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 4-6 months and beyond (p < .001), and the difference in dose response between high and low b-values reached statistical significance at 9-11 months for MD, λ‖, and λ⊥ (p < .001, p < .001, p = .005 respectively) as well as at 4-6 months for λ‖ (p = .04). Conclusions We detected dose-dependent changes across all doses, even <10 Gy. Greater changes were observed at low b-values, suggesting prominent extracellular changes possibly due to vascular permeability and neuroinflammation.

Regional susceptibility to dose-dependent white matter damage after brain radiotherapy

“…Most patients were treated to 60 Gy in 30 fractions. Other dose schedules were converted to a total 30 fraction equivalent dose using biologically equivalent dose principles [16] and an α/β ratio of 2 Gy [14]. Treatment and demographic factors are shown in Supplementary Table 1.…”

“…The diffusion tensor at each time point was calculated using mono-exponential fitting and data from all diffusion weightings (b=0, 500, 1000, 4000 s/mm 2 ). We analyzed four main diffusion metrics, each computed as a map at each time-point [14]. These diffusion metrics are defined in detail previously [14]: mean diffusivity (MD) represents the average mobility of water molecules and is sensitive to edema; fractional anisotropy (FA) is an expression of the degree of directional bias and hence a marker of microstructural white matter integrity; axial diffusivity (AD) represents diffusion along the white matter axon and is thought to be sensitive to axonal injury; radial diffusivity (RD) represents diffusion perpendicular to axonal orientation and is a marker of demyelination [20,21].…”

“…We previously analyzed DTI metrics of white matter damage after RT and found progressive, dose-dependent changes even at low doses and at time points early on after RT [14]. However, it is unclear which white matter regions of the brain are the most sensitive to radiation injury.…”

Left hippocampus sparing whole brain radiotherapy (WBRT): A planning study

“…Decreasing the hippocampal dose (D 100% ) to as low as possible was shown to predict less decline in some memory tests over time in patients irradiated for brain metastases 12,13 . More recently, white matter damage as well as thinning of the cerebral cortex after brain irradiation proved to be highly dose-dependent 18,19 . Hippocampus itself demonstrates radiation dose-dependent atrophy after treatment for brain tumors 20,21 .…”

Brain white matter fibre tracts: a review of functional neuro-oncological relevance

“…Crucially, careful surgical preservation of tracts may theoretically be undone if radiotherapy compromises important proximal tracts. Longitudinal DT measurements suggest that greater reductions in fibre tract integrity, reflecting dose-dependent effects of radiation therapy,49 predict greater cognitive declines following treatment 50. An intriguing idea, therefore, is to use DT information to minimise radiation doses delivered to portions of fibre tracts with high sensitivity to radiation effects 51.…”