Neurotransmitter Metabolism Research Articles

Exploratory Analysis of Behavioral Impulsivity, Pro-inflammatory Cytokines, and Resting-State Frontal EEG Activity Associated With Non-suicidal Self-Injury in Patients With Mood Disorder.

Introduction: Non-suicidal self-injury (NSSI) is a rapidly increasing mental health problem that requires more clinical attention. In this study, we aimed to explore the biobehavioral markers of NSSI in participants with mood disorders.Methods: A total of 45 participants with mood disorders (bipolar I, II, and major depressive disorder) were included in the study. Behavioral impulsivity was measured using the immediate memory task (IMT)/delayed memory task (DMT) and the go-no-go (GNG) tests. Plasma levels of tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1 β), and interleukin 6 (IL-6) and resting-state quantitative electroencephalography (qEEG) were measured.Results: The NSSI group had shorter GNG reaction time (GNG-RT) and higher TNF-α levels compared to the non-NSSI group. TNF-α was positively correlated with frontal theta power. In addition, GNG-RT showed a significant positive association with frontal alpha activity.Conclusion: NSSI in mood disorders was associated with increased behavioral impulsivity and greater inflammation. Increased pro-inflammatory cytokines were associated with frontal theta power. Increased inflammation might change major neurotransmitter metabolism, which eventually affects frontal function and decreases response inhibition. Further studies to explore their causal relationship are warranted.

Calcium-Involved Action of Phytochemicals: Carotenoids and Monoterpenes in the Brain.

Background: Neurodegenerative and mood disorders represent growing medical and social problems, many of which are provoked by oxidative stress, disruption in the metabolism of various neurotransmitters, and disturbances in calcium homeostasis. Biologically active plant compounds have been shown to exert a positive impact on the function of calcium in the central nervous system. Methods: The present paper reviews studies of naturally occurring terpenes and derivatives and the calcium-based aspects of their mechanisms of action, as these are known to act upon a number of targets linked to neurological prophylaxis and therapy. Results: Most of the studied phytochemicals possess anticancer, antioxidative, anti-inflammatory, and neuroprotective properties, and these have been used to reduce the risk of or treat neurological diseases. Conclusion: The neuroprotective actions of some phytochemicals may employ mechanisms based on regulation of calcium homeostasis and should be considered as therapeutic agents.

Cortical and Striatal Circuits in Huntington's Disease.

Huntington’s disease (HD) is a hereditary neurodegenerative disorder that typically manifests in midlife with motor, cognitive, and/or psychiatric symptoms. The disease is caused by a CAG triplet expansion in exon 1 of the huntingtin gene and leads to a severe neurodegeneration in the striatum and cortex. Classical electrophysiological studies in genetic HD mouse models provided important insights into the disbalance of excitatory, inhibitory and neuromodulatory inputs, as well as progressive disconnection between the cortex and striatum. However, the involvement of local cortical and striatal microcircuits still remains largely unexplored. Here we review the progress in understanding HD-related impairments in the cortical and basal ganglia circuits, and outline new opportunities that have opened with the development of modern circuit analysis methods. In particular, in vivo imaging studies in mouse HD models have demonstrated early structural and functional disturbances within the cortical network, and optogenetic manipulations of striatal cell types have started uncovering the causal roles of certain neuronal populations in disease pathogenesis. In addition, the important contribution of astrocytes to HD-related circuit defects has recently been recognized. In parallel, unbiased systems biology studies are providing insights into the possible molecular underpinnings of these functional defects at the level of synaptic signaling and neurotransmitter metabolism. With these approaches, we can now reach a deeper understanding of circuit-based HD mechanisms, which will be crucial for the development of effective and targeted therapeutic strategies.

Silk sericin intake leads to increases in L-serine and L-tyrosine levels in the mouse brain and the simultaneous facilitation of brain noradrenergic turnover.

