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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.
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Pediatric heart failure and transplantation carry associated risks for kidney failure and potential need for kidney transplant following pediatric heart transplantation (KT/pHT). This retrospective, United Network of Organ Sharing study of 10,030 pediatric heart transplants (pHTs) from 1987 to 2020 aimed to determine the incidence of waitlisting for and completion of KT/pHT, risk factors for KT/pHT, and risk factors for nonreceipt of a KT/pHT. Among pHT recipients, 3.4% were waitlisted for KT/pHT (median time of 14 years after pHT). Among those waitlisted, 70% received a KT/pHT, and 18% died on the waitlist at a median time of 0.8 years from KT/pHT waitlisting (median age of 20 years). Moderate-high sensitization at KT/pHT waitlisting (calculated panel reactive antibody, ≥ 20%) was associated with a lower likelihood of KT/pHT (adjusted hazard ratio, 0.67; 95% confidence interval, 0.47-0.95). Waitlisting for heart transplantation simultaneously with kidney transplant (adjusted hazard ratio, 3.73; 95% confidence interval, 2.01-6.92) was associated with increased risk of death on the KT/pHT waitlist. While the prevalence of KT/pHT is low, there is substantial mortality among those waitlisted for KT/pHT. These findings suggest a need to consider novel risk factors for nonreceipt of KT/pHT and death on the waitlist in prioritizing criteria/guidelines for simultaneous heart-kidney transplantation.
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Insuficiencia Cardíaca , Trasplante de Corazón , Trasplante de Riñón , Listas de Espera , Humanos , Trasplante de Corazón/efectos adversos , Trasplante de Corazón/mortalidad , Masculino , Trasplante de Riñón/efectos adversos , Femenino , Factores de Riesgo , Estudios Retrospectivos , Niño , Prevalencia , Adolescente , Preescolar , Adulto Joven , Estudios de Seguimiento , Insuficiencia Cardíaca/cirugía , Insuficiencia Cardíaca/epidemiología , Pronóstico , Adulto , Supervivencia de Injerto , Lactante , Rechazo de Injerto/etiología , Rechazo de Injerto/epidemiología , Complicaciones Posoperatorias/epidemiología , Obtención de Tejidos y Órganos , Tasa de Filtración GlomerularRESUMEN
BACKGROUND: Prevalence and risk of poor psychological outcomes following rhabdomyosarcoma (RMS) are not well-established. METHODS: Participants in this cross-sectional, case-control study (n = 713 survivors, 42.5% female; mean [SD] age, 30.5 [6.6] years; n = 706 siblings, 57.2% female; mean age, 32.8,[7.9] years) completed measures of neurocognition, emotional distress, and health-related quality of life (HRQOL). Multivariable logistic regression models identified treatments, health behaviors, and chronic conditions associated with impairment. RESULTS: Relative to siblings, more survivors reported neurocognitive impairment (task efficiency: 21.1% vs. 13.7%, emotional regulation: 16.7% vs. 11.0%, memory: 19.3% vs. 15.1%), elevated emotional distress (somatic distress: 12.9% vs. 4.7%, anxiety: 11.7% vs. 5.9%, depression: 22.8% vs. 16.9%) and poorer HRQOL (physical functioning: 11.1% vs. 2.8%, role functioning due to physical problems: 16.8% vs. 8.2%, pain: 17.5% vs. 10.0%, vitality: 22.3% vs. 13.8%, social functioning: 14.4% vs. 6.8%, emotional functioning: 17.1% vs. 10.6%). Cranial radiation increased risk for impaired task efficiency (odds ratio [OR], 2.30; 95% confidence interval [CI], 1.14-4.63), whereas chest and pelvic radiation predicted increased risk of physical functioning (OR, 2.68; 95% CI, 1.16-6.21 and OR, 3.44; 95% CI, 1.70-6.95, respectively). Smoking was associated with impaired task efficiency (OR, 2.06; 95% CI, 1.14-3.70), memory (OR, 2.23; 95% CI, 1.26-3.95), anxiety (OR, 2.71; 95% CI, 1.36-5.41) and depression (OR, 1.77; 95% CI, 1.01-3.11). Neurologic conditions increased risk of anxiety (OR, 2.30; 95% CI, 1.04-5.10), and hearing conditions increased risk of depression (OR, 1.79; 95% CI, 1.05-3.03). Neurologic and hearing conditions, respectively, were associated with impaired memory (OR, 2.44; 95% CI, 1.20-4.95 and OR, 1.87; 95% CI, 1.05-3.35) and poor health perception (OR, 2.62; 95% CI, 1.62-1.28 and OR, 2.33; 95% CI, 1.34-4.06). CONCLUSIONS: RMS survivors are at significant risk for poor psychological outcomes. Advancing therapies for local control, smoking cessation, and managing chronic medical conditions may mitigate poor outcomes following RMS.
