Journal watch: Microglial activation states drive glucose uptake and FDG-PET alterations in neurodegenerative diseases

Journal watch: Microglial activation states drive glucose uptake and FDG-PET alterations in neurodegenerative diseases

850 567 Shawn Haigh
The Background

2-Deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET) is a commonly used method to detect regional reductions in brain glucose uptake typically observed in patients with Alzheimer’s disease (AD) and other neurodegenerative disorders such as Parkinsonism.1 It is assumed that the FDG-PET signal predominantly derives from neuronal synaptic activity,2–4 but the influence of other cells contributing to the signal remains unclear.1 It has been shown that microglial activation is positively associated with cerebral FDG uptake in ageing and amyloid mouse models.5, 6 However, it is not known whether an increased FDG-PET signal is directly derived from activated microglia or a result of increased glucose uptake of neurons and astrocytes upon microglial activation.1


The Objective

To investigate whether microglial glucose uptake directly influences the FDG-PET signal in mouse models for amyloidosis and in patients with neurodegenerative diseases.1


The Strategy

Xiang X et al. first determined the glucose uptake of brain cells in mice with amyloidosis upon pharmacological depletion of microglia using PLX5622, a colony-stimulating factor 1 receptor (CSF1R) inhibitor.1 Here, longitudinal FDG-PET, 18-kDa translocator protein PET (TSPO-PET) and Ab-PET measurements were performed at baseline and at the end of the study.1 In addition, glucose uptake and microglial activation were monitored over six months in a Trem2-deficient mouse model for amyloidosis (Trem2-/- APPPS1).1

Subsequently, the proportions of FDG uptake in different brain cell types were explored in mice using cell sorting after FDG injection, followed by gamma emission measurements as direct measure of in vivo glucose uptake.1

To generate evidence for a relationship between microglial activity and FDG-PET signals in humans, 12 patients with fibrillar amyloidosis and 21 patients with possible or probable four-repeat tauopathies were analysed by FDG-PET and TSPO-PET.1


The Findings

Mice with amyloidosis showed an increased FDG-PET signal compared to wild type (WT) mice as a result of a higher number of microglia in the cortical and hippocampal regions in the mouse model.1 PLX5622 treatment of mice with amyloidosis led to strongly reduced FDG-PET signals, even below signals displayed by vehicle-treated WT mice, suggesting that the FDG-PET signal is mainly caused by microglia.1  In Trem2-deficient mice, FDG- and TSPO-PET signals were significantly reduced over time because of longitudinal microglia depletion in the mouse model.1 The opposite microglial activation states thus drove differential glucose uptake in the mouse models.1

By applying cell sorting after FDG injection, the authors showed that microglia display higher glucose uptake than neurons and astrocytes.1 Microglia showed the highest glucose uptake, exceeding FDG uptake of astrocytes and neurons by 12- and 28-fold, respectively.1

All patients with fibrillar amyloidosis and possible or probable four-repeat tauopathies that were analysed by FDG-PET and TSPO-PET also exhibited a positive association between glucose uptake and microglial activity in preserved brain regions, indicating that microglial activity strongly influences glucose uptake in the human brain.1


The Future

Microglia are responsible for a high proportion of glucose uptake in the brain and influence FDG-PET signal alterations. Therefore, microglial activation states should be taken into consideration for diagnostics and scientific studies, including FDG-PET imaging.1


The Conclusion

Microglial activity directly influences FDG-PET signal alterations in mouse models for amyloidosis and patients with neurodegenerative diseases. In turn, this may explain why structural atrophy is not necessarily associated with metabolic decline in the early stages of neurodegenerative diseases as determined by an elevated microglial FDG uptake.1

  1. Xiang X et al. Sci Trans Med. 2021;13:eabe5640
  2. Sokoloff L. Dev Neurosci. 1993;15:194–206
  3. Sokoloff L. Neurochem Res. 1999;24:321–329
  4. Sokoloff L et al. J Neurochem. 1977;28:897–916
  5. Brendel M et al. J Nucl Med. 2016;57:954–960
  6. Brendel M et al. J Nucl Med. 2017;58:1984–1990


Brainwork is supported by unrestricted grants from: