Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging

• Published in: Brain (London, England : 1878) England : 1878), 2016-04, Vol.139 (Pt 4), p.1252-1264
• Main Authors: Hamelin, Lorraine, Lagarde, Julien, Dorothée, Guillaume, Leroy, Claire, Labit, Mickael, Comley, Robert A, de Souza, Leonardo Cruz, Corne, Helene, Dauphinot, Luce, Bertoux, Maxime, Dubois, Bruno, Gervais, Philippe, Colliot, Olivier, Potier, Marie Claude, Bottlaender, Michel, Sarazin, Marie
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - metabolism; Bioengineering; Brain; Brain - metabolism; Brain - pathology; Cohort Studies; Computer Science; Computer Vision and Pattern Recognition; Engineering Sciences; Female; Fluorine Radioisotopes; Follow-Up Studies; Humans; Image Processing; Imaging; Life Sciences; Longitudinal Studies; Male; Medical Imaging; Microglia; Microglia - metabolism; Middle Aged; Neurobiology; Neurons and Cognition; Positron-Emission Tomography; Positron-Emission Tomography - methods; Prospective Studies; Pyrazoles; Pyrimidines; Signal and Image processing
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/aww017

While emerging evidence suggests that neuroinflammation plays a crucial role in Alzheimer's disease, the impact of the microglia response in Alzheimer's disease remains a matter of debate. We aimed to study microglial activation in early Alzheimer's disease and its impact on clinical progression using a second-generation 18-kDa translocator protein positron emission tomography radiotracer together with amyloid imaging using Pittsburgh compound B positron emission tomography. We enrolled 96 subjects, 64 patients with Alzheimer's disease and 32 controls, from the IMABio3 study, who had both (11)C-Pittsburgh compound B and (18)F-DPA-714 positron emission tomography imaging. Patients with Alzheimer's disease were classified as prodromal Alzheimer's disease (n = 38) and Alzheimer's disease dementia (n = 26). Translocator protein-binding was measured using a simple ratio method with cerebellar grey matter as reference tissue, taking into account regional atrophy. Images were analysed at the regional (volume of interest) and at the voxel level. Translocator protein genotyping allowed the classification of all subjects in high, mixed and low affinity binders. Thirty high+mixed affinity binders patients with Alzheimer's disease were dichotomized into slow decliners (n = 10) or fast decliners (n = 20) after 2 years of follow-up. All patients with Alzheimer's disease had an amyloid positive Pittsburgh compound B positron emission tomography. Among controls, eight had positive amyloid scans (n = 6 high+mixed affinity binders), defined as amyloidosis controls, and were analysed separately. By both volumes of interest and voxel-wise comparison, 18-kDa translocator protein-binding was higher in high affinity binders, mixed affinity binders and high+mixed affinity binders Alzheimer's disease groups compared to controls, especially at the prodromal stage, involving the temporo-parietal cortex. Translocator protein-binding was positively correlated with Mini-Mental State Examination scores and grey matter volume, as well as with Pittsburgh compound B binding. Amyloidosis controls displayed higher translocator protein-binding than controls, especially in the frontal cortex. We found higher translocator protein-binding in slow decliners than fast decliners, with no difference in Pittsburgh compound B binding. Microglial activation appears at the prodromal and possibly at the preclinical stage of Alzheimer's disease, and seems to play a protective role in the clinical progress