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Title: Cerebral Cortex Regions Selectively Vulnerable to Radiation Dose-Dependent Atrophy

Abstract

Purpose and Objectives: Neurologic deficits after brain radiation therapy (RT) typically involve decline in higher-order cognitive functions such as attention and memory rather than sensory defects or paralysis. We sought to determine whether areas of the cortex critical to cognition are selectively vulnerable to radiation dose-dependent atrophy. Methods and Materials: We measured change in cortical thickness in 54 primary brain tumor patients who underwent fractionated, partial brain RT. The study patients underwent high-resolution, volumetric magnetic resonance imaging (T1-weighted; T2 fluid-attenuated inversion recovery, FLAIR) before RT and 1 year afterward. Semiautomated software was used to segment anatomic regions of the cerebral cortex for each patient. Cortical thickness was measured for each region before RT and 1 year afterward. Two higher-order cortical regions of interest (ROIs) were tested for association between radiation dose and cortical thinning: entorhinal (memory) and inferior parietal (attention/memory). For comparison, 2 primary cortex ROIs were also tested: pericalcarine (vision) and paracentral lobule (somatosensory/motor). Linear mixed-effects analyses were used to test all other cortical regions for significant radiation dose-dependent thickness change. Statistical significance was set at α = 0.05 using 2-tailed tests. Results: Cortical atrophy was significantly associated with radiation dose in the entorhinal (P=.01) and inferior parietal ROIs (P=.02). By contrast, no significantmore » radiation dose-dependent effect was found in the primary cortex ROIs (pericalcarine and paracentral lobule). In the whole-cortex analysis, 9 regions showed significant radiation dose-dependent atrophy, including areas responsible for memory, attention, and executive function (P≤.002). Conclusions: Areas of cerebral cortex important for higher-order cognition may be most vulnerable to radiation-related atrophy. This is consistent with clinical observations that brain radiation patients experience deficits in domains of memory, executive function, and attention. Correlations of regional cortical atrophy with domain-specific cognitive functioning in prospective trials are warranted.« less

Authors:
; ; ; ;  [1]; ; ; ;  [2];  [1];  [3];  [1];  [2];  [4];  [1];  [4];  [2];  [4];  [4];  [1]
  1. Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, California (United States)
  2. Department of Radiology, University of California, San Diego, La Jolla, California (United States)
  3. Department of Psychiatry, University of California, San Diego, La Jolla, California (United States)
  4. (United States)
Publication Date:
OSTI Identifier:
22649879
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 97; Journal Issue: 5; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ATROPHY; CEREBRAL CORTEX; COMPUTER CODES; NMR IMAGING; PATIENTS; RADIATION DOSES; RADIOTHERAPY; THICKNESS

