REFERENCES
3. Lorscheider J, Buzzard K, Jokubaitis V, Spelman T, Havrdova E, et al; MSBase Study Group. Defining secondary progressive multiple sclerosis. Brain 2016;139:2395-405.
4. Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014;83:278-86.
5. Cree BAC, Hollenbach JA, Bove R, Kirkish G, Sacco S, et al; University of California, San Francisco MS-EPIC Team. Silent progression in disease activity-free relapsing multiple sclerosis. Ann Neurol 2019;85:653-66.
6. Stevenson VL, Smith SM, Matthews PM, Miller DH, Thompson AJ. Monitoring disease activity and progression in primary progressive multiple sclerosis using MRI: sub-voxel registration to identify lesion changes and to detect cerebral atrophy. J Neurol 2002;249:171-7.
7. Stevenson VL, Miller DH. Magnetic resonance imaging in the monitoring of disease progression in multiple sclerosis. Mult Scler 1999;5:268-72.
8. Stevenson VL, Miller DH, Leary SM, Rovaris M, Barkhof F, et al. One year follow up study of primary and transitional progressive multiple sclerosis. J Neurol Neurosurg Psychiatry 2000;68:713-8.
9. Baecher-Allan C, Kaskow BJ, Weiner HL. Multiple sclerosis: mechanisms and immunotherapy. Neuron 2018;97:742-68.
11. Lassmann H. Pathogenic mechanisms associated with different clinical courses of multiple sclerosis. Front Immunol 2018;9:3116.
12. Machado-Santos J, Saji E, Tröscher AR, Paunovic M, Liblau R, et al. The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells. Brain 2018;141:2066-82.
13. Calabrese M, Magliozzi R, Ciccarelli O, Geurts JJ, Reynolds R, et al. Exploring the origins of grey matter damage in multiple sclerosis. Nat Rev Neurosci 2015;16:147-58.
14. Frischer JM, Weigand SD, Guo Y, Kale N, Parisi JE, et al. Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. Ann Neurol 2015;78:710-21.
15. Haider L, Zrzavy T, Hametner S, Höftberger R, Bagnato F, et al. The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain. Brain 2016;139:807-15.
16. Kutzelnigg A, Lucchinetti CF, Stadelmann C, Brück W, Rauschka H, et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain 2005;128:2705-12.
17. Steinman L. Immunology of relapse and remission in multiple sclerosis. Annu Rev Immunol 2014;32:257-81.
18. Hochmeister S, Grundtner R, Bauer J, Engelhardt B, Lyck R, et al. Dysferlin is a new marker for leaky brain blood vessels in multiple sclerosis. J Neuropathol Exp Neurol 2006;65:855-65.
19. Kirk J, Plumb J, Mirakhur M, McQuaid S. Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood-brain barrier leakage and active demyelination. J Pathol 2003;201:319-27.
20. Meinl E, Krumbholz M, Derfuss T, Junker A, Hohlfeld R. Compartmentalization of inflammation in the CNS: a major mechanism driving progressive multiple sclerosis. J Neurol Sci 2008;274:42-4.
21. Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 2009;132:1175-89.
22. van Horssen J, Brink BP, de Vries HE, van der Valk P, Bø L. The blood-brain barrier in cortical multiple sclerosis lesions. J Neuropathol Exp Neurol 2007;66:321-8.
23. Brennan MS, Matos MF, Li B, Hronowski X, Gao B, et al. Dimethyl fumarate and monoethyl fumarate exhibit differential effects on KEAP1, NRF2 activation, and glutathione depletion in vitro. PLoS One 2015;10:e0120254.
25. Chun J, Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol 2010;33:91-101.
26. Hunter SF, Bowen JD, Reder AT. The direct effects of fingolimod in the central nervous system: implications for relapsing multiple sclerosis. CNS Drugs 2016;30:135-47.
27. Fischer MT, Wimmer I, Höftberger R, Gerlach S, Haider L, et al. Disease-specific molecular events in cortical multiple sclerosis lesions. Brain 2013;136:1799-815.
28. Prineas JW, Kwon EE, Cho ES, Sharer LR, Barnett MH, et al. Immunopathology of secondary-progressive multiple sclerosis. Ann Neurol 2001;50:646-57.
29. Elliott C, Belachew S, Wolinsky JS, Hauser SL, Kappos L, et al. Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis. Brain 2019;142:2787-99.
30. Elliott C, Wolinsky JS, Hauser SL, Kappos L, Barkhof F, et al. Slowly expanding/evolving lesions as a magnetic resonance imaging marker of chronic active multiple sclerosis lesions. Mult Scler 2019;25:1915-25.
31. Absinta M, Sati P, Fechner A, Schindler MK, Nair G, et al. Identification of chronic active multiple sclerosis lesions on 3T MRI. AJNR Am J Neuroradiol 2018;39:1233-8.
32. Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol 2012;8:647-56.
33. Klaver R, Popescu V, Voorn P, Galis-de Graaf Y, van der Valk P, et al. Neuronal and axonal loss in normal-appearing gray matter and subpial lesions in multiple sclerosis. J Neuropathol Exp Neurol 2015;74:453-8.
34. Herranz E, Giannì C, Louapre C, Treaba CA, Govindarajan ST, et al. Neuroinflammatory component of gray matter pathology in multiple sclerosis. Ann Neurol 2016;80:776-90.
35. Geurts JJ, Calabrese M, Fisher E, Rudick RA. Measurement and clinical effect of grey matter pathology in multiple sclerosis. Lancet Neurol 2012;11:1082-92.
36. Luchetti S, Fransen NL, van Eden CG, Ramaglia V, Mason M, et al. Progressive multiple sclerosis patients show substantial lesion activity that correlates with clinical disease severity and sex: a retrospective autopsy cohort analysis. Acta Neuropathol 2018;135:511-28.
37. Calabrese M, Poretto V, Favaretto A, Alessio S, Bernardi V, et al. Cortical lesion load associates with progression of disability in multiple sclerosis. Brain 2012;135:2952-61.
38. Scalfari A, Romualdi C, Nicholas RS, Mattoscio M, Magliozzi R, et al. The cortical damage, early relapses, and onset of the progressive phase in multiple sclerosis. Neurology 2018;90:e2107-18.
39. Filippi M, Rocca MA, Calabrese M, Sormani MP, Rinaldi F, et al. Intracortical lesions: relevance for new MRI diagnostic criteria for multiple sclerosis. Neurology 2010;75:1988-94.
40. Calabrese M, Romualdi C, Poretto V, Favaretto A, Morra A, et al. The changing clinical course of multiple sclerosis: a matter of gray matter. Ann Neurol 2013;74:76-83.
41. Lucchinetti CF, Popescu BF, Bunyan RF, Moll NM, Roemer SF, et al. Inflammatory cortical demyelination in early multiple sclerosis. N Engl J Med 2011;365:2188-97.
42. Treaba CA, Granberg TE, Sormani MP, Herranz E, Ouellette RA, et al. Longitudinal characterization of cortical lesion development and evolution in multiple sclerosis with 7.0-T MRI. Radiology 2019;291:740-9.
43. Giorgio A, Stromillo ML, Rossi F, Battaglini M, Hakiki B, et al. Cortical lesions in radiologically isolated syndrome. Neurology 2011;77:1896-9.
44. Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain 2007;130:1089-104.
45. Magliozzi R, Howell OW, Reeves C, Roncaroli F, Nicholas R, et al. A gradient of neuronal loss and meningeal inflammation in multiple sclerosis. Ann Neurol 2010;68:477-93.
46. Filippi M, Rocca MA. Cortical lesions on 7-T MRI in multiple sclerosis: a window into pathogenetic mechanisms? Radiology 2019;291:750-1.
47. Filippi M, Preziosa P, Banwell BL, Barkhof F, Ciccarelli O, et al. Assessment of lesions on magnetic resonance imaging in multiple sclerosis: practical guidelines. Brain 2019;142:1858-75.
48. Schindler MK, Sati P, Reich DS. Insights from ultrahigh field imaging in multiple sclerosis. Neuroimaging Clin N Am 2017;27:357-66.
49. Peterson JW, Bö L, Mörk S, Chang A, Trapp BD. Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001;50:389-400.
50. Bø L, Vedeler CA, Nyland H, Trapp BD, Mørk SJ. Intracortical multiple sclerosis lesions are not associated with increased lymphocyte infiltration. Mult Scler 2003;9:323-31.
51. Bø L, Vedeler CA, Nyland HI, Trapp BD, Mørk SJ. Subpial demyelination in the cerebral cortex of multiple sclerosis patients. J Neuropathol Exp Neurol 2003;62:723-32.
52. Strijbis EMM, Kooi EJ, van der Valk P, Geurts JJG. Cortical remyelination is heterogeneous in multiple sclerosis. J Neuropathol Exp Neurol 2017;76:390-401.
53. Chang A, Staugaitis SM, Dutta R, Batt CE, Easley KE, et al. Cortical remyelination: a new target for repair therapies in multiple sclerosis. Ann Neurol 2012;72:918-26.
54. Albert M, Antel J, Brück W, Stadelmann C. Extensive cortical remyelination in patients with chronic multiple sclerosis. Brain Pathol 2007;17:129-38.
55. Lagumersindez-Denis N, Wrzos C, Mack M, Winkler A, van der Meer F, et al. Differential contribution of immune effector mechanisms to cortical demyelination in multiple sclerosis. Acta Neuropathol 2017;134:15-34.
