies from 2 patients, a decreased fraction of desensitized receptors was observed, whereas closing of the ion channel remained fast. The glycine receptor N-terminal residues \(^{29}\)A to \(^{62}\)G were mapped as a common epitope of glycine receptor autoantibodies. An in vivo transfer into the zebrafish animal model generated a phenotype with disturbed escape behavior accompanied by a reduced number of glycine receptor clusters in the spinal cord of affected animals. Interpretation Autoantibodies against the extracellular domain mediate alterations of glycine receptor physiology. Moreover, our in vivo data demonstrate that the autoantibodies are a direct cause of the disease, because the transfer of human glycine receptor autoantibodies to zebrafish larvae generated impaired escape behavior in the animal model compatible with abnormal startle response in stiff-person syndrome or progressive encephalitis with rigidity and myoclonus patients.}, language = {en} } @article{StengelVulinovicMeieretal.2020, author = {Stengel, Felix and Vulinovic, Franca and Meier, Britta and Gr{\"u}tz, Karen and Klein, Christine and Capetian, Philipp}, title = {Impaired differentiation of human induced neural stem cells by TOR1A overexpression}, series = {Molecular Biology Reports}, volume = {47}, journal = {Molecular Biology Reports}, doi = {10.25972/OPUS-24117}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241177}, pages = {3993-4001}, year = {2020}, abstract = {DYT-TOR1A is the most common inherited dystonia caused by a three nucleotide (GAG) deletion (dE) in the TOR1A gene. Death early after birth and cortical anomalies of the full knockout in rodents underscore its developmental importance. We therefore explored the timed effects of TOR1A-wt and TOR1A-dE during differentiation in a human neural in vitro model. We used lentiviral tet-ON expression of TOR1A-wt and -dE in induced neural stem cells derived from healthy donors. Overexpression was induced during proliferation of neural precursors, during differentiation and after differentiation into mature neurons. Overexpression of both wildtype and mutated protein had no effect on the viability and cell number of neural precursors as well as mature neurons when initiated before or after differentiation. However, if induced during differentiation, overexpression of TOR1A-wt and -dE led to a pronounced reduction of mature neurons in a dose dependent manner. Our data underscores the importance of physiological expression levels of TOR1A as crucial for proper neuronal differentiation. We did not find evidence for a specific impact of the mutated TOR1A on neuronal maturation.}, language = {en} } @article{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} } @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{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{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} } @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{EssigKollikowskiPhametal.2020, author = {Essig, Fabian and Kollikowski, Alexander M. and Pham, Mirko and Solymosi, L{\´a}szl{\´o} and Stoll, Guido and Haeusler, Karl Georg and Kraft, Peter and Schuhmann, Michael K.}, title = {Immunohistological analysis of neutrophils and neutrophil extracellular traps in human thrombemboli causing acute ischemic stroke}, series = {International Journal of Molecular Sciences}, volume = {21}, journal = {International Journal of Molecular Sciences}, number = {19}, issn = {1422-0067}, doi = {10.3390/ijms21197387}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236192}, year = {2020}, abstract = {Ischemic stroke caused by thromboembolic occlusion of large cerebral arteries, such as the internal carotid (ICA) and/or the middle cerebral artery (MCA), is treated by mechanical thrombectomy (MT). MT allows salvage of the vessel-occluding thrombemboli, which most frequently originate from the left atrium or the left ventricle of the heart or from sites of plaque rupture within large arteries above the heart. Clot composition may influence the efficacy of (intravenous) thrombolysis and MT, respectively. We analyzed 37 human thrombemboli obtained from acute ischemic stroke patients during MT with special emphasis on histological staining of neutrophils and neutrophil extracellular traps (NETs). We found neutrophils as the main cellular component of cerebral thrombemboli but encountered considerable morphological heterogeneity. Neutrophils accumulated in the border region of fibrin-rich structures indicating possible interaction of neutrophils with distinct structural thrombembolus components. Web-like NETs were found in 35 of 37 thrombemboli in varying amounts. NETs were almost exclusively found within fibrin-rich areas. Importantly, stroke etiology, age and present oral anticoagulation was associated with morphological patterns and the amount of neutrophils. Correlation of histological data and imaging data revealed that relative Hounsfield units of cerebral thrombemboli positively correlated with the amount of red blood cells. In summary, our results demonstrate that neutrophils and NETs are substantial constituents of cerebral thrombemboli and contribute to their structural complexity.}, language = {en} } @article{CapetianMuellerVolkmannetal.2020, author = {Capetian, Philipp and M{\"u}ller, Lorenz and Volkmann, Jens and Heckmann, Manfred and Erg{\"u}n, S{\"u}leyman and Wagner, Nicole}, title = {Visualizing the synaptic and cellular ultrastructure in neurons differentiated from human induced neural stem cells - an optimized protocol}, series = {International Journal of Molecular Sciences}, volume = {21}, journal = {International Journal of Molecular Sciences}, number = {5}, issn = {1422-0067}, doi = {10.3390/ijms21051708}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236053}, year = {2020}, abstract = {The size of the synaptic subcomponents falls below the limits of visible light microscopy. Despite new developments in advanced microscopy techniques, the resolution of transmission electron microscopy (TEM) remains unsurpassed. The requirements of tissue preservation are very high, and human post mortem material often does not offer adequate quality. However, new reprogramming techniques that generate human neurons in vitro provide samples that can easily fulfill these requirements. The objective of this study was to identify the culture technique with the best ultrastructural preservation in combination with the best embedding and contrasting technique for visualizing neuronal elements. Two induced neural stem cell lines derived from healthy control subjects underwent differentiation either adherent on glass coverslips, embedded in a droplet of highly concentrated Matrigel, or as a compact neurosphere. Afterward, they were fixed using a combination of glutaraldehyde (GA) and paraformaldehyde (PFA) followed by three approaches (standard stain, Ruthenium red stain, high contrast en-bloc stain) using different combinations of membrane enhancing and contrasting steps before ultrathin sectioning and imaging by TEM. The compact free-floating neurospheres exhibited the best ultrastructural preservation. High-contrast en-bloc stain offered particularly sharp staining of membrane structures and the highest quality visualization of neuronal structures. In conclusion, compact neurospheres growing under free-floating conditions in combination with a high contrast en-bloc staining protocol, offer the optimal preservation and contrast with a particular focus on visualizing membrane structures as required for analyzing synaptic structures.}, language = {en} } @article{IsaiasBrumbergPozzietal.2020, author = {Isaias, Ioannis U. and Brumberg, Joachim and Pozzi, Nicol{\´o} G. and Palmisano, Chiara and Canessa, Andrea and Marotta, Giogio and Volkmann, Jens and Pezzoli, Gianni}, title = {Brain metabolic alterations herald falls in patients with Parkinson's disease}, series = {Annals of Clinical and Translational Neurology}, volume = {7}, journal = {Annals of Clinical and Translational Neurology}, number = {4}, doi = {10.1002/acn3.51013}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235982}, pages = {579-583}, year = {2020}, abstract = {Pathophysiological understanding of gait and balance disorders in Parkinson's disease is insufficient and late recognition of fall risk limits efficacious followup to prevent or delay falls. We show a distinctive reduction of glucose metabolism in the left posterior parietal cortex, with increased metabolic activity in the cerebellum, in parkinsonian patients 6-8 months before their first fall episode. Falls in Parkinson's disease may arise from altered cortical processing of body spatial orientation, possibly predicted by abnormal cortical metabolism.}, language = {en} } @article{BrumbergSchroeterBlazhenetsetal.2020, author = {Brumberg, Joachim and Schr{\"o}ter, Nils and Blazhenets, Ganna and Frings, Lars and Volkmann, Jens and Lapa, Constantin and Jost, Wolfgang H. and Isaias, Ioannis U. and Meyer, Philipp T.}, title = {Differential diagnosis of parkinsonism: a head-to-head comparison of FDG PET and MIBG scintigraphy}, series = {NPJ Parkinsons Disease}, volume = {6}, journal = {NPJ Parkinsons Disease}, doi = {10.1038/s41531-020-00141-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230675}, year = {2020}, abstract = {[\(^{18}\)F]fluorodeoxyglucose (FDG) PET and [\(^{123}\)I]metaiodobenzylguanidine (MIBG) scintigraphy may contribute to the differential diagnosis of neurodegenerative parkinsonism. To identify the superior method, we retrospectively evaluated 54 patients with suspected neurodegenerative parkinsonism, who were referred for FDG PET and MIBG scintigraphy. Two investigators visually assessed FDG PET scans using an ordinal 6-step score for disease-specific patterns of Lewy body diseases (LBD) or atypical parkinsonism (APS) and assigned the latter to the subgroups multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal syndrome. Regions-of-interest analysis on anterior planar MIBG images served to calculate the heart-to-mediastinum ratio. Movement disorder specialists blinded to imaging results established clinical follow-up diagnosis by means of guideline-derived case vignettes. Clinical follow-up (1.7 +/- 2.3 years) revealed the following diagnoses: n = 19 LBD (n = 17 Parkinson's disease [PD], n = 1 PD dementia, and n = 1 dementia with Lewy bodies), n = 31 APS (n = 28 MSA, n = 3 PSP), n = 3 non-neurodegenerative parkinsonism; n = 1 patient could not be diagnosed and was excluded. Receiver operating characteristic analyses for discriminating LBD vs. non-LBD revealed a larger area under the curve for FDG PET than for MIBG scintigraphy at statistical trend level for consensus rating (0.82 vs. 0.69, p = 0.06; significant for investigator \#1: 0.83 vs. 0.69, p = 0.04). The analysis of PD vs. MSA showed a similar difference (0.82 vs. 0.69, p = 0.11; rater \#1: 0.83 vs. 0.69, p = 0.07). Albeit the notable differences in diagnostic performance did not attain statistical significance, the authors consider this finding clinically relevant and suggest that FDG PET, which also allows for subgrouping of APS, should be preferred.