Dose-dependent white matter damage after brain radiotherapy

Abstract

Background and purpose: Brain radiotherapy is limited in part by damage to white matter, contributing to neurocognitive decline. We utilized diffusion tensor imaging (DTI) with multiple b-values (diffusion weightings) to model the dose-dependency and time course of radiation effects on white matter.

Materials and methods: Fifteen patients with high-grade gliomas treated with radiotherapy and chemotherapy underwent MRI with DTI prior to radiotherapy, and after months 1, 4-6, and 9-11. Diffusion tensors were calculated using three weightings (high, standard, and low b-values) and maps of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ_∥), and radial diffusivity (λ_⊥) were generated. The region of interest was all white matter.

Results: MD, λ_∥, and λ_⊥ increased significantly with time and dose, with corresponding decrease in FA. Greater changes were seen at lower b-values, except for FA. Time-dose interactions were highly significant at 4-6months and beyond (p<.001), and the difference in dose response between high and low b-values reached statistical significance at 9-11months for MD, λ_∥, and λ_⊥ (p<.001, p<.001, p=.005 respectively) as well as at 4-6months for λ_∥ (p=.04).

Conclusions: We detected dose-dependent changes across all doses, even <10Gy. Greater changes were observed at low b-values, suggesting prominent extracellular changes possibly due to vascular permeability and neuroinflammation.

Keywords: Diffusion tensor imaging; MRI; Radiation; Radiotherapy; White matter; b-Value.

Fig 1

a Original white matter mask. b Eroded 6-connected white matter. c FLAIR hyperintensity

Fig 2

Percent changes from baseline in MD, FA, λ_‖, and λ_⊥ for each dose bin and b-value. Hollow points: no significant change from baseline. Filled points: significant change from baseline. Asterisks: significance for paired t-tests between changes at high and low b-values at each time point (*** p < .001, ** p < .01, * p < .05)

Fig 3

Time-dose interaction coefficients at each time point and b-value. The coefficients represent percent change per Gy. Error bars represent 95% confidence intervals. Significant p-values for tests between high and low b-value coefficients are shown

Fig 4

Percent changes in MD, FA, λ_‖, and λ_⊥ for each dose bin and b-value at 9-11 months; white matter (circles) vs. white matter excluding FLAIR hyperintensity (triangles). Significant differences between ROIs are labeled