@article{ZellerHeidemeierGrigoleitetal.2017, author = {Zeller, Daniel and Heidemeier, Anke and Grigoleit, G{\"o}tz Ulrich and M{\"u}llges, Wolfgang}, title = {Case report: subacute tetraplegia in an immunocompromised patient}, series = {BMC Neurology}, volume = {17}, journal = {BMC Neurology}, number = {31}, doi = {10.1186/s12883-017-0814-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157576}, year = {2017}, abstract = {Background: Clinical reasoning in Neurology is based on general associations which help to deduce the site of the lesion. However, even "golden principles" may occasionally be deceptive. Here, we describe the case of subacute flaccid tetraparesis due to motor cortical lesions. To our knowledge, this is the first report to include an impressive illustration of nearly symmetric motor cortical involvement of encephalitis on brain MRI. Case presentation: A 51 year old immunocompromized man developed a high-grade pure motor flaccid tetraparesis over few days. Based on clinical presentation, critical illness polyneuromyopathy was suspected. However, brain MRI revealed symmetrical hyperintensities strictly limited to the subcortical precentral gyrus. An encephalitis, possibly due to CMV infection, turned out to be the most likely cause. Conclusion: While recognition of basic clinical patterns is indispensable in neurological reasoning, awareness of central conditions mimicking peripheral nervous disease may be crucial to detect unsuspected, potentially treatable conditions.}, language = {en} } @article{WangIpKlausKarikarietal.2017, author = {Wang Ip, Chi and Klaus, Laura-Christin and Karikari, Akua A. and Visanji, Naomi P. and Brotchie, Jonathan M. and Lang, Anthony E. and Volkmann, Jens and Koprich, James B.}, title = {AAV1/2-induced overexpression of A53T-α-synuclein in the substantia nigra results in degeneration of the nigrostriatal system with Lewy-like pathology and motor impairment: a new mouse model for Parkinson's disease}, series = {Acta Neuropathologica Communications}, volume = {5}, journal = {Acta Neuropathologica Communications}, number = {11}, doi = {10.1186/s40478-017-0416-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159429}, year = {2017}, abstract = {α-Synuclein is a protein implicated in the etiopathogenesis of Parkinson's disease (PD). AAV1/2-driven overexpression of human mutated A53T-α-synuclein in rat and monkey substantia nigra (SN) induces degeneration of nigral dopaminergic neurons and decreases striatal dopamine and tyrosine hydroxylase (TH). Given certain advantages of the mouse, especially it being amendable to genetic manipulation, translating the AAV1/2-A53T α-synuclein model to mice would be of significant value. AAV1/2-A53T α-synuclein or AAV1/2 empty vector (EV) at a concentration of 5.16 x 10\(^{12}\) gp/ml were unilaterally injected into the right SN of male adult C57BL/6 mice. Post-mortem examinations included immunohistochemistry to analyze nigral α-synuclein, Ser129 phosphorylated α-synuclein and TH expression, striatal dopamine transporter (DAT) levels by autoradiography and dopamine levels by high performance liquid chromatography. At 10 weeks, in AAV1/2-A53T α-synuclein mice there was a 33\% reduction in TH+ dopaminergic nigral neurons (P < 0.001), 29\% deficit in striatal DAT binding (P < 0.05), 38\% and 33\% reductions in dopamine (P < 0.001) and DOPAC (P < 0.01) levels and a 60\% increase in dopamine turnover (homovanilic acid/dopamine ratio; P < 0.001). Immunofluorescence showed that the AAV1/2-A53T α-synuclein injected mice had widespread nigral and striatal expression of vector-delivered A53T-α-synuclein. Concurrent staining with human PD SN samples using gold standard histological methodology for Lewy pathology detection by proteinase K digestion and application of specific antibody raised against human Lewy body α-synuclein (LB509) and Ser129 phosphorylated α-synuclein (81A) revealed insoluble α-synuclein aggregates in AAV1/2-A53T α-synuclein mice resembling Lewy-like neurites and bodies. In the cylinder test, we observed significant paw use asymmetry in the AAV1/2-A53T α-synuclein group when compared to EV controls at 5 and 9 weeks post injection (P < 0.001; P < 0.05). These data show that unilateral injection of AAV1/2-A53T α-synuclein into the mouse SN leads to persistent motor deficits, neurodegeneration of the nigrostriatal dopaminergic system and development of Lewy-like pathology, thereby reflecting clinical and pathological hallmarks of human PD.}, language = {en} } @phdthesis{Wagemann2017, author = {Wagemann, Esther}, title = {Biopsiediagnostik von entz{\"u}ndlichen Polyneuropathien}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-155031}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Polyneuropathien sind Erkrankungen des peripheren Nervensystems. Die Erkrankung kommt geh{\"a}uft als Zweiterkrankungen bei anderen Prim{\"a}rerkrankungen vor, daher ist es schwierig, epidemiologische Angaben zu machen. {\"A}tiologisch lassen sich Polyneuropathien in f{\"u}nf große Gruppen einteilen: Heredit{\"a}re Polyneuropathien, entz{\"u}ndliche Polyneuropathien, vaskul{\"a}r bedingte Polyneuropathien, exotoxische Polyneuropathien und endotoxisch-metabolische Polyneuropathien. Die Differentialdiagnose der Polyneuropathie richtet sich nach dem zeitlichen Verlauf der Krankheit, dem betroffenen System und danach, ob prim{\"a}r die Axone oder die Markscheiden betroffen sind. F{\"u}r die Diagnosestellung einer Polyneuropathie werden Anamnese und klinischer Befund, elektrophysiologische Untersuchungen, Laboruntersuchungen, genetische Untersuchungen und die histopathologische Untersuchung herangezogen. Entscheidend f{\"u}r die Therapie ist es, die behandelbaren Polyneuropathien zu erkennen, hierunter u.a. die entz{\"u}ndlichen Formen. Die hierf{\"u}r entnommene Suralisbiopsie ist wegen ihrer invasiven Natur erst dann indiziert, wenn die Differentialdiagnose mit nicht-invasiven Maßnahmen nicht gekl{\"a}rt werden kann, sich aber eine Behandlungskonsequenz erwarten l{\"a}sst. Die exakte Diagnose setzt bei einigen Polyneuropathien eine neuropathologische Diagnostik voraus. Die Nervenbiopsie muss optimal aufbereitet und ausgewertet werden. Hierf{\"u}r stehen verschiedene F{\"a}rbe- und Aufbereitungsmethoden zur Verf{\"u}gung. In dieser Arbeit wurde untersucht, ob anhand eines Schnellschnittes (d.h. Gefrier-Querschnitt des biopsierten Nerven mit H{\"a}matoxylin-Eosin gef{\"a}rbt) bereits Hinweise auf entz{\"u}ndliche Infiltrate als Zeichen einer Neuritis und damit einer therapiebed{\"u}rftigen und aber auch therapierbaren Neuropathie gefunden werden k{\"o}nnen. Anhand eines vordefinierten Schemas wurden die Biopsate in verblindeter Weise von einem Laien und