Sericin is a protein component of the silkworm cocoon, and contains a high proportion of L-serine, but it has been mostly disposed of as an industrial waste. However, recent studies have revealed its unique biological functionalities beneficial to human health. This study aimed to evaluate the effect of acute oral intake of sericin on amino acid and neurotransmitter metabolism in the mouse brain. Acute administration of chemically modified sericin (0.26g/30g body weight) increased L-serine and L-tyrosine levels in the serum and brain, although the L-tyrosine content in the sericin was less than 3% (w/w). In addition, sericin administration led to a significant facilitation of noradrenergic turnover via enhancement of 3-methoxy-4-hydroxyphenylethyleneglycol, a principal metabolite of noradrenaline, in several of the brain regions examined. These present findings suggest that oral intake of sericin efficiently delivers L-serine and L-tyrosine to the brain, thus stimulating noradrenergic activity in the brain.Abbreviations: DA: dopamine; 5-HIAA: 5-hydroxyindoleicetic acid; 5-HT: 5-hydroxytryptamine; HVA: homovanillic acid; MHPG: 3-methoxy-4-hydroxyphenylethyleneglycol; 3-MT: 3-methoxytyramine; NA: noradrenaline; NM: normetanephrine; Veh: vehicle.

Human Mast Cell Proteome Reveals Unique Lineage, Putative Functions, and Structural Basis for Cell Ablation

Mast cells are rare tissue-resident cells of importance to human allergies. To understand the structural basis of principle mast cell functions, we analyzed the proteome of primary human and mouse mast cells by quantitative mass spectrometry. We identified a mast-cell-specific proteome signature, indicative of a unique lineage, only distantly related to other immune cell types, including innate immune cells. Proteome comparison between human and mouse suggested evolutionary conservation of core mast cell functions. In addition to specific proteases and proteins associated with degranulation and proteoglycan biosynthesis, mast cells expressed proteins potentially involved in interactions with neurons and neurotransmitter metabolism, including cell adhesion molecules, ion channels, and G protein coupled receptors. Toward targeted cell ablation in severe allergic diseases, we used MRGPRX2 for mast cell depletion in human skin biopsies. These proteome analyses suggest a unique role of mast cells in the immune system, probably intertwined with the nervous system.

Treatable Inherited Movement Disorders in Children: Spotlight on Clinical and Biochemical Features.

About 80% of monogenic metabolic diseases causing movement disorders (MDs) emerges during the first 2 decades of life, and a number of these conditions offers the opportunity of a disease-modifying treatment. The implementation of enlarged neonatal screening programs and the impressive rapid increase of the identification of new conditions are enhancing our potential to recognize and treat several diseases causing MDs, changing their outcome and phenotypic spectrum. A literature review of monogenic disorders causing MDs amenable to treatment was conducted focusing on early clinical signs and diagnostic biomarkers. A classification in 3 broad categories based on the therapeutic approach has been proposed. Some disorders result in irreversible neurotoxic lesions that can only be prevented if treated in a presymptomatic stage, and others present with a progressive neurological impairment that a timely diagnosis and treatment may reverse or improve. Some MDs are the result of the failure of intracellular energy supply or altered glucose transport. The treatment in these conditions includes vitamins or a metabolic shift from a carbohydrate to a fatty acid catabolism, respectively. Finally, a group of highly treatable MDs are the result of defects of neurotransmitter metabolism. In these disorders, the supplementation of precursors or mimetics of neurotransmitters can deeply change the disease natural history. To prevent serious and irreversible neurological impairment, the diagnostic work-up of MDs in children should consider a number of clinical red flags and biomarkers denoting specifically treatable diseases.

Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study.

BackgroundThere is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways.Methods and findingsWe first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus [ITG] and middle frontal gyrus [MFG]), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) (neuritic plaque burden), and Braak (neurofibrillary pathology) scores. We found significant alterations in concentrations of metabolites in AD relative to CN samples, as well as associations with severity of both CERAD and Braak, mainly in the ITG. These metabolites represented biochemical reactions in the (1) methionine cycle (choline: lower in AD, p = 0.003; S-adenosyl methionine: higher in AD, p = 0.005); (2) transsulfuration and glutathione synthesis (cysteine: higher in AD, p < 0.001; reduced glutathione [GSH]: higher in AD, p < 0.001); (3) polyamine synthesis/catabolism (spermidine: higher in AD, p = 0.004); (4) urea cycle (N-acetyl glutamate: lower in AD, p < 0.001); (5) glutamate-aspartate metabolism (N-acetyl aspartate: lower in AD, p = 0.002); and (6) neurotransmitter metabolism (gamma-amino-butyric acid: lower in AD, p < 0.001). Utilizing three Gene Expression Omnibus (GEO) datasets, we then examined mRNA expression levels of 71 genes encoding enzymes regulating key reactions within these pathways in the entorhinal cortex (ERC; AD: n = 25; CN: n = 52) and hippocampus (AD: n = 29; CN: n = 56). Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression levels of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. Our study has limitations: our metabolomics assays measured only a small proportion of all metabolites participating in the pathways we examined. Our study is also cross-sectional, limiting our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression. Additionally, the relatively small number of brain tissue samples may have limited our power to detect alterations in all pathway-specific metabolites and their genetic regulators.ConclusionsIn this study, we observed broad dysregulation of transmethylation and polyamine synthesis/catabolism, including abnormalities in neurotransmitter signaling, urea cycle, aspartate-glutamate metabolism, and glutathione synthesis. Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to AD.

