Low TGF-ß1 plasma levels are associated with cognitive decline in Down syndrome.

Almost all individuals with Down's syndrome (DS) show the characteristic neuropathological features of Alzheimer's disease (AD) by the age of 40, yet not every individual with DS experiences symptoms of AD later in life. Similar to neurotypical developing subjects, AD in people with DS lasts for a long preclinical phase in which biomarkers follow a predictable order of changes. Hence, a prolonged asymptomatic period precedes the onset of dementia, underscoring the importance of identifying new biomarkers for the early detection and monitoring of cognitive decline in individuals with DS. Blood-based biomarkers may offer an alternative non-invasive strategy for the detection of peripheral biological alterations paralleling nervous system pathology in an early phase of the AD continuum. In the last few years, a strong neurobiological link has been demonstrated between the deficit of transforming growth factor-ß1 (TGF-ß1) levels, an anti-inflammatory cytokine endowed with neuroprotective activity, and early pro-inflammatory processes in the AD brain. In this clinical prospective observational study, we found significant lower plasma TGF-ß1 concentrations at the first neuropsychological evaluation (baseline = T0) both in young adult DS individuals (19-35 years) and older DS subjects without AD (35-60 years) compared to age- and sex-matched healthy controls. Interestingly, we found that the lower TGF-ß1 plasma concentrations at T0 were strongly correlated with the following cognitive decline at 12 months. In addition, in young individuals with DS, we found, for the first time, a negative correlation between low TGF-ß1 concentrations and high TNF-α plasma concentrations, a pro-inflammatory cytokine that is known to be associated with cognitive impairment in DS individuals with AD. Finally, adopting an ex vivo approach, we found that TGF-ß1 concentrations were reduced in parallel both in the plasma and in the peripheral blood mononuclear cells (PBMCs) of DS subjects, and interestingly, therapeutic concentrations of fluoxetine (FLX) applied to cultured PBMCs (1 µM for 24 h) were able to rescue TGF-ß1 concentrations in the culture media from DS PBMCs, suggesting that FLX, a selective serotonin reuptake inhibitor (SSRI) endowed with neuroprotective activity, might rescue TGF-ß1 concentrations in DS subjects at higher risk to develop cognitive decline.

Role of long non-coding RNAs in Down syndrome patients: a transcriptome analysis study.

Down syndrome (DS) is defined by the presence of a third copy of chromosome 21. Several comorbidities can be found in these patients, such as intellectual disability (ID), muscle weakness, hypotonia, congenital heart disease, and autoimmune diseases. The molecular mechanisms playing a role in the development of such comorbidities are still unclear. The regulation and expression of genes that map to chromosome 21 are dynamic and complex, so it is important to perform global gene expression studies with high statistical power to fully characterize the transcriptome in DS patients. This study was undertaken to evaluate mRNAs and lncRNA expression in patients with DS versus a matched cohort of healthy subjects. RNA sequencing was used to perform this transcriptome study. Differential expression analysis revealed 967 transcripts with padj ≤ 0.05. Among them, 447 transcripts were differentially expressed in patients with DS compared to controls. Particularly, 203 transcripts were down expressed (151 protein-coding mRNAs, 45 lncRNAs, 1 microRNA, 1 mitochondrial tRNA, 1 ribozyme, and 1 small nuclear RNA) and 244 were over expressed (210 protein-coding mRNAs and 34 lncRNAs). Interestingly, deregulated lncRNAs are involved in pathways that play a role in developmental disorders, neurological diseases, DNA replication and repair mechanisms, and cancer development in DS patients. In conclusion, these results suggest a role of lncRNAs in the phenotype of DS patients.

CCR3 gene overexpression in patients with Down syndrome.

Chromosome 21 trisomy or Down syndrome (DS) is the most common genetic cause of intellectual disability (ID). DS is also associated with hypotonia, muscle weakness, autoimmune diseases, and congenital heart disease. C-C chemokine receptor type 3 (CCR3) plays a role in inflammatory, autoimmune, and neuronal migration mechanisms. The present study aimed to evaluate the expression of the CCR3 gene by NGS and qRT-PCR in patients with DS and normal controls (NC). The CCR3 gene was over-expressed in DS patients compared to NC. These data suggest that an over-expression of the CCR3 gene is associated with the phenotype of patients with DS.

Long non-coding RNA GAS5 expression in patients with Down syndrome.

