Inflammatory intrathecal profiles and cortical damage in multiple sclerosis

R. Magliozzi, O.W. Howell, R. Nicholas, C. Cruciani, M. Castellaro, C. Romualdi, S. Rossi, M. Pitteri, M.D. Benedetti, A. Gajofatto, F.B. Pizzini, S. Montemezzi, S. Rasia, R. Capra, A. Bertoldo, F. Facchiano, S. Monaco, R. Reynolds, M. Calabrese

Research output: Contribution to journalArticle

Abstract

Objective: Gray matter (GM) damage and meningeal inflammation have been associated with early disease onset and a more aggressive disease course in multiple sclerosis (MS), but can these changes be identified in the patient early in the disease course?. Methods: To identify possible biomarkers linking meningeal inflammation, GM damage, and disease severity, gene and protein expression were analyzed in meninges and cerebrospinal fluid (CSF) from 27 postmortem secondary progressive MS and 14 control cases. Combined cytokine/chemokine CSF profiling and 3T magnetic resonance imaging (MRI) were performed at diagnosis in 2 independent cohorts of MS patients (35 and 38 subjects) and in 26 non-MS patients. Results: Increased expression of proinflammatory cytokines (IFNγ, TNF, IL2, and IL22) and molecules related to sustained B-cell activity and lymphoid-neogenesis (CXCL13, CXCL10, LTα, IL6, and IL10) was detected in the meninges and CSF of postmortem MS cases with high levels of meningeal inflammation and GM demyelination. Similar proinflammatory patterns, including increased levels of CXCL13, TNF, IFNγ, CXCL12, IL6, IL8, and IL10, together with high levels of BAFF, APRIL, LIGHT, TWEAK, sTNFR1, sCD163, MMP2, and pentraxin III, were detected in the CSF of MS patients with higher levels of GM damage at diagnosis. Interpretation: A common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at the time of diagnosis and at death. These results suggest a role for detailed CSF analysis combined with MRI as a prognostic marker for more aggressive MS. Ann Neurol 2018 Ann Neurol 2018;83:739–755. © 2018 American Neurological Association
Original languageEnglish
Pages (from-to)739-755
Number of pages17
JournalAnnals of Neurology
Volume83
Issue number4
DOIs
Publication statusPublished - 2018

Fingerprint

Multiple Sclerosis
Cerebrospinal Fluid
Meninges
Inflammation
Interleukin-10
Interleukin-6
Magnetic Resonance Imaging
Chronic Progressive Multiple Sclerosis
Cytokines
Demyelinating Diseases
Sclerosis
Interleukin-8
Chemokines
Interleukin-2
B-Lymphocytes
Biomarkers
Pathology
Gene Expression
Light
Gray Matter

Keywords

  • APRIL protein
  • B cell activating factor
  • biological marker
  • CD163 antigen
  • CD20 antigen
  • CXCL13 chemokine
  • CXCL9 chemokine
  • gamma interferon
  • gamma interferon inducible protein 10
  • gelatinase A
  • interleukin 10
  • interleukin 2
  • interleukin 22
  • interleukin 6
  • myelin oligodendrocyte glycoprotein
  • pentraxin 3
  • tumor necrosis factor
  • adult
  • aged
  • Article
  • autopsy
  • B lymphocyte
  • brain cortex lesion
  • cerebrovascular disease
  • controlled study
  • degenerative disease
  • demyelination
  • disease course
  • disease severity
  • electrochemiluminescence
  • Expanded Disability Status Scale
  • female
  • gene expression
  • headache
  • human
  • human tissue
  • male
  • meningitis
  • middle aged
  • multiple sclerosis
  • neuropathy
  • nuclear magnetic resonance imaging
  • priority journal
  • protein analysis
  • protein cerebrospinal fluid level
  • protein expression
  • RNA extraction
  • subarachnoid space
  • very elderly
  • white matter lesion

Cite this

Magliozzi, R., Howell, O. W., Nicholas, R., Cruciani, C., Castellaro, M., Romualdi, C., ... Calabrese, M. (2018). Inflammatory intrathecal profiles and cortical damage in multiple sclerosis. Annals of Neurology, 83(4), 739-755. https://doi.org/10.1002/ana.25197

Inflammatory intrathecal profiles and cortical damage in multiple sclerosis. / Magliozzi, R.; Howell, O.W.; Nicholas, R.; Cruciani, C.; Castellaro, M.; Romualdi, C.; Rossi, S.; Pitteri, M.; Benedetti, M.D.; Gajofatto, A.; Pizzini, F.B.; Montemezzi, S.; Rasia, S.; Capra, R.; Bertoldo, A.; Facchiano, F.; Monaco, S.; Reynolds, R.; Calabrese, M.

