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Article ; Online: Driving time-based identification of gaps in specialised care coverage

Lars Masanneck / Saskia Räuber / Christina B Schroeter / Sophie Lehnerer / Tjalf Ziemssen / Tobias Ruck / Sven G. Meuth / Marc Pawlitzki

Digital Health, Vol

An example of neuroinflammatory diseases in Germany

2023 Volume 9

Abstract: Objective Due to the growing complexity in monitoring and treatment of many disorders, disease-specific care and research networks offer patients certified healthcare. However, the networks’ ability to provide health services close to patients’ homes ... ...

Abstract	Objective Due to the growing complexity in monitoring and treatment of many disorders, disease-specific care and research networks offer patients certified healthcare. However, the networks’ ability to provide health services close to patients’ homes usually remains vague. Digital Health Technologies (DHTs) help to provide better care, especially if implemented in a targeted manner in regions undersupplied by specialised networks. Therefore, we used a car travel time-based isochrone approach to identify care gaps using the example of the neuroinflammation-focused German healthcare and research networks for multiple sclerosis (MS), myasthenia gravis (MG), myositis and immune-mediated neuropathy. Methods Excellence centres were mapped, and isochrones for 30, 60, 90 and 120 minutes were calculated. The resulting geometric figures were aggregated and used to mask the global human settlement population grid 2019 to estimate German inhabitants that can reach centres within the given periods. Results While 96.48% of Germans can drive to an MS-focused centre within one hour, coverage is lower for the rare disease networks for MG (48.3%), myositis (43.1%) and immune-mediated neuropathy (56.7%). Within 120 minutes, more than 80% of Germans can reach a centre of any network. Besides the generally worse covered rural regions such as North-Eastern Germany, the rare disease networks also show network-specific regional underrepresentation. Conclusion An isochrone-based approach helps identify regions where specialised care is hard to reach, which might be especially troublesome in the case of an often disabled patient collective. Patient care could be improved by focusing deployments of disease-specific DHTs on these areas.
Keywords	Computer applications to medicine. Medical informatics ; R858-859.7
Subject code	006
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	SAGE Publishing
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Eculizumab treatment alters the proteometabolome beyond the inhibition of complement

Christopher Nelke / Christina B. Schroeter / Frauke Stascheit / Niklas Huntemann / Marc Pawlitzki / Alice Willison / Saskia Räuber / Nico Melzer / Ute Distler / Stefan Tenzer / Kai Stühler / Andreas Roos / Andreas Meisel / Sven G. Meuth / Tobias Ruck

JCI Insight, Vol 8, Iss

2023 Volume 13

Abstract: Therapeutic strategies targeting complement have revolutionized the treatment of myasthenia gravis (MG). However, a deeper understanding of complement modulation in the human system is required to improve treatment responses and identify off-target ... ...

Abstract	Therapeutic strategies targeting complement have revolutionized the treatment of myasthenia gravis (MG). However, a deeper understanding of complement modulation in the human system is required to improve treatment responses and identify off-target effects shaping long-term outcomes. For this reason, we studied a cohort of patients with MG treated with either eculizumab or azathioprine as well as treatment-naive patients using a combined proteomics and metabolomics approach. This strategy validated known effects of eculizumab on the terminal complement cascade. Beyond that, eculizumab modulated the serum proteometabolome as distinct pathways were altered in eculizumab-treated patients, including the oxidative stress response, mitogen-activated protein kinase signaling, and lipid metabolism with particular emphasis on arachidonic acid signaling. We detected reduced levels of arachidonate 5-lipoxygenase (ALOX5) and leukotriene A4 in eculizumab-treated patients. Mechanistically, ligation of the C5a receptor (C5aR) is needed for ALOX5 metabolism and generation of downstream leukotrienes. As eculizumab prevents cleavage of C5 into C5a, decreased engagement of C5aR may inhibit ALOX5-mediated synthesis of pro-inflammatory leukotrienes. These findings indicate distinct off-target effects induced by eculizumab, illuminating potential mechanisms of action that may be harnessed to improve treatment outcomes.
Keywords	Autoimmunity ; Neuroscience ; Medicine ; R
Subject code	616
Language	English
Publishing date	2023-07-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Immune Response to Seasonal Influenza Vaccination in Multiple Sclerosis Patients Receiving Cladribine

