Pharmacological Modulation of Three Modalities of CA1 Hippocampal Long-Term Potentiation in the Ts65Dn Mouse Model of Down Syndrome.

The Ts65Dn mouse is the most studied animal model of Down syndrome. Past research has shown a significant reduction in CA1 hippocampal long-term potentiation (LTP) induced by theta-burst stimulation (TBS), but not in LTP induced by high-frequency stimulation (HFS), in slices from Ts65Dn mice compared with euploid mouse-derived slices. Additionally, therapeutically relevant doses of the drug memantine were shown to rescue learning and memory deficits in Ts65Dn mice. Here, we observed that 1 µM memantine had no detectable effect on HFS-induced LTP in either Ts65Dn- or control-derived slices, but it rescued TBS-induced LTP in Ts65Dn-derived slices to control euploid levels. Then, we assessed LTP induced by four HFS (4xHFS) and found that this form of LTP was significantly depressed in Ts65Dn slices when compared with LTP in euploid control slices. Memantine, however, did not rescue this phenotype. Because 4xHFS-induced LTP had not yet been characterized in Ts65Dn mice, we also investigated the effects of picrotoxin, amyloid beta oligomers, and soluble recombinant human prion protein (rPrP) on this form of LTP. Whereas ≥10 µM picrotoxin increased LTP to control levels, it also caused seizure-like oscillations. Neither amyloid beta oligomers nor rPrP had any effect on 4xHFS-induced LTP in Ts65Dn-derived slices.

Soluble prion protein and its N-terminal fragment prevent impairment of synaptic plasticity by Aß oligomers: Implications for novel therapeutic strategy in Alzheimer's disease.

The pathogenic process in Alzheimer's disease (AD) appears to be closely linked to the neurotoxic action of amyloid-ß (Aß) oligomers. Recent studies have shown that these oligomers bind with high affinity to the membrane-anchored cellular prion protein (PrP(C)). It has also been proposed that this binding might mediate some of the toxic effects of the oligomers. Here, we show that the soluble (membrane anchor-free) recombinant human prion protein (rPrP) and its N-terminal fragment N1 block Aß oligomers-induced inhibition of long-term potentiation (LTP) in hippocampal slices, an important surrogate marker of cognitive deficit associated with AD. rPrP and N1 are also strikingly potent inhibitors of Aß cytotoxicity in primary hippocampal neurons. Furthermore, experiments using hippocampal slices and neurons from wild-type and PrP(C) null mice (as well as rat neurons in which PrP(C) expression was greatly reduced by gene silencing) indicate that, in contrast to the impairment of synaptic plasticity by Aß oligomers, the cytotoxic effects of these oligomers, and the inhibition of these effects by rPrP and N1, are independent of the presence of endogenous PrP(C). This suggests fundamentally different mechanisms by which soluble rPrP and its fragments inhibit these two toxic responses to Aß. Overall, these findings provide strong support to recent suggestions that PrP-based compounds may offer new avenues for pharmacological intervention in AD.

Protein profiles associated with context fear conditioning and their modulation by memantine.

Analysis of the molecular basis of learning and memory has revealed details of the roles played by many genes and the proteins they encode. Because most individual studies focus on a small number of proteins, many complexities of the relationships among proteins and their dynamic responses to stimulation are not known. We have used the technique of reverse phase protein arrays (RPPA) to assess the levels of more than 80 proteins/protein modifications in subcellular fractions from hippocampus and cortex of mice trained in Context Fear Conditioning (CFC). Proteins include components of signaling pathways, several encoded by immediate early genes or involved in apoptosis and inflammation, and subunits of glutamate receptors. At one hour after training, levels of more than half the proteins had changed in one or more fractions, among them multiple components of the Mitogen-activated protein kinase, MAPK, and Mechanistic Target of Rapamycin, MTOR, pathways, subunits of glutamate receptors, and the NOTCH pathway modulator, NUMB homolog (Drosophila). Levels of 37 proteins changed in the nuclear fraction of hippocampus alone. Abnormalities in levels of thirteen proteins analyzed have been reported in brains of patients with Alzheimer's Disease. We therefore further investigated the protein profiles of mice treated with memantine, a drug approved for treatment of AD. In hippocampus, memantine alone induced many changes similar to those seen after CFC and altered the levels of seven proteins associated with Alzheimer's Disease abnormalities. Lastly, to further explore the relevance of these datasets, we superimposed responses to CFC and memantine onto components of the long term potentiation pathway, a process subserving learning and memory formation. Fourteen components of the long term potentiation pathway and 26 proteins interacting with components responded to CFC and/or memantine. Together, these datasets provide a novel view of the diversity and complexity in protein responses and interactions following normal learning.

