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3. GateNet: A novel Neural Network Architecture for Automated Flow Cytometry Gating

Author

Fisch, Lukas, Heming, Michael O., Schulte-Mecklenbeck, Andreas, Gross, Catharina C., Zumdick, Stefan, Barkhau, Carlotta, Emden, Daniel, Ernsting, Jan, Leenings, Ramona, Sarink, Kelvin, Winter, Nils R., Dannlowski, Udo, Wiendl, Heinz, Hörste, Gerd Meyer zu, and Hahn, Tim

Subjects
Computer Science - Machine Learning
Abstract

Flow cytometry is widely used to identify cell populations in patient-derived fluids such as peripheral blood (PB) or cerebrospinal fluid (CSF). While ubiquitous in research and clinical practice, flow cytometry requires gating, i.e. cell type identification which requires labor-intensive and error-prone manual adjustments. To facilitate this process, we designed GateNet, the first neural network architecture enabling full end-to-end automated gating without the need to correct for batch effects. We train GateNet with over 8,000,000 events based on N=127 PB and CSF samples which were manually labeled independently by four experts. We show that for novel, unseen samples, GateNet achieves human-level performance (F1 score ranging from 0.910 to 0.997). In addition we apply GateNet to a publicly available dataset confirming generalization with an F1 score of 0.936. As our implementation utilizes graphics processing units (GPU), gating only needs 15 microseconds per event. Importantly, we also show that GateNet only requires ~10 samples to reach human-level performance, rendering it widely applicable in all domains of flow cytometry.

Published
2023

6. The Development of Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody for Practical Use in Relapsing Multiple Sclerosis Treatment.

Author

Kappos, Ludwig, Bar-Or, Amit, Wiendl, Heinz, Paling, David, Williams, Mitzi, Gold, Ralf, Chan, Andrew, Milo, Ron, Das Gupta, Ayan, Karlsson, Goeril, Sullivan, Roseanne, Graham, Gordon, Merschhemke, Martin, Häring, Dieter, Vermersch, Patrick, and Hauser, Stephen

Subjects
ALITHIOS, ASCLEPIOS I/II, Anti-CD20 monoclonal antibody, Benefit-risk, Ofatumumab, Relapsing multiple sclerosis, Self-administration, Subcutaneous
Abstract

The importance of B cells in multiple sclerosis (MS) has been demonstrated through the advent of B-cell-depleting anti-CD20 antibody therapies. Ofatumumab is the first fully human anti-CD20 monoclonal antibody (mAb) developed and tested for subcutaneous (SC) self-administration at monthly doses of 20 mg, and has been approved in the US, UK, EU, and other regions and countries worldwide for the treatment of relapsing MS. The development goal of ofatumumab was to obtain a highly efficacious anti-CD20 therapy, with a safety and tolerability profile that allows for self-administration by MS patients at home and a positive benefit-risk balance for use in the broad relapsing MS population. This development goal was enabled by the unique binding site, higher affinity to B cells, and higher potency of ofatumumab compared to previous anti-CD20 mAbs; these properties of ofatumumab facilitate rapid B-cell depletion and maintenance with a low dose at a low injection volume (20 mg/0.4 ml). The high potency in turn enables the selective targeting of B cells that reside in the lymphatic system via subcutaneous (SC) administration. Through a comprehensive dose-finding program in two phase 2 studies (one intravenous and one SC) and model simulations, it was found that safety and tolerability can be further improved, and the risk of systemic injection-related reactions (IRRs) minimized, by avoiding doses ≥ 30 mg, and by reaching initial and rapid B-cell depletion via stepwise weekly administration of ofatumumab at Weeks 0, 1, and 2 (instead of a single high dose). Once near-complete B-cell depletion is reached, it can be maintained by monthly doses of 20 mg/0.4 ml. Indeed, in phase 3 trials (ASCLEPIOS I/II), rapid and sustained near-complete B-cell depletion (largely independent of body weight, race and other factors) was observed with this dosing regimen, which resulted in superior efficacy of ofatumumab versus teriflunomide on relapse rates, disability worsening, neuronal injury (serum neurofilament light chain), and imaging outcomes. Likely due to its fully human nature, ofatumumab has a low immunogenic risk profile-only 2 of 914 patients receiving ofatumumab in ASCLEPIOS I/II developed anti-drug antibodies-and this may also underlie the infrequent IRRs (20% with ofatumumab vs. 15% with the placebo injection in the teriflunomide arm) that were mostly (99.8%) mild to moderate in severity. The overall rates of infections and serious infections in patients treated with ofatumumab were similar to those in patients treated with teriflunomide (51.6% vs. 52.7% and 2.5% vs. 1.8%, respectively). The benefit-risk profile of ofatumumab was favorable compared to teriflunomide in the broad RMS population, and also in the predefined subgroups of both recently diagnosed and/or treatment-naïve patients, as well as previously disease-modifying therapy-treated patients. Interim data from the ongoing extension study (ALITHIOS) have shown that long-term treatment with ofatumumab up to 4 years is well-tolerated in RMS patients, with no new safety risks identified. In parallel to the phase 3 trials in which SC administration was carried out with a pre-filled syringe, an autoinjector pen for more convenient self-administration of the ofatumumab 20 mg dose was developed and is available for use in clinical practice.

