Down Syndrome Population Research Articles

P.036 Stroke in people with Down Syndrome: a retrospective study

Background: There are only few studies approaching the prevalence and cause of stroke in children and adults with Down Syndrome (DS). Methods: We did a retrospective study of our cohort of 4962 patients of Jerome Lejeune Institute since 2007. We collected age of stroke, clinical presentation, cause (TOAST classification), treatment and clinical course. Results: We identified 20 patients from 6 to 56 years old .In all cases, it was a stroke of ischemic origin.: 8 children with a prevalence of 0.33%. 4 had a cardio-embolic origin, 3 secondary to Moya-Moya syndrome and one of undetermined origin. 12 adults (21 to 52 years old) with a prevalence of 0.46%.The majority of the causes of these ischemic strokes are indeterminate (9 of 12), Conclusions: We found a low prevalence and an ischemic cause in all cases of stroke, which differs from the general population. For pediatric stroke, the causes are expected thromboembolic in a context of heart disease most often or secondary to a Moya-Moya syndrome. For adult strokes, the average age is younger than that in the general population and the cause is indeterminate in most cases. We must better explore our patients to identify the risk factors in DS population.

Exploring the Pathogenesis of Alzheimer Disease in Basal Forebrain Cholinergic Neurons: Converging Insights From Alternative Hypotheses.

Alzheimer disease (AD) represents an oncoming epidemic that without an effective treatment promises to exact extraordinary financial and emotional burdens (Apostolova, 2016). Studies of pathogenesis are essential for defining critical molecular and cellular events and for discovering therapies to prevent or mitigate their effects. Through studies of neuropathology, genetic and cellular, and molecular biology recent decades have provided many important insights. Several hypotheses have been suggested. Documentation in the 1980s of selective loss of cholinergic neurons of the basal forebrain, followed by clinical improvement in those treated with inhibitors of acetylycholinesterase, supported the “cholinergic hypothesis of age-related cognitive dysfunction” (Bartus et al., 1982). A second hypothesis, prompted by the selective loss of cholinergic neurons and the discovery of central nervous system (CNS) neurotrophic factors, including nerve growth factor (NGF), prompted the “deficient neurotrophic hypothesis” (Chen et al., 2018). The most persuasive hypothesis, the amyloid cascade hypothesis first proposed more than 25 years ago (Selkoe and Hardy, 2016), is supported by a wealth of observations. Genetic studies were exceptionally important, pointing to increased dose of the gene for the amyloid precursor protein (APP) in Down syndrome (DS) and a familial AD (FAD) due to duplication of APP and to mutations in APP and in the genes for Presenilin 1 and 2 (PSEN1, 2), which encode the γ-secretase enzyme that processes APP (Dorszewska et al., 2016). The “tau hypothesis” noted the prominence of tau-related pathology and its correlation with dementia (Kametani and Hasegawa, 2018). Recent interest in induction of microglial activation in the AD brain, as well as other manifestations of inflammation, supports the “inflammatory hypothesis” (Mcgeer et al., 2016). We place these findings in the context of the selective, but by no means unique, involvement of BFCNs and their trophic dependence on NGF signaling and speculate as to how pathogenesis in these neurons is initiated, amplified and ultimately results in their dysfunction and death. In so doing we attempt to show how the different hypotheses for AD may interact and reinforce one another. Finally, we address current attempts to prevent and/or treat AD in light of advances in understanding pathogenetic mechanisms and suggest that studies in the DS population may provide unique insights into AD pathogenesis and treatment.

Restoration of aberrant mTOR signaling by intranasal rapamycin reduces oxidative damage: Focus on HNE-modified proteins in a mouse model of down syndrome