Emergence of Treadmill Running Ability and Quantitative Assessment of Gait Dynamics in Young Ts65Dn Mice: A Mouse Model for Down Syndrome.

Down syndrome (DS), which results from the complete or partial trisomy of chromosome 21 (trisomy-21), is the most common genetically defined cause of intellectual disability. Trisomy-21 also produces, or is associated with, many neurodevelopmental phenotypes and neurological comorbidities, including delays and deficits in fine and gross motor development. The Ts65Dn mouse is the most studied animal model for DS and displays the largest known subset of DS-like phenotypes. To date, however, only a small number of developmental phenotypes have been quantitatively defined in these animals. Here, we used a commercially available high-speed, video-based system to record and analyze the gait of Ts65Dn and euploid control mice. Longitudinal treadmill recordings were performed from p17 to p35. One of the main findings was the detection of genotype- and sex-dependent developmental delays in the emergence of consistent, progressive-intensity gait in Ts65Dn mice when compared to control mice. Gait dynamic analysis showed wider normalized front and hind stances in Ts65Dn mice compared to control mice, which may reflect deficits in dynamic postural balance. Ts65Dn mice also displayed statistically significant differences in the variability in several normalized gait measures, which were indicative of deficits in precise motor control in generating gait.

Toward the Identification of Neurophysiological Biomarkers for Alzheimer's Disease in Down Syndrome: A Potential Role for Cross-Frequency Phase-Amplitude Coupling Analysis.

Cross-frequency coupling (CFC) mechanisms play a central role in brain activity. Pathophysiological mechanisms leading to many brain disorders, such as Alzheimer's disease (AD), may produce unique patterns of brain activity detectable by electroencephalography (EEG). Identifying biomarkers for AD diagnosis is also an ambition among research teams working in Down syndrome (DS), given the increased susceptibility of people with DS to develop early-onset AD (DS-AD). Here, we review accumulating evidence that altered theta-gamma phase-amplitude coupling (PAC) may be one of the earliest EEG signatures of AD, and therefore may serve as an adjuvant tool for detecting cognitive decline in DS-AD. We suggest that this field of research could potentially provide clues to the biophysical mechanisms underlying cognitive dysfunction in DS-AD and generate opportunities for identifying EEG-based biomarkers with diagnostic and prognostic utility in DS-AD.

Exaggerated NMDA mediated LTD in a mouse model of Down syndrome and pharmacological rescuing by memantine.

The Ts65Dn mouse is the best-studied animal model for Down syndrome. In the experiments described here, NMDA-mediated or mGluR-mediated LTD was induced in the CA1 region of hippocampal slices from Ts65Dn and euploid control mice by bath application of 20 µM NMDA for 3 min and 50 µM DHPG for 5 min, respectively. We found that Ts65Dn mice display exaggerated NMDA-induced, but not mGluR-induced, LTD in the CA1 region of the hippocampus compared with euploid control animals. In addition, this abnormal level of LTD can be pharmacologically rescued by the NMDA receptor antagonist memantine.

Evidence of Energy Metabolism Alterations in Cultured Neonatal Astrocytes Derived from the Ts65Dn Mouse Model of Down Syndrome.