Published
2023

8. Evolution of retinal degeneration and prediction of disease activity in relapsing and progressive multiple sclerosis

Author

Krämer, Julia, Balloff, Carolin, Weise, Margit, Koska, Valeria, Uthmeier, Yannik, Esderts, Isabell, Nguyen-Minh, Mai, Zimmerhof, Moritz, Hartmann, Alex, Dietrich, Michael, Ingwersen, Jens, Lee, John-Ih, Havla, Joachim, Kümpfel, Tania, Kerschensteiner, Martin, Häußler, Vivien, Heesen, Christoph, Stellmann, Jan-Patrick, Zimmermann, Hanna G., Oertel, Frederike C., Ringelstein, Marius, Brandt, Alexander U., Paul, Friedemann, Aktas, Orhan, Hartung, Hans-Peter, Wiendl, Heinz, Meuth, Sven G., and Albrecht, Philipp

Published
2024
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9. Cell-mediated cytotoxicity within CSF and brain parenchyma in spinal muscular atrophy unaltered by nusinersen treatment

Author

Lu, I-Na, Cheung, Phyllis Fung-Yi, Heming, Michael, Thomas, Christian, Giglio, Giovanni, Leo, Markus, Erdemir, Merve, Wirth, Timo, König, Simone, Dambietz, Christine A., Schroeter, Christina B., Nelke, Christopher, Siveke, Jens T., Ruck, Tobias, Klotz, Luisa, Haider, Carmen, Höftberger, Romana, Kleinschnitz, Christoph, Wiendl, Heinz, Hagenacker, Tim, and Meyer zu Horste, Gerd

Published
2024
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11. Translational imaging of TSPO reveals pronounced innate inflammation in human and murine CD8 T cell–mediated limbic encephalitis

Author

Gallus, Marco, Roll, Wolfgang, Dik, Andre, Barca, Cristina, Zinnhardt, Bastian, Hicking, Gordon, Mueller, Christoph, Naik, Venu Narayanan, Anstötz, Max, Krämer, Julia, Rolfes, Leoni, Wachsmuth, Lydia, Pitsch, Julika, van Loo, Karen MJ, Räuber, Saskia, Okada, Hideho, Wimberley, Catriona, Strippel, Christine, Golombeck, Kristin S, Johnen, Andreas, Kovac, Stjepana, Groß, Catharina C, Backhaus, Philipp, Seifert, Robert, Lewerenz, Jan, Surges, Rainer, Elger, Christian E, Wiendl, Heinz, Ruck, Tobias, Becker, Albert J, Faber, Cornelius, Jacobs, Andreas H, Bauer, Jan, Meuth, Sven G, Schäfers, Michael, and Melzer, Nico

Subjects
Biomedical and Clinical Sciences, Immunology, Neurosciences, Biomedical Imaging, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Animals, Humans, Mice, Carrier Proteins, Inflammation, Limbic Encephalitis, Positron-Emission Tomography, Receptors, GABA
Abstract

Autoimmune limbic encephalitis (ALE) presents with new-onset mesial temporal lobe seizures, progressive memory disturbance, and other behavioral and cognitive changes. CD8 T cells are considered to play a key role in those cases where autoantibodies (ABs) target intracellular antigens or no ABs were found. Assessment of such patients presents a clinical challenge, and novel noninvasive imaging biomarkers are urgently needed. Here, we demonstrate that visualization of the translocator protein (TSPO) with [18F]DPA-714-PET-MRI reveals pronounced microglia activation and reactive gliosis in the hippocampus and amygdala of patients suspected with CD8 T cell ALE, which correlates with FLAIR-MRI and EEG alterations. Back-translation into a preclinical mouse model of neuronal antigen-specific CD8 T cell-mediated ALE allowed us to corroborate our preliminary clinical findings. These translational data underline the potential of [18F]DPA-714-PET-MRI as a clinical molecular imaging method for the direct assessment of innate immunity in CD8 T cell-mediated ALE.

Published
2023

12. Visually Evoked Potential as Prognostic Biomarker for Neuroaxonal Damage in Multiple Sclerosis From a Multicenter Longitudinal Cohort

Author

Oertel, Frederike Cosima, Krämer, Julia, Motamedi, Seyedamirhosein, Keihani, Azeen, Zimmermann, Hanna G, Dimitriou, Nikolaos G, Condor-Montes, Shivany, Bereuter, Charlotte, Cordano, Christian, Abdelhak, Ahmed, Trip, Anand, Aktas, Orhan, Meuth, Sven G, Wiendl, Heinz, Ruprecht, Klemens, Bellmann-Strobl, Judith, Paul, Friedemann, Petzold, Axel, Brandt, Alexander U, Albrecht, Philipp, and Green, Ari J

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Neurodegenerative, Clinical Research, Multiple Sclerosis, Neurosciences, Eye Disease and Disorders of Vision, Brain Disorders, Autoimmune Disease, Eye, Neurological, Humans, Male, Evoked Potentials, Optic Neuritis, Prognosis, Retina, Retinal Ganglion Cells, Female, Adult, Middle Aged
Abstract

Background and objectivesWith the increasing use of visually evoked potentials (VEPs) as quantitative outcome parameters for myelin in clinical trials, an in-depth understanding of longitudinal VEP latency changes and their prognostic potential for subsequent neuronal loss will be required. In this longitudinal multicenter study, we evaluated the association and prognostic potential of VEP latency for retinal neurodegeneration, measured by optical coherence tomography (OCT), in relapsing-remitting MS (RRMS).MethodsWe included 293 eyes of 147 patients with RRMS (age [years, median ± SD] 36 ± 10, male sex 35%, F/U [years, median {IQR} 2.1 {1.5-3.9}]): 41 eyes had a history of optic neuritis (ON) ≥6 months before baseline (CHRONIC-ON), and 252 eyes had no history of ON (CHRONIC-NON). P100 latency (VEP), macular combined ganglion cell and inner plexiform layer volume (GCIPL), and peripapillary retinal nerve fiber layer thickness (pRNFL) (OCT) were quantified.ResultsP100 latency change over the first year predicted subsequent GCIPL loss (36 months) across the entire chronic cohort (p = 0.001) and in (and driven by) the CHRONIC-NON subset (p = 0.019) but not in the CHRONIC-ON subset (p = 0.680). P100 latency and pRNFL were correlated at baseline (CHRONIC-NON p = 0.004, CHRONIC-ON p < 0.001), but change in P100 latency and pRNFL were not correlated. P100 latency did not differ longitudinally between protocols or centers.DiscussionVEP in non-ON eyes seems to be a promising marker of demyelination in RRMS and of potential prognostic value for subsequent retinal ganglion cell loss. This study also provides evidence that VEP may be a useful and reliable biomarker for multicenter studies.

