Sample records for n-acetylaspartate creatine choline

  1. Increased N-Acetylaspartate/creatine ratio in the medial prefrontal cortex among unmedicated obsessive-compulsive disorder patients.

    PubMed

    Fan, Qing; Tan, Ling; You, Chao; Wang, Jijun; Ross, Colin A; Wang, Xuemei; Zhang, Tianhong; Li, Jianqi; Chen, Kemin; Xiao, Zeping

    2010-10-01

    Changes in the fronto-striato-thalamo-cortical-circuit loop have been suggested in the pathogenesis of obsessive-compulsive disorder (OCD), and have been studied using (1)H magnetic resonance spectroscopy ((1)H MRS) with interesting findings. However, whether neural metabolites are abnormal in the medial prefrontal cortex in patients with OCD is unknown. The purpose of the present study was to investigate neural metabolites in this brain region in a sample of patients with OCD. Subjects were 21 unmedicated OCD patients, including 10 who were drug-naïve, and 19 healthy controls. Single-voxel (1)H MRS was used to study the medial prefrontal cortex for each subject. Levels of N-acetylaspartate (NAA), choline-containing compounds and myoinositol were measured in terms of their ratios with creatine (Cr). The NAA/Cr ratio was significantly higher among OCD patients than among healthy controls (F = 4.76, P = 0.037). However, it did not correlate with patients' symptoms or with their illness durations. The NAA/Cr ratio also did not differ between drug-naïve and previously medicated patients. No significant group differences were found between OCD patients and normal controls for the choline-containing compounds/Cr or myoinositol/Cr ratios. In addition, a significant correlation between the NAA/Cr ratio and trait anxiety scores on the State-Trait Anxiety Inventory was found among the controls (r = 0.639, P = 0.010). The N-Acetylaspartate level relative to creatine in the medial prefrontal cortex was increased among unmedicated OCD patients. This cannot be attributed to the effect of medications. The possible significance of this finding in the pathophysiology of OCD is discussed. © 2010 Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine. Psychiatry and Clinical Neurosciences © 2010 Japanese Society of Psychiatry and Neurology.

  2. Localisation of N-acetylaspartate in oligodendrocytes/myelin.

    PubMed

    Nordengen, Kaja; Heuser, Christoph; Rinholm, Johanne Egge; Matalon, Reuben; Gundersen, Vidar

    2015-03-01

    The role of N-acetylaspartate in the brain is unclear. Here we used specific antibodies against N-acetylaspartate and immunocytochemistry of carbodiimide-fixed adult rodent brain to show that, besides staining of neuronal cell bodies in the grey matter, N-acetylaspartate labelling was present in oligodendrocytes/myelin in white matter tracts. Immunoelectron microscopy of the rat hippocampus showed that N-acetylaspartate was concentrated in the myelin. Also neuronal cell bodies and axons contained significant amounts of N-acetylaspartate, while synaptic elements and astrocytes were low in N-acetylaspartate. Mitochondria in axons and neuronal cell bodies contained higher levels of N-acetylaspartate compared to the cytosol, compatible with synthesis of N-acetylaspartate in mitochondria. In aspartoacylase knockout mice, in which catabolism of N-acetylaspartate is blocked, the levels of N-acetylaspartate were largely increased in oligodendrocytes/myelin. In these mice, the highest myelin concentration of N-acetylaspartate was found in the cerebellum, a region showing overt dysmyelination. In organotypic cortical slice cultures there was no evidence for N-acetylaspartate-induced myelin toxicity, supporting the notion that myelin damage is induced by the lack of N-acetylaspartate for lipid production. Our findings also implicate that N-acetylaspartate signals on magnetic resonance spectroscopy reflect not only vital neurons but also vital oligodendrocytes/myelin.

  3. Reduced thalamic N-acetylaspartate in idiopathic normal pressure hydrocephalus: a controlled 1H-magnetic resonance spectroscopy study of frontal deep white matter and the thalamus using absolute quantification.

    PubMed

    Lundin, F; Tisell, A; Dahlqvist Leinhard, O; Tullberg, M; Wikkelsö, C; Lundberg, P; Leijon, G

    2011-07-01

    Patients with idiopathic normal pressure hydrocephalus (INPH) frequently have a reduction in cerebral blood flow in the subcortical frontal lobe/basal ganglia/thalamic areas. With magnetic resonance spectroscopy, the metabolism in the brain can be examined. The aim of this study was to investigate if there was a compromised metabolism in the thalamus and in the subcortical frontal areas in INPH patients. This was done by measuring total creatine, myo-inositol, total choline, N-acetylaspartate (NAA), total N-acetylaspartate (tNA), glutamate and lactate levels. A comparison was made with healthy individuals (HI). 16 patients (nine males, seven females, mean age 74 years, range 49-83) diagnosed as INPH and 15 HI (nine males, six females, mean age 74 years, range 62-89) were examined. (1)H magnetic resonance spectroscopy (1.5 T, point-resolved spectroscopy, echo time/relaxation time 30/3000 ms, volume of interest 2.5-3 ml) was performed in frontal deep white matter and in the thalamus. Absolute quantification with internal water as a reference was used. INPH patients had lower NAA (p=0.02) and lower tNA (p=0.05) concentrations in the thalamus compared with HI. NAA and tNA in the frontal deep white matter did not differ between patients and HI. The absolute metabolic concentrations of total creatine, myo-inositol total choline, tNA, lactate and Cr ratios in frontal deep white matter and in the thalamus were similar in INPH patients and HI. Reduced thalamic NAA and tNA in INPH patients suggest a compromised metabolic neuronal function in these regions. Thus, the thalamus might have an important role in the pathogenesis of INPH.

  4. Recreational alcohol use induces changes in the concentrations of choline-containing compounds and total creatine in the brain: a (1)H MRS study of healthy subjects.

    PubMed

    Tunc-Skarka, Nuran; Weber-Fahr, Wolfgang; Ende, Gabriele

    2015-10-01

    It has previously been reported that even social alcohol consumption affects the magnetic resonance spectroscopy (MRS) signals of choline-containing compounds (tCho). The purpose of this study was to investigate whether the consumption of alcohol affects the concentrations of the metabolites tCho, N-acetylaspartate, creatine, or myo-inositol and/or their T 2 relaxation times. (1)H MR spectra were obtained at 3 T from a frontal white matter voxel of 25 healthy subjects with social alcohol consumption (between 0 and 25.9 g/day). Absolute brain metabolite concentrations and T 2 relaxation times of metabolites were examined via MRS measurements at different echo times. Metabolite concentrations and their T 2 relaxation times were correlated with subjects' alcohol consumption, controlling for age. We observed positive correlations of absolute tCho and phosphocreatine and creatine (tCr) concentrations with alcohol consumption but no correlation between any metabolite T 2 relaxation time and alcohol consumption. This study shows that even social alcohol consumption affects the concentrations of tCho and tCr in cerebral white matter. Future studies assessing brain tCho and tCr levels should control for the confounding factor alcohol consumption.

  5. Dorsolateral prefrontal cortex N-acetylaspartate/total creatine (NAA/tCr) loss in male recreational cannabis users.

    PubMed

    Hermann, Derik; Sartorius, Alexander; Welzel, Helga; Walter, Sigrid; Skopp, Gisela; Ende, Gabriele; Mann, Karl

    2007-06-01

    Cannabinoids present neurotoxic and neuroprotective properties in in vitro studies, inconsistent alterations in human neuroimaging studies, neuropsychological deficits, and an increased risk for psychotic episodes. Proton magnetic resonance spectroscopy ((1)H-MRS), neuropsychological testing, and hair analysis for cannabinoids was performed in 13 male nontreatment-seeking recreational cannabis users and 13 male control subjects. A significantly diminished N-acetylaspartate/total creatine (NAA/tCr) ratio in the dorsolateral prefrontal cortex (DLPFC) was observed in cannabis users (p = .0003). The NAA/tCr in the putamen/globus pallidum region correlated significantly with cannabidiol (R(2) = .66, p = .004). Results of the Wisconsin Card Sorting test, Trail making Test, and D2 test for attention were influenced by cannabinoids. Chronic recreational cannabis use is associated with an indication of diminished neuronal and axonal integrity in the DLPFC in this study. As chronic cannabis use is a risk factor for psychosis, these results are interesting because diminished NAA/tCr ratios in the DLPFC and neuropsychological deficits were also reported in schizophrenia. The strong positive correlation of NAA/tCr and cannabidiol in the putamen/globus pallidum is in line with neuroprotective properties of cannabidiol, which were also observed in in vitro model studies of Parkinson's disease.

  6. Reduced N-acetylaspartate to creatine ratio in the posterior cingulate correlates with cognition in Alzheimer's disease following four months of rivastigmine treatment.

    PubMed

    Penner, Jacob; Wells, Jennie L; Borrie, Michael J; Woolmore-Goodwin, Sarah M; Bartha, Robert

    2015-01-01

    To determine whether 4 months of rivastigmine treatment would result in metabolic changes and whether metabolic changes correlate with changes in cognition in people with Alzheimer's disease (AD). Magnetic resonance spectra were acquired from the posterior cingulate cortex of subjects with AD at 3 T. Magnetic resonance imaging scans and cognitive tests were performed before and 4 months after the beginning of the treatment. Metabolite concentrations were quantified and used to calculate the metabolite ratios. On average, the N-acetylaspartate/creatine (NAA/Cr) ratio decreased by 12.7% following 4 months of rivastigmine treatment, but changes in the NAA/Cr ratio correlated positively with changes in Mini-Mental State Examination scores. This positive correlation between changes in NAA/Cr and changes in cognitive performance suggests that the NAA/Cr ratio could be an objective indicator of a response to rivastigmine treatment. © 2014 S. Karger AG, Basel

  7. Medial Frontal Lobe Neurochemistry in Autism Spectrum Disorder Is Marked by Reduced N-Acetylaspartate and Unchanged Gamma-Aminobutyric Acid and Glutamate + Glutamine Levels

    ERIC Educational Resources Information Center

    Carvalho Pereira, Andreia; Violante, Inês R.; Mouga, Susana; Oliveira, Guiomar; Castelo-Branco, Miguel

    2018-01-01

    The nature of neurochemical changes in autism spectrum disorder (ASD) remains controversial. We compared medial prefrontal cortex (mPFC) neurochemistry of twenty high-functioning children and adolescents with ASD without associated comorbidities and fourteen controls. We observed reduced total N-acetylaspartate (tNAA) and total creatine, increased…

  8. Reduced concentrations of N-acetylaspartate (NAA) and the NAA-creatine ratio in the basal ganglia in bipolar disorder: a study using 3-Tesla proton magnetic resonance spectroscopy.

    PubMed

    Frye, Mark A; Thomas, M Albert; Yue, Kenneth; Binesh, Nader; Davanzo, Pablo; Ventura, Joseph; O'Neill, Joseph; Guze, Barry; Curran, John G; Mintz, Jim

    2007-04-15

    The N-acetylaspartate (NAA) peak is prominent in the proton magnetic resonance spectrum and is thought to reflect neuron loss or dysfunction. This study was conducted to explore NAA biochemistry and its clinical correlates in mania. Subjects comprised 16 manic patients and 17 controls who underwent a structured diagnostic interview and (1)H magnetic resonance spectroscopy (MRS) acquisition. STEAM (1)H MRS (TR/TE/TM=2000/20/8 ms) was acquired at 3 Tesla from 2 x 2 x 2 cm(3) voxels in anterior cingulate (AC), right basal ganglia (BG), and left occipital-parietal white matter (OP). Absolute metabolite concentrations and ratios to creatine were calculated using the LC Model. The mean absolute concentrations of NAA and NAA-creatine ratio in the BG were significantly lower in manic subjects than in controls. There was a significant inverse correlation between NAA in the BG and the number of prior hospitalizations for mania. These data suggest BG pathology in mania and that NAA decrements may mark prior manic episode burden. Limitations of this study include small sample size and lack of tissue segmentation. Further study is encouraged to clarify state vs. trait aspects of NAA in bipolar disorder.

  9. Effects of Creatine Monohydrate Augmentation on Brain Metabolic and Network Outcome Measures in Women With Major Depressive Disorder.

    PubMed

    Yoon, Sujung; Kim, Jieun E; Hwang, Jaeuk; Kim, Tae-Suk; Kang, Hee Jin; Namgung, Eun; Ban, Soonhyun; Oh, Subin; Yang, Jeongwon; Renshaw, Perry F; Lyoo, In Kyoon

    2016-09-15

    Creatine monohydrate (creatine) augmentation has the potential to accelerate the clinical responses to and enhance the overall efficacy of selective serotonin reuptake inhibitor treatment in women with major depressive disorder (MDD). Although it has been suggested that creatine augmentation may involve the restoration of brain energy metabolism, the mechanisms underlying its antidepressant efficacy are unknown. In a randomized, double-blind, placebo-controlled trial, 52 women with MDD were assigned to receive either creatine augmentation or placebo augmentation of escitalopram; 34 subjects participated in multimodal neuroimaging assessments at baseline and week 8. Age-matched healthy women (n = 39) were also assessed twice at the same intervals. Metabolic and network outcomes were measured for changes in prefrontal N-acetylaspartate and changes in rich club hub connections of the structural brain network using proton magnetic resonance spectroscopy and diffusion tensor imaging, respectively. We found MDD-related metabolic and network dysfunction at baseline. Improvement in depressive symptoms was greater in patients receiving creatine augmentation relative to placebo augmentation. After 8 weeks of treatment, prefrontal N-acetylaspartate levels increased significantly in the creatine augmentation group compared with the placebo augmentation group. Increment in rich club hub connections was also greater in the creatine augmentation group than in the placebo augmentation group. N-acetylaspartate levels and rich club connections increased after creatine augmentation of selective serotonin reuptake inhibitor treatment. Effects of creatine administration on brain energy metabolism and network organization may partly underlie its efficacy in treating women with MDD. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  10. Supplementation with Folic Acid, but Not Creatine, Increases Plasma Betaine, Decreases Plasma Dimethylglycine, and Prevents a Decrease in Plasma Choline in Arsenic-Exposed Bangladeshi Adults.

    PubMed

    Hall, Megan N; Howe, Caitlin G; Liu, Xinhua; Caudill, Marie A; Malysheva, Olga; Ilievski, Vesna; Lomax-Luu, Angela M; Parvez, Faruque; Siddique, Abu B; Shahriar, Hasan; Uddin, Mohammad N; Islam, Tariqul; Graziano, Joseph H; Gamble, Mary V

    2016-05-01

    Folic acid (FA) supplementation facilitates urinary excretion of arsenic, a human carcinogen. A better understanding of interactions between one-carbon metabolism intermediates may improve the ability to design nutrition interventions that further facilitate arsenic excretion. The objective was to determine if FA and/or creatine supplementation increase choline and betaine and decrease dimethylglycine (DMG). We conducted a secondary analysis of the Folic Acid and Creatine Trial, a randomized trial in arsenic-exposed Bangladeshi adults (n = 605, aged 24-55 y, 50.3% male) who received arsenic-removal water filters. We examined treatment effects of FA and/or creatine supplementation on plasma choline, betaine, and DMG concentrations, measured by LC-tandem mass spectrometry at baseline and at week 12. Group comparisons were between 1) 400 and 800 μg FA/d (FA400 and FA800, respectively) compared with placebo, 2) creatine (3 g/d) compared with placebo, and 3) creatine plus FA400 compared with FA400. Choline decreased in the placebo group (-6.6%; 95% CI: -10.2%, -2.9%) but did not change in the FA groups (FA400: 2.5%; 95% CI: -0.9%, 6.1%; FA800: 1.4%; 95% CI: -2.5%, 5.5%; P < 0.05). Betaine did not change in the placebo group (-3.5%; 95% CI: -9.3%, 2.6%) but increased in the FA groups (FA400: 14.1%; 95% CI: 9.4%, 19.0%; FA800: 13.0%; 95% CI: 7.2%, 19.1%; P < 0.01). The decrease in DMG was greater in the FA groups (FA400: -26.7%; 95% CI: -30.9%, -22.2%; FA800: -27.8%; 95% CI: -31.8%, -23.4%) than in the placebo group (-12.3%; 95% CI: -18.1%, -6.2%; P < 0.01). The percentage change in choline, betaine, and DMG did not differ between creatine treatment arms and their respective reference groups. Supplementation for 12 wk with FA, but not creatine, increases plasma betaine, decreases plasma DMG, and prevents a decrease in plasma choline in arsenic-exposed Bangladeshi adults. This trial was registered at clinicaltrials.gov as NCT01050556. © 2016 American Society for

  11. Potential of MR spectroscopy for assessment of glioma grading.

    PubMed

    Bulik, Martin; Jancalek, Radim; Vanicek, Jiri; Skoch, Antonin; Mechl, Marek

    2013-02-01

    Magnetic resonance spectroscopy (MRS) is an imaging diagnostic method based that allows non-invasive measurement of metabolites in tissues. There are a number of metabolites that can be identified by standard brain proton MRS but only a few of them has a clinical significance in diagnosis of gliomas including N-acetylaspartate, choline, creatine, myo-inositol, lactate, and lipids. In this review, we describe potential of MRS for grading of gliomas. Low-grade gliomas are generally characterized by a relatively high concentration of N-acetylaspartate, low level of choline and absence of lactate and lipids. The increase in creatine concentration indicates low-grade gliomas with earlier progression and malignant transformation. Progression in grade of a glioma is reflected in the progressive decrease in the N-acetylaspartate and myo-inositol levels on the one hand and elevation in choline level up to grade III on the other. Malignant transformation of the glial tumors is also accompanied by the presence of lactate and lipids in MR spectra of grade III but mainly grade IV gliomas. It follows that MRS is a helpful method for detection of glioma regions with aggressive growth or upgrading due to favorable correlation of the choline and N-acetylaspartate levels with histopathological proliferation index Ki-67. Thus, magnetic resonance spectroscopy is also a suitable method for the targeting of brain biopsies. Gliomas of each grade have some specific MRS features that can be used for improvement of the diagnostic value of conventional magnetic resonance imaging in non-invasive assessment of glioma grade. Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.

  12. Reduced N-acetylaspartate content in the frontal part of the brain in patients with probable Alzheimer's disease.

    PubMed

    Christiansen, P; Schlosser, A; Henriksen, O

    1995-01-01

    The fully relaxed water signal was used as an internal standard in a STEAM experiment to calculate the concentrations of the metabolites: N-acetylaspartate (NAA), creatine + phosphocreatine [Cr + PCr], and choline-containing metabolites (Cho) in the frontal part of the brain in 12 patients with probable Alzheimer's disease. Eight age-matched healthy volunteers served as controls. Furthermore, T1 and T2 relaxation times of the metabolites and signal ratios: NAA/Cho, NAA/[Cr + PCr], and [Cr + PCr]/Cho at four different echo times (TE) and two different repetition times (TR) were calculated. The experiments were carried out using a Siemens Helicon SP 63/84 wholebody MR-scanner at 1.5 T. The concentration of NAA was significantly lower in the patients with probable Alzheimer's disease than in the healthy volunteers. No significant difference was found for any other metabolite concentration. For the signal ratios the only statistically significant difference was that the NAA/Cho ratio at TE = 92 ms and TR = 1.6 s was lower in the patients with probable Alzheimer's disease compared with the control group. A trend towards a longer T2 relaxation time for NAA in the patients with probable Alzheimer's disease than among the healthy volunteers was found, but no significant difference was found concerning the T1 and T2 relaxation times.

  13. Supplementation with Folic Acid, but Not Creatine, Increases Plasma Betaine, Decreases Plasma Dimethylglycine, and Prevents a Decrease in Plasma Choline in Arsenic-Exposed Bangladeshi Adults123

    PubMed Central

    Hall, Megan N; Liu, Xinhua; Caudill, Marie A; Malysheva, Olga; Ilievski, Vesna; Lomax-Luu, Angela M; Parvez, Faruque; Siddique, Abu B; Shahriar, Hasan; Uddin, Mohammad N; Islam, Tariqul; Graziano, Joseph H; Gamble, Mary V

    2016-01-01

    Background: Folic acid (FA) supplementation facilitates urinary excretion of arsenic, a human carcinogen. A better understanding of interactions between one-carbon metabolism intermediates may improve the ability to design nutrition interventions that further facilitate arsenic excretion. Objective: The objective was to determine if FA and/or creatine supplementation increase choline and betaine and decrease dimethylglycine (DMG). Methods: We conducted a secondary analysis of the Folic Acid and Creatine Trial, a randomized trial in arsenic-exposed Bangladeshi adults (n = 605, aged 24–55 y, 50.3% male) who received arsenic-removal water filters. We examined treatment effects of FA and/or creatine supplementation on plasma choline, betaine, and DMG concentrations, measured by LC–tandem mass spectrometry at baseline and at week 12. Group comparisons were between 1) 400 and 800 μg FA/d (FA400 and FA800, respectively) compared with placebo, 2) creatine (3 g/d) compared with placebo, and 3) creatine plus FA400 compared with FA400. Results: Choline decreased in the placebo group (−6.6%; 95% CI: −10.2%, −2.9%) but did not change in the FA groups (FA400: 2.5%; 95% CI: −0.9%, 6.1%; FA800: 1.4%; 95% CI: −2.5%, 5.5%; P < 0.05). Betaine did not change in the placebo group (−3.5%; 95% CI: −9.3%, 2.6%) but increased in the FA groups (FA400: 14.1%; 95% CI: 9.4%, 19.0%; FA800: 13.0%; 95% CI: 7.2%, 19.1%; P < 0.01). The decrease in DMG was greater in the FA groups (FA400: −26.7%; 95% CI: −30.9%, −22.2%; FA800: −27.8%; 95% CI: −31.8%, −23.4%) than in the placebo group (−12.3%; 95% CI: −18.1%, −6.2%; P < 0.01). The percentage change in choline, betaine, and DMG did not differ between creatine treatment arms and their respective reference groups. Conclusion: Supplementation for 12 wk with FA, but not creatine, increases plasma betaine, decreases plasma DMG, and prevents a decrease in plasma choline in arsenic-exposed Bangladeshi adults. This trial

  14. Reduced posterior cingulate glutamate measured by magnetic resonance spectroscopy in hyperthyroidism.

    PubMed

    Liu, Xinxin; Bai, Zhilan; Liu, Feng; Li, Min; Zhang, Qiujuan; Song, Guangyi; Xu, Jing

    2012-01-01

    Patients with hyperthyroidism frequently have neuropsychiatric complaints such as lack of concentration, poor performance in memory, depression, anxiety and mania. These symptoms suggest the dysfunction of brain. However, the underlying process of this dysfunction is not well understood. At the same time, glutamatergic system has been considered important in neuropsychiatric process by recent studies. Thus, this study is to investigate the change of glutamate concentration in patients with hyperthyroidism using proton magnetic resonance spectroscopy. Fifteen untreated patients with hyperthyroidism and fifteen age- and gender- matched controls participated in the study. The region of the posterior cingulate cortex was examined by magnetic resonance spectroscopy with a technique referred as TE-averaged PRESS at 3T field strength. The concentrations of N-Acetylaspartate, creatine, choline and glutamate were assessed using jMRUI v4.0 software. Hyperthyroid patients, compared with controls, showed a decrease of glutamate concentration (P<0.047) and glutamate/creatine ratios (P<0.009) in the posterior cingulate cortex. The decrease of choline concentration (P<0.004) and choline/creatine ratios (P<0.012) were also discovered. No significant difference was found in the concentrations of N-Acetylaspartate or creatine between patients and controls. Concentration of glutamate decreased in the region of posterior cingulate cortex in patients with hyperthyroidism. This reduction indicated a possible involvement of glutamate in the brain dysfunction in hyperthyroidism.

  15. Early Support of Intracranial Perfusion

    DTIC Science & Technology

    2010-10-01

    indicated a time evolution of TBI. Schuhmann et al showed that total creatine (tCr), N-acetylaspartate (NAA), glutamate (Glu), and choline (Cho...differences were found in glutamine, myo- inositol , and taurine concentrations among the 30 three time points in either the pericontusional voxel

  16. Proton MR spectroscopy of gliomatosis cerebri: case report of elevated myoinositol with normal choline levels.

    PubMed

    Saraf-Lavi, Efrat; Bowen, Brian C; Pattany, Pradip M; Sklar, Evelyn M L; Murdoch, James B; Petito, Carol K

    2003-05-01

    A 69-year-old woman presented with clinical and imaging findings suspicious for gliomatosis cerebri, later confirmed by biopsy (moderately cellular, infiltrating glioma). Single voxel proton MR spectroscopy (TE 20 and TE 135) and spectroscopic imaging (TE 135) performed at admission showed normal choline, decreased N-acetyl, and elevated myo-inositol levels relative to creatine. The primary conclusion is that in suspected cases of gliomatosis cerebri, myo-inositol/creatine and myo-inositol/N-acetyl should be determined because they may provide evidence of tumor, even though choline/creatine is normal. A corollary to this conclusion is that choline/creatine may be misleading if used to demarcate infiltrating glioma from edema.

  17. Reduced N-acetylaspartate levels in the frontal cortex of 3,4-methylenedioxymethamphetamine (Ecstasy) users: preliminary results.

    PubMed

    Reneman, Liesbeth; Majoie, Charles B L M; Flick, Herman; den Heeten, Gerard J

    2002-02-01

    The perceived safety of the recreational drug methylenedioxymethamphetamine (MDMA), or Ecstasy, conflicts with animal evidence indicating that MDMA damages cortical serotonin (5-HT) neurons at doses similar to those used by humans. Few data are available about the effects of MDMA on the human brain. This study was designed to evaluate MDMA-related alterations in metabolite ratios with single-voxel proton ((1)H) MR spectroscopy. Fifteen male MDMA users (mean lifetime exposure, 723 tablets; mean time since last tablet, 12.0 weeks) and 12 age-matched control subjects underwent single-voxel (1)H MR spectroscopy. N-Acetylaspartate (NAA)/creatine (Cr), NAA/Choline (Cho), and myoinositol (MI)/Cr ratios were measured in midfrontal gray matter, midoccipital gray matter, and right parietal white matter. Data were analyzed with linear model-based multivariate analysis of variance. NAA/Cr (P =.04) and NAA/Cho (P =.03) ratios, markers associated with neuronal loss or dysfunction, were reduced in the frontal cortex of MDMA users. Neither NAA/Cr (P =.72) nor NAA/Cho (P =.12) ratios were different between both groups in occipital gray matter and parietal white matter (P =.18). Extent of previous MDMA use and frontal cortical NAA/Cr (rho = -.50, P =.012) or NAA/Cho (rho = -.550, P <.01) ratios were significantly associated. Reduced NAA/Cr and NAA/Cho ratios at (1)H MR spectroscopy provide evidence for neuronal abnormality in the frontal cortex of MDMA users; these are correlated with the degree of MDMA exposure. These data suggest that MDMA may be a neurotoxin in humans, as it is in animals.

  18. The concentration of N-acetyl aspartate, creatine + phosphocreatine, and choline in different parts of the brain in adulthood and senium.

    PubMed

    Christiansen, P; Toft, P; Larsson, H B; Stubgaard, M; Henriksen, O

    1993-01-01

    The fully relaxed water signal was used as an internal standard in a STEAM experiment to calculate the concentrations of the metabolites: N-acetyl aspartate (NAA), creatine + phosphocreatine (Cr + PCr), and choline (Cho) containing compounds in four different parts of the brain in two age groups of healthy volunteers (20-30 yr, n = 8) and (60-80 yr, n = 8). Furthermore, T1 and T2 relaxation time of the metabolites and signal ratios: NAA/Cho, NAA/Cr + PCr, and Cho/Cr + PCr at TE = 272 msec were calculated. The experiments were carried out using a Siemens Helicon SP 63/84 wholebody MR-scanner at 1.5 T. In the younger age group, the concentration of NAA was significantly higher in the occipital part than in the other three parts of the brain. No significant regional variation was found for any other metabolite concentration. There was a significantly higher concentration of NAA in the occipital part of the brain in the younger age group compared to the older one. No significant regional or age dependent variation was found concerning the T1 and T2 relaxation times.

  19. Localized 1H-NMR spectroscopy in patients with fibromyalgia: a controlled study of changes in cerebral glutamate/glutamine, inositol, choline, and N-acetylaspartate.

    PubMed

    Fayed, Nicolas; Garcia-Campayo, Javier; Magallón, Rosa; Andrés-Bergareche, Helena; Luciano, Juan V; Andres, Eva; Beltrán, Julián

    2010-01-01

    The purpose of this study was to investigate whether single-voxel (SV) proton magnetic resonance spectroscopy (MRS), diffusion-weighted imaging (DWI), and diffusion tensor imaging (DTI) detected differences between fibromyalgia (FM) patients and healthy controls. We also searched for correlations between neuroimaging abnormalities and neuropsychological variables. Ten patients with FM and 10 gender- and age-matched control subjects were studied. A neuropsychological examination, DWI, DTI, and proton MRS were performed on the brain areas known to be associated with pain processing. Compared with healthy controls, FM patients had significantly higher levels of glutamate + glutamine (Glx) (mean ± SD, 10.71 ± 0.50 arbitrary institutional units versus 9.89 ± 1.04; P = 0.049) and higher glutamate + glutamine/creatine (Glx/Cr) ratios (1.90 ± 0.12 versus 1.72 ± 0.23; P = 0.034) in the posterior gyrus. Myoinositol (Ins) levels of the right and left hippocampi were significantly lower in FM patients (4.49 ± 0.74 versus 5.17 ± 0.62; P = 0.008 and 4.91 ± 0.85 versus 6.09 ± 0.78; P = 0.004, respectively). In FM patients, decreased myoinositol/creatine (Ins/Cr) ratios were found in the left sensorimotor area (P = 0.05) and the left hippocampus (P = 0.002) and lower levels of choline (P = 0.019) and N-acetyl aspartate + N-acetyl aspartyl glutamate (NAA + NAG) (P = 0.034) in the left hippocampus. Significant correlations between depression, pain, and global function and the posterior gyrus Glx levels and Glx/Cr ratios were observed. Glx within the posterior gyrus could be a pathologic factor in FM. Hippocampal dysfunction may be partially responsible for the depressive symptoms of FM. Additional studies with larger samples are required to confirm these preliminary data.

  20. Localized 1H-NMR spectroscopy in patients with fibromyalgia: a controlled study of changes in cerebral glutamate/glutamine, inositol, choline, and N-acetylaspartate

    PubMed Central

    2010-01-01

    Introduction The purpose of this study was to investigate whether single-voxel (SV) proton magnetic resonance spectroscopy (MRS), diffusion-weighted imaging (DWI), and diffusion tensor imaging (DTI) detected differences between fibromyalgia (FM) patients and healthy controls. We also searched for correlations between neuroimaging abnormalities and neuropsychological variables. Methods Ten patients with FM and 10 gender- and age-matched control subjects were studied. A neuropsychological examination, DWI, DTI, and proton MRS were performed on the brain areas known to be associated with pain processing. Results Compared with healthy controls, FM patients had significantly higher levels of glutamate + glutamine (Glx) (mean ± SD, 10.71 ± 0.50 arbitrary institutional units versus 9.89 ± 1.04; P = 0.049) and higher glutamate + glutamine/creatine (Glx/Cr) ratios (1.90 ± 0.12 versus 1.72 ± 0.23; P = 0.034) in the posterior gyrus. Myoinositol (Ins) levels of the right and left hippocampi were significantly lower in FM patients (4.49 ± 0.74 versus 5.17 ± 0.62; P = 0.008 and 4.91 ± 0.85 versus 6.09 ± 0.78; P = 0.004, respectively). In FM patients, decreased myoinositol/creatine (Ins/Cr) ratios were found in the left sensorimotor area (P = 0.05) and the left hippocampus (P = 0.002) and lower levels of choline (P = 0.019) and N-acetyl aspartate + N-acetyl aspartyl glutamate (NAA + NAG) (P = 0.034) in the left hippocampus. Significant correlations between depression, pain, and global function and the posterior gyrus Glx levels and Glx/Cr ratios were observed. Conclusions Glx within the posterior gyrus could be a pathologic factor in FM. Hippocampal dysfunction may be partially responsible for the depressive symptoms of FM. Additional studies with larger samples are required to confirm these preliminary data. PMID:20609227

  1. Education mitigates age-related decline in N-Acetylaspartate levels.

    PubMed

    Erickson, Kirk I; Leckie, Regina L; Weinstein, Andrea M; Radchenkova, Polina; Sutton, Bradley P; Prakash, Ruchika Shaurya; Voss, Michelle W; Chaddock-Heyman, Laura; McAuley, Edward; Kramer, Arthur F

    2015-03-01

    Greater educational attainment is associated with better neurocognitive health in older adults and is thought to reflect a measure of cognitive reserve. In vivo neuroimaging tools have begun to identify the brain systems and networks potentially responsible for reserve. We examined the relationship between education, a commonly used proxy for cognitive reserve, and N-acetylaspartate (NAA) in neurologically healthy older adults (N=135; mean age=66 years). Using single voxel MR spectroscopy, we predicted that higher levels of education would moderate an age-related decline in NAA in the frontal cortex. After controlling for the variance associated with cardiorespiratory fitness, sex, annual income, and creatine levels, there were no significant main effects of education (B=0.016, P=0.787) or age (B=-0.058, P=0.204) on NAA levels. However, consistent with our predictions, there was a significant education X age interaction such that more years of education offset an age-related decline in NAA (B=0.025, P=0.031). When examining working memory via the backwards digit span task, longer span length was associated with greater education (P<0.01) and showed a trend with greater NAA concentrations (P<0.06); however, there was no age X education interaction on digit span performance nor a significant moderated mediation effect between age, education, and NAA on digit span performance. Taken together, these results suggest that higher levels of education may attenuate an age-related reduction in neuronal viability in the frontal cortex.

  2. Education mitigates age-related decline in N-Acetylaspartate levels

    PubMed Central

    Erickson, Kirk I; Leckie, Regina L; Weinstein, Andrea M; Radchenkova, Polina; Sutton, Bradley P; Prakash, Ruchika Shaurya; Voss, Michelle W; Chaddock-Heyman, Laura; McAuley, Edward; Kramer, Arthur F

    2015-01-01

    Background Greater educational attainment is associated with better neurocognitive health in older adults and is thought to reflect a measure of cognitive reserve. In vivo neuroimaging tools have begun to identify the brain systems and networks potentially responsible for reserve. Methods We examined the relationship between education, a commonly used proxy for cognitive reserve, and N-acetylaspartate (NAA) in neurologically healthy older adults (N = 135; mean age = 66 years). Using single voxel MR spectroscopy, we predicted that higher levels of education would moderate an age-related decline in NAA in the frontal cortex. Results After controlling for the variance associated with cardiorespiratory fitness, sex, annual income, and creatine levels, there were no significant main effects of education (B = 0.016, P = 0.787) or age (B = −0.058, P = 0.204) on NAA levels. However, consistent with our predictions, there was a significant education X age interaction such that more years of education offset an age-related decline in NAA (B = 0.025, P = 0.031). When examining working memory via the backwards digit span task, longer span length was associated with greater education (P < 0.01) and showed a trend with greater NAA concentrations (P < 0.06); however, there was no age X education interaction on digit span performance nor a significant moderated mediation effect between age, education, and NAA on digit span performance. Conclusions Taken together, these results suggest that higher levels of education may attenuate an age-related reduction in neuronal viability in the frontal cortex. PMID:25798329

  3. NOTE: The effects of paramagnetic contrast agents on metabolite protons in aqueous solution

    NASA Astrophysics Data System (ADS)

    Murphy, Philip S.; Leach, Martin O.; Rowland, Ian J.

    2002-03-01

    The longitudinal (R1) and transverse (R2) relaxivities of the clinically used contrast agents Gd(DTPA)2-, Gd(DOTA)- and Gd(DTPA-BMA) have been determined in mixed aqueous metabolite solutions for choline, creatine and N-acetylaspartate. Measurements were performed at 1.5 T using a STEAM sequence on 25 mM metabolite solutions at pH = 7.4 and 22 °C. The data showed that for all the contrast agents and metabolites, R1 ~ R2. The largest range of relaxivity values was found for Gd(DTPA)2-, where R2 = 6.8 +/- 0.3 mM-1 s-1 for choline and 1.5 +/- 0.4 mM-1 s-1 for N-acetylaspartate. Variation in relaxivity values was attributed primarily to differences between the charges of the paramagnetic agent and metabolite. The maximum potential influence of the contrast agents on in vivo metabolite signals was calculated using the measured relaxivities.

  4. Lower Choline-Containing Metabolites/Creatine (Cr) Rise and Failure to Sustain NAA/Cr Levels in the Dorsolateral Prefrontal Cortex Are Associated with Depressive Episode Recurrence under Maintenance Therapy: A Proton Magnetic Resonance Spectroscopy Retrospective Cohort Study.

    PubMed

    Henigsberg, Neven; Šarac, Helena; Radoš, Marko; Radoš, Milan; Ozretić, David; Foro, Tamara; Erdeljić Turk, Viktorija; Hrabač, Pero; Bajs Janović, Maja; Rak, Benedict; Kalember, Petra

    2017-01-01

    The aim of this study was to evaluate the relationship between changes in proton magnetic resonance spectroscopy (1H-MRS) parameters at the start of the index episode recovery phase and at recurrence in patients with recurrent depression who were treated with prolonged maintenance therapy. 1H-MRS parameters were analyzed in 48 patients with recurrent depression who required maintenance therapy with antidepressant medication prescribed by a psychiatrist and who continued with the same antidepressant during the maintenance phase, either to recurrence of depression, completion of the 10-year observation period, or the start of the withdrawal phase (tapering-off antidepressant). N-acetylaspartate (NAA), choline-containing metabolites (Cho), creatine (Cr), and glutamine/glutamate were measured at the start of the recovery phase and 6 months later. Recurrent depressive episodes occurred in 20 patients. These individuals had a smaller increase in Cho/Cr after the beginning of the recovery phase compared to the non-recurrent patient group and also exhibited a decreased NAA/Cr ratio. Sustainable NAA and increased Cho levels at the onset of the recovery phase of the index episode are early markers of antidepressant effectiveness associated with a lower risk of major depressive disorder recurrence. The NAA and Cho changes in the non-recurrent group may be attributable to increased brain resilience, contrary to the transient temporal effect observed in subjects who experienced a depressive episode.

  5. Prefrontal N-acetylaspartate is strongly associated with memory performance in (abstinent) ecstasy users: preliminary report.

    PubMed

    Reneman, L; Majoie, C B; Schmand, B; van den Brink, W; den Heeten, G J

    2001-10-01

    3,4-methylenedioxymethamphetamine (MDMA or "Ecstasy") is known to damage brain serotonin neurons in animals and possibly humans. Because serotonergic damage may adversely affect memory, we compared verbal memory function between MDMA users and MDMA-naïve control subjects and evaluated the relationship between verbal memory function and neuronal dysfunction in the MDMA users. An auditory verbal memory task (Rey Auditory Verbal Learning Test) was used to study eight abstinent MDMA users and seven control subjects. In addition 1H-MRS was used in different brain regions of all MDMA users to measure N-acetylaspartate/creatine (NAA/Cr) ratios, a marker for neuronal viability. The MDMA users recalled significantly fewer words than control subjects on delayed (p =.03) but not immediate recall (p =.08). In MDMA users, delayed memory function was strongly associated with NAA/Cr only in the prefrontal cortex (R(2) =.76, p =.01). Greater decrements in memory function predicted lower NAA/Cr levels-and by inference greater neuronal dysfunction-in the prefrontal cortex of MDMA users.

  6. Metabolite ratios to assumed stable creatine level may confound the quantification of proton brain MR spectroscopy.

    PubMed

    Li, Belinda S Y; Wang, Hao; Gonen, Oded

    2003-10-01

    In localized brain proton MR spectroscopy ((1)H-MRS), metabolites' levels are often expressed as ratios, rather than as absolute concentrations. Frequently, their denominator is the creatine [Cr], which level is explicitly assumed to be stable in normal as well as in many pathologic states. The rationale is that ratios self-correct for imager and localization method differences, gain instabilities, regional susceptibility variations and partial volume effects. The implicit assumption is that these benefits are worth their cost(w)-(w) propagation of the individual variation of each of the ratio's components. To test this hypothesis, absolute levels of N-acetylaspartate [NAA], choline [Cho] and [Cr] were quantified in various regions of the brains of 8 volunteers, using 3-dimensional (3D) (1)H-MRS at 1.5 T. The results show that in over 50% of approximately 2000 voxels examined, [NAA]/[Cr] and [Cho]/[Cr] exhibited higher coefficients of variations (CV) than [NAA] and [Cho] individually. Furthermore, in approximately 33% of these voxels, the ratios' CVs exceeded even the combined constituents' CVs. Consequently, basing metabolite quantification on ratios and assuming stable [Cr] introduces more variability into (1)H-MRS than it prevents. Therefore, its cost exceeds the benefit.

  7. A guide to the metabolic pathways and function of metabolites observed in human brain 1H magnetic resonance spectra.

    PubMed

    Rae, Caroline D

    2014-01-01

    The current knowledge of the normal biochemistry of compounds that give rise to resonances in human brain proton magnetic resonance spectra measureable at readily available field strengths (i.e. ≤3 T) is reviewed. Molecules covered include myo- and scyllo-inositol, glycerophospho- and phospho-choline and choline, creatine and phosphocreatine, N-acetylaspartate, N-acetylaspartylglutamate, glutamate, glutamine, γ-aminobutyrate, glucose, glutathione and lactate. The factors which influence changes in the levels of these compounds are discussed. As most proton resonances in the brain at low field are derived from a combination of moieties whose biochemistry is complex and interrelated, an understanding of the mechanisms underlying why these species change is crucial to meaningful interpretation of human brain spectra.

  8. Low episodic memory performance in cognitively normal elderly subjects is associated with increased posterior cingulate gray matter N-acetylaspartate: a 1H MRSI study at 7 Tesla.

    PubMed

    Schreiner, Simon J; Kirchner, Thomas; Wyss, Michael; Van Bergen, Jiri M G; Quevenco, Frances C; Steininger, Stefanie C; Griffith, Erica Y; Meier, Irene; Michels, Lars; Gietl, Anton F; Leh, Sandra E; Brickman, Adam M; Hock, Christoph; Nitsch, Roger M; Pruessmann, Klaas P; Henning, Anke; Unschuld, Paul G

    2016-12-01

    Low episodic memory performance characterizes elderly subjects at increased risk for Alzheimer's disease (AD) and may reflect neuronal dysfunction within the posterior cingulate cortex and precuneus (PCP) region. To investigate a potential association between cerebral neurometabolism and low episodic memory in the absence of cognitive impairment, tissue-specific magnetic resonance spectroscopic imaging at ultrahigh field strength of 7 Tesla was used to investigate the PCP region in a healthy elderly study population (n = 30, age 70 ± 5.7 years, Mini-Mental State Examination 29.4 ± 4.1). The Verbal Learning and Memory Test (VLMT) was administered as part of a neuropsychological battery for assessment of episodic memory performance. Significant differences between PCP gray and white matter could be observed for glutamate-glutamine (p = 0.001), choline (p = 0.01), and myo-inositol (p = 0.02). Low Verbal Learning and Memory Test performance was associated with high N-acetylaspartate in PCP gray matter (p = 0.01) but not in PCP white matter. Our data suggest that subtle decreases in episodic memory performance in the elderly may be associated with increased levels of N-acetylaspartate as a reflection of increased mitochondrial energy capacity in PCP gray matter. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Lack of effect of oral choline supplement on the concentrations of choline metabolites in human brain.

    PubMed

    Tan, J; Bluml, S; Hoang, T; Dubowitz, D; Mevenkamp, G; Ross, B

    1998-06-01

    Recent reports suggest that oral choline supplement may alter the cerebral choline/creatine (Cho/Cr) ratio and might be used to treat neurodegenerative disorders of cholinergic transmission. Using both 1H and 31P MRS, we reexamined the Cho/Cr ratio and quantified cerebral choline and its major constituents: phosphoethanolamine (PE), phosphorylcholine (PC), glycerophosphorylethanolamine (GPE), and glycerophosphorylcholine (GPC). In the four brain locations examined, no significant increases in Cho/Cr, [Cho], or in its major constituents were found in response to an oral challenge of 50 mg/kg of choline bitartrate. Oral choline did not significantly affect human cerebral metabolism in the short term.

  10. The importance of transmethylation reactions to methionine metabolism in sheep: effects of supplementation with creatine and choline.

    PubMed

    Lobley, G E; Connell, A; Revell, D

    1996-01-01

    The influence of administering the methylated products choline and creatine on methionine irreversible-loss rate (ILR) and recycling from homocysteine has been investigated in sheep fed close to energy and N equilibrium. Two methods to estimate methionine recycling were compared. The first involved [U-13C]methionine infused as part of a labelled amino acid mixture obtained from hydrolysed algal protein. In this approach the isotope dilution of methionine with all five C atoms labelled (m + 5) will represent the ILR which does not recycle through homocysteine, while that which includes molecules with C-1-C-4 labelled will allow for loss of the labelled methyl (5)-C atom and replacement by an unlabelled moiety in the remethylation of homocysteine. The second method involved a combined infusion of [1-13C]- and [S-methyl-2H3]methionine. These two approaches gave similar data for methionine ILR which does not include label recycled to the amino acid from homocysteine but differed for recycled methionine fluxes. Consequently the two procedures differed in the calculated extent of homocysteine methylation under control conditions (6 v. 28%). These extents of remethylation are within the range observed for the fed human subject, despite the fact that fewer dietary methyl groups are available for the ruminant. Using combined data from the infusions, significant depression of methionine recycling occurred in blood (P < 0.05), with a similar trend for plasma (P = 0.077), when choline plus creatine were infused. Wool growth, assessed by intradermal injection of [35S]cysteine, was not altered by supplementation with the methylated products. From changes in the label pattern of free methionine in aortal, hepatic portal and hepatic venous blood during U-13C-labelled algal hydrolysate infusion, the major sites of homocysteine remethylation appear to be the portal-drained viscera and the liver. This was confirmed by analysis of free methionine enrichments in various tissues

  11. Association between prefrontal N-acetylaspartate and insight in psychotic disorders.

    PubMed

    Larabi, Daouia I; Liemburg, Edith J; Pijnenborg, Gerdina H M; Sibeijn-Kuiper, Anita; de Vos, Annerieke E; Bais, Leonie; Knegtering, Henderikus; Ćurčić-Blake, Branislava; Aleman, André

    2017-01-01

    Insight is impaired in most patients with psychosis and has been associated with poorer prognosis. The exact neural basis of impaired insight is still unknown, but it may involve disrupted prefrontal neural connectivity. Numerous studies have indeed found white matter (WM) abnormalities in psychosis. The association between prefrontal WM abnormalities and insight has not been studied yet by means of proton magnetic resonance spectroscopy ( 1 H-MRS). 1 H-MRS can be used to measure N-acetylaspartate (NAA), which is considered to be a marker of neuronal integrity. We measured insight with the Birchwood Insight Scale (BIS) as well as item G12 of the Positive and Negative Syndrome Scale (PANSS) in 88 patients with psychosis. Prefrontal WM concentrations of NAA and ratios of NAA to creatine (Cr) were assessed with 1 H-MRS. Nonparametric partial correlational analyses were conducted between NAA concentrations and insight controlling for illness duration, standardized antipsychotic dose, symptom scores, voxel grey matter content and voxel cerebrospinal fluid content. We found a significant correlation between reduced NAA/Cr ratios and poorer insight as measured with the BIS, which remained significant after additional correction for full width at half maximum, signal/noise and age. This is the first study reporting a relationship between lower prefrontal concentrations of a marker of neuronal integrity and impaired insight, providing further evidence that prefrontal pathology may play an important role in impaired insight in psychosis. This may be explained by the involvement of the prefrontal cortex in several executive and metacognitive functions, such as cognitive flexibility and perspective taking. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Medial Frontal Lobe Neurochemistry in Autism Spectrum Disorder is Marked by Reduced N-Acetylaspartate and Unchanged Gamma-Aminobutyric Acid and Glutamate + Glutamine Levels.

    PubMed

    Carvalho Pereira, Andreia; Violante, Inês R; Mouga, Susana; Oliveira, Guiomar; Castelo-Branco, Miguel

    2018-05-01

    The nature of neurochemical changes in autism spectrum disorder (ASD) remains controversial. We compared medial prefrontal cortex (mPFC) neurochemistry of twenty high-functioning children and adolescents with ASD without associated comorbidities and fourteen controls. We observed reduced total N-acetylaspartate (tNAA) and total creatine, increased Glx/tNAA but unchanged glutamate + glutamine (Glx) and unchanged absolute or relative gamma-aminobutyric acid (GABA+) in the ASD group. Importantly, both smaller absolute and relative GABA+ levels were associated with worse communication skills and developmental delay scores assessed by the autism diagnostic interview-revised (ADI-R). We conclude that tNAA is reduced in the mPFC in ASD and that glutamatergic metabolism may be altered due to unbalanced Glx/tNAA. Moreover, GABA+ is related to autistic symptoms assessed by the ADI-R.

  13. Altered neurochemical profile in the McGill-R-Thy1-APP rat model of Alzheimer's disease: a longitudinal in vivo 1 H MRS study.

    PubMed

    Nilsen, Linn H; Melø, Torun M; Saether, Oddbjørn; Witter, Menno P; Sonnewald, Ursula

    2012-11-01

    We investigated metabolite levels during the progression of pathology in McGill-R-Thy1-APP rats, a transgenic animal model of Alzheimer's disease, and in healthy age-matched controls. Rats were subjected to in vivo (1) H magnetic resonance spectroscopy (MRS) of the dorsal hippocampus at age 3, 9 and 12 months and of frontal cortex at 9 and 12 months. At 3 months, a stage in which only Aβ oligomers are present, lower glutamate, myo-inositol and total choline content were apparent in McGill-R-Thy1-APP rats. At age 9 months, lower levels of glutamate, GABA, N-acetylaspartate and total choline and elevated myo-inositol and taurine were found in dorsal hippocampus, whereas lower levels of glutamate, GABA, glutamine and N-acetylaspartate were found in frontal cortex. At age 12 months, only the taurine level was significantly different in dorsal hippocampus, whereas taurine, myo-inositol, N-acetylaspartate and total creatine levels were significantly higher in frontal cortex. McGill-R-Thy1-APP rats did not show the same changes in metabolite levels with age as displayed in the controls, and overall, prominent and complex metabolite differences were evident in this transgenic rat model of Alzheimer's disease. The findings also demonstrate that in vivo (1) H MRS is a powerful tool to investigate disease-related metabolite changes in the brain. © 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry.

  14. Dietary guanidinoacetic acid increases brain creatine levels in healthy men.

    PubMed

    Ostojic, Sergej M; Ostojic, Jelena; Drid, Patrik; Vranes, Milan; Jovanov, Pavle

    2017-01-01

    Guanidinoacetic acid (GAA) is an experimental dietary additive that might act as a creatine source in tissues with high-energy requirements. In this case study, we evaluated brain levels of creatine in white matter, gray matter, cerebellum, and thalamus during 8 wk oral GAA administration in five healthy men and monitored the prevalence and severity of side effects of the intervention. Volunteers were supplemented daily with 36 mg/kg body weight (BW) of GAA for the first 4 wk of the intervention; afterward GAA dosage was titrated ≤60 mg/kg BW of GAA daily. At baseline, 4, and 8 wk, the participants underwent brain magnetic resonance spectroscopy, clinical chemistry studies, and open-ended questionnaire for side-effect prevalence and severity. Brain creatine levels increased in similar fashion in cerebellum, and white and gray matter after GAA supplementation, with an initial increase of 10.7% reported after 4 wk, and additional upsurge (7.7%) from the weeks 4 to 8 follow-up (P < 0.05). Thalamus creatine levels decreased after 4 wk for 6.5% (P = 0.02), and increased nonsignificantly after 8 wk for 8% (P = 0.09). GAA induced an increase in N-acetylaspartate levels at 8-wk follow-up in all brain areas evaluated (P < 0.05). No participants reported any neurologic adverse event (e.g., seizures, tingling, convulsions) during the intervention. Supplemental GAA led to a region-dependent increase of the creatine pool in the human brain. This might be relevant for restoring cellular bioenergetics in disorders characterized by low brain creatine and functional enzymatic machinery for creatine synthesis, including neurodegenerative diseases, brain tumors, or cerebrovascular disease. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Choline and N,N-dimethylethanolamine as direct substrates for methanogens.

    PubMed

    Watkins, Andrew J; Roussel, Erwan G; Webster, Gordon; Parkes, R John; Sass, Henrik

    2012-12-01

    Choline (N,N,N-trimethylethanolamine), which is widely distributed in membrane lipids and is a component of sediment biota, has been shown to be utilized anaerobically by mixed prokaryote cultures to produce methane but not by pure cultures of methanogens. Here, we show that five recently isolated Methanococcoides strains from a range of sediments (Aarhus Bay, Denmark; Severn Estuary mudflats at Portishead, United Kingdom; Darwin Mud Volcano, Gulf of Cadiz; Napoli mud volcano, eastern Mediterranean) can directly utilize choline for methanogenesis producing ethanolamine, which is not further metabolized. Di- and monomethylethanolamine are metabolic intermediates that temporarily accumulate. Consistent with this, dimethylethanolamine was shown to be another new growth substrate, but monomethylethanolamine was not. The specific methanogen inhibitor 2-bromoethanesulfonate (BES) inhibited methane production from choline. When choline and trimethylamine are provided together, diauxic growth occurs, with trimethylamine being utilized first, and then after a lag (∼7 days) choline is metabolized. Three type strains of Methanococcoides (M. methylutens, M. burtonii, and M. alaskense), in contrast, did not utilize choline. However, two of them (M. methylutens and M. burtonii) did metabolize dimethylethanolamine. These results extend the known substrates that can be directly utilized by some methanogens, giving them the advantage that they would not be reliant on bacterial syntrophs for their substrate supply.

  16. Choline and N,N-Dimethylethanolamine as Direct Substrates for Methanogens

    PubMed Central

    Watkins, Andrew J.; Roussel, Erwan G.; Webster, Gordon; Parkes, R. John

    2012-01-01

    Choline (N,N,N-trimethylethanolamine), which is widely distributed in membrane lipids and is a component of sediment biota, has been shown to be utilized anaerobically by mixed prokaryote cultures to produce methane but not by pure cultures of methanogens. Here, we show that five recently isolated Methanococcoides strains from a range of sediments (Aarhus Bay, Denmark; Severn Estuary mudflats at Portishead, United Kingdom; Darwin Mud Volcano, Gulf of Cadiz; Napoli mud volcano, eastern Mediterranean) can directly utilize choline for methanogenesis producing ethanolamine, which is not further metabolized. Di- and monomethylethanolamine are metabolic intermediates that temporarily accumulate. Consistent with this, dimethylethanolamine was shown to be another new growth substrate, but monomethylethanolamine was not. The specific methanogen inhibitor 2-bromoethanesulfonate (BES) inhibited methane production from choline. When choline and trimethylamine are provided together, diauxic growth occurs, with trimethylamine being utilized first, and then after a lag (∼7 days) choline is metabolized. Three type strains of Methanococcoides (M. methylutens, M. burtonii, and M. alaskense), in contrast, did not utilize choline. However, two of them (M. methylutens and M. burtonii) did metabolize dimethylethanolamine. These results extend the known substrates that can be directly utilized by some methanogens, giving them the advantage that they would not be reliant on bacterial syntrophs for their substrate supply. PMID:23001649

  17. Myocellular creatine and creatine transporter serine phosphorylation after starvation.

    PubMed

    Zhao, Chun-Rui; Shang, Lihong; Wang, Weiyang; Jacobs, Danny O

    2002-06-01

    Myocellular creatine, which is critically important for normal energy metabolism, increases in rat gastrocnemius muscle after starvation via unknown mechanisms. Creatine (Cr) uptake across plasma membranes is governed by a single, specific transporter (CrTr) that shares 50% amino acid sequence identity with GABA/choline/betaine transporters whose functions are modulated by phosphorylation. Gastrocnemius muscle was collected from adult male Sprague-Dawley (225-250 g) rats that were randomized to receive normal rat chow and distilled water ad libitum (CTL) or distilled water alone for 4 days (STV). Total Cr, phosphocreatine (PCr), free Cr, and ATP were measured luminometrically. CrTr protein expression and protein serine and tyrosine phosphorylation and mRNA expression were determined using immunoprecipitation and quantitative Western blotting and reverse transcription polymerase chain reaction (RT-PCR) analyses, respectively. Guanidinoacetate methyltransferase (GAMT) activity, guanidinoacetic acid (GAA) content, creatine kinase (CK) activity, and creatinine (Crn) content were assayed luminometrically or spectrophotometrically. Creatine transporter uptake activity was also measured in skeletal muscle membrane vesicles. Data were analyzed by t test. Total Cr and free Cr increased 26 and 280% in STV (32.3 +/- 1.0 and 12.9 +/- 1.4 vs 25.7 +/- 1.1 and 3.4 +/- 0.9 micromol/g wet wt, mean +/- SEM, respectively, P < 0.01) whereas PCr content decreased 18% (18.6 +/- 0.8 vs 22.8 +/- 0.9 micromol/g wet wt, STV vs CTL P < 0.05). CrTr protein and mRNA expression, ATP, GAA, CK, GAMT, and protein tyrosine phosphorylation of CrTr were not significantly different between the two groups. However, protein serine phosphorylation of CrTr was significantly reduced by 30% (P < 0.05) and creatine uptake activity was significantly increased (P < 0.05) in starved animals. Increases in myocellular creatine content after starvation are associated with reduced serine phosphorylation of the

  18. Metabolic change in the right dorsolateral prefrontal cortex and its correlation with symptom severity in patients with generalized anxiety disorder: Proton magnetic resonance spectroscopy at 3 Tesla.

    PubMed

    Moon, Chung-Man; Kang, Heoung-Keun; Jeong, Gwang-Woo

    2015-07-01

    A few neuroimaging studies have demonstrated the key brain areas associated with generalized anxiety disorder (GAD). However, the brain metabolic changes in the dorsolateral prefrontal cortex (DLPFC) of patients with GAD are unclear. This study utilized 3-Tesla proton magnetic resonance spectroscopy ((1) H-MRS) to assess the DLPFC metabolic change and its correlation with symptom severity in patients with GAD. Patients with GAD diagnosed using the DSM-IV-TR and age-matched healthy controls participated in this study. Brain metabolite concentrations were measured from a localized voxel on the DLPFC using 3-Tesla (1) H-MRS. Also, the volumetric composition of the gray matter and white matter volumes was assessed using voxel-based morphometry. The choline/creatine and choline/N-acetylaspartate ratios were significantly lower in patients than in controls. However, there were no significant differences in other metabolite ratios between the two groups. Choline concentrations were negatively correlated with anxiety levels as measured by the Hamilton Anxiety Rating Scale and the Generalized Anxiety Disorder Scale 7. There was no significant difference in the gray matter and white matter volumes in the MRS voxel between the two groups. The present study demonstrates that GAD is associated with low a level of choline/N-acetylaspartate in the DLPFC, which is closely related with symptom severity and cognitive dysfunction. This finding will be useful for an understanding of the neural mechanism associated with GAD. © 2015 The Authors. Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology.

  19. Decreased frontal N-acetylaspartate levels in adolescents concurrently using both methamphetamine and marijuana.

    PubMed

    Sung, Young-Hoon; Carey, Paul D; Stein, Dan J; Ferrett, Helen L; Spottiswoode, Bruce S; Renshaw, Perry F; Yurgelun-Todd, Deborah A

    2013-06-01

    The potential neurochemical toxicity associated with methamphetamine (MA) or marijuana (MJ) use on the developing adolescent brain is unclear, particularly with regard to individuals with concomitant use of MA and MJ (MA+MJ). In this study, proton magnetic resonance spectroscopy (MRS) was utilized to measure in vivo brain N-acetylaspartate plus N-acetylaspartyl glutamate (tNAA, an indicator of intact neuronal integrity) levels. Three adolescent groups from Cape Town, South Africa completed MRS scans as well as clinical measures including a drug use history. Subjects included (1) nine MA (age=15.7±1.37), (2) eight MA+MJ (age=16.2±1.16) using adolescents and (3) ten healthy controls (age=16.8±0.62). Single voxel spectra were acquired from midfrontal gray matter using a point-resolved spectroscopy sequence (PRESS). The MRS data were post-processed in the fully automated approach for quantitation of metabolite ratios to phosphocreatine plus creatine (PCr+Cr). A significant reduction in frontal tNAA/PCr+Cr ratios was seen in the MA+MJ group compared to the healthy controls (p=0.01, by 7.2%) and to the MA group (p=0.04, by 6.9%). Significant relationships were also observed between decreased tNAA/PCr+Cr ratios and drug use history of MA or MJ (total cumulative lifetime dose, age of onset, and duration of MA and MJ exposure) only in the MA+MJ group (all p<0.05). These findings suggest that in adolescents, concomitant heavy MA+MJ use may contribute to altered brain metabolites in frontal gray matter. The significant associations between the abnormal tNAA/PCr+Cr ratios and the drug use history suggest that MA+MJ abuse may induce neurotoxicity in a dose-responsive manner in adolescent brain. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Brain Creatine Elevation and NAA Reduction Indicates Neuronal Dysfunction in the Setting of Enhanced Glial Energy Metabolism in a Macaque Model of neuroAIDS

    PubMed Central

    Ratai, Eva-Maria; Annamalai, Lakshmanan; Burdo, Tricia; Joo, Chan-Gyu; Bombardier, Jeffrey P.; Fell, Robert; Hakimelahi, Reza; He, Julian; Lentz, Margaret R.; Campbell, Jennifer; Curran, Elizabeth; Halpern, Elkan F.; Masliah, Eliezer; Westmoreland, Susan. V.; Williams, Kenneth C.; González, R. Gilberto

    2011-01-01

    Proton magnetic resonance spectroscopy (1H MRS) has emerged as one of the most informative neuroimaging modalities for studying the effect of HIV infection in the brain, providing surrogate markers by which to assess disease progression and monitor treatment. Reductions in the level of N-Acetylaspartate (NAA) and NAA/creatine (NAA/Cr) are established markers of neuronal injury or loss. However, the biochemical basis of altered creatine levels in neuroAIDS is not well understood. This study used a rapid progression macaque model of neuroAIDS to elucidate the changes in creatine. As the disease progressed 1H MRS revealed a decrease in NAA, indicative of neuronal injury, and an increase in creatine yet to be elucidated. Subsequently, immunohistochemistry and stereology measures of decreased synaptophysin, microtubule-associated protein 2, and neuronal density confirmed neuronal injury. Furthermore, increases in ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein indicated microglial and astroglial activation, respectively. Given these data, elevated creatine may reflect enhanced high-energy phosphate turnover in highly metabolizing activated astrocytes and microglia. PMID:21381104

  1. Restriction of dietary methyl donors limits methionine availability and affects the partitioning of dietary methionine for creatine and phosphatidylcholine synthesis in the neonatal piglet.

    PubMed

    Robinson, Jason L; McBreairty, Laura E; Randell, Edward W; Brunton, Janet A; Bertolo, Robert F

    2016-09-01

    Methionine is required for protein synthesis and provides a methyl group for >50 critical transmethylation reactions including creatine and phosphatidylcholine synthesis as well as DNA and protein methylation. However, the availability of methionine depends on dietary sources as well as remethylation of demethylated methionine (i.e., homocysteine) by the dietary methyl donors folate and choline (via betaine). By restricting dietary methyl supply, we aimed to determine the extent that dietary methyl donors contribute to methionine availability for protein synthesis and transmethylation reactions in neonatal piglets. Piglets 4-8 days of age were fed a diet deficient (MD-) (n=8) or sufficient (MS+) (n=7) in folate, choline and betaine. After 5 days, dietary methionine was reduced to 80% of requirement in both groups to elicit a response. On day 8, animals were fed [(3)H-methyl]methionine for 6h to measure methionine partitioning into hepatic protein, phosphatidylcholine, creatine and DNA. MD- feeding reduced plasma choline, betaine and folate (P<.05) and increased homocysteine ~3-fold (P<.05). With MD- feeding, hepatic phosphatidylcholine synthesis was 60% higher (P<.05) at the expense of creatine synthesis, which was 30% lower during MD- feeding (P<.05); protein synthesis as well as DNA and protein methylation were unchanged. In the liver, ~30% of dietary label was traced to phosphatidylcholine and creatine together, with ~50% traced to methylation of proteins and ~20% incorporated in synthesized protein. Dietary methyl donors are integral to neonatal methionine requirements and can affect methionine availability for transmethylation pathways. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Studies on the Role of N-Acetylaspartic Acid in Mammalian Brain

    PubMed Central

    Jacobson, K. Bruce

    1959-01-01

    N-Acetylaspartic acid (NAA) occurs at relatively high concentrations exclusively in the mammalian and avian brain and undergoes rapid rise in level soon after birth (Tallan, 1957). The amount of NAA in brains of mentally abnormal human beings and of young human beings was measured. The route by which NAA is synthesized was shown to involve a direct acetylation of aspartic acid. The degradative activity of the brain toward NAA is slight. Some experiments indicate that NAA in the brain is a physiologically and metabolically active compound. PMID:14406413

  3. Unusual MR spectroscopic imaging pattern of an astrocytoma: lack of elevated choline and high myo-inositol and glycine levels.

    PubMed

    Londoño, Ana; Castillo, Mauricio; Armao, Diane; Kwock, Lester; Suzuki, Kinuko

    2003-05-01

    We present the case of a patient with an MR imaging study showing an ill-defined intra-axial mass in the right insula and frontal lobe. The mass showed high signal intensity on T2-weighted and fluid-attenuated inversion recovery images and an unusual proton MR spectroscopic imaging pattern characterized by the presence of high levels of myo-inositol/glycine, no significant elevation of choline, and mildly reduced N-acetylaspartate. The histopathologic diagnosis was of diffuse astrocytoma with oligodendroglial components (World Health Organization grade II).

  4. Creatine supplementation prevents fatty liver in rats fed choline-deficient diet: a burden of one-carbon and fatty acid metabolism.

    PubMed

    Deminice, Rafael; de Castro, Gabriela Salim Ferreira; Francisco, Lucas Vieira; da Silva, Lilian Eslaine Costa Mendes; Cardoso, João Felipe Rito; Frajacomo, Fernando Tadeu Trevisan; Teodoro, Bruno Gonzaga; Dos Reis Silveira, Leonardo; Jordao, Alceu Afonso

    2015-04-01

    To examine the effects of creatine (Cr) supplementation on liver fat accumulation in rats fed a choline-deficient diet. Twenty-four rats were divided into 3 groups of 8 based on 4 weeks of feeding an AIN-93 control diet (C), a choline-deficient diet (CDD) or a CDD supplemented with 2% Cr. The CDD diet was AIN-93 without choline. The CDD significantly increased plasma homocysteine and TNFα concentration, as well as ALT activity. In liver, the CDD enhanced concentrations of total fat (55%), cholesterol (25%), triglycerides (87%), MDA (30%), TNFα (241%) and decreased SAM concentrations (25%) and the SAM/SAH ratio (33%). Cr supplementation prevented all these metabolic changes, except for hepatic SAM and the SAM/SAH ratio. However, no changes in PEMT gene expression or liver phosphatidylcholine levels were observed among the three experimental groups, and there were no changes in hepatic triglyceride transfer protein (MTP) mRNA level. On the contrary, Cr supplementation normalized expression of the transcription factors PPARα and PPARγ that were altered by the CDD. Further, the downstream targets and fatty acids metabolism genes, UCP2, LCAD and CPT1a, were also normalized in the Cr group as compared to CDD-fed rats. Cr supplementation prevented fat liver accumulation and hepatic injures in rats fed with a CDD for 4 weeks. Our results demonstrated that one-carbon metabolism may have a small role in mitigating hepatic fat accumulation by Cr supplementation. The modulation of key genes related to fatty acid oxidation pathway suggests a new mechanism by which Cr prevents liver fat accumulation. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. 1H- 14N HSQC detection of choline-containing compounds in solutions

    NASA Astrophysics Data System (ADS)

    Mao, Jiezhen; Jiang, Ling; Jiang, Bin; Liu, Maili; Mao, Xi-an

    2010-09-01

    Choline nitrogen ( 14N) has a long relaxation time (seconds) which is due to the highly symmetric chemical environments. 14N in choline also has coupling constants with protons (0.6 Hz to methyl protons, 2.7 Hz to CH 2O protons and 0.2 Hz to NCH 2 protons). Based on these properties, we introduce a two-dimensional NMR method to detect choline and its derivatives in solutions. This method is the 1H- 14N hetero-nuclear single-quantum correlation (HSQC) experiment which has been developed in solid-state NMR in recent years. Experiments have demonstrated that the 1H- 14N HSQC technique is a sensitive method for detection of choline-containing compounds in solutions. From 1 mM choline solution in 16 min on a 500 MHz NMR spectrometer, a 1H- 14N HSQC spectrum has been recorded with a signal-to-noise ratio of 1700. Free choline, phosphocholine and glycerophosphocholine in milk can be well separated in 1H- 14N HSQC spectra. This technique would become a promising analytical approach to mixture analyses where choline-containing compounds are of interest, such as tissue extracts, body fluids and food solutions.

  6. Age-related changes in anterior cingulate cortex glutamate in schizophrenia: A (1)H MRS Study at 7 Tesla.

    PubMed

    Brandt, Allison S; Unschuld, Paul G; Pradhan, Subechhya; Lim, Issel Anne L; Churchill, Gregory; Harris, Ashley D; Hua, Jun; Barker, Peter B; Ross, Christopher A; van Zijl, Peter C M; Edden, Richard A E; Margolis, Russell L

    2016-04-01

    The extent of age-related changes in glutamate and other neurometabolites in the anterior cingulate cortex (ACC) in individuals with schizophrenia remain unclear. Magnetic resonance spectroscopy (MRS) at 7 T, which yields precise measurements of various metabolites and can distinguish glutamate from glutamine, was used to determine levels of ACC glutamate and other metabolites in 24 individuals with schizophrenia and 24 matched controls. Multiple regression analysis revealed that ACC glutamate decreased with age in patients but not controls. No changes were detected in levels of glutamine, N-acetylaspartate, N-acetylaspartylglutamic acid, myo-inositol, GABA, glutathione, total creatine, and total choline. These results suggest that age may be an important modifier of ACC glutamate in schizophrenia. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study.

    PubMed

    Cohen, B M; Renshaw, P F; Stoll, A L; Wurtman, R J; Yurgelun-Todd, D; Babb, S M

    1995-09-20

    To test the hypothesis that uptake of circulating choline into the brain decreases with age, because alterations in metabolism of choline may be a factor contributing to age-related degenerative changes in the brain. Cohort comparison in younger and older adults. Subjects were chosen consecutively from lists of healthy volunteers screened by medical and psychiatric interviews and laboratory tests. Younger adults (n = 12) were between the ages of 20 and 40 years (mean age, 32 years), and older adults (n = 16) were between the ages of 60 and 85 years (mean age, 73 years). After fasting overnight, subjects received choline, as the bitartrate, to yield free choline equal to 50 mg/kg of body weight. Blood was drawn for determination of plasma choline concentration by high-performance liquid chromatography, and proton magnetic resonance spectroscopy (1H-MRS) was performed to determine the relative concentration of cytosolic choline-containing compounds in the brain at baseline and after ingestion of choline. Plasma choline and cytosolic choline-containing compounds in the brain, estimated as the ratio of the choline resonance to the creatine resonance on 1H-MRS scans of the basal ganglia, were compared following blinded analyses of data from subject cohorts studied at baseline and 3 hours after choline ingestion. Levels of plasma choline and cytosolic choline-containing compounds in brain were similar at baseline in younger and older subjects. Following ingestion of choline, plasma choline concentration increased by similar proportions (76% and 80%) in both younger and older subjects. Brain cytosolic choline--containing compounds increased substantially in younger subjects (mean increase, 60%; P < .001 vs baseline). Older subjects showed a much smaller increase in brain choline-containing compounds (mean, 16%; P < .001 vs the increase in younger subjects). Uptake of circulating choline into the brain decreases with age. Given the key role of choline in neuronal structure

  8. Is N,N-dimethylglycine N-oxide a choline and betaine metabolite?

    PubMed

    Lever, Michael; McEntyre, Christopher J; George, Peter M; Chambers, Stephen T

    2017-06-27

    Choline metabolism is by oxidation to betaine, which is demethylated to N,N-dimethylglycine; dimethylglycine is oxidatively demethylated to sarcosine. This pathway is important for osmoregulation and as a source of methyl groups. We asked whether another metabolite was involved. We synthesized the N-oxide of dimethylglycine (DMGO) by oxidizing dimethylglycine with peracetic acid, and measured DMGO in human plasma and urine by HPLC-MS/MS with positive ion detection, using two chromatography procedures, based on ion exchange and HILIC separations. The molecular ion DMGOH+ (m/z=120) yielded four significant fragments (m/z=103, 102, 58 and 42). The suspected DMGO peak in human body fluids showed all these fragments, and co-chromatographed with added standard DMGO in both HPLC systems. Typical plasma concentrations of DMGO are under 1 μmol/l. They may be lower in metabolic syndrome patients. Urine concentrations are higher, and DMGO has a higher fractional clearance than dimethylglycine, betaine and choline. It was present in all of over 80 human urine and plasma samples assayed. Plasma DMGO concentrations correlate with plasma DMG concentrations, with betaine and choline concentrations, with the osmolyte myo-inositol, and strongly with urinary DMGO excretion. We conclude that DMGO is probably a normal human metabolite.

  9. Effects of Egg Consumption and Choline Supplementation on Plasma Choline and Trimethylamine-N-Oxide in a Young Population.

    PubMed

    Lemos, Bruno S; Medina-Vera, Isabel; Malysheva, Olga V; Caudill, Marie A; Fernandez, Maria Luz

    2018-05-15

    Plasma trimethylamine-N-oxide (TMAO) concentrations have been associated with cardiovascular disease risk. Eggs are a rich source of choline, which is a precursor of TMAO. The effects of egg intake versus daily choline supplementation were evaluated on plasma choline and TMAO in a young, healthy population. Thirty participants (14 males, 16 females; 25.6 ± 2.3 years; body mass index = 24.3 ± 2.9 kg/m 2 ) were enrolled in this 13-week crossover intervention. After a 2-week washout, participants were randomized to consume either 3 eggs/d or a choline bitartrate supplement (∼ 400 mg choline total in eggs or supplement) for 4 weeks. Following a 3-week washout, participants were switched to the alternate treatment. Dietary records were measured at the end of each period. Plasma TMAO and choline were measured at baseline and at the end of each dietary intervention. Gene expression of scavenger receptors associated with plasma TMAO were quantified at the end of each intervention. Compared to the choline supplement, intake of total fat, cholesterol, selenium, and vitamin E were higher (p < 0.05), whereas carbohydrate intake was lower (p < 0.001) with consumption of 3 eggs/d. Fasting plasma choline increased 20% (p = 0.023) with egg intake, while no changes were observed with choline supplementation. Plasma TMAO levels were not different between dietary treatments or compared to baseline. Dietary choline appears to be more bioavailable via egg consumption when compared to a choline supplement. Plasma TMAO concentrations were not affected in healthy participants after 4 weeks of taking ∼400 mg/d choline either via eggs or choline supplementation.

  10. Elevated prefrontal myo-inositol and choline following breast cancer chemotherapy.

    PubMed

    Kesler, Shelli R; Watson, Christa; Koovakkattu, Della; Lee, Clement; O'Hara, Ruth; Mahaffey, Misty L; Wefel, Jeffrey S

    2013-12-01

    Breast cancer survivors are at increased risk for cognitive dysfunction, which reduces quality of life. Neuroimaging studies provide critical insights regarding the mechanisms underlying these cognitive deficits as well as potential biologic targets for interventions. We measured several metabolite concentrations using (1)H magnetic resonance spectroscopy as well as cognitive performance in 19 female breast cancer survivors and 17 age-matched female controls. Women with breast cancer were all treated with chemotherapy. Results indicated significantly increased choline (Cho) and myo-inositol (mI) with correspondingly decreased N-acetylaspartate (NAA)/Cho and NAA/mI ratios in the breast cancer group compared to controls. The breast cancer group reported reduced executive function and memory, and subjective memory ability was correlated with mI and Cho levels in both groups. These findings provide preliminary evidence of an altered metabolic profile that increases our understanding of neurobiologic status post-breast cancer and chemotherapy.

  11. Proton magnetic resonance spectroscopy of late-life major depressive disorder.

    PubMed

    Chen, Cheng-Sheng; Chiang, I-Chan; Li, Chun-Wei; Lin, Wei-Chen; Lu, Chia-Ying; Hsieh, Tsyh-Jyi; Liu, Gin-Chung; Lin, Hsiu-Fen; Kuo, Yu-Ting

    2009-06-30

    The primary goal of this study was to examine the biochemical abnormalities of late-life major depression by using 3-tesla (3-T) proton magnetic resonance spectroscopy ((1)H-MRS). The antidepressant effects on the biochemical abnormalities were investigated as well. Study participants were 27 elderly patients with major depressive disorders (among which 9 were on antidepressant medication) and 19 comparison elderly subjects. (1)H-MRS spectra were acquired from voxels that were placed in the left frontal white matter, left periventricular white matter, and left basal ganglia. Ratios of N-acetylaspartate (NAA), choline (Cho) and myo-inositol to creatine were calculated. Patients with late-life major depressive disorder had a significantly lower NAA/creatine ratio in the left frontal white matter, and higher Cho/creatine and myo-inositol/creatine ratios in the left basal ganglia when compared with the control subjects. The myo-inositol correlated with global cognitive function among the patients. The biochemical abnormalities in late-life major depressive disorder were found on the left side of the frontal white matter and the basal ganglia. Neuron degeneration in the frontal white matter and second messenger system dysfunction or glial dysfunction in the basal ganglia are suggested to be associated with late-life depression.

  12. Genetic Variation in Choline-Metabolizing Enzymes Alters Choline Metabolism in Young Women Consuming Choline Intakes Meeting Current Recommendations.

    PubMed

    Ganz, Ariel B; Cohen, Vanessa V; Swersky, Camille C; Stover, Julie; Vitiello, Gerardo A; Lovesky, Jessica; Chuang, Jasmine C; Shields, Kelsey; Fomin, Vladislav G; Lopez, Yusnier S; Mohan, Sanjay; Ganti, Anita; Carrier, Bradley; Malysheva, Olga V; Caudill, Marie A

    2017-01-26

    Single nucleotide polymorphisms (SNPs) in choline metabolizing genes are associated with disease risk and greater susceptibility to organ dysfunction under conditions of dietary choline restriction. However, the underlying metabolic signatures of these variants are not well characterized and it is unknown whether genotypic differences persist at recommended choline intakes. Thus, we sought to determine if common genetic risk factors alter choline dynamics in pregnant, lactating, and non-pregnant women consuming choline intakes meeting and exceeding current recommendations. Women ( n = 75) consumed 480 or 930 mg choline/day (22% as a metabolic tracer, choline-d9) for 10-12 weeks in a controlled feeding study. Genotyping was performed for eight variant SNPs and genetic differences in metabolic flux and partitioning of plasma choline metabolites were evaluated using stable isotope methodology. CHKA rs10791957, CHDH rs9001, CHDH rs12676, PEMT rs4646343, PEMT rs7946, FMO3 rs2266782, SLC44A1 rs7873937, and SLC44A1 rs3199966 altered the use of choline as a methyl donor; CHDH rs9001 and BHMT rs3733890 altered the partitioning of dietary choline between betaine and phosphatidylcholine synthesis via the cytidine diphosphate (CDP)-choline pathway; and CHKA rs10791957, CHDH rs12676, PEMT rs4646343, PEMT rs7946 and SLC44A1 rs7873937 altered the distribution of dietary choline between the CDP-choline and phosphatidylethanolamine N -methyltransferase (PEMT) denovo pathway. Such metabolic differences may contribute to disease pathogenesis and prognosis over the long-term.

  13. Relationships between astrogliosis and 1H MR spectroscopic measures of brain choline/creatine and myo-inositol/creatine in a primate model.

    PubMed

    Kim, John P; Lentz, Margaret R; Westmoreland, Susan V; Greco, Jane B; Ratai, Eva M; Halpern, Elkan; Lackner, Andrew A; Masliah, Eliezer; González, R Gilberto

    2005-04-01

    In vivo 1H MR spectroscopy demonstrates elevated choline (Cho)/creatine (Cr) and myo-inositol (MI)/Cr in many neurologic diseases that has been ascribed to gliosis. We tested the hypotheses that in vivo Cho/Cr and/or MI/Cr levels are correlated with glial fibrillary acidic protein (GFAP) immunostains and that the changes are water-soluble metabolites. We performed postmortem 1H MR spectroscopy and GFAP immunohistochemistry in brains from seven rhesus macaques acutely infected with simian immunodeficiency virus (SIV) and in four controls and compared the findings with previous in vivo MR spectroscopic results. Changes in neuropathologic and MR spectroscopic markers after infection and relationships among plasma viral load, GFAP immunostaining results, and ex vivo and in vivo MR spectroscopic measures were statistically evaluated. On GFAP immunostaining and in vivo MR spectroscopy, GFAP, Cho/Cr and MI/Cr were highest near the time of peak plasma viral load at 11 days postinfection (dpi). Immunostains returned to baseline by 14 dpi, whereas Cho/Cr and MI/Cr had different time courses, with the former dropping below baseline and the latter remaining elevated. Viral load and immunostains were significantly correlated. No correlation was found between ex vivo Cho/Cr or MI/Cr and viral load or between metabolite ratios from in vivo and ex vivo MR spectroscopy. In acute SIV infection, plasma viral load was significantly correlated with brain GFAP immunostains and in vivo 1H MR spectroscopic Cho/Cr. In vivo changes in Cho/Cr and MI/Cr were principally due to contributions other than those of low-molecular-weight water-soluble metabolites.

  14. Amide Proton Transfer Imaging Allows Detection of Glioma Grades and Tumor Proliferation: Comparison with Ki-67 Expression and Proton MR Spectroscopy Imaging.

    PubMed

    Su, C; Liu, C; Zhao, L; Jiang, J; Zhang, J; Li, S; Zhu, W; Wang, J

    2017-09-01

    Prognosis in glioma depends strongly on tumor grade and proliferation. In this prospective study of patients with untreated primary cerebral gliomas, we investigated whether amide proton transfer-weighted imaging could reveal tumor proliferation and reliably distinguish low-grade from high-grade gliomas compared with Ki-67 expression and proton MR spectroscopy imaging. This study included 42 patients with low-grade ( n = 28) or high-grade ( n = 14) glioma, all of whom underwent conventional MR imaging, proton MR spectroscopy imaging, and amide proton transfer-weighted imaging on the same 3T scanner within 2 weeks before surgery. We assessed metabolites of choline and N -acetylaspartate from proton MR spectroscopy imaging and the asymmetric magnetization transfer ratio at 3.5 ppm from amide proton transfer-weighted imaging and compared them with histopathologic grade and immunohistochemical expression of the proliferation marker Ki-67 in the resected specimens. The asymmetric magnetization transfer ratio at 3.5 ppm values measured by different readers showed good concordance and were significantly higher in high-grade gliomas than in low-grade gliomas (3.61% ± 0.155 versus 2.64% ± 0.185, P = .0016), with sensitivity and specificity values of 92.9% and 71.4%, respectively, at a cutoff value of 2.93%. The asymmetric magnetization transfer ratio at 3.5 ppm values correlated with tumor grade ( r = 0.506, P = .0006) and Ki-67 labeling index ( r = 0.502, P = .002). For all patients, the asymmetric magnetization transfer ratio at 3.5 ppm correlated positively with choline ( r = 0.43, P = .009) and choline/ N -acetylaspartate ratio ( r = 0.42, P = .01) and negatively with N -acetylaspartate ( r = -0.455, P = .005). These correlations held for patients with low-grade gliomas versus those with high-grade gliomas, but the correlation coefficients were higher in high-grade gliomas (choline: r = 0.547, P = .053; N -acetylaspartate: r = -0.644, P = .017; choline/ N

  15. Genetic Variation in Choline-Metabolizing Enzymes Alters Choline Metabolism in Young Women Consuming Choline Intakes Meeting Current Recommendations

    PubMed Central

    Ganz, Ariel B.; Cohen, Vanessa V.; Swersky, Camille C.; Stover, Julie; Vitiello, Gerardo A.; Lovesky, Jessica; Chuang, Jasmine C.; Shields, Kelsey; Fomin, Vladislav G.; Lopez, Yusnier S.; Mohan, Sanjay; Ganti, Anita; Carrier, Bradley; Malysheva, Olga V.; Caudill, Marie A.

    2017-01-01

    Single nucleotide polymorphisms (SNPs) in choline metabolizing genes are associated with disease risk and greater susceptibility to organ dysfunction under conditions of dietary choline restriction. However, the underlying metabolic signatures of these variants are not well characterized and it is unknown whether genotypic differences persist at recommended choline intakes. Thus, we sought to determine if common genetic risk factors alter choline dynamics in pregnant, lactating, and non-pregnant women consuming choline intakes meeting and exceeding current recommendations. Women (n = 75) consumed 480 or 930 mg choline/day (22% as a metabolic tracer, choline-d9) for 10–12 weeks in a controlled feeding study. Genotyping was performed for eight variant SNPs and genetic differences in metabolic flux and partitioning of plasma choline metabolites were evaluated using stable isotope methodology. CHKA rs10791957, CHDH rs9001, CHDH rs12676, PEMT rs4646343, PEMT rs7946, FMO3 rs2266782, SLC44A1 rs7873937, and SLC44A1 rs3199966 altered the use of choline as a methyl donor; CHDH rs9001 and BHMT rs3733890 altered the partitioning of dietary choline between betaine and phosphatidylcholine synthesis via the cytidine diphosphate (CDP)-choline pathway; and CHKA rs10791957, CHDH rs12676, PEMT rs4646343, PEMT rs7946 and SLC44A1 rs7873937 altered the distribution of dietary choline between the CDP-choline and phosphatidylethanolamine N-methyltransferase (PEMT) denovo pathway. Such metabolic differences may contribute to disease pathogenesis and prognosis over the long-term. PMID:28134761

  16. Role of choline and glycine betaine in the formation of N,N-dimethylpiperidinium (mepiquat) under Maillard reaction conditions.

    PubMed

    Bessaire, Thomas; Tarres, Adrienne; Stadler, Richard H; Delatour, Thierry

    2014-01-01

    This study is the first to examine the role of choline and glycine betaine, naturally present in some foods, in particular in cereal grains, to generate N,N-dimethylpiperidinium (mepiquat) under Maillard conditions via transmethylation reactions involving the nucleophile piperidine. The formation of mepiquat and its intermediates piperidine - formed by cyclisation of free lysine in the presence of reducing sugars - and N-methylpiperidine were monitored over time (240°C, up to 180 min) using high-resolution mass spectrometry in a model system comprised of a ternary mixture of lysine/fructose/alkylating agent (choline or betaine). The reaction yield was compared with data recently determined for trigonelline, a known methylation agent present naturally in coffee beans. The role of choline and glycine betaine in nucleophilic displacement reactions was further supported by experiments carried out with stable isotope-labelled precursors (¹³C- and deuterium-labelled). The results unequivocally demonstrated that the piperidine ring of mepiquat originates from the carbon chain of lysine, and that either choline or glycine betaine furnishes the N-methyl groups. The kinetics of formation of the corresponding demethylated products of both choline and glycine betaine, N,N-demethyl-2-aminoethanol and N,N-dimethylglycine, respectively, were also determined using high-resolution mass spectrometry.

  17. Insular cortex metabolite changes in obstructive sleep apnea.

    PubMed

    Yadav, Santosh K; Kumar, Rajesh; Macey, Paul M; Woo, Mary A; Yan-Go, Frisca L; Harper, Ronald M

    2014-05-01

    Adults with obstructive sleep apnea (OSA) show significant autonomic and neuropsychologic deficits, which may derive from damage to insular regions that serve those functions. The aim was to assess glial and neuronal status from anterior insular metabolites in OSA versus controls, using proton magnetic resonance spectroscopy (PMRS), and thus to provide insights for neuroprotection against tissue changes, and to reduce injury consequences. Cross-sectional study. University-based medical center. Thirty-six patients with OSA, 53 controls. None. We performed PMRS in bilateral anterior insulae using a 3.0-Tesla magnetic resonance imaging scanner, calculated N-acetylaspartate/creatine (NAA/Cr), choline/creatine (Cho/Cr), myo-inositol/creatine (MI/Cr), and MI/NAA metabolite ratios, and examined daytime sleepiness (Epworth Sleepiness Scale, ESS), sleep quality (Pittsburgh Sleep Quality Index, PSQI), and neuropsychologic status (Beck Depression Inventory II [BDI-II] and Beck Anxiety Inventory [BAI]). Body mass index, BAI, BDI-II, PSQI, and ESS significantly differed between groups. NAA/ Cr ratios were significantly reduced bilaterally, and left-sided MI/Cr and MI/NAA ratios were increased in OSA over controls. Significant positive correlations emerged between left insular MI/Cr ratios and apnea-hypopnea index values, right insular Cho/Cr ratios and BDI-II and BAI scores, and negative correlations appeared between left insular NAA/Cr ratios and PSQI scores and between right-side MI/Cr ratios and baseline and nadir change in O2 saturation. Adults with obstructive sleep apnea showed bilaterally reduced N-acetylaspartate and left-side increased myo-inositol anterior insular metabolites, indicating neuronal damage and increased glial activation, respectively, which may contribute to abnormal autonomic and neuropsychologic functions in the condition. The activated glial status likely indicates increased inflammatory action that may induce more neuronal injury, and suggests

  18. Elevated prefrontal myo-inositol and choline following breast cancer chemotherapy

    PubMed Central

    Watson, Christa; Koovakkattu, Della; Lee, Clement; O’Hara, Ruth; Mahaffey, Misty L.; Wefel, Jeffrey S.

    2013-01-01

    Breast cancer survivors are at increased risk for cognitive dysfunction, which reduces quality of life. Neuroimaging studies provide critical insights regarding the mechanisms underlying these cognitive deficits as well as potential biologic targets for interventions. We measured several metabolite concentrations using 1H magnetic resonance spectroscopy as well as cognitive performance in 19 female breast cancer survivors and 17 age-matched female controls. Women with breast cancer were all treated with chemotherapy. Results indicated significantly increased choline (Cho) and myo-inositol (mI) with correspondingly decreased N-acetylaspartate (NAA)/Cho and NAA/mI ratios in the breast cancer group compared to controls. The breast cancer group reported reduced executive function and memory, and subjective memory ability was correlated with mI and Cho levels in both groups. These findings provide preliminary evidence of an altered metabolic profile that increases our understanding of neurobiologic status post-breast cancer and chemotherapy. PMID:23536015

  19. Creatine uptake in mouse hearts with genetically altered creatine levels

    PubMed Central

    Hove, Michiel ten; Makinen, Kimmo; Sebag-Montefiore, Liam; Hunyor, Imre; Fischer, Alexandra; Wallis, Julie; Isbrandt, Dirk; Lygate, Craig; Neubauer, Stefan

    2008-01-01

    Creatine plays an important role in energy metabolism in the heart. Cardiomyocytes accumulate creatine via a specific creatine transporter (CrT), the capacity of which is reduced in the failing heart, resulting in lower myocardial creatine concentration. Therefore, to gain insight into how the CrT is regulated, we studied two mouse models of severely altered myocardial creatine levels. Cardiac creatine uptake levels were measured in isolated hearts from creatine-free guanidinoacetate-N-methyl transferase knock out (GAMT−/−) mice and from mice overexpressing the myocardial CrT (CrT-OE) using 14C-radiolabeled creatine. CrT mRNA levels were measured using real time RT-PCR and creatine levels with HPLC. Hearts from GAMT−/− mice showed a 7-fold increase in Vmax of creatine uptake and a 1.4-fold increase in CrT mRNA levels. The increase in Cr uptake and in CrT mRNA levels, however, was almost completely prevented when mice were fed a creatine supplemented diet, indicating that creatine uptake is subject to negative feedback regulation. Cardiac creatine uptake levels in CrT-OE mice were increased on average 2.7-fold, showing a considerable variation, in line with a similar variation in creatine content. Total CrT mRNA levels correlated well with myocardial creatine content (r = 0.67; p < 0.0001) but endogenous CrT mRNA levels did not correlate at all with myocardial creatine content (r = 0.01; p = 0.96). This study shows that creatine uptake can be massively upregulated in the heart, by almost an order of magnitude and that this upregulation is subject to feedback inhibition. In addition, our results strongly suggest that CrT activity is predominantly regulated by mechanisms other than alterations in gene expression. PMID:18602925

  20. Comparison of accelerated 3-D spiral chemical shift imaging and single-voxel spectroscopy at 3T in the pediatric age group.

