title: In Vivo Assessment of Brain White Matter Inflammation in Multiple Sclerosis with (18)F-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 = 0.62, P < 0.05).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom Imanova Centre for Imaging Sciences, London, United Kingdom a.colasanti@imperial.ac.uk p.matthews@imperial.ac.uk.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Colasanti
authors.affiliation: Imanova Centre for Imaging Sciences, London, United Kingdom Centre for Neuroimaging Sciences, Institute of Psychiatry, King's College London, London, United Kingdom.
authors.forename: Qi
authors.initials: Q
authors.lastname: Guo
authors.affiliation: UCL Institute of Neurology, London, United Kingdom School of Psychology and Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff, United Kingdom.
authors.forename: Nils
authors.initials: N
authors.lastname: Muhlert
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Paolo
authors.initials: P
authors.lastname: Giannetti
authors.affiliation: Imanova Centre for Imaging Sciences, London, United Kingdom.
authors.forename: Mayca
authors.initials: M
authors.lastname: Onega
authors.affiliation: Imanova Centre for Imaging Sciences, London, United Kingdom.
authors.forename: Rexford D
authors.initials: RD
authors.lastname: Newbould
authors.affiliation: UCL Institute of Neurology, London, United Kingdom.
authors.forename: Olga
authors.initials: O
authors.lastname: Ciccarelli
authors.affiliation: Imperial College Healthcare NHS Trust, London, United Kingdom; and.
authors.forename: Stuart
authors.initials: S
authors.lastname: Rison
authors.affiliation: Imperial College Healthcare NHS Trust, London, United Kingdom; and.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Thomas
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom Imperial College Healthcare NHS Trust, London, United Kingdom; and.
authors.forename: Richard
authors.initials: R
authors.lastname: Nicholas
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Muraro
authors.affiliation: Imperial College Healthcare NHS Trust, London, United Kingdom; and.
authors.forename: Omar
authors.initials: O
authors.lastname: Malik
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: David R
authors.initials: DR
authors.lastname: Owen
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Paola
authors.initials: P
authors.lastname: Piccini
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom Imanova Centre for Imaging Sciences, London, United Kingdom.
authors.forename: Roger N
authors.initials: RN
authors.lastname: Gunn
authors.affiliation: Imanova Centre for Imaging Sciences, London, United Kingdom Centre for Neuroimaging Sciences, Institute of Psychiatry, King's College London, London, United Kingdom a.colasanti@imperial.ac.uk p.matthews@imperial.ac.uk.
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom Neurosciences, GlaxoSmithKline, Brentford, United Kingdom a.colasanti@imperial.ac.uk p.matthews@imperial.ac.uk.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Matthews
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007249:Inflammation / Q000000981:diagnostic imaging; D008264:Macrophages / Q000276:immunology; D008297:Male; D017628:Microglia / Q000473:pathology; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000000981:diagnostic imaging* / Q000276:immunology / Q000473:pathology; D049268:Positron-Emission Tomography; D011725:Pyridines; D015203:Reproducibility of Results; D066127:White Matter / Q000000981:diagnostic imaging* / Q000276:immunology / Q000473:pathology
chemical_list: C550561:2-(6-chloro-2-(4-(3-fluoropropoxy)phenyl)imidazo(1,2-a)pyridin-3-yl)-N,N-diethylacetamide; D011725:Pyridines
keywords: MTR; PET; TSPO; lesion; microglia; multiple sclerosis