Dysfunction In Down Syndrome Research Articles

Increased protein levels of serotonin transporter in frontal cortex of patients with Down syndrome

Serotonin transporters (SERTs) are presynaptic proteins specialized for the clearance of serotonin from the synaptic cleft. A large body of evidence exists on altered platelet serotonin uptake and metabolism in Down syndrome (DS). Besides, dysregulation of SERTs expression have been reported in various complex behavioural traits and disorders including, neurodegenerative disorders. This prompted us to investigate SERT protein levels in adult brain specimens. Western blot analyses were performed in frontal cortex and cerebellum of aged controls and patients with DS and Alzheimer's disease (AD). The result revealed that frontal cortex SERT was significantly increased ( P<0.05) in DS, whereas in AD it was comparable to controls. In cerebellum, no significant difference was observed among the study populations. A remarkable difference was noted when SERT was normalized vs. neuron specific enolase (NSE), a neuronal marker. The increase in SERT/NSE was highly significant ( P<0.01) in DS frontal cortex compared to controls. Neither AD frontal cortex nor DS and AD cerebellum did show any significant difference. These findings indicate that a region specific alteration in SERT expression may exist in DS with AD-like pathology. As little is known about the status of serotenergic synaptic markers in DS brain, the findings may contribute to an effort made to delineate the underlying causes of serotonergic dysfunction in DS and the quest for therapeutic strategies. The study also suggest caution should be taken in applying data obtained from DS to model AD biochemical defects.

Individuals with Down's syndrome demonstrate abnormal olfactory event-related potentials

Objective: Recent research has demonstrated that individuals with Down's syndrome (DS) develop plaques and tangles in the brain similar to people with Alzheimer's disease. As a result, they show increased dementia and decreased olfactory functioning compared to healthy individuals. The olfactory event-related potential (OERP) has been used as an objective quantitative measure of olfactory functioning in normal and clinical populations. The present study investigated the utility of the latency and amplitude of the OERP components in examining olfactory dysfunction in DS individuals.Methods: OERPs were recorded monopolarly at the Fz, Cz and Pz electrode sites, using amyl acetate at a 60 s inter-stimulus interval, from individuals with DS (mean age 26.0 years) and age-matched normal controls. Participants were screened for nasal health and odor thresholds were assessed. Dementia was assessed using the dementia rating scale (DRS).Results: Results indicate that DS subjects have significantly longer latencies in the sensory (N1, P2, and N2) and cognitive (P3) components of the OERP than normal controls. Odor threshold was significantly associated with sensory OERP components. In addition, DS subjects with a higher level of dementia showed significantly longer P3 latencies than those with lower dementia levels.Conclusions: The study suggests that the OERP may be a useful measure of olfactory dysfunction in DS which may precede developing dementia in this population.

Oxidative stress and neural dysfunction in Down syndrome.

Total or partial trisomy of chromosome 21 occurs with relatively high frequency and is responsible for the occurrence of Down syndrome. Phenotypically, individuals with Down syndrome display characteristic morphological features and a variety of clinical disorders. One of the challenges for researchers in this field has been to ascertain and understand the relationship between the Down syndrome phenotype with the gene dosage effect resulting from trisomy of chromosome 21. Much attention therefore, has been given towards investigating the consequences of overexpressing chromosome 21-linked genes. In particular, an extensive analysis of SOD1 and APP have provided important insights as to how perturbations in the expression of their respective genes may contribute to the Down syndrome phenotype. In this review we will highlight studies which support a key role for SOD1 and APP in the pathogenesis of neural abnormalities observed in individuals with Down syndrome. Central to this relationship is how the redox state of the cell is affected and its consequences to neural function and integrity.

Hypothalamic versus pituitary dysfunction in Down's syndrome as cause of growth retardation.

We have found that some children with Down's syndrome (DS) have growth retardation secondary to growth hormone (GH) deficiency. To test the hypothesis that hypothalamic dysfunction is the primary cause for GH deficiency and growth retardation, hypothalamic-pituitary responses of serum GH concentrations to levodopa and clonidine as well as pituitary responses in serum GH concentrations to growth-hormone-releasing hormone (GHRH) were analysed in 14 prepubertal children with DS. Levodopa and clonidine were given, and blood was drawn for determining serum GH levels. Seven prepubertal control children had both levodopa and clonidine tests done. The delta serum GH during levodopa was 5.7 +/- 6.3 ng ml-1 in DS and 13.1 +/- 9.8 ng ml-1 in controls. The delta serum GH during clonidine administration was 3.0 +/- 3.2 ng ml-1 in DS and 17.3 +/- 5.6 ng ml-1 in controls. Children with DS had a significantly lower response to levodopa and clonidine, compared with controls by the Mann-Whitney U-test (P < 0.03 and P < 0.009, respectively). Growth-hormone-releasing hormone was given at 1 microgram kg-1 i.v. bolus and bloods for GH were drawn at-15, 0, 15, 30, 60, 90 and 120 min in 14 subjects with DS and 24 normal controls, both groups prepubertal. The mean delta serum GH concentration in DS was 53.6 +/- 38.3 ng ml-1, and it was 35.6 +/- 25.1 ng ml-1 in controls with P < 0.23 non-significant by the Mann-Whitney U-test. These results indicate that levodopa and clonidine (drugs stimulating hypothalamic GHRH release and secondary pituitary GH release in normal individuals) do not stimulate GH release in DS. Furthermore, normal GH response to GHRH in DS indicates normal pituitary function (normal somatotroph response to GHRH) and supports hypothalamic dysfunction in DS.