Quantitative metabolomics of saliva using proton NMR spectroscopy in patients with Parkinson's disease and healthy controls.

Parkinson's disease (PD) is a multisystem disorder of unknown etiology, highlights a broad array of symptoms and pathological features influencing organs throughout the body. The metabolic profile of saliva in patients with PD may be influenced by malabsorption in the gastroenteric tract, neurodegeneration, and mitochondrial dysfunction. In the present study, we apply a powerful NMR metabolomics approach for biomarker identification in PD using saliva, a non-invasive bio-fluid. Metabolic profiling of saliva were studied in patients with PD (n = 76) and healthy controls (HC, n = 37) were analyzed and differentiated PD from HC. A total of 40 metabolites including aromatic amino acids, short-chain fatty acids, branched chain amino acids, taurine, and N-acetylglutamate were identified. Spectral binned data and concentration of metabolites were estimated for analysis. Increased concentration of phenylalanine, tyrosine, histidine, glycine, acetoacetate, taurine, TMAO, GABA, N-acetylglutamate, acetoin, acetate, alanine, fucose, propionate, isoleucine, and valine were observed in PD as compared to HC. Further, subgroup analysis among early PD, advanced PD, and HC groups, revealed increased metabolite concentration in early PD group as compared to advanced PD and HC group. Analysis revealed potential biomarkers and their involvement in amino acid metabolism, energy metabolism, neurotransmitters metabolism, and microflora system. Patients with early PD exhibited higher metabolite concentration as compared to advanced PD group which might be associated with dopaminergic treatment. The results of our data indicate that patients with PD might be characterized by metabolic imbalances like gut microflora system, energy metabolites, and neurotransmitters which may contribute to the PD pathogenesis.

PENTİLENTETRAZOL İLE OLUŞTURULAN TUTUŞTURMA(KİNDLİNG) MODEL EPİLEPSİDE 5HT1 AGONİST VE ANTAGONİST'LERİNİN BEYİN TNF-ALFA VE IL1- BETA DÜZEYLERİ ÜZERİNE ETKİLERİ

Objective(s): Epilepsy is a brain dysfunction characterized by neuronal hyperexcitability and synchronized electrical discharges that cause seizures to occur. Many other neurotransmitter systems such as Serotonin (5-hydroxytryptamine, 5-HT), dopamine (DA)&nbsp;and&nbsp;adrenaline are known to be involved in the mechanism of epileptogenesis. Neuroinflammation, oxidative stress, and mitochondrial dysfunction play an important role in explaining the pathophysiology of epilepsy. Inflammatory cytokine signals in the brain regulate important brain functions such as neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, dopaminergic transmission, and also affect neurogenesis. This study aimed to investigate the effect of serotonin 5HT-1 agonists and antagonists on TNF-alpha (tumor necrosis factor-alpha) and IL-1 beta (interleukin-1 beta) markers in PTZ (Pentylentetrazol)-Kindling model epileptic rats. Materials and Methods: Twenty-four male Wistar albino rats of 240-280gr were used in our study. PTZ injections were done on rats on Mondays, Wednesdays, and Fridays at a dose of 35 mg/kg to create PTZ kindling model epilepsy, then, on the days of injection, the animals' behavior was observed for 30 minutes, and the stages of epilepsy were determined according to the Racine seizure stages. The animals were then divided into four groups in a randomized way: Control (n = 8) 1ml/ kg SF, 35 mg/ kg PTZ (n = 8), 0.3 mg/ kg 8-OH-DPAT (n = 8) and 1 mg/kg WAY-100135 (n = 8), which were intraperitoneal administered. After the procedure, brain tissues were dissected from the animals. Data analyses were done with SPSS for Windows version 21.0 and evaluated using one-way variance analysis (ANOVA). Results: Between the groups, IL1-β and TNF-alpha results were evaluated. The PTZ group did not change the level of IL1-β compared to the control group (p&gt;0.05), however, there was no statistically significant difference in IL1-β levels between 8-OH-DPAT and WAY-100135 groups (p&gt;0.05). Similarly, PTZ did not change the TNF-alpha level compared to the control group, and there was no statistical difference when 8-OH-DPAT, WAY-100135 groups were compared with the PTZ group (p&gt;0.05). Conclusion: In PTZ kindling epilepsy, the treatments in the 8-OH-DPA (5HT-1 agonist) and WAY-100135 (5HT-1 antagonist) groups showed no effect at TNF-alpha and IL1-β levels, despite this, more studies are needed to investigate the new therapeutic approach to treat epilepsy.