For many decades, neurons have been the central focus of studies on the mechanisms underlying the neurodevelopmental and neurodegenerative aspects of Down syndrome (DS). Astrocytes, which were once thought to have only a passive role, are now recognized as active participants of a variety of essential physiological processes in the brain. Alterations in their physiological function have, thus, been increasingly acknowledged as likely initiators of or contributors to the pathogenesis of many nervous system disorders and diseases. In this study, we carried out a series of real-time measurements of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in hippocampal astrocytes derived from neonatal Ts65Dn and euploid control mice using a Seahorse XFp Flux Analyzer. Our results revealed a significant basal OCR increase in neonatal Ts65Dn astrocytes compared with those from control mice, indicating increased oxidative phosphorylation. ECAR did not differ between the groups. Given the importance of astrocytes in brain metabolic function and the linkage between astrocytic and neuronal energy metabolism, these data provide evidence against a pure "neurocentric" vision of DS pathophysiology and support further investigations on the potential contribution of disturbances in astrocytic energy metabolism to cognitive deficits and neurodegeneration associated with DS.

Bio-Mimicking, Electrical Excitability Phenomena Associated With Synthetic Macromolecular Systems: A Brief Review With Connections to the Cytoskeleton and Membraneless Organelles.

Electrical excitability of cells, tissues and organs is a fundamental phenomenon in biology and physiology. Signatures of excitability include transient currents resulting from a constant or varying voltage gradient across compartments. Interestingly, such signatures can be observed with non-biologically-derived, macromolecular systems. Initial key literature, dating to roughly the late 1960's into the early 1990's, is reviewed here. We suggest that excitability in response to electrical stimulation is a material phenomenon that is exploited by living organisms, but that is not exclusive to living systems. Furthermore, given the ubiquity of biological hydrogels, we also speculate that excitability in protocells of primordial organisms might have shared some of the same molecular mechanisms seen in non-biological macromolecular systems, and that vestigial traces of such mechanisms may still play important roles in modern organisms' biological hydrogels. Finally, we also speculate that bio-mimicking excitability of synthetic macromolecular systems might have practical biomedical applications.

COVID-19 Vaccination of Individuals with Down Syndrome-Data from the Trisomy 21 Research Society Survey on Safety, Efficacy, and Factors Associated with the Decision to Be Vaccinated.

Individuals with Down syndrome (DS) are among the groups with the highest risk for severe COVID-19. Better understanding of the efficacy and risks of COVID-19 vaccines for individuals with DS may help improve uptake of vaccination. The T21RS COVID-19 Initiative launched an international survey to obtain information on safety and efficacy of COVID-19 vaccines for individuals with DS. De-identified survey data collected between March and December 2021 were analyzed. Of 2172 individuals with DS, 1973 (91%) had received at least one vaccine dose (57% BNT162b2), 107 (5%) were unvaccinated by choice, and 92 (4%) were unvaccinated for other reasons. Most participants had either no side effects (54%) or mild ones such as pain at the injection site (29%), fatigue (12%), and fever (7%). Severe side effects occurred in <0.5% of participants. About 1% of the vaccinated individuals with DS contracted COVID-19 after vaccination, and all recovered. Individuals with DS who were unvaccinated by choice were more likely to be younger, previously recovered from COVID-19, and also unvaccinated against other recommended vaccines. COVID-19 vaccines have been shown to be safe for individuals with DS and effective in terms of resulting in minimal breakthrough infections and milder disease outcomes among fully vaccinated individuals with DS.

Safety, efficacy, and tolerability of memantine for cognitive and adaptive outcome measures in adolescents and young adults with Down syndrome: a randomised, double-blind, placebo-controlled phase 2 trial.

BACKGROUND: Down syndrome is a chromosomal disorder with considerable neurodevelopmental impact and neurodegenerative morbidity. In a pilot trial in young adults with Down syndrome, memantine (a drug approved for Alzheimer's disease) showed a significant effect on a secondary measure of episodic memory. We aimed to test whether memantine would improve episodic memory in adolescents and young adults with Down syndrome. METHODS: We did a randomised, double-blind, placebo-controlled phase 2 trial with a parallel design, stratified by age and sex. Participants (aged 15-32 years) with either trisomy 21 or complete unbalanced translocation of chromosome 21 and in general good health were recruited from the community at one site in Brazil and another in the USA. Participants were randomly assigned (1:1) to receive either memantine (20 mg/day orally) or placebo for 16 weeks. Computer-generated randomisation tables for both sites (allocating a placebo or drug label to each member of a unique pair of participants) were centrally produced by an independent statistician and were shared only with investigational pharmacists at participating sites until unblinding of the study. Participants and investigators were masked to treatment assignments. Neuropsychological assessments were done at baseline (T1) and week 16 (T2). The primary outcome measure was change from baseline to week 16 in the California Verbal Learning Test-second edition short-form (CVLT-II-sf) total free recall score, assessed in the per-protocol population (ie, participants who completed 16 weeks of treatment and had neuropsychological assessments at T1 and T2). Linear mixed effect models were fit to data from the per-protocol population. Safety and tolerability were monitored and analysed in all participants who started treatment. Steady-state concentrations in plasma of memantine were measured at the end of the trial. This study is registered at ClinicalTrials.gov, number NCT02304302. FINDINGS: From May 13, 2015, to July 22, 2020, 185 participants with Down syndrome were assessed for eligibility and 160 (86%) were randomly assigned either memantine (n=81) or placebo (n=79). All participants received their allocated treatment. Linear mixed effect models were fit to data from 149 (81%) participants, 73 in the memantine group and 76 in the placebo group, after 11 people (eight in the memantine group and three in the placebo group) discontinued due to COVID-19 restrictions, illness of their caregiver, adverse events, or low compliance. The primary outcome measure did not differ between groups (CVLT-II-sf total free recall score, change from baseline 0·34 points [95% CI -0·98 to 1·67], p=0·61). Memantine was well tolerated, with infrequent mild-to-moderate adverse events, the most common being viral upper respiratory infection (nine [11%] participants in the memantine group and 12 [15%] in the placebo group) and transient dizziness (eight [10%] in the memantine group and six [8%] in the placebo group). No serious adverse events were observed. Amounts of memantine in plasma were substantially lower than those considered therapeutic for Alzheimer's disease. INTERPRETATION: Memantine was well tolerated, but cognition-enhancing effects were not recorded with a 20 mg/day dose in adolescents and young adults with Down syndrome. Exploratory analyses point to a need for future work. FUNDING: Alana Foundation. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

On the promise of pharmacotherapies targeted at cognitive and neurodegenerative components of Down syndrome.

Down syndrome (DS) is the phenotypic consequence of trisomy 21 and is the most common genetically defined cause of intellectual disability. The most complete, widely available, and well-studied animal model of DS is the Ts65Dn mouse. Recent preclinical successes in rescuing learning and memory deficits in Ts65Dn mice are legitimate causes for optimism that pharmacotherapies for cognitive deficits in DS might be within reach. This article provides a snapshot of potential pharmacotherapies for DS, with emphasis on our recent results showing that the N-methyl-D-aspartate receptor antagonist memantine can reverse learning and memory deficits in Ts65Dn mice. Because memantine has already been approved for the therapy of Alzheimer's dementia, we have been able to very rapidly translate these results into human research and are currently conducting a 16-week, randomized, double-blind, placebo-controlled evaluation of the efficacy, tolerability and safety of memantine hydrochloride on enhancing the cognitive abilities of young adults with DS. The design and current status of this clinical trial will be discussed, which will be followed by some speculation on the potential impact of this and future clinical trials in the field of DS.

Machine learning methods predict locomotor response to MK-801 in mouse models of down syndrome.

Down syndrome (DS), caused by trisomy of human chromosome 21 (HSA21), is a common genetic cause of cognitive impairment. This disorder results from the overexpression of HSA21 genes and the resulting perturbations in many molecular pathways and cellular processes. Knowledge-based identification of targets for pharmacotherapies will require defining the most critical protein abnormalities among these many perturbations. Here the authors show that using the Ts65Dn and Ts1Cje mouse models of DS, which are trisomic for 88 and 69 reference protein coding genes, respectively, a simple linear Naïve Bayes classifier successfully predicts behavioral outcome (level of locomotor activity) in response to treatment with the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801. Input to the Naïve Bayes method were simple protein profiles generated from cortex and output was locomotor activity binned into three levels: low, medium, and high. When Feature Selection was used with the Naïve Bayes method, levels of three HSA21 and two non-HSA21 protein features were identified as making the most significant contributions to activity level. Using these five features, accuracies of up to 88% in prediction of locomotor activity were achieved. These predictions depend not only on genotype-specific differences but also on within-genotype individual variation in levels of molecular and behavioral parameters. With judicious choice of pathways and components, a similar approach may be useful in analysis of more complex behaviors, including those associated with learning and memory, and may facilitate identification of novel targets for pharmacotherapeutics.

An assessment of optokinetic nystagmus (OKN) in persons with Down syndrome.

Down syndrome (DS), the most common genetically defined cause of intellectual disability, is the phenotypic consequence of a supernumerary chromosome 21. Persons with DS commonly display deficits in visuomotor integration, motor coordination, and balance. Despite the key roles of the optokinetic and vestibular systems in these submodalities of motor function, a systematic investigation of the optokinetic nystagmus (OKN) and vestibulo-ocular reflex (VOR) in persons with DS had lacked in the literature. Accordingly, this study generated quantitative data on oculomotor function in persons with DS under optokinetic and sinusoidal smooth pursuit stimulation. Thirty-two participants with DS (14-36 years old, equally divided by gender) and 32 chronological age- and gender-matched typically developing controls were recruited from the community. Eye movements were recorded by binocular video oculography and an LCD projector produced visual stimulation. Assessments of the gain and frequency of slow phase of OKN beats and number and mean amplitude of intruding saccades during smooth pursuit were performed. Individuals with DS displayed angular velocity-dependent reduction in OKN gain and number of produced nystagmus beats compared to controls. The gain of the smooth pursuit was not significantly different between participants with DS and control participants. However, the number and mean amplitude of intruding saccades during smooth pursuit were increased in participants with DS compared to control participants. These findings may have implications to the understanding of the neurological basis of the motor dysfunction that affects performance in many practical tasks persons with DS encounter in their everyday lives.

An assessment of the vestibulo-ocular reflex (VOR) in persons with Down syndrome.

Down syndrome (DS), the most common genetically defined cause of intellectual disability, is the phenotypic consequence of a supernumerary chromosome 21. Persons with DS commonly display deficits in visuomotor integration, motor coordination, and balance. Despite the key roles of the optokinetic and vestibular systems in these submodalities of motor function, a systematic investigation into the optokinetic nystagmus (OKN) and vestibulo-ocular reflex (VOR) in persons with DS was lacking in the literature. Accordingly, this study generated quantitative data on oculomotor function in persons with DS under vestibular stimulation (an accompanying work describes results on the analysis of optokinetic function in the same cohort of participants). Experiments involved 32 participants with DS (14-36 years old, equally divided by gender) and 32 chronological age- and gender-matched typically developing controls. Eye movements were recorded by binocular video-oculography, and a servo-controlled rotary chair produced vestibular stimulation. Participants were assessed for VOR during step, ramp, and sinusoidal stimulations; inhibition of the VOR by visual target fixation; and VOR adaptation to conflicting visual input. Individuals with DS displayed small alterations in the VOR gain and dynamics compared to controls. In contrast, the number of VOR nystagmus beats and the ability to inhibit the VOR by visual target fixation were markedly and robustly smaller in persons with DS. Significantly increased VOR adaptation was observed in men with DS. These findings may have implications to the understanding of the neurological basis of the motor dysfunction that affects performance in many practical tasks persons with DS encounter in their everyday lives.

Microcapillary Reactors via Coaxial Electrospinning: Fabrication of Small Poly(Acrylic Acid) Gel Beads and Thin Threads of Biological Cell Dimensions.

