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Item 3D Assessment of Nasopharyngeal and Craniofacial Phenotypes in Ts65Dn Down Syndrome Mice Treated with a Dyrk1a Inhibitor(2014-04-11) Starbuck, John M.; Harrington, Emily; Kula, Katherine S.; Ghoneima, Ahmed A.; Roper, Randall J.Background: Down syndrome (DS) originates from having three copies of chromosome 21 (i.e. Trisomy 21). DS is associated with many detrimental phenotypes including intellectual disabilities, heart defects, abnormal craniofacial development, and obstructive sleep apnea, which develops from restricted nasopharyngeal airways and an underdeveloped mandible. Ts65Dn mice are trisomic for about half of the orthologs on human chromosome 21 and display many phenotypes associated with DS including craniofacial abnormalities. Dyrk1a is found in three copies in Ts65Dn mice and individuals with DS, and thought to be a root cause of the craniofacial phenotypes. Epigallocatechin 3-gallate (EGCG) is a green tea polyphenol and inhibitor of Dyrk1a activity. Purpose: We hypothesize that decreased Dyrk1a activity in Ts65Dn mice will ameliorate craniofacial dysmorphology. Methods: To test our hypothesis we compared Ts65Dn mice with two or three copies of Dyrk1a and compared Ts65Dn mice with and without prenatal EGCG treatment. EGCG treated mothers were fed 200mg/kg EGCG on gestational day 7. Six week old mice were sacrificed and their heads imaged using micro-computed tomography (μCT). From μCT images, we measured nasopharyngeal airway volume and anatomical landmarks (n = 54) from the facial skeleton, cranial vault, cranial base, and mandible. Mean nasopharyngeal airway volumes were graphically compared, and a landmark-based multivariate geometric morphometric approach known as Euclidean Distance Matrix Analysis (EDMA) was carried out to assess local differences in craniofacial morphology between trisomic mouse samples. Results: Our preliminary results indicate that EGCG treatment and reduced Dyrk1a copy number increases mean nasopharyngeal airway volume in Ts65Dn mice. Craniofacial morphometric differences were found among all samples. EGCG treatment increased portions of the mandible and decreased portions of the cranial vault and cranial base. Conclusion: Preliminary analyses suggest that both EGCG treatment and reduced Dyrk1a copy number affect craniofacial morphology.Item Abnormal mineralization of the Ts65Dn Down syndrome mouse appendicular skeleton begins during embryonic development in a Dyrk1a-independent manner(Elsevier, 2015-05) Blazek, Joshua D.; Malik, Ahmed M.; Tischbein, Maeve; Arbones, Maria L.; Moore, Clara S.; Roper, Randall J.; Biology, School of ScienceThe relationship between gene dosage imbalance and phenotypes associated with Trisomy 21, including the etiology of abnormal bone phenotypes linked to Down syndrome (DS), is not well understood. The Ts65Dn mouse model for DS exhibits appendicular skeletal defects during adolescence and adulthood but the developmental and genetic origin of these phenotypes remains unclear. It is hypothesized that the postnatal Ts65Dn skeletal phenotype originates during embryonic development and results from an increased Dyrk1a gene copy number, a gene hypothesized to play a critical role in many DS phenotypes. Ts65Dn embryos exhibit a lower percent bone volume in the E17.5 femur when compared to euploid embryos. Concomitant with gene copy number, qPCR analysis revealed a ~1.5 fold increase in Dyrk1a transcript levels in the Ts65Dn E17.5 embryonic femur as compared to euploid. Returning Dyrk1a copy number to euploid levels in Ts65Dn, Dyrk1a+/− embryos did not correct the trisomic skeletal phenotype but did return Dyrk1a gene transcript levels to normal. The size and protein expression patterns of the cartilage template during embryonic bone development appear to be unaffected at E14.5 and E17.5 in trisomic embryos. Taken together, these data suggest that the dosage imbalance of genes other than Dyrk1a is involved in the development of the prenatal bone phenotype in Ts65Dn embryos.Item Adapted Dance and Individuals With Down Syndrome: A Phenomenological Approach(Sagamore, 2022-06-01) Swinford, Rachel; Noerr, Kyra; Exercise & Kinesiology, School of Health and Human SciencesIndividuals with Down syndrome (DS) often experience lower levels of physical activity (PA) and social participation when compared to peers without DS. The purpose was to examine the lived experience of participating in the dance program and interpret the meaning of the dance program. Dancers participated in a 6-week adapted dance program and were interviewed after the program. This study investigated the lived experience of a 6-week adapted dance program for 20 individuals with Down syndrome (DS) using interpretive phenomenology. Dancer interviews