}, language = {en} } @article{BrieseSaalBauernschubertLueningschroeretal.2020, author = {Briese, Michael and Saal-Bauernschubert, Lena and L{\"u}ningschr{\"o}r, Patrick and Moradi, Mehri and Dombert, Benjamin and Surrey, Verena and Appenzeller, Silke and Deng, Chunchu and Jablonka, Sibylle and Sendtner, Michael}, title = {Loss of Tdp-43 disrupts the axonal transcriptome of motoneurons accompanied by impaired axonal translation and mitochondria function}, series = {Acta Neuropathologica Communications}, volume = {8}, journal = {Acta Neuropathologica Communications}, doi = {10.1186/s40478-020-00987-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230322}, year = {2020}, abstract = {Protein inclusions containing the RNA-binding protein TDP-43 are a pathological hallmark of amyotrophic lateral sclerosis and other neurodegenerative disorders. The loss of TDP-43 function that is associated with these inclusions affects post-transcriptional processing of RNAs in multiple ways including pre-mRNA splicing, nucleocytoplasmic transport, modulation of mRNA stability and translation. In contrast, less is known about the role of TDP-43 in axonal RNA metabolism in motoneurons. Here we show that depletion of Tdp-43 in primary motoneurons affects axon growth. This defect is accompanied by subcellular transcriptome alterations in the axonal and somatodendritic compartment. The axonal localization of transcripts encoding components of the cytoskeleton, the translational machinery and transcripts involved in mitochondrial energy metabolism were particularly affected by loss of Tdp-43. Accordingly, we observed reduced protein synthesis and disturbed mitochondrial functions in axons of Tdp-43-depleted motoneurons. Treatment with nicotinamide rescued the axon growth defect associated with loss of Tdp-43. These results show that Tdp-43 depletion in motoneurons affects several pathways integral to axon health indicating that loss of TDP-43 function could thus make a major contribution to axonal pathomechanisms in ALS.}, language = {en} } @article{JovanovicKlassenHeuschmannetal.2020, author = {Jovanovic, Ana and Klassen, Philipp and Heuschmann, Peter and Sommer, Claudia and Roberts, Mark and {\"U}{\c{c}}eyler, Nurcan}, title = {English version of the self-administered Fabry Pain Questionnaire for adult patients}, series = {Orphanet Journal of Rare Diseases}, volume = {15}, journal = {Orphanet Journal of Rare Diseases}, doi = {10.1186/s13023-020-01580-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230298}, year = {2020}, abstract = {Background Pain is an early symptom of Fabry disease (FD) and is characterized by a unique phenotype with mainly episodic acral and triggerable burning pain. Recently, we designed and validated the first pain questionnaire for adult FD patients in an interview and a self-administered version in German: the Wurzburg Fabry Pain Questionnaire (FPQ). We now report the validation of the English version of the self-administered FPQ (enFPQ). Methods After two forward-backward translations of the FPQ by native German and native English speakers, the enFPQ was applied at The Mark Holland Metabolic Unit, Manchester, UK for validation. Consecutive patients with genetically ascertained FD and current or previous FD pain underwent a face-to-face interview using the enFPQ. Two weeks later, patients filled in the self-administered enFPQ at home. The agreement between entries collected by supervised administration and self-administration of the enFPQ was assessed via Gwet's AC1-statistics (AC1) for nominal-scaled scores and intraclass correlation coefficient (ICC) for interval-scaled elements. Results Eighty-three FD patients underwent the face-to-face interview and 54 patients sent back a completed self-administered version of the enFPQ 2 weeks later. We found high agreement with a mean AC1-statistics of 0.725 for 55 items, and very high agreement with a mean ICC of 0.811 for 9 items. Conclusions We provide the validated English version of the FPQ for self-administration in adult FD patients. The enFPQ collects detailed information on the individual FD pain phenotype and thus builds a solid basis for better pain classification and treatment in patients with FD.}, language = {en} } @article{BerveWestMartinietal.2020, author = {Berve, Kristina and West, Brian L. and Martini, Rudolf and Groh, Janos}, title = {Sex- and region-biased depletion of microglia/macrophages attenuates CLN1 disease in mice}, series = {Journal of Neuroinflammation}, volume = {17}, journal = {Journal of Neuroinflammation}, doi = {10.1186/s12974-020-01996-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230234}, year = {2020}, abstract = {Background The neuronal ceroid lipofuscinoses (CLN diseases) are fatal lysosomal storage diseases causing neurodegeneration in the CNS. We have previously shown that neuroinflammation comprising innate and adaptive immune reactions drives axonal damage and neuron loss in the CNS of palmitoyl protein thioesterase 1-deficient (Ppt1\(^{-/-}\)) mice, a model of the infantile form of the diseases (CLN1). Therefore, we here explore whether pharmacological targeting of innate immune cells modifies disease outcome in CLN1 mice. Methods We applied treatment with PLX3397 (150 ppm in the chow), a potent inhibitor of the colony stimulating factor-1 receptor (CSF-1R) to target innate immune cells in CLN1 mice. Experimental long-term treatment was non-invasively monitored by longitudinal optical coherence tomography and rotarod analysis, as well as analysis of visual acuity, myoclonic jerks, and survival. Treatment effects regarding neuroinflammation, neural damage, and neurodegeneration were subsequently analyzed by histology and immunohistochemistry. Results We show that PLX3397 treatment attenuates neuroinflammation in CLN1 mice by depleting pro-inflammatory microglia/macrophages. This leads to a reduction of T lymphocyte recruitment, an amelioration of axon damage and neuron loss in the retinotectal system, as well as reduced thinning of the inner retina and total brain atrophy. Accordingly, long-term treatment with the inhibitor also ameliorates clinical outcomes in CLN1 mice, such as impaired motor coordination, visual acuity, and myoclonic jerks. However, we detected a sex- and region-biased efficacy of CSF-1R inhibition, with male microglia/macrophages showing higher responsiveness toward depletion, especially in the gray matter of the CNS. This results in a better treatment outcome in male Ppt1\(^{-/-}\) mice regarding some histopathological and clinical readouts and reflects heterogeneity of innate immune reactions in the diseased CNS. Conclusions Our results demonstrate a detrimental impact of innate immune reactions in the CNS of CLN1 mice. These findings provide insights into CLN pathogenesis and may guide in the design of immunomodulatory treatment strategies.}, language = {en} } @article{PeterkaOdorferSchwabetal.2020, author = {Peterka, Manuel and Odorfer, Thorsten and Schwab, Michael and Volkmann, Jens and Zeller, Daniel}, title = {LSVT-BIG therapy in Parkinson's disease: physiological evidence for proprioceptive recalibration}, series = {BMC Neurology}, volume = {20}, journal = {BMC Neurology}, doi = {10.1186/s12883-020-01858-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230084}, year = {2020}, abstract = {Background There is growing evidence for proprioceptive dysfunction in patients with Parkinson's disease (PD). The Lee Silvermann Voice Treatment-BIG therapy (LSVT-BIG), a special training program aiming at an increase of movement amplitudes in persons with PD (PwPD), has shown to be effective on motor symptoms. LSVT-BIG is conceptionally based on improving bradykinesia, in particular the decrement of repetitive movements, by proprioceptive recalibration. Objective To assess proprioceptive impairment in PwPD as compared to matched controls and to probe potential recalibration effects of the LSVT-BIG therapy on proprioception. Methods Proprioceptive performance and fine motor skills were assessed in 30 PwPD and 15 matched controls. Measurements with significant impairment in PwPD were chosen as outcome parameters for a standardized 4 weeks amplitude-based training intervention (LSVT-BIG) in 11 PwPD. Proprioceptive performance served as primary outcome measure. Secondary outcome measures included the motor part of the MDS-UPDRS, the nine-hole-peg test, and a questionnaire on quality of life. Post-interventional assessments were conducted at weeks 4 and 8. Results Compared to the control group, PwPD showed significantly larger pointing errors. After 4 weeks of LSVT-BIG therapy and even more so after an additional 4 weeks of continued training, proprioceptive performance improved significantly. In addition, quality of life improved as indicated by a questionnaire. Conclusion LSVT-BIG training may achieve a recalibration of proprioceptive processing in PwPD. Our data indicates a probable physiological mechanism of a symptom-specific, amplitude-based behavioral intervention in PwPD.