[18F]-DPA-714 PET as a specific in vivo marker of early microglial activation in a rat model of progressive dopaminergic degeneration

Purpose To study the feasibility of the in vivo [F-18]-DPA-714 TSPO positron emission tomography (PET) to detect glial activation in a rat model of progressive parkinsonism induced by viral-mediated overexpression of A53T mutated human alpha-synuclein (h alpha-syn) in the substantia nigra pars compacta (SNpc). Methods We conducted a cross-sectional study in a model of progressive parkinsonism. Bilateral intranigral injections with 2/9 adeno-associated viral vectors encoding either h alpha-syn (AAV-h alpha-syn) or green fluorescent protein (AAV-GFP) were performed in rats (n = 60). In vivo [F-18]-DPA-714 PET imaging was performed at different time points after inoculation (p.i.) of the viral vector (24 and 72 h and 1, 2, 3, and 16 weeks). Images were analyzed to compute values of binding potential (BP) in the SNpc and striatum using a volume of interest (VOI) analysis. Immunohistochemistry of markers of dopaminergic degeneration (tyrosine hydroxylase (TH)), microglia (Iba-1), and astrocytes (GFAP) was carried out. Binding potential (BP) of [F-18]-DPA-714 PET in the in vivo PET study was correlated with post-mortem histological markers. Results In the SNpc of AAV-h alpha-syn rats, there was higher in vivo [F-18]-DPA-714 BP (p < 0.05) and increased number of post-mortem Iba-1(+) cells (p < 0.05) from second week p.i. onwards, which were highly correlated (p < 0.05) between each other. These findings antedated the nigral reduction of TH+ cells that occurs since third week p.i. (p < 0.01). In addition, the [F-18]-DPA-714 BP was inversely correlated (p < 0.05) with the TH+ cells. In contrast, GFAP(+) cells only increased at 16 weeks p.i. and did not correlate with the in vivo results. In the striatum, no changes in the number of Iba-1(+) and GFAP(+) cells were observed, but an increment in the [F-18]-DPA-714 BP was found at 16 weeks p.i. Conclusions Our study showed that in vivo PET study with [F-18]-DPA-714 is a selective and reliable biomarker of microglial activation and could be used to study preclinical stages of Parkinson's disease (PD) and to monitor the progression of the disease.