202 Chapter 9 Visualising neuroinflammation in the CNS Neuroinflammation, associated with neuropathology of neuroinflammatory and neurodegenerative diseases is one of the many complex multicellular processes that occurs behind the ‘closed borders’ within the CNS. Two key innate immune cells that contribute to damage as well as repair are microglia and astrocytes. Given their importance in many diseases there is an urgent clinical need to monitor glial cell activity during disease as well as assess the impact of medical intervention on innate immune responses during diseases. One of the most common modalities to monitor neuroinflammation and pathological changes in neurodegenerative diseases and experimental animal models is PET imaging, which has the advantage of being able to interrogate various disease mechanisms by quantifying specific molecular targets to directly study the CNS1-3. Even though PET imaging is expensive, it can be a valuable tool to generate knowledge on the efficacy of drugs in a preclinical setting before translating to the clinic. PET imaging can also provide insights into the therapeutic effects in the CNS of patients in vivo. PET allows direct visualization of neuroinflammation in early stages of disease as well as recurrent analysis to monitor disease progression. Importantly, this approach lends itself to study the efficacy of therapies targeting molecular pathways that can be visualized by specific ligands3. PET imaging may thus serve as a tool to study disease progression or as prognostic or predictive biomarker, while allowing a detailed analysis of molecular alterations key to the pathogenesis of neurodegenerative diseases, such as cerebral blood flow, glucose metabolism, neuroinflammation, neuronal dysfunction and oxidative stress4. TSPO PET imaging is a promising molecular imaging technique that has been used over the last decades as a measurement of activated microglia in the CNS. In this thesis we examined the cellular distribution of TSPO in CNS resident cells in neurodegenerative diseases to identify whether TSPO is indeed a marker of activated microglia as has been reported by many studies (reviewed by Guilarte2). Initial reports on animal models of neuroinflammatory diseases showed that TSPO is also expressed by other cell types than microglia5-18 but these findings have been largely ignored by PET studies, and the early human studies were qualitative rather than quantitative19-21. Recently, it was shown in vitro that while primary rodent microglia upregulate TSPO expression in a proinflammatory environment, primary human microglia do not22. Thus, findings of the triggers of TSPO, and the cellular expression of TSPO in the CNS in animal models may not translate to human disease. To investigate the cellular distribution and understand the triggers of TSPO we have performed in-depth studies of TSPO expression in MS, AD and ALS and their respective animal models. In addition, we have utilised publicly available databases on TSPO regulation on multiple molecular levels (e.g. epigenetic, protein and RNA). Together, these studies have allowed a more detailed understanding of the role of microglia and astrocytes as innate immune cells of the CNS. Is TSPO a marker of only activated microglia? Early TSPO PET studies used the first‐generation TSPO ligand [11C]‐PK11195, while more recent studies use second‐generation TSPO tracers such as [11C]‐PBR28 and [18F]‐DPA‐714, which have improved uptake and binding affinity compared to older tracers23. Surprisingly, very little data is available on the precise origin of TSPO in CNS cells, on which to base interpretations of TSPO PET. Due to the fast pace of research and increasing advances in the development of radiotracers for TSPO PET, often times there is a lack of appreciation for the neurobiology of TSPO and conclusions are made about its cellular origin without proper
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