Diffusion changes in normal-appearing white matter tracts following irradiation in glioma patients

Purpose: Adjuvant radio(chemo)therapy (RT) is part of the standard treatment of gliomas. Safety margins ensuring the coverage of microscopic tumour expansion of diffusely infiltrating gliomas and compensating for systematic positioning errors inevitably result in the normal-appearing (NA) brain tissue surrounding the tumour to be affected by radiation. The aim of the study was to investigate dose- and time-dependent diffusion alterations of NA white matter (WM) structures following RT using tract-based spatial statistics (TBSS).

Methods: As part of a prospective, longitudinal study, magnetic resonance imaging (MRI) data of 24 grade II-IV glioma patients treated with photons, protons or mixed-modality therapy were acquired. MRIs before RT and 3-monthly during follow-up obtained up to three years after RT included diffusion tensor images (DTI) (TR/TE=6500/66ms, 2×2×2mm³, 32 directions, b=1000mm/s²). Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated from the DTI data. Corresponding radiation dose maps and clinical target volume (CTV) contours were aligned to MRI using ANTs. NA tissue was defined as brain tissue, excluding the CTV and areas of T2-hyperintensities. All FA images were nonlinearly registered to the “FMRI58B-FA atlas” from FSL with ANTs before applying parts of the TBSS algorithm to create a FA skeleton (Figure 1).
The FA skeleton was combined with the “JHU-ICBM-labels-1mm atlas” to measure the diffusion in 19 WM structures. Relative signal changes of each WM structure were calculated as the difference between follow-up and the corresponding baseline signal and evaluated using a paired t-test. A multivariate linear mixed effects model was applied to determine diffusion changes as function of time after RT and mean dose delivered to the corresponding structure. Data from paired structures of the right and left hemispheres were combined for the analysis. Structures containing less than 50 voxels were excluded.

Results: Figure 2 shows nine structures exhibiting significant DTI signal changes after RT. Posterior thalamic radiation showed the greatest alterations of the DTI parameters and a significant dose- and time-dependency of MD (-0.111%/month, -0.135%/Gy), RD (-0.14%/month, -0.171%/Gy) and AD (-0.09%/month, -0.1%/Gy). The strongest correlation of FA with time appeared in superior longitudinal fasciculus (0.045%/month) and with dose in internal capsula (0.056%/Gy). All significant changes represented decreasing MD, RD, and AD and increasing FA after irradiation. No significant correlations were detected in medial lemniscus.

Conclusion: Several WM structures showed significant time- and dose-dependent DTI signal changes after RT, which might indicate a stronger radiosensitivity of these structures. The results are in agreement with the investigation of the dose-dependent irradiation effects on WM diffusion already performed by Raschke et al. (Radiother Oncol. 2019;140:110–115) and Dünger et al. (Radiother Oncol. 2021;164:66–72).