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1. Review of the pharmacoeconomics of early treatment of multiple sclerosis using interferon beta

Author

Castrop F, Haslinger B, Hemmer B, and Buck D

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Florian Castrop, Bernhard Haslinger, Bernhard Hemmer, Dorothea Buck Department of Neurology, Technische Universität München, Munich, Germany Abstract: Multiple sclerosis (MS) is a common neurological disease with increasing incidence and prevalence. Onset of disease is most frequently in young adulthood when productivity is usually highest; it is of chronic nature and, in the majority of patients, it will result in accumulation of disability. Due to loss of productivity in patients and caregivers as well as high expenses for medical treatment, MS is considered a disease with high economic burden for patients and society. Several drugs have been approved for treatment of MS. While treatment ameliorates the course of the disease, it is very costly; therefore, pharmacoeconomics, evaluating costs and effects of disease-modifying treatment in MS, has become an important issue. Here, we review the economic impact and treatment strategies of MS and discuss recent studies on pharmacoeconomics of early treatment with interferon beta. Keywords: MS, pharmacoeconomics, disease-modifying therapy, interferon beta, CIS

Published
2013

2. Update on immunopathogenesis and immunotherapy in multiple sclerosis

Author

Selter RC and Hemmer B

Subjects
Multiple sclerosis, immunopathogenesis, disease-modifying therapy, Immunologic diseases. Allergy, RC581-607
Abstract

Rebecca C Selter,1 Bernhard Hemmer1–3 1Department of Neurology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany; 2Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; 3Competence Network on Multiple Sklerosis, Munich, Germany Abstract: Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. Both genetic and environmental factors are believed to contribute to the pathogenesis of the disease. Histopathological findings suggest that multiple sclerosis is an immune-mediated disease, involving both the cellular and humoral immune systems. Within the last 20 years, several disease-modifying therapies for the treatment of multiple sclerosis were established. Moreover, promising new substances are currently being tested in clinical trials and will likely broaden the therapeutic opportunities available within the upcoming years. Keywords: multiple sclerosis, immunopathogenesis, disease-modifying therapy

Published
2013

3. MRI plaque imaging reveals high-risk carotid plaques especially in diabetic patients irrespective of the degree of stenosis

Author

Holzer K, Liebig T, Winkler C, Feurer R, Sepp D, Pelisek Jaroslav, Bockelbrink Angelina, Heider P, Saam T, Esposito L, Pauly O, Sadikovic S, Hemmer B, and Poppert H

Subjects
Medical technology, R855-855.5
Abstract

Abstract Background Plaque imaging based on magnetic resonance imaging (MRI) represents a new modality for risk assessment in atherosclerosis. It allows classification of carotid plaques in high-risk and low-risk lesion types (I-VIII). Type 2 diabetes mellitus (DM 2) represents a known risk factor for atherosclerosis, but its specific influence on plaque vulnerability is not fully understood. This study investigates whether MRI-plaque imaging can reveal differences in carotid plaque features of diabetic patients compared to nondiabetics. Methods 191 patients with moderate to high-grade carotid artery stenosis were enrolled after written informed consent was obtained. Each patient underwent MRI-plaque imaging using a 1.5-T scanner with phased-array carotid coils. The carotid plaques were classified as lesion types I-VIII according to the MRI-modified AHA criteria. For 36 patients histology data was available. Results Eleven patients were excluded because of insufficient MR-image quality. DM 2 was diagnosed in 51 patients (28.3%). Concordance between histology and MRI-classification was 91.7% (33/36) and showed a Cohen's kappa value of 0.81 with a 95% CI of 0.98-1.15. MRI-defined high-risk lesion types were overrepresented in diabetic patients (n = 29; 56.8%). Multiple logistic regression analysis revealed association between DM 2 and MRI-defined high-risk lesion types (OR 2.59; 95% CI [1.15-5.81]), independent of the degree of stenosis. Conclusion DM 2 seems to represent a predictor for the development of vulnerable carotid plaques irrespective of the degree of stenosis and other risk factors. MRI-plaque imaging represents a new tool for risk stratification of diabetic patients. See Commentary: http://www.biomedcentral.com/1741-7015/8/78/abstract

Published
2010
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7. B lymphocytes in neuromyelitis optica.

Author

Zamvil, Scott, Yeaman, Michael, Von Buedingen, Hans-Christian, Bennett, JL, O'Connor, KC, Bar-Or, A, Zamvil, SS, Hemmer, B, Tedder, TF, von, H-C, Stuve, O, Yeaman, MR, and Smith, TJ

Abstract

Neuromyelitis optica (NMO) is an inflammatory autoimmune disorder of the CNS that predominantly affects the spinal cord and optic nerves. A majority (approximately 75%) of patients with NMO are seropositive for autoantibodies against the astrocyte water ch

Published
2015

8. Locus for severity implicates CNS resilience in progression of multiple sclerosis

Author

Harroud, A, Stridh, PJ, McCauley, JH, Saarela, J, van den Bosch, AMR, Engelenburg, H, Beecham, A, Alfredsson, L, Alikhani, K, Amezcua, L, Andlauer, TFM, Ban, M, Barcellos, L, Barizzone, N, Berge, T, Berthele, A, Bittner, S, Bos, S, Briggs, FBS, Caillier, S, Calabresi, P, Caputo, D, Carmona-Burgos, D, Cavalla, P, Celius, E, Cerono, G, Chinea, A, Chitnis, T, Clarelli, F, Comabella, M, Comi, G, Cotsapas, C, Cree, BCA, D'Alfonso, S, Dardiotis, E, De Jager, P, Delgado, S, Dubois, B, Engel, S, Esposito, F, Fabis-Pedrini, M, Filippi, M, Fitzgerald, K, Gasperi, C, Gomez, L, Gomez, R, Hadjigeorgiou, G, Hamann, J, Held, F, Henry, R, Hillert, J, Huang, J, Huitinga, I, Islam, T, Isobe, N, Jagodic, M, Kermode, AL, Khalil, M, Kilpatrick, T, Konidari, I, Kreft, K, Lechner-Scott, J, Leone, M, Luessi, F, Malhotra, S, Manouchehrinia, A, Manrique, C, Martinelli-Boneschi, F, Martinez, A, Martinez-Maldonado, V, Mascia, E, Metz, L, Midaglia, L, Montalban, X, Oksenberg, J, Olsson, T, Oturai, A, Paakkonen, K, Parnell, GP, Patsopoulos, N, Pericak-Vance, M, Piehl, F, Rubio, J, Santaniello, A, Santoro, S, Schaefer, C, Sellebjerg, F, Shams, H, Shchetynsky, K, Silva, C, Siokas, V, Sondergaard, H, Sorosina, M, Taylor, B, Vandebergh, M, Vasileiou, E, Vecchio, D, Voortman, M, Weiner, H, Wever, D, Yong, VW, Hafler, D, Stewart, G, Compston, A, Zipp, F, Harbo, H, Hemmer, B, Goris, A, Smolders, J, Hauser, S, Kockum, I, Sawcer, S, Baranzini, S, Jonsdottir, I, Blanco, Y, Llufriu, S, Madireddy, L, Saiz, A, Villoslada, P, Stefansson, K, Harbo, HF, Sawcer, SJ, Baranzini, SE, Harroud, A, Stridh, PJ, McCauley, JH, Saarela, J, van den Bosch, AMR, Engelenburg, H, Beecham, A, Alfredsson, L, Alikhani, K, Amezcua, L, Andlauer, TFM, Ban, M, Barcellos, L, Barizzone, N, Berge, T, Berthele, A, Bittner, S, Bos, S, Briggs, FBS, Caillier, S, Calabresi, P, Caputo, D, Carmona-Burgos, D, Cavalla, P, Celius, E, Cerono, G, Chinea, A, Chitnis, T, Clarelli, F, Comabella, M, Comi, G, Cotsapas, C, Cree, BCA, D'Alfonso, S, Dardiotis, E, De Jager, P, Delgado, S, Dubois, B, Engel, S, Esposito, F, Fabis-Pedrini, M, Filippi, M, Fitzgerald, K, Gasperi, C, Gomez, L, Gomez, R, Hadjigeorgiou, G, Hamann, J, Held, F, Henry, R, Hillert, J, Huang, J, Huitinga, I, Islam, T, Isobe, N, Jagodic, M, Kermode, AL, Khalil, M, Kilpatrick, T, Konidari, I, Kreft, K, Lechner-Scott, J, Leone, M, Luessi, F, Malhotra, S, Manouchehrinia, A, Manrique, C, Martinelli-Boneschi, F, Martinez, A, Martinez-Maldonado, V, Mascia, E, Metz, L, Midaglia, L, Montalban, X, Oksenberg, J, Olsson, T, Oturai, A, Paakkonen, K, Parnell, GP, Patsopoulos, N, Pericak-Vance, M, Piehl, F, Rubio, J, Santaniello, A, Santoro, S, Schaefer, C, Sellebjerg, F, Shams, H, Shchetynsky, K, Silva, C, Siokas, V, Sondergaard, H, Sorosina, M, Taylor, B, Vandebergh, M, Vasileiou, E, Vecchio, D, Voortman, M, Weiner, H, Wever, D, Yong, VW, Hafler, D, Stewart, G, Compston, A, Zipp, F, Harbo, H, Hemmer, B, Goris, A, Smolders, J, Hauser, S, Kockum, I, Sawcer, S, Baranzini, S, Jonsdottir, I, Blanco, Y, Llufriu, S, Madireddy, L, Saiz, A, Villoslada, P, Stefansson, K, Harbo, HF, Sawcer, SJ, and Baranzini, SE

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults1,2. Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF-ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3-PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility3, these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS.

Published
2023

9. Retinal ganglion cell loss is associated with future disability worsening in early relapsing remitting multiple sclerosis

Author

Wauschkuhn, J., Solorza Buenrostro, G., Aly, L., Asseyer, S., Wicklein, R., Hartberger, J.M., Ruprecht, K., Mühlau, M., Schmitz-Hübsch, T., Chien, C., Berthele, A., Brandt, A.U., Korn, T., Paul, F., Hemmer, B., Zimmermann, H.G., and Knier, B.

Subjects
Function and Dysfunction of the Nervous System
Abstract

BACKGROUND: Thinning of the retinal combined ganglion cell and inner plexiform layer (GCIP) as measured by optical coherence tomography (OCT) is a common finding in patients with multiple sclerosis. This study aimed to investigate whether a single retinal OCT analysis allows prediction of future disease activity after a first demyelinating event. METHODS: Observational cohort study including 201 patients with recently diagnosed clinically isolated syndrome or relapsing remitting multiple sclerosis from two German tertiary referral centers. Individuals underwent neurological examination, MRI and OCT at baseline and at yearly follow-up visits. RESULTS: Patients were included at a median disease duration of 2.0 months. During a median follow-up of 59 (interquartile range 43 - 71) months, 82% of patients had ongoing disease activity as demonstrated by failing the no evidence of disease activity (NEDA)-3 criteria and 19% presented with confirmed disability worsening. A GCIP threshold ≤ 77 μm at baseline identified patients with a high risk for NEDA-3 failure (hazard ratio 1.7 [95% CI 1.1 - 2.8], p=0.04) and GCIP measures ≤ 69 μm predicted disability worsening (hazard ratio 2.2 (95% CI, 1.2 - 4.3); p=0.01). Higher rates of annualized GCIP loss increased the risk for disability worsening (hazard ratio 2.5 per 1 μm/year increase of GCIP loss, p=0.03). CONCLUSIONS: Ganglion cell thickness as measured by OCT after the initial manifestation of multiple sclerosis may allow early risk stratification as to future disease activity and progression.