Published
2023

15. Safety experience with continued exposure to ofatumumab in patients with relapsing forms of multiple sclerosis for up to 3.5 years

Author

Hauser, Stephen L, Cross, Anne H, Winthrop, Kevin, Wiendl, Heinz, Nicholas, Jacqueline, Meuth, Sven G, Giacomini, Paul S, Saccà, Francesco, Mancione, Linda, Zielman, Ronald, Bagger, Morten, Gupta, Ayan Das, Häring, Dieter A, Jehl, Valentine, Kieseier, Bernd C, Pingili, Ratnakar, Stoneman, Dee, Su, Wendy, Willi, Roman, and Kappos, Ludwig

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Rare Diseases, Patient Safety, Infectious Diseases, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Antibodies, Monoclonal, Humanized, Humans, Multiple Sclerosis, Multiple Sclerosis, Relapsing-Remitting, Ofatumumab, multiple sclerosis, antibodies, monoclonal, relapsing multiple sclerosis, safety, Neurosciences, Neurology & Neurosurgery, Clinical sciences, Biological psychology
Abstract

BackgroundOfatumumab is approved for the treatment of relapsing multiple sclerosis (RMS). Ongoing safety reporting is crucial to understand its long-term benefit-risk profile.ObjectiveReport the safety and tolerability of ofatumumab in RMS after extended treatment up to 3.5 years.MethodsPatients completing ASCLEPIOS I/II (phase 3), APLIOS, or APOLITOS (phase 2) trials could enter ALITHIOS, a phase 3b, open-label, long-term safety study. We analyzed cumulative data of continuous ofatumumab treatment and of patients newly switched from teriflunomide.ResultsThe safety population had 1969 patients: 1292 continuously treated with ofatumumab (median time-at-risk 35.5 months, 3253 patient-years) and 677 newly switched (median time-at-risk 18.3 months, 986 patient-years). A total of 1650 patients (83.8%) had ⩾1 adverse events and 191 (9.7%) had ⩾1 serious adverse events. No opportunistic infections or progressive multifocal leukoencephalopathy events were identified; the risk of malignancies was low. Mean serum immunoglobulin (Ig) G levels remained stable. Mean IgM levels decreased but remained above the lower limit of normal in most. Serious infection incidence was low; decreased Ig levels were not associated with serious infections.ConclusionIn patients with up to 3.5 years' exposure, ofatumumab was well tolerated, with no new safety risks identified. These findings, with its established effectiveness, support a favorable benefit-risk profile of ofatumumab in RMS.

Published
2022

17. Chemokine-mediated cell migration into the central nervous system in progressive multifocal leukoencephalopathy

Author

Deffner, Marie, Schneider-Hohendorf, Tilman, Schulte-Mecklenbeck, Andreas, Falk, Simon, Lu, I-Na, Ostkamp, Patrick, Müller-Miny, Louisa, Schumann, Eva Maria, Goelz, Susan, Cahir-McFarland, Ellen, Thakur, Kiran T., De Jager, Philip L., Klotz, Luisa, Meyer zu Hörste, Gerd, Gross, Catharina C., Wiendl, Heinz, Grauer, Oliver M., and Schwab, Nicholas

Published
2024
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19. A real-world clinical validation for AI-based MRI monitoring in multiple sclerosis

Author

Barnett, Michael, Wang, Dongang, Beadnall, Heidi, Bischof, Antje, Brunacci, David, Butzkueven, Helmut, Brown, J. William L., Cabezas, Mariano, Das, Tilak, Dugal, Tej, Guilfoyle, Daniel, Klistorner, Alexander, Krieger, Stephen, Kyle, Kain, Ly, Linda, Masters, Lynette, Shieh, Andy, Tang, Zihao, van der Walt, Anneke, Ward, Kayla, Wiendl, Heinz, Zhan, Geng, Zivadinov, Robert, Barnett, Yael, and Wang, Chenyu

Published
2023
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21. Progressive multifocal leukoencephalopathy genetic risk variants for pharmacovigilance of immunosuppressant therapies

Author

Hatchwell, Eli, Smith, Edward B, Jalilzadeh, Shapour, Bruno, Christopher D, Taoufik, Yassine, Hendel-Chavez, Houria, Liblau, Roland, Brassat, David, Martin-Blondel, Guillaume, Wiendl, Heinz, Schwab, Nicholas, Cortese, Irene, Monaco, Maria Chiara, Imberti, Luisa, Capra, Ruggero, Oksenberg, Jorge R, Gasnault, Jacques, Stankoff, Bruno, Richmond, Todd A, Rancour, David M, Koralnik, Igor J, Hanson, Barbara A, Major, Eugene O, Chow, Christina R, and Eis, Peggy S

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Immunology, Genetics, Neurosciences, Neurodegenerative, Clinical Research, Hematology, Orphan Drug, Prevention, Infectious Diseases, Rare Diseases, Cancer, Brain Disorders, Autoimmune Disease, 5.1 Pharmaceuticals, Aetiology, Development of treatments and therapeutic interventions, 2.1 Biological and endogenous factors, Inflammatory and immune system, immunodeficiency, JC virus, multiple sclerosis, natalizumab, pharmacovigilance, progressive multifocal leukoencephalopathy, PML, serious adverse event, Psychology, Clinical sciences, Biological psychology
Abstract

