@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} } @phdthesis{Bellinger2020, author = {Bellinger, Daniel}, title = {Zeitwahrnehmung in der Musik bei Morbus Parkinson - eine psychophysische Studie}, doi = {10.25972/OPUS-19876}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-198766}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Parkinson Patienten sind im Gegensatz zu gesunden Probanden in der kognitiven Verarbeitung zeitlicher Parameter, im Sinne einer Diskriminierungsf{\"a}higkeit f{\"u}r zeitliche Fehler innerhalb der Musikwahrnehmung beeintr{\"a}chtigt. Dies betrifft lediglich die Zeiterkennung in h{\"o}heren Intervallbereichen (> 600ms) und ist am ehesten durch Fluktuationen der Aufmerksamkeit, des Ged{\"a}chtnisses, aber auch im Vergleich zu anderen Studien durch methodische Ans{\"a}tze zu erkl{\"a}ren. Durch die Koppelung des Audiostimulus an klare Rhythmusstrukturen weist diese Studie jedoch darauf hin, dass {\"U}berschneidungen zu anderen neuronalen Netzwerken existieren, die zur Kompensationsstrategie rekrutiert und nutzbar gemacht werden k{\"o}nnen. Dazu geh{\"o}ren etwa die Verarbeitung zeitlicher (Cerebellum) und musikperzeptiver Leistungen, wie etwa die Verarbeitung musikalischer Syntax (BA 6, 22, 44). Etwaige Wahrnehmungsdefizite k{\"o}nnen durch Mechanismen musiksyntaktischer Verarbeitung kompensiert werden, da zeitliche und syntaktische Strukturen in der Musik auf ihre Kongruenz hin abgeglichen und somit multineuronal mediiert werden (Paradigma der Zeit-Syntax-Kongruenz in der Musikwahrnehmung). Weiterhin sind vermutlich top-down-bottom-up-Prozesse als multimodale Interaktionen an diesem Kompensationsmechanismus beteiligt. Außerdem ist festzuhalten, dass das Krankheitsstadium nicht zwangsl{\"a}ufig mit einem st{\"a}rkeren Wahrnehmungsdefizit f{\"u}r zeitliche Strukturen einhergehen muss, obwohl - wenn auch noch tolerabel - mit Progression der Erkrankung dieses Kompensationsmodell {\"u}ber Prinzipien der Gestaltwahrnehmung zusammenbricht und es hier zu schlechteren perzeptiven Leistungen kommen kann. Die Ergebnisse der OFF-Testungen und jener unter DBS-Therapie lassen weiterhin aufgrund der kleinen Stichprobe keine klare Aussage zu und machen weitere Untersuchungen notwendig. Das physiologische Alter korreliert außerdem mit der sensorischen Leistung, die allerdings starken, individuellen Unterschieden ausgesetzt ist und von multifaktoriellen Voraussetzungen abh{\"a}ngt. Auch zeigt die Studie, dass Menschen mit einem hohen Musikverst{\"a}ndnis und einer musikalischen Ausbildung ein feineres Diskriminierungsverm{\"o}gen in der zeitlichen Verarbeitung besitzen, welches v.a. im zeitlich niedrigen Intervallbereich (< 500ms) evident wird.}, subject = {Parkinson}, language = {de} } @article{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{BeyerJadaszSamperAgreloetal.2020, author = {Beyer, Felix and Jadasz, Janusz and Samper Agrelo, Iria and Schira-Heinen, Jessica and Groh, Janos and Manousi, Anastasia and B{\"u}termann, Christine and Estrada, Veronica and Reiche, Laura and Cantone, Martina and Vera, Julio and Vigan{\`o}, Francesca and Dimou, Leda and M{\"u}ller, Hans Werner and Hartung, Hans-Peter and K{\"u}ry, Patrick}, title = {Heterogeneous fate choice of genetically modulated adult neural stem cells in gray and white matter of the central nervous system}, series = {Glia}, volume = {68}, journal = {Glia}, number = {2}, doi = {10.1002/glia.23724}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218566}, pages = {393 -- 406}, year = {2020}, abstract = {Apart from dedicated oligodendroglial progenitor cells, adult neural stem cells (aNSCs) can also give rise to new oligodendrocytes in the adult central nervous system (CNS). This process mainly confers myelinating glial cell replacement in