Browsing by Subject "Trisomy 21"

Now showing 1 - 10 of 21
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    A randomized controlled trial of an online health tool about Down syndrome
    (Elsevier, 2021) Chung, Jeanhee; Donelan, Karen; Macklin, Eric A.; Schwartz, Alison; Elsharkawi, Ibrahim; Torres, Amy; Hsieh, Yichuan Grace; Parker, Holly; Lorenz, Stephen; Patsiogiannis, Vasiliki; Santoro, Stephanie L.; Wylie, Mark; Clarke, Lloyd; Estey, Greg; Baker, Sandra; Bauer, Patricia E.; Bull, Marilyn; Chicoine, Brian; Cullen, Sarah; Frey-Vogel, Ariel; Gallagher, Maureen; Hasan, Reem; Lamb, Ashley; Majewski, Lisa; Mast, Jawanda; Riddell, Travis; Sepucha, Karen; Skavlem, Melissa; Skotko, Brian G.; Pediatrics, School of Medicine
    Purpose: We sought to determine if a novel online health tool, called Down Syndrome Clinic to You (DSC2U), could improve adherence to national Down syndrome (DS) guidelines. We also sought to determine if primary care providers (PCPs) and caregivers are satisfied with this personalized online health tool. Methods: In a national, randomized controlled trial of 230 caregivers who had children or dependents with DS without access to a DS specialist, 117 were randomized to receive DSC2U and 113 to receive usual care. The primary outcome was adherence to five health evaluations indicated by national guidelines for DS. DSC2U is completed electronically, in all mobile settings, by caregivers at home. The outputs-personalized checklists-are used during annual wellness visits with the patient's PCP. Results: A total of 213 participants completed a 7-month follow-up evaluation. In the intention-to-treat analysis, the intervention group had a 1.6-fold increase in the number of indicated evaluations that were recommended by the primary care provider or completed compared with controls. Both caregivers and PCPs reported high levels of satisfaction with DSC2U. Conclusions: DSC2U improved adherence to the national DS health-care guidelines with a novel modality that was highly valued by both caregivers and PCPs.
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    Alzheimer’s Drugs APPlication for Down syndrome?
    (Elsevier, 2024) Sokol, Deborah K.; Lahiri, Debomoy K.; Neurology, School of Medicine
    Accumulation of the amyloid β (Aβ) peptide, derived from Aβ precursor protein (APP), is a trait of Down syndrome (DS), as is early development of dementia that resembles Alzheimer's disease (AD). Treatments for this AD in DS simply do not. New drug therapies for AD, e.g., Lecanemab, are monoclonal antibodies designed to clear amyloid plaques composed of Aβ. The increasingly real ability to target and dispose of Aβ favors the use of these drugs in individuals with AD in DS, and, perhaps as earlier intervention for cognitive impairment. We present pertinent similarities between DS and AD in adult DS subjects, discuss challenges to target APP metabolites, and suggest that recently developed antibody treatments against Aβ may be worth investigating to treat AD in DS.
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    Clinical identification of feeding and swallowing disorders in 0-6 month old infants with Down syndrome
    (Wiley, 2019-02) Stanley, Maria A.; Shepherd, Nicole; Duvall, Nichole; Jenkinson, Sandra B.; Jalou, Hasnaa E.; Givan, Deborah C.; Steele, Gregory H.; Davis, Charlene; Bull, Marilyn J.; Watkins, Donna U.; Roper, Randall J.; Pediatrics, School of Medicine
    Feeding and swallowing disorders have been described in children with a variety of neurodevelopmental disabilities, including Down syndrome (DS). Abnormal feeding and swallowing can be associated with serious sequelae such as failure to thrive and respiratory complications, including aspiration pneumonia. Incidence of dysphagia in young infants with DS has not previously been reported. To assess the identification and incidence of feeding and swallowing problems in young infants with DS, a retrospective chart review of 174 infants, ages 0-6 months was conducted at a single specialty clinic. Fifty-seven percent (100/174) of infants had clinical concerns for feeding and swallowing disorders that warranted referral for Videofluroscopic Swallow Study (VFSS); 96/174 (55%) had some degree of oral and/or pharyngeal phase dysphagia and 69/174 (39%) had dysphagia severe enough to warrant recommendation for alteration of breast milk/formula consistency or nonoral feeds. Infants with certain comorbidities had significant risk for significant dysphagia, including those with functional airway/respiratory abnormalities (OR = 7.2). Infants with desaturation with feeds were at dramatically increased risk (OR = 15.8). All young infants with DS should be screened clinically for feeding and swallowing concerns. If concerns are identified, consideration should be given to further evaluation with VFSS for identification of dysphagia and additional feeding modifications.
