17 General introduction TSPO Oneproteinthathasbeenof interest as the target inPET imagingof ongoingneuroinflammation is the translocator protein (TSPO). TSPO is an outer mitochondrial membrane protein, expressed inmany tissues in the body, whose exact functions are unknown95-99. TSPOPET signal is markedly upregulated in many neurodegenerative and neuroinflammatory diseases95-111. However, one of the caveats of using TSPO PET is that the exact cellular origin of the TSPO PET signal in the brain is unclear. Knowing the origin of TSPO PET is necessary for clinical meaningful decisions, e.g. whether a therapeutic intervention is having the desired in vivo effects on neuroinflammation. Due to the fast pace of research and development of new TSPO radiotracers many conclusions of TSPO PET have been made without proper investigation into the cellular origin100. This has led to the belief that the TSPO PET signal mostly originates in activatedmicroglia99,105,106,109,112-124. The contribution of other cell types such as astrocytes have been largely ignored, even though there have been multiple reports of TSPO in astrocytes for many years125-141. Most of these studies have demonstrated astrocytic TSPO in animal models of CNS diseases125-138, however only a few studies have investigated expression of TSPO in astrocytes in the human CNS, most of which are qualitative rather than quantitative139-142. Additionally, human microglia do not upregulate expression of TSPO after pro-inflammatory stimulation, and human macrophages even downregulate TSPO expression143. This recent finding has sparked interest into whether TSPO is a marker of all microglia or a readout on microglial density rather than activated microglia. The use of TSPO PET also allows us to investigate the efficacy of newly developed drugs on neuroinflammation in vivo in a preclinical setting in experimental animal models. But similar to the human conundrum, we need to know what cells express TSPO (e.g. microglia or astrocytes). Of similar importance is to find out whether the TSPO gene is regulated in a similar manner in animal models compared to humans. In contrast to the human microglia and macrophages, mouse microglia and macrophages upregulate TSPO after pro-inflammatory stimulation up to 10-fold, indicating that there are differences in the regulation of the TSPO gene between humans and mice143147. This questions whether biological processes in animal and experimental models of human diseases truly reflect the pathological processes occurring in humans148-150. Due to the limitations of TSPO, other candidate markers for PET imaging of microglia have been suggested, such as cyclooxygenase-2 (COX-2), cannabinoid receptor type 2 (CB2R), purinergic ion channel receptor 7 (P2X7R). However, the radioligands for these targets each come with their own obstacles in terms of radioligand binding, sensitivity and specificity of microglia. Multiple sclerosis Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the CNS, and is the most common disabling disease affecting young adults. MS most often presents itself between 20 and 40 years of age, but may occur in younger and older people. The first report of a disease with characteristics showing similar transient neurological deficits goes back as far as the 14th century, originating in the Netherlands. Despite decades of research into the aetiology of MS, the exact cause of MS is unknown, there is however evidence that the incidence of MS increases based on several environmental risk factors including the EpsteinBarr virus (EBV)151. EBV is present in nearly all people with MS (pwMS, > 99%), however roughly 95% of the general population has had an EBV infection during their lifetime152. Nevertheless, the risk of developing MS increases with EBV antibody titer153, and is linked
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