einem erfahrenem Untersucher histologisch begutachtet und den entz{\"u}ndlichen/nicht entz{\"u}ndlichen Diagnosegruppen zugeordnet. Es wurde untersucht, ob die entz{\"u}ndlichen Ver{\"a}nderungen im H{\"a}matoxylin-Eosin-Gefrierschnitt so deutlich sind, dass auch ein Laienauswerter diese erkennen kann. Ebenso wurden die Untersuchungsergebnisse mittels H{\"a}matoxylin-Eosin- F{\"a}rbung an Gefrier- und Paraffinschnitten mit den Untersuchungsergebnissen mittels immunhistochemischer F{\"a}rbemethoden verglichen. Des weiteren wurde untersucht, ob bei histologisch gesicherter Entz{\"u}ndung klinische Einflussfaktoren ermittelt werden k{\"o}nnen, die auf die neuropathologische Diagnostik Auswirkung haben. Die Ergebnisse der Studie zeigen, dass sich die H{\"a}matoxylin-Eosin-F{\"a}rbung f{\"u}r eine erste und schnelle Diagnostik von entz{\"u}ndlichen Polyneuropathien als wertvoll erwies. Dies gilt f{\"u}r den erfahrenen und unerfahrenen Untersucher. Es zeigen sich keine klinischen Einflussfaktoren f{\"u}r die histopathologische Diagnosestellung. Die Ergebnisse der Studie zeigen, dass schon eine einfache F{\"a}rbemethode wie die H{\"a}matoxylin-Eosin-F{\"a}rbung an Gefrier-und Paraffinschnitten bei Polyneuropathie unklarer Genese hilfreich bei einer differenzierten Diagnosefindung sein kann.}, language = {de} } @article{SchuhmannLanghauserKraftetal.2017, author = {Schuhmann, Michael K. and Langhauser, Friederike and Kraft, Peter and Kleinschnitz, Christoph}, title = {B cells do not have a major pathophysiologic role in acute ischemic stroke in mice}, series = {Journal of Neuroinflammation}, volume = {14}, journal = {Journal of Neuroinflammation}, number = {112}, doi = {10.1186/s12974-017-0890-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158155}, year = {2017}, abstract = {Background Lymphocytes have been shown to play an important role in the pathophysiology of acute ischemic stroke, but the properties of B cells remain controversial. The aim of this study was to unravel the role of B cells during acute cerebral ischemia using pharmacologic B cell depletion, B cell transgenic mice, and adoptive B cell transfer experiments. Methods Transient middle cerebral artery occlusion (60 min) was induced in wild-type mice treated with an anti-CD20 antibody 24 h before stroke onset, JHD\(^{-/-}\) mice and Rag1\(^{-/-}\) mice 24 h after adoptive B cell transfer. Stroke outcome was assessed at days 1 and 3. Infarct volumes were calculated from 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain sections, and neurological scores were evaluated. The local inflammatory response was determined by real-time PCR and immunohistochemistry. Apoptosis was analyzed by TUNEL staining, and astrocyte activation was revealed using immunohistochemistry and Western blot. Results Pharmacologic depletion of B cells did not influence infarct volumes and functional outcome at day 1 after stroke. Additionally, lack of circulating B cells in JHD\(^{-/-}\) mice also failed to influence stroke outcome at days 1 and 3. Furthermore, reconstitution of Rag1\(^{-/-}\) mice with B cells had no influence on infarct volumes. Conclusion Targeting B cells in experimental stroke did not influence lesion volume and functional outcome during the acute phase. Our findings argue against a major pathophysiologic role of B cells during acute ischemic stroke.}, language = {en} } @article{SchuhmannGuthmannStolletal.2017, author = {Schuhmann, Michael K. and Guthmann, Josua and Stoll, Guido and Nieswandt, Bernhard and Kraft, Peter and Kleinschnitz, Christoph}, title = {Blocking of platelet glycoprotein receptor Ib reduces "thrombo-inflammation" in mice with acute ischemic stroke}, series = {Journal of Neuroinflammation}, volume = {14}, journal = {Journal of Neuroinflammation}, number = {18}, doi = {10.1186/s12974-017-0792-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157582}, year = {2017}, abstract = {Background: Ischemic stroke causes a strong inflammatory response that includes T cells, monocytes/macrophages, and neutrophils. Interaction of these immune cells with platelets and endothelial cells facilitates microvascular dysfunction and leads to secondary infarct growth. We recently showed that blocking of platelet glycoprotein (GP) receptor Ib improves stroke outcome without increasing the risk of intracerebral hemorrhage. Until now, it has been unclear whether GPIb only mediates thrombus formation or also contributes to the pathophysiology of local inflammation. Methods: Focal cerebral ischemia was induced in C57BL/6 mice by a 60-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with antigen-binding fragments (Fab) against the platelet surface molecules GPIb (p0p/B Fab). Rat immunoglobulin G (IgG) Fab was used as control treatment. Stroke outcome, including infarct size and functional deficits as well as the local inflammatory response, was assessed on day 1 after tMCAO. Results: Blocking of GPIb reduced stroke size and improved functional outcome on day 1 after tMCAO without increasing the risk of intracerebral hemorrhage. As expected, disruption of GPIb-mediated pathways in platelets significantly reduced thrombus burden in the cerebral microvasculature. In addition, inhibition of GPIb limited the local inflammatory response in the ischemic brain as indicated by lower numbers of infiltrating T cells and macrophages and lower expression levels of inflammatory cytokines compared with rat IgG Fab-treated controls. Conclusion: In acute ischemic stroke, thrombus formation and inflammation are closely intertwined ("thrombo-inflammation"). Blocking of platelet GPIb can ameliorate thrombo-inflammation.}, language = {en} } @article{SchuhmannFluri2017, author = {Schuhmann, Michael K. and Fluri, Felix}, title = {Effects of fullerenols on mouse brain microvascular endothelial cells}, series = {International Journal of Molecular Sciences}, volume = {18}, journal = {International Journal of Molecular Sciences}, number = {8}, issn = {1422-0067}, doi = {10.3390/ijms18081783}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158072}, year = {2017}, abstract = {Fullerenols, water-soluble C60-fullerene derivatives, have been shown to exert neuroprotective effects in vitro and in vivo, most likely due to their capability to scavenge free radicals. However, little is known about the effects of fullerenols on the blood-brain barrier (BBB), especially on cerebral endothelial cells under inflammatory conditions. Here, we investigated whether the treatment of primary mouse brain microvascular endothelial cells with fullerenols impacts basal and inflammatory blood-brain barrier (BBB) properties in vitro. While fullerenols (1, 10, and 100 µg/mL) did not change transendothelial electrical resistance under basal and inflammatory conditions, 100 µg/mL of fullerenol significantly reduced erk1/2 activation and resulted in an activation of NFκB in an inflammatory milieu. Our findings suggest that fullerenols might counteract oxidative stress via the erk1/2 and NFκB pathways, and thus are able to protect microvascular endothelial cells under inflammatory conditions.