Published
2023

10. Artificial intelligence extension of the OSCAR-IB criteria

Author

Petzold, A., Albrecht, P., Balcer, L., Bekkers, E., Brandt, A. U., Calabresi, P. A., Deborah, O. G., Graves, J. S., Green, A., Keane, P. A., Nij Bijvank, J. A., Sander, J. W., Paul, F., Saidha, S., Villoslada, P., Wagner, S. K., Yeh, E. A., Aktas, O., Antel, J., Asgari, N., Audo, I., Avasarala, J., Avril, D., Bagnato, F. R., Banwell, B., Bar-Or, A., Behbehani, R., Manterola, A. B., Bennett, J., Benson, L., Bernard, J., Bremond-Gignac, D., Britze, J., Burton, J., Calkwood, J., Carroll, W., Chandratheva, A., Cohen, J., Comi, G., Cordano, C., Costa, S., Costello, F., Courtney, A., Cruz-Herranz, A., Cutter, G., Crabb, D., Delott, L., De Seze, J., Diem, R., Dollfuss, H., El Ayoubi, N. K., Fasser, C., Finke, C., Fischer, D., Fitzgerald, K., Fonseca, P., Frederiksen, J. L., Frohman, E., Frohman, T., Fujihara, K., Cuellar, I. G., Galetta, S., Garcia-Martin, E., Giovannoni, G., Glebauskiene, B., Suarez, I. G., Jensen, G. P., Hamann, S., Hartung, H. -P., Havla, J., Hemmer, B., Huang, S. -C., Imitola, J., Jasinskas, V., Jiang, H., Kafieh, R., Kappos, L., Kardon, R., Keegan, D., Kildebeck, E., Kim, U. S., Klistorner, S., Knier, B., Kolbe, S., Korn, T., Krupp, L., Lagreze, W., Leocani, L., Levin, N., Liskova, P., Preiningerova, J. L., Lorenz, B., May, E., Miller, D., Mikolajczak, J., Said, S. M., Montalban, X., Morrow, M., Mowry, E., Murta, J., Navas, C., Nolan, R., Nowomiejska, K., Oertel, F. C., Oh, J., Oreja-Guevara, C., Orssaud, C., Osborne, B., Outteryck, O., Paiva, C., Palace, J., Papadopoulou, A., Patsopoulos, N., Pontikos, N., Preising, M., Prince, J., Reich, D., Rejdak, R., Ringelstein, M., Rodriguez de Antonio, L., Sahel, J. -A., Sanchez-Dalmau, B., Sastre-Garriga, J., Schippling, S., Schuman, J., Shindler, K., Shin, R., Shuey, N., Soelberg, K., Specovius, S., Suppiej, A., Thompson, A., Toosy, A., Torres, R., Touitou, V., Trauzettel-Klosinski, S., van der Walt, A., Vermersch, P., Vidal-Jordana, A., Waldman, A. T., Waters, C., Wheeler, R., White, O., Wilhelm, H., Winges, K. M., Wiegerinck, N., Wiehe, L., Wisnewski, T., Wong, S., Wurfel, J., Yaghi, S., You, Y., Yu, Z., Yu-Wai-Man, P., Zemaitien≐, R., Zimmermann, H., Albrecht P., Petzold A., Balcer, L., Bekkers, E., Brandt, A. U., Calabresi, P. A., Deborah, O. G., Graves, J. S., Green, A., Keane, P. A., Nij Bijvank, J. A., Sander, J. W., Paul, F., Saidha, S., Villoslada, P., Wagner, S. K., Yeh, E. A., Aktas, O., Antel, J., Asgari, N., Audo, I., Avasarala, J., Avril, D., Bagnato, F. R., Banwell, B., Bar-Or, A., Behbehani, R., Manterola, A. B., Bennett, J., Benson, L., Bernard, J., Bremond-Gignac, D., Britze, J., Burton, J., Calkwood, J., Carroll, W., Chandratheva, A., Cohen, J., Comi, G., Cordano, C., Costa, S., Costello, F., Courtney, A., Cruz-Herranz, A., Cutter, G., Crabb, D., Delott, L., De Seze, J., Diem, R., Dollfuss, H., El Ayoubi, N. K., Fasser, C., Finke, C., Fischer, D., Fitzgerald, K., Fonseca, P., Frederiksen, J. L., Frohman, E., Frohman, T., Fujihara, K., Cuellar, I. G., Galetta, S., Garcia-Martin, E., Giovannoni, G., Glebauskiene, B., Suarez, I. G., P. , Jensen, G., Hamann, S., Hartung, H. -P., Havla, J., Hemmer, B., Huang, S. -C., Imitola, J., Jasinskas, V., Jiang, H., Kafieh, R., Kappos, L., Kardon, R., Keegan, D., Kildebeck, E., Kim, U. S., Klistorner, S., Knier, B., Kolbe, S., Korn, T., Krupp, L., Lagreze, W., Leocani, L., Levin, N., Liskova, P., Preiningerova, J. L., Lorenz, B., May, E., Miller, D., Mikolajczak, J., Said, S. M., Montalban, X., Morrow, M., Mowry, E., Murta, J., Navas, C., Nolan, R., Nowomiejska, K., Oertel, F. C., Oh, J., Oreja-Guevara, C., Orssaud, C., Osborne, B., Outteryck, O., Paiva, C., Palace, J., Papadopoulou, A., Patsopoulos, N., Pontikos, N., Preising, M., Prince, J., Reich, D., Rejdak, R., Ringelstein, M., Rodriguez de Antonio, L., Sahel, J. -A., Sanchez-Dalmau, B., Sastre-Garriga, J., Schippling, S., Schuman, J., Shindler, K., Shin, R., Shuey, N., Soelberg, K., Specovius, S., Suppiej, A., Thompson, A., Toosy, A., Torres, R., Touitou, V., Trauzettel-Klosinski, S., van der Walt, A., Vermersch, P., Vidal-Jordana, A., Waldman, A. T., Waters, C., Wheeler, R., White, O., Wilhelm, H., Winges, K. M., Wiegerinck, N., Wiehe, L., Wisnewski, T., Wong, S., Wurfel, J., Yaghi, S., You, Y., Yu, Z., Yu-Wai-Man, P., Zemaitien≐, R., and Zimmermann, H.

Subjects
0301 basic medicine, Big Data, medicine.medical_specialty, Neurology, media_common.quotation_subject, Big data, MEDLINE, Reviews, Socio-culturale, Neurosciences. Biological psychiatry. Neuropsychiatry, Review, Public domain, Retina, Cohort Studies, 03 medical and health sciences, Annotation, 0302 clinical medicine, Artificial Intelligence, medicine, Humans, Quality (business), RC346-429, Tomography, media_common, Image pattern recognition, business.industry, General Neuroscience, Nervous System Diseases, Tomography, Optical Coherence, Algorithms, 030104 developmental biology, Optical Coherence, Imaging technology, RC0321, Neurology. Diseases of the nervous system, Neurology (clinical), Artificial intelligence, sense organs, business, 030217 neurology & neurosurgery, RC321-571
Abstract

Artificial intelligence (AI)‐based diagnostic algorithms have achieved ambitious aims through automated image pattern recognition. For neurological disorders, this includes neurodegeneration and inflammation. Scalable imaging technology for big data in neurology is optical coherence tomography (OCT). We highlight that OCT changes observed in the retina, as a window to the brain, are small, requiring rigorous quality control pipelines. There are existing tools for this purpose. Firstly, there are human‐led validated consensus quality control criteria (OSCAR‐IB) for OCT. Secondly, these criteria are embedded into OCT reporting guidelines (APOSTEL). The use of the described annotation of failed OCT scans advances machine learning. This is illustrated through the present review of the advantages and disadvantages of AI‐based applications to OCT data. The neurological conditions reviewed here for the use of big data include Alzheimer disease, stroke, multiple sclerosis (MS), Parkinson disease, and epilepsy. It is noted that while big data is relevant for AI, ownership is complex. For this reason, we also reached out to involve representatives from patient organizations and the public domain in addition to clinical and research centers. The evidence reviewed can be grouped in a five‐point expansion of the OSCAR‐IB criteria to embrace AI (OSCAR‐AI). The review concludes by specific recommendations on how this can be achieved practically and in compliance with existing guidelines.

Published
2021

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

Author

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

Abstract

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 preliminary. Conclusion: EBPI on immunotherapies for MS seem feasible and are appreciated by patients and treating neurologists but more implementation research is needed.

Published
2022

12. Toskana-Virus-Meningoenzephalitis in Oberbayern

Author

Wenzel, M., Afzali, A.M., Hoffmann, D., Zange, S., Georgi, E., and Hemmer, B.

Abstract

Das durch Sandmücken übertragene Toskana-Virus (TOSV), ein Phlebovirus aus der Familie der Phenuiviridae, zählt in Endemiegebieten zu den häufigsten Erregern einer Meningoenzephalitis (ME) (1). Kenntnisse über regionale Erreger sind im Hinblick auf die initiale Behandlung von besonderer Bedeutung. Zuletzt mehrten sich Meldungen über die Ausbreitung von Sandmücken (2), sodass eine endemische Zirkulation des TOSV auch in Deutschland denkbar ist.

Published
2022

13. Myelin-oligodendrocyte glycoprotein antibody-associated disease

Author

Marignier, R. Hacohen, Y. Cobo-Calvo, A. Pröbstel, A.-K. Aktas, O. Alexopoulos, H. Amato, M.-P. Asgari, N. Banwell, B. Bennett, J. Brilot, F. Capobianco, M. Chitnis, T. Ciccarelli, O. Deiva, K. De Sèze, J. Fujihara, K. Jacob, A. Kim, H.J. Kleiter, I. Lassmann, H. Leite, M.-I. Linington, C. Meinl, E. Palace, J. Paul, F. Petzold, A. Pittock, S. Reindl, M. Sato, D.K. Selmaj, K. Siva, A. Stankoff, B. Tintore, M. Traboulsee, A. Waters, P. Waubant, E. Weinshenker, B. Derfuss, T. Vukusic, S. Hemmer, B.