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Supervivientes de Cáncer , Distrés Psicológico , Calidad de Vida , Rabdomiosarcoma , Humanos , Femenino , Masculino , Supervivientes de Cáncer/psicología , Estudios de Casos y Controles , Adulto , Factores de Riesgo , Rabdomiosarcoma/psicología , Estudios Transversales , Niño , Adulto Joven , Adolescente , Ansiedad/psicología , Ansiedad/epidemiología , Ansiedad/etiologíaRESUMEN
BACKGROUND: Chronic kidney disease (CKD) is a relatively rare childhood disease that is associated with a wide array of medical comorbidities. Roughly half of all pediatric patients acquire CKD due to congenital anomalies of the kidneys and urinary tract, and of those with congenital disease, 50% will progress to end-stage kidney disease (ESKD) necessitating a kidney transplantation. The medical sequelae of advanced CKD/ESKD improve dramatically following successful kidney transplantation; however, the impact of kidney transplantation on neurocognition in children is less clear. It is generally thought that cognition improves following kidney transplantation; however, our knowledge on this topic is limited by the sparsity of high-quality data in the context of the relative rarity of pediatric CKD/ESKD. METHOD: We conducted a narrative review to gauge the scope of the literature, using the PubMed database and the following keywords: cognition, kidney, brain, pediatric, neurocognition, intelligence, executive function, transplant, immunosuppression, and neuroimaging. RESULTS: There are few published longitudinal studies, and existing work often includes wide heterogeneity in age at transplant, variable dialysis exposure/duration prior to transplant, and unaccounted cofounders which persist following transplantation, including socio-economic status. Furthermore, the impact of long-term maintenance immunosuppression on the brain and cognitive function of pediatric kidney transplant (KT) recipients remains unknown. CONCLUSION: In this educational review, we highlight what is known on the topic of neurocognition and neuroimaging in the pediatric KT population.
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Fallo Renal Crónico , Trasplante de Riñón , Insuficiencia Renal Crónica , Niño , Humanos , Fallo Renal Crónico/complicaciones , Diálisis Renal , CogniciónRESUMEN
Myotonic dystrophy type 1 is characterized by neuromuscular degeneration. Our objective was to compare change in white matter microstructure (fractional anisotropy, radial and axial diffusivity), and functional/clinical measures. Participants underwent yearly neuroimaging and neurocognitive assessments over three-years. Assessments encompassed full-scale intelligence, memory, language, visuospatial skills, attention, processing speed, and executive function, as well as clinical symptoms of muscle/motor function, apathy, and hypersomnolence. Mixed effects models were used to examine differences. 69 healthy adults (66.2% women) and 41 DM1 patients (70.7% women) provided 156 and 90 observations, respectively. There was a group by elapsed time interaction for cerebral white matter, where DM1 patients exhibited declines in white matter (all p<0.05). Likewise, DM1 patients either declined (motor), improved more slowly (intelligence), or remained stable (executive function) for functional outcomes. White matter was associated with functional performance; intelligence was predicted by axial (r = 0.832; p<0.01) and radial diffusivity (r = 0.291, p<0.05), and executive function was associated with anisotropy (r = 0.416, p<0.001), and diffusivity (axial: r = 0.237, p = 0.05 and radial: r = 0.300, p<0.05). Indices of white matter health are sensitive to progression in DM1. These results are important for clinical trial design, which utilize short intervals to establish treatment efficacy.