}, language = {en} } @phdthesis{Schubert2017, author = {Schubert, Anna-Lena}, title = {Untersuchung potenzieller Biomarker in Haut- und Nervenbiopsaten von Patienten mit schmerzhaften und schmerzlosen Polyneuropathien}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-153254}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Polyneuropathien sind eine {\"a}tiologisch heterogene Erkrankung des peripheren Nervensystems. In bis zu 30\% der F{\"a}lle ist eine Zuordnung zu einem bestimmten PNP Subtyp auch nach aufw{\"a}ndiger und zum Teil invasiver Diagnostik nicht m{\"o}glich. Bislang fehlt ein diagnostischer Biomarker bei PNP, der z.B. bei der Unterscheidung zwischen einzelnen diagnostischen Subgruppen oder entz{\"u}ndlichen und nicht-entz{\"u}ndlichen Erkrankungsformen helfen k{\"o}nnte. In einer prospektiven Studie mit insgesamt 97 Patienten mit Neuropathien verschiedenster {\"A}tiologie und 17 gesunden Kontrollpersonen erstellten wir Genexpressionsprofile von inflammatorischen Markern und Markern der Regeneration peripherer Nerven in Haut- und N. suralis-Biopsaten. Es wurden Inflammationsmarker (TAC1, CRMP2, AIF1, IL-6) und Marker, die in die Regeneration peripherer Nerven involviert sind (SCD, Netrin-1, DCC, UNC5H2, NEO1, Netrin-G1, Netrin-G2), mittels qRT-PCR untersucht. Alle Patienten erhielten eine N. suralis-Biopsie und/oder eine Hautbiopsie von Ober- beziehungsweise Unterschenkel. Weder in den Haut- noch in den N. suralis-Biopsaten konnten Unterschiede in der Genexpression dieser Marker zwischen einzelnen diagnostischen Subgruppen gefunden werden. Der Inflammationsmarker AIF1 war jedoch in Patienten-Hautproben sowohl proximal als auch distal h{\"o}her exprimiert als bei gesunden Kontrollpersonen (p < 0,05 bzw. p < 0,01). Zudem fand sich in den Hautproben von PNP-Patienten eine deutlich reduzierte Genexpression von Regenerationsmarkern aus der Netrin-Familie verglichen mit den Hautproben gesunder Probanden (Netrin-1, DCC, UNC5H2, NEO1 sowie Netrin-G1 und G2; p < 0,05 bis p < 0,001). Ferner wies Netrin-1 in distalen Hautproben bei Patienten mit einer entz{\"u}ndlichen PNP eine niedrigere Genexpression auf, als bei Patienten mit einer nicht-entz{\"u}ndlichen Erkrankungsform (p < 0,05). Die Genexpression von NEO1 in distalen Hautproben war bei schmerzloser PNP und gesunden Kontrollpersonen h{\"o}her als bei schmerzhafter PNP (p < 0,05). Sowohl eine Erh{\"o}hung bestimmter Inflammationsmarker als auch eine Verminderung von Regenerationsmarkern peripherer Nerven k{\"o}nnen bei der Pathophysiologie von Polyneuropathien involviert sein. Insbesondere Mitglieder der Netrin-Familie scheinen eine komplexe Rolle f{\"u}r das Axonwachstum, jedoch auch f{\"u}r entz{\"u}ndliche Prozesse zu spielen.}, subject = {Biomarker}, language = {de} } @article{PoetterNergerReeseSteigerwaldetal.2017, author = {P{\"o}tter-Nerger, Monika and Reese, Rene and Steigerwald, Frank and Heiden, Jan Arne and Herzog, Jan and Moll, Christian K. E. and Hamel, Wolfgang and Ramirez-Pasos, Uri and Falk, Daniela and Mehdorn, Maximilian and Gerloff, Christian and Deuschl, G{\"u}nther and Volkmann, Jens}, title = {Movement-Related Activity of Human Subthalamic Neurons during a Reach-to-Grasp Task}, series = {Frontiers in Human Neuroscience}, volume = {11}, journal = {Frontiers in Human Neuroscience}, number = {436}, doi = {10.3389/fnhum.2017.00436}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170361}, year = {2017}, abstract = {The aim of the study was to record movement-related single unit activity (SUA) in the human subthalamic nucleus (STN) during a standardized motor task of the upper limb. We performed microrecordings from the motor region of the human STN and registered kinematic data in 12 patients with Parkinson's disease (PD) undergoing deep brain stimulation surgery (seven women, mean age 62.0 ± 4.7 years) while they intraoperatively performed visually cued reach-to-grasp movements using a grip device. SUA was analyzed offline in relation to different aspects of the movement (attention, start of the movement, movement velocity, button press) in terms of firing frequency, firing pattern, and oscillation. During the reach-to-grasp movement, 75/114 isolated subthalamic neurons exhibited movement-related activity changes. The largest proportion of single units showed modulation of firing frequency during several phases of the reach and grasp (polymodal neurons, 45/114), particularly an increase of firing rate during the reaching phase of the movement, which often correlated with movement velocity. The firing pattern (bursting, irregular, or tonic) remained unchanged during movement compared to rest. Oscillatory single unit firing activity (predominantly in the theta and beta frequency) decreased with movement onset, irrespective of oscillation frequency. This study shows for the first time specific, task-related, SUA changes during the reach-to-grasp movement in humans.}, language = {en} } @article{PirothBoelmansAmtageetal.2017, author = {Piroth, Tobias and Boelmans, Kai and Amtage, Florian and Rijntjes, Michel and Wierciochin, Anna and Musacchio, Thomas and Weiller, Cornelius and Volkmann, Jens and Klebe, Stephan}, title = {Adult-Onset Niemann-Pick Disease Type C: Rapid Treatment Initiation Advised but Early Diagnosis Remains Difficult}, series = {Frontiers in Neurology}, volume = {8}, journal = {Frontiers in Neurology}, number = {108}, doi = {10.3389/fneur.2017.00108}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171001}, year = {2017}, abstract = {Niemann-Pick type C disease (NP-C) presents with heterogeneous neurological and psychiatric symptoms. Adult onset is rare and possibly underdiagnosed due to frequent lack of specific and obvious key symptoms. For both early and adolescent/adult onset, the available data from studies and case reports describe a positive effect of Miglustat (symptom relief or stabilization). However, due to the low frequency of NP-C, experience with this therapy is still limited. We describe two adult-onset cases of NP-C. In both cases, vertical supranuclear gaze palsy was not recognized at symptom onset. Correct diagnosis was delayed from onset of symptoms by more than 10 years. The video demonstrates the broad spectrum of symptoms in later stages of the disease. Compared with published data, the treatment outcome observed in our cases after delayed initiation of Miglustat therapy was disappointing, with continuing disease progression in both cases. Thus, early treatment initiation could be necessary to achieve a good symptomatic effect. Hence, early biochemical testing for NP-C should be considered in patients suffering from atypical neurological/neuropsychological and psychiatric symptoms, even in cases of uncertainty.