@article{RiedererterMeulen2020, author = {Riederer, Peter and ter Meulen, Volker}, title = {Coronaviruses: a challenge of today and a call for extended human postmortem brain analyses}, series = {Journal of Neural Transmission}, volume = {127}, journal = {Journal of Neural Transmission}, number = {9}, issn = {0300-9564}, doi = {10.1007/s00702-020-02230-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-314637}, pages = {1217-1228}, year = {2020}, abstract = {While there is abounding literature on virus-induced pathology in general and coronavirus in particular, recent evidence accumulates showing distinct and deleterious brain affection. As the respiratory tract connects to the brain without protection of the blood-brain barrier, SARS-CoV-2 might in the early invasive phase attack the cardiorespiratory centres located in the medulla/pons areas, giving rise to disturbances of respiration and cardiac problems. Furthermore, brainstem regions are at risk to lose their functional integrity. Therefore, long-term neurological as well as psychiatric symptomatology and eventual respective disorders cannot be excluded as evidenced from influenza-A triggered post-encephalitic Parkinsonism and HIV-1 triggered AIDS-dementia complex. From the available evidences for coronavirus-induced brain pathology, this review concludes a number of unmet needs for further research strategies like human postmortem brain analyses. SARS-CoV-2 mirroring experimental animal brain studies, characterization of time-dependent and region-dependent spreading behaviours of coronaviruses, enlightening of pathological mechanisms after coronavirus infection using long-term animal models and clinical observations of patients having had COVID-19 infection are calling to develop both protective strategies and drug discoveries to avoid early and late coronavirus-induced functional brain disturbances, symptoms and eventually disorders. To fight SARS-CoV-2, it is an urgent need to enforce clinical, molecular biological, neurochemical and genetic research including brain-related studies on a worldwide harmonized basis.}, language = {en} } @article{RajendranRajendranGuptaetal.2022, author = {Rajendran, Ranjithkumar and Rajendran, Vinothkumar and Gupta, Liza and Shirvanchi, Kian and Schunin, Darja and Karnati, Srikanth and Giraldo-Vel{\´a}squez, Mario and Berghoff, Martin}, title = {Interferon beta-1a versus combined interferon beta-1a and oligodendrocyte-specific FGFR1 deletion in experimental autoimmune encephalomyelitis}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {20}, issn = {1422-0067}, doi = {10.3390/ijms232012183}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290401}, year = {2022}, abstract = {Recombinant beta interferons-1 (IFNβ-1) are used as first line therapies in patients with relapsing multiple sclerosis (MS), a chronic inflammatory and neurodegenerative disease of the CNS. IFNβ-1a/b has moderate effects on the prevention of relapses and slowing of disease progression. Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) are known to play a key role in the pathology of MS and its model EAE. To investigate the effects of short-term treatment with s.c. IFNβ-1a versus the combined application of s.c. IFNβ-1a and oligodendrocyte-specific deletion of FGFR1 (Fgfr1\(^{ind-/-}\) mice) in MOG\(_{35-55}\)-induced EAE. IFNβ-1a (30 mg/kg) was applied s.c. from days 0-7 p.i. of EAE in controls and Fgfr1\(^{ind-/-}\) mice. FGFR signaling proteins associated with inflammation/degeneration in MS/EAE were analyzed by western blot in the spinal cord. Further, FGFR1 in Oli-neu oligodendrocytes were inhibited by PD166866 and treated with IFNβ-1a (400 ng/mL). Application of IFNβ-1a over 8 days resulted in less symptoms only at the peak of disease (days 9-11) compared to controls. Application of IFNβ-1a in Fgfr1\(^{ind-/-}\) mice resulted in less symptoms primarily in the chronic phase of EAE. Fgfr1\(^{ind-/-}\) mice treated with IFNβ-1a showed increased expression of pERK and BDNF. In Oli-neu oligodendrocytes, treatment with PD166866 and IFNβ-1a also showed an increased expression of pERK and BDNF/TrkB. These data suggest that the beneficial effects in the chronic phase of EAE and on signaling molecules associated with ERK and BDNF expression are caused by the modulation of FGFR1 and not by interferon beta-1a. FGFR may be a potential target for therapy in MS.