JAK inhibition decreases the autoimmune burden in Down syndrome.

Individuals with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display clear signs of immune dysregulation, including high rates of autoimmune disorders and severe complications from infections. Although it is well established that T21 causes increased interferon responses and JAK/STAT signaling, elevated autoantibodies, global immune remodeling, and hypercytokinemia, the interplay between these processes, the clinical manifestations of DS, and potential therapeutic interventions remain ill defined. Here, we report a comprehensive analysis of immune dysregulation at the clinical, cellular, and molecular level in hundreds of individuals with DS. We demonstrate multi-organ autoimmunity of pediatric onset concurrent with unexpected autoantibody-phenotype associations. Importantly, constitutive immune remodeling and hypercytokinemia occur from an early age prior to autoimmune diagnoses or autoantibody production. We then report the interim analysis of a Phase II clinical trial investigating the safety and efficacy of the JAK inhibitor tofacitinib through multiple clinical and molecular endpoints. Analysis of the first 10 participants to complete the 16-week study shows a good safety profile and no serious adverse events. Treatment reduced skin pathology in alopecia areata, psoriasis, and atopic dermatitis, while decreasing interferon scores, cytokine scores, and levels of pathogenic autoantibodies without overt immune suppression. Additional research is needed to define the effects of JAK inhibition on the broader developmental and clinical hallmarks of DS. ClinicalTrials.gov identifier: NCT04246372.

Preliminary psychometric properties of an inhibition task in young children with Down syndrome.

Background: Executive function (EF) skills are important treatment targets for people with Down syndrome (DS); however, few EF measures have been evaluated for use with young children in this population. Methods: The present study evaluated preliminary psychometric properties of a measure of the EF component of inhibition. Participants were 73 children with DS between 2.5 and 8.67 years old who completed an adapted ability to delay task using a desirable toy. Results: Across two separate trials, latencies to touch the toys were significantly correlated. Latencies increased overall with chronological and mental age, with caveats for the youngest and oldest participants. Conclusion: Findings suggest that an adapted prohibition task is an appropriate method of measuring inhibition for children with DS between 4 and 7 years old, though many children in this chronological age range are at early stages of acquiring this skill set.

Longitudinal Predictors of Neurodevelopmental Outcomes in Children with Down Syndrome.

This study examined longitudinal predictors of neurodevelopmental outcomes in children with Down syndrome (DS). Participants were assessed at Wave 1 during infancy on measures of looking behavior and caregivers provided infant sensory ratings. At Wave 2, child-age participants completed a developmental assessment and caregivers provided ratings of executive function, ADHD symptoms, and autism symptoms. Longer looking durations and greater sensory dysregulation during infancy were predictive of higher ADHD symptom ratings and other neurodevelopmental outcomes during childhood. The findings suggest that early indicators of neurodevelopmental dysregulation may be detectable during infancy in DS.

Psychometric evaluation of a working memory assessment measure in young children with Down syndrome.

BACKGROUND: Working memory involves the temporary storage and manipulation of information and is frequently an area of challenge for individuals with Down syndrome (DS). Despite the potential benefits of intervention, laboratory assessments of working memory that could capture intervention effects have not undergone rigorous evaluation for use with young children with DS. It is critical to evaluate assessments of working memory in young children with DS to ensure the reliable and accurate measurement of performance. AIM: This study evaluated an adapted laboratory measure of working memory for young children with DS 2-8 years old. METHOD: A self-ordered pointing task, the Garage Game, was administered to 78 children with DS (mean = 5.17 years; SD = 1.49). Adaptations were made to the task to minimize potential DS phenotype-related language and motor confounds. RESULTS: Results indicate that the measure is feasible, scalable, and developmentally sensitive, with minimal floor and practice effects for this population within this chronological and developmental age range. CONCLUSION: These findings demonstrate that the Garage Game is promising for use in studies of early working memory and treatment trials that aim to support the development of this critical dimension of executive functioning for children with DS.

Using the Social Skills Improvement System (SSiS) Rating Scales to assess social skills in youth with Down syndrome.

Introduction and Methods: This study provides preliminary data on the Social Skills Improvement System (SSiS) Rating Scales Parent Form to measure social skills in a sample of 124 children and adolescents with Down syndrome (DS) ages 6-17 years. Results: Overall, participants demonstrated relatively mild symptoms, with the sample's average standard score falling within 1 standard deviation from the mean of the normative sample for the social skills (M = 92, SD = 15) and problem behaviors (M = 104, SD = 12) domains (normative sample M = 100, SD = 15 for both domains). However, a wide range of scores was observed across the sample for the composite and subscale scores. Differential patterns were also observed by subscale. For some subscales (i.e., Cooperation, Assertion, Responsibility, Engagement, Externalizing, Hyperactivity/Inattention, and Autism Spectrum), a disproportionate number of participants scored in the below average (i.e., lower levels of social skills) or above average (i.e., more symptomatic in problem behaviors or autism spectrum) range relative to the normative sample; for other subscales (i.e., Communication, Empathy, Self-Control, Bullying, and Internalizing), participants' score distribution aligned more closely to that of the normative sample. SSiS composite scores correlated in the expected directions with standardized measures of autism characteristics, executive function, and expressive language. Discussion: This study provides some of the first evidence validating the use of the SSiS in youth with DS, filling a gap in standardized measures of social functioning in this population.

Evaluating Processing Speed and Reaction Time Outcome Measures in Children and Adolescents with Down Syndrome.

Reliable and valid cognitive outcome measures, including examiner-administered and computer-facilitated assessments of processing speed and reaction time, are necessary for future clinical trials that include individuals with Down syndrome (DS). The current study evaluated the score distributions and psychometric properties of four examiner-administered and three computerized processing speed and reaction time measures. Participants included 97 individuals with DS, aged 6 to 17 (M = 12.6, SD = 3.3). Two examiner-administered measures (Differential Ability Scales-II Rapid Naming and Cat/dog Stroop Congruent) met most predetermined psychometric criteria. Other assessments demonstrated good test-retest reliability and had negligible practice effects but lacked adequate feasibility. Recommendations for using processing speed and reaction time assessments in research and suggestions for modifications of measures are discussed.

Cognitive flexibility assessment in youth with Down syndrome: Reliability, practice effects, and validity.

BACKGROUND: Cognitive flexibility refers to the ability to switch between different mental sets, tasks, or strategies and is challenging for some individuals with Down syndrome (DS). The lack of reliable and valid cognitive flexibility measures for individuals with DS is a major barrier to clinical trials and intervention studies designed to address cognitive challenges specific to DS. To avoid measurement limitations that could confound interpretations of performance in clinical trials in children with DS, it is critical to use phenotype-sensitive and psychometrically sound measures of cognitive flexibility. AIM: This study aimed to evaluate the psychometric properties of three measures of cognitive flexibility including Rule-Shift, Weigl Sorting, and KiTAP Flexibility in a sample of 97 youth with DS aged 6-17 years old. METHOD: Data were collected at two time points with a two-week interval. Parents also completed adaptive behavior and cognitive flexibility questionnaires. Child cognitive and language abilities were also assessed. RESULTS: The Weigl Sorting met the most psychometric criteria, with adequate feasibility (≥ 80 %) and significant correlations with most of the broader developmental domains; however, the levels of test-retest reliability, practice effects, and convergent validity did not meet a priori criteria. Rule-Shift and KiTAP Flexibility measures did not have acceptable feasibility; although sensitivity and specificity analyses revealed that Rule-Shift may be appropriate for a subgroup of the participants. CONCLUSION: No evaluated measures met all psychometric study criteria and, therefore, additional evaluation of cognitive flexibility measures is needed for use among individuals with DS.

Outreach and Engagement Efforts in Research on Down Syndrome: An NIH INCLUDE Working Group Consensus Statement.

The National Institutes of Health formulated the Outreach and Engagement Working Group in Fall of 2019 to support the objectives of the INCLUDE Project (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE). This Working Group consisted of a multi-disciplinary team of stakeholders in research on Down syndrome that met to discuss best practices for outreach and engagement to Down syndrome communities, with an emphasis on representation and diversity. This review and consensus paper describes the importance of increasing representation in DS research for future cohort building and summarizes the priority issues identified by the Working Group members. An overview of Working Group activities is then presented, followed by consensus recommendations and a discussion of future opportunities and challenges.

Considerations for measuring individual outcomes across contexts in Down syndrome: Implications for research and clinical trials.

