IU Indianapolis ScholarWorks :: Browsing by Subject "Down syndrome (DS)"

Browsing by Subject "Down syndrome (DS)"

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ANALYSIS OF CO-OCCURRING PHENOTYPES IN INFANTS WITH DOWN SYNDROME WITH CARDIAC DEFECTS
(Office of the Vice Chancellor for Research, 2011-04-08) Shepherd, Nicole; Duvall, Nichole; Stone, Sandra B.; Davis, Charlene; Stanley, Maria; Roper, Randall J.
Down syndrome (DS), caused by a trisomy 21, is the most common chromosomal aneuploidy occurring in approximately 1 of 750 live births. Individuals with DS exhibit craniofacial dysmorphology, cardiac defects, gastrointestinal problems, and cognitive impairment, although these phenotypes vary in incidence and severity. Common cardiac defects are usually recognized in young infants with DS and include atrial septal anomalies, ventricular septal abnormalities, atrioventricular canal defects, and patent ductus arteriosus. Additional abnormalities may also affect infants with DS, but not be identified until later in life. Since multiple phenotypes are found in these individuals, we hypothesize that children with a severe congenital heart defect may be at increased risk for additional medical issues. To investigate this hypothesis, we performed a retrospective chart review of 170 infants with DS between birth and 6 months of age who were referred to the Down Syndrome Program at Riley Hospital for Children from August 2005 to July 2010. We analyzed comorbidity in infants with upper airway obstruction (UAO) or a feeding problem with and without a severe congenital heart defect. Our data show that 33% of infants without a cardiac defect have identified UAO while 44% with a severe cardiac defect have identified UAO. Additionally, 59% of infants without a cardiac defect compared to 49% with a severe cardiac defect have a feeding problem. With the knowledge of these comorbid clinical features in DS, healthcare providers may be able to identify potential complications affecting infants with DS earlier in life.
Cerebrovascular disease drives Alzheimer plasma biomarker concentrations in adults with Down syndrome
(medRxiv, 2023-11-30) Edwards, Natalie C.; Lao, Patrick J.; Alshikho, Mohamad J.; Ericsson, Olivia M.; Rizvi, Batool; Petersen, Melissa E.; O’Bryant, Sid; Flores-Aguilar, Lisi; Simoes, Sabrina; Mapstone, Mark; Tudorascu, Dana L.; Janelidze, Shorena; Hansson, Oskar; Handen, Benjamin L.; Christian, Bradley T.; Lee, Joseph H.; Lai, Florence; Rosas, H. Diana; Zaman, Shahid; Lott, Ira T.; Yassa, Michael A.; Gutierrez, José; Wilcock, Donna M.; Head, Elizabeth; Brickman, Adam M.; Neurology, School of Medicine
Importance: By age 40 years over 90% of adults with Down syndrome (DS) have Alzheimer's disease (AD) pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with DS have elevated cerebrovascular disease (CVD) markers that track with the clinical progression of AD, suggesting a role for CVD that is hypothesized to be mediated by inflammatory factors. Objective: To examine the pathways through which small vessel CVD contributes to AD-related pathophysiology and neurodegeneration in adults with DS. Design: Cross sectional analysis of neuroimaging, plasma, and clinical data. Setting: Participants were enrolled in Alzheimer's Biomarker Consortium - Down Syndrome (ABC-DS), a multisite study of AD in adults with DS. Participants: One hundred eighty-five participants (mean [SD] age=45.2 [9.3] years) with available MRI and plasma biomarker data were included. White matter hyperintensity (WMH) volumes were derived from T2-weighted FLAIR MRI scans and plasma biomarker concentrations of amyloid beta (Aβ42/Aβ40), phosphorylated tau (p-tau217), astrocytosis (glial fibrillary acidic protein, GFAP), and neurodegeneration (neurofilament light chain, NfL) were measured with ultrasensitive immunoassays. Main outcomes and measures: We examined the bivariate relationships of WMH, Aβ42/Aβ40, p-tau217, and GFAP with age-residualized NfL across AD diagnostic groups. A series of mediation and path analyses examined causal pathways linking WMH and AD pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. Results: There was a direct and indirect bidirectional effect through GFAP of WMH on p-tau217 concentration, which was associated with NfL concentration in the entire sample. Among cognitively stable participants, WMH was directly and indirectly, through GFAP, associated with p-tau217 concentration, and in those with MCI, there was a direct effect of WMH on p-tau217 and NfL concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. Conclusions and relevance: The findings suggest that among individuals with DS, CVD promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of AD. This work joins an emerging literature that implicates CVD and its interface with neuroinflammation as a core pathological feature of AD in adults with DS.
