In Vivo Assessment of Brain White Matter Inflammation in Multiple Sclerosis with¹⁸F-PBR111 PET

Abstract

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. Methods: 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. Results: 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 5 0.62, P , 0.05). Conclusion: 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.

Imaging robust microglial activation after lipopolysaccharide administration in humans with PET

“…Significantly higher TSPO expression, measured with [ 11 C]PBR28 and PET, was recently found in cortical brain regions of patients with early onset Alzheimer's disease compared with subjects with mild cognitive impairment and healthy controls (22), which highlights the potential role of neuroinflammation in the etiology of Alzheimer's disease (6). However, studies examining TSPO expression between healthy control subjects and other patient groups such as multiple sclerosis, depression, or cocaine abusers (23)(24)(25)(26)(27) have produced mixed results. A well-established and robust preclinical model uses the administration of Escherichia coli lipopolysaccharide (LPS; also called endotoxin) to trigger "classic" activation of microglia and has been used in rodents to study neurodegeneration (28)(29)(30)(31).…”

Recent imaging advances in neurology

“…Second generation TSPO radioligands such as [ 11 [142][143][144]. Increased [ 18 F]PBR111 binding has been found in MS lesions and in perilesional white matter (WM) volumes of MS patients compared to healthy controls [144].…”

Microglial positron emission tomography (PET) imaging in epilepsy: Applications, opportunities and pitfalls

“…Human studies using these secondgeneration ligands have demonstrated increased TSPO expression in a variety of CNS disorders, including Alzheimer's disease [37], amyotrophic lateral sclerosis [34], and multiple sclerosis [38].…”