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    Compromised Femoral and Lumbovertebral Bone in the Dp(16)1Yey Down Syndrome Mouse Model
    (Elsevier, 2024) Lamantia, Joshua; Sloan, Kourtney; Wallace, Joseph M.; Roper, Randall J.; Biology, School of Science
    Down syndrome (DS), affecting ∼1 in 800 live births, is caused by the triplication of human chromosome 21 (Hsa21). Individuals with DS have skeletal features including craniofacial abnormalities and decreased bone mineral density (BMD). Lowered BMD can lead to increased fracture risk, with common fracture points at the femoral neck and lumbar spine. While the femur has been studied in DS mouse models, there is little research done on the vertebrae despite evidence that humans with DS have affected vertebrae. Additionally, it is important to establish when skeletal deficits occur to find times of potential intervention. The Dp(16)1Yey DS mouse model has all genes triplicated on mouse chromosome 16 orthologous to Hsa21 and displayed deficits in long bone, including trabecular and cortical deficits in male but not female mice, at 12 weeks. We hypothesized that the long bone and lumbovertebral microarchitecture would exhibit sexually dimorphic deficits in Dp(16)1Yey mice compared to control mice and long bone strength would be diminished in Dp(16)1Yey mice at 6 weeks. The trabecular region of the 4th lumbar (L4) vertebra and the trabecular and cortical regions of the femur were analyzed via micro-computed tomography and 3-point bending in 6-week-old male and female Dp(16)1Yey and control mice. Trabecular and cortical deficits were observed in femurs from male Dp(16)1Yey mice, and cortical deficits were seen in femurs of male and female Dp(16)1Yey mice. Male Dp(16)1Yey femurs had more deficits in bone strength at whole bone and tissue-estimate level properties, but female Dp(16)1Yey mice were also affected. Additionally, the L4 of male and female Dp(16)1Yey mice show trabecular deficits, which have not been previously reported in a DS mouse model. Our results indicate that skeletal deficits associated with DS occur early in skeletal development, are dependent on skeletal compartment and site, are sex dependent, and potential interventions should likely begin early in skeletal development of DS mouse models.
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    Current Analysis of Skeletal Phenotypes in Down Syndrome
    (Springer, 2021) Thomas, Jared R.; Roper, Randall J.; Biology, School of Science
    Purpose: Down syndrome (DS) is caused by trisomy 21 (Ts21) and results in skeletal deficits including shortened stature, low bone mineral density, and a predisposition to early onset osteoporosis. Ts21 causes significant alterations in skeletal development, morphology of the appendicular skeleton, bone homeostasis, age-related bone loss, and bone strength. However, the genetic or cellular origins of DS skeletal phenotypes remain unclear. Recent findings: New studies reveal a sexual dimorphism in characteristics and onset of skeletal deficits that differ between DS and typically developing individuals. Age-related bone loss occurs earlier in the DS as compared to general population. Perturbations of DS skeletal quality arise from alterations in cellular and molecular pathways affected by the overexpression of trisomic genes. Sex-specific alterations occur in critical developmental pathways that disrupt bone accrual, remodeling, and homeostasis and are compounded by aging, resulting in increased risks for osteopenia, osteoporosis, and fracture in individuals with DS.