56. Kooi EJ, Strijbis EM, van der Valk P, Geurts JJ. Heterogeneity of cortical lesions in multiple sclerosis: clinical and pathologic implications. Neurology 2012;79:1369-76.
57. Magliozzi R, Serafini B, Rosicarelli B, Chiappetta G, Veroni C, et al. B-cell enrichment and Epstein-Barr virus infection in inflammatory cortical lesions in secondary progressive multiple sclerosis. J Neuropathol Exp Neurol 2013;72:29-41.
58. Howell OW, Schulz-Trieglaff EK, Carassiti D, Gentleman SM, Nicholas R, et al. Extensive grey matter pathology in the cerebellum in multiple sclerosis is linked to inflammation in the subarachnoid space. Neuropathol Appl Neurobiol 2015;41:798-813.
59. Nelson F, Datta S, Garcia N, Rozario NL, Perez F, et al. Intracortical lesions by 3T magnetic resonance imaging and correlation with cognitive impairment in multiple sclerosis. Mult Scler 2011;17:1122-9.
60. Sethi V, Yousry TA, Muhlert N, Ron M, Golay X, et al. Improved detection of cortical MS lesions with phase-sensitive inversion recovery MRI. J Neurol Neurosurg Psychiatry 2012;83:877-82.
61. Crespy L, Zaaraoui W, Lemaire M, Rico A, Faivre A, et al. Prevalence of grey matter pathology in early multiple sclerosis assessed by magnetization transfer ratio imaging. PLoS One 2011;6:e24969.
62. Rovaris M, Judica E, Ceccarelli A, Ghezzi A, Martinelli V, et al. A 3-year diffusion tensor MRI study of grey matter damage progression during the earliest clinical stage of MS. J Neurol 2008;255:1209-14.
63. Beck ES, Sati P, Sethi V, Kober T, Dewey B, et al. Improved visualization of cortical lesions in multiple sclerosis using 7T MP2RAGE. AJNR Am J Neuroradiol 2018;39:459-66.
64. Nelson F, Poonawalla A, Hou P, Wolinsky JS, Narayana PA. 3D MPRAGE improves classification of cortical lesions in multiple sclerosis. Mult Scler 2008;14:1214-9.
65. Kilsdonk ID, Jonkman LE, Klaver R, van Veluw SJ, Zwanenburg JJ, et al. Increased cortical grey matter lesion detection in multiple sclerosis with 7 T MRI: a post-mortem verification study. Brain 2016;139:1472-81.
66. Mainero C, Benner T, Radding A, van der Kouwe A, Jensen R, et al. In vivo imaging of cortical pathology in multiple sclerosis using ultra-high field MRI. Neurology 2009;73:941-8.
67. Geurts JJ, Roosendaal SD, Calabrese M, Ciccarelli O, Agosta F, et al; MAGNIMS Study Group. Consensus recommendations for MS cortical lesion scoring using double inversion recovery MRI. Neurology 2011;76:418-24.
68. Herranz E, Louapre C, Treaba CA, Govindarajan ST, Ouellette R, et al. Profiles of cortical inflammation in multiple sclerosis by 11C-PBR28 MR-PET and 7 Tesla imaging. Mult Scler 2019;1352458519867320.
69. Harrison DM, Roy S, Oh J, Izbudak I, Pham D, et al. Association of cortical lesion burden on 7-T magnetic resonance imaging with cognition and disability in multiple sclerosis. JAMA Neurol 2015;72:1004-12.
70. Nielsen AS, Kinkel RP, Madigan N, Tinelli E, Benner T, et al. Contribution of cortical lesion subtypes at 7T MRI to physical and cognitive performance in MS. Neurology 2013;81:641-9.
71. Walsh M, Montojo CA, Sheu YS, Marchette SA, Harrison DM, et al. Object working memory performance depends on microstructure of the frontal-occipital fasciculus. Brain Connect 2011;1:317-29.
72. Kivisäkk P, Imitola J, Rasmussen S, Elyaman W, Zhu B, et al. Localizing central nervous system immune surveillance: meningeal antigen-presenting cells activate T cells during experimental autoimmune encephalomyelitis. Ann Neurol 2009;65:457-69.
73. Reboldi A, Coisne C, Baumjohann D, Benvenuto F, Bottinelli D, et al. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol 2009;10:514-23.
74. Marik C, Felts PA, Bauer J, Lassmann H, Smith KJ. Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain 2007;130:2800-15.
75. Henderson AP, Barnett MH, Parratt JD, Prineas JW. Multiple sclerosis: distribution of inflammatory cells in newly forming lesions. Ann Neurol 2009;66:739-53.