Abstract

Myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently identified autoimmune disorder that presents in both adults and children as CNS demyelination. Although there are clinical phenotypic overlaps between MOGAD, multiple sclerosis, and aquaporin-4 antibody-associated neuromyelitis optica spectrum disorder (NMOSD) cumulative biological, clinical, and pathological evidence discriminates between these conditions. Patients should not be diagnosed with multiple sclerosis or NMOSD if they have anti-MOG antibodies in their serum. However, many questions related to the clinical characterisation of MOGAD and pathogenetic role of MOG antibodies are still unanswered. Furthermore, therapy is mainly based on standard protocols for aquaporin-4 antibody-associated NMOSD and multiple sclerosis, and more evidence is needed regarding how and when to treat patients with MOGAD. © 2021 Elsevier Ltd

Published
2021

15. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis

Author

Montalban, X., Hauser, S. L., Kappos, L., Arnold, D. L., Bar‑or, A., Comi, G., de Seze, J., Giovannoni, G., Hartung, H. -P., Hemmer, B., Lublin, F., Rammohan, K. W., Selmaj, K., Traboulsee, A., Sauter, A., Masterman, D., Fontoura, P., Belachew, S., Garren, H., Mairon, N., Chin, P., Wolinsky, J. S., Uccelli, A, for the ORATORIO Clinical Investigators, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Med Staf Spec Neurologie (9), Klinische Neurowetenschappen, Institut Català de la Salut, [Montalban X] Hospital Universitari Vall d’Hebron, Barcelona, Spain. [Hauser SL] University of California, San Francisco, United States. [Kappos L] University Hospital Basel, Basel, Switzerland. [Arnold DL, Bar-Or A] McGill University, Montreal, Canada. [Comi G] University Vita-Salute San Raffaele, Milan, Italy., Hospital Universitari Vall d'Hebron, CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA)-Hôpital de Hautepierre [Strasbourg]-Nouvel Hôpital Civil de Strasbourg, CHU Strasbourg, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], Montalban, X., Hauser, S. L., Kappos, L., Arnold, D. L., Bar or, A., Comi, Giancarlo, De Seze, J., Giovannoni, G., Hartung, H. . P., Hemmer, B., Lublin, F., Rammohan, K. W., Selmaj, K., Traboulsee, A., Sauter, A., Masterman, D., Fontoura, P., Belachew, S., Garren, H., Mairon, N., Chin, P., and Wolinsky, J. S.

Subjects
Male, 0301 basic medicine, Intention to Treat Analysi, T-Lymphocytes, Esclerosi múltiple, enfermedades del sistema nervioso::enfermedades autoinmunitarias del sistema nervioso::enfermedades autoinmunes desmielinizantes del SNC::esclerosis múltiple::esclerosis múltiple crónica progresiva [ENFERMEDADES], Other subheadings::Other subheadings::/drug therapy [Other subheadings], DOUBLE-BLIND, chemistry.chemical_compound, 0302 clinical medicine, DEMYELINATION, Monoclonal, Clinical endpoint, aminoácidos, péptidos y proteínas::proteínas::proteínas sanguíneas::inmunoproteínas::inmunoglobulinas::anticuerpos::anticuerpos monoclonales::anticuerpos monoclonales humanizados [COMPUESTOS QUÍMICOS Y DROGAS], Infusions, Intravenou, Other subheadings::/therapeutic use [Other subheadings], Otros calificadores::Otros calificadores::/inmunología [Otros calificadores], Humanized, Otros calificadores::Otros calificadores::/tratamiento farmacológico [Otros calificadores], MULTICENTER TRIAL, Enfermedades del Sistema Nervioso::Enfermedades Autoinmunes del Sistema Nervioso::Enfermedades Autoinmunes Desmielinizantes SNC::Esclerosis Múltiple::Esclerosis Múltiple Crónica Progresiva [ENFERMEDADES], DAMAGE, B-Lymphocytes, Medicine (all), Hazard ratio, B-Lymphocyte, Brain, General Medicine, Multiple Sclerosis, Chronic Progressive, Middle Aged, Magnetic Resonance Imaging, Intention to Treat Analysis, 3. Good health, Chronic Progressive, Disease Progression, Female, Intravenous, Human, medicine.drug, Adult, Infusions, medicine.medical_specialty, Multiple Sclerosis, Adolescent, CANCER-RISK, Antibodies, Monoclonal, Humanized, Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Antibodies, Monoclonal::Antibodies, Monoclonal, Humanized [CHEMICALS AND DRUGS], Placebo, Antibodies, Young Adult, 03 medical and health sciences, Double-Blind Method, Nervous System Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis::Multiple Sclerosis, Chronic Progressive [DISEASES], Other subheadings::Other subheadings::/immunology [Other subheadings], Multicenter trial, Internal medicine, medicine, Humans, CD20, Lymphocyte Count, Antigens, Intention-to-treat analysis, Otros calificadores::/uso terapéutico [Otros calificadores], business.industry, Multiple sclerosis, Antigens, CD20, medicine.disease, Infusions, Intravenous, Surgery, PATHOLOGY, 030104 developmental biology, Siponimod, T-Lymphocyte, ANTIBODY, chemistry, Ocrelizumab, Medicaments immunosupressors, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract

Ocrelizumab; Placebo; Multiple sclerosis Ocrelizumab; Placebo; Esclerosi múltiple Ocrelizumab; Placebo; Esclerosis múltiple BACKGROUND: An evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primary progressive form of the disease. METHODS: In this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis. RESULTS: The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P

Published
2017

17. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

Author

Patsopoulos, NA, Baranzini, SE, Santaniello, A, Shoostari, P, Cotsapas, C, Wong, G, Beecham, AH, James, T, Replogle, J, Vlachos, IS, McCabe, C, Pers, TH, Brandes, A, White, C, Keenan, B, Cimpean, M, Winn, P, Panteliadis, IP, Robbins, A, Andlauer, TFM, Zarzycki, O, Dubois, B, Goris, A, Sondergaard, HB, Sellebjerg, F, Sorensen, PS, Ullum, H, Thorner, LW, Saarela, J, Cournu-Rebeix, I, Damotte, V, Fontaine, B, Guillot-Noel, L, Lathrop, M, Vukusic, S, Berthele, A, Pongratz, V, Gasperi, C, Graetz, C, Grummel, V, Hemmer, B, Hoshi, M, Knier, B, Korn, T, Lill, CM, Luessi, F, Muhlau, M, Zipp, F, Dardiotis, E, Agliardi, C, Amoroso, A, Barizzone, N, Benedetti, MD, Bernardinelli, L, Cavalla, P, Clarelli, F, Comi, G, Cusi, D, Esposito, F, Ferre, L, Galimberti, D, Guaschino, C, Leone, MA, Martinelli, V, Moiola, L, Salvetti, M, Sorosina, M, Vecchio, D, Zauli, A, Santoro, S, Mancini, N, Zuccala, M, Mescheriakova, J, van Duijn, C, Bos, SD, Celius, EG, Spurkland, A, Comabella, M, Montalban, X, Alfredsson, L, Bomfim, IL, Gomez-Cabrero, D, Hillert, J, Jagodic, M, Linden, M, Piehl, F, Jelcic, I, Martin, R, Sospedra, M, Baker, A, Ban, M, Hawkins, C, Hysi, P, Kalra, S, Karpe, F, Khadake, J, Lachance, G, Molyneux, P, Neville, M, Thorpe, J, Bradshaw, E, Caillier, SJ, Calabresi, P, Cree, BAC, Cross, A, Davis, M, de Bakker, PWI, Delgado, S, Dembele, M, Edwards, K, Fitzgerald, K, Frohlich, IY, Gourraud, PA, Haines, JL, Hakonarson, H, Kimbrough, D, Isobe, N, Konidari, I, Lathi, E, Lee, MH, Li, T, An, D, Zimmer, A, Madireddy, L, Manrique, CP, Mitrovic, M, Olah, M, Patrick, E, Pericak-Vance, MA, Piccio, L, Schaefer, C, Weiner, H, Lage, K, Scott, RJ, Lechner-Scott, J, Leal, R, Moscato, P, Booth, DR, Stewart, GJ, Vucic, S, Pame, G, BamettO, M, Mason, D, GriffithS, L, Broadley, S, Tajouri, L, Baxter, A, Slee, M, Taylor, BV, Charlesworth, J, Kilpatrick, TJ, Rubio, J, Jokubaitis, V, Wiley, J, Butzkueven, H, Leslie, S, Motyer, A, Stankovich, J, Carroll, WM, Kermode, AG, Edrin, M, Barclay, M, Peyrin-Biroulet, L, Chamaillard, M, Colombe, JF, Cottone, M, Croft, A, D'Inca, R, Halfvarson, J, Hanigan, K, Henderson, P, Hugot, JP, Karban, A, Kennedy, NA, Khan, MA, Lemann, M, Levine, A, Massey, D, Milla, M, Motoey, GW, Ng, SME, Oikonomnou, J, Peeters, H, Proctor, DD, Rahier, JF, Roberts, R, Rutgeerts, P, Seibold, F, Stronati, L, Taylor, KM, Torkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, MH, Zhang, H, Zhang, W, Donnelly, P, Barroso, I, Blackwe, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Sul, Z, Vukcevic, DA, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Compston, A, Hafler, D, Harbo, HF, Hauser, SL, Stewart, G, D'Alfonso, S, Hadjigeorgiou, G, Taylor, B, Barcellos, LF, Booth, D, Hintzen, R, Kockum, I, Martinelli-Boneschi, F, McCauley, JL, Oksenberg, JR, Oturai, A, Sawcer, S, Ivinson, AJ, Olsson, T, De Jager, PL, Patsopoulos, Na, Baranzini, Se, Santaniello, A, Shoostari, P, Cotsapas, C, Wong, G, Beecham, Ah, James, T, Replogle, J, Vlachos, I, Mccabe, C, Pers, Th, Brandes, A, White, C, Keenan, B, Cimpean, M, Winn, P, Panteliadis, Ip, Robbins, A, Andlauer, Tfm, Zarzycki, O, Dubois, B, Goris, A, Sondergaard, Hb, Sellebjerg, F, Sorensen, P, Ullum, H, Thorner, Lw, Saarela, J, Cournu-Rebeix, I, Damotte, V, Fontaine, B, Guillot-Noel, L, Lathrop, M, Vukusic, S, Berthele, A, Pongratz, V, Gasperi, C, Graetz, C, Grummel, V, Hemmer, B, Hoshi, M, Knier, B, Korn, T, Lill, Cm, Luessi, F, Muhlau, M, Zipp, F, Dardiotis, E, Agliardi, C, Amoroso, A, Barizzone, N, Benedetti, Md, Bernardinelli, L, Cavalla, P, Clarelli, F, Comi, G, Cusi, D, Esposito, F, Ferre, L, Galimberti, D, Guaschino, C, Leone, Ma, Martinelli, V, Moiola, L, Salvetti, M, Sorosina, M, Vecchio, D, Zauli, A, Santoro, S, Mancini, N, Zuccala, M, Mescheriakova, J, van Duijn, C, Bos, Sd, Celius, Eg, Spurkland, A, Comabella, M, Montalban, X, Alfredsson, L, Bomfim, Il, Gomez-Cabrero, D, Hillert, J, Jagodic, M, Linden, M, Piehl, F, Jelcic, I, Martin, R, Sospedra, M, Baker, A, Ban, M, Hawkins, C, Hysi, P, Kalra, S, Karpe, F, Khadake, J, Lachance, G, Molyneux, P, Neville, M, Thorpe, J, Bradshaw, E, Caillier, Sj, Calabresi, P, Cree, Bac, Cross, A, Davis, M, de Bakker, Pwi, Delgado, S, Dembele, M, Edwards, K, Fitzgerald, K, Frohlich, Iy, Gourraud, Pa, Haines, Jl, Hakonarson, H, Kimbrough, D, Isobe, N, Konidari, I, Lathi, E, Lee, Mh, Li, T, An, D, Zimmer, A, Madireddy, L, Manrique, Cp, Mitrovic, M, Olah, M, Patrick, E, Pericak-Vance, Ma, Piccio, L, Schaefer, C, Weiner, H, Lage, K, Scott, Rj, Lechner-Scott, J, Leal, R, Moscato, P, Booth, Dr, Stewart, Gj, Vucic, S, Pame, G, Bametto, M, Mason, D, Griffiths, L, Broadley, S, Tajouri, L, Baxter, A, Slee, M, Taylor, Bv, Charlesworth, J, Kilpatrick, Tj, Rubio, J, Jokubaitis, V, Wiley, J, Butzkueven, H, Leslie, S, Motyer, A, Stankovich, J, Carroll, Wm, Kermode, Ag, Edrin, M, Barclay, M, Peyrin-Biroulet, L, Chamaillard, M, Colombe, Jf, Cottone, M, Croft, A, D'Inca, R, Halfvarson, J, Hanigan, K, Henderson, P, Hugot, Jp, Karban, A, Kennedy, Na, Khan, Ma, Lemann, M, Levine, A, Massey, D, Milla, M, Motoey, Gw, Ng, Sme, Oikonomnou, J, Peeters, H, Proctor, Dd, Rahier, Jf, Roberts, R, Rutgeerts, P, Seibold, F, Stronati, L, Taylor, Km, Torkvist, L, Ublick, K, Van Limbergen, J, Van Gossum, A, Vatn, Mh, Zhang, H, Zhang, W, Donnelly, P, Barroso, I, Blackwe, Jm, Bramon, E, Brown, Ma, Casas, Jp, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, H, Mathew, Cg, Palmer, Cna, Plomin, R, Rautanen, A, Sawcer, Sj, Trembath, Rc, Viswanathan, Ac, Wood, Nw, Spencer, Cca, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Sul, Z, Vukcevic, Da, Langford, C, Hunt, Se, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, Sj, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, Mccann, Ot, Liddle, J, Potter, Sc, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Compston, A, Hafler, D, Harbo, Hf, Hauser, Sl, Stewart, G, D'Alfonso, S, Hadjigeorgiou, G, Taylor, B, Barcellos, Lf, Booth, D, Hintzen, R, Kockum, I, Martinelli-Boneschi, F, Mccauley, Jl, Oksenberg, Jr, Oturai, A, Sawcer, S, Ivinson, Aj, Olsson, T, De Jager, Pl, Neurology, and Immunology

