Refining the risk for fragile X-associated primary ovarian insufficiency (FXPOI) by FMR1 CGG repeat size.

Purpose: Approximately 20-30% of women with an FMR1 premutation experience fragile X-associated primary ovarian insufficiency (FXPOI); however, current risk estimates based on repeat size only identify women with the midrange of repeats to be at the highest risk.

Methods: To better understand the risk by repeat size, we collected self-reported reproductive histories on 1,668 women and divided them into high-resolution repeat size bins of ~5 CGG repeats to determine a more accurate risk for FXPOI in relation to CGG repeat length.

Results: As previously reported, women with 70-100 CGG repeats were at the highest risk for FXPOI using various statistical models to compare average age at menopause and risk of FXPOI, with women with 85-89 repeats being at the highest risk.

Autism-associated synaptic vesicle transcripts are differentially expressed in maternal plasma exosomes of physiopathologic pregnancies.

Background: During intrauterine development, the formation and function of synaptic vesicles (SVs) are thought to be fundamental conditions essential for normal development of the brain. Lacking advanced technology during the intrauterine period, such as longitudinal real-time monitoring of the SV-associated transcripts (SVATs), which include six pairs of lncRNA-mRNA, has limited acquisition of the dynamic gene expression profile (GEP) of SVATs. We previously reported the differential expression of SVATs in the peripheral blood of autistic children.

Effects of Starvation on the Levels of Triglycerides, Diacylglycerol, and Activity of Lipase in Male and Female Drosophila Melanogaster.

We studied the effects of starvation on changes in neutral lipids in male and female (fruit fly) at different ages. When flies were subjected to starvation, the mortality rate was observed to be age- and gender-dependent: male flies died earlier as compared to female flies, and older flies died earlier than younger flies. There was an increase in the number of dead flies and the levels of diacylglycerol (DG) with starvation time.

Thiamme2-G, a Novel O-GlcNAcase Inhibitor, Reduces Tau Hyperphosphorylation and Rescues Cognitive Impairment in Mice.

Background: Abnormal hyperphosphorylation of microtubule-associated protein tau plays a pivotal role in Alzheimer's disease (AD). We previously found that O-GlcNAcylation inversely correlates to hyperphosphorylation of tau in AD brain, and downregulation of brain O-GlcNAcylation promotes tau hyperphosphorylation and AD-like neurodegeneration in mice.

Objective: Herein we investigated the effect of increasing O-GlcNAcylation by using intermittent dosing with low doses of a potent novel O-GlcNAcase (OGA) inhibitor on AD-like brain changes and cognitive function in a mouse model of sporadic AD (sAD) induced by intracerebroventricular (ICV) injection of streptozotocin (STZ).

Pharmacological inhibition of BKCa channels induces a specific social deficit in adult C57BL6/J mice.

Genetic variants in large conductance voltage and calcium sensitive potassium (BKCa) channels have associations with neurodevelopmental disorders such as autism spectrum disorder, fragile X syndrome, and intellectual disability. In the case of fragile X syndrome, early preclinical studies suggest that BKCa channels may be a promising treatment target for neurodevelopmental disorders. While BKCa channel dysfunction has been investigated within the context of fragile X syndrome, it is unknown whether interference with BKCa channel function is inductive for deficits in behavioral domains relevant to neurodevelopmental disorders.

Alzheimer's disease brain contains tau fractions with differential prion-like activities.

Neurofibrillary tangles (NFTs) made of abnormally hyperphosphorylated tau are a hallmark of Alzheimer's disease (AD) and related tauopathies. Regional distribution of NFTs is associated with the progression of the disease and has been proposed to be a result of prion-like propagation of misfolded tau. Tau in AD brain is heterogenous and presents in various forms.

Transcriptomics-determined chemokine-cytokine pathway presents a common pathogenic mechanism in pregnancy loss and spontaneous preterm birth.

Problem: Various etiological factors, such as infection and inflammation, may induce the adverse outcomes of pregnancy of miscarriage, stillbirth, or preterm birth. The pathogenic mechanisms associated with these adverse pregnancies are yet unclear. We hypothesized that a common pathogenic mechanism may underlie variant adverse outcomes of pregnancy, which are induced by genetic-environmental factors.

(Epi)genetic variants of the sarcomere-desmosome are associated with premature utero-contraction in spontaneous preterm labor.

Spontaneous preterm birth is a syndrome with clinical and genetic heterogeneity. Few studies have focused on the genetic and epigenetic defects and pathogenic mechanisms associated with premature uterine contraction in spontaneous preterm birth. The objective of this study was to investigate the (epi)genetic variations associated with premature uterine contraction of spontaneous preterm birth.

Sevoflurane-induced neuronal apoptosis in neonatal mice is prevented with intranasal administration of insulin.

Concerns about the potential neurotoxicity of general anesthesia to the developing brain have been increasing in recent years. Animal studies have shown that neonatal exposure to general anesthesia causes both acute neurotoxicity and behavioral abnormalities later in life. In the present study, we observed over-activation of neuronal apoptosis in the brain of neonatal mice after a single exposure to anesthesia with sevoflurane for 6 hours at the age of 7 days.

Tau in Alzheimer's Disease: Pathological Alterations and an Attractive Therapeutic Target.

Alzheimer's disease (AD) is an age-related neurodegenerative disease with two major hallmarks: extracellular amyloid plaques made of amyloid-β (Aβ) and intracellular neurofibrillary tangles (NFTs) of abnormally hyperphosphorylated tau. The number of NFTs correlates positively with the severity of dementia in AD patients. However, there is still no efficient therapy available for AD treatment and prevention so far.

Early intervention with levetiracetam prevents the development of cortical hyperexcitability and spontaneous epileptiform activity in two models of neurotrauma in rats.

This study examined the antiepileptogenic potential of the antiseizure drug (ASD) levetiracetam (LEV) using the in vitro traumatized-slice and in vivo controlled cortical impact (CCI) models of traumatic brain injury (TBI) in rats when administered early after the injury. For the in vitro model, acute coronal slices (400-450 μm) of rat neocortex (P21-32) were injured via a surgical cut that separated the superficial layers from the deeper regions. Persistent stimulus-evoked epileptiform activity developed within 1-2 h after trauma.

Evaluation of the National Task Group-Early Detection Screen for Dementia: Sensitivity to 'mild cognitive impairment' in adults with Down syndrome.

Background: The accuracy of the National Task Group-Early Detection Screen for Dementia (NTG-EDSD) was evaluated in a sample of 185 adults with Down syndrome (DS), emphasizing 'mild cognitive impairment (MCI-DS)'.

Method: Knowledgeable informants were interviewed with the NTG-EDSD, and findings were compared to an independent dementia status rating based on consensus review of detailed assessments of cognition, functional abilities and health status (including physician examination).

Results: Results indicated that sections of the NTG-EDSD were sensitive to MCI-DS, with one or more concerns within the 'Memory' or 'Language and Communication' domains being most informative.

Clinicopathological Staging of Dynamics of Neurodegeneration and Neuronal Loss in Alzheimer Disease.

Clinical and neuropathological staging of Alzheimer disease (AD) neurodegeneration and neuronal loss dynamics is the baseline for identification of treatment targets and timing. The aim of this study of 14 brain regions in 25 subjects diagnosed with AD and 13 age-matched control subjects was to establish the pattern of neurodegeneration, and the severity and rate of neuronal loss in mild cognitive impairment/mild AD (Functional Assessment Staging [FAST] test 3-4), moderate to moderately severe AD (FAST 5-6), and severe AD (FAST 7). The study revealed (1) the most severe neuronal loss in FAST 3-4; (2) the highest rate of neuronal loss in FAST 5-6, to the "critical" point limiting further increase in neuronal loss; (3) progression of neurofibrillary degeneration, but decline of neuronal loss to a floor level in FAST 7; and (4) structure-specific rate of neuronal loss caused by neurofibrillary degeneration and a large pool of neuronal loss caused by other mechanisms.

A Sensitive and Cost-Effective Chemiluminescence ELISA for Measurement of Amyloid-β 1-42 Peptide in Human Plasma.

Background: Amyloid-β42 (Aβ42) is associated with plaque formation in the brain of patients with Alzheimer's disease (AD). Studies have suggested the potential utility of plasma Aβ42 levels in the diagnosis, and in longitudinal study of AD pathology. Conventional ELISAs are used to measure Aβ42 levels in plasma but are not sensitive enough to quantitate low levels.

