[¹¹C]PBR28 imaging in a mouse model of Alexander disease

Objectives Alexander disease (AxD) is a rare neurodegenerative disorder caused by mutations in the astrocyte specific intermediate filament protein GFAP that lead to protein aggregation and reactive gliosis. [¹¹C]PBR28 targets the TSPO, which is upregulated in reactive astrocytes and microglia. The goal of this work is to investigate [¹¹C]PBR28 binding in a GFAP^+/R236H mutant mouse model of AxD, in which both cell types are activated.

Methods Three AxD mice and three matched wildtype mice underwent 60 min [¹¹C]PBR28 scans (208.7±9.71 µCi) on a Siemens Inveon Hybrid PET/CT. ROIs were hand drawn on late summed PET images (40-60 min) using a mouse brain atlas and CT as guides. The brain was divided into three regions: anterior, medial, and posterior. The anterior region contained olfactory bulb, the medial region contained cortical and subcortical structures, and the posterior region contained brainstem and cerebellum. SUVs were calculated as activity per voxel normalized to injected activity and body mass. A 2-sample t-test was performed between groups and a one-sided p-value was calculated.

Results Visual inspection of PET images showed the highest uptake in the anterior region, corresponding to olfactory bulb, a region known to contain activated astrocytes and microglia through histology. The AxD mice had SUVs of 0.47±0.13, 0.38±0.07, and 0.36±0.06, compared to wildtype mice with SUVs of 0.30±0.02, 0.27±0.04, and 0.33±0.03 for the anterior, medial, and posterior regions, respectively. Group differences are significant in the anterior (p=0.038) and medial (p=0.038) regions at α=0.05, but not in the posterior region (p=0.27), which correlates with the distribution of pathology in this model.

Conclusions [¹¹C]PBR28 SUV images showed a regionally heterogeneous distribution of TSPO binding in a mouse model of AxD. There is a significant increase in SUV of AxD mice in the anterior and medial regions of the brain. These preliminary data suggest a role for TSPO imaging in understanding the pathophysiology of AxD.

Research Support HD076892