Publications by authors named "Frauke Zipp"

250 Publications

NfL predicts relapse-free progression in a longitudinal multiple sclerosis cohort study: Serum NfL predicts relapse-free progression.

EBioMedicine 2021 Sep 24;72:103590. Epub 2021 Sep 24.

Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn(2)), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. Electronic address:

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 Neurofilamentandlongtermoutcome inMS (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: sNfL levels at baseline predict relapse-free disability progression in a prospective longitudinal cohort study 6 years later. While prediction was confirmed in an independent cohort, sNfL further discriminates patients with SPMS at follow-up and supports early identification of patients at risk for later SPMS conversion.

Funding: This work was supported by the German Research Council (CRC-TR-128), Else Kröner Fresenius Foundation and Hertie-Stiftung.
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http://dx.doi.org/10.1016/j.ebiom.2021.103590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479646PMC
September 2021

Treatment approaches to patients with multiple sclerosis and coexisting autoimmune disorders.

Ther Adv Neurol Disord 2021 23;14:17562864211035542. Epub 2021 Aug 23.

Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, Rhineland-Palatinate, Mainz 55131, Germany.

The past decades have yielded major therapeutic advances in many autoimmune conditions - such as multiple sclerosis (MS) - and thus ushered in a new era of more targeted and increasingly potent immunotherapies. Yet this growing arsenal of therapeutic immune interventions has also rendered therapy much more challenging for the attending physician, especially when treating patients with more than one autoimmune condition. Importantly, some therapeutic strategies are either approved for several autoimmune disorders or may be repurposed for other conditions, therefore opening new curative possibilities in related fields. In this article, we especially focus on frequent and therapeutically relevant concomitant autoimmune conditions faced by neurologists when treating patients with MS, namely psoriasis, rheumatoid arthritis and inflammatory bowel diseases. We provide an overview of the available disease-modifying therapies, highlight possible contraindications, show pathophysiological overlaps and finally present which therapeutics can be utilized as a combinatory treatment, in order to 'kill two birds with one stone'.
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http://dx.doi.org/10.1177/17562864211035542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388232PMC
August 2021

Multiple Sclerosis Therapy Consensus Group (MSTCG): position statement on disease-modifying therapies for multiple sclerosis (white paper).

Ther Adv Neurol Disord 2021 18;14:17562864211039648. Epub 2021 Aug 18.

Neurologie in Meerbusch, MS-Zentrum, Meerbusch, Germany.

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, and Switzerland).
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http://dx.doi.org/10.1177/17562864211039648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377320PMC
August 2021

Pro-inflammatory T helper 17 directly harms oligodendrocytes in neuroinflammation.

Proc Natl Acad Sci U S A 2021 Aug;118(34)

Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany;

T helper (Th)17 cells are considered to contribute to inflammatory mechanisms in diseases such as multiple sclerosis (MS). However, the discussion persists regarding their true role in patients. Here, we visualized central nervous system (CNS) inflammatory processes in models of MS live in vivo and in MS brains and discovered that CNS-infiltrating Th17 cells form prolonged stable contact with oligodendrocytes. Strikingly, compared to Th2 cells, direct contact with Th17 worsened experimental demyelination, caused damage to human oligodendrocyte processes, and increased cell death. Importantly, we found that in comparison to Th2 cells, both human and murine Th17 cells express higher levels of the integrin CD29, which is linked to glutamate release pathways. Of note, contact of human Th17 cells with oligodendrocytes triggered release of glutamate, which induced cell stress and changes in biosynthesis of cholesterol and lipids, as revealed by single-cell RNA-sequencing analysis. Finally, exposure to glutamate decreased myelination, whereas blockade of CD29 preserved oligodendrocyte processes from Th17-mediated injury. Our data provide evidence for the direct and deleterious attack of Th17 cells on the myelin compartment and show the potential for therapeutic opportunities in MS.
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http://dx.doi.org/10.1073/pnas.2025813118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403833PMC
August 2021

Multiple sclerosis therapy consensus group (MSTCG): answers to the discussion questions.

Neurol Res Pract 2021 Aug 6;3(1):44. Epub 2021 Aug 6.

Klinik und Poliklinik für Neurologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz, Germany.

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http://dx.doi.org/10.1186/s42466-021-00140-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344158PMC
August 2021

Targeting Immune Modulators in Glioma While Avoiding Autoimmune Conditions.

Cancers (Basel) 2021 Jul 14;13(14). Epub 2021 Jul 14.

Institute of Anatomy, Medical Faculty Carl Gustav Carus, Technische Universität Dresden School of Medicine, 01307 Dresden, Germany.

Communication signals and signaling pathways are often studied in different physiological systems. However, it has become abundantly clear that the immune system is not self-regulated, but functions in close association with the nervous system. The neural-immune interface is complex; its balance determines cancer progression, as well as autoimmune disorders. Immunotherapy remains a promising approach in the context of glioblastoma multiforme (GBM). The primary obstacle to finding effective therapies is the potent immunosuppression induced by GBM. Anti-inflammatory cytokines, induction of regulatory T cells, and the expression of immune checkpoint molecules are the key mediators for immunosuppression in the tumor microenvironment. Immune checkpoint molecules are ligand-receptor pairs that exert inhibitory or stimulatory effects on immune responses. In the past decade, they have been extensively studied in preclinical and clinical trials in diseases such as cancer or autoimmune diseases in which the immune system has failed to maintain homeostasis. In this review, we will discuss promising immune-modulatory targets that are in the focus of current clinical research in glioblastoma, but are also in the precarious position of potentially becoming starting points for the development of autoimmune diseases like multiple sclerosis.
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http://dx.doi.org/10.3390/cancers13143524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306848PMC
July 2021

[Multiple sclerosis treatment consensus group (MSTCG): position paper on disease-modifying treatment of multiple sclerosis 2021 (white paper)].

Nervenarzt 2021 Aug 23;92(8):773-801. Epub 2021 Jul 23.

Multiple Sklerose Therapie Konsensus Gruppe (MSTKG), Münster, Deutschland.

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, Switzerland).
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http://dx.doi.org/10.1007/s00115-021-01157-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300076PMC
August 2021

Ocrelizumab Extended Interval Dosing in Multiple Sclerosis in Times of COVID-19.