Citation Formats

Seibert, Tyler M., Karunamuni, Roshan, Kaifi, Samar, Burkeen, Jeffrey, Connor, Michael, Krishnan, Anitha Priya, White, Nathan S., Farid, Nikdokht, Bartsch, Hauke, Murzin, Vyacheslav, Nguyen, Tanya T., Moiseenko, Vitali, Brewer, James B., Department of Neurosciences, University of California, San Diego, La Jolla, California, McDonald, Carrie R., Department of Psychiatry, University of California, San Diego, La Jolla, California, Dale, Anders M., Department of Psychiatry, University of California, San Diego, La Jolla, California, Department of Neurosciences, University of California, San Diego, La Jolla, California, and Hattangadi-Gluth, Jona A., E-mail: jhattangadi@ucsd.edu. Cerebral Cortex Regions Selectively Vulnerable to Radiation Dose-Dependent Atrophy. United States: N. p., 2017. Web. doi:10.1016/J.IJROBP.2017.01.005.
Seibert, Tyler M., Karunamuni, Roshan, Kaifi, Samar, Burkeen, Jeffrey, Connor, Michael, Krishnan, Anitha Priya, White, Nathan S., Farid, Nikdokht, Bartsch, Hauke, Murzin, Vyacheslav, Nguyen, Tanya T., Moiseenko, Vitali, Brewer, James B., Department of Neurosciences, University of California, San Diego, La Jolla, California, McDonald, Carrie R., Department of Psychiatry, University of California, San Diego, La Jolla, California, Dale, Anders M., Department of Psychiatry, University of California, San Diego, La Jolla, California, Department of Neurosciences, University of California, San Diego, La Jolla, California, & Hattangadi-Gluth, Jona A., E-mail: jhattangadi@ucsd.edu. Cerebral Cortex Regions Selectively Vulnerable to Radiation Dose-Dependent Atrophy. United States. doi:10.1016/J.IJROBP.2017.01.005.
Seibert, Tyler M., Karunamuni, Roshan, Kaifi, Samar, Burkeen, Jeffrey, Connor, Michael, Krishnan, Anitha Priya, White, Nathan S., Farid, Nikdokht, Bartsch, Hauke, Murzin, Vyacheslav, Nguyen, Tanya T., Moiseenko, Vitali, Brewer, James B., Department of Neurosciences, University of California, San Diego, La Jolla, California, McDonald, Carrie R., Department of Psychiatry, University of California, San Diego, La Jolla, California, Dale, Anders M., Department of Psychiatry, University of California, San Diego, La Jolla, California, Department of Neurosciences, University of California, San Diego, La Jolla, California, and Hattangadi-Gluth, Jona A., E-mail: jhattangadi@ucsd.edu. Sat . "Cerebral Cortex Regions Selectively Vulnerable to Radiation Dose-Dependent Atrophy". United States. doi:10.1016/J.IJROBP.2017.01.005.
@article{osti_22649879,
title = {Cerebral Cortex Regions Selectively Vulnerable to Radiation Dose-Dependent Atrophy},
author = {Seibert, Tyler M. and Karunamuni, Roshan and Kaifi, Samar and Burkeen, Jeffrey and Connor, Michael and Krishnan, Anitha Priya and White, Nathan S. and Farid, Nikdokht and Bartsch, Hauke and Murzin, Vyacheslav and Nguyen, Tanya T. and Moiseenko, Vitali and Brewer, James B. and Department of Neurosciences, University of California, San Diego, La Jolla, California and McDonald, Carrie R. and Department of Psychiatry, University of California, San Diego, La Jolla, California and Dale, Anders M. and Department of Psychiatry, University of California, San Diego, La Jolla, California and Department of Neurosciences, University of California, San Diego, La Jolla, California and Hattangadi-Gluth, Jona A., E-mail: jhattangadi@ucsd.edu},
abstractNote = {Purpose and Objectives: Neurologic deficits after brain radiation therapy (RT) typically involve decline in higher-order cognitive functions such as attention and memory rather than sensory defects or paralysis. We sought to determine whether areas of the cortex critical to cognition are selectively vulnerable to radiation dose-dependent atrophy. Methods and Materials: We measured change in cortical thickness in 54 primary brain tumor patients who underwent fractionated, partial brain RT. The study patients underwent high-resolution, volumetric magnetic resonance imaging (T1-weighted; T2 fluid-attenuated inversion recovery, FLAIR) before RT and 1 year afterward. Semiautomated software was used to segment anatomic regions of the cerebral cortex for each patient. Cortical thickness was measured for each region before RT and 1 year afterward. Two higher-order cortical regions of interest (ROIs) were tested for association between radiation dose and cortical thinning: entorhinal (memory) and inferior parietal (attention/memory). For comparison, 2 primary cortex ROIs were also tested: pericalcarine (vision) and paracentral lobule (somatosensory/motor). Linear mixed-effects analyses were used to test all other cortical regions for significant radiation dose-dependent thickness change. Statistical significance was set at α = 0.05 using 2-tailed tests. Results: Cortical atrophy was significantly associated with radiation dose in the entorhinal (P=.01) and inferior parietal ROIs (P=.02). By contrast, no significant radiation dose-dependent effect was found in the primary cortex ROIs (pericalcarine and paracentral lobule). In the whole-cortex analysis, 9 regions showed significant radiation dose-dependent atrophy, including areas responsible for memory, attention, and executive function (P≤.002). Conclusions: Areas of cerebral cortex important for higher-order cognition may be most vulnerable to radiation-related atrophy. This is consistent with clinical observations that brain radiation patients experience deficits in domains of memory, executive function, and attention. Correlations of regional cortical atrophy with domain-specific cognitive functioning in prospective trials are warranted.},
doi = {10.1016/J.IJROBP.2017.01.005},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 5,
volume = 97,
place = {United States},
year = {Sat Apr 01 00:00:00 EDT 2017},
month = {Sat Apr 01 00:00:00 EDT 2017}
}
