Positron emissiontomography imaging of neuroinflammation in Multiple Sclerosis with a second generation translocator protein PET radioligand

Abstract

This thesis describes a new approach for molecular imaging of neuroinflammation in Multiple Sclerosis (MS). My aim was to use the 2nd generation TSPO radioligand 18F-PBR111 to explore the potential of Positron Emission Tomography (PET) targeting the 18-kDa Translocator Protein (TSPO), as an in vivo biomarker of activated microglia in MS patients. This thesis addresses three research objectives. First, I characterised 18F-PBR111 PET signal in healthy controls’ brains and tested how it is affected by the TSPO gene polymorphism at rs6971. Second, I measured 18F-PBR111 uptake across white matter volumes segmented using structural MRI measures related to MS neuropathology. Third, I explored how 18F-PBR111 uptake in the hippocampus correlated with depressive symptoms and to the brain functional connectivity of the hippocampus. Eleven patients with relapsing-remitting MS and 22 age-matched healthy controls underwent 18F-PBR111 PET and MRI scans. Structural and functional MRI sequences were used to define conventional MS neuropathological markers and for the assessment of functional connectivity, respectively. I discovered that white matter 18F-PBR111 PET signal in healthy volunteers varied with TSPO genotype and correlated positively with age. In patients with MS, signal intensity in MRI-defined lesions was higher than that in normal-appearing white matter and correlated with the historical rate of progression of their disability. Hippocampal 18F-PBR111 uptake was higher in the MS patient group than in healthy volunteers and correlated with both depressive symptoms and functional connectivity of the hippocampus with frontal, temporal and parietal cortex. I thus discovered that this 2nd generation TSPO PET radiotracer, used in humans for the first time in our study, is sensitive to MS neuropathology consistent with recognized patterns of microglial activation and that differences between subjects can be related to disability progression. I also have discovered a novel relationship between this measure of hippocampal microglial activation and affective symptoms of MS.