Neurol Neuroimmunol Neuroinflamm 2021 09 14;8(5). Epub 2021 Jul 14.

From the Department of Neurology with Institute of Translational Neurology (L.R., M.P., S.P., C.N., L.K., H.W.), University Hospital Muenster, Germany; Institute for Biometrics and Bioinformatic (A.L.), Otto-von-Guericke University, Magdeburg, Germany; Department for Neurology (R.P., C.K., K.K., R.R.), University Hospital Essen, Germany; Focus Program Translational Neurosciences (FTN) and Immunology (FZI) (K.P., S.B., F.Z.), Rhine Main Neuroscience Network (rmn2), Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Germany; Department of Neurology (C.W., Y.G., M.S.), University Hospital Cologne, Germany; and Department of Neurology (J.I., O.A., T.R., S.G.M.), Heinrich-Heine University, Duesseldorf, Germany.

Objective: To evaluate the clinical consequences of extended interval dosing (EID) of ocrelizumab in relapsing-remitting multiple sclerosis (RRMS) during the coronavirus disease 2019 (COVID-19) pandemic.

Methods: In our retrospective, multicenter cohort study, we compared patients with RRMS on EID (defined as ≥4-week delay of dose interval) with a control group on standard interval dosing (SID) at the same period (January to December 2020).

Results: Three hundred eighteen patients with RRMS were longitudinally evaluated in 5 German centers. One hundred sixteen patients received ocrelizumab on EID (median delay [interquartile range 8.68 [5.09-13.07] weeks). Three months after the last ocrelizumab infusion, 182 (90.1%) patients following SID and 105 (90.5%) EID patients remained relapse free ( 0.903). Three-month confirmed progression of disability was observed in 18 SID patients (8.9%) and 11 EID patients (9.5%, = 0.433). MRI progression was documented in 9 SID patients (4.5%) and 8 EID patients (6.9%) at 3-month follow-up ( = 0.232). Multivariate logistic regression showed no association between treatment regimen and no evidence of disease activity status at follow-up (OR: 1.266 [95% CI: 0.695-2.305]; 0.441). Clinical stability was accompanied by persistent peripheral CD19 B-cell depletion in both groups (SID vs EID: 82.6% vs 83.3%, 0.463). Disease activity in our cohort was not associated with CD19 B-cell repopulation.

Conclusion: Our data support EID of ocrelizumab as potential risk mitigation strategy in times of the COVID-19 pandemic.

Classification Of Evidence: This study provides Class IV evidence that for patients with RRMS, an EID of at least 4 weeks does not diminish effectiveness of ocrelizumab.
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http://dx.doi.org/10.1212/NXI.0000000000001035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362352PMC
September 2021

The potential of serum neurofilament as biomarker for multiple sclerosis.

Brain 2021 Jun 28. Epub 2021 Jun 28.

Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Multiple sclerosis is a highly heterogeneous disease and the detection of neuroaxonal damage as well as its quantification is a critical step for patients. Blood-based neurofilament light chain (sNfL) is currently under close investigation as an easily accessible biomarker of prognosis and treatment response for multiple sclerosis patients. There is abundant evidence that sNfL levels reflect ongoing inflammatory-driven neuroaxonal damage (e.g. relapses or MRI disease activity) and that sNfL levels predict disease activity over the next few years. In contrast, the association of sNfL with long-term clinical outcomes or its ability to reflect slow, diffuse neurodegenerative damage in multiple sclerosis is less clear. However, early results from real-world cohorts and clinical trials using sNfL as a marker of treatment response in multiple sclerosis are encouraging. Importantly, clinical algorithms should now be developed that incorporate the routine use of sNfL to guide individualized clinical decision-making in people with multiple sclerosis, together with additional fluid biomarkers and clinical and MRI measures. Here, we propose specific clinical scenarios where implementing sNfL measures may be of utility, including, among others: initial diagnosis, first treatment choice, surveillance of subclinical disease activity and guidance of therapy selection.
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http://dx.doi.org/10.1093/brain/awab241DOI Listing
June 2021

Serum neurofilament levels reflect outer retinal layer changes in multiple sclerosis.

Ther Adv Neurol Disord 2021 25;14:17562864211003478. Epub 2021 May 25.

Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn), University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, Mainz 55131, Germany.

Background: Serum neurofilament light chain (sNfL) and distinct intra-retinal layers are both promising biomarkers of neuro-axonal injury in multiple sclerosis (MS). We aimed to unravel the association of both markers in early MS, having identified that neurofilament has a distinct immunohistochemical expression pattern among intra-retinal layers.

Methods: Three-dimensional (3D) spectral domain macular optical coherence tomography scans and sNfL levels were investigated in 156 early MS patients (female/male: 109/47, mean age: 33.3 ± 9.5 years, mean disease duration: 2.0 ± 3.3 years). Out of the whole cohort, 110 patients had no history of optic neuritis (NHON) and 46 patients had a previous history of optic neuritis (HON). In addition, a subgroup of patients ( = 38) was studied longitudinally over 2 years. Support vector machine analysis was applied to test a regression model for significant changes.

Results: In our cohort, HON patients had a thinner outer plexiform layer (OPL) volume compared to NHON patients ( = -0.016, SE = 0.006,  = 0.013). Higher sNfL levels were significantly associated with thinner OPL volumes in HON patients ( = -6.734, SE = 2.514,  = 0.011). This finding was corroborated in the longitudinal subanalysis by the association of higher sNfL levels with OPL atrophy ( = 5.974, SE = 2.420,  = 0.019). sNfL levels were 75.7% accurate at predicting OPL volume in the supervised machine learning.

Conclusions: In summary, sNfL levels were a good predictor of future outer retinal thinning in MS. Changes within the neurofilament-rich OPL could be considered as an additional retinal marker linked to MS neurodegeneration.
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http://dx.doi.org/10.1177/17562864211003478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155762PMC
May 2021

The neuroinflammation collection: a vision for expanding neuro-immune crosstalk in Brain.

Brain 2021 08;144(7):e59

Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network, Johannes Gutenberg University Medical Center Mainz, Germany.

