Young Down Research Articles

Aberrant crosstalk between insulin signaling and mTOR in young Down syndrome individuals revealed by neuronal-derived extracellular vesicles.

Intellectual disability, accelerated aging, and early-onset Alzheimer-like neurodegeneration are key brain pathological features of Down syndrome (DS). Although growing research aims at the identification of molecular pathways underlying the aging trajectory of DS population, data on infants and adolescents with DS are missing. Neuronal-derived extracellular vesicles (nEVs) were isolated form healthy donors (HDs, n=17) and DS children (n=18) from 2 to 17 years of age and nEV content was interrogated for markers of insulin/mTOR pathways. nEVs isolated from DS children were characterized by a significant increase in pIRS1Ser636 , a marker of insulin resistance, and the hyperactivation of the Akt/mTOR/p70S6K axis downstream from IRS1, likely driven by the higher inhibition of Phosphatase and tensin homolog (PTEN). High levels of pGSK3βSer9 were also found. The alteration of the insulin-signaling/mTOR pathways represents an early event in DS brain and likely contributes to the cerebral dysfunction and intellectual disability observed in this unique population.

Chronic myeloid leukaemia with pulmonary leucostasis in a young Down syndrome patient

We reported a rare case of chronic myeloid leukaemia (CML) complicated with pulmonary leucostasis in an 11-year-old Down syndrome (DS) patient who presented with respiratory distress. His peripheral blood investigation showed features of CML with 17% circulating blast, with immunophenotyping showing positivity towards myeloid markers. Peripheral blood polymerase chain reaction for BCR–ABL fusion transcripts was positive, and cytogenetic studies showed Ph chromosome with trisomy 21. Despite cytoreduction therapy with hydroxyurea and leukapheresis, the patient succumbed due to shock, with multiple organ failure. Our case highlights the need for early detection and rapid referral for aggressive treatment in DS patients with CML, as the combination is associated with a poor outcome.

Coenzyme Q10 and pro-inflammatory markers in children with Down syndrome: clinical and biochemical aspects

ObjectiveEvidence of oxidative stress was reported in individuals with Down syndrome. There is a growing interest in the contribution of the immune system in Down syndrome. The aim of this study is to evaluate the coenzyme Q10 and selected pro-inflammatory markers such as interleukin 6 and tumor necrosis factor α in children with Down syndrome. MethodsEighty-six children (5–8 years of age) were enrolled in this case-control study from two public institutions. At the time of sampling, the patients and controls suffered from no acute or chronic illnesses and received no therapies or supplements. The levels of interleukin 6, tumor necrosis factor α, coenzyme Q10, fasting blood glucose, and intelligence quotient were measured. ResultsForty-three young Down syndrome children and forty-three controls were included over a period of eight months (January–August 2014). Compared with the control group, the Down syndrome patients showed significant increase in interleukin 6 and tumor necrosis factor α (p=0.002), while coenzyme Q10 was significantly decreased (p=0.002). Also, body mass index and fasting blood glucose were significantly increased in patients. There was a significantly positive correlation between coenzyme Q10 and intelligence quotient levels, as well as between interleukin 6 and tumor necrosis factor α. ConclusionInterleukin 6 and tumor necrosis factor α levels in young children with Down syndrome may be used as biomarkers reflecting the neurodegenerative process in them. Coenzyme Q10 might have a role as a good supplement in young children with Down syndrome to ameliorate the neurological symptoms.