}, language = {en} } @article{AppeltshauserBrunderHeiniusetal.2020, author = {Appeltshauser, Luise and Brunder, Anna-Michelle and Heinius, Annika and K{\"o}rtv{\´e}lyessy, Peter and Wandinger, Klaus-Peter and Junker, Ralf and Villmann, Carmen and Sommer, Claudia and Leypoldt, Frank and Doppler, Kathrin}, title = {Antiparanodal antibodies and IgG subclasses in acute autoimmune neuropathy}, series = {Neurology: Neuroimmunology \& Neuroinflammation}, volume = {7}, journal = {Neurology: Neuroimmunology \& Neuroinflammation}, number = {5}, doi = {10.1212/NXI.0000000000000817}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230079}, year = {2020}, abstract = {Objective To determine whether IgG subclasses of antiparanodal autoantibodies are related to disease course and treatment response in acute- to subacute-onset neuropathies, we retrospectively screened 161 baseline serum/CSF samples and 66 follow-up serum/CSF samples. Methods We used ELISA and immunofluorescence assays to detect antiparanodal IgG and their subclasses and titers in serum/CSF of patients with Guillain-Barre syndrome (GBS), recurrent GBS (R-GBS), Miller-Fisher syndrome, and acute- to subacute-onset chronic inflammatory demyelinating polyradiculoneuropathy (A-CIDP). We evaluated clinical data retrospectively. Results We detected antiparanodal autoantibodies with a prevalence of 4.3\% (7/161), more often in A-CIDP (4/23, 17.4\%) compared with GBS (3/114, 2.6\%). Longitudinal subclass analysis in the patients with GBS revealed IgG2/3 autoantibodies against Caspr-1 and against anti-contactin-1/Caspr-1, which disappeared at remission. At disease onset, patients with A-CIDP had IgG2/3 anti-Caspr-1 and anti-contactin-1/Caspr-1 or IgG4 anti-contactin-1 antibodies, IgG3 being associated with good response to IV immunoglobulins (IVIg). In the chronic phase of disease, IgG subclass of one patient with A-CIDP switched from IgG3 to IgG4. Conclusion Our data (1) confirm and extend previous observations that antiparanodal IgG2/3 but not IgG4 antibodies can occur in acute-onset neuropathies manifesting as monophasic GBS, (2) suggest association of IgG3 to a favorable response to IVIg, and (3) lend support to the hypothesis that in some patients, an IgG subclass switch from IgG3 to IgG4 may be the correlate of a secondary progressive or relapsing course following a GBS-like onset.}, language = {en} } @article{HartmannsbergerDopplerStauberetal.2020, author = {Hartmannsberger, Beate and Doppler, Kathrin and Stauber, Julia and Schlotter-Weigel, Beate and Young, Peter and Sereda, Michael W. and Sommer, Claudia}, title = {Intraepidermal nerve fiber density as biomarker in Charcot-Marie-Tooth disease 1A}, series = {Brain Communications}, volume = {2}, journal = {Brain Communications}, number = {1}, doi = {10.1093/braincomms/fcaa012}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229538}, year = {2020}, abstract = {Charcot-Marie-Tooth disease type 1A, caused by a duplication of the gene peripheral myelin protein 22 kDa, is the most frequent subtype of hereditary peripheral neuropathy with an estimated prevalence of 1:5000. Patients suffer from sensory deficits, muscle weakness and foot deformities. There is no treatment approved for this disease. Outcome measures in clinical trials were based mainly on clinical features but did not evaluate the actual nerve damage. In our case-control study, we aimed to provide objective and reproducible outcome measures for future clinical trials. We collected skin samples from 48 patients with Charcot-Marie-Tooth type 1A, 7 patients with chronic inflammatory demyelinating polyneuropathy, 16 patients with small fibre neuropathy and 45 healthy controls. To analyse skin innervation, 40-µm cryosections of glabrous skin taken from the lateral index finger were double-labelled by immunofluorescence. The disease severity of patients with Charcot-Marie-Tooth type 1A was assessed by the Charcot-Marie-Tooth neuropathy version 2 score, which ranged from 3 (mild) to 27 (severe) and correlated with age (P < 0.01, R = 0.4). Intraepidermal nerve fibre density was reduced in patients with Charcot-Marie-Tooth type 1A compared with the healthy control group (P < 0.01) and negatively correlated with disease severity (P < 0.05, R = -0.293). Meissner corpuscle (MC) density correlated negatively with age in patients with Charcot-Marie-Tooth type 1A (P < 0.01, R = -0.45) but not in healthy controls (P = 0.07, R = 0.28). The density of Merkel cells was reduced in patients with Charcot-Marie-Tooth type 1A compared with healthy controls (P < 0.05). Furthermore, in patients with Charcot-Marie-Tooth type 1A, the fraction of denervated Merkel cells was highly increased and correlated with age (P < 0.05, R = 0.37). Analysis of nodes of Ranvier revealed shortened paranodes and a reduced fraction of long nodes in patients compared with healthy controls (both P < 0.001). Langerhans cell density was increased in chronic inflammatory demyelinating polyneuropathy, but not different in Charcot-Marie-Tooth type 1A compared with healthy controls. Our data suggest that intraepidermal nerve fibre density might be used as an outcome measure in Charcot-Marie-Tooth type 1A disease, as it correlates with disease severity. The densities of Meissner corpuscles and Merkel cells might be an additional tool for the evaluation of the disease progression. Analysis of follow-up biopsies will clarify the effects of Charcot-Marie-Tooth type 1A disease progression on cutaneous innervation.}, language = {en} } @article{SteinhardtWiercinskaPhametal.2020, author = {Steinhardt, M. J. and Wiercinska, E. and Pham, M. and Grigoleit, G. U. and Mazzoni, A. and Da-Via, M. and Zhou, X. and Meckel, K. and Nickel, K. and Duell, J. and Krummenast, F. C. and Kraus, S. and Hopkinson, C. and Weissbrich, B. and M{\"u}llges, W. and Stoll, G. and Kort{\"u}m, K. M. and Einsele, H. and Bonig, H. and Rasche, L.}, title = {Progressive multifocal leukoencephalopathy in a patient post allo-HCT successfully treated with JC virus specific donor lymphocytes}, series = {Journal of Translational Medicine}, volume = {18}, journal = {Journal of Translational Medicine}, doi = {10.1186/s12967-020-02337-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229307}, year = {2020}, abstract = {Background Progressive multifocal leukoencephalopathy is a demyelinating CNS disorder. Reactivation of John Cunningham virus leads to oligodendrocyte infection with lysis and consequent axonal loss due to demyelination. Patients usually present with confusion and seizures. Late diagnosis and lack of adequate therapy options persistently result in permanent impairment of brain functions. Due to profound T cell depletion, impairment of T-cell function and potent immunosuppressive factors, allogeneic hematopoietic cell transplantation recipients are at high risk for JCV reactivation. To date, PML is almost universally fatal when occurring after allo-HCT. Methods To optimize therapy specificity, we enriched JCV specific T-cells out of the donor T-cell repertoire from the HLA-identical, anti-JCV-antibody positive family stem cell donor by unstimulated peripheral apheresis [1]. For this, we selected T cells responsive to five JCV peptide libraries via the Cytokine Capture System technology. It enables the enrichment of JCV specific T cells via identification of stimulus-induced interferon gamma secretion. Results Despite low frequencies of responsive T cells, we succeeded in generating a product containing 20 000 JCV reactive T cells ready for patient infusion. The adoptive cell transfer was performed without complication. Consequently, the clinical course stabilized and the patient slowly went into remission of PML with JCV negative CSF and containment of PML lesion expansion. Conclusion We report for the first time feasibility of generating T cells with possible anti-JCV activity from a seropositive family donor, a variation of virus specific T-cell therapies suitable for the post allo transplant setting. We also present the unusual case for successful treatment of PML after allo-HCT via virus specific T-cell therapy.}, language = {en} } @article{EvdokimovDinkelFranketal.2020, author = {Evdokimov, Dimitar and Dinkel, Philine and Frank, Johanna and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan}, title = {Characterization of dermal skin innervation in fibromyalgia syndrome}, series = {PLoS One}, volume = {15}, journal = {PLoS One}, number = {1}, doi = {10.1371/journal.pone.0227674}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229299}, year = {2020}, abstract = {Introduction We characterized dermal innervation in patients with fibromyalgia syndrome (FMS) as potential contribution to small fiber pathology. Methods Skin biopsies of the calf were collected (86 FMS patients, 35 healthy controls). Skin was immunoreacted with antibodies against protein gene product 9.5, calcitonine gene-related peptide, substance P, CD31, and neurofilament 200 for small fiber subtypes. We assessed two skin sections per patient; on each skin section, two dermal areas (150 x 700 mu m each) were investigated for dermal nerve fiber length (DNFL). Results In FMS patients we found reduced DNFL of fibers with vessel contact compared to healthy controls (p<0.05). There were no differences for the other nerve fiber subtypes. Discussion We found less dermal nerve fibers in contact with blood vessels in FMS patients than in controls. The pathophysiological relevance of this finding is unclear, but we suggest the possibility of a relationship with impaired thermal tolerance commonly reported by FMS patients.}, language = {en} } @article{GabrielJirůHillmannKraftetal.2020, author = {Gabriel, Katharina M. A. and J{\´i}rů-Hillmann, Steffi and Kraft, Peter and Selig, Udo and R{\"u}cker, Victoria and M{\"u}hler, Johannes and D{\"o}tter, Klaus and Keidel, Matthias and Soda, Hassan and Rascher, Alexandra and Schneider, Rolf and Pfau, Mathias and Hoffmann, Roy and Stenzel, Joachim and Benghebrid, Mohamed and Goebel, Tobias and Doerck, Sebastian and Kramer, Daniela and Haeusler, Karl Georg and Volkmann, Jens and Heuschmann, Peter U. and Fluri, Felix}, title = {Two years' experience of implementing a comprehensive telemedical stroke network comprising in mainly rural region: the Transregional Network for Stroke Intervention with Telemedicine (TRANSIT-Stroke)}, series = {BMC Neurology}, volume = {20}, journal = {BMC Neurology}, doi = {10.1186/s12883-020-01676-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229214}, year = {2020}, abstract = {Background Telemedicine improves the quality of acute stroke care in rural regions with limited access to specialized stroke care. We report the first 2 years' experience of implementing a comprehensive telemedical stroke network comprising all levels of stroke care in a defined region. Methods The TRANSIT-Stroke network covers a mainly rural region in north-western Bavaria (Germany). All hospitals providing acute stroke care in this region participate in TRANSIT-Stroke, including four hospitals with a supra-regional certified stroke unit (SU) care (level III), three of those providing teleconsultation to two hospitals with a regional certified SU (level II) and five hospitals without specialized SU care (level I). For a two-year-period (01/2015 to 12/2016), data of eight of these hospitals were available; 13 evidence-based quality indicators (QIs) related to processes during hospitalisation were evaluated quarterly and compared according to predefined target values between level-I- and level-II/III-hospitals. Results Overall, 7881 patients were included (mean age 74.6 years +/- 12.8; 48.4\% female). In level-II/III-hospitals adherence of all QIs to predefined targets was high ab initio. In level-I-hospitals, three patterns of QI-development were observed: a) high adherence ab initio (31\%), mainly in secondary stroke prevention; b) improvement over time (44\%), predominantly related to stroke specific diagnosis and in-hospital organization; c) no clear time trends (25\%). Overall, 10 out of 13 QIs reached predefined target values of quality of care at the end of the observation period. Conclusion The implementation of the comprehensive TRANSIT-Stroke network resulted in an improvement of quality of care in level-I-hospitals.