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http://dx.doi.org/10.1093/brain/awab187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370408PMC
August 2021

Implications of extreme serum neurofilament light chain levels for the management of patients with relapsing multiple sclerosis.

Ther Adv Neurol Disord 2021 20;14:17562864211001977. Epub 2021 Apr 20.

Department of Neurology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn²), University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstrasse 1, Mainz 55131, Germany.

Background: Serum neurofilament light chain (sNfL) is a promising biomarker to complement the decision-making process in multiple sclerosis (MS) patients. However, although sNfL levels are able to detect disease activity and to predict future disability, the growing evidence has not yet been translated into practicable recommendations for an implementation into clinical routine.

Methods: The observation of a patient with extensive inflammatory activity in magnetic resonance imaging (MRI) along with an extremely high sNfL level in the absence of any clinical symptoms prompted us to investigate common characteristics of our MS patients with the highest sNfL levels in a retrospective cohort study. The 97.5th percentile was chosen as a cut-off value because the mean sNfL level of the resulting extreme neurofilament light chain (NfL) cohort corresponded well to the sNfL level of the presented case. Patient characterization included clinical and MRI assessment with a focus on disease activity markers. sNfL levels were determined by single molecule array.

Results: The 97.5th percentile of our MS cohort (958 sNfL measurements in 455 patients) corresponded to a threshold value of 46.1 pg/ml. The mean sNfL level of the extreme sNfL cohort ( = 24) was 95.6 pg/ml (standard deviation 68.4). Interestingly, only 15 patients suffered from a relapse at the time point of sample collection, whereas nine patients showed no signs of clinical disease activity. sNfL levels of patients with and without relapse did not differ [median 81.3 pg/ml (interquartile range [IQR] 48.0-128) 80.2 pg/ml (IQR 46.4-97.6),  = 0.815]. The proportion of patients with contrast-enhancing lesions was high and also did not differ between patients with and without relapse (92.9% 87.5%,  = 0.538); 78.9% of the patients not receiving a high-efficacious therapy had ongoing disease activity during a 2-year follow-up.

Conclusion: Extremely high sNfL levels are indicative of subclinical disease activity and might complement treatment decisions in ambiguous cases.
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http://dx.doi.org/10.1177/17562864211001977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060778PMC
April 2021

Encephalitis with Autoantibodies against the Glutamate Kainate Receptors GluK2.

Ann Neurol 2021 07 17;90(1):101-117. Epub 2021 May 17.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.

Objective: The objective of this study was to report the identification of antibodies against the glutamate kainate receptor subunit 2 (GluK2-abs) in patients with autoimmune encephalitis, and describe the clinical-immunological features and antibody effects.

Methods: Two sera from 8 patients with similar rat brain immunostaining were used to precipitate the antigen from neuronal cultures. A cell-based assay (CBA) with GluK2-expressing HEK293 cells was used to assess 596 patients with different neurological disorders, and 23 healthy controls. GluK2-ab effects were determined by confocal microscopy in cultured neurons and electrophysiology in GluK2-expressing HEK293 cells.

Results: Patients' antibodies precipitated GluK2. GluK2 antibody-specificity was confirmed by CBA, immunoprecipitation, GluK2-immunoabsorption, and GluK2 knockout brain immunohistochemistry. In 2 of 8 samples, antibodies reacted with additional GluK2 epitopes present in GluK1 or GluK3; in both, the reactivity was abrogated after GluK2 immuno-absorption. Six of 8 patients developed acute encephalitis and clinical or magnetic resonance imaging (MRI) features of predominant cerebellar involvement (4 presenting as cerebellitis, which in 2 patients caused obstructive hydrocephalus), and 2 patients had other syndromes (1 with cerebellar symptoms). One of the samples showed mild reactivity with non-kainate receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors [AMPAR] and N-methyl-D-aspartate receptors [NMDAR]) leading to identify 6 additional cases with GluK2-abs among patients with anti-AMPAR (5/71) or anti-NMDAR encephalitis (1/73). GluK2-abs internalized GluK2 in HEK293 cells and neurons; these antibody-effects were reversible in neurons. A significant reduction of GluK2-mediated currents was observed in cells treated with patients' GluK2 serum following the time frame of antibody-mediated GluK2 internalization.

Interpretation: GluK2-abs associate with an encephalitis with prominent clinicoradiological cerebellar involvement. The antibody effects are predominantly mediated by internalization of GluK2. ANN NEUROL 2021;90:107-123.
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http://dx.doi.org/10.1002/ana.26098DOI Listing
July 2021

Epigallocatechin Gallate in Relapsing-Remitting Multiple Sclerosis: A Randomized, Placebo-Controlled Trial.

Neurol Neuroimmunol Neuroinflamm 2021 05 24;8(3). Epub 2021 Mar 24.

From the NeuroCure Clinical Research Center (J.B.-S., F.P., J.D., A.B., V.S.), Charité-Universitätsmedizin Berlin; Medical Image Analysis Center (J.W.), University Basel; Institut for Medical Immunology (C.I.-D., E.H.), Charité-Universitätsmedizin Berlin; Department of Neurology and Neuroimaging Center (B.K.), Johannes Gutenberg University, Mainz; Charité-Universitätsmedizin Berlin (C.P.); NeuroCure Clinical Research Center (H.R., R.R.), Charité-Universitätsmedizin Berlin, Germany; Department of Neurology (O.A.), Medical Faculty, Heinrich Heine University Düsseldorf; Institut für Neuroimmunologie und Multiple Sklerose (C.H.), Universitätsklinikum Hamburg-Eppendorf, Hamburg; Klinik für Neurologie (J.F.), Asklepios Klinik Lübben/Teupitz; Department of Neurology (F.H.), Krankenhaus Martha-Maria Halle-Dölau, Halle/Saale; Medizinische Klinik für Kardiologie und Angiologie (M.L.), Campus Mitte, Charité-Universitätsmedizin Berlin; Institute of Nutritional and Food Sciences (B.Z.), University of Bonn; Department of Neurology and Neuroimaging Center (NIC) (S.G., F.Z.), Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University, Mainz; and Charité-Universitätsmedizin Berlin and SOSTANA GmbH (K.-D.W.), Berlin.