Coenzyme Q10 and pro-inflammatory markers in children with Down syndrome: clinical and biochemical aspects

ObjectiveEvidence of oxidative stress was reported in individuals with Down syndrome. There is a growing interest in the contribution of the immune system in Down syndrome. The aim of this study is to evaluate the coenzyme Q10 and selected pro-inflammatory markers such as interleukin 6 and tumor necrosis factor α in children with Down syndrome. MethodsEighty-six children (5–8 years of age) were enrolled in this case-control study from two public institutions. At the time of sampling, the patients and controls suffered from no acute or chronic illnesses and received no therapies or supplements. The levels of interleukin 6, tumor necrosis factor α, coenzyme Q10, fasting blood glucose, and intelligence quotient were measured. ResultsForty-three young Down syndrome children and forty-three controls were included over a period of eight months (January–August 2014). Compared with the control group, the Down syndrome patients showed significant increase in interleukin 6 and tumor necrosis factor α (p=0.002), while coenzyme Q10 was significantly decreased (p=0.002). Also, body mass index and fasting blood glucose were significantly increased in patients. There was a significantly positive correlation between coenzyme Q10 and intelligence quotient levels, as well as between interleukin 6 and tumor necrosis factor α. ConclusionInterleukin 6 and tumor necrosis factor α levels in young children with Down syndrome may be used as biomarkers reflecting the neurodegenerative process in them. Coenzyme Q10 might have a role as a good supplement in young children with Down syndrome to ameliorate the neurological symptoms.

Melatonin counteracts age-related progression of oxidative stress in young Down syndrome patients.

Melatonin (MLT) is a pineal gland hormone known for its potent antioxidant effect associated with neural protection. The presence of three copies of the SOD gene is considered to be the main cause of oxidative stress-dependent neural degeneration and dementia that Down syndrome (DS) patients may suffer from. In this study we aim to assess a possible protective effect of MLTagainst the age-related progression of oxidative stress-induced damage in lymphocytes of DS patients. Lymphocytes from infants with DS were treated with mitomycin C (an H2O2 promoter) in order to mimic the oxidative stress status of aged patients in presence and absence of MLT. The data indicated a significant effect of MLT in downregulating the levels of the oxidative radicalsH2O2 and NO compared to untreated DS patients’ lymphocytes. This downregulation was accompanied by a profound effect of MLT in reducing the number of oxidative stress-dependent damaged chromosomes, along with a reduction in cell apoptosis and DNA protection in the p53 dependent pathway. These observations suggest that early administration of exogenous MLT in young DS patients may help in gaining control over growth-related progression of mental retardation, or at least delaying the onset of DS-related pathological complications.

Age effects on cortical thickness in young Down's syndrome subjects: a cross-sectional gender study.

The aim of this study was to determine differences in the characteristic pattern of age-related cortical thinning in men and women with Down's syndrome (DS) by means of MRI and automatic cortical thickness measurements and a cross-sectional design, in a large cohort of young subjects. Eighty-four subjects with DS, 30 females (11-35 years, mean age ± SD = 22.8 ± 5.9) and 54 males (11-35 years, mean age ± SD = 21.5 ± 6.5), were examined using a 1.5-T scanner. MRI-based quantification of cortical thickness was performed using FreeSurfer software package. For all subjects participating in the study, the Pearson product-moment correlation coefficient between age and mean cortical thickness values has been evaluated. A significant negative correlation between cortical thickness and age was found in female DS subjects, predominantly in frontal and parietal lobes, bilaterally. In male DS subjects, a significant negative correlation between cortical thickness and age was found in the right fronto-temporal lobes and cingulate regions. Whole brain mean cortical thickness values were significantly negative correlated with age only in female DS subjects. Females with Down's syndrome showed a strong correlation between cortical thickness and age, already in early age. We suggest that the cognitive impairment due to hormonal deficit in the postmenopausal period could be emphasized by the early structural decline of gray matter in female DS subjects.

To bee or not to bee, this is the question…: The inborn numerical competence of humans and honeybees.

Human inborn numerical competence means our ability to recognize object numbers precisely under circumstances which do not allow sequential counting. This archaic process has been called "subitizing," from the Latin "subito" = suddenly, immediately, indicating that the objects in question are presented to test persons only for a fraction of a second in order to prevent counting. In contrast, however, sequential counting, an outstanding cultural achievement of mankind, means to count "1, 2, 3, 4, 5, 6, 7, 8…" without a limit. The following essay will explain how the limit of numerical competence, i.e., the recognition of object numbers without counting, has been determined for humans and how this has been achieved for the first time in case of an invertebrate, the honeybee. Finally, a hypothesis explaining the influence of our limited, inborn numerical competence on counting in our times, e.g., in the Russian language, will be presented. Subitizing versus counting by young Down syndrome infants and autistics and the Savant syndrome will be discussed.

