EXPRESS: Longitudinal FDG-PET reveals early hypermetabolism associated with astrocyte changes in TgF344-AD rats

BACKGROUND: Alzheimer's disease (AD) is characterized by alterations in brain glucose metabolism, classically showing [18F]FDG-PET hypometabolism in later stages. However, emerging evidence suggests a transient phase of glucose hypermetabolism early in the disease, for which biological basis remains unclear. METHODS: F]FDG-microPET imaging, behavioral testing, and cerebrospinal fluid biomarker analysis. Cross-sectional analyses included amyloid histopathology, western blot and ex vivo glutamate uptake measurements. RESULTS: TgF344-AD rats exhibited increased cerebral glucose metabolism at 9mo, predominantly in cortical regions. This phase coincided with emerging cognitive impairment and early amyloid deposition. CSF analyses showed increased GFAP at 9-12mo and reduced S100B at 9mo, while microglial/inflammatory markers remained unchanged. WB confirmed region-specific GFAP alterations without changes in neuronal or synaptic markers. Glutamate uptake was increased in the cortex and hippocampus at 9mo. CONCLUSION: These findings identify a transient phase of increased glucose metabolism early in disease progression, associated with astrocyte-related changes, suggesting that early hypermetabolism may reflect non-neuronal processes. This has implications for the interpretation of [18F]FDG-PET as a biomarker in early AD and for understanding early physiological responses to AD pathology.