Increasing evidences support the notion that the impairment of intracellular degradative machinery is responsible for the accumulation of oxidized/misfolded proteins that ultimately results in the deposition of protein aggregates. These events are key pathological aspects of “protein misfolding diseases”, including Alzheimer disease (AD). Interestingly, Down syndrome (DS) neuropathology shares many features with AD, such as the deposition of both amyloid plaques and neurofibrillary tangles. Studies from our group and others demonstrated, in DS brain, the dysfunction of both proteasome and autophagy degradative systems, coupled with increased oxidative damage. Further, we observed the aberrant increase of mTOR signaling and of its down-stream pathways in both DS brain and in Ts65Dn mice.Based on these findings, we support the ability of intranasal rapamycin treatment (InRapa) to restore mTOR pathway but also to restrain oxidative stress resulting in the decreased accumulation of lipoxidized proteins. By proteomics approach, we were able to identify specific proteins that showed decreased levels of HNE-modification after InRapa treatment compared with vehicle group. Among MS-identified proteins, we found that reduced oxidation of arginase-1 (ARG-1) and protein phosphatase 2A (PP2A) might play a key role in reducing brain damage associated with synaptic transmission failure and tau hyperphosphorylation. InRapa treatment, by reducing ARG-1 protein-bound HNE levels, rescues its enzyme activity and conceivably contribute to the recovery of arginase-regulated functions. Further, it was shown that PP2A inhibition induces tau hyperphosphorylation and spatial memory deficits. Our data suggest that InRapa was able to rescue PP2A activity as suggested by reduced p-tau levels.In summary, considering that mTOR pathway is a central hub of multiple intracellular signaling, we propose that InRapa treatment is able to lower the lipoxidation-mediated damage to proteins, thus representing a valuable therapeutic strategy to reduce the early development of AD pathology in DS population.

TRENDS IN THE RATE OF CONGENITAL HEART DEFECTS IN NEONATES WITH DOWN SYNDROME

International studies demonstrate a phenotypic shift away from complex congenital heart disease (CHD) in neonates with Down syndrome (DS). Screening for DS changed dramatically in 2011 with widespread commercialization of cell-free DNA tests. Trends in the rate of complex CHD in the US DS population

Templates and temporality: An investigation of rhythmic motor production in a young man with Down Syndrome and hearing impairment

The musical rhythmic abilities of people with Down Syndrome (DS) reportedly exceed their general cognitive abilities. Although they display atypical rhythmic production in musical motor tasks, little is known about how their developmental and cognitive differences affect temporal perception or production. Additionally, hearing impairment often excludes potential participants from studies, further limiting our understanding. This case study examined the rhythmic ability of one young adult with DS and moderate-severe hearing impairment when producing limb-motor movements to music in auditory-only and auditory-visual conditions. His temporal accuracy was observed for gross-motor movements to music. Measurements were made of his temporal accuracy and stability when tapping on a drum at three tempi, and when tapping to non-isochronous rhythms. Results revealed temporal deficits in all tasks. However, production improved in tasks that were augmented with visuo-spatial stimuli, and in isochronous beat entrainment at the fastest tempo. Findings were compared to the participant’s cognitive and perceptual profile. Results suggest that his production was limited by developmental factors, but that auditory memory deficits and hearing may account for instability in isochronous entrainment tasks and delayed onset of timing. Recommendations are made for supporting skills in production and perception of auditory rhythms within the DS population.

Abstract WP427: Thrombolysis in With Patients With Down Syndrome and Ischemic Stroke

Background: Down Syndrome (DS) is a genetic disorder cause by trisomy 21. With improvements in medical care, the life expectancy of individuals with DS has increased. As this population ages, they are at risk of strokes. They may have a higher predisposition for cardio embolic strokes given that DS is associated with congenital heart disease. There is scarce data regarding strokes in the DS population. Methods: Nationwide Inpatient Sample (NIS) from 2005 to 2014 was utilized to identify down syndrome patients using ICD CM code 758.0 in secondary diagnostic field and acute ischemic stroke (AIS) with appropriate diagnostic codes in primary field. Intravascular thrombolysis utilization was identified by ICD9 procedure code 99.10 in any procedural field. Differences between categorical variables were tested using the chi-square test and continuous variables using the Student t-test. Results: We identified 4332783 patients with acute ischemic stroke (AIS), 1333 (0.03%) also had a diagnosis of DS. Average age was 71.2years; 47.2% were male and 52.8% female. Patients with DS and AIS were younger (45.6yo vs 71.2years; p<0.0001). They were also more likely to be female (60.7 % vs. 52.8%; p<0.0001). Despite being younger and having less comorbid conditions, patients with ischemic stroke who have DS are less likely to receive thrombolysis than those with ischemic stroke without DS (3.67% vs 5.77%; p =0.001). Although, there was no statistically significant difference in the use of mechanical thrombectomy. DS patients that received thrombolysis were more likely to be male (61.8% vs 38.2%; p=0.0011), and at a teaching hospital (p=0.0016). However, there was increased in-hospital mortality among those DS patients who received thrombolysis compared to the group without thrombolysis (20.5% vs. 5.7%; p=0.004). Conclusion: Patients with DS and AIS have a decreased rate of thrombolysis, yet similar rates of mechanical thrombectomy. However, those DS patients that received thrombolysis had increased in-hospital mortality. We postulate that this may be secondary to increased beta-amyloid peptide accumulation and risk of cerebral amyloid angiopathy in DS. Thrombolysis in this population needs to be further studied.

