Wilde JH, Sun YY, Simpson SR, Hill ER, Fu Z, Bian EJ, Kinkaid MM, Villanueva P, Weybright AF, Terrell WR, Qureshi Z, Perera SS, Sheppard HS, Stone JR, Kundu BK, Kuan CY, Neumann KD. A positron emission tomography tracer for the imaging of oxidative stress in the central nervous system. Nat Biomed Eng. 2025 Mar 5; Epub 2025 Mar 5 PubMed.
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Comments
University of Kansas
A PET ligand that reveals oxidative stress in the human brain will facilitate work within the AD research field on a number of levels. It will help investigators get a glimpse into oxidative stress in the brains of AD patients. From there, investigators can speculate why the ligand signal in AD patients may deviate from controls (if one presumes the patterns indeed deviate). This part may prove to be challenging, but within the context of other PET ligand surveys, such as a ligand that shows complex I protein levels and perhaps TSPO also, it may help to flesh out a broader picture of bioenergetic metabolism and its consequences. Most directly, though, I suspect it may get the field closer to more useful and applicable target engagement biomarkers for studies evaluating bioenergetics-targeted therapeutic targets.
University of Pennsylvania
I congratulate the authors for trying to develop an alternative strategy to imaging reactive oxygen and reactive nitrogen species (ROS/RNS) in vivo with PET. Our group developed the radiotracer, [18F]ROStrace, and we have conducted PET imaging studies to measure ROS in murine models of AD (Hsieh et al., 2022), synucleinopathy (Gallagher et al., 2024), and 4R tauopathies (Gallagher et al., 2025).
I think [18F]FEDV has great potential for translation to human imaging studies of oxidative stress, but I’d caution the authors to do a detailed characterization of the radiotracer first. They need to correlate the regional uptake with disease burden and with “gold-standard measures” of ROS/RNS, such as antibody staining for 3-nitrotyrosine (3-NT). For example, [18F]FEDV shows a global increase in uptake in the PS19 model of 4R tauopathy, whereas the uptake of [18F]ROStrace in the same model is more focal and correlates with 4R tau burden and 3-NT staining.
References:
Hsieh CJ, Hou C, Zhu Y, Lee JY, Kohli N, Gallagher E, Xu K, Lee H, Li S, McManus MJ, Mach RH. Correction: [18F]ROStrace detects oxidative stress in vivo and predicts progression of Alzheimer's disease pathology in APP/PS1 mice. EJNMMI Res. 2023 Feb 27;13(1):16. PubMed.
Gallagher E, Hou C, Zhu Y, Hsieh CJ, Lee H, Li S, Xu K, Henderson P, Chroneos R, Sheldon M, Riley S, Luk KC, Mach RH, McManus MJ. Positron Emission Tomography with [18F]ROStrace Reveals Progressive Elevations in Oxidative Stress in a Mouse Model of Alpha-Synucleinopathy. Int J Mol Sci. 2024 May 1;25(9) PubMed.
Gallagher E, Li S, Lee H, Xu H, Lee VMY, Mach RH, McManus MJ. Noninvasive Detection of Oxidative Stress in a Mouse Model of 4R Tauopathy via Positron Emission Tomography with [18F]ROStrace. https://doi.org/10.3390/ijms26051845 International Journal of Molecular Sciences
Children's Hospital of Philadelphia
I commend the authors for their exceptional characterization of the novel PET probe [18F]FEDV, which shows strong potential for detecting reactive oxygen species (ROS) in models of stroke and tauopathy. The validation of [18F]FEDV using dihydroethidium, the parent compound of [18F]ROStrace, is particularly noteworthy, as we have previously demonstrated that [18F]ROStrace effectively identifies oxidative stress across various neurodegenerative disease models driven by mitochondrial dysfunction and proteinopathy (Zhu et al., 2024; Hsieh et al., 2022; Gallagher et al., 2024; Gallagher et al., 2025).
Both [18F]ROStrace and [18F]FEDV reveal elevated oxidative stress in the PS19 tauopathy model in animals over 11 months of age (Gallagher et al., 2025). Extrapolating the specificity of these probes for particular ROS in vivo from isolated in vitro studies remains challenging, given the complexity of interconnected redox reactions within the brain. It may be more relevant to investigate whether variations among oxidative stress probes can differentiate between various sources of ROS in vivo. In this regard, Wilde et al. compare standardized uptake values (SUVs) between [18F]FN and [18F]FEDV and conclude that innate immune activation is not driving oxidative stress detected by [18F]FEDV, based on low [18F]FN signal in these animals. However, considering the established role of microglial activation in generating oxidative damage and driving neurodegeneration in stroke and tauopathy, and the paucity of data to counter this mechanism in the manuscript, their conclusion warrants further molecular validation. The low [18F]FN signal may simply suggest that it is better suited for detecting peripheral inflammation.
To enhance our understanding of the pathogenic ROS sources and evaluate therapeutic target engagement, further studies employing these PET probes with molecular tools to silence key ROS generators would be beneficial. This approach could yield critical insights into the implications of ROS for early detection of neurodegenerative disease and the efficacy of targeted antioxidant strategies.
References:
Zhu Y, Kohli N, Young A, Sheldon M, Coni J, Rajasekaran M, Robinson L, Chroneos R, Riley S, Guarnieri JW, Jose J, Patel N, Wallace DC, Li S, Lee H, Mach RH, McManus MJ. PET Imaging with [18F]ROStrace Detects Oxidative Stress and Predicts Parkinson's Disease Progression in Mice. Antioxidants (Basel). 2024 Oct 12;13(10) PubMed.
Hsieh CJ, Hou C, Zhu Y, Lee JY, Kohli N, Gallagher E, Xu K, Lee H, Li S, McManus MJ, Mach RH. Correction: [18F]ROStrace detects oxidative stress in vivo and predicts progression of Alzheimer's disease pathology in APP/PS1 mice. EJNMMI Res. 2023 Feb 27;13(1):16. PubMed.
Gallagher E, Hou C, Zhu Y, Hsieh CJ, Lee H, Li S, Xu K, Henderson P, Chroneos R, Sheldon M, Riley S, Luk KC, Mach RH, McManus MJ. Positron Emission Tomography with [18F]ROStrace Reveals Progressive Elevations in Oxidative Stress in a Mouse Model of Alpha-Synucleinopathy. Int J Mol Sci. 2024 May 1;25(9) PubMed.
Gallagher E, Li S, Lee H, Xu H, Lee VMY, Mach RH, McManus MJ. Noninvasive Detection of Oxidative Stress in a Mouse Model of 4R Tauopathy via Positron Emission Tomography with [18F]ROStrace. https://doi.org/10.3390/ijms26051845 International Journal of Molecular Sciences
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