  • Purpose: After radiation therapy (RT) to the brain, patients often experience memory impairment, which may be partially mediated by damage to the hippocampus. Hippocampal sparing in RT planning is the subject of recent and ongoing clinical trials. Calculating appropriate hippocampal dose constraints would be improved by efficient in vivo measurements of hippocampal damage. In this study we sought to determine whether brain RT was associated with dose-dependent hippocampal atrophy. Methods and Materials: Hippocampal volume was measured with magnetic resonance imaging (MRI) in 52 patients who underwent fractionated, partial brain RT for primary brain tumors. Study patients had high-resolution, 3-dimensional volumetric MRI beforemore » and 1 year after RT. Images were processed using software with clearance from the US Food and Drug Administration and Conformité Européene marking for automated measurement of hippocampal volume. Automated results were inspected visually for accuracy. Tumor and surgical changes were censored. Mean hippocampal dose was tested for correlation with hippocampal atrophy 1 year after RT. Average hippocampal volume change was also calculated for hippocampi receiving high (>40 Gy) or low (<10 Gy) mean RT dose. A multivariate analysis was conducted with linear mixed-effects modeling to evaluate other potential predictors of hippocampal volume change, including patient (random effect), age, hemisphere, sex, seizure history, and baseline volume. Statistical significance was evaluated at α = 0.05. Results: Mean hippocampal dose was significantly correlated with hippocampal volume loss (r=−0.24, P=.03). Mean hippocampal volume was significantly reduced 1 year after high-dose RT (mean −6%, P=.009) but not after low-dose RT. In multivariate analysis, both RT dose and patient age were significant predictors of hippocampal atrophy (P<.01). Conclusions: The hippocampus demonstrates radiation dose–dependent atrophy after treatment for brain tumors. Quantitative MRI is a noninvasive imaging technique capable of measuring radiation effects on intracranial structures. This technique could be investigated as a potential biomarker for development of reliable dose constraints for improved cognitive outcomes.« less
  • The specific binding of (/sup 3/H)pirenzepine was investigated in homogenates of rat cerebral cortex, cerebellar cortex, and heart. Specific binding of (/sup 3/H)pirenzepine in the cerebral cortex as defined by displacement with atropine sulfate (1..mu..M) was of high affinity (K/sub d/ = 4-10 nM, receptor density = 1.06 pmoles/mg protein), stereoselective, and competitive with drugs specific for the muscarinic receptor. In contrast, few (/sup 3/H)pirenzepine binding sites were demonstrated in cerebellar and heart homogenates.
  • Radiation can be used to induced series of developmentall malformations in the brains of rats The degree of reproducibility of the patterns has suggested their use in studies relating certain attributes of behavior with cerebral cortical structure. The patterns of brain malformiation induced by giving 150 to 200 r on each of the days of gestation. 12 to 20. are described and illustrated. Some of the histogenetic mechanisms that lead up to the cortical malformations are described. based on a study of different members of the same abnormal litter taken at successive stages of development.
  • In rat cerebral cortex, serotonin (5-HT) stimulates phosphoinositide turnover with an EC50 of 1 microM in the presence of pargyline. The EC50 is 16-fold higher in the absence of pargyline. Selective S2 antagonists inhibit 5-HT-stimulated phosphoinositide turnover. Schild analysis of the blockade by ketanserin of the 5-HT effect gives an estimated Kd of ketanserin for the phosphoinositide-linked receptor of 11.7 nM, which agrees with the Kd (3.5 nM) of (/sup 3/H)ketanserin for the S2 site. Furthermore, MK-212, 5-HT and 5-fluorotryptamine stimulate phosphoinositide turnover with potencies that resemble their potencies at the S2 but not the S1 binding site. Of 11more » agonists tested, the tryptamine derivatives tend to be more efficacious than the piperazine derivatives. The selective S1 agonist 8-hydroxy-2-(di-N-propylamino)tetralin is inactive at stimulating phosphoinositide turnover. No significant relationship exists between the regional distributions of 5-HT-stimulated phosphoinositide turnover and S2 binding sites. Furthermore, the S2 antagonist ketanserin is less potent and less efficacious in hippocampus and limbic forebrain than in cerebral cortex. These data suggest that 5-HT-stimulated phosphoinositide turnover is linked to the S2 binding site in rat cerebral cortex. However, 5-HT increases phosphoinositide turnover in subcortical regions by mechanisms other than stimulation of the S2 receptor.« less
  • Purpose: A prospective study was performed to formally relate dose-dependent radiologically defined changes in normal brain induced by radiotherapy (RT) to neurocognitive dysfunction in subjects with primary brain tumors. Methods and Materials: Adult patients receiving three-dimensional RT for central nervous system (CNS) tumors were enrolled. Positron emission tomography (PET) scanning and neuropsychological testing were performed before RT and 3 weeks and 6 months after treatment. Analyses were performed for correlations between changes in 2-deoxy-2-[{sup 18}F]-fluoro-D-glucose (FDG)-PET (metabolism), {sup 15}O-PET (relative blood flow), regional radiation dose, follow-up time, and neuropsychological test scores. Results: Eleven subjects were enrolled and 6 completed follow-upmore » studies. The PET data showed reduced FDG uptake, with average decreases of 2-6% in regions of the brain receiving greater than 40 Gy at 3 weeks' and 6 months' follow-up. The {sup 15}O-H{sub 2}O PET showed increases (<10%) at 3 weeks in relative regional blood flow in brain receiving greater than 30 Gy, but less at the 6-month follow-up studies. There were significant correlations between decreases in FDG uptake and increased scores from the Symptom Checklist-90-R, with an average increase in T score of 2 (p < 0.0001). The Wisconsin Card Sorting Test showed a significant correlation of decreased FDG uptake with increased errors and perseveration in test performance, with an average decrease in T score of 11 (p = 0.037). Conclusions: A dose-dependent response of CNS tissue was detected using FDG PET in this small number of patients. Decreases in CNS metabolism correlated with decreased performance on neuropsychological tests for problem solving, cognitive flexibility, and global measures of psychopathology. Additional research is needed to verify and define these findings.« less