revealed a primary theme of dancers experiencing joy and happiness while dancing. This research helps advocate opportunities for individuals with DS to experience dance as a social, physical, and intellectual activity. Findings can support future PA and sports initiatives for individuals with intellectual disabilities.Item Art Therapy Interventions for Individuals with Down Syndrome(2015) Tsai, Mu-Chien; King, JulietThis study was an integrative literature review exploring the research published on art therapy interventions with individuals with Down syndrome. In order to expand the collected resources, secondary sources and expanded search terms. such as developmental disabilities and intellectual disability, were used for gathering more data to support this study. Three important outcomes were categorized: Intellectual and communicative difficulties are present; 2) Developmental and behavioral art therapy approaches and haptic art materials are particularly suitable for working with developmentally impaired people; 3) Facilitating personal expression, improving social skills, enhancing self-esteem, and fostering cognitive development are four therapeutic goals for this population. Based on these outcomes and the analyses of the collected data, an art therapy treatment plan for people diagnosed with Down syndrome was generated. The limitations and recommendations were also discussed.Item Behavioral Phenotyping for Down Syndrome in Mice(Wiley, 2020-09) Roper, Randall J.; Goodlett, Charles R.; Martínez de Lagrán, María; Dierssen, Mara; Biology, School of ScienceDown syndrome (DS) is the most frequent genetic cause of intellectual disability, characterized by alterations in different behavioral symptom domains: neurodevelopment, motor behavior, and cognition. As mouse models have the potential to generate data regarding the neurological basis for the specific behavioral profile of DS, and may indicate pharmacological treatments with the potential to affect their behavioral phenotype, it is important to be able to assess disease-relevant behavioral traits in animal models in order to provide biological plausibility to the potential findings. The field is at a juncture that requires assessments that may effectively translate the findings acquired in mouse models to humans with DS. In this article, behavioral tests are described that are relevant to the domains affected in DS. A neurodevelopmental behavioral screen, the balance beam test, and the Multivariate Concentric Square Field test to assess multiple behavioral phenotypes and locomotion are described, discussing the ways to merge these findings to more fully understand cognitive strengths and weaknesses in this population. New directions for approaches to cognitive assessment in mice and humans are discussed.Item Characterizing Femoral Structure of the Ts66Yah Mouse Model of Down Syndrome(2023-08) Sloan, Kourtney; Roper, Randall J.; Li, Jiliang; McNulty, Margaret A.; Picard, Christine J.Down syndrome (DS) is caused by the partial or complete trisomy of human chromosome 21 (Hsa21) and can result in skeletal deficits, including lower bone mineral density (BMD) and increased risk of fracture and osteoporosis or osteopenia earlier than the general population. Mouse models of DS have been developed to understand the genetic mechanisms resulting in these phenotypes, but models differ due to the complex genetic nature of DS and differing genome structures between humans and mice. Ts65Dn mice have been a popular model of DS as they contain ~50% of Hsa21 orthologous genes on a freely segregating minichromosome, but there is speculation that the phenotypes are exaggerated by non-Hsa21 orthologous trisomic genes also present. To address this issue, the Ts66Yah mouse model was developed to remove the non-Hsa21 orthologous trisomic genes. In this study, male and female Ts66Yah mouse femurs were evaluated during bone accrual and peak bone mass to investigate structural differences using micro-computed tomography. Additionally, the role of trisomic Dyrk1a, a Hsa21 gene previously linked to bone deficits in Ts65Dn mice, was evaluated through genetic and pharmacological means in Ts66Yah femurs at postnatal day 36. Ts66Yah mice were found to have little or no trabecular deficits at any age evaluated, but sex-dependent cortical deficits were present at all ages investigated. Reducing Dyrk1a copy number in Ts66Yah mice significantly improved cortical deficits but did not return cortical bone to euploid levels. Pharmacological treatment with DYRK1A inhibitor L21 was confounded by multiple variables, making it difficult to draw conclusions about DYRK1A inhibition in this manner. Overall, these results indicate trabecular deficits associated with Ts65Dn mice may be due to the non-Hsa21 orthologous