@article{GoepfertTraubSelletal.2023, author = {G{\"o}pfert, Dennis and Traub, Jan and Sell, Roxane and Homola, Gy{\"o}rgy A. and Vogt, Marius and Pham, Mirko and Frantz, Stefan and St{\"o}rk, Stefan and Stoll, Guido and Frey, Anna}, title = {Profiles of cognitive impairment in chronic heart failure—A cluster analytic approach}, series = {Frontiers in Human Neuroscience}, volume = {17}, journal = {Frontiers in Human Neuroscience}, doi = {10.3389/fnhum.2023.1126553}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313429}, year = {2023}, abstract = {Background Cognitive impairment is a major comorbidity in patients with chronic heart failure (HF) with a wide range of phenotypes. In this study, we aimed to identify and compare different clusters of cognitive deficits. Methods The prospective cohort study "Cognition.Matters-HF" recruited 147 chronic HF patients (aged 64.5 ± 10.8 years; 16.2\% female) of any etiology. All patients underwent extensive neuropsychological testing. We performed a hierarchical cluster analysis of the cognitive domains, such as intensity of attention, visual/verbal memory, and executive function. Generated clusters were compared exploratively with respect to the results of cardiological, neurological, and neuroradiological examinations without correction for multiple testing. Results Dendrogram and the scree plot suggested three distinct cognitive profiles: In the first cluster, 42 patients (28.6\%) performed without any deficits in all domains. Exclusively, the intensity of attention deficits was seen in the second cluster, including 55 patients (37.4\%). A third cluster with 50 patients (34.0\%) was characterized by deficits in all cognitive domains. Age (p = 0.163) and typical clinical markers of chronic HF, such as ejection fraction (p = 0.222), 6-min walking test distance (p = 0.138), NT-proBNP (p = 0.364), and New York Heart Association class (p = 0.868) did not differ between clusters. However, we observed that women (p = 0.012) and patients with previous cardiac valve surgery (p = 0.005) prevailed in the "global deficits" cluster and the "no deficits" group had a lower prevalence of underlying arterial hypertension (p = 0.029). Total brain volume (p = 0.017) was smaller in the global deficit cluster, and serum levels of glial fibrillary acidic protein were increased (p = 0.048). Conclusion Apart from cognitively healthy and globally impaired HF patients, we identified a group with deficits only in the intensity of attention. Women and patients with previous cardiac valve surgery are at risk for global cognitive impairment when suffering HF and could benefit from special multimodal treatment addressing the psychosocial condition.}, language = {en} } @article{HeckerGruenerHartmannsbergeretal.2023, author = {Hecker, Katharina and Gr{\"u}ner, Julia and Hartmannsberger, Beate and Appeltshauser, Luise and Villmann, Carmen and Sommer, Claudia and Doppler, Kathrin}, title = {Different binding and pathogenic effect of neurofascin and contactin-1 autoantibodies in autoimmune nodopathies}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1189734}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320395}, year = {2023}, abstract = {Introduction IgG4 autoantibodies against paranodal proteins are known to induce acute-onset and often severe sensorimotor autoimmune neuropathies. How autoantibodies reach their antigens at the paranode in spite of the myelin barrier is still unclear. Methods We performed in vitro incubation experiments with patient sera on unfixed and unpermeabilized nerve fibers and in vivo intraneural and intrathecal passive transfer of patient IgG to rats, to explore the access of IgG autoantibodies directed against neurofascin-155 and contactin-1 to the paranodes and their pathogenic effect. Results We found that in vitro incubation resulted in weak paranodal binding of anti-contactin-1 autoantibodies whereas anti-neurofascin-155 autoantibodies bound to the nodes more than to the paranodes. After short-term intraneural injection, no nodal or paranodal binding was detectable when using anti-neurofascin-155 antibodies. After repeated intrathecal injections, nodal more than paranodal binding could be detected in animals treated with anti-neurofascin-155, accompanied by sensorimotor neuropathy. In contrast, no paranodal binding was visible in rats intrathecally injected with anti-contactin-1 antibodies, and animals remained unaffected. Conclusion These data support the notion of different pathogenic mechanisms of anti-neurofascin-155 and anti-contactin-1 autoantibodies and different accessibility of paranodal and nodal structures.