76. Maranzano J, Rudko DA, Nakamura K, Cook S, Cadavid D, et al. MRI evidence of acute inflammation in leukocortical lesions of patients with early multiple sclerosis. Neurology 2017;89:714-21.
77. Kuhlmann T, Ludwin S, Prat A, Antel J, Brück W, et al. An updated histological classification system for multiple sclerosis lesions. Acta Neuropathol 2017;133:13-24.
78. van Wageningen TA, Vlaar E, Kooij G, Jongenelen CAM, Geurts JJG, et al. Regulation of microglial TMEM119 and P2RY12 immunoreactivity in multiple sclerosis white and grey matter lesions is dependent on their inflammatory environment. Acta Neuropathol Commun 2019;7:206.
79. Peferoen LA, Gerritsen WH, Breur M, Ummenthum KM, Peferoen-Baert RM, et al. Small heat shock proteins are induced during multiple sclerosis lesion development in white but not grey matter. Acta Neuropathol Commun 2015;3:87.
80. Schirmer L, Velmeshev D, Holmqvist S, Kaufmann M, Werneburg S, et al. Neuronal vulnerability and multilineage diversity in multiple sclerosis. Nature 2019;573:75-82.
81. Popescu BF, Pirko I, Lucchinetti CF. Pathology of multiple sclerosis: where do we stand? Continuum (Minneap Minn) 2013;19:901-21.
82. Davalos D, Ryu JK, Merlini M, Baeten KM, Le Moan N, et al. Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation. Nat Commun 2012;3:1227.
83. Lee NJ, Ha SK, Sati P, Absinta M, Luciano NJ, et al. Spatiotemporal distribution of fibrinogen in marmoset and human inflammatory demyelination. Brain 2018;141:1637-49.
84. Ryu JK, Petersen MA, Murray SG, Baeten KM, Meyer-Franke A, et al. Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation. Nat Commun 2015;6:8164.
85. Yates RL, Esiri MM, Palace J, Jacobs B, Perera R, et al. Fibrin(ogen) and neurodegeneration in the progressive multiple sclerosis cortex. Ann Neurol 2017;82:259-70.
86. Magliozzi R, Hametner S, Facchiano F, Marastoni D, Rossi S, et al. Iron homeostasis, complement, and coagulation cascade as CSF signature of cortical lesions in early multiple sclerosis. Ann Clin Transl Neurol 2019;6:2150-63.
87. Davalos D, Mahajan KR, Trapp BD. Brain fibrinogen deposition plays a key role in MS pathophysiology - Yes. Mult Scler 2019;25:1434-5.
88. Bevan RJ, Evans R, Griffiths L, Watkins LM, Rees MI, et al. Meningeal inflammation and cortical demyelination in acute multiple sclerosis. Ann Neurol 2018;84:829-42.
89. Griffiths L, Reynolds R, Evans R, Bevan RJ, Rees MI, et al. Substantial subpial cortical demyelination in progressive multiple sclerosis: have we underestimated the extent of cortical pathology? Neuroimmunol Neuroinflammation 2020;7:51-67.
90. Calabrese M, Gallo P. Magnetic resonance evidence of cortical onset of multiple sclerosis. Mult Scler 2009;15:933-41.
91. Trapp BD, Vignos M, Dudman J, Chang A, Fisher E, et al. Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study. Lancet Neurol 2018;17:870-84.
92. Magliozzi R, Howell OW, Durrenberger P, Aricò E, James R, et al. Meningeal inflammation changes the balance of TNF signalling in cortical grey matter in multiple sclerosis. J Neuroinflammation 2019;16:259.
93. Choi SR, Howell OW, Carassiti D, Magliozzi R, Gveric D, et al. Meningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis. Brain 2012;135:2925-37.
94. Howell OW, Reeves CA, Nicholas R, Carassiti D, Radotra B, et al. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain 2011;134:2755-71.
95. Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol 2004;14:164-74.
96. Farina G, Magliozzi R, Pitteri M, Reynolds R, Rossi S, et al. Increased cortical lesion load and intrathecal inflammation is associated with oligoclonal bands in multiple sclerosis patients: a combined CSF and MRI study. J Neuroinflammation 2017;14:40.
97. Junker A, Wozniak J, Voigt D, Scheidt U, Antel J, et al. Extensive subpial cortical demyelination is specific to multiple sclerosis. Brain Pathol 2020;30:641-52.
98. Moll NM, Rietsch AM, Ransohoff AJ, Cossoy MB, Huang D, et al. Cortical demyelination in PML and MS: Similarities and differences. Neurology 2008;70:336-43.
