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A Study of the activated innate immune system of the brain in multiple sclerosis with translocator protein positron emission tomography combined with magnetic resonance imaging

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Title: A Study of the activated innate immune system of the brain in multiple sclerosis with translocator protein positron emission tomography combined with magnetic resonance imaging
Authors: Datta, Gourab
Item Type: Thesis or dissertation
Abstract: Magnetic resonance imaging (MRI) of the brain is the mainstay of diagnosis and monitoring of multiple sclerosis (MS) patients. Conventional brain MRI imaging captures characteristic multifocal demyelinating white matter lesions (WML). However, these imaging measures do not effectively predict an individual patient’s future clinical condition, limiting the ability of clinicians to rationalize therapy. In part, this is because cMRI lacks sensitivity and specificity in detecting chronic diffuse and multi-focal inflammation mediated by activated microglia/macrophages. In this work, molecular imaging using second generation translocator protein (TSPO) positron emission tomography (PET) and advanced MRI sequences are used to investigate inflammation in the brains of MS patients. A reference tissue based approach is used to quantify uptake of the TSPO PET ligands, as a marker of activated microglia/macrophages. The TSPO PET brain signal in extra-lesional white matter (so-called “normal appearing white matter” or NAWM) and individual WML of MS patients are evaluated with two TSPO radioligands, [11C]PBR28 and [18F]PBR11, and compared with a group of healthy volunteers. Individual lesions are classified based on TSPO binding to test whether heterogeneity of microglial/macrophage activation in lesions could be detected in vivo in a way analogous to histopathological studies in MS brains. An exploratory analysis is performed of the relationships between [11C]PBR28 binding and the putative astrocyte marker [myo-inositol] using single voxel proton magnetic resonance spectroscopy (MRS). Finally, a longitudinal analysis is performed to explore how differences in baseline [11C]PBR28 binding relate to future changes in WML and brain volume changes after 1 year. TSPO binding was higher in the MRI NAWM for both second generation radioligands than in the white matter of healthy volunteers. Both radioligands demonstrated considerable heterogeneity in TSPO binding in NAWM and between lesions in the patients. When considering the lesions individually, lesions with diffusely high TSPO radioligand uptake were seen in all disease stages and treatment groups. This indicates that second generation TSPO PET imaging detects a range of active inflammation not detected by conventional MRI in MS patients and that the inflammation is ongoing at all disease stages and may not be completely suppressed even in patients on the most efficacious treatments with good clinical control of symptoms. In the exploratory analysis of MRS [myo-inositol] and PET [11C]PBR28 uptake, there was no correlation between the two measures for the whole cohort of MS patients. This is consistent with the notion that changes in the two measures are related to distinct processes or to elements of a common process with different time courses. In the longitudinal analyses, NAWM and WML [11C]PBR28 binding at baseline was correlated to enlarging T2 lesion volume change after 1 year, driven by the subgroup of relapsing remitting MS patients (RRMS). Baseline white matter TSPO binding was associated with the longitudinal brain atrophy changes in the secondary progressive MS (SPMS) subgroup of patients. These observations together suggest that during the earlier disease microglial activation may contribute to greater neuroaxonal loss locally in and around lesions, while in the later stages of disease, brain innate immune inflammation becomes more diffuse and contributes to global neurodegeneration. These findings were combined into a single multimodal model where baseline MRI and [11C]PBR28 binding independently contribute to the description of the subsequent enlarging T2 lesion volume changes after 1 year.
Content Version: Open Access
Issue Date: May-2017
Date Awarded: Nov-2017
URI: http://hdl.handle.net/10044/1/54756
DOI: https://doi.org/10.25560/54756
Supervisor: Matthews, Paul
Sponsor/Funder: Wellcome Trust (London, England)
GlaxoSmithKline
Department: Department of Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses



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