Diffusion Imaging Biomarkers of Corpus Callosum Injury and Dose-Dependent Volumetric Changes Correlate with Attention and Processing Speed Changes after Brain Radiotherapy

Abstract

Attention and processing speed are core cognitive functions subserved by the corpus callosum (CC), a critical white matter structure. We hypothesized that CC volume changes and diffusion weighted imaging (DWI) biomarkers of CC injury would correlate with changes in attention and processing speed function after brain radiotherapy (RT). We prospectively studied 29 patients with primary brain tumors who received fractionated RT. Patients underwent formal neuropsychological testing and high resolution volumetric MRI with DWI (b-values 0, 500, 1500 s/mm2 fit to single tensor) prior to and 6 months post RT. Auditory attention was measured with the Weschler Adult Intelligence Scale (WAIS-IV) Digit Span Forward test; processing speed was measured with the Delis-Kaplan Executive Function System Trail Making number sequencing (TM-NS) and letter sequencing (TM-LS) subtests. Reliable change indices accounting for practice effects (RCI-PE) were calculated to determine 0-6 month change on each measure. Image processing at each time point included auto-segmentation with volume calculations of regions of interest (ROIs): the entire CC and anterior, mid-anterior, central, mid-posterior, and posterior subdivisions. Tumor, tumor bed, edema, and segmentation errors were censored. DWI biomarkers including mean diffusivity (MD, increases with injury) and fractional anisotropy (FA, decreases with injury) were calculated. Mean dose to each ROI was determined. One sample t-tests (H0=0) were performed to determine significant group cognitive decline. Pearson correlation coefficients evaluated the relationship between RCI-PEs and clinical variables, dose, changes in volume, MD, and FA. Statistical significance was set at α=0.05. Processing speed (TM-LS) significantly declined 6-months post-RT (mean change -0.472, p = 0.003). Age and years of education did not influence attention or processing speed changes. Significant dose-dependent atrophy was seen in the mid-anterior (r = -0.432, p = 0.024), mid-posterior (r = -0.408, p = 0.031), and posterior CC (r = -0.600, p = 0.001). Smaller mid-anterior CC volume was associated with worse processing speed (TM-LS, r = 0.424, p = 0.031). Decreased FA in the anterior CC was associated with worse attention (digits forward, r = 0.401, p = 0.038) and decreased FA in the posterior CC was correlated with worse processing speed (TM-LS, r = 0.444, p = 0.02). Increased MD in the anterior CC (r = -0.386, p = 0.046) was correlated with worse attention (digits forward). In this prospective study, dose-dependent atrophy of CC subdivisions was seen after fractionated brain RT. Microstructural damage, including atrophy and white matter injury, within CC subdivisions was significantly associated with worse attention and processing speed. Damage to this critical structure is highly implicated in attention/processing speed changes after brain RT.