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A study of subtle blood brain barrier disruption in a placebo-controlled trial of natalizumab in relapsing remitting multiple sclerosis

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Abstract

Natalizumab, an anti-α4 integrin antibody, significantly reduces the number of visibly enhancing multiple sclerosis (MS) lesions. In this substudy of a 2-year trial of natalizumab monotherapy versus placebo, contrast-enhanced imaging investigated for subtle blood brain barrier (BBB) leakage in relapsing remitting (RRMS) patients, and whether such leakage is modified by natalizumab. After 24 weeks on treatment, 40 patients from 3 centres (27 on natalizumab and 13 on placebo) were studied. T1 weighted images were obtained before and at set timepoints up to 46 minutes after gadolinium (Gd)-DTPA (0.3mmol/kg to 18 patients, 0.15mmol/kg to 22). Paired regions of interest were placed around non-enhancing lesions and contralateral normal appearing white matter (NAWM). BBB leakage was inferred through post-Gd T1 weighted signal intensity (SI) change. SI change was greater in T2 non-enhancing lesions than paired NAWM at all timepoints (P < 0.005), indicating BBB leakage in lesions. No significant difference in inferred BBB leakage was observed between treatment arms as measured by SI change of lesions (P > 0.05 for all timepoints, joint test P = 0.24), or in SI change of NAWM (joint test P = 0.37). T1 hypointense and isointense lesions exhibited similar SI changes (joint test P = 0.12). There is evidence of a subtle BBB leakage within visibly non-enhancing lesions in RRMS that was not modified by α4 integrin blockade in this substudy cohort.

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References

  1. Kermode AG, Thompson AJ, Tofts P, MacManus DG, Kendall BE, Kingsley DP, Moseley IF, Rudge P, McDonald WI (1990) Breakdown of the blood-brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis, Pathogenetic and clinical implications. Brain 113(Pt 5):1477–1489

    Article  PubMed  Google Scholar 

  2. Adams CW, Poston RN, Buk SJ, Sidhu YS, Vipond H (1985) Inflammatory vasculitis in multiple sclerosis. J Neurol Sci 69:269–283

    Article  PubMed  CAS  Google Scholar 

  3. Kirk J, Plumb J, Mirakhur M, McQuaid S (2003) 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 201:319–327

    Article  PubMed  Google Scholar 

  4. Kwon EE, Prineas JW (1994) Blood-brain barrier abnormalities in longstanding multiple sclerosis lesions, An immunohistochemical study. J Neuropathol Exp Neurol 53:625–636

    PubMed  CAS  Google Scholar 

  5. Claudio L, Raine CS, Brosnan CF (1995) Evidence of persistent blood-brain barrier abnormalities in chronic-progressive multiple sclerosis. Acta Neuropathol (Berl) 90:228–238

    CAS  Google Scholar 

  6. Silver NC, Tofts PS, Symms MR, Barker GJ, Thompson AJ, Miller DH (2001) Quantitative contrast-enhanced magnetic resonance imaging to evaluate blood-brain barrier integrity in multiple sclerosis: a preliminary study. Mult Scler 7:75–82

    PubMed  CAS  Google Scholar 

  7. Plumb J, McQuaid S, Mirakhur M, Kirk J (2002) Abnormal endothelial tight junctions in active lesions and normal-appearing white matter in multiple sclerosis. Brain Pathol 12:154–169

    Article  PubMed  Google Scholar 

  8. Werring DJ, Brassat D, Droogan AG, Clark CA, Symms MR, Barker GJ, MacManus DG, Thompson AJ, Miller DH (2000) The pathogenesis of lesions and normal-appearing white matter changes in multiple sclerosis: a serial diffusion MRI study. Brain 123(Pt 8):1667–1676

    Article  PubMed  Google Scholar 

  9. Kidd D, Barker GJ, Tofts PS, Gass A, Thompson AJ, McDonald WI, Miller DH (1997) The transverse magnetisation decay characteristics of longstanding lesions and normal-appearing white matter in multiple sclerosis. J Neurol 244:125–130

    Article  PubMed  CAS  Google Scholar 

  10. Griffin CM, Dehmeshki J, Chard DT, Parker GJ, Barker GJ, Thompson AJ, Miller DH (2002) T1 histograms of normal-appearing brain tissue are abnormal in early relapsing-remitting multiple sclerosis. Mult Scler 8:211–216

    Article  PubMed  CAS  Google Scholar 

  11. Bochner BS, Luscinskas FW, Gimbrone MA Jr, Newman W, Sterbinsky SA, rse-Anthony CP, Klunk D, Schleimer RP (1991) Adhesion of human basophils, eosinophils, and neutrophils to interleukin 1-activated human vascular endothelial cells: contributions of endothelial cell adhesion molecules. J Exp Med 173:1553–1557

    Article  PubMed  CAS  Google Scholar 

  12. Elices MJ, Osborn L, Takada Y, Crouse C, Luhowskyj S, Hemler ME, Lobb RR (1990) VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell 60:577–584

    Article  PubMed  CAS  Google Scholar 

  13. Carlos TM, Schwartz BR, Kovach NL, Yee E, Rosa M, Osborn L, Chi-Rosso G, Newman B, Lobb R (1990) Vascular cell adhesion molecule-1 mediates lymphocyte adherence to cytokine-activated cultured human endothelial cells. Blood 76:965–970

    PubMed  CAS  Google Scholar 

  14. Cannella B, Raine CS (1995) The adhesion molecule and cytokine profile of multiple sclerosis lesions. Ann Neurol 37:424–435

    Article  PubMed  CAS  Google Scholar 

  15. Damle NK, Aruffo A (1991) Vascular cell adhesion molecule 1 induces T-cell antigen receptor-dependent activation of CD4+T lymphocytes. Proc Natl Acad Sci USA 88:6403–6407

    Article  PubMed  CAS  Google Scholar 

  16. Madri JA, Graesser D, Haas T (1996) The roles of adhesion molecules and proteinases in lymphocyte transendothelial migration. Biochem Cell Biol 74:749–757

    Article  PubMed  CAS  Google Scholar 

  17. Burkly LC, Jakubowski A, Newman BM, Rosa MD, Chi-Rosso G, Lobb RR (1991) Signaling by vascular cell adhesion molecule-1 (VCAM-1) through VLA-4 promotes CD3-dependent T cell proliferation. Eur J Immunol 21:2871–2875

    Article  PubMed  CAS  Google Scholar 

  18. Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N (1992) Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 356:63–66

    Article  PubMed  CAS  Google Scholar 

  19. Kent SJ, Karlik SJ, Rice GP, Horner HC (1995) A monoclonal antibody to alpha 4-integrin reverses the MR-detectable signs of experimental allergic encephalomyelitis in the guinea pig. J Magn Reson Imaging 5:535–540

    Article  PubMed  CAS  Google Scholar 

  20. Leger OJ, Yednock TA, Tanner L, Horner HC, Hines DK, Keen S, Saldanha J, Jones ST, Fritz LC, Bendig MM (1997) Humanization of a mouse antibody against human alpha-4 integrin: a potential therapeutic for the treatment of multiple sclerosis. Hum Antibodies 8:3–16

    PubMed  CAS  Google Scholar 

  21. Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GP, Libonati MA, Willmer-Hulme AJ, Dalton CM, Miszkiel KA, O’Connor PW (2003) A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 348:15–23

    Article  PubMed  CAS  Google Scholar 

  22. Tubridy N, Behan PO, Capildeo R, Chaudhuri A, Forbes R, Hawkins CP, Hughes RA, Palace J, Sharrack B, Swingler R, Young C, Moseley IF, MacManus DG, Donoghue S, Miller DH (1999) The effect of anti-alpha4 integrin antibody on brain lesion activity in MS. The UK Antegren Study Group. Neurology 53:466–472

    PubMed  CAS  Google Scholar 

  23. Dalton CM, Miszkiel KA, Barker GJ, MacManus DG, Pepple TI, Panzara M, Yang M, Hulme A, O’Connor P, Miller DH (2004) Effect of natalizumab on conversion of gadolinium enhancing lesions to T1 hypointense lesions in relapsing multiple sclerosis. J Neurol 251:407–413

    Article  PubMed  CAS  Google Scholar 

  24. Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354:899–910

    Article  PubMed  CAS  Google Scholar 

  25. Tofts PS, Kermode AG (1991) Measurement of the blood-brain barrier permeability and leakage space using dynamic MR imaging. 1. Fundamental concepts. Magn Reson Med 17:357–367

    Article  PubMed  CAS  Google Scholar 

  26. van Walderveen MA, Kamphorst W, Scheltens P, van Waesberghe JH, Ravid R, Valk J, Polman CH, Barkhof F (1998) Histopathologic correlate of hypointense lesions on T1-weighted spin-echo MRI in multiple sclerosis. Neurology 50:1282–1288

    PubMed  Google Scholar 

  27. Truyen L, van Waesberghe JH, van Walderveen MA, van Oosten BW, Polman CH, Hommes OR, Ader HJ, Barkhof F (1996) Accumulation of hypointense lesions (“black holes”) on T1 spin-echo MRI correlates with disease progression in multiple sclerosis. Neurology 47:1469–1476

