Quantitative Imaging Biomarkers of Damage to Critical Memory Regions Are Associated With Post-Radiation Therapy Memory Performance in Brain Tumor Patients

Abstract

Purpose: We used quantitative magnetic resonance imaging to prospectively analyze the association between microstructural damage to memory-associated structures within the medial temporal lobe and longitudinal memory performance after brain radiation therapy (RT).

Methods and materials: Patients with a primary brain tumor receiving fractionated brain RT were enrolled on a prospective trial (n = 27). Patients underwent high-resolution volumetric brain magnetic resonance imaging, diffusion-weighted imaging, and neurocognitive testing before and 3, 6, and 12 months post-RT. Medial temporal lobe regions (hippocampus; entorhinal, parahippocampal, and temporal pole white matter [WM]) were autosegmented, quantifying volume and diffusion biomarkers of WM integrity (mean diffusivity [MD]; fractional anisotropy [FA]). Reliable change indices measured changes in verbal (Hopkins Verbal Learning Test-Revised) and visuospatial (Brief Visuospatial Memory Test-Revised [BVMT-R]) memory. Linear mixed-effects models assessed longitudinal associations between imaging parameters and memory.

Results: Visuospatial memory significantly declined at 6 months post-RT (mean reliable change indices, -1.3; P = .012). Concurrent chemotherapy and seizures trended toward a significant association with greater decline in visuospatial memory (P = .053 and P = .054, respectively). Higher mean dose to the left temporal pole WM was significantly associated with decreased FA (r = -0.667; P = .002). Over all time points, smaller right hippocampal volume (P = .021), lower right entorhinal FA (P = .023), greater right entorhinal MD (P = .047), and greater temporal pole MD (BVMT-R total recall, P = .003; BVMT-R delayed recall, P = .042) were associated with worse visuospatial memory. The interaction between right entorhinal MD (BVMT-R total recall, P = .021; BVMT-R delayed recall, P = .004) and temporal pole FA (BVMT-R delayed recall, P = .024) significantly predicted visuospatial memory performance.

Conclusions: Brain tumor patients exhibited visuospatial memory decline post-RT. Microstructural damage to critical memory regions, including the hippocampus and medial temporal lobe WM, were associated with post-RT memory decline. The integrity of medial temporal lobe structures is critical to memory performance post-RT, representing possible avoidance targets for memory preservation.

Conflict of interest statement

Potential conflicts of interest: JAH-G has research funding from Varian Medical Systems (Palo Alto, CA), unrelated to the current study. CRM has research funding from GE Healthcare, unrelated to the current study.

Copyright © 2019 Elsevier Inc. All rights reserved.

Figures

Figure 1.

Scatter plots for hippocampal volume and domain-specific memory performance including all time points for each patient up to 12 months post-RT. The trend line overlays the LOESS fit with the smoothing parameter that minimizes the AICC criterion. Significant associations between imaging parameter and memory test were determined based on the beta coefficient (β2) derived from the linear mixed effects model with random intercept and slope: MemoryScoresij=(β0+b0i)+(β1+b1i)Monthj+β2Imaging+eij Raw memory scores are shown. Hippocampal volumes are shown as mm3. (A) Smaller left hippocampal volumes were not significantly associated with poorer performance on verbal memory testing (HVLT-R Total Recall β2= 0.00038, P=.849; HVLT-R Delayed Recall, β2= 0.00008, P=.935). (B) Smaller right hippocampal volumes were significantly associated with worse performance on visuospatial memory testing (BVMT-R Total Recall, β2= 0.004 points/mm3, P=.069; BVMT-R Delayed Recall, β2= 0.00214 points/mm3, P=.021). Abbreviations: BVMT-R, Brief Visuospatial Memory Test-Revised; HVLT-R, Hopkins Verbal Learning Test-Revised

Figure 2.

Scatter plots for (A) right entorhinal and (B) right temporal WM and visuospatial memory performance including all time points for each patient up to 12 months post-RT. The trend line overlays the LOESS fit with the smoothing parameter that minimizes the AICC criterion. Significant associations between imaging parameter and memory test were determined based on the beta coefficient (β2) derived from the linear mixed effects model with random intercept and slope: MemoryScoresij=(β0+b0i)+(β1+b1i)Monthj+β2Imaging+eij Raw memory scores are shown. MD is expressed in mm2/s. FA is unitless. Outliers (n=2 and n=4 for A and B, respectively) were removed based on statistically significantly great Mahalanobis distances (P<.001). (A) Higher right entorhinal MD values were significantly associated with worse BVMT-R Total Recall (β2= −28,385 points/mm2/s, P=.047). Smaller right entorhinal FA values were significantly associated with worse BVMT-R Total Recall (β2= 49.15 points,P=.023). (B) Higher right temporal pole MD values were significantly associated with worse nonverbal memory (BVMT-R Total Recall, β2= −60,800 301 points/mm2/s , P=.003; BVMT-R Delayed Recall, β2= −17,762 301 points/mm2/s, P=.042). Abbreviations: BVMT-R, Brief Visuospatial Memory Test-Revised; HVLT-R, Hopkins Verbal Learning Test-Revised