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Distrofia Miotónica , Sustancia Blanca , Humanos , Adulto , Femenino , Masculino , Imagen de Difusión Tensora , Sustancia Blanca/diagnóstico por imagen , Distrofia Miotónica/complicaciones , Función Ejecutiva , Anisotropía , Encéfalo/diagnóstico por imagenRESUMEN
BACKGROUND: Genetic predispositions may modulate risk for developing neurocognitive late effects in childhood acute lymphoblastic leukemia (ALL) survivors. METHODS: Long-term ALL survivors (n = 212; mean = 14.3 [SD = 4.77] years; 49% female) treated with chemotherapy completed neurocognitive testing and task-based functional neuroimaging. Based on previous work from our team, genetic variants related to the folate pathway, glucocorticoid regulation, drug metabolism, oxidative stress, and attention were included as predictors of neurocognitive performance, using multivariable models adjusted for age, race, and sex. Subsequent analyses evaluated the impact of these variants on task-based functional neuroimaging. Statistical tests were 2-sided. RESULTS: Survivors exhibited higher rates of impaired attention (20.8%), motor skills (42.2%), visuo-spatial memory (49.3%-58.3%), processing speed (20.1%), and executive function (24.3%-26.1%) relative to population norms (10%; P < .001). Genetic variants implicated in attention deficit phenotypes predicted impaired attention span (synaptosome associated protein 25, F(2,172) = 4.07, P = .019) and motor skills (monoamine oxidase A, F(2,125) = 5.25, P = .007). Visuo-spatial memory and processing speed varied as a function of genetic variants in the folate pathway (methylenetetrahydrofolate reductase [MTHFRrs1801133], F(2,165) = 3.48, P = .033; methylenetetrahydrofolate dehydrogenase 1 [MTHFD1rs2236225], F(2,135) = 3.8, P = .025; respectively). Executive function performance was modulated by genetic variants in the folate pathway (MTHFD1rs2236225, F(2,158) = 3.95, P = .021; MTHFD1rs1950902, F(2,154) = 5.55, P = .005) and glucocorticoid regulation (vitamin D receptor, F(2,158) = 3.29, P = .039; FKBP prolyl isomerase 5, F(2,154) = 5.6, P = .005). Additionally, MTHFD1rs2236225 and FKBP prolyl isomerase 5 were associated with altered brain function during attention and working memory (P < .05; family wise error corrected). CONCLUSIONS: Results extend previous findings of genetic risk of neurocognitive impairment following ALL therapy and highlight the importance of examining genetic modulators in relation to neurocognitive deficits.
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Glucocorticoides , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Femenino , Masculino , Glucocorticoides/uso terapéutico , Sobrevivientes , Ácido Fólico/uso terapéutico , Neuroimagen Funcional , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Isomerasa de Peptidilprolil/uso terapéutico , Proteínas de Unión a Tacrolimus/uso terapéuticoRESUMEN
BACKGROUND: Pediatric chronic kidney disease (CKD) patients are at risk for cognitive deficits with worsening disease progression. Limited, existing cross-sectional studies suggest that cognitive deficits may improve following kidney transplantation. We sought to assess cognitive performance in relationship to kidney transplantation and kidney-specific medical variables in a sample of pediatric kidney transplant patients who provided cross-sectional and longitudinal observations. METHODS: A retrospective chart review was conducted in patients who completed pre- and/or post-transplant neurocognitive testing at the University of Iowa from 2015-2021. Cognitive outcomes were investigated with developmentally appropriate, standardized measures. Mixed linear models estimated the impact of transplant status on cognitive function (z-scores). Subsequent post-hoc t-tests on change scores were limited to patients who had provided pre- and post-transplant assessments. RESULTS: Thirty eight patients underwent cognitive assessments: 10 had both pre- and post-transplant cognitive assessments, 11 had pre-transplant assessments only, and 17 had post-transplant data only. Post-transplant status was associated with significantly lower full-scale IQ and slower processing speed compared to pre-transplant status (estimate = -0.32, 95% confidence interval [CI] = -0.52: -0.12; estimate = -0.86, CI = -1.17: -0.55, respectively). Post-hoc analyses confirmed results from the mixed models (FSIQ change score = -0.34, 95% CI = -0.56: -0.12; processing speed change score = -0.98, CI = -1.28: -0.68). Finally, being ≥80 months old at transplant was associated with substantially lower FSIQ compared to being <80 months (estimate = -1.25, 95% CI = -1.94: -0.56). CONCLUSIONS: Our results highlight the importance of monitoring cognitive function following pediatric kidney transplant and identify older transplant age as a risk factor for cognitive deficits.
