[F]-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]-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 α-synuclein (hα-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 hα-syn (AAV-hα-syn) or green fluorescent protein (AAV-GFP) were performed in rats (n = 60). In vivo [F]-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]-DPA-714 PET in the in vivo PET study was correlated with post-mortem histological markers.

Results: In the SNpc of AAV-hα-syn rats, there was higher in vivo [F]-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]-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]-DPA-714 BP was found at 16 weeks p.i.

Conclusions: Our study showed that in vivo PET study with [F]-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.