Individuals with Down syndrome (DS) are increasingly involved in clinical trials that target developmental outcomes, like cognition and behavior. The increased focus on treatment in DS has led to ongoing discussions regarding the selection of outcome measures using syndrome-informed criteria. This discourse is warranted as clinical trials can fail if the outcome measures selected are inappropriate for individuals with DS or do not take into account the behavioral phenotype commonly associated with DS. This review focuses on the challenges present in the measurement of outcomes in DS, with a specific focus on considerations made in evaluating cognitive, language, and behavioral/psychopathology outcomes. This review also provides a summary of recommendations for assessment of outcomes in these domains as well as recommendations for future research. The impact of physical health and assessment psychometrics on the measurement of outcomes is also reviewed.

Profiles of Caregiver-Reported Executive Function in Children with Down Syndrome.

Children with Down syndrome (DS) are at risk for challenges with aspects of executive function (EF). The current study explores whether heterogeneity in EF profiles can be detected within a sample of children with DS. Participants were 69 children with DS, ages 3-10 years (M = 6.23, SD = 1.91). T-scores from a caregiver-report measure of executive function were modeled using latent profile analysis, and auxiliary analyses examined the association between demographic and biomedical factors and probability of profile membership. The two-profile solution was the best fit for the sample, with a profile that involved elevated scores in working memory only ("Working Memory Only" profile; 43% of sample) and a "Multi-Domain" profile that involved elevated scores in planning, inhibition, and working memory (57%). The presence of congenital heart defects was associated with a higher probability of assignment to the Multi-Domain profile. Findings from this study contribute to the characterization of heterogeneous outcomes associated with DS.

Defining Expressive Language Benchmarks for Children with Down Syndrome.

Establishing expressive language benchmarks (ELBs) for children with Down syndrome (DS), as developed by Tager-Flusberg et al. for children with autism, is critically needed to inform the development of novel treatments, identify individualized treatment targets, and promote accurate monitoring of progress. In the present study, we assessed ELB assignments in three language domains (phonology, vocabulary, and grammar) for 53 young children with DS (CA range: 2.50-7.99 years) using standardized assessments. The participants were classified into one of four ELB levels (preverbal, first words, word combinations, and sentences) in each language domain. Associations with additional measures of language, chronological age, nonverbal cognition, and verbal short-term memory were considered. Analyses of individual ELB profiles indicated substantial variability across the three language domains, with six different patterns of variation across domains emerging. At the same time, the ELB categories were significantly associated with independent language measures and broader developmental domains. Moreover, ELB changes were observed in a small sample of children with DS reassessed 18-24 months after the initial visit. Results from the present study suggest the procedures outlined by Tager-Flusberg et al. for defining ELBs are a potentially useful tool for describing the language abilities of children with DS.

Patterns and predictors of adaptive skills in 2- to 7-year-old children with Down syndrome.

BACKGROUND: There is substantial variability in adaptive skills among individuals with Down syndrome. Few studies, however, have focused on the early developmental period or on the potential sources of variability in adaptive skills. This study characterizes adaptive skills in young children with Down syndrome and investigates child characteristics associated with adaptive skills. METHODS: Participants were 44 children with Down syndrome ranging in age from 2.50 to 7.99 years (M = 4.66 years, SD = 1.46). The Vineland Adaptive Behavior Scales-3 (VABS-3) Comprehensive Interview Form was used to assess adaptive behavior in the three core domains: socialization, daily living, and communication skills. Caregivers also reported on motor skills and autism spectrum disorder symptoms. Child cognitive abilities were assessed. RESULTS: Analyses comparing mean standard score performance across the three VABS-3 core domains demonstrated significant differences between all pairs of domains, resulting in a group-level pattern of socialization > daily living > communication skills. At the individual level, 10 different patterns of relative strength and weakness were identified, with only 18% of participants evidencing significant differences between adaptive skill domain standard scores corresponding to the group-level pattern of significant differences. Child characteristics (cognitive abilities, motor skills, and autism spectrum disorder symptoms) were significantly associated with VABS-3 adaptive domain standard scores. CONCLUSION: These findings underscore the importance of individualizing intervention programs focused on improving the adaptive skills of young children with Down syndrome based on consideration of the child's relative adaptive strengths and weaknesses.

Early Regulatory Skills and Social Communication Development in Infants with Down Syndrome.

