title: In vivo PET imaging demonstrates diminished microglial activation after fingolimod treatment in an animal model of multiple sclerosis.
abstract: There is a great need for the monitoring of microglial activation surrounding multiple sclerosis lesions because the activation of microglia is thought to drive widespread neuronal damage. Recently, second-generation PET radioligands that can reveal the extent of microglial activation by quantifying the increased expression of the 18-kDa translocator protein have been developed. Here, we investigate whether PET imaging can be used to demonstrate the reduction in microglial activation surrounding a chronic focal multiple sclerosis (MS)-like lesion after treatment with fingolimod, an established MS therapy.
  
  
  METHODS
  Chronic focal experimental autoimmune encephalitis (EAE)-like lesions were induced in Lewis rats (n = 24) via stereotactic intrastriatal injection of heat-killed bacillus Calmette-Guérin (BCG) and subsequent activation using an intradermal injection of BCG in complete Freund adjuvant. This process resulted in a delayed-type hypersensitivity (DTH)-like EAE lesion. The extent of neuroinflammation surrounding the lesion was measured using (18)F-GE180 as a PET radioligand. The imaging was performed before and after treatment with fingolimod (0.3 mg/kg/d by mouth, 28 d) or vehicle as a control. In addition to imaging, autoradiography and immunohistochemistry experiments were performed to verify the in vivo results.
  
  
  RESULTS
  The chronic DTH EAE lesion led to increased ligand binding in the ipsilateral, compared with contralateral, hemisphere when PET imaging was performed with the translocator protein-binding radioligand (18)F-GE180. Treatment with fingolimod led to a highly significant reduction in the binding potential, which could be demonstrated using both in vivo and ex vivo imaging (fingolimod vs. vehicle treatment, P < 0.0001). The area of increased (18)F-GE180 signal mapped closely to the area of activated microglial cells detected by immunohistochemistry.
  
  
  CONCLUSIONS
  PET imaging, unlike MR imaging, can be used to visualize the microglial activation surrounding a chronic DTH EAE lesion. Importantly, the treatment effect of fingolimod can be monitored in vivo by measuring the degree of microglial activation surrounding the chronic DTH EAE lesion. This work gives promise for the introduction of new outcome measures applicable in treatment studies of progressive MS.
authors.affiliation: Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland laura.airas@utu.fi.
authors.forename: Laura
authors.initials: L
authors.lastname: Airas
authors.affiliation: Medicity/Preclinical Imaging, Turku PET Centre, University of Turku, Turku, Finland.
authors.forename: Alex M
authors.initials: AM
authors.lastname: Dickens
authors.affiliation: Medicity/Preclinical Imaging, Turku PET Centre, University of Turku, Turku, Finland.
authors.forename: Petri
authors.initials: P
authors.lastname: Elo
authors.affiliation: Medicity/Preclinical Imaging, Turku PET Centre, University of Turku, Turku, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Marjamäki
authors.affiliation: Clinical Neurology, Turku PET Centre, University of Turku, Turku, Finland.
authors.forename: Jarkko
authors.initials: J
authors.lastname: Johansson
authors.affiliation: Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku, Turku, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Eskola
authors.affiliation: GE Healthcare Ltd., The Grove Centre, Amersham, United Kingdom; and.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Jones
authors.affiliation: GE Healthcare Ltd., The Grove Centre, Amersham, United Kingdom; and.
authors.forename: William
authors.initials: W
authors.lastname: Trigg
authors.affiliation: Radiopharmaceutical Chemistry Laboratory, Turku PET Centre, University of Turku, Turku, Finland.
authors.forename: Olof
authors.initials: O
authors.lastname: Solin
authors.affiliation: Medicity/Preclinical Imaging, Turku PET Centre, University of Turku, Turku, Finland.
authors.forename: Merja
authors.initials: M
authors.lastname: Haaparanta-Solin
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Anthony
authors.affiliation: Clinical Neurology, Turku PET Centre, University of Turku, Turku, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Rinne
mesh_terms: D000818:Animals; D001345:Autoradiography; D001500:BCG Vaccine / Q000737:chemistry; D002352:Carrier Proteins / Q000737:chemistry; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000000981:diagnostic imaging; D000068876:Fingolimod Hydrochloride; D005620:Freund's Adjuvant; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007249:Inflammation; D008024:Ligands; D008297:Male; D017628:Microglia / Q000000981:diagnostic imaging*; D009103:Multiple Sclerosis / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography; D011409:Propylene Glycols / Q000008:administration & dosage*; D051381:Rats; D011917:Rats, Inbred Lew; D011963:Receptors, GABA-A / Q000737:chemistry; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013997:Time Factors
chemical_list: D001500:BCG Vaccine; D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D008024:Ligands; D011409:Propylene Glycols; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; D005620:Freund's Adjuvant; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: PET imaging; TSPO; fingolimod; multiple sclerosis; neuroinflammation