BackgroundProgressive multifocal leukoencephalopathy (PML) is a rare and often lethal brain disorder caused by the common, typically benign polyomavirus 2, also known as JC virus (JCV). In a small percentage of immunosuppressed individuals, JCV is reactivated and infects the brain, causing devastating neurological defects. A wide range of immunosuppressed groups can develop PML, such as patients with: HIV/AIDS, hematological malignancies (e.g., leukemias, lymphomas, and multiple myeloma), autoimmune disorders (e.g., psoriasis, rheumatoid arthritis, and systemic lupus erythematosus), and organ transplants. In some patients, iatrogenic (i.e., drug-induced) PML occurs as a serious adverse event from exposure to immunosuppressant therapies used to treat their disease (e.g., hematological malignancies and multiple sclerosis). While JCV infection and immunosuppression are necessary, they are not sufficient to cause PML.MethodsWe hypothesized that patients may also have a genetic susceptibility from the presence of rare deleterious genetic variants in immune-relevant genes (e.g., those that cause inborn errors of immunity). In our prior genetic study of 184 PML cases, we discovered 19 candidate PML risk variants. In the current study of another 152 cases, we validated 4 of 19 variants in both population controls (gnomAD 3.1) and matched controls (JCV+ multiple sclerosis patients on a PML-linked drug ≥ 2 years).ResultsThe four variants, found in immune system genes with strong biological links, are: C8B, 1-57409459-C-A, rs139498867; LY9 (alias SLAMF3), 1-160769595-AG-A, rs763811636; FCN2, 9-137779251-G-A, rs76267164; STXBP2, 19-7712287-G-C, rs35490401. Carriers of any one of these variants are shown to be at high risk of PML when drug-exposed PML cases are compared to drug-exposed matched controls: P value = 3.50E-06, OR = 8.7 [3.7-20.6]. Measures of clinical validity and utility compare favorably to other genetic risk tests, such as BRCA1 and BRCA2 screening for breast cancer risk and HLA-B*15:02 pharmacogenetic screening for pharmacovigilance of carbamazepine to prevent Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.ConclusionFor the first time, a PML genetic risk test can be implemented for screening patients taking or considering treatment with a PML-linked drug in order to decrease the incidence of PML and enable safer use of highly effective therapies used to treat their underlying disease.

Published
2022

23. Subcutaneous efgartigimod PH20 in generalized myasthenia gravis: A phase 3 randomized noninferiority study (ADAPT-SC) and interim analyses of a long-term open-label extension study (ADAPT-SC+)

Author

Howard, James F., Jr., Vu, Tuan, Li, George, Korobko, Denis, Smilowski, Marek, Liu, Li, Gistelinck, Fien, Steeland, Sophie, Noukens, Jan, Van Hoorick, Benjamin, Podhorna, Jana, Borgions, Filip, Li, Yuebing, Utsugisawa, Kimiaki, Wiendl, Heinz, De Bleecker, Jan L., and Mantegazza, Renato

Published
2024
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24. Classification of neurological diseases using multi-dimensional cerebrospinal fluid analysis

Author

Gross, Catharina C, Schulte-Mecklenbeck, Andreas, Madireddy, Lohith, Pawlitzki, Marc, Strippel, Christine, Räuber, Saskia, Krämer, Julia, Rolfes, Leoni, Ruck, Tobias, Beuker, Carolin, Schmidt-Pogoda, Antje, Lohmann, Lisa, Schneider-Hohendorf, Tilman, Hahn, Tim, Schwab, Nicholas, Minnerup, Jens, Melzer, Nico, Klotz, Luisa, Meuth, Sven G, Hörste, Gerd Meyer zu, Baranzini, Sergio E, and Wiendl, Heinz

Subjects
Autoimmune Disease, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Neurological, Inflammatory and immune system, Good Health and Well Being, Biomarkers, Cohort Studies, Diagnosis, Differential, Female, Humans, Inflammation Mediators, Male, Nervous System Diseases, Retrospective Studies, CNS autoimmunity, multiple sclerosis, differential diagnosis, CSF, immune profile, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

Although CSF analysis routinely enables the diagnosis of neurological diseases, it is mainly used for the gross distinction between infectious, autoimmune inflammatory, and degenerative disorders of the CNS. To investigate, whether a multi-dimensional cellular blood and CSF characterization can support the diagnosis of clinically similar neurological diseases, we analysed 546 patients with autoimmune neuroinflammatory, degenerative, or vascular conditions in a cross-sectional retrospective study. By combining feature selection with dimensionality reduction and machine learning approaches we identified pan-disease parameters that were altered across all autoimmune neuroinflammatory CNS diseases and differentiated them from other neurological conditions and inter-autoimmunity classifiers that subdifferentiate variants of CNS-directed autoimmunity. Pan-disease as well as diseases-specific changes formed a continuum, reflecting clinical disease evolution. A validation cohort of 231 independent patients confirmed that combining multiple parameters into composite scores can assist the classification of neurological patients. Overall, we showed that the integrated analysis of blood and CSF parameters improves the differential diagnosis of neurological diseases, thereby facilitating early treatment decisions.