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Trasplante de Riñón , Insuficiencia Renal Crónica , Humanos , Niño , Estudios Retrospectivos , Estudios Transversales , Riñón , Insuficiencia Renal Crónica/complicacionesRESUMEN
BACKGROUND: Automated segmentation of individual calf muscle compartments in 3D MR images is gaining importance in diagnosing muscle disease, monitoring its progression, and prediction of the disease course. Although deep convolutional neural networks have ushered in a revolution in medical image segmentation, achieving clinically acceptable results is a challenging task and the availability of sufficiently large annotated datasets still limits their applicability. PURPOSE: In this paper, we present a novel approach combing deep learning and graph optimization in the paradigm of assisted annotation for solving general segmentation problems in 3D, 4D, and generally n-D with limited annotation cost. METHODS: Deep LOGISMOS combines deep-learning-based pre-segmentation of objects of interest provided by our convolutional neural network, FilterNet+, and our 3D multi-objects LOGISMOS framework (layered optimal graph image segmentation of multiple objects and surfaces) that uses newly designed trainable machine-learned cost functions. In the paradigm of assisted annotation, multi-object JEI for efficient editing of automated Deep LOGISMOS segmentation was employed to form a new larger training set with significant decrease of manual tracing effort. RESULTS: We have evaluated our method on 350 lower leg (left/right) T1-weighted MR images from 93 subjects (47 healthy, 46 patients with muscular morbidity) by fourfold cross-validation. Compared with the fully manual annotation approach, the annotation cost with assisted annotation is reduced by 95%, from 8 h to 25 min in this study. The experimental results showed average Dice similarity coefficient (DSC) of 96.56 ± 0.26 % $96.56\pm 0.26 \%$ and average absolute surface positioning error of 0.63 pixels (0.44 mm) for the five 3D muscle compartments for each leg. These results significantly improve our previously reported method and outperform the state-of-the-art nnUNet method. CONCLUSIONS: Our proposed approach can not only dramatically reduce the expert's annotation efforts but also significantly improve the segmentation performance compared to the state-of-the-art nnUNet method. The notable performance improvements suggest the clinical-use potential of our new fully automated simultaneous segmentation of calf muscle compartments.
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Procesamiento de Imagen Asistido por Computador , Pierna , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Pierna/diagnóstico por imagen , Redes Neurales de la Computación , Imagen por Resonancia Magnética/métodos , Músculos/diagnóstico por imagenRESUMEN
BACKGROUND: Juvenile-onset Huntington's disease (JOHD) is a rare form of Huntington's disease (HD) characterized by symptom onset before the age of 21 years. Observational data in this cohort is lacking. OBJECTIVES: Quantify measures of disease progression for use in clinical trials of patients with JOHD. METHODS: Participants who received a motor diagnosis of HD before the age of 21 were included in the Kids-JOHD study. The comparator group consisted of children and young adults who were at-risk for inheriting the genetic mutation that causes HD, but who were found to have a CAG repeat in the non-expanded range (gene non-expanded [GNE]). RESULTS: Data were obtained between March 17, 2006, and February 13, 2020. There were 26 JOHD participants and 78 GNE participants who were comparable on age (16.03 vs. 14.43, respectively) and sex (53.8% female vs. 57.7% female, respectively). The mean annualized decrease in striatal volume in the JOHD group was -3.99% compared to -0.06% in the GNE (mean difference [MD], -3.93%; 95% confidence intervals [CI], [-4.98 to -2.80], FDR < 0.0001). The mean increase in the Unified Huntington's Disease Rating Scale Total Motor Score per year in the JOHD group was 7.29 points compared to a mean decrease of -0.21 point in the GNE (MD, 7.5; 95% CI, [5.71-9.28], FDR < 0·0001). CONCLUSIONS: These findings demonstrate that structural brain imaging and clinical measures in JOHD may be potential biomarkers of disease progression for use in clinical trials. Collaborative efforts are required to validate these results in a larger cohort of patients with JOHD. © 2022 International Parkinson and Movement Disorder Society.