Adults with Down syndrome: a comprehensive approach to manage complexity.

Down syndrome (DS) is characterised by premature ageing that affects selected organ systems, and persons with this condition can present patterns of co-morbidities and deficits often observed in the older population without DS. However, information on the characteristics of adult persons with DS is limited. The objective of the study is to describe characteristics of adults with DS collected with a standardised, comprehensive assessment instrument. Cross-sectional study. Four hundred thirty adults with DS (age range 18/75years) from three countries (Italy, n=95; USA, n=175; and Canada, n=160). A standardised assessment instrument (interRAI intellectual disability) was used to assess sample characteristics. Mean age ranged from 35.2 (standard deviation 12.0) years in the US sample to 48.8 (standard deviation 9.0) years in the Canadian sample. Most participants in the Italian and US sample were living in private homes, while more than half of those in the Canadian sample were institutionalised. Prevalences of geriatric conditions, including cognitive deficits, disability in the common activities of daily living, symptoms of withdrawal or anhedonia, aggressive behaviour, communication problems, falls and hearing problems were high in the study sample. Gastrointestinal symptoms, skin and dental problems and obesity were also frequently observed. Adults with DS present with a high level of complexity, which may suggest the need for an approach based on a comprehensive assessment and management that can provide adequate care. Further research is needed to understand better the effectiveness of such an approach in the DS population.

Bone Mineral Density Distribution Curves in Spanish Adults With Down Syndrome

According to reports from small-sized case series, adults with Down syndrome (DS) appear to have lower bone mineral density (BMD) than the general population. The objective of our study was to further characterize the bone mass acquisition curve in an adult DS population. This is a retrospective study of 297 adults with DS from the Adult Down Syndrome Outpatient Clinic of a tertiary care hospital in Madrid, Spain, who underwent a bone densitometry (Hologic QDR-4500W), for clinical purposes between January 2010 and June 2015. The mean age of our sample population was 34 yr (±10.9); 51% were women. Bone mass peak was reached earlier and was lower than the general population (around 20–25 yr), with almost parallel curves. The mean BMD was 0.715 ± 0.12 g/cm2 in femoral neck (FN) and 0.872 ± 0.11 g/cm2 in lumbar spine (LS). According to FN scores, 52% of the subjects were classified as osteopenic and 18% as osteoporotic. According to LS scores, frequencies were 54% and 25%, respectively. BMD was considered inadequate for the age (Z-score < −2 standard deviation) in 18% of the subjects at FN and 40% at LS. BMD at LS was significantly lower in males than in females (52% vs 38%, p < 0.001). Male DS subjects had a 2.58-fold (95% confidence interval: 1.57–4.25) higher risk of developing reduced BMD at LS than females. Persons with DS reach the bone mass peak earlier and this bone mass is lower than the general population. Among subjects with DS, male gender is a risk factor for developing low BMD, especially at LS.

The prevalence of the flat foot condition and insole prescription in people with Down's syndrome: a retrospective population-based study.

[Purpose] The general approach for flat foot (FF) treatment in people with Down’s syndrome (DS) is the use of insoles. However, the appropriate timing of the first insole prescription remains unclear. An aim of this present research was to investigate the status of prevalence of FF and orthosis prescription in the DS population. [Subjects and Methods] Two hundred fifteen subjects with DS who were seen at our hospital were retrospectively investigated. Investigated parameters were: prevalence of FF and other foot diseases, ratio and timing of orthopaedic consultation, ratio and timing of orthoses prescription, and mean age at the time of orthosis prescription. [Results] The prevalence of FF was 27.0% (58 subjects), and 50 subjects (23.3%) consulted an orthopaedic surgeon. An orthosis was prescribed for 54 subjects; 88.9% of these orthoses were insoles. Foot and leg orthoses other than insoles were prescribed significantly more frequently for females than males. The mean ages at the time of the first prescription of all types of orthoses and an insole were 7.3 years and 6.4 years, respectively. [Conclusion] The prevalence of FF was low, and the age at which subjects with DS were prescribed an orthosis was relatively high at our institution compared to previous reports. Since physical therapists see patients who could potentially have FF, those with suspected FF should then be referred to an orthopaedic doctor, which would enable the earlier orthosis prescription.

