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Background: The purpose was to examine associations between treatment and chronic health conditions with neurocognitive impairment survivors of acute lymphoblastic leukemia (ALL) treated with chemotherapy only.Methods: This cross-sectional study included 1207 ALL survivors (54.0% female; mean age 30.6 years) and 2273 siblings (56.9% female; mean age 47.6 years), who completed the Childhood Cancer Survivor Study Neurocognitive Questionnaire. Multivariable logistic regression compared prevalence of neurocognitive impairment between survivors and siblings by sex. Associations between neurocognitive impairment with treatment exposures and chronic conditions (graded according to Common Terminology Criteria for Adverse Events) were also examined. Statistical tests were 2-sided.Results: Relative to same-sex siblings, male and female ALL survivors reported increased prevalence of impaired task efficiency (males: 11.7% vs 16.9%; adjusted odds ratio [OR] = 1.89, 95% confidence interval [CI] = 1.31 to 2.74; females: 12.5% vs 17.6%; OR = 1.50, 95% CI = 1.07 to 2.14), as well as impaired memory (males: 11.6% vs 19.9%, OR = 1.89, CI = 1.31 to 2.74; females: 14.78% vs 25.4%, OR = 1.96, 95% CI = 1.43 to 2.70, respectively). Among male survivors, impaired task efficiency was associated with 2-4 neurologic conditions (OR = 4.33, 95% CI = 1.76 to 10.68) and with pulmonary conditions (OR = 4.99, 95% CI = 1.51 to 16.50), and impaired memory was associated with increased cumulative dose of intrathecal methotrexate (OR = 1.68, 95% CI = 1.16 to 2.46) and with exposure to dexamethasone (OR = 2.44, 95% CI = 1.19 to 5.01). In female survivors, grade 2-4 endocrine conditions were associated with higher risk of impaired task efficiency (OR = 2.19, 95% CI = 1.20 to 3.97) and memory (OR = 2.26, 95% CI = 1.31 to 3.92).Conclusion: Neurocognitive impairment is associated with methotrexate, dexamethasone, and chronic health conditions in a sex-specific manner, highlighting the need to investigate physiological mechanisms and monitor impact through survivorship. [ABSTRACT FROM AUTHOR]

The gene (Huntingtin or HTT) causing Huntington’s disease (HD) is vital for development and is expressed throughout the brain and body lifelong. The mutant form (mHTT) may influence growth and development.To determine the impact of mHTT on human measures of growth, including height, weight and body mass index (BMI), between child and adolescent carriers of mHTT and control peers.Children ages 6–18 years of age (n = 186) at risk for HD were enrolled in the KidsHD study. For research purposes only, genetic testing was performed to classify participants as Gene-Expanded (GE = 78) or as Gene Non-Expanded (GNE = 108). Outcome measures included height, weight, and body mass index (BMI). Mixed models were used to determine if non-linear age trends differed between groups for BMI, height and weight.Differences were seen in the trajectory of BMI in which the GE group reached a plateau in late adolescence with no further increase, compared with a nearly linear increase in the GNE group. There was a significant sex interaction pattern where GE males were taller than GNE males in adolescence, in the presence of similar weight. In contrast, GE females weighed significantly less than their GNE counterparts in adolescence, in the presence of similar height.Measures of growth are abnormal in child and adolescent carriers of mHTT, decades before HD onset. Although further studies are needed for replication, the current findings suggest that developmental aberrations may be systemic and a vital part of disease pathology. [ABSTRACT FROM AUTHOR]