Children with Down syndrome (DS) demonstrate substantial variability in communication and language outcomes. One potential source of variability in this skill area may be early regulatory function. Characterizing the early link between regulatory function and early social communication may benefit infants with DS at risk of difficulties with social communication and language skill acquisition. Forty-three infants with DS were assessed at two time points, six months apart. At Time 1, the average chronological age was 9.0 months (SD = 3.9) and caregivers completed the Infant Behavior Questionnaire-Revised (IBQ-R) to assess regulatory function. Six months later, caregivers rated infant communication at the second visit using the Communication and Symbolic Behavior Scales Infant Toddler Checklist (CSBS-ITC). Infant developmental level was assessed at both visits using the Bayley Scales of Infant and Toddler Development, Third Edition and caregivers reported on developmental history and biomedical comorbidities. Infant regulatory function at Time 1 predicted social communication outcomes at Time 2, six months later. Findings from this study suggest that elevated risk for pronounced communication challenges may be detectable as early as infancy in DS.

Sensory Processing and Maladaptive Behavior: Profiles Within the Down Syndrome Phenotype.

Aim: Sensory processing impairments are well characterized in children with neurodevelopmental disorders, particularly autism, and have been associated with maladaptive behaviors. However, little is known regarding sensory processing difficulties within Down syndrome, or how these difficulties may influence maladaptive behavior. This study aims to characterize sensory processing difficulties within the Down syndrome phenotype and determine the influence of processing difficulties on maladaptive behavior. Methods: To explore this issue, we administered the Short Sensory Profile and the Developmental Behavior Checklist to parents or primary caregivers of young children with DS (N = 49; M nonverbal mental age (NVMA) = 30.92 months (SD = 12.30); M chronological age (CA) = 67.04 (SD = 25.13). Results: Results indicated that Low Energy/Weak, Under-responsive/Seeks Sensation, and Auditory Filtering were the areas of greatest sensory regulation difficulty, and that Self-Absorbed behavior and Disruptive/Antisocial behavior were elevated areas of maladaptive behavior. Multivariate regression analyses indicated that Under-responsive/Seeks Sensation was the only sensory regulation domain significantly associated with Self-Absorbed and Disruptive/Antisocial behavior. Conclusion: Findings indicate a consistent pattern of sensory processing impairments and associations with maladaptive behavior in children with DS. Implications for interventions are discussed.

Autism spectrum disorder (ASD) symptom profiles of children with comorbid Down syndrome (DS) and ASD: A comparison with children with DS-only and ASD-only.

BACKGROUND: Down syndrome (DS) is associated with increased rates of autism spectrum disorder (ASD), characterized by social-communicative impairments (SOC-COM) and repetitive behaviors and interests (RBI). However, little is known about the ASD symptom presentation in children with DS + ASD. AIMS: The current study sought to describe parent-report of SOC-COM and RBI symptoms on the Autism Diagnostic Interview -Revised (ADI-R) in children with DS (n = 22), DS + ASD (n = 11), and ASD (n = 66). METHOD: SOC-COM and RBI scores from the ADI-R were compared across the groups whose autism status was ascertained using the Autism Diagnostic Observation Schedule. RESULTS: Differences in SOC-COM and RBI symptom severity was observed. The general pattern of findings was ASD > DS+ASD > DS. Dissimilar ASD symptom profiles were observed across groups. In ASD, SOC-COM scores were higher than RBI scores; in DS + ASD, similar SOC-COM and RBI scores were observed. Lastly, SOC-COM impairments were highly related to verbal cognition in youth with DS + ASD but not in those with DS or ASD. CONCLUSIONS AND IMPLICATIONS: These findings suggest that children with DS + ASD have a distinct profile of ASD symptoms that differs from peers with either disorder in isolation. Thus, care should be taken in evaluating and designing treatments for this group.

Exploratory behavior and developmental skill acquisition in infants with Down syndrome.

Infants learn about objects by exploring them. Typically developing infants actively explore objects through visual, manual, and oral modalities. Attenuated exploratory behavior has been observed in various neurodevelopmental disorders, including Down syndrome (DS), presumably limiting learning options. However, a direct link between exploration and overall developmental functioning has not been characterized. This study used a Latent Profile Analysis framework to examine within-syndrome variability in exploratory behavior in infants with DS and the developmental correlates of different exploratory behavior profiles. Participants were 45 infants with DS (CA = 9.58 months; SD = 3.62) who completed an object exploration activity and the Bayley Scales of Infant Development-III (BSID-III; Bayley, 2006). Exploration behavior was coded for the percentage of time engaged in visual, manual, and oral exploration. Results indicated that a 2-profile solution provided the best model fit for exploratory behavior, yielding profiles that represented either an Active (57.78% of the sample) or a Passive Exploratory (42.22% of the sample) profile. The Active Exploratory profile was associated with significantly higher age equivalent scores on the BSID-III Cognitive, Communication, and Motor domains than the Passive Exploratory profile. Other factors, such as sex and biomedical risk factors, were not associated with exploratory profiles. These findings offer a more nuanced understanding of early within-syndrome heterogeneity in DS, and demonstrate that impoverished early exploratory behavior may serve as an important indicator of increased risk for more pronounced developmental delays in DS.

