Document Type : Review Article
Authors
1 Department of Cellular and molecular Biology , Islamic Azad University science and Research Branch.
2 Department of molecular genetics, Ahar Branch, Islamic Azad University, Ahar, Iran.
Abstract
Multiple sclerosis (MS), the most common inflammatory demyelinating illness of the central nervous system (CNS), presents a range of clinical symptoms. The body’s immune system attacking myelin causes the transmission block in MS, which increases the electrical capacity of axons. Studies suggest that epigenetic factors play a part in the development of MS. Longer than 200 nucleotides in length and widely distributed, lncRNAs are linear RNA transcripts that cannot code for proteins. For instance, evidence suggests that lncRNAs are essential for a number of cellular functions, including immune response regulation, epithelial mesenchymal transition (EMT), cancer cell proliferation and metastasis, cellular homeostasis, and embryonic development. Epigenetic mechanisms have been proven to have a significant impact on the pathophysiology of MS, and their participation has revealed the function of lncRNAs as epigenetic regulatory molecules in molecular processes. The major subjects of this study have been the relationship between lncRNAs and MS, the role of lncRNA in the pathophysiology of the disease, and the diagnostic and prognostic potential of lncRNA in MS.
Keywords
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2.Kołtuniuk, A.; Chojdak-Łukasiewicz, J. Adherence to Therapy in Patients with Multiple Sclerosis-Review. Int. J. Environ. Res. Public Health 2022, 19, 2203.
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7.Esposito, S.; Bonavita, S.; Sparaco, M.; Gallo, A.; Tedeschi, G. The role of diet in multiple sclerosis: A review. Nutr. Neurosci. 2018, 21, 377–390.
8.Thomsen, H.L.; Jessen, E.B.; Passali, M.; Frederiksen, J.L. The role of gluten in multiple sclerosis: A systematic review. Mult. Scler. Relat. Disord. 2019, 27, 156–163.
9.Grummt, I. Life on a planet of its own: regulation of RNA polymerase I transcription in the nucleolus. Genes Dev. 17, 1691–1702 (2003).
10.Turowski, T. W. & Tollervey, D. Transcription by RNA polymerase III: insights into mechanism and regulation. Biochem. Soc. Trans. 44, 1367–1375 (2016).
11.Statello, L., Guo, C. J., Chen, L. L. & Huarte, M. Gene regulation by long non-coding RNAs and its biological functions. Nat. Rev. Mol. Cell Biol. 22, 96–118 (2021).
12.Expression of a noncoding RNA is elevated in Alzheimer’s disease and drives rapid feed-forward regulation of beta-secretaseNat Med(2008).
13.Ulitsky, I. & Bartel, D. P. lincRNAs: genomics, evolution, and mechanisms. Cell 154, 26–46 (2013).
14.Kobelt G, Thompson A, Berg J, et al. New insights into the burden and costs of multiple sclerosis in Europe.Mult Scler 2017; 23: 1123–1136.
15.Muraro PA, Pasquini M, Atkins HL, et al. Long-termoutcomes after autologous hematopoietic stem cell transplantation for multiple sclerosis. JAMA Neurol 2017; 74: 459–469.
16.Koch MW, Ilnytskyy Y, Golubov A, Metz LM, Yong VW, Kovalchuk O. Global transcriptome profiling of mild relapsing–remitting versus primary progressive multiple sclerosis. Eur J Neurol 2018; 25: 651–658.
17.Napier MD, Poole C, Satten GA, Ashley-Koch A, Marrie RA, Williamson DM. Heavy metals, organic solvents,and multiple sclerosis: an exploratory look at gene–environment interactions. Arch Environ Occup Health 2016; 71: 26–34.
18.Hollenbach JA, Oksenberg JR. The immunogenetics of multiple sclerosis: a comprehensive review. J Autoimmun2015; 64: 13–25.
19.Montalban X, Gold R, Thompson AJ, et al. ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis. Mult Scler 2018; 24: 96–120.