Objective: To assess the safety and efficacy of epigallocatechin-3-gallate (EGCG) add-on to glatiramer acetate (GA) in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods: We enrolled patients with RRMS (aged 18-60 years, Expanded Disability Status Scale [EDSS] score 0-6.5), receiving stable GA treatment in a multicenter, prospective, double-blind, phase II, randomized controlled trial. Participants received up to 800 mg oral EGCG daily over a period of 18 months. The primary outcome was the proportion of patients without new hyperintense lesions on T2-weighted (T2w) brain MRI within 18 months. Secondary end points included additional MRI and clinical parameters. Immunologic effects of EGCG were investigated in exploratory experiments.

Results: A total of 122 patients on GA were randomly assigned to EGCG treatment (n = 62) or placebo (n = 60). We could not demonstrate a difference between groups after 18 months for the primary outcome or other radiologic (T2w lesion volume, T1w hypointense lesion number or volume, number of cumulative contrast-enhancing lesions, percent brain volume change), or clinical (EDSS, MS functional composite, and annualized relapse rate) parameter. EGCG treatment did not affect immune response to GA. Pharmacologic analysis revealed wide ranging EGCG plasma levels. The treatment was well tolerated with a similar incidence of mostly mild adverse events similar in both groups.

Conclusion: In RRMS, oral EGCG add-on to GA was not superior to placebo in influencing MRI and clinical disease activity over 18 months. The treatment was safe at a daily dosage up to 800 mg EGCG. It did not influence immune parameters, despite indication of EGCG being bioavailable in patients.

Classification Of Evidence: This study provides Class II evidence that for patients with RRMS, EGCG added to GA did not significantly affect the development of new hyperintense lesions on T2-weighted brain MRI.

Trial Registration Information: Clinical trial registration number: NCT00525668.
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http://dx.doi.org/10.1212/NXI.0000000000000981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054966PMC
May 2021

Neurofilament light chain levels reflect outcome in a patient with glutamic acid decarboxylase 65 antibody-positive autoimmune encephalitis under immune checkpoint inhibitor therapy.

Eur J Neurol 2021 03;28(3):1086-1089

Department of Neurology, Focus Program Translational Neuroscience and Immunotherapy, Rhine-Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Neurological immune-mediated side effects are rare but often severe complications of immune checkpoint inhibitor (ICI) treatment. This report describes a severe case of nivolumab/ipilimumab-associated glutamic acid decarboxylase 65-positive autoimmune encephalitis. It proposes neurofilament light chain levels, a biomarker indicating axonal damage, in the cerebrospinal fluid and serum as a putative novel biomarker for this diagnostically and therapeutically challenging entity with an often unfavorable outcome. Additionally, we provide an overview of previous reports of patients developing autoimmune encephalitis under ICI treatment.
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http://dx.doi.org/10.1111/ene.14692DOI Listing
March 2021

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity.

Proc Natl Acad Sci U S A 2021 01;118(1)

Department of Neurology, Neuroimmunological Section, University of Rostock, 18051 Rostock, Germany.

Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies ( = 946, = 990). Additionally, effect-modification by medication and photosensitivity-associated variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-β-treated patients. In carriers of :rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.
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http://dx.doi.org/10.1073/pnas.2018457118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817192PMC
January 2021

Functional characteristics of Th1, Th17, and ex-Th17 cells in EAE revealed by intravital two-photon microscopy.

J Neuroinflammation 2020 Nov 26;17(1):357. Epub 2020 Nov 26.

Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.

Background: T helper (Th) 17 cells are a highly plastic subset of T cells, which in the context of neuroinflammation, are able to acquire pathogenic features originally attributed to Th1 cells (resulting in so called ex-Th17 cells). Thus, a strict separation between the two T cell subsets in the context of experimental autoimmune encephalomyelitis (EAE) is difficult. High variability in culture and EAE induction protocols contributed to previous conflicting results concerning the differential contribution of Th1 and Th17 cells in EAE. Here, we systematically evaluate the role of different T cell differentiation and transfer protocols for EAE disease development and investigate the functional dynamics of encephalitogenic T cells directly within the inflamed central nervous system (CNS) tissue.

Methods: We compiled the currently used EAE induction protocols reported in literature and investigated the influence of the different Th1 and Th17 differentiation protocols as well as EAE induction protocols on the EAE disease course. Moreover, we assessed the cytokine profile and functional dynamics of both encephalitogenic Th1 and Th17 cells in the inflamed CNS using flow cytometry and intravital two-photon laser scanning microscopy. Lastly, we used astrocyte culture and adoptive transfer EAE to evaluate the impact of Th1 and Th17 cells on astrocyte adhesion molecule expression in vitro and in vivo.

Results: We show that EAE courses are highly dependent on in vitro differentiation and transfer protocols. Moreover, using genetically encoded reporter mice (B6.IL17A-EGFP.acRFP x 2d2/2d2.RFP), we show that the motility of interferon (IFN)γ-producing ex-Th17 cells more closely resembles Th1 cells than Th17 cells in transfer EAE. Mechanistically, IFNγ-producing Th1 cells selectively induce the expression of cellular adhesion molecules I-CAM1 while Th1 as well as ex-Th17 induce V-CAM1 on astrocytes.

Conclusions: The behavior of ex-Th17 cells in EAE lesions in vivo resembles Th1 rather than Th17 cells, underlining that their change in cytokine production is associated with functional phenotype alterations of these cells.
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http://dx.doi.org/10.1186/s12974-020-02021-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694901PMC
November 2020

The frequency of follicular T helper cells differs in acute and chronic neuroinflammation.

Sci Rep 2020 11 24;10(1):20485. Epub 2020 Nov 24.

Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, 55131, Mainz, Germany.

