Background: Prevalence of metabolic disturbances is higher among individuals with neurodevelopmental disorders (NDDs), yet this association has been poorly studied. Investigation into human disease remains challenging, as a complete pathophysiological understanding relies on accurate modeling and highly controlled variables. As such, genetically engineered mouse models are increasingly used to gain insight into the biology of human NDDs, but preclinical research focus has been mainly on behavioral and neurophysiological abnormalities. Mouse models engineered to embody human-equivalent genetic variations can display discrepancies to human phenotypes, therefore a thorough characterization of mouse phenotypes must be conducted in order to evaluate how accurately a mouse model embodies a human phenotype. Also, mouse models can help discover unsuspected abnormalities that can be further validated in humans. Objective: In this study, we sought to investigate the metabolic alterations derived from NDD-associated genetic polymorphisms in previously-validated genetic mouse models. Due to the similarities in NDD-associated phenotypic expression, we hypothesized that our NDDs of interest would express similar metabolic signatures. Further, we anticipated that we might uncover unknown metabolic anomalies, and that sex may alter these differences. Methods: We used the Comprehensive Lab Animal Monitoring System coupled to EchoMRI, as well as quantification of key plasma metabolites by liquid chromatography-mass spectrometry to characterize and compare basal metabolism in three mouse models of NDDs, namely Down syndrome (Dp(16)Yey/+ mice), 16p11.2 deletion syndrome (16p11.2df/+ mice) and Fragile X syndrome (Fmr1-/- KO mice) and their wild-type (WT) counterparts. Results: Our study reveals that each mouse model expresses a unique metabolic signature that is sex-specific, independent of the amount of food consumed and minimally influenced by physical activity. We found striking differences in body composition, respiratory exchange ratio, caloric expenditure and concentrations of circulating plasma metabolites related to mitochondrial function. Conclusion: Providing novel insight into NDD-associated metabolic alterations provides a basis for future studies aimed at understanding physiological mechanisms and provides a point of reference for research aimed at detecting changes in response to intervention.

Maintenance of gene dosage is important for proper cellular function and development, as evidenced by the natural silencing of one X-chromosome in mammalian females, and by the embryonic lethality of most autosomal aneuploidy. A notable exception is Down syndrome (DS), which occurs in 1/700 newborns. It has been known for 50+ years that DS is caused by trisomy for chromosome 21 (chr21), yet biological understanding remains wanting; even what cell types and pathways are impacted by chr21 dosage has remained unclear. Given the complexity of DS, better experimental approaches have been needed. This thesis advances understanding of DS pathobiology using an innovative approach that translates the X-inactivation mechanism via the XIST gene, to an inducible system to “silence trisomy” in DS patient-derived iPSCs and their differentiated derivatives. I investigated the most immediate and direct effects of silencing trisomy on mRNAs genome-wide. Initial studies revealed trisomy 21 (T21) impairs early developmental pathways for two major cell type processes: neurogenesis and, surprisingly, angiogenesis. Further analysis of endothelial cells showed chr21 overexpression reduces pathways relating to cell migration, projection, and signaling, and functional assays showed delayed response to angiogenic cues causing a deficit in microvessel formation. The previously unknown cell-autonomous effect of T21 on angiogenesis has broad significance for systems impacted, including brain and heart development, and comorbidities throughout life such as early-onset Alzheimer’s disease. This work also has implications for understanding of dosage sensitivity and genome balance, a fundamental but poorly understood aspect of genome biology.

Down syndrome (DS) is a developmental disorder caused by a triplication of human chromosome 21, which contains approximately 550 genes. DS is the most common autosomal aneuploidy occurring with an incidence of 1 in 793 live births. Hallmarks of DS include abnormal central nervous system (CNS) development and function resulting in intellectual disability (ID), motor dysfunction, and early onset Alzheimer’s neuropathology. Studies have elucidated widespread neurohistological abnormalities in brains of fetuses with DS as early as 20 weeks of gestation, suggesting that early dysfunction in neural development may set the stage for exacerbated CNS abnormalities throughout life. Additionally, the complex constellation of symptoms associated with DS changes over the lifespan, particularly in adolescence and in middle to old age. Thus, these periods may represent opportune windows for age-specific therapeutic interventions. Due to ethical and practical constraints, use of human samples is alone insufficient to characterize the etiological underpinnings of DS phenotypes across the lifespan. Furthermore, while human data are instructive for drug development, preclinical trials are necessary for target validation, to establish dosage, and to prove safety and efficacy of any proposed therapeutic. With the advent of mouse models of DS, informative studies on the neurobiology of DS as well as preclinical testing of proposed therapies are possible. Here, we use a multi-pronged approach to assess molecular, neuroanatomical, and behavioral phenotypes indicative of brain and SC function in three distinct mouse models of DS: Ts1Cje, Ts65Dn, and Dp16. We identify neurodevelopment phenotypes, cytoarchitectural aberrations, bioenergetic abnormalities, myelination deficits, and motor/cognitive dysfunction at multiple ages spanning the period between embryonic day 12.5 and 6-7 months in trisomic mice. Additionally, we show that while Ts65Dn mice recapitulate all known phases of histological, functional, and behavioral phenotypes typical of DS starting from prenatal development and into middle age, this is not true for the Ts1Cje or Dp16 models. Lastly, we present promising outcomes of two possible therapies for cognitive and motor dysfunction in Ts65Dn mice. Altogether our findings provide insights into the underlying neurobiology of ID and motor dysfunction in DS and elucidate molecular changes that can be targeted for future therapeutic intervention. / 2018-07-09T00:00:00Z