}, language = {en} } @article{LehriederZapantisPhametal.2023, author = {Lehrieder, Dominik and Zapantis, Nikolaos and Pham, Mirko and Schuhmann, Michael Klaus and Haarmann, Axel}, title = {Treating seronegative neuromyelitis optica spectrum disorder with inebilizumab: a case report}, series = {Frontiers in Neurology}, volume = {14}, journal = {Frontiers in Neurology}, doi = {10.3389/fneur.2023.1297341}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-354031}, year = {2023}, abstract = {Background Neuromyelitis optica spectrum disorder (NMOSD) is a devastating inflammatory disease of the central nervous system that is often severely disabling from the outset. The lack of pathognomonic aquaporin 4 (AQP4) antibodies in seronegative NMOSD not only hinders early diagnosis, but also limits therapeutic options, in contrast to AQP4 antibody-positive NMOSD, where the therapeutic landscape has recently evolved massively. Case presentation We report a 56-year-old woman with bilateral optic neuritis and longitudinally extensive myelitis as the index events of a seronegative NMOSD, who was successfully treated with inebilizumab. Conclusion Treatment with inebilizumab may be considered in aggressive seronegative NMOSD. Whether broader CD19-directed B cell depletion is more effective than treatment with rituximab remains elusive.}, language = {en} } @article{RauschenbergerPiroKasaragodetal.2023, author = {Rauschenberger, Vera and Piro, Inken and Kasaragod, Vikram Babu and H{\"o}rlin, Verena and Eckes, Anna-Lena and Kluck, Christoph J. and Schindelin, Hermann and Meinck, Hans-Michael and Wickel, Jonathan and Geis, Christian and T{\"u}z{\"u}n, Erdem and Doppler, Kathrin and Sommer, Claudia and Villmann, Carmen}, title = {Glycine receptor autoantibody binding to the extracellular domain is independent from receptor glycosylation}, series = {Frontiers in Molecular Neuroscience}, volume = {16}, journal = {Frontiers in Molecular Neuroscience}, doi = {10.3389/fnmol.2023.1089101}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304206}, year = {2023}, abstract = {Glycine receptor (GlyR) autoantibodies are associated with stiff-person syndrome and the life-threatening progressive encephalomyelitis with rigidity and myoclonus in children and adults. Patient histories show variability in symptoms and responses to therapeutic treatments. A better understanding of the autoantibody pathology is required to develop improved therapeutic strategies. So far, the underlying molecular pathomechanisms include enhanced receptor internalization and direct receptor blocking altering GlyR function. A common epitope of autoantibodies against the GlyRα1 has been previously defined to residues 1A-33G at the N-terminus of the mature GlyR extracellular domain. However, if other autoantibody binding sites exist or additional GlyR residues are involved in autoantibody binding is yet unknown. The present study investigates the importance of receptor glycosylation for binding of anti-GlyR autoantibodies. The glycine receptor α1 harbors only one glycosylation site at the amino acid residue asparagine 38 localized in close vicinity to the identified common autoantibody epitope. First, non-glycosylated GlyRs were characterized using protein biochemical approaches as well as electrophysiological recordings and molecular modeling. Molecular modeling of non-glycosylated GlyRα1 did not show major structural alterations. Moreover, non-glycosylation of the GlyRα1N38Q did not prevent the receptor from surface expression. At the functional level, the non-glycosylated GlyR demonstrated reduced glycine potency, but patient GlyR autoantibodies still bound to the surface-expressed non-glycosylated receptor protein in living cells. Efficient adsorption of GlyR autoantibodies from patient samples was possible by binding to native glycosylated and non-glycosylated GlyRα1 expressed in living not fixed transfected HEK293 cells. Binding of patient-derived GlyR autoantibodies to the non-glycosylated GlyRα1 offered the possibility to use purified non-glycosylated GlyR extracellular domain constructs coated on ELISA plates and use them as a fast screening readout for the presence of GlyR autoantibodies in patient serum samples. Following successful adsorption of patient autoantibodies by GlyR ECDs, binding to primary motoneurons and transfected cells was absent. Our results indicate that the glycine receptor autoantibody binding is independent of the receptor's glycosylation state. Purified non-glycosylated receptor domains harbouring the autoantibody epitope thus provide, an additional reliable experimental tool besides binding to native receptors in cell-based assays for detection of autoantibody presence in patient sera.