Reactive oxygen and nitrogen species (RONS) contribute to the pathogenesis of neurodegeneration, but the inability to detect RONS in vivo in the central nervous system has confounded the interpretation of results of clinical trials of antioxidants. Here we report the synthesis and characterization of a positron emission tomography (PET) probe, [¹⁸F]fluoroedaravone ([¹⁸F]FEDV), for the in vivo quantification of oxidative stress. Derived from the antioxidant edaravone, the probe can diffuse through the blood–brain barrier and is stable in human plasma. In mice, PET imaging with [¹⁸F]FEDV allowed for the detection of RONS after intrastriatal injection of sodium nitroprusside, in the middle cerebral artery after stroke by photothrombosis, and in brains with tauopathy. When using dynamic PET imaging coupled with parametric mapping, the sensitivity of [¹⁸F]FEDV-PET to RONS allowed for the detection of increased oxidative stress. [¹⁸F]FEDV-PET could be used to quantify RONS longitudinally in vivo and to assess the results of clinical studies of antioxidants.

Infectious disease remains the main cause of morbidity and mortality throughout the world. Of growing concern is the rising incidence of multidrug-resistant bacteria, derived from various selection pressures. Many of these bacterial infections are hospital-acquired and have prompted the Centers for Disease Control and Prevention in 2019 to reclassify several pathogens as urgent threats, its most perilous assignment. Consequently, there is an urgent need to improve the clinical management of bacterial infection via new methods to specifically identify bacteria and monitor antibiotic efficacy in vivo. In this work, we developed a novel radiopharmaceutical, 2-¹⁸F-fluoro-2-deoxy-mannitol (¹⁸F-fluoromannitol), which we found to specifically accumulate in both gram-positive and gram-negative bacteria but not in mammalian cells in vitro or in vivo. Methods: Clinical isolates of bacteria were serially obtained from wounds of combat service members for all in vitro and in vivo studies. Bacterial infection was quantified in vivo using PET/CT, and infected tissue was excised to confirm radioactivity counts ex vivo. We used these same tissues to confirm the presence of bacteria by extracting and correlating radioactive counts with colony-forming units of bacteria. Results:¹⁸F-fluoromannitol was able to differentiate sterile inflammation from Staphylococcus aureus and Escherichia coli infections in vivo in a murine myositis model using PET imaging. Our study was extended to a laceration wound model infected with Acinetobacter baumannii, an important pathogen in the nosocomial and battlefield setting. ¹⁸F-fluoromannitol PET rapidly and specifically detected infections caused by A. baumannii and several other important pathogens (Enterococcus faecium, S. aureus, Klebsiella pneumoniae, A. baumannii, Pseudomonas aeruginosa, and Enterobacter spp.). Importantly, ¹⁸F-fluoromannitol PET was able to monitor the therapeutic efficacy of vancomycin against S. aureus in vivo. Conclusion: The ease of production of ¹⁸F-fluoromannitol is anticipated to facilitate wide radiopharmaceutical dissemination. Furthermore, the broad sensitivity of ¹⁸F-fluoromannitol for bacterial infection in vivo suggests that it is an ideal imaging agent for clinical translation to detect and monitor infections and warrants further studies in the clinical setting. Visual Abstract

Sport concussion affects millions of athletes each year at all levels of sport. Increasing evidence demonstrates clinical and physiological recovery are becoming more divergent definitions, as evidenced by several studies examining blood-based biomarkers of inflammation and imaging studies of the central nervous system (CNS). Recent studies have shown elevated microglial activation in the CNS in active and retired American football players, as well as in active collegiate athletes who were diagnosed with a concussion and returned to sport. These data are supportive of discordance in clinical symptomology and the inflammatory response in the CNS upon symptom resolution. In this review, we will summarize recent advances in the understanding of the inflammatory response associated with sport concussion and broader mild traumatic brain injury, as well as provide an outlook for important research questions to better align clinical and physiological recovery.

Infectious diseases are a major cause of morbidity and mortality worldwide. With the increasing frequency of antibiotic resistance, efficient and noninvasive diagnostic methods are more important than ever. In this report, we interrogate the use of several intravenously administered, bacteria-specific, ¹³C-enriched metabolites whose conversion to [¹³C]CO₂ can be detected via a portable and inexpensive method, namely nondispersive infrared (NDIR) spectroscopy. The enriched metabolites [U-¹³C]maltose, [U-¹³C]maltotriose, d-[U-¹³C]mannitol, and l-[U-¹³C]arabinose were metabolized to [¹³C]CO₂ by several pathogens in vitro, while showing minimal [¹³C]CO₂ production in uninfected mice. We further demonstrated that myositis, bacteremia, pneumonia, and osteomyelitis could be detected in vivo using one or more ¹³C-enriched metabolites. Additionally, in a model of Escherichia coli myositis, [¹³C]CO₂ production correlated with bacterial burden following ceftriaxone therapy, showing that exhaled [¹³C]CO₂ could be employed to monitor antimicrobial efficacy. Finally, [¹³C]CO₂ production by Staphylococcus aureus clinical isolates treated with [U-¹³C]maltose was correlated with the performance of its cognate PET tracer [2-¹⁸F]maltose, suggesting that [¹³C]CO₂ breath testing could predict the performance of pathogen-targeted positron emission tomography (PET) tracers in vivo. [¹³C]CO₂ breath testing using an expanded metabolite toolbox and on-site detection tools represents a unique and complementary method to identify bacterial infection in clinical practice.