Published
2021

25. Risk and course of COVID-19 in immunosuppressed patients with myasthenia gravis

Author

Stascheit, Frauke, Grittner, Ulrike, Hoffmann, Sarah, Mergenthaler, Philipp, Schroeter, Michael, Ruck, Tobias, Pawlitzki, Mark, Blaes, Franz, Kaiser, Julia, Schara, Ulrike, Della-Marina, Adela, Thieme, Andrea, Hagenacker, Tim, Jacobi, Christian, Berger, Benjamin, Urban, Peter P., Knop, Karl Christian, Schalke, Berthold, Lee, De-Hyung, Kalischewski, Petra, Wiendl, Heinz, and Meisel, Andreas

Published
2023
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26. Serum neurofilament light chain reference database for individual application in paediatric care: a retrospective modelling and validation study

Author

Abdelhak, Ahmed, Petermeier, Franziska, Benkert, Pascal, Schädelin, Sabine, Oechtering, Johanna, Maleska Maceski, Aleksandra, Kabesch, Michael, Geis, Tobias, Laub, Otto, Leipold, Georg, Gobbi, Claudio, Zecca, Chiara, Green, Ari, Tumani, Hayrettin, Willemse, Eline, Wiendl, Heinz, Granziera, Cristina, Kappos, Ludwig, Leppert, David, Waubant, Emmanuelle, Wellmann, Sven, and Kuhle, Jens

Published
2023
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29. Safety and efficacy of rozanolixizumab in patients with generalised myasthenia gravis (MycarinG): a randomised, double-blind, placebo-controlled, adaptive phase 3 study

Author

Genge, Angela, Massie, Rami, Berube, Maxime, Bril, Vera, Daniyal, Lubna, Mannan, Shabber, Ng, Eduardo, Raman, Ritesh Rohan Raghu, Sarpong, Evelyn, Alcantara, Monica, Dionne, Annie, Siddiqi, Zaeem, Blackmore, Derrick, Hussain, Faraz, Matte, Genevieve, Botez, Stephan, Tyblova, Michaela, Jakubikova, Michala, Junkerova, Jana, Vissing, John, Witting, Nanna, Holm-Yildiz, Sonja, Stemmerik, Mads, Andersen, Henning, Obál, Izabella, Solé, Guilhem, Mathis, Stéphane, Violleau, Marie-Hélène, Tranchant, Christine, Messai, Sihame, Chanson, Jean-Baptiste, Nadaj-Pakleza, Aleksandra, Verloes, Arnaud, Zaidi, Leila, Sacconi, Sabrina, Gambella, Manuela, Cavalli, Michele, Stojkovic, Tanya, Demeret, Sophie, Le Guennec, Loic, Querin, Giorgia, Weiss, Nicolas, Masingue, Marion, Magy, Laurent, Ghorab, Karima, Rukhadze, Ia, Tsiskaridze, Alexander, Janelidze, Marina, Margania, Temur, Then Bergh, Florian, Hänsel, Eike, Kalb, Andrea, Meilick, Bianca, Reuschel, Mandy, Teußer, Lars-Malte, Unterlauft, Astrid, Goedel, Clemens, Hagenacker, Tim, Totzeck, Andreas, Stolte, Benjamin, Blaes, Franz, Bindler, Christine, Tsoutsikas, Vasilios, Roediger, Annekathrin, Geis, Christian, Schmidt, Jens, Zschüntzsch, Jana, Schwarz, Margret, Meyer, Stefanie, Kummer, Karsten, Glaubitz, Stefanie, Zeng, Rachel, Wiendl, Heinz, Klotz, Luisa, Lammerskitten, Anna, Lünemann, Jan, Diószeghy, Péter, Mantegazza, Renato, Maggi, Lorenzo, Rinaldi, Elena, Gastaldi, Matteo, Mazzacane, Federico, Businaro, Pietro, Iorio, Raffaele, Antonini, Giovanni, Fionda, Laura, Rinaldi, Rita, Rossi, Simone, Habetswallner, Francesco, Tuccillo, Francesco, Umehara, Haruna, Uenaka, Eiko, Takahashi, Masanori, Higashi, Keiko, Kinoshita, Makoto, Yoneda, Emika, Nakamura, Noriko, Fujita, Saeka, Kubota, Tomoya, Ono, Masami, Yamamoto, Sana, Hatano, Taku, Oikoshi, Kazuki, Yokoyama, Kazumasa, Oji, Yutaka, Tomizawa, Yuji, Uzawa, Akiyuki, Yasuda, Manato, Akita, Sachiko, Ozawa, Yukiko, Onishi, Yosuke, Takaki, Miki, Yamada, Hiromi, Minemoto, Kanako, Sanko, Miki, Izawa, Nanae, Nakayama, Mayumi, Masuda, Masayuki, Tsuji, Rune, Ido, Nobuhiro, Hyodo, Yumi, Okubo, Yoshihiko, Minohara, Akiko, Haraguchi, Nana, Naito, Makiko, Yoshida, Seiko, Fukushige, Yuri, Tsujino, Akira, Nagaoka, Atsushi, Miyazaki, Teiichiro, Yoshimura, Shunsuke, Hirayama, Takuro, Shima, Tomoaki, Okamoto, Naoko, Matsumoto, Riki, Sekiguchi, Kenji, Ueda, Takehiro, Chihara, Norio, Kirimura, Mari, Sunagawa, Emi, Suzuki, Ayaka, Suzuki, Shigeaki, Wada, Aozora, Ishizuchi, Kei, Suzuki, Yasushi, Yata, Mitsuo, Komatsu, Yuka, Tsukita, Kenichi, Watanabe, Genya, Sato, Kazuki, Kawasaki, Emiko, Yamamoto, Naoki, Ono, Hirohiko, Tsuda, Tomoko, Ohashi, Shigeki, Utsugisawa, Kimiaki, Fujisawa, Yuka, Yokota, Yumiko, Nagane, Yuriko, Ayumi, Kameda, Takematsu, Yuka, Naito, Hiroyuki, Sugimoto, Takamichi, Kuwada, Kumiko, Rejdak, Konrad, Szklener, Sebastian, Kitowska, Monika, Derkacz, Kandyda, Druzdz, Artur, Berkowicz, Tomasz, Budzinska, Paulina, Halas, Marek, Zaslavskiy, Leonid, Skornyakova, Evgeniya, Kotov, Sergey, Novikova, Ekaterina, Sidorova, Olga, Goldobin, Vitalii, Alekseeva, Tatiana, Isabekova, Patimat, Malkova, Nadezhda, Korobko, Denis, Djordjevic, Gordana, Stojanov, Aleksandar, Peric, Stojan, Lavrnic, Dragana, Bozovic, Ivo, Palibrk, Aleksa, Casasnovas, Carlos, Nedkova-Hristova, Velina, Vidal Fernández, Nuria, Cortés Vicente, Elena, Querol Gutiérrez, Luis, Salvadó Figueras, Maria, Canovas Segura, Anna, Juntas Morales, Raúl, Sanchez Tejerina, Daniel, Saiz, Albert, Blanco Morgado, Yolanda, Llufriú Durán, Sara, Sepúlveda Gázquez, María, Martínez Hernández, Eugenia María, Gutiérrez Gutiérrez, Gerardo, Iniesta, Paqui, Meca Lallana, José, Guo, Yuh-Cherng, Chiu, Hou-Chang, Yeh, Jiann-Horng, Chen, Ya Hui, Lee, Mei Fen, Lee, Yi-Chung, Lai, Kuan Lin, Beydoun, Said, Akhter, Salma, Vu, Tuan, Lam, Lucy, Thomas, Alisha, Rivner, Michael, Quarles, Brandy, Lange, Dale, Holzberg, Shara, Pavlakis, Pantelis, Goutham, Ashwathy, Kaminski, Henry, Aly, Radwa, Ashworth, Lisa, Bender, Kathryn, Bond, Karie, Buckner, Joanne, Byerly, Sara, Caress, James, Clemons, Jessyca, Farmer, Asha, Franklin, Catherine, Harris, Summer, Hiatt, Meredith, Gandhi Mehta, Rachana, Miller, Gina, Smith, Lynn, Smith, Rose, Strittmatter, Brian, Mozaffar, Tahseen, Habib, Ali A, Hernandez, Isela, Moulton, Kelsey, Karam, Chafic, Ravikumar, Pranali, Lomen-Hoerth, Catherine, Rosow, Laura, George, Hannah, Irodenko, Viktoriya, Kang, Min, Denny, Carol, Hanson, Bart, Klein, Sara, Martinez-Thompson, Jennifer, Naddaf, Elie, Padgett, Denny, Sorenson, Eric, L Sultze, Jane, Weis, Delena, Rezania, Kourosh, Thonhoff, Jason, Shroff, Sheetal, Pascuzzi, Robert, Micheels, Angela, Bodkin, Cynthia, Comer, Adam, Baras, Gelasio, Wagner, Renee, Mahuwala, Zabeen, Ryan, Stephen, Su, Kai, Sharma, Khema, Brown, Andrew, Liow, Kore, Drużdż, Artur, Grosskreutz, Julian, Boehnlein, Marion, Bozorg, Ali, Gayfieva, Maryam, Greve, Bernhard, Woltering, Franz, and Kaminski, Henry J

