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1. Machine-learning-based prediction of disability progression in multiple sclerosis: An observational, international, multi-center study

Author

McGinnis, RS, De Brouwer, E, Becker, T, Werthen-Brabants, L, Dewulf, P, Iliadis, D, Dekeyser, C, Laureys, G, Van Wijmeersch, B, Popescu, V, Dhaene, T, Deschrijver, D, Waegeman, W, De Baets, B, Stock, M, Horakova, D, Patti, F, Izquierdo, G, Eichau, S, Girard, M, Prat, A, Lugaresi, A, Grammond, P, Kalincik, T, Alroughani, R, Grand'Maison, F, Skibina, O, Terzi, M, Lechner-Scott, J, Gerlach, O, Khoury, SJ, Cartechini, E, Van Pesch, V, Sà, MJ, Weinstock-Guttman, B, Blanco, Y, Ampapa, R, Spitaleri, D, Solaro, C, Maimone, D, Soysal, A, Iuliano, G, Gouider, R, Castillo-Triviño, T, Sánchez-Menoyo, JL, van der Walt, A, Oh, J, Aguera-Morales, E, Altintas, A, Al-Asmi, A, de Gans, K, Fragoso, Y, Csepany, T, Hodgkinson, S, Deri, N, Al-Harbi, T, Taylor, B, Gray, O, Lalive, P, Rozsa, C, McGuigan, C, Kermode, A, Sempere, AP, Mihaela, S, Simo, M, Hardy, T, Decoo, D, Hughes, S, Grigoriadis, N, Sas, A, Vella, N, Moreau, Y, Peeters, L, McGinnis, RS, De Brouwer, E, Becker, T, Werthen-Brabants, L, Dewulf, P, Iliadis, D, Dekeyser, C, Laureys, G, Van Wijmeersch, B, Popescu, V, Dhaene, T, Deschrijver, D, Waegeman, W, De Baets, B, Stock, M, Horakova, D, Patti, F, Izquierdo, G, Eichau, S, Girard, M, Prat, A, Lugaresi, A, Grammond, P, Kalincik, T, Alroughani, R, Grand'Maison, F, Skibina, O, Terzi, M, Lechner-Scott, J, Gerlach, O, Khoury, SJ, Cartechini, E, Van Pesch, V, Sà, MJ, Weinstock-Guttman, B, Blanco, Y, Ampapa, R, Spitaleri, D, Solaro, C, Maimone, D, Soysal, A, Iuliano, G, Gouider, R, Castillo-Triviño, T, Sánchez-Menoyo, JL, van der Walt, A, Oh, J, Aguera-Morales, E, Altintas, A, Al-Asmi, A, de Gans, K, Fragoso, Y, Csepany, T, Hodgkinson, S, Deri, N, Al-Harbi, T, Taylor, B, Gray, O, Lalive, P, Rozsa, C, McGuigan, C, Kermode, A, Sempere, AP, Mihaela, S, Simo, M, Hardy, T, Decoo, D, Hughes, S, Grigoriadis, N, Sas, A, Vella, N, Moreau, Y, and Peeters, L

Abstract

BACKGROUND: Disability progression is a key milestone in the disease evolution of people with multiple sclerosis (PwMS). Prediction models of the probability of disability progression have not yet reached the level of trust needed to be adopted in the clinic. A common benchmark to assess model development in multiple sclerosis is also currently lacking. METHODS: Data of adult PwMS with a follow-up of at least three years from 146 MS centers, spread over 40 countries and collected by the MSBase consortium was used. With basic inclusion criteria for quality requirements, it represents a total of 15, 240 PwMS. External validation was performed and repeated five times to assess the significance of the results. Transparent Reporting for Individual Prognosis Or Diagnosis (TRIPOD) guidelines were followed. Confirmed disability progression after two years was predicted, with a confirmation window of six months. Only routinely collected variables were used such as the expanded disability status scale, treatment, relapse information, and MS course. To learn the probability of disability progression, state-of-the-art machine learning models were investigated. The discrimination performance of the models is evaluated with the area under the receiver operator curve (ROC-AUC) and under the precision recall curve (AUC-PR), and their calibration via the Brier score and the expected calibration error. All our preprocessing and model code are available at https://gitlab.com/edebrouwer/ms_benchmark, making this task an ideal benchmark for predicting disability progression in MS. FINDINGS: Machine learning models achieved a ROC-AUC of 0⋅71 ± 0⋅01, an AUC-PR of 0⋅26 ± 0⋅02, a Brier score of 0⋅1 ± 0⋅01 and an expected calibration error of 0⋅07 ± 0⋅04. The history of disability progression was identified as being more predictive for future disability progression than the treatment or relapses history. CONCLUSIONS: Good discrimination and calibration performance on an external validation s

Published
2024

2. Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis: A Randomized, Phase 3, Clinical Trial

Author

Vermersch, Patrick, Brieva-Ruiz, Luis, Fox, Robert J., Paul, Friedemann, Ramio-Torrenta, Lluis, Schwab, Matthias, Moussy, Alain, Mansfield, Colin, Hermine, Olivier, Maciejowski, Maciej, Hecham, N., Deri, N. Haydeé, Djelilovic-Vranic, J., Milanov, I., Shotekov, P., Blevins, G., Girard, J., Lapierre, Y., Camu, W., Castelnovo, G., Clavelou, P., Hautecoeur, P., Marziniak, M., Mayer, C., Oschmann, P., Reifschneider, G., Schoell, I., Tackenberg, B., Bergh, F. Then, Fakas, N., Grigoriadis, N., Kalochristianakis, D., Mitsikostas, D., Orologas, A., Tavernarakis, A., Thomaidis, T., Kovacs, K., Matyas, K., Piros, P., Satori, M., Anand, K., Shifrin, A., Banaszkiewicz, K., Bonek, R., Chahwan, M., Czernichowska - Kotiuszko, M., Darda-Ledzion, L., Debrowska - Wójcik, J., Dziki, M., Krzystanek, E., Kulka, M., Lisewski, P., Ratajczak, M., Szczudlik, A., Szczygiel, J., Tomaszewska, M., Wójcik, J., Zielonka, D., Chiru, M., Deme, S., Manescu, S., Nica, SM., Popescu, C., Szatmari, S., Fedyanin, A., Malkova, N., Popov, D., Volkova, L., Vorobeva, O., Brozman, M., Cimprichova, A., Cuchran, P., Gurcik, L., Krastev, G., Lisá, I., Nyeky, M., Poljaková, J., Turcani, P., Frost, A., Heckmann, J., Agüera, E., Coret, F., Escartin, A., Fernandez, V., Callizo, JR. Ara, Martin, G., Martinez-Rodriguez, JE., Gines, M. Martinez, Munoz, D., Olascoaga, J., Prieto, J., Ramo-Tello, C., Belal, S., Ben Ammou, S., Frih-Ayed, M., Gouider, R., Mhiri, C., Mrissa, R., Cherkez, A., Chmyr, H., Chudovska, L., Datskevych, S., Dziak, L., Galusha, A., Khavunka, M., Kobys, T., Kozyolkin, O., Lekomtseva, Y., Litovchenko, T., Moroz, O., Moskovko, G., Pashkovsky, V., Sanotskyi, Y., Shkrobot, S., Braley, T., Conway, J., Hughes, B., Katz, A., Rizvi, S., and Singer, R.

