The proteinopathies are a diverse group of neurodegenerative disorders that are collectively characterized by aberrant aggregation of proteins like alpha-synuclein (aSyn) and tau in the brain. Oxidative stress—i.e. the detrimental overproduction of reactive oxygen species (ROS)—is thought to be both a cause and a consequence of aSyn and tau aggregation in the proteinopathies. The cyclical relationship between protein aggregation and oxidative stress suggests that ROS could be leveraged as biomarkers of disease progression. However, the utility of ROS as biomarkers is currently limited by the lack of noninvasive methods for measuring levels of ROS in vivo. For my thesis research, I investigated the potential of the ROS-sensitive positron emission tomography (PET) radiotracer [18F]ROStrace as a means of detecting protein-associated oxidative stress in living animals. [18F]ROStrace imaging was performed on two widely-used mouse models of proteinopathy; the M83 line, which shows aSyn aggregation, and the PS19 line, which shows tau aggregation. The [18F]ROStrace results from these transgenic mice were compared with those from age- and sex-matched healthy controls, and a variety of behavioral and immunohistochemical assays were also performed to further characterize protein aggregation and protein-associated neurodegeneration in M83 and PS19 animals. Ultimately, I found that both M83 and PS19 mice showed increased [18F]ROStrace signal in brain relative to similarly-aged controls. These disease-associated elevations in [18F]ROStrace signal became progressively widespread within the brain over time, and paralleled progressive increases in both aSyn/tau aggregation and histological evidence of oxidative stress. Moreover, M83- and PS19-specific increases in [18F]ROStrace signal became detectable well in advance of late-stage motor symptom development and glial activation, suggesting that oxidative stress is a relatively early and long-lasting process in the pathogenesis of proteinopathy. Collectively, this work provides novel evidence that aSyn and/or tau aggregation is associated with increased oxidative stress, and it also highlights the potential of [18F]ROStrace as a means of detecting and studying protein-associated oxidative stress noninvasively.