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Amyloid deposition, tau aggregation and microglial activation in Alzheimer's disease: a PET study

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Title: Amyloid deposition, tau aggregation and microglial activation in Alzheimer's disease: a PET study
Authors: Dani, Melanie
Item Type: Thesis or dissertation
Abstract: Background The pathological mechanisms underlying Alzheimer’s disease (AD) are still not fully understood. While amyloid (Aβ) deposition and tau aggregation are cardinal features, microglial activation is also an important component. However, the relationship between the three processes is widely debated. This study used positron emission tomography (PET) imaging to evaluate this relationship in a cohort of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) subjects. Methods Nineteen healthy controls, thirty-nine MCI and nineteen AD individuals had neuropsychological testing, MRI, 18F-flutemetamol and 11C-PBR28 PET. Eight controls, twenty-five MCI and eighteen AD individuals also had 18F-AV1451 PET. For 18F-flutemetamol and 18F-AV1451, target: cerebellar ratio images were used to calculate standardised uptake value ratio (SUVR) values. For 11C-PBR28, a two-tissue compartment model and Logan graphical analysis were used to determine volumes of distribution (VT). Group comparisons, and correlations between the tracers, were examined at regional and voxel level. Results 1) Mean 11C-PBR28 binding was significantly higher in the Aβ-positive MCI group compared to the controls at a voxel level, while there was no difference between AD and controls. However, 42% of Aβ-positive AD individuals had significantly higher binding than the healthy control mean+ 2 standard deviations 2) All three processes were correlated at a voxel level; microglial activation and tau aggregation were correlated in connected regions on analysis 3) Aβ and tau load were correlated at a voxel and regional level; in addition medial temporal lobe tau binding correlated with isocortical Aβ load 4) Certain Aβ-negative individuals also demonstrated significantly increased levels of microglial activation and tau aggregation compared with controls on single-subject analysis 11 Conclusions In this study examining inter-relationships between Aβ deposition, tau aggregation and microglial activation in MCI and AD, significant positive correlations were found between all three processes. These correlations were both local (overlapping voxels) and distant, suggesting communication via neuronal networks. The findings suggest that a therapeutic approach targeting all three processes may be needed.
Content Version: Open Access
Issue Date: Oct-2017
Date Awarded: Jul-2018
URI: http://hdl.handle.net/10044/1/77787
DOI: https://doi.org/10.25560/77787
Copyright Statement: Creative Commons Attribution Non-Commercial No Derivatives licence.
Supervisor: Brooks, David James
Edison, Paul
Sponsor/Funder: Alzheimer's Research UK
Medical Research Council (Great Britain)
Funder's Grant Number: WMCN_P23750
Department: Department of Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses