Beyond the Hippocampus: White Matter Memory Network Implicated in Post-Radiation Memory Decline in Primary Brain Tumor Patients

Abstract

<h3>Purpose/Objective(s)</h3> Memory deficits after brain RT are common. Critical white matter tracts including the fornix, cingulum, and parahippocampal cingulum (PHC) connect with the hippocampus, comprising the memory network. We analyzed quantitative neuroimaging biomarkers of microstructural injury to these white matter regions of interest (ROI) and hippocampus, to understand the impact these changes have on post-RT verbal and visuospatial memory performance in brain tumor patients. <h3>Materials/Methods</h3> Primary brain tumor patients on a prospective trial receiving fractionated brain RT (n=56) underwent volumetric brain MRI, diffusion tensor imaging, and prospective memory assessments (Hopkins Verbal Learning Test-Revised [HVLT-R] Total and Delayed Recall and Brief Visuospatial Memory Test [BVMT] Total and Delayed Recall) at baseline and 3, 6, and 12 months post-RT. Bilateral hippocampi, fornix, cingulum, and parahippocampal cingulum (PHC) were autosegmented; tumor, surgical bed, and edema were censored to avoid confounding. Volume was measured in each ROI, and diffusion biomarkers also analyzed in white matter ROIs (fractional anisotropy, FA; mean diffusivity, MD). Increase in MD and decrease in FA indicate WM injury. Multivariable linear mixed-effects models assessed associations of biomarkers with time and RT dose, and as longitudinal predictors of memory scores, controlling for time and subject-specific effects. P-values were corrected for multiple comparisons. <h3>Results</h3> Volumes of all ROIs significantly decreased after 6 months (p<0.05). Over time, FA decreased in right and left fornix and cingulum (p<0.05) and MD increased in left fornix (p=0.005). Higher RT dose was associated with: atrophy in left and right hippocampi (p<0.001) and right fornix (p=0.024), decreased FA in right fornix (p=0.046) and right PHC (p=0.042), and increased MD in right PHC (p=0.03). Atrophy of right fornix was associated with worse performance on BVMT Total (p=0.019) and decreased volume of left PHC with worse performance on BVMT Delayed (p=0.039). Volume of either hippocampus was not associated with memory scores. Reduced FA in the left (p=0.010) and right (p=0.019) fornix was associated with worse performance on BVMT Total. Lower FA in the left cingulum (p=0.038) was associated with worse performance on HVLT Total while lower FA in the right PHC was associated with worse performance on HVLT Delayed. Higher MD in the left (p=0.010) and right (p=0.007) fornix and the right PHC (p=0.011) correlated with poorer BVMT Total scores, while higher MD in the right PHC (p=0.046) was correlated with poorer HVLT Total scores. <h3>Conclusion</h3> Microstructural injury in the fornix, cingulum, and PHC predicted for worse verbal and visuospatial memory post-RT, while injury to the hippocampus did not. RT dose avoidance to these white matter regions should be explored to better preserve memory in brain tumor patients.