Specificity: A Phenotypic Comparison of Communication-Relevant Domains Between Youth With Down Syndrome and Fragile X Syndrome

Despite the shared presence of an intellectual disability (ID), there is a growing literature documenting important phenotypic differences between Down syndrome (DS) and fragile X syndrome (FXS). These conclusions, however, are based on a synthesis across studies, each of which typically includes only measures of a limited number of constructs, and with differing participant characteristics. Firmer conclusions regarding specific phenotypes require a single comprehensive multi-domain assessment of participants with the syndrome groups being well matched on chronological age (CA) and cognitive functioning. The current study was designed to fill this gap by assessing several important cognitive and behavioral domains relevant to communication, such as: structural language skills, false belief understanding, as well as pragmatics and behavioral difficulties, in 30 adolescents of both sexes with DS and 39 males with FXS, matched on CA and nonverbal (NV) cognition. After statistically controlling for NV cognition, we did not find significant syndrome differences in expressive and receptive structural language or false belief understanding. In contrast, participants with DS displayed less stereotyped language and fewer behavioral difficulties compared to males with FXS. Within-syndrome associations among the targeted domains are described. Finally, females with DS were less impaired than males with DS in almost all structural language domains, whereas no significant sex-related differences were observed in NV cognition, false belief understanding, pragmatics, or behavior. Clinical and methodological implications of the findings are discussed

Semantic Verbal Fluency Pattern, Dementia Rating Scores and Adaptive Behavior Correlate With Plasma Aβ Concentrations in Down Syndrome Young Adults

Down syndrome (DS) is an intellectual disability (ID) disorder in which language and specifically, verbal fluency are strongly impaired domains; nearly all adults show neuropathology of Alzheimer's disease (AD), including amyloid deposition by their fifth decade of life. In the general population, verbal fluency deficits are considered a strong AD predictor being the semantic verbal fluency task (SVFT) a useful tool for enhancing early diagnostic. However, there is a lack of information about the association between the semantic verbal fluency pattern (SVFP) and the biological amyloidosis markers in DS. In the current study, we used the SVFT in young adults with DS to characterize their SVFP, assessing total generated words, clustering, and switching. We then explored its association with early indicators of dementia, adaptive behavior and amyloidosis biomarkers, using the Dementia Questionnaire for Persons with Intellectual Disability (DMR), the Adaptive Behavior Assessment System-Second Edition (ABAS-II), and plasma levels of Aβ peptides (Aβ and Aβ), as a potent biomarker of AD. In DS, worse performance in SVFT and poorer communication skills were associated with higher plasma Aβ concentrations, a higher DMR score and impaired communication skills (ABAS-II). The total word production and switching ability in SVFT were good indicators of plasma Aβ concentration. In conclusion, we propose the SVFT as a good screening test for early detection of dementia and amyloidosis in young adults with DS

Using Telehealth-Delivered Procedures to Collect a Parent-Implemented Expressive Language Sampling Narrative Task in Monolingual and Bilingual Families With Autism Spectrum Disorder: A Pilot Study

Language impairments are frequent, severe, and of prognostic value in autism spectrum disorder (ASD). Unfortunately, the evaluation of the efficacy of treatments targeting the language skills of those with ASD continues to be hindered by a lack of psychometrically sound outcome measures. Expressive Language Sampling (ELS) procedures offer a promising alternative to norm-referenced standardized tests for assessing expressive language in treatment studies. Until now, however, research on the validity and utility of ELS as outcome measures has been limited to administrations by a trained professional in a clinic setting and to use with English-speaking families. These limitations are a barrier for many families accessing the benefits of participation in treatment studies. The current study examines the feasibility of teaching native English-speaking parents (NESP) and native Spanish-speaking parents (NSSP) how to administer the ELS narrative task (ELS-N) to their sons and daughters with ASD (between ages 6 and 21) at home through telehealth-delivered procedures. The parent training was provided in the primary language of the participating parent (i.e., 11 NSSP and 11 NESP) and administered by the parent to the youth in the language that the parent reported to use to communicate with the youth at home (i.e., 9 Spanish and 13 English). Families were able to choose between using their own technology or be provided with the technology needed for participation. Of the 19 parents who completed the training, 16 learned to administer the ELS-N procedures. In addition, strong test-retest reliability and no practice effects over the 4-week interval were observed for ELS-N derived youth outcome measures (i.e., talkativeness, vocabulary, syntax, dysfluency, and intelligibility) for both NSSP and NESP. Results from this pilot study suggest that the home-based parent-implemented ELS-N procedures can be learned and administered at acceptable levels of fidelity by parents, with good test-retest reliability and limited practice effects observed in terms of outcome measures for youth with ASD. Implications for treatment studies and future directions are discussed

