Function In Down Syndrome Research Articles

Assessing amyloid PET positivity and cognitive function in Down syndrome to guide clinical trials targeting amyloid.

Trisomy 21, or Down syndrome (DS), predisposes individuals to early-onset Alzheimer's disease (AD). While monoclonal antibodies (mAbs) targeting amyloid are approved for older AD patients, their efficacy in DS remains unexplored. This study examines amyloid positron emission tomography (PET) positivity (A+), memory function, and clinical status across ages in DS to guide mAb trial designs. Cross-sectional data from the Alzheimer Biomarker Consortium-Down Syndrome (ABC-DS) was analyzed. PET amyloid beta in Centiloids classified amyloid status using various cutoffs. Episodic memory was assessed using the modified Cued Recall Test, and clinical status was determined through consensus processes. Four hundred nine DS adults (mean age=44.83 years) were evaluated. A+ rates increased with age, with mean amyloid load rising significantly. Memory decline and cognitive impairment are also correlated with age. These findings emphasize the necessity of tailoring mAb trials for DS, considering age-related AD characteristics. There is rapid increase in prevalence of amyloid beta (Aβ) positron emission tomography (PET) positivity in Down syndrome (DS) after the age of 40 years. Aβ PET positivity thresholds have significant impact on prevalence rates in DS. There is a significant lag between Aβ PET positivity and clinical symptom onset in DS.

Retromer Stabilization Improves Cognitive Function and Synaptic Plasticity in a Mouse Model of Down Syndrome.

Retromer complex proteins are decreased in postmortem brain tissues from Down syndrome subjects and inversely correlate with the Alzheimer's disease-like neuropathology. However, whether targeting in vivo the retromer system affects cognitive deficits and synaptic function in Down syndrome remains unknown. The aim of the current study was to examine the effects of pharmacological retromer stabilization on cognitive and synaptic functions in a mouse model of Down syndrome. Ts65dn mice were administered the pharmacological chaperone, TPT-172, or vehicle from 4 to 9 months of age and then assessed for changes in cognitive function. To assess the effects of TPT-172 on synaptic plasticity, hippocampal slices from Ts65dn mice were incubated in TPT-172 and used for field potential recordings. Chronic TPT-172 treatment improved performance in cognitive function tests, its incubation with hippocampal slices ameliorated synaptic function response. Pharmacological stabilization of the retromer complex improves synaptic plasticity and memory in a mouse model of Down syndrome. These results support the therapeutic potential of pharmacological retromer stabilization for individual with Down syndrome.

Oxidative-Stress-Associated Proteostasis Disturbances and Increased DNA Damage in the Hippocampal Granule Cells of the Ts65Dn Model of Down Syndrome.

Oxidative stress (OS) is one of the neuropathological mechanisms responsible for the deficits in cognition and neuronal function in Down syndrome (DS). The Ts65Dn (TS) mouse replicates multiple DS phenotypes including hippocampal-dependent learning and memory deficits and similar brain oxidative status. To better understand the hippocampal oxidative profile in the adult TS mouse, we analyzed cellular OS-associated alterations in hippocampal granule cells (GCs), a neuronal population that plays an important role in memory formation and that is particularly affected in DS. For this purpose, we used biochemical, molecular, immunohistochemical, and electron microscopy techniques. Our results indicate that TS GCs show important OS-associated alterations in the systems essential for neuronal homeostasis: DNA damage response and proteostasis, particularly of the proteasome and lysosomal system. Specifically, TS GCs showed: (i) increased DNA damage, (ii) reorganization of nuclear proteolytic factories accompanied by a decline in proteasome activity and cytoplasmic aggregation of ubiquitinated proteins, (iii) formation of lysosomal-related structures containing lipid droplets of cytotoxic peroxidation products, and (iv) mitochondrial ultrastructural defects. These alterations could be implicated in enhanced cellular senescence, accelerated aging and neurodegeneration, and the early development of Alzheimer's disease neuropathology present in TS mice and the DS population.

GnRH Therapy may Improve Cognitive Function in Down Syndrome.

GnRH Therapy may Improve Cognitive Function in Down Syndrome.