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    Early White Matter Microstructure Alterations in Infants with Down Syndrome
    (medRxiv, 2025-02-27) Azrak, Omar; Garic, Dea; Nasir, Aleeshah; Swanson, Meghan R.; Grzadzinski, Rebecca L.; Al-Ali, Khalid; Shen, Mark D.; Girault, Jessica B.; St. John, Tanya; Pandey, Juhi; Zwaigenbaum, Lonnie; Estes, Annette M.; Wolff, Jason J.; Dager, Stephen R.; Schultz, Robert T.; Evans, Alan C.; Elison, Jed T.; Yacoub, Essa; Kim, Sun Hyung; McKinstry, Robert C.; Gerig, Guido; Pruett, John R., Jr.; Piven, Joseph; Botteron, Kelly N.; Hazlett, Heather; Marrus, Natasha; Styner, Martin A.; Psychiatry, School of Medicine
    Importance: Down syndrome, resulting from trisomy 21, is the most prevalent chromosomal disorder and a leading cause of intellectual disability. Despite its significant impact on brain development, research on the white matter microstructure in infants with Down syndrome remains limited. Objective: To investigate early white matter microstructure in infants with Down syndrome using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI). Design: Infants were recruited and scanned between March 2019 and May 2024 as participants in prospective studies conducted by the Infant Brain Imaging Study (IBIS) Network. Data were analyzed in October 2024. Setting: Data collection occurred at five research centers in Minnesota, Missouri, North Carolina, Pennsylvania, and Washington. Participants: Down syndrome and control infants were scanned at 6 months of age. Control infants had no Down syndrome diagnosis and either had a typically developing older sibling or, if they had an older sibling with autism, were confirmed not to meet clinical best estimate criteria for an autism diagnosis. Exposure: Diagnosis of Down syndrome. Main outcomes and measures: The outcome of interest was white matter microstructure quantified using DTI and NODDI measures. Results: A total of 49 Down syndrome (28 [57.14%] female) and 37 control (18 [48.65%] female) infants were included. Infants with Down syndrome showed significant reductions in fractional anisotropy and neurite density index across multiple association tracts, particularly in the inferior fronto-occipital fasciculus and superior longitudinal fasciculus II, consistent with reduced structural integrity and neurite density. These tracts also demonstrated increased radial diffusivity, suggesting delayed myelination. The inferior fronto-occipital fasciculus and uncinate fasciculus exhibited increased neurite dispersion and fanning in Down syndrome infants, reflected by elevated orientation dispersion index. Notably, the optic tracts in Down syndrome infants exhibited a distinct pattern of elevated fractional anisotropy and axial diffusivity, and lower radial diffusivity and orientation dispersion index, suggesting an early maturation of these pathways. Conclusions and relevance: This first characterization of white matter microstructure in Down syndrome infants reveals widespread white matter developmental delays. These findings provide new insights into the early neurodevelopment of Down syndrome and may inform early therapeutic interventions.
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    Effect of Epigallocatechin-3-gallate on a pattern separation task and hippocampal neurogenesis in a mouse model of Down syndrome
    (2015) Stringer, Megan Elizabeth; Goodlett, Charles R.; Roper, Randall J.; Neal-Beliveau, Bethany S.; Grahame, Nicholas J.
    Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa21) and results in an array of phenotypes including intellectual disability. Ts65Dn mice, the most extensively studied DS model, have three copies of ~50% of the genes on Hsa21 and display many phenotypes associated with DS, including cognitive deficits. DYRK1A is found in three copies in humans with Trisomy 21 and in Ts65Dn mice, and is involved in a number of critical pathways including CNS development and osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), the main polyphenol in green tea, inhibits Dyrk1a activity. We have shown that a three-week EGCG treatment (~10mg/kg/day) during adolescence normalizes skeletal abnormalities in Ts65Dn mice, yet the same dose did not rescue deficits in the Morris water maze spatial learning task (MWM) or novel object recognition (NOR). Others have reported that An EGCG dose of 2-3 mg per day (90mg/ml) improved hippocampal-dependent task deficits in Ts65Dn mice. The current study investigated deficits in a radial arm maze pattern separation task in Ts65Dn mice. Pattern separation requires differentiation between similar memories acquired during learning episodes; distinguishing between these similar memories is thought to depend on distinctive encoding in the hippocampus. Pattern separation has been linked to functional activity of newly generated granule cells in the dentate gyrus. Recent studies in Ts65Dn mice have reported significant reductions in adult hippocampal neurogenesis, and after EGCG treatment, enhanced hippocampal neurogenesis. Thus, it was hypothesized that Ts65Dn mice would be impaired in the pattern separation task, and that EGCG would alleviate the pattern separation deficits seen in trisomic mice, in association with increased adult hippocampal neurogenesis. At weaning, Ts65Dn mice and euploid littermates were randomly assigned to the water control, or EGCG [0.4 mg/mL], with both treatments yielding average daily intakes of ~50 mg/kg/day. Beginning on postnatal day 75, all mice were trained on a radial arm maze-delayed non-matching-to-place pattern separation task. Euploid mice performed significantly better over training than Ts65Dn mice, including better performance at each of the three separations. EGCG did not significantly alleviate the pattern separation deficits in Ts65Dn mice. After the behavioral testing commenced, animals were given ad libitum food access for five days, received a 100mg/kg injection of BrdU, and were perfused two hours later. Coronal sections through the dorsal hippocampus were processed for BrdU labeling, and cells were manually counted throughout the subgranular zone of the dentate gyrus. The euploid controls had significantly more BrdU labeled cells than Ts65Dn mice, however, EGCG does not appear to increase proliferation of the hippocampal neuroprogenitor cells. This is the first report of deficits in Ts65Dn mice on a pattern separation task. To the extent that pattern separation depends on the functional involvement of newly generated neurons in an adult dentate gyrus, this approach in Ts65Dn mice may help identify more targeted pharmacotherapies for cognitive deficits in individuals with DS.
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    Effects of Trisomic Dyrk1a and EGCG Treatment on Craniofacial Development in Ts65Dn Down Syndrome Mice
    (Office of the Vice Chancellor for Research, 2015-04-17) Diallo, Mariyamou; Haley, Emily; Tumbleson, Danika; Roper, Randall J.
    Down syndrome (DS), also known as Trisomy 21, is a genetic disorder caused by an extra copy of human chromosome 21. Individuals with DS exhibit various phenotypes such as cognitive, skeletal and craniofacial abnormalities. The Ts65Dn mouse model displays similar craniofacial abnormalities as observed in humans with DS including a small, undersized mandible. To gain a better understanding of craniofacial abnormalities, we study the molecular and cellular mechanisms underlying these abnormalities. Previous studies conducted in our lab identified a deficit in neural crest (NC) cells in the first pharyngeal arch (PA1) or mandibular precursor by embryonic day 9.5 (E9.5). We hypothesize that the inherent molecular mechanism responsible for the small, undersized mandible is overexpression of dual-specificity tyrosine (Y) phosphorylation regulated kinase 1A (Dyrk1a), a gene that is found in three copies in individuals with DS and Ts65Dn mice. To test our hypothesis, we bred Ts65Dn mice with Dyrk1a knockout mice, thus reducing Dyrk1a copy number to normal levels. This study provides the foundation for understanding the function of Dyrk1a. We also treated embryos with Epigallocatechin gallate (EGCG), a green tea polyphenol that is known to inhibit Dyrk1a activity. We will examine the molecular and cellular effects of Dyrk1a and EGCG on the developing PA1 on E9.5 embryos. In both the genetic and pharmacological manipulations, we expect to find a larger overall embryonic size, a larger PA1 size and increased number of NC cells.
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    The Effects of Trisomic Dyrk1a on Ts65Dn Embryonic Craniofacial Development
    (Office of the Vice Chancellor for Research, 2015-04-17) Haley, Emily; Diallo, Mariyamou; Roper, Randall J.