}, language = {en} } @article{VogelsangEichlerHuntemannetal.2021, author = {Vogelsang, Anna and Eichler, Susann and Huntemann, Niklas and Masanneck, Lars and B{\"o}hnlein, Hannes and Sch{\"u}ngel, Lisa and Willison, Alice and Loser, Karin and Nieswandt, Bernhard and Kehrel, Beate E. and Zarbock, Alexander and G{\"o}bel, Kerstin and Meuth, Sven G.}, title = {Platelet inhibition by low-dose acetylsalicylic acid reduces neuroinflammation in an animal model of multiple sclerosis}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {18}, issn = {1422-0067}, doi = {10.3390/ijms22189915}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284535}, year = {2021}, abstract = {Aside from the established immune-mediated etiology of multiple sclerosis (MS), compelling evidence implicates platelets as important players in disease pathogenesis. Specifically, numerous studies have highlighted that activated platelets promote the central nervous system (CNS)-directed adaptive immune response early in the disease course. Platelets, therefore, present a novel opportunity for modulating the neuroinflammatory process that characterizes MS. We hypothesized that the well-known antiplatelet agent acetylsalicylic acid (ASA) could inhibit neuroinflammation by affecting platelets if applied at low-dose and investigated its effect during experimental autoimmune encephalomyelitis (EAE) as a model to study MS. We found that oral administration of low-dose ASA alleviates symptoms of EAE accompanied by reduced inflammatory infiltrates and less extensive demyelination. Remarkably, the percentage of CNS-infiltrated CD4\(^+\) T cells, the major drivers of neuroinflammation, was decreased to 40.98 ± 3.28\% in ASA-treated mice compared to 56.11 ± 1.46\% in control animals at the disease maximum as revealed by flow cytometry. More interestingly, plasma levels of thromboxane A\(_2\) were decreased, while concentrations of platelet factor 4 and glycoprotein VI were not affected by low-dose ASA treatment. Overall, we demonstrate that low-dose ASA could ameliorate the platelet-dependent neuroinflammatory response in vivo, thus indicating a potential treatment approach for MS.}, language = {en} } @article{NguemeniHiewKoegleretal.2021, author = {Nguemeni, Carine and Hiew, Shawn and K{\"o}gler, Stefanie and Homola, Gy{\"o}rgy A. and Volkmann, Jens and Zeller, Daniel}, title = {Split-belt training but not cerebellar anodal tDCS improves stability control and reduces risk of fall in patients with multiple sclerosis}, series = {Brain Sciences}, volume = {12}, journal = {Brain Sciences}, number = {1}, issn = {2076-3425}, doi = {10.3390/brainsci12010063}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252179}, year = {2021}, abstract = {The objective of this study was to examine the therapeutic potential of multiple sessions of training on a split-belt treadmill (SBT) combined with cerebellar anodal transcranial direct current stimulation (tDCS) on gait and balance in People with Multiple Sclerosis (PwMS). Twenty-two PwMS received six sessions of anodal (PwMS\(_{real}\), n = 12) or sham (PwMS\(_{sham}\), n = 10) tDCS to the cerebellum prior to performing the locomotor adaptation task on the SBT. To evaluate the effect of the intervention, functional gait assessment (FGA) scores and distance walked in 2 min (2MWT) were measured at the baseline (T0), day 6 (T5), and at the 4-week follow up (T6). Locomotor performance and changes of motor outcomes were similar in PwMS\(_{real}\) and PwMS\(_{sham}\) independently from tDCS mode applied to the cerebellum (anodal vs. sham, on FGA, p = 0.23; and 2MWT, p = 0.49). When the data were pooled across the groups to investigate the effects of multiple sessions of SBT training alone, significant improvement of gait and balance was found on T5 and T6, respectively, relative to baseline (FGA, p < 0.001 for both time points). The FGA change at T6 was significantly higher than at T5 (p = 0.01) underlining a long-lasting improvement. An improvement of the distance walked during the 2MWT was also observed on T5 and T6 relative to T0 (p = 0.002). Multiple sessions of SBT training resulted in a lasting improvement of gait stability and endurance, thus potentially reducing the risk of fall as measured by FGA and 2MWT. Application of cerebellar tDCS during SBT walking had no additional effect on locomotor outcomes.