Binkle-Ladisch L, Pironet A, Zaliani A, Alcouffe C, Mensching D, Haferkamp U, Willing A, Woo MS, Erdmann A, Jessen T, Hess SD, Gribbon P, Pless O, Vennekens R, Friese MA.

Identification and development of TRPM4 antagonists to counteract neuronal excitotoxicity.

Neurodegeneration in central nervous system disorders is linked to dysregulated neuronal calcium. Direct inhibition of glutamate-induced neuronal calcium influx, particularly via N-methyl-D-aspartate receptors (NMDAR), has led to adverse effects and clinical trial failures. A more feasible approach is to modulate NMDAR activity or calcium signaling indirectly. In this respect, the calcium-activated non-selective cation channel transient receptor potential melastatin 4 (TRPM4) has been identified as a promising target. However, high affinity and specific antagonists are lacking. Here, we conducted high-throughput screening of a compound library to identify high affinity TRPM4 antagonists. This yielded five lead compound series with nanomolar half-maximal inhibitory concentration values. Through medicinal chemistry optimization of two series, we established detailed structure-activity relationships and inhibition of excitotoxicity in neurons. Moreover, we identified their potential binding site supported by electrophysiological measurements. These potent TRPM4 antagonists are promising drugs for treating neurodegenerative disorders and TRPM4-related pathologies, potentially overcoming previous therapeutic challenges.

iScience 2024 Dec 20:27:1114225

Riemann-Lorenz K, Seddiq Zai S, Daubmann A, Pöttgen J, Heesen C.

Nutrition Knowledge and Food Literacy Among Persons with Multiple Sclerosis – Development and Validation of Patient-Reported Outcome Measures

Background/Objectives: Persons with MS (pwMSs) are often confronted with contradictory dietary advice, which is not always based on sound scientific evidence. This may lead to poor MS-specific nutrition knowledge (MSNK) and food literacy (MSFL). To date, no studies have assessed MSNK and MSFL among pwMSs. Moreover, no validated tools to measure the effects of educational interventions are available. The aim of this study was to develop and validate MS-specific instruments to measure MSNK and MSFL among pwMSs. Methods: Based on a validated food literacy (FL) screener for the general population and prior research about the information needs of pwMSs, we developed 14 MSFL items and 11 MS-specific nutrition knowledge questions. Cognitive debriefing was conducted with 10 pwMSs and resulted in a 12-item MS food literacy questionnaire (MSFLQ) and an 11-item MS nutrition knowledge questionnaire (MSNKQ). After refinement, both questionnaires were pilot tested in an online survey to explore their comprehensibility. The MSNKQ was analyzed descriptively (mean and percentage of correctly answered questions). For MSFLQ item difficulty, the discriminatory power of the items, internal consistency and convergent/divergent validity were assessed. Results: In total, 148 pwMSs (age: 47.1 years (SD = 12.5); 102 women (69%)) completed the online survey. On average, participants answered 3.51/11 MSNK questions correctly (31.9%). The MSFLQ showed good internal consistency (Cronbach’s alpha = 0.85), item difficulty was good and the discriminatory power of the items was satisfactory. Correlations between the MSFLQ and a general food literacy questionnaire was high (r = 0.626, p < 0.001), but only small with the MSNKQ (r = 0.180; p = 0.029), underlining the different constructs. Conclusions: MSNK among pwMSs in Germany is low. The MSNKQ and MSFLQ appear to be suitable instruments to assess MSNK and MSFL and might serve as outcome measures for educational interventions.

Nutrients 2024, 16(23),4043

Althoff P, Rosenthal F, Dorsch EM, Drebinger D, Arsenova R, Chroschew A, Rosenkranz SC, Bellmann-Strobl J, Heesen C, Paul F, Weygandt M, Schmitz-Hübsch T.

Cognitive-motor interference in multiple sclerosis and healthy controls: results from single, dual and triple task posturography.

Explor Neuroprot Ther. 2024;4:273-287

Keller AM, von Glasenapp B, Kotz D, Marck CH, Heesen C, Riemann-Lorenz K.

Motivators and barriers for smoking cessation in people with multiple sclerosis: a qualitative study to inform the design of a tailored intervention. 

BMC Public Health. 2024 Dec 17;24(1):3402

Lane J, Poyser C, Zhao Y, Lucas RM, Meyer B, Heesen C, Cherbuin N, Brüstle A, Macqueen S, Richardson A, Lueck C, Gold SM

Acceptability and Feasibility of the English Version of Elevida, a Self-Guided Online Fatigue Intervention for People with Multiple Sclerosis.

Background: Fatigue is common in multiple sclerosis (MS); it significantly impairs quality of life, and treatment options are limited. A randomized controlled trial of Elevida, a self-guided, online German fatigue intervention, showed significant benefit. We tested an English version of Elevida with people with MS in Australia. Methods: Participants were volunteers with MS who self-reported at least mild fatigue (≥ 43 on the Fatigue Scale for Motor and Cognitive Functions scale), some mobility (Expanded Disability Status Scale < 8), and no or mild cognitive difficulties (≤ 32 on the Multiple Sclerosis Neuropsychological Questionnaire). Participants completed the 9-week English Elevida program, commenting on and rating its acceptability. The Chalder Fatigue Scale was completed at baseline, end-of-program, and 2 months later. We undertook qualitative (thematic analysis) and quantitative (before/after differences, tested using paired t test) analyses. Results: Thirty-eight people with MS expressed an interest in the study; 26 were eligible; 20 began the study. Fifteen participants (75%) completed the program (mean [SD]: 58.9 [10.5] years of age, 67% women, 9 with relapsing MS, 6 with progressive MS). Over 90% of completing participants rated acceptability as good or very good, and approximately 70% found the program helpful. Three themes were identified: Positive or negative comments on program features, incorrect assumptions in program content, and personal experiences and reflections. Significant improvement (P < .01) in fatigue scores from baseline to program completion was maintained 2 months after program completion. Conclusions: Elevida was acceptable and effective for MS-related fatigue. Identified themes will guide further development of the program to satisfy users‘ sense of autonomy, competence, and relatedness.

Int J MS Care. 2024 Dec9;26(Q4):347-354

Haferkamp U, Telugu N, Krieg K, Schaefer W, Lam D, Binkle-Ladisch L, Friese MA, Diecke S, Pless O.

Generation of two isogenic human iPSC lines (ZIPi013-B-1, ZIPi013-B-2) carrying a CRISPR/Cas9-mediated deletion of TRPM4

 Two isogenic hiPSC lines, ZIPi013-B-1 and ZIPi013-B-2, were generated by CRISPR/Cas9-mediated indels in the TRPM4 gene of the previously published ZIPi013-B. TRPM4 belongs to the evolutionarily conserved family of transient receptor potential (TRP) channels. It is expressed ubiquitously and its activity is regulated by intracellular calcium binding, changes in membrane potential, phosphoinositide lipids in the plasma membrane and the local concentration of cytoplasmic ATP and ADP. TRPM4 has been implicated in various diseases, including neurological and immune system disorders, cardiac diseases and cancer. Both new cell lines offer the opportunity to model human diseases and test therapeutic modalities addressing these.

Stem Cell Res. 2024 Dec:81:103609

Rahn AC, Peper J, Köpke S, Antony G, Liethmann K, Vettorazzi E, Heesen C; DECIMS study group.

Erratum to „Nurse-led immunotreatment DEcision Coaching In people with Multiple Sclerosis (DECIMS) – A cluster-randomised controlled trial and mixed methods process evaluation“ [Patient Educ Couns 125 (2024) 108293]. 

No abstract available.

Patient Educ Couns. 2025 Jan:130:108363.

Therriault J, Janelidze S, Benedet AL, Ashton NJ, Arranz Martínez J, Gonzalez-Escalante A, Bellaver B, Alcolea D, Vrillon A, Karim H, Mielke MM, Hyung Hong C, Roh HW, Contador J, Puig Pijoan A, Algeciras-Schimnich A, Vemuri P, Graff-Radford J, Lowe VJ, Karikari TK, Jonaitis E, Brum W, Tissot C, Servaes S, Rahmouni N, Macedo AC, Stevenson J, Fernandez-Arias J, Wang YT, Woo MS, Friese MA, Jia WL, Dumurgier J, Hourregue C, Cognat E, Ferreira PL, Vitali P, Johnson S, Pascoal TA, Gauthier S, Lleó A, Paquet C, Petersen RC, Salmon D, Mattsson-Carlgren N, Palmqvist S, Stomrud E, Galasko D, Son SJ, Zetterberg H, Fortea J, Suárez-Calvet M, Jack CR Jr, Blennow K, Hansson O, Rosa-Neto P.

Diagnosis of Alzheimer’s disease using plasma biomarkers adjusted to clinical probability.

Recently approved anti-amyloid immunotherapies for Alzheimer’s disease (AD) require evidence of amyloid-β pathology from positron emission tomography (PET) or cerebrospinal fluid (CSF) before initiating treatment. Blood-based biomarkers promise to reduce the need for PET or CSF testing; however, their interpretation at the individual level and the circumstances requiring confirmatory testing are poorly understood. Individual-level interpretation of diagnostic test results requires knowledge of disease prevalence in relation to clinical presentation (clinical pretest probability). Here, in a study of 6,896 individuals evaluated from 11 cohort studies from six countries, we determined the positive and negative predictive value of five plasma biomarkers for amyloid-β pathology in cognitively impaired individuals in relation to clinical pretest probability. We observed that p-tau217 could rule in amyloid-β pathology in individuals with probable AD dementia (positive predictive value above 95%). In mild cognitive impairment, p-tau217 interpretation depended on patient age. Negative p-tau217 results could rule out amyloid-β pathology in individuals with non-AD dementia syndromes (negative predictive value between 90% and 99%). Our findings provide a framework for the individual-level interpretation of plasma biomarkers, suggesting that p-tau217 combined with clinical phenotyping can identify patients where amyloid-β pathology can be ruled in or out without the need for PET or CSF confirmatory testing.

Nat Aging. 2024 Nov;4(11):1529-1537.

Mougiakakos D, Sengupta R, Gold R, Schroers R, Haghikia A, Lorente M, Pendleton M, Register A, Heesen C, Kröger N, Schett G, Mackensen A, Podoll A, Gutman J, Furie R, Bayer R, Distler JHW, Dietrich S, Krönke G, Bullinger L, Walker K.

Successful generation of fully human, second generation, anti-CD19 CAR T cells for clinical use in patients with diverse autoimmune disorders. 

Background: B-cell targeting chimeric antigen receptor (CAR) T-cell therapies, which lead to profound B-cell depletion, have been well-established in hematology-oncology. This deep B-cell depletion mechanism has prompted the exploration of their use in B-cell driven autoimmune diseases. We herein report on the manufacturing of KYV-101, a fully human anti-CD19 CAR T-cell therapy, derived from patients who were treated across a spectrum of autoimmune diseases. Methods: KYV-101 was manufactured from peripheral blood-derived mononuclear cells of 20 patients across seven autoimmune disease types (neurological autoimmune diseases, n = 13; rheumatological autoimmune diseases, n = 7). Patients ranged from 18 to 75 years of age. Duration of disease ranged from <1 to 23 years since diagnosis. Patients were heavily pretreated, and most were refractory to prior immunosuppressive treatments. Apheresis was collected across nine sites, cryopreserved, and shipped to the manufacturing facility. Healthy donor apheresis samples were collected for manufacturing comparison. Manufacturing was performed using the CliniMACS Prodigy system. Cells were enriched for CD4+/CD8+ T cells, transduced with a third generation lentiviral vector encoding the CAR, expanded in vitro, and harvested. Percent cell viability, T-cell purity, cellular expansion, and transduction efficiency were assessed. Activity was assessed using cytokine release assays for KYV-101 CAR T cells co-cultured with different CD19+/- target cell lines. Results: KYV-101 was successfully manufactured for 100% of patients. Transduced cell populations were highly viable, with expansion ranging from 11 to 66 fold at Day 8, and were comparable across disease types. Healthy donor-derived controls displayed similar expansion ranges. High CAR expression and transduction rates were observed, ranging between 37 and 77% with low variation in transgene copy number (two to four per cell). Cell viability of the final KYV-101 drug product ranged from 87 to 97%. KYV-101 displayed robust CD19-dependent and effector dose-related release of the pro-inflammatory cytokine IFN-γ. Conclusions: KYV-101 manufacturing yielded a CAR T-cell product with high viability and consistent composition and functionality, regardless of disease indication, pre-treatment, and heterogeneity of the incoming material. Cryopreservation of the apheresis and final drug product enabled widespread distribution. These results support the robustness of the manufacturing process for the fully human KYV-101 anti-CD19 CAR T-cell therapy drug product for patients across diverse autoimmune disease types.

Cytotherapy. 2024 Oct 5:S1465-3249(24)00887-9

Pfeffer LK, Fischbach F, Heesen C, Friese MA.

Current state and perspectives of CAR T cell therapy in central nervous system diseases. 

B cell-directed CAR T cell therapy has fundamentally changed the treatment of hematological malignancies and its scope of application is rapidly expanding to include other diseases such as solid tumors or autoimmune disorders. Therapy-refractoriness remains an important challenge in various inflammatory and non-inflammatory disorders of the CNS. The reasons for therapy failure are diverse and include limited access of current therapies to the CNS, as well as enormous inter- and intraindividual disease heterogeneity. The tissue-penetrating properties of CAR T cells make them a promising option to overcome this problem and to tackle pathologies directly within the CNS. First application of B cell-directed CAR T cells in neuromyelitis optica spectrum disorder and multiple sclerosis patients has lately revealed promising outcomes, expanding the potential of CAR T cell therapy to encompass CNS diseases. Additionally, the optimization of CAR T cells for the therapy of gliomas is a growing field. As a further perspective, pre-clinical data reveal potential benefits of CAR T cell therapy also in the treatment of primary neurodegenerative diseases such as Alzheimer’s disease. Considering the biotechnological optimizations in the field of T cell engineering, such as the extension to target different antigens or the variation of the modified T cell subtype, new and promising fields of application for CAR T cells are rapidly opening up. These innovations offer the potencial to address the complex pathophysiological properties of CNS diseases. To optimally utilize CAR T cell therapy for CNS diseases in the future while minimizing therapy risks, there is a need for further mechanistic research as well as prospective controlled trials to seriously assess the disease and patient-specific risk-benefit ratio.

Brain. 2024 Nov 12

Woo MS, Therriault J, Jonaitis EM, Wilson R, Langhough RE, Rahmouni N, Benedet AL, Ashton NJ, Tissot C, Lantero-Rodriguez J, Macedo AC, Servaes S, Wang YT, Arias JF, Hosseini SA, Betthauser TJ, Lussier FZ, Hopewell R, Triana-Baltzer G, Kolb HC, Jeromin A, Kobayashi E, Massarweh G, Friese MA, Klostranec J, Vilali P, Pascoal TA, Gauthier S, Zetterberg H, Blennow K, Johnson SC, Rosa-Neto P.

Identification of late-stage tau accumulation using plasma phospho-tau217.

„Background: Blood-based disease staging across the Alzheimer’s disease (AD) continuum holds the promise to identify individuals that profit from disease-modifying therapies. We set out to identify Braak V+ (Braak V and/or VI) tau PET-positive individuals within amyloid-β (Aβ)-positive individuals using plasma biomarkers.
Methods: In this cross-sectional study, we assessed 289 individuals from the TRIAD cohort and 306 individuals from the WRAP study across the AD continuum. The participants were evaluated by amyloid-PET with [18F]AZD4694 or [11C]PiB and tau-PET with [18F]MK6240 and measured plasma levels included total tau, phospho-tau isoforms (pTau) pTau-181, pTau-217, pTau-231, and N-terminal tau (NTA-tau). We evaluated the performances of plasma biomarkers using different analytic platforms to predict Braak V+ positivity in Aβ+ individuals. Findings: Highest associations with Braak V+ tau positivity in Aβ+ individuals were found for plasma pTau-217+Janssen (AUC [CI95%] = 0.97 [0.94, 1.0]) and ALZpath pTau-217 (AUC [CI95%] = 0.93 [0.86, 1.0]) in TRIAD. Plasma ALZpath pTau-217 separated Braak V+ tau PET-positive individuals in the WRAP longitudinal study (AUC [CI95%] = 0.97 [0.94, 1.0]). Interpretation: Thus, we demonstrate that using adjusted cut-offs, plasma pTau-217 identifies individuals with later Braak stage tau accumulation which will be helpful to stratify patients for treatments and clinical studies.“

EBioMedicine. 2024 Nov:109:105413

Walkenhorst M, Sonner JK, Meurs N, Engler JB, Bauer S, Winschel I, Woo MS, Raich L, Winkler I, Vieira V, Unger L, Salinas G, Lantz O, Friese MA, Willing A.

Protective effect of TCR-mediated MAIT cell activation during experimental autoimmune encephalomyelitis.

Nat Commun. 2024 Oct 28;15(1):9287

Meyer B, Betz LT, Jacob GA, Krause N, Riemann-Lorenz K, Gold SM, Pöttgen J, Heesen C.

Effectiveness of a digital lifestyle management intervention (levidex) to improve quality of life in people with multiple sclerosis: results of a randomized controlled trial.

Background: Multiple Sclerosis (MS) is a chronic inflammatory neurodegenerative disease with diverse symptomatology, significantly impacting patients‘ quality of life (QoL). While pharmacological therapies focus primarily on reducing inflammation and relapse rates, non-pharmacological interventions, including digital health applications, have shown promise in improving QoL among persons with MS (PwMS). Pilot studies had shown the feasibility and acceptability of levidex, a digital health application based on cognitive behavioral therapy (CBT) principles, a broad set of behavior change techniques, and relevant lifestyle-change advice. This randomized controlled trial aimed to examine the effects of levidex on MS-related QoL over 6 months. Methods: Participants who were diagnosed with MS for at least one year were recruited via the internet in Germany, using a secure survey software platform, and were randomly assigned to the intervention group (IG), in which they received standard care + levidex, or an active control group (CG), in which they received standard care and were offered web-adapted material on the topic of lifestyle change from the German Multiple Sclerosis Society (DMSG). The primary outcome was MS-related QoL after 6 months, measured by the Hamburg Quality of Life Questionnaire in MS (HAQUAMS); secondary outcomes included QoL subscales, sick days, and health behavior, among others. Analyses of Covariance (ANCOVA) were used to examine intervention effects at 6 months. Participants were recruited between November 2020 and February 2022. Results: A total of 421 adult participants (mean age: 47.5, 78.1% women) were included and randomized (IG, n = 195, CG, n = 226). After 6 months, the IG exhibited significantly higher MS-related QoL, compared to the CG (total score HAQUAMS, adjusted group mean difference = -0.14, 95% CI: [-0.22, -0.06], p = 0.001; Cohen’s d = 0.23), with significant effects also observed on the cognitive and mood subscales. At 6 months, IG participants also reported significantly fewer sick days (median = 2 days in IG vs. 6 days in CG; W = 3939, p = 0.012) and significantly higher levels of daily activities, as measured by the Frenchay Activity Index, adjusted group mean difference = 1.37, 95% CI = [0.33, 2.40], p = 0.010; Cohen’s d = 0.16. Safety analyses showed no adverse events and good satisfaction. Conclusions: Compared to the control group, levidex facilitated clinically relevant improvements in MS-related QoL, reduced sick days, and enhanced activity in PwMS over 6 months. These findings suggest that levidex can serve as an effective non-pharmacological adjunctive treatment element to standard care and could help improve QoL among PwMS.

BMC Neurol. 2024 Sep 16;24(1):347

van der Ven e, Patra S, Riemann-Lorenz K, Kauschke K, Freese-Schwarz K, Welsch G, Krause N, Heesen C, Rosenkranz SC.

Individualized activity recommendation based on a physical fitness assessment increases short- and long-term regular physical activity in people with multiple sclerosis in a retrorespective cohort study.

Front. Neurol. 2024 Aug 23;15:1428712

Riemann-Lorenz K, Krause N, Marck CH, Daubmann A, Heesen C.

Diet and multiple sclerosis – development and mixed methods feasibility testing of a comprehensive nutritional information resource (NUTRIMS)

Purpose: Persons with multiple sclerosis (pwMS) are often confused by contradictory dietary advice. The purpose of this research was to explore the information needs and design a comprehensive, evidence-based nutritional information resource on diet and MS (NUTRIMS). Methods: A mixed-methods design with three sequential phases was adopted: (1) Needs assessment and development: Two focus groups with pwMS to explore experiences, information needs and preferred support around diet. Development of a draft NUTRIMS, (2) Feasibility Step 1: Feedback on the draft NUTRIMS from stakeholders and (3) Feasibility Step 2: Online survey among pwMS to explore content quality and acceptability. Results: Two focus groups with a total of 12 pwMS showed that MS-specific evidence on food groups/ingredients, nutrients and special diets were of most interest. The draft NUTRIMS was refined through feedback from 13 stakeholders. The pre-final NUTRIMS consisted of 81 pages including scientific references on each topic, 16 illustrations and a glossary of terms. 85 pwMS participated in the online survey and reported an intensive use and high satisfaction with the information resource, which was perceived as comprehensible, highly credible and useful for making decisions on dietary change. Conclusions: A collaborative research approach led to a well-accepted nutrition information resource.

Disabil Rehabil. 2024 Sep 1:1-12

Schell M, Mayer C, Woo MS, Leischner H, Fischer M, Grensemann J, Kluge S, Czorlich P, Gerloff C, Fiehler J, Thomalla G, Flottmann F, Schweingruber N.

Fluid excess on intensive care unit after mechanical thrombectomy after acute ischemic stroke is associated with unfavorable neurological and functional outcomes: An observational cohort study.

Introduction: Endovascular thrombectomy stands as a pivotal component in the standard care for patients experiencing acute ischemic stroke with large vessel occlusion. Subsequent care for patients often extends to a neurological intensive care unit. While fluid management is integral to intensive care, the association between early fluid balance and neurological and functional outcomes post-thrombectomy has not yet been thoroughly investigated. Methods: In a retrospective analysis of an observational, single-center study spanning from 2015 to 2021 at the University Medical Center Hamburg-Eppendorf, Germany, we enrolled stroke patients who underwent thrombectomy and received subsequent treatment in the ICU. Unfavorable functional and neurological outcome was defined as a mRS > 2 on day 90 after admission (mRS d90) or NIHSS > 5 at discharge, respectively. A multivariate regression model, adjusting for confounders, utilized the average fluid balance in the first 5 days to predict outcomes. Patients were dichotomized by their average fluid balance (>1 L vs <1 L) within the first 5 days, and a multivariate mRS d90 shift analysis was conducted after adjusting for covariates. Results: Between 2015 and 2021, 1252 patients underwent thrombectomy, and 553 patients met the inclusion criteria (299 women [54%]). Unfavorable functional outcome was significantly associated with a higher daily average fluid balance in the first 5 days in the ICU (mRS d90 ⩽ 2: 0.3 ± 0.5 L, mRS d90 > 2: 0.7 ± 0.7 L, p = 0.02). The same association was observed for the NIHSS at discharge (NIHSS ⩽ 5: 0.3 ± 0.5 L; NIHSS > 5: 0.6 ± 0.6 L; p = 0.03). The mRS d90 shift analysis revealed significance for patients with an average fluid balance <1 L for better functional outcomes (adjusted odds ratio [AOR] 2.17; 95% confidence interval [CI] 1.54-3.07; p < 0.01). Discussion: Fluid retention in post-thrombectomy stroke patients in the ICU is associated with poorer functional and neurological outcomes. Consequently, fluid retention emerges as an additional potential predictor for post-intervention stroke outcomes. Our findings provide an initial indication that preventing excessive fluid retention in stroke patients after endovascular thrombectomy could be beneficial for both functional and neurological recovery. Therefore, fluid retention might be an element to consider in optimizing fluid management for stroke patients.

Eur Stroke J. 2024 Aug 16:23969873241271642

Woo MS, Bal LC, Winschel I, Manca E, Walkenhorst M, Sevgili B, Sonner JK, Di Liberto G, Mayer C, Binkle-Ladisch L, Rothammer N, Unger L, Raich L, Hadjilaou A, Noli B, Manai AL, Vieira V, Meurs N, Wagner I, Pless O, Cocco C, Stephens SB, Glatzel M, Merkler D, Friese MA.

The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis.

J Clin Invest. 2024 Jun 18;134(16):e177692

Klyscz P, Asseyer S, Alonso R, Bereuter C, Bialer O, Bick A, Carta S, Chen JJ, Cohen L, Cohen-Tayar Y, Contentti EC, Dale RC, Flanagan EP, Gernert JA, Haas J, Havla J, Heesen C, Hellmann M, Levin N, Lopez P, Lotan I, Luis MB, Mariotto S, Mayer C, Vergara AJM, Ocampo C, Ochoa S, Oertel FC, Olszewska M, Uribe JLP, Sastre-Garriga J, Scocco D, Ramanathan S, Rattanathamsakul N, Shi FD, Shifa J, Simantov I, Siritho S, Tiosano A, Tisavipat N, Torres I, Dembinsky AV, Vidal-Jordana A, Wilf-Yarkoni A, Wu T, Zamir S, Zarco LA, Zimmermann HG, Petzold A, Paul F, Stiebel-Kalish H.

Application of the international criteria for optic neuritis in the Acute Optic Neuritis Network.

Ann Clin Transl Neurol. 2024 Aug 4.