20.Thompson AJ, Banwell BL, Barkhof F, et of multiple sclerosis: 2017 revisions of the criteria. Lancet Neurol 2018; 17: 162–173.
21.Waldman A, Ness J, Pohl D, et al. Pediatric multiple sclerosis: clinical features and outcome. Neurology 2016;87: S74–S81.
22.Jia X, Madireddy L, Caillier S, et al. Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis. Ann Neurol 2018; 84: 51–63.
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24.Cardamone, G., Paraboschi, E.M., Solda, G., Cantoni, C., Supino, D., Piccio, L., et al.,2019. Not only cancer: the long non-coding RNA MALAT1 affects the repertoire of alternatively spliced transcripts and circular RNAs in multiple sclerosis. Hum. Mol.Genet. 28, 1414–1428.
25.Dastmalchi, R., Ghafouri-Fard, S., Omrani, M.D., Mazdeh, M., Sayad, A., Taheri, M.,2018a. Dysregulation of long non-coding RNA profile in peripheral blood of multiple sclerosis patients. Mult. Scler. Relat. Disord. 25, 219–226.
26.Dastmalchi, R., Omrani, M.D., Mazdeh, M., Arsang-Jang, S., Movafagh, A., Sayad, A.,et al., 2018c. Expression of long non-coding RNAs (UCA1 and CCAT2) in the blood of multiple sclerosis patients: a case-control study. Iran Red Crescent Med J 20.
27.Goff, L.A., Rinn, J.L., 2015. Linking RNA biology to lncRNAs. Genome Res. 25,1456–1465.
28.Mahad, D.H., Trapp, B.D., Lassmann, H., 2015. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 14, 183–193.
29.Masoumi, F., Ghorbani, S., Talebi, F., Branton, W.G., Rajaei, S., Power, C., et al., 2019. Malat1 long noncoding RNA regulates inflammation and leukocyte differentiation in experimental autoimmune encephalomyelitis. J. Neuroimmunol. 328, 50–59.
30.Michalik, K.M., You, X., Manavski, Y., Doddaballapur, A., Zörnig, M., Braun, T., et al., 2014. Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circ. Res. 114, 1389–1397.
31.Mills, K.H., 2011. TLR-dependent T cell activation in autoimmunity. Nat. Rev. Immunol. 11, 807–822.Mitra, S.A., Mitra, A.P., Triche, T.J., 2012. A central role for long non-coding RNA in cancer. Front. Genet. 3, 17.
32.Jin, L., Cai, Q., Wang, S., Wang, S., Mondal, T., Wang, J., et al., 2018. Long noncoding RNA MEG3 regulates LATS2 by promoting the ubiquitination of EZH2 and inhibits proliferation and invasion in gallbladder cancer. Cell Death Dis. 9, 1017.
33.Kalliolias, G.D., Ivashkiv, L.B., 2016. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat. Rev. Rheumatol. 12, 49.
34.Kamali, A.N., Noorbakhsh, S.M., Hamedifar, H., Jadidi-Niaragh, F., Yazdani, R., Bautista,J.M., et al., 2019. A role for Th1-like Th17 cells in the pathogenesis of inflammatory and autoimmune disorders. Mol. Immunol. 105, 107–115.
35.Santoro, M., Nociti, V., Lucchini, M., De Fino, C., Losavio, F.A., Mirabella, M., 2016. Expression profile of long non-coding RNAs in serum of patients with multiple sclerosis. J. Mol. Neurosci. 59, 18 23.
36.Sawcer, S., Hellenthal, G., Pirinen, M., Spencer, C.C., Patsopoulos, N.A., Moutsianas, L.,et al., 2011. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219.
37.Schmitt, A.M., Chang, H.Y., 2017. Long noncoding RNAs: at the intersection of Cancer and chromatin biology. Cold Spring Harb. Perspect. Med. 7.
38.Shaker, O.G., Mahmoud, R.H., Abdelaleem, O.O., Ibrahem, E.G., Mohamed, A.A., Zaki,O.M., et al., 2019. LncRNAs, MALAT1 and lnc-DC as potential biomarkers for multiple sclerosis diagnosis. Biosci. Rep. 39.