In: Annals of Neurology, Vol. 83, No. 4, 2018, p. 739-755.

Research output: Contribution to journalArticle

Magliozzi, R, Howell, OW, Nicholas, R, Cruciani, C, Castellaro, M, Romualdi, C, Rossi, S, Pitteri, M, Benedetti, MD, Gajofatto, A, Pizzini, FB, Montemezzi, S, Rasia, S, Capra, R, Bertoldo, A, Facchiano, F, Monaco, S, Reynolds, R & Calabrese, M 2018, 'Inflammatory intrathecal profiles and cortical damage in multiple sclerosis', Annals of Neurology, vol. 83, no. 4, pp. 739-755. https://doi.org/10.1002/ana.25197
Magliozzi R, Howell OW, Nicholas R, Cruciani C, Castellaro M, Romualdi C et al. Inflammatory intrathecal profiles and cortical damage in multiple sclerosis. Annals of Neurology. 2018;83(4):739-755. https://doi.org/10.1002/ana.25197
Magliozzi, R. ; Howell, O.W. ; Nicholas, R. ; Cruciani, C. ; Castellaro, M. ; Romualdi, C. ; Rossi, S. ; Pitteri, M. ; Benedetti, M.D. ; Gajofatto, A. ; Pizzini, F.B. ; Montemezzi, S. ; Rasia, S. ; Capra, R. ; Bertoldo, A. ; Facchiano, F. ; Monaco, S. ; Reynolds, R. ; Calabrese, M. / Inflammatory intrathecal profiles and cortical damage in multiple sclerosis. In: Annals of Neurology. 2018 ; Vol. 83, No. 4. pp. 739-755.
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title = "Inflammatory intrathecal profiles and cortical damage in multiple sclerosis",
abstract = "Objective: Gray matter (GM) damage and meningeal inflammation have been associated with early disease onset and a more aggressive disease course in multiple sclerosis (MS), but can these changes be identified in the patient early in the disease course?. Methods: To identify possible biomarkers linking meningeal inflammation, GM damage, and disease severity, gene and protein expression were analyzed in meninges and cerebrospinal fluid (CSF) from 27 postmortem secondary progressive MS and 14 control cases. Combined cytokine/chemokine CSF profiling and 3T magnetic resonance imaging (MRI) were performed at diagnosis in 2 independent cohorts of MS patients (35 and 38 subjects) and in 26 non-MS patients. Results: Increased expression of proinflammatory cytokines (IFNγ, TNF, IL2, and IL22) and molecules related to sustained B-cell activity and lymphoid-neogenesis (CXCL13, CXCL10, LTα, IL6, and IL10) was detected in the meninges and CSF of postmortem MS cases with high levels of meningeal inflammation and GM demyelination. Similar proinflammatory patterns, including increased levels of CXCL13, TNF, IFNγ, CXCL12, IL6, IL8, and IL10, together with high levels of BAFF, APRIL, LIGHT, TWEAK, sTNFR1, sCD163, MMP2, and pentraxin III, were detected in the CSF of MS patients with higher levels of GM damage at diagnosis. Interpretation: A common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at the time of diagnosis and at death. These results suggest a role for detailed CSF analysis combined with MRI as a prognostic marker for more aggressive MS. Ann Neurol 2018 Ann Neurol 2018;83:739–755. {\circledC} 2018 American Neurological Association",
keywords = "APRIL protein, B cell activating factor, biological marker, CD163 antigen, CD20 antigen, CXCL13 chemokine, CXCL9 chemokine, gamma interferon, gamma interferon inducible protein 10, gelatinase A, interleukin 10, interleukin 2, interleukin 22, interleukin 6, myelin oligodendrocyte glycoprotein, pentraxin 3, tumor necrosis factor, adult, aged, Article, autopsy, B lymphocyte, brain cortex lesion, cerebrovascular disease, controlled study, degenerative disease, demyelination, disease course, disease severity, electrochemiluminescence, Expanded Disability Status Scale, female, gene expression, headache, human, human tissue, male, meningitis, middle aged, multiple sclerosis, neuropathy, nuclear magnetic resonance imaging, priority journal, protein analysis, protein cerebrospinal fluid level, protein expression, RNA extraction, subarachnoid space, very elderly, white matter lesion",
author = "R. Magliozzi and O.W. Howell and R. Nicholas and C. Cruciani and M. Castellaro and C. Romualdi and S. Rossi and M. Pitteri and M.D. Benedetti and A. Gajofatto and F.B. Pizzini and S. Montemezzi and S. Rasia and R. Capra and A. Bertoldo and F. Facchiano and S. Monaco and R. Reynolds and M. Calabrese",
note = "Cited By :12 Export Date: 11 April 2019 CODEN: ANNED Correspondence Address: Reynolds, R.; Division of Brain Sciences, Department of Medicine, Imperial College LondonUnited Kingdom; email: r.reynolds@imperial.ac.uk Chemicals/CAS: gamma interferon, 82115-62-6; gamma interferon inducible protein 10, 97741-20-3; gelatinase A, 146480-35-5; interleukin 2, 85898-30-2; interleukin 22, 457106-70-6, 478219-35-1, 554460-75-2 Funding details: FISM 16/17/F14, GR-2013-02-355322 Funding details: PA 0124 Funding details: Multiple Sclerosis Society Funding details: 007/14 Funding details: GR-2010-2313255 Funding details: National Space Biomedical Research Institute Funding text 1: R.M. was supported by the Italian Ministry of Health (GR-2010-2313255) and Italian MS Foundation (FISM 16/17/F14). M.Cal. was supported by the Italian Ministry of Health (GR-2013-02-355322). R.R. and R.N. were supported by the MS Society (the UK MS Society Tissue Bank, grant 007/14) and Imperial College National Institute for Health Research Biomedical Research Centre. This study was specifically supported by a Progressive Multiple Sclerosis Alliance grant (PA 0124) to M.Cal., R.R., and O.W.H. References: Graumann, U., Reynolds, R., Steck, A.J., Schaeren-Wiemers, N., Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult (2003) Brain Pathol, 13, pp. 554-573; Howell, O.W., Rundle, J.L., Garg, A., Activated microglia mediate axoglial disruption that contributes to axonal injury in multiple sclerosis (2010) J Neuropathol Exp Neurol, 69, pp. 1017-1033; Kutzelnigg, A., Lucchinetti, C.F., Stadelmann, C., Cortical demyelination and diffuse white matter injury in multiple sclerosis (2005) Brain, 128, pp. 2705-2712; Chard, D., Miller, D., Grey matter pathology in clinically early multiple sclerosis: evidence from magnetic resonance imaging (2009) J Neurol Sci, 282, pp. 5-11; Magliozzi, R., Howell, O.W., Reeves, C., A gradient of neuronal loss and meningeal inflammation in multiple sclerosis (2010) Ann Neurol, 68, pp. 477-493; Howell, O.W., Reeves, C.A., Nicholas, R., Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis (2011) Brain, 134, pp. 2755-2771; Fisniku, L.K., Chard, D.T., Jackson, J.S., Gray matter atrophy is related to long-term disability in multiple sclerosis (2008) Ann Neurol, 64, pp. 247-254; Calabrese, M., Poretto, V., Favaretto, A., Cortical lesion load associates with progression of disability in multiple sclerosis (2012) Brain, 135, pp. 2952-2961; Filippi, M., van den Heuvel, M.P., Fornito, A., Assessment of system dysfunction in the brain through MRI-based connectomics (2013) Lancet Neurol, 12, pp. 1189-1199; De Stefano, N., Guidi, L., Stromillo, M.L., Imaging