Passoke S, Stern C, Häußler V, Kümpfel T, Havla J, Engels D, Jarius S, Wildemann B, Korporal-Kuhnke M, Senel M, Stellmann JP, Warnke C, Grothe M, Schülke R, Gingele S, Kretschmer JR, Klotz L, Walter A, Then Bergh F, Aktas O, Ringelstein M, Ayzenberg I, Schwake C, Kleiter I, Sperber PS, Rust R, Schindler P, Bellmann-Strobl J, Paul F, Kopp B, Trebst C, Hümmert MW; Neuromyelitis Optica Study Group (NEMOS).

Cognition in patients with myelin oligodendrocyte glycoprotein antibody-associated disease: a prospective, longitudinal, multicentre study of 113 patients (CogniMOG-Study).

J Neurol Neurosurg Psychiatry. 2024 Jul 30

Woo MS, Mayer C, Binkle-Ladisch L, Sonner JK, Rosenkranz SC, Shaposhnykov A, Rothammer N, Tsvilovskyy V, Lorenz SM, Raich L, Bal LC, Vieira V, Wagner I, Bauer S, Glatzel M, Conrad M, Merkler D, Freichel M, Friese MA.

STING orchestrates the neuronal inflammatory stress response in multiple sclerosis.

Cell 2024 Jul 25;187(15):4043-4060

Funke M, Eveslage M, Zschüntzsch J, Hagenacker T, Ruck T, Schubert C, Schroeter M, Meisel A, Wiendl H, Hoffmann S, Lünemann JD.

Fatigue and associated factors in myasthenia gravis: a nationwide registry study

J Neurol. 2024 Aug;271(8):5665-5670

Wang YT, Ashton NJ, Servaes S, Nilsson J, Woo MS, Pascoal TA, Tissot C, Rahmouni N, Therriault J, Lussier F, Chamoun M, Gauthier S, Brinkmalm A, Zetterberg H, Blennow K, Rosa-Neto P, Benedet AL.

The relation of synaptic biomarkers with Aβ, tau, glial activation, and neurodegeneration in Alzheimer’s disease.

Editorial – No abstract Available.

Transl Neurodegener 2024 May 28;13(1):27

Volz T, Sippel A, Fischbach F, Richter J, Willison AG, Häußler V, Heesen C.

„A second birthday“? Experiences of persons with multiple sclerosis treated with autologous hematopoietic stem cell transplantation-a qualitative interview study.

Front Neurol. 2024 May 1;15:1384551

Winschel I, Willing A, Engler JB, Walkenhorst M, Meurs N, Binkle-Ladisch L, Woo MS, Pfeffer LK, Sonner JK, Borgmeyer U, Hagen SH, Grünhagel B, Claussen JM, Altfeld M, Friese MA.

Sex- and species-specific contribution of CD99 to T cell costimulation during multiple sclerosis.

Biol Sex Differ. 2024 May 15;15(1):41

Rahn AC, Peper J, Köpke S, Antony G, Liethmann K, Vettorazzi E, Heesen C; DECIMS study group.

Nurse-led immunotreatment DEcision Coaching In people with Multiple Sclerosis (DECIMS) – A cluster- randomised controlled trial and mixed methods process evaluation.

Patient Educ Couns. 2024 Aug:125:108293.

Wirth S, Schlößer A, Beiersdorfer A, Schweizer M, Woo MS, Friese MA, Lohr C, Grochowska KM.

Astrocytic uptake of posttranslationally modified amyloid-β leads to endolysosomal system disruption and induction of pro-inflammatory signaling.

Glia. 2024 Aug;72(8):1451-1468

Holz A, Obi N, Ahrens W, Berger K, Bohn B, Brenner H, Fischer B, Fricke J, Führer A, Gastell S, Greiser KH, Harth V, Heise JK, Holleczek B, Keil T, Klett-Tammen CJ, Leitzmann M, Lieb W, Meinke-Franze C, Michels KB, Mikolajczyk R, Nimptsch K, Peters A, Pischon T, Riedel O, Schikowski T, Schipf S, Schmidt B, Schulze MB, Stang A, Hellwig K, Riemann-Lorenz K, Heesen C, Becher H.

Childhood and adolescence factors and multiple sclerosis: results from the German National Cohort (NAKO).

BMC Neurol. 2024 Apr 13;24(1):123

Schubert C, Schiffmann I, Farschtschi SC, Emile JF, Friese MA.

Treatment of Cerebral Histiocytosis With Low Dose of Cobimetinib: A Report of 2 Cases.

Neurol Neuroimmunol Neuroinflamm. 2024 May;11(3):e200233

Fischbach F, Richter J, Pfeffer LK, Fehse B, Berger SC, Reinhardt S, Kuhle J, Badbaran A, Rathje K, Gagelmann N, Borie D, Seibel J, Ayuk F, Friese MA, Heesen C, Kröger N.

CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis.

Med. 2024 Jun 14;5(6):550-558

Schweingruber N, Bremer J, Wiehe A, Mader MMD, Mayer C, Woo MS, Kluge S, Grensemann J, Quandt F, Gempt J, Fischer M, Thomalla G, Gerloff C, Sauvigny J, Czorlich P.

Early prediction of ventricular peritoneal shunt dependency in aneurysmal subarachnoid haemorrhage patients by recurrent neural network-based machine learning using routine intensive care unit data.

Aneurysmal subarachnoid haemorrhage (aSAH) can lead to complications such as acute hydrocephalic congestion. Treatment of this acute condition often includes establishing an external ventricular drainage (EVD). However, chronic hydrocephalus develops in some patients, who then require placement of a permanent ventriculoperitoneal (VP) shunt. The aim of this study was to employ recurrent neural network (RNN)-based machine learning techniques to identify patients who require VP shunt placement at an early stage. This retrospective single-centre study included all patients who were diagnosed with aSAH and treated in the intensive care unit (ICU) between November 2010 and May 2020 (n = 602). More than 120 parameters were analysed, including routine neurocritical care data, vital signs and blood gas analyses. Various machine learning techniques, including RNNs and gradient boosting machines, were evaluated for their ability to predict VP shunt dependency. VP-shunt dependency could be predicted using an RNN after just one day of ICU stay, with an AUC-ROC of 0.77 (CI: 0.75-0.79). The accuracy of the prediction improved after four days of observation (Day 4: AUC-ROC 0.81, CI: 0.79-0.84). At that point, the accuracy of the prediction was 76% (CI: 75.98-83.09%), with a sensitivity of 85% (CI: 83-88%) and a specificity of 74% (CI: 71-78%). RNN-based machine learning has the potential to predict VP shunt dependency on Day 4 after ictus in aSAH patients using routine data collected in the ICU. The use of machine learning may allow early identification of patients with specific therapeutic needs and accelerate the execution of required procedures.

J Clin Monit Comput. 2024 Oct;38(5):1175-1186.

Seddiq Zai S, das Nair R, Heesen C, Buhmann C, Pedersen A, Pöttgen J.

Factors affecting driving performance in patients with Multiple Sclerosis – still an open question.

Front Neurol. 2024 Feb 28:15:1369143

Giovannetti AM, Rosato R, Galán I, Toscano A, Anglada E, Menendez R, Hoyer J, Confalonieri P, Giordano A, Pakenham KI, Pöttgen J, Solari A.

Cross-cultural validity and reliability of the comprehensive assessment of acceptance and commitment therapy processes (CompACT) in people with multiple sclerosis

Qual Life Res. 2024 May;33(5):1359-1371

Wenzel L, Haker M, Heesen C, Kasper J, Köpke S, Rahn AC.

Evaluating Relapse Knowledge in People with Multiple Sclerosis: A Cross-Sectional Study on the Development and Validation of the Relapse Knowledge Questionnaire.

Mult Scler Relat Disord. 2024 Jan 12;83:105381

Therriault J, Woo MS, Salvadó G, Gobom J, Karikari TK, Janelidze S, Servaes S, Rahmouni N, Tissot C, Ashton NJ, Benedet AL, Montoliu-Gaya L, Macedo AC, Lussier FZ, Stevenson J, Vitali P, Friese MA, Massarweh G, Soucy JP, Pascoal TA, Stomrud E, Palmqvist S, Mattsson-Carlgren N, Gauthier S, Zetterberg H, Hansson O, Blennow K, Rosa-Neto P.

Comparison of immunoassay- with mass spectrometry-derived p-tau quantification for the detection of Alzheimer’s disease pathology.

Mol Neurodegener. 2024 Jan 7;19(1):2

Braun B, Fischbach F, Richter J, Pfeffer LK, Fay H, Reinhardt S, Friese MA, Stellmann JP, Kröger NM, Heesen C, Häußler V.

Benefits of aHSCT over alemtuzumab in patients with multiple sclerosis besides disability and relapses: Sustained improvement in cognition and quality of life.

Mult Scler Relat Disord. 2024 Feb;82:105414

Duchow A, Bellmann-Strobl J, Friede T, Aktas O, Angstwurm K, Ayzenberg I, Berthele A, Dawin E, Engels D, Fischer K, Flaskamp M, Giglhuber K, Grothe M, Havla J, Hümmert MW, Jarius S, Kaste M, Kern P, Kleiter I, Klotz L, Korporal-Kuhnke M, Kraemer M, Krumbholz M, Kümpfel T, Lohmann L, Ringelstein M, Rommer P, Schindler P, Schubert C, Schwake C, Senel M, Bergh FT, Tkachenko D, Tumami H, Trebst C, Vardakas I, Walter A, Warnke C, Weber MS, Wickel J, Wildemann B, Winkelmann A, Paul F, Stellmann JP, Häußler V; Neuromyelitis Optica Study Group (NEMOS).

Time to disability milestones and annualized relapse rates in NMOSD and MOGAD.

Ann Neurol. 2024 Apr;95(4):720-732

Wendlandt M, Kürten AJ, Beiersdorfer A, Schubert Ch, Samad K, Sauer J, Pinto MC, Schulz K, Friese MA, Gee CE, Hirnet D, Lohr C.

A2A adenosine receptor-driven cAMP signaling in olfactory bulb astrocytes is unaffected in experimental autoimmune encephalomyelitis.

Front Immunol. 2023 Nov 23:14:1273837

Meyer-Arndt L, Brasanac J, Gamradt S, Bellmann-Strobl J, Maurer L, Mai K, Steward T, Spranger J, Schmitz-Hübsch T, Paul F, Gold SM, Weygandt M.

Body mass,neuro-hormonal stress processing, and disease activity in lean to obese people with multiple sclerosis.

J Neurol. 2023 Nov 27

Woo MS, Nilsson J, Therriault J, Rahmouni N, Brinkmalm A, Benedet AL, Ashton NJ, Macedo AC, Servaes S, Wang YT, Tissot C, Fernandez Arias J, Hosseini SA, Chamoun M, Lussier FZ, Karikari TK, Stevenson J, Mayer C, Ferrari-Souza JP, Kobayashi E, Massarweh G, Friese MA, Pascoal TA, Gauthier S, Zetterberg H, Blennow K, Rosa-Neto P.

14-3-3 ζ/δ-reported early synaptic injury in Alzheimer’s disease is independently mediated by sTREM2.

Neuroinflammation. 2023 Nov 24;20(1):278

Winkler I, Engler JB, Vieira V, Bauer S, Liu YH, Di Liberto G, Grochowska KM, Wagner I, Bier J, Bal LC, Rothammer N, Meurs N, Egervari K, Schattling B, Salinas G, Kreutz MR, Huang YS, Pless O, Merkler D, Friese MA.

MicroRNA-92a-CPEB3 axis protects neurons against inflammatory neurodegeneration.

Sci Adv. 2023 Nov 24;9(47):eadi6855

Gnirck AC, Philipp MS, Waterhölter A, Wunderlich M, Shaikh N, Adamiak V, Henneken L, Kautz T, Xiong T, Klaus D, Tomczyk P, Al-Bahra MM, Menche D, Walkenhorst M, Lantz O, Willing A, Friese MA, Huber TB, Krebs CF, Panzer U, Kurts C, Turner JE.

Mucosal-associated invariant T cells contribute to suppression of inflammatory myeloid cells in immune-mediated kidney disease.

Nat. Commun. 2023 Nov 15;14(1):7372

Woo MS, Tissot C, Lantero-Rodriguez J, Snellman A, Therriault J, Rahmouni N, Macedo AC, Servaes S, Wang YT, Arias JF, Hosseini SA, Chamoun M, Lussier FZ, Benedet AL, Ashton NJ, Karikari TK, Triana-Baltzer G, Kolb HC, Stevenson J, Mayer C, Kobayashi E, Massarweh G, Friese MA, Pascoal TA, Gauthier S, Zetterberg H, Blennow K, Rosa-Neto P.

Plasma pTau-217 and N-terminal tau (NTA) enhance sensitivity to identify tau PET positivity in amyloid-β positive individuals.

Alzheimers Dement. 2024 Feb;20(2):1166-1174.

Eisenhut K, Faber J, Engels D, Gerhards R, Lewerenz J, Doppler K, Sommer C, Markewitz R, Falk Kim K, Rössling R, Pruess H, Finke C, Wickel J, Geis C, Ratusnzny D, Pfeffer LK, Bittner S, Piepgras J, Kraft A, Klausewitz J, Nuscher B, Kümpfel T, Thaler FS; German Network for Research on Autoimmune Encephalitis (GENERATE).

Early Neuroaxonal Damage in Neurologic Disorders Associated With GAD65 Antibodies.

Neurol Neuroimmunol Neuroinflamm 2023 Nov 1;11(1):e200176

Dalgas U, Riemenschneider M, Gold SM, Kalron A, Beckerman H, de Groot V, Dennett R, Edwards T, Pilutti LA, Freeman J.

The MoXFo initiative – study design: Considerations related to study design and methodology in exercise research for people with multiple sclerosis.

Mult Scler 2023 Oct 26

Motl RW, Casey B, Learmonth YC, Latimer-Cheung A, Kinnett-Hopkins DL, Marck CH, Carl J, Pfeifer K, Riemann-Lorenz K, Heesen C, Coote S.

The MoXFo initiative – adherence: Exercise adherence, compliance and sustainability among people with multiple sclerosis: An overview and roadmap for research.

Mult Scler 2023 Oct 26

Kutzinski M, Krause N, Riemann-Lorenz K, Meyer B, Heesen C

Acceptability of digital health application to empower persons with multiple sclerosis with moderate to severe disability: single-arm prospective pilot study.

BMC Neurol. 2023 Oct 23;23(1):382

Daniel N, Bruns I, Casey B, Coote S, Daubmann A, Heesen C, Riemann-Lorenz K.

„Activity Matters was great – I now realize: if I move, I’m fitter.“: development and process evaluation of a web-based program for persons with multiple sclerosis.

Disabil Rehabil. 2024 Sep;46(18):4216-4225

Krause N, Derad C, von Glasenapp B, Riemann-Lorenz K, Temmes H, van de Loo M, Friede T, Asendorf T, Heesen C; POWER@MS1 study group.

Association of health behaviour and clinical manifestation in early multiple sclerosis in Germany – Baseline characteristics of the POWER@MS1 randomised controlled trial.

Mult Scler Relat Disord. 2023 Oct 5;79:105042

Chorschew A, Kesgin F, Bellmann-Strobl J, Flachenecker P, Schiffmann I, Rosenthal F, Althoff P, Drebinger D, Arsenova R, Rasche L, Dorsch EM, Heesen C, Paul F, Stellmann JP, Schmitz-Hübsch T.

Translation and validation of the multiple sclerosis walking scale 12 for the German population – the MSWS-12/D.

Health Qual Life Outcomes. 2023 Oct 9;21(1):110

Goldin K, Riemann-Lorenz K, Daubmann A ,Pöttgen J, Krause N, Schröder H, Heesen C.

Health behaviors of people with multiple sclerosis and its associations with MS related outcomes: a German clinical cohort.

Front Neurol. 2023 Sep 13:14:1172419

Bayas A, Berthele A, Blank N, Dreger P, Faissner S, Friese MA, Gerdes LA, Grauer OM, Häussler V, Heesen C, Janson D, Korporal-Kuhnke M, Kowarik M, Kröger N, Lünemann JD, Martin R, Meier U, Meuth S, Muraro P, Platten M, Schirmer L, Stürner KH, Stellmann JP, Scheid C, Bergh FT, Warnke C, Wildemann B, Ziemssen T.

Autologous haematopoietic stem cell transplantation for multiple sclerosis: a position paper and registry outline.

Ther Adv Neurol Disord. 2023 Sep 28;16:17562864231180730

Gold SM, Friede T, Meyer B, Moss-Morris R, Hudson J, Asseyer S, Bellmann-Strobl J, Leisdon A, Ißels L, Ritter K, Schymainski D, Pomeroy H, Lynch SG, Cozart JS, Thelen J, Román CAF, Cadden M, Guty E, Lau S, Pöttgen J, Ramien C, Seddiq-Zai S, Kloidt AM, Wieditz J, Penner IK, Paul F, Sicotte NL, Bruce JM, Arnett PA, Heesen C.

Internet-delivered cognitive behavioural therapy programme to reduce depressive symptoms in patients with multiple sclerosis: a multicentre, randomised, controlled, phase 3 trial.

Lancet Digit Health. 2023 Oct;5(10):e668-e678

Brehm TT, Heyer A, Woo MS, Fischer M, von der Meirschen M, Wichmann D, Jarczak D, Roedl K, Schmiedel S, Addo MM, Lütgehetmann M, Christner M, Huber S, Lohse AW, Kluge S, Schulzer Zur Wiesch J.

Comparative analysis of characteristics and outcomes in hospitalized COVID-19 patients infected with different SARS-CoV-2 variants between January 2020 and April 2022 – A retrospective single-center cohort study.

J Infect Public Health. 2023 Nov;16(11):1806-1812

Woo MS, Ufer F, Sonner JK, Belkacemi A, Tintelnot J, Sáez PJ, Krieg PF, Mayer C, Binkle-Ladisch L, Engler JB, Bauer S, Kursawe N, Vieira V, Mannebach S, Freichel M, Flockerzi V, Vargas P, Friese MA.

Calcium Channel ß3 subunit regulates ATP-dependent migration of dendritic cells.

Sci Adv. 2023 Sep;9(38):eadh1653.

Salmen A, Hoepner R, Fleischer V, Heldt M, Gisevius B, Motte J, Ruprecht K, Schneider R, Fisse AL, Grüter T, Lukas C, Berthele A, Giglhuber K, Flaskamp M, Mühlau M, Kirschke J, Bittner S, Groppa S, Lüssi F, Bayas A, Meuth S, Heesen C, Trebst C, Wildemann B, Then Bergh F, Antony G, Kümpfel T, Paul F, Nischwitz S, Tumani H, Zettl U, Hemmer B, Wiendl H, Zipp F, Gold R.

Factors associated with depressive mood at the onset of multiple sclerosis – an analysis of 781 patients of the German NationMS cohort.

Ther Adv Neurol Disord. 2023 Sep 8;16

Köhler-Forsberg O, Stiglbauer V, Brasanac J, Chae WR, Wagener F, Zimbalski K, Jefsen OH, Liu S, Seals MR, Gamradt S, Correll CU, Gold SM, Otte C.

Efficacy and Safety of Antidepressants in Patients With Comorbid Depression and Medical Disease: An Umbrella Systematic Review and Meta-Analysis.

JAMA Psychiatry. 2023 Dec 1;80(12):1196-1207.

Renner A, Bätge SJ, Filser M, Lau S, Pöttgen J, Penner IK.

Non-pharmacological randomized intervention trial for the management of neuropsychological symptoms in outpatients with progressive multiple sclerosis

Appl Neuropsychol Adult. 2023 Aug 31;1-13

Woo MS, Shafiq M, Fitzek A, Dottermusch M, Altmeppen H, Mohammadi B, Mayer C, Bal LC, Raich L, Matschke J, Krasemann S, Pfefferle S, Brehm TT, Lütgehetmann M, Schädler J, Addo MM, Schulze Zur Wiesch J, Ondruschka B, Friese MA, Glatzel M.

Vagus nerve inflammation contributes to dysautonomia in COVID-19.

Acta Neuropathol. 2023 Sep;146(3):387-394.

Rosenkranz SC, Gutmann L, Has Silemek AC, Dorr M, Häußler V, Lüpke M, Mönch A, Reinhardt S, Kuhle J, Tilsley P, Heesen C, Friese MA, Brandt A, Paul F, Zimmermann H, Stellmann JP.

Visual function resits early neurodegeneration in the visual system in primary progressive multiple sclerosis.

J Neurol Neurosurg Psychiatry. 2023 Nov;94(11):924-933

Heesen C., Solaria A.

Editorial: Shared decision-making in neurology.

Front Neurol. 2023 Jun 6;14:1222433

Tilsley P, Strohmeyer IA, Heinrich I, Rosenthal F, Patra S, Schulz KH, Rosenkranz SC, Ramien C, Pöttgen J, Heesen C, Has AC, Gold SM, Stellmann JP.

Physical fitness moderates the association between brain network impairment and both motor function and cognition in progressive multiple sclerosis.

J Neurol. 2023 JOct;270(10):4876-4888.

Peper J, Köpke S, Solari A, Giordano A, Gold SM, Hellwig K, Steinberg L, Steckelberg A, Heesen C, Rahn AC.

Knowledge and worries on motherhood choice in multiple sclerosis – a cross-sectional study on patient-reported outcome measures.

Mult Scler Relat Disord. 2023 Aug;76:104789

Mayer Ch, Woo MS,Brehm TT, Heyer A, Fischer M, Fischbach F, Bal LC, Addo MM, Kluge S,Thomalla G, Schweingruber N, Schulze zur Wiesch J.

History of cerebrovascular disease but not dementia increases the risk for secondary vascular events during SARS-CoV-2 infection with presumed Omicron variant: a retrospective observational study.

Eur J Neurol. 2023 Aug;30(8):2297-2304

Woo MS, Mayer C, Fischer M, Kluge S, Roedl 2, Gerloff C, Czorlich P, Thomalla G, Schulze zur Wiesch J, Schweingruber N.

Clinical surrogates of dysautonomia predict lethal outcome in COVID-19 on intensive care unit.

Neurol Res Pract. 2023 May 4;5(1):17

Thaler C, Sedlacik J, Forkert ND, Stellmann JP, Schön G, Fiehler J, Gellißen S.

Effect of geometric distortion correction on thickness and volume measurements of cortical parcellations in 3D T1w gradient echo sequences.

PLoS One. 2023 Apr 14;18(4):e0284440

Woo MS, Mayer C, Brehm TT, Andersen G, Weigel A, Löwe B, Lohse AW, Addo MM, Gerloff C, Knobloch JKM, Schulze zur Wiesch J, Friese MA.

Absence of self-reported neuropsychiatric and somatic symptoms after Omicron variant SARS-CoV-2 breakthrough infections.

Brain Commun. 2023 Mar 25;5(2):fcad092

Gold SM, Landray MJ, Medhurst N, Otte C.

Fast tracking informative clinical trials: lessons for mental health.

Lancet Psychiatry. 2023 Jun;10(6):376-378

Jarius S, Aktas O, Ayzenberg I, Bellmann-Strobl J, Berthele A, Giglhuber K, Häußler V, Havla J, Hellwig K, Hümmert MW, Kleiter I, Klotz L, Krumbholz M, Kümpfel T, Paul F, Ringelstein M, Ruprecht K, Senel M, Stellmann JP, Bergh FT, Tumani H, Wildemann B, Trebst C; Neuromyelitis Optica Study Group (NEMOS).

Update on the diagnosis and treatment of neuromyelits optica spectrum disorders (NMOSD) – revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part I: Diagnosis and differential diagnosis

J. Neurol. 2023 Jul;270(7):3341-3368

Chae WR, Baumert J, Nübel J, Brasanac J, Gold SM, Hapke U, Otte C.

Associations between individual depressive symptoms and immunometabolic characteristics in major depression.

Eur Neuropsychopharmacol. 2023 Mar 24;71:25-40

Heesen C, Rahn AC.

The challenge of pregnancy in women with multiple sclerosis.

Lancet Neurol. 2023 Apr;22(4):288-289.

Ufer F, Ziegler SM, Altfeld M, Friese MA.

Case report: JAK inhibition as promising treatment option of fatal RVCLS due to TREX1 mutation (pVAL235Glyfs*6).

Front Neurol. 2023 Feb 21;14:11118369

Baetge SJ, Filser M, Renner A, Raithel LM, Lau S, Pöttgen J, Penner IK.

Supporting brain health in multiple sclerosis: exploring the potential of neuroeducation combined with practical mindfulness exercises in the management of neuropsychological symptoms

Neurol Neurosurg Psychiatry. 2023 Sep;94(9):718-725.

Abu Heijleh AP, Huck K, Jähne K, Tan CL, Lanz TV, Epping L, Sonner JK, Meuth SG, Henneberg A, Opitz CA, Herold-Mende C, Sahm F, Platten M, Sahm K.

Endothelial Indoleamine-2,3-Dioxygenase-1 is not Critically Involved in Regulating Antitumor Immunity in the Central Nervous System.

Int J Tryptophan Res. 2023 Feb 9:16:11786469231153111

Hümmert MW, Stern C, Paul F, Duchow A, Bellmann-Strobl J, Ayzenberg I, Schwake C, Kleiter I, Hellwig K, Jarius S, Wildemann B, Senel M, Berthele A, Giglhuber K, Luessi F, Grothe M, Klotz L, Schülke R, Gingele S, Faiss JH, Walter A, Warnke C, Then Bergh F, Aktas O, Ringelstein M, Stellmann JP, Häußler V, Havla J, Pellkofer H, Kümpfel T, Kopp B, Trebst C.