}, language = {en} } @article{AndreskaLueningschroerWolfetal.2023, author = {Andreska, Thomas and L{\"u}ningschr{\"o}r, Patrick and Wolf, Daniel and McFleder, Rhonda L. and Ayon-Olivas, Maurilyn and Rattka, Marta and Drechsler, Christine and Perschin, Veronika and Blum, Robert and Aufmkolk, Sarah and Granado, Noelia and Moratalla, Rosario and Sauer, Markus and Monoranu, Camelia and Volkmann, Jens and Ip, Chi Wang and Stigloher, Christian and Sendtner, Michael}, title = {DRD1 signaling modulates TrkB turnover and BDNF sensitivity in direct pathway striatal medium spiny neurons}, series = {Cell Reports}, volume = {42}, journal = {Cell Reports}, number = {6}, doi = {10.1016/j.celrep.2023.112575}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349932}, year = {2023}, abstract = {Highlights • Dopamine receptor-1 activation induces TrkB cell-surface expression in striatal neurons • Dopaminergic deficits cause TrkB accumulation and clustering in the ER • TrkB clusters colocalize with cargo receptor SORCS-2 in direct pathway striatal neurons • Intracellular TrkB clusters fail to fuse with lysosomes after dopamine depletion Summary Disturbed motor control is a hallmark of Parkinson's disease (PD). Cortico-striatal synapses play a central role in motor learning and adaption, and brain-derived neurotrophic factor (BDNF) from cortico-striatal afferents modulates their plasticity via TrkB in striatal medium spiny projection neurons (SPNs). We studied the role of dopamine in modulating the sensitivity of direct pathway SPNs (dSPNs) to BDNF in cultures of fluorescence-activated cell sorting (FACS)-enriched D1-expressing SPNs and 6-hydroxydopamine (6-OHDA)-treated rats. DRD1 activation causes enhanced TrkB translocation to the cell surface and increased sensitivity for BDNF. In contrast, dopamine depletion in cultured dSPN neurons, 6-OHDA-treated rats, and postmortem brain of patients with PD reduces BDNF responsiveness and causes formation of intracellular TrkB clusters. These clusters associate with sortilin related VPS10 domain containing receptor 2 (SORCS-2) in multivesicular-like structures, which apparently protects them from lysosomal degradation. Thus, impaired TrkB processing might contribute to disturbed motor function in PD.}, 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{GarciaFernandezHoefflinRauschetal.2023, author = {Garc{\´i}a-Fern{\´a}ndez, Patricia and H{\"o}fflin, Klemens and Rausch, Antonia and Strommer, Katharina and Neumann, Astrid and Cebulla, Nadine and Reinhold, Ann-Kristin and Rittner, Heike and {\"U}{\c{c}}eyler, Nurcan and Sommer, Claudia}, title = {Systemic inflammatory markers in patients with polyneuropathies}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1067714}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304217}, year = {2023}, abstract = {Introduction In patients with peripheral neuropathies (PNP), neuropathic pain is present in 50\% of the cases, independent of the etiology. The pathophysiology of pain is poorly understood, and inflammatory processes have been found to be involved in neuro-degeneration, -regeneration and pain. While previous studies have found a local upregulation of inflammatory mediators in patients with PNP, there is a high variability described in the cytokines present systemically in sera and cerebrospinal fluid (CSF). We hypothesized that the development of PNP and neuropathic pain is associated with enhanced systemic inflammation. Methods To test our hypothesis, we performed a comprehensive analysis of the protein, lipid and gene expression of different pro- and anti-inflammatory markers in blood and CSF from patients with PNP and controls. Results While we found differences between PNP and controls in specific cytokines or lipids, such as CCL2 or oleoylcarnitine, PNP patients and controls did not present major differences in systemic inflammatory markers in general. IL-10 and CCL2 levels were related to measures of axonal damage and neuropathic pain. Lastly, we describe a strong interaction between inflammation and neurodegeneration at the nerve roots in a specific subgroup of PNP patients with blood-CSF barrier dysfunction. Conclusion In patients with PNP systemic inflammatory, markers in blood or CSF do not differ from controls in general, but specific cytokines or lipids do. Our findings further highlight the importance of CSF analysis in patients with peripheral neuropathies.}, language = {en} } @article{McFlederMakhotkinaGrohetal.2023, author = {McFleder, Rhonda L. and Makhotkina, Anastasiia and Groh, Janos and Keber, Ursula and Imdahl, Fabian and Pe{\~n}a Mosca, Josefina and Peteranderl, Alina and Wu, Jingjing and Tabuchi, Sawako and Hoffmann, Jan and Karl, Ann-Kathrin and Pagenstecher, Axel and Vogel, J{\"o}rg and Beilhack, Andreas and Koprich, James B. and Brotchie, Jonathan M. and Saliba, Antoine-Emmanuel and Volkmann, Jens and Ip, Chi Wang}, title = {Brain-to-gut trafficking of alpha-synuclein by CD11c\(^+\) cells in a mouse model of Parkinson's disease}, series = {Nature Communications}, volume = {14}, journal = {Nature Communications}, doi = {10.1038/s41467-023-43224-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357696}, year = {2023}, abstract = {Inflammation in the brain and gut is a critical component of several neurological diseases, such as Parkinson's disease (PD). One trigger of the immune system in PD is aggregation of the pre-synaptic protein, α-synuclein (αSyn). Understanding the mechanism of propagation of αSyn aggregates is essential to developing disease-modifying therapeutics. Using a brain-first mouse model of PD, we demonstrate αSyn trafficking from the brain to the ileum of male mice. Immunohistochemistry revealed that the ileal αSyn aggregations are contained within CD11c+ cells. Using single-cell RNA sequencing, we demonstrate that ileal CD11c\(^+\) cells are microglia-like and the same subtype of cells is activated in the brain and ileum of PD mice. Moreover, by utilizing mice expressing the photo-convertible protein, Dendra2, we show that CD11c\(^+\) cells traffic from the brain to the ileum. Together these data provide a mechanism of αSyn trafficking between the brain and gut.}, language = {en} } @article{GriebelSegebarthSteinetal.2023, author = {Griebel, Matthias and Segebarth, Dennis and Stein, Nikolai and Schukraft, Nina and Tovote, Philip and Blum, Robert and Flath, Christoph M.}, title = {Deep learning-enabled segmentation of ambiguous bioimages with deepflash2}, series = {Nature Communications}, volume = {14}, journal = {Nature Communications}, doi = {10.1038/s41467-023-36960-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357286}, year = {2023}, abstract = {Bioimages frequently exhibit low signal-to-noise ratios due to experimental conditions, specimen characteristics, and imaging trade-offs. Reliable segmentation of such ambiguous images is difficult and laborious. Here we introduce deepflash2, a deep learning-enabled segmentation tool for bioimage analysis. The tool addresses typical challenges that may arise during the training, evaluation, and application of deep learning models on ambiguous data. The tool's training and evaluation pipeline uses multiple expert annotations and deep model ensembles to achieve accurate results. The application pipeline supports various use-cases for expert annotations and includes a quality assurance mechanism in the form of uncertainty measures. Benchmarked against other tools, deepflash2 offers both high predictive accuracy and efficient computational resource usage. The tool is built upon established deep learning libraries and enables sharing of trained model ensembles with the research community. deepflash2 aims to simplify the integration of deep learning into bioimage analysis projects while improving accuracy and reliability.}, language = {en} } @article{IpWischhusen2023, author = {Ip, Chi Wang and Wischhusen, J{\"o}rg}, title = {Versatile guardians: regenerative regulatory T cells in Parkinson's disease rodent models}, series = {Signal Transduction and Targeted Therapy}, volume = {8}, journal = {Signal Transduction and Targeted Therapy}, doi = {10.1038/s41392-023-01681-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357674}, year = {2023}, abstract = {No abstract available.}, 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{KuzkinaRoessleSegeretal.2023, author = {Kuzkina, A. and R{\"o}ßle, J. and Seger, A. and Panzer, C. and Kohl, A. and Maltese, V. and Musacchio, T. and Blaschke, S. J. and Tamg{\"u}ney, G. and Kaulitz, S. and Rak, K. and Scherzad, A. and Zimmermann, P. H. and Klussmann, J. P. and Hackenberg, S. and Volkmann, J. and Sommer, C. and Sommerauer, M. and Doppler, K.}, title = {Combining skin and olfactory α-synuclein seed amplification assays (SAA)—towards biomarker-driven phenotyping in synucleinopathies}, series = {npj Parkinson's Disease}, volume = {9}, journal = {npj Parkinson's Disease}, issn = {2373-8057}, doi = {10.1038/s41531-023-00519-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357687}, year = {2023}, abstract = {Seed amplification assays (SAA) are becoming commonly used in synucleinopathies to detect α-synuclein aggregates. Studies in Parkinson's disease (PD) and isolated REM-sleep behavior disorder (iRBD) have shown a considerably lower sensitivity in the olfactory epithelium than in CSF or skin. To get an insight into α-synuclein (α-syn) distribution within the nervous system and reasons for low sensitivity, we compared SAA assessment of nasal brushings and skin biopsies in PD (n = 27) and iRBD patients (n = 18) and unaffected controls (n = 30). α-syn misfolding was overall found less commonly in the olfactory epithelium than in the skin, which could be partially explained by the nasal brushing matrix exerting an inhibitory effect on aggregation. Importantly, the α-syn distribution was not uniform: there was a higher deposition of misfolded α-syn across all sampled tissues in the iRBD cohort compared to PD (supporting the notion of RBD as a marker of a more malignant subtype of synucleinopathy) and in a subgroup of PD patients, misfolded α-syn was detectable only in the olfactory epithelium, suggestive of the recently proposed brain-first PD subtype. Assaying α-syn of diverse origins, such as olfactory (part of the central nervous system) and skin (peripheral nervous system), could increase diagnostic accuracy and allow better stratification of patients.