To Bee or not to Bee, this is the Question … The Inborn Numerical Competence of Humans and Honeybees

Human inborn numerical competence means our ability to recognize object numbers precisely under circumstances which do not allow sequential counting. This archaic process has been called “subitizing”, from the Latin “subito” = suddenly, immediately, indicating that the objects in question are presented to test persons only for a fraction of a second in order to prevent counting. In contrast, however, sequential counting, an outstanding cultural achievement of mankind, means to count “1, 2, 3, 4, 5, 6, 7, 8 …” without a limit. The following essay will explain how the limit of numerical competence, i.e., the recognition of object numbers without counting, has been determined for humans and how this has been achieved for the first time in case of an invertebrate, the honeybee. Finally, a hypothesis explaining the influence of our limited, inborn numerical competence on counting in our times, e.g., in the Russian language, will be presented. Subitizing versus counting by young Down syndrome infants and autistics and the Savant syndrome will be discussed.

Promoting Recreation Skills in Severely Retarded Children

The importance of physical education and recreation activities for retarded children has been stressed from many quarters. Accordingly, in a summer day camp for retarded children, behavior modification procedures were examined as a means to increase cliii­dren’s participation iii recreational activities and to demonstrate that supervised staff members can serve as experimenters in camp setting as they modify behaviors that are of concern. Four studies were conducted m which camp personnel acted as primary ex­perimenters; the subjects of these studies ranged from single subjects to entire classroom groups. In the first study, on-task classroom behavior was examined for two boys who displayed higli rates of distractible behavior (e.g., shouting, throwing materials, runnmg, etc.). A token reinforcement procedure was sequentially applied to three different activity classrooms ni a multiple-baseline design. Similar contingencies were arranged for an entire class of children in a second study. Substantial increases iii the classroom participation of ah children were functionally related to the mtroduction of the ex­perimental contingencies. In a third study, the effects of adult social reinforcement on the appropriate play with basketballs and roller skates of a young Down’s Syndrome boy were assessed using a reversal design. Observations made during free play showed increases of 75% iii appropriate play during periods of adult social reinforcement. In the fourth study, extinctjon was employed using a multiple basehine design to reduce disruptive physical contact of a physically handicapped girl. Records kept on the daily number of disruptive physical contacts directed toward two staff members showed that durmg ex­tinction phases, disruptive behavior was nearly ehiminated. Taken together, these four studies demonstrated that (1) day camps can be significant teaching settings for young handicapped children, (2) childrens’ participation in healthy, physical activities can be increased by employing behavior modification procedures, (3) indigenous camp personnel with proper trainmg and supervision can carry out behavior modification techniques and demonstrate proyects with’out disrupting the normal camp routine and as a result have more time to supervise children’s activities, and (4) conditions need to be arranged to msure children’s participation if benefits are to accrue from recreation asid physical education activities.

Down’s syndrome in diabetic patients aged <20 years: an analysis of metabolic status, glycaemic control and autoimmunity in comparison with type 1 diabetes