neuronal and axonal degeneration in multiple sclerosis (2003) Neurol Sci, 24, pp. s283-s286; Lucchinetti, C.F., Popescu, B.F., Bunyan, R.F., Inflammatory cortical demyelination in early multiple sclerosis (2011) N Engl J Med, 365, pp. 2188-2197; Serafini, B., Rosicarelli, B., Magliozzi, R., Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis (2004) Brain Pathol., 14 (2), pp. 164-174; Gardner, C., Magliozzi, R., Durrenberger, P.F., Cortical grey matter demyelination can be induced by elevated pro-inflammatory cytokines in the subarachnoid space of MOG-immunized rats (2013) Brain, 136, pp. 3596-3608; Absinta, M., Cortese, I.C.M., Vuolo, L., Leptomeningeal gadolinium enhancement across the spectrum of chronic neuroinflammatory diseases (2017) Neurology, 88, pp. 1439-1444; Haider, L., Zrzavy, T., Hametner, S., The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain (2016) Brain, 139, pp. 807-815; Magliozzi, R., Howell, O., Vora, A., Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology (2007) Brain, 130, pp. 1089-1104; Androdias, G., Reynolds, R., Chanal, M., Meningeal T cells associate with diffuse axonal loss in multiple sclerosis spinal cords (2010) Ann Neurol, 68, pp. 465-476; Howell, O.W., Schulz-Trieglaff, E.K., Carassiti, D., Extensive grey matter pathology in the cerebellum in multiple sclerosis is linked to inflammation in the subarachnoid space (2015) Neuropathol Appl Neurobiol, 41, pp. 798-813; Choi, S.R., Howell, O.W., Carassiti, D., Meningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis (2012) Brain, 135, pp. 2925-2937; Geurts, J.J., B{\"o}, L., Pouwels, P.J., Cortical lesions in multiple sclerosis: combined postmortem MR imaging and histopathology (2005) Am J Neuroradiol, 26, pp. 572-577; Seewann, A., Vrenken, H., Kooi, E.J., Imaging the tip of the iceberg: visualization of cortical lesions in multiple sclerosis (2011) Mult Scler, 17, pp. 1202-1210; Calabrese, M., De Stefano, N., Atzori, M., Detection of cortical inflammatory lesions by double inversion recovery magnetic resonance imaging in patients with multiple sclerosis (2007) Arch Neurol, 64, pp. 1416-1422; Seewann, A., Kooi, E.-J., Roosendaal, S.D., Postmortem verification of MS cortical lesion detection with 3D DIR (2012) Neurology, 78, pp. 302-308; Sethi, V., Yousry, T.A., Muhlert, N., Improved detection of cortical MS lesions with phase-sensitive inversion recovery MRI (2012) J Neurol Neurosurg Psychiatry, 83, pp. 877-882; Kilsdonk, I.D., de Graaf, W.L., Soriano, A.L., Multicontrast MR imaging at 7T in multiple sclerosis: highest lesion detection in cortical gray matter with 3D-FLAIR (2013) AJNR Am J Neuroradiol, 34, pp. 791-796; Filippi, M., Evangelou, N., Kangarlu, A., Ultra-high-field MR imaging in multiple sclerosis (2014) J Neurol Neurosurg Psychiatry, 85, pp. 60-66; Petzold, A., Steenwijk, M.D., Eikelenboom, J.M., Elevated CSF neurofilament proteins predict brain atrophy: a 15-year follow-up study (2016) Mult Scler, 22, pp. 1154-1162; Krumbholz, M., Theil, D., Cepok, S., Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment (2006) Brain, 129, pp. 200-211; Sharief, M.K., Hentges, R., Association between tumor necrosis factor-alpha and disease progression in patients with multiple sclerosis (1991) N Engl J Med, 325, pp. 467-472; Baraczka, K., N{\'e}k{\'a}m, K., Pozsonyi, T., Investigation of cytokine (tumor necrosis factor-alpha, interleukin-6, interleukin-10) concentrations