}, language = {en} } @article{OdorferYabeHiewetal.2023, author = {Odorfer, Thorsten M. and Yabe, Marie and Hiew, Shawn and Volkmann, Jens and Zeller, Daniel}, title = {Topological differences and confounders of mental rotation in cervical dystonia and blepharospasm}, series = {Scientific Reports}, volume = {13}, journal = {Scientific Reports}, doi = {10.1038/s41598-023-33262-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357713}, year = {2023}, abstract = {Mental rotation (mR) bases on imagination of actual movements. It remains unclear whether there is a specific pattern of mR impairment in focal dystonia. We aimed to investigate mR in patients with cervical dystonia (CD) and blepharospasm (BS) and to assess potential confounders. 23 CD patients and 23 healthy controls (HC) as well as 21 BS and 19 hemifacial spasm (HS) patients were matched for sex, age, and education level. Handedness, finger dexterity, general reaction time, and cognitive status were assessed. Disease severity was evaluated by clinical scales. During mR, photographs of body parts (head, hand, or foot) and a non-corporal object (car) were displayed at different angles rotated within their plane. Subjects were asked to judge laterality of the presented image by keystroke. Both speed and correctness were evaluated. Compared to HC, CD and HS patients performed worse in mR of hands, whereas BS group showed comparable performance. There was a significant association of prolonged mR reaction time (RT) with reduced MoCA scores and with increased RT in an unspecific reaction speed task. After exclusion of cognitively impaired patients, increased RT in the mR of hands was confined to CD group, but not HS. While the question of whether specific patterns of mR impairment reliably define a dystonic endophenotype remains elusive, our findings point to mR as a useful tool, when used carefully with control measures and tasks, which may be capable of identifying specific deficits that distinguish between subtypes of dystonia.}, 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} } @article{GunkelSchoetzauFluri2023, author = {Gunkel, Sarah and Sch{\"o}tzau, Andreas and Fluri, Felix}, title = {Burden of cerebral small vessel disease and changes of diastolic blood pressure affect clinical outcome after acute ischemic stroke}, series = {Scientific Reports}, volume = {13}, journal = {Scientific Reports}, doi = {10.1038/s41598-023-49502-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357669}, year = {2023}, abstract = {Elevated and low blood pressure (BP) may lead to poor functional outcome after ischemic stroke, which is conflicting. Hence, there must be another factor—such as cerebral small vessel disease (cSVD) -interacting with BP and thus, affecting outcome. Here, we investigate the relationship between BP and cSVD regarding outcome after stroke. Data of 423/503 stroke patients were prospectively analyzed. Diastolic (DBP) and systolic BP (SBP) were collected on hospital admission (BP\(_{ad}\)) and over the first 72 h (BP\(_{72h}\)). cSVD-burden was determined on MR-scans. Good functional outcome was defined as a modified Rankin Scale score ≤ 2 at hospital discharge and 12 months thereafter. cSVD was a predictor of poor outcome (OR 2.8; p < 0.001). SBPad, DBP\(_{ad}\) and SBP\(_{72h}\) were not significantly associated with outcome at any time. A significant relationship was found between DBP\(_{72h}\), (p < 0.01), cSVD (p = 0.013) and outcome at discharge. At 12 months, we found a relationship between outcome and DBP\(_{72h}\) (p = 0.018) and a statistical tendency regarding cSVD (p = 0.08). Changes in DBP72h were significantly related with outcome. There was a U-shaped relationship between DBP\(_{72h}\) and outcome at discharge. Our results suggest an individualized stroke care by either lowering or elevating DBP depending on cSVD-burden in order to influence functional outcome.