title: Central nervous system expression and PET imaging of the translocator protein in relapsing-remitting experimental autoimmune encephalomyelitis.
abstract: Glial neuroinflammation is associated with the development and progression of multiple sclerosis. PET imaging offers a unique opportunity to evaluate neuroinflammatory processes longitudinally in a noninvasive and clinically translational manner. (18)F-PBR111 is a newly developed PET radiopharmaceutical with high affinity and selectivity for the translocator protein (TSPO), expressed on activated glia. This study aimed to investigate neuroinflammation at different phases of relapsing-remitting (RR) experimental autoimmune encephalomyelitis (EAE) in the brains of SJL/J mice by postmortem histologic analysis and in vivo by PET imaging with (18)F-PBR111.
  
  
  METHODS
  RR EAE was induced by immunization with PLP(139-151) peptide in complete Freund's adjuvant. Naive female SJL/J mice and mice immunized with saline-complete Freund's adjuvant were used as controls. The biodistribution of (18)F-PBR111 was measured in 13 areas of the central nervous system and compared with PET imaging results during different phases of RR EAE. The extents of TSPO expression and glial activation were assessed with immunohistochemistry, immunofluorescence, and a real-time polymerase chain reaction.
  
  
  RESULTS
  There was significant TSPO expression in all of the central nervous system areas studied at the peak of the first clinical episode and, importantly, at the preclinical stage. In contrast, only a few TSPO-positive cells were observed at the second episode. At the third episode, there was again an increase in TSPO expression. TSPO expression was associated with microglial cells or macrophages without obvious astrocyte labeling. The dynamics of (18)F-PBR111 uptake in the brain, as measured by in vivo PET imaging and biodistribution, followed the pattern of TSPO expression during RR EAE.
  
  
  CONCLUSIONS
  PET imaging with the TSPO ligand (18)F-PBR111 clearly reflected the dynamics of microglial activation in the SJL/J mouse model of RR EAE. The results are the first to highlight the discrepancy between the clinical symptoms of EAE and TSPO expression in the brain, as measured by PET imaging at the peaks of various EAE episodes. The results suggest a significant role for PET imaging investigations of neuroinflammation in multiple sclerosis and allow for in vivo follow-up of antiinflammatory treatment strategies.
authors: Life Sciences Division, Australian Nuclear Science and Technology Organisation, Lucas Heights, New South Wales, Australia. mattnerf@gmail.com
authors: Filomena
authors: F
authors: Mattner
authors: Maria
authors: M
authors: Staykova
authors: Paula
authors: P
authors: Berghofer
authors: Heng Jian
authors: HJ
authors: Wong
authors: Susan
authors: S
authors: Fordham
authors: Paul
authors: P
authors: Callaghan
authors: Timothy
authors: T
authors: Jackson
authors: Tien
authors: T
authors: Pham
authors: Marie-Claude
authors: MC
authors: Gregoire
authors: David
authors: D
authors: Zahra
authors: Gita
authors: G
authors: Rahardjo
authors: David
authors: D
authors: Linares
authors: Andrew
authors: A
authors: Katsifis
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000378:metabolism*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy / Q000503:physiopathology; D049268:Positron-Emission Tomography / Q000379:methods*; D021381:Protein Transport; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D018079:Receptors, GABA / Q000096:biosynthesis*
chemical_list: C463819:Bzrp protein, mouse; D018079:Receptors, GABA