in the cerebrospinal fluid of female patients with multiple sclerosis and systemic lupus erythematosus (2004) Eur J Neurol, 11, pp. 37-42; Duan, H., Luo, Y., Hao, H., Soluble CD146 in cerebrospinal fluid of active multiple sclerosis (2013) Neuroscience, 235, pp. 16-26; Lovato, L., Willis, S.N., Rodig, S.J., Related B cell clones populate the meninges and parenchyma of patients with multiple sclerosis (2011) Brain, 134, pp. 534-541; Polman, C.H., Reingold, S.C., Banwell, B., Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria (2011) Ann Neurol, 69, pp. 292-302; Durrenberger, P.F., Fernando, S., Kashefi, S.N., Effects of antemortem and postmortem variables on human brain mRNA quality: a BrainNet Europe study (2010) J Neuropathol Exp Neurol, 69, pp. 70-81; Teunissen, C.E., Petzold, A., Bennett, J.L., A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking (2009) Neurology, 73, pp. 1914-1922; Geurts, J.J., Roosendaal, S.D., Calabrese, M., Consensus recommendations for MS cortical lesion scoring using double inversion recovery MRI (2011) Neurology, 76, pp. 418-424; Pham, D.L., Prince, J.L., Adaptive fuzzy segmentation of magnetic resonance images (1999) IEEE Trans Med Imaging, 18, pp. 737-752; Avants, B.B., Tustison, N.J., Song, G., A reproducible evaluation of ANTs similarity metric performance in brain image registration (2011) Neuroimage, 54, pp. 2033-2044; Schmidt, P., Gaser, C., Arsic, M., An automated tool for detection of FLAIR-hyperintense white-matter lesions in multiple sclerosis (2012) Neuroimage, 59, pp. 3774-3783; Calabrese, M., Magliozzi, R., Ciccarelli, O., Exploring the origins of grey matter damage in multiple sclerosis (2015) Nat Rev Neurosci, 16, pp. 147-158; Peters, A., Pitcher, L.A., Sullivan, J.M., Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation (2011) Immunity, 35, pp. 986-996; Corcione, A., Casazza, S., Ferretti, E., Recapitulation of B cell differentiation in the central nervous system of patients with multiple sclerosis (2004) Proc Natl Acad Sci U S A, 101, pp. 11064-11069; Haas, J., Bekeredjian-Ding, I., Milkova, M., B cells undergo unique compartmentalized redistribution in multiple sclerosis (2011) J Autoimmun, 37, pp. 289-299; Hauser, S.L., Multiple lessons for multiple sclerosis (2008) N Engl J Med, 359, pp. 1838-1841; Kappos, L., Li, D., Calabresi, P.A., Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial (2011) Lancet, 378, pp. 1779-1787; Krumbholz, M., Theil, D., Derfuss, T., BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma (2005) J Exp Med, 201, pp. 195-200; Meinl, E., Krumbholz, M., Derfuss, T., Compartmentalization of inflammation in the CNS: a major mechanism driving progressive multiple sclerosis (2008) J Neurol Sci, 274, pp. 42-44; Zarei, M., Chandran, S., Compston, A., Hodges, J., Cognitive presentation of multiple sclerosis: evidence for a cortical variant (2003) J Neurol Neurosurg Psychiatry, 74, pp. 872-877; B{\"o}, L., Geurts, J.J., M{\"o}rk, S.J., van der Valk, P., Grey matter pathology in multiple sclerosis (2006) Acta Neurol Scand Suppl, 183, pp. 48-50; Schmierer, K., Parkes, H.G., So, P.-W., High field (9.4 Tesla) magnetic resonance imaging of cortical grey matter lesions in multiple sclerosis (2010) Brain, 133, pp. 858-867",
year = "2018",
doi = "10.1002/ana.25197",
language = "English",
volume = "83",
pages = "739--755",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "4",