}, language = {en} } @article{Gonzalez‐EscamillaMuthuramanReichetal.2019, author = {Gonzalez-Escamilla, Gabriel and Muthuraman, Muthuraman and Reich, Martin M. and Koirala, Nabin and Riedel, Christian and Glaser, Martin and Lange, Florian and Deuschl, G{\"u}nther and Volkmann, Jens and Groppa, Sergiu}, title = {Cortical network fingerprints predict deep brain stimulation outcome in dystonia}, series = {Movement Disorders}, volume = {34}, journal = {Movement Disorders}, number = {10}, doi = {10.1002/mds.27808}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213532}, pages = {1536 -- 1545}, year = {2019}, abstract = {Background Deep brain stimulation (DBS) is an effective evidence-based therapy for dystonia. However, no unequivocal predictors of therapy responses exist. We investigated whether patients optimally responding to DBS present distinct brain network organization and structural patterns. Methods From a German multicenter cohort of 82 dystonia patients with segmental and generalized dystonia who received DBS implantation in the globus pallidus internus, we classified patients based on the clinical response 3 years after DBS. Patients were assigned to the superior-outcome group or moderate-outcome group, depending on whether they had above or below 70\% motor improvement, respectively. Fifty-one patients met MRI-quality and treatment response requirements (mean age, 51.3 ± 13.2 years; 25 female) and were included in further analysis. From preoperative MRI we assessed cortical thickness and structural covariance, which were then fed into network analysis using graph theory. We designed a support vector machine to classify subjects for the clinical response based on individual gray-matter fingerprints. Results The moderate-outcome group showed cortical atrophy mainly in the sensorimotor and visuomotor areas and disturbed network topology in these regions. The structural integrity of the cortical mantle explained about 45\% of the DBS stimulation amplitude for optimal response in individual subjects. Classification analyses achieved up to 88\% of accuracy using individual gray-matter atrophy patterns to predict DBS outcomes. Conclusions The analysis of cortical integrity, informed by group-level network properties, could be developed into independent predictors to identify dystonia patients who benefit from DBS.}, 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} } @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{ElhfnawyAbdEl‐RaoufVolkmannetal.2020, author = {Elhfnawy, Ahmed Mohamed and Abd El-Raouf, Mervat and Volkmann, Jens and Fluri, Felix and Elsalamawy, Doaa}, title = {Relation of infarction location and volume to vertigo in vertebrobasilar stroke}, series = {Brain and Behavior}, volume = {10}, journal = {Brain and Behavior}, number = {3}, doi = {10.1002/brb3.1564}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218047}, year = {2020}, abstract = {Objective Vertigo is a common presentation of vertebrobasilar stroke. Anecdotal reports have shown that vertigo occurs more often in multiple than in single brainstem or cerebellar infarctions. We examined the relation between the location and volume of infarction and vertigo in patients with vertebrobasilar stroke. Methods Consecutive patients with vertebrobasilar stroke were prospectively recruited. The infarction location and volume were assessed in the diffusion-weighted magnetic resonance imaging. Results Fifty-nine patients were included, 32 (54.2\%) with vertigo and 27 (45.8\%) without vertigo. The infarction volume did not correlate with National Institute of Health Stroke Scale (NIHSS) score on admission (Spearman ρ = .077, p = .56) but correlated with modified Rankin Scale (ρ = .37, p = .004) on discharge. In the vertigo group, the proportion of men was lower (53.1\% vs. 77.8\%, p = .049), fewer patients had focal neurological deficits (65.6\% vs. 96.3\%, p = .004), patients tended to present later (median [IQR] was 7.5 [4-46] vs. 4 [2-12] hours, p = .052), numerically fewer patients received intravenous thrombolysis (15.6\% vs. 37\%, p = .06), and the total infarction volume was larger (5.6 vs. 0.42 cm3, p = .008) than in nonvertigo group. In multivariate logistic regression, infarction location either in the cerebellum or in the dorsal brainstem (odds ratio [OR] 16.97, 95\% CI 3.1-92.95, p = .001) and a total infarction volume of >0.48 cm3 (OR 4.4, 95\% CI 1.05-18.58, p = .043) were related to vertigo. In another multivariate logistic regression, after adjusting for age, sex, intravenous thrombolysis, serum level of white blood cells, and atrial fibrillation, vertigo independently predicted a total infarction volume of >0.48 cm3 (OR 5.75, 95\% CI 1.43-23.08, p = .01). Conclusion Infarction location in the cerebellum and/or dorsal brainstem is an independent predictor of vertigo. Furthermore, larger infarction volume in these structures is associated with vertigo. A considerable proportion of patients with vascular vertigo present without focal neurological deficits posing a diagnostic challenge. National Institute of Health Stroke Scale is not sensitive for vertebrobasilar stroke.}, language = {en} } @article{NguemeniHomolaNakchbandietal.2020, author = {Nguemeni, Carine and Homola, Gy{\"o}rgy A. and Nakchbandi, Luis and Pham, Mirko and Volkmann, Jens and Zeller, Daniel}, title = {A Single Session of Anodal Cerebellar Transcranial Direct Current Stimulation Does Not Induce Facilitation of Locomotor Consolidation in Patients With Multiple Sclerosis}, series = {Frontiers in Human Neuroscience}, volume = {14}, journal = {Frontiers in Human Neuroscience}, issn = {1662-5161}, doi = {10.3389/fnhum.2020.588671}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-215291}, year = {2020}, abstract = {Background: Multiple sclerosis (MS) may cause variable functional impairment. The discrepancy between functional impairment and brain imaging findings in patients with MS (PwMS) might be attributed to differential adaptive and consolidation capacities. Modulating those abilities could contribute to a favorable clinical course of the disease. Objectives: We examined the effect of cerebellar transcranial direct current stimulation (c-tDCS) on locomotor adaptation and consolidation in PwMS using a split-belt treadmill (SBT) paradigm. Methods: 40 PwMS and 30 matched healthy controls performed a locomotor adaptation task on a SBT. First, we assessed locomotor adaptation in PwMS. In a second investigation, this training was followed by cerebellar anodal tDCS applied immediately after the task ipsilateral to the fast leg (T0). The SBT paradigm was repeated 24 h (T1) and 78 h (T2) post-stimulation to evaluate consolidation. Results: The gait dynamics and adaptation on the SBT were comparable between PwMS and controls. We found no effects of offline cerebellar anodal tDCS on locomotor adaptation and consolidation. Participants who received the active stimulation showed the same retention index than sham-stimulated subjects at T1 (p = 0.33) and T2 (p = 0.46). Conclusion: Locomotor adaptation is preserved in people with mild-to-moderate MS. However, cerebellar anodal tDCS applied immediately post-training does not further enhance this ability. Future studies should define the neurobiological substrates of maintained plasticity in PwMS and how these substrates can be manipulated to improve compensation. Systematic assessments of methodological variables for cerebellar tDCS are urgently needed to increase the consistency and replicability of the results across experiments in various settings.}, language = {en} } @article{UeceylerBuchholzKewenigetal.2020, author = {{\"U}{\c{c}}eyler, Nurcan and Buchholz, Hans-Georg and Kewenig, Susanne and Ament, Stephan-Johann and Birklein, Frank and Schreckenberger, Mathias and Sommer, Claudia}, title = {Cortical Binding Potential of Opioid Receptors in Patients With Fibromyalgia Syndrome and Reduced Systemic Interleukin-4 Levels - A Pilot Study}, series = {Frontiers in Neuroscience}, volume = {14}, journal = {Frontiers in Neuroscience}, issn = {1662-453X}, doi = {10.3389/fnins.2020.00512}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204457}, year = {2020}, abstract = {Objective: We investigated cerebral opioid receptor binding potential in patients with fibromyalgia syndrome (FMS) using positron-emission-tomography (PET) and correlated our results with patients' systemic interleukin-4 (IL-4) gene expression. Methods: In this pilot study, seven FMS patients (1 man, 6 women) agreed to participate in experimental PET scans. All patients underwent neurological examination, were investigated with questionnaires for pain, depression, and FMS symptoms. Additionally, blood for IL-4 gene expression analysis was withdrawn at two time points with a median latency of 1.3 years. Patients were investigated in a PET scanner using the opioid receptor ligand F-18-fluoro-ethyl-diprenorphine ([18F]FEDPN) and results were compared with laboratory normative values. Results: Neurological examination was normal in all FMS patients. Reduced opioid receptor binding was found in mid cingulate cortex compared to healthy controls (p < 0.005). Interestingly, three patients with high systemic IL-4 gene expression had increased opioid receptor binding in the fronto-basal cortex compared to those with low IL-4 gene expression (p < 0.005). Conclusion: Our data give further evidence for a reduction in cortical opioid receptor availability in FMS patients as another potential central nervous system contributor to pain in FMS.}, language = {en} } @article{PalmisanoBrandtVissanietal.2020, author = {Palmisano, Chiara and Brandt, Gregor and Vissani, Matteo and Pozzi, Nicol{\´o} G. and Canessa, Andrea and Brumberg, Joachim and Marotta, Giorgio and Volkmann, Jens and Mazzoni, Alberto and Pezzoli, Gianni and Frigo, Carlo A. and Isaias, Ioannis U.