Published
2023
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30. Exploratory clinical efficacy and patient-reported outcomes from NOVA: A randomized controlled study of intravenous natalizumab 6-week dosing versus continued 4-week dosing for relapsing-remitting multiple sclerosis

Author

Ryerson, Lana Zhovtis, Foley, John F, Defer, Gilles, Cohen, Jeffrey A, Arnold, Douglas L, Butzkueven, Helmut, Cutter, Gary, Giovannoni, Gavin, Killestein, Joep, Wiendl, Heinz, Sinks, Susie, Kuhelj, Robert, Bodhinathan, Karthik, and Lasky, Tyler

Published
2023
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32. 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.

Author

van der Lee, Sven J, Conway, Olivia J, Jansen, Iris, Carrasquillo, Minerva M, Kleineidam, Luca, van den Akker, Erik, Hernández, Isabel, van Eijk, Kristel R, Stringa, Najada, Chen, Jason A, Zettergren, Anna, Andlauer, Till FM, Diez-Fairen, Monica, Simon-Sanchez, Javier, Lleó, Alberto, Zetterberg, Henrik, Nygaard, Marianne, Blauwendraat, Cornelis, Savage, Jeanne E, Mengel-From, Jonas, Moreno-Grau, Sonia, Wagner, Michael, Fortea, Juan, Keogh, Michael J, Blennow, Kaj, Skoog, Ingmar, Friese, Manuel A, Pletnikova, Olga, Zulaica, Miren, Lage, Carmen, de Rojas, Itziar, Riedel-Heller, Steffi, Illán-Gala, Ignacio, Wei, Wei, Jeune, Bernard, Orellana, Adelina, Then Bergh, Florian, Wang, Xue, Hulsman, Marc, Beker, Nina, Tesi, Niccolo, Morris, Christopher M, Indakoetxea, Begoña, Collij, Lyduine E, Scherer, Martin, Morenas-Rodríguez, Estrella, Ironside, James W, van Berckel, Bart NM, Alcolea, Daniel, Wiendl, Heinz, Strickland, Samantha L, Pastor, Pau, Rodríguez Rodríguez, Eloy, 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, Bradley F, Petersen, Ronald C, Ferman, Tanis J, van Gerpen, Jay A, Reinders, Marcel JT, Uitti, Ryan J, Tárraga, Lluís, Maier, Wolfgang, Dols-Icardo, Oriol, Kawalia, Amit, Dalmasso, Maria Carolina, Boada, Mercè, Zettl, Uwe K, van Schoor, Natasja M, Beekman, Marian, Allen, Mariet, Masliah, Eliezer, de Munain, Adolfo López, Pantelyat, Alexander, Wszolek, Zbigniew K, Ross, Owen A, Dickson, Dennis W, Graff-Radford, Neill R, Knopman, David, Rademakers, Rosa, Lemstra, Afina W, Pijnenburg, Yolande AL, Scheltens, Philip, Gasser, Thomas, Chinnery, Patrick F, Hemmer, Bernhard, Huisman, Martijn A, Troncoso, Juan, Moreno, Fermin, Nohr, Ellen A, Sørensen, Thorkild IA, Heutink, Peter, Sánchez-Juan, Pascual, Posthuma, Danielle, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, and Clarimón, Jordi