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Enfermedad de Huntington , Trastornos del Movimiento , Niño , Adulto Joven , Humanos , Femenino , Adulto , Masculino , Enfermedad de Huntington/genética , Enfermedad de Huntington/diagnóstico , Encéfalo , Progresión de la Enfermedad , Biomarcadores , Estudios LongitudinalesRESUMEN
Introduction: Younger age at diagnosis is a risk factor for poor health-related quality of life (HRQOL) in long-term breast cancer survivors. However, few studies have specifically addressed HRQOL in young adults with breast cancer (i.e., diagnosed prior to age 40), nor have early changes in HRQOL been fully characterized. Methods: Eligible female patients with breast cancer were identified through our local cancer center. To establish HRQOL, patients completed the Functional Assessment of Cancer Therapy-Breast (FACT-B) around diagnosis and 12 months later. Sociodemographic factors, genetic susceptibility to cancer, tumor- and treatment-related factors, and comorbidities (e.g., depression/anxiety) were abstracted from medical records and the local oncology registry. Mixed-effects models were used to identify changes in FACT-B scores during the first year of treatment and to determine whether any demographic/treatment-related factors modulated changes in scores. Results: Health-related quality of life in young patients with breast cancer was within normal limits at baseline, with a FACT-B overall well-being score of 108.5 (95% confidence limits [CI] = 103.7, 113.3). Participants reported slight improvements over a 12-month period: FACT-B overall well-being scores increased 6.6 points (95% CI = 2.1, 11.1, p < 0.01), functional well-being improved 3.0 points (95% CI = 2.0, 4.1, p < 0.01), emotional well-being improved 1.9 points (95% CI = 0.9, 2.8, p < 0.01), and physical well-being improved 1.5 points (95% CI = 0.2, 2.8, p = 0.03), on average. Participants with anxiety/depression at baseline reported greater improvements in FACT-B overall well-being (change: 12.9, 95% CI = 6.4, 9.5) and functional well-being (change: 5.2, 95% CI = 3.5, 6.9) than participants who did not have anxiety/depression at baseline (change in FACT-B overall well-being: 4.9, 95% CI = 0.2, 9.7; change in functional well-being: 2.3, 95% CI = 1.1, 3.4). Marital status, reconstructive surgery, and baseline clinical staging were also significantly associated with changes in aspects of HRQOL, although their impact on change was relatively minimal. Conclusion: Young women with breast cancer do not report HRQOL concerns during the first year of treatment. Improvements in HRQOL during the first year of treatment may be attributable to a sense of relief that the cancer is being treated, which, in the short run, may outweigh the negative late effects of treatment.
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INTRODUCTION: We compared neuropsychiatric symptoms between child and adolescent huntingtin gene-mutation carriers and noncarriers. Given previous evidence of atypical striatal development in carriers, we also assessed the relationship between neuropsychiatric traits and striatal development. METHODS: Participants between 6 and 18 years old were recruited from families affected by Huntington's disease and tested for the huntingtin gene expansion. Neuropsychiatric traits were assessed using the Pediatric Behavior Scale and the Behavior Rating Inventory of Executive Function. Striatal volumes were extracted from 3T neuro-anatomical images. Multivariable linear regression models were conducted to evaluate the impact of group (i.e., gene nonexpanded [GNE] or gene expanded [GE]), age, and trajectory of striatal growth on neuropsychiatric symptoms. RESULTS: There were no group differences in any behavioral measure with the exception of depression/anxiety score, which was higher in the GNE group compared to the GE group (estimate = 4.58, t(129) = 2.52, FDR = 0.051). The growth trajectory of striatal volume predicted depression scores (estimate = 0.429, 95% CI 0.15:0.71, p = .0029), where a negative slope of striatal volume over time was associated with lower depression/anxiety. CONCLUSIONS: The current findings show that GE children may have lower depression/anxiety compared to their peers. Previously, we observed a unique pattern of early striatal hypertrophy and continued decrement in volume over time among GE children and adolescents. In contrast, GNE individuals largely show striatal volume growth. These findings suggest that the lower scores of depression and anxiety seen in GE children and adolescents may be associated with differential growth of the striatum.