}, language = {en} } @article{DingSeusingNasseroleslamietal.2023, author = {Ding, Hao and Seusing, Nelly and Nasseroleslami, Bahman and Anwar, Abdul Rauf and Strauss, Sebastian and Lotze, Martin and Grothe, Matthias and Groppa, Sergiu and Muthuraman, Muthuraman}, title = {The role of ipsilateral motor network in upper limb movement}, series = {Frontiers in Physiology}, volume = {14}, journal = {Frontiers in Physiology}, issn = {1664-042X}, doi = {10.3389/fphys.2023.1199338}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321805}, year = {2023}, abstract = {The execution of voluntary movements is primarily governed by the cerebral hemisphere contralateral to the moving limb. Previous research indicates that the ipsilateral motor network, comprising the primary motor cortex (M1), supplementary motor area (SMA), and premotor cortex (PM), plays a crucial role in the planning and execution of limb movements. However, the precise functions of this network and its interplay in different task contexts have yet to be fully understood. Twenty healthy right-handed participants (10 females, mean age 26.1 ± 4.6 years) underwent functional MRI scans while performing biceps brachii representations such as bilateral, unilateral flexion, and bilateral flexion-extension. Ipsilateral motor evoked potentials (iMEPs) were obtained from the identical set of participants in a prior study using transcranial magnetic stimulation (TMS) targeting M1 while employing the same motor tasks. The voxel time series was extracted based on the region of interest (M1, SMA, ventral PM and dorsal PM). Directed functinal connectivity was derived from the extracted time series using time-resolved partial directed coherence. We found increased connectivity from left-PMv to both sides M1, as well as right-PMv to both sides SMA, in unilateral flexion compared to bilateral flexion. Connectivity from left M1 to left-PMv, and left-SMA to right-PMd, also increased in both unilateral flexion and bilateral flexion-extension compared to bilateral flexion. However, connectivity between PMv and right-M1 to left-PMd decreased during bilateral flexion-extension compared to unilateral flexion. Additionally, during bilateral flexion-extension, the connectivity from right-M1 to right-SMA had a negative relationship with the area ratio of iMEP in the dominant side. Our results provide corroborating evidence for prior research suggesting that the ipsilateral motor network is implicated in the voluntary movements and underscores its involvement in cognitive processes such as movement planning and coordination. Moreover, ipsilateral connectivity from M1 to SMA on the dominant side can modulate the degree of ipsilateral M1 activation during bilateral antagonistic contraction.}, language = {en} } @article{SchuhmannLanghauserZimmermannetal.2023, author = {Schuhmann, Michael K. and Langhauser, Friederike and Zimmermann, Lena and Bellut, Maximilian and Kleinschnitz, Christoph and Fluri, Felix}, title = {Dimethyl fumarate attenuates lymphocyte infiltration and reduces infarct size in experimental stroke}, series = {International journal of molecular sciences}, volume = {24}, journal = {International journal of molecular sciences}, number = {21}, doi = {10.3390/ijms242115540}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357731}, year = {2023}, abstract = {Ischemic stroke is associated with exacerbated tissue damage caused by the activation of immune cells and the initiation of other inflammatory processes. Dimethyl fumarate (DMF) is known to modulate the immune response, activate antioxidative pathways, and improve the blood-brain barrier (BBB) after stroke. However, the specific impact of DMF on immune cells after cerebral ischemia remains unclear. In our study, male mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 min and received oral DMF (15 mg/kg) or a vehicle immediately after tMCAO, followed by twice-daily administrations for 7 days. Infarct volume was assessed on T2-weighted magnetic resonance images on days 1 and 7 after tMCAO. Brain-infiltrating immune cells (lymphocytes, monocytes) and microglia were quantified using fluorescence-activated cell sorting. DMF treatment significantly reduced infarct volumes and brain edema. On day 1 after tMCAO, DMF-treated mice showed reduced lymphocyte infiltration compared to controls, which was not observed on day 7. Monocyte and microglial cell counts did not differ between groups on either day. In the acute phase of stroke, DMF administration attenuated lymphocyte infiltration, probably due to its stabilizing effect on the BBB. This highlights the potential of DMF as a therapeutic candidate for mitigating immune cell-driven damage in stroke.