2-(6-chloro-2-(4-(3-fluoropropoxy)phenyl)imidazo(1-2-a)pyridin-3-yl)-n-n-diethylacetamide and Multiple-Sclerosis

The objective of this study was to assess microglial activation in lesions and in normal-appearing white matter (NAWM) of multiple sclerosis (MS) patients using PET.

Topics: Adult; Biological Transport; Brain; Female; Humans; Inflammation; Ligands; Male; Middle Aged; Multiple Sclerosis; Positron-Emission Tomography; Pyridines; Pyrimidines; White Matter

Depression, a condition commonly comorbid with multiple sclerosis (MS), is associated more generally with elevated inflammatory markers and hippocampal pathology. We hypothesized that neuroinflammation in the hippocampus is responsible for depression associated with MS. We characterized the relationship between depressive symptoms and hippocampal microglial activation in patients with MS using the 18-kDa translocator protein radioligand [(18)F]PBR111. To evaluate pathophysiologic mechanisms, we explored the relationships between hippocampal neuroinflammation, depressive symptoms, and hippocampal functional connectivities defined by resting-state functional magnetic resonance imaging.. The Beck Depression Inventory (BDI) was administered to 11 patients with MS and 22 healthy control subjects before scanning with positron emission tomography and functional magnetic resonance imaging. We tested for higher [(18)F]PBR111 uptake in the hippocampus of patients with MS relative to healthy control subjects and examined the correlations between [(18)F]PBR111 uptake, BDI scores, and hippocampal functional connectivities in the patients with MS.. Patients with MS had an increased hippocampal [(18)F]PBR111 distribution volume ratio relative to healthy control subjects (p = .024), and the hippocampal distribution volume ratio was strongly correlated with the BDI score in patients with MS (r = .86, p = .006). Hippocampal functional connectivities to the subgenual cingulate and prefrontal and parietal regions correlated with BDI scores and [(18)F]PBR111 distribution volume ratio.. Our results provide evidence that hippocampal microglial activation in MS impairs the brain functional connectivities in regions contributing to maintenance of a normal affective state. Our results suggest a rationale for the responsiveness of depression in some patients with MS to effective control of brain neuroinflammation. Our findings also lend support to further investigation of the role of inflammatory processes in the pathogenesis of depression more generally.

Topics: Adult; Connectome; Depression; Female; Hippocampus; Humans; Inflammation; Magnetic Resonance Imaging; Male; Microglia; Middle Aged; Multiple Sclerosis; Neuroimmunomodulation; Positron-Emission Tomography; Pyridines

PET radioligand binding to the 18-kD translocator protein (TSPO) in the brains of patients with multiple sclerosis (MS) primarily reflects activated microglia and macrophages. We previously developed genetic stratification for accurate quantitative estimation of TSPO using second-generation PET radioligands. In this study, we used (18)F-PBR111 PET and MR imaging to measure relative binding in the lesional, perilesional, and surrounding normal-appearing white matter of MS patients, as an index of the innate immune response.. (18)F-PBR111 binding was quantified in 11 MS patients and 11 age-matched healthy volunteers, stratified according to the rs6971 TSPO gene polymorphism. Fluid-attenuated inversion recovery and magnetization transfer ratio (MTR) MR imaging were used to segment the white matter in MS patients as lesions, perilesional volumes, nonlesional white matter with reduced MTR, and nonlesional white matter with normal MTR.. (18)F-PBR111 binding was higher in the white matter lesions and perilesional volumes of MS patients than in white matter of healthy controls (P < 0.05). Although there was substantial heterogeneity in binding between different lesions, a within-subject analysis showed higher (18)F-PBR111 binding in MS lesions (P < 0.05) and in perilesional (P < 0.05) and nonlesional white matter with reduced MTR (P < 0.005) than in nonlesional white matter with a normal MTR. A positive correlation was observed between the mean (18)F-PBR111 volume of distribution increase in lesions relative to nonlesional white matter with a normal MTR and the MS severity score (Spearman ρ = 0.62, P < 0.05).. This study demonstrates that quantitative TSPO PET with a second-generation radioligand can be used to characterize innate immune responses in MS in vivo and provides further evidence supporting an association between the white matter TSPO PET signal in lesions and disease severity. Our approach is practical for extension to studies of the role of the innate immune response in MS for differentiation of antiinflammatory effects of new medicines and their longer term impact on clinical outcome.

Topics: Adult; Aged; Case-Control Studies; Female; Humans; Inflammation; Macrophages; Male; Microglia; Middle Aged; Multiple Sclerosis; Positron-Emission Tomography; Pyridines; Reproducibility of Results; White Matter