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Background: People with Down syndrome (DS) show clinical signs of accelerated ageing. Causative mechanisms remain unknown and hypotheses range from the (essentially untreatable) amplified-chromosomal-instability explanation, to potential actions of individual supernumerary chromosome-21 genes. The latter explanation could open a route to therapeutic amelioration if the specific over-acting genes could be identified and their action toned-down., Methods: Biological age was estimated through patterns of sugar molecules attached to plasma immunoglobulin-G (IgG-glycans, an established "biological-ageing-clock") in n = 246 individuals with DS from three European populations, clinically characterised for the presence of co-morbidities, and compared to n = 256 age-, sex- and demography-matched healthy controls. Isogenic human induced pluripotent stem cell (hiPSCs) models of full and partial trisomy-21 with CRISPR-Cas9 gene editing and two kinase inhibitors were studied prior and after differentiation to cerebral organoids., Findings: Biological age in adults with DS is (on average) 18.4-19.1 years older than in chronological-age-matched controls independent of co-morbidities, and this shift remains constant throughout lifespan. Changes are detectable from early childhood, and do not require a supernumerary chromosome, but are seen in segmental duplication of only 31 genes, along with increased DNA damage and decreased levels of LaminB1 in nucleated blood cells. We demonstrate that these cell-autonomous phenotypes can be gene-dose-modelled and pharmacologically corrected in hiPSCs and derived cerebral organoids. Using isogenic hiPSC models we show that chromosome-21 gene DYRK1A overdose is sufficient and necessary to cause excess unrepaired DNA damage., Interpretation: Explanation of hitherto observed accelerated ageing in DS as a developmental progeroid syndrome driven by DYRK1A overdose provides a target for early pharmacological preventative intervention strategies., Funding: Main funding came from the "Research Cooperability" Program of the Croatian Science Foundation funded by the European Union from the European Social Fund under the Operational Programme Efficient Human Resources 2014-2020, Project PZS-2019-02-4277, and the Wellcome Trust Grants 098330/Z/12/Z and 217199/Z/19/Z (UK). All other funding is described in details in the "Acknowledgements"., Competing Interests: Declaration of interests GL is the founder and owner of Genos Ltd., a private research organisation that specialises in high-throughput glycomic analyses and has several patents in this field and is also a shareholder in GlycanAge Ltd., a company that sells the GlycanAge test of biological age. AC, FV, JJ, MPB, ASla, HD, AF, DP and JK are employees of Genos Ltd. AStr has served on the Advisory Boards of AC Immune and ProMIS Neuroscience, and is a past president of the Trisomy21 Research Society. TS is the scientific co-founder and a shareholder of Zoe Ltd., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Typically developing (TD) infants adapt to the social world in part by shifting the focus of their processing resources to the relevant aspects of a visual scene. Any impairment in visual orienting may therefore constrain learning and development in domains such as language. However, although something is known about visual orienting in infants at risk of autism, very little is known about it in infants/toddlers with other neurodevelopmental disorders. This is partly because previous studies focused on older children and rarely compared the children to both chronological age (CA)- and mental age (MA)-matched TD controls. Yet, if visual orienting is important for learning and development, then it is imperative to investigate it early in development and ascertain whether it relates to higher level cognitive functions such as language. We used eye-tracking technology to directly compare visual orienting in infants/toddlers with one of three neurodevelopmental disorders-Down syndrome (DS), fragile X syndrome (FXS) and Williams syndrome (WS)-matched on CA or MA to TD controls (~15 months). We also measured language ability using the Mullen Scales of Early Learning (MSEL). We found that the ability to disengage attention from a visual stimulus in order to shift it to another visual stimulus is related to language ability in infants/toddlers irrespective of group affiliation. We also found that, contrary to the literature, infants and toddlers with DS (but not WS) are slow at disengaging attention. Our data suggest that orienting attention constrains language development and is impaired in DS., (© 2020 John Wiley & Sons Ltd.)