Subjects
0301 basic medicine, Multiple Sclerosis, Quantitative Trait Loci, Inheritance Patterns, Cell Cycle Proteins, Genome-wide association study, Biology, Major histocompatibility complex, Polymorphism, Single Nucleotide, Major Histocompatibility Complex, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Immune system, Gene Frequency, Autoimmune Process, medicine, Humans, RNA-Seq, X chromosome, Genetics, Chromosomes, Human, X, Multidisciplinary, Microglia, Multiple sclerosis, GTPase-Activating Proteins, Chromosome Mapping, Genomics, medicine.disease, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Genetic Loci, Case-Control Studies, biology.protein, Genome-Wide Association Study, 030217 neurology & neurosurgery
Abstract

Genetic roots of multiple sclerosis The genetics underlying who develops multiple sclerosis (MS) have been difficult to work out. Examining more than 47,000 cases and 68,000 controls with multiple genome-wide association studies, the International Multiple Sclerosis Genetics Consortium identified more than 200 risk loci in MS (see the Perspective by Briggs). Focusing on the best candidate genes, including a model of the major histocompatibility complex region, the authors identified statistically independent effects at the genome level. Gene expression studies detected that every major immune cell type is enriched for MS susceptibility genes and that MS risk variants are enriched in brain-resident immune cells, especially microglia. Up to 48% of the genetic contribution of MS can be explained through this analysis. Science , this issue p. eaav7188 ; see also p. 1383

Published
2019

18. 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 Neuropathologica, (2019), 138, 2, (237-250), 10.1007/s00401-019-02026-8)

Author

van der Lee, S. J., Conway, O. J., Jansen, I., Carrasquillo, M. M., Kleineidam, L., van den Akker, E., Hernandez, I., van Eijk, K. R., Stringa, N., Chen, J. A., Zettergren, A., Andlauer, T. F. M., Diez-Fairen, M., Simon-Sanchez, J., Lleo, A., Zetterberg, H., Nygaard, M., Blauwendraat, C., Savage, J. E., Mengel-From, J., Moreno-Grau, S., Wagner, M., Fortea, J., Keogh, M. J., Blennow, K., Skoog, I., Friese, M. A., Pletnikova, O., Zulaica, M., Lage, C., de Rojas, I., Riedel-Heller, S., Illan-Gala, I., Wei, W., Jeune, B., Orellana, A., Then Bergh, F., Wang, X., Hulsman, M., Beker, N., Tesi, N., Morris, C. M., Indakoetxea, B., Collij, L. E., Scherer, M., Morenas-Rodriguez, E., Ironside, J. W., van Berckel, B. N. M., Alcolea, D., Wiendl, H., Strickland, S. L., Pastor, P., Rodriguez Rodriguez, E., Mead, S., Synofzik, M., van Swieten, J. C., Leber, I., Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Schofield, P. R., Halliday, G. M., Hodges, J. R., Piguet, O., Bartley, L., Thompson, E., Borroni, B., Padovani, A., Cruchaga, C., Cairns, N. J., Benussi, L., Binetti, G., Ghidoni, R., Forloni, G., Albani, D., Galimberti, D., Fenoglio, C., Serpente, M., Scarpini, E., Blesa, R., Landqvist Waldo, M., Nilsson, K., Nilsson, C., Mackenzie, I. R. A., Hsiung, G. -Y. R., Mann, D. M. A., Grafman, J., Attems, J., Griffiths, T. D., Mckeith, I. G., Thomas, A. J., Pietrini, P., Huey, E. D., Wassermann, E. M., Baborie, A., Jaros, E., Tierney, M. C., Razquin, C., Ortega-Cubero, S., Alonso, E., Perneczky, R., Diehl-Schmid, J., Alexopoulos, P., Kurz, A., Rainero, I., Rubino, E., Pinessi, L., Rogaeva, E., St George-Hyslop, P., Rossi, G., Tagliavini, F., Giaccone, G., Rowe, J. B., Schlachetzki, J. C. M., Uphill, J., Collinge, J., Danek, A., Van Deerlin, V. M., Grossman, M., Trojanowski, J. Q., van der Zee, J., Van Broeckhoven, C., Cappa, S. F., Hannequin, D., Golfier, V., Vercelletto, M., Brice, A., Nacmias, B., Sorbi, S., Bagnoli, S., Piaceri, I., Nielsen, J. E., Hjermind, L. E., Riemenschneider, M., Mayhaus, M., Ibach, B., Gasparoni, G., Pichler, S., Gu, W., Rossor, M. N., Fox, N. C., Warren, J. D., Spillantini, M. G., Morris, H. R., Rizzu, P., Snowden, J. S., Rollinson, S., Richardson, A., Gerhard, A., Bruni, A. C., Maletta, R., Frangipane, F., Cupidi, C., Bernardi, L., Anfossi, M., Gallo, M., Conidi, M. E., Smirne, N., Baker, M., Josephs, K. A., Parisi, J. E., Seeley, W. W., Miller, B. L., Karydas, A. M., Rosen, H., Dopper, E. G. P., Seelaar, H., Logroscino, G., Capozzo, R., Novelli, V., Puca, A. A., Franceschi, M., Postiglione, A., Milan, G., Sorrentino, P., Kristiansen, M., Chiang, H. -H., Graff, C., Pasquier, F., Rollin, A., Deramecourt, V., Lebouvier, T., Kapogiannis, D., Ferrucci, L., Pickering-Brown, S., Singleton, A. B., Hardy, J., Momeni, P., Boeve, B. F., Petersen, R. C., Ferman, T. J., van Gerpen, J. A., Reinders, M. J. T., Uitti, R. J., Tarraga, L., Maier, W., Dols-Icardo, O., Kawalia, A., Dalmasso, M. C., Boada, M., Zettl, U. K., van Schoor, N. M., Beekman, M., Allen, M., Masliah, E., de Munain, A. L., Pantelyat, A., Wszolek, Z. K., Ross, O. A., Dickson, D. W., Graff-Radford, N. R., Knopman, D., Rademakers, R., Lemstra, A. W., Pijnenburg, Y. A. L., Scheltens, P., Gasser, T., Chinnery, P. F., Hemmer, B., Huisman, M. A., Troncoso, J., Moreno, F., Nohr, E. A., Sorensen, T. I. A., Heutink, P., Sanchez-Juan, P., Posthuma, D., Coppola, G., Varpetian, A., Foroud, T. M., Levey, A. I., Kukull, W. A., Mendez, M. F., Ringman, J., Chui, H., Cotman, C., Decarli, C., Geschwind, D. H., Clarimon, J., Christensen, K., Ertekin-Taner, N., Scholz, S. W., Ramirez, A., Ruiz, A., Slagboom, E., van der Flier, W. M., Holstege, H., Neurology, Epidemiology and Data Science, Human genetics, APH - Societal Participation & Health, APH - Aging & Later Life, Amsterdam Neuroscience - Complex Trait Genetics, APH - Personalized Medicine, and APH - Methodology

Subjects
education
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

19. Aggressive multiple sclerosis (2): Treatment

Author

Arrambide, G., Iacobaeus, E., Amato, M. P., Derfuss, T., Vukusic, S., Hemmer, B., Brundin, L., Tintore, M., Berger, J., Boyko, A., Brinar, V., Brownlee, W., Ciccarelli, O., Coles, A., Correale, J., Cutter, G., Edan, G., Evangelou, N., Fernandez, O., Frederiksen, J., Gold, R., Hacohen, Y., Hartung, H. -P., Hellwig, K., Hillert, J., Imitola, J., Kalincik, T., Kappos, L., Khoury, S., Kim, H. J., Havrdova, E. K., Liblau, R., Lycke, J., Montalban, X., Muraro, P., Reingold, S., Schmierer, K., Sellebjerg, F., Sorensen, P. S., Solari, A., Sormani, M. P., Thompson, A., Trapp, B., Tremlett, H., Trojano, M., Tur, C., Uccelli, A., van Pesch, V., and Waubant, E.

Subjects
Aggressive, medicine.medical_specialty, Treatment response, relapsing–remitting, Disease, Permanent disability, multiple sclerosis, disability, highly active, treatment response, Multiple sclerosis, 03 medical and health sciences, 0302 clinical medicine, 2018 ECTRIMS Focused Workshop Group, medicine, Relapsing-remitting, 030212 general & internal medicine, Intensive care medicine, Highly active, Therapeutic window, Neurology & Neurosurgery, Disability, business.industry, 1103 Clinical Sciences, medicine.disease, ddc, Natural history, Neurology, Relapsing remitting, Neurology (clinical), business, 1109 Neurosciences, 030217 neurology & neurosurgery, Meeting Reviews
Abstract

Altres ajuts: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The workshop on which the manuscript is based was supported in its entirety by the European Committee on Treatment and Research in Multiple Sclerosis (ECTRIMS). The natural history of multiple sclerosis (MS) is highly heterogeneous. A subgroup of patients has what might be termed aggressive MS. These patients may have frequent, severe relapses with incomplete recovery and are at risk of developing greater and permanent disability at the earlier stages of the disease. Their therapeutic window of opportunity may be narrow, and while it is generally considered that they will benefit from starting early with a highly efficacious treatment, a unified definition of aggressive MS does not exist and data on its treatment are largely lacking. Based on discussions at an international focused workshop sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), we review our current knowledge about treatment of individuals with aggressive MS. We analyse the available evidence, identify gaps in knowledge and suggest future research needed to fill those gaps. A companion paper details the difficulties in developing a consensus about what defines aggressive MS.