Cognition in patients with neuromyelitis optica spectrum disorders: A prospective multicentre study of 217 patients (CogniNMO-Study).

Background: There is limited and inconsistent information on the prevalence of cognitive impairment in neuromyelitis optica spectrum disorders (NMOSD). Objective: To assess cognitive performance and changes over time in NMOSD. Methods: This study included data from 217 aquaporin-4-IgG-seropositive (80%) and double-seronegative NMOSD patients. Cognitive functions measured by Symbol Digit Modalities Test (SDMT), Paced Auditory Serial-Addition Task (PASAT), and/or Multiple Sclerosis Inventory Cognition (MuSIC) were standardized against normative data (N = 157). Intraindividual cognitive performance at 1- and 2-year follow-up was analyzed. Cognitive test scores were correlated with demographic and clinical variables and assessed with a multiple linear regression model. Results: NMOSD patients were impaired in SDMT (p = 0.007), MuSIC semantic fluency (p < 0.001), and MuSIC congruent speed (p < 0.001). No significant cognitive deterioration was found at follow-up. SDMT scores were related to motor and visual disability (pBon < 0.05). No differences were found between aquaporin-4-IgG-seropositive and double-seronegative NMOSD. Conclusions: A subset of NMOSD patients shows impairment in visual processing speed and in semantic fluency regardless of serostatus, without noticeable changes during a 2-year observation period. Neuropsychological measurements should be adapted to physical and visual disabilities.

Mult Scler. 2023 Jun;29(7):819-831

Krieg PF, Sonner JK, Kurelic R, Engler JB, Scharenberg MF, Bauer S, Nikolaev VO, Friese MA.

GPR52 regulates cAMP in T cells but is dispensable for encephalitogenic responses.

Front Immunol. 2023 Jan 24;13:1113348.

Hannah Kapell, Luca Fazio, Julia Dyckow, Sophia Schwarz, Andrés Cruz-Herranz, Christina Mayer, Joaquin Campos, Elisa D Este, Wiebke Möbius, Christian Cordano, Anne-Katrin Pröbstel, Marjan Gharagozloo, Amel Zulji, Venu Narayanan Naik, Anna-Katharina Delank, Manuela Cerina, Thomas Müntefering, Celia Lerma-Martin, Jana K Sonner, Jung H Sin, Paul Disse, Nicole Rychlik, Khalida Sabeur, Manideep Chavali, Rajneesh Srivastava, Matthias Heidenreich, Kathryn C Fitzgerald, Guiscard Seebohm, Christine Stadelmann, Bernhard Hemmer, Michael Platten, Thomas J Jentsch, Maren Engelhardt, Thomas Budde, Klaus-Armin Nave, Peter A Calabresi, Manuel A Friese, Ari J Green, Claudio Acuna, David H Rowitch , Sven G Meuth, Lucas Schirmer.

Neuron-oligodendrocyte potassium shuttling at nodes of Ranvier protects against inflammatory demyelination.

Multiple sclerosis (MS) is a progressive inflammatory-demyelinating disease of the central nervous system. Increasing evidence suggests that vulnerable neurons in MS exhibit fatal metabolic exhaustion over time, a phenomenon hypothesized to be caused by chronic hyperexcitability. Axonal Kv7 (outward rectifying) and oligodendroglial Kir4.1 (inward rectifying) potassium channels have important roles in regulating neuronal excitability at and around nodes of Ranvier. Here, we studied the spatial and functional relationship between neuronal Kv7 and oligodendroglial Kir4.1 channels and assessed the transcriptional and functional signatures of cortical and retinal projection neurons under physiological and inflammatory-demyelinating conditions. We found that both channels became dysregulated in MS and experimental autoimmune encephalomyelitis (EAE) with Kir4.1 channels being chronically downregulated and Kv7 channel subunits being transiently upregulated during inflammatory demyelination. Further, we observed that pharmacological Kv7 channel opening with retigabine reduced neuronal hyperexcitability in human and EAE neurons, improved clinical EAE signs and rescued neuronal pathology in oligodendrocyte-Kir4.1-deficient mice. In summary, our findings indicate that neuron-oligodendrocyte compensatory interactions promote resilience through Kv7 and Kir4.1 channels and suggest pharmacological activation of nodal Kv7 channels as a neuroprotective strategy against inflammatory demyelination. 

J Clin Invest. 2023 Apr 3;133(7):e164223

Martin W Hümmert, Franziska Bütow, Daria Tkachenko, Ilya Ayzenberg, Thivya Pakeerathan, Kerstin Hellwig, Luisa Klotz, Vivien Häußler, Jan-Patrick Stellmann, Clemens Warnke, Yasemin Goereci, Thorleif Etgen, Felix Luessi, Paul Bronzlik, Stefan Gingele, Ann-Sophie Lauenstein, Ingo Kleiter, Paulus S Rommer, Friedemann Paul, Judith Bellmann-Strobl, Ankelien Duchow, Florian Then Bergh, Refik Pul, Annette Walter, Hannah Pellkofer, Tania Kümpfel, Mosche Pompsch, Markus Kraemer, Philipp Albrecht, Orhan Aktas, Marius Ringelstein, Makbule Senel, Katrin Giglhuber, Achim Berthele, Sven Jarius, Brigitte Wildemann, Corinna Trebst; Neuromyelitis Optica Study Group (NEMOS)

Effects of the COVID-19 Pandemic on Patients with NMO Spectrum Disorders and MOG-Antibody-Associated Diseases: COPANMO(G)-Study.

Background and objectives: To evaluate the effects of the coronavirus disease 2019 (COVID-19) pandemic on the life of patients with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated diseases (MOGAD). Methods: This multicenter, cross-sectional study included data of 187 patients recruited from 19 different German and Austrian Neuromyelitis Optica Study Group (NEMOS) centers between July 2021 and March 2022. The effects of the pandemic on immunotherapeutic treatment and access to care, the possible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the potential effect of vaccination against SARS-CoV-2 on disease incidence and relapse risk were assessed using a patient questionnaire. Health-related quality of life (HRQoL) was measured with the EuroQoL Group 5-Dimension 5-Level Scale (EQ-5D-5L). Demographic and clinical characteristics were retrieved from the NEMOS database. Results: One hundred eighty-seven patients (75% women; median age 47 [range 21-86] years; median disease duration 5.5 [range 0-67] years; median Expanded Disability Status Scale 2.0 [range 0-8.0]; 51% aquaporin-4 immunoglobulin G (AQP4-IgG)-positive, 36% myelin oligodendrocyte glycoprotein (MOG)-IgG-positive 13% double-seronegative) were analyzed. Most patients maintained excellent access to healthcare services throughout the pandemic. Immunotherapy was not changed in 88% of patients. Ninety-one percent of all patients were satisfied with medical care during the pandemic. Nearly two-thirds (64%) of patients rated their risk of infection with SARS-CoV-2 as low or moderate. Among this study sample, 23 patients (12%) knowingly acquired an infection with SARS-CoV-2 and predominantly had a nonsevere course of illness (n = 22/23, 96%). The SARS-CoV-2 vaccination rate was 89%, with 4 cases of confirmed attack or first manifestation of NMOSD/MOGAD occurring in temporal association with the vaccination (range 2-9 days). The reported HRQoL did not decline compared with a prepandemic assessment (mean EQ-5D-5L index value 0.76, 95% bootstrap confidence interval [CI] 0.72-0.80; mean EQ-VAS 66.5, 95% bootstrap CI 63.5-69.3). Discussion: This study demonstrates that, overall, patients with NMOSD/MOGAD affiliated with specialized centers received ongoing medical care during the pandemic. Patients‘ satisfaction with medical care and HRQoL did not decrease.

Neurol Neuroimmunol Neuroinflamm. 2023 Jan 24;10(2):e200082

Jordan-Paiz A, Martrus G, Steinert FL, Kaufmann M, Sagebiel AF, Schreurs RRCE, Rechtien A, Baumdick ME, Jung JM, Möller KJ, Wegner L, Grüttner C, Richtert L, Thünauer R, Schroeder-Schwarz J, von Goudoever JB, Geijtenbeek TBH, Altfeld M, Pals ST, Perez D, Klarenbeek PL, Tomuschat C, Sauter G, Königs I, Schumacher U, Friese MA, Melling N, Reinshagen K, Bunders MJ.

CXCR5+PD-1++ CD4+ T cells colonize infant intestines early in life and promote B cell maturation

Cell Mol Immunol. 2023 Feb;20(2):201-213

Grochowska KM, Gomes GM, Raman R, Kaushik R, Sosulina L, Kaneko H, Oelschlegel AM, Yuanxiang P, Reyes-Resina I, Bayraktar G, Samer S, Spilker C, Woo MS, Morawski M, Goldschmidt J, Friese MA, Rossner S, Navarro G, Remy S, Reissner C, Karpova A, Kreutz MR.

Jacob-induced transcriptional inactivation of CREB promotes Aß-induced synapse loss in Alzheimer’s disease.

EMBO J. 2023 Feb 15;42(4):e112453

Heesen C, Rahn AC, Köpke S.

Communication with people with MS: A key role for evidence-based patient information.

Patient Educ. Couns. 2022 DE;105(12):3339-3340

Woo MS, Brehm TT, Fischer M, Heyer A, Wichmann D, Jordan S, Nörz D, Lütgehetmann M, Addo MM, Lohse AW, Schmiedel S, Kluge S, Schulze zur Wiesch J.

Sotrovimab in Hospitalized Patients with SARS-CoV-2 Omicron Variant Infection: a Propensity Score-Matched Retrospective Cohort Study.

Microbiol Spectr. 2023 Feb 14;11(1):e0410322

Lutfullin I, Eveslage M , Bittner S, Antony G , Flaskamp M, Luessi F , Salmen A, Gisevius B , Klotz L , Korsukewitz C ,  Berthele A ,  Groppa S , Then Bergh F , Wildemann B , Bayas A, Tumani H ,  Meuth SG , Trebst C , Zettl UK,  Paul F ,Heesen C, Kuempfel T, Gold R , Hemmer B, Zipp F, Wiendl H , Lünemann JD , German Competence Network Multiple Sclerosis (KKNMS)

Association of obesity with disease outcome in multiple sclerosis.

Background: Obesity reportedly increases the risk for developing multiple sclerosis (MS), but little is known about its association with disability accumulation. Methods: This nationwide longitudinal cohort study included 1066 individuals with newly diagnosed MS from the German National MS cohort. Expanded Disability Status Scale (EDSS) scores, relapse rates, MRI findings and choice of immunotherapy were compared at baseline and at years 2, 4 and 6 between obese (body mass index, BMI ≥30 kg/m2) and non-obese (BMI <30 kg/m2) patients and correlated with individual BMI values. Results: Presence of obesity at disease onset was associated with higher disability at baseline and at 2, 4 and 6 years of follow-up (p<0.001). Median time to reach EDSS 3 was 0.99 years for patients with BMI ≥30 kg/m2 and 1.46 years for non-obese patients. Risk to reach EDSS 3 over 6 years was significantly increased in patients with BMI ≥30 kg/m2 compared with patients with BMI <30 kg/m2 after adjustment for sex, age, smoking (HR 1.87; 95% CI 1.3 to 2.6; log-rank test p<0.001) and independent of disease-modifying therapies. Obesity was not significantly associated with higher relapse rates, increased number of contrast-enhancing MRI lesions or higher MRI T2 lesion burden over 6 years of follow-up. Conclusions: Obesity in newly diagnosed patients with MS is associated with higher disease severity and poorer outcome. Obesity management could improve clinical outcome of MS.

J Neurol Neruosurg Psychiatry. 2023 Jan;94(1):57-61

Has Silemek AC, Nolte G, Pöttgen J, Engel AK, Heesen C, Gold SM, Stellmann JP

Topological reorganization of brain network might contribute to the resilience of cognitive functioning in mildly disabled relapsing remitting multiple sclerosis.

J Neurosci Res. 2023 Jan;101(1):143-161

Wenzel L, Heesen C, Peper J, Grentzenberg K, Faßhauer E, Scheiderbauer J, Thale F, Meyer B, Köpke S, Rahn AC.

An interacitive web-based programme on relapse management for people with multiple sclerosis (POWER@MS2) – development, feasibility, and pilot testing of a complex intervention.

Introduction: Despite the lack of high-quality evidence regarding its long-term effectiveness, intravenous corticosteroid therapy is recommended as the standard treatment of acute multiple sclerosis relapses in Germany. High financial expenses and the equivalent effectiveness of oral corticosteroid therapy contrast with this trend. There is an urgent need to provide patients with evidence-based and comprehensible information on relapse management and to actively involve patients in relapse treatment decisions. Web-based decision support on relapse management could be an effective measure to empower people with multiple sclerosis making informed treatment decisions. Objectives: To develop a web-based programme on relapse management for people with multiple sclerosis and evaluate the feasibility and acceptability of the intervention. Methods: The study followed the first two phases of the UK Medical Research Council Framework for complex interventions. The first phase involved the development of an interactive web-based programme on relapse management. The second phase focused on the feasibility and pilot testing of the programme with people with multiple sclerosis and experts with a professional background in multiple sclerosis. Data was obtained using questionnaires with closed- and open-ended questions as well as qualitative semi-structured telephone interviews. Quantitative data was analyzed descriptively, whereas qualitative data was clustered by topic. Results: Feasibility of the intervention programme was tested with 10 people with multiple sclerosis and 10 experts. Feasibility testing indicated good practicability and acceptance of the content. After revision, the programme was piloted with seven people with multiple sclerosis and three experts. The results showed good acceptance in both groups. Based on the feedback, a final revision was performed. Conclusion: Feasibility and pilot testing indicated good user-friendliness, acceptance, and practicability of the programme. The programme is currently evaluated in a randomized controlled trial (Registration Number on ClinicalTrials.gov: NCT04233970). It is expected that the programme will have a positive impact on patients‘ relapse management and strengthen their autonomy and participation.

Front Neurol. 2022 Sep 23;13:914814

Dannemann M, Milaneschi Y, Yermakovich D, Stiglbauer V, Kariis HM, Krebs K, Friese MA, Otte C; Estonian Biobank Research Team, Lehto K, Penninx BWJH, Kelso J, Gold SM.

Neandertal introgression partitions the genetic landscape of neuropsychiatric disorders and associated behavioral phenotypes.

Despite advances in identifying the genetic basis of psychiatric and neurological disorders, fundamental questions about their evolutionary origins remain elusive. Here, introgressed variants from archaic humans such as Neandertals can serve as an intriguing research paradigm. We compared the number of associations for Neandertal variants to the number of associations of frequency-matched non-archaic variants with regard to human CNS disorders (neurological and psychiatric), nervous system drug prescriptions (as a proxy for disease), and related, non-disease phenotypes in the UK biobank (UKBB). While no enrichment for Neandertal genetic variants were observed in the UKBB for psychiatric or neurological disease categories, we found significant associations with certain behavioral phenotypes including pain, chronotype/sleep, smoking and alcohol consumption. In some instances, the enrichment signal was driven by Neandertal variants that represented the strongest association genome-wide. SNPs within a Neandertal haplotype that was associated with smoking in the UKBB could be replicated in four independent genomics datasets.Our data suggest that evolutionary processes in recent human evolution like admixture with Neandertals significantly contribute to behavioral phenotypes but not psychiatric and neurological diseases. These findings help to link genetic variants in a population to putative past beneficial effects, which likely only indirectly contribute to pathology in modern day humans. 

Transl Psychiatry. 2022 Oct5;12(1):433

Fründt O, Fadhel M, Heesen C, Seddiq Zai S, Gerloff C, Vettorazzi E, Pöttgen J, Buhmann C.

Do Impulse Control Disorders Impair Car Driving Performance in Patients with Parkinson’s Disease?

Background: Based on data regarding the prevalence of Parkinson’s disease (PD), the prevalence of impulsive control disorders (ICD) in PD, and the percentage of PD patients driving a car, it has to be assumed that at least 50,000 PD patients with ICD in Germany actively drive a car. However, these patients might be at risk for unsafe driving due to ICD-related dysfunctions such as failure to resist an impulse or temptation, to control an act or other altered neurobehavioral processes. Objective: This study determines the influence of ICD on driving ability in PD. Methods: We prospectively compared driving simulator performance of 23 PD patients with and 23 matched patients without ICD. ICD had to be socially compensated and presence was defined clinically for primary and questionnaire-based (QUIP-RS) for post-hoc analyses. Furthermore, between-group comparisons of driving-relevant neuropsychological tests were executed. Results: Except from a lower blinking frequency when changing lanes, overall driving safety of patients with ICD did not differ significantly from those without-regardless of the clinical or QUIP-RS-based ICD definition. ICD severity did not correlate with driving performance, but the latter correlated significantly with mean reaction times and certain neuropsychiatric tests (MoCA, TMT-A, TAP-M „flexibility“ and DBQ „error“). Conclusion: Clinically compensated ICD does not seem to impair driving safety in PD patients. Rather, cognitive and attentional deficits appear to be clinical markers for driving uncertainty.

J Parkinsons Dis. 2022;12(7):2261-2275

Krause N, Riemann-Lorenz K, Rahn AC, Pöttgen J, Köpke S, Meyer B, Thale F, Temmes H, van de Loo M, Gold SM, Heesen C.

„That would have been the perfect thing after diagnosis“: development of a digital lifestyle management application in multiple sclerosis.

Background: A multiple sclerosis (MS) diagnosis urges decision-making on immunotherapies, while persons with MS (PwMS) need to develop a coping concept in parallel. At this stage, PwMS ask how they themselves may contribute to controlling the disease. Evidence suggests that maintaining a healthy lifestyle (e.g. physical activity and stress management) is a key factor for healthy aging and preserving activity, while data on MS are complex. Objectives: Following the Medical Research Council framework, this study aimed to develop and investigate the feasibility of a new digital health application that conveys evidence-based patient information about lifestyle factors in MS and engages PwMS in relevant behaviour change techniques. Methods: Based on a digital health application promoting lifestyle management in breast cancer survivors, an MS-specific adaptation (‚levidex‘) was developed. Feasibility was tested with 15 PwMS and eight MS experts. Subsequently, a six-week pilot study with eight PwMS was conducted. All participants provided feedback on practicability and acceptability via a questionnaire and took part in a semi-structured telephone interview. Levidex was revised after each test phase. Results: The final levidex tool includes 16 modules, 177 references and several other functions. Feasibility results showed that PwMS and MS experts perceived levidex as understandable (14 out of 15; 6 out of 8), trustworthy (15 out of 15; 8 out of 8), and relevant (10 out of 15; 8 out of 8). Interviews revealed potential for improvement regarding the length and complexity of some content. Piloting of the revised version confirmed good feasibility and high acceptance. Most participants felt inspired to initiate (7 out of 8) or had already implemented (5 out of 8) lifestyle changes after working with levidex. Conclusion: Results suggest that levidex is feasible and well-accepted by PwMS and MS experts. It might be a useful tool to support PwMS in adapting to their diagnosis and initiating health-promoting lifestyle changes.

Ther Adv Neurol Disord. 2022 Sep 6;15:17562864221118729

Sippel A, Riemann-Lorenz K, Pöttgen J, Wiedemann R, Drixler K, Bitzer EM, Holmberg C, Lezius S, Heesen C.

Validation of the German eHealth impact questionnaire for online health information users affected by multiple sclerosis.

Background: Persons with multiple sclerosis (MS) are confronted by an overwhelming amount of online health information, which can be valuable but also vary in quality and aim. Therefore, it is of great importance for developers and providers of eHealth information to understand its impact on the users. The eHealth Impact Questionnaire (eHIQ) has been developed in the United Kingdom to measure the potential effects of health and experimental information websites. This contains user’s general attitudes towards using the internet to gain health information and attitudes towards a specific health related website. The self-complete questionnaire is divided into two independently administered and scored parts: the 11-item eHIQ part 1 and the 26-item eHIQ part 2. This study aimed to validate the psychometric properties of the German version of the eHealth Impact Questionnaire (eHIQ-G). Methods: 162 people with multiple sclerosis browsed one of two possible websites containing information on MS and completed an online survey. Internal consistency was assessed by Cronbach’s alpha and structural validity by Confirmatory Factor Analysis. Construct validity was examined by assessing correlations with the reference instruments eHealth Literacy Questionnaire and the General Self-Efficacy Scale measuring related, but dissimilar constructs. Moreover, we investigated the mean difference of the eHIQ-G score between the two websites. Data were analyzed using SPSS and AMOS software. Results: The eHIQ-G subscales showed high internal consistency with Cronbach’s alpha from 0.833 to 0.885. The 2-factor model of eHIQ part 1 achieved acceptable levels of goodness-of-fit indices, whereas the fit for the 3-factor model of eHIQ part 2 was poor and likewise for the alternative modified models. The correlations with the reference instruments were 0.08-0.62 and as expected. Older age was related with lower eHIQ part 1 score, whereas no significant effect was found for education on eHIQ part 1. Although not significant, the website ‚AMSEL‘ reached higher mean scores on eHIQ part 2. Conclusions: The eHIQ-G has good internal consistency, and sufficient structural and construct validity. This instrument will facilitate the measurement of the potential impact of eHealth tools.

BMC Med Inform Decis Mak. 2022 Aug 16;22(1):219

Roig MB, Krotka P, Burman CF, Glimm E, Gold SM, Hees K, Jacko P, Koeig F, Magirr D, Mesenbrink P, Viele K, Posch M.

On model-based time trend adjustments in platform trials with non-concurrent controls.

Background: Platform trials can evaluate the efficacy of several experimental treatments compared to a control. The number of experimental treatments is not fixed, as arms may be added or removed as the trial progresses. Platform trials are more efficient than independent parallel group trials because of using shared control groups. However, for a treatment entering the trial at a later time point, the control group is divided into concurrent controls, consisting of patients randomised to control when that treatment arm is in the platform, and non-concurrent controls, patients randomised before. Using non-concurrent controls in addition to concurrent controls can improve the trial’s efficiency by increasing power and reducing the required sample size, but can introduce bias due to time trends. Methods: We focus on a platform trial with two treatment arms and a common control arm. Assuming that the second treatment arm is added at a later time, we assess the robustness of recently proposed model-based approaches to adjust for time trends when utilizing non-concurrent controls. In particular, we consider approaches where time trends are modeled either as linear in time or as a step function, with steps at time points where treatments enter or leave the platform trial. For trials with continuous or binary outcomes, we investigate the type 1 error rate and power of testing the efficacy of the newly added arm, as well as the bias and root mean squared error of treatment effect estimates under a range of scenarios. In addition to scenarios where time trends are equal across arms, we investigate settings with different time trends or time trends that are not additive in the scale of the model. Results: A step function model, fitted on data from all treatment arms, gives increased power while controlling the type 1 error, as long as the time trends are equal for the different arms and additive on the model scale. This holds even if the shape of the time trend deviates from a step function when patients are allocated to arms by block randomisation. However, if time trends differ between arms or are not additive to treatment effects in the scale of the model, the type 1 error rate may be inflated. Conclusions: The efficiency gained by using step function models to incorporate non-concurrent controls can outweigh potential risks of biases, especially in settings with small sample sizes. Such biases may arise if the model assumptions of equality and additivity of time trends are not satisfied. However, the specifics of the trial, scientific plausibility of different time trends, and robustness of results should be carefully considered.

BMC Med Res Methodol. 2022 Aug 15;22(1):228

Rothammer N, Woo MS, Bauer S, Binkle-Ladisch L, Di Liberto G, Egervari K, Wagner I, Haferkamp U, Pless O, Merkler D, Engler JB, Friese MA.

G9a dictates neuronal vulnerability to inflammatory stress via transcriptional control of ferroptosis.

Neuroinflammation leads to neuronal stress responses that contribute to neuronal dysfunction and loss. However, treatments that stabilize neurons and prevent their destruction are still lacking. Here, we identify the histone methyltransferase G9a as a druggable epigenetic regulator of neuronal vulnerability to inflammation. In murine experimental autoimmune encephalomyelitis (EAE) and human multiple sclerosis (MS), we found that the G9a-catalyzed repressive epigenetic mark H3K9me2 was robustly induced by neuroinflammation. G9a activity repressed anti-ferroptotic genes, diminished intracellular glutathione levels, and triggered the iron-dependent programmed cell death pathway ferroptosis. Conversely, pharmacological treatment of EAE mice with a G9a inhibitor restored anti-ferroptotic gene expression, reduced inflammation-induced neuronal loss, and improved clinical outcome. Similarly, neuronal anti-ferroptotic gene expression was reduced in MS brain tissue and was boosted by G9a inhibition in human neuronal cultures. This study identifies G9a as a critical transcriptional enhancer of neuronal ferroptosis and potential therapeutic target to counteract inflammation-induced neurodegeneration.

Sci Adv. 2022 Aug 5;8(31)

Beckmann H, Heesen C, Augustin M, Blome C.

The 27-Item Multiple Sclerosis Quality of Life Questionnaire: A New Brief Measure Including Treatment Burden and Work Life.

