Does Hippocampal Atrophy Correlate with Neurocognitive Outcomes One Year Following Radiotherapy? Results from a Prospective Trial

Abstract

<h3>Purpose/Objective(s)</h3> Volumetric MRIs were collected at baseline and during follow-up in pediatric and young adult brain tumor patients (Age<35 years) to measure volumetric changes in brain substructures along with neurocognitive and quality-of-life assessments. In this planned interim analysis, we report change in hippocampus volume at 12 months following exposure to different doses from intensity-modulated proton therapy (IMPT) and its association with visual and verbal memory assessments. <h3>Materials/Methods</h3> As of February 27, 2021, 60 patients had enrolled on this prospective study and 47 had completed 12-month assessments after IMPT. Left and right hippocampus volumes were independently measured on T1 precontrast MRI at baseline, 6 months, and 12 months after IMPT. A linear mixed-effects (LME) model was applied to evaluate the effect of mean dose and other variables associated with change in hippocampus volume, assuming random effects of subjects. Patients were censored if they developed disease progression. The relationship between change in hippocampus volumes with (1) mean dose and (2) visual and verbal memory scores were assessed using Pearson's correlation coefficient. Comparisons between patients found to have below average (≤20^th percentile) vs. average or better (>20^th percentile) age-normative memory scores after IMPT were evaluated by unpaired t-test. <h3>Results</h3> Mean hippocampus dose was strongly correlated with change in hippocampus volume at 12 months after IMPT (r = −0.754, 95% CI [-0.837, -0.638], p < 0.001). In the LME model, only mean hippocampus dose was significantly associated with hippocampus volume change at 12 months (p < 0.001). The final model predicted changes in hippocampus volume of -6.2% for every 10 Gy increase in mean dose at 12 months after IMPT. Hippocampal volume was significantly reduced for mean doses >5 Gy (mean Δ -38.1% ± 20.3%, p < 0.001), while no significant change in volume was observed with mean doses ≤5 Gy (mean Δ -1.7% ± 5.0%). No significant associations were found between change in hippocampus volume and either visual or verbal memory scores at 12 months after IMPT. At 12 months, eight patients had either verbal or visual memory scores that were ≤20^th percentile. Patients who scored ≤20^th percentile on these memory scores were significantly more likely to have received higher mean doses to the hippocampus (mean dose 38.3 Gy ± 10.8, p<0.001) compared to patients with scores that were >20^th percentile (mean dose 7.8 Gy ± 9.7). <h3>Conclusion</h3> Change in hippocampus volume was correlated with hippocampus mean dose at 12 months following IMPT. No clear relationship was observed between hippocampal atrophy and memory scores at 12 months following IMPT, but patients with below average age-normative memory scores at 12 months generally received significantly higher mean doses.