}, language = {en} } @article{KolbMaeurerSunderkoetterKukowskietal.2019, author = {Kolb-M{\"a}urer, Annette and Sunderk{\"o}tter, Cord and Kukowski, Borries and Meuth, Sven G.}, title = {An update on Peginterferon beta-1a Management in Multiple Sclerosis: results from an interdisciplinary Board of German and Austrian Neurologists and dermatologists}, series = {BMC Neurology}, volume = {19}, journal = {BMC Neurology}, doi = {10.1186/s12883-019-1354-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224646}, year = {2019}, abstract = {Background: Interferon (IFN) beta drugs have been approved for the treatment of relapsing forms of multiple sclerosis (RMS) for more than 20years and are considered to offer a favourable benefit-risk profile. In July 2014, subcutaneous (SC) peginterferon beta-1a 125g dosed every 2weeks, a pegylated form of interferon beta-1a, was approved by the EMA for the treatment of adult patients with RRMS and in August 2014 by the FDA for RMS. Peginterferon beta-1a shows a prolonged half-life and increased systemic drug exposure resulting in a reduced dosing frequency compared to other available interferon-based products in MS. In the Phase 3 ADVANCE trial peginterferon beta-1a demonstrated significant positive effects on clinical and MRI outcome measures versus placebo after one year. Furthermore, in the ATTAIN extension study, sustained efficacy with long-term treatment for nearly 6years was shown. Main text In July 2016, an interdisciplinary panel of German and Austrian experts convened to discuss the management of side effects associated with peginterferon beta-1a and other interferon beta-based treatments in MS in daily practice. The panel was composed of experts from university hospitals and private clinics comprised of neurologists, dermatologists, and an MS nurse. In this paper we report recommendations regarding best practices for adverse event management, focussing on peginterferon beta-1a. Injection site reactions (ISRs) and influenza-like illness are the most common adverse effects of interferon beta therapies and can present a burden for MS patients leading to non-adherence and discontinuation of therapy. Peginterferon beta-1a shows improved pharmacological properties. In clinical trials, the adverse event (AE) profile of peginterferon beta-1a was similar to other interferon beta formulations. The most common AEs were mild to moderate ISRs, influenza-like illness, pyrexia, and headache. Current information on the underlying cause of skin reactions associated with SC interferon treatment, and the management strategies for these AEs are limited. In pivotal trials, ISRs were mainly characterized and classified by neurologists, while dermatologists were only rarely consulted. Conclusions This report addresses expert recommendations on the management of most relevant adverse effects related to peginterferon beta-1a and other interferon betas, based on literature and interdisciplinary experience.}, language = {en} } @article{RajendranBoettigerDentzienetal.2021, author = {Rajendran, Ranjithkumar and B{\"o}ttiger, Gregor and Dentzien, Niklas and Rajendran, Vinothkumar and Sharifi, Bischand and Erg{\"u}n, S{\"u}leyman and Stadelmann, Christine and Karnati, Srikanth and Berghoff, Martin}, title = {Effects of FGFR tyrosine kinase inhibition in OLN-93 oligodendrocytes}, series = {Cells}, volume = {10}, journal = {Cells}, number = {6}, issn = {2073-4409}, doi = {10.3390/cells10061318}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239600}, year = {2021}, abstract = {Fibroblast growth factor (FGF) signaling is involved in the pathogenesis of multiple sclerosis (MS). Data from neuropathology studies suggest that FGF signaling contributes to the failure of remyelination in MS. In MOG\(_{35-55}\)-induced EAE, oligodendrocyte-specific deletion of FGFR1 and FGFR2 resulted in a less severe disease course, reduced inflammation, myelin and axon degeneration and changed FGF/FGFR and BDNF/TrkB signaling. Since signaling cascades in oligodendrocytes could not be investigated in the EAE studies, we here aimed to characterize FGFR-dependent oligodendrocyte-specific signaling in vitro. FGFR inhibition was achieved by application of the multi-kinase-inhibitor dovitinib and the FGFR1/2/3-inhibitor AZD4547. Both substances are potent inhibitors of FGF signaling; they are effective in experimental tumor models and