Indiana University-Purdue University Indianapolis (IUPUI) / Down syndrome (DS) is a genetic disorder that results from triplication of human chromosome 21 (Hsa21) and occurs in around 1 in 1000 live births. All individuals with DS present with skeletal abnormalities typified by craniofacial features, short stature and low bone mineral density (BMD). Differences between males and females with DS suggest a sexual dimorphism in how trisomy affects skeletal deficits associated with trisomy 21 (Ts21). Previous investigations of skeletal abnormalities in DS have varied methodology, sample sizes and ages making the underlying causes of deficits uncertain. Mouse models of DS were used to characterize skeletal abnormalities, but the genetic and developmental origin remain unidentified. Over-expression Dyrk1a, found on Hsa21 and mouse chromosome 16 (Mmu16) has been linked to cognitive deficits and skeletal deficiencies. Dp1Tyb mice contain three copies of all of the genes on Mmu16 that are homologous to Hsa21, males and females are fertile, and therefore are an excellent model to test the hypothesis that gene dosage influences the sexual dimorphism of bone abnormalities in DS. Dp1Tyb at 6 weeks 16 weeks showed distinctive abnormalities in BMD, trabecular architecture, and reduced bone strength over time that occur generally through an interaction between sex and genotype. Increased gene dosage and sexual dimorphism in Dp1Tyb mice revealed distinct phenotypes in bone formation and resorption. To assess how Dyrk1a influences the activity and function of osteoblasts Ts65Dn female trisomic mice, female mice with a floxed Dyrk1a gene (Ts65Dn, Dyrk1afl/+) were be bred to Osx1-GFP::Cre+ mice to generate Ts65Dn animals with a reduced copy of Dyrk1a in mature osteoblast cells. Female Ts65Dn,Dyrk1a+/+/+ and Ts65Dn,Dyrk1a+/+/-displayed significant defects in both trabecular architecture and cortical geometry. Ultimate force was reduced in trisomic animals, suggesting whole bone and tissue level properties are not adversely affected by trisomy. Reduction of Dyrk1a functional copy number in female mice did not improve skeletal deficits in an otherwise trisomic animal. Dyrk1a may not alter osteoblast cellular activity in an autonomous manner in trisomic female mice. These data establish sex, gene dosage, skeletal site and age as important factors in skeletal development of the skeleton in DS mice, potentially paving the way for identification of the causal dosage-sensitive genes in both male and female animals.

Although called by our vocation and the mission of Catholic schools, students with disabilities (SWD) are underserved in Catholic education. Only approximately 1% of the nation’s SWD population (67,000 students) attend private schools with 40% identified as Catholic (U.S. Department of Education, 2018a). Despite the small number, SWD and peers that struggle are attending our schools and therefore, must be included meaningfully and served successfully. This study dispels the myths around the admission and service of students with Down syndrome in Catholic schools and informs educational leaders on how to create and sustain inclusive environments aligned with Catholic Social Teachings. A qualitative research approach comprising semi-structured interviews and document review was used in the study. The framework of Catholic social teachings and the epistemology of inclusivity were used to get answers to the two research questions: (a) how does a Catholic elementary school serve students with Down syndrome? and (b) What are the challenges in serving students with Down syndrome in a Catholic elementary school? The significance of this case study lies in witnessing and documenting one elementary Catholic school’s experience of creating, developing, establishing, and modeling an inclusion environment that serves the needs of its students with Down syndrome. This study ultimately provides data to those in similar Catholic school settings in developing and implementing fully inclusive environments. This study further expands the discussion in the field of Catholic education about the right(s) of all Catholic children, especially students with Down syndrome.

