Beyond the hippocampus: Limbic white matter injury implicated in post-radiation memory performance in primary brain tumor patients

Abstract

Background: Limbic white matter (WM) of the Papez circuit, including the fornix, dorsal cingulum, and parahippocampal cingulum (PHC), interplay with the hippocampus as key components of the memory network. We analyzed biomarkers of injury to these pathways to understand their impact on post-radiation therapy (RT) memory performance.

Methods: Primary brain tumor patients on a prospective trial receiving fractionated brain RT (n=57) underwent volumetric MRI, diffusion tensor imaging, and memory assessments (Hopkins Verbal Learning Test-Revised [HVLT-R] Total and Delayed Recall and Brief Visuospatial Memory Test -Revised [BVMT-R] Total and Delayed Recall) at baseline and 3, 6, and 12 months post-RT. MRI biomarkers included volume, fractional anisotropy (FA), and mean diffusivity (MD). Linear mixed-effects models assessed associations between biomarkers and memory performance over time.

Results: Smaller volumes in the right fornix was associated with lower BVMT-R-Total scores (p=0.019) and left PHC volume loss was associated with worse performance on BVMT-R-Delayed (p=0.039). Lower FA in the left (p=0.010) and right (p=0.019) fornix was associated with lower BVMT-R-Total performance. Lower FA in the left dorsal cingulum (p=0.038) and right PHC (p=0.039) were associated with lower HVLT-R-Total and HVLT-R-Delayed scores, respectively. Higher MD in bilateral fornix (p=0.01) and right PHC (p=0.011) correlated with lower BVMT-R-Total scores; higher MD in the right PHC (p=0.046) also correlated with lower HVLT-R-Total scores. Hippocampal volume was not associated with memory scores.

Conclusion: Poorer microstructural integrity in limbic WM tracts of the Papez circuit predicted worse memory performance, while hippocampal injury did not. Dose avoidance in these tracts may preserve memory outcomes.

Keywords: Cingulum; Fornix; Hippocampal sparing; memory; radiation.