Effective therapy for medulloblastoma, the most common brain tumor in children, is associated with neurocognitive deficits mediated by the frontal lobes, such as working memory,^1,2 processing speed, and attention². Additionally, survivors have been shown to have decreased white matter (WM) volumes,³ which are associated with decreased fractional anisotropy (FA).⁴ In this study, we hypothesized that frontal WM would be damaged at the microstructural level by disease and/or surgery, and that global volumetric changes would occur in response to this early damage.

Subjects included 129 patients with posterior fossa tumors, ranging in age from 3.2 to 20.3 years at diagnosis (median=8.6 years), treated with maximal surgical resection, risk-adapted craniospinal irradiation (CSI), and high-dose chemotherapy. Patients with minimal localized disease were assigned to the average-risk (AR) group, while all others were high-risk (HR). MRI examinations were collected at seven time points: baseline (after surgery but before additional therapy); after CSI; and 12, 18, 24, 30, and 36 months after diagnosis. Seventy-two age-similar normal healthy control subjects, ranging in age from 6.0 to 24.5 years at baseline (median=13.0 years), were imaged three times: at baseline and 12 and 24 months later. Treatment and imaging protocols were approved by the local Institutional Review Board, and written informed consent was obtained from the patient, subject, parent, or guardian, as appropriate.

Conventional T1, T2, Proton Density and FLAIR imaging was collected on all subjects using a 1.5T or 3.0T whole-body system (Siemens Medical Systems, Iselin, NJ). These images were registered both within each examination and to the baseline study of each subject before being segmented into CSF, gray and WM.⁵ Diffusion tensor imaging (DTI), acquired with 12 directions and 4 averages, was processed with the DTI toolkit under SPM8 (http://www.fil.ion.ucl.ac.uk/spm/) to generate maps of FA, radial (RAD) and axial (AX) diffusivity. Seven slices were analyzed, four slices above and two slices below an index slice containing the genu, splenium, and basal ganglia. This coverage was further divided into the left and right frontal quadrants. In addition to the regional analysis, FA maps were processed via the Tract-Based Spatial Statistics (TBSS) pipeline, part of the FMRIB Software Library (FSL, http://www.fmrib.ox. ac.uk/fsl). After statistical analysis, the significant TBSS regions were labeled anatomically using the JHU-ICBM-DTI-81 WM atlas.⁶ Linear mixed-effects modeling was performed using the restricted maximum–likelihood estimation method to analyze the longitudinal data. Estimates were computed for baseline value, change over time, and interaction between time and subject group (patient vs. control; HR vs. AR vs. control), controlling for age effects using a baseline age term for each subject.

There were a total of 758 patient examinations and 215 control examinations completed. At baseline, WM volumes in patients were similar to those in controls; FA and AX were lower bilaterally; and RAD was higher in the right frontal lobe only (Table 1). Group differences were seen for FA only, where the HR group showed significantly lower FA than the AR group (Figure 1). During follow-up, WM volumes increased in controls but remained static in the AR group and decreased in the HR group. FA values in patients increased but never reached control levels. AX and RAD were static in controls but decreased bilaterally in patients. Only the change in RAD over time was significantly different between the AR and HR groups on the right side. TBSS analysis revealed that voxels with increasing FA were predominantly located in the corpus callosum and corona radiata.Baseline results were consistent with acute, indirect axonal injury caused by disease and/or surgery, which decreased AX but did not appreciably affect WM volume.⁷ Decreased AX, RAD, and WM volume in follow-up would be consistent with possible resolution of axonal swelling combined with chronic demyelination.^7-9 Furthermore, the subsequent near-normalizing increase in FA over the three year course of treatment and follow-up combined with macroscopic WM volume loss, suggests overall loss of cellular density despite evidence of microstructural recovery, potentially due to loss of support cells (glia), axons and/or myelin, without which DTI parameters may be near-normal if axonal density is maintained.¹⁰DTI metrics at baseline indicated that patients with pediatric posterior fossa tumors suffer substantial acute microstructural damage to their WM that is caused by disease and surgical intervention. This early damage combined with the effects of radiation therapy and chemotherapy was followed by a failure of the WM volume to increase at an age-appropriate rate in patients with AR disease and decrease in those with HR disease.