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Enfermedad de Huntington , Adolescente , Ansiedad/genética , Niño , Cuerpo Estriado/diagnóstico por imagen , Humanos , Proteína Huntingtina , Enfermedad de Huntington/genética , Mutación , NeostriadoRESUMEN
BACKGROUND: Long-term survivors of pediatric acute lymphoblastic leukemia are at elevated risk for neurocognitive deficits and corresponding brain dysfunction. This study examined sex-based differences in functional neuroimaging outcomes in acute lymphoblastic leukemia survivors treated with chemotherapy alone. METHODS: Functional magnetic resonance imaging (fMRI) and neurocognitive testing were obtained in 123 survivors (46% male; median [min-max] age = 14.2 years [8.3-26.5 years]; time since diagnosis = 7.7 years [5.1-12.5 years]) treated on the St. Jude Total XV treatment protocol. Participants performed the n-back working memory task in a 3 T scanner. Functional neuroimaging data were processed (realigned, slice time corrected, normalized, smoothed) and analyzed using statistical parametric mapping with contrasts for 1-back and 2-back conditions, which reflect varying degrees of working memory and task load. Group-level fMRI contrasts were stratified by sex and adjusted for age and methotrexate exposure. Statistical tests were 2-sided (P < .05 statistical significance threshold). RESULTS: Relative to males, female survivors exhibited less activation (ie, reduced blood oxygen dependent-level signals) in the right parietal operculum, supramarginal gyrus and inferior occipital gyrus, and bilateral superior frontal medial gyrus during increased working memory load (family-wise error-corrected P = .004 to .008, adjusting for age and methotrexate dose). Female survivors were slower to correctly respond to the 2-back condition than males (P < .05), though there were no differences in overall accuracy. Performance accuracy was negatively correlated with fMRI activity in female survivors (Pearson's r = -0.39 to -0.29, P = .001 to .02), but not in males. CONCLUSIONS: These results suggest the working memory network is more impaired in female survivors than male survivors, which may contribute to ongoing functional deficits.
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Memoria a Corto Plazo , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Niño , Femenino , Humanos , Masculino , Metotrexato/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Corteza Prefrontal/patología , SobrevivientesRESUMEN
BACKGROUND: Juvenile-onset Huntington's disease (JOHD) is a rare and particularly devastating form of Huntington's disease (HD) for which clinical diagnosis is challenging and robust outcome measures are lacking. Neurofilament light protein (NfL) in plasma has emerged as a prognostic biomarker for adult-onset HD. METHODS: We performed a retrospective analysis of samples and data collected between 2009 and 2020 from the Kids-HD and Kids-JHD studies. Plasma samples from children and young adults with JOHD, premanifest HD (preHD) mutation carriers, and age-matched controls were used to quantify plasma NfL concentrations using ultrasensitive immunoassay. RESULTS: We report elevated plasma NfL concentrations in JOHD and premanifest HD mutation-carrying children. In pediatric HD mutation carriers who were within 20 years of their predicted onset and patients with JOHD, plasma NfL level was associated with caudate and putamen volumes. CONCLUSIONS: Quantifying plasma NfL concentration may assist clinical diagnosis and therapeutic trial design in the pediatric population. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
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Enfermedad de Huntington , Biomarcadores , Niño , Progresión de la Enfermedad , Humanos , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/genética , Filamentos Intermedios/metabolismo , Proteínas de Neurofilamentos , Estudios Retrospectivos , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral , Adulto JovenRESUMEN
Abnormalities of sleep are common in myotonic dystrophy type 1 (DM1), but few previous studies have combined polysomnography with detailed clinical measures and brain imaging. In the present study, domiciliary polysomnography, symptom questionnaires and cognitive evaluation were undertaken in 39 DM1-affected individuals. Structural brain MRI was completed in those without contra-indication (nâ¯=â¯32). Polysomnograms were adequate for analysis in 36 participants. Sleep efficiency was reduced, and sleep architecture altered in keeping with previous studies. Twenty participants (56%) had moderate or severe sleep-disordered breathing (apnoea-hypopnoea index [AHI] ≥ 15). In linear modelling, apnoeas were positively associated with increasing age and male sex. AHI ≥ 15 was further associated with greater daytime pCO2 and self-reported physical impairment, somnolence and fatigue. Percentage REM sleep was inversely associated with cerebral grey matter volume, stage 1 sleep was positively associated with occipital lobe volume and stage 2 sleep with amygdala volume. Hippocampus volume was positively correlated with self-reported fatigue and somnolence. Linear relationships were also observed between measures of sleep architecture and cognitive performance. Findings broadly support the hypothesis that changes in sleep architecture and excessive somnolence in DM1 reflect the primary disease process in the central nervous system.