Sclerostin Antibody Treatment Stimulates Bone Formation to Normalize Bone Mass in Male Down Syndrome Mice.

ABSTRACTDown syndrome (DS), characterized by trisomy of human chromosome 21, is associated with a variety of endocrine disorders as well as profound skeletal abnormalities. The low bone mass phenotype in DS is defined by low bone turnover due to decreased osteoclast and osteoblast activity, decreasing the utility of antiresorptive agents in people with DS. Sclerostin antibody (SclAb) is a therapeutic candidate currently being evaluated as a bone anabolic agent. Scl, the product of the sclerostin gene (SOST), inhibits bone formation through its inhibition of Wnt signaling. SclAb increases bone mass by suppressing the action of the endogenous inhibitor of bone formation, Scl. To examine the effects of SclAb on the DS bone phenotype, 8‐week‐old male wild‐type (WT) andTs65Dn DS mice were treated with 4 weekly iv injections of 100 mg/kg SclAb. Dual‐energy X‐ray absorptiometry (DXA), microCT, and dynamic histomorphometry analyses revealed that SclAb had a significant anabolic effect on both age‐matched WT littermate controls and Ts65Dn DS mice that was osteoblast mediated, without significant changes in osteoclast parameters. SclAb treatment significantly increased both cortical and trabecular bone mass at multiple sites; SclAb treatment resulted in the normalization of Ts65Dn bone mineral density (BMD) to WT levels in the proximal tibia, distal femur, and whole body. Ex vivo bone marrow cultures demonstrated that SclAb increased the recruitment of the mesenchymal progenitors into the osteoblast lineage, as indicated by increased alkaline phosphatase–positive colonies, with no effect on osteoclast differentiation. Together, in the setting of a murine model of DS and decreased bone turnover, SclAb had a potent anabolic effect. SclAb stimulated bone formation and increased osteoblastogenesis without affecting osteoclastogenesis or bone resorption. These data suggest that SclAb is a promising new therapy to improve bone mass and reduce fracture risk in the face of the low bone mass and turnover prevalent in the DS population. © 2017 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Alzheimer-Like Pattern of Hypometabolism Emerges with Elevated Amyloid-β Burden in Down Syndrome.

The Down syndrome (DS) population is genetically predisposed to amyloid-β protein precursor overproduction and Alzheimer's disease (AD). The temporal ordering and spatial association between amyloid-β, glucose metabolism, and gray matter (GM) volume in the DS population can provide insight into those associations in the more common sporadic AD. Twenty-four adults (13 male, 11 female; 39±7 years) with DS underwent [11C]PiB, [18F]FDG, and volumetric MRI scans. Voxel-wise associations between PiB SUVR, FDG SUVR, and GM volume were investigated, with and without individual adjustments for variables of interest. Positive associations of PiB and age were widespread throughout the neocortex and striatum. Negative associations of FDG and age (frontal, parietal, and temporal cortex) and of GM volume and age (frontal and insular cortex) were observed. PiB and FDG were negatively associated in parietal cortex, after adjustment for GM volume. In adults with DS, early amyloid-β accumulation in the striatum is divergent from sporadic AD; however, despite the early striatal amyloid-β, glucose hypometabolism was confined to the typical AD-associated regions, which occurs similarly in autosomal dominant AD. Importantly, the glucose hypometabolism was not explained solely by increased partial volume effect due to GM volume reductions.

Predictors of Age of Diagnosis and Survival of Alzheimer's Disease in Down Syndrome.

Background:People with Down syndrome (DS) are an ultra-high risk population for Alzheimer’s disease (AD). Understanding the factors associated with age of onset and survival in this population could highlight factors associated with modulation of the amyloid cascade.Objective:This study aimed to establish the typical age at diagnosis and survival associated with AD in DS and the risk factors associated with these.Methods:Data was obtained from the Aging with Down Syndrome and Intellectual Disabilities (ADSID) research database, consisting of data extracted from clinical records of patients seen by Community Intellectual Disability Services (CIDS) in England. Survival times when considering different risk factors were calculated.Results:The mean age of diagnosis was 55.80 years, SD 6.29. Median survival time after diagnosis was 3.78 years, and median age at death was approximately 60 years. Survival time was associated with age of diagnosis, severity of intellectual disability, living status, anti-dementia medication status, and history of epilepsy. Age at diagnosis and treatment status remained predictive of survival time following adjustment.Conclusion:This study provides the best estimate of survival in dementia within the DS population to date, and is in keeping with previous estimates from smaller studies in the DS population. This study provides important estimates and insights into possible predictors of survival and age of diagnosis of AD in adults with DS, which will inform selection of participants for treatment trials in the future.

Lingual tonsillectomy in children with Down syndrome: Is it safe?

ObjectiveEvaluate peri-operative course and morbidity in children with Down syndrome (DS) who underwent a lingual tonsillectomy (LT) for residual obstructive sleep apnea (rOSA). MethodsRetrospective case series for children with DS who underwent LT for rOSA from April 2011 to July 2016. Our primary outcomes were length of stay, readmission and complications. Surgical effectiveness was evaluated by change in the obstructive apnea-hypopnea-index(OAHI) and oxygen saturation nadir. ResultsThirty-nine patients underwent LT. The mean length of stay was 1.3 days with n = 21(72%) staying one night. One subject (2.6%) had a post-operative bleed that did not require operative intervention. No other major complications occurred. In terms of effectiveness of surgery, twenty–nine children had sufficient data for inclusion. Median OAHI did not appreciably change (p = 0.07) from before surgery. Five subjects (17%) were cured of OSA (OAHI < 2/hour) and a mix of improvement and worsening was identified. The lowest oxygen saturation improved from 78% (SD = 7) before surgery to 82% (SD = 6) after surgery (p = 0.003). ConclusionLT has a favorable post-operative course but its effectiveness at curing rOSA in the DS population has not been established/proven. Further research is indicated to determine optimal surgical management for DS children with LTH. Level of evidence4.

Long-term sequelae in survivors of childhood leukemia with Down syndrome: A childhood cancer survivor study report.

Children with Down syndrome (DS) are at increased risk of developing acute leukemia and are more prone to acute toxicities. We studied the incidence and severity of chronic health conditions among survivors of childhood leukemia with DS compared with those without DS. Chronic health conditions reported by questionnaire were compared between 154 pediatric leukemia survivors with DS and 581 without DS, matched by leukemia, age at diagnosis, race/ethnicity, sex, radiation location and chemotherapy exposure using Cox models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Subjects were selected from 7139 5-year survivors of leukemia in the Childhood Cancer Survivor Study. Risk of at least 1 late onset chronic health condition (grade 1-5) was similar in the DS population compared with the non-DS group (HR, 1.1; 95% CI, 0.7-1.5). Serious chronic health conditions (grade 3-5) were more common in DS survivors (HR, 1.7; 95% CI, 1.1-2.6), as were ≥ 3 chronic health conditions (grades 1-5) (HR, 1.7; 95% CI, 1.2-2.4). The 25-year cumulative incidence of any condition (grades 1-5) was 83% for DS survivors and 69% for non-DS survivors. Leukemia survivors with DS have therapy-related chronic health conditions comparable to those of similarly treated survivors without DS, with a few notable exceptions: 1) an increased risk of cataracts, hearing loss, and thyroid dysfunction compared with survivors without DS (though these are known risks in the DS population), 2) decreased risk of second cancers, and 3) increased risk of severe or multiple conditions. Practitioners should be aware of these risks during and after therapy. Cancer 2018;124:617-25. © 2017 American Cancer Society.

Inferential language use by youth with Down syndrome during narration

We examined inferential language use by youth with Down syndrome (DS) in the context of narrative storytelling relative to younger typically developing (TD) children and same-aged peers with fragile X syndrome (FXS) matched on nonverbal cognitive ability level. Participants’ narratives were coded for the use of different types of inferential language. Participants with DS used proportionately less inferential language overall relative to their counterparts with TD or FXS, although mean length of utterance accounted for group differences observed for the DS-TD group comparison only. Patterns of inferential language use varied across inferential subtypes and across participant groups, with mean length of utterance playing a significant role in group differences. These findings suggest potential syndrome specificity to the DS phenotype regarding impairments in inferential language use that can be partially explained by level of expressive syntactic ability and should be considered in future research. Clinical interventions within the DS population, therefore, should target to some extent the use of inferential language and complex sentence structure.

