@article{UllrichWeberPostetal.2018, author = {Ullrich, M and Weber, M and Post, A M and Popp, S and Grein, J and Zechner, M and Gonz{\´a}lez, H Guerrero and Kreis, A and Schmitt, A G and {\"U}ҫeyler, N and Lesch, K-P and Schuh, K}, title = {OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency}, series = {Molecular Psychiatry}, volume = {23}, journal = {Molecular Psychiatry}, doi = {10.1038/mp.2016.232}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232096}, pages = {444-458}, year = {2018}, abstract = {Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2\% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD.}, language = {en} } @phdthesis{Weisensee2007, author = {Weisensee, Tim Andr{\´e}}, title = {Nutzen von Stroke-Unit-Behandlung f{\"u}r die geriatrische Rehabilitationsprognose}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-24937}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2007}, abstract = {Die vorliegende Arbeit {\"u}berpr{\"u}ft an einem nach Alter, Geschlecht, Barthel-Index und Mini-Mental-State-Test gematchten geriatrischen Patientenkollektiv mit erstmaligem Schlaganfall die Wirksamkeit einer vorausgegangenen Akutbehandlung an einer Stroke Unit (n=59) gegen{\"u}ber einer allgemeinen (internistischen oder neurologischen) station{\"a}ren Akutbehandlung (n=59) f{\"u}r die Prognose im Laufe einer nachfolgenden geriatrischen Rehabilitationsbehandlung. Hintergrund dieser Frage ist der erh{\"o}hte {\"o}konomische Druck im Gesundheitswesen, der eine Effizienzpr{\"u}fung einer personell, technisch und logistisch aufw{\"a}ndigeren und damit teureren Behandlung auf einer Spezialstation verlangt. Bei Anwendung zahlreicher funktioneller Skalen und Erhebung einiger sozio{\"o}konomischer Faktoren zeigte sich auf Signifikanzniveau, dass die auf Stroke Unit Vorbehandelten bei Aufnahme in die Rehabilitation motorisch schwerer beeintr{\"a}chtigt waren (timed up and go-Test p=0,044, Lachs-Test p=0,34) und sich dann ausgepr{\"a}gter (Transferleistung p=0,024) auf ein bei Rehabilitationsende schließlich vergleichbares Leistungsniveau verbesserten. Die urspr{\"u}nglich geplante Langzeiteffizienzbetrachtung im Gruppenvergleich scheiterte an Datenschutzbedenken. Gesundheits{\"o}konomisch relevant ist, dass die Vorverweildauer im Akutkrankenhaus bei Stroke Unit-Patienten sechs Tage k{\"u}rzer war, die Rehabilitationsdauer allerdings vier Tage l{\"a}nger. Weitergehende Kostenbetrachtungen scheiterten am Unwillen zur Leistungsoffenlegung verschiedener Beteiligter im Gesundheitssystem. Eine plausible Erkl{\"a}rung f{\"u}r diese positive motorische Leistungsweiterentwicklung nach Stroke Unit-Vorbehandlung kann in einer fr{\"u}hzeitigeren und effektiveren Anstrengung durch Krankengymnastik, Ergotherapie, Logop{\"a}die, aktivierende Pflege, „enriched environment" gesucht werden, die sich positiv auf die Plastizit{\"a}t im Gehirn als wesentliche Bedingung zur Funktionswiedergewinnung auswirken k{\"o}nnte, was aber noch umstritten ist und Ziel weiterer Untersuchungen sein muss.}, subject = {Geriatrie}, language = {de} } @article{HopfnerSchormairKnaufetal.2011, author = {Hopfner, Franziska and Schormair, Barbara and Knauf, Franziska and Berthele, Achim and T{\"o}lle, Thomas R. and Baron, Ralf and Maier, Christoph and Treede, Rolf-Detlef and Binder, Andreas and Sommer, Claudia and Maih{\"o}fner, Christian and Kunz, Wolfram and Zimprich, Friedrich and Heemann, Uwe and Pfeufer, Arne and N{\"a}bauer, Michael and K{\"a}{\"a}b, Stefan and Nowak, Barbara and Gieger, Christian and Lichtner, Peter and Trenkwalder, Claudia and Oexle, Konrad and Winkelmann, Juliane}, title = {Novel SCARB2 mutation in Action Myoclonus-Renal Failure syndrome and evaluation of SCARB2 mutations in isolated AMRF features}, series = {BMC Neurology}, volume = {11}, journal = {BMC Neurology}, number = {134}, doi = {10.1186/1471-2377-11-134}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141209}, pages = {1-8}, year = {2011}, abstract = {Background: Action myoclonus-renal failure syndrome is a hereditary form of progressive myoclonus epilepsy associated with renal failure. It is considered to be an autosomal-recessive disease related to loss-of-function mutations in SCARB2. We studied a German AMRF family, additionally showing signs of demyelinating polyneuropathy and dilated cardiomyopathy. To test the hypothesis whether isolated appearance of individual AMRF syndrome features could be related to heterozygote SCARB2 mutations, we screened for SCARB2 mutations in unrelated patients showing isolated AMRF features. Methods: In the AMRF family all exons of SCARB2 were analyzed by Sanger sequencing. The mutation screening of unrelated patients with isolated AMRF features affected by either epilepsy (n = 103, progressive myoclonus epilepsy or generalized epilepsy), demyelinating polyneuropathy (n = 103), renal failure (n = 192) or dilated cardiomyopathy (n = 85) was performed as high resolution melting curve analysis of the SCARB2 exons. Results: A novel homozygous 1 bp deletion (c.111delC) in SCARB2 was found by sequencing three affected homozygous siblings of the affected family. A heterozygous sister showed generalized seizures and reduction of nerve conduction velocity in her legs. No mutations were found in the epilepsy, renal failure or dilated cardiomyopathy samples. In the polyneuropathy sample two individuals with demyelinating disease were found to be carriers of a SCARB2 frameshift mutation (c.666delCCTTA). Conclusions: Our findings indicate that demyelinating polyneuropathy and dilated cardiomyopathy are part of the action myoclonus-renal failure syndrome. Moreover, they raise the possibility that in rare cases heterozygous SCARB2 mutations may be associated with PNP features.}, language = {en} } @article{SilwedelSpeerHaarmannetal.2018, author = {Silwedel, Christine and Speer, Christian P. and Haarmann, Axel and Fehrholz, Markus and Claus, Heike and Buttmann, Mathias and Glaser, Kirsten}, title = {Novel insights into neuroinflammation: bacterial lipopolysaccharide, tumor necrosis factor α, and Ureaplasma species differentially modulate atypical chemokine receptor 3 responses in human brain microvascular endothelial cells}, series = {Journal of Neuroinflammation}, volume = {15}, journal = {Journal of Neuroinflammation}, number = {156}, doi = {10.1186/s12974-018-1170-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175952}, year = {2018}, abstract = {Background: Atypical chemokine receptor 3 (ACKR3, synonym CXCR7) is increasingly considered relevant in neuroinflammatory conditions, in which its upregulation contributes to compromised endothelial barrier function and may ultimately allow inflammatory brain injury. While an impact of ACKR3 has been recognized in several neurological autoimmune diseases, neuroinflammation may also result from infectious agents, including Ureaplasma species (spp.). Although commonly regarded as commensals of the adult urogenital tract, Ureaplasma spp. may cause invasive infections in immunocompromised adults as well as in neonates and appear to be relevant pathogens in neonatal meningitis. Nonetheless, clinical and in vitro data on Ureaplasma-induced inflammation are scarce. Methods: We established a cell culture model of Ureaplasma meningitis, aiming to analyze ACKR3 variances as a possible pathomechanism in Ureaplasma-associated neuroinflammation. Non-immortalized human brain microvascular endothelial cells (HBMEC) were exposed to bacterial lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α), and native as well as LPS-primed HBMEC were cultured with Ureaplasma urealyticum serovar 8 (Uu8) and U. parvum serovar 3 (Up3). ACKR3 responses were assessed via qRT-PCR, RNA sequencing, flow cytometry, and immunocytochemistry. Results: LPS, TNF-α, and Ureaplasma spp. influenced ACKR3 expression in HBMEC. LPS and TNF-α significantly induced ACKR3 mRNA expression (p < 0.001, vs. control), whereas Ureaplasma spp. enhanced ACKR3 protein expression in HBMEC (p < 0.01, vs. broth control). Co-stimulation with LPS and either Ureaplasma isolate intensified ACKR3 responses (p < 0.05, vs. LPS). Furthermore, stimulation wielded a differential influence on the receptor's ligands. Conclusions: We introduce an in vitro model of Ureaplasma meningitis. We are able to demonstrate a pro-inflammatory capacity of Ureaplasma spp. in native and, even more so, in LPS-primed HBMEC, underlining their clinical relevance particularly in a setting of co-infection. Furthermore, our data may indicate a novel role for ACKR3, with an impact not limited to auto-inflammatory diseases, but extending to infection-related neuroinflammation as well. AKCR3-induced blood-brain barrier breakdown might constitute a potential common pathomechanism.}, language = {en} } @article{PiroEckesKasaragodetal.2021, author = {Piro, Inken and Eckes, Anna-Lena and Kasaragod, Vikram Babu and Sommer, Claudia and Harvey, Robert J. and Schaefer, Natascha and Villmann, Carmen}, title = {Novel Functional Properties of Missense Mutations in the Glycine Receptor β Subunit in Startle Disease}, series = {Frontiers in Molecular Neuroscience}, volume = {14}, journal = {Frontiers in Molecular Neuroscience}, issn = {1662-5099}, doi = {10.3389/fnmol.2021.745275}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246676}, year = {2021}, abstract = {Startle disease is a rare disorder associated with mutations in GLRA1 and GLRB, encoding glycine receptor (GlyR) α1 and β subunits, which enable fast synaptic inhibitory transmission in the spinal cord and brainstem. The GlyR β subunit is important for synaptic localization via interactions with gephyrin and contributes to agonist binding and ion channel conductance. Here, we have studied three GLRB missense mutations, Y252S, S321F, and A455P, identified in startle disease patients. For Y252S in M1 a disrupted stacking interaction with surrounding aromatic residues in M3 and M4 is suggested which is accompanied by an increased EC\(_{50}\) value. By contrast, S321F in M3 might stabilize stacking interactions with aromatic residues in M1 and M4. No significant differences in glycine potency or efficacy were observed for S321F. The A455P variant was not predicted to impact on subunit folding but surprisingly displayed increased maximal currents which were not accompanied by enhanced surface expression, suggesting that A455P is a gain-of-function mutation. All three GlyR β variants are trafficked effectively with the α1 subunit through intracellular compartments and inserted into the cellular membrane. In vivo, the GlyR β subunit is transported together with α1 and the scaffolding protein gephyrin to synaptic sites. The interaction of these proteins was studied using eGFP-gephyrin, forming cytosolic aggregates in non-neuronal cells. eGFP-gephyrin and β subunit co-expression resulted in the recruitment of both wild-type and mutant GlyR β subunits to gephyrin aggregates. However, a significantly lower number of GlyR β aggregates was observed for Y252S, while for mutants S321F and A455P, the area and the perimeter of GlyR β subunit aggregates was increased in comparison to wild-type β. Transfection of hippocampal neurons confirmed differences in GlyR-gephyrin clustering with Y252S and A455P, leading to a significant reduction in GlyR β-positive synapses. Although none of the mutations studied is directly located within the gephyrin-binding motif in the GlyR β M3-M4 loop, we suggest that structural changes within the GlyR β subunit result in differences in GlyR β-gephyrin interactions. Hence, we conclude that loss- or gain-of-function, or alterations in synaptic GlyR clustering may underlie disease pathology in startle disease patients carrying GLRB mutations.}, language = {en} } @article{GrohStadlerButtmannetal.2014, author = {Groh, Janos and Stadler, David and Buttmann, Mathias and Martini, Rudolf}, title = {Non-invasive assessment of retinal alterations in mouse models of infantile and juvenile neuronal ceroid lipofuscinosis by spectral domain optical coherence tomography}, doi = {10.1186/2051-5960-2-54}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110566}, year = {2014}, abstract = {Introduction The neuronal ceroid lipofuscinoses constitute a group of fatal inherited lysosomal storage diseases that manifest in profound neurodegeneration in the CNS. Visual impairment usually is an early symptom and selective degeneration of retinal neurons has been described in patients suffering from distinct disease subtypes. We have previously demonstrated that palmitoyl protein thioesterase 1 deficient (Ppt1-/-) mice, a model of the infantile disease subtype, exhibit progressive axonal degeneration in the optic nerve and loss of retinal ganglion cells, faithfully reflecting disease severity in the CNS. Here we performed spectral domain optical coherence tomography (OCT) in Ppt1-/- and ceroid lipofuscinosis neuronal 3 deficient (Cln3-/-) mice, which are models of infantile and juvenile neuronal ceroid lipofuscinosis, respectively, in order to establish a non-invasive method to assess retinal alterations and monitor disease severity in vivo. Results Blue laser autofluorescence imaging revealed increased accumulation of autofluorescent storage material in the inner retinae of 7-month-old Ppt1-/- and of 16-month-old Cln3-/- mice in comparison with age-matched control littermates. Additionally, optical coherence tomography demonstrated reduced thickness of retinae in knockout mice in comparison with age-matched control littermates. High resolution scans and manual measurements allowed for separation of different retinal composite layers and revealed a thinning of layers in the inner retinae of both mouse models at distinct ages. OCT measurements correlated well with subsequent histological analysis of the same retinae. Conclusions These results demonstrate the feasibility of OCT to assess neurodegenerative disease severity in mouse models of neuronal ceroid lipofuscinosis and might have important implications for diagnostic evaluation of disease progression and therapeutic efficacy in patients. Moreover, the non-invasive method allows for longitudinal studies in experimental models, reducing the number of animals used for research.}, language = {en} } @phdthesis{Brunder2022, author = {Brunder, Anna-Michelle}, title = {Nodale und paranodale Autoantik{\"o}rper bei inflammatorischen Polyneuropathien: Nachweis, Charakterisierung und Assoziation zu klinischen Verlaufsformen}, doi = {10.25972/OPUS-28218}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-282185}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {In den letzten Jahren gewann das Konzept der Paranodopathien als eigene Krankheitsentit{\"a}t der inflammatorischen Polyneuropathien zunehmend an Bedeutung. Die Forschung konzentrierte sich dabei {\"u}berwiegend auf die chronisch inflammatorische Polyradikuloneuropathie (CIDP). In dieser Arbeit werden (para-)nodale Antik{\"o}rper gegen Neurofascin-155, panNeurofascin, Contactin-1 und Caspr-1 in einer großen Kohorte von Patienten mit Guillain-Barr{\´e}-Syndrom (GBS) und CIDP nachgewiesen. Patienten mit Anti-panNeurofascin-Antik{\"o}rpern zeigten besonders schwere Verlaufsformen. Patienten mit anderen (para-)nodalen Antik{\"o}rpern zeigten je nach IgG-Subklasse der Antik{\"o}rper spezifische klinische Merkmale und ein unterschiedliches Ansprechen auf die Therapie. Die Arbeit zeigt, dass die Bestimmung (para-)nodaler Antik{\"o}rper bei Patienten mit GBS und CIDP im klinischen Alltag zur Einordung der Prognose und Therapieplanung sinnvoll sein kann.}, subject = {Polyneuropathie}, language = {de} } @article{NguemeniStiehlHiewetal.2021, author = {Nguemeni, Carine and Stiehl, Annika and Hiew, Shawn and Zeller, Daniel}, title = {No Impact of Cerebellar Anodal Transcranial Direct Current Stimulation at Three Different Timings on Motor Learning in a Sequential Finger-Tapping Task}, series = {Frontiers in Human Neuroscience}, volume = {15}, journal = {Frontiers in Human Neuroscience}, issn = {1662-5161}, doi = {10.3389/fnhum.2021.631517}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225477}, year = {2021}, abstract = {Background: Recently, attention has grown toward cerebellar neuromodulation in motor learning using transcranial direct current stimulation (tDCS). An important point of discussion regarding this modulation is the optimal timing of tDCS, as this parameter could significantly influence the outcome. Hence, this study aimed to investigate the effects of the timing of cerebellar anodal tDCS (ca-tDCS) on motor learning using a sequential finger-tapping task (FTT). Methods: One hundred and twenty two healthy young, right-handed subjects (96 females) were randomized into four groups (During\(_{sham}\), Before, During\(_{real}\), After). They performed 2 days of FTT with their non-dominant hand on a custom keyboard. The task consisted of 40 s of typing followed by 20 s rest. Each participant received ca-tDCS (2 mA, sponge electrodes of 25 cm\(^{2}\), 20 min) at the appropriate timing and performed 20 trials on the first day (T1, 20 min). On the following day, only 10 trials of FTT were performed without tDCS (T2, 10 min). Motor skill performance and retention were assessed. Results: All participants showed a time-dependent increase in learning. Motor performance was not different between groups at the end of T1 (p = 0.59). ca-tDCS did not facilitate the retention of the motor skill in the FTT at T2 (p = 0.27). Thus, our findings indicate an absence of the effect of ca-tDCS on motor performance or retention of the FTT independently from the timing of stimulation. Conclusion: The present results suggest that the outcome of ca-tDCS is highly dependent on the task and stimulation parameters. Future studies need to establish a clear basis for the successful and reproducible clinical application of ca-tDCS.}, language = {en} } @article{BellutRaimondiHaarmannetal.2022, author = {Bellut, Maximilian and Raimondi, Anthony T. and Haarmann, Axel and Zimmermann, Lena and Stoll, Guido and Schuhmann, Michael K.}, title = {NLRP3 inhibition reduces rt-PA induced endothelial dysfunction under ischemic conditions}, series = {Biomedicines}, volume = {10}, journal = {Biomedicines}, number = {4}, issn = {2227-9059}, doi = {10.3390/biomedicines10040762}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267261}, year = {2022}, abstract = {Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is a mainstay of acute ischemic stroke treatment but is associated with bleeding complications, especially after prolonged large vessel occlusion. Recently, inhibition of the NLRP3 inflammasome led to preserved blood-brain barrier (BBB) integrity in experimental stroke in vivo. To further address the potential of NLRP3 inflammasome inhibition as adjunct stroke treatment we used immortalized brain derived endothelial cells (bEnd5) as an in vitro model of the BBB. We treated bEnd5 with rt-PA in combination with the NLRP3 specific inhibitor MCC950 or vehicle under normoxic as well as ischemic (OGD) conditions. We found that rt-PA exerted a cytotoxic effect on bEnd5 cells under OGD confirming that rt-PA is harmful to the BBB. This detrimental effect could be significantly reduced by MCC950 treatment. Moreover, under ischemic conditions, the Cell Index — a sensible indicator for a patent BBB — and the protein expression of Zonula occludens 1 stabilized after MCC950 treatment. At the same time, the extent of endothelial cell death and NLRP3 expression decreased. In conclusion, NLRP3 inhibition can protect the BBB from rt-PA-induced damage and thereby potentially increase the narrow time window for safe thrombolysis in stroke.}, language = {en} } @article{BellutPappBieberetal.2022, author = {Bellut, Maximilian and Papp, Lena and Bieber, Michael and Kraft, Peter and Stoll, Guido and Schuhmann, Michael K.}, title = {NLPR3 inflammasome inhibition alleviates hypoxic endothelial cell death in-vitro and protects blood-brain barrier integrity in murine stroke}, series = {Cell Death \& Disease}, volume = {13}, journal = {Cell Death \& Disease}, doi = {10.1038/s41419-021-04379-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265693}, year = {2022}, abstract = {In ischemic stroke (IS) impairment of the blood-brain barrier (BBB) has an important role in the secondary deterioration of neurological function. BBB disruption is associated with ischemia-induced inflammation, brain edema formation, and hemorrhagic infarct transformation, but the underlying mechanisms are incompletely understood. Dysfunction of endothelial cells (EC) may play a central role in this process. Although neuronal NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome upregulation is an established trigger of inflammation in IS, the contribution of its expression in EC is unclear. We here used brain EC, exposed them to oxygen and glucose deprivation (OGD) in vitro, and analyzed their survival depending on inflammasome inhibition with the NLRP3-specific drug MCC950. During OGD, EC death could significantly be reduced when targeting NLRP3, concomitant with diminished endothelial NLRP3 expression. Furthermore, MCC950 led to reduced levels of Caspase 1 (p20) and activated Gasdermin D as markers for pyroptosis. Moreover, inflammasome inhibition reduced the secretion of pro-inflammatory chemokines, cytokines, and matrix metalloproteinase-9 (MMP9) in EC. In a translational approach, IS was induced in C57Bl/6 mice by 60 mins transient middle cerebral artery occlusion and 23 hours of reperfusion. Stroke volume, functional outcome, the BBB integrity, and-in good agreement with the in vitro results-MMP9 secretion as well as EC survival improved significantly in MCC950-treated mice. In conclusion, our results establish the NLRP3 inflammasome as a critical pathogenic effector of stroke-induced BBB disruption by activating inflammatory signaling cascades and pyroptosis in brain EC.}, language = {en} } @article{ChenBoettgerReifetal.2010, author = {Chen, Yong and Boettger, Michael K. and Reif, Andreas and Schmitt, Angelika and Ueceyler, Nurcan and Sommer, Claudia}, title = {Nitric oxide synthase modulates CFA-induced thermal hyperalgesia through cytokine regulation in mice}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68349}, year = {2010}, abstract = {Background: Although it has been largely demonstrated that nitric oxide synthase (NOS), a key enzyme for nitric oxide (NO) production, modulates inflammatory pain, the molecular mechanisms underlying these effects remain to be clarified. Here we asked whether cytokines, which have well-described roles in inflammatory pain, are downstream targets of NO in inflammatory pain and which of the isoforms of NOS are involved in this process. Results: Intraperitoneal (i.p.) pretreatment with 7-nitroindazole sodium salt (7-NINA, a selective neuronal NOS inhibitor), aminoguanidine hydrochloride (AG, a selective inducible NOS inhibitor), L-N(G)-nitroarginine methyl ester (L-NAME, a non-selective NOS inhibitor), but not L-N(5)-(1-iminoethyl)-ornithine (L-NIO, a selective endothelial NOS inhibitor), significantly attenuated thermal hyperalgesia induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA). Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed a significant increase of nNOS, iNOS, and eNOS gene expression, as well as tumor necrosis factor-alpha (TNF), interleukin-1 beta (IL-1b), and interleukin-10 (IL-10) gene expression in plantar skin, following CFA. Pretreatment with the NOS inhibitors prevented the CFA-induced increase of the pro-inflammatory cytokines TNF and IL-1b. The increase of the antiinflammatory cytokine IL-10 was augmented in mice pretreated with 7-NINA or L-NAME, but reduced in mice receiving AG or L-NIO. NNOS-, iNOS- or eNOS-knockout (KO) mice had lower gene expression of TNF, IL-1b, and IL-10 following CFA, overall corroborating the inhibitor data. Conclusion: These findings lead us to propose that inhibition of NOS modulates inflammatory thermal hyperalgesia by regulating cytokine expression.}, subject = {Medizin}, language = {en} } @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} } @article{IsaiasSpiegelBrumbergetal.2014, author = {Isaias, Ioannis Ugo and Spiegel, J{\"o}rg and Brumberg, Joachim and Cosgrove, Kelly P. and Marotta, Giorgio and Oishi, Naoya and Higuchi, Takahiro and K{\"u}sters, Sebastian and Schiller, Markus and Dillmann, Ulrich and van Dyck, Christopher H. and Buck, Andreas and Herrmann, Ken and Schloegl, Susanne and Volkmann, Jens and Lassmann, Michael and Fassbender, Klaus and Lorenz, Reinhard and Samnick, Samuel}, title = {Nicotinic acetylcholine receptor density in cognitively intact subjects at an early stage of Parkinson's disease}, series = {Frontiers in Aging Neuroscience}, volume = {6}, journal = {Frontiers in Aging Neuroscience}, doi = {10.3389/fnagi.2014.00213}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119351}, pages = {213}, year = {2014}, abstract = {We investigated in vivo brain nicotinic acetylcholine receptor (nAChR) distribution in cognitively intact subjects with Parkinson's disease (PD) at an early stage of the disease. Fourteen patients and 13 healthy subjects were imaged with single photon emission computed tomography and the radiotracer 5-[(123)I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine ([(123)I]5IA). Patients were selected according to several criteria, including short duration of motor signs (<7 years) and normal scores at an extensive neuropsychological evaluation. In PD patients, nAChR density was significantly higher in the putamen, the insular cortex and the supplementary motor area and lower in the caudate nucleus, the orbitofrontal cortex, and the middle temporal gyrus. Disease duration positively correlated with nAChR density in the putamen ipsilateral (ρ = 0.56, p < 0.05) but not contralateral (ρ = 0.49, p = 0.07) to the clinically most affected hemibody. We observed, for the first time in vivo, higher nAChR density in brain regions of the motor and limbic basal ganglia circuits of subjects with PD. Our findings support the notion of an up-regulated cholinergic activity at the striatal and possibly cortical level in cognitively intact PD patients at an early stage of disease.