Microglial activation states drive glucose uptake and FDG-PET alterations in neurodegenerative diseases
Xianyuan Xiang1,2, Karin Wind3,4, Thomas Wiedemann3
1Biomedical Center (BMC), Division of Metabolic Biochemistry, Faculty of Medicine, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
Abstract:
2-Deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET) is widely used to study cerebral glucose metabolism. Here, we investigated whether the FDG-PET signal is directly influenced by microglial glucose uptake in mouse models and patients with neurodegenerative diseases. Using a recently developed approach for cell sorting after FDG injection, we found that, at cellular resolution, microglia displayed higher glucose uptake than neurons and astrocytes. Alterations in microglial glucose uptake were responsible for both the FDG-PET signal decrease in Trem2-deficient mice and the FDG-PET signal increase in mouse models for amyloidosis. Thus, opposite microglial activation states determine the differential FDG uptake. Consistently, 12 patients with Alzheimer’s disease and 21 patients with four-repeat tauopathies also exhibited a positive association between glucose uptake and microglial activity as determined by 18F-GE-180 18-kDa translocator protein PET (TSPO-PET) in preserved brain regions, indicating that the cerebral glucose uptake in humans is also strongly influenced by microglial activity. Our findings suggest that microglia activation states are responsible for FDG-PET signal alterations in patients with neurodegenerative diseases and mouse models for amyloidosis. Microglial activation states should therefore be considered when performing FDG-PET.
Insights
Microglial glucose uptake significantly impacts 2-Deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET) scans. Changes in microglial activation states explain FDG-PET signal alterations in neurodegenerative diseases.
Area of Science:
- Neuroscience
- Molecular Imaging
- Cell Biology
Background:
- 2-Deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET) is a key tool for assessing cerebral glucose metabolism.
- The direct contribution of microglial glucose uptake to the FDG-PET signal in neurodegenerative conditions remains unclear.
Purpose of the Study:
- To investigate the influence of microglial glucose uptake on FDG-PET signals in mouse models and human patients with neurodegenerative diseases.
- To determine if microglial activation states correlate with observed changes in cerebral glucose metabolism.
Main Methods:
- Utilized a novel cell sorting technique post-FDG injection to quantify glucose uptake at the cellular level.
- Correlated FDG-PET findings with 18F-GE-180 18-kDa translocator protein PET (TSPO-PET) data in human patients.
- Examined FDG-PET signal changes in Trem2-deficient mice and amyloidosis mouse models.
Main Results:
- Microglia exhibited higher glucose uptake than neurons and astrocytes at the cellular level.
- Microglial glucose uptake alterations explained FDG-PET signal decreases in Trem2-deficient mice and increases in amyloidosis models.
- A positive association was observed between glucose uptake and microglial activity in Alzheimer's disease and tauopathy patients.
Conclusions:
- Microglial activation states are a primary driver of FDG-PET signal changes in neurodegenerative diseases.
- Cerebral glucose uptake in humans is significantly influenced by microglial activity.
- Microglial activation status must be considered for accurate interpretation of FDG-PET scans in neurodegeneration research.