pathological situations and can hence contribute to glial heterogeneity. Our previous studies demonstrated that the p57kip2 gene encodes an intrinsic regulator of glial fate acquisition and we here investigated to what degree its modulation can affect stem cell-dependent oligodendrogenesis in different CNS environments. We therefore transplanted p57kip2 knockdown aNSCs into white and gray matter (WM and GM) regions of the mouse brain, into uninjured spinal cords as well as in the vicinity of spinal cord injuries and evaluated integration and differentiation in vivo. Our experiments revealed that under healthy conditions intrinsic suppression of p57kip2 as well as WM localization promote differentiation toward myelinating oligodendrocytes at the expense of astrocyte generation. Moreover, p57kip2 knockdown conferred a strong benefit on cell survival augmenting net oligodendrocyte generation. In the vicinity of hemisectioned spinal cords, the gene knockdown led to a similar induction of oligodendroglial features; however, newly generated oligodendrocytes appeared to suffer more from the hostile environment. This study contributes to our understanding of mechanisms of adult oligodendrogenesis and glial heterogeneity and further reveals critical factors when considering aNSC mediated cell replacement in injury and disease.}, 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{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{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} } @phdthesis{Buchwald2020, author = {Buchwald, Sina}, title = {Autoimmune Enzephalitiden am Universit{\"a}tsklinikum W{\"u}rzburg von 2006-2016}, doi = {10.25972/OPUS-20720}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-207202}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {In den Jahren von 2006 bis 2016 sind am Universit{\"a}tsklinikum W{\"u}rzburg insgesamt 26 Patienten mit der Diagnose einer Autoimmunen Enzephalitis behandelt worden. Diese Arbeit zeigt ihre Krankheitsverl{\"a}ufe, Outcome, die gefundenen Antik{\"o}rper und die Therapien der jeweiligen Patienten. Im zweiten Schritt wurden die Daten mit den in der Literatur bereits beschrieben F{\"a}llen verglichen, um Gemeinsamkeiten, aber auch Unterschiede aufzeigen zu k{\"o}nnen.}, subject = {Enzephalitis}, language = {de} } @article{CapetianMuellerVolkmannetal.2020, author = {Capetian, Philipp and M{\"u}ller, Lorenz and Volkmann, Jens and Heckmann, Manfred and Erg{\"u}n, S{\"u}leyman and Wagner, Nicole}, title = {Visualizing the synaptic and cellular ultrastructure in neurons differentiated from human induced neural stem cells - an optimized protocol}, series = {International Journal of Molecular Sciences}, volume = {21}, journal = {International Journal of Molecular Sciences}, number = {5}, issn = {1422-0067}, doi = {10.3390/ijms21051708}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236053}, year = {2020}, abstract = {The size of the synaptic subcomponents falls below the limits of visible light microscopy. Despite new developments in advanced microscopy techniques, the resolution of transmission electron microscopy (TEM) remains unsurpassed. The requirements of tissue preservation are very high, and human post mortem material often does not offer adequate quality. However, new reprogramming techniques that generate human neurons in vitro provide samples that can easily fulfill these requirements. The objective of this study was to identify the culture technique with the best ultrastructural preservation in combination with the best embedding and contrasting technique for visualizing neuronal elements. Two induced neural stem cell lines derived from healthy control subjects underwent differentiation either adherent on glass coverslips, embedded in a droplet of highly concentrated