    PubMed

    Yazbek, Sandrine; Prabhu, Sanjay P; Connaughton, Pauline; Grant, Patricia E; Gagoski, Borjan

    2015-08-01

    Single-voxel spectroscopy (SVS) is usually used in the pediatric population when a short acquisition time is crucial. To overcome the long acquisition time of 3-D phase-encoded chemical shift imaging (CSI) and lack of spatial coverage of single-voxel spectroscopy, efficient encoding schemes using spiral k-space trajectories have been successfully deployed, enabling acquisition of volumetric CSI in <5 min. We assessed feasibility of using 3-D spiral CSI sequence routinely in pediatric clinical settings by comparing its reconstructed spectra against SVS spectra. Volumetric spiral CSI obtained spectra from 2-cc isotropic voxels over a 16×16×10-cm region. SVS acquisition encoded a 3.4-cc (1.5-mm) isotropic voxel. Acquisition time was 3 min for every technique. Data were gathered prospectively from 11 random pediatric patients. Spectra from left basal ganglia were obtained using both techniques and were processed with post-processing software. The following metabolite ratios were calculated: N-acetylaspartate/creatine (NAA/Cr), choline/creatine (Cho/Cr), lactate/creatine (Lac/Cr) and N-acetylapartate/choline (NAA/Cho). We collected data on 11 children ages 4 days to 10 years. In 10/11 cases, spectral quality of both methods was acceptable. Considering 10/11 cases, we found a statistically significant difference between SVS and 3-D spiral CSI for all three ratios. However, this difference was fixed and was probably caused by a fixed bias. This means that 3-D spiral CSI can be used instead of SVS by removing the mean difference between the methods for each ratio. Accelerated 3-D CSI is feasible in pediatric patients and can potentially substitute for SVS.

  1. Assessment of changes in brain metabolites in Indian patients with type-2 diabetes mellitus using proton magnetic resonance spectroscopy.

    PubMed

    Sinha, Sanjeev; Ekka, Meera; Sharma, Uma; P, Raghunandan; Pandey, R M; Jagannathan, N R

    2014-01-17

    The brain is a target for diabetic end-organ damage, though the pathophysiology of diabetic encephalopathy is still not well understood. The aim of the present study was to investigate the effect of diabetes on the metabolic profile of brain of patients having diabetes in comparison to healthy controls, using in-vivo magnetic resonance spectroscopy to get an insight into the pathophysiology of cerebral damages caused due to diabetes. Single voxel proton magnetic resonance spectroscopy (1H-MRS) was performed at 1.5 T on right frontal, right parieto-temporal and right parieto-occipital white matter regions of the brain of 10 patients having type-2 diabetes along with 7 healthy controls. Absolute concentration of N-acetylaspartate (NAA), choline (cho), myo-inositol (mI), glutamate (Glu) and glutamine (Gln), creatine (Cr) and glucose were determined using the LC-Model and compared between the two groups. The concentration of N-acetylaspartate was significantly lower in the right frontal [4.35 ±0.69 vs. 5.23 ±0.74; p = 0.03] and right parieto-occipital region [5.44 ±0.52 vs.6.08 ±0.25; p = 0.02] of the brain of diabetics as compared to the control group. The concentrations of glutamate and glutamine were found to be significantly higher in the right frontal region of the brain [7.98 ±2.57 vs. 5.32 ±1.43; P = 0.01] in diabetics. Glucose levels were found significantly elevated in all the three regions of the brain in diabetics as compared to the control group. However, no significant changes in levels of choline, myo-inositol and creatine were observed in the three regions of the brain examined among the two groups. 1H-MRS analysis indicates that type-2 diabetes mellitus may cause subtle changes in the metabolic profile of the brain. Decreased concentrations of NAA might be indicative of decreased neuronal viability in diabetics while elevated concentrations of Gln and Glu might be related to the fluid imbalance resulting from disruption of glucose homeostasis.

  2. Indirect effects of elevated body mass index on memory performance through altered cerebral metabolite concentrations.

    PubMed

    Gonzales, Mitzi M; Tarumi, Takashi; Eagan, Danielle E; Tanaka, Hirofumi; Vaghasia, Miral; Haley, Andreana P

    2012-09-01

    Elevated body mass index (BMI) at midlife is associated with increased risk of cognitive decline in later life. The goal of the current study was to assess mechanisms of early brain vulnerability by examining if higher BMI at midlife affects current cognitive performance through alterations in cerebral neurochemistry. Fifty-five participants, aged 40 to 60 years, underwent neuropsychological testing, health screen, and proton magnetic resonance spectroscopy examining N-acetylaspartate, creatine (Cr), myo-inositol (mI), choline, and glutamate concentrations in occipitoparietal gray matter. Concentrations of N-acetylaspartate, choline, mI, and glutamate were calculated as a ratio over Cr and examined in relation to BMI using multivariate regression analyses. Structural equation modeling was used to determine if BMI had an indirect effect on cognition through cerebral metabolite levels. Higher BMI was associated with elevations in mI/Cr (F(5,45) = 3.843, p = .006, β = 0.444, p = .002), independent of age, sex, fasting glucose levels, and systolic blood pressure. Moreover, a χ(2) difference test of the direct and indirect structural equation models revealed that BMI had an indirect effect on global cognitive performance (Δχ(2) = 19.939, df = 2, p < .001). Subsequent follow-up analyses revealed that this effect was specific to memory (Δχ(2) = 22.027, df = 2, p < .001). Higher BMI was associated with elevations in mI/Cr concentrations in the occipitoparietal gray matter and indirectly related to poorer memory performance through mI/Cr levels, potentially implicating plasma hypertonicity and neuroinflammation as mechanisms underlying obesity-related brain vulnerability.

  3. Quantitative MRI in hypomyelinating disorders: Correlation with motor handicap.

    PubMed

    Steenweg, Marjan E; Wolf, Nicole I; van Wieringen, Wessel N; Barkhof, Frederik; van der Knaap, Marjo S; Pouwels, Petra J W

    2016-08-23

    To assess the correlation of tissue parameters estimated by quantitative magnetic resonance (MR) techniques and motor handicap in patients with hypomyelination. Twenty-eight patients with different causes of hypomyelination (12 males, 16 females; mean age 10 years) and 61 controls (33 males, 28 females; mean age 8 years) were prospectively investigated. We quantified T2 relaxation time, magnetization transfer ratio, fractional anisotropy, mean, axial, and radial diffusivities, and brain metabolites. We performed measurements in the splenium, parietal deep white matter, and corticospinal tracts in the centrum semiovale. We further analyzed diffusion measures using tract-based spatial statistics. We estimated severity of motor handicap by the gross motor function classification system. We evaluated correlation of handicap with MR measures by linear regression analyses. Fractional anisotropy, magnetization transfer ratio, choline, and N-acetylaspartate/creatine ratio were lower and diffusivities, T2 values, and inositol were higher in patients than in controls. Tract-based spatial statistics showed that these changes were widespread for fractional anisotropy (96% of the white matter skeleton), radial (93%) and mean (84%) diffusivity, and less so for axial diffusivity (20%). Correlation with handicap yielded radial diffusivity and N-acetylaspartate/creatine ratio as strongest independent explanatory variables. Gross motor function classification system grades are in part explained by MR measures. They indicate that mainly lack of myelin and, to a lesser degree, loss of axonal integrity codetermine the degree of motor handicap in patients with hypomyelinating disorders. These MR measures can be used to evaluate strategies that are aimed at promotion of myelination. © 2016 American Academy of Neurology.

  4. Neither short-term nor long-term administration of oral choline alters metabolite concentrations in human brain.

    PubMed

    Dechent, P; Pouwels, P J; Frahm, J

    1999-08-01

    This study reexamined conflicting proton magnetic resonance spectroscopy (MRS) reports of increased or unaffected choline-containing compounds (Cho) in human brain in response to a single dose of 50 mg/kg choline bitartrate. The present work was based on a well-established strategy for quantitative proton MRS (2.0 T, STEAM localization sequence, TR/TE/TM = 6000/20/10 ms, LCModel automated spectral evaluation) that allows the determination of cerebral metabolite concentrations rather than T1-weighted resonance intensity ratios. Moreover, the investigations were extended to a possible long-term effect of oral choline by monitoring the continuous ingestion of 2 x 16 g of lecithin per day for 4 weeks. Six young healthy volunteers participated in each study and metabolite concentrations were determined in standardized locations in gray matter, white matter, cerebellum, and thalamus. Neither for short-term nor for long-term administration of choline do the data reveal statistically significant deviations from the basal concentrations of Cho, total N-acetyl-containing compounds (neuronal markers), total creatine, and myo-inositol (glial marker) in any of the investigated brain regions. Previous reports of increased Cho are not confirmed.

  5. Maternal choline intake modulates maternal and fetal biomarkers of choline metabolism in humans.

    PubMed

    Yan, Jian; Jiang, Xinyin; West, Allyson A; Perry, Cydne A; Malysheva, Olga V; Devapatla, Srisatish; Pressman, Eva; Vermeylen, Francoise; Stabler, Sally P; Allen, Robert H; Caudill, Marie A

    2012-05-01

    In 1998 choline Adequate Intakes of 425 and 450 mg/d were established for nonpregnant and pregnant women, respectively. However, to our knowledge, no dose-response studies have been conducted to evaluate the effects of pregnancy or maternal choline intake on biomarkers of choline metabolism. We sought to quantify the effects of pregnancy and maternal choline intake on maternal and fetal indicators of choline metabolism. Healthy pregnant (n = 26; 27 wk gestation) and nonpregnant (n = 21) women were randomly assigned to receive 480 or 930 mg choline/d for 12 wk. Fasting blood samples and placental tissue and umbilical cord venous blood were collected and analyzed for choline and its metabolites. Regardless of the choline intake, pregnant women had higher circulating concentrations of choline (30%; P < 0.001) but lower concentrations of betaine, dimethylglycine, sarcosine, and methionine (13-55%; P < 0.001). Obligatory losses of urinary choline and betaine in pregnant women were ∼2-4 times as high (P ≤ 0.02) as those in nonpregnant women. A higher choline intake yielded higher concentrations of choline, betaine, dimethylglycine, and sarcosine (12-46%; P ≤ 0.08) in both pregnant and nonpregnant women without affecting urinary choline excretion. The higher maternal choline intake also led to a doubling of dimethylglycine in cord plasma (P = 0.002). These data suggest that an increment of 25 mg choline/d to meet the demands of pregnancy is insufficient and show that a higher maternal choline intake increases the use of choline as a methyl donor in both maternal and fetal compartments. This trial was registered at clinicaltrials.gov as NCT01127022.

  6. N-Acetylaspartylglutamate (NAAG) and N-Acetylaspartate (NAA) in Patients With Schizophrenia

    PubMed Central

    Jessen, Frank; Fingerhut, Natascha; Sprinkart, Alois M.; Kühn, Kai-Uwe; Petrovsky, Nadine; Maier, Wolfgang; Schild, Hans-H; Block, Wolfgang; Wagner, Michael; Träber, Frank

    2013-01-01

    Background : Imbalance of glutamatergic neurotransmission has been proposed as a key mechanism underlying symptoms of schizophrenia. The neuropetide N-acetylaspartylglutamate (NAAG) modulates glutamate release. NAAG provides a component of the proton magnetic resonance spectrum (1H-MRS) in humans. The signal of NAAG, however, largely overlaps with its precursor and degrading product N-acetylaspartate (NAA) that by itself does not act in glutamatergic neurotransmission. Methods: We quantified NAAG and NAA separately from the 1H-MRS signal in 20 patients with schizophrenia and 20 healthy comparison subjects on a 3.0 Tesla MR scanner. The 1H-MRS voxels were positioned in the anterior cingulate cortex (ACC) and in the left frontal lobe. Psychopathological symptoms and cognitive performance were assessed. Results: In the ACC, the ratio NAAG/NAA was increased (P = .041) and NAAG was increased at a trend level (P = .066) in patients, while NAA was reduced (P = .030). NAA correlated with attention performance in patients (r = .64, P = .005) in the ACC. There was no group difference of NAAG, NAA, or NAAG/NAA in the frontal lobe but an inverse correlation of NAAG with negatives symptoms (Positive and Negative Symptoms Scale [PANSS] negative, r = −.58, P = .018) and with the total symptom score (PANSS total, r = −.50, P = .049). In addition, there was a positive correlation of frontal lobe NAAG (r = .53, P = .035) and NAAG/NAA (r = .54, P = .030) with episodic memory in patients. Conclusions: In this study, we present the first in vivo evidence for altered NAAG concentration in patients with schizophrenia. PMID:21914645

  7. N-acetylaspartylglutamate (NAAG) and N-acetylaspartate (NAA) in patients with schizophrenia.

    PubMed

    Jessen, Frank; Fingerhut, Natascha; Sprinkart, Alois M; Kühn, Kai-Uwe; Petrovsky, Nadine; Maier, Wolfgang; Schild, Hans-H; Block, Wolfgang; Wagner, Michael; Träber, Frank

    2013-01-01

    BACKGROUND : Imbalance of glutamatergic neurotransmission has been proposed as a key mechanism underlying symptoms of schizophrenia. The neuropetide N-acetylaspartylglutamate (NAAG) modulates glutamate release. NAAG provides a component of the proton magnetic resonance spectrum (1H-MRS) in humans. The signal of NAAG, however, largely overlaps with its precursor and degrading product N-acetylaspartate (NAA) that by itself does not act in glutamatergic neurotransmission. We quantified NAAG and NAA separately from the 1H-MRS signal in 20 patients with schizophrenia and 20 healthy comparison subjects on a 3.0 Tesla MR scanner. The 1H-MRS voxels were positioned in the anterior cingulate cortex (ACC) and in the left frontal lobe. Psychopathological symptoms and cognitive performance were assessed. In the ACC, the ratio NAAG/NAA was increased (P = .041) and NAAG was increased at a trend level (P = .066) in patients, while NAA was reduced (P = .030). NAA correlated with attention performance in patients (r = .64, P = .005) in the ACC. There was no group difference of NAAG, NAA, or NAAG/NAA in the frontal lobe but an inverse correlation of NAAG with negatives symptoms (Positive and Negative Symptoms Scale [PANSS] negative, r = -.58, P = .018) and with the total symptom score (PANSS total, r = -.50, P = .049). In addition, there was a positive correlation of frontal lobe NAAG (r = .53, P = .035) and NAAG/NAA (r = .54, P = .030) with episodic memory in patients. In this study, we present the first in vivo evidence for altered NAAG concentration in patients with schizophrenia.

  8. Sex- and sex hormone-related variations in energy-metabolic frontal brain asymmetries: A magnetic resonance spectroscopy study.

    PubMed

    Hjelmervik, Helene; Hausmann, Markus; Craven, Alexander R; Hirnstein, Marco; Hugdahl, Kenneth; Specht, Karsten

    2018-05-15

    Creatine is a key regulator of brain energy homeostasis, and well-balanced creatine metabolism is central in healthy brain functioning. Still, the variability of brain creatine metabolism is largely unattended in magnetic resonance spectroscopy (MRS) research. In the human brain, marginal sex differences in creatine levels have been found in the prefrontal cortex. It is however not known to what degree these sex differences are stable or change with varying gonadal hormone levels. The current study therefore investigated creatine in the prefrontal cortex across the menstrual cycle. In addition, we explored cerebral asymmetries. Creatine, Choline (Cho), N-acetylaspartate (NAA), Myo inositol (mI), and glutamate + glutamine (Glx) were assessed three times in 15 women and 14 men using MRS. Women were tested in cycle phases of varying hormone levels (menstrual, follicular, and luteal phase). Prefrontal creatine was found to change across the menstrual cycle, in a hemisphere-specific manner. Women in the follicular phase showed increased left prefrontal creatine accompanied with reduced right prefrontal creatine, while this asymmetry was not present in the luteal phase. In men, the creatine levels remained stable across three testing sessions. In general, both men and women were found to have higher creatine levels in the left as compared to the right prefrontal cortex. Exploratory analyses of other metabolites showed similar asymmetries in NAA, Cho, and mI, while Cho also showed a menstrual cycle effect. This is the first time that sex hormone-related changes in creatine metabolism have been demonstrated in the human brain. These findings may have important methodological implications for MRS research, as it supports previous concerns against uncritical usage of creatine as a reference measure for other metabolites, assumed to be invariant across individuals and conditions. Copyright © 2018 University of Bergen. Published by Elsevier Inc. All rights reserved.

  9. INFLUENCE OF TOTAL BODY X-IRRADIATION ON THE LEVELS OF CREATINE PHOSPHATE, INORGANIC PHOSPHORUS AND ATP IN MUSCLE AND ON THE LEVELS OF CREATINE, CREATININE, N'-METHYL-NICOTINAMIDE AND NITROGEN IN URINE

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kumta, U.S.; Gurnani, S.U.; Sahasrabudhe, M.B.

    1957-09-01

    The influence of total-body irradiation on the levels of creatine phosphate (CP), adenosine triphosphate (ATP) and inorganic phosphorus (IP) in muscle has been investigated in rats. CP and ATP levels decrease by about 33% while those of 1P increase 4 times in irradiated rats. Studies on the influence of irradiation on the excretion of creatine, creatinine, and N'-methyl- nicotinamide in urine show that the excretion of creatine and N'-methyl- nlcotinamide is increased two-fold while that of creatinine is increased by 160%. It is suggested that the low levels of creatine phosphate are probably due to an impairment in the phosphorylationmore » of creatine or due to an adaptive breakdown of creatine phosphate leading to increased excretion of creatine and creatinine. (auth)« less

  10. Abnormal N-Glycosylation of a Novel Missense Creatine Transporter Mutant, G561R, Associated with Cerebral Creatine Deficiency Syndromes Alters Transporter Activity and Localization.

    PubMed

    Uemura, Tatsuki; Ito, Shingo; Ohta, Yusuke; Tachikawa, Masanori; Wada, Takahito; Terasaki, Tetsuya; Ohtsuki, Sumio

    2017-01-01

    Cerebral creatine deficiency syndromes (CCDSs) are caused by loss-of-function mutations in creatine transporter (CRT, SLC6A8), which transports creatine at the blood-brain barrier and into neurons of the central nervous system (CNS). This results in low cerebral creatine levels, and patients exhibit mental retardation, poor language skills and epilepsy. We identified a novel human CRT gene missense mutation (c.1681 G>C, G561R) in Japanese CCDSs patients. The purpose of the present study was to evaluate the reduction of creatine transport in G561R-mutant CRT-expressing 293 cells, and to clarify the mechanism of its functional attenuation. G561R-mutant CRT exhibited greatly reduced creatine transport activity compared to wild-type CRT (WT-CRT) when expressed in 293 cells. Also, the mutant protein is localized mainly in intracellular membrane fraction, while WT-CRT is localized in plasma membrane. Western blot analysis revealed a 68 kDa band of WT-CRT protein in plasma membrane fraction, while G561R-mutant CRT protein predominantly showed bands at 55, 110 and 165 kDa in crude membrane fraction. The bands of both WT-CRT and G561R-mutant CRT were shifted to 50 kDa by N-glycosidase treatment. Our results suggest that the functional impairment of G561R-mutant CRT was probably caused by incomplete N-linked glycosylation due to misfolding during protein maturation, leading to oligomer formation and changes of cellular localization.

  11. Noninvasive in Vivo MRI Assessment of Prostate Cancer Using Hyperpolarized 15N Choline

    DTIC Science & Technology

    2017-01-01

    for hyperpolarized 15N NMR and MRI, and (iii) to evaluate the efficacy of using hyperpolarized 15N choline as in vivo biomarker for prostate cancer...accomplished. GOAL 3. to evaluate the efficacy of using hyperpolarized 15N choline as in vivo biomarker for prostate cancer. For this Goal, the...science and technology? We currently have no metric to evaluate that the results of this project has any significant impact on public awareness or

  12. Choline intakes exceeding recommendations during human lactation improve breast milk choline content by increasing PEMT pathway metabolites.

    PubMed

    Davenport, Crystal; Yan, Jian; Taesuwan, Siraphat; Shields, Kelsey; West, Allyson A; Jiang, Xinyin; Perry, Cydne A; Malysheva, Olga V; Stabler, Sally P; Allen, Robert H; Caudill, Marie A

    2015-09-01

    Demand for the vital nutrient choline is high during lactation; however, few studies have examined choline metabolism and requirements in this reproductive state. The present study sought to discern the effects of lactation and varied choline intake on maternal biomarkers of choline metabolism and breast milk choline content. Lactating (n=28) and control (n=21) women were randomized to 480 or 930 mg choline/day for 10-12 weeks as part of a controlled feeding study. During the last 4-6 weeks, 20% of the total choline intake was provided as an isotopically labeled choline tracer (methyl-d9-choline). Blood, urine and breast milk samples were collected for choline metabolite quantification, enrichment measurements, and gene expression analysis of choline metabolic genes. Lactating (vs. control) women exhibited higher (P < .001) plasma choline concentrations but lower (P ≤ .002) urinary excretion of choline metabolites, decreased use of choline as a methyl donor (e.g., lower enrichment of d6-dimethylglycine, P ≤ .08) and lower (P ≤ .02) leukocyte expression of most choline-metabolizing genes. A higher choline intake during lactation differentially influenced breast milk d9- vs. d3-choline metabolite enrichment. Increases (P ≤ .03) were detected among the d3-metabolites, which are generated endogenously via the hepatic phosphatidylethanolamine N-methyltransferase (PEMT), but not among the d9-metabolites generated from intact exogenous choline. These data suggest that lactation induces metabolic adaptations that increase the supply of intact choline to the mammary epithelium, and that extra maternal choline enhances breast milk choline content by increasing supply of PEMT-derived choline metabolites. This trial was registered at clinicaltrials.gov as NCT01127022. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Cerebral metabolic abnormalities in congestive heart failure detected by proton magnetic resonance spectroscopy.

    PubMed

    Lee, C W; Lee, J H; Kim, J J; Park, S W; Hong, M K; Kim, S T; Lim, T H; Park, S J

    1999-04-01

    Using proton magnetic resonance spectroscopy, we investigated cerebral metabolism and its determinants in congestive heart failure (CHF), and the effects of cardiac transplantation on these measurements. Few data are available about cerebral metabolism in CHF. Fifty patients with CHF (ejection fraction < or = 35%) and 20 healthy volunteers were included for this study. Of the patients, 10 patients underwent heart transplantation. All subjects performed symptom-limited bicycle exercise test. Proton magnetic resonance spectroscopy (1H MRS) was obtained from localized regions (8 to 10 ml) of occipital gray matter (OGM) and parietal white matter (PWM). Absolute levels of the metabolites (N-acetylaspartate, creatine, choline, myo-inositol) were calculated. In PWM only creatine level was significantly lower in CHF than in control subjects, but in OGM all four metabolite levels were decreased in CHF. The creatine level was independently correlated with half-recovery time and duration of heart failure symptoms in PWM (r = -0.56, p < 0.05), and with peak oxygen consumption and serum sodium concentration in OGM (r = 0.58, p < 0.05). Cerebral metabolic abnormalities were improved after successful cardiac transplantation. This study shows that cerebral metabolism is abnormally deranged in advanced CHF and it may serve as a potential marker of the disease severity.

  14. Decreased choline and creatine concentrations in centrum semiovale in patients with generalized anxiety disorder: relationship to IQ and early trauma.

    PubMed

    Coplan, Jeremy D; Mathew, Sanjay J; Mao, Xiangling; Smith, Eric L P; Hof, Patrick R; Coplan, Paul M; Rosenblum, Leonard A; Gorman, Jack M; Shungu, Dikoma C

    2006-06-30

    We have demonstrated, using proton magnetic resonance spectroscopy imaging ((1)H-MRSI), elevations of N-acetyl-aspartate/creatine (NAA/CR) in right dorsolateral prefrontal cortex (DLPFC) in patients with generalized anxiety disorder (GAD) in comparison to healthy volunteers. A recent study indicates that the volume of prefrontal cortical white matter may be disproportionately increased in man in comparison to other primate species, with evolutionary implications. We therefore re-analyzed the identical scans with a specific focus on the centrum semiovale (CSO) as a representative region of interest of cerebral white matter. The central hypothesis was, in accordance with our gray matter findings, that patients with GAD, in comparison to healthy controls, would exhibit either an increase in NAA in CSO, or alternatively demonstrate reductions in concentrations of choline (CHO)-containing compounds and/or creatine+phosphocreatine (CR). MRSI scans that were obtained from an earlier [Mathew, S.J., Mao, X., Coplan, J.D., Smith, E.L., Sackeim, H.A., Gorman, J.M., Shungu, D.C., 2004. Dorsolateral prefrontal cortical pathology in generalized anxiety disorder: a proton magnetic resonance spectroscopic imaging study. American Journal of Psychiatry 161, 1119-1121] sample of 15 patients with GAD [6 with early trauma (ET)] and 15 healthy age- and sex-matched volunteers were analyzed further for CSO metabolite alterations. Self-reported worry was scored using the Penn State Worry Questionnaire (PSWQ) and intelligence was assessed using the Wechsler Abbreviated Scale of Intelligence (WASI). Serial multislice/multivoxel MRSI scans had been performed on a 1.5-T MRI. Using absolute quantification methods for metabolite concentrations, we examined NAA, CHO and CR. GAD patients without ET exhibited bilaterally decreased concentrations of CHO and CR in CSO in comparison to healthy volunteers, whereas GAD patients with ET were indistinguishable from controls. In patients with GAD, high IQ

  15. Plasma Creatine Kinetics After Ingestion of Microencapsulated Creatine Monohydrate with Enhanced Stability in Aqueous Solutions.

    PubMed

    Hone, Michelle; Kent, Robert M; Scotto di Palumbo, Alessandro; Bleiel, Sinead B; De Vito, Giuseppe; Egan, Brendan

    2017-07-04

    Creatine monohydrate represents one of the largest sports supplement markets. Enhancing creatine (CRE) stability in aqueous solutions, such as with microencapsulation, represents innovation potential. Ten physically active male volunteers were randomly assigned in a double-blind design to either placebo (PLA) (3-g maltodextrin; n = 5) or microencapsulated CRE (3-g creatine monohydrate; n = 5) conditions. Experimental conditions involved ingestion of the samples in a 70-mL ready-to-drink format. CRE was delivered in a novel microencapsulation matrix material consisting entirely of hydrolyzed milk protein. Three hours after ingestion, plasma creatine concentrations were unchanged during PLA, and averaged ∼45 μM. During CRE, plasma creatine concentration peaked after 30 min at 101.6 ± 14.9 μM (p < 0.05), representing a 2.3-fold increase over PLA. Thereafter, plasma creatine concentration gradually trended downwards but remained significantly elevated (∼50% above resting levels) 3 hr after ingestion. These results demonstrate that the microencapsulated form of creatine monohydrate reported herein remains bioavailable when delivered in aqueous conditions, and has potential utility in ready-to-drink formulations for creatine supplementation.

  16. Creatine and creatine forms intended for sports nutrition.

    PubMed

    Andres, Susanne; Ziegenhagen, Rainer; Trefflich, Iris; Pevny, Sophie; Schultrich, Katharina; Braun, Hans; Schänzer, Wilhelm; Hirsch-Ernst, Karen Ildico; Schäfer, Bernd; Lampen, Alfonso

    2017-06-01

    Creatine is a popular ergogenic supplement in sports nutrition. Yet, supplementation of creatine occasionally caused adverse effects such as gastrointestinal complaints, muscle cramps and an increase in body weight. Creatine monohydrate has already been evaluated by different competent authorities and several have come to the conclusion that a daily intake of 3 g creatine per person is unlikely to pose safety concerns, focusing on healthy adults with exclusion of pregnant and breastfeeding women. Possible vulnerable subgroups were also discussed in relation to the safety of creatine. The present review provides an up-to-date overview of the relevant information with special focus on human studies regarding the safety of creatine monohydrate and other marketed creatine forms, in particular creatine pyruvate, creatine citrate, creatine malate, creatine taurinate, creatine phosphate, creatine orotate, creatine ethyl ester, creatine pyroglutamate, creatine gluconate, and magnesium creatine chelate. Limited data are available with regard to the safety of the latter creatine forms. Considering an acceptable creatine intake of 3 g per day, most of the evaluated creatine forms are unlikely to pose safety concerns, however some safety concerns regarding a supplementary intake of creatine orotate, creatine phosphate, and magnesium creatine chelate are discussed here. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. N-Acetylaspartate Metabolism Outside the Brain: Lipogenesis, Histone Acetylation, and Cancer

    PubMed Central

    Bogner-Strauss, Juliane G.

    2017-01-01

    N-acetylaspartate (NAA) is a highly abundant brain metabolite. Aberrant NAA concentrations have been detected in many pathological conditions and although the function of NAA has been extensively investigated in the brain it is still controversial. Only recently, a role of NAA has been reported outside the brain. In brown adipocytes, which show high expression of the NAA-producing and the NAA-cleaving enzyme, the metabolism of NAA has been implicated in lipid synthesis and histone acetylation. Increased expression of N-acetyltransferase 8-like (Nat8l, the gene encoding the NAA synthesizing enzyme) induces de novo lipogenesis and the brown adipocyte phenotype. Accordingly silencing of aspartoacylase, the NAA-cleaving enzyme, reduced brown adipocyte differentiation mechanistically by decreasing histone acetylation and gene transcription. Notably, the expression of Nat8l and the amount of NAA were also shown to be increased in several tumors and inversely correlate with patients’ survival. Additionally, Nat8l silencing reduced cell proliferation in tumor and non-tumor cells, while NAA supplementation could rescue it. However, the mechanism behind has not yet been clarified. It remains to be addressed whether NAA per se and/or its catabolism to acetate and aspartate, metabolites that have both been implicated in tumor growth, are valuable targets for future therapies. PMID:28979238

  18. Longitudinal Whole-Brain N-acetylaspartate Concentration in Healthy Adults

    PubMed Central

    Rigotti, Daniel J.; Kirov, Ivan I.; Djavadi, Bejan; Perry, Nissa N.; Babb, James S.; Gonen, Oded

    2011-01-01

    BACKGROUND AND PURPOSE Though N-acetylaspartate (NAA) is often used as a marker of neural integrity and health in different neurological disorders, the temporal behavior of its whole-brain concentration (WBNAA) is not well characterized. Our goal, therefore, was to establish its normal variations in a cohort of healthy adults over typical clinical trial periods. METHODS Baseline amount of brain NAA, QNAA, was obtained with non-localizing proton MR spectroscopy from 9 subjects (7 women, 2 men) 31.2±5.6 years old. QNAA was converted into absolute millimole amount using phantom-replacement. The WBNAA concentration was derived by dividing QNAA with the brain parenchyma volume, VB, segmented from MRI. Temporal variations were determined with four annual scans of each participant. RESULTS The distribution of WBNAA levels was not different among time points with respect to the mean, 12.1±1.5 mM (p 0.6) nor was its intra-subject change (CV = 8.6%) significant between any two scans (p 0.5). There was a small (0.2 mL), but significant (p=0.05) annual VB decline. CONCLUSION WBNAA is stable over a three year period in healthy adults. It qualifies therefore, as a biomarker for global neuronal loss and dysfunction in diffuse neurological disorders that may be well worth considering as a secondary outcome measure candidate for clinical trials. PMID:21511862

  19. Human, rat and chicken small intestinal Na+-Cl−-creatine transporter: functional, molecular characterization and localization

    PubMed Central

    Peral, M J; García-Delgado, M; Calonge, M L; Durán, J M; De La Horra, M C; Wallimann, T; Speer, O; Ilundáin, A A

    2002-01-01

    In spite of all the fascinating properties of oral creatine supplementation, the mechanism(s) mediating its intestinal absorption has(have) not been investigated. The purpose of this study was to characterize intestinal creatine transport. [14C]Creatine uptake was measured in chicken enterocytes and rat ileum, and expression of the creatine transporter CRT was examined in human, rat and chicken small intestine by reverse transcription-polymerase chain reaction, Northern blot, in situ hybridization, immunoblotting and immunohistochemistry. Results show that enterocytes accumulate creatine against its concentration gradient. This accumulation was electrogenic, Na+- and Cl−-dependent, with a probable stoichiometry of 2 Na+: 1 Cl−: 1 creatine, and inhibited by ouabain and iodoacetic acid. The kinetic study revealed a Km for creatine of 29 μm. [14C]Creatine uptake was efficiently antagonized by non-labelled creatine, guanidinopropionic acid and cyclocreatine. More distant structural analogues of creatine, such as GABA, choline, glycine, β-alanine, taurine and betaine, had no effect on intestinal creatine uptake, indicating a high substrate specificity of the creatine transporter. Consistent with these functional data, messenger RNA for CRT was detected only in the cells lining the intestinal villus. The sequences of partial clones, and of the full-length cDNA clone, isolated from human and rat small intestine were identical to previously cloned CRT cDNAs. Immunological analysis revealed that CRT protein was mainly associated with the apical membrane of the enterocytes. This study reports for the first time that mammalian and avian enterocytes express CRT along the villus, where it mediates high-affinity, Na+- and Cl−-dependent, apical creatine uptake. PMID:12433955

  20. Maternal choline concentrations during pregnancy and choline-related genetic variants as risk factors for neural tube defects.

    PubMed

    Mills, James L; Fan, Ruzong; Brody, Lawrence C; Liu, Aiyi; Ueland, Per M; Wang, Yifan; Kirke, Peadar N; Shane, Barry; Molloy, Anne M

    2014-10-01

    Low maternal choline intake and blood concentration may be risk factors for having a child with a neural tube defect (NTD); however, the data are inconsistent. This is an important question to resolve because choline, if taken periconceptionally, might add to the protective effect currently being achieved by folic acid. We examined the relation between NTDs, choline status, and genetic polymorphisms reported to influence de novo choline synthesis to investigate claims that taking choline periconceptionally could reduce NTD rates. Two study groups of pregnant women were investigated: women who had a current NTD-affected pregnancy (AP; n = 71) and unaffected controls (n = 214) and women who had an NTD in another pregnancy but not in the current pregnancy [nonaffected pregnancy (NAP); n = 98] and unaffected controls (n = 386). Blood samples to measure betaine and total choline concentrations and single nucleotide polymorphisms related to choline metabolism were collected at their first prenatal visit. Mean (±SD) plasma total choline concentrations in the AP (2.8 ± 1.0 mmol/L) and control (2.9 ± 0.9 mmol/L) groups did not differ significantly. Betaine concentrations were not significantly different between the 2 groups. Total choline and betaine in the NAP group did not differ from controls. Cases were significantly more likely to have the G allele of phosphatidylethanolamine-N-methyltransferase (PEMT; V175M, +5465 G>A) rs7946 (P = 0.02). Our results indicate that maternal betaine and choline concentrations are not strongly associated with NTD risk. The association between PEMT rs7946 and NTDs requires confirmation. The addition of choline to folic acid supplements may not further reduce NTD risk. © 2014 American Society for Nutrition.

  1. Maternal choline supplementation programs greater activity of the phosphatidylethanolamine N-methyltransferase (PEMT) pathway in adult Ts65Dn trisomic mice

    PubMed Central

    Yan, Jian; Ginsberg, Stephen D.; Powers, Brian; Alldred, Melissa J.; Saltzman, Arthur; Strupp, Barbara J.; Caudill, Marie A.

    2014-01-01

    Maternal choline supplementation (MCS) induces lifelong cognitive benefits in the Ts65Dn mouse, a trisomic mouse model of Down syndrome and Alzheimer's disease. To gain insight into the mechanisms underlying these beneficial effects, we conducted a study to test the hypothesis that MCS alters choline metabolism in adult Ts65Dn offspring. Deuterium-labeled methyl-d9-choline was administered to adult Ts65Dn and disomic (2N) female littermates born to choline-unsupplemented or choline-supplemented Ts65Dn dams. Enrichment of d9-choline metabolites (derived from intact choline) and d3 + d6-choline metabolites [produced when choline-derived methyl groups are used by phosphatidylethanolamine N-methyltransferase (PEMT)] was measured in harvested tissues. Adult offspring (both Ts65Dn and 2N) of choline-supplemented (vs. choline-unsupplemented) dams exhibited 60% greater (P≤0.007) activity of hepatic PEMT, which functions in de novo choline synthesis and produces phosphatidylcholine (PC) enriched in docosahexaenoic acid. Higher (P<0.001) enrichment of PEMT-derived d3 and d6 metabolites was detected in liver, plasma, and brain in both genotypes but to a greater extent in the Ts65Dn adult offspring. MCS also yielded higher (P<0.05) d9 metabolite enrichments in liver, plasma, and brain. These data demonstrate that MCS exerts lasting effects on offspring choline metabolism, including up-regulation of the hepatic PEMT pathway and enhanced provision of choline and PEMT-PC to the brain.—Yan, J., Ginsberg, S. D., Powers, B., Alldred, M. J., Saltzman, A., Strupp, B. J., Caudill, M. A. Maternal choline supplementation programs greater activity of the phosphatidylethanolamine N-methyltransferase (PEMT) pathway in adult Ts65Dn trisomic mice. PMID:24963152

  2. Maternal choline concentrations during pregnancy and choline-related genetic variants as risk factors for neural tube defects123

    PubMed Central

    Mills, James L; Fan, Ruzong; Brody, Lawrence C; Liu, Aiyi; Ueland, Per M; Wang, Yifan; Kirke, Peadar N; Shane, Barry; Molloy, Anne M

    2014-01-01

    Background: Low maternal choline intake and blood concentration may be risk factors for having a child with a neural tube defect (NTD); however, the data are inconsistent. This is an important question to resolve because choline, if taken periconceptionally, might add to the protective effect currently being achieved by folic acid. Objective: We examined the relation between NTDs, choline status, and genetic polymorphisms reported to influence de novo choline synthesis to investigate claims that taking choline periconceptionally could reduce NTD rates. Design: Two study groups of pregnant women were investigated: women who had a current NTD-affected pregnancy (AP; n = 71) and unaffected controls (n = 214) and women who had an NTD in another pregnancy but not in the current pregnancy [nonaffected pregnancy (NAP); n = 98] and unaffected controls (n = 386). Blood samples to measure betaine and total choline concentrations and single nucleotide polymorphisms related to choline metabolism were collected at their first prenatal visit. Results: Mean (±SD) plasma total choline concentrations in the AP (2.8 ± 1.0 mmol/L) and control (2.9 ± 0.9 mmol/L) groups did not differ significantly. Betaine concentrations were not significantly different between the 2 groups. Total choline and betaine in the NAP group did not differ from controls. Cases were significantly more likely to have the G allele of phosphatidylethanolamine-N-methyltransferase (PEMT; V175M, +5465 G>A) rs7946 (P = 0.02). Conclusions: Our results indicate that maternal betaine and choline concentrations are not strongly associated with NTD risk. The association between PEMT rs7946 and NTDs requires confirmation. The addition of choline to folic acid supplements may not further reduce NTD risk. PMID:25240073

  3. Maternal choline supplementation programs greater activity of the phosphatidylethanolamine N-methyltransferase (PEMT) pathway in adult Ts65Dn trisomic mice.

    PubMed

    Yan, Jian; Ginsberg, Stephen D; Powers, Brian; Alldred, Melissa J; Saltzman, Arthur; Strupp, Barbara J; Caudill, Marie A

    2014-10-01

    Maternal choline supplementation (MCS) induces lifelong cognitive benefits in the Ts65Dn mouse, a trisomic mouse model of Down syndrome and Alzheimer's disease. To gain insight into the mechanisms underlying these beneficial effects, we conducted a study to test the hypothesis that MCS alters choline metabolism in adult Ts65Dn offspring. Deuterium-labeled methyl-d9-choline was administered to adult Ts65Dn and disomic (2N) female littermates born to choline-unsupplemented or choline-supplemented Ts65Dn dams. Enrichment of d9-choline metabolites (derived from intact choline) and d3 + d6-choline metabolites [produced when choline-derived methyl groups are used by phosphatidylethanolamine N-methyltransferase (PEMT)] was measured in harvested tissues. Adult offspring (both Ts65Dn and 2N) of choline-supplemented (vs. choline-unsupplemented) dams exhibited 60% greater (P≤0.007) activity of hepatic PEMT, which functions in de novo choline synthesis and produces phosphatidylcholine (PC) enriched in docosahexaenoic acid. Higher (P<0.001) enrichment of PEMT-derived d3 and d6 metabolites was detected in liver, plasma, and brain in both genotypes but to a greater extent in the Ts65Dn adult offspring. MCS also yielded higher (P<0.05) d9 metabolite enrichments in liver, plasma, and brain. These data demonstrate that MCS exerts lasting effects on offspring choline metabolism, including up-regulation of the hepatic PEMT pathway and enhanced provision of choline and PEMT-PC to the brain. © FASEB.

  4. Insular Cortex Metabolite Changes in Obstructive Sleep Apnea

    PubMed Central

    Yadav, Santosh K.; Kumar, Rajesh; Macey, Paul M.; Woo, Mary A.; Yan-Go, Frisca L.; Harper, Ronald M.

    2014-01-01

    Study Objective: Adults with obstructive sleep apnea (OSA) show significant autonomic and neuropsychologic deficits, which may derive from damage to insular regions that serve those functions. The aim was to assess glial and neuronal status from anterior insular metabolites in OSA versus controls, using proton magnetic resonance spectroscopy (PMRS), and thus to provide insights for neuroprotection against tissue changes, and to reduce injury consequences. Design: Cross-sectional study. Setting: University-based medical center. Participants: Thirty-six patients with OSA, 53 controls. Interventions: None. Measurements and Results: We performed PMRS in bilateral anterior insulae using a 3.0-Tesla magnetic resonance imaging scanner, calculated N-acetylaspartate/creatine (NAA/Cr), choline/creatine (Cho/Cr), myo-inositol/creatine (MI/Cr), and MI/NAA metabolite ratios, and examined daytime sleepiness (Epworth Sleepiness Scale, ESS), sleep quality (Pittsburgh Sleep Quality Index, PSQI), and neuropsychologic status (Beck Depression Inventory II [BDI-II] and Beck Anxiety Inventory [BAI]). Body mass index, BAI, BDI-II, PSQI, and ESS significantly differed between groups. NAA/ Cr ratios were significantly reduced bilaterally, and left-sided MI/Cr and MI/NAA ratios were increased in OSA over controls. Significant positive correlations emerged between left insular MI/Cr ratios and apnea-hypopnea index values, right insular Cho/Cr ratios and BDI-II and BAI scores, and negative correlations appeared between left insular NAA/Cr ratios and PSQI scores and between right-side MI/Cr ratios and baseline and nadir change in O2 saturation. Conclusions: Adults with obstructive sleep apnea showed bilaterally reduced N-acetylaspartate and left-side increased myo-inositol anterior insular metabolites, indicating neuronal damage and increased glial activation, respectively, which may contribute to abnormal autonomic and neuropsychologic functions in the condition. The activated glial status

  5. An MRspec database query and visualization engine with applications as a clinical diagnostic and research tool.

    PubMed

    Miscevic, Filip; Foong, Justin; Schmitt, Benjamin; Blaser, Susan; Brudno, Michael; Schulze, Andreas

    2016-12-01

    Proton magnetic resonance spectroscopy (MRspec), one of the very few techniques for in vivo assessment of neuro-metabolic profiles, is often complicated by lack of standard population norms and paucity of computational tools. 7035 scans and clinical information from 4430 pediatric patients were collected from 2008 to 2014. Scans were conducted using a 1.5T (n=3664) or 3T scanner (n=3371), and with either a long (144ms, n=5559) or short echo time (35ms, n=1476). 3055 of these scans were localized in the basal ganglia (BG), 1211 in parieto-occipital white matter (WM). 34 metabolites were quantified using LCModel. A web application using MySQL, Python and Flask was developed to facilitate the exploration of the data set. Already piloting the application revealed numerous insights. (1), N-acetylaspartate (NAA) increased throughout all ages. During early infancy, total choline was highly varied and myo-inositol demonstrated a downward trend. (2), Total creatine (tCr) and creatine increased throughout childhood and adolescence, though phosphocreatine (PCr) remained constant beyond 200days. (3), tCr was higher in BG than WM. (4), No obvious gender-related differences were observed. (5), Field strength affects quantification using LCModel for some metabolites, most prominently for tCr and total NAA. (6), Outlier analysis identified patients treated with vigabatrin through elevated γ-aminobutyrate, and patients with Klippel-Feil syndrome, Leigh disease and L2-hydroxyglutaric aciduria through low choline in BG. We have established the largest MRSpec database and developed a robust and flexible computational tool for facilitating the exploration of vast metabolite datasets that proved its value for discovering neurochemical trends for clinical diagnosis, treatment monitoring, and research. Open access will lead to its widespread use, improving the diagnostic yield and contributing to better understanding of metabolic processes and conditions in the brain. Copyright © 2016

  6. Extracellular N-Acetylaspartate in Human Traumatic Brain Injury

    PubMed Central

    Shannon, Richard J.; Carter, Eleanor L.; Jalloh, Ibrahim; Menon, David K.; Hutchinson, Peter J.; Carpenter, Keri L.H.

    2016-01-01

    Abstract N-acetylaspartate (NAA) is an amino acid derivative primarily located in the neurons of the adult brain. The function of NAA is incompletely understood. Decrease in brain tissue NAA is presently considered symptomatic and a potential biomarker of acute and chronic neuropathological conditions. The aim of this study was to use microdialysis to investigate the behavior of extracellular NAA (eNAA) levels after traumatic brain injury (TBI). Sampling for this study was performed using cerebral microdialysis catheters (M Dialysis 71) perfused at 0.3 μL/min. Extracellular NAA was measured in microdialysates by high-performance liquid chromatography in 30 patients with severe TBI and for comparison, in radiographically “normal” areas of brain in six non-TBI neurosurgical patients. We established a detailed temporal eNAA profile in eight of the severe TBI patients. Microdialysate concentrations of glucose, lactate, pyruvate, glutamate, and glycerol were measured on an ISCUS clinical microdialysis analyzer. Here, we show that the temporal profile of microdialysate eNAA was characterized by highest levels in the earliest time-points post-injury, followed by a steady decline; beyond 70 h post-injury, average levels were 40% lower than those measured in non-TBI patients. There was a significant inverse correlation between concentrations of eNAA and pyruvate; eNAA showed significant positive correlations with glycerol and the lactate/pyruvate (L/P) ratio measured in microdialysates. The results of this on-going study suggest that changes in eNAA after TBI relate to the release of intracellular components, possibly due to neuronal death or injury, as well as to adverse brain energy metabolism. PMID:26159566

  7. The Molecular Mechanisms Affecting N-Acetylaspartate Homeostasis Following Experimental Graded Traumatic Brain Injury

    PubMed Central

    Di Pietro, Valentina; Amorini, Angela Maria; Tavazzi, Barbara; Vagnozzi, Roberto; Logan, Ann; Lazzarino, Giacomo; Signoretti, Stefano; Lazzarino, Giuseppe; Belli, Antonio

    2014-01-01

    To characterize the molecular mechanisms of N-acetylaspartate (NAA) metabolism following traumatic brain injury (TBI), we measured the NAA, adenosine triphosphate (ATP) and adenosine diphosphate (ADP) concentrations and calculated the ATP/ADP ratio at different times from impact, concomitantly evaluating the gene and protein expressions controlling NAA homeostasis (the NAA synthesizing and degrading enzymes N-acetyltransferase 8-like and aspartoacylase, respectively) in rats receiving either mild or severe TBI. The reversible changes in NAA induced by mild TBI were due to a combination of transient mitochondrial malfunctioning with energy crisis (decrease in ATP and in the ATP/ADP ratio) and modulation in the gene and protein levels of N-acetyltransferase 8-like and increase of aspartoacylase levels. The irreversible decrease in NAA following severe TBI, was instead characterized by profound mitochondrial malfunctioning (constant 65% decrease of the ATP/ADP indicating permanent impairment of the mitochondrial phosphorylating capacity), dramatic repression of the N-acetyltransferase 8-like gene and concomitant remarkable increase in the aspartoacylase gene and protein levels. The mechanisms underlying changes in NAA homeostasis following graded TBI might be of note for possible new therapeutic approaches and will help in understanding the effects of repeat concussions occurring during particular periods of the complex NAA recovery process, coincident with the so called window of brain vulnerability. PMID:24515258

  8. Plasma trimethylamine N-oxide concentration is associated with choline, phospholipids, and methyl metabolism.

    PubMed

    Obeid, Rima; Awwad, Hussain M; Rabagny, Yannick; Graeber, Stefan; Herrmann, Wolfgang; Geisel, Juergen

    2016-03-01

    Elevated plasma concentrations of the gut bacteria choline metabolite trimethylamine N-oxide (TMAO) are associated with atherosclerosis. However, the determinants of TMAO in humans require additional assessment. We examined cardiometabolic risk factors and pathways associated with TMAO concentrations in humans. A total of 283 individuals (mean ± SD age: 66.7 ± 9.0 y) were included in this observational study. Plasma concentrations of trimethylamine, TMAO, choline, lipids, phospholipids, and methyl metabolites were measured. Study participants were divided into 4 groups by median concentrations of TMAO and choline (4.36 and 9.7 μmol/L, respectively). Compared with the group with TMAO and choline concentrations that were less than the median (n = 82), the group with TMAO and choline concentrations that were at least the median (n = 83) was older and had lower high-density lipoprotein (HDL) cholesterol, phospholipids, and methylation potential, higher creatinine, betaine, S-adenosylhomocysteine (SAH), and S-adenosylmethionine (SAM), and higher percentages of men and subjects with diabetes. The difference in plasma TMAO concentrations between men and women (7.3 ± 10.0 compared with 5.4 ± 5.6 μmol/L, respectively) was NS after adjustment for age and creatinine (P = 0.455). The TMAO:trimethylamine ratio was higher in men (P < 0.001). Diabetes was associated with significantly higher plasma TMAO concentration (8.6 ± 12.2 compared with 5.4 ± 5.2 μmol/L) even after adjustments. Sex and diabetes showed an interactive effect on trimethylamine concentrations (P = 0.010) but not on TMAO concentrations (P = 0.950). Positive determinants of TMAO in a stepwise regression model that applied to the whole group were SAH, trimethylamine, choline, and female sex, whereas plasma phosphatidylcholine was a negative determinant. High TMAO and choline concentrations are associated with an advanced cardiometabolic risk profile. Diabetes is related to higher plasma TMAO

  9. Choline-to-N-acetyl aspartate and lipids-lactate-to-creatine ratios together with age assemble a significant Cox's proportional-hazards regression model for prediction of survival in high-grade gliomas.

    PubMed

    Roldan-Valadez, Ernesto; Rios, Camilo; Motola-Kuba, Daniel; Matus-Santos, Juan; Villa, Antonio R; Moreno-Jimenez, Sergio

    2016-11-01

    A long-lasting concern has prevailed for the identification of predictive biomarkers for high-grade gliomas (HGGs) using MRI. However, a consensus of which imaging parameters assemble a significant survival model is still missing in the literature; we investigated the significant positive or negative contribution of several MR biomarkers in this tumour prognosis. A retrospective cohort of supratentorial HGGs [11 glioblastoma multiforme (GBM) and 17 anaplastic astrocytomas] included 28 patients (9 females and 19 males, respectively, with a mean age of 50.4 years, standard deviation: 16.28 years; range: 13-85 years). Oedema and viable tumour measurements were acquired using regions of interest in T 1 weighted, T 2 weighted, fluid-attenuated inversion recovery, apparent diffusion coefficient (ADC) and MR spectroscopy (MRS). We calculated Kaplan-Meier curves and obtained Cox's proportional hazards. During the follow-up period (3-98 months), 17 deaths were recorded. The median survival time was 1.73 years (range, 0.287-8.947 years). Only 3 out of 20 covariates (choline-to-N-acetyl aspartate and lipids-lactate-to-creatine ratios and age) showed significance in explaining the variability in the survival hazards model; score test: χ 2 (3) = 9.098, p = 0.028. MRS metabolites overcome volumetric parameters of peritumoral oedema and viable tumour, as well as tumour region ADC measurements. Specific MRS ratios (Cho/Naa, L-L/Cr) might be considered in a regular follow-up for these tumours. Advances in knowledge: Cho/Naa ratio is the strongest survival predictor with a log-hazard function of 2.672 in GBM. Low levels of lipids-lactate/Cr ratio represent up to a 41.6% reduction in the risk of death in GBM.

  10. Choline-to-N-acetyl aspartate and lipids-lactate-to-creatine ratios together with age assemble a significant Cox's proportional-hazards regression model for prediction of survival in high-grade gliomas

    PubMed Central

    Rios, Camilo; Motola-Kuba, Daniel; Matus-Santos, Juan; Villa, Antonio R; Moreno-Jimenez, Sergio

    2016-01-01

    Objective: A long-lasting concern has prevailed for the identification of predictive biomarkers for high-grade gliomas (HGGs) using MRI. However, a consensus of which imaging parameters assemble a significant survival model is still missing in the literature; we investigated the significant positive or negative contribution of several MR biomarkers in this tumour prognosis. Methods: A retrospective cohort of supratentorial HGGs [11 glioblastoma multiforme (GBM) and 17 anaplastic astrocytomas] included 28 patients (9 females and 19 males, respectively, with a mean age of 50.4 years, standard deviation: 16.28 years; range: 13–85 years). Oedema and viable tumour measurements were acquired using regions of interest in T1 weighted, T2 weighted, fluid-attenuated inversion recovery, apparent diffusion coefficient (ADC) and MR spectroscopy (MRS). We calculated Kaplan–Meier curves and obtained Cox's proportional hazards. Results: During the follow-up period (3–98 months), 17 deaths were recorded. The median survival time was 1.73 years (range, 0.287–8.947 years). Only 3 out of 20 covariates (choline-to-N-acetyl aspartate and lipids-lactate-to-creatine ratios and age) showed significance in explaining the variability in the survival hazards model; score test: χ2 (3) = 9.098, p = 0.028. Conclusion: MRS metabolites overcome volumetric parameters of peritumoral oedema and viable tumour, as well as tumour region ADC measurements. Specific MRS ratios (Cho/Naa, L-L/Cr) might be considered in a regular follow-up for these tumours. Advances in knowledge: Cho/Naa ratio is the strongest survival predictor with a log-hazard function of 2.672 in GBM. Low levels of lipids–lactate/Cr ratio represent up to a 41.6% reduction in the risk of death in GBM. PMID:27626830

  11. NMR studies on /sup 15/N-labeled creatine (CR), creatinine (CRN), phosphocreatine (PCR), and phosphocreatinine (PCRN), and on barriers to rotation in creatine kinase-bound creatine in the enzymatic reaction

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Kenyon, G.L.; Reddick, R.E.

    1986-05-01

    Recently, the authors have synthesized /sup 15/N-2-Cr, /sup 15/N-3-Crn, /sup 15/N-2-Crn, /sup 15/N-3-PCrn, /sup 15/N-3-PCr, and /sup 15/N-2-PCr. /sup 1/H, /sup 15/N, /sup 31/P NMR data show that Crn protonates exclusively at the non-methylated ring nitrogen, confirm that PCrn is phosphorylated at the exocyclic nitrogen, and demonstrate that the /sup 31/P-/sup 15/N one-bond coupling constant in /sup 15/N-3-PCr is 18 Hz, not 3 Hz as previously reported by Brindle, K.M., Porteous, R. and Radda, G.K.. The authors have found that creatine kinase is capable of catalyzing the /sup 14/N//sup 15/N positional isotope exchange of 3-/sup 15/N-PCr in the presence ofmore » MgADP, but not in its absence. Further, the exchange does not take place when labeled PCr is resynthesized exclusively from the ternary complex E X Cr X MgATP as opposed to either E X Cr or free Cr. This suggests that the enzyme both imparts an additional rotational barrier to creatine in the complex and catalyzes the transfer of phosphoryl group with essentially complete regiospecificity.« less

  12. Guanidinoacetic acid versus creatine for improved brain and muscle creatine levels: a superiority pilot trial in healthy men.

    PubMed

    Ostojic, Sergej M; Ostojic, Jelena; Drid, Patrik; Vranes, Milan

    2016-09-01

    In this randomized, double-blind, crossover trial, we evaluated whether 4-week supplementation with guanidinoacetic acid (GAA) is superior to creatine in facilitating creatine levels in healthy men (n = 5). GAA (3.0 g/day) resulted in a more powerful rise (up to 16.2%) in tissue creatine levels in vastus medialis muscle, middle-cerebellar peduncle, and paracentral grey matter, as compared with creatine (P < 0.05). These results indicate that GAA as a preferred alternative to creatine for improved bioenergetics in energy-demanding tissues.

  13. Egg n-3 fatty acid composition modulates biomarkers of choline metabolism in free-living lacto-ovo-vegetarian women of reproductive age.

    PubMed

    West, Allyson A; Shih, Yun; Wang, Wei; Oda, Keiji; Jaceldo-Siegl, Karen; Sabaté, Joan; Haddad, Ella; Rajaram, Sujatha; Caudill, Marie A; Burns-Whitmore, Bonny

    2014-10-01

    The lacto-ovo-vegetarian (LOV) dietary regimen allows eggs, which are a rich source of choline. Consumption of eggs by LOV women may be especially important during pregnancy and lactation when demand for choline is high. The aim of this single blind, randomized, crossover-feeding study was to determine how near-daily egg consumption influenced biomarkers of choline metabolism in healthy LOV women of reproductive age (n=15). Because long-chain n-3 fatty acids could influence choline metabolism, the effect of n-3-enriched vs nonenriched eggs on choline metabolites was also investigated. Three 8-week dietary treatments consisting of six n-3-enriched eggs per week, six nonenriched eggs per week, and an egg-free control phase were separated by 4-week washout periods. Choline metabolites were quantified in fasted plasma collected before and after each treatment and differences in posttreatment choline metabolite concentrations were determined with linear mixed models. The n-3-enriched and nonenriched egg treatments produced different choline metabolite profiles compared with the egg-free control; however, response to the eggs did not differ (P>0.1). Consumption of the n-3-enriched egg treatment yielded higher plasma free choline (P=0.02) and betaine (P<0.01) (vs egg-free control) concentrations, whereas consumption of the nonenriched egg treatment yielded borderline higher (P=0.06) plasma phosphatidylcholine (vs egg-free control) levels. Neither egg treatment increased levels of plasma trimethylamine oxide, a gut-flora-dependent oxidative choline metabolite implicated as a possible risk factor for cardiovascular disease. Overall these data suggest that egg fatty-acid composition modulates the metabolic use of choline. Copyright © 2014 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.

  14. Monitoring glutamate levels in the posterior cingulate cortex of thyroid dysfunction patients with TE-averaged PRESS at 3T.

    PubMed

    Zhang, Qiujuan; Bai, Zhilan; Gong, Yan; Liu, Xinxin; Dai, Xiaoqing; Wang, Shejiao; Liu, Feng

    2015-07-01

    Patients with thyroid dysfunction frequently have neuropsychiatric complaints such as lack of concentration, poor memory, depression, anxiety and mania, which suggest brain dysfunction. However, the underlying process of this dysfunction remains unclear. Recent studies of the glutamatergic system have offered important insight into the neuropsychiatric process. Thus, this study investigates changes in glutamate concentration in patients with thyroid dysfunction. It also clarifies whether Glu levels are related to thyroid hormones via proton magnetic resonance spectroscopy. 36 untreated patients with thyroid dysfunction (18 hyperthyroidism patients and 18 hypothyroidism patients) and 18 age- and gender-matched controls were included in this study. The posterior cingulate cortex was examined by MRS with TE-averaged PRESS at 3T. The intensity of glutamate, choline, N-acetylaspartate, and creatine was assessed using jMRUI v4.0 software. We found a significant difference among hyper-/hypo- and control groups in Glu (P=0.003) and Cho (P=0.015). The concentrations of glutamate increased (P=0.006) in the posterior cingulate cortex in patients with hypothyroidism and significantly decreased (P=0.002) in hyperthyroidism patients relative to controls. There were no difference in the concentrations of choline between hyperthyroidism patients and controls (P=0.679). Versus the hyperthyroidism group, the hypothyroidism group showed increased glutamate (P=0.018) and choline (P=0.001) in the posterior cingulate cortex. There was no significant difference in the concentrations of NAA or creatine across the three groups (P>0.05). The Glu level correlates with TT3 (P=0.000) and FT3 (P=0.022). The signal intensity of glutamate shows significant differences in the region of the posterior cingulate cortex in patients with thyroid dysfunction. This change indicates a potential role of glutamate in the brain dysfunction experience by patients with thyroid hormone disorders. Copyright

  15. The trimethylammonium headgroup of choline is a major determinant for substrate binding and specificity in choline oxidase.

    PubMed

    Gadda, Giovanni; Powell, Nichole L N; Menon, Prashanthi

    2004-10-15

    Choline oxidase catalyzes the oxidation of choline to glycine betaine via two sequential flavin-linked transfers of hydride equivalents to molecular oxygen and formation of a betaine aldehyde intermediate. In the present study, choline and glycine betaine analogs were used as substrates and inhibitors for the enzyme to investigate the structural determinants that are relevant for substrate recognition and specificity. Competitive inhibition patterns with respect to choline were determined for a number of substituted amines at pH 6.5 and 25 degrees C. The Kis values for the carboxylate-containing ligands glycine betaine, N,N-dimethylglycine, and N-methylglycine increased monotonically with decreasing number of methyl groups, consistent with the trimethylammonium portion of the ligand being important for binding. In contrast, the acetate portion of glycine betaine did not contribute to binding, as suggested by lack of changes in the Kis values upon substituting glycine betaine with inhibitors containing methyl, ethyl, allyl, and 2-amino-ethyl side chains. In agreement with the inhibition data, the specificity of the enzyme for the organic substrate (kcat/Km value) decreased when N,N-dimethylethanolamine, N-methylethanolamine, and the isosteric substrate 3,3-dimethyl-1-butanol were used as substrate instead of choline; a contribution of approximately 7 kcal mol(-1) toward substrate discrimination was estimated for the interaction of the trimethylammonium portion of the substrate with the active site of choline oxidase.

  16. The whole-brain N-acetylaspartate correlates with education in normal adults.

    PubMed

    Glodzik, Lidia; Wu, William E; Babb, James S; Achtnichts, Lutz; Amann, Michael; Sollberger, Marc; Monsch, Andreas U; Gass, Achim; Gonen, Oded

    2012-10-30

    N-acetylaspartate (NAA) is an index of neuronal integrity. We hypothesized that in healthy subjects its whole brain concentration (WBNAA) may be related to formal educational attainment, a common proxy for cognitive reserve. To test this hypothesis, 97 middle aged to elderly subjects (51-89 years old, 38% women) underwent brain magnetic resonance imaging and non-localizing proton spectroscopy. Their WBNAA was obtained by dividing their whole-head NAA amount by the brain volume. Intracranial volume and fractional brain volume, a metric of brain atrophy, were also determined. Each subject's educational attainment was the sum of his/her years of formal education. In the entire group higher education was associated with larger intracranial volume. The relationship between WBNAA and education was observed only in younger (51-70 years old) participants. In this group, education explained 21% of the variance in WBNAA. More WBNAA was related to more years of formal education in adults and younger elders. Prospective studies can determine whether this relationship reflects a true advantage from years of training versus innate characteristics predisposing a subject to higher achievements later in life. We propose that late-life WBNAA may be more affected by other factors acting at midlife and later. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  17. The Whole-Brain N-Acetylaspartate Correlates with Education in Normal Adults

    PubMed Central

    Glodzik, Lidia; Wu, William E.; Babb, James S.; Achtnichts, Lutz; Amann, Michael; Sollberger, Marc; Monsch, Andreas U.; Gass, Achim; Gonen, Oded

    2012-01-01

    N-acetylaspartate (NAA) is an index of neuronal integrity. We hypothesized that in healthy subjects its whole brain concentration (WBNAA) may be related to formal educational attainment, a common proxy for cognitive reserve. To test this hypothesis 97 middle aged to elderly subjects (51–89 years old, 38% women) underwent brain MRI and non-localizing proton spectroscopy. Their WBNAA was obtained by dividing their whole-head NAA amount with the brain volume. Intracranial volume and fractional brain volume, a metric of brain atrophy, were also determined. Each subject’s educational attainment was the sum of their years of formal education. In the entire group higher education was associated with larger intracranial volume. The relationship between WBNAA and education was observed only in younger (51–70 years old) participants. In this group education explained 21% variance in WBNAA. More WBNAA was related to more years of formal education in adults and younger elders. Prospective studies can determine whether this relationship reflects a true advantage from years of training versus innate characteristic predisposing to higher achievements later in life. We offer that late life WBNAA may be more affected by other like factors acting at midlife and later. PMID:23177924

  18. Mechanisms of cannabidiol neuroprotection in hypoxic-ischemic newborn pigs: role of 5HT(1A) and CB2 receptors.

    PubMed

    Pazos, M Ruth; Mohammed, Nagat; Lafuente, Hector; Santos, Martin; Martínez-Pinilla, Eva; Moreno, Estefania; Valdizan, Elsa; Romero, Julián; Pazos, Angel; Franco, Rafael; Hillard, Cecilia J; Alvarez, Francisco J; Martínez-Orgado, Jose

    2013-08-01

    The mechanisms underlying the neuroprotective effects of cannabidiol (CBD) were studied in vivo using a hypoxic-ischemic (HI) brain injury model in newborn pigs. One- to two-day-old piglets were exposed to HI for 30 min by interrupting carotid blood flow and reducing the fraction of inspired oxygen to 10%. Thirty minutes after HI, the piglets were treated with vehicle (HV) or 1 mg/kg CBD, alone (HC) or in combination with 1 mg/kg of a CB₂ receptor antagonist (AM630) or a serotonin 5HT(1A) receptor antagonist (WAY100635). HI decreased the number of viable neurons and affected the amplitude-integrated EEG background activity as well as different prognostic proton-magnetic-resonance-spectroscopy (H(±)-MRS)-detectable biomarkers (lactate/N-acetylaspartate and N-acetylaspartate/choline ratios). HI brain damage was also associated with increases in excitotoxicity (increased glutamate/N-acetylaspartate ratio), oxidative stress (decreased glutathione/creatine ratio and increased protein carbonylation) and inflammation (increased brain IL-1 levels). CBD administration after HI prevented all these alterations, although this CBD-mediated neuroprotection was reversed by co-administration of either WAY100635 or AM630, suggesting the involvement of CB₂ and 5HT(1A) receptors. The involvement of CB₂ receptors was not dependent on a CBD-mediated increase in endocannabinoids. Finally, bioluminescence resonance energy transfer studies indicated that CB₂ and 5HT(1A) receptors may form heteromers in living HEK-293T cells. In conclusion, our findings demonstrate that CBD exerts robust neuroprotective effects in vivo in HI piglets, modulating excitotoxicity, oxidative stress and inflammation, and that both CB₂ and 5HT(1A) receptors are implicated in these effects. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans.

    PubMed

    Kohlmeier, Martin; da Costa, Kerry-Ann; Fischer, Leslie M; Zeisel, Steven H

    2005-11-01

    Choline is a required nutrient, and some humans deplete quickly when fed a low-choline diet, whereas others do not. Endogenous choline synthesis can spare some of the dietary requirement and requires one-carbon groups derived from folate metabolism. We examined whether major genetic variants of folate metabolism modify susceptibility of humans to choline deficiency. Fifty-four adult men and women were fed diets containing adequate choline and folate, followed by a diet containing almost no choline, with or without added folate, until they were clinically judged to be choline-deficient, or for up to 42 days. Criteria for clinical choline deficiency were a more than five times increase in serum creatine kinase activity or a >28% increase of liver fat after consuming the low-choline diet that resolved when choline was returned to the diet. Choline deficiency was observed in more than half of the participants, usually within less than a month. Individuals who were carriers of the very common 5,10-methylenetetrahydrofolate dehydrogenase-1958A gene allele were more likely than noncarriers to develop signs of choline deficiency (odds ratio, 7.0; 95% confidence interval, 2.0-25; P < 0.01) on the low-choline diet unless they were also treated with a folic acid supplement. The effects of the C677T and A1298C polymorphisms of the 5,10-methylene tetrahydrofolate reductase gene and the A80C polymorphism of the reduced folate carrier 1 gene were not statistically significant. The most remarkable finding was the strong association in premenopausal women of the 5,10-methylenetetrahydrofolate dehydrogenase-1958A gene allele polymorphism with 15 times increased susceptibility to developing organ dysfunction on a low-choline diet.

  20. Maternal Choline Status, but Not Fetal Genotype, Influences Cord Plasma Choline Metabolite Concentrations.

    PubMed

    Visentin, Carly E; Masih, Shannon; Plumptre, Lesley; Malysheva, Olga; Nielsen, Daiva E; Sohn, Kyoung-Jin; Ly, Anna; Lausman, Andrea Y; Berger, Howard; Croxford, Ruth; El-Sohemy, Ahmed; Caudill, Marie A; O'Connor, Deborah L; Kim, Young-In

    2015-07-01

    Choline deficiency during pregnancy can lead to adverse birth outcomes, including impaired neurodevelopment and birth defects. Genetic variants of choline and one-carbon metabolism may also influence birth outcomes by altering plasma choline concentrations. The effects of maternal ad libitum choline intake during pregnancy and fetal genetic variants on maternal and cord concentrations of choline and its metabolites are unknown. This prospective study sought to assess the effect of 1) maternal dietary choline intake on maternal and cord plasma concentrations of choline and its metabolites, and 2) fetal genetic polymorphisms on cord plasma concentrations. The dietary choline intake of 368 pregnant Canadian women was assessed in early (0-16 wk) and late (23-37 wk) pregnancy with the use of a food frequency questionnaire. Plasma concentrations of free choline and its metabolites were measured in maternal samples at recruitment and delivery, and in the cord blood. Ten fetal genetic variants in choline and one-carbon metabolism were assessed for their association with cord plasma concentrations of free choline and its metabolites. Mean maternal plasma free choline, dimethylglycine, and trimethylamine N-oxide (TMAO) concentrations increased during pregnancy by 49%, 17%, and 13%, respectively (P < 0.005), whereas betaine concentrations decreased by 21% (P < 0.005). Cord plasma concentrations of free choline, betaine, dimethylglycine, and TMAO were 3.2, 2.0, 1.3, and 0.88 times corresponding maternal concentrations at delivery, respectively (all P < 0.005). Maternal plasma concentrations of betaine, dimethylglycine, and TMAO (r(2) = 0.19-0.51; P < 0.0001) at delivery were moderately strong, whereas maternal concentrations of free choline were not significant (r(2) = 0.12; P = 0.06), predictors of cord plasma concentrations of these metabolites. Neither maternal dietary intake nor fetal genetic variants predicted maternal or cord plasma concentrations of choline and its

  1. Analysis of creatine, creatinine, creatine-d3 and creatinine-d3 in urine, plasma, and red blood cells by HPLC and GC-MS to follow the fate of ingested creatine-d3.

    PubMed

    MacNeil, Lauren; Hill, Lisa; MacDonald, Daniel; Keefe, Lori; Cormier, James F; Burke, Darren G; Smith-Palmer, Truis

    2005-12-05

    Creatine, which is increasingly being used as an oral supplement, is naturally present in the body. Studies on the fate of a particular dose of creatine require that the creatine be labeled, and for studies in humans the use of a stable isotopic label is desirable. The concentrations of total creatine and total creatinine were determined using HPLC. Creatine and creatinine were then separated using cation exchange chromatography and each fraction was derivatized with trifluoroacetic anhydride and the ratio of the deuterated:undeuterated species determined using GC-MS. Ratios of creatine:creatine-d(3), and creatinine:creatinine-d(3), and the concentrations of each of these species, were able to be determined in urine, plasma and red blood cells. Thus, the uptake of labeled creatine into plasma and red blood cells and its excretion in urine could be followed for a subject who ingested creatine-d(3). Creatine-d(3) was found in the plasma and red blood cells 10 min after ingestion, while creatine-d(3) and creatinine-d(3) were found in the urine collected after the first hour.

  2. Choline exposure reduces potentiation of N-methyl-D-aspartate toxicity by corticosterone in the developing hippocampus.

    PubMed

    Mulholland, Patrick J; Self, Rachel L; Harris, Barton R; Littleton, John M; Prendergast, Mark A

    2004-11-25

    Exposure to high levels of glucocorticoids (GCs) may adversely affect neuronal viability, particularly in the developing hippocampus, via increased function or sensitivity of N-methyl-D-aspartate (NMDA)-type glutamate receptors. Conversely, choline supplementation in the developing brain may reduce the severity of subsequent insult. The present studies aimed to examine the extent to which short-term exposure to high concentrations of corticosterone would produce neuronal injury mediated by NMDA receptor activity. These studies also assessed the ability of choline to prevent this form of injury via interactions with nicotinic acetylcholine receptors (nAChRs) expressing the alpha7 subunit. Organotypic hippocampal slice cultures derived from neonatal rat were pre-treated for 72 h with corticosterone (100 nM) alone or with choline (0.1-10 mM), prior to a brief (1 h) NMDA exposure (5 microM). NMDA exposure produced significant cellular damage, reflected as increased fluorescence of the non-vital marker propidium iodide, in the CA1 region. While exposure to corticosterone alone did not produce damage, pre-treatment of cultures with corticosterone markedly exacerbated NMDA-induced toxicity. Pre-treatment with choline (> or =1 mM) alone or in combination with corticosterone markedly reduced subsequent NMDA toxicity, effects blocked by co-exposure to methyllycaconitine (100 nM), an antagonist active at nAChRs expressing the alpha7 subunit. These data suggest that even short-term exposure to high concentrations of GCs may adversely affect neuronal viability and that choline supplementation protects the brain from NMDA receptor-mediated damage, including that associated with hypercortisolemia.

  3. In vitro studies on the putative function of N-acetylaspartate as an osmoregulator.

    PubMed

    Tranberg, Mattias; Abbas, Abdul-Karim; Sandberg, Mats

    2007-07-01

    Efflux and tissue content of N-acetylaspartate (NAA) and amino acids were evaluated from cultured and acutely prepared hippocampal slices in response to changes in osmolarity. The osmoregulator taurine, but not NAA, was lost from both types of slices after moderate reductions in extracellular osmolarity (-60 mOsm) for 10-48 h. Hypoosmotic shock (-166 mOsm) for 5 min resulted in unselective efflux of several amino acids from acutely prepared slices. Notably, the efflux of taurine, but not NAA, was prominent also after the shock. Efflux of NAA was markedly enhanced by NMDA and high K(+), in particular after the stimulation period. The high K(+)-mediated efflux was decreased by high extracellular osmolarity and a NMDA-receptor antagonist. The results indicate that NAA efflux can be induced by a sudden non-physiological decrease in extracellular osmolarity but not by prolonged more moderate changes in osmolarity. The mechanisms behind the efflux of NAA by high K(+) are complex and may involve both swelling and activation of NMDA-receptors.

  4. N-Acetylaspartate in the CNS: From Neurodiagnostics to Neurobiology

    PubMed Central

    Moffett, John R.; Ross, Brian; Arun, Peethambaran; Madhavarao, Chikkathur N.; Namboodiri, M. A. A.

    2007-01-01

    The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research

  5. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide.

    PubMed

    Wang, Zeneng; Tang, W H Wilson; Buffa, Jennifer A; Fu, Xiaoming; Britt, Earl B; Koeth, Robert A; Levison, Bruce S; Fan, Yiying; Wu, Yuping; Hazen, Stanley L

    2014-04-01

    Recent metabolomics and animal model studies show trimethylamine-N-oxide (TMAO), an intestinal microbiota-dependent metabolite formed from dietary trimethylamine-containing nutrients such as phosphatidylcholine (PC), choline, and carnitine, is linked to coronary artery disease pathogenesis. Our aim was to examine the prognostic value of systemic choline and betaine levels in stable cardiac patients. We examined the relationship between fasting plasma choline and betaine levels and risk of major adverse cardiac events (MACE = death, myocardial infraction, stroke) in relation to TMAO over 3 years of follow-up in 3903 sequential stable subjects undergoing elective diagnostic coronary angiography. In our study cohort, median (IQR) TMAO, choline, and betaine levels were 3.7 (2.4-6.2)μM, 9.8 (7.9-12.2)μM, and 41.1 (32.5-52.1)μM, respectively. Modest but statistically significant correlations were noted between TMAO and choline (r = 0.33, P < 0.001) and less between TMAO and betaine (r = 0.09, P < 0.001). Higher plasma choline and betaine levels were associated with a 1.9-fold and 1.4-fold increased risk of MACE, respectively (Quartiles 4 vs. 1; P < 0.01, each). Following adjustments for traditional cardiovascular risk factors and high-sensitivity C-reactive protein, elevated choline [1.34 (1.03-1.74), P < 0.05], and betaine levels [1.33 (1.03-1.73), P < 0.05] each predicted increased MACE risk. Neither choline nor betaine predicted MACE risk when TMAO was added to the adjustment model, and choline and betaine predicted future risk for MACE only when TMAO was elevated. Elevated plasma levels of choline and betaine are each associated with incident MACE risk independent of traditional risk factors. However, high choline and betaine levels are only associated with higher risk of future MACE with concomitant increase in TMAO.

  6. Brain metabolic correlates of decision making in amnestic mild cognitive impairment.

    PubMed

    Griffith, H Randall; Okonkwo, Ozioma C; den Hollander, Jan A; Belue, Katherine; Copeland, Jacqueline; Harrell, Lindy E; Brockington, John C; Clark, David G; Marson, Daniel C

    2010-01-01

    Persons with amnestic mild cognitive impairment (MCI) have subtle impairments in medical decision-making capacity (MDC). We examined the relationship between proton magnetic resonance spectroscopy (MRS) and MDC in MCI. Twenty-nine MCI patients and 42 controls underwent MRS to obtain ratios of N-acetylaspartate (NAA)/Creatine (Cr), Choline (Cho)/Cr, and myo-Inositol (mI)/Cr of the posterior cingulate. They also completed the Capacity to Consent to Treatment Instrument (CCTI), a vignette-based instrument measuring decisional standards of expressing choice, appreciating consequences of choice, providing rational reasons for choice, and understanding treatment choices. Patients showed abnormal MRS ratios of mI/Cr and Cho/Cr compared to controls, and impairments on the CCTI understanding and reasoning Standards. Performance on the reasoning standard of the CCTI was correlated with NAA/Cr (r = .46, p < .05). The relationship of NAA/Cr with decision-making suggests a role for posterior cortical neuronal functioning in performance of complex IADLs in MCI.

  7. Unusual clinical and MRI features of a cerebellopontine angle medulloepithelioma. Case report and review of literature.

    PubMed

    Syal, Rajan; Reddy S, Jaypal; Kumar, Raj; Tyagi, Isha; Abrar, A A Wani; Krishnani, Narender; Mishra, Asht M; Gupta, Rakesh K

    2006-01-01

    We describe for the first time an unusual location and clinical presentation of medulloepithelioma, a rare embryonal tumor. A 5-year-old child presented with sudden onset of bilateral hearing loss. On imaging, the lesion appeared to be extra axial and was located in the right cerebello-pontine (CP) angle, extending into middle fossa along the trigeminal ganglion and in front of the brain stem into the opposite CP angle. It did not show any enhancement following contrast administration and had restricted diffusion on diffusion-weighted imaging, simulating an epidermoid. However, in vivo localized proton MR spectroscopy revealed a creatine peak dominated by a large choline resonance, peak of glycine with lactate/lipid and invisible N-acetylaspartate suggestive of a neoplastic lesion and not an epidermoid. Only subtotal resection could be performed and the patient had a stormy post-operative course due to extensive dissemination of the disease. Copyright 2006 S. Karger AG, Basel.

  8. Brain Biochemistry and Personality: A Magnetic Resonance Spectroscopy Study

    PubMed Central

    Ryman, Sephira G.; Gasparovic, Chuck; Bedrick, Edward J.; Flores, Ranee A.; Marshall, Alison N.; Jung, Rex E.

    2011-01-01

    To investigate the biochemical correlates of normal personality we utilized proton magnetic resonance spectroscopy (1H-MRS). Our sample consisted of 60 subjects ranging in age from 18 to 32 (27 females). Personality was assessed with the NEO Five-Factor Inventory (NEO-FFI). We measured brain biochemistry within the precuneus, the cingulate cortex, and underlying white matter. We hypothesized that brain biochemistry within these regions would predict individual differences across major domains of personality functioning. Biochemical models were fit for all personality domains including Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness. Our findings involved differing concentrations of Choline (Cho), Creatine (Cre), and N-acetylaspartate (NAA) in regions both within (i.e., posterior cingulate cortex) and white matter underlying (i.e., precuneus) the Default Mode Network (DMN). These results add to an emerging literature regarding personality neuroscience, and implicate biochemical integrity within the default mode network as constraining major personality domains within normal human subjects. PMID:22073190

  9. Oral choline decreases brain purine levels in lithium-treated subjects with rapid-cycling bipolar disorder: a double-blind trial using proton and lithium magnetic resonance spectroscopy.

    PubMed

    Lyoo, In Kyoon; Demopulos, Christina M; Hirashima, Fuyuki; Ahn, Kyung Heup; Renshaw, Perry F

    2003-08-01

    Oral choline administration has been reported to increase brain phosphatidylcholine levels. As phospholipid synthesis for maintaining membrane integrity in mammalian brain cells consumes approximately 10-15% of the total adenosine triphosphate (ATP) pool, an increased availability of brain choline may lead to an increase in ATP consumption. Given reports of genetic studies, which suggest mitochondrial dysfunction, and phosphorus (31P) magnetic resonance spectroscopy (MRS) studies, which report dysfunction in high-energy phosphate metabolism in patients with bipolar disorder, the current study is designed to evaluate the role of oral choline supplementation in modifying high-energy phosphate metabolism in subjects with bipolar disorder. Eight lithium-treated patients with DSM-IV bipolar disorder, rapid cycling type were randomly assigned to 50 mg/kg/day of choline bitartrate or placebo for 12 weeks. Brain purine, choline and lithium levels were assessed using 1H- and 7Li-MRS. Patients received four to six MRS scans, at baseline and weeks 2, 3, 5, 8, 10 and 12 of treatment (n = 40 scans). Patients were assessed using the Clinical Global Impression Scale (CGIS), the Young Mania Rating Scale (YRMS) and the Hamilton Depression Rating Scale (HDRS) at each MRS scan. There were no significant differences in change-from-baseline measures of CGIS, YMRS, and HDRS, brain choline/creatine ratios, and brain lithium levels over a 12-week assessment period between the choline and placebo groups or within each group. However, the choline treatment group showed a significant decrease in purine metabolite ratios from baseline (purine/n-acetyl aspartate: coef = -0.08, z = -2.17, df = 22, p = 0.030; purine/choline: coef = -0.12, z = -1.97, df = 22, p = 0.049) compared to the placebo group, controlling for brain lithium level changes. Brain lithium level change was not a significant predictor of purine ratios. The current study reports that oral choline supplementation resulted in a

  10. Creatine salts provide neuroprotection even after partial impairment of the creatine transporter.

    PubMed

    Adriano, E; Garbati, P; Salis, A; Damonte, G; Millo, E; Balestrino, M

    2017-01-06

    Creatine, a compound that is critical for energy metabolism of nervous cells, crosses the blood-brain barrier (BBB) and the neuronal plasma membrane with difficulty, and only using its specific transporter. In the hereditary condition where the creatine transporter is defective (creatine transporter deficiency) there is no creatine in the brain, and administration of creatine is useless lacking the transporter. The disease is severe and incurable. Creatine-derived molecules that could cross BBB and plasma membrane independently of the transporter might be useful to cure this condition. Moreover, such molecules could be useful also in stroke and other brain ischemic conditions. In this paper, we investigated three creatine salts, creatine ascorbate, creatine gluconate and creatine glucose. Of these, creatine glucose was ineffective after transporter block with guanidine acetic acid (GPA) administration. Creatine ascorbate was not superior to creatine in increasing tissue creatine and phosphocreatine content after transporter impairment, however even after such impairment it delayed synaptic failure during anoxia. Finally, creatine gluconate was superior to creatine in increasing tissue content of creatine after transporter block and slowed down PS disappearance during anoxia, an effect that creatine did not have. These findings suggest that coupling creatine to molecules having a specific transporter may be a useful strategy in creatine transporter deficiency. In particular, creatine ascorbate has effects comparable to those of creatine in normal conditions, while being superior to it under conditions of missing or impaired creatine transporter. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  11. Toward an in Vivo Neurochemical Profile: Quantification of 18 Metabolites in Short-Echo-Time 1H NMR Spectra of the Rat Brain

    NASA Astrophysics Data System (ADS)

    Pfeuffer, Josef; Tkáč , Ivan; Provencher, Stephen W.; Gruetter, Rolf

    1999-11-01

    Localized in vivo1H NMR spectroscopy was performed with 2-ms echo time in the rat brain at 9.4 T. Frequency domain analysis with LCModel showed that the in vivo spectra can be explained by 18 metabolite model solution spectra and a highly structured background, which was attributed to resonances with fivefold shorter in vivo T1 than metabolites. The high spectral resolution (full width at half maximum approximately 0.025 ppm) and sensitivity (signal-to-noise ratio approximately 45 from a 63-μL volume, 512 scans) was used for the simultaneous measurement of the concentrations of metabolites previously difficult to quantify in 1H spectra. The strongly represented signals of N-acetylaspartate, glutamate, taurine, myo-inositol, creatine, phosphocreatine, glutamine, and lactate were quantified with Cramér-Rao lower bounds below 4%. Choline groups, phosphorylethanolamine, glucose, glutathione, γ-aminobutyric acid, N-acetylaspartylglutamate, and alanine were below 13%, whereas aspartate and scyllo-inositol were below 22%. Intra-assay variation was assessed from a time series of 3-min spectra, and the coefficient of variation was similar to the calculated Cramér-Rao lower bounds. Interassay variation was determined from 31 pooled spectra, and the coefficient of variation for total creatine was 7%. Tissue concentrations were found to be in very good agreement with neurochemical data from the literature.

  12. Proton MRS in acute traumatic brain injury: role for glutamate/glutamine and choline for outcome prediction.

    PubMed

    Shutter, Lori; Tong, Karen A; Holshouser, Barbara A

    2004-12-01

    Proton magnetic resonance spectroscopy (MRS) is being used to evaluate individuals with acute traumatic brain injury and several studies have shown that changes in certain brain metabolites (N-acetylaspartate, choline) are associated with poor neurologic outcomes. The majority of previous MRS studies have been obtained relatively late after injury and none have examined the role of glutamate/ glutamine (Glx). We conducted a prospective MRS study of 42 severely injured adults to measure quantitative metabolite changes early (7 days) after injury in normal appearing brain. We used these findings to predict long-term neurologic outcome and to determine if MRS data alone or in combination with clinical outcome variables provided better prediction of long-term outcomes. We found that glutamate/glutamine (Glx) and choline (Cho) were significantly elevated in occipital gray and parietal white matter early after injury in patients with poor long-term (6-12-month) outcomes. Glx and Cho ratios predicted long-term outcome with 94% accuracy and when combined with the motor Glasgow Coma Scale score provided the highest predictive accuracy (97%). Somatosensory evoked potentials were not as accurate as MRS data in predicting outcome. Elevated Glx and Cho are more sensitive indicators of injury and predictors of poor outcome when spectroscopy is done early after injury. This may be a reflection of early excitotoxic injury (i.e., elevated Glx) and of injury associated with membrane disruption (i.e., increased Cho) secondary to diffuse axonal injury.

  13. Working memory dysfunction associated with brain functional deficits and cellular metabolic changes in patients with generalized anxiety disorder.

    PubMed

    Moon, Chung-Man; Sundaram, Thirunavukkarasu; Choi, Nam-Gil; Jeong, Gwang-Woo

    2016-08-30

    Generalized anxiety disorder (GAD) is associated with brain functional and morphological changes in connected with emotional dysregulation and cognitive deficit. This study dealt with the neural functional deficits and metabolic abnormalities in working memory (WM) task with emotion-inducing distractors in patients with GAD. Fourteen patients with GAD and 14 healthy controls underwent functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy ((1)H-MRS) at 3T. In response to the emotional distractors in WM tasks, the patients concurrently showed higher activity in the hippocampus and lower activities in the superior occipital gyrus, superior parietal gyrus, dorsolateral prefrontal cortex (DLPFC) and precentral gyrus compared to the controls. MRS revealed significantly lower choline/creatine (Cho/Cr) and choline/N-acetylaspartate (Cho/NAA) ratios in the DLPFC. In particular, the Cho ratios were positively correlated with the brain activities based on blood oxygenation level-dependent signal change in the DLPFC. This study provides the first evidence for the association between the metabolic alterations and functional deficit in WM processing with emotion-inducing distractors in GAD. These findings will be helpful to understand the neural dysfunction in connection with WM impairment in GAD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide

    PubMed Central

    Wang, Zeneng; Tang, W. H. Wilson; Buffa, Jennifer A.; Fu, Xiaoming; Britt, Earl B.; Koeth, Robert A.; Levison, Bruce S.; Fan, Yiying; Wu, Yuping; Hazen, Stanley L.

    2014-01-01

    Aims Recent metabolomics and animal model studies show trimethylamine-N-oxide (TMAO), an intestinal microbiota-dependent metabolite formed from dietary trimethylamine-containing nutrients such as phosphatidylcholine (PC), choline, and carnitine, is linked to coronary artery disease pathogenesis. Our aim was to examine the prognostic value of systemic choline and betaine levels in stable cardiac patients. Methods and results We examined the relationship between fasting plasma choline and betaine levels and risk of major adverse cardiac events (MACE = death, myocardial infraction, stroke) in relation to TMAO over 3 years of follow-up in 3903 sequential stable subjects undergoing elective diagnostic coronary angiography. In our study cohort, median (IQR) TMAO, choline, and betaine levels were 3.7 (2.4–6.2)μM, 9.8 (7.9–12.2)μM, and 41.1 (32.5–52.1)μM, respectively. Modest but statistically significant correlations were noted between TMAO and choline (r = 0.33, P < 0.001) and less between TMAO and betaine (r = 0.09, P < 0.001). Higher plasma choline and betaine levels were associated with a 1.9-fold and 1.4-fold increased risk of MACE, respectively (Quartiles 4 vs. 1; P < 0.01, each). Following adjustments for traditional cardiovascular risk factors and high-sensitivity C-reactive protein, elevated choline [1.34 (1.03–1.74), P < 0.05], and betaine levels [1.33 (1.03–1.73), P < 0.05] each predicted increased MACE risk. Neither choline nor betaine predicted MACE risk when TMAO was added to the adjustment model, and choline and betaine predicted future risk for MACE only when TMAO was elevated. Conclusion Elevated plasma levels of choline and betaine are each associated with incident MACE risk independent of traditional risk factors. However, high choline and betaine levels are only associated with higher risk of future MACE with concomitant increase in TMAO. PMID:24497336

  15. Anterior cingulate cortex choline levels in female adolescents with unipolar versus bipolar depression: A potential new tool for diagnosis

    PubMed Central

    Shi, Xian-Feng; Forrest, Lauren N.; Kuykendall, M. Danielle; Prescot, Andrew P.; Sung, Young-Hoon; Huber, Rebekah S.; Hellem, Tracy L.; Jeong, Eun-Kee; Renshaw, Perry F.; Kondo, Douglas G.

    2015-01-01

    Background Delayed diagnosis in bipolar disorder (BD) due to misdiagnosis as major depressive disorder (MDD) is a significant public health concern. Thus, identification of relevant diagnostic biomarkers is a critical unmet need, particularly early in the course of illness. The anterior cingulate cortex (ACC) is thought to play an important role in mood disorder pathophysiology. Case-control studies utilizing proton-1 magnetic resonance spectroscopy (1H-MRS) have found increased total choline levels in several brain regions in MDD. However, there are no published 1H-MRS reports directly comparing adolescents with MDD and BD. We hypothesized that ACC choline levels would be increased in adolescents with unipolar versus bipolar depression. Methods We studied depressed adolescents with MDD (n=28; mean age 17.0±2.1 years) and BD (n=9; 17.3±3.1 years). A Siemens Verio 3-Tesla clinical MRI system was used to acquire scans, using a single-voxel PRESS sequence. The voxel (18.75 cm3) was positioned on the ACC in the midsagittal plane. To remove potential gender effects, only female adolescent participants were included. Data were analyzed using the ANOVA and post-hoc Tukey tests. Results A significantly increased ACC choline/creatine ratio was observed in participants with MDD (mean=0.253±0.021) compared to BD (mean=0.219±0.020) (p=0.0002). There were no significant differences in the other 1H-MRS metabolites. Limitations Cross sectional design, single gender sample, limited sample size. Conclusions The present findings suggest that ACC total choline may have the potential to serve as a diagnostic biomarker in adolescent mood disorders. PMID:25082110

  16. Interaction between total body gamma-irradiation and choline deficiency triggers immediate modulation of choline and choline-containing moieties.

    PubMed

    Batra, Vipen; Kislay, Binita; Devasagayam, Thomas Paul Asir

    2011-12-01

    The objective of this study was to examine the effect of 60Co-gamma (γ) radiation on acute phase modulation, if any, of choline and choline-containing moieties in choline-deficient subjects. Corresponding results could provide information that might be useful in the management of adverse effects of γ-radiation. Male Swiss mice maintained on a choline-sufficient diet (CSD) and choline-free diet (CFD) based on AIN-93M formula, were subjected to whole body γ-irradiation (2-6 Gy). Liver, serum and brain samples from each group were then tested for: (i) Alterations in choline and choline-containing moieties such as phosphatidylcholine (PC) and sphingomyeline (SM); and (ii) modulation of choline profile modulating enzymes such as phospholipase D (PLD) and total sphingomyelinase (t-SMase). Liver and brain samples were also subjected to histo-pathological examinations. No significant changes were observed in folate, choline, choline-containing moieties and choline-modulating enzymes in choline-sufficient mice. In contrast, interaction between cytotoxic effects of γ-radiation and choline deficiency modulated choline and choline-containing moieties. Feeding CFD reduced hepatic concentrations of choline, PC and SM whereas PLD and t-SMase activities were significantly raised. The decrease in liver choline and choline-containing moieties was accompanied by an increase in blood choline concentration. Despite choline deficiency, the level of choline and acetylcholine synthesizing enzyme choline acetyltransfease (ChAT) significantly increased in the brain. We propose that choline deprivation and γ-radiation interact to modulate choline reserves of hepatic tissue, which might release choline to blood. Our studies also clearly showed that interaction between choline deficiency and γ-radiation might substantially enhance liver adipogenesis.

