Evolocumab in paediatric heterozygous familial hypercholesterolaemia: cognitive function during 80 weeks of open-label extension treatment.

AIMS: PCSK9 inhibition intensively lowers low density lipoprotein cholesterol and is well tolerated in adults and paediatric patients with familial hypercholesterolaemia (FH). HAUSER-RCT showed that 24 weeks of treatment with evolocumab in paediatric patients did not affect cognitive function. This study determined the effects of 80 additional weeks of evolocumab treatment on cognitive function in paediatric patients with heterozygous FH. METHODS AND RESULTS: HAUSER-OLE was an 80-week open-label extension of HAUSER-RCT, a randomized, double-blind, 24-week trial evaluating the efficacy and safety of evolocumab in paediatric patients (ages 10-17 years) with FH. During the OLE, all patients received monthly 420 mg subcutaneous evolocumab injections. Tests of psychomotor function, attention, visual learning, and executive function were administered at baseline and Weeks 24 and 80 of the OLE. Changes over time were analysed descriptively and using analysis of covariance. Cohen's d statistic was used to evaluate the magnitude of treatment effects. Analysis of covariance results indicated no decrease in performance across visits during 80 weeks of evolocumab treatment for Groton Maze Learning, One Card Learning accuracy, Identification speed, or Detection speed (all P > 0.05). Performance on all tasks was similar for those who received placebo or evolocumab in the RCT (all P > 0.05). For all tests, the least square mean differences between patients who received placebo vs. evolocumab in the parent study were trivial (all Cohen's d magnitude < 0.2). CONCLUSION: In paediatric patients with FH, 80 weeks of open-label evolocumab treatment had no negative impact on cognitive function. REGISTRATION: ClinicalTrials.gov identifier: NCT02624869.

Some children are born with a genetic disorder that causes high cholesterol, which leads to heart disease. Children with high cholesterol can be treated with evolocumab, a medication that lowers blood cholesterol. Because cholesterol is important for development and adequate function of the brain, there is a concern that lowering cholesterol in children may affect mental ability. In this study, we tested whether treating children with evolocumab for 80 weeks affected mental ability in performing several tasks. A battery of tests that measure executive function (Groton Maze Learning Test), visual learning (One Card Learning Test), visual attention (Identification Test), and psychomotor function (Detection Test) showed no decrease in performance across visits during 80 weeks of evolocumab treatment. Performance on all tasks was similar for the children who received placebo for the first 24 weeks then received evolocumab for an additional 80 weeks (placebo/evolocumab) and those who received evolocumab for 24 weeks then received evolocumab for an additional 80 weeks (evolocumab/evolocumab).

A Parent-child yoga intervention for reducing attention deficits in children with congenital heart disease: the Yoga for Little Hearts Feasibility Study Protocol.

INTRODUCTION: Preschoolers and school-aged children with congenital heart disease (CHD) are at higher risk of attention deficit hyperactivity disorder (ADHD) compared with the general population. To this day, no randomised controlled trial (RCT) aiming to improve attention has been conducted in young children with CHD. There is emerging evidence indicating that parent-child yoga interventions improve attention and reduce ADHD symptoms in both typically developing and clinical populations. METHODS AND ANALYSIS: This is a single-blind, two-centre, two-arm trial during which 24 children with CHD and their parents will be randomly assigned to (1) a parent-child yoga intervention in addition to standard clinical care or (2) standard clinical care alone. All participants will undergo standardised assessments: (1) at baseline, (2) immediately post-treatment and (3) 6 months post-treatment. Descriptive statistics will be used to estimate the feasibility and neurodevelopmental outcomes. This feasibility study will evaluate: (1) recruitment capacity; (2) retention, drop-out and withdrawal rates during the yoga programme and at the 6-month follow-up; (3) adherence to the intervention; (4) acceptability of the randomisation process by families; (5) heterogeneity in the delivery of the intervention between instructors and use of home-based exercises between participants; (6) proportion of missing data in the neurodevelopmental assessments and (7) SD of primary outcomes of the full RCT in order to determine the future appropriate sample size. ETHICS AND DISSEMINATION: Ethical approval has been obtained by the Research Ethics Board of the Sainte-Justine University Hospital. The findings will be disseminated in peer-reviewed journals and conferences and presented to the Canadian paediatric grand round meetings. TRIAL REGISTRATION NUMBER: NCT05997680.

Functional brain connectivity after corrective cardiac surgery for critical congenital heart disease: a preliminary near-infrared spectroscopy (NIRS) report.