Correction of cerebellar movement related deficits by normalizing Dyrk1a copy number in the Ts65Dn mouse model for Down syndrome
(Office of the Vice Chancellor for Research, 2016-04-08) Patel, Roshni; Stringer, Megan; Abeysekera, Irushi; Roper, Randall J.; Goodlett, Charles R.
Elucidation of the underlying mechanisms involved in brain related deficits of Down syndrome (DS) would be useful for consideration of therapeutic interventions. Several DSspecific phenotypes have been hypothesized to be linked to altered expression or function of specific trisomic genes. One such gene of interest is D YRK1A , which has been implicated in behavioral functions of the hippocampus and cerebellum. The Ts65Dn mouse model for DS includes a triplication of D yrk1a in addition to a triplication of >100 other human chromosome 21 mouse orthologs. To evaluate the role of D yrk1a in cerebellar function, we have genetically normalized the D yrk1a copy number in otherwise trisomicTs65Dn mice and reduced D yrk1a copy number in otherwise euploid mice (2N) for a total of 3 alternative genetic doses of D yrk1a: EuploidDyrk1a +/+ , EuploidDyrk1a +/, Ts65DnDyrk1a +/+/+ , and Ts65DnDyrk1a +/+/. Cerebellar movementrelated function in these knockdown models is being assessed through a novel behavioral balance beam task. Additionally, levels of D yrk1a activity in the cerebellum for all genotypes were analyzed by HPLC. We have previously demonstrated that Ts65DnDyrk1a +/+/+ mice perform worse in the balance beam task in comparison to EuploidDyrk1a +/+ mice. Preliminary results of the current study do not indicate such a difference among Ts65DnDyrk1a +/+/+ mice in comparison to EuploidDyrk1a +/+ mice. We hypothesize that the lack of replication of the previous findings may be due to differences in postweaning housing environments. Mice in the previous study were singlehoused, whereas mice in the present study were grouphoused, which may help mitigate motor deficits in the trisomic mice. Additionally, current trends display a deficit in balance beam performance of both the EuploidDyrk1a +/and the Ts65DnDyrk1a +/+/groups, which suggests that reducing the copy number of D yrk1a by one may have detrimental effects on motor coordination. Concomitant analysis of the balance beam performances and Dyrk1a activity levels may indicate the sensitivity of the balance beam task to assess the role Dyrk1a activity in cerebellar function.
Deficits in a Radial-Arm Maze Spatial Pattern Separation Task and Cell Proliferation in a Mouse Model for Down Syndrome
(Office of the Vice Chancellor for Research, 2016-04-08) Stringer, Megan; Podila, Himabindu; Dalman, Noriel; East, Audrey; Roper, Randall J.; Goodlett, Charles R.
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 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. Epigallocatechin-3-gallate (EGCG), the main polyphenol in green tea, inhibits Dyrk1a activity. We have shown that a three-week EGCG treatment normalizes skeletal abnormalities in Ts65Dn mice, yet did not rescue deficits in the Morris water maze spatial learning task or novel object recognition. 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; 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. Beginning on postnatal day 75, 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. 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.
The Effect of 200mg/kg EGCG Oral Gavage Treatment on the Cerebellar-Dependent Behavior in a Down Syndrome Mouse Model
(Office of the Vice Chancellor for Research, 2016-04-08) Dalman, Noriel; Stringer, Megan; Abeysekera, Irushi; East, Audrey; Patel, Roshni; Roper, Randall J.; Goodlett, Charles R.
Trisomy 21 (Ts21) causes deficits in motor and cognitive ability that are hallmark phenotypes in Down syndrome (DS). The Ts65Dn mouse model of DS has about 50% of the orthologous genes that are triplicated from human chromosome 21, including the Dual specificity tyrosinephosphorylation-regulated kinase 1A (Dyrk1A) gene. Three copies of Dyrk1A have been implicated in the motor and cognitive deficits and altered cerebellar structure and function may contribute these impairments in Ts65Dn mice. Epigallocatechin 3-gallate (EGCG) is a catechin found in green tea and an inhibitor of Dyrk1A activity. We hypothesize that a 200mg/kg EGCG treatment given by oral gavage will inhibit Dyrk1A activity in the cerebellum of Ts65Dn mice and rescue deficits in motor coordination while performing the balance beam task. Evidence of improvement in this task would be observed as a reduction of paw slips as the animal traverses across beams of varying widths. In previous studies, EGCG treatment was placed in the animal’s water to be consumed but EGCG rapidly degrades in solution and it is difficult to control treatment doses via treatment in drinking water, due to each animal’s consumption behavior. This study utilized a daily oral gavage treatment of EGCG to control the dose and limits loss due to degradation. Results to date indicate that the Ts65Dn mice show deficits on the balance beam task relative to the euploid mice, particularly at the narrowest beam width used. The EGCG treatment does not appear to improve the performance of the Ts65Dn mice, though the lack of observed effects of EGCG may be due to the relatively low numbers of Ts65Dn-EGCG treated mice that have completed testing so far. One notable trend is that we will continue to test additional mice to gain sufficient power to determine conclusively whether EGCG improves motor coordination performance in Ts65Dn mice.