  17. Synthesis of Creatine in X-irradiated Rats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Nerurkar, M. K.; Sahasrabudhe, M. B.

    1960-01-01

    BS>Synthesis and excretion of creatine and creatinine in total-body x- irradiated (600 n) rats were investigated. Irradiated rats exhibited a marked creatinuria, whereas creatinine excretion was only slightly increased in comparison to that of non-irradiated control animals. The increased creatine excretion after irradiation was ascribed to accelerated synthesis in the liver and greater release from the muscle. In vitro studies on the synthesis of creatine in liver homogenates revealed that the synthetic activity decreased immediately after irradiation but at later intervals showed a marked rise. The immediate fall in the creatine synthesis was not due to decreased availability of ATPmore » or glutathione. Administration of nicotinamide to animals, to inhibit the new creatine synthesis in the liver. indicated that although the creatine formation in the liver of x-irradiated rats was elevated. it could not account for more than a small fraction of the creatinuria observed. Most of the urinary creatine originated from the muscle, probably because of the impaired reconversion of creatine to phosphocreatine. Since the muscle ATP-creatine transphosphorylase activity was not affected by irradiation, it is suggested that the mobilization of muscle creatine to cause creatinuria is probably due to the diminution of glycolysis in the muscle of irradiated animals.« less

  18. Protective effects of some creatine derivatives in brain tissue anoxia.

    PubMed

    Perasso, Luisa; Lunardi, Gian Luigi; Risso, Federica; Pohvozcheva, Anna V; Leko, Maria V; Gandolfo, Carlo; Florio, Tullio; Cupello, Aroldo; Burov, Sergey V; Balestrino, Maurizio

    2008-05-01

    Some derivatives more lipophylic than creatine, thus theoretically being capable to better cross the blood-brain barrier, were studied for their protective effect in mouse hippocampal slices. We found that N-amidino-piperidine is harmful to brain tissue, and that phosphocreatine is ineffective. Creatine, creatine-Mg-complex (acetate) and phosphocreatine-Mg-complex (acetate) increased the latency to population spike disappearance during anoxia. Creatine and creatine-Mg-complex (acetate) also increased the latency of anoxic depolarization, while the delay induced by phosphocreatine-Mg-complex (acetate) was of borderline significance (P = 0.056). Phosphocreatine-Mg-complex (acetate) significantly reduced neuronal hyperexcitability during anoxia, an effect that no other compound (including creatine itself) showed. For all parameters except reduced hyperexcitability the effects statistically correlated with tissue levels of creatine or phosphocreatine. Summing up, exogenous phosphocreatine and N-amidino piperidine are not useful for brain protection, while chelates of both creatine and phosphocreatine do replicate some of the known protective effects of creatine. In addition, phosphocreatine-Mg-complex (acetate) also reduced neuronal hyperexcitability during anoxia.

  19. Changes in Brain Metabolite Concentrations after Neonatal Hypoxic-ischemic Encephalopathy.

    PubMed

    Shibasaki, Jun; Aida, Noriko; Morisaki, Naho; Tomiyasu, Moyoko; Nishi, Yuri; Toyoshima, Katsuaki

    2018-06-12

    Purpose To investigate the time-course changes and predictive utility of brain metabolite concentrations in neonatal hypoxic-ischemic encephalopathy (HIE). Materials and Methods Sixty-eight neonates (age, 35-41 gestational weeks) with HIE were admitted to a neonatal intensive care unit between September 2009 and March 2016 and examined by using proton MR spectroscopy at 18-96 hours (n = 25) and 7-14 days (n = 64) after birth (35-43 postmenstrual weeks) to estimate metabolite concentrations in the deep gray matter. Adverse outcome was defined as death or neurodevelopmental impairment at 18-22 months of age. Areas under the receiver operating characteristic curves were calculated to evaluate the prognostic values of metabolites. Results At 18-96 hours, N-acetylaspartate and creatine concentrations were lower, whereas lactate, and glutamate and glutamine (Glx) concentrations were higher in neonates with adverse outcomes than in those with favorable outcomes. Metabolite concentrations at 18-96 hours decreased during days 7-14 in neonates with adverse outcomes but did not change in those with favorable outcomes. For N-acetylaspartate, creatine, lactate, and Glx concentrations measured at 18-96 hours to predict adverse outcomes, areas under the receiver operating characteristic curve were 0.98, 0.89, 0.96, and 0.88, respectively, whereas at 7-14 days, the areas under the receiver operating characteristic curve were 0.97, 0.97, 0.59, and 0.36, respectively. Conclusion Time-dependent reductions in N-acetylaspartate and creatine concentrations at both 18-96 hours and 7-14 days accurately predicted adverse outcomes. However, higher lactate and glutamate and glutamine concentrations were often transient. © RSNA, 2018 Online supplemental material is available for this article.

  20. Can creatine supplementation form carcinogenic heterocyclic amines in humans?

    PubMed Central

    Pereira, Renato Tavares dos Santos; Dörr, Felipe Augusto; Pinto, Ernani; Solis, Marina Yazigi; Artioli, Guilherme Giannini; Fernandes, Alan Lins; Murai, Igor Hisashi; Dantas, Wagner Silva; Seguro, Antônio Carlos; Santinho, Mirela Aparecida Rodrigues; Roschel, Hamilton; Carpentier, Alain; Poortmans, Jacques Remi; Gualano, Bruno

    2015-01-01

    Abstract Creatine supplementation has been associated with increased cancer risk. In fact, there is evidence indicating that creatine and/or creatinine are important precursors of carcinogenic heterocyclic amines (HCAs). The present study aimed to investigate the acute and chronic effects of low- and high-dose creatine supplementation on the production of HCAs in healthy humans (i.e. 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx),  2-amino-(1,6-dimethylfuro[3,2-e]imidazo[4,5-b])pyridine (IFP) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx)). This was a non-counterbalanced single-blind crossover study divided into two phases, in which low- and high-dose creatine protocols were tested. After acute (1 day) and chronic supplementation (30 days), the HCAs PhIP, 8-MeIQx, IFP and 4,8-DiMeIQx were assessed through a newly developed HPLC–MS/MS method. Dietary HCA intake and blood and urinary creatinine were also evaluated. Out of 576 assessments performed (from 149 urine samples), only nine (3 from creatine and 6 from placebo) showed quantifiable levels of HCAs (8-MeIQx: n = 3; 4,8-DiMeIQx: n = 2; PhIP: n = 4). Individual analyses revealed that diet rather than creatine supplementation was the main responsible factor for HCA formation in these cases. This study provides compelling evidence that both low and high doses of creatine supplementation, given either acutely or chronically, did not cause increases in the carcinogenic HCAs PhIP, 8-MeIQx, IFP and 4,8-DiMeIQx in healthy subjects. These findings challenge the long-existing notion that creatine supplementation could potentially increase the risk of cancer by stimulating the formation of these mutagens. Key points There is a long-standing concern that creatine supplementation could be associated with cancer, possibly by facilitating the formation of carcinogenic heterocyclic amines (HCAs). This study provides compelling evidence

  1. Can creatine supplementation form carcinogenic heterocyclic amines in humans?

    PubMed

    Pereira, Renato Tavares dos Santos; Dörr, Felipe Augusto; Pinto, Ernani; Solis, Marina Yazigi; Artioli, Guilherme Giannini; Fernandes, Alan Lins; Murai, Igor Hisashi; Dantas, Wagner Silva; Seguro, Antônio Carlos; Santinho, Mirela Aparecida Rodrigues; Roschel, Hamilton; Carpentier, Alain; Poortmans, Jacques Remi; Gualano, Bruno

    2015-09-01

    There is a long-standing concern that creatine supplementation could be associated with cancer, possibly by facilitating the formation of carcinogenic heterocyclic amines (HCAs). This study provides compelling evidence that both low and high doses of creatine supplementation, given either acutely or chronically, does not cause a significant increase in HCA formation. HCAs detection was unrelated to creatine supplementation. Diet was likely to be the main factor responsible for HCAs formation after either placebo (n = 6) or creatine supplementation (n = 3). These results directly challenge the recently suggested biological plausibility for the association between creatine use and risk of testicular germ cell cancer. Creatine supplementation has been associated with increased cancer risk. In fact, there is evidence indicating that creatine and/or creatinine are important precursors of carcinogenic heterocyclic amines (HCAs). The present study aimed to investigate the acute and chronic effects of low- and high-dose creatine supplementation on the production of HCAs in healthy humans (i.e. 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (8-MeIQx), 2-amino-(1,6-dimethylfuro[3,2-e]imidazo[4,5-b])pyridine (IFP) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx)). This was a non-counterbalanced single-blind crossover study divided into two phases, in which low- and high-dose creatine protocols were tested. After acute (1 day) and chronic supplementation (30 days), the HCAs PhIP, 8-MeIQx, IFP and 4,8-DiMeIQx were assessed through a newly developed HPLC-MS/MS method. Dietary HCA intake and blood and urinary creatinine were also evaluated. Out of 576 assessments performed (from 149 urine samples), only nine (3 from creatine and 6 from placebo) showed quantifiable levels of HCAs (8-MeIQx: n = 3; 4,8-DiMeIQx: n = 2; PhIP: n = 4). Individual analyses revealed that diet rather than creatine supplementation was

  2. Label-free colorimetric sensor for sensitive detection of choline based on DNAzyme-choline oxidase coupling.

    PubMed

    Nikzad, Nasrin; Karami, Zahra

    2018-04-14

    Changes in choline levels can be associated with diseases such as Alzheimer, Parkinson, Huntington, fatty liver, interstitial lung abnormalities, autism and so on. Therefore, quantitative determination of choline is important in the biological and clinical analysis. So far, several methods have been investigated for measuring choline in the body fluids, each of which has disadvantages such as the need for specialist ability, complexity, and high cost. For this purpose, a facile and sensitive colorimetric biosensor based on DNAzyme-choline oxidase coupling used for the determination of choline. In this method, the first, choline oxidase produces H 2 O 2 and betaine in the presence of choline and oxygen, then, the DNAzyme converts colorless ABTS into green ABTS + radicals. Compared to the previous methods, the linear range and the limit of detection of this talented biosensor were 0.1-25 μM and 22 nM. Choline measurement using this biosensor has shown satisfactory selectivity and repeatability. Its recovery was 96.9-103.7%, which shows the reliability of biosensor assay in biological samples. Simplicity, low cost, naked eye, high sensitivity, and precision are the benefits of this biosensor. Taken to gather, the proposed system can be considered as a great biosensor for measuring choline levels especially in point of care diagnostic. Copyright © 2018 Elsevier B.V. All rights reserved.

  3. 21 CFR 862.1215 - Creatine phosphokinase/creatine kinase or isoenzymes test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Creatine phosphokinase/creatine kinase or... Clinical Chemistry Test Systems § 862.1215 Creatine phosphokinase/creatine kinase or isoenzymes test system. (a) Identification. A creatine phosphokinase/creatine kinase or isoenzymes test system is a device...

  4. Living Without Creatine: Unchanged Exercise Capacity and Response to Chronic Myocardial Infarction in Creatine-Deficient Mice

    PubMed Central

    Lygate, Craig A.; Aksentijevic, Dunja; Dawson, Dana; Hove, Michiel ten; Phillips, Darci; de Bono, Joseph P.; Medway, Debra J.; Sebag-Montefiore, Liam; Hunyor, Imre; Channon, Keith M.; Clarke, Kieran; Zervou, Sevasti; Watkins, Hugh; Balaban, Robert S.; Neubauer, Stefan

    2014-01-01

    Rationale Creatine is thought to be involved in the spatial and temporal buffering of ATP in energetic organs such as heart and skeletal muscle. Creatine depletion affects force generation during maximal stimulation, while reduced levels of myocardial creatine are a hallmark of the failing heart, leading to the widely held view that creatine is important at high workloads and under conditions of pathological stress. Objective We therefore hypothesised that the consequences of creatine-deficiency in mice would be impaired running capacity, and exacerbation of heart failure following myocardial infarction. Methods and Results Surprisingly, mice with whole-body creatine deficiency due to knockout of the biosynthetic enzyme (guanidinoacetate N-methyltransferase – GAMT) voluntarily ran just as fast and as far as controls (>10km/night) and performed the same level of work when tested to exhaustion on a treadmill. Furthermore, survival following myocardial infarction was not altered, nor was subsequent LV remodelling and development of chronic heart failure exacerbated, as measured by 3D-echocardiography and invasive hemodynamics. These findings could not be accounted for by compensatory adaptations, with no differences detected between WT and GAMT−/− proteomes. Alternative phosphotransfer mechanisms were explored; adenylate kinase activity was unaltered, and although GAMT−/− hearts accumulated the creatine pre-cursor guanidinoacetate, this had negligible energy-transfer activity, while mitochondria retained near normal function. Conclusions Creatine-deficient mice show unaltered maximal exercise capacity and response to chronic myocardial infarction, and no obvious metabolic adaptations. Our results question the paradigm that creatine is essential for high workload and chronic stress responses in heart and skeletal muscle. PMID:23325497

  5. Intestinal microbiota composition modulates choline bioavailability from diet and accumulation of the proatherogenic metabolite trimethylamine-N-oxide.

    PubMed

    Romano, Kymberleigh A; Vivas, Eugenio I; Amador-Noguez, Daniel; Rey, Federico E

    2015-03-17

    Choline is a water-soluble nutrient essential for human life. Gut microbial metabolism of choline results in the production of trimethylamine (TMA), which upon absorption by the host is converted in the liver to trimethylamine-N-oxide (TMAO). Recent studies revealed that TMAO exacerbates atherosclerosis in mice and positively correlates with the severity of this disease in humans. However, which microbes contribute to TMA production in the human gut, the extent to which host factors (e.g., genotype) and diet affect TMA production and colonization of these microbes, and the effects TMA-producing microbes have on the bioavailability of dietary choline remain largely unknown. We screened a collection of 79 sequenced human intestinal isolates encompassing the major phyla found in the human gut and identified nine strains capable of producing TMA from choline in vitro. Gnotobiotic mouse studies showed that TMAO accumulates in the serum of animals colonized with TMA-producing species, but not in the serum of animals colonized with intestinal isolates that do not generate TMA from choline in vitro. Remarkably, low levels of colonization by TMA-producing bacteria significantly reduced choline levels available to the host. This effect was more pronounced as the abundance of TMA-producing bacteria increased. Our findings provide a framework for designing strategies aimed at changing the representation or activity of TMA-producing bacteria in the human gut and suggest that the TMA-producing status of the gut microbiota should be considered when making recommendations about choline intake requirements for humans. Cardiovascular disease (CVD) is the leading cause of death and disability worldwide, and increased trimethylamine N-oxide (TMAO) levels have been causally linked with CVD development. This work identifies members of the human gut microbiota responsible for both the accumulation of trimethylamine (TMA), the precursor of the proatherogenic compound TMAO, and subsequent

  6. Creatine

    MedlinePlus

    ... inherited disorders that affect the senses and movement, schizophrenia, muscle breakdown in the spine, and recovery from ... the effects of creatine alone are not clear. Schizophrenia. Early research shows that taking creatine by mouth ...

  7. MDMA administration decreases serotonin but not N-acetylaspartate in the rat brain

    PubMed Central

    Perrine, Shane A.; Ghoddoussi, Farhad; Michaels, Mark S.; Hyde, Elisabeth M.; Kuhn, Donald M.; Galloway, Matthew P.

    2010-01-01

    In animals, repeated administration of 3,4-methylenedioxymethamphetamine (MDMA) reduces markers of serotonergic activity and studies show similar serotonergic deficits in human MDMA users. Using proton magnetic resonance spectroscopy (1H-MRS) at 11.7 Tesla, we measured the metabolic neurochemical profile in intact, discrete tissue punches taken from prefrontal cortex, anterior striatum, and hippocampus of rats administered MDMA (5 mg/kg IP, 4× q 2 h) or saline and euthanized 7 days after the last injection. Monoamine content was measured with HPLC in contralateral punches from striatum and hippocampus to compare the MDMA-induced loss of 5HT innervation with constituents in the 1H-MRS profile. When assessed 7 days after the last MDMA injection, levels of hippocampal and striatal serotonin (5HT) were significantly reduced, consistent with published animal studies. N-acetylaspartate (NAA) levels were significantly increased in prefrontal cortex and not affected in anterior striatum or hippocampus; myo-inositol (INS) levels were increased in prefrontal cortex and hippocampus but not anterior striatum. Glutamate levels were increased in prefrontal cortex and decreased in hippocampus, while GABA levels were decreased only in hippocampus. The data suggest that NAA may not reliably reflect MDMA-induced 5HT neurotoxicity. However, the collective pattern of changes in 5HT, INS, glutamate and GABA is consistent with persistent hippocampal neuroadaptations caused by MDMA. PMID:20800616

  8. MDMA administration decreases serotonin but not N-acetylaspartate in the rat brain.

    PubMed

    Perrine, Shane A; Ghoddoussi, Farhad; Michaels, Mark S; Hyde, Elisabeth M; Kuhn, Donald M; Galloway, Matthew P

    2010-12-01

    In animals, repeated administration of 3,4-methylenedioxymethamphetamine (MDMA) reduces markers of serotonergic activity and studies show similar serotonergic deficits in human MDMA users. Using proton-magnetic resonance spectroscopy ((1)H-MRS) at 11.7Tesla, we measured the metabolic neurochemical profile in intact, discrete tissue punches taken from prefrontal cortex, anterior striatum, and hippocampus of rats administered MDMA (5mg/kg IP, 4× q 2h) or saline and euthanized 7 days after the last injection. Monoamine content was measured with HPLC in contralateral punches from striatum and hippocampus to compare the MDMA-induced loss of 5HT innervation with constituents in the (1)H-MRS profile. When assessed 7 days after the last MDMA injection, levels of hippocampal and striatal serotonin (5HT) were significantly reduced, consistent with published animal studies. N-Acetylaspartate (NAA) levels were significantly increased in prefrontal cortex and not affected in anterior striatum or hippocampus; myo-inositol (INS) levels were increased in prefrontal cortex and hippocampus but not anterior striatum. Glutamate levels were increased in prefrontal cortex and decreased in hippocampus, while GABA levels were decreased only in hippocampus. The data suggest that NAA may not reliably reflect MDMA-induced 5HT neurotoxicity. However, the collective pattern of changes in 5HT, INS, glutamate and GABA is consistent with persistent hippocampal neuroadaptations caused by MDMA. Copyright © 2010 Elsevier Inc. All rights reserved.

  9. A brief history of choline

    PubMed Central

    Zeisel, Steven H.

    2015-01-01

    In 1850, Theodore Gobley, working in Paris, described a substance “lecithine”, which he named after the Greek “lekithos” for egg yolk. Adolph Strecker noted in 1862 that when lecithin from bile was heated, it generated a new nitrogenous chemical that he named “choline”. Three years later, Oscar Liebreich identified a new substance, “neurine”, in the brain. After a period of confusion, neurine and choline were found to be the same molecule, and the name choline was adapted. Lecithin was eventually characterized chemically as being phosphatidylcholine. In 1954, Eugene Kennedy described the cytidine 5-dihphosphocholine pathway by which choline is incorporated into phosphatidylcholine. A second route, the phosphatidylethanolamine-N-methyltransferase pathway, was identified by Jon Bremer and David Greenberg in 1960. The role of choline as part of the neurotransmitter acetylcholine was established by Otto Loewi and Henry Dale. Working in the 1930s at the University of Toronto, Charles Best showed that choline prevented fatty liver in dogs and rats. The importance of choline as an essential nutrient for human health was determined in the 1990s through controlled feeding studies in humans. Recently, an understanding of the role of genetic variation in setting the dietary requirement for choline in people is being unraveled. PMID:23183298

  10. Dietary choline and betaine intakes vary in an adult multiethnic population.

    PubMed

    Yonemori, Kim M; Lim, Unhee; Koga, Karin R; Wilkens, Lynne R; Au, Donna; Boushey, Carol J; Le Marchand, Loïc; Kolonel, Laurence N; Murphy, Suzanne P

    2013-06-01

    Choline and betaine are important nutrients for human health, but reference food composition databases for these nutrients became available only recently. We tested the feasibility of using these databases to estimate dietary choline and betaine intakes among ethnically diverse adults who participated in the Multiethnic Cohort (MEC) Study. Of the food items (n = 965) used to quantify intakes for the MEC FFQ, 189 items were exactly matched with items in the USDA Database for the Choline Content of Common Foods for total choline, choline-containing compounds, and betaine, and 547 items were matched to the USDA National Nutrient Database for Standard Reference for total choline (n = 547) and 148 for betaine. When a match was not found, choline and betaine values were imputed based on the same food with a different form (124 food items for choline, 300 for choline compounds, 236 for betaine), a similar food (n = 98, 284, and 227, respectively) or the closest item in the same food category (n = 6, 191, and 157, respectively), or the values were assumed to be zero (n = 1, 1, and 8, respectively). The resulting mean intake estimates for choline and betaine among 188,147 MEC participants (aged 45-75) varied by sex (372 and 154 mg/d in men, 304 and 128 mg/d in women, respectively; P-heterogeneity < 0.0001) and by race/ethnicity among Caucasians, African Americans, Japanese Americans, Latinos, and Native Hawaiians (P-heterogeneity < 0.0001), largely due to the variation in energy intake. Our findings demonstrate the feasibility of assessing choline and betaine intake and characterize the variation in intake that exists in a multiethnic population.

  11. Choline Metabolites: Gene by Diet Interactions

    PubMed Central

    Smallwood, Tangi; Allayee, Hooman; Bennett, Brian J.

    2015-01-01

    Purpose of review This review highlights recent advances in our understanding of the interactions between genetic polymorphisms in genes that metabolize choline and the dietary requirements of choline and how these interactions relate to human health and disease. Recent findings The importance of choline as an essential nutrient has been well established but our appreciation of the interaction between our underlying genetic architecture and dietary choline requirements is only beginning. It has been shown in both human and animal studies that choline deficiencies contribute to diseases such as non-alcoholic fatty liver disease and various neurodegenerative diseases. An adequate supply of dietary choline is important for optimum development, highlighted by the increased maternal requirements during fetal development and in breast-fed infants. We discuss recent studies investigating variants in PEMT and MTHFR1 that are associated with a variety of birth defects. In addition to genetic interactions, we discuss several recent studies that uncover changes in fetal global methylation patterns in response to maternal dietary choline intake that result in changes in gene expression in the offspring. In contrast to the developmental role of adequate choline, there is now an appreciation of the role choline has in cardiovascular disease through the gut microbiota-mediated metabolite trimethylamine N-oxide. This pathway highlights some of our understanding of how the microbiome affects nutrient processing and bioavailability. Finally, in order to better characterize the genetic architecture regulating choline requirements, we discuss recent results focused on identifying polymorphisms that regulate choline and its derivative products. Summary Here we discuss recent studies that have advanced our understanding of how specific alleles in key choline metabolism genes are related to dietary choline requirements and human disease. PMID:26655287

  12. Creatine for women: a review of the relationship between creatine and the reproductive cycle and female-specific benefits of creatine therapy.

    PubMed

    Ellery, Stacey J; Walker, David W; Dickinson, Hayley

    2016-08-01

    The creatine/phosphocreatine/creatine kinase circuit is instrumental in regulating high-energy phosphate metabolism, and the maintenance of cellular energy turnover. The mechanisms by which creatine is able to buffer and regulate cellular energy balance, maintain acid-base balance, and reduce the effects of oxidative stress have led to a large number of studies into the use of creatine supplementation in exercise performance and to treat diseases associated with cellular energy depletion. Some of these studies have identified sex-specific responses to creatine supplementation, as such; there is the perception, that females might be less receptive to the benefits of creatine supplementation and therapy, compared to males. This review will describe the differences in male and female physique and physiology that may account for such differences, and discuss the apparent endocrine modulation of creatine metabolism in females. Hormone-driven changes to endogenous creatine synthesis, creatine transport and creatine kinase expression suggest that significant changes in this cellular energy circuit occur during specific stages of a female's reproductive life, including pregnancy and menopause. Recent studies suggest that creatine supplementation may be highly beneficial for women under certain conditions, such as depression. A greater understanding of these pathways, and the consequences of alterations to creatine bioavailability in females are needed to ensure that creatine is used to full advantage as a dietary supplement to optimize and enhance health outcomes for women.

  13. Creatine metabolism: detection of creatine and guanidinoacetate in saliva of healthy subjects.

    PubMed

    Martínez, Lidia D; Bezard, Miriam; Brunotto, Mabel; Dodelson de Kremer, Raquel

    2016-04-01

    Creatine (Cr) plays an important role in storage and transmission of phosphate-bound energy. Cerebral creatine deficiency syndromes comprise three inherited defects in Cr biosynthesis and transport. The aim of this study was to investigate whether Cr and Guanidinoacetate (GAA) can be detected in saliva of healthy subjects and to establish the relationship between salivary and plasma levels of these molecules. An adapted gas chromatography (GC) method is described for the quantification of Cr and GAA biomarkers in saliva. Reference values were established for GAA and Cr in saliva. These values were age dependent (p= 0.001). No difference between genders was observed. We detected a difference between GAA and Cr concentrations in saliva and in plasma. The GC method for simultaneous determination of GAA and Cr in human saliva is fast, reliable, sensitive, non-invasive and precise to use as a biochemical approach in early detection of cerebral creatine deficiency syndromes. Sociedad Argentina de Investigación Odontológica.

  14. Creatine Use in Sports.

    PubMed

    Butts, Jessica; Jacobs, Bret; Silvis, Matthew

    The use of creatine as a dietary supplement has become increasingly popular over the past several decades. Despite the popularity of creatine, questions remain with regard to dosing, effects on sports performance, and safety. PubMed was searched for articles published between 1980 and January 2017 using the terms creatine, creatine supplementation, sports performance, and dietary supplements. An additional Google search was performed to capture National Collegiate Athletic Association-specific creatine usage data and US dietary supplement and creatine sales. Clinical review. Level 4. Short-term use of creatine is considered safe and without significant adverse effects, although caution should be advised as the number of long-term studies is limited. Suggested dosing is variable, with many different regimens showing benefits. The safety of creatine supplementation has not been studied in children and adolescents. Currently, the scientific literature best supports creatine supplementation for increased performance in short-duration, maximal-intensity resistance training. While creatine appears to be safe and effective for particular settings, whether creatine supplementation leads to improved performance on the field of play remains unknown.

  15. Effect of choline supplementation on fatigue in trained cyclists.

    PubMed

    Spector, S A; Jackman, M R; Sabounjian, L A; Sakkas, C; Landers, D M; Willis, W T

    1995-05-01

    The availability of choline, the precurser of the neurotransmitter, acetylcholine, in the diet is sufficient to provide the body's requirements under normal conditions. However, preliminary evidence indicates that depletion of choline may limit performance, while oral supplementation may delay fatigue during prolonged efforts. A double-blind cross-over design was used to determine the relationship between plasma choline and fatigue during supramaximal brief and submaximal prolonged activities. Twenty male cyclists (ages 23-29) with maximal aerobic power (VO2max) between 58 and 81 ml.min-1.kg-1 were randomly divided into BRIEF (N = 10) and PROLONGED (N = 10) groups. One hour after drinking a beverage with or without choline bitartrate (2.43 g), cyclists began riding at a power output equivalent to approximately 150% (BRIEF) and 70% (PROLONGED) of VO2max at a cadence of 80-90 rpm. Time to exhaustion, indirect calorimetry and serum choline, lactate, and glucose were measured. Increases in choline levels of 37 and 52% were seen within one hour of ingestion for BRIEF and PROLONGED groups, respectively. Neither group depleted choline during exercise under the choline or placebo conditions. Fatigue times and work performed under either test condition for the BRIEF or PROLONGED groups were similar. Consequently, trained cyclists do not deplete choline during supramaximal brief or prolonged submaximal exercise, nor do they benefit from choline supplementation to delay fatigue under these conditions.

  16. Impaired de novo choline synthesis explains why phosphatidylethanolamine N-methyltransferase-deficient mice are protected from diet-induced obesity.

    PubMed

    Jacobs, René L; Zhao, Yang; Koonen, Debby P Y; Sletten, Torunn; Su, Brian; Lingrell, Susanne; Cao, Guoqing; Peake, David A; Kuo, Ming-Shang; Proctor, Spencer D; Kennedy, Brian P; Dyck, Jason R B; Vance, Dennis E

    2010-07-16

    Phosphatidylcholine (PC) is synthesized from choline via the CDP-choline pathway. Liver cells can also synthesize PC via the sequential methylation of phosphatidylethanolamine, catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT). The current study investigates whether or not hepatic PC biosynthesis is linked to diet-induced obesity. Pemt(+/+) mice fed a high fat diet for 10 weeks increased in body mass by 60% and displayed insulin resistance, whereas Pemt(-/-) mice did not. Compared with Pemt(+/+) mice, Pemt(-/-) mice had increased energy expenditure and maintained normal peripheral insulin sensitivity; however, they developed hepatomegaly and steatosis. In contrast, mice with impaired biosynthesis of PC via the CDP-choline pathway in liver became obese when fed a high fat diet. We, therefore, hypothesized that insufficient choline, rather than decreased hepatic phosphatidylcholine, was responsible for the lack of weight gain in Pemt(-/-) mice despite the presence of 1.3 g of choline/kg high fat diet. Supplementation with an additional 2.7 g of choline (but not betaine)/kg of diet normalized energy metabolism, weight gain, and insulin resistance in high fat diet-fed Pemt(-/-) mice. Furthermore, Pemt(+/+) mice that were fed a choline-deficient diet had increased oxygen consumption, had improved glucose tolerance, and gained less weight. Thus, de novo synthesis of choline via PEMT has a previously unappreciated role in regulating whole body energy metabolism.

  17. Characterization of Metabolic, Diffusion, and Perfusion Properties in GBM: Contrast-Enhancing versus Non-Enhancing Tumor.

    PubMed

    Autry, Adam; Phillips, Joanna J; Maleschlijski, Stojan; Roy, Ritu; Molinaro, Annette M; Chang, Susan M; Cha, Soonmee; Lupo, Janine M; Nelson, Sarah J

    2017-12-01

    Although the contrast-enhancing (CE) lesion on T 1 -weighted MR images is widely used as a surrogate for glioblastoma (GBM), there are also non-enhancing regions of infiltrative tumor within the T 2 -weighted lesion, which elude radiologic detection. Because non-enhancing GBM (Enh-) challenges clinical patient management as latent disease, this study sought to characterize ex vivo metabolic profiles from Enh- and CE GBM (Enh+) samples, alongside histological and in vivo MR parameters, to assist in defining criteria for estimating total tumor burden. Fifty-six patients with newly diagnosed GBM received a multi-parametric pre-surgical MR examination. Targets for obtaining image-guided tissue samples were defined based on in vivo parameters that were suspicious for tumor. The actual location from where tissue samples were obtained was recorded, and half of each sample was analyzed for histopathology while the other half was scanned using HR-MAS spectroscopy. The Enh+ and Enh- tumor samples demonstrated comparable mitotic activity, but also significant heterogeneity in microvascular morphology. Ex vivo spectroscopic parameters indicated similar levels of total choline and N-acetylaspartate between these contrast-based radiographic subtypes of GBM, and characteristic differences in the levels of myo-inositol, creatine/phosphocreatine, and phosphoethanolamine. Analysis of in vivo parameters at the sample locations were consistent with histological and ex vivo metabolic data. The similarity between ex vivo levels of choline and NAA, and between in vivo levels of choline, NAA and nADC in Enh+ and Enh- tumor, indicate that these parameters can be used in defining non-invasive metrics of total tumor burden for patients with GBM. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Choline Supplementation Promotes Hepatic Insulin Resistance in Phosphatidylethanolamine N-Methyltransferase-deficient Mice via Increased Glucagon Action*

    PubMed Central

    Wu, Gengshu; Zhang, Liyan; Li, Tete; Zuniga, Azeret; Lopaschuk, Gary D.; Li, Liang; Jacobs, René L.; Vance, Dennis E.

    2013-01-01

    Biosynthesis of hepatic choline via phosphatidylethanolamine N-methyltransferase (PEMT) plays an important role in the development of type 2 diabetes and obesity. We investigated the mechanism(s) by which choline modulates insulin sensitivity. PEMT wild-type (Pemt+/+) and knock-out (Pemt−/−) mice received either a high fat diet (HF; 60% kcal of fat) or a high fat, high choline diet (HFHC; 4 g of choline/kg of HF diet) for 1 week. Hepatic insulin signaling and glucose and lipid homeostasis were investigated. Glucose and insulin intolerance occurred in Pemt−/− mice fed the HFHC diet, but not in their Pemt−/− littermates fed the HF diet. Plasma glucagon was elevated in Pemt−/− mice fed the HFHC diet compared with Pemt−/− mice fed the HF diet, concomitant with increased hepatic expression of glucagon receptor, phosphorylated AMP-activated protein kinase (AMPK), and phosphorylated insulin receptor substrate 1 at serine 307 (IRS1-s307). Gluconeogenesis and mitochondrial oxidative stress were markedly enhanced, whereas glucose oxidation and triacylglycerol biosynthesis were diminished in Pemt−/− mice fed the HFHC diet. A glucagon receptor antagonist (2-aminobenzimidazole) attenuated choline-induced hyperglycemia and insulin intolerance and blunted up-regulation of phosphorylated AMPK and IRS1-s307. Choline induces glucose and insulin intolerance in Pemt−/− mice through modulating plasma glucagon and its action in liver. PMID:23179947

  19. Single voxel proton magnetic resonance spectroscopy in women with and without intimate partner violence-related posttraumatic stress disorder.

    PubMed

    Seedat, Soraya; Videen, John S; Kennedy, Colleen M; Stein, Murray B

    2005-08-30

    Preliminary in vivo proton magnetic spectroscopic ((1)H-MRS) studies of N-acetylaspartate (a putative marker of neuronal viability and function) in combat veterans and maltreated children with posttraumatic stress disorder (PTSD) suggest altered neuronal integrity in anterior cingulate and medial temporal lobe structures. In this study, (1)H-MRS was used to measure N-acetylaspartate (NAA), choline (Cho) and myo-inositol (mI) relative to creatine (Cr) in the anterior cingulate of 16 women with histories of intimate partner violence (7 with a DSM-IV diagnosis of PTSD, 9 without PTSD) and 11 healthy, non-abused comparison subjects. The relationship between anterior cingulate chemistry and performance on the Stroop Color-Word task and Part B of the Trail Making Test was also examined. There were no significant differences in anterior cingulate or occipital gray matter metabolite ratios of NAA/Cr and Cho/Cr between intimate partner violence and healthy comparison subjects. Intimate partner violence subjects with PTSD had significantly higher anterior cingulate Cho/Cr than intimate partner violence subjects without PTSD. There was evidence that the subjects with PTSD suffered more severe intimate partner violence as measured by the Conflict Tactics Scale-Revised. Metabolite ratios were not significantly correlated with performance on the Stroop or Trails B. Our findings, in agreement with earlier studies, showed significant alterations in anterior cingulate chemistry in women with PTSD. In contrast to other studies, we found an increase in Cho/Cr rather than a decrease in NAA/Cr, indicating alterations in glia, instead of neuronal dropout.

  20. Whole-blood-free choline and choline metabolites in infants who require chronic parenteral nutrition therapy.

    PubMed

    Sentongo, Timothy A; Kumar, Praveen; Karza, Kristen; Keys, Lisa; Iyer, Kishore; Buchman, Alan L

    2010-02-01

    Choline deficiency is associated with hepatic dysfunction. Parenteral nutrition (PN) and lipid emulsions contain phosphatidylcholine (PtdCho) but insignificant free choline (FCho). PtdCho is sequentially degraded to glycerolphosphocholine (GPCho), phosphocholine (PCho), and finally to FCho. Biosynthesis of FCho may be insufficient during PN therapy. The aim of the study was to examine the status of FCho and related metabolites in infants on prolonged (> or =4 weeks) PN. Whole blood concentrations of FCho, PtdCho, GPCho, and PCho were measured and compared in infants on PN and infants on enteral feeds (controls). Infants on PN (n = 14) had higher birth weight but same postnatal age as controls (n = 14) (mean +/- standard deviation) 8.3 +/- 3.9 versus 7.4 +/- 3.6 weeks. Parenteral nutrition was associated with increased PtdCho 1761 +/- 452 versus 1471 +/- 221 nmol/mL, P = 0.04. Mean whole blood FCho, GPCho, and PCho concentrations did not differ significantly in PN versus controls: 40.0 +/- 15.4 versus 50.8 +/- 49.7, 16.4 +/- 14.5 versus 25.2 +/- 29.3, and 15.3 +/- 13.5 versus 22.0 +/- 14.8 nmol/mL, respectively. However, PCho was positively correlated with GPCho in controls (r = 0.91, P < 0.01) but not PN (r = 0.24, P = NS), and infants receiving >90% of daily energy intake from PN (n = 6) had decreased PCho, 5.7 +/- 4.1 nmol/mL, compared with those receiving <90% of daily energy intake (n = 8) 22.5 +/- 13.7 nmol/mL, P < 0.05, and controls, 22.0 +/- 14.8 nmol/mL, P < 0.01. Decreased whole-blood concentrations of choline suggest possible evidence of choline deficiency as illustrated by decreased whole-blood PCho. Choline supplementation should be investigated in infants who require prolonged PN, and whole-blood PCho can be used to monitor response.

  1. Choline Diet and Its Gut Microbe-Derived Metabolite, Trimethylamine N-Oxide, Exacerbate Pressure Overload-Induced Heart Failure.

    PubMed

    Organ, Chelsea L; Otsuka, Hiroyuki; Bhushan, Shashi; Wang, Zeneng; Bradley, Jessica; Trivedi, Rishi; Polhemus, David J; Tang, W H Wilson; Wu, Yuping; Hazen, Stanley L; Lefer, David J

    2016-01-01

    Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite of dietary choline and other trimethylamine-containing nutrients, is both elevated in the circulation of patients having heart failure and heralds worse overall prognosis. In animal studies, dietary choline or TMAO significantly accelerates atherosclerotic lesion development in ApoE-deficient mice, and reduction in TMAO levels inhibits atherosclerosis development in the low-density lipoprotein receptor knockout mouse. C57BL6/J mice were fed either a control diet, a diet containing choline (1.2%) or a diet containing TMAO (0.12%) starting 3 weeks before surgical transverse aortic constriction. Mice were studied for 12 weeks after transverse aortic constriction. Cardiac function and left ventricular structure were monitored at 3-week intervals using echocardiography. Twelve weeks post transverse aortic constriction, myocardial tissues were collected to evaluate cardiac and vascular fibrosis, and blood samples were evaluated for cardiac brain natriuretic peptide, choline, and TMAO levels. Pulmonary edema, cardiac enlargement, and left ventricular ejection fraction were significantly (P<0.05, each) worse in mice fed either TMAO- or choline-supplemented diets when compared with the control diet. In addition, myocardial fibrosis was also significantly greater (P<0.01, each) in the TMAO and choline groups relative to controls. Heart failure severity is significantly enhanced in mice fed diets supplemented with either choline or the gut microbe-dependent metabolite TMAO. The present results suggest that additional studies are warranted examining whether gut microbiota and the dietary choline → TMAO pathway contribute to increased heart failure susceptibility. © 2015 American Heart Association, Inc.

  2. Choline-mediated modulation of hippocampal sharp wave-ripple complexes in vitro.

    PubMed

    Fischer, Viktoria; Both, Martin; Draguhn, Andreas; Egorov, Alexei V

    2014-06-01

    The cholinergic system is critically involved in the modulation of cognitive functions, including learning and memory. Acetylcholine acts through muscarinic (mAChRs) and nicotinic receptors (nAChRs), which are both abundantly expressed in the hippocampus. Previous evidence indicates that choline, the precursor and degradation product of Acetylcholine, can itself activate nAChRs and thereby affects intrinsic and synaptic neuronal functions. Here, we asked whether the cellular actions of choline directly affect hippocampal network activity. Using mouse hippocampal slices we found that choline efficiently suppresses spontaneously occurring sharp wave-ripple complexes (SPW-R) and can induce gamma oscillations. In addition, choline reduces synaptic transmission between hippocampal subfields CA3 and CA1. Surprisingly, these effects are mediated by activation of both mAChRs and α7-containing nAChRs. Most nicotinic effects became only apparent after local, fast application of choline, indicating rapid desensitization kinetics of nAChRs. Effects were still present following block of choline uptake and are, therefore, likely because of direct actions of choline at the respective receptors. Together, choline turns out to be a potent regulator of patterned network activity within the hippocampus. These actions may be of importance for understanding state transitions in normal and pathologically altered neuronal networks. In this study we asked whether choline, the precursor and degradation product of acetylcholine, directly affects hippocampal network activity. Using mouse hippocampal slices we found that choline efficiently suppresses spontaneously occurring sharp wave-ripple complexes (SPW-R). In addition, choline reduces synaptic transmission between hippocampal subfields. These effects are mediated by direct activation of muscarinic as well as nicotinic cholinergic pathways. Together, choline turns out to be a potent regulator of patterned activity within hippocampal

  3. Arginine-guanidinoacetate-creatine pathway in preterm newborns: creatine biosynthesis in newborns.

    PubMed

    Lage, Sergio; Andrade, Fernando; Prieto, José Angel; Asla, Izaskun; Rodríguez, Amaya; Ruiz, Nerea; Echeverría, Juncal; Luz Couce, María; Sanjurjo, Pablo; Aldámiz-Echevarría, Luis

    2013-01-01

    The phosphocreatine/creatine system is fundamental for the proper development of the embryonic brain. Being born prematurely might alter the creatine biosynthesis pathway, in turn affecting creatine supply to the developing brain. We enrolled 53 preterm and very preterm infants and 55 full-term newborns. The levels of urinary guanidinoacetate, creatine, creatinine and amino acids were measured in the preterm and very preterm groups, 48 h and 9 days after birth and at discharge, and 48 h after birth in the full-term group. Guanidinoacetate concentrations of both preterm and very preterm newborns were significantly higher at discharge than the values for the full-term group at 48 h, while very preterm infants showed urinary creatine values significantly lower than those measured in the full-term group. Our results suggest an impairment of the creatine biosynthesis pathway in preterm and very preterm newborns, which could lead to creatine depletion affecting the neurological outcome in prematurely born infants.

  4. Tumor Volume and Metabolism of Prostate Cancer Determined by Proton Magnetic Resonance Spectroscopic Imaging at 3T Without Endorectal Coil Reveal Potential Clinical Implications in the Context of Radiation Oncology;Prostate cancer; Magnetic resonance spectroscopic imaging; Radiation oncology; Tumor volume; Biomarkers

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Crehange, Gilles, E-mail: gcrehange@cgfl.fr; Parfait, Sebastien; Liegard, Melanie

    2011-07-15

    Purpose: To determine whether a relationship exists between the tumor volume (TV) or relative choline content determined using magnetic resonance spectroscopy imaging (MRSI) at 3T and the clinical prognostic parameters for patients with localized prostate cancer (PCa). Methods and Materials: A total of 72 men (mean age, 67.8 {+-} 6.2 years) were stratified as having low-risk (n = 26), intermediate-risk (n = 24), or high-risk (n = 22) PCa. MRSI was performed at 3T using a phased-array coil. Spectra are expressed as the total choline/citrate, total choline plus creatine/citrate, and total choline plus polyamines plus creatine/citrate ratios. The mean ratiomore » of the most pathologic voxels and the MRSI-based TV were also determined. Results: The mean values of the total choline/citrate, total choline plus creatine/citrate, and total choline plus polyamine plus creatine/citrate ratios were greater for Stage T2b or greater tumors vs. Stage T2a or less tumors: 7.53 {+-} 13.60 vs. 2.31 {+-} 5.65 (p = .018), 8.98 {+-} 14.58 vs. 2.56 {+-} 5.70 (p = .016), and 10.32 {+-} 15.47 vs. 3.55 {+-} 6.16 (p = .014), respectively. The mean MRSI-based TV for Stage T2b or greater and Stage T2a or less tumors was significantly different (2.23 {+-} 2.62 cm{sup 3} vs. 1.26 {+-} 2.06 cm{sup 3}, respectively; p = .030). This TV correlated with increased prostate-specific antigen levels (odds ratio, 1.293; p = .012). Patients with high-risk PCa had a larger TV than did the patients with intermediate-risk PCa. A similar result was found for the intermediate-risk group compared with the low-risk group (odds ratio, 1.225; p = .041). Conclusion: Biomarkers expressing the relative choline content and TV were significant parameters for the localization of PCa and could be helpful for determining the prognosis more accurately.« less

  5. Free creatine available to the creatine phosphate energy shuttle in isolated rat atria

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Savabi, F.

    1988-10-01

    To measure the actual percentage of intracellular free creatine participating in the process of energy transport, the incorporation of (1-{sup 14}C)creatine into the free creatine and phosphocreatine (PCr) pools in spontaneously beating isolated rat atria, under various conditions, was examined. The atria were subjected to three consecutive periods, control, anoxia, and postanoxic recover, in medium containing tracers of (1-{sup 14}C)creatine. The tissue content and specific activity of creatine and PCr were determined at the end of each period. The higher specific activity found for tissue PCr (1.87 times) than creatine, independent of the percentage of total intracellular creatine that wasmore » present as free creatine, provides evidence for the existence of two separate pools of free creatine. Analysis of the data shows that in the normal oxygenated state {approx} 9% of the total intracellular creatine is actually free to participate in the process of energy transport (shuttle pool). About 36% of the total creatine is bound to unknown intracellular components and the rest exists as PCr. The creatine that was taken up and the creatine that was released from the breakdown of PCr have much greater access to the site of phosphorylation than the rest of the intracellular creatine. A sharp increase in the specific activity of residual PCr on prolongation of anoxic time was also observed. This provides evidence for a nonhomogeneous pool of PCr, for the most recently formed (radioactive) PCr appeared to be hydrolyzed last.« less

  6. Dietary Choline and Betaine Intakes Vary in an Adult Multiethnic Population123

    PubMed Central

    Yonemori, Kim M.; Lim, Unhee; Koga, Karin R.; Wilkens, Lynne R.; Au, Donna; Boushey, Carol J.; Le Marchand, Loïc; Kolonel, Laurence N.; Murphy, Suzanne P.

    2013-01-01

    Choline and betaine are important nutrients for human health, but reference food composition databases for these nutrients became available only recently. We tested the feasibility of using these databases to estimate dietary choline and betaine intakes among ethnically diverse adults who participated in the Multiethnic Cohort (MEC) Study. Of the food items (n = 965) used to quantify intakes for the MEC FFQ, 189 items were exactly matched with items in the USDA Database for the Choline Content of Common Foods for total choline, choline-containing compounds, and betaine, and 547 items were matched to the USDA National Nutrient Database for Standard Reference for total choline (n = 547) and 148 for betaine. When a match was not found, choline and betaine values were imputed based on the same food with a different form (124 food items for choline, 300 for choline compounds, 236 for betaine), a similar food (n = 98, 284, and 227, respectively) or the closest item in the same food category (n = 6, 191, and 157, respectively), or the values were assumed to be zero (n = 1, 1, and 8, respectively). The resulting mean intake estimates for choline and betaine among 188,147 MEC participants (aged 45–75) varied by sex (372 and 154 mg/d in men, 304 and 128 mg/d in women, respectively; P-heterogeneity < 0.0001) and by race/ethnicity among Caucasians, African Americans, Japanese Americans, Latinos, and Native Hawaiians (P-heterogeneity < 0.0001), largely due to the variation in energy intake. Our findings demonstrate the feasibility of assessing choline and betaine intake and characterize the variation in intake that exists in a multiethnic population. PMID:23616508

  7. Comparison among conventional and advanced MRI, 18F-FDG PET/CT, phenotype and genotype in glioblastoma.

    PubMed

    Valentini, Maria Consuelo; Mellai, Marta; Annovazzi, Laura; Melcarne, Antonio; Denysenko, Tetyana; Cassoni, Paola; Casalone, Cristina; Maurella, Cristiana; Grifoni, Silvia; Fania, Piercarlo; Cistaro, Angelina; Schiffer, Davide

    2017-10-31

    Glioblastoma (GB) is a highly heterogeneous tumor. In order to identify in vivo the most malignant tumor areas, the extent of tumor infiltration and the sites giving origin to GB stem cells (GSCs), we combined positron emission tomography/computed tomography (PET/CT) and conventional and advanced magnetic resonance imaging (MRI) with histology, immunohistochemistry and molecular genetics. Prior to dura opening and tumor resection, forty-eight biopsy specimens [23 of contrast-enhancing (CE) and 25 of non-contrast enhancing (NE) regions] from 12 GB patients were obtained by a frameless image-guided stereotactic biopsy technique. The highest values of 2-[18F]-fluoro-2-deoxy-D-glucose maximum standardized uptake value ( 18 F-FDG SUV max ), relative cerebral blood volume (rCBV), Choline/Creatine (Cho/Cr), Choline/N-acetylaspartate (Cho/NAA) and Lipids/Lactate (LL) ratio have been observed in the CE region. They corresponded to the most malignant tumor phenotype, to the greatest molecular spectrum and stem cell potential. On the contrary, apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in the CE region were very variable. 18 F-FDG SUV max , Cho/Cr and Cho/NAA ratio resulted the most suitable parameters to detect tumor infiltration. In edematous areas, reactive astrocytes and microglia/macrophages were influencing variables. Combined MRI and 18 F-FDG PET/CT allowed to recognize the specific biological significance of the different identified areas of GB.

  8. Comparison among conventional and advanced MRI, 18F-FDG PET/CT, phenotype and genotype in glioblastoma

    PubMed Central

    Valentini, Maria Consuelo; Mellai, Marta; Annovazzi, Laura; Melcarne, Antonio; Denysenko, Tetyana; Cassoni, Paola; Casalone, Cristina; Maurella, Cristiana; Grifoni, Silvia; Fania, Piercarlo; Cistaro, Angelina; Schiffer, Davide

    2017-01-01

    Glioblastoma (GB) is a highly heterogeneous tumor. In order to identify in vivo the most malignant tumor areas, the extent of tumor infiltration and the sites giving origin to GB stem cells (GSCs), we combined positron emission tomography/computed tomography (PET/CT) and conventional and advanced magnetic resonance imaging (MRI) with histology, immunohistochemistry and molecular genetics. Prior to dura opening and tumor resection, forty-eight biopsy specimens [23 of contrast-enhancing (CE) and 25 of non-contrast enhancing (NE) regions] from 12 GB patients were obtained by a frameless image-guided stereotactic biopsy technique. The highest values of 2-[18F]-fluoro-2-deoxy-D-glucose maximum standardized uptake value (18F-FDG SUVmax), relative cerebral blood volume (rCBV), Choline/Creatine (Cho/Cr), Choline/N-acetylaspartate (Cho/NAA) and Lipids/Lactate (LL) ratio have been observed in the CE region. They corresponded to the most malignant tumor phenotype, to the greatest molecular spectrum and stem cell potential. On the contrary, apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in the CE region were very variable. 18F-FDG SUVmax, Cho/Cr and Cho/NAA ratio resulted the most suitable parameters to detect tumor infiltration. In edematous areas, reactive astrocytes and microglia/macrophages were influencing variables. Combined MRI and 18F-FDG PET/CT allowed to recognize the specific biological significance of the different identified areas of GB. PMID:29207673

  9. Brain morphological alterations and cellular metabolic changes in patients with generalized anxiety disorder: A combined DARTEL-based VBM and (1)H-MRS study.

    PubMed

    Moon, Chung-Man; Jeong, Gwang-Woo

    2016-05-01

    Generalized anxiety disorder (GAD) is characterized by emotional dysregulation and cognitive deficit in conjunction with brain morphometric and metabolic alterations. This study assessed the combined neural morphological deficits and metabolic abnormality in patients with GAD. Thirteen patients with GAD and 13 healthy controls matched for age, sex, and education level underwent high-resolution T1-weighted MRI and proton magnetic resonance spectroscopy ((1)H-MRS) at 3Tesla. In this study, the combination of voxel-based morphometry (VBM) and (1)H-MRS was used to assess the brain morphometric and metabolic alterations in GAD. The patients showed significantly reduced white matter (WM) volumes in the midbrain (MB), precentral gyrus (PrG), dorsolateral prefrontal cortex (DLPFC) and anterior limb of the internal capsule (ALIC) compared to the controls. In MRS study, the choline/creatine (Cho/Cr) and choline/N-acetylaspartate (Cho/NAA) ratios in the DLPFC were significantly lower in the patients. Particularly, the WM volume variation of the DLPFC was positively correlated with both of the Cho/Cr and Cho/NAA ratios in patients with GAD. This study provides an evidence for the association between the morphometric deficit and metabolic changes in GAD. This finding would be helpful to understand the neural dysfunction and pathogenesis in connection with cognitive impairments in GAD. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Low fish intake is associated with low blood concentrations of vitamin D, choline and n-3 DHA in pregnant women.

    PubMed

    Wu, Brian T; Dyer, Roger A; King, D Janette; Innis, Sheila M

    2013-03-14

    Several studies have investigated the potential health benefits, including those associated with neurological function, of the n-3 fatty acid DHA. This has arisen in part because of the association between higher intakes of fish, which is a major dietary source of DHA, and reduced disease risk. In addition to DHA, fish also provides choline and vitamin D. The objective of the present study was to assess whether women in the first half of pregnancy with low fish intake also had low blood concentrations of vitamin D, choline and DHA. A total of 222 pregnant women at 16 weeks of gestation were examined for dietary intake, erythrocyte (phosphatidylethanolamine PE) DHA, plasma free choline and 25-hydroxyvitamin D (25(OH)D). Women who consumed ≤ 75 g fish/week (n 56) compared to ≥ 150 g fish/week (n 116) had lower dietary intake of DHA, total choline and vitamin D (P< 0·001), and lower erythrocyte PE DHA (5·25 (sd 1·27), 6·83 (sd 1·62) g/100 g total fatty acid, respectively, P< 0·01), plasma free choline (6·59 (sd 1·65), 7·40 (sd 2·05) μmol/l, respectively, P= 0·023) and 25(OH)D (50·3 (sd 20·0), 62·5 (sd 29·8) nmol/l, respectively, P< 0·01). DHA intake was positively related to the intake of vitamin D from foods (ρ 0·47, P< 0·001) and total choline (ρ 0·32, P< 0·001). Dietary intakes and biomarkers of DHA, choline and vitamin D status were assessed to be linked. This raises the possibility that unidentified concurrent nutrient inadequacies might have an impact on the results of studies addressing the benefits of supplemental DHA.

  11. Neurochemical alterations associated with borderline personality disorder.

    PubMed

    Atmaca, Murad; Karakoc, Tevfik; Mermi, Osman; Gurkan Gurok, M; Yildirim, Hanefi

    2015-01-01

    In neuroimaging on borderline personality disorder, prior studies focused on the hippocampus and amygdala, as mentioned above. However, no study investigated whether there were neurochemical changes in the patients with borderline personality disorder. Therefore, in the present study, we aimed to investigate neurochemical change of patients diagnosed with borderline disorder and hypothesized that neurochemicals would change in the hippocampus region of these patients. Seventeen patients and the same number of healthy control subjects were analyzed by using a 1.5 Tesla GE Signa Imaging System. N-acetylaspartate (NAA), choline compounds (CHO), and creatine (CRE) values of hippocampal region were measured. The mean NAA/CRE ratio in the hippocampus region was significantly reduced in the patients with borderline personality disorder compared to that of healthy control subjects, In addition, NAA/CHO ratio of the patients with borderline personality disorder was also significantly reduced when compared to that of healthy subjects. There was no difference in the ratio of CHO/CRE. In summary, we present evidence for reduced NAA in the patients with borderline personality disorder. © 2015, The Author(s).

  12. Metabolite alterations in basal ganglia associated with methamphetamine-related psychiatric symptoms. A proton MRS study.

    PubMed

    Sekine, Yoshimoto; Minabe, Yoshio; Kawai, Masayoshi; Suzuki, Katsuaki; Iyo, Masaomi; Isoda, Haruo; Sakahara, Harumi; Ashby, Charles R; Takei, Nori; Mori, Norio

    2002-09-01

    Following the chronic use of methamphetamine, some individuals experience psychosis and anxiety. One reason may be the persistence of metabolite abnormalities in the brain of currently abstinent former methamphetamine users. In this study, N-acetylaspartate (NAA), creatine plus phosphocreatine (Cr+PCr), and choline-containing compound (Cho) levels were measured in the left and right basal ganglia using proton magnetic resonance spectroscopy (MRS) in 13 abstinent methamphetamine users and 11 healthy comparison subjects with no history of illicit drug use. The methamphetamine users showed a significantly reduced Cr+PCr/Cho ratio in the bilateral basal ganglia compared with the healthy comparison subjects. Furthermore, the reduction in the Cr+PCr/Cho ratio was significantly correlated with the duration of methamphetamine use and with the severity of residual psychiatric symptoms. NAA/Cho ratios in the bilateral basal ganglia did not significantly differ between methamphetamine users and comparison subjects. These findings suggest that protracted use of methamphetamine may cause metabolite alterations in the basal ganglia. Furthermore, residual psychiatric symptoms may be attributable to the metabolite alterations in the basal ganglia.

  13. Association of human hippocampal neurochemistry, serotonin transporter genetic variation, and anxiety.

    PubMed

    Gallinat, Jürgen; Ströhle, Andreas; Lang, Undine E; Bajbouj, Malek; Kalus, Peter; Montag, Christiane; Seifert, Frank; Wernicke, Catrin; Rommelspacher, Hans; Rinneberg, Herbert; Schubert, Florian

    2005-05-15

    The impact of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) on anxiety-related behavior and related cerebral activation has facilitated the understanding of neurobiological mechanisms of anxiety. However, the influence of the 5-HTTLPR genotype on hippocampal neuronal development and neurochemistry, which is relevant to anxiety behavior, has not been investigated. In 38 healthy subjects, absolute concentrations of N-acetylaspartate (NAA) were measured as a main surrogate parameter for hippocampal neurochemistry on a 3-T scanner. A significantly lower hippocampal NAA concentration in s allele carriers was observed as compared to l/l genotype. Other metabolites (choline, creatine + phosphocreatine, glutamate) were unaffected by genotype. The hippocampal NAA concentration was negatively correlated with trait anxiety scores (STAI). Metabolites measured in the anterior cingulate cortex (reference region) were not associated with genotype. The results are in accordance with the recently reported relationship between hippocampal neuronal development and anxiety behavior in adult animals and show an association between human limbic neurochemistry and genetically driven serotonergic neurotransmission relevant to anxiety.

  14. Creatine metabolism and psychiatric disorders: Does creatine supplementation have therapeutic value?

    PubMed Central

    Allen, Patricia J.

    2012-01-01

    Athletes, body builders, and military personnel use dietary creatine as an ergogenic aid to boost physical performance in sports involving short bursts of high-intensity muscle activity. Lesser known is the essential role creatine, a natural regulator of energy homeostasis, plays in brain function and development. Creatine supplementation has shown promise as a safe, effective, and tolerable adjunct to medication for the treatment of brain-related disorders linked with dysfunctional energy metabolism, such as Huntington’s Disease and Parkinson’s Disease. Impairments in creatine metabolism have also been implicated in the pathogenesis of psychiatric disorders, leaving clinicians, researchers and patients alike wondering if dietary creatine has therapeutic value for treating mental illness. The present review summarizes the neurobiology of the creatine-phosphocreatine circuit and its relation to psychological stress, schizophrenia, mood and anxiety disorders. While present knowledge of the role of creatine in cognitive and emotional processing is in its infancy, further research on this endogenous metabolite has the potential to advance our understanding of the biological bases of psychopathology and improve current therapeutic strategies. PMID:22465051

  15. Creatine metabolism and psychiatric disorders: Does creatine supplementation have therapeutic value?

    PubMed

    Allen, Patricia J

    2012-05-01

    Athletes, body builders, and military personnel use dietary creatine as an ergogenic aid to boost physical performance in sports involving short bursts of high-intensity muscle activity. Lesser known is the essential role creatine, a natural regulator of energy homeostasis, plays in brain function and development. Creatine supplementation has shown promise as a safe, effective, and tolerable adjunct to medication for the treatment of brain-related disorders linked with dysfunctional energy metabolism, such as Huntington's Disease and Parkinson's Disease. Impairments in creatine metabolism have also been implicated in the pathogenesis of psychiatric disorders, leaving clinicians, researchers and patients alike wondering if dietary creatine has therapeutic value for treating mental illness. The present review summarizes the neurobiology of the creatine-phosphocreatine circuit and its relation to psychological stress, schizophrenia, mood and anxiety disorders. While present knowledge of the role of creatine in cognitive and emotional processing is in its infancy, further research on this endogenous metabolite has the potential to advance our understanding of the biological bases of psychopathology and improve current therapeutic strategies. Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) promote growth and inhibit differentiation of glioma stem-like cells.

    PubMed

    Long, Patrick M; Moffett, John R; Namboodiri, Aryan M A; Viapiano, Mariano S; Lawler, Sean E; Jaworski, Diane M

    2013-09-06

    Metabolic reprogramming is a pathological feature of cancer and a driver of tumor cell transformation. N-Acetylaspartate (NAA) is one of the most abundant amino acid derivatives in the brain and serves as a source of metabolic acetate for oligodendrocyte myelination and protein/histone acetylation or a precursor for the synthesis of the neurotransmitter N-acetylaspartylglutamate (NAAG). NAA and NAAG as well as aspartoacylase (ASPA), the enzyme responsible for NAA degradation, are significantly reduced in glioma tumors, suggesting a possible role for decreased acetate metabolism in tumorigenesis. This study sought to examine the effects of NAA and NAAG on primary tumor-derived glioma stem-like cells (GSCs) from oligodendroglioma as well as proneural and mesenchymal glioblastoma, relative to oligodendrocyte progenitor cells (Oli-Neu). Although the NAA dicarboxylate transporter NaDC3 is primarily thought to be expressed by astrocytes, all cell lines expressed NaDC3 and, thus, are capable of NAA up-take. Treatment with NAA or NAAG significantly increased GSC growth and suppressed differentiation of Oli-Neu cells and proneural GSCs. Interestingly, ASPA was expressed in both the cytosol and nuclei of GSCs and exhibited greatest nuclear immunoreactivity in differentiation-resistant GSCs. Both NAA and NAAG elicited the expression of a novel immunoreactive ASPA species in select GSC nuclei, suggesting differential ASPA regulation in response to these metabolites. Therefore, this study highlights a potential role for nuclear ASPA expression in GSC malignancy and suggests that the use of NAA or NAAG is not an appropriate therapeutic approach to increase acetate bioavailability in glioma. Thus, an alternative acetate source is required.

  17. Effects of choline treatment in concentrations of serum matrix metalloproteinases (MMPs), MMP tissue inhibitors (TIMPs) and immunoglobulins in an experimental model of canine sepsis.

    PubMed

    Kocaturk, Meric; Eralp-Inan, Oya; Tvarijonaviciute, A; Cansev, Mehmet; Ozyigit, M Ozgur; Ceron, J J; Yilmaz, Zeki; Kahraman, M Mufit

    2016-11-01

    The aim of the present study was to investigate effects of intravenous (i.v.) choline treatment on serum matrix metalloproteinases (MMP), MMP tissue inhibitors (TIMP) and immunoglobulins (Igs), and to determine if there were relations between serum MMPs/TIMPs and C-reactive protein (CRP) (as a marker of the acute phase response), immunoglobulin G and M (IgG and IgM) (as a maker of the Ig responses) and markers of organ damage such as muscular damage (creatine phosphokinase, [CPK]), liver damage (alanine aminotransferase [ALT]) and renal dysfunction (blood urea nitrogen [BUN] and creatinine, [Cr]) in dogs with endotoxemia. Healthy dogs (n=24) were randomized to Saline, Choline (C), Lipopolysaccharide (LPS), and LPS+C groups and received 0.9% NaCl (5mL/i.v.), choline chloride (20mg/kg/i.v.), LPS (0.02mg/kg/i.v.) and LPS (0.02mg/kg/i.v.) plus choline chloride (20mg/kg/i.v.), respectively. Serum MMPs and TIMPs concentrations were analyzed by commercial ELISA kits. MMP and TIMP increased at 1-48h (P<0.05), whereas IgG and IgM decreased at 24-48h in LPS group, compared to their baselines. Choline treatment reduced changes in serum MMPs, TIMPs and markers of organ damage, and prevented the hypoimmunoglobulinemia in LPS+C. MMPs and TIMPs were correlated positively (P<0.05) with serum CRP, CPK, ALT, BUN and Cr, but not with serum Igs. Our findings suggest that the serum MMPs, TIMPs and Igs are involved in the pathophysiology of endotoxemia, and MMPs and TIMPs are correlated with the acute phase reaction and multi-organ failure. In addition, we demonstrated a direct effect of choline administration in decreasing serum MMPs and TIMPs, and preserving serum Igs in the course of endotoxemia. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Dietary creatine supplementation during pregnancy: a study on the effects of creatine supplementation on creatine homeostasis and renal excretory function in spiny mice.

    PubMed

    Ellery, Stacey J; LaRosa, Domenic A; Kett, Michelle M; Della Gatta, Paul A; Snow, Rod J; Walker, David W; Dickinson, Hayley

    2016-08-01

    Recent evidence obtained from a rodent model of birth asphyxia shows that supplementation of the maternal diet with creatine during pregnancy protects the neonate from multi-organ damage. However, the effect of increasing creatine intake on creatine homeostasis and biosynthesis in females, particularly during pregnancy, is unknown. This study assessed the impact of creatine supplementation on creatine homeostasis, body composition, capacity for de novo creatine synthesis and renal excretory function in non-pregnant and pregnant spiny mice. Mid-gestation pregnant and virgin spiny mice were fed normal chow or chow supplemented with 5 % w/w creatine for 18 days. Weight gain, urinary creatine and electrolyte excretion were assessed during supplementation. At post mortem, body composition was assessed by Dual-energy X-ray absorptiometry, or tissues were collected to assess creatine content and mRNA expression of the creatine synthesising enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) and the creatine transporter (CrT1). Protein expression of AGAT and GAMT was also assessed by Western blot. Key findings of this study include no changes in body weight or composition with creatine supplementation; increased urinary creatine excretion in supplemented spiny mice, with increased sodium (P < 0.001) and chloride (P < 0.05) excretion in pregnant dams after 3 days of supplementation; lowered renal AGAT mRNA (P < 0.001) and protein (P < 0.001) expressions, and lowered CrT1 mRNA expression in the kidney (P < 0.01) and brain (P < 0.001). Creatine supplementation had minimal impact on creatine homeostasis in either non-pregnant or pregnant spiny mice. Increasing maternal dietary creatine consumption could be a useful treatment for birth asphyxia.

  19. Creatine and the Liver: Metabolism and Possible Interactions.

    PubMed

    Barcelos, R P; Stefanello, S T; Mauriz, J L; Gonzalez-Gallego, J; Soares, F A A

    2016-01-01

    The process of creatine synthesis occurs in two steps, catalyzed by L-arginine:glycine amidinotransferase (AGAT) and guanidinoacetate N-methyltransferase (GAMT), which take place mainly in kidney and liver, respectively. This molecule plays an important energy/pH buffer function in tissues, and to guarantee the maintenance of its total body pool, the lost creatine must be replaced from diet or de novo synthesis. Creatine administration is known to decrease the consumption of Sadenosyl methionine and also reduce the homocysteine production in liver, diminishing fat accumulation and resulting in beneficial effects in fatty liver and non-alcoholic liver disease. Different studies have shown that creatine supplementation could supply brain energy, presenting neuroprotective effects against the encephalopathy induced by hyperammonemia in acute liver failure. Creatine is also taken by many athletes for its ergogenic properties. However, little is known about the adverse effects of creatine supplementation, which are barely described in the literature, with reports of mainly hypothetical effects arising from a small number of scientific publications. Antioxidant effects have been found in several studies, although one of the theories regarding the potential for toxicity from creatine supplementation is that it can increase oxidative stress and potentially form carcinogenic compounds.

  20. Total choline and choline-containing moieties of commercially available pulses.

    PubMed

    Lewis, Erin D; Kosik, Sarah J; Zhao, Yuan-Yuan; Jacobs, René L; Curtis, Jonathan M; Field, Catherine J

    2014-06-01

    Estimating dietary choline intake can be challenging due to missing foods in the current United States Department of Agriculture (USDA) database. The objectives of the study were to quantify the choline-containing moieties and the total choline content of a variety of pulses available in North America and use the expanded compositional database to determine the potential contribution of pulses to dietary choline intake. Commonly consumed pulses (n = 32) were analyzed by hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC LC-MS/MS) and compared to the current USDA database. Cooking was found to reduce the relative percent from free choline and increased the contribution of phosphatidylcholine to total choline for most pulses (P < 0.05). Using the expanded database to estimate choline content of recipes using pulses as meat alternatives, resulted in a different estimation of choline content per serving (±30%), compared to the USDA database. These results suggest that when pulses are a large part of a meal or diet, the use of accurate food composition data should be used.

  1. Choline Diet and Its Gut Microbe Derived Metabolite, Trimethylamine N-Oxide (TMAO), Exacerbate Pressure Overload-Induced Heart Failure

    PubMed Central

    Organ, Chelsea L.; Otsuka, Hiroyuki; Bhushan, Shashi; Wang, Zeneng; Bradley, Jessica; Trivedi, Rishi; Polhemus, David J.; Tang, W. H. Wilson; Wu, Yuping; Hazen, Stanley L.; Lefer, David J.

    2015-01-01

    Background Trimethylamine N-oxide (TMAO), a gut microbe dependent metabolite of dietary choline and other trimethylamine containing nutrients, is both elevated in the circulation of patients suffering from heart failure (HF) and heralds worse overall prognosis. In animal studies, dietary choline or TMAO significantly accelerate atherosclerotic lesion development in ApoE deficient mice, and reduction in TMAO levels inhibits atherosclerosis development in the LDL receptor knockout mouse. Methods and Results C57BL6/J mice were fed either a control diet, a diet containing choline (1.2%) or a diet containing TMAO (0.12%) starting 3 weeks prior to surgical TAC. Mice were studied for 12 weeks following TAC. Cardiac function and left ventricular structure were monitored at 3-week intervals using echocardiography. Twelve weeks post-TAC myocardial tissues were collected to evaluate cardiac and vascular fibrosis, and blood samples were evaluated for cardiac BNP, choline, and TMAO levels. Pulmonary edema, cardiac enlargement, and left ventricular ejection fraction (LVEF) were significantly (p < 0.05, each) worse in mice fed either TMAO or choline supplemented diets compared to the control diet. In addition, myocardial fibrosis was also significantly greater (p < 0.01, each) in the TMAO and choline groups relative to controls. Conclusions Heart failure severity is significantly enhanced in mice fed diets supplemented in either choline or the gut microbe-dependent metabolite TMAO. The present results suggest that further studies are warranted examining whether gut microbiota and the dietary choline -> TMAO pathway contribute to increased heart failure susceptibility. PMID:26699388

  2. Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide

    PubMed Central

    Romano, Kymberleigh A.; Vivas, Eugenio I.

    2015-01-01

    ABSTRACT Choline is a water-soluble nutrient essential for human life. Gut microbial metabolism of choline results in the production of trimethylamine (TMA), which upon absorption by the host is converted in the liver to trimethylamine-N-oxide (TMAO). Recent studies revealed that TMAO exacerbates atherosclerosis in mice and positively correlates with the severity of this disease in humans. However, which microbes contribute to TMA production in the human gut, the extent to which host factors (e.g., genotype) and diet affect TMA production and colonization of these microbes, and the effects TMA-producing microbes have on the bioavailability of dietary choline remain largely unknown. We screened a collection of 79 sequenced human intestinal isolates encompassing the major phyla found in the human gut and identified nine strains capable of producing TMA from choline in vitro. Gnotobiotic mouse studies showed that TMAO accumulates in the serum of animals colonized with TMA-producing species, but not in the serum of animals colonized with intestinal isolates that do not generate TMA from choline in vitro. Remarkably, low levels of colonization by TMA-producing bacteria significantly reduced choline levels available to the host. This effect was more pronounced as the abundance of TMA-producing bacteria increased. Our findings provide a framework for designing strategies aimed at changing the representation or activity of TMA-producing bacteria in the human gut and suggest that the TMA-producing status of the gut microbiota should be considered when making recommendations about choline intake requirements for humans. PMID:25784704

  3. Choline deficiency causes reversible hepatic abnormalities in patients receiving parenteral nutrition: proof of a human choline requirement: a placebo-controlled trial.

    PubMed

    Buchman, A L; Ament, M E; Sohel, M; Dubin, M; Jenden, D J; Roch, M; Pownall, H; Farley, W; Awal, M; Ahn, C

    2001-01-01

    Previous studies have shown that plasma free choline concentrations are significantly decreased in many long-term home total parenteral nutrition (TPN) patients. Furthermore, low choline status has been associated with both hepatic morphologic and hepatic aminotransferase abnormalities. A preliminary pilot study suggested choline-supplemented TPN may be useful in reversal of these hepatic abnormalities. Fifteen patients (10 M, 5 F) who had required TPN for > or =80% of their nutritional needs were randomized to receive their usual TPN (n = 8), or TPN to which 2 g choline chloride had been added (n = 7) for 24 weeks. Baseline demographic data were similar between groups. Patients had CT scans of the liver and spleen, and blood for plasma free and phospholipid-bound choline, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, gamma glutamyl transferase (GGT), bilirubin, serum lipids, complete blood count (CBC), and chemistry profile obtained at baseline, and weeks 2, 4, 6, 12, 16, 20, 24, and 34. CT scans were analyzed for Hounsfield unit (HU) densities. There were no significant differences in any measured parameters after 2 weeks. However, at 4 weeks, a significant difference in liver HU between groups was observed (13.3+/-5.0 HU [choline] vs 5.8+/-5.2 HU [placebo], p = .04). This significant trend continued through week 24. Recurrent hepatic steatosis and decreased HU were observed at week 34, 10 weeks after choline supplementation had been discontinued. A significant increase in the liver-spleen differential HU was also observed in the choline group (10.6+/-6.2 HU [choline] vs 1.3+/-3.3 HU [placebo], p = .01). Serum ALT decreased significantly (p = .01 to .05) in the choline group vs placebo at weeks 6,12, 20, and 24. Serum AST was significantly decreased in the choline group by week 24 (p = .02). The serum alkaline phosphatase was significantly reduced in the choline group at weeks 2, 12, 20, 24, and 34 (p = .02 to 0

  4. Serial analysis of 3D H-1 MRSI for patients with newly diagnosed GBM treated with combination therapy that includes bevacizumab.

    PubMed

    Nelson, Sarah J; Li, Yan; Lupo, Janine M; Olson, Marram; Crane, Jason C; Molinaro, Annette; Roy, Ritu; Clarke, Jennifer; Butowski, Nicholas; Prados, Michael; Cha, Soonmee; Chang, Susan M

    2016-10-01

    Interpretation of changes in the T1- and T2-weighted MR images from patients with newly diagnosed glioblastoma (GBM) treated with standard of care in conjunction with anti-angiogenic agents is complicated by pseudoprogression and pseudoresponse. The hypothesis being tested in this study was that 3D H-1 magnetic resonance spectroscopic imaging (MRSI) provides estimates of levels of choline, creatine, N-acetylaspartate (NAA), lactate and lipid that change in response to treatment and that metrics describing these characteristics are associated with survival. Thirty-one patients with newly diagnosed GBM and being treated with radiation therapy (RT), temozolomide, erlotinib and bevacizumab were recruited to receive serial MR scans that included 3-D lactate edited MRSI at baseline, mid-RT, post-RT and at specific follow-up time points. The data were processed to provide estimates of metrics representing changes in metabolite levels relative to normal appearing brain. Cox proportional hazards analysis was applied to examine the relationship of these parameters with progression free survival (PFS) and overall survival (OS). There were significant reductions in parameters that describe relative levels of choline to NAA and creatine, indicating that the treatment caused a decrease in tumor cellularity. Changes in the levels of lactate and lipid relative to the NAA from contralateral brain were consistent with vascular normalization. Metabolic parameters from the first serial follow-up scan were associated with PFS and OS, when accounting for age and extent of resection. Integrating metabolic parameters into the assessment of patients with newly diagnosed GBM receiving therapies that include anti-angiogenic agents may be helpful for tracking changes in tumor burden, resolving ambiguities in anatomic images caused by non-specific treatment effects and for predicting outcome.

  5. Reexamining the role of choline transporter-like (Ctlp) proteins in choline transport.

    PubMed

    Zufferey, Rachel; Santiago, Teresa C; Brachet, Valerie; Ben Mamoun, Choukri

    2004-02-01

    In Saccharomyces cerevisiae, choline enters the cell via a single high-affinity transporter, Hnmlp. hnm1delta cells lacking HNM1 gene are viable. However, they are unable to transport choline suggesting that no additional active choline transporters are present in this organism. A complementation study of a choline auxotrophic mutant, ctrl-ise (hnm1-ise), using a cDNA library from Torpedo marmorata electric lobe identified a membrane protein named Torpedo marmorata choline transporter-like, tCtl1p. tCtllp was proposed to mediate a high-affinity choline transport (O'Regan et al., 1999, Proc. Natl. Acad. Sci.). Homologs of tCtl1p have been identified in other organisms, including yeast (Pns1p, YOR161c) and are postulated to function as choline transporters. Here we provide several lines of evidence indicating that Ctlp proteins are not involved in choline transport. Loss of PNS1 has no effect on choline transport and overexpression of either PNS1 or tCTL1 does not restore choline uptake activity of choline transport-defective mutants. The data presented here call into question the role of proteins of the CTL family in choline transport and suggest that the mechanism by which tCTL1 complements hnm1-ise mutant is independent of its ability to transport choline.

  6. Determination of picomole quantities of acetylcholine and choline in physiologic salt solutions.

    PubMed

    Gilberstadt, M L; Russell, J A

    1984-04-01

    An assay capable of detecting tens-of-picomole quantities of choline and acetylcholine in milliliter volumes of a physiological salt solution has been developed. Silica column chromatography was used to bind and separate 10-3000 pmol [14C]choline and [14C]acetylcholine standards made up in 3 ml of a bicarbonate-buffered Krebs-Ringer solution. The silica columns bound 95-98% of both choline and acetylcholine. Of the bound choline 84-87% was eluted in 1.5 ml of 0.075 N HCl, whereas 95-98% of the bound acetylcholine was eluted in a subsequent wash with 1.5 ml of 0.030 N HCl in 10% 2-butanone. Vacuum centrifugation of the eluants yielded small white pellets with losses of choline and acetylcholine of only 1%. Dried pellets of unlabeled choline and acetylcholine standards were assayed radioenzymatically using [gamma-32P]ATP, choline kinase, and acetylcholinesterase. The net disintegrations per minute of choline[32P]phosphate product was proportional to both the acetylcholine (10-3000 pmol) and choline (30-3000 pmol) standards. The "limit sensitivity" was 8.5 pmol for acetylcholine and 11.4 pmol for choline. Cross-contamination of the choline assay by acetylcholine averaged 1.3%, whereas contamination of the acetylcholine assay by choline averaged 3.1%.

  7. Dietary, anthropometric, and biochemical factors influencing plasma choline, carnitine, trimethylamine, and trimethylamine-N-oxide concentrations.

    PubMed

    Malinowska, Anna M; Szwengiel, Artur; Chmurzynska, Agata

    2017-06-01

    The objective of the study was to evaluate the nutritional, anthropometric, and biochemical factors that influence choline, l-carnitine, trimethylamine (TMA), and trimethylamine-N-oxide (TMAO) metabolism in elderly women. The volunteers' diet was assessed using a food frequency questionnaire. Dietary patterns were estimated using a self-established score method. Body mass index (BMI), serum glucose, total, HDL, LDL cholesterol, triacylglycerol, homocysteine (tHcy), free choline (fchol), L-carnitine, TMA, and TMAO were assessed. Higher concentrations of l-carnitine, fchol, and TMAO were found in those women who had more western-style dietary patterns. Nor choline or betaine intake affected plasma fchol, TMA, or TMAO. BMI was positively correlated with fchol and TMA. tHcy was positively correlated with fchol, TMA, and TMAO, while fchol was also positively correlated with TMA and TMAO. Dietary patterns and plasma tHcy concentration influence fchol, TMA, and TMAO plasma concentration. Plasma TMA and fchol may be associated with BMI.

  8. Metabolic and Structural Imaging at 7 Tesla After Repetitive Mild Traumatic Brain Injury in Immature Rats.

    PubMed

    Fidan, Emin; Foley, Lesley M; New, Lee Ann; Alexander, Henry; Kochanek, Patrick M; Hitchens, T Kevin; Bayır, Hülya

    2018-01-01

    Mild traumatic brain injury (mTBI) in children is a common and serious public health problem. Traditional neuroimaging findings in children who sustain mTBI are often normal, putting them at risk for repeated mTBI (rmTBI). There is a need for more sensitive imaging techniques capable of detecting subtle neurophysiological alterations after injury. We examined neurochemical and white matter changes using diffusion tensor imaging of the whole brain and proton magnetic resonance spectroscopy of the hippocampi at 7 Tesla in 18-day-old male rats at 7 days after mTBI and rmTBI. Traumatic axonal injury was assessed by beta-amyloid precursor protein accumulation using immunohistochemistry. A significant decrease in fractional anisotropy and increase in axial and radial diffusivity were observed in several brain regions, especially in white matter regions, after a single mTBI versus sham and more prominently after rmTBI. In addition, we observed accumulation of beta-amyloid precursor protein in the external capsule after mTBI and rmTBI. mTBI and rmTBI reduced the N-acetylaspartate/creatine ratio (NAA/Cr) and increased the myoinositol/creatine ratio (Ins/Cr) versus sham. rmTBI exacerbated the reduction in NAA/Cr versus mTBI. The choline/creatine (Cho/Cr) and (lipid/Macro Molecule 1)/creatine (Lip/Cr) ratios were also decreased after rmTBI versus sham. Diffusion tensor imaging findings along with the decrease in Cho and Lip after rmTBI may reflect damage to axonal membrane. NAA and Ins are altered at 7 days after mTBI and rmTBI likely reflecting neuro-axonal damage and glial response, respectively. These findings may be relevant to understanding the extent of disability following mTBI and rmTBI in the immature brain and may identify possible therapeutic targets.

  9. No up-regulation of the phosphatidylethanolamine N-methyltransferase pathway and choline production by sex hormones in cats.

    PubMed

    Valtolina, Chiara; Vaandrager, Arie B; Favier, Robert P; Robben, Joris H; Tuohetahuntila, Maidina; Kummeling, Anne; Jeusette, Isabelle; Rothuizen, Jan

    2015-11-09

    Feline hepatic lipidosis (FHL) is a common cholestatic disease affecting cats of any breed, age and sex. Both choline deficiency and low hepatic phosphatidylethanolamine N-methyltransferase (PEMT) activity are associated with hepatic lipidosis (HL) in humans, mice and rats. The PEMT expression is known to be upregulated by oestrogens, protecting the females in these species from the development of HL when exposed to choline deficient diets. The aim of the present study was to evaluate the influence of sex hormones on choline synthesis via the PEMT pathway in healthy male and female cats before and after spaying/neutering, when fed a diet with recommended dietary choline content. From six female and six male cats PEMT activity was assayed directly in liver biopsies taken before and after spaying/neutering, and assessed indirectly by analyses of PEMT-specific hepatic phosphatidylcholine (PC) species and plasma choline levels. Hepatic PEMT activity did not differ between intact female and male cats and no changes upon spaying/neutering were observed. Likewise, no significant differences in liver PC content and PEMT-specific polyunsaturated PC species were found between the sexes and before or after spaying/neutering. These results suggest that choline synthesis in cats differs from what is observed in humans, mice and rats. The lack of evident influence of sex hormones on the PEMT pathway makes it unlikely that spaying/neutering predisposes cats for HL by causing PC deficiency as suggested in other species.

  10. N-Acetylaspartate (NAA) and N-Acetylaspartylglutamate (NAAG) Promote Growth and Inhibit Differentiation of Glioma Stem-like Cells*

    PubMed Central

    Long, Patrick M.; Moffett, John R.; Namboodiri, Aryan M. A.; Viapiano, Mariano S.; Lawler, Sean E.; Jaworski, Diane M.

    2013-01-01

    Metabolic reprogramming is a pathological feature of cancer and a driver of tumor cell transformation. N-Acetylaspartate (NAA) is one of the most abundant amino acid derivatives in the brain and serves as a source of metabolic acetate for oligodendrocyte myelination and protein/histone acetylation or a precursor for the synthesis of the neurotransmitter N-acetylaspartylglutamate (NAAG). NAA and NAAG as well as aspartoacylase (ASPA), the enzyme responsible for NAA degradation, are significantly reduced in glioma tumors, suggesting a possible role for decreased acetate metabolism in tumorigenesis. This study sought to examine the effects of NAA and NAAG on primary tumor-derived glioma stem-like cells (GSCs) from oligodendroglioma as well as proneural and mesenchymal glioblastoma, relative to oligodendrocyte progenitor cells (Oli-Neu). Although the NAA dicarboxylate transporter NaDC3 is primarily thought to be expressed by astrocytes, all cell lines expressed NaDC3 and, thus, are capable of NAA up-take. Treatment with NAA or NAAG significantly increased GSC growth and suppressed differentiation of Oli-Neu cells and proneural GSCs. Interestingly, ASPA was expressed in both the cytosol and nuclei of GSCs and exhibited greatest nuclear immunoreactivity in differentiation-resistant GSCs. Both NAA and NAAG elicited the expression of a novel immunoreactive ASPA species in select GSC nuclei, suggesting differential ASPA regulation in response to these metabolites. Therefore, this study highlights a potential role for nuclear ASPA expression in GSC malignancy and suggests that the use of NAA or NAAG is not an appropriate therapeutic approach to increase acetate bioavailability in glioma. Thus, an alternative acetate source is required. PMID:23884408

  11. Creatine deficiency syndromes.

    PubMed

    Schulze, Andreas

    2013-01-01

    The lack of creatine in the central nervous system causes a severe but treatable neurological disease. Three inherited defects, AGAT, GAMT, and CrT deficiency, compromising synthesis and transport of creatine have been discovered recently. Together these so-called creatine deficiency syndromes (CDS) might represent the most frequent metabolic disorders with a primarily neurological phenotype. Patients with CDS present with global developmental delays, mental retardation, speech impairment especially affecting active language, seizures, extrapyramidal movement disorder, and autism spectrum disorder. The two defects in the creatine synthesis, AGAT and GAMT, are autosomal recessive disorders. They can be diagnosed by analysis of the creatine, guanidinoacetate, and creatinine in body fluids. Treatment is available and, especially when introduced in infancy, has a good outcome. The defect of creatine transport, CrT, is an X-linked condition and perhaps the most frequent reasons for X-linked mental retardation. Diagnosis is made by an increased ratio of creatine to creatinine in urine, but successful treatment still needs to be explored. CDS are under-diagnosed because easy to miss in standard diagnostic workup. Because CDS represent a frequent cause of cognitive and neurological impairment that is treatable they warrant consideration in the workup for genetic mental retardation syndromes, for intractable seizure disorders, and for neurological diseases with a predominant lack of active speech. Copyright © 2013 Elsevier B.V. All rights reserved.

  12. Creatine supplementation during pulmonary rehabilitation in chronic obstructive pulmonary disease.

    PubMed

    Fuld, J P; Kilduff, L P; Neder, J A; Pitsiladis, Y; Lean, M E J; Ward, S A; Cotton, M M

    2005-07-01

    Skeletal muscle wasting and dysfunction are strong independent predictors of mortality in patients with chronic obstructive pulmonary disease (COPD). Creatine nutritional supplementation produces increased muscle mass and exercise performance in health. A controlled study was performed to look for similar effects in 38 patients with COPD. Thirty eight patients with COPD (mean (SD) forced expiratory volume in 1 second (FEV(1)) 46 (15)% predicted) were randomised to receive placebo (glucose polymer 40.7 g) or creatine (creatine monohydrate 5.7 g, glucose 35 g) supplements in a double blind trial. After 2 weeks loading (one dose three times daily), patients participated in an outpatient pulmonary rehabilitation programme combined with maintenance (once daily) supplementation. Pulmonary function, body composition, and exercise performance (peripheral muscle strength and endurance, shuttle walking, cycle ergometry) took place at baseline (n = 38), post loading (n = 36), and post rehabilitation (n = 25). No difference was found in whole body exercise performance between the groups: for example, incremental shuttle walk distance mean -23.1 m (95% CI -71.7 to 25.5) post loading and -21.5 m (95% CI -90.6 to 47.7) post rehabilitation. Creatine increased fat-free mass by 1.09 kg (95% CI 0.43 to 1.74) post loading and 1.62 kg (95% CI 0.47 to 2.77) post rehabilitation. Peripheral muscle performance improved: knee extensor strength 4.2 N.m (95% CI 1.4 to 7.1) and endurance 411.1 J (95% CI 129.9 to 692.4) post loading, knee extensor strength 7.3 N.m (95% CI 0.69 to 13.92) and endurance 854.3 J (95% CI 131.3 to 1577.4) post rehabilitation. Creatine improved health status between baseline and post rehabilitation (St George's Respiratory Questionnaire total score -7.7 (95% CI -14.9 to -0.5)). Creatine supplementation led to increases in fat-free mass, peripheral muscle strength and endurance, health status, but not exercise capacity. Creatine may constitute a new ergogenic treatment

  13. Choline absorption and evaluation of bioavailability markers when supplementing choline to lactating dairy cows.

    PubMed

    de Veth, M J; Artegoitia, V M; Campagna, S R; Lapierre, H; Harte, F; Girard, C L

    2016-12-01

    The metabolites of choline have a central role in many mammalian biological processes, and choline supplementation to the periparturient dairy cow improves hepatic lipid metabolism. However, variability in responses to choline supplementation has highlighted a lack of understanding of choline absorption in the lactating dairy cow. Our objective was to determine net choline absorption by measuring net portal fluxes of choline and choline metabolites in cows receiving either dietary supplements of rumen-protected choline (RPC) or abomasal delivery of choline (ADC). We also evaluated markers for choline bioavailability by examining relationships between net portal absorption of choline and choline metabolites in plasma and milk. Five late-lactation Holstein cows were used in a 5×5 Latin square design, with 5-d treatment periods and a 2-d interval between periods. Treatments were (1) control (0g/d of choline), (2) 12.5g/d of choline fed as RPC, (3) 25g/d of choline fed as RPC, (4) 12.5g/d of choline provided as ADC, and (5) 25g/d of choline provided as ADC. At the end of each 5-d period, milk was sampled and 9 blood samples were collected simultaneously from an artery and portal vein at 30-min intervals. Plasma, milk, and feed ingredient concentrations of acetylcholine, betaine, free choline, glycerophosphocholine, lysophosphatidylcholine, phosphatidylcholine, phosphocholine, and sphingomyelin were quantified by hydrophilic interaction liquid chromatography-tandem mass spectrometry. With an increasing dose of ADC, the net portal flux of free choline increased and regression analysis indicated 61% net absorption of the infused dose. Among the choline metabolites, only concentrations of betaine, free choline, and phosphocholine increased in both arterial plasma (3.9, 1.9, and 0.4 times, respectively) and milk (2.5, 1.4, and 1.0 times, respectively) with 25g/d of ADC relative to the control. For RPC, the net portal flux of free choline was low relative to ADC (13

  14. Dietary choline requirements of women: effects of estrogen and genetic variation.

    PubMed

    Fischer, Leslie M; da Costa, Kerry-Ann; Kwock, Lester; Galanko, Joseph; Zeisel, Steven H

    2010-11-01

    Choline is obtained from the diet and from the biosynthesis of phosphatidylcholine. Phosphatidylcholine is catalyzed by the enzyme phosphatidylethanolamine-N-methyltransferase (PEMT), which is induced by estrogen. Because they have lower estrogen concentrations, postmenopausal women are more susceptible to the risk of organ dysfunction in response to a low-choline diet. A common genetic polymorphism (rs12325817) in the PEMT gene can also increase this risk. The objective was to determine whether the risk of low choline-related organ dysfunction increases with the number of alleles of rs12325817 in premenopausal women and whether postmenopausal women (with or without rs12325817) treated with estrogen are more resistant to developing such symptoms. Premenopausal women (n = 27) consumed a choline-sufficient diet followed by a very-low-choline diet until they developed organ dysfunction (or for 42 d), which was followed by a high-choline diet. Postmenopausal women (n = 22) were placed on the same diets but were first randomly assigned to receive estrogen or a placebo. The women were monitored for organ dysfunction and plasma choline metabolites and were genotyped for rs12325817. A dose-response effect of rs12325817 on the risk of choline-related organ dysfunction was observed in premenopausal women: 80%, 43%, and 13% of women with 2, 1, or 0 alleles, respectively, developed organ dysfunction. Among postmenopausal women, 73% who received placebo but only 18% who received estrogen developed organ dysfunction during the low-choline diet. Because of their lower estrogen concentrations, postmenopausal women have a higher dietary requirement for choline than do premenopausal women. Choline requirements for both groups of women are further increased by rs12325817. This trial was registered at clinicaltrials.gov as NCT00065546.