39.Stevenson, E.V., Alexander, J.S., Yun, J.W., Becker, F., Gonzalez-Toledo, E., Minagar, A.,2016. Mechanisms of blood–brain barrier disintegration in the pathophysiology of multiple sclerosis. In: Multiple Sclerosis. Elsevier, pp. 393–413.
40.Sun, D., Yu, Z., Fang, X., Liu, M., Pu, Y., Shao, Q., et al., 2017. LncRNA GAS5 inhibits microglial M2 polarization and exacerbates demyelination. EMBO Rep. 18,1801–1816.
41.Takahashi, K., Yan, I., Haga, H., Patel, T., 2014. Long noncoding RNA in liver diseases. Hepatology 60, 744–753.
42.Tano, K., Mizuno, R., Okada, T., Rakwal, R., Shibato, J., Masuo, Y., et al., 2010. MALAT-1enhances cell motility of lung adenocarcinoma cells by influencing the expression of motility-related genes. FEBS Lett. 584, 4575–4580.
43.Tegla, C.A., Azimzadeh, P., Andrian-Albescu, M., Martin, A., Cudrici, C.D., Trippe 3rd, R.,et al., 2014. SIRT1 is decreased during relapses in patients with multiple sclerosis.Exp. Mol. Pathol. 96, 139–148.
44.Toghianifar, N., Ashtari, F., Zarkesh-Esfahani, S.H., Mansourian, M., 2015. Effect of high dose vitamin D intake on interleukin-17 levels in multiple sclerosis: a randomized, double-blind, placebo-controlled clinical trial. J. Neuroimmunol. 285, 125–128.
45.Wosik, K., Antel, J., Kuhlmann, T., Brück, W., Massie, B., Nalbantoglu, J., 2003.Oligodendrocyte injury in multiple sclerosis: a role for p53. J. Neurochem. 85,635–644.
46.Boyko A and Melnikov M. Prevalence and incidence of multiple sclerosis in Russian federation: 30 years of studies. Brain Sci 2020; 10(5): 305.
47.Beiki O, Frumento P, Bottai M, et al. Changes in the risk of reaching multiple sclerosis disability milestones in recent decades: A nationwide population-based cohort study in Sweden. JAMA Neurol 2019; 76(6): 665–671.
48.Goodin DS, Reder AT, Ebers GC, et al. Survival in MS: A randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial. Neurology 2012; 78(17): 1315–1322.
49.Browne P, Chandraratna D, Angood C, et al. Atlas of multiple sclerosis 2013: A growing global problem with widespread inequity. Neurology 2014; 83(11): 1022–1024.
50.The Multiple Sclerosis International Federation Atlas of MS, 3rd ed, September, 2020, https://www. atlasofms.org
51.Campbell JA, Simpson S, Ahmad H, et al. Change in multiple sclerosis prevalence over time in Australia 2010-2017 utilising disease-modifying therapy prescription data. Mult Scler 2020; 26: 1315–1328.
52.Wallin MT, Culpepper WJ, Nichols E, et al. Global, regional, and national burden of multiple sclerosis 1990–2016: A systematic analysis for the global burden of disease study 2016. Lancet Neurology 2019; 8(3): 269–285.
53.Schiess N, Huether K, Fatafta T, et al. How global MS prevalence is changing: A retrospective chart review in the United Arab Emirates. Mult Scler Relat Disord 2016; 9: 73–79.
54.Aronson KJ Quality of life among persons with multiple sclerosis and their caregivers. Neurology 1997; 48: 74—80.
55.Sidhom Y, Maillart E, Tezenas du Montcel S, et al. Fast multiple sclerosis progression in North Africans: Both genetics and environment matter. Neurology 2017; 88(13): 1218–1225.
56.Holmén C, Piehl F, Hillert J, et al. A Swedish national postmarketing surveillance study of natalizumab treatment in multiple sclerosis. Mult Scler 2011; 17: 708–719.
