Quantitative Evaluation of Rabbit Brain Injury after Cerebral Hemisphere Radiation Exposure Using Generalized q-Sampling Imaging

Abstract

Radiation therapy is widely used for the treatment of brain tumors and may result in cellular, vascular and axonal injury and further behavioral deficits. The non-invasive longitudinal imaging assessment of brain injury caused by radiation therapy is important for determining patient prognoses. Several rodent studies have been performed using magnetic resonance imaging (MRI), but further studies in rabbits and large mammals with advanced magnetic resonance (MR) techniques are needed. Previously, we used diffusion tensor imaging (DTI) to evaluate radiation-induced rabbit brain injury. However, DTI is unable to resolve the complicated neural structure changes that are frequently observed during brain injury after radiation exposure. Generalized q-sampling imaging (GQI) is a more accurate and sophisticated diffusion MR approach that can extract additional information about the altered diffusion environments. Therefore, herein, a longitudinal study was performed that used GQI indices, including generalized fractional anisotropy (GFA), quantitative anisotropy (QA), and the isotropic value (ISO) of the orientation distribution function and DTI indices, including fractional anisotropy (FA) and mean diffusivity (MD) over a period of approximately half a year to observe long-term, radiation-induced changes in the different brain compartments of a rabbit model after a hemi-brain single dose (30 Gy) radiation exposure. We revealed that in the external capsule, the GFA right to left (R/L) ratio showed similar trends as the FA R/L ratio, but no clear trends in the remaining three brain compartments. Both the QA and ISO R/L ratios showed similar trends in the all four different compartments during the acute to early delayed post-irradiation phase, which could be explained and reflected the histopathological changes of the complicated dynamic interactions among astrogliosis, demyelination and vasogenic edema. We suggest that GQI is a promising non-invasive technique and as compared with DTI, it has better potential ability in detecting and monitoring the pathophysiological cascades in acute to early delayed radiation-induced brain injury by using clinical MR scanners.

Fig 1. GFA, QA, ISO, FA and MD mappings.

They were calculated from the multiple shells diffusion data with GQI and DTI methods, respectively, using DSI studio at the baseline (0) and at the 1^st to the 24^th weeks post-irradiation.

Fig 2. ROI drawings of four different compartments in one representative rabbit’s brain.

Fig 3. Longitudinal changes of the GQI indices in the different brain compartments after irradiation.

(A) In the cerebral cortex, there was no clear trend in the GFA R/L ratio. The QA and ISO R/L ratios showed a rapid increase after the 1^st week followed by a plateau and then a gradual decrease. (B) In the external capsule, the GFA R/L ratio showed a gradual decrease during the initial 2 weeks followed by a gradual recovery. The QA and ISO ratios showed a rapid increase during the initial 2 weeks followed by a plateau and then a gradual decrease. (C) In the hippocampus, there was no clear trend in the GFA R/L ratio. The QA and ISO R/L ratios showed a rapid increase after the 1^st week followed by a plateau and then a gradual decrease. (D) In the thalamus, there was no clear trend in the GFA R/L ratio. The QA and ISO R/L ratios showed a rapid increase at the 1^st week followed by a plateau and then a gradual decrease.

Fig 4. Longitudinal changes in the different brain compartments of the different GQI indices after irradiation.

(A) The GFA R/L ratio showed a gradual decrease, followed by a gradual recovery in the external capsule, but no clear trends in the remaining three brain compartments. In both the QA and ISO R/L ratios, all four different brain compartments showed similar trends with a rapid increase after the 1^st week followed by a plateau and then a gradual decrease. (B, C) Both the trends of the QA and ISO R/L ratios at the thalamus showed a more gradual slope as compared with the other three brain compartments.

Fig 5. Longitudinal changes of the GQI indices and the DTI indices in the different brain compartments after irradiation.

The GQI indices (QA and ISO) showed more clear trends compared with the DTI indices (FA and MD) in the all four compartments.

Fig 6. The change of signal intensity in the irradiated right hemisphere on T2 WI (A, B) correlated well with the gross morphology (C, D) of the sacrificed rabbit at the 48^th week post-irradiation.

It showed mixed signal intensity with a loss of the normal architecture, which presented as radiation necrosis with focal hemorrhage and yellow discoloration in the irradiated right hemisphere (EC = external capsule; HIP = hippocampus; R = right side).

Fig 7. Histopathological evaluations of the injured (right) and control (left) sides of the rabbit brain at 48 weeks post-irradiation, including H&E (A, C, E) and LFB (B, D) staining.

(A, B) No significant radiation-related alterations were observed in the left hemisphere of the brain. (C) Demyelination in the right hippocampus. Decreased coloration, indicating a loss of the myelin sheath in the right external capsule. (D) Disorganization of the myelin fibers in the right external capsule and right hippocampus. (E) Prominent hyalinization and fibrinoid deposition of the vessel walls (arrow) within the right hippocampus. (EC = external capsule; HIP = hippocampus).