49 Translocator protein expression in multiple sclerosis TSPO pixels and radioligand binding are increased in active lesions To investigate the relationship between TSPO expression and radioligand binding of [3H] PBR28 or [3H]PK11195, results from a pixel-based analysis of immunochemically-defined TSPO were integrated with TSPO radioligand autoradiography of white and grey matter lesions from sections in the same tissue blocks frommultiple sclerosis and control brains (Fig. 5). In white matter lesions, the number of TSPO+ pixels were increased by five-fold compared to control white matter (active: P<0.0001; CA rim: P=0.0003) and by nine-fold compared to NAWM (active: P<0.0001; CA rim: P<0.0001; Fig. 6A). Endothelial TSPO expression contributed minimally (up to 8% in inactive lesions) to the amount of TSPO+ pixels in the white matter (Supplementary Fig. 1A). TSPO+ pixels were found to be increased markedly in the white matter component of leukocortical lesions relative to NAWM (P<0.0001, Fig. 6D) and to control white matter (P<0.0001). A smaller increase in TSPO+ pixels was found in the grey matter (P=0.0096) of leukocortical lesions relative to NAGM. However, no significant increase in TSPO+ pixels was found in other sub-types of grey matter lesions. Endothelial TSPO expression was decreased in grey matter lesions compared to the NAGM (P<0.005) and control grey matter (P<0.05, Supplementary Fig. 1B). Furthermore, endothelial TSPO expression was up to a fourfold higher in the NAGM and control grey matter compared to NAWM (P<0.0001) and control white matter (P=0.0033) in the brains of people with multiple sclerosis (Supplementary Fig. 1B). A B C D E F G H I J K L M N O P Q R S T U V W X Total 3H-PBR28 Total 3H-PK11195 3H-PBR28 NSB 3H-PK11195 NSB PLP HLA-DR active + chronic active inactive + meninges chronic active leukocortical subpial + active GM WM GM WM GM GM WM GM HAB MAB MAB MAB Figure 5. Overview of [3H]PBR28 and [3H]PK11195 autoradiography of multiple sclerosis lesions. Scale bar (A) ranges from low radioactivity to high radioactivity (0.42 TE nCi/mg to 16.23 TE nCi/mg). Total binding of [3H]PBR28 (A,G, M & S), non-specific binding of [3H]PBR28 (B, H, N & T), total binding of [3H]PK11195 (C, I, O & U), non-specific binding of [3H]PK11195 (D, J, P & V), PLP (E, K, Q & W) and HLA-DR (F, L, R & X) images. LN3 staining denotes areas for active (red), chronic active (orange), inactive (purple) and subpial (pink) lesions, meninges (blue) and the grey and white matter border (dashed lines).
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