Published
2020

20. 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 (vol 138, pg 237, 2019)

Author

van der Lee, SJ, Conway, OJ, Jansen, I, Carrasquillo, MM, Kleineidam, L, van den Akker, E, Hernandez, I, van Eijk, KR, Stringa, N, Chen, JSA, Zettergren, A, Andlauer, TFM, Diez-Fairen, M, Simon-Sanchez, J, Lleo, 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, Illan-Gala, I, Wei, W, Jeune, B, Orellana, A, Bergh, FT, Wang, X, Hulsman, M, Beker, N, Tesi, N, Morris, CM, Indakoetxea, B, Collij, LE, Scherer, M, Morenas-Rodriguez, E, Ironside, JW, van Berckel, BNM, Alcolea, D, Wiendl, H, Strickland, SL, Pastor, P, Rodriguez, ER, Boeve, BF, Petersen, RC, Ferman, TJ, van Gerpen, JA, Reinders, MJT, Uitti, RJ, Tarraga, 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, Sorensen, TIA, Heutink, P, Sanchez-Juan, P, Posthuma, D, Clarim?on, J, Christensen, K, Ertekin-Taner, N, Scholz, SW, Ramirez, A, Ruiz, A, Slagboom, E, van der Flier, WM, and Holstege, H

Subjects
education
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

21. Aggressive multiple sclerosis (1) : Towards a definition of the phenotype

Author

Iacobaeus, E., Arrambide, G., Amato, M. P., Derfuss, T., Vukusic, S., Hemmer, B., Tintore, M., Brundin, L., Berger, J., Boyko, A., Brinar, V., Brownlee, W., Ciccarelli, O., Coles, A., Correale, J., Cutter, G., Edan, G., Evangelou, N., Fernandez, O., Frederiksen, J., Gold, R., Hacohen, Y., Hartung, H. -P., Hellwig, K., Hillert, J., Imitola, J., Kalincik, T., Kappos, L., Khoury, S., Kim, H. J., Havrdova, E. K., Liblau, R., Lycke, J., Montalban, X., Muraro, P., Reingold, S., Schmierer, K., Sellebjerg, F., Sorensen, P. S., Solari, A., Sormani, M. P., Thompson, A., Trapp, B., Tremlett, H., Trojano, M., Tur, C., Uccelli, A., van Pesch, V., Waubant, E., UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, and UCL - (SLuc) Service de neurologie

Subjects
Disease subtype, Aggressive, medicine.medical_specialty, Severe disease, Aggressive disease, multiple sclerosis, Relapsing/remitting, Multiple sclerosis, 03 medical and health sciences, 0302 clinical medicine, disability, highly active, observational studies, relapsing/remitting, 2018 ECTRIMS Focused Workshop Group, medicine, Intensive care medicine, Secondary progressive, Highly active, Observational studies, 030304 developmental biology, 0303 health sciences, Neurology & Neurosurgery, Disability, business.industry, 1103 Clinical Sciences, medicine.disease, Phenotype, Additional research, ddc, Neurology, Observational study, Neurology (clinical), 1109 Neurosciences, business, 030217 neurology & neurosurgery, Meeting Reviews
Abstract

Altres ajuts: The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: The workshop on which the manuscript is based was supported in its entirety by the European Committee on Treatment and Research in Multiple Sclerosis (ECTRIMS). While the major phenotypes of multiple sclerosis (MS) and relapsing-remitting, primary and secondary progressive MS have been well characterized, a subgroup of patients with an active, aggressive disease course and rapid disability accumulation remains difficult to define and there is no consensus about their management and treatment. The current lack of an accepted definition and treatment guidelines for aggressive MS triggered a 2018 focused workshop of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) on aggressive MS. The aim of the workshop was to discuss approaches on how to describe and define the disease phenotype and its treatments. Unfortunately, it was not possible to come to consensus on a definition because of unavailable data correlating severe disease with imaging and molecular biomarkers. However, the workshop highlighted the need for future research needed to define this disease subtype while also focusing on its treatment and management. Here, we review previous attempts to define aggressive MS and present characteristics that might, with additional research, eventually help characterize it. A companion paper summarizes data regarding treatment and management.

Published
2020

22. Aggressive multiple sclerosis (2): Treatment.

Author

Arrambide, G, Iacobaeus, E, Amato, MP, Derfuss, T, Vukusic, S, Hemmer, B, Brundin, L, Tintore, M, 2018 ECTRIMS Focused Workshop Group, Arrambide, G, Iacobaeus, E, Amato, MP, Derfuss, T, Vukusic, S, Hemmer, B, Brundin, L, Tintore, M, and 2018 ECTRIMS Focused Workshop Group

Abstract

The natural history of multiple sclerosis (MS) is highly heterogeneous. A subgroup of patients has what might be termed aggressive MS. These patients may have frequent, severe relapses with incomplete recovery and are at risk of developing greater and permanent disability at the earlier stages of the disease. Their therapeutic window of opportunity may be narrow, and while it is generally considered that they will benefit from starting early with a highly efficacious treatment, a unified definition of aggressive MS does not exist and data on its treatment are largely lacking. Based on discussions at an international focused workshop sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), we review our current knowledge about treatment of individuals with aggressive MS. We analyse the available evidence, identify gaps in knowledge and suggest future research needed to fill those gaps. A companion paper details the difficulties in developing a consensus about what defines aggressive MS.

Published
2020

23. Aggressive multiple sclerosis (1): Towards a definition of the phenotype.

Author

Iacobaeus, E, Arrambide, G, Amato, MP, Derfuss, T, Vukusic, S, Hemmer, B, Tintore, M, Brundin, L, 2018 ECTRIMS Focused Workshop Group, Iacobaeus, E, Arrambide, G, Amato, MP, Derfuss, T, Vukusic, S, Hemmer, B, Tintore, M, Brundin, L, and 2018 ECTRIMS Focused Workshop Group

Abstract

While the major phenotypes of multiple sclerosis (MS) and relapsing-remitting, primary and secondary progressive MS have been well characterized, a subgroup of patients with an active, aggressive disease course and rapid disability accumulation remains difficult to define and there is no consensus about their management and treatment. The current lack of an accepted definition and treatment guidelines for aggressive MS triggered a 2018 focused workshop of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) on aggressive MS. The aim of the workshop was to discuss approaches on how to describe and define the disease phenotype and its treatments. Unfortunately, it was not possible to come to consensus on a definition because of unavailable data correlating severe disease with imaging and molecular biomarkers. However, the workshop highlighted the need for future research needed to define this disease subtype while also focusing on its treatment and management. Here, we review previous attempts to define aggressive MS and present characteristics that might, with additional research, eventually help characterize it. A companion paper summarizes data regarding treatment and management.

Published
2020

25. Differential effects of disease modifying drugs on peripheral blood B cell subsets: A cross sectional study in multiple sclerosis patients treated with interferon-β, glatiramer acetate, dimethyl fumarate, fingolimod or natalizumab

Author

Kemmerer, C. L., primary, Pernpeintner, V., additional, Ruschil, C., additional, Abdelhak, A., additional, Scholl, M., additional, Ziemann, U., additional, Krumbholz, M., additional, Hemmer, B., additional, and Kowarik, M. C., additional

Published
2020
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27. Plasma levels of soluble AβPPβ as a biomarker for Alzheimer's disease with dementia

Author

Alexopoulos, P. Thierjung, N. Economou, P. Werle, L. Buhl, F. Kagerbauer, S. Papanastasiou, A.D. Grimmer, T. Gourzis, P. Berthele, A. Hemmer, B. Kübler, H. Martin, J. Politis, A. Perneczky, R.

Abstract

Cost- and time-effective markers of Alzheimer's disease (AD), reliable and feasible at the population level are urgently needed. Soluble amyloid-β protein precursor β (sAβPPβ) in plasma has attracted scientific attention as a potential AD biomarker candidate. Here we report that plasma sAβPPβ levels in patients with AD dementia and typical for AD cerebrospinal fluid (CSF) biomarker profiles (N=33) are significantly lower (p

Published
2019

28. Author Correction: A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis (Nature Communications, (2019), 10, 1, (2236), 10.1038/s41467-019-09773-y)

Author

Madireddy, L. (Lohith), Patsopoulos, N.A. (Nikolaos A.), Cotsapas, C. (Chris), Bos, S.D. (Steffan), Beecham, A.H. (Ashley), McCauley, J. (John William), Kim, K. (Kicheol), Jia, X. (Xiaoming), Santaniello, A. (Adam), Caillier, S.J. (Stacy), Andlauer, T.F.M. (Till F. M.), Barcellos, L.F. (Lisa), Berge, T. (Tone), Bernardinelli, L. (Luisa), Martinelli-Boneschi, F. (Filippo), Booth, D. (David), Briggs, F. (Farren), Celius, E.G. (Elisabeth), Comabella, M. (Manuel), Comi, G. (Giancarlo), Cree, B.A.C. (Bruce A. C.), Dalfonso, S., Dedham, K. (Katrina), Duquette, P. (Pierre), Dardiotis, E. (Efthimios), Esposito, F. (Francesco), Fontaine, B. (Bertrand), Gasperi, C. (Christiane), Goris, A. (An), Dubois, B. (Bénédicte), Gourraud, P.-A. (Pierre-Antoine), Hadjigeorgiou, G.M. (Georgios M.), Haines, J.L. (Jonathan), Hawkins, C. (Clive), Hemmer`, B. (Bernhard), Hintzen, R.Q. (Rogier), Horáková, D., Isobe, N. (Noriko), Kalra, S. (Seema), Kira, J.-I. (Jun-ichi), Khalil, M. (Michael), Kockum, I. (I.), Lill, C.M. (Christina), Lincoln, M.R. (Matthew R.), Luessi, F. (Felix), Martin, R. (Roland), Oturai, A. (Annette), Palotie, A. (Aarno), Kunkle, B. (Brian), Henry, R. (Roland), Saarela, O. (Olli), Ivinson, A.J. (Adrian), Olsson, T., Taylor, B. (Bruce), Stewart, G. (Graeme), Harbo, H.F. (H.), Compston, J.E. (Juliet), Hauser, S.L. (Stephen), Hafler, D.A. (David A.), Zipp, F. (Frauke), De Jager, P., Sawcer, S.J. (Stephen), Oksenberg, J.R. (Jorge), Baranzini, S.E. (Sergio), Madireddy, L. (Lohith), Patsopoulos, N.A. (Nikolaos A.), Cotsapas, C. (Chris), Bos, S.D. (Steffan), Beecham, A.H. (Ashley), McCauley, J. (John William), Kim, K. (Kicheol), Jia, X. (Xiaoming), Santaniello, A. (Adam), Caillier, S.J. (Stacy), Andlauer, T.F.M. (Till F. M.), Barcellos, L.F. (Lisa), Berge, T. (Tone), Bernardinelli, L. (Luisa), Martinelli-Boneschi, F. (Filippo), Booth, D. (David), Briggs, F. (Farren), Celius, E.G. (Elisabeth), Comabella, M. (Manuel), Comi, G. (Giancarlo), Cree, B.A.C. (Bruce A. C.), Dalfonso, S., Dedham, K. (Katrina), Duquette, P. (Pierre), Dardiotis, E. (Efthimios), Esposito, F. (Francesco), Fontaine, B. (Bertrand), Gasperi, C. (Christiane), Goris, A. (An), Dubois, B. (Bénédicte), Gourraud, P.-A. (Pierre-Antoine), Hadjigeorgiou, G.M. (Georgios M.), Haines, J.L. (Jonathan), Hawkins, C. (Clive), Hemmer`, B. (Bernhard), Hintzen, R.Q. (Rogier), Horáková, D., Isobe, N. (Noriko), Kalra, S. (Seema), Kira, J.-I. (Jun-ichi), Khalil, M. (Michael), Kockum, I. (I.), Lill, C.M. (Christina), Lincoln, M.R. (Matthew R.), Luessi, F. (Felix), Martin, R. (Roland), Oturai, A. (Annette), Palotie, A. (Aarno), Kunkle, B. (Brian), Henry, R. (Roland), Saarela, O. (Olli), Ivinson, A.J. (Adrian), Olsson, T., Taylor, B. (Bruce), Stewart, G. (Graeme), Harbo, H.F. (H.), Compston, J.E. (Juliet), Hauser, S.L. (Stephen), Hafler, D.A. (David A.), Zipp, F. (Frauke), De Jager, P., Sawcer, S.J. (Stephen), Oksenberg, J.R. (Jorge), and Baranzini, S.E. (Sergio)