Intracellular Signaling Cascades in Bipolar Disorder.

Bipolar spectrum disorders carry a significant public health burden. Disproportionately high rates of suicide, incarceration, and comorbid medical conditions necessitate an extraordinary focus on understanding the intricacies of this disease. Elucidating granular, intracellular details seems to be a necessary preamble to advancing promising therapeutic opportunities. In this chapter, we review a wide range of intracellular mechanisms including mitochondrial energetics, calcium signaling, neuroinflammation, the microbiome, neurotransmitter metabolism, glycogen synthase kinase 3-beta (GSK3β), protein kinase C (PKC) and diacylglycerol (DAG), and neurotrophins (especially BDNF), as well as the glutamatergic, dopaminergic, purinergic, and neurohormonal systems. Owing to the relative lack of understanding and effective therapeutic options compared to the rest of the spectrum, special attention is paid in the chapter to the latest developments in bipolar depression. Likewise, from a therapeutic standpoint, special attention should be paid to the pervasive mechanistic actions of lithium as a means of amalgamating numerous, disparate cascades into a digestible cognitive topology.

Traditional Chinese Medicine for Alzheimer's Disease and Other Cognitive Impairment: A Review.

Cognitive impairment (CI) refers to the dysfunction of memory, language, visual space, execution, calculation, understanding, and judgment in one or more aspects. With global aging, CI will become prevalent worldwide. At present, there is no effective cure for CI. However, Nobel laureate Tu Youyou's research on artemisinin has inspired Chinese researchers to focus on traditional Chinese herbs (TCHs) for the treatment of CI. Traditional Chinese Medicine (TCM) has led to a theory for an independent CI system. The pathogenesis of such impairment involves deficiency, phlegm, and stagnation and involves a range of organs, including the brain, kidneys, heart, liver, and spleen. Our current understanding of the etiology and pathogenesis of this condition has led to the realization that TCHs can improve cognitive dysfunction. Clinical research has shown that TCHs can improve the neuropsychological scale score of patients, the TCM symptom score, and the patient's quality of life. Research has also suggested that TCHs can retard A deposits and tauopathy, regulate the metabolism of cholinergic neurotransmitters, and so on. However, due to their complexity, little is known of the safety and efficacy of TCHs in patients with CI. It is likely that we will be able to identify the precise mechanisms associated with the action of TCHs in such patients due to the integration of multiple technologies. This paper summarizes the pharmacokinetics, curative effect, and mechanisms of action of traditional Chinese herbs in order to provide a scientific basis for the improvement of cognitive dysfunction by TCHs.