Background: Treatment- and work-related aspects have been neglected in health-related quality of life (HRQOL) measures in multiple sclerosis (MS). We aimed to develop a brief instrument covering all important impairment-, activity-, participation-, and treatment-related aspects for use in research and practice. Methods: The 27-item Multiple Sclerosis Quality of Life Questionnaire (MS-QLQ27) was developed using open item collection, a multidisciplinary expert panel, and cognitive pretesting. It was evaluated for reliability, construct validity, and responsiveness in 100 patients presenting with relapse (84 at follow-up ~14 days later). Construct validity was analyzed by correlating the MS-QLQ27 with the disease-specific Hamburg Quality of Life Questionnaire in MS (HAQUAMS) and generic HRQOL instruments. The Expanded Disability Status Scale (EDSS) was used to analyze known-groups validity. Responsiveness was determined as the correlation of changes in MS-QLQ27 scores with changes in validation criteria. Results: Internal consistency was high (Cronbach α = 0.94 at baseline and 0.93 at follow-up). Convergent validity was supported by direction and magnitude of associations with disease-specific and generic instruments. Correlations with change in convergent criteria were strong, indicating responsiveness. The HAQUAMS showed the strongest associations with the MS-QLQ27. The MS-QLQ27 showed the highest effect size compared with other patient-reported outcomes and the EDSS. It successfully distinguished between levels of disease severity. Conclusions: These results indicate that the MS-QLQ27 is a reliable, valid, and highly responsive instrument for assessing HRQOL during relapse evolution in MS. Its advantages are that it is brief yet comprehensive, covering work- and treatment-related aspects not addressed in previous measures.

Int J MS Care. 2022 Jul-Aug;24(4):147-153

Wisgalla A, Ramien C, Streitz M, Schlickeiser S, Lupu AR, Diemert A, Tolosa E, Arck PC, Bellmann-Strobl J, Siebert N, Heesen C, Paul F, Friese MA, Infante-Duarte C, Gold SM.

Alterations of NK Cell Phenotype During Pregnancy in Multiple Sclerosis.

In multiple sclerosis (MS), relapse rate is decreased by 70-80% in the third trimester of pregnancy. However, the underlying mechanisms driving this effect are poorly understood. Evidence suggests that CD56^bright NK cell frequencies increase during pregnancy. Here, we analyze pregnancy-related NK cell shifts in a large longitudinal cohort of pregnant women with and without MS, and provide in-depth phenotyping of NK cells. In healthy pregnancy and pregnancy in MS, peripheral blood NK cells showed significant frequency shifts, notably an increase of CD56^bright NK cells and a decrease of CD56^dim NK cells toward the third trimester, indicating a general rather than an MS-specific phenomenon of pregnancy. Additional follow-ups in women with MS showed a reversal of NK cell changes postpartum. Moreover, high-dimensional profiling revealed a specific CD56^bright subset with receptor expression related to cytotoxicity and cell activity (e.g., CD16⁺ NKp46^high NKG2D^high NKG2A^high phenotype) that may drive the expansion of CD56^bright NK cells during pregnancy in MS. Our data confirm that pregnancy promotes pronounced shifts of NK cells toward the regulatory CD56^bright population. Although exploratory results on in-depth CD56^bright phenotype need to be confirmed in larger studies, our findings suggest an increased regulatory NK activity, thereby potentially contributing to disease amelioration of MS during pregnancy.

Front Immunol. 2022 Jul 4;13:907994.

Schubert C, Schulz K, Träger S, Plath AL, Omriouate A, Rosenkranz SC, Morellini F, Friese MA, Hirnet D.

Neuronal Adenosine A1 Receptor is Critical for Olfactory Function but Unable to Attenuate Olfactory Dysfunction in Neuroinflammation.

Adenine nucleotides, such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), as well as the nucleoside adenosine are important modulators of neuronal function by engaging P1 and P2 purinergic receptors. In mitral cells, signaling of the G protein-coupled P1 receptor adenosine 1 receptor (A1R) affects the olfactory sensory pathway by regulating high voltage-activated calcium channels and two-pore domain potassium (K2P) channels. The inflammation of the central nervous system (CNS) impairs the olfactory function and gives rise to large amounts of extracellular ATP and adenosine, which act as pro-inflammatory and anti-inflammatory mediators, respectively. However, it is unclear whether neuronal A1R in the olfactory bulb modulates the sensory function and how this is impacted by inflammation. Here, we show that signaling via neuronal A1R is important for the physiological olfactory function, while it cannot counteract inflammation-induced hyperexcitability and olfactory deficit. Using neuron-specific A1R-deficient mice in patch-clamp recordings, we found that adenosine modulates spontaneous dendro-dendritic signaling in mitral and granule cells via A1R. Furthermore, neuronal A1R deficiency resulted in olfactory dysfunction in two separate olfactory tests. In mice with experimental autoimmune encephalomyelitis (EAE), we detected immune cell infiltration and microglia activation in the olfactory bulb as well as hyperexcitability of mitral cells and olfactory dysfunction. However, neuron-specific A1R activity was unable to attenuate glutamate excitotoxicity in the primary olfactory bulb neurons in vitro or EAE-induced olfactory dysfunction and disease severity in vivo. Together, we demonstrate that A1R modulates the dendro-dendritic inhibition (DDI) at the site of mitral and granule cells and impacts the processing of the olfactory sensory information, while A1R activity was unable to counteract inflammation-induced hyperexcitability. 

Front Cell Neurosci. 2022 Jun 30;16:912030

Basso L, Boecking B, Neff P, Brueggemann P, El-Ahmad L, Brasanac J, Rose M, Gold SM, Mazurek B

Negative Associations of Stress and Anxiety Levels with Cytotoxic and Regulatory Natural Killer Cell Frequency in Chronic Tinnitus.

Background: Depression and anxiety are known to be associated with stress-induced changes in the immune system. Bothersome tinnitus can be related to stress and often co-occurs with depression and anxiety. This study investigates associations of psychological and audiological tinnitus-related factors with inflammatory parameters and immune cell subsets in chronic tinnitus patients as well as treatment-related effects. Methods: This longitudinal study of inpatients treated with compact multimodal tinnitus-specific cognitive behavioral therapy included four repeated measurement sessions: baseline (N = 41), treatment end, 7.8-week (N = 35), and 13.8-week follow-up (N = 34). Data collection included audiometric testing, blood sampling, and psychometric questionnaires: Tinnitus Handicap Inventory (THI), Perceived Stress Questionnaire (PSQ-20), and Hospital Anxiety Depression Scale (HADS). Flow cytometry was used to analyze immune cell subsets. Statistical analyses comprised correlation and network analysis (cross-sectional), and linear mixed effect models (longitudinal). Results: Bootstrapped network analysis showed negative averaged cross-sectional associations of cytotoxic natural killer (NKc) cell frequency (CD56 + CD16+) and PSQ-20 (-0.21 [-0.48, 0]) and of regulatory natural killer (NKreg) cell frequency (CD56 + CD16dim/-) and HADS anxiety (-0.14 [-0.38, 0]). No significant treatment effects were found. A negative predictive effect of baseline PSQ-20 scores (β = -6.22 [-12.18, -0.26], p = 0.041) and a positive predictive effect of baseline ferritin levels (β = 8.90 [2.76, 15.03], p = 0.004) on NKc cell frequency across the repeated measurement sessions were observed. Conclusion: We observed negative relationships between perceived stress levels and NKc cell frequency and between anxiety levels and NKreg cell frequency in chronic tinnitus patients. These exploratory results suggest stress-/anxiety-related immune alterations in bothersome tinnitus but need to be tested in further confirmatory studies with larger sample sizes. The potential of NK cells as biomarkers of emotional distress in chronic tinnitus should be further investigated.

Front Psychol. 2022 Jun 23;13:871822

Kaufmann M, Schaupp AL, Sun R, Coscia F, Dendrou CA, Cortes A, Kaur G, Evans HG, Mollbrink A, Navarro JF, Sonner JK, Mayer C, DeLuca GC, Lundeberg J, Matthews PM, Attfield KE, Friese MA, Fugger L.

Identification of early neurodegenerative pathways in progressive multiple sclerosis.

Progressive multiple sclerosis (MS) is characterized by unrelenting neurodegeneration, which causes cumulative disability and is refractory to current treatments. Drug development to prevent disease progression is an urgent clinical need yet is constrained by an incomplete understanding of its complex pathogenesis. Using spatial transcriptomics and proteomics on fresh-frozen human MS brain tissue, we identified multicellular mechanisms of progressive MS pathogenesis and traced their origin in relation to spatially distributed stages of neurodegeneration. By resolving ligand-receptor interactions in local microenvironments, we discovered defunct trophic and anti-inflammatory intercellular communications within areas of early neuronal decline. Proteins associated with neuronal damage in patient samples showed mechanistic concordance with published in vivo knockdown and central nervous system (CNS) disease models, supporting their causal role and value as potential therapeutic targets in progressive MS. Our findings provide a new framework for drug development strategies, rooted in an understanding of the complex cellular and signaling dynamics in human diseased tissue that facilitate this debilitating disease. 

Nat Neurosci. 2022 Jul;25(7):944-955

Ghaidar D, Sippel A, Riemann-Lorenz K, Kofahl C, Morrison R, Kleiter I, Schmidt S, Dettmers C, Schulz H, Heesen C.

Experiences of persons with multiple sclerosis with rehabilitation: A qualitative study interview.

Background: Managing multiple sclerosis (MS) includes different treatment approaches. Rehabilitation is a key strategy in MS for improving functioning, activity and participation. As part of a larger study on overall patient experiences with different treatment approaches, this study aims to give an overview of different patients‘ experiences and perspectives on inpatient rehabilitation in MS. Methods: We conducted problem-centered interviews in 50 persons with MS in Germany, of whom most had relapsing-remitting MS. We used the maximum variation sampling method during recruitment. Data were analyzed thematically. Results: As a result of the analysis, three major themes were identified: 1) factors contributing to the decision-making concerning rehabilitation, 2) experience with the rehabilitation setting, 3) benefits of rehabilitation treatments. The treating physicians‘ attitude had a major impact on the decision to either opt for rehabilitation or not. Setting goals prior to rehabilitation was given a high priority. Exchanging experiences with other persons with MS presented a major benefit from rehabilitation while for some being separated from regular daily life resulted in a more ambiguous attitude ranging from appreciation of escaping daily hassles to substantial behavioral change management. Conclusion: Patients reported various experiences in the process of decision-making with regard to rehabilitation. Physicians´ advice, goal setting and the selection of the most suitable rehabilitation clinic were considered most relevant.

BMC Health Serv Res. 2022 Jun 11;22(1):770

Elkalhii-Wilhelm S, Sippel A, Riemann-Lorenz K, Kofahl C, Scheiderbauer J, Arnade S, Kleiter I, Schmidt S, Heesen C.

Experiences of persons with Multiple Sclerosis with lifestyle adjustment: A qualitative interview study.

Background: Persons with Multiple Sclerosis (pwMS) follow individual strategies to cope with this highly heterogeneous disease. As surveys show, lifestyle habits play an important role in pwMS. However, little is known about individual experiences of pwMS with different lifestyle adjustment strategies.
Objective: This study aims to describe and understand individual experiences of pwMS with lifestyle adjustments. Methods: Semi-structured interviews were conducted with 50 pwMS in Germany. Criteria for inclusion were age ≥ 18 years and a diagnosis of relapsing-remitting Multiple Sclerosis. Data were analyzed inductively and deductively according to a six-step thematic analysis. Results: The three main themes for experience-based lifestyle adjustments were: 1) nutrition and supplements, 2) exercise and physical activity, and 3) stress management. Influencing factors on the decision-making process such as active disease management, information and advice, desire for mental health and social support, and the wish for self-determination were identified. Impacts of starting or maintaining lifestyle habits included, for example, MS-specific, general, and mental health benefits, the development of coping strategies, social support, and barriers that led to a termination of lifestyle adjustments. Conclusion: This study provides a rich and nuanced amount of experiences of pwMS with lifestyle adjustments and leads to three important conclusions: 1) Further research is warranted to better describe the perceived effects of lifestyle habits on MS symptoms and progression, in particular with regard to nutrition and stress reduction; 2) patient education in MS should include the available evidence on lifestyle management and 3) patients need to be actively supported in changing their lifestyle behavior.

PLoS One. 2022 May 27;17(5):e0268988.

Steinberg L, Peper J, Köpke S, Solari A, Giordano A, Gold SM, Hellwig K, Heesen C, Rahn AC.

Motherhood choice in multiple sclerosis (MoMS) development and piloting of patient-reported outcome measures.

Background: Multiple sclerosis (MS) particularly affects women between the age of 20 and 40. Therefore, pregnancy is often an important issue for women with MS (wwMS), but misunderstandings, misinformation, and uncertainties about MS and pregnancy are common. We developed and pilot-tested two questionnaires, one on knowledge (MCKQ), and one on attitudes, coping strategies and worries (MPWQ) of wwMS regarding pregnancy. Methods: This mixed-methods study followed the MRC framework for the development and evaluation of complex interventions. Two questionnaires were developed based on an earlier questionnaire and a qualitative study, cognitively debriefed and pilot tested in a web-based survey. Qualitative data were analysed using thematic analysis. The psychometric analysis included item difficulty and reliability (for both questionnaires), convergent validity assessment and exploratory factor analysis (EFA) (for MPWQ). Results: The qualitative study (three focus groups and interviews with 15 wwMS overall and interviews with 4 experts) revealed several topics requiring evidence-based decision support. A multidisciplinary panel produced the 16-item MCKQ and the 39-item MPWQ. The cognitive debriefing of both questionnaires went smoothly. Of 128 wwMS who approached the survey, 95 (74%) completed the MCKQ and 89 (70%) the MPWQ. The mean age of wwMS was 36.7 years, 88% had a relapsing MS, and 32% had no children. Item difficulty, reliability and convergent validity were acceptable for both questionnaires. The EFA did not confirm the three-scale structure (attitude, worries and coping). Conclusion: The developed questionnaires fill a gap in self-reported measures of knowledge (MCKQ) and attitudes, worries, and coping strategies (MPWQ) of wwMS regarding motherhood. Further refinement of the MPWQ and validation in a larger sample is warranted before its large-scale use.

Mult Scler Relat Disord. 2022 Jul;63:103831

Ri Chae W, Nübel J, Baumert J, Gold SM, Otte C.

Association of depression and obesity with C-reactive protein in Germany: a large nationally representative study.

Introduction: Depression and obesity often occur comorbidly, and once both are present, they further increase the risk of developing other medical comorbidities, likely due to the underlying chronic low-grade inflammation. We investigated to what extent depression and obesity are associated with levels of high-sensitivity C-reactive protein (hsCRP) in a nationally representative sample of the German adult population. Methods: We analyzed data from the German Health Interview and Examination Survey for Adults (DEGS1, N = 7115), and its mental health module (DEGS1-MH; N = 4483). Two different depression measures were used: current depressive symptoms assessed by the self-administered German version of the Patient Health Questionnaire-9 and major depressive disorder (MDD) in the last 12 months assessed by a modified German version of the Composite International Diagnostic Interview. Obesity was defined by body mass index calculated from measured data. Associations with log(x+1)-transformed hsCRP levels were analyzed using multivariable linear regression models. Results: Obese participants with depressive symptoms had significantly higher hsCRP compared to non-obese participants with depressive symptoms adjusted for sociodemographic and behavioral variables and medication use. In non-obese individuals, depressive symptoms were inversely associated with hsCRP whereas MDD was not associated with hsCRP after adjustment for covariates. Additional analyses suggested symptom-specific associations of hsCRP as higher levels were linked to fatigue (β = 0.10, p < .001) while lower levels were linked to cognitive problems (β = -0.09, p < .001). Low SES, current smoking, lower levels of physical exercise, and the use of anti-inflammatory/anti-rheumatic medication and antidepressants were additional determinants of hsCRP in the fully adjusted models. Conclusions: Our data suggest that obesity status is more strongly associated with increased inflammation than depressive symptoms or MDD. The relationship between depression and hsCRP in our population-based sample is substantially influenced by obesity status as well as other medical factors, lifestyle, and socioeconomic status. Furthermore, our findings suggest that the association between hsCRP and depression is symptom-specific rather than generalized.

Brain Behav Immun. 2022 Jul;103:223-231

Heesen C, Mokry C, Salmen A, Hegen H, Mäurer M, Warnke C, Gehring K, Berthele A, Meier U.

German guideline for diagnosis and treatment of multiple sclerosis – a survey focusing neurologists in daily practise.

We performed a web-based survey among German-speaking neurologists to evaluate the acceptance of the 2021 German guideline in the diagnosis and treatment of multiple sclerosis. Based on 327 replies in total, the current survey largely reproduced the findings of an earlier, smaller survey on the prefinal consultation version of the guideline and confirmed high acceptance rates. Half of the participants were practising neurologists. Neurologists from MS centers with more than 500 patients per year (n=26) were more critical of the guideline. They reiterated some of the criticisms of the previous feedback, and, in particular, felt that safety aspects are overemphasized in the guideline, thereby superseding early aggressive therapy. 

Mult Scler Relat Disord. 2022 Apr 25;63:103828

Sippel A, Scheiderbauer J, Eklund D, Arnade S, Schmidt S, Kleiter I, Morrison R, Kofahl C, Heesen C.

Development and evaluation of a website with patients experiences of multiple sclerosis: a mixed methods study.

Background: A variety of management options (e.g., disease-modifying therapy, lifestyle interventions, rehabilitation) are available for persons with relapsing-remitting multiple sclerosis (MS). Besides coping with the diagnosis, persons with MS have to make complex decisions, e.g., regarding disease-modifying therapies. In addition to factual information, reports of patient experiences may support other patients in their decision-making. Therefore, we developed a website presenting patient experiences illustrated by video, audio and text files. This study aimed to test the acceptability and usability of a website with patient experiences with MS. Methods: A mixed-methods approach was applied. A total of 69 participants visited the German „Patient Experiences with MS (PExMS)“ website and among them, 50 persons with MS and 6 experts completed an online survey. In total, 18 participants took part in telephone interviews or focus groups. Data from the survey were analysed using descriptive statistics. Qualitative data were analysed using thematic analysis. Results: Both quantitative and qualitative responses suggest that the PExMS website was viewed positively by patients and experts. 94% of persons with MS agreed that the information was comprehensible and reliable. 54% felt encouraged to share their health problems with others after having studied the website. 74% claimed to use the website if they had to make a decision regarding their health. Qualitative responses deduced from the website fell into 5 key themes: (1) web design, appearance, and functionality, (2) content, (3) usability, (4) satisfaction, and (5) loyalty. The search for persons of similar age and with comparable experiences was a major driving force to navigate the website. The material on the website was perceived as diverse, covering both positive and negative experiences in daily living with MS. All participants greatly appreciated having access to other people’s experiences online and judged the material on the website as particularly helpful in decision-making for disease-modifying therapies. Conclusions: The findings suggest that the PExMS website might have the potential to be a useful source of audio-visual information for persons with MS. Given the lack of websites available to patients with experiential information, health care professionals may be encouraged to routinely inform patients about this website at regular appointments.

BMC Neurol. 2022 Apr 20;22(1):146

Brasanac J, Hetzer S, Asseyer S, Kuchling J, Bellmann-Strobl J, Ritter K, Gamradt S, Scheel M, Haynes JD, Brandt AU, Paul F, Gold SM, Weygandt M.

Central stress processing, T-cell responsitivity to stress hormones and disease severity in multiple sclerosis.

Epidemiological, clinical and neuroscientific studies support a link between psychobiological stress and multiple sclerosis. Neuroimaging suggests that blunted central stress processing goes along with higher multiple sclerosis severity, neuroendocrine studies suggest that blunted immune system sensitivity to stress hormones is linked to stronger neuroinflammation. Until now, however, no effort has been made to elucidate whether central stress processing and immune system sensitivity to stress hormones are related in a disease-specific fashion, and if so, whether this relation is clinically meaningful. Consequently, we conducted two functional MRI analyses based on a total of 39 persons with multiple sclerosis and 25 healthy persons. Motivated by findings of an altered interplay between neuroendocrine stress processing and T-cell glucocorticoid sensitivity in multiple sclerosis, we searched for neural networks whose stress task-evoked activity is differentially linked to peripheral T-cell glucocorticoid signalling in patients versus healthy persons as a potential indicator of disease-specific CNS-immune crosstalk. Subsequently, we tested whether this activity is simultaneously related to disease severity. We found that activity of a network comprising right anterior insula, right fusiform gyrus, left midcingulate and lingual gyrus was differentially coupled to T-cell glucocorticoid signalling across groups. This network’s activity was simultaneously linked to patients‘ lesion volume, clinical disability and information-processing speed. Complementary analyses revealed that T-cell glucocorticoid signalling was not directly linked to disease severity. Our findings show that alterations in the coupling between central stress processing and T-cell stress hormone sensitivity are related to key severity measures of multiple sclerosis.

Brain Commun. 2022 Apr 4;4(2)

Freund M, Schiffmann I, Rahn AC, Chard D, Lukas C, Scheiderbauer J, Sippel A, Heesen C.

Understanding Magnetic Resonance Imaging in Multiple Sclerosis (UMIMS): Development and Piloting of an Online Education Program About Magnetic Resonance Imaging for People With Multiple Sclerosis.

Background: People with multiple sclerosis (pwMS) lack sufficient magnetic resonance imaging (MRI) knowledge to truly participate in frequently occurring MRI-related therapy decisions. An evidence-based patient information (EBPI) about MRI is currently lacking. Objective: The aim of this study was to develop an evidence-based online education program about limitations and benefits of MRI for pwMS. Ultimately, our goal was to improve MRI risk-knowledge, empower pwMS, and promote shared decision-making. Methods: The program’s contents were based on literature research and a previous pilot study. It was revised following 2 evaluation rounds with pwMS, MRI experts and expert patients. In a pilot study, n = 92 pwMS received access to the program for 4 weeks. User experiences and acceptance, MRI knowledge (MRI-RIKNO 2.0 questionnaire) and emotions and attitudes toward MRI (MRI-EMA questionnaire) were assessed. Results were compared to a previous survey population of n = 508 pwMS without access to the program. Results: Participants rated the program as easy to understand, interesting, relevant, recommendable, and encouraging. In comparison to pwMS without access to the program, MRI risk-knowledge and perceived MRI competence were higher. Conclusion: Satisfaction with the program and good MRI-risk knowledge after usage demonstrates the need and applicability of EBPI about MRI in MS.

Front Neurol. 2022 Mar 28;13:856240

Fearey BC, Binkle L, Mensching D, Schulze C, Lohr C, Friese MA, Oertner TG, Gee CE.

A glibenclamide-sensitive TRPM4-mediated component von CA1 excitatory postsynaptic potentials appears in experimental autoimmune encephalomyelitis.

The transient receptor potential melastatin 4 (TRPM4) channel contributes to disease severity in the murine experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and to neuronal cell death in models of excitotoxicity and traumatic brain injury. As TRPM4 is activated by intracellular calcium and conducts monovalent cations, we hypothesized that TRPM4 may contribute to and boost excitatory synaptic transmission in CA1 pyramidal neurons of the hippocampus. Using single-spine calcium imaging and electrophysiology, we found no effect of the TRPM4 antagonists 9-phenanthrol and glibenclamide on synaptic transmission in hippocampal slices from healthy mice. In contrast, glibenclamide but not 9-phenanthrol reduced excitatory synaptic potentials in slices from EAE mice, an effect that was absent in slices from EAE mice lacking TRPM4. We conclude that TRPM4 plays little role in basal hippocampal synaptic transmission, but a glibenclamide-sensitive TRPM4-mediated contribution to excitatory postsynaptic responses is upregulated at the acute phase of EAE. 

Sci Rep. 2022 Apr 9;12(1)

Röhling HM, Althoff P, Arsenova R, Drebinger D, Gigengack N, Chorschew A, Kroneberg D, Rönnefarth M, Ellermeyer T, Rosenkranz SC, Heesen C, Behnia B, Hirano S, Kuwabara S, Paul F, Brandt AU, Schmitz-Hübsch T.

Proposal for Post Hoc Quality Control in Instrumented Motion Analysis Using Markerless Motion Capture: Development and Usability Study.

Background: Instrumented assessment of motor symptoms has emerged as a promising extension to the clinical assessment of several movement disorders. The use of mobile and inexpensive technologies such as some markerless motion capture technologies is especially promising for large-scale application but has not transitioned into clinical routine to date. A crucial step on this path is to implement standardized, clinically applicable tools that identify and control for quality concerns. Objective: The main goal of this study comprises the development of a systematic quality control (QC) procedure for data collected with markerless motion capture technology and its experimental implementation to identify specific quality concerns and thereby rate the usability of recordings. Methods: We developed a post hoc QC pipeline that was evaluated using a large set of short motor task recordings of healthy controls (2010 recordings from 162 subjects) and people with multiple sclerosis (2682 recordings from 187 subjects). For each of these recordings, 2 raters independently applied the pipeline. They provided overall usability decisions and identified technical and performance-related quality concerns, which yielded respective proportions of their occurrence as a main result. Results: The approach developed here has proven user-friendly and applicable on a large scale. Raters‘ decisions on recording usability were concordant in 71.5%-92.3% of cases, depending on the motor task. Furthermore, 39.6%-85.1% of recordings were concordantly rated as being of satisfactory quality whereas in 5.0%-26.3%, both raters agreed to discard the recording. Conclusions: We present a QC pipeline that seems feasible and useful for instant quality screening in the clinical setting. Results confirm the need of QC despite using standard test setups, testing protocols, and operator training for the employed system and by extension, for other task-based motor assessment technologies. Results of the QC process can be used to clean existing data sets, optimize quality assurance measures, as well as foster the development of automated QC approaches and therefore improve the overall reliability of kinematic data sets.

JMIR Hum Factors. 2022 Apr 1;9(2)

Dietmaier JM, von dem Knesebeck O, Heesen C, Kofahl C

Personality and its association with self-management in multiple sclerosis.