99. Höftberger R, Guo Y, Flanagan EP, Lopez-Chiriboga AS, Endmayr V, et al. The pathology of central nervous system inflammatory demyelinating disease accompanying myelin oligodendrocyte glycoprotein autoantibody. Acta Neuropathol 2020;139:875-92.
100. Androdias G, Reynolds R, Chanal M, Ritleng C, Confavreux C, et al. Meningeal T cells associate with diffuse axonal loss in multiple sclerosis spinal cords. Ann Neurol 2010;68:465-76.
101. Calabrese M, Agosta F, Rinaldi F, Mattisi I, Grossi P, et al. Cortical lesions and atrophy associated with cognitive impairment in relapsing-remitting multiple sclerosis. Arch Neurol 2009;66:1144-50.
102. Roosendaal SD, Moraal B, Pouwels PJ, Vrenken H, Castelijns JA, et al. Accumulation of cortical lesions in MS: relation with cognitive impairment. Mult Scler 2009;15:708-14.
103. Kooi EJ, Geurts JJ, van Horssen J, Bø L, van der Valk P. Meningeal inflammation is not associated with cortical demyelination in chronic multiple sclerosis. J Neuropathol Exp Neurol 2009;68:1021-8.
104. Pikor NB, Prat A, Bar-Or A, Gommerman JL. Meningeal tertiary lymphoid tissues and multiple sclerosis: a gathering place for diverse types of immune cells during CNS autoimmunity. Front Immunol 2015;6:657.
105. Krumbholz M, Theil D, Cepok S, Hemmer B, Kivisäkk P, et al. Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment. Brain 2006;129:200-11.
106. Krumbholz M, Theil D, Derfuss T, Rosenwald A, Schrader F, et al. BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma. J Exp Med 2005;201:195-200.
107. Magliozzi R, Columba-Cabezas S, Serafini B, Aloisi F. Intracerebral expression of CXCL13 and BAFF is accompanied by formation of lymphoid follicle-like structures in the meninges of mice with relapsing experimental autoimmune encephalomyelitis. J Neuroimmunol 2004;148:11-23.
108. Ragheb S, Li Y, Simon K, Vanhaerents S, Galimberti D, et al. Multiple sclerosis: BAFF and CXCL13 in cerebrospinal fluid. Mult Scler 2011;17:819-29.
109. Gardner C, Magliozzi R, Durrenberger PF, Howell OW, Rundle J, et al. Cortical grey matter demyelination can be induced by elevated pro-inflammatory cytokines in the subarachnoid space of MOG-immunized rats. Brain 2013;136:3596-608.
110. Merkler D, Ernsting T, Kerschensteiner M, Brück W, Stadelmann C. A new focal EAE model of cortical demyelination: multiple sclerosis-like lesions with rapid resolution of inflammation and extensive remyelination. Brain 2006;129:1972-83.
111. Pikor NB, Astarita JL, Summers-Deluca L, Galicia G, Qu J, et al. Integration of Th17- and lymphotoxin-derived signals initiates meningeal-resident stromal cell remodeling to propagate neuroinflammation. Immunity 2015;43:1160-73.
112. Magliozzi R, Howell OW, Nicholas R, Cruciani C, Castellaro M, et al. Inflammatory intrathecal profiles and cortical damage in multiple sclerosis. Ann Neurol 2018;83:739-55.
113. Peters A, Pitcher LA, Sullivan JM, Mitsdoerffer M, Acton SE, et al. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity 2011;35:986-96.
114. Ward LA, Lee DS, Sharma A, Wang A, Naouar I, et al. Siponimod therapy implicates Th17 cells in a preclinical model of subpial cortical injury. JCI Insight 2020;5:132522.
115. Harrison DM, Wang KY, Fiol J, Naunton K, Royal W 3rd, et al. Leptomeningeal Enhancement at 7T in Multiple Sclerosis: Frequency, Morphology, and Relationship to Cortical Volume. J Neuroimaging 2017;27:461-8.
116. Ighani M, Jonas S, Izbudak I, Choi S, Lema-Dopico A, et al. No association between cortical lesions and leptomeningeal enhancement on 7-Tesla MRI in multiple sclerosis. Mult Scler 2020;26:165-76.
117. Zurawski J, Tauhid S, Chu R, Khalid F, Healy BC, et al. 7T MRI cerebral leptomeningeal enhancement is common in relapsing-remitting multiple sclerosis and is associated with cortical and thalamic lesions. Mult Scler 2020;26:177-87.
118. Absinta M, Vuolo L, Rao A, Nair G, Sati P, et al. Gadolinium-based MRI characterization of leptomeningeal inflammation in multiple sclerosis. Neurology 2015;85:18-28.
119. Zivadinov R, Ramasamy DP, Vaneckova M, Gandhi S, Chandra A, et al. Leptomeningeal contrast enhancement is associated with progression of cortical atrophy in MS: a retrospective, pilot, observational longitudinal study. Mult Scler 2017;23:1336-45.