Published
2022
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5. Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis

Author

Daruwalla, C, Shaygannejad, V, Ozakbas, S, Havrdova, EK, Horakova, D, Alroughani, R, Boz, C, Patti, F, Onofrj, M, Lugaresi, A, Eichau, S, Girard, M, Prat, A, Duquette, P, Yamout, B, Khoury, SJ, Sajedi, SA, Turkoglu, R, Altintas, A, Skibina, O, Buzzard, K, Grammond, P, Karabudak, R, van der Walt, A, Butzkueven, H, Maimone, D, Lechner-Scott, J, Soysal, A, John, N, Prevost, J, Spitaleri, D, Ramo-Tello, C, Gerlach, O, Iuliano, G, Foschi, M, Ampapa, R, van Pesch, V, Barnett, M, Shalaby, N, D'hooghe, M, Kuhle, J, Sa, MJ, Fabis-Pedrini, M, Kermode, A, Mrabet, S, Gouider, R, Hodgkinson, S, Laureys, G, Van Hijfte, L, Macdonell, R, Oreja-Guevara, C, Cristiano, E, McCombe, P, Sanchez-Menoyo, JL, Singhal, B, Blanco, Y, Hughes, S, Garber, J, Solaro, C, McGuigan, C, Taylor, B, de Gans, K, Habek, M, Al-Asmi, A, Mihaela, S, Castillo Trivino, T, Al-Harbi, T, Rojas, JI, Gray, O, Khurana, D, Van Wijmeersch, B, Grigoriadis, N, Inshasi, J, Oh, J, Aguera-Morales, E, Fragoso, Y, Moore, F, Shaw, C, Baghbanian, SM, Shuey, N, Willekens, B, Hardy, TA, Decoo, D, Sempere, AP, Field, D, Wynford-Thomas, R, Cunniffe, NG, Roos, I, Malpas, CB, Coles, AJ, Kalincik, T, Brown, JWL, MSBase, SG, Daruwalla, C, Shaygannejad, V, Ozakbas, S, Havrdova, EK, Horakova, D, Alroughani, R, Boz, C, Patti, F, Onofrj, M, Lugaresi, A, Eichau, S, Girard, M, Prat, A, Duquette, P, Yamout, B, Khoury, SJ, Sajedi, SA, Turkoglu, R, Altintas, A, Skibina, O, Buzzard, K, Grammond, P, Karabudak, R, van der Walt, A, Butzkueven, H, Maimone, D, Lechner-Scott, J, Soysal, A, John, N, Prevost, J, Spitaleri, D, Ramo-Tello, C, Gerlach, O, Iuliano, G, Foschi, M, Ampapa, R, van Pesch, V, Barnett, M, Shalaby, N, D'hooghe, M, Kuhle, J, Sa, MJ, Fabis-Pedrini, M, Kermode, A, Mrabet, S, Gouider, R, Hodgkinson, S, Laureys, G, Van Hijfte, L, Macdonell, R, Oreja-Guevara, C, Cristiano, E, McCombe, P, Sanchez-Menoyo, JL, Singhal, B, Blanco, Y, Hughes, S, Garber, J, Solaro, C, McGuigan, C, Taylor, B, de Gans, K, Habek, M, Al-Asmi, A, Mihaela, S, Castillo Trivino, T, Al-Harbi, T, Rojas, JI, Gray, O, Khurana, D, Van Wijmeersch, B, Grigoriadis, N, Inshasi, J, Oh, J, Aguera-Morales, E, Fragoso, Y, Moore, F, Shaw, C, Baghbanian, SM, Shuey, N, Willekens, B, Hardy, TA, Decoo, D, Sempere, AP, Field, D, Wynford-Thomas, R, Cunniffe, NG, Roos, I, Malpas, CB, Coles, AJ, Kalincik, T, Brown, JWL, and MSBase, SG

Abstract

BACKGROUND: The prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear. OBJECTIVE: To determine whether early non-disabling relapses predict disability accumulation in RRMS. METHODS: We redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up. RESULTS: People who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated (n = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs (n = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs (n = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically. CONCLUSION: This study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions.

Published
2023

6. Ldlr-/-.Leiden mice develop neurodegeneration, age-dependent astrogliosis and obesity-induced changes in microglia immunophenotype which are partly reversed by complement component 5 neutralizing antibody.

Author

Seidel, F., Fluiter, K., Kleemann, R., Worms, N., Nieuwkoop, A. van, Caspers, M.P.M., Grigoriadis, N., Kiliaan, A.J., Baas, F., Michailidou, I., Morrison, M.C., Seidel, F., Fluiter, K., Kleemann, R., Worms, N., Nieuwkoop, A. van, Caspers, M.P.M., Grigoriadis, N., Kiliaan, A.J., Baas, F., Michailidou, I., and Morrison, M.C.

Abstract

Contains fulltext : 294954.pdf (Publisher’s version ) (Open Access), INTRODUCTION: Obesity has been linked to vascular dysfunction, cognitive impairment and neurodegenerative diseases. However, experimental models that recapitulate brain pathology in relation to obesity and vascular dysfunction are still lacking. METHODS: In this study we performed the histological and histochemical characterization of brains from Ldlr-/-.Leiden mice, an established model for obesity and associated vascular disease. First, HFD-fed 18 week-old and 50 week-old Ldlr-/-.Leiden male mice were compared with age-matched C57BL/6J mice. We then assessed the effect of high-fat diet (HFD)-induced obesity on brain pathology in Ldlr-/-.Leiden mice and tested whether a treatment with an anti-complement component 5 antibody, a terminal complement pathway inhibitor recently shown to reduce vascular disease, can attenuate neurodegeneration and neuroinflammation. Histological analyses were complemented with Next Generation Sequencing (NGS) analyses of the hippocampus to unravel molecular pathways underlying brain histopathology. RESULTS: We show that chow-fed Ldlr-/-.Leiden mice have more severe neurodegeneration and show an age-dependent astrogliosis that is not observed in age-matched C57BL/6J controls. This was substantiated by pathway enrichment analysis using the NGS data which showed that oxidative phosphorylation, EIF2 signaling and mitochondrial dysfunction pathways, all associated with neurodegeneration, were significantly altered in the hippocampus of Ldlr-/-.Leiden mice compared with C57BL/6J controls. Obesity-inducing HFD-feeding did not aggravate neurodegeneration and astrogliosis in Ldlr-/-.Leiden mice. However, brains from HFD-fed Ldlr-/-.Leiden mice showed reduced IBA-1 immunoreactivity and increased CD68 immunoreactivity compared with chow-fed Ldlr-/-.Leiden mice, indicating alteration of microglial immunophenotype by HFD feeding. The systemic administration of an anti-C5 treatment partially restored the HFD effect on microglial immunophenotype. In ad

Published
2023

7. Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis

Author

Altıntaş, Ayşe (ORCID 0000-0002-8524-5087 & YÖK ID 11611), Daruwalla, C.; Shaygannejad, V.; Ozakbas, S.; Havrdova, EK.; Horakova, D.; Alroughani, R.; Boz, C.; Patti, F.; Onofrj, M.; Lugaresi, A.; Eichau, S.; Girard, M.; Prat, A.; Duquette, P.; Yamout, B.; Khoury, S.J.; Sajedi, S.A.; Turkoglu, R.; Skibina, O.; Buzzard, K.; Grammond, P.; Karabudak, R.; van der Walt, A.; Butzkueven, H.; Maimone, D.; Lechner-Scott, J.; Soysal, A.; John, N.; Prevost, J.; Spitaleri, D.; Ramo-Tello, C.; Gerlach, O.; Iuliano, G.; Foschi, M.; Ampapa, R.; van Pesch, V.; Barnett, M.; Shalaby, N.; D'hooghe, M.; Kuhle, J.; Sa, M.J.; Fabis-Pedrini, M.; Kermode, A.; Mrabet, S.; Gouider, R.; Hodgkinson, S.; Laureys, G.; Van Hijfte, L.; Macdonell, R.; Oreja-Guevara, C.; Cristiano, E.; McCombe, P.; Sanchez-Menoyo, J.L.; Singhal, B.; Blanco, Y.; Hughes, S.; Garber, J.; Solaro, C.; McGuigan, C.; Taylor, B.; de Gans, K.; Habek, M.; Al-Asmi, A.; Mihaela, S.; Castillo Triviño, T.; Al-Harbi, T.; Rojas, J.I.; Gray, O.; Khuran,a D.; Van Wijmeersch, B.; Grigoriadis, N.; Inshasi, J.; Oh, J.; Aguera-Morales, E.; Fragoso, Y.; Moore, F.; Shaw, C.; Baghbanian, S.M.; Shuey, N.; Willekens, B.; Hardy, T.A.; Decoo, D.; Sempere, A.P.; Field, D.; Wynford-Thomas, R.; Cunniffe, NG.; Roos, I.; Malpas, C.B.; Coles, A.J.; Kalincik, T.; Brown, J.W.L., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Altıntaş, Ayşe (ORCID 0000-0002-8524-5087 & YÖK ID 11611), Daruwalla, C.; Shaygannejad, V.; Ozakbas, S.; Havrdova, EK.; Horakova, D.; Alroughani, R.; Boz, C.; Patti, F.; Onofrj, M.; Lugaresi, A.; Eichau, S.; Girard, M.; Prat, A.; Duquette, P.; Yamout, B.; Khoury, S.J.; Sajedi, S.A.; Turkoglu, R.; Skibina, O.; Buzzard, K.; Grammond, P.; Karabudak, R.; van der Walt, A.; Butzkueven, H.; Maimone, D.; Lechner-Scott, J.; Soysal, A.; John, N.; Prevost, J.; Spitaleri, D.; Ramo-Tello, C.; Gerlach, O.; Iuliano, G.; Foschi, M.; Ampapa, R.; van Pesch, V.; Barnett, M.; Shalaby, N.; D'hooghe, M.; Kuhle, J.; Sa, M.J.; Fabis-Pedrini, M.; Kermode, A.; Mrabet, S.; Gouider, R.; Hodgkinson, S.; Laureys, G.; Van Hijfte, L.; Macdonell, R.; Oreja-Guevara, C.; Cristiano, E.; McCombe, P.; Sanchez-Menoyo, J.L.; Singhal, B.; Blanco, Y.; Hughes, S.; Garber, J.; Solaro, C.; McGuigan, C.; Taylor, B.; de Gans, K.; Habek, M.; Al-Asmi, A.; Mihaela, S.; Castillo Triviño, T.; Al-Harbi, T.; Rojas, J.I.; Gray, O.; Khuran,a D.; Van Wijmeersch, B.; Grigoriadis, N.; Inshasi, J.; Oh, J.; Aguera-Morales, E.; Fragoso, Y.; Moore, F.; Shaw, C.; Baghbanian, S.M.; Shuey, N.; Willekens, B.; Hardy, T.A.; Decoo, D.; Sempere, A.P.; Field, D.; Wynford-Thomas, R.; Cunniffe, NG.; Roos, I.; Malpas, C.B.; Coles, A.J.; Kalincik, T.; Brown, J.W.L., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine

Abstract

Background: the prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear. Objective: to determine whether early non-disabling relapses predict disability accumulation in RRMS. Methods: we redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up. Results: people who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated (n = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs (n = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs (n = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically. Conclusion: this study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions., The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financially supported by National Health and Medical Research Council of Australia (fellowship nos.1140766 and 1080518, project grant nos. 1129189 and 1083539), the University of Melbourne (Faculty of Medicine, Dentistry and Health Sciences research fellowship), National Institute for Health and Care Research (UK) Advanced Fellowship (grant no. 301728; recipient JWLB) and Academic Clinical Fellowship (grant no. EAN/ACA-006/7488627/C; recipient CD). The MSBase Foundation is a not-for-profit organization that receives support from Roche, Merck, Biogen, Novartis, Bayer Schering, Sanofi Genzyme, and Teva. Role of the Funder/Sponsor: The National Health and Medical Research Council of Australia, the University of Melbourne and the National Institute for Health and Care Research (UK) had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Published
2023

9. Real-world experience with ocrelizumab in primary Progressive multiple sclerosis: Insights from the MSOCR-P cohort, a MSBase Registry sub-study

Author

Terzi, M., Rojas, J. I., Barnett, M., Fragoso, Y., Cartechini, E., Pucci, E., Willekens, B., Butler, E., Blanco, Y., Grigoriadis, N., Van Hijfte, L., Dirks, P., Liu, C., Rouzic, E. Muros-Le, Butzkueven, H., Al-Harbi, T., Laureys, G., Ozakbas, S., Spelman, T., Alroughani, R., Menoyo, J. L. Sanchez, Van Pesch, V., Kalincik, T., Lechner-Scott, J., Van der Walt, A., Grand'Maison, F., Boz, C., Buzzard, K., and Skibina, O.

Published
2022

10. Anti-SARS-CoV-2 vaccination in people with multiple sclerosis: Lessons learnt a year in

Author

Pugliatti, M, Hartung, HP, Oreja-Guevara, C, Pozzilli, C, Airas, L, Alkhawajah, M, Grigoriadis, N, Magyari, M, VAN WIJMEERSCH, Bart, Zakaria, M, Linker, R, Chan, A, Vermersch, P, Berger, T, Pugliatti, M, Hartung, HP, Oreja-Guevara, C, Pozzilli, C, Airas, L, Alkhawajah, M, Grigoriadis, N, Magyari, M, VAN WIJMEERSCH, Bart, Zakaria, M, Linker, R, Chan, A, Vermersch, P, and Berger, T

Subjects
SARS-CoV-2, disease modifying therapies, COVID-19, vaccines, multiple sclerosis, immune response, adverse events
Abstract

It has been over a year since people with multiple sclerosis (pwMS) have been receiving vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). With a negligible number of cases in which vaccination led to a relapse or new onset MS, experts around the world agree that the potential consequences of COVID-19 in pwMS by far outweigh the risks of vaccination. This article reviews the currently available types of anti-SARS-CoV-2 vaccines and the immune responses they elicit in pwMS treated with different DMTs. Findings to date highlight the importance of vaccine timing in relation to DMT dosing to maximize protection, and of encouraging pwMS to get booster doses when offered.

Published
2022

12. Modulation of the Microglial Nogo-A/NgR Signaling Pathway as a Therapeutic Target for Multiple Sclerosis

Author

Nheu, D, Ellen, O, Ye, S, Ozturk, E, Pagnin, M, Kertadjaja, S, Theotokis, P, Grigoriadis, N, McLean, C, Petratos, S, Nheu, D, Ellen, O, Ye, S, Ozturk, E, Pagnin, M, Kertadjaja, S, Theotokis, P, Grigoriadis, N, McLean, C, and Petratos, S

Abstract

Current therapeutics targeting chronic phases of multiple sclerosis (MS) are considerably limited in reversing the neural damage resulting from repeated inflammation and demyelination insults in the multi-focal lesions. This inflammation is propagated by the activation of microglia, the endogenous immune cell aiding in the central nervous system homeostasis. Activated microglia may transition into polarized phenotypes; namely, the classically activated proinflammatory phenotype (previously categorized as M1) and the alternatively activated anti-inflammatory phenotype (previously, M2). These transitional microglial phenotypes are dynamic states, existing as a continuum. Shifting microglial polarization to an anti-inflammatory status may be a potential therapeutic strategy that can be harnessed to limit neuroinflammation and further neurodegeneration in MS. Our research has observed that the obstruction of signaling by inhibitory myelin proteins such as myelin-associated inhibitory factor, Nogo-A, with its receptor (NgR), can regulate microglial cell function and activity in pre-clinical animal studies. Our review explores the microglial role and polarization in MS pathology. Additionally, the potential therapeutics of targeting Nogo-A/NgR cellular mechanisms on microglia migration, polarization and phagocytosis for neurorepair in MS and other demyelination diseases will be discussed.

Published
2022

14. Neurological manifestations of long-COVID syndrome: a narrative review

Author

Stefanou, M.-I. Palaiodimou, L. Bakola, E. Smyrnis, N. Papadopoulou, M. Paraskevas, G.P. Rizos, E. Boutati, E. Grigoriadis, N. Krogias, C. Giannopoulos, S. Tsiodras, S. Gaga, M. Tsivgoulis, G.

Abstract

Accumulating evidence points toward a very high prevalence of prolonged neurological symptoms among coronavirus disease 2019 (COVID-19) survivors. To date, there are no solidified criteria for ‘long-COVID’ diagnosis. Nevertheless, ‘long-COVID’ is conceptualized as a multi-organ disorder with a wide spectrum of clinical manifestations that may be indicative of underlying pulmonary, cardiovascular, endocrine, hematologic, renal, gastrointestinal, dermatologic, immunological, psychiatric, or neurological disease. Involvement of the central or peripheral nervous system is noted in more than one-third of patients with antecedent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, while an approximately threefold higher incidence of neurological symptoms is recorded in observational studies including patient-reported data. The most frequent neurological manifestations of ‘long-COVID’ encompass fatigue; ‘brain fog’; headache; cognitive impairment; sleep, mood, smell, or taste disorders; myalgias; sensorimotor deficits; and dysautonomia. Although very limited evidence exists to date on the pathophysiological mechanisms implicated in the manifestation of ‘long-COVID’, neuroinflammatory and oxidative stress processes are thought to prevail in propagating neurological ‘long-COVID’ sequelae. In this narrative review, we sought to present a comprehensive overview of our current understanding of clinical features, risk factors, and pathophysiological processes of neurological ‘long-COVID’ sequelae. Moreover, we propose diagnostic and therapeutic algorithms that may aid in the prompt recognition and management of underlying causes of neurological symptoms that persist beyond the resolution of acute COVID-19. Furthermore, as causal treatments for ‘long-COVID’ are currently unavailable, we propose therapeutic approaches for symptom-oriented management of neurological ‘long-COVID’ symptoms. In addition, we emphasize that collaborative research initiatives are urgently needed to expedite the development of preventive and therapeutic strategies for neurological ‘long-COVID’ sequelae. © The Author(s), 2022.