Poly(acrylic acid) (PAA) bulk gels and threads, typically derived via free-radical polymerization, are of interest as anionic polyelectrolyte mimics of cellular cytosol and as models for early protocells. The thread dimensions have been limited by the diameters of readily-available glass or plastic capillaries, and threads with diameters of less than 50 µm have been difficult to achieve. Here, we report a useful approach for achieving crosslinked, partially neutralized PAA, namely poly(acrylate), gel threads with diameters of a few microns when dry. This technique utilizes coaxial electrospinning to effectively produce capillaries (shells) of polystyrene loaded with a gel-forming precursor mixture composed of 3 M acrylic acid, methylene-bisacrylamide, potassium persulfate and 2.2 M NaOH in the core, followed by thermally-induced polymerization and then the removal of the polystyrene shell. Relatively long (up to 5 mm), continuous PAA threads with thicknesses of 5-15 µm are readily obtained, along with a multitude of PAA gel particles, which result from the occasional break-up of the fluid core prior to gel formation during the electrospinning process. The threads and beads are of the sizes of interest to model ancient protocells, certain functional aspects of excitable cells, such as myocytes and neurons, and various membraneless organelles.

Novel DYRK1A Inhibitor Rescues Learning and Memory Deficits in a Mouse Model of Down Syndrome.

Down syndrome (DS) is a complex genetic disorder associated with substantial physical, cognitive, and behavioral challenges. Due to better treatment options for the physical co-morbidities of DS, the life expectancy of individuals with DS is beginning to approach that of the general population. However, the cognitive deficits seen in individuals with DS still cannot be addressed pharmacologically. In young individuals with DS, the level of intellectual disability varies from mild to severe, but cognitive ability generally decreases with increasing age, and all individuals with DS have early onset Alzheimer's disease (AD) pathology by the age of 40. The present study introduces a novel inhibitor for the protein kinase DYRK1A, a key controlling kinase whose encoding gene is located on chromosome 21. The novel inhibitor is well characterized for use in mouse models and thus represents a valuable tool compound for further DYRK1A research.

Atypical electrophysiological and behavioral responses to diazepam in a leading mouse model of Down syndrome.

Mounting evidence implicates dysfunctional GABAAR-mediated neurotransmission as one of the underlying causes of learning and memory deficits observed in the Ts65Dn mouse model of Down syndrome (DS). The specific origin and nature of such dysfunction is still under investigation, which is an issue with practical consequences to preclinical and clinical research, as well as to the care of individuals with DS and anxiety disorder or those experiencing seizures in emergency room settings. Here, we investigated the effects of GABAAR positive allosteric modulation (PAM) by diazepam on brain activity, synaptic plasticity, and behavior in Ts65Dn mice. We found Ts65Dn mice to be less sensitive to diazepam, as assessed by electroencephalography, long-term potentiation, and elevated plus-maze. Still, diazepam pre-treatment displayed typical effectiveness in reducing susceptibility and severity to picrotoxin-induced seizures in Ts65Dn mice. These findings fill an important gap in the understanding of GABAergic function in a key model of DS.

High resolution structural and functional MRI of the hippocampus in young adults with Down syndrome.

Down syndrome is the phenotypic consequence of trisomy 21, with clinical presentation including both neurodevelopmental and neurodegenerative components. Although the intellectual disability typically displayed by individuals with Down syndrome is generally global, it also involves disproportionate deficits in hippocampally-mediated cognitive processes. Hippocampal dysfunction may also relate to Alzheimer's disease-type pathology, which can appear in as early as the first decade of life and becomes universal by age 40. Using 7-tesla MRI of the brain, we present an assessment of the structure and function of the hippocampus in 34 individuals with Down syndrome (mean age 24.5 years ± 6.5) and 27 age- and sex-matched typically developing healthy controls. In addition to increased whole-brain mean cortical thickness and lateral ventricle volumes (P < 1.0 × 10-4), individuals with Down syndrome showed selective volume reductions in bilateral hippocampal subfields cornu Ammonis field 1, dentate gyrus, and tail (P < 0.005). In the group with Down syndrome, bilateral hippocampi showed widespread reductions in the strength of functional connectivity, predominately to frontal regions (P < 0.02). Age was not related to hippocampal volumes or functional connectivity measures in either group, but both groups showed similar relationships of age to whole-brain volume measures (P < 0.05). Finally, we performed an exploratory analysis of a subgroup of individuals with Down syndrome with both imaging and neuropsychological assessments. This analysis indicated that measures of spatial memory were related to mean cortical thickness, total grey matter volume and right hemisphere hippocampal subfield volumes (P < 0.02). This work provides a first demonstration of the usefulness of high-field MRI to detect subtle differences in structure and function of the hippocampus in individuals with Down syndrome, and suggests the potential for development of MRI-derived measures as surrogate markers of drug efficacy in pharmacological studies designed to investigate enhancement of cognitive function.