}, language = {en} } @phdthesis{Pausch2017, author = {Pausch, Jonas Franz}, title = {Pr{\"a}ferentielle Lokalisation von Makrophagen im r{\"a}umlichen Umfeld von Ranvier'schen Schn{\"u}rringen - Morphologische Analysen zur r{\"a}umlichen Verteilung von Makrophagen in Mausmodellen f{\"u}r erbliche Neuropathien}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143801}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Die Charcot-Marie-Tooth Typ 1 Erkrankungen sind eine genetisch heterogene Gruppe, aktuell nicht kurativ therapierbarer, erblicher Neuropathien des Peripheren Nervensystems. Klinische Manifestationen reichen von Sensibilit{\"a}ts-st{\"o}rungen, verminderten Muskeleigenreflexen, sowie fortschreitenden L{\"a}hmungen, bis hin zu Muskelatrophie und bedeuten f{\"u}r die betroffenen Patienten eine starke Einschr{\"a}nkung der Lebensqualit{\"a}t. Anhand fr{\"u}herer Studien wurde Makrophagen, als Teil des angeborenen Immunsystems, eine entscheidende Rolle in der Pathogenese dreier CMT1-Unterformen zugeschrieben. Abgesehen von den morphologischen Manifestationen der demyelinisierenden CMT1-Erkrankungen, wie simultanes Auftreten von Dedifferenzierung, sowie Hypo-, und Demyelinisierung erkrankter Schwann-Zellen, sind pathologische Ver{\"a}nderungen der Dom{\"a}nengliederung der Ranvier'schen Schn{\"u}rringe betroffener Nervenfasern ebenfalls von der Aktivierung pathogener Makrophagen abh{\"a}ngig. Auf der Basis verschiedener ver{\"o}ffentlichter Studien, welche sowohl demyelinisierende Erkrankungen des ZNS, aber auch prim{\"a}r durch axonale Sch{\"a}den gekennzeichnete Erkrankungen des PNS beinhalten, besteht ein m{\"o}glicher r{\"a}umlicher Zusammenhang zwischen Architekturst{\"o}rungen der RS und aktivierten pathogenen Mikrogliazellen bzw. Makrophagen. In dieser Studie konnte, anhand morphologischer Analysen von peripherem Nervengewebe, in Wt-M{\"a}usen erstmals eine unerwartete pr{\"a}ferentielle Lokalisation von Makrophagen im r{\"a}umlichen Umfeld von RS beobachtet werden. Hierbei scheint, trotz des Fehlens einer direkten Zell-Zell-Interaktion zwischen Makrophagen und RS, vor allem im Hinblick auf die ebenfalls im r{\"a}umlichen Umfeld von RS nachweisbare EZM und Fibroblasten, eine funktionelle Relevanz der assoziierten Makrophagen f{\"u}r die Aufrechterhaltung der Dom{\"a}nengliederung bzw. elektrophysiologischen Eigenschaften myelinisierter peripherer Nervenfasern denkbar. Im Gegensatz dazu wurde trotz der signifikanten Zunahme der Makrophagenanzahlen in den drei untersuchten CMT1-Mausmodellen keine erh{\"o}hte r{\"a}umliche Assoziation mit den RS der mutierten Schwann-Zellen beobachtet. Vielmehr konnten anhand des Vergleiches mit wildtypischen Kontrollm{\"a}usen signifikant erniedrigte Assoziationsraten beider Strukturen in den CMT1-Modelltieren festgestellt werden. Folglich scheint die von der Einwanderung und Aktivierung pathogener Makrophagen abh{\"a}ngige St{\"o}rung der Dom{\"a}nengliederung der RS der mutierten Schwann-Zellen, nicht durch eine direkte Interaktion bzw. r{\"a}umliche Assoziation von Makrophagen mit RS ausgel{\"o}st zu werden.}, subject = {Makrophagen}, language = {de} } @phdthesis{Nuth2017, author = {Nuth, Linda}, title = {Niederfrequente, Tiefe Hirnstimulation bei Parkinson-Patienten mit ON-Freezing. Identifikation von Respondern anhand kinematischer Gangparameter}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-150317}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Das ON-Freezing ist ein seltenes, aber generell extrem schwer zu therapierendes Ph{\"a}nomen. Es betrifft Parkinson-Patienten mit und ohne THS. Die derzeitige Literaturlage spiegelt wider, dass es unterschiedliche Strategien gibt, diesem Ph{\"a}nomen zu begegnen. Ein allgemeing{\"u}ltiges Therapiekonzept existiert dabei nicht. F{\"u}r einige Patienten mit STN-THS konnte durch eine Reduktion der Stimulationsfrequenz eine Besserung der Gangst{\"o}rung erzielt werden. Andere profitierten vom Einsatz sogenannter Interleaving-Protokolle mit gleichzeitiger Stimulation der Substantia nigra (Sn). Im Vergleich zu anderen Arbeiten, die keine vorhersagbaren Parameter gefunden oder sich auf Symptome, Auspr{\"a}gung der Subtypen und Erkrankungsdauer oder den Zeitpunkt der Erkrankung konzentriert haben, verfolgten wir die Absicht, die Effekte der LF-Stim des STN auf Parkinson-Patienten mit Gangst{\"o}rung und Freezing-Ph{\"a}nomen zu untersuchen und herauszufinden, ob man Gangparameter identifizieren kann, an Hand derer man das Ansprechen auf eine LF-Stim vorhersagen kann. Unter der Einschr{\"a}nkung, dass die Zahl der Probanden unserer Studie sehr gering ist, haben wir herausgefunden, dass diejenigen Patienten besser auf eine LF-Stim ansprechen, die unter der Standard-HF-Stim eine signifikant h{\"o}here Ganggeschwindigkeit und eine gr{\"o}ßere Schrittl{\"a}nge aufzeigen und nur ein intermittierendes Freezing haben. Dar{\"u}ber hinaus zeigte sich ein besseres Ansprechen der LF-Stim bei Parkinson-Patienten mit akinetisch-rigidem Parkinson-Ph{\"a}notyp. Unsere Ergebnisse best{\"a}tigen die Annahme, dass sich L-Dopa additiv zur Stimulationstherapie bei manchen Parkinson-Patienten zus{\"a}tzlich positiv auf die motorischen PD-Symptome auswirken kann. In Bezug auf die Verbesserung der Gangparameter zeigte sich in unseren Ergebnissen allerdings, dass L-Dopa eher eine untergeordnete Rolle spielt. Aufgrund der niedrigen Anzahl von Respondern in unserer Studie l{\"a}sst sich daher sicherlich noch keine allgemeing{\"u}ltige Regel ableiten. Es bedarf letztlich weiterer Studien mit gr{\"o}ßeren Untersuchungszahlen, um unsere Thesen zu st{\"u}tzen und abzusichern. In jedem Fall wird aber das ON-Freezing auch weiterhin eine therapeutische Herausforderung bleiben.