Building the Future Therapies for Down Syndrome:The Third International Conference of the T21 Research Society

Research focused on Down syndrome has increased in the last several years to advance understanding of the consequences of trisomy 21 (T21) on molecular and cellular processes and, ultimately, on individuals with Down syndrome. The Trisomy 21 Research Society (T21RS) is the premier scientific organization for researchers and clinicians studying Down syndrome. The Third International Conference of T21RS, held June 6-9, 2019, in Barcelona, Spain, brought together 429 scientists, families, and industry representatives to share the latest discoveries on underlying cellular and molecular mechanisms of T21, define cognitive and behavioral challenges and better understand comorbidities associated with Down syndrome, including Alzheimer's disease and leukemia. Presentation of cutting-edge results in neuroscience, neurology, model systems, psychology, cancer, biomarkers and molecular and phar-ma-cological therapeutic approaches demonstrate the compelling interest and continuing advancement in all aspects of understanding and ameliorating conditions associated with T21

Epigallocatechin-3-gallate combined with cognitive training in young adults with Down syndrome Phase II clinical trial: Important considerations for treatment- efficacy evaluation on cognitive and functional improvement

Introducción: El síndrome de Down es un trastorno del neurodesarrollo causado por la trisomía 21 que conduce a una serie de déficits cognitivos y funcionales, un alto riesgo de desarrollo precoz de la enfermedad de Alzheimer y deterioro cognitivo en edades tempranas. Debido a un aumento de la esperanza de vida en el síndrome de Down y a la gran variabilidad a nivel cognitivo existente en esta población, es imprescindible evaluar que posibles factores explicarían estas diferencias. Este conocimiento contribuirá a un diseño más eficiente de aquellos ensayos clínicos que tienen por objetivo evaluar la eficacia de nuevas terapias para la mejora cognitiva y funcional en el síndrome de Down. Objetivos y métodos: Con el fin de detectar posibles factores de confusión en los ensayos clínicos que evalúan las mejoras cognitivas y funcionales asociadas a un nuevo tratamiento en el síndrome de Down, se llevaron a cabo cuatro estudios transversales. Evaluamos la interacción entre biomarcadores (bioquímicos y genéticos), factores del sueño (la calidad del sueño, apnea y roncopatía), el rendimiento cognitivo (la velocidad psicomotora, atención, memoria, función ejecutiva, y el lenguaje) y estado funcional (la conducta adaptativa, la calidad de vida y síntomas tempranos de demencia). Se evaluaron los siguientes biomarcadores: Estudio 1: biomarcadores de amiloidosis (Aß40 y Aß42), Estudio 2: biomarcadores de la función tiroidea (concentraciones de hormona estimulante tiroidea, tiroxina libre y la dosis de T-tiroxina), Estudio 3: el polimorfismo Val158Met de la COMT, y el polimorfismo VNTR de la DAT1 y Estudio 4: el polimorfismo de 5 -HTTLPR. Resultados: En el Estudio 1, una fluencia semántica más pobre, peores habilidades comunicativas y un mayor índice de síntomas tempranos de demencia se asociaron con mayores concentraciones de Aß42 en plasma. En el Estudio 2 se observó que las concentraciones más altas de tiroxina libre (controlando la dosis de L-tiroxina) fueron parcialmente correlacionadas con un mejor rendimiento en memoria, función ejecutiva y atención. Además el hipotiroidismo se asoció con una peor memoria visuoespacial. El Estudio 3 mostró que los portadores del alelo Met de COMTVal158Met y los homocigotos del alelo 10 de VNTR-DAT1 tienen una mejor flexibilidad mental. Los portadores del alelo Met mostraron un comportamiento adaptativo más pobre y un mayor índice de síntomas sociales tempranos de demencia que los homocigotos del alelo Val. Finalmente en el Estudio 4 se observó que una peor calidad de sueño se asoció a los homocigotos del alelo corto de 5-HTTLPR. Con respecto al rendimiento cognitivo, la mala calidad del sueño y la apnea se asociaron a una peor memoria visual. Además la apnea y el ronquido se asociaron con una peor conducta adaptativa, mientras que únicamente la presencia de ronquidos se asoció a un mayor índice de síntomas tempranos de demencia y una mayor proporción Aß42 / Aß40 en plasma. 