COVID-19 in Children with Down Syndrome: Data from the Trisomy 21 Research Society Survey.

Adults with Down Syndrome (DS) are at higher risk for severe outcomes of coronavirus disease 2019 (COVID-19) than the general population, but evidence is required to understand the risks for children with DS, which is necessary to inform COVID-19 shielding advice and vaccination priorities. We aimed to determine the epidemiological and clinical characteristics of COVID-19 in children with DS. Using data from an international survey obtained from a range of countries and control data from the United States, we compared the prevalence of symptoms and medical complications and risk factors for severe outcomes between DS and non-DS paediatric populations with COVID-19. Hospitalised COVID-19 patients <18 years with DS had a higher incidence of respiratory symptoms, fever, and several medical complications from COVID-19 than control patients without DS <18 years. Older age, obesity, and epilepsy were significant risk factors for hospitalisation among paediatric COVID-19 patients with DS, and age and thyroid disorder were significant risk factors for acute respiratory distress syndrome. Mortality rates were low in all paediatric COVID-19 patients (with and without DS), contrasting with previous findings in adults with DS (who exhibit higher mortality than those without DS). Children with DS are at increased risk for more severe presentations of COVID-19. Efforts should be made to ensure the comprehensive and early detection of COVID-19 in this population and to identify children with DS who present comorbidities that pose a risk for a severe course of COVID-19. Our results emphasize the importance of vaccinating children with DS as soon as they become eligible.

Medical vulnerability of individuals with Down syndrome to severe COVID-19-data from the Trisomy 21 Research Society and the UK ISARIC4C survey.

BACKGROUND: Health conditions, immune dysfunction, and premature aging associated with trisomy 21 (Down syndrome, DS) may impact the clinical course of COVID-19. METHODS: The T21RS COVID-19 Initiative launched an international survey for clinicians or caregivers on patients with COVID-19 and DS. Data collected between April and October 2020 (N=1046) were analysed and compared with the UK ISARIC4C survey of hospitalized COVID-19 patients with and without DS. FINDINGS: The mean age of COVID-19 patients with DS in the T21RS survey was 29 years (SD = 18). Similar to the general population, the most frequent signs and symptoms of COVID-19 were fever, cough, and shortness of breath. Joint/muscle pain and vomiting or nausea were less frequent (p < 0.01), whereas altered consciousness/confusion were more frequent (p < 0.01). Risk factors for hospitalization and mortality were similar to the general population with the addition of congenital heart defects as a risk factor for hospitalization. Mortality rates showed a rapid increase from age 40 and were higher in patients with DS (T21RS DS versus non-DS patients: risk ratio (RR) = 3.5 (95%-CI=2.6;4.4), ISARIC4C DS versus non-DS patients: RR = 2.9 (95%-CI=2.1;3.8)) even after adjusting for known risk factors for COVID-19 mortality. INTERPRETATION: Leading signs/symptoms of COVID-19 and risk factors for severe disease course are similar to the general population. However, individuals with DS present significantly higher rates of medical complications and mortality, especially from age 40. FUNDING: Down Syndrome Affiliates in Action, DSMIG-USA, GiGi's Playhouse, Jerome Lejeune Foundation, LuMind IDSC Foundation, The Matthew Foundation, NDSS, National Task Group on Intellectual Disabilities and Dementia Practices.