}, subject = {Parkinson}, language = {de} } @phdthesis{Musacchio2017, author = {Musacchio, Thomas Giuseppe}, title = {ALS und MMN mimics bei Patienten mit BSCL2 Mutationen - eine Erweiterung des klinischen Spektrums der heredit{\"a}ren Spinalparalyse SPG17}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154224}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Die heredit{\"a}re Spinalparalyse SPG17 ist eine autosomal-dominant vererbte Motoneuronerkrankung, welche durch Mutationen im BSCL2 (Seipin) Gen verursacht wird. Klassischerweise {\"a}ußert sich die Krankheit durch eine spastische Paraparese der Beine und Amyotrophie der H{\"a}nde (Silver-Syndrom) oder eine vorwiegend periphere (senso-)motorische Neuropathie. F{\"u}r die vorliegende Arbeit wurden insgesamt sieben Patienten aus vier verschiedenen Familien, bei denen heterozygote Mutationen im BSCL2 Gen nachgewiesen werden konnten, klinisch sowie elektrophysiologisch und molekulargenetisch untersucht. Es gelang hierbei zwei bisher unbekannte ph{\"a}notypische Auspr{\"a}gungen zu beschreiben, welche die Symptomatik und den Verlauf einer Multifokalen Motorischen Neuropathie (MMN) bzw. einer Amyotrophen Lateralsklerose (ALS) imitieren und hiervon nur durch den genetischen Befund zu unterscheiden sind. Anhand dieser Ergebnisse erfolgte dann nach extensiver Literaturrecherche eine Zusammenfassung aller bisher publizierten F{\"a}lle der SPG17 und eine Einordnung der hier erstbeschriebenen Ph{\"a}notypen in einen Vorschlag zur Erweiterung des bisher verwendeten Klassifikationssystems von BSCL 2 Mutationen.}, subject = {Heredit{\"a}re spastische Spinalparalyse}, language = {de} } @phdthesis{Magg2017, author = {Magg, Barbara}, title = {Etablierung und Validierung des W{\"u}rzburger Fabry Schmerzfragebogens f{\"u}r erwachsene Patienten}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154928}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {Der M. Fabry ist eine X-chromosomal vererbte lysosomale Speicherkankheit, die zu einem Multiorganversagen f{\"u}hrt. Ein fr{\"u}hes Symptom sind Schmerzen, die meist schon in der fr{\"u}hen Kindheit einsetzen. Das Besondere an diesen Schmerzen ist, dass sie sich sehr unterschiedlich u.a. bez{\"u}glich ihres Verlaufs, ihrer Dauer und ihrer Lokalisation pr{\"a}sentieren k{\"o}nnen. Diese Fabry-assoziierten Schmerzen sind meist brennend und akral betont, k{\"o}nnen aber auch andere Qualit{\"a}ten aufweisen und sehr variable K{\"o}rperpartien erfassen, was ihre diagnostische Einordnung erschwert. Bisher verf{\"u}gbare validierte Schmerzfrageb{\"o}gen k{\"o}nnen das Spektrum der Fabry-assoziierten Schmerzen nicht erfassen. In dieser Arbeit wird der erste M. Fabry spezifische Schmerzfragebogen f{\"u}r Erwachsene in zwei Versionen pr{\"a}sentiert. Die erste Version ist eine Interview Version (iFPQ), bei der der Arzt in einem pers{\"o}nlichen Gespr{\"a}ch mit dem Patienten mit Hilfe des Fragbogens alle wesentlichen Aspekte der Fabry-assoziierten Schmerzen erfragen kann. Die zweite Version kann eigenst{\"a}ndig vom Patienten ausgef{\"u}llt werden (saFPQ). Zur Etablierung der Frageb{\"o}gen wurde in einer Pilotstudie zun{\"a}chst mit 20 Patienten eine erste Version des iFPQ entwickelt. Nach Verbesserungen wurde die Interview Version mit Hilfe von 42 Studienteilnehmern validiert, die jeweils an einem Erst- und Zweitgespr{\"a}ch im Abstand von zwei Wochen teilnahmen. Hierbei wurde auch der NPSI als vergleichender Fragebogen ausgef{\"u}llt. Bei der ersten statistischen Analyse ergab sich eine gute Reliabilit{\"a}t mit ICC-Werten von 0,896 bis 0,999 aber eine unzureichende Validit{\"a}t zwischen iFPQ und NPSI mit K-Werten von 0,257 bis 0,566. Nach der ersten statistischen Analyse wurde der Fragebogen erneut {\"u}berarbeitet und mit Hilfe von 20 Studienteilnehmern erneut validiert. Anschließend zeigte sich eine gute Validit{\"a}t mit K-Werten von 0,634 bis 1,0. Der saFPQ wurde im Anschluss an die finale iFPQ Version entwickelt. Bei 40 Patienten erfolgte ein Erstgespr{\"a}ch, bei dem die Patienten die valide Version des iFPQ ausf{\"u}llten. Im Abstand von zwei Wochen schickten die Patienten dann die selbst{\"a}ndig ausgef{\"u}llte Version des saFPQ postalisch zur{\"u}ck. Die postalische Version erweitert die Flexibilit{\"a}t dieses Fragebogens. Sie ist f{\"u}r den klinischen Alltag sehr relevant. Die Resonanz der Patienten hinsichtlich beider Frageb{\"o}gen war sehr positiv. Perspektivisch ist die Entwicklung einer englischen Version geplant.}, subject = {M.Fabry}, language = {de} } @article{LueningschroerBinottiDombertetal.2017, author = {L{\"u}ningschr{\"o}r, Patrick and Binotti, Beyenech and Dombert, Benjamin and Heimann, Peter and Perez-Lara, Angel and Slotta, Carsten and Thau-Habermann, Nadine and von Collenberg, Cora R. and Karl, Franziska and Damme, Markus and Horowitz, Arie and Maystadt, Isabelle and F{\"u}chtbauer, Annette and F{\"u}chtbauer, Ernst-Martin and Jablonka, Sibylle and Blum, Robert and {\"U}{\c{c}}eyler, Nurcan and Petri, Susanne and Kaltschmidt, Barbara and Jahn, Reinhard and Kaltschmidt, Christian and Sendtner, Michael}, title = {Plekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease}, series = {Nature Communications}, volume = {8}, journal = {Nature Communications}, number = {678}, doi = {10.1038/s41467-017-00689-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170048}, year = {2017}, abstract = {Autophagy-mediated degradation of synaptic components maintains synaptic homeostasis but also constitutes a mechanism of neurodegeneration. It is unclear how autophagy of synaptic vesicles and components of presynaptic active zones is regulated. Here, we show that Pleckstrin homology containing family member 5 (Plekhg5) modulates autophagy of synaptic vesicles in axon terminals of motoneurons via its function as a guanine exchange factor for Rab26, a small GTPase that specifically directs synaptic vesicles to preautophagosomal structures. Plekhg5 gene inactivation in mice results in a late-onset motoneuron disease, characterized by degeneration of axon terminals. Plekhg5-depleted cultured motoneurons show defective axon growth and impaired autophagy of synaptic vesicles, which can be rescued by constitutively active Rab26. These findings define a mechanism for regulating autophagy in neurons that specifically targets synaptic vesicles. Disruption of this mechanism may contribute to the pathophysiology of several forms of motoneuron disease.