57.Mohr DC, Goodkin DE, Likosky W, et al. Treatment of depression improves adherence to interferon beta-1b therapy for multiple sclerosis. Arch Neurol 1997; 54: 531–533.
58.Marrie RA, Fisk JD, Yu BN, et al. Mental comorbidity and multiple sclerosis: Validating administrative data to support population-based surveillance. BMC Neurol 2013; 13: 16.
59.Rodgers J and Bland R. Psychiatric manifestations of multiple sclerosis: A review. Can J Psychiatry 1996; 41: 441–445.
60.Fisk J, Morehouse SA, Brown MG, et al. Hospitalbased psychiatric service utilization and morbidity in multiple sclerosis. Can J Neurol Sci 1998; 25: 230–235.
61.Valleroy ML and Kraft GH. Sexual dysfunction in multiple sclerosis. Arch Phys Med Rehabil 1984; 65: 125–128.
62.Zabad RK, Patten SB and Metz LM. The association of depression with disease course in multiple sclerosis. Neurology 2005; 64: 359–360.
63.Korostil M and Feinstein A. Anxiety disorders and their clinical correlates in multiple sclerosis patients. Mult Scler 2007; 13: 67–72.
64.Turner AP, Hawkins EJ, Haselkorn JK, et al. Alcohol misuse and multiple sclerosis. Arch Phys Med Rehabil 2009; 90: 842–848.
65.Fromont A, Binquet C, Rollot F, et al. Comorbidities at multiple sclerosis diagnosis. J Neurol 2013; 260: 2629–2637.
66.Romberg A, Ruutiainen J, Puukka P, et al. Fatigue in multiple sclerosis patients during inpatient rehabilitation. Disabil Rehabil 2008; 30: 1480–1485.
67.Feinstein A. Multiple sclerosis and depression. Mult Scler 2011; 17: 1276–1281.
2.Kołtuniuk, A.; Chojdak-Łukasiewicz, J. Adherence to Therapy in Patients with Multiple Sclerosis-Review. Int. J. Environ. Res. Public Health 2022, 19, 2203.
3.Rito, Y.; Torre-Villalvazo, I.; Flores, J.; Rivas, V.; Corona, T. Epigenetics in Multiple Sclerosis: Molecular Mechanisms and Dietary Intervention. Cent. Nerv. Syst. Agents Med. Chem. 2018, 18, 8 15.
4.Esposito, S.; Bonavita, S.; Sparaco, M.; Gallo, A.; Tedeschi, G. The role of diet in multiple sclerosis: A review. Nutr. Neurosci. 2018, 21, 377–390.
5.Lombardi, V.C.; De Meirleir, K.L.; Subramanian, K.; Nourani, S.M.; Dagda, R.K.; Delaney, S.L.; Palotás, A. Nutritional modulation of the intestinal microbiota; future opportunities for the prevention and treatment of neuroimmune and neuroinflammatory disease. J. Nutr. Biochem. 2018, 61, 1–16.
6.Boziki, M.K.; Kesidou, E.; Theotokis, P.; Mentis, A.-F.A.; Karafoulidou, E.; Melnikov, M.; Sviridova, A.; Rogovski, V.; Boyko, A.; Grigoriadis, N. Microbiome in Multiple Sclerosis; Where Are We, What We Know and Do Not Know. Brain Sci. 2020, 10, 234.
7.Esposito, S.; Bonavita, S.; Sparaco, M.; Gallo, A.; Tedeschi, G. The role of diet in multiple sclerosis: A review. Nutr. Neurosci. 2018, 21, 377–390.
8.Thomsen, H.L.; Jessen, E.B.; Passali, M.; Frederiksen, J.L. The role of gluten in multiple sclerosis: A systematic review. Mult. Scler. Relat. Disord. 2019, 27, 156–163.
9.Grummt, I. Life on a planet of its own: regulation of RNA polymerase I transcription in the nucleolus. Genes Dev. 17, 1691–1702 (2003).