Background: In a healthcare system which aims to empower the patient, self-management becomes increasingly important. In Multiple Sclerosis, an effective self-management is associated with various favorable health-related outcomes like improvement in quality of life, the reduction of depression and anxiety symptoms, and reduced healthcare costs. This study investigates the association between the Big Five personality traits and self-management including activity in self-help groups. Methods: People with MS were recruited via several paths within Germany (e.g. medical practices, social events and the German MS society). The final study sample consisted of 682 participants who answered a multidimensional questionnaire. This comprised the Big-Five-Inventory-10 for personality, the Health Education Impact Questionnaire (heiQ) for self-management competencies, questions for participation in self-help groups, and socio-demographic and clinical variables. Results: Multivariate regression analyses showed that personality could explain a greater amount of variance of self-management than socio-demographic and clinical variables. Neuroticism was the strongest predictor and correlated negatively with all heiQ-dimensions of self-management. In contrast, in logistic regression analysis none of the Big Five traits became significant in predicting the activity in self-help groups. Conclusion: As expected, personality plays an important role regarding self-management. Ideally, a time-saving personality assessment should be considered in routine clinical practice to identify patients at risk; however, at a minimum, personality traits should be considered in consultations with their neurologists. They may need help to understand the benefits of effective self-management and should receive support to improve their self-management skills and to reduce their neuroticism to lower the risk of secondary complications.

Mult Scler Relat Disord. 2022 May;61:103752

Ambra MG, Pöttgen J, Anglada E, Menendez R, Hoyer J, Giordano A, Pakenham KI, Galan I, Solari A.

Cross-Country Adaptation of a Psychological Flexibility Measure: The Comprehensive Assessment of Acceptance and Commitment Therapy Processes.

Purpose: The Comprehensive assessment of Acceptance and Commitment Therapy (ACT) processes (CompACT) is a 23-item self-report questionnaire assessing psychological flexibility, which is the overarching construct underpinning the ACT framework. We conducted a two-phase project to develop validated versions of the CompACT in three languages: phase 1-cross-cultural adaptation; and phase 2-psychometric validation of the questionnaire for use in Italy, Germany and Spain. This article focuses on the first phase. Methods: We translated and culturally adapted the CompACT in the three target languages, following the ISPOR TCA Task Force guidelines. The process was overseen by a translation panel (three translators, at least two multiple sclerosis (MS) researchers and a lay person), ACT experts and clinicians from the research team of each country and the original CompACT developers. We debriefed the new questionnaire versions via face-to-face interviews with a minimum of four adults from the general population (GP) and four adults with MS in each country. Results: The translation-adaptation process went smoothly in the three countries, with some items (7 in Italy, 4 in Germany, 6 in Spain) revised after feedback from ACT experts. Cognitive debriefing showed that the CompACT was deemed easy to understand and score in each target country by both GP and MS adults. Conclusions: The Italian, German and Spanish versions of the CompACT have semantic, conceptual and normative equivalence to the original scale and good content validity. Our findings are informative for researchers adapting the CompACT and other self-reported outcome measures into multiple languages and cultures.

Int J Environ Res Public Health. 2022 Mar 8;19(6):3150

Heesen C, Rosenkranz SC.

Physical exercise in multiple sclerosis is not just a symptomatic therapy, it has a disease-modifying effect: No.

Mult Scler. 2022 May;28(6):861-862

Schneider A, Fasshauer E, Scheiderbauer J, Warnke C, Köpke S, Kasper J, Toussaint M, Temmes H, Hemmer B, Schiffmann I, Rahn AB, Heesen C.

Development and evaluation of evidence-based patient information handbooks about multiple sclerosis immunotherapies.

Background: Multiple sclerosis treatment options are increasing. Evidence-based patient information (EBPI) are therefore crucial to enable patient involvement in decision making. Based on earlier work on decision support, patient information handbooks on 8 MS immunotherapies were developed, piloted and evaluated with support from the German Clinical Competence Network MS and the German MS Society. Methods: Handbooks were structured according to EBPI concepts. Drafts were commented by patient representatives and neurologists with an MS expertise. Executive boards of the German MS Society and the Competence Network as well as pharmaceutical companies‘ feedback was included. Handbooks were distributed among MS neurologists by the German MS Society. Evaluation followed applying a mixed methods approach with interviews, focus groups and surveys. One survey addressed persons with MS (pwMS) based on a questionnaire included in each handbook. Neurologists who received printed patient handbooks were invited to give feedback in a second survey. Results: Eight handbooks were developed providing absolute and relative risk information in numbers and figures as well as monitoring needs and drug fact boxes. Despite the high amount of information and the display of low absolute risk reduction rates of treatments, handbooks were overall appreciated by pwMS (n=107) and mostly also by physicians (n=24). For more than 70% of the pwMS the information was new, understandable and supportive for decision making. But patients felt uncomfortable with relative risk information. However, response rates in the evaluation were low, exposing the challenges when implementing EBPI into clinical care. Therefore, conclusions must be considered preliminarily. Conclusion: EBPI on immunotherapies for MS seem feasible and are appreciated by patients and treating neurologists but more implementation research is needed.

Mult Scler Relat Disord. 2022 Apr;60:103728.

GENERATE

Clinical, serological and genetic predictors of response to immunotherapy in anti-IgLON5 disease.

Brain. 2023 Feb 13;146(2):600-611

Artmann A, Rahn AC, Köpke S, Thomalla G, Heesen C, Alegiani AC.

Risk communication in acute stroke patients – from qualitative data to a pilot randomised controlled trial.

Objectives: The probability of recurring strokes in patients with atrial fibrillation is high. Within 1.8 years, 6.6 % of the patients suffered a new stroke. While effective secondary prevention options exist, low adherence challenges effective medical treatment. The aim of our study was to examine the risk understanding of acute stroke patients and to find the best way to communicate risk reduction. Materials and methods: Risk communication had three formats: a text, a pictogram, and a cube diagram. All three were developed on the basis of the criteria of evidence-based patient information. Patients who were admitted to the stroke unit and diagnosed with acute stroke, assessed the information material. Data on secondary prevention using acetylsalicylic acid were taken as an example, with no reference to actual patient treatment. In a first step, we interviewed a focus group to check the feasibility of the questionnaire (qualitative study). In the second step, the information material was tested in a pilot randomized controlled trial. Results: Acute stroke patients (qualitative study, n=13) understood the information and were interested in numerical risk communication. The visualized representations were superior in terms of understandability of the numbers communicated (pilot randomized controlled trial, n=60, 50 % correct answers for question 1, p value of 0.502, and 55 % correct answers for question 2, p value of 0.338). Stroke-related neurologic deficits, measured with the National Institute of Health Stroke Scale (NIHSS) on admission, revealed a significant influence on the number of correct answers to stroke risk questions, whereas the type of stroke and education did not. Conclusions: Acute stroke patients were able to understand risk communication. Visualization helped them capture information on stroke risk. 

Z Evid Fortbild Qual Gesundhwes. 2022 Apr;169:19-27

Pöttgen J, Friede T, Lau S, Gold SM, Letsch C, Bender G, Flachenecker P, Heesen C, Penner IK.

Managing neuropsychological impairment in multiple sclerosis – Controlled study on a standardized metacognitive intervention (MaTiMS)

Objective: Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system of potential autoimmune origin that is frequently associated with neuropsychiatric symptoms and cognitive deficits, as well as with fatigue, stress and psychosocial burden. In the present controlled multi-centre trial we investigated whether two specific neuropsychological interventions (1. metacognitive training (MaTiMS); 2. computerized working memory training (BrainStim) in combination with MaTiMS) applied as add-on therapies to real life standard rehabilitation lead to increased benefit in self-perceived cognitive deficits (the primary outcome) in MS patients compared to standard rehab. Methods: 288 adult persons in three German rehab centers with a confirmed diagnosis of MS were sequentially allocated to one of the three intervention groups. 249 (87%) participants completed the post assessment and 187 (63%) the online survey after 12 months. Perceived cognitive deficits, mood, fatigue, coping, and activity were evaluated by self-reports and neuropsychological tests at baseline and 4 weeks postintervention. All self-reports were additionally administered digitally at three, six, and twelve months from baseline. Results: We could not show differential effects on the primary outcome between the intervention groups and the control group (p=.369, p=.934). Immediately after each intervention we could show beneficial time effects in all three groups on self-perceived cognitive deficits as well as on most of the other outcomes. The reported effects were however not sustained at 6 months follow-up. Conclusions: Our findings could not show an additional effect of specific cognitive training on cognitive deficit perception in MS. However, findings indicate that MS rehabilitation may improve patient reported outcomes in the short term. They also underline the need for concepts to maintain rehabilitation gains when patients return back home.

Mult Scler Relat Disord. 2022 Mar;59:103687.

Brasanac J, Gamradt S, Otte C, Milaneschi Y, Monzel AS, Picard M, Gold SM.

Cellular specificity of mitochondrial and immunometabolic features in major depression.

No abstract available.

Mol Psychiatry. 2022 May;27(5):2370-2371

Testud B, Delacour C, El Ahmadi AA, Brun G, Girard N, Duhamel G, Heesen C, Häußler V, Thaler C, Has Silemek AC, Stellmann JP

Brain grey matter perfusion in primary progressive multiple sclerosis: Mild decrease over years and regional associations with cognition and hand function.

Background: Extend and dynamic of neurodegeneration in progressive Multiple Sclerosis (MS) might be reflected by global and regional brain perfusion, an outcome at the intercept between structure and function. Here, we provide a first insight in the evolution of brain perfusion and its association with disability in primary progressive MS (PPMS) over several years. Methods: 77 persons with PPMS were followed over up to 5 years. Visits included a 3T MRI with pulsed Arterial spin labelling (ASL) perfusion, the Timed-25-Foot-Walk, 9-Hole-Peg-Test (NHPT), Symbol-Digit-Modalities-Test (SDMT) and Expanded Disability Status Scale (EDSS). We extracted regional cerebral blood flow surrogates and compared them to 11 controls. Analyses focused in cortical and deep gray matter, the change over time and associations with disability on regional and global level. Results: Baseline brain perfusion of patients and controls was comparable for the cortex (p=0.716) and deep grey matter (p=0.095). EDSS disability increased mildly (p=0.023) while brain perfusion decreased during follow up (p<0.001) and with disease duration (p=0.009). Lower global perfusion correlated with higher disability as indicated by EDSS, NHPT and Timed-25-Foot-Walk (p<0.001). The motor task NHPT showed associations with twenty gray matter regions. In contrast, better SDMT performance correlated with lower perfusion (p<0.001) in seven predominantly frontal regions indicating a functional maladaptation. Conclusion: Decreasing perfusion indicates a putative association with MS disease mechanisms such as neurodegeneration, reduced metabolism, and loss of resilience. A low alteration rate limits its use in clinical practice, but regional association patterns might provide a snapshot of adaptive and maladaptive functional reorganization

Eur J Neurol. 2022 Jun;29(6):1741-1752.

Hümmert MW, Schöppe LM, Bellmann-Strobl J, Siebert N, Paul F, Duchow A, Pellkofer H, Kümpfel T, Havla J, Jarius S, Wildemann B, Berthele A, Bergh FT, Pawlitzki M, Klotz L, Kleiter I, Stangel M, Gingele S, Weber MS, Faiss JH, Pul R, Walter A, Zettl U, Senel M, Stellmann JP, Häußler V, Hellwig K, Ayzenberg I, Aktas O, Ringelstein M, Schreiber-Katz O, Trebst C; Neuromyelitis Optica Study Group (NEMOS).

Costs and Health-Related Quality of Life in Patients with NMO Spectrum Disorders and MOG-Antibody-Associated Disease: CHANGE NOM Study.

Neurology. 2022 Mar 15;98(11):e1184-e1196

Krasemann S, Haferkamp U, Pfefferle S, Woo MS, Heinrich F, Schweizer M, Appelt-Menzel A, Cubukova A, Barenberg J, Leu J, Hartmann K, Thies E, Littau JL, Sepulveda-Falla D, Zhang L, Ton K, Liang Y, Matschke J, Ricklefs F, Sauvigny T, Sperhake J, Fitzek A, Gerhartl A, Brachner A, Geiger N, König EM, Bodem J, Franzenburg S, Franke A,Moese S, Müller FJ,Geisslinger G, Claussen C, Kannt A, Zaliani A, Gribbon P, Ondruschka B, Neuhaus W, Friese MA, Glatzel M, Pless O.

The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2.

Stem Cell Reports. 2022 Jan 3;S2213-6711(21)00650-0.

Rosenkranz SC, Häußler V, Kolster M, Willing A, Matschke J, Röcken C, Stürner K, Leypoldt F, Tolosa E, Friese MA.

Treating sarcoidosis-associated progressive multifocal leukoencephalopathy with infliximab.

Brain Commun. 2021 Dec 16;4(1)

Fleischer V, Ciolac D, Gonzalez-Escamilla G, Grothe M, Strauss S, Molina Galindo LS, Radetz A, Salmen A, Lukas C, Klotz L, Meuth SG, Bayas A, Paul F, Hartung HP, Heesen C, Stangel M, Wildemann B, Bergh FT, Tackenberg B, Kümpfel T, Zettl UK, Knop M, Tumani H, Wiendl H, Gold R, Bittner S, Zipp F, Groppa S, Muthuraman M; German Competence Network Multiple Sclerosis (KKNMS).

Subcortical volumes as early predictors of fatigue in multiple sclerosis.

Ann Neurol. 2021 Dec 30

Thaler C, Hartramph I, Stellmann JP, Heesen C, Bester M, Fiehler J, Gellißen S

T1 Relaxation Times in the Cortex and Thalamus Are Associated With Working Memory and Information Processing Speed in Patients with Multiple Sclerosis

Front Neurol. 2021 Dec 3;12:789812

Mokry C, Warnke C, Gehring K, Hegen H, Salmen A, Kraemer M, Kleiter I, Fasshauer E, Scheiderbauer J, Lühmann D, Köpke S, Berthele A, Heesen C

Implementation study of the 2021 German guideline for diagnosis and treatment of multiple sclerosis

Mult Scler Relat Disord. 2022 Jan;57:103434

Mayer-Arndt L, Schmitz-Hübsch T, Bellmann-Strobl J, Brandt A, Haynes J, Gold SM, Paul F, Weygandt M.

Neural Processes of Psychological Stress and Relaxation Predict the Future Evolution of Quality of Life in Multiple Sclerosis

Health-related quality of life (HRQoL) is an essential complementary parameter in the assessment of disease burden and treatment outcome in multiple sclerosis (MS) and can be affected by neuropsychiatric symptoms, which in turn are sensitive to psychological stress. However, until now, the impact of neurobiological stress and relaxation on HRQoL in MS has not been investigated. We thus evaluated whether the activity of neural networks triggered by mild psychological stress (elicited in an fMRI task comprising mental arithmetic with feedback) or by stress termination (i.e., relaxation) at baseline (T0) predicts HRQoL variations occurring between T0 and a follow-up visit (T1) in 28 patients using a robust regression and permutation testing. The median delay between T0 and T1 was 902 (range: 363-1,169) days. We assessed HRQoL based on the Hamburg Quality of Life Questionnaire in MS (HAQUAMS) and accounted for the impact of established HRQoL predictors and the cognitive performance of the participants. Relaxation-triggered activity of a widespread neural network predicted future variations in overall HRQoL (t = 3.68, p family-wise error [FWE]-corrected = 0.008). Complementary analyses showed that relaxation-triggered activity of the same network at baseline was associated with variations in the HAQUAMS mood subscale on an αFWE = 0.1 level (t = 3.37, p FWE = 0.087). Finally, stress-induced activity of a prefronto-limbic network predicted future variations in the HAQUAMS lower limb mobility subscale (t = -3.62, p FWE = 0.020). Functional neural network measures of psychological stress and relaxation contain prognostic information for future HRQoL evolution in MS independent of clinical predictors.Keywords: functional magnet resonance imaging (fMRI); multiple sclerosis; neuropsychiatric symptoms; psychological stress; quality of life.

Front Neurol 2021 Nov 23;12:753107.

Brasanac J, Ramien C, Gamradt S, Tänzer A, Glau L, Ritter K, Patas K, Agorastos A, Wiedemann K, Demiraley C, Fischer F, Otte C, Weygandt M, Gold SM.

Immune signature of multiple sclerosis-associated depression.

Brain Behav Immun. 2021 Dec 1;S0889-1591(21)00625-5.

Lagrèze W, Küchlin S, Ihorst G, Grotejohann B, Beisse F, Volkmann M, Heinrich S, Abrecht P, Ungewiss J, Wörner M, Hug M, Wolf S, Diem R, Tone study group (Stellmann, Heesen, Rosenkranz).

Safety and efficacy of erythropoietin for the treatment of patients with optic neuritis (TONE): a randomised, double-blind, multicentre, placebo-controlled study

Background: The human cytokine erythropoietin conveys neuroprotection in animal models but has shown ambiguous results in phase 2 clinical trials in patients with optic neuritis. We assessed the safety and efficacy of erythropoietin in patients with optic neuritis as a clinically isolated syndrome in a multicentre, prospective, randomised clinical trial.Methods: This randomised, placebo-controlled, double-blind phase 3 trial, conducted at 12 tertiary referral centres in Germany, included participants aged 18-50 years, within 10 days of onset of unilateral optic neuritis, with visual acuity of 0·5 or less, and without a previous diagnosis of multiple sclerosis. Participants were randomly assigned (1:1) to receive either 33 000 IU erythropoietin or placebo intravenously for 3 days as an adjunct to high-dose intravenous methylprednisolone (1000 mg per day). Block randomisation was performed by the trial statistician using an SAS code that generated randomly varying block sizes, stratified by study site and distributed using sealed envelopes. All trial participants and all study staff were masked to treatment assignment, except the trial pharmacist. The first primary outcome was atrophy of the peripapillary retinal nerve fibre layer (pRNFL), measured by optic coherence tomography (OCT) as the difference in pRNFL thickness between the affected eye at week 26 and the unaffected eye at baseline. The second primary outcome was low contrast letter acuity at week 26, measured as the 2·5% Sloan chart score of the affected eye. Analysis was performed in the full analysis set of all randomised participants for whom treatment was started and at least one follow-up OCT measurement was available. Safety was analysed in all patients who received at least one dose of the trial medication. This trial is registered at ClinicalTrials.gov, NCT01962571.Findings: 108 participants were enrolled between Nov 25, 2014, and Oct 9, 2017, of whom 55 were assigned to erythropoietin and 53 to placebo. Five patients were excluded from the primary analysis due to not receiving the allocated medication, withdrawn consent, revised diagnosis, or loss to follow-up, yielding a full analysis set of 52 patients in the erythropoietin group and 51 in the placebo group. Mean pRNFL atrophy was 15·93 μm (SD 14·91) in the erythropoietin group and 14·65 μm (15·60) in the placebo group (adjusted mean treatment difference 1·02 μm; 95% CI -5·51 to 7·55; p=0·76). Mean low contrast letter acuity scores were 49·60 (21·31) in the erythropoietin group and 49·06 (21·93) in the placebo group (adjusted mean treatment difference -4·03; -13·06 to 5·01). Adverse events occurred in 43 (81%) participants in the erythropoietin group and in 42 (81%) in the placebo group. The most common adverse event was headache, occuring in 15 (28%) patients in the erythropoietin group and 13 (25%) patients in the placebo group. Serious adverse events occurred in eight (15%) participants in the erythropoietin and in four (8%) in the placebo group. One patient (2%) in the erythropoietin group developed a venous sinus thrombosis, which was treated with anticoagulants and resolved without sequelae.Interpretation: Erythropoietin as an adjunct to corticosteroids conveyed neither functional nor structural neuroprotection in the visual pathways after optic neuritis. Future research could focus on modified erythropoietin administration, assess its efficacy independent of corticosteroids, and investigate whether it affects the conversion of optic neuritis to multiple sclerosis.Funding: German Federal Ministry of Education and Research (BMBF).

Front Neurol 2021 Nov 23;12:753107.

Ringelstein M, Ayzenberg L, Lindenblatt G, Fischer K, Gahlen A, Novi G, Hayward-Könnecke H, Schippling S, Rommer P, Kornek B, Zrzavy T, Biotti D, Crion J, Audoin B, Berthele A, Giglhuber K, Zephir H, Kümpfel T, Berger R, Röther J, Häußler V, Stellmann J, Whittam D, Jacob A, Kraemer M, Gueguen A, Deschamps R, Bayas A, Hümmert M, Trebst C, Haarmann A, Jarius S, Wildemann, Grothe M, Siebert N, Ruprecht K, Paul F, Collongues N, Marignier R, Levy M, Karenfort M, Deppe M, Albrecht P, Hellwig K, Gold R, Hartung H, Meuth S, Kleiter I, Aktas O.

Interleukin-6 Receptor Blockade in Treatment-Refractory MOG-IgG-Associated Disease and Neuromyelitis Optica Spectrum Disorders

Background and objectives: To evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti-interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein-IgG-associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD).Methods: Annualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab.Results: Patients received TCZ for 23.8 months (median; interquartile range 13.0-51.1 months), with an IV dose of 8.0 mg/kg (median; range 6-12 mg/kg) every 31.6 days (mean; range 26-44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5-5) to 0 (range 0-0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0-5] to 0 [range 0-4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0-3.0] to 0.2 [range 0-2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD (p = 0.04; for the brain) and in AQP4-IgG+ NMOSD (p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy.Discussion: This study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD.

Neurol Neuroimmunol Neuroinflamm 2021 Nov 16;9(1):e1100.

Gamradt S, Hasselmann H, Taenzer A, Brasanac J, Stiglbauer V, Sattler A, Sajitz-Hermstein M, Kierszniowska S, Ramien C, Nowacki J, Mascarell-Maricic L, Wingenfeld K, Piber D, Ströhle A, Kotsch J, Paul F, Otte C, Gold SM.

Reduced mitochondrial respiration in T cells of patients with major depressive disorder

Converging evidence indicates that major depressive disorder (MDD) and metabolic disorders might be mediated by shared (patho)biological pathways. However, the converging cellular and molecular signatures remain unknown. Here, we investigated metabolic dysfunction on a systemic, cellular, and molecular level in unmedicated patients with MDD compared with matched healthy controls (HC). Despite comparable BMI scores and absence of cardiometabolic disease, patients with MDD presented with significant dyslipidemia. On a cellular level, T cells obtained from patients with MDD exhibited reduced respiratory and glycolytic capacity. Gene expression analysis revealed increased carnitine palmitoyltransferase IA (CPT1a) levels in T cells, the rate-limiting enzyme for mitochondrial long-chain fatty acid oxidation. Together, our results indicate metabolic dysfunction in unmedicated, non-overweight patients with MDD on a systemic, cellular, and molecular level. This evidence for reduced mitochondrial respiration in T cells of patients with MDD provides translation of previous animal studies regarding a putative role of altered immunometabolism in depression pathobiology.

iScience 2021 Oct 16;24(11):103312.

Dürr M, Nissen G, Sühs K, Schwenkenbecher P, Geis C, Ringelstein N, Hartung H, Friese MA, Kaufmann M, Malter M, Madlener M, Thaler F, Kümpfel T, Senel M, Häusler M, Schneider H, Bergh F, Kellinghaus C, Zettl U, Wandinger K, Melzer N, Gross C, Lange P, Dreyhaupt, Tumani H, Leypoldt F, Lewerenz J.

CSF Findings in Acute NMDAR and LGI1 Antibody-Associated Autoimmune Encephalitis

Background and objectives: CSF in antibody-defined autoimmune encephalitis (AE) subtypes shows subtype-dependent degrees of inflammation ranging from rare and often mild to frequent and often robust. AEs with NMDA receptor antibodies (NMDAR-E) and leucine-rich glioma-inactivated protein 1 antibodies (LGI1-E) represent opposite ends of this spectrum: NMDAR-E with typically frequent/robust and LGI1-E with rare/mild CSF inflammation. For a more in-depth analysis, we characterized CSF findings in acute, therapy-naive NMDAR-E and LGI1-E in a multicentric, retrospective, cross-sectional setting.Methods: Eighty-two patients with NMDAR-E and 36 patients with LGI1-E from the GErman NEtwork for Research of AuToimmune Encephalitis (GENERATE) with lumbar puncture within 90 days of onset and before immunotherapy were included. CSF parameters comprised leukocytes, oligoclonal bands (OCBs), and CSF/serum ratios for albumin, immunoglobulin G (IgG), A (IgA), and M (IgM), the latter 3 converted to Z scores according to Reiber formulas. The MRZ reaction was tested in 14 patients with NMDAR-E and 6 patients with LGI1-E, respectively.Results: CSF was abnormal in 94% of NMDAR-E but only in 36% of LGI1-E patients. Robust quantitative intrathecal immunoglobulin synthesis (IIS, IgG > IgM >> IgA) was characteristic for NMDAR-E, but absent in LGI-E. In NMDAR-E, CSF leukocytes were higher when IIS was present or more pronounced. In addition, in NMDAR-E, CSF leukocytes were lower and IIS occurred less often and if so to a lesser degree at older age. Patients with NMDAR-E with severe functional impairment more often had positive OCBs. In CSF obtained later than 3 weeks of onset, leukocytes were lower. In parallel, the correlation of leukocytes with IIS disappeared as IIS was partially independent of disease duration. The MRZ reaction was positive in 5 (36%) patients with NMDAR-E. All these associations were completely absent in LGI1-E. Here, younger patients showed more blood-CSF barrier dysfunction. In LGI1-E, but not in NMDAR-E, the blood-CSF barrier was more dysfunctional when CSF leukocytes were higher.Discussion: NMDAR-E and LGI-E differ in their typical extent of CSF inflammation. In addition, the patterns formed by the different inflammatory CSF parameters and their relationship with disease severity, age, and disease duration are subtype-characteristic. Moreover, signs for multiple sclerosis-like chronic inflammation are present in a subgroup of patients with NMDAR-E. These CSF patterns might be markers for the different immunopathogeneses of LGI1-E and NMDAR-E.