  15. Modulation of TNF Release by Choline Requires α7 Subunit Nicotinic Acetylcholine Receptor-Mediated Signaling

    PubMed Central

    Parrish, William R; Rosas-Ballina, Mauricio; Gallowitsch-Puerta, Margot; Ochani, Mahendar; Ochani, Kanta; Yang, Li-Hong; Hudson, LaQueta; Lin, Xinchun; Patel, Nirav; Johnson, Sarah M; Chavan, Sangeeta; Goldstein, Richard S; Czura, Christopher J; Miller, Edmund J; Al-Abed, Yousef; Tracey, Kevin J; Pavlov, Valentin A

    2008-01-01

    The α7 subunit-containing nicotinic acetylcholine receptor (α7nAChR) is an essential component in the vagus nerve-based cholinergic anti-inflammatory pathway that regulates the levels of TNF, high mobility group box 1 (HMGB1), and other cytokines during inflammation. Choline is an essential nutrient, a cell membrane constituent, a precursor in the biosynthesis of acetylcholine, and a selective natural α7nAChR agonist. Here, we studied the anti-inflammatory potential of choline in murine endotoxemia and sepsis, and the role of the α7nAChR in mediating the suppressive effect of choline on TNF release. Choline (0.1–50 mM) dose-dependently suppressed TNF release from endotoxin-activated RAW macrophage-like cells, and this effect was associated with significant inhibition of NF-κB activation. Choline (50 mg/kg, intraperitoneally [i.p.]) treatment prior to endotoxin administration in mice significantly reduced systemic TNF levels. In contrast to its TNF suppressive effect in wild type mice, choline (50 mg/kg, i.p.) failed to inhibit systemic TNF levels in α7nAChR knockout mice during endotoxemia. Choline also failed to suppress TNF release from endotoxin-activated peritoneal macrophages isolated from α7nAChR knockout mice. Choline treatment prior to endotoxin resulted in a significantly improved survival rate as compared with saline-treated endotoxemic controls. Choline also suppressed HMGB1 release in vitro and in vivo, and choline treatment initiated 24 h after cecal ligation and puncture (CLP)-induced polymicrobial sepsis significantly improved survival in mice. In addition, choline suppressed TNF release from endotoxin-activated human whole blood and macrophages. Collectively, these data characterize the anti-inflammatory efficacy of choline and demonstrate that the modulation of TNF release by choline requires α7nAChR-mediated signaling. PMID:18584048

  16. Echo-Planar Imaging-Based, J-Resolved Spectroscopic Imaging for Improved Metabolite Detection in Prostate Cancer

    DTIC Science & Technology

    2014-10-01

    Imaging (EP-JRESI); Citrate, Choline, Creatine , Spermine, 3Tesla MRI scanner, Endo-rectal MR coil, WET Water Suppression, prostate cancer (PCa...spectroscopic imaging are due to the overlap of metabolite resonances, quantifying few metabolites only (citrate (Cit), choline (Ch), creatine (Cr...concentrations of citrate (Cit), creatine (Cr), choline (Ch) and polyamines that are used to detect and diagnose PCa (2). The challenging task in 1D MRS

  17. Fiber optic choline biosensor

    NASA Astrophysics Data System (ADS)

    Wang, Hong; Cao, Xiaojian; Jia, Ke; Chai, Xueting; Lu, Hua; Lu, Zuhong

    2001-10-01

    A fiber optic fluorescence biosensor for choline is introduced in this paper. Choline is an important neurotransmitter in mammals. Due to the growing needs for on-site clinical monitoring of the choline, much effect has been devoted to develop choline biosensors. Fiber-optic fluorescence biosensors have many advantages, including miniaturization, flexibility, and lack of electrical contact and interference. The choline fiber-optic biosensor we designed implemented a bifurcated fiber to perform fluorescence measurements. The light of the blue LED is coupled into one end of the fiber as excitation and the emission spectrum from sensing film is monitored by fiber-spectrometer (S2000, Ocean Optics) through the other end of the fiber. The sensing end of the fiber is coated with Nafion film dispersed with choline oxidase and oxygen sensitive luminescent Ru(II) complex (Tris(2,2'-bipyridyl)dichlororuthenium(II), hexahydrate). Choline oxidase catalyzes the oxidation of choline to betaine and hydrogen peroxide while consuming oxygen. The fluorescence intensity of oxygen- sensitive Ru(II) are related to the choline concentration. The response of the fiber-optic sensor in choline solution is represented and discussed. The result indicates a low-cost, high-performance, portable choline biosensor.

  18. The role of dietary creatine.

    PubMed

    Brosnan, Margaret E; Brosnan, John T

    2016-08-01

    The daily requirement of a 70-kg male for creatine is about 2 g; up to half of this may be obtained from a typical omnivorous diet, with the remainder being synthesized in the body Creatine is a carninutrient, which means that it is only available to adults via animal foodstuffs, principally skeletal muscle, or via supplements. Infants receive creatine in mother's milk or in milk-based formulas. Vegans and infants fed on soy-based formulas receive no dietary creatine. Plasma and muscle creatine levels are usually somewhat lower in vegetarians than in omnivores. Human intake of creatine was probably much higher in Paleolithic times than today; some groups with extreme diets, such as Greenland and Alaskan Inuit, ingest much more than is currently typical. Creatine is synthesized from three amino acids: arginine, glycine and methionine (as S-adenosylmethionine). Humans can synthesize sufficient creatine for normal function unless they have an inborn error in a creatine-synthetic enzyme or a problem with the supply of substrate amino acids. Carnivorous animals, such as lions and wolves, ingest much larger amounts of creatine than humans would. The gastrointestinal tract and the liver are exposed to dietary creatine in higher concentrations before it is assimilated by other tissues. In this regard, our observations that creatine supplementation can prevent hepatic steatosis (Deminice et al. J Nutr 141:1799-1804, 2011) in a rodent model may be a function of the route of dietary assimilation. Creatine supplementation has also been reported to improve the intestinal barrier function of the rodent suffering from inflammatory bowel disease.

  19. Dietary choline and betaine intake, choline-metabolising genetic polymorphisms and breast cancer risk: a case-control study in China.

    PubMed

    Du, Yu-Feng; Luo, Wei-Ping; Lin, Fang-Yu; Lian, Zhen-Qiang; Mo, Xiong-Fei; Yan, Bo; Xu, Ming; Huang, Wu-Qing; Huang, Jing; Zhang, Cai-Xia

    2016-09-01

    Choline and betaine are essential nutrients involved in one-carbon metabolism and have been hypothesised to affect breast cancer risk. Functional polymorphisms in genes encoding choline-related one-carbon metabolism enzymes, including phosphatidylethanolamine N-methyltransferase (PEMT), choline dehydrogenase (CHDH) and betaine-homocysteine methyltransferase (BHMT), have important roles in choline metabolism and may thus interact with dietary choline and betaine intake to modify breast cancer risk. This study aimed to investigate the interactive effect of polymorphisms in PEMT, BHMT and CHDH genes with choline/betaine intake on breast cancer risk among Chinese women. This hospital-based case-control study consecutively recruited 570 cases with histologically confirmed breast cancer and 576 age-matched (5-year interval) controls. Choline and betaine intakes were assessed by a validated FFQ, and genotyping was conducted for PEMT rs7946, CHDH rs9001 and BHMT rs3733890. OR and 95 % CI were estimated using unconditional logistic regression. Compared with the highest quartile of choline intake, the lowest intake quartile showed a significant increased risk of breast cancer. The SNP PEMT rs7946, CHDH rs9001 and BHMT rs3733890 had no overall association with breast cancer, but a significant risk reduction was observed among postmenopausal women with AA genotype of BHMT rs3733890 (OR 0·49; 95 % CI 0·25, 0·98). Significant interactions were observed between choline intake and SNP PEMT rs7946 (P interaction=0·029) and BHMT rs3733890 (P interaction=0·006) in relation to breast cancer risk. Our results suggest that SNP PEMT rs7946 and BHMT rs3733890 may interact with choline intake on breast cancer risk.

  20. Choline concentrations are lower in postnatal plasma of preterm infants than in cord plasma.

    PubMed

    Bernhard, Wolfgang; Raith, Marco; Kunze, Rebecca; Koch, Vera; Heni, Martin; Maas, Christoph; Abele, Harald; Poets, Christian F; Franz, Axel R

    2015-08-01

    Choline is essential to human development, particularly of the brain in the form of phosphatidylcholine, sphingomyelin and acetylcholine, for bile and lipoprotein formation, and as a methyl group donator. Choline is actively transported into the fetus, and maternal supply correlates with cognitive outcome. Interruption of placental supply may therefore impair choline homeostasis in preterm infants. Determination of postnatal plasma concentrations of choline and its derivatives betaine and dimethylglycine (DMG) in preterm infants compared to cord and maternal blood matched for postmenstrual age (PMA). We collected plasma of very low-birth-weight infants undergoing neonatal intensive care (n = 162), cord plasma of term and preterm infants (n = 176, 24-42-week PMA), serum of parturients (n = 36), and plasma of healthy premenopausal women (n = 40). Target metabolites were analyzed with tandem mass spectrometry and reported as median (25th/75th percentiles). Cord plasma choline concentration was 41.4 (31.8-51.2) µmol/L and inversely correlated with PMA. In term but not in preterm infants, cord plasma choline was lower in girls than in boys. Prenatal glucocorticoid treatment did not affect choline levels in cord plasma, whereas betaine was decreased and DMG increased. In parturients and non-pregnant women, choline concentrations were 14.1 (10.3-16.9) and 8.8 (5.7-11.2) µmol/L, respectively, whereas betaine was lowest in parturients. After delivery, preterm infant plasma choline decreased to 20.8 (16.0-27.6) µmol/L within 48 h. Betaine and DMG correlated with plasma choline in all groups. In preterm infants, plasma choline decreases to 50 % of cord plasma concentrations, reflecting choline undernourishment and postnatal metabolic adaptation, and potentially contributing to impaired outcome.

  1. High affinity choline uptake (HACU) and choline acetyltransferase (ChAT) activity in neuronal cultures for mechanistic and drug discovery studies

    PubMed Central

    Ray, Balmiki; Bailey, Jason A.; Simon, Jay R.; Lahiri, Debomoy K.

    2012-01-01

    Acetylcholine (ACh) is the neurotransmitter used by cholinergic neurons at the neuromuscular junction and in parasympathetic nerve terminals in the periphery, as well as important memory-related circuits in the brain and also takes part in several critical functions. ACh is synthesized from choline and acetyl coenzyme-A by the enzyme choline acetyltransferase (ChAT). The formation of acetylcholine in cholinergic nerve terminals requires both the transport of choline into the cells from the extracellular space, and the activity of ChAT. High affinity choline uptake (HACU) represents the majority of choline uptake into the nerve terminal, and is the acutely regulated, rate-limiting step in ACh synthesis. The HACU component of choline uptake can be differentiated from non-specific choline uptake by inhibition of the choline transporter with hemicholinium. Several methods have been described previously to measure HACU and ChAT simultaneously in synaptosomes, but a well-documented protocol for cultured cells is lacking. We describe a procedure to simultaneously measure HACU and ChAT in cultured cells by simple radionuclide-based techniques. In this procedure we have quantitatively determined HACU and ChAT activity in cholinergically differentiated human neuroblastoma (SK-N-SH) cells. These simple methods can be used for neurochemical and drug discovery studies relevant to several disorders including Alzheimer’s disease, myasthenia gravis, and cardiovascular disease. PMID:22752895

  2. Cortical choline transporter function measured in vivo using choline-sensitive microelectrodes: clearance of endogenous and exogenous choline and effects of removal of cholinergic terminals.

    PubMed

    Parikh, V; Sarter, M

    2006-04-01

    The capacity of the high-affinity choline transporter (CHT) to import choline into presynaptic terminals is essential for acetylcholine synthesis. Ceramic-based microelectrodes, coated at recording sites with choline oxidase to detect extracellular choline concentration changes, were attached to multibarrel glass micropipettes and implanted into the rat frontoparietal cortex. Pressure ejections of hemicholinium-3 (HC-3), a selective CHT blocker, dose-dependently reduced the uptake rate of exogenous choline as well as that of choline generated in response to terminal depolarization. Following the removal of CHTs, choline signal recordings confirmed that the demonstration of potassium-induced choline signals and HC-3-induced decreases in choline clearance require the presence of cholinergic terminals. The results obtained from lesioned animals also confirmed the selectivity of the effects of HC-3 on choline clearance in intact animals. Residual cortical choline clearance correlated significantly with CHT-immunoreactivity in lesioned and intact animals. Finally, synaptosomal choline uptake assays were conducted under conditions reflecting in vivo basal extracellular choline concentrations. Results from these assays confirmed the capacity of CHTs measured in vivo and indicated that diffusion of substrate away from the electrode did not confound the in vivo findings. Collectively, these results indicate that increases in extracellular choline concentrations, irrespective of source, are rapidly cleared by CHTs.

  3. Does brain creatine content rely on exogenous creatine in healthy youth? A proof-of-principle study.

    PubMed

    Merege-Filho, Carlos Alberto Abujabra; Otaduy, Maria Concepción Garcia; de Sá-Pinto, Ana Lúcia; de Oliveira, Maira Okada; de Souza Gonçalves, Lívia; Hayashi, Ana Paula Tanaka; Roschel, Hamilton; Pereira, Rosa Maria Rodrigues; Silva, Clovis Artur; Brucki, Sonia Maria Dozzi; da Costa Leite, Claudia; Gualano, Bruno

    2017-02-01

    It has been hypothesized that dietary creatine could influence cognitive performance by increasing brain creatine in developing individuals. This double-blind, randomized, placebo-controlled, proof-of-principle study aimed to investigate the effects of creatine supplementation on cognitive function and brain creatine content in healthy youth. The sample comprised 67 healthy participants aged 10 to 12 years. The participants were given creatine or placebo supplementation for 7 days. At baseline and after the intervention, participants undertook a battery of cognitive tests. In a random subsample of participants, brain creatine content was also assessed in the regions of left dorsolateral prefrontal cortex, left hippocampus, and occipital lobe by proton magnetic resonance spectroscopy (1H-MRS) technique. The scores obtained from verbal learning and executive functions tests did not significantly differ between groups at baseline or after the intervention (all p > 0.05). Creatine content was not significantly different between groups in left dorsolateral prefrontal cortex, left hippocampus, and occipital lobe (all p > 0.05). In conclusion, a 7-day creatine supplementation protocol did not elicit improvements in brain creatine content or cognitive performance in healthy youth, suggesting that this population mainly relies on brain creatine synthesis rather than exogenous creatine intake to maintain brain creatine homeostasis.

  4. Associations of gut-flora-dependent metabolite trimethylamine-N-oxide, betaine and choline with non-alcoholic fatty liver disease in adults.

    PubMed

    Chen, Yu-ming; Liu, Yan; Zhou, Rui-fen; Chen, Xiao-ling; Wang, Cheng; Tan, Xu-ying; Wang, Li-jun; Zheng, Rui-dan; Zhang, Hong-wei; Ling, Wen-hua; Zhu, Hui-lian

    2016-01-08

    Many studies suggest that trimethylamine-N-oxide (TMAO), a gut-flora-dependent metabolite of choline, contributes to the risk of cardiovascular diseases, but little is known for non-alcoholic fatty liver disease (NAFLD). We examined the association of circulating TMAO, choline and betaine with the presence and severity of NAFLD in Chinese adults. We performed a hospital-based case-control study (CCS) and a cross-sectional study (CSS). In the CCS, we recruited 60 biopsy-proven NAFLD cases and 35 controls (18-60 years) and determined serum concentrations of TMAO, choline and betaine by HPLC-MS/MS. For the CSS, 1,628 community-based adults (40-75 years) completed the blood tests and ultrasonographic NAFLD evaluation. In the CCS, analyses of covariance showed adverse associations of ln-transformed serum levels of TMAO, choline and betaine/choline ratio with the scores of steatosis and total NAFLD activity (NAS) (all P-trend <0.05). The CSS revealed that a greater severity of NAFLD was independently correlated with higher TMAO but lower betaine and betaine/choline ratio (all P-trend <0.05). No significant choline-NAFLD association was observed. Our findings showed adverse associations between the circulating TMAO level and the presence and severity of NAFLD in hospital- and community-based Chinese adults, and a favorable betaine-NAFLD relationship in the community-based participants.

  5. Associations of gut-flora-dependent metabolite trimethylamine-N-oxide, betaine and choline with non-alcoholic fatty liver disease in adults

    PubMed Central

    Chen, Yu-ming; Liu, Yan; Zhou, Rui-fen; Chen, Xiao-ling; Wang, Cheng; Tan, Xu-ying; Wang, Li-jun; Zheng, Rui-dan; Zhang, Hong-wei; Ling, Wen-hua; Zhu, Hui-lian

    2016-01-01

    Many studies suggest that trimethylamine-N-oxide (TMAO), a gut-flora-dependent metabolite of choline, contributes to the risk of cardiovascular diseases, but little is known for non-alcoholic fatty liver disease (NAFLD). We examined the association of circulating TMAO, choline and betaine with the presence and severity of NAFLD in Chinese adults. We performed a hospital-based case-control study (CCS) and a cross-sectional study (CSS). In the CCS, we recruited 60 biopsy-proven NAFLD cases and 35 controls (18–60 years) and determined serum concentrations of TMAO, choline and betaine by HPLC-MS/MS. For the CSS, 1,628 community-based adults (40-75 years) completed the blood tests and ultrasonographic NAFLD evaluation. In the CCS, analyses of covariance showed adverse associations of ln-transformed serum levels of TMAO, choline and betaine/choline ratio with the scores of steatosis and total NAFLD activity (NAS) (all P-trend <0.05). The CSS revealed that a greater severity of NAFLD was independently correlated with higher TMAO but lower betaine and betaine/choline ratio (all P-trend <0.05). No significant choline-NAFLD association was observed. Our findings showed adverse associations between the circulating TMAO level and the presence and severity of NAFLD in hospital- and community-based Chinese adults, and a favorable betaine-NAFLD relationship in the community-based participants. PMID:26743949

  6. Repression of choline kinase by inositol and choline in Saccharomyces cerevisiae.

    PubMed Central

    Hosaka, K; Murakami, T; Kodaki, T; Nikawa, J; Yamashita, S

    1990-01-01

    The regulation of choline kinase (EC 2.7.1.32), the initial enzyme in the CDP-choline pathway, was examined in Saccharomyces cerevisiae. The addition of myo-inositol to a culture of wild-type cells resulted in a significant decrease in choline kinase activity. Additional supplementation of choline caused a further reduction in the activity. The coding frame of the choline kinase gene, CK1, was joined to the carboxyl terminus of lacZ and expressed in Escherichia coli as a fusion protein, which was then used to prepare an anti-choline kinase antibody. Upon Western (immuno-) and Northern (RNA) blot analyses using the antibody and a CK1 probe, respectively, the decrease in the enzyme activity was found to be correlated with decreases in the enzyme amount and mRNA abundance. The molecular mass of the enzyme was estimated to be 66 kilodaltons, in agreement with the value predicted previously from the nucleotide sequence of the gene. The coding region of CK1 was replaced with that of lacZ, and CK1 expression was measured by assaying beta-galactosidase. The expression of beta-galactosidase from this fusion was repressed by myo-inositol and choline and derepressed in a time-dependent manner upon their removal. The present findings indicate that yeast choline kinase is regulated by myo-inositol and choline at the level of mRNA abundance. Images FIG. 3 FIG. 4 PMID:2156807

  7. Creatine supplementation during pulmonary rehabilitation in chronic obstructive pulmonary disease

    PubMed Central

    Fuld, J; Kilduff, L; Neder, J; Pitsiladis, Y; Lean, M; Ward, S; Cotton, M

    2005-01-01

    Background: Skeletal muscle wasting and dysfunction are strong independent predictors of mortality in patients with chronic obstructive pulmonary disease (COPD). Creatine nutritional supplementation produces increased muscle mass and exercise performance in health. A controlled study was performed to look for similar effects in 38 patients with COPD. Methods: Thirty eight patients with COPD (mean (SD) forced expiratory volume in 1 second (FEV1) 46 (15)% predicted) were randomised to receive placebo (glucose polymer 40.7 g) or creatine (creatine monohydrate 5.7 g, glucose 35 g) supplements in a double blind trial. After 2 weeks loading (one dose three times daily), patients participated in an outpatient pulmonary rehabilitation programme combined with maintenance (once daily) supplementation. Pulmonary function, body composition, and exercise performance (peripheral muscle strength and endurance, shuttle walking, cycle ergometry) took place at baseline (n = 38), post loading (n = 36), and post rehabilitation (n = 25). Results: No difference was found in whole body exercise performance between the groups: for example, incremental shuttle walk distance mean –23.1 m (95% CI –71.7 to 25.5) post loading and –21.5 m (95% CI –90.6 to 47.7) post rehabilitation. Creatine increased fat-free mass by 1.09 kg (95% CI 0.43 to 1.74) post loading and 1.62 kg (95% CI 0.47 to 2.77) post rehabilitation. Peripheral muscle performance improved: knee extensor strength 4.2 N.m (95% CI 1.4 to 7.1) and endurance 411.1 J (95% CI 129.9 to 692.4) post loading, knee extensor strength 7.3 N.m (95% CI 0.69 to 13.92) and endurance 854.3 J (95% CI 131.3 to 1577.4) post rehabilitation. Creatine improved health status between baseline and post rehabilitation (St George's Respiratory Questionnaire total score –7.7 (95% CI –14.9 to –0.5)). Conclusions: Creatine supplementation led to increases in fat-free mass, peripheral muscle strength and endurance, health status, but not exercise

  8. Creatine phosphokinase test

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/003503.htm Creatine phosphokinase test To use the sharing features on this page, please enable JavaScript. Creatine phosphokinase (CPK) is an enzyme in the body. ...

  9. Disorders of creatine transport and metabolism.

    PubMed

    Longo, Nicola; Ardon, Orly; Vanzo, Rena; Schwartz, Elizabeth; Pasquali, Marzia

    2011-02-15

    Creatine is a nitrogen containing compound that serves as an energy shuttle between the mitochondrial sites of ATP production and the cytosol where ATP is utilized. There are two known disorders of creatine synthesis (both transmitted as autosomal recessive traits: arginine: glycine amidinotransferase (AGAT) deficiency; OMIM 602360; and guanidinoacetate methyltransferase (GAMT) deficiency (OMIM 601240)) and one disorder of creatine transport (X-linked recessive SLC6A8 creatine transporter deficiency (OMIM 300036)). All these disorders are characterized by brain creatine deficiency, detectable by magnetic resonance spectroscopy. Affected patients can have mental retardation, hypotonia, autism or behavioral problems and seizures. The diagnosis of these conditions relies on the measurement of plasma and urine creatine and guanidinoacetate. Creatine levels in plasma are reduced in both creatine synthesis defects and guanidinoacetate is increased in GAMT deficiency. The urine creatine/creatinine ratio is elevated in creatine transporter deficiency with normal plasma levels of creatine and guanidinoacetate. The diagnosis is confirmed in all cases by DNA testing or functional studies. Defects of creatine biosynthesis are treated with creatine supplements and, in GAMT deficiency, with ornithine and dietary restriction of arginine through limitation of protein intake. No causal therapy is yet available for creatine transporter deficiency and supplementation with the guanidinoacetate precursors arginine and glycine is being explored. The excellent response to therapy of early identified patients with GAMT or AGAT deficiency candidates these condition for inclusion in newborn screening programs. Copyright © 2011 Wiley-Liss, Inc.

  10. Choline is required in the diet of lactating dams to maintain maternal immune function.

    PubMed

    Dellschaft, Neele S; Ruth, Megan R; Goruk, Susan; Lewis, Erin D; Richard, Caroline; Jacobs, René L; Curtis, Jonathan M; Field, Catherine J

    2015-06-14

    Choline demands during lactation are high; however, detailed knowledge is lacking regarding the optimal dietary intake during this critical period. The present study was designed to determine the effects of varying intakes of choline on maternal immune function during lactation. Primiparous Sprague-Dawley rats (n 42) were randomised 24-48 h before birth and fed the following diets for 21 d: choline-devoid (0 g choline/kg diet; D, n 10); 1·0 g choline/kg diet (C1, n 11); 2·5 g choline/kg diet (C2·5, n 10); 6·2 g choline/kg diet (C6, n 11). Splenocytes were isolated and stimulated ex vivo with concanavalin A, lipopolysaccharide (LPS) or CD3/CD28. D and C6 dams had lower final body weight, spleen weight and average pup weight than C1 dams (P< 0·05). There was a linear relationship between free choline concentration in pup stomach contents with maternal dietary choline content (P< 0·001, r² 0·415). Compared with C1 and C2·5, D spleens had a lower proportion of mature T cells and activated suppressor cells, and this resulted in reduced cytokine production after stimulation (P< 0·05). Feeding 6·2 g choline/kg diet resulted in a higher cytokine production after stimulation with CD3/CD28 (P< 0·05). Except for a higher IL-6 production after LPS stimulation with cells from the C2·5 dams (P< 0·05), there were no differences between the C1 and C2·5 dams. For the first time, we show that feeding lactating mothers a diet free of choline has substantial effects on their immune function and on offspring growth. Additionally, excess dietary choline had adverse effects on maternal and offspring body weight but only minimal effects on maternal immune function.

  11. Choline Transport Activity Regulates Phosphatidylcholine Synthesis through Choline Transporter Hnm1 Stability*

    PubMed Central

    Fernández-Murray, J. Pedro; Ngo, Michael H.; McMaster, Christopher R.

    2013-01-01

    Choline is a precursor for the synthesis of phosphatidylcholine through the CDP-choline pathway. Saccharomyces cerevisiae expresses a single high affinity choline transporter at the plasma membrane, encoded by the HNM1 gene. We show that exposing cells to increasing levels of choline results in two different regulatory mechanisms impacting Hnm1 activity. Initial exposure to choline results in a rapid decrease in Hnm1-mediated transport at the level of transporter activity, whereas chronic exposure results in Hnm1 degradation through an endocytic mechanism that depends on the ubiquitin ligase Rsp5 and the casein kinase 1 redundant pair Yck1/Yck2. We present details of how the choline transporter is a major regulator of phosphatidylcholine synthesis. PMID:24187140

  12. Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease

    PubMed Central

    Sundgren, Pia C.; Strandberg, Olof; Zetterberg, Henrik; Minthon, Lennart; Blennow, Kaj; Wahlund, Lars-Olof; Westman, Eric

    2016-01-01

    Objective: We aimed to test whether in vivo levels of magnetic resonance spectroscopy (MRS) metabolites myo-inositol (mI), N-acetylaspartate (NAA), and choline are abnormal already during preclinical Alzheimer disease (AD), relating these changes to amyloid or tau pathology, and functional connectivity. Methods: In this cross-sectional multicenter study (a subset of the prospective Swedish BioFINDER study), we included 4 groups, representing the different stages of predementia AD: (1) cognitively healthy elderly with normal CSF β-amyloid 42 (Aβ42), (2) cognitively healthy elderly with abnormal CSF Aβ42, (3) patients with subjective cognitive decline and abnormal CSF Aβ42, (4) patients with mild cognitive decline and abnormal CSF Aβ42 (Ntotal = 352). Spectroscopic markers measured in the posterior cingulate/precuneus were considered alongside known disease biomarkers: CSF Aβ42, phosphorylated tau, total tau, [18F]-flutemetamol PET, f-MRI, and the genetic risk factor APOE. Results: Amyloid-positive cognitively healthy participants showed a significant increase in mI/creatine and mI/NAA levels compared to amyloid-negative healthy elderly (p < 0.05). In amyloid-positive healthy elderly, mI/creatine and mI/NAA correlated with cortical retention of [18F] flutemetamol tracer ( = 0.44, p = 0.02 and = 0.51, p = 0.01, respectively). Healthy elderly APOE ε4 carriers with normal CSF Aβ42 levels had significantly higher mI/creatine levels (p < 0.001) than ε4 noncarriers. Finally, elevated mI/creatine was associated with decreased functional connectivity within the default mode network (rpearson = −0.16, p = 0.02), independently of amyloid pathology. Conclusions: mI levels are elevated already at asymptomatic stages of AD. Moreover, mI/creatine concentrations were increased in healthy APOE ε4 carriers with normal CSF Aβ42 levels, suggesting that mI levels may reveal regional brain consequences of APOE ε4 before detectable amyloid pathology. PMID:27164711

  13. Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease.

    PubMed

    Voevodskaya, Olga; Sundgren, Pia C; Strandberg, Olof; Zetterberg, Henrik; Minthon, Lennart; Blennow, Kaj; Wahlund, Lars-Olof; Westman, Eric; Hansson, Oskar

    2016-05-10

    We aimed to test whether in vivo levels of magnetic resonance spectroscopy (MRS) metabolites myo-inositol (mI), N-acetylaspartate (NAA), and choline are abnormal already during preclinical Alzheimer disease (AD), relating these changes to amyloid or tau pathology, and functional connectivity. In this cross-sectional multicenter study (a subset of the prospective Swedish BioFINDER study), we included 4 groups, representing the different stages of predementia AD: (1) cognitively healthy elderly with normal CSF β-amyloid 42 (Aβ42), (2) cognitively healthy elderly with abnormal CSF Aβ42, (3) patients with subjective cognitive decline and abnormal CSF Aβ42, (4) patients with mild cognitive decline and abnormal CSF Aβ42 (Ntotal = 352). Spectroscopic markers measured in the posterior cingulate/precuneus were considered alongside known disease biomarkers: CSF Aβ42, phosphorylated tau, total tau, [(18)F]-flutemetamol PET, f-MRI, and the genetic risk factor APOE. Amyloid-positive cognitively healthy participants showed a significant increase in mI/creatine and mI/NAA levels compared to amyloid-negative healthy elderly (p < 0.05). In amyloid-positive healthy elderly, mI/creatine and mI/NAA correlated with cortical retention of [(18)F] flutemetamol tracer ([Formula: see text] = 0.44, p = 0.02 and [Formula: see text] = 0.51, p = 0.01, respectively). Healthy elderly APOE ε4 carriers with normal CSF Aβ42 levels had significantly higher mI/creatine levels (p < 0.001) than ε4 noncarriers. Finally, elevated mI/creatine was associated with decreased functional connectivity within the default mode network (rpearson = -0.16, p = 0.02), independently of amyloid pathology. mI levels are elevated already at asymptomatic stages of AD. Moreover, mI/creatine concentrations were increased in healthy APOE ε4 carriers with normal CSF Aβ42 levels, suggesting that mI levels may reveal regional brain consequences of APOE ε4 before detectable amyloid pathology. © 2016 American Academy

  14. Breast milk choline contents are associated with inflammatory status of breastfeeding women.

    PubMed

    Ozarda, Yesim; Cansev, Mehmet; Ulus, Ismail H

    2014-05-01

    Choline is an important component of human breast milk and its content varies considerably among breastfeeding women and lactation periods. The aim of this study was to assess the relationship between breast milk choline contents and inflammatory status in breastfeeding women. Breast milk choline compounds and serum C-reactive protein (CRP) concentrations were determined in breastfeeding women at 1 to 3 (n = 53) or 22 to 180 (n = 54) days postpartum, expressing colostrum or mature milk, respectively. Median concentrations of free choline, phosphocholine, glycerophosphocholine, phospholipid-bound choline, and total choline were 71, 38, 96, 194, and 407 µmol/L or 93, 351, 958, 186, and 1532 µmol/L in colostrum or mature milk, respectively. Median serum CRP concentrations were 4.13 mg/L and 0.33 mg/L at 1 to 3 days and 22 to 180 days postpartum, respectively. At 1 to 3 days postpartum, milk free choline, phosphocholine, glycerophosphocholine, and total choline as well as serum CRP concentrations were significantly higher in breastfeeding women who delivered by cesarean section than those who delivered via the vaginal route. Serum CRP concentration was positively correlated with colostrum free choline (r = 0.703; P < .001), phosphocholine (r = 0.759; P < .001), glycerophosphocholine (r = 0.706; P < .001), and total choline (r = 0.693; P < .001), whereas it was negatively correlated (r = -0.442; P < .001) with colostrum phospholipid-bound choline. Serum CRP was also negatively correlated with mature milk free choline (r = -0.278; P < .05), but no correlation was found between serum CRP and other choline compounds in mature milk. These data show that the concentrations of milk choline compounds are associated with inflammatory status of breastfeeding women, particularly during the first few days after delivery.

  15. Maternal dietary creatine supplementation does not alter the capacity for creatine synthesis in the newborn spiny mouse.

    PubMed

    Dickinson, Hayley; Ireland, Zoe J; Larosa, Domenic A; O'Connell, Bree A; Ellery, Stacey; Snow, Rod; Walker, David W

    2013-09-01

    We have previously reported that maternal creatine supplementation protects the neonate from hypoxic injury. Here, we investigated whether maternal creatine supplementation altered expression of the creatine synthesis enzymes (arginine:glycine amidinotransferase [AGAT], guanidinoaceteate methyltransferase [GAMT]) and the creatine transporter (solute carrier family 6 [neurotransmitter transporter, creatine] member 8: SLC6A8) in the term offspring. Pregnant spiny mice were fed a 5% creatine monohydrate diet from midgestation (day 20) to term (39 days). Placentas and neonatal kidney, liver, heart, and brain collected at 24 hours of age underwent quantitative polymerase chain reaction and Western blot analysis. Maternal creatine had no effect on the expression of AGAT and GAMT in neonatal kidney and liver, but mRNA expression of AGAT in brain tissues was significantly decreased in both male and female neonates born to mothers who were fed the creatine diet. SLC6A8 expression was not affected by maternal dietary creatine loading in any tissues. Maternal dietary creatine supplementation from midgestation in the spiny mouse did not alter the capacity for creatine synthesis or transport.

  16. Reduced NAA levels in the dorsolateral prefrontal cortex of young bipolar patients.

    PubMed

    Sassi, Roberto B; Stanley, Jeffrey A; Axelson, David; Brambilla, Paolo; Nicoletti, Mark A; Keshavan, Matcheri S; Ramos, Renato T; Ryan, Neal; Birmaher, Boris; Soares, Jair C

    2005-11-01

    Converging evidence implicates prefrontal circuits in the pathophysiology of bipolar disorder. Proton spectroscopy studies performed in adult bipolar patients assessing prefrontal regions have suggested decreased levels of N-acetylaspartate (NAA), a putative marker of neuronal integrity. In order to examine whether such abnormalities would also be found in younger patients, a 1H spectroscopy study was conducted that focused on the dorsolateral prefrontal cortex of children and adolescents with bipolar disorder. The authors examined the levels of NAA, creatine plus phosphocreatine, and choline-containing molecules in the left dorsolateral prefrontal cortex of 14 bipolar disorder patients (mean age=15.5 years, SD=3, eight female) and 18 healthy comparison subjects (mean age=17.3, SD=3.7, seven female) using short echo time, single-voxel in vivo 1H spectroscopy. Absolute metabolite levels were determined using the water signal as an internal reference. Bipolar patients presented significantly lower NAA levels and a significant inverse correlation between choline-containing molecules and number of previous affective episodes. No differences were found for other metabolites. These findings suggest that young bipolar patients have decreased NAA levels in the dorsolateral prefrontal cortex, similar to what was previously reported in adult patients. Such changes may reflect an underdevelopment of dendritic arborizations and synaptic connections. These neuronal abnormalities in the dorsolateral prefrontal cortex of bipolar disorder youth are unlikely to represent long-term degenerative processes, at least in the subgroup of patients where the illness had relatively early onset.

  17. Creatine and guanidinoacetate content of human milk and infant formulas: implications for creatine deficiency syndromes and amino acid metabolism.

    PubMed

    Edison, Erica E; Brosnan, Margaret E; Aziz, Khalid; Brosnan, John T

    2013-09-28

    Creatine is essential for normal neural development; children with inborn errors of creatine synthesis or transport exhibit neurological symptoms such as mental retardation, speech delay and epilepsy. Creatine accretion may occur through dietary intake or de novo creatine synthesis. The objective of the present study was to determine how much creatine an infant must synthesise de novo. We have calculated how much creatine an infant needs to account for urinary creatinine excretion (creatine's breakdown product) and new muscle lay-down. To measure an infant's dietary creatine intake, we measured creatine in mother's milk and in various commercially available infant formulas. Knowing the amount of milk/formula ingested, we calculated the amount of creatine ingested. We have found that a breast-fed infant receives about 9 % of the creatine needed in the diet and that infants fed cows' milk-based formula receive up to 36 % of the creatine needed. However, infants fed a soya-based infant formula receive negligible dietary creatine and must rely solely on de novo creatine synthesis. This is the first time that it has been shown that neonatal creatine accretion is largely due to de novo synthesis and not through dietary intake of creatine. This has important implications both for infants suffering from creatine deficiency syndromes and for neonatal amino acid metabolism.

  18. Dietary choline requirements of women: effects of estrogen and genetic variation123

    PubMed Central

    Fischer, Leslie M; da Costa, Kerry-Ann; Kwock, Lester; Galanko, Joseph

    2010-01-01

    Background: Choline is obtained from the diet and from the biosynthesis of phosphatidylcholine. Phosphatidylcholine is catalyzed by the enzyme phosphatidylethanolamine-N-methyltransferase (PEMT), which is induced by estrogen. Because they have lower estrogen concentrations, postmenopausal women are more susceptible to the risk of organ dysfunction in response to a low-choline diet. A common genetic polymorphism (rs12325817) in the PEMT gene can also increase this risk. Objective: The objective was to determine whether the risk of low choline–related organ dysfunction increases with the number of alleles of rs12325817 in premenopausal women and whether postmenopausal women (with or without rs12325817) treated with estrogen are more resistant to developing such symptoms. Design: Premenopausal women (n = 27) consumed a choline-sufficient diet followed by a very-low-choline diet until they developed organ dysfunction (or for 42 d), which was followed by a high-choline diet. Postmenopausal women (n = 22) were placed on the same diets but were first randomly assigned to receive estrogen or a placebo. The women were monitored for organ dysfunction and plasma choline metabolites and were genotyped for rs12325817. Results: A dose-response effect of rs12325817 on the risk of choline-related organ dysfunction was observed in premenopausal women: 80%, 43%, and 13% of women with 2, 1, or 0 alleles, respectively, developed organ dysfunction. Among postmenopausal women, 73% who received placebo but only 18% who received estrogen developed organ dysfunction during the low-choline diet. Conclusions: Because of their lower estrogen concentrations, postmenopausal women have a higher dietary requirement for choline than do premenopausal women. Choline requirements for both groups of women are further increased by rs12325817. This trial was registered at clinicaltrials.gov as NCT00065546. PMID:20861172

  19. Synthesis and biological evaluation of new creatine fatty esters revealed dodecyl creatine ester as a promising drug candidate for the treatment of the creatine transporter deficiency.

    PubMed

    Trotier-Faurion, Alexandra; Dézard, Sophie; Taran, Frédéric; Valayannopoulos, Vassili; de Lonlay, Pascale; Mabondzo, Aloïse

    2013-06-27

    The creatine transporter deficiency is a neurological disease caused by impairment of the creatine transporter SLC6A8, resulting in mental retardation associated with a complete absence of creatine within the brain and cellular energy perturbation of neuronal cells. One of the therapeutic hypotheses was to administer lipophilic creatine derivatives which are (1) thought to have better permeability through the cell membrane and (2) would not rely on the activity of SLC6A8 to penetrate the brain. Here, we synthesized creatine fatty esters through original organic chemistry process. A screening on an in vitro rat primary cell-based blood-brain barrier model and on a rat primary neuronal cells model demonstrated interesting properties of these prodrugs to incorporate into endothelial, astroglial, and neuronal cells according to a structure-activity relationship. Dodecyl creatine ester showed then a 20-fold increase in creatine content in pathological human fibroblasts compared with the endogenous creatine content, stating that it could be a promising drug candidate.

  20. Effect of creatine supplementation and drop-set resistance training in untrained aging adults.

    PubMed

    Johannsmeyer, Sarah; Candow, Darren G; Brahms, C Markus; Michel, Deborah; Zello, Gordon A

    2016-10-01

    To investigate the effects of creatine supplementation and drop-set resistance training in untrained aging adults. Participants were randomized to one of two groups: Creatine (CR: n=14, 7 females, 7 males; 58.0±3.0yrs, 0.1g/kg/day of creatine+0.1g/kg/day of maltodextrin) or Placebo (PLA: n=17, 7 females, 10 males; age: 57.6±5.0yrs, 0.2g/kg/day of maltodextrin) during 12weeks of drop-set resistance training (3days/week; 2 sets of leg press, chest press, hack squat and lat pull-down exercises performed to muscle fatigue at 80% baseline 1-repetition maximum [1-RM] immediately followed by repetitions to muscle fatigue at 30% baseline 1-RM). Prior to and following training and supplementation, assessments were made for body composition, muscle strength, muscle endurance, tasks of functionality, muscle protein catabolism and diet. Drop-set resistance training improved muscle mass, muscle strength, muscle endurance and tasks of functionality (p<0.05). The addition of creatine to drop-set resistance training significantly increased body mass (p=0.002) and muscle mass (p=0.007) compared to placebo. Males on creatine increased muscle strength (lat pull-down only) to a greater extent than females on creatine (p=0.005). Creatine enabled males to resistance train at a greater capacity over time compared to males on placebo (p=0.049) and females on creatine (p=0.012). Males on creatine (p=0.019) and females on placebo (p=0.014) decreased 3-MH compared to females on creatine. The addition of creatine to drop-set resistance training augments the gains in muscle mass from resistance training alone. Creatine is more effective in untrained aging males compared to untrained aging females. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Measurement of the abundance of choline and the distribution of choline-containing moieties in meat.

    PubMed

    Lewis, Erin D; Zhao, Yuan-Yuan; Richard, Caroline; Bruce, Heather L; Jacobs, René L; Field, Catherine J; Curtis, Jonathan M

    2015-01-01

    Epidemiological studies identify meat as a major source of choline; however, the most comprehensive reference for food choline content, the United States Department of Agriculture (USDA) database for dietary choline, does not include values for meats of importance in some regions. In this work, the total choline and choline-containing moieties of 20 samples of meat were analyzed by LC-MS/MS; 16 samples analyzed are absent from the USDA database and 4 samples included for comparison. Average total choline for one serving (75 g) was 50 ± 12 mg, which was 82.6% ± 5.5% phosphatidylcholine. There was general agreement between total choline levels in the meats analyzed in this work and USDA values. A strong negative correlation (r = -0.777, p < 0.001) between total choline and fat content was found. This research added choline composition data to a food group that is a major source of choline and ultimately this data will assist in obtaining more accurate estimates of dietary choline.

  2. Enzymes of creatine biosynthesis, arginine and methionine metabolism in normal and malignant cells.

    PubMed

    Bera, Soumen; Wallimann, Theo; Ray, Subhankar; Ray, Manju

    2008-12-01

    The creatine/creatine kinase system decreases drastically in sarcoma. In the present study, an investigation of catalytic activities, western blot and mRNA expression unambiguously demonstrates the prominent expression of the creatine-synthesizing enzymes l-arginine:glycine amidinotransferase and N-guanidinoacetate methyltransferase in sarcoma, Ehrlich ascites carcinoma and Sarcoma 180 cells, whereas both enzymes were virtually undetectable in normal muscle. Compared to that of normal animals, these enzymes remained unaffected in the kidney or liver of sarcoma-bearing mice. High activity and expression of mitochondrial arginase II in sarcoma indicated increased ornithine formation. Slightly or moderately higher levels of ornithine, guanidinoacetate and creatinine were observed in sarcoma compared to muscle. Despite the intrinsically low level of creatine in Ehrlich ascites carcinoma and Sarcoma 180 cells, these cells could significantly take up and release creatine, suggesting a functional creatine transport, as verified by measuring mRNA levels of creatine transporter. Transcript levels of arginase II, ornithine-decarboxylase, S-adenosyl-homocysteine hydrolase and methionine-synthase were significantly upregulated in sarcoma and in Ehrlich ascites carcinoma and Sarcoma 180 cells. Overall, the enzymes related to creatine and arginine/methionine metabolism were found to be significantly upregulated in malignant cells. However, the low levels of creatine kinase in the same malignant cells do not appear to be sufficient for the building up of an effective creatine/phosphocreatine pool. Instead of supporting creatine biosynthesis, l-arginine:glycine amidinotransferase and N-guanidinoacetate methyltransferase appear to be geared to support cancer cell metabolism in the direction of polyamine and methionine synthesis because both these compounds are in high demand in proliferating cancer cells.

  3. Whole Body Creatine and Protein Kinetics in Healthy Men and Women: Effects of creatine and amino acid supplementation

    PubMed Central

    Kalhan, Satish C; Gruca, Lourdes; Marczewski, Susan; Bennett, Carole; Kummitha, China

    2015-01-01

    Creatine kinetics were measured in young healthy subjects, eight males and seven females, age 20–30 years, after an overnight fast on creatine free diet. Whole body turnover of glycine and its appearance in creatine was quantified using [1-13C] glycine and the rate of protein turnover was quantified using L-ring [2H5] phenylalanine. The creatine pool size was estimated by the dilution of a bolus [C2H3] creatine. Studies were repeated following a five days supplement creatine 21g.day−1 and following supplement amino acids 14.3 g.day−1. Creatine caused a ten folds increase in the plasma concentration of creatine and a 50% decrease in the concentration of guanidinoacetic acid. Plasma amino acids profile showed a significant decrease in glycine, glutamine and taurine and a significant increase in citrulline, valine, lysine and cysteine. There was a significant decrease in the rate of appearance of glycine, suggesting a decrease in de-novo synthesis (p=0.006). The fractional and absolute rate of synthesis of creatine was significantly decreased by supplemental creatine. Amino acid supplement had no impact on any of the parameters. Creatine supplement caused a significant decrease in the rate of synthesis of creatine. This is the first detailed analysis of creatine kinetics and the effects of creatine supplement in healthy young men and women. These methods can be applied for the analysis of creatine kinetics in different physiological states. PMID:26480831

  4. Choline intake and genetic polymorphisms influence choline metabolite concentrations in human breast milk and plasma123

    PubMed Central

    Fischer, Leslie M; da Costa, Kerry Ann; Galanko, Joseph; Sha, Wei; Stephenson, Brigitte; Vick, Julie; Zeisel, Steven H

    2010-01-01

    Background: Choline is essential for infant nutrition, and breast milk is a rich source of this nutrient. Common single nucleotide polymorphisms (SNPs) change dietary requirements for choline intake. Objective: The aim of this study was to determine whether total choline intake and/or SNPs influence concentrations of choline and its metabolites in human breast milk and plasma. Design: We gave a total of 103 pregnant women supplemental choline or a placebo from 18 wk gestation to 45 d postpartum and genotyped the women for 370 common SNPs. At 45 d postpartum, we measured choline metabolite concentrations in breast milk and plasma and assessed the dietary intake of choline by using a 3-d food record. Results: On average, lactating women in our study ate two-thirds of the recommended intake for choline (Adequate Intake = 550 mg choline/d). Dietary choline intake (no supplement) correlated with breast-milk phosphatidylcholine and plasma choline concentrations. A supplement further increased breast-milk choline, betaine, and phosphocholine concentrations and increased plasma choline and betaine concentrations. We identified 5 SNPs in MTHFR that altered the slope of the intake–metabolite concentration relations, and we identified 2 SNPs in PEMT that shifted these curves upward. Individuals who shared sets of common SNPs were outliers in plots of intake–metabolite concentration curves; we suggest that these SNPs should be further investigated to determine how they alter choline metabolism. Conclusion: Total intake of choline and genotype can influence the concentrations of choline and its metabolites in the breast milk and blood of lactating women and thereby affect the amount of choline available to the developing infant. This study was registered at clinicaltrials.gov as NCT00678925. PMID:20534746

  5. 21 CFR 862.1215 - Creatine phosphokinase/creatine kinase or isoenzymes test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1215 Creatine phosphokinase/creatine kinase or isoenzymes test system...

  6. 21 CFR 862.1215 - Creatine phosphokinase/creatine kinase or isoenzymes test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1215 Creatine phosphokinase/creatine kinase or isoenzymes test system...

  7. 21 CFR 862.1215 - Creatine phosphokinase/creatine kinase or isoenzymes test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1215 Creatine phosphokinase/creatine kinase or isoenzymes test system...

  8. 21 CFR 862.1215 - Creatine phosphokinase/creatine kinase or isoenzymes test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862.1215 Creatine phosphokinase/creatine kinase or isoenzymes test system...

  9. N-acetylaspartate catabolism determines cytosolic acetyl-CoA levels and histone acetylation in brown adipocytes

    PubMed Central

    Prokesch, A.; Pelzmann, H. J.; Pessentheiner, A. R.; Huber, K.; Madreiter-Sokolowski, C. T.; Drougard, A.; Schittmayer, M.; Kolb, D.; Magnes, C.; Trausinger, G.; Graier, W. F.; Birner-Gruenberger, R.; Pospisilik, J. A.; Bogner-Strauss, J. G.

    2016-01-01

    Histone acetylation depends on the abundance of nucleo-cytoplasmic acetyl-CoA. Here, we present a novel route for cytoplasmic acetyl-CoA production in brown adipocytes. N-acetylaspartate (NAA) is a highly abundant brain metabolite catabolized by aspartoacylase yielding aspartate and acetate. The latter can be further used for acetyl-CoA production. Prior to this work, the presence of NAA has not been described in adipocytes. Here, we show that accumulation of NAA decreases the brown adipocyte phenotype. We increased intracellular NAA concentrations in brown adipocytes via media supplementation or knock-down of aspartoacylase and measured reduced lipolysis, thermogenic gene expression, and oxygen consumption. Combinations of approaches to increase intracellular NAA levels showed additive effects on lipolysis and gene repression, nearly abolishing the expression of Ucp1, Cidea, Prdm16, and Ppara. Transcriptome analyses of aspartoacylase knock-down cells indicate deficiencies in acetyl-CoA and lipid metabolism. Concordantly, cytoplasmic acetyl-CoA levels and global histone H3 acetylation were decreased. Further, activating histone marks (H3K27ac and H3K9ac) in promoters/enhancers of brown marker genes showed reduced acetylation status. Taken together, we present a novel route for cytoplasmic acetyl-CoA production in brown adipocytes. Thereby, we mechanistically connect the NAA pathway to the epigenomic regulation of gene expression, modulating the phenotype of brown adipocytes. PMID:27045997

  10. Psychostimulant drug effects on glutamate, Glx, and creatine in the anterior cingulate cortex and subjective response in healthy humans.

    PubMed

    White, Tara L; Monnig, Mollie A; Walsh, Edward G; Nitenson, Adam Z; Harris, Ashley D; Cohen, Ronald A; Porges, Eric C; Woods, Adam J; Lamb, Damon G; Boyd, Chelsea A; Fekir, Sinda

    2018-06-01

    Prescription psychostimulants produce rapid changes in mood, energy, and attention. These drugs are widely used and abused. However, their effects in human neocortex on glutamate and glutamine (pooled as Glx), and key neurometabolites such as N-acetylaspartate (tNAA), creatine (tCr), choline (Cho), and myo-inositol (Ins) are poorly understood. Changes in these compounds could inform the mechanism of action of psychostimulant drugs and their abuse potential in humans. We investigated the acute impact of two FDA-approved psychostimulant drugs on neurometabolites using magnetic resonance spectroscopy ( 1 H MRS). Single clinically relevant doses of d-amphetamine (AMP, 20 mg oral), methamphetamine (MA, 20 mg oral; Desoxyn®), or placebo were administered to healthy participants (n = 26) on three separate test days in a placebo-controlled, double-blinded, within-subjects crossover design. Each participant experienced all three conditions and thus served as his/her own control. 1 H MRS was conducted in the dorsal anterior cingulate cortex (dACC), an integrative neocortical hub, during the peak period of drug responses (140-150 m post ingestion). D-amphetamine increased the level of Glu (p = .0001), Glx (p = .003), and tCr (p = .0067) in the dACC. Methamphetamine increased Glu in females, producing a significant crossover interaction pattern with gender (p = .02). Drug effects on Glu, tCr, and Glx were positively correlated with subjective drug responses, predicting both the duration of AMP liking (Glu: r = +.49, p = .02; tCr: r = +.41, p = .047) and the magnitude of peak drug high to MA (Glu: r = +.52, p = .016; Glx: r = +.42, p = .049). Neither drug affected the levels of tNAA, Cho, or Ins after correction for multiple comparisons. We conclude that d-amphetamine increased the concentration of glutamate, Glx, and tCr in the dACC in male and female volunteers 2 1 / 2 hours after drug consumption. There was evidence

  11. 1H Magnetic resonance spectroscopy of the internal capsule in human brain: a feasibility study to detect lactate following contralateral motor activity.

    PubMed

    Mostert, Jop P; Sijens, Paul E; Oudkerk, Matthijs; De Keyser, Jacques

    2005-07-01

    Animal experiments suggest that astrocytic glycogen may act as an energy source for axons especially during heightened activity. In this model astrocytic glycogen breaks down to lactate that is shuttled to axons where it is metabolized oxidatively to generate ATP. The aim of this study was to investigate whether (1)H-magnetic resonance spectroscopy could be used to detect a rise in lactate levels in human white matter during enhanced axonal activation. Six healthy volunteers (four women and two men; age range 21-38 years) participated in the study. We were unable to detect any significant MR spectral change, i.e. neither in the peak areas of inositol, choline, creatine, glutamate and N-acetylaspartate nor in the lactate level, in the contralateral posterior limb of the internal capsule during intense motor activation of the hand (four successive episodes of squeezing a soft ball for 7 min followed by 7 min rest). Possible explanations are that the technique is not sensitive enough to detect a small rise in lactate, or lactate turnover is too fast to be detected, or that another monocarboxylate different from lactate may be involved in axonal energy metabolism.

  12. In vivo human brain biochemistry after aerobic exercise: preliminary report on functional magnetic resonance spectroscopy.

    PubMed

    Cağlar, Ertunga; Sabuncuoğlu, Hakan; Keskin, Tülay; Isikli, Sedat; Keskil, Semih; Korkusuz, Feza

    2005-01-01

    Our aim was to disclose whether the positive psychological changes observed after a single bout of aerobic exercise have a biochemical correlate that can be visualized by proton magnetic resonance spectroscopy (MRS) of the human brain. Right-handed male volunteers underwent psychological testing and MRS of the frontal lobe of the left hemisphere, both before and after 20 minutes of jogging at about 70% of their maximal aerobic capacity. Although there was a significant decrease on the postexercise anxiety test scores (z = -2.201, P < .05), there was no significant difference between the preexercise and postexercise scores of positive and negative affect. Considering both "amplitude" and "area under the curve" values calculated for the peaks of metabolites N-acetylaspartate (NAA), creatine, and choline, none were found to be significantly changed (P > .05) after the exercise. This is, to our knowledge, the first study to report on a functional application of MRS to mood states. Because it offers the ability to directly measure metabolic changes in the brain during neuronal activation, "functional MRS" may be a potential new tool that may be used as an adjunct to functional magnetic resonance imaging.

  13. Creatine supplementation in high school football players.

    PubMed

    McGuine, T A; Sullivan, J C; Bernhardt, D T

    2001-10-01

    To describe creatine supplementation patterns and behaviors associated with creatine supplementation in high school football players. A cross-sectional, multisite, anonymous, descriptive survey was conducted between October 1999 and February 2000. 37 public high schools in Wisconsin. A total of 1,349 high school football players, grades 9-12. Self-reported prevalence of creatine use, as well as perceived benefits and risks. In addition, sources of information and influence regarding creatine supplementation were assessed. 30% of the respondents reported using creatine. Creatine use was lowest in the 9th grade (10.4%) and highest in the 12th grade (50.5%). 41% of the players at small schools stated they used creatine compared with 29% of the players in large schools. Enhanced recovery following a workout was the most likely perceived benefit of creatine supplementation, while dehydration was cited most often as a risk of creatine use. Users were encouraged to take creatine most often by their friends while their parents discouraged creatine use. Creatine use is widespread in high school football players. High school football players who use creatine may not be aware of the risks and benefits associated with creatine supplementation. Sports medicine professionals who work with this population need to educate athletes, coaches, and parents about the use of creatine as a performance-enhancing supplement.

  14. The metabolic burden of creatine synthesis.

    PubMed

    Brosnan, John T; da Silva, Robin P; Brosnan, Margaret E

    2011-05-01

    Creatine synthesis is required in adult animals to replace creatine that is spontaneously converted to creatinine and excreted in the urine. Additionally, in growing animals it is necessary to provide creatine to the expanding tissue mass. Creatine synthesis requires three amino acids: glycine, methionine and arginine, and three enzymes: L-arginine:glycine amidinotransferase (AGAT), methionine adenosyltransferase (MAT) and guanidinoacetate methyltransferase (GAMT). The entire glycine molecule is consumed in creatine synthesis but only the methyl and amidino groups, respectively, from methionine and arginine. Creatinine loss averages approximately 2 g (14.6 mmol) for 70 kg males in the 20- to 39-year age group. Creatinine loss is lower in females and in older age groups because of lower muscle mass. Approximately half of this creatine lost to creatinine can be replaced, in omnivorous individuals, by dietary creatine. However, since dietary creatine is only provided in animal products, principally in meat and fish, virtually all of the creatine loss in vegetarians must be replaced via endogenous synthesis. Creatine synthesis does not appear to place a major burden on glycine metabolism in adults since this amino acid is readily synthesized. However, creatine synthesis does account for approximately 40% of all of the labile methyl groups provided by S-adenosylmethionine (SAM) and, as such, places an appreciable burden on the provision of such methyl groups, either from the diet or via de novo methylneogenesis. Creatine synthesis consumes some 20-30% of arginine's amidino groups, whether provided in the diet or synthesized within the body. Creatine synthesis is, therefore, a quantitatively major pathway in amino acid metabolism and imposes an appreciable burden on the metabolism of methionine and of arginine.

  15. Synthesis of guanidinoacetate and creatine from amino acids by rat pancreas.

    PubMed

    da Silva, Robin P; Clow, Kathy; Brosnan, John T; Brosnan, Margaret E

    2014-02-01

    Creatine is an important molecule involved in cellular energy metabolism. Creatine is spontaneously converted to creatinine at a rate of 1·7% per d; creatinine is lost in the urine. Creatine can be obtained from the diet or synthesised from endogenous amino acids via the enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate N-methyltransferase (GAMT). The liver has high GAMT activity and the kidney has high AGAT activity. Although the pancreas has both AGAT and GAMT activities, its possible role in creatine synthesis has not been characterised. In the present study, we examined the enzymes involved in creatine synthesis in the pancreas as well as the synthesis of guanidinoacetate (GAA) and creatine by isolated pancreatic acini. We found significant AGAT activity and somewhat lower GAMT activity in the pancreas and that pancreatic acini had measurable activities of both AGAT and GAMT and the capacity to synthesise GAA and creatine from amino acids. Creatine supplementation led to a decrease in AGAT activity in the pancreas, though it did not affect its mRNA or protein abundance. This was in contrast with the reduction of AGAT activity and mRNA and protein abundance in the kidney, suggesting that the regulatory mechanisms that control the expression of this enzyme in the pancreas are different from those in the kidney. Dietary creatine increased the concentrations of GAA, creatine and phosphocreatine in the pancreas. Unexpectedly, creatine supplementation decreased the concentrations of S-adenosylmethionine, while those of S-adenosylhomocysteine were not altered significantly.

  16. Whole body creatine and protein kinetics in healthy men and women: effects of creatine and amino acid supplementation.

    PubMed

    Kalhan, Satish C; Gruca, Lourdes; Marczewski, Susan; Bennett, Carole; Kummitha, China

    2016-03-01

    Creatine kinetics were measured in young healthy subjects, eight males and seven females, age 20-30 years, after an overnight fast on creatine-free diet. Whole body turnover of glycine and its appearance in creatine was quantified using [1-(13)C] glycine and the rate of protein turnover was quantified using L-ring [(2)H5] phenylalanine. The creatine pool size was estimated by the dilution of a bolus [C(2)H3] creatine. Studies were repeated following a five days supplement creatine 21 g.day(-1) and following supplement amino acids 14.3 g day(-1). Creatine caused a ten-fold increase in the plasma concentration of creatine and a 50 % decrease in the concentration of guanidinoacetic acid. Plasma amino acids profile showed a significant decrease in glycine, glutamine, and taurine and a significant increase in citrulline, valine, lysine, and cysteine. There was a significant decrease in the rate of appearance of glycine, suggesting a decrease in de-novo synthesis (p = 0.006). The fractional and absolute rate of synthesis of creatine was significantly decreased by supplemental creatine. Amino acid supplement had no impact on any of the parameters. This is the first detailed analysis of creatine kinetics and the effects of creatine supplement in healthy young men and women. These methods can be applied for the analysis of creatine kinetics in different physiological states.

  17. Concentrations of Water-Soluble Forms of Choline in Human Milk from Lactating Women in Canada and Cambodia

    PubMed Central

    Wiedeman, Alejandra M.; March, Kaitlin M.; Chen, Nancy N.; Kroeun, Hou; Sokhoing, Ly; Sophonneary, Prak; Dyer, Roger A.; Xu, Zhaoming; Kitts, David D.; Innis, Sheila M.

    2018-01-01

    Choline has critical roles during periods of rapid growth and development, such as infancy. In human milk, choline is mostly present in water-soluble forms (free choline, phosphocholine, and glycerophosphocholine). It is thought that milk choline concentration is influenced by maternal choline intake, and the richest food sources for choline are of animal origin. Scarce information exists on milk choline from countries differing in animal-source food availability. In this secondary analysis of samples from previous trials, the concentrations of the water-soluble forms of choline were quantified by liquid chromatography-tandem mass spectrometry in mature milk samples collected from lactating women in Canada (n = 301) and in Cambodia (n = 67). None of the water-soluble forms of choline concentrations in milk differed between Canada and Cambodia. For all milk samples (n = 368), free choline, phosphocholine, glycerophosphocholine, and the sum of water-soluble forms of choline concentrations in milk were (mean (95%CI)) 151 (141, 160, 540 (519, 562), 411 (396, 427), and 1102 (1072, 1133) µmol/L, respectively. Theoretically, only 19% of infants would meet the current Adequate Intake (AI) for choline. Our findings suggest that the concentrations in milk of water-soluble forms of choline are similar in Canada and Cambodia, and that the concentration used to set the infant AI might be inaccurate. PMID:29558412

  18. Concentrations of Water-Soluble Forms of Choline in Human Milk from Lactating Women in Canada and Cambodia.

    PubMed

    Wiedeman, Alejandra M; Whitfield, Kyly C; March, Kaitlin M; Chen, Nancy N; Kroeun, Hou; Sokhoing, Ly; Sophonneary, Prak; Dyer, Roger A; Xu, Zhaoming; Kitts, David D; Green, Timothy J; Innis, Sheila M; Barr, Susan I

    2018-03-20

    Choline has critical roles during periods of rapid growth and development, such as infancy. In human milk, choline is mostly present in water-soluble forms (free choline, phosphocholine, and glycerophosphocholine). It is thought that milk choline concentration is influenced by maternal choline intake, and the richest food sources for choline are of animal origin. Scarce information exists on milk choline from countries differing in animal-source food availability. In this secondary analysis of samples from previous trials, the concentrations of the water-soluble forms of choline were quantified by liquid chromatography-tandem mass spectrometry in mature milk samples collected from lactating women in Canada ( n = 301) and in Cambodia ( n = 67). None of the water-soluble forms of choline concentrations in milk differed between Canada and Cambodia. For all milk samples ( n = 368), free choline, phosphocholine, glycerophosphocholine, and the sum of water-soluble forms of choline concentrations in milk were (mean (95%CI)) 151 (141, 160, 540 (519, 562), 411 (396, 427), and 1102 (1072, 1133) µmol/L, respectively. Theoretically, only 19% of infants would meet the current Adequate Intake (AI) for choline. Our findings suggest that the concentrations in milk of water-soluble forms of choline are similar in Canada and Cambodia, and that the concentration used to set the infant AI might be inaccurate.

  19. Simultaneous determination of trimethylamine N-oxide, choline, betaine by UPLC-MS/MS in human plasma: An application in acute stroke patients.

    PubMed

    Yu, Weibang; Xu, Chuncao; Li, Guomin; Hong, Weipeng; Zhou, Ziyi; Xiao, Canxing; Zhao, Yuanqi; Cai, Yefeng; Huang, Min; Jin, Jing

    2018-04-15

    Trimethylamine-N-oxide (TMAO) is derived from the gut microbiome and tissues metabolism of dietary choline and betaine. These molecules are closely related to the development of cardiovascular and cerebrovascular diseases. A rapid, sensitive and accurate method has been developed and validated for the simultaneous determination of trimethylamine N-oxide (TMAO), choline and betaine in human plasma using d9-trimethylamine N-oxide (TMAO), d9-choline, d9-betaine as the internal standard (IS). After methanol precipitation with 10 μL plasma samples, the analytes were extracted and then separated on Amide column (2.1 × 100 mm, 1.7 μm, waters) with an isocratic elution program consisting of acetonitrile-water (containing 10 mM ammonium formate pH = 3.0) at a flow of 400 μL/min. The detection was achieved under the selected reaction monitoring (SRM) scan using positive electrospray ionization (ESI+) in 3 min. The mass transitions monitored were as follows: m/z 76.3 → 58.4 for TMAO, m/z 104.2 → 60.3 for choline, m/z 118.1 → 58.3 for betaine, m/z 85.1 → 66.3 for d9-TMAO, m/z 113.2 → 69.3 for d9-choline, and m/z 127.1 → 67.2 for d9-betaine, respectively. The method has been fully validated for specificity, lower limit of quantification, linearity, stability, intra- and inter-day accuracy and precision. This assay combines simple sample processing with a short run time and small plasma volumes, making it well suited for high-throughput routine clinical or research purposes. The newly developed method was successfully applied to the patients (n = 220) suffered from acute stroke, and the concentration of choline was firstly found to be closely related with the prognosis of these patients. Copyright © 2018 Elsevier B.V. All rights reserved.

  20. N-methyl-D-aspartate increases acetylcholine release from rat striatum and cortex: its effect is augmented by choline

    NASA Technical Reports Server (NTRS)

    Ulus, I. H.; Buyukuysal, R. L.; Wurtman, R. J.

    1992-01-01

    We examined the effects of N-methyl-D-aspartate (NMDA), a glutamate agonist, and of glutamate itself, on acetylcholine (ACh) release from superfused rat striatal slices. In a Mg(++)-free medium, NMDA (32-1000 microM) as well as glutamate (1 mM) increased basal ACh release by 35 to 100% (all indicated differences, P less than .05), without altering tissue ACh or choline contents. This augmentation was blocked by Mg++ (1.2 mM) or by MK-801 (10 microM). Electrical stimulation (15 Hz, 75 mA) increased ACh release 9-fold (from 400 to 3660 pmol/mg of protein): this was enhanced (to 4850 pmol/mg of protein) by NMDA (100 microM). ACh levels in stimulated slices fell by 50 or 65% depending on the absence or presence of NMDA. The addition of choline (40 microM) increased ACh release both basally (570 pmol/mg of protein) and with electrical stimulation (6900 pmol/mg of protein). In stimulated slices choline acted synergistically with NMDA, raising ACh release to 10,520 pmol/mg of protein. The presence of choline also blocked the fall in tissue ACh. No treatment affected tissue phospholipid or protein levels. NMDA (32-320 microM) also augmented basal ACh release from cortical but not hippocampal slices. Choline efflux from striatal and cortical (but not hippocampal) slices decreased by 34 to 50% in Mg(++)-free medium. These data indicate that NMDA-like drugs may be useful, particularly in combination with choline, to enhance striatal and cortical cholinergic activity. ACh release from rat hippocampus apparently is not affected by NMDA receptors.

  1. A new method to synthesize creatine derivatives.

    PubMed

    Garbati, Patrizia; Salis, Annalisa; Adriano, Enrico; Galatini, Andrea; Damonte, Gianluca; Balestrino, Maurizio; Millo, Enrico

    2013-10-01

    Creatine is an amino acid that has a pivotal role in energy metabolism of cells. Creatine acts as an "ATP shuttle", carrying ATP to the sites where it is utilized, through its reversible phosphorylation by creatine kinase. Moreover, the creatine-phosphocreatine system delays ATP depletion during anoxia or ischemia, thus exerting a neuroprotective role during those pathological conditions. Thus, its administration has been advocated as a treatment or prevention of several conditions involving the central nervous system. However, creatine crosses poorly the blood-brain barrier and the cell plasma membrane, thus its administration has but a limited effect. The use of more lipophilic creatine derivatives has thus been suggested. However, such a synthesis is complicated by the intrinsic characteristics of the creatine molecule that hardly reacts with other molecules and easily cyclizes to creatinine. We obtained amide derivatives from creatine starting from a new protected creatine molecule synthesized by us, the so-called (Boc)2-creatine. We used a temporary protection only on the creatine guanidine group while allowing a good reactivity on the carboxylic group. This temporary protection ensured efficient creatine dissolution in organic solvents and offered simultaneous protection of creatine toward intramolecular cyclization to creatinine. In this manner, it was possible to selectively conjugate molecules on the carboxylic group. The creatine guanidine group was easily released from the protection at the end of the reaction, thus obtaining the desired creatine derivative.

  2. Aerobic fitness and the brain: increased N-acetyl-aspartate and choline concentrations in endurance-trained middle-aged adults.

    PubMed

    Gonzales, Mitzi M; Tarumi, Takashi; Kaur, Sonya; Nualnim, Nantinee; Fallow, Bennett A; Pyron, Martha; Tanaka, Hirofumi; Haley, Andreana P

    2013-01-01

    Engagement in regular aerobic exercise is associated with cognitive benefits, but information on the mechanisms governing these changes in humans is limited. The goal of the current study was to compare neurometabolite concentrations relating to cellular metabolism, structure, and viability in endurance-trained and sedentary middle-aged adults. Twenty-eight endurance-trained and 27 sedentary adults, aged 40-65 years, underwent general health assessment, cardiorespiratory fitness measurement, neuropsychological testing, and proton magnetic resonance spectroscopy ((1)H MRS). (1)H MRS was used to examine N-acetyl-aspartate (NAA), creatine (Cr), myo-inositol (mI), choline (Cho), and glutamate (Glu) concentrations in frontal and occipitoparietal grey matter. Group differences in concentrations of NAA, Cho, mI, and Glu, calculated as ratios over Cr, were explored using ANOVA. There were no significant differences in global cognitive function, memory, and executive function performance between the groups. In comparison to sedentary adults, the endurance-trained group displayed significantly higher NAA/Cr in the frontal grey matter (F(1, 53) = 5.367, p = 0.024) and higher Cho/Cr in the occipitoparietal grey matter (F(1, 53) = 5.138, p = 0.028). Within our middle-aged sample, endurance-trained adults demonstrated higher levels of NAA/Cr in the frontal grey matter and higher Cho/Cr in the occipitoparietal grey matter. Higher levels of NAA may indicate greater neuronal integrity and higher cerebral metabolic efficiency in association with cardiorespiratory fitness, whereas increased Cho may represent increased phospholipid levels secondary to neural plasticity.

  3. Creatine maintains intestinal homeostasis and protects against colitis.

    PubMed

    Turer, Emre; McAlpine, William; Wang, Kuan-Wen; Lu, Tianshi; Li, Xiaohong; Tang, Miao; Zhan, Xiaoming; Wang, Tao; Zhan, Xiaowei; Bu, Chun-Hui; Murray, Anne R; Beutler, Bruce

    2017-02-14

    Creatine, a nitrogenous organic acid, replenishes cytoplasmic ATP at the expense of mitochondrial ATP via the phosphocreatine shuttle. Creatine levels are maintained by diet and endogenous synthesis from arginine and glycine. Glycine amidinotransferase (GATM) catalyzes the rate-limiting step of creatine biosynthesis: the transfer of an amidino group from arginine to glycine to form ornithine and guanidinoacetate. We screened 36,530 third-generation germline mutant mice derived from N -ethyl- N -nitrosourea-mutagenized grandsires for intestinal homeostasis abnormalities after oral administration of dextran sodium sulfate (DSS). Among 27 colitis susceptibility phenotypes identified and mapped, one was strongly correlated with a missense mutation in Gatm in a recessive model of inheritance, and causation was confirmed by CRISPR/Cas9 gene targeting. Supplementation of homozygous Gatm mutants with exogenous creatine ameliorated the colitis phenotype. CRISPR/Cas9-targeted ( Gatm c/c ) mice displayed a normal peripheral immune response and immune cell homeostasis. However, the intestinal epithelium of the Gatm c/c mice displayed increased cell death and decreased proliferation during DSS treatment. In addition, Gatm c/c colonocytes showed increased metabolic stress in response to DSS with higher levels of phospho-AMPK and lower levels of phosphorylation of mammalian target of rapamycin (phospho-mTOR). These findings establish an in vivo requirement for rapid replenishment of cytoplasmic ATP within colonic epithelial cells in the maintenance of the mucosal barrier after injury.

  4. Creatine maintains intestinal homeostasis and protects against colitis

    PubMed Central

    Turer, Emre; McAlpine, William; Wang, Kuan-wen; Lu, Tianshi; Li, Xiaohong; Tang, Miao; Zhan, Xiaoming; Wang, Tao; Zhan, Xiaowei; Bu, Chun-Hui; Murray, Anne R.; Beutler, Bruce

    2017-01-01

    Creatine, a nitrogenous organic acid, replenishes cytoplasmic ATP at the expense of mitochondrial ATP via the phosphocreatine shuttle. Creatine levels are maintained by diet and endogenous synthesis from arginine and glycine. Glycine amidinotransferase (GATM) catalyzes the rate-limiting step of creatine biosynthesis: the transfer of an amidino group from arginine to glycine to form ornithine and guanidinoacetate. We screened 36,530 third-generation germline mutant mice derived from N-ethyl-N-nitrosourea–mutagenized grandsires for intestinal homeostasis abnormalities after oral administration of dextran sodium sulfate (DSS). Among 27 colitis susceptibility phenotypes identified and mapped, one was strongly correlated with a missense mutation in Gatm in a recessive model of inheritance, and causation was confirmed by CRISPR/Cas9 gene targeting. Supplementation of homozygous Gatm mutants with exogenous creatine ameliorated the colitis phenotype. CRISPR/Cas9-targeted (Gatmc/c) mice displayed a normal peripheral immune response and immune cell homeostasis. However, the intestinal epithelium of the Gatmc/c mice displayed increased cell death and decreased proliferation during DSS treatment. In addition, Gatmc/c colonocytes showed increased metabolic stress in response to DSS with higher levels of phospho-AMPK and lower levels of phosphorylation of mammalian target of rapamycin (phospho-mTOR). These findings establish an in vivo requirement for rapid replenishment of cytoplasmic ATP within colonic epithelial cells in the maintenance of the mucosal barrier after injury. PMID:28137860

  5. Reduced creatine kinase release with statin use at the time of myocardial infarction.

    PubMed

    Bybee, Kevin A; Kopecky, Stephen L; Williams, Brent A; Murphy, Joseph G; Scott Wright, R

    2004-09-01

    Statin pre-treatment has been shown to reduce myocardial infarct size in animal models. We evaluated peak creatine kinase levels in humans based on concomitant or very early statin initiation following myocardial infarction. We identified 66 consecutive patients who received a statin within 24 h of admission to our coronary care unit for myocardial infarction. Each statin patient was matched with three patients who had not received statin therapy (n=198). Statin patients were subgrouped into those receiving statin therapy at the time of infarction (n=44) and those initiated on statin therapy within 24 h of infarction (n=22). Peak total creatine kinase concentrations were compared between groups. A linear regression model was developed to test for differences in peak creatine kinase after adjusting for differences between groups. Patients receiving statin therapy within 24 h of admission had significantly smaller median peak creatine kinase concentrations compared to those not receiving a statin (416 IU/l [258, 992] vs. 699 IU/l [339, 1728]; p=0.020). Subgroup analysis revealed that the lower peak creatine kinase concentrations within the statin group were a result of lower creatine kinase concentrations in those patients on a statin at the time of myocardial infarction (399 IU/l [255, 869] vs. 678 IU/l [276, 1870]; p<0.05). This difference retained statistical significance after adjustment for differences between groups. Statin therapy at the time of myocardial infarction is associated with lower peak creatine kinase concentrations. This suggests that statins may exhibit protective effects in the setting of myocardial ischemia and/or infarction in humans.

  6. Augmentation of Creatine in the Heart.

    PubMed

    Zervou, Sevasti; Whittington, Hannah J; Russell, Angela J; Lygate, Craig A

    2016-01-01

    Creatine is a principle component of the creatine kinase (CK) phosphagen system common to all vertebrates. It is found in excitable cells, such as cardiomyocytes, where it plays an important role in the buffering and transport of chemical energy to ensure that supply meets the dynamic demands of the heart. Multiple components of the CK system, including intracellular creatine levels, are reduced in heart failure, while ischaemia and hypoxia represent acute crises of energy provision. Elevation of myocardial creatine levels has therefore been suggested as potentially beneficial, however, achieving this goal is not trivial. This mini-review outlines the evidence in support of creatine elevation and critically examines the pharmacological approaches that are currently available. In particular, dietary creatine-supplementation does not sufficiently elevate creatine levels in the heart due to subsequent down-regulation of the plasma membrane creatine transporter (CrT). Attempts to increase passive diffusion and bypass the CrT, e.g. via creatine esters, have yet to be tested in the heart. However, studies in mice with genetic overexpression of the CrT demonstrate proof-of-principle that elevated creatine protects the heart from ischaemia-reperfusion injury. This suggests activation of the CrT as a major unmet pharmacological target. However, translation of this finding to the clinic will require a greater understanding of CrT regulation in health and disease and the development of small molecule activators.

  7. Nutritional genomics: defining the dietary requirement and effects of choline.

    PubMed

    Zeisel, Steven H

    2011-03-01

    As it becomes evident that single nucleotide polymorphisms (SNPs) in humans can create metabolic inefficiencies, it is reasonable to ask if such SNPs influence dietary requirements. Epidemiologic studies that examine SNPs relative to risks for diseases are common, but there are few examples of clinically sized nutrition studies that examine how SNPs influence metabolism. Studies on how SNPs influence the dietary requirement for choline provide a model for how we might begin examining the effects of SNPs on nutritional phenotypes using clinically sized studies (clinical nutrigenomics). Most men and postmenopausal women develop liver or muscle dysfunction when deprived of dietary choline. More than one-half of premenopausal women may be resistant to choline deficiency-induced organ dysfunction, because estrogen induces the gene [phosphatidylethanolamine-N-methyltransferase (PEMT)] that catalyzes endogenous synthesis of phosphatidylcholine, which can subsequently yield choline. Those premenopausal women that do require a dietary source of choline have a SNP in PEMT, making them unresponsive to estrogen induction of PEMT. It is important to recognize differences in dietary requirements for choline in women, because during pregnancy, maternal dietary choline modulates fetal brain development in rodent models. Because choline metabolism and folate metabolism intersect at the methylation of homocysteine, manipulations that limit folate availability also increase the use of choline as a methyl donor. People with a SNPs in MTHFD1 (a gene of folate metabolism that controls the use of folate as a methyl donor) are more likely to develop organ dysfunction when deprived of choline; their dietary requirement is increased because of increased need for choline as a methyl donor.

  8. A single-vial biphasic liquid extraction assay for choline acetyltransferease using (/sup 3/H)choline

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Rand, J.B.; Johnson, C.D.

    1981-09-15

    A single-vial liquid extraction assay for choline acetyltransferase that uses (/sup 3/H)choline as the labeled substrate has been devised. (/sup 3/H)Choline is incubated with an excess of acetyl-CoA in a small reaction vial which also serves as a scintillation vial. After a suitable reaction period, unreacted (/sup 3/H)choline is quickly and quantitatively converted to phosphoryl-(/sup 3/H)choline by the addition of an excess of choline kinase. This treatment is followed by the addition of scintillation fluid containing sodium tetraphenylboron after which the vial is capped, shaken, and counted. A two-phase system is produced in which product (/sup 3/H)choline is selectively extractedmore » into the scintillation fluid, where is is counted. Phosphoryl-(/sup 3/H)choline remains in the aqueous phase and is not counted. This assay is rapid, simple, and quite sensitive. In comparison to assays using acetyl-CoA as the labeled substrate, it is less sensitive to interference by other enzymes and thus more suitable for measuring choline acetyltransferase in crude extracts and in the initial stages of purificaton. Similar single-vial radiometric assays are described for choline kinase and acetyl-CoA hydrolases.« less

  9. Choline Supplementation During Pregnancy Protects Against Gestational Lipopolysaccharide-Induced Inflammatory Responses.

    PubMed

    Zhang, Min; Han, Xinjia; Bao, Juejie; Yang, Jinying; Shi, Shao-Qing; Garfield, Robert E; Liu, Huishu

    2018-01-01

    To estimate the effects and mechanisms of choline, an essential nutrient and a selective α7 nicotinic acetylcholine receptor (α7nAChR) agonist, on the prevention of symptoms and the effects on the cholinergic anti-inflammatory pathways (CAP) in a lipopolysaccharide (LPS)-induced inflammatory response in a rat model. Inflammation was induced by LPS treatment (1.0 μg LPS/kg body weight) on gestational day (GD) 14. Nonpregnant and pregnant Sprague Dawley rats were placed on a normal choline diet (1.1 g/kg) or supplemented choline diet (5.0 g/kg) from GDs 1 to 20. Systolic blood pressure (SBP), urinary albumin, and pregnancy outcomes were recorded. On GD 20, serum and placentas were assayed for cytokines. Western blots were used to determine the expression of placenta α7nAChR and components of the α7nAChR-CAP, including nuclear factor-κB (NF-κB) and protein kinase B (AKT). Immunohistochemistry was used to localize placental sites for the p65 subunit of NF-κB. Lipopolysaccharide significantly increased SBP and urinary albumin and decreased pregnancy outcomes, and these effects were partially reversed by higher choline treatment. Choline supplementation also significantly attenuated the LPS-induced increase in serum and placental inflammatory cytokines, decreased the expression of placental α7nAChR, lowered the activation of NF-κB signaling in placenta mononuclear cells, and inhibited placental AKT phosphorylation. This study confirms that LPS induces inflammatory conditions in pregnant rats and shows that choline supplementation protects against the inflammatory symptoms through its action on α7nAChR and CAP. These observations have important implications for the prevention and treatment of inflammatory responses associated with pregnancy.

  10. Exploratory studies of the potential anti-cancer effects of creatine.

    PubMed

    Campos-Ferraz, P L; Gualano, B; das Neves, W; Andrade, I T; Hangai, I; Pereira, R T S; Bezerra, R N; Deminice, R; Seelaender, M; Lancha, A H

    2016-08-01

    Two experiments were performed, in which male Wistar Walker 256 tumor-bearing rats were inoculated with 4 × 10(7) tumor cells subcutaneously and received either creatine (300 mg/kg body weight/day; CR) or placebo (water; PL) supplementation via intragastric gavage. In experiment 1, 50 rats were given PL (n = 22) or CR (n = 22) and a non-supplemented, non-inoculated group served as control CT (n = 6), for 40 days, and the survival rate and tumor mass were assessed. In experiment 2, 25 rats were given CR or PL for 15 days and sacrificed for biochemical analysis. Again, a non-supplemented, non-inoculated group served as control (CT; n = 6). Tumor and muscle creatine kinase (CK) activity and total creatine content, acidosis, inflammatory cytokines, and antioxidant capacity were assessed. Tumor growth was significantly reduced by approximately 30 % in CR when compared with PL (p = 0.03), although the survival rate was not significantly different between CR and PL (p = 0.65). Tumor creatine content tended to be higher in CR than PL (p = 0.096). Tumor CK activity in the cytosolic fraction was higher in CR than PL (p < 0.0001). Blood pCO2 was higher in CT and CR than PL (p = 0.0007 and p = 0.004, respectively). HCO3 was augmented in CT compared to PL (p = 0.03) and CR (p = 0.001). Plasma IL-6 was lower and IL-10 level was higher in CR than PL (p = 0.03 and p = 0.0007, respectively) and TNF-alpha featured a tendency of decrease in CR compared to PL (p = 0.08). Additionally, total antioxidant capacity tended to be lower in CT than PL (p = 0.07). Creatine supplementation was able to slow tumor growth without affecting the overall survival rate, probably due to the re-establishment of the CK-creatine system in cancer cells, leading to attenuation in acidosis, inflammation, and oxidative stress. These findings support the role of creatine as a putative anti-cancer agent as well as help in expanding our knowledge on its potential mechanisms

  11. Creatine biosynthesis and transport in health and disease.

    PubMed

    Joncquel-Chevalier Curt, Marie; Voicu, Pia-Manuela; Fontaine, Monique; Dessein, Anne-Frédérique; Porchet, Nicole; Mention-Mulliez, Karine; Dobbelaere, Dries; Soto-Ares, Gustavo; Cheillan, David; Vamecq, Joseph

    2015-12-01

    Creatine is physiologically provided equally by diet and by endogenous synthesis from arginine and glycine with successive involvements of arginine glycine amidinotransferase [AGAT] and guanidinoacetate methyl transferase [GAMT]. A specific plasma membrane transporter, creatine transporter [CRTR] (SLC6A8), further enables cells to incorporate creatine and through uptake of its precursor, guanidinoacetate, also directly contributes to creatine biosynthesis. Breakthrough in the role of creatine has arisen from studies on creatine deficiency disorders. Primary creatine disorders are inherited as autosomal recessive (mutations affecting GATM [for glycine-amidinotransferase, mitochondrial]) and GAMT genes) or X-linked (SLC6A8 gene) traits. They have highlighted the role of creatine in brain functions altered in patients (global developmental delay, intellectual disability, behavioral disorders). Creatine modulates GABAergic and glutamatergic cerebral pathways, presynaptic CRTR (SLC6A8) ensuring re-uptake of synaptic creatine. Secondary creatine disorders, addressing other genes, have stressed the extraordinary imbrication of creatine metabolism with many other cellular pathways. This high dependence on multiple pathways supports creatine as a cellular sensor, to cell methylation and energy status. Creatine biosynthesis consumes 40% of methyl groups produced as S-adenosylmethionine, and creatine uptake is controlled by AMP activated protein kinase, a ubiquitous sensor of energy depletion. Today, creatine is considered as a potential sensor of cell methylation and energy status, a neurotransmitter influencing key (GABAergic and glutamatergic) CNS neurotransmission, therapeutic agent with anaplerotic properties (towards creatine kinases [creatine-creatine phosphate cycle] and creatine neurotransmission), energetic and antioxidant compound (benefits in degenerative diseases through protection against energy depletion and oxidant species) with osmolyte behavior (retention of

  12. Augmentation of Creatine in the Heart

    PubMed Central

    Zervou, Sevasti; Whittington, Hannah J.; Russell, Angela J.; Lygate, Craig A.

    2016-01-01

    Creatine is a principle component of the creatine kinase (CK) phosphagen system common to all vertebrates. It is found in excitable cells, such as cardiomyocytes, where it plays an important role in the buffering and transport of chemical energy to ensure that supply meets the dynamic demands of the heart. Multiple components of the CK system, including intracellular creatine levels, are reduced in heart failure, while ischaemia and hypoxia represent acute crises of energy provision. Elevation of myocardial creatine levels has therefore been suggested as potentially beneficial, however, achieving this goal is not trivial. This mini-review outlines the evidence in support of creatine elevation and critically examines the pharmacological approaches that are currently available. In particular, dietary creatine-supplementation does not sufficiently elevate creatine levels in the heart due to subsequent down-regulation of the plasma membrane creatine transporter (CrT). Attempts to increase passive diffusion and bypass the CrT, e.g. via creatine esters, have yet to be tested in the heart. However, studies in mice with genetic overexpression of the CrT demonstrate proof-of-principle that elevated creatine protects the heart from ischaemia-reperfusion injury. This suggests activation of the CrT as a major unmet pharmacological target. However, translation of this finding to the clinic will require a greater understanding of CrT regulation in health and disease and the development of small molecule activators. PMID:26202199

  13. Moderate elevation of intracellular creatine by targeting the creatine transporter protects mice from acute myocardial infarction

    PubMed Central

    Lygate, Craig A.; Bohl, Steffen; ten Hove, Michiel; Faller, Kiterie M.E.; Ostrowski, Philip J.; Zervou, Sevasti; Medway, Debra J.; Aksentijevic, Dunja; Sebag-Montefiore, Liam; Wallis, Julie; Clarke, Kieran; Watkins, Hugh; Schneider, Jürgen E.; Neubauer, Stefan

    2012-01-01

    Aims Increasing energy storage capacity by elevating creatine and phosphocreatine (PCr) levels to increase ATP availability is an attractive concept for protecting against ischaemia and heart failure. However, testing this hypothesis has not been possible since oral creatine supplementation is ineffectual at elevating myocardial creatine levels. We therefore used mice overexpressing creatine transporter in the heart (CrT-OE) to test for the first time whether elevated creatine is beneficial in clinically relevant disease models of heart failure and ischaemia/reperfusion (I/R) injury. Methods and results CrT-OE mice were selected for left ventricular (LV) creatine 20–100% above wild-type values and subjected to acute and chronic coronary artery ligation. Increasing myocardial creatine up to 100% was not detrimental even in ageing CrT-OE. In chronic heart failure, creatine elevation was neither beneficial nor detrimental, with no effect on survival, LV remodelling or dysfunction. However, CrT-OE hearts were protected against I/R injury in vivo in a dose-dependent manner (average 27% less myocardial necrosis) and exhibited greatly improved functional recovery following ex vivo I/R (59% of baseline vs. 29%). Mechanisms contributing to ischaemic protection in CrT-OE hearts include elevated PCr and glycogen levels and improved energy reserve. Furthermore, creatine loading in HL-1 cells did not alter antioxidant defences, but delayed mitochondrial permeability transition pore opening in response to oxidative stress, suggesting an additional mechanism to prevent reperfusion injury. Conclusion Elevation of myocardial creatine by 20–100% reduced myocardial stunning and I/R injury via pleiotropic mechanisms, suggesting CrT activation as a novel, potentially translatable target for cardiac protection from ischaemia. PMID:22915766

  14. Phosphatidylcholine and the CDP-Choline Cycle

    PubMed Central

    Fagone, Paolo; Jackowski, Suzanne

    2012-01-01

    The CDP-choline pathway of phosphatidylcholine (PtdCho) biosynthesis was first described more than 50 years ago. Investigation of the CDP-choline pathway in yeast provides a basis for understanding the CDP-choline pathway in mammals. PtdCho is considered as an intermediate in a cycle of synthesis and degradation, and the activity of a CDP-choline cycle is linked to subcellular membrane lipid movement. The components of the mammalian CDP-choline pathway include choline transport, choline kinase, phosphocholine cytidylyltransferase, and choline phosphotransferase activities. The protein isoforms and biochemical mechanisms of regulation of the pathway enzymes are related to their cell and tissue-specific functions. Regulated PtdCho turnover mediated by phospholipases or neuropathy target esterase participates in the mammalian CDP-choline cycle. Knockout mouse models define the biological functions of the CDP-choline cycle in mammalian cells and tissues. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism. PMID:23010477

  15. Abnormal brain development in newborns with congenital heart disease.

    PubMed

    Miller, Steven P; McQuillen, Patrick S; Hamrick, Shannon; Xu, Duan; Glidden, David V; Charlton, Natalie; Karl, Tom; Azakie, Anthony; Ferriero, Donna M; Barkovich, A James; Vigneron, Daniel B

    2007-11-08

    Congenital heart disease in newborns is associated with global impairment in development. We characterized brain metabolism and microstructure, as measures of brain maturation, in newborns with congenital heart disease before they underwent heart surgery. We studied 41 term newborns with congenital heart disease--29 who had transposition of the great arteries and 12 who had single-ventricle physiology--with the use of magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) before cardiac surgery. We calculated the ratio of N-acetylaspartate to choline (which increases with brain maturation), the ratio of lactate to choline (which decreases with maturation), average diffusivity (which decreases with maturation), and fractional anisotropy of white-matter tracts (which increases with maturation). We compared these findings with those in 16 control newborns of a similar gestational age. As compared with control newborns, those with congenital heart disease had a decrease of 10% in the ratio of N-acetylaspartate to choline (P=0.003), an increase of 28% in the ratio of lactate to choline (P=0.08), an increase of 4% in average diffusivity (P<0.001), and a decrease of 12% in white-matter fractional anisotropy (P<0.001). Preoperative brain injury, as seen on MRI, was not significantly associated with findings on MRS or DTI. White-matter injury was observed in 13 newborns with congenital heart disease (32%) and in no control newborns. Term newborns with congenital heart disease have widespread brain abnormalities before they undergo cardiac surgery. The imaging findings in such newborns are similar to those in premature newborns and may reflect abnormal brain development in utero. Copyright 2007 Massachusetts Medical Society.