}, title = {Gait Initiation in Parkinson's Disease: Impact of Dopamine Depletion and Initial Stance Condition}, series = {Frontiers in Bioengineering and Biotechnology}, volume = {8}, journal = {Frontiers in Bioengineering and Biotechnology}, issn = {2296-4185}, doi = {10.3389/fbioe.2020.00137}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200801}, year = {2020}, abstract = {Postural instability, in particular at gait initiation (GI), and resulting falls are a major determinant of poor quality of life in subjects with Parkinson's disease (PD). Still, the contribution of the basal ganglia and dopamine on the feedforward postural control associated with this motor task is poorly known. In addition, the influence of anthropometric measures (AM) and initial stance condition on GI has never been consistently assessed. The biomechanical resultants of anticipatory postural adjustments contributing to GI [imbalance (IMB), unloading (UNL), and stepping phase) were studied in 26 unmedicated subjects with idiopathic PD and in 27 healthy subjects. A subset of 13 patients was analyzed under standardized medication conditions and the striatal dopaminergic innervation was studied in 22 patients using FP-CIT and SPECT. People with PD showed a significant reduction in center of pressure (CoP) displacement and velocity during the IMB phase, reduced first step length and velocity, and decreased velocity and acceleration of the center of mass (CoM) at toe off of the stance foot. All these measurements correlated with the dopaminergic innervation of the putamen and substantially improved with levodopa. These results were not influenced by anthropometric parameters or by the initial stance condition. In contrast, most of the measurements of the UNL phase were influenced by the foot placement and did not correlate with putaminal dopaminergic innervation. Our results suggest a significant role of dopamine and the putamen particularly in the elaboration of the IMB phase of anticipatory postural adjustments and in the execution of the first step. The basal ganglia circuitry may contribute to defining the optimal referent body configuration for a proper initiation of gait and possibly gait adaptation to the environment.}, language = {en} } @article{CanesiGiordanoLazzarietal.2016, author = {Canesi, Margherita and Giordano, Rosaria and Lazzari, Lorenza and Isalberti, Maurizio and Isaias, Ioannis Ugo and Benti, Riccardo and Rampini, Paolo and Marotta, Giorgio and Colombo, Aurora and Cereda, Emanuele and Dipaola, Mariangela and Montemurro, Tiziana and Vigano, Mariele and Budelli, Silvia and Montelatici, Elisa and Lavazza, Cristiana and Cortelezzi, Agostino and Pezzoli, Gianni}, title = {Finding a new therapeutic approach for no-option Parkinsonisms: mesenchymal stromal cells for progressive supranuclear palsy}, series = {Journal of Translational Medicine}, volume = {14}, journal = {Journal of Translational Medicine}, number = {127}, doi = {10.1186/s12967-016-0880-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165725}, pages = {1-11}, year = {2016}, abstract = {Background: The trophic, anti-apoptotic and regenerative effects of bone marrow mesenchymal stromal cells (MSC) may reduce neuronal cell loss in neurodegenerative disorders. Methods: We used MSC as a novel candidate therapeutic tool in a pilot phase-I study for patients affected by progressive supranuclear palsy (PSP), a rare, severe and no-option form of Parkinsonism. Five patients received the cells by infusion into the cerebral arteries. Effects were assessed using the best available motor function rating scales (UPDRS, Hoehn and Yahr, PSP rating scale), as well as neuropsychological assessments, gait analysis and brain imaging before and after cell administration. Results: One year after cell infusion, all treated patients were alive, except one, who died 9 months after the infusion for reasons not related to cell administration or to disease progression (accidental fall). In all treated patients motor function rating scales remained stable for at least six-months during the one-year follow-up. Conclusions: We have demonstrated for the first time that MSC administration is feasible in subjects with PSP. In these patients, in whom deterioration of motor function is invariably rapid, we recorded clinical stabilization for at least 6 months. These encouraging results pave the way to the next randomized, placebo-controlled phase-II study that will definitively provide information on the efficacy of this innovative approach.}, language = {en} } @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} } @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} } @article{PritchardFalkLarssonetal.2016, author = {Pritchard, Rory A. and Falk, Lovissa and Larsson, Mathilda and Leinders, Mathias and Sorkin, Linda S.}, title = {Different phosphoinositide 3-kinase isoforms mediate carrageenan nociception and inflammation}, series = {Pain}, volume = {157}, journal = {Pain}, number = {1}, doi = {10.1097/j.pain.0000000000000341}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191312}, pages = {137-146}, year = {2016}, abstract = {Phosphoinositide 3-kinases (PI3Ks) participate in signal transduction cascades that can directly activate and sensitize nociceptors and enhance pain transmission. They also play essential roles in chemotaxis and immune cell infiltration leading to inflammation. We wished to determine which PI3K isoforms were involved in each of these processes. Lightly anesthetized rats (isoflurane) were injected subcutaneously with carrageenan in their hind paws. This was preceded by a local injection of 1\% DMSO vehicle or an isoform-specific antagonist to PI3K-α (compound 15-e), -β (TGX221), -δ (Cal-101), or -γ (AS252424). We measured changes in the mechanical pain threshold and spinal c-Fos expression (4 hours after injection) as indices of nociception. Paw volume, plasma extravasation (Evans blue, 0.3 hours after injection), and neutrophil (myeloperoxidase; 1 hour after injection) and macrophage (CD11b+; 4 hour after injection) infiltration into paw tissue were the measured inflammation endpoints. Only PI3K-γ antagonist before treatment reduced the carrageenan-induced pain behavior and spinal expression of c-Fos (P <= 0.01). In contrast, pretreatment with PI3K-α, -δ, and -γ antagonists reduced early indices of inflammation. Plasma extravasation PI3K-α (P <= 0.05), -δ (P <= 0.05), and -γ (P <= 0.01), early (0-2 hour) edema -α (P <= 0.05), -δ (P <= 0.001), and -γ (P <= 0.05), and neutrophil infiltration (all P <= 0.001) were all reduced compared to vehicle pretreatment. Later (2-4 hour), edema and macrophage infiltration (P <= 0.05) were reduced by only the PI3K-δ and -γ isoform antagonists, with the PI3K-δ antagonist having a greater effect on edema. PI3K-β antagonism was ineffective in all paradigms. These data indicate that pain and clinical inflammation are pharmacologically separable and may help to explain clinical conditions in which inflammation naturally wanes or goes into remission, but pain continues unabated.}, language = {en} } @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} } @phdthesis{Raban2021, author = {Raban, Rebecca Emmi Hildegard}, title = {Sicherheit und Wirksamkeit von intrathekalem Triamcinolon bei Patienten mit chronisch-progredienter Multipler Sklerose : eine retrospektive Longitudinalstudie}, doi = {10.25972/OPUS-22047}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220478}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Im Zeitraum von 2004 bis 2016 erhielten an der Neurologischen Universit{\"a}tsklinik W{\"u}rzburg Patienten mit einer chronisch progredienten Multiplen Sklerose insgesamt 595 Injektionen von intrathekalem Triamcinolonacetonid. Diese Arbeit befasst sich mit Sicherheit, Nebenwirkungen und Wirksamkeit der intrathekalen Therapieform.}, subject = {Intrathekale Applikation}, language = {de} } @article{MartiniWillison2016, author = {Martini, Rudolf and Willison, Hugh}, title = {Neuroinflammation in the peripheral nerve: cause, modulator, or bystander in peripheral neuropathies?}, series = {GLIA}, volume = {64}, journal = {GLIA}, number = {4}, doi = {10.1002/glia.22899}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189696}, pages = {475-486}, year = {2016}, abstract = {The role of innate and adaptive inflammation as a primary driver or modifier of neuropathy in premorbidly normal nerves, and as a critical player in amplifying neuropathies of other known causes (e.g., genetic, metabolic) is incompletely understood and under-researched, despite unmet clinical need. Also, cellular and humoral components of the adaptive and innate immune system are substantial disease modifying agents in the context of neuropathies and, at least in some neuropathies, there is an identified tight interrelationship between both compartments of the immune system. Additionally, the quadruple relationship between Schwann cell, axon, macrophage, and endoneurial fibroblast, with their diverse membrane bound and soluble signalling systems, forms a distinct focus for investigation in nerve diseases with inflammation secondary to Schwann cell mutations and possibly others. Identification of key immunological effector pathways that amplify neuropathic features and associated clinical symptomatology including pain should lead to realistic and timely possibilities for translatable therapeutic interventions using existing immunomodulators, alongside the development of novel therapeutic targets.}, language = {en} } @phdthesis{Frank2021, author = {Frank, Franziska}, title = {Ver{\"a}nderung der Ranvier'schen Schn{\"u}rringarchitektur bei Patienten mit diabetischer Neuropathie}, doi = {10.25972/OPUS-21966}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219668}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {In der Krankheitsentstehung der diabetischen Neuropathie wird die paranodale Demyelinisierung als ein m{\"o}glicher Pathomechanismus diskutiert, wobei Studien mit Gewebeproben von Patienten aufgrund der Invasivit{\"a}t limitiert sind. In der vorliegenden Studie wurden periphere Nervenfasern in Hautbiopsien von Patienten mit diabetischer Neuropathie und in Patienten mit Diabetes mellitus ohne Neuropathie untersucht. Ziel war es, nodale und paranodale Ver{\"a}nderungen, wie eine Dispersion der paranodalen Proteine Caspr und Neurofascin oder der nodalen Na-Kan{\"a}le, zu detektieren und die Proben auf verl{\"a}ngerte Ranvier`sche Schn{\"u}rringe zu untersuchen. Es wurde die Hypothese {\"u}berpr{\"u}ft, dass paranodale Demyelinisierungen bei Patienten mit diabetischer Neuropathie in Hautbiopsien, als minimal-invasive Methode, nachweisbar sind. Hautproben von Patienten mit Diabetes mellitus ohne Neuropathie sollten zudem in einem fr{\"u}hen Krankheitsstadium untersucht werden. F{\"u}r die Untersuchung konnten 35 Patienten mit einer diabetischen Neuropathie, 17 Patienten mit Diabetes mellitus und 31 Kontrollen eingeschlossen werden. Immunfluoreszenzf{\"a}rbungen mit Antik{\"o}rpern gegen Caspr, Neurofascin und Natrium-Kan{\"a}len wurden zur Analyse der Ranvier`schen Schn{\"u}rringarchitektur durchgef{\"u}hrt und ausgewertet. Eine erh{\"o}hte Anzahl an verl{\"a}ngerten Schn{\"u}rringen, als Zeichen einer segmentalen Demyelinisierung, konnte in den Patienten mit diabetischer Neuropathie aber auch in Patienten mit Diabetes mellitus nachgewiesen werden. Weiterhin waren vermehrt Ver{\"a}nderungen der paranodalen Proteine, wie eine Dispersion von Caspr und Neurofascin in den Proben des Fingers der Patienten mit diabetischer Neuropathie sowie eine Dispersion von Neurofascin im Unterschenkel in beiden Patientengruppen nachweisbar. Interessanterweise waren einzelne Ver{\"a}nderungen auch in den gesunden Kontrollen auffindbar. Ver{\"a}nderungen der Schn{\"u}rringarchitektur lassen sich mithilfe der Hautbiopsie nachweisen und quantifizieren. Nodale und paranodale Ver{\"a}nderungen weisen auf demyelinisierende Prozesse in Patienten mit diabetischer Neuropathie hin und finden sich auch bereits in einem fr{\"u}hen Krankheitsstadium.