Subjects
DESGESCO, EADB, IFGC, IPDGC, RiMod-FTD, Netherlands Brain Bank, GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Acquired Cognitive Impairment, Brain Disorders, Neurodegenerative, Alzheimer's Disease, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Aging, Parkinson's Disease, Genetics, 2.1 Biological and endogenous factors, Neurological, Neurology & Neurosurgery, Clinical Sciences
Abstract

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once.

Published
2020

33. Integrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis.

Author

Schafflick, David, Xu, Chenling A, Hartlehnert, Maike, Cole, Michael, Schulte-Mecklenbeck, Andreas, Lautwein, Tobias, Wolbert, Jolien, Heming, Michael, Meuth, Sven G, Kuhlmann, Tanja, Gross, Catharina C, Wiendl, Heinz, Yosef, Nir, and Meyer Zu Horste, Gerd

Subjects
Animals, B-Lymphocytes, Blood Cells, Central Nervous System, Cerebrospinal Fluid, Encephalomyelitis, Autoimmune, Experimental, Gene Expression Profiling, Humans, Leukocytes, Mice, Multiple Sclerosis, Phenotype, Single-Cell Analysis, T-Lymphocyte Subsets, T-Lymphocytes, Helper-Inducer
Abstract

Cerebrospinal fluid (CSF) protects the central nervous system (CNS) and analyzing CSF aids the diagnosis of CNS diseases, but our understanding of CSF leukocytes remains superficial. Here, using single cell transcriptomics, we identify a specific location-associated composition and transcriptome of CSF leukocytes. Multiple sclerosis (MS) - an autoimmune disease of the CNS - increases transcriptional diversity in blood, but increases cell type diversity in CSF including a higher abundance of cytotoxic phenotype T helper cells. An analytical approach, named cell set enrichment analysis (CSEA) identifies a cluster-independent increase of follicular (TFH) cells potentially driving the known expansion of B lineage cells in the CSF in MS. In mice, TFH cells accordingly promote B cell infiltration into the CNS and the severity of MS animal models. Immune mechanisms in MS are thus highly compartmentalized and indicate ongoing local T/B cell interaction.

Published
2020

35. Review and meta-analysis of neuropsychological findings in autoimmune limbic encephalitis with autoantibodies against LGI1, CASPR2, and GAD65 and their response to immunotherapy

Author

Mueller, Christoph, Elben, Saskia, Day, Gregory S., Alves, Pedro, Hebert, Julien, Tang-Wai, David F., Holtmann, Olga, Iorio, Raffaele, Perani, Daniela, Titulaer, Maarten J., Hansen, Niels, Bartsch, Thorsten, Johnen, Andreas, Illes, Zsolt, Borm, Leah, Willison, Alice G., Wiendl, Heinz, Meuth, Sven G., Kovac, Stjepana, Bölte, Jens, and Melzer, Nico

Published
2023
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36. Skeletal muscle provides the immunological micro-milieu for specific plasma cells in anti-synthetase syndrome-associated myositis

Author

Preuße, Corinna, Paesler, Barbara, Nelke, Christopher, Cengiz, Derya, Müntefering, Thomas, Roos, Andreas, Amelin, Damien, Allenbach, Yves, Uruha, Akinori, Dittmayer, Carsten, Hentschel, Andreas, Pawlitzki, Marc, Hoffmann, Sarah, Timm, Sara, Louis, Sarah Leonard, Dengler, Nora F., Wiendl, Heinz, Lünemann, Jan D., Sickmann, Albert, Hervier, Baptiste, Meuth, Sven G., Schneider, Udo, Schänzer, Anne, Krause, Sabine, Tomaras, Stylianos, Feist, Eugen, Hasseli, Rebecca, Goebel, Hans-Hilmar, Gallay, Laure, Streichenberger, Nathalie, Benveniste, Olivier, Stenzel, Werner, and Ruck, Tobias

Published
2022
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38. Functional Signature of LRP4 Antibodies in Myasthenia Gravis

Author

Chuquisana, Omar, primary, Stascheit, Frauke, additional, Keller, Christian W., additional, Pučić-Baković, Maja, additional, Patenaude, Anne-Marie, additional, Lauc, Gordan, additional, Tzartos, Socrates, additional, Wiendl, Heinz, additional, Willcox, Nick, additional, Meisel, Andreas, additional, and Lünemann, Jan D., additional

Published
2024
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39. Prognostic Value of Serum Neurofilament Light Chain for Disease Activity in Patients with Relapsing Multiple Sclerosis: Results from Subgroup Analysis Based on Body Mass Index and Age from the Phase 3 ASCLEPIOS I/II Trials (P6-6.011)

Author

Cross, Anne, primary, Ziemssen, Tjalf, additional, Arnold, Douglas, additional, Thouvenot, Eric, additional, Zamvil, Scott, additional, Bhatt, Alit, additional, Wei, Wenjia, additional, Boer, Ibolya, additional, Alvarez, Enrique, additional, and Wiendl, Heinz, additional