Trisomy 21, also known as Down Syndrome (DS), is the most common chromosome abnormality and causes intellectual disability. Long non-coding RNA (lncRNA) growth arrest-specific 5 (GAS5), whose differential expression has recently been reported in patients with Klinefelter syndrome, has been addressed to play a role in the development of inflammatory and autoimmune diseases, vascular endothelial cells apoptosis and atherosclerosis, all being common features in patients with DS. Therefore, the aim of this study was to assess the lncRNA GAS5 expression profile in DS patients and in controls. lncRNA GAS5 levels were evaluated by qRT-PCR assay in 23 patients with DS and 23 age-matched controls. A significant lncRNA GAS5 down-regulation was observed in patients with DS by RT-PCR analysis, The RNA sequencing experiments confirmed the qRT-PCR data. LncRNA GAS5 down-expression may play a role in the development of some typical features of the patients with DS and, particularly, in inflammatory and autoimmune diseases.

Study of the MDM2 -410T-G polymorphism (rs2279744) by pyrosequencing in mothers of Down Syndrome subjects.

Trisomy 21 or Down syndrome (DS) is the most frequent genetic etiology of intellectual disability in humans. MDM2 gene expression has a potential role as a risk factor for human aneuploidy. -410T-G (rs2279744) functional polymorphism in MDM2 gene impacts on the mechanisms of chromosomal non-disjunction. We analyzed, within a case-control study, such polymorphism in mothers of subjects with DS. Nucleotide polymorphism was detected by pyrosequencing technology. The distribution of MDM2-410T-G polymorphism showed no significant difference among mothers of subjects with DS and controls. Our results suggest that MDM2 -410T-G polymorphism is not a risk factor for DS in mothers.

Searching for new pharmacological targets for the treatment of Alzheimer's disease in Down syndrome.

Individuals with Down syndrome are at increased risk of developing Alzheimer's disease due to increase gene dosage resulting from chromosome 21 triplication. Although virtually all adults with Down syndrome will exhibit the major neuropathological hallmarks that define Alzheimer's disease, not all of them will develop the clinical symptoms associated with this disorder (i.e. dementia). Therefore, a good understanding of the pathophysiology of Alzheimer's disease in Down syndrome will be crucial for the identification of novel pharmacological targets to develop disease-modifying therapies for the benefit of Down syndrome individuals and for Alzheimer's sufferers alike. The study of biomarkers will also be essential for the development of better screening tools to identify dementia at its incipient stages. This review discusses the best-validated pharmacological targets for the treatment of cognitive impairment and Alzheimer's disease in Down syndrome. We further examine the relevance of newly discovered biological markers for earlier dementia diagnosis in this population.

A polymorphism (rs1042522) in TP53 gene is a risk factor for Down Syndrome in Sicilian mothers.

OBJECTIVE: Trisomy 21 is the most frequent genetic cause of intellectual disability. Tumor Protein 53 (TP53) gene down-regulation triggers chromosomal instability. A TP53 gene polymorphism c.215G > C (rs1042522) is associated with accumulation of aneuploid cells. We analyzed the TP53 c.215G > C (rs1042522) polymorphism in Sicilian mothers of subjects with Down Syndrome (DS) within a case-control study. METHODS: Nucleotide polymorphism was detected by pyrosequencing technology. RESULTS: The distribution of TP53 c.215G > C polymorphism showed significant difference between mothers of subjects with DS and controls. CONCLUSIONS: Our data show that TP53 c.215G > C polymorphism is a risk factor for DS in Sicilian mothers.

An inflammatory and trophic disconnect biomarker profile revealed in Down syndrome plasma: Relation to cognitive decline and longitudinal evaluation.

INTRODUCTION: Given that Alzheimer's pathology develops silently over decades in Down syndrome (DS), prognostic biomarkers of dementia are a major need. METHODS: We investigated the plasma levels of Aß, proNGF, tPA, neuroserpin, metallo-proteases and inflammatory molecules in 31 individuals with DS (with and without dementia) and in 31 healthy controls. We examined associations between biomarkers and cognitive decline. RESULTS: Aß40 and Aß42 were elevated in DS plasma compared to controls, even in DS individuals without dementia. Plasma Aß correlated with the rate of cognitive decline across 2 years. ProNGF, MMP-1, MMP-3, MMP-9 activity, TNF-α, IL-6, and IL-10 were higher in DS plasma, even at AD-asymptomatic stages. Declining plasma Aß42 and increasing proNGF levels correlated with cognitive decline. A combined measure of Aß and inflammatory molecules was a strong predictor of prospective cognitive deterioration. CONCLUSIONS: Our findings support the combination of plasma and cognitive assessments for the identification of DS individuals at risk of dementia.

Low AMH levels as a marker of reduced ovarian reserve in young women affected by Down's syndrome.

