Diffusion Imaging Biomarkers of Regional White Matter Injury Correlate With Change in Executive Function and Processing Speed After Brain Radiation Therapy

Abstract

To analyze region specific biomarkers of white matter (WM) integrity using diffusion imaging and test associations with executive functioning and processing speed in a prospective clinical trial. We hypothesized that regional changes in diffusion biomarkers of WM damage would correlate with changes in executive function and processing speed at 6-months post-radiotherapy (RT). We prospectively evaluated 25 primary brain tumor patients undergoing fractionated brain RT. Study patients underwent high-resolution volumetric MRI, diffusion weighted imaging (b-values 0, 500, 1500 s/mm2fit to single tensor), and neurocognitive assessment of executive functioning (Delis-Kaplan Executive Function System [D-KEFS] letter fluency and category switching total and Wisconsin Card Sorting Test [WCST] perseverative errors) and processing speed (D-KEFS Trail Making [TM] number and letter sequencing) prior to and 6 months after RT. Freesurfer software was run at each time point to segment regions of interest (ROIs) associated with these cognitive domains: left dorsolateral and bihemispheric anterior cingulate WM for executive functioning; bihemispheric inferior parietal and total right hemispheric WM for processing speed. Tumor, edema, and segmentation errors were censored. Change in diffusion biomarkers of mean diffusivity (MD) and fractional anisotropy (FA) were calculated for each ROI. Reliable change indices were calculated for change in cognition from pre-RT to 6 months post-RT. Pearson correlation coefficients were used to test associations between clinical variables and change in diffusion parameters and cognitive scores. Statistical significance was set to α = 0.05 with two-tailed tests. Executive function (D-KEFS category switching total, mean change -0.56, P = 0.017; WCST mean change -0.51, P = 0.006) and processing speed (TM number sequencing, mean change -0.40, P = 0.045) significantly declined post-RT. Change in executive function was positively correlated with age and years of education (r = 0.54, P = 0.012; r = 0.53, P = 0.013, respectively), while processing speed was negatively correlated with age (r = -0.51, P = 0.014). FA increased in total right hemispheric WM (mean change 0.0074±0.029) and all ROIs associated with executive function and processing speed. MD decreased in executive function ROIs, but remained relatively unchanged in ROIs associated with processing speed. While WM diffusion parameters were not associated with executive function decline, MD of both left and right inferior parietal WM and right total hemispheric WM were positively correlated with processing speed (TM letter sequencing, r = 0.60, P = 0.015; r = 0.57, P = 0.016; r = 0.51, P = 0.037, respectively). Diffusion changes in bihemispheric inferior parietal and total right hemispheric WM were significantly associated with changes in processing speed in brain tumor patients after RT.