Matrigel, or as a compact neurosphere. Afterward, they were fixed using a combination of glutaraldehyde (GA) and paraformaldehyde (PFA) followed by three approaches (standard stain, Ruthenium red stain, high contrast en-bloc stain) using different combinations of membrane enhancing and contrasting steps before ultrathin sectioning and imaging by TEM. The compact free-floating neurospheres exhibited the best ultrastructural preservation. High-contrast en-bloc stain offered particularly sharp staining of membrane structures and the highest quality visualization of neuronal structures. In conclusion, compact neurospheres growing under free-floating conditions in combination with a high contrast en-bloc staining protocol, offer the optimal preservation and contrast with a particular focus on visualizing membrane structures as required for analyzing synaptic structures.}, language = {en} } @phdthesis{Egenolf2020, author = {Egenolf, Nadine}, title = {Multidimensionale morphologische und elektrophysiologische Analyse von Patienten mit Small Fiber Neuropathie}, doi = {10.25972/OPUS-20293}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202938}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Die Small Fiber Neuropathie (SFN) bildet eine Untergruppe der sensiblen Neuropathien, bei der die Aδ- und C-Fasern betroffen sind. Die Patienten berichten v.a. von brennenden Schmerzen und Dys{\"a}sthesien, seltener auch von autonomen Funktionsst{\"o}rungen. Bei fehlendem Goldstandard und normalen Nervenleitungsstudien ist die Diagnostik erschwert, da selbst nach Spezialuntersuchungen wie Hautstanzbiopsie und quantitativer sensorischer Testung (QST) viele Patienten trotz typischer Anamnese der Diagnosestellung entgehen. Wir rekrutierten 55 Patienten und 31 gesunde Kontrollen. Nach neurologischer Untersuchung und Ausschluss einer Polyneuropathie mittels Elektroneurographie wurden bei allen Studienteilnehmern Hautstanzbiopsien am Ober- und Unterschenkel zur Ermittlung der intraepidermalen Nervenfaserdichte (IENFD) entnommen sowie eine QST zur Funktionspr{\"u}fung der kleinen Nervenfasern durchgef{\"u}hrt. Die Studienteilnehmer wurden zudem mit cornealer confocaler Mikroskopie (CCM) und der Ableitung Schmerz-assoziierter evozierter Potentiale (PREP) untersucht. Zur autonomen Testung erfolgte die Messung der Schweißproduktion mittels quantitativem sudomotorischem Axonreflextest (QSART). Die neurologische Untersuchung zeigte in 55\% der Patienten Hinweise auf eine Kleinfaserpathologie. Die distale IENFD war bei 62\% der Patienten reduziert, die QST bei 22\% der Patienten auff{\"a}llig. Die PREP Latenzen waren in der Patientengruppe l{\"a}nger als bei den Kontrollen, die Amplituden niedriger. Bei der cornealen Innervation zeigte sich eine Reduktion der Nervenfaserdichte, Nervenfaserl{\"a}nge und Nervenastdichte. Die in QSART gemessenen Parameter zeigten sich zu 86\% unauff{\"a}llig. W{\"a}hrend nach klinischer Untersuchung, Hautbiopsie und QST in 53\% der F{\"a}lle in 2 von 3 Untersuchungen eine Pathologie der kleinen Fasern festgestellt werden konnte, stieg die Rate bei zus{\"a}tzlicher Anwendung von PREP und CCM auf 80\% (ohne Ber{\"u}cksichtigung von QST). Zusammenfassend sollten die klinische Untersuchung und die Hautstanzbiopsie bei allen Patienten mit Verdacht auf SFN erfolgen. PREP und CCM sind unter den verf{\"u}gbaren zus{\"a}tzlichen Untersuchungen diagnostisch am wertvollsten. Wichtig ist allerdings, dass bei fehlendem Goldstandard eine SFN auch bei unauff{\"a}lligen Tests nicht ausgeschlossen werden kann. Zus{\"a}tzlich k{\"o}nnen die Mikroneurographie und die genetische Analyse wertvolle Hinweise auf eine Kleinfaserfunktionsst{\"o}rung und deren Pathophysiologie geben.}, subject = {Neuropathischer Schmerz}, language = {de} }