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16 Superior Verbal Learning and Memory in Pediatric Brain Tumor Survivors Treated with Proton Versus Photon Radiotherapy
- Lisa E. Mash, Lisa S. Kahalley, M. Fatih Okcu, David R. Grosshans, Arnold C. Paulino, Heather Stancel, Luz A. De Leon, Elisabeth A. Wilde, Nilesh Desai, Zili D. Chu, William E. Whitehead, Murali Chintagumpala, Kimberly P Raghubar
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 17-18
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Objective:
Radiotherapy for pediatric brain tumor has been associated with late cognitive effects. Compared to conventional photon radiotherapy (XRT), proton radiotherapy (PRT) delivers less radiation to healthy brain tissue. PRT has been associated with improved long term cognitive outcomes compared to XRT. However, there is limited research comparing the effects of XRT and PRT on verbal memory outcomes.
Participants and Methods:Survivors of pediatric brain tumor treated with either XRT (n = 29) or PRT (n = 51) completed neuropsychological testing > 1 year following radiotherapy. XRT and PRT groups were similar with respect to sex, handedness, race, age at diagnosis, age at evaluation, tumor characteristics, and treatment history (i.e., craniospinal irradiation, craniotomy, shunting, chemotherapy, radiation dose). Verbal learning and memory were assessed using the age-appropriate version of the California Verbal Learning Test (CVLT-II/CVLT-C). Measures of intellectual functioning, executive functioning, attention and adaptive behavior were also collected. Performance on neuropsychological measures was compared between treatment groups (XRT vs. PRT) using analysis of covariance (ANCOVA). On the CVLT, each participant was classified as having an encoding deficit profile (i.e., impaired learning, recall, and recognition), retrieval deficit profile (i.e., impaired recall but intact recognition), intact profile, or other profile. Chi-squared tests of independence were used to compare the probability of each memory profile between treatment groups. Pearson correlation was used to examine associations between memory performance and strategy use, intellectual functioning, adaptive behavior, attention, and executive functioning.
Results:Overall, patients receiving PRT demonstrated superior verbal learning (CVLT Trials 1-5; t(76) = 2.61, p = .011), recall (CVLT Long Delay Free; t(76) = 3.57, p = .001) and strategy use (CVLT Semantic Clustering; t(76) = 2.29, p = .025) compared to those treated with XRT. Intact performance was more likely in the PRT group than the XRT group (71% PRT, 38% XRT; X2 = 8.14, p = .004). Encoding and retrieval deficits were both more common in the XRT group, with encoding problems being most prevalent (Encoding Deficits: 31% XRT, 12% PRT, X2 = 4.51, p = .034; Retrieval Deficits: 17% XRT, 4% PRT, X2 = 4.11, p = .043). Across all participants, semantic clustering predicted better encoding (r = .28, p = .011) and retrieval (r = .26, p = .022). Better encoding predicted higher intellectual (r = .56, p < .001) and adaptive functioning (r = .30, p = .011), and fewer parent-reported concerns about day-today attention (r = -.36, p = .002), and cognitive regulation (r = -.35, p = .002).
Conclusions:Results suggest that PRT is associated with superior verbal memory outcomes compared to XRT, which may be driven by encoding skills and use of learning strategies. Moreover, encoding ability predicted general intellectual ability and day-to-day functioning. Future work may help to clarify underlying neural mechanisms associated with verbal memory decline following radiotherapy, which will better inform treatment approaches for survivors of pediatric brain tumor.
2 Cognitive Sparing in Proton Versus Photon Radiotherapy for Pediatric Brain Tumor Associated with White Matter Integrity
- Lisa E. Mash, Lisa S. Kahalley, Kimberly P. Raghubar, Naomi J. Goodrich-Hunsaker, Tracy J. Abildskov, Luz A. De Leon, Marianne MacLeod, Heather Stancel, Kelley Parsons, Brian Biekman, Elisabeth A. Wilde
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 312-313
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Objective:
Radiotherapy for pediatric brain tumor is associated with reduced white matter structural integrity and neurocognitive decline. Superior cognitive outcomes have been reported following proton radiotherapy (PRT) compared to conventional photon radiotherapy (XRT), presumably due to sparing of healthy brain tissue. This study examined long-term white matter change and neuropsychological performance in pediatric brain tumor survivors treated with XRT vs. PRT.
Participants and Methods:Pediatric brain tumor survivors treated with either XRT (n = 10) or PRT (n = 12) underwent neuropsychological testing and diffusion weighted imaging > 7 years following radiotherapy. A healthy control group (n = 23) was also recruited. Groups had similar demographic characteristics, except for handedness (p = .01), mean years of age at testing (XRT = 21.7, PRT = 16.9, Control = 15.5; p = .01), and mean years since radiation (XRT =14.7, PRT = 8.9, p < .001). Age and handedness were selected as covariates; analyses were not adjusted for time since radiation due to redundancy with treatment group (i.e., standard of care transitioned from XRT to PRT in 2007). Participants completed age-appropriate versions of the Weschler Intelligence Scales (WAISIV/WISC-IV/WISC-V) and the Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI and Motor Coordination subtests). Tractography was conducted using automated fiber quantification (AFQ), and fractional anisotropy (FA) was extracted from 12 tracts of interest. Linear mixed models were used to summarize group differences in FA, with tracts nested within subjects. Neuropsychological performance and tract-level FA were compared between groups using analysis of covariance (ANCOVA). Pearson correlation was used to examine associations between cognitive functioning and tract-level FA.