}, language = {en} } @article{KraftSchuhmannGarzetal.2017, author = {Kraft, Peter and Schuhmann, Michael K. and Garz, Cornelia and Jandke, Solveig and Urlaub, Daniela and Mencl, Stine and Zernecke, Alma and Heinze, Hans-Jochen and Carare, Roxana O. and Kleinschnitz, Christoph and Schreiber, Stefanie}, title = {Hypercholesterolemia induced cerebral small vessel disease}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {8}, doi = {10.1371/journal.pone.0182822}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170493}, pages = {e0182822}, year = {2017}, abstract = {Background While hypercholesterolemia plays a causative role for the development of ischemic stroke in large vessels, its significance for cerebral small vessel disease (CSVD) remains unclear. We thus aimed to understand the detailed relationship between hypercholesterolemia and CSVD using the well described Ldlr\(^{-/-}\) mouse model. Methods We used Ldlr\(^{-/-}\) mice (n = 16) and wild-type (WT) mice (n = 15) at the age of 6 and 12 months. Ldlr\(^{-/-}\) mice develop high plasma cholesterol levels following a high fat diet. We analyzed cerebral capillaries and arterioles for intravascular erythrocyte accumulations, thrombotic vessel occlusions, blood-brain barrier (BBB) dysfunction and microbleeds. Results We found a significant increase in the number of erythrocyte stases in 6 months old Ldlr\(^{-/-}\) mice compared to all other groups (P < 0.05). Ldlr\(^{-/-}\) animals aged 12 months showed the highest number of thrombotic occlusions while in WT animals hardly any occlusions could be observed (P < 0.001). Compared to WT mice, Ldlr\(^{-/-}\) mice did not display significant gray matter BBB breakdown. Microhemorrhages were observed in one Ldlr\(^{-/-}\) mouse that was 6 months old. Results did not differ when considering subcortical and cortical regions. Conclusions In Ldlr\(^{-/-}\) mice, hypercholesterolemia is related to a thrombotic CSVD phenotype, which is different from hypertension-related CSVD that associates with a hemorrhagic CSVD phenotype. Our data demonstrate a relationship between hypercholesterolemia and the development of CSVD. Ldlr\(^{-/-}\) mice appear to be an adequate animal model for research into CSVD.}, language = {en} } @article{KraftFleischerWiedmannetal.2017, author = {Kraft, Peter and Fleischer, Anna and Wiedmann, Silke and R{\"u}cker, Viktoria and Mackenrodt, Daniel and Morbach, Caroline and Malzahn, Uwe and Kleinschnitz, Christoph and St{\"o}rk, Stefan and Heuschmann, Peter U.}, title = {Feasibility and diagnostic accuracy of point-of-care handheld echocardiography in acute ischemic stroke patients - a pilot study}, series = {BMC Neurology}, volume = {17}, journal = {BMC Neurology}, number = {159}, doi = {10.1186/s12883-017-0937-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158081}, year = {2017}, abstract = {Background: Standard echocardiography (SE) is an essential part of the routine diagnostic work-up after ischemic stroke (IS) and also serves for research purposes. However, access to SE is often limited. We aimed to assess feasibility and accuracy of point-of-care (POC) echocardiography in a stroke unit (SU) setting. Methods: IS patients were recruited on the SU of the University Hospital W{\"u}rzburg, Germany. Two SU team members were trained in POC echocardiography for a three-month period to assess a set of predefined cardiac parameters including left ventricular ejection fraction (LVEF). Diagnostic agreement was assessed by comparing POC with SE executed by an expert sonographer, and intraclass correlation coefficient (ICC) or kappa (κ) with 95\% confidence intervals (95\% CI) were calculated. Results: In the 78 patients receiving both POC and SE agreement for cardiac parameters was good, with ICC varying from 0.82 (95\% CI 0.71-0.89) to 0.93 (95\% CI 0.87-0.96), and κ from 0.39 (-95\% CI 0.14-0.92) to 0.79 (95\% CI 0.67-0.91). Detection of systolic dysfunction with POC echocardiography compared to SE was very good, with an area under the curve of 0.99 (0.96-1.00). Interrater agreement for LVEF measured by POC echocardiography was good with κ 0.63 (95\% CI 0.40-0.85). Conclusions: POC echocardiography in a SU setting is feasible enabling reliable quantification of LVEF and preliminary assessment of selected cardiac parameters that might be used for research purposes. Its potential clinical utility in triaging stroke patients who should undergo or do not necessarily require SE needs to be investigated in larger prospective diagnostic studies.}, language = {en} } @article{KarlGriesshammerUeceyleretal.2017, author = {Karl, Franziska and Grießhammer, Anne and {\"U}{\c{c}}eyler, Nurcan and Sommer, Claudia}, title = {Differential Impact of miR-21 on Pain and Associated Affective and Cognitive Behavior after Spared Nerve Injury in B7-H1 ko Mouse}, series = {Frontiers in Molecular Neuroscience}, volume = {10}, journal = {Frontiers in Molecular Neuroscience}, number = {219}, doi = {10.3389/fnmol.2017.00219}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170722}, year = {2017}, abstract = {MicroRNAs (miRNAs) are increasingly recognized as regulators of immune and neuronal gene expression and are potential master switches in neuropathic pain pathophysiology. miR-21 is a promising candidate that may link the immune and the pain system. To investigate the pathophysiological role of miR-21 in neuropathic pain, we assessed mice deficient of B7 homolog 1 (B7-H1), a major inhibitor of inflammatory responses. In previous studies, an upregulation of miR-21 had been shown in mouse lymphocytes. Young (8 weeks), middle-aged (6 months), and old (12 months) B7-H1 ko mice and wildtype littermates (WT) received a spared nerve injury (SNI). We assessed thermal withdrawal latencies and mechanical withdrawal thresholds. Further, we performed tests for anxiety-like and cognitive behavior. Quantitative real time PCR was used to determine miR-21 relative expression in peripheral nerves, and dorsal root ganglia (DRG) at distinct time points after SNI. We found mechanical hyposensitivity with increasing age of na{\"i}ve B7-H1 ko mice. Young and middle-aged B7-H1 ko mice were more sensitive to mechanical stimuli compared to WT mice (young: p < 0.01, middle-aged: p < 0.05). Both genotypes developed mechanical and heat hypersensitivity (p < 0.05) after SNI, without intergroup differences. No relevant differences were found after SNI in three tests for anxiety like behavior in B7-H1 ko and WT mice. Also, SNI had no effect on cognition. B7-H1 ko and WT mice showed a higher miR-21 expression (p < 0.05) and invasion of macrophages and T cells in the injured nerve 7 days after SNI without intergroup differences. Our study reveals that increased miR-21 expression in peripheral nerves after SNI is associated with reduced mechanical and heat withdrawal thresholds. These results point to a role of miR-21 in the pathophysiology of neuropathic pain, while affective behavior and cognition seem to be spared. Contrary to expectations, B7-H1 ko mice did not show higher miR-21 expression than WT mice, thus, a B7-H1 knockout may be of limited relevance for the study of miR-21 related pain.