  16. Choline metabolism in malignant transformation

    PubMed Central

    Glunde, Kristine; Bhujwalla, Zaver M.; Ronen, Sabrina M.

    2015-01-01

    Abnormal choline metabolism is emerging as a metabolic hallmark that is associated with oncogenesis and tumour progression. Following transformation, the modulation of enzymes that control anabolic and catabolic pathways causes increased levels of choline-containing precursors and breakdown products of membrane phospholipids. These increased levels are associated with proliferation, and recent studies emphasize the complex reciprocal interactions between oncogenic signalling and choline metabolism. Because choline-containing compounds are detected by non-invasive magnetic resonance spectroscopy (MRS), increased levels of these compounds provide a non-invasive biomarker of transformation, staging and response to therapy. Furthermore, enzymes of choline metabolism, such as choline kinase, present novel targets for image-guided cancer therapy. PMID:22089420

  17. Effect of free creatine therapy on cisplatin-induced renal damage.

    PubMed

    Genc, Gurkan; Okuyucu, Ali; Meydan, Bilge Can; Yavuz, Oguzhan; Nisbet, Ozlem; Hokelek, Murat; Bedir, Abdulkerim; Ozkaya, Ozan

    2014-08-01

    Abstract Cisplatin is one of the commonly used anticancer drugs and nephrotoxicity limits its use. The aim of this study is to investigate the possible protective effect of creatine supplementation on cisplatin-induced nephrotoxicity. Sixty male Sprague-Dawley rats were divided into three groups: Group I: Cisplatin (n=20) (7 mg/kg cisplatin intraperitoneal (i.p.) single dose), group II: Cisplatin+creatine monohydrate (n=20) (7 mg/kg cisplatin i.p. single dose and 300 mg/kg creatine p.o. daily for 30 days starting on first day of cisplatin injection), group III: Control group (n=20) (Serum physiologic, 2.5 mL/kg i.p.). Sacrifications were performed at first week and 30th day. Blood urea nitrogen (BUN) and serum creatinine levels, histopathological evaluation, mitochondrial deoxyribonucleic acid (mtDNA) common deletion rates, and body weights of rats were evaluated. A significant decrease in body weight, higher values of kidney function tests, histopathological scores, and mtDNA deletion ratios were observed in group I compared to control group at days 7 and 30 (p<0.05). In group II, there was a slight decrease in body weight at same days (p=0.931 and 0.084, respectively). Kidney function tests, histopathological scores, and mtDNA common deletion ratios were statistically better in group II than group I at 7th and 30th day (p<0.05). Although creatine significantly reversed kidney functions and pathological findings, this improvement was not sufficient to reach normal control group's results at days 7 and 30. In conclusion, the present study demonstrates that creatine administration is a promising adjuvant protective drug for reducing nephrotoxic effect of cisplatin.

  18. A comparison of choline:urea and choline:oxalic acid deep eutectic solvents at 338 K

    NASA Astrophysics Data System (ADS)

    Gilmore, Mark; Moura, Leila M.; Turner, Adam H.; Swadźba-Kwaśny, Małgorzata; Callear, Samantha K.; McCune, Jade A.; Scherman, Oren A.; Holbrey, John D.

    2018-05-01

    1:2 choline chloride:urea and 1:1 choline chloride:oxalic acid deep eutectic solvents are compared at 338 K using liquid-phase neutron diffraction with H/D isotopic substitution to obtain differential neutron scattering cross sections and fitting of models to the experimental data using Empirical Potential Structure Refinement. In comparison to the previously reported study of choline chloride:urea at 303 K, we observed significant weakening and lengthening of choline-OH⋯Cl- and choline-OH⋯hydrogen-bond acceptor correlations.

  19. Proton magnetic resonance spectroscopic creatine correlates with creatine transporter protein density in rat brain.

    PubMed

    Sartorius, Alexander; Lugenbiel, Patrick; Mahlstedt, Magdalena M; Ende, Gabriele; Schloss, Patrick; Vollmayr, Barbara

    2008-07-30

    Creatine (Cr) is an amino acid, which upon phosphorylation is utilized as an energy reservoir in cells with high-energy demand. The ongoing catabolism of creatine to creatinine requires a permanent creatine replenishment into the cells. Because neurons themselves cannot synthesize creatine, they have to take it up via the creatine transporter (CrT). Thus, the concentration of intracellular Cr available for the Cr/PCr shuttle system depends on the expression level of CrT protein. The proton magnetic resonance spectroscopy (MRS) creatine peak (total creatine=tCr) constitutes of two metabolites, namely Cr and phosphocreatine (PCr). We have quantified the level of CrT protein expression with western blotting and compared it to tCr content as estimated by in vitro MRS in Sprague-Dawley rats. Under the assumption of hemispheric symmetry, we took identical samples from left and right hemisphere, which were used for in vitro MRS (tCr) and for western blotting (CrT), respectively. Altogether, it was possible to take 90 corresponding brain samples from 31 animals. A Pearson linear regression analysis for CrT and tCr revealed p<0.0001, explaining 14% of the variance. Since MR-detectable alterations of tCr in the human brain are widespread (e.g. in most major psychiatric disorders proton MRS detectable tCr alterations have been described as regionally and usually state dependent) it is stringent to elucidate their meaning. An influence of tCr on the brain's energy regulating system seems plausible.

  20. Impaired cardiac contractile function in arginine:glycine amidinotransferase knockout mice devoid of creatine is rescued by homoarginine but not creatine

    PubMed Central

    Faller, Kiterie M E; Atzler, Dorothee; McAndrew, Debra J; Zervou, Sevasti; Whittington, Hannah J; Simon, Jillian N; Aksentijevic, Dunja; ten Hove, Michiel; Choe, Chi-un; Isbrandt, Dirk; Casadei, Barbara; Schneider, Jurgen E; Neubauer, Stefan; Lygate, Craig A

    2018-01-01

    Abstract Aims Creatine buffers cellular adenosine triphosphate (ATP) via the creatine kinase reaction. Creatine levels are reduced in heart failure, but their contribution to pathophysiology is unclear. Arginine:glycine amidinotransferase (AGAT) in the kidney catalyses both the first step in creatine biosynthesis as well as homoarginine (HA) synthesis. AGAT-/- mice fed a creatine-free diet have a whole body creatine-deficiency. We hypothesized that AGAT-/- mice would develop cardiac dysfunction and rescue by dietary creatine would imply causality. Methods and results Withdrawal of dietary creatine in AGAT-/- mice provided an estimate of myocardial creatine efflux of ∼2.7%/day; however, in vivo cardiac function was maintained despite low levels of myocardial creatine. Using AGAT-/- mice naïve to dietary creatine we confirmed absence of phosphocreatine in the heart, but crucially, ATP levels were unchanged. Potential compensatory adaptations were absent, AMPK was not activated and respiration in isolated mitochondria was normal. AGAT-/- mice had rescuable changes in body water and organ weights suggesting a role for creatine as a compatible osmolyte. Creatine-naïve AGAT-/- mice had haemodynamic impairment with low LV systolic pressure and reduced inotropy, lusitropy, and contractile reserve. Creatine supplementation only corrected systolic pressure despite normalization of myocardial creatine. AGAT-/- mice had low plasma HA and supplementation completely rescued all other haemodynamic parameters. Contractile dysfunction in AGAT-/- was confirmed in Langendorff perfused hearts and in creatine-replete isolated cardiomyocytes, indicating that HA is necessary for normal cardiac function. Conclusions Our findings argue against low myocardial creatine per se as a major contributor to cardiac dysfunction. Conversely, we show that HA deficiency can impair cardiac function, which may explain why low HA is an independent risk factor for multiple cardiovascular diseases

  1. Pregnancy alters choline dynamics: results of a randomized trial using stable isotope methodology in pregnant and nonpregnant women.

    PubMed

    Yan, Jian; Jiang, Xinyin; West, Allyson A; Perry, Cydne A; Malysheva, Olga V; Brenna, J Thomas; Stabler, Sally P; Allen, Robert H; Gregory, Jesse F; Caudill, Marie A

    2013-12-01

    Although biomarkers of choline metabolism are altered by pregnancy, little is known about the influence of human pregnancy on the dynamics of choline-related metabolic processes. This study used stable isotope methodology to examine the effects of pregnancy on choline partitioning and the metabolic activity of choline-related pathways. Healthy third-trimester pregnant (n = 26; initially week 27 of gestation) and nonpregnant (n = 21) women consumed 22% of their total choline intake (480 or 930 mg/d) as methyl-d9-choline for the final 6 wk of a 12-wk feeding study. Plasma d9-betaine:d9-phosphatidylcholine (PC) was lower (P ≤ 0.04) in pregnant than in nonpregnant women, suggesting greater partitioning of choline into the cytidine diphosphate-choline (CDP-choline) PC biosynthetic pathway relative to betaine synthesis during pregnancy. Pregnant women also used more choline-derived methyl groups for PC synthesis via phosphatidylethanolamine N-methyltransferase (PEMT) as indicated by comparable increases in PEMT-PC enrichment in pregnant and nonpregnant women despite unequal (pregnant > nonpregnant; P < 0.001) PC pool sizes. Pregnancy enhanced the hydrolysis of PEMT-PC to free choline as shown by greater (P < 0.001) plasma d3-choline:d3-PC. Notably, d3-PC enrichment increased (P ≤ 0.011) incrementally from maternal to placental to fetal compartments, signifying the selective transfer of PEMT-PC to the fetus. The enhanced use of choline for PC production via both the CDP-choline and PEMT pathways shows the substantial demand for choline during late pregnancy. Selective partitioning of PEMT-PC to the fetal compartment may imply a unique requirement of PEMT-PC by the developing fetus.

  2. Choline in anxiety and depression: the Hordaland Health Study.

    PubMed

    Bjelland, Ingvar; Tell, Grethe S; Vollset, Stein E; Konstantinova, Svetlana; Ueland, Per M

    2009-10-01

    Despite its importance in the central nervous system as a precursor for acetylcholine and membrane phosphatidylcholine, the role of choline in mental illness has been little studied. We examined the cross-sectional association between plasma choline concentrations and scores of anxiety and depression symptoms in a general population sample. We studied a subsample (n = 5918) of the Hordaland Health Study, including both sexes and 2 age groups of 46-49 and 70-74 y who had valid information on plasma choline concentrations and symptoms of anxiety and depression measured by the Hospital Anxiety and Depression Scale--the latter 2 as continuous measures and dichotomized at a score > or =8 for both subscales. The lowest choline quintile was significantly associated with high anxiety levels (odds ratio: 1.33; 95% CI: 1.06, 1.69) in the fully adjusted (age group, sex, time since last meal, educational level, and smoking habits) logistic regression model. Also, the trend test in the anxiety model was significant (P = 0.007). In the equivalent fully adjusted linear regression model, a significant inverse association was found between choline quintiles and anxiety levels (standardized regression coefficient = -0.027, P = 0.045). We found no significant associations in the corresponding analyses of the relation between plasma choline and depression symptoms. In this large population-based study, choline concentrations were negatively associated with anxiety symptoms but not with depression symptoms.

  3. Choline incorporation by Schistosoma mansoni: distribution of choline metabolites during development and after sexual differentiation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ancelin, M.L.; Torpier, G.; Vial, H.J.

    1987-06-01

    Choline metabolism was investigated in Schistosoma mansoni during the main phases of its development, namely, schistosomula, 11- and 15-day-old worms, and adults. At the physiological choline concentration used in the assay (20 microM), betaine was, along with phosphatidylcholine, one of the most abundant choline metabolites, revealing considerable choline oxidation activity. Very little radioactivity was associated with CDP-choline, whereas a sustained incorporation into phosphocholine occurred. These results provide good evidence that CTP:phosphocholine cytidylyltransferase plays a regulatory role in the de novo pathway of phosphatidylcholine biosynthesis. During development, the incorporation of choline into its various metabolites was maximal in 11-day-old worms. Atmore » this stage, the oxidative pathway predominated over the Kennedy pathway, whereas at all other stages the de novo phosphatidylcholine biosynthesis was predominant. Furthermore, choline incorporation into betaine was much more important in the adult female worm than in the male, indicating a major difference in choline incorporation and distribution between the 2 sexes of the adult worms.« less

  4. Choline Magnesium Trisalicylate

    MedlinePlus

    Choline magnesium trisalicylate is used to relieve the pain, tenderness, inflammation (swelling), and stiffness caused by arthritis ... also used to relieve pain and lower fever. Choline magnesium trisalicylate is in a class of nonsteroidal ...

  5. CDP-choline liposomes provide significant reduction in infarction over free CDP-choline in stroke

    PubMed Central

    Adibhatla, Rao Muralikrishna; Hatcher, J.F.; Tureyen, K.

    2007-01-01

    Cytidine-5′-diphosphocholine (CDP-choline, Citicoline, Somazina) is in clinical use (intravenous administration) for stroke treatment in Europe and Japan, while USA phase III stroke clinical trials (oral administration) were disappointing. Others showed that CDP-choline liposomes significantly increased brain uptake over the free drug in cerebral ischemia models. Liposomes were formulated as DPPC, DPPS, cholesterol, GM1 ganglioside; 7/4/7/1.57 molar ratio or 35.8/20.4/35.8/8.0 mol%. GM1 ganglioside confers long-circulating properties to the liposomes by suppressing phagocytosis. CDP-choline liposomes deliver the agent intact to the brain, circumventing the rate-limiting, cytidine triphosphate:phosphocholine cytidylyltransferase in phosphatidylcholine synthesis. Our data show that CDP-choline liposomes significantly ( P < 0.01) decreased cerebral infarction (by 62%) compared to the equivalent dose of free CDP-choline (by 26%) after 1 h focal cerebral ischemia and 24 h reperfusion in spontaneously hypertensive rats. Beneficial effects of CDP-choline liposomes in stroke may derive from a synergistic effect between the phospholipid components of the liposomes and the encapsulated CDP-choline. PMID:16153613

  6. Creatine affords protection against glutamate-induced nitrosative and oxidative stress.

    PubMed

    Cunha, Mauricio P; Lieberknecht, Vicente; Ramos-Hryb, Ana Belén; Olescowicz, Gislaine; Ludka, Fabiana K; Tasca, Carla I; Gabilan, Nelson H; Rodrigues, Ana Lúcia S

    2016-05-01

    Creatine has been reported to exert beneficial effects in several neurodegenerative diseases in which glutamatergic excitotoxicity and oxidative stress play an etiological role. The purpose of this study was to investigate the protective effects of creatine, as compared to the N-Methyl-d-Aspartate (NMDA) receptor antagonist dizocilpine (MK-801), against glutamate or hydrogen peroxide (H2O2)-induced injury in human neuroblastoma SH-SY5Y cells. Exposure of cells to glutamate (60-80 mM) or H2O2 (200-300 μM) for 24 h decreased cellular viability and increased dichlorofluorescein (DCF) fluorescence (indicative of increased reactive oxygen species, ROS) and nitric oxide (NO) production (assessed by mono-nitrogen oxides, NOx, levels). Creatine (1-10 mM) or MK-801 (0.1-10 μM) reduced glutamate- and H2O2-induced toxicity. The protective effect of creatine against glutamate-induced toxicity involves its antioxidant effect, since creatine, similar to MK-801, prevented the increase on DCF fluorescence induced by glutamate or H2O2. Furthermore, creatine or MK-801 blocked glutamate- and H2O2-induced increases in NOx levels. In another set of experiments, the repeated, but not acute, administration of creatine (300 mg/kg, po) in mice prevented the decreases on cellular viability and mitochondrial membrane potential (assessed by tetramethylrhodamine ethyl ester, TMRE, probe) of hippocampal slices incubated with glutamate (10 mM). Creatine concentration-dependent decreased the amount of nitrite formed in the reaction of oxygen with NO produced from sodium nitroprusside solution, suggesting that its protective effect against glutamate or H2O2-induced toxicity might be due to its scavenger activity. Overall, the results suggest that creatine may be useful as adjuvant therapy for neurodegenerative disease treatments. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Free choline and phospholipid-bound choline concentrations in serum and dialysate during peritoneal dialysis in children and adults.

    PubMed

    Ilcol, Yesim Ozarda; Dönmez, Osman; Yavuz, Mahmut; Dilek, Kamil; Yurtkuran, Mustafa; Ulus, Ismail H

    2002-06-01

    This study tested whether continuous ambulatory peritoneal dialysis (CAPD) changes free or phospholipid-bound choline concentrations in serum or peritoneal dialysis fluid of patients with end stage renal disease (ESRD). Serum and dialysate choline and phospholipid-bound choline were measured before, during and after 6 h CAPD. Serum choline concentrations were higher in patients with ESRD compared with age-matched controls. CAPD lowered serum choline concentrations significantly although it did not influence phospholipid-bound choline. Choline accumulated in the dialysate, reaching 28.4 +/- 2.7 microM in children and 18.2 +/- 1.4 microM in adults, during six hours CAPD; phospholipid-bound choline increased to 22.9 +/- 2.5 microM and 10.8 +/- 1.4 microM in children and adults, respectively. The total daily loss of choline into the dialysate was 181 +/- 20 micromoles in children and 260 +/- 18 micromoles in adults. CAPD causes a substantial loss of choline into peritoneal dialysates and reduces serum choline concentrations significantly.

  8. Fenugreek increases insulin-stimulated creatine content in L6C11 muscle myotubes.

    PubMed

    Tomcik, Kristyen A; Smiles, William J; Camera, Donny M; Hügel, Helmut M; Hawley, John A; Watts, Rani

    2017-04-01

    Creatine uptake by muscle cells is increased in the presence of insulin. Accordingly, compounds with insulin-like actions may also augment creatine uptake. The aim of this study was to investigate whether Trigonella foenum-graecum (fenugreek), an insulin mimetic, increases total intracellular creatine levels in vitro. Total cellular creatine content was measured fluorometrically in L6C11 muscle myotubes treated for 1, 4, and 24 h with 0.5 mM creatine (CR), CR and 20 μg/mL fenugreek seed extract (CR + FEN), CR and 100 nM insulin (CR + INS), and CR + INS + FEN (n = 6 per treatment group). Alterations in the expression of the sodium- and chloride-dependent creatine transporter, SLC6A8, and key signaling proteins in the PI3-K/Akt pathway were determined. Compared to control (CON), CR + INS + FEN increased total creatine content after 4 h (P < 0.05), whereas all conditions increased SLC6A8 protein expression above CON at this time (P < 0.05). Changes in insulin signaling were demonstrated via increases in Akt Thr308 phosphorylation, with CR + INS > CON and CR at 1 h (P < 0.05) and with CR + INS + FEN > CON, CR, and CR + INS at 4 h (P < 0.05). In contrast, no changes in PKCζ/λ or GLUT4 phosphorylation were detected. Fenugreek, when combined with insulin, modulates creatine content via a mechanism which is independent of the activity of SLC6A8, suggesting that an alternative mechanism is responsible for the regulation and facilitation of insulin-mediated creatine uptake in skeletal muscle cells.

  9. Investigating the metabolic alterations in a depressive-like rat model of chronic forced swim stress: An in vivo proton magnetic resonance spectroscopy study at 7T.

    PubMed

    Yoo, Chi-Hyeon; Lim, Song-I; Song, Kyu-Ho; Woo, Dong-Cheol; Choe, Bo-Young

    2018-06-01

    Although recent investigations of major depressive disorder (MDD) have focused on the monoaminergic system, accumulating evidences suggest that alternative pathophysiological models of MDD and treatment options for patients with MDD are needed. Animals subjected to chronic forced swim stress (CFSS) develop behavioral despair. The purpose of this study was to investigate the in vivo effects of CFSS on systems other than the monoamine system in the rat prefrontal cortex (PFC) with 7T and short-echo-time (16.3 ms) proton magnetic resonance spectroscopy ( 1 H MRS). Ten male Wistar rats underwent 14 days of CFSS, and in vivo 1 H MRS and forced swim tests were performed before and after CFSS. Point-resolved spectroscopy was used to quantify metabolite levels in the rat PFC. To investigate spectral overlap in glutamate and glutamine, spectral analyses in the spectra obtained in the in vivo 1 H MRS, parametrically matched spectral simulation, and in vitro experiments were performed. The results of the spectral analyses showed that the glutamate/glutamine spectral overlap was not critical, which suggested that in vivo 1 H MRS can be used to reliably assess the glutamate system. The rats showed significantly increased immobility times and decreased climbing times in the FST after CFSS, which suggested that the rats developed behavioral despair. The pre-CFSS and post-CFSS glutamate and glutamine levels did not significantly differ (p > 0.050). The levels of myo-inositol, total choline, and N-acetylaspartate, myo-inositol/creatine, and total choline/creatine increased significantly (p < 0.050). Similar findings have been reported in patients with MDD. Taken together, these results suggest that the CFSS-induced metabolic alterations were similar to those found in patients and that high-field and short-echo-time in vivo 1 H MRS can be used to investigate depression-induced metabolic alterations. Such investigations might provide alternative insights into the

  10. Choline supplementation and measures of choline and betaine status: a randomised, controlled trial in postmenopausal women.

    PubMed

    Wallace, Julie M W; McCormack, Jacqueline M; McNulty, Helene; Walsh, Paula M; Robson, Paula J; Bonham, Maxine P; Duffy, Maresa E; Ward, Mary; Molloy, Anne M; Scott, John M; Ueland, Per M; Strain, J J

    2012-10-01

    Choline is an essential nutrient and can also be obtained by de novo synthesis via an oestrogen responsive pathway. Choline can be oxidised to the methyl donor betaine, with short-term supplementation reported to lower plasma total homocysteine (tHcy); however, the effects of longer-term choline supplementation are less clear. We investigated the effect of choline supplementation on plasma concentrations of free choline, betaine and tHcy and B-vitamin status in postmenopausal women, a group more susceptible to low choline status. We also assessed whether supplementation altered plasma lipid profiles. In this randomised, double-blinded, placebo-controlled study, forty-two healthy postmenopausal women received 1 g choline per d (as choline bitartrate), or an identical placebo supplement with their habitual diet. Fasting blood samples were collected at baseline, week 6 and week 12. Administration of choline increased median choline and betaine concentrations in plasma, with significant effects evident after 6 weeks of supplementation (P<0·001) and remaining significant at 12 weeks (P<0·001); no effect was observed on folate status or on plasma lipids. Choline supplementation induced a median (25th, 75th percentile) change in plasma tHcy concentration at week 6 of -0·9 (-1·6, 0·2) μmol, a change which, when compared to that observed in the placebo group 0·6 (-0·4, 1·9) μmol, approached statistical significance (P=0·058). Choline supplementation at a dose of 1 g/d significantly increases the circulating concentration of free choline, and can also significantly increase the concentration of the methyl donor, betaine, thereby potentially enhancing the betaine-homocysteine methyltransferase-mediated remethylation of tHcy.

  11. Effect of creatine, creatinine, and creatine ethyl ester on TLR expression in macrophages.

    PubMed

    Leland, Korey M; McDonald, Thomas L; Drescher, Kristen M

    2011-09-01

    Despite the widespread availability and use of dietary supplements, minimal work has been performed to assess the potential dangers many of these supplements may have on the host's well-being, in particular the host's ability to respond to infection. One supplement extensively used by both adolescents and adults is creatine. Using Real-time PCR, we examined the impact of short-term exposure of a mouse macrophage cell line (RAW 264.7 cells) to two readily available forms of creatine used in supplements--creatine monohydrate (CR) and creatine ethyl ester (CEE) as well as the end product of creatine metabolism, creatinine (CRN), on expression of toll-like receptor-2 (TLR-2), TLR-3, TLR-4, and TLR-7. CR down-regulated TLR-2, TLR-3, TLR-4 and TLR-7 mRNA levels in RAW cells. Similar results were observed following exposure of RAW cells to CRN. Conversely CEE appears to possess immunostimulatory properties and increases expression of TLR-2, TLR-3, TLR-4, and TLR-7 in RAW cells. These data are supported by immunostaining using antibodies specific for the individual TLRs before and after exposure of RAW cells to CR, CRN, or CEE. To extend these findings, we isolated murine splenocytes and exposed the cells to CR, CEE, or CRN for 24 hours and performed immunofluorescent staining for TLR-2, TLR-3, TLR-4 and TLR-7. The results obtained from this study with primary splenocytes were consistent with the studies using RAW cells. Together, these data suggest that creatine and creatine derivatives may impact the ability of immune cells to sense a wide array of viral and bacterial pathogens. Of great interest, CRN--largely considered to be a waste product of the argenine biosynthesis pathway may also have immunosuppressive properties similar to those of CR. Copyright © 2011 Elsevier B.V. All rights reserved.

  12. Effect of creatine, creatinine, and creatine ethyl ester on TLR expression in macrophages

    PubMed Central

    Leland, Korey M.; McDonald, Thomas L.; Drescher, Kristen M.

    2011-01-01

    Despite the widespread availability and use of dietary supplements, minimal work has been performed to assess the potential dangers many of these supplements may have on the host’s well-being, in particular the host’s ability to respond to infection. One supplement extensively used by both adolescents and adults is creatine. Using Real-time PCR, we examined the impact of short-term exposure of a mouse macrophage cell line (RAW 264.7 cells) to two readily available forms of creatine used in supplements – creatine monohydrate (CR) and creatine ethyl ester (CEE) as well as the end product of creatine metabolism, creatinine (CRN), on expression of toll-like receptor-2 (TLR-2), TLR-3, TLR-4, and TLR-7. CR down-regulated TLR-2, TLR-3, TLR-4 and TLR-7 mRNA levels in RAW cells. Similar results were observed following exposure of RAW cells to CRN. Conversely CEE appears to possess immunostimulatory properties and increases expression of TLR-2, TLR-3, TLR-4, and TLR-7 in RAW cells. These data are supported by immunostaining using antibodies specific for the individual TLRs before and after exposure of RAW cells to CR, CRN, or CEE. To extend these findings, we isolated murine splenocytes and exposed the cells to CR, CEE, or CRN for 24 hours and performed immunofluorescent staining for TLR-2, TLR-3, TLR-4 and TLR-7. The results obtained from this study with primary splenocytes were consistent with the studies using RAW cells. Together, these data suggest that creatine and creatine derivatives may impact the ability of immune cells to sense a wide array of viral and bacterial pathogens. Of great interest, CRN - largely considered to be a waste product of the argenine biosynthesis pathway may also have immunosuppressive properties similar to those of CR. PMID:21575742

  13. Beyond muscles: The untapped potential of creatine.

    PubMed

    Riesberg, Lisa A; Weed, Stephanie A; McDonald, Thomas L; Eckerson, Joan M; Drescher, Kristen M

    2016-08-01

    Creatine is widely used by both elite and recreational athletes as an ergogenic aid to enhance anaerobic exercise performance. Older individuals also use creatine to prevent sarcopenia and, accordingly, may have therapeutic benefits for muscle wasting diseases. Although the effect of creatine on the musculoskeletal system has been extensively studied, less attention has been paid to its potential effects on other physiological systems. Because there is a significant pool of creatine in the brain, the utility of creatine supplementation has been examined in vitro as well as in vivo in both animal models of neurological disorders and in humans. While the data are preliminary, there is evidence to suggest that individuals with certain neurological conditions may benefit from exogenous creatine supplementation if treatment protocols can be optimized. A small number of studies that have examined the impact of creatine on the immune system have shown an alteration in soluble mediator production and the expression of molecules involved in recognizing infections, specifically toll-like receptors. Future investigations evaluating the total impact of creatine supplementation are required to better understand the benefits and risks of creatine use, particularly since there is increasing evidence that creatine may have a regulatory impact on the immune system. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Effects of Combined Creatine Plus Fenugreek Extract vs. Creatine Plus Carbohydrate Supplementation on Resistance Training Adaptations

    PubMed Central

    Taylor, Lem; Poole, Chris; Pena, Earnest; Lewing, Morgan; Kreider, Richard; Foster, Cliffa; Wilborn, Colin

    2011-01-01

    The purpose of this study was to evaluate the effects of combined creatine and fenugreek extract supplementation on strength and body composition. Forty- seven resistance trained men were matched according to body weight to ingest either 70 g of a dextrose placebo (PL), 5 g creatine/70 g of dextrose (CRD) or 3.5 g creatine/900 mg fenugreek extract (CRF) and participate in a 4-d/wk periodized resistance-training program for 8-weeks. At 0, 4, and 8-weeks, subjects were tested on body composition, muscular strength and endurance, and anaerobic capacity. Statistical analyses utilized a separate 3X3 (condition [PL vs. CRD vs. CRF] x time [T1 vs. T2 vs. T3]) ANOVAs with repeated measures for all criterion variables (p ≤ 0.05). No group x time interaction effects or main effects (p > 0.05) were observed for any measures of body composition. CRF group showed significant increases in lean mass at T2 (p = 0.001) and T3 (p = 0.001). Bench press 1RM increased in PL group (p = 0.050) from T1-T3 and in CRD from T1-T2 (p = 0. 001) while remaining significant at T3 (p < 0.001). CRF group showed a significant increase in bench press 1RM from T1-T2 (p < 0.001), and also increased from T2-T3 (p = 0.032). Leg press 1RM significantly increased at all time points for PL, CRD, and CRF groups (p < 0.05). No additional between or within group changes were observed for any performance variables and serum clinical safety profiles (p > 0.05). In conclusion, creatine plus fenugreek extract supplementation had a significant impact on upper body strength and body composition as effectively as the combination of 5g of creatine with 70g of dextrose. Thus, the use of fenugreek with creatine supplementation may be an effective means for enhancing creatine uptake while eliminating the need for excessive amounts of simple carbohydrates. Key points Fenugreek plus creatine supplementation may be a new means of increasing creatine uptake. Creatine plus fenugreek seems to be just as effective as the

  15. Feeding a diet devoid of choline to lactating rodents restricts growth and lymphocyte development in offspring.

    PubMed

    Lewis, E D; Goruk, S; Richard, C; Dellschaft, N S; Curtis, J M; Jacobs, R L; Field, C J

    2016-09-01

    The nutrient choline is necessary for membrane synthesis and methyl donation, with increased requirements during lactation. The majority of immune development occurs postnatally, but the importance of choline supply for immune development during this critical period is unknown. The objective of this study was to determine the importance of maternal supply of choline during suckling on immune function in their offspring among rodents. At parturition, Sprague-Dawley dams were randomised to either a choline-devoid (ChD; n 7) or choline-sufficient (ChS, 1 g/kg choline; n 10) diet with their offspring euthanised at 3 weeks of age. In a second experiment, offspring were weaned to a ChS diet until 10 weeks of age (ChD-ChS, n 5 and ChS-ChS, n 9). Splenocytes were isolated, and parameters of immune function were measured. The ChD offspring received less choline in breast milk and had lower final body and organ weight compared with ChS offspring (P<0·05), but this effect disappeared by week 10 with choline supplementation from weaning. ChD offspring had a higher proportion of T cells expressing activation markers (CD71 or CD28) and a lower proportion of total B cells (CD45RA+) and responded less to T cell stimulation (lower stimulation index and less IFN-γ production) ex vivo (P<0·05). ChD-ChS offspring had a lower proportion of total and activated CD4+ T cells, and produced less IL-6 after mitogen stimulation compared with cells from ChS-ChS (P<0·05). Our study suggests that choline is required in the suckling diet to facilitate immune development, and choline deprivation during this critical period has lasting effects on T cell function later in life.

  16. Creatine and creatine pyruvate reduce hypoxia-induced effects on phrenic nerve activity in the juvenile mouse respiratory system.

    PubMed

    Scheer, Monika; Bischoff, Anna M; Kruzliak, Peter; Opatrilova, Radka; Bovell, Douglas; Büsselberg, Dietrich

    2016-08-01

    Adequate concentrations of ATP are required to preserve physiological cell functions and protect tissue from hypoxic damage. Decreased oxygen concentration results in ATP synthesis relying increasingly on the presence of phosphocreatine. The lack of ATP through hypoxic insult to neurons that generate or regulate respiratory function, would lead to the cessation of breathing (apnea). It is not clear whether creatine plays a role in maintaining respiratory phrenic nerve (PN) activity during hypoxic challenge. The aim of the study was to test the effects of exogenously applied creatine or creatine pyruvate in maintaining PN induced respiratory rhythm against the deleterious effects of severe hypoxic insult using Working Heart-Brainstem (WHB) preparations of juvenile Swiss type mice. WHB's were perfused with control perfusate or perfusate containing either creatine [100μM] or creatine pyruvate [100μM] prior to hypoxic challenge and PN activity recorded throughout. Results showed that severe hypoxic challenge resulted in an initial transient increase in PN activity, followed by a reduction in that activity leading to respiratory apnea. The results demonstrated that perfusing the WHB preparation with creatine or creatine pyruvate, significantly reduced the onset of apnea compared to control conditions, with creatine pyruvate being the more effective substance. Overall, creatine and creatine pyruvate each produced time-dependent degrees of protection against severe hypoxic-induced disturbances of PN activity. The underlying protective mechanisms are unknown and need further investigations. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Intra-individual variation of plasma trimethylamine-N-oxide (TMAO), betaine and choline over 1 year.

    PubMed

    Kühn, Tilman; Rohrmann, Sabine; Sookthai, Disorn; Johnson, Theron; Katzke, Verena; Kaaks, Rudolf; von Eckardstein, Arnold; Müller, Daniel

    2017-02-01

    Circulating trimethylamine-N-oxide (TMAO) has been implicated in the development of cardiovascular and chronic kidney diseases (CKD). However, while higher TMAO levels have been associated with increased risks of cardiovascular or renal events in first prospective studies, it remained unclear how much plasma TMAO concentrations vary over time. We measured fasting plasma levels of TMAO and two of its precursors, betaine and choline by LC-MS, in two samples of 100 participants of the European Investigation into Cancer and Nutrition (EPIC)-Heidelberg study (age range: 47-80 years, 50% female) that were collected 1 year apart, and assessed their intra-individual variation by Spearman's correlation coefficients (ρ). Correlations of metabolite concentrations over 1 year were at ρ=0.29 (p=0.003) for TMAO, ρ=0.81 (p<0.001) for betaine, and ρ=0.61 (p<0.001) for choline. Plasma levels of TMAO were not significantly associated with food intake, lifestyle factors, or routine biochemistry parameters such as C-reactive protein (CRP), low-density lipoprotein (LDL)-cholesterol, or creatinine. In contrast to fasting plasma concentrations of betaine and choline, concentrations of TMAO were more strongly affected by intra-individual variation over 1 year in adults from the general population. The modest correlation of TMAO levels over time should be considered when interpreting associations between TMAO levels and disease endpoints.

  18. Total-body creatine pool size and skeletal muscle mass determination by creatine-(methyl-D3) dilution in rats.

    PubMed

    Stimpson, Stephen A; Turner, Scott M; Clifton, Lisa G; Poole, James C; Mohammed, Hussein A; Shearer, Todd W; Waitt, Greg M; Hagerty, Laura L; Remlinger, Katja S; Hellerstein, Marc K; Evans, William J

    2012-06-01

    There is currently no direct, facile method to determine total-body skeletal muscle mass for the diagnosis and treatment of skeletal muscle wasting conditions such as sarcopenia, cachexia, and disuse. We tested in rats the hypothesis that the enrichment of creatinine-(methyl-d(3)) (D(3)-creatinine) in urine after a defined oral tracer dose of D(3)-creatine can be used to determine creatine pool size and skeletal muscle mass. We determined 1) an oral tracer dose of D(3)-creatine that was completely bioavailable with minimal urinary spillage and sufficient enrichment in the body creatine pool for detection of D(3)-creatine in muscle and D(3)-creatinine in urine, and 2) the time to isotopic steady state. We used cross-sectional studies to compare total creatine pool size determined by the D(3)-creatine dilution method to lean body mass determined by independent methods. The tracer dose of D(3)-creatine (<1 mg/rat) was >99% bioavailable with 0.2-1.2% urinary spillage. Isotopic steady state was achieved within 24-48 h. Creatine pool size calculated from urinary D(3)-creatinine enrichment at 72 h significantly increased with muscle accrual in rat growth, significantly decreased with dexamethasone-induced skeletal muscle atrophy, was correlated with lean body mass (r = 0.9590; P < 0.0001), and corresponded to predicted total muscle mass. Total-body creatine pool size and skeletal muscle mass can thus be accurately and precisely determined by an orally delivered dose of D(3)-creatine followed by the measurement of D(3)-creatinine enrichment in a single urine sample and is promising as a noninvasive tool for the clinical determination of skeletal muscle mass.

  19. Exogenous fatty acids affect CDP-choline pathway to increase phosphatidylcholine synthesis in granular pneumocytes

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Chander, A.; Gullo, J.; Reicherter, J.

    1987-05-01

    Regulation of phosphatidylcholine (PC) synthesis in rat granular pneumocytes isolated by tryptic digestion of lungs and maintained in primary culture for 24 h was investigated by following effects of exogenous fatty acids on (/sup 3/H-methyl)choline incorporation into PC and disaturated PC (DSPC). At 0.1 mM choline, the rate of choline incorporation into PC and DSPC was 440 +/- and 380 +/- 50 pmol/h/ug Pi (mean +/- SE, n=3-5), respectively, and was linear for up to 3 h. PC synthesis was significantly increased by 0.1 mM each of palmitic, oleic, linoleic, or linolenic acid. However, synthesis of DSPC was increased onlymore » by palmitic acid and this increase was prevented by addition of oleic acid suggesting lack of effect on the remodeling pathway. Pulse-chase experiments with choline in absence or presence of palmitic or oleic acid showed that the label declined in choline phosphate and increased in PC more rapidly in presence of either of the fatty acids, suggesting rapid conversion of choline phosphate to PC. Microsomal choline phosphate cytidyltransferase activity in cells preincubated without or with palmitic acid for 3 h was 0.81 +/- 0.07 and 1.81 +/- 0.09 nmol choline phosphate converted/min/mg protein (n=4). These results suggest that in granular pneumocytes, exogenous fatty acids modulate PC synthesis by increasing choline phosphate cytidyltransferase activity.« less

  20. 21 CFR 862.1210 - Creatine test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Creatine test system. 862.1210 Section 862.1210....1210 Creatine test system. (a) Identification. A creatine test system is a device intended to measure creatine (a substance synthesized in the liver and pancreas and found in biological fluids) in plasma...

  1. The effect of cytidine-diphosphate choline (CDP-choline) on brain lipid changes during aging

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    De Medio, G.E.; Trovarelli, G.; Piccinin, G.L.

    1984-01-01

    Lipid synthesis has been tested in vivo in different brain areas of 12-month-old male rats. Cortex, striatum, brainstem, and subcortex of brain have been examined. The cerebellum was discarded. Mixtures of (2-/sup 3/H)glycerol and (Me-/sup 14/C)choline were injected into the lateral ventricle of the brain as lipid precursors, and their incorporation into total lipid, water-soluble intermediates and choline-containing phospholipids was examined 1 hr after isotope injection. In another series of experiments cytidine-5'-diphosphate choline (CDP-choline) was injected intraventricularly to the aged rats 10 min before sacrifice with a simultaneous injection, and radioactivity assays were performed as above. Distribution of radioactivity contentmore » of CDP-choline among brain areas 10 min after its administration showed a noticeable enrichment of the nucleotide and water-soluble-related compounds in the examined areas, but to a lesser degree in the cerebral cortex. The incorporation of labelled glycerol, which is severely depressed in aged rats in all four areas (Gaiti et al, 1982, 1983), was increased only in the cortex, and apparently decreased in the other areas. This last result is probably due to a dilution effect brought about by the administered cold CDP-choline upon the (/sup 14/C)-containing water-soluble metabolites. As a consequence, the (/sup 3/H)/(/sup 14/C) ratio in total lipid and in isolated phosphatidylcholine and choline plasmalogen increased after CDP-choline treatment.« less

  2. Choline induces opposite changes in pyramidal neuron excitability and synaptic transmission through a nicotinic receptor-independent process in hippocampal slices.

    PubMed

    Albiñana, E; Luengo, J G; Baraibar, A M; Muñoz, M D; Gandía, L; Solís, J M; Hernández-Guijo, J M

    2017-06-01

    Choline is present at cholinergic synapses as a product of acetylcholine degradation. In addition, it is considered a selective agonist for α5 and α7 nicotinic acetylcholine receptors (nAChRs). In this study, we determined how choline affects action potentials and excitatory synaptic transmission using extracellular and intracellular recording techniques in CA1 area of hippocampal slices obtained from both mice and rats. Choline caused a reversible depression of evoked field excitatory postsynaptic potentials (fEPSPs) in a concentration-dependent manner that was not affected by α7 nAChR antagonists. Moreover, this choline-induced effect was not mimicked by either selective agonists or allosteric modulators of α7 nAChRs. Additionally, this choline-mediated effect was not prevented by either selective antagonists of GABA receptors or hemicholinium, a choline uptake inhibitor. The paired pulse facilitation paradigm, which detects whether a substance affects presynaptic release of glutamate, was not modified by choline. On the other hand, choline induced a robust increase of population spike evoked by orthodromic stimulation but did not modify that evoked by antidromic stimulation. We also found that choline impaired recurrent inhibition recorded in the pyramidal cell layer through a mechanism independent of α7 nAChR activation. These choline-mediated effects on fEPSP and population spike observed in rat slices were completely reproduced in slices obtained from α7 nAChR knockout mice, which reinforces our conclusion that choline modulates synaptic transmission and neuronal excitability by a mechanism independent of nicotinic receptor activation.

  3. Small-Molecule Inhibition of Choline Catabolism in Pseudomonas aeruginosa and Other Aerobic Choline-Catabolizing Bacteria ▿ †

    PubMed Central

    Fitzsimmons, Liam F.; Flemer, Stevenson; Wurthmann, A. Sandy; Deker, P. Bruce; Sarkar, Indra Neil; Wargo, Matthew J.

    2011-01-01

    Choline is abundant in association with eukaryotes and plays roles in osmoprotection, thermoprotection, and membrane biosynthesis in many bacteria. Aerobic catabolism of choline is widespread among soil proteobacteria, particularly those associated with eukaryotes. Catabolism of choline as a carbon, nitrogen, and/or energy source may play important roles in association with eukaryotes, including pathogenesis, symbioses, and nutrient cycling. We sought to generate choline analogues to study bacterial choline catabolism in vitro and in situ. Here we report the characterization of a choline analogue, propargylcholine, which inhibits choline catabolism at the level of Dgc enzyme-catalyzed dimethylglycine demethylation in Pseudomonas aeruginosa. We used genetic analyses and 13C nuclear magnetic resonance to demonstrate that propargylcholine is catabolized to its inhibitory form, propargylmethylglycine. Chemically synthesized propargylmethylglycine was also an inhibitor of growth on choline. Bioinformatic analysis suggests that there are genes encoding DgcA homologues in a variety of proteobacteria. We examined the broader utility of propargylcholine and propargylmethylglycine by assessing growth of other members of the proteobacteria that are known to grow on choline and possess putative DgcA homologues. Propargylcholine showed utility as a growth inhibitor in P. aeruginosa but did not inhibit growth in other proteobacteria tested. In contrast, propargylmethylglycine was able to inhibit choline-dependent growth in all tested proteobacteria, including Pseudomonas mendocina, Pseudomonas fluorescens, Pseudomonas putida, Burkholderia cepacia, Burkholderia ambifaria, and Sinorhizobium meliloti. We predict that chemical inhibitors of choline catabolism will be useful for studying this pathway in clinical and environmental isolates and could be a useful tool to study proteobacterial choline catabolism in situ. PMID:21602374

  4. Creatine synthesis and exchanges between brain cells: What can be learned from human creatine deficiencies and various experimental models?

    PubMed

    Hanna-El-Daher, Layane; Braissant, Olivier

    2016-08-01

    While it has long been thought that most of cerebral creatine is of peripheral origin, the last 20 years has provided evidence that the creatine synthetic pathway (AGAT and GAMT enzymes) is expressed in the brain together with the creatine transporter (SLC6A8). It has also been shown that SLC6A8 is expressed by microcapillary endothelial cells at the blood-brain barrier, but is absent from surrounding astrocytes, raising the concept that the blood-brain barrier has a limited permeability for peripheral creatine. The first creatine deficiency syndrome in humans was also discovered 20 years ago (GAMT deficiency), followed later by AGAT and SLC6A8 deficiencies, all three diseases being characterized by creatine deficiency in the CNS and essentially affecting the brain. By reviewing the numerous and latest experimental studies addressing creatine transport and synthesis in the CNS, as well as the clinical and biochemical characteristics of creatine-deficient patients, our aim was to delineate a clearer view of the roles of the blood-brain and blood-cerebrospinal fluid barriers in the transport of creatine and guanidinoacetate between periphery and CNS, and on the intracerebral synthesis and transport of creatine. This review also addresses the question of guanidinoacetate toxicity for brain cells, as probably found under GAMT deficiency.

  5. Metabolic changes in the anterior and posterior cingulate cortices of the normal aging brain: proton magnetic resonance spectroscopy study at 3 T.

    PubMed

    Chiu, Pui-Wai; Mak, Henry Ka-Fung; Yau, Kelvin Kai-Wing; Chan, Queenie; Chang, Raymond Chuen-Chung; Chu, Leung-Wing

    2014-02-01

    Magnetic resonance spectroscopy (MRS) can explore aging at a molecular level. In this study, we investigated the relationships between regional concentrations of metabolites (such as choline, creatine, myo-inositol, and N-acetyl-aspartate) and normal aging in 30 cognitively normal subjects (15 women and 15 men, age range 22-82, mean = 49.9 ± 18.3 years) using quantitative proton magnetic resonance spectroscopy. All MR scans were performed using a 3 T scanner. Point resolved spectroscopy was used as the volume selection method for the region-of-interest and the excitation method for water suppression. Single voxel spectroscopy with short echo time of 39 ms and repetition time of 2,000 ms was employed. Single voxels were placed in the limbic regions, i.e., anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and left and right hippocampi. Cerebrospinal fluid normalization and T1 and T2 correction factors were implemented in the calculation of absolute metabolite concentrations. A standardized T1W 3D volumetric fast field echo and axial T2-weighted fast spin-echo images were also acquired. Our results showed significant positive correlation of choline (r = 0.545, p = 0.002), creatine (r = 0.571, p = 0.001), and N-acetyl-aspartate (r = 0.674, p < 0.001) in the ACC; choline (r = 0.614, p < 0.001), creatine (r = 0.670, p < 0.001), and N-acetyl-aspartate (r = 0.528, p = 0.003) in the PCC; and NAA (r = 0.409, p = 0.025) in the left hippocampus, with age. No significant gender effect on metabolite concentrations was found. In aging, increases in choline and creatine might suggest glial proliferation, and an increase in N-acetyl-aspartate might indicate neuronal hypertrophy. Such findings highlight the metabolic changes of ACC and PCC with age, which could be compensatory to an increased energy demand coupled with a lower cerebral blood flow.

  6. Maternal choline supplementation during the third trimester of pregnancy improves infant information processing speed: a randomized, double-blind, controlled feeding study.

    PubMed

    Caudill, Marie A; Strupp, Barbara J; Muscalu, Laura; Nevins, Julie E H; Canfield, Richard L

    2018-04-01

    Rodent studies demonstrate that supplementing the maternal diet with choline during pregnancy produces life-long cognitive benefits for the offspring. In contrast, the two experimental studies examining cognitive effects of maternal choline supplementation in humans produced inconsistent results, perhaps because of poor participant adherence and/or uncontrolled variation in intake of choline or other nutrients. We examined the effects of maternal choline supplementation during pregnancy on infant cognition, with intake of choline and other nutrients tightly controlled. Women entering their third trimester were randomized to consume, until delivery, either 480 mg choline/d ( n = 13) or 930 mg choline/d ( n = 13). Infant information processing speed and visuospatial memory were tested at 4, 7, 10, and 13 mo of age ( n = 24). Mean reaction time averaged across the four ages was significantly faster for infants born to mothers in the 930 ( vs. 480) mg choline/d group. This result indicates that maternal consumption of approximately twice the recommended amount of choline during the last trimester improves infant information processing speed. Furthermore, for the 480-mg choline/d group, there was a significant linear effect of exposure duration (infants exposed longer showed faster reaction times), suggesting that even modest increases in maternal choline intake during pregnancy may produce cognitive benefits for offspring.-Caudill, M. A., Strupp, B. J., Muscalu, L., Nevins, J. E. H., Canfield, R. L. Maternal choline supplementation during the third trimester of pregnancy improves infant information processing speed: a randomized, double-blind, controlled feeding study.

  7. Targeting MRS-Defined Dominant Intraprostatic Lesions with Inverse-Planned High Dose Rate Brachytherapy

    DTIC Science & Technology

    2006-02-01

    metabolite markers ( choline , citrate, creatine and polyamines): elevation of choline peak and reduction of citrate and creatine peaks in an abnormal... overdose on bladder while the other 3 patients on rectum. Under dosimetric requirement (i) and (ii), in most patients the DIL-boost increased the DIL

  8. Performance-related increases in hippocampal N-acetylaspartate (NAA) induced by spatial navigation training are restricted to BDNF Val homozygotes.

    PubMed

    Lövdén, Martin; Schaefer, Sabine; Noack, Hannes; Kanowski, Martin; Kaufmann, Jörn; Tempelmann, Claus; Bodammer, Nils Christian; Kühn, Simone; Heinze, Hans-Jochen; Lindenberger, Ulman; Düzel, Emrah; Bäckman, Lars

    2011-06-01

    Recent evidence indicates experience-dependent brain volume changes in humans, but the functional and histological nature of such changes is unknown. Here, we report that adult men performing a cognitively demanding spatial navigation task every other day over 4 months display increases in hippocampal N-acetylaspartate (NAA) as measured with magnetic resonance spectroscopy. Unlike measures of brain volume, changes in NAA are sensitive to metabolic and functional aspects of neural and glia tissue and unlikely to reflect changes in microvasculature. Training-induced changes in NAA were, however, absent in carriers of the Met substitution in the brain-derived neurotrophic factor (BDNF) gene, which is known to reduce activity-dependent secretion of BDNF. Among BDNF Val homozygotes, increases in NAA were strongly related to the degree of practice-related improvement in navigation performance and normalized to pretraining levels 4 months after the last training session. We conclude that changes in demands on spatial navigation can alter hippocampal NAA concentrations, confirming epidemiological studies suggesting that mental experience may have direct effects on neural integrity and cognitive performance. BDNF genotype moderates these plastic changes, in line with the contention that gene-context interactions shape the ontogeny of complex phenotypes.

  9. The Effects of Low-Dose Creatine Supplementation Versus Creatine Loading in Collegiate Football Players

    PubMed Central

    Deivert, Richard G.; Hagerman, Frederick; Gilders, Roger

    2001-01-01

    Objective: To compare the effects of low doses of creatine and creatine loading on strength, urinary creatinine concentration, and percentage of body fat. Design and Setting: Division IA collegiate football players took creatine monohydrate for 10 weeks during a sport-specific, periodized, off-season strength and conditioning program. One-repetition maximum (1-RM) squat, urinary creatinine concentrations, and percentage of body fat were analyzed. Subjects: Twenty-five highly trained, Division IA collegiate football players with at least 1 year of college playing experience. Measurements: We tested strength with a 1-RM squat exercise before, during, and after creatine supplementation. Percentage of body fat was measured by hydrostatic weighing before and after supplementation. Urinary creatinine concentration was measured via light spectrophotometer at 0, 1, 3, 7, 14, 21, 28, 35, 42, 48, 56, and 63 days. An analysis of variance with repeated measures was computed to compare means for all variables. Results: Creatine supplementation had no significant group, time, or interaction effects on strength, urinary creatinine concentration, or percentage of body fat. However, significant time effects were found for 1-RM squat and fat-free mass in all groups. Conclusions: Our data suggest that creatine monohydrate in any amount does not have any beneficial ergogenic effects in highly trained collegiate football players. However, a proper resistance training stimulus for 10 weeks can increase strength and fat-free mass in highly trained athletes. PMID:12937451

  10. Choline transport via choline transporter-like protein 1 in conditionally immortalized rat syncytiotrophoblast cell lines TR-TBT.

    PubMed

    Lee, N-Y; Choi, H-M; Kang, Y-S

    2009-04-01

    Choline is an essential nutrient for phospholipids and acetylcholine biosynthesis in normal development of fetus. In the present study, we investigated the functional characteristics of choline transport system and inhibitory effect of cationic drugs on choline transport in rat conditionally immortalized syncytiotrophoblast cell line (TR-TBT). Choline transport was weakly Na(+) dependent and significantly influenced by extracellular pH and by membrane depolarization. The transport process of choline is saturable with Michaelis-Menten constants (K(m)) of 68microM and 130microM in TR-TBT 18d-1 and TR-TBT 18d-2 respectively. Choline uptake in the cells was inhibited by unlabeled choline and hemicholinium-3 as well as various organic cations including guanidine, amiloride and acetylcholine. However, the prototypical organic cation tetraethylammonium and cimetidine showed very little inhibitory effect of choline uptake in TR-TBT cells. RT-PCR revealed that choline transporter-like protein 1 (CTL1) and organic cation transporter 2 (OCT2) are expressed in TR-TBT cells. The transport properties of choline in TR-TBT cells were similar or identical to that of CTL1 but not OCT2. CTL1 was also detected in human placenta. In addition, several cationic drugs such as diphenhydramine and verapamil competitively inhibited choline uptake in TR-TBT 18d-1 with K(i) of 115microM and 55microM, respectively. Our results suggest that choline transport system, which has intermediate affinity and weakly Na(+) dependent, in TR-TBT seems to occur through a CTL1 and this system may have relevance with the uptake of pharmacologically important organic cation drugs.

  11. Separation methods applicable to urinary creatine and creatinine.

    PubMed

    Smith-Palmer, Truis

    2002-12-05

    Urinary creatinine has been analyzed for many years as an indicator of glomerular filtration rate. More recently, interest in studying the uptake of creatine as a result of creatine supplementation, a practice increasingly common among bodybuilders and athletes, has lead to a need to measure urinary creatine concentrations. Creatine levels are of the same order of magnitude as creatinine levels when subjects have recently ingested creatine, while somewhat elevated urinary creatine concentrations in non-supplementing subjects can be an indication of a degenerative disease of the muscle. Urinary creatine and creatinine can be analyzed by HPLC using a variety of columns. Detection methods include absorption, fluorescence after post-column derivatization, and mass spectrometry, and some methods have been automated. Capillary zone electrophoresis and micellar electrokinetic capillary chromatography have also been used to analyze urinary creatine and creatinine. Creatine and creatinine have also been analyzed in serum and tissue using HPLC and CE, and many of these separations could also be applicable to urinary analysis.

  12. Dimethylethanolamine does not prevent liver failure in phosphatidylethanolamine N-methyltransferase-deficient mice fed a choline-deficient diet.

    PubMed

    Waite, Kristin A; Vance, Dennis E

    2004-03-22

    Mice that lack phosphatidylethanolamine-N-methyltransferase (PEMT) and are fed a choline-deficient (CD) diet suffer severe liver damage and do not survive. Since phosphatidyldimethylethanolamine (PDME) has physical properties similar to those of phosphatidylcholine (PC), we hypothesized that dimethylethanolamine (DME) would be converted into PDME that might substitute for PC, and therefore abrogate the liver damage in the Pemt -/- mice fed a CD diet. We fed Pemt -/- mice either a CD diet, a CD diet supplemented with choline, or a CD diet supplemented with DME (CD + DME). Pemt -/- mice fed the CD diet developed severe liver failure by 4 days while CD + DME-fed mice developed severe liver failure by 5 days. The hepatic PC level in choline-supplemented (CS) mice was 67 +/- 4 nmol/mg protein, whereas the PC content was reduced in CD- and CD + DME-fed mice (49 +/- 3 and 30 +/- 3 nmol/mg protein, respectively). Upon supplementation of the CD diet with DME the amount of hepatic PDME was 81 +/- 9 nmol/mg protein so that the hepatic content of PC + PDME combined was 111 nmol/mg protein. Moreover, plasma apolipoprotein B100 and Al levels were markedly lower in mice fed the CD + DME diet compared to mice fed the CS diet, as was the plasma content of PC. Thus, despite replacement of the deficit in hepatic PC with PDME in Pemt -/- mice fed a CD diet, normal liver function was not restored. We conclude that although PC and PDME exhibit similar physical properties, the three methyl groups of choline are required for hepatic function in mice.

  13. Evidence for neuroinflammation and neuroprotection in HCV infection-associated encephalopathy.

    PubMed

    Bokemeyer, M; Ding, X-Q; Goldbecker, A; Raab, P; Heeren, M; Arvanitis, D; Tillmann, H L; Lanfermann, H; Weissenborn, K

    2011-03-01

    Fatigue, mood disturbances and cognitive dysfunction are frequent in patients infected with hepatitis C virus (HCV) who have mild liver disease. The reason is still unclear. The present study aims to gain more insight into the pathomechanism by combining an extensive neuropsychological examination with magnetic resonance spectroscopy in four different brain regions in a patient group covering the whole spectrum of neuropsychiatric findings in patients afflicted with HCV who have only mild liver disease. 53 HCV-positive patients with only mild liver disease and differing degrees of neuropsychiatric symptoms were studied with single-voxel MRS of the parietal white matter, occipital grey matter, basal ganglia and pons. Brain metabolite concentrations were quantitatively analysed by using LCmodel. MRS data were compared to those of 23 healthy controls adjusted for age, and analysed for relationships with the extent of neuropsychiatric symptoms. Choline (p=0.02), creatine (p=0.047) and N-acetyl-aspartate plus N-acetyl-aspartyl-glutamate (NN, p=0.02) concentrations in the basal ganglia and choline concentrations in the white matter (p=0.045) were significantly higher in the patients than in controls. Interestingly, the difference was most evident for the patients with low fatigue scores (eg, white matter: choline: p=0.001, creatine: p=0.003, NN: p=0.031). Myo-inositol differed significantly between groups in the white (p=0.001) and grey matter (p=0.003). Fatigue correlated negatively with white matter NN, choline and creatine and myo-inositol levels in white and grey matter and basal ganglia (p<0.01). As the increase of choline, creatine and myo-inositol are usually interpreted to indicate glial activation and macrophage infiltration in chronic inflammation and slow virus infections of the brain the present data endorse the hypothesis, that HCV infection may induce neuroinflammation and brain dysfunction. The concomitant increase of NN and the negative correlation to the

  14. Some actions of substituted choline phenyl ethers, particularly of choline 2:6-xylyl ether

    PubMed Central

    Edge, N. D.; Mason, D. F. J.; Wyllie, J. H.

    1957-01-01

    Marked nicotine-like stimulant properties are possessed by choline phenyl ether and choline o-tolyl ether, and to a decreasing extent by choline 2:6-xylyl ether and choline 2:4:6-mesityl ether. The compounds all show neuromuscular blocking properties, which are of short duration and pass from mainly decamethonium-like to mainly curare-like as more methyl groups are added to the phenyl nucleus. This series of compounds also possesses muscarinic, weak anti-adrenaline and vasodilator properties, as well as long-lasting local anaesthetic effects in the two compounds tested by intradermal injection. PMID:13460236

  15. Recovery of choline oxidase activity by in vitro recombination of individual segments.

    PubMed

    Heinze, Birgit; Hoven, Nina; O'Connell, Timothy; Maurer, Karl-Heinz; Bartsch, Sebastian; Bornscheuer, Uwe T

    2008-11-01

    Initial attempts to express a choline oxidase from Arthrobacter pascens (APChO-syn) in Escherichia coli starting from a synthetic gene only led to inactive protein. However, activity was regained by the systematic exchange of individual segments of the gene with segments from a choline oxidase-encoding gene from Arthrobacter globiformis yielding a functional chimeric enzyme. Next, a sequence alignment of the exchanged segment with other choline oxidases revealed a mutation in the APChO-syn, showing that residue 200 was a threonine instead of an asparagine, which is, thus, crucial for confering enzyme activity and, hence, provides an explanation for the initial lack of activity. The active recombinant APChO-syn-T200N variant was biochemically characterized showing an optimum at pH 8.0 and at 37 degrees C. Furthermore, the substrate specificity was examined using N,N-dimethylethanolamine, N-methylethanolamine and 3,3-dimethyl-1-butanol.

  16. Characterization of choline transporters in the human placenta over gestation.

    PubMed

    Baumgartner, Heidi K; Trinder, Kinsey M; Galimanis, Carly E; Post, Annalisa; Phang, Tzu; Ross, Randal G; Winn, Virginia D

    2015-12-01

    The developing fetus relies on the maternal blood supply to provide the choline it requires for making membrane lipids, synthesizing acetylcholine, and performing important methylation reactions. It is vital, therefore, that the placenta is efficient at transporting choline from the maternal to the fetal circulation. Although choline transporters have been found in term placenta samples, little is known about what cell types express specific choline transporters and how expression of the transporters may change over gestation. The objective of this study was to characterize choline transporter expression levels and localization in the human placenta throughout placental development. We analyzed CTL1 and -2 expression over gestation in human placental biopsies from 6 to 40 weeks gestation (n = 6-10 per gestational window) by immunoblot analysis. To determine the cellular expression pattern of the choline transporters throughout gestation, immunofluorescence analysis was then performed. Both CTL1 and CTL2 were expressed in the chorionic villi from 6 weeks gestation to term. Labor did not alter expression levels of either transporter. CTL1 localized to the syncytial trophoblasts and the endothelium of the fetal vasculature within the chorionic villous structure. CTL2 localized mainly to the stroma early in gestation and by the second trimester co-localized with CTL1 at the fetal vasculature. The differential expression pattern of CTL1 and CTL2 suggests that CTL1 is the key transporter involved in choline transport from maternal circulation and both transporters are likely involved in stromal and endothelial cell choline transport. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Characterization of Choline Transporters in the Human Placenta over Gestation

    PubMed Central

    Baumgartner, Heidi K.; Trinder, Kinsey M.; Galimanis, Carly E.; Post, Annalisa; Phang, Tzu; Ross, Randal G.; Winn, Virginia D.

    2015-01-01

    INTRODUCTION The developing fetus relies on the maternal blood supply to provide the choline it requires for making membrane lipids, synthesizing acetylcholine, and performing important methylation reactions. It is vital, therefore, that the placenta is efficient at transporting choline from maternal to fetal circulation. Although choline transporters have been found in term placenta samples, little is known about what cell types express specific choline transporters and how expression of the transporters may change over gestation. The objective of this study was to characterize choline transporter expression levels and localization in the human placenta throughout placental development. METHODS We analyzed CTL1 and −2 expression over gestation in human placental biopsies from 6 to 40 weeks gestation (n=6–10 per gestational window) by immunoblot analysis. To determine the cellular expression pattern of the choline transporters throughout gestation, immunofluorescence analysis was then performed. RESULTS Both CTL1 and CTL2 were expressed in the chorionic villi from 6 weeks gestation to term. Labor did not alter expression levels of either transporter. CTL1 localized to the syncytial trophoblasts and the endothelium of the fetal vasculature within the chorionic villous structure. CTL2 localized mainly to the stroma early in gestation and by the second trimester co-localized with CTL1 at the fetal vasculature. DISCUSSION The differential expression pattern of CTL1 and CTL2 suggests that CTL1 is the key transporter involved in choline transport from maternal circulation and both transporters are likely involved in stromal and endothelial cell choline transport. PMID:26601765

  18. Serum Trimethylamine N-oxide, Carnitine, Choline, and Betaine in Relation to Colorectal Cancer Risk in the Alpha Tocopherol, Beta Carotene Cancer Prevention Study.

    PubMed

    Guertin, Kristin A; Li, Xinmin S; Graubard, Barry I; Albanes, Demetrius; Weinstein, Stephanie J; Goedert, James J; Wang, Zeneng; Hazen, Stanley L; Sinha, Rashmi

    2017-06-01

    Background: Trimethylamine N-oxide (TMAO), a choline-derived metabolite produced by gut microbiota, and its biomarker precursors have not been adequately evaluated in relation to colorectal cancer risk. Methods: We investigated the relationship between serum concentrations of TMAO and its biomarker precursors (choline, carnitine, and betaine) and incident colorectal cancer risk in a nested case-control study of male smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We measured biomarker concentrations in baseline fasting serum samples from 644 incident colorectal cancer cases and 644 controls using LC/MS-MS. Logistic regression models estimated the ORs and 95% confidence interval (CI) for colorectal cancer by quartile (Q) of serum TMAO, choline, carnitine, and betaine concentrations. Results: Men with higher serum choline at ATBC baseline had approximately 3-fold greater risk of developing colorectal cancer over the ensuing (median ± IQR) 14 ± 10 years (in fully adjusted models, Q4 vs. Q1, OR, 3.22; 95% CI, 2.24-4.61; P trend < 0.0001). The prognostic value of serum choline for prediction of incident colorectal cancer was similarly robust for proximal, distal, and rectal colon cancers (all P < 0.0001). The association between serum TMAO, carnitine, or betaine and colorectal cancer risk was not statistically significant ( P = 0.25, 0.71, and 0.61, respectively). Conclusions: Higher serum choline concentration (but not TMAO, carnitine, or betaine) was associated with increased risk of colorectal cancer. Impact: Serum choline levels showed strong prognostic value for prediction of incident colorectal cancer risk across all anatomical subsites, suggesting a role of altered choline metabolism in colorectal cancer pathogenesis. Cancer Epidemiol Biomarkers Prev; 26(6); 945-52. ©2017 AACR . ©2017 American Association for Cancer Research.

  19. The effects of polyethylene glycosylated creatine supplementation on anaerobic performance measures and body composition.

    PubMed

    Camic, Clayton L; Housh, Terry J; Zuniga, Jorge M; Traylor, Daniel A; Bergstrom, Haley C; Schmidt, Richard J; Johnson, Glen O; Housh, Dona J

    2014-03-01

    The purpose of this study was to examine the effects of 28 days of polyethylene glycosylated creatine (PEG-creatine) supplementation (1.25 and 2.50 g·d) on anaerobic performance measures (vertical and broad jumps, 40-yard dash, 20-yard shuttle run, and 3-cone drill), upper- and lower-body muscular strength and endurance (bench press and leg extension), and body composition. This study used a randomized, double-blind, placebo-controlled parallel design. Seventy-seven adult men (mean age ± SD, 22.1 ± 2.5 years; body mass, 81.7 ± 10.8 kg) volunteered to participate and were randomly assigned to a placebo (n = 23), 1.25 g·d of PEG-creatine (n = 27), or 2.50 g·d of PEG-creatine (n = 27) group. The subjects performed anaerobic performance measures, muscular strength (one-repetition maximum [1RM]), and endurance (80% 1RM) tests for bench press and leg extension, and underwater weighing for the determination of body composition at day 0 (baseline), day 14, and day 28. The results indicated that there were improvements (p < 0.0167) in vertical jump, 20-yard shuttle run, 3-cone drill, muscular endurance for bench press, and body mass for at least one of the PEG-creatine groups without changes for the placebo group. Thus, the present results demonstrated that PEG-creatine supplementation at 1.25 or 2.50 g·d had an ergogenic effect on lower-body vertical power, agility, change-of-direction ability, upper-body muscular endurance, and body mass.

  20. Assessment of Total Choline Intakes in the United States.

    PubMed

    Wallace, Taylor C; Fulgoni, Victor L

    2016-01-01

    Choline is an essential nutrient and plays a critical role in brain development, cell signaling, nerve impulse transmission, and lipid transport and metabolism. This analysis aimed to assess usual intakes of choline and compare them with the dietary reference intakes for U.S. residents aged ≥ 2 years. The National Cancer Institute method was used to assess usual intakes of choline from foods according to data for participants in the 2009-2012 National Health and Nutrition Examination Survey (NHANES; n = 16,809). Suboptimal intakes of choline are prevalent across many life-stage subpopulations in the United States. Only 10.8 ± 0.6% of 2009-2012 NHANES participants aged ≥ 2 years (15.6 ± 0.8% of males and 6.1 ± 0.6% of females) achieved the adequate intake (AI) for choline. Children aged 2-3 years were the most likely to exceed the AI (62.9 ± 3.1%), followed by children aged 4-8 years (45.4 ± 1.6%) and children aged 9-13 years (9.0 ± 1.0%), compared to adolescents aged 14-18 years (1.8 ± 0.4%) and adults aged ≥ 19 years (6.6 ± 0.5%). When comparing by age and gender, males consumed significantly more choline than females for all age groups. These data indicate that there is a need to increase awareness among health professionals and consumers regarding potential suboptimal intakes of choline in the United States, as well as the critical role that choline plays in health maintenance throughout the lifespan. Food scientists and the food and dietary supplement industries should consider working collectively with government agencies to discuss strategies to help offset the percentage of the population that does not meet the AI. Revision of the dietary reference intakes for choline should include replacement of the AI with an estimated average requirement and a recommended dietary allowance, so that more accurate population estimates of inadequate intakes may be calculated.

  1. Longitudinal cerebral metabolic changes in pig-tailed macaques infected with the neurovirulent virus SIVsmmFGb

    PubMed Central

    Li, Chun-Xia; Zhang, Xiaodong; Komery, Amelia; Li, Yingxia; Mao, Hui; Herndon, James G; Novembre, Francis J

    2014-01-01

    Longitudinal cerebral metabolite changes in pig-tailed macaques inoculated with the simian immunodeficiency virus SIVsmmFGb were evaluated with in vivo proton MRS at 3T. Blood sample collection, and MRS were carried out before and 2, 4, 8, 12, 16, 20 and 24 weeks after SIV inoculation. Significant reduction of N-acetylaspartate (NAA)/creatine (Cr) and Choline (Cho)/Cr ratios in prefrontal grey matter (PGM) and glutamate/glutamine (Glx)/Cr ratios in striatum, and increase of myo-inositol (mI)/Cr in striatum were observed during acute SIV infection. The metabolite alterations during the SIVsmmFGb infection are largely in agreement with previous findings in other non-human primate models and HIV patients. Also, NAA/Cr in PGM and striatum and Glx/Cr in striatum are negatively correlated with the percentage of CD8+ T cells after the SIV infection, suggesting the interaction between brain metabolite and immune dysfunction. The present study complements previous studies by describing the time course of alterations of brain metabolites during SIVsmmFGb infection. The findings further demonstrate the efficacy of the SIVsmmFGb-infected macaque as a model to characterize central nervous system infection using novel neuroimaging approaches and also as a tool for exploration of novel and advanced neuroimaging techniques in HIV/AIDS studies. PMID:25377443

  2. Study on the pathogenic mechanism of Broca's and Wernicke's aphasia.

    PubMed

    Zhang, Yumei; Wang, Yilong; Wang, Chunxue; Zhao, Xingquan; Gong, Xiping; Sun, Xuejin; Chen, Hongyan; Wang, Yongjun

    2006-01-01

    To study the mechanisms of aphasia by observing cerebral blood flow and metabolism changes in language functional areas of the brain using imaging, in order to develop a language rehabilitation plan for aphasia patients. Fifty-eight patients who suffered from Broca's or Wernicke's aphasia secondly to cerebral infarction were evaluated using the Western aphasia battery and Frenchay dysarthria assessment. CT and MRI were obtained to identify the location of lesions, and the language areas were analysed with magnetic resonance spectroscopy (MRS) and perfusion-weighted imaging (PWI). The results were compared with those of the contralateral hemisphere. Of the 58 patients, there were 23 Broca's aphasia patients, 29 Wernicke's aphasia patients and six other aphasia types. We excluded five patients accompanied by dysarthria, six patients with other aphasia types and 14 patients with much more disease lesions. Finally, we analysed the remaining 12 Broca's aphasia and 21 Wernicke's aphasia patients by MRS and PWI. MRS shows that the N-acetylaspartate, choline and creatine of the Broca's or Wernicke's area were reduced than those of the contralateral hemisphere, while PWI results show that the damaged Broca's or Wernicke's areas were in a hypoperfusion state. Broca's or Wernicke's area of aphasia patients exhibits hypoperfusion and hypometabolism, indicating that they might be the mechanisms of Broca's or Wernicke's aphasia.

  3. Clinical Metabolomics and Glaucoma.

    PubMed

    Barbosa-Breda, João; Himmelreich, Uwe; Ghesquière, Bart; Rocha-Sousa, Amândio; Stalmans, Ingeborg

    2018-01-01

    Glaucoma is one of the leading causes of irreversible blindness worldwide. However, there are no biomarkers that accurately help clinicians perform an early diagnosis or detect patients with a high risk of progression. Metabolomics is the study of all metabolites in an organism, and it has the potential to provide a biomarker. This review summarizes the findings of metabolomics in glaucoma patients and explains why this field is promising for new research. We identified published studies that focused on metabolomics and ophthalmology. After providing an overview of metabolomics in ophthalmology, we focused on human glaucoma studies. Five studies have been conducted in glaucoma patients and all compared patients to healthy controls. Using mass spectrometry, significant differences were found in blood plasma in the metabolic pathways that involve palmitoylcarnitine, sphingolipids, vitamin D-related compounds, and steroid precursors. For nuclear magnetic resonance spectroscopy, a high glutamine-glutamate/creatine ratio was found in the vitreous and lateral geniculate body; no differences were detected in the optic radiations, and a lower N-acetylaspartate/choline ratio was observed in the geniculocalcarine and striate areas. Metabolomics can move glaucoma care towards a personalized approach and provide new knowledge concerning the pathophysiology of glaucoma, which can lead to new therapeutic options. © 2017 S. Karger AG, Basel.

  4. Long-term normal-appearing brain tissue monitoring after irradiation using proton magnetic resonance spectroscopy in vivo: Statistical analysis of a large group of patients

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Matulewicz, Lukasz; Sokol, Maria; Michnik, Anna

    2006-11-01

    Purpose: The aim of this study was to detect the non-neoplastic white-matter changes vs. time after irradiation using {sup 1}H nuclear magnetic resonance (NMR) spectroscopy in vivo. Methods and Materials: A total of 394 {sup 1}H MR spectra were acquired from 100 patients (age 19-74 years; mean and median age, 43 years) before and during 2 years after radiation therapy (the mean absorbed doses calculated for the averaged spectroscopy voxels are similar and close to 20 Gy). Results: Ocilations were observed in choline-containing compounds (Cho)/creatine and phosphocreatine (Cr), Cho/N-acetylaspartate (NAA), and center of gravity (CG) of the lipid band inmore » the range of 0.7-1.5 ppm changes over time reveal oscillations. The parameters have the same 8-month cycle period; however the CG changes precede the other by 2 months. Conclusions: The results indicate the oscillative nature of the brain response to irradiation, which may be caused by the blood-brain barrier disruption and repair processes. These oscillations may influence the NMR results, depending on the cycle phase in which the NMR measurements are performed in. The earliest manifestation of radiation injury detected by magnetic resonance spectroscopy is the CG shift.« less

  5. Main Effects of Diagnoses, Brain Regions, and their Interaction Effects for Cerebral Metabolites in Bipolar and Unipolar Depressive Disorders

    NASA Astrophysics Data System (ADS)

    Tan, Hai-Zhu; Li, Hui; Liu, Chen-Feng; Guan, Ji-Tian; Guo, Xiao-Bo; Wen, Can-Hong; Ou, Shao-Min; Zhang, Yin-Nan; Zhang, Jie; Xu, Chong-Tao; Shen, Zhi-Wei; Wu, Ren-Hua; Wang, Xue-Qin

    2016-11-01

    Previous studies suggested patients with bipolar depressive disorder (BDd) or unipolar depressive disorder (UDd) have cerebral metabolites abnormalities. These abnormalities may stem from multiple sub-regions of gray matter in brain regions. Thirteen BDd patients, 20 UDd patients and 20 healthy controls (HC) were enrolled to investigate these abnormalities. Absolute concentrations of 5 cerebral metabolites (glutamate-glutamine (Glx), N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), creatine (Cr), parietal cortex (PC)) were measured from 4 subregions (the medial frontal cortex (mPFC), anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and parietal cortex (PC)) of gray matter. Main and interaction effects of cerebral metabolites across subregions of gray matter were evaluated. For example, the Glx was significantly higher in BDd compared with UDd, and so on. As the interaction analyses showed, some interaction effects existed. The concentrations of BDds’ Glx, Cho, Cr in the ACC and HCs’ mI and Cr in the PC were higher than that of other interaction effects. In addition, the concentrations of BDds’ Glx and Cr in the PC and HCs’ mI in the ACC were statistically significant lower than that of other interaction effects. These findings point to region-related abnormalities of cerebral metabolites across subjects with BDd and UDd.

  6. Longitudinal inter- and intra-individual human brain metabolic quantification over 3 years with proton MR spectroscopy at 3 T.

    PubMed

    Kirov, Ivan I; George, Ilena C; Jayawickrama, Nikhil; Babb, James S; Perry, Nissa N; Gonen, Oded

    2012-01-01

    The longitudinal repeatability of proton MR spectroscopy ((1) H-MRS) in the healthy human brain at high fields over long periods is not established. Therefore, we assessed the inter- and intra-subject repeatability of (1) H-MRS in an approach suited for diffuse pathologies in 10 individuals, at 3T, annually for 3 years. Spectra from 480 voxels over 360 cm(3) (∼30%) of the brain, were individually phased, frequency-aligned, and summed into one average spectrum. This dramatically increases metabolites' signal-to-noise-ratios while maintaining narrow linewidths that improve quantification precision. The resulting concentrations of the N-acetylaspartate, creatine, choline, and myo-inositol are: 8.9 ± 0.8, 5.9 ± 0.6, 1.4 ± 0.1, and 4.5 ± 0.5 mM (mean ± standard-deviation). the inter-subject coefficients of variation are 8.7%, 10.2%, 10.7%, and 11.8%; and the longitudinal (intra-subject) coefficients of variation are lower still: 6.6%, 6.8%, 6.8%, and 10%, much better than the 35%, 44%, 55%, and 62% intra-voxel coefficients of variation. The biological and nonbiological components of the summed spectra coefficients of variation had similar contributions to the overall variance. Copyright © 2011 Wiley-Liss, Inc.

  7. Longitudinal cerebral metabolic changes in pig-tailed macaques infected with the neurovirulent virus SIVsmmFGb.

    PubMed

    Li, Chun-Xia; Zhang, Xiaodong; Komery, Amelia; Li, Yingxia; Mao, Hui; Herndon, James G; Novembre, Francis J

    2014-12-01

    Longitudinal cerebral metabolite changes in pig-tailed macaques inoculated with the simian immunodeficiency virus SIVsmmFGb were evaluated with in vivo proton MRS at 3 T. Blood sample collection, and MRS were carried out before and 2, 4, 8, 12, 16, 20, and 24 weeks after SIV inoculation. Significant reduction of N-acetylaspartate (NAA)/creatine (Cr) and choline (Cho)/Cr ratios in prefrontal gray matter (PGM) and glutamate/glutamine(Glx)/Cr ratio in striatum, and increase of myo-inositol (mI)/Cr in striatum were observed during acute SIV infection. The metabolite alterations during the SIVsmmFGb infection are largely in agreement with previous findings in other non-human primate models and HIV patients. Also, NAA/Cr in PGM and striatum and Glx/Cr in striatum are negatively correlated with the percentage of CD8+ T cells after the SIV infection, suggesting the interaction between brain metabolite and immune dysfunction. The present study complements previous studies by describing the time course of alterations of brain metabolites during SIVsmmFGb infection. The findings further demonstrate the efficacy of the SIVsmmFGb-infected macaque as a model to characterize central nervous system infection using novel neuroimaging approaches and also as a tool for exploration of novel and advanced neuroimaging techniques in HIV/AIDS studies.

  8. Main Effects of Diagnoses, Brain Regions, and their Interaction Effects for Cerebral Metabolites in Bipolar and Unipolar Depressive Disorders.

    PubMed

    Tan, Hai-Zhu; Li, Hui; Liu, Chen-Feng; Guan, Ji-Tian; Guo, Xiao-Bo; Wen, Can-Hong; Ou, Shao-Min; Zhang, Yin-Nan; Zhang, Jie; Xu, Chong-Tao; Shen, Zhi-Wei; Wu, Ren-Hua; Wang, Xue-Qin

    2016-11-21

    Previous studies suggested patients with bipolar depressive disorder (BDd) or unipolar depressive disorder (UDd) have cerebral metabolites abnormalities. These abnormalities may stem from multiple sub-regions of gray matter in brain regions. Thirteen BDd patients, 20 UDd patients and 20 healthy controls (HC) were enrolled to investigate these abnormalities. Absolute concentrations of 5 cerebral metabolites (glutamate-glutamine (Glx), N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), creatine (Cr), parietal cortex (PC)) were measured from 4 subregions (the medial frontal cortex (mPFC), anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and parietal cortex (PC)) of gray matter. Main and interaction effects of cerebral metabolites across subregions of gray matter were evaluated. For example, the Glx was significantly higher in BDd compared with UDd, and so on. As the interaction analyses showed, some interaction effects existed. The concentrations of BDds' Glx, Cho, Cr in the ACC and HCs' mI and Cr in the PC were higher than that of other interaction effects. In addition, the concentrations of BDds' Glx and Cr in the PC and HCs' mI in the ACC were statistically significant lower than that of other interaction effects. These findings point to region-related abnormalities of cerebral metabolites across subjects with BDd and UDd.

  9. Proton magnetic resonance spectroscopy in obsessive-compulsive disorder: evidence for reduced neuronal integrity in the anterior cingulate.

    PubMed

    Tükel, Raşit; Aydın, Kubilay; Ertekin, Erhan; Özyıldırım, Seda Şahin; Taravari, Vedat

    2014-12-30

    Neuroimaging studies have suggested that dysfunction of the cortico-striatal-thalamo-cortical (CSTC) circuit is a key pathophysiologic feature of obsessive-compulsive disorder (OCD). Several studies using proton magnetic resonance spectroscopy ((1)H MRS) have found abnormal neural metabolite concentrations among OCD patients. The aim of this study was to investigate the metabolic integrity of the anterior cingulate, caudate and putamen in OCD. In the present study, 32 unmedicated patients with OCD, including 23 who were drug-naïve, were compared using MRS with 32 healthy controls. Metabolite levels of N-acetylaspartate (NAA), choline (Cho) and myo-inositol (mI) were measured in terms of their ratios to creatine (Cr). The ratio of NAA/Cr was significantly lower in OCD patients than in healthy controls in the anterior cingulate. There was a tendency for levels of NAA/Cr to be lower in the caudate and the putamen in patients with OCD compared with healthy controls. NAA/Cr ratios were negatively correlated with the total scores on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) in the anterior cingulate in patients with OCD. Our results support the significance and biochemical involvement of the anterior cingulate cortex (ACC) in the pathophysiology of OCD. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. Creatine Supplementation Increases Total Body Water in Soccer Players: a Deuterium Oxide Dilution Study.

    PubMed

    Deminice, R; Rosa, F T; Pfrimer, K; Ferrioli, E; Jordao, A A; Freitas, E

    2016-02-01

    This study aimed to evaluate changes in total body water (TBW) in soccer athletes using a deuterium oxide dilution method and bioelectrical impedance (BIA) formulas after 7 days of creatine supplementation. In a double-blind controlled manner, 13 healthy (under-20) soccer players were divided randomly in 2 supplementation groups: Placebo (Pla, n=6) and creatine supplementation (CR, n=7). Before and after the supplementation period (0.3 g/kg/d during 7 days), TBW was determined by deuterium oxide dilution and BIA methods. 7 days of creatine supplementation lead to a large increase in TBW (2.3±1.0 L) determined by deuterium oxide dilution, and a small but significant increase in total body weight (1.0±0.4 kg) in Cr group compared to Pla. The Pla group did not experience any significant changes in TBW or body weight. Although 5 of 6 BIA equations were sensitive to determine TBW changes induced by creatine supplementation, the Kushner et al. 16 method presented the best concordance levels when compared to deuterium dilution method. In conclusion, 7-days of creatine supplementation increased TBW determined by deuterium oxide dilution or BIA formulas. BIA can be useful to determine TBW changes promoted by creatine supplementation in soccer athletes, with special concern for formula choice. © Georg Thieme Verlag KG Stuttgart · New York.

  11. Choline distribution and metabolism in pregnant rats and fetuses are influenced by the choline content of the maternal diet.

    PubMed

    Garner, S C; Mar, M H; Zeisel, S H

    1995-11-01

    Choline supplementation of pregnant rats between d 12 and 17 of pregnancy permanently enhances the spatial memory of offspring; however, the mechanism is unknown. We examined the effect of choline supplementation on metabolism of orally ingested choline by nonmated rats and pregnant rats and their fetuses. We studied the metabolism of an acute oral dose of 14C-choline chloride in pregnant and nonmated rats with and without choline supplementation (25 mmol/L choline chloride in water) on d 12-17 of pregnancy. During the first 2 h after oral dosing, plasma radiolabeled choline was detectable, whereas plasma choline metabolites contributed little to total radioactivity at any time. The pattern of accumulation of label in placentas was similar in all groups. Fetal tissues (i.e., brain, liver and carcass remnant) contained primarily 14C-phosphatidylcholine and 14C-phosphorylcholine. Also, we examined the fetal tissue distribution of isotopically labeled (deuterated) choline derived from the diet and from the dietary choline supplement. The distribution patterns for radiolabeled choline metabolites in fetuses of supplemented dams accumulated significantly (P < 0.01) more of their total choline and its metabolites than fetuses of control dams during d 12-17 of gestation (50 vs. 20%). In fetuses from supplemented dams, betaine concentrations were greater than in fetuses from control dams in all organs assayed (by 36-57%). Phosphorylcholine concentrations in brain of fetuses from supplemented dams were also greater. These experiments identify potential metabolites of choline that might mediate the observed effects on brain development in the rats.

  12. Dietary folate, but not choline, modifies neural tube defect risk in Shmt1 knockout mice.

    PubMed

    Beaudin, Anna E; Abarinov, Elena V; Malysheva, Olga; Perry, Cheryll A; Caudill, Marie; Stover, Patrick J

    2012-01-01

    Low dietary choline intake has been proposed to increase the risk of neural tube defects (NTDs) in human populations. Mice with reduced Shmt1 expression exhibit a higher frequency of NTDs when placed on a folate- and choline-deficient diet and may represent a model of human NTDs. The individual contribution of dietary folate and choline deficiency to NTD incidence in this mouse model is not known. To dissociate the effects of dietary folate and choline deficiency on Shmt1-related NTD sensitivity, we determined NTD incidence in embryos from Shmt1-null dams fed diets deficient in either folate or choline. Shmt1(+/+) and Shmt1(-/-) dams were maintained on a standard AIN93G diet (Dyets), an AIN93G diet lacking folate (FD), or an AIN93G diet lacking choline (CD). Virgin Shmt1(+/+) and Shmt1(-/-) dams were crossed with Shmt1(+/-) males, and embryos were examined for the presence of NTDs at embryonic day (E) 11.5 or E12.5. Exencephaly was observed only in Shmt1(-/-) embryos isolated from dams maintained on the FD diet (P = 0.004). Approximately 33% of Shmt1(-/-)embryos (n = 18) isolated from dams maintained on the FD diet exhibited exencephaly. NTDs were not observed in any embryos isolated from dams maintained on the CD (n = 100) or control (n = 152) diets or in any Shmt1(+/+) (n = 78) or Shmt1(+/-) embryos (n = 182). Maternal folate deficiency alone is sufficient to induce NTDs in response to embryonic Shmt1 disruption.

  13. Creatine supplementation and swim performance: a brief review.

    PubMed

    Hopwood, Melissa J; Graham, Kenneth; Rooney, Kieron B

    2006-03-01

    Nutritional supplements are popular among athletes participating in a wide variety of sports. Creatine is one of the most commonly used dietary supplements, as it has been shown to be beneficial in improving performance during repeated bouts of high-intensity anaerobic activity. This review examines the specific effects of creatine supplementation on swimming performance, and considers the effects of creatine supplementation on various measures of power development in this population. Research performed on the effect of creatine supplementation on swimming performance indicates that whilst creatine supplementation is ineffective in improving performance during a single sprint swim, dietary creatine supplementation may benefit repeated interval swim set performance. Considering the relationship between sprint swimming performance and measurements of power, the effect of creatine supplementation on power development in swimmers has also been examined. When measured on a swim bench ergometer, power development does show some improvement following a creatine supplementation regime. How this improvement in power output transfers to performance in the pool is uncertain. Although some evidence exists to suggest a gender effect on the performance improvements seen in swimmers following creatine supplementation, the majority of research indicates that male and female swimmers respond equally to supplementation. A major limitation to previous research is the lack of consideration given to the possible stroke dependant effect of creatine supplementation on swimming performance. The majority of the research conducted to date has involved examination of the freestyle swimming stroke only. The potential for performance improvements in the breaststroke and butterfly swimming strokes is discussed, with regards to the biomechanical differences and differences in efficiency between these strokes and freestyle. Key PointsCreatine supplementation does not improve single sprint

  14. Dietary choline requirement of juvenile hybrid striped bass.

    PubMed

    Griffin, M E; Wilson, K A; White, M R; Brown, P B

    1994-09-01

    Two experiments were conducted to estimate the dietary choline requirement and to determine the effects of dietary choline on liver lipid deposition in juvenile hybrid striped bass (Monrone saxatilis x M. chrysops). Experimental diets contained 0.73 g total sulfur amino acids/100 g diet (0.47 g methionine + 0.26 g cyst(e)ine/100 g diet), thus meeting, but not exceeding, the requirement. Graded levels of choline bitartrate in Experiment 1 and choline chloride in Experiment 2 were added to the basal diet, resulting in eight dietary treatments in each experiment. Dietary treatments were 0, 250, 500, 1000, 2000, 4000, 6000 and 8000 mg choline/kg dry diet. Diets were fed for 12 and 10 wk in Experiments 1 and 2, respectively. Dietary choline concentrations significantly affected weight gain, feed efficiency, survival and total liver lipid concentrations in each experiment. Weight gain and feed efficiency were greatest in fish fed 500 mg choline/kg dry diet as choline bitartrate. Total liver lipid concentrations were variable but tended to be lowest in fish fed diets containing at least 2000 mg choline/kg diet. Survival was significantly lower in the group of fish fed 8000 mg choline/kg diet supplied by choline bitartrate. Weight gain and feed efficiency were greatest and total liver lipid concentration was lowest in groups of fish fed at least 500 mg choline/kg diet as choline chloride; survival was unaffected by dietary treatment. Therefore, choline chloride seems to be a better source of dietary choline than choline bitartrate and 500 mg choline/kg diet is adequate for maximum weight gain and prevention of increased liver lipid concentration in juvenile hybrid striped bass.

  15. Novel channel-mediated choline transport in cholinergic neurons of the mouse retina.

    PubMed

    Ishii, Toshiyuki; Homma, Kohei; Mano, Asuka; Akagi, Takumi; Shigematsu, Yasuhide; Shimoda, Yukio; Inoue, Hiroyoshi; Kakinuma, Yoshihiko; Kaneda, Makoto

    2017-10-01

    Choline uptake into the presynaptic terminal of cholinergic neurons is mediated by the high-affinity choline transporter and is essential for acetylcholine synthesis. In a previous study, we reported that P2X 2 purinoceptors are selectively expressed in OFF-cholinergic amacrine cells of the mouse retina. Under specific conditions, P2X 2 purinoceptors acquire permeability to large cations, such as N -methyl-d-glucamine, and therefore potentially could act as a noncanonical pathway for choline entry into neurons. We tested this hypothesis in OFF-cholinergic amacrine cells of the mouse retina. ATP-induced choline currents were observed in OFF-cholinergic amacrine cells, but not in ON-cholinergic amacrine cells, in mouse retinal slice preparations. High-affinity choline transporters are expressed at higher levels in ON-cholinergic amacrine cells than in OFF-cholinergic amacrine cells. In dissociated preparations of cholinergic amacrine cells, ATP-activated cation currents arose from permeation of extracellular choline. We also examined the pharmacological properties of choline currents. Pharmacologically, α,β-methylene ATP did not produce a cation current, whereas ATPγS and benzoyl-benzoyl-ATP (BzATP) activated choline currents. However, the amplitude of the choline current activated by BzATP was very small. The choline current activated by ATP was strongly inhibited by pyridoxalphosphate-6-azophenyl-2',4'-sulfonic acid. Accordingly, P2X 2 purinoceptors expressed in HEK-293T cells were permeable to choline and similarly functioned as a choline uptake pathway. Our physiological and pharmacological findings support the hypothesis that P2 purinoceptors, including P2X 2 purinoceptors, function as a novel choline transport pathway and may provide a new regulatory mechanism for cholinergic signaling transmission at synapses in OFF-cholinergic amacrine cells of the mouse retina. NEW & NOTEWORTHY Choline transport across the membrane is exerted by both the high-affinity and

  16. Choline and betaine in health and disease.

    PubMed

    Ueland, Per Magne

    2011-02-01

    Choline is an essential nutrient, but is also formed by de novo synthesis. Choline and its derivatives serve as components of structural lipoproteins, blood and membrane lipids, and as a precursor of the neurotransmitter acetylcholine. Pre-and postnatal choline availability is important for neurodevelopment in rodents. Choline is oxidized to betaine that serves as an osmoregulator and is a substrate in the betaine-homocysteine methyltransferase reaction, which links choline and betaine to the folate-dependent one-carbon metabolism. Choline and betaine are important sources of one-carbon units, in particular, during folate deficiency. Choline or betaine supplementation in humans reduces concentration of total homocysteine (tHcy), and plasma betaine is a strong predictor of plasma tHcy in individuals with low plasma concentration of folate and other B vitamins (B₂, B₆, and B₁₂) in combination TT genotype of the methylenetetrahydrofolate reductase 677 C->T polymorphism. The link to one-carbon metabolism and the recent availability of food composition data have motivated studies on choline and betaine as risk factors of chronic diseases previously studied in relation to folate and homocysteine status. High intake and plasma level of choline in the mother seems to afford reduced risk of neural tube defects. Intake of choline and betaine shows no consistent relation to cancer or cardiovascular risk or risk factors, whereas an unfavorable cardiovascular risk factor profile was associated with high choline and low betaine concentrations in plasma. Thus, choline and betaine showed opposite relations with key components of metabolic syndrome, suggesting a disruption of mitochondrial choline oxidation to betaine as part of the mitochondrial dysfunction in metabolic syndrome.