5-HTTLPR no se asoció con aspectos cognitivos o funcionales. Conclusiones: Las concentraciones plasmáticas de Aß y de tiroxina libre, la dosis de L-tiroxina, la calidad del sueño, la presencia de apnea y ronquidos y los polimorfismos genéticos de la dopamina (COMTVal158Met y VNTR-DAT) son factores de interferencia con el fenotipo cognitivo, conductual y funcional del síndrome de Down. El polimorfismo genético de la serotonina 5-HTTLPR únicamente interfiere en la calidad de sueño de esta población. Por lo tanto, estos factores que explican parte de la variabilidad fenotípica deben considerarse en la visita inicial de todo ensayo clínico que evalúe la eficacia de nuevas terapias para la mejora cognitiva, conductual y /o funcional. Este conocimiento nos permitirá balancear los factores asociados con la variabilidad fenotípica entre grupos de tratamiento para no comprometer la evaluación de la eficacia terapéutica.Introduction: Down syndrome is a neurodevelopmental disorder caused by trisomy 21, which leads to cognitive and functional deficits, high risk for of Alzheimer's disease and cognitive impairment at early ages. Due to the increased life expectancy and the existing large cognitive and functional variability in Down syndrome, it is essential to assess possible factors explaining these differences. This knowledge will contribute to a more efficient design of those clinical trials that aim to evaluate the efficacy of new therapies for cognitive and functional improvement in Down syndrome. Objectives and methods: In order to detect possible confounding factors in the assessment of cognitive and functional improvements in Down syndrome treatment-efficacy clinical trials, four original research cross-sectional studies were performed. We evaluate the interaction between biomarkers (biochemical and genetic) and sleep factors (sleep quality, apnea and snoring disorders), cognitive performance (psychomotor speed, attention, memory, executive function, and language) and functional state (adaptive behavior, quality of life, early symptoms of dementia). The following biomarkers were evaluated: Study 1: amyloidosis biomarkers (Aβ40 and Aβ42), Study2: thyroid function biomarkers (Thyroid Stimulating Hormone, free thyroxine and T-thyroxine dosage), Study 3: COMTVal158Met, VNTR-DAT1 polymorphisms and Study 4: 5-HTTLPR polymorphism. Results: In Study 1, poorer semantic verbal fluency strategies, communication skills and a higher rate of early symptoms of dementia were associated with higher plasma Aβ42 concentrations. In Study 2 we observed that higher concentrations of free thyroxine (controlling for L-thyroxine dosage) were partially correlated with a better performance in memory, executive function and attentional span. Hypothyroidism diagnosis was associated to a poorer visuospatial memory. Study 3 showed that COMTVal158Met Met allele carriers and VNTR-DAT1 10-repeat allele homozygotes displayed an improved mental flexibility. Met allele carriers showed poorer adaptive behavior and a higher rate in early social symptoms of dementia than Val allele homozygotes. Finally in Study 4, we observed that a poorer quality of sleep was associated to 5-HTTLPR Short-allele homozygotes. Regarding cognitive performance, poor sleep quality and apnea were both associated to worse visual memory skills. Furthermore apnea and snoring were associated to a lower performance in adaptive behavior, while only snoring was associated to a higher rate of early dementia symptoms and a higher Aβ42/ Aβ40 ratio in plasma. The 5-HTTLPR was neither associated to cognition, adaptive behavior nor early dementia symptoms. Conclusions: Plasma Aβ concentrations, plasma free thyroxine concentrations, L-thyroxine dosage, sleep quality, apnea and snoring diagnosis and genetic polymorphisms of the dopamine (COMTVal158Met and VNTR-DAT) neurotransmission system are factors of interference with the cognitive, behavioral and functional DS phenotype. Finally, the genetic polymorphism of the serotonin (5-HTTLPR) neurotransmission system does not interfere with cognitive or behavioral aspects, but it does with sleep quality in this population. Thus, these factors, which explain part of the phenotype variability, need to be assessed in the screening visit in the context of a drug-efficacy clinical trial for cognitive, behavioral and/or functional enhancement. In addition, it is recommended to balance those factors associated with phenotype variability across groups of treatment leading to a proper efficacy assessment

