EXPRESS: Longitudinal FDG-PET reveals early hypermetabolism associated with astrocyte changes in TgF344-AD rats
Andreia Rocha, Luiza S. Machado, Carolina Soares, Pamela C. L. Ferreira, Bruna Bellaver, Patricia Carvalho, Gabriela Lazzarotto, Pedro Vidor, Peter Kunach, Gianina T. Venturin, Samuel Greggio, Jaderson C. da Costa, Fernanda Bastos de Mello, Giedre Milinkeviciute, Stefania Forner, Kim Green, Pedro Rosa-Neto, Tharick Pascoal, Diogo Onofre Souza, Eduardo ZimmerBackground:
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:
We combined longitudinal and cross-sectional approaches in TgF344-AD rats and wild-type controls at 3, 6, 9, and 12 months. Longitudinal assessments included [ 1 8 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.