50 Chapter 2 CON WM NAWM LC WM CON GM NAGM LC GM Intracortical Subpial 0 25 50 75 100 125 150 175 [3H]PK11195 specific binding (fmol/mg TE) ** CON WM NAWM Active CA rim CA centre Inactive 0 25 50 75 100 125 150 175 [3H]PK11195 specific binding (fmol/mg TE) *** * CON WM NAWM LC WM CON GM NAGM LC GM Intracortical Subpial Transcortical 0 10 20 30 40 50 TSPO+ pixels (%) **** **** ** CON WM NAWM Active CA rim CA centre Inactive 0 10 20 30 40 50 TSPO+ pixels (%) **** *** **** **** CON WM NAWM Active CA rim CA centre Inactive 0 25 50 75 100 125 150 175 [3H]PBR28 specific binding (fmol/mg TE) ** * ** ** CON WM NAWM LC WM CON GM NAGM LC GM Intracortical Subpial 0 25 50 75 100 125 150 175 [3H]PBR28 specific binding (fmol/mg TE) * *** A D B E F H C G MAB HAB MAB HAB 0 200 400 600 800 1000 0 15 30 45 60 75 TSPO+ cells / mm2 specific binding (fmol/mg TE) [3H]PBR28 R2 = 0.4698 P = 0.0139* [3H]PK11195 R2 = 0.3229 P = 0.0271* 0 10 20 30 40 0 15 30 45 60 75 TSPO+ pixels per lesion (%) specific binding (fmol/mg TE) [3H]PBR28 R2 = 0.5017 P = 0.0327* [3H]PK11195 R2 = 0.4417 P = 0.0509n.s. Figure 6. [3H]PBR28 and [3H]PK11195 autoradiography of multiple sclerosis lesions. An increase in TSPO+ pixels was found in active and chronic active lesions compared to control and NAWM (A). [3H]PBR28 and [3H]PK11195 binding was increased in active white matter lesions and the centre of chronic active lesions (B, C). For grey matter lesions an increase was found in TSPO+ pixels in leukocortical lesion WM and GM compared to their respective normal appearing tissue (D). Similar to white matter lesions [3H]PBR28 and [3H]PK11195 binding was increased in leukocortical lesion white matter areas (E, F). An increase in specific binding in NAGM relative to NAWM was found for [3H]PBR28. Mixed affinity binders (MAB) are depicted in grey while high affinity binders are depicted in black (HAB). Correlations were found for specific binding of [3H]PBR28 and [3H]PK11195 for both TSPO+ pixels per lesion and TSPO+ cells per mm2 (G, H). CON WM = control white matter, NAWM = normal appearing white matter, CON GM = control grey matter, NAGM = normal appearing grey matter, CA = chronic active, LC = leukocortical lesion. Specific tracer binding was calculated from [3H]PBR28 and [3H]PK11195 autoradiography in lesional and non-lesional areas of white and grey matter in the multiple sclerosis brains and in control tissue (Fig. 5). No specific binding was found in four brains with low affinity binding genotypes for [3H]PBR28, identified by the rs6971 polymorphism. In all other cases, control white matter, NAWM and inactive lesions all showed relatively low binding of both ligands compared to active and chronic active lesions (Fig. 6B, C). [3H]PBR28 binding was seven times greater in active lesions compared to control white matter (P=0.0228) and three times greater than NAWM (P=0.0064). Similarly, greater binding was found in the centres of chronic active lesions compared to NAWM (P=0.0046) or control white matter (P=0.0084, Fig. 6B). [3H]PK11195 binding was approximately doubled in the active (P=0.0006) and tripled in
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