Neurol Neuroimmunol Neuroinflammn 2021 Oct 25;8(6):e1086.

Sippel A, Riemann-Lorenz K, Scheiderbauer J, Kleiter I, Morrison R, Kofahl C, Heesen C.

Patients experiences with multiple sclerosis disease-modifying therapies in daily life – a qualitative interview study

Background: Besides coping with a disease with many uncertainties, people with relapsing-remitting multiple sclerosis face complex decisions concerning disease-modifying therapies (DMTs). In an interview study, we aimed to assess patients‘ experiences with DMTs.Methods: Problem-centred interviews were conducted with 50 people with relapsing-remitting multiple sclerosis in Germany using maximum variation sampling and covering all licensed DMTs. Data were analysed thematically using deductive and inductive categories.Results: 47 of 50 patients had treatment with at least one of the approved DMTs. The main themes were: (1) starting a DMT, (2) switching to another DMT, (3) discontinuing a DMT, and (4) multiple sclerosis without starting a DMT. Different intercorrelated factors influenced the decision-making processes for or against a DMT. Individual experiences with DMTs in daily life contained the effort in administration, success, and failure of DMTs, coping strategies and well-being without DMTs. The decision-making process for or against a DMT and the use of those treatments can be understood as a constant, continually shifting process, complicated by different factors, which change over time. Experiences with DMTs were characterized by attempts to handle uncertainty and to (re)gain control and integrate adaptivity into one’s life.Conclusions: The study provides a rich and nuanced amount of patients‘ experiences with DMTs. The findings demonstrate the importance for practitioners to look at current life circumstances of patients with multiple sclerosis when recommending a DMT and to promote and enable patients to make informed decisions.Keywords: Decision making; Multiple sclerosis; Patient experiences; Qualitative study; Thematic analysis; Web-based experiential information.

BMC Health Serv Res 2021 Oct 22;21(1):1141.

Kurelic R, F.Krieg P, Sonner J, Bhaiyan G, Ramos G, Frantz S, Friese MA, Nikolaev V.

Upregulation of Phosphodiesterase 2A Augments T Cell Activation by Changing cGMP/cAMP Cross-Talk

3′,5′-cyclic adenosine monophosphate (cAMP) is well-known for its diverse immunomodulatory properties, primarily inhibitory effects during T cell activation, proliferation, and production of pro-inflammatory cytokines. A decrease in cAMP levels, due to the hydrolyzing activity of phosphodiesterases (PDE), is favoring inflammatory responses. This can be prevented by selective PDE inhibitors, which makes PDEs important therapeutic targets for autoimmune disorders. In this study, we investigated the specific roles of PDE2A and PDE3B in the regulation of intracellular cAMP levels in different mouse T cell subsets. Unexpectedly, T cell receptor (TCR) activation led to a selective upregulation of PDE2A at the protein level in conventional T cells (Tcon), whereas no changes were detected in regulatory T cells (Treg). In contrast, protein expression of PDE3B was significantly higher in both non-activated and activated Tcon subsets as compared to Treg, with no changes upon TCR engagement. Live-cell imaging of T cells expressing a highly sensitive Förster resonance energy transfer (FRET)-based biosensor, Epac1-camps, has enabled cAMP measurements in real time and revealed stronger responses to the PDE2A inhibitors in activated vs non-activated Tcon. Importantly, stimulation of intracellular cGMP levels with natriuretic peptides led to an increase of cAMP in non-activated and a decrease of cAMP in activated Tcon, suggesting that TCR activation changes the PDE3B-dependent positive to PDE2A-dependent negative cGMP/cAMP cross-talk. Functionally, this switch induced higher expression of early activation markers CD25 and CD69. This constitutes a potentially interesting feed-forward mechanism during autoimmune and inflammatory responses that may be exploited therapeutically.

Front Pharmacol 2021 Oct 5;12:748798.

Huang Y, Peng K, Popejoy A, Hu J, Nowicki T, Gold SM, Quintana-Murci L, Fuentes-Guajardo M, Shugay M, Greiff V, Burkhardt A, Alachkar H, Mangul S.

Ancestral diversity is limited in published T cell receptor sequencing studies

No abstract available

Immunity 2021 Oct 12;54(10):2177-2179.

Wenzel L, Heesen C, Scheiderbauer J, van de Loo M, Köpke S, Rahn Ac.

Evaluation of an interactive web-based programme on relapse management for people with multiple sclerosis (POWER@MS2): study protocol for a process evaluation accompanying a randomised controlled trial

Introduction: Process evaluations accompanying complex interventions examine the implementation process of the underlying intervention, identify mechanisms of impact and assess contextual factors. This paper presents the protocol for a process evaluation conducted alongside the randomised controlled trial POWER@MS2. The trial comprises the evaluation of a web-based complex intervention on relapse management in 188 people with multiple sclerosis conducted in 20 centres. The web-based intervention programme focuses on relapse treatment decision making and includes a decision aid, a nurse-led webinar and an online chat. With the process evaluation presented here, we aim to assess participants‘ responses to and interactions with the intervention to understand how and why the intervention produces change.Methods and analysis: A mixed methods design is used to explore the acceptance of the intervention as well as its use and impact on participants. Participants are people with multiple sclerosis, neurologists, nurses and stakeholders. Quantitative semistandardised evaluation forms will be collected throughout the study. Qualitative semistructured telephone interviews will be conducted at the end of the study with selected participants, especially people with multiple sclerosis and neurologists. Quantitative data will be collected and analysed descriptively. Based on the results, the qualitative interviews will be conducted and analysed thematically, and the results will be merged in a joint display table.Ethics and dissemination: The process evaluation has received ethical approval from the Ethical Committee of the University of Lübeck (reference 19-024). Findings will be disseminated in peer-reviewed journals, at conferences, meetings and on relevant patient websites.Trial registration number: NCT04233970.

BMJ Open 2021 Oct 1;11(10):e046874.

Heestermans M, Naudin C, Mailer R, Konrath S, Klaetschke, Jämsä A, Frye M, Deppermann C, Paula G, Kuta P, Friese M, Gelderblom M, Sickmann A, Preston R, Nofer J, Rose-Jahn S, Butler L, Salomon O, Stavrou E, Renné T.

Identification of the factor XII contact activation site enables sensitive coagulation diagnostics

Contact activation refers to the process of surface-induced activation of factor XII (FXII), which initiates blood coagulation and is captured by the activated partial thromboplastin time (aPTT) assay. Here, we show the mechanism and diagnostic implications of FXII contact activation. Screening of recombinant FXII mutants identified a continuous stretch of residues Gln317-Ser339 that was essential for FXII surface binding and activation, thrombin generation and coagulation. Peptides spanning these 23 residues competed with surface-induced FXII activation. Although FXII mutants lacking residues Gln317-Ser339 were susceptible to activation by plasmin and plasma kallikrein, they were ineffective in supporting arterial and venous thrombus formation in mice. Antibodies raised against the Gln317-Ser339 region induced FXII activation and triggered controllable contact activation in solution leading to thrombin generation by the intrinsic pathway of coagulation. The antibody-activated aPTT allows for standardization of particulate aPTT reagents and for sensitive monitoring of coagulation factors VIII, IX, XI.

Nat Commun 2021 Sep 22;12(1):5596.

Giovannelli J, Ciron J, Cohen M, Kim H, Kim S, Stellmann J, Kleiter I, McCreay M, Greenberg B, Deschamps R, Audoin B, Maillart E, Papeix C, Collongues N, Bourre B, Laplaud D, Ayrignac X, Durand-Dubief F, Ruet A, Vukusic S, Marignier R, Dauchet L, Zephir H.

A meta-analysis comparing first-line immunosuppressants in neuromyelitis optica

Objective: As phase III trials have shown interest in innovative but expensive drugs in the treatment of neuromyelitis optica spectrum disorder (NMOSD), data are needed to clarify strategies in the treatment of neuromyelitis optica (NMO). This meta-analysis compares the efficacy of first-line strategies using rituximab (RTX), mycophenolate mofetil (MMF), or azathioprine (AZA), which are still widely used.Methods: Studies identified by the systematic review of Huang et al. (2019) were selected if they considered at least two first-line immunosuppressants among RTX, MMF, and AZA. We updated this review. The Medline, Cochrane Central Register of Controlled Trials, Embase, and ClinicalTrials databases were queried between November 2018 and April 2020. To be included, the hazard ratio (HR) [95% CI] for the time to first relapse after first-line immunosuppression had to be available, calculable, or provided by the authors.Results: We gathered data from 919 NMO patients (232 RTX-, 294 MMF-, and 393 AZA-treated patients). The risk of first relapse after first-line immunosuppression was 1.55 [1.04, 2.31] (p = 0.03) for MMF compared with RTX, 1.42 [0.87, 2.30] (p = 0.16) for AZA compared with RTX, and 0.94 [0.58, 1.54] (p = 0.08) for MMF compared with AZA.Interpretation: The findings suggest that RTX is more efficient than MMF as a first-line therapy. Even if the results of our meta-analysis cannot conclude that RTX has a better efficacy in delaying the first relapse than AZA, the observed effect difference between both treatments combined with the results of previous studies using as outcome the annualized relapse rate may be in favor of RTX.

Ann Clin Transl Neurol 2021 Oct;8(10):2025-2037

Schwenkenbecher P, Skripuletz T, Lange P, Dürr M, Konen FF, Möhn N, Ringelstein M, Menge T, Friese MA, Melzer N, Malter MP, Häusler M, Thaler FS, Stangel M, Lewerenz J, Sühs KW.

Intrathecal Antibody Production Against Epstein-Barr, Herpes Simplex, and Other Neurotropic Viruses in Autoimmune Encephalitis

Neurol Neuroimmunol Neuroinflamm 2021 Aug 24;8(6):e1062.

Haker M, Heesen C, Wenzel L, Köpke S, Rahn AC, Jasper J.

Decision-making about corticosteroids in relapses of multiple sclerosis – development of a questionnaire based on the theory of planned behaviour

Mult Scler Relat Disord. 2021 Oct;55:103182.

Heinrich l, Rosenthal F, Patra S, Schulz KH, Welsch GH, Vettorazzi E, Rosenkranz SC, Stellmann JP, Ramien C, Pöttgen J, Gold SM, Heesen C.

Arm Ergometry to Improve Mobility in Progressive Multiple Sclerosis (AMBOS)-Results of a Pilot Randomized Controlled Trial

Background: Walking disability is one of the most frequent and burdening symptoms of progressive multiple sclerosis (MS). Most of the exercise intervention studies that showed an improvement in mobility performance were conducted in low to moderately disabled relapsing-remitting MS patients with interventions using the legs. However, MS patients with substantial walking disability hardly can perform these tasks. Earlier work has indicated that aerobic arm training might also improve walking performance and could therefore be a therapeutic option in already moderately disabled progressive MS patients. Methods: Patients with progressive MS and EDSS 4-6.5 were randomized using a computer-generated algorithm list to either a waitlist control group (CG) or an intervention group (IG). The IG performed a 12-week home-based, individualized arm ergometry exercise training program. Maximum walking distance as measured by the 6-min walking test (6MWT) was the primary endpoint. Secondary endpoints included aerobic fitness, other mobility tests, cognitive functioning, as well as fatigue and depression. Results: Of n = 86 screened patients, 53 with moderate disability (mean EDSS 5.5, SD 0.9) were included and data of 39 patients were analyzed. Patients in the IG showed strong adherence to the program with a mean of 67 (SD 26.4) training sessions. Maximum work load (P max) increased in the training group while other fitness indicators did not. Walking distance in the 6MWT improved in both training and waitlist group but not significantly more in trained patients. Similarly, other mobility measures showed no differential group effect. Cognitive functioning remained unchanged. No serious events attributable to the intervention occurred. Conclusion: Although maximum work load improved, 3 months of high-frequency arm ergometry training of low to moderate intensity could not show improved walking ability or cognitive functioning in progressive MS compared to a waitlist CG. The study was registered at www.clinicaltrials.gov (NCT03147105) and funded by the local MS self-help organization.Keywords: aerobic exercise; arm ergometry; cognition; multiple sclerosis; progressive multiple sclerosis.

Front Neurol. 2021 Jul 19;12:644533.

Melief J, Huitinga I, Gold SM.

The stress-axis in multiple sclerosis: Clinical, cellular, and molecular aspects.

Handb Clin Neurol. 2021;181:119-126

Woo MS, Haag F, Nierhaus A, Jarczak D, Roedl K, Mayer C, Brehm TT, van der Meirschen M, Hennigs A, Christopeit M, Fiedler W, Karagiannis P, Burdelski C, Schultze A, Huber S, Addo MM, Schmiedel S, Friese MA, Kluge S, Schulze Zur Wiesch J

Multi-dimensional and longitudinal systems profiling reveals predictive pattern of severe COVID-19

iScience. 2021 Jul 23;24(7):102752

Ramaglia V, Dubey M, Malpede MA, Petersen N, de Vries SI, Ahmed SM, Lee DSW, Schenk GJ, Gold SM, Huitinga I, Gommerman JL, Geurts JJG, Kole MHP

Complement-associated loss of CA2 inhibitory synapses in the demyelinated hippocampus impairs memory

Acta Neuropathol. 2021 Oct;142(4):643-667.

Ayzenberg I, Richter D, Henke E, Asseyer S, Paul F, Trebst C, Hümmert MW, Havla J, Kümpfel T, Ringelstein M, Aktas O, Wildemann B, Jarius S, Häußler V, Stellmann JP, Senel M, Klotz L, Pellkofer HL, Weber MS, Pawlitzki M, Rommer PS, Berthele A, Wernecke KD, Hellwig K, Gold R, Kleiter I, NEMOS (Neuromyelitis Optica Study Group)

Pain, Depression, and Quality of Life in Neuromyelitis Optica Spectrum Disorder: A Cross-Sectional Study of 166 AQP4 Antibody-Seropositive Patients

Neurol Neuroimmunol Neuroinflamm. 2021 Apr 20;8(3):e985

Zhang HW, Huck K, Jähne K, Cichon F, Sonner JK, Ufer F, Bauer S, Woo MS, Green E, Lu K, Kilian M, Friese MA, Platten M, Sahm K.

Activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) enhances dendritic cell vaccination in experimental melanoma

Oncoimmunology. 2021 May 14;10(1):1920739

Häußler V, Ufer F, Pöttgen J, Wolschke C, Friese MA, Kröger N, Heesen C, Stellmann JP

aHSCT is superior to alemtuzumab in maintaining NEDA and improving cognition in multiple sclerosis

Ann Clin Transl Neurol 2021 Jun;8(6):1269-1278

Pust GEA, Randerath J, Goetzmann L, Weierstall R, Korzinski M, Gold SM, Dettmers C, Ruettner B, Schmidt R.

Association of Fatigue Severity With Maladaptive Coping in Multiple Sclerosis: A Data-Driven Psychodynamic Perspective

Front Neurol. 2021 Apr 7;12:652177.

Zangemeister WH, Heesen C, Röhr D, Gold SM.

Oculomotor Fatigue and Neuropsychological Assessments mirror Multiple Sclerosis Fatigue

J Eye Mov Res. 2020 Sep 13;13(4):10.16910

Has Silemek AC, Ranjeva JP, Bertrand Audoin, Heesen C, Gold SM, Kühn S, Weygandt M, Stellmann JP.

Delayed access to conscious processing in multiple sclerosis: Reduced cortical activation and impaired structural connectivity

Hum Brain Mapp. 2021 Apr 7.

Poch T, Krause J, Casar C, Liwinski T, Glau L, Kaufmann M, Ahrenstorf AE, Hess LU, Ziegler AE, Martrus G, Lunemann S, Sebode M, Li J, Schwinge D, Krebs CF, Franke A, Friese MA, Oldhafer KJ, Fischer L, Altfeld M, Lohse AW, Huber S, Tolosa E, Gagliani N, Schramm C.

Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4+ T cells in primary sclerosing cholangitis

J Hepatol. 2021 Aug;75(2):414-423

Bellmann-Strobl J, Paul F, Wuerfel J, Dörr J, Infante-Duarte C, Heidrich E, Körtgen B, Brandt A, Pfüller C, Radbruch H, Rust R, Siffrin V, Aktas O, Heesen C, Faiss J, Hoffmann F, Lorenz M, Zimmermann B, Groppa S, Wernecke KD, Zipp F.

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

Neurol Neuroimmunol Neuroinflamm. 2021 Mar 24;8(3):e981

Kaufmann M, Evans H, Schaupp AL, Engler JB, Kaur G, Willing A, Kursawe N, Schubert C, Attfield KE, Fugger L, Friese MA.

Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis

Med (N Y). 2021 Mar 12;2(3):296-312

Stellmann JP, Wanke N, Maarouf A, Gellißen S, Heesen C, Audoin B, Gold SM, Zaaraoui W, Poettgen J.

Cognitive performance shows domain specific associations with regional cortical thickness in multiple sclerosis

Neuroimage Clin. 2021 Feb 24; 30:102606

Blome C, Carlton J, Heesen C, Janssen MF, Lloyd A, Otten M, Brazier J.

How to measure fluctuating impairments in people with MS: development of an ambulatory assessment version of the EQ-5D-5L in an exploratory study.

Qual Life Res. 2021 Jul;30(7):2081-2096

Rosenkranz SC, Kaulen B, Zimmermann HG, Bittner AK, Dorr M, Stellmann JP

Validation of Computer-Adaptive Contrast Sensitivity as a Tool to Assess Visual Impairment in Multiple Sclerosis Patients

Front Neurosci. 2021 Feb 23;15:591302

Woo MS, Ufer F, Rothammer N, Di Liberto G, Binkle L, Haferkamp U, Sonner JK, Engler JB, Nornig S, Bauer S, Wagner I,Egervari K, Raber J, Duvoisin RM, Pless O, Merkler D, Friese MA.

Neuronal metabotropic glutamate receptor 8 protects against neurodegeneration in CNS inflammation.

J Exp Med. 2021 May 3;218(5).e20201290

Graf LM, Rosenkranz SC, Hölzemer A, Hagel C, Goebell E, Jordan S, Friese MA, Addo MM, Schulze Zur Wiesch J, Beisel C.

Clinical Presentation and Disease Course of 37 Consecutive Cases of Progressive Multifocal Leukoencephalopathy (PML) at a German Tertiary-Care Hospital: A Retrospective Observational Study.

Front Neurol. 2021 Feb 4;12:632535.

Krause N, Riemann-Lorenz K, Steffen T, Rahn AC, Pöttgen J, Stellmann JP, Köpke S, Friede T, Icks A, Vomhof M, Temmes H, van de Loo M, Gold SM, Heesen C.

Study protocol for a randomised controlled trial of a web-based behavioural lifestyle programme for emPOWERment in early Mulitiple Sclerosis (POWER@MS1).

Introduction: Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system that mainly affects young adults. Uncertainty is a major psychological burden of the disease from diagnosis to prognosis, enhanced by the pressure to make early decisions on a diverse set of immunotherapies. Watchful waiting for 1-2 years while adapting goals and lifestyle habits to life with a chronic disease represents another reasonable option for persons with MS (PwMS). A behaviour change programme based on evidence-based patient information (EBPI) is not available in standard care. This randomised controlled trial (RCT) with an embedded process evaluation investigates the efficacy and cost-effectiveness of a web-based behavioural lifestyle programme to change lifestyle behaviour and reduce inflammatory disease activity in PwMS. Methods and analysis: A web-based behavioural intervention will be evaluated in an RCT aiming to recruit 328 persons with clinically isolated syndrome, suspected MS or confirmed MS for less than 1 year, who have not yet started immunotherapy. Moreover, a mixed-methods process evaluation and a health economic evaluation will be carried out. Participants will be recruited in at least 16 MS centres across Germany and randomised to an intervention group with 12 months of access to EBPI about lifestyle factors in MS, combined with a complex behaviour change programme or to a control group (optimised standard care). The combined primary endpoint is the incidence of new T2 lesions on MRI or confirmed relapses. Ethics and dissemination: The study has been approved by the Ethics Committee of the Hamburg Chamber of Physicians (PV6015). Trial results will be communicated at scientific conferences and meetings and presented on relevant patient websites and in patient education seminars.

BMJ Open. 2021 Feb 16;11(2):e041720

Rahn AC, Wenzel L, Icks A, Stahmann A, Scheiderbauer J, Grentzenberg K, Vomhof M, Montalbo J, Friede T, Heesen C, Köpke S.

Development and evaluation of an interactive web-based decision-making programme on relapse management for people with multiple sclerosis (POWER@MS2)-study protocol for a randomised controlled trial.

Trials. 2021 Feb 14;22(1):139.

Rosenkranz SC, Shaposhnykov AA, Träger S, Engler JB, Witte ME, Roth V, Vieira V, Paauw N, Bauer S, Schwencke-Westphal C, Schubert C, Bal LC, Schattling B, Pless O, van Horssen J, Freichel M, Friese MA

Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis

Elife.2021 Feb 10;10:e61798.

Thaler C, Kyselyova AA, Faizy TD, Nawka MT, Jespersen S, Hansen B, Stellmann JP, Heesen C, Stürner KH, Stark M, Fiehler J, Bester M, Gellißen S

Heterogeneity of multiple sclerosis lesions in fast diffusional kurtosis imaging

PLoS One 2021 Feb 4;16(2):e0245844.

Silveira SL, Riemann-Lorenz K, Heesen C, Motl RW.

Current and Long-Term Physical Activity Among Adults with Multiple Sclerosis in the United States: COM-B Variables as Explanatory Factors

Int J Behav Med. 2021 Oct;28(5):561-574

Barabasch A, Riemann-Lorenz K, Kofahl C, Scheiderbauer J, Eklund D, Kleiter I, Kasper J, Köpke S, Lezius S, Zapf A, Rahn AC, Heesen C.

Impact of a multimedia website with patient experiences of multiple sclerosis (PExMS) on immunotherapy decision making: study protocol for a pilot randomised controlled trial in a mixed-methods design.

Pilot Feasibility Stud. 2021 Jan 7;7(1):16.

Stiglbauer V, Gamradt S, Scherzer M, Brasanac J, Otte C, Rose M, Hofmann T, Hinkelmann K, Gold SM

Immunological substrates of depressive symptoms in patients with severe obesity: An exploratory study

Cell Biochem Funct. 2021 Apr;39(3):423-431

Heine J, Prüß H, Scheel M, Brandt AU, Gold SM, Bartsch T, Paul F, Finke C.

Transdiagnostic hippocampal damage patterns in neuroimmunological disorders

Neuroimage Clin. 2020;28:102515

Woo MS, Malsy J, Pöttgen J, Seddiq Zai S, Ufer F, Hadjilaou A, Schmiedel S, Addo MM, Gerloff C, Heesen C, Schulze Zur Wiesch J, Friese MA

Frequent neurocognitive deficits after recovery from mild COVID-19

Brain Commun. 2020 Nov 23;2(2)

Patrick Ostkamp, Anke Salmen, Béatrice Pignolet, Dennis Görlich, Till F M Andlauer, Andreas Schulte-Mecklenbeck , Gabriel Gonzalez-Escamilla, Florence Bucciarelli, Isabelle Gennero, Johanna Breuer, Gisela Antony, Tilman Schneider-Hohendorf, Nadine Mykicki, Antonios Bayas, Florian Then Bergh, Stefan Bittner, Hans-Peter Hartung, Manuel A Friese, Ralf A Linker, Felix Luessi, Klaus Lehmann-Horn, Mark Mühlau, Friedemann Paul, Martin Stangel, Björn Tackenberg, Hayrettin Tumani, Clemens Warnke, Frank Weber, Brigitte Wildemann, Uwe K Zettl, Ulf Ziemann, Bertram Müller-Myhsok, Tania Kümpfel, Luisa Klotz, Sven G Meuth, Frauke Zipp, Bernhard Hemmer, Reinhard Hohlfeld, David Brassat, Ralf Gold, Catharina C Gross , Carsten Lukas , Sergiu Groppa , Karin Loser , Heinz Wiendl , Nicholas Schwab , German Competence Network Multiple Sclerosis (KKNMS) and the BIONAT Network

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity

Proc Natl Acad Sci USA 2021 Jan 5;118(1):e2018457118

Anna C Alegiani, Anne C Rahn, Anke Steckelberg, Götz Thomalla, Christoph Heesen, Sascha Köpke

Quality of Stroke Patient Information Applied in Randomized Controlled Trials-Literature Review

Front. Neurol. 2020 Dec 7;11:526515.

Meyer-Arndt L, Hetzer S. Asseyer S, Bellmann-Strobl J, Scheel M, Stellmann JP, Heesen C, Engel AK, Brandt AU, Haynes JD, Paul F, Gold SM, Weygandt M.

Blunted neural and psychological stress processing predicts future grey matter atrophy in multiple sclerosis.

Neurobiol Stress. 2020 Jul 27;13:100244

Er-Lukowiak M, Duan Y, Rassendren F, Ulmann L, Nicke A, Ufer F, Friese MA, Koch-Nolte F, Magnus T, Rissiek B.

A P2rx7 Passenger Mutation Affects the Vitality and Function of T cells in Congenic Mice

iScience. 2020 Nov 27;23(12)

Schiffmann I, Freund M, Vettorazzi E, Stellmann JP, Heyer-Borchelt S, D'Hooghe M, Häußler V, Rahn AC, Heesen C.