  17. Relationship of dimethylglycine, choline, and betaine with oxoproline in plasma of pregnant women and their newborn infants.

    PubMed

    Friesen, Russell W; Novak, Elizabeth M; Hasman, David; Innis, Sheila M

    2007-12-01

    Choline and glycine are inter-related through their roles in methyl metabolism. Choline is metabolized to betaine, which donates a methyl group to homocysteine to form methionine, also generating dimethylglycine, which is further metabolized to glycine. Choline is transported across the placenta and is higher in fetal than maternal plasma. Placental glycine transfer, however, is limited and poor glycine status has been suggested in preterm infants. Insufficient glycine for glutathione (GSH) synthesis results in increased metabolism of gamma-glutamyl cysteine to 5-oxoproline. We measured plasma 5-oxoproline as a metabolic indicator to address whether choline, via dimethylglycine, contributes physiologically relevant amounts of glycine in pregnancy. Blood was collected from healthy term pregnant women and their newborn infants at delivery (n = 46) and nonpregnant healthy women (n = 19) as a reference group. Plasma choline, betaine, dimethylglycine, homocysteine, methionine, and 5-oxoproline were quantified by HPLC-tandem MS. Plasma choline was 45% higher, but betaine was 63% lower and dimethylglycine was 28% lower in pregnant than nonpregnant women (P < 0.01). Higher white blood cell choline dehydrogenase messenger RNA levels in a random subset of pregnant (n = 8) than nonpregnant women (n = 7) (P < 0.01) suggest increased betaine and dimethylglycine turnover rather than decreased synthesis. Plasma choline, betaine, and dimethylglycine were higher (P < 0.001) in fetal plasma (36.4 +/- 13, 29.4 +/- 1.0, and 2.44 +/- 0.12 micromol/L, respectively) than maternal plasma (15.3 +/- 0.42, 14.1 +/- 0.6 and 1.81 +/- 0.12 micromol/L, respectively). Concentrations of 5-oxoproline and dimethylglycine were inversely (P < 0.05) correlated in maternal (Spearman rho = -0.35) and fetal plasma (Spearman rho = -0.32), suggesting that choline, via dimethylglycine, contributes glycine for GSH synthesis in human development.

  18. A simple LC method with UV detection for the analysis of creatine and creatinine and its application to several creatine formulations.

    PubMed

    Dash, Alekha K; Sawhney, Angeli

    2002-07-31

    The objective of this study was to develop a simple and sensitive LC method for the determination of creatine and creatinine in various creatine supplement formulations. The chromatographic system comprised of a LC-600 pump, SCL-6B system controller, and SPD-6AV detector (Shimadzu, Japan). The mobile phase consisted of 0.045 M ammonium sulfate in water. The chromatographic separation was achieved at ambient temperature on a Betabasic C-18 column (250 x 4.6 mm, Keystone Sci.). The flow rate was maintained at 0.75 ml/min and effluents are monitored at 205 nm. 4-(2-Aminoethyl)benzene sulfonamide was used as an internal standard (IS). This method required less than 7 min of chromatographic time. The standard curves were linear over the concentration range of 1-100 microg/ml for creatine and 2-100 microg/ml for creatinine, respectively. The relative standard deviations (RSD) for the within-day and day-to-day precision for creatine were within 1.0-4.6 and 2.2-4.7%, respectively. The RSD for the accuracy of creatine assay was in the range of 2.4-4.7%. The RSD values for the within-day precision, day-to-day precision and accuracy for creatinine validation were 1.7-4.4, 2.3-5.4 and 2.4-4.8%, respectively. This method was used to determine: (i) the creatine concentration in various marketed products; (ii) saturated solubility of various creatine salts; and (iii) stability of creatine in aqueous solution. In conclusion, a simple and sensitive LC method with UV detection was developed for the simultaneous determination of creatine and creatinine in formulations. Di-creatine citrate salt showed a higher aqueous solubility (at 25 degrees C) as compared to creatine and creatine monohydrate. Some of the over-the-counter (OTC) products tested contained a very low level of creatine in contrast to their label claim. Substantial conversion of creatine into creatinine was noticed in liquid formulation.

  19. Characterization of choline trimethylamine-lyase expands the chemistry of glycyl radical enzymes.

    PubMed

    Craciun, Smaranda; Marks, Jonathan A; Balskus, Emily P

    2014-07-18

    The recently identified glycyl radical enzyme (GRE) homologue choline trimethylamine-lyase (CutC) participates in the anaerobic conversion of choline to trimethylamine (TMA), a widely distributed microbial metabolic transformation that occurs in the human gut and is linked to disease. The proposed biochemical function of CutC, C-N bond cleavage, represents new reactivity for the GRE family. Here we describe the in vitro characterization of CutC and its activating protein CutD. We have observed CutD-mediated formation of a glycyl radical on CutC using EPR spectroscopy and have demonstrated that activated CutC processes choline to trimethylamine and acetaldehyde. Surveys of potential alternate CutC substrates uncovered a strict specificity for choline. Homology modeling and mutagenesis experiments revealed essential CutC active site residues. Overall, this work establishes that CutC is a GRE of unique function and a molecular marker for anaerobic choline metabolism.

  20. Betaine can partially spare choline in chicks but only when added to diets containing a minimal level of choline.

    PubMed

    Dilger, Ryan N; Garrow, Timothy A; Baker, David H

    2007-10-01

    The ability of betaine to serve as a methyl donor in chicks was assessed in 3 bioassays using a choline-free purified diet that contained adequate methionine (Met). In assay 1, choline and betaine were each supplemented at 300 mg/kg in a 2 x 2 factorial arrangement of diets. Supplemental choline improved (P < 0.05) growth performance over the 9-d growth period, whereas betaine alone had no effect. In assay 2, graded supplements of choline produced a linear increase (P < 0.05) in growth performance criteria over a 9-d growth period. Additionally, hepatic betaine-homocysteine (Hcy) methyltransferase (BHMT) activity decreased linearly (P < 0.05), whereas plasma total Hcy remained unchanged. Addition of 260 or 600 mg/kg betaine to the choline-free basal diet did not affect growth performance or BHMT activity, but 600 mg/kg betaine reduced (P < 0.05) plasma total Hcy. Assay 3 was designed to quantify the ability of betaine to spare choline. Minimal supplemental choline requirements of 20.8 +/- 1.50 mg/d (722 mg/kg diet) and 10.5 +/- 1.03 mg/d (412 mg/kg diet) were estimated in the absence and presence of 1000 mg/kg supplemental betaine, respectively. Based on these estimates, 50% of the dietary choline requirement must be supplied as choline per se, but the remaining 50% can be replaced by betaine. Collectively, these data suggest betaine and Met have minimal choline-sparing activity in chicks fed purified diets devoid of preformed choline. However, addition of betaine to diets containing minimal choline allows a marked reduction in the total dietary choline requirement.

  1. Molecular Basis of C–N Bond Cleavage by the Glycyl Radical Enzyme Choline Trimethylamine-Lyase

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bodea, Smaranda; Funk, Michael A.; Balskus, Emily P.

    We report that deamination of choline catalyzed by the glycyl radical enzyme choline trimethylamine-lyase (CutC) has emerged as an important route for the production of trimethylamine, a microbial metabolite associated with both human disease and biological methane production. Here, we have determined five high-resolution X-ray structures of wild-type CutC and mechanistically informative mutants in the presence of choline. Within an unexpectedly polar active site, CutC orients choline through hydrogen bonding with a putative general base, and through close interactions between phenolic and carboxylate oxygen atoms of the protein scaffold and the polarized methyl groups of the trimethylammonium moiety. These structuralmore » data, along with biochemical analysis of active site mutants, support a mechanism that involves direct elimination of trimethylamine. Lastly, this work broadens our understanding of radical-based enzyme catalysis and will aid in the rational design of inhibitors of bacterial trimethylamine production.« less

  2. Hypoxia decreases creatine uptake in cardiomyocytes, while creatine supplementation enhances HIF activation.

    PubMed

    Santacruz, Lucia; Arciniegas, Antonio Jose Luis; Darrabie, Marcus; Mantilla, Jose G; Baron, Rebecca M; Bowles, Dawn E; Mishra, Rajashree; Jacobs, Danny O

    2017-08-01

    Creatine (Cr), phosphocreatine (PCr), and creatine kinases (CK) comprise an energy shuttle linking ATP production in mitochondria with cellular consumption sites. Myocytes cannot synthesize Cr: these cells depend on uptake across the cell membrane by a specialized creatine transporter (CrT) to maintain intracellular Cr levels. Hypoxia interferes with energy metabolism, including the activity of the creatine energy shuttle, and therefore affects intracellular ATP and PCr levels. Here, we report that exposing cultured cardiomyocytes to low oxygen levels rapidly diminishes Cr transport by decreasing V max and K m Pharmacological activation of AMP-activated kinase (AMPK) abrogated the reduction in Cr transport caused by hypoxia. Cr supplementation increases ATP and PCr content in cardiomyocytes subjected to hypoxia, while also significantly augmenting the cellular adaptive response to hypoxia mediated by HIF-1 activation. Our results indicate that: (1) hypoxia reduces Cr transport in cardiomyocytes in culture, (2) the cytoprotective effects of Cr supplementation are related to enhanced adaptive physiological responses to hypoxia mediated by HIF-1, and (3) Cr supplementation increases the cellular ATP and PCr content in RNCMs exposed to hypoxia. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  3. Choline, Other Methyl-Donors and Epigenetics

    PubMed Central

    Zeisel, Steven H.

    2017-01-01

    Choline dietary intake varies such that many people do not achieve adequate intakes. Diet intake of choline can modulate methylation because, via betaine homocysteine methyltransferase (BHMT), this nutrient (and its metabolite, betaine) regulate the concentrations of S-adenosylhomocysteine and S-adenosylmethionine. Some of the epigenetic mechanisms that modify gene expression without modifying the genetic code depend on the methylation of DNA or of histones; and diet availability of choline and other methyl-group donors influences both of these methylations. Examples of methyl-donor mediated epigenetic effects include the changes in coat color and body weight in offspring when pregnant agouti mice are fed high choline, high methyl diets; the changes in tail kinking in offspring when pregnant Axin(Fu) mice are fed high choline, high methyl diets; the changes in Cdkn3 methylation and altered brain development that occurs in offspring when pregnant rodents are fed low choline diets. When choline metabolism is disrupted by deleting the gene Bhmt, DNA methylation is affected (especially in a region of chromosome 13), expression of specific genes is suppressed, and liver cancers develop. Better understanding of how nutrients such as choline and methyl-donors influence epigenetic programs has importance for our understanding of not only developmental abnormalities but also for understanding the origins of chronic diseases. PMID:28468239

  4. Choline, Other Methyl-Donors and Epigenetics.

    PubMed

    Zeisel, Steven

    2017-04-29

    Choline dietary intake varies such that many people do not achieve adequate intakes. Diet intake of choline can modulate methylation because, via betaine homocysteine methyltransferase (BHMT), this nutrient (and its metabolite, betaine) regulate the concentrations of S-adenosylhomocysteine and S-adenosylmethionine. Some of the epigenetic mechanisms that modify gene expression without modifying the genetic code depend on the methylation of DNA or of histones; and diet availability of choline and other methyl-group donors influences both of these methylations. Examples of methyl-donor mediated epigenetic effects include the changes in coat color and body weight in offspring when pregnant agouti mice are fed high choline, high methyl diets; the changes in tail kinking in offspring when pregnant Axin(Fu) mice are fed high choline, high methyl diets; the changes in Cdkn3 methylation and altered brain development that occurs in offspring when pregnant rodents are fed low choline diets. When choline metabolism is disrupted by deleting the gene Bhmt, DNA methylation is affected (especially in a region of chromosome 13), expression of specific genes is suppressed, and liver cancers develop. Better understanding of how nutrients such as choline and methyl-donors influence epigenetic programs has importance for our understanding of not only developmental abnormalities but also for understanding the origins of chronic diseases.

  5. Perinatal Dietary Choline Deficiency in Sows Influences Concentrations of Choline Metabolites, Fatty Acids, and Amino Acids in Milk throughout Lactation.

    PubMed

    Mudd, Austin T; Alexander, Lindsey S; Johnson, Stacey K; Getty, Caitlyn M; Malysheva, Olga V; Caudill, Marie A; Dilger, Ryan N

    2016-11-01

    Choline is essential for synthesis of phospholipids, neurodevelopment, and DNA methylation. It is unknown whether dietary perinatal choline deficiency affects maternal milk composition. We examined whether perinatal maternal dietary choline deficiency influences porcine-milk composition. Yorkshire sows were fed choline-deficient (CD) or choline-sufficient (CS) gestation diets [544 or 1887 mg choline/kg dry matter (DM), respectively] from 65 d before to 48 h after parturition and then fed lactation diets (517 or 1591 mg choline/kg DM, respectively) through day 19 of lactation. Milk was collected from 7 sows fed each diet at days 0 (colostrum), 7-9 (mature milk), and 17-19 (preweaning) of lactation. Sow plasma was collected 65 d before and 19 d after parturition. Milk was analyzed for choline metabolite, fatty acid (FA), and amino acid composition. All outcomes were analyzed to assess main and interactive effects of choline intake and time. Plasma choline metabolites did not differ before treatment, but free choline, betaine, and dimethylglycine concentrations were lower in CD-fed than in CS-fed sows at day 19 of lactation (interaction; P < 0.05). Milk betaine concentrations responded similarly, with no differences due to choline intake at day 0 of lactation, but lower concentrations in CD-fed than in CS-fed sows at day 18 of lactation (interaction; P < 0.001). Certain milk long-chain FAs also exhibited no differences at day 0 of lactation but higher concentrations in CD-fed than in CS-fed sows at day 18 of lactation (P < 0.05). These data indicate that, in pigs, dietary choline deficiency induces alterations in plasma choline metabolites that are evident at the end of lactation. Betaine and select FAs in milk are sensitive to maternal dietary choline deficiency and day of lactation. Alterations in concentrations of these nutrients may affect early-life neonatal development. © 2016 American Society for Nutrition.

  6. Umbilical choline and related methylamines betaine and dimethylglycine in relation to birth weight.

    PubMed

    Hogeveen, Marije; den Heijer, Martin; Semmekrot, Ben A; Sporken, Jan M; Ueland, Per M; Blom, Henk J

    2013-06-01

    Low birth weight (LBW) is associated with increased morbidity and mortality for the newborn and risk of chronic disease in adulthood. Choline plays an essential role in the integrity of cell membranes, methylation reactions, and memory development. We examined whether choline, betaine, and dimethylglycine (DMG) concentrations were associated with LBW in Dutch women. Blood was sampled from umbilical cords (UCs) at delivery in singleton pregnancies (n = 1,126). Maternal blood was sampled at 30-34 wk of gestational age (GA) (n = 366). We calculated birth weights standardized for GA and defined LBW as standardized birth weight ≤ 2,500 g. Maternal concentrations were lower as compared with UC concentrations and were not associated with birth weight. UC choline and betaine were inversely associated with birth weight (β = -60 (-89, -31) and β = -65 (-94, -36), respectively), whereas UC DMG was positively associated with birth weight (β = 35 (6.1, 63)). Odds ratios for LBW were 4.12 (1.15, 14.78), 5.68 (1.24, 25.91), and 0.48 (0.09, 2.65) for the highest UC choline, betaine, and DMG quartiles, respectively, as compared with the lowest quartiles. We observed an increased risk of LBW with increased umbilical choline and betaine in venous UC blood. These results might reflect a change in choline consumption or metabolism or a disturbed placental function.

  7. The use of creatine supplements in the military.

    PubMed

    Havenetidis, Konstantinos

    2016-08-01

    Creatine is considered an effective nutritional ergogenic aid to enhance exercise performance. In spite of the publication of several reviews in the last decade on the topic of exercise performance/sports and creatine there is a need for an update related to the military given the lack of information in this area. The aim of this study was to critically assess original research addressing the use of creatine supplements in the military. A search of the electronic databases PubMed and SPORTDiscus, for the following key words: military personnel, trainees, recruit, soldier, physical fitness, physical conditioning, creatine supplementation, creatine ingestion, nutritional supplements to identify surveys and randomised clinical trials from journal articles and technical reports investigating the effect of creatine supplementation on military populations. Thirty-three out of 90 articles examined the use of creatine as a dietary supplement in military personnel. Twenty-one studies were finally selected on the basis of stated inclusion criteria for military surveys and randomised clinical trials. Most of the surveys (15/17) in the military indicate a high popularity of creatine (average 27%) among supplement users. In contrast, in most of the exercise protocols used (6/9) during randomised clinical trials creatine has produced a non-significant performance-enhancing effect. Creatine is one of the most widely used supplemental compounds in the military. It is not considered a doping infraction or related to any adverse health effects but its long-term usage needs further investigation. Experimental research suggests that creatine supplementation does not enhance physical performance in the military. However, limitations in creatine dosage, military fitness testing and sample group selection might have underestimated the ergogenic properties of creatine. Recent studies also indicate positive effects on various aspects of total force fitness such as cognitive

  8. CDP-choline: pharmacological and clinical review.

    PubMed

    Secades, J J; Frontera, G

    1995-10-01

    Cytidine 5'-diphosphocholine, CDP-choline or citicoline, is an essential intermediate in the biosynthetic pathway of the structural phospholipids of cell membranes, especially in that of phosphatidylcholine. Upon oral or parenteral administration, CDP-choline releases its two principle components, cytidine and choline. When administered orally, it is absorbed almost completely, and its bioavailability is approximately the same as when administered intravenously. Once absorbed, the cytidine and choline disperse widely throughout the organism, cross the blood-brain barrier and reach the central nervous system (CNS), where they are incorporated into the phospholipid fraction of the membrane and microsomes. CDP-choline activates the biosynthesis of structural phospholipids in the neuronal membranes, increases cerebral metabolism and acts on the levels of various neurotransmitters. Thus, it has been experimentally proven that CDP-choline increases noradrenaline and dopamine levels in the CNS. Due to these pharmacological activities, CDP-choline has a neuroprotective effect in situations of hypoxia and ischemia, as well as improved learning and memory performance in animal models of brain aging. Furthermore, it has been demonstrated that CDP-choline restores the activity of mitochondrial ATPase and of membranal Na+/K+ ATPase, inhibits the activation of phospholipase A2 and accelerates the reabsorption of cerebral edema in various experimental models. CDP-choline is a safe drug, as toxicological tests have shown; it has no serious effects on the cholinergic system and it is perfectly tolerated. These pharmacological characteristics, combined with CDP-choline's mechanisms of action, suggest that this drug may be suitable for the treatment of cerebral vascular disease, head trauma of varying severity and cognitive disorders of diverse etiology. In studies carried out on the treatment of patients with head trauma, CDP-choline accelerated the recovery from post-traumatic coma

  9. Meta-Analysis of Creatine for Neuroprotection Against Parkinson's Disease.

    PubMed

    Attia; Ahmed, Hussien; Gadelkarim, Mohamed; Morsi, Mahmoud; Awad, Kamal; Elnenny, Mohamed; Ghanem, Esraa; El-Jaafary, Shaimaa; Negida, Ahmed

    2017-01-01

    Creatine is an antioxidant agent that showed neuroprotective effects in animal models of Parkinson's disease (PD). Creatine was selected by the National Institute of Neurological Disorders and Stroke as a possible disease modifying agent for Parkinson's disease. Therefore, many clinical trials evaluated the efficacy of creatine for patients with PD. The aim of this systematic review and meta-analysis is to synthesize evidence from published randomized controlled trials (RCTs) about the efficacy of Creatine for patients with PD. We followed PRISMA statement guidelines during the preparation of this systematic review and meta-analysis. A computer literature search for PubMed, EBSCO, web of science and Ovid Midline was carried out. We included RCTs comparing creatine with placebo in terms of motor functions and quality of life. Outcomes of total Unified Parkinson's Disease Rating Scale (UPDRS), UPDRS I, UPDRS II, and UPDRS III were pooled as mean difference (MD) between two groups from baseline to the endpoint. Statistical heterogeneity was assessed by visual inspection of the forest plot and measured by chi-square and I square tests. Three RCTs (n=1935) were included in this study. The overall effect did not favor either of the two groups in terms of: UPDRS total score (MD 1.07, 95% CI [3.38 to 1.25], UPDRS III (MD 0.62, 95% CI [2.27 to 1.02]), UPDRS II (MD 0.03, 95% CI [0.81 to 0.86], or UPDRS I (MD 0.03, 95% CI [0.33 to 0.28]). Current evidence does not support the use of creatine for neuroprotection against PD. Future well-designed, randomized controlled trials are needed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. N-Acetylaspartate reductions in brain injury: impact on post-injury neuroenergetics, lipid synthesis, and protein acetylation

    PubMed Central

    Moffett, John R.; Arun, Peethambaran; Ariyannur, Prasanth S.; Namboodiri, Aryan M. A.

    2013-01-01

    N-Acetylaspartate (NAA) is employed as a non-invasive marker for neuronal health using proton magnetic resonance spectroscopy (MRS). This utility is afforded by the fact that NAA is one of the most concentrated brain metabolites and that it produces the largest peak in MRS scans of the healthy human brain. NAA levels in the brain are reduced proportionately to the degree of tissue damage after traumatic brain injury (TBI) and the reductions parallel the reductions in ATP levels. Because NAA is the most concentrated acetylated metabolite in the brain, we have hypothesized that NAA acts in part as an extensive reservoir of acetate for acetyl coenzyme A synthesis. Therefore, the loss of NAA after TBI impairs acetyl coenzyme A dependent functions including energy derivation, lipid synthesis, and protein acetylation reactions in distinct ways in different cell populations. The enzymes involved in synthesizing and metabolizing NAA are predominantly expressed in neurons and oligodendrocytes, respectively, and therefore some proportion of NAA must be transferred between cell types before the acetate can be liberated, converted to acetyl coenzyme A and utilized. Studies have indicated that glucose metabolism in neurons is reduced, but that acetate metabolism in astrocytes is increased following TBI, possibly reflecting an increased role for non-glucose energy sources in response to injury. NAA can provide additional acetate for intercellular metabolite trafficking to maintain acetyl CoA levels after injury. Here we explore changes in NAA, acetate, and acetyl coenzyme A metabolism in response to brain injury. PMID:24421768

  11. Choline supply of preterm infants: assessment of dietary intake and pathophysiological considerations.

    PubMed

    Bernhard, Wolfgang; Full, Anna; Arand, Jörg; Maas, Christoph; Poets, Christian F; Franz, Axel R

    2013-04-01

    Choline forms the head group of phosphatidylcholines, comprising 40-50 % of cellular membranes and 70-95 % of phospholipids in surfactant, bile, and lipoproteins. Moreover, choline serves as the precursor of acetylcholine and is important for brain differentiation and function. While accepted as essential for fetal and neonatal development, its role in preterm infant nutrition has not yet gained much attention. The adequate intake of choline of preterm infants was estimated from international recommendations for infants, children, and adults. Choline intake relative to other nutrients was determined retrospectively in all inborn infants below 1,000 g (extremely low birth weight) or below 28 weeks gestational age, admitted to our department in 2006 and 2007 (N = 93). Estimation of adequate intake showed that children with 290 g body weight need more choline than those with 1,200 g (31.4 and 25.2 mg/kg/day, respectively). Day-by-day variability was high for all nutrient intakes including choline. In contrast to the continuous intrauterine choline delivery, median supply reached a plateau at d11 (21.7 mg/kg/day; 25th/75th percentile: 19.6; 23.9). Individual choline supply at d0-d1 and d2-d3 was <10 mg/kg/day in 100 and 69 % of infants, respectively. Furthermore, intakes <10 mg/kg/day were frequently observed beyond day 11. Median adequate intakes (27.4 mg/kg/day at 735 g body weight) were achieved in <2 %. Nutritional intake of choline in this cohort of preterm infants was frequently less than the estimated adequate intake, with particular shortage until postnatal d10. Because choline is important for brain development, future studies are needed to investigate the effects of adequate nutritional choline intake on long-term neurodevelopment in VLBW infants.

  12. Oral choline supplementation in children with intestinal failure.

    PubMed

    Guerrerio, Anthony L; Mattis, Lynn; Conner, Kim G; Hampsey, Jenifer; Stasinopoulos, D Mikis; DeJong, Robert; Boctor, Emad M; Sheth, Shelia; Hamper, Ulrike M; Scheimann, Ann O

    2011-07-01

    Choline deficiency leads to steatohepatitis, elevated transaminases, susceptibility to septic shock, and an increased risk of central catheter thrombosis. Children with intestinal failure (IF) are at risk for choline deficiency. In an unblinded, open-label study, we studied 7 children with IF on parenteral nutrition, measured their plasma free choline level, and, if low, supplemented enterally with adequate intake (AI) doses of choline. Four to 6 weeks later we remeasured their plasma free choline. Unlike adults, infants did not respond to oral choline supplementation at AI doses. Additionally, we have calculated plasma free choline percentiles versus age for normal children.

  13. The effects of creatine pyruvate and creatine citrate on performance during high intensity exercise

    PubMed Central

    Jäger, Ralf; Metzger, Jan; Lautmann, Karin; Shushakov, Vladimir; Purpura, Martin; Geiss, Kurt-Reiner; Maassen, Norbert

    2008-01-01

    Background A double-blind, placebo-controlled, randomized study was performed to evaluate the effect of oral creatine pyruvate (Cr-Pyr) and creatine citrate (Cr-Cit) supplementation on exercise performance in healthy young athletes. Methods Performance during intermittent handgrip exercise of maximal intensity was evaluated before (pretest) and after (posttest) 28 days of Cr-Pyr (5 g/d, n = 16), Cr-Cit (5 g/d, n = 16) or placebo (pla, 5 g/d, n = 17) intake. Subjects performed ten 15-sec exercise intervals, each followed by 45 sec rest periods. Results Cr-Pyr (p < 0.001) and Cr-Cit (p < 0.01) significantly increased mean power over all intervals. Cr-Cit increased force during the first and second interval (p < 0.01) compared to placebo. The effect of Cr-Cit on force decreased over time and the improvement was not significant at the sixth and ninth interval, whereas Cr-Pyr significantly increased force during all intervals (p < 0.001). Cr-Pyr (p < 0.001) and Cr-Cit (p < 0.01) resulted in an increase in contraction velocity, whereas only Cr-Pyr intake significantly (p < 0.01) increased relaxation velocity. Oxygen consumption measured during rest periods significantly increased with Cr-Pyr (p < 0.05), whereas Cr-Cit and placebo intake did not result in significant improvements. Conclusion It is concluded that four weeks of Cr-Pyr and Cr-Cit intake significantly improves performance during intermittent handgrip exercise of maximal intensity and that Cr-Pyr might benefit endurance, due to enhanced activity of the aerobic metabolism. PMID:18269769

  14. Choline or CDP-choline alters serum lipid responses to endotoxin in dogs and rats: involvement of the peripheral nicotinic acetylcholine receptors.

    PubMed

    Ilcol, Yesim Ozarda; Yilmaz, Zeki; Cansev, Mehmet; Ulus, Ismail H

    2009-09-01

    We showed previously that choline administration protects dogs from endotoxin-induced multiple organ injury and platelet dysfunctions. Because sepsis/endotoxemia is associated with alterations in lipid metabolism, we have investigated whether choline or cytidine-5'-diphosphate choline, a choline donor, alters serum lipid responses to endotoxin in dogs and rats. In response to endotoxin, serum concentrations of triglycerides, choline-containing phospholipids, total cholesterol, and high-density lipoprotein cholesterol increased in a dose- and time-related manner. Administration of choline (20 mg/kg i.v. in dogs or 90 mg/kg i.p. in rats) or cytidine-5'-diphosphate choline (70 mg/kg i.v. in dogs) 5 min before and 4 and 8 h after endotoxin blocked or attenuated the increases in serum triglycerides, total cholesterol, and nonesterified fatty acids. Endotoxin-induced elevations in serum phospholipid levels did not change in rats and were enhanced in dogs by choline. In rats, serum lipid response to endotoxin was accompanied by severalfold elevations in serum levels of hepatorenal injury markers; their elevations were also blocked by choline. Pretreatment with hexamethonium blocked choline's effects on serum lipids and hepatorenal injury markers. Pretreatment with atropine blocked endotoxin-induced elevations in serum lipid and hepatorenal injury markers, but failed to alter choline's actions on these parameters. Choline treatment improved survival rate of rats in lethal endotoxin shock. In conclusion, these data show that choline treatment alters serum lipid responses to endotoxin and prevents hepatorenal injury during endotoxemia through a nicotinic acetylcholine receptor-mediated mechanism. Hence, choline and choline-containing compounds may have a therapeutic potential in the treatment of endotoxemia/sepsis.

  15. Three-dimensional Hadamard-encoded proton spectroscopic imaging in the human brain using time-cascaded pulses at 3 Tesla.

    PubMed

    Cohen, Ouri; Tal, Assaf; Gonen, Oded

    2014-10-01

    To reduce the specific-absorption-rate (SAR) and chemical shift displacement (CSD) of three-dimensional (3D) Hadamard spectroscopic imaging (HSI) and maintain its point spread function (PSF) benefits. A 3D hybrid of 2D longitudinal, 1D transverse HSI (L-HSI, T-HSI) sequence is introduced and demonstrated in a phantom and the human brain at 3 Tesla (T). Instead of superimposing each of the selective Hadamard radiofrequency (RF) pulses with its N single-slice components, they are cascaded in time, allowing N-fold stronger gradients, reducing the CSD. A spatially refocusing 180° RF pulse following the T-HSI encoding block provides variable, arbitrary echo time (TE) to eliminate undesirable short T2 species' signals, e.g., lipids. The sequence yields 10-15% better signal-to-noise ratio (SNR) and 8-16% less signal bleed than 3D chemical shift imaging of equal repetition time, spatial resolution and grid size. The 13 ± 6, 22 ± 7, 24 ± 8, and 31 ± 14 in vivo SNRs for myo-inositol, choline, creatine, and N-acetylaspartate were obtained in 21 min from 1 cm(3) voxels at TE ≈ 20 ms. Maximum CSD was 0.3 mm/ppm in each direction. The new hybrid HSI sequence offers a better localized PSF at reduced CSD and SAR at 3T. The short and variable TE permits acquisition of short T2 and J-coupled metabolites with higher SNR. Copyright © 2013 Wiley Periodicals, Inc.

  16. Neuronal loss is an early component of subacute sclerosing panencephalitis.

    PubMed

    Yüksel, Deniz; Diren, Barış; Ulubay, Hakan; Altunbaşak, Sakir; Anlar, Banu

    2014-09-02

    We performed diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) studies in a group of patients with subacute sclerosing panencephalitis (SSPE) in order to estimate the pathologic process underlying the phenotypic variability. Patients with SSPE who had MRI including DTI and MRS examinations were evaluated according to their clinical status as determined by the SSPE Scoring System and their mental age as determined by tests appropriate for age and developmental level. Comparisons of fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values and metabolite ratios of frontal periventricular white matter, parieto-occipital periventricular white matter, and globus pallidus in both hemispheres were made between control and SSPE groups, and between SSPE subgroups. Control (n = 18) and SSPE (n = 39) groups differed in all DTI and MRS parameters except FA, choline (Cho), and Cho/creatine (Cr). SSPE cases had higher ADC and lower N-acetylaspartate (NAA), NAA/Cho, and NAA/Cr in all regions of interest, suggesting cell loss. Disease progression rate and neurologic deficit appeared to be associated with the degree of ADC elevation and NAA reduction: the group with severe global deterioration had the lowest NAA (230.75 ± 197.97 in forceps minor), and rapid progression was associated with acute reduction in NAA. The combination of MRS and diffusion MRI findings suggests neuronal loss can be a primary target in rapidly or subacutely progressing SSPE, and preservation or regeneration of axonal structure may be beneficial in chronic cases. © 2014 American Academy of Neurology.

  17. [A machine learning model using gut microbiome data for predicting changes of trimethylamine-N-oxide in healthy volunteers after choline consumption].

    PubMed

    Lu, Jun-Qi; Wang, Shan; Yin, Jia; Wu, Shan; He, Yan; Zheng, Hui-Min; Sheng, Hua-Fang; Zhou, Hong-Wei

    2017-03-20

    To establish a machine learning model based on gut microbiota for predicting the level of trimethylamine N-oxide (TMAO) metabolism in vivo after choline intake to provide guidance of individualized precision diet and evidence for screening population at high risks of cardiovascular disease. We quantified plasma levels of TMAO in 18 healthy volunteers before and 8 h after a choline challenge (ingestion of two boiled eggs). The volunteers were divided into two groups with increased or decreased TMAO level following choline challenge. Fresh fecal samples were collected before taking fasting blood samples for amplifying 16S rRNA V4 tags, and the PCR products were sequenced using the platform of Illumina HiSeq 2000. The differences in gut microbiata between subjects with increased and decreased plasma TMAO were analyzed using QIIME. Based on the gut microbiota data and TMAO levels in the two groups, the prediction model was established using the machine learning random forest algorithm, and the validity of the model was tested using a verified dataset. An obvious difference was found in beta diversity of the gut microbota between the subjects with increased and decreased plasma TMAO level following choline challenge. The area under the curve (AUC) of the model was 86.39% (95% CI: 72.7%-100%). Using the verified dataset, the model showed a much higher probability for correctly predicting TMAO variation following choline challenge. The model is feasible and reliable for predicting the level of TMAO metabolism in vivo based on gut microbiota.

  18. Prenatal choline deficiency increases choline transporter expression in the septum and hippocampus during postnatal development and in adulthood in rats.

    PubMed

    Mellott, Tiffany J; Kowall, Neil W; Lopez-Coviella, Ignacio; Blusztajn, Jan Krzysztof

    2007-06-02

    Supplementation of maternal diet with the essential nutrient, choline, during the second half of pregnancy in rats causes long-lasting improvements in spatial memory in the offspring and protects them from the memory decline characteristic of old age. In contrast, prenatal choline deficiency is associated with poor performance in certain cognitive tasks. The mechanism by which choline influences learning and memory remains unclear; however, it may involve changes to the hippocampal cholinergic system. Previously, we showed that the hippocampi of prenatally [embryonic days (E) 11-17] choline-deficient animals have increased synthesis of acetylcholine (ACh) from choline transported by the high-affinity choline transporter (CHT) and reduced ACh content relative to the control and to the E11-17 choline-supplemented rats. In the current study, we found that, during postnatal period [postnatal days (P) 18-480], prenatal choline deficiency increased the expression of CHT mRNA in the septum and CHT mRNA and protein levels in the hippocampus and altered the pattern of CHT immunoreactivity in the dentate gyrus. CHT immunoreactivity was more prominent in the inner molecular layer in prenatally choline-deficient rats compared to controls and prenatally choline-supplemented animals. In addition, in all groups, we observed a population of hilar interneurons that were CHT-immunoreactive. These neurons are the likely source of the hippocampal CHT mRNA as their number correlated with the levels of this mRNA. The abundance of hippocampal CHT mRNA rose between P1 and P24 and then declined reaching 60% of the P1 value by P90. These data show that prenatal availability of choline alters its own metabolism (i.e., CHT expression). While the upregulated CHT expression during the period of prenatal choline deficiency may be considered as a compensatory mechanism that could enhance ACh synthesis when choline supply is low, the persistent upregulation of CHT expression subsequent to the

  19. Enterobacter aerogenes ZDY01 Attenuates Choline-Induced Trimethylamine N-Oxide Levels by Remodeling Gut Microbiota in Mice.

    PubMed

    Qiu, Liang; Yang, Dong; Tao, Xueying; Yu, Jun; Xiong, Hua; Wei, Hua

    2017-08-28

    Trimethylamine N -oxide (TMAO), which is transformed from trimethylamine (TMA) through hepatic flavin-containing monooxygenases, can promote atherosclerosis. TMA is produced from dietary carnitine, phosphatidylcholine, and choline via the gut microbes. Previous works have shown that some small molecules, such as allicin, resveratrol, and 3,3-dimethyl-1-butanol, are used to reduce circulating TMAO levels. However, the use of bacteria as an effective therapy to reduce TMAO levels has not been reported. In the present study, 82 isolates were screened from healthy Chinese fecal samples on a basal salt medium supplemented with TMA as the sole carbon source. The isolates belonged to the family Enterobacteriaceae, particularly to genera Klebsiella, Escherichia, Cronobacter , and Enterobacter . Serum TMAO and cecal TMA levels were significantly decreased in choline-fed mice treated with Enterobacter aerogenes ZDY01 compared with those in choline-fed mice treated with phosphate-buffered saline. The proportions of Bacteroidales family S24-7 were significantly increased, whereas the proportions of Helicobacteraceae and Prevotellaceae were significantly decreased through the administration of E. aerogenes ZDY01. Results indicated that the use of probiotics to act directly on the TMA in the gut might be an alternative approach to reduce serum TMAO levels and to prevent the development of atherosclerosis and "fish odor syndrome" through the effect of TMA on the gut microbiota.

  20. 21 CFR 182.8252 - Choline chloride.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Choline chloride. 182.8252 Section 182.8252 Food... HUMAN CONSUMPTION (CONTINUED) SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients § 182.8252 Choline chloride. (a) Product. Choline chloride. (b) Conditions of use. This substance is generally recognized as...

  1. 21 CFR 182.8252 - Choline chloride.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Choline chloride. 182.8252 Section 182.8252 Food... HUMAN CONSUMPTION (CONTINUED) SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients § 182.8252 Choline chloride. (a) Product. Choline chloride. (b) Conditions of use. This substance is generally recognized as...

  2. 21 CFR 182.8250 - Choline bitartrate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Choline bitartrate. 182.8250 Section 182.8250 Food... HUMAN CONSUMPTION (CONTINUED) SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients § 182.8250 Choline bitartrate. (a) Product. Choline bitartrate. (b) Conditions of use. This substance is generally recognized as...

  3. 21 CFR 182.8250 - Choline bitartrate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Choline bitartrate. 182.8250 Section 182.8250 Food... HUMAN CONSUMPTION (CONTINUED) SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients § 182.8250 Choline bitartrate. (a) Product. Choline bitartrate. (b) Conditions of use. This substance is generally recognized as...

  4. 21 CFR 182.8252 - Choline chloride.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Choline chloride. 182.8252 Section 182.8252 Food... HUMAN CONSUMPTION (CONTINUED) SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients § 182.8252 Choline chloride. (a) Product. Choline chloride. (b) Conditions of use. This substance is generally recognized as...

  5. 21 CFR 182.8252 - Choline chloride.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Choline chloride. 182.8252 Section 182.8252 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients § 182.8252 Choline chloride. (a) Product. Choline chloride. (b...

  6. 21 CFR 182.8250 - Choline bitartrate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Choline bitartrate. 182.8250 Section 182.8250 Food... HUMAN CONSUMPTION (CONTINUED) SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients § 182.8250 Choline bitartrate. (a) Product. Choline bitartrate. (b) Conditions of use. This substance is generally recognized as...

  7. 21 CFR 182.8250 - Choline bitartrate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Choline bitartrate. 182.8250 Section 182.8250 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients § 182.8250 Choline bitartrate. (a) Product. Choline bitartrate. (b...

  8. 21 CFR 182.8250 - Choline bitartrate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Choline bitartrate. 182.8250 Section 182.8250 Food... HUMAN CONSUMPTION (CONTINUED) SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients § 182.8250 Choline bitartrate. (a) Product. Choline bitartrate. (b) Conditions of use. This substance is generally recognized as...

  9. The addition of choline to parenteral nutrition.

    PubMed

    Buchman, Alan L

    2009-11-01

    Choline is a quaternary amine endogenously synthesized from the amino acid methionine or absorbed via the portal circulation. It is ubiquitous in the diet, although it has a greater presence in organ meats. Choline is an essential component of all cell membranes, and has been considered a required dietary nutrient since 1998 by the US Institute of Medicine's Food and Nutrition Board. Choline is necessary for DNA repair, mediated by its role as a methyl donor. It also serves as the precursor for the neurotransmitter acetylcholine. Evidence has accumulated that hepatic steatosis, which occurs during parenteral nutrition therapy, develops as a result of choline deficiency because endogenous production of choline from parenterally infused methionine is deficient. In addition, memory deficits and skeletal muscle abnormalities have been described, and choline deficiency appears to activate cellular apoptosis. Provision of intravenous choline ameliorates hepatic steatosis associated with parenteral nutrition infusion.

  10. Variation of betaine, N,N-dimethylglycine, choline, glycerophosphorylcholine, taurine and trimethylamine-N-oxide in the plasma and urine of overweight people with type 2 diabetes over a two-year period.

    PubMed

    McEntyre, Christopher J; Lever, Michael; Chambers, Stephen T; George, Peter M; Slow, Sandy; Elmslie, Jane L; Florkowski, Christopher M; Lunt, Helen; Krebs, Jeremy D

    2015-05-01

    Plasma betaine concentrations and urinary betaine excretions have high test-retest reliability. Abnormal betaine excretion is common in diabetes. We aimed to confirm the individuality of plasma betaine and urinary betaine excretion in an overweight population with type 2 diabetes and compare this with the individuality of other osmolytes, one-carbon metabolites and trimethylamine-N-oxide (TMAO), thus assessing their potential usefulness as disease markers. Urine and plasma were collected from overweight subjects with type 2 diabetes at four time points over a two-year period. We measured the concentrations of the osmolytes: betaine, glycerophosphorylcholine (GPC) and taurine, as well as TMAO, and the one-carbon metabolites, N,N-dimethylglycine (DMG) and free choline. Samples were measured using tandem mass spectrometry (LC-MS/MS). Betaine showed a high degree of individuality (or test-retest reliability) in the plasma (index of individuality = 0.52) and urine (index of individuality = 0.45). Betaine in the plasma had positive and negative log-normal reference change values (RCVs) of 54% and -35%, respectively. The other osmolytes, taurine and GPC were more variable in the plasma of individuals compared to the urine. DMG and choline showed high individuality in the plasma and urine. TMAO was highly variable in the plasma and urine (log-normal RCVs ranging from 403% to -80% in plasma). Betaine is highly individual in overweight people with diabetes. Betaine, its metabolite DMG, and precursor choline showed more reliability than the osmolytes, GPC and taurine. The low reliability of TMAO suggests that a single TMAO measurement has low diagnostic value. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  11. Diffusion weighted MR imaging and proton MR spectroscopy findings of central neurocytoma with pathological correlation.

    PubMed

    Tlili-Graiess, Kalthoum; Mama, Nadia; Arifa, Nadia; Kadri, Khaled; Hasni, Ibtissem; Krifa, Hedi; Mokni, Moncef

    2014-10-01

    Three cases of histopathologically confirmed central neurocytoma (CN) are presented, emphasizing diagnostic imaging issues: conventional magnetic resonance imaging with Proton magnetic resonance spectroscopy (MRS) and diffusion-weighted imaging (DWI) findings of CN. Patients age ranged from 17 to 32 years, Imaging include a CT scan and MR examination with DWI and proton MRS on a 1.5-T system. DWI and subsequent apparent diffusion coefficient (ADC) were obtained in all. Single voxel MRS was performed prior to surgery using a point resolved spectroscopy sequence (PRESS) with short 35 ms and long echotime (TE) 144 ms, associated with a two-dimensional chemical Shift Imaging (2D-CSI) with 144 ms TE (one case). Histopathological examination included immunostaining with synaptophysin. With the long TE, a variable amount of glycine with markedly increased choline, very small to almost complete loss of N-acetylaspartate and creatine, and inverted triplet of alanine-lactate were observed in all three patients. Increased glutamate and glutamine complex (Glx) was also observed in all with short TE. DWI demonstrated variable low ADC which appeared well correlated with the tumor signal intensity and cell density: the most homogeneous and highly dense cellular tumor with increased nucleus to cytoplasm ratio demonstrated the lower ADC. Histological pattern was typical in two cases and demonstrated an oligodendroglioma-like pattern in one case. Positivity for synaptophysin confirmed the neuronal origin in all. The demonstration within an intraventricular tumor of both glycine and alanine on MRS along with high choline, bulky Glx and restricted diffusion appear diagnostic of CN. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  12. MTHFR C677T genotype influences the isotopic enrichment of one-carbon metabolites in folate-compromised men consuming d9-choline.

    PubMed

    Yan, Jian; Wang, Wei; Gregory, Jesse F; Malysheva, Olga; Brenna, J Thomas; Stabler, Sally P; Allen, Robert H; Caudill, Marie A

    2011-02-01

    Homozygosity for the variant 677T allele in the methylenetetrahydrofolate reductase (MTHFR) gene increases the requirement for folate and may alter the metabolic use of choline. The choline adequate intake is 550 mg/d for men, although the metabolic consequences of consuming extra choline are unclear. Deuterium-labeled choline (d9-choline) as tracer was used to determine the differential effects of the MTHFR C677T genotype and the effect of various choline intakes on the isotopic enrichment of choline derivatives in folate-compromised men. Mexican American men with the MTHFR 677CC or 677TT genotype consumed a diet providing 300 mg choline/d plus supplemental choline chloride for total choline intakes of 550 (n = 11; 4 with 677CC and 7 with 677TT) or 1100 (n = 12; 4 with 677CC and 8 with 677TT) mg/d for 12 wk. During the last 3 wk, 15% of the total choline intake was provided as d9-choline. Low but measurable enrichments of the choline metabolites were achieved, including that of d3-phosphatidylcholine (d3-PtdCho)--a metabolite produced in the de novo pathway via choline-derived methyl groups. Men with the MTHFR 677TT genotype had a higher urinary enrichment ratio of betaine to choline (P = 0.041), a higher urinary enrichment of sarcosine (P = 0.041), and a greater plasma enrichment ratio of d9-betaine to d9-PtdCho with the 1100 mg choline/d intake (P = 0.033). These data show for the first time in humans that choline itself is a source of methyl groups for de novo PtdCho biosynthesis and indicate that the MTHFR 677TT genotype favors the use of choline as a methyl donor.

  13. The neurochemical basis of human cortical auditory processing: combining proton magnetic resonance spectroscopy and magnetoencephalography

    PubMed Central

    Sörös, Peter; Michael, Nikolaus; Tollkötter, Melanie; Pfleiderer, Bettina

    2006-01-01

    Background A combination of magnetoencephalography and proton magnetic resonance spectroscopy was used to correlate the electrophysiology of rapid auditory processing and the neurochemistry of the auditory cortex in 15 healthy adults. To assess rapid auditory processing in the left auditory cortex, the amplitude and decrement of the N1m peak, the major component of the late auditory evoked response, were measured during rapidly successive presentation of acoustic stimuli. We tested the hypothesis that: (i) the amplitude of the N1m response and (ii) its decrement during rapid stimulation are associated with the cortical neurochemistry as determined by proton magnetic resonance spectroscopy. Results Our results demonstrated a significant association between the concentrations of N-acetylaspartate, a marker of neuronal integrity, and the amplitudes of individual N1m responses. In addition, the concentrations of choline-containing compounds, representing the functional integrity of membranes, were significantly associated with N1m amplitudes. No significant association was found between the concentrations of the glutamate/glutamine pool and the amplitudes of the first N1m. No significant associations were seen between the decrement of the N1m (the relative amplitude of the second N1m peak) and the concentrations of N-acetylaspartate, choline-containing compounds, or the glutamate/glutamine pool. However, there was a trend for higher glutamate/glutamine concentrations in individuals with higher relative N1m amplitude. Conclusion These results suggest that neuronal and membrane functions are important for rapid auditory processing. This investigation provides a first link between the electrophysiology, as recorded by magnetoencephalography, and the neurochemistry, as assessed by proton magnetic resonance spectroscopy, of the auditory cortex. PMID:16884545

  14. Choline intake influences phosphatidylcholine DHA enrichment in nonpregnant women but not in pregnant women in the third trimester.

    PubMed

    West, Allyson A; Yan, Jian; Jiang, Xinyin; Perry, Cydne A; Innis, Sheila M; Caudill, Marie A

    2013-04-01

    Phosphatidylcholine (PC) produced via the S-adenosylmethionine-dependent phosphatidylethanolamine (PE) N-methyltransferase (PEMT) pathway is enriched with docosahexaenoic acid (DHA). DHA plays a critical role in fetal development and is linked to health endpoints in adulthood. It is unknown whether choline, which can serve as a source of S-adenosylmethionine methyl groups, influences PC-DHA or the PC:PE ratio in pregnant and nonpregnant women. This study tested whether choline intake affects indicators of choline-related lipid metabolism, including erythrocyte and plasma PC-DHA and PC:PE ratios, in pregnant women in the third trimester and nonpregnant women. Pregnant (n = 26) and nonpregnant (n = 21) women consumed 480 or 930 mg choline/d and a daily DHA supplement for 12 wk. Blood was collected at baseline and at the midpoint and end of the study. PC-DHA was analyzed as the proportion of total PC fatty acids. Pregnant women had greater (P = 0.002) PC-DHA concentrations than did nonpregnant women at baseline. The proportion of erythrocyte and plasma PC-DHA increased (P ≤ 0.002) in pregnant and nonpregnant women regardless of choline intake. However, in nonpregnant women, consumption of 930 mg choline/d led to greater (P < 0.001) erythrocyte PC-DHA and a more rapid increase (P < 0.001) in plasma PC-DHA. Lower (P = 0.001-0.024) erythrocyte and plasma PC:PE in pregnant women was not modified by choline intake. A higher choline intake may increase PEMT activity, resulting in greater PC-DHA enrichment of the PC molecule in nonpregnant women. Increased production of PC-DHA during pregnancy indicates elevated PEMT activity and a higher demand for methyl donors. This trial was registered at clinicaltrials.gov as NCT01127022.

  15. Choline metabolism-based molecular diagnosis of cancer: an update

    PubMed Central

    Glunde, Kristine; Penet, Marie-France; Jiang, Lu; Jacobs, Michael A; Bhujwalla, Zaver M

    2016-01-01

    Abnormal choline metabolism continues to be identified in multiple cancers. Molecular causes of abnormal choline metabolism are changes in choline kinase-α, ethanolamine kinase-α, phosphatidylcholine-specific phospholipase C and -D and glycerophosphocholine phosphodiesterases, as well as several choline transporters. The net outcome of these enzymatic changes is an increase in phosphocholine and total choline (tCho) and, in some cancers, a relative decrease of glycerophosphocholine. The increased tCho signal detected by 1H magnetic resonance spectroscopy is being evaluated as a diagnostic marker in multiple cancers. Increased expression and activity of choline transporters and choline kinase-α have spurred the development of radiolabeled choline analogs as PET imaging tracers. Both tCho 1H magnetic resonance spectroscopy and choline PET are being investigated to detect response to treatment. Enzymes mediating the abnormal choline metabolism are being explored as targets for cancer therapy. This review highlights recent molecular, therapeutic and clinical advances in choline metabolism in cancer. PMID:25921026

  16. Choline attenuates immune inflammation and suppresses oxidative stress in patients with asthma.

    PubMed

    Mehta, Amit K; Singh, Bhanu P; Arora, Naveen; Gaur, Shailendra N

    2010-07-01

    Asthma is a chronic immune inflammatory disease characterized by variable airflow obstruction and increased bronchial hyperreactivity (BHR). Therapeutic interventions reduce airway inflammation and relieve symptoms but associated with potential side effects that limit their usefulness. The present study was undertaken to assess the effect of choline on immune inflammation and BHR in asthma subjects. The patients of asthma (n=76) were recruited and treated with choline supplement (1500 mg twice) or standard pharmacotherapy for 6 months in two groups. The patients were evaluated by clinical, immunologic and biochemical parameters. The treatment with choline showed significant reduction in symptom/drug score and improvement in PC(20) FEV1 compared to baseline or standard pharmacotherapy (p<0.01). Choline therapy significantly reduced IL-4, IL-5 and TNF-alpha level as compared to baseline or standard pharmacotherapy after 6 months (p<0.01). Blood eosinophil count and total IgE levels were reduced in both the treatment groups. Cysteinyl leukotriene and leukotriene B4 were suppressed significantly by choline treatment (p<0.01). This was accompanied by decreased 8-isoprostanes, a biomarker for oxidative stress after choline treatment (p<0.01). Choline therapy modulates immune inflammation and suppresses oxidative stress in asthma patients. It can be used as an adjunct therapy for asthma patients. Copyright 2009 Elsevier GmbH. All rights reserved.

  17. Dipsogenic and feeding influences of intraventricularly infused anionic choline solutions.

    PubMed

    Mandal, M B; Badgaiyan, R D

    1991-10-01

    Chloride and bicarbonate solutions of choline were infused into the anteroventral part of the third ventricle of two different groups of rats through chronically implanted stainless steel cannulae. Dipsogenic and feeding responses elicited by these solutions were studied by observations taken at half hour intervals up to two h and then, after 24 h of infusions. Results were compared with the control response evoked by similar infusion of artificial cerebrospinal fluid (aCSF). Food and water intakes were recorded in different groups (n = 18 each) of rats. Dipsogenic response elicited by choline chloride solution in the observation taken 24 h after infusion, however, was higher only as compared to the control. Dipsogenic effect of bicarbonate solution was not significantly different from the control in the first two observations (30 and 60 min), but in the later observations (90, 120 min and 24 h), it was significantly higher. None of the choline solutions significantly alter feeding response within 2 h of infusions. However, in the observation taken 24 h after infusion, the response evoked by choline chloride was greater than that elicited by aCSF. The results support our earlier observation that chloride concentration of third ventricular CSF significantly influences water and food consumption. Intraventricularly administered choline also appears to have positive influence on these behaviors.

  18. Effect of chorioamnionitis on brain development and injury in premature newborns.

    PubMed

    Chau, Vann; Poskitt, Kenneth J; McFadden, Deborah E; Bowen-Roberts, Tim; Synnes, Anne; Brant, Rollin; Sargent, Michael A; Soulikias, Wendy; Miller, Steven P

    2009-08-01

    The association of chorioamnionitis and noncystic white matter injury, a common brain injury in premature newborns, remains controversial. Our objectives were to determine the association of chorioamnionitis and postnatal risk factors with white matter injury, and the effects of chorioamnionitis on early brain development, using advanced magnetic resonance imaging. Ninety-two preterm newborns (24-32 weeks gestation) were studied at a median age of 31.9 weeks and again at 40.3 weeks gestation. Histopathological chorioamnionitis and white matter injury were scored using validated systems. Measures of brain metabolism (N-acetylaspartate/choline and lactate/choline) on magnetic resonance spectroscopy, and microstructure (average diffusivity and fractional anisotropy) on diffusion tensor imaging were calculated from predefined brain regions. Thirty-one (34%) newborns were exposed to histopathological chorioamnionitis, and 26 (28%) had white matter injury. Histopathological chorioamnionitis was not associated with an increased risk of white matter injury (relative risk: 1.2; p = 0.6). Newborns with postnatal infections and hypotension requiring therapy were at higher risk of white matter injury (p < 0.03). Adjusting for gestational age at scan and regions of interest, histopathological chorioamnionitis did not significantly affect brain metabolic and microstructural development (p > 0.1). In contrast, white matter injury was associated with lower N-acetylaspartate/choline (-8.9%; p = 0.009) and lower white matter fractional anisotropy (-11.9%; p = 0.01). Histopathological chorioamnionitis does not appear to be associated with an increased risk of white matter injury on magnetic resonance imaging or with abnormalities of brain development. In contrast, postnatal infections and hypotension are associated with an increased risk of white matter injury in the premature newborn.

  19. Proton MR spectroscopy in herpes simplex encephalitis: Assessment of neuronal loss

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Menon, D.K.; Sargentoni, J.; Peden, C.J.

    1990-05-01

    We present here the case of an 11-year-old boy with herpes simplex encephalitis diagnosed on the basis of clinical features, serology, and response to acyclovir, who relapsed after 3 weeks of therapy. In vivo proton magnetic resonance spectroscopy (1H MRS) of the brain, at 8 and 16 weeks after the onset of symptoms, showed abnormalities, most prominently a reduction in the N-acetylaspartate/choline ratio. The role of 1H MRS in assessing disease activity is discussed.

  20. Effects of creatine supplementation on exercise performance.

    PubMed

    Demant, T W; Rhodes, E C

    1999-07-01

    While creatine has been known to man since 1835, when a French scientist reported finding this constitutent of meat, its presence in athletics as a performance enhancer is relatively new. Amid claims of increased power and strength, decreased performance time and increased muscle mass, creatine is being hailed as a true ergogenic aid. Creatinine is synthesised from the amino acids glycine, arginine and methionine in the kidneys, liver and pancreas, and is predominantly found in skeletal muscle, where it exists in 2 forms. Approximately 40% is in the free creatine form (Crfree), while the remaining 60% is in the phosphorylated form, creatine phosphate (CP). The daily turnover rate of approximately 2 g per day is equally met via exogenous intake and endogenous synthesis. Although creatine concentration (Cr) is greater in fast twitch muscle fibres, slow twitch fibres have a greater resynthesis capability due to their increased aerobic capacity. There appears to be no significant difference between males and females in Cr, and training does not appear to effect Cr. The 4 roles in which creatine is involved during performance are temporal energy buffering, spatial energy buffering, proton buffering and glycolysis regulation. Creatine supplementation of 20 g per day for at least 3 days has resulted in significant increases in total Cr for some individuals but not others, suggesting that there are 'responders' and 'nonresponders'. These increases in total concentration among responders is greatest in individuals who have the lowest initial total Cr, such as vegetarians. Increased concentrations of both Crfree and CP are believed to aid performance by providing more short term energy, as well as increase the rate of resynthesis during rest intervals. Creatine supplementation does not appear to aid endurance and incremental type exercises, and may even be detrimental. Studies investigating the effects of creatine supplementation on short term, high intensity exercises have

  1. Effects of ingesting soy or egg lecithins on serum choline, brain choline and brain acetylcholine.

    PubMed

    Magil, S G; Zeisel, S H; Wurtman, R J

    1981-01-01

    Rats were fed lecithins, derived from eggs or soybeans, to determine whether the fatty acid composition of the phosphatidylcholine altered choline availability. Rats were fed either a single meal containing 5 g phosphatidylcholine or a lecithin-containing diet for 3 weeks, including approximately 5 g phosphatidylcholine per day. Each form of dietary lecithin elevated blood choline, brain choline and brain acetylcholine significantly (P < 0.05). There was no difference in response to egg- or soy-derived lecithin.

  2. The association of serum choline with linear growth failure in young children from rural Malawi.

    PubMed

    Semba, Richard D; Zhang, Pingbo; Gonzalez-Freire, Marta; Moaddel, Ruin; Trehan, Indi; Maleta, Kenneth M; Ordiz, M Isabel; Ferrucci, Luigi; Manary, Mark J

    2016-07-01

    Choline is an essential nutrient for cell structure, cell signaling, neurotransmission, lipid transport, and bone formation. Choline can be irreversibly converted to betaine, a major source of methyl groups. Trimethylene N-oxide (TMAO), a proatherogenic molecule, is produced from the metabolism of dietary choline by the gut microbiome. The relation between serum choline and its closely related metabolites with linear growth in children is unknown. The aim was to characterize the relation between serum choline and its closely related metabolites, betaine and TMAO, with linear growth and stunting in young children. We measured serum choline, betaine, and TMAO concentrations by using liquid chromatography isotopic dilution tandem mass spectrometry in a cross-sectional study in 325 Malawian children, aged 12-59 mo, of whom 62% were stunted. Median (25th, 75th percentile) serum choline, betaine, and TMAO concentrations were 6.4 (4.8, 8.3), 12.4 (9.1, 16.3), and 1.2 (0.7, 1.8) μmol/L, respectively. Spearman correlation coefficients of age with serum choline, betaine, and TMAO were -0.57 (P < 0.0001), -0.26 (P < 0.0001), and -0.10 (P = 0.07), respectively. Correlation coefficients of height-for-age z score with serum choline, betaine-to-choline ratio, and TMAO-to-choline ratio were 0.31 (P < 0.0001), -0.24 (P < 0.0001), and -0.29 (P < 0.0001), respectively. Serum choline concentrations were strongly and significantly associated with stunting. Children with and without stunting had median (25th, 75th percentile) serum choline concentrations of 5.6 (4.4, 7.4) and 7.3 (5.9, 9.1) μmol/L (P < 0.0001). Linear growth failure in young children is associated with low serum choline and elevated betaine-to-choline and TMAO-to-choline ratios. Further work is needed to understand whether low dietary choline intake explains low circulating choline among stunted children living in low-income countries and whether increasing choline intake may correct choline deficiency and improve

  3. Does Choline PET/CT Change the Management of Prostate Cancer Patients With Biochemical Failure?

    PubMed

    Goldstein, Jeffrey; Even-Sapir, Einat; Ben-Haim, Simona; Saad, Akram; Spieler, Benjamin; Davidson, Tima; Berger, Raanan; Weiss, Ilana; Appel, Sarit; Lawrence, Yaacov R; Symon, Zvi

    2017-06-01

    The FDA approved C-11 choline PET/computed tomography (CT) for imaging patients with recurrent prostate cancer in 2012. Subsequently, the 2014 NCCN guidelines have introduced labeled choline PET/CT in the imaging algorithm of patients with suspected recurrent disease. However, there is only scarce data on the impact of labeled choline PET/CT findings on disease management. We hypothesized that labeled-choline PET/CT studies showing local or regional recurrence or distant metastases will have a direct role in selection of appropriate patient management and improve radiation planning in patients with disease that can be controlled using this mode of therapy. This retrospective study was approved by the Tel Aviv Sourasky and Sheba Medical Center's Helsinki ethical review committees. Patient characteristics including age, PSA, stage, prior treatments, and pre-PET choline treatment recommendations based on NCCN guidelines were recorded. Patients with biochemical failure and without evidence of recurrence on physical examination or standard imaging were offered the option of additional imaging with labeled choline PET/CT. Treatment recommendations post-PET/CT were compared with pre-PET/CT ones. Pathologic confirmation was obtained before prostate retreatment. A nonparametric χ test was used to compare the initial and final treatment recommendations following choline PET/CT. Between June 2010 and January 2014, 34 labeled-choline PET/CT studies were performed on 33 patients with biochemical failure following radical prostatectomy (RP) (n=6), radiation therapy (RT) (n=6), brachytherapy (n=2), RP+salvage prostate fossa RT (n=14), and RP+salvage prostate fossa/lymph node RT (n=6). Median PSA level before imaging was 2 ng/mL (range, 0.16 to 79). Labeled choline PET/CT showed prostate, prostate fossa, or pelvic lymph node increased uptake in 17 studies, remote metastatic disease in 9 studies, and failed to identify the cause for biochemical failure in 7 scans.PET/CT altered

  4. Repeatability of two-dimensional chemical shift imaging multivoxel proton magnetic resonance spectroscopy for measuring human cerebral choline-containing compounds.

    PubMed

    Puri, Basant K; Egan, Mary; Wallis, Fintan; Jakeman, Philip

    2018-03-22

    To investigate the repeatability of proton magnetic resonance spectroscopy in the in vivo measurement of human cerebral levels of choline-containing compounds (Cho). Two consecutive scans were carried out in six healthy resting subjects at a magnetic field strength of 1.5 T. On each occasion, neurospectroscopy data were collected from 64 voxels using the same 2D chemical shift imaging (CSI) sequence. The data were analyzed in the same way, using the same software, to obtain the values for each voxel of the ratio of Cho to creatine. The Wilcoxon related-samples signed-rank test, coefficient of variation (CV), repeatability coefficient (RC), and intraclass correlation coefficient (ICC) were used to assess the repeatability. The CV ranged from 2.75% to 33.99%, while the minimum RC was 5.68%. There was excellent reproducibility, as judged by significant ICC values, in 26 voxels. Just three voxels showed significant differences according to the Wilcoxon related-samples signed-rank test. It is therefore concluded that when CSI multivoxel proton neurospectroscopy is used to measure cerebral choline-containing compounds at 1.5 T, the reproducibility is highly acceptable.

  5. Effects of plyometric training and creatine supplementation on maximal-intensity exercise and endurance in female soccer players.

    PubMed

    Ramírez-Campillo, Rodrigo; González-Jurado, José Antonio; Martínez, Cristian; Nakamura, Fábio Yuzo; Peñailillo, Luis; Meylan, Cesar M P; Caniuqueo, Alexis; Cañas-Jamet, Rodrigo; Moran, Jason; Alonso-Martínez, Alicia M; Izquierdo, Mikel

    2016-08-01

    To investigate the effects of a six-week plyometric training and creatine supplementation intervention on maximal-intensity and endurance performance in female soccer players during in-season training. Randomized, double-blind, placebo-controlled trial. Young (age 22.9±2.5y) female players with similar training load and competitive background were assigned to a plyometric training group receiving placebo (PLACEBO, n=10), a plyometric training group receiving creatine supplementation (CREATINE, n=10) or a control group receiving placebo without following a plyometric program (CONTROL, n=10). Athletes were evaluated for jumping, maximal and repeated sprinting, endurance and change-of-direction speed performance before and after six weeks of training. After intervention the CONTROL group did not change, whereas both plyometric training groups improved jumps (ES=0.25-0.49), sprint (ES=0.35-0.41), repeated sprinting (ES=0.48-0.55), endurance (ES=0.32-0.34) and change-of-direction speed performance (ES=0.46-0.55). However, the CREATINE group improved more in the jumps and repeated sprinting performance tests than the CONTROL and the PLACEBO groups. Adaptations to plyometric training may be enhanced with creatine supplementation. Copyright © 2015 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

  6. Acute toxicity assessment of choline by inhalation, intraperitoneal and oral routes in Balb/c mice.

    PubMed

    Mehta, Amit Kumar; Arora, Naveen; Gaur, Shailendra Nath; Singh, Bhanu Pratap

    2009-08-01

    Studies suggest that choline has potential to be used as a dietary supplement and a drug for immune inflammatory diseases like asthma and rhinitis. But there are apprehensions regarding adverse effects of choline when given orally in high doses. To address this knowledge gap, toxicity assessment of choline chloride was carried out by intranasal (i.n.), oral and intraperitoneal (i.p.) routes in Balb/c mice for 28days. Body weight, food and water consumption of mice were recorded daily. Hematology and clinical chemistry were assessed to check hepatocellular functions and morphological alterations of the cells. Splenocyte counts were analysed for evaluating cellular immunity. Liver function test was performed by assaying different enzyme systems in serum such as, urea, blood urea nitrogen (BUN), creatinine, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Body weight, food and water consumption did not differ between mice treated with choline and the saline control group. Hematologic and biochemical variables were not affected with any increase in serum toxicity marker enzymes indicating normal liver functioning. Choline administration did not affect total cholesterol and high density lipoprotein levels as compared to their respective controls. Urea and blood urea nitrogen levels in choline treated mice were not different than controls. Creatinine level was, however, higher than control in i.p. treatment group, but other parameters were normal. In conclusion, the repeated consumption of choline chloride via i.n. and oral or i.p. routes did not cause toxicity in mice in the toxicological endpoints examined.

  7. Stress-induced stimulation of choline transport in cultured choroid plexus epithelium exposed to low concentrations of cadmium.

    PubMed

    Young, Robin K; Villalobos, Alice R A

    2014-03-01

    The choroid plexus epithelium forms the blood-cerebrospinal fluid barrier and accumulates essential minerals and heavy metals. Choroid plexus is cited as being a "sink" for heavy metals and excess minerals, serving to minimize accumulation of these potentially toxic agents in the brain. An understanding of how low doses of contaminant metals might alter transport of other solutes in the choroid plexus is limited. Using primary cultures of epithelial cells isolated from neonatal rat choroid plexus, our objective was to characterize modulation of apical uptake of the model organic cation choline elicited by low concentrations of the contaminant metal cadmium (CdCl₂). At 50-1,000 nM, cadmium did not directly decrease or increase 30-min apical uptake of 10 μM [(3)H]choline. However, extended exposure to 250-500 nM cadmium increased [(3)H]choline uptake by as much as 75% without marked cytotoxicity. In addition, cadmium induced heat shock protein 70 and heme oxygenase-1 protein expression and markedly induced metallothionein gene expression. The antioxidant N-acetylcysteine attenuated stimulation of choline uptake and induction of stress proteins. Conversely, an inhibitor of glutathione synthesis l-buthionine-sulfoximine (BSO) enhanced stimulation of choline uptake and induction of stress proteins. Cadmium also activated ERK1/2 MAP kinase. The MEK1 inhibitor PD98059 diminished ERK1/2 activation and attenuated stimulation of choline uptake. Furthermore, inhibition of ERK1/2 activation abated stimulation of choline uptake in cells exposed to cadmium with BSO. These data indicate that in the choroid plexus, exposure to low concentrations of cadmium may induce oxidative stress and consequently stimulate apical choline transport through activation of ERK1/2 MAP kinase.

  8. Does maternal-fetal transfer of creatine occur in pregnant sheep?

    PubMed

    Baharom, Syed; De Matteo, Robert; Ellery, Stacey; Della Gatta, Paul; Bruce, Clinton R; Kowalski, Greg M; Hale, Nadia; Dickinson, Hayley; Harding, Richard; Walker, David; Snow, Rodney J

    2017-07-01

    Our aim was to determine the disposition of creatine in ovine pregnancy and whether creatine is transferred across the placenta from mother to fetus. Pregnant ewes received either 1 ) a continuous intravenous infusion of creatine monohydrate or saline from 122 to 131 days gestation, with maternal and fetal arterial blood and amniotic fluid samples collected daily for creatine analysis and fetal tissues collected at necropsy at 133 days for analysis of creatine content, or 2 ) a single systemic bolus injection of [ 13 C]creatine monohydrate at 130 days of gestation, with maternal and fetal arterial blood, uterine vein blood, and amniotic fluid samples collected before and for 4 h after injection and analyzed for creatine, creatine isotopic enrichment, and guanidinoacetic acid (GAA; precursor of creatine) concentrations. Presence of the creatine transporter-1 (SLC6A8) and l-arginine:glycine amidinotransferase (AGAT; the enzyme synthesizing GAA) proteins were determined by Western blots of placental cotyledons. The 10-day creatine infusion increased maternal plasma creatine concentration three- to fourfold ( P < 0.05) without significantly changing fetal arterial, amniotic fluid, fetal tissues, or placental creatine content. Maternal arterial 13 C enrichment was increased ( P < 0.05) after bolus [ 13 C]creatine injection without change of fetal arterial 13 C enrichment. SLC6A8 and AGAT proteins were identified in placental cotyledons, and GAA concentration was significantly higher in uterine vein than maternal artery plasma. Despite the presence of SLC6A8 protein in cotyledons, these results suggest that creatine is not transferred from mother to fetus in near-term sheep and that the ovine utero-placental unit releases GAA into the maternal circulation. Copyright © 2017 the American Physiological Society.

  9. Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme

    PubMed Central

    Craciun, Smaranda; Balskus, Emily P.

    2012-01-01

    Choline and trimethylamine (TMA) are small molecules that play central roles in biological processes throughout all kingdoms of life. These ubiquitous metabolites are linked through a single biochemical transformation, the conversion of choline to TMA by anaerobic microorganisms. This metabolic activity, which contributes to methanogenesis and human disease, has been known for over a century but has eluded genetic and biochemical characterization. We have identified a gene cluster responsible for anaerobic choline degradation within the genome of a sulfate-reducing bacterium and verified its function using both a genetic knockout strategy and heterologous expression in Escherichia coli. Bioinformatics and electron paramagnetic resonance (EPR) spectroscopy revealed the involvement of a C–N bond cleaving glycyl radical enzyme in TMA production, which is unprecedented chemistry for this enzyme family. Our discovery provides the predictive capabilities needed to identify choline utilization clusters in numerous bacterial genomes, underscoring the importance and prevalence of this metabolic activity within the human microbiota and the environment. PMID:23151509

  10. Deanol affects choline metabolism in peripheral tissues of mice.

    PubMed

    Haubrich, D R; Gerber, N H; Pflueger, A B

    1981-08-01

    Administration of 2-dimethylaminoethanol (deanol) to mice induced an increase in both the concentration and the rate of turnover of free choline in blood. Treatment with deanol also caused an increase in the concentration of choline in kidneys, and markedly inhibited the rates of oxidation and phosphorylation of intravenously administered [3H-methyl]choline. In the liver, deanol inhibited the rate of phosphorylation of [3H-methyl]choline, but did not inhibit its rate of oxidation or cause an increase in the level of free choline. These findings suggest that deanol increases the choline concentration in blood by inhibition of its metabolism in tissues. Deanol may ultimately produce its central cholinergic effects by inhibition of choline metabolism in peripheral tissues, causing free choline choline to accumulate in blood, enter the brain, and stimulate cholinergic receptors.

  11. The association of serum choline with linear growth failure in young children from rural Malawi

    USDA-ARS?s Scientific Manuscript database

    Choline is an essential nutrient for cell structure, cell signaling, neurotransmission, lipid transport, and bone formation. Choline can be irreversibly converted to betaine, a major source of methyl groups. Trimethylene N-oxide (TMAO), a proatherogenic molecule, is produced from the metabolism of d...

  12. Choline and Choline Metabolite Patterns and Associations in Blood and Milk during Lactation in Dairy Cows

    PubMed Central

    Artegoitia, Virginia M.; Middleton, Jesse L.; Harte, Federico M.; Campagna, Shawn R.; de Veth, Michael J.

    2014-01-01

    Milk and dairy products are an important source of choline, a nutrient essential for human health. Infant formula derived from bovine milk contains a number of metabolic forms of choline, all contribute to the growth and development of the newborn. At present, little is known about the factors that influence the concentrations of choline metabolites in milk. The objectives of this study were to characterize and then evaluate associations for choline and its metabolites in blood and milk through the first 37 weeks of lactation in the dairy cow. Milk and blood samples from twelve Holstein cows were collected in early, mid and late lactation and analyzed for acetylcholine, free choline, betaine, glycerophosphocholine, lysophosphatidylcholine, phosphatidylcholine, phosphocholine and sphingomyelin using hydrophilic interaction liquid chromatography-tandem mass spectrometry, and quantified using stable isotope-labeled internal standards. Total choline concentration in plasma, which was almost entirely phosphatidylcholine, increased 10-times from early to late lactation (1305 to 13,535 µmol/L). In milk, phosphocholine was the main metabolite in early lactation (492 µmol/L), which is a similar concentration to that found in human milk, however, phosphocholine concentration decreased exponentially through lactation to 43 µmol/L in late lactation. In contrast, phosphatidylcholine was the main metabolite in mid and late lactation (188 µmol/L and 659 µmol/L, respectively), with the increase through lactation positively correlated with phosphatidylcholine in plasma (R 2 = 0.78). Unlike previously reported with human milk we found no correlation between plasma free choline concentration and milk choline metabolites. The changes in pattern of phosphocholine and phosphatidylcholine in milk through lactation observed in the bovine suggests that it is possible to manufacture infant formula that more closely matches these metabolites profile in human milk. PMID:25157578

  13. Metabolism and transfer of choline in hamster small intestine

    PubMed Central

    Flower, R. J.; Pollitt, R. J.; Sanford, P. A.; Smyth, D. H.

    1972-01-01

    1. The transfer and metabolism of choline was studied with sacs of everted intestine of hamster. 2. Approximately half the choline transferred from the mucosal fluid may be metabolized. High voltage electrophoresis, paper chromatography and ion exchange chromatography have been used to identify this meta bolite as betaine. 3. The concentration of choline and betaine together accumulating in the gut wall and serosal fluid are greater than that of choline present initially in the mucosal fluid indicating some kind of specific mechanism for choline transport. 4. A detailed analysis of choline transfer suggests that the movement of choline cannot be accounted for by simple diffusion. The concentration of choline accumulating in the gut wall and serosal fluid, the inhibitory effects of hemicholinium-3 and α-methylglucoside on choline transfer, and the insensitivity of betaine transfer to hemicholinium-3 suggest a specific active transport process for choline independent of active betaine transport. PMID:5085340

  14. 21 CFR 172.370 - Iron-choline citrate complex.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Iron-choline citrate complex. 172.370 Section 172... CONSUMPTION Special Dietary and Nutritional Additives § 172.370 Iron-choline citrate complex. Iron-choline citrate complex made by reacting approximately equimolecular quantities of ferric hydroxide, choline, and...

  15. Scientific basis and practical aspects of creatine supplementation for athletes.

    PubMed

    Volek, Jeff S; Rawson, Eric S

    2004-01-01

    A large number of studies have been published on creatine supplementation over the last decade. Many studies show that creatine supplementation in conjunction with resistance training augments gains in muscle strength and size. The underlying physiological mechanism(s) to explain this ergogenic effect remain unclear. Increases in muscle fiber hypertrophy and myosin heavy chain expression have been observed with creatine supplementation. Creatine supplementation increases acute weightlifting performance and training volume, which may allow for greater overload and adaptations to training. Creatine supplementation may also induce a cellular swelling in muscle cells, which in turn may affect carbohydrate and protein metabolism. Several studies point to the conclusion that elevated intramuscular creatine can enhance glycogen levels but an effect on protein synthesis/degradation has not been consistently detected. As expected there is a distribution of responses to creatine supplementation that can be largely explained by the degree of creatine uptake into muscle. Thus, there is wide interest in methods to maximize muscle creatine levels. A carbohydrate or carbohydrate/protein-induced insulin response appears to benefit creatine uptake. In summary, the predominance of research indicates that creatine supplementation represents a safe, effective, and legal method to enhance muscle size and strength responses to resistance training.

  16. N-acetylaspartate and neurofilaments as biomarkers of axonal damage in patients with progressive forms of multiple sclerosis.

    PubMed

    Trentini, Alessandro; Comabella, Manuel; Tintoré, Mar; Koel-Simmelink, Marleen J A; Killestein, Joep; Roos, Birthe; Rovira, Alex; Korth, Carsten; Ottis, Philipp; Blankenstein, Marinus A; Montalban, Xavier; Bellini, Tiziana; Teunissen, Charlotte E

    2014-12-01

    Primary and secondary progressive forms of multiple sclerosis (PPMS and SPMS) have different pathological characteristics. However, it is unknown whether neurodegenerative mechanisms are shared. We measured cerebrospinal fluid (CSF) levels of neurofilament (Nf) light and heavy isoforms and N-acetylaspartic acid (NAA) in 21 PP, 10 SPMS patients and 15 non-inflammatory neurological disease controls (NINDC). Biomarkers were related to Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) over a long period of follow-up [median (interquartile range) 9 (5.5-12.5) years] in 19 PPMS and 4 SPMS patients, and to T2 lesion load, T1 lesion load, and brain parenchymal fraction at the time of lumbar puncture. Nf light was higher in PPMS (p < 0.005) and Nf heavy was increased in both SPMS and PPMS (p < 0.05 and p < 0.01) compared to NINDC, but were comparable between the two MS subtypes. Nf heavy was a predictor of the ongoing disability measured by MSSS (R(2) = 0.17, β = 0.413; p < 0.05). Conversely, Nf light was the only predictor of the EDSS annual increase (R(2) = 0.195, β = 0.441; p < 0.05). The frequency of abnormal biomarkers did not differ between the two MS progressive subtypes. Our data suggest that PP and SPMS likely share similar mechanisms of axonal damage. Moreover, Nf heavy can be a biomarker of ongoing axonal damage. Conversely, Nf light can be used as a prognostic marker for accumulating disability suggesting it as a good tool for possible treatment monitoring in the progressive MS forms.

  17. Cerebral creatine deficiency syndromes: clinical aspects, treatment and pathophysiology.

    PubMed

    Stockler, Sylvia; Schutz, Peter W; Salomons, Gajja S

    2007-01-01

    Cerebral creatine deficiency syndromes (CCDSs) are a group of inborn errors of creatine metabolism comprising two autosomal recessive disorders that affect the biosynthesis of creatine--i.e. arginine:glycine amidinotransferase deficiency (AGAT; MIM 602360) and guanidinoacetate methyltransferase deficiency (GAMT; MIM 601240)--and an X-linked defect that affects the creatine transporter, SLC6A8 deficiency (SLC6A8; MIM 300036). The biochemical hallmarks of these disorders include cerebral creatine deficiency as detected in vivo by 1H magnetic resonance spectroscopy (MRS) of the brain, and specific disturbances in metabolites of creatine metabolism in body fluids. In urine and plasma, abnormal guanidinoacetic acid (GAA) levels are found in AGAT deficiency (reduced GAA) and in GAMT deficiency (increased GAA). In urine of males with SLC6A8 deficiency, an increased creatine/creatinine ratio is detected. The common clinical presentation in CCDS includes mental retardation, expressive speech and language delay, autistic like behaviour and epilepsy. Treatment of the creatine biosynthesis defects has yielded clinical improvement, while for creatine transporter deficiency, successful treatment strategies still need to be discovered. CCDSs may be responsible for a considerable fraction of children and adults affected with mental retardation of unknown etiology. Thus, screening for this group of disorders should be included in the differential diagnosis of this population. In this review, also the importance of CCDSs for the unravelling of the (patho)physiology of cerebral creatine metabolism is discussed.

  18. Importance of a serine proximal to the C(4a) and N(5) flavin atoms for hydride transfer in choline oxidase.

    PubMed

    Yuan, Hongling; Gadda, Giovanni

    2011-02-08

    Choline oxidase catalyzes the flavin-dependent, two-step oxidation of choline to glycine betaine with the formation of an aldehyde intermediate. In the first oxidation reaction, the alcohol substrate is initially activated to its alkoxide via proton abstraction. The substrate is oxidized via transfer of a hydride from the alkoxide α-carbon to the N(5) atom of the enzyme-bound flavin. In the wild-type enzyme, proton and hydride transfers are mechanistically and kinetically uncoupled. In this study, we have mutagenized an active site serine proximal to the C(4a) and N(5) atoms of the flavin and investigated the reactions of proton and hydride transfers by using substrate and solvent kinetic isotope effects. Replacement of Ser101 with threonine, alanine, cysteine, or valine resulted in biphasic traces in anaerobic reductions of the flavin with choline investigated in a stopped-flow spectrophotometer. Kinetic isotope effects established that the kinetic phases correspond to the proton and hydride transfer reactions catalyzed by the enzyme. Upon removal of Ser101, there is an at least 15-fold decrease in the rate constants for proton abstraction, irrespective of whether threonine, alanine, valine, or cysteine is present in the mutant enzyme. A logarithmic decrease spanning 4 orders of magnitude is seen in the rate constants for hydride transfer with increasing hydrophobicity of the side chain at position 101. This study shows that the hydrophilic character of a serine residue proximal to the C(4a) and N(5) flavin atoms is important for efficient hydride transfer.

  19. Effects of a Sativex-Like Combination of Phytocannabinoids on Disease Progression in R6/2 Mice, an Experimental Model of Huntington’s Disease

    PubMed Central

    Valdeolivas, Sara; Sagredo, Onintza; Delgado, Mercedes; Pozo, Miguel A.; Fernández-Ruiz, Javier

    2017-01-01

    Several cannabinoids afforded neuroprotection in experimental models of Huntington’s disease (HD). We investigated whether a 1:1 combination of botanical extracts enriched in either ∆9-tetrahydrocannabinol (∆9-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex®, is beneficial in R6/2 mice (a transgenic model of HD), as it was previously shown to have positive effects in neurotoxin-based models of HD. We recorded the progression of neurological deficits and the extent of striatal deterioration, using behavioral, in vivo imaging, and biochemical methods in R6/2 mice and their corresponding wild-type mice. The mice were daily treated, starting at 4 weeks after birth, with a Sativex-like combination of phytocannabinoids (equivalent to 3 mg/kg weight of pure CBD + ∆9-THC) or vehicle. R6/2 mice exhibited the characteristic deterioration in rotarod performance that initiated at 6 weeks and progressed up to 10 weeks, and elevated clasping behavior reflecting dystonia. Treatment with the Sativex-like combination of phytocannabinoids did not recover rotarod performance, but markedly attenuated clasping behavior. The in vivo positron emission tomography (PET) analysis of R6/2 animals at 10 weeks revealed a reduced metabolic activity in the basal ganglia, which was partially attenuated by treatment with the Sativex-like combination of phytocannabinoids. Proton nuclear magnetic resonance spectroscopy (H+-MRS) analysis of the ex vivo striatum of R6/2 mice at 12 weeks revealed changes in various prognostic markers reflecting events typically found in HD patients and animal models, such as energy failure, mitochondrial dysfunction, and excitotoxicity. Some of these changes (taurine/creatine, taurine/N-acetylaspartate, and N-acetylaspartate/choline ratios) were completely reversed by treatment with the Sativex-like combination of phytocannabinoids. A Sativex-like combination of phytocannabinoids administered to R6/2 mice at

  20. Effects of a Sativex-Like Combination of Phytocannabinoids on Disease Progression in R6/2 Mice, an Experimental Model of Huntington's Disease.

    PubMed

    Valdeolivas, Sara; Sagredo, Onintza; Delgado, Mercedes; Pozo, Miguel A; Fernández-Ruiz, Javier

    2017-03-23

    Several cannabinoids afforded neuroprotection in experimental models of Huntington's disease (HD). We investigated whether a 1:1 combination of botanical extracts enriched in either ∆⁸-tetrahydrocannabinol (∆⁸-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex ® , is beneficial in R6/2 mice (a transgenic model of HD), as it was previously shown to have positive effects in neurotoxin-based models of HD. We recorded the progression of neurological deficits and the extent of striatal deterioration, using behavioral, in vivo imaging, and biochemical methods in R6/2 mice and their corresponding wild-type mice. The mice were daily treated, starting at 4 weeks after birth, with a Sativex-like combination of phytocannabinoids (equivalent to 3 mg/kg weight of pure CBD + ∆⁸-THC) or vehicle. R6/2 mice exhibited the characteristic deterioration in rotarod performance that initiated at 6 weeks and progressed up to 10 weeks, and elevated clasping behavior reflecting dystonia. Treatment with the Sativex-like combination of phytocannabinoids did not recover rotarod performance, but markedly attenuated clasping behavior. The in vivo positron emission tomography (PET) analysis of R6/2 animals at 10 weeks revealed a reduced metabolic activity in the basal ganglia, which was partially attenuated by treatment with the Sativex-like combination of phytocannabinoids. Proton nuclear magnetic resonance spectroscopy (H⁺-MRS) analysis of the ex vivo striatum of R6/2 mice at 12 weeks revealed changes in various prognostic markers reflecting events typically found in HD patients and animal models, such as energy failure, mitochondrial dysfunction, and excitotoxicity. Some of these changes (taurine/creatine, taurine/ N -acetylaspartate, and N -acetylaspartate/choline ratios) were completely reversed by treatment with the Sativex-like combination of phytocannabinoids. A Sativex-like combination of phytocannabinoids administered to R6

  1. Choline: Dietary Requirements and Role in Brain Development.

    PubMed

    Sanders, Lisa M; Zeisel, Steven H

    2007-01-01

    Choline is needed for the maintenance of the structural integrity and signaling functions of cell membranes, for neurotransmission, and for transport of lipids and as a source of methyl groups. Choline can be made de novo in the body, but some individuals must also obtain choline in the diet to prevent deficiency symptoms. A number of environmental and genetic factors influence dietary requirements for choline, and average intakes in the population vary widely. Therefore, certain individuals may be at greater risk of choline deficiency. Choline is critical during fetal development, particularly during the development of the brain, where it can influence neural tube closure and lifelong memory and learning functions.

  2. Neurochemical alterations in methamphetamine-dependent patients treated with cytidine-5'-diphosphate choline: a longitudinal proton magnetic resonance spectroscopy study.

    PubMed

    Yoon, Sujung J; Lyoo, In Kyoon; Kim, Hengjun J; Kim, Tae-Suk; Sung, Young Hoon; Kim, Namkug; Lukas, Scott E; Renshaw, Perry F

    2010-04-01

    Cytidine-5'-diphosphate choline (CDP-choline), as an important intermediate for major membrane phospholipids, may exert neuroprotective effects in various neurodegenerative disorders. This longitudinal proton magnetic resonance spectroscopy ((1)H-MRS) study aimed to examine whether a 4-week CDP-choline treatment could alter neurometabolite levels in patients with methamphetamine (MA) dependence and to investigate whether changes in neurometabolite levels would be associated with MA use. We hypothesized that the prefrontal levels of N-acetyl-aspartate (NAA), a neuronal marker, and choline-containing compound (Cho), which are related to membrane turnover, would increase with CDP-choline treatment in MA-dependent patients. We further hypothesized that this increase would correlate with the total number of negative urine results. Thirty-one treatment seekers with MA dependence were randomly assigned to receive CDP-choline (n=16) or placebo (n=15) for 4 weeks. Prefrontal NAA and Cho levels were examined using (1)H-MRS before medication, and at 2 and 4 weeks after treatment. Generalized estimating equation regression analyses showed that the rate of change in prefrontal NAA (p=0.005) and Cho (p=0.03) levels were greater with CDP-choline treatment than with placebo. In the CDP-choline-treated patients, changes in prefrontal NAA levels were positively associated with the total number of negative urine results (p=0.03). Changes in the prefrontal Cho levels, however, were not associated with the total number of negative urine results. These preliminary findings suggest that CDP-choline treatment may exert potential neuroprotective effects directly or indirectly because of reductions in drug use by the MA-dependent patients. Further studies with a larger sample size of MA-dependent patients are warranted to confirm a long-term efficacy of CDP-choline in neuroprotection and abstinence.

  3. Elevated plasma creatinine due to creatine ethyl ester use.

    PubMed

    Velema, M S; de Ronde, W

    2011-02-01

    Creatine is a nutritional supplement widely used in sport, physical fitness training and bodybuilding. It is claimed to enhance performance. We describe a case in which serum creatinine is elevated due to the use of creatine ethyl esther. One week after withdrawal, the plasma creatinine had normalised. There are two types of creatine products available: creatine ethyl esther (CEE) and creatine monohydrate (CM). Plasma creatinine is not elevated in all creatine-using subjects. CEE , but not CM, is converted into creatinine in the gastrointestinal tract. As a result the use of CEE may be associated with elevated plasma creatinine levels. Since plasma creatinine is a widely used marker for renal function, the use of CEE may lead to a false assumption of renal failure.

  4. In Vivo{sup 1}H Magnetic Resonance Spectroscopy of Lactate in Patients With Stage IV Head and Neck Squamous Cell Carcinoma

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Le, Quynh-Thu; Koong, Albert; Lieskovsky, Yee Yie

    2008-07-15

    Purpose: To investigate in vivo{sup 1}H magnetic resonance spectroscopy imaging of lactate for assessing tumor hypoxia in head and neck cancers and to determine its utility in predicting the response and outcomes. Methods and Materials: Volume-localized lactate-edited {sup 1}H magnetic resonance spectroscopy at 1.5 T was performed in vivo on involved neck nodes and control subcutaneous tissues in 36 patients with Stage IV head and neck cancer. The signal intensities (SIs) of lactate, choline, and creatine and the choline/creatine ratio were measured. The tumor partial pressure of oxygen (pO{sub 2}) was obtained in the same lymph node before MRS. Patientsmore » were treated with either two cycles of induction chemotherapy (tirapazamine, cisplatin, 5-fluorouracil) followed by simultaneous chemoradiotherapy or the same regimen without tirapazamine. The lactate SI and the choline/creatine ratio correlated with the tumor pO{sub 2}, nodal response, and locoregional control. Results: The lactate SI was greater for the involved nodes (median, 0.25) than for the subcutaneous tissue (median, 0.04; p = 0.07). No significant correlation was found between the lactate SI and tumor pO{sub 2} (mean, 0.46 {+-} 0.10 for hypoxic nodes [pO{sub 2} {<=}10 mm Hg, n = 15] vs. 0.36 {+-} 0.07 for nonhypoxic nodes [pO{sub 2} >10 mm Hg, n = 21], p = 0.44). A significant correlation was found between the choline/creatine ratios and tumor pO{sub 2} (mean, 2.74 {+-} 0.34 for hypoxic nodes vs. 1.78 {+-} 0.31 for nonhypoxic nodes, p = 0.02). No correlation was found between the lactate SI and the complete nodal response (p = 0.52) or locoregional control rates. Conclusions: The lactate SI did not correlate with tumor pO{sub 2}, treatment response, or locoregional control. Additional research is needed to refine this technique.« less

  5. Creatine and Caffeine: Considerations for Concurrent Supplementation.

    PubMed

    Trexler, Eric T; Smith-Ryan, Abbie E

    2015-12-01

    Nutritional supplementation is a common practice among athletes, with creatine and caffeine among the most commonly used ergogenic aids. Hundreds of studies have investigated the ergogenic potential of creatine supplementation, with consistent improvements in strength and power reported for exercise bouts of short duration (≤ 30 s) and high intensity. Caffeine has been shown to improve endurance exercise performance, but results are mixed in the context of strength and sprint performance. Further, there is conflicting evidence from studies comparing the ergogenic effects of coffee and caffeine anhydrous supplementation. Previous research has identified independent mechanisms by which creatine and caffeine may improve strength and sprint performance, leading to the formulation of multi-ingredient supplements containing both ingredients. Although scarce, research has suggested that caffeine ingestion may blunt the ergogenic effect of creatine. While a pharmacokinetic interaction is unlikely, authors have suggested that this effect may be explained by opposing effects on muscle relaxation time or gastrointestinal side effects from simultaneous consumption. The current review aims to evaluate the ergogenic potential of creatine and caffeine in the context of high-intensity exercise. Research directly comparing coffee and caffeine anhydrous is discussed, along with previous studies evaluating the concurrent supplementation of creatine and caffeine.