Trimethylamine N-Oxide increases soluble fms-like tyrosine Kinase-1 in human placenta via NADPH oxidase dependent ROS accumulation.

Backgrounds: Preeclampsia (PE) is characterized as placental vascular disturbance and excessive secretion of soluble fms-like tyrosine kinase 1 (sFlt-1) into the maternal circulation. Trimethylamine N-oxide (TMAO, a gut microbe-derived metabolite) is strongly associated with various cardiovascular and cerebrovascular diseases. Recently, we observe that higher maternal circulating TMAO and sFlt-1 in patients with PE.

Commentary on a combined approach to the problem of developing biomarkers for the prediction of spontaneous preterm labor that leads to preterm birth.

Introduction: Globally, preterm birth has replaced congenital malformation as the major cause of perinatal mortality and morbidity. The reduced rate of congenital malformation was not achieved through a single biophysical or biochemical marker at a specific gestational age, but rather through a combination of clinical, biophysical and biochemical markers at different gestational ages. Since the aetiology of spontaneous preterm birth is also multifactorial, it is unlikely that a single biomarker test, at a specific gestational age will emerge as the definitive predictive test.

Cognitive indicators of transition to preclinical and prodromal stages of Alzheimer's disease in Down syndrome.

Introduction: There is a critical need to identify measures of cognitive functioning sensitive to early Alzheimer's disease (AD) pathophysiology in Down syndrome to advance clinical trial research in this at-risk population. The objective of the study was to longitudinally track performance on cognitive measures in relation to neocortical and striatal amyloid beta (Aβ) in non-demented Down syndrome.

Methods: The study included 118 non-demented adults with Down syndrome who participated in two to five points of data collection, spanning 1.

Alzheimer-Related Cerebrovascular Disease in Down Syndrome.

Objective: Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology by their 5th decade. Compared with the general population, traditional vascular risks in adults with DS are rare, allowing examination of cerebrovascular disease in this population and insight into its role in AD without the confound of vascular risk factors. We examined in vivo magnetic resonance imaging (MRI)-based biomarkers of cerebrovascular pathology in adults with DS, and determined their cross-sectional relationship with age, beta-amyloid pathology, and mild cognitive impairment or clinical AD diagnostic status.

Prenatal to early postnatal neurotrophic treatment prevents Alzheimer-like behavior and pathology in mice.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder of middle-aged to old individuals. The pathophysiological process of AD is believed to begin many years before the emergence of clinical symptoms. The important influence of congenital genetic aberrations on the development of AD provides a novel opportunity to initiate prenatal to early postnatal pharmacological treatment to address the role of this critical period of brain development in the disease.

Allovalency observed by transferred NOE: interactions of sulfated tyrosine residues in the N-terminal segment of CCR5 with the CCL5 chemokine.

The N-terminal segment of the chemokine receptor Human CC chemokine receptor 5 (CCR5), Nt-CCR5, contains four tyrosine residues, Y3, Y10, Y14, and Y15. Sulfation of at least two of these tyrosine residues was found to be essential for high-affinity binding of CCR5 to its chemokine ligands. Here, we show that among the monosulfated Nt-CCR5(8-20) peptide surrogates (sNt-CCR5) those sulfated at Y15 and Y14 have the highest affinity for the CC chemokine ligand 5 (CCL5) chemokine in comparison with monosulfation at position Y10.

Proteomic Study of Fetal Membrane: Inflammation-Triggered Proteolysis of Extracellular Matrix May Present a Pathogenic Pathway for Spontaneous Preterm Birth.

Introduction: Spontaneous preterm birth (sPTB), which predominantly presents as spontaneous preterm labor (sPTL) or prelabor premature rupture of membranes (PPROM), is a syndrome that accounts for 5-10% of live births annually. The long-term morbidity in surviving preterm infants is significantly higher than that in full-term neonates. The causes of sPTB are complex and not fully understood.

Autosomal dominant neuronal ceroid lipofuscinosis: Clinical features and molecular basis.

The neuronal ceroid lipofuscinoses (NCLs) are at least 13 distinct progressive neurodegenerative disorders unified by the accumulation of lysosomal auto-fluorescent material called lipofuscin. The only form that occurs via autosomal-dominant inheritance exhibits adult onset and is sometimes referred to as Parry type NCL. The manifestations may include behavioral symptoms followed by seizures, ataxia, dementia, and early death.