208 Chapter 9 Box 1 Conclusions of the studies performed in this thesis Chapter 2 Microglia but also astrocytes express TSPO in MS lesions, TSPO PET reports on cell density rather than activation state. Chapter 3 TSPO is not upregulated in activated microglia in MS lesions compared to homeostatic microglia in the NAWM and in control white matter. Chapter 4 Regulation of TSPO is phylogenetically diverse between humans and rodents, resulting in differential regulation of the TSPO gene in humans. TSPO is not increased in activated microglia and astrocytes in human CNS diseases. Chapter 5 TSPO binding, cellular origin, and functional significance is dependent on many factors such as the pathology or the experimental animal model. Chapter 6 Microglial activation in the MS spinal cord is associated with synaptic loss, resulting in progressive clinical disability. Chapter 7 Astrocytes and oligodendrocytes produce and respond to many immunomodulatory factors playing critical roles in immune responses in the CNS. Chapter 8 Microgliahave regionallydefined functions in theCNS relating todevelopment, homeostasis, ageing, neuroinflammation and in response to injury, reflecting the local needs of the CNS parenchyma. a pro-inflammatory environment. Our studies consistently show that human microglia do not upregulate expression of TSPO upon activation in neuro-inflammatory and-degenerative diseases, both in vitro and in vivo. Contrastingly, rodentmicroglia quite easily start upregulating TSPO in pro-inflammatory environments in vitro and in vivo, possibly due to phylogenetic differences in the regulation of the TSPO gene. While TSPO PET has many advantages, there are some perceived difficulties that need to be overcome to use TSPO PET as a reliable marker. First generation TSPO ligands had difficulties with specificity while second generation TSPO ligands were sensitive to genetic polymorphisms that altered binding affinity. However, there are new reports indicating that significant advances are being made in generating TSPO radioligands with improved pharmacokinetics and low levels of non-specific binding73-75. There might even be some new radioligands that show low sensitivity towards the TSPO polymorphism76-78. Development of these radiotracers provide a promising prospect to what TSPO PET might contribute towards making more informed decisions for diagnoses and therapeutic strategies for clinical therapies in the future.
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