Contribution of ICTs to the Down Syndrome Children’s Language and Cognitive Development

Down syndrome is considered to be one of the most prevalent genetic causes of intellectual disability, derived from chromosomal disorder, which accounts for dysfunctions in many organs and has a characteristic phenotype, which consists of physical and behavioral features. Many studies have shown that language is one of the most impaired areas of function in Down syndrome and perhaps, the highest barrier for their substantial inclusion into formal education and community. The aim of this paper is to investigate the specific features of this linguistic phenotype, presenting the strengths and weaknesses of their language, as well as the factors that contribute to their formation, compared to normally developing children. In addition, it scopes to highlight the role of educational mobile apps, as innovative and interactive tools for the developmental learning of Down syndrome children. The results of the research indicate that their language goes through the same, with typical development sequences, but progressively erases a slowing trajectory and results in lower performance. However, the use of ICT tools can, significantly, improve language, literacy and sort-term memory skills, but also stimulate their cognitive and fine mobile functioning, in order to upgrade their quality of life.

Digital Games for Down Syndrome Children’s Language and Cognitive Development

Down syndrome is considered to be one of the most prevalent genetic causes of intellectual disability, derived from chromosomal disorder, which accounts for dysfunctions in many organs and has a characteristic phenotype, which consists of physical and behavioral features. Many studies have shown that language is one of the most impaired areas of function in Down syndrome and perhaps, the highest barrier for their substantial inclusion into formal education and community. The aim of this paper is to investigate the specific features of this linguistic phenotype, presenting the strengths and weaknesses of their language, as well as the factors that contribute to their formation, compared to normally developing children. In addition, it scopes to highlight the role of educational mobile apps, as innovative and interactive tools for the developmental learning of Down syndrome children. The results of the research indicate that their language goes through the same, with typical development sequences, but progressively erases a slowing trajectory and results in lower performance. However, the use of digital games, especially virtual reality video games, can, significantly, improve their cognitive and fine mobile functioning and also the acquisition of literacy, language and math skills, in order to upgrade their quality of life.

Language Development and Mobile Apps for Down Syndrome Children

Down syndrome is considered to be one of the most prevalent genetic causes of intellectual disability, derived from chromosomal disorder, which accounts for dysfunctions in many organs and has a characteristic phenotype, which consists of physical and behavioral features. Many studies have shown that language is one of the most impaired areas of function in Down syndrome and perhaps, the highest barrier for their substantial inclusion into formal education and community. The aim of this paper is to investigate the specific features of this linguistic phenotype, presenting the strengths and weaknesses of their language, as well as the factors that contribute to their formation, compared to normally developing children. In addition, it scopes to highlight the role of educational mobile apps, as innovative and interactive tools for the developmental learning of Down syndrome children. The results of the research indicate that their language goes through the same, with typical development sequences, but progressively erases a slowing trajectory and results in lower performance. However, the use of mobile apps can significantly improve their cognitive functioning, in order to acquire academic and social skills that will ensure them an independent and quality life.

A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAA-\u03b15 NAM (basmisanil) on intellectual disability associated with Down syndrome

BackgroundThere are currently no pharmacological therapies to address the intellectual disability associated with Down syndrome. Excitatory/inhibitory imbalance has been hypothesized to contribute to impairments in cognitive functioning in Down syndrome. Negative modulation of the GABAA-α5 receptor is proposed as a mechanism to attenuate GABAergic function and restore the excitatory/inhibitory balance.MethodsBasmisanil, a selective GABAA-α5 negative allosteric modulator, was evaluated at 120 mg or 240 mg BID (80 or 160 mg for 12–13 years) in a 6-month, randomized, double-blind, placebo-controlled phase II trial (Clematis) for efficacy and safety in adolescents and young adults with Down syndrome. The primary endpoint was based on a composite analysis of working memory (Repeatable Battery for the Assessment of Neuropsychological Scale [RBANS]) and independent functioning and adaptive behavior (Vineland Adaptive Behavior Scales [VABS-II] or the Clinical Global Impression-Improvement [CGI-I]). Secondary measures included the Behavior Rating Inventory of Executive Functioning-Preschool (BRIEF-P), Clinical Evaluation of Language Fundamentals (CELF-4), and Pediatric Quality of Life Inventory (Peds-QL). EEG was conducted for safety monitoring and quantitatively analyzed in adolescents.ResultsBasmisanil was safe and well-tolerated; the frequency and nature of adverse events were similar in basmisanil and placebo arms. EEG revealed treatment-related changes in spectral power (increase in low ~ 4-Hz and decrease in high ~ 20-Hz frequencies) providing evidence of functional target engagement. All treatment arms had a similar proportion of participants showing above-threshold improvement on the primary composite endpoint, evaluating concomitant responses in cognition and independent functioning (29% in placebo, 20% in low dose, and 25% in high dose). Further analysis of the individual measures contributing to the primary endpoint revealed no difference between placebo and basmisanil-treated groups in either adolescents or adults. There were also no differences across the secondary endpoints assessing changes in executive function, language, or quality of life.ConclusionsBasmisanil did not meet the primary efficacy objective of concomitant improvement on cognition and adaptive functioning after 6 months of treatment, despite evidence for target engagement. This study provides key learnings for future clinical trials in Down syndrome.Trial registrationThe study was registered on December 31, 2013, at clinicaltrials.gov as NCT02024789.

