Relationship between astrocyte reactivity, using novel¹¹C-BU99008 PET, and glucose metabolism, grey matter volume and amyloid load in cognitively impaired individuals

AbstractPost mortemneuropathology suggests that astrocyte reactivity may play a significant role in neurodegeneration in Alzheimer’s disease. We explored thisin vivousing multimodal PET and MRI imaging. Twenty subjects (11 older, cognitively impaired subjects and 9 age-matched healthy controls) underwent brain scanning using the novel reactive astrocyte PET tracer11C-BU99008,18F-FDG and18F-florbetaben PET, and T1-weighted MRI. Differences between cognitively impaired subjects and healthy controls in voxel-wise levels of astrocyte reactivity, glucose metabolism and grey matter volume were explored, and their relationship to each other was assessed using Biological Parametric Mapping (BPM). Aβ-positive cognitively impaired subjects showed greater brain astrocyte reactivity, except in the temporal lobe, with further increased astrocyte reactivity in Mild Cognitive Impairment compared to Alzheimer’s subjects in the cingulate cortices. BPM correlations revealed regions which showed reduced11C-BU99008 uptake in Aβ-positive cognitively impaired subjects, such as the temporal lobe, also showed reduced18F-FDG uptake and grey matter volume. 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 withreducedastrocyte reactivity, whilst increased amyloid uptake in primary motor and sensory areas (in which amyloid load occurs later) was associated withincreasedastrocyte reactivity. 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.