Effect of EGCG on granule cell proliferation in the adult dentate gyrus of the Ts65Dn mouse
(Office of the Vice Chancellor for Research, 2015-04-17) Sheikh, Zahir; Goodlett, Charles R.
Down syndrome (DS) is the most common genetic disorder that results in cognitive abnormalities and occurs in approximately 1 in 700 live births. This disorder is caused by an extra copy of human chromosome 21 (Hsa21) which increases the dosage of the genes on that chromosome. Ts65Dn mice, which are the most studied mouse model for DS, are trisomic for segments of mouse chromosome 16 (Mmu16) which contain approximately half the genes found on Hsa21. These mice express some of the physical and behavioral abnormalities associated with DS. Previous research has shown impaired performance of Ts65Dn mice in hippocampaldependent tasks, such as in the radial arm maze task, compared to euploid control mice. Success in such tasks is thought to depend on the ability of the hippocampus to generate granule cells within the dentate gyrus. Young granule cells are highly active after integration and are required for memory formation. Previous research shows that Ts65Dn have a reduction in the formation of granule cells which leads us to hypothesize that Ts65Dn mice will perform worse in the radial arm maze compared to euploid controls. This leads us to conclude that Ts65Dn mice have reduced granule cell proliferation relative to controls. We are investigating the effects of EGCG, a polyphenolic component of green tea, on granule cell proliferation in adult mice. Different pathways are suggested to be effected by EGCG, such as by inhibiting Dyrk1a that is overproduced in DS mice or by up-regulation of the sonic hedgehog receptor Patched. Using BrdU peroxidase immunohistochemistry to label newly generated granule cells in the adult mouse dentate gyrus, we hypothesize that EGCG will increase cell proliferation in the granule cell layer of the dentate gyrus.
Effects of 50 mg/kg EGCG Treatment of Ts65Dn Down Syndrome Mice on Novel Object Recognition
(Office of the Vice Chancellor for Research, 2016-04-08) Stringer, Megan; Roper, Randall J.; Goodlett, Charles R.; Delgado Taboada, Maria Fatima
Down syndrome (DS) is caused by trisomy of chromosome 21, and affects 1/700 live births. DYRK1A, a gene found in three copies in humans with DS and Ts65Dn DS mice, has been linked to alterations in morphology and function of the brain resulting in cognitive impairment. Epigallocatechin-3-gallate (EGCG), an inhibitor of DYRK1A activity, has been proposed as a possible treatment. Using the Ts65Dn DS mouse model, we examined the effects of EGCG treatment on on hippocampal dependent learning and memory using a novel object recognition task (NOR). A previous study analyzing the effects of EGCG at a concentration 30mg/kg/day showed that there was no genotype or treatment effect in the NOR task when treatment is continuous through testing. In this study, the mice were given 50 mg/kg/day EGCG or water via their drinking water starting at 3 weeks of age. The mice were handled two days before testing and then underwent a series of behavioral tests including NOR. They underwent testing at 3 weeks and 7 weeks of treatment. Treatment was continuous throughout behavioral testing. NOR consists of a box with the objects placed diagonally from each other. The mice underwent 3 days of testing with 15 minute sessions per day consisting of habituation, exposure, and test day, all of which were recorded and analyzed to determine time spent exploring novel object in relation to familiar. The amount of time spent at each object was scored by three independent scorers, blind to genotype and treatment. We observed no genotype or treatment effect at either the 3 or 7 week test results, which is consistent with our past results. A higher dose, along with a more sensitive test of recognition memory, may be needed in order to show a treatment effect on the Ts65Dn mice.
Effects of EGCG Treatment of Ts65Dn Down Syndrome Mice on a Balance Beam Task
(Office of the Vice Chancellor for Research, 2015-04-17) Taboada, Maria Fatima Delgado; Stringer, Megan; Roper, Randall J.; Goodlett, Charles R.