Intellectual impairment in individuals with Down's syndrome and diabetes mellitus potentially limits the quality of diabetic control. In addition, these patients are at risk of having immunological abnormalities. The present study compared metabolic status and concomitant diseases in young (<20 years old) Down's syndrome patients with diabetes vs young type 1 diabetic patients. The Diabetes-Patienten-Verlaufsdaten is a longitudinal follow-up database, which collects data from 298 German and Austrian diabetes centres. Data available on diabetic patients aged <20 years were analysed statistically. We compared data for 159 Down's syndrome patients with diabetes and 41,983 type 1 diabetic patients. The former used less insulin, but showed better glycaemic control (HbA1c). Diabetes onset during the first 3 years of life occurred in 18.9% of Down's syndrome patients with diabetes and in 6.4% of type 1 diabetic patients. Antibody titres indicative of coeliac disease and thyroid peroxidase antibodies were more frequent in Down's syndrome patients with diabetes. No significant differences were found regarding the beta cell autoantibodies studied. The age-of-onset distribution showed a shift towards younger ages and was bimodal in the Down's syndrome group. The better metabolic control found, despite intellectual impairment, in young Down's syndrome patients with diabetes cannot be conclusively explained by our data, but is likely to be due to a less complex lifestyle. Our data provide further confirmation that coeliac and thyroid antibodies are more prevalent in Down's syndrome. The presence of beta cell autoantibodies supports an autoimmune cause of diabetes in some children with Down's syndrome.

Mice deficient for the chromosome 21 ortholog Itsn1 exhibit vesicle-trafficking abnormalities

Enlarged early endosomes in the neurons of young Down syndrome (DS) and pre-Alzheimer's disease (AD) brains suggest that a disturbance in endocytosis is one of the earliest hallmarks of AD pathogenesis in both conditions. We identified a chromosome 21 gene, Intersectin-1 (ITSN1) that is up-regulated in DS brains and has a putative function in endocytosis and vesicle trafficking. To elucidate the function of ITSN1 and assess its contribution to endocytic defects associated with DS and AD, we generated Itsn1 null mice. In knockout mice we found alterations in a number of parameters associated with endocytic and vesicle trafficking events. We found a reduced number of exocytosis events in chromaffin cells and a slowing of endocytosis in neurons. Endosome size was increased in neurons and NGF levels were reduced in the septal region of the brain. Our data is the first indication that Itsn1 has a role in endocytosis in an in vivo mammalian model, and that a disruption in Itsn1 expression causes a disturbance in vesicle trafficking and endocytic function in the brain. These results imply a role for ITSN1 in the early endocytic anomalies reported in DS brains which may have ramifications for the onset of AD.

The buccal cytome and micronucleus frequency is substantially altered in Down's syndrome and normal ageing compared to young healthy controls

The buccal micronucleus cytome assay was used to investigate biomarkers for DNA damage, cell death and basal cell frequency in buccal cells of healthy young, healthy old and young Down's syndrome cohorts. With normal ageing a significant increase in cells with micronuclei ( P < 0.05, average increase +366%), karyorrhectic cells ( P < 0.001, average increase +439%), condensed chromatin cells ( P < 0.01, average increase +45.8%) and basal cells ( P < 0.001, average increase +233%) is reported relative to young controls. In Down's syndrome we report a significant increase in cells with micronuclei ( P < 0.001, average increase +733%) and binucleated cells ( P < 0.001, average increase +84.5%) and a significant decrease in condensed chromatin cells ( P < 0.01, average decrease −52%), karyolytic cells ( P < 0.001, average decrease −51.8%) and pyknotic cells ( P < 0.001, average decrease −75.0%) relative to young controls. These changes show distinct differences between the cytome profile of normal ageing relative to that for a premature ageing syndrome, and highlight the diagnostic value of the cytome approach for measuring the profile of cells with DNA damage, cell death and proportion of cells with proliferative potential (i.e., basal cells). Significant correlations amongst cell death biomarkers observed in this study were used to propose a new model of the inter-relationship of cell types scored within the buccal micronucleus cytome assay. This study validates the use of a cytome approach to investigate DNA damage, cell death and cell proliferation in buccal cells with ageing.

