Temporal changes in neuroinflammation and brain glucose metabolism in a rat model of viral vector-induced...

Rat models based on viral vector-mediated overexpression of α-synuclein are regarded as highly valuable models that closely mimic cardinal features of human Parkinson's disease (PD) such as L-DOPA-dependent motor impairment, dopaminergic neurodegeneration and α-synuclein inclusions. To date, the downstream effects of dopaminergic cell loss on brain glucose metabolism, including the neuroinflammation component, have not been phenotyped in detail for this model. Cerebral glucose metabolism was monitored throughout different stages of the disease using in vivo 2-[¹⁸F]-fluoro-2-deoxy-d-glucose ([¹⁸F]FDG) positron emission tomography (PET) and was combined with in vitro [¹⁸F]DPA-714 autoradiography to assess concomitant inflammation. Rats were unilaterally injected with recombinant adeno-associated viral vector serotype 2/7 (rAAV2/7) encoding either A53T α-synuclein or eGFP. Brain [¹⁸F]FDG microPET was performed at baseline, 1, 2, 3, 4, 6, and 9 weeks post-surgery, in combination with behavioral tests. As a second experiment, [¹⁸F]DPA-714 autoradiography was executed across the same timeline. Voxel-based analysis of relative [¹⁸F]FDG uptake showed a dynamic pattern of PD-related metabolic changes throughout the disease progression (weeks 2-9). Glucose hypermetabolism covering a large bilateral area reaching from the insular, motor- and somatosensory cortex to the striatum was observed at week 2. At week 4, hypermetabolism presented in a cluster covering the ipsilateral nigra-thalamic region, whereas hypometabolism was noted in the ipsilateral striatum at week 6. Elevated [¹⁸F]FDG uptake was seen in a cluster extending across the contralateral striatum, motor- and somatosensory cortex at week 9. Increased [¹⁸F]FDG in the region of the substantia nigra was associated with increased [¹⁸F]DPA-714 binding, and correlated significantly with motor symptoms. These findings point to disease-associated metabolic and neuroinflammatory changes taking place in the primary area of dopaminergic neurodegeneration but also closely interconnected motor and somatosensory brain regions.