Published
2022

15. Author Correction: European primary forest database v2.0 (Scientific Data, (2021), 8, 1, (220), 10.1038/s41597-021-00988-7)

Author

Sabatini F. M., Bluhm H., Kun Z., Aksenov D., Atauri J. A., Buchwald E., Burrascano S., Cateau E., Diku A., Duarte I. M., Fernandez Lopez A. B., Garbarino M., Grigoriadis N., Horvath F., Keren S., Kitenberga M., Kis A., Kraut A., Ibisch P. L., Larrieu L., Lombardi F., Matovic B., Melu R. N., Meyer P., Midteng R., Mikac S., Mikolas M., Mozgeris G., Panayotov M., Pisek R., Nunes L., Ruete A., Schickhofer M., Simovski B., Stillhard J., Stojanovic D., Szwagrzyk J., Tikkanen O. -P., Toromani E., Volosyanchuk R., Vrska T., Waldherr M., Yermokhin M., Zlatanov T., Zagidullina A., Kuemmerle T., Sabatini F.M., Bluhm H., Kun Z., Aksenov D., Atauri J.A., Buchwald E., Burrascano S., Cateau E., Diku A., Duarte I.M., Fernandez Lopez A.B., Garbarino M., Grigoriadis N., Horvath F., Keren S., Kitenberga M., Kis A., Kraut A., Ibisch P.L., Larrieu L., Lombardi F., Matovic B., Melu R.N., Meyer P., Midteng R., Mikac S., Mikolas M., Mozgeris G., Panayotov M., Pisek R., Nunes L., Ruete A., Schickhofer M., Simovski B., Stillhard J., Stojanovic D., Szwagrzyk J., Tikkanen O.-P., Toromani E., Volosyanchuk R., Vrska T., Waldherr M., Yermokhin M., Zlatanov T., Zagidullina A., and Kuemmerle T.

Subjects
ComputingMethodologies_PATTERNRECOGNITION, n.a, ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries)
Abstract

The original version of this Data Descriptor omitted the following information from the Acknowledgements.

Published
2021

18. Persistent decline of hospitalizations for acute stroke and acute coronary syndrome during the second wave of the COVID-19 pandemic in Greece: collateral damage unaffected

Author

Katsouras, C. Tsivgoulis, G. Papafaklis, M. Karapanayiotides, T. Alexopoulos, D. Ntais, E. Papagiannopoulou, G. Koutroulou, I. Ziakas, A. Sianos, G. Kouparanis, A. Trivilou, P. Ballas, C. Samara, I. Kosmidou, M. Palaiodimou, L. Grigoriadis, N. Michalis, L.K. Giannopoulos, S.

Abstract

Background: An alarming cerebro/cardiovascular collateral damage, reflected by a decline in admissions for acute stroke (AS) and acute coronary syndrome (ACS), was observed during the initial phase of the COVID-19 pandemic, thereby leading to a re-design of public campaigns. However, there are limited data regarding the AS and ACS hospitalization rates during the second wave of the pandemic, which was followed by re-imposition of lockdowns. Methods: We calculated the rate of AS and ACS hospitalizations from three representative tertiary care hospitals in Greece during a 2-month period (November–December 2020) of the second wave of the COVID-19 pandemic compared with the corresponding control period in 2019 from three representative tertiary care hospitals in Greece. This was a follow-up study with identical design to our previous report evaluating AS and ACS hospitalizations during the first wave of the pandemic (March–April 2020). Results: Compared with 2019, there was a 34% relative reduction of AS hospitalizations [incidence rate ratio (IRR): 0.66, 95% confidence interval (CI): 0.48–0.92, p = 0.013] and 33% relative reduction of ACS hospitalizations (IRR: 0.67, 95% CI: 0.54–0.83, p < 0.001) during the second wave of the COVID-19 pandemic. The relative reduction was smaller and did not reach the level of statistical significance for the respective syndromes (haemorrhagic stroke: IRR 0.87, 95% CI: 0.41–1.82, p = 0.71; ST-elevation myocardial infarction: IRR 0.81, 95% CI: 0.57–1.14, p = 0.22). Conclusion: AS and ACS hospitalizations were persistently reduced during the second wave of the COVID-19 pandemic compared with 2019 in Greece. This decline was similar to the observations during the first wave despite the large differences in the epidemiological COVID-19 burden. Lockdowns, a common characteristic in both waves, appear to have a detrimental indirect impact on cerebro/cardiovascular diseases in the general population. © The Author(s), 2021.

Published
2021

19. Symbol digit modalities test: Greek normative data for the oral and written version and discriminative validity in patients with multiple sclerosis

Author

Messinis, L. Bakirtzis, C. Kosmidis, M.H. Economou, A. Nasios, G. Anyfantis, E. Konitsiotis, S. Ntoskou, A. Peristeri, E. Dardiotis, E. Grigoriadis, N. Gourzis, P. Papathanasopoulos, P.

Abstract

Objectives: The purpose of this study was to generate normative data on the Symbol Digits Modalities Test (SDMT) for the written and oral versions in the Greek adult population. We also investigated the test's validity in discriminating the performance of healthy adults from two groups of adults diagnosed with relapsing remitting (RRMS) and secondary progressive (SPMS) multiple sclerosis. Method: The sample consisted of 609 healthy men and women between the ages of 18 and 65. All participants were monolingual native Greek adult speakers. Each healthy participant was administered either the written (n = 460) or oral (n = 149) versions of the SDMT. Discriminant validity was examined by comparing 35 healthy participants who had completed the oral version of the SDMT to 35 age - and education-matched RRMS and SPMS patients. Results: Linear regression models explained between 36% and 55% of the variance in the SDMT oral and written version scores. Age was the strongest predictor of difference in SDMT written and oral version performance, followed by education that also accounted for a further proportion of the SDMT variance. On the contrary, gender was found not to contribute significantly to the variance in the SDMT for either the written or the oral versions. As a result, age- and education-adjusted norms were generated. Regarding the tests discriminative validity, we found that both MS patient groups scored significantly lower than the healthy group. Conclusions: This is the first study to provide comprehensive normative data for the SDMT in the adult population in Greece, impacting the future practice of neuropsychological assessment in this country. © 2020 The Author(s) 2020.

Published
2021

21. The Multiple Sclerosis Data Alliance Catalogue: Enabling Web-Based Discovery of Metadata from Real-World Multiple Sclerosis Data Sources.

Author

Geys, L, Parciak, T, Pirmani, A, McBurney, R, Schmidt, H, Malbaša, T, Ziemssen, T, Bergmann, A, Rojas, JI, Cristiano, E, García-Merino, JA, Fernández, Ó, Kuhle, J, Gobbi, C, Delmas, A, Simpson-Yap, S, Nag, N, Yamout, B, Steinemann, N, Seeldrayers, P, Dubois, B, van der Mei, I, Stahmann, A, Drulovic, J, Pekmezovic, T, Brola, W, Tintore, M, Kalkers, N, Ivanov, R, Zakaria, M, Naseer, MA, Van Hecke, W, Grigoriadis, N, Boziki, M, Carra, A, Pawlak, MA, Dobson, R, Hellwig, K, Gallagher, A, Leocani, L, Dalla Costa, G, de Carvalho Sousa, NA, Van Wijmeersch, B, Peeters, LM, Geys, L, Parciak, T, Pirmani, A, McBurney, R, Schmidt, H, Malbaša, T, Ziemssen, T, Bergmann, A, Rojas, JI, Cristiano, E, García-Merino, JA, Fernández, Ó, Kuhle, J, Gobbi, C, Delmas, A, Simpson-Yap, S, Nag, N, Yamout, B, Steinemann, N, Seeldrayers, P, Dubois, B, van der Mei, I, Stahmann, A, Drulovic, J, Pekmezovic, T, Brola, W, Tintore, M, Kalkers, N, Ivanov, R, Zakaria, M, Naseer, MA, Van Hecke, W, Grigoriadis, N, Boziki, M, Carra, A, Pawlak, MA, Dobson, R, Hellwig, K, Gallagher, A, Leocani, L, Dalla Costa, G, de Carvalho Sousa, NA, Van Wijmeersch, B, and Peeters, LM

