Amyloid deposition, tangle formation,
neuroinflammation and neuronal dysfunction are
pathological processes involved in
Alzheimer's disease. However, the relative role of these processes in driving
disease progression is still unclear. The aim of this positron emission tomography study was to: (i) investigate longitudinal changes of microglial activation,
amyloid and
glucose metabolism; and (ii) assess the temporospatial relationship between these three processes in
Alzheimer's disease. A group of eight patients with a diagnosis of
Alzheimer's disease (66 ± 4.8 years) and 14 healthy controls (65 ± 5.5 years) underwent T1 and T2 magnetic resonance imaging, along with (11)C-(R)-PK11195, (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose positron emission tomography scans for microglial activation,
amyloid deposition and
glucose metabolism. All patients were followed-up with repeated magnetic resonance imaging and three positron emission tomography scans after 16 months. Parametric maps were interrogated using region of interest analysis, Statistical Parametric Mapping, and between-group correlation analysis at voxel-level using
Biological Parametric Mapping. At baseline, patients with
Alzheimer's disease showed significantly increased microglial activation compared to the control subjects. During follow-up, for the first time, we found that while there is a progressive reduction of
glucose metabolism, there was a longitudinal increase of microglial activation in the majority of the patients with
Alzheimer's disease. Voxel-wise correlation analysis revealed that microglial activation in patients with
Alzheimer's disease was positively correlated with
amyloid deposition and inversely correlated with regional cerebral metabolic rate at voxel level over time. Even though one of the limitations of this study is the lack of longitudinal follow-up of healthy control subjects, this study demonstrates that there is persistent
neuroinflammation throughout the
Alzheimer's disease process with associated synaptic dysfunction and reduced
glucose metabolism. Voxel-wise correlation analysis suggests that
neuroinflammation is associated with localized
amyloid deposition and
glucose metabolism over time, however, the level of
inflammation could also occur independently of
amyloid pathology, especially in the later stages of
Alzheimer's disease.