}, language = {en} } @article{PozziBolzoniBiellaetal.2023, author = {Pozzi, Nicol{\´o} Gabriele and Bolzoni, Francesco and Biella, Gabriele Eliseo Mario and Pezzoli, Gianni and Ip, Chi Wang and Volkmann, Jens and Cavallari, Paolo and Asan, Esther and Isaias, Ioannis Ugo}, title = {Brain noradrenergic innervation supports the development of Parkinson's tremor: a study in a reserpinized rat model}, series = {Cells}, volume = {12}, journal = {Cells}, number = {21}, issn = {2073-4409}, doi = {10.3390/cells12212529}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357721}, year = {2023}, abstract = {The pathophysiology of tremor in Parkinson's disease (PD) is evolving towards a complex alteration to monoaminergic innervation, and increasing evidence suggests a key role of the locus coeruleus noradrenergic system (LC-NA). However, the difficulties in imaging LC-NA in patients challenge its direct investigation. To this end, we studied the development of tremor in a reserpinized rat model of PD, with or without a selective lesioning of LC-NA innervation with the neurotoxin DSP-4. Eight male rats (Sprague Dawley) received DSP-4 (50 mg/kg) two weeks prior to reserpine injection (10 mg/kg) (DR-group), while seven male animals received only reserpine treatment (R-group). Tremor, rigidity, hypokinesia, postural flexion and postural immobility were scored before and after 20, 40, 60, 80, 120 and 180 min of reserpine injection. Tremor was assessed visually and with accelerometers. The injection of DSP-4 induced a severe reduction in LC-NA terminal axons (DR-group: 0.024 ± 0.01 vs. R-group: 0.27 ± 0.04 axons/um\(^2\), p < 0.001) and was associated with significantly less tremor, as compared to the R-group (peak tremor score, DR-group: 0.5 ± 0.8 vs. R-group: 1.6 ± 0.5; p < 0.01). Kinematic measurement confirmed the clinical data (tremor consistency (\% of tremor during 180 s recording), DR-group: 37.9 ± 35.8 vs. R-group: 69.3 ± 29.6; p < 0.05). Akinetic-rigid symptoms did not differ between the DR- and R-groups. Our results provide preliminary causal evidence for a critical role of LC-NA innervation in the development of PD tremor and foster the development of targeted therapies for PD patients.}, language = {en} } @phdthesis{Messinger2023, author = {Messinger, Julia}, title = {Die Effekte von IVIG auf die Antik{\"o}rperbindung und Komplementablagerung bei Anti-Neurofascin-positiver Nodo-Paranodopathie}, doi = {10.25972/OPUS-32110}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321109}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Autoantik{\"o}rper gegen nodo-paranodale Proteine des Ranvier'schen Schn{\"u}rrings wie Neurofascin-155 (NF-155), Contactin-1 und Caspr wurden in der Literatur bei Patienten/Patientinnen mit Immunneuropathien beschrieben. Bei zwei bis zehn Prozent der Patienten/Patientinnen mit Immunneuropathien k{\"o}nnen Autoantik{\"o}rper gegen Isoformen des Neurofascin detektiert werden. Patienten/Patientinnen mit Autoantik{\"o}rpern gegen NF-155 weisen gemeinsame klinische Merkmale auf, unter anderem einen schweren Verlauf mit subakutem Beginn, vorwiegend motorischen Defiziten, Tremor und einem schlechten Ansprechen auf eine Therapie mit intraven{\"o}sen Immunglobulinen (IVIG). Ein Grund f{\"u}r Letzteres k{\"o}nnte sein, dass es sich {\"u}berwiegend um Autoantik{\"o}rper der Subklasse IgG4 handelt, die als anti-inflammatorisch gelten und kein Komplement aktivieren. Neben der IgG4-Subklasse k{\"o}nnen bei manchen Erkrankten auch die proinflammatorischen IgG-Subklassen 1 bis 3 nachgewiesen werden. Bei der Anti-Pan-Neurofascin (155/140/186) Polyneuropathie zeigt sich klinisch h{\"a}ufig ein fulminanter Ph{\"a}notyp mit IgG3 Pr{\"a}dominanz. Das Ziel dieser Studie war, die Autoantik{\"o}rper-induzierte Komplementablagerung zu detektieren, sowie die Rolle der IgG Subklasse und die Effekte von IVIG auf Antik{\"o}rperbindung, Komplementaktivierung und Effektorfunktionen zu untersuchen. Hierzu wurde das Serum von 212 Probanden/-innen mit der Verdachtsdiagnose einer entz{\"u}ndlichen Neuropathie auf Autoantik{\"o}rper gegen NF-155 mittels ELISA und Bindungsversuchen an M{\"a}usezupfnerven gescreent. Im Fall eines positiven Ergebnisses dienten zellbasierte Bindungsversuche mit NF-155-transfizierten HEK-293- Zellen als Best{\"a}tigungstest. Die Effekte unterschiedlicher IVIG Konzentrationen auf die Antik{\"o}rperbindung und Komplementablagerung wurden in ELISA, Komplementbindungsassays und zellbasierten Verfahren getestet. Außerdem wurde mithilfe von LDH-Zytotoxizit{\"a}tsmessungen die Komplement-induzierte Zelllyse sowie die Effekte von IVIG untersucht. Klinische Daten wurden retrospektiv ausgewertet. F{\"u}nf Patienten/Patientinnen mit hohen Autoantik{\"o}rpertitern gegen NF-155 und ein Patient mit Anti-Pan-Neurofascin Autoantik{\"o}rpern konnten in der Studie detektiert werden. Der Patient mit Autoantik{\"o}rpern gegen alle drei Isoformen des Neurofascins und IgG3-Pr{\"a}dominanz zeigte die deutlichste Komplementablagerung. Bei drei Patienten/Patientinnen, die IgG1, IgG2 und IgG4 aufwiesen, war eine Aktivierung des Komplementsystems zu beobachten, w{\"a}hrend bei zwei Patienten mit pr{\"a}dominanter IgG4-Antik{\"o}rpersubklasse keine Komplementablagerung nachweisbar war. Bei Letzteren war eine Therapie mit IVIG in der Vorgeschichte erfolglos, w{\"a}hrend es bei zwei der Patienten/Patientinnen mit anderen IgG-Subklassen und Komplementbindung unter IVIG Therapie zu einer m{\"a}ßigen bis deutlichen Symptombesserung in der Akutphase