The purpose of this thesis is to investigate the link between advanced paternal ages (APA) (i.e., APA ≥ 35 years and APA ≥ 50 years) and genetic diseases and congenital anomalies. Currently, the relationship between both advanced paternal ages and genetic diseases and congenital anomalies remains unclear. However, there is room for improvement to systematically investigate the relationship between specific congenital anomalies in newborns and advanced paternal ages. More recently, the link between advanced paternal age (as opposed to existing studies analyzing advanced maternal age alone) and genetic diseases has been recognized by researchers, epidemiologists, and various health experts. Thus, this study serves to examine the effect of advanced paternal ages on the likelihood of birth defects using a new dataset intended to discover those relationships. I create three different datasets and utilize 12 statistical models to analyze the relationship between advanced paternal ages (APA ≥ 35 years and APA ≥ 50 years) (while including advanced maternal age or AMA [AMA ≥ 35 years]) and genetic diseases and congenital anomalies. I focus on Down syndrome, cleft lip with or without cleft palate, and meningocele/spina bifida and explore the relationship between both advanced parental ages. I explore whether (a) the advanced paternal ages and (b) the advanced maternal age increase the likelihood of newborn reproductive defects: (a) Down syndrome, (b) cleft lip with or without cleft palate, and (c) meningocele/spina bifida. This study includes all U.S. births between 2016 and 2019 using the CDC Natality Registry[1] database (2020). I perform the analyses using logistic regression models (to estimate odds ratios) that provide explanations of the relationship between each birth defect and advanced paternal ages. Analysis results suggest that advanced paternal ages (APA ≥ 35 years and APA ≥ 50 years) are positively associated with Down syndrome, whereas advanced paternal age (APA ≥ 35 years) is negatively associated with cleft lip with or without cleft palate. The results from the advanced paternal ages models do not suggest any causal relationship/effect on spina bifida. The results of this study are expected to offer some insight of the following reproductive defects: (a) Down syndrome, (b) cleft lip with or without cleft palate, and (c) meningocele/spina bifida. [1] Collection of data for all variables used in this research are obtained with full permission from: United States Department of Health and Human Services (US DHHS), Centers for Disease Control and Prevention" "(CDC), National Center for Health Statistics (NCHS), Division of Vital Statistics, Natality public-use data 2016-2019, on CDC" WONDER Online Database, October 2020. Accessed at http://wonder.cdc.gov/natality-expanded-current.html on Jun 6, 2021, 1:24:47 PM;" United States Department of Health and Human Services (US DHHS), Centers for Disease Control and Prevention" "(CDC), National Center for Health Statistics (NCHS), Division of Vital Statistics, Natality public-use data 2016-2019, on CDC" "WONDER Online Database, October 2020. Accessed at http://wonder.cdc.gov/natality-expanded-current.html on Jun 6, 2021, 1:29:36 PM;" And United States Department of Health and Human Services (US DHHS), Centers for Disease Control and Prevention""(CDC), National Center for Health Statistics (NCHS), Division of Vital Statistics, Natality public-use data 2016-2019, on CDC" "WONDER Online Database, October 2020. Accessed at http://wonder.cdc.gov/natality-expanded-current.html on Jun 6, 2021, 1:07:36 PM."

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<p>Down syndrome (DS) is a genetic condition caused by the triplication of human chromosome  21 and presents with many phenotypes including decreased brain size, hypocellularity in the brain,  and assorted ocular phenotypes. Some of the ocular phenotypes seen are increased risk of cataracts,  accommodation difficulties, increased risk of refractive errors, and increased retinal thickness. The  Ts65Dn mouse model of DS is a classically used mouse model as it presents a number of  phenotypes also seen in those with DS. Some of these phenotypes include decreased brain volume,  abnormal synaptic plasticity, and ocular phenotypes. These ocular phenotypes include decreased  visual acuity, cataracts, and increased retinal thickness. The Ts65Dn mouse model is trisomic for <em>Dyrk1a</em>, a gene of interest in DS research. We hypothesize that there will be a genotypic and sex effect of retinal thickness and retinal ganglion cell (RGC) count at postnatal day 15 in the Ts65Dn  mouse model of DS. Retinal slices were taken from male and female trisomic and euploid Ts65Dn  mice at P15 and fluorescently labeled for RGCs and bipolar cells via immunohistochemistry. The  retinas were measured for total retinal thickness and RNA-binding protein (RBPMS) positive cells in the RGC layer were counted. There was no genotypic or sex effect when comparing retinal  thickness in trisomic mice as compared to euploid mice. There was a genotypic effect of RBPMS  positive cell count in which the trisomic mice had a higher number of RBPMS positive cells than  euploid mice. Increased retinal thickness along with increased RGC number have both been  implicated with decreased apoptosis in the retina. In the Ts65Dn mouse model along with in  individuals with DS, this could be due to an increase in DYRK1A protein levels reducing apoptosis.  In future studies, determining DYRK1A’s influence in retinal thickness and RGC number could  result in a treatment for overactive <em>DYRK1A</em> that could normalize retinal thickness and RGC  number in those with DS.</p>

Speech-Language Pathologists provide services to youth with Down syndrome. The purpose of this study was to (a) determine if parents are aware that speech-language pathologists can provide services to prepare their children for secondary transition; (b) identify the parents’ perceptions of the services provided by speech-language pathologists; and (c) determine if in the parents’ opinion, the speech-language pathologist provided a vital role in preparing their child for transition. Using nonprobability snowball sampling, this cross-sectional mixed-method survey study included 85 parents of youth (ages 14-22) with Down syndrome across the United States. Parents rated their experiences and described their beliefs and perceived helpfulness toward their child’s SLP(s) regarding secondary transition. To identify further thoughts regarding parents’ perceptions of their engagement in the transition process, deductive, inductive, and thematic analysis of two open-ended questions uncovered three themes of responses pertaining to SLPs in secondary transition services, noted as satisfied, career, and unsatisfactory.