Developing Magnetic Resonance Imaging Biomarkers of Neuroinflammation, Cognitive Impairment, and Survival Outcomes for Radiotherapy-Induced Brain Injury in a Preclinical Mouse Model.

OBJECTIVE

Radiotherapy-induced brain injury (RIBI) is a chronic side effect that affects up to 90% of brain tumor survivors treated with radiotherapy. Here, we used multiparametric magnetic resonance imaging (MRI) to identify noninvasive and clinically translatable biomarkers of RIBI.

METHOD: 8-week-old female, immune competent BALB/c mice were stereotactically irradiated with a single dose of 80 Gy, at a dose rate of 1.7 Gy/minute. The irradiated mice were then monitored longitudinally with MRI, behavioral tests of learning and memory, and immunohistochemistry, in comparison to nonirradiated mice.

RESULTS

Three types of MRI biomarkers of RIBI were identified. A contrast-enhanced T 1 -weighted MRI biomarker was identified as being best suited to detect the onset of injury, by detecting changes in the blood-brain barrier (BBB) permeability. Maximum BBB permeability (18.95 ± 1.75) was detected with contrast-enhanced T 1 -weighted MRI at 1-month postirradiation in irradiated mice ( P  < 0.0001, n = 3). Interestingly, maximum neuroinflammation (24.14 ± 6.72) was also detected using IBA1 and CD68 immunohistochemistry at 1-month postirradiation in irradiated mice ( P  = 0.0041, n = 3). This simultaneous maximum BBB permeability and neuroinflammation detection also coincided with the detection of the onset of transient cognitive impairment, detected using the fear-conditioning behavioral test at 1-month postirradiation in irradiated mice compared to nonirradiated mice ( P  = 0.0017, n = 10). A T 2 -weighted MRI hyperintensity biomarker was also identified, and determined to be best suited to detect intermediate injury. Maximum T 2 -weighted MRI hyperintensity (3.97 ± 2.07) was detected at 2-month postirradiation in the irradiated mice compared to nonirradiated mice ( P  = 0.0368, n = 3). This T 2 -weighted MRI hyperintensity also correlated with maximum astrogliosis (9.92 ± 4.21), which was also detected at 2-month postirradiation using GFAP immunohistochemistry in the irradiated mice compared to nonirradiated mice ( P  = 0.0215, n = 3). Finally, T 2 -weighted and T 2 *-weighted MRI hypointensity biomarkers were identified as being best suited to detect late injury, from 4-month postirradiation. These biomarkers correlated with increased iron deposition from late vascular damage, which was validated with Perls' Prussian blue histology ( P  < 0.05, n = 3). These hypointense MRI biomarkers of late injury also preceded significant weight loss, severe cognitive impairment, and decreased survival in the irradiated mice compared to the nonirradiated mice.

CONCLUSIONS

Here, we identified 3 types of translational MRI biomarkers of RIBI that could enable the noninvasive longitudinal evaluation of potential RIBI prophylactic and therapeutic agents. These translational MRI biomarkers could also play a pivotal role in the management of RIBI in brain tumor survivors.