Brain metabolic and behavioral alterations in a Down syndrome model.

Purpose: This work aimed to monitor the Down Syndrome Ts65Dn animal model across lifespan to detect time-dependent in vivo molecular alterations that may be associated with neurodegeneration and neuroinflammation in this model.

Methods: Euploid and trisomic Ts65Dn animals were longitudinally evaluated at 2, 5, 14, 20, and 24 months of age using brain [F]FDG PET and behavioral tasks (open field and novel object recognition). VOI-based SUV, Voxel-wise, and metabolic network analyses were performed. Cross-sectional post-mortem brain analysis was carried out at the same ages to measure neuronal loss and microglia activation.

Results: There was an increase in brain metabolism at 14 months of age in both genotypes, when compared to the other analyzed ages. [F]FDG uptake correlated with microglia activation measured by Iba-1 immunohistochemistry, suggesting that the tracer increased due to a neuroinflammation process. In addition, metabolic network analysis showed more accentuated desynchronization in [F]FDG uptake in older trisomic mice, than in euploid animals. At 24 months of age, trisomic animals presented a worse long-term memory recognition index and an age-dependent decrease in NeuN staining, which was not associated with [F]FDG uptake.

Conclusions: This is the first study to monitor the Ts65Dn mouse model throughout life - from 2 to 24 months of age - using [F]FDG PET imaging and metabolic network analysis. Our results collectively highlight that trisomic mice experience early disruption in brain network organization, likely contributing to functional impairments associated with aging, neurodegeneration, and neuroinflammation.