}, subject = {Ranvier-Schn{\"u}rring}, language = {de} } @article{BellingerAltenmuellerVolkmann2017, author = {Bellinger, Daniel and Altenm{\"u}ller, Eckart and Volkmann, Jens}, title = {Perception of time in music in patients with Parkinson's disease - The processing of musical syntax compensates for rhythmic deficits}, series = {Frontiers in Neuroscience}, volume = {11}, journal = {Frontiers in Neuroscience}, doi = {10.3389/fnins.2017.00068}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171805}, year = {2017}, abstract = {Objective: Perception of time as well as rhythm in musical structures rely on complex brain mechanisms and require an extended network of multiple neural sources. They are therefore sensitive to impairment. Several psychophysical studies have shown that patients with Parkinson's disease (PD) have deficits in perceiving time and rhythms due to a malfunction of the basal ganglia (BG) network. Method: In this study we investigated the time perception of PD patients during music perception by assessing their just noticeable difference (JND) in the time perception of a complex musical Gestalt. We applied a temporal discrimination task using a short melody with a clear beat-based rhythm. Among the subjects, 26 patients under L-Dopa administration and 21 age-matched controls had to detect an artificially delayed time interval in the range between 80 and 300 ms in the middle of the musical period. We analyzed the data by (a) calculating the detection threshold directly, (b) by extrapolating the JNDs, (c) relating it to musical expertise. Results: Patients differed from controls in the detection of time-intervals between 220 and 300 ms (*p = 0.0200, n = 47). Furthermore, this deficit depended on the severity of the disease (*p = 0.0452; n = 47). Surprisingly, PD patients did not show any deficit of their JND compared to healthy controls, although the results showed a trend (*p = 0.0565, n = 40). Furthermore, no significant difference of the JND was found according to the severity of the disease. Additionally, musically trained persons seemed to have lower thresholds in detecting deviations in time and syntactic structures of music (*p = 0.0343, n = 39). Conclusion: As an explanation of these results, we would like to propose the hypothesis of a time-syntax-congruency in music perception suggesting that processing of time and rhythm is a Gestalt process and that cortical areas involved in processing of musical syntax may compensate for impaired BG circuits that are responsible for time processing and rhythm perception. This mechanism may emerge more strongly as the deficits in time processing and rhythm perception progress. Furthermore, we presume that top-down-bottom-up-processes interfere additionally and interact in this context of compensation.}, language = {en} } @phdthesis{Weigl2020, author = {Weigl, Anna}, title = {Korrelation zwischen subjektiver Fatigue und objektiven physischen und kognitiven Einschr{\"a}nkungen bei Multipler Sklerose: eine Querschnittsstudie}, doi = {10.25972/OPUS-21896}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218960}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Fatigue als ein „{\"u}berw{\"a}ltigendes Gef{\"u}hl von M{\"u}digkeit, Energielosigkeit und Ersch{\"o}pfung" stellt bei Patienten mit MS ein h{\"a}ufig auftretendes und oft im Alltag beeintr{\"a}chtigendes Symptom dar, das sowohl mit k{\"o}rperlichen als auch mit kognitiven Ersch{\"o}pfungssymptomen einhergeht. Die objektive Erfassung des Schweregrades der Fatigue beim einzelnen Patienten stellt ein Problem dar, da bisher keine objektiven Messverfahren zur Erfassung der Fatigue existieren. Im klinischen Alltag kommen meist Frageb{\"o}gen zum Einsatz, die das Ausmaß der subjektiven Beeintr{\"a}chtigung durch Fatigue im Alltag quantifizieren sollen. Ziel dieser Arbeit war es, zu untersuchen, inwieweit bestimmte im klinischen Alltag erhobene Parameter R{\"u}ckschl{\"u}sse auf die subjektive Fatigue bei Patienten mit MS erlauben, auch im Hinblick darauf, ob sich einzelne Parameter besonders zur Einsch{\"a}tzung der k{\"o}rperlichen bzw. kognitiven Fatigue eignen. Zudem sollte untersucht werden, ob die untersuchten klinischen Parameter bei bestimmten Patientengruppen besser als bei anderen R{\"u}ckschl{\"u}sse auf die subjektive Fatigue erlauben. Erfasst wurde die subjektive Fatigue durch das W{\"u}rzburger Ersch{\"o}pfungsinventar bei Multipler Sklerose (WEIMuS), einer Serie von Fragen, die zwischen k{\"o}rperlicher und kognitiver Fatigue unterscheiden. Dazu wurden Korrelationsanalysen zwischen der WEIMuS-Gesamtskala bzw. deren Subskalen f{\"u}r k{\"o}rperliche und kognitive Fatigue und EDSS-Wert, MSFC Z-Score einschließlich dessen Subscores und der Zeit des 50-Meter-Gehversuchs durchgef{\"u}hrt. Bez{\"u}glich der k{\"o}rperlichen Fatigue ergaben sich zwischen der WEIMuS-Subskala f{\"u}r k{\"o}rperliche Fatigue und dem EDSS sowie der Zeit des 50-Meter-Gehversuchs im Vergleich die st{\"a}rksten, absolut gesehen als mittelstark zu wertende, Korrelationen. Bez{\"u}glich der kognitiven Fatigue ergab sich die st{\"a}rkste Korrelation zwischen der WEIMuS-Subskala f{\"u}r kognitive Fatigue und dem PASAT3, die allerdings trotzdem als gering zu werten ist. Mit EDSS und 50-Meter-Gehversuch scheinen also zwei objektive klinische Parameter zu existieren, die in einem gewissen Maß auf die subjektive Fatigue r{\"u}ckschließen lassen. Ziel weiterer Untersuchungen wird es sein m{\"u}ssen, einen geeigneten klinischen Parameter zu finden, der bessere R{\"u}ckschl{\"u}sse auf die subjektive kognitive Fatigue erlaubt als der PASAT3. Zwischen der WEIMuS-Gesamtskala bzw. deren Subskalen f{\"u}r k{\"o}rperliche und kognitive Fatigue und Alter, Geschlecht und Erkrankungsdauer fanden sich bestenfalls geringe Korrelationen, weshalb diese Parameter ungeeignet erscheinen, Aussagen {\"u}ber die subjektive Fatigue zu machen. Durch die Einteilung der Patienten nach Alter und Geschlecht konnte untersucht werden, inwieweit diese Parameter Einfluss auf die untersuchten Zusammenh{\"a}nge zwischen klinischen Parametern und subjektiver Fatigue haben. Die Korrelationen zwischen den WEIMuS-Subskalen f{\"u}r k{\"o}rperliche und kognitive Fatigue mit den untersuchten klinischen Parametern waren f{\"u}r junge Patienten {\"u}berwiegend st{\"a}rker als f{\"u}r {\"a}ltere Patienten, insbesondere {\"a}ltere M{\"a}nner. Somit scheinen die untersuchten klinischen Parameter bei j{\"u}ngeren Patienten besser geeignet, Aussagen {\"u}ber die subjektive Fatigue zu machen als bei {\"a}lteren. Insgesamt ist festzuhalten, dass EDSS und 50-Meter-Gehversuch insbesondere bei jungen Patienten zu einer besseren objektiven Beurteilbarkeit vor allem der k{\"o}rperlichen Fatigue im klinischen Alltag beitragen k{\"o}nnen.}, subject = {Multiple Sklerose}, language = {de} } @article{DipaolaPavanCattaneoetal.2016, author = {Dipaola, Mariangela and Pavan, Esteban E. and Cattaneo, Andrea and Frazzitta, Giuseppe and Pezzoli, Gianni and Cavallari, Paolo and Frigo, Carlo A. and Isaias, Ioannis U.}, title = {Mechanical Energy Recovery during Walking in Patients with Parkinson Disease}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0156420}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-179739}, year = {2016}, abstract = {The mechanisms of mechanical energy recovery during gait have been thoroughly investigated in healthy subjects, but never described in patients with Parkinson disease (PD). The aim of this study was to investigate whether such mechanisms are preserved in PD patients despite an altered pattern of locomotion. We consecutively enrolled 23 PD patients (mean age 64±9 years) with bilateral symptoms (H\&Y ≥II) if able to walk unassisted in medication-off condition (overnight suspension of all dopaminergic drugs). Ten healthy subjects (mean age 62±3 years) walked both at their 'preferred' and 'slow' speeds, to match the whole range of PD velocities. Kinematic data were recorded by means of an optoelectronic motion analyzer. For each stride we computed spatio-temporal parameters, time-course and range of motion (ROM) of hip, knee and ankle joint angles. We also measured kinetic (Wk), potential (W\(_{p}\)), total (W\(_{totCM}\)) energy variations and the energy recovery index (ER). Along with PD progression, we found a significant correlation of W\(_{totCM}\) and W\(_{p}\) with knee ROM and in particular with knee extension in terminal stance phase. W\(_{k}\) and ER were instead mainly related to gait velocity. In PD subjects, the reduction of knee ROM significantly diminished both W\(_{p}\) and W\(_{totCM}\). Rehabilitation treatments should possibly integrate passive and active mobilization of knee to prevent a reduction of gait-related energetic components.}, language = {en} } @article{UeceylerSchroeterKafkeetal.2016, author = {{\"U}{\c{c}}eyler, Nurcan and Schr{\"o}ter, Nils and Kafke, Waldemar and Kramer, Daniela and Wanner, Christoph and Weidemann, Frank and Sommer, Claudia}, title = {Skin Globotriaosylceramide 3 Load Is Increased in Men with Advanced Fabry Disease}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {11}, doi = {10.1371/journal.pone.0166484}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-178856}, year = {2016}, abstract = {Background The X-chromosomally linked life-limiting Fabry disease (FD) is associated with deposits of the sphingolipid globotriaosylceramide 3 (Gb3) in various tissues. Skin is easily accessible and may be used as an additional diagnostic and follow-up medium. Our aims were to visualize skin Gb3 deposits in FD patients applying immunofluorescence and to determine if cutaneous Gb3 load correlates with disease severity. Methods At our Fabry Center for Interdisciplinary Therapy we enrolled 84 patients with FD and 27 healthy controls. All subjects underwent 5-mm skin punch biopsy at the lateral lower leg and the back. Skin samples were processed for immunohistochemistry using antibodies against CD77 (i.e. Gb3). Cutaneous Gb3 deposition was quantified in a blinded manner and correlated to clinical data. Results We found that Gb3 load was higher in distal skin of male FD patients compared to healthy controls (p<0.05). Men (p<0.01) and women (p<0.05) with a classic FD phenotype had higher distal skin Gb3 load than healthy controls. Men with advanced disease as reflected by impaired renal function, and men and women with small fiber neuropathy had more Gb3 deposits in distal skin samples than males with normal renal function (p<0.05) and without small fiber neuropathy. Gb3 deposits were not different between patients with and without enzyme replacement therapy. Conclusions Immunofluorescence on minimally invasive skin punch biopsies may be useful as a tool for assessment and follow-up in FD patients.}, language = {en} } @phdthesis{Hirschmann2020, author = {Hirschmann, Anna}, title = {microRNA-Genexpressionsprofile in Blut-, Haut- und Nervenproben von Patienten mit Polyneuropathien}, doi = {10.25972/OPUS-21701}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-217010}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Die Polyneuropathie (PNP) ist die h{\"a}ufigste St{\"o}rung des peripheren Nervensystems bei Erwachsenen. Die Suche nach der Ursache bleibt in vielen F{\"a}llen erfolglos, ist aber unverzichtbar, da die Therapiewahl von der {\"A}tiologie der Erkrankung abh{\"a}ngt. Geeignete Biomarker k{\"o}nnten die Differentialdiagnose unter Umst{\"a}nden erleichtern. microRNAs (miRNAs) sind in dieser Hinsicht vielversprechend, da in vielen Studien bei Nervende- und regenerationsprozessen sowie in neuropathischen Schmerzmodellen eine Dysregulation beschrieben wurde. In dieser Studie wurde die Expression zweier miRNAs, miR-103a und miR-let-7d, sowie eines Zielmolek{\"u}ls der miR-103a, des Kalziumkanals Cav1,2, in einer großen Kohorte von PNP-Patienten unterschiedlicher {\"A}tiologie in Blut, Haut- und Nervenbiopsien untersucht. Insgesamt wurden 116 Patienten und 22 Kontroll-probanden in die Studie eingeschlossen. Nach der Isolation von RNA aus weißen Blutzellen (WBC), Haut- und Nervenbiopsien folgte die Expressionsbestimmung mittels qRT-PCR. W{\"a}hrend sich jeweils Unterschiede zwischen PNP-Patienten und Kontrollen und zwischen Patienten mit entz{\"u}ndlicher und solchen mit nicht-entz{\"u}ndlicher PNP zeigten, wurden keine Unterschiede in der Expression zwischen den {\"a}tiologischen Subgruppen oder zwischen Patienten mit schmerzhafter und schmerzloser PNP festgestellt. In den Nervenbiopsien der Patientenkohorte ergab sich eine inverse Korrelation der miR-103a und ihrem Zielgen Cacna1c, die darauf hinweisen k{\"o}nnte, dass Cacna1c von der miR-103a negativ reguliert wird. Da in unserer Patientenkohorte keine Unterschiede zwischen den PNP-Subgruppen auftraten, scheint der Einsatz der miR-103a und miR-let-7d als diagnostische Biomarker zur {\"a}tiologischen Einordnung einer PNP nicht gerechtfertigt. Dennoch deuten unsere Ergebnisse auf eine m{\"o}gliche Rolle der untersuchten miRNAs bei Entstehung und Verlauf von PNP hin. F{\"u}r ein tieferes pathophysiologisches Verst{\"a}ndnis der miRNAs vor allem bei entz{\"u}ndlichen Neuropathien, k{\"o}nnte die Untersuchung von weiteren miRNAs und Zielgenen Aufschluss geben.}, subject = {miRNS}, language = {de} } @phdthesis{Pozzi2020, author = {Pozzi, Nicol{\´o} Gabriele}, title = {Parkinson's disease revisited: multiple circuitopathies}, doi = {10.25972/OPUS-21671}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-216715}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Parkinson's disease (PD) is among the most common neurodegenerative conditions, and it is characterized by the progressive loss of dopaminergic neurons and a great variability in clinical expression. Despite several effective medications, it still causes disability as all patients show treatment-resistant symptoms and complications. A possible reason for this therapeutic-burden and great clinical variability lies in a probable misconception about its pathophysiology, one that focuses on neurodegeneration, while largely neglecting its functional consequences and the related compensatory changes. In this thesis, I expand on the hypothesis that some PD symptoms have a dysfunctional origin and reflect derangements of neural network dynamics, the means by which brain coordination supports any motor behaviour. In particular, I have investigated resting tremor and freezing of gait, two common symptoms with an enigmatic mechanism and suboptimal management. In the case of tremor, I predicted a pathological change in response to dopamine loss, which included the activation of noradrenergic (NA) neurons of the locus coeruleus (LC) projecting to the cerebellum. This compensatory LC activation that supports dopaminergic neurons might indeed come at the expense of tremor development. To assess the role of LC-NA in tremor development, I recorded tremor occurrence in the reserpinized rat model of PD, one of very few showing tremor, after selective lesioning (with the neurotoxin DSP-4) of the LC-NA terminal axons. DSP-4 induced a severe reduction of LC-NA terminal axons in the cerebellar cortex and this was associated with a significant reduction in tremor development. Unlike its development, tremor frequency and the akinetic rigid signs did not differ between the groups, thus suggesting a dopaminergic dependency. These findings suggest that the LC-NA innervation of the cerebellum has a critical role for PD tremor, possibly by exerting a network effect, which gates the cerebello-thalamic-cortical circuit into pathological oscillations upon a dopaminergic loss in the basal ganglia. In contrast, for the study of freezing of gait, I worked with human PD subjects and deep brain stimulation, a therapeutic neuromodulation device that in some prototypes also allows the recording of neural activity in freely-moving subjects. Gait freezing is a disabling PD symptom that suddenly impairs effective stepping, thus causing falls and disability. Also in this study, I hypothesized that the underlying pathophysiology may be represented by dysfunctional neural network dynamics that abruptly impair locomotor control by affecting the communication in the supraspinal locomotor network. To test this hypothesis, I investigated the coupling between the cortex and the subthalamic nucleus, two main nodes of the supraspinal locomotor network, in freely-moving subjects PD patients and also performed molecular brain imaging of striatal dopamine receptor density and kinematic measurements. I found that in PD patients, walking is associated with cortical-subthalamic stable coupling in a low-frequency band (i.e. θ-α rhythms). In contrast, these structures decoupled when gait freezing occurred in the brain hemisphere with less dopaminergic innervation. These findings suggest that freezing of gait is a "circuitopathy", with dysfunctional cortical-subcortical communication. Altogether the results of my experiments support the hypothesis that the pathophysiology of PD goes beyond neurodegenerative (loss-of-function) processes and that derangement of neural network dynamics coincides with some disabling PD symptoms, thus suggesting that PD can be interpreted as the combination of multiple circuitopathies.}, subject = {Parkinson-Krankheit}, language = {en} } @article{KollikowskiSchuhmannNieswandtetal.2020, author = {Kollikowski, Alexander M. and Schuhmann, Michael K. and Nieswandt, Bernhard and M{\"u}llges, Wolfgang and Stoll, Guido and Pham, Mirko}, title = {Local Leukocyte Invasion during Hyperacute Human Ischemic Stroke}, series = {Annals of Neurology}, volume = {87}, journal = {Annals of Neurology}, number = {3}, doi = {10.1002/ana.25665}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212168}, pages = {466-479}, year = {2020}, abstract = {Objective Bridging the gap between experimental stroke and patients by ischemic blood probing during the hyperacute stage of vascular occlusion is crucial to assess the role of inflammation in human stroke and for the development of adjunct treatments beyond recanalization. Methods We prospectively observed 151 consecutive ischemic stroke patients with embolic large vessel occlusion of the anterior circulation who underwent mechanical thrombectomy. In all these patients, we attempted microcatheter aspiration of 3 different arterial blood samples: (1) within the core of the occluded vascular compartment and controlled by (2) carotid and (3) femoral samples obtained under physiological flow conditions. Subsequent laboratory analyses comprised leukocyte counting and differentiation, platelet counting, and the quantification of 13 proinflammatory human chemokines/cytokines. Results Forty patients meeting all clinical, imaging, interventional, and laboratory inclusion criteria could be analyzed, showing that the total number of leukocytes significantly increased under the occlusion condition. This increase was predominantly driven by neutrophils. Significant increases were also apparent for lymphocytes and monocytes, accompanied by locally elevated plasma levels of the T-cell chemoattractant CXCL-11. Finally, we found evidence that short-term clinical outcome (National Institute of Health Stroke Scale at 72 hours) was negatively associated with neutrophil accumulation. Interpretation We provide the first direct human evidence that neutrophils, lymphocytes, and monocytes, accompanied by specific chemokine upregulation, accumulate in the ischemic vasculature during hyperacute stroke and may affect outcome. These findings strongly support experimental evidence that immune cells contribute to acute ischemic brain damage and indicate that ischemic inflammation initiates already during vascular occlusion. Ann Neurol 2020;87:466-479}, language = {en} } @phdthesis{Brandt2020, author = {Brandt, Gregor A.}, title = {Gait Initiation in Parkinson's Disease: The Interplay of Dopamine and Postural Control}, doi = {10.25972/OPUS-21463}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214636}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Deterioration of gait and alterations of physiological gait initiation contribute significantly to the burden of disease in Parkinson's disease. This paper systematically investigates disease-specific alterations during the postural phases of gait initiation and demonstrates the influence of dopaminergic networks by assessing levodopa mediated improvements in motor performance and correlation of motor behavior with loss of striatal and cortical dopaminergic neurons. Particular attention is given to known confounders such as initial stance and anthropometrics.}, subject = {Parkinson-Krankheit}, language = {en} } @article{KlitschEvdokimovFranketal.2020, author = {Klitsch, Alexander and Evdokimov, Dimitar and Frank, Johanna and Thomas, Dominique and Saffer, Nadine and Meyer zu Altenschildesche, Caren and Sisignano, Marco and Kampik, Daniel and Malik, Rayaz A. and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan}, title = {Reduced association between dendritic cells and corneal sub-basal nerve fibers in patients with fibromyalgia syndrome}, series = {Journal of the Peripheral Nervous System}, volume = {25}, journal = {Journal of the Peripheral Nervous System}, number = {1}, doi = {10.1111/jns.12360}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214150}, pages = {9-18}, year = {2020}, abstract = {In our study, we aimed at investigating corneal langerhans cells (LC) in patients with fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) as potential contributors to corneal small fiber pathology. We enrolled women with FMS (n = 134) and SFN (n = 41) who underwent neurological examination, neurophysiology, prostaglandin analysis in tear fluid, and corneal confocal microscopy (CCM). Data were compared with those of 60 age-matched female controls. After screening for dry eye disease, corneal LC were counted and sub-classified as dendritic (dLC) and non-dendritic (ndLC) cells with or without nerve fiber association. We further analyzed corneal nerve fiber density (CNFD), length (CNFL), and branch density (CNBD). Neurological examination indicated deficits of small fiber function in patients with SFN. Nerve conduction studies were normal in all participants. Dry eye disease was more prevalent in FMS (17\%) and SFN (28\%) patients than in controls (5\%). Tear fluid prostaglandin levels did not differ between FMS patients and controls. While corneal LC density in FMS and SFN patients was not different from controls, there were fewer dLC in association with nerve fibers in FMS and SFN patients than in controls (P < .01 each). Compared to controls, CNFL was lower in FMS and SFN patients (P < .05 each), CNFD was lower only in FMS patients (P < .05), and CNBD was lower only in SFN patients (P < .001). There was no difference in any CCM parameter between patients with and without dry eyes. Our data indicate changes in corneal innervation and LC distribution in FMS and SFN, potentially based on altered LC signaling.}, language = {en} } @phdthesis{Emmerich2020, author = {Emmerich, Christoph}, title = {Die Rolle der clathrin- und dynaminabh{\"a}ngigen Endozytose bei der Internalisation von anti-Amphiphysin-Autoantik{\"o}rpern im Falle des Stiff-Person-Syndroms, untersucht am Zellkulturmodell hippocampaler Neurone}, doi = {10.25972/OPUS-20936}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-209360}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {In dieser Arbeit wurde mit Hilfe von small-molecule Inhibitoren die Rolle von clathrin- und dynaminabh{\"a}ngigen Endozytosemechanismen bei der Aufnahme von anti-Amphiphysin-Autoantik{\"o}rpern am Zellkulturmodell prim{\"a}rer hippocampaler Neurone untersucht. Hierbei konnte eine Beeinflussung der Autoaantik{\"o}rperaufnahme durch die Intervention gezeigt werden. Außerdem erfolgte der Versuch der Etablierung eines siRNA knockdowns unter Zuhilfenahme unterschiedlicher Traansfektionsreaaagenzien.}, subject = {siRNA}, language = {de} } @phdthesis{Toeppner2020, author = {T{\"o}ppner, Verena}, title = {Therapie und Outcome von Patienten mit aneurysmatischer Subarachnoidalblutung am Universit{\"a}tsklinikum W{\"u}rzburg}, doi = {10.25972/OPUS-20912}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-209129}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Die aneurysmatische SAB ist trotz etablierter Therapieverfahren (Coiling und Clipping) weiterhin ein Krankheitsbild mit hoher Mortalit{\"a}t. In unserer Arbeit haben wir retrospektiv die Patientenakten der Patienten, die mit der Diagnose aneurysmatische SAB am Universit{\"a}tsklinikum W{\"u}rzburg zwischen dem 01.01.1999 und dem 31.12.2009 aufgenommen wurden, ausgewertet. Es konnte dargestellt werden das als Hauptrisikofaktoren f{\"u}r ein schlechtes Therapieergebnis ein schlechter Aufnahmestatus des Patienten und das Auftreten von Komplikationen im Verlauf verantwortlich sind.}, subject = {Subarachnoidalblutung}, language = {de} } @phdthesis{Kress2020, author = {Kreß, Luisa Sophia}, title = {Determination of cytokine and axon guidance molecule profiles in patients with small fiber neuropathy}, doi = {10.25972/OPUS-20911}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-209113}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {The pathophysiological mechanisms of pain in small fiber neuropathy (SFN) are unclear. Based on experimental and clinical studies, sensitized nociceptors in the skin are reported to be involved in pain development. These nociceptors may be sensitized by cutaneous and systemic pain mediators e.g. pro- and anti-inflammatory cytokines. The aim of our study was, to measure the systemic and local gene expression of pro- and anti-inflammatory cytokines in white blood cells (WBC) as well as in primary fibroblasts and keratinocytes obtained from human skin of patients with SFN. Furthermore, gene expression levels of axon guidance molecules and their receptors, as potential regulators of the intraepidermal nerve fiber density (IENFD), were investigated. 55 patients and 31 healthy controls were prospectively recruited. Participants underwent extensive clinical phenotyping and blood sampling, 6-mm skin punch biopsies were taken from the right lateral calf and the upper thigh. Systemic relative gene expression levels (ΔG) of the interleukin (IL)-1β, IL-2, IL-6, IL-8, and tumor necrosis factor (TNF) was measured in WBC. Skin punch biopsies were taken to determine the IENFD and to obtain primary fibroblast and keratinocyte cell cultures. Skin cells were then used for investigation of ΔG in axon guidance molecules netrin 1 (NTN1) and ephrin A4 (EPHA4) as well as their receptors Unc5b receptor, and ephrin A4 (EFNA4) as well as cytokines IL-1β, IL-4, IL-6, IL-8, IL-10, TNF, and transforming growth factor (TGF). Systemically, gene expression of IL-2, IL-8, and TNF was higher in SFN patients compared to healthy controls. In keratinocytes, higher expression levels of NTN1 and TGF were found when comparing the SFN patients to the controls. In fibroblasts higher gene expression was shown in NTN1, Unc5b, IL-6, and IL-8 when comparing patients to healthy controls. The systemically and local elevated levels of pro-inflammatory, algesic cytokines in SFN patients compared to healthy controls, confirms a potential pathophysiological role in the development of neuropathic pain. Data also indicate fibroblasts and keratinocytes to influence subepidermal and intraepidermal nerve fiber growth through the expression of NTN1 and Unc5b. Thus, skin cells may contribute to the development of neuropathic pain through local denervation.}, subject = {Neuropathischer Schmerz}, language = {en} } @phdthesis{Wind2020, author = {Wind, Teresa Elisabeth}, title = {Einfluss von Alter und Polyneuropathie auf zeitliche Wahrnehmungsschwellen somatosensorischer und kin{\"a}sthetischer Stimuli und propriozeptive Leistungsf{\"a}higkeit}, doi = {10.25972/OPUS-20804}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-208047}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Zeitliche Diskrimination somatosensorischer und kin{\"a}sthetischer Stimuli wurde als neurophysiologisches Korrelat f{\"u}r propriozeptive Pr{\"a}zision postuliert und bei verschiedenen Bewegungsst{\"o}rungen als pathologisch beschrieben. Ziel der Untersuchung war es, den Einfluss von Alter und Polyneuropathie auf die kin{\"a}sthetische (TDMT) und taktile (STDT) zeitliche Wahrnehmungsschwelle sowie die propriozeptive Genauigkeit bei Zeigeversuchen systematisch zu untersuchen. Hierf{\"u}r wurden 54 gesunde Probanden und 25 Polyneuropathie-Patienten im Alter zwischen 30 und 76 Jahren untersucht. Die STDT-Messung erfolgte mit Oberfl{\"a}chenelektroden, die an der Zeigefingerspitze bzw. am Großzehengrundgelenk angebracht wurden. Die TDMT-Werte wurden mit Hilfe einer sterilen Nadelelektrode erfasst, welche in den Musculus flexor carpi radialis bzw. Musculus tibialis anterior inseriert wurde. Die Daten zur Propriozeption wurden mit Hilfe eines Goniometers erhoben und beinhalteten dabei aktive Zeigeaufgaben (Zeigen auf eine LED, Nachahmung einer Bewegung anhand einer auf einem Computerbildschirm dargebotenen PFEIL-Darstellung unterschiedlicher L{\"a}nge) und die Einsch{\"a}tzung der Position der jeweiligen Extremit{\"a}t nach passiver Bewegung (PASSIV). Die Messungen erfolgten jeweils ohne visuelle R{\"u}ckmeldung. Die Zeigefehler (Abweichung von der Zielposition) bzw. Sch{\"a}tzfehler (Abweichung der gesch{\"a}tzten von der tats{\"a}chlichen Position nach passiver Auslenkung) wurden als Maß der propriozeptiven Pr{\"a}zision verwendet. Die Ergebnisse der gesunden Probandengruppe zeigten, dass h{\"o}heres Alter mit h{\"o}heren STDT- und TDMT-Werten korrelierte. Die Polyneuropathie-Patienten erzielten in allen Bereichen (Diskriminationsschwellen und Propriozeptionsaufgaben) signifikant schlechtere Ergebnisse als die gesunde Kontrollgruppe. Zus{\"a}tzlich konnte eine statistisch signifikante positive Korrelation zwischen der propriozeptiven Pr{\"a}zision bei den aktiven Zeige-Aufgaben (LED und PFEIL) und den zeitlichen Diskriminationsschwellen (STDT und TDMT) gezeigt werden. In Anbetracht dieser Ergebnisse sollten das Patienten-Alter und m{\"o}gliche St{\"o}rungen der peripheren Nervenleitung ber{\"u}cksichtigt werden, wenn STDT-und TDMT-Bestimmungen bei Patienten mit Bewegungsst{\"o}rungen angewendet werden. Die Korrelation zwischen den Diskriminationsschwellen und der Performance bei aktiven Zeigeversuchen (PFEIL- und LED-Aufgabe) legt nahe, dass STDT und TDMT Indikatoren der propriozeptiven Funktion sein k{\"o}nnten. Es ist weitere Forschungsarbeit notwendig, um diese Beziehung exakt zu beleuchten. Im Falle einer Best{\"a}tigung der Befunde auch bei Patienten mit Bewegungsst{\"o}rungen erscheint denkbar, dass sich STDT und TDMT als vergleichsweise leicht messbare und gut quantifizierbare Parameter der Propriozeption herausstellen mit Potenzial zur differenzialdiagnostischen Anwendung, m{\"o}glicherweise aber auch als Surrogatparameter einer gezielten rehabilitativen Behandlung.}, subject = {Propriozeption}, language = {de} }