PET Imaging with [F]ROStrace Detects Oxidative Stress and Predicts Parkinson's Disease Progression in Mice

Although the precise molecular mechanisms responsible for neuronal death and motor dysfunction in late-onset Parkinson's disease (PD) are unknown, evidence suggests that mitochondrial dysfunction and neuroinflammation occur early, leading to a collective increase in reactive oxygen species (ROS) production and oxidative stress. However, the lack of methods for tracking oxidative stress in the living brain has precluded its use as a potential biomarker. The goal of the current study is to address this need through the evaluation of the first superoxide (O)-sensitive radioactive tracer, [F]ROStrace, in a model of late-onset PD. To achieve this goal, MitoPark mice with a dopaminergic (DA) neuron-specific deletion of transcription factor A mitochondrial () were imaged with [F]ROStrace from the prodromal phase to the end-stage of PD-like disease. Our data demonstrate [F]ROStrace was sensitive to increased oxidative stress during the early stages of PD-like pathology in MitoPark mice, which persisted throughout the disease course. Similarly to PD patients, MitoPark males had the most severe parkinsonian symptoms and metabolic impairment. [F]ROStrace retention was also highest in MitoPark males, suggesting oxidative stress as a potential mechanism underlying the male sex bias of PD. Furthermore, [F]ROStrace may provide a method to identify patients at risk of Parkinson's before irreparable neurodegeneration occurs and enhance clinical trial design by identifying patients most likely to benefit from antioxidant therapies.