Sleep Abnormalities Underestimated in Young Down Patients

Sleep Abnormalities Underestimated in Young Down Patients

Evaluation of Surgical and Non‐Surgical Periodontal Therapies, and Immunological Status, of Young Down's Syndrome Patients

Individuals with Down's syndrome (DS) differ in their oral condition compared with the healthy population. Periodontal disease in persons with DS under the age of 30 years is very high. Immune deficiencies are also present. For dental practitioners it is difficult to decide on a particular course of treatment. In this study, patients with DS were selected in order to 1) evaluate the effectiveness of surgical and non-surgical periodontal therapies and 2) assess their immunological status. The population consisted of 14 DS patients (14 to 30 years old). Surgical and non-surgical periodontal therapies were compared in a split-mouth design. Clinical measurements of plaque index (PI), gingival index (GI), probing depth (PD), and clinical attachment levels (CAL) were taken at baseline, posttreatment, 6 months, and 1 year. Immunomodulatory activity of neutrophils was analyzed in vitro by chemotaxis (Boyden migration chamber), phagocytic activity, and production of super-oxide anion (NBT reduction) tests and compared between DS patients and healthy controls. Both surgical and non-surgical therapies showed a significant improvement in all the clinical parameters compared to baseline. There were no differences between surgical and nonsurgical therapy in PI or GI. There was a significant PD reduction with the non-surgical therapy at 1 to 3 mm PD. However in PD >3 mm the surgical therapy, although not statistically significant, showed better results. Neutrophil chemotaxis, phagocytic activity, and production of super-oxide anion were significantly decreased in the DS patients. After a year, both surgical and non-surgical therapies have similar periodontal clinical improvement in DS patients. There is partial impairment of immunological functions in DS individuals which does not seem to affect the clinical response to therapy.

The Effect of Thyroxine Treatment Started in the Neonatal Period on Development and Growth of Two-Year-Old Down Syndrome Children: A Randomized Clinical Trial

Young Down syndrome children appear to have a mild form of congenital hypothyroidism that is rarely detected by neonatal screening and usually left untreated. To investigate the effects of thyroxine treatment on development and growth of young Down syndrome children. Single-center, randomized, double-blind, 24-month trial (enrollment June 1999 to August 2001) with nationwide recruitment, comparing thyroxine administration with placebo in 196 Down syndrome neonates. Neonates were randomly assigned to treatment for 2 yr with either thyroxine (n = 99; initial dose 8 microg/kg) or placebo (n = 97). Daily thyroxine doses were adjusted at regular intervals to maintain plasma TSH in its normal and free T(4) concentrations in its high-normal range. Placebo dose adjustments mirrored those of thyroxine. The primary outcome was mental and motor development at age 24 months, assessed with the Bayley Scales of Infant Development II. At age 24 months, the developmental testing results of 90 thyroxine-, and 91 placebo-treated children were available for analysis. The thyroxine-treated children had a 0.7-month smaller delay in motor developmental age (95% confidence interval, -1.4 to 0), corresponding to a difference of seven motor developmental index points. The mental developmental age delay was also 0.7 month smaller in the thyroxine group (95% confidence interval, -1.5 to 0.2), but lacked statistical significance. Thyroxine-treated children had greater gains in length (1.1 cm; 95% confidence interval, 0.2 to 2.0) and weight (378 g; 95% confidence interval 55 to 701). The data of our study provide evidence to support the hypothesis that thyroxine treatment may improve development and growth of young Down syndrome children. Thyroxine treatment should be considered in Down syndrome neonates to maximize their early development and growth.

Frame-shifted amyloid precursor protein found in Alzheimer's disease and Down's syndrome increases levels of secreted amyloid beta40.

Frame-shifted amyloid precursor protein (APP(+1)), which has a truncated out-of-frame C-terminus, accumulates in the neuropathological hallmarks of patients with Alzheimer's disease pathology. To study a possible involvement of APP(+1) in the pathogenesis of Alzheimer's disease, we expressed APP695 and APP(+1) in the HEK293 cell-line and studied whether the processing of APP695 was affected. APP(+1) is a secretory protein, but high expression of APP695 and APP(+1) results in the formation of intracellular aggregate-like structures containing both proteins and Fe65, an adaptor protein that interacts with APP695. APP(+1) is shown to interact with APP695, suggesting that these structures consist of functional protein complexes. Such an interaction can also be anticipated in post-mortem brains of young Down's syndrome patients without any sign of neuropathology. Here we observed APP(+1) immunoreactivity in beaded fibres. Additional support for functional consequences on the processing of APP695 comes from a 1.4-fold increase in levels of secreted amyloid beta40 in cells co-expressing APP695 and APP(+1), although APP(+1) itself does not contain the amyloid beta sequence. Taken together, these data show that co-expression of APP695 and APP(+1) affects the processing of APP695 in a pro-amyloidogenic way and this could gradually contribute to Alzheimer's disease pathology, as has been implicated in Down's syndrome patients.