10.Turowski, T. W. & Tollervey, D. Transcription by RNA polymerase III: insights into mechanism and regulation. Biochem. Soc. Trans. 44, 1367–1375 (2016).
11.Statello, L., Guo, C. J., Chen, L. L. & Huarte, M. Gene regulation by long non-coding RNAs and its biological functions. Nat. Rev. Mol. Cell Biol. 22, 96–118 (2021).
12.Expression of a noncoding RNA is elevated in Alzheimer’s disease and drives rapid feed-forward regulation of beta-secretaseNat Med(2008).
13.Ulitsky, I. & Bartel, D. P. lincRNAs: genomics, evolution, and mechanisms. Cell 154, 26–46 (2013).
14.Kobelt G, Thompson A, Berg J, et al. New insights into the burden and costs of multiple sclerosis in Europe.Mult Scler 2017; 23: 1123–1136.
15.Muraro PA, Pasquini M, Atkins HL, et al. Long-termoutcomes after autologous hematopoietic stem cell transplantation for multiple sclerosis. JAMA Neurol 2017; 74: 459–469.
16.Koch MW, Ilnytskyy Y, Golubov A, Metz LM, Yong VW, Kovalchuk O. Global transcriptome profiling of mild relapsing–remitting versus primary progressive multiple sclerosis. Eur J Neurol 2018; 25: 651–658.
17.Napier MD, Poole C, Satten GA, Ashley-Koch A, Marrie RA, Williamson DM. Heavy metals, organic solvents,and multiple sclerosis: an exploratory look at gene–environment interactions. Arch Environ Occup Health 2016; 71: 26–34.
18.Hollenbach JA, Oksenberg JR. The immunogenetics of multiple sclerosis: a comprehensive review. J Autoimmun2015; 64: 13–25.
19.Montalban X, Gold R, Thompson AJ, et al. ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis. Mult Scler 2018; 24: 96–120.
20.Thompson AJ, Banwell BL, Barkhof F, et of multiple sclerosis: 2017 revisions of the criteria. Lancet Neurol 2018; 17: 162–173.
21.Waldman A, Ness J, Pohl D, et al. Pediatric multiple sclerosis: clinical features and outcome. Neurology 2016;87: S74–S81.
22.Jia X, Madireddy L, Caillier S, et al. Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis. Ann Neurol 2018; 84: 51–63.
23.Koch MW, Ilnytskyy Y, Golubov A, Metz LM, YongVW, Kovalchuk O. Global transcriptome profiling of mild relapsing–remitting versus primary progressive multiple sclerosis. Eur J Neurol 2018; 25: 651–658.
24.Cardamone, G., Paraboschi, E.M., Solda, G., Cantoni, C., Supino, D., Piccio, L., et al.,2019. Not only cancer: the long non-coding RNA MALAT1 affects the repertoire of alternatively spliced transcripts and circular RNAs in multiple sclerosis. Hum. Mol.Genet. 28, 1414–1428.
25.Dastmalchi, R., Ghafouri-Fard, S., Omrani, M.D., Mazdeh, M., Sayad, A., Taheri, M.,2018a. Dysregulation of long non-coding RNA profile in peripheral blood of multiple sclerosis patients. Mult. Scler. Relat. Disord. 25, 219–226.
26.Dastmalchi, R., Omrani, M.D., Mazdeh, M., Arsang-Jang, S., Movafagh, A., Sayad, A.,et al., 2018c. Expression of long non-coding RNAs (UCA1 and CCAT2) in the blood of multiple sclerosis patients: a case-control study. Iran Red Crescent Med J 20.
27.Goff, L.A., Rinn, J.L., 2015. Linking RNA biology to lncRNAs. Genome Res. 25,1456–1465.
28.Mahad, D.H., Trapp, B.D., Lassmann, H., 2015. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 14, 183–193.
29.Masoumi, F., Ghorbani, S., Talebi, F., Branton, W.G., Rajaei, S., Power, C., et al., 2019. Malat1 long noncoding RNA regulates inflammation and leukocyte differentiation in experimental autoimmune encephalomyelitis. J. Neuroimmunol. 328, 50–59.