Down syndrome (DS) is caused by trisomy of chromosome 21, and affects 1/700 live births. DS results in about 80 clinical phenotypes, including cognitive impairment. DYRK1A, a chromosome 21 gene, has been linked to alterations in morphology and function of the brain resulting in cognitive impairment. Epigallocatechin-3-gallate (EGCG), an inhibitor of DYRK1A activity, has been proposed as a possible treatment for cognitive deficits seen in individuals with DS. Using the Ts65Dn DS mouse model, we examined the effects of EGCG treatment on cerebellum dependent tasks using a balance beam test. We hypothesized that treatment with EGCG would improve Ts65Dn performance on the balance beam. In a first experiment, mice were given a dose of ~30 mg/kg/day EGCG, which showed no significant improvement in the balance beam task. In a second experiment, mice were given a dose of 100 mg/kg/day EGCG or water (control) starting at 3 weeks of age. The mice were handled two days before testing and then underwent a series of behavioral tasks including the balance beam test. The mice traversed three beams of differing widths (12, 9 and 6 mm), and three consecutive trials for each were recorded for further analysis. The balance beam recordings were scored by three independent scorers, blind to genotype and treatment, and the number of hind paw slips for each trial were scored. Our preliminary results indicate that the Ts65Dn mice are impaired at this task and have more hind paw slips compared to euploid controls. A larger number of animals should help to distinguish any differences in Ts65Dn mice due to EGCG treatment.
Effects of EGCG treatment on deficits in a radial-arm maze spatial pattern separation task in a Down syndrome mouse model
(Office of the Vice Chancellor for Research, 2015-04-17) Stringer, Megan; Stancombe, Kailey; Gainey, Sean; Sheikh, Zahir; Abeysekera, Irushi; Goodlett, Charles R.; Roper, Randall J.
Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa 21) and results in a constellation of phenotypes that include intellectual disability. Ts65Dn mice, the most extensively studied model of DS, have three copies of approximately half the genes on Hsa 21 and display many of the phenotypes associated with DS, including cognitive deficits. DYRK1A is found in three copies in humans with Trisomy 21 and has increased expression in a number of tissues. Dyrk1a is also found in three copies in Ts65Dn mice, and has been shown to be involved in a number of critical pathways including CNS development and osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), the main polyphenol found in green tea, is an inhibitor of Dyrk1a activity. We have previously shown that a three week treatment with EGCG normalizes skeletal abnormalities in Ts65Dn mice. Previous work has found that Ts65Dn mice are significantly impaired in several hippocampal-dependent tasks, including the Morris water maze and novel object recognition. Another hippocampal-dependent process, pattern separation, is the ability to differentiate between similar memories acquired during learning. Distinctive encoding of these similar memories in hippocampal formation is thought to be necessary to distinguish between them. Experimental reductions in adult neurogenesis have produced impairments in pattern separation performance. Given that recent studies in Ts65Dn mice have reported significant reductions in adult hippocampal neurogenesis, we hypothesize that Ts65Dn mice will be impaired in the pattern separation task. Furthermore, we hypothesize that treating Ts65Dn mice with EGCG throughout task learning would improve performance to control levels. A radial arm maze-delayed non-matching-toplace pattern separation task with three different degrees of spatial separation is used. Preliminary data suggests that, in contrast to control mice, Ts65Dn mice do not improve their performance over training.
Effects of Epigallcatechin-3-gallate in Novel Object Recognition of Ts65Dn Down Syndrome Mice
(Office of the Vice Chancellor for Research, 2015-04-17) Minhas, Saniya; Abeysekera, Irushi; Delgado, Fatima; Dhillon, Hardeep; Goodlett, Charles R.; Roper, Randall J.
Down syndrome (DS) is one of the most common genetic disorders and has an incidence of 1/700 births; which can lead to many impairments, both physically and mentally. All individuals with DS have cognitive impairments which results in learning and memory deficits. To study these deficits, we use the Ts65Dn mouse model that carries trisomy of approximately 50% of the genes found on human chromosome 21. DYRK1A, a gene found in three copies in both humans with DS and Ts65Dn mice has been shown to have increased expression in the brains of humans with DS. DYRK1A protein is involved in a number of critical pathways including CNS development. Epigallcatechin-3-gallate (EGCG), the main polyphenolic compound found in green tea, inhibits DYRK1A. We hypothesize that EGCG treatment help improve cognitive deficits in trisomic mice. After treatment, the mice were subjected to behavioral tasks, including the Novel Object Recognition (NOR) test. Our results indicate that there was a significant difference that existed due to trisomy in Ts65Dn mice; but there was no significant effect of a low dose EGCG treatment. Further studies are examining the effects of the NOR task after a higher dose EGCG treatment.

Browsing by Subject "Down syndrome (DS)"

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