22 Chapter 1 (a) (b) (f ) (l) WML WM GML GM (c) (g) (m) GM WM (j) (k) (e) (o) WML WM GML GM (h) (i) (d) (n) Figure 5. Immune responses in human and experimental inflammatory neurodegenerative disorders. B‐cells (arrows) are observed in white (a) and grey matter lesions (b) in multiple sclerosis (MS). (c) and (d) depict an MS leucocortical lesion. The white matter (WML) is associated with HLA+ microglia (d, WML) in contrast to the lack of HLA + microglia in the grey matter (d, GML). A similar pattern of HLA+ cells is seen in the white and grey matter in an X‐ALD case (e) and where peripheral macrophages infiltrate the white matter (f). Granulocytes (arrow) in suspected vasculitis cases (g). Ageing influences the activity of microglia in a mouse model of MS: microglia in the CNS of young mice (h; Iba1 staining) are less active than in aged mice (i). In MS cases microglia in NAWM express P2Y12 (j) and TMEM119 (k). In progressive multifocal leucoencephalopathy astrocytes (l, arrow) and activated microglia/ macrophages (m, arrow) are highly reactive in an area of demyelination. The paucity of astrocytic glial fibrillary acidic protein expression (red circle, n) is associated with an area of microglial activation (red circle, o) in acute haemorrhagic leucoencephalitis. This is likely at least partly explained by the low representation (1-2%) of the mutation in people with ALS. Animal models for AD most commonly represent either amyloid pathology by increasing Aβ, or increasing the relative ratio of Aβ42 which is prone to aggregation or tau pathology by overexpressing the microtubule-associated protein tau194. Again, both models have relatively poor translational value when it comes to disease modifying therapies as over the last decades almost no positive clinical results have been yielded. Although experimental animal models are often used to study CNS pathology they rarely reflect the multifactorial complexity of human diseases. Failure of translation of disease modifying therapies may be attributed to varying study designs, imperfect animal models or timing of therapy. Nevertheless, TSPO PET is utilised to monitor ongoing neuroinflammation in vivo in experimental animals. Indeed, increases in TSPO PET signal are found in EAE, SOD1G93A, and APP and TAUP301S experimental animal models141,195-197. However, there is no consensus on whether this increase in TSPO is due to increased microglial density, an increase in TSPO expression, or an increase in ligand binding or whether this is disease, model or contextdependent.
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