120. Absinta M, Cortese IC, Vuolo L, Nair G, de Alwis MP, et al. Leptomeningeal gadolinium enhancement across the spectrum of chronic neuroinflammatory diseases. Neurology 2017;88:1439-44.
121. James RE, Schalks R, Browne E, Eleftheriadou I, Munoz CP, et al. Persistent elevation of intrathecal pro-inflammatory cytokines leads to multiple sclerosis-like cortical demyelination and neurodegeneration. Acta Neuropathol Commun 2020;8:66.
122. Lisak RP, Nedelkoska L, Studzinski D, Bealmear B, Xu W, et al. Cytokines regulate neuronal gene expression: differential effects of Th1, Th2 and monocyte/macrophage cytokines. J Neuroimmunol 2011;238:19-33.
123. Üçal M, Haindl MT, Adzemovic MZ, Strasser J, Theisl L, et al. Widespread cortical demyelination of both hemispheres can be induced by injection of pro-inflammatory cytokines via an implanted catheter in the cortex of MOG-immunized rats. Exp Neurol 2017;294:32-44.
124. Silva BA, Leal MC, Farías MI, Avalos JC, Besada CH, et al. A new focal model resembling features of cortical pathology of the progressive forms of multiple sclerosis: Influence of innate immunity. Brain Behav Immun 2018;69:515-31.
125. Correale J. The role of microglial activation in disease progression. Mult Scler 2014;20:1288-95.
126. Correale J, Farez MF. The role of astrocytes in multiple sclerosis progression. Front Neurol 2015;6:180.
127. Lisak RP, Benjamins JA, Nedelkoska L, Barger JL, Ragheb S, et al. Secretory products of multiple sclerosis B cells are cytotoxic to oligodendroglia in vitro. J Neuroimmunol 2012;246:85-95.
128. Lisak RP, Nedelkoska L, Benjamins JA, Schalk D, Bealmear B, et al. B cells from patients with multiple sclerosis induce cell death via apoptosis in neurons in vitro. J Neuroimmunol 2017;309:88-99.
129. Benjamins JA, Nedelkoska L, Touil H, Stemmer PM, Carruthers NJ, et al. Exosome-enriched fractions from MS B cells induce oligodendrocyte death. Neurol Neuroimmunol Neuroinflamm 2019;6:e550.
130. Selmaj I, Cichalewska M, Namiecinska M, Galazka G, Horzelski W, et al. Global exosome transcriptome profiling reveals biomarkers for multiple sclerosis. Ann Neurol 2017;81:703-17.
131. Basso M, Bonetto V. Extracellular vesicles and a novel form of communication in the brain. Front Neurosci 2016;10:127.
132. Robbins PD, Morelli AE. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol 2014;14:195-208.
133. Ebrahimkhani S, Vafaee F, Young PE, Hur SSJ, Hawke S, et al. Exosomal microRNA signatures in multiple sclerosis reflect disease status. Sci Rep 2017;7:14293.
134. Pieragostino D, Cicalini I, Lanuti P, Ercolino E, di Ioia M, et al. Enhanced release of acid sphingomyelinase-enriched exosomes generates a lipidomics signature in CSF of Multiple Sclerosis patients. Sci Rep 2018;8:3071.
135. Vidaurre OG, Haines JD, Katz Sand I, Adula KP, Huynh JL, et al. Cerebrospinal fluid ceramides from patients with multiple sclerosis impair neuronal bioenergetics. Brain 2014;137:2271-86.
136. Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 2008;319:1244-7.
137. Serafini B, Rosicarelli B, Veroni C, Mazzola GA, Aloisi F. Epstein-Barr virus-specific CD8 T cells selectively infiltrate the brain in multiple sclerosis and interact locally with virus-infected cells: clue for a virus-driven immunopathological mechanism. J Virol 2019;93:e00980-19.
138. Kaskow BJ, Baecher-Allan C. Effector T cells in multiple sclerosis. Cold Spring Harb Perspect Med 2018;8:a029025.
139. Lisak RP, Benjamins JA, Bealmear B, Nedelkoska L, Studzinski D, et al. Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for molecules associated with metabolism, signaling and regulation in central nervous system mixed glial cell cultures. J Neuroinflammation 2009;6:4.
140. Lisak RP, Benjamins JA, Bealmear B, Nedelkoska L, Yao B, et al. Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for glial and neural-related molecules in central nervous system mixed glial cell cultures: neurotrophins, growth factors and structural proteins. J Neuroinflammation 2007;4:30.