Beyond the major role of T cells in the pathogenesis of the autoimmune neuroinflammatory disorder multiple sclerosis (MS), recent studies have highlighted the impact of B cells on pathogenic inflammatory processes. Follicular T helper cells (Tfh) are essential for the promotion of B cell-driven immune responses. However, their role in MS and its murine model, experimental autoimmune encephalomyelitis (EAE), is poorly investigated. A first step to achieving a better understanding of the contribution of Tfh cells to the disease is the consideration of Tfh cell localization in relation to genetic background and EAE induction method. Here, we investigated the Tfh cell distribution during disease progression in disease relevant organs in three different EAE models. An increase of Tfh frequency in the central nervous system (CNS) was observed during peak of C57BL/6 J EAE, paralleling chronic disease activity, whereas in relapsing-remitting SJL EAE mice Tfh cell frequencies were increased during remission. Furthermore, transferred Tfh-skewed cells polarized in vitro induced mild clinical symptoms in B6.Rag1 mice. We identified significantly higher levels of Tfh cells in the dura mater than in the CNS both in C57BL/6 and in SJL/J mice. Overall, our study emphasizes diverse, non-static roles of Tfh cells during autoimmune neuroinflammation.
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http://dx.doi.org/10.1038/s41598-020-77588-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686332PMC
November 2020

High anti-JCPyV serum titers coincide with high CSF cell counts in RRMS patients.

Mult Scler 2021 09 5;27(10):1491-1496. Epub 2020 Nov 5.

Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany.

Background: Progressive multifocal leukoencephalopathy (PML) can in rare cases occur in natalizumab-treated patients with high serum anti-JCPyV antibodies, hypothetically due to excessive blockade of immune cell migration.

Objective: Immune cell recruitment to the central nervous system (CNS) was assessed in relapsing-remitting multiple sclerosis (RRMS) patients stratified by low versus high anti-JCPyV antibody titers as indicator for PML risk.

Methods: Cerebrospinal fluid (CSF) cell counts of 145 RRMS patients were quantified by flow cytometry. Generalized linear models were employed to assess influence of age, sex, disease duration, Expanded Disability Status Scale (EDSS), clinical/radiological activity, current steroid or natalizumab treatment, as well as anti-JCPyV serology on CSF cell subset counts.

Results: While clinical/radiological activity was associated with increased CD4, natural killer (NK), B and plasma cell counts, natalizumab therapy reduced all subpopulations except monocytes. With and without natalizumab therapy, patients with high anti-JCPyV serum titers presented with increased CSF T-cell counts compared to patients with low anti-JCPyV serum titers. In contrast, PML patients assessed before ( = 2) or at diagnosis ( = 5) presented with comparably low CD8 and B-cell counts, which increased after plasma exchange ( = 4).

Conclusion: High anti-JCPyV indices, which could be indicative of increased viral activity, are associated with elevated immune cell recruitment to the CNS. Its excessive impairment in conjunction with viral activity could predispose for PML development.
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http://dx.doi.org/10.1177/1352458520970103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414828PMC
September 2021

Transient enlargement of brain ventricles during relapsing-remitting multiple sclerosis and experimental autoimmune encephalomyelitis.

JCI Insight 2020 11 5;5(21). Epub 2020 Nov 5.

Experimental Ultrahigh Field Magnetic Resonance, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.

The brain ventricles are part of the fluid compartments bridging the CNS with the periphery. Using MRI, we previously observed a pronounced increase in ventricle volume (VV) in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Here, we examined VV changes in EAE and MS patients in longitudinal studies with frequent serial MRI scans. EAE mice underwent serial MRI for up to 2 months, with gadolinium contrast as a proxy of inflammation, confirmed by histopathology. We performed a time-series analysis of clinical and MRI data from a prior clinical trial in which RRMS patients underwent monthly MRI scans over 1 year. VV increased dramatically during preonset EAE, resolving upon clinical remission. VV changes coincided with blood-brain barrier disruption and inflammation. VV was normal at the termination of the experiment, when mice were still symptomatic. The majority of relapsing-remitting MS (RRMS) patients showed dynamic VV fluctuations. Patients with contracting VV had lower disease severity and a shorter duration. These changes demonstrate that VV does not necessarily expand irreversibly in MS but, over short time scales, can expand and contract. Frequent monitoring of VV in patients will be essential to disentangle the disease-related processes driving short-term VV oscillations from persistent expansion resulting from atrophy.
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http://dx.doi.org/10.1172/jci.insight.140040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710287PMC
November 2020

Increased frequency of proinflammatory CD4 T cells and pathological levels of serum neurofilament light chain in adult drug-resistant epilepsy.

Epilepsia 2021 01 2;62(1):176-189. Epub 2020 Nov 2.

Research Center of the University of Montreal Hospital Center, Montreal, QC, Canada.

Objective: Adult drug-resistant epilepsy (DRE) is associated with significant morbidity. Infiltration of immune cells is observed in DRE epileptic foci; however, the relation between DRE and the peripheral immune cell compartment remains only partially understood. We aimed to investigate differences in immune cell populations, cytokines, and neurodegenerative biomarkers in the peripheral blood of subjects with epilepsy versus healthy controls, and in DRE compared to well-controlled epilepsy (WCE).

Methods: Peripheral blood mononuclear cells and serum from >120 age- and sex-matched adults suffering from focal onset epilepsy and controls were analyzed by multipanel flow cytometry, multiplex immunoassays, and ultrasensitive single molecule array.

Results: Using a data-driven analytical approach, we identified that CD4 T cells in the peripheral blood are present in a higher proportion in DRE patients. Moreover, we observed that the frequency of CD4 T cells expressing proinflammatory cytokines interleukin (IL)-17A, IL-22, tumor necrosis factor, interferon-γ, and granulocyte-macrophage colony-stimulating factor, but not anti-inflammatory cytokines IL-10 and IL-4, is elevated in the peripheral blood of DRE subjects compared to WCE. In parallel, we found that Th17-related circulating proinflammatory cytokines are elevated, but Th2-related cytokine IL-4 is reduced, in the serum of epilepsy and DRE subjects. As Th17 cells can exert neurotoxicity, we measured levels of serum neurofilament light chain (sNfL), a marker of neuronal injury. We found significantly elevated levels of sNfL in DRE compared to controls, especially among older individuals.

Significance: Our data support that DRE is associated with an expansion of the CD4 Tcell subset in the peripheral blood and with a shift toward a proinflammatory Th17/Th1 CD4 Tcell immune profile. Our results further show that pathological levels of sNfL are more frequent in DRE, supporting a potential neurodegenerative component in adult DRE. With this work, we provide evidence for novel potential inflammatory and degenerative biomarkers in DRE.
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http://dx.doi.org/10.1111/epi.16742DOI Listing
January 2021

Supplementary medication in multiple sclerosis: Real-world experience and potential interference with neurofilament light chain measurement.

