124 Chapter 5 monocyte family that also express IBA1. In this context, several reports using mouse primary glial cell cultures demonstrate that TSPO is more likely to be modified in activated (by proinflammatory stimuli) forms of microglia and astrocytes154,163,164. Finally, studies of the number of cells expressing TSPO based on immunofluorescence do not determine if a change in the number of TSPO binding sites per cell is present. Finally, although evidence is scarce, a direct implication of TSPO on the pathophysiology of the various neuropsychiatric conditions may not be ruled out. TSPOexpression inhumanCNS inhealth, ageing, andneurological disease Health and Ageing Little is known of the distribution and expression of TSPO during development, healthy aging, and how such expression differs in regions of the CNS in humans. Consideration of these features, as well as the mode of analysis, e.g. PET, autoradiography, quantitative assays, or pathology of post-mortem (PM) brain, is of key importance to explain TSPO expression in PET imaging. Much of what is known about TSPO expression in humans comes from PET imaging where differential expression may be due to the different affinity patterns for TSPO ligands. PET studies report an increased expression of TSPO with aging in healthy subjects in several cortical and subcortical areas165-167. However, little is known about the levels and cellular expression of TSPO during (early) development or in healthy elderly subjects as determined in post-mortem control tissues. Quantitative immunoblotting approaches reveal that TSPO protein levels are 2- to 70 -fold higher than those reported by in vitro binding assays and expression is widely distributed in the CNS in grey and white matter at all ages165. At birth TSPO protein levels are highest in the frontal cortex possibly reflecting expression in neuronal precursor cells although pathology studies have not yet supported this hypothesis. Levels of TSPO decline in the first 3 months after birth and subsequently increase modestly during adulthood/senescence165. The relatively high binding and protein expression reported in aging may reflect subtle changes due to senescence or, alternatively, due to changes in the morphology or phenotype of aging cells in the CNS parenchyma. Pathology studies on PM tissues of normal human brains reported that a variety of cell types express TSPO, the levels and extent of expression depending on the TSPO antibody used168. Endothelial cells, arachnoid cells, cells within the choroid plexus as well as astrocytes, microglia, and to a lesser degree oligodendrocytes and immune cells within blood vessels revealed a punctate expression typical for mitochondrial expression markers168 However, these studies were limited to tissues from aged donors and it is difficult to conclude, based on the available pathology studies, that the cellular expression of TSPO in the normal brain is due to normal aging. Neuroinflammation TSPO PET imaging is widely used to monitor inflammation in MS, a chronic inflammatory demyelinating and neurodegenerative disease with onset in young adults169. The PET signal in MS is frequently assumed to represent pathogenic microglia yet pathology studies have detailed a more widespread cellular expression. Compared to normal appearing white matter in MS tissues where TSPO is expressed in scattered HLA+ cells throughout the CNS, the expression is approximately 20-fold higher in active MS lesions and the rim of chronic active lesions170. In addition to microglia, this study revealed that expression is also observed
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