Abstract

BACKGROUND: One of the major objectives of the Multiple Sclerosis Data Alliance (MSDA) is to enable better discovery of multiple sclerosis (MS) real-world data (RWD). METHODS: We implemented the MSDA Catalogue, which is available worldwide. The current version of the MSDA Catalogue collects descriptive information on governance, purpose, inclusion criteria, procedures for data quality control, and how and which data are collected, including the use of e-health technologies and data on collection of COVID-19 variables. The current cataloguing procedure is performed in several manual steps, securing an effective catalogue. RESULTS: Herein we summarize the status of the MSDA Catalogue as of January 6, 2021. To date, 38 data sources across five continents are included in the MSDA Catalogue. These data sources differ in purpose, maturity, and variables collected, but this landscaping effort shows that there is substantial alignment on some domains. The MSDA Catalogue shows that personal data and basic disease data are the most collected categories of variables, whereas data on fatigue measurements and cognition scales are the least collected in MS registries/cohorts. CONCLUSIONS: The Web-based MSDA Catalogue provides strategic overview and allows authorized end users to browse metadata profiles of data cohorts and data sources. There are many existing and arising RWD sources in MS. Detailed cataloguing of MS RWD is a first and useful step toward reducing the time needed to discover MS RWD sets and promoting collaboration.

Published
2021

22. B-cells expressing NgR1 and NgR3 are localized to EAE-induced inflammatory infiltrates and are stimulated by BAFF

Author

Bakhuraysah, MM, Theotokis, P, Lee, JY, Alrehaili, AA, Aui, P-M, Figgett, WA, Azari, MF, Abou-Afech, J-P, Mackay, F, Siatskas, C, Alderuccio, F, Strittmatter, SM, Grigoriadis, N, Petratos, S, Bakhuraysah, MM, Theotokis, P, Lee, JY, Alrehaili, AA, Aui, P-M, Figgett, WA, Azari, MF, Abou-Afech, J-P, Mackay, F, Siatskas, C, Alderuccio, F, Strittmatter, SM, Grigoriadis, N, and Petratos, S

Abstract

We have previously reported evidence that Nogo-A activation of Nogo-receptor 1 (NgR1) can drive axonal dystrophy during the neurological progression of experimental autoimmune encephalomyelitis (EAE). However, the B-cell activating factor (BAFF/BlyS) may also be an important ligand of NgR during neuroinflammation. In the current study we define that NgR1 and its homologs may contribute to immune cell signaling during EAE. Meningeal B-cells expressing NgR1 and NgR3 were identified within the lumbosacral spinal cords of ngr1+/+ EAE-induced mice at clinical score 1. Furthermore, increased secretion of immunoglobulins that bound to central nervous system myelin were shown to be generated from isolated NgR1- and NgR3-expressing B-cells of ngr1+/+ EAE-induced mice. In vitro BAFF stimulation of NgR1- and NgR3-expressing B cells, directed them into the cell cycle DNA synthesis phase. However, when we antagonized BAFF signaling by co-incubation with recombinant BAFF-R, NgR1-Fc, or NgR3 peptides, the B cells remained in the G0/G1 phase. The data suggest that B cells express NgR1 and NgR3 during EAE, being localized to infiltrates of the meninges and that their regulation is governed by BAFF signaling.

Published
2021

27. Epidemiology of Patent Foramen Ovale in General Population and in Stroke Patients: A Narrative Review

Author

Koutroulou, I. Tsivgoulis, G. Tsalikakis, D. Karacostas, D. Grigoriadis, N. Karapanayiotides, T.

Abstract

Introduction: Percutaneous closure of patent foramen ovale (PFO) in selected patients with cryptogenic cerebrovascular ischemic events (CEs) decreases the risk of recurrent stroke; however, optimal patient selection criteria are still under investigation. Candidates for PFO closure are usually selected from the pool of CE patients with a high risk of Paradoxical Embolism (RoPE) score. The RoPE score calculates the probability that PFO is causally related to stroke, based on PFO prevalence in patients with CE compared with that in healthy subjects. The latter has been set at 25% based on the average of autopsy and transesophageal echocardiography (TEE) studies. Methods: We conducted a comprehensive review of studies investigating PFO prevalence in general population and in patients with CE and non-CE using autopsy, TEE, transcranial Doppler (TCD) or transthoracic echocardiography (TTE). Studies were excluded if they (1) reported data from referred subjects with underlying cerebrovascular disease or (2) did not specify etiologically the events. Results: In healthy/control subjects, PFO prevalence was 24.2% (1,872/7,747) in autopsy studies, 23.7% (325/1,369) in TEE, 31.3% (111/355) in TCD, and 14.7% (186/1,267) in TTE studies. All diagnostic modalities included PFO prevalence was higher in CE compared with healthy/control population [odds ratio (OR) = 3.1, 95% confidence interval (CI) = 2.5–3.8] and compared with non-CE (OR = 2.3, 95% CI = 2.0–2.6). In patients with CE, PFO prevalence in the young compared to the old was higher when the diagnostic modality was TEE (48.9 vs. 27.3%, p < 0.0001, OR = 2.6 with 95% CI = 2.0–3.3) or TCD (58.1 vs. 41%, OR = 1.9, 95% CI = 1.6–2.5), but not TTE (53.3 vs. 37.5%, p = 0.16). Regarding non-CE, PFO prevalence in the young compared to the old was higher when the diagnostic modality was TEE (20 vs. 12.9%, OR = 1.7, 95% CI = 1.0–2.8) but not TTE (10.4 vs. 7.8%, p = 0.75) or TCD (22.8 vs. 20.1%, p = 0.56). Conclusions: Given the limitations of autopsy and TEE studies, there is good reason not to take a fixed 25% PFO prevalence for granted. The estimation of degree of causality may be underestimated or overestimated in populations with PFO prevalence significantly lower or higher than the established. Given the high sensitivity, non-invasive nature, low cost, and repeatability of TCD, future large-scale TCD-based studies should investigate potential heterogeneity in PFO prevalence in different healthy racial/ethnic populations. © Copyright © 2020 Koutroulou, Tsivgoulis, Tsalikakis, Karacostas, Grigoriadis and Karapanayiotides.

Published
2020

28. Prevalence of patent foramen ovale in the Greek population is high and impacts on the interpretation of the risk of paradoxical embolism (RoPE) score

Author

Koutroulou, I. Tsivgoulis, G. Karacostas, D. Ikonomidis, I. Grigoriadis, N. Karapanayiotides, T.

Abstract

Background: The risk of paradoxical embolism (RoPE) score calculates the probability that patent foramen ovale (PFO) is causally related to stroke (PFO attributable fraction, PFOAF), based on PFO prevalence in patients with cryptogenic stroke (CS) compared with that in the general population. The latter has been estimated at 25%; however, PFO prevalence in nonselected populations varies widely. Methods: Since PFO prevalence in Greece remains unknown, we evaluated it and we calculated PFOAF stratified by RoPE score in a cohort of patients with CS ⩽55 years old. PFO was detected according to the international consensus transcranial Doppler (TCD) criteria in 124 healthy subjects (H), in 102 patients with CS, and in 56 patients with stroke of known cause (nonCS). Each subject underwent unilateral middle cerebral artery recording after infusion of agitated saline, at rest, and after a controlled Valsalva maneuver. We characterized PFO as large (>20 microbubbles or curtain), moderate (11–20), and small (⩽10). Results: PFO was detected in 42.7% of H, 49% of CS, and 25% of nonCS (p = 0.013). Large PFOs were numerically higher in CS [28.4% (29/102)] compared with H [19.3% (24/124); p = 0.1] and to nonCS [7.1% (4/56), p = 0.04]. The median RoPE score in patients with CS and PFO was seven. Even patients with very high RoPE score (9–10) had moderate PFOAF (57%). For any individual stratum up to RopE score 8, PFOAF was

Published
2020

29. Multiple sclerosis: Shall we target cd33?

Author

Siokas, V. Tsouris, Z. Aloizou, A.-M. Bakirtzis, C. Liampas, I. Koutsis, G. Anagnostouli, M. Bogdanos, D.P. Grigoriadis, N. Hadjigeorgiou, G.M. Dardiotis, E.