THE ROLE OF CHOLINERGIC INSUFFICIENCY IN COGNITIVE IMPAIRMENT AMONG PATIENTS WITH CHRONIC CEREBRAL ISCHEMIA

The aim: A correction of cholinergic insufficiency for the treatment of cognitive impairment in chronic brain ischemia. Materials and methods: In the period 2014 - 2017, 88 people aged 40 to 68 years were comprehensively examined in dynamics. Patients were divided into three groups, statistically comparable to the main disease - CCI 2 degrees, gender and age. In addition to the protocol, patients with discirculatory encephalopathy of all the investigated groups received a complex of drugs aimed at correcting neurotransmitter metabolism. Results: The statistically significant manifestations of the recovery of cognitive function (according to the MMSE scale) after the application of the developed complex therapy were associated mainly with a decrease in impulsivity due to an increase in the level of attention. The statistically significant manifestations of a decrease in the level of anxietydepressive disorders (according to the DASS-21 scale) after the application of the developed complex therapy were associated mainly with a decrease in anxiety due to the restoration of neurohumoral balance. Conclusions: The inclusion in the treatment protocol for CCI complex of drugs aimed at eliminating cholinergic deficiency, acetylcholinesterase inhibitors in combination with choline precursors, leads to the correction of cognitive impairment in chronic brain ischemia.

Monoamine Oxidase Inhibitors: From Classic to New Clinical Approaches.

Monoamine oxidases (MAOs) are involved in the oxidative deamination of different amines and neurotransmitters. This pointed them as potential targets for several disorders and along the last 70 years a wide variety of MAO inhibitors have been developed as successful drugs for the treatment of complex diseases, being the first drugs approved for depression in the late 1950s. The discovery of two MAO isozymes (MAO-A and B) with different substrate selectivity and tissue expression patterns led to novel therapeutic approaches and to the development of new classes of inhibitors, such as selective irreversible and reversible MAO-B inhibitors and reversible MAO-A inhibitors. Significantly, MAO-B inhibitors constitute a widely studied group of compounds, some of them approved for the treatment of Parkinson's disease. Further applications are under development for the treatment of Alzheimer's disease, amyotrophic lateral sclerosis, and cardiovascular diseases, among others. This review summarizes the most important aspects regarding the development and clinical use of MAO inhibitors, going through mechanistic and structural details, new indications, and future perspectives. Monoamine oxidases (MAOs) catalyze the oxidative deamination of different amines and neurotransmitters. The two different isozymes, MAO-A and MAO-B, are located at the outer mitochondrial membrane in different tissues. The enzymatic reaction involves formation of the corresponding aldehyde and releasing hydrogen peroxide (H2O2) and ammonia or a substituted amine depending on the substrate. MAO's role in neurotransmitter metabolism made them targets for major depression and Parkinson's disease, among other neurodegenerative diseases. Currently, these compounds are being studied for other diseases such as cardiovascular ones.

THE LEVEL OF SYSTEMIC INFLAMMATION AND CHANGES IN ADAPTIVE IMMUNITY IN ALCOHOLIC PSYCHOSES

The aim of the work is to study the level of systemic inflammation and changes in adaptive immunity in the early period after acute psychosis to assess their participation in the pathogenesis of alcoholic mental and cognitive disorders. We examined 28 patients with alcoholic psychosis (AP) and a control group of 17 healthy volunteers. Indicators of systemic inflammation and immunity, including key cytokines and lymphocyte subpopulations, were investigated. After acute psychosis of patients with alcoholism, pronounced activation of humoral immunity with impaired clearance of immune complexes, increased content and activity of Th2 with signs of insufficiency and dysfunction of Th1, reduced content and activity of cytotoxicity system cells and signs of systemic inflammation (increased CRP, cortisol, cytokines). Activation of Th2 response and an excess of proinflammatory mediators in patients with AP through various ways of interaction with the Central nervous system (n. vagus, choroidal plexus of the ventricles, and others) can participate in the disorders of metabolism of neurotransmitters in the Central nervous system involved in the pathogenesis of alcoholism, and in the maintenance of neuroinflammation. A high level of systemic inflammation can be both a trigger of psychosis and a manifestation of violations of neuroimmune interactions, as well as the development of excitotoxicity and damage to neurons in acute psychosis.