Patients with congenital heart disease (CHD) requiring cardiac surgery in infancy are at high risk for neurodevelopmental impairments. Neonatal imaging studies have reported disruptions of brain functional organization before surgery. Yet, the extent to which functional network alterations are present after cardiac repair remains unexplored. This preliminary study aimed at investigating cortical functional connectivity in 4-month-old infants with repaired CHD, using resting-state functional near-infrared spectroscopy (fNIRS). After fNIRS signal frequency decomposition, we compared values of magnitude-squared coherence as a measure of connectivity strength, between 21 infants with corrected CHD and 31 healthy controls. We identified a subset of connections with differences between groups at an uncorrected statistical level of p < .05 while controlling for sex and maternal socioeconomic status, with most of these connections showing reduced connectivity in infants with CHD. Although none of these differences reach statistical significance after FDR correction, likely due to the small sample size, moderate to large effect sizes were found for group-differences. If replicated, these results would therefore suggest preliminary evidence that alterations of brain functional connectivity are present in the months after cardiac surgery. Additional studies involving larger sample size are needed to replicate our data, and comparisons between pre- and postoperative findings would allow to further delineate alterations of functional brain connectivity in this population.

Cognitive function with evolocumab in pediatric heterozygous familial hypercholesterolemia.

BACKGROUND: Evolocumab is a fully human monoclonal antibody inhibitor of PCSK9 approved for lowering low-density lipoprotein cholesterol in adults and pediatric patients with familial hypercholesterolemia (FH). The cognitive safety of evolocumab has been established in adults but has not yet been described in pediatric patients. OBJECTIVE: To determine the effects of evolocumab on cognitive function in pediatric heterozygous FH. METHODS: Cognitive function was assessed during a 24-week, randomized, double-blind, placebo-controlled study (HAUSER-RCT) evaluating the efficacy, safety, and tolerability of 24 weeks of monthly subcutaneous injections of evolocumab in pediatric patients with FH. Cognitive safety endpoints included changes from baseline to week 24 in test scores in domains of psychomotor function, attention, visual learning, and executive function. Between-group differences in age-standardized mean test score changes were analyzed using analysis of covariance models and point estimates with 95% confidence interval (CI). Magnitudes of difference between treatment groups (Cohen's d) and reliable change indices were calculated for each cognitive function test. RESULTS: At week 24, changes from baseline in age-standardized cognitive test scores were similar between the treatment groups. Differences (95% CI) between the evolocumab and placebo groups in mean test score changes for the Groton Maze Learning, One-Card Learning, Identification, and Detection tests were 0.1 (-0.2, 0.4), -0.1 (-0.5, 0.4), 0.3 (0.0, 0.7), 0.3 (-0.1, 0.8), respectively. For all tests, abnormal and clinically important cognitive decline occurred with lesser frequency in the evolocumab group. CONCLUSION: In pediatric patients with FH, 24-week treatment with evolocumab did not negatively influence cognition. FUNDING: This study was funded and designed by Amgen.

Social cognition and competence in preschoolers with congenital heart disease.

OBJECTIVE: Children born with congenital heart disease (CHD) are at an increased risk for various neurodevelopmental impairments. However, little is known regarding social outcomes associated with CHD, particularly during early childhood. The present study aimed to characterize the sociocognitive profile and to assess the contribution of language, executive functions (EF), and social cognition to social competence (SC) in preschoolers with CHD. METHOD: Five-year-old children with CHD (n = 55) completed a standardized neuropsychological assessment. Performance on sociocognitive skills was compared to test norms using one-sample t tests. Hierarchical regression was conducted to examine the associations between language skills, affect recognition (AR), theory of mind (ToM), EF (performance-based and parent-rated), and social competence. RESULTS: Children with CHD performed significantly worse than norms in language and ToM, whereas EF and social competence appeared generally preserved in our sample. In hierarchical regression analysis, cognitive functions (language score, AR, ToM, EF performance) accounted for a significant 24.3% of the variance. Parent-rated EF added another 24.8% to the total explained variance. CONCLUSIONS: These findings provide new evidence for understanding social cognition and competence among preschoolers with CHD, showing vulnerability in social cognition and language skills but not in social competence more generally. The model suggests a combined contribution of social cognition, language, and EF on social outcomes. Remedial programs addressing these intervention targets could be useful in promoting social development in this vulnerable population. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The role of parenting stress in anxiety and sleep outcomes in toddlers with congenital heart disease.