Assessing the effect of an evidence-based patient online educational tool for people with multiple sclerosis called UMIMS-understanding magnetic resonance imaging in multiple sclerosis: study protocol for a double-blind, randomized controlled trial

Trials. 2020 Dec 9;21(1):1008.

Benecke M, Kasper J, Heesen C, Schäffler N, Reissmann DR.

Patient autonomy in dentistry: demonstrating the role for shared decision making

Background: Evidence-based practice, decision aids, patient preferences and autonomy preferences (AP) play an important role in making decisions with the patient. They are crucial in the process of a shared decision making (SDM) and can be incorporated into quality criteria for patient involvement in health care. However, there are few studies on SDM and AP in the field of dentistry. This study explored patients‘ autonomy preferences in dentistry in comparison to other medical domains, comparing them with patient preferences in two other cohorts of patients with different conditions and in different health care settings.

Methods: A sample of 100 dental patients attending 16 dentists was consecutively recruited in a university-based prosthodontic clinic. Patients‘ and dentists‘ preferences regarding their roles in dental decision making for commonly performed diagnostic and treatment decisions were compared using the Control Preference Scale (CPS). This was followed by cross sectional surveys to study autonomy preferences in three additional cohorts recruited from general practices (n = 100), a multiple sclerosis clinic (n = 109), and a university-based prosthodontic clinic (n = 100). A questionnaire with combined items from the Autonomy Preference Index (API) to assess general and the CPS to assess specific preferences was used in the additional cohorts.

Results: Dentists were less willing to give patients control than patients were willing to enact autonomy. However, decisions about management of tooth loss were considered relevant for a shared decision making by both parties. When comparing cohorts from different samples, the highest AP was expressed by people with multiple sclerosis and the lowest by patients in dentistry (means: dentistry 2.5, multiple sclerosis 2.1, general practice 2.4, p = .035). There were considerable intra-individual differences in autonomy preferences referring to different decision types (p < .001). In general, more autonomy was desired for treatment decisions in comparison to diagnostic decisions, for trivial compared to severe conditions, and for dental care compared to general practice (all: p < .001).

Conclusion: There is an important role of patient participation in decision making in dentistry. Furthermore, PA should be considered with respect to specific medical decisions instead of assessing autonomy preferences in general implying a need for communication skills training of health care professionals.

BMC Med. Informations 2020 Dec 2;20(1):318.

Otte C, Chae WR, Nowacki J, Kaczmarczyk M, Piber D, Roepke S, Märschenz S, Lischewski S, Schmidt S, Ettrich B, Grabe HJ, Hegerl U, Hinkelmann K, Hofmann T, Janowitz D, Junghanns K, Kahl KG, Klein JP, Krueger THC, Leicht G, Prvulovic D, Reif A, Schoettle D, Strauss M, Westermair A, Friede T, Gold SM.

Simvastatin add-on to escitalopram in patients with comorbid obesity and major depression (SIMCODE): study protocol of a multicentre, randomised, double-blind, placebo-controlled trial

Introduction: Major depressive disorder (MDD) and obesity are both common disorders associated with significant burden of disease worldwide. Importantly, MDD and obesity often co-occur, with each disorder increasing the risk for developing the other by about 50%-60%. Statins are among the most prescribed medications with well-established safety and efficacy. Statins are recommended in primary prevention of cardiovascular disease, which has been linked to both MDD and obesity. Moreover, statins are promising candidates to treat MDD because a meta-analysis of pilot randomised controlled trials has found antidepressive effects of statins as adjunct therapy to antidepressants. However, no study so far has tested the antidepressive potential of statins in patients with MDD and comorbid obesity. Importantly, this is a difficult-to-treat population that often exhibits a chronic course of MDD and is more likely to be treatment resistant. Thus, in this confirmatory randomised controlled trial, we will determine whether add-on simvastatin to standard antidepressant medication with escitalopram is more efficacious than add-on placebo over 12 weeks in 160 patients with MDD and comorbid obesity.

Methods and analysis: This is a protocol for a randomised, placebo-controlled, double-blind multicentre trial with parallel-group design (phase II). One hundred and sixty patients with MDD and comorbid obesity will be randomised 1:1 to simvastatin or placebo as add-on to standard antidepressant medication with escitalopram. The primary outcome is change in the Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week 12. Secondary outcomes include MADRS response (defined as 50% MADRS score reduction from baseline), MADRS remission (defined as MADRS score <10), mean change in patients‘ self-reported Beck Depression Inventory (BDI-II) and mean change in high-density lipoprotein, low-density lipoprotein and total cholesterol from baseline to week 12.

Ethics and dissemination: This protocol has been approved by the ethics committee of the federal state of Berlin (Ethik-Kommission des Landes Berlin, reference: 19/0226-EK 11) and by the relevant federal authority (Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), reference: 4043387). Study findings will be published in peer-reviewed journals and will be presented at (inter)national conferences.

BMJ Open. 2020 Dec 1;10(12):e040119.

Pust GEA, Untiedt B, Randerath J, Barabasch A, Köpke S, Rahn AC, Hansen H, Heesen C.

Exploring Adherence to First-Line and Second-Line Immunotherapies in Multiple Sclerosis: An Interview Study

Int J MS Care. Sep-Oct 2020;22(5):219-225.

Montes-Cobos E, Huscher B, Engler JB, Woo MS, Binkle L, Bauer S, Kursawe N, Moles M, Friese MA, Ufer F.

Voltage-Gated Proton Channel Hv1 Controls TLR9 Activation in Plasmacytoid Dendritic Cells

J Immunol. 2020 Dec 1;205(11):3001-3010

Wakonig K, Eitel F, Ritter K, Hetzer S, Schmitz-Hübsch T, Bellmann-Strobl J, Haynes JD, Brandt AU, Gold SM, Paul F, Weygandt M.

Altered Coupling of Psychological Relaxation and Regional Volume of Brain Reward Areas in Multiple Sclerosis

Front Neurol. 2020 Oct 6;11:568850.

Kosch R, Schiffmann I, Daumer M, Lederer C, Scalfari A, Galea I, Scheiderbauer J, Rahn A, Heesen C.

Long-term prognostic counselling in people with multiple sclerosis using an online analytical processing tool.

Mult Scler. 2020 Oct 26

Rahn AC, Riemann-Lorenz K, Alegiani A, Pust GEA, van de Roemer A, Schmitz L, Vettorazzi E, Köpke S, Heesen C.

Comprehension of confidence intervals in audio-visual patient information materials for people with multiple sclerosis (COCO-MS): A web-based randomised controlled, parallel group trial

Patient Educ and Couns. 2021 May;104(5):1132-1139

Giovanetti AM, Barabasch A, Giordano A, Quintas R, Barello S, Graffigna G, Alifieri S, Schiffmann I, Muche-Borowski C, Borreani C, Heesen C, Solari A; ManTra project

Construction of a User-Led Resource for People Transitioning to Secondary Progressive Multiple Sclerosis: Results of an Internation Nominal Group Study

Front. Neurol. 2020 Aug 18;11:798

Pust GEA, Dettmers C, Randerath J, Rahn AC, Heesen C, Schmidt R, Gold SM

Fatigue in Multiple Sclerosis Is Associated With Childhood Adversities

Front Psychiatry 2020 Aug 28;11:811.

Ringelstein M, Harmel J, Zimmermann H, Brandt AU, Paul F, Haarmann A, Buttmann M, Hümmert MW, Trebst C, Schroeder C, Ayzenberg I, Kleiter I, Hellwig K, Havla J, Kümpfel T, Jarius S, Wildemann B, Rommer P, Weber M, Pellkofer H, Röpke L, Geis C, Retzlaff N, Zettl U, Deppe M, Klotz L, Young K, Stellmann JP, Kaste M, Kermer P, Marouf W, Lauda F, Tumani H, Graf J, Klistorner S, Hartung HP, Aktas O, Albrecht P.

Author response: Longitudinal optic neuritis-unrelated visual evoked potential changes in NMO spectrum disorders

Neurology. 2020 Sep 29;95(13):610.

Rosenkranz SC, Shaposhnykov A, Schnappauff O, Epping L, Vieira V, Heidermann K, Schattling B, Tsvilovskyy V, Liedtke W, Meuth SG, Freichel M, Gelderblom M, Friese MA

TRPV4-mediated regulation of the blood brain barrier is abolished during inflammation

Blood-brain barrier (BBB) dysfunction is critically involved in determining the extent of several central nervous systems (CNS) pathologies and here in particular neuroinflammatory conditions. Inhibiting BBB breakdown could reduce the level of vasogenic edema and the number of immune cells invading the CNS, thereby counteracting neuronal injury. Transient receptor potential (TRP) channels have an important role as environmental sensors and constitute attractive therapeutic targets that are involved in calcium homeostasis during pathologies of the CNS. Transient receptor potential vanilloid 4 (TRPV4) is a calcium permeable, nonselective cation channel highly expressed in endothelial cells. As it is involved in the regulation of the blood brain barrier permeability and consequently cerebral edema formation, we anticipated a regulatory role of TRPV4 in CNS inflammation and subsequent neuronal damage. Here, we detected an increase in transendothelial resistance in mouse brain microvascular endothelial cells (MbMECs) after treatment with a selective TRPV4 inhibitor. However, this effect was abolished after the addition of IFNγ and TNFa indicating that inflammatory conditions override TRPV4-mediated permeability. Accordingly, we did not observe a protection of Trpv4-deficient mice when compared to wildtype controls in a preclinical model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), and no differences in infarct sizes following transient middle cerebral artery occlusion (tMCAO), the experimental stroke model, which leads to an acute postischemic inflammatory response. Furthermore, Evans Blue injections did not show differences in alterations of the blood brain barrier (BBB) permeability between genotypes in both animal models. Together, TRPV4 does not regulate brain microvascular endothelial permeability under inflammation.

Front Cell Dev Biol. 2020 Aug 27;8:849

Zhai Y, Nasseri N, Pöttgen J, Gezhelbash E, Heesen C, Stellmann JP.

Smartphone Accelerometry: A Smart and Reliable Measurement of Real-Life Physical Activity in Multiple Sclerosis and Healthy Individuals

Background: Mobility impairment is common in persons with multiple sclerosis (pwMS) and can be assessed with clinical tests and surveys that have restricted ecological validity. Commercial research-based accelerometers are considered to be more valuable as they measure real-life mobility. Smartphone accelerometry might be an easily accessible alternative. Objective: To explore smartphone accelerometry in comparison to clinical tests, surveys, and a wrist-worn ActiGraph in pwMS and controls. Methods: Sixty-seven pwMS and 70 matched controls underwent mobility tests and surveys. Real-life data were collected with a smartphone and an ActiGraph over 7 days. We explored different smartphone metrics in a technical validation course and computed afterward correlation between ActiGraph (steps per minute), smartphone accelerometry (variance of vector magnitude), clinical tests, and surveys. We also determined the ability to separate between patients and controls as well as between different disability groups. Results: Based on the technical validation, we found the variance of the vector magnitude as a reliable estimate to discriminate wear time and no wear-time of the smartphone. Due to a further association with different activity levels, it was selected for real-life analyses. In the cross-sectional study, ActiGraph correlated moderately (r = 0.43, p < 0.05) with the smartphone but less with clinical tests (rho between |0.211| and |0.337|). Smartphone data showed stronger correlations with age (rho = -0.487) and clinical tests (rho between |0.565| and |0.605|). ActiGraph only differed between pwMS and controls (p < 0.001) but not between disability groups. At the same time, the smartphone showed differences between pwMS and controls, between RRMS and PP-/SPMS, and between participants with/without ambulatory impairment (all p < 0.001). Conclusions: Smartphone accelerometry provides better estimates of mobility and disability than a wrist-worn standard accelerometer in a free-living context for both controls and pwMS. Given the fact that no additional device is needed, smartphone accelerometry might be a convenient outcome of real-life ambulation in healthy individuals and chronic diseases such as MS.

Front Neruol. 2020 Aug 14;11:688

Voskuhl RR, Patel K, Paul F, Gold SM, Scheel M, Kuchling J, Cooper G, Asseyer S, Chien C, Brandt AU, Meyer CE, MacKenzie-Graham A.

Sex differences in brain atrophy in multiple sclerosis.

Biol Sex Differ. 2020 Aug 28;11(1):49

Gold SM, Köhler-Forsberg O, Moss-Morris R, Mehnert A, Miranda JJ, Bullinger M, Steptoe A, Whooley MA, Otte C

Comorbid depression in medical diseases

Depression is one of the most common comorbidities of many chronic medical diseases including cancer and cardiovascular, metabolic, inflammatory and neurological disorders. Indeed, the prevalence of depression in these patient groups is often substantially higher than in the general population, and depression accounts for a substantial part of the psychosocial burden of these disorders. Many factors can contribute to the occurrence of comorbid depression, such as shared genetic factors, converging biological pathways, social factors, health behaviours and psychological factors. Diagnosis of depression in patients with a medical disorder can be particularly challenging owing to symptomatic overlap. Although pharmacological and psychological treatments can be effective, adjustments may need to be made for patients with a comorbid medical disorder. In addition, symptoms or treatments of medical disorders may interfere with the treatment of depression. Conversely, symptoms of depression may decrease adherence to treatment of both disorders. Thus, comprehensive treatment plans are necessary to optimize care.

Nat Rev Dis Primers. 2020 Aug 20;6(1):69

Marques RF, Engler JB, Küchler K, Jones RA, Lingner T, Salinas G, Gillingwater TH, Friese MA, Duncan KE

Aerobic Exercise Induces Functional and Structural Reorganization of CNS Networks in Multiple Sclerosis: A Randomized Controlled Trial

Front Hum Neurosci. 2020 Jun 30;15:255

Marques RF, Engler JB, Küchler K, Jones RA, Lingner T, Salinas G, Gillingwater TH, Friese MA, Duncan KE

Motor neuron translatome reveals deregulation of SYNGR4 and PLEKHB1 in mutant TDP-43 amyotrophic lateral sclerosis mutants

Hum Mol Genet. 2020 Sep 29;29(16):2647-2661

Hermann J, Bender M, Schumacher D, Woo MS, Shaposhnykov A, Rosenkranz SC, Kuryshev V, Meier C, Guse AH, Friese MA, Freichel M, Tsvilovskyy V

Contribution of NAADP to Glutamate-Evoked Changes in CA²⁺ Homeostasis in Mouse Hippocampal Neurons

Front Cell Dev. Biol 2020 Jun 25;8:496

Gasperi C, Andlauer TFM, Keatin A, Knier B, Klein A, Pernpeintner V, Lichtner P, Gold R, Zipp F, Then Bergh F, Stangel M, Tumani H, Wildemann B, Wiendl H, Bayas A, Kümpfel T, Zettl UK, Linkner RA, Ziemann U, Knop M, Warnke C, Friese MA, Paul F, Tackenberg B, Berhele A, Hemmer B.

Genetic determinants of the humoral immune response in MS

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

Golde S, Heine J, Pöttgen J, Mantwill M, Lau S, Wingenfeld K, Otte C, Penner IK, Engel AK, Heesen C, Stellmann JP, Dziobek I, Finke C, Gold SM

Distinct Functional Connectivity Signartures of Impaired Social Cognition in Multiple Sclerosis

Front Neurol. 2020 Jun 25;11:507

Woo MS, Steins D, Häußler V, Kohsar M, Haag F, Elias-Hamp B, Heesen C, Lütgehetmann M, Schulze zur Wiesch J, Friese MA.

Control of SARS-CoV-2 infection in rituximab-treated neuroimmunological patients.

Individuals with autoimmune diseases, such as multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD), that require long-term immunosuppression are regarded as particularly vulnerable in the current COVID-19 pandemic. However, few details about the effect of individual immunotherapies have been reported, which could instruct us about the immunological control of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Specific antibodies are detectable within 2–19 days and have been extensively analyzed for diagnostic purposes and vaccine development. It is unclear whether a durable antibody response is required for recovery of COVID-19 or whether it might even contribute to the pathogenesis by perpetuating hyperinflammation as has been shown for the closely related middle-east-respiratory-syndrome (MERS) coronavirus.

J Neurol. 2021 Jan;268(1):5-7

Nasseri NN, Ghezelbash E, Zhai Y, Patra S, Riemann-Lorenz K, Heesen C, Rahn AC, Stellmann JP

Feasibility of a smartphone app to enhance physical activity in progressive MS: a pilot randomized controlled pilot trial over three months.

PeerJ. 2020 Jun 23;8:e9303

Witt G, Keminer O, Leu J, Tandon R, Meiser I, Willing A, Winschel I, Abt JC, Brändl B, Sébastien I, Friese MA, Müller FJ, Neubauer JC, Claussen C, Zimmermann H, Gribbon P, Pless O

An Automated and High-Throughput-Screening Compatible Pluripotent Stem Cell-Based Test Platform for Developmental and Reproductive Toxicity Assessment of Small Molecule Compounds

Cell Biol Toxicol. 2021 Apr;37(2):229-243.

Gunbey H, Has A, Aslan K, Saglam D, Avci U, Sayit A, Incesu L.

Microstructural white matter abnormalities in hypothyroidism evaluation with diffusion tensor imaging tract-based spatial statistical analysis

Purpose: Hypothyroidism is presented in a wide range from neuropsychiatric problems including depression, memory and cognitive disorders to poor motor coordination. Against the background of morphologic, functional and molecular changes on the white and grey matter of the brain, we aimed to investigate the effects of hypothyroidism on white matter (WM) integrity using tract-based spatial statistics (TBSS).Methods: Eighteen patients with hyperthyroidism and 14 age-sex-matched healthy control subjects were included in this study. TBSS was used in the diffusion tensor imaging study for whole-brain voxel wise analysis of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) of WM.Results: When compared to the control group, the whole brain TBSS revealed extensive reductions of FA in the supratentorial WM including corticospinal tract, posterior limb of the internal capsule (PLIC), uncinate fasciculus, inferior longitudinal fasciculus (p < 0.005). The ROI analyses showed RD increment of superior longitudinal fasciculus, AD decrement of cingulum (CIN), external capsule, PLIC and corpus callosum (CC) in patients with hypothyroidism (p < 0.005). Autoimmune and non-autoimmune hypothyroidism patient subgroups showed a significant difference in terms of hippocampus FA, CIN MD, CC MD, CC AD, CIN RD, SLF RD, CC RD (p < 0.005). CIN FA values showed a negative correlation with the Beck Depression Inventory (p = 0.007, r = – 852).Conclusions: These preliminary results of TBSS analyses represented FA and AD decrement, and RD increment in several WM tracts and indicates the demyelination process underlying pathophysiology of clinical aspects of hypothyroidism.

Radiol Med 2021 Feb;126(2):283-290.

Stürner KH, Werz O, Koeberle A, Otto M, Pless O, Leypoldt F, Paul F, Heesen C.

Lipid Mediator Profiles Predict Response to Therapy With an Oral Frankincense Extract in Relapsing-Remitting Multiple Sclerosis

Sci Rep. 2020 May 29;10(1):8776

Bittner S, Steffen F, Uphaus T, Muthuraman M, Fleischer V, Salmen A, Luessi F, Berthele A, Klotz L, Meuth SG, Bayas A, Paul F, Hartung HP, Linker R, Heesen C, Stangel M, Wildemann B, Then Bergh F, Tackenberg B, Kuempfel T, Weber F, Zettl UK, Ziemann U, Tumani H, Groppa S, Mühlau M, Hemmer B, Wiendl H, Gold R, Zipp F; KKNMS consortium

Clinical Implications of Serum Neurofilament in Newly Diagnosed MS Patients: A Longitudinal Multicentre Cohort Study

EBioMedicine. 2020 Jun;56:102807

Pust GEA, Untiedt B, Weierstall-Pust R, Randerath J, Barabasch A, Rahn AC, Heesen C.

Medication beliefs in first-line and second-line treated multiple sclerosis patients

Mult Scler Relat Disord. 2020 May 4;42:102144

Gharakhanlou R, Wesselmann L, Rademacher A, Lampit A, Negaresh R, Kaviani M, Oberste M, Motl RW, Sandroff BM, Bansi J, Baker JS, Heesen C, Zimmer P, Javelle F.

Exercise training and cognitive performance in persons with multiple sclerosis: A systematic review and multilevel meta-analysis of clinical trials.

Mult Scler. 2021 Nov;27(13):1977-1993.

Abrahamyan S, Eberspächer B, Hoshi MM, Aly L, Luessi F, Groppa S, Klotz L, Meuth SG, Schroeder C, Grüter T, Tackenberg B, Paul F, Then-Bergh F, Kümpfel T, Weber F, Stangel M, Bayas A, Wildemann B, Heesen C, Zettl U, Warnke C, Antony G, Hessler N, Wiendl H, Bittner S, Hemmer B, Gold R, Salmen A, Ruprecht K; German Competence Network Multiple Sclerosis (KKNMS); Other members of the KKNMS that acted as collaborators in this study.

Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis.

J Neurol Neurosurg Psychiatry. 2020 Jul;91(7):681-686

Faergeman SL, Evans H, Attfield KE, Desel C, Kuttikkatte SB, Sommerlund M, Jensen LT, Frokiaer J, Friese MA, Matthews PM, Luchtenborg C, Brügger B, Oturai AB, Dendrou CA, Fugger L.

A novel neurodegenerative spectrum disorder in patients with MLKL deficiency.

Cell Death Dis. 2020 May 1;11(5):303

Engel S, Graetz C, Salmen A, Muthuraman M, Toenges G, Ambrosius B, Bayas A, Berthele A, Heesen C, Klotz L, Kümpfel T, Linker RA, Meuth SG, Paul F, Stangel M, Tackenberg B, Then Bergh F, Tumani H, Weber F, Wildemann B, Zettl UK, Antony G, Bittner S, Groppa S, Hemmer B, Wiendl H, Gold R, Zipp F, Lill CM, Luessi F; German Competence Network of Multiple Sclerosis.

Is APOE ε4 associated with cognitive performance in early MS?

Neurol Neuroimmunol Neuroinflamm. 2020 May 1;7(4):e728.

Topp J, Heesen C, Augustin M, Andrees V,Blome C

Challenges and lessons learned from using anchoring vignettes to explore quality of liefe response behavior

Qual Life Res. 2020 Aug;29(8):2149-2159

Heitmann H, Haller B, Tiemann L, Mühlau M, Berthele A, Tölle TR, Salmen A, Ambrosius B, Bayas A, Asseyer S, Hartung HP, Heesen C, Stangel M, Wildemann B, Haars S, Groppa S, Luessi F, Kümpfel T, Nischwitz S, Meuth SG, Klotz L, Linker RA, Zettl UK, Ziemann U, Tumani H, Tackenberg B, Zipp F, Wiendl H, Gold R, Hemmer B, Ploner M.

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

Pain. 2020 Apr;161(4):787-796

Dalgas U, Hvid LG, Kwakkel G, Motl RW, de Groot V, Feys P, Op't Eijnde B, Coote S, Beckerman H, Pfeifer K, Streber R, Peters S, Riemann-Lorenz K, Rosenkranz SC, Centonze D, Van Asch P, Bansi J, Sandroff BM, Pilutti LA, Ploughman M, Freeman J, Paul L, Dawes H, Romberg A, Kalron A, Stellmann JP, Friese MA, Heesen C.

Moving exercise research in multiple sclerosis forward (the MoXFo initiative): Developing consensus statements for research.

Mult Scler. 2020 Oct;26(11):1303-1308

Faizy TD, Thaler C, Broocks G, Flottmann F, Leischner H, Kniep H, Nawabi J, Schön G, Stellmann JP, Kemmling A, Reddy R, Heit JJ, Fiehler J, Kumar D, Hanning U.

The Myelin Water Fraction Serves as a Marker for Age-Related Myelin Alterations in the Cerebral White Matter – A Multiparametric MRI Aging Study.

Front Neurosci. 2020 Feb 24;14:136

Riemann-Lorenz K, Motl RW, Casey B, Coote S, Daubmann A, Heesen C.

Possible determinants of long-term adherence to physical activity in multiple sclerosis-theory-based development of a comprehensive questionnaire and results from a German survey study.

Disabil Rehabil. 2021 Nov;43(22):3175-3188

Aslan K, Turco V, Blobner J, Sonner JK, Liuzzi AR, Nunez NG, De Feo D, Kickingereder P, Fischer M, Green E, Sadik A, Friedrich M, Sanghvi K, Kilian M, Cichon F, Wolf L, Jähne K, von Landenberg A, Bunse L, Sahm F, Schriompf D., Meyer J, Allen A, Brugnara G, Röth R, Pfleiderer K, Niesler B, von Deimling A, Opitz C, Breckwoldt MO, Heiland S, Bendszus M, Wick W, Becher B, Platten M

Heterogeneity of Response to Immune Checkpoint Blockade in Hypermutated Expermimental Gliomas

Nat Commun 2020 Feb 178;11(1):931

Conversion to secondary progressive multiple sclerosis: Multistakeholder experiences and needs in Italy

PloS One 2020 Feb 13;15(2):e0228587

Has Silemek AC, Fischer L, Pöttgen J, Penner IK, Engel AK, Heesen C, Gold SM, Stellmann JP.

Functional and structural connectivity substrates of cognitive performance in relapsing remitting multiple sclerosis with mild disability.