Plasma amyloid β protein 1–42 levels are increased in old Down Syndrome but not in young Down Syndrome

Plasma amyloid β protein 1–40 (Aβ40) and Aβ42 levels were quantitated from 28 young Down syndrome (DS) (20–40 years old), 28 age-matched controls, 32 old DS (41–65 years old) and 32 age-matched controls in a sandwich enzyme-linked immunosorbent assay. Aβ40 levels were higher in young DS and old DS than controls. Aβ42 levels in young DS and controls were similar, however Aβ42 levels were higher in old DS than controls or young DS. The higher Aβ42 levels in old DS suggests that Aβ42 is selectively increased in plasma concurrently with the development of Alzheimer disease neuropathology.

Candida albicans Endocarditis Diagnosed by PCR-based Molecular Assay in a Critically ill Pediatric Patient

A young Down's syndrome patient developed tricuspid valve endocarditis several years after undergoing surgical closure of a congenital ventricular septal defect. Fungal etiology was established by PCR amplification of the Candida albicans ERG11 gene. Although antifungal therapy was administered, surgical replacement of the infected valve was required to eliminate the infection.

Intraneuronal abeta-amyloid precedes development of amyloid plaques in Down syndrome.

Down syndrome patients who live to middle age invariably develop the neuropathologic features of Alzheimer disease, providing a unique situation in which to study the early and sequential development of these changes. To study the development of amyloid deposits, senile plaques, astrocytic and microglial reactions, and neurofibrillary tangles in the brains of young individuals (<30 years of age) with Down syndrome. Histologic and immunocytochemical study of a series of autopsy brains (n = 14, from subjects aged 11 months to 56 years, with 9 subjects <30 years) examined at the Office of the Chief Medical Examiner of the State of Maryland and The Johns Hopkins Hospital. The principal observations included the presence of intraneuronal Abeta immunostaining in the hippocampus and cerebral cortex of very young Down syndrome patients (preceding the extracellular deposition of Abeta) and the formation of senile plaques and neurofibrillary tangles. We propose the following sequence of events in the development of neuropathologic changes of Alzheimer disease in Down syndrome: (1) intracellular accumulation of Abeta in neurons and astrocytes, (2) deposition of extracellular Abeta and formation of diffuse plaques, and (3) development of neuritic plaques and neurofibrillary tangles with activation of microglial cells.

Intraneuronal Aβ-Amyloid Precedes Development of Amyloid Plaques in Down Syndrome

Abstract Context.—Down syndrome patients who live to middle age invariably develop the neuropathologic features of Alzheimer disease, providing a unique situation in which to study the early and sequential development of these changes. Objective.—To study the development of amyloid deposits, senile plaques, astrocytic and microglial reactions, and neurofibrillary tangles in the brains of young individuals (<30 years of age) with Down syndrome. Methods.—Histologic and immunocytochemical study of a series of autopsy brains (n = 14, from subjects aged 11 months to 56 years, with 9 subjects <30 years) examined at the Office of the Chief Medical Examiner of the State of Maryland and The Johns Hopkins Hospital. Results.—The principal observations included the presence of intraneuronal Aβ immunostaining in the hippocampus and cerebral cortex of very young Down syndrome patients (preceding the extracellular deposition of Aβ) and the formation of senile plaques and neurofibrillary tangles. Conclusions.—We propose ...