Published
2024
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40. The Bruton’s Tyrosine Kinase Inhibitor Remibrutinib Exhibits No Impact on Serum Immunoglobulin Levels: Insights from Chronic Spontaneous Urticaria (P10-6.018)

Author

Bermel, Robert, primary, Carr, Warner, additional, Chitnis, Tanuja, additional, Dörner, Thomas, additional, Hayama, Koremasa, additional, Hide, Michihiro, additional, Maurer, Marcus, additional, Montalban, Xavier, additional, Sussman, Gordon, additional, Wiendl, Heinz, additional, Dahale, Swapnil, additional, DeLasHeras, Virginia, additional, Haemmerle, Sibylle, additional, Kieseier, Bernd, additional, Lheritier, Karine, additional, Zharkov, Artem, additional, Willi, Roman, additional, and Giménez-Arnau, Ana, additional

Published
2024
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41. Prognostic Value of On-treatment Serum Neurofilament Light Chain for New or Enlarging T2 Lesions in People with Relapsing Multiple Sclerosis: Pooled Analysis of the ASCLEPIOS I/II Trials (S42.003)

Author

Leist, Thomas, primary, Hauser, Stephen, additional, Derfuss, Tobias, additional, Wiendl, Heinz, additional, Arnold, Douglas, additional, Montalban, Xavier, additional, Bhatt, Alit, additional, Wei, Wenjia, additional, Boer, Ibolya, additional, Alvarez, Enrique, additional, and Ziemssen, Tjalf, additional

Published
2024
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42. Longer-term Safety and Efficacy of Ofatumumab in People with Relapsing Multiple Sclerosis for Up to 6 Years (P9-6.010)

Author

Wiendl, Heinz, primary, Hauser, Stephen, additional, Nicholas, Jacqueline, additional, De Seze, Jerome, additional, Meuth, Sven, additional, Giacomini, Paul, additional, Robertson, Derrick, additional, Wray, Sibyl, additional, Bhatt, Alit, additional, Hu, Xixi, additional, Fu, Haoyi, additional, Jehl, Valentine, additional, Sullivan, Roseanne, additional, Boer, Ibolya, additional, Cohen, Jeffrey, additional, and Kappos, Ludwig, additional

Published
2024
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43. Safety of Remibrutinib Across Immune-mediated Diseases Supports Development in Multiple Sclerosis (P8-6.015)

Author

Kieseier, Bernd, primary, Montalban, Xavier, additional, Williams, Mitzi, additional, Airas, Laura, additional, Saini, Sarbjit, additional, Hide, Michihiro, additional, Sussman, Gordon, additional, Nakahara, Jin, additional, Bermel, Robert, additional, Doerner, Thomas, additional, Loop, Brett, additional, DeLasHeras, Virginia, additional, Willi, Roman, additional, Haemmerle, Sibylle, additional, Zharkov, Artem, additional, Barbier, Nathalie, additional, Azmon, Amin, additional, Siegel, Richard, additional, Cenni, Bruno, additional, Wiendl, Heinz, additional, Maurer, Marcus, additional, Gimenez-Arnau, Ana, additional, and Chitnis, Tanuja, additional

Published
2024
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44. Outcomes of COVID-19 in Ofatumumab-treated Patients with RMS: Data from the ALITHIOS Open-label Extension Study (P1-6.010)

Author

Boer, Ibolya, primary, Cree, Bruce, additional, Wiendl, Heinz, additional, Cross, Anne, additional, Delgado, Sylvia, additional, Habek, Mario, additional, Khachanova, Natalia, additional, Ward, Brian, additional, Totolyan, Natalia, additional, Mancione, Linda, additional, Sullivan, Roseanne, additional, Zielman, Ronald, additional, Hu, Xixi, additional, Gupta, Ayan Das, additional, Montalban, Xavier, additional, and Winthrop, Kevin, additional

Published
2024
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45. B-Cell Depletion and Efficacy Outcomes of Ofatumumab Are Consistent Across Different Body Mass Index Categories: Insights from ASCLEPIOS I and II Trials (P9-6.002)

Author

Cross, Anne, primary, Hauser, Stephen, additional, Wiendl, Heinz, additional, Bar-Or, Amit, additional, Coyle, Patricia, additional, Montalban, Xavier, additional, De Seze, Jerome, additional, Fu, Haoyi, additional, Bhatt, Alit, additional, Boer, Ibolya, additional, and Kappos, Ludwig, additional

Published
2024
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46. The dilemma of neuroprotection trials in times of successful endovascular recanalization

Author

Schmidt-Pogoda, Antje, primary, Kaesmacher, Johannes, additional, Bonberg, Nadine, additional, Werring, Nils, additional, Strecker, Jan-Kolja, additional, Koecke, Mailin Hannah Marie, additional, Beuker, Carolin, additional, Gralla, Jan, additional, Meier, Raphael, additional, Wiendl, Heinz, additional, Minnerup, Heike, additional, Fischer, Urs, additional, and Minnerup, Jens, additional

Published
2024
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47. Résultats de l’étude d’extension NOVA évaluant la préférence des patients pour l’administration sous-cutanée (SC) versus intraveineuse (IV) de natalizumab (NTZ) avec le schéma Q6W (toutes les 6 semaines)

Author

Wiendl, Heinz, primary, Foley, John, additional, Defer, Gilles, additional, Ryerson, Lana Zhovtis, additional, Cohen, Jeffrey A., additional, Arnold, Douglas, additional, Butzkueven, Helmut, additional, Cutter, Gary, additional, Giovannoni, Gavin, additional, Killestein, Joep, additional, Domingo-Horne, Rose, additional, Toukam, Marie, additional, Nunn, Aimie, additional, Sinks, Susie, additional, Maghzi, Amir-Hadi, additional, Kuhelj, Robert, additional, and Lasky, Tyler, additional

Published
2024
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