Effect of ALDH2 on Sleep Disturbances in Patients with Parkinson\u2019s Disease

Monoamine neurotransmitters play essential roles in the regulation of arousal and sleep. Impaired metabolism of monoamine neurotransmitters could result in the accumulation of neurotoxic aldehyde metabolites and, hence, neuronal degeneration. Aldehyde dehydrogenases play an important role in the metabolism of the neurotoxic aldehyde metabolites, including the aldehyde metabolites of dopamine, serotonin, and noradrenaline. Deficient aldehyde dehydrogenase 2 (ALDH2) has been suggested to result in the accumulation of these biogenic aldehydes. An ALDH2 single nucleotide polymorphism (SNP), rs671 (A), results in significantly reduced ALDH2 enzyme activity. A total of 83 Parkinson’s disease (PD) patients were recruited in this study. In addition to the genotypes of rs671, the patients were assessed with the PD sleep scale-2nd version (PDSS-2) and the Epworth sleepiness scale (ESS) for symptoms of daytime and nocturnal sleep disturbances. The patients carrying rs671 (A) had more frequent dozing while lying down to rest in the afternoon (ESS item5) (F = 7.308, p = 0.008) than the rs671 (GG) patients. The patients with rs671 (A) reported a trend toward more frequent difficulty staying asleep than the patients with rs671 (GG). (F = 3.278, p = 0.074). The results indicate that patients carrying allele rs671 (A) are more likely to experience impairment in the regulation of arousal and sleep. The results also support the hypothesis that the accumulation of neurotoxic monoamine neurotransmitter aldehyde metabolites secondary to reduced ALDH2 enzyme activity may cause more severe monoaminergic neuronal loss and, hence, more severe symptoms in the regulation of wakefulness and sleep.

PATH-19. TUMOR HETEROGENEITY IN GLIOMAS: A PILOT STUDY OF HISTOPATHOLOGY-ASSOCIATED PROTEOME PROFILES ASSESSED BY LIQUID CHROMATOGRAPHY TANDEM MASS SPECTROMETRY OF FFPE SAMPLES

Abstract Herein, we aimed to scrutinize tumor heterogeneity of infiltrative gliomas based on histopathological phenotypes, through proteomic profiling of formalin-fixed, paraffin embedded (FFPE) tissue. FFPE tissues are promising samples for proteomic studies, which can support the elucidation of glioma evolution and identify therapeutically vulnerable proteins and signaling pathways that drive recurrence and resistance mechanisms. We represented 2–3 adjacent, phenotypically distinct areas from 12 grade II-IV gliomas diagnosed according to the 2016 WHO classification, in a total of 35 samples (1.0mm cores), that were analyzed employing liquid chromatography tandem mass spectrometry (LC-MS/MS) for label-free expression proteomics. The statistical analysis was performed using R and Qlucore™ omics explorer software. Overall, 9222 peptides were mapped to 1758 non-redundant proteins, 320 of which had a significant (p&lt; 0.05) differential expression in glioblastomas versus lower grade gliomas (Wilcoxon test comparing average expression). Principal component analysis (PCA) of the whole set of proteins showed clustering of the samples by tumor grade and IDH status. Unsupervised hierarchical analysis of the most significantly expressed proteins (p= 0.01, FDR= 0.05) showed that IDHwt gliomas had high expression of proteins related to cell movement, DNA structure, and fatty acid metabolism throughout the samples. IDHmut gliomas largely displayed high expression of mitochondrial enzymes related to energy production and neurotransmitter metabolism, with subsets closely related to 1p19q status and histological grade. Importantly, we demonstrated that LC-MS/MS analysis of FFPE core samples is feasible and enables recognition of different proteome signatures across histopathological phenotypes within a single tumor. This is the first study, to our knowledge, exploring proteome profiles addressing histopathological heterogeneity in gliomas by LC-MS/MS analysis of FFPE samples, which warrants further validation in independent datasets including ones that utilize frozen specimens. FUNDING: R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01 (NCI), Brain Tumor Funders Collaborative Grant, and the Ohio State University CCC (all to AC).

Neurotransmitter Imbalance in the Brain and Alzheimer's Disease Pathology.