OBJECTIVE: Women with Down's syndrome (DS) experience menopause earlier than healthy women and are twice as likely to undergo premature ovarian insufficiency. Menopause accelerates cognitive decline and is associated with a twofold increased mortality risk in DS women. Nonetheless, no previous studies investigated the ovarian reserve in this population. The aim of the present study was to evaluate the circulating antimullerian hormone (AMH) levels in DS women with regular menstrual cycles, in comparison with those observed in an age-matched group of healthy women. METHODS: Fourteen women with DS and 20 normo-ovulatory volunteers were enrolled in this study. A general physical examination was performed. Hormonal assays, including AMH, fasting insulin levels, and homeostatic model assessment-insulin resistance, were investigated in all participants. RESULTS: AMH levels were significantly lower in DS women compared with controls (1.34 ±â€Š1.11 vs 3.01 ±â€Š1.65 ng/mL, P < 0.01). Prolactin concentrations were in the normal range, although higher in DS women compared with controls (P < 0.01). After dividing the participants according to age, AMH was significantly lower in the DS group compared with controls, both below and above 30 years of age (1.77 vs 3.73 ng/mL, P < 0.01; 0.28 vs 2.20 ng/mL, P < 0.01, respectively). AMH was inversely correlated with age in both groups, and directly correlated with testosterone and dehydroepiandrosterone sulfate only in DS women. In the same participants, AMH showed a tendency toward a direct correlation with insulin levels (P = 0.055). CONCLUSIONS: AMH levels were significantly lower in DS women compared with age-matched controls. A subanalysis of data in DS participants under 30 years of age suggested an early follicular depletion related to trisomy 21.

Killer-specific secretory (Ksp37) gene expression in subjects with Down's syndrome.

Down syndrome is characterized by dysmorphic features, mental retardation and problems of immune deficiency. Chronic infection by Epstein-Barr virus is frequently present in subjects with Down syndrome. Ksp37 gene is commonly expressed by NK, CD8(+) T, γδ T and CD4(+) T cells; these data suggest that Ksp37 have cytotoxic properties. An increase of Ksp37 protein serum levels it has been showed during the acute phase of Epstein-Barr virus. In this study, we evaluated the expression of Ksp37 mRNA, in fibroblasts and leukocytes of DS subjects and in normal subjects with realtime reverse transcription-PCR. This analysis shows that in fibroblasts and leukocytes of Down syndrome subjects the KSP37 gene expression was increased compared with control subjects. The results of this study suggest that the expression of Ksp37 gene might be associated with increased susceptibility of individuals with Down syndrome to EBV infections and autoimmune problems.

The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant.

The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.

The MTRR 66A>G polymorphism and maternal risk of birth of a child with Down syndrome in Caucasian women: a case-control study and a meta-analysis.

We performed a large case-control study and a meta-analysis of the literature to address the role of the methionine synthase reductase (MTRR) c.66A>G polymorphism as a maternal risk factor for the birth of a child with Down Syndrome (DS) among Caucasian women. A total of 253 mothers of a DS child (MDS) and 298 control mothers of Italian origin were included in the case-control study. The meta-analysis of previous and present data involved a total of seven studies performed in Caucasian populations (971 MDS and 1,387 control mothers). Results from the meta-analysis indicated overall a positive significant association between MTRR c.66A>G genotype [OR 1.36 (95 % CI 1.10-1.68), dominant model] and allele frequencies [OR 1.26 (95 % CI 1.04-1.51), allele contrast model] and maternal risk of birth of a child with DS. A sensitivity analysis revealed some interesting differences between Europeans, Caucasians of European descent, and inhabitants of Mediterranean regions, suggesting the possibility of population-specific modifying factors. The case-control study revealed association of the polymorphism with increased folate levels, and a possible interaction with the methionine synthase (MTR) c.2756A>G one, that resulted in a borderline significant maternal risk of birth of a child with DS for the double heterozygous MTR 2756AG/MTRR 66AG genotype [OR 1.79 (95 % CI 1.00-3.18)]. Overall, present data suggest that the MTRR c.66A>G polymorphism represents a risk factor for the birth of a child with DS among white Caucasian women. However, the combined presence of other genetic factors and interactions with geographic and environmental ones, can modify the effect of the single polymorphism alone, leading to population specific effect sizes.

Effects of repetitive transcranial magnetic stimulation in performing eye-hand integration tasks: four preliminary studies with children showing low-functioning autism.

