Cognitive and functional performance and plasma biomarkers of early Alzheimer's disease in Down syndrome.

INTRODUCTION: People with Down syndrome (DS) have a 75% to 90% lifetime risk of Alzheimer's disease (AD). AD pathology begins a decade or more prior to onset of clinical AD dementia in people with DS. It is not clear if plasma biomarkers of AD pathology are correlated with early cognitive and functional impairments in DS, and if these biomarkers could be used to track the early stages of AD in DS or to inform inclusion criteria for clinical AD treatment trials. METHODS: This large cross-sectional cohort study investigated the associations between plasma biomarkers of amyloid beta (Aß)42/40, total tau, and neurofilament light chain (NfL) and cognitive (episodic memory, visual-motor integration, and visuospatial abilities) and functional (adaptive behavior) impairments in 260 adults with DS without dementia (aged 25-81 years). RESULTS: In general linear models lower plasma Aß42/40 was related to lower visuospatial ability, higher total tau was related to lower episodic memory, and higher NfL was related to lower visuospatial ability and lower episodic memory. DISCUSSION: Plasma biomarkers may have utility in tracking AD pathology associated with early stages of cognitive decline in adults with DS, although associations were modest. Highlights: Plasma Alzheimer's disease (AD) biomarkers correlate with cognition prior to dementia in Down syndrome.Lower plasma amyloid beta 42/40 was related to lower visuospatial abilities.Higher plasma total tau and neurofilament light chain were associated with lower cognitive performance.Plasma biomarkers show potential for tracking early stages of AD symptomology.

AT(N) biomarker profiles and Alzheimer's disease symptomology in Down syndrome.

INTRODUCTION: Down syndrome (DS) is a genetic cause of early-onset Alzheimer's disease (AD). The National Institute on Aging-Alzheimer's Association AT(N) Research Framework is a staging model for AD biomarkers but has not been assessed in DS. METHOD: Data are from the Alzheimer's Biomarker Consortium-Down Syndrome. Positron emission tomography (PET) amyloid beta (Aß; 15 mCi of [11 C]Pittsburgh compound B) and tau (10 mCi of [18 F]AV-1451) were used to classify amyloid (A) -/+ and tau (T) +/-. Hippocampal volume classified neurodegeneration (N) -/+. The modified Cued Recall Test assessed episodic memory. RESULTS: Analyses included 162 adults with DS (aged M = 38.84 years, standard deviation = 8.41). Overall, 69.8% of participants were classified as A-/T-/(N)-, 11.1% were A+/T-/(N)-, 5.6% were A+/T+/(N)-, and 9.3% were A+/T+/(N)+. Participants deemed cognitively stable were most likely to be A-T-(N)- and A+T-(N)-. Tau PET (T+) most closely aligning with memory impairment and AD clinical status. DISCUSSION: Findings add to understanding of AT(N) biomarker profiles in DS. HIGHLIGHTS: Overall, 69.8% of adults with Down syndrome (DS) aged 25 to 61 years were classified as amyloid (A)-/tau (T)-/neurodegeneration (N)-, 11.1% were A+/T-/(N)-, 5.6% were A+/T+/(N)-, and 9.3% were A+/T+/(N)+. The AT(N) profiles were associated with clinical Alzheimer's disease (AD) status and with memory performance, with the presence of T+ aligned with AD clinical symptomology. Findings inform models for predicting the transition to the prodromal stage of AD in DS.

Implications of Using the BRIEF-Preschool With School-Age Children With Down Syndrome.

This study evaluated the appropriateness of scoring the Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P) using age-equivalent scores generated from multiple measures of cognition and language among school-age children with Down syndrome (DS). Subscale T scores for 95 children with DS were contrasted using standard scoring on the Behavior Rating Inventory of Executive Function-Second edition (BRIEF-2; based on chronological age) to alternate scoring using the BRIEF-P (based on age-equivalent) for patterns of subscale intercorrelations, differences in mean scores, and agreement on findings from clinical cut-off scores. Results with children with DS suggested using (1) the BRIEF-P for children ages 2-5 years old, (2) the BRIEF-2 with chronological-age scoring or the BRIEF-P with age-equivalent scoring (with some caveats) for research on children ages 5-10 years old, and (3) the BRIEF-2 for children ages 11 and older.

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.

Timing of Alzheimer's Disease by Intellectual Disability Level in Down Syndrome.