Epigallocatechin-3-gallate combined with cognitive training in young adults with Down syndrome Phase II clinical trial: Important considerations for treatment- efficacy evaluation on cognitive and functional improvement

Introducción: El síndrome de Down es un trastorno del neurodesarrollo causado por la trisomía 21 que conduce a una serie de déficits cognitivos y funcionales, un alto riesgo de desarrollo precoz de la enfermedad de Alzheimer y deterioro cognitivo en edades tempranas. Debido a un aumento de la esperanza de vida en el síndrome de Down y a la gran variabilidad a nivel cognitivo existente en esta población, es imprescindible evaluar que posibles factores explicarían estas diferencias. Este conocimiento contribuirá a un diseño más eficiente de aquellos ensayos clínicos que tienen por objetivo evaluar la eficacia de nuevas terapias para la mejora cognitiva y funcional en el síndrome de Down. Objetivos y métodos: Con el fin de detectar posibles factores de confusión en los ensayos clínicos que evalúan las mejoras cognitivas y funcionales asociadas a un nuevo tratamiento en el síndrome de Down, se llevaron a cabo cuatro estudios transversales. Evaluamos la interacción entre biomarcadores (bioquímicos y genéticos), factores del sueño (la calidad del sueño, apnea y roncopatía), el rendimiento cognitivo (la velocidad psicomotora, atención, memoria, función ejecutiva, y el lenguaje) y estado funcional (la conducta adaptativa, la calidad de vida y síntomas tempranos de demencia). Se evaluaron los siguientes biomarcadores: Estudio 1: biomarcadores de amiloidosis (Aß40 y Aß42), Estudio 2: biomarcadores de la función tiroidea (concentraciones de hormona estimulante tiroidea, tiroxina libre y la dosis de T-tiroxina), Estudio 3: el polimorfismo Val158Met de la COMT, y el polimorfismo VNTR de la DAT1 y Estudio 4: el polimorfismo de 5 -HTTLPR. Resultados: En el Estudio 1, una fluencia semántica más pobre, peores habilidades comunicativas y un mayor índice de síntomas tempranos de demencia se asociaron con mayores concentraciones de Aß42 en plasma. En el Estudio 2 se observó que las concentraciones más altas de tiroxina libre (controlando la dosis de L-tiroxina) fueron parcialmente correlacionadas con un mejor rendimiento en memoria, función ejecutiva y atención. Además el hipotiroidismo se asoció con una peor memoria visuoespacial. El Estudio 3 mostró que los portadores del alelo Met de COMTVal158Met y los homocigotos del alelo 10 de VNTR-DAT1 tienen una mejor flexibilidad mental. Los portadores del alelo Met mostraron un comportamiento adaptativo más pobre y un mayor índice de síntomas sociales tempranos de demencia que los homocigotos del alelo Val. Finalmente en el Estudio 4 se observó que una peor calidad de sueño se asoció a los homocigotos del alelo corto de 5-HTTLPR. Con respecto al rendimiento cognitivo, la mala calidad del sueño y la apnea se asociaron a una peor memoria visual. Además la apnea y el ronquido se asociaron con una peor conducta adaptativa, mientras que únicamente la presencia de ronquidos se asoció a un mayor índice de síntomas tempranos de demencia y una mayor proporción Aß42 / Aß40 en plasma. 5-HTTLPR no se asoció con aspectos cognitivos o funcionales. Conclusiones: Las concentraciones plasmáticas de Aß y de tiroxina libre, la dosis de L-tiroxina, la calidad del sueño, la presencia de apnea y ronquidos y los polimorfismos genéticos de la dopamina (COMTVal158Met y VNTR-DAT) son factores de interferencia con el fenotipo cognitivo, conductual y funcional del síndrome de Down. El polimorfismo genético de la serotonina 5-HTTLPR únicamente interfiere en la calidad de sueño de esta población. Por lo tanto, estos factores que explican parte de la variabilidad fenotípica deben considerarse en la visita inicial de todo ensayo clínico que evalúe la eficacia de nuevas terapias