    Down syndrome (DS) is caused by Trisomy 21 in humans and leads to distinctive craniofacial features in all affected individuals. The Ts65Dn mouse model of DS has orthologs of about half of the genes found on chromosome 21 and mirrors craniofacial phenotypes seen in DS including a small dysmorphic mandible. Previous studies have shown that the small mandible is due to deficits in proliferation and migration from the neural tube of neural crest cell (NCC) craniofacial precursors. Dyrk1a is a trisomic gene found in humans with DS and Ts65Dn mice, and it is overexpressed in the 1st pharyngeal arch (PA1) of our mouse model. We hypothesize that Ts65Dn, Dyrk1a+/- embryos (otherwise trisomic with the normal 2 copies of Dyrk1a) will show similar PA1 and overall embryo size as well as NCC number when compared to euploid littermates. To test our hypothesis we bred Ts65Dn, Dyrk1a+/- mothers to generate the following genotypes; Ts65Dn, Eu, Ts65Dn, Dyrk1a+/- and Eu, Dyrk1a+/-. At E9.5 embryos were removed from mothers. Using unbiased stereology on sectioned E9.5 embryos, we measured PA1 NCC number and total embryonic volume. We propose that if Ts65Dn, Dyrk1a+/- embryos show a normalized PA1, future work should be concentrated in viable therapies to target overexpression of Dyrk1a in the Ts65Dn mouse model.
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    Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes
    (Elsevier, 2017-08) Stringer, Megan; Abeysekera, Irushi; Thomas, Jared; LaCombe, Jonathan; Stancombe, Kailey; Stewart, Robert J.; Dria, Karl J.; Wallace, Joseph M.; Goodlett, Charles R.; Roper, Randall J.; Department of Biology, School of Science
    Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa21) and results in phenotypes including intellectual disability and skeletal deficits. Ts65Dn mice have three copies of ~ 50% of the genes homologous to Hsa21 and display phenotypes associated with DS, including cognitive deficits and skeletal abnormalities. DYRK1A is found in three copies in humans with Trisomy 21 and in Ts65Dn mice, and is involved in a number of critical pathways including neurological development and osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), the main polyphenol in green tea, inhibits Dyrk1a activity. We have previously shown that EGCG treatment (~ 10 mg/kg/day) improves skeletal abnormalities in Ts65Dn mice, yet the same dose, as well as ~ 20 mg/kg/day did not rescue deficits in the Morris water maze spatial learning task (MWM), novel object recognition (NOR) or balance beam task (BB). In contrast, a recent study reported that an EGCG-containing supplement with a dose of 2–3 mg per day (~ 40–60 mg/kg/day) improved hippocampal-dependent task deficits in Ts65Dn mice. The current study investigated if an EGCG dosage similar to that study would yield similar improvements in either cognitive or skeletal deficits. Ts65Dn mice and euploid littermates were given EGCG [0.4 mg/mL] or a water control, with treatments yielding average daily intakes of ~ 50 mg/kg/day EGCG, and tested on the multivariate concentric square field (MCSF)—which assesses activity, exploratory behavior, risk assessment, risk taking, and shelter seeking—and NOR, BB, and MWM. EGCG treatment failed to improve cognitive deficits; EGCG also produced several detrimental effects on skeleton in both genotypes. In a refined HPLC-based assay, its first application in Ts65Dn mice, EGCG treatment significantly reduced kinase activity in femora but not in the cerebral cortex, cerebellum, or hippocampus. Counter to expectation, 9-week-old Ts65Dn mice exhibited a decrease in Dyrk1a protein levels in Western blot analysis in the cerebellum. The lack of beneficial therapeutic behavioral effects and potentially detrimental skeletal effects of EGCG found in Ts65Dn mice emphasize the importance of identifying dosages of EGCG that reliably improve DS phenotypes and linking those effects to actions of EGCG (or EGCG-containing supplements) in specific targets in brain and bone.