Mult Scler J Exp Transl Clin 2020 Jul-Sep;6(3):2055217320936318. Epub 2020 Aug 27.

Department of Neurology, Focus Program Translational Neuroscience (FTN), and Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg University, Germany.

Background: As vitamins and dietary supplements are obtainable without prescription, treating physicians often ignore their intake by patients with multiple sclerosis (MS) and may therefore miss potential adverse effects and interactions.

Objective: We aimed to assess the spectrum and intake frequency of supplementary medication in a cohort of MS patients and to analyse the effect of biotin intake on measurement of serum neurofilament light chain (sNfL), an emerging marker of disease activity.

Methods: MS patients visiting our neurology outpatient clinic completed a questionnaire on their past or present use of vitamins or dietary supplements. In addition, the impact of two different doses of biotin (10 and 300 mg/day) on sNfL was studied in healthy volunteers.

Results: Of 186 patients, 72.6% reported taking over-the-counter vitamins or dietary supplements currently or previously. Most frequently used was vitamin D (60.0%), followed by biotin. Female patients and patients with primary progressive MS tended to use supplements more frequently. Biotin intake did not interfere with sNfL measurement by single molecule array (Simoa).

Conclusions: The use of vitamins and dietary supplements is frequent among patients with MS. Thus, treating physicians should be aware of the pitfalls of supplementary treatment and educate their patients accordingly.
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http://dx.doi.org/10.1177/2055217320936318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457677PMC
August 2020

Genetic determinants of the humoral immune response in MS.

Neurol Neuroimmunol Neuroinflamm 2020 09 16;7(5). Epub 2020 Jul 16.

From the Department of Neurology (C.G., T.F.M.A., A. Keating, B.K., A. Klein, V.P., A. Berthele, B.H.), Klinikum rechts der Isar, School of Medicine, Technical University of Munich; Institute of Human Genetics (P.L.), Helmholtz Zentrum München, Neuherberg; Department of Neurology (R.G.), St. Josef Hospital, Ruhr-University Bochum; Department of Neurology, Focus Program Translational Neurosciences (FTN) and Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn2) (F.Z.), University Medical Center of the Johannes Gutenberg University Mainz; Department of Neurology and Translational Center for Regenerative Medicine (F.T.B.), University of Leipzig; Clinical Neuroimmunology and Neurochemistry (M.S.), Department of Neurology, Hannover Medical School, Hannover; Department of Neurology (H.T.), University of Ulm; Clinic of Neurology Dietenbronn (H.T.), Schwendi; Department of Neurology (B.W.), University Hospital Heidelberg; Department of Neurology (H.W.), University of Münster; Department of Neurology (A. Bayas), University Hospital Augsburg; Institute of Clinical Neuroimmunology (T.K.), University Hospital and Biomedical Center, Ludwig-Maximilians University Munich; Department of Neurology (U.K.Z.), Neuroimmunological Section, University of Rostock; Department of Neurology (R.A.L.), University Hospital Erlangen; Department of Neurology (R.A.L.), University of Regensburg; Department of Neurology & Stroke and Hertie-Institute for Clinical Brain Research (U.Z.), Eberhard-Karls-Universität Tübingen; Max Planck Institute of Psychiatry (M.K.), Munich; Department of Neurology (C.W.), Medical Faculty, Heinrich Heine University, Düsseldorf; Department of Neurology (C.W.), University Hospital Cologne; Institute of Neuroimmunology and Multiple Sclerosis (M.A.F), University Medical Centre Hamburg-Eppendorf, Hamburg; NeuroCure Clinical Research Center (F.P.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin; Berlin Institute of Health and Experimental and Clinical Research Center (F.P.), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin; and Center of Neuroimmunology (B.T.), Philipps-University Marburg; and Munich Cluster for Systems Neurology (SyNergy) (B.H.), Germany.

Objective: In this observational study, we investigated the impact of genetic factors at the immunoglobulin heavy chain constant locus on chromosome 14 and the major histocompatibility complex region on intrathecal immunoglobulin G, A, and M levels as well as on B cells and plasmablasts in the CSF and blood of patients with multiple sclerosis (MS).

Methods: Using regression analyses, we tested genetic variants on chromosome 14 and imputed human leukocyte antigen (HLA) alleles for associations with intrathecal immunoglobulins in 1,279 patients with MS or clinically isolated syndrome and with blood and CSF B cells and plasmablasts in 301 and 348 patients, respectively.

Results: The minor alleles of variants on chromosome 14 were associated with higher intrathecal immunoglobulin G levels (β = 0.58 [0.47 to 0.68], lowest adjusted = 2.32 × 10), and lower intrathecal immunoglobulin M (β = -0.56 [-0.67 to -0.46], = 2.06 × 10) and A (β = -0.42 [-0.54 to -0.31], = 7.48 × 10) levels. Alleles from the HLA-B*07:02-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype were associated with higher (lowest = 2.14 × 10) and HLA-B*44:02 with lower (β = -0.35 [-0.54 to -0.17], = 1.38 × 10) immunoglobulin G levels. Of interest, different HLA alleles were associated with lower intrathecal immunoglobulin M (HLA-C*02:02, β = -0.45 [-0.61 to -0.28], = 1.01 × 10) and higher immunoglobulin A levels (HLA-DQA1*01:03-DQB1*06:03-DRB1*13:01 haplotype, β = 0.40 [0.21 to 0.60], = 4.46 × 10). The impact of HLA alleles on intrathecal immunoglobulin G and M levels could mostly be explained by associations with CSF B cells and plasmablasts.

Conclusion: Although some HLA alleles seem to primarily drive the extent of humoral immune responses in the CNS by increasing CSF B cells and plasmablasts, genetic variants at the immunoglobulin heavy chain constant locus might regulate intrathecal immunoglobulins levels via different mechanisms.
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http://dx.doi.org/10.1212/NXI.0000000000000827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371373PMC
September 2020

Neuropsychological Symptoms After Anterior Cerebral Artery Ischemic Stroke.