Knowledge about cognitive late effects in survivors of childhood acute lymphoblastic leukemia (ALL) is largely based on standardized neuropsychological measures and parent reports. To examine whether cognitive neuroscience paradigms provided additional insights into neurocognitive and behavioral late effects in ALL survivors, we assessed cognition and behavior using a selection of cognitive neuroscience tasks and standardized measures probing domains previously demonstrated to be affected by chemotherapy. 130 ALL survivors and 158 control subjects, between 8 and 18 years old at time of testing, completed the n-back (working memory) and stop-signal (response inhibition) tasks. ALL survivors also completed standardized measures of intelligence (Wechsler Intelligence Scales [WISC-IV]), motor skills (Grooved Pegboard), math abilities (WIAT-III), and executive functions (Delis-Kaplan Executive Function System). Parents completed behavioral measures of executive functions (Behavior Rating Inventory of Executive Function [BRIEF]) and attention (Conners-3). ALL survivors exhibited deficiencies in working memory and response inhibition compared with controls. ALL survivors also exhibited deficits on WISC-IV working memory and processing speed, Grooved Pegboard, WIAT-III addition and subtraction fluency, and numerical operations, as well as DKEFS number-letter switching. Parent reports suggested more attention deficits (Conners-3) and behavioral difficulties (BRIEF) in ALL survivors compared with referenced norms. Low correspondence between standardized and experimental measures of working memory and response inhibition was noted. The use of cognitive neuroscience paradigms complements our understanding of the cognitive deficits evident after treatment of ALL. These measures could further delineate cognitive processes involved in neurocognitive late effects, providing opportunities to explore their underlying mechanisms. [ABSTRACT FROM AUTHOR]

Childhood cancer survivors frequently experience long-lasting consequences of chemotherapy on health outcomes. Neurocognitive late effects of chemotherapy occur in 40 – 60% of acute lymphoblastic leukemia (ALL) survivors. These deficits affect mental health, school performance, job success, and are associated with poor quality of life, therefore presenting a clinical challenge for psychiatrists. However, not all cancer survivors are impacted by treatment in the same manner and emerging evidence suggests that genetic variation may modulate neurocognitive outcomes. Much like other complex psychopathologies, neurocognitive deficits in cancer survivors are the result of complex interactions between genetic and environmental variables. This review describes adverse neurocognitive outcomes observed in survivors of acute lymphoblastic leukemia (ALL) and discusses genetic variability in biochemical pathways targeted by chemotherapeutic agents as a possible mechanism contributing to psychopathology in ALL survivors. [ABSTRACT FROM AUTHOR]

Background: Survivors of pediatric acute lymphoblastic leukemia (ALL) exhibit abnormal neurocognitive outcomes that are possibly due to exposures to neurotoxic chemotherapy agents. This study aimed to determine the feasibility of characterizing long-term neuroanatomical changes with in vivo neuroimaging in a preclinical model of treatment for ALL., Methods: Female mice (C57BL/6) were randomly assigned to a saline control group (n=10) or a treatment group (n=10) that received intrathecal methotrexate and oral dexamethasone (IT-MTX + DEX). Mice were subsequently scanned three times on a 7T MRI at ages 3, 6, and 12 months (T1, T2, and T3, respectively), which corresponds with human age-equivalents spanning early to late adulthood. Regional brain volumes were automatically segmented, and volume change between timepoints (i.e., T1 to T2; and T2 to T3) were compared between groups (i.e., saline vs. IT-MTX + DEX)., Results: Five mice in the IT-MTX + DEX group, and seven mice in the saline group completed all three scans. Between T1 and T2, volumetric change was significantly different between groups in total gray matter [estimate =2.06, 95% confidence interval (CI): 0.27-3.84], the cerebrum (estimate =1.62, 95% CI: 0.14-3.09), claustrum (estimate =0.06, 95% CI: 0.02-0.09), amygdala (estimate =0.16, 95% CI: 0.03-0.29), and striatum (estimate =0.18, 95% CI: 0.01-0.35), with the IT-MTX + DEX group exhibiting a more robust increase in volume than the saline-treated group. Between T2 and T3, group differences in structural brain development were evident for total white matter (estimate =-0.14, 95% CI: -0.27 to -0.01), and the corpus callosum (estimate =-0.09, 95% CI: -0.19 to 0.00) and amygdala (estimate =-0.05, 95% CI: -0.10 to 0.00). In contrast to the rapid brain growth observed earlier in development (i.e., T1 to T2), the IT-MTX + DEX group exhibited an attenuated increase in volume relative to the saline-treated group between T2 and T3., Conclusions: The results demonstrate feasibility of modeling pediatric ALL treatment in a preclinical model and highlight the potential of using preclinical neuroimaging models to gain insight into brain development throughout survivorship., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-23-458/coif). The authors have no conflicts of interest to declare., (2024 Translational Pediatrics. All rights reserved.)

