The Alzheimer's Biomarker Consortium-Down Syndrome: Rationale and methodology.

Introduction: Adults with Down syndrome (DS) are at exceptionally high risk for Alzheimer's disease (AD), with virtually all individuals developing key neuropathological features by age 40. Identifying biomarkers of AD progression in DS can provide valuable insights into pathogenesis and suggest targets for disease modifying treatments.

Methods: We describe the development of a multi-center, longitudinal study of biomarkers of AD in DS.

Proteomic profiles for Alzheimer's disease and mild cognitive impairment among adults with Down syndrome spanning serum and plasma: An Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study.

Introduction: Previously generated serum and plasma proteomic profiles were examined among adults with Down syndrome (DS) to determine whether these profiles could discriminate those with mild cognitive impairment (MCI-DS) and Alzheimer's disease (DS-AD) from those cognitively stable (CS).

Methods: Data were analyzed on n = 305 (n = 225 CS; n = 44 MCI-DS; n = 36 DS-AD) enrolled in the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS).

Results: Distinguishing MCI-DS from CS, the serum profile produced an area under the curve (AUC) = 0.

Early-onset cerebellar ataxia in a patient with CMT2A2.

A 9-yr 8-mo-old right-handed female presented with a history of gait difficulties, which first became apparent at age 9 mo of age, along with slurred speech and hand tremors while holding a tray. Her past medical history was significant for global developmental delay, and she was attending fourth grade special education classes. On examination, she had an ataxic gait, dysarthria, absent deep tendon reflexes, and flexor plantar responses.

Proteomic profiles of incident mild cognitive impairment and Alzheimer's disease among adults with Down syndrome.

Introduction: We sought to determine if proteomic profiles could predict risk for incident mild cognitive impairment (MCI) and Alzheimer's disease (AD) among adults with Down syndrome (DS).

Methods: In a cohort of 398 adults with DS, a total of n = 186 participants were determined to be non-demented and without MCI or AD at baseline and throughout follow-up; n = 103 had incident MCI and n = 81 had incident AD. Proteomics were conducted on banked plasma samples from a previously generated algorithm.

Proteomic profiles of prevalent mild cognitive impairment and Alzheimer's disease among adults with Down syndrome.

Introduction: We sought to determine if a proteomic profile approach developed to detect Alzheimer's disease (AD) in the general population would apply to adults with Down syndrome (DS).

Methods: Plasma samples were obtained from 398 members of a community-based cohort of adults with DS. A total of n = 186 participants were determined to be non-demented and without mild cognitive impairment (MCI) at baseline and throughout follow-up; n = 50 had prevalent MCI; n = 42 had prevalent AD.

Enhanced accumulation of N-terminally truncated Aβ with and without pyroglutamate-11 modification in parvalbumin-expressing GABAergic neurons in idiopathic and dup15q11.2-q13 autism.

Autism, the most frequent neurodevelopmental disorder of a very complex etiopathology, is associated with dysregulation of cellular homeostatic mechanisms, including processing of amyloid-β precursor protein (APP). Products of APP processing - N-terminally truncated amyloid-β peptide (N-tr-Aβ) species - are accumulated in autism in neurons and glia in the cortex, cerebellum, and subcortical structures of the brain. This process in neurons is correlated with increased oxidative stress.

syndrome in two siblings with retinitis pigmentosa and neurodegeneration with brain iron accumulation.

Whole-exome sequencing was used to identify the genetic etiology of a rapidly progressing neurological disease present in two of six siblings with early childhood onset of severe progressive spastic paraparesis and learning disabilities. A homozygous mutation (c.2005G>T, p, V669L) was found in , and the clinical phenotype is consistent with the recently described -related striatonigral degeneration, childhood-onset syndrome (SNDC) (MIM#617054).

Genomic Copy Number Variations in the Autism Clinic-Work in Progress.

The development of advanced technology for microarray-based chromosomal studies helped discover increased prevalence of genomic copy number variants (CNVs) in individuals with autism spectrum disorder (ASD). Chromosomal microarray analysis (CMA) is now an important tool for clinical investigations in patients with ASD. While this technology helps identify high proportion of CNV positive individuals among patients with autism, the clinical interpretation of such genomic rearrangements is often challenged by inconsistent genotype-phenotype correlations.

17β-Hydroxysteroid dehydrogenases and neurosteroid metabolism in the central nervous system.

17β-Hydroxysteroid dehydrogenases are indispensable for downstream enzyme steps of the neurosteroidogenesis. Neurosteroids are synthesized de novo in neurons and glia from cholesterol transported into mitochondria, or by conversion from proneurosteroids, e. g.

The role of reduced expression of fragile X mental retardation protein in neurons and increased expression in astrocytes in idiopathic and syndromic autism (duplications 15q11.2-q13).

Fragile X syndrome (FXS), caused by lack of fragile X mental retardation protein (FMRP), is associated with a high prevalence of autism. The deficit of FMRP reported in idiopathic autism suggests a mechanistic overlap between FXS and autism. The overall goal of this study is to detect neuropathological commonalities of FMRP deficits in the brains of people with idiopathic autism and with syndromic autism caused by dup15q11.

Roles of Mitochondrial 17β-Hydroxysteroid Dehydrogenase Type 10 in Alzheimer's Disease.

17β-Hydroxysteroid dehydrogenase type 10 is a multifunctional, homotetrameric, mitochondrial protein encoded by the HSD17B10 gene at Xp 11.2. This protein, 17β-HSD10, is overexpressed in brain cells of Alzheimer's disease (AD) patients.