Infant precursors of executive function in Down syndrome.

Although early features of infant cognition are predictive of executive function (EF) in typically developing (TD) children, there is little information regarding the developmental origins of EF in neurogenetic conditions, such as Down syndrome (DS). The current study compared the performance of infants with and without DS on three dimensions that are hypothesised EF precursors: visual engagement, attention shifting and action planning. Additionally, the relationship between these EF precursors at Time 1 and EF performance at Time 2 (6months later) was examined in the DS group. Participants were 36 infants with DS, M chronological age=12.65months, SD=2.11; M developmental age=8.84months, SD=2.22, and 36 TD infants, M chronological age=8.62, SD=3.06; M developmental age=8.64months, SD=3.40. Infants with DS visually engaged with objects for longer durations and demonstrated challenges with action planning compared with TD infants at Time 1. Attention shifting at Time 1 significantly predicted EF performance at Time 2 in the DS group. This study provides evidence that an early atypical presentation of EF precursors is detectable during infancy in DS and is predictive of subsequent EF performance. These findings contribute to the identification of areas of early cognitive risk in DS and can inform future interventions in this population.

New Functions in Down Syndrome

New Functions in Down Syndrome

A Representational Approach to Executive Function Impairments in Young Adults with Down Syndrome

ABSTRACT Based on a representational perspective, this paper examines executive functioning in Down syndrome. Sixteen young adults with Down syndrome, 16 mental age- and 16 age-matched controls were compared on script sequencing and sorting tasks. Participants were asked to reestablish the sequential structure of script actions given with or without irrelevant actions. Impairments in script information processing were observed only in young adults with Down syndrome, who performed more slowly than controls, making mistakes in ordering actions, but rejecting aberrant elements. These data are consistent with the view that Down syndrome impairs the syntactic but not semantic dimension of script representation.

Bite Force and Occlusal Patterns in the Mixed Dentition of Children with Down Syndrome.

Oral function in Down Syndrome (DS) patients has been of interest to clinicians and researchers. This study aimed to evaluate the parameters of occlusal force and pattern of children with Down syndrome (DS) during mixed dentition when compared to age and gender-matched controls. Thirty DS and 30 healthy children, aged 7 to 12 years, participated in the evaluation of the parameters of the occlusal pattern and occlusal force distribution analysis. Both groups underwent clinical examination, occlusal force and pattern measurements using a computerized occlusal analysis system (T-Scan 8 occlusal analysis, Tekscan, Inc., S. Boston, MA). Occlusion time, percentage of force distribution, force outliers, center of force target area, center of force trajectory and evaluation of closure arc were compared between the two groups using the Pearson's Chi Square test. Children with DS had more occlusal and vertical malocclusion compared to the control group (p < 0.001). The occlusion time for DS group (0.75 ± 0.7s) was significantly longer than the control group (0.015 ± 0.05s) (p < 0.001). The closure arc for DS group was mostly irregular (53%), while the control group showed ideal closure arc. In control group, the age had a significant influence on the occlusion time, while height, weight, and BMI had a significant influence on the mouth opening. None of these variables had such effect on children with DS. The results of this study showed high prevalence of orofacial dysfunction among DS population. The occlusal analysis showed that children with DS had longer occlusion time and a lack of ideal occlusion pattern compared to age matched controls.

