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Proton therapy enables the protection of tumor-surrounding normal tissue; nevertheless, some patients develop late radiation-induced brain injury following brain tumor treatment. In clinical follow-up, it is often difficult to differentiate between radiation-induced brain injury, pseudoprogression, or tumor recurrence. Therefore, biomarkers are needed to identify the right therapy option for the individual patient. In addition, the biological mechanisms underlying radiation-induced normal tissue damage are still not fully understood and further investigations are necessary to discover new treatment options. A promising method for in situ molecular research is MALDI imaging, an innovate type of mass spectrometry that provides lipidomics and proteomics data with high spatial resolution. We now applied this method to our mouse model for radiation-induced brain injury [1,2] following proton therapy to shed light on normal tissue side effects.

A cohort of 30 C57BL/6 mice received either sham treatment or proton irradiation of a brain subvolume with 50 Gy single fraction at the experimental beam line of the University Proton Therapy Dresden as described in [1,2]. During follow-up, the animal health was scored bi-weekly. A subset of mice was sampled at two, four and six months post irradiation after acquiring a final MRI. MALDI imaging was performed on one representative section containing the dose maximum of the beam. This tissue section was subsequently stained for H&E and evaluated by a neuropathologist.

All animals developed a skin reaction grade 1 within the irradiation field, but no other health deterioration was observed. Evaluation of contrast-enhanced volume in T1-weighed MRI showed progressing brain injury, with a large inter-individual variation at the latest time point. Some animals from the 6-month cohort had additional hypointensities in the T2-weighted MR images within the region of the dose maximum. Only minor tissue changes were detected in the H&E staining. On the other hand, MALDI imaging revealed specific mass-to-charge (m/z) values that decrease within the irradiated brain area and remain for up to 6 months, indicating declining protein and lipid levels related to radiation-induced brain injury. All imaging modalities, including a Monte-Carlo dose simulation and a mouse brain atlas were registered to the m/z distribution maps for multi-dimensional correlations.

The innovative MALDI imaging method enables unique insights into radiation-induced brain injury on a spatial level. Next, we will perform further experiments to associate the identified m/z values with their respective lipids and proteins. In the future, our data can contribute to designing new imaging biomarkers for patient diagnostics and novel therapeutic approaches.

1.        Suckert, Müller, Beyreuther et al., Radiother. Oncol. 146, 205–212 (2020).

2.        Suckert et al., Front. Oncol. 10, 2881 (2021).