Personalized reading intervention for children with Down syndrome.

The purpose of this replication study was to evaluate the potential efficacy and feasibility of an early reading intervention for children with Down syndrome. The intervention was developed in alignment with the Down syndrome behavioral phenotype. Six children between the ages of seven and ten years participated in a series of multiple-probe across lessons single-case design studies. Results indicate a functional relation between intervention and reading outcomes for four children. Results were mixed for one participant and no functional relation was demonstrated for another. The potential promise of pursuing aptitude-by-treatment interaction research for subgroups of learners with similar characteristics as an effort to personalize intervention is discussed.

Adaptive behavior in infants and toddlers with Down syndrome and fragile X syndrome.

Individuals with Down syndrome (DS) experience deficits across all domains of adaptive functioning, however little is known about the emergence and age-related changes of these impairments compared to other neurogenetic disorders with similar intellectual disability impairments, such as fragile X syndrome (FXS). Adaptive behavior is key for optimal functioning in these populations. Participants aged 5-45 months comprised three age-matched groups, DS (n = 64), FXS (n = 69), and typically developing controls (TD; n = 69). Adaptive behavior was measured on the Vineland Adaptive Behavior Scales-II. Regressions were used to examine adaptive behavior in a cross-sectional design across age. DS infants and toddlers evidenced deficits across all areas of adaptive behaviors compared to the age-matched TD group, with clear impairments present in the first year of life. Motor skills were the area of greatest weakness in children with DS with significant impairment evident at 12 months of age that remained low through 3 years. Compared to age-matched children with FXS, children with DS showed initially lower standard scores at 12 months of age, but slower declines in standard scores across age, resulting in less impaired functioning at 36 months. This is the first study to compare adaptive behavior in infants and toddlers with DS to FXS, and demonstrate the phenotypic specificity of adaptive profiles in this diagnostic group. These findings provide evidence that adaptive behavior should be a major target of intervention in children with FXS and DS, and that these differences are potentially driven by unique etiologies attributable to each disorder.

Performance and Ratings Based Measures of Executive Function in School-Aged Children with Down Syndrome.

We examined performance-based laboratory tasks and ratings-based assessments of executive function (EF) in school-aged children with Down syndrome and mental-age matched peers along with adaptive functioning. METHODS: A battery of assessments including EF laboratory tasks was collected. RESULTS: The DS group performed both working memory/inhibition and planning laboratory tasks with significant challenges. Moderate correlations were evident only between some laboratory tasks and ratings-based EF domains. However, ratings-based EF better predicted adaptive function than performance on an EF laboratory-based task. CONCLUSIONS: Findings underscore the need to address early and targeted EF intervention in children with DS.

Impact of maladaptive behavior on school function in Down syndrome.

BACKGROUND/AIMS: Individuals with Down syndrome (DS) are at an increased risk for certain maladaptive behaviors. This study characterized maladaptive behavior in school-aged children with DS and examined the extent to which maladaptive behaviors are associated with school function. METHODS AND PROCEDURES: Participants were 24 students with DS [mean nonverbal mental age (NVMA)=43.83months; mean chronological age (CA)=77.58months] who completed the Leiter Scales of Performance- Revised (Leiter-R; Roid & Miller, 1997). Their teachers completed the Behavior Assessment Scales for Children Version 2 (Reynolds & Kamphaus, 2004), and the School Function Assessment (Coster et al., 1998), measures of maladaptive and adaptive behavior as observed in the school setting. RESULTS: Findings reveal a maladaptive behavior profile of elevated areas including Aggression, Attention Problems, and Somatization. When examining the association between maladaptive behavior and school function, multivariate regression results indicated a significant association between Aggression and Compliance, and Attention Problems and Task Completion. CONCLUSIONS AND IMPLICATIONS: Results underscore the importance of developing training for educators regarding the potential impact of maladaptive behavior on school function for students with Down syndrome.