30.Michalik, K.M., You, X., Manavski, Y., Doddaballapur, A., Zörnig, M., Braun, T., et al., 2014. Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circ. Res. 114, 1389–1397.
31.Mills, K.H., 2011. TLR-dependent T cell activation in autoimmunity. Nat. Rev. Immunol. 11, 807–822.Mitra, S.A., Mitra, A.P., Triche, T.J., 2012. A central role for long non-coding RNA in cancer. Front. Genet. 3, 17.
32.Jin, L., Cai, Q., Wang, S., Wang, S., Mondal, T., Wang, J., et al., 2018. Long noncoding RNA MEG3 regulates LATS2 by promoting the ubiquitination of EZH2 and inhibits proliferation and invasion in gallbladder cancer. Cell Death Dis. 9, 1017.
33.Kalliolias, G.D., Ivashkiv, L.B., 2016. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat. Rev. Rheumatol. 12, 49.
34.Kamali, A.N., Noorbakhsh, S.M., Hamedifar, H., Jadidi-Niaragh, F., Yazdani, R., Bautista,J.M., et al., 2019. A role for Th1-like Th17 cells in the pathogenesis of inflammatory and autoimmune disorders. Mol. Immunol. 105, 107–115.
35.Santoro, M., Nociti, V., Lucchini, M., De Fino, C., Losavio, F.A., Mirabella, M., 2016. Expression profile of long non-coding RNAs in serum of patients with multiple sclerosis. J. Mol. Neurosci. 59, 18 23.
36.Sawcer, S., Hellenthal, G., Pirinen, M., Spencer, C.C., Patsopoulos, N.A., Moutsianas, L.,et al., 2011. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214–219.
37.Schmitt, A.M., Chang, H.Y., 2017. Long noncoding RNAs: at the intersection of Cancer and chromatin biology. Cold Spring Harb. Perspect. Med. 7.
38.Shaker, O.G., Mahmoud, R.H., Abdelaleem, O.O., Ibrahem, E.G., Mohamed, A.A., Zaki,O.M., et al., 2019. LncRNAs, MALAT1 and lnc-DC as potential biomarkers for multiple sclerosis diagnosis. Biosci. Rep. 39.
39.Stevenson, E.V., Alexander, J.S., Yun, J.W., Becker, F., Gonzalez-Toledo, E., Minagar, A.,2016. Mechanisms of blood–brain barrier disintegration in the pathophysiology of multiple sclerosis. In: Multiple Sclerosis. Elsevier, pp. 393–413.
40.Sun, D., Yu, Z., Fang, X., Liu, M., Pu, Y., Shao, Q., et al., 2017. LncRNA GAS5 inhibits microglial M2 polarization and exacerbates demyelination. EMBO Rep. 18,1801–1816.
41.Takahashi, K., Yan, I., Haga, H., Patel, T., 2014. Long noncoding RNA in liver diseases. Hepatology 60, 744–753.
42.Tano, K., Mizuno, R., Okada, T., Rakwal, R., Shibato, J., Masuo, Y., et al., 2010. MALAT-1enhances cell motility of lung adenocarcinoma cells by influencing the expression of motility-related genes. FEBS Lett. 584, 4575–4580.
43.Tegla, C.A., Azimzadeh, P., Andrian-Albescu, M., Martin, A., Cudrici, C.D., Trippe 3rd, R.,et al., 2014. SIRT1 is decreased during relapses in patients with multiple sclerosis.Exp. Mol. Pathol. 96, 139–148.
44.Toghianifar, N., Ashtari, F., Zarkesh-Esfahani, S.H., Mansourian, M., 2015. Effect of high dose vitamin D intake on interleukin-17 levels in multiple sclerosis: a randomized, double-blind, placebo-controlled clinical trial. J. Neuroimmunol. 285, 125–128.
45.Wosik, K., Antel, J., Kuhlmann, T., Brück, W., Massie, B., Nalbantoglu, J., 2003.Oligodendrocyte injury in multiple sclerosis: a role for p53. J. Neurochem. 85,635–644.