In this article, we focus on the causes of individual differences in Down syndrome (DS), exemplifying the multi-level, multi-method, lifespan developmental approach advocated by Karmiloff-Smith (1998, 2009, 2012, 2016). We evaluate the possibility of linking variations in infant and child development with variations in the (elevated) risk for Alzheimer's disease (AD) in adults with DS. We review the theoretical basis for this argument, considering genetics, epigenetics, brain, behaviour and environment. In studies 1 and 2, we focus on variation in language development. We utilise data from the MacArthur-Bates Communicative Development Inventories (CDI; Fenson et al., 2007), and Mullen Scales of Early Learning (MSEL) receptive and productive language subscales (Mullen, 1995) from 84 infants and children with DS (mean age 2;3, range 0;7 to 5;3). As expected, there was developmental delay in both receptive and expressive vocabulary and wide individual differences. Study 1 examined the influence of an environmental measure (socio-economic status as measured by parental occupation) on the observed variability. SES did not predict a reliable amount of the variation. Study 2 examined the predictive power of a specific genetic measure (apolipoprotein APOE genotype) which modulates risk for AD in adulthood. There was no reliable effect of APOE genotype, though weak evidence that development was faster for the genotype conferring greater AD risk (ε4 carriers), consistent with recent observations in infant attention (D'Souza, Mason et al., 2020). Study 3 considered the concerted effect of the DS genotype on early brain development. We describe new magnetic resonance imaging methods for measuring prenatal and neonatal brain structure in DS (e.g., volumes of supratentorial brain, cortex, cerebellar volume; Patkee et al., 2019). We establish the methodological viability of linking differences in early brain structure to measures of infant cognitive development, measured by the MSEL, as a potential early marker of clinical relevance. Five case studies are presented as proof of concept, but these are as yet too few to discern a pattern., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Importance: Risk of Alzheimer disease (AD) is particularly high for individuals with Down syndrome (DS). The ε4 allele of the apolipoprotein E gene (APOE ε4) is associated with an additional risk for AD. In typical development, there is evidence that the APOE ε4 genotype is associated with an early cognitive advantage. Here we investigate associations of APOE ε4 with attention across the life span of individuals with DS., Objective: To investigate associations between APOE ε4 and attentional abilities in young children and in adults with DS., Design, Settings, and Participants: In this cross-sectional study, data were collected from 80 young children with DS (8-62 months of age) and 240 adults with DS (16-71 years of age) during the period from 2013 to 2018 at a research center to examine the association between APOE status (ε4 carrier vs ε4 noncarrier) and attentional abilities., Exposure: APOE status (ε4 carrier vs ε4 noncarrier)., Main Outcomes and Measures: For the children, attentional ability was assessed using an eye-tracking paradigm, the gap-overlap task; the size of the gap effect was the primary outcome. For the adults, attentional ability was assessed using the CANTAB simple reaction time task; the standard deviation of response time latencies was the primary outcome. Cross-sectional developmental trajectories were constructed linking attentional ability with age in ε4 carriers and ε4 noncarriers for children and adults separately., Results: The child sample comprised 23 ε4 carriers and 57 ε4 noncarriers. The adult sample comprised 61 ε4 carriers and 179 ε4 noncarriers. For the children, a significant difference between trajectory intercepts (ηp2 = 0.14) indicated that ε4 carriers (B = 100.24 [95% CI, 18.52-181.96]) exhibited an attentional advantage over ε4 noncarriers (B = 314.78 [95% CI, 252.17-377.39]). There was an interaction between APOE status and age (ηp2 = 0.10); while the gap effect decreased with age for ε4 noncarriers (B = -4.58 [95% CI, -6.67 to -2.48]), reflecting the development of the attention system, there was no change across age in ε4 carriers (B = 0.77 [95% CI, -1.57 to 3.12]). For the adults, there was no main effect of ε4 carrier status, but there was an interaction between APOE status and age (B = 0.02 [95% CI, 0.004-0.07]), so that ε4 carriers had poorer attentional ability than ε4 noncarriers at older ages., Conclusions and Relevance: APOE ε4 is associated with an attentional advantage early in development and a disadvantage later in life for individuals with DS, similar to the pattern reported in typical development. Understanding the differential role of APOE across the life span is an important step toward future interventions.

