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Brain. 2016 Apr;139(Pt 4):1252-64. doi: 10.1093/brain/aww017. Epub 2016 Mar 15.

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

Author information

1
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.
2
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.
3
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.
4
Laboratoire Imagerie Moléculaire In Vivo (IMIV), CEA, Inserm, Univ Paris Sud, CNRS, Université Paris Saclay, CEA-SHFJ, 91400 Orsay, France.
5
CATI Multicenter Neuroimaging Platform, France.
6
Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
7
Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
8
Department of Neurology, Salpêtrière Hospital, APHP, Paris, France.
9
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.
10
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.
11
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.
12
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.
13
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.

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.

KEYWORDS:

Alzheimer’s disease; biomarkers; inflammation; microglia; neuroprotection

PMID:
26984188
DOI:
10.1093/brain/aww017
[Indexed for MEDLINE]

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