141. Lisak RP, Benjamins JA, Bealmear B, Yao B, Land S, et al. Differential effects of Th1, monocyte/macrophage and Th2 cytokine mixtures on early gene expression for immune-related molecules by central nervous system mixed glial cell cultures. Mult Scler 2006;12:149-68.
142. Haider L, Fischer MT, Frischer JM, Bauer J, Höftberger R, et al. Oxidative damage in multiple sclerosis lesions. Brain 2011;134:1914-24.
143. Gray E, Thomas TL, Betmouni S, Scolding N, Love S. Elevated activity and microglial expression of myeloperoxidase in demyelinated cerebral cortex in multiple sclerosis. Brain Pathol 2008;18:86-95.
144. Nikić I, Merkler D, Sorbara C, Brinkoetter M, Kreutzfeldt M, et al. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med 2011;17:495-9.
145. Vercellino M, Merola A, Piacentino C, Votta B, Capello E, et al. Altered glutamate reuptake in relapsing-remitting and secondary progressive multiple sclerosis cortex: correlation with microglia infiltration, demyelination, and neuronal and synaptic damage. J Neuropathol Exp Neurol 2007;66:732-9.
146. Mayo L, Trauger SA, Blain M, Nadeau M, Patel B, et al. Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat Med 2014;20:1147-56.
147. Quintana FJ. Astrocytes play a crucial role in the formation and evolution of MS lesions - Commentary. Mult Scler 2019;25:19-20.
148. Chao CC, Gutiérrez-Vázquez C, Rothhammer V, Mayo L, Wheeler MA, et al. Metabolic control of astrocyte pathogenic activity via cPLA2-MAVS. Cell 2019;179:1483-98.e22.
149. Wheeler MA, Clark IC, Tjon EC, Li Z, Zandee SEJ, et al. MAFG-driven astrocytes promote CNS inflammation. Nature 2020;578:593-9.
150. Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mörk S, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med 1998;338:278-85.
151. Carassiti D, Altmann DR, Petrova N, Pakkenberg B, Scaravilli F, et al. Neuronal loss, demyelination and volume change in the multiple sclerosis neocortex. Neuropathol Appl Neurobiol 2018;44:377-90.
152. Jurkiewicz MT, Crawley AP, Verrier MC, Fehlings MG, Mikulis DJ. Somatosensory cortical atrophy after spinal cord injury: a voxel-based morphometry study. Neurology 2006;66:762-4.
153. Sepulcre J, Goñi J, Masdeu JC, Bejarano B, Vélez de Mendizábal N, et al. Contribution of white matter lesions to gray matter atrophy in multiple sclerosis: evidence from voxel-based analysis of T1 lesions in the visual pathway. Arch Neurol 2009;66:173-9.
154. Fisher E, Lee JC, Nakamura K, Rudick RA. Gray matter atrophy in multiple sclerosis: a longitudinal study. Ann Neurol 2008;64:255-65.
156. Nave KA, Trapp BD. Axon-glial signaling and the glial support of axon function. Annu Rev Neurosci 2008;31:535-61.
157. Trapp BD, Stys PK. Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol 2009;8:280-91.
158. Watkins LM, Neal JW, Loveless S, Michailidou I, Ramaglia V, et al. Complement is activated in progressive multiple sclerosis cortical grey matter lesions. J Neuroinflammation 2016;13:161.
159. Brink BP, Veerhuis R, Breij EC, van der Valk P, Dijkstra CD, et al. The pathology of multiple sclerosis is location-dependent: no significant complement activation is detected in purely cortical lesions. J Neuropathol Exp Neurol 2005;64:147-55.
160. Campbell GR, Ziabreva I, Reeve AK, Krishnan KJ, Reynolds R, et al. Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann Neurol 2011;69:481-92.
161. Cristofanilli M, Rosenthal H, Cymring B, Gratch D, Pagano B, et al. Progressive multiple sclerosis cerebrospinal fluid induces inflammatory demyelination, axonal loss, and astrogliosis in mice. Exp Neurol 2014;261:620-32.
162. Zrzavy T, Hametner S, Wimmer I, Butovsky O, Weiner HL, et al. Loss of ‘homeostatic’ microglia and patterns of their activation in active multiple sclerosis. Brain 2017;140:1900-13.
163. Fischer MT, Sharma R, Lim JL, Haider L, Frischer JM, et al. NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain 2012;135:886-99.
164. Correale J, Gaitán MI, Ysrraelit MC, Fiol MP. Progressive multiple sclerosis: from pathogenic mechanisms to treatment. Brain 2017;140:527-46.
166. Campbell GR, Kraytsberg Y, Krishnan KJ, Ohno N, Ziabreva I, et al. Clonally expanded mitochondrial DNA deletions within the choroid plexus in multiple sclerosis. Acta Neuropathol 2012;124:209-20.