Can J Neurol Sci 2021 03 10;48(2):290-292. Epub 2020 Jul 10.

Department of Neurology and Neuroimaging Center (NIC) of the Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University Mainz,Mainz, Germany.

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http://dx.doi.org/10.1017/cjn.2020.142DOI Listing
March 2021

Clinical implications of serum neurofilament in newly diagnosed MS patients: A longitudinal multicentre cohort study.

EBioMedicine 2020 Jun 24;56:102807. Epub 2020 May 24.

Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.

Background: We aim to evaluate serum neurofilament light chain (sNfL), indicating neuroaxonal damage, as a biomarker at diagnosis in a large cohort of early multiple sclerosis (MS) patients.

Methods: In a multicentre prospective longitudinal observational cohort, patients with newly diagnosed relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) were recruited between August 2010 and November 2015 in 22 centers. Clinical parameters, MRI, and sNfL levels (measured by single molecule array) were assessed at baseline and up to four-year follow-up.

Findings: Of 814 patients, 54.7% (445) were diagnosed with RRMS and 45.3% (369) with CIS when applying 2010 McDonald criteria (RRMS[2010] and CIS[2010]). After reclassification of CIS[2010] patients with existing CSF analysis, according to 2017 criteria, sNfL levels were lower in CIS[2017] than RRMS[2017] patients (9.1 pg/ml, IQR 6.2-13.7 pg/ml, n = 45; 10.8 pg/ml, IQR 7.4-20.1 pg/ml, n = 213; p = 0.036). sNfL levels correlated with number of T2 and Gd+ lesions at baseline and future clinical relapses. Patients receiving disease-modifying therapy (DMT) during the first four years had higher baseline sNfL levels than DMT-naïve patients (11.8 pg/ml, IQR 7.5-20.7 pg/ml, n = 726; 9.7 pg/ml, IQR 6.4-15.3 pg/ml, n = 88). Therapy escalation decisions within this period were reflected by longitudinal changes in sNfL levels.

Interpretation: Assessment of sNfL increases diagnostic accuracy, is associated with disease course prognosis and may, particularly when measured longitudinally, facilitate therapeutic decisions.

Funding: Supported the German Federal Ministry for Education and Research, the German Research Council, and Hertie-Stiftung.
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http://dx.doi.org/10.1016/j.ebiom.2020.102807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251380PMC
June 2020

Is ε4 associated with cognitive performance in early MS?

Neurol Neuroimmunol Neuroinflamm 2020 07 1;7(4). Epub 2020 May 1.

From the Department of Neurology and Focus Program Translational Neuroscience (FTN) (S.E., C.G., M.M., S.B., S.G., F.Z., C.M.L., F.L.), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Germany; Department of Neurology (A.S.), Inselspital, Bern University Hospital, University of Bern, Switzerland; Department of Neurology (A.S., B.A., R.G.), St. Josef-Hospital, Ruhr-University Bochum; Institute of Medical Biostatistics (G.T.), Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz; Department of Neurology (A. Bayas), Klinikum Augsburg; Department of Neurology (A. Berthele, B.H.), Klinikum rechts der Isar, Technical University of Munich; Institut für Neuroimmunologie und Multiple Sklerose (C.H.), Universitätsklinikum Hamburg-Eppendorf; Clinic of Neurology (L.K., S.G.M., H.W.), University Hospital Münster, Westphalian-Wilhelms-University Münster; Institute of Clinical Neuroimmunology (T.K.), Ludwig Maximilian University of Munich; Department of Neurology (R.A.L.), University Hospital Erlangen; NeuroCure Clinical Research Center and Experimental and Clinical Research Center (F.P.), Charité - Universitätsmedizin Berlin and Max Delbrueck Center for Molecular Medicine; Department of Neurology (M.S.), Hannover Medical School; Department of Neurology (B.T.), Philipps-University Marburg; Department of Neurology (F.T.B.), University of Leipzig; Department of Neurology (H.T.), University of Ulm; Clinic of Neurology Dietenbronn (H.T.), Schwendi; Neurology (F.W.), Max-Planck-Institute of Psychiatry, Munich; Neurological Clinic (F.W.), Sana Kliniken des Landkreises Cham; Department of Neurology (B.W.), University of Heidelberg; Department. of Neurology (U.K.Z.), University of Rostock; Central Information Office (CIO) (G.A.), Philipps-University Marburg; and Genetic and Molecular Epidemiology Group (C.M.L.), Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Germany.

Objective: To assess the impact of polymorphisms on cognitive performance in patients newly diagnosed with clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS).

Methods: This multicenter cohort study included 552 untreated patients recently diagnosed with CIS or RRMS according to the 2005 revised McDonald criteria. The single nucleotide polymorphisms rs429358 (ε4) and rs7412 (ε2) of the haplotype were assessed by allelic discrimination assays Cognitive performance was evaluated using the 3-second paced auditory serial addition test and the Multiple Sclerosis Inventory Cognition (MUSIC). Sum scores were calculated to approximate the overall cognitive performance and memory-centered cognitive functions. The impact of the carrier status on cognitive performance was assessed using multiple linear regression models, also including demographic, clinical, MRI, and lifestyle factors.

Results: ε4 homozygosity was associated with lower overall cognitive performance, whereas no relevant association was observed for ε4 heterozygosity or ε2 carrier status. Furthermore, higher disability levels, MRI lesion load, and depressive symptoms were associated with lower cognitive performance. Patients consuming alcohol had higher test scores than patients not consuming alcohol. Female sex, lower disability, and alcohol consumption were associated with better performance in the memory-centered subtests of MUSIC, whereas no relevant association was observed for carrier status.

Conclusion: Along with parameters of a higher disease burden, ε4 homozygosity was identified as a potential predictor of cognitive performance in this large cohort of patients with CIS and early RRMS.
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http://dx.doi.org/10.1212/NXI.0000000000000728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217661PMC
July 2020

Ocrelizumab initiation in patients with MS: A multicenter observational study.

Neurol Neuroimmunol Neuroinflamm 2020 07 9;7(4). Epub 2020 Apr 9.