46.Boyko A and Melnikov M. Prevalence and incidence of multiple sclerosis in Russian federation: 30 years of studies. Brain Sci 2020; 10(5): 305.
47.Beiki O, Frumento P, Bottai M, et al. Changes in the risk of reaching multiple sclerosis disability milestones in recent decades: A nationwide population-based cohort study in Sweden. JAMA Neurol 2019; 76(6): 665–671.
48.Goodin DS, Reder AT, Ebers GC, et al. Survival in MS: A randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial. Neurology 2012; 78(17): 1315–1322.
49.Browne P, Chandraratna D, Angood C, et al. Atlas of multiple sclerosis 2013: A growing global problem with widespread inequity. Neurology 2014; 83(11): 1022–1024.
50.The Multiple Sclerosis International Federation Atlas of MS, 3rd ed, September, 2020, https://www. atlasofms.org
51.Campbell JA, Simpson S, Ahmad H, et al. Change in multiple sclerosis prevalence over time in Australia 2010-2017 utilising disease-modifying therapy prescription data. Mult Scler 2020; 26: 1315–1328.
52.Wallin MT, Culpepper WJ, Nichols E, et al. Global, regional, and national burden of multiple sclerosis 1990–2016: A systematic analysis for the global burden of disease study 2016. Lancet Neurology 2019; 8(3): 269–285.
53.Schiess N, Huether K, Fatafta T, et al. How global MS prevalence is changing: A retrospective chart review in the United Arab Emirates. Mult Scler Relat Disord 2016; 9: 73–79.
54.Aronson KJ Quality of life among persons with multiple sclerosis and their caregivers. Neurology 1997; 48: 74—80.
55.Sidhom Y, Maillart E, Tezenas du Montcel S, et al. Fast multiple sclerosis progression in North Africans: Both genetics and environment matter. Neurology 2017; 88(13): 1218–1225.
56.Holmén C, Piehl F, Hillert J, et al. A Swedish national postmarketing surveillance study of natalizumab treatment in multiple sclerosis. Mult Scler 2011; 17: 708–719.
57.Mohr DC, Goodkin DE, Likosky W, et al. Treatment of depression improves adherence to interferon beta-1b therapy for multiple sclerosis. Arch Neurol 1997; 54: 531–533.
58.Marrie RA, Fisk JD, Yu BN, et al. Mental comorbidity and multiple sclerosis: Validating administrative data to support population-based surveillance. BMC Neurol 2013; 13: 16.
59.Rodgers J and Bland R. Psychiatric manifestations of multiple sclerosis: A review. Can J Psychiatry 1996; 41: 441–445.
60.Fisk J, Morehouse SA, Brown MG, et al. Hospitalbased psychiatric service utilization and morbidity in multiple sclerosis. Can J Neurol Sci 1998; 25: 230–235.
61.Valleroy ML and Kraft GH. Sexual dysfunction in multiple sclerosis. Arch Phys Med Rehabil 1984; 65: 125–128.
62.Zabad RK, Patten SB and Metz LM. The association of depression with disease course in multiple sclerosis. Neurology 2005; 64: 359–360.
63.Korostil M and Feinstein A. Anxiety disorders and their clinical correlates in multiple sclerosis patients. Mult Scler 2007; 13: 67–72.
64.Turner AP, Hawkins EJ, Haselkorn JK, et al. Alcohol misuse and multiple sclerosis. Arch Phys Med Rehabil 2009; 90: 842–848.
65.Fromont A, Binquet C, Rollot F, et al. Comorbidities at multiple sclerosis diagnosis. J Neurol 2013; 260: 2629–2637.
66.Romberg A, Ruutiainen J, Puukka P, et al. Fatigue in multiple sclerosis patients during inpatient rehabilitation. Disabil Rehabil 2008; 30: 1480–1485.
67.Feinstein A. Multiple sclerosis and depression. Mult Scler 2011; 17: 1276–1281.
)