}, language = {en} } @phdthesis{Purrer2020, author = {Purrer, Veronika}, title = {Nicht-motorische Begleitsymptome bei Patienten mit Essentiellen Tremor}, doi = {10.25972/OPUS-19366}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193665}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {Der essentielle Tremor (ET) ist eine der h{\"a}ufigsten Bewegungsst{\"o}rungen, welcher lange Zeit als rein motorische St{\"o}rung angesehen wurde. Aufgrund zunehmender Belege {\"u}ber nicht-motorisch Begleitsymptome wandelte sich dieses Bild jedoch in den letzten Jahren zunehmend. In der vorliegenden Arbeit untersuchten wir 113 Probanden aus der Allgemeinbev{\"o}lkerung mit klinisch definitiven oder wahrscheinlichen ET anhand einer breiten Batterie neuro-psychologischer Testverfahren. Es gelang hierbei signifikante Unterschiede im Vergleich zu gesunden Eichstichproben im Hinblick auf neuro-psychologische Charakteristika, wie Apathie, {\"A}ngstlichkeit und exekutive Dysfunktion, sowie deren negativen Einfluss auf die Lebensqualit{\"a}t der Probanden darzustellen. Bisher werden im klinischen Alltag nicht-motorische Begleitph{\"a}nomene beim ET nicht regelhaft erfasst; aufgrund unserer Ergebnisse und der Relevanz vor allem im Hinblick auf die Lebensqualit{\"a}t des Einzelnen halten wir jedoch die Erfassung und gegebenenfalls Behandlung dieser Symptome f{\"u}r ebenso relevant.}, subject = {Essentieller Tremor}, language = {de} } @article{KraftDeMeyerKleinschnitz2012, author = {Kraft, Peter and De Meyer, Simon F. and Kleinschnitz, Christoph}, title = {Next-Generation Antithrombotics in Ischemic Stroke: Preclinical Perspective on 'Bleeding-Free Antithrombosis'}, series = {Journal of Cerebral Blood Flow and Metabolism}, volume = {32}, journal = {Journal of Cerebral Blood Flow and Metabolism}, number = {10}, doi = {10.1038/jcbfm.2012.108}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126538}, pages = {1831-1840}, year = {2012}, abstract = {The present antithrombotic drugs used to treat or prevent ischemic stroke have significant limitations: either they show only moderate efficacy (platelet inhibitors), or they significantly increase the risk for hemorrhages (thrombolytics, anticoagulants). Although most strokes are caused by thrombotic or embolic vessel occlusions, the pathophysiological role of platelets and coagulation is largely unclear. The introduction of novel transgenic mouse models and specific coagulation inhibitors facilitated a detailed analysis of molecular pathways mediating thrombus formation in models of acute ischemic stroke. Prevention of early platelet adhesion to the damaged vessel wall by blocking platelet surface receptors glycoprotein Ib alpha (GPIbα) or glycoprotein VI (GPVI) protects from stroke without provoking bleeding complications. In addition, downstream signaling of GPIbα and GPVI has a key role in platelet calcium homeostasis and activation. Finally, the intrinsic coagulation cascade, activated by coagulation factor XII (FXII), has only recently been identified as another important mediator of thrombosis in cerebrovascular disease, thereby disproving established concepts. This review summarizes the latest insights into the pathophysiology of thrombus formation in the ischemic brain. Potential clinical merits of novel platelet inhibitors and anticoagulants as powerful and safe tools to combat ischemic stroke are discussed.}, language = {en} } @article{BoltzeKleinschnitzReymannetal.2012, author = {Boltze, Johannes and Kleinschnitz, Christoph and Reymann, Klaus G. and Reiser, Georg and Wagner, Daniel-Christoph and Kranz, Alexander and Michalski, Dominik}, title = {Neurovascular pathophysiology in cerebral ischemia, dementia and the ageing brain - current trends in basic, translational and clinical research}, series = {Experimental \& Translational Stroke Medicine}, volume = {4}, journal = {Experimental \& Translational Stroke Medicine}, number = {14}, doi = {doi:10.1186/2040-7378-4-14}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126679}, year = {2012}, abstract = {The 7th International Symposium on Neuroprotection and Neurorepair was held from May 2nd to May 5th, 2012 in Potsdam, Germany. The symposium, which directly continues the successful Magdeburg meeting series, attracted over 330 colleagues from 29 countries to discuss recent findings and advances in the field. The focus of the 2012 symposium was widened from stroke and traumatic brain injury to neurodegenerative diseases, notably dementia, and more generally the ageing brain. Thereby, emphasis was given on neurovascular aspects of neurodegeneration and stroke including the blood-brain barrier, recent findings regarding the pathomechanism of Alzheimer's disease, and brain imaging approaches. In addition, neurobiochemical aspects of neuroprotection, the role of astrogliosis, the clinical progress of cell-based approaches as well as translational hurdles and opportunities were discussed in-depth. This review summarizes some of the most stimulating discussions and reports from the meeting.}, language = {en} } @article{MinnerupSutherlandBuchanetal.2012, author = {Minnerup, Jens and Sutherland, Brad A. and Buchan, Alastair M. and Kleinschnitz, Christoph}, title = {Neuroprotection for Stroke: Current Status and Future Perspectives}, series = {International Journal of Molecular Science}, volume = {13}, journal = {International Journal of Molecular Science}, number = {9}, doi = {10.3390/ijms130911753}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134730}, pages = {11753-11772}, year = {2012}, abstract = {Neuroprotection aims to prevent salvageable neurons from dying. Despite showing efficacy in experimental stroke studies, the concept of neuroprotection has failed in clinical trials. Reasons for the translational difficulties include a lack of methodological agreement between preclinical and clinical studies and the heterogeneity of stroke in humans compared to homogeneous strokes in animal models. Even when the international recommendations for preclinical stroke research, the Stroke Academic Industry Roundtable (STAIR) criteria, were followed, we have still seen limited success in the clinic, examples being NXY-059 and haematopoietic growth factors which fulfilled nearly all the STAIR criteria. However, there are a number of neuroprotective treatments under investigation in clinical trials such as hypothermia and ebselen. Moreover, promising neuroprotective treatments based on a deeper understanding of the complex pathophysiology of ischemic stroke such as inhibitors of NADPH oxidases and PSD-95 are currently evaluated in preclinical studies. Further concepts to improve translation include the investigation of neuroprotectants in multicenter preclinical Phase III-type studies, improved animal models, and close alignment between clinical trial and preclinical methodologies. Future successful translation will require both new concepts for preclinical testing and innovative approaches based on mechanistic insights into the ischemic cascade.}, language = {en} } @book{Reiners1990, author = {Reiners, Karlheinz}, title = {Neuropathie und Motorik}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-33843}, publisher = {Universit{\"a}t W{\"u}rzburg}, year = {1990}, abstract = {No abstract available}, subject = {Nervenregeneration ; Periphere Nervenverletzung ; Neuromuskul{\"a}re Krankheit ; Axonverletzung ; Entmarkung}, language = {de} } @article{IsaiasTrujilloSummersetal.2016, author = {Isaias, Ioannis U. and Trujillo, Paula and Summers, Paul and Marotta, Giorgio and Mainardi, Luca and Pezzoli, Gianni and Zecca, Luigi and Costa, Antonella}, title = {Neuromelanin Imaging and Dopaminergic Loss in Parkinson's Disease}, series = {Frontiers in Aging Neuroscience}, volume = {8}, journal = {Frontiers in Aging Neuroscience}, number = {196}, doi = {10.3389/fnagi.2016.00196}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164046}, year = {2016}, abstract = {Parkinson's disease (PD) is a progressive neurodegenerative disorder in which the major pathologic substrate is a loss of dopaminergic neurons from the substantia nigra. Our main objective was to determine the correspondence between changes in the substantia nigra, evident in neuromelanin and iron sensitive magnetic resonance imaging (MRI), and dopaminergic striatal innervation loss in patients with PD. Eighteen patients and 18 healthy control subjects were included in the study. Using neuromelanin-MRI, we measured the volume of the substantia nigra and the contrast-to-noise-ratio between substantia nigra and a background region. The apparent transverse relaxation rate and magnetic susceptibility of the substantia nigra were calculated from dual-echo MRI. Striatal dopaminergic innervation was measured as density of dopamine transporter (DAT) by means of single-photon emission computed tomography and [123I] N-ω-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) tropane. Patients showed a reduced volume of the substantia nigra and contrast-to-noise-ratio and both positively correlated with the corresponding striatal DAT density. The apparent transverse relaxation rate and magnetic susceptibility values of the substantia nigra did not differ between patients and healthy controls. The best predictor of DAT reduction was the volume of the substantia nigra. Clinical and imaging correlations were also investigated for the locus coeruleus. Our results suggest that neuromelanin-MRI can be used for quantifying substantia nigra pathology in PD where it closely correlates with dopaminergic striatal innervation loss. Longitudinal studies should further explore the role of Neuromelanin-MRI as an imaging biomarker of PD, especially for subjects at risk of developing the disease.}, language = {en} } @article{SulzerCassidyHorgaetal.2018, author = {Sulzer, David and Cassidy, Clifford and Horga, Guillermo and Kang, Un Jung and Fahn, Stanley and Casella, Luigi and Pezzoli, Gianni and Langley, Jason and Hu, Xiaoping P. and Zucca, Fabio A. and Isaias, Ioannis U. and Zecca, Luigi}, title = {Neuromelanin detection by magnetic resonance imaging (MRI) and its promise as a biomarker for Parkinson's disease}, series = {npj Parkinson's Disease}, volume = {4}, journal = {npj Parkinson's Disease}, doi = {10.1038/s41531-018-0047-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240207}, year = {2018}, abstract = {The diagnosis of Parkinson's disease (PD) occurs after pathogenesis is advanced and many substantia nigra (SN) dopamine neurons have already died. Now that therapies to block this neuronal loss are under development, it is imperative that the disease be diagnosed at earlier stages and that the response to therapies is monitored. Recent studies suggest this can be accomplished by magnetic resonance imaging (MRI) detection of neuromelanin (NM), the characteristic pigment of SN dopaminergic, and locus coeruleus (LC) noradrenergic neurons. NM is an autophagic product synthesized via oxidation of catecholamines and subsequent reactions, and in the SN and LC it increases linearly during normal aging. In PD, however, the pigment is lost when SN and LC neurons die. As shown nearly 25 years ago by Zecca and colleagues, NM's avid binding of iron provides a paramagnetic source to enable electron and nuclear magnetic resonance detection, and thus a means for safe and noninvasive measure in living human brain. Recent technical improvements now provide a means for MRI to differentiate between PD patients and age-matched healthy controls, and should be able to identify changes in SN NM with age in individuals. We discuss how MRI detects NM and how this approach might be improved. We suggest that MRI of NM can be used to confirm PD diagnosis and monitor disease progression. We recommend that for subjects at risk for PD, and perhaps generally for older people, that MRI sequences performed at regular intervals can provide a pre-clinical means to detect presymptomatic PD.}, language = {en} } @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} } @article{GrotemeyerMcFlederWuetal.2022, author = {Grotemeyer, Alexander and McFleder, Rhonda Leah and Wu, Jingjing and Wischhusen, J{\"o}rg and Ip, Chi Wang}, title = {Neuroinflammation in Parkinson's disease - putative pathomechanisms and targets for disease-modification}, series = {Frontiers in Immunology}, volume = {13}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2022.878771}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-274665}, year = {2022}, abstract = {Parkinson's disease (PD) is a progressive and debilitating chronic disease that affects more than six million people worldwide, with rising prevalence. The hallmarks of PD are motor deficits, the spreading of pathological α-synuclein clusters in the central nervous system, and neuroinflammatory processes. PD is treated symptomatically, as no causally-acting drug or procedure has been successfully established for clinical use. Various pathways contributing to dopaminergic neuron loss in PD have been investigated and described to interact with the innate and adaptive immune system. We discuss the possible contribution of interconnected pathways related to the immune response, focusing on the pathophysiology and neurodegeneration of PD. In addition, we provide an overview of clinical trials targeting neuroinflammation in PD.}, language = {en} } @article{IpKronerGrohetal.2012, author = {Ip, Chi Wang and Kroner, Antje and Groh, Janos and Huber, Marianne and Klein, Dennis and Spahn, Irene and Diem, Ricarda and Williams, Sarah K. and Nave, Klaus-Armin and Edgar, Julia M. and Martini, Rudolf}, title = {Neuroinflammation by Cytotoxic T-Lymphocytes Impairs Retrograde Axonal Transport in an Oligodendrocyte Mutant Mouse}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {8}, doi = {10.1371/journal.pone.0042554}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134982}, pages = {e42554}, year = {2012}, abstract = {Mice overexpressing proteolipid protein (PLP) develop a leukodystrophy-like disease involving cytotoxic, CD8+ T-lymphocytes. Here we show that these cytotoxic T-lymphocytes perturb retrograde axonal transport. Using fluorogold stereotactically injected into the colliculus superior, we found that PLP overexpression in oligodendrocytes led to significantly reduced retrograde axonal transport in retina ganglion cell axons. We also observed an accumulation of mitochondria in the juxtaparanodal axonal swellings, indicative for a disturbed axonal transport. PLP overexpression in the absence of T-lymphocytes rescued retrograde axonal transport defects and abolished axonal swellings. Bone marrow transfer from wildtype mice, but not from perforin- or granzyme B-deficient mutants, into lymphocyte-deficient PLP mutant mice led again to impaired axonal transport and the formation of axonal swellings, which are predominantly located at the juxtaparanodal region. This demonstrates that the adaptive immune system, including cytotoxic T-lymphocytes which release perforin and granzyme B, are necessary to perturb axonal integrity in the PLP-transgenic disease model. Based on our observations, so far not attended molecular and cellular players belonging to the immune system should be considered to understand pathogenesis in inherited myelin disorders with progressive axonal damage.}, language = {en} } @article{KarikariMcFlederRibechinietal.2022, author = {Karikari, Akua A. and McFleder, Rhonda L. and Ribechini, Eliana and Blum, Robert and Bruttel, Valentin and Knorr, Susanne and Gehmeyr, Mona and Volkmann, Jens and Brotchie, Jonathan M. and Ahsan, Fadhil and Haack, Beatrice and Monoranu, Camelia-Maria and Keber, Ursula and Yeghiazaryan, Rima and Pagenstecher, Axel and Heckel, Tobias and Bischler, Thorsten and Wischhusen, J{\"o}rg and Koprich, James B. and Lutz, Manfred B. and Ip, Chi Wang}, title = {Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson's disease mice}, series = {Brain, Behavior, and Immunity}, volume = {101}, journal = {Brain, Behavior, and Immunity}, doi = {10.1016/j.bbi.2022.01.007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300600}, pages = {194 -- 210}, year = {2022}, abstract = {Background Antigen-specific neuroinflammation and neurodegeneration are characteristic for neuroimmunological diseases. In Parkinson's disease (PD) pathogenesis, α-synuclein is a known culprit. Evidence for α-synuclein-specific T cell responses was recently obtained in PD. Still, a causative link between these α-synuclein responses and dopaminergic neurodegeneration had been lacking. We thus addressed the functional relevance of α-synuclein-specific immune responses in PD in a mouse model. Methods We utilized a mouse model of PD in which an Adeno-associated Vector 1/2 serotype (AAV1/2) expressing human mutated A53T-α-Synuclein was stereotactically injected into the substantia nigra (SN) of either wildtype C57BL/6 or Recombination-activating gene 1 (RAG1)\(^{-/-}\) mice. Brain, spleen, and lymph node tissues from different time points following injection were then analyzed via FACS, cytokine bead assay, immunohistochemistry and RNA-sequencing to determine the role of T cells and inflammation in this model. Bone marrow transfer from either CD4\(^{+}\)/CD8\(^{-}\), CD4\(^{-}\)/CD8\(^{+}\), or CD4\(^{+}\)/CD8\(^{+}\) (JHD\(^{-/-}\)) mice into the RAG-1\(^{-/-}\) mice was also employed. In addition to the in vivo studies, a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay was utilized. Results AAV-based overexpression of pathogenic human A53T-α-synuclein in dopaminergic neurons of the SN stimulated T cell infiltration. RNA-sequencing of immune cells from PD mouse brains confirmed a pro-inflammatory gene profile. T cell responses were directed against A53T-α-synuclein-peptides in the vicinity of position 53 (68-78) and surrounding the pathogenically relevant S129 (120-134). T cells were required for α-synuclein-induced neurodegeneration in vivo and in vitro, while B cell deficiency did not protect from dopaminergic neurodegeneration. Conclusions Using T cell and/or B cell deficient mice and a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay, we confirmed in vivo and in vitro that pathogenic α-synuclein peptide-specific T cell responses can cause dopaminergic neurodegeneration and thereby contribute to PD-like pathology.}, language = {en} } @article{SommerCarrollKoikeetal.2021, author = {Sommer, Claudia and Carroll, Antonia S. and Koike, Haruki and Katsuno, Masahisa and Ort, Nora and Sobue, Gen and Vucic, Steve and Spies, Judith M. and Doppler, Kathrin and Kiernan, Matthew C.}, title = {Nerve biopsy in acquired neuropathies}, series = {Journal of the Peripheral Nervous System}, volume = {26}, journal = {Journal of the Peripheral Nervous System}, number = {S2}, doi = {10.1111/jns.12464}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259555}, pages = {S21-S41}, year = {2021}, abstract = {A diagnosis of neuropathy can typically be determined through clinical assessment and focused investigation. With technological advances, including significant progress in genomics, the role of nerve biopsy has receded over recent years. However, making a specific and, in some cases, tissue-based diagnosis is essential across a wide array of potentially treatable acquired peripheral neuropathies. When laboratory investigations do not suggest a definitive diagnosis, nerve biopsy remains the final step to ascertain the etiology of the disease. The present review highlights the utility of nerve biopsy in confirming a diagnosis, while further illustrating the importance of a tissue-based diagnosis in relation to treatment strategies, particularly when linked to long-term immunosuppressive therapies,}, language = {en} } @article{RolfesRuckDavidetal.2022, author = {Rolfes, Leoni and Ruck, Tobias and David, Christina and Mencl, Stine and Bock, Stefanie and Schmidt, Mariella and Strecker, Jan-Kolja and Pfeuffer, Steffen and Mecklenbeck, Andreas-Schulte and Gross, Catharina and Gliem, Michael and Minnerup, Jens and Schuhmann, Michael K. and Kleinschnitz, Christoph and Meuth, Sven G.}, title = {Natural Killer Cells Are Present in Rag1\(^{-/-}\) Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke}, series = {Translational Stroke Research}, volume = {13}, journal = {Translational Stroke Research}, number = {1}, issn = {1868-4483}, doi = {10.1007/s12975-021-00923-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308924}, pages = {197-211}, year = {2022}, abstract = {Rag1\(^{-/-}\) mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1\(^{-/-}\) mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1\(^{null}\)IL2rg\(^{null}\) (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1\(^{-/-}\) and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1\(^{-/-}\) NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1\(^{-/-}\) were comparable in number and function to those in WT mice. Rag1\(^{-/-}\) mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1-/- controls. Our results indicate that NK cells from Rag1-/- mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke.}, language = {en} } @article{Sommer2022, author = {Sommer, Claudia}, title = {Natural course of Guillain-Barr{\´e} syndrome}, series = {European Journal of Neurology}, volume = {29}, journal = {European Journal of Neurology}, number = {10}, doi = {10.1111/ene.15498}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318757}, pages = {2881 -- 2882}, year = {2022}, language = {en} } @phdthesis{Schneider2018, author = {Schneider, Katharina}, title = {Nachweis und Analyse von Phospho-Alpha-Synuclein-Ablagerungen in Hautnerven von Patienten mit Morbus Parkinson oder Multisystematrophie}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-169694}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2018}, abstract = {Zielsetzung der Studie war es, Ablagerungen des phosphorylierten Alpha-Synucleins in der Haut von Patienten mit Morbus Parkinson und atypischen Parkinson-Syndromen zu untersuchen und deren Auswirkungen auf das periphere Nervensystem zu erforschen. Dazu wurden Hautbiopsien von 92 Patienten mit Morbus Parkinson, 12 Patienten mit MSA und 13 Patienten mit einer Tauopathie sowie 83 gesunden Kontrollpersonen immunhisto-chemisch gef{\"a}rbt und unter dem Mikroskop untersucht. Mit einer Sensitivit{\"a}t von 52 \% f{\"u}r den Morbus Parkinson und 67 \% f{\"u}r die MSA bei hoher Spezifit{\"a}t stellt der Nachweis von Phospho-Alpha-Synuclein in den kleinen Nervenfasern der Haut einen geeigneten Biomarker dar. W{\"a}hrend die Ablagerungen des phosphorylierten Alpha-Synucleins bei Patienten mit Morbus Parkinson eher in autonomen Strukturen nachweisbar waren, fanden sie sich bei Patienten mit MSA eher in sub- und intraepidermal gelegenen Nervenfasern. Phospho-Alpha-Synuclein konnte in allen untersuchten Nervenfasersubtypen nachgewiesen werden, also in CGRP-, SP-, TH- und VIP-positiven Fasern. Bei den in der vorliegenden Studie untersuchten Parkinson-Patienten waren keine Ver{\"a}nderungen in der sensiblen Neurographie des Nervus suralis erkennbar. Die intraepidermale Nervenfaserdichte sowie die Innervation der Schweißdr{\"u}sen waren jedoch teilweise vermindert und auch in der QST zeigten sich Auff{\"a}lligkeiten. Ein Zusammenhang zu dem Vorhandensein von Phospho-Alpha-Synuclein-Ablagerungen konnte jedoch nur f{\"u}r die Innervation der Musculi arrectores pilorum hergestellt werden. Bei der Untersuchung der pathophysiologischen Hintergr{\"u}nde, durch die Phospho-Alpha-Synuclein-Ablagerungen zu Nervenfasersch{\"a}digungen f{\"u}hren, konnten die Hinweise auf eine Beteiligung von axonalen Transportproteinen, Mikrotubuli oder Mitochondrien nicht erh{\"a}rtet werden.}, subject = {Synuclein }, language = {de} } @article{HornBaumannPereiraetal.2012, author = {Horn, Michael and Baumann, Reto and Pereira, Jorge A. and Sidiropoulos, P{\´a}ris N. M. and Somandin, Christian and Welzl, Hans and Stendel, Claudia and L{\"u}hmann, Tessa and Wessig, Carsten and Toyka, Klaus V. and Relvas, Jo{\~a}o B. and Senderek, Jan and Suter, Ueli}, title = {Myelin is dependent on the Charcot-Marie-Tooth Type 4H disease culprit protein FRABIN/FGD4 in Schwann cells}, series = {Brain}, volume = {135}, journal = {Brain}, doi = {10.1093/brain/aws275}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125390}, pages = {3567-3583}, year = {2012}, abstract = {Studying the function and malfunction of genes and proteins associated with inherited forms of peripheral neuropathies has provided multiple clues to our understanding of myelinated nerves in health and disease. Here, we have generated a mouse model for the peripheral neuropathy Charcot-Marie-Tooth disease type 4H by constitutively disrupting the mouse orthologue of the suspected culprit gene FGD4 that encodes the small RhoGTPase Cdc42-guanine nucleotide exchange factor Frabin. Lack of Frabin/Fgd4 causes dysmyelination in mice in early peripheral nerve development, followed by profound myelin abnormalities and demyelination at later stages. At the age of 60 weeks, this was accompanied by electrophysiological deficits. By crossing mice carrying alleles of Frabin/Fgd4 flanked by loxP sequences with animals expressing Cre recombinase in a cell type-specific manner, we show that Schwann cell-autonomous Frabin/Fgd4 function is essential for proper myelination without detectable primary contributions from neurons. Deletion of Frabin/Fgd4 in Schwann cells of fully myelinated nerve fibres revealed that this protein is not only required for correct nerve development but also for accurate myelin maintenance. Moreover, we established that correct activation of Cdc42 is dependent on Frabin/Fgd4 function in healthy peripheral nerves. Genetic disruption of Cdc42 in Schwann cells of adult myelinated nerves resulted in myelin alterations similar to those observed in Frabin/Fgd4-deficient mice, indicating that Cdc42 and the Frabin/Fgd4-Cdc42 axis are critical for myelin homeostasis. In line with known regulatory roles of Cdc42, we found that Frabin/Fgd4 regulates Schwann cell endocytosis, a process that is increasingly recognized as a relevant mechanism in peripheral nerve pathophysiology. Taken together, our results indicate that regulation of Cdc42 by Frabin/Fgd4 in Schwann cells is critical for the structure and function of the peripheral nervous system. In particular, this regulatory link is continuously required in adult fully myelinated nerve fibres. Thus, mechanisms regulated by Frabin/Fgd4-Cdc42 are promising targets that can help to identify additional regulators of myelin development and homeostasis, which may crucially contribute also to malfunctions in different types of peripheral neuropathies.