A Novel Cysteine Sulfinic Acid Decarboxylase Knock-Out Mouse: Taurine Distribution in Various Tissues With and Without Taurine Supplementation.

Taurine, a sulfur containing amino acid, has various physiological functions including development of the eye and brain, immune function, reproduction, osmo-regulatory function as well as anti-oxidant and anti-inflammatory activities. In order to understand the physiological role, we developed taurine deficient mice deleting a rate-liming enzyme, cysteine sulfinic acid decarboxylase (CSAD) for biosynthesis of taurine. Taurine was measured in various tissues including the liver, brain, lung, spleen, thymus, pancreas, heart, muscle and kidney as well as plasma from CSAD knock-out mice (CSAD KO) with and without treatment of taurine in the drinking water at the age of 2 months (2 M).

A Novel Cysteine Sulfinic Acid Decarboxylase Knock-Out Mouse: Immune Function (II).

Taurine deficient mice lacking cysteine sulfinic acid decarboxylase (CSAD KO) were developed for investigating the various physiological roles of taurine including the development of the brain and eye as well as immune function. Due to severe abnormalities of immune function in a taurine deficient cat, the immune function including adoptive and innate immunity in taurine-deficient mice have been studied. Previously we demonstrated that B cell function in CSAD KO was reduced in both females and males.

Epidemiology of estrogen and dementia in women with Down syndrome.

Several lines of investigation have shown a protective role for estrogen in Alzheimer's disease through a number of biological actions. This review examines studies of the role of estrogen-related factors in age at onset and risk for Alzheimer's disease in women with Down syndrome, a population at high risk for early onset of dementia. The studies are consistent in showing that early age at menopause and that low levels of endogenous bioavailable estradiol in postmenopausal women with Down syndrome are associated with earlier age at onset and overall risk for dementia.

-related intellectual disability syndrome: a recognisable entity.

Background: Mutations in forkhead box protein P1 () cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far.

Methods: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with defects.

Candidate gene analysis for Alzheimer's disease in adults with Down syndrome.

Individuals with Down syndrome (DS) overexpress many genes on chromosome 21 due to trisomy and have high risk of dementia due to the Alzheimer's disease (AD) neuropathology. However, there is a wide range of phenotypic differences (e.g.

Monoamine oxidase-A and B activities in the cerebellum and frontal cortex of children and young adults with autism.

Monoamine oxidases (MAOs) catalyze the metabolism of monoamine neurotransmitters, such as serotonin, dopamine, and norepinephrine, and are key regulators for brain function. In this study, we analyzed the activities of MAO-A and MAO-B in the cerebellum and frontal cortex from subjects with autism and age-matched control subjects. In the cerebellum, MAO-A activity in subjects with autism (aged 4-38 years) was significantly lower by 20.

Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene.

Purpose: To investigate the utility of whole-exome sequencing (WES) to define a molecular diagnosis for patients clinically diagnosed with congenital anomalies of kidney and urinary tract (CAKUT).

Methods: WES was performed in 62 families with CAKUT. WES data were analyzed for single-nucleotide variants (SNVs) in 35 known CAKUT genes, putatively deleterious sequence changes in new candidate genes, and potentially disease-associated copy-number variants (CNVs).

Effects of methylmercury and alcohol exposure in Drosophila melanogaster: Potential risks in neurodevelopmental disorders.

Extensive evidence suggests the role of oxidative stress in autism and other neurodevelopmental disorders. In this study, we investigated whether methylmercury (MeHg) and/or alcohol exposure has deleterious effects in Drosophila melanogaster (fruit flies). A diet containing different concentrations of MeHg in Drosophila induced free radical generation and increased lipid peroxidation (markers of oxidative stress) in a dose-dependent manner.

Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research.

Neuroactive steroids are endogenous neuromodulators synthesised in the brain that rapidly alter neuronal excitability by binding to membrane receptors, in addition to the regulation of gene expression via intracellular steroid receptors. Neuroactive steroids induce potent anxiolytic, antidepressant, anticonvulsant, sedative, analgesic and amnesic effects, mainly through interaction with the GABAA receptor. They also exert neuroprotective, neurotrophic and antiapoptotic effects in several animal models of neurodegenerative diseases.

Significant neuronal soma volume deficit in the limbic system in subjects with 15q11.2-q13 duplications.

Introduction: Autism is diagnosed in numerous genetic and genomic developmental disorders associated with an overlap in high-risk genes and loci that underlie intellectual disability (ID) and epilepsy. The aim of this stereological study of neuronal soma volume in 25 brain structures and their subdivisions in eight individuals 9 to 26 years of age who were diagnosed with chromosome 15q11.2-13.

Novel Epigenetic Regulation of Alpha-Synuclein Expression in Down Syndrome.

Alpha-synuclein (SNCA), a presynaptic protein, is significantly reduced in individuals with Down syndrome (DS) and Ts65Dn mice, a mouse model of DS. Methylation analyses of promoter proximal CpG sites indicate similar reduction in Ts65Dn mice compared to control mice. Epigallocatechin-3-gallate (EGCG), a polyphenolic catechin present in green tea extract, increases methylation of SNCA promoter proximal CpG sites and expression in Ts65Dn mice.

Glutathione redox imbalance in brain disorders.

Purpose Of Review: Glutathione (GSH) is a major endogenous antioxidant. Several studies have implicated GSH redox imbalance in brain disorders. Here, we summarize current evidence on how GSH depletion and GSH-related enzyme deficit are involved in the pathology of brain disorders such as autism, schizophrenia, bipolar disorder, Alzheimer's disease, and Parkinson's disease.