Abstract

Background: Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS). Myeloid lineage cells (microglia and macrophages) may participate in the pathogenic mechanisms leading to MS. CD33 is a transmembrane receptor, mainly expressed by myeloid lineage cells. CD33 rs3865444 is a promoter variant previously associated with Alzheimer’s disease, whose role in MS remains obscure. Objective: To assess the role of CD33 rs3865444 in MS risk. Methods: We genotyped 1396 patients with MS and 400 healthy controls for the presence of the CD33 rs3865444 variant. Odds ratios (ORs) with the respective 95% confidence intervals (CIs), were calculated with the SNPStats software, assuming five genetic models (co-dominant, dominant, recessive, over-dominant, and log-additive), with the G allele as the reference allele. The value of 0.05 was set as the threshold for statistical significance. Results: CD33 rs3865444 was associated with MS risk in the dominant (GG vs. GT + TT; OR (95% C.I.) = 0.79 (0.63–0.99), p = 0.041) and the over-dominant (GG + TT vs. GT; OR (95% C.I.) = 0.77 (0.61–0.97), p = 0.03) modes of inheritance. Given that the GG genotype was more frequent and the GT genotype was less frequent in MS patients compared to controls—while the observed frequency of the TT genotype did not differ between the two groups—the observed difference in MS risk may be stemming from either the GG (as a risk factor) or the GT (as a protective factor) genotype of CD33 rs3865444. Conclusions: Our preliminary results suggest a possible contribution of CD33 rs3865444 to MS. Therefore, larger multiethnic studies should be conducted, investigating the role of CD33 rs3865444 in MS. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Published
2020

30. Do Secondary Progressive Multiple Sclerosis patients benefit from Computer- based cognitive neurorehabilitation? A randomized sham controlled trial

Author

Messinis, L. Kosmidis, M.H. Nasios, G. Konitsiotis, S. Ntoskou, A. Bakirtzis, C. Grigoriadis, N. Patrikelis, P. Panagiotopoulos, E. Gourzis, P. Malefaki, S. Papathanasopoulos, P.

Abstract

Background: Cognitive impairment is common in multiple sclerosis (MS), but deficits tend to be more pronounced in progressive MS, negatively impacting daily functional capacity. Despite this, most cognitive rehabilitation (CR) interventions to date have focused on relapsing-remitting MS (RRMS). Moreover, information on the efficacy of CR in progressive MS is limited and controversial. The present study investigated the efficacy of a home based, computer assisted cognitive rehabilitation (HBCACR) intervention (RehaComTM software) exclusively in a Secondary Progressive Multiple Sclerosis (SPMS) sample. Methods: This was a randomized, multi site, sham controlled trial. Thirty six (36) individuals with SPMS, naïve to the RehaCom software, with cognitive deficits were randomized to the treatment (IG; n= 19) or control group condition (CG; n=17). Treatment with the RehaCom modules consisted of 24 domain and task specific, 45 minute session's over an 8-week period, three sessions per week, applied by each patient at home. The CG completed non specific computer based activities at home with the same frequency and duration. Primary cognitive outcome measures included the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery, and secondary outcome measures for depression (BDI-FS), fatigue (MFIS), and quality of life (EuroQol EQ-5D) visual analogue scale (VAS). Results: The two groups were well matched on demographic and clinical characteristics, cognitive reserve and severity of cognitive deficits at baseline assessment. At post treatment assessment the IG group showed significant improvements with large effect sizes; in verbal learning [z = -4.759, p

Published
2020

40. Helicobacter pylori infection and gastric cancer biology: tempering a double-edged sword

Author

Mentis, A.-F.A. Boziki, M. Grigoriadis, N. Papavassiliou, A.G.

Abstract

Helicobacter pylori (H. pylori) infection affects an estimated 4.4 billion people globally. Moreover, H. pylori presents the most significant risk factor for gastric cancer and low-grade mucosa-associated lymphoid tissue (MALT) lymphoma, and it is the first example of bacterial infection linked to carcinogenesis. Here, we contend that H. pylori research, which focuses on a cancer-causing pathogen resident in a relatively accessible organ, the stomach, could constitute an exemplar for microbial-related carcinogenesis in less tractable organs, such as the pancreas and lung. In this context, molecular biological approaches that could reap rewards are reviewed, including: (1) gastric cancer dynamics, particularly the role of stem cells and the heterogeneity of neoplastic cells, which are currently being investigated at the single-cell sequencing level; (2) mechanobiology, and the role of three-dimensional organoids and matrix metalloproteases; and (3) the connection between H. pylori and host pathophysiology and the gut microbiome. In the context of H. pylori’s contribution to gastric cancer, several important conundrums remain to be fully elucidated. From among them, this article discusses (1) why H. pylori infection, which causes both gastric and duodenal inflammation, is only linked to gastric cancer; (2) whether a “precision oncomicrobiology” approach could enable a fine-tuning of the expression of only cancer-implicated H. pylori genes while maintaining beneficial H. pylori-mediated factors in extra-gastric tissues; and (3) the feasibility of using antibiotics targeting the microbial DNA damage system, which shares commonalities with mechanisms for human cell replication, as chemopreventives. Additional therapeutic perspectives are also discussed. © 2019, Springer Nature Switzerland AG.

Published
2019

42. Replication study of GWAS risk loci in Greek multiple sclerosis patients

Author

Hadjigeorgiou, G.M. Kountra, P.-M. Koutsis, G. Tsimourtou, V. Siokas, V. Dardioti, M. Rikos, D. Marogianni, C. Aloizou, A.-M. Karadima, G. Ralli, S. Grigoriadis, N. Bogdanos, D. Panas, M. Dardiotis, E.

Abstract

Objectives: To validate in an ethnically homogeneous Greek multiple sclerosis (MS) cohort, genetic risk factors for the disease, identified through a number of previous multi-ethnic genome-wide association studies (GWAS). Methods: A total of 1228 MS cases and 1014 controls were recruited in the study, from 3 MS centers in Greece. We genotyped 35 susceptibility SNPs that emerged from previous GWAS or meta-analyses of GWAS. Allele and genotype single locus regression analysis, adjusted for gender and site, was performed. Permutation testing was applied to all analyses. Results: Six polymorphisms reached statistical significance (permutation p value < 0.05). In particular, rs2760524 of LOC105371664, near RGS1 (permutation p value 0.001), rs3129889 of HLA-DRA, near HLA-DRB1 (permutation p value < 1.00e-04), rs1738074 of TAGAP (permutation p value 0.007), rs703842 of METTL1/CYP27B1 (permutation p value 0.008), rs9596270 of DLEU1 (permutation p value < 1.00e-04), and rs17445836 of LincRNA, near IRF8 (permutation p value 0.001) were identified as susceptibility risk factors in our group. Conclusion: The current study replicated a number of GWAS susceptibility SNPs, which implies that some similarities between the examined Greek population and the MS genetic architecture of the GWAS populations do exist. © 2018, Springer-Verlag Italia S.r.l., part of Springer Nature.

Published
2019

43. TREM2 R47H (rs75932628) variant is unlikely to contribute to Multiple Sclerosis susceptibility and severity in a large Greek MS cohort

Author

Rikos, D. Siokas, V. Aloizou, A.-M. Tsouris, Z. Aslanidou, P. Koutsis, G. Anagnostouli, M. Bogdanos, D.P. Grigoriadis, N. Hadjigeorgiou, G.M. Dardiotis, E.

