Abstract
Post mortem neuropathology suggests that astrocyte reactivity may play a significant role in neurodegeneration in Alzheimer’s disease. We explored this in vivo using multimodal PET and MRI imaging. Twenty subjects (11 older, cognitively impaired patients and 9 age-matched healthy controls) underwent brain scanning using the novel reactive astrocyte PET tracer 11C-BU99008, 18F-FDG and 18F-florbetaben PET, and T1-weighted MRI. Differences between cognitively impaired patients and healthy controls in regional and voxel-wise levels of astrocyte reactivity, glucose metabolism, grey matter volume and amyloid load were explored, and their relationship to each other was assessed using Biological Parametric Mapping (BPM). Amyloid beta (Aβ)-positive patients showed greater 11C-BU99008 uptake compared to controls, except in the temporal lobe, whilst further increased 11C-BU99008 uptake was observed in Mild Cognitive Impairment subjects compared to those with Alzheimer’s disease in the frontal, temporal and cingulate cortices. BPM correlations revealed that regions which showed reduced 11C-BU99008 uptake in Aβ-positive patients compared to controls, such as the temporal lobe, also showed reduced 18F-FDG uptake and grey matter volume, although the correlations with 18F-FDG uptake were not replicated in the ROI analysis. BPM analysis also revealed a regionally-dynamic relationship between astrocyte reactivity and amyloid uptake: increased amyloid load in cortical association areas of the temporal lobe and cingulate cortices was associated with reduced11C-BU99008 uptake, whilst increased amyloid uptake in primary motor and sensory areas (in which amyloid deposition occurs later) was associated with increased11C-BU99008 uptake. These novel observations add to the hypothesis that while astrocyte reactivity may be triggered by early Aβ-deposition, sustained pro-inflammatory astrocyte reactivity with greater amyloid deposition may lead to astrocyte dystrophy and amyloid-associated neuropathology such as grey matter atrophy and glucose hypometabolism, although the evidence for glucose hypometabolism here is less strong.
Highlights
Astrocytes are integral to normal brain function, playing important roles in neurogenesis, synaptogenesis, control of blood-brain barrier permeability and maintaining extracellular homeostasis [1]
In this study, we used the novel imidazoline receptor PET tracer 11C-BU99008 to test for evidence of a dynamic relationship between astrocyte reactivity and amyloid-associated neurodegeneration based on tissue hypometabolism and atrophy measured using 18F-FDG PET and structural MRI, respectively
Voxel-wise correlational analyses showed that lower 11C-BU99008 uptake in Aβ-positive patients was associated with hypometabolism in the parietal, temporal and frontal lobes, even though there was no correlation at Regions of Interest (ROI) level
Summary
Astrocytes are integral to normal brain function, playing important roles in neurogenesis, synaptogenesis, control of blood-brain barrier permeability and maintaining extracellular homeostasis [1]. In Alzheimer’s disease (AD), astrocytes can assume a reactive phenotype in response to disease by undergoing morphological, molecular and functional remodeling [2]. It is suggested that astrocytes could have a beneficial and detrimental role, and this could depend on the pathological insult and the susceptibility of the host [4]. It is proposed that with higher levels of Aβ, astrocyte reactivity can produce neurotoxic reactive oxygen species and inflammatory cytokines [5]. Astrocytes in AD can lose normal neuroprotective capabilities as they become dystrophic with the progression of AD pathology [4, 6]
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