}, language = {en} } @article{BittnerBobakHofmannetal.2015, author = {Bittner, Stefan and Bobak, Nicole and Hofmann, Majella-Sophie and Schuhmann, Michael K. and Ruck, Tobias and G{\"o}bel, Kerstin and Br{\"u}ck, Wolfgang and Wiendl, Heinz and Meuth, Sven G.}, title = {Murine K\(_{2P}\)5.1 Deficiency Has No Impact on Autoimmune Neuroinflammation due to Compensatory K\(_{2P}\)3.1-and K\(_{V}\)1.3-Dependent Mechanisms}, series = {International Journal of Molecular Sciences}, volume = {16}, journal = {International Journal of Molecular Sciences}, doi = {10.3390/ijms160816880}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151454}, pages = {16880 -- 16896}, year = {2015}, abstract = {Lymphocytes express potassium channels that regulate physiological cell functions, such as activation, proliferation and migration. Expression levels of K\(_{2P}\)5.1(TASK2; KCNK5) channels belonging to the family of two-pore domain potassium channels have previously been correlated to the activity of autoreactive T lymphocytes in patients with multiple sclerosis and rheumatoid arthritis. In humans, K\(_{2P}\)5.1 channels are upregulated upon T cell stimulation and influence T cell effector functions. However, a further clinical translation of targeting K\(_{2P}\)5.1 is currently hampered by a lack of highly selective inhibitors, making it necessary to evaluate the impact of KCNK5 in established preclinical animal disease models. We here demonstrate that K\(_{2P}\)5.1 knockout (K\(_{2P}\)5.1\(^{-/-}\) mice display no significant alterations concerning T cell cytokine production, proliferation rates, surface marker molecules or signaling pathways. In an experimental model of autoimmune neuroinflammation, K\(_{2P}\)5.1\(^{-/-}\) mice show a comparable disease course to wild-type animals and no major changes in the peripheral immune system or CNS compartment. A compensatory upregulation of the potassium channels K\(_{2P}\)3.1 and K\(_{V}\)1.3 seems to counterbalance the deletion of K\(_{2P}\)5.1. As an alternative model mimicking autoimmune neuroinflammation, experimental autoimmune encephalomyelitis in the common marmoset has been proposed, especially for testing the efficacy of new potential drugs. Initial experiments show that K\(_{2P}\)5.1 is functionally expressed on marmoset T lymphocytes, opening up the possibility for assessing future K\(_{2P}\)5.1-targeting drugs.}, 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} } @article{LendersHennermannKurschatetal.2016, author = {Lenders, Malte and Hennermann, Julia B. and Kurschat, Christine and Rolfs, Arndt and Canaan-K{\"u}hl, Sima and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan and Kampmann, Christoph and Karabul, Nesrin and Giese, Anne-Katrin and Duning, Thomas and Stypmann, J{\"o}rg and Kr{\"a}mer, Johannes and Weidemann, Frank and Brand, Stefan-Martin and Wanner, Christoph and Brand, Eva}, title = {Multicenter Female Fabry Study (MFFS) - clinical survey on current treatment of females with Fabry disease}, series = {Orphanet Journal of Rare Diseases}, volume = {11}, journal = {Orphanet Journal of Rare Diseases}, number = {88}, doi = {10.1186/s13023-016-0473-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166543}, year = {2016}, abstract = {Background The aim of the present study was to assess manifestations of and applied treatment concepts for females with Fabry disease (FD) according to the current European Fabry Guidelines. Methods Between 10/2008 and 12/2014, data from the most recent visit of 261 adult female FD patients from six German Fabry centers were retrospectively analyzed. Clinical presentation and laboratory data, including plasma lyso-Gb3 levels were assessed. Results Fifty-five percent of females were on enzyme replacement therapy (ERT), according to recent European FD guidelines. Thirty-three percent of females were untreated although criteria for ERT initiation were fulfilled. In general, the presence of left ventricular hypertrophy (LVH) seemed to impact more on ERT initiation than impaired renal function. In ERT-na{\"i}ve females RAAS blockers were more often prescribed if LVH was present rather than albuminuria. Affected females with missense mutations showed a similar disease burden compared to females with nonsense mutations. Elevated plasma lyso-Gb3 levels in ERT-na{\"i}ve females seem to be a marker of disease burden, since patients showed comparable incidences of organ manifestations even if they were ~8 years younger than females with normal lyso-Gb3 levels. Conclusion The treatment of the majority of females with FD in Germany is in line with the current European FD guidelines. However, a relevant number of females remain untreated despite organ involvement, necessitating a careful reevaluation of these females.}, language = {en} } @article{NorrmenFigliaLebrunJulienetal.2014, author = {Norrmen, Camilla and Figlia, Gianluca and Lebrun-Julien, Frederic and Pereira, Jorge A. and Tr{\"o}tzm{\"u}ller, Martin and K{\"o}feler, Harald C. and Rantanen, Ville and Wessig, Carsten and van Deijk, Anne-Lieke F. and Smit, August B. and Verheijen, Mark H. G. and R{\"u}egg, Markus A. and Hall, Michael N. and Suter, Ueli}, title = {mTORC1 Controls PNS Myelination along the mTORC1-RXR gamma-SREBP-Lipid Biosynthesis Axis in Schwann Cells}, series = {Cell Reports}, volume = {9}, journal = {Cell Reports}, number = {2}, issn = {2211-1247}, doi = {10.1016/j.celrep.2014.09.001}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114847}, pages = {646-660}, year = {2014}, abstract = {Myelin formation during peripheral nervous system (PNS) development, and reformation after injury and in disease, requires multiple intrinsic and extrinsic signals. Akt/mTOR signaling has emerged as a major player involved, but the molecular mechanisms and downstream effectors are virtually unknown. Here, we have used Schwann-cell-specific conditional gene ablation of raptor and rictor, which encode essential components of the mTOR complexes 1 (mTORC1) and 2 (mTORC2), respectively, to demonstrate that mTORC1 controls PNS myelination during development. In this process, mTORC1 regulates lipid biosynthesis via sterol regulatory element-binding proteins (SREBPs). This course of action is mediated by the nuclear receptor RXRg, which transcriptionally regulates SREBP1c downstream of mTORC1. Absence of mTORC1 causes delayed myelination initiation as well as hypomyelination, together with abnormal lipid composition and decreased nerve conduction velocity. Thus, we have identified the mTORC1-RXR gamma-SREBP axis controlling lipid biosynthesis as a major contributor to proper peripheral nerve function.}, language = {en} } @article{HermSchurigMartineketal.2019, author = {Herm, Juliane and Schurig, Johannes and Martinek, Martin R. and H{\"o}ltgen, Reinhard and Schirdewan, Alexander and Kirchhof, Paulus and Wieczorek, Marcus and P{\"u}rerfellner, Helmut and Heuschmann, Peter U. and Fiebach, Jochen B. and Haeusler, Karl Georg}, title = {MRI-detected brain lesions in AF patients without further stroke risk factors undergoing ablation - a retrospective analysis of prospective studies}, series = {BMC Cardiovascular Disorders}, volume = {19}, journal = {BMC Cardiovascular Disorders}, doi = {10.1186/s12872-019-1035-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201226}, pages = {58}, year = {2019}, abstract = {Background Atrial fibrillation (AF) without other stroke risk factors is assumed to have a low annual stroke risk comparable to patients without AF. Therefore, current clinical guidelines do not recommend oral anticoagulation for stroke prevention of AF in patients without stroke risk factors. We analyzed brain magnetic resonance imaging (MRI) imaging to estimate the rate of clinically inapparent ("silent") ischemic brain lesions in these patients. Methods We pooled individual patient-level data from three prospective studies comprising stroke-free patients with symptomatic AF. All study patients underwent brain MRI within 24-48 h before planned left atrial catheter ablation. MRIs were analyzed by a neuroradiologist blinded to clinical data. Results In total, 175 patients (median age 60 (IQR 54-67) years, 32\% female, median CHA\(_2\)DS\(_2\)-VASc = 1 (IQR 0-2), 33\% persistent AF) were included. In AF patients without or with at least one stroke risk factor, at least one silent ischemic brain lesion was observed in 4 (8\%) out of 48 and 10 (8\%) out of 127 patients, respectively (p > 0.99). Presence of silent ischemic brain lesions was related to age (p = 0.03) but not to AF pattern (p = 0.77). At least one cerebral microbleed was detected in 5 (13\%) out of 30 AF patients without stroke risk factors and 25 (25\%) out of 108 AF patients with stroke risk factors (p = 0.2). Presence of cerebral microbleeds was related to male sex (p = 0.04) or peripheral artery occlusive disease (p = 0.03). Conclusion In patients with symptomatic AF scheduled for ablation, brain MRI detected silent ischemic brain lesions in approximately one in 12 patients, and microbleeds in one in 5 patients. The prevalence of silent ischemic brain lesions did not differ in AF patients with or without further stroke risk factors.}, language = {en} } @phdthesis{Hillerer2001, author = {Hillerer, Claudia}, title = {MR-Protonen-Spektroskopie des Linsenkerns bei idiopathischen Handdystonien}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-1182401}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2001}, abstract = {Die Pathogenese der idiopathischen Handdystonie ist bis heute nicht abschließend gekl{\"a}rt. Verschiedene Befunde sprechen f{\"u}r eine L{\"a}sion der Basalganglien, insbesondere des Linsenkerns. Insbesondere bildgebende Verfahren wie MRT, Sonographie, PET oder SPECT, und Untersuchungen bei sekund{\"a}ren Dystonieformen weisen in diese Richtung. Trotz vielfacher Anstrengungen, den zugrunde liegenden Pathomechanismus aufzudecken, ist es bis heute noch nicht gelungen, ein einheitliches anatomisches oder biochemisches Korrelat f{\"u}r die St{\"o}rung verantwortlich zu machen: So bieten einige pathoanatomische Studien Hinweise auf Zellverlust und Gliose im Striatum, andere zeigten Ver{\"a}nderungen in der Konzentration verschiedener Neurotransmitter. J{\"u}ngere Untersuchungen lassen einen gest{\"o}rten Komplex I der mitochondrialen Atmungskette vermuten. Da die {\"A}tiologie der Dystonien bisher letztlich nicht gekl{\"a}rt ist, bietet die Protonenspektroskopie die M{\"o}glichkeit, Stoffwechselver{\"a}nderungen sowie {\"A}nderungen der Gewebszusammensetzung und der Konzentrationen darin enthaltener Stoffe zu untersuchen und so Hypothesen zur Genese der idiopathischen Dystonie herauszuarbeiten. Wir untersuchten 14 Patienten mit idiopathischem Schreibkrampf und 11 gesunde, altersentsprechende Probanden, die nachweislich an keiner zentral-neurologischen Erkrankung litten. Zur Messung wurde eine Standard-Kopfspule ( 1,5 T Ganzk{\"o}rper MR-Tomograph, Siemens Magnetom Vision, Erlangen) verwendet. Die Spektrenerhebung erfolgte mit Hilfe einer PRESS-Sequenz (TR= 1365 ms, TE= 135 ms), das Voxel war auf das Gebiet des Linsenkerns zentriert. Die anhand der Spektren ermittelten Metabolitenverh{\"a}ltnisse von NAA:Cho, NAA:Crea, Cho:Crea und Lac:Crea ergaben keine statistisch signifikante Seitendifferenz innerhalb der Patientengruppe, auch ein Vergleich zwischen Patienten- und Kontrollgruppe blieb ohne statistische Differenz (p>0,05). Somit konnten durch die Protonenspektroskopie keine Ver{\"a}nderungen der Metabolitenkonzentrationen bei der idiopathischen Handdystonie festgestellt werden. Es ergibt sich damit kein Hinweis darauf, daß idiopathischen Dystonien ein meßbarer Verlust von Neuronen, eine damit einhergehende sekund{\"a}re Gliose oder eine meßbare St{\"o}rung des Energiehaushalts, sei es durch erh{\"o}hte Umsatzraten oder eine fehlerhafte oxidative Phosphorylierung, zugrunde liegt. Eine m{\"o}gliche Erkl{\"a}rung dieser unauff{\"a}lligen Befunde bei Dystoniepatienten k{\"o}nnte die Annahme einer St{\"o}rung des Stoffwechsels in nur wenigen Neuronen bieten, was sich der Sensitivit{\"a}t der Methode entziehen kann. Denkbar sind auch Konzentrations{\"a}nderungen von Neurotransmittern, Einlagerungen von Schwermetallen (z.B.Kupfer), Ver{\"a}nderungen der oxidativen Phosphorylierung oder {\"A}nderungen der Rezeptordichte. Generalisierte Dystonien m{\"u}ßten eine eventuell vorhandene Pathologie am deutlichsten aufweisen und w{\"a}ren deshalb ebenfalls ein interessantes Krankheitsbild. Die spektroskopische Untersuchung gestaltet sich aber wegen des bei dieser Form zu erwartenden erh{\"o}hten Auftretens von Bewegungsartefakten schwierig. Auch das Verwenden ver{\"a}nderter Meßparameter (TE, TR) oder einer h{\"o}heren Tesla-Zahl bei einem gr{\"o}ßeren Patientenkollektiv w{\"a}re zur weiteren Abkl{\"a}rung anzustreben. Insbesondere sollten Schreibkrampf-Patienten mit Hilfe der funktionellen MR-Spektroskopie w{\"a}hrend des Auftretens dystoner Verkrampfungen oder auch w{\"a}hrend der Durchf{\"u}hrung willk{\"u}rlicher Fingerbewegungen untersucht werden. Bisher latente Ver{\"a}nderungen k{\"o}nnten sich dann, unter der so erzeugten motorischen Aktivierung, manifestieren.}, 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{MezianeMoiselloPerfettietal.2015, author = {Meziane, Hadj Boumediene and Moisello, Clara and Perfetti, Bernardo and Kvint, Svetlana and Isaias, Ioannis Ugo and Quartarone, Angelo and Di Rocco, Alessandro and Ghilardi, Maria Felice}, title = {Movement preparation and bilateral modulation of beta activity in aging and Parkinson's disease}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0114817}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144147}, pages = {e0114817}, year = {2015}, abstract = {In previous studies of young subjects performing a reaction-time reaching task, we found that faster reaction times are associated with increased suppression of beta power over primary sensorimotor areas just before target presentation. Here we ascertain whether such beta decrease similarly occurs in normally aging subjects and also in patients with Parkinson's disease (PD), where deficits in movement execution and abnormalities of beta power are usually present. We found that in both groups, beta power decreased during the motor task in the electrodes over the two primary sensorimotor areas. However, before target presentation, beta decreases in PD were significantly smaller over the right than over the left areas, while they were symmetrical in controls. In both groups, functional connectivity between the two regions, measured with imaginary coherence, increased before the target appearance; however, in PD, it decreased immediately after, while in controls, it remained elevated throughout motor planning. As in previous studies with young subjects, the degree of beta power before target appearance correlated with reaction time. The values of coherence during motor planning, instead, correlated with movement time, peak velocity and acceleration. We conclude that planning of prompt and fast movements partially depends on coordinated beta activity of both sensorimotor areas, already at the time of target presentation. The delayed onset of beta decreases over the right region observed in PD is possibly related to a decreased functional connectivity between the two areas, and this might account for deficits in force programming, movement duration and velocity modulation.}, language = {en} } @phdthesis{KissnergebStenger2018, author = {Kißner [geb. Stenger], Stefanie Martina}, title = {Morphologische Untersuchungen an Myoblasten von Patienten, die an facioscapulohumeraler Muskeldystrophie (FSHD) leiden}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-156676}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2018}, abstract = {Die autosomal-dominant vererbte facioscapulohumerale Muskeldystrophie (FSHD) ist mit einer Pr{\"a}valenz von etwa 1:20.000 die dritth{\"a}ufigste Form der heredit{\"a}ren Myopathien. Erste Beschwerden werden meist in der zweiten Lebensdekade beobachtet. Betroffen sind vor allem die Muskulatur von Gesicht, Schultern, Oberarmen, die Fußhebermuskulatur und die Muskeln des H{\"u}ftg{\"u}rtels. FSHD wird durch einen Gendefekt ausgel{\"o}st, der den langen Arm des Chromosoms vier (4q35) betrifft, wobei es zur teilweisen Deletion des polymorphen Abschnitts D4Z4, der f{\"u}r das Protein DUX4 codiert, kommt. Dabei treten unter anderem St{\"o}rungen in der DUX4-Expression, Ver{\"a}nderungen der myogenen Genexpression, eine Unterdr{\"u}ckung der Muskelzelldifferenzierung und eine Inhibition der Muskelbildung auf. FSHD und eine andere Form der Muskeldystrophie, die Emery-Dreifuss-Muskeldystrophie (EDMD), zeigen trotz unterschiedlicher genetischer Ursachen ph{\"a}notypisch {\"A}hnlichkeiten in der Auspr{\"a}gung der Erkrankungen. In fr{\"u}heren Studien zeigte die Kernh{\"u}lle von EDMD-Myoblasten morphologische Auff{\"a}lligkeiten. In anderen Untersuchungen waren morphologische Ver{\"a}nderungen der Mitochondrien von FSHD-Patienten festzustellen. Daher wurden elektronenmikroskopische Untersuchungen der Kernh{\"u}lle und der Mitochondrien von FSHD-Myoblasten durchgef{\"u}hrt und mit der entsprechenden Kontrolle verglichen. Hierf{\"u}r wurden drei verschiedene Zelllinien-Paare in unterschiedlichen Passagen, das heißt unterschiedlicher Anzahl an Subkultivierungen, eingesetzt, wobei in den h{\"o}heren Passagen vermehrt morphologische Atypien beobachtet werden konnten. Die eingesetzten Zelllinien differenzieren sich durch verschiedene Parameter wie beispielsweise Alter und Geschlecht der Patienten. Dabei zeigten sich sowohl zwischen den Kontrollzellen als auch zwischen den FSHD-Myoblasten Unterschiede. Im Rahmen der Probenvorbereitung f{\"u}r die Elektronenmikroskopie kamen zwei verschiedene Fixierungsmethoden zum Einsatz: die konventionelle chemische Fixierung, Entw{\"a}sserung und Flacheinbettung von Kulturzellen und die Hochdruckgefrierung mit anschließender Gefriersubstitution. In Bezug auf die Qualit{\"a}t des Strukturerhalts, die beim Hochdruckgefrieren erreicht wird, wird dieser Art der Fixierung eine {\"U}berlegenheit gegen{\"u}ber allen anderen Verfahren zugeschrieben. Diese allgemeine Aussage kann nicht vollst{\"a}ndig auf die Untersuchungen an den Myoblasten {\"u}bertragen werden. F{\"u}r die Untersuchung der Kernmembranen sind beide Methoden geeignet, wobei der Abstand zwischen innerer und {\"a}ußerer Kernmembran nach der HPF-Fixierung sch{\"a}rfer abgebildet wurde. Bei der Darstellung der Mitochondrien zeigten die elektronenmikroskopischen Aufnahmen nach dem Hochdruckgefrieren bessere und sch{\"a}rfere Ergebnisse. Die Kernporen waren bei beiden Fixierungsmethoden gut erkennbar. Beim Vergleich der gesunden und erkrankten Myoblasten wiesen die Kontrollzellen deutlich weniger Auff{\"a}lligkeiten auf als die Myoblasten von FSHD-Patienten. Innere und {\"a}ußere Kernmembran verliefen bei den Kontrollzellen meist parallel und die Mitochondrien zeigten in den meisten F{\"a}llen eine typische wurmartige, l{\"a}ngliche Form mit Cristae. Dies traf sowohl f{\"u}r die konventionelle Fixierung als auch f{\"u}r das Hochdruckgefrieren zu. Die erkrankten Myoblasten wiesen im Vergleich zur Kontrolle bei beiden Fixierungsmethoden deutliche Auff{\"a}lligkeiten in der Mitochondrien-Morphologie auf. Neben einer oft großen Variationsbreite hinsichtlich Form und L{\"a}nge war auch das teilweise Fehlen der Cristae festzustellen. Bei Betrachtung der Kernh{\"u}lle fielen jedoch deutliche Unterschiede zwischen konventioneller und HPF-Fixierung auf. Die {\"a}ußere Kernmembran der konventionell fixierten FSHD-Myoblasten verlief unregelm{\"a}ßig und gewellt. Im Gegensatz dazu wies die Kernh{\"u}lle der HPF-fixierten erkrankten Myoblasten einen erstaunlich parallelen Verlauf auf. Da bei EDMD in vorangegangenen Untersuchungen auch fluoreszenzmikroskopisch Ver{\"a}nderungen der erkrankten Zellen auff{\"a}llig waren, wurde neben den Methoden der Elektronenmikroskopie das Vorliegen und die Verteilung verschiedener Proteine in FSHD-Myoblasten mittels indirekter Immunfluoreszenz untersucht und mit den Kontrollzellen verglichen. Zur Beurteilung der Kernh{\"u}lle wurden Antik{\"o}rper gegen Lamin A/C und Nukleoporine eingesetzt. Die Mitochondrien wurden mithilfe des Antik{\"o}rpers ANT1/2, der an den Adenin-Nukleotid-Translokator der inneren Mitochondrienmembran bindet, untersucht. Im Gegensatz zu den Untersuchungen an EDMD-Myoblasten waren die Lamine A und C sowie die Kernporen sowohl bei den Myoblasten der FSHD-Patienten als auch bei den Kontrollzellen nachweisbar und gleichm{\"a}ßig verteilt. Bei der indirekten Immunfluoreszenz mit ANT1/2 zeigten sich Unterschiede zwischen den untersuchten Myoblasten-Paaren. Durch die vorliegenden Ergebnisse ist darauf zu schließen, dass die Myoblasten von FSHD-Patienten Ver{\"a}nderungen Mitochondrien aufweisen. Die Untersuchungen der Kernh{\"u}lle liefern abh{\"a}ngig von der Fixierungsmethode unterschiedliche Ergebnisse.}, subject = {Landouzy-D{\´e}jerine-Atrophie}, language = {de} } @article{SilwedelHaarmannFehrholzetal.2019, author = {Silwedel, Christine and Haarmann, Axel and Fehrholz, Markus and Claus, Heike and Speer, Christian P. and Glaser, Kirsten}, title = {More than just inflammation: Ureaplasma species induce apoptosis in human brain microvascular endothelial cells}, series = {Journal of Neuroinflammation}, volume = {16}, journal = {Journal of Neuroinflammation}, doi = {10.1186/s12974-019-1413-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200711}, pages = {38}, year = {2019}, abstract = {Background Ureaplasma species (spp.) are commonly regarded as low-virulent commensals but may cause invasive diseases in immunocompromised adults and in neonates, including neonatal meningitis. The interactions of Ureaplasma spp. with host defense mechanisms are poorly understood. This study addressed Ureaplasma-driven cell death, concentrating on apoptosis as well as inflammatory cell death. Methods Human brain microvascular endothelial cells (HBMEC) were exposed to Ureaplasma (U.) urealyticum serovar 8 (Uu8) and U. parvum serovar 3 (Up3). Resulting numbers of dead cells as well as mRNA levels and enzyme activity of key agents in programmed cell death were assessed by flow cytometry, RNA sequencing, and qRT-PCR, respectively. xCELLigence data were used for real-time monitoring of changes in cell adhesion properties. Results Both Ureaplasma isolates induced cell death (p < 0.05, vs. broth). Furthermore, Ureaplasma spp. enhanced mRNA levels for genes in apoptosis, including caspase 3 (Up3 p < 0.05, vs. broth), caspase 7 (p < 0.01), and caspase 9 (Up3 p < 0.01). Caspase 3 activity was increased upon Uu8 exposure (p < 0.01). Vice versa, Ureaplasma isolates downregulated mRNA levels for proteins involved in inflammatory cell death, namely caspase 1 (Uu8 p < 0.01, Up3 p < 0.001), caspase 4 (Uu8 p < 0.05, Up3 p < 0.01), NOD-like receptor pyrin domain-containing 3 (Uu8 p < 0.05), and receptor-interacting protein kinase 3 (p < 0.05). Conclusions By inducing apoptosis in HBMEC as main constituents of the blood-brain barrier, Ureaplasma spp. may provoke barrier breakdown. Simultaneous suppression of inflammatory cell death may additionally attenuate host defense strategies. Ultimate consequence could be invasive and long-term CNS infections by Ureaplasma spp.}, language = {en} } @article{JariusKleiterRuprechtetal.2016, author = {Jarius, Sven and Kleiter, Ingo and Ruprecht, Klemens and Asgari, Nasrin and Pitarokoili, Kalliopi and Borisow, Nadja and H{\"u}mmert, Martin W. and Trebst, Corinna and Pache, Florence and Winkelmann, Alexander and Beume, Lena-Alexandra and Ringelstein, Marius and Stich, Oliver and Aktas, Orhan and Korporal-Kuhnke, Mirjam and Schwarz, Alexander and Lukas, Carsten and Haas, J{\"u}rgen and Fechner, Kai and Buttmann, Mathias and Bellmann-Strobl, Judith and Zimmermann, Hanna and Brandt, Alexander U. and Franciotta, Diego and Schanda, Kathrin and Paul, Friedemann and Reindl, Markus and Wildemann, Brigitte}, title = {MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: Brainstem involvement - frequency, presentation and outcome}, series = {Journal of Neuroinflammation}, volume = {13}, journal = {Journal of Neuroinflammation}, number = {281}, doi = {10.1186/s12974-016-0719-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165543}, pages = {1-23}, year = {2016}, abstract = {Background Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) are present in a subset of aquaporin-4 (AQP4)-IgG-negative patients with optic neuritis (ON) and/or myelitis. Little is known so far about brainstem involvement in MOG-IgG-positive patients. Objective To investigate the frequency, clinical and paraclinical features, course, outcome, and prognostic implications of brainstem involvement in MOG-IgG-positive ON and/or myelitis. Methods Retrospective case study. Results Among 50 patients with MOG-IgG-positive ON and/or myelitis, 15 (30 \%) with a history of brainstem encephalitis were identified. All were negative for AQP4-IgG. Symptoms included respiratory insufficiency, intractable nausea and vomiting (INV), dysarthria, dysphagia, impaired cough reflex, oculomotor nerve palsy and diplopia, nystagmus, internuclear ophthalmoplegia (INO), facial nerve paresis, trigeminal hypesthesia/dysesthesia, vertigo, hearing loss, balance difficulties, and gait and limb ataxia; brainstem involvement was asymptomatic in three cases. Brainstem inflammation was already present at or very shortly after disease onset in 7/15 (47 \%) patients. 