Leoni Rolfes / Steffen Pfeuffer / Jelena Skuljec / Xia He / Chuanxin Su / Sinem-Hilal Oezalp / Marc Pawlitzki / Tobias Ruck / Melanie Korsen / Konstanze Kleinschnitz / Derya Aslan / Tim Hagenacker / Christoph Kleinschnitz / Sven G. Meuth / Refik Pul

Cells, Vol 12, Iss 1243, p

2023 Volume 1243

Abstract: Cladribine has been approved for the treatment of multiple sclerosis (MS) and its administration results in a long-lasting depletion of lymphocytes. As lymphopenia is known to hamper immune responses to vaccination, we evaluated the immunogenicity of the ...

Abstract	Cladribine has been approved for the treatment of multiple sclerosis (MS) and its administration results in a long-lasting depletion of lymphocytes. As lymphopenia is known to hamper immune responses to vaccination, we evaluated the immunogenicity of the influenza vaccine in patients undergoing cladribine treatment at different stages vs. controls. The antibody response in 90 cladribine-treated MS patients was prospectively compared with 10 control subjects receiving platform immunotherapy (NCT05019248). Serum samples were collected before and six months after vaccination. Response to vaccination was determined by the hemagglutination-inhibition test. Postvaccination seroprotection rates against influenza A were comparable in cladribine-treated patients and controls (H1N1: 94.4% vs. 100%; H3N2: 92.2% vs. 90.0%). Influenza B response was lower in the cladribine cohort (61.1% vs. 80%). The increase in geometric mean titers was lower in the cladribine group vs. controls (H1N1: +98.5 vs. +188.1; H3N2: +225.3 vs. +300.0; influenza B: +40.0 vs. +78.4); however, titers increased in both groups for all strains. Seroprotection was achieved irrespective of vaccination timing and lymphocyte subset counts at the time of vaccination in the cladribine cohort. To conclude, cladribine-treated MS patients can mount an adequate immune response to influenza independently of treatment duration and time interval to the last cladribine administration.
Keywords	multiple sclerosis ; cladribine ; immunization ; influenza ; vaccination ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2023-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: One Brain—All Cells

Christina B. Schroeter / Alexander M. Herrmann / Stefanie Bock / Anna Vogelsang / Susann Eichler / Philipp Albrecht / Sven G. Meuth / Tobias Ruck

Cells, Vol 10, Iss 651, p

A Comprehensive Protocol to Isolate All Principal CNS-Resident Cell Types from Brain and Spinal Cord of Adult Healthy and EAE Mice

2021 Volume 651

Abstract: In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, the role of each central nervous system (CNS)-resident cell type during inflammation, neurodegeneration, and remission has been frequently addressed. Although ... ...

Abstract	In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, the role of each central nervous system (CNS)-resident cell type during inflammation, neurodegeneration, and remission has been frequently addressed. Although protocols for the isolation of different individual CNS-resident cell types exist, none can harvest all of them within a single experiment. In addition, isolation of individual cells is more demanding in adult mice and even more so from the inflamed CNS. Here, we present a protocol for the simultaneous purification of viable single-cell suspensions of all principal CNS-resident cell types (microglia, oligodendrocytes, astrocytes, and neurons) from adult mice—applicable in healthy mice as well as in EAE. After dissociation of the brain and spinal cord from adult mice, microglia, oligodendrocytes, astrocytes and, neurons were isolated via magnetic-activated cell sorting (MACS). Validations comprised flow cytometry, immunocytochemistry, as well as functional analyses (immunoassay and Sholl analysis). The purity of each cell isolation averaged 90%. All cells displayed cell-type-specific morphologies and expressed specific surface markers. In conclusion, this new protocol for the simultaneous isolation of all major CNS-resident cell types from one CNS offers a sophisticated and comprehensive way to investigate complex cellular networks ex vivo and simultaneously reduce mice numbers to be sacrificed.
Keywords	single-cell isolation ; demyelinating autoimmune diseases ; astrocytes ; microglia ; neurons ; oligodendrocytes ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Enjoy Carefully

