23 General introduction Aim of thesis Advancing techniques and increasing knowledge on cellular processes during neuroinflammation have contributed towards generating many targets for imaging neuroinflammation with PET. The aim of this thesis is to better understand the expression of TSPO in CNS diseases and respective animal models as well as investigating the role of microglia and astrocytes as innate immune cells of the brain in CNS diseases. Hypothesis The hypothesis tested in this thesis is that TSPO is not a marker of activated microglia in the human brain. We hypothesise that TSPO is not increased in activated microglia and there is a substantial contribution of other cell types to the TSPO PET signal. While TSPO PET might be a good marker for innate immune processes, increased TSPO PET signal might originate from multiple cell types in the CNS, and/or reflect cell density rather than phenotype of TSPO expressing cells. Outline Increased TSPO PET signal is widely attributed to activated pathogenic microglia in CNS diseases and the contributions of other cells, as well as the cell phenotype has been overlooked in many neuroinflammatory diseases. On this basis, the identification of the cellular expression of TSPO in MS in microglia, astrocytes and other cell types as well as their activation state was considered key to understanding the data arising from TSPO PET imaging in MS (Chapter 2). Studies of multiple sclerosis (MS) lesions reveal that TSPO is not restricted to pro-inflammatory microglia/macrophages, but also present in homeostatic or reparative microglia. Here, we investigated quantitative relationships between TSPO expression and microglia/macrophage phenotypes in white matter and lesions of brains with MS pathology (Chapter 3). Since TSPO PET is increasingly used as a marker for neuroinflammation in the CNS, characterisation of TSPO for PET in neurodegenerative diseases with inflammatory components, such as ALS and AD, is of importance. Additionally, many studies are done on animal models for CNS diseases but results do not translate well to humans. To identify possible phylogenetic diversity between humans and rodents in the expression and regulation of TSPO we directly compared ALS, and AD with their respective animal models, as well as EAE (Chapter 4). TSPO expression is altered in many neurodegenerative, neuroinflammatory, and neuropsychiatric diseases. In PET studies, the TSPO signal is often viewed as a marker of microglial cell activity. However, there is little evidence in support of a microglia-specific TSPO expression. Therefore, we described the cellular sources and functions of TSPO in animal models of disease and human studies, in health, and in CNS diseases (Chapter 5). Clinical disability of pwMS is considered primarily a result of axonal loss. Given the reported correlation between indices of spinal cord cross-sectional area (CSA) and disability, and earlier evidence suggesting axonal loss as the key driver of chronic disability. We have compared the extent of axonal loss and whether this correlates with local neuronal loss in the spinal cord of pwMS (Chapter 6).
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