Evaluation of the masticatory biomechanical function in Down syndrome and its Influence on sleep disorders, body adiposity and salivary parameters

To evaluate the phenotypic features of the masticatory biomechanics in atypical subjects with Down syndrome (DS). Its influence was analysed on sleep disorders, body adiposity and its risks, and some physicochemical properties of saliva. Seventy subjects were enrolled to assess masticatory biomechanical function and divided into two groups: DS and control groups. Electrical activities of the masseter and temporal muscles (at rest and in maximum voluntary clench-MVC), maximum bite force-MBF and maximum mouth opening-MMO were investigated. Among the atypical subjects, just 24 participants underwent the anthropometry, the polysomnography II and the saliva testing (salivary flow rate-SFR, buffer capacity-BC and salivary cortisol levels, morning/SC-AM and night/SC-PM). MVC and MBF values showed high statistical significance in the control group (P<.001) than in the DS group of 35. MMO values were slightly increased in the DS group in relation to the control group. Overweight and obesity were found in both genders. Atypical women showed higher risk to develop cardiovascular-metabolic diseases than in atypical men. OSA severe was 20% for atypical women and 42.8% for atypical men, whereas snoring index was present in all genders. SFR was reduced in 100% of atypical subjects (hyposalivation in 10% women and 28.5% men). Furthermore, 100% BC, 66.6% SC-AM and 91.6% SC-PM showed normal patterns. Masseter and temporal muscle hypotonia was found in all atypical subjects with DS. This muscle dysfunction strongly was related to overweight/obesity, risks for development of cardiovascular/metabolic diseases, OSA severity, successive snoring episodes and salivary flow reduction in DS.

High Thyroid-stimulating Hormone Level in Down's Syndrome: A Mere Resetting of Hypothalamopituitary Axis in Subclinical Hypothyroidism?

Objective:Hyperthyrotropinemia (HT) or reduced thyroid function in Down syndrome (DS) is not uncommon, causes range from glandular dysgenesis to altered hypothalamopituitary axis. In the present study, we have compared hypothyroid Indian children with and without DS (NDS), especially focusing on family history, goiter, and biochemical features.Methods:We conducted this retrospective observational study from previous medical records of children with DS (1-17 years) having an elevated TSH (≥5 mIU/L) who were consecutively referred for with HT to Endocrinology OPD of a tertiary care hospital in India. Records from hypothyroid children (1-17 years) without Down Syndrome (NDS) were evaluated as controls. Free thyroxine (FT4), anti-thyroid peroxidase (TPO) antibody were measured and congenital hypothyroidism was excluded in all subjects.Results:Thirty-four DS cases [median age 8 years (IQR: 2-14), M: F = 13:21] and 34 controls [median age 10.5 years (IQR: 7-13.25), M: F = 13:21] were comparable in terms of age and sex, Median age of presentation was significantly earlier in case of DS vs NDS [7 years vs. 10 years]. DS children had significantly less family history of thyroid disorders compared to NDS [14.7% vs 64.7%]. Goiter was significantly less common in patients with DS [DS - 32.25% vs. NDS - 73.5%, P = 0.001]. Anti-TPO antibody positivity was significantly less common in patients with DS [DS- 41% vs. NDS- 73.5%, P = 0.014].Conclusion:There is a significant difference in presentation in hypothyroid children with DS compared to NDS. DS children with hypothyroidism compared to NDS, had earlier presentation, lower incidence of traceable family history, goiter, and anti-TPO-antibody positivity.

Modeling the Relations Among Sustained Attention, Short-Term Memory, and Language in Down Syndrome.

Sustained attention (SA) and short-term memory (STM) contribute to language function in Down syndrome (DS). We proposed models in which relations of SA to language in DS are mediated by STM. Thirty-seven youth with DS aged 10-22 years (M = 15.59) completed SA, STM, and language tasks. Cross-sectional mediation analyses were run with the bootstrapping method. We found significant indirect effects of SA separately on vocabulary and syntax through auditory STM with point estimates of -.30 and -.31, respectively. Results suggest lapses in SA compromise auditory STM, which in turn impacts vocabulary and syntax in youth with DS; however, further research is needed to confirm causality. Addressing SA and STM in language therapy with youth with DS could lead to improved outcomes.

A Novel Framework to Measure Executive Function in Down Syndrome With Applications for Early Clinical Diagnosis of Dementia.

Executive function (EF) decline is a consistent early sign of Alzheimer's disease (AD) among adults with Down syndrome (DS), which means that baseline measures of EF for individuals with DS are vital to allow detection of meaningful decline. We developed a framework to extract measures of three core components of EF (memory updating, inhibitory, and temporal components) within one task. Increases in memory load, inhibitory load, and temporal demands led to significant increases in reaction times and significant decreases in accuracy among 18 adults with DS and 18 typically developing matched individuals; thus, the expected effects of all three manipulations were detected. Good test-retest reliability indicated that this framework has the potential to provide a simple, baseline EF measure for individuals with DS.