  6. Uptake of choline by rat mammary-gland epithelial cells.

    PubMed Central

    Chao, C K; Pomfret, E A; Zeisel, S H

    1988-01-01

    The neonatal mammal requires especially large amounts of choline to sustain growth. Much of this choline is derived from the newborn's only source of food, milk. The concentration of choline in rat milk [182 +/- 24 microM (S.E.M.)] was much higher than that in maternal serum (11.6 +/- 0.9 microM), suggesting that a mechanism capable of concentrating choline into milk must exist. We characterized choline uptake by mammary epithelial cells (the site of milk production) of the lactating rat. We observed two uptake processes, one saturable and obeying Michaelis-Menten kinetics, and the other non-saturable and linear. At physiological blood choline concentrations, the saturable component of choline uptake predominated. The saturable component had Kapp. = 35 +/- 16 microM, and Vmax. = 1.24 +/- 0.19 nmol/h per mg of protein. Saturable uptake of choline was inhibited by hemicholinium-3. Ca2+ was required for uptake, but Mg2+ was not. Replacement Na+ with K+, Li+ or sucrose inhibited transport. Ouabain did not inhibit choline uptake. Choline concentration in epithelial cells was 67.7 +/- 1.9 nmol/g wet wt. at the start of incubation at 37 degrees C and rose to 80.9 +/- 6.5 nmol/g wet wt. over 30 min. Much of the choline accumulated by the mammary gland (in the presence of endogenous concentrations of choline) remained in the form of choline (50 +/- 1.2%), phosphatidylcholine (12 +/- 2.3%), lysophosphatidylcholine (0.1 +/- 0.03%), betaine (7 +/- 0.3% and phosphocholine (6 +/- 0.5%). In addition, we isolated 25 +/- 1.2% of choline-derived radiolabel in an unidentified compound. Images Fig. 1. Fig. 3. PMID:3178755

  7. Stress-induced stimulation of choline transport in cultured choroid plexus epithelium exposed to low concentrations of cadmium

    PubMed Central

    Young, Robin K.

    2013-01-01

    The choroid plexus epithelium forms the blood-cerebrospinal fluid barrier and accumulates essential minerals and heavy metals. Choroid plexus is cited as being a “sink” for heavy metals and excess minerals, serving to minimize accumulation of these potentially toxic agents in the brain. An understanding of how low doses of contaminant metals might alter transport of other solutes in the choroid plexus is limited. Using primary cultures of epithelial cells isolated from neonatal rat choroid plexus, our objective was to characterize modulation of apical uptake of the model organic cation choline elicited by low concentrations of the contaminant metal cadmium (CdCl2). At 50–1,000 nM, cadmium did not directly decrease or increase 30-min apical uptake of 10 μM [3H]choline. However, extended exposure to 250–500 nM cadmium increased [3H]choline uptake by as much as 75% without marked cytotoxicity. In addition, cadmium induced heat shock protein 70 and heme oxygenase-1 protein expression and markedly induced metallothionein gene expression. The antioxidant N-acetylcysteine attenuated stimulation of choline uptake and induction of stress proteins. Conversely, an inhibitor of glutathione synthesis l-buthionine-sulfoximine (BSO) enhanced stimulation of choline uptake and induction of stress proteins. Cadmium also activated ERK1/2 MAP kinase. The MEK1 inhibitor PD98059 diminished ERK1/2 activation and attenuated stimulation of choline uptake. Furthermore, inhibition of ERK1/2 activation abated stimulation of choline uptake in cells exposed to cadmium with BSO. These data indicate that in the choroid plexus, exposure to low concentrations of cadmium may induce oxidative stress and consequently stimulate apical choline transport through activation of ERK1/2 MAP kinase. PMID:24401988

  8. Creatine biosynthesis and transport by the term human placenta.

    PubMed

    Ellery, Stacey J; Della Gatta, Paul A; Bruce, Clinton R; Kowalski, Greg M; Davies-Tuck, Miranda; Mockler, Joanne C; Murthi, Padma; Walker, David W; Snow, Rod J; Dickinson, Hayley

    2017-04-01

    Creatine is an amino acid derivative that is involved in preserving ATP homeostasis. Previous studies suggest an important role for the creatine kinase circuit for placental ATP turnover. Creatine is obtained from both the diet and endogenous synthesis, usually along the renal-hepatic axis. However, some tissues with a high-energy demand have an inherent capacity to synthesise creatine. In this study, we determined if the term human placenta has the enzymatic machinary to synthesise creatine. Eleven placentae were collected following elective term caesarean section. Samples from the 4 quadrants of each placenta were either fixed in formalin or frozen. qPCR was used to determine the mRNA expression of the creatine synthesising enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), and the creatine transporter (SLC6A8). Protein expression of AGAT and GAMT was quantified by Western blot, and observations of cell localisation of AGAT, GAMT and SLC6A8 made with immunohistochemistry. Synthesis of guanidinoacetate (GAA; creatine precursor) and creatine in placental homogenates was determined via GC-MS and HPLC, respectively. AGAT, GAMT and SLC6A8 mRNA and protein were detected in the human placenta. AGAT staining was identified in stromal and endothelial cells of the fetal capillaries. GAMT and SLC6A8 staining was localised to the syncytiotrophoblast of the fetal villi. Ex vivo, tissue homogenates produce both GAA (4.6 nmol mg protein -1 h -1 ) and creatine (52.8 nmol mg protein -1 h -1 ). The term human placenta has the capacity to synthesise creatine. These data present a new understanding of placental energy metabolism. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Contents of lecithin and choline in crude drugs.

    PubMed

    Yamasaki, K; Kikuoka, M; Nishi, H; Kokusenya, Y; Miyamoto, T; Matsuo, M; Sato, T

    1994-01-01

    The determination of lecithin and choline in crude drugs was established by a combination of high performance liquid chromatography (HPLC) with electrochemical detector (ECD) and enzyme reaction. Lecithin in crude drugs extracted with a mixture of chloroform-methanol (2:1) at room temperature was hydrolyzed by phospholipase D. The hydrolyzate was injected to HPLC, and choline was separated from impurities by reverse phase column. The choline was converted to betaine and hydrogen peroxide by passing through column packed with immobilized choline oxidase. This hydrogen peroxide was detected by ECD. The peak area of hydrogen peroxide derived from lecithin was proportional to the concentration of lecithin from 0.10 to 1.52 microgram/ml. Choline in crude drugs was extracted with ethanol under reflux and determined under the same HPLC conditions as lecithin. The peak area of hydrogen peroxide derived from choline was proportional to the concentration of choline from 0.01 to 0.45 microgram/ml. The contents of lecithin and choline in 31 kinds of crude drugs were determined by these established methods. The results showed that Cervi Parvum Cornu, Kokurozin, Foenigraeci Semen and Psoraleae Semen contained more lecithin than other crude drugs, while Angelicae Radix, Foenigraeci Semen, Psoraleae Semen, and especially Hippocampus were found to contain more choline than other crude drugs.

  10. The association of serum choline with linear growth failure in young children from rural Malawi12

    PubMed Central

    Semba, Richard D; Zhang, Pingbo; Gonzalez-Freire, Marta; Moaddel, Ruin; Trehan, Indi; Maleta, Kenneth M; Ordiz, M Isabel; Ferrucci, Luigi; Manary, Mark J

    2016-01-01

    Background: Choline is an essential nutrient for cell structure, cell signaling, neurotransmission, lipid transport, and bone formation. Choline can be irreversibly converted to betaine, a major source of methyl groups. Trimethylene N-oxide (TMAO), a proatherogenic molecule, is produced from the metabolism of dietary choline by the gut microbiome. The relation between serum choline and its closely related metabolites with linear growth in children is unknown. Objective: The aim was to characterize the relation between serum choline and its closely related metabolites, betaine and TMAO, with linear growth and stunting in young children. Design: We measured serum choline, betaine, and TMAO concentrations by using liquid chromatography isotopic dilution tandem mass spectrometry in a cross-sectional study in 325 Malawian children, aged 12–59 mo, of whom 62% were stunted. Results: Median (25th, 75th percentile) serum choline, betaine, and TMAO concentrations were 6.4 (4.8, 8.3), 12.4 (9.1, 16.3), and 1.2 (0.7, 1.8) μmol/L, respectively. Spearman correlation coefficients of age with serum choline, betaine, and TMAO were −0.57 (P < 0.0001), −0.26 (P < 0.0001), and −0.10 (P = 0.07), respectively. Correlation coefficients of height-for-age z score with serum choline, betaine-to-choline ratio, and TMAO-to-choline ratio were 0.31 (P < 0.0001), −0.24 (P < 0.0001), and −0.29 (P < 0.0001), respectively. Serum choline concentrations were strongly and significantly associated with stunting. Children with and without stunting had median (25th, 75th percentile) serum choline concentrations of 5.6 (4.4, 7.4) and 7.3 (5.9, 9.1) μmol/L (P < 0.0001). Conclusions: Linear growth failure in young children is associated with low serum choline and elevated betaine-to-choline and TMAO-to-choline ratios. Further work is needed to understand whether low dietary choline intake explains low circulating choline among stunted children living in low-income countries and whether

  11. Choline oxidation by intact spinach chloroplasts. [Spinacia oleracea L

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Weigel, P.; Lerma, C.; Hanson, A.D.

    1988-01-01

    Plants synthesize betaine by a two-step oxidation of choline (choline ..-->.. betaine aldehyde ..-->.. betaine). Protoplast-derived chloroplasts of spinach (Spinacia oleracea L.) carry out both reactions, more rapidly in light than in darkness. We investigated the light-stimulated oxidation of choline, using spinach chloroplasts isolated directly from leaves. The rates of choline oxidation obtained (dark and light rates: 10-50 and 100-300 nanomoles per hour per milligram chlorophyll, respectively) were approximately 20-fold higher than for protoplast-derived chloroplasts. Betaine aldehyde was the main product. Choline oxidation in darkness and light was suppressed by hypoxia. Neither uncouplers not the Calvin cycle inhibitor glyceraldehyde greatlymore » affected choline oxidation in the light, and maximal choline oxidation was attained far below light saturation of CO/sub 2/ fixation. The light stimulation of choline oxidation was abolished by the PSII inhibitors DCMU and dibromothymoquinone, and was partially restored by adding reduced diaminodurene, an electron donor to PSI. Both methyl viologen and phenazine methosulfate prevented choline oxidation. Adding dihydroxyacetone phosphate, which can generate NADPH in organello, doubled the dark rate of choline oxidation. These results indicate that choline oxidation in chloroplasts requires oxygen, and reducing power generated from PSI. Enzymic reactions consistent with these requirements are discussed.« less

  12. Total body skeletal muscle mass: estimation by creatine (methyl-d3) dilution in humans

    PubMed Central

    Walker, Ann C.; O'Connor-Semmes, Robin L.; Leonard, Michael S.; Miller, Ram R.; Stimpson, Stephen A.; Turner, Scott M.; Ravussin, Eric; Cefalu, William T.; Hellerstein, Marc K.; Evans, William J.

    2014-01-01

    Current methods for clinical estimation of total body skeletal muscle mass have significant limitations. We tested the hypothesis that creatine (methyl-d3) dilution (D3-creatine) measured by enrichment of urine D3-creatinine reveals total body creatine pool size, providing an accurate estimate of total body skeletal muscle mass. Healthy subjects with different muscle masses [n = 35: 20 men (19–30 yr, 70–84 yr), 15 postmenopausal women (51–62 yr, 70–84 yr)] were housed for 5 days. Optimal tracer dose was explored with single oral doses of 30, 60, or 100 mg D3-creatine given on day 1. Serial plasma samples were collected for D3-creatine pharmacokinetics. All urine was collected through day 5. Creatine and creatinine (deuterated and unlabeled) were measured by liquid chromatography mass spectrometry. Total body creatine pool size and muscle mass were calculated from D3-creatinine enrichment in urine. Muscle mass was also measured by magnetic resonance imaging (MRI), dual-energy x-ray absorptiometry (DXA), and traditional 24-h urine creatinine. D3-creatine was rapidly absorbed and cleared with variable urinary excretion. Isotopic steady-state of D3-creatinine enrichment in the urine was achieved by 30.7 ± 11.2 h. Mean steady-state enrichment in urine provided muscle mass estimates that correlated well with MRI estimates for all subjects (r = 0.868, P < 0.0001), with less bias compared with lean body mass assessment by DXA, which overestimated muscle mass compared with MRI. The dilution of an oral D3-creatine dose determined by urine D3-creatinine enrichment provides an estimate of total body muscle mass strongly correlated with estimates from serial MRI with less bias than total lean body mass assessment by DXA. PMID:24764133

  13. Total body skeletal muscle mass: estimation by creatine (methyl-d3) dilution in humans.

    PubMed

    Clark, Richard V; Walker, Ann C; O'Connor-Semmes, Robin L; Leonard, Michael S; Miller, Ram R; Stimpson, Stephen A; Turner, Scott M; Ravussin, Eric; Cefalu, William T; Hellerstein, Marc K; Evans, William J

    2014-06-15

    Current methods for clinical estimation of total body skeletal muscle mass have significant limitations. We tested the hypothesis that creatine (methyl-d3) dilution (D3-creatine) measured by enrichment of urine D3-creatinine reveals total body creatine pool size, providing an accurate estimate of total body skeletal muscle mass. Healthy subjects with different muscle masses [n = 35: 20 men (19-30 yr, 70-84 yr), 15 postmenopausal women (51-62 yr, 70-84 yr)] were housed for 5 days. Optimal tracer dose was explored with single oral doses of 30, 60, or 100 mg D3-creatine given on day 1. Serial plasma samples were collected for D3-creatine pharmacokinetics. All urine was collected through day 5. Creatine and creatinine (deuterated and unlabeled) were measured by liquid chromatography mass spectrometry. Total body creatine pool size and muscle mass were calculated from D3-creatinine enrichment in urine. Muscle mass was also measured by magnetic resonance imaging (MRI), dual-energy x-ray absorptiometry (DXA), and traditional 24-h urine creatinine. D3-creatine was rapidly absorbed and cleared with variable urinary excretion. Isotopic steady-state of D3-creatinine enrichment in the urine was achieved by 30.7 ± 11.2 h. Mean steady-state enrichment in urine provided muscle mass estimates that correlated well with MRI estimates for all subjects (r = 0.868, P < 0.0001), with less bias compared with lean body mass assessment by DXA, which overestimated muscle mass compared with MRI. The dilution of an oral D3-creatine dose determined by urine D3-creatinine enrichment provides an estimate of total body muscle mass strongly correlated with estimates from serial MRI with less bias than total lean body mass assessment by DXA. Copyright © 2014 the American Physiological Society.

  14. Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake

    PubMed Central

    Nabuurs, C I; Choe, C U; Veltien, A; Kan, H E; van Loon, L J C; Rodenburg, R J T; Matschke, J; Wieringa, B; Kemp, G J; Isbrandt, D; Heerschap, A

    2013-01-01

    Creatine (Cr) plays an important role in muscle energy homeostasis by its participation in the ATP–phosphocreatine phosphoryl exchange reaction mediated by creatine kinase. Given that the consequences of Cr depletion are incompletely understood, we assessed the morphological, metabolic and functional consequences of systemic depletion on skeletal muscle in a mouse model with deficiency of l-arginine:glycine amidinotransferase (AGAT−/−), which catalyses the first step of Cr biosynthesis. In vivo magnetic resonance spectroscopy showed a near-complete absence of Cr and phosphocreatine in resting hindlimb muscle of AGAT−/− mice. Compared with wild-type, the inorganic phosphate/β-ATP ratio was increased fourfold, while ATP levels were reduced by nearly half. Activities of proton-pumping respiratory chain enzymes were reduced, whereas F1F0-ATPase activity and overall mitochondrial content were increased. The Cr-deficient AGAT−/− mice had a reduced grip strength and suffered from severe muscle atrophy. Electron microscopy revealed increased amounts of intramyocellular lipid droplets and crystal formation within mitochondria of AGAT−/− muscle fibres. Ischaemia resulted in exacerbation of the decrease of pH and increased glycolytic ATP synthesis. Oral Cr administration led to rapid accumulation in skeletal muscle (faster than in brain) and reversed all the muscle abnormalities, revealing that the condition of the AGAT−/− mice can be switched between Cr deficient and normal simply by dietary manipulation. Systemic creatine depletion results in mitochondrial dysfunction and intracellular energy deficiency, as well as structural and physiological abnormalities. The consequences of AGAT deficiency are more pronounced than those of muscle-specific creatine kinase deficiency, which suggests a multifaceted involvement of creatine in muscle energy homeostasis in addition to its role in the phosphocreatine–creatine kinase system. PMID:23129796

  15. Neuroprotective actions of perinatal choline nutrition

    PubMed Central

    Blusztajn, Jan Krzysztof; Mellott, Tiffany J.

    2017-01-01

    Choline is an essential nutrient for humans. Studies in rats and mice have shown that high choline intake during gestation or the perinatal period improves cognitive function in adulthood, prevents memory decline of old age, and protects the brain from damage and cognitive and neurological deterioration associated with epilepsy and hereditary conditions such as Down’s and Rett syndromes. These behavioral changes are accompanied by modified patterns of expression of hundreds of cortical and hippocampal genes including those encoding proteins central for learning and memory processing. The effects of choline correlate with cerebral cortical changes in DNA and histone methylation, thus suggesting an epigenomic mechanism of action of perinatal choline. PMID:23314544

  16. Low-Dose Creatine Supplementation Lowers Plasma Guanidinoacetate, but Not Plasma Homocysteine, in a Double-Blind, Randomized, Placebo-Controlled Trial.

    PubMed

    Peters, Brandilyn A; Hall, Megan N; Liu, Xinhua; Parvez, Faruque; Siddique, Abu B; Shahriar, Hasan; Uddin, Mohammad Nasir; Islam, Tariqul; Ilievski, Vesna; Graziano, Joseph H; Gamble, Mary V

    2015-10-01

    Creatine synthesis from guanidinoacetate consumes ~50% of s-adenosylmethionine (SAM)-derived methyl groups, accounting for an equivalent proportion of s-adenosylhomocysteine (SAH) and total homocysteine (tHcys) synthesis. Dietary creatine inhibits the synthesis of guanidinoacetate, thereby lowering plasma tHcys in rats. We tested the hypotheses that creatine supplementation lowers plasma guanidinoacetate, increases blood SAM, lowers blood SAH, and lowers plasma tHcys. Bangladeshi adults were randomly assigned to receive 1 of 4 treatments for 12 wk: placebo (n = 101), 3 g/d creatine (Cr; n = 101), 400 μg/d folic acid (FA; n = 153), or 3 g/d creatine plus 400 μg/d folic acid (Cr+FA; n = 103). The outcomes of plasma guanidinoacetate and tHcys, as well as whole blood SAM and SAH, were analyzed at baseline and week 12 by HPLC. Treatment effects of creatine supplementation were examined with the use of the group comparisons of Cr vs. placebo and Cr+FA vs. FA. Plasma guanidinoacetate declined by 10.6% (95% CI: 4.9, 15.9) in the Cr group while increasing nonsignificantly in the placebo group (3.7%; 95% CI: -0.8, 8.5) (Pgroup difference = 0.0002). Similarly, plasma guanidinoacetate declined by 9.0% (95% CI: 3.4, 14.2) in the Cr+FA group while increasing in the FA group (7.0%; 95% CI: 2.0, 12.2) (Pgroup difference < 0.0001). Plasma tHcys declined by 23.4% (95% CI: 19.5, 27.1) and 21.0% (95% CI: 16.4, 25.2) in the FA and Cr+FA groups, respectively (Pgroup difference = 0.41), with no significant changes in the placebo or Cr groups (Pgroup difference = 0.35). A decrease in guanidinoacetate over time was associated with a decrease in tHcys over time in the Cr+FA group (β = 0.30; 95% CI: 0.17, 0.43; P < 0.0001). Our findings indicate that whereas creatine supplementation downregulates endogenous creatine synthesis, this may not on average lower plasma tHcys in humans. However, tHcys did decrease in those participants who experienced a decline in plasma guanidinoacetate while

  17. Functional analysis of choline transporters in rheumatoid arthritis synovial fibroblasts.

    PubMed

    Seki, Masayuki; Kawai, Yuiko; Ishii, Chikanao; Yamanaka, Tsuyoshi; Odawara, Masato; Inazu, Masato

    2017-11-01

    In this study, we examined the functional characteristics of choline uptake and sought to identify the transporters in rheumatoid arthritis synovial fibroblasts (RASFs). The expression of choline transporters was evaluated by quantitative real-time PCR, western blotting, and immunocytochemistry. Time course, Na + -dependency, and kinetics of [ 3 H]choline uptake were investigated. Effects of cationic drugs on the uptake of [ 3 H]choline, cell viability, and caspase-3/7 activity were also examined. Finally, we investigated the influence of choline uptake inhibitor, hemicholinium-3 (HC-3), and choline deficiency on cell viability and caspase-3/7 activity. Choline transporter-like protein 1 (CTL1) and CTL2 mRNA and protein were highly expressed in RASFs and were localized to the plasma membrane. [ 3 H]Choline uptake occurred via a Na + -independent and pH-dependent transport system. The cells have two different [ 3 H]choline transport systems, high- and low-affinity. Various organic cations, HC-3 and choline deficiency inhibited both [ 3 H]choline uptake and cell viability, and enhanced the caspase-3/7 activity. The functional inhibition of choline transporters could promote apoptotic cell death. In RASFs, [ 3 H]choline uptake was significantly increased compared with that in OASFs without a change in gene expression. These results suggest that CTL1 (high-affinity) and CTL2 (low-affinity) are highly expressed in RASFs and choline may be transported by a choline/H +  antiport system. Identification of this CTL1- and CTL2-mediated choline transport system should provide a potential new target for RA therapy.

  18. Asparagine 285 plays a key role in transition state stabilization in rabbit muscle creatine kinase

    PubMed Central

    Borders, Charles L.; MacGregor, Katherine M.; Edmiston, Paul L.; Gbeddy, Elikem R.K.; Thomenius, Michael J.; Mulligan, Guy B.; Snider, Mark J.

    2003-01-01

    To explore the possibility that asparagine 285 plays a key role in transition state stabilization in phosphagen kinase catalysis, the N285Q, N285D, and N285A site-directed mutants of recombinant rabbit muscle creatine kinase (rmCK) were prepared and characterized. Kinetic analysis of phosphocreatine formation showed that the catalytic efficiency of each N285 mutant was reduced by approximately four orders of magnitude, with the major cause of activity loss being a reduction in kcat in comparison to the recombinant native CK. The data for N285Q still fit a random-order, rapid-equilibrium mechanism, with either MgATP or creatine binding first with affinities very nearly equal to those for native CK. However, the affinity for the binding of the second substrate is reduced approximately 10-fold, suggesting that addition of a single methylene group at position 285 disrupts the symphony of substrate binding. The data for the N285A mutant only fit an ordered binding mechanism, with MgATP binding first. Isosteric replacement to form the N285D mutant has almost no effect on the KM values for either creatine or MgATP, thus the decrease in activity is due almost entirely to a 5000-fold reduction in kcat. Using the quenching of the intrinsic CK tryptophan fluorescence by added MgADP (Borders et al. 2002), it was found that, unlike native CK, none of the mutants have the ability to form a quaternary TSAC. We use these data to propose that asparagine 285 indeed plays a key role in transition state stabilization in the reaction catalyzed by creatine kinase and other phosphagen kinases. PMID:12592023

  19. Asparagine 285 plays a key role in transition state stabilization in rabbit muscle creatine kinase.

    PubMed

    Borders, Charles L; MacGregor, Katherine M; Edmiston, Paul L; Gbeddy, Elikem R K; Thomenius, Michael J; Mulligan, Guy B; Snider, Mark J

    2003-03-01

    To explore the possibility that asparagine 285 plays a key role in transition state stabilization in phosphagen kinase catalysis, the N285Q, N285D, and N285A site-directed mutants of recombinant rabbit muscle creatine kinase (rmCK) were prepared and characterized. Kinetic analysis of phosphocreatine formation showed that the catalytic efficiency of each N285 mutant was reduced by approximately four orders of magnitude, with the major cause of activity loss being a reduction in k(cat) in comparison to the recombinant native CK. The data for N285Q still fit a random-order, rapid-equilibrium mechanism, with either MgATP or creatine binding first with affinities very nearly equal to those for native CK. However, the affinity for the binding of the second substrate is reduced approximately 10-fold, suggesting that addition of a single methylene group at position 285 disrupts the symphony of substrate binding. The data for the N285A mutant only fit an ordered binding mechanism, with MgATP binding first. Isosteric replacement to form the N285D mutant has almost no effect on the K(M) values for either creatine or MgATP, thus the decrease in activity is due almost entirely to a 5000-fold reduction in k(cat). Using the quenching of the intrinsic CK tryptophan fluorescence by added MgADP (Borders et al. 2002), it was found that, unlike native CK, none of the mutants have the ability to form a quaternary TSAC. We use these data to propose that asparagine 285 indeed plays a key role in transition state stabilization in the reaction catalyzed by creatine kinase and other phosphagen kinases.

  20. Uptake of Free Choline by Isolated Perfused Rat Liver

    NASA Astrophysics Data System (ADS)

    Zeisel, Steven H.; Story, David L.; Wurtman, Richard J.; Brunengraber, Henri

    1980-08-01

    The uptake of free choline by isolated perfused rat liver was characterized. A saturable uptake mechanism [Ka=0.17± 0.07 mM (SD); Vmax=0.84± 0.16\\ μ mol/min × g dry weight] and a nonsaturable mechanism (through which uptake is proportional to choline concentration in the perfusate) were identified. Most of the choline transported into hepatocytes was converted to betaine, phosphorylcholine, or lecithin. Free choline also accumulated within the intracellular space, suggesting that choline oxidase activity does not always limit choline's uptake by the liver.

  1. Intestinal transfer of choline in rat and hamster

    PubMed Central

    Sanford, P. A.; Smyth, D. H.

    1971-01-01

    1. The transfer of choline was studied with sacs of everted intestine of rat and hamster. 2. The choline transfer can be divided into two components, a diffusion process and a saturable process. The latter plays a relatively greater part at low concentrations of choline, which include the physiological concentration in the plasma. The saturable process is better seen in the hamster than in the rat. 3. Intestinal transfer of choline is influenced by substances altering the availability of energy in the cell, and by some substances chemically or pharmacologically related to choline. These findings are consistent with some kind of specific mechanism for choline transfer. 4. Part of the choline taken up by the cell appears as a metabolite not yet identified. The formation of the metabolite is a saturable process and is abolished by anaerobic conditions and by homogenization. 5. The results are also discussed in relation to parameters of transfer. PMID:5090994

  2. Neurochemical Alterations in Methamphetamine-Dependent Patients Treated with Cytidine-5′-Diphosphate Choline: A Longitudinal Proton Magnetic Resonance Spectroscopy Study

    PubMed Central

    Yoon, Sujung J; Lyoo, In Kyoon; Kim, Hengjun J; Kim, Tae-Suk; Sung, Young Hoon; Kim, Namkug; Lukas, Scott E; Renshaw, Perry F

    2010-01-01

    Cytidine-5′-diphosphate choline (CDP-choline), as an important intermediate for major membrane phospholipids, may exert neuroprotective effects in various neurodegenerative disorders. This longitudinal proton magnetic resonance spectroscopy (1H-MRS) study aimed to examine whether a 4-week CDP-choline treatment could alter neurometabolite levels in patients with methamphetamine (MA) dependence and to investigate whether changes in neurometabolite levels would be associated with MA use. We hypothesized that the prefrontal levels of N-acetyl-aspartate (NAA), a neuronal marker, and choline-containing compound (Cho), which are related to membrane turnover, would increase with CDP-choline treatment in MA-dependent patients. We further hypothesized that this increase would correlate with the total number of negative urine results. Thirty-one treatment seekers with MA dependence were randomly assigned to receive CDP-choline (n=16) or placebo (n=15) for 4 weeks. Prefrontal NAA and Cho levels were examined using 1H-MRS before medication, and at 2 and 4 weeks after treatment. Generalized estimating equation regression analyses showed that the rate of change in prefrontal NAA (p=0.005) and Cho (p=0.03) levels were greater with CDP-choline treatment than with placebo. In the CDP-choline-treated patients, changes in prefrontal NAA levels were positively associated with the total number of negative urine results (p=0.03). Changes in the prefrontal Cho levels, however, were not associated with the total number of negative urine results. These preliminary findings suggest that CDP-choline treatment may exert potential neuroprotective effects directly or indirectly because of reductions in drug use by the MA-dependent patients. Further studies with a larger sample size of MA-dependent patients are warranted to confirm a long-term efficacy of CDP-choline in neuroprotection and abstinence. PMID:20043005

  3. Effect of chemical sympathectomy on the content of acetylcholine, choline and choline acetyltransferase activity in the cat spleen and iris.

    PubMed

    Consolo, S; Garattini, S; Ladinsky, H; Thoenen, H

    1972-02-01

    1. Acetylcholine and choline were measured in the spleens and irides of normal and 6-hydroxydopamine-treated cats. In addition, choline acetyltransferase activity was measured in the spleens.2. No acetylcholine or choline acetyltransferase activity were found in spleens of normal or treated cats. The choline content of normal spleens was 12.4 +/- 1.5 mug/g wet wt. (mean +/- S.E. of mean), which was not significantly altered by chemical sympathectomy.3. The acetylcholine and choline contents of the cat iris were 3.0 +/- 0.3 mug/g wet wt. and 7.7 +/- 0.9 mug/g wet wt., respectively. There was no difference in acetylcholine and choline concentrations between left and right or normal and sympathectomized irides.4. These results are discussed in relation to the question of a cholinergic link in post-ganglionic sympathetic transmission.

  4. Prenatal choline and the development of schizophrenia

    PubMed Central

    FREEDMAN, Robert; ROSS, Randal G.

    2015-01-01

    Background The primary prevention of illness at the population level, the ultimate aim of medicine, seems out of reach for schizophrenia. Schizophrenia has a strong genetic component, and its pathogenesis begins long before the emergence of psychosis, as early as fetal brain development. Cholinergic neurotransmission at nicotinic receptors is a pathophysiological mechanism related to one aspect of this genetic risk. Choline activates these nicotinic receptors during fetal brain development. Dietary supplementation of maternal choline thus emerges as a possible intervention in pregnancy to alter the earliest developmental course of the illness. Aim Review available literature on the relationship of choline supplementation or choline levels during pregnancy and fetal brain development. Methods A Medline search was used to identify studies assessing effects of choline in human fetal development. Studies of other prenatal risk factors for schizophrenia and the role of cholinergic neurotransmission in its pathophysiology were also identified. Results Dietary requirements for choline are high during pregnancy because of its several uses, including membrane biosynthesis, one-carbon metabolism, and cholinergic neurotransmission. Its ability to act directly at high concentrations as a nicotinic agonist is critical for normal brain circuit development. Dietary supplementation in the second and third trimesters with phosphatidyl-choline supports these functions and is associated generally with better fetal outcome. Improvement in inhibitory neuronal functions whose deficit is associated with schizophrenia and attention deficit disorder has been observed. Conclusion Prenatal dietary supplementation with phosphatidyl-choline and promotion of diets rich in choline-containing foods (meats, soybeans, and eggs) are possible interventions to promote fetal brain development and thereby decrease the risk of subsequent mental illnesses. The low risk and short (sixmonth) duration of the

  5. Plasma choline metabolites associate with metabolic stress among young overweight men in a genotype-specific manner

    PubMed Central

    Yan, J; Winter, L B; Burns-Whitmore, B; Vermeylen, F; Caudill, M A

    2012-01-01

    OBJECTIVES: We aimed to test the hypotheses that (i) plasma choline metabolites differ between normal (body mass index (BMI)<25 kg m−2) and overweight (BMI ⩾25 kg m−2) men, and (ii) an elevated BMI alters associations between plasma choline metabolites and indicators of metabolic stress. DESIGN: This was a cross-sectional study. A one-time fasting blood sample was obtained for measurements of the choline metabolites and metabolic stress indicators (that is, serum alanine aminotransferase (ALT), glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides and homocysteine), and for genotype determination. SUBJECTS: The analysis was conducted with 237 Mexican American men with a median age of 22 years. RESULTS: Compared with men with a normal BMI (n=98), those with an elevated BMI (n=139) had 6% lower (P=0.049) plasma betaine and an 11% lower (P=0.002) plasma betaine to choline ratio. Among men with an elevated BMI, plasma betaine and the plasma betaine to choline ratio positively associated (P⩽0.044) with a favorable serum cholesterol profile, and inversely associated (P=0.001) with serum ALT, a marker of liver dysfunction. The phosphatidylethanolamine N-methyltransferase (PEMT) 5465G→A (rs7946) genotype interacted (P⩽0.007) with the plasma betaine to choline ratio to modulate indicators of metabolic stress with stronger inverse associations observed among overweight men with the PEMT 5465GG genotype. CONCLUSIONS: Plasma choline metabolites predict metabolic stress among overweight men often in a genotype-specific manner. The diminished betaine among overweight men coupled with the inverse association between betaine and metabolic stress suggest that betaine supplementation may be effective in mitigating some of the metabolic insults arising from lipid overload. PMID:23169489

  6. Pre- and postnatal health: evidence of increased choline needs.

    PubMed

    Caudill, Marie A

    2010-08-01

    Choline, a micronutrient found in food, serves as the starting material for several important metabolites that play key roles in fetal development, particularly the brain. Although human beings' requirement for choline is unknown, an Adequate Intake level of 425 mg/day was established for women with upward adjustments to 450 and 550 mg/day during pregnancy and lactation, respectively. The importance of choline in human development is supported by observations that a human fetus receives a large supply of choline during gestation; pregnancy causes depletion of hepatic choline pools in rats consuming a normal diet; human neonates are born with blood levels that are three times higher than maternal blood concentrations; and large amounts of choline are present in human milk. The development of the central nervous system is particularly sensitive to choline availability with evidence of effects on neural tube closure and cognition. Existing data show that the majority of pregnant (and presumably lactating) women are not achieving the target intake levels and that certain common genetic variants may increase requirements for choline beyond current recommendations. Because choline is not found in most varieties of prenatal vitamins (or regular multivitamins), increased consumption of choline-rich foods may be needed to meet the high pre- and postnatal demands for choline. 2010 American Dietetic Association. Published by Elsevier Inc. All rights reserved.

  7. Is magnetic resonance spectroscopy capable of detecting metabolic abnormalities in neurofibromatosis type 1 that are not revealed in brain parenchyma of normal appearance?

    PubMed

    Rodrigues, Antonio Carlos Pondé; Ferraz-Filho, José Roberto Lopes; Torres, Ulysses S; da Rocha, Antônio José; Muniz, Marcos Pontes; Souza, Antônio Soares; Goloni-Bertollo, Eny Maria; Pavarino, Érika Cristina

    2015-03-01

    Results of magnetic resonance spectroscopy studies in normal-appearing brain and in non-neoplastic brain lesions in individuals with neurofibromatosis type 1 (NF1) have been discrepant. We used magnetic resonance spectroscopy to analyze the metabolic patterns in the basal ganglia of patients with NF1 and examine their correlation with focal hyperintense lesions in T2-weighted images (T2-weighted hyperintensities). We used magnetic resonance spectroscopy data of 42 individuals with NF1 (18 with and 24 without T2- weighted hyperintensities) and 25 controls matched for gender and age. A single-voxel technique was employed by manually placing a region of interest with a uniform size over a predetermined anatomical region including the globus pallidum and putamen (capsulolenticular region). We further analyzed the ratios of choline/creatine, N-acetyl aspartate (NAA)/creatine, and myoinositol/creatine metabolites and the occurrence of T2-weighted hyperintensities in these regions in individuals with NF1. There was a significant difference between the NF1 and control groups with regard to the mean values of myoinositol/creatine and choline/creatine, with higher metabolite values observed in the NF1 group (P < 0.001). Only the myoinositol/creatine ratio was able to discriminate between NF1 subgroups with and without T2-weighted hyperintensities. For the NAA/creatine ratio, there was no significant difference between the NF1 and the control groups. Magnetic resonance spectroscopy allows the characterization of tissue abnormalities not demonstrable in the structural images of individuals with NF1 through choline and myoinositol metabolite analysis. Yet the preserved NAA values argue against demyelination and axonal degeneration occurring in the region, suggesting instead a functional neuronal stability. Taken in association with the findings of lack of clinical manifestations and the known transient nature of T2-weighted hyperintensities in NF1 as demonstrated by other

  8. 21 CFR 582.5252 - Choline chloride.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1 § 582.5252 Choline chloride. (a) Product. Choline chloride. (b) Conditions of use. This...

  9. 21 CFR 582.5250 - Choline bitartrate.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1 § 582.5250 Choline bitartrate. (a) Product. Choline bitartrate. (b) Conditions of use. This...

  10. 21 CFR 582.5250 - Choline bitartrate.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1 § 582.5250 Choline bitartrate. (a) Product. Choline bitartrate. (b) Conditions of use. This...

  11. 21 CFR 582.5250 - Choline bitartrate.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1 § 582.5250 Choline bitartrate. (a) Product. Choline bitartrate. (b) Conditions of use. This...

  12. 21 CFR 582.5250 - Choline bitartrate.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1 § 582.5250 Choline bitartrate. (a) Product. Choline bitartrate. (b) Conditions of use. This...

  13. 21 CFR 582.5252 - Choline chloride.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1 § 582.5252 Choline chloride. (a) Product. Choline chloride. (b) Conditions of use. This...

  14. 21 CFR 582.5252 - Choline chloride.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1 § 582.5252 Choline chloride. (a) Product. Choline chloride. (b) Conditions of use. This...

  15. 21 CFR 582.5252 - Choline chloride.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1 § 582.5252 Choline chloride. (a) Product. Choline chloride. (b) Conditions of use. This...

  16. 21 CFR 582.5250 - Choline bitartrate.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1 § 582.5250 Choline bitartrate. (a) Product. Choline bitartrate. (b) Conditions of use. This...

  17. 21 CFR 582.5252 - Choline chloride.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... DRUGS, FEEDS, AND RELATED PRODUCTS SUBSTANCES GENERALLY RECOGNIZED AS SAFE Nutrients and/or Dietary Supplements 1 § 582.5252 Choline chloride. (a) Product. Choline chloride. (b) Conditions of use. This...

  18. 1H-MR spectroscopy and diffusion tensor imaging of normal-appearing temporal white matter in patients with nasopharyngeal carcinoma after irradiation: initial experience.

    PubMed

    Xiong, Wei Feng; Qiu, Shi Jun; Wang, Hong Zhuo; Lv, Xiao Fei

    2013-01-01

    To detect radiation-induced changes of temporal lobe normal-appearing white mater (NAWM) following radiation therapy (RT) for nasopharyngeal carcinoma (NPC). Seventy-five H(1)-MR spectroscopy and diffusion-tensor imaging (DTI) examinations were performed in 55 patients before and after receiving fractionated radiation therapy (total dose; 66-75GY). We divided the dataset into six groups, a pre-RT control group and five other groups based on time after completion of RT. N-acetylaspartic acid (NAA)/choline (Cho), NAA/creatine (Cr), Cho/Cr, mean diffusibility (MD), functional anisotropy (FA), radial diffusibility (λ(⊥)), and axial diffusibility (λ(||)) were calculated. NAA/Cho and NAA/Cr decreased and λ(⊥) increased significantly within 1 year after RT compared with pre-RT. After 1 year, NAA/Cho, NAA/Cr, and λ(⊥) were not significantly different from pre-RT. In all post-RT groups, FA decreased significantly. λ(||) decreased within 9 months after RT compared with pre-RT, but was not significantly different from pre-RT more than 9 months after RT. DTI and H(1)-MR spectroscopy can be used to detect early radiation-induced changes of temporal lobe NAWM following radiation therapy for NPC. Metabolic alterations and water diffusion characteristics of temporal lobe NAWM in patients with NPC after RT were dynamic and transient. Copyright © 2012 Wiley Periodicals, Inc.

  19. Towards a neurochemical profile of the amygdala using short-TE 1 H magnetic resonance spectroscopy at 3 T.

    PubMed

    Schubert, Florian; Kühn, Simone; Gallinat, Jürgen; Mekle, Ralf; Ittermann, Bernd

    2017-05-01

    The amygdala plays a key role in emotional learning and in the processing of emotions. As disturbed amygdala function has been linked to several psychiatric conditions, a knowledge of its biochemistry, especially neurotransmitter levels, is highly desirable. The spin echo full intensity acquired localized (SPECIAL) sequence, together with a transmit/receive coil, was used to perform very short-TE magnetic resonance spectroscopy at 3 T to determine the neurochemical profile in a spectroscopic voxel containing the amygdala in 21 healthy adult subjects. For spectral analysis, advanced data processing was applied in combination with a macromolecule baseline measured in the anterior cingulate for spectral fitting. The concentrations of total N-acetylaspartate, total creatine, total choline, myo-inositol and, for the first time, glutamate were quantified with high reliability (uncertainties far below 10%). For these metabolites, the inter-individual variability, reflected by the relative standard deviations for the cohort studied, varied between 12% (glutamate) and 22% (myo-inositol). Glutamine and glutathione could also be determined, albeit with lower precision. Retest on four subjects showed good reproducibility. The devised method allows the determination of metabolite concentrations in the amygdala voxel, including glutamate, provides an estimation of glutamine and glutathione, and may help in the study of disturbed amygdala metabolism in pathologies such as anxiety disorder, autism and major depression. Copyright © 2017 John Wiley & Sons, Ltd.

  20. Neurochemistry of Drug Action: Insights from Proton Magnetic Resonance Spectroscopic Imaging And Their Relevance to Addiction

    PubMed Central

    Licata, Stephanie C.; Renshaw, Perry F.

    2011-01-01

    Proton magnetic resonance spectroscopy (1H MRS) is a non-invasive imaging technique that permits measurement of particular compounds or metabolites within the tissue of interest. In the brain, 1H MRS provides a snapshot of the neurochemical environment within a defined volume of interest. A search of the literature demonstrates the widespread utility of this technique for characterizing tumors, tracking the progress of neurodegenerative disease, and for understanding the neurobiological basis of psychiatric disorders. As of relatively recently, 1H MRS has found its way into substance abuse research, and it is beginning to become recognized as a valuable complement in the brain imaging toolbox that also contains positron emission tomography (PET), single photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI). Drug abuse studies employing 1H MRS have identified a number biochemical changes in the brain. The most consistent alterations across drug class were reductions in N-acetylaspartate and elevations in myo-inositol, while changes in choline, creatine, and amino acid transmitters also were abundant. Together, the studies discussed herein provide evidence that drugs of abuse may have a profound impact on neuronal health, energy metabolism and maintenance, inflammatory processes, cell membrane turnover, and neurotransmission, and these biochemical changes may underlie the neuropathology within brain tissue that subsequently gives rise to the cognitive and behavioral impairments associated with drug addiction. PMID:20201852

  1. Reproducibility and reliability of short-TE whole-brain MR spectroscopic imaging of human brain at 3T.

    PubMed

    Ding, Xiao-Qi; Maudsley, Andrew A; Sabati, Mohammad; Sheriff, Sulaiman; Dellani, Paulo R; Lanfermann, Heinrich

    2015-03-01

    A feasibility study of an echo-planar spectroscopic imaging (EPSI) using a short echo time (TE) that trades off sensitivity, compared with other short-TE methods, to achieve whole brain coverage using inversion recovery and spatial oversampling to control lipid bleeding. Twenty subjects were scanned to examine intersubject variance. One subject was scanned five times to examine intrasubject reproducibility. Data were analyzed to determine coefficients of variance (COV) and intraclass correlation coefficient (ICC) for N-acetylaspartate (NAA), total creatine (tCr), total choline (tCho), glutamine/glutamate (Glx), and myo-inositol (mI). Regional metabolite concentrations were derived by using multi-voxel analysis based on lobar-level anatomic regions. For whole-brain mean values, the intrasubject COVs were 14%, 15%, and 20% for NAA, tCr, and tCho, respectively, and 31% for Glx and mI. The intersubject COVs were up to 6% higher. For regional distributions, the intrasubject COVs were ≤ 5% for NAA, tCr, and tCho; ≤ 9% for Glx; and ≤15% for mI, with about 6% higher intersubject COVs. The ICCs of 5 metabolites were ≥ 0.7, indicating the reliability of the measurements. The present EPSI method enables estimation of the whole-brain metabolite distributions, including Glx and mI with small voxel size, and a reasonable scan time and reproducibility. © 2014 Wiley Periodicals, Inc.

  2. Proton magnetic resonance spectroscopy (1H-MRS) reveals the presence of elevated myo-inositol in the occipital cortex of blind subjects.

    PubMed

    Bernabeu, Angela; Alfaro, Arantxa; García, Milagros; Fernández, Eduardo

    2009-10-01

    This paper is addressed to investigate whether proton magnetic resonance spectroscopy ((1)H-MRS) may provide the means to investigate changes associated to alterations of neural activity and sensory experience in the blind. We examined the relationships between different brain metabolite levels in 10 blind volunteers and 10 sighted subjects matched for age and gender. Adjusted levels of N-acetylaspartate (NAA), creatine (Cr), choline (Cho), glutamate/glutamine (Glx) and myo-inositol (mIno) in the occipital cortex region were quantified in the water-suppressed spectrum using the AMARES estimation algorithms. An unpaired two-tailed t-test was used to determine any significant difference in metabolite ratios. Our results show that none of the blind volunteers presented atrophy or any other MRI detectable degenerative change of the occipital cortex. The main finding was a significant increase of myo-inositol (mIno), a glial marker, in blind subjects compared to sighted controls. This simple sugar-like molecule can be found mainly within astrocytes, and cannot cross the blood-brain barrier. Therefore its increase could reflect glial proliferation or an increase in glial cell size. These results show that (1)H-MRS may help to understand the complex mechanisms involved in brain plasticity and suggest an active role of glial cells in the reorganization of the brain in response to visual deprivation.

  3. Effects of normal aging and SCN1A risk-gene expression on brain metabolites: evidence for an association between SCN1A and myo-inositol.

    PubMed

    Tunc-Skarka, Nuran; Meier, Sandra; Demirakca, Traute; Sack, Markus; Weber-Fahr, Wolfgang; Brusniak, Wencke; Wolf, Isabella; Matthäus, Franziska; Schulze, Thomas G; Diener, Carsten; Ende, Gabriele

    2014-02-01

    Previously reported MRS findings in the aging brain include lower N-acetylaspartate (NAA) and higher myo-inositol (mI), total creatine (Cr) and choline-containing compound (Cho) concentrations. Alterations in the sodium channel voltage gated type I, alpha subunit SCN1A variant rs10930201 have been reported to be associated with several neurological disorders with cognitive deficits. MRS studies in SCN1A-related diseases have reported striking differences in the mI concentrations between patients and controls. In a study on 'healthy aging', we investigated metabolite spectra in a sample of 83 healthy volunteers and determined their age dependence. We also investigated a potential link between SCN1A and mI. We observed a significantly negative association of NAA (p = 0.004) and significantly positive associations of mI (p ≤ 0.001), Cr (p ≤ 0.001) and Cho (p = 0.034) with age in frontal white matter. The linear association of Cho ends at the age of about 50 years and is followed by an inverted 'U'-shaped curve. Further, mI was higher in C allele carriers of the SCN1A variant rs10930201. Our results corroborated the age-related changes in metabolite concentrations, and found evidence for a link between SCN1A and frontal white matter mI in healthy subjects. Copyright © 2013 John Wiley & Sons, Ltd.

  4. Neurochemistry of drug action: insights from proton magnetic resonance spectroscopic imaging and their relevance to addiction.

    PubMed

    Licata, Stephanie C; Renshaw, Perry F

    2010-02-01

    Proton magnetic resonance spectroscopy ((1)H MRS) is a noninvasive imaging technique that permits measurement of particular compounds or metabolites within the tissue of interest. In the brain, (1)H MRS provides a snapshot of the neurochemical environment within a defined volume of interest. A search of the literature demonstrates the widespread utility of this technique for characterizing tumors, tracking the progress of neurodegenerative disease, and for understanding the neurobiological basis of psychiatric disorders. As of relatively recently, (1)H MRS has found its way into substance abuse research, and it is beginning to become recognized as a valuable complement in the brain imaging toolbox that also contains positron emission tomography, single-photon-emission computed tomography, and functional magnetic resonance imaging. Drug abuse studies using (1)H MRS have identified several biochemical changes in the brain. The most consistent alterations across drug class were reductions in N-acetylaspartate and elevations in myo-inositol, whereas changes in choline, creatine, and amino acid transmitters also were abundant. Together, the studies discussed herein provide evidence that drugs of abuse may have a profound effect on neuronal health, energy metabolism and maintenance, inflammatory processes, cell membrane turnover, and neurotransmission, and these biochemical changes may underlie the neuropathology within brain tissue that subsequently gives rise to the cognitive and behavioral impairments associated with drug addiction.

  5. Hippocampal metabolic dysfunction in juvenile myoclonic epilepsy: 3D multivoxel spectroscopy study.

    PubMed

    Ristić, Aleksandar J; Ostojić, Jelena; Kozić, Duško; Vojvodić, Nikola M; Popović, Ljubica M; Janković, Slavko; Baščarević, Vladimir; Sokić, Dragoslav V

    2011-06-15

    To investigate the metabolic differences in hippocampi of patients with juvenile myoclonic epilepsy (JME) and healthy controls using magnetic resonance spectroscopy (MRS). A 3D multivoxel SE 135 MRS study on 1.5 T scanner of both hippocampi was performed in 17 patients with JME and normal brain MRI and in 19 age and sex matched controls. Three dominant signals were measured: Choline (Cho), Creatine (tCr) and N-Acetylaspartate (NAA) and expressed as ratios of Cho:tCr, NAA:tCr, NAA:Cho and NAA:(Cho+tCr). Metabolite ratios in head, body and tail of each hippocampus in the JME group of patients were compared with ratios from corresponding structures in the control group. We found a significant difference in metabolite ratios of both hippocampi between the JME and the control groups. We detected significant differences of Cho:tCr in the head, NAA:tCr in the head, body and tail, NAA:Cho and NAA:(Cho+tCr) in the body and tail of the left hippocampus, and NAA:Cho and NAA:(Cho+tCr) in the body and tail of the right hippocampus. Although not previously recognized as a part of the epileptogenic network, our results suggest that the hippocampus, well recognized as a key player in focal epilepsies, may have a certain role in the pathogenesis of JME. Copyright © 2010. Published by Elsevier B.V.

  6. Multi-Vendor Implementation and Comparison of Volumetric Whole-Brain Echo-Planar MR Spectroscopic Imaging

    PubMed Central

    Sabati, Mohammad; Sheriff, Sulaiman; Gu, Meng; Wei, Juan; Zhu, Henry; Barker, Peter B.; Spielman, Daniel M.; Alger, Jeffry R.; Maudsley, Andrew A.

    2014-01-01

    Purpose To assess volumetric proton MR spectroscopic imaging of the human brain on multi-vendor MRI instruments. Methods Echo-planar spectroscopic imaging (EPSI) was developed on instruments from three manufacturers, with matched specifications and acquisition protocols that accounted for differences in sampling performance, RF power, and data formats. Inter-site reproducibility was evaluated for signal-normalized maps of N-acetylaspartate (NAA), Creatine (Cre) and Choline using phantom and human subject measurements. Comparative analyses included metrics for spectral quality, spatial coverage, and mean values in atlas-registered brain regions. Results Inter-site differences for phantom measurements were under 1.7% for individual metabolites and 0.2% for ratio measurements. Spatial uniformity ranged from 79% to 91%. The human studies found differences of mean values in the temporal lobe, but good agreement in other white-matter regions, with maximum differences relative to their mean of under 3.2%. For NAA/Cre, the maximum difference was 1.8%. In grey-matter a significant difference was observed for frontal lobe NAA. Primary causes of inter-site differences were attributed to shim quality, B0 drift, and accuracy of RF excitation. Correlation coefficients for measurements at each site were over 0.60, indicating good reliability. Conclusion A volumetric intensity-normalized MRSI acquisition can be implemented in a comparable manner across multi-vendor MR instruments. PMID:25354190

  7. Multivendor implementation and comparison of volumetric whole-brain echo-planar MR spectroscopic imaging.

    PubMed

    Sabati, Mohammad; Sheriff, Sulaiman; Gu, Meng; Wei, Juan; Zhu, Henry; Barker, Peter B; Spielman, Daniel M; Alger, Jeffry R; Maudsley, Andrew A

    2015-11-01

    To assess volumetric proton MR spectroscopic imaging (MRSI) of the human brain on multivendor MRI instruments. Echo-planar spectroscopic imaging was developed on instruments from three manufacturers, with matched specifications and acquisition protocols that accounted for differences in sampling performance, radiofrequency (RF) power, and data formats. Intersite reproducibility was evaluated for signal-normalized maps of N-acetylaspartate (NAA), creatine (Cre), and choline using phantom and human subject measurements. Comparative analyses included metrics for spectral quality, spatial coverage, and mean values in atlas-registered brain regions. Intersite differences for phantom measurements were less than 1.7% for individual metabolites and less than 0.2% for ratio measurements. Spatial uniformity ranged from 79% to 91%. The human studies found differences of mean values in the temporal lobe, but good agreement in other white matter regions, with maximum differences relative to their mean of under 3.2%. For NAA/Cre, the maximum difference was 1.8%. In gray matter, a significant difference was observed for frontal lobe NAA. Primary causes of intersite differences were attributed to shim quality, B0 drift, and accuracy of RF excitation. Correlation coefficients for measurements at each site were over 0.60, indicating good reliability. A volumetric intensity-normalized MRSI acquisition can be implemented in a comparable manner across multivendor MR instruments. © 2014 Wiley Periodicals, Inc.

  8. Relationship between opioid therapy, tissue-damaging procedures, and brain metabolites as measured by proton MRS in asphyxiated term neonates.

    PubMed

    Angeles, Danilyn M; Ashwal, Stephen; Wycliffe, Nathaniel D; Ebner, Charlotte; Fayard, Elba; Sowers, Lawrence; Holshouser, Barbara A

    2007-05-01

    To examine the effects of opioid and tissue-damaging procedures (TDPs) [i.e. procedures performed in the neonatal intensive care unit (NICU) known to result in pain, stress, and tissue damage] on brain metabolites, we reviewed the medical records of 28 asphyxiated term neonates (eight opioid-treated, 20 non-opioid treated) who had undergone magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (MRS) within the first month of life as well as eight newborns with no clinical findings of asphyxial injury. We found that lower creatine (Cr), myoinositol (Ins), and N-acetylaspartate (NAA)/choline (Cho) (p < or = 0.03) and higher Cho/Cr and glutamate/glutamine (Glx) Cr (p < or = 0.02) correlated with increased TDP incidence in the first 2 d of life (DOL). We also found that occipital gray matter (OGM) NAA/Cr was decreased (p = 0.03) and lactate (Lac) was present in a significantly higher amount (40%; p = 0.03) in non-opioid-treated neonates compared with opioid-treated neonates. Compared with controls, untreated neonates showed larger changes in more metabolites in basal ganglia (BG), thalami (TH), and OGM with greater significance than treated neonates. Our data suggest that TDPs affect spectral metabolites and that opioids do not cause harm in asphyxiated term neonates exposed to repetitive TDPs in the first 2-4 DOL and may provide a degree of neuroprotection.

  9. Neural metabolite changes in corpus striatum after rat multipotent mesenchymal stem cells transplanted in hemiparkinsonian rats by magnetic resonance spectroscopy.

    PubMed

    Fu, Wenyu; Zheng, Zhijuan; Zhuang, Wenxin; Chen, Dandan; Wang, Xiaocui; Sun, Xihe; Wang, Xin

    2013-12-01

    To investigate the biochemical changes in striatum after rat bone marrow mesenchymal stem cells (MSCs) were transplanted into hemiparkinsonian rats and to further confirm the therapeutic effects of rat MSCs for Parkinson's disease (PD). 5-bromo-2-deoxyuridine (BrdU)-labeled MSCs were transplanted into the corpus striatum of the 6-hydroxydopamine (6-OHDA)-injected side of six PD model rats. Before and 8 weeks after MSC transplantation, ethological changes in PD rats were assessed. The expression of tyrosine hydroxylase (TH) in substantia nigra (SN) and striatum were measured using immunohistochemical methods. The differentiation of MSCs was detected by double immunofluorescence techniques. The concentrations of neural metabolites of N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) were measured by ¹H-magnetic resonance spectroscopy (MRS). Relative concentrations of NAA/Cr and Cho/Cr were calculated. The behavior of PD rats in rotarod tests improved, and there were statistical differences in TH-positive cells in SN and TH-positive terminals in striatum after the transplantation of BrdU-labeled MSCs. Transplanted MSCs differentiated into MAP-2-positive neurons. Especially compared with pre-MSC transplantation, the neural metabolite NAA/Cr ratio of the 6-OHDA-injected side of the striatum increased (P < 0.05) and the Cho/Cr ratio decreased (P < 0.05). MSCs transplantation apparently improves neuronal function in the striatum of PD rats.

  10. Brain Metabolites in Autonomic Regulatory Insular Sites in Heart Failure

    PubMed Central

    Woo, Mary A.; Yadav, Santosh K.; Macey, Paul M.; Fonarow, Gregg C.; Harper, Ronald M.; Kumar, Rajesh

    2014-01-01

    Autonomic, pain, and neuropsychologic comorbidities appear in heart failure (HF), likely resulting from brain changes, indicated as loss of structural integrity and functional deficits. Among affected brain sites, the anterior insulae are prominent in serving major regulatory roles in many of the disrupted functions commonly seen in HF. Metabolite levels, including N-acetylaspartate (NAA), creatine (Cr), choline (Cho), and myo-inositol (MI), could indicate the nature of anterior insula tissue injury in HF. The study aim was to assess anterior insular metabolites to determine processes mediating autonomic, pain, and neuropsychologic disruptions in HF. We performed magnetic resonance spectroscopy in bilateral anterior insulae in 11 HF and 53 controls, using a 3.0-Tesla magnetic resonance imaging scanner. Peaks for NAA at 2.02ppm, Cr at 3.02ppm, Cho at 3.2ppm, and MI at 3.56ppm were assigned, peak areas calculated, and metabolites expressed as ratios, including NAA/Cr, Cho/Cr, and MI/Cr. HF patients showed significantly increased Cho/Cr ratios, indicative of glial proliferation or injury, on the left anterior insula, and reduced NAA/Cr levels, suggesting neuronal loss/dysfunction, on the right anterior insula over controls. No differences in MI/Cr ratios appeared between groups. Right anterior insular neuronal loss and left glial alterations may contribute to distorted autonomic, pain, and neuropsychologic functions found in HF. PMID:25248953

  11. Brain magnetic resonance spectroscopy in obsessive-compulsive disorder: the importance of considering subclinical symptoms of anxiety and depression.

    PubMed

    Bédard, Marie-Josée; Chantal, Sophie

    2011-04-30

    Brain metabolite concentrations have recently been assessed in different cerebral regions presumably targeted in patients with obsessive-compulsive disorder (OCD) using magnetic resonance spectroscopy (MRS). However, results have been divergent. Possible confounding variables, such as the cerebral localisation of investigated regions and metabolites considered, as well as subclinical symptoms of anxiety and depression, could have affected these MRS profiles. The main goal of this study was to assess MRS metabolite differences between 13 individuals with OCD and 12 matched healthy controls in seven brain regions potentially involved in OCD. The secondary objective was to assess the relationships between levels of anxiety and depression and brain metabolite concentrations. No difference was found for N-acetylaspartate, glutamate-glutamine, myo-inositol (mI) and choline relative to creatine (Cr) concentration in either the left or right orbitofrontal area, left or right median temporal lobe, left or right thalamus or the anterior cingulate cortex. A significant negative correlation between the mI/Cr in the left orbitofrontal area and the severity of OCD symptomatology was observed while subclinical anxiety and depression were closely related to brain metabolite ratios. Thus, these subclinical symptoms, commonly associated with OCD, should be considered in assessing brain metabolite concentrations and may be central to the comprehension of this disorder. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  12. Non-enzymatic cyclization of creatine ethyl ester to creatinine.

    PubMed

    Giese, Matthew W; Lecher, Carl S

    2009-10-16

    Creatine ethyl ester was incubated at 37 degrees C in both water and phosphate-buffered saline and the diagnostic methylene resonances in the (1)H NMR spectrum were used to identify the resultant products. It was found that mild aqueous conditions result in the cyclization of creatine ethyl ester to provide inactive creatinine as the exclusive product, and this transformation becomes nearly instantaneous as the pH approaches 7.4. This study demonstrates that mild non-enzymatic conditions are sufficient for the cyclization of creatine ethyl ester into creatinine, and together with previous results obtained under enzymatic conditions suggests that there are no physiological conditions that would result in the production of creatine. It is concluded that creatine ethyl ester is a pronutrient for creatinine rather than creatine under all physiological conditions encountered during transit through the various tissues, thus no ergogenic effect is to be expected from supplementation.

  13. Enzymatic cycling method using creatine kinase to measure creatine by real-time detection.

    PubMed

    Ueda, Shigeru; Sakasegawa, Shin-Ichi

    2016-08-01

    We have developed a novel enzymatic cycling method that uses creatine kinase (CK) to measure creatine. The method takes advantage of the reversibility of the CK reaction in which the forward (creatine phosphate forming) and reverse reactions are catalyzed in the presence of an excess amount of ATP and IDP, respectively. Real-time detection was accomplished using ADP-dependent glucokinase (ADP-GK) together with glucose-6-phosphate dehydrogenase. ADP, one of the cycling reaction products, was distinguished from IDP by using the nucleotide selectivity of the ADP-GK. The increasing level of ADP was measured from the level of reduced NADP at 340 nm. The method is appropriate for an assay that requires high sensitivity because the rate of increase in absorbance at 340 nm is proportional to the amount of CK present in the reaction mix. We reasoned that the method with CK in combination with creatinine amidohydrolase could be used to assay creatinine, an important marker of kidney function. Our results confirmed the quantitative capability of the assay. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Dysregulated choline metabolism in T-cell lymphoma: role of choline kinase-α and therapeutic targeting

    PubMed Central

    Xiong, J; Bian, J; Wang, L; Zhou, J-Y; Wang, Y; Zhao, Y; Wu, L-L; Hu, J-J; Li, B; Chen, S-J; Yan, C; Zhao, W-L

    2015-01-01

    Cancer cells have distinct metabolomic profile. Metabolic enzymes regulate key oncogenic signaling pathways and have an essential role on tumor progression. Here, serum metabolomic analysis was performed in 45 patients with T-cell lymphoma (TCL) and 50 healthy volunteers. The results showed that dysregulation of choline metabolism occurred in TCL and was related to tumor cell overexpression of choline kinase-α (Chokα). In T-lymphoma cells, pharmacological and molecular silencing of Chokα significantly decreased Ras-GTP activity, AKT and ERK phosphorylation and MYC oncoprotein expression, leading to restoration of choline metabolites and induction of tumor cell apoptosis/necropotosis. In a T-lymphoma xenograft murine model, Chokα inhibitor CK37 remarkably retarded tumor growth, suppressed Ras-AKT/ERK signaling, increased lysophosphatidylcholine levels and induced in situ cell apoptosis/necropotosis. Collectively, as a regulatory gene of aberrant choline metabolism, Chokα possessed oncogenic activity and could be a potential therapeutic target in TCL, as well as other hematological malignancies with interrupted Ras signaling pathways. PMID:25768400

  15. Evidence that the tri-cellular metabolism of N-acetylaspartate functions as the brain's "operating system": how NAA metabolism supports meaningful intercellular frequency-encoded communications.

    PubMed

    Baslow, Morris H

    2010-11-01

    N-acetylaspartate (NAA), an acetylated derivative of L-aspartate (Asp), and N-acetylaspartylglutamate (NAAG), a derivative of NAA and L-glutamate (Glu), are synthesized by neurons in brain. However, neurons cannot catabolize either of these substances, and so their metabolism requires the participation of two other cell types. Neurons release both NAA and NAAG to extra-cellular fluid (ECF) upon stimulation, where astrocytes, the target cells for NAAG, hydrolyze it releasing NAA back into ECF, and oligodendrocytes, the target cells for NAA, hydrolyze it releasing Asp to ECF for recycling to neurons. This sequence is unique as it is the only known amino acid metabolic cycle in brain that requires three cell types for its completion. The results of this cycling are two-fold. First, neuronal metabolic water is transported to ECF for its removal from brain. Second, the rate of neuronal activity is coupled with focal hyperemia, providing stimulated neurons with the energy required for transmission of meaningful frequency-encoded messages. In this paper, it is proposed that the tri-cellular metabolism of NAA functions as the "operating system" of the brain, and is essential for normal cognitive and motor activities. Evidence in support of this hypothesis is provided by the outcomes of two human inborn errors in NAA metabolism.

  16. Creatine supplementation and physical training in patients with COPD: A double blind, placebo-controlled study

    PubMed Central

    Faager, Gun; Söderlund, Karin; Sköld, Carl Magnus; Rundgren, Siw; Tollbäck, Anna; Jakobsson, Per

    2006-01-01

    Study objectives Patients with chronic obstructive pulmonary disease (COPD) have low exercise capacity and low content of high energetic phosphates in their skeletal muscles. The aim of the present study was to investigate whether creatine supplementation together with exercise training may increase physical performance compared with exercise training in patients with COPD. Design In a randomized, double-blind, placebo-controlled study, 23 patients with COPD (forced expiratory volume in one second [FEV1] < 70% of predicted) were randomized to oral creatine (n = 13) or placebo (n = 10) supplementation during an 8-week rehabilitation programme including exercise training. Physical performance was assessed by Endurance Shuttle Walking Test (ESWT), dyspnea and leg fatigue with Borg CR-10, quality of life with St George’s Respiratory Questionnaire (SGRQ). In addition, lung function test, artery blood gases, grip strength test, muscle strength and fatigue in knee extensors were measured. Results COPD patients receiving creatine supplementation increased their average walking time by 61% (ESWT) (p < 0.05) after the training period compared with 48% (p = 0.07) in the placebo group. Rated dyspnea directly after the ESWT decreased significantly from 7 to 5 (p < 0.05) in the creatine group. However, the difference between the groups was not statistically significant neither in walking time nor in rated dyspnea. Creatine supplementation did not increase the health related quality of life, lung function, artery blood gases, grip strength and knee extensor strength/fatigue. Conclusions Oral creatine supplementation in combination with exercise training showed no significant improvement in physical performance, measured as ESWT, in patients with COPD compared with exercise training alone. PMID:18044100

  17. Brain proton magnetic resonance spectroscopy for hepatic encephalopathy

    NASA Astrophysics Data System (ADS)

    Ong, Chin-Sing; McConnell, James R.; Chu, Wei-Kom

    1993-08-01

    Liver failure can induce gradations of encephalopathy from mild to stupor to deep coma. The objective of this study is to investigate and quantify the variation of biochemical compounds in the brain in patients with liver failure and encephalopathy, through the use of water- suppressed, localized in-vivo Proton Magnetic Resonance Spectroscopy (HMRS). The spectral parameters of the compounds quantitated are: N-Acetyl Aspartate (NAA) to Creatine (Cr) ratio, Choline (Cho) to Creatine ratio, Inositol (Ins) to Creatine ratio and Glutamine-Glutamate Amino Acid (AA) to Creatine ratio. The study group consisted of twelve patients with proven advanced chronic liver failure and symptoms of encephalopathy. Comparison has been done with results obtained from five normal subjects without any evidence of encephalopathy or liver diseases.

  18. Effect of chemical sympathectomy on the content of acetylcholine, choline and choline acetyltransferase activity in the cat spleen and iris

    PubMed Central

    Consolo, S.; Garattini, S.; Ladinsky, H.; Thoenen, H.

    1972-01-01

    1. Acetylcholine and choline were measured in the spleens and irides of normal and 6-hydroxydopamine-treated cats. In addition, choline acetyltransferase activity was measured in the spleens. 2. No acetylcholine or choline acetyltransferase activity were found in spleens of normal or treated cats. The choline content of normal spleens was 12·4 ± 1·5 μg/g wet wt. (mean ± S.E. of mean), which was not significantly altered by chemical sympathectomy. 3. The acetylcholine and choline contents of the cat iris were 3·0 ± 0·3 μg/g wet wt. and 7·7 ± 0·9 μg/g wet wt., respectively. There was no difference in acetylcholine and choline concentrations between left and right or normal and sympathectomized irides. 4. These results are discussed in relation to the question of a cholinergic link in post-ganglionic sympathetic transmission. PMID:4335730

  19. The role of autosuggestion in geriatric patients' quality of life: a study on psycho-neuro-endocrine-immunology pathway.

    PubMed

    Sari, Nina Kemala; Setiati, Siti; Taher, Akmal; Wiwie, Martina; Djauzi, Samsuridjal; Pandelaki, Jacub; Purba, Jan Sudir; Sadikin, Mohamad

    2017-10-01

    There has been no study conducted about the effect of autosuggestion on quality of life for geriatric patients. Our aim was to evaluate the efficacy of autosuggestion for geriatric patients' quality of life and its impact on psycho-neuro-endocrine-immune pathway. Sixty geriatric patients aged ≥60 years in a ward were randomly assigned to either receive autosuggestion or not. Autosuggestion was recorded in a tape to be heard daily for 30 days. Both groups received the standard medical therapy. Primary outcome was quality of life by COOP chart. Secondary outcomes were serum cortisol level, interleukin-2, interleukin-6, interferon-γ, and N-acetylaspartate/creatine ratio in limbic/paralimbic system by magnetic resonance spectroscopy. The study was single blinded due to the nature of the intervention studied. Out of 60 subjects, 51 finished the study. The autosuggestion group reported better scores than the control one for quality of life, COOP chart 1.95 vs. 2.22 (95% CI, p = 0.02). There were increments of serum cortisol (p = 0.03) and interleukin-6 in the autosuggestion group (p = 0.04). Interleukin-2, interferon-γ, and N-acetylaspartate/creatine ratio in prefrontal cortex showed a tendency to increase in the autosuggestion groups. Autosuggestion is associated with improvement of geriatrics' quality of life, serum cortisol level, and adaptive immunity. There is a better trend for neuroplasticity in prefrontal cortex in the autosuggestion group.

  20. Conductive choline transport by alveolar epithelial plasma membrane vesicles.

    PubMed

    Oelberg, D G; Xu, F

    1998-11-01

    Choline is an important substrate in alveolar epithelia for both surfactant production and cellular maintenance. The underlying mechanisms of uptake and sites of membrane transport remain uncertain. To test the hypothesis that choline transport occurs at the basolateral side of alveolar epithelia by both Na+-independent and -dependent mechanisms, plasma membrane vesicles were prepared from the apical and basolateral membranes of mature porcine type II pneumocytes. Choline+ transport was assayed by uptake of [3H]choline+ by enriched apical or basolateral vesicles. In the presence of imposed, inside-negative charge gradients, basolateral vesicles exhibited early overshoot of [3H]choline+ uptake unaffected by the presence or absence of external Na+ (541 +/- 53 vs 564 +/- 79 pmol/mg protein (NS)). High sensitivity to hemicholinium-3 was observed in the presence or absence of Na+. In the absence of inside-negative charge gradients, uptake was reduced 12-fold in the presence or absence of Na+, and external choline+ induced internal alkalization of acidified basolateral vesicles. Accumulative [3H]choline+ uptakes by apical vesicles in the presence or absence of inside-negative charge gradients and Na+ were insignificant. We conclude that predominant choline+ uptake by type II pneumocytes occurs at the basolateral membrane by Na+-independent, electrogenic choline+ conductance. The presence of electroneutral choline+/H+ exchange is suggested. Copyright 1998 Academic Press.

  1. Evidence for negative selection of gene variants that increase dependence on dietary choline in a Gambian cohort

    PubMed Central

    Silver, Matt J.; Corbin, Karen D.; Hellenthal, Garrett; da Costa, Kerry-Ann; Dominguez-Salas, Paula; Moore, Sophie E.; Owen, Jennifer; Prentice, Andrew M.; Hennig, Branwen J.; Zeisel, Steven H.

    2015-01-01

    Choline is an essential nutrient, and the amount needed in the diet is modulated by several factors. Given geographical differences in dietary choline intake and disparate frequencies of single-nucleotide polymorphisms (SNPs) in choline metabolism genes between ethnic groups, we tested the hypothesis that 3 SNPs that increase dependence on dietary choline would be under negative selection pressure in settings where choline intake is low: choline dehydrogenase (CHDH) rs12676, methylenetetrahydrofolate reductase 1 (MTHFD1) rs2236225, and phosphatidylethanolamine-N-methyltransferase (PEMT) rs12325817. Evidence of negative selection was assessed in 2 populations: one in The Gambia, West Africa, where there is historic evidence of a choline-poor diet, and the other in the United States, with a comparatively choline-rich diet. We used 2 independent methods, and confirmation of our hypothesis was sought via a comparison with SNP data from the Maasai, an East African population with a genetic background similar to that of Gambians but with a traditional diet that is higher in choline. Our results show that frequencies of SNPs known to increase dependence on dietary choline are significantly reduced in the low-choline setting of The Gambia. Our findings suggest that adequate intake levels of choline may have to be reevaluated in different ethnic groups and highlight a possible approach for identifying novel functional SNPs under the influence of dietary selective pressure.—Silver, M. J., Corbin, K. D., Hellenthal, G., da Costa, K.-A., Dominguez-Salas, P., Moore, S. E., Owen, J., Prentice, A. M., Hennig, B. J., Zeisel, S. H. Evidence for negative selection of gene variants that increase dependence on dietary choline in a Gambian cohort. PMID:25921832

  2. Spatial memory and hippocampal plasticity are differentially sensitive to the availability of choline in adulthood as a function of choline supply in utero

    PubMed Central

    Wong-Goodrich, Sarah J.E.; Glenn, Melissa J.; Mellott, Tiffany J.; Blusztajn, Jan K.; Meck, Warren H.; Williams, Christina L.

    2009-01-01

    Altered dietary choline availability early in life leads to persistent changes in spatial memory and hippocampal plasticity in adulthood. Developmental programming by early choline nutrition may determine the range of adult choline intake that is optimal for the types of neural plasticity involved in cognitive function. To test this, male Sprague-Dawley rats were exposed to a choline chloride deficient (DEF), sufficient (CON), or supplemented (SUP) diet during embryonic days 12-17 and then returned to a control diet (1.1 g choline chloride/kg). At 70 days of age, we found that DEF and SUP rats required fewer choices to locate 8 baited arms of a 12-arm radial maze than CON rats. When switched to a choline-deficient diet (0 g/kg), SUP rats showed impaired performance while CON and DEF rats were unaffected. In contrast, when switched to a choline-supplemented diet (5.0 g/kg), DEF rats' performance was significantly impaired while CON and SUP rats were less affected. These changes in performance were reversible when the rats were switched back to a control diet. In a second experiment, DEF, CON, and SUP rats were either maintained on a control diet, or the choline-supplemented diet. After 12 weeks, DEF rats were significantly impaired by choline supplementation on a matching-to-place water-maze task, which was also accompanied by a decrease in dentate cell proliferation in DEF rats only. IGF-1 levels were elevated by both prenatal and adult choline supplementation. Taken together, these findings suggest that the in utero availability of an essential nutrient, choline, causes differential behavioral and neuroplastic sensitivity to the adult choline supply. PMID:18778697

  3. Spatial memory and hippocampal plasticity are differentially sensitive to the availability of choline in adulthood as a function of choline supply in utero.

    PubMed

    Wong-Goodrich, Sarah J E; Glenn, Melissa J; Mellott, Tiffany J; Blusztajn, Jan K; Meck, Warren H; Williams, Christina L

    2008-10-27

    Altered dietary choline availability early in life leads to persistent changes in spatial memory and hippocampal plasticity in adulthood. Developmental programming by early choline nutrition may determine the range of adult choline intake that is optimal for the types of neural plasticity involved in cognitive function. To test this, male Sprague-Dawley rats were exposed to a choline chloride deficient (DEF), sufficient (CON), or supplemented (SUP) diet during embryonic days 12-17 and then returned to a control diet (1.1 g choline chloride/kg). At 70 days of age, we found that DEF and SUP rats required fewer choices to locate 8 baited arms of a 12-arm radial maze than CON rats. When switched to a choline-deficient diet (0 g/kg), SUP rats showed impaired performance while CON and DEF rats were unaffected. In contrast, when switched to a choline-supplemented diet (5.0 g/kg), DEF rats' performance was significantly impaired while CON and SUP rats were less affected. These changes in performance were reversible when the rats were switched back to a control diet. In a second experiment, DEF, CON, and SUP rats were either maintained on a control diet, or the choline-supplemented diet. After 12 weeks, DEF rats were significantly impaired by choline supplementation on a matching-to-place water-maze task, which was also accompanied by a decrease in dentate cell proliferation in DEF rats only. IGF-1 levels were elevated by both prenatal and adult choline supplementation. Taken together, these findings suggest that the in utero availability of an essential nutrient, choline, causes differential behavioral and neuroplastic sensitivity to the adult choline supply.

  4. Creatine supplementation and glycemic control: a systematic review.

    PubMed

    Pinto, Camila Lemos; Botelho, Patrícia Borges; Pimentel, Gustavo Duarte; Campos-Ferraz, Patrícia Lopes; Mota, João Felipe

    2016-09-01

    The focus of this review is the effects of creatine supplementation with or without exercise on glucose metabolism. A comprehensive examination of the past 16 years of study within the field provided a distillation of key data. Both in animal and human studies, creatine supplementation together with exercise training demonstrated greater beneficial effects on glucose metabolism; creatine supplementation itself demonstrated positive results in only a few of the studies. In the animal studies, the effects of creatine supplementation on glucose metabolism were even more distinct, and caution is needed in extrapolating these data to different species, especially to humans. Regarding human studies, considering the samples characteristics, the findings cannot be extrapolated to patients who have poorer glycemic control, are older, are on a different pharmacological treatment (e.g., exogenous insulin therapy) or are physically inactive. Thus, creatine supplementation is a possible nutritional therapy adjuvant with hypoglycemic effects, particularly when used in conjunction with exercise.

  5. Drug-induced parkinsonism in relation to choline-containing compounds measured by 1H-MR spectroscopy in putamen of chronically medicated patients with schizophrenia.

    PubMed

    Yamasue, Hidenori; Fukui, Tsunehiro; Fukuda, Rin; Kasai, Kiyoto; Iwanami, Akira; Kato, Nobumasa; Kato, Tadafumi

    2003-12-01

    Extrapyramidal side-effects (EPS), the most frequent and severe side-effects of antipsychotics, sometimes become irreversible and cause severe psychosocial disturbance in patients with schizophrenia. However, the neurobiological basis of EPS has not yet been elucidated. In this study, neurochemical correlates of EPS were examined by 1H-MR spectroscopy (1H-MRS). Sixteen medicated patients with schizophrenia and 15 age-, gender- and parental-socioeconomic-status-matched normal controls were examined using single-voxel 1H-MRS. Absolute concentrations of N-acetyl aspartate (NAA), choline-containing compounds (Cho), creatine/phosphocreatine, myo-inositol, and Glx (glutamate and glutamine) in the left putamen were evaluated. The patient group showed mild EPS and no significant metabolic abnormalities in this region. The more severe drug-induced parkinsonism assessed by the Simpson-Angus Scale, however, significantly correlated with the higher Cho concentration and tended to be correlated with the higher NAA concentration in the patient group. These results suggest a potential of 1H-MRS as a non-invasive monitoring method of neurobiological correlates of EPS associated with neuroleptic treatments in patients with schizophrenia.

  6. Creatine supplementation and oxidative stress in rat liver

    PubMed Central

    2013-01-01

    Background The objective of this study was to determine the effects of creatine supplementation on liver biomarkers of oxidative stress in exercise-trained rats. Methods Forty 90-day-old adult male Wistar rats were assigned to four groups for the eight-week experiment. Control group (C) rats received a balanced control diet; creatine control group (CCr) rats received a balanced diet supplemented with 2% creatine; trained group (T) rats received a balanced diet and intense exercise training equivalent to the maximal lactate steady state phase; and supplemented-trained (TCr) rats were given a balanced diet supplemented with 2% creatine and subjected to intense exercise training equivalent to the maximal lactate steady state phase. At the end of the experimental period, concentrations of creatine, hydrogen peroxide (H2O2) and thiobarbituric acid reactive substances (TBARS) were measured as well as the enzyme activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-GPx) and catalase (CAT). Liver tissue levels of reduced glutathione (GSH), oxidized glutathione (GSSG) and the GSH/GSSG ratio were also determined. Results Hepatic creatine levels were highest in the CCr and TCr groups with increased concentration of H2O2 observed in the T and TCr animal groups. SOD activity was decreased in the TCr group. GSH-GPx activity was increased in the T and TCr groups while CAT was elevated in the CCr and TCr groups. GSH, GGS and the GSH/GSSG ratio did not differ between all animal subsets. Conclusions Our results demonstrate that creatine supplementation acts in an additive manner to physical training to raise antioxidant enzymes in rat liver. However, because markers of liver oxidative stress were unchanged, this finding may also indicate that training-induced oxidative stress cannot be ameliorated by creatine supplementation. PMID:24325803

  7. Deanol acetamidobenzoate inhibits the blood-brain barrier transport of choline.

    PubMed

    Millington, W R; McCall, A L; Wurtman, R J

    1978-10-01

    Competition by deanol (dimethylaminoethanol) with choline for uptake from the bloodstream into the brain was demonstrated by simultaneous intracarotid administration of carbon 14-labeled choline with deanol (plus tritiated water and indium 113m, to calculate a brain uptake index) and by measuring the brain uptake of 14C-labeled choline mixed with sera from rats pretreated with deanol (300 or 500 mg/kg 8 or 30 minutes earlier). The inhibition constant for inhibition of choline uptake by deanol (159 micrograms) was actually lower than the Michaelis constant for choline itself (442 micrograms); hence, the affinity of the carrier mechanism for deanol is at least as great as it is for choline. Deanol administration also elevated blood choline levels; thus, the effect of the drug on brain choline (and acetylcholine) levels is the result of the increase it produces in blood choline and the suppression it causes in choline uptake. These findings may explain discrepant results from laboratories seeking increases in brain acetylcholine or clinical improvement in patients with tardive dyskinesia after deanol treatment.

  8. Neuroprotective Actions of Dietary Choline

    PubMed Central

    Blusztajn, Jan Krzysztof; Slack, Barbara E.; Mellott, Tiffany J.

    2017-01-01

    Choline is an essential nutrient for humans. It is a precursor of membrane phospholipids (e.g., phosphatidylcholine (PC)), the neurotransmitter acetylcholine, and via betaine, the methyl group donor S-adenosylmethionine. High choline intake during gestation and early postnatal development in rat and mouse models improves cognitive function in adulthood, prevents age-related memory decline, and protects the brain from the neuropathological changes associated with Alzheimer’s disease (AD), and neurological damage associated with epilepsy, fetal alcohol syndrome, and inherited conditions such as Down and Rett syndromes. These effects of choline are correlated with modifications in histone and DNA methylation in brain, and with alterations in the expression of genes that encode proteins important for learning and memory processing, suggesting a possible epigenomic mechanism of action. Dietary choline intake in the adult may also influence cognitive function via an effect on PC containing eicosapentaenoic and docosahexaenoic acids; polyunsaturated species of PC whose levels are reduced in brains from AD patients, and is associated with higher memory performance, and resistance to cognitive decline. PMID:28788094

  9. Neuroprotective Actions of Dietary Choline.

    PubMed

    Blusztajn, Jan Krzysztof; Slack, Barbara E; Mellott, Tiffany J

    2017-07-28

    Choline is an essential nutrient for humans. It is a precursor of membrane phospholipids (e.g., phosphatidylcholine (PC)), the neurotransmitter acetylcholine, and via betaine, the methyl group donor S -adenosylmethionine. High choline intake during gestation and early postnatal development in rat and mouse models improves cognitive function in adulthood, prevents age-related memory decline, and protects the brain from the neuropathological changes associated with Alzheimer's disease (AD), and neurological damage associated with epilepsy, fetal alcohol syndrome, and inherited conditions such as Down and Rett syndromes. These effects of choline are correlated with modifications in histone and DNA methylation in brain, and with alterations in the expression of genes that encode proteins important for learning and memory processing, suggesting a possible epigenomic mechanism of action. Dietary choline intake in the adult may also influence cognitive function via an effect on PC containing eicosapentaenoic and docosahexaenoic acids; polyunsaturated species of PC whose levels are reduced in brains from AD patients, and is associated with higher memory performance, and resistance to cognitive decline.

  10. Legionella bozemanae synthesizes phosphatidylcholine from exogenous choline.

    PubMed

    Palusinska-Szysz, Marta; Janczarek, Monika; Kalitynski, Rafal; Dawidowicz, Andrzej L; Russa, Ryszard

    2011-02-20

    The phospholipid class and fatty acid composition of Legionella bozemanae were determined using thin-layer chromatography, gas-liquid chromatography, and matrix-assisted laser desorption ionization-time of flight mass spectrometry. Phosphatidylcholine, phosphatidylethanolamine, and diphosphatidylglycerol were the predominant phospholipids, while phosphatidyl-N-monomethylethanolamine, phosphatidylglycerol, and phosphatidyl-N,N-dimethylethanolamine were present at low concentrations. With the use of the LC/MS technique, PC16:0/15:0, PC17:/15:0, and PE16:1/15:0 were shown to be the dominant phospholipid constituents, which may be taxonomically significant. Two independent phosphatidylcholine synthesis pathways (the three-step methylation and the one-step CDP-choline pathway) were present and functional in L. bozemanae. In the genome of L. bozemanae, genes encoding two potential phosphatidylcholine forming enzymes, phospholipid N-methyl transferase (PmtA) and phosphatidylcholine synthase (Pcs), homologous to L. longbeachae, L. drancourtii, and L. pneumophila pmtA and pcs genes were identified. Genes pmtA and pcs from L. bozemanae were sequenced and analyzed on nucleotide and amino acid levels. Bacteria grown on an artificial medium with labelled choline synthesized phosphatidylcholine predominantly via the phosphatidylcholine synthase pathway, which indicates that L. bozemanae phosphatidylcholine, similarly as in other bacteria associated with eukaryotes, is an important determinant of host-microbe interactions. Copyright © 2010 Elsevier GmbH. All rights reserved.

  11. Frontal Metabolite Concentration Deficits in Opiate Dependence Relate to Substance Use, Cognition, and Self-Regulation

    PubMed Central

    Murray, Donna E; Durazzo, Timothy C; Schmidt, Thomas P; Abé, Christoph; Guydish, Joseph; Meyerhoff, Dieter J

    2016-01-01

    Objective Proton magnetic resonance spectroscopy (1H MRS) in opiate dependence showed abnormalities in neuronal viability and glutamate concentration in the anterior cingulate cortex (ACC). Metabolite levels in dorsolateral prefrontal cortex (DLPFC) or orbitofrontal cortex (OFC) and their neuropsychological correlates have not been investigated in opiate dependence. Methods Single-volume proton MRS at 4 Tesla and neuropsychological testing were conducted in 21 opiate-dependent individuals (OD) on buprenorphine maintenance therapy. Results were compared to 28 controls (CON) and 35 alcohol-dependent individuals (ALC), commonly investigated treatment-seekers providing context for OD evaluation. Metabolite concentrations were measured from ACC, DLPFC, OFC and parieto-occipital cortical (POC) regions. Results Compared to CON, OD had lower concentrations of N-acetylaspartate (NAA), glutamate (Glu), creatine +phosphocreatine (Cr) and myo-Inositol (mI) in the DLPFC and lower NAA, Cr, and mI in the ACC. OD, ALC, and CON were equivalent on metabolite levels in the POC and γ-aminobutyric acid (GABA) concentration did not differ between groups in any region. In OD, prefrontal metabolite deficits in ACC Glu as well as DLPFC NAA and choline containing metabolites (Cho) correlated with poorer working memory, executive and visuospatial functioning; metabolite deficits in DLPFC Glu and ACC GABA and Cr correlated with substance use measures. In the OFC of OD, Glu and choline-containing metabolites were elevated and lower Cr concentration related to higher nonplanning impulsivity. Compared to 3 week abstinent ALC, OD had significant DLPFC metabolite deficits. Conclusion The anterior frontal metabolite profile of OD differed significantly from that of CON and ALC. The frontal lobe metabolite abnormalities in OD and their neuropsychological correlates may play a role in treatment outcome and could be explored as specific targets for improved OD treatment. PMID:27695638

  12. Monitoring interferon β treatment response with magnetic resonance spectroscopy in relapsing remitting multiple sclerosis.

    PubMed

    Yetkin, Mehmet Fatih; Mirza, Meral; Dönmez, Halil

    2016-09-01

    The aim of this study is to compare the white matter of multiple sclerosis (MS) patients with healthy controls and to monitor the response to the treatment with magnetic resonance spectroscopy (MRS).Fifteen healthy controls and 36 recently diagnosed MS patients never treated with interferon β were included in this study. In the patient group, MRS was performed before treatment, at 6th and 12th month after the initiation of treatment and once in control group. Patient group was divided into 3 interferon groups randomly. Physical examination findings were recorded as Expanded Disability Status Scale scores before treatment, at 6th and 12th month of interferon treatment.At the end of 1 year follow up, 26 of 36 patients completed the study. In patients' white matter lesions, N-acetylaspartate/creatine (NAA/Cr) ratios were lower than control group's white matters. NAA/Cr ratios were higher in control group's white matter than patient's normal appearing white matter but this difference was not statistically significant. There was no difference in choline/creatine (Cho/Cr) ratios between 2 groups. In follow-up period, NAA/Cr and Cho/Cr ratios obtained from patients' white matter lesions and normal appearing white matter did not change statistically.This study showed that in MS patients' white matters, especially in white matter lesions, neuron viability is reduced compared with healthy controls' normal white matter; and in the patients treated with interferon β NAA/Cr ratios remained stable. These stable levels of metabolite ratios in the patients who received interferon β therapy can be explained with either the shortness of the follow-up period post-treatment or may reflect a positive effect of the beta interferon therapy on the progress of MS.

  13. Randomized, double-blind, placebo-controlled clinical trial of choline supplementation in school-aged children with fetal alcohol spectrum disorders.

    PubMed

    Nguyen, Tanya T; Risbud, Rashmi D; Mattson, Sarah N; Chambers, Christina D; Thomas, Jennifer D

    2016-12-01

    Prenatal alcohol exposure results in a broad range of cognitive and behavioral impairments. Because of the long-lasting problems that are associated with fetal alcohol spectrum disorders (FASDs), the development of effective treatment programs is critical. Preclinical animal studies have shown that choline, which is an essential nutrient, can attenuate the severity of alcohol-related cognitive impairments. We aimed to translate preclinical findings to a clinical population to investigate whether choline supplementation can ameliorate the severity of memory, executive function, and attention deficits in children with FASDs. In the current study, which was a randomized, double-blind, placebo-controlled clinical trial, we explored the effectiveness of a choline intervention for children with FASDs who were aged 5-10 y. Fifty-five children with confirmed histories of heavy prenatal alcohol exposure were randomly assigned to either the choline (n = 29) or placebo (n = 26) treatment arms. Participants in the choline group received 625 mg choline/d for 6 wk, whereas subjects in the placebo group received an equivalent dose of an inactive placebo treatment. Primary outcomes, including the performance on neuropsychological measures of memory, executive function, and attention and hyperactivity, were assessed at baseline and postintervention. Compared with the placebo group, participants in the choline group did not differentially improve in cognitive performance in any domain. Treatment compliance and mean dietary choline intake were not predictive of treatment outcomes. Findings of the current study do not support that choline, administered at a dose of 625 mg/d for 6 wk, is an effective intervention for school-aged (5-10 y old) children with FASDs. This research provides important information about choline's therapeutic window. Combined with other studies of choline and nutritional interventions in this population, this study emphasizes a further need for the continued

  14. Choline Theft-An Inside Job.

    PubMed

    Mora-Ortiz, Marina; Claus, Sandrine Paule

    2017-09-13

    Choline is a crucial methyl donor necessary for epigenetic regulation. In this issue of Cell Host & Microbe, Romano et al. (2017) demonstrate that choline-utilizing gut bacteria compete with their host for this essential resource, calling for a systematic consideration of gut microbial composition for personalized diet recommendations. Copyright © 2017. Published by Elsevier Inc.