Background: Children with Down syndrome (DS) are at increased likelihood of Autism Spectrum Disorder (ASD) relative to the general population. To better understand the nature of this comorbidity, we examined the visuo-attentional processes associated with autistic trait expression in children with DS, focusing specifically on attentional disengagement and visual search performance., Method: We collected eye-tracking data from children with DS (n = 15) and children with idiopathic ASD (iASD, n = 16) matched according to chronological age. Seven children with DS had a formal clinical diagnosis of ASD (DS+ASD)., Results: In children with iASD, but not DS, higher autistic trait levels were associated with decreased temporal facilitation on a gap-overlap task, implying increased visuospatial orienting efficiency. In all cases, higher autistic trait levels were associated with improved visual search performance according to decreased target detection latency. On a visual search task, children with DS+ASD outperformed their peers with DS-ASD, mirroring the phenotypic advantage associated with iASD. We found no evidence of a relationship between attentional disengagement and visual search performance, providing preliminary evidence of a differentiation in terms of underlying visuo-attentional mechanism., Conclusion: We illustrate the value of progressing beyond insensitive behavioural measures of phenotypic description to examine, in a more fine-grained way, the attentional features associated with ASD comorbidity in children with DS., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Birkbeck College, University of London. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Down syndrome (DS) is often characterised by intellectual disability with particular difficulties in expressive language. However, large individual differences exist in expressive language across development in DS. In the general population, one of the factors associated with variability in this domain is parental depression. We investigated whether this is also the case in young children with DS., Methods: Thirty-eight children with DS between 8 and 48 months of age participated in this study. Their parents reported on the children's receptive and expressive vocabularies (MacArthur-Bates Communicative Development Inventory) and on parental depression. Furthermore, an experimenter-led standardized developmental assessment (Mullen Scales of Early Learning) was administered to the children to test five domains: gross motor, fine motor, visual reception, receptive language, and expressive language., Results: A cross-sectional developmental trajectories analysis demonstrated that expressive language developed at a slower rate in children with DS whose parent reported depression than in those whose parent did not. No differences between groups were found in any other domain., Conclusion: Parental depression is associated with slower rate of expressive language development in young children with DS. These findings suggest that DS and parental depression may constitute a double hit leading to increased difficulties in the development of expressive language., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This cross-syndrome study focuses on sleep and its relationship with language development. Children with neurodevelopmental disorders present with language delay. Typical language development is constrained by numerous factors including sleep. Sleep is often disrupted in adolescents/adults with neurodevelopmental disorders. We therefore hypothesised that sleep may be disrupted, and correlate with language development, in infants/toddlers with neurodevelopmental disorders. To test our hypothesis, we obtained sleep and vocabulary size data from 75 infants/toddlers with one of three neurodevelopmental disorders (Down syndrome [DS], fragile X syndrome [FXS], Williams syndrome [WS]). Sleep was indeed disrupted in these children. It was also positively associated with receptive vocabulary size in the infants/toddlers with DS and WS (we could not test the relationship between sleep and language in FXS due to lack of power). We argue that disrupted sleep may be a common occurrence in very young children with neurodevelopmental disorders, and it may relate to their ability to acquire their first language., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Down syndrome (DS) is associated with variable intellectual disability and multiple health and psychiatric comorbidities. The impact of such comorbidities on cognitive outcomes is unknown. We aimed to describe patterns of physical health and psychiatric comorbidity prevalence, and receptive language ability, in DS across the lifespan, and determine relationships with cognitive outcomes., Methods: Detailed medical histories were collected and cognitive abilities measured using standardised tests for 602 individuals with DS from England and Wales (age range 3 months to 73 years). Differences in prevalence rates between age groups and between males and females were determined using chi-squared or Fisher's exact tests. In adults, rates for psychiatric comorbidities were compared to expected population rates using standardised morbidity ratios (SMRs). Adapted ANCOVA functions were constructed to explore age and sex associations with receptive language ability across the lifespan, and regression analyses were performed to determine whether the presence of health comorbidities or physical phenotypes predicted cognitive abilities., Results: Multiple comorbidities showed prevalence differences across the lifespan, though there were few sex differences. In adults, SMRs were increased in males and decreased in females with DS for schizophrenia, bipolar disorder, and anxiety. Further, SMRs were increased in both males and females with DS for dementia, autism, ADHD, and depression, with differences more pronounced in females for dementia and autism, and in males for depression. Across the lifespan, receptive language abilities increasingly deviated from age-typical levels, and males scored poorer than females. Only autism and epilepsy were associated with poorer cognitive ability in those aged 16-35 years, with no relationships for physical health comorbidities, including congenital heart defects., Conclusions: Our results indicate the prevalence of multiple comorbidities varies across the lifespan in DS, and in adults, rates for psychiatric comorbidities show different patterns for males and females relative to expected population rates. Further, most health comorbidities are not associated with poorer cognitive outcomes in DS, apart from autism and epilepsy. It is essential for clinicians to consider such differences to provide appropriate care and treatment for those with DS and to provide prognostic information relating to cognitive outcomes in those with comorbidities.