patients with malignancies. Effects of FGFR inhibition in oligodendrocytes were studied by immunofluorescence microscopy, protein and gene analyses. Application of the tyrosine kinase inhibitors reduced FGFR1, phosphorylated ERK and Akt expression, and it enhanced BDNF and TrkB expression. Furthermore, the myelin proteins CNPase and PLP were upregulated by FGFR inhibition. In summary, inhibition of FGFR signaling in oligodendrocytes can be achieved by application of tyrosine kinase inhibitors. Decreased phosphorylation of ERK and Akt is associated with an upregulation of BDNF/TrkB signaling, which may be responsible for the increased production of myelin proteins. Furthermore, these data suggest that application of FGFR inhibitors may have the potential to promote remyelination in the CNS.}, language = {en} } @article{RajendranBoettigerStadelmannetal.2021, author = {Rajendran, Ranjithkumar and B{\"o}ttiger, Gregor and Stadelmann, Christine and Karnati, Srikanth and Berghoff, Martin}, title = {FGF/FGFR pathways in multiple sclerosis and in its disease models}, series = {Cells}, volume = {10}, journal = {Cells}, number = {4}, issn = {2073-4409}, doi = {10.3390/cells10040884}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236594}, year = {2021}, abstract = {Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) affecting more than two million people worldwide. In MS, oligodendrocytes and myelin sheaths are destroyed by autoimmune-mediated inflammation, while remyelination is impaired. Recent investigations of post-mortem tissue suggest that Fibroblast growth factor (FGF) signaling may regulate inflammation and myelination in MS. FGF2 expression seems to correlate positively with macrophages/microglia and negatively with myelination; FGF1 was suggested to promote remyelination. In myelin oligodendrocyte glycoprotein (MOG)\(_{35-55}\)-induced experimental autoimmune encephalomyelitis (EAE), systemic deletion of FGF2 suggested that FGF2 may promote remyelination. Specific deletion of FGF receptors (FGFRs) in oligodendrocytes in this EAE model resulted in a decrease of lymphocyte and macrophage/microglia infiltration as well as myelin and axon degeneration. These effects were mediated by ERK/Akt phosphorylation, a brain-derived neurotrophic factor, and downregulation of inhibitors of remyelination. In the first part of this review, the most important pharmacotherapeutic principles for MS will be illustrated, and then we will review recent advances made on FGF signaling in MS. Thus, we will suggest application of FGFR inhibitors, which are currently used in Phase II and III cancer trials, as a therapeutic option to reduce inflammation and induce remyelination in EAE and eventually MS.}, language = {en} } @article{FlacheneckerBuresGawliketal.2020, author = {Flachenecker, Peter and Bures, Anna Karoline and Gawlik, Angeli and Weiland, Ann-Christin and Kuld, Sarah and Gusowski, Klaus and Streber, Ren{\´e} and Pfeifer, Klaus and Tallner, Alexander}, title = {Efficacy of an internet-based program to promote physical activity and exercise after inpatient rehabilitation in persons with multiple sclerosis: a randomized, single-blind, controlled study}, series = {International Journal of Environmental Research and Public Health}, volume = {17}, journal = {International Journal of Environmental Research and Public Health}, number = {12}, issn = {1660-4601}, doi = {10.3390/ijerph17124544}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-207863}, year = {2020}, abstract = {Background: Multimodal rehabilitation improves fatigue and mobility in persons with multiple sclerosis (PwMS). Effects are transient and may be conserved by internet-based physical activity promotion programs. Objective: Evaluate the effects of internet-based physical activity and exercise promotion on fatigue, quality of life, and gait in PwMS after inpatient rehabilitation. Methods: PwMS (Expanded Disability Status Scale (EDSS) ≤ 6.0, fatigue: W{\"u}rzburg Fatigue Inventory for Multiple Sclerosis (WEIMuS) ≥ 32) were randomized into an intervention group (IG) or a control group (CG). After rehabilitation, IG received 3 months of internet-based physical activity promotion, while CG received no intervention. Primary outcome: self-reported fatigue (WEIMuS). Secondary outcomes: quality of life (Multiple Sclerosis Impact Scale 29, MSIS-29), gait (2min/10m walking