}

TY - JOUR

T1 - Inflammatory intrathecal profiles and cortical damage in multiple sclerosis

AU - Magliozzi, R.

AU - Howell, O.W.

AU - Nicholas, R.

AU - Cruciani, C.

AU - Castellaro, M.

AU - Romualdi, C.

AU - Rossi, S.

AU - Pitteri, M.

AU - Benedetti, M.D.

AU - Gajofatto, A.

AU - Pizzini, F.B.

AU - Montemezzi, S.

AU - Rasia, S.

AU - Capra, R.

AU - Bertoldo, A.

AU - Facchiano, F.

AU - Monaco, S.

AU - Reynolds, R.

AU - Calabrese, M.

N1 - Cited By :12 Export Date: 11 April 2019 CODEN: ANNED Correspondence Address: Reynolds, R.; Division of Brain Sciences, Department of Medicine, Imperial College LondonUnited Kingdom; email: r.reynolds@imperial.ac.uk Chemicals/CAS: gamma interferon, 82115-62-6; gamma interferon inducible protein 10, 97741-20-3; gelatinase A, 146480-35-5; interleukin 2, 85898-30-2; interleukin 22, 457106-70-6, 478219-35-1, 554460-75-2 Funding details: FISM 16/17/F14, GR-2013-02-355322 Funding details: PA 0124 Funding details: Multiple Sclerosis Society Funding details: 007/14 Funding details: GR-2010-2313255 Funding details: National Space Biomedical Research Institute Funding text 1: R.M. was supported by the Italian Ministry of Health (GR-2010-2313255) and Italian MS Foundation (FISM 16/17/F14). M.Cal. was supported by the Italian Ministry of Health (GR-2013-02-355322). R.R. and R.N. were supported by the MS Society (the UK MS Society Tissue Bank, grant 007/14) and Imperial College National Institute for Health Research Biomedical Research Centre. This study was specifically supported by a Progressive Multiple Sclerosis Alliance grant (PA 0124) to M.Cal., R.R., and O.W.H. References: Graumann, U., Reynolds, R., Steck, A.J., Schaeren-Wiemers, N., Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult (2003) Brain Pathol, 13, pp. 554-573; Howell, O.W., Rundle, J.L., Garg, A., Activated microglia mediate axoglial disruption that contributes to axonal injury in multiple sclerosis (2010) J Neuropathol Exp Neurol, 69, pp. 1017-1033; Kutzelnigg, A., Lucchinetti, C.F., Stadelmann, C., Cortical demyelination and diffuse white matter injury in multiple sclerosis (2005) Brain, 128, pp. 2705-2712; Chard, D., Miller, D., Grey matter pathology in clinically early multiple sclerosis: evidence from magnetic resonance imaging (2009) J Neurol Sci, 282, pp. 5-11; Magliozzi, R., Howell, O.W., Reeves, C., A gradient of neuronal loss and meningeal inflammation in multiple sclerosis (2010) Ann Neurol, 68, pp. 477-493; Howell, O.W., Reeves, C.A., Nicholas, R., Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis (2011) Brain, 134, pp. 2755-2771; Fisniku, L.K., Chard, D.T., Jackson, J.S., Gray matter atrophy is related to long-term disability in multiple sclerosis (2008) Ann Neurol, 64, pp. 247-254; Calabrese, M., Poretto, V., Favaretto, A., Cortical lesion load associates with progression of disability in multiple sclerosis (2012) Brain, 135, pp. 2952-2961; Filippi, M., van den Heuvel, M.P., Fornito, A., Assessment of system dysfunction in the brain through MRI-based connectomics (2013) Lancet Neurol, 12, pp. 1189-1199; De Stefano, N., Guidi, L., Stromillo, M.L., Imaging neuronal and axonal degeneration in multiple sclerosis (2003) Neurol Sci, 24, pp. s283-s286; Lucchinetti, C.F., Popescu, B.F., Bunyan, R.F., Inflammatory cortical demyelination in early multiple sclerosis (2011) N Engl J Med, 365, pp. 2188-2197; Serafini, B., Rosicarelli, B., Magliozzi, R., Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis (2004) Brain Pathol., 14 (2), pp. 164-174; Gardner, C., Magliozzi, R., Durrenberger, P.F., Cortical grey matter demyelination can be induced by elevated pro-inflammatory cytokines in the subarachnoid space of MOG-immunized rats (2013) Brain, 136, pp. 3596-3608; Absinta, M., Cortese, I.C.M., Vuolo, L., Leptomeningeal gadolinium enhancement across the spectrum of