Pharmacological interventions to improve cognition and adaptive functioning in Down syndrome: Strides to date.

Although an increasing number of clinical trials have been developed for cognition in Down syndrome, there has been limited success to date in identifying effective interventions. This review describes the progression from pre-clinical studies with mouse models to human clinical trials research using pharmacological interventions to improve cognition and adaptive functioning in Down syndrome. We also provide considerations for investigators when conducting human clinical trials and describe strategies for the pharmaceutical industry to advance the field in drug discovery for Down syndrome. Future research focusing on earlier pharmaceutical interventions, development of appropriate outcome measures, and greater collaboration between industry, academia, advocacy, and regulatory groups will be important for addressing limitations from prior studies and developing potential effective interventions for cognition in Down syndrome.

A cross-sectional analysis of executive function in Down syndrome from 2 to 35years.

Previous research has indicated a unique profile of executive function (EF) in children and adolescents with Down syndrome (DS). However, there is a paucity of research on EF in adults with DS. This study aimed to gain a broader understanding of strengths and weaknesses in EF in DS from 2 to 35years. Parents of 112 individuals with DS between 2 and 35years participated in this study. Parents either completed the Behaviour Rating Inventory of Executive Function - for individuals 6+years - or the Behaviour Rating Inventory of Executive Function Preschool Version - for children 2-5years. Results suggest not only overall difficulties but also patterns of strength and weakness within EF for individuals with DS. For the 2 to 5-year-old group, emotional control and shift were relative strengths, planning/organisation and inhibit were intermediate skills, and working memory was a relative weakness. For the 6 to 18-year-old group, emotional control and organisation of materials were relative strengths, inhibit and initiate were intermediate skills, and working memory, monitor, planning/organisation, and shift were relative weaknesses. Most abilities were consistent from 2 to 18years, except shift, which decreased in preadolescence before beginning to recover in adolescence. Across the full age range (2-35years), composite scores indicated quadratic trends in inhibit, working memory, and planning/organisation, and a cubic trend in shift, with EF abilities generally declining in middle childhood before recovering in adulthood. This study extends previous research on EF in DS by providing an initial description of EF profiles across the lifespan. More longitudinal and behavioural research is needed to further characterise the development of EF in DS.

Impact of maladaptive behavior on school function in Down syndrome

Background/aimsIndividuals 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 proceduresParticipants 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. ResultsFindings 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 implicationsResults underscore the importance of developing training for educators regarding the potential impact of maladaptive behavior on school function for students with Down syndrome.

Everyday executive functions in Down syndrome from early childhood to young adulthood: evidence for both unique and shared characteristics compared to youth with sex chromosome trisomy (XXX and XXY).

Executive functions (EF) are thought to be impaired in Down syndrome (DS) and sex chromosome trisomy (Klinefelter and Trisomy X syndromes; +1X). However, the syndromic specificity and developmental trajectories associated with EF difficulties in these groups are poorly understood. The current investigation (a) compared everyday EF difficulties in youth with DS, +1X, and typical development (TD); and (b) examined relations between age and EF difficulties in these two groups and a TD control group cross-sectionally. Study 1 investigated the syndromic specificity of EF profiles on the Behavior Rating Inventory of Executive Function (BRIEF) in DS (n = 30), +1X (n = 30), and a TD group (n = 30), ages 5–18 years. Study 2 examined age effects on EF in the same cross-sectional sample of participants included in Study 1. Study 3 sought to replicate Study 2's findings for DS by examining age-EF relations in a large independent sample of youth with DS (n = 85) and TD (n = 43), ages 4–24 years. Study 1 found evidence for both unique and shared EF impairments for the DS and +1X groups. Most notably, youth with +1X had relatively uniform EF impairments on the BRIEF scales, while the DS group showed an uneven BRIEF profile with relative strengths and weaknesses. Studies 2 and 3 provided support for fairly similar age-EF relations in the DS and TD groups. In contrast, for the +1X group, findings were mixed; 6 BRIEF scales showed similar age-EF relations to the TD group and 2 showed greater EF difficulties at older ages for +1X. These findings will be discussed within the context of efforts to identify syndrome specific cognitive-behavioral profiles for youth with different genetic syndromes in order to inform basic science investigations into the etiology of EF difficulties in these groups and to develop treatment approaches that are tailored to the needs of these groups.