Analyses of Sustained Vowels in Down Syndrome (DS): A Case Study Using Spectrograms and Perturbation Data to Investigate Voice Quality in Four Adults With DS

Automatic acoustic measures of voice quality in people with Down syndrome (DS) do not reliably reflect perceived voice qualities. This study used acoustic data and visual spectral data to investigate the relationship between perceived voice qualities and acoustic measures. Participants were four young adults (two males, two females; mean age 23.8 years) with DS and severe learning disabilities, at least one of whom had a hearing impairment. Participants imitated sustained /i/, /u/, and /a/ vowels at predetermined target pitches within their vocal range. Medial portions of vowels were analyzed, using Praat, for fundamental frequency, harmonics-to-noise ratio, jitter, and shimmer. Spectrograms were used to identify the presence and the duration of subharmonics at onset and offset, and mid-vowel. The presence of diplophonia was assessed by auditory evaluation. Perturbation data were highest for /a/ vowels and lowest for /u/ vowels. Intermittent productions of subharmonics were evident in spectrograms, some of which coincided with perceived diplophonia. The incidence, location, duration, and intensity of subharmonics differed between the four participants. Although the acoustic data do not clearly indicate atypical phonation, diplophonia and subharmonics reflect nonmodal phonation. The findings suggest that these may contribute to different perceived voice qualities in the study group and that these qualities may result from intermittent involvement of supraglottal structures. Further research is required to confirm the findings in the wider DS population, and to assess the relationships between voice quality, vowel type, and physiological measures.

Exosomal biomarkers in Down syndrome and Alzheimer's disease.

Every person with Down syndrome (DS) has the characteristic features of Alzheimer's disease (AD) neuropathology in their brain by the age of forty, and most go on to develop AD dementia. Since people with DS show highly variable levels of baseline function, it is often difficult to identify early signs of dementia in this population. The discovery of blood biomarkers predictive of dementia onset and/or progression in DS is critical for developing effective clinical diagnostics. Our recent studies show that neuron-derived exosomes, which are small extracellular vesicles secreted by most cells in the body, contain elevated levels of amyloid-beta peptides and phosphorylated-Tau that could indicate a preclinical AD phase in people with DS starting in childhood. We also found that the relative levels of these biomarkers were altered following dementia onset. Exosome release and signaling are dependent on cellular redox homeostasis as well as on inflammatory processes, and exosomes may be involved in the immune response, suggesting a dual role as both triggers of inflammation in the brain and propagators of inflammatory signals between brain regions. Based on recently reported connections between inflammatory processes and exosome release, the elevated neuroinflammatory state observed in people with DS may affect exosomal AD biomarkers. Herein, we discuss findings from studies of people with DS, people with DS and AD (DS-AD), and mouse models of DS showing new connections between neuroinflammatory pathways, oxidative stress, exosomes, and exosome-mediated signaling, which may inform future AD diagnostics, preventions, and treatments in the DS population as well as in the general population.

Bone mineral density in adults with Down syndrome.

Down syndrome (DS) in adulthood presents with a high prevalence of osteoporosis. However, in DS, bone mineral density (BMD) can be underestimated due to short stature. Furthermore, the rate of age-related decline in BMD and its association with gender in DS has been rarely evaluated or compared with the general population. The present study is aimed at assessing the variation of BMD with age and gender in a sample of adults with DS and to compare these data with those of the general population, after adjusting for anthropometric differences. Adults with DS, aged 18 or older, were assessed dual-energy-X-ray-absorptiometry (DXA) at the femoral neck and at the lumbar spine. They were compared with the general population enrolled in the National Health and Nutrition Examination Survey (NHANES) 2009-2010 dataset. Bone mineral apparent density (BMAD) was calculated for each individual. DXA was evaluated in 234 subjects with DS (mean age 36.93±11.83years, ranging from 20 to 69years; 50.4% females). In the lumbar spine both mean BMD (DS 0.880±0.141 vs. NHANES 1.062±0.167, p<0.001) and BMAD (DS 0.138±0.020 vs. NHANES 0.152±0.020, p<0.001) were significantly lower in the DS sample than in the NAHNES cohort. The same trend was observed at the femoral neck in both BMD (DS 0.658±0.128 vs. NHANES 0.835±0.137, p<0.001) and BMAD (DS 0.151±0.030 vs. NHANES 0.159±0.028, p<0.001). Age was associated with lower femoral neck BMAD in both samples; importantly, this association was significantly stronger in the DS sample. In the lumbar spine region, no significant association between BMAD and age could be observed in both samples. Adults with DS have lower bone mineral density compared to the general population and they experience a steeper decline with age. Early screening programs are needed in DS population.