In order to understand how language abilities emerge in typically and atypically developing infants and toddlers, it is important to embrace complexity in development. In this paper, we describe evidence that early language development is an experience-dependent process, shaped by diverse, interconnected, interdependent developmental mechanisms, processes, and abilities (e.g. statistical learning, sampling, functional specialization, visual attention, social interaction, motor ability). We also present evidence from our studies on neurodevelopmental disorders (e.g. Down syndrome, fragile X syndrome, Williams syndrome) that variations in these factors significantly contribute to language delay. Finally, we discuss how embracing complexity, which involves integrating data from different domains and levels of description across developmental time, may lead to a better understanding of language development and, critically, lead to more effective interventions for cases when language develops atypically.

Typically-developing (TD) infants can construct unified cross-modal percepts, such as a speaking face, by integrating auditory-visual (AV) information. This skill is a key building block upon which higher-level skills, such as word learning, are built. Because word learning is seriously delayed in most children with neurodevelopmental disorders, we assessed the hypothesis that this delay partly results from a deficit in integrating AV speech cues. AV speech integration has rarely been investigated in neurodevelopmental disorders, and never previously in infants. We probed for the McGurk effect, which occurs when the auditory component of one sound (/ba/) is paired with the visual component of another sound (/ga/), leading to the perception of an illusory third sound (/da/ or /tha/). We measured AV integration in 95 infants/toddlers with Down, fragile X, or Williams syndrome, whom we matched on Chronological and Mental Age to 25 TD infants. We also assessed a more basic AV perceptual ability: sensitivity to matching vs. mismatching AV speech stimuli. Infants with Williams syndrome failed to demonstrate a McGurk effect, indicating poor AV speech integration. Moreover, while the TD children discriminated between matching and mismatching AV stimuli, none of the other groups did, hinting at a basic deficit or delay in AV speech processing, which is likely to constrain subsequent language development., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Typically developing (TD) infants enhance their learning of spoken language by observing speakers' mouth movements. Given the fact that word learning is seriously delayed in most children with neurodevelopmental disorders, we hypothesized that this delay partly results from differences in visual face scanning, e.g., focusing attention away from the mouth. To test this hypothesis, we used an eye tracker to measure visual attention in 95 infants and toddlers with Down syndrome (DS), fragile X syndrome (FXS), and Williams syndrome (WS), and compared their data to 25 chronological- and mental-age matched 16-month-old TD controls. We presented participants with two talking faces (one on each side of the screen) and a sound (/ga/). One face (the congruent face) mouthed the syllable that the participants could hear (i.e., /ga/), while the other face (the incongruent face) mouthed a different syllable (/ba/) from the one they could hear. As expected, we found that TD children with a relatively large vocabulary made more fixations to the mouth region of the incongruent face than elsewhere. However, toddlers with FXS or WS who had a relatively large receptive vocabulary made more fixations to the eyes (rather than the mouth) of the incongruent face. In DS, by contrast, fixations to the speaker's overall face (rather than to her eyes or mouth) predicted vocabulary size. These findings suggest that, at some point in development, different processes or strategies relating to visual attention are involved in language acquisition in DS, FXS, and WS. This knowledge may help further explain why language is delayed in children with neurodevelopmental disorders. It also raises the possibility that syndrome-specific interventions should include an early focus on efficient face-scanning behaviour.