MRI evaluation of the anti-adhesion molecule antibody Natalizumab and the blood-brain barrier in Multiple Sclerosis

As Blood-brain barrier (BBB) breakdown is central to inflammatory lesion formation, it presents a potential target in the formulation of putative therapeutic agents in MS. The action of natalizumab, a monoclonal antibody acting at the BBB, is investigated through a phase III monotherapy trial (AFFIRM) and associated substudies. Subtle BBB disruption from non-inflamed lesions, which could contribute to axonal damage through leakage of inflammatory cells and associated mediators into surrounding parenchyma, is also studied. Introductory chapters (1-3) provide a brief overview of MS, clinical trials, magnetic resonance imaging (MRI), the BBB and natalizumab. Chapter four describes MRI results of AFFIRM- a 2 year multi-centre trial involving 942 patients. Compared with placebo, natalizumab reduced number of gadolinium (Gd)- enhancing lesions by 92%, new/enlarging T2-hyperintense lesions by 83%, and new T1- hypointense lesions by 76%. Chapter five describes a 57 patient AFFIRM trial substudy in which the influence of natalizumab on segmental atrophy was investigated. Atrophy was predominant in grey matter (GM) and was independent of lesion load. Fluctuations in white matter (WM) volume followed changes in inflammatory lesion load. Atrophy was not influenced by natalizumab. The effect of natalizumab on subtle BBB disruption (inferred by measuring the post-Gd %change in T1 weighted signal intensity) is studied in chapter 6. This AFFIRM substudy involved 40 patients (27 on natalizumab, 13 on placebo.) Although subtle BBB leakage was consistently detected in non-visibly enhancing lesions, natalizumab did not influence the degree of leakage. Chapter 7 describes a cross-sectional study which utilised post-Gd change in R1 (1/T1) as a marker BBB leakage. 19 patients (10 RRMS, 9 SPMS) were involved in this study. The subtle leakage observed from non-visibly enhancing lesions was distinct from leakage from visibly enhancing lesions. This was sustained over 60 minutes, greater in smaller lesions and in size-adjusted T1 hypointense lesions