chronic neuroinflammatory diseases (2017) Neurology, 88, pp. 1439-1444; Haider, L., Zrzavy, T., Hametner, S., The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain (2016) Brain, 139, pp. 807-815; Magliozzi, R., Howell, O., Vora, A., Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology (2007) Brain, 130, pp. 1089-1104; Androdias, G., Reynolds, R., Chanal, M., Meningeal T cells associate with diffuse axonal loss in multiple sclerosis spinal cords (2010) Ann Neurol, 68, pp. 465-476; Howell, O.W., Schulz-Trieglaff, E.K., Carassiti, D., Extensive grey matter pathology in the cerebellum in multiple sclerosis is linked to inflammation in the subarachnoid space (2015) Neuropathol Appl Neurobiol, 41, pp. 798-813; Choi, S.R., Howell, O.W., Carassiti, D., Meningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis (2012) Brain, 135, pp. 2925-2937; Geurts, J.J., Bö, L., Pouwels, P.J., Cortical lesions in multiple sclerosis: combined postmortem MR imaging and histopathology (2005) Am J Neuroradiol, 26, pp. 572-577; Seewann, A., Vrenken, H., Kooi, E.J., Imaging the tip of the iceberg: visualization of cortical lesions in multiple sclerosis (2011) Mult Scler, 17, pp. 1202-1210; Calabrese, M., De Stefano, N., Atzori, M., Detection of cortical inflammatory lesions by double inversion recovery magnetic resonance imaging in patients with multiple sclerosis (2007) Arch Neurol, 64, pp. 1416-1422; Seewann, A., Kooi, E.-J., Roosendaal, S.D., Postmortem verification of MS cortical lesion detection with 3D DIR (2012) Neurology, 78, pp. 302-308; Sethi, V., Yousry, T.A., Muhlert, N., Improved detection of cortical MS lesions with phase-sensitive inversion recovery MRI (2012) J Neurol Neurosurg Psychiatry, 83, pp. 877-882; Kilsdonk, I.D., de Graaf, W.L., Soriano, A.L., Multicontrast MR imaging at 7T in multiple sclerosis: highest lesion detection in cortical gray matter with 3D-FLAIR (2013) AJNR Am J Neuroradiol, 34, pp. 791-796; Filippi, M., Evangelou, N., Kangarlu, A., Ultra-high-field MR imaging in multiple sclerosis (2014) J Neurol Neurosurg Psychiatry, 85, pp. 60-66; Petzold, A., Steenwijk, M.D., Eikelenboom, J.M., Elevated CSF neurofilament proteins predict brain atrophy: a 15-year follow-up study (2016) Mult Scler, 22, pp. 1154-1162; Krumbholz, M., Theil, D., Cepok, S., Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment (2006) Brain, 129, pp. 200-211; Sharief, M.K., Hentges, R., Association between tumor necrosis factor-alpha and disease progression in patients with multiple sclerosis (1991) N Engl J Med, 325, pp. 467-472; Baraczka, K., Nékám, K., Pozsonyi, T., Investigation of cytokine (tumor necrosis factor-alpha, interleukin-6, interleukin-10) concentrations in the cerebrospinal fluid of female patients with multiple sclerosis and systemic lupus erythematosus (2004) Eur J Neurol, 11, pp. 37-42; Duan, H., Luo, Y., Hao, H., Soluble CD146 in cerebrospinal fluid of active multiple sclerosis (2013) Neuroscience, 235, pp. 16-26; Lovato, L., Willis, S.N., Rodig, S.J., Related B cell clones populate the meninges and parenchyma of patients with multiple sclerosis (2011) Brain, 134, pp. 534-541; Polman, C.H., Reingold, S.C., Banwell, B., Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria (2011) Ann Neurol, 69, pp. 292-302; Durrenberger, P.F., Fernando, S., Kashefi, S.N., Effects of antemortem and postmortem variables on human brain mRNA quality: a BrainNet Europe study (2010) J Neuropathol Exp Neurol, 69, pp. 70-81; Teunissen, C.E., Petzold, A., Bennett, J.L., A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking (2009) Neurology, 73, pp. 1914-1922; Geurts, J.J., Roosendaal, S.D., Calabrese, M., Consensus recommendations for MS cortical lesion scoring using double inversion recovery MRI (2011) Neurology, 76, pp. 418-424; 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PY - 2018