BACKGROUND: Trisomy 21 causes Down syndrome (DS) and is a recognized cause of early-onset Alzheimer's disease (AD). OBJECTIVE: The current study sought to determine if premorbid intellectual disability level (ID) was associated with variability in age-trajectories of AD biomarkers and cognitive impairments. General linear mixed models compared the age-trajectory of the AD biomarkers PET Aß and tau and cognitive decline across premorbid ID levels (mild, moderate, and severe/profound), in models controlling trisomy type, APOE status, biological sex, and site. METHODS: Analyses involved adults with DS from the Alzheimer's Biomarkers Consortium-Down Syndrome. Participants completed measures of memory, mental status, and visuospatial ability. Premorbid ID level was based on IQ or mental age scores prior to dementia concerns. PET was acquired using [11C] PiB for Aß, and [18F] AV-1451 for tau. RESULTS: Cognitive data was available for 361 participants with a mean age of 45.22 (SD = 9.92) and PET biomarker data was available for 154 participants. There was not a significant effect of premorbid ID level by age on cognitive outcomes. There was not a significant effect of premorbid ID by age on PET Aß or on tau PET. There was not a significant difference in age at time of study visit of those with mild cognitive impairment-DS or dementia by premorbid ID level. CONCLUSION: Findings provide robust evidence of a similar time course in AD trajectory across premorbid ID levels, laying the groundwork for the inclusion of individuals with DS with a variety of IQ levels in clinical AD trials.

Does Employment Complexity Promote Healthy Cognitive Aging in Down Syndrome?

Adults with Down syndrome (DS) experience high risk for Alzheimer's disease (AD), but there is variability in the timing of transition from a cognitively stable state to prodromal AD and dementia. The present study examined the association between a modifiable lifestyle factor, employment complexity, and cognitive decline across two time points in adults with DS. Employment complexity, defined as the degree of problem-solving or critical thinking required for employment activities, was operationalized using the Dictionary of Occupational Titles, a system which classifies occupations based on three categories: Data, People, and Things. Eighty-seven adults with DS (M = 36.28 years, SD = 6.90 years) were included in analyses. Partial correlations revealed that lower employment complexity involving People and Things were associated with increased dementia symptoms. Lower employment complexity involving Things was also associated with memory decline. These findings have implications for vocational programs focused on job training and placement for adults 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.

Executive Functioning, Language, and Behavioral Abilities Related to Obstructive Sleep Apnea in Down Syndrome.

OBJECTIVES: Obstructive sleep apnea (OSA) is highly prevalent among individuals with Down syndrome (DS), and the nonphysiological consequences of OSA require examination to inform treatment planning. This study aimed to investigate the association between OSA and aspects of language, executive functioning, behavioral, social abilities, and sleep problems in youth with DS aged 6 to 17 years. METHODS: Multivariate analysis of covariance was used to compare 3 groups adjusted for age, participants with DS with untreated OSA (n = 28), participants with DS without OSA (n = 38), and participants with DS with treated OSA (n = 34). To be eligible for the study, participants had to have an estimated mental age of 3 years. No children were excluded based on estimated mental age. RESULTS: After adjusting for age, participants with untreated OSA showed a common pattern of lower estimated marginal mean scores than those with treated OSA and those with no OSA in expressive and receptive vocabulary and higher estimated marginal mean scores with executive functions, everyday memory, attention, internalizing and externalizing behavior, social behavior, and sleep problems. However, only the group differences for executive function (emotional regulation) and internalizing behavior were statistically significant. CONCLUSION: Study findings corroborate and extend prior findings related to OSA and clinical outcomes for youth with DS. The study highlights the importance of OSA treatment in youth with DS and provides clinical recommendations for this population. Additional studies are necessary to control the effects of health and demographic variables.

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.

The Mediatory Role of Executive Functioning on the Association Between Sleep and Both Everyday Memory and ADHD Symptoms in Children and Youth With Down Syndrome.

People with Down syndrome (DS) commonly experience challenges with sleep, executive functioning, everyday memory, and symptoms of attention deficit hyperactivity disorder (ADHD). A path analysis was conducted to determine if executive function mediated the relationship between sleep problems and both everyday memory and ADHD symptoms. Parents of 96 children and youth with DS completed questionnaires related to sleep, executive functioning, everyday memory, and ADHD symptoms. Results showed that executive functioning fully mediated the relation between sleep and both everyday memory and ADHD symptoms. Implications for education and intervention for children and youth with DS are discussed.

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.

Executive functioning and verbal fluency performance in youth with Down syndrome.

BACKGROUND: Executive functioning (EF) is an area of challenge for individuals with Down syndrome (DS) associated with a variety of downstream difficulties. Verbal fluency performance is one potential downstream effect that is commonly assessed in individuals with DS due to the measure's utility as a predictor of dementia. Verbal fluency requires individuals to inhibit irrelevant responses, shift between groupings of related words, and monitor to prevent repetition, all skills related to EF. AIMS: This study aimed to determine the association between semantic verbal fluency performance and three EF subdomains (inhibition, shifting, and working memory) in youth with DS after taking into account vocabulary and cognitive ability. METHODS AND PROCEDURES: Neuropsychological assessments (verbal and visuospatial), and parent reports of EF, were completed at one time point by 69 youth with DS 6-17 years old and their caregivers. Expressive and receptive vocabulary skills and cognitive ability were also assessed. OUTCOMES AND RESULTS: The results revealed that verbal fluency performance was significantly associated with neuropsychological assessments of EF and parent report of inhibition even after controlling for the effects of vocabulary and cognitive ability. CONCLUSIONS AND IMPLICATIONS: The findings highlight the underlying importance of EF in verbal fluency tasks in youth with DS.