Cholinesterase inhibitors represent three of the four treatments for Alzheimer's disease (AD), and target the pathological reduction of acetylcholine levels. Here we aimed to study the role of other neurotransmitter pathways in AD pathology. This study aimed to determine associations between AD pathology at both symptomatic and asymptomatic stages of disease progression, and the metabolism of a range of non-cholinergic neurotransmitters. Tissue samples were obtained from three groups, controls, AD, and 'asymptomatic AD' (ASYMAD), i.e., cognitively normal individuals that had significant AD neuropathology. Three brain areas were studied, the middle frontal gyrus (MFG), the inferior temporal gyrus (ITG), and the cerebellum. 12 of 15 metabolites involved in neurotransmitter metabolism were shown to be associated with AD pathology. Decreases in dopamine were most pronounced in the MFG with lower levels seen in the ASYMAD group compared to control (FC = 0.78, p = 2.9×10-2). In the ITG significant changes were seen in GABAergic and serotonin metabolism between control and AD patients; however, these changes were not seen between control and ASYMAD individuals. These results indicate that dopamine could be depleted in brains with AD pathology but intact cognition, while an imbalance of several neurotransmitters is evident in the brains of AD patients.

Neuroimaging Spectrum of Inherited Neurotransmitter Disorders.

Inherited neurotransmitter disorders are rare neurometabolic conditions which encompass genetic disorders of neurotransmitter metabolism or transport. The clinical manifestations of these rare disorders are often nonspecific, ranging from encephalopathies and seizures to movement disorders. As a consequence, neurotransmitter disorders are underrecognized and often misdiagnosed. Accurate and timely diagnosis is, however, of utmost importance, given the availability of therapeutic strategies. A high index of clinical suspicion and familiarity with the neuroimaging phenotypes is therefore crucial. While the imaging features of various neurotransmitter disorders often overlap and are nonspecific, imaging can be helpful in providing useful clues to guide the diagnostic algorithm for uncommon conditions in a neonate presenting with nonspecific neurological symptoms. In this review paper, we aim to bring together current knowledge of neuroimaging phenotypes associated with inherited (primary) disorders of neurotransmitter biosynthesis. Magnetic resonance imaging phenotypes of disorders of monoamine biosynthesis, primary cerebral folate deficiency, disorders of pyridoxine metabolism, disorders of gamma-aminobutyric acid metabolism, nonketotic hyperglycinemia (glycine encephalopathy), disorders of serine biosynthesis, and cerebral creatine deficiency syndrome will be discussed and illustrated with case examples.

Spatiotemporal Role of Transforming Growth Factor Beta 2 in Developing and Mature Mouse Hindbrain Serotonergic Neurons.

Transforming growth factor betas are integral molecular components of the signalling cascades defining development and survival of several neuronal groups. Among TGF-β ligands, TGF-β2 has been considered as relatively more important during development. We have generated a conditional knockout mouse of the Tgf-β2 gene with knock-in of an EGFP reporter and subsequently a mouse line with cell-type specific deletion of TGF-β2 ligand from Krox20 expressing cells (i.e., in cells from rhombomeres r3 and r5). We performed a phenotypic analysis of the hindbrain serotonergic system during development and in adulthood, determined the neurochemical profile in hindbrain and forebrain, and assessed behavioural performance of wild type and mutant mice. Mutant mice revealed significantly decreased number of caudal 5-HT neurons at embryonic day (E) 14, and impaired development of caudal dorsal raphe, median raphe, raphe magnus, and raphe obscurus neurons at E18, a phenotype that was largely restored and even overshot in dorsal raphe of mutant adult mice. Serotonin levels were decreased in hindbrain but significantly increased in cortex of adult mutant mice, though without any behavioural consequences. These results highlight differential and temporal dependency of developing and adult neurons on TGF-β2. The results also indicate TGF-β2 being directly or indirectly potent to modulate neurotransmitter synthesis and metabolism. The novel floxed TGF-β2 mouse model is a suitable tool for analysing the in vivo functions of TGF-β2 during development and in adulthood in many organs.

Gender Difference in the Effect of Short Sleep Time on Suicide among Korean Adolescents.

A close association between the duration of sleep and suicide has been reported in previous studies. This study was designed to investigate whether there is a difference in the effects of sleep duration on suicide by gender. This study was conducted based on the results of a volunteer online survey for adolescents in middle and high school in the Republic of Korea. The results showed that the effect of a depressive mood on short sleep time and on suicide was not different between male and female adolescents. It has been reported that the direct effect of short sleep time on increasing suicidal ideation is 2.50 times higher in female than in male adolescents. Differences in the metabolism of sex hormones and sleep-associated neurotransmitters might have affected this result, but further studies are needed to clarify more obvious mechanisms. In addition, this result should be considered when establishing sleep education for adolescents.