Liesa Regner-Nelke / Christopher Nelke / Christina B. Schroeter / Rainer Dziewas / Tobias Warnecke / Tobias Ruck / Sven G. Meuth

International Journal of Molecular Sciences, Vol 22, Iss 10087, p

The Multifaceted Role of Vitamin E in Neuro-Nutrition

2021 Volume 10087

Abstract: Vitamin E is often associated with health benefits, such as antioxidant, anti-inflammatory and cholesterol-lowering effects. These properties make its supplementation a suitable therapeutic approach in neurodegenerative disorders, for example, Alzheimer’ ... ...

Abstract	Vitamin E is often associated with health benefits, such as antioxidant, anti-inflammatory and cholesterol-lowering effects. These properties make its supplementation a suitable therapeutic approach in neurodegenerative disorders, for example, Alzheimer’s or Parkinson’s disease. However, trials evaluating the effects of vitamin E supplementation are inconsistent. In randomized controlled trials, the observed associations often cannot be substantiated. This could be due to the wide variety of study designs regarding the dosage and duration of vitamin E supplementation. Furthermore, genetic variants can influence vitamin E uptake and/or metabolism, thereby distorting its overall effect. Recent studies also show adverse effects of vitamin E supplementation regarding Alzheimer’s disease due to the increased synthesis of amyloid β. These diverse effects may underline the inhomogeneous outcomes associated with its supplementation and argue for a more thoughtful usage of vitamin E. Specifically, the genetic and nutritional profile should be taken into consideration to identify suitable candidates who will benefit from supplementation. In this review, we will provide an overview of the current knowledge of vitamin E supplementation in neurodegenerative disease and give an outlook on individualized, sustainable neuro-nutrition, with a focus on vitamin E supplementation.
Keywords	vitamin E ; neurodegenerative diseases ; nutrition ; vitamin E supplementation ; Alzheimer’s disease ; personalized medicine ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Skeletal muscle as potential central link between sarcopenia and immune senescence

Christopher Nelke / Rainer Dziewas / Jens Minnerup / Sven G. Meuth / Tobias Ruck

EBioMedicine, Vol 49, Iss , Pp 381-

2019 Volume 388

Abstract: As our population grows older, age-related pathologies are becoming more prevalent. Deterioration of skeletal muscle and the immune system manifests as sarcopenia and immune senescence respectively. The disease burden of these pathologies emphasizes the ... ...

Abstract	As our population grows older, age-related pathologies are becoming more prevalent. Deterioration of skeletal muscle and the immune system manifests as sarcopenia and immune senescence respectively. The disease burden of these pathologies emphasizes the need for a better understanding of the underlying mechanisms. Skeletal muscle has emerged as a potent regulator of immune system function. As such, skeletal muscle might be the central integrator between sarcopenia and immune senescence in an aging biological system. Therapeutic approaches targeting skeletal muscle might be able to restore both muscle and immune system function. In this review, we therefore outline the current - however still fragmentary - knowledge about the potential communication pathways of muscle and immune system, how they are affected by aging of skeletal muscle and discuss possible treatment strategies. The review intends to be hypothesis-generating and should thereby stimulate further research in this important scientific field. Keywords: Skeletal muscle, Sarcopenia, Immune senescence, Myokines, IL-6, IL-7, IL-15
Keywords	Medicine ; R ; Medicine (General) ; R5-920
Subject code	006
Language	English
Publishing date	2019-11-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Merits and culprits of immunotherapies for neurological diseases in times of COVID-19

Marc Pawlitzki / Uwe K. Zettl / Tobias Ruck / Leoni Rolfes / Hans-Peter Hartung / Sven G. Meuth

EBioMedicine, Vol 56, Iss , Pp 102822- (2020)

2020

Abstract: Immunosuppression and immunomodulation are valuable therapeutic approaches for managing neuroimmunological diseases. In times of the Coronavirus disease 2019 (COVID-19) pandemic, clinicians must deal with the question of whether immunotherapy should ... ...