}, language = {en} } @phdthesis{Karl2017, author = {Karl, Franziska}, title = {The role of miR-21 in the pathophysiology of neuropathic pain using the model of B7-H1 knockout mice}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-156004}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {The impact of microRNA (miRNA) as key players in the regulation of immune and neuronal gene expression and their role as master switches in the pathophysiology of neuropathic pain is increasingly recognized. miR-21 is a promising candidate that could be linked to the immune and the nociceptive system. To further investigate the pathophysiological role of miR-21 in neuropathic pain, we assesed mice deficient of B7 homolog 1 (B7-H1 ko), a protein with suppressive effect on inflammatory responses. B7-H1 ko mice and wildtype littermates (WT) of three different age-groups, young (8 weeks), middle-aged (6 months), and old (12 months) received a spared nerve injury (SNI). Thermal withdrawal latencies and mechanical withdrawal thresholds were determined. Further, we investigated anxiety-, depression-like and cognitive behavior. Quantitative real time PCR was used to determine miR-21 relative expression in peripheral nerves, dorsal root ganglia and white blood cells (WBC) at distinct time points after SNI. Na{\"i}ve B7-H1 ko mice showed mechanical hyposensitivity with increasing age. Young and middle-aged B7-H1 ko mice displayed lower mechanical withdrawal thresholds compared to WT mice. From day three after SNI both genotypes developed mechanical and heat hypersensitivity, without intergroup differences. As supported by the results of three behavioral tests, no relevant differences were found for anxiety-like behavior after SNI in B7-H1 ko and WT mice. Also, there was no indication of depression-like behavior after SNI or any effect of SNI on cognition in both genotypes. The injured nerves of B7-H1 ko and WT mice showed higher miR-21 expression and invasion of macrophages and T cells 7 days after SNI without intergroup differences. Perineurial miR-21 inhibitor injection reversed SNI-induced mechanical and heat hypersensitivity in old B7-H1 ko and WT mice. This study reveals that reduced mechanical thresholds and heat withdrawal latencies are associated with miR-21 induction in the tibial and common peroneal nerve after SNI, which can be reversed by perineurial injection of a miR-21 inhibitor. Contrary to expectations, miR-21 expression levels were not higher in B7-H1 ko compared to WT mice. Thus, the B7-H1 ko mouse may be of minor importance for the study of miR-21 related pain. However, these results spot the contribution of miR-21 in the pathophysiology of neuropathic pain and emphasize the crucial role of miRNA in the regulation of neuronal and immune circuits that contribute to neuropathic pain.}, subject = {neuropathic pain}, language = {en} } @article{HoppNolteStetteretal.2017, author = {Hopp, Sarah and Nolte, Marc W. and Stetter, Christian and Kleinschnitz, Christoph and Sir{\´e}n, Anna-Leena and Albert-Weissenberger, Christiane}, title = {Alleviation of secondary brain injury, posttraumatic inflammation, and brain edema formation by inhibition of factor XIIa}, series = {Journal of Neuroinflammation}, volume = {14}, journal = {Journal of Neuroinflammation}, number = {39}, doi = {10.1186/s12974-017-0815-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157490}, year = {2017}, abstract = {Background: Traumatic brain injury (TBI) is a devastating neurological condition and a frequent cause of permanent disability. Posttraumatic inflammation and brain edema formation, two pathological key events contributing to secondary brain injury, are mediated by the contact-kinin system. Activation of this pathway in the plasma is triggered by activated factor XII. Hence, we set out to study in detail the influence of activated factor XII on the abovementioned pathophysiological features of TBI. Methods: Using a cortical cryogenic lesion model in mice, we investigated the impact of genetic deficiency of factor XII and inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused Infestin-4 on the release of bradykinin, the brain lesion size, and contact-kinin system-dependent pathological events. We determined protein levels of bradykinin, intracellular adhesion molecule-1, CC-chemokine ligand 2, and interleukin-1β by enzyme-linked immunosorbent assays and mRNA levels of genes related to inflammation by quantitative real-time PCR. Brain lesion size was determined by tetrazolium chloride staining. Furthermore, protein levels of the tight junction protein occludin, integrity of the blood-brain barrier, and brain water content were assessed by Western blot analysis, extravasated Evans Blue dye, and the wet weight-dry weight method, respectively. Infiltration of neutrophils and microglia/activated macrophages into the injured brain lesions was quantified by immunohistological stainings. Results: We show that both genetic deficiency of factor XII and inhibition of activated factor XII in mice diminish brain injury-induced bradykinin release by the contact-kinin system and minimize brain lesion size, blood-brain barrier leakage, brain edema formation, and inflammation in our brain injury model. Conclusions: Stimulation of bradykinin release by activated factor XII probably plays a prominent role in expanding secondary brain damage by promoting brain edema formation and inflammation. Pharmacological blocking of activated factor XII could be a useful therapeutic principle in the treatment of TBI-associated pathologic processes by alleviating posttraumatic inflammation and brain edema formation.}, language = {en} } @article{HofmannKarlSommeretal.2017, author = {Hofmann, Lukas and Karl, Franziska and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan}, title = {Affective and cognitive behavior in the alpha-galactosidase A deficient mouse model of Fabry disease}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0180601}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170745}, pages = {e0180601}, year = {2017}, abstract = {Fabry disease is an X-linked inherited lysosomal storage disorder with intracellular accumulation of globotriaosylceramide (Gb3) due to α-galactosidase A (α-Gal A) deficiency. Fabry patients frequently report of anxiety, depression, and impaired cognitive function. We characterized affective and cognitive phenotype of male mice with α-Gal A deficiency (Fabry KO) and compared results with those of age-matched male wildtype (WT) littermates. Young (3 months) and old (≥ 18 months) mice were tested in the na{\"i}ve state and after i.pl. injection of complete Freund`s adjuvant (CFA) as an inflammatory pain model. We used the elevated plus maze (EPM), the light-dark box (LDB) and the open field test (OF) to investigate anxiety-like behavior. The forced swim test (FST) and Morris water maze (MWM) were applied to assess depressive-like and learning behavior. The EPM test revealed no intergroup difference for anxiety-like behavior in na{\"i}ve young and old Fabry KO mice compared to WT littermates, except for longer time spent in open arms of the EPM for young WT mice compared to young Fabry KO mice (p<0.05). After CFA injection, young Fabry KO mice showed increased anxiety-like behavior compared to young WT littermates (p<0.05) and na{\"i}ve young Fabry KO mice (p<0.05) in the EPM as reflected by shorter time spent in EPM open arms. There were no relevant differences in the LDB and the OF test, except for longer time spent in the center zone of the OF by young WT mice compared to young Fabry KO mice (p<0.05). Complementary to this, depression-like and learning behavior were not different between genotypes and age-groups, except for the expectedly lower memory performance in older age-groups compared to young mice. Our results indicate that genetic influences on affective and cognitive symptoms in FD may be of subordinate relevance, drawing attention to potential influences of environmental and epigenetic factors.