Antithyroid antibodies and thyroid dysfunction in Saudi children with Down syndrome.

Fifty children (ages seven months to nine years) with Down syndrome compared with age and sex matched controls were tested for antithyroid antibodies. Seven (14%) of the Down group were found to be seropositive; six (12%) for antimicrosomal antibodies; three for both antimicrosomal and antithyroglobulin; none was positive for antithyroglobulin alone. All the control group were seronegative and had no clinical evidence of thyroid disease. Three (6%) of the Down group had hypothyroidism, two due to autoimmune thyroiditis and one had thyroid dysgenesis; one of the previous two had insulin dependent diabetes mellitus. One child had Graves disease. Thyroid dysfunction was not previously suspected in the two symptomatic children. In view of our findings, recommendations are made to regularly screen these children for autoantibodies and evidence of thyroid dysfunction.

Thyroid dysfunction in Down syndrome: A review

Clinical forms of hypothyroidism found in individuals with Down syndrome include transient and primary hypothyroidism, pituitary-hypothalamic hypo-thyroidism, thyroxin-binding globulin (TBG) deficiency and chronic lymphocytic thyroiditis. Hyperthyroidism also occurs occasionally. The frequency of thyroid disease is elevated in patients with Down syndrome, starting in the newborn population where it is 0.7% (or 28 times more frequent than in the general population). Twelve per cent or more of adults with Down syndrome have thyroid disease. Thyroid disease is difficult to diagnose clinically in individuals with Down syndrome because of an overlap of symptoms. This makes thyroid blood screening a particularly important part of the annual preventive medicine screening of each person with Down syndrome.

Upregulation of lymphocyte β-adrenergic receptor in Down's syndrome: a biological marker of a neuroimmune deficit

To test the hypothesis of an altered central nervous system influence upon the immune system of Down's syndrome (DS) patients and in order to establish a peripheral biological marker of neuroimmune deficit, we have studied the characteristics of the β 2-adrenergic receptor (B 2AR) system in peripheral blood monocytes (PBMC) of 12 pre-pubertal (six boys and six girls) individuals and correlated alterations in binding with changes in distribution of lymphocyte subsets. Using the very potent β-adrenergic antagonist, iodocyanopindolol ([ 125I]CYP), as a ligand, the present study shows that a typical BAR population of the β 2-subtype is present in PBMC from DS children, with binding kinetics and structural specificity similar to those measured in PBMC from patients with other (non-genetic) forms of mental retardation, or in PBMC from age-matched healthy subjects. On the other hand, this study revealed a significance increase in B 2AR binding capacity of PBMC from DS subjects ( B max = 5258 ± 470 sites/cell) compared to the values measured in the control population of retarded children ( B max = 1965 ± 280 sites/cell), characterized by an approximately three-fold increase in the B max, without changes in binding affinity ( K D = 40.5 ± 2.0 and 36.6 ± 2.5 pM in DS and retarded patients, respectively). The flowcytometric markers revealed a profound alteration in the distribution of lymphocyte subtypes with an almost 50% decrease in B cell and T-helper populations, a three-fold increase in T-cytotoxic suppressor, a seven-fold increase in lymphocyte-activated killer cells (LAK) and 30% increase in natural killer (NK) subpopulations. When fluorescence-labelled lymphocytes were visualized in the cytofluorograph and sorted for their use in the radioreceptor assay, B cells had approximately twice the number of B 2AR when compared to T cells; and cytotoxic/suppressor showed a higher binding capacity compared to T-helper cells. On the other hand, labelled lymphocytes from DS patients showed a specific increase in receptor number in B cells, T-cytotoxic suppressor and NK subpopulations. It is concluded that a profound catecholaminergic dysfunction not previously appreciated in DS is reflected by a significant alteration in lymphocyte subset distribution and by a specific up-regulation of lymphocyte B 2AR in phenotypically and functionally distinct T and B cells as well NK subpopulations, suggesting a possible denervation supersensitivity phenomenon. From the present data it seems tempting to speculate that the B 2AR might represent a valuable marker of neuroimmune dysfunction in DS and possibly other brain pathologies.