Abstract

Background: Multiple Sclerosis is a multifactorial autoimmune disease of the central nervous system, characterized by focal inflammation, demyelination and secondary axonal injury. TREM2 is a signaling protein which participates in the innate immune system by implication to inflammation, proliferation and phagocytosis. The R47H (rs75392628) rare variant of the TREM2 gene has been related to various neurological diseases and leads to impaired signaling, lipoprotein binding, lipoprotein uptake and surface uptake. Aim: To assess the role of TREM2 rs75932628 on MS risk through a genetic candidate gene association case-control study in a Greek population. Methods: 1246 MS cases and 398 controls were genotyped for this variant. Results: No MS or healthy subjects carried the variant. Conclusion: This variant does not seem to play a determining role in the pathogenesis of MS, although further studies examining the presence of TREM2 mutations in other, phylogenetically different populations and the epigenetic regulation of this gene are needed in order to thoroughly investigate its role in MS. © 2019

Published
2019

47. ‘Hidden’ factors influencing quality of life in patients with multiple sclerosis

Author

Lysandropoulos, Ap, Havrdova, E, Kieseier, Bc, Gallo, Paolo, Grigoriadis, N, Guevara, Co, Pozzilli, C, Pugliatti, M, Schippling, S, van Pesch, V, Van Wijmeersch, B, Akhawajah, M, Boyko, A, Chan, A, Hupperts, R, Linker, R, Sormani, M. p., University of Zurich, and Lysandropoulos, A P

Subjects
Coping (psychology), medicine.medical_specialty, Multiple Sclerosis, Physical disability, Cognitive function, Multiple sclerosis, Patient-centred outcomes, Psychological therapies, Quality of life, Sexual function, Neurology (clinical), Neurology, Psychological intervention, 610 Medicine & health, Disease, Outcome Assessment (Health Care), Outcome Assessment, Health Care, medicine, Humans, Social isolation, Intensive care medicine, Psychiatry, business.industry, Quality of Life, Cognition, 10040 Clinic for Neurology, Clinical trial, 2728 Neurology (clinical), 2808 Neurology, medicine.symptom, business
Abstract

Traditional outcome measures for patients with multiple sclerosis (MS), whether in clinical trials or clinical practice, are currently in question. The combination of relapses, physical disability progression and magnetic resonance imaging (MRI) disease activity reflect only part of the impact that MS has on a patient's daily life. Quality of life (QoL) is considered by many to be the ideal outcome measure. Since it captures the patient's own perspective of well-being, QoL should be the primary focus when evaluating a patient and the main objective of MS management. Nevertheless, whilst numerous instruments to measure QoL in MS patients are available or proposed, there is no current consensus regarding which is the best tool to use and under what circumstances. QoL in patients with MS is determined by several factors beyond the more obvious; these include coping with the MS diagnosis, understanding the disease and the disease process, dealing with so-called 'hidden' symptoms such as fatigue, cognitive impairment and sexual disturbances, and managing the many associated personal challenges such as social isolation, family issues and working difficulties. Evidence is emerging that psychological interventions may be beneficial in MS patients although more research is required to confirm their utility. This article examines some factors that influence QoL in MS patients which may be overlooked in the general busyness of routine clinical practice.

Published
2015
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48. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study

