title: Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging.
abstract: 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 progression of the disease at these early stages. The extent of microglial activation appears to differ between patients, and could explain the overlap in translocator protein binding values between patients with Alzheimer's disease and amyloidosis controls.
authors.affiliation: Unit of Memory and Language, Université Paris Descartes, Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, INSERM UMR S894, Centre Hospitalier Sainte Anne, Paris, France UNIACT, NeuroSpin, Institut d'Imagerie Biomédicale, Direction des sciences du vivant, Commissariat à I'Energie Atomique, Gif-sur-Yvette, France Laboratoire Imagerie Moléculaire In Vivo (IMIV), CEA, Inserm, Univ Paris Sud, CNRS, Université Paris Saclay, CEA-SHFJ, 91400 Orsay, France.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Hamelin
authors.affiliation: Unit of Memory and Language, Université Paris Descartes, Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, INSERM UMR S894, Centre Hospitalier Sainte Anne, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Lagarde
authors.affiliation: Immune System, Neuroinflammation and Neurodegenerative Diseases, Hôpital St-Antoine, INSERM, UMRS 938, CdR Saint-Antoine, F-75012, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMRS 938, CdR Saint-Antoine, Hôpital Saint-Antoine, F-75012, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Dorothée
authors.affiliation: Laboratoire Imagerie Moléculaire In Vivo (IMIV), CEA, Inserm, Univ Paris Sud, CNRS, Université Paris Saclay, CEA-SHFJ, 91400 Orsay, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Leroy
authors.affiliation: CATI Multicenter Neuroimaging Platform, France.
authors.forename: Mickael
authors.initials: M
authors.lastname: Labit
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Comley
authors.affiliation: Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
authors.forename: Leonardo Cruz
authors.initials: LC
authors.lastname: de Souza
authors.affiliation: Department of Neurology, Salpêtrière Hospital, APHP, Paris, France.
authors.forename: Helene
authors.initials: H
authors.lastname: Corne
authors.affiliation: Inserm, U1127, F-75013, Paris, France CNRS, UMR 7225 ICM, 75013, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France CNRS, U 75, Paris, France.
authors.forename: Luce
authors.initials: L
authors.lastname: Dauphinot
authors.affiliation: Unit of Memory and Language, Université Paris Descartes, Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, INSERM UMR S894, Centre Hospitalier Sainte Anne, Paris, France Department of Clinical Neurosciences, University of Cambridge, UK.
authors.forename: Maxime
authors.initials: M
authors.lastname: Bertoux
authors.affiliation: Department of Neurology, Salpêtrière Hospital, APHP, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Dubois
authors.affiliation: Laboratoire Imagerie Moléculaire In Vivo (IMIV), CEA, Inserm, Univ Paris Sud, CNRS, Université Paris Saclay, CEA-SHFJ, 91400 Orsay, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gervais
authors.affiliation: Department of Neurology, Salpêtrière Hospital, APHP, Paris, France Inserm, U1127, F-75013, Paris, France CNRS, UMR 7225 ICM, 75013, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France Inria, Aramis project-team, Centre de Recherche de Paris, France Department of Neuroradiology, Pitié-Salpêtrière Hospital, APHP, F-75013 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Colliot
authors.affiliation: Inserm, U1127, F-75013, Paris, France CNRS, UMR 7225 ICM, 75013, Paris, France Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France Institut du Cerveau et de la Moelle épinière, ICM, F-75013, Paris, France CNRS, U 75, Paris, France.
authors.forename: Marie Claude
authors.initials: MC
authors.lastname: Potier
authors.affiliation: UNIACT, NeuroSpin, Institut d'Imagerie Biomédicale, Direction des sciences du vivant, Commissariat à I'Energie Atomique, Gif-sur-Yvette, France Laboratoire Imagerie Moléculaire In Vivo (IMIV), CEA, Inserm, Univ Paris Sud, CNRS, Université Paris Saclay, CEA-SHFJ, 91400 Orsay, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Bottlaender
authors.affiliation: Unit of Memory and Language, Université Paris Descartes, Sorbonne Paris Cité, Centre de Psychiatrie et Neurosciences, INSERM UMR S894, Centre Hospitalier Sainte Anne, Paris, France m.sarazin@ch-sainte-anne.fr.
authors.forename: Marie
authors.initials: M
authors.lastname: Sarazin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D005462:Fluorine Radioisotopes; D005500:Follow-Up Studies; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D017628:Microglia / Q000378:metabolism*; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000379:methods*; D011446:Prospective Studies; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D005462:Fluorine Radioisotopes; C530129:N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide; D011720:Pyrazoles; D011743:Pyrimidines
keywords: Alzheimer’s disease; biomarkers; inflammation; microglia; neuroprotection