Amyloid deposition, tau aggregation and microglial activation in Alzheimer's disease: a PET study
File(s)
Author(s)
Dani, Melanie
Type
Thesis
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.
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.
Version
Open Access
Date Issued
2017-10
Date Awarded
2018-07
Advisor
Brooks, David James
Edison, Paul
Sponsor
Alzheimer's Research UK
Medical Research Council (Great Britain)
Grant Number
WMCN_P23750
WMCN_P33428
Publisher Department
Department of Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)