16/21 (76.2 \%) brainstem attacks were accompanied by acute myelitis and/or ON. Lesions were located in the pons (11/13), medulla oblongata (8/14), mesencephalon (cerebral peduncles; 2/14), and cerebellar peduncles (5/14), were adjacent to the fourth ventricle in 2/12, and periaqueductal in 1/12; some had concomitant diencephalic (2/13) or cerebellar lesions (1/14). MRI or laboratory signs of blood-brain barrier damage were present in 5/12. Cerebrospinal fluid pleocytosis was found in 11/14 cases, with neutrophils in 7/11 (3-34 \% of all CSF white blood cells), and oligoclonal bands in 4/14. Attacks were preceded by acute infection or vaccination in 5/15 (33.3 \%). A history of teratoma was noted in one case. The disease followed a relapsing course in 13/15 (87 \%); the brainstem was involved more than once in 6. Immunosuppression was not always effective in preventing relapses. Interferon-beta was followed by new attacks in two patients. While one patient died from central hypoventilation, partial or complete recovery was achieved in the remainder following treatment with high-dose steroids and/or plasma exchange. Brainstem involvement was associated with a more aggressive general disease course (higher relapse rate, more myelitis attacks, more frequently supratentorial brain lesions, worse EDSS at last follow-up). Conclusions Brainstem involvement is present in around one third of MOG-IgG-positive patients with ON and/or myelitis. Clinical manifestations are diverse and may include symptoms typically seen in AQP4-IgG-positive neuromyelitis optica, such as INV and respiratory insufficiency, or in multiple sclerosis, such as INO. As MOG-IgG-positive brainstem encephalitis may take a serious or even fatal course, particular attention should be paid to signs or symptoms of additional brainstem involvement in patients presenting with MOG-IgG-positive ON and/or myelitis.}, language = {en} } @article{JariusRuprechtKleiteretal.2016, author = {Jarius, Sven and Ruprecht, Klemens and Kleiter, Ingo and Borisow, Nadja and Asgari, Nasrin and Pitarokoili, Kalliopi and Pache, Florence and Stich, Oliver and Beume, Lena-Alexandra and H{\"u}mmert, Martin W. and Ringelstein, Marius and Trebst, Corinna and Winkelmann, Alexander and Schwarz, Alexander and Buttmann, Mathias and Zimmermann, Hanna and Kuchling, Joseph and Franciotta, Diego and Capobianco, Marco and Siebert, Eberhard and Lukas, Carsten and Korporal-Kuhnke, Mirjam and Haas, J{\"u}rgen and Fechner, Kai and Brandt, Alexander U. and Schanda, Kathrin and Aktas, Orhan and Paul, Friedemann and Reindl, Markus and Wildemann, Brigitte}, title = {MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome}, series = {Journal of Neuroinflammation}, volume = {13}, journal = {Journal of Neuroinflammation}, number = {280}, doi = {10.1186/s12974-016-0718-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165570}, year = {2016}, abstract = {Background A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG). Objective To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes. Methods Retrospective multicenter study. Results The sex ratio was 1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease followed a multiphasic course in 80\% (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40\% (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36\%) and markedly impaired ambulation due to paresis or ataxia (25\%) as the most common long-term sequelae. Functional blindness in one or both eyes was noted during at least one ON attack in around 70\%. Perioptic enhancement was present in several patients. Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70\%). Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44\%. Fourty-one percent had a history of simultaneous ON and myelitis. Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50\%; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one). CSF pleocytosis (partly neutrophilic) was present in 70\%, oligoclonal bands in only 13\%, and blood-CSF-barrier dysfunction in 32\%. Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal. Full recovery was achieved by plasma exchange in some cases, including after IVMP failure. Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was associated with ongoing or increasing disease activity. Rituximab and ofatumumab were effective in some patients. However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion. Coexisting autoimmunity was rare (9\%). Wingerchuk's 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28\%, 32\%, 15\%, 33\%, respectively; MS had been suspected in 36\%. Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases. Conclusion Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD. The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis.}, language = {en} } @article{JariusRuprechtKleiteretal.2016, author = {Jarius, Sven and Ruprecht, Klemens and Kleiter, Ingo and Borisow, Nadja and Asgari, Nasrin and Pitarokoili, Kalliopi and Pache, Florence and Stich, Oliver and Beume, Lena-Alexandra and H{\"u}mmert, Martin W. and Trebst, Corinna and Ringelstein, Marius and Aktas, Orhan and Winkelmann, Alexander and Buttmann, Mathias and Schwarz, Alexander and Zimmermann, Hanna and Brandt, Alexander U. and Franciotta, Diego and Capobianco, Marco and Kuchling, Joseph and Haas, J{\"u}rgen and Korporal-Kuhnke, Mirjam and Lillevang, Soeren Thue and Fechner, Kai and Schanda, Kathrin and Paul, Friedemann and Wildemann, Brigitte and Reindl, Markus}, title = {MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin}, series = {Journal of Neuroinflammation}, volume = {13}, journal = {Journal of Neuroinflammation}, number = {279}, doi = {10.1186/s12974-016-0717-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165659}, pages = {1-16}, year = {2016}, abstract = {Background Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been suggested to play a role in a subset of patients with neuromyelitis optica and related disorders. Objective To assess (i) the frequency of MOG-IgG in a large and predominantly Caucasian cohort of patients with optic neuritis (ON) and/or myelitis; (ii) the frequency of MOG-IgG among AQP4-IgG-positive patients and vice versa; (iii) the origin and frequency of MOG-IgG in the cerebrospinal fluid (CSF); (iv) the presence of MOG-IgG at disease onset; and (v) the influence of disease activity and treatment status on MOG-IgG titers. Methods 614 serum samples from patients with ON and/or myelitis and from controls, including 92 follow-up samples from 55 subjects, and 18 CSF samples were tested for MOG-IgG using a live cell-based assay (CBA) employing full-length human MOG-transfected HEK293A cells. Results MOG-IgG was detected in 95 sera from 50 patients with ON and/or myelitis, including 22/54 (40.7\%) patients with a history of both ON and myelitis, 22/103 (21.4\%) with a history of ON but no myelitis and 6/45 (13.3\%) with a history of longitudinally extensive transverse myelitis but no ON, and in 1 control patient with encephalitis and a connective tissue disorder, all of whom were negative for AQP4-IgG. MOG-IgG was absent in 221 further controls, including 83 patients with AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and 85 with multiple sclerosis (MS). MOG-IgG was found in 12/18 (67\%) CSF samples from MOG-IgG-seropositive patients; the MOG-IgG-specific antibody index was negative in all cases, indicating a predominantly peripheral origin of CSF MOG-IgG. Serum and CSF MOG-IgG belonged to the complement-activating IgG1 subclass. MOG-IgG was present already at disease onset. The antibodies remained detectable in 40/45 (89\%) follow-up samples obtained over a median period of 16.5 months (range 0-123). Serum titers were higher during attacks than during remission (p < 0.0001), highest during attacks of simultaneous myelitis and ON, lowest during acute isolated ON, and declined following treatment. Conclusions To date, this is the largest cohort studied for IgG to human full-length MOG by means of an up-to-date CBA. MOG-IgG is present in a substantial subset of patients with ON and/or myelitis, but not in classical MS. Co-existence of MOG-IgG and AQP4-IgG is highly uncommon. CSF MOG-IgG is of extrathecal origin. Serum MOG-IgG is present already at disease onset and remains detectable in the long-term course. Serum titers depend on disease activity and treatment status.}, language = {en} } @phdthesis{Merzyn2008, author = {Merzyn, Cornelia}, title = {Modulation systemischer Chemokinspiegel durch rekombinantes Interferon-beta bei Patienten mit multipler Sklerose}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-35828}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2008}, abstract = {Multiple Sklerose (MS) ist eine chronisch-entz{\"u}ndliche Erkrankung des Zentralen Nervensystems mit deutlich ausgepr{\"a}gten Autoimmunph{\"a}nomenen. Das derzeit meistverwendete Therapeutikum zur Sekund{\"a}rprophylaxe von Krankheitssch{\"u}ben ist rekombinantes Interferon-\&\#946; (IFN-\&\#946;). Wirk- und Nebenwirkungsmechanismen des Medikaments werden bisher nur partiell verstanden. In der Pathogenese der MS spielt eine Familie chemotaktisch wirksamer Zytokine, der Chemokine, eine entscheidende Rolle. Ziel dieser Studie war zu untersuchen, ob IFN-\&\#946; die systemischen Konzentrationen der Pathogenese-relevanten Chemokine CXCL10, CCL2 und außerdem des endogenen Pyrogens IL-6 ver{\"a}ndert, und ob diese Ver{\"a}nderungen mit dem Auftreten grippeartiger Nebenwirkungen korrelieren. Zu diesem Zweck wurden bei 37 Patienten mit schubf{\"o}rmiger MS zu drei Zeitpunkten - vor sowie 6 und 24 Stunden nach der Applikation von IFN-\&\#946; - die genannten Botenstoffe im Blut bestimmt. Parallel wurden subjektiv empfundene grippeartige Nebenwirkungen mit Hilfe eines standardisierten Fragebogens abgefragt, und die K{\"o}rperkerntemperatur wurde gemessen. Als Kontrollen dienten gesunde Probanden, derzeit nicht immunmodulatorisch behandelte MS-Patienten und MS-Patienten unter Therapie mit Glatirameracetat. Nur bei den mit IFN-\&\#946; behandelten Patienten zeigte sich nach 6 Stunden ein signifikanter transienter Anstieg der Konzentrationen von CXCL10, CCL2. Der Anstieg der Chemokinkonzentrationen korrelierte mit einem transienten IL-6-Anstieg und dem Auftreten grippeartiger Nebenwirkungen. Chemokine, unter denen sich zahlreiche starke endogene Pyrogene befinden, k{\"o}nnten somit f{\"u}r die h{\"a}ufig zu beobachtenden grippeartigen Nebenwirkungen mit verantwortlich sein. Die Ergebnisse werfen die weiterf{\"u}hrende Frage auf, ob die beobachtete Chemokininduktion auch relevant f{\"u}r den therapeutischen Effekt von IFN-\&\#61538; ist. Ob Chemokine sich erfolgreich als Biomarker zur Pr{\"a}diktion des Therapieerfolgs einsetzen lassen, wird derzeit in einem weiterf{\"u}hrenden Projekt untersucht.}, subject = {Multiple Sklerose}, language = {de} } @phdthesis{Nehen2021, author = {Nehen, Mathias Julius}, title = {Modulation der Schrankenfunktion prim{\"a}rer humaner zerebraler Endothelzellen durch Fumars{\"a}ureester unter inflammatorischen und nicht-inflammatorischen Bedingungen}, doi = {10.25972/OPUS-24092}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240925}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Die Multiple Sklerose ist eine bisher nicht heilbare, chronisch-inflammatorische demyelinisierende Erkrankung des zentralen Nervensystems. Trotz intensiver Forschungsbem{\"u}hungen ist der exakte Pathomechanismus nicht vollkommen verstanden. Klar ist jedoch, dass der Blut-Hirn-Schranke eine entscheidende Rolle bei der Pathogenese zukommt. Seit Februar 2014 ist mit Dimethylfumarat ein neues orales Medikament f{\"u}r die schubf{\"o}rmige Multiple Sklerose zugelassen. Die Wirkungen von Fumars{\"a}ureestern auf humane zerebrale Endothelzellen als Grundsteine der Blut-Hirn-Schranke sind allerdings nur unzureichend untersucht. Mehrere Forschungsgruppen demonstrierten an humanem Nabelschnurvenenendothel einen hemmenden Effekt von Fumars{\"a}ureestern auf die Adh{\"a}sion von Leukozyten und beschrieben eine Inhibition der Aktivierung des proinflammatorischen Transkriptionsfaktors NFB in den Endothelzellen. Aufgrund der charakteristischen Eigenschaften zerebralen Endothels ist eine {\"U}bertragung dieser Beobachtungen auf die Blut-Hirn-Schranke allerdings nicht ohne weiteres m{\"o}glich. Daher galt es potentielle Effekte von Fumars{\"a}ureestern auf prim{\"a}re humane zerebrale Endothelzellen als in vitro Modell der Blut-Hirn-Schranke zu {\"u}berpr{\"u}fen. Dabei wurden die Zellen nicht nur unter ruhenden Bedingungen, sondern auch unter inflammatorischer Stimulation mit TNF-α, IL-1 und IFN untersucht, einem Milieu, wie es in inflammatorischen MS L{\"a}sionen zu finden ist. In Leukozyten-Adh{\"a}sionsassays konnte durch Inkubation mit Monomethylfumarat und Dimethylfumarat keine funktionale Beeinflussung der Adh{\"a}sion von T-Lymphozyten an den verwendeten zerebralen Endothelzellen verzeichnet werden. Kongruent dazu fand sich in durchflusszytometrischen Analysen keine Hemmung der inflammatorisch vermittelten Expression des Adh{\"a}sionsmolek{\"u}ls ICAM-1, welches eine tragende Rolle bei der Leukozytenmigration spielt. Inflammatorische intrazellul{\"a}re Signalwege, wie die NFB-Kerntranslokation oder die Phosphorylierung von p38 wurden in HECE im Gegensatz zu HUVEC durch Fumars{\"a}ureester ebenso wenig beeinflusst. Diese in sich konsistenten Ergebnisse f{\"u}hren zu der Schlussfolgerung, dass im Gegensatz zu anderen Gef{\"a}ßbetten weder Dimethylfumarat noch Monomethylfumarat direkt am zerebralen Endothel anti-inflammatorisch wirken.}, subject = {Multiple Sklerose}, language = {de} } @article{KressHuettenhoferLandryetal.2013, author = {Kress, Michaela and H{\"u}ttenhofer, Alexander and Landry, Marc and Kuner, Rohini and Favereaux, Alexandre and Greenberg, David and Bednarik, Josef and Heppenstall, Paul and Kronenberg, Florian and Malcangio, Marzia and Rittner, Heike and {\"U}{\c{c}}eyler, Nurcan and Trajanoski, Zlatko and Mouritzen, Peter and Birklein, Frank and Sommer, Claudia and Soreq, Hermona}, title = {microRNAs in nociceptive circuits as predictors of future clinical applications}, series = {Frontiers in Molecular Neuroscience}, volume = {6}, journal = {Frontiers in Molecular Neuroscience}, number = {33}, doi = {10.3389/fnmol.2013.00033}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154597}, year = {2013}, abstract = {Neuro-immune alterations in the peripheral and central nervous system play a role in the pathophysiology of chronic pain, and non-coding RNAs - and microRNAs (miRNAs) in particular - regulate both immune and neuronal processes. Specifically, miRNAs control macromolecular complexes in neurons, glia and immune cells and regulate signals used for neuro-immune communication in the pain pathway. Therefore, miRNAs may be hypothesized as critically important master switches modulating chronic pain. In particular, understanding the concerted function of miRNA in the regulation of nociception and endogenous analgesia and defining the importance of miRNAs in the circuitries and cognitive, emotional and behavioral components involved in pain is expected to shed new light on the enigmatic pathophysiology of neuropathic pain, migraine and complex regional pain syndrome. Specific miRNAs may evolve as new druggable molecular targets for pain prevention and relief. Furthermore, predisposing miRNA expression patterns and inter-individual variations and polymorphisms in miRNAs and/or their binding sites may serve as biomarkers for pain and help to predict individual risks for certain types of pain and responsiveness to analgesic drugs. miRNA-based diagnostics are expected to develop into hands-on tools that allow better patient stratification, improved mechanism-based treatment, and targeted prevention strategies for high risk individuals.}, language = {en} } @phdthesis{Leinders2016, author = {Leinders, Mathias}, title = {microRNAs in chronic pain}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144395}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2016}, abstract = {Chronic pain is a common problem in clinical practice, not well understood clinically, and frequently tough to satisfactorily diagnose. Because the pathophysiology is so complex, finding effective treatments for people with chronic pain has been overall less than successful and typically reduced to an unsatisfactory trial-and-error process, all of which translates into a significant burden to society. Knowledge of the mechanisms underlying the development of chronic pain, and moreover why some patients experience pain and others not, may aid in developing specific treatment regimens. Although nerve injuries are major contributors to pain chronification, they cannot explain the entire phenomenon. Considerable research has underscored the importance of the immune system for the development and maintenance of chronic pain, albeit the exact factors regulating inflammatory reactions remain unclear. Understanding the putative molecular and cellular regulator switches of inflammatory reactions will open novel opportunities for immune modulatory analgesics with putatively higher specificity and less adverse effects. It has become clear that small, non- coding RNA molecules known as microRNAs are in fact potent regulators of many thousands of genes and possibly cross-communicate between cellular pathways in multiple systems acting as so-called "master-switches". Aberrant expression of miRNAs is now implicated in numerous disorders, including nerve injuries as well as in inflammatory processes. Moreover, compelling evidence supports the idea that miRNAs also regulate pain, and in analogy to the oncology field aid in the differential diagnosis of disease subtypes. In fact, first reports describing characteristic miRNA expression profiles in blood or cerebrospinal fluid of patients with distinct pain conditions are starting to emerge, however evidence linking specific miRNA expression profiles to specific pain disorders is still insufficient. The present thesis aimed at first, identifying specific miRNA signatures in two distinct chronic pain conditions, namely peripheral neuropathies of different etiologies and fibromyalgia syndrome. Second, it aimed at identifying miRNA profiles to better understand potential factors that differentiate painful from painless neuropathies and third, study the mechanistic role of miRNAs in the pathophysiology of pain, to pave the way for new druggable targets. Three studies were conducted in order to identify miRNA expression signatures that are characteristic for the given chronic pain disorder. The first study measured expression of miR-21, miR-146a and miR-155 in white blood cells, skin and nerve biopsies of patients with peripheral neuropathies. It shows that peripheral neuropathies of different etiologies are associated with increased peripheral miR-21 and miR-146a, but decreased miR-155 expression. More importantly, it was shown that painful neuropathies have increased sural nerve miR-21 and miR-155 expression, but reduced miR-146a and miR-155 expression in distal skin of painful neuropathies. These results point towards the potential use of miRNAs profiles to stratify painful neuropathies. The seconds study extends these findings and first analyzed the role of miR-132-3p in patients and subsequently in an animal model of neuropathic pain. Interestingly, miR-132-3p was upregulated in white blood cells and sural nerve biopsies of patients with painful neuropathies and in animals after spared nerve injury. Pharmacologically modulating the expression of miR-132-3p dose-dependently reversed pain behavior and pain aversion, indicating the pro-nociceptive effect of miR-132-3p in chronic pain. This study thus demonstrates the potential analgesic impact by modulating miRNA expression. Fibromyalgia is associated with chronic widespread pain and, at least in a subgroup, impairment in small nerve fiber morphology and function. Interestingly, the disease probably comprises subgroups with different underlying pathomechanisms. In accordance with this notion, the third study shows that fibromyalgia is associated with both aberrant white blood cell and cutaneous miRNA expression. Being the first of its kind, this study identified miR-let-7d and its downstream target IGF-1R as potential culprit for impaired small nerve fiber homeostasis in a subset of patients with decreased intra-epidermal nerve fiber density. The work presented in this thesis is a substantial contribution towards the goal of better characterizing chronic pain based on miRNA expression signatures and thus pave the way for new druggable targets.}, subject = {miRNS}, 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} } @article{ReinholdKrugSalvadoretal.2022, author = {Reinhold, Ann Kristin and Krug, Susanne M. and Salvador, Ellaine and Sauer, Reine S. and Karl-Sch{\"o}ller, Franziska and Malcangio, Marzia and Sommer, Claudia and Rittner, Heike L.}, title = {MicroRNA-21-5p functions via RECK/MMP9 as a proalgesic regulator of the blood nerve barrier in nerve injury}, series = {Annals of the New York Academy of Sciences}, volume = {1515}, journal = {Annals of the New York Academy of Sciences}, number = {1}, doi = {10.1111/nyas.14816}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318226}, pages = {184 -- 195}, year = {2022}, abstract = {Both nerve injury and complex regional pain syndrome (CRPS) can result in chronic pain. In traumatic neuropathy, the blood nerve barrier (BNB) shielding the nerve is impaired—partly due to dysregulated microRNAs (miRNAs). Upregulation of microRNA-21-5p (miR-21) has previously been documented in neuropathic pain, predominantly due to its proinflammatory features. However, little is known about other functions. Here, we characterized miR-21 in neuropathic pain and its impact on the BNB in a human-murine back translational approach. MiR-21 expression was elevated in plasma of patients with CRPS as well as in nerves of mice after transient and persistent nerve injury. Mice presented with BNB leakage, as well as loss of claudin-1 in both injured and spared nerves. Moreover, the putative miR-21 target RECK was decreased and downstream Mmp9 upregulated, as was Tgfb. In vitro experiments in human epithelial cells confirmed a downregulation of CLDN1 by miR-21 mimics via inhibition of the RECK/MMP9 pathway but not TGFB. Perineurial miR-21 mimic application in mice elicited mechanical hypersensitivity, while local inhibition of miR-21 after nerve injury reversed it. In summary, the data support a novel role for miR-21, independent of prior inflammation, in elicitation of pain and impairment of the BNB via RECK/MMP9.}, language = {en} } @article{GrohAbdelwahabKattimanietal.2023, author = {Groh, Janos and Abdelwahab, Tassnim and Kattimani, Yogita and H{\"o}rner, Michaela and Loserth, Silke and Gudi, Viktoria and Adalbert, Robert and Imdahl, Fabian and Saliba, Antoine-Emmanuel and Coleman, Michael and Stangel, Martin and Simons, Mikael and Martini, Rudolf}, title = {Microglia-mediated demyelination protects against CD8\(^+\) T cell-driven axon degeneration in mice carrying PLP defects}, series = {Nature Communications}, volume = {14}, journal = {Nature Communications}, doi = {10.1038/s41467-023-42570-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357641}, year = {2023}, abstract = {Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes. We show that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8\(^+\) T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce cytoskeletal alterations within myelinating glia and aberrant actomyosin constriction of axons at paranodal domains. Our study identifies detrimental axon-glia-immune interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.}, language = {en} } @phdthesis{Kewenig2014, author = {Kewenig, Susanne Katharina}, title = {Messung der zerebralen Aktivierung mittels funktioneller Nah-Infrarot-Spektroskopie bei Patienten mit Fibromyalgie-Syndrom}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-107515}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2014}, abstract = {Wir untersuchten die zerebrale Aktivierung von Patienten mit Fibromyalgie-Syndrom (FMS) mittels funktioneller Nah-Infrarot-Spektroskopie (fNIRS). Das FMS ist ein Symptomenkomplex aus Schmerzen in mehreren K{\"o}rperregionen sowie weiteren k{\"o}rperlichen und seelischen Beschwerden, wie Schlafst{\"o}rungen, kognitiven Defiziten und Depressionen. Die fNIRS ist eine neue, nicht-invasive Technik, die eine indirekte Messung der regionalen kortikalen Hirnaktivierung erlaubt. Es wurden 25 FMS-Patienten, 10 MD-Patienten ohne Schmerzen und 35 gesunde Kontrollen in die Studie eingeschlossen. Alle Patienten wurden klinisch-neurologisch untersucht. Dar{\"u}ber hinaus f{\"u}llten alle Teilnehmer Frageb{\"o}gen zu Schmerzen (GCPS, NPSI), FMS-Symptomen (FIQ), Depressionen (BDI II, ADS) und Empathief{\"a}higkeit (SPF) aus. Die kortikale Aktivierung wurde unter drei Stimulations-Bedingungen mittels fNIRS gemessen: 1.) Anwendung mechanischer (Druck-) Schmerzreize auf den dorsalen Unterarm; 2.) Anwendung visuell-emotionaler Reize in Form von neutralen, negativen und Schmerz-assoziierten Bildern; 3.) Wortfl{\"u}ssigkeitstest. Erg{\"a}nzend wurden die unter 2.) pr{\"a}sentierten Bilder bewertet sowie ein Zahlenverbindungstest durchgef{\"u}hrt. FMS-Patienten hatten in den Schmerzfrageb{\"o}gen und im FIQ-Fragebogen deutlich h{\"o}here Werte als MD-Patienten und Kontrollen (p < 0,001). In den Depressionsfrageb{\"o}gen erreichten FMS-Patienten {\"a}hnlich hohe Werte wie MD-Patienten. Die Empathief{\"a}higkeit war bei FMS-Patienten tendenziell st{\"a}rker ausgepr{\"a}gt als bei MD-Patienten und Kontrollen. FMS-Patienten zeigten niedrigere Druckschmerzschwellen bei gleicher Schmerzintensit{\"a}t als MD-Patienten und Kontrollen (p < 0,001). Auf einen unilateralen schmerzhaften Druckreiz reagierten FMS-Patienten mit einer verst{\"a}rkten bilateralen kortikalen Aktivierung, die sich im Vergleich zu Kontrollen insbesondere im rechten pr{\"a}frontalen Kortex (p < 0,05) sowie zu MD-Patienten bilateral im Frontalkortex unterschied (p < 0,05). Auf einen Druckreiz der gleichen St{\"a}rke, der f{\"u}r FMS-Patienten schmerzhaft, aber f{\"u}r Zusatzkontrollen schmerzfrei war, zeigten FMS-Patienten im Vergleich zu diesen eine verst{\"a}rkte Aktivierung im linken dorsolateralen pr{\"a}frontalen Kortex (p < 0,05). Der kortikale Aktivierungsunterschied bei Schmerz-assoziierten versus neutralen Bildern war bei FMS-Patienten im linken pr{\"a}frontalen Kortex wesentlich ausgepr{\"a}gter als bei Kontrollen (p < 0,05), w{\"a}hrend die Schmerz-assoziierten Bilder von FMS-Patienten weniger unangenehm bewertet wurden als von Kontrollen. Der Aktivierungsunterschied bei negativen versus neutralen Bildern war bei MD-Patienten im linken Frontalkortex wesentlich geringer ausgepr{\"a}gt als bei FMS-Patienten und Kontrollen (p < 0,05). Im Wortfl{\"u}ssigkeitstest und im Zahlenverbindungstest konnten keine kognitiven Defizite bzw. Aktivierungsunterschiede zwischen FMS-Patienten und Kontrollen gefunden werden. Allerdings zeigten MD-Patienten in beiden Bedingungen des Wortfl{\"u}ssigkeitstests eine geringere frontale Aktivierung als FMS-Patienten und Kontrollen (p < 0,05). Diese Studie belegt die ver{\"a}nderte zentrale Schmerzverarbeitung bei FMS-Patienten und zeigt, dass diese mittels fNIRS messbar ist. FMS-Patienten zeigten st{\"a}rkere Aktivierungen Schmerz-assoziierter Hirnareale w{\"a}hrend mechanischer und visueller Schmerzstimuli im Vergleich zu gesunden Kontrollen. Zudem best{\"a}tigt diese Studie die Unterscheidung zwischen FMS und Depression.}, subject = {Fibromyalgie}, language = {de} } @article{SchuhmannPappStolletal.2021, author = {Schuhmann, Michael K. and Papp, Lena and Stoll, Guido and Blum, Robert and Volkmann, Jens and Fluri, Felix}, title = {Mesencephalic electrical stimulation reduces neuroinflammation after photothrombotic stroke in rats by targeting the cholinergic anti-inflammatory pathway}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {3}, issn = {1422-0067}, doi = {10.3390/ijms22031254}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259099}, year = {2021}, abstract = {Inflammation is crucial in the pathophysiology of stroke and thus a promising therapeutic target. High-frequency stimulation (HFS) of the mesencephalic locomotor region (MLR) reduces perilesional inflammation after photothrombotic stroke (PTS). However, the underlying mechanism is not completely understood. Since distinct neural and immune cells respond to electrical stimulation by releasing acetylcholine, we hypothesize that HFS might trigger the cholinergic anti-inflammatory pathway via activation of the α7 nicotinic acetylcholine receptor (α7nAchR). To test this hypothesis, rats underwent PTS and implantation of a microelectrode into the MLR. Three hours after intervention, either HFS or sham-stimulation of the MLR was applied for 24 h. IFN-γ, TNF-α, and IL-1α were quantified by cytometric bead array. Choline acetyltransferase (ChAT)\(^+\) CD4\(^+\)-cells and α7nAchR\(^+\)-cells were quantified visually using immunohistochemistry. Phosphorylation of NFĸB, ERK1/2, Akt, and Stat3 was determined by Western blot analyses. IFN-γ, TNF-α, and IL-1α were decreased in the perilesional area of stimulated rats compared to controls. The number of ChAT\(^+\) CD4\(^+\)-cells increased after MLR-HFS, whereas the amount of α7nAchR\(^+\)-cells was similar in both groups. Phospho-ERK1/2 was reduced significantly in stimulated rats. The present study suggests that MLR-HFS may trigger anti-inflammatory processes within the perilesional area by modulating the cholinergic system, probably via activation of the α7nAchR.}, language = {en} } @phdthesis{Greeske2008, author = {Greeske, Juliane}, title = {Mechanismen der Makrophagen-Aktivierung in Connexin32-defizienten M{\"a}usen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-27491}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2008}, abstract = {Connexin32- defiziente M{\"a}use stellen ein Mausmodell f{\"u}r eine Form der heredit{\"a}ren peripheren Neuropahtie dar. Es konnte gezeigt werden, dass Makrophagen, m{\"o}glicherweise aktiviert durch MCP-1, die Demyelinisierung in Connexin32-defizienten M{\"a}usen vermitteln. Diese Arbeit untersucht m{\"o}gliche Signaltransduktionswege, die in den peripheren Nerven Connexin32- defizienter M{\"a}use aktiviert sein k{\"o}nnten und damit in Zusammenhang mit der Genexpression von MCP-1 und/oder Makrophagen-Aktivierung stehen k{\"o}nnten.}, subject = {Makrophage}, 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{UeceylerBikoSommer2010, author = {Ueceyler, Nurcan and Biko, Lydia and Sommer, Claudia}, title = {MDL-28170 Has No Analgesic Effect on CCI Induced Neuropathic Pain in Mice}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68359}, year = {2010}, abstract = {The calpain inhibitor MDL-28710 blocks the early local pro-inflammatory cytokine gene expression in mice after chronic constriction nerve injury (CCI). Onehundred- thirteen wild type mice of C57Bl/6J background received CCI of the right sciatic nerve. Mechanical paw withdrawal thresholds and thermal withdrawal latencies were investigated at baseline and at 1, 3, and 7 days after CCI. Three application regimens were used for MDL-28170: a) single injection 40 min before CCI; b) serial injections of MDL- 28170 40 min before and up to day three after CCI; c) sustained application via intraperitoneal osmotic pumps. The control animals received the vehicle DMSO/PEG 400. The tolerable dose of MDL-28170 for mice was 30 mg/kg body weight, higher doses were lethal within the first hours after application. Mechanical withdrawal thresholds and thermal withdrawal latencies were reduced after CCI and did not normalize after single or serial injections, nor with application of MDL-28170 via osmotic pumps. Although the calpain inhibitor MDL-28170 inhibits the early local cytokine upregulation in the sciatic nerve after CCI, pain behavior is not altered. This finding implies that local cytokine upregulation after nerve injury alone is only one factor in the induction and maintenance of neuropathic pain.}, subject = {Medizin}, language = {en} } @phdthesis{Karch2022, author = {Karch, Katharina}, title = {Mapping and Neutralization of Antibodies against Neurofascin, Contactin 1, Contactin associated protein 1 and Cortactin}, doi = {10.25972/OPUS-28022}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-280223}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Immune-mediated polyneuropathies like chronic inflammatory demyelinating polyradiculoneuropathy or Guillain-Barr{\´e} syndrome are rare diseases of the peripheral nervous system. A subgroup of patients harbors autoantibodies against nodal or paranodal antigens, associated with a distinct phenotype and treatment response. In a part of patients with pathologic paranodal or nodal immunoreactivity the autoantigens remain difficult or impossible to determine owing to limitations of the used detection approach - usually ELISAs (enzyme-linked-immunosorbent-assays) - and incomplete knowledge of the possible autoantigens. Due to their high-throughput, low sample consumption and high sensitivity as well as the possibility to display many putative nodal and paranodal autoantigens simultaneously, peptide microarray-based approaches are prime candidates for the discovery of novel autoantigens, point-of-care diagnostics and, in addition, monitoring of pathologic autoimmune response. Current applications of peptide microarrays are however limited by high false-positive rates and the associated need for detailed follow-up studies and validation. Here, robust peptide microarray-based detection of antibodies and the efficient validation of binding signals by on-chip neutralization is demonstrated. First, autoantigens were displayed as overlapping peptide libraries in microarray format. Copies of the biochips were used for the fine mapping of antibody epitopes. Next, binding signals were validated by antibody neutralization in solution. Since neutralizing peptides are obtained in the process of microarray fabrications, neither throughput nor costs are significantly altered. Similar in-situ validation approaches could contribute to future autoantibody characterization and detection methods as well as to therapeutic research. Areas of application could be expanded to any autoimmune-mediated neurological disease as a long-term vision.}, subject = {Microarray}, language = {en} } @article{PohGreenAgostinellietal.2022, author = {Poh, Eugenia Z. and Green, Courtney and Agostinelli, Luca and Penrose-Menz, Marissa and Karl, Ann-Kathrin and Harvey, Alan R. and Rodger, Jennifer}, title = {Manipulating the level of sensorimotor stimulation during LI-rTMS can improve visual circuit reorganisation in adult ephrin-A2A5\(^{-/-}\) Mice}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {5}, issn = {1422-0067}, doi = {10.3390/ijms23052418}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284090}, year = {2022}, abstract = {Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has the potential to treat a variety of neurologic and psychiatric disorders. The extent of rTMS-induced neuroplasticity may be dependent on a subject's brain state at the time of stimulation. Chronic low intensity rTMS (LI-rTMS) has previously been shown to induce beneficial structural and functional reorganisation within the abnormal visual circuits of ephrin-A2A5\(^{-/-}\) mice in ambient lighting. Here, we administered chronic LI-rTMS in adult ephrin-A2A5\(^{-/-}\) mice either in a dark environment or concurrently with voluntary locomotion. One day after the last stimulation session, optokinetic responses were assessed and fluorescent tracers were injected to map corticotectal and geniculocortical projections. We found that LI-rTMS in either treatment condition refined the geniculocortical map. Corticotectal projections were improved in locomotion+LI-rTMS subjects, but not in dark + LI-rTMS and sham groups. Visuomotor behaviour was not improved in any condition. Our results suggest that the beneficial reorganisation of abnormal visual circuits by rTMS can be significantly influenced by simultaneous, ambient visual input and is enhanced by concomitant physical exercise. Furthermore, the observed pathway-specific effects suggest that regional molecular changes and/or the relative proximity of terminals to the induced electric fields influence the outcomes of LI-rTMS on abnormal circuitry.}, language = {en} } @phdthesis{Weise2006, author = {Weise, David Thomas}, title = {Maladaptive Plastizit{\"a}t bei Schreibkrampf-Patienten}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-26734}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2006}, abstract = {Der Schreibkrampf ist eine Form der fokalen Handdystonie, die durch anhaltende, unwillk{\"u}rliche Verkrampfung der Hand beim Schreiben gekennzeichnet ist und zu unnat{\"u}rlicher, zum Teil statischer und schmerzhafter Handhaltung f{\"u}hrt. Bei pr{\"a}disponierten Personen kann dieser nach exzessiver Wiederholung von stereotypen Bewegungen auftreten. Bewegungen und sensible Stimulation f{\"u}hren durch Mechanismen neuronaler Plastizit{\"a}t zu dynamischer Modulation sensibler und motorischer kortikaler Repr{\"a}sentationen. Wird neuronale Plastizit{\"a}t nicht in nat{\"u}rlichen Grenzen gehalten, kann es zu ver{\"a}nderten, entdifferenzierten neuronalen Repr{\"a}sentationen wie sie bei fokaler Handdystonie gefunden werden, f{\"u}hren. Zellul{\"a}re Kandidatenmechanismen f{\"u}r die Bildung neuronaler Engramme sind die Langzeitpotenzierung und -depression (LTP / LTD) neuronaler Synapsen. Wir verwendeten die als ein Modell f{\"u}r assoziative LTP und LTD beim Menschen entwickelte assoziative Paarstimulation (PAS). Mit dieser Methode untersuchten wir die zeitlichen und r{\"a}umlichen Eigenschaften neuronaler Plastizit{\"a}t des Motorkortex bei Schreibkrampf-Patienten. Eine niederfrequente elektrische Stimulation eines peripheren Nerven (N. medianus (MN) oder N. ulnaris (UN)) wurde wiederholt (0,1Hz, 180 Reizpaare) mit einer transkraniellen Magnetstimulation (TMS) {\"u}ber dem homotopen kontralateralen Motorkortex mit einem Zeitintervall von 21,5ms (MN-PAS21.5; UN-PAS21.5) oder 10ms (MN-PAS10) kombiniert. Bei MN-PAS21.5 und MN-PAS10 wurde die optimale Spulenposition so gew{\"a}hlt, dass das magnetisch evozierte motorische Potential (MEP) im kontralateralen M. abductor pollicis brevis (APB) eine maximale Gr{\"o}ße annahm, f{\"u}r UN-PAS21.5 wurde die Spule {\"u}ber dem "Hotspot" des M. abductor digiti minimi (ADM) platziert. Zehn Schreibkrampf-Patienten (Alter 39±9 Jahre; Mittelwert±Standardabweichung) und 10 gesunde bez{\"u}glich Alter und Geschlecht angepasste Probanden wurden untersucht. Ver{\"a}nderungen der Exzitabilit{\"a}t wurden mittels TMS bis zu 85 min nach der jeweiligen Intervention gemessen. Nach MN-PAS21.5 oder UN-PAS21.5 stieg die Amplitude der MEPs bei den gesunden Probanden nur in den Muskeln, die homotope externe PAS Stimulation erhalten hatten (APB Zielmuskel f{\"u}r MN; ADM f{\"u}r UN), nicht aber in Muskeln, die nicht homotop stimuliert worden waren. Im Gegensatz dazu stiegen bei Schreibkrampf-Patienten nach MN-PAS21.5 oder UN-PAS21.5 die Amplituden der APB und ADM-MEPs unabh{\"a}ngig von dem Ort der peripheren oder zentralen Stimulation. Bei Schreibkrampf-Patienten war eine fr{\"u}here, st{\"a}rkere und l{\"a}ngere Zunahme der kortikalen Exzitabilit{\"a}t im Vergleich zu den Kontrollen zu verzeichnen. Qualitativ {\"a}hnliche Beobachtungen konnten in umgekehrtem Sinne (fr{\"u}here und l{\"a}ngere Abnahme der Exzitabilit{\"a}t im homo- und heterotopen Muskel) nach MN-PAS10 gemacht werden. LTP- und LTD-{\"a}hnliche Plastizit{\"a}t ist bei Schreibkrampf-Patienten demnach gesteigert und die normale strenge topographische Spezifit{\"a}t PAS-induzierter Plastizit{\"a}t aufgehoben. Diese maladaptive Plastizit{\"a}t k{\"o}nnte ein Bindeglied zwischen repetitiven Bewegungen und gest{\"o}rter sensomotorischer Repr{\"a}sentation darstellen, damit zu einem besseren Verst{\"a}ndnis der Pathophysiologie der Dystonie beitragen und letztendlich m{\"o}gliche therapeutische Konsequenzen implizieren.}, subject = {Neuronale Plastizit{\"a}t}, language = {de} } @article{WeiseStoll2012, author = {Weise, Gesa and Stoll, Guido}, title = {Magnetic resonance imaging of blood brain/nerve barrier dysfunction and leukocyte infiltration: closely related or discordant?}, series = {Frontiers in Neurology}, volume = {3}, journal = {Frontiers in Neurology}, number = {178}, doi = {10.3389/fneur.2012.00178}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123359}, year = {2012}, abstract = {Unlike other organs the nervous system is secluded from the rest of the organism by the blood brain barrier (BBB) or blood nerve barrier (BNB) preventing passive influx of fluids from the circulation. Similarly, leukocyte entry to the nervous system is tightly controlled. Breakdown of these barriers and cellular inflammation are hallmarks of inflammatory as well as ischemic neurological diseases and thus represent potential therapeutic targets. The spatiotemporal relationship between BBB/BNB disruption and leukocyte infiltration has been a matter of debate. We here review contrast-enhanced magnetic resonance imaging (MRI) as a non-invasive tool to depict barrier dysfunction and its relation to macrophage infiltration in the central and peripheral nervous system under pathological conditions. Novel experimental contrast agents like Gadofluorine M (Gf) allow more sensitive assessment of BBB dysfunction than conventional Gadolinium (Gd)-DTPA enhanced MRI. In addition, Gf facilitates visualization of functional and transient alterations of the BBB remote from lesions. Cellular contrast agents such as superparamagnetic iron oxide particles (SPIO) and perfluorocarbons enable assessment of leukocyte (mainly macrophage) infiltration by MR technology. Combined use of these MR contrast agents disclosed that leukocytes can enter the nervous system independent from a disturbance of the BBB, and vice versa, a dysfunctional BBB/BNB by itself is not sufficient to attract inflammatory cells from the circulation. We will illustrate these basic imaging findings in animal models of multiple sclerosis, cerebral ischemia, and traumatic nerve injury and review corresponding findings in patients.}, language = {en} } @article{KunzeLillaStetteretal.2018, author = {Kunze, Ekkehard and Lilla, Nadine and Stetter, Christian and Ernestus, Ralf-Ingo and Westermaier, Thomas}, title = {Magnesium protects in episodes of critical perfusion after aneurysmal SAH}, series = {Translational Neuroscience}, volume = {9}, journal = {Translational Neuroscience}, number = {1}, doi = {10.1515/tnsci-2018-0016}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177078}, pages = {99-105}, year = {2018}, abstract = {Background: To analyze whether magnesium has a neuroprotective effect during episodes that indicate a critical brain perfusion after aneurysmal subarachnoid hemorrhage (SAH). Methods: 107 patients with aSAH were randomized to continuously receive intravenous magnesium sulfate with target serum levels of 2.0 - 2.5 mmol/l (n = 54) or isotonic saline (n = 53). Neurological examination and transcranial Doppler sonography (TCD) were performed daily, Perfusion-CT (PCT) was acquired in 3-day intervals, angiography in case of suspected vasospasm. The primary endpoint was the development of secondary infarction following episodes of delayed ischemic neurological deficit (DIND), elevated mean flow velocity (MFV) in TCD or pathological findings in PCT. Results: In the magnesium group, 9 episodes of DIND were registered, none was followed by secondary infarction. In the control group, 23 episodes of DIND were registered, 9 were followed by secondary infarction (p < 0.05). In the magnesium group, 114 TCD-measurements showed an elevated MFV(> 140 cm/s). 7 were followed by new infarction. In control patients, 135 measurements showed elevated MFV, 32 were followed by new infarction (p < 0.05). 10 of 117 abnormal PCT-findings were followed by new infarction, compared to 30 of 122 in the control-group (p < 0.05). Conclusion: DIND, elevated MFV in TCD and abnormal PCT are findings which are associated with an increased risk to develop delayed secondary infarction. The results of this analysis suggest that magnesium-treatment may reduce the risk to develop infarction in a state of critical brain perfusion.}, language = {en} } @phdthesis{Schaefer2014, author = {Sch{\"a}fer, Kristina}, title = {L{\"a}sst sich eine Vaskulitische Polyneuropathie mittels B-Bild-Sonographie der Beinnerven identifizieren?}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-104712}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2014}, abstract = {{\"U}ber die Nervensonographie wurde bereits in den 1980er Jahren erstmals berichtet. Die rasche Weiterentwicklung der Technik hat dazu gef{\"u}hrt, dass es inzwischen zahlreiche Fallberichte und einige Studien gibt, die sich mit der Darstellung peripherer Nerven durch Ultraschall als Mittel zur Diagnose verschiedener Nervpathologien besch{\"a}ftigen. Besonders bei der Diagnostik des epidemiologisch h{\"a}ufigen Karpaltunnelsyndroms ist die sonographische Beurteilung des N. medianus in dieser Lokalisation vielerorts bereits etablierter Bestandteil der Diagnostik. In der hier vorgelegten Studie sollte der Stellenwert der B-Bild-Sonographie peripherer Nerven am Unterschenkel f{\"u}r die Diagnose einer Vaskulitischen Neuropathie gepr{\"u}ft werden. Dazu musste zun{\"a}chst die Ultraschalluntersuchung spezieller Nerven am Unterschenkel etabliert werden. Diese ist technisch deutlich anspruchsvoller als die Darstellung von Karpaltunnelsyndrom oder Armplexus. Durch die f{\"u}nfmalige Untersuchung zehn junger Personen wurden ultraschalltechnisch leicht reproduzierbar anatomisch auffindbare und Anisotropie-vermeidende Abschnitte von N. suralis, N. peroneus communis, profundus, superfcialis und N. tibialis definiert und als Messpunkte der Studie zu Grunde gelegt. In die von der Ethikkommission der Medizinischen Fakult{\"a}t positiv beschiedene Studie wurden 26 Patienten/-innen, die klinisch und elektrophysiologisch nachgewiesen eine Polyneuropathie hatten und bei denen zur Ursachendiagnostik eine Biopsie und histologische Aufarbeitung des N. suralis durchgef{\"u}hrt wurde (Abteilung f{\"u}r Neuropathologie des Pathologischen Instituts der Universit{\"a}t sowie Histologielabor der Neurologischen Universit{\"a}tsklinik), sowie 26 Kontrollpersonen ohne klinischen Hinweis auf eine Polyneuropathie nach informiertem Einverst{\"a}ndnis aufgenommen. F{\"u}r jede/-n Patienten/-in wurde ein/-e Proband/-in gleichen Geschlechts mit einem Altersunterschied von h{\"o}chstens f{\"u}nf Jahren in die Kontrollgruppe aufgenommen. Alle 52 Untersuchten mussten erwachsen und 160 - 180 cm groß sein. Bei allen Patienten/-innen und Kontrollpersonen wurden jeweils der GD, der KD, der LD und die QSF des N. suralis am unteren Drittel der Wade und distal im Bereich des Außenkn{\"o}chels, des N. tibialis nahe des Innenkn{\"o}chels, des N. peroneus communis im Bereich des Fibulak{\"o}pfchens, des N. peroneus profundus am Fußr{\"u}cken und nahe der Großzehen und des N. peroneus superficialis im Bereich des distalen Schienbeins bestimmt. Alle gesuchten Nerven waren bei allen Versuchspersonen eindeutig identifizierbar. Die Untersuchungen wurden durch eine Untersucherin mit demselben Ger{\"a}t, geblindet f{\"u}r das Ergebnis der Histologie, durchgef{\"u}hrt. Das gew{\"a}hrleistete eine Konstanz in der schwierigen und mit Unsicherheiten behafteten Messung der Nervenstrukturen, was ausf{\"u}hrlich diskutiert wird. Ein statistisch signifikanter Unterschied zwischen den sonographisch erhobenen Messdaten der PNP-Gruppe und der Kontrollgruppe konnte bei 20 der 28 Parameter gezeigt werden. Bei 11 der 28 Parameter konnte zwischen Vaskulitis-Patienten/-innen und allen anderen, also PNP-Patienten/-innen und der Kontrollgruppe, ein statistisch signifikanter Unterschied festgestellt werden. Außerdem ergab die statistische Analyse bei drei der 28 Messgr{\"o}ßen einen statistisch signifikanten Unterschied zwischen Patienten/-innen mit und ohne Demyelinisierung des N. suralis in der feingeweblichen Untersuchung. Die sonographischen Ergebnisse der Vakulitis-Patienten/-innen unterschieden sich nicht von denen der PNP-Patienten/-innen mit anderer {\"A}tiologie. Es wurde auch kein statistisch signifikanter Unterschied zwischen den Werten der PNP-Patienten/-innen mit und ohne histologisch gesicherte entz{\"u}ndliche Komponente beobachtet. Gem{\"a}ß der histologischen Untersuchung der Biopsate wurde bei sechs Patienten/-innen eine Vaskulitis diagnostiziert. Bei f{\"u}nf dieser Patienten/-innen fielen teilweise Kaliberspr{\"u}nge im Sinne einer Zunahme der QSF oder Abflachung im Verlauf des N. suralis, N. peroneus superficialis und N. peroneus communis auf. Aber auch bei Patienten/-innen mit einer anderen Form der Polyneuropathie und einigen Kontrollpersonen waren Besonderheiten im sonographischen Bild einzelner Nerven zu beobachten. Mit der vorgelegten Untersuchung konnte zwar nicht gezeigt werden, dass die Nervensonographie einen Beitrag zur differentialdiagnostischen Abgrenzung Vaskulitischer Polyneuropathien leisten kann, der den Goldstandard invasiver Nervenbiopse entbehrlich machen k{\"o}nnte. Das war bei der histologischen Unterschiedlichkeit der besch{\"a}digten Nervenanatomie bei Vaskulitis aber auch nicht ernsthaft zu erwarten. Die vorgelegte Arbeit zeigt aber auch, dass kranke periphere Nerven von gesunden Nerven im Ultraschall unterscheidbar sind, wenn man wie hier systematisch mit 28 Parametern an sieben Messpunkten untersucht. Dies allerdings dauert auch f{\"u}r einen Ge{\"u}bten 40 bis 60 Minuten, so dass die Polyneuropathiediagnostik oder gar Differentialdiagnostik mittels Ultraschall aktuell noch als Forschungsinstrument an großen Fallzahlen anzusehen ist. Dabei wird es k{\"u}nftig f{\"u}r die Gruppenbildung der sonographisch Untersuchten neben {\"a}tiologischer und histologischer Gruppenbildung darauf ankommen, das Krankheitsbild besser zu definieren, d.h. Ausmaß von Demyelinisierung, Remyelinisierung und axonalem Untergang in geeignete Skalen zu fassen. Auch die Magnetresonanztomographie stellt eine Option als diagnostischer Baustein bei Vaskulitischer Polyneuropathie dar. Dieses bildgebende Verfahren kann bereits zur Diagnostik von traumatischen Nervverletzungen, Kompressionensyndromen, Raumforderungen im Bereich der Nerven und Plexusneuritis eingesetzt werden.}, subject = {Ultraschalldiagnostik}, language = {de} } @phdthesis{Wirsching2019, author = {Wirsching, Isabelle}, title = {LTD-artige zentralmotorische Plastizit{\"a}t im Schubereignis bei Patienten mit Multipler Sklerose}, doi = {10.25972/OPUS-18003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-180036}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2019}, abstract = {Die Multiple Sklerose ist eine chronisch entz{\"u}ndliche Erkrankung des zentralen Nervensystems. Durch ein komplexes Zusammenspiel von Genetik, Autoimmunvorg{\"a}ngen und proinflammatorischen Prozessen kommt es zur Demyelinisierung sowie zu axonalen Sch{\"a}den und kortikalen L{\"a}sionen (Calabrese et al., 2010; Ciccarelli et al., 2014; International Multiple Sclerosis Genetics et al., 2011; Leray et al., 2015). In den Industriel{\"a}ndern ist diese Erkrankung eine der h{\"a}ufigsten Ursachen f{\"u}r langfristige Behinderung bereits im fr{\"u}hen Lebensalter (Flores-Alvarado, Gabriel- 46 Ortiz, Pacheco-Mois, \& Bitzer-Quintero, 2015). Die Diskrepanz allerdings zwischen klinischer Symptomatik und den Befunden der Bildgebung (Barkhof, 2002) gibt Anlass daf{\"u}r, Adaptionsm{\"o}glichkeiten detailliert zu erforschen. Vorg{\"a}nge der Neuroplastizit{\"a}t mit LTP und LTD als Basismechanismen erscheinen dabei zunehmend Beachtung zu finden (Dayan \& Cohen, 2011; Zeller et al., 2011). Welche Rolle diese Prozesse allerdings im akuten Schub, w{\"a}hrend der h{\"a}ufig stark ausgepr{\"a}gten Symptomatik, insbesondere aber auch w{\"a}hrend ihrer R{\"u}ckbildung spielen, bleibt bisher weitgehend ungekl{\"a}rt. Eine Untersuchung zu stimulationsinduzierter LTP-artiger Plastizit{\"a}t im Schub deutete auf einen m{\"o}glichen Zusammenhang zwischen Ausmaß der Symptomr{\"u}ckbildung und PAS25-induziertem LTP-Effekt hin (Mori et al., 2014). In der vorliegenden Arbeit wurde komplement{\"a}r hierzu die stimulationsinduzierte LTD-artige Plastizit{\"a}t bei 19 MS- bzw. CIS-Patienten w{\"a}hrend des steroidbehandelten akuten Schubes untersucht. Als Kontrollgruppe wurden alters- und geschlechtsgematchte gesunde Probanden untersucht. Die Messungen wurden mithilfe eines Protokolls der assoziativen Paarstimulation durchgef{\"u}hrt. Paarstimulation wird die Kombination aus der peripher elektrischen und transkraniell magnetischen Stimulation genannt. Das in unserer Studie verwendete Protokoll sieht ein Interstimulusintervall von 10ms vor (PAS10). Der Effekt der Paarstimulation wird durch Messungen der Exzitabilit{\"a}t des motorischen Kortex mittels motorisch evozierter Potenziale (MEP) jeweils vor und nach der Intervention gemessen. Bei den MS-Patienten wurden diese Daten zum Zeitpunkt des Schubes (t1) und 12 Wochen danach (t2) erhoben; die gesunden Kontrollen wurden nur einmal gemessen. Daneben wurde bei den Schubpatienten zur Quantifizierung der klinischen Symptomatik jeweils zum ersten und zum zweiten Zeitpunkt der MSFC erhoben. Die MS-Patienten zeigten im akuten MS-Schub im Gegensatz zu der Kontrollgruppe aus Gesunden keinen LTD-artigen, sondern einen inversen, sprich einen signifikant LTP-artigen Effekt; dieser war zum Zeitpunkt t2 nicht mehr zu erkennen. Der Unterschied zwischen den PAS10-Effekten der MS- und der Kontrollgruppe war ebenfalls signifikant. Der Vergleich der MSFC-Werte der MS-Gruppe zwischen t1 und t2 erbrachte eine signifikante klinische Besserung. Eine signifikante Korrelation zwischen 47 den neurophysiologischen und klinischen Daten bzw. ihren Ver{\"a}nderungen zwischen t1 und t2 zeigte sich nicht. Diese Ergebnisse untermauern und erweitern bereits bestehende Hinweise, dass w{\"a}hrend der akuten Inflammationsprozesse des MS-Schubes ver{\"a}nderte Voraussetzungen f{\"u}r die Induzierbarkeit von Plastizit{\"a}t gegeben sind. Nicht nur, wie bereits gezeigt, die LTP-artige, sondern offenbar auch die LTD-artige assoziative Plastizit{\"a}t zeigt sich stark von den humoralen Ver{\"a}nderungen im steroidbehandelten Schub beeinflusst. Weitere Studien in st{\"a}rker vorselektierten Patientengruppen sollten der Frage nachgehen, inwieweit LTD-artige Plastizit{\"a}t sich in verschiedenen Subgruppen mit unterschiedlichen Schubsymptomen unterscheidet. Des Weiteren ist der Frage weiter nachzugehen, ob LTD-artige Plastizit{\"a}t funktional zur Adaption im Rahmen des Schubereignisses notwendig ist und inwieweit deren Unterdr{\"u}ckung bzw. Ersatz durch Langzeitpotenzierung potenziell einer Adaption im Wege steht. Sollten potenzielle Folgestudien best{\"a}tigen, dass LTD- und LTP-artige Plastizit{\"a}t im Schub m{\"o}glicherweise h{\"a}ufig dysfunktional ausgepr{\"a}gt ist und einer optimalen Regeneration entgegensteht, w{\"a}ren daraus praktische Implikationen zu ziehen. Die Entwicklung neuer Trainingsprogramme oder elektrophysiologischer Konzepte k{\"o}nnte ein n{\"a}chstes Ziel dieses Forschungszweiges sein, um potenziell dysfunktionale Plastizit{\"a}t zu vermeiden und physiologische Prozesse bereits im Schub zu f{\"o}rdern.}, subject = {Neuronale Plastizit{\"a}t}, language = {de} } @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{EstradaKrebbersVossetal.2018, author = {Estrada, Veronica and Krebbers, Julia and Voss, Christian and Brazda, Nicole and Blazyca, Heinrich and Illgen, Jennifer and Seide, Klaus and J{\"u}rgens, Christian and M{\"u}ller, J{\"o}rg and Martini, Rudolf and Trieu, Hoc Khiem and M{\"u}ller, Hans Werner}, title = {Low-pressure micro-mechanical re-adaptation device sustainably and effectively improves locomotor recovery from complete spinal cord injury}, series = {Communications Biology}, volume = {1}, journal = {Communications Biology}, doi = {10.1038/s42003-018-0210-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227357}, year = {2018}, abstract = {Traumatic spinal cord injuries result in impairment or even complete loss of motor, sensory and autonomic functions. Recovery after complete spinal cord injury is very limited even in animal models receiving elaborate combinatorial treatments. Recently, we described an implantable microsystem (microconnector) for low-pressure re-adaption of severed spinal stumps in rat. Here we investigate the long-term structural and functional outcome following microconnector implantation after complete spinal cord transection. Re-adaptation of spinal stumps supports formation of a tissue bridge, glial and vascular cell invasion, motor axon regeneration and myelination, resulting in partial recovery of motor-evoked potentials and a thus far unmet improvement of locomotor behaviour. The recovery lasts for at least 5 months. Despite a late partial decline, motor recovery remains significantly superior to controls. Our findings demonstrate that microsystem technology can foster long-lasting functional improvement after complete spinal injury, providing a new and effective tool for combinatorial therapies.}, 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{HornKristLiebetal.2021, author = {Horn, A. and Krist, L. and Lieb, W. and Montellano, F. A. and Kohls, M. and Haas, K. and Gelbrich, G. and Bolay-Gehrig, S. J. and Morbach, C. and Reese, J. P. and St{\"o}rk, S. and Fricke, J. and Zoller, T. and Schmidt, S. and Triller, P. and Kretzler, L. and R{\"o}nnefarth, M. and Von Kalle, C. and Willich, S. N. and Kurth, F. and Steinbeis, F. and Witzenrath, M. and Bahmer, T. and Hermes, A. and Krawczak, M. and Reinke, L. and Maetzler, C. and Franzenburg, J. and Enderle, J. and Flinspach, A. and Vehreschild, J. and Schons, M. and Illig, T. and Anton, G. and Ungeth{\"u}m, K. and Finkenberg, B. C. and Gehrig, M. T. and Savaskan, N. and Heuschmann, P. U. and Keil, T. and Schreiber, S.}, title = {Long-term health sequelae and quality of life at least 6 months after infection with SARS-CoV-2: design and rationale of the COVIDOM-study as part of the NAPKON population-based cohort platform (POP)}, series = {Infection}, volume = {49}, journal = {Infection}, number = {6}, issn = {0300-8126}, doi = {10.1007/s15010-021-01707-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308960}, pages = {1277-1287}, year = {2021}, abstract = {Purpose Over the course of COVID-19 pandemic, evidence has accumulated that SARS-CoV-2 infections may affect multiple organs and have serious clinical sequelae, but on-site clinical examinations with non-hospitalized samples are rare. We, therefore, aimed to systematically assess the long-term health status of samples of hospitalized and non-hospitalized SARS-CoV-2 infected individuals from three regions in Germany. Methods The present paper describes the COVIDOM-study within the population-based cohort platform (POP) which has been established under the auspices of the NAPKON infrastructure (German National Pandemic Cohort Network) of the national Network University Medicine (NUM). Comprehensive health assessments among SARS-CoV-2 infected individuals are conducted at least 6 months after the acute infection at the study sites Kiel, W{\"u}rzburg and Berlin. Potential participants were identified and contacted via the local public health authorities, irrespective of the severity of the initial infection. A harmonized examination protocol has been implemented, consisting of detailed assessments of medical history, physical examinations, and the collection of multiple biosamples (e.g., serum, plasma, saliva, urine) for future analyses. In addition, patient-reported perception of the impact of local pandemic-related measures and infection on quality-of-life are obtained. Results As of July 2021, in total 6813 individuals infected in 2020 have been invited into the COVIDOM-study. Of these, about 36\% wished to participate and 1295 have already been examined at least once. Conclusion NAPKON-POP COVIDOM-study complements other Long COVID studies assessing the long-term consequences of an infection with SARS-CoV-2 by providing detailed health data of population-based samples, including individuals with various degrees of disease severity. Trial registration Registered at the German registry for clinical studies (DRKS00023742).}, language = {en} } @phdthesis{Fischer2004, author = {Fischer, Matthias}, title = {Lokalisierung eines Ged{\"a}chtnisses bei Drosophila melanogaster}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-8050}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2004}, abstract = {Es konnte in dieser Arbeit gezeigt werden, daß das olfaktorische Kurzzeitged{\"a}chtnis von Drosophila melanogaster in den Pilzk{\"o}rpern lokalisiert ist. Zu Beginn dieser Doktorarbeit war bekannt, daß die Pilzk{\"o}rper notwendig f{\"u}r das Geruchsged{\"a}chtnis sind. Drei unabh{\"a}ngige Methoden der Ablation bzw. Ver{\"a}nderung der biochemischen Eigenschaften der Pilzk{\"o}rper hatten zu dem selben Ergebnis gef{\"u}hrt, daß funktionierende Pilzk{\"o}rper unentbehrlich f{\"u}r den Aufbau eines Geruchsged{\"a}chtnisses sind. Noch informativer als ein Experiment, in dem durch Zerst{\"o}rung einer Struktur eine Leistung unm{\"o}glich gemacht wird ist der umgekehrte Weg, der durch einen gewebespezifischen „rescue" die Leistung wiederherstellt. Dazu wurde in dieser Arbeit das wildtypische Allel des Gens rutabaga in rut-mutanten Fliegen mit Hilfe des Gal4/UAS-Systems ausschließlich in den Pilzk{\"o}rpern, bzw., im Gegenexperiment, nur außerhalb der Pilzk{\"o}rper zur Expression gebracht. rut kodiert f{\"u}r die Adenylatcyclase I, die mit synaptischer Plastizit{\"a}t bei Drosophila, Aplysia und M{\"a}usen in Verbindung gebracht wird. Man geht davon aus, daß synaptische Plastizit{\"a}t die molekulare Grundlage f{\"u}r Lernen und Ged{\"a}chtnis ist. Die AC I stellt cAMP her, dessen Menge und pr{\"a}zise Regulation die {\"U}bertragungsst{\"a}rke an Neuronen beeinflußt. Eine St{\"o}rung dieses Signalweges z. B. durch die rut-Mutation f{\"u}hrt zu einer Beeintr{\"a}chtigung des Ged{\"a}chtnisses bei Drosophila. rut wurde mit Hilfe des in Drosophila etablierten Gal4/UAS-Systems exprimiert: Der gewebespezifisch aktive Hefe-Transkriptionsfaktor Gal4 f{\"u}hrt dazu, daß das hinter einen Gal4-spezifischen UAS-Promotor klonierte wildtypische rut-Gen in denjenigen Zellen transkribiert wird, in denen der Transkriptionsfaktor vorhanden ist. Dies wurde in einer rut-Mutante durchgef{\"u}hrt, so daß in allen anderen Zellen keine funktionierende AC I vorhanden war. Die rut-abh{\"a}ngige synaptische Plastizit{\"a}t wurde damit ausschließlich auf die gew{\"u}nschten Regionen beschr{\"a}nkt. Das Expressionsmuster der Gal4-Linien wurde durch Immuncytochemie (Anti-Tau) sichtbar gemacht. Diese Fliegen wurden in einem klassischen Konditionierungsexperiment auf ihr Geruchs-Ged{\"a}chtnis untersucht. Dazu wurden einer Gruppe von Fliegen nacheinander 2 Ger{\"u}che pr{\"a}sentiert, von denen einer mit Elektroschocks gepaart war. Nach ca. 2 min konnten diese Fliegen sich f{\"u}r einen der beiden Ger{\"u}che entscheiden, die nun gleichzeitig aus 2 unterschiedlichen Richtungen dargeboten wurden. Je nach Lernleistung entschieden sich mehr oder weniger Fliegen f{\"u}r den vorher unbestraften Geruch. Es ergab sich, daß der Ort im Gehirn, an dem die wildtypische AC I exprimiert wurde, {\"u}ber die H{\"o}he des Ged{\"a}chtniswertes entschied: Die AC I ausschließlich in den Pilzk{\"o}rpern gew{\"a}hrte ein v{\"o}llig normales Ged{\"a}chtnis, wogegen die AC I außerhalb der Pilzk{\"o}rper das Ged{\"a}chtnis nicht gegen{\"u}ber der rut-Mutante verbessern konnte. Die Analyse der Expressionsverteilung von insgesamt 9 getesteten Fliegenlinien mißt {\"u}berdies dem \&\#61543;-Lobus des Pilzk{\"o}rpers eine besondere Bedeutung bei und l{\"a}ßt den Schluß zu, daß das hier untersuchte Ged{\"a}chtnis ausschließlich in den \&\#61543;-Loben lokalisiert ist. Dieses erfolgreiche rut-„rescue" - Experiment zeigt, daß rut-abh{\"a}ngige synaptische Plastizit{\"a}t ausschließlich in den Pilzk{\"o}rpern ausreichend f{\"u}r ein wildtypisches Ged{\"a}chtnis ist. Dieses Ergebnis vervollst{\"a}ndigt die Erkenntnisse von den Pilzk{\"o}rper-Ablationsexperimenten insofern, als nun die Aussage zutrifft, daß die Pilzk{\"o}rper notwendig und hinreichend f{\"u}r das olfaktorische Kurzzeitged{\"a}chtnis sind.}, language = {de} } @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} } @article{GarciaFernandezReinholdUeceyleretal.2023, author = {Garc{\´i}a-Fern{\´a}ndez, Patricia and Reinhold, Colette and {\"U}{\c{c}}eyler, Nurcan and Sommer, Claudia}, title = {Local inflammatory mediators involved in neuropathic pain}, series = {International Journal of Molecular Sciences}, volume = {24}, journal = {International Journal of Molecular Sciences}, number = {9}, issn = {1422-0067}, doi = {10.3390/ijms24097814}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313613}, year = {2023}, abstract = {Polyneuropathy (PNP) is a term to describe diseases of the peripheral nervous system, 50\% of which present with neuropathic pain. In some types of PNP, pain is restricted to the skin distally in the leg, suggesting a local regulatory process leading to pain. In this study, we proposed a pro-inflammatory pathway mediated by NF-κB that might be involved in the development of pain in patients with painful PNP. To test this hypothesis, we have collected nerve and skin samples from patients with different etiologies and levels of pain. We performed RT-qPCR to analyze the gene expression of the proposed inflammatory pathway components in sural nerve and in distal and proximal skin samples. In sural nerve, we showed a correlation of TLR4 and TNFα to neuropathic pain, and an upregulation of TNFα in patients with severe pain. Patients with an inflammatory PNP also presented a lower expression of TRPV1 and SIRT1. In distal skin, we found a reduced expression of TLR4 and miR-146-5p, in comparison to proximal skin. Our findings thus support our hypothesis of local inflammatory processes involved in pain in PNP, and further show disturbed anti-inflammatory pathways involving TRPV1 and SIRT1 in inflammatory PNP.}, language = {en} } @article{UeceylerValetKafkeetal.2014, author = {{\"U}{\c{c}}eyler, Nurcan and Valet, Michael and Kafke, Waldemar and T{\"o}lle, Thomas R. and Sommer, Claudia}, title = {Local and Systemic Cytokine Expression in Patients with Postherpetic Neuralgia}, doi = {10.1371/journal.pone.0105269}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-113041}, year = {2014}, abstract = {Background Postherpetic neuralgia (PHN) is the painful complication of a varicella zoster virus reactivation. We investigated the systemic and local gene expression of pro- and anti-inflammatory cytokine expression in patients with PHN. Methods Thirteen patients with PHN at the torso (Th4-S1) were recruited. Skin punch biopsies were obtained from the painful and the contralateral painless body area for intraepidermal nerve fiber density (IENFD) and cytokine profiling. Additionally, blood was withdrawn for systemic cytokine expression and compared to blood values of healthy controls. We analyzed the gene expression of selected pro- and anti-inflammatory cytokines (tumor necrosis factor-alpha [TNF] and interleukins [IL]-1β, IL-2, and IL-8). Results IENFD was lower in affected skin compared to unaffected skin (p<0.05), while local gene expression of pro- and anti-inflammatory cytokines did not differ except for two patients who had 7fold higher IL-6 and 10fold higher IL-10 gene expression in the affected skin compared to the contralateral unaffected skin sample. Also, the systemic expression of cytokines in patients with PHN and in healthy controls was similar. Conclusion While the systemic and local expression of the investigated pro- and anti-inflammatory cytokines was not different from controls, this may have been influenced by study limitations like the low number of patients and different disease durations. Furthermore, other cytokines or pain mediators need to be considered.}, language = {en} } @article{PasosSteigerwaldReichetal.2019, author = {Pasos, Uri E. Ramirez and Steigerwald, Frank and Reich, Martin M. and Matthies, Cordula and Volkmann, Jens and Reese, Ren{\´e}}, title = {Levodopa modulates functional connectivity in the upper beta band between bubthalamic nucleus and muscle activity in tonic and phasic motor activity patterns in Parkinson's disease}, series = {Frontiers in Human Neuroscience}, volume = {13}, journal = {Frontiers in Human Neuroscience}, number = {223}, doi = {10.3389/fnhum.2019.00223}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201540}, year = {2019}, abstract = {Introduction: Striatal dopamine depletion disrupts basal ganglia function and causes Parkinson's disease (PD). The pathophysiology of the dopamine-dependent relationship between basal ganglia signaling and motor control, however, is not fully understood. We obtained simultaneous recordings of local field potentials (LFPs) from the subthalamic nucleus (STN) and electromyograms (EMGs) in patients with PD to investigate the impact of dopaminergic state and movement on long-range beta functional connectivity between basal ganglia and lower motor neurons. Methods: Eight PD patients were investigated 3 months after implantation of a deep brain stimulation (DBS)-system capable of recording LFPs via chronically-implanted leads (Medtronic, ACTIVA PC+S®). We analyzed STN spectral power and its coherence with EMG in the context of two different movement paradigms (tonic wrist extension vs. alternating wrist extension and flexion) and the effect of levodopa (L-Dopa) intake using an unbiased data-driven approach to determine regions of interest (ROI). Results: Two ROIs capturing prominent coherence within a grand average coherogram were identified. A trend of a dopamine effect was observed for the first ROI (50-150 ms after movement start) with higher STN-EMG coherence in medicated patients. Concerning the second ROI (300-500 ms after movement start), an interaction effect of L-Dopa medication and movement task was observed with higher coherence in the isometric contraction task compared to alternating movements in the medication ON state, a pattern which was reversed in L-Dopa OFF. Discussion: L-Dopa medication may normalize functional connectivity between remote structures of the motor system with increased upper beta coherence reflecting a physiological restriction of the amount of information conveyed between remote structures. This may be necessary to maintain simple movements like isometric contraction. Our study adds dynamic properties to the complex interplay between STN spectral beta power and the nucleus' functional connectivity to remote structures of the motor system as a function of movement and dopaminergic state. This may help to identify markers of neuronal activity relevant for more individualized programming of DBS therapy.}, language = {en} } @article{NeugebauerSchneiderKollmar2019, author = {Neugebauer, Hermann and Schneider, Hauke and Kollmar, Rainer}, title = {Letter by Neugebauer et al. regarding article "Hypothermia after decompressive hemicraniectomy in treatment of malignant middle cerebral artery stroke: comment on the randomized clinical trial"}, series = {Critical Care}, volume = {23}, journal = {Critical Care}, doi = {10.1186/s13054-019-2600-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232268}, year = {2019}, abstract = {No abstract available.}, language = {en} } @phdthesis{Fackelmann2011, author = {Fackelmann, Stefanie}, title = {Langzeitkorrelation evozierter Potentialparameter mit dem klinischen Verlauf bei Patienten mit Multipler Sklerose}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-64840}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2011}, abstract = {Evozierte Potenziale werden bereits als Hilfsmittel zur Diagnosestellung der Multiplen Sklerose herangezogen. Das Spektrum der Verl{\"a}ufe der Erkrankung ist sehr unterschiedlich. Ziel der Studie war es, zu pr{\"u}fen, ob visuell (VEP), somatosensibel (SEP) und Magnet- (MEP) evozierte Potentiale durch das Aufdecken klinisch noch stummer L{\"a}sionen eine prognostische Bedeutung haben. Es wurden 94 Patienten bei Erstvorstellung sowie zum 5-Jahres- und 10-Jahresverlaufszeitpunkt untersucht. Es wurde ein Zusammenhang von MEP- und SEP-Scores mit dem sp{\"a}teren Behinderungsgrad, gemessen in Form der EDSS nach f{\"u}nf und zehn jahren gefunden, sofern die elektrophysiologischen Untersuchungen in den ersten beiden Jahren nach Erstmanifestation klinischer Symptome durchgef{\"u}hrt worden waren (Gruppe 1, 44 Patienten). F{\"u}r Gruppe 2 (50 Patienten), deren Erstuntersuchung sp{\"a}ter im Verlauf stattgefunden hatte (im Mittel 9,6a) konnte keine prognostische Bedeutung gesehen werden. Die Durchf{\"u}hrung multimodaler evozierter Potenziale ist kann somit eine Hilfestellung zur fr{\"u}hzeitigen Therapieentscheidung geben.}, subject = {Multiple Sklerose}, 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} } @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} } @phdthesis{Grohmann2023, author = {Grohmann, Christoph}, title = {Kognitive Leistungsf{\"a}higkeit und Lebensqualit{\"a}t bei minimaler hepatischer Enzephalopathie - eine Pilotstudie zum Patient Reported Outcome in der Verlaufsdiagnostik}, doi = {10.25972/OPUS-30537}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-305375}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Die WHO definiert Gesundheit als v{\"o}lliges k{\"o}rperliches, geistiges und soziales Wohlbefinden. W{\"a}hrend diese ganzheitliche Betrachtungsweise seit Menschengedenken nahezu weltweit das Gesundheitswesen pr{\"a}gt, hat die Medizin in Europa mit der naturwissenschaftlichen Erkenntnisrevolution einen Sonderweg eingeschlagen. Hier wird der kranke Organismus in erster Linie als defekter Apparat gesehen, der mit ausgekl{\"u}gelter Technik zu reparieren ist. Aber auch pr{\"a}ziseste Qualit{\"a}tsarbeit st{\"o}ßt dabei oft an Leistungsgrenzen, weil sie als seelenlos erlebt wird. Daher sehen heute viele Fachgebiete die Notwendigkeit, ihre Behandlungskonzepte zu beseelen und ihre Behandlungserfolge auch anhand der subjektiv von Patienten empfundenen Lebensqualit{\"a}t zu beurteilen. F{\"u}r die Ermittlung dieses PRO kommen etablierte psychometrische Testverfahren in Frage, die sich auch f{\"u}r routinem{\"a}ßige Verlaufskontrollen eignen. In der vorliegenden Arbeit wurde am Beispiel der mHE gepr{\"u}ft, welchen Nutzen eine PRO-Bestimmung bei der Verlaufskontrolle haben kann. Dazu wurde eine prospektive Studie mit anf{\"a}nglich 75 Patienten durchgef{\"u}hrt. Alle hatten eine mHE und waren entweder alkoholbedingt oder aus anderen Gr{\"u}nden schwer leberkrank. An vier Terminen im Abstand von sechs Monaten wurden die kognitive Leistungsf{\"a}higkeit und der emotionale Status {\"u}berpr{\"u}ft. Die Patienten zeigten anf{\"a}nglich kognitive Einschr{\"a}nkungen, die sich im Verlauf der individuell abgestimmten Behandlung deutlich verbesserten oder ganz verschwanden. Die globale Testung mit dem MoCA ergab eine hochsignifikante Normalisierung im ersten Behandlungsjahr. Die MoCA-Werte am Studienanfang und -ende waren von der Erkrankungsursache unabh{\"a}ngig. Dieser Befund differenzierte sich in den Spezialtests TMT, PHES und NHPT. Hier zeigten die alkoholbedingt Erkrankten durchweg schlechtere Leistungen als die nicht-alkoholbedingt Erkrankten, erholten sich aber in der Regel auch deutlicher. Die seelische Gestimmtheit gem{\"a}ß BDI-II und die mit dem SF-36 MCS ermittelte psychosoziale Befindlichkeit waren in beiden Patientengruppen von Anfang an vergleichsweise g{\"u}nstig. Dabei hatten die alkoholbedingt Erkrankten die besseren Werte, speziell der BDI-II zeigte bei ihnen nach einem halben Jahr eine zus{\"a}tzliche und bleibende Stimmungsaufhellung an. Der SF-36 PCS zum K{\"o}rpererleben zeigte hingegen, dass sich die alkoholbedingt Erkrankten zu Studienbeginn in einer deutlich schlechteren Verfassung befanden. Diese verbesserte sich aber kontinuierlich, sodass nach 1,5 Jahren kein Unterschied mehr zu den nicht-alkoholbedingt Erkrankten bestand. Aus diesen Befunden und dem reichhaltigen Erfahrungsgut zur Alkoholkrankheit wird geschlossen, dass der Genesungsprozess bei alkoholbedingtem Leberversagen viel komplexer ist als bei nicht-alkoholbedingtem Leberversagen. Er k{\"o}nnte wesentlich mehr Zeit erfordern und wird offensichtlich anders erlebt. Dieser Patientengruppe k{\"o}nnten besondere physio- und gespr{\"a}chstherapeutische Angebote eine große Hilfe sein. Die Arbeit zeigt, dass es m{\"o}glich ist, mit wenig Aufwand komplement{\"a}r zu den klinischen Verlaufsbefunden einen informativen PRO-Bericht zu erhalten. Er hilft Angeh{\"o}rigen und medizinischem Personal, die pers{\"o}nlichen N{\"o}te und Hoffnungen der Patienten besser zu verstehen und gegebenenfalls einen Korrekturbedarf im Umgang zu erkennen. Hinzu kam im vorliegenden Fall die Erkenntnis, dass die alkoholbedingt Erkrankten in ihrem Kranksein anders betroffen waren. Die Gr{\"u}nde daf{\"u}r sind im Nachhinein plausibel, der Sachverhalt als solcher w{\"a}re aber ohne diese Spezialuntersuchung wohl nicht erkannt worden. Das Beispiel der PRO-Ermittlung bei der mHE macht den praktischen Wert einer Ber{\"u}cksichtigung des gesamtheitlichen Gesundheitskonzepts der WHO auch in der technikzentrierten „westlichen Medizin" deutlich.