Abstract	Immunosuppression and immunomodulation are valuable therapeutic approaches for managing neuroimmunological diseases. In times of the Coronavirus disease 2019 (COVID-19) pandemic, clinicians must deal with the question of whether immunotherapy should currently be initiated or discontinued in neurological patients. Uncertainty exists especially because different national medical associations publish different recommendations on the extent to which immunotherapies must be continued, monitored, or possibly switched during the current pandemic.Based on the most recently available data both about the novel coronavirus and the approved immunotherapies for neurological diseases, we provide an updated overview that includes current treatment strategies and the associated COVID-19 risk, but also the potential of immunotherapies to treat COVID-19.
Keywords	COVID-19 ; Multiple sclerosis ; Immunotherapies ; Infections risk ; Disease modifying therapies ; Medicine ; R ; Medicine (General) ; R5-920 ; covid19
Subject code	610
Language	English
Publishing date	2020-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Alemtuzumab in Multiple Sclerosis

Tobias Ruck / Stefan Bittner / Heinz Wiendl / Sven G. Meuth

International Journal of Molecular Sciences, Vol 16, Iss 7, Pp 16414-

Mechanism of Action and Beyond

2015 Volume 16439

Abstract: Alemtuzumab is a humanized monoclonal antibody against CD52 (cluster of differentiation 52) and is approved for the therapy of relapsing-remitting multiple sclerosis. The application of alemtuzumab leads to a rapid, but long-lasting depletion ... ...

Abstract	Alemtuzumab is a humanized monoclonal antibody against CD52 (cluster of differentiation 52) and is approved for the therapy of relapsing-remitting multiple sclerosis. The application of alemtuzumab leads to a rapid, but long-lasting depletion predominantly of CD52-bearing B and T cells with reprogramming effects on immune cell composition resulting in the restoration of tolerogenic networks. Alemtuzumab has proven high efficacy in clinical phase II and III trials, where interferon β-1a was used as active comparator. However, alemtuzumab is associated with frequent and considerable risks. Most importantly secondary autoimmune disease affects 30%–40% of patients, predominantly impairing thyroid function. Extensive monitoring and early intervention allow for an appropriate risk management. However, new and reliable biomarkers for individual risk stratification and treatment response to improve patient selection and therapy guidance are a significant unmet need. Only a deeper understanding of the underlying mechanisms of action (MOA) will reveal such markers, maximizing the best potential risk-benefit ratio for the individual patient. This review provides and analyses the current knowledge on the MOA of alemtuzumab. Most recent data on efficacy and safety of alemtuzumab are presented and future research opportunities are discussed.
Keywords	alemtuzumab ; CD52 ; mechanism of action ; secondary autoimmune disease ; multiple sclerosis ; experimental autoimmune encephalomyelitis (EAE) ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	610
Language	English
Publishing date	2015-07-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: NfL predicts relapse-free progression in a longitudinal multiple sclerosis cohort study

Timo Uphaus / Falk Steffen / Muthuraman Muthuraman / Nina Ripfel / Vinzenz Fleischer / Sergiu Groppa / Tobias Ruck / Sven G. Meuth / Refik Pul / Christoph Kleinschnitz / Erik Ellwardt / Julia Loos / Sinah Engel / Frauke Zipp / Stefan Bittner

EBioMedicine, Vol 72, Iss , Pp 103590- (2021)

2021

Abstract: Background: Easily accessible biomarkers enabling the identification of those patients with multiple sclerosis (MS) who will accumulate irreversible disability in the long term are essential to guide early therapeutic decisions. We here examine the ... ...