para la mejora cognitiva, conductual y /o funcional. Este conocimiento nos permitirá balancear los factores asociados con la variabilidad fenotípica entre grupos de tratamiento para no comprometer la evaluación de la eficacia terapéutica.Introduction: Down syndrome is a neurodevelopmental disorder caused by trisomy 21, which leads to cognitive and functional deficits, high risk for of Alzheimer's disease and cognitive impairment at early ages. Due to the increased life expectancy and the existing large cognitive and functional variability in Down syndrome, it is essential to assess possible factors explaining these differences. This knowledge will contribute to a more efficient design of those clinical trials that aim to evaluate the efficacy of new therapies for cognitive and functional improvement in Down syndrome. Objectives and methods: In order to detect possible confounding factors in the assessment of cognitive and functional improvements in Down syndrome treatment-efficacy clinical trials, four original research cross-sectional studies were performed. We evaluate the interaction between biomarkers (biochemical and genetic) and sleep factors (sleep quality, apnea and snoring disorders), cognitive performance (psychomotor speed, attention, memory, executive function, and language) and functional state (adaptive behavior, quality of life, early symptoms of dementia). The following biomarkers were evaluated: Study 1: amyloidosis biomarkers (Aβ40 and Aβ42), Study2: thyroid function biomarkers (Thyroid Stimulating Hormone, free thyroxine and T-thyroxine dosage), Study 3: COMTVal158Met, VNTR-DAT1 polymorphisms and Study 4: 5-HTTLPR polymorphism. Results: In Study 1, poorer semantic verbal fluency strategies, communication skills and a higher rate of early symptoms of dementia were associated with higher plasma Aβ42 concentrations. In Study 2 we observed that higher concentrations of free thyroxine (controlling for L-thyroxine dosage) were partially correlated with a better performance in memory, executive function and attentional span. Hypothyroidism diagnosis was associated to a poorer visuospatial memory. Study 3 showed that COMTVal158Met Met allele carriers and VNTR-DAT1 10-repeat allele homozygotes displayed an improved mental flexibility. Met allele carriers showed poorer adaptive behavior and a higher rate in early social symptoms of dementia than Val allele homozygotes. Finally in Study 4, we observed that a poorer quality of sleep was associated to 5-HTTLPR Short-allele homozygotes. Regarding cognitive performance, poor sleep quality and apnea were both associated to worse visual memory skills. Furthermore apnea and snoring were associated to a lower performance in adaptive behavior, while only snoring was associated to a higher rate of early dementia symptoms and a higher Aβ42/ Aβ40 ratio in plasma. The 5-HTTLPR was neither associated to cognition, adaptive behavior nor early dementia symptoms. Conclusions: Plasma Aβ concentrations, plasma free thyroxine concentrations, L-thyroxine dosage, sleep quality, apnea and snoring diagnosis and genetic polymorphisms of the dopamine (COMTVal158Met and VNTR-DAT) neurotransmission system are factors of interference with the cognitive, behavioral and functional DS phenotype. Finally, the genetic polymorphism of the serotonin (5-HTTLPR) neurotransmission system does not interfere with cognitive or behavioral aspects, but it does with sleep quality in this population. Thus, these factors, which explain part of the phenotype variability, need to be assessed in the screening visit in the context of a drug-efficacy clinical trial for cognitive, behavioral and/or functional enhancement. In addition, it is recommended to balance those factors associated with phenotype variability across groups of treatment leading to a proper efficacy assessment