}, language = {en} } @article{GruenewaldLangeWerneretal.2017, author = {Gr{\"u}newald, Benedikt and Lange, Maren D and Werner, Christian and O'Leary, Aet and Weishaupt, Andreas and Popp, Sandy and Pearce, David A and Wiendl, Heinz and Reif, Andreas and Pape, Hans C and Toyka, Klaus V and Sommer, Claudia and Geis, Christian}, title = {Defective synaptic transmission causes disease signs in a mouse model of juvenile neuronal ceroid lipofuscinosis}, series = {eLife}, volume = {6}, journal = {eLife}, number = {e28685}, doi = {10.7554/eLife.28685}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170004}, year = {2017}, abstract = {Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3\(^{Δex1-6}\)) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition.}, language = {en} } @article{BrumbergKuestersAlMomanietal.2017, author = {Brumberg, Joachim and K{\"u}sters, Sebastian and Al-Momani, Ehab and Marotta, Giorgio and Cosgrove, Kelly P. and van Dyck, Christopher H. and Herrmann, Ken and Homola, Gy{\"o}rgy A. and Pezzoli, Gianni and Buck, Andreas K. and Volkmann, Jens and Samnick, Samuel and Isaias, Ioannis U.}, title = {Cholinergic activity and levodopa-induced dyskinesia: a multitracer molecular imaging study}, series = {Annals of Clinical and Translational Neurology}, volume = {4}, journal = {Annals of Clinical and Translational Neurology}, number = {9}, doi = {10.1002/acn3.438}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170406}, pages = {632-639}, year = {2017}, abstract = {Objective: To investigate the association between levodopa-induced dyskinesias and striatal cholinergic activity in patients with Parkinson's disease. Methods: This study included 13 Parkinson's disease patients with peak-of-dose levodopa-induced dyskinesias, 12 nondyskinetic patients, and 12 healthy controls. Participants underwent 5-[\(^{123}\)I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine single-photon emission computed tomography, a marker of nicotinic acetylcholine receptors, [\(^{123}\)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane single-photon emission computed tomography, to measure dopamine reuptake transporter density and 2-[\(^{18}\)F]fluoro-2-deoxyglucose positron emission tomography to assess regional cerebral metabolic activity. Striatal binding potentials, uptake values at basal ganglia structures, and correlations with clinical variables were analyzed. Results: Density of nicotinic acetylcholine receptors in the caudate nucleus of dyskinetic subjects was similar to that of healthy controls and significantly higher to that of nondyskinetic patients, in particular, contralaterally to the clinically most affected side. Interpretation: Our findings support the hypothesis that the expression of dyskinesia may be related to cholinergic neuronal excitability in a dopaminergic-depleted striatum. Cholinergic signaling would play a role in maintaining striatal dopaminergic responsiveness, possibly defining disease phenotype and progression.}, language = {en} } @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} } @article{BailNotzRovitusoetal.2017, author = {Bail, Kathrin and Notz, Quirin and Rovituso, Damiano M. and Schampel, Andrea and Wunsch, Marie and Koeniger, Tobias and Schropp, Verena and Bharti, Richa and Scholz, Claus-Juergen and Foerstner, Konrad U. and Kleinschnitz, Christoph and Kuerten, Stefanie}, title = {Differential effects of FTY720 on the B cell compartment in a mouse model of multiple sclerosis.}, series = {Journal of Neuroinflammation}, volume = {14}, journal = {Journal of Neuroinflammation}, number = {148}, doi = {10.1186/s12974-017-0924-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157869}, year = {2017}, abstract = {Background: MP4-induced experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS), which enables targeted research on B cells, currently much discussed protagonists in MS pathogenesis. Here, we used this model to study the impact of the S1P1 receptor modulator FTY720 (fingolimod) on the autoreactive B cell and antibody response both in the periphery and the central nervous system (CNS). Methods: MP4-immunized mice were treated orally with FTY720 for 30 days at the peak of disease or 50 days after EAE onset. The subsequent disease course was monitored and the MP4-specific B cell/antibody response was measured by ELISPOT and ELISA. RNA sequencing was performed to determine any effects on B cell-relevant gene expression. S1P\(_{1}\) receptor expression by peripheral T and B cells, B cell subset distribution in the spleen and B cell infiltration into the CNS were studied by flow cytometry. The formation of B cell aggregates and of tertiary lymphoid organs (TLOs) was evaluated by histology and immunohistochemistry. Potential direct effects of FTY720 on B cell aggregation were studied in vitro. Results: FTY720 significantly attenuated clinical EAE when treatment was initiated at the peak of EAE. While there was a significant reduction in the number of T cells in the blood after FTY720 treatment, B cells were only slightly diminished. Yet, there was evidence for the modulation of B cell receptor-mediated signaling upon FTY720 treatment. In addition, we detected a significant increase in the percentage of B220\(^{+}\) B cells in the spleen both in acute and chronic EAE. Whereas acute treatment completely abrogated B cell aggregate formation in the CNS, the numbers of infiltrating B cells and plasma cells were comparable between vehicle- and FTY720-treated mice. In addition, there was no effect on already developed aggregates in chronic EAE. In vitro B cell aggregation assays suggested the absence of a direct effect of FTY720 on B cell aggregation. However, FTY720 impacted the evolution of B cell aggregates into TLOs. Conclusions: The data suggest differential effects of FTY720 on the B cell compartment in MP4-induced EAE.}, language = {en} }