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.

Evaluating Verbal Fluency Outcome Measures in Children With Down Syndrome.

This study evaluates the psychometric properties of a verbal fluency task for potential use as an outcome measure in future clinical trials involving children with Down syndrome. Eighty-five participants attempted a modified version of the Neuropsychological Assessment of Children, Second Edition Word Generation Task at two time points. In the full sample, the measure fell below a priori reliability and feasibility criteria, though feasibility of the semantic trials were higher than feasibility of the phonemic trials. Performance on the measure correlated with chronological age and IQ scores, and no sex-related effects were found. Additional analyses suggested that the semantic verbal fluency trials might be appropriate for children with Down syndrome 10 years of age and older.

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.

Associations among co-occurring medical conditions and cognition, language, and behavior in Down syndrome.

BACKGROUND: Specific medical conditions are more prevalent in Down syndrome (DS) compared to the general population. Medical heterogeneity has also been hypothesized to contribute to variability in outcomes in DS. AIMS: This project aimed to examine the association between medical conditions (i.e., gastrointestinal issues, hearing loss, vision problems, and congenital heart defects) and cognition, language, and behavior in children and adolescents with DS. METHODS AND PROCEDURES: Participants were 73 children and adolescents with DS, ages 6-17 years (M = 12.67, SD = 3.16). Caregivers reported on participants' medical conditions, social behaviors, maladaptive behaviors, and executive function. Child cognitive abilities were also assessed. OUTCOMES AND RESULTS: Of the 73 participants, 34.2% had gastrointestinal issues, 12.3% had uncorrected hearing loss, 26.0% had uncorrected vision problems, and 31.5% had congenital heart defects. Participants with gastrointestinal issues had significantly more challenges with social behaviors, maladaptive behaviors, and executive function compared to those without gastrointestinal issues. CONCLUSIONS AND IMPLICATIONS: The associations identified between gastrointestinal issues and caregiver-reported behavioral characteristics in youth with DS contributes to our understanding of the interrelation between co-occurring medical conditions and child outcomes and has implications for approaches to care for individuals 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.

Short-term memory outcome measures: Psychometric evaluation and performance in youth with Down syndrome.

BACKGROUND: Improving short-term memory (STM) performance for individuals with Down syndrome (DS) has been a target of recent clinical trials. Validation of STM outcome measures is essential for research rigor in trials among children and adolescents with DS. AIMS: The current study investigated the psychometric properties of four direct STM assessments and one everyday memory parent form. METHODS AND PROCEDURES: Measures were administered to a sample of 74 youth with DS at two visits, two weeks apart. Overall cognitive abilities were also assessed. OUTCOMES AND RESULTS: The OMQ-PF had good feasibility and distribution of scores, but floor effects were prominent for direct measures. Test-retest reliability was poor to moderate for all measures and practice effects were problematic for the NEPSY-II List Memory and DAS-II Recall of Objects subtests. Commonalities in responses were observed, including primacy/recency effects, and some STM scores were correlated with overall cognitive abilities. CONCLUSIONS AND IMPLICATIONS: The OMQ-PF met most study criteria, but no direct measure met sufficient criteria to be strongly recommended for future clinical trials. Because higher cognitive abilities were related to assessment completion, STM measures may require adaptation for use in broader samples of youth with DS across all levels of cognitive ability.

Child Sleep Linked to Child and Family Functioning in Children with Down Syndrome.

Sleep problems have a bi-directional impact on the daytime performance of children, parental well-being, and overall family functioning in the general population. Children with Down syndrome (DS) are at a high risk of sleep problems, yet the relationship between sleep problems, adaptive functioning, and family stress in children with DS is not well documented. We examined the relationship between sleep (i.e., duration and quality) and child and parent/family functioning. Sixty-six children with DS wore an actigraph for a week to assess their sleep duration and sleep efficiency. Their parents completed ratings on child sleep duration and parasomnias, child adaptive functioning, parental depression and sleep, and family stress. The parents' reports of their children's sleep duration were associated with parental depressive symptoms. The parents' reports of their children's restless sleep behaviors were associated with poorer performances in child-compliant/calm behaviors, worse parental sleep, and negative parental feelings and sibling relationships. The findings from actigraph measures of the children's sleep demonstrated that greater sleep efficiency was associated with greater child adaptive functioning and fewer parental depressive symptoms. The study findings provide preliminary evidence that sleep problems are related to child adaptive functioning, parental functioning, and family stress in children with DS.