Microglial activation in presymptomatic Huntington's disease gene carriers.
Microglial activation may play a role in the pathogenesis of Huntington's disease (HD). Using 11C-(R)-PK11195 (PK) positron emission tomography (PET), we investigated microglial activation in HD presymptomatic gene carriers (PGCs), its relationship with striatal neuronal dysfunction measured with 11C-raclopride (RAC) PET, and the role of PK PET as a possible marker of subclinical disease progression in PGCs. Eleven HD PGCs underwent PK and RAC PET. Their results were compared with those of healthy controls. PK and RAC binding was measured using region-of-interest analysis. Regional increases in PK binding were also localized with voxel-based statistical parametric mapping. HD PGCs had lower striatal RAC binding than the controls but significantly higher striatal and cortical PK binding. Individual levels of higher striatal PK binding in PGCs correlated with lower striatal RAC binding and, after excluding one outlier, with a higher probability of developing HD in 5 years. The inverse association between striatal PK and RAC binding in PGCs continues into early to moderate stages of HD. This study demonstrated for the first time in vivo widespread microglial activation in preclinical HD which correlated with striatal neuronal dysfunction. These findings indicate that microglial activation is an early event in the pathogenic processes of HD and is associated with subclinical progression of disease. PK PET may be a useful marker of active subclinical disease and a means of investigating the efficacy of neuroprotection strategies in PGCs.
Tai
Yen F
YF
MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
Pavese
Nicola
N
Gerhard
Alexander
A
Tabrizi
Sarah J
SJ
Barker
Roger A
RA
Brooks
David J
DJ
Piccini
Paola
P
D000328:Adult; D001931:Brain Mapping / Q000379:methods; D002250:Carbon Radioisotopes; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006579:Heterozygote; D006801:Humans; D006816:Huntington Disease / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D007091:Image Processing, Computer-Assisted / Q000379:methods; D007546:Isoquinolines; D008297:Male; D017628:Microglia / Q000502:physiology*; D008875:Middle Aged; D009474:Neurons / Q000502:physiology; D049268:Positron-Emission Tomography / Q000379:methods; D020891:Raclopride; D019275:Radiopharmaceuticals
D002250:Carbon Radioisotopes; D007546:Isoquinolines; D019275:Radiopharmaceuticals; D020891:Raclopride; C037850:PK 11195