title: An early and late peak in microglial activation in Alzheimer's disease trajectory.
abstract: Amyloid-β deposition, neuroinflammation and tau tangle formation all play a significant role in Alzheimer's disease. We hypothesized that there is microglial activation early on in Alzheimer's disease trajectory, where in the initial phase, microglia may be trying to repair the damage, while later on in the disease these microglia could be ineffective and produce proinflammatory cytokines leading to progressive neuronal damage. In this longitudinal study, we have evaluated the temporal profile of microglial activation and its relationship between fibrillar amyloid load at baseline and follow-up in subjects with mild cognitive impairment, and this was compared with subjects with Alzheimer's disease. Thirty subjects (eight mild cognitive impairment, eight Alzheimer's disease and 14 controls) aged between 54 and 77 years underwent 11C-(R)PK11195, 11C-PIB positron emission tomography and magnetic resonance imaging scans. Patients were followed-up after 14 ± 4 months. Region of interest and Statistical Parametric Mapping analysis were used to determine longitudinal alterations. Single subject analysis was performed to evaluate the individualized pathological changes over time. Correlations between levels of microglial activation and amyloid deposition at a voxel level were assessed using Biological Parametric Mapping. We demonstrated that both baseline and follow-up microglial activation in the mild cognitive impairment cohort compared to controls were increased by 41% and 21%, respectively. There was a longitudinal reduction of 18% in microglial activation in mild cognitive impairment cohort over 14 months, which was associated with a mild elevation in fibrillar amyloid load. Cortical clusters of microglial activation and amyloid deposition spatially overlapped in the subjects with mild cognitive impairment. Baseline microglial activation was increased by 36% in Alzheimer's disease subjects compared with controls. Longitudinally, Alzheimer's disease subjects showed an increase in microglial activation. In conclusion, this is one of the first longitudinal positron emission tomography studies evaluating longitudinal changes in microglial activation in mild cognitive impairment and Alzheimer's disease subjects. We found there is an initial longitudinal reduction in microglial activation in subjects with mild cognitive impairment, while subjects with Alzheimer's disease showed an increase in microglial activation. This could reflect that activated microglia in mild cognitive impairment initially may adopt a protective activation phenotype, which later change to a cidal pro-inflammatory phenotype as disease progresses and amyloid clearance fails. Thus, we speculate that there might be two peaks of microglial activation in the Alzheimer's disease trajectory; an early protective peak and a later pro-inflammatory peak. If so, anti-microglial agents targeting the pro-inflammatory phenotype would be most beneficial in the later stages of the disease.
authors.affiliation: Neurology Imaging Unit, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Neurology Imaging Unit, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.|Department of Nuclear Medicine, Institute of Medicine, Aarhus University, Denmark.
authors.forename: David J
authors.initials: DJ
authors.lastname: Brooks
authors.affiliation: Neurology Imaging Unit, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
authors.forename: Aren
authors.initials: A
authors.lastname: Okello
authors.affiliation: Neurology Imaging Unit, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Edison
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000473:pathology*; D000814:Aniline Compounds / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001931:Brain Mapping; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D003072:Cognition Disorders / Q000000981:diagnostic imaging / Q000209:etiology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D021621:Imaging, Three-Dimensional; D007546:Isoquinolines / Q000493:pharmacokinetics; D008279:Magnetic Resonance Imaging; D008297:Male; D017628:Microglia / Q000473:pathology*; D008875:Middle Aged; D049268:Positron-Emission Tomography; D013844:Thiazoles / Q000493:pharmacokinetics
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D007546:Isoquinolines; D013844:Thiazoles; C037850:PK 11195
keywords: Alzheimer’s disease; amyloid imaging; microglial activation; mild cognitive impairment; neuropathology