From the Focus Program Translational Neurosciences (FTN) and Immunology (FZI) (E.E., K.P., F.Z., S.B.), Rhine Main Neuroscience Network (rmn), Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz; Department of Neurology (L.R., T.R., H.W.), University of Muenster; Department of Neurology (J.K., M.S., C.W.), Faculty of Medicine and University Hospital Cologne, University of Cologne; and Department of Neurology (S.G.M.), Institute of Translational Neurology, University of Muenster, Germany.

Objective: To provide first real-world experience on patients with MS treated with the B cell-depleting antibody ocrelizumab.

Methods: We retrospectively collected data of patients who had received at least 1 treatment cycle (2 infusions) of ocrelizumab at 3 large neurology centers. Patients' characteristics including premedication, clinical disease course, and documented side effects were analyzed.

Results: We could identify 210 patients (125 women, mean age ± SD, 42.1 ± 11.4 years) who had received ocrelizumab with a mean disease duration of 7.3 years and a median Expanded Disability Status Scale score of 3.75 (interquartile range 2.5-5.5; range 0-8). Twenty-six percent of these patients had a primary progressive MS (PPMS), whereas 74% had a relapsing-remitting (RRMS) or active secondary progressive (aSPMS) disease course. Twenty-four percent of all patients were treatment naive, whereas 76% had received immune therapies before. After ocrelizumab initiation (median follow-up was 200 days, range 30-1,674 days), 13% of patients with RRMS/aSPMS experienced a relapse (accounting for an annualized relapse rate of 0.17, 95% CI 0.10-0.24), and 5% of all patients with MS experienced a 12-week confirmed disability progression. Treatment was generally well tolerated, albeit only short-term side effects were recorded, including direct infusion-related reactions and mild infections.

Conclusions: We provide class IV evidence that treatment with ocrelizumab can stabilize naive and pretreated patients, indicating that ocrelizumab is an option following potent MS drugs such as natalizumab and fingolimod. Further studies are warranted to confirm these findings and to reveal safety concerns in the longer-term follow-up.

Classification Of Evidence: This study provides Class IV evidence that for patients with MS, ocrelizumab can stabilize both treatment-naive and previously treated patients.
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http://dx.doi.org/10.1212/NXI.0000000000000719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176249PMC
July 2020

CNS-localized myeloid cells capture living invading T cells during neuroinflammation.

J Exp Med 2020 06;217(6)

Department of Neurology, Focus Program Translational Neuroscience and Immunotherapy, Rhine Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

To study the role of myeloid cells in the central nervous system (CNS) in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), we used intravital microscopy, assessing local cellular interactions in vivo in EAE animals and ex vivo in organotypic hippocampal slice cultures. We discovered that myeloid cells actively engulf invading living Th17 lymphocytes, a process mediated by expression of activation-dependent lectin and its T cell-binding partner, N-acetyl-D-glucosamine (GlcNAc). Stable engulfment resulted in the death of the engulfed cells, and, remarkably, enhancement of GlcNAc exposure on T cells in the CNS ameliorated clinical EAE symptoms. These findings demonstrate the ability of myeloid cells to directly react to pathogenic T cell infiltration by engulfing living T cells. Amelioration of EAE via GlcNAc treatment suggests a novel first-defense pathway of myeloid cells as an initial response to CNS invasion and demonstrates that T cell engulfment by myeloid cells can be therapeutically exploited in vivo.
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http://dx.doi.org/10.1084/jem.20190812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971133PMC
June 2020

Longitudinal prevalence and determinants of pain in multiple sclerosis: results from the German National Multiple Sclerosis Cohort study.

Pain 2020 04;161(4):787-796

Department of Neurology, Technical University of Munich (TUM), School of Medicine, Munich, Germany.

Pain is frequent in multiple sclerosis (MS) and includes different types, with neuropathic pain (NP) being most closely related to MS pathology. However, prevalence estimates vary largely, and causal relationships between pain and biopsychosocial factors in MS are largely unknown. Longitudinal studies might help to clarify the prevalence and determinants of pain in MS. To this end, we analyzed data from 410 patients with newly diagnosed clinically isolated syndrome or relapsing-remitting MS participating in the prospective multicenter German National MS Cohort Study (NationMS) at baseline and after 4 years. Pain was assessed by self-report using the PainDETECT Questionnaire. Neuropsychiatric assessment included tests for fatigue, depression, and cognition. In addition, sociodemographic and clinical data were obtained. Prevalence of pain of any type was 40% and 36% at baseline and after 4 years, respectively, whereas prevalence of NP was 2% and 5%. Pain of any type and NP were both strongly linked to fatigue, depression, and disability. This link was even stronger after 4 years than at baseline. Moreover, changes in pain, depression, and fatigue were highly correlated without any of these symptoms preceding the others. Taken together, pain of any type seems to be much more frequent than NP in early nonprogressive MS. Moreover, the close relationship between pain, fatigue, and depression in MS should be considered for treatment decisions and future research on a possible common pathophysiology.
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http://dx.doi.org/10.1097/j.pain.0000000000001767DOI Listing
April 2020

Growth-Promoting Treatment Screening for Corticospinal Neurons in Mouse and Man.

Cell Mol Neurobiol 2020 Nov 14;40(8):1327-1338. Epub 2020 Mar 14.

Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, 55131, Mainz, Germany.

Neurons of the central nervous system (CNS) that project long axons into the spinal cord have a poor axon regenerative capacity compared to neurons of the peripheral nervous system. The corticospinal tract (CST) is particularly notorious for its poor regeneration. Because of this, traumatic spinal cord injury (SCI) is a devastating condition that remains as yet uncured. Based on our recent observations that direct neuronal interleukin-4 (IL-4) signaling leads to repair of axonal swellings and beneficial effects in neuroinflammation, we hypothesized that IL-4 acts directly on the CST. Here, we developed a tissue culture model for CST regeneration and found that IL-4 promoted new growth cone formation after axon transection. Most importantly, IL-4 directly increased the regenerative capacity of both murine and human CST axons, which corroborates its regenerative effects in CNS damage. Overall, these findings serve as proof-of-concept that our CST regeneration model is suitable for fast screening of new treatments for SCI.
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http://dx.doi.org/10.1007/s10571-020-00820-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497511PMC
November 2020
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