    PubMed  CAS  Google Scholar 

  28. van Walderveen MA, Lycklama ANG, Ader HJ, Jongen PJ, Polman CH, Castelijns JA, Barkhof F (2001) Hypointense lesions on T1-weighted spin-echo magnetic resonance imaging: relation to clinical characteristics in subgroups of patients with multiple sclerosis. Arch Neurol 58:76–81

    Article  PubMed  Google Scholar 

  29. Barkhof F, Bruck W, De Groot CJ, Bergers E, Hulshof S, Geurts J, Polman CH, van der Valk P (2003) Remyelinated lesions in multiple sclerosis: magnetic resonance image appearance. Arch Neurol 60:1073–1081

    Article  PubMed  Google Scholar 

  30. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den NS, Weinshenker BY, Wolinsky JS (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127

    Article  PubMed  CAS  Google Scholar 

  31. Studholme C, Hill DLG, Hawkes DJ (1999) An overlap invariant entropy measure of 3D medical image alignment. Pattern Recognit 32:71–86

    Article  Google Scholar 

  32. Woods RP, Cherry SR, Mazziotta JC (1992) Rapid automated algorithm for aligning and reslicing PET images. J Comput Assist Tomogr 16:620–633

    Article  PubMed  CAS  Google Scholar 

  33. Plummer DL (1992) Dispimage: a display and analysis tool for medical images. Rivi Neuroradiol 5:489–495

    Google Scholar 

  34. Goldstein H (1995) Multilevel Statistical Models (Kendall’s Library of Statistics Series 3). Hodder Arnold

  35. Tofts PS, Berkowitz BA (1994) Measurement of capillary permeability from the Gd enhancement curve: a comparison of bolus and constant infusion injection methods. Magn Reson Imaging 12:81–91

    Article  PubMed  CAS  Google Scholar 

  36. Minagar A, Alexander JS (2003) Blood-brain barrier disruption in multiple sclerosis. Mult Scler 9:540–549

    Article  PubMed  CAS  Google Scholar 

  37. Silver NC, Good CD, Barker GJ, MacManus DG, Thompson AJ, Moseley IF, McDonald WI, Miller DH (1997) Sensitivity of contrast enhanced MRI in multiple sclerosis, Effects of gadolinium dose, magnetization transfer contrast and delayed imaging. Brain 120(Pt 7):1149–1161

    Article  PubMed  Google Scholar 

  38. Filippi M, Yousry T, Campi A, Kandziora C, Colombo B, Voltz R, Martinelli V, Spuler S, Bressi S, Scotti G, Comi G (1996) Comparison of triple dose versus standard dose gadolinium-DTPA for detection of MRI enhancing lesions in patients with MS. Neurology 46:379–384

    PubMed  CAS  Google Scholar 

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Acknowledgements

The authors thank the following people for their invaluable assistance and contribution: Kelvin Hunter and David MacManus for collation and preparation of the MRI data for analysis, and Minhua Yang and Frances Lynn for helpful statistical discussions. The authors would also like to thank Biogen Idec for providing the data for this study, as well as the MS Society for Great Britain and Northern Ireland and the Dutch Foundation for MS Research (Voorschoten, The Netherlands) for supporting the research in the centres involved.

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Authors and Affiliations

  1. Dept. of Neuroinflammation, Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom

    Derek Soon, Kryshani T.M. Fernando, Garin Giovannoni & David H. Miller

  2. London School of Hygiene and Tropical Medicine, London, United Kingdom

    Daniel R. Altmann

  3. VU Medisch Centrum, Amsterdam, The Netherlands

    Frederick Barkhof & Chris H. Polman

  4. St Michael’s Hospital, Toronto, Canada

    Paul O’Connor & Bruce Gray

  5. Biogen Idec, Cambridge, MA, USA

    Michael Panzara

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  1. Derek Soon
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  2. Daniel R. Altmann
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  3. Kryshani T.M. Fernando
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  4. Garin Giovannoni
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  5. Frederick Barkhof
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  7. Paul O’Connor
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  9. Michael Panzara
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  10. David H. Miller
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Correspondence to David H. Miller.

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Received in revised form: 18 June 2006

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Soon, D., Altmann, D.R., Fernando, K.T. et al. A study of subtle blood brain barrier disruption in a placebo-controlled trial of natalizumab in relapsing remitting multiple sclerosis. J Neurol 254, 306–314 (2007). https://doi.org/10.1007/s00415-006-0356-z

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  • DOI: https://doi.org/10.1007/s00415-006-0356-z

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