Neuroanatomical abnormalities related to dexamethasone exposure in survivors of childhood acute lymphoblastic leukemia

Phillips, Nicholas S.; Cheung, Yin Ting; Glass, John O.; Scoggins, Matthew; Liu, Wei; Ogg, Robert J.; Mulrooney, Daniel A.; Pui, Ching‐Hon; Robison, Leslie L.; Reddick, Wilburn E.; Hudson, Melissa M.; Krull, Kevin R.

doi:10.1002/pbc.27968

Cited by 26 publications

(46 citation statements)

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“…These studies should include measures of short- and long-term memory in addition to the measures of working memory included in this study. 13 Neuroimaging studies should include resting-state fMRI with complete coverage of the cerebellum.…”

Section: Discussionmentioning

confidence: 99%

“…12 The hippocampus and cerebellum have the highest concentrations of glucocorticoid receptors. We have previously demonstrated 13 that survivors of childhood ALL treated on chemotherapy-only protocols had smaller Downloaded From: https://jamanetwork.com/ on 12/01/2020 hippocampal, cerebellar, anterior cingulate, precuneus, and dorsolateral prefrontal cortex (DLPFC) regions compared with age-matched healthy individuals in control groups. This finding is consistent with studies that showed that glucocorticoid exposure is associated with smaller brain structures and attenuated functional activity in populations without cancer.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…We previously found that being a survivor of ALL was associated with decreased size in regions of the cerebello-thalamo-cortical network compared with age-matched individuals who did not have ALL. 13 We hypothesized that decreased size in these regions would be associated with neurocognitive impairment and would vary by treatment intensity. Furthermore, we hypothesized that the cerebellum facilitates neural communication (ie, effective connectivity) between the DLPFC and the precuneus and that this would be associated with executive dysfunction in survivors of ALL.…”

Section: Introductionmentioning

confidence: 99%

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Connectivity of the Cerebello-Thalamo-Cortical Pathway in Survivors of Childhood Leukemia Treated With Chemotherapy Only

et al. 2020

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IMPORTANCE Treatment with contemporary chemotherapy-only protocols is associated with risk for neurocognitive impairment among survivors of childhood acute lymphoblastic leukemia (ALL). OBJECTIVE To determine whether concurrent use of methotrexate and glucocorticoids is associated with interference with the antioxidant system of the brain and damage and disruption of glucocorticoid-sensitive regions of the cerebello-thalamo-cortical network. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study was conducted from December 2016 to July 2019 in a single pediatric cancer tertiary care center. Participants included survivors of childhood ALL who were more than 5 years from cancer diagnosis, age 8 years or older, and treated on an institutional chemotherapy-only protocol. Age-matched community members were recruited as a control group. Data were analyzed from August 2017 to August 2020. EXPOSURE ALL treatment using chemotherapy-only protocols. MAIN OUTCOMES AND MEASURES This study compared brain volumes between survivors and individuals in a community control group and examined associations among survivors of methotrexate and dexamethasone exposure with neurocognitive outcomes. Functional and effective connectivity measures were compared between survivors with and without cognitive impairment. The Rey-Osterrieth complex figure test, a neurocognitive evaluation in which individuals are asked to copy a figure and then draw the figure from memory, was scored according to published guidelines and transformed into age-adjusted z scores based on nationally representative reference data and used to measure organization and planning deficits. β values for neurocognitive tests represented the amount of change in cerebellar volume or chemotherapy exposure associated with 1 SD change in neurocognitive outcome by z score (mm 3 /1 SD in z score for cerebellum, mm 3 /[g×hr/L] for dexamethasone and methotrexate AUC, and mm 3 /intrathecal count for total intrathecal count). RESULTS Among 302 eligible individuals, 218 (72%) participated in the study and 176 (58%) had usable magnetic resonance imaging (MRI) results. Among these, 89 (51%) were female participants and the mean (range) age was 6.8 (1-18) years at diagnosis and 14.5 (8-27) years at evaluation. Of 100 community individuals recruited as the control group, 82 had usable MRI results; among these, 35 (43%) were female individuals and the mean (range) age was 13.8 (8-26) years at evaluation. There was no significant difference in total brain volume between survivors and individuals in the control group. Survivors of both sexes showed decreased mean (SD) cerebellar volumes compared with the control population (female: 70 568 [6465] mm 3 vs 75 134 [6780] mm 3 ; P < .001; male: 77 335 [6210] mm 3 vs 79 020 [7420] mm 3 ; P < .001). In female survivors, decreased cerebellar volume was associated with worse performance in Rey-Osterrieth complex figure test (left cerebellum: β = 55.54;

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Connectivity of the Cerebello-Thalamo-Cortical Pathway in Survivors of Childhood Leukemia Treated With Chemotherapy Only

et al. 2020

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“…Toxic agents, radiotherapy or hypoxia (Decker et al, 2017;Lv et al, 2018;Ørbo et al, 2018;Stamenova et al, 2018;Phillips et al, 2020), alcoholism (Lee et al, 2016;Mole et al, 2016;Zahr et al, 2019), alcohol withdrawal (Kühn et al, 2014), familial risk for alcohol use disorder (adolescents) (Maksimovskiy et al, 2019), cannabis use (Beale et al, 2018), cigarette smoking (Durazzo et al, 2013), preterm birth in school-aged children (Aanes et al, 2019) Stress response…”

Section: Neurotoxicitymentioning

confidence: 99%

FreeSurfer based segmentation of hippocampal subfields: a review of methods and applications, with a novel quality control procedure for ENIGMA studies and other collaborative efforts

Sämann¹,

Iglesias²,

Gutman³

et al. 2020

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Structural hippocampal abnormalities are common in many neurological and psychiatric disorders, and even variation within the normal range is related to cognitive performance and other complex phenotypes such as stress sensitivity. Hippocampal subregions are increasingly studied, as automated algorithms have become available for mapping and volume quantification. In the context of the ENIGMA Consortium, several Disease Working Groups are using the FreeSurfer software to analyze hippocampal subregion (subfield) volumes in patients with major depressive disorder, bipolar disorders, posttraumatic stress disorder, and other conditions, along with data from matched controls. In this overview, we explain the algorithm’s principle, summarize measurement reliability studies, and demonstrate two additional aspects (subfield autocorrelation and volume/reliability correlation) with illustrative data. We then explain the rationale for a standardized hippocampal subfield segmentation quality control (QC) procedure for improved pipeline harmonization. To guide researchers to make optimal use of the algorithm, we discuss how global size and age effects can be modelled, how QC steps can be incorporated and how subfields may be aggregated into composite volumes. This discussion is based on a synopsis of 162 published neuroimaging studies (01/2013–12/2019) that applied the FreeSurfer hippocampal subfield segmentation in a broad range of domains including cognition and healthy aging, brain development and neurodegeneration, affective disorders, schizophrenia, childhood trauma and posttraumatic stress disorder, inflammatory and systemic disease, alcoholism, stress regulation, neurotoxicity, as well as assessments of heritability, effects of candidate genes, genome-wide association studies and epigenetic effects. Lastly, we highlight points where FreeSurfer-based hippocampal subfield studies may be optimized.

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Late-onset Cognitive Impairment and Modifiable Risk Factors in Adult Childhood Cancer Survivors

et al. 2023

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ImportanceLong-term survivors of childhood cancer may be at elevated risk for new neurocognitive impairment and decline as they age into adulthood.ObjectiveTo determine whether aging adult childhood cancer survivors report more new-onset neurocognitive impairments compared with their siblings and to identify risk factors associated with such impairments.Design, Setting, and ParticipantsParticipants of this cohort study included adult survivors of childhood cancer from the Childhood Cancer Survivor Study and their siblings as a control group. The original cohort included survivors who received a diagnosis between January 1, 1970, and December 31, 1986, for whom longitudinal neurocognitive assessment was available. This study examined the prevalence of new-onset neurocognitive impairment between baseline (23.4 years after diagnosis) and follow-up (35.0 years after diagnosis). The analysis was performed from January 2021 to May 2022.ExposuresCancer treatment exposures were abstracted from medical records. Chronic health conditions were graded using Common Terminology Criteria for Adverse Events version 4.03.Main Outcomes and MeasuresThe primary outcome was new-onset (present at follow-up, but not present at baseline) neurocognitive impairment (defined as a score in the worst 10% of the sibling cohort). Impairment was assessed using the Childhood Cancer Survivor Study Neurocognitive questionnaire. Relative risks (RRs) and 95% CIs were used to estimate associations of neurocognitive impairment with treatment and health behaviors and conditions using generalized linear models.ResultsThe cohort comprised 2375 survivors (mean [SD] age at evaluation, 31.8 [7.5] years; 1298 women [54.6%]) of childhood cancer, including acute lymphoblastic leukemia (ALL; 1316 participants), central nervous system (CNS) tumors (488 participants), and Hodgkin lymphoma (HL; 571 participants). A total of 232 siblings (mean [SD] age at evaluation, 34.2 [8.4] years; 134 women [57.8%]) were included. Compared with siblings, a higher proportion of survivors with no impairment in memory at baseline had new-onset memory impairment at follow-up: siblings proportion, 7.8% (95% CI, 4.3%-11.4%); ALL survivors treated with chemotherapy only, 14.0% (95% CI, 10.7%-17.4%); ALL survivors treated with cranial radiation (CRT), 25.8% (95% CI, 22.6%-29.0%); CNS tumor survivors, 34.7% (95% CI, 30.0%-39.5%); and HL survivors, 16.6% (95% CI, 13.4%-19.8%). New-onset memory impairment was associated with CRT in CNS tumor survivors (RR, 1.97; 95% CI, 1.33-2.90) and alkylator chemotherapy greater than or equal to 8000 mg/m2 in ALL survivors treated without CRT (RR, 2.80; 95% CI, 1.28-6.12). Neurologic conditions mediated the impact of CRT on new-onset memory impairment in CNS survivors. Smoking, low educational attainment, and low physical activity were associated with elevated risk for new-onset memory impairment.Conclusions and RelevanceThese findings suggest that adult survivors of childhood cancer are at elevated risk for late-onset memory impairment related to modifiable risk factors identified early in survivorship.

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Neuroanatomical abnormalities related to dexamethasone exposure in survivors of childhood acute lymphoblastic leukemia

Cited by 26 publications

References 29 publications

Connectivity of the Cerebello-Thalamo-Cortical Pathway in Survivors of Childhood Leukemia Treated With Chemotherapy Only

Connectivity of the Cerebello-Thalamo-Cortical Pathway in Survivors of Childhood Leukemia Treated With Chemotherapy Only

FreeSurfer based segmentation of hippocampal subfields: a review of methods and applications, with a novel quality control procedure for ENIGMA studies and other collaborative efforts

Late-onset Cognitive Impairment and Modifiable Risk Factors in Adult Childhood Cancer Survivors

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