Abstract	Background: Easily accessible biomarkers enabling the identification of those patients with multiple sclerosis (MS) who will accumulate irreversible disability in the long term are essential to guide early therapeutic decisions. We here examine the utility of serum neurofilament light chain (sNfL) for forecasting relapse-free disability progression and conversion to secondary progressive MS (SPMS) in the prospective Neurofilament and longterm outcome in MS (NaloMS) cohort. Methods: The predictive ability of sNfL at Baseline and sNfL follow-up (FU)/ Baseline (BL) ratio with regard to disability progression was assessed within a development cohort (NaloMS, n=196 patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome) and validated with an external independent cohort (Düsseldorf, Essen, n=204). Both relapse-free EDSS-progression (RFP: inflammatory-independent EDSS-increase 12 months prior to FU) and SPMS-transition (minimum EDSS-score of 3.0) were investigated. Findings: During the study period, 17% (n=34) of NaloMS patients suffered from RFP and 14% (n=27) converted to SPMS at FU (validation cohort RFP n=42, SPMS-conversion n=24). sNfL at BL was increased in patients with RFP (10.8 pg/ml (interquartile range (IQR) 7.7-15.0) vs. 7.2 pg/ml (4.5-12.5), p<0.017). In a multivariable logistic regression model, increased sNfL levels at BL (Odds Ratio (OR) 1.02, 95% confidence interval (CI) 1.01-1.04, p=0.012) remained an independent risk factor for RFP and predicted individual RFP risk with an accuracy of 82% (NaloMS) and 83% (validation cohort) as revealed by support vector machine. In addition, the sNfL FU/BL ratio was increased in SPMS-converters (1.16 (0.89-1.70) vs. 0.96 (0.75-1.23), p=0.011). This was confirmed by a multivariable logistic regression model, as sNfL FU/BL ratio remained in the model (OR 1.476, 95%CI 1.078-2,019, p=0.015) and individual sNfL FU/BL ratios showed a predictive accuracy of 72% in NaloMS (63% in the validation cohort) as revealed by machine learning. Interpretation: ...
Keywords	Multiple sclerosis ; Disease progression ; Neurofilament light chain ; SPMS transition ; Medicine ; R ; Medicine (General) ; R5-920
Subject code	610
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Nitrosative Stress Molecules in Multiple Sclerosis

Moritz Förster / Christopher Nelke / Saskia Räuber / Hans Lassmann / Tobias Ruck / Maria Pia Sormani / Alessio Signori / Hans-Peter Hartung / Patrick Küry / Sven G. Meuth / David Kremer

Biomedicines, Vol 9, Iss 1899, p

A Meta-Analysis

2021 Volume 1899

Abstract: Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system of unknown etiology. As it is still a diagnosis of exclusion, there is an urgent need for biomarkers supporting its diagnosis. Increasing evidence suggests that ... ...

Abstract	Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system of unknown etiology. As it is still a diagnosis of exclusion, there is an urgent need for biomarkers supporting its diagnosis. Increasing evidence suggests that nitrosative stress may play a pivotal role in the pathogenesis of MS. However, previous reports supporting the role of nitrosative stress molecules as disease biomarkers are inconsistent overall. We therefore systematically analyzed the existing literature to compare the serum and cerebrospinal fluid (CSF) levels of nitrite/nitrate in MS patients with those in patients with noninflammatory other neurological diseases (NIOND) and healthy controls (HC), respectively. We searched the PubMed database and included original articles investigating nitrite/nitrate levels in MS patients and NIOND patients or HC based on predefined selection criteria. Effect sizes were estimated by the standardized mean difference using a random effects model. Our results suggest that MS is associated with higher nitrite/nitrate levels within the CSF compared with patients with NIOND (SMD of 1.51; 95% CI: 0.72, 2.30; p = 0.0008). Likewise, nitrite/nitrate in the CSF of MS patients trends towards increased levels compared with those of HC but does not reach statistical significance (SMD of 3.35; 95% CI: −0.48, 7.19; p = 0.07). Measurement of nitrite/nitrate in the CSF might be a valuable tool facilitating the differentiation of MS and NIOND. Further studies with more homogeneous study criteria are needed to corroborate this hypothesis.
Keywords	multiple sclerosis ; biomarker ; nitrosative stress ; NOx ; meta-analysis ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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