Abstract

The original version of this Article contained an error in the spelling of the author Nikolaos A. Patsopoulos, which was incorrectly given as Niklaos A. Patsopoulos, and author Efthimios Dardiotis, which was incorrectly given as Dardiotis Efthimios. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019
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29. Apheresis therapies for NMOSD attacks : a retrospective study of 207 therapeutic interventions

Author

Kleiter, I., Gahlen, A., Borisow, N., Fischer, K., Wernecke, K.D., Hellwig, K., Pache, F., Ruprecht, K., Havla, J., Kümpfel, T., Aktas, O., Hartung, H.P., Ringelstein, M., Geis, C., Kleinschnitz, C., Berthele, A., Hemmer, B., Angstwurm, K., Stellmann, J.P., 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, U.K., Faiss, J., Wildemann, B., Paul, F., Jarius, S., Trebst, C., and NEMOS (Neuromyelitis Optica Study Group)

Subjects
ddc:610, Function and Dysfunction of the Nervous System
Abstract

Objective: To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR). Methods: This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody–seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome. Results: Two hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04–144.91, p = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89–0.99, p = 0.014), the presence of AQP4-ab-antibodies (OR 33.34, 95% CI: 1.76–631.17, p = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03–21.62, p = 0.046). Conclusions: Our findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques. Classification of evidence: This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.

Published
2018

32. Prospective multicenter validation of CSF protein biomarkers in patients with CIS and early MS

Author

Huss, A., Otto, M., Tackenberg, B., Stangel, M., Aktas, O., Meuth, S., Gross, C. C., Bayas, A., Wildemann, B., Luessi, F., Seipelt, M., Puetz, M., Antony, G., Weber, F., Uhr, M., Bischof', F., Ruprecht, K., Buck, D., Retzlaff, N., Zettl, U. K., Haghikia, A., Lukas, C., Hartung, H. -P., Bergh, F. Then, Warnke, C., Zipp, F., Wiendl, H., Hemmer, B., Gold, R., Tumani, H., Huss, A., Otto, M., Tackenberg, B., Stangel, M., Aktas, O., Meuth, S., Gross, C. C., Bayas, A., Wildemann, B., Luessi, F., Seipelt, M., Puetz, M., Antony, G., Weber, F., Uhr, M., Bischof', F., Ruprecht, K., Buck, D., Retzlaff, N., Zettl, U. K., Haghikia, A., Lukas, C., Hartung, H. -P., Bergh, F. Then, Warnke, C., Zipp, F., Wiendl, H., Hemmer, B., Gold, R., and Tumani, H.

Published
2018

33. Absence of Epstein-Barr virus seronegativity in a large cohort of patients with early multiple sclerosis

Author

Abrahamyan, S., Eberspaecher, B., Ambrosius, B., Hessler, N., Antony, G., Koenig, I. R., Hoshi, M. -M., Aly, L., Luessi, F., Groppa, S., Klotz, L., Meuth, S. G., Tackenberg, B., Stoppe, M., Bergh, F. Then, Tumani, H., Kuempfel, T., Stangel, M., Heesen, C., Wildemann, B., Paul, F., Bayas, A., Warnke, C., Weber, F., Linker, R. A., Ziemann, U., Zettl, U. K., Zipp, F., Wiendl, H., Hemmer, B., Gold, R., Salmen, A., Ruprecht, K., Abrahamyan, S., Eberspaecher, B., Ambrosius, B., Hessler, N., Antony, G., Koenig, I. R., Hoshi, M. -M., Aly, L., Luessi, F., Groppa, S., Klotz, L., Meuth, S. G., Tackenberg, B., Stoppe, M., Bergh, F. Then, Tumani, H., Kuempfel, T., Stangel, M., Heesen, C., Wildemann, B., Paul, F., Bayas, A., Warnke, C., Weber, F., Linker, R. A., Ziemann, U., Zettl, U. K., Zipp, F., Wiendl, H., Hemmer, B., Gold, R., Salmen, A., and Ruprecht, K.

Published
2018

34. Changes of disease characteristics and disease-modifying treatment within one year in the National German MS cohort

Author

Ambrosius, B., Hessler, N., Antony, G., Konig, I. R., Hoshi, M-M., Aly, L., Luessi, F., Groppa, S., Klotz, L., Meuth, S. G., Tackenberg, B., Stoppe, M., Bergh, F. Then, Tumani, H., Kuempfel, T., Stangel, M., Heesen, C., Wildemann, B., Paul, F., Bayas, A., Warnke, C., Weber, F., Linker, R. A., Ziemann, U., Zettl, U. K., Zipp, F., Wiendl, H., Hemmer, B., Gold, R., Salmen, A., Ambrosius, B., Hessler, N., Antony, G., Konig, I. R., Hoshi, M-M., Aly, L., Luessi, F., Groppa, S., Klotz, L., Meuth, S. G., Tackenberg, B., Stoppe, M., Bergh, F. Then, Tumani, H., Kuempfel, T., Stangel, M., Heesen, C., Wildemann, B., Paul, F., Bayas, A., Warnke, C., Weber, F., Linker, R. A., Ziemann, U., Zettl, U. K., Zipp, F., Wiendl, H., Hemmer, B., Gold, R., and Salmen, A.

Published
2018

35. Volume versus surface-based cortical thickness measurements: A comparative study with healthy controls and multiple sclerosis patients

Author

Righart, R., Schmidt, P., Dahnke, R., Biberacher, V., Beer, A., Buck, D., Hemmer, B., Kirschke, J. S., Zimmer, C., Gaser, C., and Mühlau, M.

Subjects
Central Nervous System, Adult, Male, Computer and Information Sciences, Multiple Sclerosis, Imaging Techniques, Immunology, lcsh:Medicine, Research and Analysis Methods, Pathology and Laboratory Medicine, Nervous System, Autoimmune Diseases, Diagnostic Radiology, Signs and Symptoms, Diagnostic Medicine, Medicine and Health Sciences, Image Processing, Computer-Assisted, Humans, Animal Anatomy, Gray Matter, lcsh:Science, Cerebral Cortex, Cingulate Cortex, Software Tools, Radiology and Imaging, lcsh:R, Age Factors, Biology and Life Sciences, Brain, Software Engineering, Neurodegenerative Diseases, Demyelinating Disorders, Magnetic Resonance Imaging, Frontal Lobe, Neurology, Case-Control Studies, Lesions, Engineering and Technology, Clinical Immunology, Female, lcsh:Q, Clinical Medicine, Anatomy, Zoology, Software, Research Article
Abstract

The cerebral cortex is a highly folded outer layer of grey matter tissue that plays a key role in cognitive functions. In part, alterations of the cortex during development and disease can be captured by measuring the cortical thickness across the whole brain. Available software tools differ with regard to labor intensity and computational demands. In this study, we compared the computational anatomy toolbox (CAT), a recently proposed volume-based tool, with the well-established surface-based tool FreeSurfer. We observed that overall thickness measures were highly inter-correlated, although thickness estimates were systematically lower in CAT than in FreeSurfer. Comparison of multiple sclerosis (MS) patients with age-matched healthy control subjects showed highly comparable clusters of MS-related thinning for both methods. Likewise, both methods yielded comparable clusters of age-related cortical thinning, although correlations between age and average cortical thickness were stronger for FreeSurfer. Our data suggest that, for the analysis of cortical thickness, the volume-based CAT tool can be regarded a considerable alternative to the well-established surface-based FreeSurfer tool.

Published
2017

36. Consensus guidelines for lumbar puncture in patients with neurological diseases

Author

Engelborghs, S. (Sebastiaan), Niemantsverdriet, E. (Ellis), Struyfs, H. (Hanne), Blennow, K. (Kaj), Brouns, R. (Raf), Comabella, M. (Manuel), Dujmovic, I. (Irena), Flier, W.M. (Wiesje) van der, Frölich, L. (Lutz), Galimberti, D. (Daniela), Gnanapavan, S. (Sharmilee), Hemmer`, B. (Bernhard), Hoff, E.I. (Erik I.), Hort, J. (Jakub), Iacobaeus, E. (Ellen), Ingelsson, M. (Martin), Jan de Jong, F. (Frank), Jonsson, M. (Michael), Khalil, M. (Michael), Kuhle, J. (Jens), Lleo, A. (Alberto), De Mendonça, A. (Alexandre), Molinuevo, J.L. (José Luis), Nagels, G. (Guy), Paquet, C. (Claire), Parnetti, L., Roks, C.M.A.A. (Gerwin), Rosa-Neto, P. (Pedro), Scheltens, P. (Philip), Skarsgård, C. (Constance), Stomrud, E. (Erik), Tumani, H. (Hayrettin), Visser, P. (Pim), Wallin, A. (Anders), Winblad, B., Zetterberg, H. (Henrik), Duits, F.H. (Flora H.), Teunissen, C.E. (Charlotte), Engelborghs, S. (Sebastiaan), Niemantsverdriet, E. (Ellis), Struyfs, H. (Hanne), Blennow, K. (Kaj), Brouns, R. (Raf), Comabella, M. (Manuel), Dujmovic, I. (Irena), Flier, W.M. (Wiesje) van der, Frölich, L. (Lutz), Galimberti, D. (Daniela), Gnanapavan, S. (Sharmilee), Hemmer`, B. (Bernhard), Hoff, E.I. (Erik I.), Hort, J. (Jakub), Iacobaeus, E. (Ellen), Ingelsson, M. (Martin), Jan de Jong, F. (Frank), Jonsson, M. (Michael), Khalil, M. (Michael), Kuhle, J. (Jens), Lleo, A. (Alberto), De Mendonça, A. (Alexandre), Molinuevo, J.L. (José Luis), Nagels, G. (Guy), Paquet, C. (Claire), Parnetti, L., Roks, C.M.A.A. (Gerwin), Rosa-Neto, P. (Pedro), Scheltens, P. (Philip), Skarsgård, C. (Constance), Stomrud, E. (Erik), Tumani, H. (Hayrettin), Visser, P. (Pim), Wallin, A. (Anders), Winblad, B., Zetterberg, H. (Henrik), Duits, F.H. (Flora H.), and Teunissen, C.E. (Charlotte)

Abstract

Introduction Cerebrospinal fluid collection by lumbar puncture (LP) is performed in the diagnostic workup of several neurological brain diseases. Reluctance to perform the procedure is among others due to a lack of standards and guidelines to minimize the risk of complications, such as post-LP headache or back pain. Methods We provide consensus guidelines for the LP procedure to minimize the risk of complications. The recommendations are based on (1) data from a large multicenter LP feasibility study (evidence level II-2), (2) systematic literature review on LP needle characteristics and post-LP complications (evidence level II-2), (3) discussion of best practice within the Joint Programme Neurodegenerative Disease Research Biomarkers for Alzheimer's disease and Parkinson's Disease and Biomarkers for Multiple Sclerosis consortia (evidence level III). Results Our consensus guidelines address contraindications, as well as patient-related and procedure-related risk factors that can influence the development of post-LP complications. Discussion When an LP is performed correctly, the procedure is well tolerated and accepted with a low complication rate.