}, subject = {Encephalopathia hepatica}, language = {de} } @phdthesis{Steeg2023, author = {Steeg, Felix Leonard}, title = {Kinematische und histomorphologische Charakterisierung des DYT1 Knock-in Mausmodells mit Trauma-induzierter Dystonie}, doi = {10.25972/OPUS-34580}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-345805}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Die dem Formenkreis der Dystonien zugrundeliegenden, pathophysiologischen Grundlagen sind bislang nicht abschließend gekl{\"a}rt. F{\"u}r die DYT-TOR1A Dystonie ist bekannt, dass eine 3-bp Deletion eines GAG-Codons im TOR1A-Gen auf Chromosom 9 einen Funktionsverlust des Proteins TorsinA bewirkt. Dieser Funktionsverlust wird als ausl{\"o}sender Faktor f{\"u}r die Entstehung der DYT-TOR1A Dystonie angenommen. Nichtsdestotrotz entwickeln lediglich circa 30\% der Mutationstr{\"a}ger eine dystone Bewegungsst{\"o}rung. Als Grund daf{\"u}r wird eine Two-hit Hypothese diskutiert, die zus{\"a}tzlich zur genetischen Pr{\"a}disposition einen Umweltfaktor wie ein peripheres Trauma f{\"u}r die Entstehung von Symptomen postuliert. Durch eine standardisierte Quetschl{\"a}sion des N. ischiadicus konnte mit dieser Arbeit bei DYT1KI M{\"a}usen, die die ∆GAG-Mutation im endogenen Genom tragen, ein dystoner Ph{\"a}notyp hervorgerufen werden. Mit den Aufzeichnungen der M{\"a}use im TST wurde ein neuronales Netzwerk mittels der Software „DeepLabCut" trainiert, sodass die Dystonie-{\"a}hnlichen Bewegungen automatisiert erfasst und ausgewertet werden konnten. Das Netzwerk tr{\"a}gt dazu bei, dem vorwiegend klinischen Syndrom der Dystonie eine objektive kinematische Charakterisierung zu bieten und kann auf andere TSTs anderer Nagermodelle {\"u}bertragen werden. Ferner wurde {\"u}berpr{\"u}ft, ob die beobachteten Bewegungen durch Unterschiede in der Regeneration nach der Nervenquetschung zustande kamen. Elektroneurographien zeigten jedoch diesbez{\"u}glich keine Unterschiede zwischen wt und DYT1KI Tieren. Dar{\"u}ber hinaus sind mikromorphologische Prozesse im zentralen und peripheren Nervensystem Gegenstand dieser Studie. Einerseits konnten wir mittels Immunzellf{\"a}rbungen von T-, B-Zellen, Makrophagen und Mikroglia feststellen, dass sowohl zentral als auch peripher kein Anhalt darauf besteht, dass die beim DYT1KI Mausmodell entstandenen Dystonie-{\"a}hnlichen Bewegungen auf einer Dysfunktion oder Aktivierung des Immunsystems, wie es bei anderen neurologischen Erkrankungen bereits nachgewiesen wurde, eine Rolle spielt. Andererseits konnte anhand stereologischer Messungen gezeigt werden, dass bei den naiven DYT1KI Tieren im Vergleich zu wt Tieren dopaminerge Neurone der SN in der Anzahl verringert und im Volumen vergr{\"o}ßert sind, was auf einen Endoph{\"a}notypen hinweist. Bei den symptomatischen, nervengequetschten DYT1KI M{\"a}usen zeigte sich wiederum eine weitere, signifikante Zunahme der Hypertrophie der dopaminergen Neurone als Hinweis auf eine unmittelbar mit dem dystonen Ph{\"a}notypen in Zusammenhang stehende Ver{\"a}nderung. Zusammenfassend konnte ein symptomatisches Mausmodell von hoher translationaler Bedeutung etabliert werden, in dem sich Hinweise f{\"u}r eine dopaminerge Dysregulation ergaben und welches f{\"u}r weitere Studien, insbesondere therapeutischer Art, eingesetzt werden k{\"o}nnte.}, subject = {Dystonie}, language = {de} } @article{EhlingGoebBittneretal.2013, author = {Ehling, Petra and G{\"o}b, Eva and Bittner, Stefan and Budde, Thomas and Ludwig, Andreas and Kleinschnitz, Christoph and Meuth, Sven G.}, title = {Ischemia-induced cell depolarization: does the hyperpolarization-activated cation channel HCN2 affect the outcome after stroke in mice?}, series = {Experimental \& Translational Stroke Medicine}, volume = {5}, journal = {Experimental \& Translational Stroke Medicine}, number = {16}, doi = {10.1186/2040-7378-5-16}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131887}, year = {2013}, abstract = {Background Brain ischemia is known to include neuronal cell death and persisting neurological deficits. A lack of oxygen and glucose are considered to be key mediators of ischemic neurodegeneration while the exact mechanisms are yet unclear. In former studies the expression of two different two-pore domain potassium \((K_{2P})\) channels (TASK1, TREK1) were shown to ameliorate neuronal damage due to cerebral ischemia. In neurons, TASK channels carrying hyperpolarizing \(K^+\) leak currents, and the pacemaker channel HCN2, carrying depolarizing \(I_h\), stabilize the membrane potential by a mutual functional interaction. It is assumed that this ionic interplay between TASK and HCN2 channels enhances the resistance of neurons to insults accompanied by extracellular pH shifts. Methods In C57Bl/6 (wildtype, WT), \(hcn2^{+/+}\) and \(hcn2^{-/-}\) mice we used an in vivo model of cerebral ischemia (transient middle cerebral artery occlusion (tMCAO)) to depict a functional impact of HCN2 in stroke formation. Subsequent analyses comprise behavioural tests and hcn2 gene expression assays. Results After 60 min of tMCAO induction in WT mice, we collected tissue samples at 6, 12, and 24 h after reperfusion. In the infarcted neocortex, hcn2 expression analyses revealed a nominal peak of hcn2 expression 6 h after reperfusion with a tendency towards lower expression levels with longer reperfusion times. Hcn2 gene expression levels in infarcted basal ganglia did not change after 6 h and 12 h. Only at 24 h after reperfusion, hcn2 expression significantly decreases by ~55\%. However, 30 min of tMCAO in hcn2-/- as well as hcn2+/+ littermates induced similar infarct volumes. Behavioural tests for global neurological function (Bederson score) and motor function/coordination (grip test) were performed at day 1 after surgery. Again, we found no differences between the groups. Conclusions Here, we hypothesized that the absence of HCN2, an important functional counter player of TASK channels, affects neuronal survival during stroke-induced tissue damage. However, together with a former study on TASK3 these results implicate that both TASK3 and HCN2 which were supposed to be neuroprotective due to their pH-dependency, do not influence ischemic neurodegeneration during stroke in the tMCAO model.}, language = {en} } @article{EhlingGoebBittneretal.2013, author = {Ehling, Petra and G{\"o}b, Eva and Bittner, Stefan and Budde, Thomas and Ludwig, Andreas and Kleinschnitz, Christoph and Meuth, Sven G.}, title = {Ischemia-induced cell depolarization: does the hyperpolarization-activated cation channel HCN2 affect the outcome after stroke in mice?}, series = {Experimental \& Translational Stroke Medicine}, volume = {5}, journal = {Experimental \& Translational Stroke Medicine}, number = {16}, doi = {10.1186/2040-7378-5-16}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129240}, year = {2013}, abstract = {Background Brain ischemia is known to include neuronal cell death and persisting neurological deficits. A lack of oxygen and glucose are considered to be key mediators of ischemic neurodegeneration while the exact mechanisms are yet unclear. In former studies the expression of two different two-pore domain potassium \((K_{2P})\) channels (TASK1, TREK1) were shown to ameliorate neuronal damage due to cerebral ischemia. In neurons, TASK channels carrying hyperpolarizing \(K^+\) leak currents, and the pacemaker channel HCN2, carrying depolarizing Ih, stabilize the membrane potential by a mutual functional interaction. It is assumed that this ionic interplay between TASK and HCN2 channels enhances the resistance of neurons to insults accompanied by extracellular pH shifts. Methods In C57Bl/6 (wildtype, WT), \(hcn2^{+/+}\) and \(hcn2^{-/-}\) mice we used an in vivo model of cerebral ischemia (transient middle cerebral artery occlusion (tMCAO)) to depict a functional impact of HCN2 in stroke formation. Subsequent analyses comprise behavioural tests and hcn2 gene expression assays. Results After 60 min of tMCAO induction in WT mice, we collected tissue samples at 6, 12, and 24 h after reperfusion. In the infarcted neocortex, hcn2 expression analyses revealed a nominal peak of hcn2 expression 6 h after reperfusion with a tendency towards lower expression levels with longer reperfusion times. Hcn2 gene expression levels in infarcted basal ganglia did not change after 6 h and 12 h. Only at 24 h after reperfusion, hcn2 expression significantly decreases by ~55\%. However, 30 min of tMCAO in hcn2-/- as well as hcn2+/+ littermates induced similar infarct volumes. Behavioural tests for global neurological function (Bederson score) and motor function/coordination (grip test) were performed at day 1 after surgery. Again, we found no differences between the groups. Conclusions Here, we hypothesized that the absence of HCN2, an important functional counter player of TASK channels, affects neuronal survival during stroke-induced tissue damage. However, together with a former study on TASK3 these results implicate that both TASK3 and HCN2 which were supposed to be neuroprotective due to their pH-dependency, do not influence ischemic neurodegeneration during stroke in the tMCAO model.}, language = {en} } @article{SchreweLillLiuetal.2015, author = {Schrewe, L. and Lill, C. M. and Liu, T. and Salmen, A. and Gerdes, L. A. and Guillot-Noel, L. and Akkad, D. A. and Blaschke, P. and Graetz, C. and Hoffjan, S. and Kroner, A. and Demir, S. and B{\"o}hme, A. and Rieckmann, P. and El Ali, A. and Hagemann, N. and Hermann, D. M. and Cournu-Rebeix, I. and Zipp, F. and K{\"u}mpfel, T. and Buttmann, M. and Zettl, U. K. and Fontaine, B. and Bertram, L. and Gold, R. and Chan, A.}, title = {Investigation of sex-specific effects of apolipoprotein E on severity of EAE and MS}, series = {Journal of Neuroinflammation}, volume = {12}, journal = {Journal of Neuroinflammation}, number = {234}, doi = {10.1186/s12974-015-0429-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-136252}, year = {2015}, abstract = {Background: Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS. Methods: MOG\(_{35-55}\) induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses. Results: EAE disease course was slightly attenuated in male apoE-deficient (apoE\(^{-/-}\)) mice compared to wildtype mice (cumulative median score: apoE\(^{-/-}\) = 2 [IQR 0.0-4.5]; wildtype = 4 [IQR 1.0-5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE\(^{-/-}\) mice compared to wildtype mice (cumulative median score: apoE\(^{-/-}\) = 3 [IQR 2.0-4.5]; wildtype = 3 [IQR 0.0-4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naive animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex. Conclusions: apoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease.}, language = {en} } @article{GruendahlWackerEinseleetal.2020, author = {Gr{\"u}ndahl, Marie and Wacker, Beate and Einsele, Hermann and Heinz, Werner J.}, title = {Invasive fungal diseases in patients with new diagnosed acute lymphoblastic leukaemia}, series = {Mycoses}, volume = {63}, journal = {Mycoses}, number = {10}, doi = {10.1111/myc.13151}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-217844}, pages = {1101 -- 1106}, year = {2020}, abstract = {Background Patients with acute leukaemia have a high incidence of fungal infections. This has primarily been shown in acute myeloid leukaemia and is different for acute lymphoblastic leukaemia. Until now no benefit of mould active prophylaxis has been demonstrated in the latter population. Methods In this retrospective single-centre study, we analysed the incidence, clinical relevance, and outcome of invasive fungal diseases (IFD) as well as the impact of antifungal prophylaxis for the first 100 days following the primary diagnosis of acute lymphoblastic leukaemia. Results In 58 patients a high rate of proven, probable, and possible fungal infections could be demonstrated with a 3.4\%, 8.6\%, and 17.2\% likelihood, respectively. The incidence might be even higher, as nearly 40\% of all patients had no prolonged neutropenia for more than 10 days, excluding those from the European Organization of Research and Treatment of cancer and the Mycoses Study Group criteria for probable invasive fungal disease. The diagnosed fungal diseases had an impact on the duration of hospitalisation, which was 13 days longer for patients with proven/probable IFD compared to patients with no signs of fungal infection. Use of antifungal prophylaxis did not significantly affect the risk of fungal infection. Conclusion Patients with acute lymphoblastic leukaemia are at high risk of acquiring an invasive fungal disease. Appropriate criteria to define fungal infections, especially in this population, and strategies to reduce the risk of infection, including antifungal prophylaxis, need to be further evaluated.}, language = {en} } @article{FluriHeinenKleinschnitz2013, author = {Fluri, Felix and Heinen, Florian and Kleinschnitz, Christoph}, title = {Intravenous Thrombolysis in a Stroke Patient Receiving Rivaroxaban}, series = {Cerebrovascular Disease Extra}, volume = {2013}, journal = {Cerebrovascular Disease Extra}, number = {3}, doi = {10.1159/000355839}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128816}, pages = {153-155}, year = {2013}, abstract = {No abstract available.}, language = {en} } @article{BrechtWeissbrichBraunetal.2012, author = {Brecht, Isabel and Weissbrich, Benedikt and Braun, Julia and Toyka, Klaus Viktor and Weishaupt, Andreas and Buttmann, Mathias}, title = {Intrathecal, Polyspecific Antiviral Immune Response in Oligoclonal Band Negative Multiple Sclerosis}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {7}, doi = {10.1371/journal.pone.0040431}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134426}, pages = {e40431}, year = {2012}, abstract = {Background: Oligoclonal bands (OCB) are detected in the cerebrospinal fluid (CSF) in more than 95\% of patients with multiple sclerosis (MS) in the Western hemisphere. Here we evaluated the intrathecal, polyspecific antiviral immune response as a potential diagnostic CSF marker for OCB-negative MS patients. Methodology/Principal Findings: We tested 46 OCB-negative German patients with paraclinically well defined, definite MS. Sixteen OCB-negative patients with a clear diagnosis of other autoimmune CNS disorders and 37 neurological patients without evidence for autoimmune CNS inflammation served as control groups. Antibodies against measles, rubella, varicella zoster and herpes simplex virus in paired serum and CSF samples were determined by ELISA, and virus-specific immunoglobulin G antibody indices were calculated. An intrathecal antibody synthesis against at least one neurotropic virus was detected in 8 of 26 (31\%) patients with relapsing-remitting MS, 8 of 12 (67\%) with secondary progressive MS and 5 of 8 (63\%) with primary progressive MS, in 3 of 16 (19\%) CNS autoimmune and 3 of 37 (8\%) non-autoimmune control patients. Antibody synthesis against two or more viruses was found in 11 of 46 (24\%) MS patients but in neither of the two control groups. On average, MS patients with a positive antiviral immune response were older and had a longer disease duration than those without. Conclusion: Determination of the intrathecal, polyspecific antiviral immune response may allow to establish a CSF-supported diagnosis of MS in OCB-negative patients when two or more of the four virus antibody indices are elevated.}, language = {en} } @article{WestermaierKoehlerLinsenmannetal.2015, author = {Westermaier, Thomas and Koehler, Stefan and Linsenmann, Thomas and Kinderlen, Michael and Pakos, Paul and Ernestus, Ralf-Ingo}, title = {Intraoperative Myelography in Cervical Multilevel Stenosis Using 3D Rotational Fluoroscopy: Assessment of Feasibility and Image Quality}, series = {Radiology Research and Practice}, volume = {2015}, journal = {Radiology Research and Practice}, doi = {10.1155/2015/498936}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125779}, pages = {498936}, year = {2015}, abstract = {Background. Intraoperative myelography has been reported for decompression control in multilevel lumbar disease. Cervical myelography is technically more challenging. Modern 3D fluoroscopy may provide a new opportunity supplying multiplanar images. This study was performed to determine the feasibility and image quality of intraoperative cervical myelography using a 3D fluoroscope. Methods. The series included 9 patients with multilevel cervical stenosis. After decompression, 10 mL of water-soluble contrast agent was administered via a lumbar drainage and the operating table was tilted. Thereafter, a 3D fluoroscopy scan (O-Arm) was performed and visually evaluated. Findings. The quality of multiplanar images was sufficient to supply information about the presence of residual stenosis. After instrumentation, metal artifacts lowered image quality. In 3 cases, decompression was continued because myelography depicted residual stenosis. In one case, anterior corpectomy was not completed because myelography showed sufficient decompression after 2-level discectomy. Interpretation. Intraoperative myelography using 3D rotational fluoroscopy is useful for the control of surgical decompression in multilevel spinal stenosis providing images comparable to postmyelographic CT. The long duration of contrast delivery into the cervical spine may be solved by preoperative contrast administration. The method is susceptible to metal artifacts and, therefore, should be applied before metal implants are placed.}, 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{BraeuningerKleinschnitzStoll2010, author = {Braeuninger, Stefan and Kleinschnitz, C. and Stoll, G.}, title = {Interleukin-18 does not influence infarct volume or functional outcome in the early stage after transient focal brain ischemia in mice}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68141}, year = {2010}, abstract = {Interleukin-18 (IL-18) is a proinflammatory cytokine of the interleukin-1 family which is upregulated after cerebral ischemia. The functional role of IL-18 in cerebral ischemia is unknown. In the present study, we compared infarct size in IL-18 knock-out and wild-type mice 24 hours and 48 hours after 1-hour transient middle cerebral artery occlusion (tMCAO). Moreover, the functional outcome was evaluated in a modified Bederson score, foot fault test and grip test. There were no significant differences in infarct size or functional outcome tests between wild-type and IL-18 knock-out mice. These data indicate that the early inflammatory response to cerebral ischemia does not involve IL-18, in contrast to other interleukin-1 family members such as interleukin-1.}, subject = {Interleukin-18}, language = {en} } @article{KleinschnitzNiemczykRehbergWeberetal.2015, author = {Kleinschnitz, Christoph and Niemczyk, Gabriele and Rehberg-Weber, Karin and Wernsd{\"o}rfer, Colin}, title = {Interferon Beta-1a (AVONEX®) as a treatment option for untreated patients with multiple sclerosis (AXIOM): a prospective, observational study}, series = {International Journal of Molecular Sciences}, volume = {16}, journal = {International Journal of Molecular Sciences}, doi = {10.3390/ijms160715271}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148487}, pages = {15271-15286}, year = {2015}, abstract = {The efficacy and safety of first-line disease-modifying therapies (DMT) for relapsing-remitting multiple sclerosis (RRMS) has been demonstrated in pivotal, randomized trials, but these studies do not reflect the routine care setting where treatment gaps or switches are common. The Avonex as Treatment Option for Untreated MS Patients (AXIOM) trial assessed the efficacy of newly-initiated intramuscular interferon beta-1a (IM IFNb-1a) after a treatment-free interval, with particular consideration of the previous course of disease and therapy. The AXIOM trial was an open, 12-month, observational, non-interventional study with a retrospective and a prospective part conducted in Germany. RRMS patients with a treatment-free interval of at least three months were included and treated with IFNb-1a for up to 12 months. Relapse rate, disability progression, injection-related parameters and quality of life observed during the prospective part were compared with retrospectively-collected data. Two hundred and thirty five RRMS patients participated in AXIOM. The mean relapse rate decreased from 1.1 in the three months before baseline to 0.2 per quarter during the twelve-month observational period; the Multiple Sclerosis Functional Composite score improved during twelve months of IM IFNb-1a treatment, while the Expanded Disability Status Scale score did not change over the course of this study. Compared to previous DMTs (IM IFNb-1a, subcutaneous IFNb-1a (SC IFNb-1a), SC IFNb-1b, glatiramer acetate), the patients experienced less injection site reactions and flu-like symptoms, with a stated improved quality of life. IM IFNb-1a was effective and well accepted in RRMS patients with no or discontinued previous therapy. These results from the routine care setting may inform optimization of DMT treatment in RRMS, but need confirmation in further studies.}, language = {en} } @phdthesis{Soda2021, author = {Soda, Hassan}, title = {Interdisziplin{\"a}res Schlaganfallmanagement anhand des Stroke Manager Programms - Studiendaten und Perspektiven f{\"u}r die Schlaganfallversorgung}, doi = {10.25972/OPUS-24206}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242061}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Die Schlaganfallnachsorge in Deutschland wird von verschiedenen Leistungserbringern gepr{\"a}gt, die teilweise komplement{\"a}re und komplexe Dienstleistungen erbringen und sektoren{\"u}bergreifend arbeiten. In Bad Neustadt wurde in Kooperation mit der Universit{\"a}t W{\"u}rzburg und dem Zentrum f{\"u}r Telemedizin Bad Kissingen das Stroke Manager Programm entwickelt und evaluiert. Das strukturierte Nachsorgeprogramm Stroke Manager basiert auf einer standardisierten Informations- und Software Unterst{\"u}tzung von der Akutversorgung bis drei Monate nach Entlassung aus der station{\"a}ren Versorgung. Anhand der Ergebnisse des Stroke Manager Programms konnte eine vergleichsweise hohe Persistenz bzgl. der station{\"a}r verordneten medikament{\"o}sen Sekund{\"a}rpr{\"a}vention {\"u}ber einen Zeitraum von drei Monaten festgestellt werden, ebenso konnten wir nachweisen, dass sich das Programm positiv auf die Versorgungsqualit{\"a}t sowie die Patientenzufriedenheit nach Schlaganfall auswirken kann. Die im Stroke Manager-Programm betreuten Schlaganfallpatienten wiesen im Vergleich signifikante Unterschiede bei den Faktoren Rauchverhalten, Schlaganfallschweregrad und subjektive, globale Lebensqualit{\"a}t auf.}, subject = {Stroke Manager}, language = {de} } @article{GutknechtPoppWaideretal.2015, author = {Gutknecht, Lise and Popp, Sandy and Waider, Jonas and Sommerlandt, Frank M. J. and G{\"o}ppner, Corinna and Post, Antonia and Reif, Andreas and van den Hove, Daniel and Strekalova, Tatyana and Schmitt, Angelika and Colaςo, Maria B. N. and Sommer, Claudia and Palme, Rupert and Lesch, Klaus-Peter}, title = {Interaction of brain 5-HT synthesis deficiency, chronic stress and sex differentially impact emotional behavior in Tph2 knockout mice}, series = {Psychopharmacology}, volume = {232}, journal = {Psychopharmacology}, doi = {10.1007/s00213-015-3879-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154586}, pages = {2429 -- 2441}, year = {2015}, abstract = {Rationale While brain serotonin (5-HT) function is implicated in gene-by-environment interaction (GxE) impacting the vulnerability-resilience continuum in neuropsychiatric disorders, it remains elusive how the interplay of altered 5-HT synthesis and environmental stressors is linked to failure in emotion regulation. Objective Here, we investigated the effect of constitutively impaired 5-HT synthesis on behavioral and neuroendocrine responses to unpredictable chronic mild stress (CMS) using a mouse model of brain 5-HT deficiency resulting from targeted inactivation of the tryptophan hydroxylase-2 (Tph2) gene. Results Locomotor activity and anxiety- and depression-like behavior as well as conditioned fear responses were differentially affected by Tph2 genotype, sex, and CMS. Tph2 null mutants (Tph2\(^{-/-}\)) displayed increased general metabolism, marginally reduced anxiety- and depression-like behavior but strikingly increased conditioned fear responses. Behavioral modifications were associated with sex-specific hypothalamic-pituitary-adrenocortical (HPA) system alterations as indicated by plasma corticosterone and fecal corticosterone metabolite concentrations. Tph2\(^{-/-}\) males displayed increased impulsivity and high aggressiveness. Tph2\(^{-/-}\) females displayed greater emotional reactivity to aversive conditions as reflected by changes in behaviors at baseline including increased freezing and decreased locomotion in novel environments. However, both Tph2\(^{-/-}\) male and female mice were resilient to CMS-induced hyperlocomotion, while CMS intensified conditioned fear responses in a GxE-dependent manner. Conclusions Our results indicate that 5-HT mediates behavioral responses to environmental adversity by facilitating the encoding of stress effects leading to increased vulnerability for negative emotionality.