51 Translocator protein expression in multiple sclerosis the chronic active centre (P=0.0392) compared to NAWM (Fig. 6C). In grey matter lesions (Fig. 6E, F), binding was not greater for either [3H]PBR28 or [3H]PK11195 than in NAGM. An increased signal was found in the white matter of leukocortical lesions compared to control (P=0.0414) for [3H]PBR28 or compared to NAWM (P=0.0019) for [3H]PK11195. Specific binding in NAGMwas more than tripled relative to NAWM for [3H]PBR28 (P=0.0009). A strong positive correlation between the pixel-based analysis of TSPO expression and specific binding of the ligand [3H]PBR28 was found (R2=0.5017, P=0.0327), while only a trend was found for [3H]PK11195 (R2=0.4417, P=0.0509, Fig. 6G). Strong correlations were also found between the relative number of TSPO+ cells and specific binding for [3H]PBR28 (R2=0.4698, P=0.0139) and [3H]PK11195 (R2=0.3229, P=0.0271, Fig. 6H). Discussion TSPO is a marker of inflammation commonly attributed to microglial activation in neuroinflammatory and neurodegenerative diseases64. Surprisingly, there has been very little data on which to base precise interpretations to date65. Knowledge of the cellular and phenotypic correlates of the TSPO PET signal is important to better understand the clinical meaningfulness of the heterogeneity of TSPO PET radioligand uptake in T2-hyperintense lesions in multiple sclerosis before and after initiation of disease modifying therapies66. Here we have examined the expression and localisation of TSPO in a large cohort of post mortem multiple sclerosis in white and grey matter lesions of the brain and spinal cord. Similar to previous studies, TSPO expression was found in microglia in active and chronic active lesions36,45,46,67,68. Similar to a recent study combining quantitative susceptibility mapping and immunohistochemistry45, our studies revealed non trivial expression of TSPO in astrocytes in all sub-types of lesions examined. The astrocytic TSPO accounted for approximately 25% of the TSPO+ cells in active lesions or chronic active lesion rims and for 65% of the TSPO+ cells in the centres of chronic active and inactive lesions. Autoradiography using [3H]PBR28 and [3H]PK11195 revealed a strong correlation between TSPO+ cells and radioligand binding across all cell sub-types. This suggests that TSPO PET signal arises from astrocytes as well as microglia, which is consistent with reports that newer generation ligands for TSPO bind to reactive astrocytes32,45. Interpretation of the signal therefore needs to be context dependent. This finding is of clear importance for use of TSPO PET as an outcome measure in studies of modulation of these inflammatory processes. While some studies have found reduced TSPO binding after anti-inflammatory treatments69,70, it has also been suggested that current disease modifying therapy may have a limited impact on microglial activity66,71. However, as centres of chronic active and inactive lesions show increased expression of TSPO in reactive astrocytes, observations of TSPO expression alone are more ambiguous; treatment may reduce microglial density or activation without a reduction in TSPO PET signal, if astrocytic numbers increase simultaneously. The astrocytic contribution of the TSPO signal could also complicate differentiation of multiple sclerosis from leukodystrophies that have significant astrocytic but not microglial involvement72. While percentages of microglia in the grey matter have been reported to be significantly higher in white versus grey matter73 an increase of radioligand binding in the NAGM compared to the NAWM was observed. This may be attributed to the increased contribution of TSPO+ endothelial cells due to the reported increased vascularity of grey verses white matter74. That TSPO protein expression does not correlate with the PBR28 findings in the grey matter
RkJQdWJsaXNoZXIy MTk4NDMw