Objectives: This retrospective cohort study investigates how parenting stress, measured at 4 months of age by use of a classic three-dimensional parent-reported scale (Parenting Stress Index, 4th Ed. or PSI-4), can predict anxiety symptoms and quality of sleep at 24 months in toddlers with congenital heart disease (CHD). Study Design: Sixty-six toddlers with CHD followed at our cardiac neurodevelopmental follow-up clinic were included in this study. As part of their systematic developmental assessment program, parents completed questionnaires on their stress level (PSI-4) when their child was 4 months old, and on their child's anxiety symptoms and quality of sleep at 24 months. Eight multiple linear regression models were built on the two measures collected at 24 months using the PSI-4 scores collected at 4 months. For each measure, four models were built from the PSI-4 total score and its three subscales (Parental Distress, Parent-Child Dysfunctional Interaction, Difficult Child), controlling for sex and socioeconomic status. Results: The PSI-4 Difficult Child subscale, which focuses on parenting anxiety related to the child's behavioral problems and poor psychosocial adjustment, accounted for 17% of the child's anxiety symptoms at 24 months. The two other PSI-4 subscales (Parental Distress and Parent-Child Dysfunctional Interaction) and the PSI-4 total score did not contribute significantly to the models. None of the four regression models on perceived quality of sleep were significant. It is important to note that 33% of parents responded defensively to the PSI-4. Conclusions: Parenting stress related to the child's behavioral problems and poor psychosocial adjustment, measured when the child is 4 months old, is associated with the child's ulterior anxiety symptoms. As very few standardized tools are available to assess the behavioral and psychoaffective development of infants, this study highlights the importance of early psychosocial screening in parents of infants with CHD. The high rate of significant Defensive Responding Indices reminds us to not take parent reports at face value, as their actual stress levels might be higher.

Neurodevelopmental Outcome of Children with Congenital Heart Disease: A Cohort Study from Infancy to Preschool Age.

OBJECTIVE: To characterize the neuropsychological outcome of children with congenital heart disease (CHD) at age 5 years; the stability of cognitive and language abilities across childhood; and to identify early neurodevelopmental markers of neuropsychological outcomes in these children. STUDY DESIGN: Five-year-old children (n = 55) with complex CHD were assessed using standardized and comprehensive neuropsychological measures. Stability of language and cognitive performance was assessed by comparing standardized scores between ages 1, 2, and 5 years old. Association between 5-year-old skills and scores obtained in early childhood was studied to identify potential early markers of preschool performance. Receiver operating characteristic curves were used to evaluate the classification accuracy of Bayley Scales of Infant Development, Third Edition scales in identifying later impairments. RESULTS: At age 5 years, our cohort obtained scores significantly below the norms on most developmental domains, with 35% to 65% of participants showing impaired short-term/working memory, attention, and preacademic skills. Developmental patterns measured between ages 1 and 5 years were different for cognitive and language domains, with a decline with age for cognitive functioning and stable results for expressive language. The Bayley Scales of Infant Development, Third Edition language scores at age 2 years provided a good predictive value in identifying children with impaired language at age 5 years. CONCLUSIONS: In our cohort, we found a high prevalence of impairments affecting higher-order cognitive domains. Although language difficulties can be detected as early as 2 years of age, other neuropsychological impairments, such as attention and pre-academic skills, only appear later during development, which reinforces the need for long-term monitoring and systematic assessment before school entry.

Description and classification of neurodevelopmental disabilities.

Classification is a tool for communication so that when clinicians, policy-makers, or researchers refer to some features they talk about the same thing. The classification of neurodevelopmental problems in children and adolescents is crucial to better understand their prevalence and the intervention or treatment that should be provided. However, such classification might be challenging, especially when development aspects have to be taken into account. This chapter aims to provide a better understanding of the classification of neurodevelopmental disabilities. Thus, we provide an overview of the different classification systems that are the most commonly used, such as the well-known Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD). Moreover, we address opportunities and challenges inherent to the classification of neurodevelopmental disorders and the implications for clinical practice and research areas.

Functional Brain Connectivity of Language Functions in Children Revealed by EEG and MEG: A Systematic Review.

The development of language functions is of great interest to neuroscientists, as these functions are among the fundamental capacities of human cognition. For many years, researchers aimed at identifying cerebral correlates of language abilities. More recently, the development of new data analysis tools has generated a shift toward the investigation of complex cerebral networks. In 2015, Weiss-Croft and Baldeweg published a very interesting systematic review on the development of functional language networks, explored through the use of functional magnetic resonance imaging (fMRI). Compared to fMRI and because of their excellent temporal resolution, magnetoencephalography (MEG) and electroencephalography (EEG) provide different and important information on brain activity. Both therefore constitute crucial neuroimaging techniques for the investigation of the maturation of functional language brain networks. The main objective of this systematic review is to provide a state of knowledge on the investigation of language-related cerebral networks in children, through the use of EEG and MEG, as well as a detailed portrait of relevant MEG and EEG data analysis methods used in that specific research context. To do so, we have summarized the results and systematically compared the methodological approach of 24 peer-reviewed EEG or MEG scientific studies that included healthy children and children with or at high risk of language disabilities, from birth up to 18 years of age. All included studies employed functional and effective connectivity measures, such as coherence, phase locking value, and Phase Slope Index, and did so using different experimental paradigms (e.g., at rest or during language-related tasks). This review will provide more insight into the use of EEG and MEG for the study of language networks in children, contribute to the current state of knowledge on the developmental path of functional connectivity in language networks during childhood and adolescence, and finally allow future studies to choose the most appropriate type of connectivity analysis.