Y1 - 2018

N2 - Objective: Gray matter (GM) damage and meningeal inflammation have been associated with early disease onset and a more aggressive disease course in multiple sclerosis (MS), but can these changes be identified in the patient early in the disease course?. Methods: To identify possible biomarkers linking meningeal inflammation, GM damage, and disease severity, gene and protein expression were analyzed in meninges and cerebrospinal fluid (CSF) from 27 postmortem secondary progressive MS and 14 control cases. Combined cytokine/chemokine CSF profiling and 3T magnetic resonance imaging (MRI) were performed at diagnosis in 2 independent cohorts of MS patients (35 and 38 subjects) and in 26 non-MS patients. Results: Increased expression of proinflammatory cytokines (IFNγ, TNF, IL2, and IL22) and molecules related to sustained B-cell activity and lymphoid-neogenesis (CXCL13, CXCL10, LTα, IL6, and IL10) was detected in the meninges and CSF of postmortem MS cases with high levels of meningeal inflammation and GM demyelination. Similar proinflammatory patterns, including increased levels of CXCL13, TNF, IFNγ, CXCL12, IL6, IL8, and IL10, together with high levels of BAFF, APRIL, LIGHT, TWEAK, sTNFR1, sCD163, MMP2, and pentraxin III, were detected in the CSF of MS patients with higher levels of GM damage at diagnosis. Interpretation: A common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at the time of diagnosis and at death. These results suggest a role for detailed CSF analysis combined with MRI as a prognostic marker for more aggressive MS. Ann Neurol 2018 Ann Neurol 2018;83:739–755. © 2018 American Neurological Association

AB - Objective: Gray matter (GM) damage and meningeal inflammation have been associated with early disease onset and a more aggressive disease course in multiple sclerosis (MS), but can these changes be identified in the patient early in the disease course?. Methods: To identify possible biomarkers linking meningeal inflammation, GM damage, and disease severity, gene and protein expression were analyzed in meninges and cerebrospinal fluid (CSF) from 27 postmortem secondary progressive MS and 14 control cases. Combined cytokine/chemokine CSF profiling and 3T magnetic resonance imaging (MRI) were performed at diagnosis in 2 independent cohorts of MS patients (35 and 38 subjects) and in 26 non-MS patients. Results: Increased expression of proinflammatory cytokines (IFNγ, TNF, IL2, and IL22) and molecules related to sustained B-cell activity and lymphoid-neogenesis (CXCL13, CXCL10, LTα, IL6, and IL10) was detected in the meninges and CSF of postmortem MS cases with high levels of meningeal inflammation and GM demyelination. Similar proinflammatory patterns, including increased levels of CXCL13, TNF, IFNγ, CXCL12, IL6, IL8, and IL10, together with high levels of BAFF, APRIL, LIGHT, TWEAK, sTNFR1, sCD163, MMP2, and pentraxin III, were detected in the CSF of MS patients with higher levels of GM damage at diagnosis. Interpretation: A common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at the time of diagnosis and at death. These results suggest a role for detailed CSF analysis combined with MRI as a prognostic marker for more aggressive MS. Ann Neurol 2018 Ann Neurol 2018;83:739–755. © 2018 American Neurological Association

KW - APRIL protein

KW - B cell activating factor

KW - biological marker

KW - CD163 antigen

KW - CD20 antigen

KW - CXCL13 chemokine

KW - CXCL9 chemokine

KW - gamma interferon

KW - gamma interferon inducible protein 10

KW - gelatinase A

KW - interleukin 10

KW - interleukin 2

KW - interleukin 22

KW - interleukin 6

KW - myelin oligodendrocyte glycoprotein

KW - pentraxin 3

KW - tumor necrosis factor

KW - adult

KW - aged

KW - Article

KW - autopsy

KW - B lymphocyte

KW - brain cortex lesion

KW - cerebrovascular disease

KW - controlled study

KW - degenerative disease

KW - demyelination

KW - disease course

KW - disease severity

KW - electrochemiluminescence

KW - Expanded Disability Status Scale

KW - female

KW - gene expression

KW - headache

KW - human

KW - human tissue

KW - male

KW - meningitis

KW - middle aged

KW - multiple sclerosis

KW - neuropathy

KW - nuclear magnetic resonance imaging

KW - priority journal

KW - protein analysis

KW - protein cerebrospinal fluid level

KW - protein expression

KW - RNA extraction

KW - subarachnoid space

KW - very elderly

KW - white matter lesion

U2 - 10.1002/ana.25197

DO - 10.1002/ana.25197

M3 - Article

VL - 83

SP - 739

EP - 755

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 4

ER -