Diffusion decrease in normal-appearing white matter structures following photon or proton irradiation indicates differences in regional radiosensitivity.

PURPOSE: Radio(chemo)therapy (RCT) as part of the standard treatment of glioma patients, inevitably leads to radiation exposure of the tumor-surrounding normal-appearing (NA) tissues. The effect of radiotherapy on the brain microstructure can be assessed by magnetic resonance imaging (MRI) using diffusion tensor imaging (DTI). The aim of this study was to analyze regional DTI changes of white matter (WM) structures and to determine their dose- and time-dependency. METHODS: As part of a longitudinal prospective clinical study (NCT02824731), MRI data of 23 glioma patients treated with proton or photon beam therapy were acquired at three-monthly intervals until 36 months following irradiation. Mean, radial and axial diffusivity (MD, RD, AD) as well as fractional anisotropy (FA) were investigated in the NA tissue of 15 WM structures and their dependence on radiation dose, follow-up time and distance to the clinical target volume (CTV) was analyzed in a multivariate linear regression model. Due to the small and non-comparable patient numbers for proton and photon beam irradiation, a separate assessment of the findings per treatment modality was not performed. RESULTS: Four WM structures (i.e., internal capsule, corona radiata, posterior thalamic radiation, and superior longitudinal fasciculus) showed statistically significantly decreased RD and MD after RT, whereas AD decrease and FA increase occurred less frequently. The posterior thalamic radiation showed the most pronounced changes after RCT [i.e., ΔRD = -8.51 % (p = 0.012), ΔMD = -6.14 % (p = 0.012)]. The DTI changes depended significantly on mean dose and time. CONCLUSION: Significant changes in DTI for WM substructures were found even at low radiation doses. These findings may prompt new radiation dose constraints sparing the vulnerable structures from damage and subsequent side-effects.

Unchanged perfusion in normal-appearing white and grey matter of glioma patients nine months after proton beam irradiation.

PURPOSE: Radio(chemo)therapy is used as a standard treatment for glioma patients. The surrounding normal tissue is inevitably affected by the irradiation. The aim of this longitudinal study was to investigate perfusion alterations in the normal-appearing tissue after proton irradiation and assess the dose sensitivity of the normal tissue perfusion. METHODS: In 14 glioma patients, a sub-cohort of a prospective clinical trial (NCT02824731), perfusion changes in normal-appearing white matter (WM), grey matter (GM) and subcortical GM structures, i.e. caudate nucleus, hippocampus, amygdala, putamen, pallidum and thalamus, were evaluated before treatment and at three-monthly intervals after proton beam irradiation. The relative cerebral blood volume (rCBV) was assessed with dynamic susceptibility contrast MRI and analysed as the percentage ratio between follow-up and baseline image (ΔrCBV). Radiation-induced alterations were evaluated using Wilcoxon signed rank test. Dose and time correlations were investigated with univariate and multivariate linear regression models. RESULTS: No significant ΔrCBV changes were found in any normal-appearing WM and GM region after proton beam irradiation. A positive correlation with radiation dose was observed in the multivariate regression model applied to the combined ΔrCBV values of low (1-20 Gy), intermediate (21-40 Gy) and high (41-60 Gy) dose regions of GM (p < 0.001), while no time dependency was detected in any normal-appearing area. CONCLUSION: The perfusion in normal-appearing brain tissue remained unaltered after proton beam therapy. In further studies, a direct comparison with changes after photon therapy is recommended to confirm the different effect of proton therapy on the normal-appearing tissue.

Dose dependent cerebellar atrophy in glioma patients after radio(chemo)therapy.

BACKGROUND AND PURPOSE: Radiotherapy is a standard treatment option for high-grade gliomas. Brain atrophy has previously been associated with radiotherapy. The goal of this study was to investigate dose dependent cerebellar atrophy using prospective, longitudinal MR data from adult glioma patients who received radiotherapy. MATERIALS AND METHODS: Cerebellar volumes were measured using T1-weighted MR images from 91 glioma patients before radiotherapy (N = 91) and from longitudinal follow-ups acquired in three monthly intervals (N = 349). Relative cerebellar volumes were calculated as ratios to the corresponding baseline values. Univariate mixed effects models were used to determine factors that were significantly associated with relative cerebellar volumes. These factors were subsequently included as fixed effects in a final multivariate linear mixed effects model. RESULTS: In multivariate analysis, cerebellar volume decreased significantly as a function of time (p < 0.001), time × dose (p < 0.001) and patient age (p = 0.007). Considering a 55 year patient receiving a mean cerebellar dose of 0 Gy (10 Gy), the linear mixed effects model predicts a relative cerebellar volume loss of 0.4% (2.0%) after 1 year and 0.7% (3.6%) after 2 years. Compared to patients treated with photons, the cerebellar dose was significantly lower in patients treated with proton therapy (p < 0.001, r = 0.62). CONCLUSION: Cerebellar volume decreased significantly and irreversibly after radiotherapy as function of time and mean cerebellar dose. Further work is now needed to correlate these results with cognitive function and motor performance.

Echo time dependence of BOLD fMRI studies of the piriform cortex.

BACKGROUND AND PURPOSE: In functional magnetic resonance imaging (fMRI) studies, brain areas that are commonly associated with the processing of olfactory stimuli, i.e., piriform cortex and orbitofrontal cortex, are often obscured by susceptibility-induced signal loss. The authors hypothesized that using a short echo time (TE) should not only reduce susceptibility artifacts but also increase the overall signal-to-noise ratio and allow to retrieve a blood oxygenation level-dependent (BOLD) signal in regions normally affected by these artifacts. MATERIAL AND METHODS: Two sequences with TEs of 60 and 32 ms were compared using a 1.5-T MRI scanner: in a standard motor paradigm, activations of the contralateral motor cortex were measured. In an olfactory stimulation paradigm, activations in piriform cortex were compared. RESULTS: Reducing TE from 60 to 32 ms reduced the observed signal intensity changes in the motor paradigm by 51%. Concomitant to this, geometric distortions and signal dropout artifacts were decreased at orbitofrontal and temporomesial brain areas in both paradigms. Contrary to the authors' expectations, the signal intensity changes in the piriform cortex were also reduced by 48% in the olfactory paradigm. Moreover, piriform cortex activation was detected in less subjects at TE = 32 ms than at TE = 60 ms. Changes in cortical activation were significant in the right, but not in the left piriform cortex. CONCLUSION: Although a shorter TE reduces signal dropouts due to susceptibility artifacts, this shorter TE is not sufficient to recover the BOLD signal from regions affected by susceptibility artifacts such as the piriform cortex. Thus, reducing the TE to the T2* of the investigated region is not an effective approach to improve the results of olfactory fMRI studies.