kam. Eine Koinkubation mit IVIG f{\"u}hrte in den ELISA basierten und zellbasierten Versuchen zu keinem Effekt auf die Autoantik{\"o}rperbindung an das Zielantigen, jedoch zu einer deutlichen Reduktion der Antik{\"o}rper-vermittelten Komplementbindung. Diese Reduktion war sowohl bei Koinkuabtion von IVIG mit dem Komplementfaktor C1q als auch bei Pr{\"a}inkubation von IVIG vor C1q Gabe zu sehen. Bei zwei der Patienten/Patientinnen mit hohen Komplementablagerungen konnte eine erh{\"o}hte Zytotoxizit{\"a}t nachgewiesen werden, welche bei Zugabe von IVIG verringert wurde. Schlussfolgernd ist die Autoantik{\"o}rper-induzierte Komplementablagerung abh{\"a}ngig von der pr{\"a}dominanten IgG Subklasse. IVIG f{\"u}hrt zu einer deutlichen, konzentrationsabh{\"a}ngigen Reduktion der Komplementablagerung, sowie m{\"o}glicher zytotoxischer Effektorfunktionen wie die Zytolyse myelinisierter Schwannzellen oder Nervenaxonen. Dar{\"u}ber hinaus k{\"o}nnte die Subklassenanalyse von Erkrankten das Therapieansprechen auf IVIG vorhersagen und sollte daher eine wichtige Rolle in der Diagnostik der Nodo-Paranodopathie spielen. IVIG sowie andere {\"u}ber das Komplementsystem wirkende Therapeutika k{\"o}nnen in der Behandlung der schwer betroffenen Patienten/Patientinnen, insbesondere bei Anti-Pan-Neurofascin positiver Neuropathie, in Betracht gezogen werden.}, subject = {Komplement }, language = {de} } @phdthesis{Behnke2023, author = {Behnke, Jennifer Kim}, title = {Charakterisierung der Krankheitsprogression im genetischen hm\(^2\)α-SYN-39 Mausmodell des Morbus Parkinson}, doi = {10.25972/OPUS-30204}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-302040}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {In dieser Arbeit wurde die Krankheitsprogression im Parkinson-Mausmodell hm2α-SYN-39 mit zunehmendem Alter charakterisiert. Die M{\"a}use wurden in 4 Altersgruppen (2-3, 7-8, 11-12, 16-17 Monate) mit motorischen Verhaltenstests auf einen Parkinson-Ph{\"a}notyp untersucht. Zudem erfolgten Untersuchungen des dopaminergen Systems zur Detektion von neurochemischen Ver{\"a}nderungen und einer Neurodegeneration im nigrostriatalen Trakt. Weiterhin wurden neuroinflammatorische Prozesse des adaptiven und angeborenen IS in der SN und im Striatum mittels immunhistochemischer F{\"a}rbungen beurteilt. Ein Parkinson-Ph{\"a}notyp in diesem Mausmodell zeigte sich nur leicht ausgepr{\"a}gt, sodass der Rotarod- und Zylinder-Test lediglich den Hinweis auf eine nicht-signifikante Einschr{\"a}nkung der Motorik erbrachte. Dennoch ergab die stereologische Quantifizierung TH- und Nissl-positiver Zellen in der SNpc der hm2α-SYN-39 M{\"a}use eine altersabh{\"a}ngige, signifikant-progrediente Reduktion der dopaminergen Neurone mit zunehmendem Alter. Eine signifikant niedrigere TH-positive Zellzahl dieser tg M{\"a}use zeigte sich ab einem Alter von 16-17 Monaten verglichen zu gleichaltrigen wt Tieren. Dagegen war die Neurodegeneration im Striatum etwas weniger ausgepr{\"a}gt. Die tg M{\"a}use pr{\"a}sentierten im Alter von 16-17 Monaten eine nicht-signifikante Erniedrigung der dopaminergen Terminalen verglichen zu gleichaltrigen wt Tieren. Ein DA-Mangel im Striatum der tg M{\"a}use konnte mittels HPLC best{\"a}tigt werden. Bis zum Alter von 16-17 Monaten wurde eine signifikante Reduktion der DA-Level von 23,2 \% verglichen zu gleichaltrigen wt M{\"a}usen gezeigt. Außerdem erniedrigt waren die striatalen Level von NA und 5-HAT bei tg M{\"a}usen, passend zu den bisherigen Ergebnissen bei Parkinson-Patienten. Immunhistochemische Untersuchungen einer Neuroinflammation im nigrostriatalen Trakt ergaben eine tendenziell erh{\"o}hte Infiltration von CD4- und CD8-positiven T-Zellen bei hm2α-SYN-39 M{\"a}usen mit zunehmendem Alter, wobei die Infiltration CD8-positiver Zellen ausgepr{\"a}gter war als bei CD4-positiven Zellen. Eine noch deutlichere neuroinflammatorische Reaktion zeigte das angeborene IS. Hierbei ergab die immunhistologische Quantifizierung CD11b-positiver mikroglialer Zellen einen hochsignifikanten Anstieg im nigrostriatalen Trakt bei hm2α-SYN-39 M{\"a}usen schon im jungen Alter. Zusammenfassend pr{\"a}sentierte dieses Parkinson-Mausmodell eine langsam-progrediente Parkinson-Pathologie mit begleitender Neuroinflammation im nigrostriatalen Trakt w{\"a}hrend des Alterns, wobei die Immunantwort der mikroglialen Zellen zu einem fr{\"u}heren Zeitpunkt einsetzte als die T-Zellinfiltration und Neurodegeneration. Dieses Mausmodell bietet zahlreiche M{\"o}glichkeiten zur zuk{\"u}nftigen Erforschung der Pathophysiologie beim MP. Generell weist diese Arbeit auf eine bedeutende Rolle neuroinflammatorischer Prozesse in der Krankheitsprogression der Parkinsonerkrankung hin und soll dazu ermutigen Neuroinflammation durchaus intensiver in tg Tiermodellen zu untersuchen.}, subject = {Parkinson-Krankheit}, language = {de} }