Published
2017
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37. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis

Author

Hauser, S. L., Bar-Or, A., Comi, G., Giovannoni, G., Hartung, H. -P., Hemmer, B., Lublin, F., Montalban, X., Rammohan, K. W., Selmaj, K., Traboulsee, A., Wolinsky, J. S., Arnold, D. L., Klingelschmitt, G., Masterman, D., Fontoura, P., Belachew, S., Chin, P., Mairon, N., Garren, H., Kappos, L., Opera, I and OPERA II Clinical Investigator, Mirabella, M., Mirabella, M. (ORCID:0000-0002-7783-114X), Hauser, S. L., Bar-Or, A., Comi, G., Giovannoni, G., Hartung, H. -P., Hemmer, B., Lublin, F., Montalban, X., Rammohan, K. W., Selmaj, K., Traboulsee, A., Wolinsky, J. S., Arnold, D. L., Klingelschmitt, G., Masterman, D., Fontoura, P., Belachew, S., Chin, P., Mairon, N., Garren, H., Kappos, L., Opera, I and OPERA II Clinical Investigator, Mirabella, M., and Mirabella, M. (ORCID:0000-0002-7783-114X)

Abstract

BACKGROUND B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. METHODS In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 Î1⁄4g three times weekly for 96 weeks. The primary end point was the annualized relapse rate. RESULTS The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P = 0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P = 0.004) but not in trial 1 (0.21 vs. 0.17, P = 0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those t

Published
2017

40. Association of genetic markers with CSF oligoclonal bands in multiple sclerosis patients

Author

Leone, M, Barizzone, N, Esposito, F, Harbo, H, Goris, A, Kockum, I, Oturai, A, Celius, E, Mero, I, Dubois, B, Olsson, T, Søndergaard, H, Cusi, D, Lupoli, S, Andreassen, B, Barcellos, L, Booth, D, Comabella, M, Compston, A, D'Alfonso, S, De Jager, P, Fontaine, B, Hafler, D, Haines, J, Hauser, S, Hawkins, C, Hemmer, B, Hillert, J, Ivinson, A, Martin, R, Martinelli Boneschi, F, Mccauley, J, Oksenberg, J, Patsopoulos, N, Pericak Vance, M, Saarela, J, Sawcer, S, Spurkland, A, Stewart, G, Zipp, F, Myhr, K, Guerini, F, Naldi, P, Galimberti, D, Scarpini, E, Bergamaschi, R, Di Sapio, A, Caputo, D, Rosso, G, Cordera, S, Cavalla, P, Cavallo, R, Benedetti, M, Salvetti, M, Capra, R, Ghezzi, A, Annovazzi, P, Coniglio, G, Liberatore, G, Rodegher, M, Moiola, L, Colombo, B, Radaelli, M, Rossi, P, Martinelli, V, Comi, G, D'Alfonso, S., LUCENTI, AUSILIATRICE, Leone, M, Barizzone, N, Esposito, F, Lucenti, A, Harbo, H, Goris, A, Kockum, I, Oturai, A, Celius, E, Mero, I, Dubois, B, Olsson, T, Søndergaard, H, Cusi, D, Lupoli, S, Andreassen, B, Barcellos, L, Booth, D, Comabella, M, Compston, A, D'Alfonso, S, De Jager, P, Fontaine, B, Hafler, D, Haines, J, Hauser, S, Hawkins, C, Hemmer, B, Hillert, J, Ivinson, A, Martin, R, Martinelli Boneschi, F, Mccauley, J, Oksenberg, J, Patsopoulos, N, Pericak Vance, M, Saarela, J, Sawcer, S, Spurkland, A, Stewart, G, Zipp, F, Myhr, K, Guerini, F, Naldi, P, Galimberti, D, Scarpini, E, Bergamaschi, R, Di Sapio, A, Caputo, D, Rosso, G, Cordera, S, Cavalla, P, Cavallo, R, Benedetti, M, Salvetti, M, Capra, R, Ghezzi, A, Annovazzi, P, Coniglio, G, Liberatore, G, Rodegher, M, Moiola, L, Colombo, B, Radaelli, M, Rossi, P, Martinelli, V, Comi, G, and Villoslada, Pablo

Subjects
Oncology, Male, lcsh:Medicine, Genome-wide association study, Biochemistry, Major Histocompatibility Complex, 0302 clinical medicine, Genetic Marker, Multiple Sclerosi, Genetics of the Immune System, 2.1 Biological and endogenous factors, Aetiology, lcsh:Science, Genetics, adult, female, genetic markers, hla-drb1 chains, humans, male, meta-analysis as topic, middle aged, multiple sclerosis, oligoclonal bands, polymorphism, single nucleotide, young adult, genome-wide association study, biochemistry, genetics and molecular biology (all), agricultural and biological sciences (all), 0303 health sciences, Multidisciplinary, Medicine (all), Single Nucleotide, Middle Aged, Neurology, Medicine, HLA-DRB1 Chain, Female, Research Article, Human, Genetic Markers, Adult, medicine.medical_specialty, Multiple Sclerosis, General Science & Technology, Immunology, Single-nucleotide polymorphism, Human leukocyte antigen, Biology, Autoimmune Disease, Polymorphism, Single Nucleotide, Autoimmune Diseases, 03 medical and health sciences, Young Adult, Meta-Analysis as Topic, Oligoclonal Band, Clinical Research, Internal medicine, medicine, Genetic predisposition, SNP, Humans, PROGRESSO Group, Polymorphism, 030304 developmental biology, Evolutionary Biology, Biochemistry, Genetics and Molecular Biology (all), Population Biology, Multiple sclerosis, Wellcome Trust Case Control Consortium 2, Oligoclonal Bands, Human Genome, lcsh:R, Proteins, Computational Biology, Odds ratio, Major Histocompatibility Antigens, medicine.disease, Demyelinating Disorders, International Multiple Sclerosis Genetics Consortium, PROGEMUS Group, Agricultural and Biological Sciences (all), Genetic marker, Genetic Polymorphism, Clinical Immunology, lcsh:Q, 030217 neurology & neurosurgery, Population Genetics, HLA-DRB1 Chains, Genome-Wide Association Study
Abstract

Objective:to explore the association between genetic markers and Oligoclonal Bands (OCB) in the Cerebro Spinal Fluid (CSF) of Italian Multiple Sclerosis patients.Methods:We genotyped 1115 Italian patients for HLA-DRB1*15 and HLA-A*02. In a subset of 925 patients we tested association with 52 non-HLA SNPs associated with MS susceptibility and we calculated a weighted Genetic Risk Score. Finally, we performed a Genome Wide Association Study (GWAS) with OCB status on a subset of 562 patients. The best associated SNPs of the Italian GWAS were replicated in silico in Scandinavian and Belgian populations, and meta-analyzed.Results:HLA-DRB1*15 is associated with OCB+: p = 0.03, Odds Ratio (OR) = 1.6, 95% Confidence Limits (CL) = 1.1-2.4. None of the 52 non-HLA MS susceptibility loci was associated with OCB, except one SNP (rs2546890) near IL12B gene (OR: 1.45; 1.09-1.92). The weighted Genetic Risk Score mean was significantly (p = 0.0008) higher in OCB+ (7.668) than in OCB- (7.412) patients. After meta-analysis on the three datasets (Italian, Scandinavian and Belgian) for the best associated signals resulted from the Italian GWAS, the strongest signal was a SNP (rs9320598) on chromosome 6q (p = 9.4×10-7) outside the HLA region (65 Mb).Discussion:genetic factors predispose to the development of OCB. © 2013 Leone et al.

Published
2013

43. Exome Array GWAS in 10,000 Germans Identifies Association between MUC22 and Multiple Sclerosis

Author

Dankowski, T., Buck, D., Andlauer, T. F., Antony, G., Bayas, A., Bechmann, Lars Peter, Berthele, A., Bettecken, T., Chan, A., Franke, A., Gold, R., Graetz, C., Haas, J., Hecker, M., Herms, S., Hohlfeld, R., Infante-Duarte, C., Jöckel, Karl-Heinz, Kieseier, B. C., Knier, B., Knop, M., Lichtner, P., Lieb, W., Lill, C. M., Limmroth, V., Linker, R. A., Loleit, V., Meuth, S., Moebus, Susanne, Mueller-Myhsok, B., Nischwitz, S., Noethen, M. M., Friedemann, P., Pütz, Martin, Ruck, T., Salmen, A., Stangel, M., Stellmann, J. -. P., Strauch, K., Stuerner, K. H., Tackenberg, B., Bergh, F. T. h. e. n., Tumani, H., Waldenberger, M., Weber, F., Wiend, H., Wildemann, B., Zettl, U. K., Ziemann, U., Zipp, F., Hemmer, B., and Ziegler, A.

Subjects
Medizin
Published
2015

44. JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants

Author

Sundqvist, E, Buck, D, Warnke, C, Albrecht, E, Gieger, C, Khademi, M, Lima Bomfim, I, Fogdell-Hahn, A, Link, J, Alfredsson, L, Søndergaard, HB, Hillert, J, Barcellos, L, Booth, D, McCauley, JL, Comabella, M, Compston, A, DAlfonso, S, De Jager, P, Fontaine, B, Goris, A, Hafler, D, Haines, J, Harbo, HF, Hauser, SL, Hawkins, C, Hemmer, B, Ivinson, A, Kockum, I, Martin, R, Boneschi, FM, Oksenberg, J, Olsson, T, Oturai, A, Patsopoulos, N, Pericak-Vance, M, Saarela, J, Sawcer, S, Spurkland, A, Stewart, G, Zipp, F, Oturai, AB, and Hemme, B

Subjects
viruses, virus diseases
Abstract

JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50-60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0.42, p = 7×10-15) and controls (OR = 0.53, p = 2×10-5). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR = 1.63, p = 0.006), and controls (OR = 2.69, p = 1×10-5). The German dataset confirmed these findings (OR = 0.54, p = 1×10-4and OR = 1.58, p = 0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention. © 2014 Sundqvist et al.