This report, based on four studies with children with low-functioning autism, aimed at evaluating the effects of repetitive transcranial magnetic stimulation delivered on the left and right premotor cortices on eye-hand integration tasks; defining the long-lasting effects of high-frequency repetitive transcranial magnetic stimulation; and investigating the real efficacy of high-frequency repetitive transcranial magnetic stimulation by comparing three kinds of treatments (high-frequency repetitive transcranial magnetic stimulation, a traditional eye-hand integration training, and both treatments combined). Results showed a significant increase in eye-hand performances only when high-frequency repetitive transcranial magnetic stimulation was delivered on the left premotor cortex; a persistent improvement up to 1 h after the end of the stimulation; better outcomes in the treatment combining high-frequency repetitive transcranial magnetic stimulation and eye-hand integration training. Based on these preliminary findings, further evaluations on the usefulness of high-frequency repetitive transcranial magnetic stimulation in rehabilitation of children with autism are strongly recommended.

3q29 microdeletion syndrome: Cognitive and behavioral phenotype in four patients.

The 3q29 microdeletion syndrome is a rare, recurrent genomic disorder, associated with a variable phenotype, despite the same deletion size, consisting in neurodevelopmental features, such as intellectual disability (ID), schizophrenia, autism, bipolar disorder, depression and mild facial morphological anomalies/congenital malformations. A thorough neuropsychiatric evaluation has never been reported in patients with such syndrome. We analyzed the clinical phenotype of four individuals with 3q29 microdeletion syndrome, with special emphasis on the cognitive and behavioral assessment, in order to delineate the neuropsychiatric phenotype related to this condition. We assessed these patients with standardized scales or checklists measuring the cognitive (WISC III or LIPS-R), behavioral (CBCL) and adaptive (VABS) performances. An accurate evaluation in our sample highlights different degrees of ID, variable behavioral disorders, and a preservation of communicative skills among remaining adaptive areas, as the neuropsychiatric hallmark of 3q29 microdeletion syndrome.

The MTR 2756A>G polymorphism and maternal risk of birth of a child with Down syndrome: a case-control study and a meta-analysis.

Methionine synthase (MTR) is required for the conversion of homocysteine (hcy) to methionine in the one-carbon metabolic pathway. Previous studies investigating a common MTR 2756A>G polymorphism as a maternal risk factor for the birth of a child with Down syndrome (DS) are conflicting and limited by small case-control cohorts, and its contribution to circulating hcy levels is still debated. We performed a large case-control study and a meta-analysis of the literature to further address the role of MTR 2756A>G as a maternal risk factor for the birth of a child with DS. 286 mothers of a DS child (MDS) and 305 control mothers of Italian origin were included in the case-control study. Genotyping was performed by means of PCR/RFLP technique. Data on circulating levels of hcy, folates, and vitamin B12 were available for 189 MDS and 194 control mothers. The meta analysis of previous and present data involved a total of 8 studies (1,171 MDS and 1,402 control mothers). Both the case-control study and the meta-analysis showed no association of MTR 2756A>G with the maternal risk of birth of a child with DS (OR = 1.15; 95 % CI 0.85-1.55, and OR = 1.08; 95 % CI 0.93-1.25, respectively), even after stratification of the overall data available for the meta-analysis into ethnic groups. No association of the studied polymorphism with circulating levels of hcy, folates, and vitamin B12 was observed. Present data do not support a role for MTR 2756A>G as independent maternal risk factor for a DS birth.

Pericentrin expression in Down's syndrome.

Down's syndrome (DS) is the most frequent genetic cause of intellectual disability and is a chromosomal abnormality of chromosome 21 trisomy. The pericentrin gene (PCNT) has sequenced in 21q22.3 inside of the minimal critical region for Down's syndrome. Alterations of PCNT gene are associated with dwarfism, cardiomyopathy and other pathologies. In this study, we have evaluated the possible differential expression of PCNT mRNA, by qRT-PCR, in peripheral blood leukocytes of DS subjects compared with the normal population. In the present case-control study, PCNT gene expression was increased by 72.72% in 16 out 22 DS samples compared with normal subjects. Our data suggest that changes in the expression levels of PCNT in DS subjects may be involved into the molecular mechanism of Down's syndrome.

KIF21A mRNA expression in patients with Down syndrome.

Down syndrome (DS) is a chromosomal disorder caused by chromosome 21 trisomy and is the most frequent genetic cause of intellectual disability. The gene for the kinesin family member 21A (KIF21A), is a member of the kinesin superfamily involved in the anterograde fast axonal transport. In this study, we have evaluated the possible differential expression of KIF21A mRNA, by qRT-PCR, in peripheral blood leukocytes of DS subjects and it compared with the normal population. In the assumption that changes in KIF21A gene expression levels may affect the axonal transport and the development of the nervous system of subjects with DS. In the present case-control study, KIF21A gene expression was increased in 72.72 % of DS samples compared with normal subjects. This finding suggests that changes in the expression levels of KIF21A in DS subjects may affect the axonal transport and the development of the nervous system.