167. Campbell GR, Worrall JT, Mahad DJ. The central role of mitochondria in axonal degeneration in multiple sclerosis. Mult Scler 2014;20:1806-13.
168. Touil H, Kobert A, Lebeurrier N, Rieger A, Saikali P, et al; Canadian B Cell Team in MS. Human central nervous system astrocytes support survival and activation of B cells: implications for MS pathogenesis. J Neuroinflammation 2018;15:114.
169. Michel L, Touil H, Pikor NB, Gommerman JL, Prat A, et al. B cells in the multiple sclerosis central nervous system: trafficking and contribution to CNS-compartmentalized inflammation. Front Immunol 2015;6:636.
170. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, et al; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2017;376:221-34.
171. Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, et al; ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017;376:209-20.
172. Cross AH, Stark JL, Lauber J, Ramsbottom MJ, Lyons JA. Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol 2006;180:63-70.
173. Petereit HF, Moeller-Hartmann W, Reske D, Rubbert A. Rituximab in a patient with multiple sclerosis--effect on B cells, plasma cells and intrathecal IgG synthesis. Acta Neurol Scand 2008;117:399-403.
174. Bhargava P, Wicken C, Smith MD, Strowd RE, Cortese I, et al. Trial of intrathecal rituximab in progressive multiple sclerosis patients with evidence of leptomeningeal contrast enhancement. Mult Scler Relat Disord 2019;30:136-40.
175. Greenfield AL, Hauser SL. B-cell therapy for multiple sclerosis: entering an era. Ann Neurol 2018;83:13-26.
176. Kappos L, Bar-or A, Cree BAC, Fox RJ, Giovannoni G, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet 2018;391:1263-73.
177. Gentile A, Musella A, Bullitta S, Fresegna D, De Vito F, et al. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J Neuroinflammation 2016;13:207.
178. Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, et al; CLARITY Study Group. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 2010;362:416-26.
179. Rice GP, Filippi M, Comi G. Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Cladribine MRI Study Group. Neurology 2000;54:1145-55.
180. Jørgensen LØ, Hyrlov KH, Elkjaer ML, Weber AB, Pedersen AE, et al. Cladribine modifies functional properties of microglia. Clin Exp Immunol 2020;201:328-40.
181. Musella A, Mandolesi G, Gentile A, Rossi S, Studer V, et al. Cladribine interferes with IL-1β synaptic effects in experimental multiple sclerosis. J Neuroimmunol 2013;264:8-13.
182. Beutler E, Sipe JC, Romine JS, Koziol JA, McMillan R, et al. The treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci U S A 1996;93:1716-20.
183. Sipe JC, Romine JS, Koziol JA, McMillan R, Zyroff J, et al. Cladribine in treatment of chronic progressive multiple sclerosis. Lancet 1994;344:9-13.
184. Lubetzki C, Zalc B, Williams A, Stadelmann C, Stankoff B. Remyelination in multiple sclerosis: from basic science to clinical translation. Lancet Neurol 2020;19:678-88.
185. Villoslada P, Steinman L. New targets and therapeutics for neuroprotection, remyelination and repair in multiple sclerosis. Expert Opin Investig Drugs 2020;29:443-59.
186. Calabrese M, De Stefano N, Atzori M, Bernardi V, Mattisi I, et al. Detection of cortical inflammatory lesions by double inversion recovery magnetic resonance imaging in patients with multiple sclerosis. Arch Neurol 2007;64:1416-22.
187. Calabrese M, Rocca MA, Atzori M, Mattisi I, Bernardi V, et al. Cortical lesions in primary progressive multiple sclerosis: a 2-year longitudinal MR study. Neurology 2009;72:1330-6.
188. Calabrese M, Rocca MA, Atzori M, Mattisi I, Favaretto A, et al. A 3-year magnetic resonance imaging study of cortical lesions in relapse-onset multiple sclerosis. Ann Neurol 2010;67:376-83.
189. Bagnato F, Salman Z, Kane R, Auh S, Cantor FK, et al. T1 cortical hypointensities and their association with cognitive disability in multiple sclerosis. Mult Scler 2010;16:1203-12.
190. Mike A, Glanz BI, Hildenbrand P, Meier D, Bolden K, et al. Identification and clinical impact of multiple sclerosis cortical lesions as assessed by routine 3T MR imaging. AJNR Am J Neuroradiol 2011;32:515-21.
191. Kolber P, Montag S, Fleischer V, Luessi F, Wilting J, et al. Identification of cortical lesions using DIR and FLAIR in early stages of multiple sclerosis. J Neurol 2015;262:1473-82.
192. Geisseler O, Pflugshaupt T, Bezzola L, Reuter K, Weller D, et al. The relevance of cortical lesions in patients with multiple sclerosis. BMC Neurol 2016;16:204.
