Evaluation of the Effect of Fingolimod Treatment on Microglial Activation Using Serial PET Imaging in Multiple Sclerosis.
Traditionally, multiple sclerosis (MS) has been considered a white matter disease with focal inflammatory lesions. It is, however, becoming clear that significant pathology, such as microglial activation, also takes place outside the plaque areas, that is, in areas of normal-appearing white matter (NAWM) and gray matter (GM). Microglial activation can be detected in vivo using 18-kDa translocator protein (TSPO)-binding radioligands and PET. It is unknown whether fingolimod affects microglial activation in MS. The aim of this study was to investigate whether serial PET can be used to evaluate the effect of fingolimod treatment on microglial activation.Methods:Ten relapsing-remitting MS patients were studied using the TSPO radioligand11C-(R)-PK11195. Imaging was performed at baseline and after 8 and 24 wk of fingolimod treatment. Eight healthy individuals were imaged for comparison. Microglial activation was evaluated as distribution volume ratio of11C-(R)-PK11195.Results:The patients had MS for an average of 7.9 ± 4.3 y (mean ± SD), their total relapses averaged 4 ± 2.4, and their Expanded Disability Status Scale was 2.7 ± 0.5. The patients were switched to fingolimod because of safety reasons or therapy escalation. The mean washout period before the initiation of fingolimod was 2.3 ± 1.1 mo. The patients were clinically stable on fingolimod. At baseline, microglial activation was significantly higher in the combined NAWM and GM areas of MS patients than in healthy controls (P =0.021).11C-(R)-PK11195 binding was reduced (-12.31%) within the combined T2 lesion area after 6 mo of fingolimod treatment (P =0.040) but not in the areas of NAWM or GM.Conclusion:Fingolimod treatment reduced microglial/macrophage activation at the site of focal inflammatory lesions, presumably by preventing leukocyte trafficking from the periphery. It did not affect the widespread, diffuse microglial activation in the NAWM and GM. The study opens new vistas for designing future therapeutic studies in MS that use the evaluation of microglial activation as an imaging outcome measure.
Division of Clinical Neurosciences, Turku University Hospital, Kiinamyllynkatu 4-8, Turku, Finland; and marcus.sucksdorff@tyks.fi.|Turku PET Centre, Clinical Neurology, University of Turku, Kiinamyllynkatu 4-8, Turku, Finland.
Marcus
M
Sucksdorff
Division of Clinical Neurosciences, Turku University Hospital, Kiinamyllynkatu 4-8, Turku, Finland; and.|Turku PET Centre, Clinical Neurology, University of Turku, Kiinamyllynkatu 4-8, Turku, Finland.
Eero
E
Rissanen
Turku PET Centre, Clinical Neurology, University of Turku, Kiinamyllynkatu 4-8, Turku, Finland.
Jouni
J
Tuisku
Division of Clinical Neurosciences, Turku University Hospital, Kiinamyllynkatu 4-8, Turku, Finland; and.
Salla
S
Nuutinen
Turku PET Centre, Clinical Neurology, University of Turku, Kiinamyllynkatu 4-8, Turku, Finland.
Teemu
T
Paavilainen
Turku PET Centre, Clinical Neurology, University of Turku, Kiinamyllynkatu 4-8, Turku, Finland.
Johanna
J
Rokka
Division of Clinical Neurosciences, Turku University Hospital, Kiinamyllynkatu 4-8, Turku, Finland; and.|Turku PET Centre, Clinical Neurology, University of Turku, Kiinamyllynkatu 4-8, Turku, Finland.
Juha
J
Rinne
Division of Clinical Neurosciences, Turku University Hospital, Kiinamyllynkatu 4-8, Turku, Finland; and.|Turku PET Centre, Clinical Neurology, University of Turku, Kiinamyllynkatu 4-8, Turku, Finland.
Laura
L
Airas
D000293:Adolescent; D000328:Adult; D000368:Aged; D002250:Carbon Radioisotopes; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000473:pathology; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049268:Positron-Emission Tomography; D066127:White Matter / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D055815:Young Adult
D002250:Carbon Radioisotopes; D007546:Isoquinolines; D000068876:Fingolimod Hydrochloride; C037850:PK 11195
PET imaging; TSPO; fingolimod; microglia; multiple sclerosis