}, language = {en} } @phdthesis{Weis2018, author = {Weis, Jessica}, title = {Innervation von Schweißdr{\"u}sen bei Patienten mit Morbus Parkinson}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161505}, school = {Universit{\"a}t W{\"u}rzburg}, pages = {97}, year = {2018}, abstract = {Die Forschung auf dem Gebiet der Parkinson-Erkrankung erlebt einen großen Wandel. Eindeutig ist mittlerweile, dass es zu kurz gefasst w{\"a}re diese Erkrankung auf die motorischen Symptome zu beschr{\"a}nken. In den letzten Jahren wurde durch intensive Forschung bewiesen, dass der idiopathische M. Parkinson eine multisystemische Erkrankung ist, welche verschiedene Teile des Nervensystems betreffen kann. Um die zugrundeliegende Pathophysiologie und die Beteiligung des autonomen Nervensystems bei M. Parkinson n{\"a}her zu untersuchen, wurden f{\"u}r diese Studie 30 Patienten mit idiopathischem M. Parkinson, 19 Patienten mit atypischem Parkinsonsyndrom und 30 gesunde Probanden am Universit{\"a}tsklinikum W{\"u}rzburg und an der Paracelsus-Elena-Klinik Kassel rekrutiert. Um Beeintr{\"a}chtigungen von groß-und kleinkalibrigen Nervenfasern einsch{\"a}tzen zu k{\"o}nnen, wurden eine Neurografie des N. suralis sowie eine quantitativ sensorische Testung durchgef{\"u}hrt. Zur Bewertung einer m{\"o}glichen toxischen Komponente von Levodopa gegen{\"u}ber einer direkten Sch{\"a}digung peripherer Nerven durch p-α-Synuclein wurden am Vitamin B12 Stoffwechsel beteiligte Proteine im Blut bestimmt. Alle Patienten und Probanden erhielten Hautbiopsien an Unterschenkel, Oberschenkel, R{\"u}cken und Finger, um anschließend eine immunhistochemische Aufarbeitung der Pr{\"a}parate durchf{\"u}hren zu k{\"o}nnen. Einerseits wurde die Beteiligung somatosensibler Nervenfasern mithilfe der Ausz{\"a}hlung intraepidermaler Nervenfasern (PGP 9.5) bewertet. Andererseits wurden die Schweißdr{\"u}sen auf Pathologien der sympathischen Nervenfasern (VIP, TH, SP, CGRP) und der sudomotorischen Synapsen (SNCA, Synaptophysin, SNAP 25) untersucht. Weiterhin wurde versucht p-α-Synuclein, als Biomarker der Parkinson-Erkrankung, in der Haut nachzuweisen. Positive Ergebnisse konnten hinsichtlich pathologischer Prozesse an den Synapsen erzielt werden. Es zeigte sich sowohl eine Reduktion von nativem α-Synuclein (Unterschenkel, p=0,009 und R{\"u}cken, p=0,013), Synaptophysin (Unterschenkel, p=0,007) als auch SNAP 25 (Unterschenkel, p=0,023) an den untersuchten Schweißdr{\"u}sen der Patientengruppe. Bei der Untersuchung von SNAP 25 zeigte sich des Weiteren eine negative Korrelation zwischen der SNAP 25 Dichte im Unterschenkel und p-α-Synuclein (p=0,007). Bei der Suche nach p-α-Synuclein wurden beinahe 72\% der Parkinson-Patienten positiv getestet, wohingegen keiner der gesunden Probanden p-α-Synuclein in der Haut zeigte. Weiterhin konnte bei 75\% der positiv getesteten Patienten mit Multisystematrophie p-α-Synuclein an somatosensiblen Nervenfasern des subepidermalen Plexus nachgewiesen werden, wohingegen es bei den M. Parkinson Patienten nur 13\% waren. Die Ergebnisse der zugrundeliegenden Arbeit zeigen, dass die Hautbiopsie als fr{\"u}hdiagnostisches Mittel und in der Differentialdiagnose ein hohes Potenzial hat. Die Erforschung von Pathologien an Synapsen wird in der Zukunft an großer Bedeutung gewinnen und scheint ein wichtiger Ansatz, um die Pathophysiologie des M. Parkinson genauer zu verstehen. Die Hautbiopsie k{\"o}nnte dabei von Vorteil sein, da sich Pathologien in vivo untersuchen lassen und man nicht auf Ergebnisse von Autopsien angewiesen ist.}, subject = {Parkinson-Krankheit}, language = {de} } @article{WieseDennstaedtHollmannetal.2021, author = {Wiese, Teresa and Dennst{\"a}dt, Fabio and Hollmann, Claudia and Stonawski, Saskia and Wurst, Catherina and Fink, Julian and Gorte, Erika and Mandasari, Putri and Domschke, Katharina and Hommers, Leif and Vanhove, Bernard and Schumacher, Fabian and Kleuser, Burkard and Seibel, J{\"u}rgen and Rohr, Jan and Buttmann, Mathias and Menke, Andreas and Schneider-Schaulies, J{\"u}rgen and Beyersdorf, Niklas}, title = {Inhibition of acid sphingomyelinase increases regulatory T cells in humans}, series = {Brain Communications}, volume = {3}, journal = {Brain Communications}, number = {2}, doi = {10.1093/braincomms/fcab020}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259868}, year = {2021}, abstract = {Genetic deficiency for acid sphingomyelinase or its pharmacological inhibition has been shown to increase Foxp3\(^+\) regulatory T-cell frequencies among CD4\(^+\) T cells in mice. We now investigated whether pharmacological targeting of the acid sphingomyelinase, which catalyzes the cleavage of sphingomyelin to ceramide and phosphorylcholine, also allows to manipulate relative CD4\(^+\) Foxp3\(^+\) regulatory T-cell frequencies in humans. Pharmacological acid sphingomyelinase inhibition with antidepressants like sertraline, but not those without an inhibitory effect on acid sphingomyelinase activity like citalopram, increased the frequency of Foxp3\(^+\) regulatory T cell among human CD4\(^+\) T cells in vitro. In an observational prospective clinical study with patients suffering from major depression, we observed that acid sphingomyelinase-inhibiting antidepressants induced a stronger relative increase in the frequency of CD4\(^+\) Foxp3\(^+\) regulatory T cells in peripheral blood than acid sphingomyelinase-non- or weakly inhibiting antidepressants. This was particularly true for CD45RA\(^-\) CD25\(^{high}\) effector CD4\(^+\) Foxp3\(^+\) regulatory T cells. Mechanistically, our data indicate that the positive effect of acid sphingomyelinase inhibition on CD4\(^+\) Foxp3\(^+\) regulatory T cells required CD28 co-stimulation, suggesting that enhanced CD28 co-stimulation was the driver of the observed increase in the frequency of Foxp3+ regulatory T cells among human CD4\(^+\) T cells. In summary, the widely induced pharmacological inhibition of acid sphingomyelinase activity in patients leads to an increase in Foxp3+ regulatory T-cell frequencies among CD4\(^+\) T cells in humans both in vivo and in vitro.}, language = {en} } @phdthesis{Feierabend2006, author = {Feierabend, Stefanie}, title = {Informationsgehalt und Akzeptanz zweier K{\"o}rperschemata bei Patienten mit orofazialen Schmerzen}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-20970}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2006}, abstract = {Ziel dieser prospektiven multizentrischen Studie war der Vergleich 2 verschiedener Schemata zur Schmerzzeichnung bei Patienten mit orofazialen Schmerzen. 204 Patienten, die wegen orofazialer Schmerzen einen (Zahn)arzt aufsuchten, erhielten randomisiert 2 unterschiedliche K{\"o}rperschemata zur Schmerzzeichnung und einen Fragebogen zu deren Beurteilung. Ein Schema war dem Deutschen Schmerzfragebogen entnommen (Bogen A), das andere war mit der Intention entwickelt worden, den K{\"o}rper symmetrisch darzustellen und eine computergest{\"u}tzte Auswertung zu erm{\"o}glichen (Bogen B). Diese Zeichnung war großformatiger und enthielt ein vergr{\"o}ßertes Kopfschema. Die Antworten wurden bzgl. Pr{\"a}ferenz, Anzahl und Verteilung der Schmerzgebiete und {\"U}bereinstimmung zwischen den Schemata ausgewertet sowie mit Patientendaten korreliert. Die Daten von 183 Patienten waren auswertbar. Von 100/183 Patienten wurde Bogen B bevorzugt, von 57/183 Bogen A, unabh{\"a}ngig von Geschlecht, Alter und Erkrankungsdauer. Fast alle Patienten gaben mehr als ein Schmerzgebiet an, nur 43/183 Patienten Schmerzen ausschließlich in der Gesichts- und Kopfregion. Anzahl und Lokalisation der Schmerzgebiete waren zwischen den Schemata nicht unterschiedlich. Detaillierte Kopf- und K{\"o}rperschemata k{\"o}nnen ohne {\"U}berforderung der Patienten sinnvoll in die Diagnostik orofazialer Schmerzen eingesetzt werden und sind n{\"u}tzlich, um Komorbidit{\"a}ten zu erkennen.}, language = {de} } @article{SchischlevskijCordtsGuentheretal.2021, author = {Schischlevskij, Pavel and Cordts, Isabell and G{\"u}nther, Ren{\´e} and Stolte, Benjamin and Zeller, Daniel and Schr{\"o}ter, Carsten and Weyen, Ute and Regensburger, Martin and Wolf, Joachim and Schneider, Ilka and Hermann, Andreas and Metelmann, Moritz and Kohl, Zacharias and Linker, Ralf A. and Koch, Jan Christoph and Stendel, Claudia and M{\"u}schen, Lars H. and Osmanovic, Alma and Binz, Camilla and Klopstock, Thomas and Dorst, Johannes and Ludolph, Albert C. and Boentert, Matthias and Hagenacker, Tim and Deschauer, Marcus and Lingor, Paul and Petri, Susanne and Schreiber-Katz, Olivia}, title = {Informal caregiving in amyotrophic lateral sclerosis (ALS): a high caregiver burden and drastic consequences on caregivers' lives}, series = {Brain Sciences}, volume = {11}, journal = {Brain Sciences}, number = {6}, issn = {2076-3425}, doi = {10.3390/brainsci11060748}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240981}, year = {2021}, abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients' informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers' burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients' CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients' functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King's Stages for ALS. The caregivers' burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers' burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients' functional status (r\(_p\) = -0.555, p < 0.001, n = 242). It was influenced by the CGs' own mental health issues due to caregiving (+11.36, 95\% CI [6.84; 15.87], p < 0.001), patients' wheelchair dependency (+9.30, 95\% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs' depression (r\(_p\) = 0.627, p < 0.001, n = 234), anxiety (r\(_p\) = 0.550, p < 0.001, n = 234), and poorer physical condition (r\(_p\) = -0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients' impairment in daily routine (r\(_s\) = -0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs' lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs' work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required.}, language = {en} } @article{KreisslStoutWongetal.2011, author = {Kreissl, Michael C. and Stout, David B. and Wong, Koon-Pong and Wu, Hsiao-Ming and Caglayan, Evren and Ladno, Waldemar and Zhang, Xiaoli and Prior, John and Reiners, Christoph and Huang, Sung-Cheng and Schelbert, Heinrich R.}, title = {Influence of Dietary Interventions and Insulin on Myocardial, Skeletal Muscle and Brain [18F]-Fluorodeoxyglucose Kinetics in Mice}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68775}, year = {2011}, abstract = {Background: We evaluated the effect of insulin stimulation and dietary changes on myocardial, skeletal muscle and brain [18F]-fluorodeoxyglucose (FDG) kinetics and uptake in vivo in intact mice. Methods: Mice were anesthetized with isoflurane and imaged under different conditions: non-fasted (n = 7; "controls"), non-fasted with insulin (2 IU/kg body weight) injected subcutaneously immediately prior to FDG (n = 6), fasted (n = 5), and fasted with insulin injection (n = 5). A 60-min small-animal PET with serial blood sampling and kinetic modeling was performed. Results: We found comparable FDG standardized uptake values (SUVs) in myocardium in the non-fasted controls and non-fasted-insulin injected group (SUV 45-60 min, 9.58 ± 1.62 vs. 9.98 ± 2.44; p = 0.74), a lower myocardial SUV was noted in the fasted group (3.48 ± 1.73; p < 0.001). In contrast, the FDG uptake rate constant (Ki) for myocardium increased significantly by 47\% in non-fasted mice by insulin (13.4 ± 3.9 ml/min/100 g vs. 19.8 ± 3.3 ml/min/100 g; p = 0.030); in fasted mice, a lower myocardial Ki as compared to controls was observed (3.3 ± 1.9 ml/min/100 g; p < 0.001). Skeletal muscle SUVs and Ki values were increased by insulin independent of dietary state, whereas in the brain, those parameters were not influenced by fasting or administration of insulin. Fasting led to a reduction in glucose metabolic rate in the myocardium (19.41 ± 5.39 vs. 3.26 ± 1.97 mg/min/100 g; p < 0.001), the skeletal muscle (1.06 ± 0.34 vs. 0.34 ± 0.08 mg/min/100 g; p = 0.001) but not the brain (3.21 ± 0.53 vs. 2.85 ± 0.25 mg/min/100 g; p = 0.19). Conclusions: Changes in organ SUVs, uptake rate constants and metabolic rates induced by fasting and insulin administration as observed in intact mice by small-animal PET imaging are consistent with those observed in isolated heart/muscle preparations and, more importantly, in vivo studies in larger animals and in humans. When assessing the effect of insulin on the myocardial glucose metabolism of non-fasted mice, it is not sufficient to just calculate the SUV - dynamic imaging with kinetic modeling is necessary.}, subject = {Insulin}, language = {en} } @article{BaumToykaBlueheretal.2021, author = {Baum, Petra and Toyka, Klaus V. and Bl{\"u}her, Matthias and Kosacka, Joanna and Nowicki, Marcin}, title = {Inflammatory mechanisms in the pathophysiology of diabetic peripheral neuropathy (DN) — new aspects}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {19}, issn = {1422-0067}, doi = {10.3390/ijms221910835}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284556}, year = {2021}, abstract = {The pathogenesis of diabetic neuropathy is complex, and various pathogenic pathways have been proposed. A better understanding of the pathophysiology is warranted for developing novel therapeutic strategies. Here, we summarize recent evidence from experiments using animal models of type 1 and type 2 diabetes showing that low-grade intraneural inflammation is a facet of diabetic neuropathy. Our experimental data suggest that these mild inflammatory processes are a likely common terminal pathway in diabetic neuropathy associated with the degeneration of intraepidermal nerve fibers. In contrast to earlier reports claiming toxic effects of high-iron content, we found the opposite, i.e., nutritional iron deficiency caused low-grade inflammation and fiber degeneration while in normal or high non-heme iron nutrition no or only extremely mild inflammatory signs were identified in nerve tissue. Obesity and dyslipidemia also appear to trigger mild inflammation of peripheral nerves, associated with neuropathy even in the absence of overt diabetes mellitus. Our finding may be the experimental analog of recent observations identifying systemic proinflammatory activity in human sensorimotor diabetic neuropathy. In a rat model of type 1 diabetes, a mild neuropathy with inflammatory components could be induced by insulin treatment causing an abrupt reduction in HbA1c. This is in line with observations in patients with severe diabetes developing a small fiber neuropathy upon treatment-induced rapid HbA1c reduction. If the inflammatory pathogenesis could be further substantiated by data from human tissues and intervention studies, anti-inflammatory compounds with different modes of action may become candidates for the treatment or prevention of diabetic neuropathy.}, language = {en} } @article{GrotemeyerFischerKoprichetal.2023, author = {Grotemeyer, Alexander and Fischer, Judith F. and Koprich, James B. and Brotchie, Jonathan M. and Blum, Robert and Volkmann, Jens and Ip, Chi Wang}, title = {Inflammasome inhibition protects dopaminergic neurons from α-synuclein pathology in a model of progressive Parkinson's disease}, series = {Journal of Neuroinflammation}, volume = {20}, journal = {Journal of Neuroinflammation}, doi = {10.1186/s12974-023-02759-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357652}, year = {2023}, abstract = {Neuroinflammation has been suggested as a pathogenetic mechanism contributing to Parkinson's disease (PD). However, anti-inflammatory treatment strategies have not yet been established as a therapeutic option for PD patients. We have used a human α-synuclein mouse model of progressive PD to examine the anti-inflammatory and neuroprotective effects of inflammasome inhibition on dopaminergic (DA) neurons in the substantia nigra (SN). As the NLRP3 (NOD-, LRR- and pyrin domain-containing 3)-inflammasome is a core interface for both adaptive and innate inflammation and is also highly druggable, we investigated the implications of its inhibition. Repeat administration of MCC950, an inhibitor of NLRP3, in a PD model with ongoing pathology reduced CD4\(^+\) and CD8\(^+\) T cell infiltration into the SN. Furthermore, the anti-inflammasome treatment mitigated microglial activation and modified the aggregation of α-synuclein protein in DA neurons. MCC950-treated mice showed significantly less neurodegeneration of DA neurons and a reduction in PD-related motor behavior. In summary, early inflammasome inhibition can reduce neuroinflammation and prevent DA cell death in an α-synuclein mouse model for progressive PD.}, language = {en} } @article{GoebVollZimmermannetal.2021, author = {G{\"o}b, Vanessa and Voll, Maximilian G. and Zimmermann, Lena and Hemmen, Katharina and Stoll, Guido and Nieswandt, Bernhard and Schuhmann, Michael K. and Heinze, Katrin G. and Stegner, David}, title = {Infarct growth precedes cerebral thrombosis following experimental stroke in mice}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-021-02360-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265791}, year = {2021}, abstract = {Ischemic stroke is among the leading causes of disability and death worldwide. In acute ischemic stroke, successful recanalization of occluded vessels is the primary therapeutic aim, but even if it is achieved, not all patients benefit. Although blockade of platelet aggregation did not prevent infarct progression, cerebral thrombosis as cause of secondary infarct growth has remained a matter of debate. As cerebral thrombi are frequently observed after experimental stroke, a thrombus-induced impairment of the brain microcirculation is considered to contribute to tissue damage. Here, we combine the model of transient middle cerebral artery occlusion (tMCAO) with light sheet fluorescence microscopy and immunohistochemistry of brain slices to investigate the kinetics of thrombus formation and infarct progression. Our data reveal that tissue damage already peaks after 8 h of reperfusion following 60 min MCAO, while cerebral thrombi are only observed at later time points. Thus, cerebral thrombosis is not causative for secondary infarct growth during ischemic stroke.}, language = {en} } @article{OdorferHomolaReichetal.2019, author = {Odorfer, Thorsten M. and Homola, Gy{\"o}rgy A. and Reich, Martin M. and Volkmann, Jens and Zeller, Daniel}, title = {Increased finger-tapping related cerebellar activation in cervical dystonia, enhanced by transcranial stimulation: an indicator of compensation?}, series = {Frontiers in Neurology}, volume = {10}, journal = {Frontiers in Neurology}, number = {231}, issn = {1664-2295}, doi = {10.3389/fneur.2019.00231}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196249}, year = {2019}, abstract = {Background: Cervical dystonia is a movement disorder causing abnormal postures and movements of the head. While the exact pathophysiology of cervical dystonia has not yet been fully elucidated, a growing body of evidence points to the cerebellum as an important node. Methods: Here, we examined the impact of cerebellar interference by transcranial magnetic stimulation on finger-tapping related brain activation and neurophysiological measures of cortical excitability and inhibition in cervical dystonia and controls. Bilateral continuous theta-burst stimulation was used to modulate cerebellar cortical excitability in 16 patients and matched healthy controls. In a functional magnetic resonance imaging arm, data were acquired during simple finger tapping before and after cerebellar stimulation. In a neurophysiological arm, assessment comprised motor-evoked potentials amplitude and cortical silent period duration. Theta-burst stimulation over the dorsal premotor cortex and sham stimulation (neurophysiological arm only) served as control conditions. Results: At baseline, finger tapping was associated with increased activation in the ipsilateral cerebellum in patients compared to controls. Following cerebellar theta-burst stimulation, this pattern was even more pronounced, along with an additional movement-related activation in the contralateral somatosensory region and angular gyrus. Baseline motor-evoked potential amplitudes were higher and cortical silent period duration shorter in patients compared to controls. After cerebellar theta-burst stimulation, cortical silent period duration increased significantly in dystonia patients. Conclusion: We conclude that in cervical dystonia, finger movements—though clinically non-dystonic—are associated with increased activation of the lateral cerebellum, possibly pointing to general motor disorganization, which remains subclinical in most body regions. Enhancement of this activation together with an increase of silent period duration by cerebellar continuous theta-burst stimulation may indicate predominant disinhibitory effects on Purkinje cells, eventually resulting in an inhibition of cerebello-thalamocortical circuits.}, language = {en} } @article{UeceylerKewenigKittelSchneideretal.2015, author = {{\"U}{\c{c}}eyler, Nurcan and Kewenig, Susanne and Kittel-Schneider, Sarah and Fallgatter, Andreas J. and Sommer, Claudia}, title = {Increased cortical activation upon painful stimulation in fibromyalgia syndrome}, series = {BMC Neurology}, volume = {15}, journal = {BMC Neurology}, number = {210}, doi = {10.1186/s12883-015-0472-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125230}, year = {2015}, abstract = {Background Fibromyalgia syndrome (FMS) is a chronic condition characterized by widespread pain and associated symptoms. We investigated cerebral activation in FMS patients by functional near-infrared spectroscopy (fNIRS). Methods Two stimulation paradigms were applied: a) painful pressure stimulation at the dorsal forearm; b) verbal fluency test (VFT). We prospectively recruited 25 FMS patients, ten patients with unipolar major depression (MD) without pain, and 35 healthy controls. All patients underwent neurological examination and all subjects were investigated with questionnaires (pain, depression, FMS, empathy). Results FMS patients had lower pressure pain thresholds than patients with MD and controls (p < 0.001) and reported higher pain intensity (p < 0.001). Upon unilateral pressure pain stimulation fNIRS recordings revealed increased bilateral cortical activation in FMS patients compared to controls (p < 0.05). FMS patients also displayed a stronger contralateral activity over the dorsolateral prefrontal cortex in direct comparison to patients with MD (p < 0.05). While all three groups performed equally well in the VFT, a frontal deficit in cortical activation was only found in patients with depression (p < 0.05). Performance and cortical activation correlated negatively in FMS patients (p < 0.05) and positively in patients with MD (p < 0.05). Conclusion Our data give further evidence for altered central nervous processing in patients with FMS and the distinction between FMS and MD.}, language = {en} } @article{UeceylerHomolaGonzalezetal.2014, author = {{\"U}{\c{c}}eyler, Nurcan and Homola, Gy{\"o}rgy A. and Gonz{\´a}lez, Hans Guerrero and Kramer, Daniela and Wanner, Christoph and Weidemann, Frank and Solymosi, L{\´a}szl{\´o} and Sommer, Claudia}, title = {Increased Arterial Diameters in the Posterior Cerebral Circulation in Men with Fabry Disease}, doi = {10.1371/journal.pone.0087054}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112614}, year = {2014}, abstract = {A high load of white matter lesions and enlarged basilar arteries have been shown in selected patients with Fabry disease, a disorder associated with an increased stroke risk. We studied a large cohort of patients with Fabry disease to differentially investigate white matter lesion load and cerebral artery diameters. We retrospectively analyzed cranial magnetic resonance imaging scans of 87 consecutive Fabry patients, 20 patients with ischemic stroke, and 36 controls. We determined the white matter lesion load applying the Fazekas score on fluid-attenuated inversion recovery sequences and measured the diameters of cerebral arteries on 3D-reconstructions of the time-of-flight-MR-angiography scans. Data of different Fabry patient subgroups (males - females; normal - impaired renal function) were compared with data of patients with stroke and controls. A history of stroke or transient ischemic attacks was present in 4/30 males (13\%) and 5/57 (9\%) females with Fabry disease, all in the anterior circulation. Only one man with Fabry disease showed confluent cerebral white matter lesions in the Fazekas score assessment (1\%). Male Fabry patients had a larger basilar artery (p<0.01) and posterior cerebral artery diameter (p<0.05) compared to male controls. This was independent of disease severity as measured by renal function and did not lead to changes in arterial blood flow properties. A basilar artery diameter of >3.2 mm distinguished between men with Fabry disease and controls (sensitivity: 87\%, specificity: 86\%, p<0.001), but not from stroke patients. Enlarged arterial diameters of the posterior circulation are present only in men with Fabry disease independent of disease severity.}, language = {en} } @article{WeiseBasseLuesebrinkKleinschnitzetal.2011, author = {Weise, Gesa and Basse-L{\"u}sebrink, Thomas C. and Kleinschnitz, Christoph and Kampf, Thomas and Jakob, Peter M. and Stoll, Guido}, title = {In Vivo Imaging of Stepwise Vessel Occlusion in Cerebral Photothrombosis of Mice by \(^{19}\)F MRI}, series = {PLoS One}, volume = {6}, journal = {PLoS One}, number = {12}, doi = {10.1371/journal.pone.0028143}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137792}, pages = {e28143}, year = {2011}, abstract = {Background \(^{19}\)F magnetic resonance imaging (MRI) was recently introduced as a promising technique for in vivo cell tracking. In the present study we compared \(^{19}\)F MRI with iron-enhanced MRI in mice with photothrombosis (PT) at 7 Tesla. PT represents a model of focal cerebral ischemia exhibiting acute vessel occlusion and delayed neuroinflammation. Methods/Principal Findings Perfluorocarbons (PFC) or superparamagnetic iron oxide particles (SPIO) were injected intravenously at different time points after photothrombotic infarction. While administration of PFC directly after PT induction led to a strong \(^{19}\)F signal throughout the entire lesion, two hours delayed application resulted in a rim-like \(^{19}\)F signal at the outer edge of the lesion. These findings closely resembled the distribution of signal loss on T2-weighted MRI seen after SPIO injection reflecting intravascular accumulation of iron particles trapped in vessel thrombi as confirmed histologically. By sequential administration of two chemically shifted PFC compounds 0 and 2 hours after illumination the different spatial distribution of the \(^{19}\)F markers (infarct core/rim) could be visualized in the same animal. When PFC were applied at day 6 the fluorine marker was only detected after long acquisition times ex vivo. SPIO-enhanced MRI showed slight signal loss in vivo which was much more prominent ex vivo indicative for neuroinflammation at this late lesion stage. Conclusion Our study shows that vessel occlusion can be followed in vivo by \(^{19}\)F and SPIO-enhanced high-field MRI while in vivo imaging of neuroinflammation remains challenging. The timing of contrast agent application was the major determinant of the underlying processes depicted by both imaging techniques. Importantly, sequential application of different PFC compounds allowed depiction of ongoing vessel occlusion from the core to the margin of the ischemic lesions in a single MRI measurement.}, language = {en} }