Limited data exists regarding the disease course of Huntington's Disease (HD) in children and young adults. Here, we evaluate the trajectory of various cognitive skill development as a function of cytosine-adenine-guanine (CAG) repeat length in children and adolescents that carry the mutation that causes HD. We discovered that the development of verbal skills seems to plateau earlier as CAG repeat length increases. These findings increase our understanding of the relationship between neurodegeneration and neurodevelopment and may have far-reaching implications for future gene-therapy treatment strategies. ANN NEUROL 2021;89:1036-1040., (© 2021 American Neurological Association.)

Background: Quantitative muscle MRI as a sensitive marker of early muscle pathology and disease progression in adult-onset myotonic dystrophy type 1. The utility of muscle MRI as a marker of muscle pathology and disease progression in adult-onset myotonic dystrophy type 1 (DM1) was evaluated., Methods: This prospective, longitudinal study included 67 observations from 36 DM1 patients (50% female), and 92 observations from 49 healthy adults (49% female). Lower-leg 3T magnetic resonance imaging (MRI) scans were acquired. Volume and fat fraction (FF) were estimated using a three-point Dixon method, and T2-relaxometry was determined using a multi-echo spin-echo sequence. Muscles were segmented automatically. Mixed linear models were conducted to determine group differences across muscles and image modality, accounting for age, sex, and repeated observations. Differences in rate of change in volume, T2-relaxometry, and FF were also determined with mixed linear regression that included a group by elapsed time interaction., Results: Compared with healthy adults, DM1 patients exhibited reduced volume of the tibialis anterior, soleus, and gastrocnemius (GAS) (all, P < .05). T2-relaxometry and FF were increased across all calf muscles in DM1 compared to controls. (all, P < .01). Signs of muscle pathology, including reduced volume, and increased T2-relaxometry and FF were already noted in DM1 patients who did not exhibit clinical motor symptoms of DM1. As a group, DM1 patients exhibited a more rapid change than did controls in tibialis posterior volume (P = .05) and GAS T2-relaxometry (P = .03) and FF (P = .06)., Conclusions: Muscle MRI renders sensitive, early markers of muscle pathology and disease progression in DM1. T2 relaxometry may be particularly sensitive to early muscle changes related to DM1., (© 2021 Wiley Periodicals LLC.)

Studies have shown relationships between white matter abnormalities and cognitive dysfunction in myotonic dystrophy type 1 (DM1), but comprehensive analysis of potential structure-function relationships are lacking. Fifty adult-onset DM1 individuals (33 female) and 68 unaffected adults (45 female) completed the Wechsler Adult Intelligence Scale-IV (WAIS-IV) to determine the levels and patterns of intellectual functioning. Neuroimages were acquired with a 3T scanner and were processed with BrainsTools. Regional brain volumes (regions of interest, ROIs) were adjusted for inter-scanner variation and intracranial volume. Linear regression models were conducted to assess if group by ROI interaction terms significantly predicted WAIS-IV composite scores. Models were adjusted for age and sex. The DM1 group had lower Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and Processing Speed Index (PSI) scores than the unaffected group (PRI t (113)  = -3.28, p = 0.0014; WMI t (114)  = -3.49, p = 0.0007; PSI t (114)  = -2.98, p = 0.0035). The group by hippocampus interaction term was significant for both PRI and PSI (PRI (t (111)  = -2.82, p = 0.0057; PSI (t (112)  = -2.87, p = 0.0049)). There was an inverse association between hippocampal volume and both PRI and PSI in the DM1 group (the higher the volume, the lower the intelligence quotient scores), but no such association was observed in the unaffected group. Enlarged hippocampal volume may underlie some aspects of cognitive dysfunction in adult-onset DM1, suggesting that increased volume of the hippocampus may be pathological., (© 2020 Wiley Periodicals, Inc.)