HIGH PREVALENCE OF VASCULAR AND METABOLIC RISK FACTORS AMONG DOWN SYNDROME PATIENTS WITH ALZHEIMER’S DISEASE: A SURVEY REPORT OF THE NATIONAL DOWN SYNDROME REGISTRY (DS-CONNECT)

Down syndrome (DS) patients have approximately five times greater risk of developing Alzheimer's disease (AD) compared to the general population, partially due to the presence of the amyloid precursor protein gene on chromosome 21. By age 40, nearly all individuals with DS have significant levels of the characteristic beta-amyloid plaques, yet not all of these individuals demonstrate cognitive decline. Given the high prevalence of AD within the DS population, it may prove that studying shared incidences of the two diseases will reveal specific risk factors for AD. We performed a preliminary study to investigate the prevalence of lifestyle-related health factors, such as type 2 diabetes, hypothyroidism, and lipid profile surveillance, among the DS population and their potential associations with AD. The survey analysis was performed using the de-identified national Down Syndrome Registry and aggregate data within the NIH database DS-Connect, the first web-based, voluntary DS registry and data resource. We identified 13 individuals with DS and AD. All individuals had filled out surveys, which included the diagnoses of disease variables and data on lifestyle risk factors. We identified 13 individuals with DS aged ≥ 30 who were concurrently diagnosed with AD. The mean age was approximately 45.8 years. The prevalences of hypothyroidism (58.3% vs. 48.5%) and thyroid dysfunction (76.9% vs. 55.7%) were higher in this population compared to DS patients without AD. DS patients with diabetes also saw a greater incidence of AD compared to DS patients without diabetes (33.3% vs. 14.8%). Additionally, DS patients who monitored their cholesterol on a yearly basis saw a decreased prevalence of AD (9.0% vs. 14.8%). Preliminary data from the Down Syndrome Registry shows that individuals with DS and AD have a higher prevalence of metabolic risk factors. Since these risk factors are modifiable, and their aggressive management and reversal have shown to reduce the pathophysiological markers of AD in non-DS populations, future studies are needed to investigate the association between metabolic and vascular risk factors and AD among the DS population, and explore mechanisms of prevention of cognitive impairment by management of these factors.

DEFINING COGNITIVE DECLINE IN ADULTS WITH DOWN SYNDROME

Down syndrome (DS) is associated with a specific mechanism for Alzheimer's disease related to overproduction of amyloid due to APP gene triplication on chromosome 21. DS is therefore an important population in which to consider amyloid targeting treatments to prevent or delay onset of clinical symptoms. Although amyloid pathology suggestive of Alzheimer's disease (AD) are present in the brains of nearly all individuals with Down syndrome (DS) after the age of 30, there is considerable variability in age of onset of clinical symptoms. We need a better understanding of the natural history of AD in DS and clinical progression as well as associated biomarkers in order to conduct such trials. The London Down syndrome consortium has been conducting an in-depth longitudinal cognitive phenotyping study of >400 adults with DS using a variety of cognitive tasks including tests of memory and executive functions (using CANTAB computer tasks and table-top tasks) and symptoms of dementia (using CAMDEX-DS). All participants donated blood or sputum for DNA and genetic analysis. We will present data on the sequence of cognitive decline with aging in DS, clinical predictors of decline, and clinical differences associated with APOE and other genetic markers. Such data may be used to develop reliable cognitive outcome measures and to stratify and plan clinical trials to prevent or delay AD in the DS population. Some of the issues related to conducting clinical trials in this population will be highlighted alongside potential solutions.