Author

Kappos, L., Bar-Or, A., Cree, B. A. C., Fox, R. J., Giovannoni, G., Gold, R., Vermersch, P., Arnold, D. L., Arnould, S., Scherz, T., Wolf, C., Wallstrom, E., Dahlke, F., Achiron, A., Achtnichts, L., Agan, K., Akman-Demir, G., Allen, A. B., Antel, J. P., Antiguedad, A. R., Apperson, M., Applebee, A. M., Ayuso, G. I., Baba, M., Bajenaru, O., Balasa, R., Balci, B. P., Barnett, M., Bass, A., Becker, V. U., Bejinariu, M., Bergh, F. T., Bergmann, A., Bernitsas, E., Berthele, A., Bhan, V., Bischof, F., Bjork, R. J., Blevins, G., Boehringer, M., Boerner, T., Bonek, R., Bowen, J. D., Bowling, A., Boyko, A. N., Boz, C., Bracknies, V., Braune, S., Brescia Morra, V., Brochet, B., Brola, W., Brownstone, P. K., Brozman, M., Brunet, D., Buraga, I., Burnett, M., Buttmann, M., Butzkueven, H., Cahill, J., Calkwood, J. C., Camu, W., Cascione, M., Castelnovo, G., Centonze, D., Cerqueira, J., Chan, A., Cimprichova, A., Cohan, S., Comi, G., Conway, J., Cooper, J. A., Corboy, J., Correale, J., Costell, B., Cottrell, D. A., Coyle, P. K., Craner, M., Cui, L., Cunha, L., Czlonkowska, A., da Silva, A. M., de Sa, J., de Seze, J., Debouverie, M., Debruyne, J., Decoo, D., Defer, G., Derfuss, T., Deri, N. H., Dihenia, B., Dioszeghy, P., Donath, V., Dubois, B., Duddy, M., Duquette, P., Edan, G., Efendi, H., Elias, S., Emrich, P. J., Estruch, B. C., Evdoshenko, E. P., Faiss, J., Fedyanin, A. S., Feneberg, W., Fermont, J., Fernandez, O. F., Ferrer, F. C., Fink, K., Ford, H., Ford, C., Francia, A., Freedman, M., Frishberg, B., Galgani, S., Garmany, G. P., Gehring, K., Gitt, J., Gobbi, C., Goldstick, L. P., Gonzalez, R. A., Grandmaison, F., Grigoriadis, N., Grigorova, O., Grimaldi, L. M. E., Gross, J., Gross-Paju, K., Gudesblatt, M., Guillaume, D., Haas, J., Hancinova, V., Hancu, A., Hardiman, O., Harmjanz, A., Heidenreich, F. R., Hengstman, G. J. D., Herbert, J., Herring, M., Hodgkinson, S., Hoffmann, O. M., Hofmann, W. E., Honeycutt, W. D., Hua, L. H., Huang, D., Huang, Y., Hupperts, R., Imre, P., Jacobs, A. K., Jakab, G., Jasinska, E., Kaida, K., Kalnina, J., Kaprelyan, A., Karelis, G., Karussis, D., Katz, A., Khabirov, F. A., Khatri, B., Kimura, T., Kister, I., Kizlaitiene, R., Klimova, E., Koehler, J., Komatineni, A., Kornhuber, A., Kovacs, K., Koves, A., Kozubski, W., Krastev, G., Krupp, L. B., Kurca, E., Lassek, C., Laureys, G., Lee, L., Lensch, E., Leutmezer, F., Li, H., Linker, R. A., Linnebank, M., Liskova, P., Llanera, C., Lu, J., Lutterotti, A., Lycke, J., Macdonell, R., Maciejowski, M., Maeurer, M., Magzhanov, R. V., Maida, E. -M., Malciene, L., Mao-Draayer, Y., Marfia, G. A., Markowitz, C., Mastorodimos, V., Matyas, K., Meca-Lallana, J., Merino, J. A. G., Mihetiu, I. G., Milanov, I., Miller, A. E., Millers, A., Mirabella, M., Mizuno, M., Montalban, X., Montoya, L., Mori, M., Mueller, S., Nakahara, J., Nakatsuji, Y., Newsome, S., Nicholas, R., Nielsen, A. S., Nikfekr, E., Nocentini, U., Nohara, C., Nomura, K., Odinak, M. M., Olsson, T., van Oosten, B. W., Oreja-Guevara, C., Oschmann, P., Overell, J., Pachner, A., Panczel, G., Pandolfo, M., Papeix, C., Patrucco, L., Pelletier, J., Piedrabuena, R., Pless, M., Polzer, U., Pozsegovits, K., Rastenyte, D., Rauer, S., Reifschneider, G., Rey, R., Rizvi, S. A., Robertson, D., Rodriguez, J. M., Rog, D., Roshanisefat, H., Rowe, V., Rozsa, C., Rubin, S., Rusek, S., Sacca, F., Saida, T., Salgado, A. V., Sanchez, V. E. F., Sanders, K., Satori, M., Sazonov, D. V., Scarpini, E. A., Schlegel, E., Schluep, M., Schmidt, S., Scholz, E., Schrijver, H. M., Schwab, M., Schwartz, R., Scott, J., Selmaj, K., Shafer, S., Sharrack, B., Shchukin, I. A., Shimizu, Y., Shotekov, P., Siever, A., Sigel, K. -O., Silliman, S., Simo, M., Simu, M., Sinay, V., Siquier, A. E., Siva, A., Skoda, O., Solomon, A., Stangel, M., Stefoski, D., Steingo, B., Stolyarov, I. D., Stourac, P., Strassburger-Krogias, K., Strauss, E., Stuve, O., Tarnev, I., Tavernarakis, A., Tello, C. R., Terzi, M., Ticha, V., Ticmeanu, M., Tiel-Wilck, K., Toomsoo, T., Tubridy, N., Tullman, M. J., Tumani, H., Turcani, P., Turner, B., Uccelli, A., Urtaza, F. J. O., Vachova, M., Valikovics, A., Walter, S., Van Wijmeersch, B., Vanopdenbosch, L., Weber, J. R., Weiss, S., Weissert, R., West, T., Wiendl, H., Wiertlewski, S., Wildemann, B., Willekens, B., Visser, L. H., Vorobeychik, G., Xu, X., Yamamura, T., Yang, Y. N., Yelamos, S. M., Yeung, M., Zacharias, A., Zelkowitz, M., Zettl, U., Zhang, M., Zhou, H., Zieman, U., Ziemssen, T., Bergmann A., Haas J., Mirabella M. (ORCID:0000-0002-7783-114X), Terzi M., Kappos, L., Bar-Or, A., Cree, B. A. C., Fox, R. J., Giovannoni, G., Gold, R., Vermersch, P., Arnold, D. L., Arnould, S., Scherz, T., Wolf, C., Wallstrom, E., Dahlke, F., Achiron, A., Achtnichts, L., Agan, K., Akman-Demir, G., Allen, A. B., Antel, J. P., Antiguedad, A. R., Apperson, M., Applebee, A. M., Ayuso, G. I., Baba, M., Bajenaru, O., Balasa, R., Balci, B. P., Barnett, M., Bass, A., Becker, V. U., Bejinariu, M., Bergh, F. T., Bergmann, A., Bernitsas, E., Berthele, A., Bhan, V., Bischof, F., Bjork, R. J., Blevins, G., Boehringer, M., Boerner, T., Bonek, R., Bowen, J. D., Bowling, A., Boyko, A. N., Boz, C., Bracknies, V., Braune, S., Brescia Morra, V., Brochet, B., Brola, W., Brownstone, P. K., Brozman, M., Brunet, D., Buraga, I., Burnett, M., Buttmann, M., Butzkueven, H., Cahill, J., Calkwood, J. C., Camu, W., Cascione, M., Castelnovo, G., Centonze, D., Cerqueira, J., Chan, A., Cimprichova, A., Cohan, S., Comi, G., Conway, J., Cooper, J. A., Corboy, J., Correale, J., Costell, B., Cottrell, D. A., Coyle, P. K., Craner, M., Cui, L., Cunha, L., Czlonkowska, A., da Silva, A. M., de Sa, J., de Seze, J., Debouverie, M., Debruyne, J., Decoo, D., Defer, G., Derfuss, T., Deri, N. H., Dihenia, B., Dioszeghy, P., Donath, V., Dubois, B., Duddy, M., Duquette, P., Edan, G., Efendi, H., Elias, S., Emrich, P. J., Estruch, B. C., Evdoshenko, E. P., Faiss, J., Fedyanin, A. S., Feneberg, W., Fermont, J., Fernandez, O. F., Ferrer, F. C., Fink, K., Ford, H., Ford, C., Francia, A., Freedman, M., Frishberg, B., Galgani, S., Garmany, G. P., Gehring, K., Gitt, J., Gobbi, C., Goldstick, L. P., Gonzalez, R. A., Grandmaison, F., Grigoriadis, N., Grigorova, O., Grimaldi, L. M. E., Gross, J., Gross-Paju, K., Gudesblatt, M., Guillaume, D., Haas, J., Hancinova, V., Hancu, A., Hardiman, O., Harmjanz, A., Heidenreich, F. R., Hengstman, G. J. D., Herbert, J., Herring, M., Hodgkinson, S., Hoffmann, O. M., Hofmann, W. E., Honeycutt, W. D., Hua, L. H., Huang, D., Huang, Y., Hupperts, R., Imre, P., Jacobs, A. K., Jakab, G., Jasinska, E., Kaida, K., Kalnina, J., Kaprelyan, A., Karelis, G., Karussis, D., Katz, A., Khabirov, F. A., Khatri, B., Kimura, T., Kister, I., Kizlaitiene, R., Klimova, E., Koehler, J., Komatineni, A., Kornhuber, A., Kovacs, K., Koves, A., Kozubski, W., Krastev, G., Krupp, L. B., Kurca, E., Lassek, C., Laureys, G., Lee, L., Lensch, E., Leutmezer, F., Li, H., Linker, R. A., Linnebank, M., Liskova, P., Llanera, C., Lu, J., Lutterotti, A., Lycke, J., Macdonell, R., Maciejowski, M., Maeurer, M., Magzhanov, R. V., Maida, E. -M., Malciene, L., Mao-Draayer, Y., Marfia, G. A., Markowitz, C., Mastorodimos, V., Matyas, K., Meca-Lallana, J., Merino, J. A. G., Mihetiu, I. G., Milanov, I., Miller, A. E., Millers, A., Mirabella, M., Mizuno, M., Montalban, X., Montoya, L., Mori, M., Mueller, S., Nakahara, J., Nakatsuji, Y., Newsome, S., Nicholas, R., Nielsen, A. S., Nikfekr, E., Nocentini, U., Nohara, C., Nomura, K., Odinak, M. M., Olsson, T., van Oosten, B. W., Oreja-Guevara, C., Oschmann, P., Overell, J., Pachner, A., Panczel, G., Pandolfo, M., Papeix, C., Patrucco, L., Pelletier, J., Piedrabuena, R., Pless, M., Polzer, U., Pozsegovits, K., Rastenyte, D., Rauer, S., Reifschneider, G., Rey, R., Rizvi, S. A., Robertson, D., Rodriguez, J. M., Rog, D., Roshanisefat, H., Rowe, V., Rozsa, C., Rubin, S., Rusek, S., Sacca, F., Saida, T., Salgado, A. V., Sanchez, V. E. F., Sanders, K., Satori, M., Sazonov, D. V., Scarpini, E. A., Schlegel, E., Schluep, M., Schmidt, S., Scholz, E., Schrijver, H. M., Schwab, M., Schwartz, R., Scott, J., Selmaj, K., Shafer, S., Sharrack, B., Shchukin, I. A., Shimizu, Y., Shotekov, P., Siever, A., Sigel, K. -O., Silliman, S., Simo, M., Simu, M., Sinay, V., Siquier, A. E., Siva, A., Skoda, O., Solomon, A., Stangel, M., Stefoski, D., Steingo, B., Stolyarov, I. D., Stourac, P., Strassburger-Krogias, K., Strauss, E., Stuve, O., Tarnev, I., Tavernarakis, A., Tello, C. R., Terzi, M., Ticha, V., Ticmeanu, M., Tiel-Wilck, K., Toomsoo, T., Tubridy, N., Tullman, M. J., Tumani, H., Turcani, P., Turner, B., Uccelli, A., Urtaza, F. J. O., Vachova, M., Valikovics, A., Walter, S., Van Wijmeersch, B., Vanopdenbosch, L., Weber, J. R., Weiss, S., Weissert, R., West, T., Wiendl, H., Wiertlewski, S., Wildemann, B., Willekens, B., Visser, L. H., Vorobeychik, G., Xu, X., Yamamura, T., Yang, Y. N., Yelamos, S. M., Yeung, M., Zacharias, A., Zelkowitz, M., Zettl, U., Zhang, M., Zhou, H., Zieman, U., Ziemssen, T., Bergmann A., Haas J., Mirabella M. (ORCID:0000-0002-7783-114X), and Terzi M.

Abstract

Background: No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor1,5 modulator, on disability progression in patients with SPMS. Methods: This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. Findings: 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative

Published
2018

50. Long-term effects of autoimmune CNS inflammation on adult hippocampal neurogenesis

Author

Giannakopoulou, A. Lyras, G.A. Grigoriadis, N.

Subjects
nervous system
Abstract

Neurogenesis is a well-characterized phenomenon within the dentate gyrus (DG) of the adult hippocampus. Aging and chronic degenerative disorders have been shown to impair hippocampal neurogenesis, but the consequence of chronic inflammation remains controversial. In this study the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis was used to investigate the long-term effects of T cell–mediated central nervous system inflammation on hippocampal neurogenesis. 5-Bromodeoxyuridine (BrdU)-labeled subpopulations of hippocampal cells in EAE and control mice (coexpressing GFAP, doublecortin, NeuN, calretinin, and S100) were quantified at the recovery phase, 21 days after BrdU administration, to estimate alterations on the rate and differentiation pattern of the neurogenesis process. The core features of EAE mice DG are (i) elevated number of newborn (BrdU+) cells indicating vigorous proliferation, which in the long term subsided; (ii) enhanced migration of newborn cells into the granule cell layer; (iii) increased level of immature neuronal markers (including calretinin and doublecortin); (iv) trending decrease in the percentage of newborn mature neurons; and (v) augmented gliogenesis and differentiation of newborn neural precursor cells (NPCs) to mature astrocytes (BrdU+/S100+). Although the inflammatory environment in the brain of EAE mice enhances the proliferation of hippocampal NPCs, in the long term neurogenesis is progressively depleted, giving prominence to gliogenesis. The discrepancy between the high number of immature cells and the low number of mature newborn cells could be the result of a caused defect in the maturation pathway. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Published
2017

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