trisomic genes, and more Hsa21 orthologous trisomic genes are necessary to produce trabecular deficits in DS model mice. As more mouse models of DS are developed, multiple models need to be assessed to accurately define DS-associated phenotypes and test potential treatments.Item 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 MedicineFeeding 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.Item Correction of Craniofacial Deficits using Epigallocatechin-3’-gallate Treatment in a Down Syndrome Mouse Model(Office of the Vice Chancellor for Research, 2014-04-11) Tumbleson, Danika M.; Haley, Emily M.; Diallo, Mariyamou; Deitz, Samantha L.; Roper, Randall J.Down syndrome (DS) is caused by trisomy of human chromosome (HSA21). Individuals with DS display distinct craniofacial abnormalities including an undersized, dismorphic mandible which leads to difficulty with eating, breathing, and swallowing. Using the Ts65Dn DS mouse model (three copies of ~50% HSA21 homologs), we have traced the mandibular deficit to a neural crest cell (NCC) deficiency and reduction in first pharyngeal arch (PA1 or mandibular precursor) at embryonic day 9.5. Previous studies have shown that this deficit is caused when NCC fail to migrate from the neural tube to populate the PA1 and fail to proliferate in the PA1. At E9.5, Dyrk1A, a triplicated DS candidate gene, is overexpressed in the PA1 and may cause the NCC and PA1 deficits. We hypothesize that treatment of pregnant Ts65Dn mothers with Epigallocatechin-3’-gallate (EGCG), a known Dyrk1A inhibitor, will correct NCC deficits and rescue the undersized PA1 in trisomic E9.5 embryos. To test our hypothesis, we treated pregnant Ts65Dn mothers with EGCG, where embryos received treatment from either E7-E8 or E0-E9.5. Our preliminary study found variable increases in PA1 volume and NCC number between treatment regimens, with several treatment groups indicating EGCG treatment has the potential to rescue the NCC deficit in the mandibular precursor. We found an increase in NCC number and PA1 volume with E7-E8 EGCG treatment in 21-24 somite embryos from trisomic mothers and in euploid embryos from euploid mothers treated from E0-E9.5. With EGCG treatment, we also observed a decrease in the average somite number of embryos from trisomic mothers, but an increase in those mothers’ average litter size. This study is important because it helps define the specific dosage and timing of ECGC and how it may affect specific DS phenotypes. These findings provide preclinical testing for a potential therapy for craniofacial disorders linked to DS.Item Cross-Sectional Exploration of Plasma Biomarkers of Alzheimer's Disease in Down Syndrome: Early Data from the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) Study(MDPI, 2021-04-28) Hendrix, James A.; Airey, David C.; Britton, Angela; Burke, Anna D.; Capone, George T.; Chavez, Ronelyn; Chen, Jacqueline; Chicoine, Brian; Costa, Alberto C.S.; Dage, Jeffrey L.; Doran, Eric; Esbensen, Anna; Evans, Casey L.; Faber, Kelley M.; Foroud, Tatiana M.; Hart, Sarah; Haugen, Kelsey; Head, Elizabeth; Hendrix, Suzanne; Hillerstrom, Hampus; Kishnani, Priya S.; Krell, Kavita; Ledesma, Duvia Lara; Lai, Florence; Lott, Ira; Ochoa-Lubinoff, Cesar; Mason, Jennifer; Nicodemus-Johnson, Jessie; Proctor, Nicholas Kyle; Pulsifer, Margaret B.; Revta, Carolyn; Rosas, H. Diana; Rosser, Tracie C.; Santoro, Stephanie; Schafer, Kim; Scheidemantel, Thomas; Schmitt, Frederick; Skotko, Brian G.; Stasko, Melissa R.; Talboy, Amy; Torres, Amy; Wilmes, Kristi; Woodward, Jason; Zimmer, Jennifer A.; Feldman, Howard H.; Mobley, William; Medical and Molecular Genetics, School of MedicineWith improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer's disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid β peptides (Aβ1-40, Aβ1-42), and glial fibrillary acidic protein (GFAP) were undertaken with previously published methods. The clinical data from the baseline visit include demographics as well as the cognitive measures under the Severe Impairment Battery (SIB) and Down Syndrome Mental Status Examination (DS-MSE). Biomarker distributions are described with strong statistical associations observed with participant age. The biomarker data contributes to understanding DS-AD across the spectrum of disease. Collectively, the biomarker data show evidence of DS-AD progression beginning at approximately 40 years of age. Exploring these data across the full LIFE-DSR longitudinal study population will be an important resource in understanding the onset, progression, and clinical profiles of DS-AD pathophysiology.Item Current Analysis of Skeletal Phenotypes in Down Syndrome(Springer, 2021) Thomas, Jared R.; Roper, Randall J.; Biology, School of SciencePurpose: 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.