Published
2014

45. Genetic variants are major determinants of CSF antibody levels in multiple sclerosis

Author

Goris, A., Pauwels, I., Gustavsen, M.W., van Son, B., Hilven, K., Bos, S.D., Celius, E.G., Berg-Hansen, P., Aarseth, J., Myhr, K-M, D'Alfonso, S., Barizzone, N., Leone, M.A., Martinelli Boneschi, F., Sorosina, M., Liberatore, G., Kockum, I., Olsson, T., Hillert, J., Alfredsson, L., Bedri, S.K., Hemmer, B., Buck, D., Berthele, A., Knier, B., Biberacher, V., van Pesch, V., Sindic, C., Bang Oturai, A., Sondergaard, H.B., Sellebjerg, F., Jensen, P.E.H., Comabella, M., Montalban, X., Perez-Boza, J., Malhotra, S., Lechner-Scott, J., Broadley, S., Slee, M., Taylor, B., Kermode, A.G., Gourraud, P-A, Sawcer, S.J., Andreassen, B.K., Dubois, B., Harbo, H.F., Goris, A., Pauwels, I., Gustavsen, M.W., van Son, B., Hilven, K., Bos, S.D., Celius, E.G., Berg-Hansen, P., Aarseth, J., Myhr, K-M, D'Alfonso, S., Barizzone, N., Leone, M.A., Martinelli Boneschi, F., Sorosina, M., Liberatore, G., Kockum, I., Olsson, T., Hillert, J., Alfredsson, L., Bedri, S.K., Hemmer, B., Buck, D., Berthele, A., Knier, B., Biberacher, V., van Pesch, V., Sindic, C., Bang Oturai, A., Sondergaard, H.B., Sellebjerg, F., Jensen, P.E.H., Comabella, M., Montalban, X., Perez-Boza, J., Malhotra, S., Lechner-Scott, J., Broadley, S., Slee, M., Taylor, B., Kermode, A.G., Gourraud, P-A, Sawcer, S.J., Andreassen, B.K., Dubois, B., and Harbo, H.F.

Abstract

Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index—the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10−16). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10−7). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10−37). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10−22), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10−6). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender

Published
2015

47. A 'Candidate-Interactome' Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

Author

Mechelli, R, Umeton, R, Policano, C, Annibali, V, Coarelli, G, Ricigliano, VAG, Vittori, D, Fornasiero, A, Buscarinu, MC, Romano, S, Salvetti, M, Ristori, G, Sawcer, S, Hellenthal, G, Pirinen, M, Spencer, CCA, Patsopoulos, NA, Moutsianas, L, Dilthey, A, Su, Z, Freeman, C, Hunt, SE, Edkins, S, Gray, E, Booth, DR, Potter, SC, Goris, A, Band, G, Oturai, AB, Strange, A, Saarela, J, Bellenguez, C, Fontaine, B, Gillman, M, Hemmer, B, Gwilliam, R, Zipp, F, Jayakumar, A, Martin, R, Leslie, S, Hawkins, S, Giannoulatou, E, D'alfonso, S, Blackburn, H, Boneschi, FM, Liddle, J, Harbo, HF, Perez, ML, Spurkland, A, Waller, MJ, Mycko, MP, Ricketts, M, Comabella, M, Hammond, N, and Kockum, I

Abstract

Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms. © 2013 Mechelli et al.

Published
2013

48. Review and analysis of international case-control studies on CCSVI and multiple sclerosis [Übersicht und Analyse internationaler Fall-Kontroll-Studien zu 'chronischen zerebrospinalen venösen Insuffizienz' (CCSVI) und Multipler Sklerose]

Author

Krogias, C. Tsivgoulis, G. Grond, M. Hartung, H.P. Hemmer, B. Oertel, W. Wiendl, H. Gold, R.

Abstract

Background: A constellation of neurosonological findings called "chronic cerebrospinal venous insufficiencyo" (CCSVI) was introduced as a highly specific and highly sensitive finding in multiple sclerosis (MS) patients. It was postulated that impaired venous cerebral drainage initiates the pathological processes of MS. Several published case-control of studies evaluating the association of CCSVI with MS report inconsistent findings. Methods: Besides an overview of the postulated concept of "venous hypothesiso", we performed a meta-analysis of the results from published case-control studies evaluating the association of CCSVI with MS using ultrasound criteria. Results: In 25 eligible studies, 2 012 MS patients and 1 425 healthy controls were investigated. The constellation of CCSVI was described in 876 (41.7%) of the patients and in 147 (10.3%) of the controls (OR=3.2; 95% CI=2.5-4.0). However, considerable heterogeneity (I2=82%) across these studies was documented. The analysis of the 3 German studies revealed a very low prevalence of CCSVI of only about 2% in both groups (OR=0.5; 95% CI=0.1-3.1) without heterogeneity (I2=0%). Conclusions: Compared to the first description, no subsequent international case-control study could reproduce the high specificity and sensitivity of CCSVI in MS. There is high heterogeneity across the different studies, so that further comprehensive meta-analyses with additional sensitivity analyses are required. The studies conducted in Germany have clearly and consistently shown no evidence for the "venous multiple sclerosis hypothesiso". Interventional procedures should therefore not be performed outside the setting of randomised clinical trials. © Georg Thieme Verlag KG Stuttgart, New York.

Published
2013

49. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

Author

Beecham, AH, Patsopoulos, NA, Xifara, DK, Davis, MF, Kemppinen, A, Cotsapas, C, Shah, TS, Spencer, C, Booth, D, Goris, A, Oturai, A, Saarela, J, Fontaine, B, Hemmer, B, Martin, C, Zipp, F, D'Alfonso, S, Martinelli-Boneschi, F, Taylor, B, Harbo, HF, Kockum, I, Hillert, J, Olsson, T, Ban, M, Oksenberg, JR, Hintzen, R, Barcellos, LF, Agliardi, C, Alfredsson, L, Alizadeh, M, Anderson, C, Andrews, R, Søndergaard, HB, Baker, A, Band, G, Baranzini, SE, Barizzone, N, Barrett, J, Bellenguez, C, Bergamaschi, L, Bernardinelli, L, Berthele, A, Biberacher, V, Binder, TMC, Blackburn, H, Bomfim, IL, Brambilla, P, Broadley, S, Brochet, B, Brundin, L, Buck, D, Butzkueven, H, Caillier, SJ, Camu, W, Carpentier, W, Cavalla, P, Celius, EG, Coman, I, Comi, G, Corrado, L, Cosemans, L, Cournu-Rebeix, I, Cree, BAC, Cusi, D, Damotte, V, Defer, G, Delgado, SR, Deloukas, P, Di Sapio, A, Dilthey, AT, Donnelly, P, Dubois, B, Duddy, M, Edkins, S, Elovaara, I, Esposito, F, Evangelou, N, Fiddes, B, Field, J, and Franke, A

Abstract

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10 -4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10 -8), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals. © 2013 Nature America, Inc. All rights reserved.

Published
2013

50. Oligoclonal band status in Scandinavian multiple sclerosis patients is associated with specific genetic risk alleles

Author

Mero, I., Gustavsen, M.W., Sã¦ther, H.S., Flã¥m, S.T., Berg-Hansen, P., Sã¸ndergaard, H.B., Jensen, P.E.H., Berge, T., Bjã¸lgerud, A., Muggerud, A., Aarseth, J.H., International Multiple Sclerosis Genetics Consortium, Myhr, K., Celius, E.G., Sellebjerg, F., Hillert, J., Alfredsson, L., Olsson, T., Oturai, A.B., Kockum, I., Lie, B.A., Andreassen, B.K., Harbo, Collaborators: Barcellos L, H.F., Booth, D., Comabella, M., Compston, A., D'Alfonso, S., De Jager, P., Fontaine, B., Goris, A., Hafler, D., Haines, J., Harbo, H., Hauser, S., Hawkins, C., Hemmer, B., Ivinson, A., Martin, R., Martinelli Boneschi, F., Mccauley, J., Oksenberg, J., Oturai, A., Patsopoulos, N., Pericak-Vance, M., Saarela, J., Sawcer, S., Spurkland, A., Stewart, G., and Zipp, F.

Subjects
Male, Genetics and Molecular Biology (all), Oncology, Non-Clinical Medicine, Denmark, lcsh:Medicine, Genome-wide association study, Biochemistry, Adult, Alleles, Case-Control Studies, Female, Gene Frequency, Genotype, HLA-DRB1 Chains, Humans, Multiple Sclerosis, Norway, Oligoclonal Bands, Polymorphism, Single Nucleotide, Sweden, Genome-Wide Association Study, Medicine (all), Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), 0302 clinical medicine, lcsh:Science, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, Single Nucleotide, 3. Good health, Neurology, Medicine, Settore MED/26 - Neurologia, Research Article, medicine.medical_specialty, Oligoclonal band, Population, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, Internal medicine, Genome-Wide Association Studies, medicine, Polymorphism, Risk factor, education, Allele frequency, Genetic Association Studies, 030304 developmental biology, Health Care Policy, Multiple sclerosis, lcsh:R, Case-control study, Health Risk Analysis, Human Genetics, medicine.disease, Demyelinating Disorders, Genetics of Disease, lcsh:Q, 030217 neurology & neurosurgery
Abstract

The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in multiple sclerosis (MS). We applied data from Norwegian, Swedish and Danish (i.e. Scandinavian) MS patients from a genome-wide association study (GWAS) to search for genetic differences in MS relating to OCB status. GWAS data was compared in 1367 OCB positive and 161 OCB negative Scandinavian MS patients, and nine of the most associated SNPs were genotyped for replication in 3403 Scandinavian MS patients. HLA-DRB1 genotypes were analyzed in a subset of the OCB positive (n = 2781) and OCB negative (n = 292) MS patients and compared to 890 healthy controls. Results from the genome-wide analyses showed that single nucleotide polymorphisms (SNPs) from the HLA complex and six other loci were associated to OCB status. In SNPs selected for replication, combined analyses showed genome-wide significant association for two SNPs in the HLA complex; rs3129871 (p = 5.7×10(-15)) and rs3817963 (p = 5.7×10(-10)) correlating with the HLA-DRB1*15 and the HLA-DRB1*04 alleles, respectively. We also found suggestive association to one SNP in the Calsyntenin-2 gene (p = 8.83×10(-7)). In HLA-DRB1 analyses HLA-DRB1*15∶01 was a stronger risk factor for OCB positive than OCB negative MS, whereas HLA-DRB1*04∶04 was associated with increased risk of OCB negative MS and reduced risk of OCB positive MS. Protective effects of HLA-DRB1*01∶01 and HLA-DRB1*07∶01 were detected in both groups. The groups were different with regard to age at onset (AAO), MS outcome measures and gender. This study confirms both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicates different clinical characteristics between the groups. This suggests differences in disease mechanisms between OCB negative and OCB positive MS with implications for patient management, which need to be further studied.

Published
2013

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