  15. Nonoisotopic Assay for the Presynaptic Choline Transporter Reveals Capacity for Allosteric Modulation of Choline Uptake

    PubMed Central

    2012-01-01

    Current therapies to enhance CNS cholinergic function rely primarily on extracellular acetylcholinesterase (AChE) inhibition, a pharmacotherapeutic strategy that produces dose-limiting side effects. The Na+-dependent, high-affinity choline transporter (CHT) is an unexplored target for cholinergic medication development. Although functional at the plasma membrane, CHT at steady-state is localized to synaptic vesicles such that vesicular fusion can support a biosynthetic response to neuronal excitation. To identify allosteric potentiators of CHT activity, we mapped endocytic sequences in the C-terminus of human CHT, identifying transporter mutants that exhibit significantly increased transport function. A stable HEK-293 cell line was generated from one of these mutants (CHT LV-AA) and used to establish a high-throughput screen (HTS) compatible assay based on the electrogenic nature of the transporter. We established that the addition of choline to these cells, at concentrations appropriate for high-affinity choline transport at presynaptic terminals, generates a hemicholinium-3 (HC-3)-sensitive, membrane depolarization that can be used for the screening of CHT inhibitors and activators. Using this assay, we discovered that staurosporine increased CHT LV-AA choline uptake activity, an effect mediated by a decrease in choline KM with no change in Vmax. As staurosporine did not change surface levels of CHT, nor inhibit HC-3 binding, we propose that its action is directly or indirectly allosteric in nature. Surprisingly, staurosporine reduced choline-induced membrane depolarization, suggesting that increased substrate coupling to ion gradients, arising at the expense of nonstoichiometric ion flow, accompanies a shift of CHT to a higher-affinity state. Our findings provide a new approach for the identification of CHT modulators that is compatible with high-throughput screening approaches and presents a novel model by which small molecules can enhance substrate flux

  16. Nonoisotopic assay for the presynaptic choline transporter reveals capacity for allosteric modulation of choline uptake.

    PubMed

    Ruggiero, Alicia M; Wright, Jane; Ferguson, Shawn M; Lewis, Michelle; Emerson, Katie S; Iwamoto, Hideki; Ivy, Michael T; Holmstrand, Ericka C; Ennis, Elizabeth A; Weaver, C David; Blakely, Randy D

    2012-10-17

    Current therapies to enhance CNS cholinergic function rely primarily on extracellular acetylcholinesterase (AChE) inhibition, a pharmacotherapeutic strategy that produces dose-limiting side effects. The Na(+)-dependent, high-affinity choline transporter (CHT) is an unexplored target for cholinergic medication development. Although functional at the plasma membrane, CHT at steady-state is localized to synaptic vesicles such that vesicular fusion can support a biosynthetic response to neuronal excitation. To identify allosteric potentiators of CHT activity, we mapped endocytic sequences in the C-terminus of human CHT, identifying transporter mutants that exhibit significantly increased transport function. A stable HEK-293 cell line was generated from one of these mutants (CHT LV-AA) and used to establish a high-throughput screen (HTS) compatible assay based on the electrogenic nature of the transporter. We established that the addition of choline to these cells, at concentrations appropriate for high-affinity choline transport at presynaptic terminals, generates a hemicholinium-3 (HC-3)-sensitive, membrane depolarization that can be used for the screening of CHT inhibitors and activators. Using this assay, we discovered that staurosporine increased CHT LV-AA choline uptake activity, an effect mediated by a decrease in choline K(M) with no change in V(max). As staurosporine did not change surface levels of CHT, nor inhibit HC-3 binding, we propose that its action is directly or indirectly allosteric in nature. Surprisingly, staurosporine reduced choline-induced membrane depolarization, suggesting that increased substrate coupling to ion gradients, arising at the expense of nonstoichiometric ion flow, accompanies a shift of CHT to a higher-affinity state. Our findings provide a new approach for the identification of CHT modulators that is compatible with high-throughput screening approaches and presents a novel model by which small molecules can enhance substrate flux

  17. Dichloroacetate treatment in Leigh syndrome caused by mitochondrial DNA mutation.

    PubMed

    Takanashi, J; Sugita, K; Tanabe, Y; Maemoto, T; Niimi, H

    1997-01-01

    Sodium dichloroacetate (DCA) was administered to a 1-year-old female case of Leigh syndrome, who had a T > G point mutation at nt 8993 of mitochondrial DNA. Her biochemical and clinical symptoms improved gradually, but proton magnetic resonance spectroscopy revealed reduction of the N-acetylaspartate/creatine ratio, and magnetic resonance imaging showed progressive cerebral atrophy despite the DCA therapy. These results suggest that DCA therapy may not retard the progress of the primary disease in Leigh syndrome, but produced clinical improvement most likely by reducing toxic accumulation of lactate.

  18. Diagnostic Performance of 11C-choline PET/CT and FDG PET/CT in Prostate Cancer.

    PubMed

    Kitajima, Kazuhiro; Yamamoto, Shingo; Odawara, Soichi; Kobayashi, Kaoru; Fujiwara, Masayuki; Kamikonya, Norihiko; Fukushima, Kazuhito; Nakanishi, Yukako; Hashimoto, Takahiko; Yamada, Yusuke; Suzuki, Toru; Kanematsu, Akihiro; Nojima, Michio; Yamakado, Koichiro

    2018-06-01

    We compared 11C-choline and FDG PET/CT scan findings for the staging and restaging of prostate cancer. Twenty Japanese prostate cancer patients underwent 11C-choline and FDG PET/CT before (n=5) or after (n=15) treatment. Using a five-point scale, we compared these scanning modalities regarding patient- and lesion-based diagnostic performance for local recurrence, untreated primary tumor, and lymph node and bony metastases. Of the 20 patients, documented local lesions, and node and bony metastases were present in 11 (55.0%), 9 (45.0%), and 13 (65.0%), respectively. The patient-based sensitivity/specificity/accuracy/area under the receiver-operating-characteristic curve (AUC) values for 11C-choline-PET/CT for diagnosing local lesions were 90.9% /100%/ 95.0% / 1.0, whereas those for FDG-PET/CT were 45.5% /100%/ 75.0% / 0.773. Those for 11C-choline-PET/CT for node metastasis were 88.9% /100%/ 95.0% / 0.944, and those for FDG-PET/CT were 44.4%/100%/75.0%/0.722. Those for 11C-choline-PET/CT for bone metastasis were 84.6%/100%/90.0%/0.951, and those for FDG-PET/CT were 76.9% /100%/ 85.0% / 0.962. The AUCs for local lesion and node metastasis differed significantly (p=0.0039, p=0.011, respectively). The lesion-based detection rates of 11C-choline compared to FDG PET/CT for local lesion, and node and bone metastases were 91.7% vs. 41.7%, 92.0% vs. 32.0%, and 94.8% vs. 83.0% (p=0.041, p=0.0030, p<0.0001), respectively. 11C-choline-PET/CT is more useful for the staging and restaging of prostate cancer than FDG-PET/CT in Japanese men.

  19. Simultaneous targeted analysis of trimethylamine-N-oxide, choline, betaine, and carnitine by high performance liquid chromatography tandem mass spectrometry.

    PubMed

    Liu, Jia; Zhao, Mingming; Zhou, Juntuo; Liu, Changjie; Zheng, Lemin; Yin, Yuxin

    2016-11-01

    Trimethylamine-N-oxide (TMAO) is a metabolite generated from choline, betaine and carnitine in a gut microbiota-dependent way. This molecule is associated with development of atherosclerosis and cardiovascular events. A sensitive liquid chromatographic electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) has been developed and validated for the simultaneous determination of TMAO related molecules including TMAO, betaine, choline, and carnitine in mouse plasma. Analytes are extracted after protein precipitation by methanol and subjected to LC-ESI-MS/MS without preliminary derivatization. Separation of analytes was achieved on an amide column with acetonitrile-water as the mobile phase. This method has been fully validated in this study in terms of selectivity, linearity, sensitivity, precision, accuracy, and carryover effect, and the stability of the analyte under various conditions has been confirmed. This developed method has successfully been applied to plasma samples of our mouse model. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Fine-tuning of choline metabolism is important for pneumococcal colonization.

    PubMed

    Johnston, Calum; Hauser, Christoph; Hermans, Peter W M; Martin, Bernard; Polard, Patrice; Bootsma, Hester J; Claverys, Jean-Pierre

    2016-06-01

    The human pathogen Streptococcus pneumoniae (the pneumococcus) is rare in having a strict requirement for the amino alcohol choline, which decorates pneumococcal teichoic acids. This process relies on the lic locus, containing the lic1 and lic2 operons. These operons produce eight proteins that import and metabolize choline, generate teichoic acid precursors and decorate these with choline. Three promoters control expression of lic operons, with Plic1P1 and Plic1P2 controlling lic1 and Plic2 controlling lic2. To investigate the importance of lic regulation for pneumococci, we assayed the activity of transcriptional fusions of the three lic promoters to the luciferase reporter gene. Plic1P1 , whose activity depends on the response regulator CiaR, responded to fluctuations in extracellular choline, with activity increasing greatly upon choline depletion. We uncovered a complex regulatory mechanism controlling Plic1P1 , involving activity driven by CiaR, repression by putative repressor LicR in the presence of choline, and derepression upon choline depletion mediated by LicC, a choline metabolism enzyme. Finally, the ability to regulate Plic1P1 in response to choline was important for pneumococcal colonization. We suggest that derepression of Plic1P1 upon choline depletion maximizing choline internalization constitutes an adaptive response mechanism allowing pneumococci to optimize growth and survival in environments where choline is scarce. © 2016 John Wiley & Sons Ltd.

  1. Effect of dietary choline levels on growth performance, lipid deposition and metabolism in juvenile yellow catfish Pelteobagrus fulvidraco.

    PubMed

    Luo, Zhi; Wei, Chuan-Chuan; Ye, Han-Mei; Zhao, Hai-Ping; Song, Yu-Feng; Wu, Kun

    2016-12-01

    The present experiment was conducted to determine the effect and mechanism of dietary choline levels on growth performance and lipid deposition of yellow catfish Pelteobagrus fulvidraco. Dietary choline was included at three levels of 239.2 (control (without extra choline addition), 1156.4 and 2273.6mg choline per kg diet, respectively) and fed to yellow catfish (mean initial weight: 3.45±0.02g mean±standard errors of mean (SEM)) for 8weeks. Fish fed the diet containing 1156.4mgkg -1 choline showed the higher weight gain (WG), specific growth rate (SGR) and feed intake (FI), but the lower feed conversion rate (FCR), than those in control and highest choline group. Hepatosomatic index (HSI) and hepatic lipid content declined with increasing dietary choline levels. Muscle lipid content was the lowest for fish fed adequate choline diets and showed no significant difference between other two groups. Choline contents in liver and muscle increased with increasing dietary choline levels. Dietary choline levels significantly influenced mRNA levels of genes involved in lipid homeostasis in muscle and liver, such as CTP:phosphocholine cytidylyltransferase a (CCTa), phosphatidylethanolamine N-methyl-transferase (PEMT), microsomal triglyceride transfer protein (MTP), apolipoprotein b (APOBb), apolipoprotein E (ApoE) and lipoprotein lipase (LPL), and effects of dietary choline levels on lipid deposition and metabolism were tissue-specific. Different responses of these genes at the mRNA levels partially explained the profiles of lipid deposition in liver and muscle for fish fed different choline diets. To our knowledge, this is the first to explore the effect of dietary choline level on mRNA expression of these genes, which provides new insights into choline nutrition in fish. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Concentrations of choline-containing compounds and betaine in common foods.

    PubMed

    Zeisel, Steven H; Mar, Mei-Heng; Howe, Juliette C; Holden, Joanne M

    2003-05-01

    Choline is important for normal membrane function, acetylcholine synthesis and methyl group metabolism; the choline requirement for humans is 550 mg/d for men (Adequate Intake). Betaine, a choline derivative, is important because of its role in the donation of methyl groups to homocysteine to form methionine. In tissues and foods, there are multiple choline compounds that contribute to total choline concentration (choline, glycerophosphocholine, phosphocholine, phosphatidylcholine and sphingomyelin). In this study, we collected representative food samples and analyzed the choline concentration of 145 common foods using liquid chromatography-mass spectrometry. Foods with the highest total choline concentration (mg/100 g) were: beef liver (418), chicken liver (290), eggs (251), wheat germ (152), bacon (125), dried soybeans (116) and pork (103). The foods with the highest betaine concentration (mg/100 g) were: wheat bran (1339), wheat germ (1241), spinach (645), pretzels (237), shrimp (218) and wheat bread (201). A number of epidemiologic studies have examined the relationship between dietary folic acid and cancer or heart disease. It may be helpful to also consider choline intake as a confounding factor because folate and choline methyl donation can be interchangeable.

  3. Longitudinal 1H MR spectroscopy of rat forebrain from infancy to adulthood reveals adolescence as a distinctive phase of neurometabolite development

    PubMed Central

    Morgan, Jonathan J.; Kleven, Gale A.; Tulbert, Christina D.; Olson, John; Horita, David A.; Ronca, April E.

    2013-01-01

    The present study represents the first longitudinal, within-subject 1H MRS investigation of the developing rat brain spanning infancy, adolescence, and early adulthood. We obtained neurometabolite profiles from a voxel located in a central location of the forebrain, centered on the striatum, with smaller contributions for cortex, thalamus, and hypothalamus, on postnatal days 7, 35, and 60. Water-scaled metabolite signals were corrected for T1 effects and quantified using the automated processing software LCModel, yielding molal concentrations. Our findings indicate age-related concentration changes in N-acetylaspartate + N-acetylaspartylglutamate, myo-inositol, glutamate + glutamine, taurine, creatine + phosphocreatine, and glycerophosphocholine + phosphocholine. Using a repeated measures design and analysis, we identified significant neurodevelopment change across all three developmental ages and identified adolescence as a distinctive phase in normative neurometabolic brain development. Between postnatal days 35 and 60, changes were observed in concentrations of N-acetylaspartate + N-acetylaspartylglutamate, glutamate + glutamine, and glycerophosphocholine + phosphocholine observed between postnatal days 35 and 60. Our data replicate past studies of early neurometabolite development and, for the first time, link maturational profiles in the same subjects across infancy, adolescence, and adulthood. PMID:23322706

  4. Legionella dumoffii Utilizes Exogenous Choline for Phosphatidylcholine Synthesis

    PubMed Central

    Palusinska-Szysz, Marta; Szuster-Ciesielska, Agnieszka; Kania, Magdalena; Janczarek, Monika; Chmiel, Elżbieta; Danikiewicz, Witold

    2014-01-01

    Phosphatidycholine (PC) is the major membrane-forming phospholipid in eukaryotes but it has been found in only a limited number of prokaryotes. Bacteria synthesize PC via the phospholipid N-methylation pathway (Pmt) or via the phosphatidylcholine synthase pathway (Pcs) or both. Here, we demonstrated that Legionella dumoffii has the ability to utilize exogenous choline for phosphatidylcholine (PC) synthesis when bacteria grow in the presence of choline. The Pcs seems to be a primary pathway for synthesis of this phospholipid in L. dumoffii. Structurally different PC species were distributed in the outer and inner membranes. As shown by the LC/ESI-MS analyses, PC15:0/15:0, PC16:0/15:0, and PC17:0/17:1 were identified in the outer membrane and PC14:0/16:0, PC16:0/17:1, and PC20:0/15:0 in the inner membrane. L. dumoffii pcsA gene encoding phosphatidylcholine synthase revealed the highest sequence identity to pcsA of L. bozemanae (82%) and L. longbeachae (81%) and lower identity to pcsA of L. drancourtii (78%) and L. pneumophila (71%). The level of TNF-α in THP1-differentiated cells induced by live and temperature-killed L. dumoffii cultured on a medium supplemented with choline was assessed. Live L. dumoffii bacteria cultured on the choline-supplemented medium induced TNF-α three-fold less efficiently than cells grown on the non-supplemented medium. There is an evident effect of PC modification, which impairs the macrophage inflammatory response. PMID:24821544

  5. Stable isotope dilution microquantification of creatine metabolites in plasma, whole blood and dried blood spots for pharmacological studies in mouse models of creatine deficiency.

    PubMed

    Tran, C; Yazdanpanah, M; Kyriakopoulou, L; Levandovskiy, V; Zahid, H; Naufer, A; Isbrandt, D; Schulze, A

    2014-09-25

    To develop an accurate stable isotope dilution assay for simultaneous quantification of creatine metabolites ornithine, arginine, creatine, creatinine, and guanidinoacetate in very small blood sample volumes to study creatine metabolism in mice. Liquid-chromatography (C18) tandem mass spectrometry with butylation was performed in positive ionization mode. Stable isotope dilution assay with external calibration was applied to three different specimen types, plasma, whole blood and dried blood spot (DBS). Analytical separation, sensitivity, accuracy, and linearity of the assay were adequate. The stable isotope dilution assay in plasma revealed no significant bias to gold standard methods for the respective analytes. Compared to plasma, we observed an overestimate of creatine and creatinine (2- to 5-fold and 1.2- to 2-fold, respectively) in whole-blood and DBS, and an underestimate of arginine (2.5-fold) in DBS. Validation of the assay in mouse models of creatine deficiency revealed plasma creatine metabolite pattern in good accordance with those observed in human GAMT and AGAT deficiency. Single dose intraperitoneal application of ornithine in wild-type mice lead to fast ornithine uptake (Tmax ≤ 10 min) and elimination (T1/2=24 min), and a decline of guanidinoacetate. The assay is fast and reliable to study creatine metabolism and pharmacokinetics in mouse models of creatine deficiency. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Creatine pretreatment protects cortical axons from energy depletion in vitro

    PubMed Central

    Shen, Hua; Goldberg, Mark P.

    2012-01-01

    Creatine is a natural nitrogenous guanidino compound involved in bioenergy metabolism. Although creatine has been shown to protect neurons of the central nervous system (CNS) from experimental hypoxia/ischemia, it remains unclear if creatine may also protect CNS axons, and if the potential axonal protection depends on glial cells. To evaluate the direct impact of creatine on CNS axons, cortical axons were cultured in a separate compartment from their somas and proximal neurites using a modified two-compartment culture device. Axons in the axon compartment were subjected to acute energy depletion, an in vitro model of white matter ischemia, by exposure to 6 mM sodium azide for 30 min in the absence of glucose and pyruvate. Energy depletion reduced axonal ATP by 65%, depolarized axonal resting potential, and damaged 75% of axons. Application of creatine (10 mM) to both compartments of the culture at 24 h prior to energy depletion significantly reduced axonal damage by 50%. In line with the role of creatine in the bioenergy metabolism, this application also alleviated the axonal ATP loss and depolarization. Inhibition of axonal depolarization by blocking sodium influx with tetrodotoxin also effectively reduced the axonal damage caused by energy depletion. Further study revealed that the creatine effect was independent of glial cells, as axonal protection was sustained even when creatine was applied only to the axon compartment (free from somas and glial cells) for as little as 2 h. In contrast, application of creatine after energy depletion did not protect axons. The data provide the first evidence that creatine pretreatment may directly protect CNS axons from energy deficiency. PMID:22521466

  7. Hepatotoxicity and endothelial dysfunction induced by high choline diet and the protective effects of phloretin in mice.

    PubMed

    Ren, Daoyuan; Liu, Yafei; Zhao, Yan; Yang, Xingbin

    2016-08-01

    The involvement of choline and its metabolite trimethylamine-N-oxide (TMAO) in endothelial dysfunction and atherosclerosis has been repeatedly confirmed. Phloretin, a dihydrochalcone flavonoid usually present in apples, possesses a variety of biological activities including vascular nutrition. This study was designed to investigate whether phloretin could alleviate or prevent high choline-induced vascular endothelial dysfunction and liver injury in mice. Mice were provided with 3% high choline water and given phloretin orally daily for 10 weeks. The high choline-treated mice showed the significant dyslipidemia and hyperglycemia with the impaired liver and vascular endothelium (p < 0.01). Administration of phloretin at 200 and 400 mg/kg bw significantly reduced the choline-induced elevation of serum TC, TG, LDL-C, AST, ALT, ET-1 and TXA2 (p < 0.01), and markedly antagonized the choline-induced decrease of serum PGI2, HDL-C and NO levels. Furthermore, phloretin elevated hepatic SOD and GSH-Px activities and decreased hepatic MDA levels of the mice exposed to high choline water. Moreover, histopathological test with the H&E and Oil Red O staining of liver sections confirmed the high choline diet-caused liver steatosis and the hepatoprotective effect of phloretin. These findings suggest that high choline causes oxidative damage, and phloretin alleviate vascular endothelial dysfunction and liver injury. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Creatine Enhances Mitochondrial-Mediated Oligodendrocyte Survival After Demyelinating Injury.

    PubMed

    Chamberlain, Kelly A; Chapey, Kristen S; Nanescu, Sonia E; Huang, Jeffrey K

    2017-02-08

    Chronic oligodendrocyte loss, which occurs in the demyelinating disorder multiple sclerosis (MS), contributes to axonal dysfunction and neurodegeneration. Current therapies are able to reduce MS severity, but do not prevent transition into the progressive phase of the disease, which is characterized by chronic neurodegeneration. Therefore, pharmacological compounds that promote oligodendrocyte survival could be beneficial for neuroprotection in MS. Here, we investigated the role of creatine, an organic acid involved in adenosine triphosphate (ATP) buffering, in oligodendrocyte function. We found that creatine increased mitochondrial ATP production directly in oligodendrocyte lineage cell cultures and exerted robust protection on oligodendrocytes by preventing cell death in both naive and lipopolysaccharide-treated mixed glia. Moreover, lysolecithin-mediated demyelination in mice deficient in the creatine-synthesizing enzyme guanidinoacetate-methyltransferase ( Gamt ) did not affect oligodendrocyte precursor cell recruitment, but resulted in exacerbated apoptosis of regenerated oligodendrocytes in central nervous system (CNS) lesions. Remarkably, creatine administration into Gamt -deficient and wild-type mice with demyelinating injury reduced oligodendrocyte apoptosis, thereby increasing oligodendrocyte density and myelin basic protein staining in CNS lesions. We found that creatine did not affect the recruitment of macrophages/microglia into lesions, suggesting that creatine affects oligodendrocyte survival independently of inflammation. Together, our results demonstrate a novel function for creatine in promoting oligodendrocyte viability during CNS remyelination. SIGNIFICANCE STATEMENT We report that creatine enhances oligodendrocyte mitochondrial function and protects against caspase-dependent oligodendrocyte apoptosis during CNS remyelination. This work has important implications for the development of therapeutic targets for diseases characterized by

  9. Creatine Enhances Mitochondrial-Mediated Oligodendrocyte Survival After Demyelinating Injury

    PubMed Central

    Nanescu, Sonia E.

    2017-01-01

    Chronic oligodendrocyte loss, which occurs in the demyelinating disorder multiple sclerosis (MS), contributes to axonal dysfunction and neurodegeneration. Current therapies are able to reduce MS severity, but do not prevent transition into the progressive phase of the disease, which is characterized by chronic neurodegeneration. Therefore, pharmacological compounds that promote oligodendrocyte survival could be beneficial for neuroprotection in MS. Here, we investigated the role of creatine, an organic acid involved in adenosine triphosphate (ATP) buffering, in oligodendrocyte function. We found that creatine increased mitochondrial ATP production directly in oligodendrocyte lineage cell cultures and exerted robust protection on oligodendrocytes by preventing cell death in both naive and lipopolysaccharide-treated mixed glia. Moreover, lysolecithin-mediated demyelination in mice deficient in the creatine-synthesizing enzyme guanidinoacetate-methyltransferase (Gamt) did not affect oligodendrocyte precursor cell recruitment, but resulted in exacerbated apoptosis of regenerated oligodendrocytes in central nervous system (CNS) lesions. Remarkably, creatine administration into Gamt-deficient and wild-type mice with demyelinating injury reduced oligodendrocyte apoptosis, thereby increasing oligodendrocyte density and myelin basic protein staining in CNS lesions. We found that creatine did not affect the recruitment of macrophages/microglia into lesions, suggesting that creatine affects oligodendrocyte survival independently of inflammation. Together, our results demonstrate a novel function for creatine in promoting oligodendrocyte viability during CNS remyelination. SIGNIFICANCE STATEMENT We report that creatine enhances oligodendrocyte mitochondrial function and protects against caspase-dependent oligodendrocyte apoptosis during CNS remyelination. This work has important implications for the development of therapeutic targets for diseases characterized by

  10. Basolateral choline transport in isolated rabbit renal proximal tubules.

    PubMed

    Dantzler, W H; Evans, K K; Wright, S H

    1998-11-01

    Choline can undergo both net secretion and net reabsorption by renal proximal tubules, but at physiological plasma levels net reabsorption occurs. During this process, choline enters the cells at the luminal side down an electrochemical gradient via a specific transporter with a high affinity for choline. It appeared likely that choline was then transported out of the cells against an electrochemical gradient at the basolateral membrane by countertransport for another organic cation. This possibility was examined by studying net transepithelial reabsorption and basolateral uptake and efflux of [14C]choline in isolated S2 segments of rabbit renal proximal tubules. Basolateral uptake, which was inhibited by other organic cations such as tetraethylammonium (TEA), appeared to occur by the standard organic cation transport pathway. However, the addition of TEA to the bathing medium not only failed to trans-stimulate net transepithelial reabsorption and basolateral efflux of [14C]choline but it actually inhibited transepithelial reabsorption by @60%. The results do not support the presence of a countertransport step for choline against an electrochemical gradient at the basolateral membrane. Instead, they suggest that choline crosses this membrane by some form of carrier-mediated diffusion even during the reabsorptive process.

  11. Effects of creatine supplementation on biomarkers of hepatic and renal function in young trained rats.

    PubMed

    Souza, William Marciel; Heck, Thiago Gomes; Wronski, Evanio Castor; Ulbrich, Anderson Zampier; Boff, Everton

    2013-11-01

    Creatine supplementation has been widely used by athletes and young physical exercise practioneers in order of increasing muscle mass and enhancing athletic performance, but their use/overuse may represent a health risk on hepatic and renal impaired function. In this study, we evaluated the effects of 40 days of oral creatine supplementation on hepatic and renal function biomarkers in a young animal model. Wistar rats (5 weeks old) were divided in five groups (n = 7): control (CONTR), oral creatine supplementation (CREAT), moderate exercise training (EXERC), moderate exercise training plus oral creatine supplementation (EXERC + CREAT) and pathological group (positive control for liver and kidney injury) by the administration of rifampicin (RIFAMPICIN). Exercise groups were submitted to 60 min/day of swimming exercise session with a 4% of body weight workload for six weeks. The EXERC + CREAT showed the higher body weight at the end of the training protocol. The CREAT and EXERC + CREAT group showed an increase in hepatic (Aspartate transaminase and gamma-glutamyl transpeptidase) and renal (urea and creatinine) biomarkers levels (p < 0.05). Our study showed that the oral creatine supplementation promoted hepatic and renal function challenge in young rats submitted to moderate exercise training.

  12. Creatine supplementation with specific view to exercise/sports performance: an update

    PubMed Central

    2012-01-01

    Creatine is one of the most popular and widely researched natural supplements. The majority of studies have focused on the effects of creatine monohydrate on performance and health; however, many other forms of creatine exist and are commercially available in the sports nutrition/supplement market. Regardless of the form, supplementation with creatine has regularly shown to increase strength, fat free mass, and muscle morphology with concurrent heavy resistance training more than resistance training alone. Creatine may be of benefit in other modes of exercise such as high-intensity sprints or endurance training. However, it appears that the effects of creatine diminish as the length of time spent exercising increases. Even though not all individuals respond similarly to creatine supplementation, it is generally accepted that its supplementation increases creatine storage and promotes a faster regeneration of adenosine triphosphate between high intensity exercises. These improved outcomes will increase performance and promote greater training adaptations. More recent research suggests that creatine supplementation in amounts of 0.1 g/kg of body weight combined with resistance training improves training adaptations at a cellular and sub-cellular level. Finally, although presently ingesting creatine as an oral supplement is considered safe and ethical, the perception of safety cannot be guaranteed, especially when administered for long period of time to different populations (athletes, sedentary, patient, active, young or elderly). PMID:22817979

  13. Effects of Choline on Meat Quality and Intramuscular Fat in Intrauterine Growth Retardation Pigs.

    PubMed

    Li, Bo; Li, Wei; Ahmad, Hussain; Zhang, Lili; Wang, Chao; Wang, Tian

    2015-01-01

    The aim of this study was to investigate the effects of choline supplementation on intramuscular fat (IMF) and lipid oxidation in IUGR pigs. Twelve normal body weight (NBW) and twelve intrauterine growth retardation (IUGR) newborn piglets were collected and distributed into 4 treatments (Normal: N, Normal+Choline: N+C, IUGR: I, and IUGR+Choline: I+C) with 6 piglets in each treatment. At 23 d of age, NBW and IUGR pigs were fed basal or choline supplemented diets. The results showed that the IUGR pigs had significantly lower (P<0.05) BW as compared with the NBW pigs at 23 d, 73 d, and 120 d of age, however, there was a slight decreased (P>0.05) in BW of IUGR pigs than the NBW pigs at 200 d. Compared with the NBW pigs, pH of meat longissimus dorsi muscle was significantly lower (P<0.05), and the meat color was improved in IUGR pigs. The malondialdehyde (MDA) levels were significantly decreased (P<0.05), while triglyceride (TG) and IMF contents were significantly higher (P<0.05) in the IUGR pigs than the NBW pigs. IUGR up-regulated the mRNA gene expression of fatty acid synthetase (FAS) and acetyl-CoA carboxylase (ACC). Dietary choline significantly increased (P<0.05) the BW at 120d of age, however, significantly decreased (P<0.05) the TG and IMF contents in both IUGR and NBW pigs. FAS and sterol regulatory element-binding proteins 1 (SREBP1) mRNA gene expressions were increased (P<0.05) while the muscle-carnitine palmityl transferase (M-CPT) and peroxisome proliferators-activated receptorγ (PPARγ) mRNA (P<0.05) gene expressions were decreased in the muscles of the IUGR pigs by choline supplementation. Furthermore, choline supplementation significantly increased (P<0.05) the MDA content as well as the O2•¯ scavenging activity in meat of IUGR pigs. The results suggested that IUGR pigs showed a permanent stunting effect on the growth performance, increased fat deposition and oxidative stress in muscles. However, dietary supplementation of choline improved the fat

  14. Effects of Choline on Meat Quality and Intramuscular Fat in Intrauterine Growth Retardation Pigs

    PubMed Central

    Li, Bo; Li, Wei; Ahmad, Hussain; Zhang, Lili; Wang, Chao; Wang, Tian

    2015-01-01

    The aim of this study was to investigate the effects of choline supplementation on intramuscular fat (IMF) and lipid oxidation in IUGR pigs. Twelve normal body weight (NBW) and twelve intrauterine growth retardation (IUGR) newborn piglets were collected and distributed into 4 treatments (Normal: N, Normal+Choline: N+C, IUGR: I, and IUGR+Choline: I+C) with 6 piglets in each treatment. At 23 d of age, NBW and IUGR pigs were fed basal or choline supplemented diets. The results showed that the IUGR pigs had significantly lower (P<0.05) BW as compared with the NBW pigs at 23 d, 73 d, and 120 d of age, however, there was a slight decreased (P>0.05) in BW of IUGR pigs than the NBW pigs at 200 d. Compared with the NBW pigs, pH of meat longissimus dorsi muscle was significantly lower (P<0.05), and the meat color was improved in IUGR pigs. The malondialdehyde (MDA) levels were significantly decreased (P<0.05), while triglyceride (TG) and IMF contents were significantly higher (P<0.05) in the IUGR pigs than the NBW pigs. IUGR up-regulated the mRNA gene expression of fatty acid synthetase (FAS) and acetyl-CoA carboxylase (ACC). Dietary choline significantly increased (P<0.05) the BW at 120d of age, however, significantly decreased (P<0.05) the TG and IMF contents in both IUGR and NBW pigs. FAS and sterol regulatory element-binding proteins 1 (SREBP1) mRNA gene expressions were increased (P<0.05) while the muscle-carnitine palmityl transferase (M-CPT) and peroxisome proliferators-activated receptorγ (PPARγ) mRNA (P<0.05) gene expressions were decreased in the muscles of the IUGR pigs by choline supplementation. Furthermore, choline supplementation significantly increased (P<0.05) the MDA content as well as the O2•¯ scavenging activity in meat of IUGR pigs. The results suggested that IUGR pigs showed a permanent stunting effect on the growth performance, increased fat deposition and oxidative stress in muscles. However, dietary supplementation of choline improved the fat

  15. 21 CFR 573.580 - Iron-choline citrate complex.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS FOOD ADDITIVES PERMITTED IN FEED AND DRINKING WATER OF ANIMALS Food Additive Listing § 573.580 Iron-choline citrate complex. Iron-choline citrate complex made by... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Iron-choline citrate complex. 573.580 Section 573...

  16. 21 CFR 573.580 - Iron-choline citrate complex.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS FOOD ADDITIVES PERMITTED IN FEED AND DRINKING WATER OF ANIMALS Food Additive Listing § 573.580 Iron-choline citrate complex. Iron-choline citrate complex made by... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Iron-choline citrate complex. 573.580 Section 573...

  17. 21 CFR 573.580 - Iron-choline citrate complex.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS FOOD ADDITIVES PERMITTED IN FEED AND DRINKING WATER OF ANIMALS Food Additive Listing § 573.580 Iron-choline citrate complex. Iron-choline citrate complex made by... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Iron-choline citrate complex. 573.580 Section 573...

  18. 21 CFR 573.580 - Iron-choline citrate complex.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS FOOD ADDITIVES PERMITTED IN FEED AND DRINKING WATER OF ANIMALS Food Additive Listing § 573.580 Iron-choline citrate complex. Iron-choline citrate complex made by... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Iron-choline citrate complex. 573.580 Section 573...

  19. 21 CFR 573.580 - Iron-choline citrate complex.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS FOOD ADDITIVES PERMITTED IN FEED AND DRINKING WATER OF ANIMALS Food Additive Listing § 573.580 Iron-choline citrate complex. Iron-choline citrate complex made by... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Iron-choline citrate complex. 573.580 Section 573...

  20. Low-Dose Creatine Supplementation Lowers Plasma Guanidinoacetate, but Not Plasma Homocysteine, in a Double-Blind, Randomized, Placebo-Controlled Trial123

    PubMed Central

    Peters, Brandilyn A; Hall, Megan N; Liu, Xinhua; Parvez, Faruque; Siddique, Abu B; Shahriar, Hasan; Uddin, Mohammad Nasir; Islam, Tariqul; Ilievski, Vesna; Graziano, Joseph H; Gamble, Mary V

    2015-01-01

    Background: Creatine synthesis from guanidinoacetate consumes ∼50% of s-adenosylmethionine (SAM)–derived methyl groups, accounting for an equivalent proportion of s-adenosylhomocysteine (SAH) and total homocysteine (tHcys) synthesis. Dietary creatine inhibits the synthesis of guanidinoacetate, thereby lowering plasma tHcys in rats. Objective: We tested the hypotheses that creatine supplementation lowers plasma guanidinoacetate, increases blood SAM, lowers blood SAH, and lowers plasma tHcys. Methods: Bangladeshi adults were randomly assigned to receive 1 of 4 treatments for 12 wk: placebo (n = 101), 3 g/d creatine (Cr; n = 101), 400 μg/d folic acid (FA; n = 153), or 3 g/d creatine plus 400 μg/d folic acid (Cr+FA; n = 103). The outcomes of plasma guanidinoacetate and tHcys, as well as whole blood SAM and SAH, were analyzed at baseline and week 12 by HPLC. Treatment effects of creatine supplementation were examined with the use of the group comparisons of Cr vs. placebo and Cr+FA vs. FA. Results: Plasma guanidinoacetate declined by 10.6% (95% CI: 4.9, 15.9) in the Cr group while increasing nonsignificantly in the placebo group (3.7%; 95% CI: −0.8, 8.5) (Pgroup difference = 0.0002). Similarly, plasma guanidinoacetate declined by 9.0% (95% CI: 3.4, 14.2) in the Cr+FA group while increasing in the FA group (7.0%; 95% CI: 2.0, 12.2) (Pgroup difference < 0.0001). Plasma tHcys declined by 23.4% (95% CI: 19.5, 27.1) and 21.0% (95% CI: 16.4, 25.2) in the FA and Cr+FA groups, respectively (Pgroup difference = 0.41), with no significant changes in the placebo or Cr groups (Pgroup difference = 0.35). A decrease in guanidinoacetate over time was associated with a decrease in tHcys over time in the Cr+FA group (β = 0.30; 95% CI: 0.17, 0.43; P < 0.0001). Conclusions: Our findings indicate that whereas creatine supplementation downregulates endogenous creatine synthesis, this may not on average lower plasma tHcys in humans. However, tHcys did decrease in those participants

  1. Oral choline supplementation for postoperative pain

    PubMed Central

    Sidhu, N.; Davies, S.; Nadarajah, A.; Rivera, J.; Whittington, R.; Mercier, R. J.; Virag, L.; Wang, S.; Flood, P.

    2013-01-01

    Background Activation of nicotinic receptors with nicotine has been shown to reduce post-surgical pain in clinical and preclinical studies. Choline is a selective agonist at α7-type nicotinic receptors that does not have addictive or sympathetic activating properties. It is anti-nociceptive in animal studies. We conducted a double-blind randomized trial of oral choline supplementation with lecithin to aid in the treatment of pain after gynaecological surgery. Methods Sixty women having open gynaecological surgery were randomly assigned to receive 20 g of lecithin before surgery or placebo. Plasma choline concentration and tumour necrosis factor (TNF) were measured. Pain report was the primary outcome measure. Results We achieved a small but statistically significant increase in choline after surgery with oral supplementation. Plasma TNF was not decreased and pain report was not different between groups at rest or with movement. There were no adverse effects of treatment. Conclusions Oral supplementation with lecithin during the perioperative period resulted in very slow absorption and thus only a small increase in plasma choline was achieved. This concentration was inadequate to reduce TNF as has been shown in other studies. The absence of an anti-inflammatory effect was likely related to our failure to demonstrate efficacy in pain reduction. PMID:23568851

  2. Cancer-specific production of N-acetylaspartate via NAT8L overexpression in non-small cell lung cancer and its potential as a circulating biomarker

    PubMed Central

    Lou, Tzu-Fang; Sethuraman, Deepa; Dospoy, Patrick; Srivastva, Pallevi; Kim, Hyun Seok; Kim, Joongsoo; Ma, Xiaotu; Chen, Pei-Hsuan; Huffman, Kenneth E.; Frink, Robin E.; Larsen, Jill E.; Lewis, Cheryl; Um, Sang-Won; Kim, Duk-Hwan; Ahn, Jung-Mo; DeBerardinis, Ralph J.; White, Michael A.; Minna, John D.; Yoo, Hyuntae

    2015-01-01

    In order to identify new cancer-associated metabolites that may be useful for early detection of lung cancer, we performed a global metabolite profiling of a non-small cell lung cancer (NSCLC) line and immortalized normal lung epithelial cells from the same patient. Among several metabolites with significant cancer/normal differences, we identified a unique metabolic compound, N-acetylaspartate (NAA) in cancer cells — undetectable in normal lung epithelium. NAA’s cancer-specific detection was validated in additional cancer and control lung cells as well as selected NSCLC patient tumors and control tissues. NAA’s cancer-specificity was further supported in our analysis of NAA synthetase (gene symbol: NAT8L) gene expression levels in The Cancer Genome Atlas: elevated NAT8L expression in approximately 40% of adenocarcinoma and squamous cell carcinoma cases (N=577), with minimal expression in all non-malignant lung tissues (N=74). We then showed that NAT8L is functionally involved in NAA production of NSCLC cells through siRNA-mediated suppression of NAT8L, which caused selective reduction of intracellular and secreted NAA. Our cell culture experiments also indicated that NAA biosynthesis in NSCLC cells depends on glutamine availability. For preliminary evaluation of NAA’s clinical potential as a circulating biomarker, we developed a sensitive NAA blood assay and found that NAA blood levels were elevated in 46% of NSCLC patients (N=13) in comparison with age-matched healthy controls (N=21) among individuals aged 55 years or younger. Taken together, these results indicate that NAA is produced specifically in NSCLC tumors through NAT8L overexpression and its extracellular secretion can be detected in blood. PMID:26511490

  3. Studies on choline permeation through the plasma membrane and its incorporation into phosphatidyl choline of Ehrlich-Lettré-ascites tumor cells in vitro.

    PubMed

    Haeffner, E W

    1975-02-03

    The initial rate of incorporation of 14C or 3H-labeled choline into Ehrlich-Lettre ascites cells of the glycogen-free strain seven days after inoculation was investigated in vitro. 1. At choline concentrations in the medium between 6 to 30 muM and 100 to 500 muM the choline uptake by the cells followed Michaelis-Menton Kinetics with V values between 31 to 100 and 59 to 500 pmol per minute at a given cell density, and average Q10-values of 2.1 at the high and of 2.4 at the low choline molarity. The K-m-values increased from 27 muM to 58.8 muM at low and from 0.11 mM to 0.22 mM at high choline concentrations over a temperature range between 15 degrees C and 37 degrees C. Arrhenius plot of the V values gave two lines, one with a transition temperature at 25 degrees C at low and one straight line at high choline concentrations, from which the energy of activation for choline uptake was determined to be 16 kcal/mol. 2. It is assumed that two systems exist for the choline uptake by the ascites cells. One, operative at low substrate concentrations, which is saturable and probably is to be classified as a carrier-mediated facilitated diffusion process, can be strongly inhibited by deoxyglucose or 2,4-dinitrophenol and also by substrate analogues such as chlorocholine or benzoylcholine. Ouabain affects this system to a lesser extent. The other system functioning at high choline concentrations may be a simple diffusion process, which is little inhibited by substrate analogues, ouabain and deoxyglucose; however, it is also inhibited by 2,4-dinitrophenol and p-chloromercuribenzoate. 3. Choline incorporation into the acid-insoluble material (lecithin) gave linear Michaelis-Menton kinetics at the low and the high substrate concentration respectively. K-m-values decreased with an increase in temperature at low and increased with rising temperature at high substrate concentrations thus reflecting a close relationship between choline uptake and its metabolism. Labeling of lecithin

  4. The CREST-E study of creatine for Huntington disease

    PubMed Central

    Schifitto, Giovanni; Oakes, David; Bredlau, Amy-Lee; Meyers, Catherine M.; Nahin, Richard; Rosas, Herminia Diana

    2017-01-01

    Objective: To investigate whether creatine administration could slow progressive functional decline in adults with early symptoms of Huntington disease. Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled study of up to 40 g daily of creatine monohydrate in participants with stage I and II HD treated for up to 48 months. The primary outcome measure was the rate of change in total functional capacity (TFC) between baseline and end of follow-up. Secondary outcome measures included changes in additional clinical scores, tolerability, and quality of life. Safety was assessed by adverse events and laboratory studies. Results: At 46 sites in North America, Australia, and New Zealand, 553 participants were randomized to creatine (275) or placebo (278). The trial was designed to enroll 650 patients, but was halted for futility after the first interim analysis. The estimated rates of decline in the primary outcome measure (TFC) were 0.82 points per year for participants on creatine, 0.70 points per year for participants on placebo, favoring placebo (nominal 95% confidence limits −0.11 to 0.35). Adverse events, mainly gastrointestinal, were significantly more common in participants on creatine. Serious adverse events, including deaths, were more frequent in the placebo group. Subgroup analysis suggested that men and women may respond differently to creatine treatment. Conclusions: Our data do not support the use of creatine treatment for delaying functional decline in early manifest HD. Clinicaltrials.gov identifier: NCT00712426. Classification of evidence: This study provides Class II evidence that for patients with early symptomatic HD, creatine monohydrate is not beneficial for slowing functional decline. PMID:28701493

  5. Creatine Revealed Anticonvulsant Properties on Chemically and Electrically Induced Seizures in Mice.

    PubMed

    Shafaroodi, Hamed; Shahbek, Farnaz; Faizi, Mehrdad; Ebrahimi, Farzad; Moezi, Leila

    2016-01-01

    Creatine exerts beneficial effects on a variety of pathologies in which energy metabolism and oxidative stress play an etiological role. Creatine supplements have shown beneficial effects on neurological disorders including Parkinson׳s disease, Huntington›s disease, amyotrophic lateral sclerosis, as well as Alzheimer›s disease and stroke. However, the potential benefits of creatine for patients with convulsive disorders remain poorly defined. While some authors did not suggest any anti- or pro-convulsant roles for creatine treatment, others suggest that creatine may be an anticonvulsant agent. In this study, we investigated the effects of creatine on seizures in mice. Three models were used to explore the role of creatine on seizures in mice including intravenous pentylenetetrazole (PTZ), intraperitoneal PTZ, and electroshock models. Acute creatine treatment (10, 20, 40 and 80 mg/Kg) significantly increased the clonic seizure threshold in the intravenous PTZ model. Sub-chronic administration of creatine (10 and 20 mg/Kg) revealed a significant anticonvulsant effect in intravenous PTZ model. Acute creatine administration (10, 20 and 40 mg/Kg) significantly decreased the frequency of clonic seizures in the intraperitoneal PTZ model. Besides, acute creatine (40 and 80 mg/Kg) decreased the incidence of tonic seizures after electroshock. In conclusion, creatine exerts anticonvulsant effects in three seizure models; therefore, it may act as a potential drug to help patients with convulsions. However, further investigations should be done to clarify these results more.

  6. Creatine Revealed Anticonvulsant Properties on Chemically and Electrically Induced Seizures in Mice

    PubMed Central

    Shafaroodi, Hamed; Shahbek, Farnaz; Faizi, Mehrdad; Ebrahimi, Farzad; Moezi, Leila

    2016-01-01

    Creatine exerts beneficial effects on a variety of pathologies in which energy metabolism and oxidative stress play an etiological role. Creatine supplements have shown beneficial effects on neurological disorders including Parkinson׳s disease, Huntington›s disease, amyotrophic lateral sclerosis, as well as Alzheimer›s disease and stroke. However, the potential benefits of creatine for patients with convulsive disorders remain poorly defined. While some authors did not suggest any anti- or pro-convulsant roles for creatine treatment, others suggest that creatine may be an anticonvulsant agent. In this study, we investigated the effects of creatine on seizures in mice. Three models were used to explore the role of creatine on seizures in mice including intravenous pentylenetetrazole (PTZ), intraperitoneal PTZ, and electroshock models. Acute creatine treatment (10, 20, 40 and 80 mg/Kg) significantly increased the clonic seizure threshold in the intravenous PTZ model. Sub-chronic administration of creatine (10 and 20 mg/Kg) revealed a significant anticonvulsant effect in intravenous PTZ model. Acute creatine administration (10, 20 and 40 mg/Kg) significantly decreased the frequency of clonic seizures in the intraperitoneal PTZ model. Besides, acute creatine (40 and 80 mg/Kg) decreased the incidence of tonic seizures after electroshock. In conclusion, creatine exerts anticonvulsant effects in three seizure models; therefore, it may act as a potential drug to help patients with convulsions. However, further investigations should be done to clarify these results more. PMID:28243281

  7. AzoCholine Enables Optical Control of Alpha 7 Nicotinic Acetylcholine Receptors in Neural Networks.

    PubMed

    Damijonaitis, Arunas; Broichhagen, Johannes; Urushima, Tatsuya; Hüll, Katharina; Nagpal, Jatin; Laprell, Laura; Schönberger, Matthias; Woodmansee, David H; Rafiq, Amir; Sumser, Martin P; Kummer, Wolfgang; Gottschalk, Alexander; Trauner, Dirk

    2015-05-20

    Nicotinic acetylcholine receptors (nAChRs) are essential for cellular communication in higher organisms. Even though a vast pharmacological toolset to study cholinergic systems has been developed, control of endogenous neuronal nAChRs with high spatiotemporal precision has been lacking. To address this issue, we have generated photoswitchable nAChR agonists and re-evaluated the known photochromic ligand, BisQ. Using electrophysiology, we found that one of our new compounds, AzoCholine, is an excellent photoswitchable agonist for neuronal α7 nAChRs, whereas BisQ was confirmed to be an agonist for the muscle-type nAChR. AzoCholine could be used to modulate cholinergic activity in a brain slice and in dorsal root ganglion neurons. In addition, we demonstrate light-dependent perturbation of behavior in the nematode, Caenorhabditis elegans.

  8. Increasing N-acetylaspartate in the Brain during Postnatal Myelination Does Not Cause the CNS Pathologies of Canavan Disease

    PubMed Central

    Appu, Abhilash P.; Moffett, John R.; Arun, Peethambaran; Moran, Sean; Nambiar, Vikram; Krishnan, Jishnu K. S.; Puthillathu, Narayanan; Namboodiri, Aryan M. A.

    2017-01-01

    Canavan disease is caused by mutations in the gene encoding aspartoacylase (ASPA), a deacetylase that catabolizes N-acetylaspartate (NAA). The precise involvement of elevated NAA in the pathogenesis of Canavan disease is an ongoing debate. In the present study, we tested the effects of elevated NAA in the brain during postnatal development. Mice were administered high doses of the hydrophobic methyl ester of NAA (M-NAA) twice daily starting on day 7 after birth. This treatment increased NAA levels in the brain to those observed in the brains of Nur7 mice, an established model of Canavan disease. We evaluated various serological parameters, oxidative stress, inflammatory and neurodegeneration markers and the results showed that there were no pathological alterations in any measure with increased brain NAA levels. We examined oxidative stress markers, malondialdehyde content (indicator of lipid peroxidation), expression of NADPH oxidase and nuclear translocation of the stress-responsive transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF-2) in brain. We also examined additional pathological markers by immunohistochemistry and the expression of activated caspase-3 and interleukin-6 by Western blot. None of the markers were increased in the brains of M-NAA treated mice, and no vacuoles were observed in any brain region. These results show that ASPA expression prevents the pathologies associated with excessive NAA concentrations in the brain during postnatal myelination. We hypothesize that the pathogenesis of Canavan disease involves not only disrupted NAA metabolism, but also excessive NAA related signaling processes in oligodendrocytes that have not been fully determined and we discuss some of the potential mechanisms. PMID:28626388

  9. Exercise and neuromodulators: choline and acetylcholine in marathon runners

    NASA Technical Reports Server (NTRS)

    Conlay, L. A.; Sabounjian, L. A.; Wurtman, R. J.

    1992-01-01

    Certain neurotransmitters (i.e., acetylcholine, catecholamines, and serotonin) are formed from dietary constituents (i.e., choline, tyrosine and tryptophan). Changing the consumption of these precursors alters release of their respective neurotransmitter products. The neurotransmitter acetylcholine is released from the neuromuscular junction and from brain. It is formed from choline, a common constituent in fish, liver, and eggs. Choline is also incorporated into cell membranes; membranes may likewise serve as an alternative choline source for acetylcholine synthesis. In trained athletes, running a 26 km marathon reduced plasma choline by approximately 40%, from 14.1 to 8.4 uM. Changes of similar magnitude have been shown to reduce acetylcholine release from the neuromuscular junction in vivo. Thus, the reductions in plasma choline associated with strenuous exercise may reduce acetylcholine release, and could thereby affect endurance or performance.

  10. Does Litomosoides sigmodontis synthesize dimethylethanolamine from choline?

    PubMed

    Houston, K M; Babayan, S A; Allen, J E; Harnett, W

    2008-01-01

    Juvenile female Litomosoides sigmodontis secrete a protein (Juv-p120) highly modified with dimethylethanolamine (DMAE). In an attempt to establish the source of this decoration worms were pulsed with [3H]-choline and [3H]-ethanolamine and the radio-isotope labelled products analysed. Both isotope labels were successfully taken up by the worms, as demonstrated by labelling of phospholipids with [3H]-choline, being predominantly incorporated into phosphatidylcholine and [3H]-ethanolamine into phosphatidylethanolamine. Isotope labelling of phosphatidylethanolamine was particularly striking with the worms taking up approximately 30 times as much labelled ethanolamine as choline. It was possible to detect faint labelling of Juv-p120 with [3H]-ethanolamine after prolonged exposure periods but, unlike the situation with the phospholipids, it was much more readily labelled with [3H]-choline. When pulsing with [3H]-ethanolamine it was also possible to detect isotope-labelled phosphatidylcholine, which may ultimately account for the low levels of labelling of Juv-p120. Overall our results raise the previously unconsidered but intriguing possibility that in L. sigmodontis, choline may be the precursor of DMAE.

  11. Hemicholinium-3 sensitive choline transport in human T lymphocytes: Evidence for use as a proxy for brain choline transporter (CHT) capacity.

    PubMed

    Koshy Cherian, Ajeesh; Parikh, Vinay; Wu, Qi; Mao-Draayer, Yang; Wang, Qin; Blakely, Randy D; Sarter, Martin

    2017-09-01

    The synaptic uptake of choline via the high-affinity, hemicholinium-3-dependent choline transporter (CHT) strongly influences the capacity of cholinergic neurons to sustain acetylcholine (ACh) synthesis and release. To advance research on the impact of CHT capacity in humans, we established the presence of the neuronal CHT protein in human T lymphocytes. Next, we demonstrated CHT-mediated choline transport in human T cells. To address the validity of T cell-based choline uptake as a proxy for brain CHT capacity, we isolated T cells from the spleen, and synaptosomes from cortex and striatum, of wild type and CHT-overexpressing mice (CHT-OXP). Choline uptake capacity in T cells from CHT-OXP mice was two-fold higher than in wild type mice, mirroring the impact of CHT over-expression on synaptosomal CHT-mediated choline uptake. Monitoring T lymphocyte CHT protein and activity may be useful for estimating human CNS cholinergic capacity and for testing hypotheses concerning the contribution of CHT and, more generally, ACh signaling in cognition, neuroinflammation and disease. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Creatine protects against mitochondrial dysfunction associated with HIV-1 Tat-induced neuronal injury

    PubMed Central

    Stevens, Patrick R.; Gawryluk, Jeremy W.; Hui, Liang; Chen, Xuesong; Geiger, Jonathan D.

    2015-01-01

    HIV-1 infected individuals are living longer but experiencing a prevalence rate of over 50% for HIV-1 associated neurocognitive disorders (HAND) for which no effective treatment is available. Viral and cellular factors secreted by HIV-1 infected cells leads to neuronal injury and HIV-1 Tat continues to be implicated in the pathogenesis of HAND. Here we tested the hypothesis that creatine protected against HIV-1 Tat-induced neuronal injury by preventing mitochondrial bioenergetic crisis and/or redox catastrophe. Creatine blocked HIV-1 Tat1-72-induced increases in neuron cell death and synaptic area loss. Creatine protected against HIV-1 Tat-induced decreases in ATP. Creatine and creatine plus HIV-1 Tat increased cellular levels of creatine, and creatine plus HIV-1 Tat further decreased ratios of phosphocreatine to creatine observed with creatine or HIV-1 Tat treatments alone. Additionally, creatine protected against HIV-1 Tat-induced mitochondrial hypopolarization and HIV-1 Tat-induced mitochondrial permeability transition pore opening. Thus, creatine may be a useful adjunctive therapy against HAND. PMID:25613139

  13. Creatine protects against mitochondrial dysfunction associated with HIV-1 Tat-induced neuronal injury.

    PubMed

    Stevens, Patrick R; Gawryluk, Jeremy W; Hui, Liang; Chen, Xuesong; Geiger, Jonathan D

    2014-01-01

    HIV-1 infected individuals live longer but experience a prevalence rate of over 50% for HIV-1 associated neurocognitive disorders (HAND) for which no effective treatment is available. Viral and cellular factors secreted by HIV-1 infected cells lead to neuronal injury and HIV-1 Tat continues to be implicated in the pathogenesis of HAND. Here we tested the hypothesis that creatine protected against HIV-1 Tat-induced neuronal injury by preventing mitochondrial bioenergetic crisis and/or redox catastrophe. Creatine blocked HIV-1 Tat(1-72)-induced increases in neuron cell death and synaptic area loss. Creatine protected against HIV-1 Tat-induced decreases in ATP. Creatine and creatine plus HIV-1 Tat increased cellular levels of creatine, and creatine plus HIV-1 Tat further decreased ratios of phosphocreatine to creatine observed with creatine or HIV-1 Tat treatments alone. Additionally, creatine protected against HIV-1 Tat-induced mitochondrial hypopolarization and HIV-1 Tat-induced mitochondrial permeability transition pore opening. Thus, creatine may be a useful adjunctive therapy against HAND.

  14. Creatine in the central nervous system: From magnetic resonance spectroscopy to creatine deficiencies.

    PubMed

    Rackayova, Veronika; Cudalbu, Cristina; Pouwels, Petra J W; Braissant, Olivier

    2017-07-15

    Creatine (Cr) is an important organic compound acting as intracellular high-energy phosphate shuttle and in energy storage. While located in most cells where it plays its main roles in energy metabolism and cytoprotection, Cr is highly concentrated in muscle and brain tissues, in which Cr also appears to act in osmoregulation and neurotransmission. This review discusses the basis of Cr metabolism, synthesis and transport within brain cells. The importance of Cr in brain function and the consequences of its impaired metabolism in primary and secondary Cr deficiencies are also discussed. Cr and phosphocreatine (PCr) in living systems can be well characterized using in vivo magnetic resonance spectroscopy (MRS). This review describes how 1 H MRS allows the measurement of Cr and PCr, and how 31 P MRS makes it possible to estimate the creatine kinase (CK) rate constant and so detect dynamic changes in the Cr/PCr/CK system. Absolute quantification by MRS using creatine as internal reference is also debated. The use of in vivo MRS to study brain Cr in a non-invasive way is presented, as well as its use in clinical and preclinical studies, including diagnosis and treatment follow-up in patients. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. A simple screening method using ion chromatography for the diagnosis of cerebral creatine deficiency syndromes.

    PubMed

    Wada, Takahito; Shimbo, Hiroko; Osaka, Hitoshi

    2012-08-01

    Cerebral creatine deficiency syndromes (CCDS) are caused by genetic defects in L-arginine:glycine amidinotransferase, guanidinoacetate methyltransferase or creatine transporter 1. CCDS are characterized by abnormal concentrations of urinary creatine (CR), guanidinoacetic acid (GA), or creatinine (CN). In this study, we describe a simple HPLC method to determine the concentrations of CR, GA, and CN using a weak-acid ion chromatography column with a UV detector without any derivatization. CR, GA, and CN were separated clearly with the retention times (mean ± SD, n = 3) of 5.54 ± 0.0035 min for CR, 6.41 ± 0.0079 min for GA, and 13.53 ± 0.046 min for CN. This new method should provide a simple screening test for the diagnosis of CCDS.

  16. 68Ga-PSMA-PET/CT in Patients With Biochemical Prostate Cancer Recurrence and Negative 18F-Choline-PET/CT.

    PubMed

    Bluemel, Christina; Krebs, Markus; Polat, Bülent; Linke, Fränze; Eiber, Matthias; Samnick, Samuel; Lapa, Constantin; Lassmann, Michael; Riedmiller, Hubertus; Czernin, Johannes; Rubello, Domenico; Bley, Thorsten; Kropf, Saskia; Wester, Hans-Juergen; Buck, Andreas K; Herrmann, Ken

    2016-07-01

    Investigating the value of Ga-PSMA-PET/CT in biochemically recurring prostate cancer patients with negative F-choline-PET/CT. One hundred thirty-nine consecutive patients with biochemical recurrence after curative (surgery and/or radiotherapy) therapy were offered participation in this sequential clinical imaging approach. Patients first underwent an F-choline-PET/CT. If negative, an additional Ga-PSMA-PET/CT was offered. One hundred twenty-five of 139 eligible patients were included in the study; 32 patients underwent additional Ga-PSMA-PET/CT. Patients with equivocal findings (n = 5) on F-choline-PET/CT and those who declined the additional Ga-PSMA-PET/CT (n = 9) were excluded. Images were analyzed visually for the presence of suspicious lesions. Findings on PET/CT were correlated with PSA level, PSA doubling time (dt), and PSA velocity (vel). The overall detection rates were 85.6% (107/125) for the sequential imaging approach and 74.4% (93/125) for F-choline-PET/CT alone. Ga-PSMA-PET/CT detected sites of recurrence in 43.8% (14/32) of the choline-negative patients. Detection rates of the sequential imaging approach and F-choline-PET/CT alone increased with higher serum PSA levels and PSA vel. Subgroup analysis of Ga-PSMA-PET/CT in F-choline negative patients revealed detection rates of 28.6%, 45.5%, and 71.4% for PSA levels of 0.2 or greater to less than 1 ng/mL, 1 to 2 ng/mL, and greater than 2 ng/mL, respectively. The sequential imaging approach designed to limit Ga-PSMA imaging to patients with negative choline scans resulted in high detection rates. Ga-PSMA-PET/CT identified sites of recurrent disease in 43.8% of the patients with negative F-choline PET/CT scans.

  17. Creatine for women in pregnancy for neuroprotection of the fetus.

    PubMed

    Dickinson, Hayley; Bain, Emily; Wilkinson, Dominic; Middleton, Philippa; Crowther, Caroline A; Walker, David W

    2014-12-19

    Creatine is an amino acid derivative and, when phosphorylated (phosphocreatine), is involved in replenishing adenosine triphosphate (ATP) via the creatine kinase reaction. Cells obtain creatine from a diet rich in fish, meat, or dairy and by endogenous synthesis from the amino acids arginine, glycine, and methionine in an approximate 50:50 ratio. Animal studies have shown that creatine may provide fetal neuroprotection when given to the mother through her diet in pregnancy. It is important to assess whether maternally administered creatine in human pregnancy (at times of known, suspected, or potential fetal compromise) may offer neuroprotection to the fetus and may accordingly reduce the risk of adverse neurodevelopmental outcomes, such as cerebral palsy and associated impairments and disabilities arising from fetal brain injury. To assess the effects of creatine when used for neuroprotection of the fetus. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 November 2014). We planned to include all published, unpublished, and ongoing randomised trials and quasi-randomised trials. We planned to include studies reported as abstracts only as well as full-text manuscripts. Trials using a cross-over or cluster-randomised design were not eligible for inclusion.We planned to include trials comparing creatine given to women in pregnancy for fetal neuroprotection (regardless of the route, timing, dose, or duration of administration) with placebo, no treatment, or with an alternative agent aimed at providing fetal neuroprotection. We also planned to include comparisons of different regimens for administration of creatine. We identified no completed or ongoing randomised controlled trials. We found no randomised controlled trials for inclusion in this review. As we did not identify any randomised controlled trials for inclusion in this review, we are unable to comment on implications for practice. Although evidence from animal studies has supported a

  18. 21 CFR 182.8252 - Choline chloride.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Choline chloride. 182.8252 Section 182.8252 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR... chloride. (a) Product. Choline chloride. (b) Conditions of use. This substance is generally recognized as...

  19. Effect of choline carboxylate ionic liquids on biological membranes

    PubMed Central

    Rengstl, Doris; Kraus, Birgit; Van Vorst, Matthew; Elliott, Gloria D.; Kunz, Werner

    2015-01-01

    Choline carboxylates, ChCm, with m = 2–10 and choline oleate are known as biocompatible substances, yet their influence on biological membranes is not well-known, and the effect on human skin has not previously been investigated. The short chain choline carboxylates ChCm with m = 2, 4, 6 act as hydrotropes, solubilizing hydrophobic compounds in aqueous solution, while the longer chain choline carboxylates ChCm with m = 8,10 and oleate are able to form micelles. In the present study, the cytotoxicity of choline carboxylates was tested using HeLa and SK-MEL-28 cells. The influence of these substances on liposomes prepared from dipalmitoylphosphatidylcholine (DPPC) was also evaluated to provide insights on membrane interactions. It was observed that the choline carboxylates with a chain length of m > 8 distinctly influence the bilayer, while the shorter ones had minimal interaction with the liposomes. PMID:25444662

  20. An introduction to the nutrition and metabolism of choline.

    PubMed

    Hollenbeck, Clarie B

    2012-06-01

    Choline is a ubiquitous water soluble nutrient, often associated with the B vitamins; however, not yet officially defined as a B vitamin. It is important in the synthesis of phospholipid components of cell membranes, and plasma lipoproteins, providing structural integrity as well as being important in cell signaling; it is also important in the synthesis of the neurotransmitter acetylcholine, and the oxidized form of choline, glycine betaine, serves as an important methyl donor in the methionine cycle. It is present in a wide variety of foods, and is endogenously synthesized in humans through the sequential methylation of phosphatidylethanolamine. The present article represents an introduction to the nutrition, metabolism, and physiological functions of choline and choline derivatives in humans. The association of choline and choline derivatives in risk of chronic disease, including: neural tube defects, coronary artery disease, cancer, Alzheimer's disease, dementia, and memory, and cystic fibrosis is reviewed.

  1. The Form of Choline in the Maternal Diet Affects Immune Development in Suckled Rat Offspring.

    PubMed

    Lewis, Erin D; Richard, Caroline; Goruk, Susan; Dellschaft, Neele S; Curtis, Jonathan M; Jacobs, René L; Field, Catherine J

    2016-04-01

    Lipid-soluble phosphatidylcholine (PC) and aqueous free choline are absorbed and metabolized differently, but the metabolic effects of feeding these 2 forms of choline have not been thoroughly investigated. We sought to compare the effects of PC and free choline in the maternal diet on the development of the offspring's immune system. During lactation, Sprague-Dawley dams (n= 10) were randomly assigned to 1 of 2 diet groups containing the same concentration of total choline (1 g/kg diet) as free choline (choline bitartrate) or PC (egg lecithin). The splenocytes of pups aged 21 d were isolated and stimulated ex vivo with concanavalin A (ConA) or lipopolysaccharide (LPS), and the choline concentrations of stomach content, plasma, and the spleen were measured. Pups from PC-fed dams had a lower proportion of cells involved in antigen presentation but produced 54% more interleukin (IL)-2, 163% more IL-6, and 107% more IFN-γ after ConA stimulation and 110% more IL-6 and 43% more tumor necrosis factor (TNF)-α after LPS stimulation (allP< 0.05). The PC concentrations were significantly higher in the plasma and spleen of pups from PC-fed dams (P< 0.05). Increasing the supply of PC in the form of lysophosphatidylcholine to splenocytes in vitro increased the rate of proliferation and IL-2 production and the surface expression of CD25, CD28, CD71, and CD152 on CD8+ T cells, suggesting 1 possible mechanism. The results of this study demonstrate that providing choline to rats in the form of PC (compared to free choline), possibly by increasing the supply of PC to the suckling pups, promotes maturation and improves function of the offspring's immune system. © 2016 American Society for Nutrition.

  2. CDP-choline modulates matrix metalloproteinases in rat sciatic injury.

    PubMed

    Gundogdu, Elif Basaran; Bekar, Ahmet; Turkyilmaz, Mesut; Gumus, Abdullah; Kafa, Ilker Mustafa; Cansev, Mehmet

    2016-02-01

    CDP-choline (cytidine-5'-diphosphocholine) improves functional recovery, promotes nerve regeneration, and decreases perineural scarring in rat peripheral nerve injury. The aim of the present study was to investigate the mechanism of action of CDP-choline with regard to matrix metalloproteinase (MMP) activity in the rat-transected sciatic nerve injury model. Male Wistar rats were randomized into Sham, Saline, and CDP-choline groups. Rats in Sham group received Sham surgery, whereas rats in Saline and CDP-choline groups underwent right sciatic nerve transection followed by immediate primary saturation and injected intraperitoneally with 0.9% NaCl (1 mL/kg) and CDP-choline (600 μg/kg), respectively. Sciatic nerve samples were obtained 1, 3, and 7 d after the surgery and analyzed for levels and activities of MMP-2 and MMP-9, levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) and TIMP-3, and axonal regeneration. CDP-choline treatment decreased the levels and activities of MMP-2 and MMP-9, whereas increasing levels of TIMP-1 and TIMP-3 significantly on the third and seventh day after injury compared to Saline group. In addition, CDP-choline administration resulted in new axon formation and formation and advancement of myelination on newly formed islets (compartments) of axonal regrowth. Our data show, for the first time, that CDP-choline modulates MMP activity and promotes the expression of TIMPs to stimulate axonal regeneration. These data help to explain one mechanism by which CDP-choline provides neuroprotection in peripheral nerve injury. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Choline and Inositol Distribution in Algae and Fungi1

    PubMed Central

    Ikawa, Miyoshi; Borowski, Paul T.; Chakravarti, Ashima

    1968-01-01

    Inositol and choline were present in varying amounts among the species of Rhodophyta, Phaeophyta, Chlorophyta, and Euglenophyta examined. However, in the two members of the order Fucales (division Phaeophyta) examined, no detectable amounts of choline were found. In contrast, the species of Cyanophyta examined contained no detectable amounts of either choline or inositol. All species of the fungal classes Phycomyceteae, Ascomyceteae, and Basidiomyceteae collected contained both inositol and choline in varying amounts. The red, brown, and blue-green algae usually contained much less inositol and choline than do plant and animals sources, but the fungi and the algae Chlorella and Euglena contained amounts comparable to those present in plant sources. PMID:5647522

  4. Caffeine potentiates the enhancement by choline of striatal acetylcholine release

    NASA Technical Reports Server (NTRS)

    Johnson, D. A.; Ulus, I. H.; Wurtman, R. J.

    1992-01-01

    We investigated the effect of peripherally administered caffeine (50 mg/kg), choline (30, 60, or 120 mg/kg) or combinations of both drugs on the spontaneous release of acetylcholine (ACh) from the corpus striatum of anesthetized rats using in vivo microdialysis. Caffeine alone or choline in the 30 or 60 mg/kg dose failed to increase ACh in microdialysis samples; the 120 mg/kg choline dose significantly enhanced ACh during the 80 min following drug administration. Coadministration of caffeine with choline significantly increased ACh release after each of the choline doses tested. Peak microdialysate levels with the 120 mg/kg dose were increased 112% when caffeine was additionally administered, as compared with 54% without caffeine. These results indicate that choline administration can enhance spontaneous ACh release from neurons, and that caffeine, a drug known to block adenosine receptors on these neurons, can amplify the choline effect.

  5. Metabolite ratios in the posterior cingulate cortex do not track cognitive decline in Parkinson's disease in a clinical setting.

    PubMed

    Almuqbel, Mustafa; Melzer, Tracy R; Myall, Daniel J; MacAskill, Michael R; Pitcher, Toni L; Livingston, Leslie; Wood, Kyla-Louise; Keenan, Ross J; Dalrymple-Alford, John C; Anderson, Tim J

    2016-01-01

    Parkinson's Disease (PD) is classified as a motor disorder, but most patients develop cognitive impairment, and eventual dementia (PDD). Predictive neurobiomarkers may be useful in the identification of those patients at imminent risk of PDD. Given the compromised cerebral integrity in PDD, we investigated whether brain metabolites track disease progression over time. Proton Magnetic Resonance Spectroscopy (MRS) was used to identify brain metabolic changes associated with cognitive impairment and dementia in PD. Forty-nine healthy participants and 130 PD patients underwent serial single voxel proton MRS and neuropsychological testing. At baseline patients were classified as either having normal cognitive status (PDN, n = 77), mild cognitive impairment (PDMCI, n = 33), or dementia (PDD, n = 20). Posterior cingulate cortex (PCC) was examined to quantify N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and myo-inositol (mI). A hierarchical Bayesian model was used to assess whether cognitive ability and other covariates were related to baseline MRS values and changes in MRS over time. At baseline, relative to controls, PDD had significantly decreased NAA/Cr and increased Cho/Cr. However, these differences did not remain significant after accounting for age, sex, and MDS-UPDRS III. At follow-up, no significant changes in MRS metabolite ratios were detected, with no relationship found between MRS measures and change in cognitive status. Unlike Alzheimer's disease, single voxel MR spectroscopy of the PCC failed to show any significant association with cognitive status at baseline or over time. This suggests that MRS of PCC is not a clinically useful biomarker for tracking or predicting cognitive impairment in Parkinson's disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Accuracy of noninvasive quantification of brain NAA concentrations using PRESS sequence: verification in a swine model with external standard.

    PubMed

    Wu, R H; Lin, R; Li, H; Xiao, Z W; Rao, H B; Luo, W H; Guo, G; Huang, K; Zhang, X G; Lang, Z J

    2005-01-01

    The metabolite ratios had been employed in the field of MR spectroscopy (MRS) for a long period. The main drawback of metabolite ratio is that ratio results are not comparable with absolute metabolite concentration in vivo. The purpose of this study was to examine the accuracy of noninvasive quantification of brain N-acetylaspartate (NAA) concentrations using previously reported MR external standard method. Eight swine were scanned on a GE 1.5 T scanner with a standard head coil. The external standard method was utilized with a sphere filled with NAA, GABA, glutamine, glutamate, creatine, choline chloride, and myo-inositol. The position resolved spectroscopy (PRESS) sequence was used with TE=135 msec, TR=1500 msec, and 128 scan averages. The analysis of MRS was done with SAGE/IDL program. In vivo NAA concentration was obtained using the equation S=N * e(-TE/T2) * [1-e(-TR/T1). In vitro NAA concentration was measured by high performance liquid chromatography (HPLC). In the MRS group, the mean concentration of NAA was 10.03 plusmn 0.74 mmol/kg. In the HPLC group, the mean concentration of NAA was 9.22 plusmn 0.55 mmol/kg. There was no significant difference between the two groups (p = 0.46). However, slightly higher value was observed in the MRS group (7/8 swine), compared with HPLC group. The range of differences was between 0.02~2.05 mmol/kg. MRS external reference method could be more accurate than internal reference method. 1H MRS does not distinguish between N-acetyl resonance frequencies and other N-acetylated amino acids.

  7. Whole-brain patterns of (1)H-magnetic resonance spectroscopy imaging in Alzheimer's disease and dementia with Lewy bodies.

    PubMed

    Su, L; Blamire, A M; Watson, R; He, J; Hayes, L; O'Brien, J T

    2016-08-30

    Magnetic resonance spectroscopy has demonstrated metabolite changes in neurodegenerative disorders such as Alzheimer's disease (AD) and dementia with Lewy bodies (DLB); however, their pattern and relationship to clinical symptoms is unclear. To determine whether the spatial patterns of brain-metabolite changes in AD and DLB are regional or diffused, and to examine whether the key metabolite levels are associated with cognitive and non-cognitive symptoms, we acquired whole-brain spatially resolved 3T magnetic resonance spectroscopic imaging (MRSI) data from subjects with AD (N=36), DLB (N=35) and similarly aged controls (N=35). Voxel-wise measurement of N-acetylaspartate to creatine (NAA/Cr), choline to Cr (Cho/Cr), myo-inositol to Cr (mI/Cr) as well as glutamate and glutamine to Cr (Glx/Cr) ratios were determined using MRSI. Compared with controls, AD and DLB groups showed a significant decrease in most brain metabolites, with NAA/Cr, Cho/Cr and mI/Cr levels being reduced in posterior cingulate, thalamus, frontotemporal areas and basal ganglia. The Glx/Cr level was more widely decreased in DLB (posterior cingulate, hippocampus, temporal regions and caudate) than in AD (only in posterior cingulate). DLB was also associated with increased levels of Cho/Cr, NAA/Cr and mI/Cr in occipital regions. Changes in metabolism in the brain were correlated with cognitive and non-cognitive symptoms in the DLB but not in the AD group. The different patterns between AD and DLB may have implications for improving diagnosis, better understanding disease-specific neurobiology and targeting therapeutics. In addition, the study raised important questions about the role of occipital neuroinflammation and glial activation as well as the glutamatergic treatment in DLB.

  8. The supply of choline is important for fetal progenitor cells

    PubMed Central

    Zeisel, Steven H.

    2011-01-01

    Fetal progenitor cells proliferate, migrate, differentiate and undergo apoptosis at specific times during fetal development. Choline is needed by these cells for membrane synthesis and for methylation. There is growing evidence that this nutrient also modulates epigenetic regulation of gene expression in both neuronal and endothelial progenitor cells, thereby modifying brain development. It is likely that these mechanisms explain why, in rodent models, maternal dietary intake of choline influences both angiogenesis and neurogenesis in fetal hippocampus, and results in life-long changes in memory function. This also may explain why women eating diets low in choline have a greater risk of having a baby with a birth defect. Choline is mainly found in foods that contain fat and cholesterol, and intake of such foods has diminished in response dietary advice from nutritionists and physicians. Forty years ago, diets commonly contained choline-rich foods but now women in the USA tend to eat diets low in choline content. Premenopausal women normally may require less choline in their diet than do men and postmenopausal women, because estrogen induces the gene for the enzyme catalyzing endogenous biosynthesis of the choline-containing phospholipid phosphatidylcholine. However, many women have a single nucleotide polymorphism (SNP) that blocks the induction of endogenous biosynthesis, thereby making them require more dietary choline. When these women eat diets low in choline, the supply of this nutrient to the fetus is likely to be inadequate, and may perturb progenitor cell proliferation, migration, differentiation and apoptosis. PMID:21693194

  9. Randomized, double-blind, placebo-controlled clinical trial of choline supplementation in school-aged children with fetal alcohol spectrum disorders1

    PubMed Central

    Risbud, Rashmi D; Mattson, Sarah N; Chambers, Christina D; Thomas, Jennifer D

    2016-01-01

    Background: Prenatal alcohol exposure results in a broad range of cognitive and behavioral impairments. Because of the long-lasting problems that are associated with fetal alcohol spectrum disorders (FASDs), the development of effective treatment programs is critical. Preclinical animal studies have shown that choline, which is an essential nutrient, can attenuate the severity of alcohol-related cognitive impairments. Objective: We aimed to translate preclinical findings to a clinical population to investigate whether choline supplementation can ameliorate the severity of memory, executive function, and attention deficits in children with FASDs. Design: In the current study, which was a randomized, double-blind, placebo-controlled clinical trial, we explored the effectiveness of a choline intervention for children with FASDs who were aged 5–10 y. Fifty-five children with confirmed histories of heavy prenatal alcohol exposure were randomly assigned to either the choline (n = 29) or placebo (n = 26) treatment arms. Participants in the choline group received 625 mg choline/d for 6 wk, whereas subjects in the placebo group received an equivalent dose of an inactive placebo treatment. Primary outcomes, including the performance on neuropsychological measures of memory, executive function, and attention and hyperactivity, were assessed at baseline and postintervention. Results: Compared with the placebo group, participants in the choline group did not differentially improve in cognitive performance in any domain. Treatment compliance and mean dietary choline intake were not predictive of treatment outcomes. Conclusions: Findings of the current study do not support that choline, administered at a dose of 625 mg/d for 6 wk, is an effective intervention for school-aged (5–10 y old) children with FASDs. This research provides important information about choline’s therapeutic window. Combined with other studies of choline and nutritional interventions in this population

  10. Simultaneous detection of creatine and creatinine using a sequential injection analysis/biosensor system.

    PubMed

    Stefan-van Staden, Raluca-Ioana; Bokretsion, Rahel Girmai; van Staden, Jacobus F; Aboul-Enein, Hassan Y

    2006-01-01

    Carbon paste based biosensors for the determination of creatine and creatinine have been integrated into a sequential injection system. Applying the multi-enzyme sequence of creatininase (CA), and/or creatinase (CI) and sarcosine oxidase (SO), hydrogen peroxide has been detected amperometrically. The linear concentration ranges are of pmol/L to nmol/L magnitude, with very low limits of detection. The proposed SIA system can be utilized reliably for the on-line simultaneous detection of creatine and creatinine in pharmaceutical products, as well as in serum samples, with a rate of 34 samples per hour and RSD values better than 0.16% (n=10).

  11. Choline deficiency increases lymphocyte apoptosis and DNA damage in humans.

    PubMed

    da Costa, Kerry-Ann; Niculescu, Mihai D; Craciunescu, Corneliu N; Fischer, Leslie M; Zeisel, Steven H

    2006-07-01

    Whereas deficiency of the essential nutrient choline is associated with DNA damage and apoptosis in cell and rodent models, it has not been shown in humans. The objective was to ascertain whether lymphocytes from choline-deficient humans had greater DNA damage and apoptosis than did those from choline-sufficient humans. Fifty-one men and women aged 18-70 y were fed a diet containing the recommended adequate intake of choline (control) for 10 d. They then were fed a choline-deficient diet for up to 42 d before repletion with 138-550 mg choline/d. Blood was collected at the end of each phase, and peripheral lymphocytes were isolated. DNA damage and apoptosis were then assessed by activation of caspase-3, terminal deoxynucleotide transferase-mediated dUTP nick end-labeling, and single-cell gel electrophoresis (COMET) assays. All subjects fed the choline-deficient diet had lymphocyte DNA damage, as assessed by COMET assay, twice that found when they were fed the control diet. The subjects who developed organ dysfunction (liver or muscle) when fed the choline-deficient diet had significantly more apoptotic lymphocytes, as assessed by the activated caspase-3 assay, than when fed the control diet. A choline-deficient diet increased DNA damage in humans. Subjects in whom these diets induced liver or muscle dysfunction also had higher rates of apoptosis in their peripheral lymphocytes than did subjects who did not develop organ dysfunction. Assessment of DNA damage and apoptosis in lymphocytes appears to be a clinically useful measure in humans (such as those receiving parenteral nutrition) in whom choline deficiency is suspected.

  12. Maternal choline supplementation differentially alters the basal forebrain cholinergic system of young-adult Ts65Dn and disomic mice

    PubMed Central

    Kelley, Christy M.; Powers, Brian E.; Velazquez, Ramon; Ash, Jessica A.; Ginsberg, Stephen D.; Strupp, Barbara J.; Mufson, Elliott J.

    2014-01-01

    Down syndrome (DS), trisomy 21, is a multifaceted condition marked by intellectual disability and early presentation of Alzheimer’s disease (AD) neuropathological lesions including degeneration of the basal forebrain cholinergic neuron (BFCN) system. While DS is diagnosable during gestation, there is no treatment option for expectant mothers or DS individuals. Using the Ts65Dn mouse model of DS that displays age-related degeneration of the BFCN system, we investigated the effects of maternal choline supplementation on the BFCN system in adult Ts65Dn mice and disomic (2N) littermates at 4.3–7.5 mos of age. Ts65Dn dams were maintained on a choline supplemented diet (5.1 g/kg choline chloride) or a control, unsupplemented diet with adequate amounts of choline (1 g/kg choline chloride) from conception until weaning of offspring; postweaning, offspring were fed the control diet. Mice were transcardially perfused with paraformaldehyde, brains were sectioned, and immunolabeled for choline acetyltransferase (ChAT) or p75-neurotrophin receptor (p75NTR). BFCN number and size, the area of the regions, and the intensity of hippocampal labeling were determined. Ts65Dn unsupplemented mice displayed region- and immunolabel-dependent increased BFCN number, larger areas, smaller BFCNs, and overall increased hippocampal ChAT intensity compared with 2N unsupplemented mice. These effects were partially normalized by maternal choline supplementation. Taken together, the results suggest a developmental imbalance in the Ts65Dn BFCN system. Early maternal-diet choline supplementation attenuates some of the genotype-dependent alterations in the BFCN system, suggesting this naturally occurring nutrient as a treatment option for pregnant mothers with knowledge that their offspring is trisomy 21. PMID:24178831

  13. Maternal dietary intake of choline in mice regulates development of the cerebral cortex in the offspring

    PubMed Central

    Wang, Yanyan; Surzenko, Natalia; Friday, Walter B.; Zeisel, Steven H.

    2015-01-01

    Maternal diets low in choline, an essential nutrient, increase the risk of neural tube defects and lead to low performance on cognitive tests in children. However, the consequences of maternal dietary choline deficiency for the development and structural organization of the cerebral cortex remain unknown. In this study, we fed mouse dams either control (CT) or low-choline (LC) diets and investigated the effects of choline on cortical development in the offspring. As a result of a low choline supply between embryonic day (E)11 and E17 of gestation, the number of 2 types of cortical neural progenitor cells (NPCs)—radial glial cells and intermediate progenitor cells—was reduced in fetal brains (P < 0.01). Furthermore, the number of upper layer cortical neurons was decreased in the offspring of dams fed an LC diet at both E17 (P < 0.001) and 4 mo of age (P < 0.001). These effects of LC maternal diet were mediated by a decrease in epidermal growth factor receptor (EGFR) signaling in NPCs related to the disruption of EGFR posttranscriptional regulation. Our findings describe a novel mechanism whereby low maternal dietary intake of choline alters brain development.—Wang, Y., Surzenko, N., Friday, W. B., Zeisel, S. H. Maternal dietary intake of choline in mice regulates development of the cerebral cortex in the offspring. PMID:26700730

  14. Maternal dietary intake of choline in mice regulates development of the cerebral cortex in the offspring.

    PubMed

    Wang, Yanyan; Surzenko, Natalia; Friday, Walter B; Zeisel, Steven H

    2016-04-01

    Maternal diets low in choline, an essential nutrient, increase the risk of neural tube defects and lead to low performance on cognitive tests in children. However, the consequences of maternal dietary choline deficiency for the development and structural organization of the cerebral cortex remain unknown. In this study, we fed mouse dams either control (CT) or low-choline (LC) diets and investigated the effects of choline on cortical development in the offspring. As a result of a low choline supply between embryonic day (E)11 and E17 of gestation, the number of 2 types of cortical neural progenitor cells (NPCs)-radial glial cells and intermediate progenitor cells-was reduced in fetal brains (P< 0.01). Furthermore, the number of upper layer cortical neurons was decreased in the offspring of dams fed an LC diet at both E17 (P< 0.001) and 4 mo of age (P< 0.001). These effects of LC maternal diet were mediated by a decrease in epidermal growth factor receptor (EGFR) signaling in NPCs related to the disruption of EGFR posttranscriptional regulation. Our findings describe a novel mechanism whereby low maternal dietary intake of choline alters brain development.-Wang, Y., Surzenko, N., Friday, W. B., Zeisel, S. H. Maternal dietary intake of choline in mice regulates development of the cerebral cortex in the offspring. © FASEB.

  15. Structural asymmetry and intersubunit communication in muscle creatine kinase.

    PubMed

    Ohren, Jeffrey F; Kundracik, Melisa L; Borders, Charles L; Edmiston, Paul; Viola, Ronald E

    2007-03-01

    The structure of a transition-state analog complex of a highly soluble mutant (R134K) of rabbit muscle creatine kinase (rmCK) has been determined to 1.65 A resolution in order to elucidate the structural changes that are required to support and regulate catalysis. Significant structural asymmetry is seen within the functional homodimer of rmCK, with one monomer found in a closed conformation with the active site occupied by the transition-state analog components creatine, MgADP and nitrate. The other monomer has the two loops that control access to the active site in an open conformation and only MgADP is bound. The N-terminal region of each monomer makes a substantial contribution to the dimer interface; however, the conformation of this region is dramatically different in each subunit. Based on this structural evidence, two mutational modifications of rmCK were conducted in order to better understand the role of the amino-terminus in controlling creatine kinase activity. The deletion of the first 15 residues of rmCK and a single point mutant (P20G) both disrupt subunit cohesion, causing the dissociation of the functional homodimer into monomers with reduced catalytic activity. This study provides support for a structural role for the amino-terminus in subunit association and a mechanistic role in active-site communication and catalytic regulation.

  16. Creatine Supplementation Does Not Prevent the Development of Alcoholic Steatosis.

    PubMed

    Ganesan, Murali; Feng, Dan; Barton, Ryan W; Thomes, Paul G; McVicker, Benita L; Tuma, Dean J; Osna, Natalia A; Kharbanda, Kusum K

    2016-11-01

    Alcohol-induced reduction in the hepatocellular S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) ratio impairs the activities of many SAM-dependent methyltransferases. These impairments ultimately lead to the generation of several hallmark features of alcoholic liver injury including steatosis. Guanidinoacetate methyltransferase (GAMT) is an important enzyme that catalyzes the final reaction in the creatine biosynthetic process. The liver is a major site for creatine synthesis which places a substantial methylation burden on this organ as GAMT-mediated reactions consume as much as 40% of all the SAM-derived methyl groups. We hypothesized that dietary creatine supplementation could potentially spare SAM, preserve the hepatocellular SAM:SAH ratio, and thereby prevent the development of alcoholic steatosis and other consequences of impaired methylation reactions. For these studies, male Wistar rats were pair-fed the Lieber-DeCarli control or ethanol (EtOH) diet with or without 1% creatine supplementation. At the end of 4 to 5 weeks of feeding, relevant biochemical and histological analyses were performed. We observed that creatine supplementation neither prevented alcoholic steatosis nor attenuated the alcohol-induced impairments in proteasome activity. The lower hepatocellular SAM:SAH ratio seen in the EtOH-fed rats was also not normalized or SAM levels spared when these rats were fed the creatine-supplemented EtOH diet. However, a >10-fold increased level of creatine was observed in the liver, serum, and hearts of rats fed the creatine-supplemented diets. Overall, dietary creatine supplementation did not prevent alcoholic liver injury despite its known efficacy in preventing high-fat-diet-induced steatosis. Betaine, a promethylating agent that maintains the hepatocellular SAM:SAH, still remains our best option for treating alcoholic steatosis. Copyright © 2016 by the Research Society on Alcoholism.

  17. Maternal choline supplementation: a nutritional approach for improving offspring health?

    PubMed

    Jiang, Xinyin; West, Allyson A; Caudill, Marie A

    2014-05-01

    The modulatory role of choline on the fetal epigenome and the impact of in utero choline supply on fetal programming and health are of great interest. Studies in animals and/or humans suggest that maternal choline supplementation during pregnancy benefits important physiologic systems such as offspring cognitive function, response to stress, and cerebral inhibition. Because alterations in offspring phenotype frequently coincide with epigenetic modifications and changes in gene expression, maternal choline supplementation may be a nutritional strategy to improve lifelong health of the child. Future studies are warranted to elucidate further the effect of choline on the fetal epigenome and to determine the level of maternal choline intake required for optimal offspring physiologic function. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Creatine Protects against Excitoxicity in an In Vitro Model of Neurodegeneration

    PubMed Central

    Genius, Just; Geiger, Johanna; Bender, Andreas; Möller, Hans-Jürgen; Klopstock, Thomas; Rujescu, Dan

    2012-01-01

    Creatine has been shown to be neuroprotective in aging, neurodegenerative conditions and brain injury. As a common molecular background, oxidative stress and disturbed cellular energy homeostasis are key aspects in these conditions. Moreover, in a recent report we could demonstrate a life-enhancing and health-promoting potential of creatine in rodents, mainly due to its neuroprotective action. In order to investigate the underlying pharmacology mediating these mainly neuroprotective properties of creatine, cultured primary embryonal hippocampal and cortical cells were challenged with glutamate or H2O2. In good agreement with our in vivo data, creatine mediated a direct effect on the bioenergetic balance, leading to an enhanced cellular energy charge, thereby acting as a neuroprotectant. Moreover, creatine effectively antagonized the H2O2-induced ATP depletion and the excitotoxic response towards glutamate, while not directly acting as an antioxidant. Additionally, creatine mediated a direct inhibitory action on the NMDA receptor-mediated calcium response, which initiates the excitotoxic cascade. Even excessive concentrations of creatine had no neurotoxic effects, so that high-dose creatine supplementation as a health-promoting agent in specific pathological situations or as a primary prophylactic compound in risk populations seems feasible. In conclusion, we were able to demonstrate that the protective potential of creatine was primarily mediated by its impact on cellular energy metabolism and NMDA receptor function, along with reduced glutamate spillover, oxidative stress and subsequent excitotoxicity. PMID:22347384

  19. Thermotropic phase behavior of choline soaps.

    PubMed

    Klein, Regina; Dutton, Helen; Diat, Olivier; Tiddy, Gordon J T; Kunz, Werner

    2011-04-14

    Choline carboxylates (ChCm with m = 12-18) are simple biocompatible anionic surfactants with very low Krafft temperatures, possessing a rich aqueous phase behavior. In the present work, we have investigated the thermotropic mesomorphism of anhydrous ChCm salts for m = 12-18. Transition temperatures and enthalpies determined by differential scanning calorimetry reveal that all investigated compounds exhibit three different phases between -20 and 95 °C. The phases were further characterized by optical polarizing microscopy, NMR spin-spin relaxation, and X-ray scattering measurements. The nature of the phases was identified with increasing temperature as crystalline, semicrystalline, and liquid-crystalline lamellar. Even long-chain choline carboxylates (m = 18) were found to melt into a lamellar liquid-crystalline phase below 100 °C. Accordingly, with choline as counterion in simple fatty acid soaps, not only the water solubility is considerably enhanced but also the melting points are substantially reduced, hence facilitating thermotropic mesomorphism at temperatures between 35 and 95 °C. Thus, simple choline soaps with m = 12-18 may be classified as ionic liquids.

  20. Analytical approaches to determination of total choline in foods and dietary supplements.

    PubMed

    Phillips, Melissa M

    2012-06-01

    Choline is a quaternary amine that is synthesized in the body or consumed through the diet. Choline is critical for cell membrane structure and function and in synthesis of the neurotransmitter acetylcholine. Although the human body produces this micronutrient, dietary supplementation of choline is necessary for good health. The major challenge in the analysis of choline in foods and dietary supplements is in the extraction and/or hydrolysis approach. In many products, choline is present as choline esters, which can be quantitated individually or treated with acid, base, or enzymes in order to release choline ions for analysis. A critical review of approaches based on extraction and quantitation of each choline ester as well as hydrolysis-based methods for determination of total choline in foods and dietary supplements is presented.