Neuroimage Clin. 2020 Jan 12;25:102177

van der Lee SJ, Conway OJ, Jansen I, Carrasquillo MM, Kleineidam L, van den Akker E, Hernández I, van Eijk KR, Stringa N, Chen JA, Zettergren A, Andlauer TFM, Diez-Fairen M, Simon-Sanchez J, Lleó A, Zetterberg H, Nygaard M, Blauwendraat C, Savage JE, Mengel-From J, Moreno-Grau S, Wagner M, Fortea J, Keogh MJ, Blennow K, Skoog I, Friese MA, Pletnikova O, Zulaica M, Lage C, de Rojas I, Riedel-Heller S, Illán-Gala I, Wei W, Jeune B, Orellana A, Then Bergh F, Wang X, Hulsman M, Beker N, Tesi N, Morris CM, Indakoetxea B, Collij LE, Scherer M, Morenas-Rodríguez E, Ironside JW, van Berckel BNM, Alcolea D, Wiendl H, Strickland SL, Pastor P, Rodríguez Rodríguez E; DESGESCO (Dementia Genetics Spanish Consortium); EADB (Alzheimer Disease European DNA biobank); IFGC (International FTD-Genomics Consortium); IPDGC (The International Parkinson Disease Genomics Consortium); RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia); Netherlands Brain Bank (NBB), Boeve BF, Petersen RC, Ferman TJ, van Gerpen JA, Reinders MJT, Uitti RJ, Tárraga L, Maier W, Dols-Icardo O, Kawalia A, Dalmasso MC, Boada M, Zettl UK, van Schoor NM, Beekman M, Allen M, Masliah E, de Munain AL, Pantelyat A, Wszolek ZK, Ross OA, Dickson DW, Graff-Radford NR, Knopman D, Rademakers R, Lemstra AW, Pijnenburg YAL, Scheltens P, Gasser T, Chinnery PF, Hemmer B, Huisman MA, Troncoso J, Moreno F, Nohr EA, Sørensen TIA, Heutink P, Sánchez-Juan P, Posthuma D; GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Clarimón J, Christensen K, Ertekin-Taner N, Scholz SW, Ramirez A, Ruiz A, Slagboom E, van der Flier WM, Holstege H.

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

Acta Neuropathol 2020 May;139(5):959-962.

Stürner KH, Siembab I, Schön G, Stellmann JP, Heidari N, Fehse B, Heesen C, Eiermann TH, Martin R, Binder TM.

Is multiple sclerosis progression associated with the HLA-DR15 haplotype?

Mult Scler J Exp Transl Clin. 2019 Dec 9;5(4)

Ringelstein M, Harmel J, Zimmermann H, Brandt AU, Paul F, Haarmann A, Buttmann M, Hümmert MW, Trebst C, Schroeder C, Ayzenberg I, Kleiter I, Hellwig K, Havla J, Kümpfel T, Jarius S, Wildemann B, Rommer P, Weber MS, Pellkofer H, Röpke L, Geis C, Retzlaff N, Zettl U, Deppe M, Klotz L, Young K, Stellmann JP, Kaste M, Kermer P, Marouf W, Lauda F, Tumani H, Graf J, Klistorner A, Hartung HP, Aktas O, Albrecht P; Neuromyelitis Optica Study Group (NEMOS).

Longitudinal optic neuritis-unrelated visual evoked potential changes in NMO spectrum disorders.

Neurology. 2020 Jan 28;94(4):e407-e418

Gold SM, Otte C.

Differential impact of affective and cognitive symptoms on remission of major depression.

Lancet Psychiatry. 2019 Dec;6(12):980.

Topp J, Andrees V, Heesen C, Augustin M, Blome C

Recall of health-related quality of life: how does memory affect the SF-6D in patients with psoriasis or multiple sclerosis? A prospective observational study in Germany.

BMJ Open. 2019 Nov 21;9(11):e032859

Sonner, J. K., Keil, M., Falk-Paulsen, M., Mishra, N., Rehman, A., Kramer, M., Deumelandt, K., Röwe, J., Sanghvi, K., Wolf, L., von Landenberg, A., Wolff, H., Bharti, R., Oezen, I., Lanz, T. V., Wanke, F., Tang, Y., Brandao, I., Mohapatra, S. R., Epping, L., Grill, A., Röth, R., Niesler, B., Meuth, S. G., Opitz, C. A., Okun, J. G., Reinhardt, C., Kurschus, F. C., Wick, W., Bode, H. B., Rosenstiel, P., Platten, M.

Dietary Tryptophan Links Encephalogenicity of Autoreactive T Cells With Gut Microbial Ecology

Nat Commun 2019 Oct 25;10(1):4877

Ramien C, Yusko EC, Engler JB, Gamradt S, Patas K, Schweingruber N, Willing A, Rosenkranz SC, Diemert A, Harrison A, Vignali M, Sanders C, Robins HS, Tolosa E, Heesen C, Arck PC, Scheffold A, Chan K, Emerson RO, Friese MA, Gold SM.

T Cell Repertoire Dynamics during Pregnancy in Multiple Sclerosis.

Cell Rep. 2019 Oct 22;29(4):810-815

Palotai M, Nazeri A, Cavallari M, Healy BC, Glanz B, Gold SM, Weiner HL, Chitnis T, Guttmann CRG

History of fatigue in multiple sclerosis is associated with grey matter atrophy.

Fatigue in multiple sclerosis (MS) has been associated with brain damage with low replicability. Temporal fatigue fluctuations have not been considered. We assessed whether sustained fatigue (SF) associates more strongly with grey matter (GM) changes than reversible fatigue (RF). Patients were stratified into three groups according to historical fatigue levels: SF (n = 30, i.e. patients who reported fatigue at the latest ≥2 assessments), RF (n = 31, i.e. patients not fatigued at the latest assessment, but reported fatigue previously), and never fatigued (NF, n = 37). Groups were compared for brain GM volume using cross-sectional voxel-based and volumetric analyses of 3T T1-weighted MRI. Confounding effects of depression and related medications were also investigated. SF and RF patients showed similar anatomical distribution of GM atrophy. While we robustly replicated the anatomical patterns of GM atrophy described in previous work, we also found an association between hippocampal atrophy and fatigue. Depression showed confounding effects in frontal, parietal, occipital, accumbal and thalamic regions. Assessed treatments showed confounding effects in frontal, parietal and striatal areas. Our results suggest that history of clinically-relevant fatigue in currently non-fatigued patients is associated with GM atrophy, potentially explaining inconsistent findings of previous studies that stratified patients using a single fatigue assessment.

Sci Rep. 2019 Oct 14;9(1):14781.

Largey F, Jelcic I, Sospedra M, Heesen C, Martin R, Jelcic I.

Effects of natalizumab therapy on intrathecal antiviral antibody responses in MS

Neurol Neuroimmunol Neuroinflamm. 2019 Sep 25;6(6)

Solari A, Giovannetti AM, Giordano A, Tortorella C, Torri Clerici V, Brichetto G, Granella F, Lugaresi A, Patti F, Salvetti M, Pesci I, Pucci E, Centonze D, Danni MC, Bonavita S, Ferraro D, Gallo A, Gajofatto A, Nociti V, Grimaldi L, Grobberio M, Lanzillo R, Di Giovanni R, Gregori S, Manni A, Pietrolongo E, Bertagnoli S, Ronzoni M, Compagnucci L, Fantozzi R, Allegri B, Arena S, Buscarinu MC, Sabattini L, Quartuccio ME, Tsantes E, Confaloneri P, Tacchino A, Schiffmann I, Rahn AC, Kleiter I, Messmer Uccelli M, Barabasch A, Heesen C, The ManTra Project

Conversion to Secondary Progressive Multiple Sclerosis: Patient Awareness and Needs. Results From an Online Survey in Italy and Germany.

Front Neurol. 2019 Aug 22;10:916.

Golde S., Wingenfeld K, Riepenhausen A, Schröter N, Fleischer J, Prüssner J, Grimm S, Fan Y, Hellmann-Regen J, Beck A, Gold SM, Otte C.

Healthy women with severe early life trauma show altered neural facilitation of emotion inhibition under acute stress.

Psychol Med. 2020; 50(12):2075-2084

Engler JB, Heckmann NF, Jäger J, Gold SM, Friese MA.

Pregnancy Enables Expansion of Disease-Specific Regulatory T Cells in an Animal Model of Multiple Sclerosis.

J Immunol. 2019 Oct 1;203(7):1743-1752.

Kesgin F, Suddick K, Heesen c, Wright J.

Developing a fall prevention program: what are the views and opinions of people with multiple sclerosis?

Dishabil. Rehabil. 2021 Apr;43(8):1065-1073

Schirmer L, Velmeshev D, Holmqvist S, Kaufmann M, Werneburg S, Jung D, Vistnes S, Stockley JH, Young A, Steindel M, Tung B, Goyal N, Bhaduri A, Mayer S, Engler JB, Bayraktar OA, Franklin RJM, Haeussler M, Reynolds R, Schafer DP, Friese MA, Shiow LR, Kriegstein AR, Rowitch DH.

Neuronal vulnerability and multilineage diversity in multiple sclerosis.

Nature. 2019 Sep;573(7772):75-82.

Bittner S, Engel S, Lange C, Weber MS, Haghikia A, Luessi F, Korn T, Klotz L, Bayas A, Paul F, Heesen C, Stangel M, Wildemann B, Bergh FT, Tackenberg B, Trebst C, Warnke C, Linker R, Kerschensteiner M, Zettl U, Tumani H, Brück W, Meuth SG1 Kümpfel T, Hemmer B, Wiendl H, Gold R, Zipp F.

Diagnostics and treatment of tuberculosis under immunotherapy for multiple sclerosis : Current status and recommendations in Germany.

Nervenarzt. 2019 Dec;90(12):1245-1253

Andrees V, Westenhöfer J, Blome C, Heesen C, Augustin M, Topp J.

Towards patients‘ understanding of health-related quality of life-a mixed-method study in psoriasis and multiple sclerosis.

Qual Life Res. 2019 Oct;28(10):2717-2729.

Weygandt M, Behrens J, Brasanac J, Söder E, Meyer-Arndt L, Wakonig K, Ritter K, Brandt AU, Bellmann-Strobl J, Gold SM, Haynes JD, Paul F.

Neural mechanisms of perceptual decision-making and their link to neuropsychiatric symptoms in multiple sclerosis.

Mult Scler Relat Disord. 2019 May 30;33:139-145

Alegiani AC, Albrecht S, Rahn AC, Köpke S, Thomalla G, Heesen C.

Reasons for delayed admission after stroke: results of a qualitative and quantitative survey.

Patient Prefer Adherence. 2019 May 8;13:739-747

van der Lee SJ, Conway OJ, Jansen I, Carrasquillo MM, Kleineidam L, van den Akker E, Hernández I, van Eijk KR, Stringa N, Chen JA, Zettergren A, Andlauer TFM, Diez-Fairen M, Simon-Sanchez J, Lleó A, Zetterberg H, Nygaard M, Blauwendraat C, Savage JE, Mengel-From J, Moreno-Grau S, Wagner M, Fortea J, Keogh MJ, Blennow K, Skoog I, Friese MA, Pletnikova O, Zulaica M, Lage C, de Rojas I, Riedel-Heller S, Illán-Gala I, Wei W, Jeune B, Orellana A, Then Bergh F, Wang X, Hulsman M, Beker N, Tesi N Morris CM, Indakoetxea B, Collij LE, Scherer M, Morenas-Rodríguez E, Ironside JW, van Berckel BNM, Alcolea D, Wiendl H, Strickland SL, Pastor P, Rodríguez Rodríguez E; DESGESCO (Dementia Genetics Spanish Consortium), EADB (Alzheimer Disease European DNA biobank); EADB (Alzheimer Disease European DNA biobank); IFGC (International FTD-Genomics Consortium), IPDGC (The International Parkinson Disease Genomics Consortium); IPDGC (The International Parkinson Disease Genomics Consortium); RiMod-FTD (Risk and Modifying factors in Fronto-Temporal Dementia); Netherlands Brain Bank (NBB), Boeve BF, Petersen RC, Ferman TJ, van Gerpen JA, Reinders MJT, Uitti RJ, Tárraga L, Maier W6,, Dols-Icardo O, Kawalia A, Dalmasso MC, Boada M, Zettl UK, van Schoor NM, Beekman M, Allen M, Masliah E, de Munain AL, Pantelyat A, Wszolek ZK, Ross OA, Dickson DW, Graff-Radford NR, Knopman D, Rademakers R, Lemstra AW, Pijnenburg YAL, Scheltens P, Gasser T5, Chinnery PF, Hemmer B, Huisman MA, Troncoso J, Moreno F, Nohr EA, Sørensen TIA, Heutink P, Sánchez-Juan P, Posthuma D; GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Clarimón J, Christensen K, Ertekin-Taner N, Scholz SW, Ramirez A, Ruiz A, Slagboom E, van der Flier WM, Holstege H.

A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.

Acta Neuropathol. 2019 Aug;138(2):237-250

Faizy TD, Broocks G, Frischmuth I, Westermann C, Flottmann F, Schönfeld MH2, Nawabi J, Leischner H, Kutzner D2, Stellmann JP, Heesen C, Fiehler J, Gellißen S, Hanning U.

Spectrally fat-suppressed coronal 2D TSE sequences may be more sensitive than 2D STIR for the detection of hyperintense optic nerve lesions.

Eur Radiol. 2019 Nov;29(11):6266-6274

Schattling B, Engler JB, Volkmann C, Rothammer N, Woo MS, Petersen M, Winkler I, Kaufmann M, Rosenkranz SC, Fejtova A, Thomas U, Bose A, Bauer S, Träger S, Miller KK, Brück W, Duncan KE, Salinas G, Soba P, Gundelfinger ED, Merkler D, Friese MA.

Bassoon proteinopathy drives neurodegeneration in multiple sclerosis.

Nat Neurosci. 2019 Jun;22(6):887-896

Pust GEA, Pöttgen J, Randerath J, Lau S, Heesen C, Gold SM, Penner IK

In search of distinct MS-related fatigue subtypes: results from a multi-cohort analysis in 1.403 MS patients.

J Neurol. 2019 Jul;266(7):1663-1673

Chae WR, Nagel JM, Kuehl LK, Gold SM, Wingenfeld K, Otte C.

Predictors of response and remission in a naturalistic inpatient sample undergoing multimodal treatment for depression.

J Affect Disord. 2019 Jun 1;252:99-106

Riemann-Lorenz K, Wienert J, Streber R, Motl RW, Coote S, Heesen C

Long-term physical activity in people with multiple sclerosis: exploring expert views on facilitators and barriers.

Disabil Rehabil. 2019 Mar 23:1-13

Schuster S, Ozga AK, Stellmann JP, Deb-Chatterji M, Häußler V, Matschke J, Gerloff C, Thomalla G, Magnus T.

Relapse rates and long-term outcome in primary angiitis of the central nervous system.

J Neurol. 2019 Jun;266(6):1481-1489

Schaefer LM, Poettgen J, Fischer A, Gold S, Stellmann JP, Heesen C

Impairment and restrictions in possibly benign multiple sclerosis.

Brain Behav. 2019 April;9(4):e01259

Faizy TD, Broocks G, Thaler C, Rauch G, Gebert P, Stürner KH, Flottmann F, Leischner H, Kniep HC, Stellmann JP, Heesen C, Fiehler J, Gellißen S, Hanning U

Development of Cortical Lesion Volumes on Double Inversion Recovery MRI in Patients With Relapse-Onset Multiple Sclerosis.

Front Neurol. 2019 Feb 22;10:133

Engels K, Schiffmann I, Weierstall R, Rahn AC, Daubmann A, Pust G, Chard D, Lukas C, Scheiderbauer J, Stellmann JP, Heesen C

Emotions towards magnetic resonance imaging in people with multiple sclerosis.

Acta Neurol Scand. 2019 Jun;139(6):497-504.

Tintelnot J, Ufer F, Engler JB, Winkler H, Lücke K, Mittrücker HW, Friese MA

Arc/Arg3.1 defines dendritic cells and Langerhans cells with superior migratory ability independent of phenotype and ontogeny in mice

Eur J Immunol. 2019 May;49(5):724-736

Schreurs RRCE, Baumdick ME, Sagebiel AF, Kaufmann M, Mokry M, Klarenbeek PL, Schaltenberg N, Steinert FL, van Rijn JM, Drewniak A, The SML, Bakx R, Derikx JPM, de Vries N, Corpeleijn WE, Pals ST, Gagliani N, Friese MA, Middendorp S, Nieuwenhuis EES, Reinshagen K, Geijtenbeek TBH, van Goudoever JB, Bunders MJ.

Human Fetal TNF-α-Cytokine-Producing CD4+ Effector Memory T Cells Promote Intestinal Development and Mediate Inflammation Early in Life.

Immunity. 2019 Feb 19;50(2):462-476

Stork L, Brück W, von Gottberg P, Pulkowski U, Kirsten F, Glatzel M, Rauer S, Scheibe F, Radbruch H, Hammer E, Stürner KH, Kaulen B, Heesen C, Hoffmann F, Brock S, Pawlitzki M, Bopp T, Metz I.

Severe meningo-/encephalitis after daclizumab therapy for multiple sclerosis.

Mult Scler. 2019 Oct;25(12):1618-1632

Beckmann H, Augustin M, Heesen C, Poettgen J, Blome C.

Benefit evaluation in multiple sclerosis relapse treatment from the patients‘ perspective – Development and validation of a new questionnaire

Mult Scler Relat Disord. 2018 Dec 17;28:256-261

Hierweger AM, Engler JB, Friese MA, Reichardt HM, Lydon J, DeMayo F, Mittrücker HW, Arck PC.

Progesterone modulates the T cell response via glucocorticoid receptor-dependent pathways.

Am J Reprod Immunol. 2019 Feb.;81(2):e13084

Baquet L, Hasselmann H, Patra S, Stellmann JP, Vettorazzi E, Engel AK, Rosenkranz SC, Poettgen J, Gold SM, Schulz KH, Heesen C.

Short-term interval aerobic exercise training does not improve memory functioning in relapsing-remitting multiple sclerosis-a randomized controlled trial.

PeerJ. 2018 Dec 12;6:e6037

Heesen C., Rahn AC.

Guest Editorial: Shared Decision Making in Managing Multiple Sclerosis: Revisiting the Research Agenda.

Int J MS Care. 2018 Nov-Dec;20(6)

Hasselmann H, Gamradt S, Taenzer A, Nowacki J, Zain R, Patas K, Ramien C, Paul F, Wingenfeld K, Piber D, Gold SM, Otte C.

Pro-inflammatory Monocyte Phenotype and Cell-Specific Steroid Signaling Alterations in Unmedicated Patients With Major Depressive Disorder.

Front Immunol. 2018 Nov 23;9:2693

Johnen A, Bürkner PC, Landmeyer NC, Ambrosius B, Calabrese P, Motte J, Hessler N, Antony G, König IR, Klotz L, Hoshi MM, Aly L, Groppa S, Luessi F, Paul F, Tackenberg B, Bergh FT, Kümpfel T, Tumani H, Stangel M, Weber F, Bayas A, Wildemann B, Heesen C, Zettl UK, Zipp F, Hemmer B, Meuth SG, Gold R, Wiendl H, Salmen A; German Competence Network Multiple Sclerosis (KKNMS).

Can we predict cognitive decline after initial diagnosis of multiple sclerosis? Results from the German National early MS cohort (KKNMS).

J Neurol. 2019 Feb;266(2):386-397

Giordano A, Liethmann K, Köpke S, Poettgen J, Rahn AC, Drulovic J, Beckmann Y, Sastre-Garriga J, Galea I, Heerings M, Jongen PJ, Vettorazzi E, Solari A, Heesen C; AutoMS group

Risk knowledge of people with relapsing-remitting multiple sclerosis – Results of an international survey

PLoS One. 2018 Nov 29;13(11):e0208004.

Kleiter I, Gahlen A, Borisow N, Fischer K, Wernecke KD, Hellwig K, Pache F, Ruprecht K, Havla J, Kümpfel T, Aktas O, Hartung HP, Ringelstein M, Geis C, Kleinschnitz C, Berthele A, Hemmer B, Angstwurm K, Stellmann JP, Schuster S, Stangel M, Lauda F, Tumani H, Mayer C, Krumbholz M, Zeltner L, Ziemann U, Linker R, Schwab M, Marziniak M, Then Bergh F, Hofstadt-van Oy U, Neuhaus O, Zettl UK, Faiss J, Wildemann B, Paul F, Jarius S, Trebst C; NEMOS (Neuromyelitis Optica Study Group).

Apheresis therapies for NMOSD attacks: A retrospective study of 207 therapeutic interventions.

Neurol Neuroimmunol Neuroinflamm. 2018 Sep 26;5(6):e504

International Multiple Sclerosis Genetics Consortium. Electronic address: chris.cotsapas@yale.edu; International Multiple Sclerosis Genetics Consortium. Mitrovič M, Patsopoulos NA, Beecham AH, Dankowski T, Goris A, Dubois B, D'hooghe MB, Lemmens R, Van Damme P, Søndergaard HB, Sellebjerg F, Sorensen PS, Ullum H, Thørner LW, Werge T, Saarela J, Cournu-Rebeix I, Damotte V, Fontaine B, Guillot-Noel L, Lathrop M, Vukusik S, Gourraud PA, Andlauer TFM, Pongratz V, Buck D, Gasperi C, Bayas A, Heesen C, Kümpfel T, Linker R, Paul F, Stangel M, Tackenberg B, Bergh FT, Warnke C, Wiendl H, Wildemann B, Zettl U, Ziemann U, Tumani H, Gold R, Grummel V, Hemmer B, Knier B, Lill CM, Luessi F, Dardiotis E, Agliardi C, Barizzone N, Mascia E, Bernardinelli L, Comi G, Cusi D, Esposito F, Ferrè L, Comi C, Galimberti D, Leone MA, Sorosina M, Mescheriakova J, Hintzen R, van Duijn C, Theunissen CE, Bos SD, Myhr KM, Celius EG, Lie BA, Spurkland A, Comabella M, Montalban X, Alfredsson L, Stridh P, Hillert J, Jagodic M, Piehl F, Jelčić I, Martin R, Sospedra M, Ban M, Hawkins C, Hysi P, Kalra S, Karpe F, Khadake J, Lachance G, Neville M, Santaniello A, Caillier SJ, Calabresi PA, Cree BAC, Cross A, Davis MF, Haines JL, de Bakker PIW, Delgado S, Dembele M, Edwards K, Fitzgerald KC, Hakonarson H, Konidari I, Lathi E, Manrique CP, Pericak-Vance MA, Piccio L, Schaefer C, McCabe C, Weiner H, Goldstein J, Olsson T, Hadjigeorgiou G, Taylor B, Tajouri L, Charlesworth J, Booth DR, Harbo HF, Ivinson AJ, Hauser SL, Compston A, Stewart G, Zipp F, Barcellos LF, Baranzini SE, Martinelli-Boneschi F, D'Alfonso S, Ziegler A, Oturai A, McCauley JL, Sawcer SJ, Oksenberg JR, De Jager PL, Kockum I, Hafler DA, Cotsapas C.

Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk.

Cell. 2018 Nov 29;175(6):1679-1687

Heesen C, Scalfari A, Galea I.

Prognostic information for people with MS: Impossible or inevitable?

Mult Scler. 2020 Jun;26(7):771-773.

Tezer FI, Erdal A, Gumusyayla S, Has AC, Gocmen R, Oguz KK

Differences in diffusion tensor imaging changes between narcolepsy with and without cataplexy.

Sleep Med. 2018 Sep 18;52:128-133

Faizy TD, Kumar D, Broocks G, Thaler C, Flottmann F, Leischner H, Kutzner D, Hewera S, Dotzauer D, Stellmann JP,, Reddy R, Fiehler J, Sedlacik J, Gellißen S.

Age-Related Measurements of the Myelin Water Fraction derived from 3D multi-echo GRASE reflect Myelin Content of the Cerebral White Matter.

Sci Rep. 2018 Oct 9;8(1):14991

Faizy TD, Kumar D, Broocks G, Thaler C, Flottmann F, Leischner H, Kutzner D, Hewera S, Dotzauer D, Stellmann JP, Reddy R, Fiehler J, Sedlacik J, Gellißen S.

Age-Related Measurements of the Myelin Water Fraction derived from 3D multi-echo GRASE reflect Myelin Content of the Cerebral White Matter.

Sci Rep. 2018 Oct 9;8(1):14991.

Stanelle-Bertram S, Walendy-Gnirß K, Speiseder T, Thiele S, Asante IA, Dreier C, Kouassi NM, Preuß A, Pilnitz-Stolze G, Müller U, Thanisch S, Richter M, Scharrenberg R, Kraus V, Dörk R, Schau L, Herder V, Gerhauser I, Pfankuche VM, Käufer C, Walt I , Moraes T, Sellau J, Hoenow S, Schmidt-Chanasit J, Jansen S, Schattling B, Ittrich H, Bartsch U, Renné T, Bartenschlager R, Arck P, Cadar D, Friese MA, Vapalahti O, Lotter H, Benites S, Rolling L, Gabriel M, Baumgärtner W, Morellini F, Hölter SM, Amarie O, Fuchs H, Hrabe de Angelis M, Löscher W, Calderon de Anda F, Gabriel G

Male offspring born to mildly ZIKV-infected mice are at risk of developing neurocognitive disorders in adulthood.

Nat Microbiol. 2018 Oct;3(10):1161-1174.

Filser M, Schreiber H, Pöttgen J, Ullrich S, Lang M, Penner IK.

The Brief International Cognitive Assessment in Multiple Sclerosis (BICAMS): results from the German validation study.

J Neurol. 2018 Nov;265(11):2587-2593