test, Tinetti score). Measurements: beginning (T0) and end (T1) of inpatient rehabilitation, 3 (T2) and 6 (T3) months afterwards. Results: 64 of 84 PwMS were analyzed (IG: 34, CG: 30). After rehabilitation, fatigue decreased in both groups. At T2 and T3, fatigue increased again in CG but was improved in IG (p < 0.001). MSIS-29 improved in both groups at T1 but remained improved at T2 and T3 only in IG. Gait improvements were more pronounced in IG at T2. Conclusions: The study provides Class II evidence that the effects of rehabilitation on fatigue, quality of life, and gait can be maintained for 3-6 months with an internet-based physical activity and exercise promotion program.}, language = {en} } @article{GomezFernandezLopezdeLapuentePortillaAstobizaetal.2020, author = {G{\´o}mez-Fern{\´a}ndez, Paloma and Lopez de Lapuente Portilla, Aitzkoa and Astobiza, Ianire and Mena, Jorge and Urtasun, Andoni and Altmann, Vivian and Matesanz, Fuencisla and Otaegui, David and Urcelay, Elena and Antig{\"u}edad, Alfredo and Malhotra, Sunny and Montalban, Xavier and Castillo-Trivi{\~n}o, Tamara and Espino-Pais{\´a}n, Laura and Aktas, Orhan and Buttmann, Mathias and Chan, Andrew and Fontaine, Bertrand and Gourraud, Pierre-Antoine and Hecker, Michael and Hoffjan, Sabine and Kubisch, Christian and K{\"u}mpfel, Tania and Luessi, Felix and Zettl, Uwe K. and Zipp, Frauke and Alloza, Iraide and Comabella, Manuel and Lill, Christina M. and Vandenbroeck, Koen}, title = {The rare IL22RA2 signal peptide coding variant rs28385692 decreases secretion of IL-22BP isoform-1, -2 and -3 and is associated with risk for multiple sclerosis}, series = {Cells}, volume = {9}, journal = {Cells}, number = {1}, issn = {2073-4409}, doi = {10.3390/cells9010175}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200769}, year = {2020}, abstract = {The IL22RA2 locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly (p = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by IL22RA2 (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset (p = 3.17 × 10\(^{-4}\)). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50\%-60\% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS.}, language = {en} } @article{HiewNguemeniZeller2022, author = {Hiew, Shawn and Nguemeni, Carine and Zeller, Daniel}, title = {Efficacy of transcranial direct current stimulation in people with multiple sclerosis: a review}, series = {European Journal of Neurology}, volume = {29}, journal = {European Journal of Neurology}, number = {2}, doi = {10.1111/ene.15163}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259424}, pages = {648-664}, year = {2022}, abstract = {Background and purpose Multiple sclerosis (MS) is a chronic inflammatory disease causing a wide range of symptoms including motor and cognitive impairment, fatigue and pain. Over the last two decades, non-invasive brain stimulation, especially transcranial direct current stimulation (tDCS), has increasingly been used to modulate brain function in various physiological and pathological conditions. However, its experimental applications for people with MS were noted only as recently as 2010 and have been growing since then. The efficacy for use in people with MS remains questionable with the results of existing studies being largely conflicting. Hence, the aim of this review is to paint a picture of the current state of tDCS in MS research grounded on studies applying tDCS that have been done to date. Methods A keyword search was performed to retrieve articles from the earliest article identified until 14 February 2021 using a combination of the groups (1) 'multiple sclerosis', 'MS' and 'encephalomyelitis' and (2) 'tDCS' and 'transcranial direct current stimulation'. Results The analysis of the 30 articles included in this review underlined inconsistent effects of tDCS on the motor symptoms of MS based on small sample sizes. However, tDCS showed promising benefits in ameliorating fatigue, pain and cognitive symptoms. Conclusion Transcranial direct current stimulation is attractive as a non-drug approach in ameliorating MS symptoms, where other treatment options remain limited. The development of protocols tailored to the individual's own neuroanatomy using high definition tDCS and the introduction of network mapping in the experimental designs might help to overcome the variability between studies.}, language = {en} }