Results:Across all tracts, FA was significantly lower in the XRT group than the PRT group (t(514) = -2.58, p = .01), but did not differ between PRT and Control groups (t(514) = .65, p = .51). For individual tracts, FA differed significantly between treatment groups (XRT < PRT) in the left inferior fronto-occipital fasciculus (IFOF), right IFOF, left inferior longitudinal fasciculus (ILF) and right uncinate (all t < -2.05, all p < .05). No significant differences in FA were found between PRT and Control participants for any tract. All neuropsychological scores were significantly lower for XRT than PRT patients (all p < .03), while PRT and Control groups performed similarly on these measures (all p >.19). Cognitive functioning was most consistently associated with FA of the corpus callosum major forceps (4/7 domains; all r > .33, all p < .04) and the left ILF (4/7 domains; all r > .37, all p <.02).
Conclusions:Both white matter integrity and neuropsychological performance were generally reduced in patients with a history of XRT, but not in those who received PRT. The PRT group was similar to healthy control participants with respect to both FA and cognitive scores, suggesting improved long-term outcomes compared to patients receiving XRT. This exploratory study is the first to provide direct support for white matter integrity as a mechanism of cognitive sparing in PRT. Future work with larger samples is necessary to replicate these findings.
18 Executive Dysfunction Following Treatment for Pediatric Low Grade Brain Tumors: Increased Risk Associated with Infratentorial Tumor Location
- Luz A De Leon, Lisa E Mash, Sebastian R Espinoza, Kelley Parsons, Everett Adkins, Cameron Martin, Maheen Rizvi, Natasha Feuerbach, Marianne Macleod, Heather Stancel, Kimberly P Raghubar, Lisa S Kahalley
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 19-20
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Objective:
Treatment for pediatric brain tumors (PBTs) is associated with neurocognitive risk, including declines in IQ, executive function, and visual motor processing. Low grade tumors require less intensive treatment (i.e., focal radiotherapy (RT) or surgical resection alone), and have been associated with more favorable cognitive outcomes. However, these patients remain at risk of cognitive problems, which may present differently depending on tumor location. Executive functioning (EF), in particular, has been broadly associated with both frontal-subcortical networks (supratentorial) and the cerebellum (infratentorial). The current study examined intellectual functioning, executive functioning (set-shifting and inhibition), and visual motor skills in patients who were treated for low-grade tumors located in either the supratentorial or infratentorial region.
Participants and Methods:Participants were survivors (age 8-18) previously treated with focal proton RT or surgery alone for infratentorial (n=21) or supratentorial (n=34) low grade glioma (83.6%) or low grade glioneuronal tumors (16.4%). Survivors >2.5 years post-treatment completed cognitive testing (WISC-IV/WAIS-IV; D-KEFS Verbal Fluency (VF), Color-Word Interference (CW), Trail Making Test (TM); Beery Visual-Motor Integration). We compared outcomes between infratentorial and supratentorial groups using analysis of covariance (ANCOVA). Demographic and clinical variables were compared using Welch’s t-tests. ANCOVAs were adjusted for age at evaluation, age at treatment, and history of posterior fossa syndrome due to significant or marginally significant differences between groups.
Results:Tumor groups did not significantly differ with respect to sex (49.0% male), length of follow-up (M 4.4 years), or treatment type (74.5% surgery alone, 25.5% proton RT). Marginally significant group differences were found for age at evaluation (infratentorial M = 12.4y, supratentorial M = 14.1y, p = .054) and age at treatment (infratentorial M = 7.9y, supratentorial M = 9.7y, p =.074). Posterior fossa syndrome only occurred with infratentorial tumors (n=5, p = .003). Adjusting for covariates, the supratentorial group exhibited significantly superior performance on a measure of inhibition and set-shifting (CW Switching Time (t(32) = -2.05, p=.048, n2 =.11). There was a marginal group difference in the same direction on CW Inhibition Time (t(32 = -1.77, p = .086, n2 =.08). On the other hand, the supratentorial group showed significantly lower working memory than the infratentorial group (t(50) = 2.45, p = .018, n2 = .11), and trends toward lower verbal reasoning (t(50)=1.96, p = .056, n2 = .07) and full-scale IQ (t(50)=1.73, p = .090, n2 = .055). No other group differences were identified across intellectual, EF, and visualmotor measures.
Conclusions:Infratentorial tumor location was associated with weaker switching and inhibition performance, while supratentorial tumor location was associated with lower performance on intellectual measures, particularly working memory. These findings suggest that even with relatively conservative treatment (i.e., focal proton RT or surgery alone), there remains neurocognitive risk in children treated for low-grade brain tumors. Moreover, tumor location may predict distinct patterns of long-term neurocognitive outcomes, depending on which brain networks are involved.