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Trastornos de Somnolencia Excesiva , Distrofia Miotónica , Trastornos de Somnolencia Excesiva/complicaciones , Trastornos de Somnolencia Excesiva/etiología , Fatiga/complicaciones , Fatiga/etiología , Humanos , Masculino , Distrofia Miotónica/complicaciones , Distrofia Miotónica/diagnóstico por imagen , Sueño , SomnolenciaRESUMEN
BACKGROUND: Molecular studies provide evidence that mutant huntingtin (mHTT) affects early cortical development; however, cortical development has not been evaluated in child and adolescent carriers of mHTT. OBJECTIVE: To evaluate the impact of mHTT on the developmental trajectories of cortical thickness and surface area. METHODS: Children and adolescents (6-18 years) participated in the KidsHD study. mHTT carrier status was determined for research purposes only to classify participants as gene expanded (GE) and gene non-expanded (GNE). Cortical features were extracted from 3T neuroimaging using FreeSurfer. Nonlinear mixed effects models were conducted to determine if age, group, and CAG repeat were associated with cortical morphometry. RESULTS: Age-related changes in cortical morphometry were similar across groups. Expanded CAG repeat was not significantly associated with cortical features. CONCLUSION: While striatal development is markedly different in GE and GNE, developmental change of the cortex appears grossly normal among child and adolescent carrier of mHTT.
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Enfermedad de Huntington , Adolescente , Niño , Humanos , Proteína Huntingtina/genética , Enfermedad de Huntington/genéticaRESUMEN
OBJECTIVE: To investigate the associations between neurocognition and white matter integrity in children with chronic kidney disease (CKD). STUDY DESIGN: This cross-sectional study included 17 boys (age 6-16 years) with a diagnosis of mild to moderate (stages 1-3, nondialysis/nontransplant) CKD because of congenital anomalies of the kidney and urinary tract and 20 typically developing community controls. Participants underwent 3T neuroimaging and diffusion-weighted magnetic resonance imaging to assess white matter fractional anisotropy. Multivariable linear regression models were used to evaluate the impact of each group (controls vs CKD) on white matter fractional anisotropy, adjusting for age. Associations between white matter fractional anisotropy and neurocognitive abilities within the CKD group were also evaluated using regression models that were adjusted for age. The false discovery rate was used to account for multiple comparisons; wherein false discovery values <0.10 were considered significant. RESULTS: Global white matter fractional anisotropy was reduced in patients with CKD relative to controls (standardized estimate = -0.38, 95% CI -0.69:-0.07), driven by reductions within the body of the corpus callosum (standardized estimate = -0.44, 95% CI -0.75:-0.13), cerebral peduncle (SE = -0.37, 95% CI -0.67:-0.07), cingulum (hippocampus) (standardized estimate = -0.45, 95% CI -0.75:-0.14), and posterior limb of the internal capsule (standardized estimate = -0.46, 95% CI -0.76:-0.15). Medical variables and neurocognitive abilities were not significantly associated with white matter fractional anisotropy. CONCLUSIONS: White matter development is vulnerable in children with CKD because of congenital causes, even prior to the need for dialysis or transplantation.
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Insuficiencia Renal Crónica , Sustancia Blanca , Adolescente , Anisotropía , Encéfalo/diagnóstico por imagen , Niño , Estudios Transversales , Imagen de Difusión por Resonancia Magnética , Imagen de Difusión Tensora , Femenino , Humanos , Masculino , Sustancia Blanca/diagnóstico por imagenRESUMEN
BACKGROUND: Recent shifts from radiation to chemotherapy-based treatment for acute lymphoblastic leukemia (ALL) have contributed to reduced long-term morbidity. Despite this, ALL survivors remain at increased risk for long-term cognitive impairments. AIM: To identify demographic and treatment factors associated with school performance in pediatric survivors of ALL. METHODS: We collected standardized test scores for reading, math, and science obtained in a school setting from grades 3-11 in 63 ALL survivors (46.0% boys). Most participants were assessed across multiple grades (median number of grades n = 5, range 1-7), and 269 observations were considered in the analyses. Treatment exposures were extracted from medical records. Socio-economic status was estimated using participation in free/reduced lunch programs at school. Mixed effects linear regression models were conducted to determine factors associated with school performance. RESULTS: ALL survivors' scores were comparable to state norms on reading, math, and science performances. On multivariable analysis, participation in free/reduced lunch programs was significantly associated with lower reading scores (ß = -12.52; 95% CI -22.26:-2.77, p = .01). Exposure to radiation during treatment was also associated with lower reading test scores (ß = -30.81, 95% CI -52.00:-9.62, p = .01). No significant associations between demographics and treatment parameters were observed for math and science test scores. CONCLUSIONS: We utilized population-based achievement tests conducted from grades 3-11 to characterize school performance in ALL survivors. Our results imply that survivors with low socio-economic status and those exposed to radiation during treatment could benefit from early monitoring and intervention to maximize academic success.